,Title,Authors,Link,Abstract
1,Macrophages redeploy functional cancer cell surface proteins following phagocytosis,"Regan F Volk, Sara W Casebeer, Andrew C Condon, Bahar Zirak, Nayelis Manon, Iryna Irkliyenko, Huajun Liao, Shao Tao, Tommaso Pollini, Vijay Ramani, Ajay Maker, Trevor Fidler, Hani Goodarzi, Balyn W Zaro",https://www.biorxiv.org/content/10.1101/2024.09.23.613776v1,"Macrophage-mediated phagocytosis is a vital innate immune process altered in cancer. We show here that tumor-associated macrophages (TAMs) redeploy intact cell surface proteins from cancer cells to their own cell surface. We initially observed the canonical epithelial cancer surface marker EPCAM on the surface of TAMs in primary human solid tumors but not paired peripheral blood macrophages. In a murine model of metastatic breast cancer, we also observed EPCAM on the surface of primary TAMs that have phagocytosed breast cancer cells. In a model of a myeloproliferative neoplasm, we again found engulfed cell-derived surface proteins on the surface of macrophages following phagocytosis. A co-culture system and proteomics assay that tags proteins based on their cell-of-origin revealed hundreds of cell surface proteins synthesized in cancer cells are present and fully intact on the surface of macrophages following phagocytosis. Furthermore, macrophages that redeploy a neutral amino acid transporter correspondingly show increased transport of an unnatural amino acid substrate. Widespread acquisition of proteins from engulfed cells may contribute to two critical TAM phenotypes: the inability to phagocytose and reprogrammed metabolism."
2,Cancer-immune coevolution dictated by antigenic mutation accumulation,"Long Wang, Christo Morison, Weini Huang",https://www.biorxiv.org/content/10.1101/2024.09.10.612074v2,"The immune system is one of the first lines of defence against the emergence of cancer. When effector cells attempt to suppress the tumour, the cancer cells can respond in kind by evolving methods of escape or inhibition. Knowledge of this coevolutionary system and the selection taking place within it can help us understand tumour-immune dynamics both during tumorigenesis but also when treatments such as immunotherapies are applied. Here, we present an individual-based branching process model of mutation accumulation, where random mutations arising in cancer cells trigger corresponding specialised immune responses. Different from previous research, we explicitly model interactions between cancer and effector cells, while incorporating stochastic effects, which are especially important for the expansion and extinction of small populations. We find that the parameters governing interactions between the cancer and effector cells induce different outcomes of tumour progress, such as suppression and evasion. While it is hard to measure the cancer-immune dynamics directly in patients, genetic information of the cancer may indicate the presence of such interactions. Our model demonstrates signatures of selection in sequencing-derived summary statistics, such as the single-cell mutational burden. Thus, bulk and single-cell sequencing of a tumour may give information about the coevolutionary dynamics."
3,High-Throughput Empirical and Virtual Screening to Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer,"Yushu Ma, Chien-Hung Shih, Jinxiong Cheng, Hsiao-Chun Chen, Li-Ju Wang, Yanhao Tan, Yu-Chiao Chiu, Yu-Chih Chen",https://www.biorxiv.org/content/10.1101/2024.09.23.614522v1,"Therapy resistance in breast cancer is increasingly attributed to polyploid giant cancer cells (PGCCs), which arise through whole-genome doubling and exhibit heightened resilience to standard treatments. Characterized by enlarged nuclei and increased DNA content, these cells tend to be dormant under therapeutic stress, driving disease relapse. Despite their critical role in resistance, strategies to effectively target PGCCs are limited, largely due to the lack of high-throughput methods for assessing their viability. Traditional assays lack the sensitivity needed to detect PGCC-specific elimination, prompting the development of novel approaches. To address this challenge, we developed a high-throughput single-cell morphological analysis workflow designed to differentiate compounds that selectively inhibit non-PGCCs, PGCCs, or both. Using this method, we screened a library of 2,726 FDA Phase 1-approved drugs, identifying promising anti-PGCC candidates, including proteasome inhibitors, FOXM1, CHK, and macrocyclic lactones. Notably, RNA-Seq analysis of cells treated with the macrocyclic lactone Pyronaridine revealed AXL inhibition as a potential strategy for targeting PGCCs. Although our single-cell morphological analysis pipeline is powerful, empirically testing all existing compounds is impractical and inefficient. To overcome this limitation, we trained a machine learning model to predict anti-PGCC efficacy in silico, integrating chemical fingerprints and compound descriptions from prior publications and databases. The model demonstrated a high correlation with experimental outcomes and predicted efficacious compounds in an expanded library of over 6,000 drugs. Among the top-ranked predictions, we experimentally validated two compounds as potent PGCC inhibitors. These findings underscore the synergistic potential of integrating high-throughput empirical screening with machine learning-based virtual screening to accelerate the discovery of novel therapies, particularly for targeting therapy-resistant PGCCs in breast cancer."
5,Drug-Induced p53 Activation Limits Pancreatic Cancer Initiation,"Jennifer J Twardowski, Thomas I Heist, Zamira Guerra Soares, Emily S Berry, Luis I Ruffolo, Christoph Pröschel, Stephano S Mello",https://www.biorxiv.org/content/10.1101/2024.05.29.595146v2,"Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, initiated predominantly by mutations in Kras, which induce acinar-to-ductal metaplasia (ADM) and subsequent formation of precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN). Progression to PDAC is frequently associated with mutations in the tumor suppressor TP53, presumably via disrupting p53-mediated cellular senescence of PanINs. Whether TP53 also has tumor-suppressive activity in earlier phases of PDAC initiation has been less clear. In this study, we investigate the impact of pharmacological stabilization of the wild-type p53 protein on the formation of ADM in a KrasG12D-driven mouse model of PDAC. Our findings demonstrate that p53 stabilization via Nutlin-3a significantly reduces both ADM and PanIN formation by promoting the differentiation of ADM into acinar cells. This differentiation coincides with p53-dependent upregulation of the transcription factor Mist1 (Bhlha15), a critical inducer of acinar cell identity. Our results reveal a role for p53 in tissue repair and maintenance of homeostasis in tumor suppression and suggest pharmacological engagement of p53 as an intervention strategy to prevent PDAC initiation."
6,Intravital imaging of pulmonary lymphatics in inflammation and metastatic cancer,"Simon J. Cleary, Longhui Qiu, Yurim Seo, Peter Baluk, Dan Liu, Nina K. Serwas, Jason G. Cyster, Donald M. McDonald, Matthew F. Krummel, Mark R. Looney",https://www.biorxiv.org/content/10.1101/2024.09.12.612619v1,"Intravital microscopy has enabled the study of immune dynamics in the pulmonary microvasculature, but many key events remain unseen because they occur in deeper lung regions. We therefore developed a technique for stabilized intravital imaging of bronchovascular cuffs and collecting lymphatics surrounding pulmonary veins in mice. Intravital imaging of pulmonary lymphatics revealed ventilation-dependence of steady-state lung lymph flow and ventilation-independent lymph flow during inflammation. We imaged the rapid exodus of migratory dendritic cells through lung lymphatics following inflammation and measured effects of pharmacologic and genetic interventions targeting chemokine signaling. Intravital imaging also captured lymphatic immune surveillance of lung-metastatic cancers and lymphatic metastasis of cancer cells. To our knowledge, this is the first imaging of lymph flow and leukocyte migration through intact pulmonary lymphatics. This approach will enable studies of protective and maladaptive processes unfolding within the lungs and in other previously inaccessible locations."
7,Pan-Cancer Genetic Analysis of Mitochondrial DNA Repair Gene Set,"Angela Dong, Ayana Meegol Rasteh, Hengrui Liu",https://www.biorxiv.org/content/10.1101/2024.09.14.613048v1,"Background The mitochondrial DNA repair has gained attention for its potential impact on pan-cancer genetic analysis. This study investigates the clinical relevance of mitochondrial DNA repair genes: PARP1, DNA 2, PRIMPOL, TP53, MGME1."
8,SOX2 drives fetal reprogramming and reversible dormancy in colorectal cancer,"Anna Baulies, Veronica Moncho-Amor, Diana Drago-Garcia, Ania Kucharska, Probir Chakravarty, Manuel Moreno-Valladares, Sara Cruces-Salguero, Florian Hubl, Colin Hutton, Hanue Kim, Ander Matheu, Robin Lovell-Badge, Vivian S. W. Li",https://www.biorxiv.org/content/10.1101/2024.09.11.612412v1,"Cellular plasticity plays critical roles in tissue regeneration, tumour progression and therapeutic resistance. However, the mechanism underlying this cell state transition remains elusive. Here, we show that the transcription factor SOX2 induces fetal reprogramming and reversible dormancy in colorectal cancer (CRC). SOX2 expression correlates with fetal reprogramming and poor prognosis in human primary and metastatic colorectal adenocarcinomas. In mouse CRC models, rare slow-cycling SOX2+SCA1+ cells are detected in early Apc-deleted mouse tumours that undergo slow clonal expansion over time. In contrast, the SOX2+ clones were found proliferative in advanced Apc-/-;KrasG12D/+;p53-/-;Tgfbr2-/-(AKPT) tumours, accompanied by dynamic cell state reprogramming from LGR5+ to LGR5-SCA1+ cells. Using transgenic mouse models, we demonstrate that ectopic expression of SOX2 inhibits intestinal lineage differentiation and induces fetal reprogramming. SOX2+ cells adopt dynamic cell cycle states depending on its expression level. High SOX2 expression results in hyperproliferation, whereas low SOX2 levels induce senescence-mediated dormancy. We find that loss of p53 can reverse SOX2-induced senescence, in line with the dormant cell state exit of the SOX2+ cells observed in advanced tumours. Finally, SOX2 expression is induced by 5-FU treatment in CRC. SOX2-expressing organoids exhibit increased tolerance to chemotherapy treatment, whilst deletion of SOX2 in AKPT tumour organoids sensitises drug responses. We propose that SOX2-induced plasticity and reversible dormancy promotes tumour progression and drug tolerance in CRC."
9,Stress granule formation enables anchorage-independence survival in cancer cells,"Seungwon Yang, Anaïs Aulas, Paul J. Anderson, Pavel Ivanov",https://www.biorxiv.org/content/10.1101/2024.09.14.613064v1,"Stress granules (SGs) are dynamic cytoplasmic structures assembled in response to various stress stimuli that enhance cell survival under adverse environmental conditions. Here we show that SGs contribute to breast cancer progression by enhancing the survival of cells subjected to anoikis stress. SG assembly is triggered by inhibition of Focal Adhesion Kinase (FAK) or loss of adhesion signals. Combined proteomic analysis and functional studies reveal that SG formation enhances cancer cell proliferation, resistance to metabolic stress, anoikis resistance, and migration. Importantly, inhibiting SG formation promotes the sensitivity of cancer cells to FAK inhibitors being developed as cancer therapeutics. Furthermore, we identify the Rho-ROCK- PERK-eIF2α axis as a critical signaling pathway activated by loss of adhesion signals and inhibition of the FAK-mTOR-eIF4F complex in breast cancer cells. By triggering SG assembly and AKT activation in response to anoikis stress, PERK functions as an oncoprotein in breast cancer cells. Overall, our study highlights the significance of SG formation in breast cancer progression and suggests that therapeutic inhibition of SG assembly may reverse anoikis resistance in treatment-resistant cancers such as triple-negative breast cancer (TNBC)."
11,PSMA-specific CAR-engineered macrophages for therapy of prostate cancer,"Yangli Xu, Duoli Xie, Chunhao Cao, Yue Ju, Xinxin Chen, Lili Guan, Xuelong Li, Luo Zhang, Chao Liang, Xiushan Yin",https://www.biorxiv.org/content/10.1101/2024.09.07.611792v1,"Chimeric antigen receptor (CAR)-modified macrophages (CAR-Ms) are a promising approach for the treatment of solid tumors due to its high infiltration and immune-regulation activity. Prostate cancer is a typical solid tumor associated with highly immunosuppressive microenvironment. To date, the potential application of CAR-M cell therapy in prostate cancer has been infrequently explored. The prostate-specific membrane antigen (PSMA) functions as a specific biomarker for prostate cancer. In this study, we assessed the antitumor efficacy of PSMA-targeted CAR-Ms in preclinical models. CAR-Ms were engineered to express a PSMA-specific single-chain variable fragment (scFv) and co-stimulatory domains. In vitro data demonstrated specific cytotoxicity of CAR-Ms against PSMA-expressing prostate cancer cells, which was further supported by transcriptome analysis demonstrating the pro-inflammatory phenotypes of CAR-Ms. In vivo studies using xenograft mouse models confirmed significant tumor regression after administration of PSMA-targeted CAR-Ms compared to controls. Histopathological analysis showed infiltration of CAR-Ms into tumor tissues without off-target toxicity. These results highlight the strong antitumor activity and safety of PSMA-targeted CAR-Ms, supporting their potential as a new immunotherapy for prostate cancer."
13,Regulation of Age-Related Lipid Metabolism in Ovarian Cancer,"Jihua Feng, Clay Douglas Rouse, Isabella Coogan, Olivia Byrd, Ethan Nguyen, Lila Taylor, Santiago Garcia, Hannah Lee, Andrew Berchuck, Susan K. Murphy, Zhiqing Huang",https://www.biorxiv.org/content/10.1101/2024.09.06.611709v1,"Although a lot of effort has been dedicated to ovarian cancer (OC) research, the mortality rate is still among the highest in female gynecologic malignancies. The effects of the aged tumor microenvironment are still being undermined despite age being the highest risk factor in ovarian cancer development and progression. In this study, we have conducted RNA sequencing and lipidomics analysis of gonadal adipose tissues from young and aged rat xenografts before and after ovarian cancer formation. We have found significantly higher tumor formation rates and volumes in aged OC xenograft rat models compared to their young counterparts (p<0.05), suggesting the aged adipose microenvironment (AME) is more susceptible to OC outgrowth. We have revealed significant shifts in the gene expression enrichment from groups of young vs. aged rats before tumor formation, groups of young vs. aged rats when the tumor formed, and groups of aged rats before and after tumor formation. We also observed shifts in the lipid components of the gonadal adipose tissues between young and aged rat xenografts when tumors were generated."
14,An antibiotic that mediates immune destruction of senescent cancer cells,"Gabriele Casagrande Raffi, Jian Chen, Xuezhao Feng, Zhen Chen, Cor Lieftink, Shuang Deng, Jinzhe Mo, Chuting Zeng, Marit Steur, Jing Wang, Onno B. Bleijerveld, Liesbeth Hoekman, Nicole van der Wel, Feng Wang, Roderick Beijersbergen, Jian Zheng, Rene Bernards, Liqin Wang",https://www.biorxiv.org/content/10.1101/2024.09.05.611241v1,"Drugs that eliminate senescent cells, senolytics, can be powerful when combined with pro-senescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a PANoptosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via JNK pathway activation. We show that a combination of a DR5 agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent NK and CD8+ T cell mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine IL18."
15,Invasive cancer and spontaneous regression two weeks after papillomavirus infection,"Andrea Bilger, Ella T. Ward-Shaw, Denis L. Lee, Renee E. King, Michael A. Newton, Darya Buehler, Kristina A. Matkowskyj, John P. Sundberg, Rong Hu, Paul F. Lambert",https://www.biorxiv.org/content/10.1101/2024.09.04.611275v1,"Development of invasive cancer in mammals is thought to require months or years after initial events such as mutation or viral infection. Rarely, invasive cancers regress spontaneously. We show that cancers can develop and regress on a timescale of weeks, not months or years. Invasive squamous cell carcinomas developed in normal adult, immune-competent mice as soon as 2 weeks after infection with mouse papillomavirus MmuPV1. Tumor development, regression or persistence was tissue- and strain-dependent. Cancers in infected mice developed rapidly at sites also prone to papillomavirus-induced tumors and cancers in humans – the throat, anus, and skin – and their frequency was increased in mice constitutively expressing the papillomavirus E5 oncogene, which MmuPV1 lacks. Cancers and dysplasia in the throat and anus regressed completely within 4-8 weeks of infection; however, skin lesions in the ear persisted. T-cell depletion in the mouse showed that regression of throat and anal tumors requires T cells. We conclude that papillomavirus infection suffices for rapid onset of invasive cancer, and persistence of lesions depends on factors including tissue type and host immunity. The speed of these events should promote rapid progress in the study of viral cancer development, persistence, and regression."
16,A Comprehensive Meta-Analysis of Breast Cancer Gene Expression,"Ifeanyichukwu O. Nwosu, Stephen R. Piccolo",https://www.biorxiv.org/content/10.1101/2024.08.30.610515v3,"Background Triple-negative breast cancers (TNBC) occur more frequently in African Americans and are associated with worse outcomes when compared to other subtypes of breast cancer. These cancers lack expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) and have limited treatment options. To shed light on mechanisms behind these differences and suggest novel treatments, we used a meta-analytic approach to identify gene expression differences in breast tumors for people with self-reported African or European ancestry; additionally, we compared gene expression levels based on ER, PR, HER2 and TNBC status."
17,Many erroneous noncoding transcripts in cancer cells can highly specifically regulate cancer-related genes and pathways,"Sha He, Wei Xiong, Jianping Huo, Jie Lin, Jianmin Li, Hao Zhu",https://www.biorxiv.org/content/10.1101/2024.07.13.603398v1,"Transcription and splicing errors in cancer cells generate erroneous transcripts. Since erroneous transcripts are degraded by the nonsense-mediated mRNA decay (NMD) pathway, whether they are junk or could be functional has been overlooked and understudied. We addressed this question by first performing a pan-cancer analysis and identified substantial erroneous noncoding transcripts (ENT) in cancers. Given that RNA/DNA binding domains (DBD) were predicted in ENTs, we deleted predicted DBDs in multiple ENTs in multiple cell lines, with RNA-sequencing and cell experiments before and after DBD deletion. DBD deletion caused significantly changed expression of ENTs’ target genes (whose promoter regions contain ENTs’ DNA binding sites, DBS) and changed cell migration and proliferation ability, indicating that many ENTs can transcriptionally regulate genes. Tightly coupled data analysis and experiments reveal that ENTs’ functions are highly cancer- and cellular-context specific, making ENTs a new class of safe and specific targets for noncoding RNA-based cancer therapeutics."
18,Inferring cancer type-specific patterns of metastatic spread,"Divya Koyyalagunta, Karuna Ganesh, Quaid Morris",https://www.biorxiv.org/content/10.1101/2024.07.09.602790v2,"The metastatic spread of a cancer can be reconstructed from DNA sequencing of primary and metastatic tumours, but doing so requires solving a challenging combinatorial optimization problem. This problem often has multiple solutions that cannot be distinguished based on current maximum parsimony principles alone. Current algorithms use ad hoc criteria to select among these solutions, and decide, a priori, what patterns of metastatic spread are more likely, which is itself a key question posed by studies of metastasis seeking to use these tools. Here we introduce Metient, a freely available open-source tool which proposes multiple possible hypotheses of metastatic spread in a cohort of patients and rescores these hypotheses using independent data on genetic distance of metastasizing clones and organotropism. Metient is more accurate and is up to 50x faster than current state-of-the-art. Given a cohort of patients, Metient can calibrate its parsimony criteria, thereby identifying shared patterns of metastatic dissemination in the cohort. Reanalyzing metastasis in 169 patients based on 490 tumors, Metient automatically identifies cancer type-specific trends of metastatic dissemination in melanoma, high-risk neuroblastoma and non-small cell lung cancer. Metient’s reconstructions usually agree with semi-manual expert analysis, however, in many patients, Metient identifies more plausible migration histories than experts, and further finds that polyclonal seeding of metastases is more common than previously reported. By removing the need for hard constraints on what patterns of metastatic spread are most likely, Metient introduces a way to further our understanding of cancer type-specific metastatic spread."
19,Cancer Cell Removing Using a Reinforcement Learning Agent,Ali Mousavi Fard,https://www.biorxiv.org/content/10.1101/2024.09.01.610680v1,"Cancer cell is a deadly problem which is the main cause of global death. Unfortunately, the conventional therapies like chemo/radio therapy are not viable ways to remove all of the cancer cells. Although Robotic achievements have been increased in cancer therapy, these devices do not have the decision-making ability to grasp their environment like biologists. In this paper, a cancer cell removing method based on Artificial Intelligence techniques is introduced. The proposed idea adopts a combination of object detection and reinforcement model in order to detect the cancer cells and take some actions to remove them. To implement this idea, YOLOv9 is trained on a cancer cell image dataset to detect and segment the cancer cell and create a set point for RL model then in the next step, Soft Actor Critic (SAC) is considered as a RL model to grasp the desired environment and take some appropriate actions to reach the target. The experimental result of this model shows that the proposed model can be adopted in different cancer therapy robots like micro/wireless soft robots to boost their performance in terms of their decision-making ability."
20,The Universal Breast cancer Subtyping 93 finds that claudin-low breast cancer may originate from basal breast cancer,"Jing Li, Ke Liu",https://www.biorxiv.org/content/10.1101/2024.06.02.597060v2,"Background Breast cancer is a complex disease with diverse molecular characteristics, significantly impacting patient prognosis, outcomes, and treatment decisions. Previous studies have introduced PAM50 classifiers and claudin-low classifiers based on bulk RNA-seq samples. However, single-cell analysis has revealed the existence of distinct subtypes within the same tumor, indicating that classifiers relying on gene signatures derived from bulk samples may not accurately capture the true molecular features of breast cancer."
21,Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer via concurrent integrin and MET signaling,"Qianqian Hu, Lily L. Remsing Rix, Bina Desai, Daria Miroshnychenko, Xueli Li, Eric A. Welsh, Bin Fang, Gabriela M. Wright, Neelkamal Chaudhary, Jodi L. Kroeger, Robert C. Doebele, John M. Koomen, Eric B. Haura, Andriy Marusyk, Uwe Rix",https://www.biorxiv.org/content/10.1101/2024.08.27.609975v1,"Cancer-associated fibroblasts (CAFs) are associated with tumor progression and modulate drug sensitivity of cancer cells. However, the underlying mechanisms are often incompletely understood and crosstalk between tumor cells and CAFs involves soluble secreted as well as adhesion proteins. Interrogating a panel of non-small cell lung cancer (NSCLC) cell lines driven by EML4-ALK fusions, we observed substantial CAF-mediated drug resistance to clinical ALK tyrosine kinase inhibitors (TKIs). Array-based cytokine profiling of fibroblast-derived conditioned- media identified HGF-MET signaling as a major contributor to CAF-mediated paracrine resistance that can be overcome by MET TKIs. However, ‘Cell Type specific labeling using Amino acid Precursors’ (CTAP)-based expression and phosphoproteomics in direct coculture also highlighted a critical role for the fibronectin-integrin pathway. Flow cytometry analysis confirmed activation of integrin β1 (ITGB1) in lung cancer cells by CAF coculture. Treatment with pharmacological inhibitors, cancer cell-specific silencing or CRISPR-Cas9-mediated knockout of ITGB1 overcame adhesion protein-mediated resistance. Concurrent targeting of MET and integrin signaling effectively abrogated CAF-mediated resistance of EML4-ALK-driven NSCLC cells to ALK TKIs in vitro. Consistently, combination of the ALK TKI alectinib with the MET TKI capmatinib and/or the integrin inhibitor cilengitide was significantly more efficacious than single agent treatment in suppressing tumor growth using an in vivo EML4-ALK-dependent allograft mouse model of NSCLC. In summary, these findings emphasize the complexity of resistance-associated crosstalk between CAFs and cancer cells, which can involve multiple concurrent signaling pathways, and illustrate how comprehensive elucidation of paracrine and juxtacrine resistance mechanisms can inform on more effective therapeutic approaches."
22,Polyploid cancer cells reveal signatures of chemotherapy resistance,"Michael J. Schmidt, Amin Naghdloo, Rishvanth K. Prabakar, Mohamed Kamal, Radu Cadaneanu, Isla P. Garraway, Michael Lewis, Ana Aparicio, Amado Zurita-Saavedra, Paul Corn, Peter Kuhn, Kenneth J. Pienta, Sarah R. Amend, James Hicks",https://www.biorxiv.org/content/10.1101/2024.08.19.608632v1,"Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of circulating tumor cells with increased genomic content (CTC-IGC) was significantly associated with poorer progression- free survival. Single cell copy number profiling of CTC-IGC displayed clonal origins with typical CTCs, suggesting complete polyploidization. Induced polyploid cancer cells from PC3 and MDA-MB-231 cell lines treated with docetaxel or cisplatin were examined through single cell DNA sequencing, RNA sequencing, and protein immunofluorescence. Novel RNA and protein markers, including HOMER1, TNFRSF9, and LRP1, were identified as linked to chemotherapy resistance. These markers were also present in a subset of patient CTCs and associated with recurrence in public gene expression data. This study highlights the prognostic significance of large polyploid tumor cells, their role in chemotherapy resistance, and their expression of markers tied to cancer relapse, offering new potential avenues for therapeutic development."
23,DNA methylation protects cancer cells against non-canonical senescence,"Xiaoying Chen, Kosuke Yamaguchi, Brianna Rodgers, Delphine Goerhig, David Vindrieux, Xavier Lahaye, Matthieu Nolot, Laure Ferry, Pierre Dubus, Fumihito Miura, Takashi Ito, Nicolas Manel, David Bernard, Pierre-Antoine Defossez",https://www.biorxiv.org/content/10.1101/2024.08.23.609297v1,"Aberrant DNA methylation patterns are a hallmark of human cancers, prompting targeting of DNA methylation machinery to be explored as an anti-tumor strategy. DNA methyltransferase 1 (DNMT1) and ubiquitin like With PHD and Ring finger domains 1 (UHRF1) are crucial enzymes for DNA methylation maintenance. Unlike DNMT1, UHRF1 is overexpressed in most cancers and is a proven oncogene in vivo. Our previous work revealed that the degree of DNA methylation loss induced by UHRF1 depletion is more severe than DNMT1 depletion in colorectal cancer cells, indicating that targeting UHRF1 may be a more effective approach. Using an advanced chemical/genetic system, the auxin-inducible degron (AID) technology, we monitored the long-term effects of removing UHRF1 and/or DNMT1 in cancer cells, deciphering the mechanistic basis through bioinformatic tools. We found that chronic DNA demethylation triggers cancer cells to undergo cellular senescence. The loss of UHRF1 results in a more rapid and profound senescence phenotype than DNMT1 loss. Intriguingly, this senescence is not accompanied by DNA damage and functions independently of canonical senescence pathways such as p53 and p16/pRB. Non-canonical pathway investigations revealed that cytosolic p21 accumulation contributes to antiapoptosis during senescence. The suppression of cyclic GMP-AMP synthase (cGAS) also alleviates the senescence-associated secretory phenotype (SASP) and lysosomal activity, and this process is independent of stimulator of interferon genes (STING). Finally, xenograft experiments verified our findings in vivo. Our results highlight how DNA methylation protects cancer cells from non-canonical senescence and demonstrate the potential of targeting UHRF1 as a novel avenue for anticancer treatments."
25,Low extracellular pH protects cancer cells from ammonia toxicity,"Maria Dravecka, Ingvild Mikkola, Terje Johansen, Ole Morten Seternes, Jakob Mejlvang",https://www.biorxiv.org/content/10.1101/2024.08.20.608758v1,"Ammonia is a natural waste product of cellular metabolism which, through its lysosomotropic ability, can have detrimental effects on various cellular functions. Increased levels of ammonia were recently detected in the interstitial fluid of various tumours, substantiating that high ammonia concentrations are a pathophysiological condition in the tumour microenvironment, alongside hypoxia and acidosis. Since little is known about how cancer cells respond to elevated levels of ammonia in the tumour microenvironment, we investigated how a panel of cancer cell lines derived from solid tumours behaved when exposed to increasing concentrations of ammonia. We found that ammonia represses cell growth, induces genome instability, and inhibits lysosome-mediated proteolysis in a dose-dependent manner. Unexpectedly, we also found that small fluctuations in the pH of the extracellular environment, had a significant impact on the cytotoxic effects of ammonia. In summary, our data suggest that the balance of pH and ammonia within the interstitial fluids of cancerous tumours can have a significant impact on the behaviour and fate of cancer cells."
26,"Metadichol, a modulator that controls expression of Toll Like Receptors in Cancer Cell Lines",P.R. Raghavan,https://www.biorxiv.org/content/10.1101/2024.08.18.608483v3,"Toll-like receptors are essential players in the innate immune signaling system and play critical roles in recognizing pathogen-associated and damage-associated molecular patterns. Its presence in various cancer cells, including breast, ovarian, cervical, colon, hepatocellular carcinoma, prostate, lung cancer, melanoma, and neuroblastoma cells, has been associated with cancer progression, immune evasion, apoptosis, and chemoresistance. Despite extensive research, no small molecules can induce the expression of all TLRs in cancer cells have been identified. This study investigated the effects of metadichol, a nanoemulsion of long-chain alcohols, on the expression of TLR receptor families 1–10 in cancer cell lines. Using quantitative polymerase chain reaction (qPCR) and other molecular biology techniques, we assessed the concentration-dependent effects of metadichol on TLR expression, which ranged from 1 picogram per ml to 100 nanograms per ml. Our results show that metadichol can modulate TLR expression in a cancer cell type-specific manner, with TLR4 being upregulated in lung cancer cells, enhancing antitumor effects but downregulated in other cancer lines, reducing inflammation."
27,Oncolytic vaccinia virus as a precision cancer vaccine platform,"S Komant, J Wang, N Favis, C Alex, DH Evans, RS Noyce, TA Baldwin",https://www.biorxiv.org/content/10.1101/2024.08.16.608170v1,"Oncolytic viruses (OVs) are a unique immunotherapeutic tool as they possess the ability to selectively replicate in and kill tumor cells while also having the potential to induce potent antitumor immune responses. Further, the use of OVs as payload delivery systems to the tumor offers a precision approach to enhancing immune responses generated during OV therapy through the viral expression of immune stimulating molecules in the tumor. Notably, Vaccinia virus (VACV) is a strong oncolytic candidate due to its ability to infect a wide range of cancer cells, and a genome capable of harbouring large inserts of exogenous DNA. Peptide-Major Histocompatibility Complexes (pMHC-I) are vital components of the immune recognition of tumors, leading to the activation of antigen specific T cells and targeted killing of cells. Here, we examined the use of an oncolytic VACV (VACVΔ4x) expressing a single chain trimer (SCT) pMHC-I complex (VACVΔ4x -SCT) encoding a tumor associated or specific antigen. VACVΔ4x -SCT treatment was investigated in two immunologically cold tumor models, B16F10 melanoma and EMT6 breast cancer. VACV expression of tumor specific SCTs lead to drastic differences in tumor growth between the two models, where enhanced tumor clearance was observed in the EMT6 model. Tumor antigen specific CD8+ T cells were isolated from both tumor and spleen following VACV-SCT treatment, indicating the ability to induce targeted tumor specific responses with viral therapy. Initial tumor clearance was also observed to be protective in the EMT6 model, leading to tumor rejection upon subsequent challenge. Overall, we demonstrate the ability to generate a personalized cancer vaccine capable of inducing system recognition and elimination of tumor cells, validating VACV as a potential vaccine platform."
28,Deconvolution of cancer methylation patterns determines that altered methylation in cancer is dominated by a non-disease associated proliferation signal,"H Lalchungnunga, H Atasoy, EC Schwalbe, CM Bacon, G Strathdee",https://www.biorxiv.org/content/10.1101/2024.08.22.609153v1,"All cancers are associated with massive reorganisation of cellular epigenetic patterns, including extensive changes in the genomic patterns of DNA methylation. However, the huge scale of these changes has made it very challenging to identify key DNA methylation changes responsible for driving cancer development. Here, we present a novel approach to address this problem called methylation mapping. Through comparison of multiple types of B-lymphocyte derived malignancies and normal cell populations, this approach can define the origins of methylation changes as proliferation-driven, differentiation-driven and disease-driven (including both cancer-specific changes and cancer absent changes). Each of these categories of methylation change were found to occur at genomic regions that vary in sequence context, chromatin structure and associated transcription factors, implying underlying mechanistic differences behind the acquisition of methylation at each category. This analysis determined that only a very small fraction (about 3%) of DNA methylation changes in B-cell cancers are disease related, with the overwhelming majority (97%) being driven by normal biological processes, predominantly cell proliferation. Furthermore, the low level of true disease-specific changes can potentially simplify identification of functionally relevant DNA methylation changes, allowing identification of previously unappreciated candidate drivers of cancer development, as illustrated here by the identification and functional confirmation of SLC22A15 as a novel tumour suppressor candidate in acute lymphoblastic leukaemia. Overall, this approach should lead to a clearer understanding of the role of altered DNA methylation in cancer development, facilitate the identification of DNA methylation targeted genes with genuine functional roles in cancer development and thus identify novel therapeutic targets."
29,PhyClone: Accurate Bayesian reconstruction of cancer phylogenies from bulk sequencing,"Emilia Hurtado, Alexandre Bouchard-Côté, Andrew Roth",https://www.biorxiv.org/content/10.1101/2024.08.14.607069v1,"Motivation Cancer is driven by somatic mutations that result in the expansion of genomically distinct sub-populations of cells called clones. Identifying the clonal composition of tumours and understanding the evolutionary relationships between clones is a crucial task in cancer genomics. Bulk DNA sequencing is commonly used for studying the clonal composition of tumours, but it is challenging to infer the genetic relationship between different clones due to the mixture of different cell populations."
30,Tunnelling nanotubules are druggable mediators of cancer-niche crosstalk,"Sean Hockney, Jess Parker, Babis Tzivelekis, Helen Blair, Kenny Dalgarno, Deepali Pal",https://www.biorxiv.org/content/10.1101/2023.06.20.545732v4,"Treatment resistance, conferred onto cancer cells largely by the oncogenic niche, remains a clinically unmet need in leukaemia. Tractable and clinically translatable models that mimic cancer-niche crosstalk remain limited, consequently means of clinically drugging microenvironment-driven cancer treatment resistance remain underexplored. Here we develop a prototype bone marrow (BM) like extracellular matrix (ECM), Vitronectin-Alginate-Laminin (VAL), which comprises animal-free components, displays viscoelastic properties like the human BM, and engrafts a range of patient-derived-xenograft acute lymphoblastic leukaemia (PDX-ALL) samples. We discover that following treatment with oxidative stress-inducing apoptotic therapies, such as dexamethasone, ABT-199 and dexamethasone-ABT-199 combination, PDX-ALL cells reach out to MSC via the formation of tunnelling nanotubes (TNT). Nevertheless, we reveal that ALL-VAL-MSC-TNTs are clinically druggable, as they are absent following treatment with CDH2 antagonist ADH-1, a compound well-tolerated in solid cancer Phase I trials. We ultimately expose a triple drug combination of dexamethasone-ABT-199 and ADH-1, with most synergy area (MSA) scores of >30, that shows high efficacy and disrupts functional cancer-niche-TNTs in 4 different high risk PDX-ALL samples. In summary, here we develop prototype cancer-ECM-niche organoids and using leukaemia as a disease paradigm, we provide proof-of-concept insights enabling the beginning of research into drugging functional cancer cell crosstalk with its surrounding cellular and ECM niche."
33,MUC2 Expression Modulates Immune Infiltration in Colorectal Cancer,"Christophe M. Raynaud, Ayesha Jabeen, Eiman I. Ahmed, Satanay Hubrack, Apryl Sanchez, Shimaa Sherif, Ahmad A Al-Shaibi, Jessica Roelands, Bernice Lo, Davide Bedognetti, Wouter Hendrickx",https://www.biorxiv.org/content/10.1101/2024.08.06.594842v1,"Introduction Colorectal cancer (CRC) is a prevalent malignancy with significant morbidity and mortality worldwide. A deeper understanding of the interaction of cancer cells with other cells in the tumor microenvironment is crucial for devising effective therapeutic strategies. MUC2, a major component of the protective mucus layer in the gastrointestinal tract, has been implicated in CRC progression and immune response regulation."
34,Genomic evolution of pancreatic cancer at single-cell resolution,"Haochen Zhang, Palash Sashittal, Elias-Ramzey Karnoub, Akhil Jakatdar, Shigeaki Umeda, Jungeui Hong, Anne Marie Noronha, Agustin Cardenas III, Amanda Erakky, Caitlin A. McIntyre, Akimasa Hayashi, Nicolas Lecomte, Wungki Park, Nan Pang, Eileen M. O’Reilly, Alice C. Wei, Benjamin J Raphael, Christine A. Iacobuzio-Donahue",https://www.biorxiv.org/content/10.1101/2024.08.03.605165v1,"We adapted a previously developed targeted single-nucleus DNA sequencing (snDNA-seq) method and constructed a new suite of computational analysis tools to study 137,491 single-nucleus DNA libraries from 24 pancreatic cancers collected under a variety of clinical scenarios including early and late diagnoses, different metastatic sites and before- and after-treatment. We refined the mutational landscape of pancreatic cancer by capturing events missed by bulk sequencing, and validated the evolution pattern of early fixation of driver single-nucleotide variants (SNVs) followed by generation of intratumoral heterogeneity for copy number variations (CNVs). Intertumoral convergent evolution was common, including subclonal inactivation of TGF-β pathway by mutating various components of it; intratumoral convergence was rarely observed, likely due to strong selective force in pancreatic cancer development. Continuous evolution was frequently seen manifesting as CNVs. In the context of non-targeted treatments, no particular pattern was found across metastases or through treatment. In six pancreatic cancers with germline BRCA2 mutation, we discovered varied timing of biallelic inactivation of BRCA2, which sculpted different evolutionary trajectories and could presumably contribute to differential response to treatment. As the first large-scale application of targeted snDNA-seq on pancreatic cancer, this work provides a sample processing and computational analysis pipeline that warrants further clinical utility."
36,A Lung Cancer Mouse Model Database,"Ling Cai, Ying Gao, Ralph J. DeBerardinis, George Acquaah-Mensah, Vassilis Aidinis, Jennifer E. Beane, Shyam Biswal, Ting Chen, Carla P. Concepcion-Crisol, Barbara M. Grüner, Deshui Jia, Robert Jones, Jonathan M. Kurie, Min Gyu Lee, Per Lindahl, Yonathan Lissanu, Maria Corina Lorz Lopez, Rosanna Martinelli, Pawel K. Mazur, Sarah A. Mazzilli, Shinji Mii, Herwig Moll, Roger Moorehead, Edward E. Morrisey, Sheng Rong Ng, Matthew G. Oser, Arun R. Pandiri, Charles A. Powell, Giorgio Ramadori, Mirentxu Santos Lafuente, Eric Snyder, Rocio Sotillo, Kang-Yi Su, Tetsuro Taki, Kekoa Taparra, Yifeng Xia, Ed van Veen, Monte M. Winslow, Guanghua Xiao, Charles M. Rudin, Trudy G. Oliver, Yang Xie, John D. Minna",https://www.biorxiv.org/content/10.1101/2024.02.28.582577v2,"Lung cancer, the leading cause of cancer mortality, exhibits diverse histological subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. Here we established the Lung Cancer Mouse Model Database (LCMMDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMMs), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors have produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCMMDB aligns 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in GEMMs. Accompanying this resource, we developed a web application that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCMMDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance."
37,Analysis of Unmapped RNA-seq Data from Cancer Spatial Transcriptome to Decipher Cancer Microbiome,"Seo Hye Park, Jeongbin Park, Jiwon Kim, Hongyoon Choi, In Gul Kim, Eun-Jae Chung, Kwon Joong Na",https://www.biorxiv.org/content/10.1101/2024.06.09.598160v1,"Recent research increasingly emphasizes the importance of the microbiome in the development and progression of cancer. Thus, exploring the microbiome modulation in tumor microenvironment and understanding its composition and function are becoming important. The introduction of spatial transcriptomics has provided new insights into microbiome research, as it enables how microbiome affects tumor microenvironment. In this study, we analyzed the spatial distribution of microbial RNA observed through PathSeq and our extended method for unmapped RNA reads in oral squamous cell carcinoma, head and neck cancer, and colorectal cancer samples. Our novel method is designed to identify and classify microbial RNA, using a custom reference that includes species-specific microbial 16S rRNA sequences to enhance the accuracy of species-level microbiome analysis. The results of this study showed a potential for a deeper understanding of the microbial distribution and their functional roles within cancer tissues. These findings will reevaluate the role of the microbiome in cancer research, providing an insight for the development of microbiome-based therapies in the future."
38,Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer,"Aaron P. Havas, Kathryn Lande, Adarsh Rajesh, K. Garrett Evensen, Siva Karthik Varanasi, Linshan Shang, Elizabeth Schmidt, Jin Lee, Kenneth Kim, Marcos Garcia Teneche, Filipe Hoffmann, Michael LaPorte, Andrew Davis, Abby Grier, Julie A. Reisz, Kevin Tharp, Armin Gandhi, Xue Lei, Jessica Proulx, Karl N. Miller, Alessandra Sacco, Gerald S. Shadel, Laura Niedernhofer, Gen-Sheng Feng, Angelo D’Alessandro, Susan Kaech, April Williams, Peter D. Adams",https://www.biorxiv.org/content/10.1101/2024.07.31.606057v1,"Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of “precarious balance”, due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN-signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences."
41,Tumor sialylation controls effective anti-cancer immunity in breast cancer,"Stefan Mereiter, Gustav Jonsson, Tiago Oliveira, Johannes Helm, David Hoffmann, Markus Abeln, Ann-Kristin Jochum, Wolfram Jochum, Max J. Kellner, Marek Feith, Vanessa Tkalec, Karolina Wasilewska, Jie Jiao, Lukas Emsenhuber, Felix Holstein, Anna C. Obenauf, Leonardo Lordello, Jean-Yves Scoazec, Guido Kroemer, Laurence Zitvogel, Omar Hasan Ali, Lukas Flatz, Rita Gerardy-Schahn, Anja Münster-Kühnel, Johannes Stadlmann, Josef M. Penninger",https://www.biorxiv.org/content/10.1101/2023.09.20.558571v3,"Breast cancer is the most common cancer among women. However, the use of immune checkpoint inhibitors, that have revolutionized treatment of multiple cancers, unfortunately remain largely ineffective in most breast cancer patients. Here, we report the most comprehensive glycoproteome map in breast tumor cells, pointing to a key role of sialic acid modifications in mammary cancer. Genetic and pharmacologic inhibition of sialylation repolarizes the tumor microenvironment, leading to a reduction in myeloid-derived suppressor cells and a significant increase in Tcf7+ memory and CD8+ effector T cells. Mechanistically, sialylation controls cell surface expression of MHC class I and PD-1-ligand on the tumor cells. Functionally, in vivo interference with sialylation on breast cancer cells licenses CD8+ T cells to effectively kill the tumors. In multiple immunotherapy-resistant breast tumor models, we also show that the abrogation of sialylation sensitizes to anti-PD-1 immune checkpoint therapy. We further demonstrate that hyper-sialylation occurs in over half of human breast cancers tested and correlates with poor T cell infiltration. Our results establish sialylation as a central immunoregulator in breast cancer, orchestrating multiple pathways of immune evasion. Targeting tumor sialylation licenses immunologically inert mammary tumors to be efficiently eliminated by anti-cancer immunity and sensitizes to immune checkpoint therapy."
43,Hyaluronidase inhibitor delphinidin inhibits cancer metastasis,"Jeremy McGuire, Taketo Taguchi, Gregory Tombline, Victoria Paige, Michelle Janelsins, Nikesha Gilmore, Andrei Seluanov, Vera Gorbunova",https://www.biorxiv.org/content/10.1101/2024.04.28.591469v1,"Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular mass hyaluronic acid, a major non-protein component of extracellular matrix, protects naked mole rats from cancer and reduces cancer incidence in mice. Hyaluronidase plays a critical role in degrading hyaluronic acid and is frequently overexpressed in metastatic cancer. Here we investigated the potential of targeting hyaluronidases to reduce metastasis. High throughput screen identified delphinidin, a natural plant compound found in fruits and vegetables, as a potent hyaluronidase inhibitor. Delphinidin-mediated inhibition of hyaluronidase activity led to an increase in high molecular weight hyaluronic acid in cell culture and in mouse tissues, and reduced migration and invasion behavior of breast, prostate, and melanoma cancer cells. Moreover, delphinidin treatment suppressed melanoma metastasis in mice. Our study provides a proof of principle that inhibition of hyaluronidase activity suppresses cancer cell migration, invasion and metastasis. Furthermore, we identify a natural compound delphinidin as a potential anticancer therapeutic. Thus, we have identified a path for clinical translation of the cancer resistance mechanism identified in the naked mole rat."
44,A comprehensive analysis of the potential biological functions and prognostic values of SREBF1 for multiple cancer types including colorectal cancer,"Dongling Li, Fan Xu, Qinrui Cai, Ling Lin, Xiaoya Zhou, Li Li, Yao Chen, Tianlin Feng, Yuanxiu Gan, Chenhua Zhang, Fan Yang",https://www.biorxiv.org/content/10.1101/2024.07.26.605404v1,"As an important molecule involved in lipid metabolism, Sterol Regulatory Element-Binding Protein 1 (SREBF1) plays a critical role in governing cellular lipid synthesis and uptake. However, a comprehensive understanding of the biological significance of SREBF1 in pan-cancer remains elusive. In this study, we aimed to comprehensively analyze the functional characteristics of SREBF1 in human cancers, including colorectal cancer (CRC). Our study utilized various databases and tools such as TCGA, GEO, TIMER2.0, GEPIA2.0, UALCAN, and the Human Protein Atlas to examine SREBF1 expression, genetic alterations, immune infiltration, single-cell sequencing, survival analysis, and gene enrichment. The results revealed that the expression of SREBF1 exhibited significant variations across different cancer types, and was closely associated with patient prognosis and immune infiltration. Moreover, the gene function assays indicated SREBF1 significantly affect cell growth and migration. Overall, the findings suggest that SREBF1 could serve as a potential prognostic biomarker and a novel therapeutic target in different cancer types."
45,Inflammatory Neuropathy in Mouse and Primate Models of Colorectal Cancer,"Caitlyn M. Gaffney, Angela M. Casaril, Iqbal Mahmud, Bo Wei, Karen M. Valadez, Elizabeth A. Kolb, Fisher R. Cherry, Theresa A. Guise, Philip L. Lorenzi, Lei Shi, Carolyn L. Hodo, Andrew J. Shepherd",https://www.biorxiv.org/content/10.1101/2024.07.19.604274v1,"Colorectal cancer survivors are at increased risk of developing neurological issues, particularly peripheral neuropathy and chronic pain. Although pre-existing neuropathy is a risk factor for chronic pain, tumor-induced neuropathy has not been firmly established in pre-clinical models. Consistent with clinical observations, we show that mice with colorectal cancer develop peripheral neuropathy, which was associated with subtle locomotor deficits, without overt hypersensitivity. We detected widespread differences in pro-inflammatory cytokines and lipid metabolites in peripheral nerves from tumor-bearing mice. Macrophage accumulation, myelin decompaction and ryanodine receptor oxidation were associated with dysfunctional calcium homeostasis and reduced spike amplitude in sensory neurons. Inflammatory neuropathy and macrophage accumulation were also observed in peripheral nerves of rhesus macaques with colorectal cancer. These findings suggest colorectal cancer is causally linked to a subacute form of chronic inflammatory demyelinating polyneuropathy across species, which may represent an under-reported, yet important risk factor for neurological dysfunction in colorectal cancer survivors."
50,Transport Cocktails for Cancer Therapeutics,"Michail E. Kavousanakis, Omkar Bhatavdekar, Remco Bastiaannet, Yannis Kevrekidis, Stavroula Sofou",https://www.biorxiv.org/content/10.1101/2024.01.23.576806v1,"Beyond biological cell heterogeneity, evidenced by different resistances to therapeutics, “delivery heterogeneity” crucially limits treatment efficacy for advanced solid tumors: variations in therapeutic drug delivery to different tumor areas (perivascular, perinecrotic) leading to nonuniform drug concentrations/doses and to unsuccessful treatment (cancer cell kill). Short-range (40-80 µm), high energy (1-5 MeV) alpha-particles successfully address the biological heterogeneity: the double-strand DNA breaks they cause make them impervious to cell resistance mechanisms. Multiresponsive nanocarriers and/or engineered antibody-drug-conjugates are elegant approaches to delivering such alpha-particle emitters. Delivery heterogeneity, however, remains a challenge in established (i.e. large, vascularized) tumors. Remarkably, delivery properties enabling efficacy at the cell scale (targeting selectivity, affinity, cell drug uptake) may act against spatial delivery uniformity at the tumor scale (binding-site barrier effect1). We have previously demonstrated, in different mouse models, that spatial delivery uniformity, key to the effective killing of solid tumors, can be achieved utilizing combinations of different, distinct delivery carriers of the same emitter, but with different, complementary delivery properties, “leaving no cancer cell behind”. We build first principles reaction-transport models (quantitatively informed by experiments) that explain the “geographically complementary” behaviors of such carrier cocktails, and help optimally design these cocktails and their delivery protocols."
51,Expanded detection and impact of BAP1 alterations in cancer,"Ian R. Sturgill, Jesse R. Raab, Katherine A. Hoadley",https://www.biorxiv.org/content/10.1101/2023.11.21.568094v2,"Aberrant expression of the BAP1 tumor suppressor gene is a prominent risk factor for several tumor types and is important in tumor evolution and progression. Here we performed integrated multi-omic analyses using data from The Cancer Genome Atlas (TCGA) for 33 cancer types and over 10,000 individuals to identify alterations leading to BAP1 disruption. We combined existing variant calls and new calls derived from a de novo local realignment pipeline across multiple independent variant callers, increasing somatic variant detection by 41% from 182 to 257, including 11 indels ≥40bp. The expanded detection of mutations highlights the power of new tools to uncover longer indels and impactful mutations. We developed an expression-based BAP1 activity score and identified a transcriptional profile associated with BAP1 disruption in cancer. BAP1 has been proposed to play a critical role in controlling tumor plasticity and normal cell fate. Leveraging human and mouse liver datasets, BAP1 loss in normal cells resulted in lower BAP1 activity scores and lower scores were associated with a less-differentiated phenotype in embryonic cells. Together, our expanded BAP1 mutant samples revealed a transcriptional signature in cancer cells, supporting BAP1’s influences on cellular plasticity and cell identity maintenance."
52,Localized in vivo gene editing of murine cancer-associated fibroblasts,"Nicholas F. Kuhn, Itzia Zaleta-Linares, William A. Nyberg, Justin Eyquem, Matthew F. Krummel",https://www.biorxiv.org/content/10.1101/2024.07.11.603114v1,"Discovering the role of fibroblasts residing in the tumor microenvironment (TME) requires controlled, localized perturbations because fibroblasts play critical roles in regulating immunity and tumor biology at multiple sites. Systemic perturbations can lead to unintended, confounding secondary effects, and methods to locally genetically engineer fibroblasts are lacking. To specifically investigate murine stromal cell perturbations restricted to the TME, we developed an adeno-associated virus (AAV)-based method to target any gene-of-interest in fibroblasts at high efficiency (>80%). As proof of concept, we generated single (sKO) and double gene KOs (dKO) of Osmr, Tgfbr2, and Il1r1 in cancer-associated fibroblasts (CAFs) and investigated how their cell states and those of other cells of the TME subsequently change in mouse models of melanoma and pancreatic ductal adenocarcinoma (PDAC). Furthermore, we developed an in vivo knockin-knockout (KIKO) strategy to achieve long-term tracking of CAFs with target gene KO via knocked-in reporter gene expression. This validated in vivo gene editing toolbox is fast, affordable, and modular, and thus holds great potential for further exploration of gene function in stromal cells residing in tumors and beyond."
53,Cells in the Polyaneuploid Cancer Cell State are Pro-Metastatic,"Mikaela M. Mallin, Louis T.A. Rolle, Michael J. Schmidt, Shilpa Priyadarsini Nair, Amado J. Zurita, Peter Kuhn, James Hicks, Kenneth J. Pienta, Sarah R. Amend",https://www.biorxiv.org/content/10.1101/2024.07.12.603285v1,"There remains a large need for a greater understanding of the metastatic process within the prostate cancer field. Our research aims to understand the adaptive – ergo potentially metastatic – responses of cancer to changing microenvironments. Emerging evidence has implicated a role of the Polyaneuploid Cancer Cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mounting in vitro evidence supports increased metastatic potential of cells in the PACC state. Additionally, our recent retrospective study of prostate cancer patients revealed that PACC presence in the prostate at the time of radical prostatectomy was predictive of future metastatic progression. To test for a causative relationship between PACC state biology and metastasis, we leveraged a novel method designed for flow-cytometric detection of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in subcutaneous, caudal artery, and intracardiac mouse models of metastasis. This approach provides both quantitative and qualitative information about the number and PACC-status of recovered CTCs and DTCs. Collating data from all models, we found that 74% of recovered CTCs and DTCs were in the PACC state. In vivo colonization assays proved PACC populations can regain proliferative capacity at metastatic sites following dormancy. Additional direct and indirect mechanistic in vitro analyses revealed a PACC-specific partial Epithelial-to-Mesenchymal-Transition phenotype and a pro-metastatic secretory profile, together providing preliminary evidence that PACCs are mechanistically linked to metastasis."
54,Mathematical Modelling of Reoviruses in Cancer Cell Cultures,"Arwa Abdulla Baabdulla, Francisca Cristi, Maya Shmulevitz, Thomas Hillen",https://www.biorxiv.org/content/10.1101/2024.07.12.603333v1,"Oncolytic virotherapy has emerged as a potential cancer therapy, utilizing viruses to selectively target and replicate within cancer cells while preserving normal cells. In this paper, we investigate the oncolytic potential of unmodified reovirus T3wt relative to a mutated variant SV5. In animal cancer cell monolayer experiments it was found that SV5 was more oncolytic relative to T3wt. SV5 forms larger sized plaques on cancer cell monolayers and spreads to farther distances from the initial site of infection as compared to T3wt. Paradoxically, SV5 attaches to cancer cells less efficiently than T3wt, which lead us to hypothesize that there might be an optimal binding affinity with maximal oncolytic activity. To understand the relationship between the binding process and virus spread for T3wt and SV5, we employ mathematical modelling. A reaction-diffusion model is applied, which is fit to the available data and then validated on data that were not used for the fit. Analysis of our model shows that there is an optimal binding rate that leads to maximum viral infection of the cancer monolayer, and we estimate this value for T3wt and SV5. Moreover, we find that the viral burst size is an important parameter for viral spread, and that a combination of efficient binding and large burst sizes is a promising direction to further develop anti-cancer viruses."
55,Quantifying ‘just-right’ APC inactivation for colorectal cancer initiation,"Meritxell Brunet Guasch, Nathalie Feeley, Ignacio Soriano, Steve Thorn, Ian Tomlinson, Michael D. Nicholson, Tibor Antal",https://www.biorxiv.org/content/10.1101/2024.07.10.602868v2,"Dysregulation of the tumour suppressor gene Adenomatous Polyposis Coli (APC) is a canonical step in colorectal cancer development. Curiously, most colorectal tumours carry biallelic mutations that result in only partial loss of APC function, suggesting that a ‘just-right’ level of APC inactivation, and hence Wnt signalling, provides the optimal conditions for tumorigenesis. Mutational processes act variably across the APC gene, which could contribute to the bias against complete APC inactivation. Thus the selective consequences of partial APC loss are unclear. Here we propose a mathematical model to quantify the tumorigenic effect of biallelic APC genotypes, controlling for somatic mutational processes. Analysing sequence data from >2500 colorectal cancers, we find that APC genotypes resulting in partial protein function confer about 50 times higher probability of progressing to cancer compared to complete APC inactivation. The optimal inactivation level varies with anatomical location and additional mutations of Wnt pathway regulators. We use this context dependency to assess the regulatory effect of secondary Wnt drivers in combination with APC in vivo, and provide evidence that mutant AMER1 combines with APC genotypes that lead to relatively low Wnt. The fitness landscape of APC inactivation is consistent across microsatellite unstable and POLE-deficient colorectal cancers and tumours in patients with Familial Adenomatous Polyposis suggesting a general ‘just-right’ optimum, and pointing to Wnt hyperactivation as a potential cancer vulnerability."
56,NF-κB Epigenetic Attractor Landscape Drives Breast Cancer Heterogeneity,"Francisco Lopes, Bruno R. B. Pires, Alexandre A. B. Lima, Renata Binato, Eliana Abdelhay",https://www.biorxiv.org/content/10.1101/2024.07.10.602798v1,"Development of subtype heterogeneity in breast cancer requires stochastic transitions between cell types. Here, we sought to characterize how NF-κB contributes to breast cancer progression. We built a gene regulatory network model and calibrated it to the expression levels of NF-κB, TWIST1, SIP1, and SLUG in HER2+ and TNBC cell line, using patient and in vitro published data for validation. The model’s epigenetic landscape exhibits two attractor basins separated by a fluctuation-susceptible slow route. NF-κB stochastic fluctuations induce irreversible transitions from HER2+ to TNBC basins at different times, increasing heterogeneity. Mutations altering the availability of NF-κB change the size of the subtype basins, changing the transition probabilities. Our findings enhance the established attractor landscape formulation and deepen understanding of breast cancer heterogeneity."
57,Targeting cancer with small molecule pan-KRAS degraders,"Johannes Popow, William Farnaby, Andreas Gollner, Christiane Kofink, Gerhard Fischer, Melanie Wurm, David Zollman, Andre Wijaya, Nikolai Mischerikow, Carina Hasenoehrl, Polina Prokofeva, Heribert Arnhof, Silvia Arce-Solano, Sammy Bell, Georg Boeck, Emelyne Diers, Aileen B. Frost, Jake Goodwin-Tindall, Jale Karolyi-Oezguer, Shakil Khan, Theresa Klawatsch, Manfred Koegl, Roland Kousek, Barbara Kratochvil, Katrin Kropatsch, Arnel A. Lauber, Ross McLennan, Sabine Olt, Daniel Peter, Oliver Petermann, Vanessa Roessler, Peggy Stolt-Bergner, Patrick Strack, Eva Strauss, Nicole Trainor, Vesna Vetma, Claire Whitworth, Siying Zhong, Jens Quant, Harald Weinstabl, Bernhard Kuster, Peter Ettmayer, Alessio Ciulli",https://www.biorxiv.org/content/10.1101/2023.10.24.563163v2,"Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue (1). However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand (2). Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders."
58,Oncogenic NOVA1 expression dysregulates alternative splicing in breast cancer,"Daniel F Moakley, Chaolin Zhang",https://www.biorxiv.org/content/10.1101/2024.07.08.602566v1,"Neuro-Oncological Ventral Antigen 1 (NOVA1) is best known for its role in mediating an alternative splicing (AS) program in neurons, yet was first discovered as an antigen expressed in breast tumors, causing rare autoimmune reactions and paraneoplastic neurological disorders (PNDs). The PND model suggests a plausible role of the tumor antigen expression in tumor suppression, whereas it has emerged that NOVA may function as an oncogene in a variety of cancers. In addition, whether NOVA mediates AS in breast cancer remains unanswered. Here we examine the AS profiles of breast invasive carcinoma (BRCA) tumor samples and demonstrate that ectopic NOVA1 expression led to the activation of neuron-like splicing patterns in many genes, including exons targeted by NOVA in the brain. The splicing dysregulation is especially prevalent in cell periphery and cytoskeleton genes related to cell-cell communication, actin-based movement, and neuronal functions. We find that NOVA1-mediated AS is most prominent in Luminal A tumors and high NOVA1 expression in this subtype is associated with poorer prognosis. Our results suggest that ectopic NOVA1 in tumors has regulatory activity affecting pathways with high relevance to tumor progression and that this might be a more general mechanism for PND antigens."
59,Aging promotes lung cancer metastasis through epigenetic ATF4 induction,"Angana A.H. Patel, Jozefina Dzanan, Kevin X. Ali, Ella A. Eklund, Samantha W. Alvarez, Ilayda Altinönder, Dorota Raj, Ahmed Ezat El Zowalaty, Sama I. Sayin, Martin Dankis, Maria Schwarz, Emma Jonasson, Kristell Le Gal, Heba Albatrok, Roger Olofsson Bagge, Anetta Härtlova, Anders Ståhlberg, Andreas Hallqvist, Clotilde Wiel, Volkan I. Sayin",https://www.biorxiv.org/content/10.1101/2024.07.03.601209v1,"Lung cancer is primarily a disease of the elderly. Despite shared molecular changes between aging and cancer 1 – such as permissive chromatin states and deregulated protein homeostasis – studies on physiologically aged models of human lung cancer are lacking. Here, we show that aging alters the progression of KRAS-driven non-small cell lung cancer (NSCLC), promoting metastasis while suppressing primary lung tumor growth. Clinically, a multicenter analysis of all consecutively diagnosed NSCLC cases in Western Sweden over a 3-year period confirmed increased metastasis and smaller primary tumor size with age in KRAS-driven NSCLC. In addition, primary lung tumor cultures derived from older mice demonstrated an increased metastatic phenotype. Unbiased transcriptomic and epigenomic analyses identified ATF4, a major arm of the unfolded protein response (UPR), as a driver of aging-induced lung cancer metastasis. Furthermore, we found that the age-associated increase in ATF4 fuels metastatic dissemination through metabolic rewiring, including increased glutaminolysis. Finally, we report that pharmacological inhibition of glutaminase effectively suppressed aging-induced metastasis. Our findings suggest a novel adjuvant therapy for human lung cancer by targeting aging-induced metabolic plasticity, highlighting the need to consider the biology of aging in the development of cancer therapy."
60,Deep learning identifies heterogeneous subpopulations in breast cancer cell lines,"Tyler A. Jost, Andrea L. Gardner, Daylin Morgan, Amy Brock",https://www.biorxiv.org/content/10.1101/2024.07.02.601576v1,"Motivation Cells exhibit a wide array of morphological features, enabling computer vision methods to identify and track relevant parameters. Morphological analysis has long been implemented to identify specific cell types and cell responses. Here we asked whether morphological features might also be used to classify transcriptomic subpopulations within in vitro cancer cell lines. Identifying cell subpopulations furthers our understanding of morphology as a reflection of underlying cell phenotype and could enable a better understanding of how subsets of cells compete and cooperate in disease progression and treatment."
61,Mechanical evolution of metastatic cancer cells in three-dimensional microenvironment,"Karlin Hilai, Daniil Grubich, Marcus Akrawi, Hui Zhu, Razanne Zaghloul, Chenjun Shi, Man Do, Dongxiao Zhu, Jitao Zhang",https://www.biorxiv.org/content/10.1101/2024.06.27.601015v1,"Cellular biomechanics plays critical roles in cancer metastasis and tumor progression. Existing studies on cancer cell biomechanics are mostly conducted in flat 2D conditions, where cells’ behavior can differ considerably from those in 3D physiological environments. Despite great advances in developing 3D in vitro models, probing cellular elasticity in 3D conditions remains a major challenge for existing technologies. In this work, we utilize optical Brillouin microscopy to longitudinally acquire mechanical images of growing cancerous spheroids over the period of eight days. The dense mechanical mapping from Brillouin microscopy enables us to extract spatially resolved and temporally evolving mechanical features that were previously inaccessible. Using an established machine learning algorithm, we demonstrate that incorporating these extracted mechanical features significantly improves the classification accuracy of cancer cells, from 74% to 95%. Building on this finding, we have developed a deep learning pipeline capable of accurately differentiating cancerous spheroids from normal ones solely using Brillouin images, suggesting the mechanical features of cancer cells could potentially serve as a new biomarker in cancer classification and detection."
62,Quantitative cancer-immunity cycle modeling for predicting disease progression in advanced metastatic colorectal cancer,"Chenghang Li, Yongchang Wei, Jinzhi Lei",https://www.biorxiv.org/content/10.1101/2024.04.30.591845v1,"Patients diagnosed with advanced metastatic colorectal cancer (mCRC) often exhibit heterogeneous disease progression and face poor survival prospects. In order to comprehensively analyze the varied treatment responses among individuals and the challenge of tumor recurrence resistant to drugs in advanced mRCR, we developed a novel quantitative cancer-immunity cycle (QCIC) model. The proposed model was meticulously crafted utilizing a blend of differential equations and randomized modeling techniques to quantitatively elucidate the intricate mechanisms governing the cancer-immunity cycle and forecast tumor dynamics under different treatment modalities. Furthermore, by integrating diverse clinical datasets and rigorous model analyses, we introduced two pivotal concepts: the treatment response index (TRI) and the death probability function (DPF). These concepts are crucial tools for translating model predictions into clinically relevant evaluation indexes. Using virtual patient technology, we extrapolated tumor predictive biomarkers from the model to predict survival outcomes for mCRC patients. Our findings underscore the significance of tumor-infiltrating CD8+CTL cell density as a key predictive biomarker for short-term treatment responses in advanced mCRC while emphasizing the potential predict value of the tumor-infiltrating CD4+Th1/Treg ratio in determining patient survival. This study presents a pioneering methodology bridging the divide between diverse clinical data sources and the generation of virtual patients, offering invaluable insights into understanding inter-individual treatment variations and forecasting survival outcomes in mCRC patients."
63,BulkRNABert: Cancer prognosis from bulk RNA-seq based language models,"Maxence Gélard, Guillaume Richard, Thomas Pierrot, Paul-Henry Cournède",https://www.biorxiv.org/content/10.1101/2024.06.18.599483v3,"RNA sequencing (RNA-seq) has become a key technology in precision medicine, especially for cancer prognosis. However, the high dimensionality of such data may restrict classic statistical methods, thus raising the need to learn dense representations from them. Transformers models have exhibited capacities in providing representations for long sequences and thus are well suited for transcriptomics data. In this paper, we develop a pre-trained transformer-based language model through self-supervised learning using bulk RNA-seq from both non-cancer and cancer tissues, following BERT’s masking method. By probing learned embeddings from the model or using parameter-efficient fine-tuning, we then build downstream models for cancer type classification and survival time prediction. Leveraging the TCGA dataset, we demonstrate the performance of our method, BulkRNABert, on both tasks, with significant improvement compared to state-of-the-art methods in the pan-cancer setting for classification and survival analysis. We also show the transfer-learning capabilities of the model in the survival analysis setting on unseen cohorts. Code available at https://github.com/instadeepai/multiomics-open-research"
64,Caspase-Activated DNase Localizes to Cancer Causing Translocation Breakpoints During Cell Differentiation,"Dalal Alsowaida, Brian D. Larsen, Sarah Hachmer, Mehri Azimi, Eric Arezza, Steve Brunette, Steven Tur, Carmen G. Palii, Bassam Albraidy, Claus S. Sorensen, Marjorie Brand, F. Jeffrey Dilworth, Lynn A Megeney",https://www.biorxiv.org/content/10.1101/2024.09.24.614809v1,"Caspase activated DNase (CAD) induced DNA breaks promote cell differentiation and therapy- induced cancer cell resistance. CAD targeting activity is assumed to be unique to each condition, as differentiation and cancer genesis are divergent cell fates. Here, we made the surprising discovery that a subset of CAD-bound targets in differentiating muscle cells are the same genes involvedinthegenesisofcancer-causingtranslocations. Inmusclecells,aprominentCAD-bound gene pair is Pax7 and Foxo1a, the mismatched reciprocal loci that give rise to alveolar rhabdomyosarcoma. We show that CAD-targeted breaks in the Pax7 gene are physiologic to reduce Pax7 expression, a prerequisite for muscle cell differentiation. A cohort of these CAD gene targets are also conserved in early differentiating T cells and include genes that spur leukemia/lymphoma translocations. Our results suggest the CAD targeting of translocation prone oncogenic genes is non-pathologic biology and aligns with initiation of cell fate transitions."
65,Tumor microenvironment distinctions between esophageal cancer subtypes explain varied immunotherapy responses,"Seungbyn Baek, Junha Cha, Min-Hee Hong, Gamin Kim, Yoon Woo Koh, Dahee Kim, Martin Hemberg, Seong Yong Park, Hye Ryun Kim, Insuk Lee",https://www.biorxiv.org/content/10.1101/2024.09.24.614705v1,"Esophageal cancer comprises two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Previous studies have revealed distinct genomic characteristics between these subtypes, with ESCC sharing similarities with head and neck squamous cell carcinoma (HNSCC), and EAC aligning with gastric adenocarcinoma (GAC). Additionally, recent immunotherapy clinical trials have shown a higher response rate in ESCC and HNSCC compared to EAC and GAC. However, how the tumor microenvironment contributes to these varied immunotherapy responses remains unclear. In this study, through a comparative analysis of single-cell tumor transcriptomes from 35 patients with ESCC, EAC, HNSCC, or GAC, we identified two groups with tumor microenvironment distinctions: ESCC and HNSCC versus EAC and GAC, consistent with their genomic classifications. Malignant epithelial cells displayed distinct separations based on histological origin. In the tumor immune microenvironment, we observed an enrichment of CXCL13+CD8+ T cells and CXCL9+CXCL10+ tumor-associated macrophages (TAMs) in ESCC and HNSCC, which activate cellular immunity through interferon-γ. In contrast, EAC and GAC exhibited a high presence of heat-shock protein-expressing CD8+ T cells and MARCO+ TAMs. These immune signatures help explain the varied immunotherapy responses among these cancer subtypes and successfully predict immunotherapy outcomes across diverse cancer types, underscoring their clinical significance."
66,Integrating spatial profiles and cancer genomics to identify immune-infiltrated mismatch repair proficient colorectal cancers,"Jeremiah Wala, Ino de Bruijn, Shannon Coy, Andreanne Gagne, Sabrina Chan, Yu-An Chen, John Hoffer, Jeremy Muhlich, Nikolaus Schultz, Sandro Santagata, Peter Sorger",https://www.biorxiv.org/content/10.1101/2024.09.24.614701v1,"Predicting the progression of solid cancers based solely on genetics is challenging due to the influence of the tumor microenvironment (TME). For colorectal cancer (CRC), tumors deficient in mismatch repair (dMMR) are more immune infiltrated than mismatch repair proficient (pMMR) tumors and have better prognosis following resection. Here we quantify features of the CRC TME by combining spatial profiling with genetic analysis and release our findings via a spatially enhanced version of cBioPortal that facilitates multi-modal data exploration and analysis. We find that ~20% of pMMR tumors exhibit similar levels of T cell infiltration as dMMR tumors and that this is associated with better survival but not any specific somatic mutation. These T cell-infiltrated pMMR (tipMMR) tumors contain abundant cells expressing PD1 and PDL1 as well as T regulatory cells, consistent with a suppressed immune response. Thus, like dMMR CRC, tipMMR CRC may benefit from immune checkpoint inhibitor therapy."
67,Interplay of YEATS2 and GCDH mediates histone crotonylation and drives EMT in head and neck cancer,"Deepak Pant, PARIK KAKANI, Rushikesh Joshi, Shruti Agrawal, Atul Samaiya, Sanjeev Shukla",https://www.biorxiv.org/content/10.1101/2024.09.24.614679v1,"The regulation of gene expression is an integral cellular process orchestrated by epigenetic marks like histone modifications. Perturbations in the activity or abundance of epigenetic factors can lead to tumorigenesis. Remarkably, several metabolites influence the epigenetic landscape in cells. Here, we investigated the interplay between a highly expressed epigenetic factor, YEATS2, and a metabolic enzyme, GCDH, in regulating epithelial-to-mesenchymal transition in head and neck cancer. We report that the histone reader YEATS2 is responsible for increased invasive potential in head and neck cancer in an SP1-dependent manner. YEATS2 functions by maintaining histone crotonylation, and its abrogation leads to a global decrease in the H3K27Cr mark. Mechanistically, we report that YEATS2 maintains high H3K27Cr levels at the promoter of the EMT-promoting gene SPARC. Further, we found that the addition of the H3K27Cr mark is also dependent on the crotonyl-CoA-producing enzyme GCDH. Overall, we describe a novel mechanism of interplay between epigenetics and metabolism in head and neck tumorigenesis, which results in the enhanced expression of EMT-related genes in a histone crotonylation-dependent manner."
68,Characterising cancer cell responses to cyclic hypoxia using mathematical modelling,"Giulia Celora, Ruby Nixson, Joe Pitt-Francis, Philip Maini, Helen Byrne",https://www.biorxiv.org/content/10.1101/2024.06.25.600569v1,"In vivo observations show that oxygen levels in tumours can fluctuate on fast and slow timescales. As a result, cancer cells can be periodically exposed to pathologically low oxygen levels; a phenomenon known as cyclic hypoxia. Yet, little is known about the response and adaptation of cancer cells to cyclic, rather than, constant hypoxia. Further, existing in vitro models of cyclic hypoxia fail to capture the complex and heterogeneous oxygen dynamics of tumours growing in vivo. Mathematical models can help to overcome current experimental limitations and, in so doing, offer new insights into the biology of tumour cyclic hypoxia by predicting cell responses to a wide range of cyclic dynamics. We develop an individual-based model to investigate how cell cycle progression and cell fate determination of cancer cells are altered following exposure to cyclic hypoxia. Our model can simulate standard in vitro experiments, such as clonogenic assays and cell cycle experiments, allowing for efficient screening of cell responses under a wide range of cyclic hypoxia conditions. Simulation results show that the same cell line can exhibit markedly different responses to cyclic hypoxia depending on the dynamics of the oxygen fluctuations. We also use our model to investigate the impact of changes to cell cycle checkpoint activation and damage repair on cell responses to cyclic hypoxia. Our simulations suggest that cyclic hypoxia can promote heterogeneity in cellular damage repair activity within vascular tumours."
69,Breast cancer spheroids prefer activated macrophages as an accomplice: An in vitro study,"Abhishek Teli, Ranjani Iyer, Karthik Shanbhag, Rahul Gawarguru, Sukanya Gayan, Sumaiya Shaikh, Anup Tamhankar, Siddhesh S Kamat, Tuli Dey",https://www.biorxiv.org/content/10.1101/2024.09.24.614655v1,"Cancer, a heterogeneous disease in nature, often requires help from diverse pro-tumor or tumor-associated- cells, which are recruited and persevered within the stroma. Pro-tumor stromal cells provide the essential support needed for tumor growth, metastasis, and development of drug resistance in due time. Tumor-associated macrophages, one of such cells, are essential to tumor microenvironment and tumor survival. In recent years, TAMs have been identified as potential drug targets and therapeutic agents, which encourages the in-depth characterization of their crosstalk with the tumors. The current study has successfully developed a cost-effective in vitro platform for Chemokine Assisted Recruitment of Macrophages to spheroids mimicking the physiology of TAM recruitment. Firstly, monocytic cell line (u937) were converted into activated naive macrophages (M0) and pro-and anti-inflammatory (M1 and M2) subtypes. Monocytes, M0, M1, and M2 macrophages are characterized extensively. Secondly, the naive and polarized macrophages were subjected to chemokine-dependent recruitment into monotypic and heterotypic breast cancer spheroids. The nature of the recruitment is further investigated by assessing the profile of chemokines and chemokine receptors. Recruited macrophages are also observed to manipulate spheroid behavior in many ways. The recruited macrophages also exhibit an increased level of Siglec-1 (CD169), one of the potential TAM markers. The current platform's potential for application can be extended to understand the recruitment process of other immune/stromal cells to solid tumors. It could be a potential addition to the arrays of in vitro platforms developed to screen the efficiency of cell-based immunotherapeutics in the future."
70,Detection of intra-tumoral microbiota from transcriptomic sequencing of Asian breast cancer,"Li-Fang Yeo, Audrey Weng Yan Lee, Phoebe Yon Ern Tee, Joyce Seow Fong Chin, Bernard KB Lim, Joanna Lim, Soo-Hwang Teo, Jia-Wern Pan",https://www.biorxiv.org/content/10.1101/2024.09.25.614900v1,"The human microbiome has garnered significant interest in recent years as an important driver of human health and disease. Likewise, it has been suggested that the intra-tumoral microbiome may be associated with specific features of cancer such as tumour progression and metastasis. However, additional research is needed to validate these findings in diverse populations. In this study, we characterized the intra-tumoral microbiota of 883 Malaysian breast cancer patients using transcriptomic data from bulk tumours and investigated their association with clinical variables and immune scores. We found that the tumour microbiome was not associated with breast cancer molecular subtype, cancer stage, tumour grade, or patient age, but was weakly associated with immune scores. We also found that the tumour microbiome was able to predict immune scores in our cohort using random forest models, suggesting the possibility of an interaction between the tumour microbiome and the tumour immune microenvironment in Asian breast cancer."
71,nSMase2-mediated exosome secretion shapes the tumor microenvironment to immunologically support pancreatic cancer,"Audrey M Hendley, Sudipta Ashe, Atsushi Urano, Martin Ng, Tuan Anh Phu, Xianlu L Peng, Changfei Luan, Anna-Marie Finger, Gun Ho Jang, Natanya R Kerper, David I Berrios, David Jin, Jonghyun Lee, Irene R Riahi, Oghenekevwe M Gbenedio, Christina Chung, Jeroen Roose, Jen Jen Yeh, Steven Gallinger, Andrew V Biankin, Grainne M OKane, Vasilis Ntranos, David Chang, David W Dawson, Grace E Kim, Valerie M Weaver, Robert L Raffai, Matthias Hebrok",https://www.biorxiv.org/content/10.1101/2024.09.23.614610v1,"The pleiotropic roles of nSMase2-generated ceramide include regulation of intracellular ceramide signaling and exosome biogenesis. We investigated the effects of eliminating nSMase2 on early and advanced PDA, including its influence on the microenvironment. Employing the KPC mouse model of pancreatic cancer, we demonstrate that pancreatic epithelial nSMase2 ablation reduces neoplasia and promotes a PDA subtype switch from aggressive basal-like to classical. nSMase2 elimination prolongs survival of KPC mice, hinders vasculature development, and fosters a robust immune response. nSMase2 loss leads to recruitment of cytotoxic T cells, N1-like neutrophils, and abundant infiltration of anti-tumorigenic macrophages in the pancreatic preneoplastic microenvironment. Mechanistically, we demonstrate that nSMase2-expressing PDA cell small extracellular vesicles (sEVs) reduce survival of KPC mice; PDA cell sEVs generated independently of nSMase2 prolong survival of KPC mice and reprogram macrophages to a proinflammatory phenotype. Collectively, our study highlights previously unappreciated opposing roles for exosomes, based on biogenesis pathway, during PDA progression."
72,Oxidative Phosphorylation Inhibition in Different Prostate Cancer Models and the Interplay with Androgen Receptor Signaling,"Minas Sakellakis, Sumankalai Ramachandran, Priyanshu Jain, Mark A Titus",https://www.biorxiv.org/content/10.1101/2024.09.23.614600v1,"Introduction: In prostate cancer (PCa), androgen receptor signaling stimulates both glycolysis and oxidative phosphorylation (OxPhos). Early-stage prostate cancer is particularly reliant on OxPhos for its bioenergetic needs. OxPhos inhibitors have entered clinical trials. Here we investigated their interplay with androgens in different PCa cell lines.
Methods: We investigated the effects on PCa cell viability of an ATPase inhibitor (oligomycin) and a complex 1 inhibitor (IACS-010759) in the presence or absence of low testosterone concentrations in vitro. Both androgen-sensitive and insensitive PCa cell lines were used.  The effects were assessed using MTT assay, flow cytometry and cell morphology. 
Results: Treatment with oligomycin resulted in massive apoptotic death of VCAP cells in castrate conditions within 48 hours, but the simultaneous addition of low testosterone levels restored VCAP cell viability. However, complex 1 inhibition with IACS-010759 increased cell viability, which was further promoted in the presence of testosterone. Both oligomycin and IACS-010759 dramatically decreased viability in LNCaP cells, while testosterone had a small but statistically non-significant effect. The antitumor effect of OxPhos inhibitors was smaller in LNCaP-C4-2B compared to LNCaP cells. OxPhos inhibitors slightly decreased proliferation rates in androgen-independent PC3 cells and HEK293 cells. Oligomycin on LNCaP-C4-2B and PC3 cells resulted in an increased number of cells in G0-G1 phase  and decreased in S-phase and G2M phase, rather than massive apoptosis.
Conclusion: There is an interplay between androgen signaling and OxPhos in androgen-dependent PCa cells. Complex 1 inhibitors should be used with caution, given potential pro-tumorigenic effects in subsets of PCa cells."
73,IGF2BP3 promotes the progression of gastric cancer by activating cGMP-PKG signaling pathway via targeting FBXO32,"Yi Si, Bo Tian, Rui Zhang, Mingda Xuan, Kunyi Liu, Jiao Jiao, Shuangshuang Han, Hongfei Li, Yanhong Hu, Hongyan Zhao, Wenjing He, Jia Wang, Ting Liu, Weifang Yu",https://www.biorxiv.org/content/10.1101/2024.06.28.601102v2,"N6-methyladenosine (m6A) represents the most prevalent chemical modification on eukaryotic mRNA, with an accumulating body of literature indicating its pivotal significance in the pathogenesis of human cancers. Nevertheless, the precise molecular interplay between the m6A reader protein IGF2BP3 and gastric cancer remains to be thoroughly delineated. Our study uncovered that the expression of IGF2BP3 in gastric cancer tissues is markedly elevated in comparison to adjacent normal tissues, and this upregulation is tightly correlated with the incidence of lymph node metastasis, more advanced TNM stages, and deeper invasion depth of tumor in patients. In vitro experiments demonstrated that IGF2BP3 potentiates the proliferative, migratory, and invasive capacities of gastric cancer cells, while concurrently inhibiting apoptosis and augmenting the intracellular levels of aerobic glycolysis. In vivo experiments revealed that IGF2BP3 contributes to the growth of gastric cancer. Mechanistically, IGF2BP3 can increase the expression of FBXO32 protein by recognizing and binding to the m6A binding site on FBXO32 mRNA and further activate the downstream cGMP-PKG signaling pathway, thereby modulating various biological functions of gastric cancer cells and ultimately promoting the progression of gastric cancer. In summary, our findings suggest that IGF2BP3 upregulates the expression of FBXO32 protein in an m6A dependent manner and subsequently activates the cGMP-PKG signaling pathway, ultimately leading to the onset and progression of gastric cancer. Consequently, the targeting of the IGF2BP3/FBXO32/cGMP-PKG axis emerges as a promising therapeutic modality for the treatment of gastric cancer."
74,TGFβ signaling in cancer-associated fibroblasts drives a hepatic gp130-dependent pro-metastatic inflammatory program in CMS4 colorectal cancer subtype,"TJ Harryvan, S Abudukelimu, I Stouten, EJ van der Wel, SGT Janson, KJ Lenos, TRM Lannagan, M White, OJ Sansom, EME Verdegaal, LJAC Hawinkels",https://www.biorxiv.org/content/10.1101/2024.06.25.600311v1,"Current molecular classification of colorectal cancer (CRC), the Consensus Molecular Subtypes (CMS), has highlighted the biological heterogeneity of CRC and enables patient stratification based on the molecular subtype of their tumor. The CMS4 subtype shows the worst prognosis and is linked to the highest occurrence of hepatic metastasis but the underlying molecular mechanisms remain unclear. In this study, we show that the molecular features that largely define CMS4 classification, i.e. abundance of cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) and active TGFβ signaling, converge to promote liver metastasis. Studying TGFβ signaling in CRC patient-derived CAFs from the primary tumor revealed that all three TGFβ isoforms induce expression of different IL-6 cytokine family members, particularly IL-6 and IL-11. This primary tumor-derived IL-6 and IL-11 in turn induce upregulation of myeloid chemoattractants, including SAA1, in hepatocytes. Chemical inhibition and genetic ablation experiments revealed that gp130, the IL-6 family of cytokine co-receptor, through JAK/STAT signaling is crucial for the induction of neutrophil chemoattractants by hepatocytes and mediates the migration of potential pro-metastatic neutrophils towards the liver. This IL-6 family-JAK/STAT stromal signaling axis is active in both a murine model of CMS4 as well as in human CRC patients in vivo. Combined, our data reveal that TGFβ signaling in CAFs actively contributes to the formation of a neutrophil-dependent, pre-metastatic hepatic niche and that this mechanism might play a role in the metastatic phenotype of CMS4 subtype CRC."
75,Bifidobacterium pseudocatenulatum capsular exopolysaccharide enhances systemic anti-tumour immunity in pre-clinical breast cancer,"Christopher A Price, Alicia Nicklin, Magdalena Kujawska, Todor T Koev, Nilda Ilker, Wesley J Fowler, Alastair M McKee, Luke Mitchel, Mitchel Rowe, James A.G.E Taylor, Christopher J Benwell, Sally A Dreger, Julia Muller, Lindsay J Hall, Stephen Douglas Robinson",https://www.biorxiv.org/content/10.1101/2024.09.23.614466v1,"Gut microbes have merged as powerful regulators of cancer responses, with Bifidobacterium species and strains playing a key role in promoting anti-tumour immunity. While they represent promising candidates for cancer therapeutics, the specific underlying microbial mechanisms driving their efficacy remains poorly understood. In this study, we demonstrate the broad potential of Bifidobacterium species to inhibit breast cancer progression across multiple pre-clinical mouse models. We identify a novel strain, Bifidobacterium pseudocatenulatum 210, which induces systemic anti-tumour immunity and enhances responses to standard-of-care therapies via its cell surface capsular exopolysaccharide (EPS). B. pseudocatenulatum 210 EPS promotes dendritic cell activation and increases systemic cDC1 infiltration, leading to robust CD8+ T cell-mediated anti-tumour activity. Our findings position Bifidobacterium EPS as a novel class of therapeutic compounds with significant potential for cancer treatment."
76,Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition,"Chuwei Lin, Catherine M. Sniezek, Christopher D. McGann, Rashmi Karki, Ross M. Giglio, Benjamin A. Garcia, José L. McFaline-Figueroa, Devin K. Schweppe",https://www.biorxiv.org/content/10.1101/2024.05.23.592075v3,"Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogenous and dependent on factors such as the genetic background, metabolic state, and on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line or using a small number of compounds. To more comprehensively profile the effects of  small-molecule perturbations and their influence on these heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative molecular profiling of 10,621 proteins, these data reveal coordinated molecular remodeling of HDACi treated cancer cells. HDACi-regulated proteins differ greatly across cell lines with  consistent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) cell-state effectors. Together these data provide valuable insight into cell-type driven and heterogeneous responses that must be taken into consideration when monitoring molecular perturbations in culture models."
77,Mutational order and epistasis determine the consequences of FBXW7 mutations during colorectal cancer evolution,"Dedrick Kok Hong Chan, Amit Mandal, Yi Zhou, Scott David Collins, Richard Owen, James Bundred, Hannah Fuchs, Sabrina James, Iolanda Vendrell, Sarah Flannery, David Fawkner-Corbett, Jacob Househam, Trevor A Graham, Roman Fischer, Alison Simmons, Xin Lu, Simon James Alexander Buczacki",https://www.biorxiv.org/content/10.1101/2023.08.25.554836v2,"Somatic driver mutations, in genes such as FBXW7, have been discovered in phenotypically normal colonic tissue, however their role in cancer initiation remains elusive. Using normal and gene-edited patient-derived human colon organoids as models of early tumour evolution we observed that FBXW7-/- mutations exerted an epistatic effect on subsequent transcription depending on the mutational background of the cell. Specifically, the timing of acquiring an FBXW7-/- mutation respective to an APC mutation, led to profound phenotypic and transcriptomic differences. When FBXW7 was mutated before APC, a near-normal cell state was maintained alongside repression of the APC transcriptional response. However, when APC was mutated before FBXW7, cells acquired classical cancer-stem cell features. Single-cell RNA sequencing revealed that mutation of FBXW7 in normal tissue subtly switched cells from adult to a foetal/regenerative stem cell state. Further analysis using transposase-accessible chromatin sequencing identified this cellular plasticity was driven by changes in chromatin accessibility of transcriptional start site regions associated with TEAD, SNAI1 and AP-1 motifs, which in turn activate the foetal-like state. Taken together, we demonstrate a critical role of FBXW7 mutations in preventing colorectal cancer initiation and provide exemplar evidence for the importance of epistasis and mutational order in cancer biology."
78,Heterogeneous Kinetics of Nanobubble Ultrasound Contrast Agent and Angiogenic Signaling in Head and Neck Cancer,"Benjamin Van Court, Mark Ciccaglione, Brooke Neupert, Michael W. Knitz, Sean P. Maroney, Diemmy Nguyen, Khalid N.M. Abdelazeem, Agata A. Exner, Anthony J. Saviola, Richard K.P. Benninger, Sana D. Karam",https://www.biorxiv.org/content/10.1101/2024.09.22.614362v1,"Recently developed nanobubble ultrasound contrast agents are a promising tool for imaging and drug delivery in tumors. To better understand their unusual kinetics, we implemented a novel pixel clustering analysis, which provides unique information by accounting for spatial heterogeneity. By combining ultrasound results with proteomics of the imaged tumors, we show that this analysis is highly predictive of protein expression and that specific types of nanobubble time-intensity curve are associated with upregulation of different metabolic pathways. We applied this method to study the effects of two proteins, EphB4 and ephrinB2, which control tumor angiogenesis through bidirectional juxtacrine signaling, in mouse models of head and neck cancer. We show that ephrinB2 expression by endothelial cells and EphB4 expression by cancer cells have similar effects on tumor vasculature, despite sometimes opposite effects on tumor growth. This implicates a cancer-cell-intrinsic effect of EphB4 forward signaling and not angiogenesis in EphB4's action as a tumor suppressor."
79,Functional impact of the hyperduplication genomophenotype in high copy number endometrial cancer,"Angela Florio, James Smadbeck, Sarah Johnson, Wan-Hsin Lin, Dorsay Sadeghian, Sotiris Sotiriou, Rebecca Salvatori, Ryan Feathers, Taylor Berry, Lindsey Kinsella, Faye Harris, Alexa McCune, Stephen James Murphy, Mohamed Ali, Mammad Pezeshki, Michael T Barrett, Leah Grcevich, Ilaria Capasso, Luigi Antonio DeVitis, Gabriella Schivardi, Tommaso Occhiali, Alyssa M Larish, John Weroha, Mitesh James Borad, John Cheville, Panos Z Anastasiadis, Andrea Mariani, George Vasmatzis",https://www.biorxiv.org/content/10.1101/2024.09.20.613693v1,"High copy number endometrial cancers (HCNEC) are dominated by excessive duplications scattered across the genome, termed here as the HyperDuplication GenomoPhenotype (HDGP). Although correlated with cancer progression, its biological significance and implications for therapy have not yet been established. We identified locations and sizes of duplications in 171 endometrial cancer cases and designated 71 HCNEC cases as HDGP. We also investigated the response to the pan-ERBB inhibitor afatinib in a subset of HDGP-EC cases with ERBB2/ERBB3 duplications using a patient-derived three-dimensional culture model. Our analysis demonstrates that beyond tandem duplications there is a more general pattern involving coordinated duplication of multiple distant regions of the genome, demonstrating preferential selectivity to over-expressed potential oncogenes within a broad network. This suggests that HDGP increases tumor fitness and resistance to therapy by perturbing important gene networks in concert rather than only driver genes, suggesting a mechanistic basis for the ineffectiveness of targeted drugs in these patients and highlighting the need for combination therapies in these highly aggressive cases."
80,A Machine Learning-Based Investigation of Integrin Expression Patterns in Cancer and Metastasis,"Hossain Shadman, Saghar Gomrok, Qianyi Cheng, Yu Jiang, Xiaohua Huang, Jesse Dylan Ziebarth, Yongmei Wang",https://www.biorxiv.org/content/10.1101/2024.09.19.613933v1,"Background
Integrins, a family of transmembrane receptor proteins, play complex roles in cancer development and metastasis. These roles could be better delineated through machine learning of transcriptomic data to reveal relationships between integrin expression patterns and cancer.
Methods
We collected publicly available RNA-Seq integrin expression from 8 healthy tissues and their corresponding tumors, along with data from metastatic breast cancer. We then used machine learning methods, including t-SNE visualization and Random Forest classification, to investigate changes in integrin expression patterns.
Results
Integrin expression varied across tissues and cancers, and between healthy and cancer samples from the same tissue, enabling the creation of models that classify samples by tissue or disease status. The integrins whose expression was important to these classifiers were identified. For example, ITGA7 was key to classification of breast samples by disease status. Analysis in breast tissue revealed that cancer rewires co-expression for most integrins, but the co-expression relationships of some integrins remain unchanged in healthy and cancer samples. Integrin expression in primary breast tumors differed from their metastases, with liver metastasis notably having reduced expression.
Conclusions
Integrin expression patterns vary widely across tissues and are greatly impacted by cancer. Machine learning of these patterns can effectively distinguish samples by tissue or disease status."
81,The theory of massively repeated evolution and full identifications of Cancer Driving Nucleotides (CDNs),"Lingjie Zhang, Tong Deng, Zhongqi Liufu, Xueyu Liu, Bingjie Chen, Zheng Hu, Chenli Liu, Xuemei Lu, Miles E. Tracy, Hai-Jun Wen, Chung-I Wu",https://www.biorxiv.org/content/10.1101/2024.05.29.596366v3,"Tumorigenesis, like most complex genetic traits, is driven by the joint actions of many mutations. At the nucleotide level, such mutations are Cancer Driving Nucleotides (CDNs). The full sets of CDNs are necessary, and perhaps even sufficient, for the understanding and treatment of each cancer patient. Currently, only a small fraction of CDNs is known as most mutations accrued in tumors are not drivers. We now develop the theory of CDNs on the basis that cancer evolution is massively repeated in millions of individuals. Hence, any advantageous mutation should recur frequently and, conversely, any mutation that does not is either a passenger or deleterious mutation. In the TCGA cancer database (sample size n = 300 - 1000), point mutations may recur in i out of n patients. This study explores a wide range of mutation characteristics to determine the limit of recurrences (i*) driven solely by neutral evolution. Since no neutral mutation can reach i* = 3, all mutations recurring at i ≥ 3 are CDNs. The theory shows the feasibility of identifying almost all CDNs if n increases to 100,000 for each cancer type. At present, only < 10% of CDNs have been identified. When the full sets of CDNs are identified, the evolutionary mechanism of tumorigenesis in each case can be known and, importantly, gene targeted therapy will be far more effective in treatment and robust against drug resistance."
83,mosna reveals different types of cellular interactions predictive of response to immunotherapies and survival in cancer,"Alexis Coullomb, Paul Monsarrat, Vera Pancaldi",https://www.biorxiv.org/content/10.1101/2023.03.16.532947v2,"Spatially resolved omics enable the discovery of tissue organization of biological or clinical importance. Despite the existence of several methods, performing a rational analysis including multiple algorithms while integrating different conditions such as clinical data is still not trivial. To make such investigations more accessible, we developed mosna, a Python package to analyze spatial omics data with respect to clinical or biological data and to gain insight on cell interaction patterns or tissue architecture of biological relevance. mosna is compatible with all spatial omics methods, it leverages tysserand to build accurate spatial networks, and is compatible with Squidpy. It proposes an analysis pipeline, in which increasingly complex features computed at each step can be explored in integration with clinical data, either with easy-to-use descriptive statistics and data visualization, or by seamlessly training machine learning models and identifying variables with the most predictive power."
84,CanDrivR-CS: A Cancer-Specific Machine Learning Framework for Distinguishing Recurrent and Rare Variants,"Amy Francis, Colin Campbell, Tom Gaunt",https://www.biorxiv.org/content/10.1101/2024.09.19.613896v1,"Motivation Missense variants play a crucial role in cancer development, and distinguishing between those that frequently occur in cancer genomes and those that are rare may provide valuable insights into important functional mechanisms and consequences. Specifically, if common variants confer growth advantages, they may have undergone positive selection across different patients due to similar selection pressures. Moreover, studies have demonstrated the significance of rare mutations that arise as resistance mechanisms in response to drug treatment. This highlights the importance of understanding the role of both recurrent and rare variants in cancer. In addition to this, most existing tools for variant prediction focus on distinguishing variants found in normal and disease populations, often without considering the specific disease contexts in which these variants arise. Instead, they typically build predictors that generalise across all diseases. Here, we introduce CanDrivR-CS, a set of cancer-specific gradient boosting models designed to distinguish between rare and recurrent cancer variants."
85,Dicarbonyl stress debilitates mesothelial defense against metastasizing ovarian cancer,"Satyarthi Mishra, Kottpalli Vidhipriya, Anchita Gopikrishnan, Sudiksha Mishra, CVS Prasanna, Prosenjit Sen, Ramray Bhat",https://www.biorxiv.org/content/10.1101/2024.06.18.599500v1,"Chronic metabolic disorders and aging result in accumulation of active dicarbonyls that glycate biomolecules rendering them dysfunctional. Although metabolic aberrations are known to be epidemiologically associated with faster cancer progression, cell biological determinants of such associations remain elusive. The formation of micro-metastases in epithelial ovarian cancer involves its colonization of visceral peritonea through clearance of mesothelia that line the coelom. In this study, we observe that cocultures of immortalized human coelomic MeT-5A mesothelia with human ovarian cancer cells OVCAR-3 and SK-OV-3 show greater infiltration by the latter when exposed to increasing concentrations of the dicarbonyl methylglyoxal (MG). Treatment with increasing concentrations of MG caused death and senescence within human and murine serosal mesothelia. Cells showed higher levels of advanced glycation end products, dysregulated occludens junction protein ZO-1, and disrupted localization of cortical filamentous actin and its regulator ezrin, indicating poor inter-cell adhesion. Time lapse imaging also showed impaired migration for MG-treated single mesothelia and for their collective monolayers. Agent-based computer modeling of coculture dynamics predicted that a combined effect of confluence and migration allows inter-adherent mesothelia to contain the spread of colonizing cancer cells, which was confirmed through coculture time lapses of cancer colonization within higher and lower mesothelial densities. We found ovarian cancer cells showed higher levels of glyoxalase-1 (GLO-1) enzyme, which catabolizes MG, suggesting how they escaped its cytotoxic effects. Consistent with this, treatment of OVCAR-3 with MG concurrently with pharmacological inhibition of GLO-1 showed greater cell death. Our results suggest dicarbonyl stress helps colonizing cancer cells overcome the resistance of natural homoeostatic barriers and its inhibition may, in supplementation with chemotherapy, stem metastasis."
88,Family-Wide Photoproximity Profiling of Integrin Protein Social Networks in Cancer,"Anthony J. Carlos, Dongbo Yang, Deborah M. Thomas, Shuyuan Huang, Keira I. Harter, Raymond E. Moellering",https://www.biorxiv.org/content/10.1101/2024.09.18.613588v1,"Integrin family transmembrane receptors mediate dynamic interactions between cells and their extracellular microenvironment. The heterogeneous interaction partners of integrins directly regulate cell adhesion, motility, proliferation, and intracellular signaling. Despite the recognized importance of protein-protein interactions and the formation of signaling hubs around integrins, the ability to detect and quantify these dynamic binding partners with high spatial and temporal resolution remains challenging. Here, we developed an integrin-family-directed quantitative photoproximity protein interaction (PhotoPPI) profiling method to detect and quantify native integrin-centered protein social networks on live cells and tissues without the need for genetic manipulation, antibodies, or non-physiologic cell culture conditions. We drafted quantitative maps of integrin-centered protein social networks, highlighting conserved and unique binding partners between different cell types and cellular microenvironments. Comparison of integrin social networks in cancer cell lines of diverse tissue of origin and disease state identified specific AND-gate binding partners involved cell migration, microenvironmental interactions and proliferation that serve as markers of tumor cell metastatic state. Finally, we identified unique combinations – or barcodes - of integrin-proximal proteins on the surface of pre- and post-metastatic triple negative breast cancer (TNBC) cells whose expression strongly correlate with both positive and negative disease progression and outcomes in TNBC patients. Taken together, these data provide the first family-wide high-resolution maps of native protein interactors on live cells and identify dynamic integrin-centered social networks as potential AND-gate markers of cell identity, microenvironmental context and disease state."
90,Targeting cancer-associated glycosylation for adoptive T cell therapy of gastro-intestinal and gynecological cancers,"Andreas Zingg, Reto Ritschard, Helen Thut, Mélanie Buchi, Andreas Holbro, Anton Oseledchyk, Viola Heinzelmann, Andreas Buser, Mascha Binder, Alfred Zippelius, Natalia Rodrigues Mantuano, Matthias Matter, Heinz Läubli",https://www.biorxiv.org/content/10.1101/2024.09.12.612750v2,"CAR-T cell therapy has provided a significant improvement for patients with chemotherapy-resistant B cell malignancies. However, CAR-T cell treatment of patients with solid cancers has been more difficult, in part because of the heterogeneous expression of tumor-specific cell surface antigens. Here, we describe the generation of a fully human CAR targeting altered glycosylation in secretory epithelial cancers. The expression of the target antigen – the truncated, sialylated O-glycan sialyl-Thomsen-Nouveau antigen (STn) – was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastro-intestinal cancers including pancreatic cancers and in gynecological cancers, in particular ovarian and endometrial tumors. T cells expressing anti-STn CAR were tested in vitro and in vivo. Anti-STn CAR-T cells showed activity in mouse models as well as in assays with primary ovarian cancer samples. No significant toxicity was observed in mouse models, although some intraluminal expression of STn was found in gastro-intestinal mouse tissue. Taken together, this fully human anti-STn CAR construct shows promising activity in preclinical tumor models supporting its further evaluation in early clinical trials."
91,Merging Metabolic Modeling and Imaging for Screening Therapeutic Targets in Colorectal Cancer,"Niki Tavakoli, Emma J. Fong, Abigail Coleman, Yu-Kai Huang, Mathias Bigger, Michael E. Doche, Seungil Kim, Heinz-Josef Lenz, Nicholas A. Graham, Paul Macklin, Stacey D. Finley, Shannon M. Mumenthaler",https://www.biorxiv.org/content/10.1101/2024.05.24.595756v2,"Cancer-associated fibroblasts (CAFs) play a key role in metabolic reprogramming and are well-established contributors to drug resistance in colorectal cancer (CRC). To exploit this metabolic crosstalk, we integrated a systems biology approach that identified key metabolic targets in a data-driven method and validated them experimentally. This process involved a novel machine learning-based method to computationally screen, in a high-throughput manner, the effects of enzyme perturbations predicted by a computational model of CRC metabolism. This approach reveals the network-wide effects of metabolic perturbations. Our results highlighted hexokinase (HK) as the crucial target, which subsequently became our focus for experimental validation using patient-derived tumor organoids (PDTOs). Through metabolic imaging and viability assays, we found that PDTOs cultured in CAF-conditioned media exhibited increased sensitivity to HK inhibition, confirming the model predictions. Our approach emphasizes the critical role of integrating computational and experimental techniques in exploring and exploiting CRC-CAF crosstalk."
92,"Neuroendocrine Prostate Cancer Drivers SOX2 and BRN2 Confer Differential Responses to Imipridones ONC201, ONC206, and ONC212 in Prostate Cancer Cell Lines","Connor Purcell, Praveen R. Srinivasan, Maximilian Pinho-Schwermann, William J. MacDonald, Elizabeth Ding, Wafik S. El-Deiry",https://www.biorxiv.org/content/10.1101/2024.08.28.610184v1,"Prostate cancer (PCa) is the leading cause death from cancer in men worldwide. Approximately 30% of castrate-resistant PCa’s become refractory to therapy due to neuroendocrine differentiation (NED) that is present in <1% of androgen-sensitive tumors. First-in-class imipridone ONC201/TIC10 has shown clinical activity against midline gliomas, neuroendocrine tumors and PCa. We explored the question of whether NED promotes sensitivity to imipridones ONC201 and ONC206 by inducible overexpression of SOX2 and BRN2, well-known neuroendocrine drivers, in human PCa cell lines DU145 or LNCaP. Slight protection from ONC201 or ONC206 with SOX2 and BRN2 overexpression was observed in the inducible LNCaP cells but not in the DU145 cells. At 2 months, there was an apparent increase in CLpP expression in LNCaP SOX2-overexpressing cells but this did not confer enhanced sensitivity to ONC201. DU145 SOX2-overexpressing cells had a significantly reduced ONC201 sensitivity than DU145 control cells. The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer."
93,Tenascin-C in the early lung cancer tumor microenvironment promotes progression through integrin αvβ1 and FAK,"Shiela C. Samson, Anthony Rojas, Rebecca G. Zitnay, Keith R. Carney, Wakeiyo Hettinga, Mary C. Schaelling, Delphine Sicard, Wei Zhang, Melissa Gilbert-Ross, Grace K. Dy, Michael J. Cavnar, Muhammad Furqan, Robert F. Browning Jr., Abdul R. Naqash, Bryan P. Schneider, Ahmad Tarhini, Daniel J. Tschumperlin, Alessandro Venosa, Adam I. Marcus, Lyska L. Emerson, Benjamin T. Spike, Beatrice S. Knudsen, Michelle C. Mendoza",https://www.biorxiv.org/content/10.1101/2024.09.17.613509v1,"Pre-cancerous lung lesions are commonly initiated by activating mutations in the RAS pathway, but do not transition to lung adenocarcinomas (LUAD) without additional oncogenic signals. Here, we show that expression of the extracellular matrix protein Tenascin-C (TNC) is increased in and promotes the earliest stages of LUAD development in oncogenic KRAS-driven lung cancer mouse models and in human LUAD. TNC is initially expressed by fibroblasts and its expression extends to tumor cells as the tumor becomes invasive. Genetic deletion of TNC in the mouse models reduces early tumor burden and high-grade pathology and diminishes tumor cell proliferation, invasion, and focal adhesion kinase (FAK) activity. TNC stimulates cultured LUAD tumor cell proliferation and migration through engagement of αv-containing integrins and subsequent FAK activation. Intringuingly, lung injury causes sustained TNC accumulation in mouse lungs, suggesting injury can induce additional TNC signaling for early tumor cell transition to invasive LUAD. Biospecimens from patients with stage I/II LUAD show TNC in regions of FAK activation and an association of TNC with tumor recurrence after primary tumor resection. These results suggest that exogenous insults that elevate TNC in the lung parenchyma interact with tumor-initiating mutations to drive early LUAD progression and local recurrence."
95,GeneSurv: Multi-Gene Cancer Survival Analysis Tool,"Zikang Xu, Jamin Wu, Sung-young Shin, Lan K. Nguyen",https://www.biorxiv.org/content/10.1101/2024.03.17.583882v1,"Summary Traditional cancer survival analysis tools often restrict their analysis to single genes, thereby limiting their analytical scope. GeneSurv, a novel Web-Based Multi-Gene Cancer Survival Analysis Tool, addresses this limitation by enabling multi-gene analyses that correlates the expression of multiple genes, without restriction on their number, in various combinations, with patient survival outcomes. GeneSurv offers dynamic functionalities and an intuitive interface for flexible and precise adjustments of gene expression thresholds. Among its demonstrated applications, GeneSurv identified a significant association between high expression of CCND1 and CDK4 with poor breast cancer prognosis, and related the combined expression of five genes to patient survival, showcasing its capacity to unravel the complexities of genetic interactions and their impact on patient outcomes."
96,Cancer cell-derived extracellular matrix promotes differentiation of fibroblasts into cancer-associated fibroblasts,"Eyup Yondem, Devrim Pesen-Okvur",https://www.biorxiv.org/content/10.1101/2024.04.15.589578v1,"Breast cancer is the most common cancer and the leading cause of cancer-related mortality in women. In addition to cancer cells, the bulk of a breast tumor comprises a range of stromal cell types, including fibroblasts. Cancer-associated fibroblasts (CAF) are crucial players in the tumor microenvironment; however, the process by which fibroblasts differentiate into CAFs is not fully understood. Extracellular matrix (ECM) is known to modulate cell phenotypes. Decellularized ECM (dECM) is a useful tool for studying in-vitro cell-ECM interactions. Yet, whether cancer cell-derived ECM (ccECM) has a role in CAF formation is not known. Here, we optimized the culture duration (5 days) and the extraction method (freeze-thaw) for obtaining ccECM. We confirmed the presence of ccECM using coomassie blue staining and scanning electron microscopy. We showed that ccECM contained fibronectin and laminin using immunofluorescence staining. In addition, we showed that the presence of ccECM but not glass surface or TGFβ promoted the initial adhesion of fibroblasts, as expected. Finally, using quantitative immunofluorescence microscopy, we demonstrated that in contrast to fibroblasts cultured on glass surfaces in the presence and absence of TGFβ, fibroblasts cultured on ccECM showed increased expression of CAF markers vimentin (2.8 fold), FAP (3.4 fold) and PDGFR β (1.8 fold), but not FSP1/s100A4. Overall, our results indicate that ccECM promotes the differentiation of fibroblasts into CAFs."
97,Plasma exosomes from individuals with type 2 diabetes drive breast cancer aggression in patient-derived organoids,"Christina S. Ennis, Michael Seen, Andrew Chen, Heejoo Kang, Adrian Ilinski, Kiana Mahdaviani, Naomi Ko, Stefano Monti, Gerald V. Denis",https://www.biorxiv.org/content/10.1101/2024.09.13.612950v1,"Women with obesity-driven diabetes are predisposed to more aggressive breast cancers. However, patient metabolic status does not fully inform the current standard of care. We previously identified plasma exosomes as functionally critical actors in intercellular communication and drivers of tumor progression. Here, we generated patient-derived organoids (PDOs) from breast tumor resections to model signaling within the tumor microenvironment (TME). Novel techniques and a short (1-week) culture preserved native tumor-infiltrating lymphocytes for the first time in breast tumor PDOs. After 3-day exosome treatment, we measured the impact of exosomal signaling on PDOs via single-cell RNA sequencing. Exosomes derived from Type 2 diabetic patient plasma significantly upregulated pathways associated with epithelial-to-mesenchymal transition, invasiveness, and cancer stemness, compared to non-diabetic exosome controls. Intratumoral heterogeneity and immune evasion increased in the diabetic context, consistent with enhanced tumor aggressiveness and metastatic potential of these PDOs. Our model of systemic metabolic dysregulation and perturbed transcriptional networks enhances understanding of dynamic interactions within the TME in obesity-driven diabetes and offers new insights into novel exosomal communication."
98,SurvBoard: standardized benchmarking for multi-omics cancer survival models,"David Wissel, Nikita Janakarajan, Aayush Grover, Enrico Toniato, María Rodríguez Martínez, Valentina Boeva",https://www.biorxiv.org/content/10.1101/2022.11.18.517043v3,"Multi-omics data, which include genomic, transcriptomic, epigenetic, and proteomic data, are gaining increasing importance for determining the clinical outcomes of cancer patients. Several recent studies have evaluated various multi-modal integration strategies for cancer survival prediction, highlighting the need for standardizing model performance results. Addressing this issue, we introduce SurvBoard, a benchmark framework that standardizes key experimental design choices. SurvBoard enables comparisons between single-cancer and pan-cancer data models and assesses the benefits of using patient data with missing modalities. We also address common pitfalls in preprocessing and validating multi-omics cancer survival models. We apply SurvBoard to several exemplary use cases, further confirming that statistical models tend to outperform deep learning methods, especially for metrics measuring survival function calibration. Moreover, most models exhibit better performance when trained in a pan-cancer context and can benefit from leveraging samples for which data of some omics modalities are missing. We provide a web service for model evaluation and to make our benchmark results easily accessible and viewable: https://www.survboard.science/. All code is available on GitHub: https://github.com/BoevaLab/survboard/. All benchmark outputs are available on Zenodo: https://zenodo.org/records/11066227."
99,Tumor microenvironment noise-induced polarization: the main challenge in macrophages’ immunotherapy for cancer,"Jesus Sierra, Ugo Avila-Ponce de León, Pablo Padilla-Longoria",https://www.biorxiv.org/content/10.1101/2024.05.02.592270v2,"Disturbance of epigenetic processes can lead to altered gene function and malignant cellular transformation. In particular, changes in the epigenetic landscape are a central topic in cancer biology. The initiation and progression of cancer are now recognized to involve both epigenetic and genetic alterations. In this paper, we study the epigenetic mechanism (related to the tumor microenvironment) responsible for increasing tumor-associated macrophages that promote the occurrence and metastasis of tumor cells, support tumor angiogenesis, inhibit T cell-mediated anti-tumor immune response, and lead to tumor progression. We show that the tumor benefits from the macrophages’ high degree of plasticity and larger epigenetic basins corresponding to phenotypes that favor cancer development through a process that we call noise-induced polarization. Moreover, we propose a mechanism to promote the appropriate epigenetic stability for immunotherapies involving macrophages, which includes p53 and APR-246 (eprenetapopt). Our results show that a combination therapy may be necessary to ensure the proper epigenetic stability of macrophages, which otherwise will contribute to cancer progression. On the other hand, we conclude that macrophages may remain in the anti-tumoral state in types of cancer that exhibit less TP53 mutation, like colorectal cancer; in these cases, macrophages’ immunotherapy may be more suitable. We finally mention the relevance of the epigenetic potential (Waddington’s landscape) as the backbone for our study, which encapsulates the biological information of the system."
100,Systemic CD8+ T cell effector signature predicts prognosis of lung cancer immunotherapy,"Hyungtai Sim, Geun-Ho Park, Woong-Yang Park, Se-Hoon Lee, Murim Choi",https://www.biorxiv.org/content/10.1101/2024.09.16.613381v1,"Background While immune checkpoint inhibitors (ICIs) are adopted as standard therapy in non-small cell lung cancer (NSCLC) patients, factors that influence variable prognosis still remain elusive. Therefore, a deeper understanding is needed of how germline variants regulate the transcriptomes of circulating immune cells in metastasis, and ultimately influence immunotherapy outcomes."
101,Screening activity of brain cancer-derived factors on primary human brain pericytes,"Samuel JC McCullough, Eliene Albers, Akshata Anchan, Jane Yu, Bronwen Connor, E. Scott Graham",https://www.biorxiv.org/content/10.1101/2024.09.11.612547v1,"Brain cancers offer poor prognoses to patients accompanied by symptoms that drastically impact the patient and their family. Brain tumours recruit local non-transformed cells to provide trophic support and immunosuppression within the tumour microenvironment, supporting tumour progression. Given the localization and supportive role of pericytes at the brain vasculature, we explored the potential for brain pericytes to contribute to the brain cancer microenvironment. To investigate this, primary brain pericytes were treated with factors commonly upregulated in brain cancers. Changes to brain pericyte cell signalling, inflammatory secretion, and phagocytosis were investigated. The TGFβ superfamily cytokines TGFβ and GDF-15 activated SMAD2/3 and inhibited C/EBP-δ, revealing a potential mechanism behind the pleiotropic action of TGFβ on brain pericytes. IL-17 induced secretion of IL-6 without activating NFκB, STAT1, SMAD2/3, or C/EBP-δ signalling pathways. IL-27 and IFNγ induced STAT1 signalling and significantly reduced pericyte phagocytosis. The remaining brain cancer-derived factors did not induce a measured response, indicating that these factors may act on other cell types or require co-stimulation with other factors to produce significant effects. Together, these findings show potential mechanisms by which brain pericytes contribute to aspects of inflammation and starts to uncover the supportive role brain pericytes may play in brain cancers."
102,The gut microbiome-linked long chain fatty acid stearate suppresses colorectal cancer,"Mina Tsenkova, Madita Brauer, Vitaly Pozdeev, Marat Kasakin, Susheel Bhanu Busi, Maryse Schmoetten, Dean Cheung, Marianne Meyers, Fabien Rodriguez, Anthoula Gaigneaux, Eric Koncina, Cedric Gilson, Lisa Schlicker, Diran Herebian, Martine Schmitz, Laura de Nies, Ertan Mayatepek, Serge Haan, Carine de Beaufort, Thorsten Cramer, Johannes Meiser, Carole L. Linster, Paul Wilmes, Elisabeth Letellier",https://www.biorxiv.org/content/10.1101/2023.12.07.570549v3,"Colorectal cancer (CRC) patients have been shown to possess an altered gut microbiome. Diet is a well-established modulator of the microbiome, and thus, dietary interventions might have a beneficial effect on CRC. An attenuating effect of the ketogenic diet (KD) on CRC cell growth has been previously observed, however the role of the gut microbiome in driving this effect remains unknown. Here, we describe a reduced colonic tumor burden upon KD consumption in a CRC mouse model with a humanized microbiome. Importantly, we demonstrate a causal relationship through microbiome transplantation into germ-free mice, whereby alterations in the gut microbiota were maintained in the absence of continued selective pressure from the KD. Specifically, we identify a shift toward bacterial species that produce stearic acid in ketogenic conditions, whereas consumers were depleted, resulting in elevated levels of free stearate in the gut lumen. This microbial product demonstrated tumor-suppressing properties by inducing apoptosis in cancer cells and decreasing colonic Th17 immune cell populations. Taken together, the beneficial effects of the KD are mediated through alterations in the gut microbiome, including, among others, increased stearic acid production, which in turn significantly reduces intestinal tumor growth."
105,Collateral damage of NUDT15 deficiency in cancer provides a cancer pharmacogenetic therapeutic window with thiopurines,"Jacob C. Massey, Joseph Magagnoli, S. Scott Sutton, Phillip J. Buckhaults, Michael D. Wyatt",https://www.biorxiv.org/content/10.1101/2024.04.08.588560v1,"Genome instability is a hallmark of cancer and are driven by mutations in oncogenes and tumor suppressor genes. Despite successes seen with select targeted therapeutics, this type of personalized medicine is only beneficial for a small subpopulation of cancer patients who have one of a few actionable genetic changes. Most tumors also contain hundreds of passenger mutations that offered no fitness advantage or disadvantage during tumor evolution. Mutations in known pharmacogenetic (PGx) loci for which germline variants encode variability in drug response can cause somatically acquired drug sensitivity. The NUDT15 gene is a known PGx locus that participates in the rate-limiting metabolism of thiopurines. People with two defective germline alleles of NUDT15 are hypersensitive to the toxic effects of thiopurines. NUDT15 is located adjacent to the Retinoblastoma (RB1) tumor suppressor gene, which often undergoes homozygous deletion in retinoblastomas and other epithelial cancers. We observed that RB1 undergoes homozygous deletions in 9.4% of prostate adenocarcinomas and 2.5% of ovarian cancers, and in nearly all of these cases NUDT15 is also lost. Moreover, 44% of prostate adenocarcinomas and over 60% of ovarian cancers have lost one allele of NUDT15, which predicts that a majority of all prostate and ovarian cancers have somatically acquired hypersensitivity to thiopurine treatment. We performed a retrospective analysis of >16,000 patients in the US Veterans Administration health care system and found concurrent xanthine oxidase inhibition (XOi) and thiopurine usage for non-cancer indications is significantly associated with reduced incidence of prostate cancer. The hazard ratio for the development of prostate cancer in patients treated with thiopurines and XOi was 0.562 (0.301-1.051) for the unmatched cohort and 0.389 (0.185-0.819) for the propensity score matched cohort. We experimentally depleted NUDT15 from ovarian and prostate cancer cell lines and observed a dramatic sensitization to thiopurine-induced and DNA damage-dependent toxicity. These results indicate that somatic loss of NUDT15 predicts therapeutic sensitivity to a low cost and well tolerated drug with a broad therapeutic window."
106,TopBP1 biomolecular condensates: a new therapeutic target in advanced-stage colorectal cancer,"Laura Morano, Nadia Vezzio-Vié, Adam Aissanou, Tom Egger, Antoine Aze, Solène Fiachetti, Hervé Seitz, Louis-Antoine Milazzo, Véronique Garambois, Nathalie Bonnefoy, Céline Gongora, Angelos Constantinou, Jihane Basbous",https://www.biorxiv.org/content/10.1101/2024.09.10.612204v1,"In cancer cells, ATR signaling is crucial to tolerate the intrinsically high damage levels that normally block replication fork progression. Assembly of TopBP1, a multifunctional scaffolding protein, into condensates is required to amplify ATR kinase activity to the levels needed to coordinate the DNA damage response and manage DNA replication stress. Many ATR inhibitors are tested for cancer treatment in clinical trials, but their overall effectiveness is often compromised by the emergence of resistance and toxicities. In this proof-of-concept study, we propose to disrupt the ATR pathway by targeting TopBP1 condensation. First, we screened a molecule-based library using a previously developed optogenetic approach and identified several TopBP1 condensation inhibitors. Amongst them, AZD2858 disrupted TopBP1 assembly induced by the clinically relevant topoisomerase I inhibitor SN-38, thereby inhibiting the ATR/Chk1 signaling pathway. We found that AZD2858 exerted its effects by disrupting TopBP1 self-interaction and binding to ATR in mammalian cells, and by increasing its chromatin recruitment in cell-free Xenopus laevis egg extracts. Moreover, AZD2858 prevented S-phase checkpoint induction by SN-38, leading to increased DNA damage and apoptosis in a colorectal cancer cell line. Lastly, AZD2858 showed synergistic effect in combination with the FOLFIRI chemotherapy regimen in a spheroid model of colorectal cancer."
108,BST2 induces vascular smooth muscle cell plasticity and phenotype switching during cancer progression,"Caitlin F. Bell, Richard A. Baylis, Nicolas G. Lopez, Wei Feng Ma, Hua Gao, Fudi Wang, Sharika Bamezai, Changhao Fu, Yoko Kojima, Shaunak S. Adkar, Lingfeng Luo, Clint L. Miller, Nicholas J. Leeper",https://www.biorxiv.org/content/10.1101/2024.09.10.612298v1,"Background Smooth muscle cell (SMC) plasticity and phenotypic switching play prominent roles in the pathogenesis of multiple diseases, but their role in tumorigenesis is unknown. We investigated whether and how SMC diversity and plasticity plays a role in tumor angiogenesis and the tumor microenvironment."
109,On the design and stability of cancer adaptive therapy cycles: deterministic and stochastic models,"Yuri G. Vilela, Artur C. Fassoni, Armando G. M. Neves",https://www.biorxiv.org/content/10.1101/2024.09.10.612338v1,"Adaptive therapy is a promising paradigm for treating cancers, that exploits competitive interactions between drug-sensitive and drug-resistant cells, thereby avoiding or delaying treatment failure due to evolution of drug resistance within the tumor. Previous studies have shown the mathematical possibility of building cyclic schemes of drug administration which restore tumor composition to its exact initial value in deterministic models. However, algorithms for cycle design, the conditions on which such algorithms are certain to work, as well as conditions for cycle stability remain elusive. Here, we state biologically motivated hypotheses that guarantee existence of such cycles in two deterministic classes of mathematical models already considered in the literature: Lotka-Volterra and adjusted replicator dynamics. We stress that not only existence of cyclic schemes, but also stability of such cycles is a relevant feature for applications in real clinical scenarios. We also analyze stochastic versions of the above deterministic models, a necessary step if we want to take into account that real tumors are composed by a finite population of cells subject to randomness, a relevant feature in the context of low tumor burden. We argue that the stability of the deterministic cycles is also relevant for the stochastic version of the models. In fact, Dua, Ma and Newton [Cancers (2021)] and Park and Newton [Phys. Rev. E (2023)] observed breakdown of deterministic cycles in a stochastic model (Moran process) for a tumor. Our findings indicate that the breakdown phenomenon is not due to stochasticity itself, but to the deterministic instability inherent in the cycles of the referenced papers. We then illustrate how stable deterministic cycles avoid for very large times the breakdown of cyclic treatments in stochastic tumor models."
110,A brain-body feedback loop driving HPA-axis dysfunction in breast cancer,"Adrian Gomez, Yue Wu, Chao Zhang, Leah Boyd, Tse-Luen Wee, Joseph Gewolb, Corina Amor, Lucas Cheadle, Jeremy C. Borniger",https://www.biorxiv.org/content/10.1101/2024.09.13.612923v1,"Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality1–3. The exact cause of this phenomenon — whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVNCRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVNCRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVNCRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVNCRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVNCRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression."
111,NEK9 ablation rewires docetaxel resistance through induction of ERK-mediated cancer cell pyroptosis,"Shamima Azma Ansari, Sibasish Mohanty, Pallavi Mohapatra, Rachna Rath, Dillip Muduli, Saroj Kumar Das Majumdar, Rajeeb K. Swain, Rupesh Dash",https://www.biorxiv.org/content/10.1101/2024.09.10.612209v1,"Docetaxel alone or in combination with other drugs is the most common chemotherapy regimen for several neoplasms including advanced OSCC. Unfortunately, chemoresistance leads to relapse and continued tumor growth. It is therefore important to explore the causative factors for docetaxel resistance. In this study, we performed a CRISPR-based kinome screening that identified Never In Mitosis Gene-A Related Kinase-9 (NEK9) as a major player of docetaxel resistance in OSCC, prostate, and pancreatic cancer lines. NEK9 expression was upregulated in tumor samples of chemotherapy non-responders compared to responder OSCC patients. Our validation data suggests selectively knocking out NEK9 sensitizes cancer cells to docetaxel. Mechanistically, we found that ablation of NEK9 induces DNA damage, activating ERK(p-T202/Y204) that leads to Gasdermin-E mediated Cancer Cell pyroptosis. The in-vitro kinase activity assay identified fostamatinib as a potent inhibitor of NEK9. The xenograft data suggest that fostamatinib restores docetaxel sensitivity and facilitates a significant reduction of tumor burden. Overall, our data suggests a novel combination of fostamatinib and docetaxel needs further clinical investigation in advanced OSCC."
112,RAD50 is a potential biomarker for breast cancer diagnosis and prognosis,"Kunwer S. Chhatwal, Hengrui Liu",https://www.biorxiv.org/content/10.1101/2024.09.07.611821v1,"BACKGROUND RAD50 is one of the most critical genes in DNA double-strand break processing, which can lead to a single 3’ strand of DNA overhang and is potentially involved in forcing incomplete DNA repair. This research study aims to investigate the role of RAD50 in breast cancer diagnosis and prognosis."
114,Computational metabolic modeling unveils gut microbiome’s role in metabolic shifts during murine cancer cachexia,"Torben Kuehnast, Isabella Pototschnig, Manuela Träger, Christian Diener, Hansjörg Habisch, Andrea Vogel, Lisa Wink, Alexander Mahnert, Tobias Madl, Thomas Weichhart, Martina Schweiger, Christine Moissl-Eichinger",https://www.biorxiv.org/content/10.1101/2024.09.13.612865v1,"Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss, muscle wasting, systemic inflammation, and metabolic alterations, affecting up to 87% of pancreatic and gastric cancer patients. Unlike simple starvation, cachexia is driven by metabolic disruption involving both host physiology and the gut microbiome. While microbiome changes in cachexia have been documented, a coherent understanding of how these changes translate into functional metabolic shifts remains elusive."
115,Mitochondrial metabolism is a key determinant of chemotherapy sensitivity in Colorectal Cancer,"Deborah Y. Moss, Connor Brown, Andrew Shaw, Christopher McCann, Nikita Lewis, Aaron Phillips, Sarah Gallagher, William J. McDaid, Andrew Roe, Aisling Y. Coughlan, Brenton Cavanagh, Callum Ormsby, Fiammetta Falcone, Rachel McCole, Scott Monteith, Emily Rogan, Matilda Downs, Sudhir B. Malla, Alexandra J Emerson, Letitia Mohammed-Smith, Shaun Sharkey, Peter F. Gallagher, Arindam Banerjee, Sufyan Pandor, Brett Greer, Christopher Elliott, Aideen Ryan, Philip D. Dunne, Vicky Coyle, Ian G. Mills, Simon S. McDade, Owen Sansom, Triona Ni Chonghaile, Daniel B. Longley, Melissa J. LaBonte, Emma M. Kerr",https://www.biorxiv.org/content/10.1101/2024.09.12.611189v1,"Therapy resistance is attributed to over 80% of cancer deaths per year emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. Here, we investigate the transcriptional responses of CRC cells to 5FU treatment, revealing significant metabolic reprogramming towards heightened mitochondrial activity. Utilizing CRC models, we demonstrate sustained enhancement of mitochondrial biogenesis and function following 5FU treatment, leading to resistance in both in vitro and in vivo settings. Furthermore, we show that targeting mitochondrial metabolism, specifically by inhibiting Complex I (CI), sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, our analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes."
116,The CYP1A1 connection between enterolactone and breast cancer risk,"Juana Hatwik, Ningthoujam Sonia, Anil M. Limaye",https://www.biorxiv.org/content/10.1101/2024.06.06.597836v1,"Enterolactone (EL), a mammalian enterolignan, is a gut microbe-generated plant-lignan derivative. Although observational data are controversial, meta-analyses have affirmed that plant lignan-rich diets, or high serum EL reduce breast cancer risk, or the associated mortality, in post-menopausal women. However, the mechanistic basis is unknown. Here we show that EL antagonizes AHR to reduce CYP1A1 mRNA expression in MCF-7 breast cancer cells. Intriguingly, it increases CYP1A1 protein, a mediator of xenobiotic response, which is frequently expressed in breast tumors, and implicated in cell proliferation and survival. EL’s effect on CYP1A1 expression is similar to estrogen, and mediated via ERα. But, by virtue of partial ERα agonism/antagonism, EL attenuates estrogen-mediated increase in CYP1A1 protein. These data suggest potential mechanisms underlying EL’s beneficial effects in breast cancer. In the face of xenobiotic exposure, its AHR antagonism may reduce the generation of cancer-inducing genotoxic agents. With declining levels of estrogen in post-menopausal women, EL may antagonize estrogen-mediated induction of CYP1A1 protein, and the associated proliferation of mammary epithelial cells."
118,The geometry of normal tissue and cancer gene expression manifolds,"Joan Nieves, Augusto Gonzalez",https://www.biorxiv.org/content/10.1101/2021.08.20.457160v5,"A recent paper shows that in gene expression space the manifold spanned by normal tissues and the manifold spanned by the corresponding tumors are disjoint. The statement is based on a two-dimensional projection of gene expression data. In the present paper, we show that, for the multi-dimensional vectors defining the centers of cloud samples: 1. The closest tumor to a given normal tissue is the tumor developed in that tissue, 2. Two normal tissues define quasi-orthogonal directions, 3. A tumor may have a projection onto its corresponding normal tissue, but it is quasi-orthogonal to all other normal tissues, and 4. The cancer manifold is roughly obtained by translating the normal tissue manifold along an orthogonal direction defined by a global cancer progression axis. These geometrical properties add a new characterization of normal tissues and tumors and may have biological significance. Indeed, normal tissues at the vertices of a high-dimensional simplex could indicate genotype optimization for given tissue functions, and a way of avoiding errors in embryonary development. On the other hand, the cancer progression axis could define relevant pan-cancer genes and seems to be consistent with the atavistic theory of tumors."
122,Single cell genome and epigenome co-profiling reveals hardwiring and plasticity in breast cancer,"Kaile Wang, Yun Yan, Heba Elgamal, Jianzhuo Li, Chenling Tang, Shanshan Bai, Zhenna Xiao, Emi Sei, Yiyun Lin, Junke Wang, Jessica Montalvan, Changandeep Nagi, Alastair M. Thompson, Nicholas Navin",https://www.biorxiv.org/content/10.1101/2024.09.06.611519v1,"Understanding the impact of genetic alterations on epigenomic phenotypes during breast cancer progression is challenging with unimodal measurements. Here, we report wellDA-seq, the first high-genomic resolution, high-throughput method that can simultaneously measure the whole genome and chromatin accessibility profiles of thousands of single cells. Using wellDA-seq, we profiled 22,123 single cells from 2 normal and 9 tumors breast tissues. By directly mapping the epigenomic phenotypes to genetic lineages across cancer subclones, we found evidence of both genetic hardwiring and epigenetic plasticity. In 6 estrogen-receptor positive breast cancers, we directly identified the ancestral cancer cells, and found that their epithelial cell-of-origin was Luminal Hormone Responsive cells. We also identified cell types with copy number aberrations (CNA) in normal breast tissues and discovered non-epithelial cell types in the microenvironment with CNAs in breast cancers. These data provide insights into the complex relationship between genetic alterations and epigenomic phenotypes during breast tumor evolution."
124,Comparative analysis of transcriptomic and proteomic expression between two non-small cell lung cancer subtypes,"Ben Nicholas, Alistair Bailey, Katy J McCann, Peter Johnson, Tim Elliott, Christian Ottensmeier, Paul Skipp",https://www.biorxiv.org/content/10.1101/2024.09.05.611373v1,"Non-small cell lung cancer (NSCLC) is frequently diagnosed at an advanced stage and has poor survival. NSCLC subtypes require different treatment regimes, hence there are extensive efforts to find more precise and non-invasive differential diagnostics tools. Complementing these efforts, we examined two NSCLC subtypes for differences that may inform treatment options and identify potential novel therapeutic pathways."
125,IMMUNOTAR - Integrative prioritization of cell surface targets for cancer immunotherapy,"Rawan Shraim, Brian Mooney, Karina L. Conkrite, Amber K. Weiner, Gregg B. Morin, Poul H. Sorensen, John M. Maris, Sharon J. Diskin, Ahmet Sacan",https://www.biorxiv.org/content/10.1101/2024.06.04.597422v1,"Cancer remains a leading cause of mortality globally. Recent improvements in survival have been facilitated by the development of less toxic immunotherapies; however, identifying targets for immunotherapies remains a challenge in the field. To address this challenge, we developed IMMUNOTAR, a computational tool that systematically prioritizes and identifies candidate immunotherapeutic targets. IMMUNOTAR integrates user-provided RNA-sequencing or proteomics data with quantitative features extracted from publicly available databases based on predefined optimal immunotherapeutic target criteria and quantitatively prioritizes potential surface protein targets. We demonstrate the utility and flexibility of IMMUNOTAR using three distinct datasets, validating its effectiveness in identifying both known and new potential immunotherapeutic targets within the analyzed cancer phenotypes. Overall, IMMUNOTAR enables the compilation of data from multiple sources into a unified platform, allowing users to simultaneously evaluate surface proteins across diverse criteria. By streamlining target identification, IMMUNOTAR empowers researchers to efficiently allocate resources and accelerate immunotherapy development."
127,Research on the Mechanism of Lphn1 Knockout in Inhibiting Colorectal Cancer,Yi Wang,https://www.biorxiv.org/content/10.1101/2024.08.07.606975v4,"Decades ago, colorectal cancer was rarely diagnosed. Today, it is the fourth leading cause of cancer-related deaths worldwide, with nearly 90,000 fatalities each year."
130,Optimistic and pessimistic cognitive judgement bias modulates the stress response and cancer progression in zebrafish,"Felipe Espigares, M. Victoria Alvarado, Diana Abad-Tortosa, Susana A. M. Varela, Daniel Sobral, Pedro Faísca, Tiago Paixão, Rui F. Oliveira",https://www.biorxiv.org/content/10.1101/2024.05.29.596384v2,"Cognitive judgement bias in decision-making under ambiguity occurs both in animals and humans, with some individuals interpreting ambiguous stimulus as positive (optimism) and others as negative (pessimism). We hypothesize that judgement bias is a personality trait and that individuals with a pessimistic bias would be more reactive to stressors and therefore more susceptible to stress-related diseases than optimistic ones. Here, we show that zebrafish judgment bias is a consistent behavioral trait over time, and that pessimistic and optimistic fish express phenotype-specific neurogenomic responses to stress. Furthermore, both phenotypes show differential activation of the hypothalamic-pituitary-interrenal axis in response to chronic stress, suggesting that optimists have a lower stress reactivity. Accordingly, optimists seem to be more resilient to disease than pessimists, as shown by a lower tumorigenesis in a zebrafish melanoma line [Tg(mtifa:HRAS-GFP)]. Together these results indicate that judgement bias is paralleled by differences in the stress response with implications for disease resilience."
132,Combination of cycling hyperthermia and Echinacoside creates synergistic curing effect on pancreatic cancer PANC-1 cells,"Wei-Ting Chen, You-Ming Chen, Guan-Bo Lin, Yu-Yi Kuo, Hsu-Hsiang Liu, Chih-Yu Chao",https://www.biorxiv.org/content/10.1101/2024.09.04.611320v1,"Therapy targeting the suppression of human MutT homolog 1 (MTH1) has been gaining ground in recent years, thanks to its resulting significant increase of 8-hydroxy-2’-deoxyguanosine triphosphate (8-oxo-dGTP) accumulation in genomic DNA, causing DNA damage and apoptotic cell death. Echinacoside (Ech), a natural phenylethanoid glycoside first extracted from Echinacea angustifolia or desert plant Cistanches is one of a few natural products which are capable of inhibiting the MTH1 function. It, however, is difficult to apply it in clinical trials, due to high cost for effective dosage in need. In the study, we show that combination with thermal-cycling hyperthermia (TC-HT), a novel physical treatment, can amplify the curative effect of Ech, reducing its dosage in need significantly. The combination resulted in a multipronged mechanism targeting multiple key apoptotic regulating proteins such as Bcl-2 and MAPK family proteins. Its effect is expected to be comparable to the treatment strategy containing MTH1, Bcl-2, and ERK inhibitors, posing as new promising approach in cancer treatment."
133,The effect of glucose restriction on cancer cell contractility: A threshold response in U-87 glioma,"Albert Kong, Alessia Pallaoro, Donald Yapp, Gwynn J. Elfring, Mattia Bacca",https://www.biorxiv.org/content/10.1101/2024.09.05.611526v1,"Cells rely on contractility to proliferate, and cancerous ones exhibit an increased glucose dependence. It is therefore hypothesized that glucose restriction can mitigate cancer cell proliferation by ’stunting’ their contractility. However, glucose-restriction studies have mostly been based on experiments that have yielded conflicting results; some cells become less contractile under glucose-restriction, intuitively, while, others become surprisingly more contractile. Active mechanistic modeling may prove fruitful in resolving these conflicts. In this study, we develop a model for glucose-mediated cell contractility to capture the mechanical implications of glucose restriction. The model is calibrated on cell contraction data taken from 2D-cultured glioma cells, laying on a collagen substrate. The model predicts the existence of a critical level of glucose restriction that must be exceeded for contractility to be affected, and this is validated by our experiments. Our model provides an initial step toward a fundamental understanding of the metabolic implications of cell contractility, particularly in the context of glucose restriction: an essential step in cancer studies."
134,Engineering Asian elephant TP53: TP53 retrogene knockouts activate common and unique cancer-relevant pathways,"Emil Karpinski, Nikil Badey, Esther Mintzer, Asaf Ashkenazy-Titelman, George M. Church",https://www.biorxiv.org/content/10.1101/2024.09.07.611789v1,"TP53 functions as a central regulator in response to DNA damage and other cell stressors by inducing the expression of many protective pathways such as cell cycle arrest and apoptosis. Consequently, this gene is often found disrupted in human cancers. Elephants are a particularly interesting species for the study of cancer, by virtue of their large number of cell divisions and long lives yet low incidence of cancer. Elephants also possess multiple retrogene copies of TP53, which have previously been shown to induce strong cellular responses to DNA damage. However, most previous studies have largely focused only on African elephant TP53 retrogenes and often in non-native backgrounds. Here we generated CRISPR-Cas9 knockouts of TP53, all 29 TP53 retrogenes, or both in combination in Asian elephant fibroblasts. We find that while there is considerable overlap in the DNA damage responses of the TP53 and retrogene knockouts, there are also many unique pathways enriched in both. In particular, the retrogene knockouts exhibit strong enrichment of many extracellular pathways suggesting they may play a large role in the tumor microenvironment and mitigating metastatic growth. We also find that only a small fraction of these 29 retrogenes appear to be expressed across a variety of tissues and identify three loci that are likely driving this response. This work shows for the first time the transcriptomic effect of these retrogenes within their native background and establishes a foundation for future research into the relative contributions of these genes."
135,Modeling cancer dependency with deep graph models,"Hengyi Fu, Bojin Zhao, Peng Wang",https://www.biorxiv.org/content/10.1101/2024.02.26.582022v1,"A fundamental premise for precision oncology is a catalog of diverse actionable targets that could enable personalized treatment. Large scale Genome-wide lost-of-function screens such as cancer dependency map have systematically identified single gene vulnerabilities in numerous cell lines. However, it remains challenging to scale such analyses to many clinical samples and untangle molecular networks underlying observed vulnerabilities. We developed a deep learning framework, DepGPS, combing graph neural networks with transformers to model the network interactions underlying tumor vulnerabilities. Our model demonstrated an improved ability to predict context-specific vulnerabilities over existing models and showed a higher responsiveness in perturbation analysis. Furthermore, perturbation induced dependency changes by our model demonstrated utility to support context-aware identification of synthetic lethal genes. Overall, our model represents a valuable tool to extend tumor vulnerability analyses to broader range of subjects and could help to decipher molecular networks dictating context-specific tumor vulnerabilities."
136,Exploring the effect of capsaicin on gene expression and chemotherapy sensitization in gastric cancer cells,"Weijian Meng, Sophia Xie, Rui Zhang, Jie Shen",https://www.biorxiv.org/content/10.1101/2024.09.04.611214v1,"Purpose Capsaicin has previously been demonstrated to exhibit anti-tumor effect in various cancer type. However, the effect of capsaicin on gene expression and its potential mechanism on chemotherapy sensitization were still uncertain."
137,CD4+Foxp3E2+ regulatory T cell frequency predicts breast cancer prognosis and recurrence,"Clorinda Fusco, Francesca Di Rella, Antonietta Liotti, Alessandra Colamatteo, Anne Lise Ferrara, Vincenzo Gigantino, Francesca Collina, Emanuela Esposito, Ivana Donzelli, Antonio Porcellini, Antonia Feola, Teresa Micillo, Francesco Perna, Federica Garziano, Giorgia Teresa Maniscalco, Gilda Varricchi, Maria Mottola, Bruno Zuccarelli, Bruna De Simone, Maurizio di Bonito, Giuseppe Matarese, Antonello Accurso, Martina Pontillo, Daniela Russo, Luigi Insabato, Alessandra Spaziano, Irene Cantone, Antonio Pezone, Veronica De Rosa",https://www.biorxiv.org/content/10.1101/2024.09.04.611142v1,"CD4+Foxp3+ regulatory T cells (Tregs) are key to maintain peripheral self-tolerance and suppress immune responses to tumors. Their accumulation in the tumor microenvironment (TME) correlates with poor clinical outcome in several human cancers, including breast cancer (BC). However, the properties of intratumoral Tregs remain largely unknown. Here, we found that a functionally distinct subpopulation of tumor-infiltrating Tregs, which express the Foxp3 splicing variant retaining exon 2 (Foxp3E2), is prominent in the TME and peripheral blood of hormone receptor- positive (HR+) BC subjects with poor prognosis. Notably, a comprehensive examination of the Tumor Cell Genome Atlas (TCGA) validated Foxp3E2 as an independent prognostic marker in all other BC subtypes. We found that FOXP3E2 expression underlies BCs with highly immune suppressive landscape, defective mismatch repair and a stem-like signature thus highlighting pathways involved in tumor immune evasion. Finally, we confirmed the higher immunosuppressive capacity of BC patients-derived Foxp3E2+ Tregs by functional assays. Our study suggests Foxp3E2+ Tregs might be used as an independent biomarker to predict BC prognosis and recurrence, and to develop super-targeted depletion-based immunotherapies."
138,A novel combination therapy for ER+ breast cancer suppresses drug resistance via an evolutionary double-bind,"Rena Emond, Jeffrey West, Vince Grolmusz, Patrick Cosgrove, Aritro Nath, Alexander R.A. Anderson, Andrea H. Bild",https://www.biorxiv.org/content/10.1101/2024.09.03.611032v1,"Chemotherapy remains a commonly used and important treatment option for metastatic breast cancer. A majority of ER+ metastatic breast cancer patients ultimately develop resistance to chemotherapy, resulting in disease progression. We hypothesized that an “evolutionary double-bind”, where treatment with one drug improves the response to a different agent, would improve the effectiveness and durability of responses to chemotherapy. This approach exploits vulnerabilities in acquired resistance mechanisms. Evolutionary models can be used in refractory cancer to identify alternative treatment strategies that capitalize on acquired vulnerabilities and resistance traits for improved outcomes. To develop and test these models, ER+ breast cancer cell lineages sensitive and resistant to chemotherapy are grown in spheroids with varied initial population frequencies to measure cross-sensitivity and efficacy of chemotherapy and add-on treatments such as disulfiram combination treatment. Different treatment schedules then assessed the best strategy for reducing the selection of resistant populations. We developed and parameterized a game-theoretic mathematical model from this in vitro experimental data, and used it to predict the existence of a double-bind where selection for resistance to chemotherapy induces sensitivity to disulfiram. The model predicts a dose-dependent re-sensitization (a double-bind) to chemotherapy for monotherapy disulfiram."
139,Comprehensive analysis of the RBP regulome reveals functional modules and drug candidates in liver cancer,"Mateusz Garbulowski, Riccardo Mosca, Carlos J. Gallardo-Dodd, Claudia Kutter, Erik L. L. Sonnhammer",https://www.biorxiv.org/content/10.1101/2024.09.04.611258v1,"RNA binding proteins (RBPs) are essential components of the transcriptomic regulome. Identifying the RBP regulome in cancer cells is crucial to discovering and understanding carcinogenesis mechanisms and providing new therapeutic targets. Here, we aimed to reveal the regulome of liver cancer upon specific perturbations. To this end, we applied a consensus Gene Regulatory Network (GRN) approach using knockdown data for the liver cancer cell line HepG2. By incorporating multiple GRNs from diverse inference methods, we constructed a highly precise GRN. To validate our results, we comprehensively evaluated the consensus GRN, focusing on characterizing the most relevant aspects of the liver cancer regulome. This included utilizing eCLIP-seq and RAPseq data to verify RBP interactions and binding sites. In addition, we performed an enrichment analysis of network modules and drug repurposing based on the inferred GRN. Taken together, our findings demonstrate the critical roles of RBP regulatory interactions in liver cancer that can be employed to improve treatment strategies."
141,Inactivation of necroptosis-promoting protein MLKL creates a therapeutic vulnerability in colorectal cancer cells,"Peijia Jiang, Sandhya Chipurupalli, Byong Hoon Yoo, Xiaoyang Liu, Kirill V. Rosen",https://www.biorxiv.org/content/10.1101/2024.09.05.611491v1,"Mortality from colorectal cancer (CRC) is significant, and novel CRC therapies are needed. A pseudokinase MLKL typically executes necroptotic cell death, and MLKL inactivation protects cells from such death. However, we found unexpectedly that MLKL gene knockout enhanced CRC cell death caused by a protein synthesis inhibitor homoharringtonine used for chronic myeloid leukemia treatment. In an effort to explain this finding, we observed that MLKL gene knockout reduced CRC cell autophagy and rendered such autophagy critically dependent on the presence of VPS37A, a component of the ESCRT-I complex. Moreover, homoharringtonine-induced activation of p38 MAP kinase (p38MAPK) prevented VPS37A from supporting autophagy in MLKL-deficient cells and triggered their parthanatos, a cell death type driven by poly(ADP-ribose) polymerase hyperactivation. Finally, a pharmacological MLKL inhibitor necrosulfonamide strongly cooperated with homoharringtonine in suppressing CRC cell tumorigenicity in mice. Thus, while MLKL mediates necroptosis, MLKL protects CRC cells from death caused by drugs blocking basal autophagy, e.g., homoharringtonine, and MLKL inhibition creates a therapeutic vulnerability that could be utilized for CRC treatment."
142,Macrophage subtypes inhibit breast cancer proliferation in culture,"Sophia R.S. Varady, Daniel Greiner, Minna Roh-Johnson",https://www.biorxiv.org/content/10.1101/2024.06.01.596963v1,"Macrophages are a highly plastic cell type that adopt distinct subtypes and functional states depending on environmental cues. These functional states can vary wildly, with distinct macrophages capable of displaying opposing functions. We sought to understand how macrophage subtypes that exist on two ends of a spectrum influence the function of other cells. We used a co-culture system with primary human macrophages to probe the effects of macrophage subtypes on breast cancer cell proliferation. Our studies revealed a surprising phenotype in which both macrophage subtypes inhibited cancer cell proliferation compared to cancer cells alone. Of particular interest, using two different proliferation assays with two different breast cancer cell lines, we showed that differentiating macrophages into a “pro-tumor” subtype inhibited breast cancer cell proliferation. These findings are inconsistent with the prevailing interpretation that “pro-tumor” macrophages promote cancer cell proliferation and suggest a re-evaluation of how these interpretations are made."
145,CCR2 silencing in sensory neurons blocks bone cancer progression,"Élora Midavaine, Jérôme Côté, Alexandra Trépanier, Sakeen W. Kashem, Marc-André Dansereau, Jean-Michel Longpré, Martine Charbonneau, Claire Dubois, Ashley M. Jacobi, Scott D. Rose, Mark A. Belkhe, Philippe Sarret",https://www.biorxiv.org/content/10.1101/2024.05.29.596531v1,"The peripheral nervous system has been shown to contribute to cancer growth by expanding the immunological niche. How the nervous system affects bone cancer progression and how neuroimmune pathways can be targeted for cancer treatment are not yet clear. Here, we demonstrate a profound influence of the peripheral nervous system on tumor progression, which can be targeted by silencing neuronal chemokine receptor signaling. We show that axotomy in animals with bone cancer inhibits tumor progression. Conversely, intrathecal injection of a known tumor-associated proinflammatory chemokine, CCL2, promotes tumor growth and allodynia. Silencing CCR2 in DRG neurons through a newly developed gene therapy successfully impedes tumor progression and bone remodeling and relieves bone cancer-associated pain. We demonstrate that the mechanism underlying CCR2-mediated tumor progression involves decreased neuropeptide secretion by peripheral nerves that promote expansion of the tumor-associated macrophage population. Silencing the CCR2 receptor in DRG neurons successfully normalizes the neuropeptide milieu and ameliorates altered bone remodeling. Thus, we have developed a novel therapeutic pathway for targeting a neuroimmune axis that contributes to cancer progression."
146,A PARP14/TARG1-Regulated RACK1 MARylation Cycle Drives Stress Granule Dynamics in Ovarian Cancer Cells,"Sridevi Challa, Tulip Nandu, Hyung Bum Kim, Xuan Gong, Charles W. Renshaw, Wan-Chen Li, Xinrui Tan, Marwa W. Aljardali, Cristel V. Camacho, Jin Chen, W. Lee Kraus",https://www.biorxiv.org/content/10.1101/2023.10.13.562273v2,"Mono(ADP-ribosyl)ation (MARylation) is emerging as a critical regulator of ribosome function and translation. Herein, we demonstrate that RACK1, an integral component of the ribosome, is MARylated on three acidic residues by the mono(ADP-ribosyl) transferase (MART) PARP14 in ovarian cancer cells. MARylation of RACK1 is required for stress granule formation and promotes the colocalization of RACK1 in stress granules with G3BP1, eIF3η, and 40S ribosomal proteins. In parallel, we observed reduced translation of a subset of mRNAs, including those encoding key cancer regulators (e.g., AKT). Treatment with a PARP14 inhibitor or mutation of the sites of MARylation on RACK1 blocks these outcomes, as well as the growth of ovarian cancer cells in culture and in vivo. To re-set the system after prolonged stress and recovery, the ADP-ribosyl hydrolase TARG1 deMARylates RACK1, leading to the dissociation of the stress granules and the restoration of translation. Collectively, our results demonstrate a therapeutically targetable pathway that controls stress granule assembly and disassembly in ovarian cancer cells."
147,Resistance patterns in drug-adapted cancer cell lines reflect the complex evolution in clinical tumours,"Helen E. Grimsley, Magdalena Antczak, Ian G. Reddin, Katie-May McLaughlin, Andrea Nist, Marco Mernberger, Thorsten Stiewe, Tim R. Fenton, Daniel Speidel, Catherine Harper-Wynne, Karina Cox, Jindrich Cinatl jr., Mark N. Wass, Michelle D. Garrett, Martin Michaelis",https://www.biorxiv.org/content/10.1101/2024.01.20.576412v2,"Background Here, we introduce a novel set of triple-negative breast cancer (TNBC) cell lines consisting of MDA-MB-468, HCC38, and HCC1806 and their sublines adapted to cisplatin, doxorubicin, eribulin, paclitaxel, gemcitabine, or 5-fluorouracil."
148,A multidimensional Pan-cancer analysis of CDKN1A identifies CDKN1A as an Immunological and Prognostic Biomarker,"Wenyang Zhang, Qinglong Ma, Wenrun Li, Honghui Zhao, Linghui Zhong, Yinan Xiao, Yaru Ren, Kaixin Yang, Yonghong Li, Lei Shi",https://www.biorxiv.org/content/10.1101/2024.09.03.610958v1,"CDKN1A/p21 is well recognized for its role in cell cycle regulation and genomic stability. However, its functions in the Tumor microenvironment (TME) and tumor immunity are not yet fully understood. Hereby, we explored CDKN1A expression and immunological/prognostic values via various databases and analytical methods including cBioPortal, Kaplan-Meier, UCSCXenaShiny, TIMER, Single-cell RNA sequencing (scRNA-seq) analysis, etc. In addition, we explored different approaches including CCK8, EdU, Colony formation, Drug sensitivity and Annixin-V assay to explore the influence of p21 in proliferative capacity in cancer cells. We found that CDKN1A is lowly expressed in BLCA, BRCA, COAD, KICH, LUAD, LUSC, PRAD, READ and STAD compared to normal samples, whereas it is highly expressed in CHOL, HNSC, KIRC, KIRP and THCA compared to normal cohorts. CDKN1A expression is significantly correlated with overall survival, disease-specific survival, disease-free survival and progression-free interval different cancer types. Additionally, CDKN1A is associated with CD4+ T cell, CD8+ T cell, Neutrophil, Macrophage and Myeloid dendritic cell infiltration in diverse cancer types. Functional experiments reveal that p21 overexpression leads to a significant reduction in proliferative capacity, facilitates cell apoptosis and senescence in multiple cancer cell lines. In contrast, silenced p21 facilitates cell growth and wound closure, prevent cell senescence in different cancer cell lines. In conclusion, our findings suggest that CDKN1A may serve as a valuable prognostic and immunotherapeutic marker in diverse cancer."
149,Cancer-cell derived S100A11 promotes macrophage recruitment in ER+ breast cancer,"Sanghoon Lee, Youngbin Cho, Yiting Li, Ruxuan Li, Daniel Brown, Priscilla McAuliffe, Adrian V Lee, Steffi Oesterreich, Ioannis K. Zervantonakis, Hatice Ulku Osmanbeyoglu",https://www.biorxiv.org/content/10.1101/2024.03.21.586041v1,"Macrophages are pivotal in driving breast tumor development, progression, and resistance to treatment, particularly in estrogen receptor-positive (ER+) tumors, where they infiltrate the tumor microenvironment (TME) influenced by cancer cell-secreted factors. By analyzing single-cell RNA-sequencing data from 25 ER+ tumors, we elucidated interactions between cancer cells and macrophages, correlating macrophage density with epithelial cancer cell density. We identified that S100A11, a previously unexplored factor in macrophage-cancer crosstalk, predicts high macrophage density and poor outcomes in ER+ tumors. We found that recombinant S100A11 enhances macrophage infiltration and migration in a dose-dependent manner. Additionally, in 3D models, we showed that S100A11 expression levels in ER+ cancer cells predict macrophage infiltration patterns. Neutralizing S100A11 decreased macrophage recruitment, both in cancer cell lines and in a clinically relevant patient-derived organoid model, underscoring its role as a paracrine regulator of cancer-macrophage interactions in the pro-tumorigenic TME. This study offers novel insights into the interplay between macrophages and cancer cells in ER+ breast tumors, highlighting S100A11 as a potential therapeutic target to modulate the macrophage-rich tumor microenvironment."
150,ERVcancer: a web resource designed for querying activation of human endogenous retroviruses across major cancer types,"Xiaoyun Lei, Song Mao, Yinshuang Li, Shi Huang, Jinchen Li, Wei Du, Chunmei Kuang, Kai Yuan",https://www.biorxiv.org/content/10.1101/2024.09.02.610762v1,"Human endogenous retroviruses (HERVs) compose approximately 8% of the human genome, co-opted into the dynamic regulatory network of cellular potency in early embryonic development. In recent studies, resurgent HERVs’ transcriptional activity has been frequently observed in many types of human cancers, suggesting their potential functions in the occurrence and progression of malignancy. However, a web resource dedicated to querying the relationship between activation of HERVs and cancer development is lacking. Here, we have constructed a database to explore the sequence information, expression profiles, survival prognosis, and genetic interactions of HERVs in diverse cancer types. Our database currently incorporates RNA sequencing (RNA-seq) data of 580 HERVs across 16246 samples, comprising 151 early embryonic data from the Gene Expression Omnibus (GEO) database, 8051 human adult tissues’ data from the Genotype-Tissue Expression (GTEx) project, 932 cancer cell lines’ data from the Cancer Cell Line Encyclopedia (CCLE) project, 6478 tumoral and 634 normal tissue samples’ data from The Cancer Genome Atlas (TCGA) project. The primary goal is to provide an easily accessible and user-friendly database for professionals in the fields of bioinformatics, pathology, pharmacology, and related areas, enabling them to efficiently screen the activity of HERVs of interest in normal and cancerous tissues and evaluate the clinical relevance. The ERVcancer database is available at http://kyuanlab.com/ervcancer/."
151,CD300e as a Driver of Immunosuppressive Tumor Microenvironment in Colorectal Cancer,"Annica Barizza, Stefania Vassallo, Laura Masatti, Silvia Lonardi, Mattia Bugatti, Sara Coletta, Sofia Giacometti, Simone Pizzini, William Vermi, Fabio Munari, Nicolò Gnoato, Matteo Fassan, Giulia Nigro, Gaya Spolverato, Enrica Calura, Gaia Codolo",https://www.biorxiv.org/content/10.1101/2024.09.01.610700v1,"Tumor-associated macrophages (TAMs) are the predominant immune population within the tumor microenvironment (TME), playing a key role in promoting tumor growth and establishing an immunosuppressive environment that facilitate immune evasion. Here we report that the immune receptor CD300e is highly expressed by TAM in colorectal (CRC) and drives their immunosuppressive and pro-tumorigenic, correlating with reduced expression of MHC-II molecules, essential for antigen presentation. In vitro, CD300e-deficient macrophages exhibit enhanced pro-inflammatory activity and phagocytic capacity, coupled with reduced efferocytosis, suggesting a critical role for CD300e in promoting tumor progression. The depletion of CD300e, in vivo, results in a reduced tumor burden and enhanced survival in CRC mouse models, accompanied by a more robust anti-tumor immune response characterized by increased infiltration of activated CD4+ and CD8+ T cells producing IFN-γ. Our study provides comprehensive insights into the roles of CD300e in myeloid cells in CRC, highlighting its potential as a therapeutic target for reprogramming TAMs to support anti-tumor immunity."
153,The Impact of TLR9 Expression Loss on Breast Cancer Tumor Cells,"Emily Sible, Gregory Weitsman, Salome Amoyal, Guillaume Roblot, Marie Marotel, Rémi Pescarmona, Nathalie Bendriss-Vermare, Cheryl Gillet, Amie Ceesay, Marie Cecile Michallet, Christophe Caux, Francois-Loic Cosset, Umaima Al Alem, Tony Ng, Uzma Ayesha Hasan",https://www.biorxiv.org/content/10.1101/2024.07.04.601915v2,"Toll-like receptor 9 (TLR9), primarily expressed in human dendritic and B cells, recognizes double-stranded DNA motifs from pathogens, initiating an inflammatory response. Recent studies have revealed TLR9’s involvement beyond its conventional role in immune response, notably during the tumorigenesis of various cancers such as head and neck, cervical, and ovarian cancers. Here we show by immunohistochemistry analysis demonstrated significantly lower TLR9 levels in breast cancer tumors compared to normal breast tissue epithelium. Similarly, TLR9 downregulation was also observed in several transformed breast cancer cell lines versus untransformed breast epithelial cell lines. Furthermore, overexpression of TLR9 led to reduced proliferation potential of breast cancer cell associated with activation of senescence as was evident by upregulation of proinflammatory cytokine IL-6, chemokines IL-8 and CXCL1; and growth factor GM-CSF. These findings support TLR9’s regulatory role in mitigating breast cancer and highlight its critical connection between the inflammatory response and tumor immunity."
155,Unraveling tumor heterogeneity: Quantitative insights from scRNA-seq analysis in breast cancer subtypes,"Daniela Senra, Nara Guisoni, Luis Diambra",https://www.biorxiv.org/content/10.1101/2024.08.30.610531v1,"Tumors are complex systems characterized by genetic, transcriptomic, phenotypic, and microenvironmental variations. The complexity of this heterogeneity plays a crucial role in metastasis, tumor progression, and recurrence. In this work, we utilized publicly available single-cell transcriptomics data from human breast cancer samples (ER+, HER2+, and triple-negative) to evaluate key concepts pertinent to cancer biology. Quantitative assessments included measures based on copy number alterations (CNAs), entropy, transcriptomic heterogeneity, and different protein-protein interaction networks (PPINs)."
156,Clonal evolution of hematopoietic stem cells after cancer chemotherapy,"Hidetaka Uryu, Koichi Saeki, Hiroshi Haeno, Chiraag Deepak Kapadia, Ken Furudate, Jyoti Nangalia, Michael Spencer Chapman, Li Zhao, Joanne I. Hsu, Chong Zhao, Shujuan Chen, Tomoyuki Tanaka, Zongrui Li, Hui Yang, Courtney DiNardo, Naval Daver, Naveen Pemmaraju, Nitin Jain, Farhad Ravandi, Jianhua Zhang, Xingzhi Song, Erika Thompson, Hongli Tang, Latasha Little, Curtis Gumbs, Robert Z. Orlowski, Muzaffar Qazilbash, Kapil Bhalla, Simona Colla, Hagop Kantarjian, Rashmi Kanagal Shamanna, Carlos Bueso- Ramos, Daisuke Nakada, P. Andrew Futreal, Elizabeth Shpall, Margaret Goodell, Guillermo Garcia-Manero, Koichi Takahashi",https://www.biorxiv.org/content/10.1101/2024.05.23.595594v1,"Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the development of myeloid malignancies1. The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal HSPCs is not well defined. We conducted whole-genome sequencing on 1,032 single-cell-derived HSPC colonies from 10 patients with multiple myeloma (MM), who had undergone various chemotherapy regimens. Our findings reveal that melphalan treatment distinctly increases mutational burden with a unique mutation signature, whereas other MM chemotherapies do not significantly affect the normal mutation rate of HSPCs. Among these therapy-induced mutations were several oncogenic drivers such as TET2 and PPM1D. Phylogenetic analysis showed a clonal architecture in post-treatment HSPCs characterized by extensive convergent evolution of mutations in genes such as TP53 and PPM1D. Consequently, the clonal diversity and structure of post-treatment HSPCs mirror those observed in normal elderly individuals, suggesting an accelerated clonal aging due to chemotherapy. Furthermore, analysis of matched therapy-related myeloid neoplasm (t-MN) samples, which occurred 1-8 years later, enabled us to trace the clonal origin of t-MNs to a single HSPC clone among a group of clones with competing malignant potential, indicating the critical role of secondary mutations in dictating clonal dominance and malignant transformation. Our findings suggest that cancer chemotherapy promotes an oligoclonal architecture with multiple HSPC clones possessing competing leukemic potentials, setting the stage for the selective emergence of a singular clone that evolves into t-MNs after acquiring secondary mutations. These results underscore the importance of further systematic research to elucidate the long-term hematological consequences of cancer chemotherapy."
157,Structural enrichment attenuates colitis-associated colon cancer,"Delawrence J. Sykes, Sumeet Solanki, Sahiti Chukkapalli, Keyonna Williams, Erika A. Newman, Kenneth Resnicow, Yatrik M Shah",https://www.biorxiv.org/content/10.1101/2024.02.13.580099v1,"Colorectal cancer (CRC) is a major public health concern and disproportionately impacts racial/ethnic minority populations in the US. Animal models are helpful in examining human health disparities because many stress-induced human health conditions can be recapitulated using mouse models. Azoxymethane (AOM)/ dextran sodium sulfate (DSS) treatment can be used to model colitis-associated cancers. While colitis-associated cancers account for only 2% of colon cancers, the AOM/DSS model is useful for examining links between inflammation, immunity, and colon cancer. Mice were housed in enriched and impoverished environments for 1-month prior to behavioral testing. Following behavioral testing the mice were subjected to the AOM/DSS model. While our analysis revealed no significant behavioral variances between the impoverished and enriched housing conditions, we found significant effects in tumorigenesis. Enriched mice had fewer tumors and smaller tumor volumes compared to impoverished mice. African Americans are at higher risk for early onset colorectal cancers in part due to social economic status. Furthermore, housing conditions and environment may reflect social economic status. Research aimed at understanding links between social economic status and colorectal cancer progression is important for eliminating disparities in health outcomes."
159,"Design, Synthesis, and Efficacy of Novel Trojan Horse Compounds Targeting Metabolic Vulnerabilities in Prostate Cancer","L Bogue Edgerton, E F Hayball, F O’Connell, MP Ward, S O’Toole, CM Martin, S Selemidis, RD Brooks, P Tewari, DA Brooks, JJ O’Leary",https://www.biorxiv.org/content/10.1101/2024.08.29.610353v1,"Background and purpose Prostate cancer (PCa) remains a significant global health concern, warranting the development of new therapeutic strategies.1 Metabolic reprogramming, an emerging hallmark of PCa progression characterized by aberrant nutrient utilization, has become a focus area in developing new treatments. Among these metabolic alterations, the Warburg effect—a shift towards aerobic glycolysis— has garnered significant attention as a potential therapeutic target. 2 To explore this, we synthesised a novel class of Trojan Horse compounds designed to exploit the unique metabolic profile of cancer cells and investigated their therapeutic potential using cell based models of PCa, as a proof of principle strategy."
160,Neuroendocrine differentiation (ND) in sensitivity of neuroendocrine tumor (NET) cells to ONC201/TIC10 cancer therapeutic,"Elizabeth Ding, Maximillian Pinho-Schwermann, Shengliang Zhang, Connor Purcell, Wafik S. El-Deiry",https://www.biorxiv.org/content/10.1101/2024.08.28.610183v1,"Prostate cancer (PCa) neuroendocrine tumor (NET)-like cells with low or absent androgen receptor (AR) signaling cause hormone therapy resistance and poor prognosis. Small cell lung carcinoma (SCLC), a high-grade NET, presents with metastasis early and has poor survival. ONC201/TIC10 is a first-in-class cancer therapeutic with clinical activity in diffuse gliomas and neuroendocrine tumors. We hypothesized that markers of neuroendocrine differentiation, activation of the integrated stress response (ISR) and the TRAIL pathway, as well as the expression of ClpP, contribute to neuroendocrine tumor cell death and sensitivity to ONC201. We show that PCa and SCLC cell lines (N=6) are sensitive to ONC201, regardless of the extent of neuroendocrine differentiation. Endogenous levels of some NET markers (CgA, FoxO1, ENO2, PGP9.5, SOX2) are present in a spectrum in PCa and SCLC cell lines. Overexpression of neural transcription factor BRN2 in DU145 PCa cells does not increase expression of NET differentiation markers FoxO1, ENO2, PGP9.5, and CgA at 48 hours. However, the transient BRN2 overexpression showed slight decreases in some NET markers on the spectrum while maintaining sensitivity of PCa cells to ONC201 before any phenotypic change related to NET differentiation. Our results show that ONC201 has preclinical activity against PCa including those without NET markers or in PCa cells with transient overexpression of neural transcription factor BRN2. Our results have relevance to activity of ONC201 in PCa where most castrate-resistant androgen-independent cancers are not therapy resistant due to NET differentiation. Importantly, NET differentiation does not promote resistance to ONC201 supporting further clinical investigations across the spectrum of PCa."
161,AI-Generated Hallmarks of Aging and Cancer: A Computational Approach Using Causal Emergence and Dependency Networks,Jianghui Xiong,https://www.biorxiv.org/content/10.1101/2024.08.28.610200v1,"This study introduces “hallmarks engineering,” a computational approach to generate quantifiable hallmarks of aging and cancer. We evaluated these hallmarks using genome-wide DNA methylation data from ten age-related diseases. Causal emergence analysis revealed that hallmark-level features show stronger disease associations than individual genes, with improvements up to 9.7 orders of magnitude. Hallmark-based models achieved comparable predictive performance with fewer predictors compared to regular pathway-based models. Dependency network analysis uncovered regulatory networks with power-law distributions and identified top-level “super-regulators” such as genomic stability. Notably, the inclusion of neurodegenerative and cancer hallmarks enhanced representation for their respective disease categories. Our findings suggest that top-down modeling using computationally generated hallmarks may reveal common mechanisms across multiple diseases, offering a promising approach for modeling multimorbidity."
164,Unveiling the influence of tumor and immune signatures on immune checkpoint therapy in advanced lung cancer,"Nayoung Kim, Sehhoon Park, Areum Jo, Hye Hyeon Eum, Hong Kwan Kim, Kyungjong Lee, Jong Ho Cho, Bo Mi Ku, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Jung-Il Lee, Jung Won Choi, Dasom Jeong, Minsu Na, Huiram Kang, Jeong Yeon Kim, Jung Kyoon Choi, Hae-Ock Lee, Myung-Ju Ahn",https://www.biorxiv.org/content/10.1101/2024.04.15.589544v2,"This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICI). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (AUC) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC."
165,The assembly of cancer-specific ribosomes by the lncRNA LISRR suppresses melanoma anti-tumour immunity,"Sonia Cinque, Yvessa Verheyden, Sara Adnane, Alessandro Marino, Vicky Katopodi, Ewout Demesmaeker, Zorica Knezevic, Sarah Hanache, Roberto Vendramin, Alessandro Cuomo, Joanna Pozniak, Alvaro Cortes Calabuig, Marcella Baldewijns, Sébastien Tabruyn, Oliver Bechter, Maria Francesca Baietti, Elisabetta Groaz, Tiziana Bonaldi, Eleonora Leucci",https://www.biorxiv.org/content/10.1101/2023.01.06.523012v2,"Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, resistance mechanisms limit its clinical benefit. Here we characterise LISRR, a cancer-specific lncRNA highly expressed in melanoma patients refractory to ICB. In cells undergoing (therapeutic) stress, LISRR recruits DAZAP1 (Deleted in AZoospermia Associated Protein 1) to polysomes and drives the assembly of a subset of ribosomes at the endoplasmic reticulum, directing the synthesis of an immunosuppressive translatome. This includes the immune checkpoint PD-L1 and the enzymes necessary for building the glycocalyx, the sugar coat surrounding the cells. Notably, proper glycocalyx assembly is required for spermatozoa immune evasion during fertilization. Accordingly, targeting LISRR activates immune responses and re-sensitizes to ICB in co-culture models, ex vivo in patient explants, and in vivo in humanized patient-derived models. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based cancer-specific strategy to overcome intrinsic resistance to ICB."
167,Break-induced replication drives large-scale genomic amplifications in cancer cells,"Mouadh Benamar, Rebeka Eki, Kang-Ping Du, Tarek Abbas",https://www.biorxiv.org/content/10.1101/2024.08.27.609980v1,"DNA double-strand breaks (DSBs) are highly toxic lesions that underly the efficacy of ionizing radiation (IR) and a large number of cytotoxic chemotherapies1–3. Yet, abnormal repair of DSBs is associated with genomic instability and may contribute to cancer heterogeneity and tumour evolution. Here, we show that DSBs induced by IR, by DSB-inducing chemotherapeutics, or by the expression of a rare-cutting restriction endonuclease induce large-scale genomic amplification in human cancer cells. Importantly, the extent of DSB-induced genomic amplification (DIGA) in a panel of melanoma cell lines correlated with the degree of cytotoxicity elicited by IR, suggesting that DIGA contributes significantly to DSB-induced cancer cell lethality. DIGA, which is mediated through conservative DNA synthesis, does not require origin re-licensing, and is enhanced by the depletion or deletion of the methyltransferases SET8 and SUV4-20H1, which function sequentially to mono- and di-methylate histone H4 lysine 20 (H4K20) at DSBs to facilitate the recruitment of 53BP1-RIF1 and its downstream effector shieldin complex to DSBs to prevent hyper-resection4–11. Consistently, DIGA was enhanced in cells lacking 53BP1 or RIF1, or in cells that lacked components of the shieldin complex or of other factors that help recruit 53BP1 to DSBs. Mechanistically, DIGA requires MRE11/CtIP and EXO1, factors that promote resection and hyper-resection at DSBs, and is dependent on the catalytic activity of the RAD51 recombinase. Furthermore, deletion or depletion of POLD3, POLD4, or RAD52, proteins involved in break-induced replication (BIR), significantly inhibited DIGA, suggesting that DIGA is mediated through a RAD51-dependent BIR-like process. DIGA induction was maximal if the cells encountered DSBs in early and mid S-phase, whereas cells competent for homologous recombination (in late S and G2) exhibited less DIGA induction. We propose that unshielded, hyper-resected ends of DSBs may nucleate a replication-like intermediate that enables cytotoxic long-range genomic DNA amplification mediated through BIR."
168,Imputation of cancer proteomics data with a deep model that learns from many datasets,"Lincoln Harris, William S. Noble",https://www.biorxiv.org/content/10.1101/2024.08.26.609780v2,"Missing values are a major challenge in the analysis of mass spectrometry proteomics data. Missing values hinder reproducibility, decrease statistical power for identifying differentially expressed (DE) proteins and make it challenging to analyze low-abundance proteins. We present Lupine, a deep learning-based method for imputing, or estimating, missing values in tandem mass tag (TMT) proteomics data. Lupine is, to our knowledge, the first imputation method that is designed to learn jointly from many datasets, and we provide evidence that this approach leads to more accurate predictions. We validated Lupine by applying it to TMT data from >1,000 cancer patient samples spanning ten cancer types from the Clinical Proteomics Tumor Atlas Consortium (CPTAC). Lupine outperforms the state of the art for TMT imputation, identifies more DE proteins than other methods, corrects for TMT batch effects, and learns a meaningful representation of proteins and patient samples. Lupine is implemented as an open source Python package."
169,The transcriptional landscape of metastatic hormone-naïve prostate cancer,"Natalia Martin-Martin, Saioa Garcia-Longarte, Jon Corres-Mendizabal, Uxue Lazcano, Ianire Astobiza, Laura Bozal-Basterra, Nicolas Herranz, Hielke van Splunder, Onintza Carlevaris, Mikel Pujana-Vaquerizo, María Teresa Blasco, Ana M. Aransay, Antonio Rosino, Julian Tudela, Daniel Jimenez, Alberto Martinez, Andrei Salca, Aida Santos-Martín, Sofía Rey, Aitziber Ugalde-Olano, David Gonzalo, Mariona Graupera, Roger R. Gomis, Joaquin Mateo, Miguel Unda, Enrique Gonzalez-Billalabeitia, Ana Loizaga-Iriarte, Isabel Mendizabal, Arkaitz Carracedo",https://www.biorxiv.org/content/10.1101/2024.05.20.594913v1,"Metastatic hormone-naïve prostate cancer (mHNPC) is an infrequent form of this tumour type that is characterized by metastasis at the time of diagnosis and accounts for 50% of prostate cancer-related deaths. Despite the extensive characterization of localized and metastatic castration resistant prostate cancer (mCRPC), the molecular characteristics of mHNPC remain largely unexplored. Here we provide the first extensive transcriptomics characterization of mHNPC. We generated discovery and validation bulk and single-cell RNA-Seq datasets and performed integrative computational analysis in combination with experimental studies. Our results provide unprecedented evidence of the distinctive transcriptional profile of mHNPC and identify stroma remodelling as a predominant feature of these tumours. Importantly, we discover a central role for the transcription factor SOX11 in triggering a heterotypic communication that is associated to the acquisition of metastatic properties. Our study will constitute an invaluable resource for a profound understanding of mHNPC that can influence patient management."
170,Comparison of spatial transcriptomics technologies across six cancer types,"Sergi Cervilla, Daniela Grases, Elena Perez, Francisco X. Real, Eva Musulen, Manel Esteller, Eduard Porta-Pardo",https://www.biorxiv.org/content/10.1101/2024.05.21.593407v1,"Spatial biology experiments integrate the molecular and histological landscape of tissues to provide a previously inaccessible view of tissue biology, unlocking the architecture of complex multicellular tissues. Within spatial biology, spatial transcriptomics platforms are among the most advanced, allowing researchers to characterize the expression of thousands of genes across space. These new technologies are transforming our understanding of how cells are organized in space and communicate with each other to determine emergent phenotypes with unprecedented granularity. This is particularly important in cancer research, as it is becoming evident that tumor evolution is shaped not only by the genetic properties of cancer cells but also by how they interact with the tumor microenvironment and their spatial organization. While many platforms can generate spatial transcriptomics profiles, it is still unclear in which context each platform better suits the needs of its users. Here we compare the results obtained using 4 different spatial transcriptomics (VISIUM, VISIUM CytAssist, Xenium and CosMx) and one spatial proteomics (VISIUM CytAssist) platforms across serial sections of 6 FFPE samples from primary human tumors covering some of the most common forms of the disease (lung, breast, colorectal, bladder, lymphoma and ovary). We observed that the VISIUM platform with CytAssist chemistry yielded superior data quality. Xenium consistently produced more reliable results for in situ platforms, with better gene clustering and fewer false positives than CosMx. Interestingly, these platform-based variations didn’t significantly affect cell type identification. Finally, by comparing VISIUM protein profiles with the spatial transcriptomics data from all four platforms on each sample, we identified several genes with mismatched RNA and protein expression patterns, highlighting the importance of multi-omics profiling to reveal the true biology of human tumors."
171,Senescent cell-derived extracellular vesicles inhibit cancer recurrence by coordinating immune surveillance,"Tahereh Ziglari, Nicholas L. Calistri, Jennifer M. Finan, Daniel Derrick, Ernesto S. Nakayasu, Meagan C. Burnet, Jennifer E. Kyle, Matthew Hoare, Laura M. Heiser, Ferdinando Pucci",https://www.biorxiv.org/content/10.1101/2022.06.30.498366v3,"Extracellular vesicles (EVs) are key signaling mediators. To explore the role of senescent cell-derived extracellular vesicles (senEVs) in inflammatory responses to senescence, we developed an engraftment-based senescence model in wild-type mice and genetically blocked senEV release in vivo, without significantly affecting soluble mediators. Our results demonstrate that senEVs are both necessary and sufficient to trigger immune-mediated clearance of senescent cells, thereby suppressing tumor growth. In the absence of senEVs, the recruitment of MHC-II+ antigen-presenting cells to the senescence microenvironment was markedly impaired. Blocking senEV release redirected the primary target of senescent cell signaling from antigen-presenting cells to neutrophils."
172,Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer,"Stephen L. DeAngelo, Liang Zhao, Sofia Dziechciarz, Myungsun Shin, Sumeet Solanki, Andrii Balia, Marwa O El-Derany, Cristina Castillo, Yao Qin, Nupur K. Das, Hannah Noelle Bell, Joao A. Paulo, Yuezhong Zhang, Nicholas J. Rossiter, Elizabeth C. McCulla, Jianping He, Indrani Talukder, Billy Wai-Lung Ng, Zachary T. Schafer, Nouri Neamati, Joseph D. Mancias, Markos Koutmos, Yatrik M. Shah",https://www.biorxiv.org/content/10.1101/2024.03.29.587381v2,"Ferroptosis is a non-apoptotic form of cell death resulting from the iron-dependent accumulation of lipid peroxides. Colorectal cancer (CRC) cells accumulate high levels of intracellular iron and reactive oxygen species (ROS) and are thus particularly sensitive to ferroptosis. The compound (S)-RSL3 ([1S,3R]-RSL3) is a commonly used ferroptosis inducing compound that is currently characterized as a selective inhibitor of the selenocysteine containing enzyme (selenoprotein) Gluathione Peroxidase 4 (GPx4), an enzyme that utilizes glutathione to directly detoxify lipid peroxides. However, through chemical controls utilizing the (R) stereoisomer of RSL3 ([1R,3R]-RSL3) that does not bind GPx4, combined with inducible genetic knockdowns of GPx4 in CRC cell lines, we revealed that GPx4 dependency does not always align with (S)-RSL3 sensitivity, questioning the current characterization of GPx4 as the central regulator of ferroptosis. Utilizing affinity pull-down mass spectrometry with chemically modified (S)-RSL3 probes we discovered that the effects of (S)-RSL3 extend far beyond GPx4 inhibition, revealing that (S)-RSL3 is a broad and non-selective inhibitor of selenoproteins. To further investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed additional chemical and genetic approaches. We found that the selenoprotein inhibitor auranofin, an FDA approved gold-salt, chemically induced oxidative cell death and ferroptosis in both in-vitro and in-vivo models of CRC. Consistent with these data, we found that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translation of selenoproteins, is essential for the in-vitro growth and xenograft survival of CRC cell lines. In summary, these findings recharacterize the mechanism of action of the most commonly used ferroptosis inducing molecule, (S)-RSL3, and reveal that broad inhibition of selenoproteins is a promising novel therapeutic angle for the treatment of CRC."
173,Multi-gradient Permutation Survival Analysis Identifies Mitosis and Immune Signatures Steadily Associated with Cancer Patient Prognosis,"Xinlei Cai, Yi Ye, Xiaoping Liu, Zhaoyuan Fang, Luonan Chen, Fei Li, Hongbin Ji",https://www.biorxiv.org/content/10.1101/2024.02.20.581166v2,"The inconsistency of the association between genes and cancer prognosis is often attributed to many variables that contribute to patient survival. Whether there exist the Genes Steadily Associated with Prognosis (GEARs) and what their functions are remain largely elusive. We have developed a novel method called “Multi-gradient Permutation Survival Analysis” (MEMORY) to screen the GEARs using RNA-seq data from the TCGA database. Then we employed a network construction approach to identify hub genes from GEARs, and utilized them for cancer classification. In the case of LUAD, the GEARs were found to be related to mitosis. Our analysis suggested that LUAD cell lines carrying PIK3CA mutations exhibit increased drug resistance. For BRCA, the GEARs were related to immunity. The analysis revealed that CDH1 mutation might influence immune infiltration through the EMT process in BRCA. We further explored the prognostic relevance of mitosis and immunity through their respective scores. This study offers significant biological insights into GEARs and highlights their potential as robust prognostic indicators across diverse cancer types."
174,Cancer Stemness Online: A resource for investigating cancer stemness and associations with immune response,"Weiwei Zhou, Minghai Su, Tiantongfei Jiang, Yunjin Xie, Jingyi Shi, Yingying Ma, Kang Xu, Gang Xu, Yongsheng Li, Juan Xu",https://www.biorxiv.org/content/10.1101/2024.03.14.585118v1,"Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features, which are potential culprit in immunotherapy resistance. Although the state-of-art predictive computational methods have facilitated predicting the cancer stemness, currently there is no efficient resource that can meet various requirements of usage. Here, we presented the Cancer Stemness Online, an integrated resource for efficiently scoring cancer stemness potential at bulk and single-cell level. The resource integrates 8 robust predictive algorithms as well as 27 signature gene sets associated with cancer stemness for predicting the stemness scores. Downstream analyses were performed from five different aspects, including identifying the signature genes of cancer stemness, exploring the association with cancer hallmarks, cellular states, immune response and communication with immune cells, investigating the contributions for patient survival and the robustness analysis of cancer stemness among different methods. Moreover, the pre-calculated cancer stemness atlas for more than 40 cancer types can be accessed by users. Both the tables and diverse visualization for the analytical results are available for download. Together, Cancer Stemness Online is a powerful resource for scoring cancer stemness and going deeper and wider in the downstream functional interpretation, including immune response as well as cancer hallmark. Cancer Stemness Online is freely accessible at http://bio-bigdata.hrbmu.edu.cn/CancerStemnessOnline."
176,Immunophenotypic changes in peripheral blood of colorectal cancer patients: a potential diagnostic marker for CD4+ monocytes,"Khin Aye Thin, Andrew Cross, Phonthep Angsuwatcharakon, Apiwat Mutirangura, Charoenchai Puttipanyalears, Thomas Pike, Robert Jones, Paul Skaife, Steven W Edwards",https://www.biorxiv.org/content/10.1101/2024.08.26.609793v1,"Colorectal cancer (CRC) can induce stresses on the immune system that can affect both the numbers and function of these cells and the ability of the tumours to evade immune-surveillance. Changes in immune functions can also occur during ageing and these may affect both the ability to fight infections and to protect against cancers. As the incidence of CRC is age-related, the aim of this work was to identify changes in immune cell subtypes that are specific to CRC and not merely due to age-related changes. The immunophenotypes of peripheral blood lymphocytes and monocytes of CRC patients and age-matched healthy controls (HC) were analysed using flow cytometry and surface marker staining. Compared to HC, a lower L:M ratio was observed starting from the early stages of CRC, while numbers of B lymphocytes were lower and CD4+ monocytes were higher in CRC patients. In most patients with CRC, the numbers of helper T cells were lower, while cytotoxic T cells and NK T cells together with CD4+ NKT and CD8+ NKT cells were higher: classical monocytes were lower while intermediate monocytes were higher throughout the stages of CRC, and HLA-DRlow monocytes were also higher. NKbright cells were higher while NKdim cells were lower in patients with large tumours. Most of the increased numbers of T cells and monocytes in CRC relate to immunosuppressive phenotypes that may aid tumour evasion. The increase in CD4+ monocytes is likely related to increased numbers of intermediate monocytes, and a threshold of 11.6% CD4+ monocytes can be used as diagnostic marker for CRC with a 60% sensitivity and 88% specificity."
177,An Integrative Study to Investigate Sex-Specific Biomarkers in Bladder Cancer Patients,"Yizhou Wang, Priyanka Bhandary, Kevin Griffin, Jason H. Moore, Xue Li, Zhiping Paul Wang",https://www.biorxiv.org/content/10.1101/2024.08.26.609709v1,"Bladder cancer shows distinct sex-related patterns, with male patients experiencing significantly higher incidence and female patients facing worse survival outcomes. In this paper, we aimed to address the lack of understanding of the biological mechanisms responsible for this sex-based divergence through an integrative analysis using bladder cancer data from TCGA and GTEx. Our study analyzed various bladder cancer data types, including genomic mutation data, gene expression data, and clinical data. We conducted an in-depth study of protein-protein interactions, pathway analysis, survival analysis, and immune cell correlations. Notably, we discovered that the androgen receptor (AR) related pathways were unique to male hub genes, while the Wnt signaling pathway was unique to female hub genes. Additionally, we identified 14 hub genes with significant sex-biased survival rates, including known DLGAP5, SOX2, LAMA2, and COL5A2, as well as new discoveries of male-specific markers ERCC5, NID1, and ANK2, and female-specific RAD51C, COL22A1 and COL5A2. Furthermore, we identified four male hub genes—DAXX, IKBKB, PDGFRA, and PPARG—that overlapped with immune-related genes. The expression of these genes exhibited differential interactions with immune cells between males and females. These insights could pave the way for more personalized and effective therapeutic interventions tailored to male and female patients."
178,BEHAV3D Tumor Profiler to map heterogeneous cancer cell behavior in the tumor microenvironment,"Emilio Rios-Jimenez, Anoek Zomer, Raphael Collot, Mario Barrera Román, Hendrikus Ariese, Ravian L. van Ineveld, Michiel Kleinnijenhuis, Nils Bessler, Hannah Johnson, Anne Rios, Maria Alieva",https://www.biorxiv.org/content/10.1101/2024.08.23.609358v1,"Intravital microscopy (IVM) enables live imaging of animals at single-cell level, offering essential insights into cancer progression. This technique allows for the observation of single-cell behaviors within their natural 3D tissue environments, shedding light on how genetic and microenvironmental changes influence the complex dynamics of tumors. The complexity of data generated by IVM often surpasses the capabilities of conventional analyses accessible to biomedical scientists, thereby neglecting single-cell heterogeneity and limiting the exploration of microenvironmental influences on cellular behavior without bias. To address this challenge, here we introduce BEHAV3D Tumor Profiler (BEHAV3D-TP), a user-friendly computational framework designed for the comprehensive analysis of single tumor cell behaviors and their interactions with the tumor microenvironment (TME). BEHAV3D-TP facilitates unbiased profiling of cancer cell dynamics without requiring advanced computational expertise. Here, we apply BEHAV3D-TP to study diffuse midline glioma (DMG), a highly aggressive pediatric brain tumor characterized by invasive growth. Our analysis reveals that distinct migratory behaviors of DMG cells correlate with specific TME components such as tumor-associated macrophages and vasculature. This approach, initially aimed at uncovering tumor invasive patterns and their interactions with the TME, holds promise for understanding additional cancer cell behaviors like intravasation and metastasis. BEHAV3D-TP represents a significant advancement in democratizing the analysis of heterogeneous cancer cell behaviors and their TME interactions, providing accessible computational insights into tumor dynamics."
180,Androgen deprivation-mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion,"Fen Ma, Sen Chen, Carla Calagua, Seiji Arai, Fang Xie, Olga Voznesensky, Larysa Poluben, Eva Corey, Changmeng Cai, Yuzhuo Wang, David J. Einstein, Mary-Ellen Taplin, Huihui Ye, Adam G. Sowalsky, Joshua W. Russo, Xin Yuan, Steven P. Balk",https://www.biorxiv.org/content/10.1101/2024.08.26.609679v1,"The TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under the androgen receptor (AR) regulated expression of TMPRSS2. The T:E fusion is frequently associated with PTEN loss, and is highly correlated with decreased expression of INPP4B, both of which may compensate for ERG-mediated suppression of PI3K/AKT signaling. We confirmed in PCa cells and a mouse PCa model that ERG suppresses AKT activation, and that one potential mechanism is through downregulation of IRS2. In contrast, ERG knockdown did not increase INPP4B, suggesting its decreased expression is indirect and reflects selective pressure to suppress INPP4B function. Notably, INPP4B expression is similarly decreased in PTEN-intact and PTEN-deficient T:E fusion tumors, suggesting selection for a function distinct from regulation of PI3K activity. As ERG expression in T:E fusion tumors is AR regulated, we further assessed the extent to which AR inhibition increased AKT activity in T:E fusion tumors. T:E fusion positive versus negative PDXs had greater increases in AKT activity after castration. Moreover, in a neoadjuvant trial of AR inhibition prior to radical prostatectomy we similarly found greater increases in AKT activation in the T:E fusion tumors. Together these findings indicate that AKT activation may mitigate the efficacy of AR targeted therapy in T:E fusion PCa, and that these patients may most benefit from combination therapy targeting AR and AKT."
182,Proteolysis targeting chimera extracellular vesicles for therapeutic development treating triple negative breast cancer,"Nina Erwin, Umasankar De, Yufeng Xiao, Lei Wang, Chandra Maharjan, Xiaoshu Pan, Nikee Awasthee, Guangrong Zheng, Daiqing Liao, Weizhou Zhang, Mei He",https://www.biorxiv.org/content/10.1101/2024.08.25.609564v1,"Proteolysis targeting chimeras (PROTACs) are an emerging targeted cancer therapy approach, but wide-spread clinical use of PROTAC is limited due to poor cell targeting and penetration, and instability in vivo. To overcome such issues and enhance the in vivo efficacy of PROTAC drugs, microfluidic droplet-based electroporation (µDES) was developed as a novel extracellular vesicle (EVs) transfection system, which enables the high-efficient PROTAC loading and effective delivery in vivo. Our previously developed YX968 PROTAC drug had shown the selectively degradation of HDAC3 and 8, which effectively suppresses the growth of breast tumor cell lines, including MDA-MB-231 triple negative breast cancer (TNBC) line, via dual degradation without provoking a global histone hyperacetylation. In this study, we demonstrated that µDES-based PROTAC loading in EVs significantly enhanced therapeutic function of PROTAC drug in vivo in the TNBC breast tumor mouse model. NSG mice with pre-established MDA-MB-231 tumors and treated with intraperitoneal injection of EVs for tumor inhibition study, which showed significantly higher HDAC 3 and 8 degradation efficiency and tumor inhibition than PROTAC only group. The liver, spleen, kidney, lung, heart, and brain were collected for safety testing, which exhibited improved toxicity. The EV delivery of PROTAC drug enhances drug stability and bioavailability in vivo, transportability, and drug targeting ability, which fills an important gap in current development of PROTAC therapeutic functionality in vivo and clinical translation. This novel EV-based drug transfection and delivery strategy could be applicable to various therapeutics for enhancing in vivo delivery, efficacy, and safety."
183,E-cigarettes increase the risk of adenoma formation in murine colorectal cancer model,"Ibrahim M Sayed, Anirban Chakraborty, Kaili Inouye, Leanne Dugan, Stefania Tocci, Ira Advani, Kenneth Park, Tapas K Hazra, Soumita Das, Laura E. Crotty Alexander",https://www.biorxiv.org/content/10.1101/2024.08.23.609469v1,"Background E-cigarettes (E.cigs) cause inflammation and damage to human organs, including the lungs and heart. In the gut, E.cig vaping promotes inflammation and gut leakiness. Further, E.cig vaping increases tumorigenesis in oral and lung epithelial cells by inducing mutations and suppressing host DNA repair enzymes. It is well known that cigarette (cig) smoking increases the risk of colorectal cancer (CRC). To date, it is unknown whether E.cig vaping impacts CRC development."
184,A forward genetic screen identifies Sirtuin1 as a driver of neuroendocrine prostate cancer,"Francisca Nunes de Almeida, Alessandro Vasciaveo, Ainsley Mike Antao, Min Zou, Matteo Di Bernardo, Simone de Brot, Antonio Rodriguez-Calero, Alexander Chui, Alexander L.E. Wang, Nicolas Floc’h, Jaime Y. Kim, Stephanie N. Afari, Timur Mukhammadov, Juan Martín Arriaga, Jinqiu Lu, Michael M. Shen, Mark A. Rubin, Andrea Califano, Cory Abate-Shen",https://www.biorxiv.org/content/10.1101/2024.08.24.609538v1,"Although localized prostate cancer is relatively indolent, advanced prostate cancer manifests with aggressive and often lethal variants, including neuroendocrine prostate cancer (NEPC). To identify drivers of aggressive prostate cancer, we leveraged Sleeping Beauty (SB) transposon mutagenesis in a mouse model based on prostate-specific loss-of-function of Pten and Tp53. Compared with control mice, SB mice developed more aggressive prostate tumors, with increased incidence of metastasis. Notably, a significant percentage of the SB prostate tumors display NEPC phenotypes, and the transcriptomic features of these SB mouse tumors recapitulated those of human NEPC. We identified common SB transposon insertion sites (CIS) and prioritized associated CIS-genes differentially expressed in NEPC versus non-NEPC SB tumors. Integrated analysis of CIS-genes encoding for proteins representing upstream, post-translational modulators of master regulators controlling the transcriptional state of SB-mouse and human NEPC tumors identified sirtuin 1 (Sirt1) as a candidate mechanistic determinant of NEPC. Gain-of-function studies in human prostate cancer cell lines confirmed that SIRT1 promotes NEPC, while its loss-of-function or pharmacological inhibition abrogates NEPC. This integrative analysis is generalizable and can be used to identify novel cancer drivers for other malignancies."
185,Statins attenuate Wnt/β-catenin signaling by targeting SATB family proteins in colorectal cancer,"Sneha Tripathi, Ekta Gupta, Rutika Naik, Satyajeet Khare, Rafeeq Mir, Saarthi Desai, Swati Humane, Subhash Yadav, Munita Bal, Avanish Saklani, Prachi Patil, Siddhesh Kamat, Sanjeev Galande",https://www.biorxiv.org/content/10.1101/2024.08.23.609189v1,"Colorectal cancer is the second leading cause of cancer-related deaths worldwide, highlighting the need for improved treatments and advanced molecular research. A recent therapeutic approach focuses on repurposing drugs to target dysregulated pathways involved in tumorigenesis. Among these, statins, commonly known for lowering cholesterol, have attracted attention for their potential anti-cancer properties. Here, we provide direct evidence for the same by assessing the impact of statin treatment on lipid, transcript, and protein levels. Our findings reveal that statins specifically target key components of the Wnt/β-catenin pathway, a major factor in adenoma formation, including the SATB (Special AT-rich Binding protein) family proteins. While SATB1 is recognized as a regulator of tumorigenesis, particularly under Wnt signaling, SATB2 appears to exert an opposing role. We demonstrate that statin treatment reciprocally alters the expression pattern of these proteins. Furthermore, a human clinical trial evaluating statins as an anti-cancer therapy supports the hypothesis that differential expression of SATB proteins is crucial in tumorigenic outcomes. In conclusion, this modulation by statin treatment suggests promising new therapeutic avenues through drug repurposing."
186,Longitudinally cultured precision cut lung slices as a predictive ex vivo model for lung cancer,"Ara Sargsian, Hermon Girmatsion, Vincent Lenders, Bart Ghesquière, Camila Takeno Cologna, Stefaan J. Soenen, Bella B. Manshian",https://www.biorxiv.org/content/10.1101/2024.08.23.609442v1,"Exploring alternatives to in vivo models, this study validates Precision Cut Lung Slices (PCLS) as a viable ex vivo platform for lung cancer research. We established the prolonged viability and structural preservation of PCLS, essential for accurate drug response studies. Using Paclitaxel as a benchmark drug and a therapeutically promising silver nanoparticles in combination with immunotherapy, we conducted a pioneering comparative analysis of its therapeutic effects on PCLS against traditional in vivo models. Results revealed that PCLS closely mimics in vivo responses, demonstrating comparable drug efficacy in tumor growth inhibition. This direct comparison not only confirms the utility of PCLS in simulating real-world outcomes but also emphasizes its potential in reducing animal testing. By providing a reliable, ethical, and efficient alternative for lung cancer studies, PCLS could significantly enhance preclinical research and drug development, marking a critical step towards more humane and representative scientific investigations."
187,Adipose microenvironment promotes hypersialylation of ovarian cancer cells,"Alexandra Fox, Garry D. Leonard, Nicholas Adzibolosu, Terrence Wong, Roslyn Tedja, Sapna Sharma, Radhika Gogoi, Robert Morris, Gil Mor, Charlie Fehl, Ayesha B. Alvero",https://www.biorxiv.org/content/10.1101/2024.05.13.593990v1,"Sialylation, the addition of negatively charged sialic acid sugars to terminal ends of glycans, is upregulated in most cancers. Hypersialylation supports multiple pro-tumor mechanisms such as enhanced migration and invasion, resistance to apoptosis and immune evasion. A current gap in knowledge is the lack of understanding on how the tumor microenvironment regulates cancer cell sialylation. The adipose niche is a main component of most peritoneal cancers’ microenvironment. This includes ovarian cancer (OC), which causes most deaths from all gynecologic cancers. In this report, we demonstrate that the adipose microenvironment is a critical regulator of OC cell sialylation. In vitro adipose conditioning led to an increase in both ⍺2,3- and ⍺2,6-linked cell surface sialic acids in both human and mouse models of OC. Adipose-induced sialylation reprogramming was also observed in vivo from intra-peritoneal OC tumors seeded in the adipose-rich omentum. Mechanistically, we observed upregulation of at least three sialyltransferases, ST3GAL1, ST6GAL1 and ST3GALNAC3. Hypersialylated OC cells consistently formed intra-peritoneal tumors in both immune-competent mice and immune-compromised athymic nude mice. In contrast, hyposiaylated OC cells persistently formed tumors only in athymic nude mice demonstrating that sialylation impacts OC tumor formation in an immune dependent manner. To our knowledge, this is the first demonstration of the effect of adipose microenvironment on OC tumor sialylation. Our results set the stage for translational applications targeting sialic acid pathways in OC and other peritoneal cancers."
188,Super-enhancer-driven ZFP36L1 promotes PD-L1 expression in infiltrative gastric cancer,"Xujin Wei, Jie Liu, Jia Cheng, Wangyu Cai, Wen Xie, Kang Wang, Lingyun Lin, Jingjing Hou, Jianchun Cai, Huiqin Zhuo",https://www.biorxiv.org/content/10.1101/2024.05.22.595316v2,"Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial."
189,Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes,"Xianlu Laura Peng, Elena V. Kharitonova, Yi Xu, Joseph F. Kearney, Changfei Luan, Priscilla S. Chan, Arthi Hariharan, Ian C. McCabe, John R. Leary, Ashley B. Morrison, Hannah E. Trembath, Michelle E. LaBella, Silvia G. Herera Loeza, Ashley Cliff, Hong Jin Kim, Brian A. Belt, Roheena Z. Panni, David C. Linehan, Jeffrey S Damrauer, Alina C. Iuga, William Y. Kim, Naim U. Rashid, Jen Jen Yeh",https://www.biorxiv.org/content/10.1101/2024.05.14.594197v1,"Cancer-associated fibroblast (CAF) subpopulations in pancreatic ductal adenocarcinoma (PDAC) have been identified using single-cell RNA sequencing (scRNAseq) with divergent characteristics, but their clinical relevance remains unclear. We translate scRNAseq-derived CAF cell-subpopulation-specific marker genes to bulk RNAseq data, and develop a single- sample classifier, DeCAF, for the classification of clinically restraining and permissive CAF subtypes. We validate DeCAF in 19 independent bulk transcriptomic datasets across four tumor types (PDAC, mesothelioma, bladder and renal cell carcinoma). DeCAF subtypes have distinct histology features, immune landscapes, and are prognostic and predict response to therapy across cancer types. We demonstrate that DeCAF is clinically replicable and robust for the classification of CAF subtypes in patients for multiple tumor types, providing a better framework for the future development and translation of therapies against permissive CAF subtypes and preservation of restraining CAF subtypes."
191,Methyltransferase DNMT3B promotes colorectal cancer cell proliferation by inhibiting PLCG2,"Yong Ji, Yang Wang, Jiacheng Zou, Guanghao Liu, Mingyu Xia, Jun Ren, Daorong Wang",https://www.biorxiv.org/content/10.1101/2024.05.13.594025v1,Background Aberrant DNA methylation patterns in the promoter region of PLCG2 have been associated with dysregulated signaling pathways and cellular functions. Its role in colorectal cancer cells is still unknown.
192,Multiplexed Glycan Immunofluorescence Identification of Pancreatic Cancer Cell Subpopulations in Both Tumor and Blood Samples,"Braelyn Binkowski, Zachary Klamer, ChongFeng Gao, Ben Staal, Anna Repesh, Hoang-Le Tran, David M. Brass, Pamela Bartlett, Steven Gallinger, Maria Blomqvist, J. Bradley Morrow, Peter Allen, Chanjuan Shi, Aatur Singhi, Randall Brand, Ying Huang, Galen Hostetter, Brian B. Haab",https://www.biorxiv.org/content/10.1101/2024.08.22.609143v1,"Pancreatic ductal adenocarcinoma (PDAC) tumor heterogeneity impedes the development of biomarker assays suitable for early disease detection that would improve patient outcomes. The CA19-9 glycan is currently used as a standalone biomarker for PDAC. Furthermore, previous studies have shown that cancer cells may display aberrant membrane-associated glycans. We therefore hypothesized that PDAC cancer cell subpopulations could be distinguished by aberrant glycan signatures. We used multiplexed glycan immunofluorescence combined with pathologist annotation and automated image processing to distinguish between PDAC cancer cell subpopulations within tumor tissue. Using a training-set/test-set approach, we found that PDAC cancer cells may be identified by signatures comprising 4 aberrant glycans (VVL, CA19-9, sTRA, and GM2) and that there are three glycan-defined PDAC tumor types: sTRA type, CA19-9 type, and intermixed. To determine whether the aberrant glycan signatures could be detected in blood samples, we developed hybrid glycan sandwich assays for membrane-associated glycans. In both patient-matched tumor and blood samples, the proportion of aberrant glycans detected was consistent. Furthermore, our multiplexed glycan immunofluorescent approach proved to be more sensitive and more specific than CA19-9 alone. Our results provide proof of concept for a novel methodology to improve early PDAC detection and patient outcomes."
193,Restoring mechanophenotype reverts malignant properties of ECM-enriched vocal fold cancer,"Jasmin Kaivola, Karolina Punovuori, Megan R. Chastney, Yekaterina A. Miroshnikova, Hind Abdo, Fabien Bertillot, Fabian Krautgasser, Jasmin Di Franco, James R.W. Conway, Gautier Follain, Jaana Hagström, Antti Mäkitie, Heikki Irjala, Sami Ventelä, Hellyeh Hamidi, Giorgio Scita, Roberto Cerbino, Sara A. Wickström, Johanna Ivaska",https://www.biorxiv.org/content/10.1101/2024.08.22.609159v1,"Increased extracellular matrix (ECM) and matrix stiffness promote solid tumor progression. However, mechanotransduction in cancers arising in mechanically active tissues remains underexplored. Here, we report upregulation of multiple ECM components accompanied by tissue stiffening in vocal fold cancer (VFC). We compare non-cancerous (NC) and patient- derived VFC cells – from early (mobile, T1) to advanced-stage (immobile, T3) cancers – revealing an association between VFC progression and cell-surface receptor heterogeneity, reduced laminin-binding integrin cell-cell junction localization and a flocking mode of collective cell motility. Mimicking physiological movement of healthy vocal fold tissue (stretching/vibration), decreases oncogenic nuclear β-catenin and YAP levels in VFC. Multiplex immunohistochemistry of VFC tumors uncovered a correlation between ECM content, nuclear YAP and patient survival, concordant with VFC sensitivity to YAP-TEAD inhibitors in vitro. Our findings present evidence that VFC is a mechanically sensitive malignancy and restoration of tumor mechanophenotype or YAP/TAZ targeting, represents a tractable anti-oncogenic therapeutic avenue for VFC."
196,Integration of expression datasets to identify biomarkers for accurate Gleason scoring in Prostate Cancer,"Pedro Matos-Filipe, Baldo Oliva, Judith Farrés, José Manuel Mas",https://www.biorxiv.org/content/10.1101/2024.08.21.608965v1,"Prostate cancer is a significant global health issue with considerable mortality rates, emphasising the urgent need for advanced treatment options and improved diagnostic methods. Current diagnostic standards for prostate cancer, including PSA testing and digital rectal examination, often produce false positives, resulting in unnecessary biopsies for patients. This limitation highlights the critical requirement to incorporate more precise biomarkers to enhance diagnostic accuracy and reduce unnecessary procedures. This study aims to investigate biomarker candidates that can effectively determine prostate cancer aggressiveness. By integrating diverse prostate tissue expression datasets and employing machine-learning techniques, this approach seeks to refine diagnostics and provide insights into the molecular underpinnings of the disease, potentially transforming early detection and patient management strategies. Our proposed biomarkers achieve a minimum precision of 0.80, addressing the false positives limitations associated with classical prostate cancer biomarkers. Moreover, the ROC-AUC profiles of most of the candidates proposed in this study align with those exhibited by other innovative biomarkers recently proposed (ROC-AUC ≥ 0.70). We believe these biomarkers are promising candidates for further in vivo and in vitro investigation."
198,Conventional therapy induces tumor immunoediting and modulates the immune contexture in colorectal cancer,"Georgios Fotakis, Dietmar Rieder, Zuzana Loncova, Sandro Carollo, Eckhard Klieser, Daniel Neureiter, Florian Huemer, Sandra Hoegler, Martina Tomberger, Anne Krogsdam, Lukas Kenner, Paul K. Ziegler, Richard Greil, Lukas Weiss, Zlatko Trajanoski",https://www.biorxiv.org/content/10.1101/2024.08.21.608938v1,"Background Cancer immunotherapies for patients with colorectal cancer (CRC) continue to lag behind other solid cancer types with the exception of 4% of patients with microsatellite-instable tumors. Thus, there is an urgent need to broaden the clinical benefit of checkpoint blockers to CRC by combining conventional therapies to sensitise tumors to immunotherapy. However, the impact of conventional drugs on immunoediting, potentially promoting the positive selection of less immunogenic variants, and on the tumor immune contexture in CRC, remain elusive."
199,Single nuclei and spatial transcriptomes suggest a stratification of papillary and anaplastic thyroid cancer cells,"Adrien Tourneur, Joel Rodrigues Vitória, Manuel Saiselet, Ligia Craciun, Denis Larsimont, Anne Lefort, Frederick Libert, Carine Maenhaut, Sabine Costagliola, Maxime Tarabichi, Mirian Romitti, Vincent Detours",https://www.biorxiv.org/content/10.1101/2024.02.15.580495v2,"Sixty percent of papillary thyroid cancers (PTCs) are driven by BRAFV600E, a mutation associated with high inter- and intra-tumoral heterogeneity. PTCs may become highly aggressive anaplastic thyroid cancers (ATC). While single cell transcriptomics may resolve this heterogeneity, it is potentially confounded by batch effects whose correction may dampen inter-tumor variations. We profiled ATCs and BRAFV600E PTCs with single nuclei RNA-seq and spatial transcriptomics, and an experimental design disentangling biological and technical variations. It reveals that much transcriptional variation in cancer cells and several immune cell types is idiosyncratic, i.e. tumor-specific. It is associated in some cases with genomic aberrations and global tissue states like hypoxia. Beyond idiosyncrasies, differentiation markers SLC5A5 (N/S), TPO, TG and TSHR are lost in a sequence mirrored by their gain during human thyroid organoids maturation, suggesting a new classification of cancer cell states. PTC cells retain TSHR expression and show features of partial EMT with a massive expression of FN1, which promotes proliferation via an autocrine loop. In contrast, ATCs undergo full blown EMT, with expression of mesenchymal extracellular components and loss of TSHR. Finally, we show that the microenvironment of cancer cells is driven by inflammation. These findings may help future stratifications of BRAFV600E PTCs."
201,Dissecting the oncogenic mechanisms of POT1 cancer mutations through deep scanning mutagenesis,"Annika Martin, Johannes Schabort, Rebecca Bartke-Croughan, Stella Tran, Atul Preetham, Robert Lu, Richard Ho, Jianpu Gao, Shirin Jenkins, John Boyle, George E. Ghanim, Milind Jagota, Yun S. Song, Hanqin Li, Dirk Hockemeyer",https://www.biorxiv.org/content/10.1101/2024.08.19.608636v1,"Mutations in the shelterin protein POT1 are associated with diverse cancers, but their role in cancer progression remains unclear. To resolve this, we performed deep scanning mutagenesis in POT1 locally haploid human stem cells to assess the impact of POT1 variants on cellular viability and cancer-associated telomeric phenotypes. Though POT1 is essential, frame-shift mutants are rescued by chemical ATR inhibition, indicating that POT1 is not required for telomere replication or lagging strand synthesis. In contrast, a substantial fraction of clinically-validated pathogenic mutations support normal cellular proliferation, but still drive ATR-dependent telomeric DNA damage signaling and ATR-independent telomere elongation. Moreover, this class of cancer-associated POT1 variants elongates telomeres more rapidly than POT1 frame-shifts, indicating they actively drive oncogenesis and are not simple loss-of-function mutations."
202,Comprehensive analysis of microbial content in whole-genome sequencing samples from The Cancer Genome Atlas project,"Yuchen Ge, Jennifer Lu, Daniela Puiu, Mahler Revsine, Steven L. Salzberg",https://www.biorxiv.org/content/10.1101/2024.05.24.595788v3,"In recent years, a growing number of publications have reported the presence of microbial species in human tumors and of mixtures of microbes that appear to be highly specific to different cancer types. Our recent re-analysis of data from three cancer types revealed that technical errors have caused erroneous reports of numerous microbial species found in sequencing data from The Cancer Genome Atlas (TCGA) project. Here we have expanded our analysis to cover all 5,734 whole-genome sequencing (WGS) data sets currently available from TCGA, covering 25 distinct types of cancer. We analyzed the microbial content using updated computational methods and databases, and compared our results to those from two major recent studies that focused on bacteria, viruses, and fungi in cancer. Our results expand upon and reinforce our recent findings, which showed that the presence of microbes is far smaller than had been previously reported, and that many species identified in TCGA data are either not present at all, or are known contaminants rather than microbes residing within tumors. As part of this expanded analysis, and to help others avoid being misled by flawed data, we have released a dataset that contains detailed read counts for bacteria, viruses, archaea, and fungi detected in all 5,734 TCGA samples, which can serve as a public reference for future investigations."
204,Hepatic iNKT cells facilitate colorectal cancer metastasis by inducing a fibrotic niche in the liver,"Marc Nater, Michael Brügger, Virginia Cecconi, Paulo Pereira, Geo Forni, Hakan Köksal, Despoina Dimakou, Michael Herbst, Anna Laura Calvanese, Giulia Lucchiari, Christoph Schneider, Tomas Valenta, Maries van den Broek",https://www.biorxiv.org/content/10.1101/2024.08.19.608250v1,"The liver is an important metastatic organ that contains many innate immune cells, yet little is known about their role in anti-metastatic defense. We investigated how invariant natural killer T (iNKT) cells influence colorectal cancer-derived liver metastasis using different models in immunocompetent mice. We found that hepatic iNKT cells promote metastasis by creating a supportive niche for disseminated cancer cells. Mechanistically, iNKT cells respond to disseminating cancer cells by producing the fibrogenic cytokines IL-4 and IL-13 in a TCR-independent manner. Selective abrogation of IL-4 and IL-13 sensing in hepatic stellate cells prevented their transdifferentiation into extracellular matrix-producing myofibroblasts, which hindered metastatic outgrowth of disseminated cancer cells. This study highlights a novel tumor-promoting axis driven by iNKT cells in the initial stages of metastasis."
205,SUV39H1 Preserves Cancer Stem Cell Chromatin State and Properties in Glioblastoma,"Chunying Li, Qiqi Xie, Sugata Ghosh, Bihui Cao, Yuanning Du, Giau Van Vo, Timothy Y. Huang, Charles Spruck, Y. Alan Wang, Kenneth P. Nephew, Jia Shen",https://www.biorxiv.org/content/10.1101/2024.08.15.607856v1,"Of the more than 100 types of brain cancer, glioblastoma (GBM) is the deadliest. As GBM stem cells (GSCs) are considered to be responsible for therapeutic resistance and tumor recurrence, effective targeting and elimination of GSCs could hold promise for preventing GBM recurrence and achieving potential cures. We show here that SUV39H1, which encodes a histone-3, lysine-9 methyltransferase, plays a critical role in GSC maintenance and GBM progression. Upregulation of SUV39H1 was observed in GBM samples compared to normal brain tissues, and knockdown of SUV39H1 in patient-derived GSCs impaired their proliferation and stemness. Single-cell RNA-seq analysis demonstrated restricted expression of SUV39H1 is in GSCs relative to non-stem GBM cells, likely due to super-enhancer-mediated transcriptional activation, while whole cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq (assay for transposase-accessible chromatin followed by sequencing), we further demonstrated altered chromatin accessibility in key genes associated with these pathways following SUV39H1 knockdown. Treatment with chaetocin, a SUV39H1 inhibitor, mimicked the functional effects of SUV39H1 knockdown in GSCs and sensitized GSCs to the GBM chemotherapy drug temozolomide. Furthermore, targeting SUV39H1 in vivo using a patient-derived xenograft model for GBM inhibited GSC-driven tumor formation. This is the first report demonstrating a critical role for SUV39H1 in GSC maintenance. SUV39H1-mediated targeting of GSCs could enhance the efficacy of existing chemotherapy, presenting a promising strategy for improving GBM treatment and patient outcomes."
206,"Primary culture of high grade serous ovarian cancer cells, selection and derivation of three cell lines","Maria Vias, Carolin M Sauer, Ian Goldlust, Chandra Chilamakuri, Douglas Hall, Teodora Goranova, Elke Van Oudenhove, Gabriel Funingana, Anna Piskorz, Elizabeth Moore, Helena M. Earl, James D. Brenton",https://www.biorxiv.org/content/10.1101/2024.08.15.607946v1,"Cell line models for high grade serous ovarian cancer (HGSOC) are limited in number and are poorly clinically annotated. Consequently, existing models often fail to recapitulate common features of HGSOC, inhibiting mechanistic and therapeutic discovery. We generated and characterised three spontaneously immortalized continuous HGSOC cell lines named CIOV1, CIOV2, and CIOV3 and confirmed that each cell line retained the genomic and pathologic characteristics of its parental tumour. We show that subclonal cell populations present at initiation, expanded and contracted during the culturing process before converging on a stable immortalized line. These lines are new valuable models to study acquired chemoresistance of HGSOC."
207,Are the Next-Generation Pathogenicity Predictors Applicable to Cancer?,"Daria Ostroverkhova, Yiru Sheng, Anna Panchenko",https://www.biorxiv.org/content/10.1101/2024.05.06.592789v1,"Next-generation pathogenicity predictors are designed to identify pathogenic mutations in genetic disorders but are increasingly used to detect driver mutations in cancer. Despite this, their suitability for cancer is not fully established. Here we have assessed the effectiveness of next-generation pathogenicity predictors when applied to cancer by using a comprehensive experimental benchmark of cancer driver and neutral mutations. Our findings indicate that state-of-the-art methods AlphaMissense and VARITY demonstrate commendable performance despite generally underperforming compared to cancer-specific methods. This is notable considering that these methods do not explicitly incorporate cancer-specific information in their training and have made concerted efforts to prevent data leakage from the human-curated training and test sets. Nevertheless, it should be mentioned that a significant limitation of using pathogenicity predictors for cancer arises from their inability to detect cancer potential driver mutations specific for a particular cancer type."
209,Threshold-awareness in adaptive cancer therapy,"MingYi Wang, Jacob G. Scott, Alexander Vladimirsky",https://www.biorxiv.org/content/10.1101/2022.06.17.496649v3,"Although adaptive cancer therapy shows promise in integrating evolutionary dynamics into treatment scheduling, the stochastic nature of cancer evolution has seldom been taken into account. Various sources of random perturbations can impact the evolution of heterogeneous tumors, making performance metrics of any treatment policy random as well. In this paper, we propose an efficient method for selecting optimal adaptive treatment policies under randomly evolving tumor dynamics. The goal is to improve the cumulative “cost” of treatment, a combination of the total amount of drugs used and the total treatment time. As this cost also becomes random in any stochastic setting, we maximize the probability of reaching the treatment goals (tumor stabilization or eradication) without exceeding a pre-specified threshold (or a “budget”). We use a novel Stochastic Optimal Control formulation and Dynamic Programming to find such “threshold-aware” optimal treatment policies. Our approach enables an efficient algorithm to compute these policies for a range of threshold values simultaneously. Compared to treatment plans shown to be optimal in a deterministic setting, the new “threshold-aware” policies significantly improve the chances of the therapy succeeding under the budget, which is correlated with a lower general drug usage. We illustrate this method using two specific examples, but our approach is far more general and provides a new tool for optimizing adaptive therapies based on a broad range of stochastic cancer models."
210,Y chromosome-coded HSATII repeats may contribute to higher incidence of cancer in men,"Hedi Hegyi, Matej Lexa",https://www.biorxiv.org/content/10.1101/2024.08.16.608341v1,"It has been observed that men have a shorter lifespan and higher incidence of certain cancers than women. We postulate here that this phenomenon may be attributed to the “toxic Y chromosome”, owing to the expression of normally silent HSATII repeats in cancer, abundantly present on chromosome Y. Investigating the contribution of all repetitive elements to chromatin interactions using a genome-wide HiC set derived from a colon cancer cell line (HCT116), we found several anomalies regarding satellite HSATII elements when compared to other genomic repeat types: (i) HSATII repeats tend to form HiC pairs mostly with their own kind, and depleted in most heterologous repeat pairs, whereas other types of repeats readily form heterologous HiC pairs; (ii) when treated with 5aza, a chemotherapeutic agent, the number of long-distance HSATII-overlapping HiC pairs significantly decreased when compared to the untreated samples; (iii) and most importantly, in the treated samples interchromosomal HiC read pairs involving a chromosome Y-located repeat and an HSATII repeat on either end almost completely disappear. (iv) We also found that HSATII repeats lack overlap with other types of repeats."
211,Classifying epithelial-mesenchymal transition states in single cell cancer data using large language models,"Shi Pan, Eloise Withnell, Maria Secrier",https://www.biorxiv.org/content/10.1101/2024.08.16.608311v1,"Epithelial–mesenchymal plasticity plays a significant role in various biological processes including tumour progression and chemoresistance. However, the expression programmes underlying the epithelial–mesenchymal transition (EMT) in cancer are diverse, and accurately defining the EMT status of tumour cells remains a challenging task. In this study, we employed a pre-trained single-cell large language model (LLM) to develop an EMT-language model (EMT-LM) that allows us to capture discrete states within the EMT continuum in single cell cancer data. In capturing EMT states, we achieved an average Area Under the Receiver Operating Characteristic curve (AUROC) of 90% across multiple cancer types. We propose a new metric, ADESI, to aid the biological interpretability of our model, and derive EMT signatures liked with energy metabolism and motility reprogramming underlying these state switches. We further employ our model to explore the emergence of EMT states in spatial transcriptomics data, uncovering hybrid EMT niches with contrasting potential for antitumour immunity or immune evasion. Our study provides a proof of concept that LLMs can be applied to characterise cell states in single cell data, and proposes a generalisable framework to predict EMT in single cell RNA-seq that can be adapted and expanded to characterise other cellular states."
212,How Modulation of the Tumor Microenvironment Drives Cancer Immune Escape Dynamics,"Pujan Shrestha, Zahra S. Ghoreyshi, Jason T. George",https://www.biorxiv.org/content/10.1101/2024.08.16.608314v1,"Metastatic disease is the leading cause of cancer-related death, despite recent advances in therapeutic interventions. Prior modeling approaches have accounted for the adaptive immune system’s role in combating tumors, which has led to the development of stochastic models that explain cancer immunoediting and tumor-immune co-evolution. However, cancer immunemediated dormancy, wherein the adaptive immune system maintains a micrometastatic population by keeping its growth in check, remains poorly understood. Immune-mediated dormancy can significantly delay the emergence (and therefore detection) of metastasis. An improved quantitative understanding of this process will thereby improve our ability to identify and treat cancer during the micrometastatic period. Here, we introduce a generalized stochastic model that incorporates the dynamic effects of immunomodulation within the tumor microenvironment on T cell-mediated cancer killing. This broad class of nonlinear birth-death model can account for a variety of cytotoxic T cell immunosuppressive effects, including regulatory T cells, cancer-associated fibroblasts, and myeloid-derived suppressor cells. We develop analytic expressions for the likelihood and mean time of immune escape. We also develop a method for identifying a corresponding diffusion approximation applicable to estimating population dynamics across a wide range of nonlinear birth-death processes. Lastly, we apply our model to estimate the nature and extent of immunomodulation that best explains the timing of disease recurrence in bladder and breast cancer patients. Our findings quantify the effects that stochastic tumor-immune interaction dynamics can play in the timing and likelihood of disease progression. Our analytical approximations provide a method of studying population escape in other ecological contexts involving nonlinear transition rates."
214,Computational modeling of cancer cell metabolism along the catabolic-anabolic axes,"Javier Villela-Castrejon, Herbert Levine, José N. Onuchic, Jason T. George, Dongya Jia",https://www.biorxiv.org/content/10.1101/2024.08.15.608169v1,"Abnormal metabolism is a hallmark of cancer. Initially recognized through the observation of aerobic glycolysis in cancer nearly a century ago. Also, we now know that mitochondrial respiration is also used by cancer for progression and metastasis. However, it remains largely unclear the mechanisms by which cancer cells mix and match different metabolic modalities (oxidative/reductive) and leverage various metabolic ingredients (glucose, fatty acids, glutamine) to meet their bioenergetic and biosynthetic needs. Here, we formulate a phenotypic model for cancer metabolism by coupling master gene regulators (AMPK, HIF-1, Myc) with key metabolic substrates (glucose, fatty acid, and glutamine). The model predicts that cancer cells can acquire four metabolic phenotypes: a catabolic phenotype characterized by vigorous oxidative processes - O, an anabolic phenotype characterized by pronounced reductive activities - W, and two complementary hybrid metabolic states - one exhibiting both high catabolic and high anabolic activity - W/O, and the other relying mainly on glutamine oxidation - Q. Using this framework, we quantified gene and metabolic pathway activity respectively by developing scoring metrics based on gene expression. We validated the model-predicted gene-metabolic pathway association and the characterization of the four metabolic phenotypes by analyzing RNA-seq data of tumor samples from TCGA. Strikingly, carcinoma samples exhibiting hybrid metabolic phenotypes are often associated with the worst survival outcomes relative to other metabolic phenotypes. Our mathematical model and scoring metrics serve as a platform to quantify cancer metabolism and study how cancer cells adapt their metabolism upon perturbations, which ultimately could facilitate an effective treatment targeting cancer metabolic plasticity."
215,Machine learning based identification of candidate miRNA biomarkers for micro-invasive breast cancer diagnosis,"Jayanta K. Pal, Bhadresh R. Rami",https://www.biorxiv.org/content/10.1101/2024.08.16.608025v1,"Purpose Early detection of cancer can be done by analyzing miRNA expression patterns. miRNAs play a significant role in biological processes, and they have been identified as one of the major biomarkers in cancer. miRNAs can also be detected in human blood (micro-invasive way of sample collection), which makes the diagnostic procedure much less stressful for the patients. In this article, we emphasize on identification of miRNAs as biomarkers (collected from blood sample) that are associated with breast cancer."
216,"Pan-cancer molecular signatures connecting aspartate transaminase (AST) to cancer prognosis, metabolic and immune signatures","Geoffrey H. Siwo, Amit G. Singal, Akbar K. Waljee",https://www.biorxiv.org/content/10.1101/2024.03.01.582939v1,"Background Serum aspartate transaminase (sAST) level is used routinely in conjunction with other clinical assays to assess liver health and disease. Increasing evidence suggests that sAST is associated with all-cause mortality and has prognostic value in several cancers, including gastrointestinal and urothelial cancers. Here, we undertake a systems approach to unravel molecular connections between AST and cancer prognosis, metabolism, and immune signatures at the transcriptomic and proteomic levels."
217,MetaGXplore: Integrating Multi-Omics Data with Graph Convolutional Networks for Pan-cancer Patient Metastasis Identification,"Tao Jiang, Haiyang Jiang, Xinyi Ma, Minghao Xu, Yan Liang, Wentao Zhang",https://www.biorxiv.org/content/10.1101/2024.06.30.601445v2,"The spread of cancer cells from the primary tumor to distant anatomical sites, known as tumor metastasis, poses a significant challenge in clinical prognosis, impairing treatment efficacy and reducing patient survival time. Current methods for predicting and diagnosing tumor metastasis rely heavily on extensive examinations and subjective clinical judgments. Accurate and rapid prediction of tumor metastasis likelihood remains an unresolved challenge, crucial for guiding effective clinical interventions and extending patient survival. Additionally, identifying key genes highly associated with metastasis probability is a pressing issue, essential for providing valuable insights into the potential identification of tumor metastasis-specific biomarkers. We developed MetaGXplore, a pioneering Graph Convolutional Neural Network (GCN)-based framework designed to predict metastasis probability by integrating pan-cancer multi-omic datasets with a protein-protein interaction network, while also identifying key genes involved in the metastatic process. Multi-omics datasets offer a comprehensive view of cancer biology, enhancing accuracy in metastasis forecasting through superior deep learning algorithms. Our classification model results were interpreted with GNNExplainer. The efficacy of MetaGXplore was validated via model evaluations, graph structure analysis, and multi-omics data assessment. Enrichment analysis of key genes further explored their biological roles."
218,"Insomnia score: predictive ability of insomnia, high-diagnostic and prognostic value for cancer","Chuandong Zhou, Yixin Lan, Haohan Zhang, Siyu Li, Song Liu, Yan Liu, Hongwei Shao",https://www.biorxiv.org/content/10.1101/2024.08.13.607749v1,Objective This study utilized bioinformatics methods to investigate the association between insomnia and cancer.
219,Netrin signaling mediates survival of dormant epithelial ovarian cancer cells,"Pirunthan Perampalam, James I. MacDonald, Komila Zakirova, Daniel T. Passos, Sumaiyah Wasif, Yudith Ramos-Valdes, Maëva Hervieu, Patrick Mehlen, Rob Rottapel, Benjamin Gibert, Rohann Correa, Trevor G. Shepherd, Frederick A. Dick",https://www.biorxiv.org/content/10.1101/2023.08.29.555435v2,"Dormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We created a suspension culture model of high grade serous ovarian cancer (HGSOC) dormancy and devised a novel CRISPR screening approach to identify survival genes in this context. In combination with RNA-seq, we discovered the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1, -3, and its receptors are essential for low level ERK activation to promote survival, and that Netrin activation of ERK is unable to induce proliferation. Deletion of all UNC5 family receptors blocks Netrin signaling in HGSOC cells and compromises viability during the dormancy step of dissemination in xenograft assays. Furthermore, we demonstrate that Netrin-1 and -3 overexpression in HGSOC correlates with poor outcome. Specifically, our experiments reveal that Netrin overexpression elevates cell survival in dormant culture conditions and contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis."
220,Electrical Synapse Rectification Enables Dual-Network Activity in the crab Cancer borealis,"Savanna-Rae H Fahoum, Farzan Nadim, Dawn M Blitz",https://www.biorxiv.org/content/10.1101/2024.08.15.608183v1,"Flexibility of rhythmic networks includes neuromodulator-elicited changes in neuronal participation between networks. We are examining the role of rectifying electrical synapses in this neuronal switching. Electrical synapses can have complex, non-intuitive effects on network output. However, it is often difficult to measure and manipulate rectification across conditions to determine their functional contributions. Here, we use the Jonah crab Cancer borealis to investigate rectification in well-described rhythmic networks. In an established modulatory state, stimulating the projection neuron MCN5 or bath applying its neuropeptide Gly1-SIFamide causes the two LPG neurons to switch from pyloric rhythm-only (food filtering, ∼1 Hz) activity to dual pyloric and gastric mill rhythm (chewing, ∼0.1 Hz) activity. Typically, LPG is co-active with the two PD and single AB pyloric pacemaker neurons due to rectifying electrical coupling. In Gly1-SIFamide, LPG continues to burst in pyloric time with AB/PD but periodically “escapes” and generates intrinsic longer-duration gastric mill-timed bursts, decreasing its overall synchrony with AB/PD, while AB/PD retain their synchronous pyloric timing. Using two-electrode voltage clamp recordings, we find that Gly1-SIFamide does not alter electrical coupling strength or the rectification between LPG and AB/PD. However, in a computational model, rectification is necessary for LPG to escape AB/PD electrical coupling and generate longer, gastric mill-timed bursts. This was confirmed in the biological system by adding a dynamic clamp non-rectifying electrical synapse between LPG and PD, which decreased LPG’s escape from AB/PD and its gastric mill-timed activity. Thus, rectification between electrically coupled oscillators can underlie modulator-elicited changes in their synchrony."
222,"An epigenetic memory at the CYP1A gene in cancer-resistant, pollution-adapted killifish","Samantha Carrothers, Rafael Trevisan, Nishad Jayasundara, Nicole Pelletier, Emma Weeks, Joel N. Meyer, Richard Di Giulio, Caren Weinhouse",https://www.biorxiv.org/content/10.1101/2024.08.14.607951v1,"Human exposure to polycyclic aromatic hydrocarbons (PAH) is a significant and growing public health problem. Frequent, high dose exposures are likely to increase due to a warming climate and increased frequency of large-scale wildfires. Here, we characterize an epigenetic memory at the cytochrome P450 1A (CYP1A) gene in a population of wild Fundulus heteroclitus that has adapted to chronic, extreme PAH pollution. In wild-type fish, CYP1A is highly induced by PAH. In PAH-tolerant fish, CYP1A induction is blunted. Since CYP1A metabolically activates PAH, this memory protects these fish from PAH-mediated cancer. However, PAH-tolerant fish reared in clean water recover CYP1A inducibility, indicating that blunted induction is a non-genetic memory of prior exposure. To explore this possibility, we bred depurated wild fish from PAH-sensitive and -tolerant populations, manually fertilized exposure-naïve embryos, and challenged them with PAH. We observed epigenetic control of the reversible memory of generational PAH stress in F1 PAH-tolerant embryos. Specifically, we observed a bivalent domain in the CYP1A promoter enhancer comprising both activating and repressive histone post-translational modifications. Activating modifications, relative to repressive ones, showed greater increases in response to PAH in sensitive embryos, relative to tolerant, consistent with greater gene activation. Also, PAH-tolerant adult fish showed persistent induction of CYP1A long after exposure cessation, which is consistent with defective CYP1A shutoff and recovery to baseline. Since CYP1A expression is inversely correlated with cancer risk, these results indicate that PAH-tolerant fish have epigenetic protection against PAH-induced cancer in early life that degrades in response to continuous gene activation."
224,Discovery of Z1362873773: A Novel Fascin Inhibitor from a Large Chemical Library for Colorectal Cancer,"Alejandro Rodríguez-Martínez, Lucía Giraldo-Ruiz, Maria C. Ramos, Irene Luque, Diogo Ribeiro, Fátima Postigo-Corrales, Begoña Alburquerque-González, Silvia Montoro-García, Ana Belén Arroyo-Rodríguez, Pablo Conesa-Zamora, Ana María Hurtado, Ginés Luengo-Gil, Horacio Pérez-Sánchez",https://www.biorxiv.org/content/10.1101/2024.08.13.606007v1,"Metastasis is one of the leading causes of cancer-related death worldwide. Fascin is involved in this process by bundling actin filaments and producing protrusions in cancer cells, which facilitate their migration. It has been shown that the overexpression of this protein is related to the appearance of different types of cancer, such as colorectal cancer. In this study, we conducted an in silico screening against the enamine library, a compound library with a broad chemical space (≈1.4M compounds), followed by further validation with physicochemical assays and cellular migration and cytotoxicity tests, thereby obtaining a molecule with considerable fascin inhibitory and migration-arresting capacity similar to other inhibitors already known in the literature."
225,Prognostic importance of splicing-triggered aberrations of protein complex interfaces in cancer,"Khalique Newaz, Christoph Schaefers, Katja Weisel, Jan Baumbach, Dmitrij Frishman",https://www.biorxiv.org/content/10.1101/2024.05.06.592695v2,"Aberrant alternative splicing (AS) is a prominent hallmark of cancer. AS can perturb protein-protein interactions (PPIs) by adding or removing interface regions encoded by individual exons. Identifying prognostic exon-exon interactions (EEIs) from PPI interfaces can help discover AS-affected cancer-driving PPIs that can serve as potential drug targets. Here, we assessed the prognostic significance of EEIs across 15 cancer types by integrating RNA-seq data with three-dimensional (3D) structures of protein complexes. By analyzing the resulting EEI network we identified patient-specific perturbed EEIs (i.e., EEIs present in healthy samples but absent from the paired cancer samples or vice versa) that were significantly associated with survival. We provide the first evidence that EEIs can be used as prognostic biomarkers for cancer patient survival. Our findings provide mechanistic insights into AS-affected PPI interfaces. Given the ongoing expansion of available RNA-seq data and the number of 3D structurally-resolved (or confidently predicted) protein complexes, our computational framework will help accelerate the discovery of clinically important cancer-promoting AS events."
226,Chemotherapy causes a reversible decrease in VMP1/MIR21 DNA methylation in granulocytes from breast cancer survivors,"Marie-Louise Abrahamsen, Zuzanna Jachowicz, Kristian Buch-Larsen, Djordje Marina, Michael Andersson, Peter Schwarz, Flemming Dela, Linn Gillberg",https://www.biorxiv.org/content/10.1101/2024.08.15.608076v1,"Background DNA methylation alterations within the VMP1/MIR21 gene region, a potential epigenetic biomarker of systemic inflammation, have been demonstrated in mononuclear blood cells from early breast cancer (BC) patients after chemotherapy. Whether these changes are present in granulocytes, persist in the years after treatment, and affect VMP1 or MIR21 gene expression, remains unknown."
227,The temporal evolution of cancer hallmarks,"Lucie Gourmet, Daniele Ramazzoti, Parag Mallick, Simon Walker-Samuel, Luis Zapata",https://www.biorxiv.org/content/10.1101/2024.01.21.576566v1,"Cancer hallmarks describe key physiological characteristics that distinguish cancers from normal tissues. The temporal order in which these hallmarks appear during cancer pathogenesis is of interest from both evolutionary and clinical perspectives but has not been investigated before. Here, we order hallmarks based on the allele frequency and selective advantage of mutations in cancer hallmark genes across >10k untreated primary tumors and >8K healthy tissues. Using this novel approach, we identified a common evolutionary trajectory for 27 of 32 cancer types with genomic instability as the first and immune evasion as the last hallmark. We demonstrated widespread positive selection in cancer and strong negative selection in normal tissues for all hallmarks. Notable exceptions to the hallmark ordering in tumours were melanomas (uveal and skin) suggesting that strong environmental factors could disrupt common evolutionary paths. Clustering of hallmark trajectories across patients revealed 2 clusters defined by early or late genomic instability, with differential prognosis. Our study is the first to identify the temporal order of cancer hallmarks during tumorigenesis and demonstrate a prognostic value that could be exploited for early detection and risk stratification across multiple cancer types."
229,Intestinal LKB1 loss drives a pre-malignant program along the serrated cancer pathway,"S.F. Plugge, H. Ma, J.Y. van der Vaart, J. Sprangers, F.H.M. Morsink, D. Xanthakis, C. Jamieson, A.R. Keijzer, T. Margaritis, T. Candelli, R. Straver, J. de Ridder, F.C.P. Holstege, W.W.J. de Leng, G.J.A. Offerhaus, A. Merenda, M.M. Maurice",https://www.biorxiv.org/content/10.1101/2023.07.17.548873v3,"Background & Aims Heterozygous inactivating mutations of Liver Kinase B1 (LKB1) are causative to the Peutz-Jeghers syndrome (PJS), a hereditary disease characterized by gastrointestinal polyposis and increased cancer susceptibility. While LKB1 loss-induced polyp formation has been ascribed to non-epithelial tissues, how LKB1 deficiency increases cancer risk of patients by altering the phenotypical landscape and hierarchical organization of epithelial tissues remains poorly understood."
230,Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models,"Alessandro Sammarco, Giorgia Guerra, Katharina M. Eyme, Kelly Kennewick, Yu Qiao, Joelle El Hokayem, Kevin J. Williams, Baolong Su, Valentina Zappulli, Steven J. Bensinger, Christian E. Badr",https://www.biorxiv.org/content/10.1101/2024.05.06.592766v1,"Breast cancer brain metastases (BCBM) are a significant cause of mortality and are incurable. Thus, identifying BCBM targets that reduce morbidity and mortality is critical. BCBM upregulate Stearoyl-CoA Desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids, suggesting a potential metabolic vulnerability of BCBM. In this study, we tested the effect of a brain-penetrant clinical-stage inhibitor of SCD (SCDi), on breast cancer cells and mouse models of BCBM. Lipidomics, qPCR, and western blot were used to study the in vitro effects of SCDi. Single-cell RNA sequencing was used to explore the effects of SCDi on cancer and immune cells in a BCBM mouse model. Pharmacological inhibition of SCD markedly reshaped the lipidome of breast cancer cells and resulted in endoplasmic reticulum stress, DNA damage, loss of DNA damage repair, and cytotoxicity. Importantly, SCDi alone or combined with a PARP inhibitor prolonged the survival of BCBM-bearing mice. When tested in a syngeneic mouse model of BCBM, scRNAseq revealed that pharmacological inhibition of SCD enhanced antigen presentation by dendritic cells, was associated with a higher interferon signaling, increased the infiltration of cytotoxic T cells, and decreased the proportion of exhausted T cells and regulatory T cells in the tumor microenvironment (TME). Additionally, pharmacological inhibition of SCD decreased engagement of immunosuppressive pathways, including the PD-1:PD-L1/PD-L2 and PVR/TIGIT axes. These findings suggest that SCD inhibition could be an effective strategy to intrinsically reduce tumor growth and reprogram anti-tumor immunity in the brain microenvironment to treat BCBM."
231,Upregulation of DEK Expression in Uterine Myomas and Cervical Cancer as a Potential Prognostic Factor,"Amelia Janiak, Xinyue Liu, Renata Koviazina, PengCheng Tan, Ferdinand Kappes, Fangrong Sheng, Felice Petraglia, Chiara Donati, Anastasia Tsigkou",https://www.biorxiv.org/content/10.1101/2024.08.12.607532v1,Objective To investigate the role of DEK in uterine myomas and cervical cancer as a potential prognostic factor
235,CaMutQC: An R Package for Integrative Quality Control of Cancer Somatic Mutations,"Xin Wang, Tengjia Jiang, Ao Shen, Yaru Chen, Yanqing Zhou, Jie Liu, Shuhan Zhao, Shifu Chen, Jian Ren, Qi Zhao",https://www.biorxiv.org/content/10.1101/2024.08.12.606123v1,"The quality control and filtration of cancer somatic mutations (CAMs), including the elimination of false positives resulting from technical bias and the selection of key mutation candidates, is crucial for downstream analysis in cancer genomics. Due to diverse needs and the absence of standardized filtering criteria, the filtering strategies employed vary from study to study, often leading to reduced efficiency, accuracy, and comparability across similar analyses. Here we present CaMutQC, a heuristic quality control and soft-filtering R/Bioconductor package for CAMs. With CaMutQC, the removal of false positives, selection of potential mutation candidates, and Tumor Mutation Burden estimation can be executed in a single line of code, using default or customized parameters. A filter report and a code log generated after the filtration process assist with recording and comparison. The application of CaMutQC on a Whole-exome Sequencing (WES) benchmark dataset demonstrated its impressive capability by eliminating 85.55% of false positive mutations while retaining 90.72% of true positive mutations. Additionally, an extra 11.56% of true positive mutations were recused by the union strategy embedded in CaMutQC. CaMutQC is now available through Bioconductor at https://bioconductor.org/packages/CaMutQC/ under the GPL v3 license, and it will be updated regularly to incorporate top filtration strategy and parameter sets shared within the community."
236,A multiscale model of immune surveillance in micrometastases: towards cancer patient digital twins,"Heber L. Rocha, Boris Aguilar, Michael Getz, Ilya Shmulevich, Paul Macklin",https://www.biorxiv.org/content/10.1101/2023.10.17.562733v3,"Metastasis is the leading cause of death in patients with cancer, driving considerable scientific and clinical interest in immunosurveillance of micrometastases. We investigated this process by creating a multiscale mathematical model to study the interactions between the immune system and the progression of micrometastases in general epithelial tissue. We analyzed the parameter space of the model using high-throughput computing resources to generate over 100,000 virtual patient trajectories. We demonstrated that the model could recapitulate a wide variety of virtual patient trajectories, including uncontrolled growth, partial response, and complete immune response to tumor growth. We classified the virtual patients and identified key patient parameters with the greatest effect on the simulated immunosurveillance. We highlight the lessons derived from this analysis and their impact on the nascent field of cancer patient digital twins (CPDTs). While CPDTs could enable clinicians to systematically dissect the complexity of cancer in each individual patient and inform treatment choices, our work shows that key challenges remain before we can reach this vision. In particular, we show that there remain considerable uncertainties in immune responses, dysfunctional data stratification, and unpredictable personalized treatment. Nonetheless, we also show that in spite of these challenges, patient-specific models suggest strategies to increase control of clinically undetectable micrometastases even without complete parameter certainty."
237,Triple Negative Breast Cancer Cells Acquire Lymphocyte Proteins and Genomic DNA During Trogocytosis with T Cells,"Anutr Sivakoses, Haley Q. Marcarian, Anika M. Arias, Allison R. Lam, Olivia C. Ihedioha, Juan A. Santamaria, Geoffrey C. Gurtner, Alfred L.M. Bothwell",https://www.biorxiv.org/content/10.1101/2024.08.09.607029v1,"Trogocytosis is the process by which a recipient cell siphons small membrane fragments and proteins from a donor cell and may be utilized by cancer cells to avoid immune detection. We observed lymphocyte specific protein expressed by TNBC cells via immunofluorescence imaging of patient samples. Image analysis of CD45RA expression, a T cell specific protein, revealed that all stages of TNBCs express CD45RA. Flow cytometry revealed TNBC cells trogocytose CD45 protein from T cells. We also showed that the acquisition of these lymphoid markers is contact dependent. Confocal and super-resolution imaging further revealed CD45+ spherical structures containing T cell genomic DNA inside TNBC cells after co-culture. Trogocytosis between T cells and TNBC cells altered cancer cell gene expression. Our results revealed that CD45 is obtained by TNBC cells from T cells via trogocytosis and that TNBC cells express CD45 intracellularly and on the membrane."
239,Global chromatin reorganization and regulation of genes of specific evolutionary age in differentiation and cancer,"Flavien Raynal, Kaustav Sengupta, Dariusz Plewczynski, Benoît Aliaga, Vera Pancaldi",https://www.biorxiv.org/content/10.1101/2023.10.30.564438v3,"Oncogenesis is accompanied by chromatin organization alterations and reactivation of unicellular phenotypes at the metabolic and transcriptional level. The mechanisms connecting these two observations are unexplored, despite its relevance in cancer biology."
240,Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity,"Jillian S. Weissenrieder, Jessica Peura, Usha Paudel, Nikita Bhalerao, Natalie Weinmann, Calvin Johnson, Maximilian Wengyn, Rebecca Drager, Emma Elizabeth Furth, Karl Simin, Marcus Ruscetti, Ben Z. Stanger, Anil K. Rustgi, Jason R. Pitarresi, J. Kevin Foskett",https://www.biorxiv.org/content/10.1101/2024.08.08.607195v1,"Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFβ. Snail re-expression and TGFβ treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis."
241,BMP antagonist CHRDL2 enhances the cancer stem-cell phenotype and increases chemotherapy resistance in Colorectal Cancer,"Eloise Clarkson, Annabelle Lewis",https://www.biorxiv.org/content/10.1101/2024.01.23.576664v2,"BMP antagonists have been increasingly linked to the development of Colorectal cancer (CRC). BMP signalling operates in opposition to the WNT signalling pathway, which sustains stem-cell maintenance and self-renewal of the normal intestinal epithelium. Reduced BMP and elevated WNT signalling lead to expansion of the stem-cell compartment and the hyperproliferation of epithelial cells, a defining characteristic of CRC. Chordin-like-2 (CHRDL2) is a secreted BMP antagonist, with overexpression linked to poor prognosis and variants in the gene shown to be associated with an elevated CRC risk. Despite this the functional role of CHRDL2 in CRC is unknown."
243,Breast cancer cell-derived extracellular vesicles accelerate collagen fibrillogenesis and integrate into the matrix,"Nicky W. Tam, Rumiana Dimova, Amaia Cipitria",https://www.biorxiv.org/content/10.1101/2024.08.08.607183v1,"Extracellular vesicle (EV) and nanoparticle interactions with extracellular matrix (ECM) environments are often studied through a paradigm whereby particles are a passive element whose diffusion and behaviour are subject to the composition and structure of the environment they are in. While EV diffusion and distribution in tissues are indeed governed by matrix interactions, accumulating evidence suggests that EVs contain much of the cellular machinery required for actively remodeling ECM as well. Using rheology and confocal reflectance microscopy to investigate the gelation of collagen I hydrogels formed in the presence of EVs, we show that EVs can play an active role in the formation of new ECM. EVs appear to nucleate new fibrils, recruiting collagen molecules from solution and accelerating their polymerization. Trypsinization of EVs to digest their surface proteins shows that proteins are primarily responsible for this phenomenon. The use of extruded plasma membrane vesicles shows that membrane composition plays an important role in determining final fibril length and matrix structure. EVs also become integrated into the fibril structures that they help form, reminiscent of matrix vesicles found in situ within tissues. This represents a plausible way by which EVs are deposited into the extracellular environment, becoming important contextual signaling cues for resident cells. Our data show that EV-matrix interactions are dynamic and reciprocal, contributing to the remodeling of tissue microenvironments."
244,Efficient and effective identification of cancer neoantigens from tumor only RNA-seq,"Danilo Tatoni, Mattia Dalsass, Giulia Brunelli, Guido Grandi, Mario Chiariello, Romina D’Aurizio",https://www.biorxiv.org/content/10.1101/2024.08.08.607127v1,"The growing accessibility of sequencing experiments has significantly accelerated the development of personalized immunotherapies based on the identification of cancer neoantigens. Still, the prediction of neoantigens involves lengthy and inefficient protocols, requiring simultaneous analysis of sequencing data from paired tumor/normal exomes and tumor transcriptome, often resulting in a low success rate. To date, the feasibility of adopting a more efficient strategy has not been fully evaluated. To this end, we developed ENEO, a computational approach to detect cancer neoantigens using solely the tumor RNA-seq data while addressing the lack of matched control through a Bayesian probabilistic model. ENEO was assessed on TESLA benchmark dataset, reporting efficient identification of DNA-alterations derived neoantigens and compelling results against state-of-art exome-based methods. We further validated the method on two independent cohorts, encompassing different tumor types and experimental procedures. Our work demonstrates that a tumor-only RNA-based approach, such as the one implemented in ENEO, maintains accuracy in identifying mutated peptides resulting from expressed genomic alterations, while also broadening the pool of potential pMHCs with RNAspecific mutations in a faster and cost-effective way. ENEO is freely available at https://github.com/ctglab/ENEO"
245,Tumor localization strategies of multi-cancer early detection tests: a quantitative assessment,"Christopher Tyson, Kevin H. Li, Xiting Cao, James M. O’Brien, Elliot K. Fishman, Elizabeth K. O’Donnell, Carlos Duran, Vijay Parthasarathy, Seema P. Rego, Omair A. Choudhry, Tomasz M. Beer",https://www.biorxiv.org/content/10.1101/2024.08.07.607020v1,"Introduction Blood-based multi-cancer early detection (MCED) tests may expand the number of “screenable” cancers. Defining an optimal approach to diagnostic resolution for individuals with positive MCED test results is critical. Two prospective trials employed distinct diagnostic resolution approaches; one employed a molecular signal to predict tissue of origin (TOO) and the other used an imaging-based diagnostic strategy. Using mathematical modeling, we compared the diagnostic burden of each approach and characterized the risk of excess cancer incidence that may be attributable to radiation exposure associated with a false positive (FP) MCED test result and an imaging-based diagnostic strategy."
248,Loss of multi-level 3D genome organization during breast cancer progression,"Roberto Rossini, Mohammadsaleh Oshaghi, Maxim Nekrasov, Aurélie Bellanger, Renae Domaschenz, Yasmin Dijkwel, Mohamed Abdelhalim, Philippe Collas, David Tremethick, Jonas Paulsen",https://www.biorxiv.org/content/10.1101/2023.11.26.568711v2,"Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that while the fundamental properties of topologically associating domains (TADs) are overall maintained, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observe a restructuring of TAD-TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identify a previously unrecognized interchromosomal insertion event, wherein a locus on chromosome 8 housing the MYC oncogene is inserted into a highly active subcompartment on chromosome 10. This insertion is accompanied by the formation of de novo enhancer contacts and activation of MYC, illustrating how structural genomic variants can alter the 3D genome to drive oncogenic states. In summary, our findings provide evidence for the loss of genome organization at multiple scales during breast cancer progression revealing novel relationships between genome 3D structure and oncogenic processes."
249,SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma,"Ameer L. Elaimy, Marwa O. El-Derany, Jadyn James, Zhuwen Wang, Ashley N. Pearson, Erin A. Holcomb, Amanda K. Huber, Miguel Gijón, Hannah N. Bell, Viraj R. Sanghvi, Timothy L. Frankel, Grace L. Su, Elliot B. Tapper, Andrew W. Tai, Nithya Ramnath, Christopher P. Centonze, Irina Dobrosotskaya, Julie A. Moeller, Alex K. Bryant, David A. Elliott, Enid Choi, Joseph R. Evans, Kyle C. Cuneo, Thomas J. Fitzgerald, Daniel R. Wahl, Meredith A. Morgan, Daniel T. Chang, Max S. Wicha, Theodore S. Lawrence, Yatrik M. Shah, Michael D. Green",https://www.biorxiv.org/content/10.1101/2024.08.06.606899v1,"End stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell properties in vitro and tumor initiation in vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia lowering agents as potential therapies to mitigate HCC incidence and aggressiveness."
250,Identifying crosstalks among post-translational modifications in lung cancer proteomic data,"Shengzhi Lai, Shuaijian Dai, Peize Zhao, Chen Zhou, Ning Li, Weichuan Yu",https://www.biorxiv.org/content/10.1101/2024.08.06.606765v1,"In a lung squamous cell carcinoma data set containing over 20 million tandem mass spectra, we identified 860 peptides with post-translational modifications (PTMs) that were significantly upregulated in lung cancer samples as compared to normal samples using our new search engine named PIPI3. Among the modified peptides related to upregulated gene ontology terms, about 50% carried multiple PTMs. PIPI3 demonstrated its enabling power to provide insight into PTM crosstalk research."
251,Deciphering tumour microenvironment and elucidating the origin of cancer cells in ovarian clear cell carcinoma,"Uma S Kamaraj, Pradeep Gautam, Terence Cheng, Tham Su Chin, Sun Kuie Tay, Tew Hong Ho, Ravichandran Nadarajah, Ronald Chin Hong Goh, Shing Lih Wong, Sangeeta Mantoo, Inny Busmanis, Hu Li, Minh TN Le, Qi-Jing Li, Elaine Hsuen Lim, Yuin-Han Loh",https://www.biorxiv.org/content/10.1101/2024.08.06.606821v1,"Ovarian clear cell carcinoma (CCC) has an East Asian preponderance. It is associated with endometriosis, a benign condition where endometrial (inner lining of the uterus) tissue is found outside the uterus and on the peritoneal surface, in the abdominal or pelvic space. CCC is relatively more resistant to conventional chemotherapy compared to other ovarian cancer subtypes and is associated with a poorer prognosis. In this study, we recruited and obtained tumour tissues from seven patients across the four stages of CCC. The tumour and the tumour microenvironment (TME) from 7 CCC patients spanning clinical stages 1-4 were transcriptionally profiled using high-resolution scRNA-seq to gain insight into CCC’s biological mechanisms. Firstly, we built a scRNA-seq resource for the CCC tumour microenvironment (TME). Secondly, we identified the different cell type proportions and found high levels of immune infiltration in CCC. Thirdly, since CCC is associated with endometriosis, we compared CCC with two publicly available endometriosis scRNA-seq datasets. The CCC malignant cells showed similarities with glandular secretory and ciliated epithelial cells found in endometriosis. Finally, we determined the differences in cell-cell communication between various cell types present in CCC TME and endometriosis conditions to gain insights into the transformations in CCC."
252,Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis initiation,"Islam E. Elkholi, Amélie Robert, Camille Malouf, Hellen Kuasne, Stanislav Drapela, Graham Macleod, Steven Hébert, Alain Pacis, Virginie Calderon, Claudia L. Kleinman, Ana P. Gomes, Julio A. Aguirre-Ghiso, Morag Park, Stéphane Angers, Jean-François Côté",https://www.biorxiv.org/content/10.1101/2023.08.02.551681v3,"Halting breast cancer metastatic relapses following primary tumor removal and the clinical dormant phase, remains challenging, due to a lack of specific vulnerabilities to target during dormancy. To address this, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). We discovered that loss of class-III PI3K, Pik3c3, revealed a unique vulnerability in 4T07 cells. Surprisingly, dormancy-prone 4T07 cells exhibited higher mTORC1 activity than 4T1 cells, due to lysosome-dependent signaling occurring at the cell periphery. Pharmacological inhibition of Pik3c3 counteracted this phenotype in 4T07 cells, and selectively reduced metastasis burden only in the 4T07 dormancy-prone model. This mechanism was also detected in human breast cancer cell lines in addition to a breast cancer patient-derived xenograft supporting that it may be relevant in humans. Our findings suggest dormant cancer cell-initiated metastasis may be prevented in patients carrying tumor cells that display PIK3C3-peripheral lysosomal signaling to mTORC1."
254,A multiscale functional map of somatic mutations in cancer integrating protein structure and network topology,"Yingying Zhang, Alden K. Leung, Jin Joo Kang, Yu Sun, Guanxi Wu, Le Li, Jiayang Sun, Lily Cheng, Tian Qiu, Junke Zhang, Shayne Wierbowski, Shagun Gupta, James Booth, Haiyuan Yu",https://www.biorxiv.org/content/10.1101/2023.03.06.531441v2,"A major goal of cancer biology is to understand the mechanisms underlying tumorigenesis driven by somatically acquired mutations. Two distinct types of computational methodologies have emerged: one focuses on analyzing clustering of mutations within protein sequences and 3D structures, while the other characterizes mutations by leveraging the topology of protein-protein interaction network. Their insights are largely non-overlapping, offering complementary strengths. Here, we established a unified, end-to-end 3D structurally-informed protein interaction network propagation framework, NetFlow3D, that systematically maps the multiscale mechanistic effects of somatic mutations in cancer. The establishment of NetFlow3D hinges upon the Human Protein Structurome, a comprehensive repository we compiled that incorporates the 3D structures of every single protein as well as the binding interfaces of all known protein interactions in humans. NetFlow3D leverages the Structurome to integrate information across atomic, residue, protein and network levels: It conducts 3D clustering of mutations across atomic and residue levels on protein structures to identify potential driver mutations. It then anisotropically propagates their impacts across the protein interaction network, with propagation guided by the specific 3D structural interfaces involved, to identify significantly interconnected network “modules”, thereby uncovering key biological processes underlying disease etiology. Applied to 1,038,899 somatic protein-altering mutations in 9,946 TCGA tumors across 33 cancer types, NetFlow3D identified 1,4444 significant 3D clusters throughout the Human Protein Structurome, of which ~55% would not have been found if using only experimentally-determined structures. It then identified 26 significantly interconnected modules that encompass ~8-fold more proteins than applying standard network analyses. NetFlow3D and our pan-cancer results can be accessed from http://netflow3d.yulab.org."
255,Discovery of the first-efficacious A2AR negative allosteric modulators for high adenosine cancer immunotherapies,"Margot Boujut, Margaux Héritier, Aurélie Gouiller, Camille Süess, Alessandro Scapozza, Thibaut De Smedt, Maxime Guibert, Sébastien Tardy, Hesham Hamed, David Pejoski, Leonardo Scapozza",https://www.biorxiv.org/content/10.1101/2024.08.05.606339v1,"Inhibition of adenosine 2A receptor (A2AR) is recognized as a promising immunotherapeutic strategy but is challenged by the ubiquity of A2AR function in the immune system. To develop a safe yet efficacious immunotherapy, the discovery of a novel negative allosteric modulator (NAM) was preferred. Leveraging an in-house, sensitive, high-throughput screening cellular assay, novel A2AR NAM scaffolds were identified followed by an extensive structure-activity relationship (SAR) study, leading to the discovery of potent 2-amino-3,5-dicyanopyridine derivatives. Allosteric mode of action of active compounds was confirmed by shift assay, non-linearity of the Schild plot analysis, biophysical measurements, and retained satisfactory potencies in high-adenosine concentrations. Further correlation of A2AR engagement and downstream signaling was done in a human blood translational assay, clearly showcasing the potential of A2AR allosteric modulation as a novel approach for efficient and safer cancer immunotherapies."
256,ThermoTargetMiner as a proteome integral solubility alteration target database for prospective drugs against lung cancer,"Hezheng Lyu, Hassan Gharibi, Bohdana Sokolova, Anna Voiland, Brady Nilsson, Zhaowei Meng, Massimiliano Gaetani, Amir Ata Saei, Roman A. Zubarev",https://www.biorxiv.org/content/10.1101/2024.08.06.606599v1,"Knowledge of the targets of therapeutic compounds is vital for understanding their action mechanisms and side effects, but such valuable data is seldom available. The multiple complementary techniques needed for comprehensive target characterization must combine data reliability with sufficient analysis throughput. Here, we leveraged the Proteome Integral Solubility Alteration (PISA) assay to comprehensively characterize the targets of 67 approved drugs and candidate compounds against lung cancer. The analysis was performed on two cell lines representing different lung cancer phenotypes and novel targets for 77% of the tested molecules were found. Comparison of the protein solubility shifts in lysate vs. living cells highlighted the targets directly interacting with the compounds. As PISA analysis is now joining the arsenal of fast and reliable target characterization techniques, the presented database, ThermoTargetMiner, will become a useful resource in lung cancer research."
257,"Reproductive state controls transcription in the murine liver, with implications for breast cancer liver metastasis","Michelle K. Ozaki, Yi Zhang, Alexandra Q. Bartlett, Elise de Wilde, Xiangnan Guan, Alex Yang, Zheng Xia, Pepper Schedin",https://www.biorxiv.org/content/10.1101/2024.08.02.606434v1,"Liver biology is functionally linked to lactation, as liver size and metabolic output increase during lactation to support synthesis of breast milk. Upon weaning, the rodent liver returns to baseline homeostasis via hepatocyte cell death, in a process considered liver involution. To explore liver biology changes across a lactation-wean cycle, we employed transcriptomic profiling. We identified elevated hepatocyte proliferation and anabolic metabolism gene signatures during lactation, consistent with the liver being a major producer of substrates needed for milk production. Rapid loss of these capacities upon weaning correlated with catabolic metabolism, lysosomal-mediated cell death, and an influx of immune suppressive cells. Furthermore, we identified that the transcriptional profiles associated with liver involution share similarities with the gene expression patterns of liver pre-metastatic niches. This work identifies features of reproductive control of liver biology that sets a foundation for better understanding the potential role of the liver in maternal health."
259,Low-Cost Robotic Manipulation of Live Microtissues for Cancer Drug Testing,"Ivan Stepanov, Noah R. Gottshall, Alireza Ahmadianyazdi, Daksh Sinha, Ethan J. Lockhart, Tran N.H. Nguyen, Sarmad Hassan, Lisa F. Horowitz, Raymond S. Yeung, Taranjit S. Gujral, Albert Folch",https://www.biorxiv.org/content/10.1101/2024.03.21.586169v2,"The scarcity of human biopsies available for drug testing is a paramount challenge for developing new therapeutics, disease models, and personalized treatments. Microtechnologies that combine the microscale manipulation of tissues and fluids offer the exciting possibility of miniaturizing both disease models and drug testing workflows on scarce human biopsies. Unfortunately, these technologies presently require microfluidic devices or robotic dispensers that are not widely accessible. We have rapidly-prototyped an inexpensive platform based on an off-the-shelf robot that can microfluidically manipulate live microtissues into/out of culture plates without using complicated accessories such as microscopes or pneumatic controllers. The robot integrates complex functions with a simple, cost-effective and compact construction, allowing placement inside a tissue culture hood for sterile workflows. We demonstrated a proof-of-concept cancer drug evaluation workflow of potential clinical utility using patient tumor biopsies with multiple drugs on 384-well plates. Our user-friendly, low-cost platform promises to make drug testing of microtissues broadly accessible to pharmaceutical, clinical, and biological laboratories."
260,Ih Block Reveals Separation of Timescales in Pyloric Rhythm Response to Temperature Changes in Cancer borealis,"Kyra A Schapiro, JD Rittenberg, Max Kenngott, Eve Marder",https://www.biorxiv.org/content/10.1101/2024.05.04.592541v3,"Motor systems operate over a range of frequencies and relative timing (phase). We studied the contribution of the hyperpolarization-activated inward current (Ih) to frequency and phase in the pyloric rhythm of the stomatogastric ganglion (STG) of the crab, Cancer borealis as temperature was altered from 11°C to 21°C. Under control conditions, the frequency of the rhythm increased monotonically with temperature, while the phases of the pyloric dilator (PD), lateral pyloric (LP), and pyloric (PY) neurons remained constant. When we blocked Ih with cesium (Cs+) PD offset, LP onset, and LP offset were all phase advanced in Cs+ at 11°C, and the latter two further advanced as temperature increased. In Cs+ the steady state increase in pyloric frequency with temperature diminished and the Q10 of the pyloric frequency dropped from ∼1.75 to ∼1.35. Unexpectedly in Cs+, the frequency displayed non-monotonic dynamics during temperature transitions; the frequency initially dropped as temperature increased, then rose once temperature stabilized, creating a characteristic “jag”. Interestingly, these jags were still present during temperature transitions in Cs+ when the pacemaker was isolated by picrotoxin, although the temperature-induced change in frequency recovered to control levels. Overall, these data suggest that Ih plays an important role in the ability of this circuit to produce smooth transitory responses and persistent frequency increases by different mechanisms during temperature fluctuations."
261,Design and Biophysical Characterization of Second-Generation Cyclic Peptide LAG-3 Inhibitors for Cancer Immunotherapy,"Laura Calvo-Barreiro, Longfei Zhang, Yaser Ali, Ashfaq Ur Rehman, Moustafa Gabr",https://www.biorxiv.org/content/10.1101/2024.08.04.606540v1,"Lymphocyte activation gene 3 (LAG-3) is an inhibitory immune checkpoint crucial for suppressing the immune response against cancer. Blocking LAG-3 interactions enables T cells to recover their cytotoxic capabilities and diminishes the immunosuppressive effects of regulatory T cells. A cyclic peptide (Cys-Val-Pro-Met-Thr-Tyr-Arg-Ala-Cys, disulfide bridge: 1-9) was recently reported as a LAG-3 inhibitor. Based on this peptide, we designed 19 derivatives by substituting tyrosine residue to maximize LAG-3 inhibition. Screening via TR-FRET assay identified 8 outperforming derivatives, with cyclic peptides 12 [Tyr6(L-3-CN-Phe)], 13 [Tyr6(L-4-NH2-Phe)], and 17 [Tyr6(L-3,5-DiF-Phe)] as top candidates. Cyclic peptide 12 exhibited the highest inhibition (IC50 = 4.45 ± 1.36 µM). MST analysis showed cyclic peptides 12 and 13 bound LAG-3 with KD values of 2.66 ± 2.06 µM and 1.81 ± 1.42 µM, respectively, surpassing the original peptide (9.94 ± 4.13 µM). Docking simulations indicated enhanced binding for cyclic peptide 12, with a docking score of -7.236 kcal/mol compared to -5.236 kcal/mol for the original peptide."
262,Molecular and functional profiling unravels targetable vulnerabilities in colorectal cancer,"Efstathios-Iason Vlachavas, Konstantinos Voutetakis, Vivian Kosmidou, Spyridon Tsikalakis, Spyridon Roditis, Konstantinos Pateas, Ryangguk Kim, Kymberleigh Pagel, Stephan Wolf, Gregor Warsow, Antonia Dimitrakopoulou-Strauss, Georgios N Zografos, Alexander Pintzas, Johannes Betge, Olga Papadodima, Stefan Wiemann",https://www.biorxiv.org/content/10.1101/2024.04.17.589725v2,"While colorectal cancer (CRC) patients with microsatellite instability (MSI) respond well to immunotherapy those with microsatellite stable (MSS) tumors rely on conventional chemotherapy, often with poor outcomes. Both types frequently carry mutations in KRAS or BRAF proto-oncogenes, rendering them more resistant to treatment. New therapeutic biomarkers and treatments remain a clinical need, especially for MSS tumors. We performed whole exome and RNA-Sequencing from 28 tumors of the Athens Comprehensive Cancer Center CRC cohort, and molecularly characterized colorectal cancer patients based on their MSI status, SNVs/CNAs, and pathway/transcription factor activities at the individual patient level. Variants were classified using a new computational score for integrative cancer variant annotation and prioritization. Complementing this molecular data with public multi-omics datasets, we identified activation of transforming growth factor beta (TGFβ) signaling to be stronger activated in the MSS patients whereas JAK-STAT and MAPK molecular cascades were activated specifically in MSI. We unraveled mechanisms consistently perturbed in the transcriptional and mutational circuits and identified RUNX transcription factors as putative novel targets. Assessing the immunogenicity of CRC tumors in the context of RAS/RAF mutations and MSI/MSS status revealed a critical impact KRAS mutations have on immunogenicity particularly in the MSS patient subgroup, with implications for diagnosis and treatment."
263,Single-cell multi-omics reveals tumor microenvironment factors underlying poor immunotherapy responses in ALK-positive lung cancer,"Seungbyn Baek, Euijeong Sung, Gamin Kim, Min-Hee Hong, Chang Young Lee, Hyo Sup Shim, Seong Yong Park, Hye Ryun Kim, Insuk Lee",https://www.biorxiv.org/content/10.1101/2024.09.24.614708v1,"Anaplastic lymphoma kinase (ALK) rearrangement is a major oncogenic driver in non-small cell lung cancer (NSCLC). While ALK tyrosine kinase inhibitors have shown promising therapeutic effects, overcoming resistance with immunotherapy becomes necessary when resistance develops. However, various clinical trials have revealed that their efficacies remain limited. To investigate the tumor microenvironment (TME) factors contributing to poor immune checkpoint blockade responses in ALK-positive patients, we performed single-cell RNA and ATAC sequencing on lung adenocarcinoma (LUAD) tumors with and without ALK rearrangements. Integrative analysis with additional public LUAD cohorts revealed distinct immune landscapes in ALK-positive tumors, marked by enriched innate immunity and depleted adaptive immunity. ALK-positive malignant cells exhibit higher stemness and aggressive phenotype. Tumor-associated macrophages (TAMs) in these tumors predominantly maintain pro-tumoral M2-like states, reinforcing immune suppression. B cells show reduced immune reactivity and impaired tertiary lymphoid structure formation, while CD8+ T cells display bystander-like signatures and reduced tumor reactivity. Single-cell chromatin accessibility profiles combined with regulatory network analysis suggest that differences in transcription factor activities, rather than chromatin accessibility, may underlie T cell dysfunction. These findings provide insights into the immunosuppressive TME of ALK-positive LUAD, potentially explaining the failure of recent immunotherapy trials and highlighting targets for improving efficacy."
265,Exercise-induced extracellular vesicles mediate apoptosis in human colon cancer cells in an exercise intensity-dependent manner,"Berkay Özerkliğ, Ibrahim Turkel, Merve Yilmaz, Refika Dilara Vaizoglu, Handan Sevim Akan, Z. Gunnur Dikmen, Ayesha Saleem, Sukran N. Kosar",https://www.biorxiv.org/content/10.1101/2024.09.24.614165v1,"Regular exercise is known to reduce incidence rates and improve the prognosis of all cancers, but the underlying mechanisms remain elusive. Ample evidence suggests that exercise exerts therapeutic effects through extracellular vesicles (EVs), essential for cellular communication. Here, we hypothesized that exercise-induced EVs from serum of healthy young male participants will exert anti-tumorigenic effects on human colon cancer HT-29 cells, in an exercise intensity-dependent manner. 10 healthy young active males (25.4±6.2yrs, with maximal oxygen consumption (VO2max) = 45±3.7 ml.min-1.kg-1 participated in a randomized crossover trial. Participants underwent two different workload-matched, acute bouts of exercise: (1) moderate-intensity continuous exercise (MICE) at 50-55% V02max, and (2) high-intensity interval exercise (HIIE) at 90% V02max on a cycle ergometer. A control session of rest (PRE) was included. EVs were isolated from serum samples collected during PRE and immediately after each exercise session. EVs were co-incubated with colon cancer HT-29 cells (100 μg EVs/ml, 48-72h), and effect on cell viability, migration, and apoptosis measured. EV treatment reduced cell viability in all groups (PRE, MICE, HIIE) by 35%, 43% and 47% respectively, vs. PBS. EVs from HIIE group showed a significantly greater reduction in cell viability vs. PRE, therefore further analysis used these groups only. PRE-EVs reduced migration by 27%, and HIIE-EVs by 39%. EV from HIIE group increased expression of pro-apoptotic markers: Bax/Bcl-2 ratio by 56% and Caspase-3 by 30% vs. PBS, with no change observed in the PRE group. Further, 16% of cells in PRE, and 28% of cells in HIIE were TUNEL-positive, indicating DNA fragmentation, a hallmark feature of apoptosis. Our data show that exercise-induced EVs reduced cell viability, in an exercise intensity-dependent manner. HIIE-derived EVs exerted the most anti-tumorigenic effects: decreased cell viability, reduced cell migration, increase in pro-apoptotic protein expression, and elevated DNA fragmentation. It is likely these changes were mediated by altered EV Cargo induced by exercise, as the amount of EVs was the same in each treatment group. To our knowledge, this is the first human study that illustrates the therapeutic potential of exercise-induced EVs in cancer treatment."
266,Proteogenomics guided identification of functional neoantigens in non-small cell lung cancer,"Ben Nicholas, Alistair Bailey, Katy J McCann, Oliver Wood, Eve Currall, Peter Johnson, Tim Elliott, Christian Ottensmeier, Paul Skipp",https://www.biorxiv.org/content/10.1101/2024.05.30.596609v2,"Non-small cell lung cancer (NSCLC) has poor survival even for those receiving modern checkpoint inhibitor therapies. Personalised vaccines based on short peptide neoantigens containing tumour mutations, presented to cytotoxic T-cells by human leukocyte antigen (HLA) molecules, are an attractive strategy. However, identifying therapeutically relevant neoantigens is challenging, with existing methods yielding positive responses in only 6% of candidates tested, and neoantigen-based vaccines in melanoma, glioblastoma and pancreatic cancer producing an immune responses in about 50% of patients."
267,Hexa-acylated lipopolysaccharides from the gut microbiota enhance cancer immunotherapy responses,"Benjamin S. Beresford-Jones, Puspendu Sardar, Wangmingyu Xia, Omar Shabana, Satoshi Suyama, Ruben J. Jesus Faustino Ramos, Amelia T. Soderholm, Panagiotis Tourlomousis, Paula Kuo, Alexander C. Evans, Charlotte J. Imianowski, Alberto G. Conti, Alexander J. Wesolowski, Klaus Okkenhaug, Sarah K. Whiteside, Rahul Roychoudhuri, Clare E. Bryant, Justin R. Cross, Virginia A. Pedicord",https://www.biorxiv.org/content/10.1101/2024.06.24.600291v2,"Immune checkpoint inhibitors (ICI), such as anti-PD-1, have revolutionized cancer treatment, but they are only effective for a minority of patients. The gut microbiome plays a crucial role in modulating immunotherapy treatment responses, and previous studies correlated lipopolysaccharide (LPS)-producing gut microbes with poorer prognosis. However, LPS from diverse bacterial species have activities ranging from immunostimulatory to inhibitory. By functionally analyzing fecal metagenomes from 112 melanoma patients prior to anti-PD-1 therapy, we found that a subset of LPS-producing bacteria encoding immunostimulatory hexa-acylated LPS was enriched in the microbiomes of clinical responders. We confirmed robust activation of the NF-kB pathway by hexa-acylated LPS in vitro, and this activation was significantly inhibited by penta-acylated LPS in a dose-dependent manner. Importantly, oral administration of hexa-acylated LPS augmented anti-PD-1-mediated anti-tumor immunity in an in vivo mouse model of cancer immunotherapy. Microbiome hexa-acylated LPS may therefore represent an accessible predictor and potential enhancer of clinical anti- PD-1 immunotherapy responses."
268,Intratumoral Delivery of Chlorine Dioxide Exploits its ROS-like Properties: A Novel Paradigm for Effective Cancer Therapy,"Xuewu Liu, Zhaoyang Liu, Xueyan Liu, Shuangning Liu, Jiao Zhang",https://www.biorxiv.org/content/10.1101/2023.11.24.568512v2,"Our study underscores the potential of chlorine dioxide, resembling reactive oxygen species, in promoting tissue regeneration and executing similar functions. Direct intratumoral administration of chlorine dioxide conveniently and sustainably kills cancer cells, without the risk of developing drug resistance. Given that tumors are viewed as non-healing wounds, the regenerative capabilities of chlorine dioxide offer an innovative method to expedite wound healing and enhance patient outcomes in cancer treatment. Compared to traditional methods, chlorine dioxide treatment reduces complications and risks, presenting a safer alternative. Notably, higher concentrations of chlorine dioxide in promoting tumor ablation can particularly demonstrate the potential to disrupt tumor vasculature. We advocate for the intratumoral injection of chlorine dioxide to achieve direct tumor ablation and boost antitumor immunity while minimizing harm to healthy tissues. Although initial findings indicate that chlorine dioxide stimulates an antitumor immune response, further investigation is essential. As oncology advances with the use of immune checkpoint inhibitors, intratumoral chlorine dioxide administration emerges as a promising strategy, potentially extending survival and alleviating treatment burdens. Future research should focus on refining chlorine dioxide protocols, exploring synergistic therapies, and understanding its systemic immune effects, thereby establishing chlorine dioxide's role in cancer therapy."
269,Sequential transcriptional waves and NF-κB-driven chromatin remodeling direct drug-induced dedifferentiation in cancer,"Yapeng Su, Chunmei Liu, Xiang Lu, Guideng Li, Shiqun Shao, Yan Kong, Jihoon W. Lee, Rachel H. Ng, Stephanie Wong, Lidia Robert, Charles Warden, Victoria Liu, Jie Chen, Zhuo Wang, Guangrong Qin, Yin Tang, Hanjun Cheng, Alphonsus H. C. Ng, Songming Peng, Min Xue, Dazy Johnson, Yu Xu, Jinhui Wang, Xiwei Wu, Ilya Shmulevich, Qihui Shi, Raphael Levine, Antoni Ribas, David Baltimore, Jun Guo, James R. Heath, Wei Wei",https://www.biorxiv.org/content/10.1101/724740v2,"Drug-induced dedifferentiation towards a drug-tolerant persister state is a common mechanism cancer cells exploit to escape therapies, posing a significant obstacle to sustained therapeutic efficacy. The dynamic coordination of epigenomic and transcriptomic programs at the early-stage of drug exposure, which initiates and orchestrates these reversible dedifferentiation events, remains largely unexplored. Here we employ high-temporal-resolution multi-omics profiling, information-theoretic approaches, and dynamic system modeling to probe these processes in BRAF-mutant melanoma models and patient specimens. We uncover a hysteretic transition trajectory of melanoma cells in response to oncogene inhibition and subsequent release, driven by the sequential operation of two tightly coupled transcriptional waves, which orchestrate genome-scale chromatin state reconfiguration. Modeling of the transcriptional wave interactions predicts NF-κB/RelA-driven chromatin remodeling as the underlying mechanism of cell-state dedifferentiation, a finding we validate experimentally. Our results identify critical RelA-target genes that are epigenetically modulated to drive this process, establishing a quantitative epigenome gauge to measure cell-state plasticity in melanomas, which supports the potential use of drugs targeting epigenetic machineries to potentiate oncogene inhibition. Extending our investigation to other cancer models, we identify oxidative stress-mediated NF-κB/RelA activation as a common mechanism driving cellular transitions towards drug-tolerant persister states, revealing a novel and pivotal role for the NF-κB signaling axis in linking cellular oxidative stress to cancer progression."
270,Using virtual patient cohorts to uncover immune response differences in cancer and immunosuppressed COVID-19 patients,"Sonia Gazeau, Xiaoyan Deng, Elsa Brunet-Ratnasingham, Daniel E. Kaufmann, Catherine Larochelle, Penelope A. Morel, Jane M. Heffernan, Courtney L. Davis, Amber M. Smith, Adrianne L. Jenner, Morgan Craig",https://www.biorxiv.org/content/10.1101/2024.08.01.605860v1,"The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in millions of deaths globally. Adults with immunosuppression (e.g., solid organ transplant recipients) and those undergoing active cancer treatments experience worse infections and more severe COVID-19. It is difficult to conduct clinical studies in these populations, resulting in a restricted amount of data that can be used to relate mechanisms of immune dysfunction to COVID-19 outcomes in these vulnerable groups. To study immune dynamics after infection with SARS-CoV-2 and to investigate drivers of COVID-19 severity in individuals with cancer and immunosuppression, we adapted our mathematical model of the immune response during COVID-19 and generated virtual patient cohorts of cancer and immunosuppressed patients. The cohorts of plausible patients recapitulated available longitudinal clinical data collected from patients in Montréal, Canada area hospitals. Our model predicted that both cancer and immunosuppressed virtual patients with severe COVID-19 had decreased CD8+ T cells, elevated interleukin-6 concentrations, and delayed type I interferon peaks compared to those with mild COVID-19 outcomes. Additionally, our results suggest that cancer patients experience higher viral loads (however, with no direct relation with severity), likely because of decreased initial neutrophil counts (i.e., neutropenia), a frequent toxic side effect of anti-cancer therapy. Furthermore, severe cancer and immunosuppressed virtual patients suffered a high degree of tissue damage associated with elevated neutrophils. Lastly, parameter values associated with monocyte recruitment by infected cells were found to be elevated in severe cancer and immunosuppressed patients with respect to the COVID-19 reference group. Together, our study highlights that dysfunction in type I interferon and CD8+ T cells are key drivers of immune dysregulation in COVID-19, particularly in cancer patients and immunosuppressed individuals."
271,P53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect,"Roba Abukwaik, Elias Vera-Siguenza, Daniel Tennant, Fabian Spill",https://www.biorxiv.org/content/10.1101/2024.04.26.591290v2,"Cancer cells exhibit significant alterations in their metabolism, characterised by a reduction in oxidative phosphorylation (OXPHOS) and an increased reliance on glycolysis, even in the presence of oxygen. This metabolic shift, known as the Warburg effect, is pivotal in fuelling cancer’s uncontrolled growth, invasion, and therapeutic resistance. While dysregulation of many genes contributes to this metabolic shift, the tumour suppressor gene p53 emerges as a master player. Yet, the molecular mechanisms remain elusive. This study introduces a comprehensive mathematical model, integrating essential p53 targets, offering insights into how p53 orchestrates its targets to redirect cancer metabolism towards an OXPHOS-dominant state. Simulation outcomes align closely with experimental data comparing glucose metabolism in colon cancer cells with wild-type and mutated p53. Additionally, our findings reveal the dynamic capability of elevated p53 activation to fully reverse the Warburg effect, highlighting the significance of its activity levels not just in triggering apoptosis (programmed cell death) post-chemotherapy but also in modifying the metabolic pathways implicated in treatment resistance. In scenarios of p53 mutations, our analysis suggests targeting glycolysis-instigating signalling pathways as an alternative strategy, whereas targeting solely synthesis of cytochrome c oxidase 2 (SCO2) does support mitochondrial respiration but may not effectively suppress the glycolysis pathway, potentially boosting the energy production and cancer cell viability."
272,Robust estimation of cancer and immune cell-type proportions from bulk tumor ATAC-Seq data,"Aurélie AG Gabriel, Julien Racle, Maryline Falquet, Camilla Jandus, David Gfeller",https://www.biorxiv.org/content/10.1101/2023.10.11.561826v4,"Assay for Transposase-Accessible Chromatin sequencing (ATAC-Seq) is a widely used technique to explore gene regulatory mechanisms. For most ATAC-Seq data from healthy and diseased tissues such as tumors, chromatin accessibility measurement represents a mixed signal from multiple cell types. In this work, we derive reliable chromatin accessibility marker peaks and reference profiles for most non-malignant cell types frequently observed in the micro-environment of human tumors. We then integrate these data into the EPIC deconvolution framework (Racle et al., 2017) to quantify cell-type heterogeneity in bulk ATAC-Seq data. Our EPIC-ATAC tool accurately predicts non-malignant and malignant cell fractions in tumor samples. When applied to a human breast cancer cohort, EPIC-ATAC accurately infers the immune contexture of the main breast cancer subtypes."
273,Fibroblast Stromal Support Model for Predicting Human Papillomavirus-Associated Cancer Drug Responses,"Claire D. James, Rachel L. Lewis, Alexis L. Fakunmoju, Austin J. Witt, Aya H. Youssef, Xu Wang, Nabiha M. Rais, Apurva Tadimari Prabhakar, J. Mathew Machado, Raymonde Otoa, Molly L. Bristol",https://www.biorxiv.org/content/10.1101/2024.04.09.588680v3,"Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV+OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ERα) is overexpressed in HPV+OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome. Utilizing this HPV+ specific overexpression profile, we previously demonstrated that estrogen attenuates the growth and cell viability of HPV+ keratinocytes and HPV+ cancer cells in vitro. Expansion of this work in vivo failed to replicate this sensitization. The role of stromal support from the tumor microenvironment (TME) has previously been tied to both the HPV lifecycle and in vivo therapeutic responses. Our investigations revealed that in vitro co-culture with fibroblasts attenuated HPV+ specific estrogen growth responses. Continuing to monopolize on the HPV+ specific overexpression of ERα, our co-culture models then assessed the suitability of the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, and showed growth attenuation in a variety of our models to one or both of these drugs in vitro. Utilization of these SERMs in vivo closely resembled the sensitization predicted by our co-culture models. Therefore, the in vitro fibroblast co-culture model better predicts in vivo responses. We propose that utilization of our co-culture in vitro model can accelerate cancer therapeutic drug discovery."
274,Spatial multi-omics reveal intratumoral humoral immunity niches associated with tertiary lymphoid structures in pancreatic cancer immunotherapy pathologic responders,"Dimitrios N. Sidiropoulos, Sarah M. Shin, Meredith Wetzel, Alexander A. Girgis, Daniel Bergman, Ludmila Danilova, Susheel Perikala, Daniel H. Shu, Janelle M. Montagne, Atul Deshpande, James Leatherman, Lucie Dequiedt, Victoria Jacobs, Aleksandra Ogurtsova, Guanglan Mo, Xuan Yuan, Dmitrijs Lvovs, Genevieve Stein-O'Brien, Mark Yarchoan, Qingfeng Zhu, Elizabeth I. Harper, Ashani T. Weeraratna, Ashley L. Kiemen, Elizabeth M. Jaffee, Lei Zheng, Won Jin Ho, Robert A. Anders, Elana J. Fertig, Luciane T. Kagohara",https://www.biorxiv.org/content/10.1101/2024.09.22.613714v1,"Pancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. We generated a spatial multi-omics atlas encompassing 26 PDAC tumors from patients treated with combination immunotherapies. Using machine learning-enabled H&E image classification models and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within TLS niches spanning across distinct morphologies and immunotherapies. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation in pathological responders, confirmed with spatial proteomics and BCR profiling. Our study also identifies spatial features of pathologic immune responses, revealing TLS maturation colocalizing with IgG/IgA distribution and extracellular matrix remodeling."
275,A genetic toolbox for the turquoise killifish identifies sporadic age-related cancer,"Itai Rozenberg, Roman Franek, Eitan Moses, Tehila Atlan, Mathias Diehl, Adi Oron-Gottesman, Marva Bergman, Gwendoline Astre, Benyamin Rosental, Uri Goshtchevsky, Henrik von Chrzanowski, Itamar Harel",https://www.biorxiv.org/content/10.1101/2023.05.01.538839v2,"Aging is accompanied by a progressive loss of tissue homeostasis, including declining stem-cell function and increased cancer susceptibility. The naturally short-lived African turquoise killifish has emerged as a powerful system for investigating vertebrate aging. However, a critical mass of advanced genetic tools for mechanistic studies has been largely missing. Here, we develop the Killibow, a multispectral transgenic line for life-long lineage tracing, an immunocompromised rag2 mutant for transplantation studies, and genetic mutants for investigating genomic instability and cancer (i.e. atm and tp53). We performed a series of experiments using this platform, including lineage tracing following germline stem-cell transplantation, and identifying naturally occurring age-related melanoma using engraftment into rag2 mutants. Exploring tumor dynamics reveals an intriguing age-related interplay between genomic instability and adaptive immunity, accompanied by an evolutionarily conserved decline in immune functions. Together, this toolkit streamlines the investigation of the molecular mechanisms underlying the loss of tissue homeostasis during aging and disease."
276,Selective loss of Y chromosomes in lung adenocarcinoma modulates the tumor immune environment through cancer/testis antigens,"Jonas Fischer, Katherine H. Shutta, Chen Chen, Viola Fanfani, Enakshi Saha, Panagiotis Mandros, Marouen Ben Guebila, Joanne Xiu, Jorge Nieva, Stephen Liu, Dipesh Uprety, David Spetzler, Camila M. Lopes-Ramos, Dawn DeMeo, John Quackenbush",https://www.biorxiv.org/content/10.1101/2024.09.19.613876v1,"There is increasing recognition that the sex chromosomes, X and Y, play an important role in health and disease that goes beyond the determination of biological sex. Loss of the Y chromosome (LOY) in blood, which occurs naturally in aging men, has been found to be a driver of cardiac fibrosis and heart failure mortality. LOY also occurs in most solid tumors in males and is often associated with worse survival, suggesting that LOY may give tumor cells a growth or survival advantage. We analyzed LOY in lung adenocarcinoma (LUAD) using both bulk and single-cell expression data and found evidence suggesting that LOY affects the tumor immune environment by altering cancer/testis antigen expression and consequently facilitating tumor immune evasion. Analyzing immunotherapy data, we show that LOY and changes in expression of particular cancer/testis antigens are associated with response to pembrolizumab treatment and outcome, providing a new and powerful biomarker for predicting immunotherapy response in LUAD tumors in males."
284,"Remote organ cancer adversely alters renal function and induces kidney injury, inflammation, and fibrosis","Dana Hammouri, Andrew Orwick, Mark Doll, Dianet Sanchez Vega, Parag P. Shah, Christopher J. Clarke, Brian Clem, Levi J. Beverly, Leah J. Siskind",https://www.biorxiv.org/content/10.1101/2024.07.29.605635v2,"Approximately 30% of cancer patients experience kidney complications, which hinder optimal cancer management, imposing a burden on patients’ quality of life and the healthcare system. The etiology of kidney complications in cancer patients is often attributed to nephrotoxic oncological therapies. However, the direct impact of cancer on kidney health is underestimated, as most nephrotoxic oncological therapies have been studied in animal models that do not have cancer. Our previous study demonstrated that metastatic lung cancer adversely alters kidney physiology and function, and exacerbates chemotherapy-induced nephrotoxicity, indicating lung cancer-kidney crosstalk. The current study examines whether this phenomenon is specific to the employed cancer model. Female and male mice of various strains were injected with different cell lines representing human and mouse lung cancer, breast cancer, and melanoma, and their kidney tissues were analyzed for toxicity and fibrosis. The impact of cancer on the kidney varied by cancer type. Breast cancer and specific subtypes of lung cancer, including KRAS- and EGFR-mutant cancer, pathologically altered kidney physiology and function in a manner dependent on the metastatic potential of the cell line. This was independent of mouse strain, sex, and cancer cell line origin. Moreover, tumor DNA was not detected in the renal tissue, excluding metastases to the kidney as a causative factor for the observed pathological alterations. Lewis lung carcinoma and B16 melanoma did not cause nephrotoxicity, regardless of the tumor size. Our results confirm cancer-kidney crosstalk in specific cancer types and highlight gaps in understanding the risk of renal complications in cancer patients. In the era of precision medicine, further research is essential to identify at-risk oncology populations, enabling early detection and management of renal complications."
285,diaPASEF analysis for HLA-I peptides enables quantification of common cancer neoantigens,"Denys Oliinyk, Hem Gurung, Zhenru Zhou, Kristin Leskoske, Christopher M. Rose, Susan Klaeger",https://www.biorxiv.org/content/10.1101/2024.07.30.605861v1,"Human leukocyte antigen class I (HLA-I) molecules present short peptide sequences from endogenous or foreign proteins to cytotoxic T cells. The low abundance of HLA-I peptides poses significant technical challenges for their identification and accurate quantification. While mass spectrometry (MS) is currently a method of choice for direct system-wide identification of cellular immunopeptidome, there is still a need for enhanced sensitivity in detecting and quantifying tumor specific epitopes. As gas phase separation in data-dependent MS data acquisition (DDA) increased HLA-I peptide detection by up to 50%, here, we aimed to evaluate the performance of data-independent acquisition (DIA) in combination with ion mobility (diaPASEF) for high-sensitivity identification of HLA presented peptides. Our streamlined diaPASEF workflow enabled identification of 11,412 unique peptides from 12.5 million A375 cells and 3,426 8-11mers from as low as 500,000 cells with high reproducibility. By taking advantage of HLA binder-specific in-silico predicted spectral libraries, we were able to further increase the number of identified HLA-I peptides. We applied SILAC-DIA to a mixture of labeled HLA-I peptides, calculated heavy-to-light ratios for 7,742 peptides across 5 conditions and demonstrated that diaPASEF achieves high quantitative accuracy up to 4-fold dilution. Finally, we identified and quantified shared neoantigens in a monoallelic C1R cell line model. By spiking in heavy synthetic peptides, we verified the identification of the peptide sequences and calculated relative abundances for 13 neoantigens. Taken together, diaPASEF analysis workflows for HLA-I peptides can increase the peptidome coverage for lower sample amounts. The sensitivity and quantitative precision provided by DIA can enable the detection and quantification of less abundant peptide species such as neoantigens across samples from the same background."
287,Exploring potential targets for quercetin treatment of colorectal cancer through network pharmacology and molecular docking technology,"Yuanyuan Qian, Zhaojunli Wang, Jiancheng Ji, Wenlong Fu",https://www.biorxiv.org/content/10.1101/2024.07.29.605708v1,Objective To explore the potential targets of quercetin in the treatment of colorectal cancer through network pharmacology and molecular docking technology.
290,How cancer-associated fibroblasts promote T-cell exclusion in human lung tumors: a physical perspective,"Joseph Ackermann, Chiara Bernard, Philemon Sirven, Hélène Salmon, Massimiliano Fraldi, Martine Ben Amar",https://www.biorxiv.org/content/10.1101/2024.01.16.575824v2,"The tumor stroma is a tissue composed primarily of extracellular matrix, fibroblasts, immune cells, and vasculature. Its structure and functions, such as nutrient support and waste removal, are altered during malignancy. Tumor cells transform fibroblasts into cancer-associated fibroblasts, which have an important immunosuppressive activity on which growth, invasion, and metastasis depend. These activated fibroblasts prevent immune cell infiltration into the tumor nest, thereby promoting cancer progression and inhibiting T-cell-based immunotherapy. To understand these complex interactions, we measure the density of different cell types in the stroma using immunohistochemistry techniques on tumor samples from lung cancer patients. We incorporate these data, and also known information on cell proliferation rates and relevant biochemical interactions, into a minimal dynamical system with few parameters. A spatio-temporal approach to the inhomogeneous environment explains the cell distribution and fate of lung carcinomas. The model reproduces that cancer-associated fibroblasts act as a barrier to tumor growth, but also reduce the efficiency of the immune response. The final outcome depends on the parameter values for each patient and leads to either tumor invasion, persistence or eradication as a result of the interplay between cancer cell growth, T-cell cytotoxic activity and fibroblast attraction, activation and spatial dynamics. Our conclusion is that a wide spectrum of scenarios exists as a result of the competition between the characteristic times of cancer cell growth and the activity rates of the other species. Nevertheless, distinct trajectories and patterns allow quantitative predictions that may help in the selection of new therapies and personalized protocols."
291,A Stapled Peptide Inhibitor of METTL3-METTL14 for Cancer Therapy,"Zenghui Li, Yuqing Feng, Hong Han, Xingyue Jiang, Weiyu Chen, Xuezhen Ma, Yang Mei, Dan Yuan, Dingxiao Zhang, Junfeng Shi",https://www.biorxiv.org/content/10.1101/2023.09.04.556216v2,"METTL3, a primary methyltransferase catalyzing RNA N6-methyladenosine (m6A) modification, has been identified as an oncogene in several cancer types and thus nominated as a potentially effective target for therapeutic inhibition, although current options using this strategy are limited. In this study, we targeted protein-protein interactions at the METTL3-METTL14 binding interface to inhibit complex formation and subsequent catalysis of RNA m6A modification. Among candidate peptides, RM3 exhibited the highest anti-cancer potency, inhibiting METTL3 activity while also facilitating its proteasomal degradation. We then designed a stapled peptide inhibitor (RSM3) with enhanced peptide stability and formation of the α-helical secondary structure required for METTL3 interaction. Functional and transcriptomic analysis in vivo indicated that RSM3 induced upregulation of programmed cell death-related genes while inhibiting cancer-promoting signals. Furthermore, tumor growth was significantly suppressed while apoptosis was enhanced upon RSM3 treatment, accompanied by in-creased METTL3 degradation, and reduced global RNA methylation levels in two in vivo tumor models. This peptide inhibitor thus exploits a mechanism distinct from other competitive-binding small molecules to inhibit oncogenic METTL3 activity. Our findings collectively highlight the potential of targeting METTL3 in cancer therapies through peptide-based inhibition of complex formation and proteolytic degradation."
293,Computational Screening of Zanthoxylum armatum DC Phytochemicals for inhibiting Mutant P53 in Throat Cancer Therapy,"Ampi Taring, Senggam Wakhet Singpho, Lobsang Lamu, Bipul Chandra Kalita, Hui Tag, Pallabi Kalita Hui",https://www.biorxiv.org/content/10.1101/2024.07.26.605249v1,Aim To investigate the potential of phytochemicals from Zanthoxylum armatum DC in targeting mutant p53 as a therapeutic strategy for throat cancer using an in-silico approach.
295,Development of capsaicin derivatives as prohibitin ligands to modulate the Aurora kinase A/PHB2 interaction in cancer cells,"Amel Djehal, Claire Caron, Deborah Giordano, Valentina Pizza, Kimberley Farin, Angelo Facchiano, Laurent Désaubry, Giulia Bertolin",https://www.biorxiv.org/content/10.1101/2024.06.14.598962v2,"Aurora kinase A/AURKA is a serine/threonine kinase overexpressed in a variety of solid and hematological malignancies. In the last decades, clinical trials aiming to counteract the overexpression of AURKA turned out to be largely unsuccessful. Meanwhile, recent discoveries pointed at new functions of AURKA at the subcellular level, including at mitochondria. At this location, AURKA induces organelle clearance by mitophagy by acting in complex with the mitophagy mediator LC3, and its inner mitochondrial membrane receptor PHB2. The natural polyphenol xanthohumol was shown to act as a PHB2 ligand, altering the interaction between AURKA and PHB2 and restoring mitochondrial functions in cancer cells. However, its chemical nature prevents its broader use as an anti-cancer agent."
296,RCoxNet: deep learning framework for enhanced cancer survival prediction integrating random walk with restart with mutation and clinical data,"Stuti Kumari, Sakshi Gujral, Smruti Panda, Prashant Gupta, Gaurav Ahuja, Debarka Sengupta",https://www.biorxiv.org/content/10.1101/2024.09.17.613428v2,"Cancer poses a significant global health challenge, characterized by a complex disease progression and disrupted growth regulation. A thorough understanding of cellular and molecular biological mechanisms is essential for developing novel treatments and improving the accuracy of patient survival predictions. While prior studies have leveraged gene expression and clinical data to forecast survival outcomes through current machine learning and deep learning approaches, gene mutation data—despite being a widely recognized metric—has rarely been incorporated due to its limited information, inadequate representation of gene relationships, and data sparsity, which negatively affects the robustness, effectiveness, and interpretability of current survival analysis approaches. To overcome the challenges of mutation data sparsity, we propose RCoxNet, a novel deep learning neural network framework that integrates the Random Walk with Restart (RWR) algorithm with a deep learning Cox Proportional Hazards model. By applying this framework to mutation data from cBioportal, our model achieved an average concordance index of 0.62 ± 0.05 across four cancer types, outperforming existing deep neural network models. Additionally, we identified clinical features critical for differentiating between predicted high- and low-risk patients, with the relevance of these features being partially supported by previous studies."
297,TGFβ-ANGPT2-Tie2 axis in cancer-associated fibroblasts reprograms oral cancer cells to embryonic-like cell state with predictive significance of poor prognosis,"Paromita Mitra, Uday Saha, Kingsly Joshua Stephen, Priyanka Prasad, Ankit Kumar Patel, BV Harshvardhan, Santosh Kumar Mondal, Sillarine Kurkalang, Sumitava Roy, Arnab Ghosh, Shantanu Saha Roy, Jayasri Das Sarma, Nidhan Kumar Biswas, Moulinath Acharya, Rajeev Sharan, Pattatheyil Arun, Mohit Kumar Jolly, Arindam Maitra, Sandeep Singh",https://www.biorxiv.org/content/10.1101/2024.06.29.601319v1,"Myofibroblastic cancer-associated fibroblasts (CAFs) in tumor stroma is identified as poor-prognostic indicator in oral cancer; however, biological mechanisms are largely unexplored. Here, we discovered the role of autocrine or exogenous transforming growth factor beta (TGFβ) in inducing Tunica Interna Endothelial cell kinase 2 (Tie2) -signaling through histone deacetylase-mediated downregulation of Tie2-antagonist, Angiopoietin-2 in CAFs, responsible for induction and maintenance of myofibroblastic differentiation. To understand the influence of CAF-specific Tie2-signaling on cancer cell properties, we performed CAF-Cancer cell co-culture and its single-cell RNA sequencing (scRNA-Seq). Distinct clustering of CAFs suggested their transcriptional heterogeneity, driven by TGFβ-Tie2 activation. Interestingly, CAF-specific Tie2-signaling was responsible to reprogram cancer cells, producing embryonic-like cell state with increased stemness and EMT signatures. Importantly, both the Tie2-specific gene expression signature as well as reprogrammed cancer cell specific gene expression modules were validated respectively in fibroblasts clusters and malignant cell clusters in two independent earlier reported scRNAseq studies of HNSCC tumors. Highlighting the translatability of our study, the gene expression signature derived from reprogrammed cancer cells showed significant association with poor prognosis in HNSCC patient of TCGA cohort. Pharmacological inhibition of Tie2-signaling in CAFs, significantly abrogated the tumor initiating ability of co-cultured oral cancer cell lines. Overall, combining our molecular and computational analysis, we may propose Tie2 as a novel factor responsible for CAF mediated cancer cell plasticity, associated with aggressive nature of oral cancer."
298,HYENA detects oncogenes activated by distal enhancers in cancer,"Anqi Yu, Ali E. Yesilkanal, Ashish Thakur, Fan Wang, Yang Yang, William Phillips, Xiaoyang Wu, Alexander Muir, Xin He, Francois Spitz, Lixing Yang",https://www.biorxiv.org/content/10.1101/2023.01.09.523321v3,"Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm “HYENA” to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1,146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression."
299,STING-Activating Polymer-Drug Conjugates for Cancer Immunotherapy,"Taylor L. Sheehy, Alexander J. Kwiatkowski, Karan Arora, Blaise R. Kimmel, Jacob A. Schulman, Katherine N. Gibson-Corley, John T. Wilson",https://www.biorxiv.org/content/10.1101/2024.03.23.585817v2,"The stimulator of interferon genes (STING) pathway links innate and adaptive antitumor immunity and therefore plays an important role in cancer immune surveillance. This has prompted widespread development of STING agonists for cancer immunotherapy, but pharmacological barriers continue to limit the clinical impact of STING agonists and motivate the development of drug delivery systems to improve their efficacy and/or safety. To address these challenges, we developed SAPCon, a STING-activating polymer-drug conjugate platform based on strain-promoted azide-alkyne cycloaddition of dimeric-amidobenzimidazole (diABZI) STING agonists to hydrophilic polymer chains through an enzyme-responsive chemical linker. To synthesize a first-generation SAPCon, we designed a diABZI prodrug modified with a DBCO reactive handle with a cathepsin B-cleavable spacer for intracellular drug release and conjugated this to pendant azide groups on a 100kDa poly(dimethyla acrylamide-co-azide methacrylate) copolymer backbone to increase circulation time and enable passive tumor accumulation. We found that intravenously administered SAPCon accumulated at tumor sites, where it was endocytosed by tumor-associated myeloid cells, resulting in increased STING activation in tumor tissue. Consequently, SAPCon promoted an immunogenic tumor microenvironment, characterized by increased frequency of activated macrophages and dendritic cells and improved infiltration of CD8+ T cells, resulting in inhibition of tumor growth, prolonged survival, and enhanced response to anti-PD-1 immune checkpoint blockade in orthotopic breast cancer models. Collectively, these studies position SAPCon as a modular and programmable platform for improving the efficacy of systemically administered STING agonists for cancer immunotherapy."
302,Mechano-metabolism of metastatic breast cancer cells in 2D and 3D microenvironments,"Anuja Jaganathan, Joshua Toth, Xingyu Chen, Ramin Basir, Laurent Pieuchot, Yihui Shen, Cynthia Reinhart-King, Vivek B. Shenoy",https://www.biorxiv.org/content/10.1101/2024.04.30.591879v2,"Cells regulate their shape and metabolic activity in response to the mechano-chemical properties of their microenvironment. To elucidate the impact of matrix stiffness and ligand density on the bioenergetics of mesenchymal cells, we developed a nonequilibrium, active chemo-mechanical model that accounts for the mechanical energy of the cell and matrix, chemical energy from ATP hydrolysis, interfacial energy, and mechano-sensitive regulation of stress fiber assembly through signaling. By integrating the kinetics and energetics of these processes, we define the cell “metabolic potential” that, when minimized, provides testable predictions of cell contractility, shape, and ATP consumption. Specifically, we show that the morphology of MDA-MB-231 breast cancer cells in 3D collagen changes from spherical to elongated to spherical with increasing matrix stiffness, which is consistent with experimental observations. On 2D hydrogels, our model predicts a hemispherical-to-spindle-to-disc shape transition with increasing gel stiffness. In both cases, we show that these shape transitions emerge from competition between the energy of ATP hydrolysis associated with increased contractility that drives cell elongation and the interfacial energy that favors a rounded shape. Furthermore, our model can predict how increased energy demand in stiffer microenvironments is met by AMPK activation, which is confirmed experimentally in both 2D and 3D microenvironments and found to correlate with the upregulation of mitochondrial potential, glucose uptake, and ATP levels, as well as provide estimates of changes in intracellular adenosine nucleotide concentrations with changing environmental stiffness. Overall, we present a framework for relating adherent cell energy levels and contractility through biochemical regulation of underlying physical processes."
305,Monitoring of Cell-free Human Papillomavirus DNA in Metastatic or Recurrent Cervical Cancer: Clinical Significance and Treatment Implications,"Zhuomin Yin, Tao Feng, Qing Xu, Wumin Dai, Maowei Ni, Juan Ni, Hanmei Lou",https://www.biorxiv.org/content/10.1101/2024.09.16.613189v1,"Purpose Monitoring of circulating human papillomavirus (HPV) cell-free DNA (cfDNA) is a minimally invasive approach for surveillance in HPV-associated cancers, particularly cervical cancer. The aim of this study was to monitor circulating HPV cfDNA levels in patients with recurrent or metastatic cervical cancer during treatment and follow-up to assess the utility of HPV cfDNA as a tumor marker for disease surveillance and in guiding clinical treatment decisions."
306,Drug-loaded nanoparticles for cancer therapy: a high-throughput multicellular agent-based modeling study,"Yafei Wang, Elmar Bucher, Heber Rocha, Vikram Jadhao, John Metzcar, Randy Heiland, Hermann B. Frieboes, Paul Macklin",https://www.biorxiv.org/content/10.1101/2024.04.09.588498v2,"Interactions between biological systems and engineered nanomaterials have become an important area of study due to the application of nanomaterials in medicine. In particular, the application of nanomaterials for cancer diagnosis or treatment presents a challenging opportunity due to the complex biology of this disease spanning multiple time and spatial scales. A system-level analysis would benefit from mathematical modeling and computational simulation to explore the interactions between anticancer drug-loaded nanoparticles (NPs), cells, and tissues, and the associated parameters driving this system and a patient’s overall response. Although a number of models have explored these interactions in the past, few have focused on simulating individual cell-NP interactions. This study develops a multicellular agent-based model of cancer nanotherapy that simulates NP internalization, drug release within the cell cytoplasm, “inheritance” of NPs by daughter cells at cell division, cell pharmacodynamic response to the intracellular drug, and overall drug effect on tumor dynamics. A large-scale parallel computational framework is used to investigate the impact of pharmacokinetic design parameters (NP internalization rate, NP decay rate, anticancer drug release rate) and therapeutic strategies (NP doses and injection frequency) on the tumor dynamics. In particular, through the exploration of NP “inheritance” at cell division, the results indicate that cancer treatment may be improved when NPs are inherited at cell division for cytotoxic chemotherapy. Moreover, smaller dosage of cytostatic chemotherapy may also improve inhibition of tumor growth when cell division is not completely inhibited."
308,MiCK: a database of gut microbial genes linked with chemoresistance in cancer patients,"Muhammad Shahzaib, Haseeb Manzoor, Hasnain Zubair, Farzana Jabeen, Masood Ur Rehman Kayani",https://www.biorxiv.org/content/10.1101/2024.07.24.604921v1,"Cancer remains a global health challenge, with significant morbidity and mortality rates. In 2020, cancer caused nearly 10 million deaths, making it the second leading cause of death worldwide. However, the emergence of chemoresistance becomes a major hurdle in successfully treating patients. Human gut microbes have been recognized for their role in modulating drug efficacy through their metabolites, ultimately leading to chemoresistance. The available databases are currently limited to knowledge regarding the interactions between gut microbiome and drugs. However, a database containing the human gut microbial gene sequences, and their effect on the efficacy of chemotherapy for cancer patients has not yet been reported. To address this challenge, we present the Microbial Chemoresistance Knowledgebase (MiCK), a comprehensive database cataloging microbial gene sequences associated with chemoresistance cancers. MiCK contains 1.6 million sequences of 29 gene types linked to chemoresistance and drug metabolism, curated manually from recent literature and sequence databases. The database supports efficient data retrieval and analysis, providing a user-friendly web interface for sequence search and download functionalities. MiCK aims to facilitate the understanding and mitigation of chemoresistance in cancers by serving as a valuable resource for researchers."
310,Systematic Multi-Omics Investigation of Androgen Receptor Driven Gene Expression and Epigenetics changes in Prostate Cancer,"Lin Li, Kyung Hyun Cho, Xiuping Yu, Siyuan Cheng",https://www.biorxiv.org/content/10.1101/2024.07.22.604505v1,"Background: Prostate cancer, a common malignancy, is driven by androgen receptor (AR) signaling. Understanding the function of AR signaling is critical for prostate cancer research. Methods: We performed multi-omics data analysis for the AR+, androgen-sensitive LNCaP cell line, focusing on gene expression (RNAseq), chromatin accessibility (ATACseq), and transcription factor binding (ChIPseq). High-quality datasets were curated from public repositories and processed using state-of-the-art bioinformatics tools. Results: Our analysis identified 1004 up-regulated and 707 down-regulated genes in response to androgen deprivation therapy (ADT) which diminished AR signaling activity. Gene-set enrichment analysis revealed that AR signaling influences pathways related to neuron differentiation, cell adhesion, P53 signaling, and inflammation. ATACseq and ChIPseq data demonstrated that as a transcription factor, AR primarily binds to distal enhancers, influencing chromatin modifications without affecting proximal promoter regions. In addition, the AR-induced genes maintained higher active chromatin states than AR-inhibited genes, even under ADT conditions. Furthermore, ADT did not directly induce neuroendocrine differentiation in LNCaP cells, suggesting a complex mechanism behind neuroendocrine prostate cancer development. In addition, a publicly available online application LNCaP-ADT (https://pcatools.shinyapps.io/shinyADT/) was launched for users to visualize and browse data generated by this study. Conclusion: This study provides a comprehensive multi-omics dataset, elucidating the role of AR signaling in prostate cancer at the transcriptomic and epigenomic levels. The reprocessed data is publicly available, offering a valuable resource for future prostate cancer research."
311,The Orphan G Protein-Coupled Receptor GPR52 is a Novel Regulator of Breast Cancer Multicellular Organization,"Sarah Z. Hanif, CheukMan Cherie Au, Ingrid Torregroza, Syeda Y. Jannath, Tabassum Fabiha, Bhavneet Bhinder, Michael Washburn, Dominic Devost, Shuchen Liu, Priya Bhardwaj, Todd Evans, Pradeep Kumar Anand, Robert Tarran, Sailesh Palikhe, Olivier Elemento, Lukas Dow, John Blenis, Terence E. Hébert, Kristy A. Brown",https://www.biorxiv.org/content/10.1101/2024.07.22.604482v1,"G protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors and transmit critical signals from the extracellular to the intracellular spaces. Transcriptomic data of resected breast tumors shows that low mRNA expression of the orphan GPCR GPR52 correlates with reduced overall survival in breast cancer patients, leading to the hypothesis that loss of GPR52 supports breast cancer progression. CRISPR-Cas9 was used to knockout GPR52 in human triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, and in the non-cancerous breast epithelial cell line, MCF10A. Loss of GPR52 was found to be associated with increased cell-cell interaction in 2D cultures, altered 3D spheroid morphology, and increased propensity to organize and invade collectively in Matrigel. Furthermore, GPR52 loss was associated with features of EMT in MDA-MB-468 cells. To determine the in vivo impact of GPR52 loss, MDA-MB-468 cells were injected into zebrafish and loss of GPR52 was associated with a greater total cancer area compared to control cells. RNA-sequencing and proteomic analyses of GPR52-null breast cancer cells reveal an increased cAMP signaling signature. Consistently, we found that treatment of wild-type (WT) cells with forskolin, which stimulates production of cAMP, induces some phenotypic changes associated with GPR52 loss, and inhibition of cAMP production rescued some of the GPR52 KO phenotypes. Overall, our results reveal GPR52 loss as a potential mechanism by which breast cancer progression may occur and support the investigation of GPR52 agonism as a therapeutic option in breast cancer."
312,DriverOmicsNet: An Integrated Graph Convolutional Network for Multi-Omics Exploration of Cancer Driver Genes,"Yang-Hong Dai, Chia-Jun Chang, Po-Chien Shen, Wun-Long Jheng, Yu-Guang Chen",https://www.biorxiv.org/content/10.1101/2024.07.21.604474v1,Background Cancer is a complex and heterogeneous group of diseases driven by genetic mutations and molecular changes. Identifying and characterizing cancer driver genes (CDgs) is crucial for understanding cancer biology and guiding precision oncology. Integrating multi-omics data can reveal the intricate molecular interactions underlying cancer progression and treatment responses.
313,A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism,"Omid Hajihassani, Mehrdad Zarei, Asael Roichman, Alexander Loftus, Christina S. Boutros, Jonathan Hue, Parnian Naji, Jacob Boyer, Soubhi Tahan, Peter Gallagher, William Beegan, James Choi, Shihong Lei, Christine Kim, Moeez Rathore, Faith Nakazzi, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J. Lund, Luke D. Rothermel, Joshua D. Rabinowitz, Jordan M. Winter",https://www.biorxiv.org/content/10.1101/2024.07.19.604377v1,"Pancreatic cancer is the third leading cause of cancer death in the United States, and while conventional chemotherapy remains the standard treatment, responses are poor. Safe and alternative therapeutic strategies are urgently needed1. A ketogenic diet has been shown to have anti-tumor effects across diverse cancer types but will unlikely have a significant effect alone. However, the diet shifts metabolism in tumors to create new vulnerabilities that can be targeted (1). Modulators of glutamine metabolism have shown promise in pre-clinical models but have failed to have a marked impact against cancer in the clinic. We show that a ketogenic diet increases TCA and glutamine-associated metabolites in murine pancreatic cancer models and under metabolic conditions that simulate a ketogenic diet in vitro. The metabolic shift leads to increased reliance on glutamine-mediated anaplerosis to compensate for low glucose abundance associated with a ketogenic diet. As a result, glutamine metabolism inhibitors, such as DON and CB839 in combination with a ketogenic diet had robust anti-cancer effects. These findings provide rationale to study the use of a ketogenic diet with glutamine targeted therapies in a clinical context."
314,Downregulation of acetyl-CoA carboxylase suppresses the malignant progression of oral cancer,Guodong Jia,https://www.biorxiv.org/content/10.1101/2024.07.21.604509v1,"In this study, we aimed to investigate the specific role of the acetyl-CoA carboxylase (ACACA) gene in Oral squamous cell carcinoma (OSCC). we constructed Human Tongue Carcinoma Cell Line (SAS cell line) with low ACACA expression and evaluated changes in their cell cycle, proliferation, and metabolite levels. Furthermore, the effect of ACACA on tumor formation in vivo was determined. ACACA knockdown significantly reduced the proliferation ability of SAS cells, while also significantly increasing the number of apoptotic cells. In vivo experiments demonstrated lower tumor volume and weight in the ACACA knockdown group than those in the control group. Exploring the combined effect of ACACA knockdown and cisplatin treatment revealed a promising synergistic effect against ferroptosis signaling and downstream signaling pathways in SAS cells and in vivo. These findings suggest that targeting the ACACA gene has the potential to be a novel therapeutic strategy for oral cancer treatment."
318,Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment,"Zhuoyao Chen, Gamma Chi, Timea Balo, Xiangrong Chen, Beatriz Montes, Steven C Clifford, Timea Szabo, Arpad Kiss, András Herner, András Kotschy, Alex N Bullock",https://www.biorxiv.org/content/10.1101/2024.09.12.612738v1,"Neomorphic mutations and drugs can elicit unanticipated effects that hinder mechanistic understanding for clinical practice. Recurrent indel mutations in the Kelch domain of the KBTBD4 E3 ligase rewire epigenetic programs for stemness in medulloblastoma by recruiting LSD1-CoREST-HDAC1/2 complexes as neo-substrates for ubiquitination and degradation. Remarkably, UM171, an investigational drug for haematopoietic stem cell transplantation, was found to degrade LSD1-CoREST-HDAC1/2 complexes in a wild-type KBTBD4-dependent manner, suggesting a potential common mode of action. We identified that these neomorphic interactions were mediated by the HDAC deacetylase domain. Cryo-EM studies of both wild-type and mutant KBTBD4 captured 2:1 and 2:2 KBTBD4-HDAC2 complexes at resolutions spanning 2.7 Å to 3.1 Å. The mutant and drug-induced complexes adopted similar structural assemblies requiring both Kelch domains in the KBTBD4 dimer for each HDAC2 interaction. UM171 was identified as a bona fide molecular glue binding across the ternary interface. Most strikingly, the indel mutation reshaped the same surface of KBTBD4 providing the first example of a natural mimic of a molecular glue. Together, the structures provide mechanistic understanding of neomorphic KBTBD4 and help to explain the structure-activity relationships of UM171 derivatives for future drug design."
319,bayesReact: Expression-coupled regulatory motif analysis detects microRNA activity in cancer and at the single cell level,"Asta M. Rasmussen, Alexandre Bouchard-Côté, Jakob S. Pedersen",https://www.biorxiv.org/content/10.1101/2024.09.10.612047v1,"Motivation Regulatory constraints are crucial in maintaining tissue and cell integrity, and play important roles during developmental processes and environmental responses. Yet many regulatory mechanisms remain unobserved at the single-cell level and statistical inference may, in some cases, help elucidate their condition-specific activity and perturbation during disease progression."
320,Computational investigation of missense somatic mutations in cancer and potential links to pH-dependence and proteostasis,"Shalaw Sallah, Jim Warwicker",https://www.biorxiv.org/content/10.1101/2024.07.17.603952v1,"Metabolic changes during tumour development lead to acidification of the extracellular environment and a smaller increase of intracellular pH. Searches for somatic missense mutations that could reveal adaptation to altered pH have focussed on arginine to histidine changes, part of a general arginine depletion that originates from DNA mutational mechanisms. Analysis of mutations to histidine, potentially a simple route to the introduction of pH-sensing, shows no clear biophysical separation overall of subsets that are more and less frequently mutated in cancer genomes. Within the more frequently mutated subset, individual sites predicted to mediate pH-dependence upon mutation include NDST1 (a Golgi-resident heparan sulphate modifying enzyme), the HLA-C chain of MHCI complex, and the water channel AQP-7. Arginine depletion is a general feature that persists in the more frequently mutated subset, and is complemented by over-representation of mutations to lysine. Arginine to lysine balance is a known factor in determining protein solubility, with higher lysine content being more favourable. Proteins with greater change in arginine to lysine balance are enriched for cell periphery location, where proteostasis is likely to be challenged in tumour cells. Somatic missense mutations in a cancer genome number only in the 10s typically, although can be much higher. Whether the altered arginine to lysine balance is of sufficient scale to play a role in tumour development is unknown."
321,TIPE drives a cancer stem-like phenotype by promoting glycolysis via PKM2/HIF-1α axis in melanoma,"Maojin Tian, Le Yang, Ziqian Zhao, Jigang Li, Lianqing Wang, Qingqing Yin, Wei Hu, Yunwei Lou, Jianxin Du, Peiqing Zhao",https://www.biorxiv.org/content/10.1101/2023.11.14.567124v3,"TIPE (TNFAIP8) has been identified as an oncogene and participates in tumor biology. However, how its role in the metabolism of tumor cells during melanoma development remains unclear. Here, we demonstrated that TIPE promoted glycolysis by interacting with pyruvate kinase M2 (PKM2) in melanoma. We found that TIPE induced PKM2 dimerization, thereby facilitating its translocation from the cytoplasm to the nucleus. TIPE-mediated PKM2 dimerization consequently promoted HIF-1α activation and glycolysis, which contributed to melanoma progression and increased its stemness features. Notably, TIPE specifically phosphorylated PKM2 at Ser 37 in an ERK-dependent manner. Consistently, the expression of TIPE was positively correlated with the levels of PKM2 Ser37 phosphorylation and cancer stem cell markers in melanoma tissues from clinical samples and tumor bearing mice. In summary, our findings indicate that the TIPE/PKM2/HIF-1α signaling pathway plays a pivotal role in promoting cancer stem cell properties by facilitating the glycolysis, which would provide a promising therapeutic target for melanoma intervention."
322,A critical role of protein damage response in mediating cancer drug resistance,"Fangyuan Shao, Jie Li, Hao Xiao, Ling Li, Bo Li, YuJun Chen, Xiangpeng Chu, Maoxin Ran, Dongyang Tang, Yuzhong Peng, Yujian Huang, Lijian Wang, Yanxia Shi, Nan Shao, Kai Miao, Changhua Zhang, Ying Lin, Jun Yan, Kin Yip Tam, Xiaoling Xu, Chu-Xia Deng",https://www.biorxiv.org/content/10.1101/2024.07.17.603840v1,"Multidrug resistance (MDR) frequently occurs during cancer therapy and remains a major obstacle for the cure of most cancers(1, 2). Drug resistance could exist intrinsically or be acquired by drug treatment(3–5), yet factors that regulate the resistance remain elusive. Here, we show that most anticancer drugs damage neosynthesized proteins prior to reaching their canonic targets and elicit profound cytotoxicity, which is largely compensated by protein damage response (PDR). We demonstrate that the PDR includes damage recognition and clearance that are mainly mediated by ubiquitin and proteasome systems, although some other factors, including cellular ATP levels and proliferation status, are also involved. We show that cancer stem cells (CSCs), which have lower protein synthesis, and drug resistance acquired cells (DRAC), which have higher proteasome activity, are more resistant than other cells. We further demonstrate that ATP promotes protein synthesis and suppresses proteasome activity, thus, increasing mitochondrial ATP production by PDK1 inhibition and using proteasome inhibitor to block protein damage clearance render CSCs and DRACs more vulnerable to anticancer drugs. Thus, patients with drug-resistant cancers and treatment-naïve patients with low ATP levels and/or high proteasome activity can be identified and subtyped, and therapies containing PDK1-I and/or proteasome-I may be effective options for these patients."
323,A foundation model for generalizable cancer diagnosis and survival prediction from histopathological images,"Zhaochang Yang, Ting Wei, Ying Liang, Xin Yuan, Ruitian Gao, Yujia Xia, Jie Zhou, Yue Zhang, Zhangsheng Yu",https://www.biorxiv.org/content/10.1101/2024.05.16.594499v2,"Computational pathology, utilizing whole slide image (WSI) for pathological diagnosis, has advanced the development of intelligent healthcare. However, the scarcity of annotated data and histological differences hinder the general application of existing methods. Extensive histopathological data and the robustness of self-supervised models in small-scale data demonstrate promising prospects for developing foundation pathology models. Due to the need for deployment, lightweight foundation models also need to be developed. In this work, we propose the BEPH (BEiT-based model Pre-training on Histopathological images), a general lightweight foundation model that leverages self-supervised learning to learn meaningful representations from 11 million unlabeled histopathological images. These representations are then efficiently adapted to various tasks, including 2 cancer patch-level recognition tasks, 3 cancer WSI-level classification tasks, and 6 cancer subtypes survival prediction tasks. Experimental results demonstrate that our model consistently outperforms several comparative models with similar parameters, even with limited training data reduced to 50%. Especially when the downstream structure is the same, the model can improve ResNet and DINO by up to a maximum increase of 8.8% and 7.2% (WSI level classification), and 6.44% and 3.28% on average (survival prediction), respectively. Therefore, BEPH offers a universal solution to enhance model performance, reduce the burden of expert annotations, and enable widespread clinical applications of artificial intelligence. The code and models can be obtained at https://github.com/Zhcyoung/BEPH. And currently, online fine-tuning of WSI classification tasks is available for use on http://yulab-sjtu.natapp1.cc/BEPH."
324,Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells,"Kira Pugh, Rhys DO Jones, Gibin Powathil, Sara Hamis",https://www.biorxiv.org/content/10.1101/2024.04.29.591633v2,"The interplay between drug-sensitive and drug-resistant cancer cells has been observed to impact cell-to-cell interactions in experimental settings. However, the role that space plays in these interactions remains unclear. In this study, we develop mathematical models to investigate how spatial factors affect cell-to-cell competition between drug-sensitive and drug-resistant cancer cells in silico. We develop two baseline models to study cells from the epithelial FaDu cell line subjected to two drugs, specifically the ATR inhibitor ceralasertib and the PARP inhibitor olaparib, that target DNA damage response pathways. Our baseline models are: (1) a temporally resolved ordinary differential equation (ODE) model, and (2) a spatio-temporally resolved agent-based model (ABM). The models simulate cells in well-mixed and spatially structured cell systems, respectively. The ODE model is calibrated against in vitro data and is thereafter mapped onto the baseline ABM which, in turn, is extended to enable a simulation-based investigation on how spatial factors impact cell-to-cell competition. Simulation results from the extended ABMs demonstrate that the in silico treatment responses are simultaneously affected by: (i) the initial spatial cell configurations, (ii) the initial fraction of drug-resistant cells, (iii) the drugs to which cells express resistance, (iv) drug combinations, (v) drug doses, and (vi) the doubling time of drug-resistant cells compared to the doubling time of drug-sensitive cells. These results reveal that spatial structures of the simulated cancer cells affect both cell-to-cell interactions, and the impact that these interactions have on the ensuing population dynamics. This leads us to suggest that the role that space plays in cell-to-cell interactions should be further investigated and quantified in experimental settings."
325,Learning and actioning general principles of cancer cell drug sensitivity,"Francesco Carli, Pierluigi Di Chiaro, Mariangela Morelli, Chakit Arora, Luisa Bisceglia, Natalia De Oliveira Rosa, Alice Cortesi, Sara Franceschi, Francesca Lessi, Anna Luisa Di Stefano, Orazio Santonocito, Francesco Pasqualetti, Paolo Aretini, Pasquale Miglionico, Giuseppe R. Diaferia, Fosca Giannotti, Pietro Liò, Miquel Duran-Frigola, Chiara Maria Mazzanti, Gioacchino Natoli, Francesco Raimondi",https://www.biorxiv.org/content/10.1101/2024.03.28.586783v2,"High-throughput screening platforms for the profiling of drug sensitivity of hundreds of cancer cell lines (CCLs) have generated large datasets that hold the potential to unlock targeted, anti-tumor therapies."
326,HERV-derived epitopes represent new targets for T-cell based immunotherapies in ovarian cancer,"Paola Bonaventura, Olivier Tabone, Yann Estornes, Audrey Page, Virginie Mutez, Marie Delles, Sarah Moran, Clarisse Dubois, Marjorie Lacourrege, Dina Tawfik, Ema Etchegaray, Adrian Valente, Rasha E. Boulos, Gabriel Jimenez Dominguez, Nicolas Chuvin, Nicolas Gadot, Qing Wang, Jenny Valladeau-Guilemond, Stéphane Depil",https://www.biorxiv.org/content/10.1101/2024.07.13.603392v1,Background Ovarian cancer represents the most lethal gynecological cancer with poor results of checkpoint inhibitors. Human endogenous retroviruses (HERVs) are aberrantly expressed by tumor cells and may represent a source of shared T cell epitopes for cancer immunotherapy regardless of the tumor mutational burden.
327,Androgen receptor plays critical role in regulating cervical cancer cell migration,"Sarpita Bose, Subhrangshu Das, Sebabrata Maity, Oishee Chakrabarti, Saikat Chakrabarti",https://www.biorxiv.org/content/10.1101/2024.07.13.603408v1,"Cervical cancer (CC) is the second most common cancer among women in India and the fourth worldwide. While major genes and pathways have been studied, further research is needed to identify candidates for targeted therapy in metastatic disease. This study used a network biology approach to identify key genes in disease progression. Stage-specific cervical cancer protein-protein interaction networks (PPIN) were constructed by overlaying stage-specific, patient-derived transcriptomics data onto a human protein-protein interaction network (HPPIN). Graph-theory-based network analysis identified important interacting proteins (IIPs) with maximum connectivity, high centrality scores, and significant global and local network perturbation scores. Among the identified IIPs, the Androgen receptor (AR) emerged as one of the crucial yet understudied regulator in cervical cancer. Patient samples and in vitro experiments showed significant downregulation in cervical cancer. Ligand-dependent overexpression of AR reduced cancer cell migration while failed to induce apoptosis in CC cell lines. Downregulation of mesenchymal markers and restoration of epithelial markers suggested AR’s potential in reversing invasive properties of cervical cancer cells. AR overexpression upregulated its downstream target PTEN and restored GSK3β activity by interfering with AKT phosphorylation, probably leading to degradation of mesenchymal markers. Further studies showed AR reduced cell motility by hindering focal adhesion formation and Actin filament assembly. An increased G-Actin ratio suggested AR disrupted cytoskeletal dynamics through the RhoA/ROCK1/LIMK1/CFL1 pathway, impeding cervical cancer cell spread."
328,Engineering PEG10 assembled endogenous virus-like particles with genetically encoded neoantigen peptides for cancer vaccination,"Ruijing Tang, Luobin Guo, Tingyu Wei, Tingting Chen, Huan Yang, Honghao Ye, Fangzhou Lin, Yongyi Zeng, Haijun Yu, Zhixiong Cai, Xiaolong Liu",https://www.biorxiv.org/content/10.1101/2024.04.25.591213v2,"Tumor neoantigen peptide vaccines hold potential for boosting cancer immunotherapy, yet efficiently co-delivering peptides and adjuvants to antigen-presenting cells in vivo remains challenging. Virus-like particle (VLP), which is a kind of multiprotein structure organized as virus, can deliver therapeutic substances into cells and stimulate immune response. However, the weak targeted delivery of VLP in vivo and its susceptibility to neutralization by antibodies hinder their clinical applications. Here, we firstly designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous VLP (eVLP) with high protein loading and transfection efficiency. Then, an engineered tumor vaccine, named ePAC, was developed by packaging genetically encoded neoantigen into eVLP with further modification of CpG-ODN on its surface to serve as an adjuvant and targeting unit to dendritic cells (DCs). Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells. Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy. Overall, these results support that ePAC could be safely utilized as cancer vaccines for antitumor therapy, showing significant potential for clinical translation."
329,MAGE-A4-Responsive Plasma Cells Promote Non-Small Cell Lung Cancer,"Dominique Armstrong, Cheng-Yen Chang, Monica J. Hong, Linda Green, William Hudson, Yichao Shen, Li-Zhen Song, Sheetal Jammi, Benjamin Casal, Chad J. Creighton, Alexandre Carisey, Xiang H.-F. Zhang, Neil J. McKenna, Sung Wook Kang, Hyun-Sung Lee, David B. Corry, Farrah Kheradmand",https://www.biorxiv.org/content/10.1101/2024.07.10.602985v1,"Adaptive immunity is critical to eliminate malignant cells, while multiple tumor-intrinsic factors can alter this protective function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in several solid tumors and correlates with poor survival in non-small cell lung cancer (NSCLC), but its role in altering antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of PTEN, a tumor suppressor, in human NSCLC. Here we show that constitutive expression of human MAGE-A4 combined with the loss of Pten in mouse airway epithelial cells results in metastatic adenocarcinoma enriched in CD138+ CXCR4+ plasma cells, predominantly expressing IgA. Consistently, human NSCLC expressing MAGE-A4 showed increased CD138+ IgA+ plasma cell density surrounding tumors. The abrogation of MAGE-A4-responsive plasma cells (MARPs) decreased tumor burden, increased T cell infiltration and activation, and reduced CD163+CD206+ macrophages in mouse lungs. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA+ MARPs in the lungs."
330,Unbiased functional genetic screens reveal essential RNA modifications in human cancer and drug resistance,"Cornelius Pauli, Michael Kienhöfer, Maximilian Felix Blank, Oguzhan Begik, Christian Rohde, Daniel Heid, Fu Xu, Sarah Miriam Naomi Zimmermann, Katharina Weidenauer, Sylvain Delaunay, Nadja Krall, Katrin Trunk, Duoduo Zhao, Fengbiao Zhou, Anke Heit-Mondrzyk, Uwe Platzbecker, Claudia Baldus, Hubert Serve, Martin Bornhäuser, Cathrine Broberg Vågbø, Salvador Aznar Benitah, Jeroen Krijgsveld, Eva Maria Novoa, Carsten Müller-Tidow, Michaela Frye",https://www.biorxiv.org/content/10.1101/2024.07.13.603368v1,"RNA modification pathways are mis-regulated in multiple types of human cancer. To comprehensively identify cancer-relevant RNA modifications and their regulators, we screened all 150 annotated human RNA modifying proteins across 18 different normal and cancer cell lines using a CRISPR-based genetic knockout system. Fifty RNA modifying proteins were essential for survival of at least one cell type. A third of these essential genes were amplified in 38 different human primary cancer types and potentially drive cancer growth. Unexpectedly, the number of essential genes per cell line varied considerably, and this variation was not due to tissue of origin. Instead, we found that cancer cell-specific mitochondrial metabolic plasticity was responsible for the unique requirement of certain RNA modifications. For example, leukemia cells with high intrinsic drug tolerance required mitochondrial flexibility to survive treatment with the anti-leukemic drugs cytarabine and venetoclax. Synthetic lethality screens revealed that drug-resistance is abolished by deleting the mitochondrial methyltransferase TRMT5, which is responsible for the formation of N1-methylguanosine (m1G) in the tRNA anticodon loop. In summary, our study identifies cancer-relevant RNA modifying enzymes, and reveals a novel promising drug target for therapy-resistant acute myeloid leukemia."
332,An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment,"Kai Chen, Patrick Ernst, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D. Ringel, Xiaoguang “Margaret” Liu, Lufang Zhou",https://www.biorxiv.org/content/10.1101/2024.03.24.584499v1,"Targeting cancer cell mitochondria holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we introduce mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. We synthesize a blue light-gated channelrhodopsin (CoChR) in the IMM and co-express a blue bioluminescence-emitting Nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes are selectively delivered to cancer cells in vivo by using adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV. Induction with NLuc luciferin elicits robust endogenous bioluminescence, which activates mitochondrial CoChR, triggering cancer cell IMM permeability disruption, mitochondrial damage, and subsequent cell death. Importantly, mLumiOpto demonstrates remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma or triple-negative breast cancer xenografted mouse models. These findings establish mLumiOpto as a novel and promising therapeutic strategy by targeting cancer cell mitochondria in vivo."
334,Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production,"Allison C. Sharrow, Emily Megill, Amanda J. Chen, Afifa Farooqi, Stacy McGonigal, Nadine Hempel, Nathaniel W. Snyder, Ronald J. Buckanovich, Katherine M. Aird",https://www.biorxiv.org/content/10.1101/2024.07.12.603313v1,"Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response."
335,Sulfonylurea receptor coupled conductances alter the performace of two central pattern generating circuits in Cancer borealis,"Sonal Kedia, Naziru M. Awal, Jackie Seddon, Eve Marder",https://www.biorxiv.org/content/10.1101/2024.07.09.602760v1,"Neuronal activity and energy supply must maintain a fine balance for neuronal fitness. Various channels of communication between the two could impact network output in different ways. Sulfonylurea receptors (SURs) are a modification of ATP-binding cassette proteins (ABCs) that confer ATP-dependent gating on their associated ion channels. They are widely expressed and link metabolic states directly to neuronal activity. The role they play varies in different circuits, both enabling bursting and inhibiting activity in pathological conditions. The crab, Cancer borealis, has central patterns generators (CPGs) that fire in rhythmic bursts nearly constantly and it is unknown how energy availability influences these networks. The pyloric network of the stomatogastric ganglion (STG) and cardiac ganglion (GC) control rhythmic contractions of the foregut and heart respectively. Pharmacological manipulation of SURs results in opposite effects in the two CPGs. Neuronal firing completely stops in the STG when SUR-associated channels are open, and firing increases when the channels are closed. This results from a decrease in the excitability of pyloric dilator (PD) neurons, which are a part of the pacemaker kernel. The neurons of the CG, paradoxically, increase firing within bursts when SUR-associated channels are opened, and bursting slows when SUR-associated channels are closed. The channel permeability and sensitivities analyses present novel SUR-conductance biophysics, which nevertheless change activity in ways reminiscent of the predominantly studied mammalian receptor/channels. We suggest that SUR-associated conductances allow different neurons to respond to energy states in different ways through a common mechanism."
336,Overcoming Observation Bias for Cancer Progression Modeling,"Rudolf Schill, Maren Klever, Andreas Lösch, Y. Linda Hu, Stefan Vocht, Kevin Rupp, Lars Grasedyck, Rainer Spang, Niko Beerenwinkel",https://www.biorxiv.org/content/10.1101/2023.12.03.569824v1,"Cancers evolve by accumulating genetic alterations, such as mutations and copy number changes. The chronological order of these events is important for understanding the disease, but not directly observable from cross-sectional genomic data. Cancer progression models (CPMs), such as Mutual Hazard Networks (MHNs), reconstruct the progression dynamics of tumors by learning a network of causal interactions between genetic events from their co-occurrence patterns. However, current CPMs fail to include effects of genetic events on the observation of the tumor itself and assume that observation occurs independently of all genetic events. Since a dataset contains by definition only tumors at their moment of observation, neglecting any causal effects on this event leads to the “conditioning on a collider” bias: Events that make the tumor more likely to be observed appear anti-correlated, which results in spurious suppressive effects or masks promoting effects among genetic events. Here, we extend MHNs by modeling effects from genetic progression events on the observation event, thereby correcting for the collider bias. We derive an efficient tensor formula for the likelihood function and learn two models on somatic mutation datasets from the MSK-IMPACT study. In colon adenocarcinoma, we find a strong effect on observation by mutations in TP53, and in lung adenocarcinoma by mutations in EGFR. Compared to classical MHNs, this explains away many spurious suppressive interactions and uncovers several promoting effects."
337,Transcription Factor HNF4A is Involved in Breast Cancer Recurrence,"Rahul Valiya Veettil, Noah Eyal Altman, Ruth Hashkes, Eitan Rubin",https://www.biorxiv.org/content/10.1101/2024.03.23.586428v1,"Recurrence is a major challenge for breast cancer (BC) management, yet its mechanism is poorly understood. Although computational analysis of expression compendia has proved useful for studying BC recurrence, some recently developed methods have not been used for this purpose. Here we present a bioinformatics reanalysis of a compendium containing 1519 cases with documentation of expression and information about recurrence with >5y follow-up. A compendium of expression profiles were divided into sub-cohorts by time to recurrence, and genes were ranked by the relative significance of expression differences. The top 1% of the genes (131 genes) were used in enrichment and induced network module analyses. The findings were validated in two independent cohorts, E-MTAB-365 and GSE20685. HNF4A was found to be the major hub in the genes whose expression differs most strikingly between short and long/no recurrence patients: it is highly connected to differentially expressed genes, and high expression of HNF4A is associated with longer recurrence-free survival in the compendium, even when it was split by ER status. These results were further validated in two independent cohorts of ER+ + endocrine + chemotherapy-treated patients and found to be concordant. Here we re-analyze a previously published compendium and find that HNF4A is pivotal to expression differences between early and late/non-recurring BC patients. HNF4A has been reported to be associated with cancer risk in several cancers and is speculated to be recurrence-associated in BC. However, we establish for the first time an association between BC time-to-recurrence and HNF4A expression. Further research is required to check if HNF4A expression is causative or just correlative to recurrence. Yet since linoleic acid is a ligand of HNF4A, our finding may explain why consumption of linoleic acid was proposed to affect recurrence risk in BC."
338,Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer,"Mia Hofstad, Andrea Woods, Karla Parra, Zoi E. Sychev, Alice Mazzagatti, Lan Yu, Collin Gilbreath, Peter Ly, Justin M. Drake, Ralf Kittler",https://www.biorxiv.org/content/10.1101/2024.07.10.602941v2,"In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated (ATM) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo, and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients."
339,"RBN-2397, a PARP7 Inhibitor, Synergizes with Paclitaxel to Inhibit Proliferation and Migration of Ovarian Cancer Cells","Alexandra N. Spirtos, Marwa W. Aljardali, Sridevi Challa, Sneh Koul, Jayanthi S. Lea, W. Lee Kraus, Cristel V. Camacho",https://www.biorxiv.org/content/10.1101/2024.08.20.608802v2,"Objectives Mono(ADP-ribosyl)ation (MARylation), a post translational modification of proteins, is emerging as an important regulator of the biology of cancer cells. PARP7 (TiPARP), a mono (ADP-ribosyl) transferase (MART), MARylates its substrate α-tubulin in ovarian cancer cells, promoting destabilization of microtubules, cell growth, and migration. Recent development of RBN-2397, a potent inhibitor that selectively acts on PARP7, has provided a new tool for exploring the role of PARP7 catalytic activity in biological processes. In this study, we investigated the role of PARP7 catalytic activity in the regulation of ovarian cancer cell biology via MARylation of α-tubulin."
341,TAK1-mediated phosphorylation of PLCE1 represses PIP2 hydrolysis to impede esophageal squamous cancer metastasis,"Qianqian Ju, Wenjing Sheng, Meichen Zhang, Jing Chen, Liucheng Wu, Xiaoyu Liu, Wentao Fang, Hui Shi, Cheng Sun",https://www.biorxiv.org/content/10.1101/2024.03.22.586256v2,"TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer cell (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1), and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of PIP2 hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1 induced phosphorylation of PLCE1 at S1060."
343,A cancer immunotherapy modality based on dendritic cell reprogramming in vivo,"Ervin Ascic, Fritiof Åkerström, Malavika Sreekumar Nair, André Rosa, Ilia Kurochkin, Olga Zimmermannova, Xavier Catena, Nadezhda Rotankova, Charlotte Veser, Michal Rudnik, Tommaso Ballocci, Tiffany Schärer, Xiaoli Huang, Maria de Rosa Torres, Emilie Renaud, Marta Velasco Santiago, Özcan Met, David Askmyr, Malin Lindstedt, Lennart Greiff, Laure-Anne Ligeon, Irina Agarkova, Inge Marie Svane, Cristiana F. Pires, Fábio F. Rosa, Carlos-Filipe Pereira",https://www.biorxiv.org/content/10.1101/2024.07.08.602356v1,"Immunotherapy leads to long-term survival of cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced complete tumor regressions, and established long-term systemic immunity in different mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for first-in-human trials and other applications of immune cell reprogramming in vivo."
345,Engineering programmable CAR-T cells with tunable controls as fail-safe mechanisms during cancer immunotherapy,"Mikail Dogan, Lina Kozhaya, Lindsey Placek, Ece Karhan, Mesut Yigit, Christina Mohammed, Qi Zhao, Derya Unutmaz",https://www.biorxiv.org/content/10.1101/2024.07.09.602762v1,"Chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in treating various cancers, but significant risks of severe adverse effects remain. In this study, we present a synthetic biology toolbox for engineering CAR-T cells with tunable and controllable features to mitigate these risks. Using this toolbox, we programmed cytotoxic CAR-T cells to be turned on and off using synthetic genes with tetracycline response elements, referred to as iOnCAR and iOffCAR. We achieved temporal regulation of CAR expression using the synthetic Notch receptor system and “AND-gate” programs, which allow for additional control using doxycycline. We also engineered cooperation among T cells through CD4 help to CD8 T cells in targeting cancer cells via synthetic Notch receptors controlled by doxycycline treatment. Additionally, we developed a T cell fratricide system by triggering a genetic “Battle Royale” mechanism that enables CAR-T cells to eliminate each other. In this system, surviving T cells become activated, proliferate, and display high cytotoxicity to target cells. In conclusion, our synthetic biology toolbox provides targeted fail-safe solutions for improving the safety and potency of CAR-T cell therapies by integrating different genetic circuits with a commonly used antibiotic."
346,Distal super-enhancer drives aberrant CXCL13 expression in Cancer cells driving growth and p53 dysregulation via CXCR5-CXCL13 axis,"Santosh Kumar Gothwal, Pieta K. Mattila, Jacqueline H Barlow",https://www.biorxiv.org/content/10.1101/2024.08.31.609994v2,"The CXCL13 chemokine plays a crucial role in guiding B cell migration to the light zones (LZs) during the germinal center (GC) reaction. While CXCL13 expression is absent in most cell types, aberrant amplification of the CXCR5-CXCL13 signaling is observed in various cancers, including germinal center-derived B-lymphomas (GCDBL), colorectal adenocarcinoma (COAD), and liver hepatocellular carcinoma (LIHC). However, the molecular mechanisms underlying abnormal CXCL13 transcription in cancer cells and its functional consequences remain elusive. We identify DNA-CpG methylation binding protein 1 (MBD1) as a suppressor of CXCL13 expression. Chromosomal conformation capture (3C) analysis reveals a distal super-enhancer located near CCNG2 that interacts with the CXCL13 promoter in GCDBL, suggesting that enhancer-hijacking drives the aberrant expression. Our functional validation demonstrates that CXCR5-CXCL13 signaling suppresses p53 and its target genes in GCDBLs, COAD, and LIHC. Notably, CXCL13 in the GCDBL cell line Raji disrupts CXCR5-mediated migration, a mechanism essential for (light zone) LZ-entry and affinity maturation of GC B cells. These findings highlight the dual role of the CXCR5-CXCL13 axis in immune response and cancer proliferation."
349,Modulation of ribosomal subunit associations by eIF6 is critical for mitotic exit and cancer progression,"Poonam Roshan, Aparna Biswas, Stella Anagnos, Riley Luebbers, Kavya Harish, Sinthyia Ahmed, Megan Li, Nicholas Nguyen, Gao Zhou, Frank Tedeschi, Vivian Hathuc, Zhenguo Lin, Zachary Hamilton, Sofia Origanti",https://www.biorxiv.org/content/10.1101/2024.06.24.600220v2,"Moderating the pool of active ribosomal subunits is critical for maintaining global translation rates. A factor crucial for modulating the 60S ribosomal subunits is eukaryotic translation initiation factor 6. Release of eIF6 from 60S is essential to permit 60S interactions with 40S. Here, using the N106S mutant of eIF6, we show that disrupting eIF6 interaction with 60S leads to an increase in vacant 80S. It further highlights a dichotomy in the anti-association activity of eIF6 that is distinct from its role in 60S biogenesis and shows that the nucleolar localization of eIF6 is not dependent on uL14-BCCIP interactions. Limiting active ribosomal pools markedly deregulates translation especially in mitosis and leads to chromosome segregation defects, mitotic exit delays and mitotic catastrophe. Ribo-Seq analysis of the eIF6-N106S mutant shows a significant downregulation in the translation efficiencies of mitotic factors and specifically transcripts with long 3′UTRs. eIF6-N106S mutation also limits cancer invasion, and this role is correlated with the overexpression of eIF6 only in high-grade invasive cancers suggesting that deregulation of eIF6 is probably not an early event in cancers. Thus, this study highlights the segregation of eIF6 functions and its role in moderating 80S availability for mitotic translation and cancer progression."
351,HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer,"D. Ranti, H. Yu, Y.A. Wang, C. Bieber, T. Strandgaard, B. Salomé, Sean Houghton, J. Kim, H. Ravichandran, I. Okulate, E. Merritt, S. Bang, A. Demetriou, Z. Li, S. V. Lindskrog, D.F. Ruan, J. Daza, R. Rai, E. Hegewisch-Solloa, E.M. Mace, R. Fernandez-Rodriguez, S. Izadmehr, G. Doherty, A. Narasimhan, A.M. Farkas, P. Cruz-Encarnacion, S. Shroff, F. Patel, M. Tran, S.J. Park, J. Qi, M. Patel, D. Geanon, G. Kelly, R.M. de Real, B. Lee, K. Nie, S. Miake-Iye, K. Angeliadis, E. Radkevich, T.H. Thin, M. Garcia-Barros, H. Brown, B. Martin, A. Mateo, A. Soto, R. Sussman, S. Shiwlani, S. Francisco-Simon, K.G. Beaumont, Y. Hu, Y-C. Wang, L. Wang, R.P. Sebra, S. Smith, M. Skobe, E. Clancy-Thompson, D. Palmer, S. Hammond, B. D. Hopkins, P. Wiklund, J. Zhu, J.J. Bravo-Cordero, R. Brody, B. Hopkins, Z. Chen, S. Kim-Schulze, L. Dyrskjøt, O. Elemento, A. Tocheva, W-M. Song, N. Bhardwaj, M.D. Galsky, J.P. Sfakianos, A. Horowitz",https://www.biorxiv.org/content/10.1101/2024.09.02.610816v1,"Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the primary treatment for non-muscle-invasive bladder cancer (NMIBC), known to stimulate inflammatory cytokines, notably interferon (IFN)-γ. We observed that prolonged IFN-γ exposure fosters adaptive resistance in recurrent tumors, aiding immune evasion and tumor proliferation. We identify HLA-E and NKG2A, part of a novel NK and T cell checkpoint pathway, as key mediators of resistance in BCG-unresponsive NMIBC. IFN-γ enhances HLA-E and PD-L1 expression in recurrent tumors, with an enrichment of intra-tumoral NKG2A-expressing NK and CD8 T cells. CXCL9+ macrophages and dendritic cells and CXCL12-expressing stromal cells likely recruit CXCR3/CXCR4-expressing NK and T cells and CXCR7+ HLA-EHIGH tumor cells. NK and CD8 T cells remain functional within BCG-unresponsive tumors but are inhibited by HLA-E and PD-L1, providing a framework for combined NKG2A and PD-L1 blockade strategy for bladder-sparing treatment of BCG-unresponsive NMIBC."
352,Comparative transcriptome of normal and cancer-associated fibroblasts,"Apoorva Abikar, Mohammad Mehaboob Subhani Mustafa, Radhika Rajiv Athalye, Namratha Nadig, Ninad Tamboli, Vinod Babu, Ramaiah Keshavamurthy, Prathibha Ranganathan",https://www.biorxiv.org/content/10.1101/2024.03.18.585496v1,The characteristics of a tumor are largely determined by its interaction with the surrounding micro-environment (TME). TME consists of both cellular and non-cellular components. Cancer associated fibroblasts (CAFs) are a major component of the TME. They are a source of many secreted factors that influence the survival and progression of tumors as well as their response to drugs. Identification of markers either overexpressed in CAFs or unique to CAFs would pave the way for novel therapeutic strategies that would combine conventional chemotherapy and TME-targeted therapy for a better outcome. We have used fibroblast derived from Benign Prostatic Hyperplasia (BPH) and prostate cancer to perform a transcriptome analysis in order to get a comparative profile of normal and cancer-associated fibroblasts. This has identified 818 differentially expressed mRNAs and 17 lincRNAs between normal and cancer-associated fibroblasts.
353,ChIP-seq of Urinary Cell-Free Chromatin Infers Tissue Origin and Detects Tumor-Derived Cell-Free DNA in Bladder Cancer,"Matan Lotem, Israa Sharkia, Batia Azria, Tal Michaeli, Nir Friedman",https://www.biorxiv.org/content/10.1101/2024.09.01.610671v1,"Urinary Cell-free DNA (cfDNA) holds valuable molecular insights into the processes occurring within the urinary system. The analysis of epigenetic markers such as histone post-translational modifications in both cells and in blood circulation offers detailed information regarding cell identity and underlying state. However it remains unclear whether urine contains cell-free chromatin with intact epigenetic marks. Here, we extend the use of cell-free chromatin immunoprecipitation followed by sequencing (cfChIP-seq) to human urine. We demonstrate that cell-free nucleosomes captured in urine preserve multiple histone post-translational modifications indicative of activation and repression. By analyzing the H3K4me3 promoter mark, we identified the primary tissues contributing to cfDNA in healthy individuals. Notably, we observe distinct populations of circulating nucleosomes in urine and plasma samples with a contribution from the kidney in healthy donors that are not detected in matched urine exfoliated cells or matching plasma samples. Additionally, we show that urine cf-nucleosomes can be used to detect pathologically driven changes in the urine of bladder cancer patients, reflecting tumor-associated transcriptional programs and immune responses. The cfChIP-seq signal from cancer and immune origins can be used to accurately identify cancer patient samples, achieving an area under the curve (AUC) of 0.97 in a validation set. Our findings highlight the potential of urine cell-free nucleosomes as accessible, noninvasive biomarkers for both basic research in renal physiology and monitoring urinary pathologies."
354,Estrogen receptor alpha (ERα) driven trans-regulation of mitotic checkpoint complex (MCC) components affects the clinical outcome of breast cancer,"Suryendu Saha, Debanil Dhar, Stuti Roy, Ratnadip Paul, Anindya Mukhopadhyay, Arnab Gupta, Somsubhra Nath",https://www.biorxiv.org/content/10.1101/2024.08.31.610592v1,"Hormone receptors (HR), namely estrogen receptor (ER) and progesterone receptor (PR), are prevalent in most malignant tumors. Although previous literature provided clues for ERα in regulating mitosis and ploidy status in breast cancer (BC) cells, reports on the mitotic regulators being the targets of HR are sparse. To delve deeper into ERα’s impact on mitotic execution, our study focuses on examining its transcriptional activity on the core mitotic checkpoint complex (MCC) components, which are involved in ploidy maintenance. The expression of the core MCC components (Bub3, Mad2, and BubR1) was analyzed by quantitative-PCR and immunohistochemistry in breast tumors and adjacent normal tissues from the cancer genome atlas-breast invasive carcinoma collection (TCGA BRCA) dataset and in a prospective cohort of Eastern Indian breast cancer affected individuals. The preliminary data from these cohorts indicated an influence of ERα on the two MCC components, namely Mad2 and BubR1. Subsequently, luciferase reporter assays and chromatin immunoprecipitation were performed which revealed that ERα promotes transcriptional activation of MAD2 and BUB1B through direct recruitment on these promoters, showing affects in mitotic outcome. Interestingly, the ectopic introduction of ERα, in an HR-ve breast cancer line, MDA-MB-231, significantly reduced the percent aneuploidy. Moreover, we found that overexpression of MAD2 and BUB1B is associated with poorer survival in HR-positive (HR+ve) patients in both cohorts. Our findings provide insights into the specific role of ERα-mediated transcriptional regulation of mitosis and ploidy outcome. Targeting the deregulated MCC components thus offers translational potential for the therapeutic management of breast cancer."
355,Biguanide-PROTACs: Modulating Mitochondrial Proteins in Pancreatic Cancer Cells,"Julie Vatté, Véronique Bourdeau, Gerardo Ferbeyre, Andreea R. Schmitzer",https://www.biorxiv.org/content/10.1101/2024.03.17.585436v1,"This study focuses on the synthesis of Biguanide-PROTACs, formed by conjugating the biguanide motif with diverse E3 enzyme ligands and spacers. Evaluation of their activity on pancreatic cancer cell (KP4) proliferation established a correlation between membrane permeability and median effective concentration. Mechanistic insights revealed that only two compounds exhibited biguanide-like AMPK activation, while only one hydrophobic compound uniquely altered mitochondrial protein levels. The prospect of developing and expanding the Biguanide-PROTAC library holds promises, offering potential insights into biguanide mechanisms and the creation of more potent anticancer agents. This study contributes to understanding the intricate interplay between compound structure, permeability, and anticancer activity, paving the way for targeted drug development in pancreatic cancer treatment."
356,Generation of a biliary tract cancer cell line atlas reveals molecular subtypes and therapeutic targets,"Vindhya Vijay, Negin Karisani, Lei Shi, Yu-Han Hung, Phuong Vu, Prabhat Kattel, Lauren Kenney, Joshua Merritt, Ramzi Adil, Qibiao Wu, Yuanli Zhen, Robert Morris, Johannes Kreuzer, Meena Kathiresan, Xcanda Ixchel Herrera Lopez, Haley Ellis, Ilaria Gritti, Lilian Lecorgne, Ines Farag, Alexandra Popa, William Shen, Hiroyuki Kato, Qin Xu, Eranga R. Balasooriya, Meng-Ju Wu, Saireudee Chaturantabut, Robin K. Kelley, James M. Cleary, Michael S. Lawrence, David Root, Cyril H. Benes, Vikram Deshpande, Dejan Juric, William R. Sellers, Cristina R. Ferrone, Wilhelm Haas, Francisca Vazquez, Gad Getz, Nabeel Bardeesy",https://www.biorxiv.org/content/10.1101/2024.07.04.601970v1,"Biliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research."
357,Targeting prostate cancer by new bispecific monocyte engager directed to prostate-specific membrane antigen,"Gargi Das, Jakub Ptacek, Barbora Havlinova, Jana Nedvedova, Cyril Barinka, Zora Novakova",https://www.biorxiv.org/content/10.1101/2024.07.05.602163v1,"Prostate cancer (PCa) ranks as the second leading cause of cancer-related deaths among men in the United States. Prostate-specific membrane antigen (PSMA) represents a well-established biomarker of PCa and its levels correlate positively with the disease progression, culminating at the stage of metastatic castration-resistant prostate cancer. Due to its tissue-specific expression and cell surface localization, PSMA shows superior potential for precise imaging and therapy of PCa. Antibody-based immunotherapy targeting PSMA offers the promise of selectively engaging the host immune system with minimal off-target effects."
358,"The protease ADAMTS5 controls ovarian cancer cell invasion, downstream of Rab25","Shengnan Yuan, Rachele Bacchetti, Jamie Adams, Elena Rainero",https://www.biorxiv.org/content/10.1101/2024.07.08.602517v1,"Ovarian cancer is the 3rd most common gynaecological malignancy worldwide, with a 5-year survival rate of less than 30% in the presence of metastasis. Metastatic progression is characterised by extensive remodelling of the extracellular matrix, primarily mediated by secreted matrix metalloproteinases, including members of the ‘a disintegrin and metalloprotease with thrombospondin motif’ (ADAMTS) family. In particular, ADAMTS5 has been reported to be upregulated in ovarian malignant tumours compared to borderline and benign lesions, suggesting it might play a role in metastatic progression. Furthermore, it has been suggested that Rab25, a small GTPase of the Ras family, might upregulate ADAMTS5 expression in ovarian cancer cells. Here we demonstrated that Rab25 promotes ADAMTS5 expression, through the activation of the NF-κB signalling pathway. Furthermore, ADAMTS5 was necessary and sufficient to stimulate ovarian cancer cell migration through complex fibroblast-secreted matrices, while ADAMTS5 inhibition prevented ovarian cancer spheroid invasion in 3D systems. Finally, in ovarian cancer patients high ADAMTS5 expression correlated with poor prognosis. Altogether, these data identify ADAMTS5 as a novel regulator of ovarian cancer cell migration and invasion, suggesting it might represent a novel therapeutic target to prevent ovarian metastasis."
360,STAMBPL1 activates the GRHL3/HIF1A/VEGFA axis through interaction with FOXO1 to promote angiogenesis in triple-negative breast cancer,"Huan Fang, Huichun Liang, Chuanyu Yang, Dewei Jiang, Qianmei Luo, Wenming Cao, Huifeng Zhang, Ceshi Chen",https://www.biorxiv.org/content/10.1101/2024.08.31.610659v1,"In the clinic, anti-tumor angiogenesis is commonly employed for treating recurrent, metastatic, drug-resistant triple-negative and advanced breast cancer. Our previous research revealed that the deubiquitinase STAMBPL1 enhances the stability of MKP-1, thereby promoting cisplatin resistance in breast cancer. In this study, we discovered that STAMBPL1 could upregulate the expression of the hypoxia-inducible factor HIF1α in breast cancer cells. Therefore, we investigated whether STAMBPL1 promotes tumor angiogenesis. We demonstrated that STAMBPL1 increased HIF1A transcription in a non-enzymatic manner, thereby activating the HIF1α/VEGFA signaling pathway to facilitate TNBC angiogenesis. Through RNA-seq analysis, we identified the transcription factor GRHL3 as a downstream target of STAMBPL1 that is responsible for mediating HIF1A transcription. Furthermore, we discovered that STAMBPL1 regulates GRHL3 transcription by interacting with the transcription factor FOXO1. These findings shed light on the role and mechanism of STAMBPL1 in the pathogenesis of breast cancer, offering novel targets and avenues for the treatment of triple-negative and advanced breast cancer."
361,A mathematical model for pancreatic cancer during intraepithelial neoplasia,"Joshua Briones-Andrade, Guillermo Ramírez-Santiago, J. Roberto Romero-Arias",https://www.biorxiv.org/content/10.1101/2024.03.16.585362v1,"Cancer is the result of complex interactions of intrinsic and extrinsic cell processes, which promote sustained proliferation, resistance to apoptosis, reprogramming and reorganization. To understand the evolution of any type of cancer it is necessary to understand the role of the microenvironmental conditions and the impact of some molecular complexes and mechanisms on certain signalling pathways. As in most cancer quantitative models, the understanding of the early onset of cancer requires a multiscale analysis of the cellular microenvironment. In this paper we analyse a multiscale model of pancreatic adenocarcinoma by modelling the cellular microenvironment through elastic cell interactions and their intercellular communication mechanisms, such as growth factors and cytokines. We focus on the low-grade dysplasia (PanIN 1) and moderate dysplasia (PanIN 2) stages of the pancreatic adenocarcinoma. To this end we propose a gene regulatory network associated with the processes of proliferation and apoptosis of pancreatic cells and its kinetics in terms delayed differential equations to mimic cell development. Likewise, we couple the cell cycle with the spatial distribution of cells and the transport of growth factors to show that the adenocarcinoma evolution is triggered by inflammatory processes. We show that the oncogene RAS may be an important target to develop anti-inflammatory strategies that limit the emergence of more aggressive adenocarcinomas."
362,High-frequency extracellular spiking in electrically-active cancer cells,"Rustamzhon Melikov, Francesco De Angelis, Rosalia Moreddu",https://www.biorxiv.org/content/10.1101/2024.03.16.585162v1,"Microelectrode matrices have been extensively used in the past 30 years as a reliable platform to record the extracellular activity of cells traditionally regarded to as excitable, i.e. brain cells and muscle cells. Meanwhile, fundamental biology studies on cancer cells since the 1970s reveal that they exhibit altered functionalities of ion channels, membrane potentials, metabolism, and communication mechanisms when compared to their healthy counterparts. In this work, we present for the first time the presence of extracellular voltage spikes occurring at high frequencies (0.1-3.5 kHz) in breast cancer cells, resembling the ones observed in excitable cells, and the possibility to record them with 30 µm TiN microelectrode matrices. These preliminary findings may open a new path for exploration in a variety of research fields, enabling the access to bioelectrical dynamics in cancer cells and cell networks, targeting bioelectricity as a tool in anticancer drug development and cancer diagnostics, as well as provide a market expansion for companies commercializing microelectrodes and microelectrode recording systems."
364,Prdm1 Positively Regulates Liver Group 1 ILCs Cancer Immune Surveillance and Preserves Functional Heterogeneity,"Jitian He, Le Gao, Peiying Wang, Wing Keung Chan, Yiran Zheng, Yumo Zhang, Jiaman Sun, Xue Li, Jiming Wang, Xiaohong Li, Huaiyong Chen, Zhouxin Yang, Youwei Wang",https://www.biorxiv.org/content/10.1101/2023.10.20.563222v4,"Group 1 innate lymphoid cells (ILCs) comprise conventional natural killer (cNK) cells and type 1 innate lymphoid cells (ILC1s). The main functions of liver cNK cells and ILC1s not only include directly killing target cells but also regulating local immune microenvironment of the liver through the secretion of cytokines. Uncovering the intricate mechanisms by which transcriptional factors regulate and influence the functions of liver cNK cells and ILC1s, particularly within the context of liver tumors, presents a significant opportunity to amplify the effectiveness of immunotherapies against liver malignancies. Using Ncr1-drived conditional knockout mouse model, our study reveals the regulatory role of Prdm1 in shaping the composition and maturation of cNK cells. Although Prdm1 did not affect the killing function of cNK cells in an in vivo cytotoxicity model, a significant increase in cancer metastasis was observed in Prdm1 knockout mice. Interferon-gamma (IFN-γ), granzyme B, and perforin secretion decreased significantly in Prdm1 deficient cNK cells and liver ILC1s. scRNA sequencing data also provided evidences that Prdm1 maintains functional subsets of cNK cells and liver ILC1s and facilitates communications between cNK cells, liver ILC1s and macrophages. The present study unveiled a novel regulatory mechanism of Prdm1 in cNK cells and liver ILC1s, showing promising potential for developing innovative immune therapy strategies against liver cancer."
366,Systematic annotation of orphan RNAs reveals blood-accessible molecular barcodes of cancer identity and cancer-emergent oncogenic drivers,"Jeffrey Wang, Jung Min Suh, Brian J Woo, Albertas Navickas, Kristle Garcia, Keyi Yin, Lisa Fish, Taylor Cavazos, Benjamin Hänisch, Daniel Markett, Shaorong Yu, Gillian Hirst, Lamorna Brown-Swigart, Laura J. Esserman, Laura J. van ‘t Veer, Hani Goodarzi",https://www.biorxiv.org/content/10.1101/2024.03.19.585748v1,"From extrachromosomal DNA to neo-peptides, the broad reprogramming of the cancer genome leads to the emergence of molecules that are specific to the cancer state. We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-specific small RNAs with the potential to play functional roles in breast cancer progression1. Here, we report a systematic and comprehensive search to identify, annotate, and characterize cancer-emergent oncRNAs across 32 tumor types. We also leverage large-scale in vivo genetic screens in xenografted mice to functionally identify driver oncRNAs in multiple tumor types. We have not only discovered a large repertoire of oncRNAs, but also found that their presence and absence represent a digital molecular barcode that faithfully captures the types and subtypes of cancer. Importantly, we discovered that this molecular barcode is partially accessible from the cell-free space as some oncRNAs are secreted by cancer cells. In a large retrospective study across 192 breast cancer patients, we showed that oncRNAs can be reliably detected in the blood and that changes in the cell-free oncRNA burden captures both short-term and long-term clinical outcomes upon completion of a neoadjuvant chemotherapy regimen. Together, our findings establish oncRNAs as an emergent class of cancer-specific non-coding RNAs with potential roles in tumor progression and clinical utility in liquid biopsies and disease monitoring."
367,"Pan-cancer subclonal mutation analysis of 7,827 tumors predicts clinical outcome","Yujie Jiang, Matthew D Montierth, Kaixian Yu, Shuangxi Ji, Shuai Guo, Quang Tran, Xiaoqian Liu, Seung Jun Shin, Shaolong Cao, Ruonan Li, Yuxin Tang, Tom Lesluyes, Scott Kopetz, Jaffer Ajani, Pavlos Msaouel, Sumit K Subudhi, Ana Aparicio, Padmanee Sharma, John Paul Shen, Anil K. Sood, Maxime Tarabichi, Jennifer R. Wang, Marek Kimmel, Peter Van Loo, Hongtu Zhu, Wenyi Wang",https://www.biorxiv.org/content/10.1101/2024.07.03.601939v1,"Intra-tumor heterogeneity is an important driver of tumor evolution and therapy response. Advances in precision cancer treatment will require understanding of mutation clonality and subclonal architecture. Currently the slow computational speed of subclonal reconstruction hinders large cohort studies. To overcome this bottleneck, we developed Clonal structure identification through Pairwise Penalization, or CliPP, which clusters subclonal mutations using a regularized likelihood model. CliPP reliably processed whole-genome and whole-exome sequencing data from over 12,000 tumor samples within 24 hours, thus enabling large-scale downstream association analyses between subclonal structures and clinical outcomes. Through a pan-cancer investigation of 7,827 tumors from 32 cancer types, we found that high subclonal mutational load (sML), a measure of latency time in tumor evolution, was significantly associated with better patient outcomes in 16 cancer types with low to moderate tumor mutation burden (TMB). In a cohort of prostate cancer patients participating in an immunotherapy clinical trial, high sML was indicative of favorable response to immune checkpoint blockade. This comprehensive study using CliPP underscores sML as a key feature of cancer. sML may be essential for linking mutation dynamics with immunotherapy response in the large population of non-high TMB cancers."
368,Genetic ancestry-specific meQTLs control immune function regulation in a breast cancer cohort of African and European patients,"Kyriaki Founta, Nyasha Chambwe",https://www.biorxiv.org/content/10.1101/2024.08.29.610316v1,"We explored the impact of genetic ancestry on DNA methylation (DNAm) in African and European ancestry breast cancer patients. Analyzing data from 578 subjects in The Cancer Genome Atlas (TCGA) cohort, we identified 757 differentially methylated sites associated with genetic ancestry (aDMS). Methylation quantitative trait loci (meQTL) mapping showed that the majority of aDMS are regulated by multiple SNPs differentially prevalent by ancestry. Notably, expression quantitative methylation (eQTM) mapping linked 95% of aDMS to local gene expression, indicating potential impact on gene regulation."
370,G-quadruplex formation in long non-coding RNAs dysregulated in colorectal cancer,"Shubham Sharma, Chinmayee Shukla, Jérémie Mitteaux, Angélique Pipier, Marc Pirrotta, Marie-José Penouilh, David Monchaud, Bhaskar Datta",https://www.biorxiv.org/content/10.1101/2024.07.04.602106v1,"Non-coding RNAs (ncRNAs) in human cells do not lead to protein synthesis and constitute a substantial portion of the transcriptome. Human long non-coding RNAs (lncRNAs) orchestrate critical cellular functions influencing development, differentiation, and metabolism. Dysregulation of lncRNAs has been correlated with several pathological conditions such as neurodegenerative and autoimmune disorders, diabetes, and cancer. Recent reports have suggested the involvement of G4s in lncRNAs to regulate colorectal cancer (CRC) carcinogenesis. In this study, we investigate the occurrence and distribution of G4s in the LINC01589, MELTF-AS1, and UXT-AS1 lncRNAs, which have been reported to be dysregulated in CRC. Using a combination of in silico tools and in vitro biophysical techniques, we show that these lncRNAs form stable, parallel, and intramolecular G4s. Furthermore, we establish the formation of G4s within these lncRNAs in CRC using cell-based assays, including RNA G4-Immuno-FISH and G4RP-RT-qPCR. This is the first systematic study of G4s in lncRNAs dysregulated in CRC, and our findings highlight the diagnostic and therapeutic potential of G4s in CRC."
371,Sensitive detection of synthetic response to cancer immunotherapy driven by gene paralog pairs,"Chuanpeng Dong, Feifei Zhang, Emily He, Ping Ren, Nipun Verma, Xinxin Zhu, Di Feng, Hongyu Zhao, Sidi Chen",https://www.biorxiv.org/content/10.1101/2024.07.02.601809v1,"Emerging immunotherapies such as immune checkpoint blockade (ICB) and chimeric antigen receptor T-cell (CAR-T) therapy have revolutionized cancer treatment and have improved the survival of patients with multiple cancer types. Despite this success many patients are unresponsive to these treatments or relapse following treatment. CRISPR activation and knockout (KO) screens have been used to identify novel single gene targets that can enhance effector T cell function and promote immune cell targeting and eradication of tumors. However, cancer cells often employ multiple genes to promote an immunosuppressive pathway and thus modulating individual genes often has a limited effect. Paralogs are genes that originate from common ancestors and retain similar functions. They often have complex effects on a particular phenotype depending on factors like gene family similarity, each individual gene’s expression and the physiological or pathological context. Some paralogs exhibit synthetic lethal interactions in cancer cell survival; however, a thorough investigation of paralog pairs that could enhance the efficacy of cancer immunotherapy is lacking. Here we introduce a sensitive computational approach that uses sgRNA sets enrichment analysis to identify cancer-intrinsic paralog pairs which have the potential to synergistically enhance T cell-mediated tumor destruction. We have further developed an ensemble learning model that uses an XGBoost classifier and incorporates features such as gene characteristics, sequence and structural similarities, protein-protein interaction (PPI) networks, and gene coevolution data to predict paralog pairs that are likely to enhance immunotherapy efficacy. We experimentally validated the functional significance of these predicted paralog pairs using double knockout (DKO) of identified paralog gene pairs as compared to single gene knockouts (SKOs). These data and analyses collectively provide a sensitive approach to identify previously undetected paralog pairs that can enhance cancer immunotherapy even when individual genes within the pair has a limited effect."
373,FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis,"Matthew Yorek, Xingshan Jiang, Shanshan Liu, Jiaqing Hao, Jianyu Yu, Anthony Avellino, Zhanxu Liu, Melissa Curry, Henry Keen, Jianqiang Shao, Anand Kanagasabapathy, Maiying Kong, Yiqin Xiong, Edward R. Sauter, Sonia L. Sugg, Bing Li",https://www.biorxiv.org/content/10.1101/2024.07.02.601733v1,"A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer."
376,HCV- and HBV-mediated liver cancer converge on similar transcriptomic landscapes and immune profiles,"Elizabeth S. Borden, Annika Jorgensen, Heini M. Natri, Karen Taraszka Hastings, Kenneth H. Buetow, Melissa A. Wilson",https://www.biorxiv.org/content/10.1101/2024.07.01.601493v1,"Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, and a large proportion of HCC is attributable to viral causes including hepatitis B (HBV) and C virus (HCV). The pathogenesis of viral-mediated HCC can differ between HBV and HCV, but it is unclear how much these differences influence the tumors’ final molecular and immune profiles. Additionally, there are known sex differences in the molecular etiology of HCC, but sex differences have not been explored in the context of viral-mediated HCC. To determine the extent to which the viral status and sex impact the molecular and immune profiles of HCC, we performed differential expression and immune cell deconvolution analyses. We identified a large number of differentially expressed genes unique to the HBV or HCV tumor:tumor-adjacent comparison. Pathway enrichment analyses demonstrated that the changes unique to the HCV tumor:tumor-adjacent tissue were predominated by changes in the immune pathways. Immune cell deconvolution demonstrated that HCV tumor-adjacent tissue had the largest immune cell infiltrate, with no difference in the immune profiles within HBV and HCV tumor samples. We subsequently segregated the differential expression analyses by sex, but demonstrated that the low number of female samples led to an overestimate of differentially expressed genes unique to male tumors. This limitation highlights the importance of additional sampling of female HCC tumors to allow for a more complete analysis of the sex differences in HCC. Overall, this work demonstrates the convergence of HBV- and HCV-mediated HCC on a similar transcriptomic landscape and immune profile despite differences in the surrounding tissue."
377,Early ctDNA kinetics as a dynamic biomarker of cancer treatment response,"Aaron Li, Emil Lou, Kevin Leder, Jasmine Foo",https://www.biorxiv.org/content/10.1101/2024.07.01.601508v1,"Circulating tumor DNA assays are promising tools for the prediction of cancer treatment response. Here, we build a framework for the design of ctDNA biomarkers of therapy response that incorporate variations in ctDNA dynamics driven by specific treatment mechanisms. We develop mathematical models of ctDNA kinetics driven by tumor response to several therapy classes, and utilize them to simulate randomized virtual patient cohorts to test candidate biomarkers. Using this approach, we propose specific biomarkers, based on ctDNA longitudinal features, for targeted therapy, chemotherapy and radiation therapy. We evaluate and demonstrate the efficacy of these biomarkers in predicting treatment response within a randomized virtual patient cohort dataset. These biomarkers are based on novel proposals for ctDNA sampling protocols, consisting of frequent sampling within a compact time window surrounding therapy initiation – which we hypothesize to hold valuable prognostic information on longer-term treatment response. This study highlights a need for tailoring ctDNA sampling protocols and interpretation methodology to specific biological mechanisms of therapy response, and it provides a novel modeling and simulation framework for doing so. In addition, it highlights the potential of ctDNA assays for making early, rapid predictions of treatment response within the first days or weeks of treatment, and generates hypotheses for further clinical testing."
379,Inhibition of IAPs induces programmed cell death and inflammatory signaling in patient-derived metastatic breast cancer organoids,"Kaja Nicole Wächtershäuser, Jana V. Schneider, Alec Gessner, Geoffroy Andrieux, Ivan Kur, Nadine Duschek, Andreas Weigert, Melanie Boerries, Michael A. Rieger, Ernst H.K. Stelzer, Francesco Pampaloni, Sjoerd J.L. van Wijk",https://www.biorxiv.org/content/10.1101/2024.08.28.610103v1,"Breast cancer (BC) is the most common type of cancer among women worldwide and underlies relapse, disease progression and metastasis. Resistance to chemotherapy and programmed cell death (PCD), including apoptosis, strongly affects therapy success and remains a major challenge. Representative and translational models to understand, manipulate and cultivate advanced BC and to model PCD resistance are therefore urgently required. Smac mimetics are promising compounds to circumvent apoptosis resistance and are able to induce caspase-independent necroptosis, a lytic and inflammatory mode of PCD. Here, we apply primary, patient-derived human mammary organoids (hMOs) to investigate alternative forms of PCD to overcome apoptosis resistance. Using time lapse brightfield with immunofluorescent confocal microscopy, biochemistry and gene expression analysis, we demonstrate that Smac mimetics induce apoptosis in primary hMOs. By mimicking apoptosis resistance via caspase inhibition, hMOs undergo necroptosis, associated with expression and secretion of inflammatory mediators. Inhibition of linear ubiquitination by the LUBAC inhibitor HOIPIN-8 prevents necroptosis, as well as the expression and release of inflammatory mediators in hMOs. Our findings demonstrate that primary hMOs are effective models to model, study and manipulate PCD responses and inflammation in in primary BC organoids and open new therapeutic screening options for chemotherapy-resistant BC."
381,GeneLLM: A Large cfRNA Language Model for Cancer Screening from Raw Reads,"Siwei Deng, Lei Sha, Yongcheng Jin, Tianyao Zhou, Chengen Wang, Qianpu Liu, Hongjie Guo, Chengjie Xiong, Yangtao Xue, Xiaoguang Li, Yuanming Li, Yaping Gao, Mengyu Hong, Junjie Xu, Shanwen Chen, Pengyuan Wang",https://www.biorxiv.org/content/10.1101/2024.06.29.601341v1,"Plasma cell-free RNA (cfRNA) has recently emerged as a promising biomarker for non-invasive early cancer detection and treatment monitoring [8, 28, 31, 32, 38, 40]. Here, we introduce GeneLLM, a novel large language model de-signed to interpret cfRNA sequences directly, bypassing the need for genome annotations. GeneLLM significantly advances the detection accuracy of various cancer types. Our study demonstrates that this method achieves higher accuracy than traditional biomarkers and effectively handles large datasets from different centres, even with low sequencing depth. By avoiding the use of bioinformatics tools to count known genes, GeneLLM also discovered cfRNAs from previously unknown genes, referred to as ‘dark matters’ in the genome, as cancer detec-tion ‘pseudo-biomarkers’. Our results showcase the potential of GeneLLM to revolutionise cancer detection, making it more accessible and cost-effective. By offering a method that does not depend on bioinformatics tools to count known genes, GeneLLM opens new avenues for biomarker discovery and enhances our understanding of intercellular communication through novel RNA molecules."
382,Identification of cuproptosis and ferroptosis-related subtypes and development of a prognostic signature in colon cancer,"Yinghao He, Fuqiang Liu, Zheng Jiang",https://www.biorxiv.org/content/10.1101/2024.06.30.601455v1,"Colon cancer, as a highly prevalent malignant tumor globally, poses a significant threat to human health. In recent years, ferroptosis and cuproptosis, as two novel forms of cell death, have attracted widespread attention for their potential roles in the development and treatment of colon cancer. However, the investigation into the subtypes and their impact on the survival of colon cancer patients remains understudied. In this study, utilizing data from TCGA and GEO databases, we examined the expression differences of ferroptosis and cuproptosis-related genes in colon cancer and identified two subtypes. Through functional analysis and bioinformatics methods, we elucidated pathway differences and biological characteristics between these two subtypes. By leveraging differential genes between the two subtypes, we constructed a prognostic model using univariate Cox regression and multivariate Cox regression analysis as well as LASSO regression analysis. Further survival analysis and receiver operating characteristic curve analysis demonstrated the model’s high accuracy. To enhance its clinical utility, we evaluated the clinical significance of the model and constructed a nomogram, significantly improving the predictive ability of the model and providing a new tool for prognostic assessment of colon cancer patients. Subsequently, through immune-related analysis, we revealed differences in immune cell infiltration and immune function between high- and low-risk groups. Further analysis of the relationship between the model and immune cells and functions revealed potential therapeutic targets. Drug sensitivity analysis revealed associations between the expression of model-related genes and drug sensitivity, suggesting their involvement in tumor resistance through certain mechanisms. AZD8055_1059, Bortezomib_1191, Dihydrorotenone_1827, and MG-132_1862 were more sensitive in the high-risk group. Finally, we analyzed differential expression of model-related genes between tumor tissues and normal tissues, validated through real-time quantitative PCR. In summary, our study provides a relatively accurate prognostic tool for colon cancer patients, offering guidance for treatment selection and indicating the potential of immunotherapy in colon cancer."
383,Atypical contribution of caspase-3 to melanoma cancer cell motility by regulation of coronin 1B activity,"Kevin Berthenet, Serena Diazzi, Catherine Jamard, Kinga Stopa, Stefan Dragan, Deborah Fanfone, Trang Nguyen, Nathalie Al, Francois Virard, Olivier Meurette, Nikolay Popgeorgiev, Hector Hernandez-Vargas, Julien Ablain, Gabriel Ichim",https://www.biorxiv.org/content/10.1101/2024.06.27.601010v1,"Recent studies have unveiled unexpected connections between cell death and cell motility. While traditionally recognized for their pro-apoptotic roles, caspases have emerged as regulators of physiological processes beyond cell death, including cellular differentiation and motility. In some particularly aggressive cancers like melanoma, caspase-3, a prominent executioner caspase, is unexpectedly and inexplicably highly expressed. Here, we describe a novel non-apoptotic role for caspase-3 in melanoma cell motility. Through comprehensive molecular and cellular analyses, we demonstrate that caspase-3 is constitutively associated with the cytoskeleton and crucially regulates melanoma cell migration and invasion in vitro and in vivo. Mechanistically, caspase-3 interacts with and modulates the activity of coronin 1B, a key regulator of actin polymerization, thereby promoting melanoma cell motility, independently of its apoptotic protease function. Furthermore, we identify specificity protein 1 (SP1) as a transcriptional regulator of CASP3 expression, and show that its inhibition reduces caspase-3 expression and impairs melanoma cell migration. Overall, this study provides insights into the multifaceted roles of caspase-3 in cancer progression, highlighting its relevance as a novel target for anti-metastatic therapies."
384,"A hypercubic Mk model framework for capturing reversibility in disease, cancer, and evolutionary accumulation modelling","Iain G. Johnston, Ramon Diaz-Uriarte",https://www.biorxiv.org/content/10.1101/2024.06.27.600959v1,"Accumulation models, where a system progressively acquires binary features over time, are common in the study of cancer progression, evolutionary biology, and other fields. Many approaches have been developed to infer the accumulation pathways by which features (for example, mutations) are acquired over time. However, most of these approaches do not support reversibility: the loss of a feature once it has been acquired (for example, the clearing of a mutation from a tumour or population). Here, we demonstrate how the well-established Mk model from evolutionary biology, embedded on a hypercubic transition graph, can be used to infer the dynamics of accumulation processes, including the possibility of reversible transitions, from data which may be uncertain and cross-sectional, longitudinal, or phylogenetically / phylogenomically embedded. Positive and negative interactions between arbitrary sets of features (not limited to pairwise interactions) are supported. We demonstrate this approach with synthetic datasets and real data on bacterial drug resistance and cancer progression. While this implementation is limited in the number of features that can be considered, we discuss how this limitation may be relaxed to deal with larger systems."
385,RBM7 deficiency promotes breast cancer metastasis by coordinating MFGE8 splicing switch and NF-kB pathway,"Fang Huang, Zhenwei Dai, Jinmiao Yu, Kainan Wang, Chaoqun Chen, Dan Chen, Jinrui Zhang, Jinyao Zhao, Mei Li, Wenjing Zhang, Xiaojie Li, Yangfan Qi, Yang Wang",https://www.biorxiv.org/content/10.1101/2024.01.03.574004v4,"Aberrant alternative splicing is well-known to be closely associated with tumorigenesis of various cancers. However, the intricate mechanisms underlying breast cancer metastasis driven by deregulated splicing events remain largely unexplored. Here, we unveiled that RBM7 is decreased in lymph node and distant organ metastases of breast cancer as compared to primary lesions and low expression of RBM7 is correlated with the reduced disease-free survival of breast cancer patients. Breast cancer cells with RBM7 depletion exhibited an increased potential for lung metastasis compared to scramble control cells. The absence of RBM7 stimulated breast cancer cell migration, invasion, and angiogenesis. Mechanistically, RBM7 controlled the splicing switch of MFGE8, favoring the production of the predominant isoform of MFGE8, MFGE8-L. This resulted in the attenuation of STAT1 phosphorylation and alterations in cell adhesion molecules. MFGE8-L exerted an inhibitory effect on the migratory and invasive capability of breast cancer cells, while the truncated isoform MFGE8-S, which lack the second F5/8 type C domain had the opposite effect. In addition, RBM7 negatively regulates the NF-κB cascade and an NF-κB inhibitor could obstruct the increase in HUVEC tube formation caused by RBM7 silencing. Clinically, we noticed a positive correlation between RBM7 expression and MFGE8 exon7 inclusion in breast cancer tissues, providing new mechanistic insights for molecular-targeted therapy in combating breast cancer."
386,Graph neural networks best guide phenotypic virtual screening on cancer cell lines,"Sachin Vishwakarma, Saiveth Hernandez-Hernandez, Pedro J. Ballester",https://www.biorxiv.org/content/10.1101/2024.06.26.600790v1,"Artificial intelligence is increasingly driving early drug design, offering novel approaches to virtual screening. Phenotypic virtual screening (PVS) aims to predict how cancer cell lines respond to different compounds by focusing on observable characteristics rather than specific molecular targets. Some studies have suggested that deep learning may not be the best approach for PVS. However, these studies are limited by the small number of tested molecules as well as not employing suitable performance metrics and dissimilar-molecules splits better mimicking the challenging chemical diversity of real-world screening libraries. Here we prepared 60 datasets, each containing approximately 30,000 to 50000 molecules tested for their growth inhibitory activities on one of the NCI-60 cancer cell lines. We evaluated the performance of five machine learning algorithms for PVS on these 60 problem instances. To provide a comprehensive evaluation, we employed two model validation types: the random split and the dissimilar-molecules split. The models were primarily evaluated using hit rate, a more suitable metric in VS contexts. The results show that all models are more challenged by test molecules that are substantially different from those in the training data. In both validation types, the D-MPNN algorithm, a graph-based deep neural network, was found to be the most suitable for building predictive models for this PVS problem."
388,Evolution of the Spatial transcriptomic landscape during the progression of high-grade pancreatic intraductal papillary mucinous neoplasms to invasive cancer,"Sirui Peng, Qiangxing Chen, Zixin Chen, Mengling Yao, Yunqiang Cai, Du He, Yu Cai, Ke Cheng, Jun Li, He Cai, Pan Gao, Xiafei Gu, Xin Wang, Yongbin Li, Man Zhang, Lingwei Meng, Qi Xia, Panpan Xu, Jin Zhou, Zhong Wu, Bing Peng",https://www.biorxiv.org/content/10.1101/2024.08.24.608470v1,"Intraductal papillary mucinous neoplasms (IPMN) is one of the known precancerous lesions. Patients’ prognosis is aggravated as IPMN transforms into invasive Pancreatic Ductal Adenocarcinoma (PDAC). The molecular mechanisms underlying this progression lack effective experimental models and urgently need to be elaborated. We performed spatial transcriptomics (ST) on fresh tissue samples from the same patient including normal pancreas, high-grade IPMN, and invasive PDAC, and described the step-by-step development of transcriptional landscape including clone evolution and adjacent TME feature variation. Our findings identified the master transcript factors and critical signaling pathways promoting IPMN progression to invasive PDAC. Additionally, both IPMN and PDAC harbored the ELF3, MYC, and KLF4 amplification. The Spatial CNV profile demonstrated significant heterogeneity among PDAC in their spatial distribution compared to IPMN, with seven distinct subclones showing diverse functions, such as hypoxia, oxidative phosphorylation, and epithelial-mesenchymal Transition. We observed a marked shift in the immune landscape, with the depletion of CD4+ T-cells and dendritic cells and an increase in immune-suppressive M2 macrophages in invasive PDAC, indicating a transition to an immune-evasive microenvironment. Additionally, cancer-associated fibroblasts (CAFs), particularly myofibroblastic CAFs, were enriched adjacent to invasive PDAC, suggesting their active role in tumor progression. By leveraging spatial transcriptomic analysis, our study provides comprehensive insights into the intricate molecular landscape that underlies the progression of IPMNs to invasive PDAC. These findings not only enhance our understanding of this complex process but also offer valuable knowledge for early diagnosis and intervention."
389,Synthetic augmentation of cancer cell line multi-omic datasets using unsupervised deep learning,"Zhaoxiang Cai, Sofia Apolinário, Ana R. Baião, Clare Pacini, Miguel D. Sousa, Susana Vinga, Roger R Reddel, Phillip J. Robinson, Mathew J. Garnett, Qing Zhong, Emanuel Gonçalves",https://www.biorxiv.org/content/10.1101/2024.06.26.600742v1,"Multi-omic characterization and integration remains a challenge due to data complexity and sparsity. Addressing this, our study introduces an unsupervised deep learning model, MOVE (Multi-Omic Variational Encoder), specifically designed to integrate and augment the Cancer Dependency Map (DepMap). Harnessing orthogonal multi-omic information, this model successfully generates molecular and phenotypic profiles, resulting in an increase of 32.7% in the number of multi-omic profiles and thereby generating a complete DepMap for 1,523 cancer cell lines. The synthetically enhanced data increases statistical power, uncovering less studied mechanisms associated with drug resistance, and refines the identification of genetic associations and clustering of cancer cell lines. By applying SHAP for model interpretation, MOVE reveals multi-omic features essential for cell clustering and biomarker identification related to drug and gene dependencies. This understanding is crucial for the development of much-needed, effective strategies in prioritizing cancer targets."
390,Aggressive KRAS mutations direct TGF-β response towards partial EMT in patient-derived colorectal cancer tumoroids,"Theresia Mair, Philip König, Milena Mijović, Loan Tran, Pedro Morata Saldaña, Carlos Uziel Pérez Malla, Kristina Draganić, Janette Pfneissl, Andreas Tiefenbacher, Julijan Kabiljo, Velina S. Atanasova, Jessica Kalla, Lisa Wozelka-Oltjan, Leonhard Müllauer, Michael Bergmann, Raheleh Sheibani-Tezerji, Gerda Egger",https://www.biorxiv.org/content/10.1101/2024.06.25.600620v1,"Transforming growth factor beta (TGF-β) exhibits complex and context-dependent cellular responses. While it mostly induces tumor-suppressive effects in early stages of tumorigenesis, its tumor promoting properties are evident in advanced disease. This TGF-β duality is still not fully understood, and whether TGF-β supports invasion and metastasis by influencing cancer cells directly, or rather through the stromal tumor compartment remains a matter of debate. Here, we utilized a library of colorectal cancer (CRC) patient-derived tumoroids (PDTs), representing a spectrum of tumor stages, to study cancer cell-specific responses to TGF-β. Using medium conditions allowing for the differentiation of PDTs, we observed TGF-β induced tumor-suppressive effects in early-stage tumoroids. PDTs with TGF-β pathway mutations or PDTs derived from metastatic tumors were insensitive to the treatment. Notably, one tumoroid line harboring an atypical KRASQ22K mutation underwent partial epithelial-to-mesenchymal transition (EMT), associated with morphological changes and increased invasiveness. On a molecular level, this was accompanied by elevated expression of mesenchymal genes, as well as deregulation of pathways associated with matrix remodeling and cell adhesion. Our results suggest that tumor cell intrinsic responses to TGF-β are critical in determining its tumor-suppressive or -promoting effects."
391,Exploring the role of EMT in Ovarian Cancer Progression: Insights from a multiscale mathematical model,"Samuel Oliver, Michael Williams, Mohit Kumar Jolly, Deyarina Gonzalez, Gibin Powathil",https://www.biorxiv.org/content/10.1101/2024.06.25.600568v1,"Epithelial-to-mesenchymal transition (EMT) plays a key role in the progression of cancer tumours and can make treatment significantly less successful for patients. EMT occurs when a cell gains a different phenotype and possesses different behaviours to those previously exhibited. This may result in enhanced drug resistance, higher cell plasticity, and increased metastatic abilities. It has therefore has become essential to encapsulate this change and study tumour progression and its response to treatments. Here, we use a 3D agent-based multiscale modelling framework based on Physicell to investigate the role of EMT over time in two cell lines, OVCAR-3 and SKOV-3. The impact of conditions in the microenvironment are incorporated into the model by modifying cellular behaviours dependant on variables such as substrate concentrations and proximity to neighbouring cells. OVCAR-3 and SKOV-3 cell lines possess highly contrasting tumour layouts, allowing a vast array of different tumour dynamics and morphologies to be tested and studied. The model encapsulates the biological observations and trends seen in tumour growth and development, thus can help to obtain further insights into OVCAR-3 and SKOV-3 cell line dynamics. Sensitivity analysis was performed to investigate the impact of parameter sensitivity on model outcome. Sensitivity analysis showed that parameters used in generating the rate of EMT and cycle rates within the cells are relatively more sensitive than other parameters used."
392,Intraperitoneal activation of myeloid cells clears ascites and reveals IL27-dependent regression of metastatic ovarian cancer,"Brennah Murphy, Taito Miyamoto, Bryan S. Manning, Gauri Mirji, Alessio Ugolini, Toshitha Kannan, Kohei Hamada, Yanfang Peipei Zhu, Daniel T. Claiborne, Lu Huang, Rugang Zhang, Yulia Nefedova, Andrew Kossenkov, Filippo Veglia, Rahul Shinde, Nan Zhang",https://www.biorxiv.org/content/10.1101/2024.06.25.600597v1,"Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of less than 30% due to persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa."
393,MAPK14/p38α Shapes the Molecular Landscape of Endometrial Cancer and promotes Tumorigenic Characteristics,"Sayali Joseph, Xingyuan Zhang, Gaith Droby, Di Wu, Victoria Bae-Jump, Scott Lyons, Angie Mordant, Allie Mills, Laura Herring, Blake Rushing, Jessica Bowser, Cyrus Vaziri",https://www.biorxiv.org/content/10.1101/2024.06.25.600674v1,"The molecular underpinnings of High Grade Endometrial Carcinoma (HGEC) metastatic growth and survival are poorly understood. Here we show that ascites-derived and primary tumor HGEC cell lines in 3D spheroid culture faithfully recapitulate key features of malignant peritoneal effusion and exhibit fundamentally distinct transcriptomic, proteomic and metabolomic landscapes when compared with conventional 2D monolayers. Using genetic screening platform we identify MAPK14 (which encodes the protein kinase p38α) as a specific requirement for HGEC in spheroid culture. MAPK14/p38α has broad roles in programing the phosphoproteome, transcriptome and metabolome of HGEC spheroids, yet has negligible impact on monolayer cultures. MAPK14 promotes tumorigenicity in vivo and is specifically required to sustain a sub-population of spheroid cells that is enriched in cancer stemness markers. Therefore, spheroid growth of HGEC activates unique biological programs, including p38α signaling, that cannot be captured using 2D culture models and are highly relevant to malignant disease pathology."
394,Stabilization of GTSE1 by cyclin D1-CDK4/6 promotes cell proliferation: relevance in cancer prognosis,"Nelson García-Vázquez, Tania J. González-Robles, Ethan Lane, Daria Spasskaya, Qingyue Zhang, Marc Kerzhnerman, YeonTae Jeong, Marta Collu, Daniele Simoneschi, Kelly V. Ruggles, Gergely Rona, Michele Pagano, Sharon Kaisari",https://www.biorxiv.org/content/10.1101/2024.06.26.600797v1,"Cyclin D1 is the activating subunit of the cell cycle kinases CDK4 and CDK6, and its dysregulation is a well-known oncogenic driver in many human cancers. The biological function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G2 and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unknown substrate of cyclin D1-CDK4/6. The phosphorylation of GTSE1 mediated by cyclin D1-CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 also during the G1 phase of the cell cycle. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation."
395,"Confinement, jamming, and adhesion in cancer cells dissociating from a collectively invading strand","Wei Wang, Robert A. Law, Emiliano Perez Ipiña, Konstantinos Konstantopoulos, Brian A. Camley",https://www.biorxiv.org/content/10.1101/2024.06.28.601053v1,"When cells in a primary tumor work together to invade into nearby tissue, this can lead to cell dissociations—cancer cells breaking off from the invading front—leading to metastasis. What controls the dissociation of cells, and whether they break off singly or in small groups? Can this be determined by cell-cell adhesion or chemotactic cues given to cells? We develop a physical model for this question, based on experiments that mimic aspects of cancer cell invasion using microfluidic devices with microchannels of different widths. Experimentally, most dissociation events (“ruptures”) involve single cells breaking off, but we observe some ruptures of large groups (∼ 20 cells) in wider channels. The rupture probability is nearly independent of channel width. We recapitulate the experimental results with a phase field cell motility model by introducing three different cell states (follower, guided, and high-motility metabolically active leader cells) based on their spatial position. These leader cells may explain why single-cell rupture is the universal most probable outcome. Our simulation results show that cell-channel adhesion is necessary for cells in narrow channels to invade, and strong cell-cell adhesion leads to fewer but larger ruptures. Chemotaxis also influences the rupture behavior: Strong chemotaxis strength leads to larger and faster ruptures. Finally, we study the relationship between biological jamming transitions and cell dissociations. Our results suggest unjamming is necessary but not sufficient to create ruptures."
396,G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian cancer,"Jenna Robinson, Gem Flint, Ian Garner, Silvia Galli, Thomas E. Maher, Marina K. Kuimova, Ramon Vilar, Iain A. McNeish, Robert Brown, Hector Keun, Marco Di Antonio",https://www.biorxiv.org/content/10.1101/2024.06.24.600010v1,"Epigenetic evolution is a common mechanism used by cancer cells to evade the therapeutic effects of drug treatment. In ovarian cancers, epigenetically-driven resistance may be responsible for a large number of late-stage patient deaths. Here, we describe the first investigation into the role of G-quadruplex (G4) DNA secondary structures in mediating epigenetic regulation in drug-resistant ovarian cancer cells. Through genome-wide mapping of G4s in paired drug-sensitive and drug-resistant cell lines, we find that increased G4 formation is associated with significant increase in gene expression, with high enrichment in signalling pathways previously established to promote drug-resistant states. However, in contrast to previous studies, the expression-enhancing effects of G4s were not found at gene promoters, but intergenic and intronic regions, indicating that G4s promote long-range transcriptional regulation in drug-resistant cells. Furthermore, we discovered that clusters of G4s (super-G4s) are associated with particularly high levels of transcriptional enhancement that surpass the effects of super-enhancers, which act as well established regulatory sites in many cancers. Finally, we demonstrate that targeting G4s with small molecules results in significant down-regulation of pathways associated with drug-resistance, which results in resensitisation of resistant cells to chemotherapy agents. These findings indicate that G4 structures are critical for the epigenetic regulatory networks of drug-resistant cells and may represent a promising target to treat drug-tolerant ovarian cancer."
397,Lipidic and senescent macrophages predict progression and response to combinatorial immunotherapy in triple-negative breast cancer,"Chun Lai Chan, Alex To, Shihui Zhang, Jason Wing Hon Wong, Yuanhua Huang, Yiming Chao, Ryohichi Sugimura",https://www.biorxiv.org/content/10.1101/2024.06.24.600550v1,"Immune cell subsets in the tumor predict prognosis. Identifying reliable subsets consistently in multiple patients is clinically important. What’s more advantageous to the field is if such subsets can be a target of immunotherapy. Here we analyzed single-cell RNA-sequencing datasets of patients with triple-negative breast cancer and identified APOE or FABP5-expressing macrophages correlated with poor prognosis. Further validation with TCGA-BRCA cohort detailed molecular signatures of these macrophages as lipidic and senescent. Our receptor-ligand mapping identified lipidic and senescent macrophages both suppress T-lymphoid and myeloid immunogenicity. Finally, we discovered that immune checkpoint therapy combined with chemotherapy reprogrammed anti-tumor microenvironment enriched with FOLR2+ macrophages facilitated T-cell activations. This suggests that lipidic and senescent macrophages could be a therapeutic target of immune checkpoint therapy."
399,Recurrent disruption of tumour suppressor genes in cancer by somatic mutations in cleavage and polyadenylation signals,"Yaroslav Kainov, Fursham Hamid, Eugene V. Makeyev",https://www.biorxiv.org/content/10.1101/2024.06.23.600297v1,"The expression of eukaryotic genes relies on the precise 3’-terminal cleavage and polyadenylation of newly synthesized pre-mRNA transcripts. Defects in these processes have been associated with various diseases, including cancer. While cancer-focused sequencing studies have identified numerous driver mutations in protein-coding sequences, noncoding drivers – particularly those affecting the cis-elements required for pre-mRNA cleavage and polyadenylation – have received less attention. Here, we systematically analysed cancer somatic mutations affecting 3’UTR polyadenylation signals using the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset. We found a striking enrichment of cancer-specific somatic mutations that disrupt strong and evolutionarily conserved cleavage and polyadenylation signals within tumour suppressor genes. Further bioinformatics and experimental analyses conducted as a part of our study suggest that these mutations have a profound capacity to downregulate the expression of tumour suppressor genes. Thus, this work uncovers a novel class of noncoding somatic mutations with significant potential to drive cancer progression."
401,EPLINα controls integrin recycling from Rab21 endosomes to drive breast cancer cell migration,"Niklas Z. Jäntti, Paulina Moreno-Layseca, Megan R. Chastney, Michal Dibus, James R. W. Conway, Veli-Matti Leppänen, Hellyeh Hamidi, Kathrin Eylmann, Leticia Oliveira-Ferrer, Stefan Veltel, Johanna Ivaska",https://www.biorxiv.org/content/10.1101/2024.06.27.600789v1,"EPLIN, an actin-binding protein, has been described as both a tumour promoter and tumour suppressor in different cancers. EPLIN isoform(α or β)-specific functions, which remain largely unknown, could explain these opposing roles. We observed distinct EPLIN-isoform localization; EPLINα is recruited to actin in plasma membrane ruffles and endosomes, while EPLINβ resides on actin stress fibers. We identified two EPLIN actin-binding regions and demonstrated EPLINα interaction with Rab21, an established regulator of β1-integrin endosomal traffic. EPLINα co-localizes with Rab21 and F-actin on recycling endosomes in an actin binding-dependent manner and supports β1-integrin recycling and cell migration. Using BioID, we identified coronin 1C as an EPLIN proximal protein, which localizes at Rab21-containing endosomes in an EPLINα-dependent manner. EPLINα expression was linked to increased breast cancer cell motility, and high EPLINα-to-EPLINβ ratio correlated with a mesenchymal phenotype in patient samples. Our work unveils unprecedented EPLIN isoform-specific functions relevant to breast cancer and beyond."
402,TimiGP-Response: the pan-cancer immune landscape associated with response to immunotherapy,"Chenyang Li, Wei Hong, Alexandre Reuben, Linghua Wang, Anirban Maitra, Jianjun Zhang, Chao Cheng",https://www.biorxiv.org/content/10.1101/2024.06.21.600089v1,"Accumulating evidence suggests that the tumor immune microenvironment (TIME) significantly influences the response to immunotherapy, yet this complex relationship remains elusive. To address this issue, we developed TimiGP-Response (TIME Illustration based on Gene Pairing designed for immunotherapy Response), a computational framework leveraging single-cell and bulk transcriptomic data, along with response information, to construct cell-cell interaction networks associated with responders and estimate the role of immune cells in treatment response. This framework was showcased in triple-negative breast cancer treated with immune checkpoint inhibitors targeting the PD-1:PD-L1 interaction, and orthogonally validated with imaging mass cytometry. As a result, we identified CD8+ GZMB+ T cells associated with responders and its interaction with regulatory T cells emerged as a potential feature for selecting patients who may benefit from these therapies. Subsequently, we analyzed 3,410 patients with seven cancer types (melanoma, non-small cell lung cancer, renal cell carcinoma, metastatic urothelial carcinoma, hepatocellular carcinoma, breast cancer, and esophageal cancer) treated with various immunotherapies and combination therapies, as well as several chemo- and targeted therapies as controls. Using TimiGP-Response, we depicted the pan-cancer immune landscape associated with immunotherapy response at different resolutions. At the TIME level, CD8 T cells and CD4 memory T cells were associated with responders, while anti-inflammatory (M2) macrophages and mast cells were linked to non-responders across most cancer types and datasets. Given that T cells are the primary targets of these immunotherapies and our TIME analysis highlights their importance in response to treatment, we portrayed the pan-caner landscape on 40 T cell subtypes. Notably, CD8+ and CD4+ GZMK+ effector memory T cells emerged as crucial across all cancer types and treatments, while IL-17-producing CD8+ T cells were top candidates associated with immunotherapy non-responders. In summary, this study provides a computational method to study the association between TIME and response across the pan-cancer immune landscape, offering resources and insights into immune cell interactions and their impact on treatment efficacy."
403,"Towards routine proteome profiling of FFPE tissue: Insights from a 1,200 case pan-cancer study","Johanna Tüshaus, Stephan Eckert, Marius Fraefel, Yuxiang Zhou, Pauline Pfeiffer, Christiane Halves, Federico Fusco, Johannes Weigl, Lisa Hönikl, Vicki Butenschön, Rumyana Todorova, Hilka Rauert-Wunderlich, Matthew The, Andreas Rosenwald, Volker Heinemann, Julian Holch, Bernhard Meyer, Wilko Weichert, Carolin Mogler, Peer Hendrik-Kuhn, Bernhard Kuster",https://www.biorxiv.org/content/10.1101/2024.06.21.600043v1,"Proteome profiling of formalin-fixed paraffin-embedded (FFPE) specimens has gained traction for the analysis of cancer tissue for the discovery of molecular biomarkers. However, reports so far focused on single cancer entities, comprised relatively few cases and did not assess the long-term performance of experimental workflows. Here, we did so by analyzing 1,220 tumors from six cancer entities processed over the course of three years. Key findings include the need for a new normalization method ensuring equal and reproducible sample loading for LC-MS/MS analysis across cohorts, showing that tumors can, on average, be profiled to a depth of >4,000 proteins and discovering that current software fails to process such large data sets. We report the first comprehensive pan-cancer proteome expression resource for FFPE material comprising 11,000 proteins which is of immediate utility to the scientific community by way of a web resource. It enables a range of analysis including quantitative comparisons of proteins between patients or cohorts or the discovery of protein fingerprints representing the tissue of origin, or proteins enriched in certain cancer entities."
404,CDK4/6 inhibitors promote senescence-associated lysosomal alterations and enhance sensitivity to lysosomotropic agents in breast cancer,"Jamil Nehme, Sjors Maassen, Sara Bravaccini, Michele Zanoni, Caterina Gianni, Ugo De Giorgi, Abel Soto-Gamez, Abdullah Altulea, Teodora Gheorghe, Boshi Wang, Marco Demaria",https://www.biorxiv.org/content/10.1101/2024.08.22.609150v1,"Breast cancer remains a leading cause of mortality globally, emphasizing the need to develop more effective and well-tolerated treatments. Pharmacological inhibitors of Cyclin-Dependent Kinases (CDK) 4 and 6 (CDK4/6i) can inhibit breast cancer growth by inducing a senescent-like state. However, long-term treatment efficacy remains hindered by the development of drug resistance and restoration of cell proliferation. Thus, clearance of senescent-like cancer cells may extend the durability of treatment. In this study, we showed that CDK4/6i-treated breast cancer cells exhibit various senescence-associated phenotypes that remain insensitive to common senolytic compounds. By searching for novel vulnerabilities, we identified a significantly increased lysosomal mass and altered lysosomal structure across various breast cancer cell types upon exposure to CDK4/6i in preclinical systems and clinical specimens. We demonstrated that these lysosomal alterations render breast cancer cells sensitive to lysosomotropic agents, such as L-leucyl-L-leucine methyl ester (LLOMe) and salinomycin. Importantly, sequential treatment with CDK4/6i/lysosomotropic agents effectively reduced the growth of both Hormone Receptor-positive (HR+) and triple-negative breast cancer (TNBC) cells in vivo. This sequential therapeutic strategy offers a promising approach to eliminate CDK4/6i-induced senescent(-like) cells, potentially reducing tumor recurrence and enhancing the overall efficacy of breast cancer therapy."
406,CYB561 supports the neuroendocrine phenotype in castration-resistant prostate cancer,"Romie Angelo G. Azur, Kevin Christian V. Olarte, Weand S. Ybañez, Alessandria Maeve M. Ocampo, Pia D. Bagamasbad",https://www.biorxiv.org/content/10.1101/2024.02.29.582710v1,"Castration-resistant prostate cancer (CRPC) is associated with resistance to androgen deprivation therapy, and an increase in the population of neuroendocrine (NE) differentiated cells. It is hypothesized that NE differentiated cells secrete neuropeptides that support androgen-independent tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. The cytochrome b561 (CYB561) gene, which codes for a secretory vesicle transmembrane protein, is constitutively expressed in NE cells and highly expressed in CRPC. CYB561 is involved in the α-amidation-dependent activation of neuropeptides, and contributes to regulating iron metabolism which is often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression and maintenance of the highly aggressive NE phenotype in CRPC. In our study, we found that CYB561 expression is upregulated in metastatic and NE prostate cancer (NEPC) tumors and cell lines compared to normal prostate epithelia, and that its expression is independent of androgen regulation. Knockdown of CYB561 in androgen-deprived LNCaP cells dampened NE differentiation potential and transdifferentiation-induced increase in iron levels. In NEPC PC-3 cells, depletion of CYB561 reduced the secretion of growth-promoting factors, lowered intracellular ferrous iron concentration, and mitigated the highly aggressive nature of these cells in complementary assays for cancer hallmarks. These findings demonstrate the role of CYB561 in facilitating transdifferentiation and maintenance of NE phenotype in CRPC through its involvement in neuropeptide biosynthesis and iron metabolism pathways."
408,Inference of chromosome selection parameters and missegregation rate in cancer from DNA-sequencing data,"Zijin Xiang, Zhihan Liu, Khanh N. Dinh",https://www.biorxiv.org/content/10.1101/2024.04.05.588351v2,"Aneuploidy is frequently observed in cancers and has been linked to poor patient outcome. Analysis of aneuploidy in DNA-sequencing (DNA-seq) data necessitates untangling the effects of the Copy Number Aberration (CNA) occurrence rates and the selection coefficients that act upon the resulting karyotypes. We introduce a parameter inference algorithm that takes advantage of both bulk and single-cell DNA-seq cohorts. The method is based on Approximate Bayesian Computation (ABC) and utilizes CINner, our recently introduced simulation algorithm of chromosomal instability in cancer. We examine three groups of statistics to summarize the data in the ABC routine: (A) Copy Number-based measures, (B) phylogeny tip statistics, and (C) phylogeny balance indices. Using these statistics, our method can recover both the CNA probabilities and selection parameters from ground truth data, and performs well even for data cohorts of relatively small sizes. We find that only statistics in groups A and C are well-suited for identifying CNA probabilities, and only group A carries the signals for estimating selection parameters. Moreover, the low number of CNA events at large scale compared to cell counts in single-cell samples means that statistics in group B cannot be estimated accurately using phylogeny reconstruction algorithms at the chromosome level. As data from both bulk and single-cell DNA-sequencing techniques becomes increasingly available, our inference framework promises to facilitate the analysis of distinct cancer types, differentiation between selection and neutral drift, and prediction of cancer clonal dynamics."
409,ERK3/MAPK6 promotes triple-negative breast cancer progression through collective migration and EMT plasticity,"Sofia Morazzo, Soraia Fernandes, Marina Fortea, Helena Skálová, Marco Cassani, Kamila Vrzalová, Filip Kafka, Jan Vrbský, Daniel Pereira de Sousa, Veronika Bosáková, Jaeyoung Shin, Jan Fric, Kristina Haase, Giancarlo Forte",https://www.biorxiv.org/content/10.1101/2024.06.20.599916v1,"Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and is associated with high cell plasticity, recurrence, and metastatic rate. During epithelial-to-mesenchymal transition (EMT), cancer cells display EMT plasticity, or partial-EMT features, which are required for breast cancer metastasis, such as collective migration. ERK3 has been implicated in promoting migration and invasion of breast cancer, but the mechanisms remain elusive. Here, we investigated ERK3 expression across patient-derived datasets of breast cancer and established its association with aggressive breast cancer phenotypes and poor clinical outcomes. Leveraging the hypothesis that ERK3 contributes to TNBC progression by supporting a partial-EMT state, we showed that ERK3 is essential in different steps of the metastatic process, especially by enabling collective migration but also by modulating cell-extracellular matrix adhesion, anchorage-independent growth, extravasation and colonization. In conclusion, our results demonstrate that ERK3 contributes to TNBC progression and potentially metastasis by promoting EMT plasticity and collective migration."
411,High-Performance Classification of Breast Cancer Histopathological Images Using Fine-Tuned Vision Transformers on the BreakHis Dataset,Venkat Gella,https://www.biorxiv.org/content/10.1101/2024.08.17.608410v1,"Breast cancer remains one of the most prevalent and deadly cancers worldwide, making accurate diagnosis critical for effective treatment. Histopathological image classification is a key task in medical diagnostics for cancer detection. This paper presents state-of-the-art performance in histopathological image classification of breast cancer using a novel approach with the Vision Transformer (ViT) model fine-tuned using the BreakHis dataset. The BreakHis dataset, comprising of 7,909 breast cancer histopathological images across various magnification levels, serves as a crucial benchmark for evaluating machine learning models in this domain. While previous works have explored the use of ViTs for this task, our approach fine-tunes a ViT pre-trained on ImageNet using the Ranger optimizer, achieving unprecedented performance. The experimental results show that our fine-tuned ViT model achieves an accuracy of 99.99%, precision of 99.98%, recall of 99.99%, F1 score of 99.99%, specificity of 100.00%, false discovery rate (FDR) of 0.00%, false negative rate (FNR) of 0.02%, false positive rate (FPR) of 0.00%, Matthews correlation coefficient (MCC) of 99.97%, and negative predictive value (NPV) of 99.96%. This model and approach represents the highest accuracy ever achieved for BreakHis binary classification in machine learning using any model, underscoring the potential of Vision Transformers to substantially enhance diagnostic accuracy in histopathological image analysis and improve clinical outcomes. Transfer learning was also performed on the BACH and a histopathological image dataset for breast invasive ductal carcinomas (IDC)."
414,Functionality of BRCA1 supports the survival of prostate cancer cells during the development of castration resistance,"Saiganesh Sriraman, Verneri Virtanen, Antti Kukkula, Mervi Toriseva, Anne Rokka, Anni Lumiainen, Johanna K. Ahlskog, Gun West, Matti Poutanen, Pekka Taimen, Maria Sundvall",https://www.biorxiv.org/content/10.1101/2024.06.19.599365v1,"Androgen deprivation therapy (ADT; castration) is the main treatment option for metastatic prostate cancer (PCa), but eventually, castration-resistant prostate cancer (CRPC) develops with no curative treatments. In CRPC, more than 20% of men carry mutations in DNA damage response (DDR) genes, including BRCA1/2. In this study, we elucidated the prostate tissue-specific functional role of BRCA1 protein. Our results indicate that DDR is dynamically regulated by androgen receptor (AR) signaling, and AR activation by the natural ligand dihydrotestosterone strongly downregulates the expression of BRCA1 in multiple cell lines. Consistent with these findings, our analyses of patient samples and mouse xenografts showed that DNA damage and BRCA1 expression were sustained after ADT. With unbiased mass spectrometry and bioinformatics approaches as well as experimentally, we found that BRCA1 interacts with Raptor, an mTORC1 component, and regulates the mTOR signaling pathway and PCa growth in vitro. Furthermore, we found that mTOR inhibition reduced the recruitment of DDR proteins, BRCA1 and Rad51, to DNA damage sites, creating a vulnerability towards DNA damage-inducing androgen deprivation. Moreover, we observed that BRCA1 supported ADT-induced activation of the oxidative stress sensor NRF2. Our findings shed further light on the complex DDR–AR interplay in PCa and suggest that, during PCa progression, BRCA1 expression may be retained due to the beneficial modulation of mTORC1 signaling in the AR environment by BRCA1."
415,Multimodal histopathologic models stratify hormone receptor-positive early breast cancer,"Kevin M. Boehm, Omar S. M. El Nahhas, Antonio Marra, Pier Selenica, Hannah Y. Wen, Britta Weigelt, Evan D. Paul, Pavol Cekan, Ramona Erber, Chiara M. L. Loeffler, Elena Guerini-Rocco, Nicola Fusco, Chiara Frascarelli, Eltjona Mane, Elisabetta Munzone, Silvia Dellapasqua, Paola Zagami, Giuseppe Curigliano, Pedram Razavi, Jorge S. Reis-Filho, Fresia Pareja, Sarat Chandarlapaty, Sohrab P. Shah, Jakob Nikolas Kather",https://www.biorxiv.org/content/10.1101/2024.02.23.581806v1,"For patients with hormone receptor-positive, early breast cancer without HER2 amplification, multigene expression assays including Oncotype DX ® recurrence score (RS) have been clinically validated to identify patients who stand to derive added benefit from adjuvant cytotoxic chemotherapy. However, cost and turnaround time have limited its global adoption despite recommendation by practice guidelines. We investigated if routinely available hematoxylin and eosin (H&E)-stained pathology slides could act as a surrogate triaging data substrate by predicting RS using machine learning methods. We trained and validated a multimodal transformer model, Orpheus, using 6,203 patients across three independent cohorts, taking both H&E images and their corresponding synoptic text reports as input. We showed accurate inference of recurrence score from whole-slide images (r = 0.63 (95% C.I. 0.58 - 0.68); n = 1,029), the raw text of their corresponding reports (r = 0.58 (95% C.I. 0.51 - 0.64); n = 972), and their combination (r = 0.68 (95% C.I. 0.64 - 0.73); n = 964) as measured by Pearson’s correlation. To predict high-risk disease (RS>25), our model achieved an area under the receiver operating characteristic curve (AUROC) of 0.89 (95% C.I. 0.83 - 0.94), and area under the precision recall curve (AUPRC) of 0.64 (95% C.I. 0.60 - 0.82), compared to 0.49 (95% C.I. 0.36 - 0.64) for an existing nomogram based on clinical and pathologic features. Moreover, our model generalizes well to external international cohorts, effectively identifying recurrence risk (r = 0.61, p < 10-4, n = 452; r = 0.60, p < 10-4, n = 575) and high-risk status (AUROC = 0.80, p < 10-4, AUPRC = 0.68, p < 10-4, n = 452; AUROC = 0.83, p < 10-4, AUPRC = 0.73, p < 10-4, n = 575) from whole-slide images. Probing the biologic underpinnings of the model decisions uncovered tumor cell size heterogeneity, immune cell infiltration, a proliferative transcription program, and stromal fraction as correlates of higher-risk predictions. We conclude that at an operating point of 94.4% precision and 33.3% recall, this model could help increase global adoption and shorten lag between resection and adjuvant therapy."
416,Induction of Ferroptosis by an Amalgam of Extracellular Vesicles and Iron Oxide Nanoparticles Overcomes Cisplatin Resistance in Lung Cancer,"Anjugam Paramanantham, Rahmat Asfiya, Yariswamy Manjunath, Lei Xu, Grace McCully, Siddharth Das, Hu Yang, Jussuf T. Kaifi, Akhil Srivastava",https://www.biorxiv.org/content/10.1101/2024.08.19.608664v1,"Extracellular vesicles (EVs) hold potential as effective carriers for drug delivery, providing a promising approach to resolving challenges in lung cancer treatment. Traditional treatments, such as with the chemotherapy drug cisplatin, encounter resistance in standard cell death pathways like apoptosis, prompting the need to explore alternative approaches. This study investigates the potential of iron oxide nanoparticles (IONP) and EVs to induce ferroptosis—a regulated cell death mechanism—in lung cancer cells. We formulated a novel EV and IONP-based system, namely ‘ExoFeR’, and observed that ExoFeR demonstrated efficient ferroptosis induction, evidenced by downregulation of ferroptosis markers (xCT/SLC7A11 and GPX4), increased intracellular and mitochondrial ferrous iron levels, and morphological changes in mitochondria. To enhance efficacy, tumor-targeting transferrin (TF)-conjugated ExoFeR (ExoFeRTF) was developed. ExoFeRTF outperformed ExoFeR, exhibiting higher uptake and cell death in lung cancer cells. Mechanistically, nuclear factor erythroid 2-related factor 2 (Nrf2)—a key regulator of genes involved in glutathione biosynthesis, antioxidant responses, lipid metabolism, and iron metabolism—was found downregulated in the ferroptotic cells. Inhibition of Nrf2 intracellular translocation in ExoFeRTF-treated cells was also observed, emphasizing the role of Nrf2 in modulating ferroptosis-dependent cell death. Furthermore, ExoFeR and ExoFeRTF demonstrated the ability to sensitize chemo-resistant cancer cells, including cisplatin-resistant lung cancer patient-derived tumoroid organoids. In summary, ExoFeRTF presents a promising and multifaceted therapeutic approach for combating lung cancer by intrinsically inducing ferroptosis and sensitizing chemo-resistant cells."
418,Changes in miRNA secondary structure can predict mutations associated with cancer and other diseases,"Javor K. Novev, Sebastian E. Ahnert",https://www.biorxiv.org/content/10.1101/2024.06.19.599688v1,"MicroRNAs (miRNAs) are ubiquitous short RNAs regulating gene expression in many organisms, including humans. How the secondary structure (SS) of a mature miRNA affects its regulatory function remains an open question. Here we investigate this question through computational SS predictions of miRNA point mutants. We explore the mutational neighborhoods of miRNAs with association to human diseases, including cancer. We focus on possible SS changes independent of target-site complementarity, by leaving the seed region unchanged. We formulate metrics of the SS differences between such mutants and their wild types (WTs), and test whether these metrics predict disease association by comparing our results with the miRNASNP-v3 database. We find that disease-related mutants tend to have a higher probability of being fully unfolded than their WT; this and other SS-related measures are statistically significant at the database level. With the same approach, we identify a subset of individual miRNAs for which SS changes are most likely to predict disease-related mutations. These are hsa-miR-1269b, hsa-miR-4537, hsa-miR-4477b, hsa-miR-4641, and hsa-miR-6821-3p. In addition, we show that there are pairs of known miRNA WTs differing only by disease-related point mutations outside the seed region and exhibit very different SS. These pairs include hsa-miR-1269a—hsa-miR-1269b, and hsa-miR-3689a-3p—hsa-miR-3689b-3p."
419,Development of Machine Learning-based QSAR Models for the Designing of Novel Anti-cancer Therapeutics Against Malignant Glioma,"Fareed Asaad, Mehreen Zaka, Serdar Durdağı",https://www.biorxiv.org/content/10.1101/2024.08.19.608549v1,"In the early drug design and discovery phase, virtual screening of diverse small molecule libraries is crucial. Machine learning (ML)-based algorithms have made this process easier and faster. In this study, we have applied ML-based algorithms to generate the QSAR models for virtual screening. The aim of study is to design the statistically significant models for the screening of small molecule libraries to identify the novel hits against IDH1 mutant receptor crucial for glioblastoma multiforme (GBM). To construct the models, we have used both cell lines data (U87 and U251 cells) and the inhibitors of IDH1 mutant reported in the literature and used the pIC50 activity data to train our models. Furthermore, ligand-based 3D QSAR models and structure-based pharmacophore models were also constructed and validated."
423,Pan-cancer Analysis Reveals m6A Variation and Cell-specific Regulatory Network in Different Cancer Types,"Yao Lin, Jingyi Li, Shuaiyi Liang, Yaxin Chen, Yueqi Li, Yixian Cun, Lei Tian, Yuanli Zhou, Yitong Chen, Jiemei Chu, Hubin Chen, Qiang Luo, Ruili Zheng, Gang Wang, Hao Liang, Ping Cui, Sanqi An",https://www.biorxiv.org/content/10.1101/2023.12.11.571179v1,"As the most abundant mRNA modification in mRNA, N6-methyladenosine (m6A) plays a crucial role in RNA fate, impacting cellular and physiological processes in various tumor types. However, our understanding of the function and role of the m6A methylome in tumor heterogeneity remains limited. Herein, we collected and analyzed m6A methylomes across nine human tissues from 97 m6A-seq and RNA-seq samples. Our findings demonstrate that m6A exhibits different heterogeneity in most tumor tissues compared to normal tissues, which contributes to the diverse clinical outcomes in different cancer types. We also found that the cancer type-specific m6A level regulated the expression of different cancer-related genes in distinct cancer types. Utilizing a novel and reliable method called “m6A-express”, we predicted m6A– regulated genes and revealed that cancer type-specific m6A-regulated genes contributed to the prognosis, tumor origin and infiltration level of immune cells in diverse patient populations. Furthermore, we identified cell-specific m6A regulators that regulate cancer-specific m6A and constructed a regulatory network. Experimental validation was performed, confirming that the cell-specific m6A regulator CAPRIN1 controls the m6A level of TP53. Overall, our work reveals the clinical relevance of m6A in various tumor tissues and explains how such heterogeneity is established. These results further suggest the potential of m6A for cancer precision medicine for patients with different cancer types."
424,Identification of druggable targets from the interactome of the Androgen Receptor and Serum Response Factor pathways in prostate cancer,"Haleema Azam, Colin Veale, Kim Zitzmann, Simone Marcone, William M. Gallagher, Maria Prencipe",https://www.biorxiv.org/content/10.1101/2024.08.15.608046v1,"Objectives The Androgen Receptor (AR) is crucial for prostate cancer (PCa) progression. Despite the introduction of second-generation AR antagonist, majority of patients develop resistance. The Serum Response Factor (SRF) was identified as a player involved in a crosstalk with AR signalling pathway and associated resistance. Elevated SRF levels in PCa patients were associated with disease progression and resistance to enzalutamide. However, the molecular mediators of the crosstalk between SRF and AR still need to be elucidated. The objective of this study was to identify common interactors of the AR/SRF crosstalk as therapeutic targets."
425,Friction-induced budding of a cancer cell monolayer,"Mathieu Dedenon, Jorge Barbazán, Carlos Pérez-González, Danijela Matic Vignjevic, Pierre Sens",https://www.biorxiv.org/content/10.1101/2024.02.26.582028v1,"The environment surrounding a tumor plays a crucial role in cancer cell dissemination. Within this microenvironment, cancer-associated fibroblasts (CAFs) generate compressive forces and actively remodel tumors. Using in vitro circular clusters of cancer cell monolayers surrounded by CAFs, we generate structures that are reminiscent of multicellular buds observed in vivo for colo-rectal cancer. A supracellular contractile ring spontaneously assembles at the inner edge of the CAF monolayer and drives its closure on top of the cancer cells through a purse-string mechanism. The frictional shear stress exerted by CAFs triggers multilayering of cancer cells, followed by the emergence of a multicellular bud constricted by the CAF ring. To explain this observation, we developed a theoretical model based on continuum mechanics. This model outlines the early transformations in the shape of cancer cell monolayer and links the layering of cells to a general criterion involving height deformation. It identifies the specific physical conditions that favors budding, and reproduces the observed dependence of the budding probability and bud sizes with the diameter of the cancer cell cluster. Our findings highlight the importance of active mechanical interactions between the tumor and its micro-environment on aggressive modes of cancer invasion."
426,Loss of chromosome cytoband 13q14.2 orchestrates breast cancer pathogenesis and drug response,"Parastoo Shahrouzi, Youness Azimzade, Wioletta Brankiewicz, Sugandha Bhatia, David Kunke, Derek Richard, Xavier Tekpli, Vessela N. Kristensen, Pascal H.G. Duijf",https://www.biorxiv.org/content/10.1101/2024.06.18.599481v1,"Breast cancer (BCa) is a major global health challenge, characterized by chromosomal instability (CIN) and subsequent acquisition of extensive somatic copy number alterations (CNAs). CNAs including amplifications and deletions, significantly influence intra-tumor heterogeneity and the tumor microenvironment (TME). Among these, the loss of chromosome 13q14.2 emerges as a considerable factor in BCa pathogenesis and treatment responses. We provide evidence that this genomic alteration is under positive selective pressure, correlating with poorer patient survival. Furthermore, through multi-omic and in vitro analyses, we uncover a dual role of 13q14.2 loss: it confers a survival advantage to tumor cells and modulate the cell cycle and pro-apoptotic pathways in cancer cells, affecting macrophages population in the TME, while paradoxically increasing tumor susceptibility to BCL2 inhibitors. These findings suggest that targeting 13q14.2 as a biomarker in BCa could enhance the efficacy of existing treatments and offer a new avenue for improving clinical outcomes in BCa."
427,"The DiffInvex evolutionary model for conditional somatic selection identifies chemotherapy resistance genes in 10,000 cancer genomes","Ahmed Khalil, Fran Supek",https://www.biorxiv.org/content/10.1101/2024.06.17.599362v1,"Tumors often show an initial response to chemotherapy, but then develop resistance, leading to relapse and poor prognosis. We hypothesized that a genomic comparison of mutations in pre-treated versus treatment-naive tumors would serve to identify genes that confer resistance. A challenge in such an analysis is that therapy alters mutation burdens and signatures, confounding association studies and complicating identifying causal, selected mutations. We developed DiffInvex, a framework for identifying changes in selection acting on individual genes in somatic genomes. Crucially, DiffInvex draws on a mutation rate baseline that accounts for these shifts in neutral mutagenesis during cancer evolution. We applied DiffInvex to 9,953 cancer whole-genomes from 29 cancer types from 8 studies, containing both WGS of treatment-naive tumors and tumors pre-treated by various drugs, identifying genes where point mutations are under conditional positive or negative selection for a certain chemotherapeutic, suggesting resistance mechanisms occurring via point mutation. DiffInvex confirmed well-known chemoresistance-driver mutations in EGFR, ESR1, KIT and AR genes as being under conditional positive selection, with additional cancer types identified for EGFR and KIT. Additionally, DiffInvex identified 11 genes with treatment-associated selection for different classes of therapeutics. In most cases, these genes were common cancer genes including PIK3CA, APC, MAP2K4 and MAP3K1. This suggests that tumor resistance to therapy via mutation often occurs via selective advantages conferred by known driver genes, rather than via mutations in specialized resistance genes. Various gene-chemotherapy associations were further supported in tests for functional impact of mutations, again implemented in a conditional selection setting, as well as replicating in independent panel or exome sequencing data. In addition to nominating drug resistance genes that could be targeted by future therapeutics, DiffInvex can also be applied to diverse analysis in cancer evolution, such as comparing normal and tumoral tissues, or analyzing subclonal evolution, identifying changes in selection over time."
428,Bridging the Gap in Cancer Cell Behavior Against Matrix Stiffening: Insights from a Trizonal Model,"Mohammad E. Torki, Fan Liu, Rongguang Xu, Yunfeng Chen, Jeffery Fredberg, Zi Chen",https://www.biorxiv.org/content/10.1101/2023.12.02.569730v2,"The intricate interplay between actomyosin contractility and extracellular matrix (ECM) strain stiffening is pivotal in cancer invasion. Despite the admitted impact of such feedback, current models are inadequate in predicting the largely overlapping ranges of cell shapes and their corresponding motility levels at intermediate ranges of collagen density. To address this gap, we introduce a free energy-based, trizonal model for cell shape transition under ECM stiffening, which delineates two distinct and one overlapping motility zones entitled with their implications for cancer progression: a low-motility zone with minimal invasiveness, a high-motility zone indicative of significantly invasive cells, and a mesoregion which harbors cells at crossroads of both states. This model integrates critical factors influencing the bidirectional interaction between the cell and ECM, thereby offering a deeper grasp of cancer cell behavior. Our findings reveal that the combined effects of ECM strain stiffening and cellular contractility are key drivers of cell population heterogeneity and invasiveness. This model goes beyond existing paradigms by accurately determining the optimal cell elongation at matrix-driven steady-state equilibrium, factoring in collagen density, contractility density, stress polarization, membrane-cortical tension, and integrin dynamics through the lens of total free energy minimization. The model’s predictive capability is further validated against measured cell shapes from histological sections. Altogether, this research not only bridges a crucial knowledge gap, but also provides a robust computational framework for predicting and replicating cell shape transitions observed in human functional tissue assays, thereby enhancing our ability to understand and potentially combat cancer invasion."
429,Targeting SEZ6L2 in Colon Cancer: Efficacy of Bexarotene and Implications for Survival,"Huajun Zheng, Jianying Zheng, Yan Shen",https://www.biorxiv.org/content/10.1101/2024.06.19.599786v1,"Background Bexarotene, also recognized as Targretin, is categorized as a retinoid, a type of cancer drug. Nevertheless, the precise mechanisms of Bexarotene in relation to colon cancer remain unclear. In colon cancer, SEZ6L2 was suggested as one of the biomarkers and targets. This study presents a comprehensive exploration of the role of SEZ6L2 in colon cancer."
430,Transformer-based modeling of Clonal Selection and Expression Dynamics (TraCSED) reveals resistance signatures in breast cancer,"Nathan Maulding, Jun Zou, Wei Zhou, Ciara Metcalfe, Josh Stuart, Xin Ye, Marc Hafner",https://www.biorxiv.org/content/10.1101/2024.06.15.599136v2,"Understanding transcriptional heterogeneity in cancer cells and its implication for treatment response is critical to identify how resistance occurs and may be targeted. Such heterogeneity can be captured by in vitro studies through clonal barcoding methods. We present TraCSED (Transformer-based modeling of Clonal Selection and Expression Dynamics), a dynamic deep learning approach for modeling clonal selection. Using single-cell gene expression and the fitness of barcoded clones, TraCSED identifies interpretable gene programs and the timepoints at which they are associated with clonal selection. When applied to cells treated with either giredestrant, an estrogen receptor (ER) antagonist and degrader, or palbociclib, a CDK4/6 inhibitor, time-dependent resistance pathways are revealed. For example, ER activity is associated with positive selection around day four under palbociclib treatment and this adaptive response can be suppressed by combining the drugs. Yet, in the combination treatment, one clone still emerged. Clustering based on partial least squares regression found that high baseline expression of both SNHG25 and SNCG genes was the primary marker of positive selection to co-treatment and thus potentially associated with innate resistance – an aspect that traditional differential analysis methods missed. In conclusion, TraCSED enables associating pathways with phenotypes in a time-dependent manner from scRNA-seq data."
432,Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants,"Jacob Bowman, Vincent J. Lynch",https://www.biorxiv.org/content/10.1101/2024.02.27.582135v1,"Elephants have emerged as a model system to study the evolution of body size and cancer resistance because, despite their immense size, they have a very low prevalence of cancer. Previous studies have found that duplication of tumor suppressors at least partly contributes to the evolution of anti-cancer cellular phenotypes in elephants. Still, many other mechanisms must have contributed to their augmented cancer resistance. Here, we use a suite of codon-based maximum-likelihood methods and a dataset of 13,310 protein-coding gene alignments from 261 Eutherian mammals to identify positively selected and rapidly evolving elephant genes. We found 496 genes (3.73% of alignments tested) with statistically significant evidence for positive selection and 660 genes (4.96% of alignments tested) that likely evolved rapidly in elephants. Positively selected and rapidly evolving genes are statistically enriched in gene ontology terms and biological pathways related to regulated cell death mechanisms, DNA damage repair, cell cycle regulation, epidermal growth factor receptor (EGFR) signaling, and immune functions, particularly neutrophil granules and degranulation. All of these biological factors are plausibly related to the evolution of cancer resistance. Thus, these positively selected and rapidly evolving genes are promising candidates for genes contributing to elephant-specific traits, including the evolution of molecular and cellular characteristics that enhance cancer resistance."
434,Drug combination prediction for cancer treatment using disease-specific drug response profiles and single-cell transcriptional signatures,"Daniel Osorio, Parastoo Shahrouzi, Xavier Tekpli, Vessela N. Kristensen, Marieke L. Kuijjer",https://www.biorxiv.org/content/10.1101/2022.03.31.486602v3,"Developing novel cancer treatments is a challenging task that can benefit from computational techniques matching transcriptional signatures to large-scale drug response data. Here, we present ‘retriever,’ a tool that extracts robust disease-specific transcriptional drug response profiles based on cellular response profiles to hundreds of compounds from the LINCS-L1000 project. We used retriever to extract transcriptional drug response signatures of triple-negative breast cancer (TNBC) cell lines and combined these with a single-cell RNA-seq breast cancer atlas to predict drug combinations that antagonize TNBC-specific disease signatures. After systematically testing 152 drug response profiles and 11,476 drug combinations, we identified the combination of kinase inhibitors QL-XII-47 and GSK-690693 as the topmost promising candidate for TNBC treatment. Our new computational approach allows the identification of drugs and drug combinations targeting specific tumor cell types and subpopulations in individual patients. It is, therefore, highly suitable for the development of new personalized cancer treatment strategies."
435,MPAC: a computational framework for inferring cancer pathway activities from multi-omic data,"Peng Liu, David Page, Paul Ahlquist, Irene M. Ong, Anthony Gitter",https://www.biorxiv.org/content/10.1101/2024.06.15.599113v1,"Fully capturing cellular state requires examining genomic, epigenomic, transcriptomic, proteomic, and other assays for a biological sample and comprehensive computational modeling to reason with the complex and sometimes conflicting measurements. Modeling these so-called multi-omic data is especially beneficial in disease analysis, where observations across omic data types may reveal unexpected patient groupings and inform clinical outcomes and treatments. We present Multi-omic Pathway Analysis of Cancer (MPAC), a computational framework that interprets multi-omic data through prior knowledge from biological pathways. MPAC uses network relationships encoded in pathways using a factor graph to infer consensus activity levels for proteins and associated pathway entities from multi-omic data, runs permutation testing to eliminate spurious activity predictions, and groups biological samples by pathway activities to prioritize proteins with potential clinical relevance. Using DNA copy number alteration and RNA-seq data from head and neck squamous cell carcinoma patients from The Cancer Genome Atlas as an example, we demonstrate that MPAC predicts a patient subgroup related to immune responses not identified by analysis with either input omic data type alone. Key proteins identified via this subgroup have pathway activities related to clinical outcome as well as immune cell compositions. Our MPAC R package, available at https://bioconductor.org/packages/MPAC, enables similar multi-omic analyses on new datasets."
436,An ALK1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases,"Mehrnaz Safaee Talkhoncheh, Jonas Sjölund, Paulina Bolivar, Ewa Kurzejamska, Eugenia Cordero, Teia Vallès Pagès, Sara Larsson, Sophie Lehn, Gustav Frimannsson, Viktor Ingesson, Sebastian Braun, Jessica Pantaleo, Clara Oudenaarden, Martin Lauss, R. Scott Pearsall, Göran B. Jönsson, Charlotte Rolny, Matteo Bocci, Kristian Pietras",https://www.biorxiv.org/content/10.1101/2024.06.15.599147v1,"The biology centered around the TGF-β type I receptor ALK1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy."
437,NOK promotes tumorigenesis through coordinating epidermal growth factor receptor to boost the downstream signaling in breast cancer,"Yinyin Wang, Bingdong Zhang, Chunhua He, Bo Tian, Sihan Liu, Jianghua Li, Jiayu Wang, Shigao Yang, Bingtao Zhu, Xiaoguang Wang, Zhijie Chang, Chenxi Cao",https://www.biorxiv.org/content/10.1101/2024.08.14.608018v1,BACKGROUND Epidermal growth factor receptor (EGFR) forms a homodimer or heterodimer with other ErbB receptor family members to activate different downstream cytoplasmic signaling proteins during tumorigenesis.
438,Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis,"Michala G. Rolver, Juan C. Roda, Yifan Dai, Mette Flinck, Renata Ialchina, Julie Hindkær, Rigmor T. Dyhr, August N. Bodilsen, Nanditha S. Prasad, Jonathan Baldan, Jiayi Yao, Albin Sandelin, Luis Arnes, Stine F. Pedersen",https://www.biorxiv.org/content/10.1101/2024.06.14.599032v1,"The acidic tumor microenvironment favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether acidic environments select for cancer stem cell (CSC) properties. Bulk RNA-seq of Panc-1 human pancreatic cancer cells adapted to extracellular pH 6.5 revealed upregulation of CSC markers including CD44, EpCam, Nestin and aldehyde dehydrogenases, and CSC pathway enrichment. We therefore assessed CSC characteristics of acid-adapted (AA) and non-adapted (Ctrl) PaTu8988s and MiaPaca-2 pancreatic cancer cells. Compared to Ctrl, AA cells exhibited increased ALDH- and β-catenin activity and pancreatosphere-forming efficiency, classical CSC characteristics. Panc-1, PaTu8988s and MiaPaCa-2 AA cells differed in CSC marker expression, and AA cells did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing identified the acid adaptation-induced emergence of a population with clear CSC characteristics. Finally, in an orthotopic mouse model, AA Panc-1 cells drove strongly increased aggressiveness and liver metastasis compared to Ctrl cells."
441,Porphyrin overdrive rewires pan-cancer cell metabolism,"Swamy R. Adapa, Gregory A. Hunter, Narmin E. Amin, Christopher Marinescu, Andrew Borsky, Elizabeth M. Sagatys, Said M. Sebti, Gary W. Reuther, Gloria C. Ferreira, Rays H.Y. Jiang",https://www.biorxiv.org/content/10.1101/2022.02.18.481061v2,"Porphyrin overdrive rewires pan-cancer cell metabolism All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways for their oncogenic growth. We coined this essential metabolic rewiring ‘porphyrin overdrive’ and determined that it is cancer-universal, cancer-essential, and cancer-specific. While porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single cell RNAseq, and in early embryogenesis. Among the major drivers are proteins involved in biosynthesis of heme intermediates and heme trafficking. CRISPR/Cas9 editing to engineer leukemia cells with impaired heme biosynthetic steps confirmed our whole genomic data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel “bait-and-kill” strategy to eradicate malignant cells."
442,Integrating Multi-Modal Cancer Data Using Deep Latent Variable Path Modelling,"Alex Ing, Alvaro Andrades, Marco Raffaele Cosenza, Jan O. Korbel",https://www.biorxiv.org/content/10.1101/2024.06.13.598616v1,"Cancers are commonly characterised by a complex pathology encompassing genetic, microscopic and macroscopic features, which can be probed individually using imaging and omics technologies. Integrating this data to obtain a full understanding of pathology remains challenging. We introduce a new method called Deep Latent Variable Path Modelling (DLVPM), which combines the representational power of deep learning with the capacity of path modelling to identify relationships between interacting elements in a complex system. To evaluate the capabilities of DLVPM, we initially trained a foundational model to map dependencies between SNV, Methylation, miRNA-Seq, RNA-Seq and Histological data using Breast Cancer data from The Cancer Genome Atlas (TCGA). This method exhibited superior performance in mapping associations between data types compared to classical path modelling. We additionally performed successful applications of the model to: stratify single-cell data, identify synthetic lethal interactions using CRISPR-Cas9 screens derived from cell-lines, and detect histologic-transcriptional associations using spatial transcriptomic data. Results from each of these data types can then be understood with reference to the same holistic model of illness."
443,Deciphering the impact of cancer cell’s secretome and its derived-peptide VGF on breast cancer brain metastasis,"Rita Carvalho, Liliana Santos, Inês Conde, Ricardo Leitão, Hugo R. S. Ferreira, Célia Gomes, Ana Paula Silva, Fernando Schmitt, Carina Carvalho-Maia, João Lobo, Carmen Jerónimo, Joana Paredes, Ana Sofia Ribeiro",https://www.biorxiv.org/content/10.1101/2024.02.22.581537v1,"Brain metastases (BM) are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we have searched for a brain-tropic metastatic signature on BC cells’ secretome, as a promising source for the discovery of new biomarkers involved in brain metastatic progression."
444,"Tertiary lymphoid structures are associated with enhanced macrophage activation, immune checkpoint expression and predict outcome in cervical cancer","Laurent Gorvel, Marylou Panouillot, Marie-Sarah Rouvière, Emilien Billon, Stéphane Fattori, Jumaporn Sonongbua, Nicolas Boucherit, Amira Ben Amara, Olivia Quilichini, Samuel Granjeaud, Clara Degos, Jacques A. Nunes, Xavier Carcopino, Eric Lambaudie, Anne-Sophie Chretien, Renaud Sabatier, Marie-Caroline Dieu-Nosjean, Daniel Olive",https://www.biorxiv.org/content/10.1101/2023.08.17.552583v2,"Background Cervical tumors are usually treated using surgery, chemotherapy, and radiotherapy, and would benefit from immunotherapies. However, the immune microenvironment in cervical cancer remains poorly described. Tertiary lymphoid structures (TLS) were recently described as markers for better immunotherapy response and overall better prognosis in cancer patients."
445,Deciphering BRCAness Phenotype in Cancer: A Graph Convolutional Neural Network Approach with Layer-wise Relevance Propagation Analysis,"Jingyu Yang, Hryhorii Chereda, Jürgen Dönitz, Annalen Bleckmann, Tim Beißbarth",https://www.biorxiv.org/content/10.1101/2024.06.26.600328v3,"Background Cancer variability among patients underscores the need for personalized therapy based on genomic understanding. BRCAness, characterized by vulnerabilities similar to BRCA mutations, particularly in homologous recombination repair, shows potential sensitivity to DNA-damaging agents like PARP inhibitors, highlighting it’s clinical significance."
446,Unraveling lncRNA Diversity at a Single Cell Resolution and in a Spatial Context across Different Cancer Types,"P. Prakrithi, Tuan Vo, Hani Vu, Albert Xiong, Loan Nguyen, Andrew Newman, Vicki Whitehall, Jazmina L. Gonzalez Cruz, Ishaan Gupta, Quan Nguyen",https://www.biorxiv.org/content/10.1101/2024.08.12.607523v1,"Long non-coding RNAs (lncRNAs) play pivotal roles in gene regulation and disease, including cancer. Overcoming the limitations of lncRNA analysis with bulk data, we analyzed single-cell and spatial transcriptomics data to uncover 354937 novel lncRNAs and their functions across 13 cancer types. LncRNA functions were assessed by identifying their cell-type specificity and distinct spatial distributions across different tissue regions. First, lncRNAs were computationally validated by comparing to existing databases, and experimentally validated using spatial long read sequencing methods. Further, genome-wide computation of spatial-autocorrelation identified coexpression of lncRNAs with cancer-associated protein coding genes across the tissue. Additionally, genomic co-localization of lncRNAs with regulatory features and disease-associated genetic variants suggest possible functional association. The identified lncRNAs were analyzed for responses to immunotherapy and prognostic value, revealing cancer-outcome associated lncRNAs. We have made this novel resource available as an open website ‘SPanC-Lnc’ hosted on AWS cloud to serve as a pan-cancer atlas of single cell- and spatially-resolved lncRNAs. These can complement established biomarkers because they reflect the unique characteristics of specific cell populations within tumors, offering new insights into disease progression and treatment response."
448,Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis,"Yizhou Zhu, Hayan Lee, Shannon White, Annika K. Weimer, Emma Monte, Aaron Horning, Stephanie A. Nevins, Edward D. Esplin, Kristina Paul, Gat Krieger, Zohar Shipony, Roxanne Chiu, Rozelle Laquindanum, Thomas V. Karathanos, Melissa WY Chua, Meredith Mills, Uri Ladabaum, Teri Longacre, Jeanne Shen, Ariel Jaimovich, Doron Lipson, Anshul Kundaje, William J. Greenleaf, Christina Curtis, James M. Ford, Michael P. Snyder",https://www.biorxiv.org/content/10.1101/2022.08.26.505505v2,"Although 3D genome architecture can be essential for gene regulation, the biological implications of long-range chromatin interactions in disease remain elusive. In this study, we traced the early evolution and malignant transformation of colorectal cancer by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth from polyps of Familial Adenomatous Polyposis (FAP) patients. Our analysis reveals a substantial progressive loss of genome-wide cis-regulatory connectivity at early stages of malignancy, which correlates with a non-linear effect on gene regulation. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa are not correlated with elevated baseline expression, but instead tend to be up-regulated at advanced stages. Inhibition of highly connected promoters preferentially represses gene expression in colorectal cancer cells relative to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels. Overall, our study illuminates the intricate interplay between 3D genome architecture and gene regulation during early colorectal cancer progression, and provides valuable insights for potential therapeutic interventions targeting the connectivity of cis-regulatory elements."
449,MYC and HSF1 Cooperate to Drive PLK1 inhibitor Sensitivity in High Grade Serous Ovarian Cancer,"Imade Williams, Haddie DeHart, Matthew O’Malley, Bobby Walker, Vrushabh Ulhaskumar, Haimanti Ray, Joe R. Delaney, Kenneth P. Nephew, Richard L. Carpenter",https://www.biorxiv.org/content/10.1101/2024.06.11.598486v1,"Ovarian cancer is a deadly female cancer with high rates of recurrence. The primary treatment strategy for patients is platinum-based therapy regimens that almost universally develop resistance. Consequently, new therapeutic avenues are needed to overcome the plateau that current therapies have on patient outcomes. We describe a gene amplification involving both HSF1 and MYC, wherein these two genes on chromosome 8q are co-amplified in over 7% of human tumors that is enriched to over 30% of patients with ovarian cancer. We further found that HSF1 and MYC transcriptional activity is correlated in human tumors and ovarian cancer cell lines, suggesting they may cooperate in ovarian cancer cells. CUT&RUN for HSF1 and MYC in co-amplified ovarian cancer cells revealed that HSF1 and MYC have overlapping binding at a substantial number of locations throughout the genome where their binding peaks are near identical. Consistent with these data, a protein-protein interaction between HSF1 and MYC was detected in ovarian cancer cells, implying these two transcription factors have a molecular cooperation. Further supporting their cooperation, growth of HSF1-MYC co-amplified ovarian cancer cells were found to be dependent on both HSF1 and MYC. In an attempt to identify a therapeutic target that could take advantage of this dependency on both HSF1 and MYC, PLK1 was identified as being correlated with HSF1 and MYC in primary human tumor specimens, consistent with a previously established effect of PLK1 on HSF1 and MYC protein levels. Targeting PLK1 with the compound volasertib (BI-6727) revealed a greater than 200-fold increased potency of volasertib in HSF1-MYC co-amplified ovarian cancer cells compared to ovarian cancer cells wild-type HSF1 and MYC copy number, which extended to several growth assays, including spheroid growth. Volasertib, and other PLK1 inhibitors, have not shown great success in clinical trials and this study suggests that targeting PLK1 may be viable in a precision medicine approach using HSF1-MYC co-amplification as a biomarker for response."
450,A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis,"Theresa K Leslie, Aurelien Tripp, Andrew D James, Scott P Fraser, Michaela Nelson, Nattanan Sajjaboontawee, Michael Toss, Wakkas Fadhil, Samantha C Salvage, Mar Arias Garcia, Melina Beykou, Emad Rakha, Valerie Speirs, Chris Bakal, George Poulogiannis, Mustafa B A Djamgoz, Antony P Jackson, Hugh R Matthews, Christopher L-H Huang, Andrew N Holding, Sangeeta Chawla, William J Brackenbury",https://www.biorxiv.org/content/10.1101/2023.06.16.545273v2,"Solid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knock down of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases glycolysis in breast cancer cells, likely by up-regulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment."
451,Multimodal Phasor Approach to study breast cancer cells invasion in 3D spheroid model,"Giulia Tedeschi, Francesco Palomba, Lorenzo Scipioni, Michelle A. Digman",https://www.biorxiv.org/content/10.1101/2024.06.10.598307v1,"We implemented a multimodal set of functional imaging techniques optimized for deep-tissue imaging to investigate how cancer cells invade surrounding tissues and how their physiological properties change in the process. As a model for cancer invasion of the extracellular matrix, we created 3D spheroids from triple-negative breast cancer cells (MDA-MB-231) and non-tumorigenic breast epithelial cells (MCF-10A). We analyzed multiple hallmarks of cancer within the same spheroid by combining a number of imaging techniques, such as metabolic imaging of NADH by Fluorescence Lifetime Imaging Microscopy (NADH-FLIM), hyperspectral imaging of a solvatochromic lipophilic dye (Nile Red) and extracellular matrix imaging by Second Harmonic Generation (SHG). We included phasor-based bioimage analysis of spheroids at three different time points, tracking both morphological and biological properties, including cellular metabolism, fatty acids storage, and collagen organization. Employing this multimodal deep-imaging framework, we observed and quantified cancer cell plasticity in response to changes in the environment composition."
453,Combining Scalable Organ Chip Platform with Deep Learning-Based Imaging Analysis for Cancer Therapeutic Screening,"Yu-Chieh Yuan, Beibei Xu, Jenna McCormack, XuHai Huang, Jingzhe Ma, Thomas Marshall, Yacong Sun, Hardeep Singh, Alyssa Fanelli, Paige Gilbride, Xiaohua Qian, Zhiyong Xie, Longlong Si, Xin Xie, Haiqing Bai",https://www.biorxiv.org/content/10.1101/2024.06.10.598272v1,"Functional precision oncology represents an emerging approach to genomic approaches by testing treatment options directly on patient-derived models. Current assays, including the use of patient-derived xenograft (PDX) and patient-derived organoid (PDOs), faces major barriers in clinical use due to technical challenges, such as standardization, cost, assay time, scalability, and faithful mimicry of patient tumor microenvironment (TME). Here, we introduce an Organ Chip (OC) device constructed entirely from thermoplastic materials, free of porous membrane or other barrier structures, and optimized for high-content imaging (HCI). This automation-compatible device supports tissue-specific extracellular matrices and coculture for a wide spectrum of organ and disease types, including the TME. As a proof-of-concept, we demonstrate the growth of pancreatic, lung, and colon cancer cell lines and primary lung cancer cells and the testing of cancer drugs in these models. HCI-based phenotypic profiling enabled accurate quantification of drug response, with better performance than traditional biochemical assays. Moreover, we developed a deep-learning method for assessing drug responses using bright field images. The integration of a low-cost, scalable, and faithful OC models with automatic high-content image analysis represents a significant stride towards functional precision oncology and cancer drug discovery."
454,Immune Checkpoint Blockade Delays Cancer and Extends Survival in Murine DNA Polymerase Mutator Syndromes,"Akshada Sawant, Fuqian Shi, Eduardo Cararo Lopes, Zhixian Hu, Somer Abdelfattah, Jennele Baul, Jesse Powers, Christian S. Hinrichs, Joshua D. Rabinowitz, Chang S. Chan, Edmund C. Lattime, Shridar Ganesan, Eileen White",https://www.biorxiv.org/content/10.1101/2024.06.10.597960v1,"Mutations in polymerases Pold1 and Pole exonuclease domains in humans are associated with increased cancer incidence, elevated tumor mutation burden (TMB) and response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond. Here we generated Pold1 and Pole proofreading mutator mice and show that ICB treatment of mice with high TMB tumors did not improve survival as only a subset of tumors responded. Similarly, introducing the mutator alleles into mice with Kras/p53 lung cancer did not improve survival, however, passaging mutator tumor cells in vitro without immune editing caused rejection in immune-competent hosts, demonstrating the efficiency by which cells with antigenic mutations are eliminated. Finally, ICB treatment of mutator mice earlier, before observable tumors delayed cancer onset, improved survival, and selected for tumors without aneuploidy, suggesting the use of ICB in individuals at high risk for cancer prevention."
455,Nucleosome reorganisation in breast cancer tissues,"Divya R. Jacob, Wilfried M. Guiblet, Hulkar Mamayusupova, Mariya Shtumpf, Isabella Ciuta, Luminita Ruje, Svetlana Gretton, Milena Bikova, Clark Correa, Emily Dellow, Shivam P. Agrawal, Navid Shafiei, Anastasija Drobysevskaja, Chris M. Armstrong, Jonathan D. G. Lam, Yevhen Vainshtein, Christopher T. Clarkson, Graeme J. Thorn, Kai Sohn, Madapura M. Pradeepa, Sankaran Chandrasekharan, Greg N. Brooke, Elena Klenova, Victor B. Zhurkin, Vladimir B. Teif",https://www.biorxiv.org/content/10.1101/2023.04.17.537031v3,"Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. Here we have generated high resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. This analysis has detected single-nucleosome repositioning at key regulatory regions in a patient-specific manner and common cancer-specific patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with ∼20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. In addition, tumour tissues were characterised by a 5-10 bp decrease in the average distance between nucleosomes (nucleosome repeat length, NRL), which is qualitatively similar to the differences between pluripotent and differentiated cells. These effects were correlated with gene activity, DNA sequence repeats abundance, differential DNA methylation and binding of linker histone variants H1.4 and H1X. Our findings provide a new mechanistic understanding of nucleosome repositioning in tumour tissues that can be valuable for patient stratification and monitoring using liquid biopsies."
456,Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer,"Mikayla Borthwick Bowen, Brenda Melendez, Qian Zhang, Diana Moreno, Leah Peralta, Wai Kin Chan, Collene Jeter, Lin Tan, M. Anna Zal, Philip L. Lorenzi, Kenneth Dunner Jr, Richard K Yang, Russell R. Broaddus, Joseph Celestino, Nisha Gokul, Elizabeth Whitley, Rosemarie Schmandt, Karen Lu, Hyun-Eui Kim, Melinda S. Yates",https://www.biorxiv.org/content/10.1101/2024.06.10.596841v1,"Lynch syndrome (LS) is defined by inherited mutations in DNA mismatch repair genes, including MSH2, and carries 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, specific mechanisms for LS-associated endometrial carcinogenesis are not well understood. Here, we assessed the effects of MSH2 loss on EC pathogenesis using a novel mouse model (PR-Cre Msh2flox/flox, abbreviated Msh2KO), primary cell lines established from this model, human tissues, and human EC cell lines with isogenic MSH2 knockdown. Beginning at eight months of age, 30% of Msh2KO mice exhibited endometrial atypical hyperplasia (AH), a precancerous lesion. At 12 to 16 months of age, 47% of Msh2KO mice exhibited either AH or ECs with histologic features similar to human LS-related ECs. Transcriptomic profiling of EC from Msh2KO mice revealed a transcriptomic signature for mitochondrial dysfunction. Studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: marked mitochondrial content reduction, along with pronounced disruptions to the integrity of retained mitochondria. Human LS-related ECs also exhibited mitochondrial content reduction compared with non-LS-related ECs. Functional studies revealed metabolic reprogramming of MSH2-deficient EC cells in vitro, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. We are the first to identify mitochondrial dysfunction and metabolic disruption as a consequence of MSH2 deficiency-related EC. Mitochondrial and metabolic aberrations should be evaluated as novel biomarkers for endometrial carcinogenesis or risk stratification and could serve as targets for cancer interception in women with LS."
457,Targeting Ribosome Biogenesis as a Novel Therapeutic Approach to Overcome EMT-related Chemoresistance in Breast Cancer,"Yi Ban, Yue Zou, Yingzhuo Liu, Sharrell B. Lee, Robert B. Bednarczyk, Jianting Sheng, Yuliang Cao, Stephen T. C. Wong, Dingcheng Gao",https://www.biorxiv.org/content/10.1101/2023.06.28.546927v2,"Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer."
459,Differences in systemic immune parameters in individuals with lung cancer according to race,"Mitchell S. von Itzstein, Jialiang Liu, Hong Mu-Mosley, Farjana Fattah, Jason Y. Park, Jeffrey A. SoRelle, J. David Farrar, Mary E. Gwin, David Hsiehchen, Yvonne Gloria-McCutchen, Edward K. Wakeland, Suzanne Cole, Sheena Bhalla, Radhika Kainthla, Igor Puzanov, Benjamin Switzer, Gregory A. Daniels, Yousef Zakharia, Montaser Shaheen, Jianjun Zhang, Yang Xie, David E. Gerber",https://www.biorxiv.org/content/10.1101/2024.06.07.597754v1,"Introduction Racial and ethnic disparities in the presentation and outcomes of lung cancer are widely known. To evaluate potential factors contributing to these observations, we measured systemic immune parameters in Black and White patients with lung cancer."
461,Spatial self-organization of cancer stem cell niches revealed by live single-cell imaging,"Mathilde Brulé, Anaïs Horochowska, Emeline Fontaine, Raoul Torero-Ibad, Flavie Woesteland, Marie Denoulte, Jean Pesez, Eric Adriaenssens, Robert-Alain Toillon, Xuefen Le Bourhis, Benjamin Pfeuty, Chann Lagadec, François Anquez",https://www.biorxiv.org/content/10.1101/2024.06.07.597918v1,"Phenotypic plasticity is a major factor of tumor heterogeneity and treatment resistance. In particular, cancer stem cells (CSCs) represent a small subpopulation within tumors with self-renewal and tumor-forming capabilities. Understanding reprogramming, maintenance, and lineage properties of CSCs requires dedicated tools to disentangle the respective influences of phenotypic inheritance and cell-cell interactions. Here we set up ultra-wide field microscopy of breast cancer cell lines expressing a stemness fluorescent reporter for several days. The fluorescent reporter distinguishes three phenotypes: cancer stem cells (CSCs), cancer differentiated cells (CDCs) and intermediate/transiting cancer cells (iCCs). Spatial statistics indicate significant zonation, aka phenotypic niches, with CSC clustering near each other but away from CDCs. Surprisingly, single cell time series reveal spontaneous reprogramming events from CDC to CSC even in unperturbed populations. We identify that such transitions are prone to arise during the cell cycle. Moreover, lineage analysis shows that the phenotype is partially inherited from ancestor cells. However, such heredity is not sufficient to explain the spatial properties of the cell population, which also depend on cell-cell interactions. Indeed, we identified that phenotypic transitions of cancer cells are influenced by the phenotypic state of neighboring cells. Reprogramming into CSCs is respectively promoted and inhibited by the presence of CSCs and CDCs in the neighborhood. Altogether, our results disentangle how phenotypic inheritance and intercellular interactions orchestrate the spatio-temporal self-organization of cancer cell heterogeneity, maintaining a subpopulation of CSCs within niches."
463,The Association between the JAK-STAT Pathway and Hypertension among Kenyan Women Diagnosed with Breast Cancer,"John Gitau, Godfrey Kinyori, Shahin Sayed, Mohammad Saleem, Francis W Makokha, Annet Kirabo",https://www.biorxiv.org/content/10.1101/2024.06.07.597892v1,"Background Breast cancer is the most common malignant tumor in women worldwide, and disproportionately affects Sub-Saharan Africa compared to high income countries. The global disease burden is growing, with Sub-Saharan Africa reporting majority of the cases. In Kenya, breast cancer is the most commonly diagnosed cancer, with an annual incidence of 7,243 new cases in 2022, representing 25.5% of all reported cancers in women. Evidence suggests that women receiving breast cancer treatment are at a greater risk of developing hypertension than women without breast cancer. Hypertension prevalence has been on the rise in SSA, with poor detection, treatment and control. The JAK-STAT signaling is activated in hormone receptor-positive breast tumors, leading to inflammation, cell proliferation, and treatment resistance in cancer cells. We sought to understand the association between the expression of JAK-STAT Pathway genes and hypertension among Kenyan women diagnosed with breast cancer."
464,An organoid platform reveals MEK-PARP co-targeting to enhance radiation response in rectal cancer,"Qiyun Xiao, Julian E. Riedesser, Theresa Mulholland, Zhenchong Li, Jonas Buchloh, Philipp Albrecht, Moying Li, Nachiyappan Venkatachalam, Olga Skabkina, Anna Klupsch, Ella Eichhorn, Li Wang, Sebastian Belle, Nadine Schulte, Daniel Schmitz, Matthias F. Froelich, Erica Valentini, Kim E. Boonekamp, Yvonne Petersen, Thilo Miersch, Elke Burgermeister, Carsten Herskind, Marlon R. Veldwijk, Christoph Brochhausen, Robert Ihnatko, Jeroen Krijgsveld, Ina Kurth, Michael Boutros, Matthias P. Ebert, Tianzuo Zhan, Johannes Betge",https://www.biorxiv.org/content/10.1101/2024.06.06.597640v1,"Locally advanced rectal cancer is usually treated by neoadjuvant chemoradiotherapy. However, tumor response rates to this treatment vary greatly. Thus, most patients do not reach a complete remission and have to undergo tumor resection. In the present study, we introduce a patient-derived rectal cancer organoid platform that reflects clinical radiosensitivity and use this to screen 1596 drug-radiation combinations. We identify inhibitors of RAS-MAPK signaling, especially MEK inhibitors, strongly synergizing with radiation response. Mechanistically, MEK inhibitors suppressed radiation-induced activation of RAS-MAPK signaling, and selectively downregulated the homologous recombination DNA repair pathway component RAD51, thereby achieving radio-enhancement. Through testing drug-drug-radiation combinations in organoids and cell lines, we identified synergism between PARP and MEK inhibitors to further enhance the effect of radiation. Our data support clinical testing of combined MEK and PARP inhibition with radiotherapy in locally advanced rectal cancers."
466,High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils,"Alexander Emmanuelli, Camilla Salvagno, Sung Min-Hwang, Deepika Awasthi, Tito A. Sandoval, Chang-Suk Chae, Jin-Gyu Cheong, Chen Tan, Takao Iwawaki, Juan R. Cubillos-Ruiz",https://www.biorxiv.org/content/10.1101/2024.08.05.606646v1,"High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ∼50% of treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease."
467,Unraveling biological processes and EGFR pathway regulation by the protein tyrosine phosphatase PTPRH in non-small cell lung cancer,"Mylena M. O. Ortiz, Deeya M. Patel, Matthew Swiatnicki, Eran Andrechek",https://www.biorxiv.org/content/10.1101/2024.06.13.598886v2,"The delicate balance of protein phosphorylation is often disrupted in cancers, with hyperactivity of kinases and inactivation of phosphatases driving cell proliferation and survival pathways. PTPRH, a protein tyrosine phosphatase, is deregulated or mutated in certain cancers, including non-small cell lung cancer (NSCLC). However, the biological processes that PTPRH is involved in and how they may contribute to tumorigenesis are unknown. Previous studies have linked PTPRH to the regulation of the EGFR pathway but the full extension of this regulation and the underlying mechanisms remain to be elucidated. We found that PTPRH knockout tends to increase the phosphorylation levels of EGFR at the tyrosine residue 1173 (1197), whereas overexpression of PTPRH wild-type significantly decreases phosphorylation in one of the NSCLC cell lines. Surprisingly, disruption of the extracellular or intracellular domains of the phosphatase leads to EGFR dephosphorylation in a similar manner. Co-immunoprecipitation and proximity-dependent biotinylation (BioID) experiments demonstrated that PTPRH do not directly interact with EGFR, but rather with CDK5RAP3 and EIF2AK2, two proteins reported to regulate the downstream pathway NF-κB. In addition, BioID revealed 55 novel PTPRH interactors in NSCLC cells, which are enrichedin translation and RNA-associated pathways. Guided by RNA sequencing analysis, we observed that overexpression of the phosphatase downregulates multiple oncogenic signature pathways and modulates the gene expression of 34 protein tyrosine phosphatases and 45 tyrosine kinases, EGFR included. Together, these results shed light on the importance of PTPRH in regulating biological and cellular processes and how its inactivation may support cancer progression."
468,Clonal evolutionary analysis reveals patterns of malignant transformation in pancreatic cancer from Intraductal Papillary Mucinous IPMN Neoplasms (IPMN),"Antonio Pea, Xiaotong He, Rosie Upstill-Goddard, Claudio Luchini, Leonor Patricia Schubert Santana, Stephan Dreyer, Fraser Duthie, Nigel B. Jamieson, Colin J. McKay, Euan J. Dickson, Alessandra Pulvirenti, Selma Rebus, Genomics Innovation Alliance, Scottish Genome Partnership, Paola Piccoli, Nicola Sperandio, Rita T. Lawlor, Michele Milella, Fieke E. M. Froeling, Roberto Salvia, Aldo Scarpa, Andrew V. Bainkin, David C. Wedge, David K. Chang",https://www.biorxiv.org/content/10.1101/2024.08.02.606217v2,"Intraductal papillary mucinous neoplasms (IPMNs) are critical precursors to pancreatic ductal adenocarcinoma (PDAC), a highly lethal cancer due to late detection and rapid progression. Using multi-region whole-genome and transcriptome sequencing, we traced the evolution of PDAC from IPMN, constructing detailed phylogenetic trees to provide insights into subclonal architectures and progression pathways. Our analysis identified two distinct evolutionary trajectories: one driven by a single ancestral clone, and another involving multiple independent ancestral clones, potentially influencing the timing and nature of PDAC onset. We further explored the roles of mutational signatures and structural variants (SVs) in promoting clonal evolution. Complementing these genomic findings, our transcriptomic analysis revealed unique gene expression profiles and variations in the immune landscape, correlating with the different progression stages from IPMN to PDAC. These insights reveal the complex molecular dynamics of IPMN progression to PDAC, highlighting the need to refine early detection and treatment strategies."
469,Integration of immune cell-target cell conjugate dynamics changes the time scale of immune control of cancer,"Qianci Yang, Arne Traulsen, Philipp Altrock",https://www.biorxiv.org/content/10.1101/2024.08.02.606336v1,"The human immune system can recognize, attack, and eliminate cancer cells, but cancers can escape this immune surveillance. The dynamics of these cancer control mechanisms by cells of the adaptive immune system can be captured by variants of ecological predator-prey models. These dynamical systems can describe the interaction of cancer cells and, e.g., effector T cells to form tumor cell-immune cell conjugates, cancer cell killing, immune cell activation, and T cell exhaustion. Target (tumor) cell-T cell conjugation is integral to the adaptive immune system’s cancer control or immunotherapy dynamics. However, it is incompletely understood whether conjugate dynamics should be explicitly included in mathematical models of cancer-immune interactions. Here, we analyze the dynamics of a cancer-effector T cell system regarding the impact of explicitly modeling the conjugate compartment to elucidate the role of cellular conjugate dynamics. We formulate a deterministic modeling framework to compare possible equilibria and their stability, such as tumor extinction, tumor-immune coexistence (tumor control), or tumor escape. We also formulate the stochastic analog of this system to analyze the impact of demographic fluctuations that arise when cell populations are small. We find that explicit consideration of a conjugate compartment can change long-term steady-state, critically change the time to reach an equilibrium, alter the probability of tumor escape, and lead to very different extinction time distributions. Thus, we demonstrate the importance of the conjugate compartment in defining tumor-effector interactions. Accounting for transitionary compartments of cellular interactions may better capture the dynamics of tumor control and progression."
470,Cancer-associated fibroblasts serve as decoys to suppress NK cell anti-cancer cytotoxicity,"Aviad Ben-Shmuel, Yael Gruper, Oshrat Levi-Galibov, Hallel Rosenberg-Fogler, Giulia Carradori, Yaniv Stein, Maya Dadiani, Mariia Naumova, Reinat Nevo, Dana Morzaev-Sulzbach, Gal Yagel, Shimrit Mayer, Einav Nili Gal-Yam, Ruth Scherz-Shouval",https://www.biorxiv.org/content/10.1101/2023.11.23.568355v1,"Cancer associated fibroblasts (CAFs) are among the most abundant components of the breast tumor microenvironment (TME) and major contributors to immune modulation. CAFs are well-known to regulate the activity of diverse types of immune cells including T cells, macrophages and dendritic cells, however little is known about their interaction with Natural killer (NK) cells, which constitute an important arm of anti-tumor immunity. Here we find, using mouse models of cancer and ex-vivo co-cultures, that CAFs inhibit NK cell cytotoxicity towards cancer cells. We unravel the mechanism by which this suppression occurs, through ligand-receptor engagement between NK cells and CAFs leading to CAF cytolysis, which in turn diminishes the expression of activating receptors on NK cells, promoting cancer escape from NK cell surveillance. Analysis of breast cancer patient samples reveals enrichment of NK cells in CAF-rich regions, and upregulation of NK binding ligands on CAFs which is correlated with poor disease outcome. These results reveal a CAF-mediated immunosuppressive decoy mechanism with implications for treatment of solid tumors."
471,MiRNA-21-5p and MiRNA-125-5p Serve as Biomarkers for Diagnosis and Prognosis of Gastric Cancer,"Xin Zhang, Yao Xiang, Junpu Wang",https://www.biorxiv.org/content/10.1101/2024.08.02.606443v1,"Background Gastric cancer is one of the most common diseases worldwide. MicroRNAs (miRNAs) are small non-coding RNAs, typically 19-25 nucleotides in length, which represent potential targets for therapeutic intervention."
472,Learning directed acyclic graphs for ligands and receptors based on spatially resolved transcriptomic analysis of ovarian cancer,"Shrabanti Chowdhury, Sammy Ferri-Borgogno, Anna P Calinawan, Peng Yang, Wenyi Wang, Jie Peng, Samuel C Mok, Pei Wang",https://www.biorxiv.org/content/10.1101/2021.08.03.454931v3,"To unravel the mechanism of immune activation and suppression within tumors, a critical step is to identify transcriptional signals governing cell-cell communication between tumor and immune/stromal cells in the tumor microenvironment. Central to this communication are interactions between secreted ligands and cell-surface receptors, creating a highly connected signaling network among cells. Recent advancement in in situ-omics profiling, particularly spatial transcriptomic (ST) technology, provide unique opportunities to directly characterize ligand-receptor signaling networks that powers cell-cell communication. In this paper, we propose a novel statistical method, LRnetST, to characterize the ligand-receptor interaction networks between adjacent tumor and stroma cells based on ST data. LRnetST utilizes a directed acyclic graph (DAG) model with a novel treatment to handle the zero-inflated distribution observed in the ST data. It also leverages existing ligand-receptor regulation databases as prior information, and employs a bootstrap aggregation strategy to achieve robust network estimation. Application of LRnetST to ST data of high-grade serous ovarian tumor samples revealed both common and distinct ligand-receptor regulations across different tumors. Some of these interactions were validated through a MERFISH data set of independent ovarian tumor samples. These results cast light on biological processes relating to the communication between tumor and immune/stromal cells in ovarian tumors. An open-source R package of LRnetST is available on GitHub at https://github.com/jie108/LRnetST."
473,Quantifying the seed sensitivity of cancer subclonal reconstruction algorithms,"Philippa L. Steinberg, Lydia Y. Liu, Anna Neiman-Golden, Yash Patel, Paul C. Boutros",https://www.biorxiv.org/content/10.1101/2024.02.05.579021v1,"Background Intra-tumoural heterogeneity complicates cancer prognosis and impairs treatment success. One of the ways subclonal reconstruction (SRC) quantifies intra-tumoural heterogeneity is by estimating the number of subclones present in bulk DNA sequencing data. SRC algorithms are probabilistic and need to be initialized by a random seed. However, the seeds used in bioinformatics algorithms are rarely reported in the literature. Thus, the impact of the initializing seed on SRC solutions has not been studied. To address this gap, we generated a set of ten random seeds to systematically benchmark the seed sensitivity of three probabilistic SRC algorithms: PyClone-VI, DPClust, and PhyloWGS."
474,A modified dual preparatory method for improved isolation of nucleic acids from laser microdissected fresh-frozen human cancer tissue specimens,"Danielle C. Kimble, Tracy J. Litzi, Gabrielle Snyder, Victoria Olowu, Sakiyah TaQee, Kelly A. Conrads, Jeremy Loffredo, Nicholas W. Bateman, Camille Alba, Elizabeth Rice, Craig D. Shriver, George L. Maxwell, Clifton Dalgard, Thomas P. Conrads",https://www.biorxiv.org/content/10.1101/2024.08.02.606193v2,"A central theme in cancer research is to increase our understanding of the cancer tissue microenvironment (TME), which is comprised of a complex and spatially heterogeneous ecosystem of malignant and non-malignant cells, both of which actively contribute to an intervening extracellular matrix. Laser microdissection (LMD) enables histology selective harvest of cellular subpopulations from the tissue microenvironment for their independent molecular investigation, such as by high-throughput DNA and RNA sequencing. Although enabling, LMD often requires a labor-intensive investment to harvest enough cells to achieve the necessary DNA and/or RNA input requirements for conventional next generation sequencing workflows. To increase efficiencies, we sought to use a commonplace dual preparatory (DP) procedure to isolate DNA and RNA from the same LMD harvested tissue samples. While the yield of DNA from the DP protocol was satisfactory, the RNA yield from the LMD harvested tissue samples was significantly poorer compared to a dedicated RNA preparation procedure. We identified that this low yield of RNA was due to incomplete partitioning of RNA in this widely used DP protocol. Here we describe a modified DP protocol that effectively partitions nucleic acids and results in significantly improved RNA yields from LMD harvested cells."
475,Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity,"Kai R. Trepka, Wesley A. Kidder, Than S. Kyaw, Christine A. Olson, Vaibhav Upadhyay, Cecilia Noecker, Dalila Stanfield, Paige Steiding, Peter Spanogiannopoulos, Darren Dumlao, Jessie A. Turnbaugh, Matthew D. Stachler, Erin L. Van Blarigan, Alan P. Venook, Chloe E. Atreya, Peter J. Turnbaugh",https://www.biorxiv.org/content/10.1101/2024.06.04.597471v1,"Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. 16S rRNA gene and metagenomic sequencing revealed significant shifts in gut microbial community structure during treatment with oral fluoropyrimidines, which was validated in an independent cohort. Gene abundance was also markedly changed by oral fluoropyrimidines, including an enrichment for the preTA operon, which is sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). Higher levels of preTA led to increased 5-FU depletion by the gut microbiota grown ex vivo. Germ-free and antibiotic-treated mice had increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA+ E. coli, or CRC patient stool with high preTA levels. preTA abundance was negatively associated with patient toxicities. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach is generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease."
476,Cancer radiomic feature variations due to reconstruction kernel choice and integral tube current,"Elfried Salanon, Anqi Fu, Aditya P. Apte, Usman Mahmoud, Zehor Belkhatir, Amita Shukla-Dave, Joseph O. Deasy",https://www.biorxiv.org/content/10.1101/2024.06.04.596806v1,"Purpose Radiological cancer imaging features, or radiomics features, can be derived to diagnose disease or predict treatment response. However, variability between vendors, scanners, protocols, and even reconstruction software versions is an obstacle to the clinical use of radiomics features. This study aimed to characterize the impact of kernel reconstruction differences and integral tube current settings on radiomic features extracted from computed tomography (CT) scans."
477,An organoid co-culture model for probing systemic anti-tumor immunity in lung cancer,"Kaiyi Li, Chang Liu, Chao Li, Ting Zhang, Tian Zhao, Dong Zhang, Hainan Wu, Yuhan Liu, Shuai Wang, Yingshun Yang, Baobao Lin, Wenyan Wang, Jun Wang, Xizhao Sui, Xiaofang Chen, Peng Liu",https://www.biorxiv.org/content/10.1101/2024.06.04.597327v1,"Deciphering the interactions between tumor micro- and systemic immune macro-environment is essential for developing more effective cancer diagnosis and treatment strategies. Here, we established a gel-liquid interface (GLI) co-culture of lung cancer organoids (LCOs) and paired peripheral blood mononuclear cells (PBMCs), featuring with enhanced interactions of immune cells and tumor organoids, to mimic the in vivo systemic anti-tumor immunity induced by immune checkpoint inhibitors (ICI). The co-culture model recapitulates the in vivo ICI-induced T cell recruitment and subsequent tumor regression, predicting the clinical results precisely. We demonstrated that circulating tumor-reactive T cells, which are effector memory-like with high expression levels of GNLY, CD44 and CD9, can serve as an indicator of the immunotherapy efficacy. Interestingly, enhanced inflammatory signaling in blood T cells is accompanied with prompted exhaustion and compromised anti-tumor function, when encountering with organoids. Our findings suggest that the GLI co-culture can be used for developing diagnostic strategies for precision immunotherapies as well as understanding the underlying mechanisms."
478,Complement-Activating Multimeric Immunotherapeutic Complexes for HER2-breast cancer immunotherapy,"Carole Seguin-Devaux, Bianca Brandus, Jean-Marc Plesseria, Gilles Iserentant, Jean-Yves Servais, Georgia Kanli, Iris Behrmann, Jacques Zimmer, Jacques H M Cohen, Xavier Dervillez",https://www.biorxiv.org/content/10.1101/2024.02.02.578619v1,Background Directing selective complement activation towards tumor cells is an attractive strategy to promote their elimination. We have generated Complement-activating Multimeric immunotherapeutic compleXes (CoMiX) that selectively stimulate the alternative pathway using Factor H Related protein 4 (FHR4) or the classical complement pathways using triple Fc dimers on HER2-expressing tumor cells.
481,CircPVT1 sponges miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer,"Alina Catalina Palcau, Claudio Pulito, Valentina De Pascale, Luca Casadei, Maria Cristina Valerio, Andrea Sacconi, Daniela Rutigliano, Sara Donzelli, Romana Francesca Auciello, Fulvia Pimpinelli, Paola Muti, Claudio Botti, Sabrina Strano, Giovanni Blandino",https://www.biorxiv.org/content/10.1101/2024.06.04.597315v1,"Altered metabolism is one of the cancer hallmarks. The role of circRNAs in cancer metabolism is still unexplored. Herein, we initially found that the expression of circPVT1 was significantly higher in tumoral tissues than in non-tumoral breast tissues. Basal like breast cancer patients with higher levels of circPVT1 exhibited shorter disease-free survival compared to those with lower expression. CircPVT1 ectopic expression rendered fully transformed MCF-10A immortalized breast cells and increased tumorigenicity of TNBC cell lines. Depletion of endogenous circPVT1 reduced tumorigenicity of SUM-159PT and MDA-MB-468 cells. 1H-NMR spectroscopy metabolic profiling of circPVT1 depleted breast cancer cell lines revealed reduced glycolysis and glutaminolitic fluxes. Conversely, MCF-10A cells stably overexpressing circPVT1 exhibited increased glutaminolysis. Mechanistically, circPVT1 sponges miR-33a-5p, a well know metabolic microRNA, which in turn releases c-MYC activity which promotes transcriptionally glutaminase, which converts glutamine to glutamate. CircPVT1 depletion synergizes with GLS1 inhibitors BPTES or CB839 to reduce cell viability of breast cancer cell lines and breast cancer-derived organoids. In aggregate, our findings unveil the circPVT1/miR-33a-5p/Myc/GLS1 axis as a pro-tumorigenic metabolic event sustaining breast cancer transformation with potential therapeutic implications."
483,The promoter mutation paucity as part of the dark matter of the cancer genome,"Nicholas Abad, Irina Glas, Chen Hong, Annika Small, Yoann Pageaud, Ana Maia, Dieter Weichenhan, Christoph Plass, Barbara Hutter, Benedikt Brors, Cindy Körner, Lars Feuerbach",https://www.biorxiv.org/content/10.1101/2024.06.03.597231v1,"Cancer is a heterogeneous disease caused by genetic alterations. Computational analysis of cancer genomes led to the expansion of the catalog of driver mutations. While individual high-impact mutations have been discovered also in gene promoters, frequency-based approaches have only characterized a few novel candidates. To investigate the promoter mutation paucity in cancer, we developed the REMIND-Cancer workflow to predict activating promoter mutations in silico, irrespective of their recurrence frequency, and applied it to the PCAWG dataset. We positively validated 7 candidates by luciferase assay including mutations within the promoters of ANKRD53 and MYB. Our analysis indicates that particular mutational signatures and necessary co-alterations constrain the creation and positive selection of functional promoter mutations. We conclude that activating promoter mutations are more frequent in the PCAWG dataset than previously observed, which has potential implications for personalized oncology."
484,Multi-task deep latent spaces for cancer survival and drug sensitivity prediction,"Teemu J. Rintala, Francesco Napolitano, Vittorio Fortino",https://www.biorxiv.org/content/10.1101/2024.03.18.585492v2,"Motivation Cancer is a very heterogeneous disease that can be difficult to treat without addressing the specific mechanisms driving tumour progression in a given patient. High-throughput screening and sequencing data from cancer cell-lines has driven many developments in drug development, however, there are important aspects crucial to precision medicine that are often overlooked, namely the inherent differences between tumours in patients and the cell-lines used to model them in vitro. Recent developments in transfer learning methods for patient and cell-line data have shown progress in translating results from cell-lines to individual patients in silico. However, transfer learning can be forceful and there is a risk that clinically relevant patterns in the omics profiles of patients are lost in the process."
485,Hepatic Macrophage Migration Inhibitory Factor Promotes Pancreatic Cancer Liver Metastasis in NAFLD,"Qian Yu, Hui Song, Liang Zhu, Xiao-ya Shi, Hai-zhen Wang, Ying-luo Wang, Rui-ning Gong, Jiu-fa Cui, Xiao-nan Yang, Ji-gang Wang, Yu Liang, Ying Chen, Xiao-wu Dong, Guo-tao Lu, Chang Li, Huan Zhang, Yan-tao Tian, Hai-tao Hu, Xin-xin Shao, Ya-bin Hu, Ashok K. Saluja, Yue Li, Ming-guang Mo, He Ren",https://www.biorxiv.org/content/10.1101/2024.06.02.595997v1,"How pathological livers shape tumors, thereby driving pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, is poorly understood. In the present study, we focus on examining key molecules implicated in this process and assessing their translational significance. We demonstrated that patients with combined non-alcoholic fatty liver disease (NAFLD) have approximately a ninefold increased risk of developing liver metastasis compared to those without NAFLD. In mice model, NAFLD fosters an immunosuppressive microenvironment with increased tumor cell pluripotency and focal adhesion. Mechanistically, NAFLD-induced MIF mediated the progression of PDAC liver metastasis by attracting CD44 positive pancreatic cells. Hepatic MIF knockdown significantly reduced metastases burden with decreased stem-like cancer cells, tumor associated macrophages (TAMs) infiltration and focal adhesion. Targeting the MIF-CD44 axis by either a MIF tautomerase inhibitor, IPG1576, or by CD44 knockdown in tumor cells significantly attenuate liver metastasis of PDAC within the NAFLD context. Patients with PDAC liver metastasis and NAFLD had elevated hepatic MIF expression and increased number of stem-cell like cancer cells. Collectively, our study highlights a pivotal role for MIF-CD44 axis in cancer stemness and offer novel avenues for tailoring therapeutic strategies to individual patients with NAFLD as an underlying condition."
486,A prostate cancer gastrointestinal transcriptional phenotype may be associated with diminished response to AR-targeted therapy,"Aishwarya Subramanian, Meng Zhang, Marina Sharifi, Thaidy Moreno-Rodriguez, Eric Feng, Nicholas R. Rydzewski, Raunak Shrestha, Xiaolin Zhu, Shuang G. Zhao, Rahul Aggarwal, Eric J. Small, Chien-Kuang Cornelia Ding, David A. Quigley, Martin Sjöström",https://www.biorxiv.org/content/10.1101/2024.06.02.595931v1,"Background Prostate cancer is a heterogenous disease, but once it becomes metastatic it eventually becomes treatment resistant. One mechanism of resistance to AR-targeting therapy is lineage plasticity, where the tumor undergoes a transformation to an AR-indifferent phenotype, most studied in the context of neuroendocrine prostate cancer (NEPC). However, activation of additional de- or trans-differentiation programs, including a gastrointestinal (GI) gene expression program, has been suggested as an alternative method of resistance. In this study, we explored the previously identified GI prostate cancer phenotype (PCa-GI) in a large cohort of metastatic castration-resistant prostate cancer (mCRPC) patient biopsy samples."
487,Deciphering the Functional Roles of Individual Cancer Alleles Across Comprehensive Cancer Genomic Studies,"Jiayan (Yoshii) Ma, Stephanie Ting, Bartholomew Tam, Timothy Pham, Michael Reich, Jill Mesirov, Pablo Tamayo, William Kim",https://www.biorxiv.org/content/10.1101/2023.11.14.567106v1,"Cancer genome data has been growing in both size and complexity, primarily driven by advances in next-generation sequencing technologies, such as Pan-cancer data from TCGA, ICGC, and single-cell sequencing. Yet, discerning the functional role of individual genomic lesions remains a substantial challenge due to the complexity and scale of the data. Previously, we introduced REVEALER, which identifies groups of genomic alterations that significantly associate with target functional profiles or phenotypes, such as pathway activation, gene dependency, or drug response. In this paper, we present a new mathematical formulation of the algorithm. This version (REVEALER 2.0) is considerably more powerful than the original, allowing for rapid processing and analysis of much larger datasets and facilitating higher-resolution discoveries at the level of individual alleles. REVEALER 2.0 employs the Conditional Information Coefficient (CIC) to pinpoint features that are either complementary or mutually exclusive but still correlate with the target functional profile. The aggregation of these features provides a better explanation for the target functional profile than any single alteration on its own. This is indicative of scenarios where several activating genomic lesions can initiate or stimulate a key pathway or process. We replaced the initial three-dimensional kernel estimation with multiple precomputed one-dimensional kernel estimations, resulting in an approximate 150x increase in speed and efficiency. This improvement, combined with its efficient execution, makes REVEALER 2.0 suitable for much larger datasets and a more extensive range of genomic challenges."
488,P-cadherin mechanoactivates tumor–mesothelium metabolic coupling to promote ovarian cancer metastasis,"Jing Ma, Sally K. Y. To, Katie S. W. Fung, Kun Wang, Jiangwen Zhang, Alfonso H. W. Ngan, Susan Yung, Tak-Mao Chan, Carmen C. L. Wong, Philip P. C. Ip, Ling Peng, Hong-Yan Guo, Chi Bun Chan, Alice S.T. Wong",https://www.biorxiv.org/content/10.1101/2024.06.02.597059v1,"Peritoneal metastasis exacerbates the prognosis of ovarian cancer patients. Adhesion of cancer cells to mesothelium is a rate-limiting prerequisite for this process. How metastatic cells sense and respond to the dynamic biomechanical microenvironment at the mesothelial niche to initiate metastatic lesions remains unclear. Here, the study demonstrates that highly metastatic (HM), but not non-metastatic (NM) ovarian cancer cells, selectively activate the peritoneal mesothelium. Atomic force microscopy reveals that HM cells exert increased adhesive force on mesothelial cells via P-cadherin, a cell-cell adhesion molecule abundant in late-stage tumors. Transcriptomic and molecular analyses show that mechanical induction of P-cadherin enhances lipogenic gene expression and lipid content in HM cells by SREBP1. P-cadherin activation does not affect lipogenic activity but induces glycolysis in the interacting mesothelium. Targeted lipidomic analysis reveals that lactate produced by the glycolytic mesothelium facilitates metastatic outgrowth as a direct substrate for de novo lipogenesis. Inhibiting lactate shuttling via nanodelivery of siRNA targeting P-cadherin or MCT1/4 transporters significantly suppresses metastasis in mice. The association of high fatty acid synthase in patient metastatic samples and increased P-cadherin expression supports enhanced de novo lipogenesis in the metastatic niche. The study reveals P-cadherin-mediated mechano-metabolic coupling as a promising target to restrain peritoneal metastasis."
489,Targeting aberrant fatty acid synthesis and storage in endocrine resistant breast cancer cells,"Ashley V. Ward, Duncan Riley, Jessica Finlay-Schultz, Heather M. Brechbuhl, Kaitlyn B. Hill, Rohan R. Varshney, Peter Kabos, Michael C. Rudolph, Carol A. Sartorius",https://www.biorxiv.org/content/10.1101/2024.05.30.596684v1,Background Lipid metabolic reprogramming is an emerging characteristic of endocrine therapy (ET) resistance in estrogen receptor-positive (ER+) breast cancer. We explored changes in lipid metabolism in ER+ breast cancer cell lines following acquired resistance to common endocrine treatments and tested efficacy of an inhibitor in current clinical trials.
490,Generative AI impact on protein stability prediction in breast cancer genes,"Rohan Gnanaolivu, Steven N Hart",https://www.biorxiv.org/content/10.1101/2024.06.03.597089v1,"The functional classification of a missense variant in cancer predisposition genes is often challenging due to how rare the variant is observed in the population. When available, clinicians utilize a combination of family history, in vitro functional assays and in silico methods to infer protein function. In silico methods, such as missense predictors (predict changes in protein function) and protein stability predictors (predict changes in free energy) have been used to help classify a missense variant in accordance with the American College of Medical Genetics and Genomics (ACMG) guideline. To measure protein stability, many in silico algorithms predict stability based on the change of free energy and most accurate protein stability predictors require a wild-type protein template. In this study, we examine the use of generative AI to predict high-resolution protein structures as templates analyzed with protein stability methods to evaluate loss of function (LOF) activity in cancer predisposition genes BRCA1, BRCA2, PALB2 and RAD51C upon the presence of missense variant. Utilizing multiplexed assay of variant effect measurements and variant classifications from ClinVar, we find that prediction of Gibbs free energy (ΔΔG) from AlphaFold2 (AF2) structures analyzed with FoldX predicts LOF better than experimental-derived wild type structures in the BRCT domain of BRCA1 and the DNA binding domain (DBD) of BRCA2, but not in PALB2 and RAD51C. We also find that AF2 structures in the BRCT domain of BRCA1 and DBD-Dss1 domain of BRCA2 analyzed with FoldX measure homologous DNA recombination (HDR) activity significantly better than Rosetta and DDGun3D. Our study also revealed that there are other factors that contribute to predicting loss of function activity other than protein stability, with AlphaMissense ranking the best overall predictor of LOF activity in these tumor suppressor breast cancer genes."
491,Integrin conformation-dependent neutrophil slowing obstructs the capillaries of the pre-metastatic lung in a model of breast cancer,"Frédéric Fercoq, Gemma S. Cairns, Marco De Donatis, John B. G. Mackey, Alessia Floerchinger, Amanda McFarlane, Ximena L. Raffo-Iraolagoitia, Declan Whyte, Lindsey W. G. Arnott, Colin Nixon, Robert Wiesheu, Anna Kilbey, Leah Brown, Sarwah Al-Khalidi, Jim C. Norman, Edward W. Roberts, Karen Blyth, Seth B. Coffelt, Leo M. Carlin",https://www.biorxiv.org/content/10.1101/2024.03.19.585724v2,"Neutrophils are thought to be critical to the process whereby breast cancers establish an immunosuppressive and tumour cell nurturing ‘pre-metastatic’ niche before overt metastasis can be detected. However, the spatial localization of neutrophils and their interaction with other cell types in the lung pre-metastatic niche is not well described. We used a spontaneously metastatic mammary cancer model combined with a multiplexed three- and four-dimensional imaging approach to investigate the behaviour of neutrophils in the pre-metastatic niche. Volume fixed tissue three-dimensional imaging showed that approximately 40% of CD8+ T cells are adjacent to neutrophils at this stage. In live tissue, we found neutrophils with impaired intravascular motility congested the capillaries of pre-metastatic lungs potentially obstructing CD8+ T cells. Slowed neutrophil transit was dependent on the conformation of β2-integrin and could be recapitulated by treating non-tumour bearing mice with G-CSF, a potent systemic mediator of granulopoiesis. We found a decrease in L-selectin (CD62L) on neutrophils in the lungs of both mammary tumour bearing and G-CSF treated mice. Finally, we observed differential accumulation of intravenously injected micro-beads in the lung, suggestive of transient circulatory dead spaces which were also dependent on β2-integrin inactivation. Overall, our study proposes that integrin-mediated neutrophil congestion of the alveolar capillaries could contribute to the generation of the pulmonary pre-metastatic niche."
495,Computational identification of surface markers for isolating distinct subpopulations from heterogeneous cancer cell populations,"Andrea L. Gardner, Tyler A. Jost, Amy Brock",https://www.biorxiv.org/content/10.1101/2024.05.28.596337v1,"Intratumor heterogeneity reduces treatment efficacy and complicates our understanding of tumor progression. There is a pressing need to understand the functions of heterogeneous tumor cell subpopulations within a tumor, yet biological systems to study these processes in vitro are limited. With the advent of single-cell RNA sequencing (scRNA-seq), it has become clear that some cancer cell line models include distinct subpopulations. Heterogeneous cell lines offer a unique opportunity to study the dynamics and evolution of genetically similar cancer cell subpopulations in controlled experimental settings. Here, we present clusterCleaver, a computational package that uses metrics of statistical distance to identify candidate surface markers maximally unique to transcriptomic subpopulations in scRNA-seq which may be used for FACS isolation. clusterCleaver was experimentally validated using the MDA-MB-231 and MDA-MB-436 breast cancer cell lines. ESAM and BST2/tetherin were experimentally confirmed as surface markers which identify and separate major transcriptomic subpopulations within MDA-MB-231 and MDA-MB-436 cells, respectively. clusterCleaver is a computationally efficient and experimentally validated workflow for identification and enrichment of distinct subpopulations within cell lines which paves the way for studies on the coexistence of cancer cell subpopulations in well-defined in vitro systems."
497,"Synergistic combination therapy with ONC201 or ONC206, Enzalutamide and Darolutamide in preclinical studies of castration-resistant prostate cancer","Laura Wu, Maximilian Pinho-Schwermann, Lanlan Zhou, Leiqing Zhang, Kelsey E. Huntington, Ryan Malpass, Attila A. Seyhan, Benedito A. Carneiro, Wafik S. El-Deiry",https://www.biorxiv.org/content/10.1101/2024.07.31.606054v1,"Androgen receptor (AR) signaling plays a primary role in prostate cancer progression. Non-steroidal anti- androgens (NSAA) including enzalutamide, and apalutamide have been used to treat patients with advanced disease. However, patients with metastatic castration-resistant prostate cancer (mCPRC) develop resistance, resulting in limited overall survival benefit. Darolutamide is a novel next-generation androgen receptor- signaling inhibitor that is FDA approved for non-metastatic castration resistant prostate cancer (nmCRPC). Imipridone ONC201/TIC10 is first-in-class small molecule that activates the integrated stress response (ISR) and upregulates TNF-related apoptosis-inducing ligand (TRAIL). Our study investigates ISR and AR signaling in anti-tumor efficacy with ONC201 and enzalutamide or darolutamide against mCRPC cells. mCRPC cell lines 22RV1, LNCaP, DU145 and PC3 were treated with ONC201, darolutamide, and enzalutamide as single agents or in combinations. Combinations of ONC201 and darolutamide or enzalutamide demonstrated synergistic effects in mCRPC cells. Combinations of ONC201 and darolutamide or enzalutamide reduced PSA levels in LNCaP cells and induced of ATF4 in both LNCaP and 22RV1 cell lines. Darolutamide synergized with ONC201 regardless of AR status or castration sensitivity in vitro. Flow cytometric analysis showed increased intra-tumoral NK cells in mice treated with ONC201 and combination of ONC201 and darolutamide. Trends of increased TRAIL activation within NK cells were also observed in treatment groups. ONC201 and darolutamide demonstrated anti-tumor effects in vivo in the 22RV1 CRPC model. Our results prompt further translational and clinical studies with imipridones ONC201 or ONC201 in combination with enzalutamide or darolutamide for treatment of castrate resistant advanced or metastatic prostate cancer."
499,Oxygen Sensor-Guided Fine Needle Biopsy Studies of Human Cancer Xenografts in Mice,"Robert C. McDonald, Andrew H. Fischer, Mary Rusckowski",https://www.biorxiv.org/content/10.1101/2024.05.27.596060v1,"An oxygen sensor-mounted fine-needle biopsy tool was used for in vivo measurement of oxygen levels in tumor xenografts. The system provides a means of measuring the oxygen content in harvested tumor tissue from specific locations. Oxygen in human tumor xenografts in a murine model was observed for over 1 min. Tissues were mapped in relation to oxygen tension (pO2) readings and sampled for conventional cytological examination. Careful modeling of the pO2 readings over 60 seconds yielded a diffusion coefficient for oxygen at the sensor tip, providing additional diagnostic information about the tissue before sampling. Oxygen level measurement may provide a useful adjunct to the use of biomarkers in tumor diagnosis."
502,A novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models,"Ryan R Kowash, Manoj Sabnani, Laura T Gray, Qing Deng, Luc Girard, Yujiro Naito, Kentaro Masuhiro, John D Minna, David E Gerber, Shohei Koyama, Zhiqian Lucy Liu, Hemanta Baruah, Esra A Akbay",https://www.biorxiv.org/content/10.1101/2024.07.30.605880v1,"Concurrent KRAS LKB1 (STK11, KL) mutant Non-Small Cell Lung Cancers (NSCLC) is particularly difficult to treat and does not respond well to current immune checkpoint blockade (ICB) therapies. This is due to numerous mechanisms including low antigen presentation limiting T cell mediated killing. To activate anti-tumor immunity, we targeted tumor cell – natural killer (NK) cell interactions. We tested whether a novel antibody based therapeutic strategy that predominantly activates natural killer (NK) cells demonstrates efficacy in pre-clinical mouse models of KL NSCLC. NK cells rely on binding of ligands, such as Major Histocompatibility Complex (MHC) class I-related chain A or B (MICA/B), to the activating receptor NKG2D. Importantly MICA and MICB are widely expressed in elevated levels across NSCLC subtypes including KL lung cancers. Proteases with the tumor microenvironment (TME) can cleave these proteins rendering tumor cells less visible to NK cells. We therefore developed a MICA monoclonal antibody, AHA-1031, which utilizes two NK cell activating receptors. AHA1031 prevents ligand shedding without interfering with binding to NKG2D while targeting cancer cells to antibody mediated cell dependent cytotoxicity (ADCC). Our therapeutic novel antibody has significant monotherapy activity in KL cancer models including xenografts of human cell lines and patient derived xenografts. Activating NK cells through MICA/B stabilization and inducing ADCC offers an alternative and potent therapy option in KL tumors. MICA/B are shed across different tumors making this therapeutic strategy universally applicable."
504,Modeling metastatic progression from cross-sectional cancer genomics data,"Kevin Rupp, Andreas Lösch, Y. Linda Hu, Chenxi Nie, Rudolf Schill, Maren Klever, Simon Pfahler, Lars Grasedyck, Tilo Wettig, Niko Beerenwinkel, Rainer Spang",https://www.biorxiv.org/content/10.1101/2024.01.30.577989v1,"Metastasis formation is a hallmark of cancer lethality. Yet, metastases are generally unobservable during their early stages of dissemination and spread to distant organs. Genomic datasets of matched primary tumors and metastases may offer insights into the underpinnings and the dynamics of metastasis formation. We present metMHN, a cancer progression model designed to deduce the joint progression of primary tumors and metastases using cross-sectional cancer genomics data. The model elucidates the statistical dependencies among genomic events, the formation of metastasis, and the clinical emergence of both primary tumors and their metastatic counterparts. metMHN enables the chronological reconstruction of mutational sequences and facilitates estimation of the timing of metastatic seeding. In a study of nearly 5000 lung adenocarcinomas, metMHN pinpointed TP53 and EGFR as mediators of metastasis formation. Furthermore, the study revealed that post-seeding adaptation is predominantly influenced by frequent copy number alterations. All datasets and code are available on GitHub at https://github.com/cbg-ethz/metMHN."
508,Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity,"Irene Schwartz, Valentina Budroni, Mathilde Meyenberg, Harald Hornegger, Kathrin Hacker, Siegfried Schwartz, Zuzana Hodakova, Daniel B. Grabarczyk, Julian F. Ehrmann, Sara Scinicariello, David Haselbach, Jörg Menche, Tim Clausen, G. Elif Karagöz, Gijs A. Versteeg",https://www.biorxiv.org/content/10.1101/2024.04.23.590688v2,Highlights
510,Mechanical compressive forces increase PI3K output signaling in breast and pancreatic cancer cells,"M. Di-Luoffo, C. Schmitter, E.C. Barrere, N. Therville, M. Chaouki, R. D’Angelo, S. Arcucci, B. Thibault, M. Delarue, J. Guillermet-Guibert",https://www.biorxiv.org/content/10.1101/2021.10.18.464825v4,"Context Mechanical stresses, including compression, arise during cancer progression. In solid cancer, especially breast and pancreatic cancers, the rapid tumor growth and the environment remodeling explain their high intensity of compressive forces. However, the sensitivity of compressed cells to targeted therapies remains poorly known."
511,Exploring the Mechanism of Gentiana in Treating Pancreatic Cancer Based on Network Pharmacology and Molecular Docking Techniques,"Yuanyuan Qian, Zhaojunli Wang, Jiancheng Ji",https://www.biorxiv.org/content/10.1101/2024.07.18.604197v2,Objective This study aims to investigate the mechanism of Gentiana in treating pancreatic cancer using network pharmacology and molecular docking techniques.
512,ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1,"Jordina Rincon-Torroella, Marco Dal Molin, Brian Mog, Gyuri Han, Evangeline Watson, Nicolas Wyhs, Shun Ishiyama, Taha Ahmedna, Il Minn, Nilofer S. Azad, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler, Shibin Zhou, Bert Vogelstein, Kathleen Gabrielson, Surojit Sur",https://www.biorxiv.org/content/10.1101/2023.07.23.550207v2,"Nearly 30% of Pancreatic ductal adenocarcinoma (PDAC)s exhibit a marked overexpression of Monocarboxylate Transporter 1 (MCT1) offering a unique opportunity for therapy. However, biochemical inhibitors of MCT1 have proven unsuccessful in clinical trials. In this study we present an alternative approach using 3-Bromopyruvate (3BP) to target MCT1 overexpressing PDACs. 3BP is a cytotoxic agent that is known to be transported into cells via MCT1, but its clinical usefulness has been hampered by difficulties in delivering the drug systemically. We describe here a novel microencapsulated formulation of 3BP (ME3BP-7), that is effective against a variety of PDAC cells in vitro and remains stable in serum. Furthermore, systemically administered ME3BP-7 significantly reduces pancreatic cancer growth and metastatic spread in multiple orthotopic models of pancreatic cancer with manageable toxicity. ME3BP-7 is, therefore, a prototype of a promising new drug, in which the targeting moiety and the cytotoxic moiety are both contained within the same single small molecule."
513,A large-scale cancer-specific protein-DNA interaction network,"Yunwei Lu, Anna Berenson, Ryan Lane, Isabelle Guelin, Zhaorong Li, Yilin Chen, Sakshi Shah, Meimei Yin, Luis Fernando Soto-Ugaldi, Ana Fiszbein, Juan Ignacio Fuxman Bass",https://www.biorxiv.org/content/10.1101/2024.01.24.577099v1,"Cancer development and progression are generally associated with dysregulation of gene expression, often resulting from changes in transcription factor (TF) sequence or expression. Identifying key TFs involved in cancer gene regulation provides a framework for potential new therapeutics. This study presents a large-scale cancer gene TF-DNA interaction network as well as an extensive promoter clone resource for future studies. Most highly connected TFs do not show a preference for binding to promoters of genes associated with either good or poor cancer prognosis, suggesting that emerging strategies aimed at shifting gene expression balance between these two prognostic groups may be inherently complex. However, we identified potential for oncogene targeted therapeutics, with half of the tested oncogenes being potentially repressed by influencing specific activator or bifunctional TFs. Finally, we investigate the role of intrinsically disordered regions within the key cancer-related TF estrogen receptor ɑ (ESR1) on DNA binding and transcriptional activity, and found that these regions can have complex trade-offs in TF function. Altogether, our study not only broadens our knowledge of TFs involved in the cancer gene regulatory network but also provides a valuable resource for future studies, laying a foundation for potential therapeutic strategies targeting TFs in cancer."
514,Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy,"Xiaopei Zhang, Hannah Taylor, Alain Valdivia, Rajaneekar Dasari, Andrew Buckley, Emily Bonacquisti, Juliane Nguyen, Krishna Kanchi, David L. Corcoran, Laura E. Herring, Dennis A. Steindler, Albert Baldwin, Shawn Hingtgen, Andrew Benson Satterlee",https://www.biorxiv.org/content/10.1101/2024.05.24.595724v1,"Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate as their parental fibroblasts, and the TRAIL produced by iNSCs were naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays showed that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts around 3000-fold greater than treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a new easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer."
515,Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer cell lines and isogenic models,"Kristin M. Adams, Jae-Rim Wendt, Josie Wood, Sydney Olson, Ryan Moreno, Zhongmou Jin, Srihari Gopalan, Jessica D. Lang",https://www.biorxiv.org/content/10.1101/2024.07.26.605381v1,"Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making as of yet. Two particular challenges faced in mechanistically deciphering platinum responsiveness in ovarian cancer have been the suitability of cell line models for ovarian cancer subtypes and the availability of information on comparatively how sensitive ovarian cancer cell lines are to platinum. We performed one of the most comprehensive profiles to date on 36 ovarian cancer cell lines across over seven subtypes and integrated drug response and multiomic data to improve on our understanding of the best cell line models for platinum responsiveness in ovarian cancer. RNA-seq analysis of the 36 cell lines in a single batch experiment largely conforms with the currently accepted subtyping of ovarian cancers, further supporting other studies that have reclassified cell lines and demonstrate that commonly used cell lines are poor models of high-grade serous ovarian carcinoma. We performed drug dose response assays in the 32 of these cell lines for cisplatin and carboplatin, providing a quantitative database of IC50s for these drugs. Our results demonstrate that cell lines largely fall either well above or below the equivalent dose of the clinical maximally achievable dose (Cmax) of each compound, allowing designation of cell lines as sensitive or resistant. We performed differential expression analysis for high-grade serous ovarian carcinoma cell lines to identify gene expression correlating with platinum-response. Further, we generated two platinum-resistant derivatives each for OVCAR3 and OVCAR4, as well as leveraged clinically-resistant PEO1/PEO4/PEO6 and PEA1/PEA2 isogenic models to perform differential expression analysis for seven total isogenic pairs of platinum resistant cell lines. While gene expression changes overall were heterogeneous and vast, common themes were innate immunity/STAT activation, epithelial to mesenchymal transition and stemness, and platinum influx/efflux regulators. In addition to gene expression analyses, we performed copy number signature analysis and orthogonal measures of homologous recombination deficiency (HRD) scar scores and copy number burden, which is the first report to our knowledge applying field-standard copy number signatures to ovarian cancer cell lines. We also examined markers and functional readouts of stemness that revealed that cell lines are poor models for examination of stemness contributions to platinum resistance, likely pointing to the fact that this is a transient state. Overall this study serves as a resource to determine the best cell lines to utilize for ovarian cancer research on certain subtypes and platinum response studies, as well as sparks new hypotheses for future study in ovarian cancer."
517,Clonal spheroids capture functional and genetic heterogeneity of head and neck cancer,"Jyoti Pandey, Md. Zubbair Malik, Ritis K Shyanti, Palak Parashar, Praveen K Kujur, Deepali Mishra, Dhanir Tailor, Jee Min Lee, Tejinder Kataria, Deepak Gupta, Hitesh Verma, Sanjay V Malhotra, Suneel Kateriya, Vibha Tandon, Rupesh Chaturvedi, Rana P Singh",https://www.biorxiv.org/content/10.1101/2024.05.24.595655v1,"Head and neck cancer squamous cell carcinoma (HNSCC) cells exhibit both structural and functional diversity, making them valuable models for understanding tumor heterogeneity at clinical levels. In this study, we generated single-cell-derived spheroids (SCDS) from HNSCC cell lines and patient tumor cells using scaffold- and non-scaffold-based methods to assess this variability. A distinct structural variability among these SCDS, categorized as hypo- and hyperproliferative spheroids based on size, was observed. Hyperproliferative spheroids demonstrated heightened proliferative and tumorigenic potential and increased sensitivity to cisplatin and radiation, while hypoproliferative spheroids exhibited enhanced migratory capabilities. Single-cell RNA sequencing (scRNA-seq) of hypo- and hyperproliferative spheroids provided insights into the transcriptional landscape of HNSCC cells, validating the observed structural and functional heterogeneities within primary tumors. These functionally and genetically characterized spheroids offer valuable tools for the development of next-generation therapeutics."
518,Stromal mediated DNA damage promotes high grade serous ovarian cancer initiation,"Geyon L. Garcia, Taylor Orellana, Grace Gorecki, Leonard G. Frisbie, Roja Baruwal, Ester Goldfield, Ian Beddows, Ian P. MacFawn, Ananya K. Britt, Macy M. Hale, Hui Shen, Ronald Buckanovich, Toren Finkel, Ronny Drapkin, T. Rinda Soong, Tullia C. Bruno, Huda I. Atiya, Lan Coffman",https://www.biorxiv.org/content/10.1101/2024.05.23.595550v1,"The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear, thus providing critical barriers to the development of prevention or early detection strategies for this deadly disease. Increasing evidence demonstrates most HGSOC starts in the fallopian tube epithelium (FTE). Current models propose HGSOC initiates when FTE cells acquire increasing numbers of mutations allowing cells to evolve into serous tubal intraepithelial carcinoma (STIC) precursors and then to full blown cancer. Here we report that epigenetically altered mesenchymal stem cells (termed high risk MSC-hrMSCs) can be detected prior to the formation of ovarian cancer precursor lesions. These hrMSCs drive DNA damage in the form of DNA double strand breaks in FTE cells while also promoting the survival of FTE cells in the face of DNA damage. Indicating the hrMSC may actually drive cancer initiation, we find hrMSCs induce full malignant transformation of otherwise healthy, primary FTE resulting in metastatic cancer in vivo. Further supporting a role for hrMSCs in cancer initiation in humans, we demonstrate that hrMSCs are highly enriched in BRCA1/2 mutation carriers and increase with age. Combined these findings indicate that hrMSCs may incite ovarian cancer initiation. These findings have important implications for ovarian cancer detection and prevention."
519,Tumour specimen cold ischemia time impacts molecular cancer drug target discovery,"Silvia von der Heyde, Nithya Raman, Nina Gabelia, Xavier Matias-Guiu, Takayuki Yoshino, Yuichiro Tsukada, Gerry Melino, John L. Marshall, Anton Wellstein, Hartmut Juhl, Jobst Landgrebe",https://www.biorxiv.org/content/10.1101/2024.05.23.595517v1,"Tumour tissue collections are used to uncover pathways associated with disease outcomes that can also serve as targets for cancer treatment, ideally by comparing the molecular properties of cancer tissues to matching normal tissues. The quality of such collections determines the value of the data and information generated from their analyses including expression and modifications of nucleic acids and proteins. These biomolecules are dysregulated upon ischemia and decomposed once the living cells start to decay into inanimate matter. Therefore, ischemia time before final tissue preservation is the most important determinant of the quality of a tissue collection. Here we show the impact of ischemia time on tumour and matching adjacent normal tissue samples for mRNAs in 1,664, proteins in 1,818 and phosphoproteins in 1,800 cases (tumour and matching normal samples) of four solid tumour types (CRC, HCC, LUAD and LUSC NSCLC subtypes). In CRC, ischemia times exceeding 15 minutes impacted 12.5% (mRNA), 25% (protein) and 50% (phosphosites) of differentially expressed molecules in tumour versus normal tissues. This hypoxia- and decay-induced dysregulation increased with longer ischemia times and was observed across tumour types. Interestingly, the proteomics analysis revealed that specimen ischemia time above 15 minutes is mostly associated with a dysregulation of proteins in the immune response pathway and less so with metabolic processes. We conclude that ischemia time is a crucial quality parameter for tissue collections used for target discovery and validation in prognostic cancer research."
520,MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer,"Beatriz German, Jagpreet N. Singh, Marcos AdS Fonseca, Deborah L. Burkhart, Anjali Sheahan, Hannah Bergom, Katherine L. Morel, Himisha Beltran, Justin H. Hwang, Kate Lawrenson, Leigh Ellis",https://www.biorxiv.org/content/10.1101/2024.01.31.578216v1,"Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in prostate cancer (PCa) patients. While underlying molecular causations driving phenotypic plasticity have been identified, therapeutic success is yet to be achieved. To identify putative master regulator transcription factors (MR-TF) driving phenotypic plasticity in PCa, this work utilized a multiomic approach using genetically engineered mouse models of prostate cancer combined with patient data to identify MYBL2 as a significantly enriched transcription factor in PCa exhibiting phenotypic plasticity. Genetic inhibition of Mybl2 using independent murine PCa cell lines representing phenotypic plasticity demonstrated Mybl2 loss significantly decreased in vivo growth as well as cell fitness and repressed gene expression signatures involved in pluripotency and stemness. Because MYBL2 is currently not druggable, a MYBL2 gene signature was employed to identify cyclin-dependent kinase-2 (CDK2) as a potential therapeutic target. CDK2 inhibition phenocopied genetic loss of Mybl2 and significantly decreased in vivo tumor growth associated with enrichment of DNA damage. Together, this work demonstrates MYBL2 as an important MR-TF driving phenotypic plasticity in PCa. Further, high MYBL2 activity identifies PCa that would be responsive to CDK2 inhibition."
521,Mitochondrial DNA is a sensitive surrogate and oxidative stress target in oral cancer cells,"Jingyu Tan, Xinlin Dong, Haiwen Liu",https://www.biorxiv.org/content/10.1101/2024.05.23.595508v1,"Cellular oxidative stress mediated by intrinsic and/or extrinsic reactive oxygen species (ROS) is associated with disease pathogenesis. Oxidative DNA damage can naturally be substituted by mitochondrial DNA (mtDNA), leading to base lesion/strand break formation, copy number changes, and mutations. In this study, we devised a single test for the sensitive quantification of acute mtDNA damage, repair, and copy number changes using supercoiling-sensitive quantitative PCR (ss-qPCR) and examined how oxidative stress-related mtDNA damage responses occur in oral cancer cells. We observed that exogenous hydrogen peroxide (H2O2) induced dynamic mtDNA damage responses, as reflected by early structural DNA damage, followed by DNA repair if damage did not exceed a particular threshold. However, high oxidative stress levels induced persistent mtDNA damage and caused a 5–30-fold depletion in mtDNA copy numbers over late responses. This dramatic depletion was associated with significant growth arrest and apoptosis, suggesting persistent functional consequences. Moreover, oral cancer cells responded differentially to oxidative injury when compared with normal cells, and different ROS species triggered different biological consequences under stress conditions. In conclusion, we developed a new method for the sensitive detection of mtDNA damage and copy number changes, with exogenous H2O2 inducing dynamic mtDNA damage responses associated with functional changes in stressed cancer cells. Finally, our method can help characterize oxidative DNA damage in cancer and other human diseases."
522,Targeting a shared neoepitope derived from non-canonical translation of c-MYC oncogene in cancer cells,"E. Baulu, A. Bolon, E. Etchegaray, F. Raimundo, A. Merienne, J. Martin, J. Grandsire, T. Richard, L. Tonon, C. Dubois, Y. Estornes, R. Boulos, O. Tabone, P. Bonaventura, A. Page, C. Gardet, V. Alcazer, S. Hughes, B. Gillet, N. Gervois, N. Labarrière, Q. Wang, J. Valladeau-Guilemond, N. Chuvin, V. Marcel, J- J. Diaz, S. Depil",https://www.biorxiv.org/content/10.1101/2024.05.23.595486v1,"Cancer cells rely on alternative modes of translation for protein synthesis, promoting internal ribosome entry site (IRES)-dependent translation of mRNA encoding pro-oncogenic factors. Furthermore, ribosomes translate mRNA with lower fidelity in tumor cells. We proposed that these translational modifications in cancer produce shared tumor-specific epitopes derived from IRES-containing oncogenes. To identify such neoepitopes, we developed an in silico-based method that we applied to c-MYC. We showed that the non-canonical translation of c-MYC mRNA in cancer cells, involving a (+1) ribosomal frameshift, generates a shared neoepitope which induces high-avidity T cells able to kill tumor cells in vitro and in vivo while sparing normal cells. Our data provide preclinical rationale for developing immunotherapies targeting this c-MYC-derived neoepitope and validate a new type of shared translation-associated neoantigens."
524,"Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4+ cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype","Camila D Arcuschin, Kamin Kahrizi, Rosalyn W Sayaman, Carolina DiBenedetto, Yizhuo Shen, Pedro J Salaberry, Ons Zakroui, Cecilia Schwarzer, Alessandro Scapozza, Paola Betancur, Julie D Saba, Jean-Philippe Coppé, Mary Helen Barcellos-Hoff, Dietmar Kappes, Laura van 't Veer, Ignacio E Schor, Denise P Muñoz",https://www.biorxiv.org/content/10.1101/2024.09.21.614267v2,"Despite efforts to understand breast cancer biology, metastatic disease remains a clinical challenge. Identifying suppressors of breast cancer progression and mechanisms of transition to more invasive phenotypes could provide game changing therapeutic opportunities. Transcriptional deregulation is central to all malignancies, highlighted by the extensive reprogramming of regulatory elements that underlie oncogenic programs. Among these, super-enhancers (SEs) stand out due to their enrichment in genes controlling cancer hallmarks. To reveal novel breast cancer dependencies, we integrated the analysis of the SE landscape with master regulator activity inference for a series of breast cancer cell lines. As a result, we identified T-helper-inducing Poxviruses and Zinc-finger (POZ)/Krüppel-like factor (ThPOK, ZBTB7B), a CD4+ cell lineage commitment factor, as a breast cancer master regulator that is recurrently associated with a SE. ThPOK expression is highest in luminal breast cancer but is significantly reduced in the basal subtype. Manipulation of ThPOK levels in cell lines shows that its repressive function restricts breast cancer cells to an epithelial phenotype by suppressing the expression of genes involved in the epithelial-mesenchymal transition (EMT), WNT/β-catenin target genes, and the pro-metastatic TGFβ pathway. Our study reveals ThPOK as a master transcription factor that restricts the acquisition of metastatic features in breast cancer cells."
525,Apoptosis-coupled senescence causes cancer cell senotherapy,Byung-Soo Youn,https://www.biorxiv.org/content/10.1101/2023.09.22.558973v1,"Although new generations of anti-cancer modalities have been accumulated involving immuno-oncology cancers remain prevailing. This implies the current understanding of cancer cell biology is far from satisfactory. Curation of cancers is extremely rare. We hypothesized what could be the easiest Achilles’ Hill of cancer cells such that simple administration can jab cancer cells to be knocked out. Of conspicuous differences between cancer cells and normal cells, for example, metabolism, hypoxia, anaerobic glycolysis, uncontrolled cell proliferation, etc. exist. What could be the easiest and the most reliable anti-cancer modalities? We discovered one was cancer cell senescence (CCS) because cancer cells are the most presenescent (old) cells. We utilized a synthetic polyphenol designated as ONG41008. ONG41008 was able to induce massive senescence of pathologic myofibroblasts (pMFBs) and a vast majority of representative human cancer cells as well as a line of primary NSCLCs. All these cells turned out to be senescence-associated beta-galactosidase (SAbGAL) positive to different degrees, which does not mean real senescence is occurring in these cells. ONG41008 did not harm normal cells and elicited massive senescence in pMFBs without apoptosis. However, ONG41008 caused massive senescence as well as apoptosis in cancer cells. In other words, ONG41008 was capable of sensing intracellular molecular environments between normal cells, cancer cells, and pMFBs. This molecular recognition capability prompted us to explore how ONG4008 behaved on A549 (a human lung adenocarcinoma), PANC1(malignant human ductal adenocarcinoma), and mdr+PC3 (multidrug-resistant human prostate cancer). TP53, p21, and p16 were induced and/or nuclear relocated, suggesting that ONG41008 was recognized by these cells. ONG41008 drove A549 and PANC1 at G2/M phase arrest during 48 hrs, resulting in massive mitotic collapse. All cells died. Moreover, the cisplatin-resistant mdr+PC3 was also eliminated by ONG41008. An array of common components of apoptosis were activated, and especially, induction of Mcl1 was especially notable. These senolytics features were reported to oncogene-induced-senescence (OIS), in which the expression of over two activated oncogenes in the embryonic fibroblasts caused massive senescence and cell death as well. And the signature expression of Mcl1, an anti-apoptotic protein (a long form), was notable but two kinds of short forms are pro-apoptotic proteins. OIS was conducted in vitro cell culture models and whether or not the presence of OIS counterpart in vivo remains to be delineated."
526,Brain and cancer associated binding domain mutations provide insight into CTCF′s relationship with chromatin and its contribution to gene regulation,"Catherine Do, Guimei Jiang, Giulia Cova, Christos C Katsifis, Domenic N Narducci, Theodoros Sakellaropoulos, Raphael Vidal, Priscillia Lhoumaud, Aristotelis Tsirigos, Faye Fara Regis, Nata Kakabadze, Elphege P Nora, Marcus Noyes, Anders S Hansen, Jane A Skok",https://www.biorxiv.org/content/10.1101/2024.01.11.575070v5,"Here we used a series of CTCF mutations to explore CTCF′s relationship with chromatin and its contribution to gene regulation. CTCF′s impact depends on the genomic context of bound sites and the unique binding properties of WT and mutant CTCF proteins. Specifically, CTCF′s signal strength is linked to changes in accessibility, and the ability to block cohesin is linked to its binding stability. Multivariate modelling reveals that both CTCF and accessibility contribute independently to cohesin binding and insulation, however CTCF signal strength has a stronger effect. CTCF and chromatin have a bidirectional relationship such that at CTCF sites, accessibility is reduced in a cohesin-dependent, mutant specific fashion. In addition, each mutant alters TF binding and accessibility in an indirect manner, changes which impart the most influence on rewiring transcriptional networks and the cell′s ability to be reprogrammed. Collectively, the mutant perturbations provide a rich resource for determining CTCF′s site-specific effects."
528,Colocalization of Cancer Associated Biomarkers on Single Extracellular Vesicles for Early Cancer Detection,"Daniel P. Salem, Laura T. Bortolin, Dan Gusenleitner, Jonian Grosha, Ibukunoluwapo O. Zabroski, Kelly M. Biette, Sanchari Banerjee, Christopher R. Sedlak, Delaney M. Byrne, Bilal F. Hamzeh, MacKenzie S. King, Lauren T. Cuoco, Timothy Santos-Heiman, Peter A. Duff, Emily S. Winn-Deen, Toumy Guettouche, Dawn R. Mattoon, Eric K. Huang, Randy Schekman, Anthony D. Couvillon, Joseph C. Sedlak",https://www.biorxiv.org/content/10.1101/2023.02.07.527360v2,"Detection of cancer early, when it is most treatable, remains a significant challenge due to the lack of diagnostic methods sufficiently sensitive to detect nascent tumors. Early-stage tumors are small relative to their tissue of origin, heterogeneous, and infrequently manifest in clinical symptoms. Detection of their presence is made more difficult by a lack of abundant tumor-specific indicators (i.e., protein biomarkers, circulating tumor DNA, etc.) that would enable detection using a non-invasive diagnostic assay. In addition, many benign conditions manifest in a similar manner, thus discriminating an early-stage cancerous lesion from a benign tumor can present additional challenges and result in unnecessary medical procedures. To overcome these obstacles, we have developed a liquid biopsy assay that interrogates circulating extracellular vesicles (EVs) to detect tumor-specific biomarkers colocalized on the surface of individual EVs. Extracellular vesicles from all cell types, including early-stage tumors, are known to be abundant in blood, are remarkably stable, and serve as a biopsy of their cell of origin. The detection of a colocalized combination of cancer associated biomarkers that provide tumor specificity on the surface of extracellular vesicles enables the discrimination of early- and late-stage cancer from non-malignant conditions."
529,Characterization and implication of the Orai3 channel and ABC type transporters in the phenomenon of chemoresistance to cisplatin and pemetrexed in lung cancer.,Redoane Daoudi,https://www.biorxiv.org/content/10.1101/2024.09.22.613742v1,"Orai3 channels have been associated with cell proliferation, survival and metastasis in several cancers. Previous studies have shown that Orai3 seems to be involved in the development of acquired chemo-resistance of cisplatin in non-small cell lung cancer via ABC transporters that transport certain chemotherapeutic agents, such as cisplatin, out of the cells. Based on these studies, we hypothesize that Orai3 may be involved in the development of acquired chemo-resistance of pemetrexed. By using MTT assay, we show that pemetrexed is efficient and signiftcantly decreases cell viability in a dose dependent manner. Furthermore, we demonstrate using siRNA-mediated Orai3 knockdown that Orai3 silencing has no effect on the chemoresistance against pemetrexed. Then, calcium imaging reveals that pemetrexed does not affect the activity of calcium channels like Orai3. As transcription factors are central to the regulation of gene expression, we wonder if pemetrexed could impact on Orai3 expression. To address the issue, Mn2+ -quench assays are performed in siOrai3 transfected A549 cells incubated with 1uM pemetrexed for 72h. Finally, RT-PCR is used in order to determine the mRNA expression proftle for Orai3 and ABC transporters in A549 cells. We demonstrate that pemetrexed increases Orai3 expression. Taken together, these results suggest that Orai3 is not involved in the development of acquired chemo-resistance of pemetrexed in non small cell lung cancer. Pemetrexed upregulates Orai3 expression but does not affect the activity of Orai3 channels. As Orai3 channels are known to be involved in the development of acquired chemoresistance of cisplatin in non-small cell lung cancer, pemetrexed could reduce the therapeutic efficacy of cisplatin if Orai3 protein levels are linked to Orai3 mRNA levels. Moreover, cisplatin has been shown to increase both expression and function of Orai3, resulting in increased chemoresistance. Therefore, our results show that Orai3 could constitute a robust therapeutic target in non-small cell lung cancer."
530,MYC and p53 alterations cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer,"Katherine C. Murphy, Kelly D. DeMarco, Lin Zhou, Yvette Lopez-Diaz, Yu-jui Ho, Junhui Li, Shi Bai, Karl Simin, Lihua Julie Zhu, Arthur M. Mercurio, Marcus Ruscetti",https://www.biorxiv.org/content/10.1101/2024.07.24.604943v1,"Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted and immunotherapies. Whether genetic alterations acquired during the evolution of CRPC impact immune and immunotherapy responses is largely unknown. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which by signaling through VEGFR2 expressed on CD8+ T cells, could directly inhibit T cell activity. Targeting VEGF-VEGFR2 signaling in vivo led to CD8+ T cell-mediated tumor and metastasis growth suppression and significantly increased overall survival in MYC and p53 altered CPRC. VEGFR2 blockade also led to induction of PD-L1, and in combination with PD-L1 immune checkpoint blockade produced anti-tumor efficacy in multiple preclinical CRPC mouse models. Thus, our results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC."
532,Linking metastatic potential and viscoelastic properties of breast cancer spheroids via dynamic compression and relaxation in microfluidics,"Margherita Tavasso, Ankur D. Bordoloi, Elsa Tanré, Sanne A. H. Dekker, Valeria Garbin, Pouyan E. Boukany",https://www.biorxiv.org/content/10.1101/2024.07.23.604808v1,"The growth and invasion of solid tumors are associated with changes in their viscoelastic properties, influenced by both internal cellular factors and physical forces in the tumor microenvironment. Due to the lack of a comprehensive investigation of tumor tissue viscoelasticity, the relationship between such physical properties and cancer malignancy remains poorly understood. Here, the viscoelastic properties of breast cancer spheroids, 3D (in vitro) tumor models, are studied in relation to their metastatic potentials by imposing controlled, dynamic compression within a microfluidic constriction, and subsequently monitoring the relaxation of the imposed deformation. By adopting a modified Maxwell model to extract viscoelastic properties from the compression data, the benign (MCF-10A) spheroids are found to have higher bulk elastic modulus and viscosity compared to malignant spheroids (MCF-7 and MDA-MB-231). The relaxation is characterized by two timescales, captured by a double exponential fitting function, which reveals a similar fast rebound for MCF-7 and MCF-10A. Both the malignant spheroids exhibit similar long-term relaxation and display residual deformation. However, they differ significantly in morphology, particularly in intercellular movements. These differences between malignant spheroids are demonstrated to be linked to their cytoskeletal organization, by microscopic imaging of F-actin within the spheroids, together with cell-cell adhesion strength."
535,"Cryptococcosis, tuberculosis, and a kidney cancer fail to fit the atherosclerosis paradigm for foam cell lipid content","Valentina Guerrini, Brendan Prideaux, Rehan Khan, Selvakumar Subbian, Yina Wang, Evita Sadimin, Siddhi Pawar, Rahul Ukey, Eric A. Singer, Chaoyang Xue, Maria Laura Gennaro",https://www.biorxiv.org/content/10.1101/2023.06.08.542766v4,"Foam cells are dysfunctional, lipid-laden macrophages associated with chronic inflammation of diverse origin. The long-standing paradigm that foam cells are cholesterol-laden derives from atherosclerosis research. We previously showed that, in tuberculosis, foam cells surprisingly accumulate triglycerides. Here, we utilized bacterial (Mycobacterium tuberculosis), fungal (Cryptococcus neoformans), and human papillary renal cell carcinoma (pRCC) models to address the need for a new explanation of foam cell biogenesis. We applied mass spectrometry-based imaging to assess the spatial distribution of storage lipids relative to foam-cell-rich areas in lesional tissues, and we characterized lipid-laden macrophages generated under corresponding in vitro conditions. The in vivo data and the in vitro findings showed that cryptococcus-infected macrophages accumulate triglycerides, while macrophages exposed to pRCC- conditioned-medium accumulated both triglycerides and cholesterol. Moreover, cryptococcus- and mycobacterium-infected macrophages accumulated triglycerides in different ways. Collectively, the data show that the molecular events underlying foam cell formation are specific to disease and microenvironment. Since foam cells are potential therapeutic targets, recognizing that their formation is disease-specific opens new biomedical research directions."
536,Deciphering drug response and phenotypic heterogeneity of cancer cells using gene ensembles of regulatory units defined by chromatin domains,"Neetesh Pandey, Madhu Sharma, Arpit Mathur, Chukwuemeka George Anene-Nzel, Muhammad Hakimullah, Priyanka Patel, Indra Prakash Jha, Omkar Chandra, Shreya Mishra, Jui Bhattacharya, Ankur Sharma, Roger Foo, Kuljeet Sandhu, Amit Mandoli, Ramanuj DasGupta, Vibhor Kumar",https://www.biorxiv.org/content/10.1101/2023.01.15.524115v3,"The effect of co-localization of genes in the topologically associated domains (TADs) and their activity as a regulatory unit in cancer samples and cells, together with drug-response, needs comprehensive analysis. Here, we analyzed the activity of TADs using cancer-cell transcriptomes along with chromatin-interaction and epigenome profiles to understand their relationship with drug-response. Our analysis of 819 cancer cell-line transcriptomes revealed that their response to multiple drugs was more correlated with the activity of individual TADs than genes. Applying our approach to 9014 cancer patients’ data (20 different cancer types) also revealed a higher association between survival and the activity of thousands of individual TADs in comparison to their genes. CRISPR-mediated knock-out of regulatory sites inside a TAD associated with cisplatin-response of oral cancer cells and discovery of primate-specific gain of synteny of genes within a TAD containing EGFR gene and its contribution towards cancer malignancy demonstrate greater utility of TAD-activity based analysis."
537,Structural characterization and AlphaFold modeling of human T cell receptor recognition of NRAS cancer neoantigens,"Daichao Wu, Rui Yin, Guodong Chen, Helder V. Ribeiro-Filho, Melyssa Cheung, Paul F. Robbins, Roy A. Mariuzza, Brian G. Pierce",https://www.biorxiv.org/content/10.1101/2024.05.21.595215v1,"T cell receptors (TCRs) that recognize cancer neoantigens are important for anti-cancer immune responses and immunotherapy. Understanding the structural basis of TCR recognition of neoantigens provides insights into their exquisite specificity and can enable design of optimized TCRs. We determined crystal structures of a human TCR in complex with NRAS Q61K and Q61R neoantigen peptides and HLA-A1 MHC, revealing the molecular underpinnings for dual recognition and specificity versus wild-type NRAS peptide. We then used multiple versions of AlphaFold to model the corresponding complex structures, given the challenge of immune recognition for such methods. Interestingly, one implementation of AlphaFold2 (TCRmodel2) was able to generate accurate models of the complexes, while AlphaFold3 also showed strong performance, although success was lower for other complexes. This study provides insights into TCR recognition of a shared cancer neoantigen, as well as the utility and practical considerations for using AlphaFold to model TCR–peptide–MHC complexes."
538,Phosphodiesterase 1A physically interacts with YTHDF2 and reinforces the progression of non-small cell lung cancer,"Chong Zhang, Zuoyan Zhang, Yuchen Wu, Jing Cheng, Kaizhi Luo, Zhidi Li, Manman Zhang, Jian Wang, Yangling Li",https://www.biorxiv.org/content/10.1101/2024.05.21.595220v1,"Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and the prognosis is poor due to distant metastasis and drug resistance. Thus, there is an urgent need to discover novel therapeutic targets and strategies to overcome cisplatin resistance and metastasis. A series of in vitro and in vivo phenotype experiments were performed to investigate the role of PDE1A in NSCLC. The RIP assay, mRNA stability assay and LC- MS/MS were performed to investigate the molecular mechanisms of PDE1A in NSCLC progression. We demonstrated that phosphodiesterase 1A (PDE1A) promoted metastasis and EMT progression of NSCLC. In addition, NSCLC cells overexpressing PDE1A promoted angiogenesis by regulating exosome release. IL-6/JAK/STAT3 signaling pathway was highly enriched in PDE1A- coexpresssed genes, and PDE1A promoted NSCLC metastasis by activating the STAT3 pathway. GO enrichment analysis of PDE1A-interacting genes showed that PDE1A might interact with YTHDF2 and participate in m6A- containing RNA binding. The binding between PDE1A and YTHDF2 was verified, and PDE1A regulated the STAT3 pathway by interacting with YTHDF2. The mechanism of YTHDF2/PDE1A complex in regulating STAT3 pathway was predicted by overlapping YTHDF2-interacting-RNAs, and genes coexpressed with YTHDF2 and STAT3. The interactions between YTHDF2 and target mRNAs were predicted, and there were three predicted targets of YTHDF2 with high scores: NRF2, SOCS2, and MET. Indeed, PDE1A interacted with YTHDF2, destabilized SOCS2, and activated STAT3 pathway. Moreover, PDE1A suppression sensitized anti-NSCLC activity of cisplatin via regulating NRF2 and MET. This work not only uncovers a novel PDE1A/YTHDF2/STAT3 pathway in NSCLC progression but also provides therapeutic strategies for treating NSCLC patients with metastasis or cisplatin- resistance."
539,Pancreatic cancer mutationscape: revealing the link between modular restructuring and intervention efficacy amidst common mutations,"Daniel Plaugher, David Murrugarra",https://www.biorxiv.org/content/10.1101/2024.01.27.577546v2,"There is increasing evidence that biological systems are modular in both structure and function. Complex biological signaling networks such as gene regulatory networks (GRNs) are proving to be composed of subcategories that are interconnected and hierarchically ranked. These networks contain highly dynamic processes that ultimately dictate cellular function over time, as well as influence phenotypic fate transitions. In this work, we use a stochastic multicellular signaling network of pancreatic cancer (PC) to show that the variance in topological rankings of the most phenotypically influential modules implies a strong relationship between structure and function. We further show that induction of mutations alters the modular structure, which analogously influences the aggression and controllability of the disease in silico. We finally present evidence that the impact and location of mutations with respect to PC modular structure directly corresponds to the efficacy of single agent treatments in silico, because topologically deep mutations require deep targets for control."
540,ZNF251 haploinsufficiency confers PARP inhibitors resistance in BRCA1-mutated cancer cells through activation of homologous recombination,"Huan Li, Srinivas Chatla, Xiaolei Liu, Zhen Tian, Umeshkumar Vekariya, Peng Wang, Dongwook Kim, Stacia Octaviani, Zhaorui Lian, George Morton, Zijie Feng, Dan Yang, Katherine Sullivan-Reed, Wayne Childers, Xiang Yu, Kumaraswamy Naidu Chitrala, Jozef Madzo, Tomasz Skorski, Jian Huang",https://www.biorxiv.org/content/10.1101/2022.09.29.510119v4,"Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a promising new class of agents that have demonstrated efficacy in treating various cancers, particularly those with BRCA1/2 mutations. Cancer-associated BRCA1/2 mutations disrupt DNA double-strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPis) have been used to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting the accumulation of toxic DSBs. Unfortunately, resistance to PARPis is common and can occur through multiple mechanisms, including the restoration of HR and/or stabilization of replication forks. To gain a better understanding of the mechanisms underlying PARPis resistance, we conducted an unbiased CRISPR-pooled genome-wide library screen to identify new genes whose deficiency confers resistance to the PARPi olaparib. Our research revealed that haploinsufficiency of the ZNF251 gene, which encodes zinc finger protein 251, is associated with resistance to PARPis in various breast and ovarian cancer cell lines carrying BRCA1 mutations. Mechanistically, we discovered that ZNF251 haploinsufficiency leads to stimulation of RAD51-mediated HR repair of DSBs in olaparib-treated BRCA1-mutated cancer cells. Moreover, we demonstrated that a RAD51 inhibitor reversed PARPi resistance in ZNF251 haploinsufficient cancer cells harboring BRCA1 mutations. Our findings provide important insights into the mechanisms underlying PARPis resistance by highlighting the role of RAD51 in this phenomenon."
541,Glutamine-addiction in cisplatin resistant cancer cells is mediated by SLC7A11 and can be targeted with asparaginase therapy,"Jiantao Wang, Robert Strauss, Jiri Bartek, Sean G Rudd",https://www.biorxiv.org/content/10.1101/2024.07.19.604261v1,"Linking disease phenotypes with molecular targets is key to the rational design of treatment interventions. Resistance to the chemotherapeutic cisplatin is one of the major factors limiting the clinical utility of this therapy, which is central to the treatment of a variety of solid malignancies. In this study, we couple the upregulation of a chemoresistant factor, the glutamate-cystine antiporter SLC7A11, with the addiction of cisplatin-resistant cancer cells to extracellular glutamine. In doing so, we thus provide a putative biomarker for this acquired metabolic dependency of chemoresistance. Subsequently, we evaluate various therapeutic strategies to selectively kill SLC7A11high cisplatin-resistant cancer cells, identifying cross-resistance to ferroptosis-inducing compounds and hypersensitivity to glutaminase inhibitor CB-839. We identify enzymatic depletion of extracellular glutamine using the long-standing anti-leukemic therapy asparaginase (ASNase), which possesses glutaminase activity, as a potential approach, and show this can be successfully combined with cisplatin in cell models. In summary, this study mechanistically links an acquired metabolic dependency of chemoresistant cancer cells with a putative biomarker and provides a potentially actionable strategy to target these drug resistant cells warranting further investigation."
542,Association between genetic clades and cancer prevalence suggested by French-wide study of oncogenic small ruminant beta-retroviruses diversity,"Riocreux-Verney Benjamin, Verneret Marie, Diesler Rémi, Dolmazon Christine, Gineys Barbara, Cadoré Jean-Luc, Turpin Jocelyn, Leroux Caroline",https://www.biorxiv.org/content/10.1101/2024.07.18.604097v1,"ENTV (Enzootic Nasal Tumor Virus) and JSRV (Jaagsiekte Sheep Retrovirus) are β-retroviruses responsible for respiratory cancers in sheep and goats. In this study, we analyzed the genetic features of the sheep and goat β-retrovirus (29 JSRV and 24 ENTV strains) circulating in France to identify molecular signatures associated with disease severity in flocks. We developed a highly specific PCR to amplify and sequence exogenous targeted regions or near full length proviruses based on limited discriminating motifs along their genomes. The phylogenetic reconstructions based on the LTR and env regions suggest that one major strain is circulating on the French territory for ENTV-1 and ENTV-2 while not clustering with already published Spanish, Canadian or Chinese strains. JSRV strains circulating in French sheep flocks were distributed in 2 distinct genetic clades clustering with sequences originating from North America, Africa and United-Kingdom. JSRV clade I was found to be associated with a higher incidence of cancer in French flocks. Specific motifs spanning the entire JSRV genome particularly in the LTRs and in the intracytoplasmic domain of the envelope were detected between the two genetic subtypes."
543,LncCE: Landscape of Cellular-Elevated LncRNAs in Single Cells Across Normal and Cancer Tissues,"Kang Xu, Yujie Liu, Chongwen Lv, Ya Luo, Jingyi Shi, Haozhe Zou, Weiwei Zhou, Dezhong Lv, Changbo Yang, Yongsheng Li, Juan Xu",https://www.biorxiv.org/content/10.1101/2024.05.17.594684v1,"Long non-coding RNAs (lncRNAs) have emerged as significant players for maintaining the morphology and function of tissues or cells. The precise regulatory effectiveness of lncRNA is closely associated with the spatial expression patterns across tissues and cells. Here, we proposed the Cellular-Elevated LncRNA (LncCE) database to systematically explore cellular-elevated (CE) lncRNAs across normal and cancer tissues in single cells. LncCE encompasses 87,946 CE lncRNAs of 149 cell types by analyzing 181 single-cell RNA sequencing (scRNA-seq) datasets, involved in 20 fetal normal tissues, 59 adult normal tissues, as well as 32 adult and 5 pediatric cancer tissues.Two main search options were provided via a given lncRNA name or a cell type. The output results emphasize both qualitative and quantitative expression features of lncRNAs across different cell types, co-expression with protein-coding genes as well as their involved in biological functions. For cancers, LncCE particularly provided quantitative figures for exhibiting their expression changes compared to control samples and clinical associations with patient overall survivals. Together, LncCE offers an extensive, quantitative and user-friendly interface to investigate cellular-elevated expression atlas for lncRNAs across normal and cancers tissues at single-cell level. The LncCE database is available at http://bio-bigdata.hrbmu.edu.cn/LncCE."
544,Tumor-derived colorectal cancer organoids induce a unique Treg cell population through direct modulation of CD4+ T cell differentiation,"Sonia Aristin Revilla, Cynthia Lisanne Frederiks, Stefan Prekovic, Enric Mocholi, Onno Kranenburg, Paul James Coffer",https://www.biorxiv.org/content/10.1101/2024.07.18.604049v1,"In colorectal cancer (CRC), increased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells correlate with tumor development and immunotherapy failure, leading to poor prognosis. However, the molecular and cellular mechanisms governing Treg recruitment, expansion, or differentiation remain unclear. Here, we developed an in vitro co-culture system to assess the capacity of CRC tumors to directly modulate Treg cell differentiation. CD4+ T cells from Foxp3eGFP mice were co-cultured with murine tumor-derived CRC organoids, resulting in a significant increase in Treg cell numbers. This induction of Treg cells was not due to increased proliferation, but rather through differentiation of CD4+ T cells in a TGFβ-dependent manner. Human CRC tumor organoids similarly induced Treg cells that exhibited enhanced suppressive capacity compared to TGFβ-induced Treg cells. RNA-sequencing analysis identified distinct transcriptional profiles between CRC organoid-induced Treg cells and TGFβ-induced Treg cells, with upregulation of key functional signature genes linked to CRC Treg cells in vivo. High expression of genes upregulated in CRC organoid-induced Treg cells correlates with shorter progression free interval and overall survival of CRC patients, highlighting their prognostic potential. Taken together, CRC tumor organoids drive CD4+ differentiation to Treg cells with a phenotype resembling tumor-infiltrating Treg cells. This model can be applied to both understand the molecular mechanisms by which tumors can directly modulate CD4+ T cell differentiation and identify approaches to disrupt Treg cell function and stimulate anti-tumor immunity."
546,Pro-survival roles for p21(Cip1/Waf1) in Non-Small Cell Lung Cancer,"SJ Cutty, FA Hughes, P Ortega-Prieto, S Desai, P Thomas, LV Fets, M Secrier, AR Barr",https://www.biorxiv.org/content/10.1101/2024.05.21.595102v1,"Quiescence is a reversible state of proliferative arrest, distinct from senescence. While cancer is a disease of dysregulated proliferation, cancer cells can retain the ability to enter quiescence which confers advantages to tumour cells by protecting them from chemotherapy or by allowing metastasis to distant sites. Multiple mechanisms exist to induce and maintain quiescence that are not yet fully understood. Here, we show that high expression of the CDK inhibitor p21Cip1/Waf1 correlates with a poor prognosis in TP53 wild-type, but not TP53 mutant, non-small cell lung cancer (NSCLC) patients. Using quantitative single-cell imaging of genetically-engineered NSCLC reporter cell lines, we show that TP53 wild-type NSCLC cells can enter a p21-dependent spontaneous quiescent state, downstream of replication stress. Furthermore, p21 expression confers survival advantages to TP53 wild-type NSCLC cells, both under normal proliferation and in response to chemotherapy. We also show that p21 can promote tumour relapse by allowing cells to recover from both G1 and G2 arrest states after drug removal. Together, our data suggest that targeting p21 function in TP53 wild-type tumours could lead to better outcomes for chemotherapy treatment in NSCLC patients."
548,Targeted intracellular delivery to hypoxic human breast cancer stem cells,"Ashley V Makela, Anthony Tundo, Huiping Liu, Terry Hermiston, Christopher H Contag",https://www.biorxiv.org/content/10.1101/2024.01.12.575071v1,"Cancer stem cells (CSCs) comprise the root of cancers and remain a therapeutic challenge since they are quiescent, resist traditional therapies and are fundamentally tumorigenic. Therefore, effective cancer treatments require CSC-targeted approaches that function in representative CSC microenvironments. CSCs exhibit few distinguishable and targetable characteristics, however phosphatidylserine (PS) exposure on the cell surface and localization to hypoxic regions of the tumor are speculated traits. We have reported that a truncated protein S (GlaS) binds PS and is internalized, enabling intracellular delivery of molecular payloads. GlaS delivery was evaluated in patient-derived CD44+ mammary CSCs under different oxygen concentrations. A higher percentage of CD44+GlaS+ cells were observed in hypoxia compared to cells in physoxia or hyperoxia that tracked to small CD44+ cells, which are likely aggressive tumorigenic CSCs. Delivery of therapeutics to the cytoplasm of CSCs will enable new therapies directed at intracellular targets, ultimately eliminating CSCs."
549,Netrin G1 Ligand is a new stromal immunomodulator that promotes pancreatic cancer,"Débora B. Vendramini-Costa, Ralph Francescone, Janusz Franco-Barraza, Tiffany Luong, Myree Graves, Ariana Musa de Aquino, Nina Steele, Jaye C. Gardiner, Sérgio Alexandre Alcantara dos Santos, Charline Ogier, Emily Malloy, Leila Borghaei, Esteban Martinez, Dmitry I. Zhigarev, Yinfei Tan, Hayan Lee, Yan Zhou, Kathy Q. Cai, Andres J. Klein-Szanto, Huamin Wang, Mark Andrake, Roland L. Dunbrack, Kerry Campbell, Edna Cukierman",https://www.biorxiv.org/content/10.1101/2024.05.15.594354v1,"Understanding pancreatic cancer biology is fundamental for identifying new targets and for developing more effective therapies. In particular, the contribution of the stromal microenvironment to pancreatic cancer tumorigenesis requires further exploration. Here, we report the stromal roles of the synaptic protein Netrin G1 Ligand (NGL-1) in pancreatic cancer, uncovering its pro-tumor functions in cancer-associated fibroblasts and in immune cells. We observed that the stromal expression of NGL-1 inversely correlated with patients’ overall survival. Moreover, germline knockout (KO) mice for NGL-1 presented decreased tumor burden, with a microenvironment that is less supportive of tumor growth. Of note, tumors from NGL-1 KO mice produced less immunosuppressive cytokines and displayed an increased percentage of CD8+ T cells than those from control mice, while preserving the physical structure of the tumor microenvironment. These effects were shown to be mediated by NGL-1 in both immune cells and in the local stroma, in a TGF-β-dependent manner. While myeloid cells lacking NGL-1 decreased the production of immunosuppressive cytokines, NGL-1 KO T cells showed increased proliferation rates and overall polyfunctionality compared to control T cells. CAFs lacking NGL-1 were less immunosuppressive than controls, with overall decreased production of pro-tumor cytokines and compromised ability to inhibit CD8+ T cells activation. Mechanistically, these CAFs downregulated components of the TGF-β pathway, AP-1 and NFAT transcription factor families, resulting in a less tumor-supportive phenotype. Finally, targeting NGL-1 genetically or using a functionally antagonistic small peptide phenocopied the effects of chemotherapy, while modulating the immunosuppressive tumor microenvironment (TME), rather than eliminating it. We propose NGL-1 as a new local stroma and immunomodulatory molecule, with pro-tumor roles in pancreatic cancer."
550,Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism,"Ielizaveta Gorodetska, Vasyl Lukiyanchuk, Marta Gawin, Myroslava Sliusar, Annett Linge, Fabian Lohaus, Tobias Hölscher, Kati Erdmann, Susanne Fuessel, Angelika Borkowetz, Mark Reardon, Ananya Choudhury, Yasmin Antonelli, Aldo Leal-Egaña, Ayse Sedef Köseer, Uğur Kahya, Jakob Püschel, Daria Klusa, Claudia Peitzsch, Romy Kronstein-Wiedemann, Torsten Tonn, Christian Thomas, Piotr Widłak, Monika Pietrowska, Mechthild Krause, Anna Dubrovska",https://www.biorxiv.org/content/10.1101/2024.07.16.603771v1,"Background Prostate cancer (PCa) is the second most common type of tumor diagnosed in men and the fifth leading cause of cancer-related death in male patients. The response of metastatic disease to standard treatment is heterogeneous. As for now, there is no curative treatment option available for metastatic PCa, and the clinical tests capable of predicting metastatic dissemination and metastatic response to the therapies are lacking. Our recent study identifies aldehyde dehydrogenases ALDH1A1 and ALDH1A3 as critical regulators of PCa metastases. Still, the exact mechanisms mediating the role of these proteins in PCa metastatic dissemination remain not fully understood, and plasma-based biomarkers of these metastatic mechanisms are also not available."
552,In Search of the Perfect Model: How Cancer Cell Lines Relate to Native Cancers,"Rahel Paloots, Ziying Yang, Michael Baudis",https://www.biorxiv.org/content/10.1101/2024.05.15.594310v1,"Cancer cell lines are frequently used in biological and translational research to study cellular mechanisms and explore treatment options. However, cancer cell lines may display mutational profiles divergent from native cancers or may be misidentified or contaminated. We explored how similar cancer cell lines are to native cancers to find the most suitable representations for the corresponding diseases by utilising large collections of copy number variation (CNV) profiles and applied machine learning (ML) algorithms to predict cell line classifications."
553,CRISPR Double Knockout Library Reveals Synthetic Lethal Gene Pairs in Triple-Negative Breast Cancer,"Shuai Shao, Shangjia Li, Shan Tang, Kunjie Fan, Lang Li",https://www.biorxiv.org/content/10.1101/2024.05.14.594157v1,"Synthetic lethality, a genetic interaction involving two or more genes whose combined loss results in cell death, has emerged as a promising strategy for targeted cancer therapy. By exploiting synthetic lethal interactions, cancer cells can be selectively targeted and eradicated while preserving healthy cells, minimizing off-target effects, and reducing toxicity. The development of PARP inhibitors for ovarian and breast cancer patients with BRCA mutations exemplifies the potential of synthetic lethality-based therapy. Various experimental approaches, including CRISPR/Cas9 screens, have been employed to identify synthetic lethal gene pairs. Our lab has developed a CRISPR double knockout library, leveraging the XDeathDB database for candidate gene selection. This comprehensive platform offers insights into 12 cell death modes and 149 cell death hallmark genes. We aim to construct a cell-death double knock-out library using these genes and perform double knock-out screening on MDA-MB-231, a representative cell line for TNBC chemo poor responders. The identified synergistic lethal gene pairs may serve as potential drug targets for treating TNBC."
554,Intercellular extrachromosomal DNA copy number heterogeneity drives cancer cell state diversity,"Maja C Stöber, Rocío Chamorro González, Lotte Brückner, Thomas Conrad, Nadine Wittstruck, Annabell Szymansky, Angelika Eggert, Johannes H Schulte, Richard P Koche, Anton G Henssen, Roland F Schwarz, Kerstin Haase",https://www.biorxiv.org/content/10.1101/2023.01.21.525014v3,"Neuroblastoma is characterised by extensive inter- and intra-tumour genetic heterogeneity and varying clinical outcomes. One possible driver for this heterogeneity are extrachromosomal DNAs (ecDNA), which segregate independently to the daughter cells during cell division and can lead to rapid amplification of oncogenes. While ecDNA-mediated oncogene amplification has been shown to be associated with poor prognosis in many cancer entities, the effects of ecDNA copy number heterogeneity on intermediate phenotypes are still poorly understood."
555,Pre-existing stem cell heterogeneity dictates clonal responses to acquisition of cancer driver mutations,"Indranil Singh, Daniel Fernandez Perez, Pedro Sánchez, Alejo E. Rodriguez-Fraticelli",https://www.biorxiv.org/content/10.1101/2024.05.14.594084v1,"Cancer cells display wide phenotypic variation even across patients with the same mutations. Differences in the cell of origin provide a potential explanation, but these assays have traditionally relied on surface markers, lacking the clonal resolution to distinguish heterogeneous subsets of stem and progenitor cells. To address this challenge, we developed STRACK, an unbiased framework to longitudinally trace clonal gene expression and expansion dynamics before and after acquisition of cancer mutations. We studied two different leukemia driver mutations, Dnmt3a-R882H and Npm1cA, and found that the response to both mutations was highly variable across different stem cell states. Specifically, a subset of differentiation-biased stem cells, which normally become outcompeted with time, can efficiently expand with both mutations. Npm1c mutations surprisingly reversed the intrinsic bias of the clone-of-origin, with stem-biased clones giving rise to more mature malignant states. We propose a clonal “reaction norm”, in which pre-existing clonal states dictate different cancer phenotypic potential."
556,Heterotypic competition between cancer cells and hepatocytes generates heterogeneous context-dependent phenotypes,"Andrea Spinazzola, Tânia Carvalho, Miguel Alexandre Ferreira Pinto, Mariana Marques-Reis, Andrés Gutiérrez-García, Davide Accardi, Eduardo Moreno",https://www.biorxiv.org/content/10.1101/2024.05.15.593526v1,"Competitive interactions between tumor cells and surrounding healthy cells are constantly present during the progression of a solid tumor, and their outcome has been proposed to affect the clinical behavior. Previous studies have described various mechanistic and molecular aspects that characterize this process, overall indicating that cancer cells behave as supercompetitors, which eliminate neighboring healthy cells to gain vital space for growth and infiltration of the tissue. Nevertheless, there is a lack of systematic characterization of these competitive interactions, particularly in the context of cancer in mammals. Furthermore, previous studies in the field of cell competition have primarily focused on homotypic cell competition, involving different clones of the same cell or cells deriving from the same tissue. Data are scarce regarding heterotypic cell competition between two unrelated cell types, which is particularly critical for the understanding of metastatic tumors. In this research, we study cell competition in the context of liver metastases, providing a broad characterization of this process in different relevant scenarios, including cells growing in vitro in 2D and 3D, and in vivo. Results show that in vitro, only a subset of cancer cell lines are coherently strong or moderate competitors against hepatocytes, while the remaining demonstrate poor competitiveness. The competitive proficiency can vary depending on the experimental growth system that is employed, and often predicts the phenotype of liver metastases in terms of aggressiveness and morphology. Finally, our data point towards an involvement of mechanical competition in determining the supercompetitor trait of cancer cells. Altogether, our research provides the first comprehensive characterization of heterotypic cell competition, and indicates that cancer cells possess heterogeneous competitive proficiency towards hepatocytes which can be affected by the growth conditions."
557,"Identification and Pharmacological Targeting of Treatment-Resistant, Stem-like Breast Cancer Cells for Combination Therapy","Jeremy Worley, Heeju Noh, Daoqi You, Mikko M. Turunen, Hongxu Ding, Evan Paull, Aaron T. Griffin, Adina Grunn, Mingxuan Zhang, Kristina Guillan, Erin C. Bush, Samantha J. Brosius, Hanina Hibshoosh, Prabhjot S. Mundi, Peter Sims, Piero Dalerba, Filemon S. Dela Cruz, Andrew L. Kung, Andrea Califano",https://www.biorxiv.org/content/10.1101/2023.11.08.562798v2,"Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential—often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy. Interrogation of single-cell RNA sequencing profiles from seven metastatic breast cancer patients, using perturbational profiles of clinically relevant drugs, identified drugs predicted to invert the activity of MR proteins governing the transcriptional state of chemoresistant CSLCs, which were then validated by CROP-seq assays. The top drug, the anthelmintic albendazole, depleted this subpopulation in vivo without noticeable cytotoxicity. Moreover, sequential cycles of albendazole and paclitaxel—a commonly used chemotherapeutic —displayed significant synergy in a patient-derived xenograft (PDX) from a TNBC patient, suggesting that network-based approaches can help develop mechanism-based combinatorial therapies targeting complementary subpopulations."
559,Screening and identification of gene expression in large cohorts of clinical lung cancer samples unveils the major involvement of EZH2 and SOX2,"Niharika, Ankan Roy, Ratan Sadhukhan, Samir Kumar Patra",https://www.biorxiv.org/content/10.1101/2024.09.17.613500v1,"Lung adenocarcinoma (LUAD), the primary subtype of Non-Small Cell Lung Cancer (NSCLC), accounts for 80% to 85% of cases. Due to suboptimal screening method, LUAD is often detected in late stage, leading to aggressive progression and poor outcomes. Therefore, early disease prognosis for the LUAD is high priority. In order to identify early detection biomarkers, we conducted a meta-analysis of mRNA expression TCGA and GTEx datasets from LUAD patients. A total of 795 differentially expressed genes (DEGs) were identified by exploring the Network-Analyst tool and utilizing combined effect size methods. DEGs refer to genes whose expression levels are significantly different (either higher or lower) compared to their normal baseline expression levels. KEGG pathway enrichment analysis highlighted the TNF signaling pathway as being prominently associated with these DEGs. Subsequently, using the MCODE and CytoHubba plugins in Cytoscape software, we filtered out the top 10 genes. Among these, SOX2 was the only gene exhibiting higher expression, while the others were downregulated. Consequently, our subsequent research focused on SOX2. Further transcription factor-gene network analysis revealed that enhancer of zeste homolog 2 (EZH2) is a significant partner of SOX2, potentially playing a crucial role in euchromatin-heterochromatin dynamics. Structure of SOX2 protein suggest that it is a non-druggable transcription factor, literature survey suggests the same; hence, we drove our focus to investigate on potential drug(s) targeting EZH2. Molecular docking analyses predicted most probable inhibitors of EZH2. We employed several predictive analysis tools and identified GSK343, as a promising inhibitor of EZH2."
560,Drug resistant pancreatic cancer cells exhibit altered biophysical interactions with stromal fibroblasts in imaging studies of 3D co-culture models,"Eric Struth, Maryam Labaf, Vida Karimnia, Yiran Liu, Gwendolyn Cramer, Joanna B. Dahl, Frank J. Slack, Kourosh Zarringhalam, Jonathan P. Celli",https://www.biorxiv.org/content/10.1101/2024.07.14.602133v1,"Interactions between tumor and stromal cells are well known to play a prominent roles in progression of pancreatic ductal adenocarcinoma (PDAC). As knowledge of stromal crosstalk in PDAC has evolved, it has become clear that cancer associated fibroblasts can play both tumor promoting and tumor suppressive roles through a combination of paracrine crosstalk and juxtacrine interactions involving direct physical contact. Another major contributor to dismal survival statistics for PDAC is development of resistance to chemotherapy drugs. Though less is known about how the acquisition of chemoresistance impacts upon tumor-stromal crosstalk. Here, we use 3D co-culture geometries to recapitulate juxtacrine interactions between epithelial and stromal cells. In particular, extracellular matrix (ECM) overlay cultures in which stromal cells (pancreatic stellate cells, or normal human fibroblasts) are placed adjacent to PDAC cells (PANC1), result in direct heterotypic cell adhesions accompanied by dramatic fibroblast contractility which leads to highly condensed macroscopic multicellular aggregates as detected using particle image velocimetry (PIV) analysis to quantify cell velocities over the course of time lapse movie sequences. To investigate how drug resistance impacts these juxtacrine interactions we contrast cultures in which PANC1 are substituted with a drug resistant subline (PANC1-OR) previously established in our lab. We find that heterotypic cell-cell interactions are highly suppressed in drug-resistant cells relative to the parental PANC1 cells. To investigate further we conduct RNA-seq and bioinformatics analysis to identify differential gene expression in PANC1 and PANC1-OR, which shows that negative regulation of cell adhesion molecules, consistent with increased epithelial mesenchymal transition (EMT), is also consistent with loss of hetrotypic cell-cell contact necessary for the contractile behavior observed in drug naïve cultures. Overall these findings elucidate the role of drug-resistance in inhibiting an avenue of stromal crosstalk which is associated with tumor suppression and also help to establish cell culture conditions useful for further mechanistic investigation."
561,Targeting circadian transcriptional programs in triple negative breast cancer through a cis-regulatory mechanism,"Yuanzhong Pan, Tsu-Pei Chiu, Lili Zhou, Priscilla Chan, Tia Tyrsett Kuo, Francesca Battaglin, Shivani Soni, Priya Jayachandran, Jingyi Jessica Li, Heinz-Josef Lenz, Shannon M. Mumenthaler, Remo Rohs, Evanthia Roussos Torres, Steve A. Kay",https://www.biorxiv.org/content/10.1101/2024.04.26.590360v2,"Circadian clock genes are emerging targets in many types of cancer, but their mechanistic contributions to tumor progression are still largely unknown. This makes it challenging to stratify patient populations and develop corresponding treatments. In this work, we show that in breast cancer, the disrupted expression of circadian genes has the potential to serve as biomarkers. We also show that the master circadian transcription factors (TFs) BMAL1 and CLOCK are required for the proliferation of metastatic mesenchymal stem-like (mMSL) triple-negative breast cancer (TNBC) cells. Using currently available small molecule modulators, we found that a stabilizer of cryptochrome 2 (CRY2), the direct repressor of BMAL1 and CLOCK transcriptional activity, synergizes with inhibitors of proteasome, which is required for BMAL1 and CLOCK function, to repress a transcriptional program comprising circadian cycling genes in mMSL TNBC cells. Omics analyses on drug-treated cells implied that this repression of transcription is mediated by the transcription factor binding sites (TFBSs) features in the cis-regulatory elements (CRE) of clock-controlled genes. Through a massive parallel reporter assay, we defined a set of CRE features that are potentially repressed by the specific drug combination. The identification of cis-element enrichment may serve as a new way of defining and targeting tumor types through the modulation of cis-regulatory programs, and ultimately provide a new paradigm of therapy design for cancer types with unclear drivers like TNBC."
562,Loss of ZNRF3/RNF43 Unleashes EGFR in Cancer,"Fei Yue, Amy T. Ku, Payton D. Stevens, Megan N. Michalski, Weiyu Jiang, Jianghua Tu, Zhongcheng Shi, Yongchao Dou, Yi Wang, Xin-Hua Feng, Galen Hostetter, Xiangwei Wu, Shixia Huang, Noah F. Shroyer, Bing Zhang, Bart O. Williams, Qingyun Liu, Xia Lin, Yi Li",https://www.biorxiv.org/content/10.1101/2024.01.10.574969v1,"ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the most negatively correlated protein with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of ZNRF3/RNF43 stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data highlight ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptor, uncovering a novel mechanism underlying the frequent co-activation of EGFR and WNT signaling in development and cancer."
563,Spike-in enhanced phosphoproteomics uncovers synergistic signaling responses to MEK inhibition in colon cancer cells,"Mirjam van Bentum, Bertram Klinger, Anja Sieber, Nadine Lehmann, Sheyda Naghiloo, Mohamed Haji, Sylvia Niquet, Philipp Mertins, Nils Blüthgen, Matthias Selbach",https://www.biorxiv.org/content/10.1101/2024.05.13.593849v1,"Targeted kinase inhibitors are a cornerstone of cancer therapy, but their success is often hindered by the complexity of cellular signaling networks that can lead to resistance. Overcoming this challenge necessitates a deep understanding of cellular signaling responses. While standard global phosphoproteomics offers extensive insights, lengthy processing times, the complexity of data interpretation, and frequent omission of crucial phosphorylation sites limit its utility. Here, we combine data-independent acquisition (DIA) with spike-in of synthetic heavy stable isotope-labeled phosphopeptides to facilitate the targeted detection of particularly informative phosphorylation sites. Our spike-in enhanced detection in DIA (SPIED-DIA) approach integrates the improved sensitivity of spike-in-based targeted detection with the discovery potential of global phosphoproteomics into a simple workflow. We employed this method to investigate synergistic signaling responses in colorectal cancer cell lines following MEK inhibition. Our findings highlight that combining MEK inhibition with growth factor stimulation synergistically activates JNK signaling in HCT116 cells. This synergy emphasizes the therapeutic potential of concurrently targeting MEK and JNK pathways, as evidenced by the significantly impaired growth of HCT116 cells when treated with both inhibitors. Our results demonstrate that SPIED-DIA effectively identifies synergistic signaling responses in colorectal cancer cells, presenting a valuable tool for uncovering new therapeutic targets and strategies in cancer treatment."
564,Metabolic heterogeneity of colorectal cancer as a prognostic factor: insights gained from fluorescence lifetime imaging,"Anastasia D Komarova, Snezhana D Sinyushkina, Ilia D Shchechkin, Irina N Druzhkova, Sofia A Smirnova, Vitaliy M Terekhov, Artem M Mozherov, Nadezhda I Ignatova, Elena E Nikonova, Evgeny A Shirshin, Liubov E Shimolina, Sergey V Gamayunov, Vladislav I Shcheslavskiy, Marina V Shirmanova",https://www.biorxiv.org/content/10.1101/2024.01.02.573874v2,"Heterogeneity of tumor metabolism is an important, but still poorly understood aspect of tumor biology. Present work is focused on the visualization and quantification of cellular metabolic heterogeneity of colorectal cancer using fluorescence lifetime imaging (FLIM) of redox cofactor NAD(P)H. FLIM-microscopy of NAD(P)H was performed in vitro in four cancer cell lines, in vivo in the four types of tumors in mice and ex vivo in patients’ tumor samples. The dispersion and bimodality of the decay parameters were evaluated to quantify the intercellular metabolic heterogeneity. Our results demonstrate that patients’ tumors have significantly higher heterogeneity of energy metabolism compared with cultured cells and tumor xenografts, which was displayed as a wider and frequently bimodal distribution of a contribution of a free (glycolytic) fraction of NAD(P)H within a sample. Among patients’ tumors, the dispersion was larger in the high-grade and early stage ones, without, however, any association with bimodality. These results indicate that cell-level metabolic heterogeneity assessed from NAD(P)H FLIM has a potential to become a clinical prognostic factor."
565,Pooled genetic screens identify breast cancer risk genes involved in evasion from T cell-mediated killing,"Wei Shi, Yi Luo, Jacqueline M. Burrows, Debra Black, Andrew Civitarese, Laura Perlaza-Jimenez, Ping Zhang, Murray Manning, Natasha Tuano, Miguel E. Rentería, Christos Xiao, Siok-Keen Tey, Joseph Rosenbluh, Corey Smith, Georgia Chenevix-Trench, Jonathan Beesley",https://www.biorxiv.org/content/10.1101/2024.05.10.593465v2,"Genome-wide association studies have identified more than 220 loci associated with breast cancer susceptibility. A major challenge is now to identify the effector genes with plausible functions in the context of breast cancer risk. We have previously performed pooled CRISPR screens to identify target genes at risk loci that drive cancer hallmarks including proliferation or modulating DNA damage response. We now extend these screens to identify genes involved in response to cytotoxic T lymphocyte (CTL) killing. We performed knockout and inhibition screens to identify genes that affect the response of the MCF7 human breast cancer cell line to CTL killing in an in vitro co-culture system. We identified 33 candidate risk genes associated with resistance or sensitisation to T cell-mediated killing. Using single gene perturbation, we showed that deletion of candidate risk genes IRF1, ATF7IP, CCDC170 and CASP8 induced resistance, while ablation of CFLAR, CREBBP, and PRMT7 sensitized cells to CTL killing. We used reporter assays to show that the risk-associated alleles at rs736801 and rs3769821 reduced transactivation of the IRF1 and CASP8 promoters, respectively. We showed that pharmacological inhibition of PRMT7 rendered breast cells sensitive to CTL killing and PRMT7 levels were negatively correlated with CD8+ infiltration and patient survival in luminal A breast cancer patient cohorts. Our results demonstrate that phenotypic pooled CRISPR screens are a useful approach for high throughput functional follow-up of GWAS findings, identifying genes which alter immune responses to breast cancer which offer opportunities to enhance immunotherapy."
566,Filtering for highly variable genes and high quality spots improves phylogenetic analysis of cancer spatial transcriptomics Visium data,"Alexandra “Sasha” Gavryushkina, Holly R Pinkney, Sarah D Diermeier, Alex Gavryushkin",https://www.biorxiv.org/content/10.1101/2024.07.11.603166v1,"Phylogenetic relationship of cells within tumours can help us to understand how cancer develops in space and time, iden-tify driver mutations and other evolutionary events that enable can-cer growth and spread. Numerous studies have reconstructed phylo-genies from single-cell DNA-seq data. Here we are looking into the problem of phylogenetic analysis of spatially resolved near single-cell RNA-seq data, which is a cost-efficient alternative (or complemen-tary) data source that integrates multiple sources of evolutionary information including point mutations, copy-number changes, and epimutations. Recent attempts to use such data, although promis-ing, raised many methodological challenges. Here, we explored data-preprocessing and modelling approaches for evolutionary analyses of Visium spatial transcriptomics data. We conclude that using only highly variable genes and accounting for heterogeneous RNA capture across tissue-covered spots improves the reconstructed topological relationships and influences estimated branch lengths."
567,KBTBD4 Cancer Hotspot Mutations Drive Neomorphic Degradation of HDAC1/2 Corepressor Complexes,"Xiaowen Xie, Olivia Zhang, Megan J.R. Yeo, Ceejay Lee, Stefan A. Harry, Leena Paul, Yiran Li, N. Connor Payne, Eunju Nam, Hui Si Kwok, Hanjie Jiang, Haibin Mao, Jennifer L. Hadley, Hong Lin, Melissa Batts, Pallavi M. Gosavi, Vincenzo D’Angiolella, Philip A. Cole, Ralph Mazitschek, Paul A. Northcott, Ning Zheng, Brian B. Liau",https://www.biorxiv.org/content/10.1101/2024.05.14.593970v1,"Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function1. As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB)2, the most common embryonal brain tumor in children, and pineoblastoma3. These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST4. However, their mechanism of action remains unresolved. Here, we elucidate the mechanistic basis by which KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2, the direct neomorphic target of the substrate receptor. Using deep mutational scanning, we systematically map the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy (cryo-EM) analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat propeller domains. The interface between HDAC1 and one of the KBTBD4 propellers is stabilized by the MB mutations, which directly insert a bulky side chain into the active site pocket of HDAC1. Our structural and mutational analyses inform how this hotspot E3-neo-substrate interface can be chemically modulated. First, our results unveil a converging shape complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface, the aberrant degradation of CoREST, and the growth of KBTBD4-mutant MB models. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions and pharmacological strategies to modulate their action for therapeutic applications."
568,Development of a humanized anti-FABP4 monoclonal antibody for treatment of breast cancer,"Jiaqing Hao, Rong Jin, Yanmei Yi, Xingshan Jiang, Jianyu Yu, Zhen Xu, Nicholas J. Schnicker, Michael S. Chimenti, Sonia L. Sugg, Bing Li",https://www.biorxiv.org/content/10.1101/2024.05.12.593748v1,"Background Breast cancer, lung cancer, and colorectal cancer are the primary contributors to newly diagnosed cases among women, with breast cancer representing the second highest proportion of the total. The treatment protocols vary depends on different stages of breast cancer, and numerous clinical trials are ongoing based on the data derived from laboratory. Our studies demonstrate that circulating adipose fatty acid binding protein (A-FABP, or FABP4) links obesity-induced dysregulated lipid metabolism and breast cancer risk, thus offering a new target for breast cancer treatment."
570,Exploiting gene expression profiles of circulating extracellular vesicles for breast cancer detection,"Aritra Gupta, Rosina Ahmed, Sanjit Agarwal, Geetashree Mukherjee, Kartiki V. Desai",https://www.biorxiv.org/content/10.1101/2024.05.09.593454v1,"Background Liquid biopsy-based biomarkers offer several advantages since they are minimally invasive, can be useful in longitudinal monitoring of the disease and have higher patient compliance. We hypothesize that RNA content of circulating EVs differs in breast cancer patients and healthy women. EV RNAs may provide an opportunity to diagnose, detect subtypes and metastatic states."
571,Unravelling the Impact of miR-21 Overexpression on the MicroRNA Network and Cancer Pathways,"Meredith Hill, Sarah Stapleton, Phuong Thao Nguyen, Dayna Sais, Fiona Deutsch, Valarie Gay, Deborah Marsh, Nham Tran",https://www.biorxiv.org/content/10.1101/2024.05.10.593469v1,"MicroRNAs (miRNA, miRs) are small noncoding RNAs that are ubiquitously expressed in all mammalian cells. Their primary function is the regulation of nascent RNA transcripts by direct binding to regions on the target. There is now exciting data to suggest that these miRNAs can bind to other miRNAs, and this may have a broader impact on gene regulation in disease states. The oncomiR miR-21 is one of the highest-expressing miRNAs in cancer cells, and in this study, we characterise which miRNAs could be potential targets of miR-21. In cancer cells delivered with a miR-21 mimic, there was an observable shift of the miRNA milieu. We demonstrate that the miR-17-92a cluster, which harbours six miRNA members, may be a target of miR-21 regulation. Additionally, the primary transcript of miR-17-92a was reduced in the presence of miR-21. In the broader context of gene regulation, overexpression of miR-21 shifted the expression of more than 150 miRNAs, including those known to regulate genes encoding proteins in cancer pathways such as the MAPK signalling and FoxO pathways. This study expands upon our limited understanding of miR:miR regulatory network and reinforces the concept that miRNAs can regulate each other, thereby influencing broader gene regulatory networks."
572,Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression,"Evgenii N. Tcyganov, Taekyoung Kwak, Xue Yang, Adi Narayana Reddy Poli, Colin Hart, Avishek Bhuniya, Joel Cassel, Andrew Kossenkov, Noam Auslander, Lily Lu, Paridhima Sharma, Maria De Grecia Cauti Mendoza, Dmitry Zhigarev, Mark Gregory Cadungog, Stephanie Jean, Sudeshna Chatterjee-Paer, David Weiner, Laxminarasimha Donthireddy, Bryan Bristow, Rugang Zhang, Vladimir A. Tyurin, Yulia Y. Tyurina, Hülya Bayir, Valerian E. Kagan, Joseph M. Salvino, Luis J. Montaner",https://www.biorxiv.org/content/10.1101/2024.05.10.593562v1,"Ovarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained by tumor- associated macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. Here we show that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket, causes cell death in TAMs by induction of ER stress, p53 and mitochondria-related cell death pathways. A reduction of pro-tumor Rbhigh M2-type macrophages from TME in vivo enhanced T cell infiltration and inhibited cancer progression. We demonstrate an increased Rb expression in TAMs in women with ovarian cancer is associated with poorer prognosis. Ex vivo, we show analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from ovarian cancer patients. Overall, our data elucidates therapeutic targeting of the Rb LxCxE cleft pocket as a novel promising approach for ovarian cancer treatment through depletion of TAMs and re-shaping TME immune landscape."
573,Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages,"Ya-Mei Hu, Faming Zhao, Julie N. Graff, Canping Chen, Xiyue Zhao, George V. Thomas, Hui Wu, Adel Kardosh, Gordon B. Mills, Joshi J. Alumkal, Amy E. Moran, Zheng Xia",https://www.biorxiv.org/content/10.1101/2024.05.08.593181v1,"There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity."
574,Tumor immune microenvironment permissive to metastatic progression of ING4-deficient breast cancer,"Emily Tsutsumi, Anne M. Macy, Janine LoBello, Karen T. Hastings, Suwon Kim",https://www.biorxiv.org/content/10.1101/2024.05.09.593418v1,"Deficiencies in the ING4 tumor suppressor are associated with advanced stage tumors and poor patient survival in cancer. ING4 was shown to inhibit NF-κB in several cancers. As NF-κB is a key mediator of immune response, the ING4/NF-κB axis is likely to manifest in tumor-immune modulation but has not been investigated. To characterize the tumor immune microenvironment associated with ING4-deficient tumors, three approaches were employed in this study: First, tissue microarrays composed of 246 primary breast tumors including 97 ING4-deficient tumors were evaluated for the presence of selective immune markers, CD68, CD4, CD8, and PD-1, using immunohistochemical staining. Second, an immune-competent mouse model of ING4-deficient breast cancer was devised utilizing CRISPR-mediated deletion of Ing4 in a Tp53 deletion-derived mammary tumor cell line; mammary tumors were evaluated for immune markers using flow cytometry. Lastly, the METABRIC gene expression dataset was evaluated for patient survival related to the immune markers associated with Ing4-deleted tumors. The results showed that CD68, CD4, CD8, or PD-1, was not significantly associated with ING4-deficient breast tumors, indicating no enrichment of macrophages, T cells, or exhausted T cell types. In mice, Ing4-deleted mammary tumors had a growth rate comparable to Ing4-intact tumors but showed increased tumor penetrance and metastasis. Immune marker analyses of Ing4-deleted tumors revealed a significant increase in tumor-associated macrophages (Gr-1loCD11b+F4/80+) and a decrease in granzyme B-positive (GzmB+) CD4+ T cells, indicating a suppressive and/or less tumoricidal immune microenvironment. The METABRIC data analyses showed that low expression of GZMB was significantly associated with poor patient survival, as was ING4-low expression, in the basal subtype of breast cancer. Patients with GZMB-low/ING4-low tumors had the worst survival outcomes (HR=2.80, 95% CI 1.36-5.75, p=0.0004), supportive of the idea that the GZMB-low immune environment contributes to ING4-deficient tumor progression. Collectively, the study results demonstrate that ING4-deficient tumors harbor a microenvironment that contributes to immune evasion and metastasis."
575,Clinically relevant humanized mouse models of metastatic prostate cancer to evaluate cancer therapies,"Raymond J. Kostlan, John T. Phoenix, Audris Budreika, Marina G. Ferrari, Neetika Khurana, Jae Eun Cho, Kristin Juckette, Brooke L. McCollum, Russell Moskal, Rahul Mannan, Yuanyuan Qiao, Donald J. Vander Griend, Arul M. Chinnaiyan, Steven Kregel",https://www.biorxiv.org/content/10.1101/2023.10.13.562280v1,"There is tremendous need for improved prostate cancer (PCa) models. The mouse prostate does not spontaneously form tumors and is anatomically and developmentally different from the human prostate. Engineered mouse models lack the heterogeneity of human cancer and rarely establish metastatic growth. Human xenografts represent an alternative but rely on an immunocompromised host. Accordingly, we generated PCa murine xenograft models with an intact human immune system (huNOG and huNOG-EXL mice) to test whether humanizing tumor-immune interactions would improve modeling of metastatic PCa and the impact of hormonal and immunotherapies. These mice maintain multiple human cell lineages, including functional human T-cells and myeloid cells. In 22Rv1 xenografts, subcutaneous tumor size was not significantly altered across conditions; however, metastasis to secondary sites differed in castrate huNOG vs background-matched immunocompromised mice treated with enzalutamide (enza). VCaP xenograft tumors showed decreases in growth with enza and anti-Programed-Death-1 treatments in huNOG mice, and no effect was seen with treatment in NOG mice. Enza responses in huNOG and NOG mice were distinct and associated with increased T-cells within tumors of enza treated huNOG mice, and increased T-cell activation. In huNOG-EXL mice, which support human myeloid development, there was a strong population of immunosuppressive regulatory T-cells and Myeloid-Derived-Suppressor-Cells (MDSCs), and enza treatment showed no difference in metastasis. Results illustrate, to our knowledge, the first model of human PCa that metastasizes to clinically relevant locations, has an intact human immune system, responds appropriately to standard-of-care hormonal therapies, and can model both an immunosuppressive and checkpoint-inhibition responsive immune microenvironment."
576,Impedance-based assay for pan-cancer early and rapid detection of cell-free DNA,"Tejal Dube, Puja Prasad, Pragya Swami, Ankita Singh, Meenakshi Verma, Parul Tanwar, Shantanu Chowdhury, Shalini Gupta",https://www.biorxiv.org/content/10.1101/2024.05.10.593096v1,"Aberrant DNA methylation is a hallmark of cancer, and plasma cell-free DNA (cfDNA) containing these abnormal methylation patterns has emerged as a promising non-invasive biomarker for pan-cancer detection. However, intrinsic challenges remain that continue to limit its broad clinical application. Here we show a simple and rapid impedance biosensor called Asima™ Rev that can detect cancer cfDNA in under 5 min without the need for any molecular labelling, electrode modification, signal amplification, or target enrichment steps. Using 216 clinical samples (50 healthy) from 15 different cancer types (all stages) we show an overall sensitivity and specificity of 96.4% and 94.0%, respectively. Differences in methylation content between cancerous and healthy cfDNA lead to distinct solvation behaviour and electro-physicochemical property that remain consistent across cancer types regardless of the distribution patterns of methyl cytosine. Our test exploits this inherent difference."
577,"Migration, proliferation, and elasticity of bladder cancer cells on lectin-coated surfaces","Marcin Luty, Renata Szydlak, Joanna Pabijan, Ingrid H Øvreeide, Victorien E. Prot, Joanna Zemła, Bjørn T. Stokke, Małgorzata Lekka",https://www.biorxiv.org/content/10.1101/2024.05.12.593008v1,"The alterations in migration, proliferation, and mechanics of cells observed during cancer progression can potentially be linked to enhanced tumor invasiveness. These properties are frequently attributed to the ability to form distant metastasis; however, the direct mutual connection between these properties is not always proven. Here, we studied the migratory, proliferative, and mechanical phenotype of three bladder cancer cells originating from various stages of cancer progression, i.e., non-malignant cell cancer of ureter (HCV29 cells), bladder carcinoma (HT1376 cells) and transitional bladder carcinoma (T24 cells). The results were linked with the organization of actin filaments because of their major role in cell migration. The results classified cells into non-malignant, non-invasive, and invasive, revealing the significant impact of actin filaments in bladder cancer invasion. Based on the reported changes in cancer cell glycosylation, the potential applicability of the observed cancer-related changes to identify invasive cells was demonstrated for the lectin-coated surfaces, which is the potential surface modification for biosensors."
578,Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping,"Carolin Ector, Christoph Schmal, Jeff Didier, Sébastien De Landtsheer, Anna-Marie Finger, Francesca Müller-Marquardt, Johannes Schulte, Thomas Sauter, Ulrich Keilholz, Hanspeter Herzel, Achim Kramer, Adrián E. Granada",https://www.biorxiv.org/content/10.1101/2023.11.30.569380v2,"The circadian clock, a fundamental biological regulator, governs essential cellular processes in health and disease. Circadian-based therapeutic strategies are increasingly gaining recognition as promising avenues. Aligning drug administration with the circadian rhythm can enhance treatment efficacy and minimize side effects. Yet, uncovering the optimal treatment timings remains challenging, limiting their widespread adoption. In this work, we introduce a novel high-throughput approach integrating live-imaging and data analysis techniques to deep-phenotype cancer cell models, evaluating their circadian rhythms, growth, and drug responses. We devised a streamlined process for profiling drug sensitivities across different times of the day, identifying optimal treatment windows and responsive cell types and drug combinations. Finally, we implement multiple computational tools to uncover cellular and genetic factors shaping time-of-day drug sensitivity. Our versatile approach is adaptable to various biological models, facilitating its broad application and relevance. Ultimately, this research leverages circadian rhythms to optimize anti-cancer drug treatments, promising improved outcomes and transformative treatment strategies."
580,eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer,"Jacob A. Boyer, Malvika Sharma, Madeline A. Dorso, Nicholas Mai, Corina Amor, Jason M. Reiter, Ram Kannan, Sunyana Gadal, Jianing Xu, Matthew Miele, Zhuoning Li, Xiaoping Chen, Qing Chang, Fresia Pareja, Stephan Worland, Douglas Warner, Sam Sperry, Gary G. Chiang, Peggy A. Thompson, Guangli Yang, Ouathek Ouerfelli, Elisa de Stanchina, Hans-Guido Wendel, Ezra Y. Rosen, Sarat Chandarlapaty, Neal Rosen",https://www.biorxiv.org/content/10.1101/2024.05.08.593195v1,"The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5’ UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant—an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer."
581,"Multifunctional molecular hybrid for targeted colorectal cancer cells: Integrating doxorubicin, AS1411 aptamer, and T9/U4 ASO","Kanpitcha Jiramitmongkon, Pichayanoot Rotkrua, Paisan Khanchaitit, Jiraporn Arunpanichlert, Boonchoy Soontornworajit",https://www.biorxiv.org/content/10.1101/2024.05.08.593145v1,"Colorectal cancer (CRC) is one of the public-health concerns worldwide and it requires an effective treatment. However, existing treatment approaches encounter challenges related to specificity and efficacy. To address this issue, a platform for multifunctional drug delivery has been developed, combining bioactive materials with anticancer elements and specific recognition ligands into a single molecule. This study aimed to create a molecular hybrid (MH) containing doxorubicin, AS1411 aptamer, and T9/U4 ASO to regulate SW480 cell proliferation. The AS1411 aptamer targets nucleolin, overexpressed on cancer cell membranes, while T9/U4 ASO inhibits human telomerase RNA activity, further hindering cancer cell proliferation. AS-T9/U4_MH was synthesized via oligonucleotide hybridization, followed by doxorubicin loading and evaluation of its impact on cell proliferation. Binding capability of this MH was verified using fluorescence microscopy and flow cytometry, demonstrating specific recognition of SW480 cells due to nucleolin availability on the cell surface. These findings were corroborated by both microscopy and flow cytometry. AS-T9/U4_MH exhibited anti-proliferative effects, with the doxorubicin-loaded system demonstrating encapsulation and reduced toxicity. Moreover, the presence of Dox within AS-T9/U4_MH led to a notable reduction in hTERT and vimentin expression in SW480 cells. Additionally, examination of apoptotic pathways unveiled a marked decrease in Bcl-2 expression and a simultaneous increase in Bax expression in SW480 cells treated with Dox-loaded AS-T9/U4_MH, indicating its impact on promoting apoptosis. These results suggest that the molecular hybrid holds promise as a system for integrating chemotherapeutic drugs with bioactive materials for cancer treatment delivery."
582,BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer,"Sushmitha Sriramulu, Shivani Thoidingjam, Wei-Min Chen, Oudai Hassan, Farzan Siddiqui, Stephen L Brown, Benjamin Movsas, Michael D Green, Anthony J Davis, Corey Speers, Eleanor Walker, Shyam Nyati",https://www.biorxiv.org/content/10.1101/2024.05.07.592812v1,"Background Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment."
584,Reporter-based screening identifies RAS-RAF mutations as drivers of resistance to active-state RAS inhibition in colorectal cancer,"Oleksandra Aust, Eric Blanc, Mareen Lüthen, Viola Hollek, Rosario Astaburuaga-García, Bertram Klinger, Alexandra Trinks, Dieter Beule, Björn Papke, David Horst, Nils Blüthgen, Christine Sers, Channing J. Der, Markus Morkel",https://www.biorxiv.org/content/10.1101/2024.07.01.601542v2,"Therapy-induced acquired resistance limits the clinical effectiveness of mutation-specific RAS inhibitors in colorectal cancer. It is unknown whether broad-spectrum active-state RAS inhibitors meet similar limitations. Here, we identify and categorize mechanisms of resistance to the broad-spectrum active-state RAS inhibitor RMC-7977 in colorectal cancer cell lines. We found that KRAS-mutant colorectal cancer cell lines are universally sensitive to RMC-7977, inhibiting the RAS-RAF-MEK-ERK axis, halting proliferation and in some cases inducing apoptosis. To monitor KRAS downstream effector pathway activity, we developed a compartment-specific dual-color ERK activity reporter. RMC-7977 treatment reduced reporter activity. However, long-term dose escalation with RMC-7977 revealed multiple patterns of reporter reactivation in emerging resistant cell populations that correlated with phosphorylation states of compartment-specific ERK targets. Cells sorted for high, low, or cytoplasmic reporter activity exhibited distinct patterns of genomic mutations, phospho-protein, and transcriptional activities. Notably, all resistant subpopulations showed dynamic ERK regulation in the presence of the RAS inhibitor, unlike the parental sensitive cell lines. High levels of RAS downstream activities were observed in cells characterized by a KRAS Y71H resistance mutation. In contrast, RAS inhibitor-resistant populations with low, or cytoplasmic ERK reporter reactivation displayed different genetic alterations, among them RAF1 S257L and S259P mutations. Colorectal cancer cells resistant to RMC-7977 and harboring the RAF1 mutation specifically exhibited synergistic sensitivity to concurrent RAS and RAF inhibition. Our findings endorse reporter-assisted screening together with single-cell analyses as a powerful approach for dissecting the complex landscape of therapy resistance. The strategy offers opportunities to develop clinically relevant combinatorial treatments to counteract emergence of resistant cancer cells."
585,Increased inflammatory signature in myeloid cells of non-small cell lung cancer patients with high clonal hematopoiesis burden,"Hyungtai Sim, Hyun Jung Park, Geun-Ho Park, Yeon Jeong Kim, Woong-Yang Park, Se-Hoon Lee, Murim Choi",https://www.biorxiv.org/content/10.1101/2024.01.02.573827v2,"Clonal hematopoiesis of indeterminate potential (CHIP) allows estimation of clonal dynamics and documentation of somatic mutations in the hematopoietic system. Recent studies utilizing large cohorts of the general population and patients have revealed significant associations of CHIP burden with age and disease status, including in cancer and chronic diseases. An increasing number of cancer patients are treated with immune checkpoint inhibitors (ICI), but the association of ICI response in non-small cell lung cancer (NSCLC) patients with CHIP burden remains to be determined. We collected blood samples from 100 metastatic NSCLC patients before and after ICI for high-depth sequencing of the CHIP panel and 63 samples for blood single-cell RNA sequencing(scRNA-seq). Whole exome sequencing (WES) was performed in an independent replication cohort of 180 patients. The impact of CHIP status on the immunotherapy response was not significant. However, metastatic lung cancer patients showed higher CHIP prevalence (44/100 for patients vs 5/42 for controls; P = 0.01). In addition, lung squamous cell carcinoma patients showed increased burden of larger clones compared to lung adenocarcinoma patients (8/43 for LUSC vs 2/50 for LUAD; P = 0.04). Furthermore, single cell RNA-seq analysis of the matched patients showed significant enrichment of inflammatory pathways mediated by NF-ĸB in myeloid clusters of the severe CHIP group. Our findings suggest minimal involvement of CHIP mutation and clonal dynamics during immunotherapy but a possible role of CHIP as an indicator of immunologic response in NSCLC patients."
588,Oncogenic KRAS Mutations Confer a Unique Mechanotransduction Response to Peristalsis in Colorectal Cancer Cells,"Abigail J. Clevenger, Claudia A. Collier, John Paul M. Gorley, Maygan K. McFarlin, Spencer C. Solberg, E. Scott Kopetz, Amber N. Stratman, Shreya A. Raghavan",https://www.biorxiv.org/content/10.1101/2024.05.07.593070v1,"Colorectal cancer (CRC) tumors start as precancerous polyps on the inner lining of the colon or rectum, where they are exposed to the mechanics of colonic peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in colorectal cancer cells. However, this malignant mechanotransductive response was confined to select CRC lines that harbored an oncogenic mutation in the KRAS gene. In this work, therefore, we explored the involvement of activating KRAS mutations on peristalsis-associated mechanotransduction in CRC. Peristalsis enriched the cancer stem cell marker LGR5 in KRAS mutant (G13D, etc.) lines, in a Wnt-independent manner. Conversely, LGR5 enrichment in wild type KRAS lines exposed to peristalsis were minimal. LGR5 enrichment downstream of peristalsis translated to increased tumorigenicity in vivo in KRAS mutant vs. wild type lines. Differences in mechanotransduction response was additionally apparent via unbiased gene set enrichment analysis, where many unique pathways were enriched in wild type vs. mutant lines, in response to peristalsis. Interestingly, peristalsis also triggered β-catenin nuclear localization independent of Wnt, particularly in KRAS mutant lines. The central involvement of KRAS in the mechanotransductive responses was validated via gain and loss of function strategies. β-catenin activation and LGR5 enrichment downstream of peristalsis converged to the activation of the MEK/ERK kinase cascade, that remains active in cells that harbor oncogenic KRAS mutations. Taken together, our results demonstrated that oncogenic KRAS mutations conferred a unique peristalsis-associated mechanotransduction response to colorectal cancer cells, resulting in cancer stem cell enrichment and increased tumorigenicity. These mechanosensory connections can be leveraged in improving the sensitivity of emerging therapies that target oncogenic KRAS."
589,From hyperinsulinemia to cancer progression: how diminishing glucose storage capacity fuels insulin resistance,Irina Kareva,https://www.biorxiv.org/content/10.1101/2024.05.05.592630v1,"Type 2 diabetes (T2D) is a complex metabolic disorder characterized by insulin resistance, hyperglycemia and hyperinsulinemia, with a quarter to half of people with T2D unaware of their diagnosis until the disease has reached advanced stages. T2D is associated with increased risk and worse prognosis of cardiovascular disease, cognitive decline, and cancer. Here we propose an updated framework for describing emergence of insulin resistance that precedes development of T2D. We show that diminishing capacity to store excess glucose can qualitatively capture the transition from normal to diabetic phenotype as captured by responses to oral glucose tolerance tests (OGTTs). We then show that an emerging tumor can either progress or regress depending on the metabolic environment of the host, consistent with experimental results of Hopkins et al. (2018), who showed that drug-induced transient diabetic phenotype, and specifically hyperinsulinemia, resulted in loss of therapeutic efficacy, and its reversal restored drug sensitivity and response to therapy. Given the prevalence of hyperinsulinemia in individuals with normoglycemia, addressing this condition emerges as a promising avenue to augment cancer therapy outcomes."
591,CDK4/6 inhibitors promote PARP1 degradation and act synergistically with PARP inhibitors in non-small cell lung cancer,"Carlos M Roggero, Anwesha B Ghosh, Anvita Devineni, Shihong Ma, Eliot Blatt, Ganesh V. Raj, Yi Yin",https://www.biorxiv.org/content/10.1101/2024.07.07.602389v1,"Despite the widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), the clinical trials with CDK4/6 inhibitors (CDK4/6is) as a monotherapy have shown poor antitumor activity. However, our preclinical studies have revealed a significant potential for CDK4/6is to collaborate by influencing DNA damage repair pathways during radiotherapy. Given the considerable upregulation of PARP1 expression in NSCLC, we analyzed the efficacy of combined PARP and CDK4/6 inhibition in NSCLC models. Our findings demonstrate that CDK4/6is synergize with PARP inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy is associated with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. We showed that CDK4/6is mechanically promote PARP1 protein degradation, leading to decreased availability of DNA repair factors involved in homologous recombination and suppression of DNA repair competency. Furthermore, we showed that PARP trapping is required for this synergy. We then confirmed that combining PARPi and CDK4/6i blocked the growth of NSCLC xenografts in vivo and patient-derived explant models ex vivo. These findings reveal a previously uncharacterized impact of CDK4/6i on PARP1 levels in RB-proficient NSCLC models and the requirement of PARP trapping to render synergy between CDK4/6i and PARPi. Our research suggests that combining CDK4/6i with PARPi could be a promising therapeutic strategy for patients with RB-proficient NSCLC, potentially opening up new and more effective avenues for treatment."
592,"AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer","Sumaira Sardar, Christopher M. McNair, Lakshmi Ravindranath, Saswati N. Chand, Wei Yuan, Denisa Bogdan, Jon Welti, Adam Sharp, Natalie K. Ryan, Matthew J. Schiewer, Elise G. DeArment, Thomas Janas, Xiaofeng A. Su, Lisa M. Butler, Johann S. de Bono, Kris Frese, Nigel Brooks, Neil Pegg, Karen E. Knudsen, Ayesha A. Shafi",https://www.biorxiv.org/content/10.1101/2024.05.07.592966v1,"Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies."
593,Long-read sequencing reveals aberrant fragmentation patterns and origins of circulating DNA in cancer,"Benjamin P. Berman, Sarah A. Erdman, Jean-Valery Turatsinze, Justin Cayford, Theresa K. Kelly",https://www.biorxiv.org/content/10.1101/2024.05.02.592182v1,"Circulating cell-free DNA (cfDNA), which includes tumor and immune-derived fragments, is often elevated in cancer patients relative to healthy individuals. This can be accompanied by changes in cfDNA fragmentation patterns, including fragment length distributions, fragment end sequences, and genomic context. Here, we survey fragmentation changes across 12 cancer types using Oxford Nanopore Technologies (ONT) shallow whole-genome sequencing. We confirm a hyperfragmentation pattern across a large fraction of the cancers and associate this with markers of altered DNase activity and elevation of circulating DNA and nucleosome levels. We also identify a cluster of cancers with fragments greater than 1 kilobase and distinguish these long fragments from genomic contamination based on length distribution and a DNASE1L3 fragmentation signature. Future studies using ONT sequencing will determine the prevalence and implications of this hypofragmentation phenotype across cancer."
594,"“Tumor-selective treatment of metastatic pancreatic cancer with an engineered, probiotic living drug”","Amanda R. Decker-Farrell, Stephen A. Sastra, Tetsuhiro Harimoto, Marie C. Hasselluhn, Carmine F. Palermo, Edward R. Ballister, Michael A. Badgley, Tal Danino, Kenneth P. Olive",https://www.biorxiv.org/content/10.1101/2024.05.02.592216v1,"Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges for effective treatment, with systemic chemotherapy often proving inadequate due to poor drug delivery and the tumor’s immunosuppressive microenvironment. Engineered bacteria present a novel approach to target PDAC, leveraging their ability to colonize tumors and deliver therapeutic payloads. Here, we engineered probiotic Escherichia coli Nissle 1917 (EcN) to produce the pore-forming Theta toxin (Nis-Theta) and evaluated its efficacy in a preclinical model of PDAC. Probiotic administration resulted in selective colonization of tumor tissue, leading to improved overall survival compared to standard chemotherapy. Moreover, this strain exhibited cytotoxic effects on both primary and distant tumor lesions while sparing normal tissues. Importantly, treatment also modulated the tumor microenvironment by increasing anti-tumor immune cell populations and reducing immunosuppressive markers. These findings demonstrate the potential of engineered probiotic bacteria as a safe and effective therapeutic approach for PDAC, offering promise for improved patient outcomes."
595,In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency,"Casie S. Kubota, Stephanie L. Myers, Toni T. Seppälä, Richard A. Burkhart, Peter J. Espenshade",https://www.biorxiv.org/content/10.1101/2024.05.03.592368v1,"Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins (SREBPs) act as modulators of lipid homeostasis by acting as transcriptional activators of genes required for fatty acid and cholesterol synthesis and uptake. SREBPs have been recognized as chemotherapeutic targets in multiple cancers, however it is not well understood which SREBP target genes are essential for tumorigenesis. Using parallel in vitro and in vivo CRISPR knockout screens, we identified terpenoid backbone biosynthesis genes as essential for pancreatic ductal adenocarcinoma (PDAC) tumor development. Specifically, we identified the non-sterol isoprenoid product of the mevalonate pathway, geranylgeranyl diphosphate (GGPP), as an essential lipid for tumor growth. Mechanistically, we observed that restricting mevalonate pathway activity using statins and SREBP inhibitors synergistically induced apoptosis and caused disruptions in small G protein prenylation that have pleiotropic effects on cellular signaling pathways. Finally, we demonstrated that geranylgeranyl diphosphate synthase 1 (GGPS1) knockdown significantly reduces tumor burden in an orthotopic xenograft mouse model. These findings indicate that PDAC tumors selectively require GGPP over other lipids such as cholesterol and fatty acids and that this is a targetable vulnerability of pancreatic cancer cells."
599,Progressive plasticity during colorectal cancer metastasis,"AR Moorman, F Cambuli, EK Benitez, Q Jiang, Y Xie, A Mahmoud, M Lumish, S Hartner, S Balkaran, J Bermeo, S Asawa, C Firat, A Saxena, A Luthra, V Sgambati, K Luckett, F Wu, Y Li, Z Yi, I Masilionis, K Soares, E Pappou, R Yaeger, P Kingham, W Jarnagin, P Paty, MR Weiser, L Mazutis, M D’Angelica, J Shia, J Garcia-Aguilar, T Nawy, TJ Hollmann, R Chaligné, F Sanchez-Vega, R Sharma, D Pe’er, K Ganesh",https://www.biorxiv.org/content/10.1101/2023.08.18.553925v1,"Metastasis is the principal cause of cancer death, yet we lack an understanding of metastatic cell states, their relationship to primary tumor states, and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that while primary tumors largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Loss of intestinal cell states is accompanied by reprogramming into a highly conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states, which is exacerbated by chemotherapy and associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cancer cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a stabilizer of intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming."
600,A novel HER2 protein identification methodology in breast cancer cells using Raman spectroscopy and Raman imaging: an analytical validation study,"H. Abramczyk, J. Surmacki, M. Kopeć",https://www.biorxiv.org/content/10.1101/2024.07.04.602049v1,"Background Conventional assays such as immunohistochemistry (IHC) and in situ hybridization (ISH) used in clinical procedures for quantification of the human epidermal growth factor receptor-2 (HER2) status in breast cancer have many limitations. Our results suggest that a new Raman method may improve specificity that will result in better patients selection for HER2 targeted therapy. In the current study, we have used HER2 expression in a broad range of breast cancer phenotypes to explore the potential utility of a novel immunodetection technique, using Raman spectroscopy and Raman imaging combined with artificial intelligence models."
602,Aberrant cytoplasmic localization of MLH1 characterizes a sub-clonal breast cancer cell population that seeds recurrence,"A Mazumder, JT DeWitt, E Oropeza, N Punturi, D Lozano, M Raghunathan, JM Piscitelli, E Sajjadi, E Guerini-Rocco, K Venetis, M Ivanova, E Mane, N Fusco, MN Bainbridge, CM Manhart, S Haricharan",https://www.biorxiv.org/content/10.1101/2024.02.27.582389v3,"Estrogen receptor positive (ER+) breast cancer is one of the most common causes of cancer-related death in women. Mortality is largely driven by recurrence of treatment-resistant disease after many years of apparent response, making the molecular events that cause recurrence a critical area of investigation. Loss of expression of MLH1, a tumor suppressor best studied in its role in mismatch repair, induces resistance of ER+ breast cancer cells to standard estrogen-targeting therapies. It does so by delinking cell cycle progression from estrogen regulation, a role distinct from its function in mismatch repair. MLH1 loss, as currently clinically diagnosed by detecting genomic instability or by immunohistochemistry for absence of protein, occurs in 12-15% of all cancers. Here, we demonstrate that sub-clonal, patient-derived mutations in MLH1, which neither impact protein abundance nor contribute sufficiently to genomic instability to be detected diagnostically, seed endocrine treatment resistance by enabling estrogen-independent growth in vitro, ex vivo in patient-derived organoids (p=0.005) and in vivo (p=0.0001). The mechanism underlying this endocrine treatment resistance is aberrant localization of MLH1 to the cytoplasm in vitro and in vivo (p=0.04), which precludes cell cycle arrest in response to endocrine therapy while simultaneously rendering cells acutely dependent on CDK4/6 activity. Consequently, administration of CDK4/6 inhibitors causes extreme regression in cells with cytoplasmic MLH1 compared to control cell populations with nuclear localization of MLH1 in vitro (p=0.00000009), ex vivo (p=0.01) and in vivo (p=0.01). As aberrant cytoplasmic localization occurs in an additional ∼12% of ER+ breast cancer patients, it constitutes a new, major contributor to MLH1 dysregulation. The potential applicability of cytoplasmic MLH1 as a predictor of responsiveness to existing targeted therapies in a hard-to-treat breast cancer subtype posits an update of current clinical diagnostic criteria and therapeutic strategies. This is particularly important in the adjuvant setting where identification of biomarkers predicting responsiveness to CDK4/6 inhibitors remains an urgent, unmet clinical need."
603,Unveiling Novel Double-Negative Prostate Cancer Subtypes Through Single-Cell RNA Sequencing Analysis,"Siyuan Cheng, Lin Li, Yunshin Yeh, Yingli Shi, Omar Franco, Eva Corey, Xiuping Yu",https://www.biorxiv.org/content/10.1101/2023.08.11.553009v3,"Recent advancements in single-cell RNA sequencing (scRNAseq) have facilitated the discovery of previously unrecognized subtypes within prostate cancer (PCa), offering new insights into disease heterogeneity and progression. In this study, we integrated scRNAseq data from multiple studies, comprising both publicly available cohorts and data generated by our research team, and established the HuPSA (Human Prostate Single cell Atlas) and the MoPSA (Mouse Prostate Single cell Atlas) datasets. Through comprehensive analysis, we identified two novel double-negative PCa populations: KRT7 cells characterized by elevated KRT7 expression, and progenitor-like cells marked by SOX2 and FOXA2 expression, distinct from NEPCa, and displaying stem/progenitor features. Furthermore, HuPSA-based deconvolution allowed for the re-classification of human PCa specimens, validating the presence of these novel subtypes. Leveraging these findings, we developed a user-friendly web application, “HuPSA-MoPSA” (https://pcatools.shinyapps.io/HuPSA-MoPSA/), for visualizing gene expression across all newly-established datasets. Our study provides comprehensive tools for PCa research and uncovers novel cancer subtypes that can inform clinical diagnosis and treatment strategies."
604,Periostin facilitates ovarian cancer recurrence by enhancing cancer stemness,"Zhiqing Huang, Olivia Byrd, Sarah Tan, Bailey Knight, Gaomong Lo, Lila Taylor, Andrew Berchuck, Susan K. Murphy",https://www.biorxiv.org/content/10.1101/2023.03.30.534465v1,"Ovarian cancer (OC) is the deadliest reproductive system cancer. Its high lethality is due to the high recurrence rate and the development of chemotherapeutic resistance, which requires synergy between cancer cells and non-cancerous cells of the tumor microenvironment (TME). Analysis of gene expression microarray data from paired primary and recurrent OC tissues revealed significantly elevated expression of the gene encoding periostin (POSTN) in recurrent OC compared to matched primary tumors (p=0.014). Finding POSTN primarily localized to the TME, we investigated the role of TME POSTN in OC cell viability, migration/invasion, and chemosensitivity. Conditioned media with high levels of POSTN (CMPOSTNhigh) was generated using POSTN-transfected fibroblastic preadipocyte 3T3-L1 cells. CMPOSTNhigh-cultured OC cells exhibited faster migration, more invasiveness (p=0.006), and more chemoresistance (p<0.05) compared to OC cells cultured with control medium (CMCTL). Furthermore, CMPOSTNhigh-cultured HEYA8 cells demonstrated increased resistance to paxlitaxel-induced apoptosis. Multiple OC cell lines (HEYA8, CAOV2, and SKOV3) cultured with CMPOSTNhighshowed increases in stem cell side population relative to CMCTL-cultured cells. POSTN-transfected 3T3-L1 cells exhibited more intracellular and extracellular lipids, and this was linked to increased cancer cell expression of the oncogene fatty acid synthetase (FASN). Additionally, POSTN functions in the TME were linked to Akt pathway activities. In a xenograft mouse model of OC, the mean tumor volume in mice injected with CMPOSTNhigh-grown OC cells was larger than that in mice injected with CMCTL-grown OC cells (p=0.0023). Altogether, higher POSTN expression is present in recurrent OC and promotes a more aggressive and chemoresistant oncogenic phenotype in vitro. Within cancer TME fibroblasts, POSTN can stimulate lipid production and is associated with increased OC stem cell side population, consistent with its known role in maintaining stemness. Our results bolster the need for further study of POSTN as a potential therapeutic target in treatment and potential prevention of recurrent ovarian cancer."
609,Metabolic readouts of tumor instructed normal tissues (TINT) identify aggressive prostate cancer subgroups for tailored therapy,"Ilona Dudka, Pernilla Wikström, Anders Bergh, Gerhard Gröbner",https://www.biorxiv.org/content/10.1101/2024.04.29.591591v1,"Background Prostate cancer (PC) diagnosis relies on histopathological examination of prostate biopsies, which is restricted by insufficient sampling of all tumors present. Including samples from non-PC but tumor instructed normal tissues (TINT) may increase the diagnostic power by exploring the adaptive responses in benign tissues near tumors."
610,Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism,"Bojie Cong, Teena Thakur, Alejandro Huerta Uribe, Evangelia Stamou, Sindhura Gopinath, Oliver Maddocks, Ross Cagan",https://www.biorxiv.org/content/10.1101/2023.12.21.572817v1,"Colorectal cancer (CRC) is the second most deadly cancer worldwide. One key reason is the failure of therapies that target RAS proteins, which represent approximately 40% of CRC cases. Despite the recent discovery of multiple alternative signalling pathways that contribute to resistance, durable therapies remain an unmet need. Here, we use liquid chromatography/ mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway—a toxin clearance pathway—as upregulated in trametinib-resistant RAS/APC/P53 (“RAP”) tumours compared to trametinib-sensitive RASG12V tumours. Elevating glucuronidation was sufficient to direct trametinib resistance in RASG12Vanimals while, conversely, inhibiting different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib. For example, blocking an initial HDAC1-mediated deacetylation step with the FDA-approved drug vorinostat strongly suppressed trametinib resistance in Drosophila RAP tumours. We provide functional evidence that pairing oncogenic RAS with hyperactive WNT activity strongly elevates PI3K/AKT/GLUT signalling, which in turn directs elevated glucose and subsequent glucuronidation. Finally, we show that this mechanism of trametinib resistance is conserved in an KRAS/APC/TP53 mouse CRC tumour organoid model. Our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC. The majority of targeted therapies are glucuronidated, and our results provide a specific path towards abrogating this resistance in clinical trials.s"
611,Enhancing HLA-DR in Cytotoxic T Lymphocytes is crucial for the development of efficient adoptive T cell Therapies for Breast Cancer,"R Salvador, BF Correia, D Grosa, T Martins, SC Soares Baal, DP Saraiva, S Cristóvão-Ferreira, IL Pereira, C Rebelo de Almeida, R Fior, A Jacinto, C Mathias, S Braga, MG Cabral",https://www.biorxiv.org/content/10.1101/2024.09.03.610810v1,"Background Despite advances in breast cancer (BC) therapies, more effective interventions are needed, especially for chemotherapy-resistant tumors. Immune checkpoint inhibitors show promise for triple-negative breast cancer, but their effectiveness across all BC subtypes remains challenging. Therefore, novel strategies, including adoptive cellular therapy, employing patients’ own T lymphocytes expanded ex vivo, are under investigation."
612,Influenza A defective viral genomes and non-infectious particles are increased by host PI3K inhibition via anti-cancer drug alpelisib,"Ilechukwu Agu, Ivy José, Abhineet Ram, Daniel Oberbauer, John Albeck, Samuel L. Díaz Muñoz",https://www.biorxiv.org/content/10.1101/2024.07.03.601932v1,"RNA viruses produce abundant defective viral genomes during replication, setting the stage for interactions between viral genomes that alter the course of pathogenesis. Harnessing these interactions to develop antivirals has become a recent goal of intense research focus. Despite decades of research, the mechanisms that regulate the production and interactions of Influenza A defective viral genomes are still unclear. The role of the host is essentially unexplored; specifically, it remains unknown whether host metabolism can influence the formation of defective viral genomes and the particles that house them. To address this question, we manipulated host cell anabolic signaling activity and monitored the production of defective viral genomes and particles by A/H1N1 and A/H3N2 strains, using a combination of single-cell immunofluorescence quantification, third-generation long-read sequencing, and the cluster-forming assay, a method we developed to titer defective and fully-infectious particles simultaneously. Here we show that alpelisib (Piqray), a highly selective inhibitor of mammalian Class 1a phosphoinositide-3 kinase (PI3K) receptors, significantly changed the proportion of defective particles and viral genomes (specifically deletion-containing viral genomes) in a strain-specific manner, under conditions that minimize multiple cycles of replication. Alpelisib pre-treatment of cells led to an increase in defective particles in the A/H3N2 strain, while the A/H1N1 strain showed a decrease in total viral particles. In the same infections, we found that defective viral genomes of polymerase and antigenic segments increased in the A/H1N1 strain, while the total particles decreased suggesting defective interference. We also found that the average deletion size in polymerase complex viral genomes increased in both the A/H3N2 and A/H1N1 strains. The A/H1N1 strain, additionally showed a dose-dependent increase in total number of defective viral genomes. In sum, we provide evidence that host cell metabolism can increase the production of defective viral genomes and particles at an early stage of infection, shifting the makeup of the infection and potential interactions among virions. Given that Influenza A defective viral genomes can inhibit pathogenesis, our study presents a new line of investigation into metabolic states associated with less severe flu infection and the potential induction of these states with metabolic drugs."
614,An Amplification Mechanism for Weak ELF Magnetic Fields Quantum-Bio Effects in Cancer Cells,"Amirali Zandieh, Seyed Peyman Shariatpanahi, AmirAbbas Ravasipour, Javad Azadipour, Maryam NezamTaheri, Zahra Habibi-Kelishomi, Mojtaba Ghanizadeh, Ali Same, Keivan Majidzadeh, Amir Taheri, Alireza Madjid Ansari, Mohammad Amin Javidi, Adel Pirnia, Bahram Goliaei",https://www.biorxiv.org/content/10.1101/2024.04.28.591462v1,"Observing quantum mechanical characteristics in biological processes is a surprising and important discovery. One example, which is gaining more experimental evidence and practical applications, is the effect of weak magnetic fields with extremely low frequencies on cells, especially cancerous ones. In this study, we use a mathematical model of ROS dynamics in cancer cells to show how ROS oscillatory patterns can act as a resonator to amplify the small effects of the magnetic fields on the radical pair dynamics in mitochondrial Complex III. We suggest such a resonator can act in two modes for distinct states in cancer cells: 1) cells at the edge of mitochondrial oscillation and 2) cells with local oscillatory patches. When exposed to magnetic fields, the first group exhibits high-amplitude oscillations, while the second group synchronizes to reach a whole-cell oscillation. Both types of amplification are frequency-dependent in the range of hertz and sub-hertz. We use UV radiation as a positive control to observe the two states of cells in DU and HELA cell lines. Application of magnetic fields shows frequency-dependent results on both the ROS and mitochondrial potential which agree with the model for both type of cells. We also observe the oscillatory behavior in the time-lapse fluorescence microscopy for 0.02 Hz magnetic fields. Finally, we investigate the dependence of the results on the field strength and propose a quantum spin-forbidden mechanism for the effect of magnetic fields on superoxide production in QO site of mitochondrial Complex III."
615,The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer,"John K. Eaton, Priya Chatterji, Laura Furst, Sneha Basak, Ayesha M. Patel, Yan Y. Sweat, Luke L. Cai, Krishna Dave, Rachelle A. Victorio, Elizabeth Pizzi, Javad Noorbakhsh, Gaochao Tian, Jennifer A. Roth, John Hynes Jr, Gang Xing, Mathias J. Wawer, Vasanthi S. Viswanathan",https://www.biorxiv.org/content/10.1101/2024.04.28.591552v1,"Despite glutathione’s long-recognized role as a major cellular antioxidant and its central role in ferroptosis defense, inhibition of glutathione biosynthetic enzymes has received little attention as a target for the therapeutic induction of ferroptosis. Here, we report that small-molecule inhibition of glutamate–cysteine ligase (GCL), the rate-limiting enzyme of glutathione biosynthesis, selectively and potently kills cancer cells by ferroptosis. We further describe novel GCL inhibitors including KOJ-1 and KOJ-2, compounds with excellent cellular potency and pharmacological properties, representing valuable tools to study the biology of ferroptosis and glutathione."
616,Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations,"Sihang Zhou, Simon Lizarazo, Leela Mouli, Sandip Chorghade, Ruiying Cheng, K C Rajendra, Auinash Kalsotra, Kevin Van Bortle",https://www.biorxiv.org/content/10.1101/2024.07.02.601767v1,"RNA polymerase III (Pol III) activity in cancer is linked to the production of small noncoding (nc)RNAs that are otherwise silent in most tissues. snaR-A (small NF90-associated RNA isoform A) - a hominid-specific ncRNA shown to enhance cell proliferation, migration, and invasion - is a cancer-emergent Pol III product that remains largely uncharacterized despite promoting growth phenotypes. Here, we applied a combination of genomic and biochemical approaches to study the biogenesis and subsequent protein interactions of snaR-A and to better understand its role as a putative driver of cancer progression. By profiling the chromatin landscapes across a multitude of primary tumor types, we show that predicted snaR-A upregulation is broadly linked with unfavorable outcomes among cancer patients. At the molecular level, we unexpectedly discover widespread interactions between snaR-A and mRNA splicing factors, including SF3B2 - a core component of the U2 small nuclear ribonucleoprotein (snRNP). We find that SF3B2 levels are sensitive to high snaR-A abundance and that depletion of snaR-A alone is sufficient to decrease intron retention levels across subpopulations of mRNA enriched for U2 snRNP occupancy. snaR-A sensitive genes are characterized by high GC content, close spatial proximity to nuclear bodies concentrated in pre-mRNA splicing factors, and functional enrichment for proteins involved in deacetylation and autophagy. We highlight examples of splicing misregulation and increased protein levels following snaR-A depletion for a wide-ranging set of factors, suggesting snaR-A-driven splicing defects may have far-reaching effects that re-shape the cellular proteome. These findings clarify the molecular activities and consequences of snaR-A in cancer, and altogether establish a novel mechanism through which Pol III overactivity may promote tumorigenesis."
617,Validation of ferroptosis in canine cancer cells to enable comparative oncology and translational medicine,"Priya Chatterji, Gang Xing, Laura Furst, Krishna Dave, Qiong Zhou, Daniel V. LaBarbera, Douglas H. Thamm, John K. Eaton, Mathias J. Wawer, Vasanthi S. Viswanathan",https://www.biorxiv.org/content/10.1101/2024.04.28.591561v1,"Ferroptosis is a cell death mechanism that has attracted significant attention as a potential basis for the development of new cancer therapies. Validation of ferroptosis biology in species commonly used in translation and pre-clinical development is a necessary foundation for enabling the advancement of such ferroptosis modulating drugs. Here, we demonstrate that canine cancer cells exhibit sensitivity to a wide range of ferroptosis-inducing perturbations in a manner indistinguishable from human cancer cells, and recapitulate characteristic patterns of ferroptotic response across tumor types seen in the human setting. The foundation provided herein establishes the dog as a relevant efficacy and toxicology model for ferroptosis and creates new opportunities to leverage the canine comparative oncology paradigm to accelerate the development of ferroptosis-inducing drugs for human cancer patients."
618,Complementary methods for the study of interactions between eosinophils and cancer cells,"Caterina Antonucci, Adriana Rosa Gambardella, Valentina Tirelli, Fabrizio Mattei, Giovanna Schiavoni",https://www.biorxiv.org/content/10.1101/2024.04.25.590232v1,"Eosinophils are a rare immune cell subset with important roles in Th2 immunity and, recently, in cancer. Interleukin IL-33 (IL-33) is well recognized for its important roles in the activation of eosinophils in Th2 immunity. On the other hand, IL-33 has been recently discovered to play central roles in cancer, in particular by activating eosinophils and increase their degranulation consequent to an intrinsic tumor cell killing function. We propose a dual approach methodology to extrapolate functional interactions of eosinophils with tumor cells, as a result of eosinophil stimulation. Human eosinophils (Eos) isolated from the blood of healthy donors by dextran sedimentation followed by magnetic sorting are exposed to IL-33 (Eos33) or IL-5 (Eos5, control) for 18 h. These pre-conditioned cells are then co-cultured with A375P melanoma cells to monitor cell-cell interactions. Acoustic focusing flow cytometry analysis is employed to evaluate the presence of Eos-tumor cell conjugates after 1h incubation of human eosinophils and A375P melanoma cells. Moreover, a 24 h time-lapse video recording approach is employed to obtain single cell tracking Eos profiles. This allows to quantitatively determine the interaction extent of Eos33, as opposed to Eos5 (control condition), with tumor cells. In conclusion, our protocols easily and quickly allow the extrapolation of relevant kinematic and biologically relevant parameters for tumor reactive eosinophils. Furthermore, these methods are adaptable to various models with other types of immune cell subsets and cancer cells and can be implemented on different video microscopy platforms and advanced flow cytometry systems."
620,Testis Specific Serine Kinase 6 (TSSK6) is abnormally expressed in colorectal cancer and promotes oncogenic behaviors,"Magdalena Delgado, Zachary Gallegos, Steve Stippec, Kathleen McGlynn, Melanie H. Cobb, Angelique W. Whitehurst",https://www.biorxiv.org/content/10.1101/2024.01.08.574658v2,"Cancer testis antigens (CTAs) are a collection of proteins whose expression is normally restricted to the gamete, but abnormally activated in a wide variety of tumors. The CTA, Testis specific serine kinase 6 (TSSK6), is essential for male fertility in mice. Functional relevance of TSSK6 to cancer, if any, has not previously been investigated. Here we find that TSSK6 is frequently anomalously expressed in colorectal cancer and patients with elevated TSSK6 expression have reduced relapse free survival. Depletion of TSSK6 from colorectal cancer cells attenuates anchorage independent growth, invasion and growth in vivo. Conversely, overexpression of TSSK6 enhances anchorage independence and invasion in vitro as well as in vivo tumor growth. Notably, ectopic expression of TSSK6 in semi-transformed human colonic epithelial cells is sufficient to confer anchorage independence and enhance invasion. In somatic cells, TSSK6 co-localizes with and enhances the formation of paxillin and tensin positive foci at the cell periphery, suggesting a function in focal adhesion formation. Importantly, TSSK6 kinase activity is essential to induce these tumorigenic behaviors. Our findings establish that TSSK6 exhibits oncogenic activity when abnormally expressed in colorectal cancer cells. Thus, TSSK6 is a previously unrecognized intervention target for therapy, which could exhibit an exceptionally broad therapeutic window."
621,Epithelial IL-2 is critical for NK cell-mediated cancer immunosurveillance in mammary glands,"Lei Wang, Chandra K Maharjan, Nicholas Borcherding, Rohan P Master, Jiao Mo, Tanzia Islam Tithi, Myung-Chul Kim, Madison E Carelock, Anuj P. Master, Katherine N. Gibson-Corley, Ryan H. Kolb, Kendall A. Smith, Weizhou Zhang",https://www.biorxiv.org/content/10.1101/2024.04.25.591178v2,"Interleukin 2 (IL-2) is the first identified cytokine and its interaction with receptors has been known to shape the immune responses in many lymphoid or non-lymphoid tissues for more than four decades. Active T cells are the primary cellular source for IL-2 production and epithelial cells have never been considered the major cellular source of IL-2 under physiological conditions. It is, however, tempting to speculate that epithelial cells could potentially express IL-2 that regulates the intricate interactions between epithelial cells and lymphocytes. Datamining our recently published single-cell RNAseq in the mouse mammary gland identified IL-2 expression in mammary epithelial cells, which is induced by prolactin via the STAT5 signaling pathway. Furthermore, epithelial IL-2 plays a crucial role in maintaining the physiological functions of natural killer (NK) cells within the mammary glands. IL-2 deletion in the mammary epithelial cells leads to a significant reduction in the number and function of NK cells, which in turn results in defective immunosurveillance, expansion of luminal epithelial cells, and tumor development. Interestingly, T cells in the mammary glands are not changed, indicating the specific regulation of NK cells by epithelial IL-2 production. In agreement, we also found that human epithelial cells express IL-2 and NK cells express the highest level of IL2RB among all the immune cells. Here, we provide the first evidence that epithelial cells produce IL-2, which is critical for maintaining the physiological functions of NK cells in immunosurveillance."
623,Prognostic Significance of Potential Target Networks and P16INK4a In Early Diagnosis of Non-Small Cell Lung Cancer,"Varnika Kundadka, Radha Vatsa, Navrinder Kaur",https://www.biorxiv.org/content/10.1101/2024.06.28.600894v1,"This study aimed to identify the prognostic signature of p16INK4a and related genes in non-small cell lung cancer (NSCLC). Since non-small cell lung cancer shows a poor prognosis, the 5-year survival rate in advanced stages is low. This emphasizes the need to identify more reliable diagnostic biomarkers for the early diagnosis of NSCLC and understand the molecular mechanisms underlying the progression of the disease. The role of P16 in essential cellular pathways are still unknown. Understanding its function and the mechanisms underlying its dysregulation could potentially lead to the development of targeted therapies for certain cancers. To address this, bioinformatics analyses revealed differential expression of genes in lung tumour tissues vs control samples. The interactions among the identified DEGs can help better understand the underlying molecular mechanism of NSCLC. We investigated the correlation between p16INK4a expression and genes involved in the relevant interactive pathways in early-stage NSCLC. These can serve as potential diagnostic and therapeutic biomarkers for NSCLC."
624,Oscillatory Hypoxia Induced Unfolded Protein Folding Response Gene Expression Predicts Low Survival in Human Breast Cancer Patients,"Yasir Suhail, Yamin Liu, Wenqiang Du, Junaid Afzal, Xihua Qiu, Amina Atiq, Paola Vera-Licona, Eran Agmon, Kshitiz",https://www.biorxiv.org/content/10.1101/2024.01.25.577274v2,"Hypoxia is one of the key factors in the tumor microenvironment regulating nearly all steps in the metastatic cascade in many cancers, including in breast cancer. The hypoxic regions can however be dynamic with the availability of oxygen fluctuating or oscillating. The canonical response to hypoxia is relayed by transcription factor HIF-1, which is stabilized in hypoxia and acts as the master regulator of a large number of downstream genes. However, HIF-1 transcriptional activity can also fluctuate either due to unstable hypoxia, or by lactate mediated non-canonical degradation of HIF-1. Our understanding of how oscillatory hypoxia or HIF-1 activity specifically influence cancer malignancy is very limited. Here, using MDA-MB-231 cells as a model of triple negative breast cancer characterized by severe hypoxia, we measured the gene expression changes induced specifically by oscillatory hypoxia. We found that oscillatory hypoxia can specifically regulate gene expression differently, and at times opposite to stable hypoxia. Using The Cancer Genome Atlas (TCGA) RNAseq data of human cancer samples, we show that the oscillatory specific gene expression signature in MDA-MB-231 is enriched in most human cancers, and prognosticate low survival in breast cancer patients. In particular, we found that oscillatory hypoxia, unlike stable hypoxia, induces unfolded protein folding response (UPR) in cells resulting in gene expression predicting reduced survival."
626,"Marine transmissible cancer navigates urbanised waters, threatening to spillover","M. Hammel, F. Touchard, E. A. V. Burioli, L. Paradis, F. Cerqueira, E. Chailler, I. Bernard, H. Cochet, A. Simon, F. Thomas, D. Destoumieux-Garzón, G. M. Charrière, N. Bierne",https://www.biorxiv.org/content/10.1101/2023.04.14.536605v2,"Inter-individual transmission of cancer cells represents a unique form of microparasites increasingly reported in marine bivalves. In this study, we sought to understand the ecology of the propagation of Mytilus trossulus Bivalve Transmissible Neoplasia 2 (MtrBTN2), a transmissible cancer affecting four Mytilus mussel species worldwide. We investigated the prevalence of MtrBTN2 in the mosaic hybrid zone of M. edulis and M. galloprovincialis along the French Atlantic coast, sampling contrasting natural and anthropogenic habitats. We observed a similar prevalence in both species, likely due to the spatial proximity of the two species in this region. Our results showed that ports had higher prevalence of MtrBTN2, with a possible hotspot observed at a shuttle landing dock. No cancer was found in natural beds except for two sites close to the hotspot, suggesting spillover. Ports may provide favourable conditions for the transmission of MtrBTN2, such as high mussel density, stressful conditions, sheltered and confined shores, or buffered temperatures. Ships may also spread the disease through biofouling. Our results suggest ports may serve as epidemiological hubs, with maritime routes providing artificial gateways for MtrBTN2 propagation. This highlights the importance of preventing biofouling on docks and ship hulls to limit the spread of marine pathogens hosted by fouling species."
627,Organoid Models Derived from Primary Tumors and Patient-Derive Xenograft Tumors Reflect Platinum Sensitivity of Ovarian Cancer Patients,"Parisa Nikeghbal, Danielle Burke, Mara P. Steinkamp",https://www.biorxiv.org/content/10.1101/2024.06.28.601283v1,"Ovarian cancer (OC) remains the deadliest gynecological cancer, primarily due to late stage diagnosis and high rates of chemotherapy resistance and recurrence. Lack of representative preclinical models exacerbates the challenges of discovering effective therapies to treat platinum-resistant OC. Patient-derived xenograft (PDX) models maintain the genetic characteristics of the original tumor, but require considerable development time and have limited screening capabilities. Organoid models mimic the tumor’s 3D structure and preserve intra-tumoral heterogeneity, so are ideal for drug screening. The purpose of this study was to determine if PDX-derived organoids (PDXOs) can reflect patient responses to chemotherapy similar to organoids derived from primary patient tumors (PDOs). In drug response assays, PDXOs and PDOs demonstrated similar sensitivity to standard chemotherapy. Furthermore, both PDXOs and PDOs reliably reflected patient response based on the clinical designation of platinum sensitivity. Seven out of eight models derived from six platinum-sensitive cases showed a significant reduction in cell viability when treated with carboplatin, paclitaxel, or the combination therapy. Six of seven organoid models derived from four platinum-resistant or refractory patients demonstrated little to no reduction in cell viability with carboplatin or combination treatment. In these platinum-resistant models, response to single agent paclitaxel was mixed, suggesting that organoid models could predict response to second-line paclitaxel. This study demonstrates that PDXOs can effectively mirror patient responses to chemotherapy, underscoring their potential as valuable, renewable models for screening novel therapies and developing personalized treatment strategies in OC."
628,"EstroGene2.0: A multi-omic database of response to estrogens, ER-modulators, and resistance to endocrine therapies in breast cancer","Zheqi Li, Fangyuan Chen, Li Chen, Jiebin Liu, Danielle Tseng, Fazal Hadi, Soleilmane Omarjee, Kamal Kishore, Joshua Kent, Joanna Kirkpatrick, Clive D’Santos, Mandy Lawson, Jason Gertz, Matthew J. Sikora, Donald P. McDonnell, Jason S. Carroll, Kornelia Polyak, Steffi Oesterreich, Adrian V. Lee",https://www.biorxiv.org/content/10.1101/2024.06.28.601163v1,"Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Understanding the molecular mechanisms is thus key to optimize the existing drugs and to develop new ER-modulators. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities (https://estrogeneii.web.app/). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed substantial diversity in response to different classes of ER-modulators including SERMs, SERDs, SERCA and LDD/PROTAC. Notably, endocrine resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signaling, which is recapitulated clinically. Furthermore, dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of genome-edited versus ectopic overexpression model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer’s response to endocrine therapies and explore resistance mechanisms."
629,GeneBag: training a cell foundation model for broad-spectrum cancer diagnosis and prognosis with bulk RNA-seq data,"Yuhu Liang, Dan Li, Aguix Guohua Xu, Yan Shao, Kun Tang",https://www.biorxiv.org/content/10.1101/2024.06.27.601098v1,"Numerous Pre-trained cell foundation models (CFM) have been crafted to encapsulate the comprehensive gene-gene interaction network within cells, leveraging extensive single-cell sequencing data. These models have shown promise in various cell biology applications, including cell type annotation, perturbation inference, and cell state embedding, etc. However, their clinical utility, particularly in cancer diagnosis and prognosis, remains an open question. We introduce the GeneBag model, a novel CFM that represents a cell as “a bag of unordered genes” with continuous expression values and a full-length gene list. Pre-trained on single-cell data and fine-tuned on bulk RNA-seq datasets, GeneBag achieves superior performance across cancer diagnosis and prognosis scenarios. In a zero-shot learning setting, GeneBag can classify cancer and non-cancer tissues with approximately 96.2% accuracy. With fine-tuning, it can annotate 40 different types of cancers and corresponding normal biopsies with an overall accuracy of ∼97.2%. It notably excels in classifying challenging cancers such as bladder (93%) and stomach (90%). Furthermore, GeneBag is capable of cancer staging with 68.5% accuracy and 5-year survival prediction with an AUC of ∼80.4%. This study marks the first to demonstrate the potential of CFMs in RNA-based cancer diagnostics and prognostics, indicating a promising avenue for AI-assisted molecular diagnosis."
631,Structure-Activity Relationship Study Identifies a Novel Lipophilic Amiloride Derivative that Efficiently Kills Chemoresistant Breast Cancer Cells,"Michelle Hu, Ruiwu Liu, Noemi Castro, Liliana Loza Sanchez, Julie Learn, Ruiqi Huang, Kit S. Lam, Kermit L. Carraway III",https://www.biorxiv.org/content/10.1101/2023.05.25.542364v2,"Derivatives of the potassium-sparing diuretic amiloride are preferentially cytotoxic toward tumor cells relative to normal cells, and have the capacity to target tumor cell populations resistant to currently employed therapeutic agents. However, a major barrier to clinical translation of the amilorides is their modest cytotoxic potency, with estimated IC50 values in the high micromolar range. Here we report the synthesis of ten novel amiloride derivatives and the characterization of their cytotoxic potency toward MCF7 (ER/PR-positive), SKBR3 (HER2-positive) and MDA-MB-231 (triple negative) cell line models of breast cancer. Comparisons of derivative structure with cytotoxic potency toward these cell lines underscore the importance of an intact guanidine group, and uncover a strong link between drug-induced cytotoxicity and drug lipophilicity. We demonstrate that our most potent derivative called LLC1 is preferentially cytotoxic toward mouse mammary tumor over normal epithelial organoids, acts in the single digit micromolar range on breast cancer cell line models representing all major subtypes, acts on cell lines that exhibit both transient and sustained resistance to chemotherapeutic agents, but exhibits limited anti-tumor effects in a mouse model of metastatic breast cancer. Nonetheless, our observations offer a roadmap for the future optimization of amiloride-based compounds with preferential cytotoxicity toward breast tumor cells."
632,PD-L1 blockade immunotherapy rewires cancer emergency myelopoiesis,"Athina Boumpas, Antonis Papaioannou, Pavlos Bousounis, Maria Grigoriou, Veronica Bergo, Iosif Papafragkos, Athanasios Tasis, Michael Iskas, Louis Boon, Manousos Makridakis, Antonia Vlachou, Eleni Gavriilaki, Aikaterini Hatzioannou, Ioannis Mitroulis, Eirini Trompouki, Panayotis Verginis",https://www.biorxiv.org/content/10.1101/2023.12.20.572561v1,"Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Herein, we reveal that immunotherapy with PD-L1 blockage antibody (αPDL1) in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (ΒΜ), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, from both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice shifting towards an inflammatory state. Functionally, transplantation of HSPCs isolated from αPDL1-treated tumor-bearing mice exhibited resistance to cancer-associated myelopoiesis as evident by the generation of reduced frequencies of myeloid-derived suppressor cells (MDSCs) compared to cells from control-treated mice. Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of emergency myelopoiesis."
633,CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer,"Chunge Zhong, Wen-Jie Jiang, Yingjia Yao, Zexu Li, You Li, Shengnan Wang, Xiaofeng Wang, Wenjuan Zhu, Siqi Wu, Jing Wang, Shuangshuang Fan, Shixin Ma, Yeshu Liu, Han Zhang, Wenchang Zhao, Lu Zhao, Yi Feng, Zihan Li, Ruifang Guo, Li Yu, Fengyun Pei, Jun Hu, Xingzhi Feng, Zihuan Yang, Zhengjia Yang, Xueying Yang, Yue Hou, Danni Zhang, Dake Xu, Ren Sheng, Yihao Li, Lijun Liu, Hua-Jun Wu, Jun Huang, Teng Fei",https://www.biorxiv.org/content/10.1101/2024.04.24.591030v1,"Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance."
634,A latent variable model for evaluating mutual exclusivity and co-occurrence between driver mutations in cancer,"Ahmed Shuaibi, Uthsav Chitra, Benjamin J. Raphael",https://www.biorxiv.org/content/10.1101/2024.04.24.590995v1,"A key challenge in cancer genomics is understanding the functional relationships and dependencies between combinations of somatic mutations that drive cancer development. Such driver mutations frequently exhibit patterns of mutual exclusivity or co-occurrence across tumors, and many methods have been developed to identify such dependency patterns from bulk DNA sequencing data of a cohort of patients. However, while mutual exclusivity and co-occurrence are described as properties of driver mutations, existing methods do not explicitly disentangle functional, driver mutations from neutral, passenger mutations. In particular, nearly all existing methods evaluate mutual exclusivity or co-occurrence at the gene level, marking a gene as mutated if any mutation – driver or passenger – is present. Since some genes have a large number of passenger mutations, existing methods either restrict their analyses to a small subset of suspected driver genes – limiting their ability to identify novel dependencies – or make spurious inferences of mutual exclusivity and co-occurrence involving genes with many passenger mutations. We introduce DIALECT, an algorithm to identify dependencies between pairs of driver mutations from somatic mutation counts. We derive a latent variable mixture model for drivers and passengers that combines existing probabilistic models of passenger mutation rates with a latent variable describing the unknown status of a mutation as a driver or passenger. We use an expectation maximization (EM) algorithm to estimate the parameters of our model, including the rates of mutually exclusivity and co-occurrence between drivers. We demonstrate that DIALECT more accurately infers mutual exclusivity and co-occurrence between driver mutations compared to existing methods on both simulated mutation data and somatic mutation data from 5 cancer types in The Cancer Genome Atlas (TCGA)."
635,Mild Hyperthermia Enhanced Liposomal Doxorubicin Delivery and CD8+ T cell Infiltration in Triple Negative Breast Cancer,"Farzaneh Rezazadeh, Wajfa Saadat, Ryan Smith, Alexander Pattyn, Mohammad Malik, Fuad Yazdani, Allen-Dexter Saliganan, Mohammad Mehrmohammadi, Nerissa T. Viola",https://www.biorxiv.org/content/10.1101/2024.04.25.591226v1,"Mild hyperthermia (MHTh) is often used in combination with chemotherapy and radiotherapy for cancer treatment. In the current study, the effect of MHTh on the enhanced uptake of the FDA-approved chemotherapy drug, liposomal doxorubicin (dox) in syngeneic 4T1 tumors was investigated. Doxorubicin has inherent fluorescence properties having an emission signal at 590 nm upon excitation with a 480 nm laser. A group of mice administered with doxorubicin (dox) were exposed to MHTh (42 °C) for 30 minutes whereas control group given dox did not receive MHTh. Ex vivo optical imaging of harvested tumors confirmed higher uptake of dox in treated versus the control untreated tumors. Confocal microscopy of tumor sections indicates higher fluorescent intensity due to increased accumulation of dox in MHTh-treated compared to untreated tumors. We examined the effect of MHTh to enhance CD8 tumor infiltration, production of interferon-γ (IFN-γ) and expression of programmed death ligand-1 (PD-L1). mRNA in situ hybridization was performed to test for transcripts of CD8, IFN-γ and PD-L1. Results showed that higher expression of CD8 mRNA was observed in MHTh-administered tumors versus untreated cohorts. The signal for IFN-γ and PD-L1 in both groups were not significantly different. Taken together, our findings imply that MHTh can improve tumor uptake of dox. Importantly, our data suggests that MHTh can boost CD8+ T cell infiltration."
637,Proteomic analysis reveals the dominant effect of ipomoeassin F on the synthesis of membrane and secretory proteins in triple-negative breast cancer cells,"Brihget Sicairos, Jianhong Zhou, Zhijian Hu, Qingyang Zhang, Wei Q Shi, Yuchun Du",https://www.biorxiv.org/content/10.1101/2024.07.28.605505v2,"Ipomoeassin F (Ipom-F) is a natural compound with embedded carbohydrates that exhibits a potent cytotoxic effect on triple-negative breast cancer (TNBC) cells. The mechanism behind this selective potency remains unclear. To elucidate this mechanism, we analyzed the proteome profiles of the TNBC MDA-MB-231 cells after exposure to Ipom-F at different time points and increasing doses using a quantitative proteomic method. Our proteomic data demonstrate that the major effect of Ipom-F on MDA-MB-231 cells is the inhibition of membrane and secreted protein expression. Our proteomic data are consistent with the recently uncovered molecular mechanism of action of Ipom-F, which binds to Sec61-α and inhibits the co-translational import of proteins into the endoplasmic reticulum. We have defined a subset of membrane and secreted proteins particularly sensitive to Ipom-F. Analysis of the expression of these Ipom-F-sensitive proteins in cancer cell lines and breast cancer tissues demonstrates that some of these proteins are upregulated in TNBC cells. Thus, it is likely that TNBC cells may have adapted to the elevated levels of some proteins identified as sensitive to Ipom-F in this study; inhibition of the expression of these proteins leads to a crisis in proliferation and/or survival for the cells."
638,Investigating Combined Hypoxia and Stemness Indices for Prognostic Transcripts in Gastric Cancer: Machine Learning and Network Analysis Approaches,"Sharareh Mahmoudian-Hamedani, Maryam Lotfi-Shahreza, Parvaneh Nikpour",https://www.biorxiv.org/content/10.1101/2024.06.26.600775v1,"Introduction Gastric cancer (GC) is among the deadliest malignancies globally, characterized by hypoxia-driven pathways that promote cancer progression, including mechanisms associated with stemness facilitating invasion and metastasis. This study aimed to develop a prognostic decision tree using genes implicated in hypoxia and stemness pathways to predict outcomes in GC patients."
639,PSMAx-Guided PROTAC Degraders for Tumor-Specific Protein Degradation in Prostate Cancer,"Xiaolei Meng, Xiaolin Hu, Siqi Zhang, Sai Zhang, Xiao Wang, Shumin Ma, Chong Qin",https://www.biorxiv.org/content/10.1101/2024.04.25.591100v1,"PROTACs, degrading target protein to treat diseases, represent a highly promising drug design strategy. However, the degradation of target proteins by PROTACs in non-disease tissues may lead to systemic toxicity. Herein, capitalizing on the characteristic overexpression of PSMA in prostate cancer tumor tissues, we devised a PSMA-guided PROTACs specific targeting to prostate cancer. By conjugating AR degraders and BET degraders separately with PSMA ligands via cleavable linkers, two classes of PSMA-guided PROTACs were obtained. In vitro experiments demonstrated that PSMA-guided PROTAC molecules selectively degraded target proteins in PSMA-overexpressing prostate cancer cells, without affecting target proteins in non-PSMA-overexpressing cells. In vivo studies revealed that compared to conventional PROTACs, PSMA-guided PROTACs enhanced drug exposure in prostate cancer tumor tissues, prolonged half-life, and consequently achieved stronger and more sustained therapeutic effects. The PSMA-guided PROTAC strategy provides a novel avenue for disease tissue-specific PROTAC research, holding significant implications for targeted therapy in prostate cancer."
641,Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within Interleukin-6 family cytokines,"Anne Huber, Amr H. Allam, Christine Dijkstra, Stefan Thiem, Jennifer Huynh, Ashleigh R. Poh, Joshua Konecnik, Saumya P. Jacob, Rita Busuttil, Yang Liao, David Chisanga, Wei Shi, Mariah G. Alorro, Stephen Forrow, Daniele V.F. Tauriello, Eduard Batlle, Alex Boussioutas, David S. Williams, Michael Buchert, Matthias Ernst, Moritz F. Eissmann",https://www.biorxiv.org/content/10.1101/2024.04.22.590499v1,"Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in glandular epithelium of KrasG12D; Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047Ris sufficient to induce adenomas, and that lesions progress to carcinoma when also harboring Pten-deletions. Additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with poorer survival of patients with high IL6 expression, we identify IL6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer."
642,Molecular portraits of colorectal cancer morphological regions,"Eva Budinská, Martina Hrivňáková, Tina Catela Ivkovic, Marie Madrzyk, Rudolf Nenutil, Beatrix Bencsiková, Dagmar Al Tukmachi, Michaela Ručková, Lenka Zdražilová Dubská, Ondřej Slabý, Josef Feit, Mihnea-Paul Dragomir, Petra Borilova Linhartova, Sabine Tejpar, Vlad Popovici",https://www.biorxiv.org/content/10.1101/2023.01.24.525310v3,Heterogeneity of colorectal carcinoma (CRC) represents a major hurdle towards personalized medicine. Efforts based on whole tumor profiling demonstrated that the CRC molecular subtypes were associated with specific tumor morphological patterns representing tumor subregions. We hypothesize that whole- tumor molecular descriptors depend on the morphological heterogeneity with significant impact on current molecular predictors.
643,The spatial and cellular portrait of Transposable Element expression during Gastric Cancer,Braulio Valdebenito-Maturana,https://www.biorxiv.org/content/10.1101/2024.04.19.590342v1,"Gastric Cancer (GC) is a lethal malignancy, with urgent need for the discovery of novel biomarkers for its early detection. I previously showed that Transposable Elements (TEs) become activated in early GC (EGC), suggesting a role in gene expression. Here, I follow-up on that evidence using single-cell data from gastritis to EGC, and show that TEs are expressed and follow the disease progression, with 2,430 of them being cell populations markers. Pseudotemporal trajectory modeling revealed 111 TEs associated with the origination of cancer cells. Analysis of spatial data from GC also confirms TE expression, with 204 TEs being spatially enriched. Finally, a network of TE-mediated gene regulation was modeled, indicating that ∼2,000 genes could be modulated by TEs, with ∼500 of them already implicated in cancer. These results suggest that TEs might play a functional role in GC progression, and highlights them as potential biomarker for its early detection."
644,A machine learning and drug repurposing approach to target ferroptosis in colorectal cancer stratified by sex and KRAS,"Hong Yan, Xinyi Shen, Yisha Yao, Sajid A. Khan, Shuangge Ma, Caroline H. Johnson",https://www.biorxiv.org/content/10.1101/2024.06.24.600340v1,"The landscape of sex differences in Colorectal Cancer (CRC) has not been well characterized with respect to the mechanisms of action for oncogenes such as KRAS. However, our recent study showed that tumors from male patients with KRAS mutations have decreased iron-dependent cell death called ferroptosis. Building on these findings, we further examined ferroptosis in CRC, considering both sex of the patient and KRAS mutations, using public databases and our in-house CRC tumor cohort."
646,BUB1 inhibition sensitizes lung cancer cell lines to radiotherapy and chemoradiotherapy,"Shivani Thoidingjam, Sushmitha Sriramulu, Oudai Hassan, Stephen L. Brown, Farzan Siddiqui, Benjamin Movsas, Shirish Gadgeel, Shyam Nyati",https://www.biorxiv.org/content/10.1101/2024.04.19.590355v1,"Background Lung cancer is a major public health concern, with high incidence and mortality. Despite advances in targeted therapy and immunotherapy, microtubule stabilizers (paclitaxel, docetaxel), DNA intercalating platinum drugs (cisplatin) and radiation therapy continue to play a critical role in the management of locally advanced and metastatic lung cancer. Novel molecular targets would provide opportunities for improving the efficacies of radiotherapy and chemotherapy."
647,Aberrant regulation of serine metabolism drives extracellular vesicle release and cancer progression,"Tomofumi Yamamoto, Jun Nakayama, Fumihiko Urabe, Kagenori Ito, Nao Nishida-Aoki, Masami Kitagawa, Akira Yokoi, Masahiko Kuroda, Yutaka Hattori, Yusuke Yamamoto, Takahiro Ochiya",https://www.biorxiv.org/content/10.1101/2022.05.10.491299v2,"Cancer cells secrete extracellular vesicles (EVs) to regulate cells in the tumor microenvironment to benefit their own growth and survive in the patient’s body. Although emerging evidence has demonstrated the molecular mechanisms of EV release, regulating cancer-specific EV secretion remains challenging. In this study, we applied a microRNA library to reveal the universal mechanisms of EV secretion from cancer cells. Here, we identified miR-891b and its direct target gene, phosphoserine aminotransferase 1 (PSAT1), which promotes EV secretion through the serine-ceramide synthesis pathway. Inhibition of PSAT1 affected EV secretion in multiple types of cancer, suggesting that the miR-891b/PSAT1 axis shares a common mechanism of EV secretion from cancer cells. Interestingly, aberrant PSAT1 expression also regulated cancer metastasis via EV secretion. Our data link between the PSAT1-controlled EV secretion mechanism and cancer metastasis and show the potential of this mechanism as a therapeutic target in multiple types of cancer."
648,Early-stage cancer results in a multiplicative increase in cell-free DNA originating from healthy tissue,"Konstantinos Mamis, Ivana Bozic",https://www.biorxiv.org/content/10.1101/2024.01.26.577500v2,"Cell-free DNA is a promising biomarker for cancer detection. However, both the sources of elevated cell-free DNA (cfDNA) in patients with early-stage cancer, and the mechanisms by which cfDNA is shed into, and subsequently cleared from, the circulation are still poorly understood. Leveraging a rich dataset of cfDNA in healthy individuals and early-stage cancer patients, we find that early-stage cancer results in a multiplicative increase in the concentration of cfDNA. Our results demonstrate that this increase in cfDNA does not originate from the tumor, but from healthy-tissue, implying that the presence of cancer either increases cell turnover of healthy cfDNA-shedding cells, or slows down clearance of cfDNA by a cancer-type specific factor. This finding is further corroborated by the fact that, for each cancer type, we observe similar multiplicative increases in the concentration of mutant DNA fragments in plasma that contain mutations originating from non-tumor sources. The magnitude of the multiplicative increase in cfDNA concentration varies greatly between cancer types, ranging from a ∼1.3-fold increase in lung cancer, to a ∼12-fold increase in patients with liver cancer. As cfDNA is cleared in the liver, the large increase in patients with liver cancer may imply that the systemic increase in cfDNA levels in the presence of cancer is due to slower clearance rate rather than higher cell turnover. Our findings quantify cfDNA dynamics in patients with cancer, with implications for improving the accuracy of liquid biopsies for early cancer detection."
649,Transformer-based deep learning integrates multi-omic data with cancer pathways,"Zhaoxiang Cai, Rebecca C. Poulos, Adel Aref, Phillip J. Robinson, Roger R. Reddel, Qing Zhong",https://www.biorxiv.org/content/10.1101/2022.10.27.514141v2,"Multi-omic data analysis incorporating machine learning has the potential to significantly improve cancer diagnosis and prognosis. Traditional machine learning methods are usually limited to omic measurements, omitting existing domain knowledge, such as the biological networks that link molecular entities in various omic data types. Here we develop a Transformer-based explainable deep learning model, DeePathNet, which integrates cancer-specific pathway information into multi-omic data analysis. Using a variety of big datasets, including ProCan-DepMapSanger, CCLE, and TCGA, we demonstrate and validate that DeePathNet outperforms traditional methods for predicting drug response and classifying cancer type and subtype. Combining biomedical knowledge and state-of-the-art deep learning methods, DeePathNet enables biomarker discovery at the pathway level, maximizing the power of data-driven approaches to cancer research. DeePathNet is available on GitHub at https://github.com/CMRI-ProCan/DeePathNet."
651,Identifying drug sensitivity of multifocal primary prostate cancer,"Juening Kang, Panagiotis Chouvardas, Katja Ovchinnikova, George N. Thalmann, Sofia Karkampouna, Marianna Kruithof-de Julio",https://www.biorxiv.org/content/10.1101/2023.12.12.569525v1,"The pronounced intra-patient variability in multifocal primary prostate cancer (PCa) has curtailed the efficacy of current treatment options. Patient-derived organoids (PDOs) have emerged as a pivotal model for functional testing due to their capability to retain the histopathological and molecular characteristics of parental tissues, allowing timely acquisition of drug response outcomes. In our study, employing twin biopsies from multiple lesions with matched PDO models in vitro, we investigated the molecular heterogeneity of PCa, and how it is linked to in vitro PDO pharmacological heterogeneity. Our functional testing approach leverages PDOs to screen standard-of-care treatment and FDA-approved compounds for other malignancies, aiming to repurpose their use in PCa and explore alternatives to androgen deprivation therapy. By integrating gene expression data from parental tissue with drug response results from PDOs, we have established a transcriptomics-based drug prediction models. The machine learning-based prediction model can predict the experimental PDO response to a specific drug, for the majority of screened drugs. This study offers a preclinical approach to potentially procure drug prediction outcomes and validate them in PDO models, as a prior step to clinical trial investigations or for selection of targeted therapeutic options."
652,Network pharmacological evaluation of active ingredients and potential targets of San Huang Decoction in the treatment of breast cancer,"Shuai Chao, Shiqiang Liu, Kun Wang, Mingming Xie, Beibei Liu",https://www.biorxiv.org/content/10.1101/2024.06.20.599797v1,"Objective Using the method of network pharmacology, the possible targets and related signaling pathways of San Huang Decoction against breast cancer were explored."
653,Gfi1 controls the formation of exhausted effector-like CD8 T cells during chronic infection and cancer,"Oluwagbemiga A Ojo, Hongxing Shen, Jennifer T Ingram, James A Bonner, Robert S Welner, Georges Lacaud, Allan J Zajac, Lewis Z Shi",https://www.biorxiv.org/content/10.1101/2024.04.18.579535v1,"During chronic infections and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to Ly108− CX3CR1+ effector-like cells. Generation of these effector-like cells is essential for the control of chronic infections and tumors, albeit limited. However, the precise cues and mechanisms directing the formation and maintenance of exhausted effector-like are incompletely understood. Using genetic mouse models challenged with LCMV Clone 13 or syngeneic tumors, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in exhausted CD8 T cells, which in turn regulates the formation of exhausted effector-like cells. Gfi1 deletion in T cells dysregulates the chromatin accessibility and transcriptomic programs associated with the differentiation of LCMV Clone 13-specific CD8 T cell exhaustion, preventing the formation of effector-like and terminally exhausted cells while maintaining progenitors and a newly identified Ly108+CX3CR1+ state. These Ly108+CX3CR1+ cells have a distinct chromatin profile and may represent an alternative target for therapeutic interventions to combat chronic infections and cancer. In sum, we show that Gfi1 is a critical regulator of the formation of exhausted effector-like cells."
654,Multiscale Rheology of Aging Cancer Spheroids,"Kajangi Gnanachandran, Massimiliano Berardi, Asmus Skar, Grażyna Pyka-Fościak, Joanna Pabijan, Javier Lopez Alonso, B. Imran Akca, Małgorzata Lekka",https://www.biorxiv.org/content/10.1101/2023.07.31.550652v1,"Cancer spheroids offer a valuable experimental model that mimics the complexity and heterogeneity of solid tumors. Characterizing their mechanical response is crucial for understanding tumor development, progression, and drug response. Currently, whole live spheroids are analyzed primarily using image analysis, which is challenging, requires extended incubation times, and has limited imaging depth. Here, we present a new label-free approach for characterizing sub-superficial structures of bladder cancer spheroids and measuring their mechanical response at three distinct stages of cancer progression. We study the microrheological changes induced by aging at the cellular and cluster levels by conducting a multi-physics characterization and modeling approach. We find that spheroids exhibit viscoelastic behavior that can be described by fractional models. We show that spheroids are mechanically heterogeneous, with strong depth and time-dependent variations associated with evolving structural features. Our approach opens new possibilities to study 3D in vitro models, paving the way for the discovery of novel and more precise procedure in cancer diagnosis based on the use of mechanomarkers."
655,Knowledge Graph-based Thought: a knowledge graph enhanced LLMs framework for pan-cancer question answering,"Yichun Feng, Lu Zhou, Yikai Zheng, Ruikun He, Chao Ma, Yixue Li",https://www.biorxiv.org/content/10.1101/2024.04.17.589873v1,"Background In recent years, Large Language Models (LLMs) have shown promise in various domains, notably in biomedical sciences. However, their real-world application is often limited by issues like erroneous outputs and hallucinatory responses."
656,"Propofol overcome Tamoxifen resistance in breast cancer by modulating tumorogenesis, immune response and metabolism","Runyang Yin, Jing Gao, Chunyan Guo, Yang Liu",https://www.biorxiv.org/content/10.1101/2024.04.15.589641v1,"Although 70% of estrogen receptor (ER)-positive breast cancer patients benefit from Tamoxifen therapy, the developing resistance to Tamoxifen leads to high rates of metastasis and poor prognosis. Propofol, a commonly used anesthetic, has been shown to inhibit the occurrence and development of breast cancer. However, its role in anti-endocrine resistance in ER-positive breast cancer remains unclear. In this study, we found that Propofol significantly promotes cell cycle arrest, induces apoptosis, and inhibits proliferation in Tamoxifen-resistant breast cancer cells. Furthermore, transcriptome sequencing analysis revealed 1065 differentially expressed genes (DEGs) between Propofol-treated Tamoxifen-resistant MCF-7 (MCF7-TR) cells and none-treated MCF7-TR cells. Gene ontology annotation enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis (KEGG), and gene set enrichment analysis (GSEA) showed that Propofol affects the expression of genes located in the plasma membrane and cell periphery, mainly regulating signals involved in cell cycle regulation, immune response modulation, and metabolism. Our results provide new insights into the mechanism by which Propofol controls resistance to Tamoxifen in breast cancer progression and offer a theoretical basis for clinical treatment."
657,FOXA1 is required for ErbB2 expression and luminal differentiation in HER2-positive breast cancer,"Jaekwang Jeong, Jongwon Lee, Jaechul Lim, Jaehun Shin, Kwangmin Yoo, Jonghun Kim, Yoshiaki Tanaka, Hyun Seop Tae, Lark Kyun Kim, In-Hyun Park, John Wysolmerski, Jungmin Choi",https://www.biorxiv.org/content/10.1101/2024.04.16.589460v1,"Forkhead box protein A1 (FOXA1), a pioneering transcriptional factor known for its critical roles in prostate and ERα−positive breast cancer, is also expressed in human epidermal growth factor receptor-2 (HER2/ErbB2)-positive breast cancers. However, its role in HER2-pos tumors is less well understood. Here we investigate the function of FOXA1 in HER2/ErbB2- positive breast cancers. The loss of FOXA1 was associated with a marked decrease in the viability of HER2-positive and HER2 amplified cell lines, suggesting a pivotal involvement of FOXA1 in these breast cancers. Employing patient-derived single-cell RNA sequencing and spatial transcriptomics, we demonstrate that FOXA1 is co-expressed with ErbB2 in HER2- positive breast cancers. Suppression of FOXA1 expression led to the reduction of HER2 expression and signaling. Chromatin Immunoprecipitation Sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) identified FOXA1 binding motifs in the ErbB2 promoter and regulatory element regions, which controlled ErbB2 gene expression. Notably, FOXA1 knockdown was observed to enhance Epithelial-Mesenchymal Transition (EMT) signaling and impede luminal tumor differentiation. Furthermore, we find that FOXA1 and TRPS1 combine to regulate TEAD/YAP-TAZ activity. Taken together, these findings highlight the essential role of FOXA1 in maintaining HER2 expression and a luminal cell phenotype in HER2-positive breast cancers."
658,Tumoroid-on-a-Plate (ToP): Physiologically Relevant Cancer Model Generation and Therapeutic Screening,"Amir Seyfoori, Kaiwen Liu, Hector Caruncho, Patrick Walter, Mohsen Akbari",https://www.biorxiv.org/content/10.1101/2024.04.15.589651v1,"Employing three-dimensional (3D) in vitro models, including tumor organoids and spheroids, stands pivotal in enhancing cancer therapy. These models bridge the gap between 2D cell cultures and complex in vivo environments, effectively mimicking the intricate cellular interplay and microenvironmental factors found in solid tumors. Consequently, they offer versatile tools for comprehensive studies into cancer progression, drug responses, and tailored therapies. In this study, we present a novel open-surface microfluidic-integrated platform called the Tumoroid-on-a-Plate (ToP) device, designed for generating intricate predictive 3D solid tumor models. By incorporating a tumor mass, stromal cells, and extracellular matrix components, we successfully replicate the complexity of glioblastoma (GBM) and pancreatic adenocarcinoma (PDAC) within our system. Using our advanced ToP model, we were able to successfully screen the effect of various GBM extracellular matrix compositions, such as Collagen and Reelin, on the invasiveness of the GBM cells with the ToP model. The ToP in vitro model also allowed for the screening of chemotherapeutic drugs such as temozolomide and iron-chelators in a single and binary treatment setting on the complex ECM-embedded tumoroids. This helped to investigate the toxic effect of different therapeutics on the viability and apoptosis of our in vitro GBM and PDAC cancer models. Additionally, by co-culturing human-derived fibroblast cells with PDAC tumoroids, the pro-invasive impact of the stromal component of the tumor microenvironment on growth behaviour and drug response of the tumoroids was revealed. This study underscores the transformative role of predictive 3D models in deciphering cancer intricacies and highlights the promise of ToP in advancing therapeutic understanding."
659,Poly-unsaturated Fatty Acids from Thamnidium elegans and Mortierella alpina Suppress Prostate Cancer Cells Proliferation and Migration,"Georgios Kalampounias, Panagiotis Dritsas, Dimitris Karayannis, Theodosia Androutsopoulou, Chrysavgi Gardeli, Seraphim Papanikolaou, George Aggelis, Panagiotis Katsoris",https://www.biorxiv.org/content/10.1101/2024.06.05.597505v2,"Thamnidium elegans and Mortierella alpina are two oleaginous fungi that belong to Mucoromycota that synthesize polyunsaturated fatty acids which are credited with multiple health benefits and possible anticancer properties. These fungi were cultivated on culture media with glucose or glycerol as a carbon source. After extracting the lipids, we transformed them into fatty acid lithium salts (FALS), which are water-soluble and absorbable mammalian cells, including DU-145 and PC-3 cancer cells. The two cell lines, both long-established prostate cancer models, were treated with FALS and indicated increased susceptibility to the lipid derivatives. The viability and proliferation rates were significantly reduced, as well as their migratory capabilities, which were significantly impaired compared to olive-oil-derived FALS, which were used as a control substance. We conclude that the FALS derivatives of microbial lipids from these organisms exhibit anticancer effects by suppressing the proliferation and migration of human prostate cancer cell lines."
660,Combating pancreatic cancer with ovarian cancer cells,"Xiao Lin, Chunmei Cui, Qinghua Cui",https://www.biorxiv.org/content/10.1101/2022.09.01.506158v2,"With overall five-year survival rate less than 10%, pancreatic cancer (PC) represents the most lethal one in all human cancers. Given that the incidence of PC is still increasing and current cancer treatment strategies are often inefficacious, its therapy is still a huge challenge. Here, we first revealed ovarian serous carcinoma is mostly anti-correlated with pancreatic cancer in gene expression signatures. Based on this observation, we proposed that ovarian cancer cells could defense PC. To confirm this strategy, we first showed that ovarian cancer cell SKOV3 can significantly inhibit the proliferation of pancreatic cancer cell SW1990 when they were co-cultured. We further validated this strategy by an animal model of pancreatic cancer xenografts. The result showed that the injection of SKOV3 significantly inhibits pancreatic cancer xenografts. Moreover, we found that SKOV3 with transgenic African elephant TP53 gene further enhances the therapeutic effect. RNA-sequencing analysis revealed that the ovarian cancer cell treatment strikingly induced changes of genes being involved in pancreas function and phenotype (e.g. enhancing pancreas function, pancreas regeneration, and cell adhesion) but not immune and inflammation related functions, suggesting that the proposed strategy is different from immunotherapy and could be a novel strategy for cancer treatment."
661,Induced electric fields inhibit breast cancer growth and metastasis by modulating the immune tumor microenvironment,"Manish Charan, Travis H. Jones, Dinesh K. Ahirwar, Nandini Acharya, Vish V. Subramaniam, Ramesh K Ganju, Jonathan W Song",https://www.biorxiv.org/content/10.1101/2024.04.14.589256v1,"Despite tremendous advances in oncology, metastatic triple-negative breast cancer remains difficult to treat and manage with established therapies. Here, we show in mice with orthotopic triple-negative breast tumors that alternating (100 kHz), and low intensity (<1 mV/cm) induced electric fields (iEFs) significantly reduced primary tumor growth and distant lung metastases. Non-contact iEF treatment can be delivered safely and non-invasively in vivo via a hollow, rectangular solenoid coil. We discovered that iEF treatment enhances anti-tumor immune responses at both the primary breast and secondary lung sites. In addition, iEF reduces immunosuppressive TME by reducing effector CD8+ T cell exhaustion and the infiltration of immunosuppressive immune cells. Furthermore, iEF treatment reduced lung metastasis by increasing CD8+ T cells and reducing immunosuppressive Gr1+ neutrophils in the lung microenvironment. We also observed that iEFs reduced the metastatic potential of cancer cells by inhibiting epithelial-to-mesenchymal transition. By introducing a non-invasive and non-toxic electrotherapeutic for inhibiting metastatic outgrowth and enhancing anti-tumor immune response in vivo, treatment with iEF technology could add to a paradigm-shifting strategy for cancer therapy."
663,Advancing childhood cancer research through young investigator and advocate collaboration,"Amber K. Weiner, Antonia Palmer, Melanie Frost Moll, Gavin Lindberg, Kevin Reidy, Sharon J. Diskin, Crystal L. Mackall, John M. Maris, Patrick J. Sullivan",https://www.biorxiv.org/content/10.1101/2023.12.03.569769v1,"Cancer advocates and researchers share the same goal of driving science forward to create new therapies to cure more patients. The power of combining cancer researchers and advocates has become of increased importance due to their complementary expertise. Therefore, advocacy is a critical component of grant structures and has become embedded into the Stand Up 2 Cancer (SU2C) applications. To date, the optimal way to combine these skillsets and experiences to benefit the cancer community is currently unknown. The Saint Baldrick’s Foundation (SBF)–SU2C now called St. Baldrick’s Empowering Pediatric Immunotherapies for Childhood Cancer (EPICC) Team is comprised of a collaborative network across nine institutions in the United States and Canada. Since SU2C encourages incorporating advocacy into the team structure, we have assembled a diverse team of advocates and scientists by nominating a young investigator (YI) and advocate from each site. In order to further bridge this interaction beyond virtual monthly and yearly in person meetings, we have developed a questionnaire and conducted interviews. The questionnaire is focused on understanding each member’s experience at the intersection between science/advocacy, comparing to previous experiences, providing advice on incorporating advocacy into team science and discussing how we can build on our work. Through creating a YI and advocate infrastructure, we have cultivated a supportive environment for meaningful conversation that impacts the entire research team. We see this as a model for team science by combining expertise to drive innovation forward and positively impact pediatric cancer patients, and perhaps those with adult malignancies."
664,In Vitro Anti-cancer potential of Aloe emodin against Oral Squamous Cell Carcinoma,"Jesse Joel T, Jagadish Kumar Suluvoy, Harish babu Kolla",https://www.biorxiv.org/content/10.1101/2024.04.12.589239v1,"Oral squamous cell carcinoma is caused due to smoking, chewing of tobacco, high exposure of UV radiation and infectious agents such as human papilloma virus (HPV). Epigenetic dysregulation and uncontrolled cell growth are main factors that drives towards tumor development. Risk factors such as smoking, tobacco and viral agent’s up regulates its activity and leads to the cancer. Although chemotherapy, surgery and radiation were preferred for treating cancer but patients, feel extreme psychological stress and depression. Natural products are been investigated for their numerous diseases and in that they can be treated against cancer without side effects. Aloe emodin is one such natural molecule available, which possess various pharmacological activities for human beneficial. In this current study, we investigated the anti-cancer activity of aloe emodin in vitro. The KB 3-1 cell line were treated with different concentrations of Aloe emodin and its anti-cancer potential was determined through DNA fragmentation and cell viability assays."
666,Regulation of lung cancer initiation and progression by the stem cell determinant Musashi,"Alison G. Barber, Cynthia M. Quintero, Michael Hamilton, Nirakar Rajbhandari, Roman Sasik, Yan Zhang, Carla F. Kim, Hatim Husain, Xin Sun, Tannishtha Reya",https://www.biorxiv.org/content/10.1101/2024.04.11.589053v1,"Despite advances in therapeutic approaches, lung cancer remains the leading cause of cancer-related deaths. To understand the molecular programs underlying lung cancer initiation and maintenance, we focused on stem cell programs that are normally extinguished with differentiation but can be reactivated during oncogenesis. Here we have used extensive genetic modeling and patient derived xenografts to identify a dual role for Msi2: as a signal that acts initially to sensitize cells to transformation, and subsequently to drive tumor propagation. Using Msi reporter mice, we found that Msi2-expressing cells were marked by a pro-oncogenic landscape and a preferential ability to respond to Ras and p53 mutations. Consistent with this, genetic deletion of Msi2 in an autochthonous Ras/p53 driven lung cancer model resulted in a marked reduction of tumor burden, delayed progression, and a doubling of median survival. Additionally, this dependency was conserved in human disease as inhibition of Msi2 impaired tumor growth in patient-derived xenografts. Mechanistically, Msi2 triggered a broad range of pathways critical for tumor growth, including several novel effectors of lung adenocarcinoma. Collectively, these findings reveal a critical role for Msi2 in aggressive lung adenocarcinoma, lend new insight into the biology of this disease, and identify potential new therapeutic targets."
669,Metabolic and imaging phenotypes associated with RB1 loss in castrate resistant prostate cancer,"Fahim Ahmad, Margaret White, Kazutoshi Yamamoto, Daniel R. Crooks, Supreet Agarwal, Ye Yang, Brian Capaldo, Sonam Raj, Aian Neil Alilin, Anita Ton, Stephen Adler, Jurgen Seidel, Colleen Olkowski, Murali Krishna Cherukuri, Peter L Choyke, Kathleen Kelly, Jeffrey R. Brender",https://www.biorxiv.org/content/10.1101/2023.11.15.567250v2,"Purpose Advanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but the majority of patients eventually develop resistance and progress to castrate resistant prostate cancer (CRPC). Loss of RB1 in CRPC tumors is correlated with rapid progression and poor patient survival, and in combination with TP53 loss, predisposes to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressing CRPC is clinically associated with higher 18FDG-PET SUVmax values, it is unknown whether inactivation of RB1 and/or TP53 is a driver of increased glucose import."
671,Genomic characterization of Escherichia coli harbor a polyketide synthase (pks) island associated with colorectal cancer (CRC) development,"Chao Lv, Mohd Abdullah, Weiye Chen, Nan Zhou, Zile Cheng, Yiwen Chen, Min Li, Kenneth W. Simpson, Ahmed Elsaadi, Yongzhang Zhu, Steven M. Lipkin, Yung-Fu Chang",https://www.biorxiv.org/content/10.1101/2024.06.16.599199v1,"The E. coli strain harboring the polyketide synthase (Pks) island encodes the genotoxin colibactin, a secondary metabolite reported to have severe implications for human health and for the progression of colorectal cancer. The present study involved whole-genome-wide comparison and phylogenetic analysis of pks harboring E. coli isolates to gain insight into the distribution and evolution of these organism. Fifteen E. coli strains isolated from patients with ulcerative colitis were sequenced, 13 of which harbored pks islands. In addition, 2,654 genomes from the public database were also screened for pks harboring E. coli genomes, 158 of which were pks-positive isolates. Whole-genome-wide comparison and phylogenetic analysis revealed that 171 (158+13) pks-positive isolates belonged to phylogroup B2, and most of the isolates associated to sequence types ST73 and ST95. One isolate from an ulcerative colitis (UC) patient was of the sequence type ST8303. The maximum likelihood tree based on the core genome of pks-positive isolates revealed horizontal gene transfer across sequence types and serotypes. Virulome and resistome analyses revealed the preponderance of virulence genes and a reduced number of antimicrobial genes in Pks-positive isolates. This study strongly contributes to understanding the evolution of pks islands in E. coli."
672,Resting natural killer cells promote the progress of colon cancer liver metastasis by elevating tumor-derived sSCF,"Chenchen Mao, Yanyu Chen, Dong Xing, Teming Zhang, Yangxuan Lin, Cong Long, Jiaye Yu, Yunhui Luo, Tao Ming, Wangkai Xie, Zheng Han, Dianfeng Mei, Dan Xiang, Mingdong Lu, Xian Shen, Xiangyang Xue",https://www.biorxiv.org/content/10.1101/2024.02.27.582307v2,"Purpose The abundance and biological contribution of Natural killer (NK) cells in cancer are controversial. Here, we aim to uncover clinical relevance and cellular roles of NK cells in colon cancer liver metastasis (CCLM)"
673,Valproic Acid Treatment Enhances Chromosome Flexibility and Electron Transport in MCF7 Breast Cancer Cells,"Tanya Agrawal, Debashish Paul, Amita Mishra, Arunkumar Ganesan, Suchetan Pal, Tatini Rakshit",https://www.biorxiv.org/content/10.1101/2024.04.08.588551v1,"The structural integrity of the chromosomes is essential to every functional process within the eukaryotic nuclei. Chromosomes are DNA-histone complexes essential for the inheritance of genetic information to the offspring and any defect in it is linked to mitotic errors, cancer growth, and cellular aging. Changes in the mechanical properties of a chromosome could lead to its compromised function and stability, leading to chromosome breaks. Here, we studied the changes in chromosome physical properties using metaphase chromosomes isolated from human breast cancer cells (MCF7) exposed to Valproic Acid (VPA), a known epigenetic modifier drug involved in histone hyperacetylation and DNA demethylation. Due to chromosomal structural intricacy, preparative and technical limitations of analytical tools, we employed a label-free atomic force microscopy approach for simultaneously visualizing and mapping single chromosome elasticity. Additionally, we performed electron transport characteristics of metaphase chromosomes to elucidate the effect of VPA. Our multi-parametric strategy of probing physical properties of chromosomes offers a new scope in terms of analytical tools for studying chromosomal structural changes/aberrations and associated structure-function relationships pertinent to cancer."
675,Proteasome inhibition induces DNA methylation alteration by attenuating the synthesis of DNA methyltransferase 1 and 3B in colorectal cancer,"Wenwen Zhou, Yuling Sheng, Dingxue Hu, Yunyun An, Mengqi Yang, Wanqiu Wang, Shiva Basnet, Jingyu Yan, Shuxia Zhang, Qi Liu, Yunze Li, Yi Tan, Jing Gao, Kun Sun, Changzheng Du",https://www.biorxiv.org/content/10.1101/2024.06.14.598995v1,"Proteasome is an essential organelle in guarding cellular protein homeostasis. Here, we report that inhibition of proteasome leads to alterations in DNA methylation patterns in colorectal cancer (CRC) by surpressing the synthesis of DNA methyltransferases (DNMTs). We found that treating CRC cells with proteasome inhibitors results in attenuated translation of DNMT1 and DNMT3B, mediated by the inactivation of AKT and mammalian target of rapamycin (mTOR), which is dependent on the accumulation of p300, an acetyltransferase that inhibits AKT through acetylation modification. Furthermore, we demonstrated that downregulation of DNMT1 and DNMT3B confers protection against proteasome inhibitor treatment, potentially through reprogramming the transcriptome of CRC cells, highlighting the significant role of DNMTs in response to disruptions in protein homeostasis. Interestingly, the proteasome inhibitor-induced downregulation of DNMT1 and DNMT3B appears to be CRC specific, notwithstanding the underlying mechanism remains unclear. Altogether, our findings reveal an epigenetic effect of proteasome on DNA methylation in CRC through its regulation of DNA methyltransferase synthesis."
676,Non-destructive viability assessment of cancer cell spheroids using dynamic optical coherence tomography with trypan blue validation,"Ko Hui Tan, Joel Lang Yi Ang, Alexander Si Kai Yong, Stefanie Zi En Lim, Jessica Sze Jia Kng, Kaicheng Liang",https://www.biorxiv.org/content/10.1101/2024.06.14.598971v1,"3D cell cultures are widely used in biomedical research for the recapitulation of in vivo microenvironments. Viability assessment and monitoring of these intricate conformations remain an open problem as standard cell viability protocols based on colorimetry or microscopy are not directly applicable to intact 3D samples. Optical coherence tomography (OCT) has been explored extensively for subsurface structural and quasi-functional analysis of 3D cell cultures and tissue. Recent studies of dynamic OCT as a source of cellular contrast have found qualitative associations with necrosis in cell spheroids, suggesting potential as a viability marker. We present empirical and validated evidence for dynamic OCT as a quantitative indicator of cell viability in 3D cultures. We analysed over 240 MCF-7 cancer cell spheroids with dynamic OCT and corresponding viability measurements using the trypan blue exclusion assay. Significant effects of common reagents Dimethyl sulfoxide (DMSO) and Phosphate-Buffered Saline (PBS) on OCT readouts were noted. We proposed a regression-based OCT brightness normalisation technique that removed reagent-induced OCT intensity biases and helped improve correspondence to the viability assay. These results offer a quantitative biological foundation for further advances of dynamic OCT as a novel non-invasive modality for 3D culture monitoring."
678,Mitosis sets nuclear homeostasis of cancer cells under confinement,"Malèke Mouelhi, Alexis Saffon, Morgane Roinard, Hélène Delanoë-Ayari, Sylvain Monnier, Charlotte Rivière",https://www.biorxiv.org/content/10.1101/2023.05.11.540326v2,"During their life, mammalian cells are subjected to numerous mechanical constraints, especially in pathological contexts such as cancer. Recent studies have highlighted the central role of the nucleus in sensing mechanical cues, but they only focus on short periods of time, and so far, whether cells can adapt to prolonged confinement remains unknown. Here, we reveal the unsuspected role of mitosis in the long-term adaptation of nuclei to prolonged uniaxial confinement. For the colorectal cancer cell line investigated, following the first confined cell division, a new homeostatic state was reached by nuclei: they were smaller, and had reset the tension of their envelope. This adaptation through mitosis relied both on the nuclear tension sensor cPLA2 and the contractility machinery. We report for the first time a mechano-adaptation during mitosis, a process that could be crucial to adapt to stresses in the tumor microenvironment. We therefore anticipate that our work could provide new insight into cancer cell plasticity and cancer relapse."
679,Ultrasensitive amplification-free quantification of a methyl CpG-rich cancer biomarker by single-molecule kinetic fingerprinting,"Liuhan Dai, Alexander Johnson-Buck, Peter W. Laird, Muneesh Tewari, Nils G. Walter",https://www.biorxiv.org/content/10.1101/2024.04.06.587997v1,"The most well-studied epigenetic marker in humans is the 5-methyl modification of cytosine in DNA, which has great potential as a disease biomarker in liquid biopsies of cell-free DNA. Currently, quantification of DNA methylation relies heavily on bisulfite conversion followed by PCR amplification and NGS or microarray analysis. PCR is subject to potential bias in differential amplification of bisulfite-converted methylated versus unmethylated sequences. Here, we combine bisulfite conversion with single-molecule kinetic fingerprinting to develop an amplification-free assay for DNA methylation at the branched-chain amino acid transaminase 1 (BCAT1) promoter. Our assay selectively responds to methylated sequences with a limit of detection below 1 fM and a specificity of 99.9999%. Evaluating complex genomic DNA matrices, we reliably distinguish 2-5% DNA methylation at the BCAT1 promoter in whole blood DNA from completely unmethylated whole-genome amplified DNA. Taken together, these results demonstrate the feasibility and sensitivity of our amplification-free, single-molecule quantification approach to improve the early detection of methylated cancer DNA biomarkers."
680,Investigating the impact of the interstitial fluid flow and hypoxia interface on cancer biology using a spheroid-on-chip perfusion system,"Emily Pyne, Mark Reardon, Martin Christensen, Pablo Rodriguez Mateos, Scott Taylor, Alexander Iles, Ananya Choudhury, Nicole Pamme, Isabel M. Pires",https://www.biorxiv.org/content/10.1101/2024.08.21.608919v1,"Solid tumours are complex and heterogeneous systems, which exist in a dynamic biophysical microenvironment. Conventional cancer research methods have long relied on two-dimensional (2D) static cultures which neglect the dynamic, three-dimensional (3D) nature of the biophysical tumour microenvironment (TME), especially the role and impact of interstitial fluid flow (IFF). To address this, we undertook a transcriptome-wide analysis of the impact of IFF-like perfusion flow using a spheroid-on-chip microfluidic platform, which allows 3D cancer spheroids to be integrated into extracellular matrices (ECM)-like hydrogels and exposed to continuous perfusion, to mimic IFF in the TME. Importantly, we have performed these studies both in experimental (normoxia) and pathophysiological (hypoxia) oxygen conditions. Our data indicated that gene expression was altered by flow when compared to static conditions, and for the first time showed that these gene expression patterns differed in different oxygen tensions, reflecting a differential role of spheroid perfusion in IFF-like flow in tumour-relevant hypoxic conditions in the biophysical TME. We were also able to identify factors primarily linked with IFF-like conditions which are linked with prognostic value in cancer patients and therefore could correspond to a potential novel biomarker of IFF in cancer. This study therefore highlights the need to consider relevant oxygen conditions when studying the impact of flow in cancer biology, as well as demonstrating the potential of microfluidic models of flow to identify IFF-relevant tumour biomarkers."
686,Validation of a Microfluidic Device Prototype for Cancer Detection and Identification: Circulating Tumor Cells Classification Based on Cell Trajectory Analysis Leveraging Cell-Based Modeling and Machine Learning,"Rifat Rejuan, Eugenio Aulisa, Wei Li, Travis Thompson, Sanjoy Kumar, Suncica Canic, Yifan Wang",https://www.biorxiv.org/content/10.1101/2024.08.19.608572v1,"Microfluidic devices (MDs) present a novel method for detecting circulating tumor cells (CTCs), enhancing the process through targeted techniques and visual inspection. However, current approaches often yield heterogeneous CTC populations, necessitating additional processing for comprehensive analysis and phenotype identification. These procedures are often expensive, time-consuming, and need to be performed by skilled technicians. In this study, we investigate the potential of a cost-effective and efficient hyperuniform micropost MD approach for CTC classification. Our approach combines mathematical modeling of fluid-structure interactions in a simulated microfluidic channel with machine learning techniques. Specifically, we developed a cell-based modeling framework to assess CTC dynamics in erythrocyte-laden plasma flow, generating a large dataset of CTC trajectories that account for two distinct CTC phenotypes. Convolutional Neural Network (CNN) and Recurrent Neural Network (RNN) were then employed to analyze the dataset and classify these phenotypes. The results demonstrate the potential effectiveness of the hyperuniform micropost MD design and analysis approach in distinguishing between different CTC phenotypes based on cell trajectory, offering a promising avenue for early cancer detection."
687,Comparative effects of proton and photon irradiation on the molecular and cellular profiles of triple-negative breast cancer: the crucial impact of VEGFC on tumor microenvironment remodeling,"Saharnaz Sarlak, Delphine Marotte, Florent Morfoisse, Alessandra Pierantoni, Jessy Sirera, Meng-Chen Tsai, Marie Vidal, Joël Hérault, Barbara Garmy-Susini, Jérôme Doyen, Frédéric Luciano, Gilles Pagès",https://www.biorxiv.org/content/10.1101/2024.08.19.608614v1,"Metastatic triple-negative breast cancers (TNBC) are among the most aggressive types of breast cancer and are often treated with adjuvant radiotherapy and chemotherapy. Despite initial efficacy, relapses are common, leading to poor prognosis. Understanding the response of tumor microenvironment to radiotherapy is crucial, particularly comparing photon (X) and proton (P) radiotherapy due to proton radiation’s reduced side effects."
688,VaxOptiML: Leveraging Machine Learning for Accurate Prediction of MHC-I & II Epitopes for Optimized Cancer Immunotherapy,"Dhanushkumar T, Sunila B G, Sripad Rama Hebbar, Prasanna Kumar Selvam, Karthick Vasudevan",https://www.biorxiv.org/content/10.1101/2024.06.10.598389v2,"In the realm of cancer immunotherapy, the ability to accurately predict epitopes is crucial for advancing vaccine development. Here, we introduce VaxOptiML (available at https://vaxoptiml.streamlit.app/), an integrated pipeline designed to enhance epitope prediction and prioritization. Utilizing a curated dataset of experimentally validated epitopes and sophisticated machine learning techniques, VaxOptiML features three distinct models that predict epitopes from target sequences, pair them with personalized HLA types, and prioritize them based on immunogenicity scores. Our rigorous process of data cleaning, feature extraction, and model building has resulted in a tool that demonstrates exceptional accuracy, sensitivity, specificity, and F1-score, surpassing existing prediction methods. The robustness and efficacy of VaxOptiML are further illustrated through comprehensive visual representations, underscoring its potential to significantly expedite epitope discovery and vaccine design in cancer immunotherapy, Additionally, we have deployed the trained ML model using Streamlit for public usage, enhancing accessibility and usability for researchers and clinician."
689,Identifying cooperative genes causing cancer progression with dynamic causal inference,"Andres M. Cifuentes-Bernal, Lin Liu, Jiuyong Li, Thuc Duy Le",https://www.biorxiv.org/content/10.1101/2023.11.22.568367v1,"It is well known that some gene aberrations can cause cancer by disrupting the delicate balance of critical biological processes at the cellular level. Such aberrations are rare and are not limited to gene mutations alone and hence are difficult to be identified from data. Moreover, focusing exclusively on gene aberrations neglects other significant aspects of cancer development such as the fact that cancer occurs due to gene interactions evolving as a dynamical system. Therefore, expanding our knowledge about the dynamics of genetic mechanisms that cause cancer is crucial for a comprehensive understanding of cancer development. In this paper, a novel causal method for identifying collaborative networks of cancer drivers based on dynamic system analysis is introduced. The method integrates the temporal dimension of the data throughout cancer progression and provides a way of testing for the causality of candidate genes in cancer. We have applied our method to single-cell and bulk sequencing datasets of breast cancer. The evaluation results show that our method systematically identifies bona fide driver genes and detects sets of genes strongly linked to cancer progression. The results suggest that our method can discover mutated and non mutated drivers of cancer to provide a comprehensive view of cancer development."
690,Long-term maintenance of patient-specific characteristics in tumoroids from six cancer indications in a common base culture media system,"Colin D. Paul, Chris Yankaskas, Pradip Shahi Thakuri, Brittany Balhouse, Shyanne Salen, Amber Bullock, Sylvia Beam, Anthony Chatman, Sybelle Djikeng, Jenny Yang, Garrett Wong, Isha Dey, Spencer Holmes, Abigail Dockey, Lindsay Bailey-Steinitz, Lina Zheng, Weizhong Li, Vivek Chandra, Jakhan Nguyen, Jason Sharp, Erik Willems, Mark Kennedy, Matt Dallas, David Kuninger",https://www.biorxiv.org/content/10.1101/2024.06.10.598331v1,"Tumoroids, also known as cancer organoids, are patient-derived cancer cells grown as 3D, self-organized multicellular structures that maintain key characteristics (e.g., genotype, gene expression levels) of the tumor from which they originated. These models have emerged as valuable tools for studying tumor biology, cytotoxicity, and response of patient-derived cells to cancer therapies. However, the establishment and maintenance of tumoroids has historically been challenging, labor intensive, and highly variable from lab to lab, hindering their widespread use. Here, we characterize the establishment and/or expansion of colorectal, lung, head and neck, breast, pancreas, and endometrial tumoroids using the standardized, serum-free Gibco OncoPro Tumoroid Culture Medium. Newly derived tumoroid lines (n=20) were analyzed by targeted genomic profiling and RNA sequencing and were representative of tumor tissue samples. Tumoroid lines were stable for over 250 days in culture and freeze-thaw competent. Previously established tumoroid lines were also transitioned to OncoPro medium and exhibited, on average, similar growth rates and conserved donor-specific characteristics when compared to original media systems. Additionally, OncoPro medium was compatible with both embedded culture in extracellular matrix and growth in a suspension format for facile culture and scale up. An example application of these models for assessing the cytotoxicity of a natural killer cell line and primary natural killer cells over time and at various doses demonstrated the compatibility of these models with assays used in compound and cell therapy development. We anticipate that the standardization and versatility of this approach will have important benefits for basic cancer research, drug discovery, and personalized medicine and help make tumoroid models more accessible to the cancer research community."
692,Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis,"Tobias Ackermann, Engy Shokry, Ruhi Deshmukh, Jayanthi Anand, Laura C.A. Galbraith, Louise Mitchell, Giovanny Rodriguez-Blanco, Victor H. Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito",https://www.biorxiv.org/content/10.1101/2023.06.13.544588v2,"The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour."
693,Machine learning predictions improve identification of real-world cancer driver mutations,"Thinh N. Tran, Chris Fong, Karl Pichotta, Anisha Luthra, Ronglai Shen, Yuan Chen, Michele Waters, Susie Kim, Michael F Berger, Gregory Riely, Marc Ladanyi, Debyani Chakravarty, Nikolaus Schultz, Justin Jee",https://www.biorxiv.org/content/10.1101/2024.03.31.587410v2,"Characterizing and validating which mutations influence development of cancer is challenging. Machine learning has delivered significant advances in protein structure prediction, but its utility for identifying cancer drivers is less explored. We evaluated multiple computational methods for identifying cancer driver alterations. For identifying known drivers, methods incorporating protein structure or functional genomic data outperformed methods trained only on evolutionary data. We further validated VUSs annotated as pathogenic by testing their association with overall survival in two cohorts of patients with non-small cell lung cancer (N=7,965 and 977). “Pathogenic” VUSs in KEAP1 and SMARCA4 identified by several methods were associated with worse survival, unlike “benign” VUSs. “Pathogenic” VUSs exhibited mutual exclusivity with known oncogenic alterations at the pathway level, further suggesting biological validity. Despite training primarily on germline, rather than somatic, mutation data, computational predictions contribute to a more comprehensive understanding of tumor genetics as validated by real-world data."
694,"Sensitive tumor detection, accurate quantification, and cancer subtype classification using low-pass whole methylome sequencing of plasma DNA","Marta Paoli, Francesca Galardi, Agostina Nardone, Chiara Biagioni, Dario Romagnoli, Samantha Di Donato, Gian Marco Franceschini, Luca Livraghi, Marta Pestrin, Giuseppina Sanna, Emanuela Risi, Ilenia Migliaccio, Erica Moretti, Luca Malorni, Laura Biganzoli, Francesca Demichelis, Matteo Benelli",https://www.biorxiv.org/content/10.1101/2024.06.10.598204v1,"The analysis of circulating tumor DNA (ctDNA) is increasingly used for monitoring disease in patients with metastatic cancer. Here, we introduce a robust and reproducible strategy combining low-pass whole methylome sequencing of plasma DNA with METER, a novel computational tool. Engaging prediction models trained on independent available datasets, METER enables the detection and quantification of tumor content (TC) and performs molecular cancer subtyping. Applied to plasma methylomes from early metastatic breast cancer patients, our method demonstrated reliable quantification, sensitive tumor detection below 3% of TC, and the ability to perform accurate Estrogen Receptor (ER) subtyping. METER provided clinically relevant predictions, underscored by associations with relevant prognostic factors, robust correlation with matched circulating tumor cells, and highly correlated with patients’ outcomes in challenging scenarios as TC<3%. Our strategy provides comprehensive and sensitive analysis of plasma samples, serving as a valuable yet cost-effective precision oncology tool."
696,Life history and cancer in birds: clutch size predicts cancer,"Stefania E. Kapsetaki, Zachary Compton, Jordyn Dolan, Valerie K. Harris, Shawn M. Rupp, Elizabeth G. Duke, Tara M. Harrison, Selin Aksoy, Mathieu Giraudeau, Orsolya Vincze, Kevin J. McGraw, Athena Aktipis, Marc Tollis, Amy M. Boddy, Carlo C. Maley",https://www.biorxiv.org/content/10.1101/2023.02.11.528100v1,"Cancer is a disease that affects nearly all multicellular life, including birds. However, little is known about what factors explain the variance in cancer prevalence among species. Litter size is positively correlated with cancer prevalence in managed species of mammals, and larger body size, but not incubation or nestling period, is linked to tumor prevalence in wild birds. Also, birds that produce more elaborate sexual traits are expected to have fewer resources for cancer defenses and thus higher cancer prevalence. In this study, we examined whether cancer prevalence is associated with a wide variety of life history traits (clutch size, incubation length, body mass, lifespan, and the extent of sexual dimorphism) across 108 species of managed birds in 25 different zoological facilities, sanctuaries, and veterinary clinics. We found that clutch size was positively correlated with cancer and neoplasia (both benign and malignant) prevalence, even after controlling for body mass. Cancer prevalence was not associated with incubation length, body mass, lifespan, or sexual dimorphism. The positive correlations of clutch size with cancer prevalence and neoplasia prevalence suggest that there may be life-history trade-offs between reproductive investment and somatic maintenance (in the form of cancer prevention mechanisms) in managed birds."
697,Integrated cancer cell-specific single-cell RNA-seq datasets of immune checkpoint blockade-treated patients,"Mahnoor N. Gondal, Marcin Cieslik, Arul M. Chinnaiyan",https://www.biorxiv.org/content/10.1101/2024.01.17.576110v2,"Immune checkpoint blockade (ICB) therapies have emerged as a promising avenue for the treatment of various cancers. Despite their success, the efficacy of these treatments is variable across patients and cancer types. Numerous single-cell RNA-sequencing (scRNA-seq) studies have been conducted to unravel cell-specific responses to ICB treatment. However, these studies are limited in their sample sizes and require advanced coding skills for exploration. Here, we have compiled eight scRNA-seq datasets from nine cancer types, encompassing 174 patients, and 90,270 cancer cells. This compilation forms a unique resource tailored for investigating how cancer cells respond to ICB treatment across cancer types. We meticulously curated, quality-checked, pre-processed, and analyzed the data, ensuring easy access for researchers. Moreover, we designed a user-friendly interface for seamless exploration. By sharing the code and data for creating these interfaces, we aim to assist fellow researchers. These resources offer valuable support to those interested in leveraging and exploring single-cell datasets across diverse cancer types, facilitating a comprehensive understanding of ICB responses."
701,Proteomic Assessment of SKBR3/HER2+ Breast Cancer Cellular Response to Lapatinib and Investigational Ipatasertib Kinase Inhibitors,"Arba Karcini, Nicole R. Mercier, Iulia M. Lazar",https://www.biorxiv.org/content/10.1101/2024.04.02.587656v1,"Modern cancer treatment approaches aim at achieving cancer remission by using targeted and personalized therapies, as well as harnessing the power of the immune system to recognize and eliminate the cancer cells. To overcome a relatively short-lived response due to the development of resistance to the administered drugs, combination therapies have been pursued, as well. To expand the outlook of combination therapies, the objective of this study was to use high-throughput data generation technologies such as mass spectrometry and proteomics to investigate the response of HER2+ breast cancer cells to a mixture of two kinase inhibitors that has not been adopted yet as a standard treatment regime. The broader landscape of biological processes that are affected by inhibiting two major pathways that sustain the growth and survival of cancer cells, i.e., EGFR and PI3K/AKT, was investigated by treating SKBR3/HER2+ breast cancer cells with Lapatinib or a mixture of Lapatinib/Ipatasertib small molecule drugs. Changes in protein expression and/or activity in response to the drug treatments were assessed by using two complementary quantitative proteomic approaches based on peak area and peptide spectrum match measurements. Over 900 proteins matched by three unique peptide sequences (FDR<0.05) were affected by the exposure of cells to the drugs. The work corroborated the anti-proliferative activity of Lapatinib and Ipatasertib, and, in addition to cell cycle and growth arrest processes enabled the identification of several multi-functional proteins with roles in cancer-supportive hallmark processes. Among these, immune response, adhesion and migration emerged as particularly relevant to the ability to effectively suppress the proliferation and dissemination of cancer cells. The supplementation of Lapatinib with Ipatasertib further affected the expression or activity of additional transcription factors and proteins involved in gene expression, trafficking, DNA repair, and development of multidrug resistance. Furthermore, over fifty of the affected proteins represented approved or investigational targets in the DrugBank database, which through their protein-protein interaction networks can inform the selection of effective therapeutic partners. Altogether, our findings exposed a broad plethora of yet untapped opportunities that can be further explored for enhancing the anti-cancer effects of each drug as well as of many other multi-drug therapies that target the EGFR/ERBB2 and PI3K/AKT pathways. The data are available via ProteomeXchange with identifier PXD051094."
702,LASSO Based Analysis for Prediction of Prognostic Signature Genes Associated with Breast Cancer,Souvik Guha,https://www.biorxiv.org/content/10.1101/2024.04.02.587421v1,"Background Cancer is a genetic disease, where gene alterations play a significant role in the disease onset and pathogenesis. Analysis of the underlying gene interaction pathways could reveal new biomarkers and could also potentially help in the development of targeted drugs for therapeutics. Microarray techniques have emerged as powerful tools capable of simultaneously measuring the expression levels of thousands of genes, making them invaluable in cancer biology research. However, the processing of the resultant datasets poses significant challenges due to their high dimensionality. Also, feature extraction becomes essential to discern the crucial features within these extensive datasets. To mitigate these difficulties advanced computational techniques like Machine Learning (ML) could be instrumental. LASSO-regression-based classification is an advanced ML technique that can help in feature selection by evaluating individual parameters like genes."
703,RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression,"Augusto Bleve, Francesca Maria Consonni, Martina Incerti, Valentina Garlatti, Chiara Pandolfo, Marta Noemi Monari, Simone Serio, Daniela Pistillo, Marina Sironi, Chiara Alì, Marcello Manfredi, Giovanna Finocchiaro, Cristina Panico, Gianluigi Condorelli, Antonio Sica",https://www.biorxiv.org/content/10.1101/2023.11.19.567414v1,"Despite well-documented metabolic and hematopoietic alterations during tumor development1, the mechanisms underlying this crucial immunometabolic intersection have remained elusive. Of particular interest is the ligand-activated transcription factor retinoic acid-related orphan receptor 1 (RORC1/RORγ), whose activity is boosted by cholesterol metabolites2, acting as a modulator of cancer-related emergency myelopoiesis3, while hypercholesterolemia itself is associated with dysregulated myelopoiesis4,5. Here we show that both cancer growth and hypercholesterolemic diet can independently or cooperatively activate RORγ-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2 polarization of tumor-associated macrophages (TAMs), thereby supporting cancer spread. Moreover, we report that tumor development enhances the hepatic production of IL-1β and IL-6, which in turn promote upregulation of hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, as we confirmed in models of fibrosarcoma, melanoma, colorectal (CRC), and lung cancer, as well as in CRC, non-small-cell lung cancer (NSCLC), breast (BRC), pancreatic ductal adenocarcinoma (PDAC), biliary tract carcinoma (BTC) and pancreatic neuroendocrine tumor (PNET) patients. Importantly, lowering cholesterol levels prevents MDSC expansion and M2 TAM accumulation in a RORγ-dependent manner, unleashing specific anti-tumor immunity and improving the efficacy of anti-PD-1 immunotherapy. Overall, we identify RORγ as a novel sensor of lipid disorders in cancer bearers, bridging hypercholesterolemia and pro-tumor myelopoiesis."
706,Premature cleavage and polyadenylation in the minor intron of PTEN modulate its expression and generates a functional long non-coding RNA in breast cancer,"Mariam Elesnawy, Rim Elghandour, Hana Hasna, Aisha Fakhroo, Boshra Al-Sulaiti, Ihab Younis",https://www.biorxiv.org/content/10.1101/2024.08.15.608023v1,"Minor introns constitute 0.4% of all introns in human cells, but they are unique in their ability to regulate the genes in which they are embedded such that their low splicing efficiency can be a rate limiting step in gene expression. The first intron of the tumor suppressor gene, PTEN, has been documented to be a minor intron, but very little is known about its regulation. Regulation of PTEN levels in cancer cells, especially breast cancer is tightly controlled as a very small reduction in its expression can lead to tumorigenesis. Indeed, many genetic, epigenetic, post-transcriptional and post-translational mechanisms are employed to reduce PTEN levels or activities, leading to cancer. Here, we uncover a previously unexplored mechanism for modulating PTEN expression utilizing its minor intron. The minor intron of PTEN minor intron has one of the lowest splicing efficacies in breast cancer cells, causing at least 50% of PTEN pre-mRNA to retain it, and thus not produce a functional protein. We also show that, unlike other minor introns, the retained intron in PTEN pre-mRNA is not used as a molecular switch that would be spliced out when needed but is rather processed by premature cleavage and polyadenylation into a long noncoding RNA (lncRNA) that we termed PINC. Exogenous expression of PINC caused significant alterations to cellular proliferation, including breast cancer cells that harbor a genetic mutation in the PTEN gene and do not produce a functional PTEN protein. This shows that this novel lncRNA functions independently of the encoded protein of the host gene."
708,Anti-EGFR aptamer exhibits direct anti-cancer effects in NSCLC cells harboring EGFR L858R mutations,"Brian J. Thomas, Sania Z. Awan, Trupti Joshi, Mark A. Daniels, David Porciani, Donald H. Burke",https://www.biorxiv.org/content/10.1101/2024.04.01.587576v1,"Non-small cell lung cancer (NSCLC) adenocarcinoma (LUAD) is a leading cause of death worldwide. Activating mutations in the tyrosine kinase domain of the oncogene epidermal growth factor receptor (EGFR) are responsible for ∼10-50% of all LUAD cases. Although EGFR tyrosine kinase inhibitors (TKIs) have been effective in prolonging NSCLC patient survival and quality of life, acquired resistance mechanisms and disease progression are inevitable. Contemporary second- and third-line treatments, such as immunotherapy, remain ineffective for these patients, presenting a clear and unmet need for alternative or adjuvant therapeutics for the treatment of mutant EGFR positive NSCLC. Here we show that an anti-EGFR aptamer (EGFRapt) decreases viability of NSCLC cell lines harboring the L858R ± T790M mutation in EGFR but not cell lines harboring wild-type or exon 19 deletions. In a humanized xenograft mouse model of NSCLC, EGFRapt decreased tumor burden compared to controls when delivered intratumorally over multiple doses. To elucidate the mechanism by which EGFRapt exerts these effects, we monitored cellular processes associated with kinase-dependent and kinase-independent mechanisms and found that the anti-cancer effects of EGFRapt are cell line dependent, inhibiting cellular proliferation in one cell line and inducing cell death in another. Post hoc transcriptomics analysis supported these findings and provided additional mechanistic insights. Overall, these data establish that EGFRapt has direct anti-cancer activity in mutant EGFR positive NSCLC via targetable mechanisms that are independent of existing approaches, and they provide a foundation for further development of nucleic acid-based therapies that target EGFR."
710,Explorative Discovery of Gene Signatures and Clinotypes in Glioblastoma Cancer Through GeneTerrain Knowledge Map Representation,"Ehsan Saghapour, Zongliang Yue, Rahul Sharma, Sidharth Kumar, Zhandos Sembay, Christopher D. Willey, Jake Y. Chen",https://www.biorxiv.org/content/10.1101/2024.04.01.587278v1,"This study introduces the GeneTerrain Knowledge Map Representation (GTKM), a novel method for visualizing gene expression data in cancer research. GTKM leverages protein-protein interactions to graphically display differentially expressed genes (DEGs) on a 2-dimensional contour plot, offering a more nuanced understanding of gene interactions and expression patterns compared to traditional heatmap methods. The research demonstrates GTKM’s utility through four case studies on glioblastoma (GBM) datasets, focusing on survival analysis, subtype identification, IDH1 mutation analysis, and drug sensitivities of different tumor cell lines. Additionally, a prototype website has been developed to showcase these findings, indicating the method’s adaptability for various cancer types. The study reveals that GTKM effectively identifies gene patterns associated with different clinical outcomes in GBM, and its profiles enable the identification of sub-gene signature patterns crucial for predicting survival. The methodology promises significant advancements in precision medicine, providing a powerful tool for understanding complex gene interactions and identifying potential therapeutic targets in cancer treatment."
711,Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit advanced forms of therapy resistant ovarian cancer,"Esther P.B. Rodman, Michael J. Emch, Xiaonan Hou, Archit Bajaj, Nicole A. Pearson, August J. John, Yamillie Ortiz, Adam D. Bass, Saloni Singh, Gustavo Baldassarre, Scott H. Kaufmann, S. John Weroha, John R. Hawse",https://www.biorxiv.org/content/10.1101/2024.06.06.597753v1,"Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited JNK and ERK activity, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer."
712,Identification of robust RT-qPCR reference genes for studying changes in gene expression in response to hypoxia in breast cancer cell lines,"Jodie R. Malcolm, Katherine S. Bridge, Andrew N. Holding, William J. Brackenbury",https://www.biorxiv.org/content/10.1101/2024.08.02.606329v2,"Hypoxia is common in breast tumours and is linked to therapy resistance and advanced disease. To understand hypoxia-driven breast cancer progression, RT-qPCR quantifies transcriptional changes important for malignant development. Reference genes (RGs) are endogenous RT-qPCR controls used to normalise mRNA levels, allowing accurate assessment of transcriptional changes. However, hypoxia reprograms transcription and post-transcriptional processing of RNA such that favoured RGs including GAPDH or PGK1 are unsuitable for this purpose. To address the need for robust RGs to study hypoxic breast cancer cell lines, we identified 10 RG candidates by analysing public RNA-seq data of MCF-7, T-47D, MDA-MB-231 and MDA-MB-468 cells cultured in normoxia or hypoxia. RT-qPCR determined RG candidate levels in normoxic breast cancer cells, removing TBP and EPAS1 from downstream analysis due to insufficient transcript abundance. Assessing primer efficiency further removed ACTB, CCSER2 and GUSB from consideration. Following culture in normoxia, or acute or chronic hypoxia, we ascertained robust non-variable RGs using RefFinder. Here we present RPLP1 and RPL27 as optimal RGs for breast cancer cell lines cultured in normoxia or hypoxia. Our result enables accurate evaluation of gene expression in hypoxic breast cancer cell lines and provides an essential resource for assessing hypoxia’s impact in breast cancer progression."
714,Rapid differentiation of estrogen receptor status in patient biopsy breast cancer aspirates with an optical nanosensor,"Pooja V. Gaikwad, Nazifa Rahman, Pratyusha Ghosh, Dianna Ng, Ryan M. Williams",https://www.biorxiv.org/content/10.1101/2024.03.29.587397v1,"Breast cancer is a substantial source of morbidity and mortality worldwide. It is particularly more difficult to treat at later stages, and treatment regimens depend heavily on both staging and the molecular subtype of the tumor. However, both detection and molecular analyses rely on standard imaging and histological method, which are costly, time-consuming, and lack necessary sensitivity/specificity. The estrogen receptor (ER) is, along with the progesterone receptor (PR) and human epidermal growth factor (HER-2), among the primary molecular markers which inform treatment. Patients who are negative for all three markers (triple negative breast cancer, TNBC), have fewer treatment options and a poorer prognosis. Therapeutics for ER+ patients are effective at preventing disease progression, though it is necessary to improve the speed of subtyping and distribution of rapid detection methods. In this work, we designed a near-infrared optical nanosensor using single-walled carbon nanotubes (SWCNT) as the transducer and an anti-ERα antibody as the recognition element. The nanosensor was evaluated for its response to recombinant ERα in buffer and serum prior to evaluation with ER- and ER+ immortal cell lines. We then used a minimal volume of just 10 µL from 26 breast cancer biopsy samples which were aspirated to mimic fine needle aspirates. 20 samples were ER+, while 6 were ER-, representing 13 unique patients. We evaluated the potential of the nanosensor by investigating several SWCNT chiralities through direct incubation or fractionation deployment methods. We found that the nanosensor can differentiate ER-from ER+ patient biopsies through a shift in its center wavelength upon sample addition. This was true regardless of which of the three SWCNT chiralities we observed. Receiver operating characteristic area under the curve analyses determined that the strongest classifier with an AUC of 0.94 was the (7,5) chirality after direct incubation and measurement, and without further processing. We anticipate that further testing and development of this nanosensor may push its utility toward field-deployable, rapid ER subtyping with potential for additional molecular marker profiling."
715,Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer,"Jeffrey Barr, Austin Walz, Anthony C. Restaino, Moran Amit, Sarah M. Barclay, Elisabeth G. Vichaya, William C. Spanos, Robert Dantzer, Sebastien Talbot, Paola D. Vermeer",https://www.biorxiv.org/content/10.1101/2023.10.18.562990v3,"Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a mouse model for head and neck cancer and neuronal tracing we show that tumor-infiltrating nerves connect to distinct brain areas. The activation of this neuronal circuitry altered behaviors (decreased nest-building, increased latency to eat a cookie, and reduced wheel running). Tumor-infiltrating nociceptor neurons exhibited heightened calcium activity and brain regions receiving these neural projections showed elevated Fos as well as increased calcium responses compared to non-tumor-bearing counterparts."
716,CDHu40: a novel marker gene set of neuroendocrine prostate cancer (NEPC),"Sheng Liu, Hye Seung Nam, Ziyu Zeng, Xuehong Deng, Elnaz Pashaei, Yong Zang, Lei Yang, Chenglong Li, Jiaoti Huang, Michael K Wendt, Xin Lu, Rong Huang, Jun Wan",https://www.biorxiv.org/content/10.1101/2024.03.28.587205v1,"Prostate cancer (PCa) is the most prevalent cancer affecting American men. Castration-resistant prostate cancer (CRPC) can emerge during hormone therapy for PCa, manifesting with elevated serum prostate-specific antigen (PSA) levels, continued disease progression, and/or metastasis to the new sites, resulting in a poor prognosis. A subset of CRPC patients shows a neuroendocrine (NE) phenotype, signifying reduced or no reliance on androgen receptor (AR) signaling and a particularly unfavorable prognosis. In this study, we incorporated computational approaches based on both gene expression profiles and protein-protein interaction (PPI) networks. We identified 500 potential marker genes, which are significantly enriched in cell cycle and neuronal processes. The top 40 candidates, collectively named as CDHu40, demonstrated superior performance in distinguishing NE prostate cancer (NEPC) and non-NEPC samples based on gene expression profiles compared to other published marker sets. Notably, some novel marker genes in CDHu40, absent in the other marker sets, have been reported to be associated with NEPC in the literature, such as DDC, FOLH1, BEX1, MAST1, and CACNA1A. Importantly, elevated CDHu40 scores derived from our predictive model showed a robust correlation with unfavorable survival outcomes in patients, indicating the potential of the CDHu40 score as a promising indicator for predicting the survival prognosis of those patients with the NE phenotype. Motif enrichment analysis on the top candidates suggests that REST and E2F6 may serve as key regulators in the NEPC progression."
717,Transcriptional stress induces the generation of DoGs in cancer cells,"Francisco Ríos, Maritere Urióstegui-Arcos, Mario Zurita",https://www.biorxiv.org/content/10.1101/2023.11.15.567248v1,"A characteristic of the cellular response to stress, is the production of RNAs generated from readthrough transcription of genes, called downstream-of-gene-(DoG) containing transcripts. Additionally, transcription inhibitor drugs are candidates for fighting cancer. In this work, we report the results of a bioinformatic analysis showing that one of the responses to transcription inhibition is the generation of DoGs in cancer cells. Although some genes that form DoGs were shared between the two cancer lines, there did not appear to be a functional correlation between them. However, our findings show that DoGs are generated as part of the cellular response to transcription inhibition like other types of cellular stress, suggesting that it may be part of the defense against transcriptional stress."
719,TAD hierarchy restricts poised LTR activation and loss of TAD hierarchy promotes LTR co-option in cancer,"Elissa W. P. Wong, Merve Sahin, Rui Yang, UkJin Lee, Yingqian A. Zhan, Rohan Misra, Fanny Tomas, Nawaf Alomran, Alexander Polyzos, Cindy J. Lee, Tuan Trieu, Alexander M. Fundichely, Thomas Wiesner, Andrew Rosowicz, Shuyuan Cheng, Christina Liu, Morgan Lallo, Taha Merghoub, Pierre-Jacques Hamard, Richard Koche, Ekta Khurana, Effie Apostolou, Deyou Zheng, Yu Chen, Christina S. Leslie, Ping Chi",https://www.biorxiv.org/content/10.1101/2024.05.31.596845v1,"Transposable elements (TEs) are abundant in the human genome, and they provide the sources for genetic and functional diversity. The regulation of TEs expression and their functional consequences in physiological conditions and cancer development remain to be fully elucidated. Previous studies suggested TEs are repressed by DNA methylation and chromatin modifications. The effect of 3D chromatin topology on TE regulation remains elusive. Here, by integrating transcriptome and 3D genome architecture studies, we showed that haploinsufficient loss of NIPBL selectively activates alternative promoters at the long terminal repeats (LTRs) of the TE subclasses. This activation occurs through the reorganization of topologically associating domain (TAD) hierarchical structures and recruitment of proximal enhancers. These observations indicate that TAD hierarchy restricts transcriptional activation of LTRs that already possess open chromatin features. In cancer, perturbation of the hierarchical chromatin topology can lead to co-option of LTRs as functional alternative promoters in a context-dependent manner and drive aberrant transcriptional activation of novel oncogenes and other divergent transcripts. These data uncovered a new layer of regulatory mechanism of TE expression beyond DNA and chromatin modification in human genome. They also posit the TAD hierarchy dysregulation as a novel mechanism for alternative promoter-mediated oncogene activation and transcriptional diversity in cancer, which may be exploited therapeutically."
721,PIWIL1 is recruited to Centrosomes during Mitosis in Colorectal Cancer Cells and is linked to cell cycle progression,"M.R. Garcia-Silva, S. Montenegro, S. Dacosta, J.P. Tosar, A Cayota",https://www.biorxiv.org/content/10.1101/2024.06.04.597425v1,"PIWI proteins, traditionally associated with germline development, have recently gained attention for their expression in various cancers, including colorectal cancer (CRC). However, the molecular mechanisms underlying their reactivation and impact on cancer initiation and progression remain elusive. Here, we found that PIWIL1 is expressed at relatively high levels in CRC-derived samples and cell lines, where it undergoes a dynamic re-localization to the centrosome during mitosis. Knockdown of PIWIL1 induces G2/M arrest associated to disruption of mitotic spindle and aberrant metaphase events, highlighting its role in cell cycle progression. We have also found that expression of PIWIL1 is lost during differentiation of Caco-2 cells into enterocytes and that PIWIL1 is expressed in cells at the base of intestinal crypts in normal human colon tissue, where intestinal stem cells are known to reside. Thus, it is possible that the presence of PIWIL1 in cancer cells reflects a physiological role of this protein in stem cell maintenance, what would argue in favor of the proposed stem cell origin of CRC. Supporting this view, dedifferentiation of human fibroblasts into induced pluripotent stem cells (iPSc) implies reactivation of PIWIL2 expression, another member of the PIWI protein family. Overall, our findings suggest a role of PIWIL1 in mediating cell cycle dynamics, both in colorectal cancer cells and possibly also in intestinal stem cells. In a broader aspect, we provide support for an involvement of PIWI proteins in somatic stem cell maintenance, expanding nongonadal functions for this protein family."
722,Computational Identification of Potential Inhibitors Targeting cdk1 in Colorectal Cancer,"Uchechukwu C. Ogbodo, Ojochenemi A. Enejoh, Chinelo H. Okonkwo, Pranavathiyani Gnanasekar, Pauline W. Gachanja, Shamim Osata, Halimat C. Atanda, Emmanuel A. Iwuchukwu, Ikechukwu Achilonu, Olaitan I. Awe",https://www.biorxiv.org/content/10.1101/2023.11.09.566358v1,"Despite improved treatment options, colorectal cancer (CRC) remains a huge public health concern with a significant impact on affected individuals. Cell cycle dysregulation and overexpression of certain regulators and checkpoint activators are important recurring events in the progression of cancer. Cyclin-dependent kinase 1 (CDK1), a key regulator of the cell cycle component central to the uncontrolled proliferation of malignant cells, has been reportedly implicated in CRC. This study aimed to identify CDK1 inhibitors with potential for clinical drug research in CRC. Ten thousand (10,000) naturally occurring compounds were evaluated for their inhibitory efficacies against CDK1 through molecular docking studies. The stability of the lead compounds in complex with CDK1 was evaluated using molecular dynamics simulation for one thousand (1,000) nanoseconds. The top-scoring candidates’ ADME characteristics and drug-likeness were profiled using SwissADME. Four hit compounds namely spiraeoside, robinetin, 6-hydroxyluteolin, and quercetagetin were identified from molecular docking analysis to possess the least binding scores. Molecular dynamics simulation revealed that robinetin and 6-hydroxyluteolin complexes were stable within the binding pocket of the CDK1 protein. The findings from this study provide insight into novel candidates with specific inhibitory CDK1 activities that can be further investigated through animal testing, clinical trials, and drug development research for CRC treatment."
724,Characterization of immune cell populations in the tumor microenvironment of colorectal cancer using high definition spatial profiling,"Michelli F. Oliveira, Juan P. Romero, Meii Chung, Stephen Williams, Andrew D. Gottscho, Anushka Gupta, Susan E. Pilipauskas, Syrus Mohabbat, Nandhini Raman, David Sukovich, David Patterson, Visium HD Development Team, Sarah E. B. Taylor",https://www.biorxiv.org/content/10.1101/2024.06.04.597233v1,"Colorectal cancer (CRC) is the second-deadliest cancer in the world, yet a deeper understanding of spatial patterns of gene expression in the tumor microenvironment (TME) remains elusive. Here, we introduce the Visium HD platform (10x Genomics) and use it to investigate human CRC and normal adjacent mucosal tissues from formalin fixed paraffin embedded (FFPE) samples. The first assay available on Visium HD is a probe-based spatial transcriptomics workflow that was developed to enable whole transcriptome single cell scale analysis. We demonstrate highly refined unsupervised spatial clustering in Visium HD data that aligns with the hallmarks of colon tissue morphology and is notably improved over earlier Visium assays. Using serial sections from the same FFPE blocks we generate a single cell atlas of our samples, then we integrate the data to comprehensively characterize the immune cell types present in the TME, specifically at the tumor periphery. We observed enrichment of two pro-tumor macrophage subpopulations with differential gene expression profiles that were localized within distinct tumor regions. Further characterization of the T cells present in one of the samples revealed a clonal expansion that we were able to localize in the tissue using in situ gene expression analysis. In situ analysis also allowed us to perform in-depth characterization of the microenvironment of the clonally expanded T cell population and we identified a third macrophage subpopulation with gene expression profiles consistent with an anti-tumor response. Our study provides a comprehensive map of the cellular composition of the CRC TME and identifies phenotypically and spatially distinct immune cell populations within it. We show that the single cell-scale resolution afforded by Visium HD and the whole transcriptome nature of the assay allows investigations into cellular function and interaction at the tumor periphery in FFPE tissues, which has not been previously possible."
725,Spatially resolved niche and tumor microenvironmental alterations in gastric cancer peritoneal metastases,"Joseph J. Zhao, Johnny Chin-Ann Ong, Supriya Srivatsava, Daryl Kai Ann Chia, Haoran Ma, Kiekyon Huang, Taotao Sheng, Kalpana Ramnarayanan, Xuewen Ong, Su Ting Tay, Takeshi Hagihara, Angie Lay Keng Tan, Melissa Ching Ching Teo, Qiu Xuan Tan, Gillian Ng, Joey Wee-Shan Tan, Matthew Chau Hsien Ng, Yong Xiang Gwee, Robert Walsh, Asim Shabbir, Guowei Kim, Yvonne Tay, Zhisheng Her, Giuseppe Leoncini, Bin Tean Teh, Jing Han Hong, Ryan Yong Kiat Tay, Chong Boon Teo, Mark P. G. Dings, Maarten Bijlsma, Jeffrey Huey Yew Lum, Jia Hao Law, Filippo Pietrantonio, Steven M. Blum, Hanneke van Laarhoven, Samuel J. Klempner, Wei Peng Yong, Jimmy Bok Yan So, Qingfeng Chen, Patrick Tan, Raghav Sundar",https://www.biorxiv.org/content/10.1101/2024.03.21.585686v1,"Peritoneal metastases (PM) in gastric cancer (GC) portend a poor prognosis, yet our understanding of tumor microenvironmental (TME) characteristics associated with GCPM remain limited. Here, we analyzed intrinsic genomic alterations and transcriptomic programs predictive of GCPM in a prospective cohort of 248 patients, identifying CDH1, PIGR, and ELF3 mutations as predictors. By inspecting the spatial dynamics of the TME, we find that tumor compartment infiltration of pro-tumorigenic cell types such as inflammatory cancer-associated fibroblasts (CAFs) predict peritoneal recurrence. Next, in a cross-sectional study of 205 samples from 55 patients, distinct pathways and immune compositions in GCPM relative to liver metastases highlight the TME’s significance in transcoelomic metastases. Notably, several putative therapeutic targets exhibited distinct expression patterns between PTs and PMs. We also observed increased immune infiltration in GCPMs treated with systemic immunotherapy and intraperitoneal chemotherapy. Our findings highlight transcriptomic variations and niche reprogramming in the GCPM peritoneal environment, revealing roles of myeloid dendritic cells, effector memory CD8+ T cells, and CAFs in metastatic progression."
726,Identifying and targeting key driver genes for collagen production within the 11q13/14 breast cancer amplicon,"Daniela Araiza-Olivera, Tatiana Y. Prudnikova, Cristina Uribe-Alvarez, Kathy Q. Cai, Janusz Franco-Barraza, Jesús M. Dones, Ronald T. Raines, Jonathan Chernoff",https://www.biorxiv.org/content/10.1101/2024.03.27.587019v1,"Genetic studies indicate that breast cancer can be divided into several basic molecular groups. One of these groups, termed IntClust-2, is characterized by amplification of a small portion of chromosome 11 and has a median survival of only five years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study we used a gene editing method to knock out, one by one, each of 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1, we identified two different genes (SERPINH1 and P4HA3), that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function on IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers."
727,Stable and Oscillatory Hypoxia Differentially Regulate Invasibility of Breast Cancer Associated Fibroblasts,"Wenqiang Du, Ashkan Novin, Yamin Liu, Junaid Afzal, Shaofei Liu, Yasir Suhail, Kshitiz",https://www.biorxiv.org/content/10.1101/2024.03.26.586706v1,"As local regions in the tumor outstrip their oxygen supply, hypoxia can develop, affecting not only the cancer cells, but also other cells in the microenvironment, including cancer associated fibroblasts (CAFs). Hypoxia is also not necessarily stable over time, and can fluctuate or oscillate. Hypoxia Inducible Factor-1 is the master regulator of cellular response to hypoxia, and can also exhibit oscillations in its activity. To understand how stable, and fluctuating hypoxia influence breast CAFs, we measured changes in gene expression in CAFs in normoxia, hypoxia, and oscillatory hypoxia, as well as measured change in their capacity to resist, or assist breast cancer invasion. We show that hypoxia has a profound effect on breast CAFs causing activation of key pathways associated with fibroblast activation, but reduce myofibroblast activation and traction force generation. We also found that oscillatory hypoxia, while expectedly resulted in a “sub-hypoxic” response in gene expression, it resulted in specific activation of pathways associated with actin polymerization and actomyosin maturation. Using traction force microscopy, and a nanopatterned stromal invasion assay, we show that oscillatory hypoxia increases contractile force generation vs stable hypoxia, and increases heterogeneity in force generation response, while also additively enhancing invasibility of CAFs to MDA-MB-231 invasion. Our data show that stable and unstable hypoxia can regulate many mechnobiological characteristics of CAFs, and can contribute to transformation of CAFs to assist cancer dissemination and onset of metastasis."
728,Patient-derived response estimates from zero-passage organoids of luminal breast cancer,"Róża K Przanowska, Najwa Labban, Piotr Przanowski, Russell B Hawes, Kristen A Atkins, Shayna L Showalter, Kevin A Janes",https://www.biorxiv.org/content/10.1101/2024.03.24.586432v1,"Background Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations."
729,Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules,"Phillip Thienger, Philip D. Rubin, Xiaosai Yao, Andrej Benjak, Sagar R. Shah, Alden King-Yung Leung, Simone de Brot, Alina Naveed, Minyi Shi, Julien Tremblay, Joanna Triscott, Giada Cassanmagnago, Marco Bolis, Lia Mela, Himisha Beltran, Yu Chen, Salvatore Piscuoglio, Haiyuan Yu, Charlotte K Y Ng, Robert L. Yauch, Mark A. Rubin",https://www.biorxiv.org/content/10.1101/2024.03.24.586276v1,"The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex is frequently deregulated during progression to castration-resistant prostate cancer (CRPC). Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent CRPC (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF ATPase targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT), which accounts for about 10% of all clinical CRPC cases. In CRPC-WNT models, we discovered that SWI/SNF ATPase SMARCA4 depletion interfered with WNT signaling via the master transcriptional regulator TCF7L2 (TCF4). Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC by forming a complex with β-Catenin and AP-1 transcription factor c-JUN. These data suggest a mechanistic rationale for MAPK inhibition or interventions that disrupt the formation of the pro-proliferative TCF7L2-β-Catenin-JUN complex in the CRPC-WNT subclass of advanced prostate cancer."
730,An interpretable integration model improving disease-free survival prediction for gastric cancer based on CT images and clinical parameters,"Xiaoping Cen, Can Hu, Li Yuan, Xiangdong Cheng, Wei Dong, Run Zhou, Yuanmei Wang, Jiansheng Zou, Tianyu Lu, Huanming Yang, Yahan Tong",https://www.biorxiv.org/content/10.1101/2024.04.01.587508v2,"Preoperative prediction of disease-free survival of gastric cancer is significantly important in clinical practice. Existing studies showed the potentials of CT images in identifying predicting the disease-free survival of gastric cancer. However, no studies to date have combined deep features with radiomics features and clinical features. In this study, we proposed a model which embedded radiomics features and clinical features into deep learning model for improving the prediction performance. Our models showed a 3%-5% C-index improvement and 10% AUC improvement in predicting DFS and disease event. Interpretation analysis including T-SNE visualization and Grad-CAM visualization revealed that the model extract biologically meaning features, which are potentially useful in predicting disease trajectory and reveal tumor heterogeneity. The embedding of radiomics features and clinical features into deep learning model could guide the deep learning to learn biologically meaningful information and further improve the performance on the DFS prediction of gastric cancer. The proposed model would be extendable to related problems, at least in few-shot medical image learning."
731,Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response,"Gioia Heravi, Zhenjie Liu, Mackenzie Herroon, Alexis Wilson, Yang-Yi Fan, Yang Jiang, Nivisa Vakeesan, Li Tao, Zheyun Peng, Kezhong Zhang, Jing Li, Robert S. Chapkin, Izabela Podgorski, Wanqing Liu",https://www.biorxiv.org/content/10.1101/2024.03.23.586426v1,"Monounsaturated fatty acids (MUFAs) play a pivotal role in maintaining endoplasmic reticulum (ER) homeostasis, an emerging hallmark of cancer. However, the role of polyunsaturated fatty acid (PUFAs) desaturation in persistent ER stress driven by oncogenic abnormalities remains elusive. Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain PUFAs. Our previous research has demonstrated the significant role of FADS1 in cancer survival, especially in kidney cancers. We explored the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 effectively inhibits renal cancer cell proliferation and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we show that while FADS1 inhibition induces ER stress, its expression is also augmented by ER-stress inducers. Notably, FADS1-inhibition sensitized cellular response to ER stress inducers, providing evidence of FADS1’s role in modulating the ER stress response in cancer cells. We show that, while FADS1 inhibition-induced ER stress leads to activation of ATF3, ATF3-knockdown rescues the FADS1 inhibition-induced ER stress and cell growth suppression. In addition, FADS1 inhibition results in the impaired biosynthesis of nucleotides and decreases the level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target."
732,A novel visual analysis interface enables integrative analyses of cancer transcriptomics data and iden-tifies potential markers of immunotherapy response via machine learning,"M. Emre Kus, Cagatay Sahin, Emre Kilic, Arda Askin, M. Mert Ozgur, Gokhan Karahanogulları, Ahmet Aksit, Ryan M. O’Connell, H. Atakan Ekiz",https://www.biorxiv.org/content/10.1101/2023.08.14.553075v2,"The Cancer Genome Atlas (TCGA) initiative has been essential for revealing key mechanisms in human cancer leading to the development of novel therapeutics. Analysis of the cancer transcriptomics data in the TCGA and other public repositories require coding skills that are associated with a steep learning curve for most non-specialists. To enable a wider utilization of these data, we introduce The Cancer Genome Explorer (TCGEx), a web-based visual data analysis interface that can perform a number of sophisticated analyses ranging from survival modeling and gene set enrichment analysis to unsupervised clustering and linear regression-based machine learning. In addition to providing access to preprocessed data from TCGA and immune checkpoint inhibition studies on cBioportal and CRI-iAtlas, the TCGEx platform allows users to upload and investigate their own data. Using this tool, we investigated the molecular subsets of human melanoma and identified microRNAs associated with intratumoral interferon signaling. We validated these findings using independent data from clinical trials involving immune check-point inhibitors for melanoma and other cancers. Moreover, our analyses unveiled a subset of cytokines predictive of positive responses to diverse immune checkpoint inhibitors prior to treatment initiation. Built on the R/Shiny framework, TCGEx modules offer customizable features to tailor the analysis to different study contexts and help generate publication-ready plots. TCGEx is freely available at https://tcgex.iyte.edu.tr, and it provides an interactive solution to extract meaningful insights from cancer transcriptomics data and guide scientific inquiry."
733,TCCIA: A Comprehensive Resource for Exploring CircRNA in Cancer Immunotherapy,"Shixiang Wang, Yi Xiong, Yihao Zhang, Haitao Wang, Minjun Chen, Jianfeng Li, Peng Luo, Yung-Hung Luo, Markus Hecht, Benjamin Frey, Udo S Gaipl, Xuejun Li, Qi Zhao, Hu Ma, Jian-Guo Zhou",https://www.biorxiv.org/content/10.1101/2023.08.24.554049v2,"Background Immunotherapies targeting immune checkpoints have gained increasing attention in cancer treatment, emphasizing the need for predictive biomarkers. Circular RNAs (circRNAs) have emerged as critical regulators of tumor immunity, particularly in the PD-1/PD-L1 pathway, and have shown potential in predicting immunotherapy efficacy. Yet, the detailed roles of circRNAs in cancer immunotherapy are not fully understood. While existing databases focus on either circRNA profiles or immunotherapy cohorts, there is currently no platform that enables the exploration of the intricate interplay between circRNAs and anti-tumor immunotherapy. A comprehensive resource combining circRNA profiles, immunotherapy responses, and clinical outcomes is essential to advance our understanding of circRNA-mediated tumor-immune interactions and to develop effective biomarkers."
734,Protein structural context of cancer mutations reveals molecular mechanisms and identifies novel candidate driver genes,"Diego Chillón Pino, Mihaly Badonyi, Colin A. Semple, Joseph A. Marsh",https://www.biorxiv.org/content/10.1101/2024.03.21.586131v1,"Advances in structure determination and computational modelling are enabling us to study the protein structural context of human genetic variants at an unprecedented scale. Here, we investigate millions of human cancer-associated missense mutations in terms of their structural locations and predicted perturbative effects. We find that, while cancer-driving mutations have properties similar to other known disease-causing mutations, this is obscured by the abundance of passenger mutations in cancer sequencing datasets. Nevertheless, by considering the collective properties of mutations at the level of individual proteins, we identify distinct mutational signatures associated with tumour suppressors and oncogenes. Tumour suppressors are enriched in structurally damaging mutations, consistent with loss-of-function mechanisms. In contrast, oncogene mutations tend to be structurally mild, reflecting selection for gain-of-function driver mutations and against loss-of-function mutations. Although oncogenes are difficult to distinguish from genes with no role in cancer using only structural damage, we find that an alternate metric based on the clustering of mutations in three-dimensional space is highly predictive of oncogenes, particularly when mutation recurrence is considered. These observations allow us to identify novel candidate driver genes and speculate about their molecular roles, which we expect to have general utility in the analysis of cancer sequencing data."
735,Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy,"Or-Yam Revach, Angelina M. Cicerchia, Ofir Shorer, Boryana Petrova, Seth Anderson, Joshua Park, Lee Chen, Arnav Mehta, Samuel J. Wright, Niamh McNamee, Aya Tal-Mason, Giulia Cattaneo, Payal Tiwari, Hongyan Xie, Johanna M. Sweere, Li-Chun Cheng, Natalia Sigal, Elizabeth Enrico, Marisa Miljkovic, Shane A. Evans, Ngan Nguyen, Mark E. Whidden, Ramji Srinivasan, Matthew H. Spitzer, Yi Sun, Tatyana Sharova, Aleigha R. Lawless, William A. Michaud, Martin Q. Rasmussen, Jacy Fang, Claire A. Palin, Feng Chen, Xinhui Wang, Cristina R. Ferrone, Donald P. Lawrence, Ryan J. Sullivan, David Liu, Uma M. Sachdeva, Debattama R. Sen, Keith T. Flaherty, Robert T. Manguso, Lloyd Bod, Manolis Kellis, Genevieve M. Boland, Keren Yizhak, Jiekun Yang, Naama Kanarek, Moshe Sade-Feldman, Nir Hacohen, Russell W. Jenkins",https://www.biorxiv.org/content/10.1101/2024.02.12.579184v3,"A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma1,2. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance3. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models."
736,Tissue-resident NK cells support survival in pancreatic cancer through promotion of cDC1-CD8T activity,"Simei Go, Constantinos Demetriou, Giampiero Valenzano, Sophie Hughes, Simone Lanfredini, Helen Ferry, Edward Arbe-Barnes, Shivan Sivakumar, Rachael Bashford-Rogers, Mark R. Middleton, Somnath Mukherjee, Jennifer Morton, Keaton Jones, Eric O’Neill",https://www.biorxiv.org/content/10.1101/2023.10.14.562332v2,"The immunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC) prevents tumor control and strategies to restore anti-cancer immunity (i.e. by increasing CD8 T cell activity) have had limited success. Here we demonstrate how inducing localized physical damage using ionizing radiation (IR) unmasks the benefit of immunotherapy by increasing tissue-resident NK (trNK) cells that support CD8 T activity. Our data confirms that targeting mouse orthotopic PDAC tumors with IR together with CCR5 inhibition and PD1 blockade reduces E-cadherin positive tumor cells by recruiting a hypoactive NKG2D-ve NK population, phenotypically reminiscent of trNK cells, that supports CD8 T cell involvement. We show an equivalent population in human PDAC cohorts that represents immunomodulatory trNK cells that could similarly support CD8 T cell levels in a cDC1-dependent manner. Importantly, a trNK signature associates with survival in PDAC and solid malignancies revealing a potential beneficial role for trNK in improving adaptive anti-tumor responses and supporting CCR5i/αPD1 and IR-induced damage as a novel therapeutic approach."
737,Transcription network of SLC7A11 (xCT) in colon cancer provides clinical targets for metabolic regulation and cell proliferation,"Keren Zohar, Thomas Wartmann, Marco Strecker, Maximilian Doelling, Mihailo Andric, Wenjie Shi, Roland S Croner, Or Kakhlon, Yue Zhao, Ulf D Kahlert, Michal Linial",https://www.biorxiv.org/content/10.1101/2024.06.03.597098v1,"Colorectal cancer (CRC) represents the third leading cause of cancer-related deaths. Knowledge covering diverse cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present in-depth comparative RNA-seq analysis of 32 CRC patients pairing tumor and healthy tissues (total of 73 samples). Strict thresholds for differential expression genes (DEG) analysis revealed an interconnection between nutrients, metabolic program, and cell cycle pathways. Among the upregulated DEGs, we focused on the Xc- system, composed of the proteins from SLC7A11 (xCT) and SLC3A2 genes, along with several interacting genes. To assess the oncogenic potency of the Xc- system in a cellular setting, we applied a knowledge-based approach, analyzing gene perturbations from CRISPR screens. The study focused on a set of 27 co-dependent genes that were strongly correlated with the fitness of SLC7A11 and SLC3A2 across many cell types. Alterations in these genes in 13 large-scale studies (e.g., by mutations and copy number variation) were found to enhance overall survival and progression-free survival in CRC patients. In agreement, the overexpression of these genes in cancer cells drives cancer progression by allowing effective management of the redox level, induction of stress response mechanisms, and most notably, enhanced activity of ion/amino acid transporters, and enzymes acting in de novo nucleotide synthesis. We also highlight the positive correlation between the Xc- system gene expression level, patient responsiveness to different chemotherapy treatments, and immune cell infiltration (e.g., myeloid-derived suppressor cells) in CRC tumors as a measure for their immunosuppressive activity. This study illustrates that knowledge-based interpretation by synthesizing multiple layers of data leads to functional and mechanistic insights into the role of SLC7A11 and its associated genes in CRC tumorigenesis and therapeutics."
738,"Robust diagnosis of infectious disease, autoimmunity and cancer from the paratope networks of adaptive immune receptors","Zichang Xu, Hendra S Ismanto, Dianita S Saputri, Soichiro Haruna, Guanqun Sun, Jan Wilamowski, Shunsuke Teraguchi, Ayan Sengupta, Songling Li, Daron M Standley",https://www.biorxiv.org/content/10.1101/2023.11.28.569125v5,"Liquid biopsies based on peripheral blood offer a minimally invasive alternative to solid tissue biopsies for the detection of diseases, primarily cancers. However, such tests currently consider only the serum component of blood, overlooking a potentially rich source of biomarkers: adaptive immune receptors (AIRs) expressed on circulating B and T cells. Machine learning-based classifiers trained on AIRs have been reported to accurately identify not only cancers, but also autoimmune and infectious diseases as well. However, when using the conventional “clonotype cluster” representation of AIRs, donors within a disease or healthy cohort exhibit vastly different features, limiting the generalizability of these classifiers. This paper addresses the challenge of classifying specific diseases from circulating B or T cells by developing a novel representation of AIRs based on similarity networks constructed from their antigen-binding regions (paratopes). Features based on this novel representation, paratope cluster occupancies (PCOs), significantly improved disease classification performance for infectious disease, autoimmunity and cancer. Under identical methodological conditions, classifiers trained on PCOs achieved a mean ROC AUC of 0.893 when applied to new donors, compared to clonotype cluster-based classifiers (0.714) or the best-performing published classifier (0.777). Surprisingly, for cancer patients, we observed that some of the AIRs that were important for classification were significantly more abundant in healthy controls than in individuals with disease. These “healthy-biased” AIRs were predicted to target known cancer-associated antigens at dramatically higher rates than healthy AIRs as a whole (Z scores > 75), suggesting the existence of an overlooked reservoir of cancer-targeting immune cells that are diagnostic and identifiable from a routine blood test. Consequently, PCOs not only enhance classification of a broad range of diseases but also identify immune cells with therapeutic potential."
739,"Generative Adversarial Networks Accurately Reconstruct Pan-Cancer Histology from Pathologic, Genomic, and Radiographic Latent Features","Frederick M. Howard, Hanna M. Hieromnimon, Siddhi Ramesh, James Dolezal, Sara Kochanny, Qianchen Zhang, Brad Feiger, Joseph Peterson, Cheng Fan, Charles M. Perou, Jasmine Vickery, Megan Sullivan, Kimberly Cole, Galina Khramtsova, Alexander T. Pearson",https://www.biorxiv.org/content/10.1101/2024.03.22.586306v1,"Artificial intelligence models have been increasingly used in the analysis of tumor histology to perform tasks ranging from routine classification to identification of novel molecular features. These approaches distill cancer histologic images into high-level features which are used in predictions, but understanding the biologic meaning of such features remains challenging. We present and validate a custom generative adversarial network – HistoXGAN – capable of reconstructing representative histology using feature vectors produced by common feature extractors. We evaluate HistoXGAN across 29 cancer subtypes and demonstrate that reconstructed images retain information regarding tumor grade, histologic subtype, and gene expression patterns. We leverage HistoXGAN to illustrate the underlying histologic features for deep learning models for actionable mutations, identify model reliance on histologic batch effect in predictions, and demonstrate accurate reconstruction of tumor histology from radiographic imaging for a ‘virtual biopsy’."
740,Altered liver metabolism post-wean abolishes efficacy of vitamin D for breast cancer prevention in a mouse model,"Sarah M Bernhardt, Michelle K Ozaki, Courtney Betts, Lisa A Bleyle, Andrea E DeBarber, Jaime Fornetti, Abigail L Liberty, Elise De Wilde, Yi Zhang, Zheng Xia, Pepper Schedin",https://www.biorxiv.org/content/10.1101/2024.05.28.596304v1,"Young women have increased risk of vitamin D deficiency, which may increase breast cancer incidence. Here, we assessed the anti-cancer efficacy of vitamin D in mouse models of young-onset breast cancer. In never-pregnant mice, vitamin D supplementation increased serum 25(OH)D and hepatic 1,25(OH)2D3, reduced tumor size, and associated with anti-tumor immunity. These anti-tumor effects were not replicated in a mouse model of postpartum breast cancer, where hepatic metabolism of vitamin D was suppressed post-wean, which resulted in deficient serum 25(OH)D and reduced hepatic 1,25(OH)2D3. Treatment with active 1,25(OH)2D3 induced hypercalcemia exclusively in post-wean mice, highlighting metabolic imbalance post-wean. RNAseq revealed suppressed CYP450 expression postpartum. In sum, we provide evidence that vitamin D anti-tumor activity is mediated through immunomodulatory mechanisms and is ineffective in the post-wean window due to altered hepatic metabolism. These findings have implications for suppressed xenobiotic metabolism in postpartum women beyond vitamin D."
741,Analysis of gene expression profiles to elucidate racial differences in African American and White patients with Triple-negative breast cancer,"Hailey McAndrew, Jessica Rigler, Suneetha Yeguvapalli, Kumaraswamy Naidu Chitrala",https://www.biorxiv.org/content/10.1101/2024.05.29.596478v1,"Triple-negative breast cancer (TNBC) is the second most diagnosed subtype of breast cancer. It is known to be the most aggressive one that lacks known targetable receptors. One of the concerns in TNBC is the disparities in its prevalence and tumor pathogenesis among women with non-Hispanic African American backgrounds. Despite extensive research, the genetic underpinnings that lead to these disparities remain elusive. The current study aims to provide initiative for further clinical research in the development of targeted therapy for TNBC. Gene expression profiles from African American (AA) and European American (EA) patients with TNBC were collected from Gene Expression Omnibus and performed differential gene expression (DEG)analysis. Candidate genes for a significant correlation between expression and survival rates for breast invasive carcinoma were analyzed using UALCAN. The DAVID annotation tool, Enrichr web server, KEGG database, and Gene Ontology (GO) database were used for functional enrichment analysis of target genes. The Network Analyst server was used to identify ligands with strong affinities, SeamDock server for molecular docking between the biomarkers/associated ligands and examined protein-protein interactions (PPI) from the STRING server. Data from public breast cancer cohorts was utilized to identify expression patterns associated with poor survival outcomes of AA patients with TNBC. Our results showed three genes of interest (CCT3, LSM2, and MRPS16) and potential ligands for molecular docking. Molecular docking was performed for the ICG001 ligand to CCT3 (binding affinities of -9.3 kcal/mol and -8.9 kcal/mol) and other interacting proteins (CDC20 and PPP2CA) with high degrees of connectivity. The results determined molecular docking of ICG001 to the CDC20 protein resulted in the highest binding affinity. Our results demonstrated that CCT3 and its interacting partners could serve as potential biomarkers due to their association with the survival outcome of AA patients with TNBC and ICG 001 could be the therapeutic lead for these biomarkers."
742,Multicompartmentalized microvascularized tumor-on-a-chip to study tumor-stroma interactions and drug resistance in ovarian cancer,"Simona Plesselova, Kristin Calar, Hailey Axemaker, Emma Sahly, Pilar de la Puente",https://www.biorxiv.org/content/10.1101/2024.05.29.596456v1,"Introduction The majority of ovarian cancer (OC) patients receiving standard of care chemotherapy develop chemoresistance within 5 years. The tumor microenvironment (TME) is a dynamic and influential player in disease progression and therapeutic response. However, there is a lack of models that allow us to elucidate the compartmentalized nature of TME in a controllable, yet physiologically relevant manner and its critical role in modulating drug resistance."
745,Antiproliferative Activity of Cephalotaxus Esters: Overcoming Chemoresistance in Cancer Therapy,"Vladimir Yong-Gonzalez, Constantine Radu, Paul A. Calder, David Shum, David Y. Gin, Mark G. Frattini, Hakim Djaballah",https://www.biorxiv.org/content/10.1101/2023.11.06.565820v1,"Omacetaxine, a semisynthetic form of Homoharringtonine (HHT), was approved for the treatment of chronic myeloid leukemia (CML). Previously, we published the synthesis of this natural alkaloid and three of its derivatives: deoxyharringtonine (DHT), deoxyhomoharringtonine (DHHT), and bis(demethyl)-deoxyharringtonine (BDHT); and reported on its refractory activity against the HL-60/RV+ cells over-expressing P-glycoprotein 1 (MDR1). In this study, we explored the extent of this resistance by first expanding the panel of established cell lines and second, using a panel of 21 leukemia patient derived primary cells. Here, we report a consistent resistance to HTT in K562 derived cells and in MES-SA/MX2 derived cells resistant to mitoxanthrone; all of them over-express MDR1, while we found U87MG-ABCG2 and H69AR cells to be very sensitive to HTT. In contrast, DHT, DHHT, and BDHT seemingly overcome this resistance due to the changes made to the acyl chain of HTT rendering the derivatives less susceptible to efflux. Surprisingly, the leukemia primary cells were very sensitive to HHT and its derivatives with low nanomolar potencies, followed by a new class of CDC7 kinase inhibitors, the anthracycline class of topoisomerase inhibitors, the DNA intercalator actinomycin-D, and the vinca alkaloid class of microtubule inhibitors. The mechanism of cell death induced by HTT and DHHT was found to be mediated via Caspase 3 cleavage leading to apoptosis. Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers."
746,A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy,"Bocheng Wu, Subhasish Tapadar, Zhiping Ruan, Carrie Q. Sun, Rebecca S. Arnold, Alexis Johnston, Jeremiah O. Olugbami, Uche Arunsi, David A. Gaul, John A. Petros, Tatsuya Kobayashi, Dan G. Duda, Adegboyega K. Oyelere",https://www.biorxiv.org/content/10.1101/2024.03.27.587062v2,"Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs — an effective treatment for lymphomas — has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 (3) showed a favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, STR-V-53 showed greater in vivo efficacy. Moreover, STR-V-53 combined with anti-PD1 therapy increased the CD8+ to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Transcriptomic analysis revealed that STR-V-53 primed HCC cells to immunotherapy through HDAC inhibition, impaired glucose-regulated transcription, impaired DNA synthesis, upregulated apoptosis, and stimulated the immune response pathway. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy."
747,Optimized LC-MS/MS method for Doxorubicin quantification: validating drug uptake and tumor reduction in zebrafish xenograft model of breast cancer,"Ghazala Rahman, Atanu Pramanik, Susmita Das, Anindya Roy, Anamika Bhargava",https://www.biorxiv.org/content/10.1101/2024.08.09.607268v1,"Doxorubicin, a potent chemotherapeutic drug, is widely used against various cancers, notably breast cancer. While its efficacy is well-documented, precise dosage determination in experimental models remains challenging. Zebrafish xenografts of various cancers confirm doxorubicin’s anti-cancerous effect; however, since doxorubicin treatment of zebrafish larva is done by adding doxorubicin to fish water, the precise chemotherapeutic dosage for zebrafish larva remains unknown. In this study, we provide a liquid chromatography tandem mass-spectrometry (LC-MS/MS) method for quantifying doxorubicin uptake in zebrafish larvae and thus provide a direct estimate of doses required for the therapeutic effect. Alongside quantification, we measured the therapeutic effect of doxorubicin in zebrafish larvae xenografted with triple negative breast cancer cell line, MDA-MB-231. LD50 value of doxorubicin was first determined by incubating 3-days post fertilization (dpf) larvae with different doses of doxorubicin for 72 h. Doxorubicin was quantified both from zebrafish larval homogenate and treatment solution. Analysis was performed by selected-reaction monitoring (SRM) scans in positive ionization mode. LD50 value for 72 h calculated to be 35.95 mg/L. As expected, doxorubicin-treated xenografts exhibited a significant reduction in tumor growth. The range of limit of detection (LOD) and limit of quantification (LOQ) for doxorubicin were 2 and 5 μg/L respectively. Intra- and inter-day accuracy was within the range of 82-114%. Overall, in this study we describe a reliable method for quantifying doxorubicin in zebrafish larvae. Our study facilitates precise dosage estimation, enhancing the relevance of zebrafish xenograft model in cancer research and potentially improving translational applications of chemotherapeutic treatments."
749,Bestrophin-4 relays Hes4 and interacts with Twist1 to suppress epithelial-to-mesenchymal transition in colorectal cancer cells,"Zijing Wang, Bihan Xia, Shaochong Qi, Xian Zhang, Xiaoshuang Zhang, Yan Li, Huimin Wang, Miao Zhang, Ziyi Zhao, David Kerr, Li Yang, Shijie Cai, Jinlin Yang",https://www.biorxiv.org/content/10.1101/2023.07.03.547525v2,"Bestrophin isoform 4 (BEST4) is a newly identified subtype of the calcium-activated chloride channel family. Analysis of colonic epithelial cell diversity by single cell RNA-sequencing has revealed the existence of a cluster of BEST4+ mature colonocytes in humans. However, if the role of BEST4 is involved in regulating tumour progression remains largely unknown. In this study, we demonstrate that BEST4 overexpression attenuates cell proliferation, colony formation, and mobility in colorectal cancer (CRC) in vitro, and impedes the tumor growth and the liver metastasis in vivo. BEST4 is coexpressed with hairy/enhancer of split 4 (Hes4) in the nucleus of cells, and Hes4 signals BEST4 by interacting with the upstream region of the BEST4 promoter. BEST4 is epistatic to Hes4 and downregulates Twist1, thereby inhibiting epithelial-to-mesenchymal transition (EMT) in CRC. Conversely, knockout of BEST4 using CRISPR/Cas9 in CRC cells revitalises tumor growth and induces EMT. Furthermore, the low level of the BEST4 mRNA is correlated with advanced and the worse prognosis, suggesting its potential role in regulating CRC progression."
750,Machine Learning Approaches in Label-Free Small Extracellular Vesicles Analysis with Surface-Enhanced Raman Scattering (SERS) for Cancer Diagnostics,"Der Vang, Maria S. Kelly, Manisha Sheokand, Manju Sharma, Leyla Esfandiari, Ruxandra I. Dima, Pietro Strobbia",https://www.biorxiv.org/content/10.1101/2024.02.19.581099v2,"Early diagnosis remains of pivotal importance in reducing patient morbidity and mortality in cancer. To this end, liquid biopsy is emerging as a tool to perform broad cancer screenings. Small extracellular vesicles (sEVs), also called exosomes, found in bodily fluids can serve as important cancer biomarkers in these screenings. Our group has recently developed a label-free electrokinetic microchip to purify sEVs from blood. Herein, we demonstrate the feasibility to integrate this approach with surface-enhanced Raman scattering (SERS) analysis. SERS can be used to characterized extracted sEVs through their vibrational fingerprint that changes depending on the origin of sEVs. While these changes are not easily identified in spectra, they can be modeled with machine learning (ML) approaches. Common ML approaches in the field of spectral analysis use dimensionality reduction method that often function as a black box. To avoid this pitfall, we used Shapley additive explanations (SHAP) is a type of explainable AI (XAI) that bridges ML models and human comprehension by calculating the specific contribution of individual features to a model’s predictions, directly correlating model/decisions with the original data. Using these approaches we demonstrated a proof-of-concept model predictive of cancer from isolated sEVs, integrating the electrokinetic device and SERS. This work explores the use of explainable AI to perform diagnostic analysis on complex SERS data of clinical samples, while reporting interpretable biochemical information."
751,Tissue-adjusted pathway analysis of cancer (TPAC),H. Robert Frost,https://www.biorxiv.org/content/10.1101/2022.03.17.484779v3,"We describe a novel single sample pathway analysis method for cancer transcriptomics data named tissue-adjusted pathway analysis of cancer (TPAC). The TPAC method leverages information about the normal tissue-specificity of human genes to compute a robust multivariate distance score that quantifies pathway dysregulation in each profiled tumor. Because the null distribution of the TPAC scores has an accurate gamma approximation, both population and sample-level inference is supported. As we demonstrate through an analysis of gene expression data from The Cancer Genome Atlas (TCGA), TPAC pathway scores are more strongly associated with both patient prognosis and tumor stage than the scores generated by existing single sample pathway analysis methods. An R package implementing the TPAC method can be found at https://hrfrost.host.dartmouth.edu/TPAC."
753,Bulky glycocalyx drives cancer invasiveness by modulating substrate-specific adhesion,"Amlan Barai, Niyati Piplani, V Gomathi, Mayank M Ghogale, Sushil Kumar, Madhura Kulkarni, Shamik Sen",https://www.biorxiv.org/content/10.1101/2023.08.03.551677v2,"Majority of the eukaryotic cell surface is decorated with a layer of membrane attached polysaccharides and glycoproteins collectively referred to as the glycocalyx. While formation of a bulky glycocalyx has been associated with cancer progression, the mechanisms by which the glycocalyx regulates cancer invasiveness is incompletely understood. We address this question by first documenting sub-type specific expression of the major glycocalyx glycoprotein Mucin-1 (MUC1) in breast cancer patient samples and breast cancer cell lines. Strikingly, glycocalyx disruption led to inhibition of 2D motility, loss of 3D invasion and reduction of clonal scattering of breast cancer cells at the population level. Tracking of 2D cell motility and 3D invasiveness of MUC1-based sorted sub-populations revealed fastest motility and invasiveness in intermediate MUC1-expressing cells, with glycocalyx disruption abolishing these effects. While differential sensitivity in 2D motility is attributed to a non-monotonic dependence of focal adhesion size on MUC1 levels, higher MUC1 levels enhance 3D invasiveness via increased traction generation. In contrast to inducing cell rounding on collagen-coated substrates, high MUC1 level promotes cell adhesion and confers resistance to shear flow on substrates coated with the endothelial surface protein E-selectin. Collectively, our findings illustrate how MUC1 drives cancer invasiveness by differentially regulating cell-substrate adhesion in a substrate-dependent manner."
754,Dissection and reconstruction of the colorectal cancer tumor microenvironment,"Nicolas Broguiere, Luis Francisco Lorenzo Martin, Simone Ragusa, François Rivest, Nathalie Brandenberg, Sylke Hoehnel-Ka, Devanjali Dutta, Marième Gueye, Daniel Alpern, Bart Deplancke, Lana Kandalaft, George Coukos, Krisztian Homicsko, Matthias P. Lutolf",https://www.biorxiv.org/content/10.1101/2023.11.01.565169v1,"Patient-derived organoids (PDOs) are the reference in vitro human disease models. However, the utility of colorectal cancer (CRC) PDOs is hindered by the lack of a tumor microenvironment (TME). To address this limitation, we built a living biobank of CRC PDOs with autologous stromal and immune TME. We characterized the original tumors and traditional monocultures using single-cell RNA-seq (scRNA-seq) and whole exome sequencing (WES) to obtain insights into cell type selection and phenotypic drift in culture. Subsequently, we developed culture conditions supporting all cell types to recapitulate the CRC-TME around PDOs. From the transcriptomes of >180k cells obtained from 260 such co-cultures, we illuminated the mutual influence of cells within CRC tumors. Based on original tumor data, atlases of predicted interactions and transcriptional networks elucidated why monocultures were altered and suggested that TME reconstruction more accurately reflected original tumor behavior. We found that inflammatory signals were absent in vitro and recovered upon co-culture with tumor-infiltrating lymphocytes (TILs). We also functionally confirmed that stromal, not cancer cells, mediated immune evasion. Additionally, stroma induced an invasive phenotype in cancer cells. From this deep dive into CRC-TME interactions, we built the human CRC-TME atlas (https://crc-tme.com/), an online portal for interactive exploration of gene expression data, prediction of cell-cell interactions at the pathway and receptor/ligand levels, transcriptional networks, and more. We anticipate PDO cultures with reconstructed TMEs will be valuable for discovery efforts, preclinical studies, and personalized medicine, with the atlas as a framework and inspiration for future CRC-TME studies."
755,How clinically relevant are prostate cancer cell lines? A comprehensive characterisation and multiomics comparison,"Zahra Ahmed, Warda Mosabbir, Devansh Tandon, Snehal Pinto Pereira, Umber Cheema, Marilena Loizidou, John Withington, Caroline Moore, Uzoamaka Okoli, Susan Heavey",https://www.biorxiv.org/content/10.1101/2024.03.20.585982v2,"Cell line experiments arguably remain the most used tool in preclinical cancer research, despite their limitations. With almost 95% drugs entering human trials failing, and up to 90% preclinical research failing before even being tested in humans, we must shift the pre-clinical paradigm. A range of in silico, in vitro, in vivo and ex vivo approaches are gaining popularity, with the aim of potentially replacing cell line use. However, we cannot ignore the plethora of historical data from cell lines, nor write off their future use– especially within advanced bioengineered models. Therefore, we must question if and how cell lines hold clinical relevance. This study evaluates the clinical characteristics of 46 prostate cancer cell lines against worldwide data and investigates the biological features of seven cell lines in depth, comparing them to over 10,000 well characterised human cases from 24 studies in nine countries. Clinical features compared included age, ethnicity, Gleason grade, cancer type, treatment history and multiomics variables included mutations, copy number alterations, structural variants, microsatellite instability, mRNA and protein expression, and tumour mutational burden. We found that the most used cell lines accurately represent a minute proportion of prostate cancer patients. Furthermore, we recommend a pipeline for tailoring selection of clinically relevant cell lines with the ultimate aim of increasing the scientific methodology behind choosing a cell line."
757,"Role of SCAL1 in Modulating Oxidative Stress, Cancer Stemness, Apoptotic Resistance in Tumorigenic Differentiation of Cigarette Smoke-Exposed BEAS-2B Cells","Debmalya Sengupta, Souradeep Banerjee, Mainak Sengupta",https://www.biorxiv.org/content/10.1101/2024.08.05.606632v1,"The smoke and cancer-associated lncRNA 1 (SCAL1) is an emergent biomarker in lung cancer. However, the precise role of SCAL1 as a mediator of tobacco smoke-induced lung carcinogenesis remains unclear. BEAS-2B cells were cultured and exposed to 20% cigarette smoke extract (CSE), followed by quantification of SCAL1. We evaluated the impact of SCAL1 on cell viability, ROS mitigation, cancer stemness, tumorigenic differentiation, cellular invasiveness, and apoptosis for different CSE incubation time points through SCAL1 expressional modulation using SCAL1-specific siRNAs and scrambled controls. We observed an upregulation of SCAL1 in cells exposed to CSE for 2, 4, and 6 hours, with the highest expression observed at 6 hours (p<0.001). Exposure of BEAS-2B cells to CSE showed the formation of focal adhesions and stress fibers resembling tunneling nanotubes. Intracellular ROS levels significantly increased upon CSE exposure compared to control cells (p<0.05). We found increased levels of anti-apoptotic and cancer stem (CSC) cell markers like BCL2, ALDH1A1, CD133, CD44, and TCTP and decreased levels of TP53 in CSE-exposed cells. Knockdown of SCAL1 using siRNA transfection reversed these effects at all time points. Additionally, we observed a significant decrease in the number of spheroid colonies in siSCAL1 (+) cells compared to siSCAL1 (-) cells (p<0.01) exposed to CSE. SCAL1 is pivotal in mediating cellular responses to cigarette smoke, leading to tumorigenic differentiation of BEAS-2B cells. Understanding the mechanisms could provide valuable insights into lung cancer pathogenesis and therapeutic approaches."
758,A regulatory B cell subpopulation expressing CD301b lectin promotes breast cancer growth,"Amy V. Paschall, Zahra Nawaz, Fikri Y Avci",https://www.biorxiv.org/content/10.1101/2024.03.13.584829v2,"Tumor-associated carbohydrate antigens (TACAs) can promote tumor growth by regulating the anti-tumor immune response. The accumulation of immune suppressor cells within the tumor in response to TACAs suggests a critical pathway to suppress immune targeting of the tumor. Employing murine breast cancer models, we isolated a regulatory B cell subpopulation in the breast tumor microenvironment that displays an immune suppressive phenotype through its Tn TACA-binding lectin, CD301b. We then demonstrated that depleting CD301b+ cells facilitated tumor control and mouse survival, whereas increasing Tn antigen expression decreased mouse survival. As tumor cells use Tn expression to overcome immune targeting, interfering with or blocking the Tn-CD301 axis may unleash the immune system, specifically within the aberrantly glycosylated tumor microenvironment, offering new immunotherapy for breast and other cancers."
761,Consequences of platelet-educated cancer cells on the expression of inflammatory and metastatic glycoproteins,"Mélanie Langiu, Lydie Crescence, Diane Mège, Christophe Dubois, Laurence Panicot-Dubois",https://www.biorxiv.org/content/10.1101/2024.03.20.585903v1,"Cancer-associated thrombosis, a major cause of mortality in cancer patients, exhibits a 4 to 7 times higher incidence compared to the general population. Platelet activation by tumor cells contributes to this pro-thrombotic state. Cancer cell-educated platelets have also been described to be implicated in promoting metastasis. Intriguingly, our team, among others, unveils a reverse process, wherein platelets educate cancer cells by transferring lipids, RNAs, and proteins. Here, focusing on colorectal and pancreatic cancers, our study investigates genes and proteins mediating platelet education of cancer cells. We demonstrated, for the first time, that platelets can educate cancer cells by inducing changes in the transcription of genes related to glycosylation, inflammation, and metastasis in cancer cells themselves. These results indicate a direct impact of platelets on cancer cell phenotype. This novel insight suggests potential therapeutic avenues for cancer treatment, disrupting platelet-mediated alterations and influencing the course of cancer progression."
762,BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer,"Wen Mi, Jianwei You, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Li Yang, Fei Li, Yi Xu, Junfeng Bi, Pingyu Liu, Li Chen, Fuming Li",https://www.biorxiv.org/content/10.1101/2024.03.20.585859v1,"Bromodomain and extra-terminal domain (BET) proteins, which function partly through MYC, are critical epigenetic readers and emerging therapeutic targets in cancer. Whether and how BET inhibition simultaneously induces metabolic remodeling remains unclear. Here we find that even transient BET inhibition by JQ-1 and other pan-BET inhibitors blunts liver cancer cell proliferation and tumor growth. BET inhibition decreases glycolytic gene expression but enhances mitochondrial glucose and glutamine oxidative metabolism revealed by metabolomics and isotope labeling analysis. Specifically, BET inhibition downregulates miR-30a to upregulate glutamate dehydrogenase 1 (GDH1) independent of MYC, which produces α-ketoglutarate for mitochondrial oxidative phosphorylation (OXPHOS). Targeting GDH1 or OXPHOS is synthetic lethal to BET inhibiton, and combined BET and OXPHOS inhibition therapeutically prevents liver tumor growth in vitro and in vivo. Together, we uncover an important epigenetic-metabolic crosstalk whereby BET inhibition induces MYC- independent and GDH1-dependendent glutamine metabolic remodeling that can be exploited for innovative combination therapy of liver cancer."
763,CADTAD: CAncer Driver Topologically Associated Domains identify oncogenic and tumor suppressive lncRNAs,"Ziyan Rao, Min Zhang, Shaodong Huang, Chenyang Wu, Yuheng Zhou, Weijie Zhang, Xia Lin, Dongyu Zhao",https://www.biorxiv.org/content/10.1101/2024.03.19.585685v1,"Cancer lncRNAs have been identified by both experimental and in silico methods. However, the current approaches for mining cancer lncRNAs are not sufficient and accurate. To deeply discover them, we focus on the core cancer driver lncRNAs (CDLs) which directly interact with cancer driver protein-coding genes. We investigated various aspects of cancer-related lncRNAs (CRLs), including their genomic locations, expression patterns, and their direct interactions with cancer driver protein-coding genes. We found that most CRLs located in cancer driver topologically associated domains (CDTs). Moreover, some CRLs showed a high tendency for co-expression and binding sites with cancer driver protein-coding genes. Utilizing these distinctive characteristics and integrating >4000 multi-omics data, we developed a pipeline CADTAD to unearth conserved candidate CDLs in pan-cancer, including 256 oncogenic lncRNAs, 177 tumor suppressive lncRNAs, and 75 dual-function lncRNAs, as well as some specific candidate CDLs in three individual cancer types and validated their cancer-related characteristics. Importantly, the function of 10 putative CDLs in prostate cancer was subsequently validated through cell studies. In light of these findings, our study offers a new perspective from the 3D genome to study the roles of lncRNAs in cancer. Furthermore, we provide a valuable set of potential lncRNAs that could deepen our understanding of the oncogenic mechanism of CDLs."
765,Self-Supervised Learning Reveals Clinically Relevant Histomorphological Patterns for Therapeutic Strategies in Colon Cancer,"Bojing Liu, Meaghan Polack, Nicolas Coudray, Adalberto Claudio Quiros, Theodore Sakellaropoulos, Augustinus S.L.P. Crobach, J. Han J.M. van Krieken, Ke Yuan, Rob A.E.M. Tollenaar, Wilma E. Mesker, Aristotelis Tsirigos",https://www.biorxiv.org/content/10.1101/2024.02.26.582106v2,"Self-supervised learning (SSL) automates the extraction and interpretation of histopathology features on unannotated hematoxylin-and-eosin-stained whole-slide images (WSIs). We trained an SSL Barlow Twins-encoder on 435 TCGA colon adenocarcinoma WSIs to extract features from small image patches. Leiden community detection then grouped tiles into histomorphological phenotype clusters (HPCs). HPC reproducibility and predictive ability for overall survival was confirmed in an independent clinical trial cohort (N=1213 WSIs). This unbiased atlas resulted in 47 HPCs displaying unique and sharing clinically significant histomorphological traits, highlighting tissue type, quantity, and architecture, especially in the context of tumor stroma. Through in-depth analysis of these HPCs, including immune landscape and gene set enrichment analysis, and association to clinical outcomes, we shed light on the factors influencing survival and responses to treatments like standard adjuvant chemotherapy and experimental therapies. Further exploration of HPCs may unveil new insights and aid decision-making and personalized treatments for colon cancer patients."
768,Estrogen regulation and functional role of FGFR4 in estrogen receptor positive breast cancer,"Kai Ding, Lyuqin Chen, Kevin Levine, Matthew Sikora, Nilgun Tasdemir, David Dabbs, Rachel Jankowitz, Rachel Hazan, Osama S Shah, Jennifer M Atkinson, Adrian V Lee, Steffi Oesterreich",https://www.biorxiv.org/content/10.1101/2024.03.18.585626v1,"Background Resistance to endocrine therapy is a major challenge of managing estrogen receptor positive (ER+) breast cancer. We previously reported frequent overexpression of FGFR4 in endocrine resistant cell lines and breast cancers that recurred and metastasized following endocrine therapy, suggesting FGFR4 as a potential driver of endocrine resistance. In this study, we investigated the role of FGFR4 in mediating endocrine resistance and explored the therapeutic potential of targeting FGFR4 in advanced breast cancer."
769,Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer,"Caleb Cheng, Jing Hu, Rahul Mannan, Rupam Bhattacharyya, Nicholas J. Rossiter, Brian Magnuson, Jasmine P. Wisniewski, Yang Zheng, Lanbo Xiao, Chungen Li, Dominik Awad, Tongchen He, Yi Bao, Yuping Zhang, Xuhong Cao, Zhen Wang, Rohit Mehra, Pietro Morlacchi, Vaibhav Sahai, Marina Pasca di Magliano, Yatrik M. Shah, Ke Ding, Yuanyuan Qiao, Costas A. Lyssiotis, Arul M. Chinnaiyan",https://www.biorxiv.org/content/10.1101/2024.03.18.585580v1,"Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism1 2. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning7, as a novel and targetable vulnerability in PDAC. In human patient and murine PDAC samples, we discovered that PIKFYVE is overexpressed in PDAC cells compared to adjacent normal cells. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulate de novo lipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, by upregulating genes such as FASN and ACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC."
772,A molecularly engineered lectin destroys EGFR and inhibits the growth of non-small cell lung cancer,"Susana M. Chan, Zoe Raglow, Anupama Pal, Scott D. Gitlin, Maureen Legendre, Dafydd Thomas, Ranjit K Mehta, Mingjia Tan, Mukesh K. Nyati, Alnawaz Rehemtulla, David M. Markovitz",https://www.biorxiv.org/content/10.1101/2024.03.18.585535v1,"Survival rates for non-small cell lung cancer (NSCLC) remain low despite the advent of novel therapeutics. Tyrosine kinase inhibitors (TKIs) targeting mutant epidermal growth factor receptor (EGFR) in NSCLC have significantly improved mortality but are plagued with challenges--they can only be used in the small fraction of patients who have susceptible driver mutations, and resistance inevitably develops."
773,Myeloid-instructed CD14+CD4+ T cells within the tumor microenvironment are associated with TNF⍺ signaling and prolonged survival in non-small cell lung cancer,"Claire Marceaux, Kenta Yokote, Velimir Gayevskiy, Daniel Batey, Ilariya Tarasova, Laurie Choux, Lucy Riley, Nina Tubau Ribera, Jack Hywood, Michael Christie, Phillip Antippa, Terence P Speed, Kelly L. Rogers, Belinda Phipson, Marie-Liesse Asselin-Labat",https://www.biorxiv.org/content/10.1101/2024.08.02.606259v1,"Immune cells from the adaptive and innate immune systems coexist in the tumor immune microenvironment (TME) to mediate tumor cell immunosurveillance and prevent tumor relapse. Relapse-free survival after surgical resection is heterogeneous in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), the two major subtypes of non-small cell lung cancer. Yet, little is known about the composition and spatial organisation of the TME that could explain the different prognoses for lung cancer patients. Using spatial multi-omics analyses, we show that LUAD and LUSC have distinct TMEs and that neutrophil-enriched tumors are associated with worse survival, while the accumulation of myeloid-instructed CD14+ T cells in the tumor core was associated with prolonged patient survival. CD14+CD4+ T cells express prototypic markers of myeloid cells and were found to be clonally expanded tumor-specific activated T cells. TNFα signaling was activated in tumors with high infiltration of CD14+CD4+ T cells in the tumor core. Our results demonstrate that innate immune cells impact adaptive immune cell activity to support the deployment of discrete T cell populations with anti-tumor activity."
774,Multifaceted roles of SAMHD1 in cancer,"Katie-May McLaughlin, Jindrich Cinatl jr., Mark N. Wass, Martin Michaelis",https://www.biorxiv.org/content/10.1101/2021.07.03.451003v2,"SAMHD1 is discussed as a tumour suppressor protein, but its potential role in cancer has only been investigated in very few cancer types. Here, we performed a systematic analysis of the TCGA (adult cancer) and TARGET (paediatric cancer) databases, the results of which did not suggest that SAMHD1 should be regarded as a bona fide tumour suppressor. SAMHD1 mutations that interfere with SAMHD1 function were not associated with poor outcome, which would be expected for a tumour suppressor. High SAMHD1 tumour levels were associated with increased survival in some cancer entities and reduced survival in others. Moreover, the data suggested differences in the role of SAMHD1 between males and females and between different races. Often, there was no significant relationship between SAMHD1 levels and cancer outcome. Taken together, our results indicate that SAMHD1 may exert pro-or anti-tumourigenic effects and that SAMHD1 is involved in the oncogenic process in a minority of cancer cases. These findings seem to be in disaccord with a perception and narrative forming in the field suggesting that SAMHD1 is a tumour suppressor. A systematic literature review confirmed that most of the available scientific articles focus on a potential role of SAMHD1 as a tumour suppressor. The reasons for this remain unclear but may include confirmation bias and publication bias. Our findings emphasise that hypotheses, perceptions, and assumptions need to be continuously challenged by using all available data and evidence."
775,Conformal prediction of molecule-induced cancer cell growth inhibition challenged by strong distribution shifts,"Saiveth Hernandez-Hernandez, Qianrong Guo, Pedro J. Ballester",https://www.biorxiv.org/content/10.1101/2024.03.15.585269v1,"The drug discovery process often employs phenotypic and target-based virtual screening to identify potential drug candidates. Despite the longstanding dominance of target-based approaches, phenotypic virtual screening is undergoing a resurgence due to its potential being now better understood. In the context of cancer cell lines, a well-established experimental system for phenotypic screens, molecules are tested to identify their whole-cell activity, as summarized by their half-maximal inhibitory concentrations. Machine learning has emerged as a potent tool for computationally guiding such screens, yet important research gaps persist. Consequently, this study focuses on the application of Conformal Prediction (CP) to predict the activities of novel molecules on specific cancer cell lines. Two CP models were constructed and evaluated on each cell line, resulting in a total of 120 performance evaluations (60 cell lines x 2 CP models) per training-test partition. From this comprehensive evaluation, we concluded that, regardless of the cell line or model, novel molecules with smaller CP-calculated confidence intervals tend to have smaller predicted errors once measured activities are revealed. It was also possible to anticipate the activities of dissimilar test molecules across 50 or more cell lines. These outcomes demonstrate the robust efficacy that CP models can achieve in realistic and challenging scenarios, thereby providing valuable insights for enhancing decision-making processes in drug discovery."
776,Quantitative effects of co-culture on T cell motility and cancer-T cell interactions,"Xinyue Li, Taoli Jin, Lisha Wang, Ming Li, Weijing Han, Xuefei Li",https://www.biorxiv.org/content/10.1101/2024.03.15.585166v1,"One of the primary challenges in current cancer immunotherapy is the insufficient infiltration of cytotoxic T cells into solid tumors. Despite ongoing investigations, the mechanisms restricting T cell infiltration in immune-cold tumors remains elusive, hindered by the intricate tumor microenvironment. Here, we co-cultured mouse cancer cell lines with cancer-specific cytotoxic T cells to study the influence of cancer-T cell interactions on T cell motility, a crucial factor for effective tumor infiltration. By quantifying T cell motility patterns, we found that cancer-specific T cells exhibited extended contact time with cancer-cell clusters and higher directional persistence than non-specific T cells. Computational modelling suggested that T cells with stronger persistence could facilitate efficient searching for cancer clusters. Transcriptomic profiling revealed T cells recognizing cancer cells orchestrate accumulation on cancer cell clusters by activating adhesion proteins on both cancer cells and T cells, thereby fostering prolonged interaction on cancer cells. Furthermore, we observed that there were two distinct subpopulations of cancer cells after co-culturing with cancer-specific T cells: one expressing elevated levels of T-cell attractants and antigen-presentation molecules, while the other expressing immunosuppressive molecules and undergoing epithelial-to-mesenchymal transition. These dynamic insights into the complex interplay of cancer-T cell interactions and their impact on T cell motility hold implications for refining more efficacious cancer immunotherapy strategies."
777,A Novel ex-vivo platform for personalized treatment in metastatic ovarian cancer,"Alain Valdivia, Adebimpe Adefolaju, Morrent Thang, Luz Andrea Cuaboy, Catherine John, Breanna Mann, Andrew Satterlee, Victoria L Bae-Jump, Shawn Hingtgen",https://www.biorxiv.org/content/10.1101/2024.03.14.585117v1,"The lack of functional precision models that recapitulate the pathology and structure/function relationship of advanced ovarian cancer (OC) within an appropriate anatomic setting constitutes a hurdle on the path to developing more reliable therapies and matching those therapies with the right patients. Here, we developed and characterized an Organotypic Mesentery Membrane Culture (OMMC) model as a novel ex-vivo platform where freshly resected human patient OC tumor tissue or established cell lines are seeded directly atop living intact rat mesenteric membranes, rapidly engraft, and enable functional assessment of treatment response to FDA-approved standard care of treatment as single and combination drug therapies within just five days. This study showed successful survival of dissected mesentery tissue, survival and engraftment of tumor cells and patient tumor tissue seeded on OMMCs, mesentery-tumor cell interaction, and quantification of tumor response to treatment and off-target toxicity. Summarized “drug sensitivity scores”, using a multi-parametric algorithm, were also calculated for each patient’s treatment response, enabling us to suggest the most effective therapeutic option. Finally, we compared drug sensitivity results from patient tumor tissue on OMMCs to matched outcomes of individual patients in the clinic and identified positive correlations in drug sensitivity, beginning to validate the functionality of OMMCs as a functional predictor of treatment response."
779,A Library of Custom PEG-Lipids reveals a Double-PEG-Lipid with Drastically Enhanced Paclitaxel Solubility and Human Cancer Cell Cytotoxicity when used in Fluid Micellar Nanoparticles,"Aria Ghasemizadeh, Lili Wan, Aiko Hirose, Jacqueline Diep, Kai K. Ewert, Cyrus R. Safinya",https://www.biorxiv.org/content/10.1101/2024.08.01.606138v1,"Paclitaxel (PTX) is one of the most widely utilized chemotherapeutics globally. However, the extremely poor water solubility of paclitaxel necessitates a mechanism of delivery within blood. Fluid lipid PTX nanocarriers (lipids in the chain-melted state) show promise as PTX delivery vectors, but remain limited by their solubility of PTX within the membrane. To improve pharmacokinetics, membrane surfaces are typically coated with polyethylene glycol (PEG). Recent work has demonstrated the generation of a population of micelles within fluid lipid formulations containing a 2kDa PEG-lipid at a 10 mol% ratio. Driven by the positive curvature of the PEG-lipid (i.e. area of head group > area of tails), micelle-containing formulations were found to exhibit significantly higher uptake in cancer cells, cytotoxicity, and in vivo antitumor efficacy compared to formulations containing solely liposomes. Here, we describe the custom synthesis of a library of high-curvature micelle-inducing PEG-lipids and examine the effects of PEG chain length, chain branching (single- or double-PEG-lipid), and cationic charge on PTX solubility and cytotoxicity. We examined PEG-lipids at standard (10 mol%) and high (100-x mol%, where x=PTX mol%) formulation ratios. Remarkably, all formulations containing the synthesized high-curvature PEG-lipids had improved PTX solubility over unPEGylated formulations and commercially available DOPE-5k. The highest PTX solubility was found within the 100–xptx mol% PEG-lipid micellar formulations, with particles made from 2k2 (two PEG2k chains) encapsulating 13 mol% PTX for up to 24 h. The pancreatic cancer cell line PC3 exhibited higher sensitivity to formulations containing PEG-lipid at 100–xptx mol%, the most potent of which being formulations made from 2k2 (IC50 = 14 nM). The work presented here suggests formulations employing high-curvature PEG-lipids, particularly the double-PEG-lipid 2k2, hold great potential as next-generation PTX delivery systems owing to their high PTX solubility, enhanced cell cytotoxicity, and ability for precision targeting by affixation of ligands to the PEG molecules."
780,An EYA3/NF-κB/CCL2 signaling axis suppresses cytotoxic NK cells in the pre-metastatic niche to promote triple negative breast cancer metastasis,"Sheera R. Rosenbaum, Connor J. Hughes, Kaiah M. Fields, Stephen Connor Purdy, Annika Gustafson, Arthur Wolin, Drake Hampton, Nicholas Turner, Christopher Ebmeier, James C. Costello, Heide L. Ford",https://www.biorxiv.org/content/10.1101/2024.07.31.606072v1,"Patients with Triple Negative Breast Cancer (TNBC) exhibit high rates of metastases and poor prognoses. The Eyes absent (EYA) family of proteins are developmental transcriptional cofactors/phosphatases that are re-expressed and/or upregulated in numerous cancers. Herein, we demonstrate that EYA3 correlates with decreased survival in breast cancer, and that it strongly, and specifically, regulates metastasis via a novel mechanism that involves NF-kB signaling and an altered innate immune profile at the pre-metastatic niche (PMN)."
781,Revealing cancer driver genes through integrative transcriptomic and epigenomic analyses with Moonlight,"Mona Nourbakhsh, Yuanning Zheng, Humaira Noor, Matteo Tiberti, Olivier Gevaert, Elena Papaleo",https://www.biorxiv.org/content/10.1101/2024.03.14.584946v1,"Cancer involves dynamic changes caused by (epi)genetic alterations such as mutations or abnormal DNA methylation patterns which occur in cancer driver genes. These driver genes are divided into oncogenes and tumor suppressors depending on their function and mechanism of action. Discovering driver genes in different cancer (sub)types is important not only for increasing current understanding of carcinogenesis but also from prognostic and therapeutic perspectives. We have previously developed a framework called Moonlight which uses a systems biology multi-omics approach for prediction of driver genes. Here, we present further updates to Moonlight by incorporating a DNA methylation layer which provides epigenetic evidence for deregulated expression profiles of driver genes. To this end, we present a novel functionality called Gene Methylation Analysis (GMA) which investigates abnormal DNA methylation patterns to predict driver genes. This is achieved by integrating the tool EpiMix which is designed to detect such aberrant DNA methylation patterns in a cohort of patients and further couples these patterns with changes in gene expression. To showcase GMA, we applied it to three cancer (sub)types (basal-like breast cancer, lung adenocarcinoma, and thyroid carcinoma) where we discovered 33, 190, and 263 epigenetically driven genes, respectively. A subset of these driver genes had prognostic effects with expression levels significantly affecting survival of the patients. Moreover, a subset of the driver genes demonstrated therapeutic potential as drug targets. This study provides a framework for exploring the driving forces behind cancer and provides novel insights into the landscape of three cancer sub(types) by integrating gene expression and methylation data. Moonlight2R is available on GitHub (https://github.com/ELELAB/Moonlight2R) and BioCondcutor (https://bioconductor.org/packages/release/bioc/html/Moonlight2R.html) and the associated case studies presented in this study are available on GitHub (https://github.com/ELELAB/Moonlight2_GMA_case_studies) and OSF (https://osf.io/j4n8q/)."
783,Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming,"Ola Hassan, Mattia Pizzagalli, Laura Jinxuan Wu, David Karambizi, John P. Zepecki, Eduardo Fajardo, Andras Fiser, Nikos Tapinos",https://www.biorxiv.org/content/10.1101/2024.03.12.584656v1,"Class IIa histone deacetylases (HDACs) are a family of enzymes that despite their name, do not have any measurable histone deacetylase activity but they function as multi-protein interaction hubs due to the presence of a prolonged N-terminal domain. Here we show that HDAC7, a member of the Class IIa HDAC family, is a chaperone for Histone H3.3 and, interacts with H3.3 and HIRA on chromatin. Specific inhibition of HDAC7 expression with subtype specific siRNAs results in inhibition of the interaction of H3.3 with HIRA, while the association of H3.3 with DAXX and H3K9me3 is significantly increased, resulting in H3.3 being deposited on H3K9me3+/DAPI+ heterochromatin nuclear foci. Inhibition of HDAC7 triggers a significant increase of heterochromatin marks H3K9me3 and H3K27me3, global heterochromatin spreading in cancer cells, and reprogramming of the H3.3 chromatin landscape. This drives substantial alteration of cancer cell gene expression as well as inhibition of the stemness phenotype for cancer cells. Our work demonstrates the involvement of HDAC7 in the euchromatic H3.3 chaperone network and shows that inhibiting HDAC7 induces H3.3 landscape reprogramming, heterochromatin spreading, and epigenetic restriction in cancer cells."
785,Circulating Small Extracellular Vesicle RNA Profiling for the Detection of T1a stage Colorectal Cancer and Precancerous Advanced Adenoma,"Li Min, Fanqin Bu, Jingxin Meng, Xiang Liu, Qingdong Guo, Libo Zhao, Zhi Li, Xiangji Li, Shengtao Zhu, Shutian Zhang",https://www.biorxiv.org/content/10.1101/2023.06.04.543604v4,"It takes more than twenty years for normal colorectal mucosa to develop into metastatic carcinoma. The long time window provides a golden opportunity for early detection to terminate the malignant progression. Here we aim to enable liquid biopsy of T1a stage colorectal cancer (CRC) and precancerous advanced adenoma (AA) by profiling circulating small extracellular vesicle (sEV)-derived RNAs. We exhibited a full RNA landscape for the circulating sEVs isolated from 60 participants. A total of 58,333 annotated RNAs were detected from plasma sEVs, among which 1,615 and 888 sEV-RNAs were found differentially expressed in plasma from T1a stage CRC and AA compared to normal controls (NC). Then we further categorized these sEV-RNAs into 6 modules by a weighted gene coexpression network analysis and constructed a 60-gene t-SNE model consisting of the top 10 RNAs of each module that could well distinguish T1a stage CRC/AA from NC samples. Some sEV-RNAs were also identified as indicators of specific endoscopic and morphological features of different colorectal lesions. The top-ranked biomarkers were further verified by RT-qPCR, proving that these candidate sEV-RNAs successfully identified T1a stage CRC/AA from NC in another cohort of 124 participants. Finally, we adopted different algorithms to improve the performance of RT-qPCR-based models and successfully constructed an optimized classifier with 79.3% specificity and 99.0% sensitivity. In conclusion, circulating sEVs of T1a stage CRC and AA patients have distinct RNA profiles, which successfully enable the detection of both T1a stage CRC and AA via liquid biopsy."
786,Explainable deep learning on 7500 whole genomes elucidates cancer-specific patterns of chromosomal instability,"Mohamed Ali al-Badri, William CH Cross, Chris P Barnes",https://www.biorxiv.org/content/10.1101/2024.03.08.584160v1,"Chromosomal instability (CIN) refers to an increased rate of chromosomal changes within cells. It is highly prevalent in cancer cells and leads to abnormalities in chromosome number (aneuploidy) and structure. CIN contributes to genetic diversity within a tumour, which facilitates tumour progression, drug resistance, and metastasis. Here, we present a deep learning method and an exploration of the chromosome copy aberrations (CNAs) resultant from CIN, across 7,500 high-depth, whole genome sequences, representing 13 cancer types. We found that the types of CNAs can act as a highly specific classifier for primary site. Using an explainable AI approach, we revealed both established and novel loci that contributed to cancer type, and focusing on highly significant chromosome loci within cancer types, we demonstrated prognostic relevance. We outline how the developed methodology can provide several applications for researchers, including drug target and biomarker discovery, as well as the identification of cancers of unknown primary site."
787,The Cyclin-Like Protein Spy1 Mediates Tumourigenic Potential of Triple Negative Breast Cancer,"Bre-Anne Fifield, Claudia Pecoraro, Amy Basilious, Catalin Gramisteanu, Emily Mailloux, Rosa-Maria Ferraiuolo, Lisa A. Porter",https://www.biorxiv.org/content/10.1101/2024.03.11.584461v1,"Triple negative breast cancer is an aggressive subtype of breast cancer that relies on systemic chemotherapy as its primary means of treatment. Cell cycle regulators are enriched in drug resistant forms of the disease supporting the potential of targeting cell cycle checkpoints as a therapeutic direction to re-sensitize patients to treatment. Spy1 is an atypical cyclin-like protein that can override cell cycle checkpoints and is elevated in triple negative breast cancer. We report for the first time the effects of CRISPR-Cas9 mediated knockout of Spy1 on functional characteristics of triple negative breast cancer cells and perform unbiased analysis of protein expression to assess global changes in expression which correlate with functional changes in cell properties. Loss of Spy1 reduced rates of proliferation, decreased metastatic potential, and led to a reduction in stemness properties of triple negative breast cancer cells. Importantly, knockout of Spy1 delayed tumour onset in an in vivo model and significantly increased response to chemotherapy, pushing cells towards a senescent state. This data reveals that changes in expression of proteins that are not essential for proliferation and only transiently expressed can have significant impacts on cell dynamics and provides support for targeting the Spy1-CDK2 complex as a new therapeutic avenue in triple negative breast cancer."
788,Evolutionary double-bind treatment using radiotherapy and NK cell-based immunotherapy in prostate cancer,"Kimberly A Luddy, Jeffrey West, Mark Robertson-Tessi, Bina Desai, Taylor M. Bursell, Sarah Barrett, Jacintha O’Sullivan, Laure Marignol, Robert A Gatenby, Joel S Brown, Alexander RA Anderson, Cliona O’Farrelly",https://www.biorxiv.org/content/10.1101/2024.03.11.584452v1,"Evolution-informed therapies exploit ecological and evolutionary consequences of drug resistance to inhibit the expansion of treatment-resistant populations and prolong time to progression. One strategy, termed an evolutionary double-bind, uses an initial therapy to elicit a specific adaptive response by the cancer cells, which is then selectively targeted by a follow-on therapy. Here we examine the combination of radiation therapy and immunotherapy as a quantifiable double-bind strategy. Radiotherapy (RT) induces lethal double-strand DNA breaks, but cancer cells can adapt by upregulating DNA damage response pathways. While this evolutionary strategy increases resistance to DNA damaging agents, it also results in enhanced expression of natural killer (NK) cell ligands potentially increasing vulnerability to an immune response."
790,ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer,"Paloma Moreno, Yuuki Ohara, Amanda J. Craig, Huaitian Liu, Shouhui Yang, Lin Zhang, Gatikrushna Panigrahi, Tiffany H. Dorsey, Helen Cawley, Azadeh Azizian, Jochen Gaedcke, Michael Ghadimi, Nader Hanna, S. Perwez Hussain",https://www.biorxiv.org/content/10.1101/2024.03.12.584316v1,"Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC."
791,DrugMap: A quantitative pan-cancer analysis of cysteine ligandability,"Mariko Takahashi, Harrison B. Chong, Siwen Zhang, Matthew J. Lazarov, Stefan Harry, Michelle Maynard, Ryan White, Heather E. Murrey, Brendan Hilbert, Jason R. Neil, Magdy Gohar, Maolin Ge, Junbing Zhang, Benedikt R. Durr, Gregory Kryukov, Chih-Chiang Tsou, Natasja Brooijmans, Aliyu Sidi Omar Alghali, Karla Rubio, Antonio Vilanueva, Drew Harrison, Ann-Sophie Koglin, Samuel Ojeda, Barbara Karakyriakou, Alexander Healy, Jonathan Assaad, Farah Makram, Inbal Rachman, Neha Khandelwal, Pei-Chieh Tien, George Popoola, Nicholas Chen, Kira Vordermark, Marianne Richter, Himani Patel, Tzu-yi Yang, Hanna Griesshaber, Tobias Hosp, Sanne van den Ouweland, Toshiro Hara, Lily Bussema, Rui Dong, Lei Shi, Martin Q. Rasmussen, Ana Carolina Domingues, Aleigha Lawless, Jacy Fang, Satoshi Yoda, Linh Phuong Nguyen, Sarah Marie Reeves, Farrah Nicole Wakefield, Adam Acker, Sarah Elizabeth Clark, Taronish Dubash, David E. Fisher, Shyamala Maheswaran, Daniel A. Haber, Genevieve Boland, Moshe Sade-Feldman, Russel Jenkins, Aaron Hata, Nabeel Bardeesy, Mario L. Suva, Brent Martin, Brian Liau, Christopher Ott, Miguel N. Rivera, Michael S. Lawrence, Liron Bar-Peled",https://www.biorxiv.org/content/10.1101/2023.10.20.563287v1,"Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap, an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity."
792,Identification of Biomarkers and Trajectories of Prostate Cancer Progression: A Bioinformatics Fusion of Weighted Correlation Network Analysis and Machine Learning,"Raheleh Sheibani-Tezerji, Carlos Uziel Pérez Malla, Gabriel Wasinger, Katarina Misura, Astrid Haase, Anna Malzer, Jessica Kalla, Loan Tran, Gerda Egger",https://www.biorxiv.org/content/10.1101/2023.03.02.530740v2,"Background Prostate cancer diagnosis and prognosis is currently limited by the availability of sensitive and specific biomarkers. There is an urgent need to develop molecular biomarkers that allow for the distinction of indolent from aggressive disease, the sensitive detection of heterogeneous tumors, or the evaluation of micro-metastases. The availability of multi-omics datasets in publicly accessible databases provides a valuable foundation to develop computational workflows for the identification of suitable biomarkers for clinical management of cancer patients."
795,Lack of TGFβ signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade,"Jade Moore, Jim Gkantalis, Ines Guix, William Chou, Kobe Yuen, Ann A. Lazar, Mathew Spitzer, Alexis J. Combes, Mary Helen Barcellos-Hoff",https://www.biorxiv.org/content/10.1101/2024.03.06.583752v2,"Background Transforming growth factor beta (TGFβ) is well-recognized as an immunosuppressive player in the tumor microenvironment but also has a significant impact on cancer cell phenotypes. Loss of TGFβ signaling impairs DNA repair competency, which is described by a transcriptomic score, βAlt. Cancers with high βAlt have more genomic damage and are more responsive to genotoxic therapy. The growing appreciation that cancer DNA repair deficits are important determinants of immune response prompted us to investigate the association of βAlt with response to immune checkpoint blockade (ICB). We predicted that high βAlt tumors would be infiltrated with lymphocytes because of DNA damage burden and hence responsive to ICB."
796,Spatial Transcriptomics Reveals Spatially Diverse Cancer-Associated Fibroblast in Lung Squamous Cell Carcinoma Linked to Tumor Progression,"Hongyoon Choi, Kwon Joong Na, Yeonjae Jung, Myunghyun Lim, Dongjoo Lee, Jae Eun Lee, Hyung-Jun Im, Daeseung Lee, Jaemoon Koh, Young Tae Kim",https://www.biorxiv.org/content/10.1101/2024.05.16.594592v1,"While cancer-associated fibroblasts (CAFs) are crucial in influencing tumor growth and immune responses in lung cancer, we still lack a comprehensive understanding of their spatial organization associated with tumor progression and clinical outcomes. This gap highlights the need to elucidate how the intricate spatial arrangement of CAFs affects their interactions within the tumor microenvironment, ultimately shaping cancer progression and patient prognosis. Here, we unveil the spatial diversity of CAFs in lung squamous cell carcinoma (LUSC), a prevalent and aggressive lung cancer type, elucidating their impact on tumor progression and patient outcomes using spatial transcriptomics (ST). Image-based ST data from 33 LUSC patients demonstrated a significant association of spatial interactions of tumor epithelium and CAFs with tumor size and metabolic activity measured by [18F]fluorodeoxyglucose PET. Furthermore, the proximity of fibroblasts to tumor epithelial cells was linked to recurrence-free survival in LUSC patients. By characterizing CAFs based on their spatial relationship, we identified distinct molecular signatures related to spatially distinct fibroblast subpopulations. In addition, barcode-based ST data from 8 LUSC patients revealed spatially overlapping fibroblast regions characterized by upregulated glycolysis pathways. Our study underscores the importance of the complex spatial dynamics of the tumor microenvironment revealed by ST and its implications for patient outcomes in LUSC."
797,The gatekeeper to gastric cancer; gastric microbiota invade the lamina propria in Helicobacter pylori-associated gastric carcinogenesis,"Harriet J. Giddings, Ana Teodósio, Jack L. McMurray, Kelly Hunter, Zainab Abdawn, Jeffrey A. Cole, Claire D. Shannon-Lowe, Amanda E. Rossiter-Pearson",https://www.biorxiv.org/content/10.1101/2024.04.22.590522v2,"Stomach cancer is the fourth leading cause of cancer-related deaths worldwide. Helicobacter pylori is the main risk factor for gastric adenocarcinoma (GAC), yet the mechanism underpinning this association remains uncharacterised. Gastric intestinal metaplasia (GIM) represents the pre-cancerous stage and follows H. pylori-associated chronic gastritis (CG). Sequencing studies have revealed fewer H. pylori and more non-H. pylori bacteria in GAC. However, the spatial organisation of the gastric microbiota in health and disease is unknown. Here, we have combined RNA in situ hybridisation and immunohistochemistry to detect H. pylori, non-H. pylori bacteria and host cell markers (E-cadherin, Mucins 5AC and 2) from patients with CG (n=9), GIM (n=12), GAC and normal tissue adjacent to tumours (NATs) (n=3). Quantitative analysis of whole slide scans revealed significant correlations of H. pylori and other bacteria in CG and GIM samples. In contrast to sequencing studies, significantly fewer non-H. pylori bacteria were detected in H. pylori-negative patients. Importantly, whilst H. pylori exclusively colonised the gastric glands, non-H. pylori bacteria invaded the lamina propria in 3/4 CG and 5/6 GIM H. pylori-positive patients. Bacterial invasion was observed in 3/3 GAC samples and at higher levels than matched NATs. We propose that H. pylori ‘holds the keys’ to disrupt the gastric epithelial barrier, facilitating the opportunistic invasion of non-H. pylori bacteria to the lamina propria. Bacterial invasion could be a significant driver of inflammation in H. pylori-associated carcinogenesis. This proposed mechanism would both explain the synergistic roles of H. pylori and other bacteria and redirect attempts to prevent, diagnose and treat GAC."
798,Repression of PRMT activities sensitize homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment,"Youyou Zhang, Mu Xu, Jiao Yuan, Zhongyi Hu, Junjie Jiang, Jie Huang, Bingwei Wang, Jianfeng Shen, Meixiao Long, Yi Fan, Kathleen T. Montone, Janos L. Tanyi, Omid Tavana, Ho Man Chan, Xiaowen Hu, Lin Zhang",https://www.biorxiv.org/content/10.1101/2024.05.21.595159v1,"An “induced PARP inhibitor (PARPi) sensitivity by epigenetic modulation” strategy is being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARPi treatments. To expand its clinical applications and identify more efficient combinations, we performed a drug screen by combining PARPi with 74 well-characterized epigenetic modulators that target five major classes of epigenetic enzymes. Both type I PRMT inhibitor and PRMT5 inhibitor exhibit high combination and clinical priority scores in our screen. PRMT inhibition significantly enhances PARPi treatment-induced DNA damage in HR-proficient ovarian and breast cancer cells. Mechanistically, PRMTs maintain the expression of genes associated with DNA damage repair and BRCAness and regulate intrinsic innate immune pathways in cancer cells. Analyzing large-scale genomic and functional profiles from TCGA and DepMap further confirms that PRMT1, PRMT4, and PRMT5 are potential therapeutic targets in oncology. Finally, PRMT1 and PRMT5 inhibition act synergistically to enhance PARPi sensitivity. Our studies provide a strong rationale for the clinical application of a combination of PRMT and PARP inhibitors in patients with HR-proficient ovarian or breast cancer."
802,DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer,"Benjamin B. Morris, Simon Heeke, Yuanxin Xi, Lixia Diao, Qi Wang, Pedro Rocha, Edurne Arriola, Myung Chang Lee, Darren R. Tyson, Kyle Concannon, Kavya Ramkumar, C. Allison Stewart, Robert J. Cardnell, Runsheng Wang, Vito Quaranta, Jing Wang, John V. Heymach, Barzin Y. Nabet, David S. Shames, Carl M. Gay, Lauren A. Byers",https://www.biorxiv.org/content/10.1101/2024.07.29.605595v1,"Introduction A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes."
803,Rarγ -Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer,"Dario De Felice, Alessandro Alaimo, Davide Bressan, Sacha Genovesi, Elisa Marmocchi, Nicole Annesi, Giulia Beccaceci, Davide Dalfovo, Federico Cutrupi, Veronica Foletto, Marco Lorenzoni, Francesco Gandolfi, Srinivasaraghavan Kannan, Chandra S. Verma, Alessandro Vasciaveo, Michael M. Shen, Alessandro Romanel, Fulvio Chiacchiera, Francesco Cambuli, Andrea Lunardi",https://www.biorxiv.org/content/10.1101/2024.03.06.583256v1,"Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in directing body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling promotes cell lineage identity in different tissues is often missing."
805,Pan-cancer analysis reveals multifaceted roles of retrotransposon-fusion RNAs,"Boram Lee, Junseok Park, Adam Voshall, Eduardo Maury, Yeeok Kang, Yoen Jeong Kim, Jin-Young Lee, Hye-Ran Shim, Hyo-Ju Kim, Jung-Woo Lee, Min-Hyeok Jung, Si-Cho Kim, Hoang Bao Khanh Chu, Da-Won Kim, Minjeong Kim, Eun-Ji Choi, Ok Kyung Hwang, Ho Won Lee, Kyungsoo Ha, Jung Kyoon Choi, Yongjoon Kim, Yoonjoo Choi, Woong-Yang Park, Eunjung Alice Lee",https://www.biorxiv.org/content/10.1101/2023.10.16.562422v1,"Transposon-derived transcripts are abundant in RNA sequences, yet their landscape and function, especially for fusion transcripts derived from unannotated or somatically acquired transposons, remains underexplored. Here, we developed a new bioinformatic tool to detect transposon-fusion transcripts in RNA-sequencing data and performed a pan-cancer analysis of 10,257 cancer samples across 34 cancer types as well as 3,088 normal tissue samples. We identified 52,277 cancer-specific fusions with ∼30 events per cancer and hotspot loci within transposons vulnerable to fusion formation. Exonization of intronic transposons was the most prevalent genic fusions, while somatic L1 insertions constituted a small fraction of cancer-specific fusions. Source L1s and HERVs, but not Alus showed decreased DNA methylation in cancer upon fusion formation. Overall cancer-specific L1 fusions were enriched in tumor suppressors while Alu fusions were enriched in oncogenes, including recurrent Alu fusions in EZH2 predictive of patient survival. We also demonstrated that transposon-derived peptides triggered CD8+ T-cell activation to the extent comparable to EBV viruses. Our findings reveal distinct epigenetic and tumorigenic mechanisms underlying transposon fusions across different families and highlight transposons as novel therapeutic targets and the source of potent neoantigens."
806,Empowering High Throughput Screening of 3D Models: Automated Dispensing of Cervical and Endometrial Cancer Cells,"Samantha Seymour, Ines Cadena, Mackenzie Johnson, Molly Jenne, Iman Adem, Alyssa Almer, Rachel Frankovic, Danielle Spence, Andrea Haddadin, Kaitlin C. Fogg",https://www.biorxiv.org/content/10.1101/2024.03.06.583783v1,"Purpose Cervical and endometrial cancers pose significant challenges in women’s healthcare due to their high mortality rates and limited treatment options. High throughput screening (HTS) of cervical and endometrial cancer in vitro models offer a promising avenue for drug repurposing and broadening patient treatment options. Traditional two-dimensional (2D) cell-based screenings have limited capabilities to capture crucial multicellular interactions, that are improved upon in three dimensional (3D) multicellular tissue engineered models. However, manual fabrication of the 3D platforms is both time consuming and subject to variability. Thus, the goal of this study was to utilize automated cell dispensing to fabricate 3D cell-based HTS platforms using the HP D100 Single Cell Dispenser to dispense cervical and endometrial cancer cells."
807,Rational design of HER2-targeted combination therapies to reverse drug resistance in fibroblast-protected HER2+ breast cancer cells,"Matthew D. Poskus, Jacob McDonald, Matthew Laird, Ruxuan Li, Kyle Norcoss, Ioannis K. Zervantonakis",https://www.biorxiv.org/content/10.1101/2024.05.18.594826v1,"Introduction Fibroblasts, an abundant cell type in the breast tumor microenvironment, interact with cancer cells and orchestrate tumor progression and drug resistance. However, the mechanisms by which fibroblast-derived factors impact drug sensitivity remain poorly understood. Here, we develop rational combination therapies that are informed by proteomic profiling to overcome fibroblast-mediated therapeutic resistance in HER2+ breast cancer cells."
808,RUNX2 Isoform II Protects Cancer Cells from Ferroptosis by Promoting PRDX2 Expression in Oral Squamous Cell Carcinoma,"Junjun Huang, Rong Jia, Jihua Guo",https://www.biorxiv.org/content/10.1101/2024.05.17.594656v1,"Ferroptosis is a distinct iron-dependent programmed cell death and plays important roles in tumor suppression. However, the regulatory mechanisms of ferroptosis need further exploration. RUNT-related transcription factor 2 (RUNX2), a transcription factor, is essential for osteogenesis. RUNX2 has two types of transcripts produced by two alternative promoters. In the present study, we surprisingly find that RUNX2 isoform II is a novel ferroptosis suppressor. RUNX2 isoform II can bind to the promoter of peroxiredoxin-2 (PRDX2), a ferroptosis inhibitor, and activate its expression. Knockdown of RUNX2 isoform II suppresses cell proliferation in vitro and tumorigenesis in vivo in oral squamous cell carcinoma (OSCC). Interestingly, homeobox A10 (HOXA10), an upstream positive regulator of RUNX2 isoform II, is required for the inhibition of ferroptosis through the RUNX2 isoform II/PRDX2 pathway. Consistently, RUNX2 isoform II is overexpressed in OSCC, and associated with OSCC progression and poor prognosis. Collectively, OSCC cancer cells can up-regulate RUNX2 isoform II to inhibit ferroptosis and facilitate tumorigenesis through the novel HOXA10/RUNX2 isoform II/PRDX2 pathway."
810,Childhood cancer mutagenesis caused by a domesticated DNA transposase,"Ross Keller, Makiko Yamada, Daniel Cameron, Hiromichi Suzuki, Reeti Sanghrajka, Jake Vaynshteyn, Jeffrey Gerwin, Francesco Maura, William Hooper, Minita Shah, Nicolas Robine, Philip Demarest, N. Sumru Bayin, Luz Jubierre, Casie Reed, Michael D. Taylor, Alexandra L. Joyner, G. Praveen Raju, Alex Kentsis",https://www.biorxiv.org/content/10.1101/2022.07.05.498128v2,"Genomic rearrangements are a hallmark of most solid tumors, including medulloblastoma, one of the most common brain tumors in children. Childhood cancers involve dysregulated cell development, but their mutational causes remain largely unknown. One of the most common forms of medulloblastoma is caused by ectopic activation of Sonic Hedgehog (SHH) signaling in cerebellar granule cell progenitors, associated with genetic deletions, amplifications, and other oncogenic chromosomal rearrangements. Here, we show that PiggyBac Transposable Element Derived 5 (Pgbd5) promotes tumor development in multiple developmentally-accurate mouse models of SHH medulloblastoma. Most mice with Pgbd5 deficiency do not develop tumors, while Pgbd5-deficient mice maintain largely normal cerebellar development. Mouse medulloblastomas expressing Pgbd5 exhibit significantly increased numbers of somatic structural DNA rearrangements, with PGBD5-specific transposon sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. Therefore, this study identifies PGBD5 as a primary medulloblastoma mutator and provides a genetic mechanism responsible for the generation of somatic oncogenic DNA rearrangements in childhood cancer."
812,Two distinct integrin binding sites on MMP9 drive cancer invasion by mediating integrin membrane trafficking & stabilization,"Sarbajeet Dutta, Soumili Sarkar, Simran Tolani, Asrafuddoza Hazari, Shamik Sen",https://www.biorxiv.org/content/10.1101/2024.04.01.587542v2,"Matrix stiffening has been established to drive cancer progression through increased activity of matrix metalloproteases (MMPs) which degrade the matrix creating paths for migration. However, the non-proteolytic functions of MMPs in cancer invasion remain relatively less understood. Here we have probed the importance of proteolytic and non-proteolytic functions of MMP9, which exhibits robust stiffness dependent expression and secretion in highly invasive cancer cells. We show that while MMP9 sustains spreading and 2D migration non-proteolytically by stabilizing focal adhesions, MMP9 proteolytic activity is essential for 3D invasion. We then establish the function of two distinct integrin β1 (ITG β1) binding sites on MMP9, with the hemopexin domain mediating co-packaging and co-transport of ITG β1/MMP9 to the cell periphery, and the RGD domain stabilizing ITG β1 on the cell membrane prior to matrix degradation. Together, our results illustrate how MMP9 optimizes cancer invasion by spatiotemporally integrating matrix remodeling with adhesion formation."
813,Signaling events at TMEM doorways provide potential targets for inhibiting breast cancer dissemination,"Chinmay R. Surve, Camille L. Duran, Xianjun Ye, Xiaoming Chen, Yu Lin, Allison S. Harney, Yarong Wang, Ved P. Sharma, E. Richard Stanley, Dianne Cox, John C. McAuliffe, David Entenberg, Maja H. Oktay, John S. Condeelis",https://www.biorxiv.org/content/10.1101/2024.01.08.574676v2,"Tumor cell intravasation is essential for metastatic dissemination, but its exact mechanism is incompletely understood. We have previously shown that in breast cancer, the direct and stable association of a tumor cell expressing Mena, a Tie2hi/VEGFhi macrophage, and a vascular endothelial cell, creates an intravasation portal, called a “tumor microenvironment of metastasis” (TMEM) doorway, for tumor cell intravasation, leading to dissemination to distant sites. The density of TMEM doorways, also called TMEM doorway score, is a clinically validated prognostic marker of distant metastasis in breast cancer patients. Although we know that tumor cells utilize TMEM doorway-associated transient vascular openings to intravasate, the precise signaling mechanisms involved in TMEM doorway function are only partially understood. Using two mouse models of breast cancer and an in vitro assay of intravasation, we report that CSF-1 secreted by the TMEM doorway tumor cell stimulates local secretion of VEGF-A from the Tie2hi TMEM doorway macrophage, leading to the dissociation of endothelial junctions between TMEM doorway associated endothelial cells, supporting tumor cell intravasation. Acute blockade of CSF-1R signaling decreases macrophage VEGF-A secretion as well as TMEM doorway-associated vascular opening, tumor cell trans-endothelial migration, and dissemination. These new insights into signaling events regulating TMEM doorway function should be explored further as treatment strategies for metastatic disease."
815,Proteogenomic analysis reveals adaptive strategies to alleviate the consequences of aneuploidy in cancer,"Jan-Eric Boekenkamp, Kristina Keuper, Stefan Redel, Karen Barthel, Leah Johnson, Angela Wieland, Markus Räschle, Zuzana Storchova",https://www.biorxiv.org/content/10.1101/2024.03.05.583460v1,"Aneuploidy is prevalent in cancer and associates with fitness advantage and poor patient prognosis. Yet, experimentally induced aneuploidy initially leads to adverse effects and impaired proliferation, suggesting that cancer cells must adapt to aneuploidy. We performed in vitro evolution of cells with extra chromosomes and obtained cell lines with improved proliferation and gene expression changes congruent with changes in aneuploid cancers. Integrated analysis of cancer multi-omics data and model cells revealed increased expression of DNA replicative and repair factors, reduced genomic instability, and reduced lysosomal degradation. We identified E2F4 and FOXM1 as transcription factors required for adaptation to aneuploidy in vitro and in cancers and validated this finding. The adaptation to aneuploidy also coincided with specific copy number aberrations that correlate with poor patient prognosis. Chromosomal engineering mimicking these aberrations improved aneuploid cell proliferation, while loss of previously present extra chromosome impaired it. The identified common adaptation strategies suggest replication stress, genomic instability, and lysosomal stress as common liabilities of aneuploid cancers."
817,Chronic Interferon Stimulated Gene Transcription Promotes Oncogene Induced Breast Cancer,"Hexiao Wang, Claudia Canasto-Chibuque, Jun Hyun Kim, Marcel Hohl, Christina Leslie, Jorge S Reis-Filho, John HJ Petrini",https://www.biorxiv.org/content/10.1101/2023.10.16.562529v1,"The Mre11 complex (comprising Mre11, Rad50, Nbs1) is integral to the maintenance of genome stability. We previously showed that a hypomorphic Mre11 mutant mouse strain (Mre11ATLD1/ATLD1) was highly susceptible to oncogene induced breast cancer. Here we used a mammary organoid system to examine which Mre11 dependent responses are tumor suppressive. We found that Mre11ATLD1/ATLD1 organoids exhibited an elevated interferon stimulated gene (ISG) signature and sustained changes in chromatin accessibility. This Mre11ATLD1/ATLD1 phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation of Ifi205 in Mre11ATLD1/ATLD1 organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed in WT. Implantation of Mre11ATLD1/ATLD1 organoids and activation of oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implanted Ifi205-/- Mre11ATLD1/ATLD1 organoids. These data reveal a connection between innate immune signaling and tumor suppression in mammary epithelium. Given the abundance of aberrant DNA structures that arise in the context of genome instability syndromes, the data further suggest that cancer predisposition in those contexts may be partially attributable to tonic innate immune transcriptional programs."
818,TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer,"Nicholas Sim, Jean-Michel Carter, Kamalakshi Deka, Benita Kiat Tee Tan, Yirong Sim, Suet-Mien Tan, Yinghui Li",https://www.biorxiv.org/content/10.1101/2024.05.15.594291v1,"Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from limited targeted treatment options. Following recent reports correlating Fn14 receptor overexpression in ER-negative breast cancers with metastatic events, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of NAMPT, which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients."
819,"Tumor-Associated Macrophages Expand Chemoresistant, Ovarian Cancer Stem-Like Cells","Allison C Sharrow, Madeline Ho, Aakriti Dua, Raquel Buj, Kim R.M. Blenman, Sandra Orsulic, Ronald Buckanovich, Katherine M Aird, Lily Wu",https://www.biorxiv.org/content/10.1101/2023.07.17.549067v2,"The persistence of ovarian cancer stem-like cells (OvCSCs) after chemotherapy resistance has been implicated in relapse. However, the ability of these relatively quiescent cells to produce the robust tumor regrowth necessary for relapse remains an enigma. Since normal stem cells exist in a niche, and tumor-associated macrophages (TAMs) are the highest abundance immune cell within ovarian tumors, we hypothesized that TAMs may influence OvCSC proliferation. To test this, we optimized OvCSC enrichment by sphere culture and in vitro polarization of monocytes to a TAM-like M2 phenotype. Using cocultures that permitted the exchange of only soluble factors, we found that M2 macrophages increased the proliferation of sphere cells. Longer-term exposure (5-7 days) to soluble TAM factors led to retention of some stem cell features by OvCSCs but loss of others, suggesting that TAMs may support an intermediate stemness phenotype in OvCSCs. Although TAM coculture decreased the percentage of OvCSCs surviving chemotherapy, it increased the overall number. We therefore sought to determine the influence of this interaction on chemotherapy efficacy in vivo and found that inhibiting macrophages improved chemotherapy response. Comparing the gene expression changes in OvCSCs cocultured with TAMs to publicly available patient data identified 34 genes upregulated in OvCSCs by exposure to soluble TAM factors whose expression correlates with outcome. Overall, these data suggest that TAMs may influence OvCSC proliferation and impact therapeutic response."
820,PFKP regulates AXL-MET oncogenic and metabolic pathways in lung cancer,"Yuze Sun, Huijie Zhao, Huijing Feng, Yue Liu, Yu Li, Sijie Chen, Zhiqing Zhou, Yuhui Du, Xiaofei Zeng, Huan Ren, Wenmei Su, Qi Mei, Guoan Chen",https://www.biorxiv.org/content/10.1101/2024.03.03.583230v1,"Objective PFKP (Phosphofructokinase, Platelet Type isoform), as an essential metabolic enzyme, contributes to the high glycolysis rates seen in cancers, while its role in oncogenic pathways, especially from a non-metabolic aspect, is not fully understood."
821,Misspellings or “miscellings”-non-verifiable cell lines in cancer research publications,"Danielle J. Oste, Pranujan Pathmendra, Reese A. K. Richardson, Gracen Johnson, Yida Ao, Maya D. Arya, Naomi R. Enochs, Muhammed Hussein, Jinghan Kang, Aaron Lee, Jonathan J. Danon, Guillaume Cabanac, Cyril Labbé, Amanda Capes Davis, Thomas Stoeger, Jennifer A. Byrne",https://www.biorxiv.org/content/10.1101/2024.02.29.582220v1,"Reproducible laboratory research relies on correctly identified reagents. We have previously described human gene research papers with wrongly identified nucleotide sequence reagent(s), including papers studying miR-145. Manually verifying reagent identities in more recent miR-145 papers found 20/36 (56%) and 6/36 (17%) miR-145 papers with misidentified nucleotide sequence reagent(s) and human cell line(s), respectively. We also found 5 cell line identifiers in two miR-145 papers with wrongly identified nucleotide sequences and cell lines, and 18 identifiers published elsewhere that did not correspond to indexed cell lines. These cell line identifiers were described as non-verifiable, as their identities appeared uncertain. Studying 420 papers that mentioned 8 different non-verifiable cell line identifier(s) found 235 papers (56%) that appeared to refer to BGC-803, BSG-803, BSG-823, GSE-1, HGC-7901, HGC-803 and/or MGC-823 as independent cell lines. We could not find publications describing how these cell lines were established, and they were not indexed in claimed externally accessible cell line repositories. While some papers stated that STR profiles had been generated for BGC-803, GSE-1 and/or MGC-823 cells, no STR profiles were identified. In summary, non-verifiable human cell lines represent new challenges to research reproducibility and require further investigation to clarify their identities."
822,CHEMOKINE SIGNALING IN BREAST CANCER: FOCUS ON CC-MOTIF CHEMOKINE LIGANDS,Sedat Kacar,https://www.biorxiv.org/content/10.1101/2024.03.01.583061v1,"Based on 2020 data from GLOBOCAN, breast cancer holds the highest incidence rate in the majority of countries (159 out of 185 countries) and is the leading cause of mortality in 110 countries Chemokines are 8-10 kDa proteins activating through transmembrane G-coupled receptors (GPCRs) with 24 CC-motif type known human cytokines and 10 respective receptors. Chemokines and chemokines receptors have the potential for new breast cancer therapeutics modalities. In the complex chemokine world, not only one chemokine can bind to multiple receptors but also one receptor can be activated by several chemokine ligands. The fact that immune cells possess the potential to express multiple receptors and also secrete a diverse number of chemokines further intensifies the intricate and challenging to grasp chemokines interaction with receptors and microenvironment. In addition, the implication of chemokines in the malignant activation of tumor cells makes them indispensable contributors to the cancer microenvironment and influences the fate of tumor cells and the overall survival of the patients. Therefore, herein, we aimed in this study at attracting the researchers’ attention to the particular function of all known CC-motif chemokines and to-date findings, their expressional changes in normal, tumor and tumor adjacent tissues, important key effects in breast cancer and more importantly, we analyzed the breast tumor samples’ expression data retrieved from TCGA, Xena UCSC as well as UALCAN database regarding to showing any potential to be a general, subclass-specific or stage-specific marker as well as effects of overall survival of the patients and their correlation with literature findings. Basically, we desire this study to be a sort of reference insights for effects of human CC-motif chemokines in breast cancer or provide ready-to-use source and insights for researchers with the graphs and analyzes from different databases."
823,IL6 mediated cFLIP downregulation increases the migratory and invasive potential of triple negative breast cancer cell,"Samraj Sinha, Rajdeep Roy, Nilesh Barman, Purandar Sarkar, Abhik Saha, Nabendu Biswas",https://www.biorxiv.org/content/10.1101/2024.01.14.575471v2,"c-FLIP (cellular FLICE-Like Inhibitor of Apoptotic protein) which belongs to the negative regulators of the death receptor pathway, control apoptosis in a number of cancers. literatures suggest that its overexpression facilitate cancer progression and also helps in the drug resistance. However, there is a very few data available to show how it control metastasis. Moreover, how cFLIP is regulated during the progression of cancer into advanced stage and its mechanism of action on tumor cell migration and invasion is yet to be known. Our TCGA data analysis has shown that cFLIP is downregulated in many cancers, including breast cancer, especially at the later stages. when, we analysed and compared early-stage breast carcinoma cell line MCF7 (luminal) and advanced stage triple negative cell line MDAMB-231, which is highly metastatic, we found a negative correlation between cFLIP expression and metastasis. Our results indicated that Il6, one of the most prominent cytokines inside tumor microenvironment, activated p38 and the later helped in cFLIP downregulation in MDA-MB-231 cell line. Moreover, we have found that cFLIP negatively regulated autophagy and this autophagy downregulation resulted in decrease in metastasis. Thus, we have shown, for the first time, a complete interconnecting pathway in which IL6 mediated p38 activation directly influences metastasis by regulating autophagy via cFLIP downregulation."
824,MurSS: Multi-resolution Selective Segmentation Model for Breast Cancer,"Joonho Lee, Geongyu Lee, Tae-Young Kwak, Sunwoo Kim, Min-Sun Jin, Chungyeul Kim, Hyeyoon Chang",https://www.biorxiv.org/content/10.1101/2023.10.10.561807v1,"We propose the Multi-resolution Selective Segmentation model (MurSS) for segmenting benign, Ductal Carcinoma In Situ, and Invasive Ductal Carcinoma in breast resection Hematoxylin and Eosin stained Whole Slide Images. MurSS simultaneously trains on context information from a wide area at low resolution and content information from a local area at high resolution, aiming for a more accurate diagnosis. Additionally, through the selection stage, it provides solutions for ambiguous tissue regions. Our proposed MurSS achieves a mean Intersection of Union performance of 91.1%, which is at least 16.8% and at most 19.0% higher than well-known image segmentation models."
828,Construction of a breast cancer predictive nomogram based on diverse cell death methods and reveal tumor microenvironment characterization,"Rihan Wu, Zirui Wang, Chunhui Dong, Yihui Liu, Ling Chen",https://www.biorxiv.org/content/10.1101/2024.05.09.593462v1,Objective To develop a robust predictive model and nomogram for breast cancer (BC) linked to genes associated with diverse cell death methods.
830,Changes in Walking Function and Neural Control following Pelvic Cancer Surgery with Reconstruction,"Geng Li, Di Ao, Marleny M. Vega, Payam Zandiyeh, Shuo-Hsiu Chang, A.N. Penny, Valerae O. Lewis, Benjamin J. Fregly",https://www.biorxiv.org/content/10.1101/2024.02.27.582423v1,"Surgical planning and custom prosthesis design for pelvic cancer patients is challenging due to the unique clinical characteristics of each patient and the significant amount of pelvic bone and hip musculature often removed. Limb-sparing internal hemipelvectomy surgery with custom prosthesis reconstruction has become a viable option for this patient population. However, little is known about how post-surgery walking function and neural control change from pre-surgery conditions. This case study combined comprehensive human movement data collection with personalized neuromusculoskeletal computer modeling to provide a thorough assessment of pre-to post-surgery changes in walking function and neural control for a single pelvic sarcoma patient who received internal hemipelvectomy surgery with custom prosthesis reconstruction. Extensive walking data (video motion capture, ground reaction, and EMG) were collected from the patient before surgery and after plateau in recovery after surgery. Pre- and post-surgery personalized neuromusculoskeletal computer models of the patient were then constructed using the patient’s pre- and post-surgery walking data. These models were used to calculate the patient’s pre- and post-surgery joint motions, joint moments, and muscle synergies. The calculated muscle synergies were described by time-invariant synergy vectors and time-varying synergy activations, were consistent with the patient’s experimental EMG data, and produced the patient’s experimental joint moments found via inverse dynamics. The patient’s post-surgery walking function was marked by a slower self-selected walking speed coupled with several compensatory mechanisms necessitated by lost or impaired hip muscle function, while the patient’s post-surgery neural control demonstrated a dramatic change in coordination strategy (as evidenced by modified synergy vectors) with little change in recruitment timing (as evidenced by conserved synergy activations). Furthermore, the patient’s post-surgery muscle activations were fitted accurately using the patient’s pre-surgery synergy activations but poorly using the patient’s pre-surgery synergy vectors. These results provide valuable information about which aspects of post-surgery walking function could potentially be improved through modifications to surgical decisions, custom prosthesis design, or rehabilitation protocol, as well as how computational simulations could be formulated to predict post-surgery walking function reliably given a patient’s pre-surgery walking data and the planned surgical decisions and custom prosthesis design."
832,The landscape of cancer rewired GPCR signaling axes,"Chakit Arora, Marin Matic, Pierluigi DiChiaro, Natalia De Oliveira Rosa, Francesco Carli, Lauren Clubb, Lorenzo Amir Nemati Fard, Giorgos Kargas, Giuseppe Diaferia, Ranka Vukotic, Luana Licata, Guanming Wu, Gioacchino Natoli, J. Silvio Gutkind, Francesco Raimondi",https://www.biorxiv.org/content/10.1101/2023.03.13.532291v3,"We explored the dysregulation of GPCR ligand signaling systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes, which revealed that multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes. We showed that biosynthetic pathway enrichment from enzyme expression recapitulated pathway activity signatures from metabolomics datasets, providing valuable surrogate information for GPCRs responding to organic ligands. We found that several GPCRs signaling components were significantly associated with patient survival in a cancer type-specific fashion. The expression of both receptor-ligand (or enzymes) partners improved patient stratification, suggesting a synergistic role for the activation of GPCR networks in modulating cancer phenotypes. Remarkably, we identified many such axes across several cancer molecular subtypes, including many pairs involving receptor- biosynthetic enzymes for neurotransmitters. We found that GPCRs from these actionable axes, including e.g., muscarinic, adenosine, 5-hydroxytryptamine and chemokine receptors, are the targets of multiple drugs displaying anti-growth effects in large-scale, cancer cell drug screens. We have made the results generated in this study freely available through a webapp (gpcrcanceraxes.bioinfolab.sns.it)."
833,Discovery and evaluation of novel biomarkers reveal dasatinib as a potential treatment for a specific subtype of Triple-Negative Breast Cancer,"D Ortega-Álvarez, D Tébar-García, M Casado-Pelaez, E Castillo-Agea, J Balibrea-Rull, D Olivares-Osuna, D Pérez-Parra, C Guardia, E Musulén, E Vinuesa-Pitarch, E Sánchez-López, F Postigo-Corrales, E Ballana, A Martínez-Cardús, M Margelí, M Esteller, PL Fernández-Ruiz, G Luengo-Gil, E Mereu, EM Galán-Moya, V Rodilla",https://www.biorxiv.org/content/10.1101/2024.07.24.603752v1,"Triple-negative breast cancer (TNBC) represents the most heterogeneous and aggressive subtype of breast carcinomas, characterized by the absence of clinical biomarkers (ERα, PR, and HER2) and the lack of targeted therapies. In this regard, several clinical trials have consistently failed to effectively stratify patients and identify specific treatments that elicit substantial responses. This study aims to pinpoint biomarkers expressed exclusively in the basal mammary epithelial compartment, facilitating a refined subclassification of this breast cancer subtype. Using computational analyses of single-cell RNA sequencing data, we have identified a list of genes associated with basal identity (BC-markers). Histological validation in 137 human samples has enabled us to categorize TNBC patients into BC-positive and BC-negative TNBC subtypes. Significantly, the presence of these markers correlates with a poorer prognosis in TNBC patients. Functional analyses have revealed a pivotal role for TAGLN in cell migration, likely influencing tumor aggressiveness. Further, we discovered that BC-marker expression is associated with the mesenchymal phenotype and increased sensitivity to the tyrosine kinase inhibitor dasatinib, particularly in BC-positive TNBC, suggesting novel therapeutic avenues. In our study, TAGLN emerged as a potential predictive biomarker for dasatinib responsiveness, offering new directions for personalized therapy for TNBC patients."
835,Induction of cytoplasmic dsDNA and cGAS-STING immune signaling after exposure of breast cancer cells to X-rays or high energetic carbon ions,"C. Totis, N. B. Averbeck, B. Jakob, M. Schork, G. Volpi, D.F. Hintze, M. Durante, C. Fournier, A. Helm",https://www.biorxiv.org/content/10.1101/2024.07.23.604756v1,"Radiotherapy can trigger activation of the cGAS-STING axis via cytoplasmic dsDNA fragment induction. The activation of cGAS–STING initiates innate immune signaling mediated by interferon type-I that can contribute to eradicate the malignancy. The effect was shown to depend on the fractionation scheme employed. We hypothesized that the innate immune response can also depend on radiation quality because densely ionizing radiation, such as carbon ions, have different effects on DNA lesion quality. We show here that carbon ions induced a significantly higher yield of cytosolic dsDNA fragments per unit dose as compared to photons in an in vitro 4T1 breast cancer model. The higher efficiency also translated in expression and release of interferon-β by the tumor cells. Cytoplasmic dsDNA fragments as well as interferon-β release increased with doses up to 24 Gy and no differences for a fractionation scheme (3x8 Gy) were found as compared to the single high doses of photons. In conclusion, we found that the release of interferon-β after radiation is increasing with the radiation dose up to 20 Gy and that carbon ions have the potential to elicit a strong innate immune signaling."
836,Pan-cancer analysis reveals embryonic and hematopoietic stem cell signatures to distinguish different cancer subtypes,"Jiali Lei, Jiangti Luo, Qian Liu, Xiaosheng Wang",https://www.biorxiv.org/content/10.1101/2023.07.05.547742v1,"Purpose Stem cells-like properties in cancer cells may confer cancer development and therapy resistance. With the advancement of multi-omics technology, the multi-omics-based exploration of cancer stemness has attracted certain interests. However, subtyping of cancer based on the combination of different types of stem cell signatures remains scarce."
838,Structural basis of Fusobacterium nucleatum adhesin Fap2 interaction with receptors on cancer and immune cells,"Felix Schöpf, Gian L. Marongiu, Klaudia Milaj, Thiemo Sprink, Judith Kikhney, Annette Moter, Daniel Roderer",https://www.biorxiv.org/content/10.1101/2024.02.28.582045v1,"The intestinal microbiome (IM) is decisive for the human host’s health. Numerous microbiota drive the progression of colorectal cancer (CRC), the third-most common cancer worldwide. The Gram-negative Fusobacterium nucleatum (Fn) is overrepresented in the IM of CRC patients and has been correlated with the emergence, progression, and metastasis of tumors. A key pathogenic factor of Fn is the adhesin Fap2, an autotransporter protein that facilitates association to cancer and immune cells via two receptors, the glycan Gal-GalNAc and the T-cell protein TIGIT, respectively. The latter interaction leads to deactivation of immune cells. Mechanistic details of the Fap2/TIGIT interaction remain elusive due to the lack of high-resolution structural data. Here, we report a system to recombinantly express functional Fap2 on the Escherichia coli surface, which interacts with Gal-GalNAc on cancer cells and with purified TIGIT with submicromolar affinity. Cryo-EM structures of Fap2, alone and in complex with TIGIT, show that the ∼50 nm long rod-shaped Fap2 extracellular region binds to TIGIT on its membrane-distal tip via an extension of a β-helix domain. Moreover, by combining structure predictions, cryo-EM, docking and MD simulations, we identified a binding pit for Gal-GalNAc on the tip of Fap2. Our data represent the first purification and high-resolution structural analysis of a Fn autotransporter adhesin and its receptor association."
839,Exploring a large cancer cell line RNA-sequencing dataset with k-mers,"Chloé Bessière, Haoliang Xue, Benoit Guibert, Anthony Boureux, Florence Rufflé, Julien Viot, Rayan Chikhi, Mikaël Salson, Camille Marchet, Thérèse Commes, Daniel Gautheret",https://www.biorxiv.org/content/10.1101/2024.02.27.581927v1,"Analyzing the immense diversity of RNA isoforms in large RNA-seq repositories requires laborious data processing using specialized tools. Indexing techniques based on k-mers have previously been effective at searching for RNA sequences across thousands of RNA-seq libraries but falling short of enabling direct RNA quantification. We show here that RNAs queried in the form of k-mer sets can be quantified in seconds, with a precision akin to that of conventional RNA quantification methods. We showcase several applications by exploring an index of the Cancer Cell Line Encyclopedia (CCLE) collection consisting of 1019 RNA-seq samples. Non-reference RNA sequences such as RNAs harboring driver mutations and fusions, splicing isoforms or RNAs derived from repetitive elements, can be retrieved with high accuracy. Moreover, we show that k-mer indexing offers a powerful means to reveal variant RNAs induced by specific gene alterations, for instance in splicing factors. A web server allows public queries in CCLE and other indexes: https://transipedia.fr. Code is provided to allow users to set up their own server from any RNA-seq dataset."
842,Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer,"Elena Grassi, Valentina Vurchio, George D. Cresswell, Irene Catalano, Barbara Lupo, Francesco Sassi, Francesco Galimi, Sofia Borgato, Martina Ferri, Marco Viviani, Simone Pompei, Gianvito Urgese, Bingjie Chen, Eugenia R. Zanella, Francesca Cottino, Alberto Bardelli, Marco Cosentino Lagomarsino, Andrea Sottoriva, Livio Trusolino, Andrea Bertotti",https://www.biorxiv.org/content/10.1101/2024.02.26.582054v1,"DNA sequence mutability in tumors with chromosomal instability is conventionally believed to remain uniform, constant, and low, based on the assumption that further mutational accrual in a context of marked aneuploidy is evolutionarily disadvantageous. However, this concept lacks robust experimental verification. We adapted the principles of mutation accumulation experiments, traditionally performed in lower organisms, to clonal populations of patient-derived tumoroids and empirically measured the spontaneous rates of accumulation of new DNA sequence variations in seven chromosomally unstable, microsatellite stable colorectal cancers (CRCs) and one microsatellite unstable CRC. Our findings revealed heterogeneous mutation rates (MRs) across different tumors, with variations in magnitude within microsatellite stable tumors as prominent as those distinguishing them from microsatellite unstable tumors. Moreover, comparative assessment of microsatellite stable primary tumors and matched synchronous metastases consistently documented a pattern of MR intensification during tumor progression. Therefore, wide-range diversity and progression-associated evolvability of DNA sequence mutational instability emerge as unforeseen hallmarks of microsatellite stable CRC, complementing karyotype alterations as selectable traits to increase genetic variation."
843,MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer,"Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Aktan Alpsoy, Francesca Minicozzi, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E. Demerdash, David L. Spector, David A. Tuveson, Paolo Cifani, Christopher R. Vakoc",https://www.biorxiv.org/content/10.1101/2024.02.26.582171v1,"The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts anti-tumor activity in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression."
844,"Olive phenolic compounds, potent tankyrase 1 inhibitor exhibit anti colon cancer effects by blocking Wnt/β-catenin pathway","Arindam Sain, Soumen Barman, Dipsikha Khamrai, M Srinivas, Prerna Singh, Bhargav Simpi, Mayuri Varshney, Debdut Naskar",https://www.biorxiv.org/content/10.1101/2024.05.08.593091v1,"Colon cancer (CC) needs special attention to develop novel targets and therapeutic approaches, as the total number of morbidity and mortality is growing rapidly. Although Olive has been long reported for its anti-CC activities but the mode is not completely understood yet. Here, we targeted tankysare 1 (TNKS), an important mediator of the Wnt/β-catenin pathway, crucial in colon carcinogenesis. Bioinformatics analysis revealed that the mutation and copy number alterations of TNKS is found to be 12% whereas the proteins expression of TNKS is moderate to high in tumor groups vs normal in CC datasets. On the more, TNKS and its positively associated genes are found to be concomitant with several carcinogenesis related biological processes and signaling pathways. Further, three olive phytochemicals (apigenin, luteolin, and quercetin), which were shortlisted by employing filters like drug likeness and toxicity screening, molecular docking and finally molecular dynamics simulations, can target tankyrase 1. These ployphenols demonstrated cytotoxic effect in CC (HT-29) cells either alone or in combination. Further, these compounds successfully reduced β-catenin level and its target genes (CCND1, CDK4, and MYC). Overall, inhibition of the Wnt/β-catenin pathway by targeting tankyrase 1 was revealed as one of the anti-CC mechanisms of olive polyphenols."
846,Deciphering Cancer Genomes with GenomeSpy: A Grammar-Based Visualization Toolkit,"Kari Lavikka, Jaana Oikkonen, Yilin Li, Taru Muranen, Giulia Micoli, Giovanni Marchi, Alexandra Lahtinen, Kaisa Huhtinen, Rainer Lehtonen, Sakari Hietanen, Johanna Hynninen, Anni Virtanen, Sampsa Hautaniemi",https://www.biorxiv.org/content/10.1101/2023.10.06.561159v1,"Background Visualization is an indispensable facet of genomic data analysis. Despite the abundance of specialized visualization tools, there remains a distinct need for tailored solutions. However, their implementation typically requires extensive programming expertise from bioinformaticians and software developers, especially when building interactive applications. Toolkits based on visualization grammars offer a more accessible, declarative way to author new visualizations. Nevertheless, current grammar-based solutions fall short in adequately supporting the interactive analysis of large data sets with extensive sample collections, a pivotal task often encountered in cancer research."
847,Exosomal miRNA-124 is involved in the immune regulation of cervical cancer by regulating CD45 alternative splicing,"Minxing Liang, Yuyang Yuan, Chengyi Chen, Qiyu Wang, Bo Lan, Jun Yang, Xin Li, Yue Yin",https://www.biorxiv.org/content/10.1101/2024.05.06.592634v1,Objective To investigate the regulatory mechanism of miRNA-124 in tumor immune regulation of cervical cancer.
849,Cell Fate Simulation Reveals Cancer Cell Features in the Tumor Microenvironment,"Sachiko Sato, Ann Rancourt, Masahiko S. Satoh",https://www.biorxiv.org/content/10.1101/508705v4,"To elucidate the dynamic evolution of cancer cell characteristics within the tumor microenvironment (TME), we developed an integrative method combining single-cell tracking, cell fate simulation, and three-dimensional (3D) TME modeling. We began our investigation by analyzing the spatiotemporal behavior of individual cancer cells in cultured pancreatic and cervical cancer cell lines, with a focus on the α2-6 sialic acid (2-6Sia) modification on glycans, which is associated with cell stemness. Our findings revealed that pancreatic cancer cells exhibited significantly higher levels of 2-6Sia modification, correlating with enhanced reproductive capabilities, whereas cervical cancer cells showed less prevalence of this modification. To accommodate the in vivo variability of 2-6Sia levels, we employed a cell fate simulation algorithm that digitally generates cell populations based on our observed data, simulating cell growth patterns. Subsequently, we constructed a 3D TME model incorporating these deduced cell populations along with specific immune cell landscapes derived from 193 cervical and 172 pancreatic cancer cases. Our analysis suggests that pancreatic cancer cells are less influenced by the immune cell landscape within the TME compared to cervical cancer cells, highlighting that the fate of cancer cells is shaped by both the surrounding immune landscape and the intrinsic characteristics of the cancer cells."
850,Overcoming the nutritional immunity by engineering iron scavenging bacteria for cancer therapy,"Sin-Wei Huang, See-Khai Lim, Yao-An Yu, Yi-Chung Pan, Wan-Ju Lien, Chung-Yuan Mou, Che-Ming Jack Hu, Kurt Yun Mou",https://www.biorxiv.org/content/10.1101/2023.07.25.550605v3,"Certain bacteria demonstrate the ability to target and colonize the tumor microenvironment, a characteristic that positions them as innovative carriers for delivering various therapeutic agents in cancer therapy. Nevertheless, our understanding of how bacteria adapt their physiological condition to the tumor microenvironment remains elusive. In this work, we employed liquid chromatography-tandem mass spectrometry to examine the proteome of E. coli colonized in murine tumors. Comparing to E. coli cultivated in the rich medium, we found that E. coli colonized in tumors notably upregulated the processes related to ferric ions, including the enterobactin biosynthesis and iron homeostasis. This finding indicated that the tumor is an iron-deficient environment to E. coli. We also found that the colonization of E. coli in the tumor led to an increased expression of lipocalin 2 (LCN2), a host’s protein that can sequester the enterobactin. We therefore engineered E. coli in order to evade the nutritional immunity provided by LCN2. By introducing the IroA cluster, the E. coli synthesizes the glycosylated enterobactin, which creates steric hindrance to avoid the LCN2 sequestration. The IroA-E. coli showed enhanced resistance to LCN2 and significantly improved the anti-tumor activity in mice. Moreover, the mice cured by the IroA-E. coli treatment became resistant to the tumor re-challenge, indicating the establishment of immunological memory. Overall, our study underscores the crucial role of bacteria’s ability to acquire ferric ions within the tumor microenvironment for effective cancer therapy."
851,Fair molecular feature selection unveils universally tumor lineage-informative methylation sites in colorectal cancer,"Xuan Cindy Li, Yuelin Liu, Alejandro A. Schäffer, Stephen M. Mount, S. Cenk Sahinalp",https://www.biorxiv.org/content/10.1101/2024.02.22.580595v1,"In the era of precision medicine, performing comparative analysis over diverse patient populations is a fundamental step towards tailoring healthcare interventions. However, the critical aspect of equitably selecting molecular features across multiple patients is often overlooked. To address this challenge, we introduce FALAFL (FAir muLti-sAmple Feature seLection), an algorithmic approach based on combinatorial optimization. FALAFL is designed to bridge the gap between molecular feature selection and algorithmic fairness, ensuring a fair selection of molecular features from all patient samples in a cohort."
852,SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis,"Ricardo Coelho, Brinton Seashore-Ludlow, Sarah Schütz, Flavio Christopher Lombardo, Elisabeth Moussaud-Lamodière, Ruben Casanova, Joanna Ficek-Pascual, Kathrin Brunhilde Labrosse, Michal Hensler, Monica Lopez-Nunez, Natalie Rimmer, Andre Fedier, Renata Lima, Céline Montavon Sartorius, Christian Kurzeder, Franziska Singer, Anne Bertolini, Tumor Profiler Consortium, Jitka Fucikova, Gunnar Rätsch, Bernd Bodenmiller, Olli Kallioniemi, Päivi Östling, Leonor David, Viola Heinzelmann-Schwarz, Francis Jacob",https://www.biorxiv.org/content/10.1101/2024.01.24.576987v2,"Resistance to chemotherapy and PARPi inhibitors remains a critical challenge in the treatment of epithelial ovarian cancer, mainly due to disabled apoptotic responses in tumor cells. Given mesothelin’s pivotal role in ovarian cancer and its restricted expression in healthy tissues, we conducted a drug-screening discovery analysis across a range of genetically modified cancer cells to unveil mesothelin’s therapeutic impact. We observed enhanced cell death in cancer cells with low mesothelin expression when exposed to a second mitochondria-derived activator of caspases (SMAC) mimetics, and demonstrated a compelling synergy when combined with chemotherapy in ex vivo patient-derived cultures and zebrafish tumor xenografts. Mechanistically, the addition of the SMAC mimetics drug birinapant to either carboplatin or paclitaxel triggered the activation of the Caspase 8-dependent apoptotic program facilitated by TNFLJ signaling. Multimodal analysis of neoadjuvant-treated patient samples further revealed an association between tumor-associated macrophages and the activation of TNFLJ-related pathways. Our proposed bimodal treatment shows promise in enhancing the clinical management of patients by harnessing the potential of SMAC mimetics alongside conventional chemotherapy."
853,Pan-Cancer Drug Response Prediction Using Integrative Principal Component Regression,"Qingzhi Liu, Gen Li, Veerabhadran Baladandayuthapani",https://www.biorxiv.org/content/10.1101/2023.10.03.560366v1,"The pursuit of precision oncology heavily relies on large-scale genomic and pharmacological data garnered from preclinical cancer model systems such as cell lines. While cell lines are instrumental in understanding the interplay between genomic programs and drug response, it well-established that they are not fully representative of patient tumors. Development of integrative methods that can systematically assess the commonalities between patient tumors and cell-lines can help bridge this gap. To this end, we introduce the Integrative Principal Component Regression (iPCR) model which uncovers both joint and model-specific structured variations in the genomic data of cell lines and patient tumors through matrix decompositions. The extracted joint variation is then used to predict patient drug responses based on the pharmacological data from preclinical models. Moreover, the interpretability of our model allows for the identification of key driver genes and pathways associated with the treatment-specific response in patients across multiple cancers. We demonstrate that the outputs of the iPCR model can assist in inferring both model-specific and shared co-expression networks between cell lines and patients. We show that iPCR performs favorably compared to competing approaches in predicting patient drug responses, in both simulation studies and real-world applications, in addition to identifying key genomic drivers of cancer drug responses."
854,Electroacupuncture regulates microglia activation through the STING/NF-κB pathway to reduce pain in bone cancer pain model,"Ying Liang, Wenhao Liu, Zhiyi Shen, Xu Yan, Yihan He, Nenggui Xu",https://www.biorxiv.org/content/10.1101/2024.05.08.593142v1,"Cancer pain is a global public health problem. The mechanism of cancer pain is complex, and opioid analgesics, which are widely used clinically, have obvious addiction and side effects, which seriously affect patients’life functions and may aggravate their anxiety, depression and other negative emotions. Acupuncture has a history of thousands of years in China, and acupuncture analgesia has been confirmed by many studies. This study investigated whether electroacupuncture can alleviate abnormal pain in bone cancer pain (BCP) mouse models and its possible central mechanism. A bone cancer pain model was established by injecting Lewis lung cancer cells into the left femoral cavity of adult male mice. Mechanical paw withdrawal threshold was tested baseline before surgery and 1, 4, 7, 10, 14 and 21 days after surgery. On day 21, behaviours related to depression emotions were tested. After the behaviours, the femurs were removed to observe pathological changes, the neck was broken and brain tissue was collected from the basal lateral amygdala (BLA) area for subsequent Western Blot and ELISA experiments were performed to verify the expression of (stimulator of interferon genes, STING) STING/NF-κB pathway proteins and the expression of inflammatory factors. Immunofluorescence of Ionized calcium-binding adapter molecule-1 (Iba-1) and STING in the basal lateral amygdala (BLA) brain region was also performed. The results show that electroacupuncture can increase the pain threshold of the bone cancer pain model and alleviate the depressive-like emotional phenotype. Electroacupuncture inhibited the expression of STING/NF-κB pathway proteins, activation of microglia and release of inflammatory factors in the basal lateral amygdala (BLA) area. Therefore, this study shows that electroacupuncture may relieve bone cancer pain by regulating microglial activation and inflammatory factor release through the STING/NF-κB pathway."
855,mTOR controls growth and internal architecture of human breast cancer spheroids,"Katharina Hötte, Sabine C. Fischer, Alexander Schmitz, Michael Koch, Sanam Saeifar, Ernst H.K. Stelzer, Francesco Pampaloni",https://www.biorxiv.org/content/10.1101/2024.02.24.580871v1,"mTOR is a serine/threonine kinase participating in two distinct functional complexes: mTORC1 and mTORC2. mTORC1 regulates protein translation, cell cycle progression and autophagy. mTORC2 controls cell survival, proliferation and actin cytoskeleton reorganization. mTOR signaling is often deregulated during breast cancer. We investigated how mTOR and its downstream process autophagy determine the inner architecture of solid tumor aggregates at multiple levels. We focused on structures, which are morphologically altered during progression of cancer, including: nuclei number and volume, cell density, number, shape and volume of polarized structures. We developed a breast cancer spheroid model, in which the effects of mTOR and autophagy modulation were investigated by pharmacological inhibition mTOR signaling and induction autophagy, as well as using ATG7 KO spheroids. Spheroids were imaged with light sheet-based fluorescence microscopy and data were quantitatively analyzed. Our data suggest that mTORC1 regulates the spheroid volume, cell number and size. mTORC2 controls nuclei volume and determines growth and elongation of polarized acini inside a spheroid."
857,Identifying targetable metabolic dependencies across colorectal cancer progression,"Danny N. Legge, Ewelina Stanko, Amy K. Holt, Caroline J. Bull, Tracey J. Collard, Madhu Kollareddy, Jake Bellamy, Sarah Groves, Eric H. Ma, Emma Hazelwood, David Qualtrough, Borko Amulic, Karim Malik, Ann C. Williams, Nicholas Jones, Emma E. Vincent",https://www.biorxiv.org/content/10.1101/2022.03.23.485483v5,"Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system – comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease."
858,AI-driven Classification of Cancer-Associated Fibroblasts Using Morphodynamic and Motile Features,"Minwoo Kang, Chanhong Min, D. Somayadineshraj, Jennifer H. Shin",https://www.biorxiv.org/content/10.1101/2024.02.22.581611v1,"The heterogeneous natures of cancer-associated fibroblasts (CAFs) play critical roles in cancer progression, with some promoting tumor growth while others inhibit it. To utilize CAFs as a target for cancer treatment, issues with subtypes of CAFs must be resolved such that specific pro-tumorigenic subtypes can be suppressed or reprogrammed into anti-tumorigenic ones. Currently, single-cell RNA sequencing (scRNA-Seq) is a prevalent strategy for classifying CAFs, primarily based on their biomolecular features."
859,Systematic Analysis of Human Colorectal Cancer scRNA-seq Revealed Limited Pro-tumoral IL-17 Production Potential in Gamma Delta T Cells,"Ran Ran, Martin Trapecar, Douglas K. Brubaker",https://www.biorxiv.org/content/10.1101/2024.07.18.604156v1,"Gamma delta (γδ) T cells play a crucial role in anti-tumor immunity due to their cytotoxic properties. However, the role and extent of γδ T cells in production of pro-tumorigenic interleukin-17 (IL-17) within the tumor microenvironment (TME) of colorectal cancer (CRC) remains controversial. In this study, we re-analyzed nine published human CRC whole-tissue single-cell RNA sequencing (scRNA-seq) datasets, identifying 18,483 γδ T cells out of 951,785 total cells, in the neoplastic or adjacent normal tissue of 165 human CRC patients. Our results confirm that tumor-infiltrating γδ T cells exhibit high cytotoxicity-related transcription in both tumor and adjacent normal tissues, but critically, none of the γδ T cell clusters showed IL-17 production potential. We also identified various γδ T cell subsets, including Teff, TRM, Tpex, and Tex, and noted an increased expression of cytotoxic molecules in tumor-infiltrating γδ T cells compared to their normal area counterparts. Our work demonstrates that γδ T cells in CRC primarily function as cytotoxic effector cells rather than IL-17 producers, mitigating the concerns about their potential pro-tumorigenic roles in CRC, highlighting the importance of accurately characterizing these cells for cancer immunotherapy research and the unneglectable cross-species discrepancy between the mouse and human immune system in the study of cancer immunology."
860,Arrested Agonist Paradigm For Selective Radiosensitization of Prostate Cancer,"Jonathan B. Coulter, Michael C. Haffner, Yonggang Zhang, Haoming Zhou, Minh-Tam Pham, Jiayu Chen, Roshan Chikarmane, Alok Mishra, Maire S. Mehl, Stella Kazibwe, Kirsten Choi, Ava Archey, Sarayu Valluri, Shawn E. Lupold, Daniel Song, Angelo De Marzo, William G. Nelson, Theodore L. DeWeese, Srinivasan Yegnasubramanian",https://www.biorxiv.org/content/10.1101/2023.10.01.560227v1,"As a prototypical nuclear hormone receptor, the androgen receptor (AR) signals via a sequential cascade triggered by binding to androgenic ligands such as testosterone and dihydrotestosterone (DHT). This cascade includes dimerization of the ligand-receptor complex, nuclear translocation, chromatin binding to response elements, recruitment of TOP2B and co-activator complexes, and induction of an effector transcriptional program. In prostate cancers, this AR signaling cascade is an essential driver of growth and survival, yet its activity confers potential vulnerabilities through transient TOP2B-mediated DNA double strand breaks. We investigated the ability of non-steroidal AR ligands to activate initial steps of the AR signaling cascade up to the point of AR- and TOP2B-mediated double strand breaks, with subsequent arrest of the signaling cascade to prevent induction of pro-growth/survival transcriptional programs in prostate cancer cells. We identified hydroxyflutamide (FLU) as such an androgen receptor arrested agonist; in androgen-deprived conditions, FLU induced AR nuclear translocation, chromatin binding, and TOP2B-mediated double strand breaks, but failed to induce AR target gene expression and prostate cancer cell growth. The FLU-mediated arrest in the signaling cascade could be attributed to the inability of FLU to allow association of AR with SMARCD2, a critical component of the BAF chromatin remodeling complex required for androgen induced AR co-activation. Interestingly, the FLU-induced, AR- and TOP2B-mediated double strand breaks could be used to selectively sensitize AR-positive prostate cancer cells to ionizing radiation in vitro and in vivo. These findings support a novel arrested agonist paradigm for selective radiosensitization of prostate cancer cells without inducing AR-mediated pro-growth and survival transcriptional programs."
861,A senescence-like state is beneficial for ovarian cancer treatment,"Michael Skulimowski, Llilians Calvo, Shuofei Cheng, Isabelle Clément, Lise Portelance, Yu Zhan, Euridice Carmona, Julie Lafontaine, Manon de Ladurantaye, Kurosh Rahimi, Diane Provencher, Anne-Marie Mes-Masson, Francis Rodier",https://www.biorxiv.org/content/10.1101/2023.09.30.560300v1,"High-grade serous ovarian carcinoma (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that tissue-derived primary HGSOC epithelial cultures reflecting the original disease primarily undergo therapy-induced senescence in response to DNA damage and first-line carboplatin/paclitaxel chemotherapy. Unlike previous observations using cell lines, primary HGSOC cell TIS displays a stable senescence proliferation arrest and p16INK4A expression, and is accompanied by persistent DNA damage, an inflammatory secretome, and senolytic sensitivity, suggesting new avenues for selective pharmacological manipulation of these cells. Whether cell senescence induced by cancer therapy is beneficial or detrimental to clinical outcomes remains unknown. Single cell comparison of pre- and post-chemotherapy patient HGSOC tissue samples revealed changes in physio-pathological senescence biomarkers supporting a post-treatment senescence-like state. Importantly, patients with stronger senescence signatures post-chemotherapy displayed better 5-year survival suggesting that senescence accounts, at least in part, for beneficial cellular responses to treatment. Given that ovarian cancer epithelial cells almost universally retain the capacity to undergo senescence and that senescence appears beneficial in this context, HGSOC senescence-centric therapeutic avenues should be further explored."
862,An Introductory Implementation of Breast Cancer Detection from Mammograms and Pixel Intensity with Efficient-Net Other Neural Nets,"Sheekar Banerjee, Humayun Kabir",https://www.biorxiv.org/content/10.1101/2024.05.04.592536v1,"In the world of civilized medical scientific progression, cancer has become a very serious threat for the natural survival of human beings where breast cancer stays to be the second most dangerous type. Mostly women are embracing very pathetic death because of the delayed detection of the cancer cell in the certain period of their life. Machine Learning mechanism can definitely help at the stage of medical imaging which can escalate the diagnosis of the cancer cells at a very early age of its biological formation and development. We focused upon the deep learning approach to classify the normal and abnormal breast according to the medical imaging from the MIAS dataset of Mammograms and Pixel Intensity. The Convolution Neural Network (CNN) alongside ResNet, AmoebaNet and EfficientNet have been used for the detection with 330 mammograms in which 194 images are normal and 136 are having the identification of abnormal breasts. The accuracy of the entire experimental results was carrying the torch of potential legacy of deep learning in the medical imaging arena. The research is ongoing for the further development and optimization of CNN, AmoebaNet-C and EfficientNet architecture for the Pixel Intensity with higher accuracy, proper segmentation and masking. Source code of this research is available here: https://github.com/ac005sheekar/Breast-Cancer-Detection-with-Pixel-Intensity/"
864,Identifying cancer cells from calling single-nucleotide variants in scRNA-seq data,"Valérie Marot-Lassauzaie, Sergi Beneyto-Calabuig, Benedikt Obermayer, Lars Velten, Dieter Beule, Laleh Haghverdi",https://www.biorxiv.org/content/10.1101/2024.02.21.581377v1,"Single cell RNA sequencing (scRNA-seq) data is widely used to study cancer cell states and their heterogeneity. However, the tumour microenvironment is usually a mixture of healthy and cancerous cells and it can be difficult to fully separate these two populations based on transcriptomics alone. If available, somatic single nucleotide variants (SNVs) observed in the scRNA-seq data could be used to identify the cancer population. However, calling somatic SNVs in scRNA-seq data is a challenging task, as most variants seen in the short read data are not somatic, but can instead be germline variants, RNA edits or transcription, sequencing or processing errors. Additionally, only variants present in actively transcribed regions for each individual cell will be seen in the data. To address these challenges, we develop CCLONE (Cancer Cell Labelling On Noisy Expression), an interpretable tool adapted to handle the uncertainty and sparsity of SNVs called from scRNA-seq data. CCLONE jointly identifies cancer clonal populations, and their associated variants. We apply CCLONE on two acute myeloid leukaemia datasets and one lung adenocarcinoma dataset and show that CCLONE captures both genetic clones and somatic events for multiple patients. These results show how CCLONE can be used to gather insight into the course of the disease and the origin of cancer cells in scRNA-seq data."
865,Peptide Amphiphiles Hitchhike on Endogenous Biomolecules for Enhanced Cancer Imaging and Therapy,"Jared M. Fischer, Morgan Stewart, Mingchong Dai, Samuel Drennan, Samantha Holland, Arnaud Quentel, Sinan Sabuncu, Benjamin R. Kingston, Isabel Dengos, Li Xiang, Karla Bonic, Florian Goncalves, Xin Yi, Srivathsan Ranganathan, Bruce P. Branchaud, Leslie L. Muldoon, Ramon F. Barajas Jr, Adem Yildirim",https://www.biorxiv.org/content/10.1101/2024.02.21.580762v1,"The interactions of nanomaterials with biomolecules in vivo determine their biological fate. Here, we show that a self-assembled peptide amphiphile nanostructure (namely SA-E) dynamically interacts with endogenous biomolecules and takes advantage of naturally occurring processes to target a broad range of solid tumors. Upon in vivo administration, self-assembled nanostructures of SA-E disassemble and reassemble with lipoproteins in circulation. Hitchhiking on lipoproteins prolongs the blood circulation of SA-E and allows it to cross endothelial barriers through transcytosis. At the tumor site, SA-E internalizes into cancer cells by mainly interacting with lipid-raft domains on cell membranes. By exploiting these endogenous interactions, SA-E demonstrated high tumor accumulation with extended retention in various xenograft, syngeneic, patient-derived xenograft, or transgenic mouse and rat models. In addition, SA-E enabled the effective delivery of highly potent chemotherapy to breast and glioma tumors with reduced side effects. With its simple and modular design and universal tumor accumulation mechanism, SA-E represents a promising platform for broad applications in cancer imaging and therapy."
866,Imaging and quantification of prostate cancer-associated bone by polarization-sensitive optical coherence tomography,"Chris Zhou, Naomi Jung, Samuel Xu, Felipe Eltit-Guersetti, Xin Lu, Qiong Wang, Doris Liang, Colm Morrissey, Eva Corey, Lawrence D. True, Rizhi Wang, Shuo Tang, Michael E. Cox",https://www.biorxiv.org/content/10.1101/2024.02.21.581336v1,"Prostate cancer frequently metastasizes to bone, leading to a spectrum of osteosclerotic and osteolytic lesions that cause debilitating symptoms. Accurate differentiation of bone tissue or lesion types can provide opportunity for local pathologic investigation, which is critical for understanding the bone metastasis and remains challenging. Current imaging methods lack the ability to directly differentiate tissues based on collagen organization and may induce invasive effect on bone tissues. We introduce Polarization-Sensitive Optical Coherence Tomography (PS-OCT) to investigate normal, osteosclerotic, and osteolytic bone tissues. High-resolution PS-OCT imaging reveals collagen fiber arrangement, enabling nuanced distinction of degree of collagen alignment among different bone tissue types or regions. We present a novel feature named degree of ordered organization (DOO), derived from the multiple contrasts of PS-OCT that can quantitatively evaluate bone samples from different pathologic groups, including control,osteoblastic and osteolytic tissues. The capacity of PS-OCT to differentiate trabecular/lamellar and irregular (woven bone) regions within the same specimen is tested and validated on ex-vivo samples extracted from 13 subjects. Our study is the first time that PS-OCT is applied to metastatic bone disease with the aim of enhancing the understanding of bone-related pathologies, and potentially impacting clinical practice. This work demonstrates that PS-OCT can provide useful insight into bone microstructures, and thus it has potential applications across diverse bone disorders."
867,Probiotic neoantigen delivery vectors for precision cancer immunotherapy,"Andrew Redenti, Jongwon Im, Benjamin Redenti, Fangda Li, Mathieu Rouanne, Zeren Sheng, William Sun, Candice R. Gurbatri, Shunyu Huang, Meghna Komaranchath, YoungUk Jang, Jaeseung Hahn, Edward R. Ballister, Rosa L. Vincent, Ana Vardoshivilli, Tal Danino, Nicholas Arpaia",https://www.biorxiv.org/content/10.1101/2023.09.29.560228v1,"Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo1–4. With emerging evidence that bacteria naturally home to tumors5–7 and modulate anti-tumor immunity8,9, one promising application is the development of bacterial vectors as precision cancer vaccines10–12. In this study, we engineered probiotic E. coli Nissle 1917 (EcN) as an anti-tumor vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system which drives potent and specific T cell–mediated anti-cancer immunity that effectively controls or eliminates tumor growth and extends survival in advanced murine primary and metastatic solid tumors. We demonstrate that the elicited anti-tumor immune response involves extensive priming and activation of neoantigen-specific CD4+ and CD8+ T cells, broader activation of both T and NK cells, and a reduction of tumor-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumor-specific neoantigen–derived epitopes within the optimal context to induce specific, effective, and durable systemic anti-tumor immunity."
868,Modulation of H3K4 trimethylation by KDM5A and MLLs impacts metabolic adaptability in prostate and cervical cancer cells,"R. Kirtana, Soumen Manna, Samir Kumar Patra",https://www.biorxiv.org/content/10.1101/2024.05.02.592178v1,"Chemical modifications of chromatin modulate gene expression and induce essential metabolic plasticity for tumor growth. Accumulation of H3K4me3 in the promoter of a gene activates transcription by making the promoter accessible to the polymerases. Methylation of H3K4 is catalysed by MLLs and demethylation of H3K4me3 is catalysed by KDM5 family proteins. Herein, we investigated if genes encoding the enzymes involved in glucose metabolism are dependent on KDM5A and MLL1, and if targeting the H3K4me3 would help in modulating the resilience of cancer cells. We present that KDM5A modulates most of the metabolic genes in a demethylase dependent manner as assesses by H3K4me3 occupancy on G6PD and catalase promoters. Targeting its expression would indeed help in sensitizing cancer cells to ROS dependent apoptotic cell death. We elucidated the differences in the epigenetic regulation in cancerous cells originated from cervical and prostate tissues and used a normal skin keratinocyte for comparison. In cervical and prostate cancers - KDM5A activated glycolysis but downregulates other metabolic processes. In cervical cancer, which majorly depends on PPP, changes in KDM5A did not modulate the G6PD expression. Further, we have shown that curcumin treatment enhanced KDM5A expression and downregulated MLL2 in cancer cell lines but not in keratinocyte cells. Curcumin inhibited metabolic pathways and enhanced apoptosis in cancer cells without affecting keratinocyte cells by modulating KDM5A and MLL levels. This work also strengthens the basic concept that, epigenetic modulations of genes in a tissue precisely depends on signal and sites of modification(s)."
870,CD24a knockout transforms the tumor microenvironment from cold to hot by promoting tumor-killing immune cell infiltration in a murine triple-negative breast cancer model,"Shih-Hsuan Chan, Hsuan-Jung Tseng, Lu-Hai Wang",https://www.biorxiv.org/content/10.1101/2024.07.15.603489v1,"Background CD24 plays a crucial role not only in promoting tumor progression and metastasis but also in modulating macrophage-mediated anti-tumor immunity. However, the impact of tumor CD24 on the immune landscape of the tumor microenvironment (TME) remains poorly explored. Here, we investigated the role of CD24a, murine CD24 gene, in the progression and immune dynamics of the tumor microenvironment (TME) in the 4T1 murine model of triple-negative breast cancer (TNBC). Methods: We employed Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 technology to perform a gene knockout of Cd24a in 4T1 cells. Flow cytometry was utilized to analyze the distribution and number of immune cells, including myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, T cells, and macrophages, within tumors, spleens, and bone marrow. Immunofluorescence (IF) staining was used to detect these immune cells in tumor sections. Additionally, ANDOR Dragonfly High-Speed Confocal was used to perform three-dimensional (3D) mapping of mouse tumors."
872,A Mathematical Framework for Comparison of Intermittent versus Continuous Adaptive Chemotherapy Dosing in Cancer,"Cordelia McGehee, Yoichiro Mori",https://www.biorxiv.org/content/10.1101/2024.02.19.580916v1,"Chemotherapy resistance in cancer remains a barrier to curative therapy in advanced disease. Dosing of chemotherapy is often chosen based on the maximum tolerated dosing principle; drugs that are more toxic to normal tissue are typically given in on-off cycles, whereas those with little toxicity are dosed daily. When intra-tumoral cell-cell competition between sensitive and resistant cells drives chemotherapy resistance development, it has been proposed that adaptive chemotherapy dosing regimens, whereby a drug is given intermittently at a fixed dose or continuously at a variable dose based on tumor size, may lengthen progression free survival over traditional dosing [1]. Indeed, in mathematical models using modified Lotka Volterra systems to study dose timing, rapid competitive release of the resistant population and tumor outgrowth is apparent when cytotoxic chemotherapy is maximally dosed [2]. This effect is ameliorated with continuous (dose modulation) or intermittent (dose skipping) adaptive therapy in mathematical models and experimentally, however, direct comparison between these two modalities has been limited. Here, we develop a mathematical framework to formally analyze intermittent adaptive therapy in the context of bang-bang control theory. We prove that continuous adaptive therapy is superior to intermittent adaptive therapy in its robustness to uncertainty in initial conditions, time to disease progression, and cumulative toxicity. We additionally show that under certain conditions, resistant population extinction is possible under adaptive therapy or fixed-dose continuous therapy. Here, continuous fixed-dose therapy is more robust to uncertainty in initial conditions than adaptive therapy, suggesting an advantage of traditional dosing paradigms."
873,Macropinocytosis mediates resistance to loss of glutamine transport in triple-negative breast cancer,"Kanu Wahi, Natasha Freidman, Qian Wang, Michelle Devadason, Lake-Ee Quek, Angel Pang, Larissa Lloyd, Mark Larance, Fabio Zanini, Kate Harvey, Sandra O’Toole, Yi Fang Guan, Jeff Holst",https://www.biorxiv.org/content/10.1101/2024.02.21.581493v1,"Triple-negative breast cancer (TNBC) relies on glutamine uptake by the transporter ASCT2 to sustain their unique glutamine metabolism and growth. Despite previous data showing cell growth inhibition after ASCT2 knockdown, ASCT2 CRISPR knockout was well-tolerated by breast cancer cell lines. Despite the loss of a glutamine transporter and low rate of glutamine uptake, intracellular glutamine steady state levels were higher in ASCT2 knockout compared to control TNBC cells. Proteomics data revealed upregulation of macropinocytosis, reduction in glutamine efflux and glutamine synthesis in ASCT2 knockout cells. Loss of ASCT2 in TNBC cell line HCC1806 induced a 5-10-fold increase in macropinocytosis across 5 separate ASCT2 knockout clones, compared to a modest 2-fold increase in the shRNA ASCT2 knockdown. By comparison, ASCT2 knockout impaired cell proliferation in a non-macropinocytic breast cancer cell line, HCC1569. These data suggest that macropinocytosis provides a novel resistance mechanism to strategies targeting glutamine uptake alone. Despite this adaptation, TNBC cells continue to rely on glutamine metabolism for their growth, which suggests therapeutic targeting may need to focus on downstream glutamine metabolism pathways."
874,Proteomic Insights into Breast Cancer Response to Brain Cell-Secreted Factors,"Shreya Ahuja, Iulia M. Lazar",https://www.biorxiv.org/content/10.1101/2023.10.22.563488v2,"The most devastating feature of cancer cells is their ability to metastasize to distant sites in the body. HER2+ and TN breast cancers frequently metastasize to the brain and stay potentially dormant for years until favorable conditions support their proliferation. The sheltered and delicate nature of the brain prevents, however, early disease detection and effective delivery of therapeutic drugs. Moreover, the challenges associated with the acquisition of brain biopsies add compounding difficulties to exploring the mechanistic aspects of tumor development, leading to slow progress in understanding the drivers of disease progression and response to therapy. To provide insights into the determinants of cancer cell behavior at the brain metastatic site, this study was aimed at exploring the early response of HER2+ breast cancer cells (SKBR3) to factors present in the brain perivascular niche. The neural microenvironment was simulated by using the secretome of a set of brain cells that come first in contact with the cancer cells upon crossing the blood brain barrier, i.e., endothelial cells (HBEC5i), astrocytes (NHA), and microglia (HMC3). Cytokine microarrays were used to investigate the secretome mediators of intercellular communication, and proteomic technologies for assessing the changes in the behavior of cancer cells upon exposure to the brain cell-secreted factors. The cytokines, growth factors and enzymes detected in the brain secretomes were supportive of inflammatory conditions, indicating a collective functional contribution to cell activation, defense, inflammatory responses, chemotaxis, adhesion, angiogenesis, and ECM organization. The SKBR3 cells, on the other hand, secreted numerous cancer-promoting growth factors that were either absent or present in lower abundance in the brain cell cultures, indicating that upon exposure the SKBR3 cells may have been deprived of favorable conditions for optimal growth. Altogether, the results suggest that the subjection of SKBR3 cells to the brain cell-secreted factors altered their growth potential and drove them toward a state of quiescence, with broader overall outcomes that affected cellular metabolism, adhesion and immune response processes. The findings of this study underscore the key role played by the neural niche in shaping the behavior of metastasized cancer cells, provide insights into the cellular cross-talk that may lead cancer cells into dormancy, and highlight novel opportunities for the development of metastatic breast cancer therapeutic strategies."
876,Oxygen carrying nanoemulsions and respiratory hyperoxia eliminate tumor hypoxia-induced suppression and improve cancer immunotherapy,"Katarina Halpin-Veszeleiova, Michael Mallouh, Ashley Apro, Nuria Romero, Camille Bahr, Maureen Shin, Kelly Ward, Laura Rosenberg, Michail V. Sitkovsky, Bruce Spiess, Stephen M. Hatfield",https://www.biorxiv.org/content/10.1101/2024.02.17.580835v1,"Hypoxia-HIF-1α-driven immunosuppressive transcription and cAMP-elevating signaling through A2A-adenosine receptors (A2AR) represent a major tumor-protecting pathway that enables immune evasion. Recent promising clinical outcomes due to the blockade of the adenosine-generating enzyme CD73 and A2AR in patient’s refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a novel and feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). It is shown that oxygenation agent therapy i) eliminates tumor hypoxia, ii) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby iii) promotes regression of tumors in different anatomical locations. We show that both T cells and NK cells avoid hypoxic tumor areas and that reversal of hypoxia by oxygenation agent therapy increases intratumoral infiltration of activated T cells and NK cells due to re-programming of the tumor microenvironment (TME). Thus, repurposing oxygenation agents in combination with supplemental oxygen may improve current cancer immunotherapies by preventing hypoxia-adenosinergic suppression, promoting immune cell infiltration and enhancing effector responses. These data also suggest that pretreating patients with oxygenation agent therapy may reprogram the TME from immune-suppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy."
877,Spatial Transcriptomics in Breast Cancer Reveals Tumour Microenvironment-Driven Drug Responses and Clonal Therapeutic Heterogeneity,"María José Jiménez-Santos, Santiago García-Martín, Marcos Rubio-Fernández, Gonzalo Gómez-López, Fátima Al-Shahrour",https://www.biorxiv.org/content/10.1101/2024.02.18.580660v1,"Breast cancer is a heterogeneous disease that has the highest incidence and mortality rate among cancers in women worldwide. Breast cancer patients are stratified into three clinical subtypes with different treatment strategies and prognostic values. The development of targeted therapies against the biomarkers that define these strata constitutes one of the precedents of precision oncology, which aims to provide tailored treatments to cancer patients by targeting the molecular alterations found in each tumour. Although this approach has increased patient outcomes, many treatment failure cases still exist. Drug ineffectiveness and relapse have been associated with the coexistence of several malignant subpopulations with different drug sensitivities within the same lesion, a phenomenon known as intratumor heterogeneity. This heterogeneity has been extensively studied from a tumour-centric view, but recently, it has become evident that the tumour microenvironment plays a crucial role in intratumor heterogeneity. However, few studies consider the tumour-microenvironment interplay and its influence on drug sensitivity. In this work, we predict the sensitivity of 10x Visium spatial transcriptomics data from 9 breast cancer patients to >1,200 drugs and verify different response patterns across the tumour, interphase and microenvironment regions. We uncover a sensitivity continuum from the tumour core to the periphery accompanied by a functional gradient. Moreover, we identify conserved therapeutic clusters with distinct response patterns within the tumour region. We link the specific drug sensitivities of each therapeutic cluster to different ligand-receptor interactions that underpin distinct biological functions. Finally, we demonstrate that genetically identical cancer spots may belong to different therapeutic clusters and that this therapeutic heterogeneity is related to their location at the edge or core of tumour ducts. These results highlight the importance of considering the distance to the tumour core and the microenvironment composition when identifying suitable treatments to target intratumor heterogeneity."
878,Mechano-inhibition of Endocytosis Sensitizes Cancer Cells to Fas-induced Apoptosis,"Mehmet H. Kural, Umidahan Djakbarova, Bilal Cakir, Yoshiaki Tanaka, Yasaman Madraki, Emily T. Chan, Valeria Arteaga Muniz, Hong Qian, Jinkyu Park, Lorenzo R. Sewanan, In-Hyun Park, Laura E. Niklason, Comert Kural",https://www.biorxiv.org/content/10.1101/2022.06.14.496195v2,"The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis."
879,Accumulation of Oncogenic Mutations During Progression from Healthy Tissue to Cancer,"Ruibo Zhang, Ivana Bozic",https://www.biorxiv.org/content/10.1101/2024.02.18.580841v1,"Cancers typically result from sequential accumulation of driver mutations in a previously healthy cell. Some of these mutations, such as inactivation of the first copy of a tumor suppressor gene, can be neutral, and some, like those resulting in activation of oncogenes, may provide cells with a selective growth advantage. We study a multi-type branching process that starts with healthy tissue in home-ostasis and models accumulation of neutral and advantageous mutations on the way to cancer. We provide results regarding the sizes of premalignant populations and the waiting times to the first cell with a particular combination of mutations, including the waiting time to malignancy. Finally, we apply our results to two specific biological settings: initiation of colorectal cancer and age incidence of chronic myeloid leukemia. Our model allows for any order of neutral and advantageous mutations and can be applied to other evolutionary settings."
880,Feature Selection Using Lasso Regression Enhances Deep Learning Model Performance For Diagnosis Of Lung Cancer from Transcriptomic Data,Souvik Guha,https://www.biorxiv.org/content/10.1101/2024.05.01.592076v1,"Cancer is a genetic disease where gene mutations are pivotal in disease initiation and pathophysiology. The gene expression profile follows a specific pattern exclusive to each cancer which can be utilized for early and accurate diagnosis. Microarray techniques have emerged as powerful tools capable of simultaneously capturing the expression profiles of thousands of genes. However, because of the high dimensionality of the produced transcriptome data, analysis of the resulting datasets is challenging. Recent advancements in Artificial Intelligence (AI) techniques like Machine Learning (ML) and Deep Learning can be instrumental in efficiently processing these high-dimensional datasets. LASSO-regression is a ML technique that can help to rank the features which could help in feature selection leading to dimensionality reduction. Deep Learning is one of the most sophisticated ML techniques that can process high-dimensional data owing to the presence of more number of hidden layers in its neural network. We designed a Deep Neural Network (DNN) classifier model fused with a LASSO-based significant feature extractor for classifying the gene expression dataset containing a total of 51 samples of which 24 samples are of lung cancer patients and the remaining 27 samples are of normal individuals. A LASSO regression model was implemented to identify the genes that played a significant role in the classification. These significant gene expressions were then fed into a convergent Deep Neural Architecture. The classifier was trained with 70% data and the rest 30% was used for validation. The proposed classifier proved to provide better classification as compared to LASSO regression and DNN used individually. The two classes were classified with an average accuracy of 96.25%, average precision of 99.67%, average specificity of 99.45% and average sensitivity of 91.73% measured over thirty independent assessments. In some cases, the model was able to obtain a classification accuracy of 100%. This could open the path to early and better diagnosis of cancers from transcriptome data."
881,Annotated Compendium of 102 Breast Cancer Gene-Expression Datasets,"Ifeanyichukwu O. Nwosu, Daniel D. Tabler, Greg Chipman, Stephen R. Piccolo",https://www.biorxiv.org/content/10.1101/2023.09.22.559045v2,"Transcriptomic data from breast-cancer patients are widely available in public repositories. However, before a researcher can perform statistical inferences or make biological interpretations from such data, they must find relevant datasets, download the data, and perform quality checks. In many cases, it is also useful to normalize and standardize the data for consistency and to use updated genome annotations. Additionally, researchers need to parse and interpret metadata: clinical and demographic characteristics of patients. Each of these steps requires computational and/or biomedical expertise, thus imposing a barrier to reuse for many researchers. We have identified and curated 102 publicly available, breast-cancer datasets representing 17,151 patients. We created a reproducible, computational pipeline to download the data, perform quality checks, renormalize the raw gene-expression measurements (when available), assign gene identifiers from multiple databases, and annotate the metadata against the National Cancer Institute Thesaurus, thus making it easier to infer semantic meaning and compare insights across datasets. We have made the curated data and pipeline freely available for other researchers to use. Having these resources in one place promises to accelerate breast-cancer research, enabling researchers to address diverse types of questions, using data from a variety of patient populations and study contexts."
882,HOCMO: A Tensor-based Higher-Order Correlation Model to Deconvolute Epigenetic Microenvironment in Breast Cancer,"Charles Lu, Rintsen Sherpa, Liubou Klindziuk, Stefanie Kriel, Shamim Mollah",https://www.biorxiv.org/content/10.1101/2020.12.01.406249v3,"An in-depth understanding of epithelial breast cell response to growth-promoting ligands is required to elucidate how signals from the microenvironment affect cell-intrinsic regulatory networks and their resultant cellular phenotypes, such as cell growth, progression, and differentiation. Understanding the cellular response to these signals is particularly important in understanding the mechanisms of breast cancer initiation and progression. There is increasing evidence that aberrant epigenetic marks are present in cells of the breast tumor microenvironment and are known to affect these cellular processes. However, the mechanisms by which epigenetic microenvironment signals influence these cellular phenotypes are complex and currently not well established. To deconvolute the complexity of the epigenetic microenvironment signals in breast cancer, we developed a novel tensor-based correlation method: HOCMO (Higher-Order Correlation Model), applying to proteomics time series data to reveal the four-way regulatory dynamics among signaling proteins, histones, and growth-promoting ligands across multiple time points in the breast epithelial cells. HOCMO reveals two functional modules and the onset of specific protein-histone signatures in response to growth ligands contributing to distinct cellular phenotypes indicative of breast cancer initiation and progression. We evaluate robustness of our tensor model against baseline method TensorLy and achieved slight improvement in terms of reconstruction error and execution time. HOCMO is a data independent self-supervised learning method with superior interpretability that can capture the strength of complex interactions such as inter- and intra-pathway cellular signaling networks in any diseases or biological systems."
883,Tumor removal limits prostate cancer cell dissemination in bone and osteoblasts induce cancer cell dormancy through focal adhesion kinase,"Ruihua Liu, Shang Su, Jing Xing, Ke Liu, Yawei Zhao, Mary Stangis, Diego P. Jacho, Eda D. Yildirim-Ayan, Cara M. Gatto-Weis, Bin Chen, Xiaohong Li",https://www.biorxiv.org/content/10.1101/2022.09.02.506436v3,"Background Disseminated tumor cells (DTCs) can enter a dormant state and cause no symptoms in cancer patients. On the other hand, the dormant DTCs can reactivate and cause metastases progression and lethal relapses. In prostate cancer (PCa), relapse can happen after curative treatments such as primary tumor removal. The impact of surgical removal on PCa dissemination and dormancy remains elusive. Furthermore, as dormant DTCs are asymptomatic, dormancy-inducing can be an operational cure for preventing metastases and relapse of PCa patients."
884,Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes,"Divyesh Patel, Ville Tiusanen, Päivi Pihlajamaa, Biswajyoti Sahu",https://www.biorxiv.org/content/10.1101/2024.01.15.575744v2,"The combination of immunotherapy and epigenetic therapy is emerging as a promising approach for cancer therapy. Epigenetic therapy can induce derepression of transposable elements (TEs) that play a major role in activation of immune response against cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) and in the context of p53 is still elusive. Here, we used epigenetic drugs to inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal and esophageal cancer cells. We show that distinct TEs subfamilies are derepressed by inhibition of different CMEs in a cell-type specific manner with loss of p53 resulting in stronger TE derepression. We show that KAP1, a known repressor of TEs, associates with stronger derepression of specific TE subfamilies such as LTR12C, indicating that KAP1 also has an activating role in TE regulation in cancer cells upon co-inhibition of DNMT and HDAC. Co-inhibition of DNMT and HDAC activates immune response by inducing inverted repeat Alu expression, reducing ADAR1-mediated Alu RNA editing and inducing cell type-specific TE-chimeric transcript expression. Collectively, our study demonstrates that inhibition of different CMEs results in derepression of distinct TEs in cell type-specific manner and by utilizing distinct mechanistic pathways, providing insights for epigenetic therapies that could selectively enhance anti-tumor immunity in distinct cancer types."
886,Luminal breast epithelial cells from wildtype and BRCA mutation carriers harbor copy number alterations commonly associated with breast cancer,"Marc J. Williams, Michael UJ Oliphant, Vinci Au, Cathy Liu, Caroline Baril, Ciara O’Flanagan, Daniel Lai, Sean Beatty, Michael Van Vliet, Jacky CH Yiu, Lauren O’Connor, Walter L Goh, Alicia Pollaci, Adam C. Weiner, Diljot Grewal, Andrew McPherson, McKenna Moore, Vikas Prabhakar, Shailesh Agarwal, Judy E. Garber, Deborah Dillon, Sohrab P. Shah, Joan Brugge, Samuel Aparicio",https://www.biorxiv.org/content/10.1101/2024.05.01.591587v1,"Cancer-associated mutations have been documented in normal tissues, but the prevalence and nature of somatic copy number alterations and their role in tumor initiation and evolution is not well understood. Here, using single cell DNA sequencing, we describe the landscape of CNAs in >42,000 breast epithelial cells from women with normal or high risk of developing breast cancer. Accumulation of individual cells with one or two of a specific subset of CNAs (e.g. 1q gain and 16q, 22q, 7q, and 10q loss) is detectable in almost all breast tissues and, in those from BRCA1 or BRCA2 mutations carriers, occurs prior to loss of heterozygosity (LOH) of the wildtype alleles. These CNAs, which are among the most common associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, are enriched almost exclusively in luminal cells not basal myoepithelial cells. Allele-specific analysis of the enriched CNAs reveals that each allele was independently altered, demonstrating convergent evolution of these CNAs in an individual breast. Tissues from BRCA1 or BRCA2 mutation carriers contain a small percentage of cells with extreme aneuploidy, featuring loss of TP53, LOH of BRCA1 or BRCA2, and multiple breast cancer-associated CNAs in addition to one or more of the common CNAs in 1q, 10q or 16q. Notably, cells with intermediate levels of CNAs are not detected, arguing against a stepwise gradual accumulation of CNAs. Overall, our findings demonstrate that chromosomal alterations in normal breast epithelium partially mirror those of established cancer genomes and are chromosome- and cell lineage-specific."
887,Myoglobin Inhibits Breast Cancer Cell Fatty Acid Oxidation and Migration via Heme-dependent Oxidant Production and Not Fatty Acid Binding,"Aaron R. Johnson, Krithika Rao, Bob B. Zhang, Steven Mullet, Eric Goetzman, Stacy Gelhaus, Jesus Tejero, uti Shiva Sr",https://www.biorxiv.org/content/10.1101/2024.04.30.591659v1,"The monomeric heme protein myoglobin (Mb), traditionally thought to be expressed exclusively in cardiac and skeletal muscle, is now known to be expressed in approximately 40% of breast tumors. While Mb expression is associated with better patient prognosis, the molecular mechanisms by which Mb limits cancer progression are unclear. In muscle, Mb’s predominant function is oxygen storage and delivery, which is dependent on the protein’s heme moiety. However, prior studies demonstrate that the low levels of Mb expressed in cancer cells preclude this function. Recent studies propose a novel fatty acid binding function for Mb via a lysine residue (K46) in the heme pocket. Given that cancer cells can upregulate fatty acid oxidation (FAO) to maintain energy production for cytoskeletal remodeling during cell migration, we tested whether Mb-mediated fatty acid binding modulates FAO to decrease breast cancer cell migration. We demonstrate that the stable expression of human Mb in MDA-MB-231 breast cancer cells decreases cell migration and FAO. Site-directed mutagenesis of Mb to disrupt Mb fatty acid binding did not reverse Mb-mediated attenuation of FAO or cell migration in these cells. In contrast, cells expressing Apo-Mb, in which heme incorporation was disrupted, showed a reversal of Mb-mediated attenuation of FAO and cell migration, suggesting that Mb attenuates FAO and migration via a heme-dependent mechanism rather than through fatty acid binding. To this end, we show that Mb’s heme-dependent oxidant generation propagates dysregulated gene expression of migratory genes, and this is reversed by catalase treatment. Collectively, these data demonstrate that Mb decreases breast cancer cell migration, and this effect is due to heme-mediated oxidant production rather than fatty acid binding. The implication of these results will be discussed in the context of therapeutic strategies to modulate oxidant production and Mb in tumors."
888,maGENEgerZ: An Efficient AI-Based Framework Can Extract More Expressed Genes and Biological Insights Underlying Breast Cancer Drug Response Mechanism,"Turki Turki, Y-h. Taguchi",https://www.biorxiv.org/content/10.1101/2023.12.29.573686v2,"Understanding breast cancer drug response mechanism can play a crucial role in improving the treatment outcomes and survival rates. Existing bioinformatics-based approaches are far from perfect and do not adopt computational methods based on advanced artificial intelligence concepts. Therefore, we introduce a novel computational framework based on an efficient support vector machines (esvm) working as follows. First, we downloaded and processed three gene expression datasets related to breast cancer responding and non-responding to the treatments from the gene expression omnibus (GEO) according to the following GEO accession numbers: GSE130787, GSE140494, and GSE196093. Our method esvm is formulated as a constrained optimization problem in the dual form as a function of λ. We recover the importance of each gene as a function of λ, y, and x. Then, we select p genes out of n, provided as input to enrichment analysis tools, Enrichr and Metascape. Compared to existing baseline methods including deep learning, results demonstrate superiority and efficiency of esvm achieving high performance results and having more expressed genes in well-established breast cancer cell lines including MD-MB231, MCF7, and HS578T. Moreover, esvm is able to identify (1) various drugs including clinically approved ones (e.g., tamoxifen and erlotinib); (2) seventy-four unique genes (including tumor suppression genes such as TP53 and BRCA1); and (3) thirty-six unique TFs (including SP1 and RELA). These results have been reported to be linked to breast cancer drug response mechanism, progression, and metastasizing. Our method is available publicly in the maGENEgerZ web server at https://aibio.shinyapps.io/maGENEgerZ/."
889,Revealing 3D cancer tissue structures using holotomography and virtual hematoxylin and eosin staining via deep learning,"Juyeon Park, Su-Jin Shin, Minji Kim, Geon Kim, Hyungjoo Cho, Dongmin Ryu, Daewoong Ahn, Ji Eun Heo, Inyeop Jang, Hyun-seok Min, Kwang Suk Lee, Tae Hyun Hwang, YongKeun Park",https://www.biorxiv.org/content/10.1101/2023.12.04.569853v2,"In standard histopathology, hematoxylin and eosin (H&E) staining stands as a pivotal tool for cancer tissue analysis. However, this method is limited to two-dimensional (2D) analysis or requires labor-intensive preparation for three-dimensional (3D) inspection of cancer tissues. In this study, we present a method for 3D virtual H&E staining of label-free cancer tissues, employing holotomography and deep learning. Holotomography is used to measure the 3D refractive index (RI) distribution of the label-free cancer slides. A deep learning-based image-to-image translation framework is integrated into the resulting 3D RI distribution, enabling virtual H&E staining in 3D. Our method has been applied to colon cancer tissue slides with thicknesses up to 20 μm, with conventional chemical H&E staining providing a direct validation for the method. This framework not only bypasses the conventional staining process but also provides 3D structures of glands, lumens, and individual nuclei. The results demonstrate enhancement in histopathological efficiency and the extension of the standard histopathology into the 3D realm. To validate the repeatability and scalability of the approach, we applied the framework to the gastric cancer slides obtained from different institute and imaging devices."
891,"HER2 Cellular Localization, Cell-Cell Contacts, and Cell Density Regulate Cancer Cell Plasticity in HER2+ Breast Cancer","Saba Sameri, Durdam Das, Shabnam Shahrivari, Vladan Milosevic, Shamim Sarhadi, Huiqin Koerkel-Qu, Carolina Fisch, Miriam Kokal, Michael Schletter, Paul S. Hahn, Lisa Seider, Marisa Schübel, Stefanie Michaelis, Joachim Wegener, Florian Weber, Martin Hoffmann, Christian Werno, Kathrin Weidele, Astrid Bruckmann, Arne Östman, Ernst R. Tamm, Yuting Li, Christoph A. Klein, Hedayatollah Hosseini",https://www.biorxiv.org/content/10.1101/2023.09.28.559965v1,"Phenotypic plasticity in HER2+ breast cancer presents a significant challenge in comprehending and treating early-stage metastasis. We conducted an extensive study employing in vitro models and patient samples to investigate the relationships among cell density, HER2 expression, HER2 cellular localization, and their impact on the plasticity program of HER2+ breast cancer cells."
892,NADPH composite index analysis quantifies the relationship between compartmentalized NADPH dynamics and growth rates in cancer cells,"Sun Jin Moon, Anush Chiappino Pepe, Wentao Dong, Joanne K. Kelleher, Matthew G. Vander Heiden, Gregory N. Stephanopoulos, Hadley D. Sikes",https://www.biorxiv.org/content/10.1101/2024.04.27.591477v1,"NADPH, a highly compartmentalized electron donor in mammalian cells, plays essential roles in cell metabolism. However, little is known about how cytosolic and mitochondrial NADPH dynamics relate to cancer cell growth rates in response to varying nutrient conditions. To address this issue, we present NADPH composite index analysis, which quantifies the relationship between compartmentalized NADPH dynamics and growth rates using genetically encoded NADPH sensors, automated image analysis pipeline, and correlation analysis. Through this analysis, we demonstrated that compartmentalized NADPH dynamics patterns were cancer cell-type dependent. Specifically, cytosolic and mitochondrial NADPH dynamics of MDA-MB-231 decreased in response to serine deprivation, while those of HCT-116 increased in response to serine or glutamine deprivation. Furthermore, by introducing a fractional contribution parameter, we correlated cytosolic and mitochondrial NADPH dynamics to growth rates. Using this parameter, we identified cancer cell lines whose growth rates were selectively inhibited by targeting cytosolic or mitochondrial NADPH metabolism. Mechanistically, we identified citrate transporter as a key mitochondrial transporter that maintains compartmentalized NADPH dynamics and growth rates. Altogether, our results present a significant advance in quantifying the relationship between compartmentalized NADPH dynamics and cancer cell growth rates, highlighting a potential of targeting compartmentalized NADPH metabolism for selective cancer cell growth inhibitions."
893,Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation,"Yu Wang, Hui Xue, Xiaohui Zhu, Dong Lin, Xin Dong, Zheng Chen, Junru Chen, Mingchen Shi, Yuchao Ni, Jonathan Cao, Rebecca Wu, Ning Kang, Xinyao Pang, Francesco Crea, Yen-Yi Lin, Colin C. Collins, Martin E. Gleave, Abhijit Parolia, Arul Chinnaiyan, Christopher J. Ong, Yuzhuo Wang",https://www.biorxiv.org/content/10.1101/2024.04.27.591428v1,"Background and Objective Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation."
894,Novel sulfatase cancer therapeutics negatively impact Bacteroidota of the colonic microbiota in a non-sulfatase dependent manner,"Conor J. Crawford, Christian Gunawan, Zongjia Chen, Dominic P Byrne, Cosette Darby, Ana S Luis, Stefano Elli, Edwin A Yates, David N Bolam, Sjoerd van der Post, Spencer J Williams, Alan Cartmell",https://www.biorxiv.org/content/10.1101/2024.04.27.591440v1,"The S1 family of sulfatases is the sole family of enzymes that desulfate carbohydrates, linking them to inflammatory bowel diseases and various cancers. There is an unmet need for therapeutics against carbohydrate sulfatases, and while effective, orally available inhibitors of S1 steroid sulfatases exist, their efficacy against S1 carbohydrate sulfatases remains largely unexplored. In this study we assess a library of aryl- and carbohydrate sulfamates/sulfonates for their ability to inhibit carbohydrate sulfatases from human colonic bacteria. Surprisingly, these compounds prove ineffective. We show that arylsulfamate inhibitors inhibit the growth of anti-cancer human gut microbiota species independent of sulfatase activity. Leveraging thermal proteome profiling, we identify the non-sulfatase targets responsible for these effects. This work highlights the imperative for developing specific inhibitors targeting carbohydrate sulfatases and unveils the adverse effects of arylsulfamates, a class of drugs designed for hormone cancer treatment, on the human gut microbiota, potentially influencing their therapeutic efficacy."
897,Glyoxalase 1: emerging biomarker and therapeutic target in cervical cancer progression,"Ji-Young Kim, Ji-Hye Jung, Soryung Jung, Sanghyuk Lee, Hyang Ah Lee, Yung-Taek Ouh, Seok-Ho Hong",https://www.biorxiv.org/content/10.1101/2024.02.11.579832v1,"Introduction Cervical cancer presents a significant global health challenge, disproportionately impacting underserved populations with limited access to healthcare. Early detection and effective management are vital in addressing this public health concern. This study focuses on Glyoxalase-1 (GLO1), an enzyme crucial for methylglyoxal detoxification, in the context of cervical cancer."
899,Divergent iron-regulatory states contribute to heterogeneity in breast cancer aggressiveness,"William D. Leineweber, Maya Z. Rowell, Sural Ranamukhaarachchi, Alyssa Walker, Yajuan Li, Jorge Villazon, Aida Mestre Farrera, Zhimin Hu, Jing Yang, Lingyan Shi, Stephanie I. Fraley",https://www.biorxiv.org/content/10.1101/2023.06.23.546216v2,"Primary tumors with similar mutational profiles can progress to vastly different outcomes where transcriptional state, rather than mutational profile, predicts prognosis. A key challenge is to understand how distinct tumor cell states are induced and maintained. In triple negative breast cancer cells, invasive behaviors and aggressive transcriptional signatures linked to poor patient prognosis can emerge in response to contact with collagen type I. Herein, collagen-induced migration heterogeneity within a TNBC cell line was leveraged to identify transcriptional programs associated with invasive versus non-invasive phenotypes and implicate molecular switches. Phenotype-guided sequencing revealed that invasive cells upregulate iron uptake and utilization machinery, anapleurotic TCA cycle genes, actin polymerization promoters, and a distinct signature of Rho GTPase activity and contractility regulating genes. The non-invasive cell state is characterized by actin and iron sequestration modules along with glycolysis gene expression. These unique tumor cell states are evident in patient tumors and predict divergent outcomes for TNBC patients. Glucose tracing confirmed that non-invasive cells are more glycolytic than invasive cells, and functional studies in cell lines and PDO models demonstrated a causal relationship between phenotype and metabolic state. Mechanistically, the OXPHOS dependent invasive state resulted from transient HO-1 upregulation triggered by contact with dense collagen that reduced heme levels and mitochondrial chelatable iron levels. This induced expression of low cytoplasmic iron response genes regulated by ACO1/IRP1. Knockdown or inhibition of HO-1, ACO1/IRP1, MRCK, or OXPHOS abrogated invasion. These findings support an emerging theory that heme and iron flux serve as important regulators of TNBC aggressiveness."
901,The nuclear speckles protein SRRM2 is a new therapeutic target molecule on the surface of cancer cells,"Markus Kellner, Julia Hörmann, Susanne Fackler, Hu Yuanyu, Zhou Tielin, Lu Lin, Ibrahim Ilik, Tugce Aktas, Regina Feederle, Stefanie M. Hauck, Olivier Gires, Kathrin Gärtner, Li Lietao, Reinhard Zeidler",https://www.biorxiv.org/content/10.1101/2024.04.26.591288v1,"The membrane composition of extracellular vesicles (EVs) largely reflects that of the plasma membrane of the cell of origin. We therefore hypothesized that EVs are a source for the detection of hitherto unknown tumor-associated druggable target molecules. For this, we used EVs derived from cancer cell lines for an immunization of a rat. From this immunization, we obtained a monoclonal antibody specific for SRRM2, a protein involved in splicing a major component of nuclear speckles. Here, we used this antibody to demonstrate that SRRM2 is exposed at the surface of most cancer cell lines from various entities and, even more important, on cancer cells in vivo. Moreover, we demonstrate that SRRM2-specific CAR-T cells are killing SRRM2-positive cancer cells electively. Collectively, we identified SRRM2 as a promising new target molecule exposed on the cancer cell surface and show that our SRRM2-specific antibody can be used as a basis for the development of new targeted cancer therapies."
903,UXS1 regulates UDP-GlcA levels to support growth of UGDH-high cancer cells,"Yunyi Wang, Chen Zhou, Berna Bou-Tayeh, Richard Lisle, Skirmantas Kriaucionis, Yang Shi",https://www.biorxiv.org/content/10.1101/2024.02.08.579288v1,"Identifying genes that are crucial for cancer cell survival but dispensable in normal cells holds immense therapeutic potential. The DepMap Consortium’s extensive datasets have paved the way for uncovering such selectively essential genes in cancer. However, it remained challenging to efficiently prioritize understudied, selectively essential genes for validation and characterization. To this end, our lab has previously ranked and prioritized potentially understudied, selectively essential genes based on their PubMed publication numbers. This approach led to successful identification and detailed characterization of two top understudied genes. Building on this methodology, our current research identified UXS1, an enzyme responsible for catalyzing the conversion from UDP-glucuronic acid (UDP-GlcA) to UDP-xylose, as a selectively essential gene in cancer cells expressing elevated levels of UGDH, an enzyme responsible for producing UDP-GlcA. Through an integrated approach combining genetic and biochemical assays, we discovered that UXS1 plays a critical role in these UGDH-overexpressing cancer cells by preventing the harmful buildup of UDP-GlcA, which otherwise would lead to cellular toxicity. Our findings not only validate our strategy for prioritizing underexplored but potentially pivotal selectively essential genes but also highlight UXS1 as a potential vulnerability and therapeutic target in cancers characterized by high UGDH expression."
904,In Silico designed cell-penetrating anti-cancer peptide specifically inhibits VEGF-A expression,"Nilanjan Banerjee, Laboni Roy, Suman Panda, Tanaya Roychowdhury, Subhrangsu Chatterjee",https://www.biorxiv.org/content/10.1101/2024.02.08.579410v1,"Vascular Endothelial Growth Factor-A (VEGF-A), a pluripotent cytokine and angiogenic growth factor mediates the switch to an angiogenic phenotype in cancer cells. The interaction of VEGF-A protein with the VEGF receptors (VEGFR-1and VEGFR-2) starts downstream effect that promotes angiogenesis by mediating migration and increasing the permeability of endothelial cells. A cis-regulatory elements consisting of a polypurine/polypyrimidine (pPu/pPy) tract in the proximal 36-bp region (–85 to −50), can participate in the formation of a stable higher order G-quadruplex structure (G4) which is essential for VEGF promoter activity. During cancer progression the VEGF-A G4 succumbs to cellular pressure and fails to maintain the stable structure. This shifts the balance to form duplex structure thereby increasing the rate of transcription. Earlier research has tried to develop small-molecule ligands to target and stabilize G4, however they either lack specificity or non-toxicity. Peptide on the other hand are very less studied. Here we used bioinformatics in-silico tool to develop peptides which can successfully bind and stabilize the VEGF-A G4 while reducing its gene expression. This further alters the expression fate of the VEGF-A signalling cascade and prevents angiogenesis in cancer cells. We used high resolution Nuclear magnetic resonance and molecular dynamics simulation to map the chemistry of the interaction while the qPCR and western blot allowed us to check the expression pattern of the molecules of VEGF-A signalling cascade. In this investigation, we navigate the complex interplay between peptides and quadruplex structures, unravelling valuable insights that can enhance the crafting of pharmacophores directed at the dynamic quadruplex structure. The outcomes of our study are promising, paving the way for progress in the realms of research, characterization, and optimization of peptides binding to G-quadruplexes, with potential implications for therapeutic applications."
905,"Inbreeding and gallbladder cancer risk: Homozygosity associations adjusted for indigenous American ancestry, BMI and genetic risk of gallstone disease","Francisco Ceballos, Felix Boekstegers, Dominique Scherer, Carol Barahona Ponce, Katherine Marcelain, Valentina Gárate-Calderón, Melanie Waldenberger, Erik Morales, Armando Rojas, César Munoz, Javier Retamales, Gonzalo de Toro, Allan Vera Kortmann, Olga Barajas, María Teresa Rivera, Analía Cortés, Denisse Loader, Javiera Saavedra, Lorena Gutiérrez, Alejandro Ortega, Maria Enriqueta Bertrán, Leonardo Bartolotti, Fernando Gabler, Mónica Campos, Juan Alvarado, Fabricio Moisán, Loreto Spencer, Bruno Nervi, Daniel Carvajal-Hausdorf, Héctor Losada, Mauricio Almau, Plinio Fernández, Jordi Olloquequi, Francisco Rothhammer, Justo Lorenzo Bermejo",https://www.biorxiv.org/content/10.1101/2024.04.22.590517v1,"Latin Americans have a rich genetic make-up that translates into heterogeneous fractions of the autosomal genome in runs of homozygosity (FROH), and heterogeneous types and proportions of indigenous American ancestry. While autozygosity has been linked to several human diseases, very little is known about the relationship between inbreeding, genetic ancestry and cancer risk in Latin Americans."
909,Ultrasound-mediated drug-free theranostics for treatment of prostate cancer,"Reshani Himashika Perera, Felipe Matias Berg, Eric Chua Abenojar, Pinunta Nittayacharn, Youjoung Kim, Xinning Wang, James P. Basilion, Agata A. Exner",https://www.biorxiv.org/content/10.1101/2023.09.13.555594v1,"Rationale Lipid-shelled nanobubbles (NBs) can be visualized and activated using noninvasive ultrasound (US) stimulation, leading to significant bioeffects. We have previously shown that active targeting of NBs to prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer (PCa) enhances the cellular internalization and prolongs retention of NBs with persistent acoustic activity (∼hrs.). In this work, we hypothesized that tumor-accumulated PSMA-NBs combined with low frequency therapeutic US (TUS) will lead to selective damage and induce a therapeutic effect in PSMA-expressing tumors compared to PSMA-negative tumors."
911,The Single-cell Pediatric Cancer Atlas: Data portal and open-source tools for single-cell transcriptomics of pediatric tumors,"Allegra G. Hawkins, Joshua A. Shapiro, Stephanie J. Spielman, David S. Mejia, Deepashree Venkatesh Prasad, Nozomi Ichihara, Arkadii Yakovets, Kurt G. Wheeler, Chante J. Bethell, Steven M. Foltz, Jennifer O’Malley, Casey S. Greene, Jaclyn N. Taroni",https://www.biorxiv.org/content/10.1101/2024.04.19.590243v1,"The Single-cell Pediatric Cancer Atlas (ScPCA) Portal (https://scpca.alexslemonade.org/) is a data resource for uniformly processed single-cell and single-nuclei RNA sequencing (RNA-seq) data and de-identified metadata from pediatric tumor samples. Originally comprised of data from 10 projects funded by Alex’s Lemonade Stand Foundation, the Portal currently contains summarized gene expression data for over 500 samples from over 50 types of cancers from ALSF-funded and community-contributed datasets. In addition to gene expression data from single-cell and single-nuclei RNA-seq, the Portal holds data obtained from bulk RNA-seq, spatial transcriptomics, and feature barcoding methods, such as CITE-seq and cell hashing."
912,RNA Splicing Junction Landscape Reveals Abundant Tumor-Specific Transcripts in Human Cancer,"Qin Li, Ziteng Li, Bing Chen, Jingjing Zhao, Hongwu Yu, Jia Hu, Hongyan Lai, Hena Zhang, Yan Li, Zhiqiang Meng, Zhixiang Hu, Shenglin Huang",https://www.biorxiv.org/content/10.1101/2024.02.06.579246v1,"RNA splicing is a critical process governing gene expression and transcriptomic diversity. Despite its importance, a detailed examination of transcript variation at the splicing junction level remains scarce. Here, we perform a thorough analysis of RNA splicing junctions in 34,775 samples across multiple sample types. We identified 29,051 tumor-specific transcripts (TSTs) in pan-cancer, with a majority of these TSTs being unannotated. Our findings show that TSTs are positively correlated with tumor stemness and linked to unfavorable outcomes in cancer patients. Additionally, TSTs display mutual exclusivity with somatic mutations and are overrepresented in transposable element-derived transcripts possessing oncogenic functions. Importantly, TSTs can generate neoepitopes that bind to MHC class I molecules for immunotherapy. Moreover, TSTs can be detected in blood extracellular vesicles from cancer patients. Our results shed light on the intricacies of RNA splicing and offer promising avenues for cancer diagnosis and therapy."
913,Defining the conformational states that enable transglutaminase 2 to promote cancer cell survival versus cell death,"Cody Aplin, Kara A. Zielinski, Suzette Pabit, Deborah Ogunribido, William P. Katt, Lois Pollack, Richard A. Cerione, Shawn K. Milano",https://www.biorxiv.org/content/10.1101/2024.02.04.578794v1,"Transglutaminase 2 (TG2) is a GTP-binding/protein-crosslinking enzyme that has been investigated as a therapeutic target for Celiac disease, neurological disorders, and aggressive cancers. TG2 has been suggested to adopt two conformational states that regulate its functions: a GTP-bound, closed conformation, and a calcium-bound, crosslinking-active open conformation. TG2 mutants that constitutively adopt an open conformation are cytotoxic to cancer cells. Thus, small molecules that maintain the open conformation of TG2 could offer a new therapeutic strategy. Here, we investigate TG2, using static and time-resolved small-angle X-ray scattering (SAXS) and single-particle cryoelectron microscopy (cryo-EM), to determine the conformational states responsible for conferring its biological effects. We also describe a newly developed TG2 inhibitor, LM11, that potently kills glioblastoma cells and use SAXS to investigate how LM11 affects the conformational states of TG2. Using SAXS and cryo-EM, we show that guanine nucleotide-bound TG2 adopts a monomeric closed conformation while calcium-bound TG2 assumes an open conformational state that can form higher order oligomers. SAXS analysis also suggests how a TG2 mutant that constitutively adopts the open state binds nucleotides through an alternative mechanism to wildtype TG2. Furthermore, we use time-resolved SAXS to show that LM11 increases the ability of calcium to drive TG2 to an open conformation, which is not reversible by guanine nucleotides and is cytotoxic to cancer cells. Taken together, our findings demonstrate that the conformational dynamics of TG2 are more complex than previously suggested and highlight how conformational stabilization of TG2 by LM11 maintains TG2 in a cytotoxic conformational state."
915,LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment,"Jeffrey Reina, Queralt Vallmajo-Martin, Jia Ning, Aubrey N. Michi, Kay Yeung, Geoffrey M. Wahl, Tony Hunter",https://www.biorxiv.org/content/10.1101/2024.04.19.590151v1,"Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks an effective targeted therapy. To identify new therapeutic targets, we investigated the phosphohistidine phosphatase, LHPP, which has been implicated in the development of several types of cancer. However, the full significance of LHPP in cancer progression remains unclear due to our limited understanding of its molecular mechanism. We found that levels of the LHPP phosphohistidine phosphatase were significantly increased in human breast cancer patients compared to normal adjacent tissues, with the highest levels in the TNBC subtype. When LHPP was knocked out in the MDA-MB-231 human TNBC cell line, cell proliferation, wound healing capacity, and invasion were significantly reduced. However, LHPP knockout in TNBC cells did not affect the phosphohistidine protein levels. Interestingly, LHPP knockout in MDA-MB-231 cells delayed tumor growth and reduced metastasis when orthotopically transplanted into mouse mammary glands. To investigate LHPP’s role in breast cancer progression, we used next-generation sequencing and proximity-labeling proteomics, and found that LHPP regulates gene expression in chemokine-mediated signaling and actin cytoskeleton organization. Depletion of LHPP reduced the presence of tumor-infiltrating macrophages in mouse xenografts. Our results uncover a new tumor promoter role for LHPP phosphohistidine phosphatase in TNBC and suggest that targeting LHPP phosphatase could be a potential therapeutic strategy for TNBC."
916,Peptide-stimulation of autologous T cells reverts immune checkpoint inhibitor resistance of hypermutated colorectal cancer cells,"Sandra Schwarz, Su Zhaoran, Mathias Krohn, Markus W. Löffler, Andreas Schlosser, Michael Linnebacher",https://www.biorxiv.org/content/10.1101/2024.02.06.579061v1,"Two hypermutated colon cancer cases with patient-derived cell lines, peripheral and tumor-infiltrating T cells available were selected for detailed investigation of immunological response."
917,Sex differences in bile acid homeostasis and excretion underlie the disparity in liver cancer incidence between males and females,"Megan E. Patton, Sherwin Kelekar, Lauren J. Taylor, Angela E. Dean, Qianying Zuo, Rhishikesh N Thakare, Sung Hwan Lee, Emily Gentry, Morgan Panitchpakdi, Pieter Dorrestein, Yazen Alnouti, Zeynep Madak-Erdogan, Ju-Seog Lee, Milton J. Finegold, Sayeepriyadarshini Anakk",https://www.biorxiv.org/content/10.1101/2020.06.25.172635v2,"Hepatocellular carcinoma (HCC), the most common liver cancer, exhibits a higher incidence in males. Here, we report that mice lacking the bile acid regulators, Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and FXR and SHP double knockout livers identified female-specific changes in metabolism, including amino acids, lipids and steroids. We examined if the obtained transcriptomic signatures correlate with the survival outcomes for HCC patients to assess the translational potential of this murine HCC model. Gene signature that is unique to the knockout females correspond with low-grade tumors and better survival. Ovariectomy blunts the metabolic changes in female livers and promotes tumorigenesis that, intriguingly, coincides with increases in serum bile acid (BA) levels. Despite similar genetics, we found higher serum BA concentrations in males, whereas female knockout mice excreted more BAs. Decreasing enterohepatic BA recirculation using cholestyramine, an FDA-approved resin, dramatically reduced the liver cancer burden in male mice. Overall, we reveal that sex-specific BA metabolism leading to lower circulating BA concentration protects female livers from developing cancer. Thus, targeting BA excretion may be a promising therapeutic strategy against HCC."
918,A comparative study of circulating tumor cell isolation and enumeration technologies in lung cancer,"Volga M Saini, Ezgi Oner, Mark Ward, Sinead Hurley, Brian David Henderson, Faye Lewis, Stephen P Finn, John O’Leary, Sharon O’Toole, Lorraine O’Driscoll, Kathy Gately",https://www.biorxiv.org/content/10.1101/2024.02.05.578972v1,"Circulating tumor cells (CTCs) have potential as diagnostic, prognostic and predictive biomarkers in solid tumors. Despite FDA approval of CTC devices in various cancers, their rarity and limited comparison between analysis methods hinder their clinical integration for lung cancer. This study aimed to evaluate five CTC isolation technologies using a standardized spike-in protocol: the CellMag™ (EpCAM-based enrichment), EasySep™ and RosetteSep™ (blood cell depletion), and the Parsortix® PR1 and next generation Parsortix® Plus (PX+) (size-based enrichment). The Parsortix® systems were also evaluated for any difference in recovery rates between cell harvest versus in- cassette staining. Healthy donor blood (5 mL) was spiked with 100 fluorescently labeled H1975 lung adenocarcinoma cell line, processed through each system and the isolation efficiency was calculated. All tested systems yielded discordant recovery rates with the CellMag™ having the highest mean recovery (70 ± 14%) followed by the PR1 (in-cassette staining) with a recovery of 49 ± 2% while the EasySep™ had the lowest recovery (18 ± 8%). The CellMag™ and Parsortix® PR1 may have potential clinical applications for lung cancer patients, albeit needing further optimization and validation."
919,"Phenotypic, genomic, and transcriptomic heterogeneity in a pancreatic cancer cell line","Gengqiang Xie, Liting Zhang, Olalekan H Usman, Sampath Kumar, Chaity Modak, Dhenu Patel, Megan Kavanaugh, Xian Mallory, Yue Julia Wang, Jerome Irianto",https://www.biorxiv.org/content/10.1101/2022.11.11.516211v3,"Objectives To evaluate the suitability of the MIA PaCa-2 cell line for studying pancreatic cancer intratumor heterogeneity, we aim to further characterize the nature of MIA PaCa-2 cells’ phenotypic, genomic, and transcriptomic heterogeneity."
920,CD81-guided heterologous EVs present heterogeneous interactions with breast cancer cells,"Elena Gurrieri, Giulia Carradori, Michela Roccuzzo, Michael Pancher, Daniele Peroni, Romina Belli, Caterina Trevisan, Michela Notarangelo, Wen-Qiu Huang, Agata SA Carreira, Alessandro Quattrone, Guido Jenster, Timo L.M. Ten Hagen, Vito Giuseppe D’Agostino",https://www.biorxiv.org/content/10.1101/2024.02.06.579138v1,"Extracellular vesicles (EVs) are cell-secreted particles conceived as natural vehicles for intercellular communication. The intrinsic biocompatibility, stability in biofluids, and heterogeneous molecular cargo of EVs promise advancements in targeted therapy applications. However, predicting cell-targeting spectrum and cargo delivery are fundamental challenges for exploiting EVs or hybrid formulations. In this work, we combined cell-based and biochemical approaches to understand if secreted EVs show predictable EV-cell interactions and consequent cargo delivery. We exploited the tetraspanin CD81 to encode full-length recombinant proteins with a C-terminal GFP reporter encompassing or not Trastuzumab light chains targeting the HER2 receptor. These fusion proteins participated in vesicular trafficking dynamics and accumulated on secreted EVs when transiently over-expressed in HEK293T cells. Despite the presence of GFP, secreted EV populations retained a HER2 receptor-binding capacity and were used in EV-cell interaction assays. In time-frames where the global GFP spot distribution did not change between HER2-positive (SK-BR-3) or –negative (MDA-MB-231) breast cancer cell lines, the HER2 manipulation in isogenic cells remarkably affected the tropism of heterologous EVs. In this line, secreted doxorubicin-EVs, which showed improved efficacy compared to the free drug, had a reduced cell-killing activity on SK-BR-3 with a knocked-out HER2 receptor. Interestingly, the fusion protein-corresponding transcripts also present as full-length mRNAs in recombinant EVs could reach orthotopic breast tumors in JIMT-1-xenografted mice, as detected by ddPCR in tissue biopsies, improving our sensitivity in detecting bioavailable cargoes. These data show multiple mechanisms underlying EV-cell interactions and prioritize the profiling of surfaceomes for better comprehension of cell engagement and design new generations of EV-based nanovehicles."
921,Identification of Potential EGFR Inhibitors for Type 2 Diabetes and Pancreatic Cancer Treatment: A Computational Approach,Ricardo Romero,https://www.biorxiv.org/content/10.1101/2023.09.05.556125v3,"This study conducted a differential gene expression analysis in two independent studies of type 2 diabetes using pancreatic samples, specifically Langerhans cells. Through protein-protein interaction network analysis, the Epidermal Growth Factor Receptor (EGFR) emerged as the top hub gene among the upregulated genes in both studies. Furthermore, functional enrichment analysis revealed the involvement of EGFR in pancreatic cancer signaling pathways, indicating its potential role beyond diabetes."
922,Cancer Immunotherapy through Tissue Adhering Polymers,"Neil J. Borthwick, Caitlin L. Maikawa, Sven Weller, Thomas L. Andresen, Anders E. Hansen, Anton A.A. Autzen",https://www.biorxiv.org/content/10.1101/2023.03.23.533909v2,"TLR 7/8 agonists are highly potent immunostimulators, though their clinical translation has been met with mixed success, due to their high toxicity as a result of an unregulated systemic immune activation. There is enormous potential to augment cancer immunotherapies with synthetic TLR 7/8 agonists, though a thorough control of pharmacokinetics and localization is needed for the general use of TLR 7/8 agonists in cancer immunotherapy. Herein, we control localization of TLR 7/8 agonists, by exploiting the extensive tissue retention of poly(acrylic acid-co-styrene). In a murine CT26 model, we find that covalently attaching TLR 7/8 agonists to the copolymer allows for retaining the drug in the tumor microenvironment for at least 15 weeks, after intratumoral injection, and results in a curative monotherapy. The copolymer itself is a new avenue for attaining prolonged tissue rentention for covalently attached drugs."
923,Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6),"Charline Ogier, Akino Mercy Charles Solomon, Zhen Lu, Ludmila Recoules, Alena Klochkova, Linara Gabitova-Cornell, Battuya Bayarmagnai, Diana Restifo, Aizhan Surumbayeva, Débora B. Vendramini-Costa, Alexander Y. Deneka, Ralph Francescone, Anna C. Lilly, Alyssa Sipman, Jaye C. Gardiner, Tiffany Luong, Janusz Franco-Barraza, Nina Ibeme, Kathy Q. Cai, Margret B. Einarson, Emmanuelle Nicolas, Andrei Efimov, Emily Megill, Nathaniel W. Snyder, Corinne Bousquet, Jerome Cros, Yunyun Zhou, Erica A. Golemis, Bojana Gligorijevic, Jonathan Soboloff, Serge Y. Fuchs, Edna Cukierman, Igor Astsaturov",https://www.biorxiv.org/content/10.1101/2023.09.15.557802v1,"In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy."
924,Engrailed-1 Promotes Pancreatic Cancer Metastasis,"Jihao Xu, Jae-Seok Roe, EunJung Lee, Claudia Tonelli, Tim D.D. Somerville, Melissa Yao, Joseph P. Milazzo, Herve Tiriac, Ania M. Kolarzyk, Esak Lee, Jean L. Grem, Audrey J. Lazenby, James A. Grunkemeyer, Michael A. Hollingsworth, Alexander D. Borowsky, Youngkyu Park, Christopher R. Vakoc, David A. Tuveson, Chang-Il Hwang",https://www.biorxiv.org/content/10.1101/2023.04.10.536259v1,"Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, we report that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating a role in the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. Our findings nominate the targeting of EN1 and downstream pathways in aggressive PDA."
925,Single-cell multi-omics reveals insights into differentiation of rare cell types in mucinous colorectal cancer,"Christopher A. Ladaika, Ahmed H. Ghobashi, William C. Boulton, Samuel A. Miller, Heather M. O’Hagan",https://www.biorxiv.org/content/10.1101/2024.02.01.578409v1,"Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mucinous CRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics was used to uncover epigenetic alterations that accompany EEC differentiation, identify STAT3 as a novel regulator of EEC specification, and discover a rare cancer-specific cell type with enteric neuron-like characteristics. Further experiments demonstrated that lysine-specific demethylase 1 (LSD1) and CoREST2 mediate STAT3 demethylation and regulate STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. In culmination, these results provide rationale for new LSD1 inhibitors that target the interaction between LSD1 with STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC."
926,Unprocessed Genomic Uracil as a Source of DNA Replication Stress in Cancer Cells,"Sneha Saxena, Parasvi S. Patel, Christopher S. Nabel, Ajinkya S. Kawale, Caroline R. Crosby, Matthew G. Vander Heiden, Aaron N. Hata, Lee Zou",https://www.biorxiv.org/content/10.1101/2024.02.05.578390v1,"Alterations of bases in DNA constitute a major source of genomic instability. It is believed that base alterations trigger base excision repair (BER), generating DNA repair intermediates interfering with DNA replication. Here, we show that genomic uracil, a common base alteration, induces DNA replication stress (RS) without being processed by BER. In the absence of uracil DNA glycosylase (UNG), genomic uracil accumulates to high levels, DNA replication forks slow down, and PrimPol-mediated repriming is enhanced, generating single-stranded gaps in nascent DNA. ATR inhibition in UNG-deficient cells blocks repair of uracil-induced gaps, increasing replication fork collapse and cell death. Notably, a subset of cancer cells harboring high levels of genomic uracil upregulate UNG2 to limit RS, and these cancer cells are hypersensitive to co-treatment with ATR inhibitors and drugs increasing genomic uracil. These results reveal unprocessed genomic uracil as an unexpected source of RS and a targetable vulnerability of cancer cells."
928,Immune Profiling among Colorectal Cancer Subtypes using Dependent Mixture Models,"Yunshan Duan, Shuai Guo, Wenyi Wang, Peter Mueller",https://www.biorxiv.org/content/10.1101/2023.07.24.550400v2,"Comparison of transcriptomic data across different conditions is of interest in many biomedical studies. In this paper, we consider comparative immune cell profiling for early-onset (EO) versus late-onset (LO) colorectal cancer (CRC). EOCRC, diagnosed between ages 18-45, is a rising public health concern that needs to be urgently addressed. However, its etiology remains to be poorly understood. We work towards filling this gap by identifying homogeneous T cell subpopulations that show significantly distinct characteristics across the two tumor types, and to identify others that are shared between EOCRC and LOCRC. Such inference may reveal underlying determinants of clinically observed differences in the two disease subpopulations. We develop dependent finite mixture models where immune subtypes enriched under a specific condition are characterized by terms in the mixture model with common atoms but distinct weights across conditions, whereas common subtypes are characterized by sharing both atoms and relative weights. The proposed model defines a variation of mixtures of finite mixture models, facilitating the desired comparison by introducing highly structured multi-layer Dirichlet priors. The model allows us to explicitly compare features across conditions. We illustrate inference with simulation studies and data examples. Results identify EO-enriched and LO-enriched T cells subtypes whose biomarkers are found to be linked to mechanisms of tumor progression. The findings reveal distinct characteristics of the immune profiles in EOCRC and LOCRC, and potentially motivate insights into treatment and management of CRC."
933,Assessment of the Degree of Coincidence between Differentially Expressed Genes in Pancreatic Cancer with and without CAR T Cell treatment,"Alibeth E. Luna-Alvear, Deiver Suárez-Gómez, Andrea A. Sanchez-Castro, Alexandra C. Rentas-Echeverria, Mauricio Cabrera-Ríos, Clara E. Isaza",https://www.biorxiv.org/content/10.1101/2024.04.15.589636v1,"Treatment of cancer with CAR T Cells has steadily become a viable and promising cellular therapy approach in recent years. It is well known that liquid cancers are better suited for this kind of treatment, as opposed to solid cancers. This work focuses on contrasting lists of differentially expressed genes (DEGs) found in pancreatic cancer -a solid cancer-against lists of DEGs found in post-CAR T Cell treatment of pancreatic cancer. It is postulated that the degree of coincidence in these lists could positively correlate with treatment effectiveness. OBAMA, a proprietary mathematical optimization-based analysis pipeline that minimizes user selection bias is employed here to preserve objectivity. The study utilized publicly available microarray experiments. The results indicate overall low degrees of coincidence, which partially support the postulate of this work."
934,Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts,"Stuart A. Clayton, Alan D. Mizener, Marcella Whetsell, Lauren E. Rentz, Ethan Meadows, Werner Geldenhuys, Emidio E. Pistilli",https://www.biorxiv.org/content/10.1101/2024.04.15.589557v1,"Breast cancer (BC) is the most prevalent cancer worldwide and is accompanied by fatigue during both active disease and remission in the majority of cases. Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle."
935,Gra-CRC-miRTar: The pre-trained nucleotide-to-graph neural networks to identify potential miRNA targets in colorectal cancer,"Rui Yin, Hongru Zhao, Lu Li, Qiang Yang, Min Zeng, Carl Yang, Jiang Bian, Mingyi Xie",https://www.biorxiv.org/content/10.1101/2024.04.15.589599v1,"Colorectal cancer (CRC) is the third most diagnosed cancer and the second deadliest cancer worldwide representing a major public health problem. In recent years, increasing evidence has shown that microRNA (miRNA) can control the expression of targeted human messenger RNA (mRNA) by reducing their abundance or translation, acting as oncogenes or tumor suppressors in various cancers, including CRC. Due to the significant up-regulation of oncogenic miRNAs in CRC, elucidating the underlying mechanism and identifying dysregulated miRNA targets may provide a basis for improving current therapeutic interventions. In this paper, we proposed Gra-CRC-miRTar, a pre-trained nucleotide-to-graph neural network framework, for identifying potential miRNA targets in CRC. Different from previous studies, we constructed two pre-trained models to encode RNA sequences and transformed them into de Bruijn graphs. We employed different graph neural networks to learn the latent representations. The embeddings generated from de Bruijn graphs were then fed into a Multilayer Perceptron (MLP) to perform the prediction tasks. Our extensive experiments show that Gra-CRC-miRTar achieves better performance than other deep learning algorithms and existing predictors. In addition, our analyses also successfully revealed 172 out of 201 functional interactions through experimentally validated miRNA-mRNA pairs in CRC. Collectively, our effort provides an accurate and efficient framework to identify potential miRNA targets in CRC, which can also be used to reveal miRNA target interactions in other malignancies, facilitating the development of novel therapeutics."
936,"The ERK1/2-Elk1, JNK-cJun, and JAK-STAT Transcriptional Axes as Potential Bortezomib Resistance Mediators in Prostate Cancer","Georgios Kalampounias, Kalliopi Zafeiropoulou, Theodosia Androutsopoulou, Spyridon Alexis, Argiris Symeonidis, Panagiotis Katsoris",https://www.biorxiv.org/content/10.1101/2024.04.15.589569v1,"The effectiveness of proteasome inhibitors against solid tumors is limited as the emergence of resistance is rapid. Although many mechanisms have been proposed and verified, no definite answer has been given, highlighting the complexity of the resistant phenotype. In this study, a Bortezomib-resistant prostate cancer cell line is created, and a broad-spectrum signaling pathway analysis is performed to identify differences and adaptations the resistant cells exhibit. Our findings highlight the upregulation and activation of Nf-κB, STAT3, cJun, and Elk1 transcription factors in the resistant cells and the subsequent evasion of apoptosis and induction of autophagy, which is constantly activated and substitutes the role of the ubiquitin-proteasome system (UPS). Additionally, assessment of the intracellular reactive oxygen species in resistant cells confirms their downregulation, which is theorized to be a consequence of metabolic changes, increased autophagic flux, and antioxidative enzyme action. The results of this study highlight the potential therapeutic targeting of key kinases and transcription factors, participating in the main signaling pathways and gene regulation of Bortezomib-resistant cells, that could re-sensitize the cells to proteasome inhibitors, thus surpassing the current limitations."
937,Telomerase inhibition by MST-312 sensitises breast cancer cells to anti-cancer properties of Plumbagin,"Safoura Sameni, Ramya Viswanathan, Gavin Yong-NG Quan, Wilner Martinez-Lopezm, Prakash Hande",https://www.biorxiv.org/content/10.1101/2023.05.29.542688v1,"Breast cancer is the most common cause of malignancy and the second most common cause of cancer death in women. This heterogeneous disease is currently broadly classified as ER, PG positive luminal tumours, HER2 amplified tumours and triple-negative breast cancers (TNBC). Natural plant derived compounds are proven to be promising anti-cancer chemotherapeutics agents with minimal cytotoxic effects on healthy cells. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) is a phytochemical derived from the roots of Plumbago zeylanica and it is known to possess anti-cancer properties similar to other compounds of naphthoquinones. In about 90 % of cancer cells, the telomerase enzyme activity is revived to add telomeric repeats to evade apoptosis. In this study, a combinatorial approach of combining anti-cancer compound Plumbagin to induce genotoxicity and a potent telomerase inhibitor, MST-312 (synthetic derivative of tea-catechins) was used to determine the synthetic lethality in breast cancer cells such as MDA-MB-231 (TNBC) and MCF-7 (lumina) cells. MDA-MB-231 cells were responsive to combination treatment to both short-term (48 hours) and long-term treatment (14 days) in a synergistic manner, whereas in MCF-7, the combination treatment was more effective in the long-term regimen. Furthermore, the cytotoxic effects of the Plumbagin and MST-312 combination treatment were not recoverable after the short-term treatment. In conclusion, combination treatment of MST-312 and Plumbagin is proven to be more effective than single Plumbagin compound treatment, in inducing DNA damage and telomere dysfunction leading to greater genome instability, cell cycle arrest and eventually cell death in cancer cells."
938,miR-6883 downregulates HIF1α in colorectal and breast cancer cells,"Nicole Jensen-Velez, Lindsey Carlsen, Wafik El-Deiry",https://www.biorxiv.org/content/10.1101/2023.09.05.556385v1,"Colorectal cancer (CRC) and breast cancer (BC) are deadly diseases that rank as the second and fourth leading causes of cancer-related deaths, respectively. We have previously shown that miR-6883 targets CDK4/6 and that palbociclib-mediated CDK4/6 inhibition destabilizes HIF1α. We hypothesize that miR-6883 downregulates HIF1α in CRC and BC cells. miR-6883 was transfected under normoxia or hypoxia and western blot analysis revealed that miR-6883 downregulates CDK4/6 and HIF1α in CRC and BC cells, pointing to miR-6883 as a promising therapeutic to target hypoxic cancers or HIF1α-deregulated tumor cells. Future studies will further investigate miR-6883 as a cancer biomarker, effects on HIF–related proteins and therapeutic uses in vivo."
939,DropBlot: single-cell western blotting of chemically fixed cancer cells,"Yang Liu, Amy E. Herr",https://www.biorxiv.org/content/10.1101/2023.09.04.556277v1,"To further realize proteomics of archived tissues for translational research, we introduce a hybrid microfluidic platform for high-specificity, high-sensitivity protein detection from individual chemically fixed cells. To streamline processing-to-analysis workflows and minimize signal loss, DropBlot serially integrates sample preparation using droplet-based antigen retrieval from single fixed cells with unified analysis-on-a-chip comprising microwell-based antigen extraction followed by chip-based single-cell western blotting. A water-in-oil droplet formulation proves robust to the harsh chemical (SDS, 6M urea) and thermal conditions (98°C, 1-2 hr.) required for sufficient antigen retrieval, and the electromechanical conditions required for electrotransfer of retrieved antigen from microwell-encapsulated droplets to single-cell electrophoresis. Protein-target retrieval was demonstrated for unfixed, paraformaldehyde-(PFA), and methanol-fixed cells. We observed higher protein electrophoresis separation resolution from PFA-fixed cells with sufficient immunoreactivity confirmed for key targets (HER2, GAPDH, EpCAM, Vimentin) from both fixation chemistries. Multiple forms of EpCAM and Vimentin were detected, a hallmark strength of western-blot analysis. DropBlot of PFA-fixed human-derived breast tumor specimens (n = 5) showed antigen retrieval from cells archived frozen for 6 yrs. DropBlot could provide a precision integrated workflow for single-cell resolution protein-biomarker mining of precious biospecimen repositories."
941,Development of a Deep Learning model Tailored for HER2 Detection in Breast Cancer to aid pathologists in interpreting HER2-Low cases,"Pierre-Antoine Bannier, Glenn Broeckx, Loïc Herpin, Rémy Dubois, Lydwine Van Praet, Charles Maussion, Frederik Deman, Ellen Amonoo, Anca Mera, Jasmine Timbres, Cheryl Gillett, Elinor Sawyer, Patrycja Gazińska, Piotr Ziolkowski, Magali Lacroix-Triki, Roberto Salgado, Sheeba Irshad",https://www.biorxiv.org/content/10.1101/2024.07.01.601397v1,"Introduction Over 50% of breast cancer cases are ""Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)"", characterized by HER2 immunohistochemistry (IHC) scores of 1+ or 2+ alongside no amplification on fluorescence in situ hybridization (FISH) testing. The development of new anti-HER2 antibody-drug conjugates (ADCs) for treating HER2-low breast cancers illustrates the importance of accurately assessing HER2 status, particularly HER2-low breast cancer. In this study, we evaluated the performance of a deep learning (DL) model for the assessment of HER2, including an assessment of the causes of discordances of HER2-Null between a pathologist and the DL model. We specifically focussed on aligning the DL model rules with the ASCO/CAP guidelines, including stained cells’ staining intensity and completeness of membrane staining."
943,Distinct states of nucleolar stress induced by anti-cancer drugs,"Tamara A. Potapova, Jay R. Unruh, Juliana Conkright-Fincham, Charles A. S. Banks, Laurence Florens, David A. Schneider, Jennifer L. Gerton",https://www.biorxiv.org/content/10.1101/2022.11.18.517150v3,"Ribosome biogenesis is a vital and energy-consuming cellular function occurring primarily in the nucleolus. Cancer cells have an especially high demand for ribosomes to sustain continuous proliferation. This study evaluated the impact of existing anticancer drugs on the nucleolus by screening a library of anticancer compounds for drugs that induce nucleolar stress. For a readout, a novel parameter termed “nucleolar normality score” was developed that measures the ratio of the fibrillar center and granular component proteins in the nucleolus and nucleoplasm. Multiple classes of drugs were found to induce nucleolar stress, including DNA intercalators, inhibitors of mTOR/PI3K, heat shock proteins, proteasome, and cyclin-dependent kinases (CDKs). Each class of drugs induced morphologically and molecularly distinct states of nucleolar stress accompanied by changes in nucleolar biophysical properties. In-depth characterization focused on the nucleolar stress induced by inhibition of transcriptional CDKs, particularly CDK9, the main CDK that regulates RNA Pol II. Multiple CDK substrates were identified in the nucleolus, including RNA Pol I – recruiting protein Treacle, which was phosphorylated by CDK9 in vitro. These results revealed a concerted regulation of RNA Pol I and Pol II by transcriptional CDKs. Our findings exposed many classes of chemotherapy compounds that are capable of inducing nucleolar stress, and we recommend considering this in anticancer drug development."
944,MAIT Cells Modulate Innate Immune Cells and Inhibit Colon Cancer Growth,"Olivia J. Cheng, Eric J. Lebish, Owen Jensen, Damian Jacenik, Shubhanshi Trivedi, Jackson Cacioppo, Jeffrey Aubé, Ellen J. Beswick, Daniel T. Leung",https://www.biorxiv.org/content/10.1101/2024.01.16.575894v2,"Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we show that peritumoral injection of in vivo-expanded MAIT cells into RAG1-/- mice with MC38-derived tumors inhibits tumor growth compared to control. Multiplex cytokine analyses show that tumors from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting an association between eosinophil recruitment and tumor inhibition. In a human peripheral leukocyte co-culture model, we show that leukocytes stimulated with MAIT ligand show an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we show that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy."
946,Heterogeneity and genomic evolution of metastatic prostate cancer,"Sijia Wu, Zhennan Lu, Yanfei Wang, Xiaobo Zhou, Liyu Huang",https://www.biorxiv.org/content/10.1101/2023.09.01.556000v1,"Background Metastasis is the primary cause of prostate cancer-related deaths. However, the underlying molecular mechanisms and evolutionary patterns remain largely uncharacterized."
948,Exploring the genetic and epigenetic underpinnings of early-onset cancers: Variant prioritization for long read whole genome sequencing from family cancer pedigrees,"Melissa Kramer, Sara Goodwin, Robert Wappel, Matilde Borio, Kenneth Offit, Darren R. Feldman, Zsofia K. Stadler, W. Richard McCombie",https://www.biorxiv.org/content/10.1101/2024.06.27.601096v1,"Despite significant advances in our understanding of genetic cancer susceptibility, known inherited cancer predisposition syndromes explain at most 20% of early-onset cancers. As early-onset cancer prevalence continues to increase, the need to assess previously inaccessible areas of the human genome, harnessing a trio or quad family-based architecture for variant filtration, may reveal further insights into cancer susceptibility. To assess a broader spectrum of variation than can be ascertained by multi-gene panel sequencing, or even whole genome sequencing with short reads, we employed long read whole genome sequencing using an Oxford Nanopore Technology (ONT) PromethION of 3 families containing an early-onset cancer proband using a trio or quad family architecture. Analysis included 2 early-onset colorectal cancer family trios and one quad consisting of two siblings with testicular cancer, all with unaffected parents. Structural variants (SVs), epigenetic profiles and single nucleotide variants (SNVs) were determined for each individual, and a filtering strategy was employed to refine and prioritize candidate variants based on the family architecture. The family architecture enabled us to focus on inapposite variants while filtering variants shared with the unaffected parents, significantly decreasing background variation that can hamper identification of potentially disease causing differences. Candidate de novo and compound heterozygous variants were identified in this way. Gene expression, in matched neoplastic and pre-neoplastic lesions, was assessed for one trio. Our study demonstrates the feasibility of a streamlined analysis of genomic variants from long read ONT whole genome sequencing and a way to prioritize key variants for further evaluation of pathogenicity, while revealing what may be missing from panel based analyses."
949,Targeting PD-L1 in solid cancer with myeloid cells expressing a CAR-like immune receptor,"Kayla Myers Chen, Daniel Grun, Brian Gautier, Shivaprasad Venkatesha, Michael Maddox, Ai-Hong Zhang, Peter Andersen",https://www.biorxiv.org/content/10.1101/2024.01.29.577873v1,"Myeloid cells are prevalent in solid cancers, but they frequently exhibit a pro-tumor phenotype, hindering cancer immunotherapy. Their abundance makes engineered myeloid cell therapy an intriguing approach to tackle challenges posed by solid cancers, such as tumor trafficking and infiltration along with tumor cell heterogenicity and immunosuppressive tumor microenvironment (TME). Solid cancers often upregulate the checkpoint molecule PD-L1 to evade immune responses. Thus, we devised an adoptive cell therapy strategy based on myeloid cells expressing a Chimeric Antigen Receptor (CAR)-like immune receptor (CARIR). The extracellular domain of CARIR is derived from the natural inhibitory receptor PD-1, while the intracellular domain(s) are derived from CD40 and/or CD3ξ. To assess the efficacy of CARIR-engineered myeloid cells, we conducted proof-of-principle experiments using co-culture and flow cytometry-based phagocytosis assays in vitro. Additionally, we employed a fully immune-competent syngeneic tumor mouse model to evaluate the strategy’s effectiveness in vivo. Co-culturing CARIR-expressing human monocytic THP-1 cells with PD-L1+ target cells lead to upregulation of the co-stimulatory molecule CD86 along with expression of proinflammatory cytokines TNF-1α and IL-1β. Moreover, CARIR expression significantly enhanced phagocytosis of multiple PD-L1+ human solid tumor cell lines in vitro. Similar outcomes were observed with CARIR-expressing human primary macrophages. In experiments conducted on Balb/c mice bearing aggressive 4T1 mammary tumors, infusing murine myeloid cells expressing a murine version of CARIR significantly slowed tumor growth and prolonged survival. Taken together, our results demonstrate that adoptive transfer of PD-1 CARIR-engineered myeloid cells may be an effective strategy in treating PD-L1+ solid tumors."
950,Modeling platinum resistance in a stem-like patient-derived ovarian cancer sample,"Tise Suzuki, Ashlyn Conant, Yeonkyu Jung, Ryan Bax, Ashley Antonissen, Wanqiu Chen, Gary Yu, Yevgeniya J. Ioffe, Charles Wang, Juli J. Unternaehrer",https://www.biorxiv.org/content/10.1101/2024.01.30.577975v1,"Background Chemoresistance and tumor recurrence remain a significant challenge in ovarian cancer. Particularly in the context of platinum resistance, many mechanisms have been identified, including the activation of cellular processes like epithelial-mesenchymal transition (EMT), which generates cells with stemness characteristics. Current models of platinum resistance are limited or not adequate representations of the heterogeneity of the disease. Thus, to advance our understanding of chemoresistance in the context of cancer stem cells (CSC) in ovarian cancer, this study aims to develop an effective model for cisplatin resistance using a patient-derived cancer stem-like sample."
951,BioXNet: a biologically inspired neural network for deciphering anti-cancer drug response in precision medicine,"Jiannan Yang, William Ka Kei Wu, Rina Yee Man Hui, Ian Chi Kei Wong, Qingpeng Zhang",https://www.biorxiv.org/content/10.1101/2024.01.29.576766v1,"Accurate prediction of anti-cancer drug responses in preclinical and clinical studies is crucial for drug discovery and personalized medicine. While machine learning models have demonstrated promising prediction accuracy in this task, their translational value in cancer therapy is constrained by the lack of model interpretability and insufficient patients’ data with genomic profiles to calibrate models. The rich cell line data has the potential to supplement patients’ data, but the difference between the drug response mechanisms in cell lines and human body needs to be characterized quantitatively. To address these challenges, we proposed the BioXNet, which captures drug response mechanisms by seamlessly integrating drug target information with genomic profiles (genetic and epigenetic modifications) into a single biologically inspired neural network. BioXNet exhibited superior performance in drug response prediction tasks in both preclinical and clinical settings. An analysis of BioXNet’s interpretability revealed its ability to identify significant differences in drug response mechanisms between cell lines and the human body. Notably, the key factor of drug response is the drug targeting genes in cell lines but methylation modifications in the human body. Furthermore, we developed an online human-readable interface of BioXNet for drug response exploration by medical professionals and laymen. BioXNet represents a step further towards unifying drug, cell line and patients’ data under a holistic interpretable machine learning framework for precision medicine in cancer therapy."
952,LncRNA GAS6-AS1 contributes to 5-fluorouracil resistance in colorectal cancer,"Zhonglin Zhu, Minghan Li, Junyong Weng, Shanbao Li, Tianan Guo, Yang Guo, Ye Xu",https://www.biorxiv.org/content/10.1101/2024.01.30.577984v1,"5-Fluorouracil (5-FU) resistance has always been a formidable obstacle in the adjuvant treatment of advanced colorectal cancer (CRC). In recent years, long non-coding RNAs have emerged as key regulators in various pathophysiological processes including 5-FU resistance. Here, RNA-seq combined with weighted gene correlation network analysis confirmed the close association of GAS6-AS1 with TRG grades. GAS6-AS1 expression was positively correlated with advanced clinicopathological features and poor prognosis in CRC. GAS6-AS1 increased the 50% inhibiting concentration of 5-FU, enhanced cell proliferation, and accelerated G1/S transition in CRC cells, both with and without 5-FU, both in vitro and in vivo. Mechanistically, GAS6-AS1 enhanced the stability of MCM3 mRNA by recruiting PCBP1, consequently increasing MCM3 expression. Furthermore, PCBP1 and MCM3 counteracted the effects of GAS6-AS1 on 5-FU resistance. Notably, the PDX model indicated that combining chemotherapeutic drugs with GAS6-AS1 knockdown yielded superior outcomes in vivo. Together, our findings elucidate that GAS6-AS1 directly binds to PCBP1, enhancing MCM3 expression and thereby promoting 5-FU resistance. GAS6-AS1 may serve as a robust biomarker and potential therapeutic target for combination therapy in CRC."
953,"Frequently Together, Among Model Systems Molecular Alterations: Cancer Maintenance Markers with Translational Study Design","Maya Ylagan, Qi Xu, Jeanne Kowalski",https://www.biorxiv.org/content/10.1101/2024.01.26.577415v1,"In contrast to cancer driver gene alterations, genes with alterations occurring frequently together are unlikely to play a direct role in tumor development, and more likely to contribute to normal cellular functions necessary for the ongoing maintenance and survival of the tumor, with the most robust of these genes preserved across model systems. We introduce two molecular signature-centric methods, RECO (recurring and co-occurring) and Crosstalk, to identify gene sets characterized by molecular alterations that occur frequently together across sample model systems. Our overall approach builds a cancer information exchange among samples systems based on an analysis of gene and sample-level signature pairs using RECO and Crosstalk methods. The results may be used to design translational studies from gene signature discovery in patients to its application in cell lines and patient-derived xenograft models, alongside the discovery of potential cancer maintenance markers. We demonstrate the capabilities of our approach by exploring the discovery of frequently together molecular alterations between patient tumors and cell lines, and between histologically similar tumors with different sites of origin, and their associations with outcomes in several cancers. As understudied, expanded markers, genes with frequently occurring molecular alterations between systems offer potentially new insights into similar cancer etiology and treatment targets outside the norm, in addition to informing on translational study design."
958,Restoring O-glycosylation and expression of MUC2 limits progression of colorectal cancer,"Yian Yang, Yuesong Yin, Wei Xu, Yan Kang, Jiawei Chen, Yanfeng Zou, Zhigang Xiao, Zheng Li, Peiguo Cao",https://www.biorxiv.org/content/10.1101/2024.01.25.577208v1,"This study investigated the molecular mechanisms underlying the regulation of MUC2 expression and O-glycosylation modification in colorectal cancer. In addition, the potential of rosiglitazone to inhibit colorectal cancer by improving MUC2 glycosylation to protect intestinal barrier function was explored. In vitro, lectin staining combined with Co-IP assay was used to detect glycosyltransferases regulating MUC2 O-glycosylation. ChIP and Luciferase experiments were used to verify the transcription factors regulating MUC2 expression level. Samples from CRC patients were used to detect differences in multimolecular expression. The AOM/DSS mouse model was used to validate the effect of rosiglitazone on inhibiting colorectal cancer progression. Our results showed that B3GNT6 acts as a glycosyltransferase to enhance the O-glycosylation level of MUC2 and maintain protein stability to resist degradation by StcE secreting from pathogenic bacteria. Furthermore, KLF4 directly promotes the transcription of B3GNT6 and MUC2, which are regulated by PPARg. Rosiglitazone activated PPARg-KLF4-B3GNT6 axis which increased the expression level and glycosylation of MUC2 and further improved the intestinal mucosal barrier function to delay the development of colorectal cancer in mice. These data suggest that O-glycosylation and expression of MUC2 is key to the maintenance of functional intestinal mucosa and rosiglitazone is a potential colorectal cancer therapeutic agent."
959,CODEX: COunterfactual Deep learning for the in-silico EXploration of cancer cell line perturbations,"Stefan Schrod, Tim Beißbarth, Helena U. Zacharias, Anne-Christin Hauschild, Michael Altenbuchinger",https://www.biorxiv.org/content/10.1101/2024.01.24.577020v1,"Motivation High-throughput screens (HTS) provide a powerful tool to decipher the causal effects of chemical and genetic perturbations on cancer cell lines. Their ability to evaluate a wide spectrum of interventions, from single drugs to intricate drug combinations and CRISPR-interference, has established them as an invaluable resource for the development of novel therapeutic approaches. Nevertheless, the combinatorial complexity of potential interventions makes a comprehensive exploration intractable. Hence, prioritizing interventions for further experimental investigation becomes of utmost importance."
960,Islands of genomic stability in the face of genetically unstable metastatic cancer,"Kirsten Bowland, Jiaying Lai, Alyza Skaist, Yan Zhang, Selina Shiqing K Teh, Nicholas J. Roberts, Elizabeth Thompson, Sarah J. Wheelan, Ralph H. Hruban, Rachel Karchin, Christine A. Iacobuzio-Donahue, James R. Eshleman",https://www.biorxiv.org/content/10.1101/2024.01.26.577508v1,"Introduction Metastatic cancer affects millions of people worldwide annually and is the leading cause of cancer-related deaths. Most patients with metastatic disease are not eligible for surgical resection, and current therapeutic regimens have varying success rates, some with 5-year survival rates below 5%. Here we test the hypothesis that metastatic cancer can be genetically targeted by exploiting single base substitution mutations unique to individual cells that occur as part of normal aging prior to transformation. These mutations are targetable because ∼10% of them form novel tumor-specific “NGG” protospacer adjacent motif (PAM) sites targetable by CRISPR-Cas9."
961,GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15,"Caroline Chang, Ya-Yun Cheng, Shriya Kamlapurkar, Sierra R. White, Priscilla W. Tang, Amal T. Elhaw, Zaineb Javed, Katherine M. Aird, Karthikeyan Mythreye, Rébécca Phaëton, Nadine Hempel",https://www.biorxiv.org/content/10.1101/2024.01.24.577037v1,"Objective We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3’s pro-tumorigenic function."
962,Cell competition for cancer treatment with Urine Progenitor Cells,"Juli R. Bagó, Dhwani Radhakrishnan, Matouš Hrdinka, Tomasz Cichoń, Ryszard Smolarczyk, Sandra Charvátová, Benjamin Motais, Sebastian Giebel, Roman Hájek",https://www.biorxiv.org/content/10.1101/2023.08.27.554858v1,"Here, we provide evidence that urine progenitor cells (UPCs) might offer a novel therapeutic strategy for treating different types of cancer. We found that UPCs have inherent antitumor properties due to cell-cell competition, and we described their mechanism of action against different tumor cell lines. In vitro time-lapse analysis showed that the UPCs have tumor tropic properties, homing to various tumor-conditioned mediums. Besides, UPCs engineered for the expression of cytotoxic agents (the Tumor Necrosis Factor ligand superfamily member 10 and Herpesvirus-thymidine kinase) significantly increased their antitumor properties against several tumor cell lines and proved to serve as highly effective drug-delivery vehicles. Finally, using a mouse model of human triple-negative breast cancer, we observed a 150-fold decrease in tumor volumes in mice treated with engineered UPCs compared to controls. Collectively, our findings demonstrate for the first time the antitumor properties of the UPCs and form a foundation to continue exploring the new concept of cell-cell competition in progenitor cells to treat different types of cancer."
963,Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression,"Dipon K. Mondal, Christopher Xie, Simone Buraschi, Renato V. Iozzo",https://www.biorxiv.org/content/10.1101/2023.08.28.555187v1,"The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a pro-survival program and to sustain a pro-angiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we discovered that decorin downregulated a cluster of tumor-associated genes involved in lymphatic vessel development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of lymphatic vessels, were markedly suppressed at both the mRNA and protein levels and this suppression correlated with a significant reduction in tumor lymphatic vessels. We further discovered that soluble decorin, but not its homologous proteoglycan biglycan, inhibited lymphatic vessel sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with VEGFR3, the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we discovered that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a new biological factor with anti-lymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis."
965,L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor,"Bruna Victorasso Jardim-Perassi, Pietro Irrera, Dominique Abrahams, Veronica C. Estrella, Bryce Ordway, Samantha R. Byrne, Andrew A. Ojeda, Christopher J. Whelan, Jongphil Kim, Matthew S. Beatty, Sultan Damgaci-Erturk, Dario Livio Longo, Kim J. Gaspar, Gabrielle M. Siegers, Barbara A. Centeno, Justin Y.C. Lau, Arig Ibrahim-Hashim, Shari A. Pilon-Thomas, Robert J. Gillies",https://www.biorxiv.org/content/10.1101/2023.08.28.555194v1,"Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds CEACAM6, a cell surface protein highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Our results demonstrate that combining L DOS47 with anti-PD1 significantly increases the efficacy of anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks."
966,Absence of Lipopolysccharide (LPS) expression in Breast Cancer Cells,"Noel FCC de Miranda, Vincent THBM Smit, Manon van der Ploeg, Jelle Wesseling, Jacques Neefjes",https://www.biorxiv.org/content/10.1101/2023.08.28.555057v1,"The association between bacterial activity and tumorigenesis has gained attention in recent years, alongside the well-established link between viruses and cancer. A recent study proposed the presence of intracellular bacteria in cancer cells, particularly in melanomas and breast cancers, with detectable bacterial DNA. The authors suggested that these bacteria contribute to the tumors’ development. We sought to replicate these findings using the same experimental methods on different tissue microarrays. Our investigation included 129 breast cancer samples, but we found no evidence of LPS expression within cancer cells. Instead, LPS immunoreactivity was observed in ducts or immune cells, specifically macrophages. The discrepancies in LPS staining warrant caution in interpreting the reported observations, and further research is needed to elucidate the potential role of intracellular bacteria in cancer development."
968,Evaluation of the gene fusion landscape in early onset sporadic rectal cancer reveals association with chromatin architecture and genome stability,"Asmita Gupta, Sumedha Avadhanula, Murali Dharan Bashyam",https://www.biorxiv.org/content/10.1101/2024.04.09.588655v1,"Gene fusions represent a distinct class of structural variants identified frequently in cancer genomes across cancer types. Several gene fusions exhibit gain of oncogenic function and thus have been the focus of development of efficient targeted therapies. However, investigation of fusion landscape in early-onset sporadic rectal cancer, a poorly studied colorectal cancer subtype prevalent in developing countries, has not been performed. Here, we present a comprehensive landscape of gene fusions in EOSRC and CRC using patient derived tumor samples and data from The Cancer Genome Atlas, respectively. Gene Ontology analysis revealed enrichment of unique biological process terms associated with 5’- and 3’- fusion partner genes. Extensive network analysis highlighted genes exhibiting significant promiscuity in fusion formation and their association with chromosome fragile sites. Investigation of fusion formation in the context of global chromatin architecture unravelled a novel mode of gene activation that arose from fusion between genes located in orthogonal chromatin compartments. The study provides novel evidence linking fusions to genome stability and architecture and unearthed a hitherto unidentified mode of gene activation in cancer."
969,Metabolomics and 13C Labelled Glucose Tracing to Identify Carbon Incorporation into Aberrant Cell Membrane Glycans in Cancer,"Alfredo Reyes-Oliveras, Abigail E. Ellis, Ryan D. Sheldon, Brian Haab",https://www.biorxiv.org/content/10.1101/2024.04.08.588353v1,"Cell membrane glycans contribute to immune recognition, signaling, and cellular adhesion and migration, and altered membrane glycosylation is a feature of cancer cells that contributes to cancer progression. The uptake and metabolism of glucose and other nutrients essential for glycan synthesis could underlie altered membrane glycosylation, but the relationship between shifts in nutrient metabolism and the effects on glycans have not been directly examined. To address this possibility, we created a novel method that combines stable isotope tracing with metabolomics to enable direct observations of glucose allocation to nucleotide sugars and cell-membrane glycans. We compared the glucose allocation to membrane glycans of two pancreatic cancer cell lines that are genetically identical but have differing energy requirements. The 8988-S cells had higher glucose allocation to membrane glycans and intracellular pathways relating to glycan synthesis, but the 8988-T cells had higher glucose uptake and commitment of glucose to non-glycosylation pathways. The cells lines differed in requirements of glucose for energy production, resulting in differences in glucose bioavailability for glycan synthesis. The workflow demonstrated here enables studies on the effects of metabolic shifts on the commitment of media nutrients to cell-membrane glycans. The results support a flux-based regulation of glucose commitment glycosylation and a mode of metabolic control of cell functions such signaling, immune recognition, and adhesion and migration."
970,Dual-targeted nanoparticulate drug delivery systems for enhancing triple-negative breast cancer treatment,"Shunzhe Zheng, Meng Li, Wenqian Xu, Jiaxin Zhang, Guanting Li, Hongying Xiao, Xinying Liu, Jianbin Shi, Fengli Xia, Chutong Tian, Ken-ichiro Kamei",https://www.biorxiv.org/content/10.1101/2024.01.23.576787v1,"The efficacy of DNA-damaging agents, such as the topoisomerase I inhibitor SN38, is often compromised by the robust DNA repair mechanisms in tumor cells, notably homologous recombination (HR) repair. Addressing this challenge, we introduce a novel nano-strategy utilizing binary tumor-killing mechanisms to enhance the therapeutic impact of DNA damage and mitochondrial dysfunction in cancer treatment. Our approach employs a synergistic drug pair comprising SN38 and the BET inhibitor JQ-1. We synthesized two prodrugs by conjugating linoleic acid (LA) to SN38 and JQ-1 via a cinnamaldehyde thioacetal (CT) bond, facilitating co-delivery. These prodrugs co-assemble into a nanostructure, referred to as SJNP, in an optimal synergistic ratio. SJNP was validated for its efficacy at both the cellular and tissue levels, where it primarily disrupts the transcription factor protein BRD4. This disruption leads to downregulation of BRCA1 and RAD51, impairing the HR process and exacerbating DNA damage. Additionally, SJNP releases cinnamaldehyde (CA) upon CT linkage cleavage, elevating intracellular ROS levels in a self-amplifying manner and inducing ROS-mediated mitochondrial dysfunction. Our results indicate that SJNP effectively targets murine triple-negative breast cancer (TNBC) with minimal adverse toxicity, showcasing its potential as a formidable opponent in the fight against cancer."
971,Elucidating the kinetic and thermodynamic insight into regulation of glycolysis by lactate dehydrogenase and its impact on tricarboxylic acid cycle and oxidative phosphorylation in cancer cells,"Siying Zeng, Yuqi Wang, Minfeng Ying, Chengmeng Jin, Chang Ying, Di Wang, Hao Wu, Xun Hu",https://www.biorxiv.org/content/10.1101/2024.06.26.600909v1,"Lactate dehydrogenase (LDH) stands at the intersection of pyruvate metabolism. While it is believed that inhibition of LDH redirects pyruvate to mitochondrial metabolism, suppressing glycolysis and boosting oxidative phosphorylation, the mechanism remains largely unexplored. We found that individual LDH A or B knockouts had minimal impact on glycolysis, tricarboxylic acid cycle (TCAC), or oxidative phosphorylation (OXPHOS). However, combining LDH knockout with LDH inhibitor GNE-140 significantly suppressed these processes. Inhibition of LDH led to an increase in free NADH concentration and a decrease in free NAD+ concentration, the reduced free NAD+ concentration inhibited GAPDH, disrupting the balance of glycolytic intermediates, which were linked with thermodynamic shift of the Gibbs free energy of reactions between phosphofructokinase 1 (PFK1) and phosphoglycerate mutase (PGAM) in the glycolytic pathway, favoring their reverse direction. This disrupted glycolysis led to impaired TCAC and mitochondrial respiration due to reduced pyruvate and glutamine carbon influx into TCAC. Under hypoxia, LDH inhibition had a stronger effect, inducing energy crisis, redox imbalance, and cancer cell death. Our study reveals LDH’s intricate control over glycolysis, TCAC, and mitochondrial respiration, highlighting the interplay of enzyme kinetics and thermodynamics in metabolic pathways—a crucial aspect for understanding metabolic regulation."
972,Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer,"Esther Wortmann, Annika Osswald, David Wylensek, Stephanie Kuhls, Olivia I. Coleman, Quinten Ducarmon, Wei Liang, Nicole Treichel, Fabian Schumacher, Colin Volet, Silke Matysik, Karin Kleigrewe, Michael Gigl, Sascha Rohn, Burkhard Kleuser, Gerhard Liebisch, Angelika Schnieke, Rizlan Bernier-Latmani, Georg Zeller, Dirk Haller, Krzysztof Flisikowski, Soeren Ocvirk, Thomas Clavel",https://www.biorxiv.org/content/10.1101/2023.03.17.533140v3,"Western diet is an important risk factor for the development of sporadic colorectal cancer (CRC). Dietary fat stimulates bile acid (BA) production by the host and their conversion to secondary BAs by 7α-dehydroxylating (7αDH+) bacteria, but causal proof of their tumor-promoting effects in vivo is lacking. To address this, we performed feeding studies in a genetically engineered pig model of CRC combined with multi-omics analyses and gnotobiotic mouse studies. Western diet worsened the disease phenotype in APC1311/+ pigs. This was accompanied by microbiota changes, increased levels of the secondary bile acid deoxycholic acid (DCA), and higher colonic epithelial cell proliferation. The latter was counteracted by using the BA-scavenging drug colestyramine. Metagenomic analysis across multiple cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in stool of CRC subjects (n = 1,034). Using two gnotobiotic mouse models of CRC, we demonstrate that colonization with 7αDH+ bacteria (C. scindens or Extibacter muris) increased colonic tumor loads. This work provides clear evidence for the causal role of microbiome-derived DCA production in CRC under detrimental dietary conditions, opening avenues for future preventive strategies."
974,Self-amplifying ROS-sensitive SN38 Dimeric Prodrug nanoparticles for Combined Chemotherapy and Ferroptosis in Cancer Treatment,"Yu Qin, Fenghui Wang, Zeping Gao, Chutong Tian, Ken-ichiro Kamei",https://www.biorxiv.org/content/10.1101/2024.01.22.576778v1,"Chemotherapy drugs are often limited by their own clinical shortcomings and serious adverse consequences. To solve these problems, we developed a self-amplifying reactive oxygen species (ROS)-sensitive dimeric prodrug nanoparticles, namely SN38-CA@FC NPs for tumor treatment. A ROS-sensitive 7-ethyl-10-hydroxycamptothecin (SN38) prodrug (SN38-CA) was synthesized by a thioacetal linker between SN38 and the ROS generator cinnamaldehyde (CA). The subsequent release of SN38 inflicts DNA damage, exerting chemotherapeutic effects, while the liberated CA intensifies ferroptosis through Fenton reaction-mediated disruption of the redox balance. This dual-action strategy not only leverages chemotherapy but also induces ferroptosis, establishing a synergistic therapeutic paradigm. The system is uniquely characterized by a positive feedback loop where ROS instigates the release of SN38/CA, which in turn promotes further ROS production. In experimental evaluations, this combination therapy exhibited potent antitumor activity against both A549 and LLC cancer cell lines, as well as in xenograft LLC-bearing C57BL/6 mouse models. Collectively, our findings introduce a transformative Nano-Drug Delivery System (NDDS) that holds significant promise for advancing cancer chemotherapy and ferroptosis-based therapies."
975,Identifying new cancer genes based on the integration of annotated gene sets via hypergraph neural networks,"Chao Deng, Hong-Dong Li, Li-Shen Zhang, Yi-Wei Liu, Yaohang Li, Jianxin Wang",https://www.biorxiv.org/content/10.1101/2024.01.22.576645v1,"Motivation Identifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer genes have been shown to cluster in hallmark signaling pathways and biological processes. The knowledge of annotated gene sets is critical for discovering cancer genes but remains to be fully exploited."
976,Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer,"Rou Zhang, Meng Hu, Yu Liu, Wanmeng Li, Zhiqiang Xu, Siyu He, Ying Lu, Yanqiu Gong, Xiuxuan Wang, Shan Hai, Shuangqing Li, Shiqian Qi, Yuan Li, Yang Shu, Dan Du, Huiyuan Zhang, Heng Xu, Zongguang Zhou, Peng Lei, Hai-Ning Chen, Lunzhi Dai",https://www.biorxiv.org/content/10.1101/2024.01.22.576593v1,"Magnesium (Mg) deficiency is associated with increased risk and malignancy of colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomics and phosphoproteomics indicated that low tumorous Mg content may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p upregulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which, in turn, enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may offer a promising preventive and therapeutic strategy for CRC."
977,Characterization of Cancer Stem Cells in Laryngeal Squamous Cell Carcinoma by Single-Cell RNA Sequencing,"Yanguo Li, Chen Lin, Yidian Chu, Zhengyu Wei, Qi Ding, Shanshan Gu, Hongxia Deng, Qi Liao, Zhisen Shen",https://www.biorxiv.org/content/10.1101/2024.01.21.576534v1,"Cancer stem cells (CSCs) constitute a pivotal element within the tumor microenvironment (TME), driving the initiation and progression of cancer. However, the identification of CSCs and their underlying molecular mechanisms in laryngeal squamous cell carcinoma (LSCC) remains a formidable challenge. We employed single-cell RNA sequencing of matched primary tumor tissues, paracancerous tissues, and local lymph nodes from three LSCC patients. Two distinct clusters of stem cells originating from epithelial populations were delineated and verified as CSCs and normal stem cells (NSCs) respectively. CSCs were abundant in the paracancerous tissues compared to the tumor tissues. CSCs showed high expression of stem cell marker genes such as PROM1, ALDH1A1, and SOX4, and increased activity of tumor-related hypoxia, Wnt/β-catenin, and notch signaling pathways. We then explored the intricate crosstalk between CSCs and the TME cells and identified targets within the TME that related with CSCs. We also find eight marker genes of CSCs that correlated significantly with the prognosis of LSCC patients. Furthermore, bioinformatics analyses showed that drugs such as erlotinib, OSI-027, and ibrutinib selectively targeted the CSC-specifically expressed genes. In conclusion, our results represent the first comprehensive characterization of CSCs properties in LSCC at the single-cell level."
980,Cancer-associated fibroblast ADAM17 mediates a feed-forward loop promoting cancer cell migration,"Maria L Perciato, Simon A Whawell, Daniel W Lambert",https://www.biorxiv.org/content/10.1101/2023.05.14.540677v1,"One of the ways in which cancer associated fibroblasts (CAF) influence the tumour-microenvironment (TME) is by releasing soluble factors to elicit responses in nearby cells. These factors may be released by modification of the extracellular matrix (ECM), secretion from intracellular compartments, or proteolytic cleavage from the cell surface. A major mediator of proteolytic processing of cell surface proteins is the ‘a disintegrin and metalloproteinase’ (ADAM) family, commonly ADAM17. The role of ADAM17 in CAF, however, remains largely unknown."
981,Graph attention-based fusion of pathology images and gene expression for prediction of cancer survival,"Yi Zheng, Regan D. Conrad, Emily J. Green, Eric J. Burks, Margrit Betke, Jennifer E. Beane, Vijaya B. Kolachalama",https://www.biorxiv.org/content/10.1101/2023.10.26.564236v2,"Multimodal machine learning models are being developed to analyze pathology images and other modalities, such as gene expression, to gain clinical and biological in-sights. However, most frameworks for multimodal data fusion do not fully account for the interactions between different modalities. Here, we present an attention-based fusion architecture that integrates a graph representation of pathology images with gene expression data and concomitantly learns from the fused information to predict patient-specific survival. In our approach, pathology images are represented as undirected graphs, and their embeddings are combined with embeddings of gene expression signatures using an attention mechanism to stratify tumors by patient survival. We show that our framework improves the survival prediction of human non-small cell lung cancers, out-performing existing state-of-the-art approaches that lever-age multimodal data. Our framework can facilitate spatial molecular profiling to identify tumor heterogeneity using pathology images and gene expression data, complementing results obtained from more expensive spatial transcriptomic and proteomic technologies."
982,Collagen mineralization decreases NK cell-mediated cytotoxicity of breast cancer cells via increased glycocalyx thickness,"Sangwoo Park, Siyoung Choi, Adrian A. Shimpi, Lara A. Estroff, Claudia Fischbach, Matthew J. Paszek",https://www.biorxiv.org/content/10.1101/2024.01.20.576377v1,"Skeletal metastasis is common in patients with advanced breast cancer, and often caused by immune evasion of disseminated tumor cells (DTCs). In the skeleton, tumor cells not only disseminate to the bone marrow, but also to osteogenic niches in which they interact with newly mineralizing bone extracellular matrix (ECM). However, it remains unclear how mineralization of collagen type I, the primary component of bone ECM, regulates tumor-immune cell interactions. Here, we have utilized a combination of synthetic bone matrix models with controlled mineral content, nanoscale optical imaging, and flow cytometry to evaluate how collagen type I mineralization affects the biochemical and biophysical properties of the tumor cell glycocalyx, a dense layer of glycosylated proteins and lipids decorating their cell surface. Our results suggest that collagen mineralization upregulates mucin-type O-glycosylation and sialylation by tumor cells, which increased their glycocalyx thickness while enhancing resistance to attack by Natural Killer (NK) cells. These changes were functionally linked as treatment with a sialylation inhibitor decreased mineralization-dependent glycocalyx thickness and made tumor cells more susceptible to NK cell attack. Together, our results suggest that interference with glycocalyx sialylation may represent a therapeutic strategy to enhance cancer immunotherapies targeting bone-metastatic breast cancer."
983,Muscle weakness and mitochondrial stress occur before metastasis in a novel mouse model of ovarian cancer cachexia,"Luca J. Delfinis, Leslie M. Ogilvie, Shahrzad Khajehzadehshoushtar, Shivam Gandhi, Madison C. Garibotti, Arshdeep K. Thuhan, Kathy Matuszewska, Madison Pereira, Ronald G. Jones III, Arthur J. Cheng, Thomas J. Hawke, Nicholas P. Greene, Kevin A. Murach, Jeremy A. Simpson, Jim Petrik, Christopher G.R. Perry",https://www.biorxiv.org/content/10.1101/2024.04.08.588639v1,"Objectives A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice."
987,LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer,"A Mandl, S Jasmine, TEG Krueger, R Kumar, IM Coleman, SL Dalrymple, L Antony, DM Rosen, Y Jing, B Hanratty, RA Patel, L Jin-Yih, J Dias, CA Celatka, AE Tapper, M Kleppe, M Kanayama, V Speranzini, YZ Wang, J Luo, E Corey, LA Sena, RA Casero Jr, T Lotan, BJ Trock, SK Kachhap, SR Denmeade, MA Carducci, A Mattevi, MC Haffner, PS Nelson, HY Rienhoff Jr., JT Isaacs, WN Brennen",https://www.biorxiv.org/content/10.1101/2024.01.17.576106v1,"Lysine-specific demethylase 1 (LSD1 or KDM1A) has emerged as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Among mCRPC subtypes, neuroendocrine prostate cancer (NEPC) is an exceptionally aggressive variant driven by lineage plasticity, an adaptive resistance mechanism to androgen receptor axis-targeted therapies. Our study shows that LSD1 expression is elevated in NEPC and associated with unfavorable clinical outcomes. Using genetic approaches, we validated the on-target effects of LSD1 inhibition across various models. We investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor with low nanomolar potency. Our findings demonstrate potent antitumor activity against CRPC models, including tumor regressions in NEPC patient-derived xenografts. Mechanistically, our study uncovers that LSD1 inhibition suppresses the neuronal transcriptional program by downregulating ASCL1 through disrupting LSD1:INSM1 interactions and de-repressing YAP1 silencing. Our data support the clinical development of LSD1 inhibitors for treating CRPC – especially the aggressive NE phenotype."
989,Tracing back primed resistance in cancer via sister cells,"Jun Dai, Shuyu Zheng, Matías M. Falco, Jie Bao, Johanna Eriksson, Sanna Pikkusaari, Sofia Forstén, Jing Jiang, Wenyu Wang, Luping Gao, Fernando Perez-Villatoro, Olli Dufva, Khalid Saeed, Yinyin Wang, Ali Amiryousefi, Anniina Färkkilä, Satu Mustjoki, Liisa Kauppi, Jing Tang, Anna Vähärautio",https://www.biorxiv.org/content/10.1101/2022.07.06.498926v2,"Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods. However, transcriptional changes that drive cells into resistant fates may be subtle, necessitating high resolution analysis. We developed ReSisTrace that uses shared transcriptomic features of synchronised sister cells to predict the states that prime treatment resistance. We applied ReSisTrace in ovarian cancer cells perturbed with olaparib, carboplatin or natural killer (NK) cells. The pre-resistant phenotypes were defined by cell cycle and proteostatic features, reflecting the traits enriched in the upcoming subclonal selection. Furthermore, DNA repair deficiency rendered cells susceptible to both DNA damaging agents and NK killing in a context-dependent manner. Finally, we leveraged the pre-resistance profiles to predict and validate small molecules driving cells to sensitive states prior to treatment. In summary, ReSisTrace resolves pre-existing transcriptional features of treatment vulnerability, facilitating both molecular patient stratification and discovery of synergistic pre-sensitizing therapies."
990,Developing folate-conjugated miR-34a therapeutic for prostate cancer treatment: Challenges and promises,"Wen (Jess) Li, Yunfei Wang, Xiaozhuo Liu, Shan Wu, Moyi Wang, Steven G. Turowski, Joseph A. Spernyak, Amanda Tracz, Ahmed M. Abdelaal, Kasireddy Sudarshan, Igor Puzanov, Gurkamal Chatta, Andrea L. Kasinski, Dean G. Tang",https://www.biorxiv.org/content/10.1101/2023.11.25.568612v2,"Prostate cancer (PCa) remains a common cancer with high mortality in men due to its heterogeneity and the emergence of drug resistance. A critical factor contributing to its lethality is the presence of prostate cancer stem cells (PCSCs), which can self-renew, long-term propagate tumors and mediate treatment resistance. MicroRNA-34a (miR-34a) has shown promise as an anti-PCSC therapeutic by targeting critical molecules involved in cancer stem cell (CSC) survival and functions. Despite extensive efforts, the development of miR-34a therapeutics still faces challenges, including non-specific delivery and delivery-associated toxicity. One emerging delivery approach is ligand-mediated conjugation, aiming to achieve specific delivery of miR-34a to cancer cells, thereby enhancing efficacy while minimizing toxicity. Folate-conjugated miR-34a (folate-miR-34a) has demonstrated promising anti-tumor efficacy in breast and lung cancers by targeting folate receptor α (FOLR1). Here, we first show that miR-34a, a TP53 transcriptional target, is reduced in PCa that harbors TP53 loss or mutations and that miR-34a mimic, when transfected into PCa cells, downregulated multiple miR-34a targets and inhibited cell growth. When exploring the therapeutic potential of folate-miR-34a, we found that folate-miR-34a exhibited impressive inhibitory effects on breast, ovarian and cervical cancer cells but showed minimal effects on and targeted delivery to PCa cells due to a lack of appreciable expression of FOLR1 in PCa cells. Folate-miR-34a also did not display any apparent effect on PCa cells expressing prostate-specific membrane antigen (PMSA) despite the reported folate’s binding capability to PSMA. These results highlight challenges in specific delivery of folate-miR-34a to PCa due to lack of target (receptor) expression. Our study offers novel insights on the challenges and promises within the field and cast light on the development of ligand-conjugated miR-34a therapeutics for PCa."
991,CPT1a regulates the delivery of extracellular fatty acids for cardiolipin turnover in prostate cancer cells,"Nancy T Santiappillai, Mariam F Hakeem-Sanni, Anabel Withy, Lisa M Butler, Lake-Ee Quek, Andrew J Hoy",https://www.biorxiv.org/content/10.1101/2024.01.16.575611v1,"Mitochondrial fatty acid oxidation (FAO) has been proposed to be a major bioenergetic pathway in prostate cancer. However, this concept fails to consider FAO relative to other mitochondrial substrates. Here, we found extracellular long-chain fatty acids (LCFAs), including palmitate, stearate, oleate, linoleate, linolenate, are minor sources of carbon entering the TCA cycle compared to glucose and glutamine in prostate cancer cells, despite being assimilated in the mitochondria as acyl-carnitines. In contrast, cardiolipins were a prominent LCFAs sink, with some species achieving greater than 50% 13C-labelling within 6 hours, suggesting high cardiolipin turnover using extracellular LCFAs. Knockdown of CPT1a, the rate-limiting enzyme of LCFA entry into mitochondria, reduced the incorporation of extracellular linoleate into cardiolipins. These results demonstrate that FAO is not a major input for the TCA cycle and provide evidence for an underappreciated role for CPT1a in regulating LCFAs entry into mitochondria for cardiolipin remodelling."
992,Digital profiling of cancer transcriptomes from histology images with grouped vision attention,"Yuanning Zheng, Marija Pizurica, Francisco Carrillo-Perez, Humaira Noor, Wei Yao, Christian Wohlfart, Kathleen Marchal, Antoaneta Vladimirova, Olivier Gevaert",https://www.biorxiv.org/content/10.1101/2023.09.28.560068v4,"Cancer is a heterogeneous disease that demands precise molecular profiling for better understanding and management. Recently, deep learning has demonstrated potentials for cost-efficient prediction of molecular alterations from histology images. While transformer-based deep learning architectures have enabled significant progress in non-medical domains, their application to histology images remains limited due to small dataset sizes coupled with the explosion of trainable parameters. Here, we develop SEQUOIA, a transformer model to predict cancer transcriptomes from whole-slide histology images. To enable the full potential of transformers, we first pre-train the model using data from 1,802 normal tissues. Then, we fine-tune and evaluate the model in 4,331 tumor samples across nine cancer types. The prediction performance is assessed at individual gene levels and pathway levels through Pearson correlation analysis and root mean square error. The generalization capacity is validated across two independent cohorts comprising 1,305 tumors. In predicting the expression levels of 25,749 genes, the highest performance is observed in cancers from breast, kidney and lung, where SEQUOIA accurately predicts the expression of 11,069, 10,086 and 8,759 genes, respectively. The accurately predicted genes are associated with the regulation of inflammatory response, cell cycles and metabolisms. While the model is trained at the tissue level, we showcase its potential in predicting spatial gene expression patterns using spatial transcriptomics datasets. Leveraging the prediction performance, we develop a digital gene expression signature that predicts the risk of recurrence in breast cancer. SEQUOIA deciphers clinically relevant gene expression patterns from histology images, opening avenues for improved cancer management and personalized therapies."
993,Mitochondrially targeted deferasirox kills cancer cells via simultaneous iron deprivation and ferroptosis induction,"Sukanya B Jadhav, Cristian Sandoval-Acuña, Yaiza Pacior, Kristyna Klanicova, Kristyna Blazkova, Radislav Sedlacek, Jan Stursa, Lukas Werner, Jaroslav Truksa",https://www.biorxiv.org/content/10.1101/2024.01.17.575692v1,"Iron chelation has been proposed as an anti-cancer approach; however, iron chelators are generally non-specific for cancer cells and rely on the higher sensitivity of malignant cells to iron deprivation and accumulation of the drug in tumor tissue via the enhanced permeability and retention effect. Here, we present mitochondrially targeted deferasirox (mitoDFX), a redox-active iron chelator that deprives cells of biologically active iron, as evidenced by a decrease in [Fe-S] cluster and heme-containing proteins. Notably, mitoDFX also depletes the major cellular antioxidant glutathione and induces lipid peroxidation, both of which are hallmarks of ferroptosis, resulting in selective induction of cell death in cancer cells. In summary, targeting deferasirox into the mitochondria results in an agent that has a unique ability to elicit iron deprivation and produce toxic lipid peroxides via its redox activity, thus harnessing the dual nature of iron in a single molecule to combat cancer."
995,Multimodal single-cell profiling reveals cancer crosstalk between macrophages and stromal cells in poor prognostic cholangiocarcinoma patients,"Lara Heij, Sikander Hayat, Konrad Reichel, Sidrah Maryam, Colm J. O’Rourke, Xiuxiang Tan, Marlous van den Braber, Jan Verhoeff, Maurice Halder, Fabian Peisker, Georg Wiltberger, Jan Bednarsch, Daniel Heise, Julia Campello Deierl, Sven A. Lang, Florian Ulmer, Tom Luedde, Edgar Dahl, Danny Jonigk, Jochen Nolting, Shivan Sivakumar, Jens Siveke, Flavio G. Rocha, Hideo A. Baba, Jesper B. Andersen, Juan J. Garcia Vallejo, Rafael Kramann, Ulf Neumann",https://www.biorxiv.org/content/10.1101/2024.02.03.578669v2,"Background and aims Cholangiocarcinoma (CCA) is a deadly disease, and this cancer entity is characterized by an abundant stroma. The tumor microenvironment (TME) plays an important role in aggressive behavior and poor response to therapeutics; however, underlying pathways are unknown."
996,Tissue-engineered models of lung cancer premalignancy,"Rachel Blomberg, Kayla Sompel, Caroline Hauer, Brisa Peña, Jennifer Driscoll, Patrick S. Hume, Daniel T. Merrick, Meredith A. Tennis, Chelsea M. Magin",https://www.biorxiv.org/content/10.1101/2023.03.15.532835v1,"Lung cancer is the leading global cause of cancer-related deaths. Although smoking cessation is the best preventive action, nearly 50% of all lung cancer diagnoses occur in people who have already quit smoking. Research into treatment options for these high-risk patients has been constrained to rodent models of chemical carcinogenesis, which are time-consuming, expensive, and require large numbers of animals. Here we show that embedding precision-cut lung slices within an engineered hydrogel and exposing this tissue to a carcinogen from cigarette smoke creates an in vitro model of lung cancer premalignancy. Hydrogel formulations were selected to promote early lung cancer cellular phenotypes and extend PCLS viability up to six weeks. In this study, hydrogel-embedded lung slices were exposed to the cigarette smoke derived carcinogen vinyl carbamate, which induces adenocarcinoma in mice. At six weeks, analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content revealed that vinyl carbamate induced the formation of premalignant lesions with a mixed adenoma/squamous phenotype. Two putative chemoprevention agents were able to freely diffuse through the hydrogel and induce tissue-level changes. The design parameters selected using murine tissue were validated with hydrogel-embedded human PCLS and results showed increased proliferation and premalignant lesion gene expression patterns. This tissue-engineered model of human lung cancer premalignancy is the starting point for more sophisticated ex vivo models and a foundation for the study of carcinogenesis and chemoprevention strategies."
997,"Information theoretic inference of magnitude and direction of gene flow in metapopulation networks using nyemtaay, with potential for applications in metastasizing cancer clonal cell origin analysis","Adrian N. Ortiz-Velez, Jeet Sukumaran",https://www.biorxiv.org/content/10.1101/2024.06.04.596026v3,"Background We introduce nyemtaay, a Python package for the calculation of classical population genetic statistics and inference of gene flow network connections and directionality in metapopulation networks using information theory. This genetic information flow network inference approach provided here is the only existing implementation of [1], and is applicable not only to ecological and evolutionary organism and landscape scale studies, but also has potential applications in, for example, cancer biology for analyzing clonal cell origins in metastasizing tumors."
998,The pharmacogenomic assessment of molecular epithelial-mesenchymal transition signatures reveals drug susceptibilities in cancer cell lines,"Alexander J. Ohnmacht, Göksu Avar, Marisa K. Schübel, Thomas J. O’Neill, Daniel Krappmann, Michael P. Menden",https://www.biorxiv.org/content/10.1101/2024.01.16.575190v1,"The epithelial-mesenchymal transition (EMT) is characterised by the loss of cell-cell adhesion and cell polarity, which is often exploited by cancer cells to adopt a motile, invasive and metastatic phenotype. Whilst EMT is often linked with cancer progression and therapy resistance, strategies for its selective targeting remain limited. In order to address this, we infer EMT states of cancer cell lines from their molecular signatures and use predictive and causal modelling to estimate the effect of EMT on drug susceptibility in high-throughput drug screens. For example, we show that EMT signatures in melanoma cells can predict favourable responses to the HSP90 inhibitor luminespib and demonstrate that epithelial-like melanoma cells can be sensitised to luminespib upon stimulation of EMT by TGF-β. Thus, we provide an analysis that systematically yields a set of potent drugs by exploiting vulnerabilities of cancer cells undergoing EMT, which may pave the way for therapies to target these cells."
999,Exploratory mass cytometry analysis reveals immunophenotypes of cancer treatment-related pneumonitis,"Toyoshi Yanagihara, Kentaro Hata, Keisuke Matsubara, Kazufumi Kunimura, Kunihiro Suzuki, Kazuya Tsubouchi, Satoshi Ikegame, Yoshihiro Baba, Yoshinori Fukui, Isamu Okamoto",https://www.biorxiv.org/content/10.1101/2023.02.21.529383v3,"Anti-cancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis."
1000,Exploration of the link between COVID-19 and gastric cancer from the perspective of bioinformatics and systems biology,"Xiao Ma, Tengda Huang, Xiaoquan Li, Xinyi Zhou, Hongyuan Pan, Ao Du, Yong Zeng, Kefei Yuan, Zhen Wang",https://www.biorxiv.org/content/10.1101/2024.04.03.587916v1,"Background Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused a global pandemic. Gastric cancer (GC) poses a great threat to people’s health, which is a high- risk factor for COVID-19. Previous studies have found some associations between GC and COVID-19, whereas the underlying molecular mechanisms are not well understood."
1001,VPAC2 receptor signaling promotes pancreatic cancer cell growth and decreases the immunogenicity of the tumor microenvironment,"Tenzin Passang, Shuhua Wang, Hanwen Zhang, Fanyuan Zeng, Po-Chih Hsu, Wenxi Wang, Jian Ming Li, Yuan Liu, Sruthi Ravindranathan, Gregory B. Lesinski, Edmund K. Waller",https://www.biorxiv.org/content/10.1101/2024.01.16.575872v1,"Identifying mechanisms underlying tumor growth and immune resistance is needed to treat pancreatic ductal adenocarcinoma (PDAC) effectively. The complexity of the tumor microenvironment (TME) suggests that the crosstalk between cells in the TME could drive drug resistance and relapse in PDAC. We have previously determined that vasoactive intestinal peptide (VIP) is overexpressed in PDAC and that VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to anti-PD1 therapy. In this study, we show that pancreatic cancer cells engage in autocrine signaling of VIP through VIP-receptor 2 (VPAC2), and that high co-expression of VIP with VPAC2 leads to reduced relapse-free survival in PDAC patients. Mechanistically, we identified piwi-like RNA-mediated gene silencing2 (Piwil2) as a tumor-cell intrinsic protein downstream of VPAC2 that regulates cancer cell growth. In addition, we discovered TGFβ-1 as a potential tumor-extrinsic inhibitor of T cell function induced by VPAC2 signaling. In vivo, knock out and knockdown of VPAC2 on PDAC cells led to reduced tumor growth rate and increased sensitivity to anti-PD-1 therapy in various mouse models of PDAC that were T-cell dependent. Overall, these findings emphasize the implications of VIP/VPAC2 signaling in the PDAC tumor microenvironment and further support the rationale for developing VPAC2-specific antagonists."
1002,Germline mutation rate predicts cancer mortality across 37 vertebrate species,"Stefania E. Kapsetaki, Zachary T. Compton, Walker Mellon, Orsolya Vincze, Mathieu Giraudeau, Tara M. Harrison, Lisa M. Abegglen, Amy M. Boddy, Carlo C. Maley, Joshua D. Schiffman",https://www.biorxiv.org/content/10.1101/2023.08.13.553123v1,"The explanation for why some species are more susceptible to cancer than others remains an area of intense investigation. Cancer evolves in part through the accumulation of mutations and, therefore, we hypothesized that germline mutation rates would be associated with cancer prevalence and mortality across species. We collected previously published data on germline mutation rate and cancer mortality data for 37 vertebrate species. Germline mutation rate was positively correlated with cancer mortality (P = 0.008). Why animals with increased germline mutation rates die more from cancer remains an open question, however they may benefit from close monitoring for tumors due to hereditary cancer predisposition syndromes. Early diagnoses of cancer in these species may increase their chances of treatment and overall survival."
1003,Cholesterol biosynthesis inhibition synergizes with AKT inhibitors in triple-negative breast cancer,"Alissandra L. Hillis, Timothy D. Martin, Haley E. Manchester, Jenny M. Hogstrom, Na Zhang, Emmalyn Lecky, Nina Kozlova, Nicole S. Persky, David E. Root, Myles Brown, Karen Cichowski, Stephen J. Elledge, Taru Muranen, David A. Fruman, Simon T. Barry, John G. Clohessy, Ralitsa R. Madsen, Alex Toker",https://www.biorxiv.org/content/10.1101/2024.01.16.575899v1,"Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer deaths due to its molecular heterogeneity, high recurrence rate and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. We performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. We identified cholesterol homeostasis as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro, in mouse TNBC xenografts and in patient-derived, estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single agent or combination treatment with AKT inhibitor and pitavastatin. This was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. Our work motivates combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC."
1004,Exploiting Epigenetic Targets to Overcome Taxane Resistance in Prostate Cancer,"Buse Cevatemre, Ipek Bulut, Beyza Dedeoglu, Arda Isiklar, Hamzah Syed, Ozlem Yedier Bayram, Tugba Bagci-Onder, Ceyda Acilan Ayhan",https://www.biorxiv.org/content/10.1101/2023.08.10.552560v1,"The development of taxane resistance remains a major challenge for castration resistant prostate cancer (CR-PCa), despite the effectiveness of taxanes in prolonging patient survival. To uncover novel targets, we performed an epigenetic drug screen on taxane (docetaxel and cabazitaxel) resistant CR-PCa cells. We identified BRPF reader proteins, along with several epigenetic groups (CBP/p300, Menin-MLL, PRMT5 and SIRT1) that act as targets effectively reversing the resistance mediated by ABCB1. Targeting BRPFs specifically resulted in the resensitization of resistant cells, while no such effect was observed on the sensitive compartment. These cells were successfully arrested at the G2/M phase of cell cycle and underwent apoptosis upon BRPF inhibition, confirming the restoration of taxane susceptibility. Pharmacological inhibition of BRPFs reduced ABCB1 activity, indicating that BRPFs may be involved in an efflux-related mechanism. Indeed, ChIP-qPCR analysis confirmed binding of BRPF1 to the ABCB1 promoter suggesting direct regulation of the ABCB1 gene at the transcriptional level. RNA-seq analysis revealed that BRPF1 knockdown affects the genes enriched in mTORC1 and UPR signaling pathways, revealing potential mechanisms underlying its functional impact, which is further supported by the enhancement of taxane response through the combined inhibition of ABCB1 and mTOR pathways, providing evidence for the involvement of multiple BRPF1-regulated pathways. Beyond clinical attributes (Gleason score, tumor stage, therapy outcome, recurrence), metastatic PCa databases further supported the significance of BRPF1 in taxane resistance, as evidenced by its upregulation in taxane-exposed PCa patients."
1005,"Structural Basis for Substrate Binding, Catalysis and Inhibition of Breast Cancer Target Mitochondrial Creatine Kinase by Covalent Inhibitor via Cryo-EM","Merve Demir, Laura Koepping, Ya Li, Lynn Fujimoto, Andrey Bobkov, Jianhua Zhao, Taro Hitosugi, Eduard Sergienko",https://www.biorxiv.org/content/10.1101/2024.06.18.598884v2,"Mitochondrial creatine kinases are key players in maintaining energy homeostasis in cells by working in conjunction with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. High levels of MtCK observed in Her2+ breast cancer and inhibition of breast cancer cell growth by substrate analog, cyclocreatine, indicate dependence of cancer cells on the ‘energy shuttle’ for cell growth and survival. Hence, understanding the key mechanistic features of creatine kinases and their inhibition plays an important role in the development of cancer therapeutics. Herein, we present the mutational and structural investigation on understudied ubiquitous mitochondrial creatine kinase (uMtCK). Our cryo-EM structures and biochemical data on uMtCK showed closure of the loop comprising residue His61 is specific to and relies on creatine binding and the reaction mechanism of phosphoryl transfer depends on electrostatics in the active site. In addition, the previously identified covalent inhibitor CKi showed inhibition in breast cancer BT474 cells, however our biochemical and structural data indicated that CKi is not a potent inhibitor for breast cancer due to strong dependency on the covalent link formation and inability to induce conformational changes upon binding."
1006,Pan-cancer analysis of pyrimidine metabolism reveals signaling pathways connections with chemoresistance role,"Vignesh Ramesh, Mert Demirdizen, Luisa Pinna, Thomas Koed Doktor, Mohammad Aarif Siddiqui, Paolo Ceppi",https://www.biorxiv.org/content/10.1101/2023.12.06.570388v2,"Deregulated nucleotide metabolism, and in particular increased pyrimidine metabolism (PyMet), has been shown to contribute to various pathological features of cancer including chemoresistance and epithelial-to-mesenchymal transition. However, cancer often encompasses complex signaling and metabolic pathway cascades for its progression, and understanding of these molecular regulatory processes in pyrimidine metabolism is quite limited. Therefore, a comprehensive pan-cancer analysis in around 10,000 gene expression profiles of 32 cancer types was employed using a pathway-based approach utilizing gene-sets representing various signaling and metabolic pathways. The analysis identified several top connections with PyMet including TERT, MTOR, DAX1, HOXA1, TP53 and TNC implying an inter-dependency of regulations which in turn was linked to the chemoresistance mechanisms. PyMet-signaling interactions were validated with in vitro derived gene-sets from endogenous thymidylate synthase (TYMS)-promoter activity reporter, from TYMS knockdown and from brequinar treatment, and further at single cell transcriptome level. Strikingly, brequinar treatment profile showed a strong inverse association pattern with doxorubicin chemoresistance in multiple cancer types. The study highlights the PyMet-pathway interactions and its role in chemoresistance, thereby providing an effective tool for improving PyMet targeting strategy in cancer. The analysis as an accessible resource is available at: www.pype.compbio.sdu.dk"
1007,Shifting KRAS hotspot mutations inhibition paradigm in colorectal cancer,"Ana Rita Brás, Ana Lopes, Nuno Mendes, Paulo J. Costa, Anabela Ferreira, Sara Granja, Ana Paula Silva, Francisco Tortosa, Fátima Baltazar, Fátima Gärtner, Maria João Sousa, Andreia Valente, Ana Preto",https://www.biorxiv.org/content/10.1101/2023.08.09.552513v1,"KRAS hotspot mutations are difficult to target, highlighting the need of developing new specific target drugs for cancers driven by these mutations, like colorectal cancer (CRC). Here, we discover a new ruthenium compound, PMC79, that inhibits specifically mutated KRAS and the downstream signaling ERK and AKT proteins both “in vitro” and “in vivo”. We demonstrated that PMC79 inhibits KRAS mutated kinase activity and is selective for KRAS mutations not affecting the KRAS wild-type protein. KRAS inhibition is not dependent on actin polymerization or on proteasome. Molecular docking analysis suggests that this effect might result from protein dynamics associated with the mutations. We demonstrated that low doses of PMC79 potentiate 5-fluorouracil anticancer effect. “In vivo” PMC79 “proof of concept” showed that it reduces tumor growth in the CAM-xenograft model and induces necrosis of the tumor in the xenograft mice model. PMC79 is a promising new “magic bullet” for CRCs harboring mutated KRAS."
1008,Role of Adenosine Deaminase in Prostate Cancer Progression,"Christy Charles, Stacy M. Lloyd, Danthasinghe Waduge Badrajee Piyarathna, Jie Gohlke, Uttam Rasaily, Vasanta Putluri, Brian W. Simons, Alexander Zaslavsky, Srinivas Nallandhighal, Nallasivam Palanisamy, Nora Navone, Jeffrey A. Jones, Michael M. Ittmann, Nagireddy Putluri, David R. Rowley, Simpa S. Salami, Ganesh S. Palapattu, Arun Sreekumar",https://www.biorxiv.org/content/10.1101/2023.08.09.552704v1,"Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African American (AA) men when compared to European-American (EA) men. PCa tends to be a highly heterogeneous malignancy with a complex biology that is not fully understood. We use metabolomics as a tool to understand the mechanisms behind PCa progression and disparities in its clinical outcome. A key enzyme in the purine metabolic pathway, Adenosine deaminase (ADA) was found upregulated in PCa. ADA was also associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio which is a surrogate for ADA activity was high in the urine of PCa patients and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in the expression of ADA during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis reveals that this tumor growth could be driven by the activation of mTOR signaling. Chronic ADA overexpression shows alterations in the cells’ adhesion machinery and a decrease in the adhesion potential of the cells to the extracellular matrix in vitro. Loss of cell-matrix interaction is critical for metastatic dissemination, suggestive of ADA’s role in promoting metastasis. This is consistent with the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination."
1011,E7-mediated repression of miR-203 promotes LASP1-dependent proliferation in HPV-positive cervical cancer,"Molly R. Patterson, Aniek S. Meijers, Emma L. Ryder, James A. Scarth, Debra Evans, Amy L. Turner, Christopher W. Wasson, Janne E. Darell, Daisy Theobald, Joseph Cogan, Claire D. James, Miao Wang, John E. Ladbury, Iain M. Morgan, Adel Samson, Ethan L. Morgan, Andrew Macdonald",https://www.biorxiv.org/content/10.1101/2024.01.08.574687v2,"Human papillomaviruses (HPV) are a major cause of malignancy, contributing to ∼5% of all human cancers worldwide, including most cervical cancer cases and a growing number of ano-genital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited proliferation in vitro, whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we show that the LASP1 SH3 domain is essential for LASP1-mediated proliferation in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulated LASP1 mRNA levels by binding to its 3’UTR. Finally, we demonstrated that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival role in cervical cancer, thus identifying a potential therapeutic target in these cancers."
1012,Single-cell mapping links neurogenesis and angiogenesis in aggressive breast cancer,"Elisabeth Wik, Sura Aziz, Kenneth Finne, Dimitrios Kleftogiannis, Cecilie Askeland, Gøril Knutsvik, Kristi Krüger, Amalie A. Svanøe, Even Birkeland, Silje Kjølle, Benedicte Davidsen, Ingunn M. Stefansson, Heidrun Vethe, Lars A. Akslen",https://www.biorxiv.org/content/10.1101/2022.01.28.477898v3,"The tumor microenvironment (TME) is important for cancer growth and progression. While angiogenesis is an established hallmark of cancer, the role of nerve fibers is less studied. Here, we investigated neurogenesis and angiogenesis in breast cancer and found them to be closely associated. Single-cell based spatial mapping by imaging mass cytometry (IMC) indicated close proximity between neural and vascular structures. Subsequent validation by tissue-based markers of neurogenesis and angiogenesis, supported by proteomics and transcriptomics data of tissues and cell lines, supported a link between these processes. A consolidated neuro-angiogenic signature score was linked to high-grade breast cancer and reduced patient survival, also within the low-grade luminal tumor subgroup. Our findings support that neurogenesis and angiogenesis are related in aggressive breast cancer and might possibly improve tumor stratification and clinical management."
1013,"A genuinely hybrid, multiscale 3D cancer invasion and metastasis modelling framework","Dimitrios Katsaounis, Nicholas Harbour, Thomas Williams, Mark Chaplain, Nikolaos Sfakianakis",https://www.biorxiv.org/content/10.1101/2024.01.12.575361v1,"We introduce in this paper substantial enhancements to a previously proposed hybrid multiscale cancer invasion modelling framework to better reflect the biological reality and dynamics of cancer. These model updates contribute to a more accurate representation of cancer dynamics, they provide deeper insights and enhance our predictive capabilities."
1014,Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer,"Ailith Ewing, Alison Meynert, Ryan Silk, Stuart Aitken, Devin P. Bendixsen, Michael Churchman, Stuart L. Brown, Alhafidz Hamdan, Joanne Mattocks, Graeme R. Grimes, Tracy Ballinger, Robert L. Hollis, C. Simon Herrington, John P. Thomson, Kitty Sherwood, Thomas Parry, Edward Esiri-Bloom, Clare Bartos, Ian Croy, Michelle Ferguson, Mairi Lennie, Trevor McGoldrick, Neil McPhail, Nadeem Siddiqui, Rosalind Glasspool, Melanie Mackean, Fiona Nussey, Brian McDade, Darren Ennis, The Scottish Genomes Partnership, Lynn McMahon, Athena Matakidou, Brian Dougherty, Ruth March, J. Carl Barrett, Iain A. McNeish, Andrew V. Biankin, Patricia Roxburgh, Charlie Gourley, Colin A. Semple",https://www.biorxiv.org/content/10.1101/2024.01.12.575376v1,"Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. We comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N=324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification."
1016,"PITAR, a DNA damage-inducible Cancer/Testis long noncoding RNA, inactivates p53 by binding and stabilizing TRIM28 mRNA","Samarjit Jana, Mainak Mondal, Sagar Mahale, Bhavana Gupta, Kaval Reddy Prasasvi, Lekha Kandasami, Neha Jha, Abhishek Chowdhury, Vani Santosh, Chandrasekhar Kanduri, Kumaravel Somasundaram",https://www.biorxiv.org/content/10.1101/2023.04.11.536370v2,"In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR (p53 Inactivating TRIM28 associated RNA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28-dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR, which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target."
1017,DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation,"Nicholas J. Mullen, Surendra K. Shukla, Ravi Thakur, Sai Sundeep Kollala, Dezhen Wang, Nina Chaika, Juan F. Santana, William R. Miklavcic, Drew A. LaBreck, Jayapal Reddy Mallareddy, David H. Price, Amarnath Natarajan, Kamiya Mehla, David B. Sykes, Michael A. Hollingsworth, Pankaj K. Singh",https://www.biorxiv.org/content/10.1101/2023.04.03.535399v2,"Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is 1) strictly dependent on pyrimidine nucleotide depletion, 2) independent of canonical antigen presentation pathway transcriptional regulators, and 3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade."
1018,Type I interferon drives a cellular state inert to TCR-stimulation and could impede effective T-cell differentiation in cancer,"Dillon Corvino, Martin Batstone, Brett G.M Hughes, Tim Kempchen, Susanna S Ng, Nazhifah Salim, Franziska Schneppenheim, Denise Rommel, Ananthi Kumar, Sally Pearson, Jason Madore, Lambross T. Koufariotis, Lisa Maria Steinheuer, Dilan Pathirana, Kevin Thurley, Michael Hölzel, Nicholas Borcherding, Matthias Braun, Tobias Bald",https://www.biorxiv.org/content/10.1101/2024.03.28.587179v1,"Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium of the oral cavity, pharynx, or larynx and is linked to exposure to classical carcinogens and human papillomavirus (HPV) infection. Due to molecular, immunological, and clinical disparities between HPV+ and HPV-HNSCC, they are recognized as distinct cancer types. While immune checkpoint inhibition (ICI) has demonstrated efficacy in recurrent/metastatic HNSCC, response variability persists irrespective of HPV status. To gain insights into the CD8+ T-cell landscape of HPV-HNSCC, we performed multimodal sequencing (RNA and TCR) of CD8+ tumor-infiltrating lymphocytes (TILs) from treatment-naïve HPV-HNSCC patients. Additionally, we subjected cells to ex vivo TCR-stimulation, facilitating the tracing of clonal transcriptomic responses. Our analysis revealed a subset of CD8+ TILs highly enriched for interferon-stimulated genes (ISG), which were found to be clonally related to a subset of granzyme K (GZMK)-expressing cells. Trajectory inference suggests ISG transition via GZMK cells towards terminal effector states. However, unlike GZMK cells, which rapidly an effector-like phenotype in response to TCR stimulation, ISG cells remain transcriptionally inert. Consequently, ISG cells may impede effective T-cell differentiation within the TME. Although, the functional consequences of ISG cells are poorly understood, we revealed that they possess receptors and ligands enabling cell-cell communication networks with key TME immunomodulators such as dendritic cells. Additionally, ISG cells were found to be a core feature across various tumor entities and were specifically enriched within tumor tissue. Thus, our findings illuminate the complexity of T-cell heterogeneity in HPV-HNSCC and reveal an overlooked population of IFN-stimulated CD8+ TILs. Further exploration of their functional significance may offer insights into therapeutic strategies for HPV-HNSCC and other cancer types."
1019,Targeted LNPs deliver mRNA encoding IL-15 superagonists to balance efficacy and toxicity in cancer therapy,"Juntao Yu, Qian Li, Shenggen Luo, Xiaona Wang, Qiang Cheng, Rongkuan Hu",https://www.biorxiv.org/content/10.1101/2024.01.11.575299v1,"Interleukin-15 (IL-15) emerges as a promising immunotherapeutic candidate in oncology because of its pivotal role in modulating both innate and adaptive immunity. However, the therapeutic utility remains concern due to the unexpected toxicity. We propose here that the mRNA lipid nanoparticle (mRNA-LNP) system can balance the issue through targeted delivery to increase IL-15 concentration in the tumor area and reduce leakage into the circulation. Utilizing the Structure-driven TARgeting (STAR) platform, we acquired intellectual property LNP vectors for effective and selective mRNA delivery to local (LNPLocal) and to pulmonary (LNPLung). Then the promising IL-15 superagonists mRNAs were obtained through structural optimization and sequence screening, showing better activity compared with benchmarker N-803. Subsequently, the anti-tumor efficacy of IL-15 superagonists mRNAs were evaluated by intratumoural (i.t.) injection and intravenous (i.v.) injection via LNPLocal and LNPLung, respectively. As a result, such superagonists exhibited better anti-tumor activity, less systematic exposure, and less cytokine related risks than N-803. We finally verified the selective delivery and well tolerability of LNPLung in non-human primates (NHPs), confirming the potential for clinical application. This finding may open up new possibilities for the treatment of lung cancers and lung metastasis cancers."
1021,High-throughput formulation of reproducible 3D cancer microenvironments for drug testing in myelogenous leukemia,"M. Rudzinska-Radecka, L. Turos-Korgul, D. Mukherjee, P. Podszywalow-Bartnicka, K. Piwocka, J. Guzowski",https://www.biorxiv.org/content/10.1101/2024.01.10.575000v1,"Targeting cancer microenvironment is currently one of the major directions in drug development and preclinical studies in leukemia. Despite the variety of available chronic myelogenous leukemia 3D culture models, the reproducible generation of miniaturized leukemia microenvironments, suitable for high-throughput drug testing, has remained a challenge. Here, we use microfluidics to generate over ten thousand highly monodisperse leukemic-bone marrow hydrogel microbeads per minute. We employ gelatin methacrylate (GelMA) as a model extracellular matrix (ECM) and tune the concentration of the biopolymer, as well as other possible components of the ECM (fibrin, hyaluronic acid), cell concentration and the ratio of leukemic cells to bone marrow cells within the microbeads. This allows to achieve optimal cell viability and the propensity of the encapsulated cells to microtissue formation, while also warranting long-term stability of the microbeads in culture. We administer model kinase inhibitor, imatinib, at various concentrations to the microbeads and, via comparing mono-and co-culture conditions (cancer alone vs cancer-stroma), we find that the stroma-leukemia crosstalk systematically protects the encapsulated cells against the drug-induced cytotoxicity, confirming therefore that our system mimics the physiological stroma-dependent protection. We finally discuss applicability of our model to (i) studying the role of direct-or close-contact interactions between leukemia and bone marrow cells embedded in 3D ECM on the stroma-mediated protection, and (ii) high-throughput screening of anti-cancer therapeutics in personalized therapies."
1022,Multi-Omics Analysis Reveals the Attenuation of the Interferon Pathway as a Driver of Chemo-Refractory Ovarian Cancer,"Daria Afenteva, Rong Yu, Anna Rajavuori, Marina Salvadores, Inga-Maria Launonen, Kari Lavikka, Kaiyang Zhang, Giovanni Marchi, Sanaz Jamalzadeh, Veli-Matti Isoviita, Yilin Li, Giulia Micoli, Erdogan Pekcan Erkan, Matias M. Falco, Daniela Ungureanu, Alexandra Lahtinen, Jaana Oikkonen, Sakari Hietanen, Anna Vähärautio, Inderpreet Sur, Anni Virtanen, Anniina Färkkilä, Johanna Hynninen, Taru A. Muranen, Jussi Taipale, Sampsa Hautaniemi",https://www.biorxiv.org/content/10.1101/2024.03.28.587131v1,"Ovarian high-grade serous carcinoma (HGSC) represents the deadliest gynecological malignancy, with 10-15% of patients exhibiting primary resistance to first-line chemotherapy. These primarily chemo-refractory patients have particularly poor survival outcomes, emphasizing the urgent need for developing predictive biomarkers and novel therapeutic approaches. Here, we show that interferon type I (IFN-I) pathway activity in cancer cells is a crucial determinant of chemotherapy response in HGSC. Through a comprehensive multi-omics analysis within the DECIDER observational trial (ClinicalTrials.gov identifier NCT04846933) cohort, we identified that chemo-refractory HGSC is characterized by diminished IFN-I and enhanced hypoxia pathway activities. Importantly, IFN-I pathway activity was independently prognostic for patient survival, highlighting its potential as a biomarker. Our results elucidate the heterogeneity of treatment response at the molecular level and suggest that augmentation of IFN-I response could enhance chemosensitivity in refractory cases. This study underscores the potential of the IFN-I pathway as a therapeutic target and advocates for the initiation of clinical trials testing external modulators of the IFN-I response, promising a significant stride forward in the treatment of refractory HGSC."
1023,Liver cancer initiation is dependent on metabolic zonation but decoupled from premalignant clonal expansion,"Andrew Chung, Jason Guo, Yunguan Wang, Yuemeng Jia, Natasha Corbitt, Lin Li, Yonglong Wei, Min Zhu, Zixi Wang, Holly Guo, Purva Gopal, Guanghua Xiao, Tao Wang, Hao Zhu",https://www.biorxiv.org/content/10.1101/2024.01.10.575013v1,"The origin of cancer is poorly understood because cells that obtain truncal mutations are rarely fate mapped in their native environments. A defining feature of the liver is zonation, or the compartmentalization of metabolic functions in hepatocytes located in distinct regions of the lobule 1. However, it is unknown if cancers develop in some zones but not others, and if there are metabolic determinants of cancer risk that track with cellular position. To study cancer initiation, we examined the effect of activating mutations in Ctnnb1 and loss of function mutations in Arid2, two of the most commonly co-mutated genes in hepatocellular carcinoma (HCC) 2. We exploited glutamine synthetase (GS) as a faithful fate mapping marker of Ctnnb1 mutant hepatocytes. By introducing mutations in distinct zones in a mosaic fashion, we showed that position and metabolic context regulate clone expansion. Mutant clones were maintained in zone 1 but largely outcompeted in zone 3. Paradoxically, clonal maintenance was anti-correlated with cancer initiation, as zone 3 mutant livers showed increased tumorigenesis. To define mechanisms, we individually deleted eleven zone specific genes in HCC mouse models, revealing that Gstm2 and Gstm3 were required for efficient HCC initiation in zone 3. These data indicate that liver cancer initiation is dependent on zonation but independent of clonal expansion."
1024,Remodeling Ca2+ dynamics by targeting a promising E-box containing G-quadruplex at ORAI1 promoter in triple-negative breast cancer,"Oishika Chatterjee, Jagannath Jana, Suman Panda, Anindya Dutta, Akshay Sharma, Suman Saurav, Rajender K. Motiani, Klaus Weisz, Subhrangsu Chatterjee",https://www.biorxiv.org/content/10.1101/2024.03.28.587164v1,"ORAI1 is an intrinsic component of store-operated calcium entry (SOCE) that strictly regulates Ca2+ influx in most non-excitable cells. ORAI1 has been extensively studied to have been overexpressed in various cancer phenotypes, and its signal transduction has been associated with oncotherapy resistance. There is extensive proteomic interaction of ORAI1 with other channels and effectors, resulting in various altered phenotypes. However, the transcription regulation of this gene is not well understood. We have found a putative G-quadruplex (G4) motif, ORAI1-Pu, in the upstream promoter region of the gene, having regulatory functions. High-resolution 3-D NMR structure elucidation suggests that ORAI1-Pu is a stable parallel-stranded G4, having an unusual 8-nt loop imparting dynamics without affecting the structural stability. The protruded loop further houses an E-box motif that provides a docking site for transcription factors like Zeb1. The G4 structure was also endogenously observed using Chromatin Immunoprecipitation (ChIP) with anti-G4 antibody (BG4) in the MDA-MB-231 cell line overexpressing ORAI1. Ligand-mediated stabilization suggested that the stabilized G4 represses transcription in cancer cell line MDA-MB-231. Downregulation of transcription further cascaded down to a decrease in Ca2+ entry by the SOCE pathway, as observed by Fura-2 confocal Ca2+ imaging."
1025,Mitochondrial DNA released by senescent cells triggers immunosuppression in cancer,"Ping Lai, Lei Liu, Nicolò Bancaro, Martina Troiani, Bianca Calì, Jingjing Chen, Prafull Kumar Singh, Rydell Alvarez Arzola, Giuseppe Attanasio, Nicolò Pernigoni, Emiliano Pasquini, Simone Mosole, Andrea Rinaldi, Jacopo Sgrignani, Yuxin Li, Shi Qiu, Pan Song, Yingrui Li, Maria Andrea Desbats, Azucena Rendón Ángel, Ricardo Pereira Mestre, Lucio Barile, Andrea Cavalli, Johann de Bono, Andrea Alimonti",https://www.biorxiv.org/content/10.1101/2023.08.06.551763v1,"DNA is a potent damage-associated molecular pattern signaling that, once in the extracellular space, triggers the activation of the innate immune system. Here we find that senescent cells release mtDNA to both the cytosol and the extracellular space. In cells undergoing cellular senescence, the release of mtDNA precedes that of nuclear DNA resulting in the activation of the cGAS/STING pathway and establishment of cellular senescence. Intriguingly, by exploiting co-culture and in vivo cross-species experiments, we show that extracellular mtDNA released by senescent tumors cells is specifically captured by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment (TME). Mechanistically we find that PMN-MDSCs uptake mtDNA to enhance their immunosuppressive ability. Pharmacological inhibition of mtDNA released from senescent tumor cells blocks the PMN-MDSCs immunosuppressive activity, improving the efficacy of therapy-induced senescence (TIS) in cancer. These results reveal the crucial role of mtDNA in initiating cellular senescence and immunosuppression independently of the SASP. Thus, targeting mtDNA release-mediated pathway may hold promise to reprogram the immune suppressive microenvironment in patients treated with chemotherapy."
1026,CURCUMIN HAS LOWER IC50 VALUES AGAINST A549 LUNG CANCER CELLS,"Sedat Kaçar, Özlem Tomsuk, Varol Şahintürk",https://www.biorxiv.org/content/10.1101/2023.08.06.552182v1,"In this study, we aimed to determine the toxic effect of curcumin on A549 lung cancer cells and to show how this effect is reflected in morphology. Firstly, the toxic doses of curcumin against A549 lung cancer cells were determined via MTT and neutral red cytotoxicity tests by using the doses of 6.25, 12.5, 25, 50, 100, 200 and 400 µM. The morphological examination was performed using inverted microscope and light microscope with hematoxylin-eosin eosin.As a result, the IC50 dose of curcumin against A549 cells was 33 µM according to MTT cytotoxicity test and 52 µM according to the neutral red cytotoxicity test. When these doses were administered, the rounded and shrunken cells were visible in the inverted microscope, while apoptotic hallmarks such as nucleus condensation, renal nucleus structure and cellular shrinkage were detected in hematoxylin-eosin staining. In conclusion, the low IC50 values of curcumin for 24 hours indicate that curcumin is effective against A549 cells. It has the potential to be used either alone or in combination with other agents in cancer studies in case its low toxic effect on normal was assured."
1028,Quantifying the advantage of multimodal data fusion for survival prediction in cancer patients,"Nikolaos Nikolaou, Domingo Salazar, Harish RaviPrakash, Miguel Gonçalves, Rob Mulla, Nikolay Burlutskiy, Natasha Markuzon, Etai Jacob",https://www.biorxiv.org/content/10.1101/2024.01.08.574756v1,"The last decade has seen an unprecedented advance in technologies at the level of high-throughput molecular assays and image capturing and analysis, as well as clinical phenotyping and digitization of patient data. For decades, genotyping (identification of genomic alterations), the casual anchor in biological processes, has been an essential component in interrogating disease progression and a guiding step in clinical decision making. Indeed, survival rates in patients tested with next-generation sequencing have been found to be significantly higher in those who received a genome-guided therapy than in those who did not. Nevertheless, DNA is only a small part of the complex pathophysiology of cancer development and progression. To assess a more complete picture, researchers have been using data taken from multiple modalities, such as transcripts, proteins, metabolites, and epigenetic factors, that are routinely captured for many patients. Multimodal machine learning offers the potential to leverage information across different bioinformatics modalities to improve predictions of patient outcome. Identifying a multiomics data fusion strategy that clearly demonstrates an improved performance over unimodal approaches is challenging, primarily due to increased dimensionality and other factors, such as small sample sizes and the sparsity and heterogeneity of data. Here we present a flexible pipeline for systematically exploring and comparing multiple multimodal fusion strategies. Using multiple independent data sets from The Cancer Genome Atlas, we developed a late fusion strategy that consistently outperformed unimodal models, clearly demonstrating the advantage of a multimodal fusion model."
1029,ANP32E drives vulnerability to ATR inhibitors by inducing R-loops-dependent Transcription Replication Conflicts in Triple Negative Breast Cancer,"Sara Lago, Vittoria Poli, Lisa Fol, Mattia Botteon, Alessandra Fasciani, Alice Turdo, Miriam Gaggianesi, Matilde Todaro, Yari Ciani, Giacomo D’Amato, Francesca Demichelis, Alessio Zippo",https://www.biorxiv.org/content/10.1101/2024.03.25.586539v1,"Oncogene-induced replicative stress (RS) plays a central role in tumor progression, leading to genomic instability by eliciting transcription replication conflicts (TRCs), which represent the major source of R-loops, that ultimately favors the onset of the DNA damage response (DDR). We investigated the pathogenic contribution of chromatin factors in increasing TRCs and R-loop frequencies in cancer. We found that in breast cancer patients the concomitant upregulation of MYC and the H2A.Z-specific chaperone ANP32E correlated with an increase genome instability. Genome-wide profiling revealed that the ANP32E-dependent increases turnover of H2A.Z altered RNApol II processivity, leading to accumulation of long R-loops at TRCs. We showed that ANP32E upregulation increases TRCs and activates an ATR-dependent DDR, which predispose cancer cells to R-loop-mediated genomic fragility. By exploiting the vulnerability of ANP32E-expressing cancer cells to ATR inhibitors, we found that tumors relied on this DDR pathway, whose inhibition halted their pro-metastatic capacity."
1030,Spatial Effects of Infiltrating T cells on Neighbouring Cancer Cells and Prognosis in Stage III CRC patients,"Mohammadreza Azimi, Sanghee Cho, Emir Bozkurt, Elizabeth McDonough, Batuhan Kisakol, Anna Matveeva, Manuela Salvucci, Heiko Dussmann, Simon McDade, Canan Firat, Nil Urganci, Jinru Shia, Daniel B. Longley, Fiona Ginty, Jochen H. M. Prehn",https://www.biorxiv.org/content/10.1101/2024.01.30.577720v2,"Colorectal cancer (CRC) is one of the most frequently occurring cancers, but prognostic biomarkers identifying patients at risk of recurrence are still lacking. In this study, we aimed to investigate in more detail the spatial relationship between intratumoural T cells, cancer cells, and cancer cell hallmarks, as prognostic biomarkers in stage III colorectal cancer patients. We conducted multiplexed imaging of 56 protein markers at single cell resolution on resected fixed tissue from stage III CRC patients who received adjuvant 5-fluorouracil-based chemotherapy. Images underwent segmentation for tumour, stroma and immune cells, and cancer cell ‘state’ protein marker expression was quantified at a cellular level. We developed a Python package for estimation of spatial proximity, nearest neighbour analysis focusing on cancer cell – T cell interactions at single-cell level. In our discovery cohort (MSK), we processed 462 core samples (total number of cells: 1,669,228) from 221 adjuvant 5FU-treated stage III patients. The validation cohort (HV) consisted of 272 samples (total number of cells: 853,398) from 98 stage III CRC patients. While there were trends for an association between percentage of cytotoxic T cells (across the whole cancer core), it did not reach significance (Discovery cohort: p = 0.07, Validation cohort: p = 0.19). We next utilized our region-based nearest neighbourhood approach to determine the spatial relationships between cytotoxic T cells, helper T cells and cancer cell clusters. In the both cohorts, we found that lower distance between cytotoxic T cells, T helper cells and cancer cells was significantly associated with increased disease-free survival. An unsupervised trained model that clustered patients based on the median distance between immune cells and cancer cells, as well as protein expression profiles, successfully classified patients into low-risk and high-risk groups (Discovery cohort: p = 0.01, Validation cohort: p = 0.003)."
1032,RFX6 at locus 6q22 confers metastasis and drug resistance in prostate cancer,"Mengjie Zhong, Wenjie Xu, Pan Tian, Qin Zhang, Zixian Wang, Limiao Liang, Qixiang Zhang, Yuehong Yang, Ying Lu, Gong-Hong Wei",https://www.biorxiv.org/content/10.1101/2024.01.08.574758v1,"Genetic and nonmutational epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and contributing to tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with recent multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. We uncover that rs339331 resides at a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy under androgen signaling. We establish that RFX6 is an AR-regulated gene, intricately linked with rs339331, exhibiting synergistic prognostic value for PCa recurrence and metastasis. Through comprehensive in vitro and in vivo studies, we establish the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates transcription factor HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) process and modulating the TGFβ/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores responsiveness of enzalutamide-resistant PCa cells and tumors to treatment. Our study highlights an interplay of disrupted genetic and epigenetic mechanisms converging on prostate lineage AR signaling, resulting in abnormal expression of RFX6 conferring PCa pathogenesis and enzalutamide resistance."
1033,Games and the treatment convexity of cancer,"Péter Bayer, Jeffrey West",https://www.biorxiv.org/content/10.1101/2023.02.27.530257v1,"Evolutionary game theory has been highly valuable in studying frequency-dependent selection and growth between competing cancer phenotypes. We study the connection between the type of competition as defined by properties of the game, and the convexity of the treatment response function. Convexity is predictive of differences in the tumor’s response to treatments with identical cumulative doses delivered with different variances. We rely on a classification of 2 × 2 games based on the signs of ‘dilemma strengths’, containing information about the kind of selection through the game’s equilibrium structure. With the disease starting in one game class, we map the type of effects treatment may have on the game depending on dosage and the implications of treatment convexity. Treatment response is a linear function of dose if the game is a prisoner’s dilemma, coordination, or harmony game and does not change game class, but may be convex or concave for anti-coordination games. If the game changes class, there is a rich variety in response types including convex-concave and concave-convex responses for transitions involving anti-coordination games, response discontinuity in case of a transition out of coordination games, and hysteresis in case of a transition through coordination games."
1034,Cytoplasmic Viscosity is a Potential Biomarker for Metastatic Breast Cancer Cells,"Marie Dessard, Jean-Baptiste Manneville, Jean-François Berret",https://www.biorxiv.org/content/10.1101/2023.10.25.564072v2,"Cellular microrheology has shown that cancer cells with high metastatic potential are softer compared to non-tumorigenic normal cells. These findings rely on measuring the apparent Young modulus of whole cells using primarily atomic force microscopy. The present study aims to explore whether alternative mechanical parameters have discriminating features with regard to metastatic potential. Magnetic rotational spectroscopy (MRS) is employed in the examination of mammary epithelial cell lines: MCF-7 and MDA-MB-231, representing low and high metastatic potential, alongside normal-like MCF-10A cells. MRS utilizes active micron-sized magnetic wires in a rotating magnetic field to measure the viscosity and elastic modulus of the cytoplasm. All three cell lines display viscoelastic behavior, with cytoplasmic viscosities ranging from 10-70 Pa s and elastic moduli from 30-80 Pa. It is found that the tumorigenic MCF-7 and MDA-MB-231 cells are softer than the MCF-10A cells, with a twofold decrease in elastic modulus. To differentiate cells with low and high malignancy however, viscosity emerges as the more discriminating parameter, as MCF-7 exhibits a 5 times higher viscosity as compared to MDA-MB-231. These findings highlight the sensitivity of cytoplasmic viscosity to metastatic potential, suggesting its potential utility as a mechanical marker for malignant cancer cells."
1035,Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2,"Fan Sun, Pengrong Yan, Yadong Xiao, Hongqiao Zhang, Steven D. Shapiro, Gutian Xiao, Zhaoxia Qu",https://www.biorxiv.org/content/10.1101/2023.07.23.550248v2,"Background Immune checkpoint inhibitors (ICIs) and their combination with other therapies such as chemotherapy, fail in most cancer patients. We previously identified the PDZ-LIM domain-containing protein 2 (PDLIM2) as a bona fide tumor suppressor that is repressed in lung cancer to drive cancer and its chemo and immunotherapy resistance, suggesting a new target for lung cancer therapy improvement."
1036,3D live imaging and phenotyping of the subcellular cytotoxicity in cancer immunotherapy using event-triggered Bessel oblique plane microscopy,"Zhaofei Wang, Jie Wang, Yuxuan Zhao, Jin Jin, Wentian Si, Longbiao Chen, Man Zhang, Yao Zhou, Shiqi Mao, Yicheng Zhang, Chunhong Zheng, Liting Chen, Peng Fei",https://www.biorxiv.org/content/10.1101/2024.03.23.586380v1,"Clarification of the cytotoxic function of T cells is crucial for understanding human immune responses and immunotherapy procedures. Here, we report an event-triggered Bessel oblique plane microscopy (EBOPM) platform capable of smart 3D live imaging and phenotyping of chimeric antigen receptor (CAR)-modified T-cell cytotoxicity in cancer immunotherapy; the EBOPM platform has the following characteristics: an isotropic subcellular resolution of 320 nm, large-scale scouting over 400 interacting cell pairs, long-term observation across 5 hours, and quantitative analysis of the Terabyte-scale 3D, multichannel, time-lapse image datasets. Using this advanced microscopy platform, several key subcellular events in CAR-T cells were captured and comprehensively analyzed; these events included the instantaneous formation of immune synapses and the sustained changes in the microtubing morphology. Furthermore, we identified the actin retrograde flow speed, the actin depletion coefficient, the microtubule polarization and the contact area of the CAR-T/target cell conjugates as essential parameters strongly correlated with CAR-T-cell cytotoxic function. Our approach will be useful for establishing criteria for quantifying T-cell function in individual patients for all T-cell-based immunotherapies."
1037,Rheological transition driven by matrix makes cancer spheroids resilient under confinement,"Tavishi Dutt, Jimpi Langthasa, U Monica, Satyarthi Mishra, Siddharth Bothra, Annapurna Vadaparty, Prosenjit Sen, Ramray Bhat",https://www.biorxiv.org/content/10.1101/2022.02.09.479678v3,"Cancer metastasis through a confining peritoneal fluid microenvironment is mediated by spheroids: clusters of disseminated transformed cells. Ovarian cancer spheroids are frequently cavitated and their ‘blastuloid’ morphology is correlated with an extracellular matrix (ECM) coat. Here, we investigate the effects of such morphology on the mechanical integrity of confined cancer spheroids. Atomic force microscopy showed higher elastic modulus for blastuloid spheroids relative to their prefiguring non-lumen ‘moruloid’ counterparts. Subsequently, spheroids were flowed through microfluidic conditions mimicking peritoneal confinement. Traversing moruloids exhibited asymmetric cell flows during entry, often deformed and disintegrated through travel, and showed an incomplete- and slow shape recovery upon exit. In contrast, blastuloids traveled faster, exhibited rapid and efficient shape recovery upon exit, symmetric vector flows, and lesser disintegration. A multiscale computational model predicted higher intercellular adhesion and a dynamical lumen make blastuloids resilient. Although, E-cadherin overexpression in moruloids did not affect their resilience, blastuloid ECM-debridement decreased E-cadherin membrane localization, obliterated the lumen, and reversed the rheological properties of blastuloids to those typifying moruloids. The ECM-induced lumen therefore drives spheroidal transition from a labile viscoplastic to a resilient elastic state allowing them to survive spatially-constrained peritoneal flows."
1038,The three YTHDF paralogs and VIRMA are the major tumor drivers among the m6A core genes in a pan-cancer analysis,"Eliana Destefanis, Denise Sighel, Davide Dalfovo, Riccardo Gilmozzi, Francesca Broso, Andrea Cappannini, Janusz M. Bujnicki, Alessandro Romanel, Erik Dassi, Alessandro Quattrone",https://www.biorxiv.org/content/10.1101/2024.06.13.598899v1,"N6-methyladenosine (m6A) is the most abundant internal modification in mRNAs. Despite accumulating evidence for the profound impact of m6A on cancer biology, there are conflicting reports that alterations in genes encoding the m6A machinery proteins can either promote or suppress cancer, even in the same tumor type. Using data from The Cancer Genome Atlas, we performed a pan-cancer investigation of 15 m6A core factors in nearly 10,000 samples from 31 tumor types to reveal underlying cross-tumor patterns. Altered expression, largely driven by copy number variations at the chromosome arm level, results in the most common mode of dysregulation of these factors. YTHDF1, YTHDF2, YTHDF3, and VIRMA are the most frequently altered factors and the only ones to be uniquely altered when tumors are grouped according to the expression pattern of the m6A factors. These genes are also the only ones with coherent, pan-cancer predictive power for progression-free survival. On the contrary, METTL3, the most intensively studied m6A factor as a cancer target, shows much lower levels of alteration and no predictive power for patient survival. Therefore, we propose the non-enzymatic YTHDF and VIRMA genes as preferred subjects to dissect the role of m6A in cancer and as priority cancer targets."
1039,Spatial transcriptomic analysis drives PET imaging of tight junction protein expression in pancreatic cancer theranostics,"James Wang, Jai Woong Seo, Aris J. Kare, Martin Schneider, Spencer K. Tumbale, Bo Wu, Marina N. Raie, Mallesh Pandrala, Andrei Iagaru, Ryan L. Brunsing, Gregory W. Charville, Walter G. Park, Katherine W. Ferrara",https://www.biorxiv.org/content/10.1101/2024.01.07.574209v1,"We apply spatial transcriptomics and proteomics to select pancreatic cancer surface receptor targets for molecular imaging and theranostics using an approach that can be applied to many cancers. Selected cancer surfaceome epithelial markers were spatially correlated and provided specific cancer localization, whereas the spatial correlation between cancer markers and immune- cell or fibroblast markers was low. While molecular imaging of cancer-associated fibroblasts and integrins has been proposed for pancreatic cancer, our data point to the tight junction protein claudin-4 as a theranostic target. Claudin-4 expression increased ∼16 fold in cancer as compared with normal pancreas, and the tight junction localization conferred low background for imaging in normal tissue. We developed a peptide-based molecular imaging agent targeted to claudin-4 with accumulation to ∼25% injected activity per cc (IA/cc) in metastases and ∼18% IA/cc in tumors. Our work motivates a new approach for data-driven selection of molecular targets."
1040,Endoplasmic reticulum stress signaling actively contributes to therapy resistance in colorectal cancer,"Daisuke Sasaki, Natsuki Sato, Dirk Wilhelm, Julius Fischer, Julia Gissibl, Masatoshi Nakatsuji, Dirk Haller, Hideki Ishihara, Klaus-Peter Janssen",https://www.biorxiv.org/content/10.1101/2024.01.07.574523v1,"Purpose We investigated the involvement of endoplasmic reticulum (ER) stress signaling in cancer cell responses to chemo- and radiotherapy, focusing on three main ER stress mediators, the transcription factors ATF4, XBP1 and ATF6."
1041,Bioorthogonal labeling and enrichment of histone monoaminylation reveal its accumulation and regulatory function in cancer cell chromatin,"Nan Zhang, Jinghua Wu, Farzana Hossain, Haidong Peng, Huapeng Li, Connor Gibson, Min Chen, Huan Zhang, Shuaixin Gao, Xinru Zheng, Yongdong Wang, Jiangjiang Zhu, Jing J. Wang, Ian Maze, Qingfei Zheng",https://www.biorxiv.org/content/10.1101/2024.03.20.586010v3,"Histone monoaminylation (i.e., serotonylation and dopaminylation) is an emerging category of epigenetic mark occurring on the fifth glutamine (Q5) residue of H3 N-terminal tail, which plays significant roles in gene transcription. Current analysis of histone monoaminylation is mainly based on site-specific antibodies and mass spectrometry, which either lacks high resolution or is time-consuming. In this study, we report the development of chemical probes for bioorthogonal labeling and enrichment of histone serotonylation and dopaminylation. These probes were successfully applied for the monoaminylation analysis of in vitro biochemical assays, cells, and tissue samples. The enrichment of monoaminylated histones by the probes further confirmed the crosstalk between H3Q5 monoaminylation and H3K4 methylation. Finally, combining the ex vivo and in vitro analyses based on the developed probes, we have shown that both histone serotonylation and dopaminylation are highly enriched in tumor tissues that overexpress transglutaminase 2 (TGM2) and regulate the three-dimensional architecture of cellular chromatin."
1043,Major data analysis errors invalidate cancer microbiome findings,"Abraham Gihawi, Yuchen Ge, Jennifer Lu, Daniela Puiu, Amanda Xu, Colin S. Cooper, Daniel S. Brewer, Mihaela Pertea, Steven L. Salzberg",https://www.biorxiv.org/content/10.1101/2023.07.28.550993v1,"We re-analyzed the data from a recent large-scale study that reported strong correlations between microbial organisms and 33 different cancer types, and that created machine learning predictors with near-perfect accuracy at distinguishing among cancers. We found at least two fundamental flaws in the reported data and in the methods: (1) errors in the genome database and the associated computational methods led to millions of false positive findings of bacterial reads across all samples, largely because most of the sequences identified as bacteria were instead human; and (2) errors in transformation of the raw data created an artificial signature, even for microbes with no reads detected, tagging each tumor type with a distinct signal that the machine learning programs then used to create an apparently accurate classifier. Each of these problems invalidates the results, leading to the conclusion that the microbiome-based classifiers for identifying cancer presented in the study are entirely wrong. These flaws have subsequently affected more than a dozen additional published studies that used the same data and whose results are likely invalid as well."
1044,Non-B DNA-Informed Mutation Burden as a Marker of Treatment Response and Outcome in Cancer,"Qi Xu, Jeanne Kowalski",https://www.biorxiv.org/content/10.1101/2024.01.04.574248v1,"Background Genomic instability plays a key role in tumorigenesis and cancer research, with Tumor Mutation Burden (TMB) being a crucial biomarker quantifying total mutation to indicate therapeutic effectiveness, particularly in immunotherapy. However, TMB is not always a reliable predictor of treatment response and displays heterogeneity. Non-B DNA, alternative DNA forms have the potential to increase susceptibility to mutations that lead to the development of cancer. The tendency of these structures to induce mutations highlights their critical role in cancer onset and advancement, indicating their potential merit when combined with mutation information for enhanced markers in cancer with potential novel insights."
1047,Recurrent FBXW7 mutations bypass Wnt/β-catenin addiction in cancer,"Zheng Zhong, David M. Virshup",https://www.biorxiv.org/content/10.1101/2023.07.28.550933v2,"Pathologic Wnt/β-catenin signaling drives various cancers, leading to multiple approaches to drug this pathway. Appropriate patient selection can maximize success of these interventions. Wnt ligand addiction is a druggable vulnerability in RNF43-mutant/RSPO-fusion cancers. However, pharmacologically targeting the biogenesis of Wnt ligands, e.g., with PORCN inhibitors, has shown mixed therapeutic responses, possibly due to tumor heterogeneity. Here we show that the tumor suppressor FBXW7 is frequently mutated in RNF43-mutant/RSPO-fusion tumors, and FBXW7 mutations cause intrinsic resistance to anti-Wnt therapies. Mechanistically, inactivation of FBXW7 stabilizes multiple oncoproteins including Cyclin E and MYC, and antagonizes the cytostatic effect of Wnt inhibitors. Moreover, although FBXW7 mutations do not mitigate β-catenin degradation upon Wnt inhibition, FBXW7-mutant RNF43-mutant/RSPO-fusion cancers instead lose dependence on β-catenin signaling, accompanied by dedifferentiation and loss of lineage specificity. These FBXW7-mutant Wnt/β-catenin-independent tumors are susceptible to multi-CDK inhibition by dinaciclib. An in depth understanding of primary resistance to anti-Wnt/β-catenin therapies allows for more appropriate patient selection and use of alternative mechanism-based therapies."
1049,Interactions of netrin-1 through its glycosylation sites immobilize Deleted in Colorectal Cancer (DCC) by favoring its constitutive clustering,"Karen Uriot, Olivier Blanc, Nicolas Audugé, Orestis Faklaris, Olivier Blanc, Nathalie Chaverot, Evelyne Bloch-Gallego, Nicolas Borghi, Maïté Coppey-Moisan, Philippe P. Girard",https://www.biorxiv.org/content/10.1101/2023.10.26.563740v2,"Netrin-1 is a protein that attracts neurons expressing the membrane receptor Deleted in Colorectal Cancer DCC. In colon carcinoma, the interaction between netrin-1 and DCC prevents apoptosis. Crystallographic data suggest that these processes involve the clustering of DCC, the observation of which in cells remains elusive, as do the molecular determinants of DCC-netrin-1 interactions and their impact on DCC organization and mobility. To address these questions, we used fluorescence photobleaching, single-particle tracking and super-resolution techniques to characterize DCC organization and mobility on the cell surface. Our results show that netrin-1 impedes DCC mobility in the plasma membrane by promoting the growth of constitutive DCC nanoclusters at the expense of free DCC. Furthermore, we show that these effects are mediated primarily by the three glycosylation sites in the LamVI domain of netrin-1 and, to a lesser extent, by the C-terminal domain and its RGD binding site."
1050,"Predicting functionally important breast cancer SNPs using pleiotropy, conservation, and protein structure","Meredith A. Carpenter, Alan C. Cheng",https://www.biorxiv.org/content/10.1101/2024.01.01.573831v1,"Motivation With over 24,000 SNPs associated with breast cancer in ClinVar, there is a need to prioritize the subset most likely to be causally linked to diagnostic, prognostic, and other clinical outcomes of disease. Building off currently known breast cancer oncogenes and SNPs, we identify the subset of SNPs with pleiotropic effects, with the goal of identifying mutations functionally relevant to disease progression. We further use sequence and structure analysis to prioritize missense mutations most likely to impact protein function."
1051,Valine Catabolism Drives Bioenergetic and Lipogenic Fuel Plasticity in Prostate Cancer,"Charles L. Bidgood, Lisa K. Philp, Anja Rockstroh, Melanie Lehman, Colleen C. Nelson, Martin C. Sadowski, Jennifer H. Gunter",https://www.biorxiv.org/content/10.1101/2024.01.01.573829v1,"Metabolic reprogramming is a hallmark of cancer and fundamental for disease progression. The remodelling of oxidative phosphorylation and enhanced lipogenesis are key characteristics of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours with upregulation of enzymes associated with branched-chain amino acid (BCAA) catabolism. We hypothesised that the degradation of BCAAs, particularly valine may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool. Through suppression of valine availability, we report strongly reduced lipid content despite compensatory upregulation of fatty acid uptake, indicating valine is an important lipogenic fuel in PCa. Inhibition of the enzyme 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) also resulted in selective inhibition of cellular proliferation of malignant but not benign prostate cells and impaired succinate production. In combination with a comprehensive multi-omic investigation of patient and cell line data, our work highlights a therapeutic target for selective inhibition of metabolic reprogramming in PCa."
1053,Downstream-of-gene (DoG) transcripts contribute to an imbalance in the cancer cell transcriptome,"Pedro A. Avila-Lopez, Jessica Xu, Nefertiti Muhammad, Guang-Yu Yang, Shannon M. Lauberth",https://www.biorxiv.org/content/10.1101/2024.01.01.573830v1,"Downstream-of-gene (DoG) transcripts are an emerging class of noncoding RNAs. However, it remains largely unknown how DoG RNA production is regulated and whether alterations in DoG RNA signatures exist in major cancers. Here, through transcriptomic analyses of matched tumors and non-neoplastic tissues and cancer cell lines, we reveal a comprehensive catalogue of DoG RNA signatures. Through separate lines of evidence, we support the biological importance of DoG RNAs in carcinogenesis. First, we reveal DoG RNAs are tissue-specific and differentially expressed in tumors versus paired normal tissues with their respective host genes involved in tumor promoting versus tumor suppressor pathways. Second, increased DoG RNA number and length is associated with poor patient prognosis. Third, depletion of essential enzyme Topoisomerase I in colon cancer alters RNA polymerase II chromatin engagement leading to termination defects and induction of DoG RNAs. Our results underlie the significance of DoG RNAs in diversifying the cancer transcriptome."
1054,Discovering genetic biomarkers for targeted cancer therapeutics with eXplainable AI,"Debaditya Chakraborty, Elizabeth Gutierrez-Chakraborty, Cristian Rodriguez-Aguayo, Hakan Başağaoğlu, Gabriel Lopez-Berestein, Paola Amero",https://www.biorxiv.org/content/10.1101/2023.07.24.550346v1,"Explainable Artificial Intelligence (XAI) enables a holistic understanding of the complex and nonlinear relationships between genes and prognostic outcomes of cancer patients. In this study, we focus on a distinct aspect of XAI – to generate accurate and biologically relevant hypotheses and provide a shorter and more creative path to advance medical research. We present an XAI-driven approach to discover otherwise unknown genetic biomarkers as potential therapeutic targets in high-grade serous ovarian cancer, evidenced by the discovery of IL27RA, which leads to reduced peritoneal metastases when knocked down in tumor-carrying mice given IL27-siRNA-DOPC nanoparticles."
1055,Cancer-associated DNA Hypermethylation of Polycomb Targets Requires DNMT3A Dual Recognition of Histone H2AK119 Ubiquitination and the Nucleosome Acidic Patch,"Kristjan H. Gretarsson, Stephen Abini-Agbomson, Susan L Gloor, Daniel N Weinberg, Jamie L McCuiston, Vishnu Udayakumar Sunitha Kumary, Allison R Hickman, Varun Sahu, Rachel Lee, Xinjing Xu, Natalie Lipieta, Samuel Flashner, Oluwatobi A. Adeleke, Irina K Popova, Hailey F Taylor, Kelsey Noll, Carolina Lin Windham, Danielle N Maryanski, Bryan J Venters, Hiroshi Nakagawa, Michael-Christopher Keogh, Karim-Jean Armache, Chao Lu",https://www.biorxiv.org/content/10.1101/2024.03.18.585588v1,"During tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) catalyze CpG methylation at PRC-regulated regions remains unclear. Here we report a cryo-EM structure of the DNMT3A long isoform (DNMT3A1) N-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine 119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Furthermore, aberrant redistribution of DNMT3A1 to Polycomb target genes inhibits their transcriptional activation during cell differentiation and recapitulates the cancer-associated DNA hypermethylation signature. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for countering promoter CGI DNA hypermethylation, a major molecular hallmark of cancer."
1057,Small Molecule Protein Assembly Modulators with Pan-Cancer Therapeutic Efficacy,"Anuradha F. Lingappa, Olayemi Akintunde, Connie Ewald, Markus Froehlich, Niloufar Ziari, Maya Michon, Shao Feng Yu, Suguna Mallesh, Jim Lin, Anatoliy Kitaygorodskyy, Dennis Solas, Jonathan C. Reed, Jaisri R. Lingappa, Andreas Mueller-Schiffmann, Carsten Korth, Dharma Prasad, Aysegul Nalca, Emily Aston, Brad Fabbri, Sanjeev Anand, Thomas W. Campi, Emma Petrouski, Debendranath Dey, David W. Andrews, Vishwanath R. Lingappa",https://www.biorxiv.org/content/10.1101/2022.09.28.509937v2,"Two structurally-unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951 with antiviral activity in cell culture against monkeypox virus (MPXV) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity, reasonable pharmacokinetics, and non-toxicity in mice at active concentrations. Anti-tumor properties of both chemotypes, were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex containing the protein TRIM28/KAP1, an allosteric modulator known to regulate mechanisms underlying viral and nonviral disease states including cancer. Treatment with these compounds alters the target multi-protein complexes in a manner consistent with allosteric modulation as their mechanism of action. These compounds appear to remove a block, crucial for cancer survival and progression, on the homeostatic linkage of uncontrolled cellular proliferation to apoptosis. These compounds provide starting points for development of next-generation non-toxic, pan-cancer therapeutics."
1058,Defining focal neuroendocrine differentiation as a transcriptionally distinct form of prostate cancer pathology characterized by the expression of androgen receptors,"Rosalia Quezada Urban, Shivakumar Keerthikumar, Ashlee Clark, Hong Wang, Belinda Phipson, Andrew Bakshi, Andrew Ryan, Heather Thorne, Renea A Taylor, Mitchell G Lawrence, Gail Risbridger, Roxanne Toivanen, David L Goode",https://www.biorxiv.org/content/10.1101/2024.03.17.585125v1,"Background Men with neuroendocrine prostate cancer (NEPC) have a poor prognosis. NEPC is commonly diagnosed by immunohistochemical markers (CHGA, SYP and NCAM1) and genomic features (mutations in RB1, PTEN, TP53). But by pathology, NEPC tumours are variable, leading to a classification of NE subtypes such as small cell and large cell neuroendocrine carcinomas, focal neuroendocrine differentiation (Focal NED), and Amphicrine. We postulated the diversity observed in NEPC pathologies might arise from differences in transcriptional profiles and the aim of this study is to utilize single-cell RNA sequencing to define the transcriptional differences between NEPC subtype pathologies."
1059,ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma,"Valen Zhuoyou Yu, Shan Shan So, Bryan Chee-chad Lung, George Zhaozheng Hou, Carissa Wing-yan Wong, Larry Ka-yue Chow, Michael King-yung Chung, Ian Yu-hong Wong, Claudia Lai-yin Wong, Desmond Kwan-kit Chan, Fion Siu-yin Chan, Betty Tsz-ting Law, Kaiyan Xu, Zack Zhen Tan, Ka-on Lam, Anthony Wing-ip Lo, Alfred King-yin Lam, Dora Lai-wan Kwong, Josephine Mun-yee Ko, Wei Dai, Simon Law, Maria Li Lung",https://www.biorxiv.org/content/10.1101/2024.03.17.585449v1,"Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63-IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses."
1060,"Id1, Spp1 and Pak3 are biomarkers of Smad4 and TGF-β1 dependency in conditional intestinal adenoma, organoids and colorectal cancer","Mirvat Surakhy, Julia Matheson, David Barnes, Emma J. Carter, Jennifer Hughes, Claudia Bühnemann, Sabina Sanegre, Hans Morreau, Paul Metz, Charlotte J. Imianowski, A. Bassim Hassan",https://www.biorxiv.org/content/10.1101/2024.03.15.584288v1,"The evolutionarily conserved TGF-β signalling pathway suppresses cell growth, yet loss of function results in cancer phenotypes. Here, we evaluate loss of the TGF-β pathway signal transduction regulator, Mothers against decapentaplegic homolog 4 (Smad4) with respect to intestinal adenoma phenotypes and specific TGF-β dependent gene expression. Conditional Lgr5-Cre activation (Apcfl/flSmad4fl/flLgr5CreERT2) resulted in loss of function of Apc and Smad4, reduced small intestinal adenoma burden, yet discordant development of large caecal adenoma with nuclear localisation of phospho-Smad2/3. ApcΔ/ΔSmad4Δ/Δ adenoma organoids resisted TGF-β1 induced cell death and EMT (IC50 534pM) compared to ApcΔ/ΔSmad4+/+ (IC50 24pM). TGF-β1 (390pM) modified adenoma bulk mRNA gene expression (RNA-Seq), with decreased Id1 and high Spp1 in ApcΔ/ΔSmad4Δ/Δ. Single cell RNAseq of caecal adenoma identified Lgr5low, Pak3high and Id1lowprogenitor populations in ApcΔ/ΔSmad4Δ/Δ, that also correlated with poor prognosis in colorectal cancer (TCGA). Smad4 loss of function-TGF-β1 dependent Id1low, Spp1high and Pak3 high in intestinal epithelial progenitor cells are specific gene-pathway biomarkers for further evaluation in intestinal cancers."
1061,The effects of cell-cell orientation in modeling the hallmarks of lung cancer in vitro,"Andres S. Espinoza, Rachael N. McVicar, Darren Finlay, Rabi Murad, Kristiina Vuori, Bethany A. Grimmig, Anne Bush, Emily Smith, Thomas Mandel-Clausen, Heather M. McGee, Evan Y. Snyder, Sandra L. Leibel",https://www.biorxiv.org/content/10.1101/2023.12.30.573475v1,"To better understand and develop treatments for lung cancer, it is important to have reliable and physiologically relevant culture models. Traditional methods of growing lung cancer cells in two- dimensional (2D) monolayers have limitations in mimicking the complex architecture and microenvironment of lung tumors in vivo, limiting their value as reliably informative disease models. In this study, we introduce a new cell culture platform called “tumoroids,” which involves growing HCC827 lung cancer cells in three-dimensional (3D) configurations. By comparing transcriptional profiles of HCC827 cells grown as tumoroids versus the same cells grown in 2D monolayers, we investigate how cell-cell orientation and signaling impact the cancer-driving properties of lung cancer. We examine key features associated with cancer progression, such as epithelial mesenchymal transition, replicative ability, and induction of angiogenesis. Additionally, we assess the functional characteristics of the 3D tumoroid culture system by subjecting the cells to irradiation. Through comparing the gene expression profiles of the 3D tumoroid and 2D cultures with those of primary human lung adenocarcinoma, we find that the 3D tumoroid cultures more closely resemble the characteristics of primary human lung cancer. This suggests that the 3D tumoroid culture platform can serve as a valuable in vitro model for studying lung cancer, offering greater clinical relevance compared to traditional 2D cultures. Overall, this study highlights the importance of using advanced culture models like 3D tumoroids to improve our understanding of lung cancer and facilitate the development of effective treatments."
1062,"Structures of the human transcription factor brachyury offer insights into DNA recognition, and identify small molecule binders for the development of degraders for cancer therapy","Joseph A Newman, Angeline E Gavard, Nergis Imprachim, Hazel Aitkenhead, Hadley E. Sheppard, Paul A. Clarke, Mohammad Anwar Hossain, Louisa Temme, Hans J. Oh, Carrow I. Wells, Zachary W. Davis-Gilbert, Paul Workman, Opher Gileadi, David H. Drewry",https://www.biorxiv.org/content/10.1101/2024.06.06.597736v1,"The transcription factor brachyury is a member of the T-Box family of transcription factors. It is active during embryogenesis and is required for the formation of the posterior mesoderm and the notochord in vertebrates. Aside from its role in embryogenesis, brachyury plays an essential role in tumour growth of the rare chordoma bone cancer and is implicated in other solid tumours. Given that brachyury is minimally expressed in healthy tissues, these findings suggest that brachyury is a potential therapeutic target in cancer. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable. To investigate direct targeting of brachyury by small molecules, we initially determined the structure of human brachyury both in complex with its cognate DNA and in the absence of DNA. Analysis of these structures provided insights into brachyury DNA binding and the structural context of the G177D variant which is strongly associated with chordoma risk. We used these structures to perform a crystallographic fragment screen of brachyury and identify hotspot regions on numerous pockets on the brachyury surface. Finally, we have performed follow-up chemistry on fragment hits and describe the structure-based progression of a thiazole-containing chemical series. Excitingly, we have produced brachyury binders with low µM potency that can serve as starting point for further medicinal chemistry efforts. These data show that brachyury is ligandable and provides an example of how crystallographic fragment screening may be used to find ligands to target protein classes that are traditionally difficult to address using other approaches."
1063,Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion,"Angélica Díaz-Basabe, Georgia Lattanzi, Federica Perillo, Chiara Amoroso, Alberto Baeri, Andrea Farini, Yvan Torrente, Giuseppe Penna, Maria Rescigno, Michele Ghidini, Elisa Cassinotti, Ludovica Baldari, Luigi Boni, Maurizio Vecchi, Flavio Caprioli, Federica Facciotti, Francesco Strati",https://www.biorxiv.org/content/10.1101/2023.12.29.573607v1,"The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). Porphyromonas gingivalis is a keystone oral pathogen associated with CRC. The oral pathobiont Fusobacterium nucleatum influences the anti-tumour functions of CRC-infiltrating iNKT cells. However, the impact of other oral bacteria, like P. gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumour microenvironment in CRC. Mechanistically, in vivo and in vitro experiments show that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery though increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing iNKT cells to upregulate CHI3L1, thus impairing iNKT cell cytotoxicity and promoting host tumour immune evasion."
1064,Acetyl-CoA carboxylase 1-dependent lipogenesis drives breast cancer progression,"Keely Tan, Thomas Owen, Holly P. McEwen, Peter Simpson, Andrew J. Hoy, David E. James, Anthony S. Don, Matthew J. Naylor",https://www.biorxiv.org/content/10.1101/2023.07.20.549828v1,"Dysregulation of cellular energetics, including lipid synthesis mediated through de novo lipogenesis, is a feature of many cancers. Here we report that acetyl-coenzyme A carboxylase (ACC) 1, the rate-limiting enzyme of de novo lipogenesis, is a key regulator of breast cancer progression and cancer cell phenotype. Mammary epithelial-specific deletion of ACC1 impaired tumour progression and decreased cancer cell proliferation in the PyMT model of breast cancer in vivo. ACC1 knockout in human breast cancer cell lines resulted in decreased cell number and altered cell and membrane morphology. Lipidomic profiling demonstrated reduced levels of acyl-carnitines (CARs) and several phospholipid (PL) classes, whilst also shifting the lipid profiles to exhibit more elongated and less saturated lipids in ACC1 knockout breast cancer cells. Palmitate rescue of ACC1 deletion phenotypes demonstrated a critical role for ACC1 driven de novo lipogenesis in breast cancer cell function. Analysis of human breast tumour-microarrays identified strong ACC1 expression at all breast cancer stages, grade and metastasis, compared to normal adjacent tissue. Together our data demonstrate a novel role for ACC1 in breast cancer progression and cancer cell function, mediated through its lipogenic role, that together with its expression profile, identify ACC1 as a potential therapeutic target in breast cancer."
1065,cGAS-activating lupus autoantibody for cancer immunotherapy,"Xiaoyong Chen, Xiangjun Tang, Benedette J. Cuffari, Caroline Tang, Xingchun Gao, Philip W. Noble, Melissa R. Young, Olivia M. Turk, Anupama Shirali, Joseph Gera, Robert N. Nishimura, Jiangbing Zhou, James E. Hansen",https://www.biorxiv.org/content/10.1101/2023.02.11.527649v1,"Cytoplasmic DNA triggers a cGAS-mediated signaling cascade that promotes an innate immune response and is potentially actionable in cancer immunotherapy. Here we show that a cytoplasmic-localizing lupus anti-DNA autoantibody activates cGAS and facilitates an immune-mediated prolongation of survival in orthotopic models of glioblastoma (GBM). Mechanistically, cellular penetration and blood-brain barrier crossing by the anti-DNA autoantibody is linked to nucleoside transport. Pulldown, knockdown, signaling, and cytotoxicity assays demonstrate autoantibody association with and activation of cGAS. In orthotopic GBM models, the autoantibody localizes to brain tumor, increases tumor CD8+ T cell content, and prolongs survival in immunocompetent but not immunodeficient mice. This work introduces the new concept of a cGAS-activating anti-DNA autoantibody, which impacts theories on mechanisms of autoimmunity and has translational applications in cancer immunotherapy."
1066,Long-read single-cell RNA sequencing enables the study of cancer subclone-specific genotype and phenotype in chronic lymphocytic leukemia,"Gage S. Black, Xiaomeng Huang, Yi Qiao, Philip Moos, Deepa Sampath, Deborah M. Stephens, Jennifer A. Woyach, Gabor T. Marth",https://www.biorxiv.org/content/10.1101/2024.03.15.585298v1,"Bruton’s tyrosine kinase (BTK) inhibitors are effective for the treatment of chronic lymphocytic leukemia (CLL) due to BTK’s role in B cell survival and proliferation. Treatment resistance is most commonly caused by the emergence of the hallmark BTKC481S mutation that inhibits drug binding. In this study, we aimed to investigate whether the presence of additional CLL driver mutations in cancer subclones harboring a BTKC481S mutation accelerates subclone expansion. In addition, we sought to determine whether BTK-mutated subclones exhibit distinct transcriptomic behavior when compared to other cancer subclones. To achieve these goals, we employ our recently published method (Qiao et al. 2024) that combines bulk DNA sequencing and single-cell RNA sequencing (scRNA-seq) data to genotype individual cells for the presence or absence of subclone-defining mutations. While the most common approach for scRNA-seq includes short-read sequencing, transcript coverage is limited due to the vast majority of the reads being concentrated at the priming end of the transcript. Here, we utilized MAS-seq, a long-read scRNAseq technology, to substantially increase transcript coverage across the entire length of the transcripts and expand the set of informative mutations to link cells to cancer subclones in six CLL patients who acquired BTKC481S mutations during BTK inhibitor treatment. We found that BTK-mutated subclones often acquire additional mutations in CLL driver genes, leading to faster subclone proliferation. When examining subclone-specific gene expression, we found that in one patient, BTK-mutated subclones are transcriptionally distinct from the rest of the malignant B cell population with an overexpression of CLL-relevant genes."
1067,Therapy-induced normal tissue damage promotes breast cancer metastasis,"Douglas W. Perkins, Ivana Steiner, Syed Haider, David Robertson, Richard Buus, Lynda O’Leary, Clare M. Isacke",https://www.biorxiv.org/content/10.1101/2020.10.17.343590v4,"Disseminated tumour cells frequently exhibit a period of dormancy that renders them insensitive to targeting by chemotherapeutic agents, conversely the systemic delivery of chemotherapies can result in normal tissue damage. Using multiple mouse and human breast cancer models, we demonstrate that prior chemotherapy administration enhances metastatic colonisation and outgrowth. In vitro, chemotherapy treatment induces fibroblast senescence associated with a senescence associated secretory phenotype (SASP) that accelerates 3D tumour spheroid growth. These chemotherapy-treated fibroblasts, and their pro-tumourigenic function, can be effectively eliminated by targeting the anti-apoptotic protein BCL-xL. In vivo, chemotherapy treatment induces SASP expression in normal tissues, however the accumulation of senescent cells is limited and BCL-xL inhibitors are unable to reduce chemotherapy-enhanced metastasis. This likely reflects that chemotherapy-exposed normal tissues support metastatic colonisation via the secretion of pro-tumourigenic factors and remodelling of the extracellular matrix, but that damaged stromal cells do not enter a full BCL-xL-dependent senescence or switch their dependency to other anti-apoptotic BCL-2 family members. In summary, this study highlights the role of the metastatic microenvironment in controlling outgrowth of disseminated tumour cells and the need to identify novel therapeutic approaches to effectively limit the pro-tumourigenic effects of chemotherapy-induced normal tissue damage."
1068,Identification and characterization of neoantigen-reactive CD8+ T cells following checkpoint blockade therapy in a pan-cancer setting,"Keith Henry Moss, Ulla Kring Hansen, Vinicius Araújo Barosa de Lima, Annie Borch, Esteban Sanchez Marquez, Anne-Mette Bjerregaard, Østrup Olga, Amalie Kai Bentzen, Andrea Marion Marquard, Mohammed kadivar, Inge Marie Svane, Ulrik Lassen, Sine Reker Hadrup",https://www.biorxiv.org/content/10.1101/2024.03.17.585416v1,"Background Immune checkpoint blockade (ICB) has been approved as first-line or second-line therapies for an expanding list of malignancies. T cells recognizing mutation-derived neoantigens are hypothesized to play a major role in tumor elimination. However, the dynamics and characteristics of such neoantigen-reactive T cells (NARTs) in the context of ICB are still limitedly understood."
1070,Mapping the breast tumor microenvironment: proximity analysis reveals spatial relationships between macrophage subtypes and metastasis-initiating cancer cells,"Eloise M. Grasset, Atul Desphande, Jae W. Lee, Yeonju Cho, Sarah M. Shin, Erin M. Coyne, Alexei Hernandez, Xuan Yuan, Zhehao Zhang, Ashley Cimino-Matthews, Andrew J. Ewald, Won Jin Ho",https://www.biorxiv.org/content/10.1101/2024.03.15.585195v1,"The development of metastasis, responsible for the majority of cancer-related fatalities, is the most dangerous aspect of breast cancer, the predominant malignancy affecting women. We previously identified specific cancer cell populations responsible for metastatic events which are cytokeratin-14 (CK14) and E-cadherin positive in luminal tumors, and E-cadherin and vimentin positive in triple-negative tumors. Since cancer cells evolve within a complex ecosystem comprised of immune cells and stromal cells, we sought to decipher the spatial interactions of these aggressive cancer cell populations within the tumor microenvironment (TME). We used imaging mass cytometry to detect 36 proteins in tumor microarrays containing paired primary and metastatic lesions from luminal or triple-negative breast cancers (TNBC), resulting in a dataset of 1,477,337 annotated cells. Focusing on metastasis-initiating cell populations, we observed close proximity to specific fibroblast and macrophage subtypes, a relationship maintained between primary and metastatic tumors. Notably, high CK14 in luminal cancer cells and high vimentin in TNBC cells correlated with close proximity to specific macrophage subtypes (CD163intCD206intPDL1intHLA-DR+ or PDL1highARG1high). Our in-depth spatial analysis elucidates that metastasis-initiating cancer cells exhibit with distinct cell populations within the TME, implicating the role of these cell-cell interactions in promoting metastasis."
1071,Homeostatic Dysregulation of Systemic CD8+ T Cell Compartment in Lung Cancer Patients,"Sung-Woo Lee, Ju Sik Yun, Young Ju Kim, Hee-Ok Kim, Hyun-Ju Cho, Cheol-Kyu Park, In-Jae Oh, Jae-Ho Cho",https://www.biorxiv.org/content/10.1101/2023.12.27.573474v1,"Cancer adapts various resistance mechanisms to counteract CD8+ T cell attacks. While this suppression of antigen-specific CD8+ T cells is common within the tumor microenvironment, little is known about how tumors affect CD8+ T cells systemically. Here we show a new link between tumor-associated homeostatic dysregulation and uncontrolled differentiation of peripheral blood CD8+ T cells. These CD8+ T cells exhibited progressive alterations indicative of diminished quiescence, increased spontaneous activation, and more-differentiated proliferation-incompetent effector cells. This phenomenon was not limited to tumor-reactive cells but broadly applicable to non-specific cells, correlating with poor clinical responses to immune checkpoint inhibitor therapy. These findings provide a new mechanism by which cancer impairs CD8+ T cells by dysregulating the homeostasis of systemic CD8+ T cell populations."
1072,Benchmarking Variational AutoEncoders on cancer transcriptomics data,"Mostafa Eltager, Tamim Abdelaal, Mohammed Charrout, Ahmed Mahfouz, Marcel J.T. Reinders, Stavros Makrodimitris",https://www.biorxiv.org/content/10.1101/2023.02.09.527832v1,"Deep generative models, such as variational autoencoders (VAE), have gained increasing attention in computational biology due to their ability to capture complex data manifolds which subsequently can be used to achieve better performance in downstream tasks, such as cancer type prediction or subtyping of cancer. However, these models are difficult to train due to the large number of hyperparameters that need to be tuned. To get a better understanding of the importance of the different hyperparameters, we examined six different VAE models when trained on TCGA transcriptomics data and evaluated on the downstream task of cluster agreement with cancer subtypes. We studied the effect of the latent space dimensionality, learning rate, optimizer and initialization on the quality of subsequent clustering of the TCGA samples. We found β-TCVAE and DIP-VAE to have a good performance, on average, despite being more sensitive to hyperparameters selection. Based on these experiments, we derived recommendations for selecting the different hyperparameters settings. In addition, we examined whether the learned latent spaces capture biologically relevant information. Hereto, we correlated the different representations with various data characteristics such as age, days to metastasis, immune infiltration, and mutation signatures. We found that for all models the latent factors, in general, do not uniquely correlate with one of the data characteristics even for models specifically designed for disentanglement."
1074,Palmitoyl transferase ZDHHC20 promotes pancreatic cancer metastasis,"Goran Tomić, Clare Sheridan, Alice Y. Refermat, Marc P. Baggelaar, James Sipthorp, Bhuvana Sudarshan, Cory A. Ocasio, Alejandro Suárez-Bonnet, Simon L. Priestnall, Eleanor Herbert, Edward W. Tate, Julian Downward",https://www.biorxiv.org/content/10.1101/2023.02.08.527637v2,"Metastasis is one of the defining features of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor prognosis. In this study, the palmitoyl transferase ZDHHC20 was identified in an in vivo shRNA screen as critical for metastatic outgrowth, with no effect on proliferation and migration in vitro, or primary PDAC growth in mice. This phenotype is abrogated in immunocompromised animals, and in animals with depleted natural killer (NK) cells, indicating that ZDHHC20 affects the interaction of tumour cells and the innate immune system. Using a chemical genetics platform for ZDHHC20-specific substrate profiling, a number of novel substrates of this enzyme were identified. These results describe a role for palmitoylation in enabling distant metastasis that could not have been detected using in vitro screening approaches and identify potential effectors through which ZDHHC20 promotes metastasis of PDAC."
1075,"Loss of FBXO31-mediated γH2AX foci formation impairs initiation of NHEJ and HR repair pathways, and sensitizes breast cancer to therapy","Osheen Sahay, Ganesh Kumar Barik, Samya Dey, Sehbanul Islam, Debasish Paul, Praneeta Pradip Bhavsar, Somsubhra Nath, Srikanth Rapole, Manas Kumar Santra",https://www.biorxiv.org/content/10.1101/2024.06.03.596644v1,"In response to genotoxic stress, cell initiates complex signalling cascades to combat genomic insults through simultaneous initiation of growth arrest and DNA damage repair process. γH2AX functions as a crucial initiator in DNA double strand damage repair process. Therefore, γH2AX foci formation onto the damage sites is essential to initiate the recruitment of repair proteins involved in NHEJ (Non-homologous DNA-end joining) or HR (Homologous recombination) repair process. However, molecular events associated with γH2AX foci formation onto the DNA damage sites are poorly understood. Here, we show that FBXO31, the first ubiquitin ligase, mediated Lys-63-linked ubiquitination of γH2AX is essential for its foci formation onto the DNA damage sites to initiate recruitment of proteins involved in NHEJ and HR-mediated DNA damage repair. Therefore, tumors with FBXO31 deficiency show enhanced growth suppression following chemotherapeutic drug treatment because of synthetic lethality, indicating that FBXO31 could be used as a marker for predicting the outcome of chemotherapy treatment."
1076,A Systematic Identification of RBPs Driving Aberrant Splicing in Cancer,"Marian Gimeno, César Lobato-Fernández, Ane San Martín, Ana Anorbe, Angel Rubio, Juan A. Ferrer-Bonsoms",https://www.biorxiv.org/content/10.1101/2023.07.17.549307v1,"Alternative Splicing (AS) is a post-transcriptional process by which a single RNA can lead to different mRNA and, in some cases, several proteins. Various processes (probably many of them yet to be discovered) are involved in the regulation of alternative splicing. This work focuses on the regulation by RNA-binding proteins (RBPs). In addition to splicing regulation, these proteins are related to cancer prognosis and are emerging therapeutic targets for cancer treatment. CLIP-seq experiments target selected RBPs and result in uncovering the loci of the nascent transcriptome to where the RBP binds to. The presence of changes in the splicing status surrounding these loci is a good starting point to establishing a causal relationship. The selection of the specific RBP(s) to target in the CLIP-seq experiment is not straightforward; in many cases, this selection is driven by apriori hypotheses."
1077,Parallel Analyses by Mass Spectrometry (MS) and Reverse Phase Protein Array (RPPA) Reveal Complementary Proteomic Profiles in Triple-Negative Breast Cancer (TNBC) Patient Tissues and Cell Cultures,"Nan Wang, Yiying Zhu, Lianshui Wang, Wenshuang Dai, Taobo Hu, Zhentao Song, Xia Li, Qi Zhang, Jianfei Ma, Qianghua Xia, Jin Li, Yiqiang Liu, Mengping Long, Zhiyong Ding",https://www.biorxiv.org/content/10.1101/2024.05.30.596640v1,"High-plex proteomic technologies have made substantial contributions to mechanism studies and biomarker discovery in complex diseases, particularly cancer. Despite technological advancements, inherent limitations in individual proteomic approaches persist, impeding the achievement of comprehensive quantitative insights into the proteome. In this study, we employed two widely used proteomic technologies, Mass Spectrometry (MS) and Reverse Phase Protein Array (RPPA) to analyze identical samples, aiming to systematically assess the outcomes and performance of the different technologies. Additionally, we sought to establish an integrated workflow by combining these two proteomic approaches to augment the coverage of protein targets for discovery purposes. We used fresh frozen tissue samples from triple-negative breast cancer (TNBC) and cell line samples to evaluate both technologies and implement this dual-proteomic strategy. Using a single-step protein denaturation and extraction protocol, protein samples were subjected to reverse phase chromatography (LC) followed by electrospray ionization (ESI)-mediated MS/MS for proteomic profiling. Concurrently, identical sample aliquots were analyzed by RPPA for profiling of over 300 proteins and phosphoproteins that are in key signaling pathways or druggable targets in cancer. Both proteomic methods demonstrated the expected ability to differentiate samples by groups, revealing distinct proteomic patterns under various experimental conditions, albeit with minimal overlap in identified targets. Mechanism-based analysis uncovered divergent biological processes identified with the two proteomic technologies, capitalizing on their complementary exploratory potential."
1078,p53 amyloid pathology with cancer grades and p53 mutations,"Shinjinee Sengupta, Namrata Singh, Ajoy Paul, Debalina Datta, Debdeep Chatterjee, Semanti Mukherjee, Laxmikant Gadhe, Jyoti Devi, M Yeshwant, Mohit Kumar Jolly, Samir K. Maji",https://www.biorxiv.org/content/10.1101/2023.07.14.547625v1,"p53 mutation and amyloid formation are implicated with cancer pathogenesis, but the direct demonstration of the link between p53 amyloid load and cancer progression is lacking. Using multi-disciplinary techniques and a cohort of 59 tumor tissues (53 from Indian cancer patients and six normal tissues) of oral and stomach cancer types, we showed that p53 amyloid load and cancer grades are highly correlated. Further, next-generation sequencing (NGS) data suggest that not only mutant p53 (e.g., SNVs, deletions, and insertions) but wild-type p53 also formed amyloids either in the nucleus (50%) and/or in the cytoplasm in most cancer tissues. Interestingly, in all these cancer tissues, p53 displays a loss of DNA binding and transcriptional activities, which is highly aggravated with the amyloid load and cancer grades. The p53 amyloids also sequester higher amounts of p63/p73 isoforms in higher-grade of tumor tissues. The data suggest p53 misfolding/aggregation and subsequent amyloid formation lead to loss and gain of p53 tumorigenic function, aggravation of which might determine the cancers grades."
1079,"CDK4 and CDK6 upregulation promotes DNA replication stress, genomic instability and resistance to EGFR targeted therapy in lung cancer","Beatrice Gini, Philippe Gui, Wei Wu, D. Lucas Kerr, Lisa Tan, Dora Barbosa, Victor Olivas, Carlos Gomez, Sarah Elmes, Veronica Steri, Turja Chakrabarti, Trever G. Bivona, Collin M. Blakely",https://www.biorxiv.org/content/10.1101/2024.03.12.584638v1,"Genetic interactions impact both normal human physiology and human diseases, such as cancer. Here, we study genetic interactions through the lens of human lung cancers driven by oncogenic forms of the epidermal growth factor receptor (EGFR), which we and others previously showed harbor a rich landscape of genetic co-alterations and potential genetic interactions. Among the most common genetic co-alterations with oncogenic EGFR are genomic amplifications of cell cycle regulators CDK4 or CDK6, which have been implicated in EGFR inhibitor clinical resistance, although the mechanism underlying this effect is not well characterized. We show that CDK4/6 upregulation overcomes EGFR inhibitor-induced G1/S cell cycle arrest in association with increased replication stress, DNA damage and genomic instability. These biological effects arising in CDK4/6 upregulated tumors help to enable resistance to EGFR targeted therapies through established genetic resistance mechanisms. Combinatorial EGFR and CDK4/6 inhibitor treatment alleviated genomic instability and EGFR inhibitor resistance in patient-derived preclinical models. This study reveals mechanistic and clinical impacts of the genetic interaction between oncogenic EGFR and CDK4/6 co-alterations in human lung cancer."
1080,Discovery of novel brain permeable human ACSS2 inhibitors for blocking breast cancer brain metastatic growth,"Emily Esquea, Lorela Ciraku, Riley G. Young, Jessica Merzy, Alexandra N. Talarico, Adel Ahmed Rashad, Simon Cocklin, Nicole L. Simone, Joris Beld, Mauricio J. Reginato, Alexej Dick",https://www.biorxiv.org/content/10.1101/2023.12.22.573073v1,"Breast-cancer brain metastasis (BCBM) poses a significant clinical challenge, resulting in an end-stage diagnosis and hindered by limited therapeutic options. The blood-brain barrier (BBB) acts as an anatomical and physiological hurdle for therapeutic compounds, restricting the effective delivery of therapies to the brain. In order to grow and survive in a nutrient-poor environment, tumors in the brain must adapt to their metabolic needs, becoming highly dependent on acetate. These tumors rely on the conversion of acetate to acetyl-CoA by the enzyme Acetyl-CoA synthetase 2 (ACSS2), a key metabolic enzyme involved in regulating fatty acid synthesis and protein acetylation in tumor cells. ACSS2 has emerged as a crucial enzyme required for the growth of tumors in the brain. Here, we utilized a computational pipeline, combining pharmacophore-based shape screen methodology with ADME property predictions to identify novel brain-permeable ACSS2 inhibitors. From a small molecule library, this approach identified 30 potential ACSS2 binders, from which two candidates, AD-5584 and AD-8007, were validated for their binding affinity, predicted metabolic stability, and, notably, their ability to traverse the BBB. We show that treatment of BCBM cells, MDA-MB-231BR, with AD-5584 and AD-8007 leads to a significant reduction in lipid storage, reduction in colony formation, and increase in cell death in vitro. Utilizing an ex vivo orthotopic brain-slice tumor model, we show that treatment with AD-8007 and AD-5584 significantly reduces tumor size and synergizes with radiation in blocking BCBM tumor growth ex vivo. Importantly, we show that following intraperitoneal injections with AD-5584 and AD-8007, we can detect these compounds in the brain, confirming their BBB permeability. Thus, we have identified and validated novel ACSS2 inhibitor candidates for further drug development and optimization as agents for treating patients with breast cancer brain metastasis."
1082,An Immunological Synapse Formation Between T Regulatory Cells and Cancer-Associated Fibroblasts Promotes Tumor Development,"Athina Varveri, Miranta Papadopoulou, Zacharias Papadovasilakis, Ewoud B. Compeer, Aigli-Ioanna Legaki, Anastasios Delis, Vasileia Damaskou, Louis Boon, Sevasti Papadogiorgaki, Martina Samiotaki, Periklis G. Foukas, Aikaterini Hatzioannou, Themis Alissafi, Michael L. Dustin, Panayotis Verginis",https://www.biorxiv.org/content/10.1101/2023.12.22.572969v1,"Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumor microenvironment, serving diverse functions in tumor progression, invasion, matrix remodeling and resistance to therapy; yet, the precise mechanisms via which CAFs imprint on the anti-tumor immunity remain poorly understood. Extensive molecular characterization revealed an increased heterogeneity in the CAF compartment and proposed an interaction between CAFs and tumor-infiltrating immune cells, which may shape tumor immune evasion. Herein, we describe a synapse formation between α-SMA+ CAFs and regulatory T cells (Tregs) in the TME. Foxp3+ Tregs were localized close to α-SMA+ CAFs in diverse types of tumor models as well as biopsies from melanoma and colorectal cancer patients. Notably, phenotypically tolerogenic α-SMA+ CAFs demonstrated the ability to phagocytose and process tumor antigens, instructing Treg movement arrest, activation and proliferation, in an antigen-specific manner. Of interest, α-SMA+ CAFs were characterized by the presence of double-membrane structures, resembling autophagosomes, in their cytoplasm, while analysis of single-cell transcriptomic data pointed autophagy and antigen processing/presentation pathways to be enriched in α-SMA-expressing CAF clusters. In a mechanistic view, conditional knockout of the autophagy pathway in α-SMA+ CAFs promoted an inflammatory re-programming of CAFs, reduced Treg infiltration, attenuated tumor development, and potentiated the efficacy of immune checkpoint inhibitor immunotherapy. Overall, our findings reveal an immunosuppressive mechanism operating in the TME, which entails the formation of synapses between α-SMA+ CAFs and Tregs in an autophagy-dependent fashion and raises the potential for the development of CAF-targeted therapies in cancer."
1084,NOS2 and COX2 Provide Key Spatial Targets that Determine Outcome in ER-Breast Cancer,"Lisa A Ridnour, William F Heinz, Robert YS Cheng, Adelaide L Wink, Noemi Kedei, Milind Pore, Fatima Imtiaz, Elise L Femino, Ana L Gonzalez, Leandro Coutinho, Donna Butcher, Elijah F Edmondson, M. Cristina Rangel, Robert J Kinders, Stanley Lipkowitz, Stephen TC Wong, Stephen K Anderson, Danial W McVicar, Xiaoxian Li, Sharon A Glynn, Timothy R Billiar, Jenny C Chang, Stephen M Hewitt, Stefan Ambs, Stephen J Lockett, David A Wink",https://www.biorxiv.org/content/10.1101/2023.12.21.572859v1,"Estrogen receptor-negative (ER-) breast cancer is an aggressive breast cancer subtype with limited therapeutic options. Upregulated expression of both inducible nitric oxide synthase (NOS2) and cyclo-oxygenase (COX2) in breast tumors predicts poor clinical outcomes. Signaling molecules released by these enzymes activate oncogenic pathways, driving cancer stemness, metastasis, and immune suppression. The influence of tumor NOS2/COX2 expression on the landscape of immune markers using multiplex fluorescence imaging of 21 ER-breast tumors were stratified for survival. A powerful relationship between tumor NOS2/COX2 expression and distinct CD8+ T cell phenotypes was observed at 5 years post-diagnosis. These results were confirmed in a validation cohort using gene expression data showing that ratios of NOS2 to CD8 and COX2 to CD8 are strongly associated with poor outcomes in high NOS2/COX2-expressing tumors. Importantly, multiplex imaging identified distinct CD8+ T cell phenotypes relative to tumor NOS2/COX2 expression in Deceased vs Alive patient tumors at 5-year survival. CD8+NOS2-COX2-phenotypes defined fully inflamed tumors with significantly elevated CD8+ T cell infiltration in Alive tumors expressing low NOS2/COX2. In contrast, two distinct phenotypes including inflamed CD8+NOS2+COX2+ regions with stroma-restricted CD8+ T cells and CD8-NOS2-COX2+ immune desert regions with abated CD8+ T cell penetration, were significantly elevated in Deceased tumors with high NOS2/COX2 expression. These results were supported by applying an unsupervised nonlinear dimensionality-reduction technique, UMAP, correlating specific spatial CD8/NOS2/COX2 expression patterns with patient survival. Moreover, spatial analysis of the CD44v6 and EpCAM cancer stem cell (CSC) markers within the CD8/NOS2/COX2 expression landscape revealed positive correlations between EpCAM and inflamed stroma-restricted CD8+NOS2+COX2+ phenotypes at the tumor/stroma interface in deceased patients. Also, positive correlations between CD44v6 and COX2 were identified in immune desert regions in deceased patients. Furthermore, migrating tumor cells were shown to occur only in the CD8-NOS2+COX2+ regions, identifying a metastatic hot spot. Taken together, this study shows the strength of spatial localization analyses of the CD8/NOS2/COX2 landscape, how it shapes the tumor immune microenvironment and the selection of aggressive tumor phenotypes in distinct regions that lead to poor clinical outcomes. This technique could be beneficial for describing tumor niches with increased aggressiveness that may respond to clinically available NOS2/COX2 inhibitors or immune-modulatory agents."
1085,A Mimicry-Based Strategy Between Human and Commensal Antigens for the Development of a New Family of Immune Therapies for Cancer,"Alice Talpin, Ana Maia, Jean-Marie Carpier, Guillaume Kulakowski, Camille Gaal, Francesco Strozzi, Coline Billerey, Lucie Aubergeon, Ludivine Amable, Jérôme Kervevan, Tifanny Mersceman, Alexandrine Garnier, Catia Pereira Oliveira, Carolina Calderon, Diana Bachrouche, Chloé Ventujol, Jennifer Martinez, Michaël Bonnet, Julie Noguerol, Karl Laviolette, Laura Boullerot, Marine Malfroy, Grégoire Chevalier, Olivier Adotevi, Olivier Joffre, Ahmed Idbaih, Maria Vieito, François Ghiringhelli, Agostina Stradella, Ghazaleh Tabatabai, Michael C. Burger, Iris Mildenberger, Ulrich Herrlinger, David A. Reardon, Wolfgang Wick, Cécile Gouttefangeas, Christophe Bonny, Laurent Chêne, Joao Gamelas Magalhaes",https://www.biorxiv.org/content/10.1101/2024.05.27.596102v1,"Peptide vaccines have emerged as a promising strategy for cancer immunotherapy, yet often lack of strong, specific and sustained immune responses against tumor antigens. To achieve a robust immune response, the effective selection of tumour antigens is crucial. While neoantigens trigger potent immune responses, their use suffers from patient specificity and their rarity in low-mutational tumors. Alternatively, the immunogenic potential of tumor-associated antigens (TAAs) is limited by central immune tolerance. Molecular mimicry and T cell cross-reactivity is a proposed mechanism to trigger a robust T cell-mediated antitumor response. Although molecular mimicry between pathogens and tumor antigens has been described, the potential benefits of exploiting this molecular mimicry with commensal bacterial antigens in antitumor immunity have not been thoroughly investigated despite strong evidence that the composition of the human microbiota significantly influences immune competency. Our new approach called OncoMimics™, which uses molecular mimicry between commensal bacterial and tumoral antigens to induce cross-reactive cytotoxic T cells against tumor cells. In preclinical studies, vaccination with OncoMimic™ peptides (OMPs) led to the expansion of CD8+ T cells reacting against homologous tumor-associated antigen peptides and elicits cytotoxic activity against tumor cells. OMPs are efficiently recognized by a prevalent T cell population within the peripheral blood mononuclear cells of healthy individuals. An ongoing clinical trial (NCT04116658) using OncoMimics™ in patients with glioblastoma demonstrates early, durable, and cross-reactive tumor antigen CD8+ T cell responses with pronounced memory persistence. By overcoming the current vaccine limitations, OncoMimics™ constitutes a promising strategy for enhancing cancer immunity and improving patient outcomes."
1086,WNT Signalling Promotes NF-κB Activation and Drug Resistance in KRAS-Mutant Colorectal Cancer,"Bojie Cong, Evangelia Stamou, Kathryn Pennel, Molly Mckenzie, Amna Matly, Sindhura Gopinath, Joanne Edwards, Ross Cagan",https://www.biorxiv.org/content/10.1101/2023.12.21.572810v1,"Approximately 40% of colorectal cancer (CRC) cases are characterized by KRAS mutations, rendering them insensitive to most CRC therapies. While the reasons for this resistance remain incompletely understood, one key aspect is genetic complexity: in CRC, oncogenic KRAS is most commonly paired with mutations that alter WNT and P53 activities (“RAP”). Here, we demonstrate that elevated WNT activity upregulates canonical (NF-κB) signalling in both Drosophila and human RAS mutant tumours. This upregulation required Toll-1 and Toll-9 and resulted in reduced efficacy of RAS pathway targeted drugs such as the MEK inhibitor trametinib. Inhibiting WNT activity pharmacologically significantly suppressed trametinib resistance in RAP tumours and more genetically complex RAP-containing ‘patient avatar’ models. WNT/MEK drug inhibitor combinations were further improved by targeting brm, shg, ago, rhoGAPp190 and upf1, highlighting these genes as candidate biomarkers for patients sensitive to this duel approach. These findings shed light on how genetic complexity impacts drug resistance and proposes a therapeutic strategy to reverse this resistance."
1087,3D culture of pancreatic cancer cells in vitro recapitulates an aberrant mitochondrial oxidative phosphorylation genotype observed in vivo,"Krzysztof Kuś, J. Mark Treherne, David L. Earnshaw, Renata Krzykawska, Beata Biesaga, Małgorzata Statkiewicz, Katarzyna Unrug-Bielawska, Zuzanna Sandowska-Markiewicz, Michal Mikula, Javier Antonio Alfaro, Marcin Przemyslaw Krzykawski",https://www.biorxiv.org/content/10.1101/2024.03.08.583569v1,"The treatment of many aggressive cancers remains a significant unmet medical need. An aberrant dependence of tumors on mitochondrial oxidative phosphorylation pathways has been well characterized in mediating the progression of pancreatic cancers, as well as some other malignancies. However, the discovery and development of new therapeutic strategies targeting or manipulating this pathway in pancreatic tumors has been relatively slow when compared with other cancers, limiting the current options for treating patients. One key technical challenge in discovering new therapies has been the limited ability of cancer cell lines when grown in 2D conditions to recapitulate the mitochondrial oxidative phosphorylation pathways in vitro that have been observed in vivo. In part, this is because 2D cultures fail to mimic the extracellular 3D tumoral environment. More generally, the translation of data based on 2D pancreatic cancer cell culture systems have also been constraining options for discovering new therapies. Conversely, 3D cultures can provide an improved technology platform in which pathologically relevant pathways in tumors can be recapitulated and analyzed in vitro. In this study, we have demonstrated in 3D cultures the reconstruction of the mitochondrial oxidative phosphorylation genotype in vitro, which more closely resembles that observed in vivo. Our study highlights the value of using transcriptomic readouts as a method to demonstrate the relevance and utility of 3D preclinical models in vitro, when grown in a more physiological extracellular environment. This key technological advance can now better enable the discovery and subsequent development of new therapeutic strategies targeting disease-relevant pathways found in pancreatic and other tumors."
1089,CLCluster: a redundancy-reduction contrastive learning-based clustering method of cancer subtype based on multi-omics data,"Hong Wang, Yi Zhang, Wen Li, Zhenlong Wang, Zhen Wei, Mengyuan Yang",https://www.biorxiv.org/content/10.1101/2024.03.07.584010v1,"Alternative splicing (AS) enables the regulated generation of multiple mRNA and protein products from a single gene. Cancer cells have general, cancer type-specific, and subtype-specific alterations in the splicing process that can have predictive value and contribute to cancer diagnosis, prognosis, and treatment. Currently, multi-omics data have been used to identify the molecular subtype of cancer. However, alternative splicing is rarely used to identify the cancer subtypes. Here, we propose a redundancy-reduction contrastive learning-based method (CLCluster) based on copy number variation, DNA methylation, gene expression, miRNA expression, and alternative splicing for cancer subtype clustering of 33 cancer types. Experimental results demonstrate the superior performance of the proposed CLCluster model in identifying cancer subtypes over the currently available state-of-the-art clustering methods. Moreover, ablation experiments demonstrate the advantages of alternative splicing data for cancer subtyping tasks. We performed multiple analyses for cancer subtype-related AS events, including open reading frame annotation, and RNA binding protein-associated alternative splicing regulation. From our analysis, we identified 2,930 AS events that were associated with patient survival, and ORF analysis showed that 417 of them could cause in-frame and 420 could cause frameshift. we also identified 1,752 RBP-AS regulatory pairs that could be associated with patient survival. Accurate classification of the cancer type using CLCluster, and effective annotation of cancer subtype related AS events can effectively facilitate the identification of patient’s therapeutically targetable AS events."
1090,Differential predictive value of resident memory CD8+T cell subpopulations in non-small-cell lung cancer patients treated by immunotherapy,"Léa Paolini, Thi Tran, Stéphanie Corgnac, Jean-Philippe Villemin, Marie Wislez, Jennifer Arrondeau, Ludger Johannes, Jonathan Ulmer, Louis-Victorien Vieillard, Joséphine Pineau, Alain Gey, Valentin Quiniou, Pierre Barennes, Hang Phuong Pham, Nadège Gruel, Milena Hasan, Valentina Libri, Sébastien Mella, Sixtine De Percin, Pascaline Boudou-Rouquette, Isabelle Cremer, Hélène Blons, Karen Leroy, Pierre Laurent-Puig, Hortense De Saint Basile, Laure Gibault, Patrice Ravel, Fathia Mami- Chouaib, François Goldwasser, Elizabeth Fabre, Diane Damotte, Eric Tartour",https://www.biorxiv.org/content/10.1101/2024.03.07.583820v1,"A high density of resident memory T cells (TRM) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. However, in preclinical models, only some subpopulations of TRM are associated with cancer vaccine efficacy."
1091,“Non-viral CRISPR/Cas9 Mutagenesis for Streamlined Generation of Mouse Lung Cancer Models.”,"Irene Lara-Saez, Angeles Mencia, Enrique Recuero, Yinghao Li, Marta García, Marta Oteo, Marta I Gallego, Ana Belen Enguita, Diana de Prado-Verdún, A Sigen, Wenxin Wang, Ramón García-Escudero, Rodolfo Murillas, Mirentxu Santos",https://www.biorxiv.org/content/10.1101/2023.12.21.572771v1,"Functional analysis in mouse models is necessary to establish the involvement of a set of genetic variations in tumor development. Many lung cancer models have been developed using genetic techniques to create gain- or loss-of-function alleles in genes involved in tumorigenesis; however, because of their labor- and time-intensive nature, these models are not suitable for quick and flexible hypothesis testing. Here we introduce a lung mutagenesis platform that utilizes CRISPR/Cas9 RNPs delivered via cationic polymers. This approach allows for the simultaneous inactivation of multiple genes. We validate the effectiveness of this system by targeting a group of tumor suppressor genes, specifically Rb1, Rbl1, Pten, and Trp53, which were chosen for their potential to cause lung tumors, namely Small Cell Lung Carcinoma (SCLC). This polymer-based delivery platform enables the modeling of lung tumorigenesis independently of the genetic background, thus simplifying and expediting the process without the need for modifying the mouse germline or creating custom viral vectors."
1092,Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism,"Kathrin Laue, Sabina Pozzi, Yael Cohen-Sharir, Tom Winkler, Yonatan Eliezer, Sahar Israeli Dangoor, Alicia I. Leikin-Frenkel, Katharina Lange, Johanna Zerbib, Alessia A. Ricci, Andrea Sacconi, Jean Berthelet, Alexander Schäffer, Wei Shi, Yang Liao, Iris Barshack, Hind Medyouf, Delphine Merino, Giovanni Blandino, Luca Bertero, Ronit Satchi-Fainaro, Uri Ben-David",https://www.biorxiv.org/content/10.1101/2023.12.20.572490v1,"Brain metastasis (BM) is a dire prognosis across cancer types. It is largely unknown why some tumors metastasize to the brain whereas others do not. We analyzed genomic and transcriptional data from clinical samples of breast cancer BM (BCBM) and found that nearly all of them carried p53-inactivating genetic alterations through mutations, copy-number loss, or both. Importantly, p53 pathway activity was already perturbed in primary tumors giving rise to BCBM, often by loss of the entire 17p chromosome-arm. This association was recapitulated across other carcinomas. Experimentally, p53 knockout was sufficient to drastically increase BCBM formation and growth in vivo, providing a causal link between p53 inactivation and brain tropism. Mechanistically, p53-deficient BC cells exhibited altered lipid metabolism, particularly increased fatty acid (FA) synthesis and uptake, which are characteristic of brain-metastasizing cancer cells. FA metabolism was further enhanced by astrocytes in a p53-dependent manner, as astrocyte-conditioned medium increased FASN, SCD1, and CD36 expression and activity, and enhanced the survival, proliferation and migration of p53-deficient cancer cells. Consequently, these cells were more sensitive than p53-competent cells to FA synthesis inhibitors, in isogenic cell cultures, in BCBM-derived spheroids, and across dozens of BC cell lines. Lastly, a significant association was observed between p53 inactivation, astrocyte infiltration, and SCD1 expression in clinical human BCBM samples. In summary, our study identifies p53 inactivation as a driver of BCBM and potentially of BM in general; suggests a p53-dependent effect of astrocytes on BC cell behavior; and reveals FA metabolism as an underlying, therapeutically-targetable molecular mechanism."
1093,Stress-induced Rab11a-exosomes induce AREG-mediated cetuximab resistance in colorectal cancer,"John D. Mason, Ewan Marks, Shih-Jung Fan, Kristie McCormick, Clive Wilson, Adrian L. Harris, Freddie C. Hamdy, Chris Cunningham, Deborah C. I. Goberdhan",https://www.biorxiv.org/content/10.1101/2023.12.19.572341v1,"Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the Epidermal Growth Factor Receptor (EGFR) ligand, Amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS."
1094,Spatial and Compositional Biomarkers in Tumor Microenvironment Predicts Clinical Outcomes in Triple-Negative Breast Cancer,"Haoyang Mi, Ravi Varadhan, Ashley M. Cimino-Mathews, Leisha A. Emens, Cesar A. Santa-Maria, Aleksander S. Popel",https://www.biorxiv.org/content/10.1101/2023.12.18.572234v1,"Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options, which warrants identification of novel therapeutic targets. Deciphering nuances in the tumor microenvironment (TME) may unveil insightful links between anti-tumor immunity and clinical outcomes, yet such connections remain underexplored. Here we employed a dataset derived from imaging mass cytometry of 58 TNBC patient specimens at single-cell resolution and performed in-depth quantifications with a suite of multi-scale computational algorithms. We detected distinct cell distribution patterns among clinical subgroups, potentially stemming from different infiltration related to tumor vasculature and fibroblast heterogeneity. Spatial analysis also identified ten recurrent cellular neighborhoods (CNs) - a collection of local TME characteristics with unique cell components. Coupling of the prevalence of pan-immune and perivasculature immune hotspot CNs, enrichment of inter-CN interactions was associated with improved survival. Using a deep learning model trained on engineered spatial data, we can with high accuracy (mean AUC of 5-fold cross-validation = 0.71) how a separate cohort of patients in the NeoTRIP clinical trial will respond to treatment based on baseline TME features. These data reinforce that the TME architecture is structured in cellular compositions, spatial organizations, vasculature biology, and molecular profiles, and suggest novel imaging-based biomarkers for treatment development in the context of TNBC."
1095,Evolution of resistance to KRASG12C inhibitor in a non-small cell lung cancer responder,"Jia-Hui Xu, Shi-Jia Wang, Ziming Wang, Jumin Huang, Chun Xie, Yabing Cao, Ming Chen, Elaine Lai-Han Leung",https://www.biorxiv.org/content/10.1101/2023.12.18.572090v1,"Despite initial therapeutic successes, most patients with non-small cell lung cancer (NSCLC) who carry the KRASG12C mutation ultimately exhibit resistance to targeted treatments. To improve our comprehension of how acquired resistance develops, we present an unprecedented longitudinal case study profiling the transcriptome of peripheral blood mononuclear cells (PBMCs) over 5 months from an NSCLC patient with the KRASG12C mutation and initial response to sotorasib followed by resistance and death. Single-cell RNA sequencing analysis uncovered notable fluctuations in immune cell populations throughout treatment with sotorasib. Specifically, we observed a decline in circulating CD8+CD161hi T cells correlating with periods of therapeutic response, followed by a resurgence during phases of nonresponse. This study established a high-resolution atlas detailing the evolutionary trajectory of resistance to sotorasib and characterizes a CD8+CD161hi T cells population in KRASG12C mutation patient."
1096,A novel machine learning algorithm selects proteome signature to specifically identify cancer exosomes,"Bingrui Li, Fernanda G. Kugeratski, Raghu Kalluri",https://www.biorxiv.org/content/10.1101/2023.07.18.549557v2,"Non-invasive early cancer diagnosis remains challenging due to the low sensitivity and specificity of current diagnostic approaches. Exosomes are membrane-bound nanovesicles secreted by all cells that contain DNA, RNA, and proteins that are representative of the parent cells. This property, along with the abundance of exosomes in biological fluids makes them compelling candidates as biomarkers. However, a rapid and flexible exosome-based diagnostic method to distinguish human cancers across cancer types in diverse biological fluids is yet to be defined. Here, we describe a novel machine learning-based computational method to distinguish cancers using a panel of proteins associated with exosomes. Employing datasets of exosome proteins from human cell lines, tissue, plasma, serum and urine samples from a variety of cancers, we identify Clathrin Heavy Chain (CLTC), Ezrin, (EZR), Talin-1 (TLN1), Adenylyl cyclase-associated protein 1 (CAP1) and Moesin (MSN) as highly abundant universal biomarkers for exosomes and define three panels of pan-cancer exosome proteins that distinguish cancer exosomes from other exosomes and aid in classifying cancer subtypes employing random forest models. All the models using proteins from plasma, serum, or urine-derived exosomes yield AUROC scores higher than 0.91 and demonstrate superior performance compared to Support Vector Machine, K Nearest Neighbor Classifier and Gaussian Naive Bayes. This study provides a reliable protein biomarker signature associated with cancer exosomes with scalable machine learning capability for a sensitive and specific non-invasive method of cancer diagnosis."
1097,RNA-to-image multi-cancer synthesis using cascaded diffusion models,"Francisco Carrillo-Perez, Marija Pizurica, Yuanning Zheng, Tarak Nath Nandi, Ravi Madduri, Jeanne Shen, Olivier Gevaert",https://www.biorxiv.org/content/10.1101/2023.01.13.523899v3,"Data scarcity presents a significant obstacle in the field of biomedicine, where acquiring diverse and sufficient datasets can be costly and challenging. Synthetic data generation offers a potential solution to this problem by expanding dataset sizes, thereby enabling the training of more robust and generalizable machine learning models. Although previous studies have explored synthetic data generation for cancer diagnosis, they have predominantly focused on single modality settings, such as whole-slide image tiles or RNA-Seq data. To bridge this gap, we propose a novel approach, RNA-Cascaded-Diffusion-Model or RNA-CDM, for performing RNA-to-image synthesis in a multi-cancer context, drawing inspiration from successful text-to-image synthesis models used in natural images. In our approach, we employ a variational auto-encoder to reduce the dimensionality of a patient’s gene expression profile, effectively distinguishing between different types of cancer. Subsequently, we employ a cascaded diffusion model to synthesize realistic whole-slide image tiles using the latent representation derived from the patient’s RNA-Seq data. Our results demonstrate that the generated tiles accurately preserve the distribution of cell types observed in real-world data, with state-of-the-art cell identification models successfully detecting important cell types in the synthetic samples. Furthermore, we illustrate that the synthetic tiles maintain the cell fraction observed in bulk RNA-Seq data and that modifications in gene expression affect the composition of cell types in the synthetic tiles. Next, we utilize the synthetic data generated by RNA-CDM to pretrain machine learning models and observe improved performance compared to training from scratch. Our study emphasizes the potential usefulness of synthetic data in developing machine learning models in sarce-data settings, while also highlighting the possibility of imputing missing data modalities by leveraging the available information. In conclusion, our proposed RNA-CDM approach for synthetic data generation in biomedicine, particularly in the context of cancer diagnosis, offers a novel and promising solution to address data scarcity. By generating synthetic data that aligns with real-world distributions and leveraging it to pretrain machine learning models, we contribute to the development of robust clinical decision support systems and potential advancements in precision medicine."
1098,Serum Proteome Profiling Identifies N-Cadherin and C-Met as Early Marker Candidates of Therapeutic Response to Neoadjuvant Chemotherapy in Breast Cancer,"Ines Derya Steenbuck, Miguel Cosenza-Contreras, Klemens Fröhlich, Bettina Mayer, Konrad Kurowski, Tilman Werner, Meike Reinold, Matthias Fahrner, Frank Hause, Adrianna Seredynska, Tobias Feilen, Andrea Ritter, Armelle Guénégou-Arnoux, Martin L. Biniossek, Daniela Weiss, Claudia Nöthling, Markus Jäger, Thalia Erbes, Oliver Schilling",https://www.biorxiv.org/content/10.1101/2024.05.24.595719v1,"Breast cancer remains the most common cancer in women worldwide. Neoadjuvant chemotherapy (NACT) is often preferred to adjuvant chemotherapy to achieve tumour shrinkage, monitor response to therapy and facilitate surgical removal in the absence of metastases. In addition, there is strong evidence that pathological complete remission (pCR) is associated with prolonged survival. In this study, we sought to identify candidate markers that signal response or resistance to therapy. We present a retrospective longitudinal serum proteomic study of 22 breast cancer patients (11 with pCR and 11 with non-pCR) matched with 21 healthy controls. Serum was analysed by LC-MS/MS after depletion of abundant proteins by immunoaffinity, trypsinisation, isobaric labelling and fractionation by reversed-phase HPLC. We observed an inverse behaviour of the serum proteins c-Met and N-cadherin after the second cycle of chemotherapy with a high predictive value (AUC 0.93). More pronounced changes were observed after the 6th cycle of NACT, with significant changes in the intensity of the proteins contactin-1, centrosomal protein, sex hormone-binding globuline and cholinesterase. Our study highlights the possibility of monitoring response to NACT using serum as a liquid biopsy."
1099,Anti-cancer drug Tamoxifen interferes with Mycobacterium tuberculosis PhoPR mediated signaling and inhibits mycobacterial growth,"Abhishek Garg, Mansi Pandit, Vandana Malhotra, Deepak Kumar Saini",https://www.biorxiv.org/content/10.1101/2023.12.19.571805v1,"Two-component signaling (TCS) systems empower all bacteria, including intracellular pathogens like Mycobacterium tuberculosis (M. tb) to regulate key pathways governing growth, physiology and virulence. Amongst all M. tb TCS systems, PhoPR and DevRS have been studied extensively for their roles in regulating persistence and virulence. Here, we report that besides its cognate response regulator PhoP, the PhoR sensor kinase displays several non-cognate interactions that augment its role in pathogenesis. We demonstrate that PhoR phosphorylates the DevR response regulator and furthermore, is itself subjected to O-phosphorylation by PknK, a Ser/Thr protein kinase (STPK), connecting TCS pathways with “eukaryotic-like” STPK driven phosphosignaling. This intersection of non-canonical regulatory pathways and the coregulation of PhoP and DevR regulons make M. tb PhoR a potentially attractive drug target. We rationalized that disruption of PhoPR signaling cascade and the resulting dysregulation may result in decreased virulence of M. tb. We tested this hypothesis by performing a high-throughput screen for compounds that inhibit autophosphorylation of PhoR sensor kinase. Screening of pharmacologically active, small molecule libraries yielded 11 potential inhibitors, of which one compound, Tamoxifen was able to attenuate PhoR autophosphorylation at micromolar concentrations in vitro and in vivo. Tamoxifen not only inhibited growth of Mycobacterium bovis BCG in culture but also interrupted PhoPR-mediated downstream signaling. Quantitative expression analysis revealed suppression of target gene, aprA under acidic conditions. Our findings highlight TCS sensor kinases as promising drug targets and underscore the applicability of clinically relevant anti-cancer drug tamoxifen as a repurposed anti-TB drug."
1100,A compendium of Amplification-Related Gain Of Sensitivity (ARGOS) genes in human cancer,"Veronica Rendo, Michael Schubert, Nicholas Khuu, Maria F Suarez Peredo Rodriguez, Kaimeng Huang, Michelle Swift, Yizhou He, Johanna Zerbib, Ross Smith, Jonne Raaijmakers, Pratiti Bandopadhayay, Lillian M. Guenther, Justin H. Hwang, Amanda Iniguez, Susan Moody, Ji-Heui Seo, Elizabeth Stover, Levi Garraway, William C. Hahn, Kimberly Stegmaier, René H. Medema, Dipanjan Chowdhury, Maria Colomé-Tatché, Uri Ben-David, Rameen Beroukhim, Floris Foijer",https://www.biorxiv.org/content/10.1101/2023.12.16.571980v1,"Chromosomal gains are among the most frequent somatic genetic alterations occurring in cancer. While the effect of sustained oncogene expression has been characterized, the impact of copy-number gains affecting collaterally-amplified “bystander” genes on cellular fitness remains less understood. To investigate this, we built a comprehensive map of dosage compensations across human cancers by integrating expression and copy number profiles from over 8,000 TCGA tumors and CCLE cell lines. Further, we analyzed the effect of gene overexpression across 17 human cancer ORF screens to provide an overview of genes that prove toxic to cancer cells when overexpressed. Combining these two independent approaches we propose a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes. These genes are located in commonly amplified regions of the genome, have lower expression levels than expected by their copy-number status, and are toxic to cancer cells when overexpressed. We experimentally validated CDKN1A and RBM14 as high-confidence pan-cancer ARGOS genes in lung and breast cancer cell line models. We additionally suggest that RBM14’s mechanism of toxicity involves altered DNA damage response and innate immune signaling processes following gene overexpression. Finally, we provide a comprehensive catalog of compensated, toxic, and ARGOS genes as a community resource."
1101,CytoCellDB: A Resource Database For Classification and Analysis of Extrachromosomal DNA in Cancer,"Jacob Fessler, Stephanie Ting, Hong Yi, Santiago Haase, Jingting Chen, Saygin Gulec, Yue Wang, Nathan Smyers, Kohen Goble, Danielle Cannon, Aarav Mehta, Christina Ford, Elizabeth Brunk",https://www.biorxiv.org/content/10.1101/2023.12.18.572197v1,"Extrachromosomal DNA (ecDNA), or double minute chromosomes, are established cytogenetic markers for malignancy and genome instability. More recently, the cancer community has gained a heightened awareness of the roles of ecDNA in cancer proliferation, drug resistance and epigenetic remodeling. A current hindrance to understanding the biological roles of ecDNA is the lack of available cell line model systems with experimental cytogenetic data that confirm ecDNA status. Although several recent landmark studies have identified common cell lines and tumor models with ecDNA, the current sample size limits our ability to detect ecDNA-driven molecular differences due to limitations in power. Increasing the number of model systems known to express ecDNA would provide new avenues for understanding the fundamental underpinnings of ecDNA biology and would unlock a wealth of potential targeting strategies for ecDNA-driven cancers. To bridge this gap, we created CytoCellDB, a resource that provides karyotype annotations and leverages publicly available global cell line data from the Cancer Dependency Map (DepMap) and the Cancer Cell Line Encyclopedia (CCLE). Here, we identify 139 cell lines that express ecDNA, which is a 200% increase from the current sample size. We expanded the total number of cancer cell lines with ecDNA annotations to 577, which is a 400% increase or 31% of cell lines in CCLE/ DepMap. We demonstrate that a strength of CytoCellDB is the ability to interrogate ecDNA, and a compendium of other chromosomal aberrations, in the context of cancer-specific vulnerabilities, drug sensitivities, and molecular data (genomics, transcriptomics, methylation, proteomics). We anticipate that CytoCellDB will advance cytogenomics research and population-scale discoveries related to ecDNA as well as provide insights into strategies and best practices for determining novel therapeutics that overcome ecDNA-driven drug resistance."
1102,Cancer tissue of origin constrains the growth and metabolism of metastases,"Sharanya Sivanand, Yetis Gultekin, Peter S. Winter, Sidney Y. Vermeulen, Konstantine Tchourine, Keene L. Abbott, Laura V. Danai, Florian Gourgue, Brian T. Do, Kayla Crowder, Tenzin Kunchok, Allison N. Lau, Alicia M. Darnell, Alexandria Jefferson, Satoru Morita, Dan G. Duda, Andrew Aguirre, Brian M. Wolpin, Nicole Henning, Virginia Spanoudaki, Laura Maiorino, Darrell J. Irvine, Omer H. Yilmaz, Caroline A. Lewis, Dennis Vitkup, Alex K. Shalek, Matthew G. Vander Heiden",https://www.biorxiv.org/content/10.1101/2022.08.17.504141v2,"Metastases arise from a subset of cancer cells that disseminate from the primary tumor; however, the factors that contribute to proliferation of cancer cells in a secondary site are incompletely understood. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize. Specific cancer types metastasize to consistent subsets of tissues, suggesting that factors associated with the primary tumor influence the tissue environments where cancers can grow. Using pancreatic cancer as a model, we find that primary and metastatic tumors share many metabolic similarities and that the tumor initiating capacity and proliferation of both primary- and metastasis-derived cells is favored in the primary site relative to the metastatic site. Moreover, propagating lung or liver metastatic cells in vivo to enrich for tumor cells adapted to grow in the lung or the liver does not enhance their relative ability to form large tumors in those sites, change their preference to grow in the primary site, nor stably alter some aspects of their metabolism relative to primary tumors. We also analyzed primary liver and lung cancer cells and find that these cells also exhibit a preference to grow in their primary site relative to metastatic sites. Together, these data suggest that the cancer tissue-of-origin influences the metabolism of both primary and metastatic tumors and may impact whether cancer cells can thrive in a metastatic site."
1104,[225Ac]Ac/[89Zr]Zr-labeled N4MU01 radioimmunoconjugates as theranostics against nectin-4 positive triple negative breast cancer,"Hanan Babeker, Fabrice Ngoh Njotu, Jessica Pougoue Ketchemen, Anjong Florence Tikum, Alireza Doroudi, Emmanuel Nwangele, Maruti Uppalapati, Humphrey Fonge",https://www.biorxiv.org/content/10.1101/2024.03.04.583420v1,"Purpose Nectin-4 is an overexpressed biomarker in 60-70% of triple-negative breast cancer (TNBC), and an ideal target for radiotherapy and PET imaging. In this study, we have developed theranostic radioimmunoconjugates (RICs) based on a fully-human anti-nectin-4 antibody, N4MU01. We characterized and evaluated the efficacy of these RICs for applications in molecular imaging and radiotherapy of aggressive TNBC models."
1106,In vivo perturb-seq of cancer and microenvironment cells dissects oncologic drivers and radiotherapy responses in glioblastoma,"S. John Liu, Joanna Pak, Christopher Zou, Timothy Casey-Clyde, Ashir A. Borah, David Wu, Kyounghee Seo, Thomas O’Loughlin, Daniel A. Lim, Tomoko Ozawa, Mitchel S. Berger, William A. Weiss, David R. Raleigh, Luke A. Gilbert",https://www.biorxiv.org/content/10.1101/2023.09.01.555831v3,"Genetic perturbation screens with single cell readouts have enabled rich phenotyping of gene function and regulatory networks. These approaches have been challenging in vivo, especially in adult disease models such as cancer, which include mixtures of malignant and microenvironment cells. Glioblastoma (GBM) is a fatal cancer, and methods of systematically interrogating gene function and therapeutic targets in vivo, especially in combination with standard of care treatment such as radiotherapy, are lacking. Here, we iteratively develop a multiplex in vivo perturb-seq CRISPRi platform for single cell genetic screens in cancer and tumor microenvironment cells that leverages intracranial convection enhanced delivery (CED) of sgRNA libraries into models of GBM. Our platform enables potent silencing of drivers of in vivo growth and tumor maintenance, as well as genes that sensitize GBM to radiotherapy. We find radiotherapy rewires transcriptional responses to genetic perturbations in an in vivo dependent manner, revealing heterogenous patterns of treatment sensitization or resistance in GBM. Furthermore, we demonstrate targeting of genes that function in the tumor microenvironment, enabling alterations of ligand-receptor interactions between immune/stromal cells following in vivo CRISPRi perturbations. In sum, we demonstrate the utility of multiplexed perturb-seq for in vivo single cell dissection of adult cancer and normal tissue biology across multiple cell types in the context of therapeutic intervention, a platform with potential for broad application."
1107,Comprehensive gene expression analysis of organoid-derived healthy human colonic epithelium and cancer cell line by stimulated with live probiotic bacteria,"Akira Sen, Atsuki Imai, Eiji Miyauchi, Kota Yanagisawa, Tsukasa Oda, Fuki Sasaki, Shintaro Uchida, Takuhisa Okada, Takehiko Yokobori, Hiroshi Saeki, Toshitaka Odamaki, Nobuo Sasaki",https://www.biorxiv.org/content/10.1101/2024.05.23.595631v1,"The large intestine has a dense milieu of indigenous bacteria, generating a complex ecosystem with crosstalk between individual bacteria and host cells. In vitro host cell modeling and bacterial interactions at the anaerobic interphase have elucidated the crosstalk molecular basis. Although classical cell lines derived from patients with colorectal cancer including Caco-2 are used, whether they adequately mimic normal colonic epithelial physiology is unclear. To address this, we performed transcriptome profiling of Caco-2 and Monolayer-cultured epithelial cells derived from healthy Human Colonic Organoids (MHCO) cultured hemi-anaerobically. Coculture with the anaerobic gut bacteria, Bifidobacterium longum subsp. longum differentiated the probiotic effects of test cells from those of physiologically normal intestinal and colorectal cancer cells. We cataloged non- or overlapping gene signatures where gene profiles of Caco-2 represented absorptive cells in the small intestinal epithelium, and MHCO showed complete colonic epithelium signature, including stem/progenitor, goblet, and enteroendocrine cells colonocytes. Characteristic gene expression changes related to lipid metabolism, inflammation, and cell-cell adhesion were observed in cocultured live Bifidobacterium longum and Caco-2 or MHCO. B. longum-stimulated MHCO exhibited barrier-enhancing characteristics, as demonstrated in clinical trials. Our data represent a valuable resource for understanding gut microbe and host cell communication."
1108,EFA6R suppresses ovarian cancer cell migration and invasion,"Salman Tamaddon-Jahromi, Kate Murphy, William Walker, Venkateswarlu Kanamarlapudi",https://www.biorxiv.org/content/10.1101/2022.01.21.477266v3,"Exchange factor for ADP-ribosylation factor (Arf)6 (EFA6)R expression loss in ovarian cancer has shown to decrease patient survival. EFA6R contains the catalytic Sec7, pleckstrin homology (PH), and coiled-coil (CC) domains. To gain further insight into the role of EFA6R, this study further investigated EFA6R expression in OC and its putative role as a metastatic suppressor. EFA6R mRNA expression, assessed by RT-qPCR, was significantly downregulated in OC tissues and cell lines. OC tissue microarray staining with EFA6R antibody showed that loss of protein expression correlated with increased cancer grade. Furthermore, EFA6R protein levels, assessed by immunoblotting, were significantly reduced in OC tissues and cell lines. Treatment of SKOV-3 cells with 5-aza-2’deoxycytidine, an epigenetic regulator, restored EFA6R expression and attenuated functional cell migration and invasion, which was reversed by siRNA-mediated knockdown of EFA6R expression. This study also revelated that exogenously expressed EFA6R localises to the plasma membrane, through its PH domain, and thereby inhibits cell migration and invasion in the CC domain-dependent and an Arf6-independent manner. EFA6R loss-of-function involves epigenetic mechanisms in which downregulation increases OC tumour cell migration and invasion."
1109,The p90 Ribosomal S6 Kinases 2 and 4 promote Prostate Cancer cell proliferation in androgen-dependent and independent ways,"Ryan Cronin, Aygun Azadova, Antonio Marco, Philippe P. Laissue, Greg N. Brooke, Filippo Prischi",https://www.biorxiv.org/content/10.1101/2024.03.04.582739v1,"Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways are frequent events in Prostate Cancer (PCa) that have been correlated to tumour formation, disease progression and therapeutic resistance. At the intersection of these two pathways lies the p90 ribosomal S6 kinase (RSKs) family, which regulates many proteins involved in cell survival, growth and proliferation. As such, deregulated RSKs activity has been associated with multiple cancer types, including PCa. However, the full extent of the RSKs involvement in prostate tumorigenesis remains to be determined. Here we have shown that RSKs levels are increased in PCa samples and cell lines. The RSKs were found to enhance Androgen Receptor (AR) activity, the key oncogenic driver in PCa. Indeed, all RSKs were found to interact in close proximity to the AR. However, RSK2/4, but not RSK1/3, showed changes in cell localisation following AR nuclear translocation. Consistently, silencing of RSK2/4, but not RSK1/3, inhibited PCa proliferation in an androgen-dependent and independent manner, respectively, and induced different signaling events downstream of the AR. The data suggests that RSK2 and RSK4 activity is required for PCa cell proliferation, but they are likely regulating growth via different mechanisms."
1110,Application of Cancer Cell Line Encyclopedia for Measuring Correlation Between Transcriptomics and Proteomics as a Guide for System-level Insights,"Blake Williams, Darryl Perry, Peter Aspesi, Jefferson Parker, Ted Johnson, Wendy Su, Eduardo Tabacman, Kirk Delisle, Kayvon Avishan, Vic Myer, Felipa Mapa, Michael Hinterberg, Alan Williams, Lori Jennings, Nebojsa Janjic, Joseph Loureiro",https://www.biorxiv.org/content/10.1101/2024.03.03.583123v1,"Robust and reliable proteome measurements provide mechanistic insights in biomedical research. SOMAmer (Slow Off-rate Modified Aptamer) reagents are modified, DNA-based, affinity reagents that measure defined target proteins with reproducibility and accuracy similar to monoclonal antibodies. Applying SOMAmer reagent technology, we developed SomaScan, a clinical proteome profiling platform with capability to measure 7,523 proteoforms for 6,594 human proteins by UniprotID in small sample volumes (e.g., 55μl plasma or serum). We evaluated the platform by profiling the proteome of a panel of well characterized Cell Line Encyclopedia (CCLE) cancer models. Unsupervised machine learning analyses demonstrate the SomaScan assay distinguishing cell lines on the basis of their proteome signatures, and identifying both tissue-specific and oncogenic pathways. The proteome measured by SomaScan correlates with published CCLE transcriptome at a level comparable to other published transcript to proteome studies. Taken together, we demonstrate that the SomaScan platform is a technically reproducible system suitable for biomedical and clinical applications that reliably illuminates underlying biomolecular mechanisms."
1111,PDE4 inhibitor Rolipram represses hedgehog signaling via ubiquitin-mediated proteolysis of GLI transcription factors to regress breast cancer,"Arka Bagchi, Anuran Bhattacharya, Urmi Chatterji, Arunima Biswas",https://www.biorxiv.org/content/10.1101/2024.03.03.583221v1,"Aberrant activation of the hedgehog signaling pathway positively correlates with progression, invasion and metastasis of several cancers, including breast cancer. Although numerous inhibitors of the Hedgehog signaling pathway are available, several oncogenic mutations of key components of the pathway, including Smoothened (Smo), have limited their capability to be developed as putative anti-cancer drugs. In this study, we have modulated the Hedgehog signaling pathway in breast cancer cell lines and tumor-bearing BALB/c mice, using a specific phosphodiesterase 4 (PDE4) inhibitor rolipram. The results indicated that increased levels of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA), due to the treatment with rolipram on MCF-7 and MDA-MB-231 cells, induced PKA-mediated ubiquitination of Glioma-associated oncogene homolog 2 full length (GLI2FL) and GLI3FL, leading to their transformation to respective repressor forms. This in turn reduced the level of Glioma-associated oncogene homolog 1 (GLI1) transcription factor in a time-dependent manner. We have also shown that elevated level of PKA reduced the level of phosphorylated glycogen synthase kinase 3β (GSK3β), which is known to augment PKA-mediated phosphorylation of GLI2FL and GLI3FL. Rolipram also significantly altered the wound healing capability as well as key markers of wound healing in MCF-7 and MDA-MB-231 cells. Moreover, rolipram caused significant reduction in tumor weight and volume in tumor-bearing mice model. The histological analysis revealed significant reduction in the number of multi-nucleated cells in tumor tissue and substantially reduced levels of cellular infiltration in the lung of rolipram treated tumor-bearing mice. Rolipram also reduced the levels of GLI1 in tumor-bearing mice by enhancing the PKA levels. Therefore, it may be concluded that rolipram can be used as an effective inhibitor of Hedgehog signaling pathway downstream of Smo to control breast cancer progression and metastasis in both hormone-responsive and triple negative breast cancers."
1112,miR-203 drives breast cancer cell differentiation,"Nuria G. Martínez-Illescas, Silvia Leal, Patricia González, Osvaldo Graña-Castro, Juan José Muñoz-Oliveira, Alfonso Cortés-Peña, Miguel Quintela-Fandino, Eva Ciruelos, Consuelo Sanz, Sofía Aragón, Leisy Sotolongo, Sara Jiménez, Eduardo J. Caleiras, Francisca Mulero, Cristina Sánchez, Marcos Malumbres, María Salazar-Roa",https://www.biorxiv.org/content/10.1101/2023.01.23.525208v1,"A hallmark of many malignant tumors is dedifferentiated (immature) cells bearing slight or no resemblance to the normal cells from which the cancer originated. Tumor dedifferentiated cells exhibit a higher capacity to survive to chemo and radiotherapies and have the ability to incite tumor relapse. Inducing cancer cell differentiation would abolish their self-renewal and invasive capacity and could be combined with the current standard of care, especially in poorly differentiated and aggressive tumors (with worst prognosis). However, differentiation therapy is still in its early stages and the intrinsic complexity of solid tumor heterogeneity demands innovative approaches in order to be efficiently translated into the clinic. We demonstrate here that microRNA 203, a potent driver of differentiation in pluripotent stem cells (ESCs and iPSCs), promotes the differentiation of mammary gland tumor cells. Combining mouse in vivo approaches and both mouse and human-derived tridimensional organoid cultures, we report here that miR-203 influences the self-renewal capacity, plasticity and differentiation potential of breast cancer cells, and prevents tumor cell growth in vivo. Our work sheds light on differentiation-based antitumor therapies and offers miR-203 as a promising tool for directly confronting the tumor-maintaining and regeneration capability of cancer cells."
1113,Development of a Bipyrimidineamide based α-Helix Mimetic Lead Compound for efficient Targeting of MDM2 in Triple-Negative Breast Cancer,"Jasmin Linh On, Vitalij Woloschin, Franziska Gier, Jia-Wey Tu, Sanil Bhatia, Thomas Lenz, Andrea Kulik, Kai Stühler, Dieter Niederacher, Hans Neubauer, Tanja Fehm, Thomas Kurz, Knud Esser",https://www.biorxiv.org/content/10.1101/2024.03.02.582899v1,"Triple-negative breast cancer (TNBC) represents the most aggressive form among breast carcinoma subtypes. Due to limited therapy options, identification of novel active pharmacological compounds is an urgent medical need. A promising approach in cancer treatment is the pharmacological inhibition of murine double minutes 2 (MDM2)-p53/p73 interactions inducing apoptosis in tumors. We here describe a novel bipyrimidineamide based α-helix mimetic 9 (VWK603) which was designed as a lead candidate to target MDM2. 9 (VWK603) potently induced cell death in the TNBC cell lines MDA-MB-231, MDA-MB-436 and MDA-MB-468 with IC50 values ranging between 3.7 µM and 6.6 µM. The anti-tumor activity was about four more potent higher than determined for the MDM2-specific inhibitor Nutlin-3a. Mechanistic analysis revealed induction of cellular apoptosis as the underlying mode of action of 9 (VWK603) anti-tumor activity. Since toxicity was observed to be reduced in non-cancerous breast cells, these studies make 9 (VWK603) a promising candidate for further preclinical MDM2 inhibitor development."
1114,A genome wide CRISPR screen reveals that HOXA9 promotes Enzalutamide resistance in prostate cancer,"Michael V. Roes, Frederick A. Dick",https://www.biorxiv.org/content/10.1101/2023.12.15.571833v1,"Androgen receptor inhibitors are commonly used for prostate cancer treatment, but acquired resistance is a significant problem. Co-deletion of RB and p53 is common in castration resistant prostate cancers, however they are difficult to target pharmacologically. To comprehensively identify gene loss events that contribute to enzalutamide response, we performed a genome-wide CRISPR knockout screen in LNCaP prostate cancer cells. This revealed novel genes implicated in resistance that are largely unstudied. Gene loss events that confer enzalutamide sensitivity are enriched for GSEA categories related to stem cell and epigenetic regulation. We investigated the myeloid lineage stem cell factor HOXA9 as a candidate gene whose loss promotes sensitivity to enzalutamide. Cancer genomic data reveals that HOXA9 overexpression correlates with poor prognosis and characteristics of advanced prostate cancer. In cell culture, HOXA9 depletion sensitizes cells to enzalutamide, whereas overexpression drives enzalutamide resistance. Combination of the HOXA9 inhibitor DB818 with enzalutamide demonstrates synergy. This demonstrates the utility of our CRISPR screen data in discovering new approaches for treating enzalutamide resistant prostate cancer."
1118,Melanoma innervation is associated with cancer progression in a zebrafish xenograft model,"Francesca Lorenzini, Johanna Marines, Julien Le Friec, Nam Do Khoa, Maria Angela Nieto, Berta Sanchez-Laorden, Maria Caterina Mione, Laura Fontenille, Karima Kissa",https://www.biorxiv.org/content/10.1101/2023.12.13.571512v1,"The peripheral nervous system has a key role in regulating tumour biology in different types of cancer. Here, by modelling aggressive melanoma in larval zebrafish xenografts, we highlight the dynamics of tumour innervation in the tumour microenvironment (TME). Axonogenesis and dendritogenesis are detected in the motoneurons surrounding the melanoma niche and neurogenesis is observed in the nearby population of the enteric nervous system. We also demonstrate the crucial role of catecholamines in promoting melanoma progression, supporting in vivo cancer cell dissemination and invasion. This zebrafish model will allow to uncover neural markers associated with melanoma progression to help in the design of innovative anti-neurogenic therapies targeting specifically the neuronal signals that regulate melanoma progression."
1119,cancercelllines.org - a Novel Resource for Genomic Variants in Cancer Cell Lines,"Rahel Paloots, Michael Baudis",https://www.biorxiv.org/content/10.1101/2023.12.12.571281v1,"Cancer cell lines are an important component in biological and medical research, enabling studies of cellular mechanisms as well as the development and testing of pharmaceuticals. Genomic alterations in cancer cell lines are widely studied as models for oncogenetic events and are represented in a wide range of primary resources. We have created a comprehensive, curated knowledge resource - cancercelllines.org - with the aim to enable easy access to genomic profiling data in cancer cell lines, curated from a variety of resources and integrating both copy number and single nucleotide variants (SNVs) data. We have gathered over 5,600 copy number profiles as well as SNV annotations for 16,000 cell lines and provide this data with mappings to the GRCh38 reference genome. Both genomic variations and associated curated metadata can be queried through the GA4GH Beacon v2 API and a graphical user interface with extensive data retrieval enabled using GA4GH data schemas under a permissive licensing scheme."
1120,Exosome derived multi-gene biomarker panel identifies the risk of liver metastasis in lung cancer patients,"Kanisha A Shah, Rakesh M Rawal",https://www.biorxiv.org/content/10.1101/2023.12.12.571044v1,"Background The lack of non-invasive methods for detection of early metastasis is a crucial reason for the poor prognosis of lung cancer (LC) liver metastasis (LM) patients. In this study, the goal was to identify circulating biomarkers based on a biomarker model for the early diagnosis and monitoring of patients with LCLM."
1122,Function-associated scRNA-seq on single lung cancer organoids unravels the immune landscape of tumor parenchyma,"Chang Liu, Kaiyi Li, Xizhao Sui, Tian Zhao, Ting Zhang, Zhongyao Chen, Hainan Wu, Chao Li, Hao Li, Fan Yang, Zhidong Liu, You-Yong Lu, Jun Wang, Xiaofang Chen, Peng Liu",https://www.biorxiv.org/content/10.1101/2023.12.11.571047v1,"In vitro models coupled with multimodal approaches are urgently needed to decipher the local tumor immune microenvironment (TIME) owing to the heterogeneous nature of immune cells and their diverse spatial distributions. Here we generate primary lung cancer organoids (pLCOs) by isolating the tumor cell clusters, including the infiltrated immune cells, from dissected lung cancer samples. A FascRNA-seq platform allowing both phenotypic evaluation and the scRNA-seq of all the single cells in an organoid was developed to dissect the TIME in individual pLCOs. Our analysis on 171 individual pLCOs derived from 7 patients revealed that pLCOs retained the fundamental features as well as intra-tumor heterogeneity of local TIME in the parenchyma of parental tumor tissues, providing a series of models with consistent genetic background but various TIME. Linking the single cell transcriptome data of individual pLCOs with their responses to ICB allowed us to confirm the pivotal role of CD8+ Ts in ICB induced anti-tumor immunity, to identify the potential tumor-reactive T cells with a set of 10 genes, and to unravel the factors regulating T cell activity."
1123,Guggulsterone Enhances NKX3.1 Expression and Induces Apoptosis in Prostate Cancer Cells: Implications for Chemoprevention,"Garima Jain, Neha, Prashant Ranjan, Chandra Devi, Aditi Atri, Clara Cieza-Borrella, Parimal Das",https://www.biorxiv.org/content/10.1101/2023.12.08.570071v2,"Aim Prostate cancer is a leading cause of cancer-related mortality, necessitating novel therapeutic and preventive strategies. This study aimed to investigate the anti-cancer properties of Guggulsterone (GS) on prostate cancer cells, specifically focusing on its effects on homeobox protein NKX3.1, apoptosis, and mitochondrial function."
1124,Radiation-Induced Metabolic Reprogramming of Fibroblasts Regulates the Breast Cancer Microenvironment,"Kevin C. Corn, Lucy S. Britto, Youssef K. Mohamed, Yoanna I. Ivanova, Tian Zhu, Marjan Rafat",https://www.biorxiv.org/content/10.1101/2022.05.17.492249v2,"Patients with triple negative breast cancer (TNBC) continue to have high recurrence rates despite current interventions, including radiation therapy (RT). Radiation-resistant TNBC cells and circulating tumor cells thought to be involved in recurrence survive due to changes in their metabolic profiles, which may be influenced by their interactions with radiation-damaged stromal cells, such as fibroblasts, following treatment. How fibroblasts metabolically respond to RT and influence the metabolism of TNBC cells is poorly understood. In this study, we identify that radiation-damaged fibroblasts accumulate lipids due to increased autophagic flux. The radiation damage response allows fibroblasts to maintain increased fatty acid oxidation, overall mitochondrial respiration, and aerobic glycolysis rates, leading to increased lactate secretion. TNBC cells respond to these metabolic changes by increasing migration rates and tumor spheroid growth. Our work reveals how metabolic crosstalk between irradiated fibroblasts and TNBC cells leads to a microenvironment conducive to recurrence."
1126,Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer,"Tongchen He, Caleb Cheng, Yuanyuan Qiao, Hanbyul Cho, Eleanor Young, Rahul Mannan, Somnath Mahapatra, Stephanie J. Miner, Yang Zheng, NamHoon Kim, Victoria Z. Zeng, Jasmine P. Wisniewski, Siyu Hou, Bailey Jackson, Xuhong Cao, Fengyun Su, Rui Wang, Yu Chang, Bilash Kuila, Subhendu Mukherjee, Sandeep Dukare, Kiran B. Aithal, Samiulla D.S., Chandrasekhar Abbineni, Costas A. Lyssiotis, Abhijit Parolia, Lanbo Xiao, Arul M. Chinnaiyan",https://www.biorxiv.org/content/10.1101/2024.02.29.582768v1,"Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 (BRD4) and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise."
1127,Decoding Prognostic Markers: Bioinformatics Insights into PIH1D1 and p53 in Children’s Brain Cancer,"Dhiraj Kumar, Prashant Ranjan, Amit Kumar Verma, Riyaz Ahmad Mir",https://www.biorxiv.org/content/10.1101/2023.12.09.570938v1,"Genetic alterations in normal brain cells lead to the development of brain tumors (BT). The incidence of newly diagnosed cases is on the rise over time. Understanding the molecular biology of pediatric brain tumors is crucial for advancing novel therapeutic approaches to prevent or effectively manage this disease. The R2TP complex, a conserved co-chaperone from yeast to mammals, including RUVBL1, RUVBL2, PIH1D1, and RPAP3 in humans, plays a crucial role in the assembly and maturation of various multi-subunit complexes. This study evaluates the expression of PIH1D1 and p53 in pediatric brain cancers using The Cancer Genome Atlas (TCGA) data through the UALCAN platform—a novel, user-friendly resource for cancer OMICS data analysis."
1128,"Biochemical reconstitution of a major age-related cancer mutational signature by heat-induced spontaneous deamination of 5-methylcytosine residues, repair of uracil residues, and DNA replication",Tomohiko Sugiyama,https://www.biorxiv.org/content/10.1101/2024.05.22.595323v1,"Non-enzymatic spontaneous deamination of 5-methylcytosine, producing thymine, is the proposed etiology of cancer mutational signature 1, which is the most predominant signature in all cancers. Here, the proposed mutational process was reconstituted using synthetic DNA and purified proteins. First, single-stranded DNA containing 5-methylcytosine at CpG context was incubated at an elevated temperature to accelerate spontaneous DNA damage. Then, the DNA was treated with uracil DNA glycosylase to remove uracil residues that were formed by deamination of cytosine. The resulting DNA was then used as a template for DNA synthesis by yeast DNA polymerase δ. The DNA products were analyzed by next-generation DNA sequencing, and mutation frequencies were quantified. The observed mutations after this process were exclusively C>T mutations at CpG context, which was very similar to signature 1. When 5-methylcytosine modification and uracil DNA glycosylase were both omitted, C>T mutations were produced on C residues in all sequence contexts, but these mutations were diminished by uracil DNA glycosylase-treatment. These results indicate that the CpG>TpG mutations were produced by the deamination of 5-methylcytosine. Additional mutations, mainly C>G, were introduced by yeast DNA polymerase ζ on the heat-damaged DNA, indicating that G residues of the templates were also damaged. However, the damage on G residues was not converted to mutations with DNA polymerase δ or ε. These results provide biochemical evidence to support that the majority of mutations in cancers are produced by ordinary DNA replication on spontaneously damaged DNA."
1129,"Biological activity of a stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor, 60c, in metastatic, triple-negative breast cancer","Damilola Oluwalana, Kelli L Adeleye, Raisa I Krutilina, Hao Chen, Hilaire Playa, Shanshan Deng, Deanna N Parke, John Abernathy, Leona Middleton, Alexandra Cullom, Bhargavi Thalluri, Dejian Ma, Bernd Meibohm, Duane D Miller, Tiffany N Seagroves, Wei Li",https://www.biorxiv.org/content/10.1101/2024.05.22.595349v1,"Background Improving survival for patients diagnosed with metastatic disease and overcoming chemoresistance remain significant clinical challenges in treating breast cancer. Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by a lack of therapeutically targetable receptors (ER/PR/HER2). TNBC therapy includes a combination of cytotoxic chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA-approved MTAs that bind to the colchicine-binding site. Approximately 70% of patients who initially respond to paclitaxel will develop taxane resistance (TxR). We previously reported that an orally bioavailable colchicine-binding site inhibitor (CBSI), VERU-111, inhibits TNBC tumor growth and treats pre-established metastatic disease. To further improve the potency and metabolic stability of VERU-111, we created next-generation derivatives of its scaffold, including 60c."
1131,Spatial transcriptomics profiling of gallbladder adenocarcinoma: a detailed two-case study of progression from precursor lesions to cancer,"Sophie Pirenne, Fátima Manzano-Núñez, Axelle Loriot, Sabine Cordi, Lieven Desmet, Selda Aydin, Catherine Hubert, Sébastien Toffoli, Nisha Limaye, Christine Sempoux, Mina Komuta, Laurent Gatto, Frédéric P. Lemaigre",https://www.biorxiv.org/content/10.1101/2024.02.27.582232v1,"Background Most studies on tumour progression from precursor lesion toward gallbladder adenocarcinoma investigate lesions sampled from distinct patients, providing an overarching view of pathogenic cascades. Whether this reflects the tumourigenic process in individual patients remains insufficiently explored. Genomic and epigenomic studies suggest that a subset of gallbladder cancers originate from biliary intraepithelial neoplasia (BilIN) precursor lesions, whereas others form independently from BilINs. Spatial transcriptomic data supporting these conclusions are missing. Moreover, multiple areas with precursor or adenocarcinoma lesions can be detected within the same pathological sample. Yet, knowledge about intra-patient variability of such lesions is lacking."
1132,Structural insights into specific recognition of PTENα/β-NTE by WDR5 in cancer progression,"Xiaolei Huang, Cheng Zhang, Xinci Shang, Yichang Chen, Qin Xiao, Zhengguo Wei, Guanghui Wang, Xuechu Zhen, Guoqiang Xu, Jinrong Min, Shaoming Shen, Yanli Liu",https://www.biorxiv.org/content/10.1101/2023.12.09.570908v1,"PTENα/β, two variants of PTEN, play a key role in promoting tumor growth by interacting with WDR5 through their N-terminal extensions (NTEs). This interaction facilitates the recruitment of the SET1/MLL methyltransferase complex, resulting in histone H3K4 trimethylation and upregulation of oncogenes such as NOTCH3, which in turn promotes tumor growth. However, the molecular mechanism underlying this interaction has remained elusive. In this study, we determined the crystal structure of PTENα-NTE in complex with WDR5, which reveal that PTENα specifically binds to the WIN site of WDR5 through a novel binding motif specifically found in the NTE domain of PTENα/β. Disruption of this interaction significantly impedes cell proliferation and tumor growth, highlighting the potential of the WIN site inhibitors of WDR5 as therapeutic agents for PTENα/β associated cancers. These findings not only shed light on the important role of the PTENα/β-WDR5 interaction in carcinogenesis, but also present a promising avenue for developing cancer treatments that target this pathway."
1133,13C-SpaceM: Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer,"Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R. Molenaar, Shahraz Mohammed, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J. Patti, Almut Schulze, Marteinn T. Snaebjornsson, Theodore Alexandrov",https://www.biorxiv.org/content/10.1101/2023.08.18.553810v2,"Metabolism has emerged as a key factor in homeostasis and disease including cancer. Yet, little is known about the heterogeneity of metabolic activity of cancer cells due to the lack of tools to directly probe it. Here, we present a novel method, 13C-SpaceM for spatial single-cell isotope tracing of glucose-dependent de novo lipogenesis. The method combines imaging mass spectrometry for spatially-resolved detection of 13C6-glucose-derived 13C label incorporated into esterified fatty acids with microscopy and computational methods for data integration and analysis. We validated 13C-SpaceM on a spatially-heterogeneous normoxia-hypoxia model of liver cancer cells. Investigating cultured cells, we revealed single-cell heterogeneity of lipogenic acetyl-CoA pool labelling degree upon ACLY knockdown that is hidden in the bulk analysis and its effect on synthesis of individual fatty acids. Next, we adapted 13C-SpaceM to analyze tissue sections of mice harboring isocitrate dehydrogenase (IDH)-mutant gliomas. We found a strong induction of de novo fatty acid synthesis in the tumor tissue compared to the surrounding brain. Comparison of fatty acid isotopologue patterns revealed elevated uptake of mono-unsaturated and essential fatty acids in the tumor. Furthermore, our analysis uncovered substantial spatial heterogeneity in the labelling of the lipogenic acetyl-CoA pool indicative of metabolic reprogramming during microenvironmental adaptation. Overall, 13C-SpaceM enables novel ways for spatial probing of metabolic activity at the single cell level. Additionally, this methodology provides unprecedented insight into fatty acid uptake, synthesis and modification in normal and cancerous tissues."
1134,Clustering of HR+/HER2- breast cancer in an Asian cohort is driven by immune phenotypes,"Jia-Wern Pan, Mohana Ragu, Wei-Qin Chan, Siti Norhidayu Hasan, Tania Islam, Li-Ying Teoh, Suniza Jamaris, Mee-Hoong See, Cheng-Har Yip, Pathmanathan Rajadurai, Lai-Meng Looi, Nur Aishah Mohd Taib, Oscar M. Rueda, Carlos Caldas, Suet-Feung Chin, Joanna Lim, Soo Hwang Teo",https://www.biorxiv.org/content/10.1101/2023.12.07.570545v1,"Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast cancer within the Asian population, by analysing the transcriptomic profiles of 934 breast cancer patients from a Malaysian cohort. Our findings reveal that the HR+/HER2-breast cancer samples display a distinct clustering pattern based on immune phenotypes, rather than conforming to the conventional luminal A-luminal B paradigm previously reported in breast cancers from women of European descent. This suggests that the activation of the immune system may play a more important role in Asian HR+/HER2-breast cancer than has been previously recognized. Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR+/HER2-samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population."
1135,Comprehensive chromatome profiling identifies metabolic enzymes on chromatin in healthy and cancer cells,"S Kourtis, M Guirola, N Pardo-Lorente, R Ghose, M Garcia-Cao, A Gañez-Zapater, S Haynes, F Fontaine, A Muller, S Sdelci",https://www.biorxiv.org/content/10.1101/2023.12.06.570368v1,"Metabolic and epigenetic rewiring are widely considered hallmarks of cancer, with emerging evidence of crosstalk between them. Anecdotal evidence of metabolic enzymes moonlighting in the chromatin environment has suggested how this crosstalk might be facilitated, but the extent of nuclear relocalization of metabolic enzymes remains elusive. Here, we provide a comprehensive chromatin proteomics resource across cancer lineages as well as healthy samples and demonstrate that metabolic enzyme moonlighting on chromatin is widespread across tissues and pathways. We show that the abundance of metabolic enzymes on chromatin is tissue-specific, with oxidative phosphorylation proteins depleted in lung cancer samples, perhaps suggesting an interplay between cell identity and nuclear metabolism. Finally, we explore metabolic functions in the chromatin environment and show that one-carbon folate enzymes are associated with DNA damage and repair processes, providing an approach to explore non-canonical functions of metabolic enzymes."
1136,BRDriver: Breast Cancer Driver Gene Predictor,"Rajitha Perera, Roshan Perera",https://www.biorxiv.org/content/10.1101/2023.01.09.523362v1,"The breast cancer mortality rate is high in developing countries as the early detection of cancer is deficient in patients. The identification of the genes that drive cancer is one of the major approaches in the early detection of breast cancer. Several computational tools have been developed to predict the cancer driver genes. However, there is no gold-standard method for identifying breast cancer driver genes. Therefore, this study aims to develop a model to predict high-confidence breast cancer diver genes using already-developed computational tools and already-produced breast cancer data. Primary breast cancer data were retrieved from the Cancer Genome Atlas Program (TCGA). Here we use twenty-seven different gene prediction tools that calculate each gene’s effect and variant in the primary gene dataset. The primary dataset feeds as the input for each tool. The results retrieved from each tool are recorded as the secondary dataset. The latest breast cancer driver gene set was retrieved from DriverDBv3 and included as the target attribute. Training and testing subsets were selected using k-fold cross-validation from the secondary dataset. Attributes from the secondary dataset were ranked according to their correlation with breast cancer driver genes. The ranked data were trained using different supervised machine-learning algorithms. The attributes and the learning algorithm which produced the highest classification accuracy were selected to build the new model, BReast cancer Driver (BRDriver). The new model BRDriver achieved 0.999 area under the curve and 0.999 classification accuracy on breast invasive carcinoma data. TP53 was the most predicted breast cancer drive gene (n=246) predicted by BRDriver. Interestingly, our BRDriver model predicted CDKN2A and NFE2L2 genes as new breast cancer driver genes. Further in vivo and in vitro studies are required to determine whether these genes are indeed cancer-driver genes. Many computational tools developed to identify the cancer driver genes and variants. A few methodologies were developed to combine these tools and increase efficiency for detecting breast cancer driver genes. Our BRDriver overcomes the difficulties and produces high-confidence breast cancer driver genes."
1137,Development and validation of a gene expression score to account for tumour purity and improve prognostication in breast cancer,"Marco Barreca, Matteo Dugo, Barbara Galbardi, Balázs Győrffy, NA-PHER2 consortium, NeoTRIP consortium, Pinuccia Valagussa, Daniela Besozzi, Giuseppe Viale, Giampaolo Bianchini, Luca Gianni, Maurizio Callari",https://www.biorxiv.org/content/10.1101/2024.02.23.581701v1,"The prevalence of malignant cells in clinical specimens, or tumour purity, is affected by both intrinsic biological factors and extrinsic sampling bias. Molecular characterization of large clinical cohorts is typically performed on bulk samples; data analysis and interpretation can be biased by tumour purity variability. Transcription-based strategies to estimate tumour purity have been proposed, but no breast cancer specific method is available yet."
1138,Experimental and Computational Analysis of HIFU Thermal Ablation in Breast Cancer Cells: Monolayers vs. Spheroids,"Heba Badawe, Jean Paul Harouz, Kareem Abu, Petra Raad, Kamel Abou Ghali, Wassim Abou Kheir, Massoud Khrariche",https://www.biorxiv.org/content/10.1101/2023.12.04.569950v1,"Objective The primary objective of our study was to investigate the efficiency of high intensity focused ultrasound (HIFU) ablation in two distinct cellular configurations, 2D monolayers and 3D spheroids of epithelial breast cancer cell lines. The study also compares empirical findings from experiments with results obtained through numerical simulations using a bioheat computational model. This comparison is intended to provide a comprehensive understanding of the acoustic energy conversion within the biological system during HIFU treatment."
1139,A modified RGB trichrome (HemRGB) for improving nuclear staining: application to colorectal cancer histopathology,Francisco Gaytán,https://www.biorxiv.org/content/10.1101/2023.12.04.569959v1,"The RGB trichrome staining method has been used to highlight two major components of the extracellular matrix, collagen and glycosaminoglycans. While the RGB trichrome efficiently stains extracellular matrix components, it lacks a nuclear stain, limiting its application in histopathology. To address this issue, a modification of the original stain, named HemRGB trichrome, has been developed. This modification incorporates iron hematoxylin for improving nuclear staining while retaining specificity for the staining of extracellular matrix. The application of HemRGB trichrome staining to samples from both normal colonic tissues and colorectal adenocarcinomas (CRC) provides a robust nuclear staining, together with a high-contrasted staining of tumor microenvironmental components, such as infiltrating immune cells, collagen and ground substance, extracellular mucins, as well as contrasted interfaces between CRC metastases and liver parenchyma. This study underscores the potential of HemRGB trichrome as a valuable tool for histopathological studies, especially for cancer evaluation, where nuclear characteristics are particularly relevant."
1140,A multiprotein signaling complex sustains AKT and mTOR/S6K activity necessary for the survival of cancer cells undergoing stress,"Oriana Y. Teran Pumar, Matthew R. Zanotelli, Miao-chong Joy Lin, Rebecca R. Schmitt, Kai Su Green, Katherine S. Rojas, Irene Y. Hwang, Richard A. Cerione, Kristin F. Wilson",https://www.biorxiv.org/content/10.1101/2023.01.03.522657v2,"Cancer cells encounter stresses during tumor progression and metastatic spread, however, how they survive these challenges is not fully understood. We now identify a mechanism for cancer cell survival through the discovery of a multiprotein signaling complex that includes the GTPase Cdc42, the Cdc42 GEF/effector protein Dock7, AKT, mTOR and the mTORC1 regulatory partners TSC1, TSC2, and Rheb. This pro-survival signaling complex sustains the activated state of AKT by preventing its dephosphorylation at Ser473 during serum starvation, resulting in a low but critical activation of a Raptor-independent mTOR/S6K activity. We demonstrate that the Dock7 DHR1 domain, previously of unknown function, is responsible for preserving AKT phosphorylation through an interaction requiring its C2-like motif. Collectively, these findings help address long-standing questions of how Cdc42 signals mTOR activation by elucidating the unique functions of its signaling partner Dock7 as an AKT regulator necessary for resistance to anoikis and apoptosis in cancer cells."
1141,Gravity-based microfiltration reveals unexpected prevalence of circulating tumor cell clusters in ovarian and colorectal cancer,"Anne Meunier, Javier Alejandro Hernández-Castro, Nicholas Chahley, Laudine Communal, Sara Kheireddine, Newsha Koushki, Nadia Davoudvandi, Sara Al Habyan, Benjamin Péant, Anthoula Lazaris, Andy Ng, Teodor Veres, Luke McCaffrey, Diane Provencher, Peter Metrakos, Anne-Marie Mes-Masson, David Juncker",https://www.biorxiv.org/content/10.1101/773507v2,"Circulating tumor cells (CTCs) are rare (few cells per milliliter of blood) and mostly isolated as single cell CTCs (scCTCs). CTC clusters (cCTCs), even rarer, are of growing interest, notably because of their higher metastatic potential, but very difficult to isolate. Here, we introduce gravity-based microfiltration (GµF) for facile isolation of cCTCs while minimizing unwanted cluster disaggregation, with ∼85% capture efficiency. GµF from orthotopic ovarian cancer mouse models, from 17 epithelial ovarian cancer (EOC) with either localized or metastatic disease, and from 13 metastatic colorectal cancer liver metastasis (CRCLM) patients uncovered cCTCs in every case, with between 2-100+ cells. cCTCs represented between 5-30% of all CTC capture events, and 10-80% of CTCs were clustered; remarkably, in 10 patients, most CTCs were circulating not as scCTCs, but as cCTCs. GµF uncovered the unexpected prevalence and frequency of cCTCs including sometimes very large ones in EOC patients, and motivates additional studies to uncover their properties and role in disease progression."
1143,Towards A Wireless Image Sensor for Real-Time Fluorescence Microscopy in Cancer Therapy,"Rozhan Rabbani, Hossein Najafiaghdam, Micah Roschelle, Efthymios Philip Papageorgiou, Biqi Rebekah Zhao, Mohammad Meraj Ghanbari, Rikky Muller, Vladimir Stojanovic, Mekhail Anwar",https://www.biorxiv.org/content/10.1101/2023.12.03.569779v1,"We present a mm-sized, ultrasonically powered lensless CMOS image sensor as a progress towards wireless fluorescence microscopy. Access to biological information within the tissue has the potential to provide insights guiding diagnosis and treatment across numerous medical conditions including cancer therapy. This information, in conjunction with current clinical imaging techniques that have limitations in obtaining images continuously and lack wireless compatibility, can improve continual detection of multicell clusters deep within tissue. The proposed platform incorporates a 2.4×4.7 mm2 integrated circuit (IC) fabricated in TSMC 0.18 μm, a micro laser diode (μLD), a single piezoceramic and off-chip storage capacitors. The IC consists of a 36×40 array of capacitive trans-impedance amplifier-based pixels, wireless power management and communication via ultrasound and a laser driver all controlled by a Finite State Machine. The piezoceramic harvests energy from the acoustic waves at a depth of 2 cm to power up the IC and transfer 11.5 kbits/frame via backscattering. During Charge-Up, the off-chip capacitor stores charge to later supply a high-power 78 mW μLD during Imaging. Proof of concept of the imaging front end is shown by imaging distributions of CD8 T-cells, an indicator of the immune response to cancer, ex vivo, in the lymph nodes of a functional immune system (BL6 mice) against colorectal cancer consistent with the results of a fluorescence microscope. The overall system performance is verified by detecting 140 μm features on a USAF resolution target with 32 ms exposure time and 389 ms ultrasound backscattering."
1144,Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells,"Sefora Conti, Valeria Venturini, Adrià Cañellas-Socias, Carme Cortina, Juan F. Abenza, Camille Stephan-Otto Attolini, Emily Middendorp Guerra, Catherine K Xu, Jia Hui Li, Leone Rossetti, Giorgio Stassi, Pere Roca-Cusachs, Alba Diz-Muñoz, Verena Ruprecht, Jochen Guck, Eduard Batlle, Anna Labernadie, Xavier Trepat",https://www.biorxiv.org/content/10.1101/2023.12.04.569244v1,"Colorectal cancer tumors are composed of heterogeneous and plastic cell populations, including a pool of cancer stem cells that express LGR5. Whether these distinct cell populations display different mechanical properties, and how these properties might contribute to metastasis is unknown. Using CRC patient derived organoids (PDOs), we found that compared to LGR5- cells, LGR5+ cancer stem cells are stiffer, adhere better to the extracellular matrix (ECM), move slower both as single cells and clusters, display higher nuclear YAP, show a higher survival rate in response to mechanical confinement, and form larger transendothelial gaps. These differences are largely explained by the downregulation of the membrane to cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) in the LGR5+ cells. By analyzing scRNA-seq expression patterns from a patient cohort, we show that this downregulation is a robust signature of colorectal tumors. Our results show that LGR5- cells display a mechanically dynamic phenotype suitable for dissemination from the primary tumor whereas LGR5+ cells display a mechanically stable and resilient phenotype suitable for extravasation and metastatic growth."
1145,VDAC1 selective molecules promote patients’-derived cancer organoids death through mitochondrial-dependent metabolic interference,"Stefano Conti Nibali, Silvia De Siervi, Enrico Luchinat, Andrea Magrì, Lorenza Brocca, Stefania Mantovani, Barbara Oliviero, Mario U. Mondelli, Vito De Pinto, Cristian Turato, Cristina Arrigoni, Marco Lolicato",https://www.biorxiv.org/content/10.1101/2023.12.04.569205v1,"In the continuous pursuit of advanced cancer therapeutics, our research unveils the potential to selectively target Voltage-Dependent Anion-selective Channel isoform 1 (VDAC1), a pivotal component in cellular metabolism and apoptosis. VDAC1’s role in metabolic rewiring and its subsequent prominence in many cancer types offer a unique intervention point. The incorporation of a systematic, in silico to in vitro methodology identified novel VA (VDAC-Antagonist) molecules with the capability to selectively bind to VDAC1, displaying a substantial specificity towards cancer cells while sparing healthy ones."
1147,Democratizing computational pathology: optimized Whole Slide Image representations for The Cancer Genome Atlas,"Tristan Lazard, Marvin Lerousseau, Sophie Gardrat, Anne Vincent-Salomon, Marc-Henri Stern, Manuel Rodrigues, Etienne Decencière, Thomas Walter",https://www.biorxiv.org/content/10.1101/2023.12.04.569894v1,"Automatic analysis of hematoxylin and eosin (H&E) stained Whole Slide Images (WSI) bears great promise for computer assisted diagnosis and biomarker discovery. However, scarcity of annotated datasets leads to underperforming models. Furthermore, the size and complexity of the image data limit their integration into bioinformatic workflows and thus their adoption by the bioinformatics community. Here, we present Giga-SSL, a self-supervised method for learning WSI representations without any annotation. We show that applying a simple linear classifier on the Giga-SSL representations improves classification performance over the fully supervised alternative on five benchmarked tasks and across different datasets. Moreover, we observe a substantial performance increase for small datasets (average gain of 7 AUC point) and a doubling of the number of mutations predictable from WSIs in a pan-cancer setting (from 45 to 93). We make the WSI representations available, compressing the TCGA-FFPE images from 12TB to 23MB and enabling fast analysis on a laptop CPU. We hope this resource will facilitate multimodal data integration in order to analyze WSI in their genomic and transcriptomic context."
1148,Imaging of MAP kinase dynamics reveals endocytic regulation of pulsatile signalling and network re-wiring in response to targeted therapy in EGFR-mutant non-small cell lung cancer,"Alix Le Marois, Sasha Bailey, Steven Hooper, Sunil Kumar, Hugh Sparks, Yuriy Alexandrov, Deborah Caswell, Fabian Frӧhlich, Karin Schlegelmilch, Karishma Valand, Matthew Martin, Ana Narvaez, Charles Swanton, Julian Downward, Christopher Dunsby, Paul French, Erik Sahai",https://www.biorxiv.org/content/10.1101/2024.05.14.594112v1,"A better understanding of the signalling mechanisms underlying transitions from drug-sensitive to drug-tolerant states is required to overcome therapy failure. We combined single-cell biosensor imaging with functional perturbations to investigate the regulation of oncogenic signalling in EGFR-mutant lung adenocarcinoma. We find that despite the constant presence of the mutant oncogene, ERK signalling exhibits pulsatile dynamics, with pulse characteristics determined by the endocytic machinery. Analysis of drug-tolerant persisters (DTPs) revealed that, after an initial phase of complete pathway shut-down, signalling was rewired leading to renewed ERK pulses that drive cell cycle progression. FAK- and SRC-regulated adhesion complexes replace mutant EGFR as the driver of reactivated ERK pulses in DTPs, yet they remain controlled by the membrane trafficking machinery. We show that DTPs rely on additional survival pathways including YAP signalling, and that the phosphatase PTPRS represents a key node in therapy resistant cells, coordinating regulation of ERK, the cytoskeleton, and YAP."
1150,Prostate cancer-induced endothelial-to-osteoblast transition generates an immunosuppressive bone tumor microenvironment,"Guoyu Yu, Paul G. Corn, Celia Sze Ling Mak, Xin Liang, Miao Zhang, Patricia Troncoso, Jian H. Song, Song-Chang Lin, Xingzhi Song, Jingjing Liu, Jianhua Zhang, Christopher J. Logothetis, Marite P. Melancon, Theocharis Panaretakis, Guocan Wang, Sue-Hwa Lin",https://www.biorxiv.org/content/10.1101/2023.11.30.569496v1,"Immune checkpoint therapy has limited efficacy for patients with bone metastatic castrate-resistant prostate cancer (bmCRPC). In this study, we revealed a novel mechanism that may account for the relative resistance of bmCRPC to immune checkpoint therapy. We found that prostate cancer (PCa)-induced bone via endothelial-to-osteoblast (EC-to-OSB) transition causes an ingress of M2-like macrophages, leading to an immunosuppressive bone tumor microenvironment (bone-TME). Analysis of a bmCRPC RNA-seq dataset revealed shorter overall survival in patients with an M2-high versus M2-low signature. Immunohistochemical (IHC) analysis showed CD206+ M2-like macrophages were enriched in bmCRPC specimens compared with primary tumors or lymph node metastasis. In osteogenic PCa xenografts, CD206+ macrophages were enriched adjacent to tumor-induced bone. FACS analysis showed an increase in CD206+ cells in osteogenic tumors compared to non-osteogenic tumors. Genetic or pharmacological inhibition of the EC-to-OSB transition reduced aberrant bone and M2-like macrophages in osteogenic tumors. RNAseq analysis of tumor-associated macrophages from osteogenic (bone-TAMs) versus non-osteogenic (ctrl-TAMs) tumors showed high expression of an M2-like gene signature, canonical and non-canonical Wnt pathways, and a decrease in an M1-like gene signature. Isolated bone-TAMs suppressed T-cell proliferation while ctrl-TAMs did not. Mechanistically, EC-OSB hybrid cells produced paracrine factors, including Wnts, CXCL14 and LOX, which induced M2 polarization and recruited M2-like TAMs to bone-TME. Our study thus links the unique EC-to-OSB transition as an “upstream” event that drives “downstream” immunosuppression in the bone-TME. These studies suggest that therapeutic strategies that inhibit PCa-induced EC-to-OSB transition may reverse immunosuppression to promote immunotherapeutic outcomes in bmCRPC."
1151,Cancer associated fibroblasts serve as an ovarian cancer stem cell niche through noncanonical Wnt5a signaling,"Yiming Fang, Xue Xiao, Ji Wang, Subramanyam Dasari, David Pepin, Kenneth P. Nephew, Dmitriy Zamarin, Anirban K. Mitra",https://www.biorxiv.org/content/10.1101/2023.02.28.530455v1,"Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (CAFs) are a major constituent of the OC tumor microenvironment and we show that CAFs and CSCs are enriched following chemotherapy in patient tumors. CAFs significantly increased OC cell resistance to carboplatin. Using heterotypic CAF-OC cocultures and in vivo limiting dilution assay, we confirmed that the CAFs act by enriching the CSC population. CAFs were found to increase the symmetric division of CSCs as well as the dedifferentiation of bulk OC cells into CSCs. The effect of CAFs was limited to OC cells in their immediate neighborhood, which could be prevented by inhibiting Wnt. Analysis of single cell RNA-seq data from OC patients revealed that Wnt5a as the highest expressed Wnt in CAFs and that certain subpopulations of CAFs express higher levels of Wnt5a. We found that Wnt5a from CAFs activated a noncanonical Wnt signaling pathway involving the ROR2/PKC/CERB1 axis in the neighboring CSCs. While canonical Wnt signaling was predominant in interactions between cancer cells in patients, non-canonical Wnt pathway was activated by CAF-OC crosstalk. Treatment with a Wnt5a inhibitor sensitized tumors to carboplatin in vivo. Together, our findings demonstrate a novel mechanism of CSC maintenance by signals from the microenvironmental CAFs, which can be targeted to treat OC chemoresistance and relapse."
1153,Molecular subtypes of high-grade serous ovarian cancer across racial groups and gene expression platforms,"Natalie R. Davidson, Mollie E. Barnard, Ariel A. Hippen, Amy Campbell, Courtney E. Johnson, Gregory P. Way, Brian K. Dalley, Andrew Berchuck, Lucas A. Salas, Lauren C. Peres, Jeffrey R. Marks, Joellen M. Schildkraut, Casey S. Greene, Jennifer A. Doherty",https://www.biorxiv.org/content/10.1101/2023.11.01.565179v2,Introduction High-grade serous carcinoma (HGSC) gene expression subtypes are associated with differential survival. We characterized HGSC gene expression in Black individuals and considered whether gene expression differences by race may contribute to poorer HGSC survival among Black versus non-Hispanic White individuals.
1154,Neotelomeres and Telomere-Spanning Chromosomal Arm Fusions in Cancer Genomes Revealed by Long-Read Sequencing,"Kar-Tong Tan, Michael K. Slevin, Mitchell L. Leibowitz, Max Garrity-Janger, Heng Li, Matthew Meyerson",https://www.biorxiv.org/content/10.1101/2023.11.30.569101v1,"Alterations in the structure and location of telomeres are key events in cancer genome evolution. However, previous genomic approaches, unable to span long telomeric repeat arrays, could not characterize the nature of these alterations. Here, we applied both long-read and short-read genome sequencing to assess telomere repeat-containing structures in cancers and cancer cell lines. Using long-read genome sequences that span telomeric repeat arrays, we defined four types of telomere repeat variations in cancer cells: neotelomeres where telomere addition heals chromosome breaks, chromosomal arm fusions spanning telomere repeats, fusions of neotelomeres, and peri-centromeric fusions with adjoined telomere and centromere repeats. Analysis of lung adenocarcinoma genome sequences identified somatic neotelomere and telomere-spanning fusion alterations. These results provide a framework for systematic study of telomeric repeat arrays in cancer genomes, that could serve as a model for understanding the somatic evolution of other repetitive genomic elements."
1155,Ridge regression baseline model outperforms deep learning method for cancer genetic dependency prediction,"Daniel Chang, Xiang Zhang",https://www.biorxiv.org/content/10.1101/2023.11.29.569083v1,"Accurately predicting genetic or other cellular vulnerabilities of unscreened, or difficult to screen, cancer samples will allow vast advancements in precision oncology. We re-analyzed a recently published deep learning method for predicting cancer genetic dependencies from their omics profiles. After implementing a ridge regression baseline model with an alternative, simplified problem setup, we achieved a model that outperforms the original deep learning method. Our study demonstrates the importance of problem formulation in machine learning applications and underscores the need for rigorous comparisons with baseline approaches."
1156,The Apurinic/Apyrimidinic Endodeoxyribonuclease 1 is an RNA G-quadruplex binding protein and regulates miR-92b expression in cancer cells,"Alessia Bellina, Matilde Clarissa Malfatti, Gilmar Salgado, Aaron M. Fleming, Giulia Antoniali, Nicolò Gualandi, Sara La Manna, Daniela Marasco, Erik Dassi, Cynthia J. Burrows, Gianluca Tell",https://www.biorxiv.org/content/10.1101/2024.02.22.581538v1,"In the last decade, several novel functions of the mammalian Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1) have been discovered, going far beyond its canonical function as a DNA repair enzyme, unveiling its potential roles in cancer development. Indeed, it was shown to be involved in DNA G-quadruplex biology and RNA metabolism, most importantly in the miRNA maturation pathway and the decay of oxidized- or abasic-miRNAs during oxidative stress conditions. Furthermore, in recent years several non-canonical pathways of miRNA biogenesis have been described, with a specific focus on guanosine-rich precursors that can form RNA G-quadruplex (rG4) structures. In this study, we show that several miRNA precursors, dysregulated upon APE1-depletion, contain an rG4 motif and that their corresponding target genes are upregulated after APE1-depletion. We also show, both by in vitro assays and by using a HeLa cell model, that APE1 can bind and regulate the folding of an rG4 structure contained in pre-miR92b, with a mechanism strictly dependent on critical lysine residues present in the N-terminal disordered region. Furthermore, APE1 depletion in HeLa cells alters the maturation process of miR-92b, mainly affecting the shuttling between the nucleus and cytosol. Lastly, bioinformatic analysis of APE1-regulated rG4-containing miRNAs supports the relevance of our findings for cancer biology. Specifically, these miRNAs exhibit high prognostic significance in lung, cervical, and liver cancer, as suggested by their involvement in several cancer-related pathways."
1157,The spatial landscape of Cancer Hallmarks reveals patterns of tumor ecology,"Mustafa Sibai, Sergi Cervilla, Daniela Grases, Eva Musulen, Rossana Lazcano, Chia-Kuei Mo, Veronica Davalos, Arola Fortian, Adrià Bernat, Margarita Romeo, Collin Tokheim, Enrique Grande, Francisco Real, Jordi Barretina, Alexander J Lazar, Li Ding, Manel Esteller, Matthew H Bailey, Eduard Porta-Pardo",https://www.biorxiv.org/content/10.1101/2022.06.18.496114v2,"Tumors are complex ecosystems with dozens of interacting cell types. The concept of Cancer Hallmarks distills this complexity into a set of underlying principles that govern tumor growth. Here, we exploit this abstraction to explore the physical distribution of Cancer Hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that Hallmark activity is spatially organized–with 7 out of 13 Hallmarks consistently more active in cancer cells than within the non-cancerous tumor microenvironment (TME). The opposite is true for the remaining six Hallmarks. Additionally, we discovered that genomic distance between tumor subclones correlates with differences in Cancer Hallmark activity, even leading to clone-Hallmark specialization in some cases. Finally, we demonstrate interdependent relationships between Cancer Hallmarks at the junctions of TME and cancer compartments. In conclusion, including the spatial dimension, particularly through the lens of Cancer Hallmarks, can improve our understanding of tumor ecology."
1158,JUN mediates senescence and immune cell recruitment to prevent prostate cancer progression,"Torben Redmer, Martin Raigel, Christina Sternberg, Roman Ziegler, Clara Probst, Desiree Lindner, Astrid Aufinger, Tanja Limberger, Karolina Trachtova, Petra Kodajova, Sandra Högler, Michaela Schlederer, Stefan Stoiber, Monika Oberhuber, Marco Bolis, Heidi A. Neubauer, Sara Miranda, Martina Tomberger, Nora S. Harbusch, Ines Garces de los Fayos Alonso, Felix Sternberg, Richard Moriggl, Jean-Philippe Theurillat, Boris Tichy, Vojtech Bystry, Jenny L. Persson, Stephan Mathas, Fritz Aberger, Birgit Strobl, Sarka Pospisilova, Olaf Merkel, Gerda Egger, Sabine Lagger, Lukas Kenner",https://www.biorxiv.org/content/10.1101/2023.11.29.569178v1,"Background Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood."
1159,Cancer-on-a-chip model shows that the adenomatous polyposis coli mutation impairs T cell engagement and killing of cancer spheroids,"Valentin Bonnet, Erik Maikranz, Marianne Madec, Nadia Vertti-Quintero, Céline Cuche, Marta Mastrogiovanni, Andrés Alcover, Vincenzo Di Bartolo, Charles N. Baroud",https://www.biorxiv.org/content/10.1101/2023.10.17.562521v1,"Evaluating the ability of cytotoxic T lymphocytes (CTLs) to eliminate tumor cells is crucial, for instance to predict the efficiency of cell therapy in personalized medicine. However, the destruction of a tumor by CTLs involves CTL migration in the extra-tumoral environment, accumulation on the tumor, antigen recognition, and cooperation in killing the cancer cells. Therefore, identifying the limiting steps in this complex process requires spatio-temporal measurements of different cellular events over long periods. Here, we use a cancer-on-a-chip platform to evaluate the impact of adenomatous polyposis coli (APC) mutation on CTL migration and cytotoxicity against 3D tumor spheroids. The APC mutated CTLs are found to have a reduced ability to destroy tumor spheroids compared with control cells, even though APC mutants migrate in the extra-tumoral space and accumulate on the spheroids as efficiently as control cells. Once in contact with the tumor however, mutated CTLs display reduced engagement with the cancer cells, as measured by a new metric that distinguishes different modes of CTL migration. Realigning the CTL trajectories around localized killing cascades reveals that all CTLs transition to high engagement in the two hours preceding the cascades, which confirms that the low engagement is the cause of reduced cytotoxicity. Beyond the study of APC mutations, this platform offers a robust way to compare cytotoxic cell efficiency of even closely related cell types, by relying on a multiscale cytometry approach to disentangle complex interactions and to identify the steps that limit the tumor destruction."
1160,High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer,"Tobias T. Schmidt, Carly Tyer, Preeyesh Rughani, Candy Haggblom, Jeffrey R. Jones, Xiaoguang Dai, Kelly A. Frazer, Fred H. Gage, Sissel Juul, Scott Hickey, Jan Karlseder",https://www.biorxiv.org/content/10.1101/2023.11.28.569082v1,"Telomeres are the protective nucleoprotein structures at the end of linear eukaryotic chromosomes. Telomeres’ repetitive nature and length have traditionally challenged the precise assessment of the composition and length of individual human telomeres. Here, we present Telo-seq to resolve bulk, chromosome arm-specific and allele-specific human telomere lengths using Oxford Nanopore Technologies’ native long-read sequencing. Telo-seq resolves telomere shortening in five population doubling increments and reveals intrasample, chromosome arm-specific, allele-specific telomere length heterogeneity. Telo-seq can reliably discriminate between telomerase- and ALT-positive cancer cell lines. Thus, Telo-seq is a novel tool to study telomere biology during development, aging, and cancer at unprecedented resolution."
1162,Anastasis induced by bee venom in normal cells compared to persistent cell death in breast cancer cells,"Sinan Tetikoğlu, Ugur Uzuner, Selcen Çelik Uzuner",https://www.biorxiv.org/content/10.1101/2024.02.18.579605v1,"Anastasis is a phenomenon that has been recently defined as a return from induced apoptosis. Its mechanism has not been clearly elucidated. Anastasis is thought to be involved in the development of drug resistance in cancer cells, however the distinct regulation of anastasis in normal and cancerous cells during anti-cancer therapy has not been discovered. One of the most privileged therapy strategies focuses on the drugs that are selectively cytotoxic in cancer cells but not negatively affect normal cell proliferation. This study for the first time comparatively evaluated the anastatic effect of a common synthetic cytotoxic agent, cisplatin and a natural cytotoxic agent, bee venom. The study showed that bee venom induced anastasis in normal cells (MCF10A, NIH3T3 and ARPE19) but cancer cells (MDA-MB-231 and MCF7) were irreversibly in cell death process. Liver cancer cells (HEPG2) were more resistant to bee venom-induced persistent cell death and tended to recover at higher concentrations compared to breast cancer cells. However, cisplatin induced persistent cell death in both normal and cancerous cells. Besides, selectivity indexes of bee venom in terms of IC50 values were higher than cisplatin. This study indicates that bee venom produces such an effect by selectively inducing anastasis only in normal cells suggesting that bee venom has prominent potential for cancer therapy, in particular for breast cancer, with recovery and maintenance of normal cells’ viability."
1163,A biodegradable “one-for-all” nanoparticle for multimodality imaging and enhanced photothermal treatment of breast cancer,"Jessica C. Hsu, Diego Barragan, Alexander E. Tward, Maryam Hajfathalian, Ahmad Amirshaghaghi, Katherine J. Mossburg, Derick N. Rosario-Berríos, Mathilde Bouché, Alexander K. Andrianov, E. James Delikatny, David P. Cormode",https://www.biorxiv.org/content/10.1101/2023.11.28.568885v1,"Silver sulfide nanoparticles (Ag2S-NP) have been proposed for various optical-based biomedical applications, such as near-infrared fluorescence (NIRF) imaging, photoacoustics (PA) and photothermal therapy (PTT). However, their absorbance is relatively low in the NIR window used in these applications, and previous formulations were synthesized using toxic precursors under harsh conditions and have clearance issues due to their large size. Herein, we synthesized sub-5 nm Ag2S-NP and encapsulated them in biodegradable, polymeric nanoparticles (AgPCPP). All syntheses were conducted using biocompatible reagents in the aqueous phase and under ambient conditions. We found that the encapsulation of Ag2S-NP in polymeric nanospheres greatly increases their NIR absorbance, resulting in enhanced optical imaging and photothermal heating effects. We therefore found that AgPCPP have potent contrast properties for PA and NIRF imaging, as well as for computed tomography (CT). We demonstrated the applicability of AgPCPP nanoparticles as a multimodal imaging probe that readily improves the conspicuity of breast tumors in vivo. PTT was performed using AgPCPP with NIR laser irradiation, which led to significant reduction in breast tumor growth and prolonged survival compared to free Ag2S-NP. Lastly, we observed a gradual decrease in AgPCPP retention in tissues over time with no signs of acute toxicity, thus providing strong evidence of safety and biodegradability. Therefore, AgPCPP may serve as a “one-for-all” theranostic agent that degrades into small components for excretion once the diagnostic and therapeutic tasks are fulfilled, thus providing good prospects for translation to clinical use."
1164,Tumor-derived exosomal miR-222-3p induce cancer-associated fibroblasts activation to foster progression of renal cancer,"Yang Yang, Jie Zhu, Dong-lai Shen, Ce Han, Chen-feng Wang, Bo Cui, Wen-mei Fan, Yan Huang, Xiu-bin Li, Xu Zhang, Yu Gao",https://www.biorxiv.org/content/10.1101/2023.06.22.546057v1,"The interaction between tumor-derived exosomes and stroma is crucial for tumor progression. However, the mechanisms by which tumor cells influence stromal changes are not yet fully understood. Our study revealed that high-metastatic renal cancer cells are more effective in converting normal fibroblasts into cancer-associated fibroblasts (CAFs) compared to low-metastatic renal cancer cells. Meanwhile, high-metastatic renal cancer cells secrete more exosomal miR-222-3p, which can directly target PANK3, activate NF-kB signaling pathway in fibroblasts and induce intracellular metabolic reprogramming to produce more lactic acid through Warburg effect. The activated CAFs further promote renal cancer progression by secreting lactic acid and inflammatory cytokines, including IL-6 and IL-8. Patients with renal cancer who have high levels of serum exocrine miR-222-3p are more likely to experience progression. These findings suggest that the intercellular communication between renal cancer cells and fibroblasts is facilitated by tumor exosomes. Targeting this communication may hold promise for the prevention and treatment of renal cancer."
1166,Jianpi Jiedu Recipe inhibits proliferation through reactive oxygen species-induced incomplete autophagy and reduces PD-L1 expression in colon cancer,"Lingling Cheng, Liangfeng Xu, Hua Yuan, Qihao Zhao, Wei Yue, Shuang Ma, Xiaojing Wu, Dandan Gu, Yurong Sun, Haifeng Shi, Jianlin Xu",https://www.biorxiv.org/content/10.1101/2024.02.15.580471v1,"Background Jianpi Jiedu Recipe has been used to treat digestive tract tumors in China since ancient times, and its reliability has been proven by clinical research. Currently, the specific biological mechanism of JPJDR in treating tumors is unclear."
1168,"Signaling pathway evaluation of leading ATRi, PARPi and CDK7i cancer compounds targeting the DNA Damage Response using Causal Inference","Nina Truter, Wikus Bergh, Martine van den Heever, Shade Horn, Klarissa Shaw, Dan Leggate, Neil Wilkie, Raminderpal Singh",https://www.biorxiv.org/content/10.1101/2024.02.15.580418v1,"Introduction There are many cancer drugs in development which target the DNA damage response (DDR), following early successes of drugs such as olaparib. However, various challenges to the success of these inhibitors exist, including the emergence of resistance, the identification of appropriate biomarkers to identify patients who will respond to treatment, as well as the identification of combination therapies that improve efficacy without a concomitant increase in toxicity. While the identification of biomarkers of resistance could aid in overcoming these challenges, current methods mostly generate lists of potential genes, proteins that display changes in cancer patients, without exposing the underlying, and often critical, mechanisms of resistance."
1169,A robust protocol for the systematic collection and expansion of cells from ER+ breast cancer tumors and their matching tumor-adjacent tissues,"Diana Topolnitska, Camila Lopez Moreno, Alen Paiva, Edward Buchel, Janice Safneck, Afshin Raouf",https://www.biorxiv.org/content/10.1101/2024.06.09.598157v1,"Therapy resistance and tumor recurrence are major challenges in the clinical management of breast cancer. Current data indicates that the breast tumor microenvironment (TME) and the tumor immune microenvironment (TIME) are important modulators of breast cancer cell response to chemotherapies and the development of therapy resistance. To this end, the ability to recreate the tumor microenvironment in the laboratory using autologous primary cells that make up the breast TME has become an indispensable tool for cancer researchers as it allows the study of tumor immunobiology in the context of therapy resistance. Moreover, the clinical relevance of data obtained from single cell transcriptomics and proteomics platforms would be greatly improved if primary autologous tumor cells were used. In this article, we report a robust and efficient workflow to obtain autologous cancer cells, cancer-associated fibroblasts, and tumor-infiltrating immune cells from primary human breast cancer tumors obtained from mastectomy procedures. As well, we show that this protocol can be used to obtain normal-like epithelial cells, fibroblasts, and immune cells from the matching tumor-adjacent breast tissue samples. Also, a robust methodology to expand each of these primary cell types in vitro is presented that allows the maintenance of the primary tumor cell phenotype. The availability of a large number of autologous primary human breast tumor cells and their matching tumor-adjacent tissues will facilitate the study of differential and cancer cell-specific gene expression patterns that will further our understanding of how the TME and TIME influence therapy resistance in the breast tumor context."
1170,Dual Targeting of STING and PI3Kγ Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy,"Chengyi Li, Shuai Mao, Hongyi Zhao, Miao He, Meilin Wang, Zhongwei Liu, Hanning Wen, Zhixin Yu, Bo Wen, Djibo Mahamadou, Jinsong Tao, Yingzi Bu, Wei Gao, Duxin Sun",https://www.biorxiv.org/content/10.1101/2024.02.14.580378v1,"The immune suppression in tumors and lymph nodes of pancreatic ductal adenocarcinoma (PDAC), regulated by suppressive myeloid cells and regulatory B (Breg) cells, hinders the effectiveness of immunotherapy. Although STING agonists activate myeloid cells to overcome immune suppression, it expands Breg cells, conferring STING resistance in PDAC. We discovered that blocking PI3Kγ during STING activation abolished IRF3 phosphorylation to eliminate Breg cells, while PI3Kγ inhibition sustained STING-induced IRF3 phosphorylation to preserve STING function in myeloid cells. Therefore, we developed a dual functional compound SH-273 and its albumin nanoformulation Nano-273, which stimulates STING to activate myeloid cells and inhibits PI3Kγ to eliminates Breg cells overcoming STING resistance. Nano-273 achieved systemic antitumor immunity through intravenous administration, which decreases Breg cells and remodels microenvironment in tumors and lymph nodes. Nano-273, combined with anti-PD-1, extended median survival to 200 days in transgenic KPC PDAC mice (KrasG12D-P53R172H-Cre), offering potential for PDAC treatment."
1172,Cancer-Specific Alterations in Nuclear Matrix Proteins Determined by Multi-omics Analyses of Ductal Carcinoma in Situ,"Ali Almutairy, Abdullah Alhamed, Stephen G. Grant, Miranda J. Sarachine Falso, Billy W. Day, Colton R. Simmons, Jean J. Latimer",https://www.biorxiv.org/content/10.1101/2024.02.13.580215v1,"Breast cancer (BC) is the most common cancer affecting women in the United States. Ductal carcinoma in situ (DCIS) is the earliest identifiable pre-invasive BC lesion. Estimates show that 14 to 50% of DCIS cases progress to invasive BC. Our objective was to identify nuclear matrix proteins (NMP) with specifically altered expression in DCIS and later stages of BC compared to non-diseased breast reduction mammoplasty and a contralateral breast explant using mass spectrometry and RNA sequencing to accurately identify aggressive DCIS. Sixty NMPs were significantly differentially expressed between the DCIS and non-diseased breast epithelium in an isogenic contralateral pair of patient-derived extended explants. Ten of the sixty showed significant mRNA expression level differences that matched the protein expression. These 10 proteins were similarly expressed in non-diseased breast reduction cells. Three NMPs (RPL7A, RPL11, RPL31) were significantly upregulated in DCIS and all other BC stages compared to the matching contralateral breast culture and an unrelated non-diseased breast reduction culture. RNA sequencing analyses showed that these three genes were upregulated increasingly with BC progression. Finally, we identified three NMPs (AHNAK, CDC37 and DNAJB1) that were significantly downregulated in DCIS and all other BC stages compared to the isogenically matched contralateral culture and the non-diseased breast reduction culture using both proteomics and RNA sequencing techniques."
1173,"CRM1 regulates androgen receptor stability and impacts DNA repair pathways in prostate cancer, independent of the androgen receptor","Rajendra Kumar, Janet Mendonca, Abhishek Shetty, Yuhan Yang, Olutosin Owoyemi, Lillian Wilson, Kavya Boyapati, Deven Topiwala, Naiju Thomas, Huong Nguyen, Jun Luo, Channing J. Paller, Samuel Denmeade, Michael A. Carducci, Sushant K. Kachhap",https://www.biorxiv.org/content/10.1101/2024.02.13.579966v1,"Among the known nuclear exportins, CRM1 is the most studied prototype. Dysregulation of CRM1 occurs in many cancers, hence, understanding the role of CRM1 in cancer can help in developing synergistic therapeutics. The study investigates how CRM1 affects prostate cancer growth and survival. It examines the role of CRM1 in regulating androgen receptor (AR) and DNA repair in prostate cancer. Our findings reveal that CRM1 influences AR mRNA and protein stability, leading to a loss of AR protein upon CRM1 inhibition. Furthermore, it highlights the involvement of HSP90 alpha, a known AR chaperone, in the CRM1-dependent regulation of AR protein stability. The combination of CRM1 inhibition with an HSP90 inhibitor demonstrates potent effects on decreasing prostate cancer cell growth and survival. The study further explores the influence of CRM1 on DNA repair proteins and proposes a strategy of combining CRM1 inhibitors with DNA repair pathway inhibitors to decrease prostate cancer growth. Overall, the findings suggest that CRM1 plays a crucial role in prostate cancer growth, and a combination of inhibitors targeting CRM1 and DNA repair pathways could be a promising therapeutic strategy."
1175,Aging and freezing of active nematic dynamics of cancer-associated fibroblasts by fibronectin matrix remodeling,"Cécile Jacques, Joseph Ackermann, Samuel Bell, Clément Hallopeau, Carlos Perez- Gonzalez, Lakshmi Balasubramaniam, Xavier Trepat, Benoît Ladoux, Ananyo Maitra, Raphael Voituriez, Danijela Matic Vignjevic",https://www.biorxiv.org/content/10.1101/2023.11.22.568216v1,"In the initial cancer stages, cancer-associated fibroblasts (CAFs) create a capsule around tumors. Exhibiting an elongated morphology, CAFs align with each other, closely resembling nematic ordering in liquid crystal physics. While these aligned CAFs may act as a defensive barrier hindering tumor expansion, inherent topological defects could represent weak spots, facilitating cancer cell dissemination. CAFs play a pivotal role in the genesis and remodeling of the extracellular matrix (ECM), with ECM proteins, especially fibronectin, reciprocally modulating CAF alignment and coherence. Yet, the intricate feedback loops between fibronectin deposition and CAF structuring remain largely unexplored. Here, we combined CAF live imaging, traction force microscopy, ECM microfabrication, and theoretical modeling to assess how the ECM influences the dynamics of nematically ordered CAFs. We found that CAFs dynamically orchestrate a fibronectin network that mirrors their nematic ordering. Over time, this passive nematic ordering of fibronectin, in turn, steers CAF rearrangement. Contrary to most cellular systems where defects remain dynamic at a steady state, our data highlights that the ECM/CAF interplay profoundly alters the behavior of both CAF and ECM nematics, leading to aging – massive slow down and even freezing of defect dynamics. This leads to a scenario where aligned areas and defects in CAFs layer are spatially and temporally fixed, yet active – exerting forces at the substate and transmitting forces between cells. Such a state could introduce localized vulnerabilities in the CAF layer, potentially promoting cancer cell spreading."
1176,Helicobacter pylori cancer associated CagA protein drives intestinal metaplastic transition in human gastric organoids,"Mar Reines, Meike Soerensen, Hilmar Berger, Mihir Patel, Philipp Schlärmann, Thomas F. Meyer",https://www.biorxiv.org/content/10.1101/2023.11.22.567682v1,"Gastric intestinal metaplasia (GIM) constitutes a pre-neoplastic stage in the development of stomach cancer. While strong evidence points to a role of infection with CagA positive Helicobacter pylori in the development of GIM, currently available experimental models have not provided mechanistic clues on this association. Here, we ectopically expressed the H. pylori CagA protein in human gastric organoids derived from normal, primary epithelial cells. Native CagA protein was produced and rapidly processed to yield a tyrosine-phosphorylated C-terminal fragment of ∼35 kDa. It led to an activation of the STAT3 pathway and aberrant elevation of CDX2 expression, a marker of intestinal type of cells, as well as other intestinal markers. Thus, CagA drives re-programming of gastric cells towards an intestinal-like phenotype, towards GIM. In summary, we describe a cooperative mechanism of CagA-induced STAT3 signaling and intestinal-like trans-differentiation, promoting a pre-neoplastic state. Our model provides mechanistic evidence for a direct role of CagA in driving premalignancy in gastric pathogenesis."
1178,Characterization of methylation status of the nuclear hormone receptor DAX-1 in human cancer,"Caroline P. Riedstra, Michael B. Heskett, Christina Tzagarakis-Foster",https://www.biorxiv.org/content/10.1101/2023.11.21.568180v1,"The orphan receptor DAX-1 plays an essential role in human development, steroid hormone synthesis and the maintenance of embryonic stem cell pluripotency. Recent studies have demonstrated DAX-1 is involved in cancer development, and, depending on the specific cancer type, has a negative or positive effect on cancer growth. In order to better understand the mechanism of DAX-1 gene regulation in various cancer cell lines, the epigenetic regulation of DAX-1 was investigated. Following confirming levels of DAX-1 expression at both the mRNA and protein levels, the overall methylation status of the DAX-1 gene was probed using methylation-sensitive restriction enzyme analysis. To determine the molecular mechanism of DNA methylation of the DAX-1 gene, chromatin immunoprecipitation assays identified key methylating proteins that localize to specific CpG islands in the DAX-1 promoter. In conclusion, this study demonstrates that methylation of key cytosine residues in CpG islands within the DAX-1 promoter play a central role in regulating DAX-1 expression and varying degrees of methylation result in differences in DAX-1 expression in human cancer cell lines."
1182,Accurate identification of structural variations from cancer samples,"Le Li, Chenyang Hong, Jie Xu, Claire Yik-Lok Chung, Alden King-Yung Leung, Delbert Almerick T. Boncan, Lixin Cheng, Kwok-Wai Lo, Paul B. S. Lai, John Wong, Jingying Zhou, Alfred Sze-Lok Cheng, Ting-Fung Chan, Feng Yue, Kevin Y. Yip",https://www.biorxiv.org/content/10.1101/2023.05.31.543104v1,"Structural variations (SVs) are commonly found in cancer genomes. They can cause gene amplification, deletion, and fusion, among other functional consequences. With an average read length of hundreds of kilobases, nano-channel-based optical DNA mapping is powerful in detecting large SVs. However, existing SV calling methods are not tailored for cancer samples, which have special properties such as mixed cell types and sub-clones. Here we propose the COMSV method that is specifically designed for cancer samples. It shows high sensitivity and specificity in benchmark comparisons. Applying to cancer cell lines and patient samples, COMSV identifies hundreds of novel SVs per sample."
1183,Phase-separating fusion proteins drive cancer by dysregulating transcription through ectopic condensates,"Nazanin Farahi, Tamas Lazar, Peter Tompa, Bálint Mészáros, Rita Pancsa",https://www.biorxiv.org/content/10.1101/2023.09.20.558425v2,"Numerous cellular processes rely on biomolecular condensates formed through liquid-liquid phase separation (LLPS), thus, perturbations of LLPS underlie various diseases. We found that proteins initiating LLPS are frequently implicated in somatic cancers, even surpassing their involvement in neurodegeneration. Cancer-associated LLPS scaffolds are connected to all cancer hallmarks and tend to be oncogenes with dominant genetic effects lacking therapeutic options. Since most of them act as oncogenic fusion proteins (OFPs), we undertook a systematic analysis of cancer driver OFPs by assessing their module-level molecular functions. We identified both known and novel combinations of molecular functions that are specific to OFPs and thus have a high potential for driving tumorigenesis. Protein regions driving condensate formation show an increased association with DNA- or chromatin-binding domains of transcription regulators within OFPs, indicating a common molecular mechanism underlying several soft tissue sarcomas and hematologic malignancies where phase-separation-prone OFPs form abnormal, ectopic condensates along the DNA, and thereby dysregulate gene expression programs."
1184,Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA Damage Response inhibitors,"Orsolya Papp, Viktória Jordán, Szabolcs Hetey, Róbert Balázs, Árpád Bartha, Nóra N. Ordasi, Sebestyén Kamp, Bálint Farkas, Jay Mettetal, Jonathan R. Dry, Duncan Young, Ben Sidders, Krishna C. Bulusu, Daniel V. Veres",https://www.biorxiv.org/content/10.1101/2023.11.20.567526v1,"Combination therapy is well established as a key intervention strategy for cancer treatment, with the potential to overcome monotherapy resistance and deliver a more durable efficacy. However, given the scale of unexplored potential target space and the resulting combinatorial explosion, identifying efficacious drug combinations is a critical unmet need that is still evolving. In this paper, we demonstrate a network biology-driven, simulation-based solution, the Simulated Cell. Integration of omics data with a curated signaling network enables the accurate and interpretable prediction of 66,348 combination-cell line pairs obtained from a large-scale combinatorial drug sensitivity screen of 684 combinations across 97 cancer cell lines (BAC= 0.62, AUC=0.7). We highlight drug combination pairs that interact with DNA Damage Response pathways and are predicted to be synergistic, and deep network insight to identify biomarkers driving combination synergy. We demonstrate that the cancer cell ‘avatars’ capture the biological complexity of their in vitro counterparts, enabling the identification of pathway-level mechanisms of combination benefit to guide clinical translatability."
1185,E-cadherin is a structuring component of invadopodia in pancreatic cancer,"Aurélie Dobric, Sébastien Germain, Françoise Silvy, Rénaté Bonier, Stéphane Audebert, Luc Camoin, Nelson Dusetti, Philippe Soubeyran, Juan Iovanna, Véronique Rigot, Frédéric André",https://www.biorxiv.org/content/10.1101/2020.10.09.332783v2,"Background The appearance of hybrid epithelial-mesenchymal (E/M) cells expressing E-cadherin is favourable for the establishment of pro-invasive function. However, the molecular mechanism and potential roles of E-cadherin in cancer cell invasion stay unexplored."
1188,Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy,"Ozen Leylek, Megan E. Honeywell, Michael J. Lee, Michael T. Hemann, Gulnihal Ozcan",https://www.biorxiv.org/content/10.1101/2023.10.07.561351v2,"The rational combination of anticancer agents is critical to improving patient outcomes in cancer. Nonetheless, most combination regimens in the clinic result from empirical methodologies disregarding insight into the mechanism of action and missing the opportunity to improve therapy outcomes incrementally. Deciphering the genetic dependencies and vulnerabilities responsible for synergistic interactions is crucial for rationally developing effective anticancer drug combinations. Hence, we screened pairwise pharmacological interactions between molecular-targeted agents and conventional chemotherapeutics and examined the genome-scale genetic dependencies in gastric adenocarcinoma cell models. Since this type of cancer is mainly chemoresistant and incurable, clinical situations demand effective combination strategies. Our pairwise combination screen revealed SN38/erlotinib as the drug pair with the most robust synergism. Genome-wide CRISPR screening and a shRNA-based signature assay indicated that the genetic dependency/vulnerability signature of SN38/erlotinib is the same as SN38 alone. Additional investigation revealed that the enhanced cell death with improved death kinetics caused by the SN38/erlotinib combination is surprisingly due to erlotinib’s off-target effect that inhibits ABCG2 but not its on-target effect on EGFR. Our results confirm that a genetic dependency signature different from the single-drug application may not be necessary for the synergistic interaction of molecular-targeted agents with conventional chemotherapeutics in gastric adenocarcinoma. The findings also demonstrated the efficacy of functional genomics approaches in unveiling biologically validated mechanisms of pharmacological interactions."
1189,MCAK Inhibitors Induce Aneuploidy in Triple Negative Breast Cancer Models,"John C. Smith, Stefan Husted, Jay Pilrose, Stephanie C. Ems-McClung, Jane R. Stout, Richard L. Carpenter, Claire E. Walczak",https://www.biorxiv.org/content/10.1101/2023.05.31.543118v1,"Standard of care for triple negative breast cancer (TNBC) involves the use of microtubule poisons like paclitaxel, which are proposed to work by inducing lethal levels of aneuploidy in tumor cells. While these drugs are initially effective in treating cancer, dose-limiting peripheral neuropathies are common. Unfortunately, patients often relapse with drug resistant tumors. Identifying agents against targets that limit aneuploidy may be a valuable approach for therapeutic development. One potential target is the microtubule depolymerizing kinesin, MCAK, which limits aneuploidy by regulating microtubule dynamics during mitosis. Using publicly available datasets, we found that MCAK is upregulated in triple negative breast cancer and is associated with poorer prognoses. Knockdown of MCAK in tumor-derived cell lines caused a two- to five-fold reduction in the IC50 for paclitaxel, without affecting normal cells. Using FRET and image-based assays, we screened compounds from the ChemBridge 50k library and discovered three putative MCAK inhibitors. These compounds reproduced the aneuploidy-inducing phenotype of MCAK loss, reduced clonogenic survival of TNBC cells regardless of taxane-resistance, and the most potent of the three, C4, sensitized TNBC cells to paclitaxel. Collectively, our work shows promise that MCAK may serve as both a biomarker of prognosis and as a therapeutic target."
1190,Combining evolution and protein language models for an interpretable cancer driver mutation prediction with D2Deep,"Konstantina Tzavella, Adrian Diaz, Catharina Olsen, Wim Vranken",https://www.biorxiv.org/content/10.1101/2023.11.17.567550v1,"Background The mutations driving cancer are being increasingly exposed through tumor-specific genomic data. However, differentiating between cancer-causing driver mutations and random passenger mutations remains challenging. State-of-the-art predictors contain built-in biases and are often ill-suited to the intricacies of cancer biology. Most of them fail to offer result interpretation, creating a barrier to their effective utilization in the clinical setting."
1193,FOXK2 amplification and overexpression promotes breast cancer development and chemoresistance,"Yang Yu, Wen-Ming Cao, Feng Cheng, Zhongcheng Shi, Lili Han, Jin-Ling Yi, Edaise M da Silva, Higinio Dopeso, Hui Chen, Jianhua Yang, Xiaosong Wang, Chunchao Zhang, Hong Zhang",https://www.biorxiv.org/content/10.1101/2023.05.28.542643v1,"Activation of oncogenes through DNA amplification/overexpression plays an important role in cancer initiation and progression. Chromosome 17 has many cancer-associated genetic anomalies. This cytogenetic anomaly is strongly associated with poor prognosis of breast cancer. FOXK2 gene is located on 17q25 and encodes a transcriptional factor with a forkhead DNA binding domain. By integrative analysis of public genomic datasets of breast cancers, we found that FOXK2 is frequently amplified and overexpressed in breast cancers. FOXK2 overexpression in breast cancer patients is associated with poor overall survival. FOXK2 knockdown significantly inhibits cell proliferation, invasion and metastasis, and anchorage-independent growth, as well as causes G0/G1 cell cycle arrest in breast cancer cells. Moreover, inhibition of FOXK2 expression sensitizes breast cancer cells to frontline anti-tumor chemotherapies. More importantly, co-overexpression of FOXK2 and PI3KCA with oncogenic mutations (E545K or H1047R) induces cellular transformation in non-tumorigenic MCF10A cells, suggesting that FOXK2 is an oncogene in breast cancer and is involved in PI3KCA-driven tumorigenesis. Our study identified CCNE2, PDK1, and Estrogen receptor alpha (ESR1) as direct transcriptional targets of FOXK2 in MCF-7 cells. Blocking CCNE2- and PDK1-mediated signaling by using small molecule inhibitors has synergistic anti-tumor effects in breast cancer cells. Furthermore, FOXK2 inhibition by gene knockdown or inhibitors for its transcriptional targets (CCNE2 and PDK1) in combination with PI3KCA inhibitor, Alpelisib, showed synergistic anti-tumor effects on breast cancer cells with PI3KCA oncogenic mutations. In summary, we provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis and targeting FOXK2-mediated pathways may be a potential therapeutic strategy in breast cancer."
1194,YAP localization mediates mechanical adaptation of human cancer cells during extravasation in vivo,"Woong Young So, Claudia S. Wong, Udochi F. Azubuike, Colin D. Paul, Paniz Rezvan Sangsari, Patricia B. Gordon, Hyeyeon Gong, Tapan K. Maity, Perry Lim, Zhilin Yang, Christian A. Haryanto, Eric Batchelor, Lisa M. Jenkins, Nicole Y. Morgan, Kandice Tanner",https://www.biorxiv.org/content/10.1101/2023.11.14.567015v1,"Biophysical profiling of primary tumors has revealed that individual tumor cells fall along a highly heterogeneous continuum of mechanical phenotypes. One idea is that a subset of tumor cells is “softer” to facilitate detachment and escape from the primary site, a step required to initiate metastasis. However, it has also been postulated that cells must be able to deform and generate sufficient force to exit into distant sites. Here, we aimed to dissect the mechanical changes that occur during extravasation and organ colonization. Using multiplexed methods of intravital microscopy and optical tweezer based active microrheology, we obtained longitudinal images and mechanical profiles of cells during organ colonization in vivo. We determined that cells were softer, more liquid like upon exit of the vasculature but stiffened and became more solid like once in the new organ microenvironment. We also determined that a YAP mediated mechanogenotype influenced the global dissemination in our in vivo and in vitro models and that reducing mechanical heterogeneity could reduce extravasation. Moreover, our high throughput analysis of mechanical phenotypes of patient samples revealed that this mechanics was in part regulated by the external hydrodynamic forces that the cancer cells experienced within capillary mimetics. Our findings indicate that disseminated cancer cells can keep mutating with a continuum landscape of mechano-phenotypes, governed by the YAP-mediated mechanosensing of hydrodynamic flow."
1196,SANTA FE OXA: Self-assembled oxaliplatin nanomicelle for enhanced cascade cancer chemotherapy via self-sensitized ferroptosis,"Jianbin Shi, Wenjing Ma, Shunzhe Zheng, Fengli Xia, Xinying Liu, Ayumi Kikkawa, Kaho Tanaka, Ken-ichiro Kamei, Chutong Tian",https://www.biorxiv.org/content/10.1101/2023.11.13.566938v1,"The clinical utility of chemotherapy is often compromised by its limited efficacy and significant side effects. Addressing these concerns, we develop a self-assembled nanomicelle, namely SANTA FE OXA, which is composed of hyaluronic acid (HA) conjugated with ferrocene methanol (FC-OH), oxaliplatin prodrug (OXA(□)) and glycol-coupled linoleic acid (EG-LA). Targeted delivery is achieved as HA binds to the CD44 receptors that are overexpressed on tumor cells, facilitating drug uptake. Once internalized, hyaluronidase (HAase) catalyzes the digestions of the SANTA FE OXA, releasing FC and reducing OXA(□) into an active form. Active OXA induces DNA damage, while simultaneously promoting intracellular hydrogen peroxide levels via cascade reactions. In parallel, FC disrupts the redox balance within tumor cells, inducing ferroptosis. The synergistic combination of cascade chemotherapy and self-sensitized ferroptosis therapy has demonstrated remarkable anti-cancer efficacy in both in vitro and in vivo models. Moreover, this SANTA FE OXA significantly mitigates the systemic toxicity commonly associated with platinum-based chemotherapeutics. Our findings suggest a compelling advancement in nanomedicine for enhanced cascade cancer therapy."
1198,Gait speed is a biomarker of cancer-associated cachexia decline and recovery,"Ishan Roy, Ben Binder-Markey, Danielle Sychowski, Amber Willbanks, Tenisha Phipps, Donna McAllister, Akash Bhakta, Emily Marquez, Dominic D’Andrea, Colin Franz, Rajeswari Pichika, Michael B. Dwinell, Prakash Jayabalan, Richard L. Lieber",https://www.biorxiv.org/content/10.1101/2023.11.13.566852v1,"Background Progressive functional decline is a key element of cancer-associated cachexia. No therapies have successfully translated to the clinic due to an inability to measure and improve physical function in cachectic patients. Major barriers to translating pre-clinical therapies to the clinic include lack of cancer models that accurately mimic functional decline and use of non-specific outcome measures of function, like grip strength. New approaches are needed to investigate cachexia-related function at both the basic and clinical science levels."
1200,"Network pharmacology, single gene survival analysis and molecular docking to study the mechanism of Sotetsuflavone in the treatment of pancreatic cancer","Zi-Yong Chu, Xue-Jiao Zi",https://www.biorxiv.org/content/10.1101/2024.04.30.580419v1,"Pancreatic cancer is a highly lethal cancer with limited treatment options. The number of pancreatic cancer patients is increasing rapidly worldwide. Many natural products have been shown to have anticancer activity in a range of studies. Sotetsuflavone is derived from Cycas revoluta Thunb. and exhibits anticancer activity. The present study incorporates network pharmacology, single gene survival analysis, gene expression analysis and molecular docking to reveal the mechanism of Sotetsuflavone in the treatment of pancreatic cancer. Initially, it was evaluated through multiple databases for a comprehensive pharmacological evaluation of Sotetsuflavone. Then, the target information of Sotetsuflavone and pancreatic cancer was searched and screened using public databases. According to the results of matching the potential targets of Sotetsuflavone with the targets of pancreatic cancer, the protein-protein interaction (PPI) network was constructed by using the STRING database and imported into Cytoscape 3.9.0 for the network analysis to screen the hub targets, and then classify and co-expression analysis was carried out on the hub targets. Then, we conducted Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential and hub targets and discovered that these targets were involved in pancreatic cancer-related signalling pathways. In addition, the GEPIA 2 platform was used to be performed for single gene survival analysis and gene expression analysis, and AutoDock Vina was employed for molecular docking analysis. In total, we have acquired 31 hub targets for the treatment of pancreatic cancer by Sotetsuflavone, namely ABCB1, AURKA, CDK1, and so on. Kaplan-Meier survival analyses demonstrated that ABCB1, AURKA, CDK1, HDAC6, MET, and MMP3 are promising hub targets that can be used as biomarkers for pancreatic cancer diagnosis and prognosis. These hub targets are highly expressed in pancreatic cancer tissues compared to normal tissues. The molecular docking results showed a strong binding capacity of Sotetsuflavone to these hub targets. In summary, it is proposed that Sotetsuflavone is a new anticancer drug, which can regulate cancer-related signalling pathways such as pancreatic cancer by inhibiting the activities of ABCB1, AURKA, CDK1, HDAC6, MET, and MMP3, which are hub targets with up-regulated expression in pancreatic cancer tissues, in order to treat pancreatic cancer. However, it also requires a series of in vivo and in vitro studies to ensure its safety and efficacy."
1202,Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer,"Ziyi Zhao, Jiandong Wang, Weimin Kong, Ziwei Fang, Michael Coleman, Ginger Milne, Wesley C. Burkett, Meredith A. Newton, Douglas Lee, Beor Deng, Xiaochang Shen, Hongyan Suo, Wenchuan Sun, Stephen Hursting, Chunxiao Zhou, Victoria L Bae-Jump",https://www.biorxiv.org/content/10.1101/2024.02.02.578679v1,"Objective Overweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential abilities of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC."
1203,Combinatorial in silico approach for cancer-associated 4Fe-4S protein discovery,"Winnie W. L. Tam, Michael H. W. Cheng, Xiaoyong Mo, Bei-Bei He, Ulrike F. M. Ngo, Nicholas M. H. Yuen, Angela Y. L. Yau, Nicholas C. Wu, Edmund C. M. Tse",https://www.biorxiv.org/content/10.1101/2023.11.08.566327v1,"Iron-sulfur (Fe-S) proteins play vital roles in multiple cellular processes, including mediating redox balance as well as DNA replication and repair. Given the role of Fe-S cofactors in genome maintenance, mutations in such metalloproteins could be associated with cancer. Nevertheless, only a few cancer-associated Fe-S proteins have been identified. In vitro, Fe-S cluster is susceptible to degradation in oxic environment. It could also be replaced by other metal ions during protein purification, mis-labelled as zinc finger or Zn-containing proteins. In silico, bioinorganic Fe-S cluster lacks unique sequence characteristics that distinguish itself from other metal-coordination sites, making motif prediction based solely on protein sequence difficult. Thus, in this study, three traits have been employed to discover putative cancer-associated 4Fe-4S proteins. Here, we have analyzed the human proteome via a three-pronged approach: (i) the presence of a triamino acid motif, (ii) the geometric arrangements of the cysteines, and (iii) the mutations of cancer-associated cysteines. In addition to MUTYH, a known 4Fe-4S human DNA glycosylase, 21 novel proteins were discovered as potential cancer-associated 4Fe-4S proteins. While 6 receptor proteins and 3 growth factors have been identified as potential targets in this study, 5 histone lysine methyltransferases with SET domains were also predicted to contain 4Fe-4S metallocofactors. This work provides insights for rational adjustments in experimental design and novel cancer biomarker discovery."
1204,Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells,"Daniel Maxim Iascone, Xue Zhang, Patricia Bafford, Clementina Mesaros, Yogev Sela, Samuel Hofbauer, Shirley L. Zhang, Kieona Cook, Pavel Pivarshev, Ben Z. Stanger, Stewart Anderson, Chi V. Dang, Amita Sehgal",https://www.biorxiv.org/content/10.1101/2023.11.08.566310v1,"Crosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in an in vitro mouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells."
1205,A pancreatic cancer mouse model with human immunity,"Norio Miyamura, Kodai Suzuki, Richard A. Friedman, Aristidis Floratos, Yuki Kunisada, Kazuya Masuda, Andrew M. Lowy, Moriya Tsuji, Kazuki N. Sugahara",https://www.biorxiv.org/content/10.1101/2023.05.24.542127v1,"Pancreatic ductal adenocarcinoma (PDAC) is characterized by a tumor immune microenvironment (TIME) that promotes resistance to immunotherapy. A preclinical model system that facilitates studies of the TIME and its impact on the responsiveness of human PDAC to immunotherapies remains an unmet need. We report a novel mouse model, which develops metastatic human PDAC that becomes infiltrated by human immune cells recapitulating the TIME of human PDAC. The model may serve as a versatile platform to study the nature of human PDAC TIME and its response to various treatments."
1206,Cholesterol Metabolite 27-Hydroxycholesterol Enhances the Secretion of Cancer Promoting Extracellular Vesicles by a Mitochondrial ROS-Induced Impairment of Lysosomal Function,"Anasuya Das Gupta, Jaena Park, Janet E. Sorrells, Hannah Kim, Natalia Krawczynska, Hashni Epa Vidana Gamage, Adam T. Nelczyk, Stephen A. Boppart, Marni D. Boppart, Erik R. Nelson",https://www.biorxiv.org/content/10.1101/2024.05.01.591500v1,"Extracellular vesicles (EVs) serve as crucial mediators of cell-to-cell communication in normal physiology as well as in diseased states, and have been largely studied in regard to their role in cancer progression. However, the mechanisms by which their biogenesis and secretion are regulated by metabolic or endocrine factors remain unknown. Here, we delineate a mechanism by which EV secretion is regulated by a cholesterol metabolite, 27-Hydroxycholesterol (27HC), where treatment of myeloid immune cells (RAW 264.7 and J774A.1) with 27HC impairs lysosomal homeostasis, leading to shunting of multivesicular bodies (MVBs) away from lysosomal degradation, towards secretion as EVs. This impairment of lysosomal function is caused by mitochondrial dysfunction and subsequent increase in reactive oxygen species (ROS). Interestingly, cotreatment with a mitochondria-targeted antioxidant rescued the lysosomal impairment and attenuated the 27HC-mediated increase in EV secretion. Overall, our findings establish how a cholesterol metabolite regulates EV secretion and paves the way for the development of strategies to regulate cancer progression by controlling EV secretion."
1207,Discovery of medicinal herbal compounds with potential anti-cancer activities against microtubule affinity-regulating kinase (MARK4) in cancer therapy,"Nayana Narayanan, K.C Sivakumar",https://www.biorxiv.org/content/10.1101/2023.05.30.542909v2,"MARK4 belongs to the serine/threonine family and is found to be involved in apoptosis and many other regulatory pathways. Therefore, MARK4 is considered a potential target for cancer therapy. HTVS and XP of LOTUS and NPACT revealed that Ligand 11 and Ligand 7 respectively show good binding affinity along with ADME properties towards MARK 4. Further MD simulations for 50 ns suggested that the binding mechanism of Ligand 11 and 7 stabilizes the MARK4 by forming a stable complex. Both the ligands were bound to the active site of MARK4. This work provides a new insight into the use of Ligand 7 and Ligand 11, which were obtained from herbal extracts belonging to the class of Flavonoids and Megastigmanes, respectively, showing anticancer activities. The MD simulation studies suggest that Ligand 11 and Ligand 7 can be considered as potential inhibitors to MARK 4. Overall, this study provides an experimental evaluation of the herbal compounds identified during the study against MARK 4-associated cancers"
1208,Age-related phenotypes in breast cancer: a population-based study,"Amalie A. Svanøe, Rasmus O.C. Humlevik, Gøril Knutsvik, Anna K.M. Sæle, Cecilie Askeland, Lise M. Ingebriktsen, Ulrikke Hugaas, Amalie B. Kvamme, Amalie F. Tegnander, Kristi Krüger, Benedicte Davidsen, Erling A. Hoivik, Turid Aas, Ingunn M. Stefansson, Lars A. Akslen, Elisabeth Wik",https://www.biorxiv.org/content/10.1101/2023.05.22.541427v1,"Breast cancer in young (<40 years) is associated with a higher frequency of aggressive tumor types and poor prognosis. It remains unclear if there is an underlying age-related biology that contributes to the unfavorable outcome. We aim to investigate the relationship between age and breast cancer biology, with emphasis on proliferation. Clinico-pathologic information, immunohistochemical markers, and follow-up data were obtained for all patients aged <50 (Bergen cohort-1; n=355) and compared to previously obtained information on patients aged 50-69 (Bergen cohort-2; n=540), who participated in the Norwegian Breast Cancer Screening Program. Data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) was applied for validation and for analyses of gene expression signatures. Young breast cancer patients presented more aggressive tumor features such as hormone receptor negativity, HER2 positivity, lymph-node metastasis, the HER2-enriched and triple negative subtypes, and shorter survival. Age <40 was significantly associated with features of stemness and higher proliferation (by Ki67), also in molecular subsets. Ki67 showed weaker prognostic value in young patients. We point to aggressive phenotypes, increased tumor cell proliferation and stem-like features in breast cancer of the young. Hence, tumors of young breast cancer patients may have a unique biology, also when accounting for screen/interval differences, that may open for new clinical opportunities, stratifying treatment by age."
1209,2D and 3D multiplexed subcellular profiling of nuclear instability in human cancer,"Shannon Coy, Brian Cheng, Jong Suk Lee, Rumana Rashid, Lindsay Browning, Yilin Xu, Sankha S. Chakrabarty, Clarence Yapp, Sabrina Chan, Juliann B. Tefft, Emily Scott, Alexander Spektor, Keith L. Ligon, Gregory J. Baker, David Pellman, Peter K. Sorger, Sandro Santagata",https://www.biorxiv.org/content/10.1101/2023.11.07.566063v1,"Nuclear atypia, including altered nuclear size, contour, and chromatin organization, is ubiquitous in cancer cells. Atypical primary nuclei and micronuclei can rupture during interphase; however, the frequency, causes, and consequences of nuclear rupture are unknown in most cancers. We demonstrate that nuclear envelope rupture is surprisingly common in many human cancers, particularly glioblastoma. Using highly-multiplexed 2D and super-resolution 3D-imaging of glioblastoma tissues and patient-derived xenografts and cells, we link primary nuclear rupture with reduced lamin A/C and micronuclear rupture with reduced lamin B1. Moreover, ruptured glioblastoma cells activate cGAS-STING-signaling involved in innate immunity. We observe that local patterning of cell states influences tumor spatial organization and is linked to both lamin expression and rupture frequency, with neural-progenitor-cell-like states exhibiting the lowest lamin A/C levels and greatest susceptibility to primary nuclear rupture. Our study reveals that nuclear instability is a core feature of cancer, and links nuclear integrity, cell state, and immune signaling."
1210,High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue,"Ning Zhang, Luuk Harbers, Michele Simonetti, Constantin Diekmann, Quentin Verron, Enrico Berrino, Sara E. Bellomo, Gabriel M.C. Longo, Michael Ratz, Niklas Schultz, Firas Tarish, Peng Su, Bo Han, Wanzhong Wang, Sofia Onorato, Silvia Giordano, Qifeng Yang, Anna Sapino, Jonas Frisén, Kanar Alkass, Henrik Druid, Vassilis Roukos, Thomas Helleday, Caterina Marchiò, Magda Bienko, Nicola Crosetto",https://www.biorxiv.org/content/10.1101/2023.11.07.566123v1,"Somatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their surrounding normal tissues are poorly characterized. Here, we performed multi-region, single-cell DNA sequencing to characterize the SCNA landscape across multiple tumor-rich and normal tissue regions (∼125 mm3 tissue cubes) obtained from prostatectomy performed in two patients with localized prostate cancer. We identified two distinct populations of cells with abnormal karyotypes, one marked by sparse deletions or amplifications (‘pseudo-diploid’ cells) and the second characterized by genome-wide copy number changes reminiscent of ‘monster’ cells previously described in colorectal cancer. Pseudo-diploid cells formed numerous small-sized subclones ranging from highly spatially localized to broadly spread subclones mainly featuring (sub-)chromosomal arm deletions. In contrast, monster cells harbored whole-chromosome gains and losses and were mostly singular events detected throughout the prostate, including normal tissue regions. Targeted deep sequencing of cancer-associated genes revealed a more confined pattern of mutations overlapping with tumor-rich regions, although we also detected mutations in regions deemed normal based on morphological assessment and bulk RNA-seq. Highly localized pseudo-diploid subclones were confined within tumor-rich regions and typically carried deletions involving chromosome (chr) 6 and 13, resulting in simultaneous loss of multiple tumor-suppressor genes, including FOXO1 and FOXO3 encoding two transcription factors belonging to the Forkhead family previously implicated in prostate carcinogenesis. Tumor-rich regions also contained mutations in genes frequently mutated in prostate cancer, including FOXA1, LRP1B, SPOP, and SPTA1. Our study reveals that SCNAs are widespread in both normal and tumor regions across the prostate gland of patients with localized prostate cancer and suggests that a subset of pseudo-diploid cells harboring chromosomal deletions that result in the loss of specific tumor-suppressor genes drive tumorigenesis in the aging prostate."
1211,Adipose-derived exosomal miR-421 targets CBX7 and promotes metastatic potential in ovarian cancer cells,"Yi Zhang, Roslyn Tedja, Michael Millman, Terrence Wong, Alexandra Fox, Hussein Chehade, Meyer Gershater, Nicholas Adzibolosu, Radhika Gogoi, Matthew Anderson, Thomas Rutherford, Zhenggang Zhang, Michael Chopp, Gil Mor, Ayesha B. Alvero",https://www.biorxiv.org/content/10.1101/2023.11.07.566022v1,"Background Chromobox protein homolog 7 (CBX7), a member of the Polycomb repressor complex, is a potent epigenetic regulator and gene silencer. Our group has previously reported that CBX7 functions as a tumor suppressor in ovarian cancer cells and its loss accelerated formation of carcinomatosis and drove tumor progression in an ovarian cancer mouse model. The goal of this study is to identify specific signaling pathways in the ovarian tumor microenvironment that down-regulate CBX7. Given that adipocytes are an integral component of the peritoneal cavity and the ovarian tumor microenvironment, we hypothesize that the adipose microenvironment is an important regulator of CBX7 expression."
1212,Chemoresistance to additive PARP/PI3K dual inhibition in triple-negative breast cancer cell lines is associated with adaptive stem cell-like prevalence,"Paula E. Petrella, Jason W. Chen, Gabrielle O. Ravelo, Benjamin D. Cosgrove",https://www.biorxiv.org/content/10.1101/2024.04.28.591568v1,"Cancer stem-like cells (CSCs) are posited to exhibit specialized oncogenic capacity to drive malignancies. CSCs are distinguished by enhanced hallmarks of cancer, including apoptosis avoidance, phenotypic plasticity and aberrant growth pathway signaling. Standard-of-care chemotherapies targeted to rapidly cycling cells routinely fail to eliminate this resistant subpopulation, leading to disease recurrence and metastasis. Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, is enriched for tumor-propagating CD44+/CD24−/low CSCs, which are poorly ablated by chemotherapeutics and are associated with poor prognosis. CD44 governs sustained PI3K signaling in breast cancer, which is essential for CSC maintenance. PI3K inhibition can elicit DNA damage and down-regulate BRCA1 expression, which in turn enhance the synthetic lethality of PARP inhibitors. Here, we examined a dual chemotherapeutic approach targeting these pathways by combining a pan-PI3K inhibitor (Buparlisib) and a PARP1 inhibitor (Olaparib) on a panel of TNBC cell lines with distinct mutational profiles and proportions of CSCs. We observed differential sensitivity to this dual inhibition strategy and varying cellular stress and resistance responses across eight TNBC lines. The dual chemotherapeutic effect is associated with a reduction in S-phase cells, an increased in apoptotic cells and elevated expression of cleaved PARP, indicating a provoked replicative stress response. We observed that PARP/PI3K inhibition efficacy was potentiated by repeated administration in some TNBC lines and identified critical treatment schedules, which further potentiated the dual chemotherapeutic effect. Dual inhibition induced small but significant increases in CSC relative abundance as marked by CD44+/CD24−/low or ALDH1+ cells and increased stress and survival signaling in multiple TNBC cell lines, suggesting this sub-population contributes to TNBC chemoresistance. These results suggest the additive effects of PARP and PI3K inhibition against CSC phenotypes may be enhanced by temporally-staged administration in TNBC cells."
1214,Transcriptional signals of dedifferentiation in human cancer,"Gerda Kildisiute, Maria Kalyva, Rasa Elmentaite, Stijn van Dongen, Christine Thevanesan, Alice Piapi, Kirsty Ambridge, Elena Prigmore, Muzlifah Haniffa, Sarah A. Teichmann, Karin Straathof, Isidro Cortés-Ciriano, Sam Behjati, Matthew D. Young",https://www.biorxiv.org/content/10.1101/2022.11.28.518191v1,"As normal cells transform into cancers, their cell state changes (or “dedifferentiates”), which may drive cancer cells into a stem-like or more primordial, foetal or embryonic cell state. Here, we used single cell atlases to study dedifferentiation in transcriptional terms across a wide spectrum of adult and childhood cancers. At the level of the whole transcriptome, we find that adult cancers rarely return to an embryonic state, but rather that a foetal state is a near-universal feature of childhood cancers. We extend these bulk transcriptomic findings to a single cell resolution analysis of colorectal and liver cancers, confirming the lack of reversion to a primordial state in adult tumours and the retention of foetal signals in childhood cancers. Our findings provide a nuanced picture of dedifferentiation in these two groups of neoplasms, indicating cancer-specific rather than universal patterns of dedifferentiation pervade adult epithelial cancers."
1215,"Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer","Luis Aparicio, Laura Crowley, John R. Christin, Caroline J. Laplaca, Hanina Hibshoosh, Raul Rabadan, Michael M. Shen",https://www.biorxiv.org/content/10.1101/2024.01.30.578066v1,"Recent advances in single-cell RNA-sequencing (scRNA-seq) technology have facilitated studies of cell states and plasticity in tissue maintenance and cancer, including in the prostate. Here we present meta-analyses of multiple new and published scRNA-seq datasets to establish reference cell type classifications for the normal mouse and human prostate. Our analyses demonstrate transcriptomic similarities between epithelial cell states in the normal prostate, in the regressed prostate after androgen-deprivation, and in primary prostate tumors. During regression in the mouse prostate, all epithelial cells shift their expression profiles towards a proximal periurethral (PrU) state, demonstrating an androgen-dependent plasticity that is restored to normal during androgen restoration and regeneration. In the human prostate, we find progressive rewiring of transcriptional programs across epithelial cell types in benign prostate hyperplasia and treatment-naïve prostate cancer. Notably, we detect copy number variants predominantly within Luminal Acinar cells in prostate tumors, suggesting a bias in their cell type of origin, as well as a larger field of transcriptomic alterations in non-tumor cells. Finally, we observe that Luminal Acinar tumor cells in treatment-naïve prostate cancer display heterogeneous androgen receptor (AR) signaling activity, including a split between high-AR and low-AR profiles with similarity to PrU-like states. Taken together, our analyses of cellular heterogeneity and plasticity provide important translational insights into the origin and treatment response of prostate cancer."
1216,Simple droplet microfluidics platform for drug screening on cancer spheroids,"Caroline Parent, Kiran Raj Melayil, Ya Zhou, Vivian Aubert, Didier Surdez, Olivier Delattre, Claire Wilhelm, Jean-Louis Viovy",https://www.biorxiv.org/content/10.1101/2023.05.16.540960v1,"3D in vitro biological systems are progressively replacing 2D systems to increase the physiological relevance of cellular studies. Microfluidics-based approaches can be powerful tools towards such biomimetic systems, but often require high-end complicated and expensive processes and equipments for microfabrication. Herein, a drug screening platform is proposed, minimizing technicality and manufacturing steps. It provides an alternate way of spheroid generation in droplets in tubes. Droplets microfluidics then elicit multiple droplets merging events at programmable times, to submit sequentially the spheroids to chemotherapy and to reagents for cytotoxicity screening. After a comprehensive study of tumorigenesis within the droplets, the system is validated for drug screening (IC50) with chemotherapies in cancer cell lines as well as cells from patient-derived-xenografts (PDX). As compared to microtiter plates methods, our sytem reduces the initial amout of cell up to 10 times and opens new avenues towards primary tumors drug screening approaches."
1217,The circulating immune cell landscape stratifies metastatic burden in breast cancer patients,"S Mangiola, R Brown, J Berthelet, S Guleria, C Liyanage, S Ostrouska, J Wilcox, M Merdas, PF Larsen, C Bell, J Schroder, L Mielke, J Mariadason, S Chang-Hao Tsao, Y Chen, VK Yadav, RL Anderson, S Vodala, D Merino, A Behren, B Yeo, AT Papenfuss, B Pal",https://www.biorxiv.org/content/10.1101/2023.11.01.565223v1,"Advanced breast cancers show varying degrees of metastasis; however, reliable biomarkers of metastatic disease progression remain unknown. In circulation, immune cells are the first line of defence against tumour cells. Herein, using >109,591 peripheral blood mononuclear cells from healthy individuals and breast cancer patients, we tested whether molecular traits of the circulating immune cells, probed with single-cell transcriptomics, can be used to segregate metastatic profiles. Our analyses revealed significant compositional and transcriptional differences in PBMCs of patients with restricted or high metastatic burden versus healthy subjects. The abundance of T cell and monocyte subtypes segregated cancer patients from healthy individuals, while memory and unconventional T cells were enriched in low metastatic burden disease. The cell communication axes were also found to be tightly associated with the extent of metastatic burden. Additionally, we identified a PBMC-derived metastatic gene signature capable of discerning metastatic condition from a healthy state. Our study provides unique molecular insights into the peripheral immune system operating in metastatic breast cancer, revealing potential new biomarkers of the extent of the metastatic state. Tracking such immune traits associated with metastatic spread could complement existing diagnostic tools."
1220,FET fusion oncoproteins disrupt physiologic DNA repair networks in cancer,"Shruti Menon, Marcus R. Breese, Yone Phar Lin, Hannah Allegakoen, Shruthi Perati, Ann Heslin, Max A. Horlbeck, Jonathan Weissman, E. Alejandro Sweet-Cordero, Trever G. Bivona, Asmin Tulpule",https://www.biorxiv.org/content/10.1101/2023.04.30.538578v2,"While oncogenes promote cancer cell growth, unrestrained proliferation represents a significant stressor to cellular homeostasis networks such as the DNA damage response (DDR). To enable oncogene tolerance, many cancers disable tumor suppressive DDR signaling through genetic loss of DDR pathways and downstream effectors (e.g., ATM or p53 tumor suppressor mutations). Whether and how oncogenes can help “self-tolerize” by creating analogous functional deficiencies in physiologic DDR networks is not known. Here we focus on Ewing sarcoma, a FET fusion oncoprotein (EWS-FLI1) driven pediatric bone tumor, as a model for the class of FET rearranged cancers. Native FET protein family members are among the earliest factors recruited to DNA double-strand breaks (DSBs) during the DDR, though the function of both native FET proteins and FET fusion oncoproteins in DNA repair remains to be defined. Using preclinical mechanistic studies of the DDR and clinical genomic datasets from patient tumors, we discover that the EWS-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native FET (EWS) protein function in activating the DNA damage sensor ATM. As a consequence of FET fusion-mediated interference with the DDR, we establish functional ATM deficiency as the principal DNA repair defect in Ewing sarcoma and the compensatory ATR signaling axis as a collateral dependency and therapeutic target in multiple FET rearranged cancers. More generally, we find that aberrant recruitment of a fusion oncoprotein to sites of DNA damage can disrupt physiologic DSB repair, revealing a mechanism for how growth-promoting oncogenes can also create a functional deficiency within tumor suppressive DDR networks."
1221,Ascites in malignant ovarian cancer confer ovarian cancer cells chemoresistance to platinum. Combination treatment with crizotinib and 2-hydroxyestradiol restores platinum sensitivity,"Yifat Koren Carmi, Abed Agbarya, Hazem Khamaisi, Raymond Farah, Yelena Shechtman, Roman Korobochka, Jacob Gopas, Jamal Mahajna",https://www.biorxiv.org/content/10.1101/2023.09.24.559160v1,"Ovarian cancer (OC), the second most common form of gynecologic malignancy, has a poor prognosis and is often discovered in the late stages. Platinum-based chemotherapy is the first line of therapy. Nevertheless, treatment OC has proven challenging due to toxicity and the development of acquired resistance to therapy. Tumor microenvironment (TME) has been associated with platinum chemoresistance."
1222,Evaluation of homologous recombination repair status in metastatic prostate cancer by next-generation sequencing and functional tissue-based immunofluorescence assays,"Sara Arce-Gallego, Pablo Cresta Morgado, Luisa Delgado-Serrano, Sara Simonetti, Macarena Gonzalez, David Marmolejo, Rafael Morales-Barrera, Gisela Mir, Maria Eugenia Semidey, Paula Romero Lozano, Sarai Cordoba-Terreros, Richard Mast, Matias de Albert, Jacques Planas, Mercè Cuadras, Xavier Maldonado, Cristina Suarez, Irene Casanova-Salas, Lara Nonell, Rodrigo Dienstmann, Paolo Nuciforo, Ana Vivancos, Alba Llop-Guevara, Joan Carles, Violeta Serra, Joaquin Mateo",https://www.biorxiv.org/content/10.1101/2024.01.28.577367v1,"Purpose Metastatic prostate cancer (mPC) is enriched for homologous recombination repair (HRR) gene alterations; these biomarkers have prognostic and predictive value. Next-generation sequencing (NGS) allows for patient stratification based on these biomarkers, but widespread clinical implementation is still limited. Moreover, not all mutations in HRR genes result in functional HRR loss in the tumor. We investigated the correlation between genomic and functional loss of HRR, using NGS and an optimized RAD51 immunofluorescence (RAD51-IF) assay in mPC clinical biopsies."
1223,Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer,"Ozge Saatci, Rashed Alam, Kim-Tuyen Huynh-Dam, Aynur Isik, Meral Uner, Nevin Belder, Pelin Gulizar Ersan, Metin Cetin, Unal Metin Tokat, Mustafa Emre Gedik, Hilal Bal, Ozlem Sener Sahin, Yasser Riazalhosseini, Denis Thieffry, Daniel Gautheret, Besim Ogretmen, Sercan Aksoy, Aysegul Uner, Aytekin Akyol, Ozgur Sahin",https://www.biorxiv.org/content/10.1101/2023.11.05.565697v1,"Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER+) breast cancer, constituting around 75% of all cases. However, emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance via blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of cAMP/PKA/CREB axis and increased expression of TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels. These ultimately induce lipid peroxidation and ferroptotic cell death in combination with tamoxifen. Overexpressing PDE4D rescues LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of ferroptosis induction and tamoxifen sensitization, thereby revealing LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer."
1224,Genomic structures and regulation patterns at HPV integration sites in cervical cancer,"Vanessa L. Porter, Kieran O’Neill, Signe MacLennan, Richard D. Corbett, Michelle Ng, Luka Culibrk, Zeid Hamadeh, Marissa Iden, Rachel Schmidt, Shirng-Wern Tsaih, Glenn Chang, Jeremy Fan, Ka Ming Nip, Vahid Akbari, Simon K. Chan, James Hopkins, Richard A. Moore, Eric Chuah, Karen L. Mungall, Andrew J. Mungall, Inanc Birol, Steven J. M. Jones, Janet S. Rader, Marco A. Marra",https://www.biorxiv.org/content/10.1101/2023.11.04.564800v1,"Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer."
1225,Dual targeting of MAPK and PI3K pathways unlocks redifferentiation of Braf-mutated thyroid cancer organoids,"Hélène Lasolle, Andrea Schiavo, Adrien Tourneur, Pierre Gillotay, Bárbara de Faria da Fonseca, Lucieli Ceolin, Olivier Monestier, Benilda Aganahi, Laura Chomette, Marina Malta Letro Kizys, Lieven Haenebalcke, Tim Pieters, Steven Goossens, Jody Haigh, Vincent Detours, Ana Luiza Silva Maia, Sabine Costagliola, Mírian Romitti",https://www.biorxiv.org/content/10.1101/2023.03.30.534915v4,"Thyroid cancer is the most common endocrine malignancy and several genetic events have been described to promote the development of thyroid carcinogenesis. Besides the effects of specific mutations on thyroid cancer development, the molecular mechanisms controlling tumorigenesis, tumor behavior, and drug resistance are still largely unknown. Cancer organoids have been proposed as a powerful tool to study aspects related to tumor development and progression and appear promising to test individual responses to therapies. Here, using mESC-derived thyroid organoids, we developed a BrafV637E- inducible model able to recapitulate the features of papillary thyroid cancer in vitro. Overexpression of the murine BrafV637E mutation, equivalent to BrafV600E in humans, rapidly triggers to MAPK activation, cell dedifferentiation, and disruption of follicular organization. BrafV637E-expressing organoids show a transcriptomic signature for p53, focal adhesion, ECM-receptor interactions, EMT, and inflammatory signaling pathways. Finally, PTC-like thyroid organoids were used for drug screening assays. The combination of MAPK and PI3K inhibitors reversed BrafV637E oncogene-promoted cell dedifferentiation while restoring thyroid follicle organization and function in vitro. Our results demonstrate that pluripotent stem cells-derived thyroid cancer organoids can mimic tumor development and features while providing an efficient tool for testing novel targeted therapies."
1226,The roles of DDR2 and substrate stiffness on cancer cell transcriptome and proliferation,"Theadora Vessella, Steven Xiang, Cong Xiao, Madelyn Stilwell, Jason Shohet, Esteban Rozen, Susan Zhou, Qi Wen",https://www.biorxiv.org/content/10.1101/2023.10.29.564363v2,"The interactions between cancer cells and the ECM regulate carcinogenesis. The collagen receptor kinase DDR2 is dysregulated in certain cancer cells, but its precise role in these malignancies remains unclear. In this study, we perform RNA-seq to determine how DDR2 and the biomechanical environment regulate cancer cell behaviors. We show that DDR2 knockdown in SH-SY5Y neuroblastoma cells inhibits proliferation and promotes senescence by regulating relevant genes. Increasing substrate stiffness reduces proliferation and promotes cell spreading but does not change senescence or transcriptome. Furthermore, DDR2 knockdown modulates cellular responses to substrate stiffness changes, unraveling a crosstalk between DDR2 and mechanosensing. These findings indicate DDR2 and ECM biomechanics regulate cancer cell behavior through distinct mechanisms, providing new mechanistic insights of cancer progression."
1227,The role of alternative polyadenylation in Epithelial-mesenchymal transition of non-small cell lung cancer,"Sijia Wu, Xinyu Qin, Liyu Huang",https://www.biorxiv.org/content/10.1101/2023.11.02.565398v1,"The metastatic non-small cell lung cancer (NSCLC) is one of the cancers with high incidence, poor survival, and limited treatment. Epithelial-mesenchymal transition (EMT) is the first step by which an early tumor converts to an invasive one. Studying the underlying mechanisms of EMT can help the understanding of cancer metastasis and improve the treatment. In this study, 1,013 NSCLC patients and 123 NSCLC cell lines are deeply analyzed for the potential roles of alternative polyadenylation (APA) in the EMT process. A trend of shorter 3’-UTRs is discovered in the mesenchymal samples. The identification of EMT-related APA events highlights the proximal poly(A) selection of CARM1. It is a pathological biomarker of mesenchymal tumor and cancer metastasis through losing miRNA binding to upregulate the EMT inducer of CARM1 and releasing miRNAs to downregulate the EMT inhibitor of RBM47. The crucial role of this APA event in EMT also guides its effect on drug responses. The patients with shorter 3’-UTR of CARM1 are more benefit from chemotherapy drugs, especially cisplatin. A stratification of NSCLC patients based on this APA event is useful for chemotherapy design in future clinics."
1228,MicroRNA-145 enhances lung cancer cell progression after exposure to lyophilized fertile hydatid cyst fluid of Echinococcus granulosus sensu stricto,"Hosein Mosajakhah, Dariush Shanehbandi, Ehsan Ahmadpour, Mahmoud Mahami-Oskouei, Khadijeh Sadeghi Janghoor, Adel Spotin",https://www.biorxiv.org/content/10.1101/2024.01.26.577517v1,"There is increasing evidence that the secretory/excretory antigens of the larval stage of Echinococcus granulosus (hydatid cyst fluid; HCF) can induce both anticancer and oncogenesis effects between parasite-derived metabolites and various cancer lines. The dual role of miR-145 as a tumor suppressor or oncogene has been previously reported in cancers. Nevertheless, it remains unknown, how miR-145 induces apoptosis in HCF-treated lung cancer cells. The fertile HCF was obtained from sheep and subjected to purification and lyophilization. H1299 human lung cancer cells were cultured into two groups: HCF-treated H1299 lung cancer cells and control cells. To evaluate the effects of HCF on the H1299 cells, cell viability was performed by MTT assay. The caspase-3 activity was assessed using fluorometric assay. Furthermore, the mRNA expression of VGEF, Vimentin, caspase-3, miRNA-145, Bax and Bcl-2 genes were characterized by Real-time PCR. A scratch test was done to assess the effects of HCF on cell mobility. MTT assay revealed that there is an increasing slope in the growth of H1299 cells when treated with 60 μg/mL of fertile HCF for 24 h. The fold change of caspase-3, miRNA-145, Bax/Bcl-2 ratio and caspase-3 activity was lower in the HCF-treated H1299 cells than in the control cell. The fold change of VGEF and Vimentin genes in the HCF-treated H1299 cells was higher than that in the control cell. The scratch outcome demonstrated that the mobility of H1299 cells was increased at 24 and 48 hours of scratched time after exposure to HCF. Our results suggest that induction of low expression of miR-145 in patients with hydatid cysts could be a possible oncogenic regulator of lung cancer growth. We conclude that miR-145 may be a promising marker for the diagnosis of lung cancer patients co-infected with pulmonary hydatid cysts. To validate this assumption, further study is needed to assess microRNA profile and potent oncogenes in vivo setting."
1229,A single-cell strategy for the identification of intronic variants related to mis-splicing in pancreatic cancer,"Emre Taylan Duman, Maren Sitte, Karly Conrads, Adi Makay, Fabian Ludewig, Philipp Ströbel, Volker Ellenrieder, Elisabeth Hessman, Argyris Papantonis, Gabriela Salinas",https://www.biorxiv.org/content/10.1101/2023.05.08.539836v2,"Most clinical diagnostic and genomic research setups focus almost exclusively on coding regions and essential splice sites, thereby overlooking other non-coding variants. As a result, intronic variants that can promote mis-splicing events across a range of diseases, including cancer, are yet to be systematically investigated. Such investigations would require both genomic and transcriptomic data, but there currently exist very few datasets that satisfy these requirements. We address this by developing a single-nucleus full-length RNA-sequencing approach that allows for the detection of potentially pathogenic intronic variants. We exemplify the potency of our approach by applying pancreatic cancer tumor and tumor-derived specimens and linking intronic variants to splicing dysregulation. We specifically find that prominent intron retention and pseudo-exon activation events are shared by the tumors and affect genes encoding key transcriptional regulators. Our work paves the way for the assessment and exploitation of intronic mutations as powerful prognostic markers and potential therapeutic targets in cancer."
1230,The interplay between dormant mutated cells and tumor promotion by chronic tissue damage in determining cancer risk,"Yun Rose Li, Eve Kandyba, Kyle Halliwill, Reyno Delrosario, Quan Tran, Nora Bayani, Di Wu, Olga Mirzoeva, Melissa McCreery Reeves, Mishu Islam, Laura Riva, Eric Bergstrom, Kavya Achanta, John Digiovanni, Ludmil Alexandrov, Allan Balmain",https://www.biorxiv.org/content/10.1101/2024.01.24.577147v1,"While the causal role of mutagenic carcinogens in tumor development is well established, the relative contribution of environmental tumor promoting factors, wounding, and chronic inflammation is still unclear. Recent sequencing studies have suggested that most environmental carcinogens act as promoters rather than through mechanisms that involve direct induction of point mutations, but whether cancer risk factors such as obesity, chronic inflammation, wounding, or tumor promoters contribute directly or indirectly to mutation burden, or induce novel signatures, has not been investigated. Here, we present WGS analysis of over 100 mouse skin tumors to compare the effects of exposure to mutagens, the tumor promoter TPA, chronic wounding, obesity, or chemotherapy, on mutational burden and cancer risk. All tumors initiated by the carcinogen Dimethylbenzanthracene (DMBA) show a very strong A>T mutational signature (SBS.DMBA) attributable to a single exposure to this carcinogen. The number of SBS.DMBA mutations also showed a strong correlation with the “clock” signature SBS5, suggesting that one treatment with this mutagen can induce mutational signatures attributed to endogenous processes. No specific signatures could be attributed to obesity, high fat diet, wounding, or TPA. Cells carrying thousands of mutations persist over very long periods without inducing tumors or causing pathological changes but can give rise to tumors after short term exposure to TPA. Furthermore, normal cell turnover and proliferation during fetal and adult growth, is not sufficient for promotion, but tissue damage followed by regenerative proliferation seems to be required for tumor development. We conclude that tumor promoters, chronic inflammation, wounding, and obesity do not contribute significantly to tumor mutational burden, and that the rate-limiting determinant of tumor growth is exposure to a tumor promoter rather than the nature or number of genomic point mutations. These data are highly relevant to the recent demonstration of persistent oncogenic mutations in histologically normal human tissues during ageing."
1231,Unveiling Driver Modules in Lung Cancer: A Clustering-Based Gene-Gene Interaction Network Analysis,"Golnaz Taheri, Marcell Szalai, Mahnaz Habibi, Panagiotis Papapetrou",https://www.biorxiv.org/content/10.1101/2023.11.01.565104v1,"Lung cancer, which is the leading cause of cancer-related death worldwide and is characterized by genetic changes and hetero-geneity, presents a significant treatment challenge. Existing approaches utilizing Machine Learning (ML) techniques for identifying driver modules lack specificity, particularly for lung cancer. This study addresses this limitation by proposing a novel method that combines gene-gene interaction network construction with ML-based clustering to identify lung cancer-specific driver modules. The methodology involves mapping biological processes to genes and constructing a weighted gene-gene interaction network to identify correlations within gene clusters. A clustering algorithm is then applied to identify potential cancer-driver modules, focusing on biologically relevant modules that contribute to lung cancer development. The results highlight the effectiveness and robustness of the clustering approach, identifying 110 unique clusters ranging in size from 4 to 10. These clusters surpass evaluation requirements and demonstrate significant relevance to critical cancer-related pathways. The identified driver modules hold promise for influencing future approaches to lung cancer diagnosis, prognosis, and treatment. This research expands our understanding of lung cancer and sets the stage for further investigations and potential clinical advancements."
1232,Systems profiling reveals recurrently dysregulated cytokine signaling responses in ER+ breast cancer patients’ blood,"Brian Orcutt-Jahns, Joao Rodrigues Lima Junior, Russell C. Rockne, Adina Matache, Sergio Branciamore, Ethan Hung, Andrei S. Rodin, Peter P. Lee, Aaron S. Meyer",https://www.biorxiv.org/content/10.1101/2023.10.31.564987v1,"Cytokines mediate cell-to-cell communication across the immune system and therefore are critical to immunosurveillance in cancer and other diseases. Several cytokines show dysregulated abundance or signaling responses in breast cancer, associated with the disease and differences in survival and progression. Cytokines operate in a coordinated manner to affect immune surveillance and regulate one another, necessitating a systems approach for a complete picture of this dysregulation. Here, we profiled cytokine signaling responses of peripheral immune cells from breast cancer patients as compared to healthy controls in a multidimensional manner across ligands, cell populations, and responsive pathways. We find alterations in cytokine responsiveness across pathways and cell types that are best defined by integrated signatures across dimensions. Alterations in the abundance of a cytokine’s cognate receptor do not explain differences in responsiveness. Rather, alterations in baseline signaling and receptor abundance suggesting immune cell reprogramming are associated with altered responses. These integrated features suggest a global reprogramming of immune cell communication in breast cancer."
1233,Intermediate basal cell population in prostate homeostasis and cancer initiation,"Wangxin Guo, Xiaoyu Zhang, Lin Li, Pengfei Shao, Hongjiong Zhang, Kuo Liu, Chao Liang, Shuoming Wang, Yunyi Peng, Yi Ju, Chen Yu, Luonan Chen, Bin Zhou, Dong Gao",https://www.biorxiv.org/content/10.1101/2023.05.12.540502v1,"Many glandular epithelia are mainly composed of basal cells and luminal cells, including the prostate gland. Adult prostate basal and luminal cells are independently self-sustained by unipotent stem cells that can reactivate multipotency under prostate inflammation and carcinogenesis contexts. However, the defined basal stem cell populations responsible for prostate regeneration and their cell fates in prostate homeostasis, inflammation and carcinogenesis remain unclear. Using a genetic proliferation tracer (ProTracer) system, we found that basal cells exhibited extensive cell loss and proliferation during androgen-mediated prostate regression and regeneration, respectively. A rare intermediate basal cell population that expresses luminal cell markers (Nkx3.1 and Pbsn) (termed Basal-B) and a large basal cell population (termed Basal-A) were identified in mouse prostates by single-cell RNA sequencing. Basal-B cells exhibited a greater capacity for organoid formation and luminal cell differentiation in vitro. Genetic lineage tracing using dual recombinases showed that prostate homeostasis and regeneration are not driven by specific basal cell types. Fate-mapping results showed that Basal-B cells had a greater tendency to generate luminal cells under bacteria-induced prostate inflammation. Deletion of Pten in basal cells resulted in Basal-A-to-Basal-B-to-luminal transition and prostatic intraepithelial neoplasia. Moreover, the human Basal-B-cell population was significantly increased in human benign prostate hyperplasia and prostatic intraepithelial neoplasia samples compared with normal prostate samples. This study identifies intermediate Basal-B cells as a potential stem cell population and provides genetic evidence of prostate basal cell lineage plasticity under physiological and pathological contexts."
1234,Genomic hypomethylation in cell-free DNA predicts responses to checkpoint blockade in lung and breast cancer,"Kyeonghui Kim, Hyemin Kim, Inkyung Shin, Seung-Jae Noh, Jeong Yeon Kim, Koung Jin Suh, Yoo-Na Kim, Jung-Yun Lee, Dae-Yeon Cho, Se Hyun Kim, Jee Hyun Kim, Se-Hoon Lee, Jung Kyoon Choi",https://www.biorxiv.org/content/10.1101/2023.10.31.565052v1,"Genomic hypomethylation has recently been identified as a determinant of therapeutic responses to immune checkpoint blockade (ICB). However, tumor tissue is often unattainable, and tissue-based methylation profiling suffers from low tumor purity. In this study, we developed an assay named iMethyl to estimate the genomic hypomethylation status from cell-free DNA (cfDNA) as well as tissue by deep targeted sequencing of young LINE-1 elements with > 400,000 reads per sample. iMethyl was applied to a total of 653 ICB samples encompassing lung cancer (cfDNA n=167; tissue n=137; cfDNA early during treatment n=40), breast cancer (cfDNA n=91; tissue n=50; PBMC n=50; cfDNA at progression n=44), and ovarian cancer (tissue n=74). iMethyl-tissue had better predictive power than tumor mutation burden and PD-L1 expression. Furthermore, iMethyl-liquid predicted ICB responses accurately regardless of the tumor purity of tissue samples. iMethyl-liquid was also able to monitor therapeutic responses early during treatment (3 or 6 weeks after initiation of ICB) and detect progressive hypomethylation accompanying tumor progression. In conclusion, our method allows for reliable noninvasive prediction, early evaluation, and monitoring of clinical responses to ICB therapy."
1235,Peptide aggregation-induced immunogenic cell death in a breast cancer spheroid model,"Gokhan Gunay, Katelyn N. Maier, Seren Hamsici, Filipa Carvalho, Tristan A. Timog, Handan Acar",https://www.biorxiv.org/content/10.1101/2023.10.31.565012v1,"Utilizing multicellular aggregates (spheroids) for in vitro cancer research offers a physiologically relevant model that closely mirrors the intricate tumor microenvironment, capturing properties of solid tumors such as cell interactions and drug resistance. In this research, we investigated the Peptide-Aggregation Induced Immunogenic Response (PAIIR), an innovative method employing engineered peptides we designed specifically to induce immunogenic cell death (ICD). We contrasted PAIIR-induced ICD with standard ICD and non-ICD inducer chemotherapeutics within the context of three-dimensional breast cancer tumor spheroids. Our findings reveal that PAIIR outperforms traditional chemotherapeutics in its efficacy to stimulate ICD. This is marked by the release of key damage-associated molecular patterns (DAMPs), which bolster the phagocytic clearance of dying cancer cells by dendritic cells (DCs) and, in turn, activate powerful anti-tumor immune responses. Additionally, we observed that PAIIR results in elevated dendritic cell activation and increased antitumor cytokine presence. This study not only showcases the utility of tumor spheroids for efficient high-throughput screening but also emphasizes PAIIR’s potential as a formidable immunotherapeutic strategy against breast cancer, setting the stage for deeper exploration and potential clinical implementation."
1237,Ultrahigh Resolution Lipid Mass Spectrometry Imaging of High-Grade Serous Ovarian Cancer Mouse Models,"Xin Ma, Andro Botros, Sylvia R. Yun, Eun Young Park, Olga Kim, Ruihong Chen, Murugesan Palaniappan, Martin M. Matzuk, Jaeyeon Kim, Facundo M. Fernández",https://www.biorxiv.org/content/10.1101/2023.10.30.564760v1,"No effective screening tools for ovarian cancer (OC) exist, making it one of the deadliest cancers among women. Considering little is known about the detailed progression and metastasis mechanism of OC at a molecular level, it is crucial to gain more insights on how metabolic and signaling alterations accompany its development. Herein, we present a comprehensive study using ultra-high-resolution Fourier transform ion cyclotron resonance matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to investigate the spatial distribution and alterations of lipids in ovarian tissues collected from double knockout (n = 4) and a triple mutant mouse models (n = 4) of high-grade serous ovarian cancer (HGSC). Lipids belonging to a total of 15 different classes were annotated and their abundance changes compared to those in healthy mouse reproductive tissue (n = 4), mapping onto major lipid pathways involved in OC progression. From intermediate-stage OC to advanced HGSC, we provide a direct visualization of lipid distributions and their biological links to inflammatory response, cellular stress, cell proliferation, and other processes. We also show the ability to distinguish tumors at different stages from healthy tissues via a number of highly specific lipid biomarkers, providing targets for future panels that could be useful in diagnosis."
1238,Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer,"Angela L. Hughson, Gary Hannon, Noah A. Salama, Tara G. Vrooman, Caroline A. Stockwell, Bradley N. Mills, Jesse Garrett-Larsen, Haoming Qiu, Roula Katerji, Lauren Benoodt, Carl J. Johnston, Joseph D. Murphy, Emma Kruger, Jian Ye, Nicholas W. Gavras, David C. Keeley, Shuyang S. Qin, Maggie L. Lesch, Jason B. Muhitch, Tanzy M.T. Love, Laura M. Calvi, Edith M. Lord, Nadia Luheshi, Jim Elyes, David C. Linehan, Scott A. Gerber",https://www.biorxiv.org/content/10.1101/2023.10.30.564833v1,"The immunosuppressive milieu in pancreatic cancer (PC) is a significant hurdle to treatments, resulting in survival statistics that have barely changed in 5 decades. Here we present a combination treatment consisting of stereotactic body radiation therapy (SBRT) and IL-12 mRNA lipid nanoparticles delivered directly to pancreatic murine tumors. This treatment was effective against primary and metastatic models, achieving cures in both settings. IL-12 protein concentrations were transient and localized primarily to the tumor. Depleting CD4 and CD8 T cells abrogated treatment efficacy, confirming they were essential to treatment response. Single cell RNA sequencing from SBRT/IL-12 mRNA treated tumors demonstrated not only a complete loss of T cell exhaustion, but also an abundance of highly proliferative and effector T cell subtypes. SBRT elicited T cell receptor clonal expansion, whereas IL-12 licensed these cells with effector function. This is the first report demonstrating the utility of SBRT and IL-12 mRNA in PC."
1241,Extreme gradient boosting machine learning algorithm identifies genome-wide genetic variants in prostate cancer risk prediction,"David Enoma, Victor Chukwudi Osamor, Ogunlana Olubanke",https://www.biorxiv.org/content/10.1101/2023.10.27.564373v1,"Genome-wide association studies (GWAS) identify the variants (Single Nucleotide polymorphisms) associated with a disease phenotype within populations. These genetic differences are essential in variations in incidence and mortalities, especially for Prostate cancer in the African population. Given the complexity of cancer, it is imperative to identify the variants that contribute to the development of the disease. The standard univariate analysis employed in GWAS may not capture the non-linear additive interactions between variants, which might affect the risk of developing Prostate cancer. This is because the interactions in complex diseases such as prostate cancer are usually non-linear and would benefit from a non-linear Machine Learning gradient boosting viz XGBoost (extreme gradient boosting). We applied the XGBoost algorithm and an iterative SNP selection algorithm to find the top features (SNPs) that best predict the risk of developing prostate cancer with a Support Vector Machine (SVM). The number of subjects was 907, and input features were 1,798,727 after appropriate quality control. The algorithm involved ten trials of 5-fold cross-validation to optimize the dataset’s hyperparameters and the prediction task’s second module (utilizing SVM). The model achieved AUC-ROC cure of 0.66, 0.57 and 0.55 on the Train, Dev and Test sets, respectively. The area under the Precision-Recall Curve was 0.69, 0.60 and 0.57 on the Train, Dev and Test sets, respectively. Furthermore, the final number of predictive risk variants was 2798, associated with 847 Ensembl genes. Interaction analysis showed that Nodes were 339 and the edges were 622 in the gene interaction network. This shows evidence that the non-linear Machine learning approach offers excellent possibilities for understanding the genetic basis of complex diseases."
1242,Colon cancer arises from differentiated cell lineages in the context of inflammation,"Mathijs P. Verhagen, Rosalie Joosten, Mark Schmitt, Niko Välimäki, Andrea Sacchetti, Kristiina Rajamäki, Jiahn Choi, Paola Procopio, Sara Silva, Berdine van der Steen, Thierry P.P. van den Bosch, Danielle Seinstra, Michail Doukas, Leonard H. Augenlicht, Lauri A. Aaltonen, Riccardo Fodde",https://www.biorxiv.org/content/10.1101/2023.10.02.560432v2,"According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, was shown to suppress intestinal stemness. Here, we employed Paneth cells (PCs) as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation. Upon inflammation, PC-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in inflammatory bowel disease (IBD) patients but also of a larger fraction of sporadic colon cancers. The latter is likely due to the inflammatory consequences of Western-style dietary habits, the major colon cancer risk factor. Computational methods designed to predict the cell-of-origin of cancer confirmed that, in a substantial fraction of sporadic colon cancers the cells-of-origin are secretory lineages and not stem cells."
1243,Automated machine learning and explainable AI (AutoML-XAI) for metabolomics: improving cancer diagnostics,"Olatomiwa O. Bifarin, Facundo M. Fernández",https://www.biorxiv.org/content/10.1101/2023.10.26.564244v1,"Motivation Metabolomics generates complex data necessitating advanced computational methods for generating biological insight. While machine learning (ML) is promising, the challenges of selecting the best algorithms and tuning hyperparameters, particularly for nonexperts, remain. Automated machine learning (AutoML) can streamline this process; however, the issue of interpretability could persist. This research introduces a unified pipeline that combines AutoML with explainable AI (XAI) techniques to optimize metabolomics analysis."
1245,"Prognostic Significance of preoperative serum CA125, CA19-9, CA72-4, CEA, and AFP in Patients with Endometrial cancer","Zi-hao Wang, Yun-zheng Zhang, Shu-wen Ge, Luhe-Shan, Bo Wang, Zi-yu Zhang, Qi-jun Wu, Xiao-xin Ma",https://www.biorxiv.org/content/10.1101/2024.01.23.576857v1,"Objective To determine preoperative serum CA125, CA19-9, CA72-4, CEA, and AFP with prognostic value, and to establish a risk score based on CA125, CEA, AFP levels for predicting the overall survival (OS) and progression-free survival (PFS) of endometrial cancer (EC) patients."
1246,Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mapping,"Herman Netskar, Aline Pfefferle, Jodie P Goodridge, Ebba Sohlberg, Olli Dufva, Sara A Teichmann, Trevor Clancy, Amir Horowitz, Karl-Johan Malmberg",https://www.biorxiv.org/content/10.1101/2023.10.26.564050v1,"The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic receptor-ligand interactions, and adaptive-like responses to viral infections. Here, we generated a single-cell transcriptional reference map of healthy human blood and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene regulator networks defining NK cell differentiation. Using transfer learning, transcriptomes of tumor-infiltrating NK cells from seven solid tumor types (427 patients), combined from 39 datasets, were incorporated into the reference map and interrogated for tumor microenvironment (TME)-induced perturbations. We identified six functionally distinct NK cellular states in healthy and malignant tissues, two of which were commonly enriched for across tumor types: a dysfunctional ‘stressed’ CD56bright state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant ‘effector’ CD56dim state. The ratio of ‘stressed’ CD56bright and ‘effector’ CD56dim was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of novel NK cell therapies and can be extended endlessly through transfer learning to interrogate new datasets from experimental perturbations or disease conditions."
1249,Replicability of bulk RNA-Seq differential expression and enrichment analysis results in cancer research,"Peter Degen, Matúš Medo",https://www.biorxiv.org/content/10.1101/2023.10.25.563901v1,"The high-dimensional and heterogeneous nature of transcriptomics data from RNA sequencing (RNA-Seq) experiments poses a challenge to routine down-stream analysis steps, such as differential expression analysis and enrichment analysis. Additionally, due to practical and financial constraints, RNA-Seq experiments are often limited to a small number of biological replicates; three replicates is a commonly employed minimum cohort size. In light of recent studies on the low replicability of preclinical cancer research, it is essential to understand how the combination of population heterogeneity and underpowered cohort sizes affects the replicability of RNA-Seq research. Using 7’000 simulated RNA-Seq experiments based on real gene expression data from seven different cancer types, we find that the analysis results from underpowered experiments exhibit inflated effect sizes and are unlikely to replicate well. However, the ground-truth results obtained by analyzing large cohorts show that the precision of differentially expressed genes can be high even for small cohort sizes. The poor replicability of underpowered experiments is thus a direct consequence of their low recall (sensitivity). In other words, the low replicability of underpowered RNA-Seq cancer studies does not necessarily indicate a high prevalence of false positives. Instead, the results obtained from such studies are limited to small and mostly random subsets of a larger ground truth. We conclude with a set of practical recommendations to alleviate problems with underpowered RNA-Seq studies."
1250,Exploring Okra-Derived Compounds as Prospective Aromatase Inhibitors: A Computational Study for Enhanced Breast Cancer Therapy,"B Lavanya, Dhrithi Jayasimha Mallur, Sheshadri S Temkar, V Arun, Benedict Paul C",https://www.biorxiv.org/content/10.1101/2023.10.25.563890v1,"Breast cancer with estrogen receptor positivity represents itself as the most prevalent malignancy among postmenopausal women. One of the promising therapeutic approach involves the use of Aromatase Inhibitors, which competitively bind to aromatase, reducing estrone and estradiol levels. While current drugs have improved survival rates, they are not without adverse effects. Consequently, this study explores the computational screening of medicinally relevant compounds derived from Okra for potential Aromatase Inhibition. Molecular Docking, employing AMDock v1.5.2, was utilized to assess binding affinities with aromatase (PDB:3EQM). Subsequently, in-depth molecular interactions were examined using Discovery Studio Visualizer v4.5, and the stability of docked complexes was evaluated via Molecular Dynamics with the GROMACS package, focusing on RMSD, RMSF, H-bond count, and SASA. The pharmacokinetic properties of the Okra compounds were predicted using admetSAR v2.0. Our findings highlight Quercetin 3-gentiobioside as a standout candidate, demonstrating superior binding affinity (-10 kcal/mol) and an Estimated Ki of 46.77 nM compared to Letrozole and other Okra compounds. Molecular dynamics analysis confirms the stability of Quercetin 3-gentiobioside binding in terms of H-bonds and conformational integrity. In conclusion, our computational investigation identifies Quercetin 3-gentiobioside, along with Quercetin 3-O-rutinoside and Hyperin, as promising candidates for preclinical studies in the pursuit of potential Aromatase Inhibitors."
1251,Small cell lung cancer co-culture organoids provide insights into cancer cell survival after chemotherapy,"Chandani Sen, Caroline Koloff, Souvik Kundu, Dan C Wilkinson, Juliette Yang, David W Shia, Luisa K Meneses, Tammy M Rickabaugh, Brigitte N Gomperts",https://www.biorxiv.org/content/10.1101/2023.01.03.522668v2,"Small-cell-lung-cancer (SCLC) has the worst prognosis of all lung cancers because of a high incidence of relapse after therapy. We developed a bioengineered 3-dimensional (3D) SCLC co-culture organoid as a phenotypic tool to study SCLC tumor kinetics and SCLC-fibroblast interactions during relapse. We used functionalized alginate microbeads as a scaffold to mimic lung alveolar architecture and co-cultured SCLC cell lines with primary adult lung fibroblasts (ALF). We found that SCLCs in the model proliferated extensively, invaded the microbead scaffold and formed tumors within just 7 days. We compared the bioengineered tumors with patient tumors and found them to recapitulate the pathology and immunophenotyping of the patient tumors better than the PDX model developed from the same SCLC cell line. When treated with standard chemotherapy drugs, etoposide and cisplatin, the organoid recapitulated relapse after chemotherapy. Co-culture of the SCLC cells with ALFs revealed that the fibroblasts play a key role in inducing faster and more robust SCLC cell regrowth in the model. This was a paracrine effect as conditioned medium from the same fibroblasts was responsible for this accelerated cell regrowth. This model is also amenable to high throughput phenotypic or targeted drug screening to find new therapeutics for SCLC."
1253,Alternative splice variants of the mitochondrial fission protein DNM1L/Drp1 regulate mitochondrial dynamics and tumor progression in ovarian cancer,"Zaineb Javed, Dong Hui Shin, Weihua Pan, Sierra R. White, Yeon Soo Kim, Amal Taher Elhaw, Shriya Kamlapurkar, Ya-Yun Cheng, J Cory Benson, Ahmed Emam Abdelnaby, Rébécca Phaëton, Hong-Gang Wang, Shengyu Yang, Mara L.G. Sullivan, Claudette M. St.Croix, Simon C. Watkins, Steven J. Mullett, Stacy L. Gelhaus, Nam Lee, Lan G. Coffman, Katherine M. Aird, Mohamed Trebak, Karthikeyan Mythreye, Vonn Walter, Nadine Hempel",https://www.biorxiv.org/content/10.1101/2023.09.20.558501v2,"Aberrant mitochondrial fission/fusion dynamics have been reported in cancer cells. While post translational modifications are known regulators of the mitochondrial fission/fusion machinery, we show that alternative splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. Ovarian cancer specimens express an alternative splice transcript variant of Drp1 lacking exon 16 of the variable domain, and high expression of this splice variant relative to other transcripts is associated with poor patient outcome. Unlike the full-length variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration, and TCA cycle metabolites, and is associated with a more metastatic phenotype in vitro and in vivo. These pro-tumorigenic effects can also be inhibited by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternative splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies."
1256,Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer,"Leslie Duplaquet, Kevin So, Alexander W. Ying, Xinyue Li, Yixiang Li, Xintao Qiu, Rong Li, Shilpa Singh, Xiaoli S. Wu, Qi Liu, Jun Qi, Tim D.D. Somerville, Hillary Heiling, Emanuele Mazzola, Yenarae Lee, Thomas Zoller, Christopher R. Vakoc, John G. Doench, William C. Forrester, Tinya Abrams, Henry W. Long, Matthew J. Niederst, Cigall Kadoch, Matthew G. Oser",https://www.biorxiv.org/content/10.1101/2024.01.21.576304v1,"Small cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes, including non-canonical BAF (ncBAF) complexes, as top dependencies specific to POU2F3-positive SCLC. Notably, clinical-grade pharmacologic mSWI/SNF inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survival in vivo. Taken together, these results characterize mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for SCLC."
1257,Methods in cancer research: Assessing therapy response of spheroid cultures by life cell imaging using a Cost-Effective Live-Dead Staining Protocol,"Jaison Phour, Erik Vassella",https://www.biorxiv.org/content/10.1101/2024.04.17.589882v1,"Spheroid cultures of cancer cell lines or primary cells represent a more clinically relevant model for predicting therapy response compared to two-dimensional cell culture. However, current live-dead staining protocols used for treatment response in spheroid cultures are often expensive, toxic to the cells, or limited in their ability to monitor therapy response over an extended period due to reduced stability. In our study, we have developed a cost-effective method utilizing calcein-AM and Helix NP™ Blue for live-dead staining, enabling the monitoring of therapy response of spheroid cultures for up to 10 days. Using the example of glioblastoma cell lines and primary glioblastoma cells we show that spheroid cultures typically exhibit a green outer layer of viable cells, a turquoise mantle of hypoxic quiescent cells, and a blue core of necrotic cells when visualized using confocal microscopy. Upon treatment of spheroids with the alkylating agent temozolomide, we observed a reduction in the viability of glioblastoma cells after an incubation period of six to seven days. This method can also be adapted for monitoring therapy response in different cancer systems, offering a versatile and cost-effective approach for assessing therapy efficacy in three-dimensional culture models."
1258,Replication stress underlies genomic instability at CTCF/cohesin-binding sites in cancer,"Elangoli Ebrahimkutty Faseela, Dimple Notani, Radhakrishnan Sabarinathan",https://www.biorxiv.org/content/10.1101/2023.10.24.563697v1,"CCCTC-binding factor (CTCF) and cohesin play a significant role in the formation of chromatin loops and topologically associating domains (TADs), which influence gene expression and DNA replication. CTCF/cohesin-binding sites (CBSs) present at the loop anchors and TAD boundaries are frequently mutated in cancer; however, the molecular mechanisms underlying this remain unclear. Here, we investigate whether the binding of CTCF/cohesin on DNA imposes constraints on DNA replication, leading to replication stress and genomic instability. Our results reveal that CTCF and cohesin remain bound to DNA during replication (S phase) in cancer cells (HeLa). Further, examination of replication stress through imaging revealed colocalization of DNA damage response proteins (MRE11 and STN1) with CTCF/cohesin in the S phase. In addition, ChIP-seq of the DNA damage response/repair proteins (MRE11, STN1, γH2AX and RAD51) showed high enrichment of these proteins at CBSs (as compared to their immediate flanking regions and control sites) and positively correlated with the binding strength of CTCF/cohesin at CBSs in the S phase. Moreover, analysis of somatic mutations from cancer genomes supports that the enrichment of mutations at CBSs is significantly higher in samples harbouring somatic copy number deletion in MRE11 and STN1 compared to wild-type samples. Together, these results demonstrate that the binding of CTCF/cohesin on the DNA during the S phase causes replication stress and DNA strand breaks, and this could lead to genome instability at CBSs observed in cancer."
1261,MET Inhibitor Capmatinib Radiosensitizes MET Exon 14-Mutated and MET-Amplified Non-Small Cell Lung Cancer,"Shrey Ramesh, Ahmet Cifci, Saahil Javeri, Rachel Minne, Colin A. Longhurst, Kwangok P. Nickel, Randall J. Kimple, Andrew M. Baschnagel",https://www.biorxiv.org/content/10.1101/2023.10.26.564232v1,"Purpose The objective of this study was to investigate the effects of inhibiting the MET receptor with capmatinib, a potent and clinically relevant ATP-competitive tyrosine kinase inhibitor, in combination with radiation in MET exon 14-mutated and MET-amplified non-small cell lung (NSCLC) cancer models."
1264,Claudin-4 modulates autophagy via SLC1A5/LAT1 as a tolerance mechanism for genomic instability in ovarian cancer,"Fabian R. Villagomez, Julie Lang, Patricia Webb, Margaret Neville, Elizabeth R. Woodruff, Benjamin G. Bitler",https://www.biorxiv.org/content/10.1101/2024.01.18.576263v2,"Genome instability is key for tumor heterogeneity and derives from defects in cell division and DNA damage repair. Tumors show tolerance for this characteristic, but its accumulation is regulated somehow to avoid catastrophic chromosomal alterations and cell death. Claudin-4 is upregulated and closely associated with genome instability and worse patient outcome in ovarian cancer. This protein is commonly described as a junctional protein participating in processes such as cell proliferation and DNA repair. However, its biological association with genomic instability is still poorly-understood. Here, we used CRISPRi and a claudin mimic peptide (CMP) to modulate the cladudin-4 expression and its function, respectively in in-vitro (high-grade serous carcinoma cells) and in-vivo (patient-derived xenograft in a humanized-mice model) systems. We found that claudin-4 promotes a protective cellular-mechanism that links cell-cell junctions to genome integrity. Disruption of this axis leads to irregular cellular connections and cell cycle that results in chromosomal alterations, a phenomenon associated with a novel functional link between claudin-4 and SLC1A5/LAT1 in regulating autophagy. Consequently, claudin-4’s disruption increased autophagy and associated with engulfment of cytoplasm-localized DNA. Furthermore, the claudin-4/SLC1A5/LAT1 biological axis correlates with decrease ovarian cancer patient survival and targeting claudin-4 in-vivo with CMP resulted in increased niraparib (PARPi) efficacy, correlating with increased tumoral infiltration of T CD8+ lymphocytes. Our results show that the upregulation of claudin-4 enables a mechanism that promotes tolerance to genomic instability and immune evasion in ovarian cancer; thus, suggesting the potential of claudin-4 as a translational target for enhancing ovarian cancer treatment."
1265,Targeting metabolic fluxes reverts metastatic transitions in ovarian cancer,"Garhima Arora, Jimpi Langthasa, Mallar Banerjee, Ramray Bhat, Samrat Chatterjee",https://www.biorxiv.org/content/10.1101/2023.05.02.538518v1,"Spheroids formation during epithelial ovarian cancer progression correlates with peritoneal organ colonization, disease recurrence, and poor prognosis. Although cancer progression has been demonstrated to be associated with and driven by metabolic changes within transformed cells, possible associations between metabolic dynamics and metastatic morphological transitions remain unexplored. To address this problem, we performed quantitative proteomics to identify protein signatures associated with three distinct morphologies (2D monolayers and two geometrically individual three-dimensional spheroidal states) of the high-grade serous ovarian cancer line OVCAR-3. Integrating the protein states onto genome-scale metabolic models allowed us to construct context-specific metabolic models for each morphological stage of the OVCAR-3 cell line and systematically evaluate their metabolic functionalities. We obtained disease-driving metabolic reaction modules using these models and elucidated gene knockout strategies to reduce metabolic alterations associated with disease progression. We explored the DrugBank database to mine pharmacological agents and evaluated the effect of drugs in impairing cancer progression. Finally, we experimentally validated our predictions by confirming the ability of one of our predicted drugs: the neuraminidase inhibitor oseltamivir, to disrupt the metastatic spheroidal morphologies without any cytotoxic effect on untransformed stromal mesothelial monolayers."
1266,Estrogen-related differences in antitumor immunity and the gut microbiome contribute to sexual dimorphism of colorectal cancer,"Georgia Lattanzi, Federica Perillo, Angélica Díaz-Basabe, Bruna Caridi, Chiara Amoroso, Alberto Baeri, Elisa Cirrincione, Michele Ghidini, Barbara Galassi, Elisa Cassinotti, Ludovica Baldari, Luigi Boni, Maurizio Vecchi, Flavio Caprioli, Federica Facciotti, Francesco Strati",https://www.biorxiv.org/content/10.1101/2024.01.17.576009v1,"Colorectal cancer (CRC) is a multifaceted disease whose development and progression varies depending on tumor location, age of patients, infiltration of immune cells within cancer lesions, and the tumor microenvironment. These pathophysiological characteristics are additionally influenced by sex-related differences. The gut microbiome plays a pivotal role in the initiation and progression of CRC, and shapes anti-tumor immune responses but how the responsiveness of the immune system to the intestinal microbiota may contribute to the sexual dimorphism of CRC is largely unknown. Here, we studied survival, tumor-infiltrating immune cell populations and tumor-associated microbiome of a cohort of n=184 male and female CRC patients and functionally tested the immune system-microbiome interactions in in vivo and in vitro models of the disease. High-dimensional single-cell flow cytometry showed that female patients are enriched by tumor-infiltrating iNKT cells but depleted by cytotoxic T lymphocytes. The enrichment of oral pathobionts and a reduction of β-glucuronidase activity are distinctive traits characterizing the gut microbiome of women affected by CRC. Functional assays using a collection of human primary iNKT cell lines demonstrated that the gut microbiota of female patients functionally impairs iNKT cell anti-tumor functions interfering with the granzyme-perforin cytotoxic pathway. These results highlight a sex-dependent functional relationship between the gut microbiome, estrogen metabolism, and the decline of cytotoxic T cell responses, contributing to the sexual dimorphism observed in CRC patients with relevant implications for precision medicine and the design of targeted therapeutic approaches addressing sex bias in cancer."
1267,Mapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities,"Yuka Takemon, Erin D. Pleasance, Alessia Gagliardi, Christopher S. Hughes, Veronika Csizmok, Kathleen Wee, Diane L. Trinh, Ryan D. Huff, Andrew J. Mungall, Richard A. Moore, Eric Chuah, Karen L. Mungall, Eleanor Lewis, Jessica Nelson, Howard J. Lim, Daniel J. Renouf, Steven JM. Jones, Janessa Laskin, Marco A. Marra",https://www.biorxiv.org/content/10.1101/2024.01.17.575929v1,"Loss-of-function (LOF) alterations in tumour suppressor genes cannot be directly targeted. Approaches characterising gene function and vulnerabilities conferred by such mutations are required. Here, we computationally map genetic networks of KMT2D, a tumour suppressor gene frequently mutated in several cancer types. Using KMT2D loss-of-function (KMT2DLOF) mutations as a model, we illustrate the utility of in silico genetic networks in uncovering novel functional associations and vulnerabilities in cancer cells with LOF alterations affecting tumour suppressor genes. We revealed genetic interactors with functions in histone modification, metabolism, and immune response, and synthetic lethal (SL) candidates, including some encoding existing therapeutic targets. Analysing patient data from The Cancer Genome Atlas and the Personalized OncoGenomics Project, we showed, for example, elevated immune checkpoint response markers in KMT2DLOF cases, possibly supporting KMT2DLOF as an immune checkpoint inhibitor biomarker. Our study illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities."
1268,Proteomic Stratification of Prognosis and Treatment Options for Small Cell Lung Cancer,"Zitian Huo, Yaqi Duan, Dongdong Zhan, Xizhen Xu, Nairen Zheng, Jing Cai, Ruifang Sun, Jianping Wang, Fang Cheng, Zhan Gao, Caixia Xu, Wanlin Liu, Yuting Dong, Sailong Ma, Qian Zhang, Yiyun Zheng, Liping Lou, Dong Kuang, Qian Chu, Jun Qin, Guoping Wang, Yi Wang",https://www.biorxiv.org/content/10.1101/2023.10.22.563494v2,"Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current TNM or Veterans Administration Lung Study Group (VALG) staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent center, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggest potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better Progression Free Survival (PFS) and Overall Survival (OS) after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments."
1269,Support Vector Machine based prediction models for drug repurposing and designing novel drugs for colorectal cancer,"Avik Sengupta, Rahul Kumar",https://www.biorxiv.org/content/10.1101/2023.10.20.563215v1,"Colorectal cancer (CRC) has witnessed a concerning increase in incidence and poses a significant therapeutic challenge due to its poor prognosis. There is a pressing demand to identify novel drug therapies to combat CRC. In this study, we addressed this need by utilizing the library of CRC pharmacological profiles of anticancer drugs and developed QSAR models for prediction of alternative and promiscuous anti-cancer compounds for CRC treatment. Our QSAR models demonstrated their robustness by achieving high correlation of determination (R2) after 10-fold cross validation. For 12 CRC cell lines, R2 ranges from 0.609-0.827. Highest performance was achieved for SW1417 and GP5d cell lines with R2, 0.827 and 0.786, respectively. Further, we listed the most common descriptors in the drug profiles of the CRC cell lines and we also checked the correlation of the descriptors with the drug activity. The KRFP314 fingerprint was the predominantly occurring descriptor, with the KRFPC314 fingerprint following closely in prevalence within the drug profiles of the CRC cell lines. Beyond predictive modeling, we also successfully validated drug-to-oncogene relationship via in-silico methods and identified FDA-approved drugs which could be used as potential anti-CRC drugs, paving the way for subsequent in vitro or in vivo experiments to validate their efficacy. To provide easy accessibility and utility of our research findings, we have incorporated these models into a free-to-use user-friendly prediction webserver named, “ColoRecPred” hosted on project.iith.ac.in/cgntlab/colorecpred. This web-based tool can be used to screen for potential anti-cancer compounds for CRC."
1270,Antibody-conjugating nanogel (Conjugel) with two immune checkpoint inhibitors for enhanced cancer immunotherapy,"Yun Jin Chae, Kang-Gon Lee, Doogie Oh, Su-Kyoung Lee, Yongdoo Park, Jongseong Kim",https://www.biorxiv.org/content/10.1101/2023.10.19.563185v1,"Cancer immunotherapy by immune checkpoint inhibitors (ICI) acts on antitumor responses by stimulating the immune system to attack cancer cells. However, this powerful therapy is hampered by its high treatment cost and limited efficacy. Here, we show the development of an antibody-conjugating system (Conjugel) that potentiates the efficacy of bispecific immunotherapy that simultaneously targets CTLA-4 and PD-L1. The Conjugel, consisting of highly deformable nanogels and antibody-binding protein, was loaded with two ICI monoclonal antibodies (mAb). Compared with mAb treatment alone, treatment with a bispecific Conjugel loaded with the both ICIs significantly decreased both the survival of MCF-7 and MDA-MB-231 breast cancer cells in vitro and the size of 4T1-Luc2-derived orthotopic syngeneic tumors in vivo. Furthermore, the ICI-loaded Conjugel was less toxic in vivo than the combination treatment delivered as a bolus. Our findings have important implications for Conjugel-based immunotherapy, developing the safer and higher efficacy of ICIs to treat breast cancers."
1271,"SARS-CoV-2 spike S2 subunit inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells","Shengliang Zhang, Wafik S. El-Deiry",https://www.biorxiv.org/content/10.1101/2024.04.12.589252v1,"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 infection has led to worsened outcomes for patients with cancer. SARS-CoV-2 spike protein mediates host cell infection and cell-cell fusion that causes stabilization of tumor suppressor p53 protein. In-silico analysis previously suggested that SARS-CoV-2 spike interacts with p53 directly but this putative interaction has not been demonstrated in cells. We examined the interaction between SARS-CoV-2 spike, p53 and MDM2 (E3 ligase, which mediates p53 degradation) in cancer cells using an immunoprecipitation assay. We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells. We further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike S2-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity. In fact, cisplatin-treated tumor cells expressing spike S2 were found to have increased cell viability as compared to control cells. Further observations on γ-H2AX expression in spike S2-expressing cells treated with cisplatin may indicate altered DNA damage sensing in the DNA damage response pathway. The preliminary observations reported here warrant further studies to unravel the impact of SARS-CoV-2 and its various encoded proteins including spike on pathways of tumorigenesis and response to cancer therapeutics."
1273,Multilevel Plasticity and Altered Glycosylation Drive Aggressiveness in Hypoxic and Glucose-Deprived Bladder Cancer Cells,"Andreia Peixoto, Dylan Ferreira, Andreia Miranda, Marta Relvas-Santos, Rui Freitas, Tim S. Veth, Andreia Brandão, Eduardo Ferreira, Paula Paulo, Marta Cardoso, Cristiana Gaiteiro, Sofia Cotton, Janine Soares, Luís Lima, Filipe Teixeira, Rita Ferreira, Carlos Palmeira, Albert J. R. Heck, Maria José Oliveira, André M. N. Silva, Lúcio Lara Santos, José Alexandre Ferreira",https://www.biorxiv.org/content/10.1101/2023.10.21.561355v1,"Bladder tumours with aggressive characteristics often present with microenvironmental niches marked by low oxygen levels (hypoxia) and limited glucose supply due to inadequate vascularization. The molecular mechanisms facilitating cellular adaptation to these stimuli remain largely elusive. Employing a multi-omics approach, we discovered that hypoxic and glucose- deprived cancer cells enter a quiescent state supported by mitophagy, fatty acid β-oxidation, and amino acid catabolism, concurrently enhancing their invasive capabilities. Reoxygenation and glucose restoration efficiently reversed cell quiescence without affecting cellular viability, highlighting significant molecular plasticity in adapting to microenvironmental challenges. Furthermore, cancer cells exhibited substantial perturbation of protein O-glycosylation, leading to simplified glycophenotypes with shorter glycosidic chains. Exploiting glycoengineered cell models, we established that immature glycosylation contributes to reduced cell proliferation and increased invasion. Our findings collectively indicate that hypoxia and glucose deprivation trigger cancer aggressiveness, reflecting an adaptive escape mechanism underpinned by altered metabolism and protein glycosylation, providing grounds for clinical intervention."
1274,Lipids with negative spontaneous curvature decrease the solubility of the cancer drug paclitaxel in liposomes,"Victoria Steffes, Scott MacDonald, John Crowe, Meena Murali, Kai K. Ewert, Youli Li, Cyrus R. Safinya",https://www.biorxiv.org/content/10.1101/2023.10.18.563006v1,"Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development of improved lipid-based carriers of PTX is an important objective to generate chemotherapeutics with fewer side effects. The lipids 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and glyceryl monooleate (GMO) show propensity for fusion with other lipid membranes, which has led to their use in lipid vectors of nucleic acids. We hypothesized that DOPE and GMO could enhance PTX delivery to cells through a similar membrane fusion mechanism. As an important measure of drug carrier performance, we evaluated PTX solubility in cationic liposomes containing GMO or DOPE. Solubility was determined by time-dependent kinetic phase diagrams generated from direct observations of PTX crystal formation using differential-interference-contrast optical microscopy. Remarkably, PTX was much less soluble in these liposomes than in control cationic liposomes containing univalent cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), which are not fusogenic. In particular, PTX was not substantially soluble in GMO-based cationic liposomes. The fusogenicity of DOPE and GMO is related to the negative spontaneous curvature of membranes containing these lipids, which drives formation of nonlamellar self-assembled phases (inverted hexagonal or gyroid cubic). We used synchrotron small-angle x-ray scattering to determine whether PTX solubility is governed by lipid membrane structure (condensed with DNA in pellet form) or by local intermolecular interactions. The results suggest that local intermolecular interactions are of greater importance and that the negative spontaneous curvature-inducing lipids DOPE and GMO are not suitable components of lipid carriers for PTX delivery regardless of carrier structure."
1275,Utilizing a dual endogenous reporter system to identify functional regulators of aberrant stem cell and differentiation activity in colorectal cancer,"Sandor Spisak, David Chen, Pornlada Likasitwatanakul, Paul Doan, Zhixin Li, Pratyusha Bala, Laura Vizkeleti, Viktoria Tisza, Pushpamail De Silva, Marios Giannakis, Brian Wolpin, Jun Qi, Nilay S. Sethi",https://www.biorxiv.org/content/10.1101/2023.06.21.545895v2,"Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators that regulate these key cellular programs in CRC, we developed an endogenous reporter system by genome-editing human CRC cell lines with knock-in fluorescent reporters at the SOX9 and KRT20 locus to report aberrant stem cell-like activity and differentiation, respectively, and then performed pooled genetic perturbation screens. Constructing a dual reporter system that simultaneously monitored aberrant stem cell-like and differentiation activity in the same CRC cell line improved our signal to noise discrimination. Using a focused-library CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs, we identified factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominated SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency in CRC and required for in vivo growth of human CRC models. These studies highlight the utility of a biologically designed endogenous reporter system to uncover novel therapeutic targets for drug development."
1276,Replicative Instability Drives Cancer Progression,"Benjamin B. Morris, Jason P. Smith, Qi Zhang, Zhijie Jiang, Oliver A. Hampton, Michelle L. Churchman, Susanne M. Arnold, Dwight H. Owen, Jhanelle E. Gray, Patrick M. Dillon, Hatem H. Soliman, Daniel G. Stover, Howard Colman, Arnab Chakravarti, Kenneth H. Shain, Ariosto S. Silva, John L. Villano, Michael A. Vogelbaum, Virginia F. Borges, Wallace L. Akerley, Ryan D. Gentzler, Richard D. Hall, Cindy B. Matsen, C. M. Ulrich, Andrew R. Post, David A. Nix, Eric A. Singer, James M. Larner, P. Todd Stukenberg, David R. Jones, Marty W. Mayo",https://www.biorxiv.org/content/10.1101/2022.05.06.490945v1,"In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress have been shown to exhibit genomic instability and poor survival rates across tumor types. Here we utilize-omics data from two independent consortia to identify the genetic underpinnings of replication stress, therapy resistance, and primary carcinoma to brain metastasis in BRCA wildtype tumors. In doing so, we have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by genomic evolution secondary to replicative challenge. Our data supports a model whereby defective single-strand break repair, translesion synthesis, and non-homologous end joining effectors drive RIN. Collectively, we find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution."
1277,Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness,"Alican Kuşoğlu, Deniz Örnek, Aslı Dansık, Ceren Uzun, Sena Nur Özkan, Sevgi Sarıca, Kardelen Yangın, Şevval Özdinç, Duygu Turan Sorhun, Nuriye Solcan, Efe Can Doğanalp, Øystein Arlov, Katherine Cunningham, İsmail C. Karaoğlu, Seda Kizilel, Ihsan Solaroglu, Pınar Bulutay, Pınar Fırat, Suat Erus, Serhan Tanju, Şükrü Dilege, Gordana Vunjak-Novakovic, Nurcan Tuncbag, Ece Öztürk",https://www.biorxiv.org/content/10.1101/2023.10.17.562578v1,"Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, we demonstrate that PGs are heavily expressed in lung adenocarcinoma patients in correlation with invasive phenotype and poor prognosis. We developed a bioengineered human lung tumor model which recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density and porosity. Our model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition and stemness in cancer cells. We identified the FAK-PI3K-mTOR signaling axis as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. We demonstrate that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors through employing integrative omics and network modeling approaches."
1279,Yes1-mediated Cul9 phosphorylation promotes the metabolic reprogramming in gastric cancer,"Youliang Wu, Heng Zhang, Shangxin Zhang, Mingliang Wang, Huizhen Wang, He Huang, Xuehui Hong, Zhiyong Zhang, Yongxiang Li",https://www.biorxiv.org/content/10.1101/2023.10.18.562906v1,"Although Cul9 has been implicated in human carcinogenesis, its upstream regulators and roles remain unknown. Herein, we indicate that the Cul9 promoter is hypermethylated in GCs. Bioinformatics, mass spectrometry, and unbiased-kinase screen identify the tyrosine kinase Yes1 as a key regulator of Cul9. Yes1 phosphorylates Cul9 at Y1505, promoting its selective autophagy. Patient-associated mutation of Yes1 or helicobacter pylori infection induces Cul9-Y1505 phosphorylation which switches Cul9 from a tumor-suppressor to an oncogene, as evidenced by the fact that Cul9-Y1505D knockin mice are more susceptible to gastric tumorigenesis than wild-type counterparts. Metabolic profiling and ATAC sequencing reveal that Cul9-Y1505D mutant promotes pyrimidine and purine synthesis pathways in GC. DNA-demethylating drug decitabine or HG78 compound upregulates Cul9 expression and limits GC cell proliferation in a Yes1-dependent manner. The Yes1 inhibitor CH6953755 or Leflunomide and Mycophenolate mofetil (MMF) also impair the malignancy of GC with Cul9 dysregulation. Cul9 in turn binds Yes1 and disrupts Yes1 stability, establishing a feedback circuit. Collectively, our project reveals an unrecognized role of the Yes1-Cul9 loop in GC, suggesting potential therapeutic targets."
1280,A Nanoparticle RIG-I Agonist for Cancer Immunotherapy,"Lihong Wang-Bishop, Mohamed Wehbe, Lucinda E. Pastora, Jinming Yang, Kyle M. Garland, Kyle W. Becker, Carcia S. Carson, Katherine N. Gibson-Corley, David Ulkoski, Venkata Krishnamurthy, Olga Fedorova, Ann Richmond, Anna Marie Pyle, John T. Wilson",https://www.biorxiv.org/content/10.1101/2023.04.25.537919v1,"Pharmacological activation of the retinoic acid-inducible gene I (RIG-I) pathway holds promise for increasing tumor immunogenicity and improving response to immune checkpoint inhibitors (ICI). However, the potency and clinical efficacy of 5’-triphosphate RNA (3pRNA) agonists of RIG-I is hindered by multiple pharmacological barriers, including poor pharmacokinetics, nuclease degradation, and inefficient delivery to the cytosol where RIG-I is localized. Here, we address these challenges through the design and evaluation of ionizable lipid nanoparticles (LNPs) for the delivery of 3p-modified stem-loop RNAs (SLRs). Packaging of SLRs into LNPs (SLR-LNPs) yielded surface charge-neutral nanoparticles with a size of ∼100 nm that activated RIG-I signaling in vitro and in vivo. SLR-LNPs were safely administered to mice via both intratumoral and intravenous routes, resulting in RIG-I activation in the tumor microenvironment (TME) and inhibition of tumor growth in mouse models of poorly immunogenic melanoma and breast cancer. Significantly, we found that systemic administration of SLR-LNPs reprogrammed the breast TME to enhance the infiltration of CD8+ and CD4+ T cells with antitumor function, resulting in enhanced response to αPD-1 ICI in an orthotopic EO771 model of triple negative breast cancer. Therapeutic efficacy was further demonstrated in a metastatic B16.F10 melanoma model, with systemically administered SLR-LNPs significantly reducing lung metastatic burden compared to combined αPD-1 + αCTLA-4 ICI. Collectively, these studies have established SLR-LNPs as a translationally promising immunotherapeutic nanomedicine for potent and selective activation of RIG-I with potential to enhance response to ICIs and other immunotherapeutic modalities."
1282,Cancer-mediated Axonal Guidance of Sensory Neurons in a Microelectrode-based Innervation MPS,"Matthijs van der Moolen, Andrea Lovera, Fulya Ersoy, Sacha Mommo, Peter Loskill, Paolo Cesare",https://www.biorxiv.org/content/10.1101/2023.10.18.562227v1,"Despite recent advances in the field of microphysiological systems (MPS), availability of models capable of mimicking the interactions between the nervous system and innervated tissues is still limited. This represents a significant challenge in identifying the underlying processes of various pathological conditions, including neuropathic, cardiovascular and metabolic disorders. In this study, we introduce a compartmentalized 3D coculture system that enables physiologically relevant tissue innervation while recording neuronal excitability. By integrating custom microelectrode arrays into tailored glass chips microfabricated via selective laser-etching, we developed an entirely novel class of innervation MPSs (INV-MPS). This INV-MPS allows for manipulation, visualization, and electrophysiological analysis of individual axons innervating complex 3D tissues. Here, we focused on sensory innervation of 3D tumor tissue as a model case study since cancer-induced pain represents a major unmet medical need. The system was compared with existing nociception models and successfully replicated axonal chemoattraction mediated by nerve growth factor (NGF). Remarkably, in the absence of NGF, 3D cancer spheroids cocultured in the adjacent compartment induced sensory neurons to consistently cross the separating barrier and establish fine innervation. Moreover, we observed that crossing sensory fibers could be chemically excited by distal application of known pain-inducing agonists only when cocultured with cancer cells. To our knowledge, this is the first system showcasing morphological and electrophysiological analysis of 3D-innervated tumor tissue in vitro, paving the way for a plethora of studies into innervation-related diseases and improving our understanding of underlying pathophysiology."
1283,Pulsed low-dose-rate radiation (PLDR) reduces the tumor-promoting responses induced by conventional chemoradiation in pancreatic cancer-associated fibroblasts,"Janusz Franco-Barraza, Tiffany Luong, Jessica K. Wong, Kristopher Raghavan, Elizabeth Handorf, Débora B. Vendramini-Costa, Ralph Francescone, Jaye C. Gardiner, Joshua E. Meyer, Edna Cukierman",https://www.biorxiv.org/content/10.1101/2024.01.13.575510v1,"Pancreatic cancer is becoming increasingly deadly, with treatment options limited due to, among others, the complex tumor microenvironment (TME). This short communications study investigates pulsed low-dose-rate radiation (PLDR) as a potential alternative to conventional radiotherapy for pancreatic cancer neoadjuvant treatment."
1284,Integrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic drivers,"Katarina Mandić, Nina Milutin Gašperov, Ksenija Božinović, Emil Dediol, Jure Krasić, Nino Sinčić, Magdalena Grce, Ivan Sabol, Anja Barešić",https://www.biorxiv.org/content/10.1101/2024.01.11.575141v2,"Background Head and neck cancer is the sixth most common malignancy worldwide, with the relatively low 5-year survival rate, mainly because it is diagnosed at a late stage. Infection with HPV is well known etiology, which affects nature of these cancers and patients’ survival. Besides, it is considered that the main driving force for this type of cancer could be epigenetics. In this study we aimed to find potential epigenetic biomarkers, by integrating miRNome, methylome, and transcriptome analyses."
1286,Quantifiable TCR repertoire changes in pre-diagnostic blood specimens among high-grade ovarian cancer patients,"Xuexin Yu, Jianfeng Ye, Cassandra A. Hathaway, Shelley Tworoger, Jayanthi Lea, Bo Li",https://www.biorxiv.org/content/10.1101/2023.10.12.562056v2,"High grade serous ovarian cancer (HGOC) is a major cause of death in women. Early detection of HGOC usually leads to a cure, yet it remains a clinical challenge with over 90% HGOCs diagnosed at advanced stages. This is mainly because conventional biomarkers are not sensitive to detect the microscopic yet metastatic early HGOC lesions. In this study, we sequenced the blood T cell receptor (TCR) repertoires of 466 ovarian cancer patients and controls, and systematically investigated the immune repertoire signatures in HGOCs. We observed quantifiable changes of selected TCRs in HGOCs that are reproducible in multiple independent cohorts. Importantly, these changes are stronger during stage I. Using pre-diagnostic patient blood samples from the Nurses’ Health Study, we confirmed that HGOC signals can be detected in the blood TCR repertoire up to 4 years proceeding conventional diagnosis. Our findings may provide the basis of an immune-based HGOC early detection criterion."
1288,Detecting significantly recurrent genomic connections from simple and complex rearrangements in the cancer genome,"Shu Zhang, Kiran H. Kumar, Ofer Shapira, Xiaotong Yao, Jeremiah Wala, Frank Dubois, Rose Gold, James E. Haber, Andrew Cherniack, Marcin Imielinski, Simona Dalin, Rameen Beroukhim",https://www.biorxiv.org/content/10.1101/2023.10.13.561748v1,"The detection of somatic genetic alterations that recur across cancer genomes more than expected by chance has been a major goal of cancer genomics, as these alterations are enriched for “driver” events that promote cancer. Multiple methods have been developed to detect driver point mutations and copy-number variants, but methods to detect driver rearrangements have largely not been pursued. Unlike point mutations and copy-number alterations, which can be assigned to a single genomic locus, rearrangements connect two distant genomic loci, and possibly more in the case of complex or clustered events. Here, we explore genomic features that predict the rate at which any pair of loci will be connected by rearrangements and describe two methods to detect rearrangements that recur more often than this background rate. The first, SVSig-2D, detects pairs of loci that are directly connected by a single rearrangement; the second, SVSig-2Dc also detects loci that are recurrently connected indirectly through two or more rearrangements. When applied to a pan-cancer dataset of over 2,500 cancers, these methods identified 80 significantly recurrent simple rearrangements and 29 complex rearrangements, including both known and novel events. Intriguingly, though both recurrent simple and complex rearrangements tended to be tissue-specific, this was less true for the complex events. The detection of recurrent rearrangements with methods such as these will be an essential component of cancer genomics in the whole-genome sequencing era."
1289,MTGCL: Multi-Task Graph Contrastive Learning for Identifying Cancer Driver Genes from Multi-omics Data,"Ming-Yu Xie, Shao-Wu Zhang, Tong Zhang, Yan Li, Xiaodong Cui",https://www.biorxiv.org/content/10.1101/2023.10.13.562159v1,"Cancer is a complex disease that typically arises from the accumulation of mutations in driver genes. Identification of cancer driver genes is crucial for understanding the molecular mechanisms of cancer, and developing the targeted therapeutic approaches. With the development of high-throughput biological technology, a large amount of genomic data and protein interaction network data have been generated, which provides abundant data resources for identifying cancer driver genes through computational methods. Given the ability of graph neural networks to effectively integrate graph structure topology information and node features information, some graph neural network-based methods have been developed for identifying cancer driver genes. However, these methods suffer from the sparse supervised signals, and also neglect a large amount of unlabeled node information, thereby affecting their ability to identify cancer driver genes. To tackle these issues, in this work we propose a novel Multi-Task Graph Contrastive Learning framework (called MTGCL) to identify cancer driver genes. By using self-supervised graph contrastive learning to fully utilize the unlabeled node information, MTGCL designs an auxiliary task module to enhance the performance of the main task of driver gene identification. MTGCL simultaneously trains the auxiliary task and main task, and shares the graph convolutional encoder weights, so that the main task enhances the discriminative ability of the auxiliary task via supervised learning, whereas the auxiliary task exploits the unlabeled node information to refine the node representation learning of the main task. The experimental results on pan-cancer and some specific cancers demonstrate the effectiveness of MTGCL in identifying the cancer driver genes. In addition, integrating multi-omics features extracted from multiple cancer-related databases can greatly enhance the performance of identifying cancer driver genes, especially, somatic mutation features can effectively improve the performance of identifying specific cancer driver genes. The source code and data are available at https://github.com/NWPU-903PR/MTGCL."
1290,Multiparameter flow cytometric detection and analysis of rare cells in in vivo models of cancer metastasis,"Mikaela M Mallin, Kenneth J. Pienta, Sarah R. Amend",https://www.biorxiv.org/content/10.1101/2023.10.12.562110v1,"Rapid and reliable circulating tumor cell (CTC) and disseminated tumor cell (DTC) detection forms a major underpinning of rigorous in vivo metastasis research. While many cancer cells initiate metastasis, very few can complete it. Clinical data evidences that each successive step of metastatic cascade presents increasing barriers to metastatic success, limiting the number of successful metastatic cells to fewer than 1 in 1,500,000,000. As such, it is critical to employ metastasis research approaches that allow scientists to discern which step(s) of the cascade present metastatic barriers to their model systems, and in which steps their model systems might display competency. Here, we present a novel flow-cytometry based method that allows for the simultaneous comparison of multiple steps of the cascade within one model system via the co-identification of CTC and DTCs from single animals. This approach is not only highly reliable and reproducible, but also broadly applicable and highly adaptable to a wide range of scientific inquiries."
1291,The circadian clock is disrupted in pancreatic cancer,"Patrick B. Schwartz, Manabu Nukaya, Mark E. Berres, Clifford D. Rubinstein, Gang Wu, John B. Hogenesch, Christopher A. Bradfield, Sean M. Ronnekleiv-Kelly",https://www.biorxiv.org/content/10.1101/2022.11.01.514735v4,"Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer – one of the deadliest malignancies – have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression."
1292,Cytokine expression patterns: A single-cell RNA sequencing and machine learning based roadmap for cancer classification,"Zhixiang Ren, Yiming Ren, Pengfei Liu, Huan Xu",https://www.biorxiv.org/content/10.1101/2023.06.01.542694v3,"Cytokines are small protein molecules that exhibit potent immunoregulatory properties, which are known as the essential components of the tumor immune microenvironment (TIME). While some cytokines are known to be universally upregulated in TIME, the unique cytokine expression patterns have not been fully resolved in specific types of cancers. To address this challenge, we develop a TIME single-cell RNA sequencing (scRNA-seq) dataset, which is designed to study cytokine expression patterns for precise cancer classification. The dataset, including 39 cancers, is constructed by integrating 695 tumor scRNA-seq samples from multiple public repositories. After screening and processing, the dataset retains only the expression data of immune cells. With a machine learning classification model, unique cytokine expression patterns are identified for various cancer categories and pioneering applied to cancer classification with an accuracy rate of 78.01%. Our method will not only boost the understanding of cancer-type-specific immune modulations in TIME but also serve as a crucial reference for future diagnostic and therapeutic research in cancer immunity."
1293,DNA Methylation Signatures in Breast Cancer: A Systematic Review and Meta-Analysis,"Antonio Manuel Trasierras-Fresco, Helena Gómez-Martínez, Z Andreu, Marta R. Hidalgo, Borja Gómez-Cabañes, Miriam Poley Gil, Pablo Malmierca-Merlo, Sergio Romera-Giner, Daniel Crespo, Roberto Serna-Blasco, Atocha Romero, Jose A Lopez-Guerrero, María de la Iglesia-Vaya, Francisco García-García",https://www.biorxiv.org/content/10.1101/2022.10.15.512358v4,"Epigenetic changes are involved in the onset and progression of cancer, and the detection of DNA methylation signatures may foster the improvement of diagnosis and prognosis. While the emergence of innovative technologies has fostered numerous studies in breast cancer, many lack statistical power due to the small sample sizes generally involved. In this study, we present a novel meta-analysis that identifies a common pattern of DNA methylation in all breast cancer subtypes. We obtained DNA methylation signatures at the gene and biological function level, identifying those significant groups of genes and functional pathways affected. To achieve this, we conducted a thorough systematic review following PRISMA statement guidelines for the selection of studies on DNA methylation in breast cancer. In total, we gathered four studies (GSE52865, GSE141338, GSE59901 and GSE101443) that were split into 13 comparisons comprising a set of 144 individuals. We discovered that most breast cancer subtypes share a significant deregulation in the immune system and alterations to the cell cycle. This integrative approach combines all available information from public data repositories and possesses greater statistical power than any individual study. Further evaluations of the identified differential biological processes and pathways may support the identification of novel biomarkers and therapeutic targets."
1294,Insulin-like Growth Factor 2 mRNA-binding protein 2 (IGF2BP2) Promotes Castration-Resistant Prostate Cancer Progression by Regulating AR-V7 mRNA Stability,"Taruna Saini, Devesh Srivastava, Rajnikant Raut, Parul Mishra, Ashish Misra",https://www.biorxiv.org/content/10.1101/2024.04.07.588211v1,"The emergence of constitutively active androgen receptor (AR) splice variant AR-V7 poses a formidable challenge in treating prostate cancer, as it lacks the ligand binding region targeted by androgen deprivation therapies such as enzalutamide and abiraterone. AR-V7 is critical for castration-resistant prostate cancer (CRPC) development and progression, however the molecular mechanisms regulating its expression and biological function remain poorly understood. Here, we investigate the role of IGF2BP2 in regulating AR-V7 expression and CRPC progression. We demonstrate that IGF2BP2 silencing leads to downregulation of AR-V7 and its downstream target genes without affecting AR levels. Additionally, IGF2BP2 knockdown also enhances the sensitivity of CRPC cells to enzalutamide while overexpression increases AR-V7 expression and confers increased resistance to enzalutamide. Mechanistically, our experiments demonstrate that IGF2BP2 binds to the intronic splicing enhancer (ISE) region of AR-V7, thereby enhancing its mRNA stability Furthermore, our domain-deletion analysis pinpoints the role of KH3 and KH4 domains of IGF2BP2 in regulating AR-V7 stability and enzalutamide resistance. Taken together, our findings suggest that IGF2BP2 plays a critical role in regulating AR-V7 expression and stability, offering a novel target for developing therapeutic interventions for CRPC."
1296,A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis,"Jiamin Lin, Pingping Zhang, Wei Liu, Guorong Liu, Juan Zhang, Min Yan, Yuyou Duan, Na Yang",https://www.biorxiv.org/content/10.1101/2023.04.03.535330v3,"Lipid metabolism plays a critical role in cancer metastasis. However, the mechanisms through which metastatic genes regulate lipid metabolism remain unclear. Here, we describe a new oncogenic-metabolic feedback loop between the epithelial-mesenchymal transition (EMT) transcription factor ZEB2 and the key lipid enzyme ACSL4 (long-chain acyl-CoA synthetase 4), resulting in enhanced cellular lipid storage and fatty acid oxidation to drive breast cancer metastasis. Functionally, Depletion of ZEB2 or ACSL4 significantly reduced lipid droplets (LD) abundance and cell migration. ACSL4 overexpression rescued the invasive capabilities of the ZEB2 knockdown cells, suggesting that ACSL4 is crucial for ZEB2-mediated metastasis. Mechanistically, ZEB2 activated ACSL4 expression by directly binding to the ACSL4 promoter. ACSL4 binds to and stabilizes ZEB2 by reducing ZEB2 ubiquitination. Notably, ACSL4 not only promotes the intracellular lipogenesis and lipid droplet accumulation but also enhances fatty acid oxidation (FAO) and ATP production by upregulating the FAO rate-limiting enzyme CPT1A (carnitine palmitoyltransferase 1 isoform A). Finally, we demonstrated that ACSL4 knockdown significantly reduced metastatic lung nodes in vivo. In conclusion, we reveal a novel positive regulatory loop between ZEB2 and ACSL4, which promotes LD storage to meet the energy needs of breast cancer metastasis, and identify the ZEB2-ACSL4 signaling axis as an attractive therapeutic target for overcoming breast cancer metastasis."
1298,Colorectal cancer as a model for biological evolution,"Marco Ledda, Alessandro Pluchino, Marco Ragusa",https://www.biorxiv.org/content/10.1101/2023.04.13.536757v1,"Complexity in cancer research has led to the creation of powerful analytical tools for helping experimental in vivo and in vitro methods. These tools range from systems of differential equations resolved in computer simulations, to lattice models and agent-based models (ABMs). These analytical methods are focused on studying cell behavior and dynamic cell populations. Among these, those that are increasingly used are ABMs because they can incorporate multi-scale features ranging from the individual up to the population level, mixing rules based on mathematical and conceptual parameters, and combining statistical/population assumptions with individual heterogeneity. In this work, we present an ABM that simulates tumor progression in a colonic crypt, with the aim of providing an experimental in silico environment for testing results achieved in traditional lab research, and developing alternative scenarios of tumor development. As the first part of an ongoing project, the long-term goal is to reproduce and study, the general evolutionary mechanisms of a biological system."
1299,Pan-cancer quantification of neoantigen-mediated immunoediting in cancer evolution,"Tao Wu, Guangshuai Wang, Xuan Wang, Shixiang Wang, Xiangyu Zhao, Chenxu Wu, Wei Ning, Ziyu Tao, Fuxiang Chen, Xue-Song Liu",https://www.biorxiv.org/content/10.1101/2022.04.08.487711v1,"Immunoediting, which includes three temporally distinct stages, termed elimination, equilibrium, and escape, has been proposed to explain the interactions between cancer cells and the immune system during the evolution of cancer. However the status of immunoediting in cancer remains unclear, and the existence of neoantigen depletion signal in untreated cancer has been debated. Here we developed a distribution pattern based method for quantifying neoantigen mediated negative selection in cancer evolution. Our method provides a robust and reliable quantification for immunoediting signal in an individual cancer patient. The prevalence of immunoediting signal in immunotherapy untreated cancer genome has been demonstrated with this method. Importantly, the elimination and escape stages of immunoediting can be quantified separately, tumor types with strong immunoediting-elimination tend to have weak immunoediting-escape signal, and vice versa. Quantified immunoediting-elimination signal predicts cancer immunotherapy clinical response. Immunoediting quantification provides an evolutional perspective for evaluating the antigenicity of neoantigen, and reveals a potential biomarker for cancer precision immunotherapy."
1302,Oncogenic KEAP1 mutations activate TRAF2-NFκB signaling to prevent apoptosis in lung cancer cells,"Ashik Jawahar Deen, Simone Adinolfi, Jouni Härkönen, Tommi Patinen, Xiaonan Liu, Tuomo Laitinen, Piia Takabe, Kirsi Kainulainen, Sanna Pasonen-Seppänen, Lisa M Gawriyski, Uma Thanigai Arasu, Ilakya Selvarajan, Petri Mäkinen, Hanna Laitinen, Emilia Kansanen, Minna U Kaikkonen, Antti Poso, Markku Varjosalo, Anna-Liisa Levonen",https://www.biorxiv.org/content/10.1101/2023.10.10.561664v1,"The Kelch-like ECH-associated protein 1 (KEAP1) – Nuclear factor erythroid 2-related factor 2 (NRF2) pathway is the major transcriptional stress response system in cells against oxidative and electrophilic stress. NRF2 is frequently constitutively active in many cancers, rendering the cells resistant to chemo- and radiotherapy. Loss-of-function (LOF) mutations in the repressor protein KEAP1 are common in non-small cell lung cancer, particularly adenocarcinoma. While the mutations can occur throughout the gene, they are enriched in certain areas, indicating that these may have unique functional importance. In this study, we show that in the GSEA analysis of TCGA lung adenocarcinoma RNA-seq data, the KEAP1 mutations in R320 and R470 were associated with enhanced Tumor Necrosis Factor alpha (TNFα) – Nuclear Factor kappa subunit B (NFκB) signaling as well as MYC and MTORC1 pathways. To address the functional role of these hotspot mutations, affinity purification and mass spectrometry (AP-MS) analysis of wild type (wt) KEAP1 and the mutants was employed to interrogate differences in the protein interactome. We identified TNF receptor associated factor 2 (TRAF2) as a putative protein interaction partner. Both mutant KEAP1 forms showed increased interaction with TRAF2 and other anti-apoptotic proteins, suggesting that apoptosis signalling could be affected by the protein interactions. A549 lung adenocarcinoma cells overexpressing mutant KEAP1 showed high TRAF2-mediated NFκB activity and increased protection against apoptosis, XIAP being one of the key proteins involved in anti-apoptotic signalling. To conclude, KEAP1 R320Q and R470C and its interaction with TRAF2 leads to activation of NFκB pathway, thereby protecting against apoptosis."
1303,GABRD promotes the progression of breast cancer through CDK1-dependent cell cycle regulation,"Qingyao Shang, Fei Ren, Kexin Feng, Chenxuan Yang, Shuangtao Zhao, Jiaxiang Liu, Xiyu Kang, Jiaxian Yue, Ruixuan Zhang, Xiangzhi Meng, Xiang Wang, Xin Wang",https://www.biorxiv.org/content/10.1101/2023.10.10.561812v1,"Purpose Y-aminobutyric acid (GABA) is an important inhibitory amino acid neurotransmitter that exerts its biological function by binding to GABA receptors, which not only play an important role in neuromodulation, but also involved in regulating the development of tumors. Gamma-aminobutyric acid type A receptor subunit delta (GABRD) encodes the δ subunit of GABAA receptor, its impact on breast cancer has not been clearly studied. This study is aiming to reveal the relationship between GABRD and breast cancer development."
1304,CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion,"Gengyi Zou, Yuanjian Huang, Shengzhe Zhang, Kyung-Pil Ko, Bongjun Kim, Jie Zhang, Vishwa Venkatesan, Melissa P. Pizzi, Yibo Fan, Sohee Jun, Na Niu, Huamin Wang, Shumei Song, Jaffer A. Ajani, Jae-Il Park",https://www.biorxiv.org/content/10.1101/2023.03.23.533976v3,"Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 gene mutations, causing E-Cadherin loss, its role in sporadic DGAC is unclear. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared to KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC’s molecular diversity and potential for personalized treatment in CDH1-inactivated patients."
1305,A “ tug-of-war” between the NuRD and SWI/SNF chromatin remodelers regulates the coordinated activation of Epithelial-Mesenchymal Transition and inflammation in oral cancer,"Roberto Stabile, Francesco A. Tucci, Mathijs P. Verhagen, Carmen Embregts, Thierry P.P. van den Bosch, Rosalie Joosten, Maria J. De Herdt, Berdine van der Steen, Alex L. Nigg, Senada Koljenović, Jose A. Hardillo, C. Peter Verrijzer, Adrian Biddle, Robert J. Baatenburg de Jong, Pieter J.M. Leenen, Riccardo Fodde",https://www.biorxiv.org/content/10.1101/2024.04.05.588102v1,"Phenotypic plasticity and inflammation, two well-established hallmarks of cancer, play key roles in local invasion and distant metastasis by enabling rapid adaptation of tumor cells to dynamic micro- environmental changes. Here, we show that in oral squamous carcinoma cell carcinoma (OSCC), the competition between the NuRD and SWI/SNF chromatin remodeling complexes plays a pivotal role in regulating both epithelial-mesenchymal plasticity (EMP) and inflammation. By perturbing these complexes, we demonstrate their opposing downstream effects on inflammatory pathways and EMP regulation. In particular, downregulation of the BRG1-specific SWI/SNF complex deregulates key inflammatory genes such as TNF-α and IL6 in opposite ways when compared with loss of CDK2AP1, a key member of the NuRD complex. We show that CDK2AP1 genetic ablation triggers a pro-inflammatory secretome encompassing several chemo- and cytokines thus promoting the recruitment of monocytes into the tumor microenvironment (TME). Furthermore, CDK2AP1 deletion stimulates their differentiation into M2-like macrophages, as also validated on tumor microarrays from OSCC patient- derived tumor samples. Further analysis of the inverse correlation between CDK2AP1 expression and TME immune infiltration revealed specific downstream effects on CD68+ macrophage abundance and localization. Our study sheds light on the role of chromatin remodeling complexes in OSCC locoregional invasion and points at the potential of CDK2AP1 and other members of the NuRD and SWI/SNF chromatin remodeling complexes as prognostic markers and therapeutic targets."
1306,Cell type specific long non-coding RNA targets identified by integrative analysis of single-cell and bulk colorectal cancer transcriptomes,"Ante Mihaljevic, Philip Rubin, Panagiotis Chouvardas, Roberta Esposito",https://www.biorxiv.org/content/10.1101/2024.01.08.574618v1,"Long non-coding RNAs (lncRNAs) represent an emerging class of genes which play significant and diverse roles in human cancers. Nevertheless, the functional repertoires of lncRNAs in cancer cell subtypes remains unknown since most studies are focused on protein coding genes. Here, we explored the contribution of lncRNAs in Colorectal Cancer (CRC) heterogeneity. We analyzed 49,436 single-cells from 29 CRC patients and showed that lncRNAs are significantly more cell type specific compared to protein-coding genes. We identified 996 lncRNAs strongly enriched in epithelial cells. Among these, 98 were found to be differentially expressed in tumor samples compared to normal controls, when integrating 270 bulk CRC profiles. We validated the upregulation of two of them (CASC19 and LINC00460) in CRC cell lines and showed their involvement in CRC proliferation by CRISPR-Cas9 knock down experiments. This study highlights a list of novel RNA targets for potential CRC therapeutics, substantiated through experimental validation."
1307,Stromal localization of inactive CD8+ T cells in metastatic mismatch repair deficient colorectal cancer,"Emre Küçükköse, Matthijs J.D. Baars, Mojtaba Amini, Suzanna J. Schraa, Evelien Floor, Guus M. Bol, Inne H.M. Borel Rinkes, Jeanine M.L. Roodhart, Miriam Koopman, Jamila Laoukili, Onno Kranenburg, Yvonne Vercoulen",https://www.biorxiv.org/content/10.1101/2023.10.09.561039v1,"Background The determinants of metastasis in mismatch repair deficiency with high levels of microsatellite instability (MSI-H) in colorectal cancer (CRC) are poorly understood. Here, we hypothesized that distinct immune and stromal microenvironments in primary tumors may discriminate between non-metastatic MSI-H CRC and metastatic MSI-H CRC."
1308,Direct excitatory synapses between neurons and tumor cells drive brain metastatic seeding of breast cancer and melanoma,"V. Venkataramani, M.A. Karreman, L.C. Nguyen, C. Tehranian, N. Hebach, C.D. Mayer, L. Meyer, S.S. Mughal, G. Reifenberger, J. Felsberg, K. Köhrer, M.C. Schubert, D. Westphal, M.O. Breckwoldt, B. Brors, W. Wick, T. Kuner, F. Winkler",https://www.biorxiv.org/content/10.1101/2024.01.08.574608v1,"Interactions between neurons and cancer cells are found in many malignancies, but their relevance for metastatic organ colonization remain largely unknown. It is also unclear whether any direct synaptic communication between neurons and cancer cells of non-neural tumor types exists, and if so, whether this can support metastasis and thus cancer progression. Here we show that excitatory synapses are formed between neurons and brain-metastatic melanoma and breast cancer cells. This starts at an early microscopic stage after extravasation into the brain parenchyma, during residence of cancer cells in the perivascular niche, a critical step for their survival. These neuron-cancer synapses showed a bona fide synaptic ultrastructure, and generated excitatory postsynaptic currents mediated by glutamate receptors of the AMPA subtype in cancer cells. In accordance, AMPA receptor signatures were consistently detected in preclinical and patient samples of melanoma and breast cancer brain metastases. Genetic perturbation and pharmacological inhibition of AMPA receptors with the approved antiepileptic drug perampanel in models of breast and melanoma cancer reduced the number of brain metastases and overall brain metastatic burden. These findings demonstrate for the first time that neurons can form biologically relevant direct synapses with non-neural cancer cells. In brain metastasis, a particularly challenging complication of many common malignancies, this non-canonical stimulatory synaptic interaction offers novel therapeutic opportunities."
1310,"Integrated Analysis of Single-Cell and Bulk RNA-Seq Data reveals that Ferroptosis-Related Genes Mediated the Tumor Microenvironment predicts Prognosis, and guides Drug Selection in Triple-Negative Breast Cancer","Xuantong Gong, Lishuang Gu, Di Yang, Yu He, Qian Li, Hao Qin, Yong Wang",https://www.biorxiv.org/content/10.1101/2024.07.04.602021v1,"Background TNBC is aggressive, lacking methods to predict recurrence and drug sensitivity. Ferroptotic heterogeneity varies in TNBC subtypes. However, the TME mediated by ferroptosis genes is unclear. Our study aims to integrate single-cell and bulk RNA-seq data to reveal the ferroptosis-mediated TME in TNBC, predicting prognosis and guiding treatment."
1311,The Minimal Dataset for Cancer of the 1+Million Genomes Initiative,"Michela Riba, Cinzia Sala, Aedin Culhane, Åsmund Flobak, Attila Patocs, Kjetil Boye, Karla Plevova, Šárka Pospíšilová, Giorgia Gandolfi, Marco J Morelli, Gabriele Bucci, Anders Edsjö, Ulrik Lassen, Fátima Al-Shahrour, Nuria Lopez-Bigas, Randi Hovland, Edwin Cuppen, Alfonso Valencia, Helene Antoine-Poirel, Richard Rosenquist Brandell, Serena Scollen, Juan Arenas Marquez, Jeroen Belien, Arcangela De Nicolo, Ruggero De Maria, David Torrents, Giovanni Tonon",https://www.biorxiv.org/content/10.1101/2023.10.07.561259v1,"For a real impact on healthcare, precision cancer medicine requires accessibility and interoperability of clinical and genomic data across centres and countries. Due to the heterogeneous digitization in Europe and worldwide, the definition of models for standardised data collection and usability becomes mandatory if countries want to work together on this mission. The European Union 1+Million Genomes (1+MG) initiative, supported by the Horizon 2020 Beyond 1 Million Genomes project, aims at outlining data models, guidance, best practices, and technical infrastructures for transnational access to sequenced genomes, including cancer genomes. Within the framework of the cancer-focused Working Group 9, we developed the 1+MG-Minimal Dataset for Cancer (1+MG-MDC)–a data model encompassing 140 items and organized in eight conceptual domains for the collection of cancer-related clinical information and genomics metadata. The 1+MG-MDC, which results from a multidisciplinary effort, leverages pre-existing models and emphasizes the annotation and traceability of multiple aspects relevant to the complex longitudinal path of the cancer disease and its treatment. We strived to make the 1+MG-MDC easy to adopt, yet comprehensive, addressing the needs of both clinicians and researchers. We will periodically revise and update it to ensure it remains fit for purpose. We propose the 1+MG-MDC as a model to create homogeneous databases, which would, in turn, guide discussions on clinical and genomic features with prognostic or therapeutic value and foster real-world data research."
1312,Exploring the tumor micro-environment in ovarian cancer histotypes and tumor sites,"Bingqing Xie, Susan Olalekan, Rebecca Back, Naa Asheley Ashitey, Heather Eckart, Anindita Basu",https://www.biorxiv.org/content/10.1101/2023.10.07.561344v1,"Ovarian cancer is a highly heterogeneous disease consisting of at least five different histological subtypes with varying clinical features, cells of origin, molecular composition, risk factors, and treatments. While most single-cell studies have focused on High grade serous ovarian cancer, a comprehensive landscape of the constituent cell types and their interactions within the tumor microenvironment are yet to be established in the different ovarian cancer histotypes. Further characterization of tumor progression, metastasis, and various histotypes are also needed to connect molecular signatures to pathological grading for personalized diagnosis and tailored treatment. In this study, we leveraged high-resolution single-cell RNA sequencing technology to elucidate the cellular compositions on 21 solid tumor samples collected from 12 patients with six ovarian cancer histotypes and both primary (ovaries) and metastatic (omentum, rectum) sites. The diverse collection allowed us to deconstruct the histotypes and tumor site-specific expression patterns of cells in the tumor and identify key marker genes and ligand-receptor pairs that are active in the ovarian tumor microenvironment. Our findings can be used in improving precision disease stratification and optimizing treatment options."
1313,Characterization of Cancer Evolution Landscape Based on Accurate Detection of Somatic Mutations in Single Tumor Cells,"Muchun Niu, Yang Zhang, Jiayi Luo, Jefferson C. Sinson, Alastair M. Thompson, Chenghang Zong",https://www.biorxiv.org/content/10.1101/2023.10.09.561356v1,"Accurate detection of somatic mutations in single tumor cells is greatly desired as it allows us to quantify the single-cell mutation burden and construct the mutation-based phylogenetic tree. Here we developed scNanoSeq chemistry and profiled 842 single cells from 21 human breast cancer samples. The majority of the mutation-based phylogenetic trees comprise a characteristic stem evolution followed by the clonal sweep. We observed the subtype-dependent lengths in the stem evolution. To explain this phenomenon, we propose that the differences are related to different reprogramming required for different subtypes of breast cancer. Furthermore, we reason that the time that the tumor-initiating cell took to acquire the critical clonal-sweep-initiating mutation by random chance set the time limit for the reprogramming process. We refer to this model as a reprogramming and critical mutation co-timing (RCMC) subtype model. Next, in the sweeping clone, we observed that tumor cells undergo a branched evolution with rapidly decreasing selection. In the most recent clades, effectively neutral evolution has been reached, resulting in a substantially large number of mutational heterogeneities. Integrative analysis with 522-713X ultra-deep bulk whole genome sequencing (WGS) further validated this evolution mode. Mutation-based phylogenetic trees also allow us to identify the early branched cells in a few samples, whose phylogenetic trees support the gradual evolution of copy number variations (CNVs). Overall, the development of scNanoSeq allows us to unveil novel insights into breast cancer evolution."
1314,G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer,"Taijin Lan, Sara Arastu, Samuel Wang, Jarrick Lam, Wenping Wang, Vrushank Bhatt, Eduardo Cararo Lopes, Zhixian Hu, Michael Sun, Xuefei Luo, Jonathan M. Ghergurovich, Changlong Li, Xiaoyang Su, Joshua D. Rabinowitz, Eileen White, Jessie Yanxiang Guo",https://www.biorxiv.org/content/10.1101/2023.10.06.561131v1,"Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NAPDH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer model, we show that ablation of G6PD significantly suppresses KrasG12D/+;Lkb1-/-(KL) but not KrasG12D/+;p53-/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics revealed that G6PD ablation significantly impaired NADPH generation, redox balance and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation caused p53 activation that suppressed tumor growth. As tumor progressed, G6PD-deficient KL tumors increased an alternative NADPH source, serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations."
1316,A zero-agnostic model for copy number evolution in cancer,"Henri Schmidt, Palash Sashittal, Benjamin J. Raphael",https://www.biorxiv.org/content/10.1101/2023.04.10.536302v1,"Motivation New low-coverage single-cell DNA sequencing technologies enable the measurement of copy number profiles from thousands of individual cells within tumors. From this data, one can infer the evolutionary history of the tumor by modeling transformations of the genome via copy number aberrations. A widely used model to infer such copy number phylogenies is the copy number transformation (CNT) model in which a genome is represented by an integer vector and a copy number aberration is an event that either increases or decreases the number of copies of a contiguous segment of the genome. The CNT distance between a pair of copy number profiles is the minimum number of events required to transform one profile to another. While this distance can be computed efficiently, no efficient algorithm has been developed to find the most parsimonious phylogeny under the CNT model."
1317,Serum Lipidome Profiling Reveals a Distinct Signature of Ovarian Cancer in Korean Women,"Samyukta Sah, Olatomiwa O. Bifarin, Samuel G. Moore, David A. Gaul, Hyewon Chung, Hanbyoul Cho, Chi-Heum Cho, Jae-Hoon Kim, Jaeyeon Kim, Facundo M. Fernández",https://www.biorxiv.org/content/10.1101/2023.10.05.560751v1,"Distinguishing ovarian cancer (OC) from other gynecological malignancies remains a critical unmet medical need with significant implications for patient survival. However, non-specific symptoms along with our lack of understanding of OC pathogenesis hinder its diagnosis, preventing many women from receiving appropriate medical assistance. Accumulating evidence suggests a link between OC and deregulated lipid metabolism. Most studies, however, are limited by small sample size, particularly for early-stage cases. Furthermore, racial/ethnic differences in OC survival and incidence have been reported, yet most of the studies consist largely of non-Hispanic white women or women with European ancestry. Studies of more diverse racial/ethnic populations are needed to make OC diagnosis and prevention more inclusive. Here, we profiled the serum lipidome of 208 OC, including 93 patients with early-stage OC, and 117 non-OC (other gynecological malignancies) patients of Korean descent. Serum samples were analyzed with a high-coverage liquid chromatography high-resolution mass spectrometry platform, and lipidome alterations were investigated via statistical and machine learning approaches. Results show that lipidome alterations unique to OC were present in Korean women as early as when the cancer is localized, and those changes increase in magnitude as the diseases progresses. Analysis of relative lipid abundances revealed specific patterns for various lipid classes, with most classes showing decreased abundance in OC in comparison to other gynecological diseases. Machine learning methods selected a panel of 17 lipids that discriminated OC from non-OC cases with an AUC of 0.85 for an independent test set. This study provides a systemic analysis of lipidome alterations in human OC, specifically in Korean women, emphasizing the potential of circulating lipids in distinguishing OC from non-OC conditions."
1318,CREB activation drives acinar to ductal reprogramming and promote pancreatic cancer progression in animal models of alcoholic chronic pancreatitis,"Supriya Srinivasan, Siddharth Mehra, Anna Bianchi, Samara Singh, Austin R. Dosch, Haleh Amirian, Sudhakar Jinka, Varunkumar Krishnamoorthy, Iago De Castro Silva, Edmond Worley Box III, Vanessa Garrido, Tulasigeri M. Totiger, Zhiqun Zhou, Yuguang Ban, Jashodeep Datta, Michael VanSaun, Nipun Merchant, Nagaraj S. Nagathihalli",https://www.biorxiv.org/content/10.1101/2024.01.05.574376v1,"BACKGROUND AND AIMS In vivo induction of alcoholic chronic pancreatitis (ACP) causes significant acinar damage, increased fibroinflammatory response, and heightened activation of cyclic response element binding protein 1 (CREB) when compared with alcohol (A) or chronic pancreatitis (CP) mediated pancreatic damage. However, the study elucidating the cooperative interaction between CREB and the oncogenic KrasG12D/+(Kras*) in promoting pancreatic cancer progression with ACP remains unexplored."
1320,NBBC: Quantifying the Prevalence of Non-B DNA Motifs as a Marker of Non-B Burden in Cancer,"Qi Xu, Jeanne Kowalski",https://www.biorxiv.org/content/10.1101/2024.01.04.574106v1,"Alternative DNA structures, such as Z-DNA, G-quadruplexes, and mirror repeats, have shown potential involvement in cancer etiology. NBBC (Non-B DNA Burden in Cancer) is a web-based tool designed for quantifying and analyzing non-B DNA motifs within a cancer context. Herein, we provide a step-by-step protocol for employing NBBC, starting with data input and proceeding through the quantification and normalization of non-B DNA motifs that result in calculation of non-B burden. With detailed instructions for performing various motif-centric analyses based on cancer gene signatures, including DNA damage repair and response pathways for exploring genomic stability, and sample-level gene mutation signatures, a user is able to explore non-B associative correlations within current cancer biology. We provide additional detail on input queries into NBBC, interpret the quantitative results, and apply normalization techniques to ensure accurate comparisons across different genomic regions and non-B DNA structures. NBBC offers a powerful and user-friendly interface for the cancer research community. This chapter serves as an essential, enhanced instructional guide for researchers to leverage NBBC in their cancer biomarker investigations for an understanding of the potential role of non-B DNA in contributing to them."
1321,High-throughput single-nucleus hybrid sequencing reveals genome-transcriptome correlations in cancer,"Siran Li, Joan Alexander, Jude Kendall, Peter Andrews, Elizabeth Rose, Hope Orjuela, Sarah Park, Craig Podszus, Liam Shanley, Rong Ma, Nissim Ranade, Michael Ronemus, Arvind Rishi, David L. Donoho, Gary L. Goldberg, Dan Levy, Michael Wigler",https://www.biorxiv.org/content/10.1101/2023.10.04.560973v1,"Single-cell genomic analyses can provide information on cellular mutation and tumor heterogeneity, whereas single-cell transcriptomic analyses can distinguish cell types and states. However, the disconnect between genomic and transcriptomic spaces limits our understanding of cancer development. To address this, we developed a novel high-throughput method that simultaneously captures both DNA and RNA from single nuclei and new algorithms for the quantitative clustering and filtering of single-cell data. We applied this hybrid protocol to 65,499 single nuclei extracted from frozen biopsies of five different endometrial cancer patients and separately clustered the genome and expression data. We also analyzed 34,651 and 21,432 nuclei using RNA-only and DNA-only protocols, respectively, from the same samples to verify the clustering. Multiple tumor genome and/or expression clusters were often present within an individual patient, and different tumor clones could project into distinct or shared expression states. Almost all possible genome-transcriptome correlations were observed in the cohort. Stromal clusters were largely shared between patients, but some patients possessed unique stromal components, or mutant stroma with a significant loss of the X chromosome. This study reveals the complex landscape involving genome and transcriptome interactions at single-cell level, and provides new insights into mutant stroma as a potential clinical biomarker."
1323,Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles,"Jing Xie, Yafei Xu, Xuhua Liu, Li Long, Ji Chen, Chunyan Huang, Yan Shao, Zhiqing Cai, Zhimin Zhang, Ruixin Zhou, Jiarong Leng, Xiaochun Bai, Qiancheng Song",https://www.biorxiv.org/content/10.1101/2023.06.14.544869v2,"Although preclinical and clinical studies have shown that exercise can inhibit bone metastasis progression, the mechanism remains poorly understood. Here, we found that non-small cell lung cancer (NSCLC) cells adjacent to bone tissue had a much lower proliferative capacity than the surrounding tumor cells. Subsequently, it was demonstrated that osteocytes, sensing mechanical stimulation generated by exercise, inhibit NSCLC cell proliferation and sustain the dormancy thereof by releasing small extracellular vesicles with tumor suppressor microRNAs, such as miR-99b-3p. Furthermore, mechanical loading of the tibia inhibited the bone metastasis progression of NSCLC. Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects. Moreover, exercise preconditioning effectively suppressed bone metastasis progression. This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression."
1324,Mitosis exit followed by death in interphase prevents the development of polyploid giant cancer cells,"Juan Jesus Vicente, Kainat Khan, Grant Tillinghast, José L. McFaline-Figueroa, Yasemin Sancak, Nephi Stella",https://www.biorxiv.org/content/10.1101/2023.08.31.555795v2,"Microtubule targeting agents (MTAs) are commonly prescribed to treat cancers and predominantly kill cancer cells in mitosis. Significantly, some MTA-treated cancer cells can escape death in mitosis and exit mitosis, and become malignant polyploid giant cancer cells (PGCC). Considering the low number of malignant cells undergoing mitosis in tumor tissue, killing these cells in interphase may represent a favored antitumor approach. We discovered that ST-401, a mild inhibitor of microtubule assembly, preferentially kills cancer cells in interphase as opposed to mitosis, and avoids the development of PGCC. Single cell RNA sequencing identified mRNA transcripts regulated by ST-401, including mRNAs involved in ribosome and mitochondrial functions. Accordingly, ST-401 induces an integrated stress response and promotes mitochondria fission accompanied by a reduction in energy metabolism. This cell response may underly death in interphase and avoid the development of PGCC."
1325,GATA3 ZnF2-defective mutant condensation underlies type I IFN-activating in breast cancer,"Yatao Chen, Yajie Wan, Xiaoying Pei, Tan Wang, Zhifang Ma, Liming Chen",https://www.biorxiv.org/content/10.1101/2023.05.02.538687v2,"Zinc finger (ZnF) transcription factors (TFs) consist of ZnF-containing DNA-binding domains (DBDs) and intrinsically disordered region (IDR)-containing activation domains (ADs). Recent studies have suggested that liquid-liquid phase separation (LLPS) is the fundamental mechanism underlying human health and disease, with ZnF TFs activating gene expression through the LLPS capacity of their IDR-containing ADs. However, little is known about how the well-folded DBD of ZnF TFs is involved in their LLPS mechanism. GATA3 is one of the most frequently mutated genes in breast cancer, and its encoded protein GATA3, which contains two ZnFs (ZnF1 and ZnF2) in its DBD, is a master regulator of immunity. Here, we show that GATA3 undergoes LLPS in cells and in vitro, and its DBD plays an important regulatory role. Mechanistically, ZnF2 in the DBD contains two arginine amino acids (R329 and R330) that provide critical charges to regulate GATA3 LLPS and DNA binding by generating multivalent electrostatic interactions. Functionally, we demonstrated that ZnF2-regulated GATA3 LLPS is the mechanism underlying the multifaceted function of GATA3 in breast cancer development and immune regulation, where aberrant GATA3 LLPS caused by artificial or breast cancer-associated ZnF2-defective mutations by reducing Suv39H1 protein stability showed significantly reduced potential in promoting breast cancer development and exhibited remarkably enhanced capacities for activating type I interferon signaling. Since ZnF is a common feature in the DBDs of ZnF TFs, by describing GATA3 as a proof-of-principle, our data suggest that ZnF-regulated LLPS may be a general mechanism underlying the multifaceted function of ZnF TFs in human health and disease."
1327,SFyNCS detects oncogenic fusions involving non-coding sequences in cancer,"Xiaoming Zhong, Jingyun Luan, Anqi Yu, Anna Lee-Hassett, Yuxuan Miao, Lixing Yang",https://www.biorxiv.org/content/10.1101/2023.04.03.535462v1,"Fusion genes are well-known cancer drivers. However, very few known oncogenic fusions involve non-coding sequences. We develop SFyNCS with superior performance to detect fusions of both protein-coding genes and non-coding sequences from transcriptomic sequencing data. We validate fusions using somatic structural variations detected from the genomes. This allows us to comprehensively evaluate various fusion detection and filtering strategies and parameters. We detect 165,139 fusions in 9,565 tumor samples across 33 tumor types in the Cancer Genome Atlas cohort. Among them, 72% of the fusions involve non-coding sequences and many are recurrent. We discover two long non-coding RNAs recurrently fused with various partner genes in 32% of dedifferentiated liposarcomas and experimentally validated the oncogenic functions in mouse model."
1328,Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer,"Atma Ivancevic, David M. Simpson, Olivia M. Joyner, Stacey M. Bagby, Lily L. Nguyen, Ben G. Bitler, Todd M. Pitts, Edward B. Chuong",https://www.biorxiv.org/content/10.1101/2021.10.28.466196v3,"Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the mechanisms underlying the formation of these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are a rich source of enhancers displaying cancer-specific activity. In colorectal cancer and other epithelial tumors, oncogenic AP1/MAPK signaling drives the activation of enhancers derived from the primate-specific ERV family LTR10. Functional studies in colorectal cancer cells revealed that LTR10 elements regulate tumor-specific expression of multiple genes associated with tumorigenesis, such as ATG12 and XRCC4. Within the human population, individual LTR10 elements exhibit germline and somatic structural variation resulting from a highly mutable internal tandem repeat region, which affects AP1 binding activity. Our findings reveal that ERV-derived enhancers contribute to transcriptional dysregulation in response to oncogenic signaling and shape the evolution of cancer-specific regulatory networks."
1329,Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy,"Zhihua Kang, Pan Fu, Hui Ma, Tao Li, Kevin Lu, Juan Liu, Vasudeva Ginjala, Peter Romanienko, Zhaohui Feng, Ming Guan, Shridar Ganesan, Bing Xia",https://www.biorxiv.org/content/10.1101/2023.10.03.560719v1,"EHTM1 (GLP) and EHMT2 (G9a) are closely related protein lysine methyltransferases often thought to function together as a heterodimer to methylate histone H3 and non-histone substrates in diverse cellular processes including transcriptional regulation, genome methylation, and DNA repair. Here we show that EHMT1/2 inhibitors cause ATM-mediated slowdown of replication fork progression, accumulation of single-stranded replication gaps, emergence of cytosolic DNA, and increased expression of STING. EHMT1/2 inhibition strongly potentiates the efficacy of alkylating chemotherapy and anti-PD-1 immunotherapy in mouse models of tripe negative breast cancer. The effects on DNA replication and alkylating agent sensitivity are largely caused by the loss of EHMT1-mediated methylation of LIG1, whereas the elevated STING expression and remarkable response to immunotherapy appear mainly elicited by the loss of EHMT2 activity. Depletion of UHRF1, a protein known to be associated with EHMT1/2 and LIG1, also induces STING expression, and depletion of either EHMT2 or UHRF1 leads to demethylation of specific CpG sites in the STING1 promoter, suggestive of a distinct EHMT2-UHRF1 axis that regulates DNA methylation and gene transcription. These results highlight distinct functions of the two EHMT paralogs and provide enlightening paradigms and corresponding molecular basis for combination therapies involving alkylating agents and immune checkpoint inhibitors."
1331,Hybrid cancer stem cells utilise vascular tracks for collective streaming invasion in a metastasis-on-a-chip device,"Alice Scemama, Sophia Lunetto, Artysha Tailor, Stefania Di Cio, Leah Ambler, Abigail Coetzee, Hannah Cottom, Syed Ali Khurram, Julien Gautrot, Adrian Biddle",https://www.biorxiv.org/content/10.1101/2024.01.02.573897v1,"Cancer stem cells (CSCs) drive cancer metastatic dissemination. They do not do so in a vacuum, and the important influence of the tumour microenvironment (TME) on metastatic dissemination is becoming increasingly recognised. Therapeutic targeting of CSC-TME interactions may be a promising route to suppression of tumour metastasis. However, we must first understand how interactions with the TME influence CSC metastatic dissemination. To achieve this understanding, there is a need for experimental models that enable the analysis of dynamic interactions at single cell resolution within a complex environment. To this end, we utilise a metastasis-on-a-chip device to produce a 3D in vitro model of CSC interaction with a developing microvasculature, that is amenable to precise imaging and real time studies at single cell resolution. We show that the invasive phenotype of oral squamous cell carcinoma (OSCC) cells is markedly altered when in proximity to a microvasculature, with a switch to a hybrid CSC phenotype that undergoes collective streaming invasion. Mechanistically, ECM compression by the developing vasculature creates an environment that is refractory to cancer invasion, whilst leaving abandoned vascular tracks that can be utilised by hybrid CSCs for collective streaming invasion. Human tissue studies identify streaming invasion in association with vascularised regions in OSCC specimens. These findings elucidate the influence of the vasculature on CSC metastatic dissemination in OSCC, and the role of hybrid CSC invasion plasticity in overcoming this TME constraint."
1332,Aged Breast Matrix Bound Vesicles Promote Breast Cancer Invasiveness,"Jun Yang, Gokhan Bahcecioglu, George Ronan, Pinar Zorlutuna",https://www.biorxiv.org/content/10.1101/2023.04.03.535436v1,"Aging is one of the inherent risk factors for breast cancer. Although the influence of age-related cellular alterations on breast cancer development has been extensively explored, little is known about the alterations in the aging breast tissue microenvironment, specifically the extracellular matrix (ECM). Here, for the first time in literature, we have identified tissue resident matrix bound vesicles (MBVs) within the healthy mouse breast ECM, investigated and compared their characteristics in young and aged healthy breast tissues, and studied the effects of these MBVs on normal (KTB21) and cancerous (MDA-MB-231) human mammary epithelial cells with respect to the tissue age that they are extracted from. Using vesicle labeling technology, we were able to visualize cellular uptake of the MBVs directly from the native decellularized tissue sections, showing that these MBVs have regulatory roles in the tissue microenvironment. We mimicked the ECM by embedding the MBVs in collagen gels, and showed that MBVs could be taken up by the cells. The miRNA and cytokine profiling showed that MBVs shifted towards a more tumorigenic and invasive phenotype with age, as evidenced by the more pronounced presence of cancer-associated cytokines, and higher expression levels of oncomiRs miR-10b, miR-30e, and miR-210 in MBVs isolated from aged mice. When treated with MBVs or these upregulated factors, KTB21 and MDA-MB-231 cells showed significantly higher motility and invasion compared to untreated controls. Treatment of cells with a cocktail of miRNAs (miR-10b, miR-30e, and miR-210) or with the agonist of adiponectin (AdipoRon), which both were enriched in the aged MBVs, recapitulated the effect of aged MBVs on cells. This study shows for the first time that the MBVs have a regulatory role in the tissue microenvironment and that the MBV contents change towards cancer-promoting upon aging. Studying the effects of MBVs and their cargos on cellular behavior could lead to a better understanding of the critical roles of MBVs played in breast cancer progression and metastasis."
1333,Colorectal cancer detection and treatment with engineered probiotics,"Candice R. Gurbatri, Georgette Radford, Laura Vrbanac, Courtney Coker, Jong-won Im, Samuel R. Taylor, YoungUk Jang, Ayelet Sivan, Kyu Rhee, Anas A. Saleh, Tiffany Chien, Fereshteh Zandkarimi, Ioana Lia, Tamsin RM Lannagan, Tongtong Wang, Josephine A Wright, Elaine Thomas, Hiroki Kobayashi, Jia Q Ng, Matt Lawrence, Tarik Sammour, Michelle Thomas, Mark Lewis, Lito Papanicolas, Joanne Perry, Tracy Fitzsimmons, Patricia Kaazan, Amanda Lim, Julie Marker, Cheri Ostroff, Geraint Rogers, Nicholas Arpaia, Daniel L Worthley, Susan L Woods, Tal Danino",https://www.biorxiv.org/content/10.1101/2023.04.03.535370v1,"Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment strategies. Here, we demonstrate the phenomenon of selective, long-term colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition. We show that, after oral administration, adenomas can be monitored over time by recovering EcN from stool. We also demonstrate specific colonization of EcN to solitary neoplastic lesions in an orthotopic murine model of CRC. We then exploit this neoplasia-homing property of EcN to develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate, and demonstrate that oral delivery of this strain results in significantly increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. We also assess EcN engineered to locally release immunotherapeutics at the neoplastic site. Oral delivery to mice bearing adenomas, reduced adenoma burden by ∼50%, with notable differences in the spatial distribution of T cell populations within diseased and healthy intestinal tissue, suggesting local induction of robust anti-tumor immunity. Together, these results support the use of EcN as an orally-delivered platform to detect disease and treat CRC through its production of screening and therapeutic molecules."
1335,Controlling pericellular oxygen tension in cell culture reveals distinct breast cancer responses to low oxygen tensions,"Zachary J. Rogers, Thibault Colombani, Saad Khan, Khushbu Bhatt, Alexandra Nukovic, Guanyu Zhou, Benjamin M. Woolston, Cormac T. Taylor, Daniele M. Gilkes, Nikolai Slavov, Sidi A. Bencherif",https://www.biorxiv.org/content/10.1101/2023.10.02.560369v1,"Oxygen (O2) tension plays a key role in tissue function and pathophysiology. O2-controlled cell culture, in which the O2 concentration in an incubator’s gas phase is controlled, is an indispensable tool to study the role of O2 in vivo. For this technique, it is presumed that the incubator setpoint is equal to the O2 tension that cells experience (i.e., pericellular O2). We discovered that physioxic (5% O2) and hypoxic (1% O2) setpoints regularly induce anoxic (0.0% O2) pericellular tensions in both adherent and suspension cell cultures. Electron transport chain inhibition ablates this effect, indicating that cellular O2 consumption is the driving factor. RNA-seq revealed that primary human hepatocytes cultured in physioxia experience ischemia-reperfusion injury due to anoxic exposure followed by rapid reoxygenation. To better understand the relationship between incubator gas phase and pericellular O2 tensions, we developed a reaction-diffusion model that predicts pericellular O2 tension a priori. This model revealed that the effect of cellular O2 consumption is greatest in smaller volume culture vessels (e.g., 96-well plate). By controlling pericellular O2 tension in cell culture, we discovered that MCF7 cells have stronger glycolytic and glutamine metabolism responses in anoxia vs. hypoxia. MCF7 also expressed higher levels of HIF2A, CD73, NDUFA4L2, etc. and lower levels of HIF1A, CA9, VEGFA, etc. in response to hypoxia vs. anoxia. Proteomics revealed that 4T1 cells had an upregulated epithelial-to-mesenchymal transition (EMT) response and downregulated reactive oxygen species (ROS) management, glycolysis, and fatty acid metabolism pathways in hypoxia vs. anoxia. Collectively, these results reveal that breast cancer cells respond non-monotonically to low O2, suggesting that anoxic cell culture is not suitable to model hypoxia. We demonstrate that controlling atmospheric O2 tension in cell culture incubators is insufficient to control O2 in cell culture and introduce the concept of pericellular O2-controlled cell culture."
1336,Predicting efficacy of immunotherapy in mice with triple negative breast cancer using a cholesterol PET radiotracer,"Nicholas G. Ciavattone, Jenny Guan, Alex Farfel, Timothy Desmond, Benjamin L. Viglianti, Peter JH Scott, Allen F. Brooks, Gary D. Luker",https://www.biorxiv.org/content/10.1101/2023.10.02.560577v1,"Predicting the response to cancer immunotherapy remains an unmet challenge in triple-negative breast cancer (TNBC) and other malignancies. T cells, the major target of current checkpoint inhibitor immunotherapies, accumulate cholesterol during activation to support proliferation and signaling. The requirement of cholesterol for anti-tumor functions of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged a novel positron emission tomography (PET) radiotracer, FNP-59. FNP-59 is an analog of cholesterol that our group has validated as an imaging biomarker for cholesterol uptake in pre-clinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing immune checkpoint inhibitor (ICI)-responsive EO771 tumors to non-responsive AT-3 tumors, we found significantly higher uptake of a fluorescent cholesterol analog in T cells of the ICI-responsive tumors both in vitro and in vivo. Using the FNP-59 radiotracer, we discovered that accumulation of cholesterol by T cells increased further in ICI-responding tumors that received ant-PD-1 checkpoint immunotherapy. We verified these data by mining single cell sequencing data from patients with TNBC. Patients with tumors containing cycling T cells showed gene expression signatures of cholesterol uptake and trafficking. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells predict T cell activation and success of ICI therapy."
1337,Natural killer cell regulation of breast cancer stem cells mediates metastatic dormancy,"Grace G. Bushnell, Deeksha Sharma, Henry C. Wilmot, Michelle Zheng, Toluwaleke D. Fashina, Chloe M. Hutchens, Samuel Osipov, Max S. Wicha",https://www.biorxiv.org/content/10.1101/2023.10.02.560493v1,"Breast cancer patients with estrogen receptor positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cells display “stem like” properties (CSCs), which may be regulated by the immune system. Although many studies have examined tumor cell intrinsic characteristics of dormancy, the role of the immune system in controlling dormancy and its escape is not well understood. This scientific gap is due, in part, to a lack of immunocompetent mouse models of breast cancer dormancy with many studies involving human xenografts in immunodeficient mice. To overcome this limitation, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. We find that PyMT, Met-1 and D2.0R cell lines contain CSCs that display both short- and long-term metastatic dormancy in vivo, which is dependent on the host immune system. Natural killer cells were key for the metastatic dormancy phenotype observed for D2.0R and the role of NK cells in regulating CSCs was further investigated. Quiescent D2.0R CSC are resistant to NK cytotoxicity, while proliferative D2.0R CSC were sensitive to NK cytotoxicity both in vitro and in vivo. This resistance was mediated, in part, by the expression of Bach1 and Sox2 transcription factors. NK killing was enhanced by the STING agonist MSA-2. Collectively, our findings demonstrate the important role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon."
1338,Splitpea: quantifying protein interaction network rewiring changes due to alternative splicing in cancer,"Ruth Dannenfelser, Vicky Yao",https://www.biorxiv.org/content/10.1101/2023.09.04.556262v2,"Protein-protein interactions play an essential role in nearly all biological processes, and it has become increasingly clear that in order to better understand the fundamental processes that underlie disease, we must develop a strong understanding of both their context specificity (e.g., tissue-specificity) as well as their dynamic nature (e.g., how they respond to environmental changes). While network-based approaches have found much initial success in the application of protein-protein interactions (PPIs) towards systems-level explorations of biology, they often overlook the fact that large numbers of proteins undergo alternative splicing. Alternative splicing has not only been shown to diversify protein function through the generation of multiple protein isoforms, but also remodel PPIs and affect a wide range diseases, including cancer. Isoform-specific interactions are not well characterized, so we develop a computational approach that uses domain-domain interactions in concert with differential exon usage data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression project (GTEx). Using this approach, we can characterize PPIs likely disrupted or possibly even increased due to splicing events for individual TCGA cancer patient samples relative to a matched GTEx normal tissue background."
1341,ARF6-dependent endocytic trafficking of the Interferon-γ receptor drives adaptive immune resistance in cancer,"Yinshen Wee, Junhua Wang, Emily C. Wilson, Coulson P. Rich, Aaron Rogers, Zongzhong Tong, Evelyn DeGroot, Y.N. Vashisht Gopal, Michael A. Davies, H. Atakan Ekiz, Joshua K.H. Tay, Chris Stubben, Kenneth M. Boucher, Juan M. Oviedo, Keke C. Fairfax, Matthew A. Williams, Sheri L. Holmen, Roger K. Wolff, Allie H. Grossmann",https://www.biorxiv.org/content/10.1101/2023.09.29.560199v1,"Adaptive immune resistance (AIR) is a protective process used by cancer to escape elimination by CD8+ T cells. Inhibition of immune checkpoints PD-1 and CTLA-4 specifically target Interferon-gamma (IFNγ)-driven AIR. AIR begins at the plasma membrane where tumor cell-intrinsic cytokine signaling is initiated. Thus, plasma membrane remodeling by endomembrane trafficking could regulate AIR. Herein we report that the trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR. ARF6 prevents transport of the receptor to the lysosome, augmenting IFNγR expression, tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to immune checkpoint blockade (ICB). Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent AIR, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor influences outcomes of ICB."
1344,Keystone pathobionts associated with colorectal cancer promote oncogenic reprograming,"Josh Jones, Qiaojuan Shi, Rahul R. Nath, Ilana L. Brito",https://www.biorxiv.org/content/10.1101/2023.04.03.535410v1,"Fusobacterium nucleatum (Fn) and enterotoxigenic Bacteroides fragilis (ETBF) are two pathobionts consistently enriched in the gut microbiomes of patients with colorectal cancer (CRC) compared to healthy counterparts and frequently observed for their direct association within tumors. Although several molecular mechanisms have been identified that directly link these organisms to features of CRC in specific cell types, their specific effects on the epithelium and local immune compartment are not well-understood. To fill this gap, we leveraged single-cell RNA sequencing (scRNA-seq) on wildtype mice and mouse model of CRC. We find that Fn and ETBF exacerbate cancer-like transcriptional phenotypes in transit-amplifying and mature enterocytes in a mouse model of CRC. We also observed increased T cells in the pathobiont-exposed mice, but these pathobiont-specific differences observed in wildtype mice were abrogated in the mouse model of CRC. Although there are similarities in the responses provoked by each organism, we find pathobiont-specific effects in Myc-signaling and fatty acid metabolism. These findings support a role for Fn and ETBF in potentiating tumorigenesis via the induction of a cancer stem cell-like transit-amplifying and enterocyte population and the disruption of CTL cytotoxic function."
1345,Engineering living immunotherapeutic agents for improved cancer treatment,"Tinotenda Gwisai, Sina Günther, Matej Vizovisek, Mira Jacobs, Simone Schuerle",https://www.biorxiv.org/content/10.1101/2023.03.31.535049v1,"Bacteria-based biohybrid agents are emerging as a promising strategy for cancer therapy due to their ability to actively target tumors, trigger localized inflammation and induce tumor regression. There has been growing interest in using bacteria that are responsive to external cues, such as magnetic fields, to facilitate the formation of robust colonies in tumor the achieve the threshold for clinical efficacy. Several studied have demonstrated the potential of innately magnetically responsive bacteria, known as magnetotactic bacteria (MTB), as steerable agents, however, their immunostimulatory properties and therapeutic effects are yet to be explored. Here, we characterize key properties of human immune cell responses and the behavior of the MTB strain Magnetospirillum magneticum AMB-1 in physiological environments. This work investigates the ability of MTB to maintain magnetic properties, viability in whole blood, cytokine production by macrophages, and the ability to increase uptake of cancer cell material by dendritic cells. This study also explores the use of MTB-liposome complexes for effective delivery of therapeutic payloads. Overall, this study establishes the potential of MTB as a versatile, combined drug delivery platform for immune-mediated cancer therapy."
1347,CXCR2-mediated recruitment of adaptive NK cells with NKG2C/HLA-E dependent antigen-specific memory enhances tumor killing in ovarian cancer,"Yizhe Sun, Andrea Rodgers-Furones, Okan Gultekin, Shruti Khare, Shi Yong Neo, Wenyang Shi, Lidia Moyano Galceran, Kong-Peng Lam, Ramanuj Dasgupta, Jonas Fuxe, Sahar Salehi, Kaisa Lehti, Dhifaf Sarhan",https://www.biorxiv.org/content/10.1101/2024.03.28.585607v1,"Natural killer (NK) cells have emerged as promising effectors in cancer immunotherapy due to their ability to recognize and eliminate tumor cells. To investigate the immunological memory and tumor reactivity of adaptive (a)NK cells in the context of desmoplastic tumors, we used human ovarian cancer as a model. Through in vitro culture systems resembling dendritic cell (DC)-mediated T cell activation, we demonstrated that aNK cells exhibit antigen-specific cytotoxic responses and memory generation towards ovarian tumor antigens. Furthermore, mature DCs presenting tumor-associated antigens induced the expansion of aNK cells, suggesting antigen-specific proliferation. Single-cell transcriptomics revealed a distinct genetic signature of aNK cells in tumor samples, characterized by a cytotoxic phenotype and interactions with myeloid cells, particularly DCs. The spatial analysis confirmed the intratumoral presence of aNK cells, with higher abundance in the tumor nest compared to conventional (c)NK cells. Functional assays demonstrated the cytotoxicity of expanded aNK cells against autologous ovarian tumors, accompanied by an activated receptor profile. Importantly, aNK cells displayed antigen-specific memory responses towards primary tumors, maintaining specificity over time. Blockade of NKG2C and HLA-E influenced aNK cell recall responses, indicating their roles in the adaptive NK cell immune memory. Additionally, CXCR2 was essential for efficient aNK cell migration toward tumors. These findings shed light on the therapeutic potential of aNK cells in ovarian cancer immunotherapy, highlighting their ability to develop immunological memory and effectively eradicate tumor cells."
1350,"Crude extract of Ruellia tuberosa L. flower induces intracellular ROS, promotes DNA damage and apoptosis in Triple Negative Breast Cancer Cells","Subhabrata Guha, Debojit Talukdar, Gautam Kumar Mandal, Rimi Mukherjee, Srestha Ghosh, Rahul Naskar, Prosenjit Saha, Nabendu Murmu, Gaurav Das",https://www.biorxiv.org/content/10.1101/2024.03.26.586749v1,"Ethnophamacological relevance In the traditional folklore medicine system, the primary uses of Ruellia tuberosa L. include as a diuretic, anti-hypertensive, antipyretic, anti-diabetic, analgesic, and gastroprotective agent. Some reports also demonstrated that it has been used to treat gonorrhea-like diseases."
1351,Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer associated fibroblasts,"Richard J. Burt, Aditi Dey, Ayse Akarca, Hermione Allen, Rodothea Amerikanou, Samantha Atkinson, David Auty, Jenny Chatzigerou, Emily Cutler, Jose Afonso Guerra-Assuncao, Kristina Kirschner, Ruchi Kumari, Jiten Manji, Teresa Marafiotti, Adele K. Fielding",https://www.biorxiv.org/content/10.1101/2023.09.26.559490v1,"Cancer associated fibroblasts (CAF) arising from bone marrow-derived mesenchymal stromal cells (MSC) are prominent in B-precursor acute lymphoblastic leukaemia (B-ALL). We have previously shown that CAF formation is triggered by exposure to reactive oxygen species-inducing chemotherapy and that CAF support chemoresistance by donating mitochondria to the cancer cells, through tunnelling nanotubes. In the present study, we show that exposure of MSC to ALL cell lines, PDX and primary cells or their conditioned media can also trigger CAF formation, in an oncogene-dependent manner. Using bulk RNA sequencing in cell lines, we show that the MSC to CAF transition is accompanied by a robust interferon pathway response and we have validated this finding in primary cells. Using confocal microscopy and flow cytometry, we identify the take up of leukaemia cell-derived mitochondrial dsRNA by MSC as a proximate trigger for the MSC to CAF transition. We show that degradation of dsRNA in ALL cell conditioned media by DMSO ablates the ability of the conditioned media to stimulate MSC to CAF transition. Since we find that only specific primary driver genetic subtypes of B-ALL possess the property to directly generate CAFs, we propose this phenomenon as the first mechanistic insight into the strong relationship between acute lymphoblastic leukaemia genetic subtype and survival outcomes."
1352,Targeting wild-type IDH1 enhances chemosensitivity in pancreatic cancer,"Mehrdad Zarei, Omid Hajihassani, Jonathan J. Hue, Hallie J. Graor, Luke D. Rothermel, Jordan M. Winter",https://www.biorxiv.org/content/10.1101/2023.03.29.534596v1,"Pancreatic cancer (PC) is one of the most aggressive types of cancer, with a five-year overall survival rate of 11% among all-comers. Current systemic therapeutic options are limited to cytotoxic chemotherapies which have limited clinical efficacy and are often associated with development of drug resistance. Analysis of The Cancer Genome Atlas showed that wild-type isocitrate dehydrogenase (wtIDH1) is overexpressed in pancreatic tumors. In this study, we focus on the potential roles of wtIDH1 in pancreatic cancer chemoresistance. We found that treatment of pancreatic cancer cells with chemotherapy induced expression of wtIDH1, and this serves as a key resistance factor. The enzyme is protective to cancer cells under chemotherapy-induced oxidative stress by producing NADPH and alpha-ketoglutarate to maintain redox balance and mitochondrial function. An FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtDH1 inhibitor under a nutrient-deprived microenvironment, reflective of the pancreatic cancer microenvironment. Suppression of wtIDH1 impairs redox balance, results in increased ROS levels, and enhances chemotherapy induced apoptosis in pancreatic cancer vis ROS damage in vitro. In vivo experiments further revealed that inhibiting wtIDH1 enhances chemotherapy anti-tumor effects in patient-derived xenografts and murine models of pancreatic cancer. Pharmacologic wtIDH1 inhibition with ivosidenib represents an attractive option for combination therapies with cytotoxic chemotherapy for patients with pancreatic cancer. Based on these data, we have initiated phase Ib trial combining ivosidenib and multi-agent chemotherapy in patients with pancreatic cancer (NCT05209074)."
1353,EZH2 deletion does not impact acinar cell regeneration but restricts progression to pancreatic cancer in mice,"Emilie Jaune-Pons, Xiaoyi Wang, Fatemeh Mousavi, Samad Elkaoutari, Kurt Berger, Charis Johnson, Mickenzie M. Martin, Saloni Aggarwal, Sukhman Brar, Khalid Muhammad, Joanna Ryan, Parisa Shooshtari, Angela J. Mathison, Nelson Dusetti, Raul Urrutia, Gwen Lomberk, Christopher L. Pin",https://www.biorxiv.org/content/10.1101/2023.09.25.559339v1,"Enhancer of Zeste Homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which induces trimethylation of lysine 27 on histone 3 (H3K27me3) and promotes genes repression. EZH2 is overexpressed in many cancers including pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice attributed both pro-oncogenic and tumor suppressive functions to EZH2. Deletion of the EZH2 enhances de novo KRAS-driven neoplasia following pancreatic injury by preventing acinar cell regeneration, while increased EZH2 expression in PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 function in pre-and early neoplastic stages of PDAC. Using an inducible model to generate deletion of EZH2 only in adult acinar cells (EZH2ΔSET), we showed loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D), nor lead to increased PanIN formation in the presence of KRASG12D in adult mice. However, loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a PDAC model, promoted widespread PDAC progression. Loss of EZH2 function also correlated to remodeling of the tumor microenvironment, which favors cancer cell progression. This study suggests expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumour microenvironment and acinar cell differentiation."
1355,The immune response to a fungus in pancreatic cancer samples,"KJ Brayer, JA Hanson, S Cingam, C Martinez, SA Ness, I Rabinowitz",https://www.biorxiv.org/content/10.1101/2023.03.28.534606v1,"Pancreatic ductal adenocarcinoma (PDAC) is a poor prognosis cancer with an .aggressive growth profile that is often diagnosed at late stage and that has few curative or therapeutic options. PDAC growth has been linked to alterations in the pancreas microbiome, which could include the presence of the fungus Malassezia. We used RNA-sequencing to compare 14 paired tumor and normal (tumor adjacent) pancreatic cancer samples and found Malassezia RNA in both the PDAC and normal tissues. Although the presence of Malassezia was not correlated with tumor growth, a set of immune- and inflammatory-related genes were up-regulated in the PDAC compared to the normal samples, suggesting that they are involved in tumor progression. Gene set enrichment analysis suggests that activation of the complement cascade pathway and inflammation could be involved in pro PDAC growth."
1356,Interpretable Deep Learning for Breast Cancer Cell Phenotyping Using Diffraction Images from Lens-Free Digital In-Line Holography,"Tzu-Hsi Song, Mengzhi Cao, Jouha Min, Hyungsoon Im, Hakho Lee, Kwonmoo Lee",https://www.biorxiv.org/content/10.1101/2021.05.29.446284v2,"Lens-free digital in-line holography (LDIH) offers a wide field of view at micrometer-scale resolution, surpassing the capabilities of lens-based microscopes, making it a promising diagnostic tool for high-throughput cellular analysis. However, the complex nature of holograms renders them challenging for human interpretation, necessitating time- consuming computational processing to reconstruct object images. To address this, we present HoloNet, a novel deep learning architecture specifically designed for direct analysis of holographic images from LDIH in cellular phenotyping. HoloNet extracts both global features from diffraction patterns and local features from convolutional layers, achieving superior performance and interpretability compared to other deep learning methods. By leveraging raw holograms of breast cancer cells stained with well-known markers ER/PR and HER2, HoloNet demonstrates its effectiveness in classifying breast cancer cell types and quantifying molecular marker intensities. Furthermore, we introduce the feature-fusion HoloNet model, which extracts diffraction features associated with breast cancer cell types and their marker intensities. This hologram embedding approach allows for the identification of previously unknown subtypes of breast cancer cells, facilitating a comprehensive analysis of cell phenotype heterogeneity, leading to precise breast cancer diagnosis."
1357,NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model,"Ismail M Meraz, Mourad Majidi, Renduo Song, Meng Feng, Lihui Gao, Qi Wang, Jing Wang, Elizabeth Shpall, Jack A Roth",https://www.biorxiv.org/content/10.1101/2024.03.26.586829v1,"NPRL2/TUSC4 is a tumor suppressor gene whose expression is reduced in many cancers including NSCLC. Restoration of NPRL2 expression in cancer cells induces DNA damage which leads to cell cycle arrest and apoptosis. We investigated the antitumor immune responses to NPRL2 gene therapy in aPD1R/ KRAS/STK11mt NSCLC in a humanized mouse model. Humanized mice were generated by transplanting fresh human cord blood derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung metastases were developed from KRAS/STK11mt/aPD1R A549 cells in humanized mice and treated with NPRL2 gene-loaded cationic lipid nanoparticles (DOTAP-NPRL2) with or without pembrolizumab (aPD1). NPRL2 treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. The antitumor effect was greater in humanized than non-humanized mice suggesting that an immune response contributed to antitumor activity. NPRL2 combined with pembrolizumab was not synergistic in the KRAS/STK11mt/aPD1R tumors but was synergistic in the KRASwt/aPD1S H1299 tumors. Consistent with the A549 humanized mouse model, NPRL2 showed a significantly strong antitumor effect on KRASmt/aPD1R LLC2 syngeneic tumors, whereas aPD1 was ineffective. The antitumor effect of NPRL2 was correlated with increased infiltration of human cytotoxic immune cells and Ag-presenting HLA-DR+ DC, CD11c DC, and downregulation of myeloid and regulatory T cells in the TME. The antitumor effect of NPRL2 was significantly abolished upon in-vivo depletion of CD8 T, macrophages, and CD4 T cells. However, the antitumor effect remained unaffected upon in-vivo depletion of NK cells. A distinct pattern of gene expression profile was found in lung met after NPRL2 treatment in humanized mice. The expression of genes associated with T cell functions, including IFNγ, CD8b, CD7, TNFSF18, ITGA1, GATA3, and TBX21 was significantly increased, whereas the expression of genes associated with negative regulation of T cell functions, including FOXP3, TGFB1, TGFB2, and IL-10RA were strongly inhibited upon NPRL2 treatment. NPRL2 downregulated the expression of T cell co-inhibitory molecules, including CTLA4, ICOS, LAG3, PDCD1, CD274, IDO1, PDCD1LG2, CD47, and KLRB1. Tumors established from NPRL2 stably expressing cells in humanized mice exhibited significantly slower growth compared to controls. TME analysis showed an increased presence of human CD45+, CD3+ T, CD8+ T cells, and HLA-DR+ dendritic cells and a decreased percentage of Treg, CD3+PD1+T cells, MDSC, and CD163+ TAM in NPRL2-expressing tumors. In-vitro, NPRL2 stably expressing cells showed a substantial increase in colony formation inhibition and heightened sensitivity to carboplatin in colony formation, apoptosis, and PARP cleavage assays. Stable expression of NPRL2 resulted in the downregulation of MAPK and AKT-mTOR growth signaling through inhibition of pAKT, pmTOR, pPRAS40, p4E-BP1, and pS6 expression. Taken together, these data suggest that NPRL2 gene therapy induces antitumor activity on KRAS/STK11mt/aPD1R tumors through DC-mediated antigen presentation and cytotoxic immune cell activation."
1358,An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing,"Zhongxiao Li, Bin Zhang, Jia Jia Chan, Hossein Tabatabaeian, Qing Yun Tong, Xiao Hong Chew, Xiaonan Fan, Patrick Driguez, Charlene Chan, Faith Cheong, Shi Wang, Bei En Siew, Ian Jse-Wei Tan, Kai-Yin Lee, Bettina Lieske, Wai-Kit Cheong, Dennis Kappei, Ker-Kan Tan, Xin Gao, Yvonne Tay",https://www.biorxiv.org/content/10.1101/2023.04.21.536771v3,"Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. In recent years, short-read single-cell RNA sequencing (scRNA-seq) has been instrumental in deciphering tumor cell heterogeneities. However, these studies only enable gene-level expression quantification but neglect alterations in transcript structures, which arise from alternative end processing or splicing, and are frequently observed in cancer. In this study, we integrated short- and long-read scRNA-seq of CRC patient samples to build the first isoform-resolution CRC transcriptomic atlas. We identified 394 dysregulated transcript structures in tumor epithelial cells, including 299 resulting from various combinations of multiple splicing events. Secondly, we characterized genes and isoforms associated with epithelial lineages and subpopulations that exhibit distinct prognoses. Finally, we built an algorithm that integrated novel peptides derived from predicted ORFs of recurrent tumor-specific transcripts with mass spectrometry data and identified a panel of recurring neoepitopes that may aid the development of neoantigen-based cancer vaccines."
1360,"Orphan nuclear receptor NR2E3 and its small-molecule agonist induce cancer cell apoptosis through regulating p53, IFNα and MYC pathways","Yidan Wang, Todd Kroll, Linhui Hao, Ansul Sharma, Vivian Zhou, Luke Moat, John Mayer, Sanjay S. Shukla, Scott Hebbring, Song Guo, Marissa Iden, Adam Bissonnette, Gene Ananiev, Deepak Parashar, Janet S. Rader, Siegfried Janz, Zhi Wen",https://www.biorxiv.org/content/10.1101/2023.12.26.573366v1,"Orphan nuclear receptor NR2E3 activates p53 and induces cancer cell apoptosis. Further studies on p53-dependent and -independent functions of wild-type and mutated NR2E3 are needed. Herein, we showed that NR2E3 enhanced p53-DNA interactions in diverse cancer cells and up-regulated p53 and IFNα pathways while down-regulating MYC pathway in cervical cancer cells. Studies of “All of Us” and TCGA databases showed NR2E3 nonsynonymous mutations’ associating with four cancers. We stratified NR2E3 SNVs for their cancer implications with the p53 reporter. A cancer-associated NR2E3R97Hmutation not only lost the wild-type’s tumor-suppressing functions but also prohibited the wild-type from enhancing p53 acetylation. These observations implicated the potential for pharmaceutically activating NR2E3 to suppress cancer. Indeed, NR2E3’s small-molecule agonist 11a repressed 2-D and 3-D cultures of primary cells and cell lines of cervical cancer, in which screening FDA-approved anti-cancer drugs identified HDAC-1/2 inhibitor Romidepsin operating synergistically with 11a. The underlying molecular mechanisms included 11a’s down-regulating the transcription of Multidrug Resistance Protein ABCB1 that Romidepsin up-regulated. Transcriptomics studies revealed three synergy modes: (1) “sum-up” mode that the p53 pathway activated individually by 11a and Romidepsin got stronger by the combo; (2) “antagonism” mode that Romidepsin counteracted the activation of the Kras pathway by 11a; and (3) “de novo” mode that the combo instead of each individual drug repressed the MYC pathway. Conclusively, our experiments provide new data supporting tumor-suppressor like functions for wild-type NR2E3, reveal roles of mutated NR2E3 in cancer, and address values of NR2E3’s agonist 11a in cancer therapy alone and combined."
1361,Detection of reproducible liver cancer specific ligand-receptor signaling in blood,"Aram Safrastyan, Damian Wollny",https://www.biorxiv.org/content/10.1101/2023.09.25.559274v1,"Cell-cell communication mediated by ligand-receptor interactions (LRI) is critical to coordinating diverse biological processes in homeostasis and disease. Lately, our understanding of these processes has greatly expanded through the inference of cellular communication, utilizing RNA extracted from bulk tissue or individual cells. Considering the challenge of obtaining tissue biopsies for these approaches, we considered the potential of studying cell-free RNA obtained from blood. To test the feasibility of this approach, we used the BulkSignalR algorithm across 295 cell-free RNA samples and compared the LRI profiles across multiple cancer types and healthy donors. Interestingly, we detected specific and reproducible LRIs particularly in the blood of liver cancer patients compared to healthy donors. We found an increase in the magnitude of hepatocyte interactions, notably hepatocyte autocrine interactions in liver cancer patients. Additionally, a robust panel of 30 liver cancer-specific LRIs presents a bridge linking liver cancer pathogenesis to discernible blood markers. In summary, our approach shows the plausibility of detecting liver LRIs in blood and builds upon the biological understanding of cell-free transcriptomes."
1362,Surface-engineered extracellular vesicles to modulate antigen-specific T cell expansion for cancer immunotherapy,"Xiabing Lyu, Tomoyoshi Yamano, Shota Imai, Toan Van Le, Dilireba Bolidong, Makie Ueda, Shota Warashina, Hidefumi Mukai, Seigo Hayashi, Kazutaka Matoba, Taito Nishino, Rikinari Hanayama",https://www.biorxiv.org/content/10.1101/2023.09.25.559260v1,"Extracellular vesicles (EVs), including exosomes, are emerging as novel mediators of cell-cell communications, involved in various processes such as immune activation and immunosuppression. Despite the recent development of several EVs-based cancer immunotherapies, their clinical efficacy remained limited. Here, using fusion with tetraspanin as one of the EV engineering techniques, we created antigen-presenting extracellular vesicles (AP-EVs) to reproduce the functional characteristics of professional antigen-presenting cells (APCs). AP-EVs were also equipped with surface-bound IL-2, a feature not inherent to APCs, which facilitated selective delivery of IL-2 to antigen-specific CD8+ T cells. AP-EVs were engineered to express a peptide-major histocompatibility class I (pMHCI) complex, a costimulatory CD80 molecule, and IL-2, allowing the simultaneous presentation of multiple immune modulators to antigen-specific CD8+ T cells. This promoted the clonal expansion and differentiation of antigen-specific cytotoxic T lymphocytes, leading to potent anticancer immune responses. Combination therapy with AP-EVs and anti-PD-1 demonstrated enhanced anticancer immunity against established tumors compared with anti-PD-1 monotherapy. Our engineered EVs represent a novel effective strategy for cancer immunotherapy."
1363,Analysis of evolutionary dynamics and clonal architecture in prostate cancer,"Jake R. Conway, Alok K. Tewari, Sabrina Y. Camp, Seunghun Han, Jett Crowdis, Meng Xiao He, Yaw A. Nyame, Saud H. AlDubayan, Nikolaus Schultz, Zoltan Szallasi, Mark M. Pomerantz, Matthew L. Freedman, Lawrence Fong, Peter S. Nelson, Myles Brown, Keyan Salari, Eliezer Van Allen",https://www.biorxiv.org/content/10.1101/2023.03.23.533974v1,"The extent to which clinical and genomic characteristics associate with prostate cancer clonal architecture, tumor evolution, and therapeutic response remains unclear. Here, we reconstructed the clonal architecture and evolutionary trajectories of 845 prostate cancer tumors with harmonized clinical and molecular data. We observed that tumors from patients who self-reported as Black had more linear and monoclonal architectures, despite these men having higher rates of biochemical recurrence. This finding contrasts with prior observations relating polyclonal architecture to adverse clinical outcomes. Additionally, we utilized a novel approach to mutational signature analysis that leverages clonal architecture to uncover additional cases of homologous recombination and mismatch repair deficiency in primary and metastatic tumors and link the origin of mutational signatures to specific subclones. Broadly, prostate cancer clonal architecture analysis reveals novel biological insights that may be immediately clinically actionable and provide multiple opportunities for subsequent investigation."
1365,Multi-omics biomarkers aid prostate cancer prognostication,"Zhuoran Xu, Mohamed Omar, Elisa Benedetti, Jacob Rosenthal, Renato Umeton, Jan Krumsiek, Mark Pomerantz, Eddie Imada, Massimo Loda, Luigi Marchionni",https://www.biorxiv.org/content/10.1101/2022.09.20.508244v1,"Effective biomarkers and diagnostic tools are urgently needed in clinical settings for improved management of prostate cancer patients, especially to reduce over-treatment of indolent tumors and for early identification of aggressive disease. Gene expression signatures are currently the “gold standard” to provide guide clinical decision, however their clinical utility and interpretability is questionable. Multi-modal molecular profiling provides an holistic approach to systematically unravel the biological complexity underlying cancer pathogenesis, hence biomarkers developed using such an integrated approach hold the potential to more accurately capture cancer-driving alterations than signatures based on a single omics modality. Currently, however, robust and reproducible multi-omics biomarkers are still lacking for prostate cancer. In this study, we analyzed transcriptomics and metabolomics profiles jointly in a prostate cancer cohort and identified two prognostic signatures with high statistical powers (signature 1: EGLN3, succinate, trans-4-hydroxyprolin; and signature 2: IL6, SLC22A2, histamine). Our approach leveraged a priori biological knowledge of the cellular metabolism and gene circuitry, enabling the identification of dysregulated network modules. Functional bioinformatics analyses suggest that these signatures can capture relevant molecular alterations in prostate cancer tissues, including dysregulations of cellular signaling, cell cycle progression, and immune system modulation, stratifying patients in distinct risk groups. Next, we trained two gene expression signatures as a proxy for the multi-omics ones, extending our investigation to publicly available data, further confirming their prognostic values in independent patient cohorts. In summary, the analysis of multi-modal molecular grounded in cellular network biology represents a promising approach for the development of robust prognostic biomarkers of detecting and discriminating high grade disease."
1366,KRAS inhibition activates an actionable CD24 ‘don’t eat me’ signal in pancreas cancer,"Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Madelaine S. Theady, Jungho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Yong Zhou, Hong Zhao, Andrea Viale, Huamin Wang, Dan Zhao, Ronald A. DePinho, Wantong Yao, Haoqiang Ying",https://www.biorxiv.org/content/10.1101/2023.09.21.558891v1,"KRASG12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the tumor biology of the KRASG12C allele and possible bypass mechanisms, we developed a novel autochthonous KRASG12C-driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a ‘hot’ tumor immune microenvironment. Immunoprofiling revealed that CD24, a ‘do-not-eat-me’ signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Our study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC."
1367,Stable breast cancer prognosis,"Xiaomei Li, Lin Liu, Jiuyong Li, Thuc D. Le",https://www.biorxiv.org/content/10.1101/2021.09.13.460002v1,"Predicting breast cancer prognosis helps improve the treatment and management of the disease. In the last decades, many prediction models have been developed for breast cancer prognosis based on transcriptomic data. A common assumption made by these models is that the test and training data follow the same distribution. However, in practice, due to the heterogeneity of breast cancer and the different environments (e.g. hospitals) where data are collected, the distribution of the test data may shift from that of the training data. For example, new patients likely have different breast cancer stage distribution from those in the training dataset. Thus these existing methods may not provide stable prediction performance for breast cancer prognosis in situations with the shift of data distribution. In this paper, we present a novel stable prediction method for reliable breast cancer prognosis under data distribution shift. Our model, known as Deep Global Balancing Cox regression (DGBCox), is based on the causal inference theory. In DGBCox, firstly high-dimensional gene expression data is transferred to latent network-based representations by a deep auto-encoder neural network. Then after balancing the latent representations using a proposed causality-based approach, causal latent features are selected for breast cancer prognosis. Causal features have persistent relationships with survival outcomes even under distribution shift across different environments according to the causal inference theory. Therefore, the proposed DGBCox method is robust and stable for breast cancer prognosis. We apply DGBCox to 12 test datasets from different breast cancer studies. The results show that DGBCox outperforms benchmark methods in terms of both prediction accuracy and stability. We also propose a permutation importance algorithm to rank the genes in the DGBCox model. The top 50 ranked genes suggest that the cell cycle and the organelle organisation could be the most relevant biological processes for stable breast cancer prognosis."
1368,Chemical proteomic approach for in-depth glycosylation profiling of plasma carcinoembryonic antigen in cancer patients,"Jin Chen, Lijun Yang, Chang Li, Luobin Zhang, Weina Gao, Ruilian Xu, Ruijun Tian",https://www.biorxiv.org/content/10.1101/2023.09.22.558933v1,"Carcinoembryonic antigen (CEA) of human plasma is a biomarker of many cancer diseases, and its N-glycosylation accounts for 60% of molecular mass. It is highly desirable to characterize its glycoforms for providing additional dimension of features to increase its performance in prognosis and diagnosis of cancers. However, to systematically characterize its site-specific glycosylation is challenging due to its low abundance. Here, we developed a highly sensitive strategy for in-depth glycosylation profiling of plasma CEA through chemical proteomics combined with multi-enzymatic digestion. A trifunctional probe was utilized to generate covalent bond of plasma CEA and its antibody upon UV irradiation. As low as 1 ng/mL CEA in plasma could be captured and digested with trypsin and chymotrypsin for intact glycopeptide characterization. Twenty six out of 28 potential N-glycosylation sites were well identified, which were the most comprehensive N-glycosylation site characterization of CEA on intact glycopeptide level as far as we known. Importantly, this strategy was applied to the glycosylation analysis of plasma CEA in cancer patients. Differential site-specific glycoforms of plasma CEA were observed in patients with colorectal carcinomas (CRC) and lung cancer. The distributions of site-specific glycoforms were different as the progression of CRC, and most site-specific glycoforms were overexpressed in stage II of CRC. Overall, we established a highly sensitive chemical proteomic method to profile site-specific glycosylation of plasma CEA, which should generally applicable to other well-established cancer glycoprotein biomarkers for improving their cancer diagnosis and monitoring performance."
1369,Pyruvate dehydrogenase kinase expression profile is a biomarker for cancer sensitivity to dichloroacetate-mediated growth inhibition,"Bevan P Gang, Melissa Rooke, Ramon C Sun, Samagya Banskota, Sheenu Mishra, Jane E Dahlstrom, Anneke C Blackburn",https://www.biorxiv.org/content/10.1101/2023.09.18.557101v1,"Background Cancer cells favour glycolysis and lactate production over mitochondrial metabolism despite the presence of oxygen (the Warburg effect). Increased pyruvate dehydrogenase kinase (PDK) activity contributes to this glycolytic phenotype. Dichloroacetate (DCA) is a PDK inhibitor with anti-cancer potential that inhibits all four isoforms of PDK but with differing potencies, thus expression of different isoforms may determine sensitivity to DCA."
1370,A resource-based mechanistic framework for castration-resistant prostate cancer (CRPC),"B. Vibishan, B.V. Harshavardhan, Sutirth Dey",https://www.biorxiv.org/content/10.1101/2023.09.19.558379v1,"Cancer therapy often leads to the selective elimination of drug-sensitive cells from the tumour. This can favour the growth of cells resistant to the therapeutic agent, ultimately causing a tumour relapse. Castration-resistant prostate cancer (CRPC) is a well-characterised instance of this phenomenon. In CRPC, after systemic androgen deprivation therapy (ADT), a subset of drug-resistant cancer cells autonomously produce testosterone, thus enabling tumour regrowth. A previous theoretical study has shown that such a tumour relapse can be delayed by inhibiting the growth of drug-resistant cells using biotic competition from drug-sensitive cells. In this context, the centrality of resource dynamics to intra-tumour competition in the CRPC system indicates clear scope for the construction of theoretical models that can explicitly incorporate the underlying mechanisms of tumour ecology. In the current study, we use a modified logistic framework to model cell-cell interactions in terms of the production and consumption of resources. Our results show that steady state composition of CRPC can be understood as a composite function of the availability and utilisation efficiency of two resources-oxygen and testosterone. In particular, we show that the effect of changing resource availability or use efficiency is conditioned by their general abundance regimes. Testosterone typically functions in trace amounts and thus affects steady state behaviour of the CRPC system differently from oxygen, which is usually available at higher levels. Our data thus indicate that explicit consideration of resource dynamics can produce novel and useful mechanistic understanding of CRPC. Furthermore, such a modelling approach also incorporates variables into the system’s description that can be directly measured in a clinical context. This is therefore a promising avenue of research in cancer ecology that could lead to therapeutic approaches that are more clearly rooted in the biology of CRPC."
1372,Patient-Derived Medullary Thyroid Cancer Organoids; a Model for Patient-tailored Drug and PET-Tracer Screening,"Luc H.J. Sondorp, Eline C. Jager, Inês F. Antunes, Rufina Maturi, Liesbeth Jansen, Wouter T. Zandee, Adrienne H. Brouwers, Thera P. Links, Robert P. Coppes, Schelto Kruijff",https://www.biorxiv.org/content/10.1101/2023.09.18.558266v1,"Background Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from the parafollicular C-cells of the thyroid gland. PET imaging, with various PET tracers, is performed when distant metastatic disease is suspected. After the recognition of progressive disease on imaging, targeted therapy may be initiated to prolong survival. Mutations in the gene encoding the REarranged during Transfection (RET) tyrosine kinase play a key role in the development of MTC. It seems that tyrosine kinase inhibitors (TKIs) inhibit tumor proliferation, but it remains challenging to determine the best patient specific treatment option. Here, we aim to set up an in vitro MTC organoid model to study its potential for patient-tailored drug-screening and uptake of PET tracers."
1373,Leveraging the p53 signaling pathway as a radio-sensitization strategy in endometrial cancer,"Roberto Vargas, Aaron Petty, Brian Yard, Arda Durmaz, Kristi Lin-Rahardja, Ofer Reizes, Robert Debernardo, Jacob Scott",https://www.biorxiv.org/content/10.1101/2022.09.06.505009v3,"Endometrial cancer (EC) is the most common type of gynecologic malignancy in the United States, with over 66, 200 new cases expected in 2023. The number of mortalities per year now approximate that of ovarian cancer. Despite our ability to identify different biologic clusters of EC, we have yet to understand the functional impact of key genomic alterations associated with discrepant prognoses and exploit this knowledge for therapeutic benefit. Given this, we set out to determine how alterations in p53 signaling, as conferred my TP53 mutations, impact radiotherapy response in EC. We also explored if manipulation of this signaling pathway could be utilized as a radio-sensitization strategy in EC. Our work demonstrates that p53 signaling plays a significant role in radiotherapy response for EC and that leveraging this genomic data may allow us to exploit this pathway as a viable radiotherapeutic target in a significant number of EC cases."
1374,Discovery of multi-state gene cluster switches determining the adaptive mitochondrial and metabolic landscape of breast cancer,"Michela Menegollo, Robert B. Bentham, Tiago Henriques, Seow Qi Ng, Ziyu Ren, Clarinde Esculier, Sia Agarwal, Emily Tong, Clement Lo, Sanjana Ilangovan, Zorka Szabadkai, Matteo Suman, Neill Patani, Avinash Ghanate, Kevin Bryson, Robert C. Stein, Mariia Yuneva, Gyorgy Szabadkai",https://www.biorxiv.org/content/10.1101/2023.02.17.528922v3,"Adaptive metabolic switches are proposed to underlie conversions between cellular states during normal development as well as in cancer evolution, where they represent important therapeutic targets. However, the full spectrum, characteristics and regulation of existing metabolic switches are unknown. We propose that metabolic switches can be recognised by locating large alternating gene expression patterns and associate them with specific metabolic states. We developed a method to identify interspersed genesets by massive correlated biclustering (MCbiclust) and to predict their metabolic wiring. Testing the method on major breast cancer transcriptome datasets we discovered a series of gene sets with switch-like behaviour, predicting mitochondrial content, activity and central carbon fluxes in tumours associated with different switch positions. The predictions were experimentally validated by bioenergetic profiling and metabolic flux analysis of 13C-labelled substrates and were ultimately extended by geneset analysis to link metabolic alterations to cellular states, thus predicting tumour pathology, prognosis and chemosensitivity. The method is applicable to any large and heterogeneous transcriptome dataset to discover metabolic and associated pathophysiological states."
1377,Lactose blocks intercellular spreading of Galectin-1 from cancer cells to T-cells and activates tumor immunological control,"Yu Hong, Xiaofang Si, Wenjing Liu, Xueying Mai, Yu Zhang",https://www.biorxiv.org/content/10.1101/2023.12.19.572484v1,"Understanding the mechanisms by which the immune system surveils cancer is the key to developing better tumor immunotherapy strategies. By CRISPR/Cas9 screenings, we identified that inactivation of beta-1,4-galactosyltransferase-1 (B4GALT1), a key enzyme in glycoconjugate biosynthesis, leads to enhanced T-cell receptor (TCR) activation and functions of CD8+ T-cells. Via proximity-dependent-intercellular-protein-spreading (PDICPS), cancer cells transfer surface-bound galectin-1 (Gal-1) proteins, which recognize and bind galactosylated membrane proteins, to CD8+ T-cells, thereby suppressing T-cell-mediated cytolysis. B4GALT1-deficiency leads to reduced cell-surface galactosylation and Gal-1 binding of CD8+ T-cells. Proteomic analysis revealed reduced binding of Gal-1 with TCR and its coreceptor CD8 on B4GALT1-deficient CD8+ T-cells, leading to enhanced TCR-CD8 colocalization and T-cell activation. Lactose, a structure-mimicking competitive inhibitor of N-glycan galactosylation, enhances the functions of CD8+ T-cells and tumor immunosurveillance. Results from various preclinical tumor models demonstrate that lactose and its derivatives are a new class of immune checkpoint inhibitors for tumor immunotherapy."
1379,Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14,"Chi Zhang, Luiza Tunes, Meng-Hsiung Hsieh, Ping Wang, Ashwani Kumar, Brijesh B. Khadgi, YenYu Yang, Katelyn A. Doxtader, Emily Herrell, Oliwia Koczy, Rohit Setlem, Xunzhi Zhang, Bret Evers, Yinsheng Wang, Chao Xing, Hao Zhu, Yunsun Nam",https://www.biorxiv.org/content/10.1101/2023.03.16.532618v1,"Chemical modification of RNAs is important for post-transcriptional gene regulation. The METTL3-METTL14 complex generates most N6-methyladenosine (m6A) modifications in mRNAs, and dysregulated methyltransferase expression has been linked to numerous cancers. Here we show that changes in m6A modification location can impact oncogenesis. A gain-of-function missense mutation found in cancer patients, METTL14R298P, promotes malignant cell growth in culture and in transgenic mice. The mutant methyltransferase preferentially modifies noncanonical sites containing a GGAU motif and transforms gene expression without increasing global m6A levels in mRNAs. The altered substrate specificity is intrinsic to METTL3-METTL14, helping us to propose a structural model for how the METTL3-METTL14 complex selects the cognate RNA sequences for modification. Together, our work highlights that sequence-specific m6A deposition is important for proper function of the modification and that noncanonical methylation events can impact aberrant gene expression and oncogenesis."
1382,Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity,"Kathleen E. Houlahan, Aziz Khan, Noah F Greenwald, Robert B. West, Michael Angelo, Christina Curtis",https://www.biorxiv.org/content/10.1101/2023.03.15.532870v1,"Cancer represents a broad spectrum of molecularly and morphologically diverse diseases. Individuals with the same clinical diagnosis can have tumors with drastically different molecular profiles and clinical response to treatment. It remains unclear when these differences arise during disease course and why some tumors are addicted to one oncogenic pathway over another. Somatic genomic aberrations occur within the context of an individual’s germline genome, which can vary across millions of polymorphic sites. An open question is whether germline differences influence somatic tumor evolution. Interrogating 3,855 breast cancer lesions, spanning pre-invasive to metastatic disease, we demonstrate that germline variants in highly expressed and amplified genes influence somatic evolution by modulating immunoediting at early stages of tumor development. Specifically, we show that the burden of germline-derived epitopes in recurrently amplified genes selects against somatic gene amplification in breast cancer. For example, individuals with a high burden of germline-derived epitopes in ERBB2, encoding human epidermal growth factor receptor 2 (HER2), are significantly less likely to develop HER2-positive breast cancer compared to other subtypes. The same holds true for recurrent amplicons that define four subgroups of ER-positive breast cancers at high risk of distant relapse. High epitope burden in these recurrently amplified regions is associated with decreased likelihood of developing high risk ER-positive cancer. Tumors that overcome such immune-mediated negative selection are more aggressive and demonstrate an “immune cold” phenotype. These data show the germline genome plays a previously unappreciated role in dictating somatic evolution. Exploiting germline-mediated immunoediting may inform the development of biomarkers that refine risk stratification within breast cancer subtypes."
1383,Mechanical regulation of cell fate transitions underlying colorectal cancer metastasis formation,"Mirjam C van der Net, Marjolein J Vliem, Lars JS Kemp, Carlos Perez-Gonzalez, Esther A Strating, Ana Krotenberg-Garcia, Ronja M Houtekamer, Karen B van den Anker, Jooske L Monster, Hugo JG Snippert, Antoine A Khalil, Jacco van Rheenen, Saskia JE Suijkerbuijk, Onno Kranenburg, Danijela Matic Vignjevic, Martijn Gloerich",https://www.biorxiv.org/content/10.1101/2023.09.17.557771v1,"Colorectal cancer (CRC) cells exhibit high plasticity and transition between different cellular states during the development of metastasis. Lgr5-expressing cancer stem cells fuel the growth of the primary tumor and metastasis, yet disseminated tumor cells arriving at the metastatic site are devoid of Lgr5 expression. It is currently unknown how CRC cell fate transitions are regulated during the metastatic process and how tumor cells give rise to metastatic lesions despite being Lgr5neg. Here, we show that the reprogramming of disseminating CRC cells is driven by mechanical interactions with the Collagen I-rich interstitial matrix. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a fetal-like state. The fetal-like state is maintained after reaching the blood circulation and promotes metastasis-initiation of disseminated CRC cells in the liver. Our findings indicate a key contribution of mechanical signals in controlling cell fate transitions that underlie the metastatic potential of CRC, involving an interplay between different mechanosensitive mechanisms."
1384,Auranofin induces lethality driven by reactive oxygen species in high-grade serous ovarian cancer cells,"Farah H. Abdalbari, Elvis Martinez-Jaramillo, Benjamin N. Forgie, Estelle Tran, Edith Zorytcha, Alicia A. Goyeneche, Carlos M. Telleria",https://www.biorxiv.org/content/10.1101/2023.09.13.557629v1,"High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases in the clinical setting; the survival rate for this disease remains remarkably low due to the lack of long-term consolidation therapies following the standard platinum-based chemotherapy, which is not long lasting as the disease recurs as platinum resistant. The purpose of this study was to explore a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant agent through the inhibition of thioredoxin reductase (TrxR), an antioxidant enzyme that is overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant agent, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrate that AF potently inhibits TrxR activity and reduces the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We show that AF induces accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Yet, AF-induced cell death is abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF is associated with the activation of caspases-3/7 and the generation of DNA damage, effects that are also prevented by the presence of NAC. Finally, when AF and L-BSO are combined, we observed a synergistic lethality against HGSOC cells, which is mediated by a further increase in ROS together with a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their platinum sensitivities suggesting that depletion of antioxidants is an efficient route for treating this disease."
1385,Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides,"James H. Schofield, Joseph Longo, Ryan D. Sheldon, Emma Albano, Mark A. Hawk, Sean Murphy, Loan Duong, Sharif Rahmy, Xin Lu, Russell G. Jones, Zachary T. Schafer",https://www.biorxiv.org/content/10.1101/2023.09.14.557799v1,"Targeting PD-1 is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment (TME). Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1 resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naïve CD8+ T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+ T cell proliferation is not dependent on secretion of ITA, but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy."
1386,Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells,"Elliot Ensink, Tessa Jordan, Hyllana C D Medeiros, Galloway Thurston, Anmol Pardal, Lei Yu, Sophia Y. Lunt",https://www.biorxiv.org/content/10.1101/2023.09.15.557984v1,"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality and limited efficacious therapeutic options. PDAC cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. One critical metabolic shift in PDAC cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PK). Pancreatic cancer cells preferentially upregulate pyruvate kinase muscle isoform 2 isoform (PKM2). PKM2 expression reprograms many metabolic pathways, but little is known about its impact on cystine metabolism. Cystine metabolism is critical for supporting survival through its role in defense against ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by unchecked lipid peroxidation. To improve our understanding of the role of PKM2 in cystine metabolism and ferroptosis in PDAC, we generated PKM2 knockout (KO) human PDAC cells. Fascinatingly, PKM2KO cells demonstrate a remarkable resistance to cystine starvation mediated ferroptosis. This resistance to ferroptosis is caused by decreased PK activity, rather than an isoform-specific effect. We further utilized stable isotope tracing to evaluate the impact of glucose and glutamine reprogramming in PKM2KO cells. PKM2KO cells depend on glutamine metabolism to support antioxidant defenses against lipid peroxidation, primarily by increased glutamine flux through the malate aspartate shuttle and utilization of ME1 to produce NADPH. Ferroptosis can be synergistically induced by the combination of PKM2 activation and inhibition of the cystine/glutamate antiporter in vitro. Proof-of-concept in vivo experiments demonstrate the efficacy of this mechanism as a novel treatment strategy for PDAC."
1388,Reduced glutamate decarboxylase 1 underlies morphine-promoted lung metastasis of triple-negative breast cancer in mice,"Shih-Hong Chen, Chien-Hung Shih, Ting-Ling Ke, Chia-Ni Hsiung, Kuo-Chin Chen, Zi-Xuan Huang, Tsung-Hsien Chuang, Li-Kuei Chen, Linyi Chen",https://www.biorxiv.org/content/10.1101/2023.09.14.557710v1,Introduction Morphine is commonly used for cancer-related pain management. Long-term morphine use is not only addictive but also has been associated with risk factor for cancer.
1389,Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer,"Tej Tummala, Ashley Sanchez Sevilla Uruchurtu, Arielle De La Cruz, Kelsey E. Huntington, Andrew George, Nicholas R. Liguori, Leiqing Zhang, Lanlan Zhou, Abbas E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry",https://www.biorxiv.org/content/10.1101/2023.09.13.557653v1,"Pancreatic cancer is a devastating disease with a poor prognosis. Novel chemotherapeutics in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin stalls and degrades RNA Polymerase II and introduces breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin’s highly efficient killing of human-derived pancreatic tumor cell lines PANC-1, BxPC-3, and HPAF-II as a single agent. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of γH2AX, a DNA damage marker, and the Chk1/ATR pathway, involved in replicative stress and DNA damage response. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-fluorouracil (5-FU) results in highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer."
1390,Increased ‘selfness’ in the tumor emerges as a possible immune sculpting mechanism: A pan-cancer data analysis of 32 solid tumors in TCGA,"Naren Chandran Sakthivel, Anoushka Chinmayi, Nagasuma Chandra",https://www.biorxiv.org/content/10.1101/2024.03.18.585489v1,"Tumors pose a unique challenge to the immune system since they straddle the boundary between ‘self’ and ‘non-self’. T-cells recognize tumors that contain ‘non-self’ neo-antigens. They can also recognize tumors that contain aberrantly expressed self-antigens, highlighting the importance of the central tolerance and the tuning of the T-cell repertoire in the thymus. Therefore, the similarity to the thymic expression profiles must have information in it to influence the T-cell repertoire and what self-peptides are recognized. We utilize this principle in a pan-cancer analysis and develop a thymus-like or ‘selfness’ score (TLS) based on the gene-expression similarity to thymi, indicative of recognizability of tumors by T-cells. We show that the TLS is indicative of patient survival in 8 different TCGA cohorts, indicating gene expression modulation to mimic that in thymi as a potential immune sculpting mechanism. Surprisingly, we also see an inverse relationship between TLS and the degree of immune infiltration."
1391,ULK1-dependent phosphorylation of PKM2 antagonizes O-GlcNAcylation and inhibits the Warburg effect in breast cancer,"Zibin Zhou, Xiyuan Zheng, Jianxin Zhao, Aiyun Yuan, Guangcan Shao, Bin Peng, Meng-Qiu Dong, Quan Xu, Xingzhi Xu, Jing Li",https://www.biorxiv.org/content/10.1101/2023.09.14.557850v1,"Pyruvate kinase M2 (PKM2) is a central metabolic enzyme driving the Warburg effect in tumor growth. Previous investigations have demonstrated that PKM2 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification, which is a nutrient-sensitive post-translational modification. Here we found that unc-51 like autophagy activating kinase 1 (ULK1), a glucose-sensitive kinase, interacts with PKM2 and phosphorylates PKM2 at Ser333. Ser333 phosphorylation antagonizes PKM2 O-GlcNAcylation, promotes its tetramer formation and enzymatic activity, and decreases its nuclear localization. By downregulating glucose consumption and lactate production, PKM2 pS333 attenuates the Warburg effect. Through mouse xenograft assays, we demonstrate that the phospho-deficient PKM2-S333A mutant promotes tumor growth in vivo. In conclusion, we identified a ULK1-PKM2-c-Myc axis in inhibiting breast cancer, and a glucose-sensitive phosphorylation of PKM2 in modulating the Warburg effect."
1393,CCR2-targeting pepducins reduce T cell-nociceptor interaction driving bone cancer pain,"Élora Midavaine, Rebecca L. Brouillette, Élizabeth Théberge, Christine E. Mona, Sakeen W. Kashem, Jérôme Côté, Vera Zeugin, Élie Besserer-Offroy, Jean-Michel Longpré, Éric Marsault, Philippe Sarret",https://www.biorxiv.org/content/10.1101/2023.09.15.556569v1,"Inhibition of the CCL2/CCR2 chemokine signaling represents a promising avenue for the development of non-opioid pain treatment, particularly for painful bone metastases. To investigate the involvement of CCR2 in cancer-induced bone pain, we generated and characterized the functional activities of a novel cell-penetrating pepducin, namely PP101, acting as an intracellular negative allosteric modulator of CCR2. In vivo, PP101 was effective in relieving neuropathic and bone cancer pain. By targeting CCR2, PP101 reduced bone cancer pain by preventing infiltration of CD4+ and CD8+ T cells and by decreasing the neuroimmune communication network within the dorsal root ganglia. Importantly, reduced neuroinflammatory milieu in the dorsal root ganglia induced by PP101 did not result in deleterious tumor progression or behavioral adverse effects. Thus, targeting the neuroimmune crosstalk through allosteric inhibition of CCR2 may represent an effective and safe avenue for the management of bone cancer pain."
1394,Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography,"Hannah E. Greenwood, Richard S. Edwards, Will E. Tyrrell, Abigail R. Barber, Friedrich Baark, Muhammet Tanc, Eman Khalil, Aimee Falzone, Nathan P. Ward, Janine M. DeBlasi, Laura Torrente, David R. Pearce, George Firth, Lydia M. Smith, Oskar Vilhelmsson Timmermand, Ariana Huebner, Madeleine E. George, Charles Swanton, Robert E. Hynds, Gina M. DeNicola, Timothy H. Witney",https://www.biorxiv.org/content/10.1101/2023.12.16.572007v1,"Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system xc−, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)-ʟ-glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system xc− activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system xc− is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [18F]FSPG as predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway."
1396,Loss-of-function cancer-associated mutations in the EIF4G2 non-canonical translation initiation factor,"Sara Meril, Marcela Bahlsen, Miriam Eisenstein, Alon Savidor, Yishai Levin, Shani Bialik, Shmuel Pietrokovski, Adi Kimchi",https://www.biorxiv.org/content/10.1101/2023.08.22.554280v2,"Tumor cells often exploit the protein translation machinery, resulting in enhanced protein expression essential for tumor growth. Since canonical translation initiation is often suppressed due to cell stress in the tumor microenvironment, non-canonical translation initiation mechanisms become particularly important for shaping the tumor proteome. EIF4G2 is a non-canonical translation initiation factor that mediates internal ribosome entry site [IRES] and upstream open reading frame [uORF] dependent initiation mechanisms, which can be used to modulate protein expression in cancer. Here we explored the contribution of EIF4G2 to cancer by screening the COSMIC database for EIF4G2 somatic mutations in cancer patients. Functional examination of missense mutations revealed deleterious effects on EIF4G2 protein-protein interactions, and importantly, on its ability to mediate non-canonical translation initiation. Specifically, one mutation, R178Q, led to reductions in protein expression and near complete loss-of-function. Two other mutations within the MIF4G domain specifically affected EIF4G2’s ability to mediate IRES-dependent translation initiation but not that of target mRNAs with uORFs. These results shed light on both the structure-function of EIF4G2 and its potential tumor suppressor effects."
1397,Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer,"Mustafa Emre Gedik, Ozge Saatci, Nathaniel Oberholtzer, Meral Uner, Ozge Akbulut, Metin Cetin, Mertkaya Aras, Kubra Ibis, Burcu Caliskan, Erden Banoglu, Stefan Wiemann, Aysegul Uner, Sercan Aksoy, Shikhar Mehrotra, Ozgur Sahin",https://www.biorxiv.org/content/10.1101/2023.09.12.557273v1,"Immunogenic cell death (ICD), an immune-priming form of cell death, has been shown to be induced by several different anti-cancer therapies. Despite being the first and one of the most successful antibody-drug conjugates (ADCs) approved for refractory HER2-positive breast cancer, little is known if response and resistance to trastuzumab emtansine (T-DM1) involves ICD modulation that can be leveraged to enhance T-DM1 response. Here, we report that T-DM1 induces spindle assembly checkpoint (SAC)-dependent ICD in sensitive cells by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which are lost in resistance. Accordingly, an ICD-related gene signature correlates with clinical response to T-DM1-containing therapy. We found that transforming acidic coiled-coil containing 3 (TACC3) is overexpressed in T-DM1 resistant cells, and that T-DM1 responsive patients have reduced TACC3 protein while the non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 revives T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition elicits ICD in vivo shown by vaccination assay, and it potentiates T-DM1 by inducing dendritic cell (DC) maturation and enhancing infiltration of cytotoxic T cells in the human HER2-overexpressing MMTV.f.huHER2#5 (Fo5) transgenic model. Together, our results show that ICD is a key mechanism of action of T-DM1 which is lost in resistance, and that targeting TACC3 restores T-DM1-mediated ICD and overcomes resistance."
1398,Contrasting roles of different mismatch repair proteins in basal-like breast cancer,"Jiao Mo, Nicholas Borcherding, Sung Jo, Tanzia Islam Tithi, Edward Cho, Kailey E Cash, Masayoshi Honda, Lei Wang, Kawther K. Ahmed, Ronald Weigel, Maria Spies, Ryan Kolb, Weizhou Zhang",https://www.biorxiv.org/content/10.1101/2023.07.20.549745v2,"The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely unknown. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS). MSH2 expression is frequently elevated due to genomic amplification or gain-of-expression in BLBC, which results in increased MSH2 protein to pair with MSH6 (collectively referred to as MutSα). Genetic deletion of MSH2 or MLH1 results in a contrasting phenotype in metastasis, with MSH2-deletion leading to reduced metastasis and MLH1-deletion to enhanced liver or lung metastasis. Mechanistically, MSH2-deletion induces the expression of a panel of chemokines in BLBC via epigenetic and/or transcriptional regulation, which leads to an immune reactive tumor microenvironment (TME) and elevated immune cell infiltrations. MLH1 is not correlated with chemokine expression and/or immune cell infiltration in BLBC, but its deletion results in strong accumulation of neutrophils that are known for metastasis promotion. Our study supports the differential functions of MSH2 and MLH1 in BLBC progression and metastasis, which challenges the paradigm of the MMR pathway as a universal tumor suppressive mechanism."
1399,"Metabolomic, proteomic and single cell proteomic analysis of cancer cells treated with the KRASG12D inhibitor MRTX1133",Benjamin C. Orsburn,https://www.biorxiv.org/content/10.1101/2023.03.23.533981v2,"Mutations in KRAS are common drivers of human cancers and are often those with the poorest overall prognosis for patients. A recently developed compound, MRTX1133, has shown promise in inhibiting the activity of KRASG12D mutant proteins, one of the main drivers in pancreatic cancer. To better understand the mechanism of action of this compound I performed both proteomics and metabolomics on four KRASG12D mutant pancreatic cancer cell lines. To obtain increased granularity in the proteomic observations, single cell proteomics was successfully performed on two of these lines. Following quality filtering, a total of 1,498 single cells were analyzed. From these cells 3,140 total proteins were identified with approximately 953 proteins quantified per cell. At 48 hours of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing total abundance of the KRAS protein in each respective cell, results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at the www.massive.ucsd.edu at accessions PXD039597, PXD039601 and PXD039600."
1400,IMPALA: A Comprehensive Pipeline for Detecting and Elucidating Mechanisms of Allele Specific Expression in Cancer,"Glenn Chang, Vanessa L. Porter, Kieran O’Neill, Luka Culibrk, Vahid Akbari, Marco A. Marra, Steven J. M. Jones",https://www.biorxiv.org/content/10.1101/2023.09.11.555771v1,"Summary Allele-specific expression (ASE), where transcripts from one allele are more abundant than transcripts from the other, can arise from various genetic mechanisms and has implications for gene regulation and disease. We present IMPALA (Integrated Mapping and Profiling of Allelically-expressed Loci with Annotations), a versioned and containerized pipeline for detecting ASE in samples including cancer genomes. IMPALA leverages RNA sequencing data and, optionally, phased variant, copy number variant (CNV), allelic methylation, and mutation data to identify ASE genes and uncover underlying regulatory mechanisms. IMPALA incorporates the MBASED framework for ASE detection, and outputs a comprehensive summary table and informative figures to visualize the genomic distribution of ASE genes and their correlation with potential regulatory causes. We applied IMPALA to a cancer sample and identified thousands of genes with ASE and highlighted potential somatic events that may have influenced ASE of these genes. ASE data can be used to detect the downstream consequences of genomic alterations, which facilitates the identification of dysregulated cancer-related genes. IMPALA thus provides researchers with a powerful tool for both ASE analysis and for investigating genetic factors correlated with ASE."
1401,The role of heparan sulfate in enhancing the chemotherapeutic response in triple-negative breast cancer,"Jasmine M Manouchehri, Lynn Marcho, Mathew A Cherian",https://www.biorxiv.org/content/10.1101/2023.09.08.556819v1,"Background Among women worldwide, breast cancer has the highest incidence and is the leading cause of cancer-related death. Patients with the triple-negative breast cancer (TNBC) subtype have an inferior prognosis in comparison to other breast cancers because current therapies do not facilitate long-lasting responses. Thus, there is a demand for more innovative therapies that induce durable responses."
1402,Simplicity: web-based visualization and analysis of high-throughput cancer cell line screens,"Alexander L. Ling, Weijie Zhang, Adam Lee, Yunong Xia, Mei-Chi Su, Robert F. Gruener, Sampreeti Jena, Yingbo Huang, Siddhika Pareek, Yuting Shan, R. Stephanie Huang",https://www.biorxiv.org/content/10.1101/2023.09.08.556619v1,"High-throughput drug screens are a powerful tool for cancer drug development. However, the results of such screens are often made available only as raw data, which is intractable for researchers without informatic skills, or as highly processed summary statistics, which can lack essential information for translating screening results into clinically meaningful discoveries. To improve the usability of these datasets, we developed Simplicity, a robust and user-friendly web interface for visualizing, exploring, and summarizing raw and processed data from high-throughput drug screens. Importantly, Simplicity allows for easy recalculation of summary statistics at user-defined drug concentrations. This allows Simplicity’s outputs to be used with methods that rely on statistics being calculated at clinically relevant doses. Simplicity can be freely accessed at https://oncotherapyinformatics.org/simplicity/."
1405,Clinically relevant orthotopic pancreatic cancer models for adoptive T cell therapy,"Natalie K. Horvat, Isaac Karpovsky, Maggie Phillips, Megan Wyatt, Margaret A. Hall, Cameron Herting, Jacklyn Hammons, Zaid Mahdi, Richard A. Moffitt, Chrystal M. Paulos, Gregory B. Lesinski",https://www.biorxiv.org/content/10.1101/2023.09.07.556707v1,"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease; ∼12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted outcomes in PDAC patients, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMM) for PDAC are considered a “gold-standard” as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and cost of colony maintenance. We characterized the immunologic features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC models using two mouse cell lines, KPC-Luc and MT-5, isolated from KPC-GEMM mouse models (KrasLSL-G12D/+p53-/- and KrasLSL-G12D/+p53LSL-R172H/+, respectively). The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate KPC-Luc tumors, which have less stroma. Albeit CD4+ T cells were similarly detected in MT-5 tumors compared to KPC-GEMM in mice. Interestingly, we found that CAR T cells redirected to recognize mesothelin on these tumors that signal via CD3σ and 41BB (Meso-41BBσ-CAR T cells) post antigen recognition infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors. Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve in-depth study of how to overcome barriers that limit anti-tumor activity of adoptively transferred T cells."
1406,Blocking Orai1 constitutive activity inhibits B-cell cancer migration and synergistically acts with drugs to reduce B-CLL cell survival,"Julien Scaviner, Cristina Bagacean, Berthou Christian, Yves Renaudineau, Olivier Mignen, Souleymane Abdoul-Azize",https://www.biorxiv.org/content/10.1101/2023.12.12.571243v1,"Orai1 channel capacity to control store-operated Ca2+ entry (SOCE) and B-cell functions is poorly understood and more specifically in B-cell cancers, including human lymphoma and leukemia. As compared to normal B-cells, Orai1 is overexpressed in B-chronic lymphocytic leukemia (B-CLL) and contributes in resting B-CLL to mediate an elevated basal Ca2+ level through a constitutive Ca2+ entry, and in BCR-activated B-cell to regulate the Ca2+ signaling response. Such observations were confirmed in human B-cell lymphoma and leukemia lines, including RAMOS, JOK-1, MEC-1 and JVM-3 cells. Next, the use of pharmacological Orai1 inhibitors (GSK-7975A and Synta66) blocks constitutive Ca2+ entry and in turn affects B-cell cancer (primary and cell lines) survival and migration, controls cell cycle, and induces apoptosis through a mitochondrial and caspase-3 independent pathway. Finally, the added value of Orai1 inhibitors in combination with B-CLL drugs (ibrutinib, idelalisib, rituximab, and venetoclax) on B-CLL survival was tested, showing an additive/synergistic effect including in the B-cell cancer lines. To conclude, this study highlights the pathophysiological role of the Ca2+ channel Orai1 in B-cell cancers, and pave the way for the use of ORAI1 modulators as a plausible therapeutic strategy."
1407,Pan-cancer characterization and clinical outcome of ecDNA-enhancer mediated transcriptional dysregulation,"Tengwei Zhong, Huan zhao, Yupeng Liu, Danyang Yan, Yuguo Li, Zhiyun Guo",https://www.biorxiv.org/content/10.1101/2023.09.06.556610v1,"Extrachromosomal circular DNAs (ecDNAs) are extrachromosomal circular DNA elements harboring enhancers that can function as mobile transcriptional enhancers to promote oncogene amplification in diverse human cancers. However, little is known about the mechanism how ecDNA and relevant enhancers influence the transcription control in different cancers. Here, we performed a comprehensive pan-cancer analysis to explore the potential transcriptional regulatory network between ecDNA and enhancer, and the association with clinical outcomes in different human cancers. Firstly, we identified 18,385 enhancers on ecDNA in 1,921 samples of 20 TCGA tumors. By integrating corresponding RNA-seq data, we found that the expression levels of enhancer RNAs (eRNAs) were significantly different between ecDNA regions and corresponding linear chromosomes. This suggested that enhancers on ecDNA may employ eRNA to perform transcriptional regulation. Furthermore, we identified enhancer co-amplification with oncogenes and found that enhancers on ecDNA significantly affect the expression of co-amplified cancer genes and consequently influence the survival of cancer patients. In addition, we found that, compared to corresponding linear chromosomes, enhancers on ecDNA generally have lower levels of methylation, which may be mainly caused by the enhancer co-amplification with oncogenes. Genome-wide analysis of open chromatin regions revealed significantly higher levels of chromatin accessibility and certain chromosomal preferences in ecDNA regions comparing corresponding linear chromosomes. Moreover, we found that the downregulation of antigen presentation genes and the suppression of antigen presentation pathways may cause the tumor immune evasion mediated by ecDNA. Finally, we identified tumor-infiltrating activated mast cells in ecDNA-positive patients, which are associated with poorer prognosis. In summary, through pan-cancer analysis, we illustrate the characteristics and regulatory mechanisms of ecDNA and its enhancers in cancers, providing insights for future cancer treatment."
1408,CAR T cell infiltration and cytotoxic killing within the core of 3D breast cancer spheroids under control of antigen sensing in microwell arrays,"Youngbin Cho, Matthew Laird, Teddi Bishop, Ruxuan Li, Elisa Ruffo, Jason Lohmueller, Ioannis K. Zervantonakis",https://www.biorxiv.org/content/10.1101/2024.03.14.585033v1,"The success of chimeric antigen receptor (CAR) T cells in blood cancers has intensified efforts to develop CAR T therapies for solid cancers. In the solid tumor microenvironment, CAR T cell trafficking and suppression of cytotoxic killing represent limiting factors for therapeutic efficacy. Here, we present a microwell platform to study CAR T cell interactions with 3D tumor spheroids and determine predictors of anti-tumor CAR T cell function. To precisely control antigen sensing by CAR T cells, we utilized a switchable adaptor CAR system, that instead of directly binding to an antigen of interest, covalently attaches to co-administered antibody adaptors that mediate tumor antigen recognition. Following addition of an anti-HER2 adaptor antibody, primary human CAR T cells exhibited higher infiltration and clustering compared to the no adaptor control. By tracking CAR T cell killing at the individual spheroid level, we showed the suppressive effects of spheroid size and identified the initial CAR T cell : spheroid area ratio as a predictor of cytotoxicity. Spatiotemporal analysis revealed lower CAR T cell numbers and cytotoxicity in the spheroid core compared to the periphery. Finally, increasing CAR T cell seeding density, resulted in higher CAR T cell infiltration and cancer cell elimination in the spheroid core. Our findings provide new quantitative insights into CAR T cell-mediated killing of HER2+ breast tumor cells. Given the miniaturized nature and live imaging capabilities, our microfabricated system holds promise for discovering cell-cell interaction mechanisms that orchestrate antitumor CAR T cell functions and screening cellular immunotherapies in 3D tumor models."
1409,Inducible mucosa-like differentiation of head and neck cancer cells drives the epigenetically determined loss of cell malignancy,"Felix Oppel, Sarah Gendreizig, Laura Martinez-Ruiz, Javier Florido, Alba López-Rodríguez, Harkiren Pabla, Lakshna Loganathan, Leonie Hose, Philipp Kühnel, Pascal Schmidt, Matthias Schürmann, Judith Martha Neumann, Flavian Viyof Ful, Lars Uwe Scholtz, Dina Ligum, Frank Brasch, Karsten Niehaus, Germaine Escames, Tobias Busche, Jörn Kalinowski, Peter Goon, Holger Sudhoff",https://www.biorxiv.org/content/10.1101/2023.06.30.547265v2,"Background Human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease with high death rates that have remained substantially unaltered for decades. Therefore, new treatment approaches are urgently needed. Human papillomavirus-negative tumors harbor areas of terminally differentiated tissue that are characterized by cornification. Dissecting this intrinsic ability of HNSCC cells to irreversibly differentiate into non-malignant cells may have striking tumor-targeting potential."
1410,"Preclinical Results: Canine Phase I Safety Study of CM-101, a Tumor Capillary Specific Streptococcal Polysaccharide Toxin, for application in Spontaneous Canine Cancer","Rhett W Stout, Bonnie Boudreaux, I Horia Inegulescu, Roger A Laine",https://www.biorxiv.org/content/10.1101/2024.03.12.584502v1,"Background The study purpose was to evaluate canine safety of CM101, a polysaccharide Group B Streptococcus agalactiae tumor hemorrhagic toxin therapeutic."
1411,Stiffness regulates dendritic cell and macrophage subtype development and increased stiffness induces a tumor-associated macrophage phenotype in cancer co-cultures,Carla Guenther,https://www.biorxiv.org/content/10.1101/2024.03.11.584525v1,"Mechanical properties of tissues including their stiffness change throughout our lives, during both healthy development but also during chronic diseases like cancer (1-4). How changes to stiffness, occurring during cancer progression, impact leukocytes is unknown. To address this, myeloid phenotypes resulting from mono- and cancer co-cultures of primary murine and human myeloid cells on 2D and 3D hydrogels with varying stiffnesses were analyzed. On soft hydrogels, conventional DCs (cDCs) developed, whereas on stiff hydrogels plasmacytoid DCs (pDCs) developed. Cell populations expressing macrophage markers CD14, Ly6C, and CD16 also increased on stiff hydrogels. In cancer co-cultures, CD86+ populations decreased on higher stiffnesses across four different cancer types. High stiffness also led to increased vascular endothelial growth factor A (VEGFA), matrix metalloproteinases (MMP) and CD206 expression; ‘M2’ markers expressed by tumour-associated macrophages (TAMs) (5). Indeed, the majority of CD11c+ cells expressed CD206 across human cancer models. Targeting the PI3K/Akt pathway led to a decrease in CD206+ cells in murine cultures only, while human CD86+ cells increased."
1412,Inhibition of Replication Origins and ATR Synergistically Activates the Innate Immune System in Cancer Cells,"Kai Doberstein, Johannes Panther, Sebastian Berlit, Benjamin Tuschy, Marc Sütterlin, Frederik Marmé",https://www.biorxiv.org/content/10.1101/2023.09.08.556350v1,"Sufficient numbers of activated replication origins are essential for successful DNA replication. While normal cells load replication origins in abundance to the genome, cancer cells often load fewer origins of replication due to genomic alterations such as CCNE1 amplifications."
1414,Robust Feature Selection strategy detects a panel of microRNAs as putative diagnostic biomarkers in Breast Cancer,"Maria Claudia Costa, Teresa Maria Rosaria Noviello, Michele Ceccarelli, Luigi Cerulo",https://www.biorxiv.org/content/10.1101/2023.07.03.547377v3,"MicroRNAs represent a comprehensive class of short, single-stranded, non-coding RNA transcripts able to interfere with the translation of their targets or degrade them. Since these molecules are dysregulated in several malignancies, they represent reliable biomarkers in various contexts. In this study, the application of several Feature Selection methods uncovers a panel of 20 microRNAs, of which hsa-mir-337, hsa-mir-378c, and hsa-mir-483 are still poorly investigated in the context of Breast Cancer. This signature is capable of discriminating between healthy and tumoral samples, showing better classification performance when compared with differentially expressed microRNAs. Furthermore, a network-based centrality analysis on the gene targets of these transcripts highlighted CDC25, TPX2, KIF18B, CDCA3, TGFBR2, CAV1, TNS1, and LHFPL6 as key dysregulated genes. This study provides in silico hypotheses as new insights for future in vivo or in vitro studies uncovering the role of these putative diagnostic biomarkers in Breast Cancer."
1415,Low albumin status accompanies multi-layered immunosuppressive phenotypes in metastatic breast cancer patients,"Yuki Nakamura, Mayuko Yoda, Yoshihiro Izumi, Yukie Kashima, Masatomo Takahashi, Kohta Nakatani, Takeshi Bamba, Chenfeng He, Riyo Konishi, Don Pietro Saldajeno, Alexis Vandenbon, Yutaka Suzuki, Masakazu Toi, Kosuke Kawaguchi, Shinpei Kawaoka",https://www.biorxiv.org/content/10.1101/2023.09.05.556440v1,"Low albumin status is prevalent in advanced cancer patients, but the pathophysiology associated with this anomaly remains largely unexplored. To address this, we aim to search correlations of albumin levels with the transcriptome against peripheral blood mononuclear cells and the plasma metabolome within the same patients having metastatic breast cancers. We confirm that metastatic breast cancer patients exhibit low albumin levels in varying degrees without prominent systemic inflammation. Our data demonstrate that low albumin levels correlate with transcriptome signatures indicative of “neutrophil activation and T-cell down-regulation,” an immunosuppressive phenotype. We also find that immunoregulatory metabolites, such as arginine, are reduced in plasma in an albumin-correlated manner, further corroborating systemic immunosuppression. These results are verified using a mouse model of breast cancer. We conclude that low albumin status in metastatic breast cancer patients accompanies immunosuppressive phenotypes, which is likely unfavorable for anti-cancer immunotherapy and thus can be a cause of unsuccessful treatment outcomes."
1416,Targeting tumor-stromal interactions in triple-negative breast cancer using a human vascularized micro-tumor model,"Stephanie J. Hachey, Christopher J. Hatch, Daniela Gaebler, Aneela Mocherla, Kevin Nee, Kai Kessenbrock, Christopher C.W. Hughes",https://www.biorxiv.org/content/10.1101/2023.09.06.556584v1,"Triple-negative breast cancer (TNBC) is highly aggressive with limited available treatments. Stromal cells in the tumor microenvironment (TME) are crucial in TNBC progression; however, understanding the molecular basis of stromal cell activation and tumor-stromal crosstalk in TNBC is limited. To investigate therapeutic targets in the TNBC stromal niche, we used an advanced human in vitro microphysiological system called the vascularized micro-tumor (VMT). Using single-cell RNA sequencing (scRNA-seq), we revealed that normal breast-tissue stromal cells activate neoplastic signaling pathways in the TNBC TME. By comparing interactions in VMTs with clinical data, we identified therapeutic targets at the tumor-stromal interface with potential clinical significance. Combining treatments targeting Tie2 signaling with paclitaxel resulted in vessel normalization and increased efficacy of paclitaxel in the TNBC VMT. Dual inhibition of Her3 and Akt also demonstrated efficacy against TNBC. These data demonstrate the potential of inducing a favorable TME as a targeted therapeutic approach in TNBC."
1417,Wireless Electrical-Molecular Quantum Signalling for Cancer Cell Induced Death,"Akhil Jain, Jonathan Gosling, Shaochuang Liu, Haowei Wang, Eloise M. Stone, Lluïsa Pérez-García, David B. Amabilino, Mark Fromhold, Stuart Smith, Ruman Rahman, Yitao Long, Lyudmila Turyanska, Frankie J. Rawson",https://www.biorxiv.org/content/10.1101/2023.03.02.529075v2,"Quantum biological tunnelling for electron transfer (QBET) is involved in controlling cellular behaviour. Control of electrical-molecular communication could revolutionise the development of disruptive technologies for understanding and modulating electrically induced molecular signalling. Current communication technology is not appropriate for interfacing with cells at a spatial/temporal level equivalent to the native biological signalling. This limits our ability to tune cell function by controlling single molecular events. Here, we merge wireless nano-electrochemical tools with cancer cells. Gold-bipolar nanoelectrodes functionalised with redox active species were developed as electric field stimulated bio-actuators, that we term bio-nanoantennae. We show that a remote electrical input regulates electron transport between the redox molecules on the bio-nanoantennae in a selective manner. The wireless modulation of electron transport results in QBET triggering apoptosis in patient-derived cancer cells, representing electrical-induced induced controlled molecular signalling. Transcriptomics data highlight the electric field-induced nanoantenna targets the cancer cells in a unique manner. The insight concerning action and functional nanomaterials opens a plethora of applications in healthcare. This approach may lead to new quantum-based medical diagnostics and treatments, as well as a fundamental understanding of biological physics."
1418,Long-term Hematopoietic Transfer of the Anti-Cancer and Lifespan-Extending Capabilities of A Genetically Engineered Blood System by Transplantation of Bone Marrow Mononuclear Cells,"Jing-Ping Wang, Chun-Hao Hung, Yao-Huei Liou, Ching-Chen Liu, Kun-Hai Yeh, Keh-Yang Wang, Zheng-Sheng Lai, Biswanath Chatterjee, Tzu-Chi Hsu, Tung-Liang Lee, Yu-Chiau Shyu, Pei-Wen Hsiao, Liuh-Yow Chen, Trees-Juen Chuang, Chen-Hsin Albert Yu, Nah-Shih Liao, Che-Kun James Shen",https://www.biorxiv.org/content/10.1101/2023.04.21.537849v4,"A causal relationship exists among the aging process, organ decay and dis-function, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed Klf1K74R/K74R or Klf1(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/ EKLF has been generated that possesses extended lifespan and healthy characteristics including cancer resistance. We show that the healthy longevity characteristics of the Klf1(K74R) mice, as exemplified by their higher anti- cancer capability, are likely gender-, age- and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Klf1(K74R) mice could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild type NK cells. Targeted/global gene expression profiling analysis has identified changes of the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the Klf1(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/ blood system for long-term anti-cancer and, potentially, for anti-aging."
1420,Targeted Proteomics of Plasma Extracellular Vesicles Uncovers MUC1 as Combinatorial Biomarker for the Early Detection of High-grade Serous Ovarian Cancer,"Tyler T. Cooper, Dylan Z. Dieters-Castator, Jiahui Liu, Gabrielle M. Siegers, Desmond Pink, Lorena Veliz, John D. Lewis, François Lagugné-Labarthet, Yangxin Fu, Helen Steed, Gilles A. Lajoie, Lynne-Marie Postovit",https://www.biorxiv.org/content/10.1101/2022.03.31.486596v2,"Purpose The five-year prognosis for patients with late-stage high-grade serous carcinoma (HGSC) remains dismal, underscoring the critical need for identifying early-stage biomarkers. This study explores the potential of extracellular vesicles (EVs) circulating in blood, which are believed to harbor proteomic cargo reflective of the HGSC microenvironment, as a source for biomarker discovery."
1421,Interpretable prognostic modeling of endometrial cancer,"Bulat Zagidullin, Annukka Pasanen, Mikko Loukovaara, Ralf Bützow, Jing Tang",https://www.biorxiv.org/content/10.1101/2022.08.23.504935v1,"Endometrial carcinoma (EC) is one of the most common gynecological cancers in the world. In this work we apply Cox proportional hazards (CPH) and optimal survival tree (OST) algorithms to the retrospective prognostic modeling of disease-specific survival in 842 EC patients. We demonstrate that the linear CPH models are preferred for the EC risk assessment based on clinical features alone, while the interpretable, non-linear OST models are favored when patient profiles are enriched with tumor molecular data. By studying the OST decision path structure, we show how explainable tree models recapitulate existing clinical knowledge prioritizing L1 cell-adhesion molecule and estrogen receptor status indicators as key risk factors in the p53 abnormal EC subgroup. We believe that visually interpretable tree algorithms are a promising method to explore feature interactions and generate novel research hypotheses. To aid further clinical adoption of advanced machine learning techniques, we stress the importance of quantifying model discrimination and calibration performance in the development of explainable clinical prediction models."
1424,STAT3 is a genetic modifier of TGF-beta induced EMT in KRAS mutant pancreatic cancer,"Stephen D’Amico, Varvara Kirillov, Oleksi Petrenko, Nancy C. Reich",https://www.biorxiv.org/content/10.1101/2023.09.01.555946v1,"Oncogenic mutations in KRAS are among the most common in cancer. Classical models suggest that loss of epithelial characteristics and the acquisition of mesenchymal traits are associated with cancer aggressiveness and therapy resistance. However, the mechanistic link between these phenotypes and mutant KRAS biology remains to be established. Here we identify STAT3 as a genetic modifier of TGF-beta-induced epithelial to mesenchymal transition. Gene expression profiling of pancreatic cancer cells identifies more than 200 genes commonly regulated by STAT3 and oncogenic KRAS. Functional classification of STAT3 responsive program reveals its major role in tumor maintenance and epithelial homeostasis. The signatures of STAT3-activated cell states can be projected onto human KRAS mutant tumors, suggesting that they faithfully reflect characteristics of human disease. These observations have implications for therapeutic intervention and tumor aggressiveness."
1425,TPX2 expression promotes sensitivity to dasatinib in breast cancer by activating the YAP transcriptional signaling,"Carlos Marugán, Beatriz Ortigosa, Natalia Sanz-Gómez, Ana Monfort-Vengut, Cristina Bertinetti, Ana Teijo, Marta González, Alicia Alonso de la Vega, María José Lallena, Gema Moreno-Bueno, Guillermo de Cárcer",https://www.biorxiv.org/content/10.1101/2023.09.04.556165v1,"Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of TPX2 enhances sensitivity to the SRC inhibitor dasatinib due to activation of the YAP pathway. Furthermore, using breast cancer data from the TCGA and a cohort of cancer-derived patient samples, we find that both TPX2 expression and YAP activation are present in a significant percentage of cancer tumor samples, providing poor prognosis, being therefore putative biomarkers for dasatinib therapy."
1426,Assessment of ferroptosis inducers and Nrf2 inhibitors as radiosensitisers in 2D and 3D breast cancer cell cultures,"AA Alzufairi, C Souilhol, N Jordan-Mahy, NA Cross",https://www.biorxiv.org/content/10.1101/2023.12.08.570735v1,"Ferroptosis is a form of programmed cell death that is modulated in some cancer cells as a pro-survival mechanism. Induction of ferroptosis is a potential anti-cancer strategy, and enhancement of ferroptosis using ferroptosis inducers has the potential to enhance current anti-tumour mechanisms. In this study, we assessed the effect of the ferroptosis inducers Erastin, RSL-3 and FIN-56 on radiosensitivity in 2D cell culture, and in 3D alginate tumour spheroids from breast cancer cell lines. Since some tumours modulate ferroptosis via increased Nrf2 production, and MCF-7 and MDA-MB-231 both produce Nrf2 protein, we also assessed the effects of the Nrf2 inhibitor ML385 on radiosensitivity. MDA-MB-231 was highly sensitive to all ferroptosis inducers, and ferroptosis was reversed by the ferroptosis inhibitors Ferrostatin-1, Liproxstatin-1 and Deferoxamine. MCF-7 was resistant to all ferroptosis inducers. MDA-MB-231 and MCF-7 cells were sensitive to irradiation in 2D cell culture but resistant to irradiation in 3D alginate spheroids. Ferroptosis inducers did not synergistically enhance irradiation-induced cell death in 2D cell cultures. There was also no robust enhancement to irradiation effects with ferroptosis inducers in 2D or 3D cell culture. Ferroptosis inducers did, however, show a heterogeneous response in 3D cell culture, in that isogenic spheroids responded differently within the same spheroid. The Nrf2 inhibitor ML385 showed no synergistic enhancement of ferroptotic cell death when combined with irradiation. These studies suggest targeting ferroptosis does not induce short-term enhancement of ferroptotic cell death."
1427,A Poisson distribution-based general model of cancer rates and a cancer risk-dependent theory of aging,"Wenbo Yu, Tessa Gargett",https://www.biorxiv.org/content/10.1101/2023.03.08.531809v1,"This article presents a formula for modeling the lifetime incidence of cancer in humans. The formula utilizes a Poisson distribution-based “np” model to predict cancer incidence, with “n” representing the effective number of cell turnover and “p” representing the probability of single-cell transformation. The model accurately predicts the observed incidence of cancer in humans when cell turnover reduction is taken into account. The model also suggests that cancer development is ultimately inevitable. The article proposes a theory of aging based on this concept, called the “np” theory (Nuts Poisoned). According to this theory, an organism maintains its order by balancing cellular entropy through continuous proliferation. However, cellular information entropy increases irreversibly over time, restricting the total number of cells an organism can generate throughout its lifetime. When cell division slows down and fails to compensate for the entropy increase of the system, aging occurs. Essentially, aging is the phenomenon of running out of predetermined cell resources. Different species have evolved separate strategies to utilize their limited cell resources throughout their life cycle."
1428,Descriptive pan-cancer genetic analysis of disulfidptosis-related gene set,"Hengrui Liu, Tao Tang",https://www.biorxiv.org/content/10.1101/2023.02.25.529997v1,"Background A recent study has identified a novel programmed cell death pathway, termed disulfidoptosis, which is based on disulfide proteins. This discovery provides new insight into the mechanisms of cell death and may have implications for therapeutic strategies targeting cell death pathways. This study aimed to evaluate the pan-cancer genomics and clinical association of disulfidptosis and disulfidptosis-related cell death genes, including SLC7A11, NADPH, INF2, CD2AP, PDLIM1, ACTN4, MYH9, MYH10, IQGAP1, FLNA, FLNB, TLN1, MYL6, ACTB, DSTN, and CAPZB."
1429,TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer,"Célie Cokelaere, Rüveyda Dok, Emanuela E. Cortesi, Peihua Zhao, Anna Sablina, Sandra Nuyts, Rita Derua, Veerle Janssens",https://www.biorxiv.org/content/10.1101/2023.08.30.555468v1,"TIPRL1 (target of rapamycin signaling pathway regulator-like 1) is a known interactor and inhibitor of protein phosphatases PP2A, PP4 and PP6 – all pleiotropic modulators of the DNA Damage Response (DDR). Here, we describe a new role for TIPRL1 in the radiotherapy (RT) response of Head and Neck Squamous Cell Carcinoma (HNSCC). TIPRL1 expression was found increased in tumor versus non- tumor tissue, with high tumoral TIPRL1 expression associating with lower locoregional control and decreased survival of RT-treated patients. TIPRL1 deletion in HNSCC cells resulted in increased RT sensitivity, a faster but prolonged cell cycle arrest, increased micronuclei formation and an altered proteome-wide DDR. Upon irradiation, ATM phosphorylates TIPRL1 at Ser265, contributing to TIPRL1-mediated RT resistance. Mass spectrometry analysis identified DNA-PKcs, RAD51 and nucleosomal histones as novel TIPRL1 interactors. Histone binding, although stimulated by RT, was adversely affected by TIPRL1 Ser265 phosphorylation. Our findings underscore a clinically relevant role for TIPRL1 and its ATM-dependent phosphorylation in RT resistance through modulation of DNA damage checkpoint activation and repair."
1431,"A Linkable, Polycarbonate Gut Microbiome-Distal Tumor Chip Platform for Interrogating Cancer Promoting Mechanisms","Danielle S.K. Brasino, Sean D. Speese, Kevin Schilling, Carolyn E. Schutt, Michelle C. Barton",https://www.biorxiv.org/content/10.1101/2023.08.31.555803v1,"Gut microbiome composition has been tied to diseases ranging from arthritis to cancer to depression. However, mechanisms of action are poorly understood, limiting development of relevant therapeutics. Organ-on-chip platforms, which model minimal functional units of tissues and can tightly control communication between them, are ideal platforms to study these relationships. Many gut microbiome models have been published to date but devices are typically fabricated using oxygen permeable PDMS, requiring interventions to support anaerobic bacteria. To address this challenge, a novel platform was developed where the chips were fabricated entirely from gas-impermeable polycarbonate without tapes or gaskets. These chips replicated polarized villus-like structures of the native tissue. Further, they enabled co-cultures of commensal anaerobic bacteria Blautia coccoides on the surface of gut epithelia for two days within a standard incubator. Another complication of PDMS devices is high ad-/absorption, limiting applications in high-resolution microscopy and biomolecule interaction studies. For future communication studies between gut microbiota and distal tumors, an additional polycarbonate chip design was developed to support hydrogel-embedded tissue culture. These chips enable high-resolution microscopy with all relevant processing done on-chip. Designed for facile linking, this platform will make a variety of mechanistic studies possible."
1432,Losartan rewires ovarian cancer tumor-immune microenvironment and suppresses IGF-1 to amplify chemo-immunotherapy sensitivity,"Yao Sun, Zhenzhen Yin, Limeng Wu, Changli Yue, Yanling Zhang, Sonu Subudhi, Pinji Lei, Alona Muzikansky, Luo Zhang, Bo R. Rueda, Rakesh K. Jain, Lei Xu",https://www.biorxiv.org/content/10.1101/2023.08.31.555783v1,"Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint inhibitors, which have revolutionized the treatment of multiple malignancies, have had limited efficacy in OvCa patients. Here, using syngeneic OvCa models and genetic and pharmacologic perturbations, we discovered that losartan – a widely prescribed anti-hypertensive drug – exhibits dual effects on both the tumor microenvironment and cancer cells to sensitize OvCa to chemo-immunotherapy. Specifically, losartan treatment i) reprograms the tumor microenvironment leading to increased vascular perfusion, and thus enhances drug delivery and immune effector cell intratumoral infiltration and function; and ii) rewires the OvCa cells by suppressing the IGF-1 signaling, resulting in enhanced chemosensitivity. As a result of the combined tumor and stromal effects, losartan treatment enhances the efficacy of chemo-immunotherapy in OvCa models. The safety and low cost (less than $1-2/day) of losartan warrant rapid translation of our findings to patients with OvCa."
1433,Evolution of chromosome arm aberrations in breast cancer through genetic network rewiring,"Elena Kuzmin, Toby M. Baker, Tom Lesluyes, Jean Monlong, Kento T. Abe, Paula P. Coelho, Michael Schwartz, Dongmei Zou, Genevieve Morin, Alain Pacis, Yang Yang, Constanza Martinez, Jarrett Barber, Hellen Kuasne, Rui Li, Mathieu Bourgey, Anne-Marie Fortier, Peter G. Davison, Atilla Omeroglu, Marie-Christine Guiot, Quaid Morris, Claudia L. Kleinman, Sidong Huang, Anne-Claude Gingras, Jiannis Ragoussis, Guillaume Bourque, Peter Van Loo, Morag Park",https://www.biorxiv.org/content/10.1101/2023.06.10.544434v8,"The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize the evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. TCGA data analysis showed recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a unique panel of 23 primary tumor/patient-derived xenograft basal breast cancers revealed early evolution of chr4p deletion. Mechanistically we show that Chr4p loss is associated with enhanced proliferation. Gene function studies identified an unknown gene, C4orf19, within chr4p, which suppressed proliferation when overexpressed and is a novel member of a PDCD10-GCKIII kinase module, we name as PGCA1. Genome-wide pooled overexpression screens using a barcoded library of human open reading frames, identified chromosomal regions, including chr4p, that suppress proliferation when overexpressed in a context-dependent manner implicating network interactions. Together this sheds light on the early emergence of complex aneuploid karyotypes involving chr4p and adaptive landscapes shaping breast cancer genomes."
1434,Landscape and functional repertoires of long noncoding RNAs in the pan-cancer tumor microenvironment using single-nucleus total RNA sequencing,"Tongqiang Fan, Shengyu Ni, Haide Chen, Ziye Xu, Longjiang Fan, Yongcheng Wang",https://www.biorxiv.org/content/10.1101/2023.12.03.569806v1,"Intratumor heterogeneity (ITH) plays crucial roles in tumor progression. However, the atlas of long noncoding RNAs (lncRNAs) in the context of ITH across multiple cancer types remains largely unexplored. Here, we analyze over 800,000 cells from ten different cancer types generated from the random-primed single-nucleus total RNA sequencing and provide a systematic landscape of lncRNAs in tumor microenvironment (TME) and malignant programs. Our study employe a robust cell annotation pipeline called scAnnotation, which allows us to identify 39 distinct cell types within the pan-cancer TME. By applying stringent criteria, we identify thousands of reliable marker genes, including both mRNAs and lncRNAs. Next, we identify sets of cell type-specific lncRNA-mRNA pairs by our LncPairs algorithm. Moreover, we identify nine expression meta-programs (MPs) associated with diverse biological processes in malignant cells across multiple cancer types. MP-specific lncRNA-transcription factor (TF) regulatory networks are further constructed and key lncRNAs and regulons that exert control over MP-specific gene expression are identified. The comprehensive atlas of lncRNAs in the pan-cancer context, coupled with the bioinformatics tools tailored for the random-primed datasets, is expected to accelerate advancements in the field of lncRNA research at the single-cell resolution."
1435,Neutron capture enhances dose and reduces cancer cell viability in and out of beam during helium and carbon ion therapy,"Nicholas Howell, Ryan J. Middleton, Frederic Sierro, Naomi A. Wyatt, Andrew Chacon, Benjamin H. Fraser, Keith Bambery, Elle Livio, Christopher Dobie, Joseph J. Bevitt, Justin Davies, Anthony Dosseto, Daniel R. Franklin, Ulf Garbe, Susanna Guatelli, Ryoichi Hirayama, Naruhiro Matsufuji, Akram Mohammadi, Karl Mutimer, Louis M. Rendina, Anatoly B. Rosenfeld, Mitra Safavi-Naeini",https://www.biorxiv.org/content/10.1101/2023.12.03.569810v1,"Purpose Neutron Capture Enhanced Particle Therapy (NCEPT) is a proposed augmentation of charged particle therapy which exploits thermal neutrons generated internally, within the treatment volume via nuclear fragmentation, to deliver a biochemically targeted radiation dose to cancer cells. This work is the first experimental demonstration of NCEPT, performed using both carbon and helium ion beams with two different targeted neutron capture agents (NCAs)."
1436,A comparison between full-length 16S rRNA Oxford Nanopore sequencing and Illumina V3-V4 16S rRNA sequencing in head and neck cancer tissues,"Kenny Yeo, James Connell, George Bouras, Eric Smith, William Murphy, John-Charles Hodge, Suren Krishnan, Peter-John Wormald, Rowan Valentine, Alkis James Psaltis, Sarah Vreugde, Kevin Aaron Fenix",https://www.biorxiv.org/content/10.1101/2024.03.08.584026v1,"Introduction Describing the microbial community within the tumour has been a key aspect in understanding the pathophysiology of the tumour microenvironment. In head and neck cancer (HNC), most studies on tissue samples have only performed 16S ribosomal RNA (rRNA) short-read sequencing (SRS) on V3-V5 region. SRS is mostly limited to genus level identification. In this study, we compared full-length 16S rRNA long-read sequencing (FL-ONT) from Oxford Nanopore Technology (ONT) to V3-V4 Illumina SRS (V3V4-Illumina). To date, this is the largest study using HNC tissues samples to perform FL-ONT of the 16S rRNA using ONT."
1437,Conformational switch of a peptide provides a novel strategy to design peptide loaded porous organic polymer for Pyroptosis pathway mediated cancer therapy,"Snehasis Mishra, Achinta Sannigrahi, Santu Ruidas, Sujan Chatterjee, Kamalesh Roy, Deblina Misra, Barun Kumar Maity, Rabindranath Paul, Krishna Das Saha, Asim Bhaumik, Krishnananda Chattopadhyay",https://www.biorxiv.org/content/10.1101/2024.03.05.583621v1,"While peptide-based drug development is now extensively explored, this strategy does have limitations, which come from their rapid excretion from the body (or shorter half-life in the body), and vulnerability to protease-mediated degradation. To overcome these limitations, here we introduce a novel strategy for the development of a peptide-based anticancer agent using the conformation switch property of a chameleon sequence stretch, which we derived from a mycobacterium secretory protein, MPT63. Then, we loaded this peptide in a new porous organic polymer (PG-DFC-POP) synthesized using phloroglucinol and acresolderivative via condensation reaction for delivering the peptide selectively to the cancer cells. Employing an ensemble and single molecule approaches, we demonstrate that this peptide undergoes a disordered to alpha-helical conformational transition, which is triggered by a low pH environment inside cancer cells. This adopted alpha-helical conformation results in the formation of proteolysis-resistant oligomers, which show efficient membrane pore-forming activity selectively for negatively charged phospholipid which is accumulated in cancer cell membrane. Our in vitro and in vivo experimental results demonstrate that the peptide-loaded nanomaterial PG-DFC-POP-PEP 1 exhibits significant cytotoxicity in cancer cells, leading to cell death through the Pyroptosis pathway that is confirmed by monitoring numerous associated events starting from lysosome membrane damage to GSDMD-induced cell membrane demolition. We believe that this novel conformational switch-based drug design strategy has great potential in endogenous environment-responsive cancer therapy and the development of future drug candidates to mitigate cancers."
1438,Single-cell analysis of an engineered organoid-based model of pancreatic cancer identifies hypoxia as a contributing factor in the determination of transcriptional subtypes,"Natalie Landon-Brace, Brendan T. Innes, Simon Latour, Jose L. Cadavid, Ileana L. Co, Cassidy M. Tan, Ferris Nowlan, Sybil Drissler, Faiyaz Notta, Hartland Warren Jackson, Gary D. Bader, Alison P. McGuigan",https://www.biorxiv.org/content/10.1101/2024.03.05.583412v1,"Pancreatic ductal adenocarcinoma (PDAC) is a high-mortality cancer characterized by its aggressive, treatment-resistant phenotype and a complex tumour microenvironment (TME) featuring significant hypoxia. Bulk transcriptomic analysis has identified the “classical” and “basal-like” transcriptional subtypes which have prognostic value in PDAC; however, it remains unclear how microenvironmental heterogeneity contributes to the expression of these transcriptional signatures. Here, we used single cell transcriptome analysis of the organoid TRACER platform to explore the effect of oxygen and other microenvironmental gradients on PDAC organoid cells. We found that the microenvironmental gradients present in TRACER significantly impact the distribution of organoid transcriptional phenotypes and the enrichment of gene sets linked to cancer progression and treatment resistance. More significantly, we found that microenvironmental gradients drive changes in the expression of the classical and basal-like transcriptional subtype gene signatures. This effect is likely dominated by the oxygen gradients in TRACER, as hypoxia alone induced decreases in the expression of classical marker GATA6 at both the gene and protein level in PDAC cells. This work suggests that hypoxia contributes to determining transcriptional subtypes in PDAC and broadly underscores the importance of considering microenvironmental gradients in organoid-based transcriptomic studies of PDAC."
1439,A microfluidic model of colonocyte-microbiota interaction mimicking the colorectal cancer microenvironment,"Daniel Penarete-Acosta, Rachel Stading, Laura Emerson, Mitchell Horn, Sanjukta Chakraborty, Arum Han, Arul Jayaraman",https://www.biorxiv.org/content/10.1101/2023.08.29.555442v1,"Changes in the abundance of certain bacterial species within the colorectal microbiota correlate with colorectal cancer development. While carcinogenic mechanisms of single pathogenic bacteria have been characterized in vitro, limited tools are available to investigate interactions between pathogenic bacteria and both commensal microbiota and colonocytes in a physiologically relevant tumor microenvironment. To address this, we developed a microfluidic device that can be used to co-culture colonocytes and colorectal microbiota. The device was used to explore the effect of Fusobacterium nucleatum, an opportunistic pathogen associated with colorectal cancer development in humans, on colonocyte gene expression and microbiota composition. F. nucleatum altered the transcription of genes involved in cytokine production, epithelial-to-mesenchymal transition, and proliferation in colonocytes in a contact-independent manner; however, most of these effects were diminished by the presence of fecal microbiota. Interestingly, F. nucleatum significantly altered the abundance of multiple bacterial clades associated with mucosal immune responses and cancer development in the colon. Our results highlight the importance of evaluating the potential carcinogenic activity of pathogens in the context of a commensal microbiota, and the potential to discover novel inter-species microbial interactions in the colorectal cancer microenvironment."
1440,Power-law growth models explain incidences and sizes of pancreatic cancer precursor lesions and confirm spatial genomic findings,"Ashley L. Kiemen, Pei-Hsun Wu, Alicia M. Braxton, Toby C. Cornish, Ralph H. Hruban, Laura Wood, Denis Wirtz, David Zwicker",https://www.biorxiv.org/content/10.1101/2023.12.01.569633v1,"Pancreatic ductal adenocarcinoma is a rare but lethal cancer. Recent evidence reveals that pancreatic intraepithelial neoplasms (PanINs), the microscopic precursor lesions in the pancreatic ducts that can give rise to invasive pancreatic cancer, are significantly larger and more prevalent than previously believed. Better understanding of the growth law dynamics of PanINs may improve our ability to understand how a miniscule fraction of these lesions makes the transition to invasive cancer. Here, using artificial intelligence (AI)-based three-dimensional (3D) tissue mapping method, we measured the volumes of >1,000 PanIN and found that lesion size is distributed according to a power law with a fitted exponent of -1.7 over > 3 orders of magnitude. Our data also suggest that PanIN growth is not very sensitive to the pancreatic microenvironment or an individual’s age, family history, and lifestyle, and is rather shaped by general growth behavior. We analyze several models of PanIN growth and fit the predicted size distributions to the observed data. The best fitting models suggest that both intraductal spread of PanIN lesions and fusing of multiple lesions into large, highly branched structures drive PanIN growth patterns. This work lays the groundwork for future mathematical modeling efforts integrating PanIN incidence, morphology, genomic, and transcriptomic features to understand pancreas tumorigenesis, and demonstrates the utility of combining experimental measurement of human tissues with dynamic modeling for understanding cancer tumorigenesis."
1444,KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo,"Arafath K. Najumudeen, Sigrid K. Fey, Laura M. Millett, Catriona Ford, Kathryn Gilroy, Nuray Gunduz, Rachel A. Ridgway, Eve Anderson, Douglas Strathdee, William Clark, Colin Nixon, Jennifer P. Morton, Andrew D. Campbell, Owen J. Sansom",https://www.biorxiv.org/content/10.1101/2023.08.29.555396v1,"Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, there is still much debate over the function of wild-type KRAS in tumour initiation, progression and therapeutic response. We have developed a genetically engineered mouse model which allows deletion of the wild-type copy of Kras in the context of an intact oncogenic Kras in colorectal cancer. We observe that in the presence of oncogenic Kras, wild-type Kras acts to restrain tumour growth. Mechanistically, deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while presence of wild-type Kras is associated with resistance to inhibition of MEK1/2 in KRASG12D driven tumours. Importantly, loss of wild-type Kras in oncogenic KRAS-driven aggressive tumours significantly alters tumour progression, metastasis while impacting tumour immune cell infiltration. This study demonstrates a suppressive role for wild-type Kras during colon tumour initiation and highlights the critical impact of wild-type Kras upon therapeutic response to MAPK and tumour progression in Kras mutant cancers."
1446,An autochthonous model of lung cancer in the Naked Mole-Rat (Heterocephalus glaber),"Alyssa Shepard, Scott Troutman, Sany Hoxha, Daniel Lester, Walid Khaled, Ewan St. John Smith, Thomas Park, Rochelle Buffenstein, Dongliang Du, Mingxiang Teng, Christine Crish, Kenneth Y. Tsai, Elsa R. Flores, Andrea Ventura, Joseph L. Kissil",https://www.biorxiv.org/content/10.1101/2023.08.28.555115v1,"Studies on cancer resistance in the naked mole-rat (NMR) have generally failed to interrogate possible resistance mechanisms in a physiological context. Here, we provide evidence that the NMR presents as a novel model of tumor initiation. We developed an endogenous lung cancer model in NMRs, driven by an oncogenic Eml4-Alk fusion protein introduced through CRISPR- mediated genome editing. While this is sufficient to drive tumorigenesis in mice, the development of progressive disease in NMRs required the additional loss of key tumor suppressors. Our results show that tumor initiation in NMRs more closely recapitulates that of human tumors. This suggests that the proposed “resistance” of NMRs to cancer development may stem from tumor initiation events that are likely to be comparable to the mechanisms in human cells."
1447,Integration of Multiple Spatial Omics Modalities Reveals Unique Insights into Molecular Heterogeneity of Prostate Cancer,"Wanqiu Zhang, Xander Spotbeen, Sebastiaan Vanuytven, Sam Kint, Tassiani Sarretto, Fabio Socciarelli, Katy Vandereyken, Jonas Dehairs, Jakub Idkowiak, David Wouters, Jose Ignacio Alvira Larizgoitia, Gabriele Partel, Alice Ly, Vincent de Laat, Maria José Q Mantas, Thomas Gevaert, Wout Devlies, Chui Yan Mah, Lisa M Butler, Massimo Loda, Steven Joniau, Bart De Moor, Alejandro Sifrim, Shane R. Ellis, Thierry Voet, Marc Claesen, Nico Verbeeck, Johannes V. Swinnen",https://www.biorxiv.org/content/10.1101/2023.08.28.555056v1,"Recent advances in spatial omics methods are revolutionising biomedical research by enabling detailed molecular analyses of cells and their interactions in their native state. As most technologies capture only a specific type of molecules, there is an unmet need to enable integration of multiple spatial-omics datasets. This, however, presents several challenges as these analyses typically operate on separate tissue sections at disparate spatial resolutions. Here, we established a spatial multi-omics integration pipeline enabling co-registration and granularity matching, and applied it to integrate spatial transcriptomics, mass spectrometry-based lipidomics, single nucleus RNA-seq and histomorphological information from human prostate cancer patient samples. This approach revealed unique correlations between lipids and gene expression profiles that are linked to distinct cell populations and histopathological disease states and uncovered molecularly different subregions not discernible by morphology alone. By its ability to correlate datasets that span across the biomolecular and spatial scale, the application of this novel spatial multi-omics integration pipeline provides unprecedented insight into the intricate interplay between different classes of molecules in a tissue context. In addition, it has unique hypothesis-generating potential, and holds promise for applications in molecular pathology, biomarker and target discovery and other tissue-based research fields."
1448,Impact of resistance on therapeutic design: a Moran model of cancer growth,"Mason S. Lacy, Adrianne L. Jenner",https://www.biorxiv.org/content/10.1101/2023.08.28.555214v1,"Resistance of cancers to treatments, such as chemotherapy, largely arise due to cell mutations. These mutations allow cells to resist apoptosis and inevitably lead to recurrence and often progression to more aggressive cancer forms. Sustained-low dose therapies are being considered as an alternative over maximum tolerated dose treatments, whereby a smaller drug dosage is given over a longer period of time. However, understanding the impact that the presence of treatment-resistant clones may have on these new treatment modalities is crucial to validating them as a therapeutic avenue. In this study, a Moran process is used to capture stochastic mutations arising in cancer cells, inferring treatment resistance. The model is used to predict the probability of cancer recurrence given varying treatment modalities. The simulations predict that sustained-low dose therapies would be virtually ineffective for a cancer with a non-negligible probability of developing a sub-clone with resistance tendencies. Furthermore, calibrating the model to in vivo measurements for breast cancer treatment with Herceptin, the model suggests that standard treatment regimens are ineffective in this mouse model. Using a simple Moran model, it is possible to explore the likelihood of treatment success given a non-negligible probability of treatment resistant mutations and suggest more robust therapeutic schedules."
1452,Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion,"Rei Kudo, Anton Safonov, Edaise da Silva, Qing Li, Hong Shao, Marie Will, Atsushi Fushimi, Harikrishna Nakshatri, Jorge S. Reis-Filho, Shom Goel, Andrew Koff, Britta Weigelt, Qamar J. Khan, Pedram Razavi, Sarat Chandarlapaty",https://www.biorxiv.org/content/10.1101/2023.08.25.554716v1,"Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a clinically-annotated cohort of patients with metastatic HR+ breast cancer, we identified TP53 loss (28.8%) and MDM2 amplification (6.7%) to be associated with lack of long-term disease control. Human breast cancer models revealed that p53 loss did not affect CDK4/6 activity or G1-blockade, but instead promoted drug-insensitive p130 phosphorylation by CDK2. Persistence of phospho-p130 prevented DREAM complex assembly, enabling cell cycle reentry and tumor progression. Inhibitors of CDK2 could overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically-diverse HR+ breast cancers."
1453,Template-Directed RIG-I Agonist Assembly for Targeted Cancer Immunotherapy,"Subrata K. Ghosh, Neil Robertson, Edward Crosier, Michael Dudley, Qiyong P. Liu, Zdravka Medarova",https://www.biorxiv.org/content/10.1101/2022.12.08.519592v2,"Recent developments in the use of pattern recognition receptors (PRRs) aim to harness the innate power of the immune system for cancer therapy. Understanding how to recruit PRRs, such as RIG-I, in a tumor-selective manner is critical for its adoption in the clinic. We describe the use of a tumor-selective template-based agonist of RIG-I to induce type-I IFN signaling and tumor cell apoptosis. The agonist, termed ss-ppp-miRNA-21, comprises a single stranded RNA oligonucleotide modified with a 5’-triphosphate and complementary to an endogenous miRNA enriched in tumor cells. We demonstrate the efficacy of the template-directed approach and detail mechanistic studies validating the hypothesis of a template-directed RIG-I agonist assembly using miRNA-21 as a target. The template-directed strategy described here moves us closer to making RIG-I a clinically relevant target in oncology because it achieves targeted activation of innate immunity in the tumor microenvironment in the context of systemic agonist injection."
1454,Integrating Knowledge Graphs into Machine Learning Models for Survival Prediction and Biomarker Discovery in Patients with Non–Small-Cell Lung Cancer,"Chao Fang, Gustavo Alonso Arango Argoty, Ioannis Kagiampakis, Mohammad Hassan Khalid, Etai Jacob, Krishna Bulusu, Natasha Markuzon",https://www.biorxiv.org/content/10.1101/2024.02.29.582842v1,"Survival prediction is a critical aspect of clinical study design and biomarker discovery. It is a highly complex task, given the large number of “omics” and clinical features, as well as the high degrees of freedom that drive patient survival. Prior knowledge can play a critical role in uncovering the complexity of a disease and understanding the driving factors affecting a patient’s survival. We introduce a methodology for incorporating prior knowledge into machine learning–based models for prediction of patient survival through knowledge graphs, demonstrating the advantage of such an approach for patients with non–small-cell lung cancer. Using data from patients treated with immuno-oncologic therapies in the POPLAR (NCT01903993) and OAK (NCT02008227) clinical trials, we found that the use of knowledge graphs yielded significantly improved hazard ratios, including in the POPLAR cohort, for models based on biomarker tumor mutation burden compared with those based on knowledge graphs. Use of a model-defined mutational 10-gene signature led to significant overall survival differentiation for both trials. We provide parameterized code for incorporating knowledge graphs into survival analyses for use by the wider scientific community."
1455,Metabolism-focused CRISPR screen unveils Mitochondrial Pyruvate Carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer,"Takashi Furusawa, Renzo Cavero, Yue Liu, Haojian Li, Xia Xu, Thorkell Andresson, William Reinhold, Olivia White, Myriem Boufraqech, Thomas J. Meyer, Oliver Hartmann, Markus E. Diefenbacher, Yves Pommier, Urbain Weyemi",https://www.biorxiv.org/content/10.1101/2023.11.29.569226v1,"Homologous recombination (HR) and poly ADP-ribosylation are partially redundant pathways for repair of DNA damage in normal and cancer cells. In cell lines that are deficient in HR, inhibition of poly (ADP-ribose) polymerase (PARP1/2) is a proven target with several PARP inhibitors (PARPi) currently in clinical use. Resistance to PARP inhibitors often develops, usually involving genetic alterations in DNA repair signaling cascades, but also metabolic rewiring particularly in HR-proficient cells. PARP1/2 utilize NAD+ (nicotinamide adenine dinucleotide), an essential substrate not only for PARPs but also for multiple pathways in cellular metabolism, TCA cycle and mitochondrial functions. Thus, NAD+ is central to many key cellular functions. Both activation of PARPs by DNA damage and their inhibition by drugs such as olaparib affect NAD+ consumption. We surmised that alterations in NAD+ metabolism by cancer drugs such as Olaparib might be involved in the development of resistance to drug therapy. To test this hypothesis, we conducted a metabolism-focused CRISPR knockout (KO) screen to identify genes which undergo alterations during treatment of tumor cells with PARP inhibitors. Of about 3000 genes in the screen, our data revealed that mitochondrial pyruvate carrier 1 (MPC1) is an essential factor in desensitizing NSCLC lung cancer lines to PARP inhibition. In contrast to NSCLC lung cancer cells, triple negative breast cancer cells do not exhibit such desensitization following MPC1 loss and reprogram the TCA cycle and oxidative phosphorylation pathways to overcome PARP inhibitor treatment. Our findings unveil a previously unknown synergistic response between MPC1 loss and PARP inhibition in lung cancer cells."
1457,The MLL3/TP53/PIK3CA cancer driver mutations promote HIF1α-dependent recruitment and differentiation of pro-tumor ICOShiGITRhi Blimp-1+ effector regulatory T cells in breast tumors,"Marie Boutet, Kenta Nishitani, Piril Erler, Nicole Couturier, Zheng Zhang, Anna Maria Militello, Marcelo Coutinho De Miranda, Emeline Barbieux, Erik Guillen, Masako Suzuki, Joseph A. Sparano, Cristina Montagna, Wenjun Guo, Gregoire Lauvau",https://www.biorxiv.org/content/10.1101/2022.10.02.510540v2,"While essential gatekeepers of immune homeostasis, Foxp3+ regulatory T (Treg) cells infiltrating tumors acquire distinct phenotypes and become highly immunosuppressive, promoting tumor immune escape and growth. How this occurs and relates to tumor-driver mutations is largely uncharacterized. Herein, we created a mouse mammary stem cell-based tumor model using CRISPR gene editing in which we introduced known human cancer-driver mutations. These included functional loss of the MLL3 histone methyltransferase and p53, and constitutive PI3-kinase activation, recapitulating the genetic makeup of aggressive breast cancers. We show that MLL3 loss fosters tumorigenesis by promoting the rapid establishment of an immunosuppressive microenvironment through induction of HIF1α, which increases the secretion of the chemokine CCL2 by tumor cells and the recruitment of higher numbers of Foxp3+ Treg cells via CCR2. Greater infiltration of Treg cells also correlates with MLL3 downregulation and mutations in human breast cancer biopsies. Interestingly, HIF1α enforces the differentiation of tumor-infiltrating Treg cells into highly immunosuppressive ICOShiGITRhi Blimp-1hi effector Treg cells that enable rapid tumor escape. Monoclonal antibody targeting of ICOS or GITR inhibits tumorigenesis in most mice even two months after the cessation of treatment as well as the growth of established tumors, suggesting possible therapeutic opportunities for MLL3-mutant breast cancers."
1458,HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells,"Xinxin Kou, Xiaoxia Yang, Zheng Zhao, Lei Li",https://www.biorxiv.org/content/10.1101/2023.08.24.554577v1,"Background Currently, platinum agents remain the mainstay of chemotherapy for ovarian cancer (OC). However, cisplatin (DDP) resistance is a major reason for chemotherapy failure. Thus, it is extremely important to elucidate the mechanism of resistance to DDP."
1459,An improved PDE6D inhibitor combines with Sildenafil to synergistically inhibit KRAS mutant cancer cell growth,"Pelin Kaya, Elisabeth Schaffner-Reckinger, Ganesh babu Manoharan, Vladimir Vukic, Alexandros Kiriazis, Mirko Ledda, Maria Burgos, Karolina Pavic, Anthoula Gaigneaux, Enrico Glaab, Daniel Kwaku Abankwa",https://www.biorxiv.org/content/10.1101/2023.08.23.554263v1,"The trafficking chaperone PDE6D (or PDEƍ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl-binding pocket. These inhibitors suffered from low solubility and intracellular potency, preventing their clinical development."
1460,From Cell-Lines to Cancer Patients: Personalized Drug Synergy Prediction,"Halil Ibrahim Kuru, A. Ercument Cicek, Oznur Tastan",https://www.biorxiv.org/content/10.1101/2023.02.13.528276v2,"Combination drug therapies are effective treatments for cancer. However, the genetic heterogeneity of the patients and exponentially large space of drug pairings pose significant challenges for finding the right combination for a specific patient. Current in silico prediction methods can be instrumental in reducing the vast number of candidate drug combinations. However, existing powerful methods are trained with cancer cell line gene expression data, which limits their applicability in clinical settings. While synergy measurements on cell lines models are available at large scale, patient-derived samples are too few to train a complex model. On the other hand, patient-specific single-drug response data are relatively more available. In this work, we propose a deep learning framework, Personalized Deep Synergy Predictor (PDSP), that enables us to use the patient-specific single drug response data for customizing patient drug synergy predictions. PDSP is first trained to learn synergy scores of drug pairs and their single drug presonses for a given cell line using drug structures and large scale cell line gene expression data. Then, the model is fine-tuned for patients with their patient gene expression data and associated single drug response measured on the patient ex vivo samples. In this study, we evaluate PDSP on data from three leukemia patients and observe that it improves the prediction accuracy by 27% compared to models trained on cancer cell line data. PDSP is built and available at https://github.com/hikuru/PDSP"
1461,Patient-Specific Analysis of Co-expression Networks for Predicting Clinical Outcomes in Breast Cancer,"Lanying Wei, Yucui Xin, Mengchen Pu, Yingsheng Zhang",https://www.biorxiv.org/content/10.1101/2023.08.23.554466v1,"To effectively understand the underlying mechanisms of disease and inform the development of personalized therapies, it is critical to harness the power of differential co-expression network analysis. Despite the promise of differential co-expression network analysis in precision medicine, current approaches have a major limitation: they measure an average differential network across multiple samples, which means the specific etiology of individual patients is often overlooked. To address this, we present Cosinet, a differential co-expression-based single-sample network rewiring degree quantification tool. By analyzing two breast cancer datasets, we demonstrate that Cosinet can identify important differences in gene co-expression patterns between individual patients and generate scores for each individual that are significantly associated with overall survival, recurrence-free interval, and other clinical outcomes, even after adjusting for risk factors such as age, tumor size, HER2 status and PAM50 subtypes. Cosinet represents a remarkable development toward unlocking the potential of differential co-expression analysis in the context of precision medicine."
1462,Unravelling cancer subtype-specific driver genes in single-cell transcriptomics data with CSDGI,"Meng Huang, Jiangtao Ma, Guangqi An, Xiucai Ye",https://www.biorxiv.org/content/10.1101/2023.08.23.554393v1,"Cancer is known as a heterogeneous disease. Cancer driver genes (CDGs) need to be inferred for understanding tumor heterogeneity in cancer. However, the existing computational methods have identified many common CDGs. A key challenge exploring cancer progression is to infer cancer subtype-specific driver genes (CSDGs), which provides guidane for the diagnosis, treatment and prognosis of cancer. The significant advancements in single-cell RNA-sequencing (scRNA-seq) technologies have opened up new possibilities for studying human cancers at the individual cell level. In this study, we develop a novel unsupervised method, CSDGI (Cancer Subtype-specific Driver Gene Inference), which applies Encoder-Decoder-Framework consisting of low-rank residual neural networks to inferring driver genes corresponding to potential cancer subtypes at single-cell level. To infer CSDGs, we apply CSDGI to the tumor single-cell transcriptomics data. To filter the redundant genes before driver gene inference, we perform the differential expression genes (DEGs). The experimental results demonstrate CSDGI is effective to infer driver genes that are cancer subtype-specific. Functional and disease enrichment analysis shows these inferred CSDGs indicate the key biological processes and disease pathways. CSDGI is the first method to explore cancer driver genes at the cancer subtype level. We believe that it can be a useful method to understand the mechanisms of cell transformation driving tumours."
1463,cGAS/STING and NLRP3 cooperatively activate CD8+ T cell-mediated anti-tumor immunity in colorectal cancer,"Courtney Mowat, Daniel Schiller, Kristi Baker",https://www.biorxiv.org/content/10.1101/2023.08.22.554371v1,"Colorectal cancer (CRC) is a highly prevalent and deadly disease that is largely refractory to immunotherapy. The only CRC subset that responds to these therapies is characterized by prevalent microsatellite instability (MSI), extensive CD8+ T cell infiltration and high expression of innate immune signaling pathways. Endogenous activation of the cGAS/STING pathway is essential for the CD8+ T cell antitumor response in MSI CRCs, suggesting that activating it in other CRCs could boost immunotherapy response rates. We show that cGAS/STING signaling can be enhanced by costimulation of the NLRP3 inflammasome and that dual stimulation increases CD8+ T cell-mediated antitumor immunity in both MSI and non-MSI CRCs. The ability of NLRP3 to boost cGAS/STING signaling was specific and did not occur with activation of other innate immune pathways such as AIM2 or TLRs. Cooperativity between cGAS/STING and NLRP3 proceeded via a positive feedback loop that was inflammasome-independent and required early crosstalk between the signaling mediators and regulation of their gene expression. Notably, increased cGAS/STING signaling enhanced CD8+ T cell activation when in conjunction with anti-PD1 immunotherapy, suggesting that signaling via NLRP3 could further boost this response and render otherwise resistant CRC susceptible to immunotherapy."
1467,The isoflavonoid brazilin inhibits viability and cell migration in breast cancer cells,"Alberto Hernández-Moreno, Dania A. Nava-Tapia, Jorge Bello-Martínez, Monserrat Olea-Flores, Tadeo Hernández-Moreno, Miriam D. Zuñiga-Eulogio, Napoleón Navarro-Tito",https://www.biorxiv.org/content/10.1101/2023.08.17.553723v1,"Breast cancer is the most common neoplasm diagnosed in women and is the leading cause of cancer death worldwide. In recent years, compounds isolated from natural sources have been proposed as potential molecules in therapy for breast cancer. In this regard, brazilin has been evaluated in various biological sceneries and has shown pharmacological functions, including anticancer and anti-inflammatory activities. Brazilin was obtained from Haematoxylum brasiletto. The chemical structure was confirmed by spectroscopic data (1H-NMR, 13C-NMR). Concerning biological activity, by MTT assays, brazilin showed cytotoxic effects on MCF7 and MDA-MB-231 breast cancer cell lines. Interestingly, brazilin was not toxic in MCF10A non-tumorigenic breast epithelial cells. We also observed morphological changes to a rounded phenotype associated with apoptosis in breast cancer cell lines and decreased cell migration in a dose and time-dependent manner. By in silico analysis, we found that brazilin interacts with JAK1, JAK2, and iNOS, essential molecules driven cell migration and metastasis in cancer. These data suggest that brazilin can potentially be used as an anti-cancer agent in the future."
1468,A noncanonical repressor function of JUN restrains YAP activity and suppresses YAP-dependent liver cancer growth,"Yuliya Kurlishchuk, Anita Cindric Vranesic, Marco Jessen, Alexandra Kipping, KyungMok Kim, Paul Cramer, Björn von Eyss",https://www.biorxiv.org/content/10.1101/2023.08.20.554005v1,"Yes-associated protein (YAP) and its homologue, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effector of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor formation in a short time, underscoring the evolutionary need for tight control of these two transcriptional coactivators. The AP-1 complex binds together with YAP/TAZ to many common sites and they form a positive feed-forward to induce gene expression."
1469,Artificial Intelligence Helps to Predict Recurrence and Mortality for Prostate Cancer Using Histology Images,"Okyaz Eminaga, Fred Saad, Zhe Tian, Ulrich Wolffgang, Pierre I. Karakiewicz, Véronique Ouellet, Feryel Azzi, Tilmann Spieker, Burkhard M. Helmke, Markus Graefen, Xiaoyi Jiang, Lei Xing, Jorn H. Witt, Dominique Trudel, Sami-Ramzi Leyh-Bannurah",https://www.biorxiv.org/content/10.1101/2023.07.27.550781v2,"Besides grading, deep learning could improve expert consensus to predict prostate cancer (PCa) recurrence. We developed a novel PCa recurrence prediction system based on artificial intelligence (AI). We validated it using multi-institutional and international datasets comprising 2,647 PCa patients with at least a 10-year follow-up. Survival analyses were performed and goodness-of-fit of multivariate models was evaluated using partial likelihood ratio tests, Akaike’s test, or Bayesian information criteria to determine the superiority of our system over existing grading systems. Comprehensive survival analyses demonstrated the effectiveness of our AI- system in categorizing PCa into four distinct risk groups. The system was independent and superior to the existing five grade groups for malignancies. A high consensus level was observed among five blinded genitourinary pathology experts in ranking images according to our prediction system. Therefore, AI may help develop an accurate and clinically interpretable PCa recurrence prediction system, facilitating informed decision-making for PCa patients."
1470,LncRNA SNHG16 modulates paclitaxel resistance in breast cancer by regulating Let-7a-5p/DUSP7,"Hui Zhao, Lei Wang, Yueqing Feng, Junzheng Yang",https://www.biorxiv.org/content/10.1101/2023.08.18.553807v1,"Objective To investigate the effect of long chain non coding RNA (lncRNA) small nucleolar RNA host gene 6 (SNHG16) on paclitaxel (PTX) resistance in breast cancer and to understand its underlying mechanism, to lay a foundation for decreasing the PTX resistance in breast cancer treatment and improving the therapeutic quality for breast cancer patients."
1471,Morphometry and mechanical instability at the onset of epithelial bladder cancer,"Franziska L. Lampart, Roman Vetter, Yifan Wang, Kevin A. Yamauchi, Nico Strohmeyer, Florian Meer, Marie-Didiée Hussherr, Gieri Camenisch, Hans-Helge Seifert, Cyrill A. Rentsch, Clémentine Le Magnen, Daniel J. Müller, Lukas Bubendorf, Dagmar Iber",https://www.biorxiv.org/content/10.1101/2023.08.17.553533v2,"Malignancies of epithelial tissues, called carcinomas, account for the majority of cancer cases. Much cancer research has focused on genetic alterations and their relation to different carcinoma phenotypes. Besides a rewiring in the signalling networks, carcinoma progression is accompanied by mechanical changes in the epithelial cells and the extracellular matrix. Here, we reveal intricate morphologies in the basement membrane at the onset of bladder cancer, and propose that they emerge from a mechanical buckling instability upon epithelial overgrowth. Using a combination of microscopy imaging of the mouse and human bladder tissue, elasticity theory, and numerical simulations of differential growth in the bladder mucosa, we find that aberrant tissue morphologies can emerge through stiffness changes in the different mucosa layers. The resulting thickening, wrinkles and folds exhibit qualitative and quantitative similarity with imaged early papillary tumors and carcinomas in situ. Atomic force microscopy indeed reveals local stiffness changes in the pathological basement membrane. Our findings suggest a mechanical origin of the different carcinoma subtypes in the bladder, which have vastly different clinical prognosis. They might provide the basis for a new line of attack in medical carcinoma treatment and prophylaxis."
1473,Biocompatibility characterisation of CMOS-based Lab-on-Chip electrochemical sensors for in vitro cancer cell culture applications,"Melina Beykou, Vicky Bousgouni, Nicolas Moser, Pantelis Georgiou, Chris Bakal",https://www.biorxiv.org/content/10.1101/2023.11.23.568427v1,"Lab-on-Chip electrochemical sensors, such as Ion-Sensitive Field-Effect Transistors (ISFETs), are being developed for use in point-of-care diagnostics, such as pH detection of tumour microenvironments, due to their integration with standard Complementary Metal Oxide Semiconductor technology. With this approach, the passivation of the CMOS process is used as a sensing layer to minimise post-processing, and Silicon Nitride (Si3N4) is the most common material at the microchip surface. ISFETs have the potential to be used for cell-based assays however, there is a poor understanding of the biocompatibility of microchip surfaces. Here, we quantitatively evaluated cell adhesion, morphogenesis, proliferation and mechano-responsiveness of both normal and cancer cells cultured on a Si3N4, sensor surface. We demonstrate that both normal and cancer cell adhesion decreased on Si3N4. Activation of the mechano-responsive transcription regulators, YAP/TAZ, are significantly decreased in cancer cells on Si3N4 in comparison to standard cell culture plastic, whilst proliferation marker, Ki67, expression markedly increased. Non-tumorigenic cells on chip showed less sensitivity to culture on Si3N4 than cancer cells. Treatment with extracellular matrix components increased cell adhesion in normal and cancer cell cultures, surpassing the adhesiveness of plastic alone. Moreover, poly-l-ornithine and laminin treatment restored YAP/TAZ levels in both non-tumorigenic and cancer cells to levels comparable to those observed on plastic. Thus, engineering the electrochemical sensor surface with treatments will provide a more physiologically relevant environment for future cell-based assay development on chip."
1474,A fluorescence-based sensor screen identifies MED12 as a potential microsatellite instability regulator in colon cancer,"João M. Fernandes Neto, Subramanian Venkatesan, Matheus Dias, Cor Lieftink, Ben Morris, Kaspar Bresser, Loredana Vecchione, Bastiaan Evers, Ferenc Scheeren, Ton Schumacher, Roderick L. Beijersbergen, René Bernards",https://www.biorxiv.org/content/10.1101/2023.08.17.553681v1,"Inactivation of the DNA mismatch repair (MMR) system, due to (epi)genetic alterations of MMR genes, increases the frequency of mutations across the genome, creating a phenotype known as microsatellite instability (MSI). Cancers with this phenotype have been associated with a better prognosis for some time, but only since recently it has been recognised as a predictive biomarker of response to immunotherapy. Because MSI tumours accumulate more insertions and/or deletions in coding regions of the genome containing microsatellites, there is an increase in neoantigens resulting from reading frame shifts, which promotes immunogenicity. To investigate if additional genes exist that can cause an MSI phenotype, we developed a fluorescence-based sensor to identify genes whose inactivation increases the rate of frameshift mutations on microsatellite sequences in cancer cells. Using genome-scale CRISPR/Cas9 screens, we identified MED12 as a potential new regulator of microsatellite instability. Consistent with this, we found that MED12 mutant colon cancers that lack mutations in the known MMR genes are more likely to be of the MSI phenotype."
1475,Colibactin-induced genotoxicity and colorectal cancer exacerbation critically depends on adhesin-mediated epithelial binding,"Maude Jans, Magdalena Kolata, Gillian Blancke, Maarten Ciers, Anders B. Dohlman, Takato Kusakabe, Mozes Sze, Alexandra Thiran, Geert Berx, Sabine Tejpar, Geert van Loo, Iliyan D. Iliev, Han Remaut, Lars Vereecke",https://www.biorxiv.org/content/10.1101/2023.08.16.553526v1,"Various bacteria are suggested to contribute to colorectal cancer (CRC) development, including pks+ E. coli which produce the genotoxin colibactin that induces characteristic mutational signatures in host epithelial cells. It remains unclear how the highly unstable colibactin molecule is able to access host epithelial cells and its DNA to cause harm. Using the microbiota-dependent ZEB2-transgenic mouse model of invasive CRC, we found that pks+ E. coli drives CRC exacerbation and tissue invasion in a colibactin-dependent manner. Using isogenic mutant strains, we further demonstrate that CRC exacerbation critically depends on expression of the E. coli type-1 pilus adhesin FimH and the F9-pilus adhesin FmlH. Blocking bacterial adhesion using a pharmacological FimH inhibitor attenuates colibactin-mediated genotoxicity and CRC exacerbation. Together, we show that the oncogenic potential of pks+ E. coli critically depends on bacterial adhesion to host epithelial cells and is critically mediated by specific bacterial adhesins. Adhesin-mediated epithelial binding subsequently allows production of the genotoxin colibactin in close proximity to host epithelial cells, which promotes DNA damage and drives CRC development. These findings present promising therapeutic avenues for the development of anti-adhesive therapies aiming at mitigating colibactin-induced DNA damage and inhibiting the initiation and progression of CRC, particularly in individuals at risk for developing CRC."
1476,High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment,"Tzu-Ting Wei, Eric Blanc, Stefan Peidli, Philip Bischoff, Alexandra Trinks, David Horst, Christine Sers, Nils Blüthgen, Dieter Beule, Markus Morkel, Benedikt Obermayer",https://www.biorxiv.org/content/10.1101/2024.02.23.581690v1,"Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could potentially adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non-cancer epithelial cells in single-cell data. In colorectal cancer datasets, we find that our method and others based on gene expression or allelic imbalances identify overlapping sets of cancer versus normal epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem-like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo-time range of normal colon stem-like cells in a cancer context. We identify cancer-associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible."
1477,Development and validation of a reliable DNA copy-number-based machine learning algorithm (CopyClust) for breast cancer integrative cluster classification,"Cameron C. Young, Katherine Eason, Raquel Manzano Garcia, Richard Moulange, Sach Mukherjee, Suet-Feung Chin, Carlos Caldas, Oscar M. Rueda",https://www.biorxiv.org/content/10.1101/2023.11.21.568129v1,"The Integrative Clusters (IntClusts) provide a framework for the classification of breast cancer tumors into 10 distinct genomic subtypes based on DNA copy number and gene expression. Current classifiers achieve only low accuracy without gene expression data, warranting the development of new approaches to copy-number-only-based IntClust classification. A novel XGBoost-driven classification algorithm, CopyClust, was trained using genomic features from METABRIC and validated on TCGA achieving a nine-percentage point or greater improvement in overall IntClust subtype classification accuracy."
1478,Tafazzin Mediates Tamoxifen Resistance by Regulating Cellular Phospholipid Composition in ER-Positive Breast Cancer,"Xuan Li, Yuan Zhang, Tengjiang Zhang, Luyang Zhao, Christopher G. Lin, Haitian Hu, Hanqiu Zheng",https://www.biorxiv.org/content/10.1101/2023.08.15.553336v1,"Tamoxifen is the frontline therapeutic agent for the estrogen receptor-positive (ER+) subtype of breast cancer patients, which accounts for 70-80% of total breast cancer incidents. However, clinical resistance to tamoxifen has become increasingly common, highlighting the need to identify the underlying cellular mechanisms. In our study, we employed a genome-scale CRISPR-Cas9 loss-of-function screen and validation experiments to discover that Tafazzin (TAZ), a mitochondrial transacylase, is crucial for maintaining the cellular sensitivity of ER+ breast cancer cells to tamoxifen and other chemotherapies. Mechanistically, we found that cardiolipin, whose synthesis and maturation rely on TAZ, is required to maintain cellular resistance to tamoxifen. Loss of metabolic enzymatic activity of TAZ causes ERα downregulation and therapy resistance. Interestingly, we observed that TAZ deficiency also led to the upregulation of lysophosphatidylcholine (LPC), which in turn suppressed ERα expression and nuclear localization, thereby contributing to tamoxifen resistance. LPC is further metabolized to lysophosphatidic acid (LPA), a bioactive molecule that supports cell survival. Thus, our findings suggest that the depletion of TAZ promotes tamoxifen resistance through an LPC-LPA phospholipid synthesis axis, and targeting this lipid metabolic pathway could restore cell susceptibility to tamoxifen treatment."
1481,The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities,"Xingyuan Zhang, Sayali Joseph, Di Wu, Jessica L. Bowser, Cyrus Vaziri",https://www.biorxiv.org/content/10.1101/2023.11.20.567919v1,"Genome maintenance is an enabling characteristic that allows neoplastic cells to tolerate the inherent stresses of tumorigenesis and evade therapy-induced genotoxicity. Neoplastic cells also deploy mis-expressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and survival. Here, we present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to conventional histological and molecular subtypes. We show endometrial serous carcinoma (ESC), an aggressive endometrial cancer subtype, is defined by gene expression signatures comprising members of the Replication Fork Protection Complex (RFPC) and Fanconi Anemia (FA) pathway and CTAs with mitotic functions. DDR and CTA- based profiling also defines a subset of highly aggressive endometrioid endometrial carcinomas (EEC) with poor clinical outcomes that share similar profiles to ESC yet have distinct characteristics based on conventional histological and genomic features. Using an unbiased CRISPR-based genetic screen and a candidate gene approach, we confirm that DDR and CTA genes that constitute the ESC and related EEC gene signatures are required for proliferation and therapy-resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and reveals new vulnerabilities of aggressive endometrial cancer where none currently exist."
1482,The Hippo kinase LATS1 controls CTCF chromatin occupancy and the hormonal response of three-dimensionally grown breast cancer cells,"Julieta Ramirez, Roberto Ferrari, Rosario T. Sanz, Marta Valverde-Santiago, A. Silvina Nacht, David Castillo, Francois Le Dily, Maria Victoria Neguembor, Marco Malatesta, Marc A. Marti-Renom, Miguel Beato, Guillermo P. Vicent",https://www.biorxiv.org/content/10.1101/2023.11.20.566232v1,"The cancer epigenome has been studied in cells cultured in 2D monolayers on plastic surfaces, but recent studies highlight the impact of the extracellular matrix (ECM) and the 3D environment on multiple cellular functions. Here, we report the physical, biochemical and genomic differences between T47D breast cancer cells cultured in 2D monolayer and as 3D spheroids in Matrigel. Cells within 3D spheroids exhibit a rounder nucleus with less accessible, more compacted chromatin, and altered expression of over 2,000 genes, the majority of which become repressed. Hi-C analysis reveals that cells grown in 3D exhibit enrichment in regions belonging to the B compartment, decrease on chromatin bound CTCF and increased fusion of Topologically Associating Domains (TADs). Upregulation of the Hippo pathway in 3D spheroids results in the activation of the LATS1 kinase, which promotes phosphorylation and displacement of CTCF from DNA, likely responsible for the observed TAD fusions. Cells grown in 3D exhibit higher progesterone receptor (PR) binding to chromatin, leading to an increase in the number hormone-regulated genes. This effect is in part mediated by the LATS1 activation, which favors cytoplasmic retention of YAP and CTCF removal."
1484,Simultaneous targeting of AMPK and mTOR is a novel therapeutic strategy against prostate cancer,"Gangyin Zhao, Gabriel Forn-Cuní, Marvin Scheers, Pier Pieterszoon Lindenbergh, Jie Yin, Quint van Loosen, Leonardo Passarini, Lanpeng Chen, B. Ewa Snaar-Jagalska",https://www.biorxiv.org/content/10.1101/2023.08.14.553275v1,"Metastatic colonization by circulating cancer cells is a highly inefficient process. To colonize distant organs, disseminating cancer cells must overcome many obstacles in foreign microenvironments, and only a small fraction of them survives this process. How these disseminating cancer cells cope with stress and initiate metastatic process is not fully understood. In this study, we report that the metastatic onset of prostate cancer cells is associated with the dynamic conversion of metabolism signaling pathways governed by the energy sensors AMPK and mTOR. While in circulation in blood flow, the disseminating cancer cells display decreased mTOR and increased AMPK activities that protect them from stress-induced death. However, after metastatic onset, the mTOR-AMPK activities are reversed, enabling mTOR-dependent tumor growth. Suppression of this dynamic conversion by co-targeting of AMPK and mTOR signaling significantly suppresses prostate cancer cell and tumor organoid growth in vitro and experimental metastasis in vivo, suggesting that this can be a therapeutic approach against metastasizing prostate cancer."
1485,Gene expression signature for predicting homologous recombination deficiency in triple-negative breast cancer,"Jia-Wern Pan, Zi-Ching Tan, Pei-Sze Ng, Muhammad Mamduh Ahmad Zabidi, Putri Nur Fatin, Jie-Ying Teo, Siti Norhidayu Hasan, Tania Islam, Li-Ying Teoh, Suniza Jamaris, Mee-Hoong See, Cheng-Har Yip, Pathmanathan Rajadurai, Lai-Meng Looi, Nur Aishah Mohd Taib, Oscar M. Rueda, Carlos Caldas, Suet-Feung Chin, Joanna Lim, Soo-Hwang Teo",https://www.biorxiv.org/content/10.1101/2022.06.08.495296v2,"Triple-negative breast cancers (TNBCs) are a subset of breast cancers that have remained difficult to treat. Roughly 1 in 10 of TNBCs arise in individuals with pathogenic variants in BRCA1 or BRCA2, and treating BRCA-associated TNBCs with PARP inhibitors results in improved survival. A proportion of TNBCs arising in non-carriers of BRCA pathogenic variants have genomic features that are similar to BRCA carriers, and we postulated that gene expression may identify individuals with such features who might also benefit from PARP inhibitor treatment. Using genomic data from 129 TNBC samples from the Malaysian Breast Cancer (MyBrCa) cohort, we classified tumours as having high or low homologous recombination deficiency (HRD) and developed a gene expression-based machine learning classifier for HRD in TNBCs. The classifier identified samples with HRD mutational signature at an AUROC of 0.94 in the MyBrCa validation dataset, and strongly segregated HRD-associated genomic features in TNBCs from TCGA and METABRIC. Further validation of the classifier using the NanoString nCounter platform showed that the RNA-seq results correlated strongly with NanoString results (r = 0.90) from fresh frozen tissue as well as NanoString results from FFPE tissue (r = 0.84). Thus, our gene expression classifier may identify triple-negative breast cancer patients with homologous recombination deficiency, suggesting an alternative method to identify individuals who may benefit from treatment with PARP inhibitors or platinum chemotherapy."
1487,Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor,"Carolyn Jablonowski, Waise Quarni, Shivendra Singh, Haiyan Tan, Dhanushka Hewa Bostanthirige, Hongjian Jin, Jie Fang, Ti-Cheng Chang, David Finkelstein, Ji-Hoon Cho, Dongli Hu, Vishwajeeth Pagala, Sadie Miki Sakurada, Shondra M. Pruett-Miller, Ruoning Wang, Andrew Murphy, Kevin Freeman, Junmin Peng, Andrew M Davidoff, Gang Wu, Jun Yang",https://www.biorxiv.org/content/10.1101/2023.06.26.546606v2,"Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a “molecular glue” that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers."
1488,Oncogenic Mutant p53 Sensitizes Non-Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress-Dependent Induction of Mitochondrial Apoptosis,"Kranthi Kumar Chougoni, Victoria Neely, Boxiao Ding, Eziafa Oduah, Vianna Lam, Bin Hu, Jennifer E. Koblinski, Bradford E. Windle, Swati Palit Deb, Sumitra Deb, Senthil K. Radhakrishnan, Hisashi Harada, Steven R. Grossman",https://www.biorxiv.org/content/10.1101/2024.02.22.581532v1,"Non-small cell lung cancer (NSCLC) cells with oncogenic mutant p53 alleles (Onc-p53) exhibit significantly higher levels of proteasome activity, indicating that Onc-p53 induces proteotoxic stress which may be leveraged as a therapeutic vulnerability. Proteasome inhibitors (PIs), such as bortezomib (BTZ), can induce toxic levels of oxidative stress in cancer cells and thus we investigated whether PIs exhibit preferential cytotoxicity in Onc-p53 NSCLC cells. Indeed, BTZ and other PIs exhibited the IC50 6-7-fold lower in Onc-p53 cells vs. wild-type (WT) p53 cells. BTZ cytotoxic effects in Onc-p53 cells were nearly completely rescued by antioxidants such as N-acetyl cysteine, indicating that oxidative stress is the critical driver of BTZ-dependent cytotoxic effects in Onc-p53 cells. Importantly, we observed oxidative stress-dependent transcriptional induction of the pro-apoptotic NOXA with downstream cleaved caspase-3, consistent with apoptotic cell death in Onc-p53 but not in WT p53 cells treated with BTZ, and BTZ-generated oxidative stress was linked to nuclear translocation of NRF2 and transcriptional activation of ATF3, which in turn was required for NOXA induction. Validating BTZ’s translational potential in Onc-p53 NSCLC, BTZ and carboplatin or the BH3-mimetic navitoclax were synergistically cytotoxic in Onc-p53 but not WT p53 cells in vitro, and BTZ effectively limited growth of Onc-p53 NSCLC xenografts when combined with either carboplatin or navitoclax in vivo. Our data therefore support further investigation of the therapeutic utility of PIs combined with carboplatin or BH3-mimetics in Onc-p53 human NSCLC as novel therapeutic strategies."
1489,Uncovering the lung cancer mechanisms through the chromosome structural ensemble characteristics,"Wen-Ting Chu, Jin Wang",https://www.biorxiv.org/content/10.1101/2023.08.13.553145v1,"Lung cancer is one of the most common cancers in human. However, it is still lack of understanding the mechanisms of a normal cell developing to the cancer cell. Here we develop the chromosome dynamic structural model and quantify the important characteristics of the chromosome structural ensemble of the normal lung cell and the lung cancer A549 cell. Our results demonstrate the essential relationship among the chromosome ensemble, the epigenetic marks, and the gene expressions, which suggests the linkage between chromosome structure and function. The analysis reveals that the lung cancer cell may have higher level of relative ensemble fluctuation as well as higher degree of the phase separation between the two compartments than the normal lung cells. In addition, the significant conformational “switching off” events (from compartment A to B) are more than the significant conformational “switching on” events during the lung cancerization. The kinetic lung cancerization pathway is not the same as the reversion pathway by characterizing the hot spots and interaction networks of the lung cancer transitions. These investigations have revealed the cell fate determination mechanism of the lung cancer process, which will be helpful for the further prevention and control of cancers."
1490,Development of Gemcitabine-Modified miRNA Mimics as Cancer Therapeutics for Pancreatic Ductal Adenocarcinoma,"John G. Yuen, Ga-Ram Hwang, Andrew Fesler, Erick Intriago, Amartya Pal, Anushka Ojha, Jingfang Ju",https://www.biorxiv.org/content/10.1101/2023.08.14.553255v1,"Pancreatic cancer, including its most common subtype, pancreatic adenocarcinoma (PDAC), has the lowest five-year survival rate among patients with pancreatic cancer in the United States. Despite advancements in anticancer treatment, the overall median survival for patients with PDAC has not dramatically improved. Therefore, there is an urgent need to develop new strategies of treatment to address this issue. Non-coding RNAs, including microRNAs (miRNAs), have been found to have major roles in carcinogenesis and the subsequent treatment of various cancer types like PDAC. In this study, we developed a treatment strategy by modifying tumor suppressor miRNAs, hsa-miRNA-15a (miR-15a) and hsa-miRNA-194-1 (miR-194), with the nucleoside analog chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics of miR-15a (Gem-miR-15a) and miR-194 (Gem-miR-194). In a panel of PDAC cell lines, we found that Gem-miR-15a and Gem-miR-194 induce cell cycle arrest and apoptosis, and these mimics are potent inhibitors with IC50 values up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a and Gem-miR-194 retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a, and FOXA1 for Gem-miR-194. We also found that our Gem-modified miRNA mimics exhibit an enhanced efficacy compared to Gem alone in patient-derived PDAC organoids. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of Gem-modified miRNAs as a treatment strategy for PDAC."
1492,Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutamate export and glutaminase,"Hoon Choi, Mamta Gupta, Christopher Hensley, Hsiaoju Lee, Yu-Ting Lu, Austin Pantel, David Mankoff, Rong Zhou",https://www.biorxiv.org/content/10.1101/2023.11.19.567663v1,"In triple-negative breast cancer (TNBC) that relies on catabolism of amino acid glutamine, glutaminase (GLS) converts glutamine to glutamate, which facilitates glutathione synthesis by mediating the enrichment of intracellular cystine via xCT antiporter activity. To overcome chemo resistant TNBC, we have tested a strategy of disrupting cellular redox balance by inhibition of GLS and xCT by CB839 and Erastin, respectively. Key findings of our study include: 1. Dual metabolic inhibition (CB839+Erastin) led to significant increases of cellular superoxide level in both parent and chemo resistant TNBC cells, but superoxide level was distinctly lower in resistant cells. 2. Dual metabolic inhibition combined with doxorubicin or cisplatin induced significant apoptosis in TNBC cells and is associated with high degrees of GSH depletion. In vivo, dual metabolic inhibition plus cisplatin led to significant growth delay of chemo resistant human TNBC xenografts. 3. Ferroptosis is induced by doxorubicin (DOX) but not by cisplatin or paclitaxel. Addition of dual metabolic inhibition to DOX chemotherapy significantly enhanced ferroptotic cell death. 4. Significant changes in cellular metabolites concentration preceded transcriptome changes revealed by single cell RNA sequencing, underscoring the potential of capturing early changes in metabolites as pharmacodynamic markers of metabolic inhibitors. Here we demonstrated that 4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) PET detected xCT blockade by Erastin or its analog in mice bearing human TNBC xenografts. In summary, our study provides compelling evidence for the therapeutic benefit and feasibility of non-invasive monitoring of dual metabolic blockade as a translational strategy to sensitize chemo resistant TNBC to cytotoxic chemotherapy."
1494,Nuclear Transformation In Metalloenzyme. A Novel And High Potential Cancer Treatment Research,"Tran Van Luyen, Truong Hoang Tuan",https://www.biorxiv.org/content/10.1101/2023.08.10.552823v1,"In this study, we have introduced a novel approach to cancer treatment involving the deactivation of metalloenzymes through the utilization of radioisotopes. The concept of leveraging radioisotopes to interact with metalloenzymes represents a groundbreaking theoretical advancement. Through simulations utilizing the MIRD code and based on the consistent concentration of stable Mg within stage 2A cancerous tissue, we have quantified the potential success rates."
1495,Expression patterns of m6A RNA methylation regulators under apoptotic conditions in various human cancer cell lines,"Azime Akçaöz-Alasar, Buket Sağlam, Ipek Erdogan Vatansever, Bünyamin Akgül",https://www.biorxiv.org/content/10.1101/2023.08.10.551971v1,"The emerging evidence suggests that epitranscriptomics changes play a crucial role in the pathogenesis of cancer. However, expression patterns of m6A RNA modifiers under apoptotic conditions are unknown. We measured the transcript abundance of m6A RNA modifiers under cisplatin- and tumor necrosis factor alpha (TNF-α)-induced apoptotic conditions. In general, the abundance of m6A modifiers is increased upon cisplatin treatment whereas TNF-α treatment has led to a reduction in their expression. Specifically, cisplatin-induced apoptosis, but not TNF-α mediated apoptosis, lowered the abundance of METTL14 and FTO transcripts. Additionally, cisplatin treatment plummeted the abundance of IGF2BP2 and IGF2BP3 readers following cisplatin treatment. These results suggest that differential response of cancer cells to apoptotic inducers could be partially due to m6A RNA modifiers."
1496,Accurate pan-cancer tumor purity estimation from gene expression data,"Egor Revkov, Tanmay Kulshrestha, Ken Wing-Kin Sung, Anders Jacobsen Skanderup",https://www.biorxiv.org/content/10.1101/2022.06.01.494462v2,"Tumors are complex masses composed of malignant and non-malignant cells. Variation in tumor purity (proportion of cancer cells in a sample) can both confound integrative analysis and enable studies of tumor heterogeneity. Here we developed PUREE, which uses a weakly supervised learning approach to infer tumor purity from a tumor gene expression profile. PUREE was trained on gene expression data and genomic consensus purity estimates from 7864 solid tumor samples. PUREE predicted purity with high accuracy across distinct solid tumor types and generalized to tumor samples from unseen tumor types and cohorts. Gene features of PUREE were further validated using single-cell RNA-seq data from distinct tumor types. In a comprehensive benchmark, PUREE outperformed existing transcriptome-based purity estimation approaches. Overall, PUREE is a highly accurate and versatile method for estimating tumor purity and interrogating tumor heterogeneity from bulk tumor gene expression data."
1497,Establishing conditions for the generation and maintenance of estrogen receptor-positive organoid models of breast cancer,"Michael UJ Oliphant, Dipikaa Akshinthala, Senthil K Muthuswamy",https://www.biorxiv.org/content/10.1101/2023.08.09.552657v1,"Patient-derived organoid models of estrogen receptor-positive (ER+) breast cancer would provide a much-needed tool to better understand drug resistance and disease progression. However, the establishment and long-term maintenance of ER expression, function, and response in vitro remains a significant challenge. Here, we report the development of an ER+ breast tumor organoid medium (BTOM-ER) that conserves ER expression, estrogen responsiveness, and dependence, as well as sensitivity to endocrine therapy of ER+ patient-derived xenograft organoids (PDXO). Our findings demonstrate the utility of subtype-specific culture conditions that better mimic the characteristics of the breast epithelial biology and microenvironment, providing a powerful platform for investigating therapy response and disease progression of ER+ breast cancer."
1498,Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy,"Lei Wang, Yufeng Xiao, Yuewan Luo, Rohan P Master, Jiao Mo, Myung-Chul Kim, Yi Liu, Urvi M Patel, Xiangming Li, Donald Shaffer, Kevin R Guertin, Emily Moser, Keiran S. Smalley, Daohong Zhou, Guangrong Zheng, Weizhou Zhang",https://www.biorxiv.org/content/10.1101/2023.08.09.552650v1,"An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti- cancer immune responses and offers a new avenue for treating various types of cancer."
1499,Synergistic effects of inhibitors targeting PI3K and Aurora Kinase A in preclinical inflammatory breast cancer models,"Nadia Al Ali, Jacob Kment, Stephanie Young, Andrew W.B. Craig",https://www.biorxiv.org/content/10.1101/2023.08.11.552992v1,"Background Inflammatory breast cancer (IBC) is an aggressive clinical subtype of breast cancer often diagnosed in young women. Lymph node and distant metastases are frequently detected at diagnosis of IBC, and improvements in systemic therapies are needed. For IBC that lack hormone or HER2 expression, no targeted therapies are available. Since the phosphatidyl inositol 3’ kinase (PI3K) pathway is frequently deregulated in IBC, some studies have tested the pan PI3K inhibitor Buparlisib (BKM120). Although the SUM149 IBC cell line was resistant to Buparlisib, a functional genomic screen showed that silencing of Aurora kinase A (AURKA) sensitized cells to killing by Buparlisib. In this study, we tested whether combination treatments of PI3K and AURKA inhibitors act synergistically to kill IBC cells and tumors."
1500,Pancreatic cancer risk predicted from disease trajectories using deep learning,"Davide Placido, Bo Yuan, Jessica X. Hjaltelin, Chunlei Zheng, Amalie D. Haue, Piotr J Chmura, Chen Yuan, Jihye Kim, Renato Umeton, Gregory Antell, Alexander Chowdhury, Alexandra Franz, Lauren Brais, Elizabeth Andrews, Debora S. Marks, Aviv Regev, Siamack Ayandeh, Mary Brophy, Nhan Do, Peter Kraft, Brian M. Wolpin, Nathanael Fillmore, Michael Rosenthal, Søren Brunak, Chris Sander",https://www.biorxiv.org/content/10.1101/2021.06.27.449937v3,"Pancreatic cancer is an aggressive disease that typically presents late with poor patient outcomes. There is a pronounced medical need for early detection of pancreatic cancer, which can be addressed by identifying high-risk populations. Here we apply artificial intelligence (AI) methods to a dataset of 6 million patient records with 24,000 pancreatic cancer cases in the Danish National Patient Registry (DNPR) and, for comparison, a dataset of three million records with 3,900 pancreatic cancer cases in the United States Department of Veterans Affairs (US-VA) healthcare system. In contrast to existing methods that do not use temporal information, we explicitly train machine learning models on the time sequence of diseases in patient clinical histories and test the ability to predict cancer occurrence in time intervals of 3 to 60 months after risk assessment."
1502,Androgen receptor signaling blockade enhances NK cell-mediated killing of prostate cancer cells and sensitivity to NK cell checkpoint blockade,"Maximilian Pinho-Schwermann, Benedito A. Carneiro, Lindsey Carlsen, Kelsey E. Huntington, Praveen R. Srinivasan, Andrew George, Vida Tajiknia, William MacDonald, Connor Purcell, Lanlan Zhou, Andre De Souza, Howard P. Safran, Wafik S. El-Deiry",https://www.biorxiv.org/content/10.1101/2023.11.15.567201v1,"Background The blockade of the androgen receptor (AR) pathway is an effective treatment for prostate cancer (PCa), but many patients progress to metastatic castration-resistant prostate cancer (mCRPC). Therapies for mCRPC include AR inhibitors (ARi), chemotherapy, PARP inhibitors, and radioligands. Checkpoint inhibitor activity is limited to a small subset of MSI-H mCRPC. AR signaling modulates CD8+ T cell function, but its impact on NK cell (NKc) cytotoxicity is unknown. We investigated the effect of ARi on NKc activation, cytokine secretion, expression of inhibitory receptor NKG2A, and killing of PCa cells in vitro."
1503,Coordination games in cancer,"Péter Bayer, Robert A. Gatenby, Patricia H. McDonald, Derek R. Duckett, Kateřina Staňková, Joel S. Brown",https://www.biorxiv.org/content/10.1101/2021.06.22.449436v1,"We propose a model of cancer initiation and progression where tumor growth is modulated by an evolutionary coordination game. Evolutionary games of cancer are widely used to model frequency-dependent cell interactions with the most studied games being the Prisoner’s Dilemma and public goods games. Coordination games, by their more obscure and less evocative nature, are left understudied, despite the fact that, as we argue, they offer great potential in understanding and treating cancer. In this paper we present the conditions under which coordination games between cancer cells evolve, we propose aspects of cancer that can be modeled as results of coordination games, and explore the ways through which coordination games of cancer can be exploited for therapy."
1504,"Architecture and topologies of gene regulatory networks associated with breast cancer, adjacent normal, and normal tissues","Swapnil Kumar, Vaibhav Vindal",https://www.biorxiv.org/content/10.1101/2022.10.10.511680v2,"Most cancer studies employ adjacent normal tissues to tumors (ANTs) as controls, which are not completely normal and represent a pre-cancerous state. However, the regulatory landscape of ANTs and how it differs from tumor and non-tumor-bearing normal tissues is largely unexplored. Among cancers, breast cancer is the most commonly diagnosed cancer and a leading cause of death in women worldwide, with a lack of sufficient treatment regimens due to various reasons. Hence, we aimed to gain deeper insights into normal, pre-cancerous, and cancerous regulatory systems of the breast tissues towards the identification of ANT and subtype-specific candidate genes. For this, we constructed and analyzed eight gene regulatory networks (GRNs), including five different subtypes (viz. Basal, Her2, LuminalA, LuminalB, and Normal-Like), one ANT, and two normal tissue networks. Whereas several topological properties of these GRNs enabled us to identify tumor-related features of ANT; escape velocity centrality (EVC+) identified 24 functionally significant common genes, including well-known genes such as E2F1, FOXA1, JUN, BRCA1, GATA3, ERBB2, and ERBB3 across different subtypes and ANT. Similarly, the EVC+ also helped us to identify tissue-specific key genes (Basal: 18, Her2: 6, LuminalA: 5, LuminalB: 5, Normal-Like: 2, and ANT: 7). Additionally, differential correlation along with functional, pathway, and disease annotations highlighted the cancer-associated role of these genes. In a nutshell, the present study revealed ANT and subtype-specific regulatory features and key candidate genes which can be explored further using in vitro and in vivo experiments for better and effective disease management at an early stage."
1505,CDK19 and CDK8 Mediator kinases drive androgen-independent in vivo growth of castration-resistant prostate cancer,"Jing Li, Thomas A. Hilimire, Yueying Liu, Lili Wang, Jiaxin Liang, Balazs Gyorffy, Vitali Sikirzhytski, Hao Ji, Li Zhang, Chen Cheng, Xiaokai Ding, Kendall R. Kerr, Charles E. Dowling, Alexander A. Chumanevich, Gary P. Schools, Chang-uk Lim, Xiaolin Zi, Donald C. Porter, Eugenia V. Broude, Campbell McInnes, George Wilding, Michael B. Lilly, Igor B. Roninson, Mengqian Chen",https://www.biorxiv.org/content/10.1101/2023.08.08.552491v1,"Castration-resistant prostate cancer (CRPC) remains incurable due to its high plasticity. We found that Mediator kinases CDK8 and CDK19, pleiotropic regulators of transcriptional reprogramming, are differentially affected by androgen, which downregulates CDK8 and upregulates CDK19. Accordingly, expression of CDK8 decreases while CDK19 increases during prostate carcinogenesis, but both CDK19 and CDK8 are upregulated in metastatic CRPC. Genetic inactivation of CDK8 and CDK19 suppresses CRPC tumor growth in castrated male mice and renders CRPC responsive to androgen deprivation. Restoration of active CDK19 or CDK8 kinases reverses this phenotype, indicating that CRPC becomes dependent on Mediator kinase activity for in vivo growth under the conditions of androgen deprivation. Selective CDK8/19 inhibitors suppress androgen-independent growth of cell line-based and patient-derived CRPC xenografts, whereas prolonged inhibitor treatment induces tumor regression and even leads to cures. Mediator kinase activity was found to affect tumor and stromal gene expression preferentially in castrated mice, orchestrating castration-induced transcriptional reprogramming. These results warrant the exploration of Mediator kinase inhibitors for CRPC therapy."
1506,Identification of novel myeloid-derived cell states with implication in cancer outcome,"Gabriela Rapozo Guimarães, Giovanna Resk Maklouf, Cristiane Esteves Teixeira, Leandro de Oliveira Santos, Nayara Gusmão Tessarollo, Marco Antônio Pretti, Nayara Evelin Toledo, Jéssica Gonçalves Vieira da Cruz, Marcelo Falchetti, Mylla M. Dimas, Alessandra Freitas Serain, Fabiane Carvalho de Macedo, Fabiana Resende Rodrigues, Nina Carrossini Bastos, Jesse Lopes da Silva, Edroaldo Lummertz da Rocha, Cláudia Bessa Pereira Chaves, Andreia Cristina de Melo, Pedro Manoel Mendes Moraes-Vieira, Marcelo A. Mori, Mariana Boroni",https://www.biorxiv.org/content/10.1101/2023.01.04.522727v2,"Tumor-associated myeloid-derived cells (MDCs) significantly impact cancer prognosis and treatment response due to their remarkable plasticity and tumorigenic behaviors. We integrated single-cell RNA-Sequencing datasets from seven different cancers, resulting in a comprehensive collection of 29 MDC subpopulations in the tumor microenvironment (TME). Distinguishing resident-tissue from monocyte-derived macrophages, we discovered a resident-tissue-like subpopulation within monocyte-derived macrophages. Additionally, hypoxia-driven macrophages emerged as a prominent TME component. Deconvolution of these profiles revealed five subpopulations as independent prognostic markers across various cancer types. Validation in large cohorts confirmed the FOLR2-expressing macrophage association with poor clinical outcomes in ovarian and triple-negative breast cancer. Moreover, the marker TREM2, commonly used to define immunosuppressive tumor-associated macrophages, cannot solely predict cancer prognosis, as different polarization states of macrophages express this marker in a context-dependent manner. This comprehensive MDC atlas offers valuable insights and a foundation for novel analyses, advancing strategies for treating solid cancers."
1507,Epigenetic heritability of cell plasticity drives cancer drug resistance through one-to-many genotype to phenotype mapping,"Javier Fernandez-Mateos, Salvatore Milite, Erica Oliveira, Georgios Vlachogiannis, Bingjie Chen, Erika Yara, George D Cresswell, Chela James, Lucrezia Patruno, Gianluca Ascolani, Ahmet Acar, Timon Heide, Inma Spiteri, Alex Graudenzi, Giulio Caravagna, Trevor Graham, Luca Magnani, Nicola Valeri, Andrea Sottoriva",https://www.biorxiv.org/content/10.1101/2023.11.15.567140v1,"Drug resistance is a largely unsolved problem in oncology. Despite the explanatory power of the genetic model of cancer initiation, most treatment resistance is unexplained by genetics alone. Even when known resistance mutations are present, they are often found in a small proportion of the cells in the tumour. So where is the cellular memory that leads to treatment failure? New evidence suggests resistance is multi-factorial, resulting from the contribution of heritable genetic and epigenetic changes, but also non-heritable phenotypic plasticity. However, cell plasticity has proven hard to study as it dynamically changes over time and needs to be distinguished from clonal evolution where cell phenotypes change because of Darwinian selective bottlenecks. Here we dissected the contribution of different evolutionary processes to drug resistance by perturbing patient-derived organoids with multiple drugs in sequence. We combined dense longitudinal tracking, single cell multi- omics, evolutionary modelling, and machine learning archetypal analysis. We found that different drugs select for distinct subclones, an essential requirement for the use of evolutionary therapy with sequential drug treatment. The data supports a model in which the cellular memory is encoded as a heritable configuration of the epigenome, which however produces multiple transcriptional programmes. Those emerge in different proportions depending on the environment, giving rise to cellular plasticity. Epigenetically encoded programmes include reactivation of developmental genes and cell regeneration. A one-to-many (epi)genotype→phenotype map explains how clonal expansions and non- heritable phenotypic plasticity manifest together, including drug tolerant states. This ensures the robustness of drug resistance subclones that can exhibit distinct phenotypes in changing environments while still preserving the cellular memory encoding their selective advantage."
1508,Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis,"Ann-Kathrin Daum, Lisa Schlicker, Marc A. Schneider, Thomas Muley, Ursula Klingmüller, Almut Schulze, Michael Thomas, Petros Christopoulos, Holger Sültmann",https://www.biorxiv.org/content/10.1101/2023.08.08.552439v1,"Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in ALK-rearranged lung adenocarcinomas, yet resistances occur almost inevitably. Apart from tumor cell-intrinsic resistance mechanisms, accumulating evidence supports a role of cancer-associated fibroblasts (CAFs) in affecting the therapeutic vulnerability of lung cancer cells. Here, we aimed to investigate underlying molecular networks shaping the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells via tumor microenvironmental cues using three-dimensional (3D) spheroid co-culture settings. We show that CAFs promote therapy resistance of lung tumor cells against ALK inhibition by reducing apoptotic cell death and increasing cell proliferation. Using single-cell RNA-sequencing analysis, we show that genes involved in lipogenesis constitute the major transcriptional difference between TKI-treated homo- and heterotypic lung tumor spheroids. CAF-conditioned medium and CAF-secreted factors HGF and NRG1 were both able to promote resistance of 3D-cultured ALK-rearranged lung tumor cells via AKT signaling, which was accompanied by enhanced de novo lipogenesis and supression of lipid peroxidation. Notably, simultaneous targeting of ALK and SREBP-1 was able to overcome the established CAF-driven lipid metabolic-supportive niche of TKI-resistant lung tumor spheroids. Our findings highlight a crucial role of CAFs in mediating ALK-TKI resistance via lipid metabolic reprogramming and suggest new ways to overcome resistance towards molecular directed drugs by targeting vulnerabilities downstream of oncogenic signaling."
1510,Global and local redistribution of somatic mutations enable the prediction of functional XPD mutations in bladder cancer,"Jayne A. Barbour, Tong Ou, Hu Fang, Noel C. Yue, Xiaoqiang Zhu, Michelle W. Wong-Brown, Haocheng Yang, Yuen T. Wong, Nikola A. Bowden, Song Wu, Jason W. H. Wong",https://www.biorxiv.org/content/10.1101/2022.01.21.477237v3,"Xeroderma pigmentosum group D (XPD) is a DNA helicase with critical functions in transcription initiation and nucleotide excision repair. Missense mutations in XPD are putative drivers in around 10% of bladder cancers (BLCA), but the associated mutational process remains poorly understood. Here, we examine the somatic mutational landscape of XPD wild-type (n=343) and mutant (n=39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in XPD mutants, affecting both APOBEC and non-APOBEC associated mutational processes. Specifically, XPD mutants are enriched in T[C>T]N mutations (SBS2) with altered correlation with replication timing. At a locoregional genomic level, mutant XPD BLCA had striking T>G mutation hotspots at CTCF-cohesin binding sites (CBS) with evidence linking XPD to genomic uracil repair. Leveraging differential distribution of somatic mutations, we developed a machine-learning model for predicting pathogenic XPD mutations, which we validated in an independent TCGA cohort with 100% accuracy. Our model enabled the discovery of missed XPD mutation calls and uncovered pathogenic non-hotspot XPD mutations in bladder cancer. Our study reveals how XPD mutations redistribute somatic mutations in cancer genomes and provides a genome sequencing approach to differentiate driver and passenger XPD mutations."
1511,Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer both in vitro and in vivo,"Kirankumar Nalla, Biji Chatterjee, Jagadeesh Poyya, Aishwarya Swain, Krishna Ghosh, Archana Pan, Chandrashekhar G Joshi, Bramanandam Manavathi, Santosh R Kanade",https://www.biorxiv.org/content/10.1101/2024.02.18.580855v1,"Histone methyltransferases are selectively catalyzing the methylation of lysine or arginine residues of target histone and non-histone proteins, classified as lysine methyltransferases and arginine methyltransferases. The EZH2 and PRMT5 catalyze trimethylation of H3 at K27 and symmetric dimethylation of H4 at R3 respectively. These histone repressive marks have been considered as hallmarks in cancer. Both PRMT5 and EZH2 over expressed in several cancers and have been considered as important target of drug development. As a result, many synthetic molecules as inhibitors of both PRMT5 and EZH2 are at different level of preclinical and clinical phases. Cancer atlas data analysis revealed that both PRMT5 and EZH2 had shown more than 90% amplification in breast cancer alone. We screened an array of phytocompounds towards the inhibition of PRMT5 and EZH2 using in silico, in vitro assays. Among them Epigallocatechin-3-gallate (EGCG) has interacted with human PRMT5: MEP50 and EZH2 efficiently. The EGCG interacted within the SAM binding site, with a π-cation interaction at Lys 333 and H-bonds with Tyr324, Tyr334, Gly365, Leu437, and Glu444. Surface plasmon resonance analysis revealed that EGCG has strong binding affinity in nanomolar concentrations with both PRMT5-MEP50 than EZH2. Further in vitro methylation and cell-based assays proved the inhibitory potential of EGCG by reducing the catalytic products of PRMT5 and EZH2 i.e., H4R3me2s & H3K27me3 respectively and showed that it induced autophagy and apoptosis. Furthermore in vivo, mouse xenografts studies demonstrated that oral dosage, reduced tumor size significantly with reduction in proliferation marker Ki67 and these histone repressive marks. Finally conclude that inhibition of PRMT5 and EZH2 by EGCG potentially can be used to develop combined therapeutic approaches."
1512,"Theileria annulata Infection Promotes p53 suppression, Genomic Instability and DNA deaminase APOBEC3H upregulation leading to cancer-like phenotype in host cells","Debabrata Dandesena, Akash Suresh, Roli Budhwar, Jeffrey Godwin, Sakshi Singh, Madhusmita Subudhi, Amruthanjali T, Sonti Roy, Vengatachala Moorthy A, Vasundhra Bhandari, Paresh Sharma",https://www.biorxiv.org/content/10.1101/2024.02.20.581323v1,"Theileria annulata-infected host leukocytes display cancer-like phenotypes, though the precise mechanism is yet to be fully understood. The occurrence of cancer-like phenotypes in Theileria-infected leukocytes may be attributed to various factors, including genomic instability and acquired mutations, a crucial trait that underpins the genetic foundation of cancer. This paper presents WGS data and bioinformatic analyses to reveal point mutations and large-scale alterations in six clinically relevant T. annulata-infected cell lines. We identified 7867 exon-linked somatic mutations common to all cell lines, and cancer association analysis showed significant accumulation in oncogenes (FLT4, NOTCH2, MAP3K1, DAXX, FCGR2B, ROS1) and tumor suppressor genes (BARD1, KMT2C, GRIN2A, BAP1) implicated in established critical cancer processes. We demonstrated that a crizotinib-induced blockade of the ROS1 oncogenic protein, which harbored the most mutations, led to the death of infected leukocytes. This is consistent with the significant role of ROS1 in parasite-induced leukocyte transformation. In addition, we found somatic mutations in genes involved in genome instability and the DDR pathway. Our findings support the notion that ROS1 and Nutulin 3a are valid targets for intervention, and the suppression of TP53, a crucial tumor suppressor gene, may play a significant role in cell immortalization. We also show that upon infection with the parasite, bovine cells upregulate the expression of APOBEC3H, a DNA mutator likely responsible for the detected mutations. Our study highlights how T. annulata transforms leukocytes to gain selective advantage via mutation, and our observations could steer future research towards a mechanistic understanding of disease pathogenesis."
1513,No evidence for the presence and control of tumor growth by cytoplasmic stress granules in pancreatic cancer,"Maxime Libert, Jean Fain, Christelle Bouchart, Tatjana Arsenijevic, Jean-Luc Van Laethem, Patrick Jacquemin",https://www.biorxiv.org/content/10.1101/2023.11.13.566518v1,"Cytoplasmic stress granules (SG) are attracting growing attention in cancer research1. As such, a study published in Cell2 has certainly served as a trigger for this trend which currently asserts that SG are a relevant therapeutic target. Here, we would like to express a warning about the conclusions of this article, as well as of the subsequent study3, and more generally on a methodological approach frequently used in research studying SG in cancer and which we believe to be misleading."
1514,Molecular Jackhammers Eradicate Cancer Cells by Vibronic-Driven Action,"Ciceron Ayala-Orozco, Diego Galvez-Aranda, Arnoldo Corona, Jorge M. Seminario, Roberto Rangel, Jeffrey N. Myers, James M. Tour",https://www.biorxiv.org/content/10.1101/2023.01.25.525400v1,"Through the actuation of vibronic modes in cell-membrane-associated aminocyanines, a new type of molecular mechanical action can be exploited to rapidly kill cells by necrosis. This is done using near-infrared light, a low energy source hitherto thought to be insufficient to permit molecular mechanical disruption of a cell membrane. Vibronic-driven action (VDA) is distinct from both photodynamic therapy and photothermal therapy in that the VDA mechanical effect on the cell membrane is not retarded by high doses of inhibitors of reactive oxygen species (ROS), and VDA does not itself induce an increase in the temperature of the media; it is also unaffected by cooling the media to 2 °C. The picosecond concerted whole-molecule-vibrations of VDA-induced mechanical disruption can be done with very low concentrations (500 nM) of the aminocyanines or low doses of light (12 Jcm-2, 80 mWcm-2 for 2.5 min) to cause in vitro necrotic cell death in >99% of human melanoma cells. The effect is also studied in vivo in murine B16-F10 and human A375 melanoma in mice, underscoring the high efficiency of this approach, achieving a survival rate of 60% at day 120, and 50% of the mice becoming tumor free. The molecules that destroy cell membranes through VDA are termed molecular jackhammers (MJH) because they undergo concerted whole-molecule vibrations. Different than traditional chemotherapy, it is unlikely that a cell could develop a resistance to molecular mechanical forces, thereby providing a new modality for inducing cancer cell death."
1515,Conformational changes in saliva proteome guides discovery of cancer aggressiveness related markers,"Daniela C. Granato, Ana Gabriela C. Normando, Carolina M. Carnielli, Luciana D. Trino, Ariane F. Busso-Lopes, Guilherme A. Câmara, Helder V. R. Filho, Romênia R. Domingues, Sami Yokoo, Bianca A. Pauletti, Fabio M. Patroni, Alan R. Santos-Silva, Márcio A. Lopes, Thaís Brandão, Ana Carolina Prado-Ribeiro, Paulo. S. L. de Oliveira, Guilherme P. Telles, Adriana F. Paes Leme",https://www.biorxiv.org/content/10.1101/2023.08.04.552034v1,"Diverse proteomics-based strategies have been applied to saliva to quantitatively identify diagnostic and prognostic targets for oral cancer. Considering that these potential diagnostic and prognostic factors may be regulated by events that do not imply variation in protein abundance levels, we investigated the hypothesis that changes in protein conformation can be associated with diagnosis and prognosis, revealing biological processes and novel targets of clinical relevance. For this, we employed limited proteolysis-mass spectrometry in saliva samples to explore structural alterations, comparing the proteome of healthy control and oral squamous cell carcinoma (OSCC) patients, with and without lymph node metastasis. Fifty-one proteins with potential structural rearrangements were associated with clinical patient features. Post-translational modifications, such as glycosylation, disulfide bond, and phosphorylation, were also investigated in our data using different search engines and in silico analysis indicating that they might contribute to structural rearrangements of the potential diagnostic and prognostic markers here identified. Altogether, this powerful approach allows for a deep investigation of complex biofluids, such as saliva, advancing the search for targets for oral cancer diagnosis and prognosis."
1517,Reprogramming of 3D chromatin domains by antagonizing the β-catenin/CBP interaction attenuates insulin signaling in pancreatic cancer,"Yufan Zhou, Tian Li, Zhijing He, Lavanya Choppavarapu, Xiaohui Hu, Ruifeng Cao, Gustavo W. Leone, Michael Kahn, Victor X. Jin",https://www.biorxiv.org/content/10.1101/2023.11.10.566585v1,"The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the β-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit."
1518,Capture of circulating metastatic cancer cell clusters from a lung cancer patient can reveal a unique genomic profile and potential anti-metastatic molecular targets: A proof of concept study,"Kourosh Kouhmareh, Erika Martin, Darren Finlay, Anukriti Bhadada, Hector Hernandez-Vargas, Francisco Downey, Jeffrey K. Allen, Peter Teriete",https://www.biorxiv.org/content/10.1101/2023.09.19.558270v2,"Metastasis remains the leading cause of cancer deaths worldwide and lung cancer, known for its highly metastatic progression, remains among the most lethal of malignancies. The heterogeneous genomic profile of lung cancer metastases is often unknown. Since different metastatic events can selectively spread to multiple organs, strongly suggests more studies are needed to understand and target these different pathways. Unfortunately, access to the primary driver of metastases, the metastatic cancer cell clusters (MCCCs), remains difficult and limited. These metastatic clusters have been shown to be 100-fold more tumorigenic than individual cancer cells. Capturing and characterizing MCCCs is a key limiting factor in efforts to help treat and ultimately prevent cancer metastasis. Elucidating differentially regulated biological pathways in MCCCs will help uncover new therapeutic drug targets to help combat cancer metastases. We demonstrate a novel, proof of principle technology, to capture MCCCs directly from patients’ whole blood. Our platform can be readily tuned for different solid tumor types by combining a biomimicry-based margination effect coupled with immunoaffinity to isolate MCCCs. Adopting a selective capture approach based on overexpressed CD44 in MCCCs provides a methodology that preferentially isolates them from whole blood. Furthermore, we demonstrate a high capture efficiency of more than 90% when spiking MCCC-like model cell clusters into whole blood. Characterization of the captured MCCCs from lung cancer patients by immunofluorescence staining and genomic analyses, suggests highly differential morphologies and genomic profiles., This study lays the foundation to identify potential drug targets thus unlocking a new area of anti-metastatic therapeutics."
1519,An AI-assisted Investigation of Tumor-Associated Macrophages and their Polarization in Colorectal Cancer,"Ekta Dadlani, Tirtharaj Dash, Debashis Sahoo",https://www.biorxiv.org/content/10.1101/2023.08.01.551559v2,"Tumor-associated Macrophages (or TAMs) are amongst the most common cells that play a significant role in the initiation and progression of colorectal cancer (CRC). Recently, Ghosh et al.1 proposed distinguishing signatures for identifying macrophage polarization states, namely, immuno-reactive and immuno-tolerant, using the concept of Boolean implications and Boolean networks. Their signature, called the Signature of Macrophage Reactivity and Tolerance (SMaRT), comprises of 338 human genes (equivalently, 298 mouse genes). However, SMaRT was constructed using datasets that were not specialized towards any particular disease. In this paper, (a) we perform a comprehensive analysis of the SMaRT signature on single-cell human and mouse colorectal cancer RNA-seq datasets; (b) we then adopt a technique akin to transfer learning to construct a “refined” SMaRT signature for investigating TAMs and their polarization in the CRC tumor microenvironment. Towards validation of our refined gene signature, we use (a) 5 pseudo-bulk RNA-seq datasets derived from single-cell human datasets; and (b) 5 large-cohort microarray datasets from humans. Furthermore, we investigate the translational potential of our refined gene signature in problems related to MSS/MSI (4 datasets) and CIMP+/CIMP-status (4 datasets). Overall, our refined gene signature and its extensive validation provide a path for its adoption in clinical practice in diagnosing colorectal cancer and associated attributes."
1520,MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis,"Juliana Cazarin, Rachel E. DeRollo, Siti Noor Ain Binti Ahmad Shahidan, Jamison B. Burchett, Daniel Mwangi, Saikumari Krishnaiah, Annie L. Hsieh, Zandra E. Walton, Rebekah Brooks, Stephano S. Mello, Aalim M. Weljie, Chi V. Dang, Brian J. Altman",https://www.biorxiv.org/content/10.1101/2023.01.03.522637v3,"The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites in healthy tissues, is disrupted across many human cancers. Deregulated expression of the MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC or its paralog N-MYC (collectively termed MYC herein) suppress oscillation of gene expression and metabolism to upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC were examined, using time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression pathways, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells."
1521,Overcome Prostate Cancer Resistance to Immune Checkpoint Therapy with Ketogenic Diet-Induced Epigenetic Reprogramming,"Sean Murphy, Sharif Rahmy, Dailin Gan, Yini Zhu, Maxim Manyak, Jun Li, Xuemin Lu, Xin Lu",https://www.biorxiv.org/content/10.1101/2023.08.07.552383v1,"Advanced prostate cancer (PCa) is overwhelmingly resistant to immune checkpoint blockade (ICB) therapy, representing a formidable clinical challenge. In this study, we developed a syngeneic murine PCa model with acquired ICB resistance. Using this model, synergistic efficacy was achieved by combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or supplementation of ketone body β-hydroxybutyrate (BHB, endogenous HDACi) via 1,3-butanediol-admixed food. CKD and BHB supplementation delayed PCa tumors as monotherapy, and both BHB and adaptive immunity are required for the anti-tumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that the HDACi and ketogenesis-enhanced ICB therapy involves cancer-cell-intrinsic (upregulated MHC class I molecules) and extrinsic mechanisms (CD8+ T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen presenting cells, and diminished neutrophils). Overall, these findings underscore the potential of using HDACi and optimized KD to enhance ICB therapy for PCa."
1523,A novel lncRNA PROCA11 regulates cell plasticity in response to androgen deprivation of prostate cancer cells,"Rocco Cipolla, Marc Gabriel, Giorgia Ianese Regin, Micaela Piemontese, Ugo Szachnowski, Virginie Firlej, Marina Pinskaya, Antonin Morillon",https://www.biorxiv.org/content/10.1101/2023.08.07.552355v1,"Long non-coding RNAs (lncRNAs) represent vast and yet poorly characterized family of genes that can fine tune cellular plasticity, thereby allowing the emergence of aggressive therapy-resistant and metastatic cancers. Androgen deprivation therapies (ADT) are commonly used to treat prostate cancer by inactivating the Androgen Receptor (AR). However, castration-resistant prostate cancer (CRPC) with neuroendocrine subtypes (NEPC) often emerge. In this study, we explore the role of lncRNAs in response to androgen deprivation. Using a dynamic prostate cancer cell system mimicking the CRPC and NEPC onset, we identified 15 novel lncRNAs, with PROCA11 standing out as a first-choice candidate, being also highly abundant in high-risk prostate cancer tumors. This majorly nuclear lncRNA is expressed at low levels in androgen-dependent conditions of growth and strongly activated upon hormone withdrawal, preceding neuroendocrine genes and persisting at high levels in neuroendocrine cells. Extensive computational analysis of clinical data and functional studies in cells revealed PROCA11 association with basal-to-luminal transformation of the transcriptomic landscape and activation of metabolic and signaling pathways reminiscent of neurogenesis and of maintenance of AR signaling. We propose that PROCA11 is involved in the intricate circuits regulating cellular plasticity enabling cell survival and proliferation and emergence of the NE phenotype in response to ADT."
1524,microRNA profile of endometrial cancer from Indian patients-Identification of potential biomarkers for prognosis,"Shraddha Hegde, Kalpesh Wagh, Apoorva Abikar, Sughosha Nambiar, Shriraksha Ananthamurthy, Navyashree Hosahalli Narayana, Pallavi Venkateshaiah Reddihalli, Savitha Chandraiah, Suma Mysore Narayana, Prathibha Ranganathan",https://www.biorxiv.org/content/10.1101/2023.08.07.552324v1,"Endometrial cancer is one of the major cancers in women throughout the world. If diagnosed early, these cancers are treatable and the prognosis is usually good. However, one major problem in treating endometrial cancer is accurate diagnosis and staging. Till date, the choice method for diagnosis and staging is histopathology. Although there are few molecular markers identified, they are not always sufficient in making accurate diagnosis and deciding on therapeutic strategy. As a result, very often patients are under treated or over treated. In this study, our group has profiled microRNAs (miRNA) from Indian patients using NGS-based approach. We have identified differentially expressed microRNAs in endometrial cancer. These microRNAs have also been compared to data from TCGA (The Cancer Genome Atlas), which represent other populations and also correlated to relevance in overall survival. Using in-silico approaches, mRNA targets of the miRNAs have been predicted. After comparing with TCGA, we have identified 16 miRNA-mRNA pairs which could be potential prognostic biomarkers for endometrial cancer. This is the first miRNA profiling report from Indian cohort and one of the very few studies which have identified potential biomarkers of prognosis in endometrial cancer."
1525,Mathematical Modeling of Field Cancerization through the Lens of Cancer Behavioral Ecology,"Anuraag Bukkuri, Frederick R. Adler",https://www.biorxiv.org/content/10.1101/2023.08.07.552382v1,"Field cancerization is a process in which a normal tissue is replaced with pre-cancerous but histologically normal tissue. This transformed field can give rise to malignancy and contribute to tumor relapse. In this paper, we create a mathematical model of field cancerization from the perspective of cancer behavioral ecology. In our model, field cancerization arises from a breakdown in signaling integrity and control, and investigate implications for acute wounding, chronic wounding, aging, and therapeutic interventions. We find that restoration of communication networks can lead to cancer regression in the context of acute injury. Conversely, long term loss of controls, such as through chronic wounding or aging, can promote oncogenesis."
1526,Targeting CD74-positive macrophages improves neoadjuvant therapy in cervical cancer as revealed by single-cell transcriptomics analysis,"Zixiang Wang, Bingyu Wang, Yuan Feng, Jinwen Ye, Zhonghao Mao, Teng Zhang, Meining Xu, Wenjing Zhang, Xinlin Jiao, Youzhong Zhang, Baoxia Cui",https://www.biorxiv.org/content/10.1101/2023.11.09.566505v1,"Uterine cervical cancer (UCC) has the second-highest mortality rate among malignant tumors of the female reproductive system. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic strategy for cervical cancer. However, the efficacy of PD-1 (programmed cell death protein 1) blockade combined with neoadjuvant chemotherapy (NACT) and the ensuing alterations within the tumor microenvironment need further investigation. We conducted single-cell RNA sequencing using 46,950 cells from nine sequential human cervical cancer tissues representing different stages of NACT and PD-1 blockade combination therapy. We delineated the trajectory of cervical epithelial cells and unveiled crucial factors involved in the combination therapy. Cell communication analysis revealed the inferred interaction strength decreased between T cell-cancer cells, while the communication between macrophage-cancer cells intensified after NACT therapy. We verified that macrophages are necessary for PD-1 blockade combination to exert antitumor effects in vitro. Detailed analysis unraveled the CD74-positive macrophages frequently interacted with the immunoreactive Epi 3 subgroup during neoadjuvant combination therapy. CD74 upregulation limited phagocytosis and stimulated M2 polarization. The CD74 blockade enhanced macrophage phagocytosis, resulting in decreased viability of cervical cancer cells in vitro and in vivo. This study unveils the dynamic microenvironment of UCC influenced by NACT and PD-1 blockade combination therapy, and targeting CD74 was a potential strategy to augment the therapy efficacy."
1527,The roles of RNA editing in cancer immunity through interacting with interferon,"Sijia Wu, Xinyu Qin, Zhennan Lu, Jianguo Wen, Mengyuan Yang, Pora Kim, Xiaobo Zhou, Liyu Huang",https://www.biorxiv.org/content/10.1101/2023.08.06.552142v1,"The interferon-activated tumor innate immunity can be primed by specific double-stranded RNA (dsRNA) sensors upon stimulation. A-to-I RNA editing in the dsRNA regions can have a potential function to regulate interferon-related cancer immunity. A systematical analysis of both the editing enzyme and specific enriched editing region in patients, tissues, and cell lines is performed to reveal the underlying mechanisms. We then validate the preferred editing of dsRNA regions, identify the hyper-editing in severe tumors, and discover the negative effect of editing on cancer immunity. Specifically, RNA editing acts as an inhibitor of PKR- and MDA5-related interferon pathways through the regulations of miRNAs and RNA-binding proteins and the deactivation of dsRNA sensors. With the alteration of interferons, subsequently, RNA editing represses the infiltration of CD8 and CD4 T cells and reduces the sensitivities of cancer drugs, such as cisplatin. These analyses on A-to-I RNA editing can improve the knowledge of tumorigenesis, immunology, and cancer-targeted immunotherapy."
1529,A genetic basis for cancer sex differences revealed in Xp11 translocation renal cell carcinoma,"Mingkee Achom, Ananthan Sadagopan, Chunyang Bao, Fiona McBride, Qingru Xu, Prathyusha Konda, Richard W. Tourdot, Jiao Li, Maria Nakhoul, Daniel S. Gallant, Usman Ali Ahmed, Jillian O’Toole, Dory Freeman, Gwo-Shu Mary Lee, Jonathan L. Hecht, Eric C. Kauffman, David J Einstein, Toni K. Choueiri, Cheng-Zhong Zhang, Srinivas R. Viswanathan",https://www.biorxiv.org/content/10.1101/2023.08.04.552029v1,"Xp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between the TFE3 gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlie TFE3 fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenic TFE3 fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show that TFE3 fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio in TFE3 fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences."
1531,Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts,"Zoi E. Sychev, Abderrahman Day, Hannah E. Bergom, Gabrianne Larson, Atef Ali, Megan Ludwig, Ella Boytim, Ilsa Coleman, Eva Corey, Stephen R. Plymate, Peter S. Nelson, Justin H. Hwang, Justin M. Drake",https://www.biorxiv.org/content/10.1101/2023.08.02.551697v1,"Resistance to androgen deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform to emergent aggressive variant prostate cancer (AVPC) which has neuroendocrine (NE)-like features. To this end, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflects and retains key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. When we compared 15 NE versus 33 AdCa PDX samples, we identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of protein and RNA concordance from these tumors revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa."
1532,DNA tetrahedron as a carrier of doxorubicin for metastatic breast cancer treatment,"Payal Vaswani, Naveena A Hema, Krupa Kansara, Landon Dahle, Ashutosh Kumar, Dhiraj Bhatia",https://www.biorxiv.org/content/10.1101/2023.08.02.551657v1,"Metastatic breast cancer is a significant clinical challenge calling for novel and efficient therapeutic approaches. DNA tetrahedron, a highly programmable nanocage, offers some promising attributes including biocompatibility, stability, and functionalization making it an attractive candidate for drug delivery. In this study, we have explored the potential of DNA tetrahedron as a carrier of doxorubicin, a DNA and RNA synthesis-inhibiting chemotherapy drug. We have encapsulated doxorubicin in DNA tetrahedron (TD: Dox) and subsequently focused on metastatic breast cancer cells for the effect of the same. We showed that TD: Dox has the potential to inhibit the migration of cancerous cells in the 2D model and inhibit the invasion of tumor cells in the 3D model as well. This system also can be uptaken in in vivo zebrafish model as well. Overall, this study promises the TD: Dox system as an ideal drug delivery model and a viable approach for metastatic breast cancer treatment."
1533,Functional synapses between small cell lung cancer and glutamatergic neurons,"Anna Schmitt, Vignesh Sakthivelu, Kristiano Ndoci, Gulzar A Wani, Marian Touet, Isabel Pintelon, Ilmars Kisis, Olta Ibruli, Julia Weber, Roman Maresch, Christina M Bebber, Jonas Goergens, Milica Jevtic, Franka Odenthal, Aleksandra Placzek, Alexandru A Hennrich, Karl-Klaus Conzelmann, Maike Boecker, Alena Heimsoeth, Gülce S Gülcüler, Ron D Jachimowicz, Julie George, Johannes Brägelmann, Silvia von Karstedt, Martin Peifer, Thorsten Persigehl, Holger Grüll, Martin L Sos, Jens Brüning, Guido Reifenberger, Matthias Fischer, Dirk Adriaensen, Reinhard Büttner, Inge Brouns, Roland Rad, Roman K Thomas, Matteo Bergami, Elisa Motori, Hans Christian Reinhardt, Filippo Beleggia",https://www.biorxiv.org/content/10.1101/2023.01.19.524045v1,"Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, clinical recurrence and high rate of mortality. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified a strong and consistent signal for neuronal, synaptic, and glutamatergic signaling gene sets in murine and human SCLC. We show that SCLC cells have the ability to develop intimate contacts with neuronal glutamatergic terminals in vitro, in autochthonous primary lung tumors and in brain-engrafted tumors. These contacts can develop into bona fide synapses, allowing SCLC cells to receive glutamatergic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we show that SCLC cells derive a robust proliferation advantage when co-cultured with neurons. Moreover, the repression of glutamate release and the stimulation of the inhibitory glutamate receptor GRM8 displayed therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells appear to hijack glutamatergic signaling to sustain tumor growth, thereby exposing a novel entry route for therapeutic intervention."
1536,Machine learning-based meta-analysis of colorectal cancer and inflammatory bowel disease,"Aria Sardari, Hamid Usefi",https://www.biorxiv.org/content/10.1101/2023.08.04.551970v1,"Colorectal cancer (CRC) is a major global health concern, resulting in numerous cancer-related deaths. CRC detection, treatment, and prevention can be improved by identifying genes and biomarkers. Despite extensive research, the underlying mechanisms of CRC remain elusive, and previously identified biomarkers have not yielded satisfactory insights. This shortfall may be attributed to the predominance of univariate analysis methods, which overlook potential combinations of variants and genes contributing to disease development. Here, we address this knowledge gap by presenting a novel multivariate machine-learning strategy to pinpoint genes associated with CRC. Additionally, we applied our analysis pipeline to Inflammatory Bowel Disease (IBD), as IBD patients face substantial CRC risk. The importance of the identified genes was substantiated by rigorous validation across numerous independent datasets. Several of the discovered genes have been previously linked to CRC, while others represent novel findings warranting further investigation."
1538,Deciphering the function of intrinsic and genomics-driven epigenetic heterogeneity in head and neck cancer progression with single-nucleus CUT&RUN,"Howard J. Womersley, Daniel Muliaditan, Ramanuj DasGupta, Lih Feng Cheow",https://www.biorxiv.org/content/10.1101/2024.02.14.580230v1,"Interrogating regulatory epigenetic alterations during tumor progression at the resolution of single cells has remained an understudied area of research. Here we developed a highly sensitive single-nucleus CUT&RUN (snCUT&RUN) assay to profile histone modifications in isogenic primary, metastatic, and cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) patient-derived tumor cell lines. We find that the epigenome can be involved in diverse modes to contribute towards HNSCC progression. First, we demonstrate that gene expression changes during HNSCC progression can be co-modulated by alterations in both copy number and chromatin activity, driving epigenetic rewiring of cell-states. Furthermore, intratumour epigenetic heterogeneity (ITeH) may predispose sub-clonal populations within the primary tumour to adapt to selective pressures and foster the acquisition of malignant characteristics. In conclusion, snCUT&RUN serves as a valuable addition to the existing toolkit of single-cell epigenomic assays and can be used to dissect the functionality of the epigenome during cancer progression."
1539,Pauperization of Emerin from nuclear envelope during chromatin bridge resolution drives prostate cancer cell migration and invasiveness,"Marta Popęda, Kamil Kowalski, Tomasz Wenta, Galina V. Beznoussenko, Michał Rychłowski, Alexander Mironov, Zeno Lavagnino, Sara Barozzi, Julia Richert, Rebecca Bertolio, Jolanta Szade, Kevin Miszewski, Marcin Matuszewski, Anna J. Żaczek, Luca Braga, Giannino Del Sal, Natalia Bednarz-Knoll, Paolo Maiuri, Paulina Nastały",https://www.biorxiv.org/content/10.1101/2023.11.06.565767v2,"Micronuclei (MN) can arise from many causes, including the breakage of aberrant cytokinetic chromatin bridge. The frequent observation of MN in tumors raises the specter that they might not merely be passive elements but could instead play active roles in tumor progression. Here, we test the hypothesis that the presence of micronuclei could induce specific phenotypic and functional changes to the cell and lead to increased cancer invasive potential. With a variety of imaging and molecular methods in vitro and in clinical samples from prostate cancer (PCa) patients, we show that chromosome bridge resolution can lead to EMD accumulation and formation of EMD-rich MN. Such structure is negative for Lamin A/C and positive for LBR and Sec6β. It can cause EMD pauperization from NE affecting migratory and invasive properties of a cell and can be translated to PCa patient’s poor prognosis."
1540,Combined kinome inhibition states are predictive of cancer cell line sensitivity to kinase inhibitor combination therapies,"Chinmaya U. Joisa, Kevin A. Chen, Samantha Beville, Timothy Stuhlmiller, Matthew E. Berginski, Denis Okumu, Brian T. Golitz, Gary L. Johnson, Shawn M. Gomez",https://www.biorxiv.org/content/10.1101/2023.08.01.551346v1,"Protein kinases are a primary focus in targeted therapy development for cancer, owing to their role as regulators in nearly all areas of cell life. Kinase inhibitors are one of the fastest growing drug classes in oncology, but resistance acquisition to kinase-targeting monotherapies is inevitable due to the dynamic and interconnected nature of the kinome in response to perturbation. Recent strategies targeting the kinome with combination therapies have shown promise, such as the approval of Trametinib and Dabrafenib in advanced melanoma, but similar empirical combination design for less characterized pathways remains a challenge. Computational combination screening is an attractive alternative, allowing in-silico screening prior to in-vitro or in-vivo testing of drastically fewer leads, increasing efficiency and effectiveness of drug development pipelines. In this work, we generate combined kinome inhibition states of 40,000 kinase inhibitor combinations from kinobeads-based kinome profiling across 64 doses. We then integrated these with baseline transcriptomics from CCLE to build robust machine learning models to predict cell line sensitivity from NCI-ALMANAC across nine cancer types, with model accuracy R2 ∼ 0.75-0.9 after feature selection using elastic-net regression. We further validated the model’s ability to extend to real-world examples by using the best-performing breast cancer model to generate predictions for kinase inhibitor combination sensitivity and synergy in a PDX-derived TNBC cell line and saw reasonable global accuracy in our experimental validation (R2 ∼ 0.7) as well as high accuracy in predicting synergy using four popular metrics (R2 ∼ 0.9). Additionally, the model was able to predict a highly synergistic combination of Trametinib (MEK inhibitor) and Omipalisib (PI3K inhibitor) for TNBC treatment, which incidentally was recently in phase I clinical trials for TNBC. Our choice of tree-based models over networks for greater interpretability also allowed us to further interrogate which specific kinases were highly predictive of cell sensitivity in each cancer type, and we saw confirmatory strong predictive power in the inhibition of MAPK, CDK, and STK kinases. Overall, these results suggest that kinome inhibition states of kinase inhibitor combinations are strongly predictive of cell line responses and have great potential for integration into computational drug screening pipelines. This approach may facilitate the identification of effective kinase inhibitor combinations and accelerate the development of novel cancer therapies, ultimately improving patient outcomes."
1541,Caution Regarding the Specificities of Pan-Cancer Microbial Structure,"Abraham Gihawi, Colin S. Cooper, Daniel S. Brewer",https://www.biorxiv.org/content/10.1101/2023.01.16.523562v1,"The results published in Poore and Kopylova et al. 2020[1] revealed the possibility of being able to almost perfectly differentiate between types of tumour based on their microbial composition using machine learning models. Whilst we believe that there is the potential for microbial composition to be used in this manner, we have concerns with the manuscript that make us question the certainty of the conclusions drawn. We believe there are issues in the areas of the contribution of contamination, handling of batch effects, false positive classifications and limitations in the machine learning approaches used. This makes it difficult to identify whether the authors have identified true biological signal and how robust these models would be in use as clinical biomarkers. We commend Poore and Kopylova et al. on their approach to open data and reproducibility that has enabled this analysis. We hope that this discourse assists the future development of machine learning models and hypothesis generation in microbiome research."
1542,RNA sequencing identifies lung cancer lineage and facilitates drug repositioning,"Longjin Zeng, Longyao Zhang, Lingchen Li, Xingyun Liao, Chenrui Yin, Lincheng Zhang, Xiewan Chen, Jianguo Sun",https://www.biorxiv.org/content/10.1101/2023.01.18.524544v1,"Breakthrough therapies recently improve survival in lung adenocarcinoma (LUAD), yet we still lack a paradigm to support prospective confirmation. To classify three clusters including bronchioid, neuroendocrine, and squamoid, the non-negative matrix factorization (NMF) algorithm was first performed at The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), Gene Expression Omnibus (GEO) and preclinical models. In terms of prognostic value, the squamoid cluster is of poor prognostic factor. The neuroendocrine cluster is characterized by STK11 mutations and 14q13.3 amplifications. From an immunological perspective, the bronchioid cluster is considered an immune activation because of the highest immune-related genetic perturbation. Further analysis is the estimation of the relative cell abundance of the tumor microenvironment (TME), specific cell types can be reflected among three clusters. Meanwhile, the higher portion of immune cell infiltration belonged to bronchioid and squamous, not neuroendocrine cluster. Taken together, the neuroendocrine cluster show resistance to PD-L1 blockade. While pemetrexed or platinum-based therapies are suitable for bronchioid and squamoid clusters, respectively. Our emphasis was on phenotype-based action to explore compounds. Large-scale drug sensitivity databases including ConnectivityMap (CMAP), Cancer Cell Line Encyclopedia (CCLE), and Genomics of Drug Sensitivity in Cancer (GDSC) were analyzed. MEK inhibitors exhibited resistance in the bronchioid, while sensitive to the squamous cluster. Dinaciclib and alvocidib showed similar activity and sensitivity in the neuroendocrine cluster. A lineage factor named KLF5 recognized by two networks could be suppressed by verteporfin. This work adds to the knowledge of the lung cancer lineage and facilitates drug repositioning."
1544,A whole-genome CRISPR screen identifies the spindle accessory checkpoint as a locus of nab-paclitaxel resistance in pancreatic cancer cells,"Priya Mondal, George Alyateem, Allison V. Mitchell, Michael M. Gottesman",https://www.biorxiv.org/content/10.1101/2024.02.15.580539v1,"Pancreatic adenocarcinoma is one of the most aggressive and lethal forms of cancer. Chemotherapy is the primary treatment for pancreatic cancer, but resistance to the drugs used remains a major challenge. A genome-wide CRISPR interference and knockout screen in the PANC-1 cell line with the drug nab-paclitaxel has identified a group of spindle assembly checkpoint (SAC) genes that enhance survival in nab-paclitaxel. Knockdown of these SAC genes (BUB1B, BUB3, and TTK) attenuates paclitaxel-induced cell death. Cells treated with the small molecule inhibitors BAY 1217389 or MPI 0479605, targeting the threonine tyrosine kinase (TTK), also enhance survival in paclitaxel. Overexpression of these SAC genes does not affect sensitivity to paclitaxel. These discoveries have helped to elucidate the mechanisms behind paclitaxel cytotoxicity. The outcomes of this investigation may pave the way for a deeper comprehension of the diverse responses of pancreatic cancer to therapies including paclitaxel. Additionally, they could facilitate the formulation of novel treatment approaches for pancreatic cancer."
1545,"The relationship between diet, plasma glucose, and cancer prevalence across vertebrates","Stefania E. Kapsetaki, Anthony J. Basile, Zachary T. Compton, Shawn M. Rupp, Elizabeth G. Duke, Amy M. Boddy, Tara M. Harrison, Karen L. Sweazea, Carlo C. Maley",https://www.biorxiv.org/content/10.1101/2023.07.31.551378v1,"Could diet and mean plasma glucose concentration (MPGluC) explain the variation in cancer prevalence across species? We collected diet, MPGluC, and neoplasia data for 160 vertebrate species from existing databases. We found that MPGluC negatively correlates with cancer and neoplasia prevalence, mostly of gastrointestinal organs. Trophic level positively correlates with cancer and neoplasia prevalence even after controlling for species MPGluC. Most species with high MPGluC (50/78 species = 64.1%) were birds. Most species in high trophic levels (42/53 species = 79.2%) were reptiles and mammals. Our results may be explained by the evolution of insulin resistance in birds which selected for loss or downregulation of genes related to insulin-mediated glucose import in cells. This led to higher MPGluC, intracellular caloric restriction, production of fewer reactive oxygen species and inflammatory cytokines, and longer telomeres contributing to longer longevity and lower neoplasia prevalence in extant birds relative to other vertebrates."
1546,Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer,"Henning Tim Langer, Shakti Ramsamooj, Ezequiel Dantas, Anirudh Murthy, Mujmmail Ahmed, Seo-Kyoung Hwang, Rahul Grover, Rita Pozovskiy, Roger J. Liang, Andre Lima Queiroz, Justin C Brown, Eileen P. White, Tobias Janowitz, Marcus D. Goncalves",https://www.biorxiv.org/content/10.1101/2023.07.31.551241v1,"The cancer associated cachexia syndrome (CACS) is a systemic metabolic disorder resulting in loss of body weight due to skeletal muscle and adipose tissues atrophy. CACS is particularly prominent in lung cancer patients, where it contributes to poor quality of life and excess mortality. Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone. Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer."
1547,Combinatorial CRISPR screen reveals FYN and KDM4 as targets for synergistic drug combination for treating triple negative breast cancer,"Tackhoon Kim, Byung-Sun Park, Soobeen Heo, Heeju Jeon, Jaeyeal Kim, Donghwa Kim, Sang Kook Lee, So-Youn Jung, Sun-Young Kong, Timothy K. Lu",https://www.biorxiv.org/content/10.1101/2023.11.08.566220v1,"Tyrosine kinases play a crucial role in cell proliferation and survival and are extensively investigated as targets for cancer treatment. However, the efficacy of most tyrosine kinase inhibitors (TKIs) in cancer therapy is limited due to resistance. In this study, we identify a synergistic combination therapy involving TKIs for the treatment of triple negative breast cancer. By employing massively parallel combinatorial CRISPR screens, we identify FYN and KDM4 as critical targets whose inhibition enhances the effectiveness of TKIs, such as NVP-ADW742 (IGF-1R inhibitor), gefitinib (EGFR inhibitor), and Imatinib (ABL inhibitor) both in vitro and in vivo. Mechanistically, treatment with TKIs upregulates the transcription of KDM4, which in turn demethylates H3K9me3 at FYN enhancer for FYN transcription. This compensatory activation of FYN and KDM4 contributes to the resistance against TKIs. We highlight FYN as a broadly applicable mediator of therapy resistance and persistence by demonstrating its upregulation in various experimental models of drug-tolerant persisters and residual disease following targeted therapy, chemotherapy, and radiotherapy. Collectively, our study provides novel targets and mechanistic insights that can guide the development of effective combinatorial targeted therapies, thus maximizing the therapeutic benefits of TKIs."
1549,DNA repair and anti-cancer mechanisms in the longest-living mammal: the bowhead whale,"Denis Firsanov, Max Zacher, Xiao Tian, Yang Zhao, John C. George, Todd L. Sformo, Greg Tombline, Seyed Ali Biashad, Abbey Gilman, Nicholas Hamilton, Avnee Patel, Maggie Straight, Minseon Lee, J. Yuyang Lu, Ena Haseljic, Alyssa Williams, Nalani Miller, Vadim N. Gladyshev, Zhengdong Zhang, Jan Vijg, Andrei Seluanov, Vera Gorbunova",https://www.biorxiv.org/content/10.1101/2023.05.07.539748v2,"At over 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg1. In spite of its very large number of cells, the bowhead is not highly cancer-prone, an incongruity termed Peto’s Paradox2. This has been explained by the evolution of additional tumor suppressor genes in larger animals, which is supported by research on elephants demonstrating expansion of the p53 gene3–5. However, we show here that bowhead whale fibroblasts undergo oncogenic transformation after disruption of fewer tumor suppressors than required for human fibroblasts. Instead, analysis of DNA repair revealed that bowhead cells repair double-strand breaks with uniquely high efficiency and accuracy compared to other mammals. Further, we identified two proteins, CIRBP and RPA2, that are present at high levels in bowhead fibroblasts and increase the efficiency and fidelity of DNA repair in human cells. These results suggest that rather than possessing additional tumor suppressor genes as barriers to oncogenesis, the bowhead whale relies on more accurate and efficient DNA repair to preserve genome integrity. This strategy that does not eliminate cells but repairs them may be critical for the long and cancer-free lifespan of the bowhead whale. Our work demonstrates the value of studying long-lived organisms in identifying novel longevity mechanisms and their potential for translation to humans."
1550,Spatial Omics Driven Crossmodal Pretraining Applied to Graph-based Deep Learning for Cancer Pathology Analysis,"Zarif Azher, Michael Fatemi, Yunrui Lu, Gokul Srinivasan, Alos Diallo, Brock Christensen, Lucas Salas, Fred Kolling IV, Laurent Perreard, Scott Palisoul, Louis Vaickus, Joshua Levy",https://www.biorxiv.org/content/10.1101/2023.07.30.551187v1,"Graph-based deep learning has shown great promise in cancer histopathology image analysis by contextualizing complex morphology and structure across whole slide images to make high quality downstream outcome predictions (ex: prognostication). These methods rely on informative representations (i.e., embeddings) of image patches comprising larger slides, which are used as node attributes in slide graphs. Spatial omics data, including spatial transcriptomics, is a novel paradigm offering a wealth of detailed information. Pairing this data with corresponding histological imaging localized at 50-micron resolution, may facilitate the development of algorithms which better appreciate the morphological and molecular underpinnings of carcinogenesis. Here, we explore the utility of leveraging spatial transcriptomics data with a contrastive crossmodal pretraining mechanism to generate deep learning models that can extract molecular and histological information for graph-based learning tasks. Performance on cancer staging, lymph node metastasis prediction, survival prediction, and tissue clustering analyses indicate that the proposed methods bring improvement to graph based deep learning models for histopathological slides compared to leveraging histological information from existing schemes, demonstrating the promise of mining spatial omics data to enhance deep learning for pathology workflows."
1551,Racial Disparities in the Genetic Landscape of Acute Myeloid Leukaemia from The Cancer Genome Atlas: Insights from a Bioinformatics Analysis,"Panji Nkhoma, Kevin Dzobo, Doris Kafita, Geoffrey Kwenda, Sody Munsaka, Sinkala Musalula",https://www.biorxiv.org/content/10.1101/2023.11.06.565754v1,"Acute myeloid leukaemia (AML) is a heterogeneous disease with complex pathogenesis that affects hematopoietic stem cells. Ethnic and racial disparities have been reported to affect treatment and survival outcomes in AML patients. Here, we analysed clinical and transcriptomic data from The Cancer Genome Atlas (TCGA) to investigate potential differences in the genetic landscape of AML between African and European individuals. We found several differentially expressed mRNA transcripts between the AML of Africans and Europeans. Notably, AML in African patients exhibited enrichment for several pathways, including signalling by G-protein-coupled receptors, oncostatin M, and codeine and morphine metabolism. In contrast, AML in European patients showed enrichment for pathways related to the glial cell-line derived neurotrophic factor/rearranged during transfection signalling axis, gamma-aminobutyric acid receptor activation, and ligand-gated ion transport channels. Additionally, kinase enrichment analysis identified shared and distinct kinases in AML among Africans and Europeans: Africans showed an enrichment of cyclin-dependent kinases, while Europeans exhibited an enrichment of ULK2, CSNK2B, and CAMK1. Our study highlights the potential importance of considering race when evaluating the genetic landscape of AML, which may improve treatment strategies for this disease."
1552,Malignant tumors engender and employ cancer-specific organelles for self-protection and metastasis,"Tingfang Yi, Gerhard Wagner",https://www.biorxiv.org/content/10.1101/2023.07.15.549159v2,"Cancer is a leading source of human lethality but current therapies have had limited efficacy in many cancers, which highlights an unmet need to assess the underlying mechanisms that govern cancer progression in vivo. Here we show that, upon malignant transformation, aggressive oncocells generate extracellular membranous compartments, cytocapsulas or cytocapsular tubes (CCTs), to enclose oncocells and engender cytocapsular oncocells in vivo. Cytocapsular oncocells are universally present in solid cancers and appear in hematologic cancers in the immune organs. Networks of cytocapsular tubes provide membrane-enclosed freeways for protected cancer metastasis. CCT networks interconnect cytocapsular tumors creating cytocapsular tumor network systems. Our findings suggest that cytocapsular oncocells drive membrane-encompassed cancer progression. Thus, interconnected cytocapsular oncocells, CCT networks and cytocapsular tumor network systems coordinate cancer progression in the integrated cytocapsular membrane systems."
1553,Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer,"Michael A. Carpenter, Nuri A. Temiz, Mahmoud A. Ibrahim, Matthew C. Jarvis, Margaret R. Brown, Prokopios P. Argyris, William L. Brown, Douglas Yee, Reuben S. Harris",https://www.biorxiv.org/content/10.1101/2022.04.26.489523v3,"A prominent source of mutation in cancer is single-stranded DNA cytosine deamination by cellular APOBEC3 enzymes, which results in signature C-to-T and C-to-G mutations in TCA and TCT motifs. Although multiple enzymes have been implicated, reports conflict and it is unclear which protein(s) are responsible. Here we report the development of a selectable system to quantify genome mutation and demonstrate its utility by comparing the mutagenic activities of three leading candidates - APOBEC3A, APOBEC3B, and APOBEC3H. The human cell line, HAP1, is engineered to express the thymidine kinase (TK) gene of HSV-1, which confers sensitivity to ganciclovir. Expression of APOBEC3A and APOBEC3B, but not catalytic mutant controls or APOBEC3H, triggers increased frequencies of TK mutation and nearly indistinguishable TC-biased cytosine mutation profiles in the selectable TK reporter gene. Whole genome sequences from TK mutant clones enabled an analysis of thousands of single base substitution mutations and extraction of local sequence preferences with APOBEC3A preferring YTCW motifs over 70% of the time and APOBEC3B just under 50% of the time (Y=C/T; W=A/T). Signature comparisons with breast tumor whole genome sequences indicate that most malignancies manifest intermediate percentages of APOBEC3 signature mutations in YTCW motifs, mostly between 50 and 70%, suggesting that both enzymes are contributing in a combinatorial manner to the overall mutation landscape. Although the vast majority of APOBEC3A- and APOBEC3B-induced single base substitution mutations occur outside of predicted chromosomal DNA hairpin structures, whole genome sequence analyses and supporting biochemical studies also indicate that both enzymes are capable of deaminating the single-stranded loop regions of DNA hairpins at elevated rates relative to control conditions. These studies combine to help resolve a long-standing etiologic debate on the source of APOBEC3 signature mutations in cancer and indicate that future diagnostic and therapeutic efforts should focus on both APOBEC3A and APOBEC3B."
1554,The cytidine deaminase APOBEC3G drives cancer mutagenesis and clonal evolution in bladder cancer,"Weisi Liu, Kevin P. Newhall, Francesca Khani, LaMont Barlow, Duy Nguyen, Lilly Gu, Ken Eng, Bhavneet Bhinder, Manik Uppal, Charlotte Récapet, Andrea Sboner, Susan R. Ross, Olivier Elemento, Linda Chelico, Bishoy M. Faltas",https://www.biorxiv.org/content/10.1101/2022.09.05.503899v1,"Mutagenic processes leave distinct signatures in cancer genomes. The mutational signatures attributed to APOBEC3 cytidine deaminases are pervasive in human cancers. However, data linking individual APOBEC3 proteins to cancer mutagenesis in vivo are limited. Here, we show that transgenic expression of human APOBEC3G promotes mutagenesis, genomic instability, and kataegis, leading to shorter survival in a murine bladder cancer model. Acting as mutagenic fuel, APOBEC3G increases the clonal diversity of bladder cancers, driving divergent cancer evolution. We characterize the single base substitution signature induced by APOBEC3G in vivo, showing the induction of a mutational signature different from that caused by APOBEC3A and APOBEC3B. Analysis of thousands of human cancers reveals the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Our findings define the role of APOBEC3G in cancer mutagenesis and clonal heterogeneity. These results potentially inform future therapeutic efforts that restrict tumor evolution."
1555,Fine tuning of CpG spatial distribution with DNA origami for improved therapeutic cancer vaccination,"Yang C. Zeng, Olivia J. Young, Christopher M. Wintersinger, Frances M. Anastassacos, James I. MacDonald, Giorgia Isinelli, Maxence O. Dellacherie, Miguel Sobral, Haiqing Bai, Amanda R. Graveline, Andyna Vernet, Melinda Sanchez, Kathleen Mulligan, Youngjin Choi, Thomas C. Ferrante, Derin B. Keskin, Geoffrey G. Fell, Donna Neuberg, Catherine J. Wu, David J. Mooney, Ick Chan Kwon, Ju Hee Ryu, William M. Shih",https://www.biorxiv.org/content/10.1101/2022.06.08.495340v3,"Multivalent presentation of ligands often enhances receptor activation and downstream signaling. DNA origami offers precise nanoscale spacing of ligands, a potentially useful feature for therapeutic nanoparticles. Here we introduce a “square block” DNA origami platform to explore the importance of spacing of CpG oligonucleotides, which engage Toll-like receptors and thereby act as danger signals for dendritic cells. Through in vitro cell-culture studies and in vivo tumor-treatment models, we demonstrate that square blocks induce Th1 immune polarization when CpG is spaced at 3.5 nm. We observe that this DNA origami vaccine enhances DC activation, antigen cross-presentation, CD8 T cell activation, Th1-polarized CD4 activation and NK cell activation. The vaccine also synergizes effectively with anti-PD-L1 for improved cancer immunotherapy in melanoma and lymphoma models and induces long-term T cell memory. Our results suggest that DNA origami may serve as an advanced vaccine platform for controlling adjuvant spacing and co-delivering antigens."
1556,"Pathways in the brain, heart and lung influenced by SARS-CoV-2 NSP6 and SARS-CoV-2 regulated miRNAs: an in silico study hinting cancer incidence","Shrabonti Chatterjee, Joydeep Mahata, Suneel Kateriya, Gireesh Anirudhan",https://www.biorxiv.org/content/10.1101/2024.02.11.578752v1,"The influence of SARS-CoV-2 non-structural protein in the host’s tissue-specific complexities remains a mystery and needs more in-depth attention because of COVID-19 recurrence and long COVID. Here we investigated the influence of SARS-CoV-2 transmembrane protein NSP6 (Non-structural protein 6) in three major organs - the brain, heart, and lung in silico. To elucidate the interplay between NSP6 and host proteins, we analyzed the protein-protein interaction network of proteins interacting with NSP6 interacting proteins. Reported host interacting partners of NSP6 were ATP5MG, ATP6AP1, ATP13A3, and SIGMAR1. Pathway enrichment analyses provided global insights into biological pathways governed by differentially regulated genes in the three tissues after COVID-19 infection. Hub genes of tissue-specific protein interactome were analysed for drug targets and many were found. miRNA-gene network for the tissue-specific regulated proteins was sought. Comparing this list with the gene list targetted by SARS-CoV-2 regulated miRNAs, we found three and two common genes in the brain and lung respectively. Among the five common proteins revealed as potential therapeutic targets across the three tissues, four non-approved drugs and one approved drug could target Galectin 3 (LGALS3) and AIFM1 respectively. Increased expression of LGALS3 (that was upregulated in the heart after COVID-19 infection) is observed in multiple cancers and acts as a modulator for tumor progression. COVID-19 infection also causes myocardial inflammation and heart failure (HF). HF is observed to be increasing cancer incidence. The present scenario of long COVID-19 and recurrent COVID-19 infections warrants in-depth studies to probe the effect of COVID-19 infection on increased cancer incidence."
1557,Novel CAF-identifiers via transcriptomic analysis in oral cancer patients,"Nehanjali Dwivedi, Nidhi Shukla, Manjula Das, Sujan K Dhar",https://www.biorxiv.org/content/10.1101/2023.01.10.523511v1,"Background Cancer-associated fibroblasts (CAFs), a prominent component of the tumor microenvironment, plays an important role in tumor development, invasion, and drug resistance. The expression of distinct “CAF markers,” which separates CAFs from normal fibroblasts and epithelial cells, have traditionally been used to identify them. These commonly used CAF markers have been reported to differ greatly across microenvironmental subpopulations even within a cancer site."
1558,"Mutation of NOTCH1 is selected within normal esophageal tissues, yet leads to selective epistasis suppressive of further evolution into cancer","Kira A. Glasmacher, Vincent L. Cannataro, Jeffrey D. Mandell, Mia Jackson, J. Nic Fisk, Jeffrey P. Townsend",https://www.biorxiv.org/content/10.1101/2023.11.03.565535v1,"Sequencing of tissues from histologically normal esophagus, among other organs, has revealed that normal tissues harbor somatic variants that are also found in cancers arising from the same tissue types. Our understanding of how somatic mutations commonly found in normal tissue can contribute to tumorigenesis is limited: common somatic mutations may or may not confer phenotypes compatible with oncogenesis. However, the strength of selection for somatic variants that appear in both normal and cancer tissues can be quantified in each context using evolutionary modeling approaches. We studied the evolutionary trajectory from normal esophageal tissue to esophageal squamous-cell carcinoma (ESCC) by analysis of 2171 sequenced samples from previous studies on normal esophageal epithelium and ESCC to reveal the stepwise contributions of somatic mutations to increased cellular division and survival. We also analyzed pairwise selective epistasis between somatically mutated genes that may lead to stepwise substitution patterns. We found that NOTCH1 substitutions are highly selected along the trajectory from embryogenesis to adult normal esophageal tissue, explaining their high prevalence in the tissue. In contrast, there is little to no positive selection for NOTCH1 mutations along the trajectory from adult normal tissue to ESCC, suggesting that NOTCH1 substitutions do not drive tumorigenesis. Furthermore, mutations in NOTCH1 exhibit antagonistic epistasis with well-known cancer drivers including TP53, reducing selection for progressive mutations in tumorigenesis. This antagonistic epistasis likely corresponds with a low likelihood of tumor progression in the presence of NOTCH1 mutations in the esophagus."
1559,Cell-autonomous GP130 activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment,"Christina Sternberg, Tanja Limberger, Martin Raigel, Karolína Trachtová, Michaela Schlederer, Desiree Lindner, Petra Kodajova, Jiaye Yang, Roman Ziegler, Heidi A. Neubauer, Saptaswa Dey, Torben Redmer, Stefan Stoiber, Václav Hejret, Boris Tichy, Martina Tomberger, Nora S. Harbusch, Simone Tangermann, Monika Oberhuber, Vojtech Bystry, Jenny L. Persson, Sarka Pospisilova, Peter Wolf, Felix Sternberg, Sandra Högler, Sabine Lagger, Stefan Rose-John, Lukas Kenner",https://www.biorxiv.org/content/10.1101/2024.02.11.579838v1,"Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles GP130-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. Here, we find that genetic cell-autonomous activation of the GP130 receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of GP130 signaling mediates senescence via the STAT3/ARF/p53 axis and anti-tumor immunity via recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high GP130 mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. Our findings reveal a context-dependent role of GP130/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development. We challenge the prevailing concept of blocking GP130/STAT3 signaling as functional prostate cancer treatment and instead propose cell-autonomous GP130 activation as a novel therapeutic strategy."
1561,"The relationships between genetic ancestry, somatic mutation frequency, and histologic subtypes in high-grade endometrial cancer","Ryan Bremseth-Vining, Victor Borda, Douglas Craig, Julie J. Ruterbusch, Julie Boerner, Juliana Fucinari, Rouba Ali-Fehmi, Mohamed Elshaikh, Hassan Abdallah, G. Larry Maxwell, Kathleen M. Darcy, Gregory Dyson, Thomas Conrads, Nicholas W. Bateman, Michele L. Cote, Timothy D. O’Connor",https://www.biorxiv.org/content/10.1101/2023.07.26.550722v1,"High-grade endometrial cancer, like numerous other cancer types, exhibits clear racial disparities in the United States for both the incidence and outcomes of the disease. While institutional factors are likely the primary contributor to these disparities, other underlying causes cannot be ignored (i.e., molecular, genetic, and histopathologic factors). This study seeks to interrogate the role that germline genetic influences, specifically genetic ancestry, may play in contributing to characteristics of high-grade endometrial cancer. This is mainly accomplished by examining the relationship between local ancestry inferences and somatic mutation frequency as well as histologic subtypes. An association between clinical characteristics and patient survival was also interrogated, and while global ancestry was seen to have no significant effect, tumor mutation burden (TMB) did impact patient survival. Here, we identify associations between local ancestry segments on chromosomes 1 and 14 and an increased TMB in self-described (SD) Black patients. We also highlight a complex relationship between heterozygous ancestry combinations within genomic regions (i.e., [European/African] vs. [African/African]) and an increase in local somatic mutation frequency."
1562,VLIB: Unveiling insights through Visual and Linguistic Integration of Biorxiv data relevant to cancer via Multimodal Large Language Model,"Vignesh Prabhakar, Kai Liu",https://www.biorxiv.org/content/10.1101/2023.10.31.565037v1,"The field of cancer research has greatly benefited from the wealth of new knowledge provided by research articles and preprints on platforms like Biorxiv. This study investigates the role of scientific figures and their accompanying captions in enhancing our comprehension of cancer. Leveraging the capabilities of Multimodal Large Language Models (MLLMs), we conduct a comprehensive analysis of both visual and linguistic data in biomedical literature. Our work introduces VLIB, a substantial scientific figure-caption dataset generated from cancer biology papers on Biorxiv. After thorough preprocessing, which includes figure-caption pair extraction, sub-figure identification, and text normalization, VLIB comprises over 500,000 figures from more than 70,000 papers, each accompanied by relevant captions. We fine-tune baseline MLLMs using our VLIB dataset for downstream vision-language tasks, such as image captioning and visual question answering (VQA), to assess their performance. Our experimental results underscore the vital role played by scientific figures, including molecular structures, histological images, and data visualizations, in conjunction with their captions, in facilitating knowledge translation through MLLMs. Specifically, we achieved a ROUGE score of 0.66 for VQA and 0.68 for image captioning, as well as a BLEU score of 0.72 for VQA and 0.70 for image captioning. Furthermore, our investigation highlights the potential of MLLMs to bridge the gap between artificial intelligence and domain experts in the field of cancer biology."
1563,Validation of polymorphic Gompertzian model of cancer through in vitro and in vivo data,"Arina Soboleva, Artem Kaznatcheev, Rachel Cavill, Katharina Schneider, Kateřina Staňková",https://www.biorxiv.org/content/10.1101/2023.04.19.537467v2,"Mathematical modeling plays an important role in our understanding and targeting therapy resistance mechanisms in cancer. The polymorphic Gompertzian model, analyzed theoretically by Viossat and Noble, describes a heterogeneous cancer population consisting of therapy sensitive and resistant cells. This theoretically promising model has not previously been validated with real-world data. In this study, we provide this validation. We demonstrate that the polymorphic Gompertzian model successfully captures trends in both in vitro and in vivo data on non-small cell lung cancer (NSCLC) dynamics under treatment. Additionally, for the in vivo data of tumor dynamics in patients undergoing treatment, we compare the polymorphic Gompertzian model to the classical oncologic models, which were previously identified as the models that fit this data best. We show that the polymorphic Gompertzian model can successfully capture the U-shape trend in tumor size during cancer relapse, which can not be fitted with the classical oncologic models. In general, the polymorphic Gompertzian model corresponds well to both in vitro and in vivo real-world data, suggesting it as a candidate for improving the efficacy of cancer therapy, for example through evolutionary/adaptive therapies."
1564,Filament formation drives catalysis by glutaminase enzymes important in cancer progression,"Shi Feng, Cody Aplin, Thuy-Tien T. Nguyen, Shawn K. Milano, Richard A. Cerione",https://www.biorxiv.org/content/10.1101/2023.02.16.528860v3,"The glutaminase enzymes GAC and GLS2 catalyze the hydrolysis of glutamine to glutamate, satisfying the ‘glutamine addiction’ of cancer cells. They are the targets of anti-cancer drugs; however, their mechanisms of activation and catalytic activity have been unclear. Here we demonstrate that the ability of GAC and GLS2 to form filaments is directly coupled to their catalytic activity and present their cryo-EM structures which provide an unprecedented view of the conformational states essential for catalysis. Filament formation guides an ‘activation loop’ to assume a specific conformation that works together with a ‘lid’ to close over the active site and position glutamine for nucleophilic attack by an essential serine. Our findings highlight how ankyrin repeats on GLS2 regulate enzymatic activity, while allosteric activators stabilize, and clinically relevant inhibitors block, filament formation that enables glutaminases to catalyze glutaminolysis and support cancer progression."
1565,γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids,"Junxue Dong, David Holthaus, Christian Peters, Stefanie Koster, Marzieh Ehsani, Alvaro Quevedo-Olmos, Hilmar Berger, Michal Zarobkiewicz, Mandy Mangler, Rajendra Kumar Gurumurthy, Nina Hedemann, Cindrilla Chumduri, Dieter Kabelitz, Thomas F. Meyer",https://www.biorxiv.org/content/10.1101/2023.07.25.550464v1,"Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies."
1567,Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer,"Lukas Klein, Mengyu Tu, Niklas Krebs, Laura Urbach, Daniela Grimm, Muhammad Umair Latif, Frederike Penz, Nathan Chan, Kazeera Aliar, Foram Vyas, Uday Kishore, Elisabeth Hessmann, Andreas Trumpp, Elisa Espinet, Argyris Papantonis, Rama Khokha, Volker Ellenrieder, Barbara T. Grünwald, Shiv K. Singh",https://www.biorxiv.org/content/10.1101/2023.10.30.563552v1,"Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence of classical and basal-like programs is evident in multi-scale transcriptomic and spatial analyses of resected, advanced-stage and chemotherapy-treated specimens and reciprocally linked to a diverse stromal immune microenvironment as well as worse clinical outcome. However, the underlying mechanisms of intratumoral subtype heterogeneity remain largely unclear. Here, by combining preclinical models, multi-center clinical, bulk and compartment-specific transcriptomic, proteomic, and bioimaging data from human specimens, we identified an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic CD68+ macrophages as a driver of intratumoral subtype co-existence along with an immunosuppressive tumor microenvironment with T cell exclusion. Our ATAC-, ChIP-, and RNA-seq analyses revealed that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory immune signatures in tumor cells, antagonizing cJUN/AP1 signaling to favor a therapy-responsive classical neoplastic identity. Through the tumor microenvironment, this dichotomous regulation was further amplified via regional macrophage populations. Moreover, CD68+/TNF-α+ cells associated with a reactive phenotype and reduced CD8+ T cell infiltration in human PDAC tumors. Consequently, combined anti-TNF-α immunotherapy and chemotherapy resulted in reduced macrophage counts and promoted CD3+/CD8+ T cell infiltration in basal-like PDAC, leading to improved survival in preclinical murine models. We conclude that tumor cell intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression."
1568,Anti-CD47 immunotherapy as a therapeutic strategy for the treatment of breast cancer brain metastasis,"Jessica D. Mackert, Elizabeth R. Stirling, Adam S. Wilson, Brian Westwood, Dawen Zhao, Hui-Wen Lo, Linda Metheny-Barlow, Katherine L. Cook, Glenn J. Lesser, David R. Soto-Pantoja",https://www.biorxiv.org/content/10.1101/2023.07.25.550566v1,"The presence of cell surface protein CD47 allows cancer cells to evade innate and adaptive immune surveillance resulting in metastatic spread. CD47 binds to and activates SIRPα on the surface of myeloid cells, inhibiting their phagocytic activity. On the other hand, CD47 binds the matricellular protein Thrombospondin-1, limiting T-cell activation. Thus, blocking CD47 is a potential therapeutic strategy for preventing brain metastasis. To test this hypothesis, breast cancer patient biopsies were stained with antibodies against CD47 to determine differences in protein expression. An anti-CD47 antibody was used in a syngeneic orthotopic triple-negative breast cancer model, and CD47 null mice were used in a breast cancer brain metastasis model by intracardiac injection of the E0771-Br-Luc cell line. Immunohistochemical staining of patient biopsies revealed an 89% increase in CD47 expression in metastatic brain tumors compared to normal adjacent tissue (p ≤ 0.05). Anti-CD47 treatment in mice bearing brain metastatic 4T1br3 orthotopic tumors reduced tumor volume and tumor weight by over 50% compared to control mice (p ≤ 0.05) and increased IBA1 macrophage/microglia marker 5-fold in tumors compared to control (p ≤ 0.05). Additionally, CD47 blockade increased the M1/M2 macrophage ratio in tumors 2.5-fold (p ≤ 0.05). CD47 null mice had an 89% decrease in metastatic brain burden (p ≤ 0.05) compared to control mice in a brain metastasis model. Additionally, RNA sequencing revealed several uniquely expressed genes and significantly enriched genes related to tissue development, cell death, and cell migration tumors treated with anti-CD47 antibodies. Thus, demonstrating that CD47 blockade affects cancer cell and tumor microenvironment signaling to limit metastatic spread and may be an effective therapeutic for triple-negative breast cancer brain metastasis."
1570,Adaptive therapy achieves long-term control of chemotherapy resistance in high grade ovarian cancer,"Helen Hockings, Eszter Lakatos, Weini Huang, Maximilian Mossner, Mohammed Ateeb Khan, Stephen Metcalf, Francesco Nicolini, Kane Smith, Ann-Marie Baker, Trevor A. Graham, Michelle Lockley",https://www.biorxiv.org/content/10.1101/2023.07.21.549688v1,"Drug resistance results in poor outcomes for most patients with metastatic cancer. Adaptive Therapy (AT) proposes to address this by exploiting presumed fitness costs incurred by drug-resistant cells when drug is absent, and prescribing dose reductions to allow fitter, sensitive cells to re-grow and re- sensitise the tumour. However, empirical evidence for treatment-induced fitness change is lacking. We show that fitness costs in chemotherapy-resistant ovarian cancer cause selective decline and apoptosis of resistant populations in low-resource conditions. Moreover, carboplatin AT caused fluctuations in sensitive/resistant tumour population size in vitro and significantly extended survival of tumour-bearing mice. In sequential blood-derived cell-free DNA and tumour samples obtained longitudinally from ovarian cancer patients during treatment, we inferred resistant cancer cell population size through therapy and observed it correlated strongly with disease burden. These data have enabled us to launch a multicentre, phase 2 randomised controlled trial (ACTOv) to evaluate AT in ovarian cancer."
1571,Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma,"Christel FA Ramirez, Daniel Taranto, Masami Ando-Kuri, Marnix HP de Groot, Efi Tsouri, Zhijie Huang, Daniel de Groot, Roelof JC Kluin, Daan J Kloosterman, Joanne Verheij, Jing Xu, Serena Vegna, Leila Akkari",https://www.biorxiv.org/content/10.1101/2023.10.29.564350v1,"Myeloid cells are abundant and plastic immune cell subsets in the liver, to which pro-tumorigenic, inflammatory and immunosuppressive roles have been assigned in the course of tumorigenesis. Yet several aspects underlying their dynamic alterations in hepatocellular carcinoma (HCC) progression remain elusive, including the impact of distinct genetic mutations in shaping a cancer-permissive tumor microenvironment (TME). Here, we generated somatic HCC mouse models bearing clinically-relevant oncogenic driver combinations and subsequent pathway activation that faithfully recapitulated different human HCC subclasses. We identified cancer genetics’ specific and stage-dependent alterations of the liver TME associated with distinct histopathological and malignant HCC features. These models ranged from T cell-rich, more indolent HCC to aggressive tumors exhibiting heightened myeloid cell infiltration. Interestingly, MAPK-activated, NrasG12D-driven tumors presented a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME, contrasting with NrasG12V HCC, enriched in adaptive immune cells. Mechanistically, we identified a NrasG12D cancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6Clow cells. GM-CSF blockade curbed the accumulation of this myeloid cell subset, reduced inflammation, induced cancer cell death and prolonged animal survival. Furthermore, the anti-tumor effect of GM-CSF neutralization synergized with the clinically-approved inhibition of the vascular endothelial growth factor (VEGF) to inhibit HCC outgrowth. These findings underscore the striking alterations of the myeloid TME consequential to MAPK pathway activation intensity and the potential of GM-CSF inhibition as a myeloid-centric therapy tailored to subsets of HCC patients."
1572,Inferring therapeutic vulnerability within tumors through integration of pan-cancer cell line and single-cell transcriptomic profiles,"Weijie Zhang, Danielle Maeser, Adam Lee, Yingbo Huang, Robert F. Gruener, Israa G. Abdelbar, Sampreeti Jena, Anand G. Patel, R. Stephanie Huang",https://www.biorxiv.org/content/10.1101/2023.10.29.564598v1,"Single-cell RNA sequencing greatly advanced our understanding of intratumoral heterogeneity through identifying tumor subpopulations with distinct biologies. However, translating biological differences into treatment strategies is challenging, as we still lack tools to facilitate efficient drug discovery that tackles heterogeneous tumors. One key component of such approaches tackles accurate prediction of drug response at the single-cell level to offer therapeutic options to specific cell subpopulations. Here, we present a transparent computational framework (nicknamed scIDUC) to predict therapeutic efficacies on an individual-cell basis by integrating single-cell transcriptomic profiles with large, data-rich pan-cancer cell line screening datasets. Our method achieves high accuracy, with predicted sensitivities easily able to separate cells into their true cellular drug resistance status as measured by effect size (Cohen’s d > 1.0). More importantly, we examine our method’s utility with three distinct prospective tests covering different diseases (rhabdomyosarcoma, pancreatic ductal adenocarcinoma, and castration-resistant prostate cancer), and in each our predicted results are accurate and mirrored biological expectations. In the first two, we identified drugs for cell subpopulations that are resistant to standard-of-care (SOC) therapies due to intrinsic resistance or effects of tumor microenvironments. Our results showed high consistency with experimental findings from the original studies. In the third test, we generated SOC therapy resistant cell lines, used scIDUC to identify efficacious drugs for the resistant line, and validated the predictions with in-vitro experiments. Together, scIDUC quickly translates scRNA-seq data into drug response for individual cells, displaying the potential as a first-line tool for nuanced and heterogeneity-aware drug discovery."
1576,The balance between shear flow and extracellular matrix in ovarian cancer-on-chip,"Changchong Chen, Alphonse Boché, Elliot Lopez, Juan Peng, Franck Carreiras, Marie-Claire Schanne-Klein, Yong Chen, Ambroise Lambert, Carole Aimé",https://www.biorxiv.org/content/10.1101/2023.07.20.549914v1,"Ovarian cancer is the most lethal gynecologic cancer in developed countries. Silent onset of the metastatic activity of ovarian tumor cells is factor for poor outcomes. In the tumor microenvironment, the extracellular matrix (ECM) and flow shear stress are known to play key roles in directing cell invasion. Hence, acute and tunable tools are critical to mimic scaffold and fluid for building clinically relevant in vitro models. We have built an ovarian tumor-on-chip where tunable ECM models are easily seeded with tumor spheroids and integrated within a microfluidic chip. This allows the investigation of the crosstalk between the characteristics of the ECM models and shear stress on the migratory behavior and cellular heterogeneity of ovarian tumor cells. We vary the composition of the ECM playing with type I and IV collagens and laminin, and control the shear stress in the chip. This work shows that in the shear stress regime of the peritoneal cavity, the ECM plays a major role in driving individual or collective modes of migration. In the presence of basement membrane proteins, migration is more collective that on type I collagen regardless of shear stress level. In addition, with increasing shear stress, individual cell migration was enhanced, while no significant impact on collective migration could be measured. This highlights our ability to discriminate relevant parameters for onset and shifts of cell behavior using our in vitro models. Furthermore, we described the ability to shift cells from an epithelial phenotype to a more mesenchymal phenotype, which could allow us to describe the role of these parameters during epithelial-to-mesenchymal (EMT) transition as a continuous process. Finally, we conclude that the ECM should hold a central position in in vitro cancer models, to understand cell response and develop platforms for therapeutic development."
1578,Decoding spatial organization maps and context-specific landscapes of breast cancer and its microenvironment via high-resolution spatial transcriptomic analysis,"Eun Seop Seo, Boram Lee, Inwoo Hwang, Ji-Yeon Kim, Kyeongmee Park, Woong-Yang Park",https://www.biorxiv.org/content/10.1101/2023.10.25.563904v2,"Single-cell RNA transcriptomics has revealed the intricate heterogeneity of both tumors and their microenvironment. However, a notable limitation is its inability to retain spatial context, a crucial aspect of understanding cell identity and function. In this study, we employed imaging-based single-cell spatial transcriptomics to elucidate the tumor and immunological landscapes of two breast cancer samples. By resolving over 400 000 cells per slide, we demonstrated that transcriptional differences lead to structural disparities within and between tumors. Additionally, we observed that the composition of the tumor microenvironment varies depending on its spatial location. Notably, we detected immune cell gradients transitioning from the tumor periphery to its core regions and from tertiary lymphoid structure to immune inflamed regions, in alignment with the specific function of each cell type. This finding facilitated a more precise classification of the tumor immune microenvironment. This study provides a comprehensive dataset for breast cancer researchers and underscores the significance of spatial context in understanding the multifaceted heterogeneity of cancer and its environment."
1579,Nuclear fascin regulates cancer cell survival,"Campbell D. Lawson, Samantha Peel, Asier Jayo, Adam Corrigan, Preeti Iyer, Mabel Baxter Dalrymple, Richard J. Marsh, Susan Cox, Isabel Van Audenhove, Jan Gettemans, Maddy Parsons",https://www.biorxiv.org/content/10.1101/2022.06.17.496538v1,"Fascin is an important regulator of F-actin bundling leading to enhanced filopodia assembly. Fascin is also overexpressed in most solid tumours where it supports invasion through control of F-actin structures at the periphery and nuclear envelope. Recently fascin has been identified in the nucleus of a broad range of cell types but the contributions of nuclear fascin to cancer cell behaviour remain unknown. Here we demonstrate that fascin bundles F-actin within the nucleus to support chromatin organisation and efficient DNA damage response. Fascin associates directly with phosphorylated Histone H3 leading to regulated levels of nuclear fascin to support these phenotypes. Forcing nuclear fascin accumulation through the expression of nuclear-targeted fascin-specific nanobodies or inhibition of Histone H3 kinases results in enhanced and sustained nuclear F-actin bundling leading to reduced invasion, viability and nuclear fascin-specific/driven apoptosis. These findings represent an additional important route through which fascin can support tumorigenesis and provide insight into potential pathways for targeted fascin-dependent cancer cell killing."
1580,Comparative Genomics Exploration of Shared lncRNA-coding genes in Human and All Annotated Plant Genomes: Potential Implications for Cancer Research,Ligia Mateiu,https://www.biorxiv.org/content/10.1101/2023.10.25.563922v1,"Since their discovery in 1990, lncRNAs have been heavily investigated. It is already known that the genomes of plants and animals express large numbers of lncRNAs. In humans, many lncRNA are considered essential players in cancer biology, mainly acting as gene expression regulators in processes like cell proliferation, apoptosis, migration, invasion and stemness. In plants, lncRNAs are involved in vegetative growths, reproduction and stress responses. Yet, in the entirety of the animal and plant kingdoms, the functions and mechanisms of action for the majority of lncRNAs remain largely undiscovered, as do their orthology relationships. The poor conservation of the DNA sequences encoding for these transcripts is hindering the identification of lncRNAs orthologs especially among very distant evolutionary species. In this short study, using an uncomplicated, but creative bioinformatic approach, I searched for sequence homologies between human DNA and 175 annotated plant genomes from NCBI. Using stringent filtering, I found 20 human lncRNA-encoding genes overlapping plant genomic features, including lncRNAs. Evenmore, 3 of these human lncRNA-encoding genes with a potential plant ortholog are reported in multiple databases for lncRNA involved in cancers. This study opens the road for investigating the tumorigenesis in a deep homology context of lncRNAs."
1581,Dearth of smoking-induced mutations in NSRO-driven non-small-cell lung cancer despite smoking exposure,"Chen-Yang Huang, Nanhai Jiang, Meixin Shen, Gillianne Lai, Aaron C. Tan, Amit Jain, Stephanie P. Saw, Mei-Kim Ang, Quan Sing Ng, Darren Wan-Teck Lim, Ravindran Kanesvaran, Eng-Huat Tan, Wan Ling Tan, Boon-Hean Ong, Kevin L. Chua, Devanand Anantham, Angela Takano, Tony K.H. Lim, Wai Leong Tam, Ngak Leng Sim, Anders J. Skanderup, Daniel S.W. Tan, Steven G. Rozen",https://www.biorxiv.org/content/10.1101/2023.07.04.547310v2,"Non-small cell lung cancers (NSCLCs) in non-smokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET, and fusions involving ALK and RET. We term these “non-smoking-related oncogenes” (NSROs). In addition to occurring in non-smokers, NSRO-driven tumors also occur in smokers, and the clonal architecture and genomic landscape of these tumors remain unknown. We investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 patients with NSRO-driven or typical-smoking NSCLCs. NSRO-driven NSCLCs in smokers and non-smokers have similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to regulation of the cell cycle, suggesting that smoking still affects tumor phenotype independently of genomic alterations."
1583,Post-translational regulation of the Numb/Notch pathway in neurogenesis and cancer by Dlk2,"Stephanie.B Telerman, Russell.S Hamilton, Ben Shaw, Jordan.D Dimitrov, Ben Steventon, Anne.C Ferguson-Smith",https://www.biorxiv.org/content/10.1101/2023.07.20.549453v1,"Perturbations in fundamental developmental pathways have a profound influence on tumorigenesis. Numb plays a pivotal role in vertebrate development, including neurogenesis and is a key negative regulator of Notch signaling1, 2. Perturbation of Numb expression affects brain morphology and cell fate3. While extensive research has been conducted on canonical Notch ligands, regulation by vertebrate-specific non-canonical ligands is not understood. Here we identify Delta like non-canonical Notch ligand 2/EGFL9 (Dlk2) as a regulator of zebrafish neurogenesis with mutants exhibiting early increase and subsequent depletion of neural stem cells, decreased radial glial cells density, impaired neuronal cell distribution, and hypersensitivity to stimuli mimicking the embryonic murine Numb/Numblike null phenotype3. Numb function is inactivated by aberrant phosphorylation4, and we show that Dlk2 protein exhibits a high affinity direct interaction with Numb, with loss of Dlk2 in zebrafish telencephalon increasing Numb Ser276 phosphorylation with a concomitant increase in Notch signaling. Patients with tumors exhibiting reduced levels of Dlk2 have a poorer prognosis, while overexpression of Dlk2 in human cancer cell lines reduces cell proliferation. Our findings identify Dlk2 as a key partner of Numb, a gatekeeper of its activity, and an important player in a network of protein interactions regulating both neurogenesis and cancer with potential therapeutic implications."
1585,A Conservative Approach for Describing Cancer Progression,"Nicolò Rossi, Nicola Gigante, Nicola Vitacolonna, Carla Piazza",https://www.biorxiv.org/content/10.1101/2022.06.11.495730v1,"The field of tumor phylogenetics focuses on studying the differences within cancer cell populations and many efforts are done within the scientific community to build cancer progression models trying to understand the heterogeneity of such diseases. These models are highly dependent on the kind of data used for their construction and, as the experimental technologies evolve, it is of major importance to exploit their peculiarities. In this work we describe a cancer progression model based on Single Cell DNA Sequencing data. When constructing the model, we focus on tailoring the formalism on the specificity of the data, by defining a minimal set of assumptions to reconstruct a flexible DAG structured model, capable of identifying progression beyond the limitation of the infinite site assumption. We provide simulations and analytical results to show the features of our model, test it on real data, show how it can be integrated with other approaches to cope with input noise. Moreover, our framework can be exploited to produce simulated data that follows our theoretical assumptions. Finally, we provide an open source R implementation of our approach that is publicly available on BioConductor."
1587,Transcriptional regulation of Dyskerin via canonical WNT signaling modulates sphingolipid biosynthesis and drives colorectal cancer,"Shivansh Nigam, Umar K. Khan, Ayush Praveen, Akshay Shendre, Shannon Carskadon, Abhimanyu Kapoor, Anjali Tiwari, Abhijit Chandra, Nallasivam Palanisamy, Bushra Ateeq",https://www.biorxiv.org/content/10.1101/2023.07.18.549480v1,"Targeting EGFR has been effective in RAS/RAF wild-type colorectal cancer (CRC) patients. However, residual tumor relapses, necessitating the importance of biomarker-guided novel therapeutics. We show elevated DKC1 in ∼88% of CRC patients with poor recurrence-free survival. Clinically, DKC1-positive patients exhibit similarity with CMS2 class, the canonical subtype with active WNT signaling. We show functional significance of DKC1 in cell proliferation, stemness, DNA repair, and survival. Further, mice bearing DKC1 knockdown xenografts show ∼81% reduction in tumor burden. Mechanistically, WNT/β-catenin signaling orchestrates DKC1 expression, then, DKC1/SOX2 complex regulates SGPP2, modulating sphingolipids metabolism. Downregulation of DKC1 in CRC lead to reduced SGPP2 levels leading to dysregulation of sphingolipid biosynthesis. Of note, DKC1-high CRC patients show accumulation of ceramides, namely C23 and C24, signifying their utility in diagnosis. Collectively, we delineate the mechanistic circuitry involved in DKC1-mediated CRC progression, propose ceramides as biomarker, and underscore WNT-based therapeutics for DKC1-positive patients."
1588,Profiling the Expression of Transportome Genes in cancer: A systematic approach,"Luca Visentin, Giorgia Scarpellino, Luca Munaron, Federico Alessandro Ruffinatti",https://www.biorxiv.org/content/10.1101/2023.07.18.549498v1,"The transportome, the -omic layer encompassing all Ion Channels and Transporters (ICTs), is crucial for cell physiology. It is therefore reasonable to hypothesize a role of the transportome in disease, and in particular in cancer. Here, we present the Membrane Transport Protein DataBase (MTP-DB), a database collecting information on ICTs, and a pipeline that takes expression data and the MTP-DB as input to produce a broad overview of transportome dysregulation in cancer. The MTP-DB may prove useful for the study of the transportome in general, and the pipeline may be used to study the transportome in other diseases. Both tools are open source and can be found on GitHub at TCP-Lab/mtp-db and TCP-Lab/transportome_profiler, under permissive licenses. We detect that the transportome is dysregulated in cancer, and that dysregulation patterns are shared among different cancer types. It is still unclear how these patterns are linked to cancer patho-physiology."
1589,Single-cell long-read targeted sequencing reveals transcriptional variation in ovarian cancer,"Ashley Byrne, Daniel Le, Kostianna Sereti, Hari Menon, Neha Patel, Jessica Lund, Ana Xavier-Magalhaes, Minyi Shi, Timothy Sterne-Weiler, Zora Modrusan, William Stephenson",https://www.biorxiv.org/content/10.1101/2023.07.17.549422v1,"Single-cell RNA sequencing predominantly employs short-read sequencing to characterize cell types, states and dynamics; however, it is inadequate for comprehensive characterization of RNA isoforms. Long-read sequencing technologies enable single-cell RNA isoform detection but are hampered by lower throughput and unintended sequencing of artifacts. Here we developed Single-cell Targeted Isoform Long-Read Sequencing (scTaILoR-seq), a hybridization capture method which targets over a thousand genes of interest, improving the median number of unique transcripts per cell by 29-fold. We used scTaILoR-seq to identify and quantify RNA isoforms from ovarian cancer cell lines and primary tumors, yielding 10,796 single-cell transcriptomes. Using long-read variant calling we revealed associations of expressed single nucleotide variants (SNVs) with alternative transcript structures. In addition, phasing of SNVs across transcripts facilitated measurement of allelic imbalance within distinct cell populations. Overall, scTaILoR-seq is a long-read targeted RNA sequencing method and analytical framework for exploring transcriptional variation at single-cell resolution."
1590,AATF-mediated Liver Damage and Inflammation to Cancer: Therapeutic Intervention by Curcumin in Experimental MASH-HCC,"Akshatha N. Srinivas, Diwakar Suresh, Saravana Babu Chidambaram, Prasanna K. Santhekadur, Divya P. Kumar",https://www.biorxiv.org/content/10.1101/2023.05.26.542402v2,"In tandem with the expanding obesity pandemic, the prevalence of metabolic dysfunction associated steatohepatitis (MASH, formerly known as NASH)-driven hepatocellular carcinoma (HCC) is predicted to rise globally, creating a significant need for therapeutic interventions. We previously identified the upregulation of apoptosis antagonizing transcription factor (AATF), which is implicated in facilitating the progression from MASH to HCC. The objective of this study was to examine whether the intervention of curcumin could alleviate AATF-mediated MASH, inhibit tumor growth, and elucidate the underlying mechanism. A preclinical murine model mimicking human MASH-HCC was employed, subjecting mice to either a chow diet normal water (CDNW) or western diet sugar water (WDSW) along with very low dose of carbon tetrachloride (CCl4-0.2 μl/g, weekly). Mice receiving curcumin (CUR) alongside WDSW/CCl4 exhibited significant improvements, including reduced liver enzymes, dyslipidemia, steatosis, inflammation, and hepatocellular ballooning. Curcumin treatment also suppressed hepatic expression of inflammatory, fibrogenic, and oncogenic markers. Of note, there was a significant reduction in the expression of AATF upon curcumin treatment in WDSW/CCl4 mice and human HCC cells. In contrast, curcumin upregulated Kruppel-like factor 4 (KLF4) in MASH liver and HCC cells, which is known to downregulate sp1 (specificity protein-1) expression. Thus, curcumin treatment effectively inhibited the progression of MASH to HCC by downregulating the expression of AATF via the KLF4-Sp1 signaling pathway. These preclinical findings establish a novel molecular connection between curcumin and AATF in reducing hepatocarcinogenesis, and provide a strong rationale for the development of curcumin as a viable treatment for MASH-HCC in humans."
1591,A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer,"Jia-Hao Zheng, Yu-Heng Zhu, Jian Yang, Pei-Xuan Ji, Rui-Kang Zhao, Zong-Hao Duan, Hong-Fei Yao, Qin-Yuan Jia, Yi-Fan Yin, Li-Peng Hu, Qing Li, Shu-Heng Jiang, Yan-Miao Huo, Wei Liu, Yong-Wei Sun, De-Jun Liu",https://www.biorxiv.org/content/10.1101/2023.10.27.564288v1,"BACKGROUND & AIMS PDAC is characterized by significant matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, it is not clear the connection between matrix stiffness and the Warburg effect and the mechanisms of action in tumor progression."
1593,Evolutionary unpredictability in cancer model system,"Subhayan Chattopadhyay, Jenny Karlsson, Adriana Mañas, Ryu Kanzaki, Elina Fredlund, Andrew J. Murphy, Christopher L. Morton, Natalie Andersson, Mary A. Woolard, Karin Hansson, Katarzyna Radke, Andrew M. Davidhoff, Sofie Mohlin, Kristian Pietras, Daniel Bexell, David Gisselsson",https://www.biorxiv.org/content/10.1101/2022.06.01.494285v3,"Despite the advent of personalized medicine, it is still difficult to predict how a cancer develops over time at the level of the individual patient or even in cancer model systems which begs the question whether certain aspects of cancer can ever be predicted or if there is an inherent unpredictability in cancer, similar to other complex biological systems, We demonstrate by a combination of agent-based mathematical modelling and analysis of data from patient-derived xenograft systems from multiple cancer types that certain conditions may invoke chaotic fluctuations in the clonal landscape of cancer cells. Our findings indicate that under those conditions, the cancer genome behaves as a complex dynamic system, making its long-term evolution inherently unpredictable."
1594,PanCanSurvPlot: A Large-scale Pan-cancer Survival Analysis Web Application,"Anqi Lin, Hong Yang, Ying Shi, Quan Cheng, Zaoqu Liu, Jian Zhang, Peng Luo",https://www.biorxiv.org/content/10.1101/2022.12.25.521884v1,"The identification of reliable tumor prognostic markers can help clinicians and researchers predict tumor development and patient survival outcomes more accurately, which plays a vital role in clinical diagnosis, treatment effectiveness assessment, and prognostic evaluation. Existing web tools supporting online survival analysis are gradually failing to meet the increasing demands of researchers in terms of the dataset size, richness of survival analysis methods, and diversity of customization features. Therefore, there is an urgent need for a large-scale, one-stop pan-cancer survival analysis web server. We developed PanCanSurvPlot (https://smuonco.shinyapps.io/PanCanSurvPlot/), a Shiny web tool that has incorporated a total of 215 cancer-related datasets from the GEO and TCGA databases, covering nearly 100,000 genes (mRNAs, miRNAs, and lncRNAs), approximately 45,000 samples, 51 different cancer types, and 13 different survival outcomes. The website also provides two cutoff methods based on median and optimal cutpoints. All survival analysis results from the log-rank test and univariate Cox regression are presented in a clear and straightforward summary table. Finally, users can customize color schemes and cutpoint levels to quickly obtain high-quality Kaplan-Meier survival plots that meet publication requirements."
1595,A 3D microtumour system that faithfully represents ovarian cancer minimal residual disease,"Xingyun Yang, Mara Artibani, Yongcheng Jin, Aneesh Aggarwal, Yujia Zhang, Sandra Muñoz-Galvan, Ellina Mikhailova, Lena Rai, Nobina Mukherjee, Ravinash Krishna Kumar, Ashwag Albukhari, Linna Zhou, Ahmed Ashour Ahmed, Hagan Bayley",https://www.biorxiv.org/content/10.1101/2023.07.15.549155v1,"Background Bulk cancer and minimal residual disease (MRD) are characterised by different molecular drivers and therefore necessitate different therapeutic strategies. However, there are currently no 3D models that can faithfully recapitulate MRD ex vivo for therapy development."
1596,Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer,"Brittany L. Angarola, Siddhartha Sharma, Neerja Katiyar, Hyeon Gu Kang, Djamel Nehar-Belaid, SungHee Park, Rachel Gott, Giray N. Eryilmaz, Mark A. LaBarge, Karolina Palucka, Jeffrey H. Chuang, Ron Korstanje, Duygu Ucar, Olga Anczukow",https://www.biorxiv.org/content/10.1101/2023.10.20.563147v1,"Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. We investigate how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory, or cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveal co-localization of aged immune and epithelial cells in situ. Lastly, transcriptional signatures of aging mammary cells are found in human breast tumors, suggesting mechanistic links between aging and cancer. Together, these data uncover that epithelial, immune, and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment, and neoplasia risk."
1598,Cooperativity of c-MYC with Krüppel-Like Factor 6 Splice Variant 1 induces phenotypic plasticity and promotes prostate cancer progression and metastasis,"Sudeh Izadmehr, Heriberto Fernandez-Hernandez, Danica Wiredja, Alexander Kirschenbaum, Christine Lee-Poturalski, Peyman Tavassoli, Shen Yao, Daniela Schlatzer, Divya Hoon, Analisa Difeo, Alice C. Levine, Juan-Miguel Mosquera, Matthew D. Galsky, Carlos Cordon-Cardo, Goutham Narla",https://www.biorxiv.org/content/10.1101/2024.01.30.577982v1,"Metastasis remains a major cause of morbidity and mortality in men with prostate cancer, and the functional impact of the genetic alterations, alone or in combination, driving metastatic disease remains incompletely understood. The proto-oncogene c-MYC, commonly deregulated in prostate cancer. Transgenic expression of c-MYC is sufficient to drive the progression to prostatic intraepithelial neoplasia and ultimately to moderately differentiated localized primary tumors, however, c-MYC-driven tumors are unable to progress through the metastatic cascade, suggesting that a “second-hit” is necessary in the milieu of aberrant c-MYC-driven signaling. Here, we identified cooperativity between c-MYC and KLF6-SV1, an oncogenic splice variant of the KLF6 gene. Transgenic mice that co-expressed KLF6-SV1 and c-MYC developed progressive and metastatic prostate cancer with a histological and molecular phenotype like human prostate cancer. Silencing c-MYC expression significantly reduced tumor burden in these mice supporting the necessity for c-MYC in tumor maintenance. Unbiased global proteomic analysis of tumors from these mice revealed significantly enriched vimentin, a dedifferentiation and pro-metastatic marker, induced by KLF6-SV1. c-MYC-positive tumors were also significantly enriched for KLF6-SV1 in human prostate cancer specimens. Our findings provide evidence that KLF6-SV1 is an enhancer of c-MYC-driven prostate cancer progression and metastasis, and a correlated genetic event in human prostate cancer with potential translational significance."
1600,Engineering cGAS-agonistic oligonucleotides as therapeutics and vaccine adjuvants for cancer immunotherapy,"Shurong Zhou, Ting Su, Furong Cheng, Janet Cole, Xiang Liu, Bei Zhang, Shaheer Alam, Jinze Liu, Guizhi Zhu",https://www.biorxiv.org/content/10.1101/2023.07.13.548237v1,"Current cancer immunotherapy (e.g., immune checkpoint blockade (ICB)) has only benefited a small subset of patients. Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation holds the potential to improve cancer immunotherapy by eliciting type-I interferon (IFN-I) responses in cancer cells and myeloid cells. Yet, current approaches to this end, mostly by targeting STING, have marginal clinical therapeutic efficacy. Here, we report a cGAS-specific agonistic oligonucleotide, Svg3, as a novel approach to cGAS-STING activation for versatile cancer immunotherapy. Featured with a hairpin structure with consecutive guanosines flanking the stem, Svg3 binds to cGAS and enhances cGAS-Svg3 phase separation to form liquid-like droplets. This results in cGAS activation by Svg3 for robust and dose-dependent IFN-I responses, which outperforms several state-of-the-art STING agonists in murine and human immune cells, and human tumor tissues. Nanocarriers efficiently delivers Svg3 to tissues, cells, and cytosol where cGAS is located. Svg3 reduces tumor immunosuppression and potentiates ICB therapeutic efficacy of multiple syngeneic tumors, in wildtype but neither cGas-/- nor goldenticket Sting-/- mice. Further, as an immunostimulant adjuvant, Svg3 enhances the immunogenicity of peptide antigens to elicit potent T cell responses for robust ICB combination immunotherapy of tumors. Overall, cGAS-agonistic Svg3 is promising for versatile cancer combination immunotherapy."
1602,Lipid remodeling by hypoxia aggravates migratory potential in pancreatic cancer while maintaining membrane homeostasis,"Prema Kumari Agarwala, Shuai Nie, Gavin E. Reid, Shobhna Kapoor",https://www.biorxiv.org/content/10.1101/2022.12.08.519694v3,"Membranes are crucial cell components underlying optimal cellular functioning under diverse conditions including cancer. The membrane physiology requires acute maintenance of biophysical properties and a regulation of cellular lipidome. Homeostatic adaptation of membranes to temperature, pressure and anti-cancer drugs is a well-recognized. However, how the same is regulated under the influence of oxygen deprivation in pancreatic cancers-highly hypoxic cancer- is not known. Here, we report robust lipidomic remodelling in response to HIF-1α induction in pancreatic cancer cells and significant accumulation of lipid droplets. The lipidome rewiring span changes across various lipid classes, levels of unsaturation and acyl chain lengths. Interestingly, despite extensive lipidome alteration, cellular membrane homeostatic response ensures no major modulation of membrane biophysical properties underlying enhanced migratory potential. The correlation of lipidome changes, with pathway analysis and proteomics provide the basis for mutually exclusive regulation of lipidome and membrane properties. These findings help to understand the hypoxic regulation of pancreatic membrane homeostasis."
1603,Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells,"Kosuke Yamaguchi, Xiaoying Chen, Brianna Rodgers, Fumihito Miura, Pavel Bashtrykov, Laure Ferry, Olivier Kirsh, Marthe Laisné, Frédéric Bonhomme, Catalina Salinas-Luypaert, Andrea Scelfo, Enes Ugur, Paola B. Arimondo, Heinrich Leonhardt, Masato T. Kanemaki, Daniele Fachinetti, Albert Jeltsch, Takashi Ito, Pierre-Antoine Defossez",https://www.biorxiv.org/content/10.1101/2023.07.11.548318v1,"DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease."
1604,Metastatic prognostic ability of lung cancer stromal cells from a single-cell RNA-seq perspective,"Hyunjin Moon, Jonghwan Kim, Hajin Jeon, Jin Ok Yang",https://www.biorxiv.org/content/10.1101/2023.07.10.548323v1,"Single-cell RNA sequencing (scRNA-seq) has been widely studied and analyzed to understand cancer heterogeneity. Metastasis and invasion through communication with immune cells have been widely studied; stromal cells are known to change during cancer progression and cause metastasis, but little is known about their inherent metastasis prognostic abilities. This study investigated the abilities of stromal cells by analyzing the scRNA-seq data of adjacent, tumor, and metastasized tissues, biopsied from 15 patients. We considered fibroblast and smooth muscle cells as cell subtypes of stromal cells. We detected decorin (DCN) and insulin-like growth factor-binding protein 7 (IGFBP7) as sub-cell type markers conserved in tumor and metastasis. We found an organic relationship that affects metastasis by assessing the interaction between the expression and related pathways among the assigned stromal cell subtypes. In addition to the interactions of sub-cell-types within stromal cells, we also studied communication between stromal cells and the five assigned lung cancer cell types, and observed its relation with migration and metastasis; the role of DCN as a mediating factor was also studied. Results of our study indicated that DCN and IGFBP7 are factors that can be monitored in the follow-up of prognostic metastasis factors in patients with lung cancer. Therefore, DCN and IGFBP7, which are the assigned sub-cell types marker in lung cancer stromal cells, can be used as potential biomarkers for follow-up in lung cancer metastasis. Our study assigned stromal cell subtypes of lung cancer and detected markers that can be used as monitoring factors during metastasis of lung cancer. This suggests that DCN and IGFBP7 are potential biomarkers to evaluate metastatic ability and follow-up as metastatic prognostic factors in lung cancer patients."
1605,Failed reprogramming of transformed cells due to induction of apoptosis and senescence impairs tumor progression in lung cancer,"Pablo Pedrosa, Zhenguang Zhang, David Macias, Jianfeng Ge, Mary Denholm, Anna Dyas, Victor Nuñez-Quintela, Valentin Estevez-Souto, Patricia Lado-Fernandez, Patricia Gonzalez, Maria Gomez, Jose Ezequiel Martin, Sabela Da Silva-Alvarez, Manuel Collado, Daniel Muñoz-Espín",https://www.biorxiv.org/content/10.1101/2023.10.19.563086v1,"Cell reprogramming to pluripotency applied to the study of cancer has identified transformation and pluripotency as two independent and incompatible cell fates. A detailed knowledge of the relationship between transformation and reprogramming could lead to the identification of new vulnerabilities and therapeutic targets in cancer. Here, we explore this interplay and find that OSKM expression limits tumor cell growth by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that OSKM expression impairs tumor growth and reduces tumor burden."
1607,MethNet: a robust approach to identify regulatory hubs and their distal targets in cancer,"Theodore Sakellaropoulos, Catherine Do, Guimei Jiang, Giulia Cova, Peter Meyn, Dacia Dimartino, Sitharam Ramaswami, Adriana Heguy, Aristotelis Tsirigos, Jane A Skok",https://www.biorxiv.org/content/10.1101/2023.07.07.548142v1,"Aberrations in the capacity of DNA/chromatin modifiers and transcription factors to bind non-coding regions can lead to changes in gene regulation and impact disease phenotypes. However, identifying distal regulatory elements and connecting them with their target genes remains challenging. Here, we present MethNet, a pipeline that integrates large-scale DNA methylation and gene expression data across multiple cancers, to uncover novel cis regulatory elements (CREs) in a 1Mb region around every promoter in the genome. MethNet identifies clusters of highly ranked CREs, referred to as ‘hubs’, which contribute to the regulation of multiple genes and significantly affect patient survival. Promoter-capture Hi-C confirmed that highly ranked associations involve physical interactions between CREs and their gene targets, and CRISPRi based scRNA Perturb-seq validated the functional impact of CREs. Thus, MethNet-identified CREs represent a valuable resource for unraveling complex mechanisms underlying gene expression, and for prioritizing the verification of predicted non-coding disease hotspots."
1608,"Computational discovery of co-expressed antigens as dual targeting candidates for cancer therapy through bulk, single-cell, and spatial transcriptomics","Evgenii Chekalin, Shreya Paithankar, Rama Shankar, Jing Xing, Wenfeng Xu, Bin Chen",https://www.biorxiv.org/content/10.1101/2023.10.17.562711v1,"Motivation Bispecific antibodies (bsAbs) that bind to two distinct surface antigens on cancer cells are emerging as an appealing therapeutic strategy in cancer immunotherapy. However, considering the vast number of surface proteins, experimental identification of potential antigen pairs that are selectively expressed in cancer cells and not in normal cells is both costly and time-consuming. Recent studies have utilized large bulk RNA-seq databases to propose bispecific targets for various cancers. But, co-expressed pairs derived from bulk RNA-seq do not necessarily indicate true co-expression of both markers in the same cell. Single-cell RNA-seq (scRNA-seq) can circumvent this issue but the issues in dropouts and low-coverage of transcripts impede the large-scale characterization of co-expressed pairs."
1609,Hypoxic memory of tumor intrinsic type I interferon suppression promotes breast cancer metastasis,"Oihana Iriondo, Desirea Mecenas, Yilin Li, Christopher R. Chin, Amal Thomas, Yonatan Amzaleg, Aidan Moriarty, Veronica Ortiz, Matthew MacKay, Amber Dickerson, Grace Lee, Sevana Harotoonian, Bérénice A. Benayoun, Andrew Smith, Christopher Mason, Evanthia T. Roussos Torres, Remi Klotz, Min Yu",https://www.biorxiv.org/content/10.1101/2022.05.12.491632v2,"Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis and has been associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs), but the long-lasting effect of hypoxia beyond the immediate HIF regulation remains less understood. Here we show that hypoxia exerts a prolonged effect to promote metastasis. Using breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, we found that hypoxia downregulates tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced IFN/AP suppression can last longer than the hypoxic exposure, presenting a “hypoxic memory” phenotype. Hypoxic memory of IFN/AP downregulation is established by specific hypoxic priming, and cells with hypoxic memory have an enhanced ability for tumorigenesis and metastasis. The histone deacetylase inhibitor (HDACi) Entinostat can erase the hypoxic memory and improve the immune clearance of tumor cells when combined with checkpoint immunotherapies in a syngeneic breast cancer mouse model. These results point to a novel mechanism for hypoxia facilitated tumor progression, through a long-lasting memory that provides advantages for CTCs during the metastatic cascade."
1610,Accurate identification of cancer cells in complex pre-clinical models using deep-learning: a transfection-free approach,"Marilisa Cortesi, Dongli Liu, Elyse Powell, Ellen Barlow, Kristina Warton, Caroline E. Ford",https://www.biorxiv.org/content/10.1101/2023.10.15.562411v1,"3D co-cultures are key tools for in vitro biomedical research as they recapitulate more closely the in vivo environment, while allowing control of the density and type of cells included in the analysis, as well as the experimental conditions in which they are maintained. More widespread application of these models is hampered however by the limited technologies available for their analysis. The separation of the contribution of the different cell types, in particular, is a fundamental challenge."
1612,"An Evaluation of the Tumor Microenvironment through CALR, IL1R1, IFNB1, and IFNG to Assess Prognosis and Immunotherapy Response in Bladder Cancer Patients","Lilong Liu, Zhenghao Liu, Lei Fan, Zhipeng Yao, Junyi Hu, Yaxin Hou, Yang Li, Yuhong Ding, Yingchun Kuang, Ke Chen, Yi Hao, Zheng Liu",https://www.biorxiv.org/content/10.1101/2024.01.24.577030v1,"Immunogenic cell death (ICD) is a type of cell death sparking adaptive immune responses, can reshape the tumor microenvironment (TME). Exploring key ICD-related genes in bladder cancer (BLCA) could enhance personalized treatment. TCGA BLCA patients were divided into two ICD subtypes: ICD-high and ICD-low. High ICD expression linked to increased immune cell infiltration and longer survival, but with potentially suppressed immune function. The high ICD group responded better to PD1-targeted therapy. A risk-scoring model with four ICD-related genes (CALR, IL1R1, IFNB1, IFNG) was validated across TCGA, GEO datasets, and tissue samples, showing higher risk-score correlated with weaker anti-tumor immune function, more tumor-promoting elements, lower immunotherapy response rates, and shorter patient survival.This study connects ICD-related genes to BLCA prognosis and immune infiltration, offering a vital tool for personalized treatment guidance."
1613,A Cancer-Associated Fibroblast Classification Framework for Single-Cell Data,"Lena Cords, Sandra Tietscher, Tobias Anzeneder, Claus Langwieder, Martin Rees, Natalie de Souza, Bernd Bodenmiller",https://www.biorxiv.org/content/10.1101/2022.12.14.520398v1,"Cancer-associated fibroblasts (CAFs) are a diverse cell population within the tumour microenvironment, where they have critical effects on tumour evolution and patient prognosis. To define CAF phenotypes, we analysed a single-cell RNA sequencing (scRNA-seq) dataset of over 16,000 stromal cells from tumours of 14 breast cancer patients, based on which we defined and functionally annotated nine CAF phenotypes and one class of pericytes. We validated this classification system in four additional cancer types and used highly multiplexed imaging mass cytometry on matched breast cancer samples to confirm our defined CAF phenotypes at the protein level and to analyse their spatial distribution within tumours. This general CAF classification scheme will allow comparison of CAF phenotypes across studies, facilitate analysis of their functional roles, and potentially guide development of new treatment strategies in the future."
1619,TRIB1 modulates transcriptional programming in breast cancer cells to regulate cell proliferation,"Hamish D. McMillan, Evangelia K. Papachristou, Jody Hazlett, Soleilmane Omarjee, Jason S. Carroll, Michael A. Black, Peter D. Mace, Anita K. Dunbier",https://www.biorxiv.org/content/10.1101/2023.07.06.547928v1,"The pseudokinase Tribbles Homolog 1 (TRIB1) is a known driver of tumorigenesis in acute myeloid leukemia and is encoded upstream of the oncogene MYC at the 8q24 locus. We observed that TRIB1/MYC co-amplification is associated with decreased relapse-free and overall survival in breast cancer patients, but the role of TRIB1 in this disease has not been well characterized. TRIB1 knockdown in multiple breast cancer cell lines inhibited cell proliferation and suppressed MYC expression, implicating TRIB1 in breast cancer cell proliferation. Transcriptomic and cell cycle analysis revealed cell cycle regulation as the likely mechanism through which TRIB1 influences breast cancer cell proliferation. TRIB1 knockdown also resulted in significant changes in both estrogen receptor (ER) and β-catenin associated transcription. Interrogating the TRIB1 interactome in breast cancer cells by qPLEX-RIME reinforced the known association between TRIB1 and ubiquitination, while revealing a range of previously undescribed TRIB1 associated factors. Further analysis of the association between TRIB1, β-catenin and FERMT2 suggests TRIB1 may regulate β-catenin activity by controlling the levels of both β-catenin, and its co-factor FERMT2. Together, these results suggest that coregulation of β-catenin and ER-driven transcription by TRIB1, facilitates regulation of MYC expression and breast cancer cell proliferation."
1620,Network-based prediction approach for cancer-specific driver missense mutations using a graph neural network,"Narumi Hatano, Mayumi Kamada, Ryosuke Kojima, Yasushi Okuno",https://www.biorxiv.org/content/10.1101/2023.07.05.547896v1,"Background In cancer genomic medicine, finding driver mutations involved in cancer development and tumor growth is crucial. Machine-learning methods to predict driver missense mutations have been developed because variants are frequently detected by genomic sequencing. However, even though the abnormalities in molecular networks are associated with cancer, many of these methods focus on individual variants and do not consider molecular networks. Here we propose a new network-based method, Net-DMPred, to predict driver missense mutations considering molecular networks. Net-DMPred consists of the graph part and the prediction part. In the graph part, molecular networks are learned by a graph neural network (GNN). The prediction part learns whether variants are driver variants using features of individual variants combined with the graph features learned in the graph part."
1621,Weakly supervised contrastive learning predicts tumor infiltrating macrophages and immunotherapy benefit in breast cancer from unannotated pathology images,"Guobang Yu, Yi Zuo, Bin Wang, Hui Liu",https://www.biorxiv.org/content/10.1101/2023.04.30.538851v4,"The efficacy of immune checkpoint inhibitors is significantly influenced by the tumor immune microenvironment (TIME). RNA sequencing of tumor biopsies or surgical specimens can offer valuable insights into TIME, but its high cost and long turnaround time seriously restrict its utility in routine clinical examinations. Several recent studies have suggested that ultra-high resolution pathology images can infer cellular and molecular characteristics. However, studies on revealing TIME from pathology images are still limited.In this paper, we proposed a novel weakly supervised contrastive learning model to deduce tumor immune microenvironment features from whole slide images (WSIs) of H&E stained pathological sections. The high-resolution WSIs are split into tiles, and then contrastive learning is applied to extract features of each tile. After aggregating the features at the tile level, we employ weak supervisory signals to fine-tune the encoder for various downstream tasks. Comprehensive downstream experiments on two independent breast cancer cohorts and spatial transcriptomics data demonstrate that our computational pathological features accurately predict the proportion of tumor infiltrating immune cells, particularly the infiltration level of macrophages, as well as the immune subtypes and biomarker gene expression levels. These findings demonstrate that our model effectively captures pathological features beyond human vision, establishing a mapping relationship between cellular compositions and histological morphology, thus expanding the clinical applications of digital pathology images."
1622,The role of Absorbing Markov Chains in childhood cancer,"David H. Margarit, Marcela V. Reale, Ariel F. Scagliotti, Lilia M. Romanelli",https://www.biorxiv.org/content/10.1101/2022.12.12.520113v1,"Absorbing Markov Chains are an important mathematical tool used for different applications in science. On the other hand, cancer and its metastases in children have a significant impact on health due to their degree of lethality. Therefore, the aim of this work is to model the metastatic pathways of the main childhood cancers worldwide. The probabilities of generating metastases, from a primary site to secondary and tertiary sites, were characterized by constructing a directed graph and the associated transition matrix. In addition, the time of absorption and the probabilities of absorption by each absorbing state were calculated."
1623,Tristetraproline in breast cancer: treat or trick?,"Kropyvko Serhii, Hubiernatorova Anastasiia, Mankovska Oksana, Syvak Liubov, Verovkina Nataliia, Lyalkin Sergii, Lavrynenko Kyrylo, Ivasechko Iryna, Stoika Rostyslav, Rynditch Alla",https://www.biorxiv.org/content/10.1101/2022.05.23.493030v1,"Breast cancer is one of the most common types of cancer. It is very heterogeneous, hence still complicated to diagnose despite of decades of research. Post-transcriptional regulation of gene expression is crucial for modulation of cell networking and is performed via different regulatory molecules. Tristetraproline (TTP) is RNA-binding protein which binds to AU-rich elements within its target mRNAs and negatively regulates multiple transcripts, including pro-inflammatory and pro-oncogenic. Its expression level correlates with patient outcomes in different types of cancer and is considered as a potential molecular marker. Here we examined TTPs expression level in different molecular subtypes of breast cancer. Our findings show that TTP expression is significantly higher in HER2-enriched breast cancer compared to other types and adjacent tissues. We also investigated changes in the TTPs methylation status under temozolomide and doxorubicin treatment in MCF-7 cell line and found that temozolomide decreased TTPs methylation, which can potentially improve patient prognosis. In contrast, another well-known anticancer agent, doxorubicin, promoted TTPs methylation, which may impair an expected therapeutic effect of this drug."
1624,Modeling and Predicting Cancer Clonal Evolution with Reinforcement Learning,"Stefan Ivanovic, Mohammed El-Kebir",https://www.biorxiv.org/content/10.1101/2022.12.11.519917v1,"Cancer results from an evolutionary process that typically yields multiple clones with varying sets of mutations within the same tumor. Accurately modeling this process is key to understanding and predicting cancer evolution. Here, we introduce CloMu (Clone To Mutation), a flexible and low-parameter tree-generative model of cancer evolution. CloMu uses a two-layer neural network trained via reinforcement learning to determine the probability of new mutations based on the existing mutations on a clone. CloMu supports several prediction tasks, including the determination of evolutionary trajectories, tree selection, causality and interchangeability between mutations, and mutation fitness. Importantly, previous methods support only some of these tasks, and many suffer from overfitting on datasets with a large number of mutations. Using simulations, we demonstrate that CloMu either matches or outperforms current methods on a wide variety of prediction tasks. In particular, for simulated data with interchangeable mutations, current methods are unable to uncover causal relationships as effectively as CloMu. On breast cancer and leukemia cohorts, we show that CloMu determines similarities and causal relationships between mutations as well as the fitness of mutations. We validate CloMu’s inferred mutation fitness values for the leukemia cohort by comparing them to clonal proportion data not used during training, showing high concordance. In summary, CloMu’s low-parameter model facilitates a wide range of prediction tasks regarding cancer evolution on increasingly available cohort-level datasets."
1626,"Cancer-specific association between Tau (MAPT) and cellular pathways, clinical outcome, and drug response","Maurizio Callari, Martina Sola, Claudia Magrin, Andrea Rinaldi, Marco Bolis, Paolo Paganetti, Luca Colnaghi, Stéphanie Papin",https://www.biorxiv.org/content/10.1101/2023.07.04.547660v1,"Tau (MAPT) is a microtubule-associated protein causing common neurodegenerative diseases or inherited frontotemporal lobar degenerations. Emerging evidence for non-canonical functions of Tau in DNA repair and P53 regulation suggests its involvement in cancer. Indeed, preliminary studies have correlated Tau expression with cancer survival or response to therapies. To bring new evidence for a relevant role of Tau in cancer, we carried out an in silico pan-cancer analysis of MAPT transcriptomic profile in over 10000 clinical samples from 32 cancer types and over 1300 pre-clinical samples from 28 cancer types provided by the TCGA and the DEPMAP datasets respectively. MAPT expression associated with key cancer hallmarks including inflammation, proliferation, and epithelial to mesenchymal transition, showing cancer-specific patterns. In some cancer types, MAPT functional networks were affected by P53 mutational status. We identified new associations of MAPT with clinical outcomes and drug response in a context-specific manner. Overall, our findings indicate that the MAPT gene is a potential major player in multiple types of cancer. Importantly, the impact of Tau on cancer seems to be heavily influenced by the specific cellular environment."
1627,A Novel Humanized Immune Stroma PDX Cancer Model for Therapeutic Studies,"Dongli Yang, Ian Beddows, Huijuan Tang, Sandra Cascio, Stacy C. McGonigal, Shoumei Bai, Benjamin K. Johnson, John J. Powers, Rajesh Acharya, Riyue Bao, Tullia C. Bruno, Thing R. Soong, Jose R. Conejo-Garcia, Hui Shen, Moses T. Bility, Ronald J. Buckanovich",https://www.biorxiv.org/content/10.1101/2023.07.03.547206v1,"Standard preclinical human tumor models lack a human tumor stroma. However, as stroma contributes to therapeutic resistance, the lack of human stroma may make current models less stringent for testing new therapies. To address this, using patient-derived tumor cells, patient derived cancer-associated mesenchymal stem/progenitor cells, and human endothelial cells, we created a Human Stroma-Patient Derived Xenograft (HS-PDX) tumor model. HS-PDX, compared to the standard PDX model, demonstrate greater resistance to targeted therapy and chemotherapy, and better reflect patient response to therapy. Furthermore, HS-PDX can be grown in mice with humanized bone marrow to create humanized immune stroma patient-derived xenograft (HIS-PDX) models. The HIS-PDX model contains human connective tissues, vascular and immune cell infiltrates. RNA sequencing analysis demonstrated a 94-96% correlation with primary human tumor. Using this model, we demonstrate the impact of human tumor stroma on response to CAR-T cell therapy and immune checkpoint inhibitor therapy. We show an immunosuppressive role for human tumor stroma and that this model can be used to identify immunotherapeutic combinations to overcome stromally mediated immunosuppression. Combined, our data confirm a critical role for human stoma in therapeutic response and indicate that HIS-PDX can be an important tool for preclinical drug testing."
1628,FADS1/2-mediated lipid metabolic reprogramming drives ferroptosis sensitivity in triple-negative breast cancer,"Nicla Lorito, Angela Subbiani, Alfredo Smiriglia, Marina Bacci, Francesca Bonechi, Laura Tronci, Alessia Corrado, Dario Livio Longo, Marta Iozzo, Luigi Ippolito, Giuseppina Comito, Elisa Giannoni, Icro Meattini, Alexandra Avgustinova, Paola Chiarugi, Angela Bachi, Andrea Morandi",https://www.biorxiv.org/content/10.1101/2023.06.30.547227v1,"Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value."
1629,"A CANCER PERSISTENT DNA REPAIR CIRCUIT DRIVEN BY MDM2, MDM4 (MDMX), AND MUTANT P53 FOR RECRUITMENT OF MDC1 AND 53BP1 TO CHROMATIN","Viola Ellison, Alla Polotskaia, Gu Xiao, Pamella Leybengrub, Weigang Qiu, Rusia Lee, Ronald Hendrickson, Wenwei Hu, Jill Bargonetti",https://www.biorxiv.org/content/10.1101/2024.01.20.576487v1,"The influence of the metastasis promoting proteins mutant p53 (mtp53) and MDM2 on Cancer Persistent Repair (CPR) to promote cancer cell survival is understudied. Interactions between the DNA repair choice protein 53BP1 and wild type tumor suppressor protein p53 (wtp53) regulates cell cycle control. Cancer cells often express elevated levels of transcriptionally inactive missense mutant p53 (mtp53) that interacts with MDM2 and MDM4/MDMX (herein called MDMX). The ability of mtp53 to maintain a 53BP1 interaction while in the context of interactions with MDM2 and MDMX has not been described. We asked if MDM2 regulates chromatin-based phosphorylation events in the context of mtp53 by comparing the chromatin of T47D breast cancer cells with and without MDM2 in a phospho-peptide stable isotope labeling in cell culture (SILAC) screen. We found reduced phospho-53BP1 chromatin association, which we confirmed by chromatin fractionation and immunofluorescence in multiple breast cancer cell lines. We used the Proximity Ligation Assay (PLA) in breast cancer cell lines and detected 53BP1 in close proximity to mtp53, MDM2, and the DNA repair protein MDC1. Through disruption of the mtp53-MDM2 interaction, by either Nutlin 3a or a mtp53 R273H C-terminal deletion, we uncovered that mtp53 was required for MDM2-53BP1 interaction foci. Our data suggests that mtp53 works with MDM2 and 53BP1 to promote CPR and cell survival."
1630,Fusobacterium nucleatum present in the saliva of oral cancer subjects can activate niche defense of oral squamous cell carcinoma,"Partha Jyoti Saikia, Lekhika Pathak, Shirsajit Mitra, Tutumoni Baishya, Rupam Das, Ibrahim S Akeel, Bidisha Pal, Bikul Das",https://www.biorxiv.org/content/10.1101/2023.10.10.561552v1,"Oral cancer is a subset of head and neck cancer (HNC), has a high incidence rate in this malignancy group. Cancer Stem Cells (CSCs) are population of the heterogeneous malignant cells present within oral tumor microenvironment. CSCs’ stemness permits them to control several signaling pathways and so play a role in cancer progression and relapse. A number of studies have recently demonstrated the presence of specific oral bacteria populations and their lipopolysaccharides (LPS) in the tumor microenvironment. The precise mechanism of action in the initiation, progression, and relapse of oral cancer by the oral bacteria are yet to be determined. We previously reported pathogenic bacterial internalization in CSCs. Based on the findings; we have developed an in-vitro model to investigate how oral microbiota may integrate into the tumor microenvironment’s CSC population and control its activity. Notably, we found that live bacteria and their LPS, mostly Fusobacterium nucleatum isolated from clinical subjects, were capable of invading CSCs in the in-vitro experimental design setup. Post the host-pathogen interaction; it enabled the activation of a niche modulatory tumor stemness defense (TSD) phenotype in the CSCs. These aggressive CSCs with the TSD phenotype have been found to have a critical role in the progression and relapse of oral cancer."
1631,Microbiota may affect the tumor type but not overall tumor development in two models of heritable cancer,"Jessica Spring, Sandeep Gurbuxani, Tatyana Golovkina",https://www.biorxiv.org/content/10.1101/2023.10.11.561890v1,"Microbial impact on tumorigenesis of heritable cancers proximal to the gut is well documented. Whether the microbiota influences cancers arising from inborn mutations at sites distal to the gut is undetermined. Using two models of heritable cancer, we found the microbiota to be inconsequential for tumor development. However, the type of tumor that develops may be influenced by the microbiota. This work furthers our understanding of the microbial impact on tumor development."
1632,RNF185 control of COL3A1 expression limits prostate cancer migration and metastatic potential,"Benjamin Van Espen, Htoo Zarni Oo, Colin Collins, Ladan Fazli, Alfredo Molinolo, Rabi Murad, Martin Gleave, Ze’ev A. Ronai",https://www.biorxiv.org/content/10.1101/2023.06.29.547118v1,"RNF185 is a RING finger domain-containing ubiquitin ligase implicated in ER-associated degradation. Prostate tumor patient data analysis revealed a negative correlation between RNF185 expression and prostate cancer progression and metastasis. Likewise, several prostate cancer cell lines exhibited greater migration and invasion capabilities in culture upon RNF185 depletion. Subcutaneous inoculation of mouse prostate cancer MPC3 cells stably expressing shRNA against RNF185 into mice resulted in larger tumors and more frequent lung metastases. RNA-sequencing and Ingenuity Pathway Analysis identified wound healing and cellular movement among the most significant pathways upregulated in RNF185-depleted, compared to control prostate cancer cells. Gene Set Enrichment Analyses performed in samples from patients harboring low RNF185 expression and in RNF185-depleted lines confirmed the deregulation of genes implicated in EMT. Among those, COL3A1 was identified as the primary mediator of RNF185’s ability to impact migration phenotypes. Correspondingly, enhanced migration and metastasis of RNF185 KD prostate cancer cells were attenuated upon co-inhibition of COL3A1. Our results identify RNF185 as a gatekeeper of prostate cancer metastasis, partly via its control of COL3A1 availability."
1633,Pan-cancer characterization of ncRNA synergistic competition uncovers potential carcinogenic biomarkers,"Junpeng Zhang, Lin Liu, Xuemei Wei, Chunwen Zhao, Sijing Li, Jiuyong Li, Thuc Duy Le",https://www.biorxiv.org/content/10.1101/2023.06.29.547005v2,"Non-coding RNAs (ncRNAs) act as important modulators of gene expression and they have been confirmed to play critical roles in the physiology and development of malignant tumors. Understanding the synergism of multiple ncRNAs in competing endogenous RNA (ceRNA) regulation can provide important insights into the mechanisms of malignant tumors caused by ncRNA regulation. In this work, we present a framework, SCOM, for identifying ncRNA synergistic competition. We systematically construct the landscape of ncRNA synergistic competition across 31 malignant tumors, and reveal that malignant tumors tend to share hub ncRNAs rather than the ncRNA interactions involved in the synergistic competition. In addition, the synergistic competition ncRNAs (i.e. ncRNAs involved in the synergistic competition) are likely to be involved in drug resistance, contribute to distinguishing molecular subtypes of malignant tumors, and participate in immune regulation. Furthermore, SCOM can help to infer ncRNA synergistic competition across malignant tumors and uncover potential diagnostic and prognostic biomarkers of malignant tumors. Altogether, the SCOM framework and the resulting web-based database SCOMdb (www.comblab.cn/SCOMdb/) serve as a useful resource for exploring ncRNA regulation and to accelerate the identification of carcinogenic biomarkers."
1634,BCLncRDB: A comprehensive database of LncRNAs associated with breast cancer,"Swapnil Kumar, Avantika Agarwal, Vaibhav Vindal",https://www.biorxiv.org/content/10.1101/2022.12.05.519223v1,"Motivation Breast cancer, the most common cancer in women, is characterized by high morbidity and mortality worldwide. Recent evidence has shown that long non-coding RNAs (lncRNAs) play a crucial role in the development and progression of breast cancer. Despite this, no database exists primarily for lncRNAs associated with only breast cancer."
1635,Visualizing somatic alterations in spatial transcriptomics data of skin cancer,"Limin Chen, Darwin Chang, Bishal Tandukar, Delahny Deivendran, Raymond Cho, Jeffrey Cheng, Boris C. Bastian, Andrew L. Ji, A. Hunter Shain",https://www.biorxiv.org/content/10.1101/2022.12.05.519162v1,"Tools to visualize genetic alterations within tissues remain underdeveloped despite the growth of spatial transcriptomic technologies, which measure gene expression in different regions of tissues. Since genetic alterations can be detected in RNA-sequencing data, we explored the feasibility of observing somatic alterations in spatial transcriptomics data. Extracting genetic information from spatial transcriptomic data would illuminate the spatial distribution of clones and allow for correlations with regional changes in gene expression to support genotype-phenotype studies. Recent work demonstrates that copy number alterations can be inferred from spatial transcriptomics data1. Here, we describe new software to further enhance the inference of copy number from spatial transcriptomics data. Moreover, we demonstrate that single nucleotide variants are also detectable in spatial transcriptomic data. We applied these approaches to map the location of point mutations, copy number alterations, and allelic imbalances in spatial transcriptomic data of two cutaneous squamous cell carcinomas. We show that both tumors are dominated by a single clone of cells, suggesting that their regional variations in gene expression2 are likely driven by non-genetic factors. Furthermore, we observe mutant cells in histologically normal tissue surrounding one tumor, which were not discernible upon histopathologic evaluation. Finally, we detected mono-allelic expression of immunoglobulin heavy chains in B-cells, revealing clonal populations of plasma cells surrounding one tumor. In summary, we put forward solutions to add the genetic dimension to spatial transcriptomic datasets, augmenting the potential of this new technology."
1636,LRRK2 G2019S promotes the development of colon cancer via modulating intestinal inflammation,"Yuhang Wang, Joyce Z Gao, Taylor Sakaguchi, Thorsten Maretzky, Prajwal Gurung, Sarah Short, Yiqin Xiong, Zizhen Kang",https://www.biorxiv.org/content/10.1101/2023.06.28.546897v1,"LRRK2 G2019S is the most prevalent variant associated with Parkinson’s disease (PD), found in 1-3% of sporadic and 4-8% of familial PD cases. Intriguingly, emerging clinical studies have suggested that LRRK2 G2019S carriers have an increased risk of cancers including colorectal cancer. However, the underlying mechanisms of the positive correlation between LRRK2-G2019S and colorectal cancer remain unknown. Using a mouse model of colitis-associated cancer (CAC) and LRRK2 G2019S knockin (KI) mice, here we report that LRRK2 G2019S promotes the pathogenesis of colon cancer as evidenced by increased tumor number and tumor size in LRRK2 G2019S KI mice. LRRK2 G2019S promoted intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, we found that LRRK2 G2019S KI mice are more susceptible to dextran sulfate sodium (DSS)-induced colitis. Suppressing the kinase activity of LRRK2 ameliorated the severity of colitis in both LRRK2 G2019S KI and WT mice. At the molecular level, our investigation unveiled that LRRK2 G2019S promotes the production of reactive oxygen species, triggers inflammasome activation, and induces cell necrosis in the gut epithelium in a mouse model of colitis. Collectively, our data provide direct evidence that gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, implicating LRRK2 as a potential target in colon cancer patients with hyper LRRK2 kinase activity."
1639,In silico approaches to identify the role of lncRNAs in Prostate cancer and Androgen receptor-targeted proteins,"Barkha Khilwani, Bhumandeep Kour, Nidhi Shukla, Bhargavi R, Sugunakar Vure, Abdul S. Ansari, Nirmal K. Lohiya, Renuka Suravajhala, Prashanth Suravajhala",https://www.biorxiv.org/content/10.1101/2023.10.07.561330v1,"Long non-coding RNA (lncRNAs) are known to have a role in pathogenesis of a broad spectrum of malignancies.These are found to have a significant role as signal transduction mediators in cancer signaling pathways. Prostate Cancer (PCa) is emerging with increasing cases worldwide even as advanced approaches in clinical diagnosis and treatment of PCa are still challenging to address. To enhance patient stratification, there is an indefatigable need to understand risk that can allow new approaches of treatment based on prognosis. While PCa is known to have mediated androgen receptor (AR) stimulation, the latter plays a key role in regulating transcription of genes via nuclear translocation which in turn leads to response to androgens. LncRNAs have been implicated in developing clinical diagnostic and prognostic biomarkers in a broad spectrum of cancers. In our present study, 12 lncRNAs identified from clinical samples from our erstwhile PCa patients were docked with PCa and AR targeted 36 proteins. We identified three lncRNAs, viz. SCARNA10, NPBWR1, ANKRD20A9P are common between the targeted proteins and discern that SCARNA10 lncRNA could serve as a prognostic signature for PCa and AR biogenesis. We also sought to check the coding potential of interfacial residues associated with lncRNA docking sites.x"
1640,Regional Mutational Signature Activities in Cancer Genomes,"Caitlin Timmons, Quaid Morris, Caitlin F. Harrigan",https://www.biorxiv.org/content/10.1101/2022.01.23.477261v4,"Cancer genomes harbor a catalog of somatic mutations. The type and genomic context of these mutations depend on their causes, and allow their attribution to particular mutational signatures. Previous work has shown that mutational signature activities change over the course of tumor development, but investigations of genomic region variability in mutational signatures have been limited. Here, we expand upon this work by constructing regional profiles of mutational signature activities over 2,203 whole genomes across 25 tumor types, using data aggregated by the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium. We present GenomeTrackSig as an extension to the TrackSig R package to construct regional signature profiles using optimal segmentation and the expectation-maximization (EM) algorithm. We find that 426 genomes from 20 tumor types display at least one change in mutational signature activities (changepoint), and 257 genomes contain at least one of 54 recurrent changepoints shared by seven or more genomes of the same tumor type. Five recurrent changepoint locations are shared by multiple tumor types. Within these regions, the particular signature changes are often consistent across samples of the same type and some, but not all, are characterized by signatures associated with subclonal expansion. The changepoints we found cannot strictly be explained by gene density, mutation density, or cell-of-origin chromatin state. We hypothesize that they reflect a confluence of factors including evolutionary timing of mutational processes, regional differences in somatic mutation rate, large-scale changes in chromatin state that may be tissue type-specific, and changes in chromatin accessibility during subclonal expansion. These results provide insight into the regional effects of DNA damage and repair processes, and may help us localize genomic and epigenomic changes that occur during cancer development."
1641,Identification of pan-cancer/testis genes and validation of therapeutic targeting in triple-negative breast cancer: Lin28a- and Siglece-based vaccination induces anti-tumor immunity and inhibits metastasis,"Jason A. Carter, Bharati Matta, Jenna Battaglia, Carter Somerville, Benjamin D. Harris, Margaret LaPan, Gurinder S. Atwal, Betsy J. Barnes",https://www.biorxiv.org/content/10.1101/2023.05.09.539617v1,"Background Cancer-testis (CT) genes are targets for tumor antigen-specific immunotherapy given that their expression is normally restricted to the immune-privileged testis in healthy individuals with aberrant expression in tumor tissues. While they represent targetable germ-tissue antigens and play important functional roles in tumorigenesis, there is currently no standardized approach for identifying clinically relevant CT genes. Optimized algorithms and validated methods for accurate prediction of reliable CT antigens with high immunogenicity are also lacking."
1642,Clinical Significance of the Stromatic Component in Ovarian Cancer: Quantity Over Quality in Outcome Prediction,"Emil Lou, Valentino Clemente, Marcel Grube, Axel Svedbom, Andrew Nelson, Freya Blome, Annette Staebler, Stefan Kommoss, Martina Bazzaro",https://www.biorxiv.org/content/10.1101/2023.06.27.546712v1,"Background The tumor stroma is composed of a complex network of non-cancerous cells and extracellular matrix elements that collectively are crucial for cancer progression and treatment response. Within the realm of ovarian cancer, the expression of the stromal gene cluster has been linked to poorer progression-free and overall survival rates. However, in the age of precision medicine and genome sequencing, the notion that the simple measurement of tumor-stroma proportion alone can serve as a biomarker for clinical outcome is a topic that continues to generate controversy and provoke discussion. Our current study reveals that it is the quantity of stroma, rather than its quality, that serves as a clinically significant indicator of patient outcome in ovarian cancer."
1645,Single-cell transcriptomes identify patient-tailored therapies for selective co-inhibition of cancer clones,"Aleksandr Ianevski, Kristen Nader, Daria Bulanova, Anil K Giri, Tanja Ruokoranta, Heikki Kuusanmäki, Nemo Ikonen, Philipp Sergeev, Markus Vähä-Koskela, Anna Vähärautio, Mika Kontro, Kimmo Porkka, Caroline A. Heckman, Krister Wennerberg, Tero Aittokallio",https://www.biorxiv.org/content/10.1101/2023.06.26.546571v1,"Intratumoral cellular heterogeneity necessitates multi-targeting therapies for improved clinical benefits in patients with advanced malignancies. However, systematic identification of patient-specific treatments that selectively co-inhibit cancerous cell populations poses a combinatorial challenge, since the number of possible drug-dose combinations vastly exceeds what could be tested in scarce patient cells. Here, we developed scTherapy, a machine learning model that leverages single-cell transcriptomic profiles to prioritize multi-targeting treatment options for individual patients with hematological cancers or solid tumors."
1646,Non-targeted metabolomics identifies erythronate accumulation in cancer cells,"Jie Zhang, Mark A. Keibler, Wentao Dong, Jenny Ghelfi, Thekla Cordes, Tamara Kanashova, Arnaud Pailot, Carole Linster, Gunnar Dittmar, Christian M. Metallo, Tim Lautenschlaeger, Karsten Hiller, Gregory Stephanopoulos",https://www.biorxiv.org/content/10.1101/2022.12.04.519010v1,"Using a non-targeted isotope-assisted metabolomics approach, we identified erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We provide data supporting a possible alternative route to erythronate production involving the dephosphorylation of the pentose phosphate pathway intermediate erythrose-4-phosphate to form erythrose, followed by the oxidation of erythrose by an aldehyde dehydrogenase. Finally, we detected increased erythronate concentrations in tumors relative to adjacent normal tissues from lung cancer patients. These findings suggest the accumulation of erythronate to be an example of metabolic reprogramming in cancer cells, raising the possibility that elevated level of erythronate may serve as a biomarker of certain types of cancer."
1647,Group A Streptococcal Collagen-like Protein 1 Restricts Tumor Growth in Murine Pancreatic Adenocarcinoma and Inhibits Cancer-Promoting Neutrophil Extracellular Traps,"Emily A. Henderson, Abby Ivey, Soo Choi, Stell Santiago, Dudley McNitt, Tracy W. Liu, Slawomir Lukomski, Brian A. Boone",https://www.biorxiv.org/content/10.1101/2024.01.17.576060v1,"Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer associated with an immunosuppressive environment. Neutrophil extracellular traps (NETs) were initially described in the context of infection but have more recently been implicated in contributing to the tolerogenic immune response in PDAC. Thus, NETs are an attractive target for new therapeutic strategies. Group A Streptococcus (GAS) has developed defensive strategies to inhibit NETs. In the present work, we propose utilizing intra-tumoral GAS injection to stimulate anti-tumor activity by inhibiting cancer-promoting NETs. Injection of three different M-type GAS strains reduced subcutaneous pancreatic tumor volume compared to control in two different murine PDAC models. Limitation of tumor growth was dependent on streptococcal collagen-like protein 1 (Scl1), as isogenic mutant strain devoid of Scl1 did not reduce tumor size. We further show that Scl1 plays a role in localizing GAS to the tumor site, thereby limiting the systemic spread of bacteria and off-target effects. While mice did elicit a humoral immune response to GAS antigens, tested sera were negative toward Scl1 antigen following intra-tumoral treatment with Scl1-expressing GAS. M1 GAS inhibited NET formation when co-cultured with neutrophils while Scl1-devoid mutant strain did not. Recombinant Scl1 protein inhibited NETs ex vivo in a dose-dependent manner by suppressing myeloperoxidase activity. Altogether, we demonstrate that intra-tumoral GAS injections reduce PDAC growth, which is facilitated by Scl1, in part through inhibition of cancer promoting NETs. This work offers a novel strategy by which NETs can be targeted through Scl1 protein and potentiates its use as a cancer therapeutic."
1649,Glycoprofiling of proteins as prostate cancer biomarkers: a multinational population study,"Andrea Pinkeova, Adela Tomikova, Aniko Bertokova, Eva Fabinyova, Radka Bartova, Eduard Jane, Stefania Hroncekova, Karl-Dietrich Sievert, Roman Sokol, Michal Jirasko, Radek Kucera, Iris E. Eder, Wolfgang Horninger, Helmut Klocker, Petra Ďubjaková, Juraj Fillo, Tomas Bertok, Jan Tkac",https://www.biorxiv.org/content/10.1101/2023.06.27.546717v1,"The glycoprofiling of two proteins, the free form of the prostate-specific antigen (fPSA) and zinc-α-2-glycoprotein (ZA2G), was assessed to determine their suitability as prostate cancer (PCa) biomarkers. The glycoprofiling of proteins was performed by analysing changes in the glycan composition on fPSA and ZA2G using lectins (proteins recognising glycans, i.e. complex carbohydrates). The specific glycoprofiling of the proteins was performed using magnetic beads (MBs) modified with horseradish peroxidase (HRP) and antibodies that selectively enriched fPSA or ZA2G from human serum samples. Subsequently, the antibody-captured glycoproteins were incubated on lectin-coated ELISA plates. In addition, a novel glycoprotein standard (GPS) was used to calibrate the assay. The glycoprofiling of fPSA and ZA2G was performed in human serum samples obtained from men undergoing prostate biopsy after an elevated serum PSA, and prostate cancer patients with or without prior therapy. The results are presented in the form of a ROC (Receiver Operating Curve). A DCA (Decision Curve Analysis) to evaluate the clinical performance and net benefit of fPSA glycan-based biomarkers was also performed. While the glycoprofiling of ZA2G showed little promise as a potential PCa biomarker, the glycoprofiling of fPSA would appear to have significant clinical potential. Hence, the GIA (Glycobiopsy ImmunoAssay) test integrates the glycoprofiling of fPSA (i.e. two glycan forms of fPSA). The GIA test could be used for early diagnoses of PCa (AUC=0.84; n=501 samples) with a potential for use in therapy-monitoring (AUC=0.85; n=168 samples). Moreover, the analysis of a subset of serum samples (n=215) revealed that the GIA test (AUC=0.81) outperformed the PHI (Prostate Health Index) test (AUC=0.69) in discriminating between men with prostate cancer and those with benign serum PSA elevation."
1650,Employing a honeybee olfactory neural circuit as a novel gas sensor for the detection of human lung cancer biomarkers,"Michael Parnas, Elyssa Cox, Simon Sanchez, Alexander Farnum, Noël Lefevre, Sydney Miller, Debajit Saha",https://www.biorxiv.org/content/10.1101/2023.10.04.560899v1,"Human breath contains biomarkers (odorants) that can be targeted for early disease detection. It is well known that honeybees have a keen sense of smell and can detect a wide variety of odors at low concentrations. Here, for the first time, we employ honeybee olfactory neuronal circuitry to classify human lung cancer volatile biomarkers and their mixtures at concentration ranges relevant to human breath, parts-per-billion to parts-per-trillion. Different lung cancer biomarkers evoked distinct spiking response dynamics in the honeybee antennal lobe neurons indicating that those neurons encoded biomarker-specific information. By investigating lung cancer biomarker-evoked population neuronal responses from the honeybee antennal lobe, we could classify individual human lung cancer biomarkers successfully (88% success rate). When we mixed six lung cancer biomarkers at different concentrations to create ‘synthetic lung cancer’ vs. ‘synthetic healthy breath’, honeybee population neuronal responses were also able to classify those complex breath mixtures successfully (100% success rate with a leave-one-trial-out method). Finally, we used separate training and testing datasets containing responses to the synthetic lung cancer and healthy breath mixtures. We identified a simple metric, the peak response of the neuronal ensemble, with the ability to distinguish synthetic lung cancer breath from the healthy breath with 86.7% success rate. This study provides proof-of-concept results that a powerful biological gas sensor, the honeybee olfactory system, can be used to detect human lung cancer biomarkers and their complex mixtures at biological concentrations."
1651,Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer,"Na Zhao, Elena B. Kabotyanski, Alexander B. Saltzman, Anna Malovannaya, Xueying Yuan, Lucas C. Reineke, Nadia Lieu, Yang Gao, Diego A Pedroza, Sebastian J Calderon, Alex J Smith, Clark Hamor, Kazem Safari, Sara Savage, Bing Zhang, Jianling Zhou, Luisa M. Solis, Susan G. Hilsenbeck, Cheng Fan, Charles M. Perou, Jeffrey M. Rosen",https://www.biorxiv.org/content/10.1101/2023.09.28.559973v1,"Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A by Zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages towards an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade."
1652,Anthracycline-induced cardiotoxicity associates with a shared gene expression response signature to TOP2-inhibiting breast cancer drugs in cardiomyocytes,"E. Renee Matthews, Omar D. Johnson, Kandace J. Horn, José A. Gutiérrez, Simon R. Powell, Michelle C. Ward",https://www.biorxiv.org/content/10.1101/2023.10.03.560405v1,"TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified eight genes in loci associated with AC toxicity by GWAS or TWAS. All eight genes, including RARG and SLC28A3, respond to at least two ACs, and their expression correlates with the release of cardiotoxicity markers. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity."
1653,Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype,"Amanda Fitzpatrick, Marjan Iravani, Adam Mills, David Vicente, Thanussuyah Alaguthurai, Ioannis Roxanis, Nicholas C. Turner, Syed Haider, Andrew N.J. Tutt, Clare M. Isacke",https://www.biorxiv.org/content/10.1101/2023.01.20.524591v2,"Breast cancer leptomeningeal metastasis (BCLM), where tumour cells grow along the lining of the brain and spinal cord, is a devastating development for patients. Investigating this metastatic site is hampered by difficulty in accessing tumour material. Here, we utilise cerebrospinal fluid (CSF) cell-free DNA (cfDNA) and CSF disseminated tumour cells (DTCs) to explore the clonal evolution of BCLM and heterogeneity between leptomeningeal and extracranial metastatic sites. Somatic alterations with potential therapeutic actionability were detected in 81% (17/21) of BCLM cases, with 19% detectable in CSF cfDNA only. BCLM was enriched in genomic aberrations in adherens junction and cytoskeletal genes, revealing a lobular-like breast cancer phenotype. CSF DTCs were cultured in 3D to establish BCLM patient-derived organoids, and used for the successful generation of BCLM in vivo models. These data reveal that BCLM possess a unique genomic aberration profile and highlights potential cellular dependencies in this hard-to-treat form of metastatic disease."
1654,Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice,"Ivana Barravecchia, Jennifer M. Lee, Jason Manassa, Brian Magnuson, Sophia Cavanaugh, Nina G. Steele, Carlos Espinoza, Craig J. Galban, Nithya Ramnath, Timothy L. Frankel, Marina Pasca di Magliano, Stefanie Galban",https://www.biorxiv.org/content/10.1101/2023.06.20.545616v1,"Idiopathic Pulmonary Fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. IPF patients have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer. Understanding the molecular pathogenesis of IPF-associated lung cancer is imperative for identifying diagnostic biomarkers and targeted therapies that will facilitate prevention of IPF and progression to lung cancer. To understand how IPF-associated fibroblast activation, matrix remodeling, epithelial-mesenchymal transition, and immune modulation influences lung cancer predisposition, we developed a mouse model to recapitulate the molecular pathogenesis of pulmonary fibrosis-associated lung cancer using the bleomycin and the Lewis Lung Carcinoma models. Models of pulmonary fibrosis, particularly bleomycin-induced fibrosis, do not recapitulate all aspects of human disease; however, to simplify nomenclature, we refer to our bleomycin-induced fibrosis model as IPF. We demonstrate that development of pulmonary fibrosis-associated lung cancer is linked to increased recruitment or reprogramming of tumor-associated macrophages and a unique gene signature that supports an immune-suppressive microenvironment through secreted factors. Not surprisingly, pre-existing fibrosis provides a pre-metastatic niche and results in augmented tumor growth. Tumors associated with bleomycin-induced fibrosis are characterized by an epithelial-to-mesenchymal transition characterized by dramatic loss of cytokeratin expression."
1660,Loss of STIM2 in colorectal cancer drives growth and metastasis through metabolic reprogramming and PERK-ATF4 endoplasmic reticulum stress pathway,"Trayambak Pathak, J. Cory Benson, Martin T. Johnson, Ping Xin, Ahmed Emam Abdelnaby, Vonn Walter, Walter A. Koltun, Gregory S. Yochum, Nadine Hempel, Mohamed Trebak",https://www.biorxiv.org/content/10.1101/2023.10.02.560521v1,"The endoplasmic reticulum (ER) stores large amounts of calcium (Ca2+), and the controlled release of ER Ca2+ regulates a myriad of cellular functions. Although altered ER Ca2+ homeostasis is known to induce ER stress, the mechanisms by which ER Ca2+ imbalance activate ER stress pathways are poorly understood. Stromal-interacting molecules STIM1 and STIM2 are two structurally homologous ER-resident Ca2+ sensors that synergistically regulate Ca2+ influx into the cytosol through Orai Ca2+ channels for subsequent signaling to transcription and ER Ca2+ refilling. Here, we demonstrate that reduced STIM2, but not STIM1, in colorectal cancer (CRC) is associated with poor patient prognosis. Loss of STIM2 causes SERCA2-dependent increase in ER Ca2+, increased protein translation and transcriptional and metabolic rewiring supporting increased tumor size, invasion, and metastasis. Mechanistically, STIM2 loss activates cMyc and the PERK/ATF4 branch of ER stress in an Orai-independent manner. Therefore, STIM2 and PERK/ATF4 could be exploited for prognosis or in targeted therapies to inhibit CRC tumor growth and metastasis."
1661,"The molecular prognostic score, a classifier for risk stratification of high-grade serous ovarian cancer","Siddik Sarkar, Sarbar Ali Saha, Poulomi Sarkar, Sarthak Banerjee, Pralay Mitra",https://www.biorxiv.org/content/10.1101/2023.06.19.545525v1,"The clinicopathological parameters such as residual tumor, grade, FIGO score are often used to predict the survival of ovarian cancer patients, but the 5-year survival of high grade serous ovarian cancer (HGSOC) still remains around 30%. In recent years, a gene expression based molecular prognostic score (mPS) was developed that showed improved prognosis in several cancers including ovarian cancer."
1662,An EGF-modified PLGA-lanthanide nanoplatform for combined NIR-II cancer imaging and targeted drug delivery,"Yuanyuan He, Zhenfeng Yu, Timo Schomann, Hong Zhang, Christina Eich, Luis J. Cruz",https://www.biorxiv.org/content/10.1101/2023.06.18.545497v1,"The use of multifunctional nanoplatforms for synergistic therapy and imaging is a promising approach in cancer treatment. In this study, we exploited the imaging properties of lanthanides by encapsulating CaF2:Y, Nd along with the chemotherapeutic drug doxorubicin (DOX) into poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to prepare a nanoplatform suitable for imaging in the second near-infrared (NIR-II) window and simultaneous anti-cancer therapy. To facilitate the accumulation of CaF2:Y, Nd+DOX@PLGA NPs in breast cancer cells, we modified the NPs with EGF. The diameter of the obtained CaF2:Y, Nd+DOX@PLGA/PEG/EGF NPs was approximately 150 nm, with a nearly round shape and homogeneous size distribution. In addition, analysis of the drug release behaviour showed that DOX was released more readily and had a longer release time in acidic environments. Accordingly, MTS results indicated that DOX-loaded NPs were significantly cytotoxic. Furthermore, fluorescence microscopy and flow cytometry studies revealed that CaF2:Y, Nd+DOX@PLGA/PEG and CaF2:Y, Nd+DOX@PLGA/PEG/EGF NPs were gradually taken up by 4T1 breast cancer cells over time, and EGF-coated Nd+DOX@PLGA NPs exhibited increased uptake rates after 72 h. Moreover, we found that EGF increased the solubility of Nd+DOX@PLGA NPs in water by comparing the aqueous solutions of the different NPs formulations. Finally, NIR imaging demonstrated strong fluorescence of PLGA NPs carrying CaF2:Y, Nd NPs at 900-1200 nm under 808 nm laser excitation. In conclusion, the developed CaF2:Y, Nd+DOX@PLGA/PEG/EGF NPs could be monitored for an extended period of time, and co-encapsulated DOX could be efficiently released to kill breast cancer cells."
1664,Lysosomal acid lipase-activity as a novel target to efficiently address triple-negative breast cancer high malignancy,"H. Steigerwald, T. Bozzetti, M. Tams, J. On, G. Hoffmann, J. Lambertz, K. Weidele, S. Treitschke, F. Reinhard, A. Kulik, N. Krawczyk, D. Niederacher, H. Neubauer, C. Werno, T. Rau, T. Fehm, K Esser",https://www.biorxiv.org/content/10.1101/2023.10.01.560038v1,"Increased metabolism of neutral lipids, e.g. triglycerides and cholesterol esters, is a hallmark of malignant cancers such as triple-negative breast cancer (TNBC). Predominantly, cancer cells with a high epigenetic stem cell-associated signature increasingly utilize neutral lipids to maintain their high degree of tumor stemness, linking metabolic aberrations to epigenetically dysregulated differentiation processes. Lysosomal acid lipase (LIPA) is a central enzyme in the cellular utilization of exogenous and endogenous neutral lipids; however, the role of LIPA-activity in TNBC remains unexplored. We here show for the first time that pharmacological inhibition of LIPA, highly expressed in TNBC, reduces the expression markers of breast cancer stemness in cell culture models of TNBC. A role of LIPA in maintaining TNBC high cellular stemness was stressed by specific siRNA knock-down. Furthermore, inhibition of LIPA sensitized TNBC cells to therapy with Paclitaxel and Doxorubicin, two important chemotherapeutics in current TNBC treatment. When LIPA-activity was inhibited in a three-dinensional (3D) patient derived organoid model, we observed a significant reduction in TNBC cellular viability. Importantly, LIPA inhibition prevented tumor metastasis in a TNBC-zebrafish xenograft model in vivo. These findings introduce LIPA-activity as a novel pharmacological target in TNBC therapy to specifically address its high cancer malignancy with a potential for implementation of LIPA inhibitors into personalized treatment in the future."
1665,Multi-modal transcriptomic analysis unravels enrichment of hybrid epithelial/mesenchymal state and enhanced phenotypic heterogeneity in basal breast cancer,"Sarthak Sahoo, Soundharya Ramu, Madhumathy G Nair, Maalavika Pillai, Beatriz P San Juan, Heloisa Zaccaron Milioli, Susmita Mandal, Chandrakala M Naidu, Apoorva D Mavatkar, Harini Subramaniam, Arpita G Neogi, Christine L Chaffer, Jyothi S Prabhu, Jason A Somarelli, Mohit Kumar Jolly",https://www.biorxiv.org/content/10.1101/2023.09.30.558960v1,"Intra-tumoral phenotypic heterogeneity promotes tumor relapse and therapeutic resistance and remains an unsolved clinical challenge. It manifests along multiple phenotypic axes and decoding the interconnections among these different axes is crucial to understand its molecular origins and to develop novel therapeutic strategies to control it. Here, we use multi-modal transcriptomic data analysis – bulk, single-cell and spatial transcriptomics – from breast cancer cell lines and primary tumor samples, to identify associations between epithelial-mesenchymal transition (EMT) and luminal-basal plasticity – two key processes that enable heterogeneity. We show that luminal breast cancer strongly associates with an epithelial cell state, but basal breast cancer is associated with hybrid epithelial/mesenchymal phenotype(s) and higher phenotypic heterogeneity. These patterns were inherent in methylation profiles, suggesting an epigenetic crosstalk between EMT and lineage plasticity in breast cancer. Mathematical modelling of core underlying gene regulatory networks representative of the crosstalk between the luminal-basal and epithelial-mesenchymal axes recapitulate and thus elucidate mechanistic underpinnings of the observed associations from transcriptomic data. Our systems-based approach integrating multi-modal data analysis with mechanism-based modeling offers a predictive framework to characterize intra-tumor heterogeneity and to identify possible interventions to restrict it."
1666,The Breast Cancer Epigenomics Track Hub,"Giovanna Ambrosini, Andrea Agnoletto, Cathrin Brisken, Philipp Bucher",https://www.biorxiv.org/content/10.1101/2022.05.01.490187v1,"Background Pioneering research has shown that high-throughput epigenomics assays such as ChlP-seq and ATAC-seq are applicable to patient-derived breast tumor samples. A host of public data has been accumulated since then, which are potentially of high value for basic research as well as personalized medicine. Such data sets constitute encyclopedias of biological knowledge. However, their impact has so far been limited by access obstacles, especially with regard to extraction and visualization of small portions of data that could potentially answer specific questions arising in a research context."
1667,Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair,"Fabien Aubé, Nicolas Fontrodona, Laura Guiguettaz, Elodie Vallin, Audrey Lapendry, Emiliano P. Ricci, Didier Auboeuf",https://www.biorxiv.org/content/10.1101/2023.06.19.544800v1,"Amino acid bioavailability impacts mRNA translation in a codon depending manner. Here, we report that the anti-cancer MAPK inhibitors (MAPKi) decrease the intracellular concentration of aspartate and glutamate in melanoma cells. This results in the accumulation of ribosomes on codons corresponding to these amino acids and triggers the translation-dependent degradation of mRNAs encoding aspartate- and glutamate-rich proteins mostly involved in DNA metabolism. Consequently, cells that survive to MAPKi degrade aspartate and glutamate to generate energy, which simultaneously decreases their needs in amino acids owing to the downregulation of aspartate- and glutamate-rich proteins involved in cell proliferation. Concomitantly, the downregulation of aspartate- and glutamate-rich proteins involved in DNA repair increases DNA damage loads. Thus, DNA repair defects, and therefore mutations, are, at least in part, a secondary effect of the metabolic adaptation of cells exposed to MAPKi."
1668,"Dopamine functionalized, red carbon quantum dots for in vivo bioimaging, cancer therapeutics, and neuronal differentiation","Pankaj Yadav, Dawson Benner, Ritu Varshney, Krupa Kansara, Krupa Shah, Landon Dahle, Ashutosh Kumar, Rakesh Rawal, Sharad Gupta, Dhiraj Bhatia",https://www.biorxiv.org/content/10.1101/2023.06.16.545347v1,"One of the crucial requirements of quantum dots for biological applications is their surface modifications for very specific and enhanced biological recognition and uptake. Toward this, we present the green synthesis of bright, red-emitting carbon quantum dots derived from mango leaf extract (mQDs). These mQDs are conjugated electrostatically with dopamine to form mQDs-dopamine (mQDs: DOPA) bioconjugates. Bright red fluorescence of mQDs was used for bioimaging and uptake in multiple cell lines, tissues, and in vivo models like zebrafish. mQDs exhibited the highest uptake in brain tissue as compared to others. mQD:DOPA conjugate induced cellular toxicity only in cancer cells while showing increased uptake in epithelial cells and zebrafish. Additionally, the mQDs: DOPA promoted neuronal differentiation of SH-SY5Y cells to complete neurons. Both mQDs and mQDs: DOPA exhibited potential for higher collective cell migrations implicating their future potential as next-generation tools for advanced biological and biomedical applications."
1670,O-GlcNAcylation promotes YTHDF1 cytosolic localization and colorectal cancer tumorigenesis,"Jie Li, Muhammad Ahmad, Lei Sang, Yahui Zhan, Yibo Wang, Yonghong Yan, Yue Liu, Weixiao Mi, Mei Lu, Yu Dai, Rou Zhang, Meng-Qiu Dong, Yun-Gui Yang, Xiaohui Wang, Jianwei Sun, Jing Li",https://www.biorxiv.org/content/10.1101/2022.11.21.517456v1,"O-linked N-acetylglucosamine (O-GlcNAc) is an emerging post-translation modification that couples metabolism with cellular signal transduction by crosstalking with phosphorylation and ubiquitination to orchestrate various biological processes. Herein we show that it modifies the N6-methyladenosine (m6A)-mRNA reader YTHDF1 and fine-tunes its nuclear translocation by the exportin protein Crm1. First we present evidence that YTHDF1 interacts with the sole O-GlcNAc transferase (OGT). Second, we verified the YTHDF1 O-GlcNAcylation sites to be Ser196/Ser197/Ser198, as described in previous numerous chemoproteomic studies. Then we constructed the O-GlcNAc-deficient YTHDF1-S196AS197FS198A (AFA) mutants, which significantly attentuated O-GlcNAc signals. Moreover, we revealed that YTHDF1 is a nucleocytoplasmic protein, whose nuclear export is mediated by Crm1. Furthermore, O-GlcNAcylation increases the cytosolic portion of YTHDF1 by enhancing binding with Crm1, thus upregulating the downstream target (e.g. c-Myc) expression. Molecular dynamics simulations suggest that O-GlcNAcylation at S197 might promote the binding between the nuclear export signal motif and Crm1 through increasing hydrogen bonding. Mouse xenograft assays further demonstrate that YTHDF1-AFA mutants decreased the colon cancer mass and size via decreasing c-Myc expression. In sum, we found that YTHDF1 is a nucleocytoplasmic protein, whose cytosolic localization is dependent on O-GlcNAc modification. We propose that the OGT-YTHDF1-c-Myc axis might underlie colorectal cancer tumorigenesis."
1671,Computational Pipeline to Identify Gene signatures that Define Cancer Subtypes,"Ekansh Mittal, Vatsal Parikh, Raphael Kirchgaessner",https://www.biorxiv.org/content/10.1101/2022.11.20.517258v1,"Motivation The heterogeneous nature of cancers with multiple subtypes makes them challenging to treat. However, multi-omics data can be used to identify new therapeutic targets and we established a computational strategy to improve data mining."
1673,TCR-engineered T-cells directed against Ropporin-1 constitute a safe and effective treatment for triple-negative breast cancer in near-clinical models,"Dian Kortleve, Dora Hammerl, Mandy v Brakel, Rebecca Wijers, Daphne Roelofs, Kim Kroese, Mieke Timmermans, Chen-Yi Liao, Anita Trapman-Jansen, Renée Foekens, Justine Michaux, Monique de Beijer, Sonja I. Buschow, Jeroen A.A. Demmers, Marleen Kok, Erik H.J. Danen, Michal Bassani-Sternberg, John W. Martens, Rachel J.M. Abbott, Reno Debets",https://www.biorxiv.org/content/10.1101/2024.01.10.574978v1,"Triple-negative breast cancer (TNBC) shows an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T-cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. HLA-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCRs) from naïve repertoires. Following gene introduction into T-cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize non-cognate epitopes from alternative source proteins. Notably, this TCR mediated killing of three-dimensional tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T-cells as a treatment for the vast majority of TNBC patients."
1676,Uncovering Alterations in Cancer Epigenetics via Trans-Dimensional Markov Chain Monte Carlo and Hidden Markov Models*,"Farhad Shokoohi, Saeedeh Hajebi Khaniki",https://www.biorxiv.org/content/10.1101/2023.06.15.545168v1,"Epigenetic alterations are key drivers in the development and progression of cancer. Identifying differentially methylated cytosines (DMCs) in cancer samples is a crucial step toward understanding these changes. In this paper, we propose a trans-dimensional Markov chain Monte Carlo (TMCMC) approach that uses hidden Markov models (HMMs) with binomial emission, and bisulfite sequencing (BS-Seq) data, called DMCTHM, to identify DMCs in cancer epigenetic studies. We introduce the Expander-Collider penalty to tackle under and overestimation in TMCMC-HMMs. We address all known challenges inherent in BS-Seq data by introducing novel approaches for capturing functional patterns and autocorrelation structure of the data, as well as for handling missing values, multiple covariates, multiple comparisons, and family-wise errors. We demonstrate the effectiveness of DMCTHM through comprehensive simulation studies. The results show that our proposed method outperforms other competing methods in identifying DMCs. Notably, with DMCTHM, we uncovered new DMCs and genes in Colorectal cancer that were significantly enriched in the Tp53 pathway."
1677,Deconvolution reveals compositional differences in high-grade serous ovarian cancer subtypes,"Ariel A. Hippen, Natalie R. Davidson, Mollie E. Barnard, Lukas M. Weber, Jason Gertz, Jennifer A. Doherty, Stephanie C. Hicks, Casey S. Greene",https://www.biorxiv.org/content/10.1101/2023.06.14.544991v1,"Ovarian cancer is a deadly disease with few effective therapies. The most common form is high-grade serous ovarian cancer (HGSOC). Transcriptomic subtypes of HGSOC have shown promise in characterizing tumor heterogeneity and are associated with survival. Gene expression signatures for the subtypes suggest variation in stromal cell types in the tumor microenvironment (TME). Here, we characterize the TME composition of HGSOC on a population scale by performing deconvolution on bulk transcriptomic data. We use comprehensive cell type profiles from 164 HGSOC tumor samples from two independent reference datasets, in order to compare cell type proportions across and within bulk transcriptomic datasets, and assess their alignment to the subtypes proposed by The Cancer Genome Atlas. We also assess the relationship between tumor composition and clinical outcomes. Our results suggest that HGSOC transcriptomic subtypes are driven by TME composition, specifically fibroblast and immune cell content, and we propose a modified HGSOC subtype model informed by cell composition."
1678,ADAM11 a novel regulator of Wnt and BMP4 signaling in neural crest and cancer,"Ankit Pandey, Hélène Cousin, Brett Horr, Dominique Alfandari",https://www.biorxiv.org/content/10.1101/2023.06.13.544797v1,"Cranial neural crest (CNC) cells are induced at the border of the neural plate by a combination of FGF, Wnt, and BMP4 signaling. CNC then migrate ventrally and invade ventral structures where they contribute to craniofacial development. Here we show that a non-proteolytic ADAM, Adam11, originally identified as a putative tumor suppressor binds to proteins of the Wnt and BMP4 signaling pathway. Mechanistic studies concerning these non-proteolytic ADAM lack almost entirely. We show that Adam11 positively regulates BMP4 signaling while negatively regulating β-catenin activity. By modulating these pathways, Adam11 controls the timing of neural tube closure and the proliferation and migration of CNC. Using both human tumor data and mouse B16 melanoma cells, we further show that ADAM11 levels similarly correlate with Wnt or BMP4 activation levels. We propose that ADAM11 preserve naïve cells by maintaining low Sox3 and Snail/Slug levels through stimulation of BMP4 and repression of Wnt signaling, while loss of ADAM11 results in increased Wnt signaling, increased proliferation and early epithelium to mesenchyme transition."
1680,Phosphatidylserine-exposing medium/large extracellular vesicles: potential cancer biomarkers,"Gloria I. Perez, Matthew P. Bernard, Daniel Vocelle, Ahmed A. Zarea, Doug Schneider, Maxine Bauzon, Terry Hermiston, Masamitsu Kanada",https://www.biorxiv.org/content/10.1101/2022.11.17.516966v1,"Under physiological conditions, phosphatidylserine (PS) predominantly localizes to the cytosolic leaflet of the plasma membrane of cells. During apoptosis, PS is exposed on the cell surface and serves as an “eat-me” signal for macrophages to prevent releasing self-immunogenic cellular components from dying cells which could potentially lead to autoimmunity. However, increasing evidence indicates that viable cells can also expose PS on their surface. Interestingly, tumor cell-derived extracellular vesicles (EVs) also externalize PS. Recent studies have proposed PS-exposing EVs as a potential biomarker for the early detection of cancer and other diseases. However, there are confounding results regarding subtypes of PS-positive EVs, and knowledge of PS exposure on the EV surface requires further elucidation. In this study, we enriched small EVs (sEVs) and medium/large EVs (m/lEVs) from conditioned media of breast cancer cells (MDA-MB-231, MDA-MB-468) and non-cancerous cells (keratinocytes, fibroblasts). Since several PS-binding molecules are available to date, we compared recombinant proteins of annexin A5 and the carboxylated glutamic acid domain of Protein S (GlaS), also specific for PS, to detect PS-exposing EVs. Firstly, PS externalization in each EV fraction was analyzed using a bead-based EV assay, which combines EV capture using microbeads and analysis of PS-exposing EVs by flow cytometry. The bulk EV assay showed higher PS externalization in m/lEVs derived from MDA-MB-468 cells but not from MDA-MB-231 cells, while higher binding of GlaS was also observed in m/lEVs from fibroblasts. Second, using single EV flow cytometry, PS externalization was also analyzed on individual sEVs and m/lEVs. Significantly higher PS externalization was detected in m/lEVs (annexin A1+) derived from cancer cells compared to m/lEVs (annexin A1+) from non-cancerous cells. These results emphasize the significance of PS-exposing m/lEVs as an undervalued EV subtype for early cancer detection and provide a better understanding of PS externalization in disease-associated EV subtypes."
1681,Hyperglycosylation of prosaposin in tumor DCs promotes immune escape in cancer,"Pankaj Sharma, Xiaolong Zhang, Kevin Ly, Ji Hyung Kim, Qi Wan, Jessica Kim, Mumeng Lou, Lisa Kain, Luc Teyton, Florian Winau",https://www.biorxiv.org/content/10.1101/2023.06.14.545005v1,"Tumors develop strategies to evade immunity by suppressing antigen presentation. Here, we show that prosaposin drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor DCs leads to cancer immune escape. We found that lysosomal prosaposin and its single saposin cognates mediated disintegration of tumor cell-derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, TGF-β induced hyperglycosylation of prosaposin and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. In melanoma patients, we found similar prosaposin hyperglycosylation in tumor-associated DCs, and reconstitution with prosaposin rescued activation of tumor-infiltrating T cells. Targeting tumor DCs with recombinant prosaposin triggered cancer protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of prosaposin in tumor immunity and escape and introduce a novel principle of prosaposin-based cancer immunotherapy."
1682,Musashi-2 (MSI2) regulation of DNA damage response in lung cancer,"Igor Bychkov, Alexander Deneka, Iuliia Topchu, Rajendra P. Pangeni, Christopher Lengner, John Karanicolas, Erica A. Golemis, Petr Makhov, Yanis Boumber",https://www.biorxiv.org/content/10.1101/2023.06.13.544756v1,"Lung cancer is one of the most common types of cancers worldwide. Non-small cell lung cancer (NSCLC), typically caused by KRAS and TP53 driver mutations, represents the majority of all new lung cancer diagnoses. Overexpression of the RNA-binding protein (RBP) Musashi-2 (MSI2) has been associated with NSCLC progression. To investigate the role of MSI2 in NSCLC development, we compared the tumorigenesis in mice with lung-specific Kras-activating mutation and Trp53 deletion, with and without Msi2 deletion (KP versus KPM2 mice). KPM2 mice showed decreased lung tumorigenesis in comparison with KP mice what supports published data. In addition, using cell lines from KP and KPM2 tumors, and human NSCLC cell lines, we found that MSI2 directly binds ATM/Atm mRNA and regulates its translation. MSI2 depletion impaired DNA damage response (DDR) signaling and sensitized human and murine NSCLC cells to treatment with PARP inhibitors in vitro and in vivo. Taken together, we conclude that MSI2 supports lung tumorigenesis, in part, by direct positive regulation of ATM protein expression and DDR. This adds the knowledge of MSI2 function in lung cancer development. Targeting MSI2 may be a promising strategy to treat lung cancer."
1684,The homeodomain drives favorable DNA binding energetics of prostate cancer target ONECUT2,"Avradip Chatterjee, Brad Gallent, Madhusudhanarao Katiki, Chen Qian, Matthew R. Harter, Michael R. Freeman, Ramachandran Murali",https://www.biorxiv.org/content/10.1101/2023.06.13.544830v1,"The ONECUT transcription factors feature a CUT and a homeodomain, evolutionarily conserved elements that bind DNA cooperatively, but the process remains mechanistically enigmatic. Using an integrative DNA binding analysis of ONECUT2, a driver of aggressive prostate cancer, we show that the homeodomain energetically stabilizes the ONECUT2-DNA complex through allosteric modulation of CUT. Further, evolutionarily conserved base-interactions in both the CUT and homeodomain are necessary for the favorable thermodynamics. We have identified a novel arginine pair unique to the ONECUT family homeodomain that can adapt to DNA sequence variations. Base interactions in general, including by this arginine pair, are critical for optimal DNA binding and transcription in a prostate cancer model. These findings provide fundamental insights into DNA binding by CUT-homeodomain proteins with potential therapeutic implications."
1685,The repertoire of copy number alteration signatures in human cancer,"Ziyu Tao, Shixiang Wang, Chenxu Wu, Tao Wu, Xiangyu Zhao, Wei Ning, Guangshuai Wang, Jinyu Wang, Jing Chen, Kaixuan Diao, Fuxiang Chen, Xue-Song Liu",https://www.biorxiv.org/content/10.1101/2022.11.14.516412v1,"Copy number alterations (CNAs) are a predominant source of genetic alterations in human cancer and play an important role in cancer progression. However comprehensive understanding of the mutational processes and signatures of CNA is still lacking. Here we developed a mechanism-agnostic method to categorize CNA based on various fragment properties, which reflect the consequences of mutagenic processes and can be extracted from different types of data, including whole genome sequencing (WGS) and SNP array. The 14 signatures of CNA have been extracted from 2778 pan-cancer analysis of whole genomes (PCAWG) WGS samples, and further validated with 10851 the cancer genome atlas (TCGA) SNP array dataset. Novel patterns of CNA have been revealed through this study. The activities of some CNA signatures consistently predict cancer patients’ prognosis. This study provides a repertoire for understanding the signatures of CNA in cancer, with potential implications for cancer prognosis, evolution, and etiology."
1686,The Application of Label-free Detection Using a Tapered Optical Fiber System for Head and Neck Cancer and Infectious Biomolecules,"Casey Collet, Cong Deng, Chaminda Ranathunga, Partha P. Banerjee, De-Chen Lin, Uttam Sinha",https://www.biorxiv.org/content/10.1101/2023.09.25.559133v1,"Introduction Head and neck squamous cell carcinoma (HNSCC) is associated with high morbidity and mortality due to late detection. Tapered optical fiber sensors (TOFS) are biosensors with the potential application as a point-of-care device for detection of HNSCC biomarkers. TOFS uses optical fibers as transduction elements and antigen-antibody binding for the detection of target biomolecules. The present TOFS system was designed to achieve high specificity, sensitivity, and repeatability. To explore its application in HNSCC, we targeted the proinflammatory cytokine IL-8, known for its role in promoting tumorigenicity, metastasis, and angiogenesis in HNSCC. To validate our proof-of-concept experiment, a viral surrogate of SARS-CoV-2, Human Coronavirus OC43 (HCoV-OC43), was also tested."
1687,IRAK1 is a critical mediator of low molecular weight hyaluronic acid-induced stemness in high-grade serous ovarian cancer,"David Standing, Prasad Dandawate, Sumedha Gunewardena, Obdulia Covarrubias-Zambrano, Katherine F. Roby, Dineo Khabele, Andrea Jewell, Ossama Tawfik, Stefan H. Bossmann, Andrew K. Godwin, Scott J. Weir, Roy A. Jensen, Shrikant Anant",https://www.biorxiv.org/content/10.1101/2023.09.25.559366v1,"Advanced epithelial ovarian cancer (EOC) survival rates are dishearteningly low, with ∼25% surviving beyond 5 years. Evidence suggests that cancer stem cells (CSCs) contribute to acquired chemoresistance and tumor recurrence. Here, we show that IRAK1 is upregulated in EOC tissues, and enhanced expression correlates with poorer overall survival. IRAK1 and BRCA1/2 mutation status are mutually exclusive. Moreover, low molecular weight hyaluronic acid (LMW HA), which is abundant in malignant ascites from patients with advanced EOC, induced IRAK1 phosphorylation leading to STAT3 activation and enhanced spheroid formation. Knockdown of IRAK1 impaired tumor growth in peritoneal disease models, and impaired HA-induced spheroid growth and STAT3 phosphorylation. Finally, we determined that TCS2210, a known inducer of neuronal differentiation in mesenchymal stem cells, is a selective inhibitor of IRAK1. TCS2210 significantly inhibited EOC growth in vitro and in vivo both as monotherapy, and in combination with cisplatin. Collectively, these data demonstrate IRAK1 as a druggable target for EOC."
1688,Targeting Ras signaling excitability in cancer cells through combined inhibition of FAK and PI3K,"Chao-Cheng Chen, Suyang Wang, Jr-Ming Yang, Chuan-Hsiang Huang",https://www.biorxiv.org/content/10.1101/2023.06.12.544386v1,"The Ras/PI3K/ERK signaling network is frequently mutated in various human cancers including cervical cancer and pancreatic cancer. Previous studies showed that the Ras/PI3K/ERK signaling network displays features of excitable systems including propagation of activity waves, all-or-none responses, and refractoriness. Oncogenic mutations lead to enhanced excitability of the network. A positive feedback loop between Ras, PI3K, the cytoskeleton, and FAK was identified as a driver of excitability. In this study, we investigated the effectiveness of targeting signaling excitability by inhibiting both FAK and PI3K in cervical and pancreatic cancer cells. We found that the combination of FAK and PI3K inhibitors synergistically suppressed the growth of select cervical and pancreatic cancer cell lines through increased apoptosis and decreased mitosis. In particular, FAK inhibition caused downregulation of PI3K and ERK signaling in cervical cancer but not pancreatic cancer cells. Interestingly, PI3K inhibitors activated multiple receptor tyrosine kinases (RTKs), including insulin receptor and IGF-1R in cervical cancer cells, as well as EGFR, Her2, Her3, Axl, and EphA2 in pancreatic cancer cells. Our results highlight the potential of combining FAK and PI3K inhibition for treating cervical and pancreatic cancer, although appropriate biomarkers for drug sensitivity are needed, and concurrent targeting of RTKs may be required for resistant cells."
1690,Cell-free chromatin particles activate immune checkpoints in human T cells: Implications for cancer therapy,"Snehal Shabrish, Kavita Pal, Naveen Kumar Khare, Dharana Satsangi, Aishwarya Pilankar, Vishalkumar Jadhav, Sushma Shinde, Nimisha Raphael, Gaurav Sriram, Relestina Lopes, Gorantla V. Raghuram, Harshali Tandel, Indraneel Mittra",https://www.biorxiv.org/content/10.1101/2023.06.09.544311v1,"Immune checkpoint blockade is an exciting breakthrough in cancer therapy, but how immune checkpoints are activated is unknown. We have earlier reported that cell-free chromatin particles (cfChPs) that circulate in the blood, or those that are released locally from dying cells, are readily internalized by healthy cells with biological consequences. Here we show that treatment of human lymphocytes with cfChPs isolated from sera of cancer patients led to marked activation of immune checkpoints viz. PD-1, CTLA-4, LAG-3, NKG2A, and TIM-3. Concurrently activated were stress-related markers cJun, cFos, JunB, FosB, NFКB, and EGR1. The above immune checkpoints were also activated when lymphocytes were treated with cfChPs released from dying HeLa cells; the latter could be abrogated by three cfChPs deactivating agents. These results suggest that immune checkpoints are activated by lymphocytes as stress response to cfChPs. Simultaneous downregulation of multiple immune checkpoints may herald a new approach to immunotherapy of cancer."
1691,Identifying gastric cancer molecular subtypes by integrating DNA-based hierarchical classification strategy and clinical stratification,"Binyu Yang, Siying Liu, Jiemin Xie, Xi Tang, Pan Guan, Yifan Zhu, Li C. Xia",https://www.biorxiv.org/content/10.1101/2023.06.09.544302v1,"Background Molecular subtyping has been introduced to better understand the genetic landscape of gastric cancer (GC), but current subtyping methods only had limited success because of the mixed use of molecular features, a lack of strategy optimization, and the limited availability of GC samples. The community urgently calls for a precise, and easily adoptable subtyping method to enable DNA-based early screening and treatment."
1692,Integrative pan-cancer analysis reveals a common architecture of dysregulated transcriptional networks characterized by loss of enhancer methylation,"Jørgen Ankill, Zhi Zhao, Xavier Tekpli, Elin H. Kure, Vessela N. Kristensen, Anthony Mathelier, Thomas Fleischer",https://www.biorxiv.org/content/10.1101/2023.09.22.559009v1,"Aberrant DNA methylation contributes to gene expression deregulation in cancer. However, these alterations’ precise regulatory role and clinical implications are still not fully understood. In this study, we performed expression-methylation Quantitative Trait Loci (emQTL) analysis to identify deregulated cancer-driving transcriptional networks linked to CpG demethylation pan-cancer. By analyzing 33 cancer types from The Cancer Genome Atlas, we identified and confirmed significant correlations between CpG methylation and gene expression (emQTL) in cis and trans, both across and within cancer types. Bipartite network analysis of the emQTL revealed groups of CpGs and genes related to important biological processes involved in carcinogenesis; specifically, we identified three types of emQTL networks associated with alterations linked to the regulation of proliferation, metabolism, and hormone-signaling. These bipartite communities were characterized by loss of enhancer methylation in transcription factor binding regions (TFBRs) located in enhancers. The underlying CpGs were topologically linked to upregulated genes through chromatin loops. Loss of enhancer methylation and target genes were exemplified in pancreatic cancer. Penalized Cox regression analysis showed a significant prognostic impact of the pan-cancer emQTL. Taken together, our integrative pan-cancer analysis reveals a common architecture of aberrant DNA demethylation that illustrates a convergence of pathological regulatory mechanisms across cancer types."
1693,ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer,"Yuuki Ohara, Amanda J. Craig, Huaitian Liu, Shouhui Yang, Paloma Moreno, Tiffany H. Dorsey, Helen Cawley, Azadeh Azizian, Jochen Gaedcke, Michael Ghadimi, Nader Hanna, Stefan Ambs, S. Perwez Hussain",https://www.biorxiv.org/content/10.1101/2023.09.23.558894v1,"Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes classified as classical/progenitor and basal-like/squamous. We hypothesized that integrative transcriptomic and metabolomic approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and validation cohorts. We found that decreased ELAPOR1 expression was significantly associated with high pathological grade, advanced disease stage, the basal-like/squamous subtype, and decreased survival in PDAC patients. In vitro experiments showed that ELAPOR1 transgene expression inhibited migration and invasion of PDAC cells. Metabolomic analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-methylnicotinamide, an oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptomic and metabolomic characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. This positions ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC."
1694,Chitinase 3-like-1 (CHI3L1) in the Pathogenesis of Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer,"Suchitra Kamle, Bing Ma, Gail Schor, Madison Bailey, Brianna Pham, Inyoung Cho, Hina Khan, Christopher Azzoli, Mara Hofstetter, Chang-Min Lee, Roy Herbst, Katerina Politi, Chun Geun Lee, Jack A. Elias",https://www.biorxiv.org/content/10.1101/2023.09.21.558861v1,"Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In NSCLC, 10-20% of Caucasian patients and 30-50% of Asian patients have tumors with activating mutations in the Epidermal Growth Factor Receptor (EGFR). A high percentage of these patients exhibit favorable responses to treatment with tyrosine kinase inhibitors (TKI). Unfortunately, a majority of these patients develop therapeutic resistance with progression free survival lasting 9-18 months. The mechanisms that underlie the tumorigenic effects of EGFR and the ability of NSCLC to develop resistance to TKI therapies, however, are poorly understood. Here we demonstrate that CHI3L1 is produced by EGFR activation of normal epithelial cells, transformed epithelial cells with wild type EGFR and cells with cancer-associated, activating EGFR mutations. We also demonstrate that CHI3L1 auto-induces itself and feeds back to stimulate EGFR and its ligands. Highly specific antibodies against CHI3L1 (anti-CHI3L1/FRG) and TKI, individually and in combination, abrogated the effects of EGFR activation on CHI3L1 and the ability of CHI3L1 to stimulate the EGFR axis. Anti-CHI3L1 also interacted with osimertinib to reverse TKI therapeutic resistance and induce tumor cell death and inhibit pulmonary metastasis while stimulating tumor suppressor genes including KEAP1. CHI3L1 is a downstream target of EGFR that feeds back to stimulate and activate the EGFR axis. Anti-CHI3L1 is an exciting potential therapeutic for EGFR mutant NSCLC, alone and in combination with osimertinib or other TKIs."
1696,Oncogenic functions of the m6A demethylase FTO in breast cancer cells involving translational upregulation of C/EBPβ-LIP,"Hidde R. Zuidhof, Christine Müller, Gertrud Kortman, René Wardenaar, Ekaterina Stepanova, Fabricio Loayza-Puch, Cornelis F. Calkhoven",https://www.biorxiv.org/content/10.1101/2023.09.21.558784v1,"N6-methyladenosine (m6A) is a prevalent posttranscriptional mRNA modification involved in the regulation of transcript turnover, translation, and other aspects of RNA fate. The modification is mediated by multicomponent methyltransferase complexes (so-called writers) and is reversed through the action of the m6A-demethylases fat mass and obesity-associated (FTO) and alkB homolog 5 (ALKBH5) (so-called erasers). FTO promotes cell proliferation, colony formation and metastasis in models of triple-negative breast cancer (TNBC). However, little is known about genome-wide or specific downstream regulation by FTO. Here, we examined changes in the genome-wide transcriptome and translatome following FTO-knockdown in TNBC cells. Unexpectedly, FTO knockdown had a limited effect on the translatome, while transcriptome analysis revealed that genes related to extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) are being regulated through yet unidentified mechanisms. Differential translation of the CEBPB mRNA into the C/EBPβ transcription factor isoform C/EBPβ-LIP is known to act pro-oncogenic in TNBC cells through regulation of EMT genes. Here we show that FTO is required for efficient C/EBPβ-LIP expression, suggesting that FTO has oncogenic functions through regulation of C/EBPβ-LIP."
1697,Generalization of deep learning models for predicting spatial gene expression profiles using histology images: A breast cancer case study,"Yuanhao Jiang, Jacky Xie, Xiao Tan, Nan Ye, Quan Nguyen",https://www.biorxiv.org/content/10.1101/2023.09.20.558624v1,"Spatial transcriptomics is a breakthrough technology that enables spatially-resolved measurement of molecular profiles in tissues, opening the opportunity for integrated analyses of morphology and transcriptional profiles through paired imaging and gene expression data. However, the high cost of generating data has limited its widespread adoption. Predicting gene expression profiles from histology images only can be an effective and cost-efficient in-silico spatial transcriptomics solution but is computationally challenging and current methods are limited in model performance. To advance research in this emerging and important field, this study makes the following contributions. We first provide a systematic review of deep learning methods for predicting gene expression profiles from histology images, highlighting similarities and differences in algorithm, model architecture, and data processing pipelines. Second, we performed extensive experiments to evaluate the generalization performance of the reviewed methods on several spatial transcriptomics datasets for breast cancer, where the datasets are generated using different technologies. Lastly, we propose several ideas for model improvement and empirically investigate their effectiveness. Our results shed insight on key features in a neural network model that either improve or not the performance of in-silico spatial transcriptomics, and we highlight challenges in developing algorithms with strong generalization performance."
1698,The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer,"W. J. McDaid, L. Wilson, H. Adderley, M. J. Baker, J. Searle, L. Ginn, T. Budden, M. Aldea, A. Marinello, J. Aredo, A. Viros, B. Besse, H. A. Wakelee, F. Blackhall, C. R. Lindsay, A. Malliri",https://www.biorxiv.org/content/10.1101/2023.09.20.558592v1,"Introduction KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms."
1701,"3-epicaryoptin induces G2/M phase cell cycle arrest and apoptosis in human breast cancer cells by disrupting the microtubule network, an in vitro and in silico investigation","Manabendu Barman, Sujit Roy, Nanda Singh, Debanjan Sarkar, Niharendu Barman, Amit Pal, Sankar Bhattacharyya, Sanjib Ray",https://www.biorxiv.org/content/10.1101/2024.01.04.574171v1,"Breast cancer (BC) is a prevalent form of cancer observed in women across the globe, constituting over a quarter of all female BC cases. The treatment of BC continues to require significant efficacy, aiming to achieve high success rates while minimizing adverse effects on the body as a whole. In the current study, 3-epicaryoptin was tested for the molecular mechanism of its anti-cancer activity in the human breast cancer cell line, MCF-7. We investigated cell viability by MTT assay, cell cycle kinetics and apoptosis, immunofluorescence straining, molecular modelling, and ADMET profiling. MTT assay results showed that 3-epicaryoptin was found cytotoxic against MCF-7 cells with an IC50 value of 344.64 µg mL-1 for 48 h. Flow cytometric analysis exhibited that 3-epicaryoptin halted the MCF-7 cells in the G2/M phase and subsequently induced apoptosis in a time-dependent manner. Our immunofluorescence studies indicated that 3-epicaryoptin inhibited microtubule polymerization in MCF-7 cells. Furthermore, molecular docking followed by molecular dynamics (MD) simulation studies demonstrated the ability of 3-epicaryoptin to interact with the tubulin protein at the colchicine binding pockets. Overall, our results suggest that 3-epicaryoptin can inhibit the proliferation of human breast cancer cells by depolymerizing of cellular microtubule networks, which causes cell cycle arrest and promotes apoptotic cell death. Therefore, it has been indicated that the natural product 3-epicaryoptin exhibited considerable promise as a potent therapeutic agent capable of inducing apoptosis in breast cancer cells."
1702,PAX8 expressing epithelial cells are a cancer-prone source of clonal cyclical regeneration of endometrial epithelium,"Dah-Jiun Fu, Andrea J. De Micheli, Mallikarjun Bidarimath, Lora H. Ellenson, Benjamin D. Cosgrove, Andrea Flesken-Nikitin, Alexander Yu Nikitin",https://www.biorxiv.org/content/10.1101/853994v2,"bioRxiv has withdrawn this manuscript after a formal investigation by Cornell University that concluded that it was submitted and made public without listing all contributing authors. The list of authors in this preprint should have been: Dah-Jiun Fu, Andrea J. De Micheli, Blaine A. Harlan, Mallikarjun Bidarimath, Minseok Kim, Lora H. Ellenson, Benjamin D. Cosgrove, Andrea Flesken-Nikitin and Alexander Yu. Nikitin, with DJF, AJDM and BAH indicated as equal contributors. Therefore, this work should not be cited as reference for the project. If you have any questions, please contact the corresponding authors."
1703,Pan-cancer analysis of patient tumor single-cell transcriptomes identifies promising selective and safe CAR targets in head and neck cancer,"Sanna Madan, Sanju Sinha, Silvio J. Gutkind, Ezra E. W. Cohen, Alejandro A. Schäffer, Eytan Ruppin",https://www.biorxiv.org/content/10.1101/2021.09.29.462485v2,"BACKGROUND: Chimeric antigen receptor (CAR) T cell therapies have yielded transformative clinical success for patients with blood tumors, but their full potential remains to be unleashed against solid tumors. One challenge is finding selective targets: cell surface proteins that are expressed widely by cancer cells and minimally by healthy cells in the tumor microenvironment and other normal tissues."
1704,Prostate-derived circulating microRNAs add prognostic value to prostate cancer risk calculators,"Morgan L. Zenner, Brenna Kirkpatrick, Trevor R. Leonardo, Michael J. Schlicht, Alejandra Cavazos Saldana, Candice Loitz, Klara Valyi-Nagy, Mark Maienschein-Cline, Peter H. Gann, Michael Abern, Larisa Nonn",https://www.biorxiv.org/content/10.1101/2023.05.10.540236v2,"Prostate cancer is the second leading cause of malignancy-related deaths among American men. Active surveillance is a safe option for many men with less aggressive disease, yet definitively determining low-risk cancer is challenging with biopsy alone. Herein, we sought to identify prostate-derived microRNAs in patient sera and serum extracellular vesicles, and determine if those microRNAs improve upon the current clinical risk calculators for prostate cancer prognosis before and after biopsy. Prostate-derived intracellular and extracellular vesicle-contained microRNAs were identified by small RNA sequencing of prostate cancer patient explants and primary cells. Abundant microRNAs were included in a custom microRNA PCR panel that was queried in whole serum and serum extracellular vesicles from a diverse cohort of men diagnosed with prostate cancer. The levels of these circulating microRNAs significantly differed between indolent and aggressive disease and improved the area under the curve for pretreatment nomograms of prostate cancer disease risk. The microRNAs within the extracellular vesicles had improved prognostic value compared to the microRNAs in the whole serum. In summary, quantifying microRNAs circulating in extracellular vesicles is a clinically feasible assay that may provide additional information for assessing prostate cancer risk stratification."
1705,"Single-cell RNA-seq analysis profiling characterizes differences in cell composition and physiology between normal tissue, treatment naive, and cisplatin-treated ovarian cancer","Fang Guo, Zhi Yang, Jalid Sehouli, Andreas M. Kaufmann",https://www.biorxiv.org/content/10.1101/2024.01.02.573967v1,"Background Intense efforts have focused on identifying heterogeneity of the cellular composition in ovarian cancer. However, tissue composition and physiological conditions of cancer cells in cisplatin-sensitive ovarian cancer remains largely unknown. Moreover, comparisons of different cellular states in normal tissue, in treatment naive ovarian cancer, and in cisplatin-treated tissue after adjuvant therapy of cisplatin-sensitive ovarian cancer at the single-cell level might offer clues for ovarian cancer treatment and prevention of cisplatin-resistance formation."
1706,Tumor relapse-free survival prognosis related consistency between cancer tissue and adjacent normal tissue in drug repurposing for solid tumor via connectivity map,"Mingyue Hao, Dandan Li, Yuanyuan Qiao, Ming Xiong, Jun Li, Wei Ma",https://www.biorxiv.org/content/10.1101/2024.01.03.573997v1,"Traditional drug discovery encounters challenges, including high costs, time-intensive processes, and inherent risks. Drug repurposing emerges as a compelling alternative strategy to identify new indications for investigational or approved drugs, circumventing these obstacles. Among the various drug repurposing methods, the Disease-specific Signature-based Connectivity Map (Cmap) approach is widely utilized. However, the commonly employed method for constructing disease-specific signatures, known as Differentially Expressed Genes (DEG), faces issues related to inconsistencies between dysregulated genes and the prognosis of genes in tumor tissue, as well as discrepancies in prognosis genes between tumor and normal tissues."
1707,Global changes in open reading frame dominance of RNAs during cancer initiation and progression,"Yusuke Suenaga, Hiroyuki Kogashi, Kazuma Nakatani, Jason Lin, Yoshinori Hasegawa, Kazuto Kugou, Yusuke Kawashima, Eisaku Furukawa, Kazuhiro Okumura, Emiri Kita, Yuichi Wakabayashi, Mamoru Kato, Masahito Kawazu, Yoshitaka Hippo",https://www.biorxiv.org/content/10.1101/2023.06.02.543339v1,"Cancer cells express unique RNA transcripts; however, the factors determining their translation have remained unclear. We recently developed open reading frame (ORF) dominance as a measure that correlates with coding potential of RNAs. Upon calculating the ORF dominance of cancer-specific transcripts across 24 human tumor types, 14 exhibited significantly higher ORF dominance in cancer than in normal tissues. In organoid-based mouse genetic models, ORF dominance increased with carcinogenesis. Gene ontology analysis revealed that gene sets with increased ORF dominance were associated with cell proliferation, while those with decreased ORF dominance were linked to DNA damage response. Translatome analyses demonstrated that elevated ORF dominance during carcinogenesis resulted in higher translation frequencies of ribosome-bound RNAs. As cancer progressed, ORF dominance showed that the boundary between coding and noncoding transcripts became blurred prior to distant metastasis, indicating decreased proliferative cell populations and increased generation of RNA isoforms that potentially translate neoantigens before the development of metastatic tumors. These findings suggest that cancer evolution leads to dynamic changes in ORF dominance, resulting in global translational alterations in transcriptomes."
1708,ESR1 fusion proteins invoke breast cancer subtype-dependent enrichment of ligand independent pro-oncogenic signatures and phenotypes,"Megan E. Yates, Zheqi Li, Yiting Li, Hannah Guzolik, Xiaosong Wang, Tiantong Liu, Jagmohan Hooda, Jennifer M. Atkinson, Adrian V. Lee, Steffi Oesterreich",https://www.biorxiv.org/content/10.1101/2023.09.18.558175v1,"Breast cancer is a leading cause of female mortality and despite advancements in diagnostics and personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. Fortunately, identification of mechanisms of therapeutic resistance have rapidly transformed our understanding of cancer evasion and is enabling targeted treatment regimens. When the druggable estrogen receptor (ER, ESR1), expressed in two-thirds of all breast cancer, is exposed to endocrine therapy, there is risk of somatic mutation development in approximately 30% of cases and subsequent treatment resistance. A more recently discovered mechanism of ER mediated endocrine resistance is the expression of ER fusion proteins. ER fusions, which retain the protein’s DNA binding domain, harbor ESR1 exons 1-6 fused to an in-frame gene partner resulting in loss of the 3’ ER ligand binding domain (LBD). In this report we demonstrate that in no-special type (NST) and invasive lobular carcinoma (ILC) cell line models, ER fusion proteins exhibit robust hyperactivation of canonical ER signaling pathways independent of the ligand estradiol or anti-endocrine therapies such as Fulvestrant and Tamoxifen. We employ cell line models stably overexpressing ER fusion proteins with concurrent endogenous ER knockdown to minimize the influence of endogenous wildtype ER. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably the MYC pathway. The heterogeneous 3’ fusion partners, particularly transcription factors SOX9 and YAP1, evoked varying degrees of transcriptomic and cistromic activity that translated into unique phenotypic readouts. Herein we report that cell line activity is subtype-, fusion-, and assay-specific suggesting that the loss of the LBD, the 3’ fusion partner, and the cellular landscape all influence fusion activity. Therefore, it will be critical to generate additional data on frequency of the ER fusions, in the context of the clinicopathological features of the tumor."
1709,The pharmacoepigenomic landscape of cancer cell lines reveals the epigenetic component of drug sensitivity,"AJ Ohnmacht, A Rajamani, G Avar, G Kutkaite, E Gonçalves, D Saur, MP Menden",https://www.biorxiv.org/content/10.1101/2023.06.01.543264v1,"Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analysed 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detected the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constituted drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduced anticipated associations, and in addition, we found that the NEK9 promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation of NEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology."
1712,Integrated Analyses of Multi-omic Data Derived from Paired Primary Lung Cancer and Brain Metastasis Reveals the Metabolic Vulnerability as a Novel Therapeutic Target,"Hao Duan, Jianlan Ren, Shiyou Wei, Chuan Li, Zhenning Wang, Meichen Li, Zhi Wei, Zhenyu Yang, Yu Liu, Yuan Xie, Suwen Wu, Wanming Hu, Chengcheng Guo, Xiangheng Zhang, Lun Liang, Chengwei Yu, Yanhao Mou, Yu Jiang, Houde Li, Eric Sugarman, Rebecca A. Deek, Zexin Chen, Likun Chen, Yaohui Chen, Maojin Yao, Lunxu Liu, Gao Zhang, Yonggao Mou",https://www.biorxiv.org/content/10.1101/2024.01.02.573855v1,"Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Here, we performed integrated analyses of genomic, transcriptomic, proteomic and metabolomic data which were derived from a total number of 174 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. We uncovered that LC-BrMs exhibited significantly higher intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry and multiplexed immunofluorescence staining of patients’ paired tumor specimens. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids specific to LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs."
1713,Path analysis of intra-metastatic hypoxia in breast cancer,"Sergio Rey-Keim, Luana Schito",https://www.biorxiv.org/content/10.1101/2022.11.03.515032v1,"Hypoxia (low O2) signals into the nucleus of cancer cells through hypoxia-inducible factor (HIF)-1α-dependent transcription triggering proliferative, metabolic and vascular adaptations linked to therapy resistance and mortality due to overt metastasis. In contrast with the wealth of molecular data on primary intra-tumoral hypoxia, there is a dearth of statistical modelling studies addressing the mechanisms of intra-metastatic hypoxia. In this study, we used path analysis to model intra-metastatic hypoxia (Hx), HIF-1α expression and microvascular area (MVA) as functions of metastatic cross-sectional area (MCSA) in an advanced mouse breast cancer model; in this context, we tested the effect of conventional, maximum-tolerated dose (MTD) or low-dose metronomic (LDM) chemotherapy. Iterative analysis of 34 non-isomorphic paths yielded four well-fitting, configuration-invariant models [χ2(6,171) ≥ 6.12; P ≥ 0.328; CFI ≥ 0.998; RMSEA ≤ 0.07]. All four models contained HIF-1α as a mediating variable within the MCSA↔Hx↔MVA path, as well as significant Hx↔MVA interactions. LDM disrupted the HIF-1α↔MCSA→Hx and HIF-1α↔MVA paths; furthermore, all LDM and MTD combinations impaired Hx↔HIF-1α. These results confirmed well-established hypoxic interactions, whilst uncovering possible differential effects of chemotherapeutic modalities upon metastatic size, hypoxia, HIF-1α and vascularisation. Our data indicate that MVA can act as a downstream readout, rather than an adaptive angiogenic mechanism alleviating intra-metastatic hypoxia. Moreover, well-fitting path models locate HIF-1α activity either upstream or downstream of hypoxia, thereby allowing us to posit the existence of bi-directional feedback loops driving vascularisation and growth in metastatic tumours, of relevance for targeted therapies."
1715,Loss of EIF4G2 Mediates Aggressiveness in Distinct Human Endometrial Cancer Subpopulations with Poorer Survival Outcome in Patients,"Sara Meril, Maya Muhlbauer Avni, Chen Lior, Marcela Bahlsen, Tsviya Olender, Alon Savidor, Judit Krausz, Hila Belhanes Peled, Hila Birisi, Nofar David, Shani Bialik, Ruth Scherz-Shouval, Yehuda Ben David, Adi Kimchi",https://www.biorxiv.org/content/10.1101/2023.09.14.557672v1,"The non-canonical translation initiation factor EIF4G2 plays essential roles in embryonic development and differentiation, and contributes to the cellular stress response via translation of selective mRNA cohorts. Currently there is limited and conflicting information regarding the potential involvement of EIF4G2 in cancer development and progression. Endometrial cancer (EC) is the most pervasive gynecological cancer in the developed world, with increasing incidence every year. High grade ECs are largely refractory to conventional treatments, presenting poor survival rates and lacking suitable prognostic markers. Here we assayed a cohort of 280 EC patients across different types, grades, and stages, and found that low EIF4G2 expression highly correlated with poor overall and recurrence free survival in Grade 2 EC patients, monitored over a period of up to 12 years. To establish a causative connection between low EIF4G2 expression and cancer progression, we analyzed in parallel two independent human EC cell lines and demonstrated that stable EIF4G2 knock-down resulted in increased resistance to conventional therapies. Depletion of EIF4G2 also increased the prevalence of molecular markers for aggressive cell subsets, and altered their transcriptional and proteomic landscapes. Prominent among the proteins with decreased abundance were Kinesin-1 motor proteins KIF5B and KLC1, 2, 3. Multiplexed imaging of the tumors from this EC patient cohort showed a correlation between decreased protein expression of either KIF5B or KLC1, and poor survival in patients of certain grades and stages. The findings herein reveal potential novel biomarkers for Grade 2 EC with potential ramifications for patient stratification and therapeutic interventions."
1717,Integrative identification of non-coding regulatory regions driving metastatic prostate cancer,"Brian J Woo, Ruhollah Moussavi-Baygi, Heather Karner, Mehran Karimzadeh, Kristle Garcia, Tanvi Joshi, Keyi Yin, Albertas Navickas, Luke A. Gilbert, Bo Wang, Hosseinali Asgharian, Felix Y. Feng, Hani Goodarzi",https://www.biorxiv.org/content/10.1101/2023.04.14.535921v2,"Large-scale sequencing efforts of thousands of tumor samples have been undertaken to understand the mutational landscape of the coding genome. However, the vast majority of germline and somatic variants occur within non-coding portions of the genome. These genomic regions do not directly encode for specific proteins, but can play key roles in cancer progression, for example by driving aberrant gene expression control. Here, we designed an integrative computational and experimental framework to identify recurrently mutated non-coding regulatory regions that drive tumor progression. Application of this approach to whole-genome sequencing (WGS) data from a large cohort of metastatic castration-resistant prostate cancer (mCRPC) revealed a large set of recurrently mutated regions. We used (i) in silico prioritization of functional non-coding mutations, (ii) massively parallel reporter assays, and (iii) in vivo CRISPR-interference (CRISPRi) screens in xenografted mice to systematically identify and validate driver regulatory regions that drive mCRPC. We discovered that one of these enhancer regions, GH22I030351, acts on a bidirectional promoter to simultaneously modulate expression of U2-associated splicing factor SF3A1 and chromosomal protein CCDC157. We found that both SF3A1 and CCDC157 are promoters of tumor growth in xenograft models of prostate cancer. We nominated a number of transcription factors, including SOX6, to be responsible for higher expression of SF3A1 and CCDC157. Collectively, we have established and confirmed an integrative computational and experimental approach that enables the systematic detection of non-coding regulatory regions that drive the progression of human cancers."
1719,The ALDH1A3 Reporter Construct: A Novel Mechanism of Identifying and Tracking the Breast Cancer Stem Cell Population,"Nick Philbin, Ellen M. Laurie, Bre-Anne Fifield, Lisa Ann Porter",https://www.biorxiv.org/content/10.1101/2023.09.14.557721v2,"Cancer stem cells lie at the heart of progression and relapse for many solid tumours including breast cancers. The Breast Cancer Stem Cell (BCSC) population is typically isolated via a combination of markers utilizing various staining techniques which prevents the ability to track dynamic changes in expression and to dissect the role in pathogenesis overtime. Here we report the development of a reporter for the expression of Aldehyde Dehydrogenase 1A3 (ALDH1A3), a marker of high clinical importance in many breast cancers, and other solid tumours. BCSCs displaying increased transcriptional activation of ALDH1A3 demonstrate an increase in self-renewal capabilities. This tool improves the ability to reliably follow select cancer stem cell populations over time."
1721,Pan-cancer Analysis Predicts Kindlin-associated Global Mechanochemical Perturbation,"Debojyoti Chowdhury, Ayush Mistry, Riti Bhatia, Simran Wadan, Soham Chakraborty, Shubhasis Haldar",https://www.biorxiv.org/content/10.1101/2022.10.31.514453v1,"Kindlins are mechanosensitive adapter proteins that connect extracellular mechanical cues to intracellular chemical events. Any alterations in these proteins thus alter cellular signaling, which could result in cancer progression. However, their involvement in global mechanochemical signals remains elusive in cancers. Here we analyze pan-cancer samples to decipher how kindlin alterations aid cancer progression. We show that kindlin alterations, at both the genetic and mRNA level, dysregulates cellular behavior which significantly correlate with poor survival. We find that while these alterations are cancer-specific, they are prevalent in advanced tumor stages and metastatic onset. We observe that kindlins co-alter with a substantial fraction of human mechanochemical proteome in various tumors. Our analysis suggests how kindlin alterations aid tumor-promoting signals with a synergistic effect from alterations of cancer-hallmark genes. Notably, we demonstrate a consistent alteration of epithelial-mesenchymal-transition markers with kindlin activity. Overall, our study highlights how kindlin alterations could affect metabolism, genomic instability, and signal disruption via their interactome network, causing cancer and suggests targeting them as a therapeutic strategy."
1722,Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes,"Anisha Ramessur, Bana Ambasager, Iker Valle Aramburu, Freddie Peakman, Kelly Gleason, Christoph Lehmann, Venizelos Papayannopoulos, Raoul Charles Coombes, Ilaria Malanchi",https://www.biorxiv.org/content/10.1101/2023.04.19.537022v2,"Purpose A high number of circulating neutrophils is a poor prognostic factor for breast cancer, where evidence of bone marrow cancer-dependent priming is found. However, how early this priming is detectable remains unclear."
1723,Toblerone: detecting exon deletion events in cancer using RNA-seq,"Andrew Lonsdale, Andreas Halman, Lauren M Brown, Hansen J Kosasih, Paul G Ekert, Alicia Oshlack",https://www.biorxiv.org/content/10.1101/2022.10.27.514132v2,"Cancer is driven by mutations of the genome that can result in the activation of oncogenes or repression of tumour suppressor genes. In acute lymphoblastic leukemia (ALL) focal deletions in IKAROS family zinc finger 1 (IKZF1) result in the loss of zinc-finger DNA-binding domains and a dominant negative isoform that is associated with higher rates of relapse and poorer patient outcomes. Clinically, the presence of IKZF1 deletions informs prognosis and treatment options. In this work we developed a method for detecting exon deletions in genes using RNA-seq with application to IKZF1. We developed a pipeline that first uses a custom transcriptome reference consisting of transcripts with exon deletions. Next, RNA-seq reads are mapped using a pseudoalignment algorithm to identify reads that uniquely support deletions. These are then evaluated for evidence of the deletion with respect to gene expression and other samples. We applied the algorithm, named Toblerone, to a cohort of 99 B-ALL paediatric samples including validated IKZF1 deletions. Furthermore, we developed a graphical desktop app for non-bioinformatics users that can quickly and easily identify and report deletions in IKZF1 from RNA-seq data with informative graphical outputs."
1724,Functional Genomics of Gastrointestinal Escherichia coli Isolated from Patients with Cancer and Diarrhea,"Hannah Carter, Justin Clark, Lily G. Carlin, Ellen Vaughan, Anubama Rajan, Adilene Olvera, Xiaomin Yu, Xi-Lei Zeng, Amal Kambal, Michael Holder, Xiang Qin, Richard A. Gibbs, Joseph F. Petrosino, Donna M. Muzny, Harsha Doddapaneni, Vipin K. Menon, Kristi L. Hoffman, Qingchang Meng, Matthew C. Ross, Sara J. Javornik Cregeen, Ginger Metcalf, Robert Jenq, Sarah Blutt, Mary K. Estes, TMC-GCID team, Anthony Maresso, Pablo C. Okhuysen",https://www.biorxiv.org/content/10.1101/2023.05.31.543115v1,"We describe the epidemiology and clinical characteristics of 29 patients with cancer and diarrhea in whom Enteroaggregative Escherichia coli (EAEC) was initially identified by GI BioFire panel multiplex. E. coli strains were successfully isolated from fecal cultures in 14 of 29 patients. Six of the 14 strains were identified as EAEC and 8 belonged to other diverse E. coli groups of unknown pathogenesis. We investigated these strains by their adherence to human intestinal organoids, cytotoxic responses, antibiotic resistance profile, full sequencing of their genomes, and annotation of their functional virulome. Interestingly, we discovered novel and enhanced adherence and aggregative patterns for several diarrheagenic pathotypes that were not previously seen when co-cultured with immortalized cell lines. EAEC isolates displayed exceptional adherence and aggregation to human colonoids compared not only to diverse GI E. coli, but also compared to prototype strains of other diarrheagenic E. coli. Some of the diverse E. coli strains that could not be classified as a conventional pathotype also showed an enhanced aggregative and cytotoxic response. Notably, we found a high carriage rate of antibiotic resistance genes in both EAEC strains and diverse GI E. coli isolates and observed a positive correlation between adherence to colonoids and the number of metal acquisition genes carried in both EAEC and the diverse E. coli strains. This work indicates that E. coli from cancer patients constitute strains of remarkable pathotypic and genomic divergence, including strains of unknown disease etiology with unique virulomes. Future studies will allow for the opportunity to re-define E. coli pathotypes with greater diagnostic accuracy and into more clinically relevant groupings."
1725,A cleaved METTL3 potentiates the METTL3-WTAP interaction and breast cancer progression,"Chaojun Yan, Jingjing Xiong, Zirui Zhou, Qifang Li, Chuan Gao, Mengyao Zhang, Liya Yu, Jinpeng Li, Ming-Ming Hu, Chen-Song Zhang, Cheguo Cai, Haojian Zhang, Jing Zhang",https://www.biorxiv.org/content/10.1101/2023.02.17.528944v3,"N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3). We find that METTL3a is required for the METTL3-WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mTOR activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer."
1727,A transcriptome-wide meta-analysis reveals lack of cancer-cell intrinsic determinants of response to immune checkpoint blockade,"Yu Amanda Guo, Tanmay Kulshrestha, Mei Mei Chang, Irfahan Kassam, Egor Revkov, Simone Rizzetto, Aaron C. Tan, Daniel S.W. Tan, Iain Beehuat Tan, Anders Jacobsen Skanderup",https://www.biorxiv.org/content/10.1101/2023.07.30.551135v2,"Immune-checkpoint therapy (ICB) has conferred significant and durable clinical benefit to some cancer patients. However, most patients do not respond to ICB, and reliable biomarkers of ICB response are needed to improve patient stratification. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors from ICB-treated patients and tumors with expected ICB outcomes based on microsatellite status. Using a robust transcriptome deconvolution approach, we inferred cancer and stroma-specific gene expression differences and identified cell-type specific features of ICB response across cancer types. Consistent with current knowledge, stromal expression of CXCL9, CXCL13, and IFNG were the top determinants of favorable ICB response. In addition, we identified a group of potential immune-suppressive genes, including FCER1A, associated with poor response to ICB. Strikingly, PD-L1 expression in stromal cells, but not cancer cells, is correlated with ICB response across cancer types. Furthermore, the unbiased transcriptome-wide analysis failed to identify cancer-cell intrinsic features of ICB response conserved across tumor types. Overall, our results challenge the prevailing dogma that cancer cells present tissue-agnostic molecular markers that modulate immune activity and ICB treatment response. These results have implications for the development of improved ICB treatments and diagnostics."
1728,A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer,"EunJung Lee, Suyakarn Archasappawat, Keely Ji, Jocelyn Pena, Virneliz Fernandez-Vega, Ritika Gangaraju, Nitin Sai Beesabathuni, Martin Jean Kim, Qi Tian, Priya Shah, Louis Scampavia, Timothy Spicer, Chang-Il Hwang",https://www.biorxiv.org/content/10.1101/2023.05.30.542934v1,"Pancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, ∼10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways (e.g., BRCA2). Personalized medicine approaches tailored toward patients’ mutations would improve patients’ outcome. To identify novel vulnerabilities of BRCA2-deficient pancreatic cancer, we generated isogenic Brca2-deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that Brca2-deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that BRCA2 deficiency increased autophagic flux, which was further enhanced by BET inhibition in Brca2-deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for BRCA2-deficient pancreatic cancer."
1729,Intestinal microbiota modulates the anti-tumor effect of oncolytic virus vaccine in colorectal cancer,"Xia Chen, Guang-Jun Wang, Ling Qin, Bing Hu, Jun Li",https://www.biorxiv.org/content/10.1101/2023.05.28.542655v1,"Background Immunotherapy such as oncolytic virus has become a powerful cancer treatment but only a part of cancer patients can benefit from it, especially to advanced-stage cancer patients are required new therapeutic strategies to facilitate extended survival. Intestinal microbiota may contribute to colorectal cancer (CRC) carcinogenesis and response to immunotherapy. However, whether and how the modulating effect of intestinal microbiota on oncolytic virus vaccine (OVV) in CRC remains to be investigated."
1731,Membrane-active peptides escape drug-resistance in cancer,"Aurélie H. Benfield, Felicitas Vernen, Reuben S.E. Young, Ferran Nadal-Bufí, Heinz Hammerlindl, David J. Craik, Helmut Schaider, Nicole Lawrence, Stephen J. Blanksby, Sónia Troeira Henriques",https://www.biorxiv.org/content/10.1101/2022.10.27.513961v1,"Acquired drug-resistance is a recurring problem in cancer treatment, and this is particularly true for patients with metastatic melanoma that carry a BRAF V600E mutation. In the current study, we explored the use of membrane-active peptides as an alternative therapeutic modality to target drug-resistant melanoma cells. We produced slow-cycling and drug-resistant melanoma cells using dabrafenib, a small molecule drug that targets tumor cells with BRAF V600E mutation, and characterised their lipidome and proteome to investigate the role of membrane lipids in acquired drug-resistance. Despite some changes in the lipid composition, tested anti-melanoma membrane-active cyclic peptides (cTI and cGm) killed melanoma cells that are sensitive, tolerant, or resistant to dabrafenib. Importantly, melanoma cells did not develop resistance to cTI or cGm, nor changed their lipid composition with long-term peptide treatment. Therefore, these peptides are well suited as templates to design therapeutic leads to target drug-resistant metastatic melanoma cells and/or as co-treatment with small molecule drugs."
1733,The colocatome as a spatial -omic reveals shared microenvironment features between tumour–stroma assembloids and human lung cancer,"Gina Bouchard, Weiruo Zhang, Irene Li, Ilayda Ilerten, Asmita Bhattacharya, Yuanyuan Li, Winston Trope, Joseph B Shrager, Calvin Kuo, Lu Tian, Amato J Giaccia, Sylvia K Plevritis",https://www.biorxiv.org/content/10.1101/2023.09.11.557278v1,"Computational frameworks to quantify and compare microenvironment spatial features of in-vitro patient-derived models and clinical specimens are needed. Here, we acquired and analysed multiplexed immunofluorescence images of human lung adenocarcinoma (LUAD) alongside tumour– stroma assembloids constructed with organoids and fibroblasts harvested from the leading edge (Tumour-Adjacent Fibroblasts;TAFs) or core (Tumour Core Fibroblasts;TCFs) of human LUAD. We introduce the concept of the “colocatome” as a spatial -omic dimension to catalogue all proximate and distant colocalisations between malignant and fibroblast subpopulations in both the assembloids and clinical specimens. The colocatome expands upon the colocalisation quotient (CLQ) through a nomalisation strategy that involves permutation analysis and thereby allows comparisons of CLQs under different conditions. Using colocatome analysis, we report that both TAFs and TCFs protected cancer cells from targeted oncogene treatment by uniquely reorganising the tumour–stroma cytoarchitecture, rather than by promoting cellular heterogeneity or selection. Moreover, we show that the assembloids’ colocatome recapitulates the tumour–stroma cytoarchitecture defining the tumour microenvironment of LUAD clinical samples and thereby can serve as a functional spatial readout to guide translational discoveries."
1734,In Silico Analysis of Drug Off-Target Effects on Diverse Isoforms of Cervical Cancer for Enhanced Therapeutic Strategies,"Azhar Iqbal, Faisal Ali, Moawaz Aziz, Asad Ullah Shakil, Shanza Choudhary, Adiba Qayyum, Fiza Arshad, Sarah Ashraf, Sheikh Arslan Sehgal, Momina Hussain, Muhammad Sajid",https://www.biorxiv.org/content/10.1101/2023.09.09.556929v1,"Cervical cancer is a severe medical issue as 500,000 new cases of cervical cancer are identified in the world every year. The selection and analysis of the suitable gene target are the most crucial in the early phases of drug design. The emphasis at one protein while ignoring its several isoforms or splice variations may have unexpected therapeutic or harmful side effects. In this work, we provide a computational analysis of interactions between cervical cancer drugs and their targets that are influenced by alternative splicing. By using open-accessible databases, we targeted 45 FDA-approved cervical cancer drugs targeting various genes having more than two distinct protein-coding isoforms. Binding pocket interactions revealed that many drugs do not have possible targets at the isoform level. In terms of size, shape, electrostatic characteristics, and structural analysis have shown that various isoforms of the same gene with distinct ligand-binding pocket configurations. Our results emphasized the risks of ignoring possibly significant interactions at the isoform level by concentrating just on the canonical isoform and promoting consideration of the impacts of cervical cancer drugs on- and off-target at the isoform level to further research."
1735,Next-generation sequencing-based liquid biopsy can be used for detection of residual disease and cancer recurrence monitoring in dogs,"Angela L. McCleary-Wheeler, Patrick C. Fiaux, Carlos A. Ruiz-Perez, Lisa M. McLennan, John A. Tynan, Susan C. Hicks, Jill M. Rafalko, Daniel S. Grosu, Jason Chibuk, Allison L. O’Kell, Todd A. Cohen, Brian K. Flesner, Ilya Chorny, Dana W.Y. Tsui, Kristina M. Kruglyak, Andi Flory",https://www.biorxiv.org/content/10.1101/2023.09.08.556935v1,Objective The purpose of this study was to evaluate the performance of a next-generation sequencing-based liquid biopsy test for cancer monitoring in dogs.
1736,Cancer phylogenetic tree inference at scale from 1000s of single cell genomes,"Sohrab Salehi, Fatemeh Dorri, Kevin Chern, Farhia Kabeer, Nicole Rusk, Tyler Funnell, Marc J Williams, Daniel Lai, Mirela Andronescu, Kieran R. Campbell, Andrew McPherson, Samuel Aparicio, Andrew Roth, Sohrab Shah, Alexandre Bouchard-Côté",https://www.biorxiv.org/content/10.1101/2020.05.06.058180v5,"A new generation of scalable single cell whole genome sequencing (scWGS) methods allows unprecedented high resolution measurement of the evolutionary dynamics of cancer cell populations. Phylogenetic reconstruction is central to identifying sub-populations and distinguishing the mutational processes that gave rise to them. Existing phylogenetic tree building models do not scale to the tens of thousands of high resolution genomes achievable with current scWGS methods. We constructed a phylogenetic model and associated Bayesian inference procedure, sitka, specifically for scWGS data. The method is based on a novel phylogenetic encoding of copy number (CN) data, the sitka transformation, that simplifies the site dependencies induced by rearrangements while still forming a sound foundation to phylogenetic inference. The sitka transformation allows us to design novel scalable Markov chain Monte Carlo (MCMC) algorithms. Moreover, we introduce a novel point mutation calling method that incorporates the CN data and the underlying phylogenetic tree to overcome the low per-cell coverage of scWGS. We demonstrate our method on three single cell datasets, including a novel PDX series, and analyse the topological properties of the inferred trees. Sitka is freely available at https://github.com/UBC-Stat-ML/sitkatree.git."
1737,SpliceMutr enables pan-cancer analysis of splicing-derived neoantigen burden in tumors,"Theron Palmer, Michael D Kessler, Xiaoshan M. Shao, Archana Balan, Mark Yarchoan, Neeha Zaidi, Tamara Y Lopez-Vidal, Ali Saeed, Jessica Gore, Nilofer S Azad, Elizabeth M Jaffee, Alexander V Favorov, Valsamo Anagnostou, Rachel Karchin, Daria A Gaykalova, Ludmila Danilova, Elana J Fertig",https://www.biorxiv.org/content/10.1101/2023.05.26.542165v2,"Aberrant alternative splicing can generate neoantigens, which can themselves stimulate immune responses and surveillance. Previous methods for quantifying splicing-derived neoantigens are limited by independent references and potential batch effects. Here, we introduce SpliceMutr, a bioinformatics approach and pipeline for identifying splicing derived neoantigens from tumor and normal data. SpliceMutr facilitates the identification of tumor-specific antigenic splice variants, predicts MHC-binding affinity, and estimates splicing antigenicity scores per gene. By applying this tool to genomic data from The Cancer Genome Atlas (TCGA), we generate splicing-derived neoantigens and neoantigenicity scores per sample and across all cancer types and find numerous correlations between splicing antigenicity and well-established biomarkers of anti-tumor immunity. Notably, carriers of mutations within splicing machinery genes have higher splicing antigenicity, which provides support for our approach. Further analysis of splicing antigenicity in cohorts of melanoma patients treated with mono-or combined immune checkpoint inhibition suggest that the abundance of splicing antigens is reduced post-treatment from baseline in patients who progress, likely because of an immunoediting process. We also observe increased splicing antigenicity in responders to immunotherapy, which may relate to an increased capacity to mount an immune response to splicing-derived antigens. We find the splicing antigenicity to be higher in tumor samples when compared to normal, that mutations in the splicing machinery result in increased splicing antigenicity in some cancers, and higher splicing antigenicity is associated with positive response to immune checkpoint inhibitor therapies. Further, this new computational pipeline provides novel analytical capabilities for splicing antigenicity and is openly available for further immuno-oncologic analysis."
1738,Metallo-protease Peptidase M84 from Bacillus altitudinis induces ROS dependent apoptosis in ovarian cancer cells by targeting PAR-1,"Niraj Nag, Tanusree Ray, Rima Tapader, Animesh Gope, Rajdeep Das, Elizabeth Mahapatra, Saibal Saha, Ananda Pal, Parash Prasad, Shruti Chatterjee, Sib Sankar Roy, Amit Pal",https://www.biorxiv.org/content/10.1101/2023.09.06.556500v2,"In pursuit of isolating novel anticancer proteases from environmental microbial isolates, we have purified and identified an extracellular metallo-protease from Bacillus altitudinis named Peptidase M84. This protease selectively triggered apoptosis in human ovarian adenocarcinoma cells (PA-1, SKOV3) and mouse ovarian carcinoma cells (ID8), in addition to exhibiting no significant effect on normal human epithelial ovarian cell (IOSE) and mouse peritoneal macrophage (PEMФ) cell viabilities. Protease activated receptor-1 (PAR-1); a GPCR which is reported to be overexpressed in ovarian cancer cells was identified as a novel target of Peptidase M84. We observed that Peptidase M84 induced PAR-1 overexpression along with activating its downstream signalling effectors NFκB and MAPK to promote excessive reactive oxygen species (ROS) generation in ovarian cancer cells. This disrupted mitochondrial membrane potential, allowed cytosolic release of mitochondrial cytochrome c, increased the Bax (pro-apoptotic) to Bcl-2 (anti-apoptotic) ratio and promoted DNA damage to evoke apoptotic death of the ovarian cancer cells. Peptidase M84 also reduced nuclear ki-67 expression in these malignant cells to render an anti-proliferative role. In in vivo set-up, weekly intraperitoneal administration of Peptidase M84 (12 µg/kg body-weight) in the ID8 mice model significantly diminished ascitic fluid accumulation through induction of oxidative stress, increasing murine survival rates by 60%. Collectively, our in vitro and in vivo findings suggested that Peptidase M84 triggered PAR-1 mediated oxidative stress to act as an apoptosis inducer in ovarian cancer cells. This established Peptidase M84 as a promising drug candidate for receptor mediated targeted-therapy of ovarian cancer."
1739,Urothelium-specific expression of mutationally activated Pik3ca initiates early lesions of non-invasive bladder cancer,"Lauren Shuman, Jonathan Pham, Thomas Wildermuth, Xue-Ru Wu, Vonn Walter, Joshua I. Warrick, David J. DeGraff",https://www.biorxiv.org/content/10.1101/2023.05.22.541489v2,"Despite the fact that ∼70% of bladder cancers are non-invasive and have high recurrence rates, early stage disease is understudied. The relative lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. While mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, a Upk2-Cre/Pik3caH1047R mouse model expressing one or two R26-Pik3caH1047R alleles in a urothelium-specific manner was created. Pik3caH1047R functionality was confirmed by quantifying Akt phosphorylation and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. At 6 months, Pik3caH1047R mice developed increased urothelial thickness and nuclear atypia, however, at 12 months, Pik3caH1047R mice did not exhibit progressive disease. Immunohistochemistry shows urothelium maintained luminal differentiation characterized by high Foxa1 and Pparγ expression. In addition, mice were subjected to low-dose carcinogen exposure (N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN)). Surprisingly, Pik3caH1047R mice exhibited no significant differences after exposure relative to mice without exposure. Furthermore, ssGSEA analysis of invasive human tumors showed those with mutant PIK3CA do not exhibit significantly increased PI3K/AKT pathway activity compared to wildtype PIK3CA tumors. Overall, these data suggest that Pik3caH1047R can elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations."
1740,Tyramine promotes colon cancer risk and development by inducing DNA damage and inflammation,"Maria Glymenaki, Sophie Curio, Smeeta Shrestha, Mona El-Bahrawy, Yulan Wang, Nigel J. Gooderham, Nadia Guerra, Jia V. Li",https://www.biorxiv.org/content/10.1101/2023.05.25.542254v1,"High dietary consumption of processed meat is associated with increased colorectal cancer (CRC) risk, but mechanistic links remain largely unknown. Tyramine is a biogenic amine found in processed food and a gut bacterial product from tyrosine. However, the impact of tyramine on gut health has not been studied. We found that tyramine induced necrosis and promoted cell proliferation and DNA damage in HCT116 cells. Ingestion of tyramine increased colonic tumor size, intestinal cell proliferation and inflammation (e.g., increased mRNA expression of IL-17A and a higher number of Ly6G+ neutrophils) in ApcMin/+ mice. Furthermore, tyramine-treated wild-type mice exhibited visible adenomas and significantly enhanced intestinal tissue DNA damage, together with altered gene pathways involved in epithelial barrier function. In addition, natural killer cell numbers were lower and polymorphonuclear-myeloid derived suppressor cells were higher in tumors from tyramine-treated ApcMin/+ mice, suggesting a suppressive anti-tumor immune response. Thus, tyramine not only increases CRC risk, but also facilitates tumor development. Modulating the levels of tyramine in food and monitoring high-risk individuals could aid in better prognosis and management of CRC."
1741,Adaptive therapy in cancer: the role of restrictions in the accumulation of mutations,"David Fontaneda, Ramon Diaz-Uriarte",https://www.biorxiv.org/content/10.1101/2023.05.18.541330v2,"BACKGROUND Cancer is currently one of the leading causes of premature death in the world, and is predicted to continue rising even despite the continuous discovery of novel treatments. New approaches, like adaptive therapy, try to minimize the problem of drug resistance, but there are still many open questions and unstudied phenomena that need to be tackled in order to make this approaches viable in real patients; among these, the possible effects that restrictions in the order of accumulation of mutations could have."
1743,Ethnopharmacological disease classification and bioprospecting: the diversity of plant drugs used to treat cancer,"Jamie Thompson, Julie Hawkins",https://www.biorxiv.org/content/10.1101/2023.05.22.541754v1,"Cancer is a highly-diverse disease and as the second-leading cause of death worldwide is a focus of drug discovery research. Natural products have been shown to be a useful source of novel molecules for the treatment of cancer. It is likely there are many plants with undiscovered molecules of therapeutic value, however identifying new leads from among the vast diversity of plants is very challenging. Traditional knowledge might inform bioprospecting by predicting lineages of plants rich in therapeutically useful molecules. Here, we characterise the phylogenetic diversity of plants used traditionally to manage cancer. We demonstrate the independent and repeated targeting of specific lineages of plants by different peoples in different parts of the world. That the same lineages are used to treat different cancers is suggestive of independent discovery of therapeutic value. However, the lineages we report here as rich in plants used traditionally to treat cancer coincide with those for other ethnobotanical applications, and contain few plants with proven anti-cancer activity. It is likely that the traditional knowledge recorded and explored here is shaped by selection of plants conferring milder effects for treating wider symptoms, such as tiredness or nausea, rather than for halting tumour growth. Accurate prediction of useful plant lineages for cancer management requires more nuanced information than is commonly provided in ethnobotanical records."
1744,Histopathological Domain Adaptation with Generative Adversarial Networks Bridging the Domain Gap Between Thyroid Cancer Histopathology Datasets,"William Dee, Rana Alaaeldin Ibrahim, Eirini Marouli",https://www.biorxiv.org/content/10.1101/2023.05.22.541691v1,"Deep learning techniques are increasingly being used to classify medical imaging data with high accuracy. Despite this, due to often limited training data, these models can lack sufficient generalizability to predict unseen test data, produced in a different domain, with comparable performance. This study focuses on thyroid histopathology image classification and investigates whether a Generative Adversarial Network (GAN), trained with just 156 patient samples, can produce high quality synthetic images to sufficiently augment training data and improve overall model generalizability. Utilizing a StyleGAN2-ADA approach, the generative network produced images with an FID score of 5.05, matching state-of-the-art GAN results in non-medical domains with comparable dataset sizes. Augmenting the training data with these GAN-generated images increased model generalizability significantly when tested on external data, improving overall accuracy and F1 scores by 36% and 42% respectively. Most importantly, this performance improvement was observed on minority class images, tumour subtypes which are known to suffer from high levels of inter-observer variability when classified by trained pathologists."
1745,Lung cancer-intrinsic SOX2 expression mediates resistance to checkpoint blockade therapy by inducing Treg-dependent CD8+ T cell exclusion,"Elen Torres-Mejia, Sally Weng, Kim Nguyen, Ellen Duong, Leon Yim, Stefani Spranger",https://www.biorxiv.org/content/10.1101/2023.09.06.556520v1,"Tumor-intrinsic signaling pathways can drastically affect the tumor immune microenvironment (TME), promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor-cell intrinsic pathways have been reported to affect myeloid cell infiltration and downstream T cell infiltration. Clinical evidence suggests that the exclusion of cytotoxic T cells from the tumor core likewise mediates resistance. Here, we find that tumor cell-intrinsic SOX2 expression induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. CD8+ T cell exclusion was dependent on regulatory T cell-mediated suppression of tumor vasculature. Depleting tumor-infiltrating regulatory T cells via Glucocorticoid-Induced TNFR-Related (GITR) restored CD8+ T cell infiltration and reduced tumor growth in combination with checkpoint blockade therapy."
1747,Trellis Single-Cell Screening Reveals Stromal Regulation of Patient-Derived Organoid Drug Responses,"María Ramos Zapatero, Alexander Tong, Jahangir Sufi, Petra Vlckova, Ferran Cardoso Rodriguez, Callum Nattress, Xiao Qin, Daniel Hochhauser, Smita Krishnaswamy, Christopher J. Tape",https://www.biorxiv.org/content/10.1101/2022.10.19.512668v2,"Patient-derived organoids (PDOs) can model personalized therapy responses, however current screening technologies cannot reveal drug response mechanisms or study how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly-multiplexed mass cytometry platform to measure post translational modification (PTM) signaling in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment-specific drug responses in thousands of single-cell datasets, we developed Trellis — a highly-scalable, hierarchical tree-based treatment effect analysis method. Trellis single-cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is patient-specific. We found drug-induced apoptosis does not correlate with genotype or clinical staging but does align with cell-intrinsic PTM signaling in PDOs. CAFs protect chemosensitive PDOs by shifting cancer cells into a slow-cycling cell-state and CAF chemoprotection can be reversed by inhibiting YAP."
1748,Targeted Vibration-Induced Necrosis in Cancer Cells using Paramagnetic Microrobots,"Sudipta Mallick, Max Sokolich, David Rivas, Sambeeta Das",https://www.biorxiv.org/content/10.1101/2022.10.19.512945v1,"Therapeutic delivery of anti-cancer drugs is a major goal of modern medicine. In particular, microrobots (MRs) have recently been studied for their ability to navigate difficult-to-reach regions in the human body to deliver therapeutics for microscopically localized interventions. However, the control of individual and swarms of MRs to precisely target localized cellular regions remains a significant challenge, preventing their applications as delivery systems in cancer research. In this study, magnetic MRs were used to target cancer cells and create localized magnetic oscillations which resulted in magnetolysis of cancer cells. The magnetic MRs were selectively steered towards Hepatocarcinoma cells (HepG2 cells) using our custom-built magnetic controller under a rotating magnetic field at different frequencies. After internalization of the microrobots by cancer cells, magnetic oscillation of varying dosages was applied to disrupt the internal structure of cancer cells which leads to subsequent cell death."
1750,Detection of isoforms and genomic alterations by high-throughput full-length single-cell RNA sequencing in ovarian cancer,"Arthur Dondi, Ulrike Lischetti, Francis Jacob, Franziska Singer, Nico Borgsmüller, Ricardo Coelho, Tumor Profiler Consortium, Viola Heinzelmann-Schwarz, Christian Beisel, Niko Beerenwinkel",https://www.biorxiv.org/content/10.1101/2022.12.12.520051v3,"Understanding the complex background of cancer requires genotype-phenotype information in single-cell resolution. Here, we perform long-read single-cell RNA sequencing (scRNA-seq) on clinical samples from three ovarian cancer patients presenting with omental metastasis and increase the PacBio sequencing depth to 12,000 reads per cell. Our approach captures 152,000 isoforms, of which over 52,000 are novel. Isoform-level analysis accounting for non-coding isoforms reveals 20% overestimation of protein-coding gene expression on average. We also detect cell type-specific isoform and poly-adenylation site usage in tumor and mesothelial cells, and find that mesothelial cells transition into cancer-associated fibroblasts in the metastasis, partly through the TGF-β/miR-29/Collagen axis. Furthermore, we identify gene fusions, including an experimentally validated IGF2BP2::TESPA1 fusion, which is misclassified as high TESPA1 expression in matched short-read data, and call mutations confirmed by targeted NGS cancer gene panel results. With these findings, we envision long-read scRNA-seq to become increasingly relevant in oncology and personalized medicine."
1752,Stochastic differential equation modelling of cancer cell migration and tissue invasion,"Dimitrios Katsaounis, Mark A.J. Chaplain, Nikolaos Sfakianakis",https://www.biorxiv.org/content/10.1101/2022.11.14.516390v2,"Invasion of the surrounding tissue is a key aspect of cancer growth and spread involving a coordinated effort between cell migration and matrix degradation, and has been the subject of mathematical modelling for almost 30 years. In this current paper we address a long-standing question in the field of cancer cell migration modelling. Namely, identify the migratory pattern and spread of individual cancer cells, or small clusters of cancer cells, when the macroscopic evolution of the cancer cell colony is dictated by a specific partial differential equation (PDE)."
1753,Mathematical modeling of clonal interference by density-dependent selection in heterogeneous cancer cell lines,"Thomas Veith, Saeed Alahmari, Andrew Schultz, Joseph Johnson, Konstantin Maksin, Noemi Andor",https://www.biorxiv.org/content/10.1101/2023.05.08.539618v2,"Many cancer cell lines are aneuploid and heterogeneous, with multiple karyotypes co-existing within the same cell line. Karyotype heterogeneity has been shown to manifest phenotypically, affecting how cells respond to drugs or to minor differences in culture media. Knowing how to interpret karyotype heterogeneity phenotypically, would give insights into cellular phenotypes before they unfold temporally. Here we reanalyze single cell RNA (scRNA)- and scDNA sequencing data from eight stomach cancer cell lines by placing gene expression programs into a phenotypic context. We quantify differences in growth rate and contact inhibition between the eight cell lines using live-cell imaging, and use these differences to prioritize transcriptomic biomarkers of growth rate and carrying capacity. Using these biomarkers, we find significant differences in the predicted growth rate or carrying capacity between multiple karyotypes detected within the same cell line. We use these predictions to simulate how the clonal composition of a cell line will change depending on the timing of splitting cells. Once validated, these models can aid the design of experiments that steer evolution with density dependent selection."
1756,Engineering High Throughput Screening Platforms of Cervical Cancer,"Ines A Cadena, Mina R Buchanan, Conor G Harris, Molly A Jenne, Willie E Rochefort, Dylan Nelson, Kaitlin C Fogg",https://www.biorxiv.org/content/10.1101/2022.10.16.512447v1,"There is a critical need for complex multicellular three-dimensional physiomimetic models of cancer that can interface with high throughput drug screening methods to assess anti-metastatic and anti-angiogenic drug efficacy in a rapid yet high content manner. We report a multilayer multicellular platform of human cervical cancer cell lines and primary human microvascular endothelial cells that incorporates critical biophysical and extracellular matrix cues, interfaces with standard high throughput drug screening methods, and can evaluate cervical cancer invasion and endothelial microvessel formation over time. Through the use of Design of Experiments statistical optimization, we identified the specific concentrations of collagen I, fibrinogen, fibronectin, GelMA, and PEGDA in each hydrogel layer that maximized cervical cancer invasion and endothelial microvessel length simultaneously. We then validated the optimized platform and assessed the viscoelastic properties of the composite hydrogels as well as their individual constituents. Finally, using this optimized platform, we conducted a targeted drug screen of four clinically relevant drugs on two cervical cancer cell lines. From these data we identified each of the cervical cancer cell lines (SiHa and Ca Ski) as either responsive or refractive to Paclitaxel, Dasitinib, Dovitinib, or Pazopanib. Overall, we developed a phenotypic drug screening platform of cervical cancer that captures cell behavior present in the cervical cancer tumor microenvironment, captures patient to patient variability, and integrates with standard high throughput high content drug screening methods. This work provides a valuable platform that can be used to screen large compound libraries for mechanistic studies, drug discovery, and precision oncology for cervical cancer patients."
1757,preon: Fast and accurate entity normalization for drug names and cancer types in precision oncology,"Arik Ermshaus, Michael Piechotta, Gina Rüter, Ulrich Keilholz, Ulf Leser, Manuela Benary",https://www.biorxiv.org/content/10.1101/2023.05.22.540912v1,"Motivation In precision oncology, clinicians are aiming to find the best treatment for any patient based on their molecular characterization. A major bottleneck is the annotation and evaluation of individual variants, for which usually a range of knowledge bases are manually screened. To incorporate and integrate the vast information of different databases, fast and accurate methods for harmonization are necessary."
1758,Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients,"Lisa A. Ridnour, Robert Y.S. Cheng, William F. Heinz, Milind Pore, Ana L. Gonzalez, Elise L. Femino, Rebecca Moffat, Adelaide L. Wink, Fatima Imtiaz, Leandro Coutinho, Donna Butcher, Elijah F. Edmondson, M. Cristina Rangel, Stephen T.C. Wong, Stanley Lipkowitz, Sharon Glynn, Michael P. Vitek, Daniel W. McVicar, Xiaoxian Li, Stephen K. Anderson, Nazareno Paolocci, Stephen M. Hewitt, Stefan Ambs, Timothy R. Billiar, Jenny C. Chang, Stephen J. Lockett, David A. Wink",https://www.biorxiv.org/content/10.1101/2023.12.21.572867v1,"Multiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER- breast cancers."
1759,"Kaempferide induces apoptosis in cervical cancer by attenuating the HPV oncoproteins, E6 and E7","Lekshmi R Nath, Vijai V Alex, Sreekumar U Aiswarya, Tennyson P Rayginia, Nair Hariprasad Haritha, Chenicheri K. Keerthana, Arun Kumar T. Thulasidasan, Mundanattu Swetha, Ravi Shankar Lankalapalli, Ruby John Anto",https://www.biorxiv.org/content/10.1101/2023.05.19.541414v1,"Despite the advancement in HPV prevention strategies, cervical cancer is a leading cause of cancer death in women worldwide. The anticancer potential of kaempferide, which was derived from Chromolaena odorata, was previously revealed in our in-vitro study. The current investigation aims to confirm the therapeutic efficacy of the molecule against cervical cancer, in-vitro and in-vivo. In NOD-SCID mice with HeLa Luc+ xenografts, kaempferide significantly increases ROS production resulting in a drastic decrease in the luc activity and growth of cervical tumours. It also exhibits down-regulation of oncoproteins E6, E7 and MDM2 and concurrent up-regulation of p53, p21 and pRb. The degradation of phospho-pRb, along with a strong expression of cleaved PARP, TUNEL positivity and a significant decrease in PCNA expression, confirms apoptotic mode of cell death in the treated tissues. Taken together, our study reveals the antioncogenic potential of kaempferide, which regulates oncoproteins and tumor suppressors accordingly. This is the first report depicting kaempferide as an inhibitor of HPV oncoproteins and hence as a candidate drug molecule against cervical cancer."
1760,Calorie Restriction Outperforms Bariatric Surgery in a Murine Model of Obesity and Triple-Negative Breast Cancer,"Michael F Coleman, Kristina K Camp, Tori L McFarlane, Steven S Doerstling, Subreen A Khatib, Erika T Rezeli, Alfor G Lewis, Alex J Pfeil, Laura A Smith, Laura W Bowers, Farnaz Fouladi, Weida Gong, Elaine M Glenny, Joel S Parker, Ginger L Milne, Ian M Carroll, Anthony A Fodor, Randy J Seeley, Stephen D Hursting",https://www.biorxiv.org/content/10.1101/2023.05.19.541484v1,"Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity- driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR. Each intervention generated weight and fat loss and suppressed tumor growth relative to obese mice (greatest suppression with CR). VSG and CR regimens exerted both similar and unique effects, as assessed using multi-omic approaches, in reversing obesity-associated transcriptional, epigenetic, secretome, and microbiota changes and restoring antitumor immunity. Thus, in a murine model of TNBC, bariatric surgery and CR each reverse obesity-driven tumor growth via shared and distinct antitumor mechanisms, and CR is superior to VSG in reversing obesity’s procancer effects."
1761,Deconstructing the contributions of heterogeneity to combination treatment of hormone sensitive breast cancer,"Samantha Linn, Jenna A. Moore-Ott, Robyn Shuttleworth, Wenjing Zhang, Morgan Craig, Adrianne L. Jenner",https://www.biorxiv.org/content/10.1101/2023.05.19.541369v1,"Combination therapies are fundamental to cancer treatments, including in breast cancer the most common invasive malignancy in women. Breast cancer treatment is determined based on molecular subtypes, and since 2016, combination palbociclib and fulvestrant has been used to treat hormone receptor-positive breast cancer. However, the impact of heterogeneity of the tumour landscape and tumour composition dynamics on scheduling decisions remains poorly understood. To elucidate the contributions of variability at multiple scales to treatment outcomes in hormone receptor-positive breast cancer, we developed a simple mathematical model of two unique estrogen receptor positive (ER+) breast cancer cell types and their response to combination treatment with palbociclib and fulvestrant. We used this model to understand how the initial fraction of either cell type may impact the fraction remaining after treatment and examined how heterogeneity in pharmacokinetics and pharmacodynamics result in a large distribution of outcomes. Our results suggest that the pharmacokinetics and pharmacodynamics of fulvestrant were the major drivers of final tumour size and composition. We then leveraged our model to guide therapeutic scheduling of combination palbociclib and fulvestrant, demonstrating the use of mathematical modelling to improve our understanding of cancer biology and treatments."
1763,Oncogenic reactivation of young L1s is a hallmark of colon cancer,"Devin Neu, Stevephen Hung, Cynthia F. Bartels, Zachary J. Faber, Katreya Lovrenert, W. Dean Pontius, Laura Morgan, Maharshi Chakraborty, Will Liao, Diana Chin, Ellen S. Hong, Jeremy Gray, Victor Moreno, Matthew Kalady, Ulrike Peters, Berkley Gryder, Richard C. Sallari, Peter C. Scacheri",https://www.biorxiv.org/content/10.1101/2023.05.17.541189v1,"Transposable elements become increasingly active in both cancerous and aging cells, driven by loss of DNA methylation as cells divide. Here we leverage the epigenomes of colon cancers with matched adjacent tissue, in addition to non-cancerous normals and cell line models, to assess the role of transposable elements as drivers or passengers in cancer development. Using the baseline of activity from normal and adjacent tissue, we show that the youngest subfamilies of the LINE1 (L1) family exhibit a degree of activity and recurrence across patients that goes beyond what is expected from hypomethylation and cell division, suggesting an additional mechanism of oncogenic reactivation. We characterize this mechanism and find that the loss of the tumor suppressor PLZF drives young L1 reactivation in a cell-division-independent manner. PLZF de-repression exposes abundant motifs for tumor core factors in the L1 5’UTR. Active young L1s act as oncogenic enhancers, interacting with oncogenes via gained chromatin loops. We uncover oncogenic L1 reactivation as a hallmark of colon cancer, where young L1s activate universally in our cohort at high levels of recurrence, act as enhancers to oncogenes, and become wired into the core regulatory circuitry of colon cancer."
1764,"A common druggable signature of oncogenic CMYC, mutant KRAS and mutant p53 reveals functional redundancy and competition of the oncogenes in cancer","Maria Grześ, Akanksha Jaiswar, Marcin Grochowski, Weronika Wojtyś, Wojciech Kaźmierczak, Tomasz Olesiński, Małgorzata Lenarcik, Magdalena Nowak-Niezgoda, Małgorzata Kołos, Giulia Canarutto, Silvano Piazza, Jacek R. Wiśniewski, Dawid Walerych",https://www.biorxiv.org/content/10.1101/2023.12.20.572548v1,"Major driver oncogenes CMYC, mutant KRAS and mutant TP53 often co-exist and cooperate in promoting human neoplasia. By CRISPR-Cas9-mediated downregulation we determined their proteomics and transcriptomics downstream programs in a panel of cell lines with activated either single or three oncogenes – in cancers of lung, colon and pancreas. This allowed to define and screen the oncogenes’ common functional program for anti-cancer target candidates, and find protocols which efficiently kill cancer cells and organoids by targeting pathways represented by a signature of three genes: RUVBL1, HSPA9 and XPO1. We found that these genes were controlled by the driver oncoproteins in a redundant or competitive manner, rather than by cooperation. Each oncoprotein individually was able to upregulate the three target genes, while upon oncogene co-expression each target was controlled preferably by a specific oncoprotein which reduced the influence of the others. Mechanistically this redundancy was mediated by parallel routes of the target gene activation – as in the case of mutant KRAS signaling to C-JUN and GLI-2 transcription factors bypassing CMYC, and by competition – as in the case of mutant p53 and CMYC competing for biding to the target promoters. The transcriptomics data from the cell lines and patient samples indicate that the redundancy of the oncogenic programs is a broad phenomenon which may comprise even a majority of the genes dependent on the oncoprotein, as shown for mutant p53 in colon and lung cancer cell lines. Nevertheless, we demonstrate that the redundant oncogene programs harbor targets of efficient anti-cancer drug combinations, bypassing limitations of a direct oncoprotein inhibition."
1766,Tumor-educated Gr1+CD11b+ cells instigate breast cancer metastasis by twisting cancer cells plasticity via OSM/IL6–JAK signaling,"Sanam Peyvandi, Manon Bulliard, Annamaria Kauzlaric, Oriana Coquoz, Yu-Ting Huang, Nathalie Duffey, Laetitia Gafner, Girieca Lorusso, Nadine Fournier, Qiang Lan, Curzio Rüegg",https://www.biorxiv.org/content/10.1101/2022.10.26.513889v2,"Cancer cell plasticity contributes to tumor therapy resistance and metastasis formation, which represent the main causes of cancer-related death for most cancers, including breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis and, thus, unravelling the underlying cues may provide novel effective strategies to manage metastatic disease. Here, we show that stem cell antigen-1 positive (Sca-1+) murine breast cancer cells enriched during tumor progression and metastasis have higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and initiate primary tumors rich in Gr1highCD11b+Ly6Clow cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently convert low metastatic 4T1-Sca-1- cells into highly metastatic 4T1-Sca-1+ cells via secreted OSM and IL6. Moreover, chemotherapy- resistant and highly metastatic 4T1-derived cells maintain high Sca-1+ frequency through cell autonomous IL6 production. Inhibition of OSM, IL6 or JAK suppressed Tu-Gr1+CD11b+-induced Sca-1+ population enrichment in vitro, while JAK inhibition abrogated metastasis of chemotherapy-enriched Sca-1+ cells in vivo. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter OS and RFS in breast cancer patients. Collectively, our data identified OSM/IL6-JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity triggering metastasis."
1767,HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer,"Yiran Liang, Yajie Wang, Yan Zhang, Fangzhou Ye, Dan Luo, Yaming Li, Yuhan Jin, Dianwen Han, Zekun Wang, Bing Chen, Wenjing Zhao, Lijuan Wang, Xi Chen, Tingting Ma, Xiaoli Kong, Qifeng Yang",https://www.biorxiv.org/content/10.1101/2022.10.25.513668v1,"Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating the chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered as an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ikβ-α and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-κB signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer, while targeting HSPB1 could be an effective strategy against breast cancer."
1769,Neratinib Synergizes with Trastuzumab Antibody Drug Conjugate or with Vinorelbine to Treat HER2 Mutated Breast Cancer Patient Derived Xenografts and Organoids,"Shunqiang Li, Tina M. Primeau, Maureen K. Highkin, Stephanie L. Pratt, Ashley R. Tipton, Nagalaxmi Vemalapally, John Monsey, Yu Tao, Jingqin Luo, Ian S. Hagemann, Chieh-Yu Lin, Lisa D. Eli, Cynthia X. Ma, Ron Bose",https://www.biorxiv.org/content/10.1101/2023.12.19.572069v1,"HER2 (ERBB2) is a major therapeutic drug target in breast cancer and The Cancer Genome Atlas (TCGA) Breast Cancer project and other studies have identified HER2 activating mutations in breast cancers without HER2 gene amplification. HER2 activating mutations occur in 2-5% of metastatic breast cancer patients (MBC), and clinical trials have shown that the irreversible pan-HER tyrosine kinase inhibitor, neratinib, produces a 31-40% clinical benefit rate for HER2 mutated MBC patients. We developed breast cancer patient-derived xenografts (PDX) from ER+, HER2 mutated MBC patients and used them to test neratinib-based drug combinations. Using organoid culture of these PDX breast cancer cells, we performed rapid, high-throughput ex vivo screening assays to test novel drug combinations. These organoid culture experiments identified drug synergy with the neratinib plus ado-trastuzumab emtansine (T-DM1) and neratinib plus vinorelbine combinations and we validated these results with in vivo PDX experiments."
1770,The translational role of SOS1 in colorectal cancer,"Diego Alem, Xinrui Yang, Francisca Beato, Bhaswati Sarcar, Alexandra F. Tassielli, Ruifan Dai, Tara L. Hogenson, Margaret A. Park, Kun Jiang, Jianfeng Cai, Yu Yuan, Martin E. Fernandez-Zapico, Aik Choon Tan, Jason B. Fleming, Hao Xie",https://www.biorxiv.org/content/10.1101/2022.10.14.512156v1,"Background It has been challenging to develop agents directly targeting KRAS driver mutations in colorectal cancer (CRC). Recent efforts have focused on developing inhibitors targeting SOS1 as an attractive approach for KRAS-mutant cancers. Here, we aimed to study the translational role of SOS1 in CRC using patient-derived organoids (PDOs)."
1771,Single-cell spatial atlas of tertiary lymphoid structures in ovarian cancer,"Joona Sarkkinen, Ada Junquera, Ella Anttila, Angela Szabo, Fernando Perez, Inga-Maria Launonen, Anna Laury, Julia Casado, Eliisa Kekäläinen, Anniina Färkkilä",https://www.biorxiv.org/content/10.1101/2023.05.16.540946v1,"Background Recent advances in highly-multiplexed tissue technologies and image analysis tools have enabled a more detailed investigation of the tumor microenvironment (TME) and its spatial features, including tertiary lymphoid structures (TLSs), at single-cell resolution. TLSs play a major part in antitumor immune responses, however, their role in antitumor immunity in ovarian cancer remains largely unexplored."
1772,Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing,"Ying Liu, Ezequiel Dantas, Miriam Ferrer, Yifang Liu, Aram Comjean, Emma E. Davidson, Yanhui Hu, Marcus D. Goncalves, Tobias Janowitz, Norbert Perrimon",https://www.biorxiv.org/content/10.1101/2023.05.15.540823v1,"Summary A primary cause of death in cancer patients is cachexia, a wasting syndrome attributed to tumor-induced metabolic dysregulation. Despite the major impact of cachexia on the treatment, quality of life, and survival of cancer patients, relatively little is known about the underlying pathogenic mechanisms. Hyperglycemia detected in glucose tolerance test is one of the earliest metabolic abnormalities observed in cancer patients; however, the pathogenesis by which tumors influence blood sugar levels remains poorly understood. Here, utilizing a Drosophila model, we demonstrate that the tumor secreted interleukin-like cytokine Upd3 induces fat body expression of Pepck1 and Pdk, two key regulatory enzymes of gluconeogenesis, contributing to hyperglycemia. Our data further indicate a conserved regulation of these genes by IL-6/JAK STAT signaling in mouse models. Importantly, in both fly and mouse cancer cachexia models, elevated gluconeogenesis gene levels are associated with poor prognosis. Altogether, our study uncovers a conserved role of Upd3/IL-6/JAK-STAT signaling in inducing tumor-associated hyperglycemia, which provides insights into the pathogenesis of IL-6 signaling in cancer cachexia."
1773,Estrogen receptor alpha mutations regulate gene expression and cell growth in breast cancer through microRNAs,"Spencer Arnesen, Jacob T. Polaski, Zannel Blanchard, Kyle S. Osborne, Alana L. Welm, Ryan M. O’Connell, Jason Gertz",https://www.biorxiv.org/content/10.1101/2022.10.07.511340v2,"Estrogen receptor α (ER) mutations occur in up to 30% of metastatic ER-positive breast cancers. Recent data has shown that ER mutations impact the expression of thousands of genes not typically regulated by wildtype ER. While the majority of these altered genes can be explained by constant activity of mutant ER or genomic changes such as altered ER binding and chromatin accessibility, as much as 33% remain unexplained, indicating the potential for post-transcriptional effects. Here we explored the role of microRNAs in mutant ER-driven gene regulation and identified several microRNAs that are dysregulated in ER mutant cells. These differentially regulated microRNAs target a significant portion of mutant-specific genes involved in key cellular processes. When the activity of microRNAs is altered using mimics or inhibitors, significant changes are observed in gene expression and cellular proliferation related to mutant ER. An in-depth evaluation of miR-301b led us to discover an important role for PRKD3 in the proliferation of ER mutant cells. Our findings show that microRNAs contribute to mutant ER gene regulation and cellular effects in breast cancer cells."
1775,CRACD loss promotes small cell lung cancer tumorigenesis via EZH2-mediated immune evasion,"Shengzhe Zhang, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Kyung-Pil Ko, Gengyi Zou, Jie Zhang, Sohee Jun, Nicole A. Kirk, Ye Eun Hwang, Young Ho Ban, Joseph M. Chan, Charles M. Rudin, Kwon-Sik Park, Jae-Il Park",https://www.biorxiv.org/content/10.1101/2023.02.15.528365v2,"The mechanisms underlying immune evasion and immunotherapy resistance in small cell lung cancer (SCLC) remain unclear. Herein, we investigate the role of CRACD tumor suppressor in SCLC. We found that CRACD is frequently inactivated in SCLC, and Cracd knockout (KO) significantly accelerates SCLC development driven by loss of Rb1, Trp53, and Rbl2. Notably, the Cracd-deficient SCLC tumors display CD8+ T cell depletion and suppression of antigen presentation pathway. Mechanistically, CRACD loss silences the MHC-I pathway through EZH2. EZH2 blockade is sufficient to restore the MHC-I pathway and inhibit CRACD loss-associated SCLC tumorigenesis. Unsupervised single-cell transcriptomic analysis identifies SCLC patient tumors with concomitant inactivation of CRACD, impairment of tumor antigen presentation, and downregulation of EZH2 target genes. Our findings define CRACD loss as a new molecular signature associated with immune evasion of SCLC cells and proposed EZH2 blockade as a viable option for CRACD-negative SCLC treatment."
1777,The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes,"Amaia Jauregi-Miguel, Simon Söderholm, Tamina Weiss, Anna Nordin, Valeria Ghezzi, Salome M. Brütsch, Pierfrancesco Pagella, Yorick van de Grift, Gianluca Zambanini, Jacopo Ulisse, Alessandro Mattia, Ruslan Deviatiiarov, Elena Faustini, Lavanya Moparthi, Francisca Lottersberger, Stefan Koch, Andreas E. Moor, Xiao-Feng Sun, Eleonore von Castelmur, Guojun Sheng, Claudio Cantù",https://www.biorxiv.org/content/10.1101/2023.12.18.571901v1,"Wnt signaling orchestrates gene expression in a plethora of processes during development and adult cell homeostasis via the action of nuclear β-catenin. Furthermore, neoplasia of the colorectal epithelium begins with aberrant Wnt/β-catenin signaling. Yet, little is known about how β-catenin generates context-specific transcriptional outcomes. We have previously identified the developmental transcription factor TBX3 as a tissue-specific component of the Wnt/β-catenin nuclear complex during mouse forelimb development. In this study, we show that TBX3 is present and functionally active in human colorectal cancers. TBX3’s genomic binding pattern suggests a regulatory role that broadly coincides with that of Wnt/β-catenin. Moreover, proteomics proximity labelling indicated that, during Wnt pathway activation, TBX3 is vicinal to several protein partners, including the transcription factors TCF/LEF and chromatin remodeling complexes which are usually found at Wnt responsive elements. Sequence and structure analysis revealed that TBX3 possesses an exposed Asp-Pro-Phe (NPF) motif predicted by AlphaFold2 Multimer to mediate direct interactions with several Wnt-activated TBX3 partners. Deletion of NPF abrogates TBX3 proximity to these partners and its ability to modulate Wnt-dependent transcription. TBX3 emerges as a key modulator of the oncogenic activity of Wnt/β-catenin in colorectal cancer, and its mechanism of action exposes a novel druggable protein-interaction surface."
1778,Selective Impact of ALK and MELK Inhibition on ERα Stability and Cell Proliferation in Cell Lines Representing Distinct Molecular Phenotypes of Breast Cancer,"Stefania Bartoloni, Sara Pescatori, Fabrizio Bianchi, Manuela Cipolletti, Filippo Acconcia",https://www.biorxiv.org/content/10.1101/2023.12.19.572304v1,"Breast cancer (BC) is a leading cause of global cancer-related mortality in women, necessitating accurate tumor classification for timely intervention. Molecular and histological factors, including PAM50 classification, estrogen receptor α (ERα), breast cancer type 1 susceptibility protein (BRCA1), progesterone receptor (PR), and HER2 expression, contribute to intricate BC subtyping. Through in silico screenings and multiple BC cell line investigations, we identified enhanced sensitivity of ERα-positive BC cell lines to ALK and MELK inhibitors, inducing ERα degradation and diminishing proliferation in specific BC subtypes. MELK inhibition attenuated ERα transcriptional activity, impeding E2-induced gene expression, and hampering proliferation in MCF-7 cells. Synergies between MELK inhibition with 4OH-tamoxifen (Tam) and ALK inhibition with HER2 inhibitors revealed potential therapeutic avenues for ERα-positive/PR-positive/HER2-negative and ERα-positive/PR-negative/HER2-positive tumors, respectively. Our findings propose MELK as a promising target for ERα-positive/PR-positive/HER2-negative BC and highlight ALK as a potential focus for ERα-positive/PR-negative/HER2-positive BC. The synergistic anti-proliferative effects of MELK with Tam and ALK with HER2 inhibitors underscore kinase inhibitors’ potential for selective treatment in diverse BC subtypes, paving the way for personalized and effective therapeutic strategies in BC management."
1781,Multiscale model of the different modes of cancer cell invasion,"Marco Ruscone, Arnau Montagud, Philippe Chavrier, Olivier Destaing, Isabelle Bonnet, Andrei Zinovyev, Emmanuel Barillot, Vincent Noël, Laurence Calzone",https://www.biorxiv.org/content/10.1101/2022.10.07.511296v3,"Mathematical models of biological processes implicated in cancer are built using the knowledge of complex networks of signaling pathways, describing the molecular regulations inside different cell types, such as tumor cells, immune and other stromal cells. If these models mainly focus on intracellular information, they often omit a description of the spatial organization among cells and their interactions, and with the tumoral microenvironment. We present here a model of tumor cell invasion simulated with PhysiBoSS, a multiscale framework which combines agent-based modeling and continuous time Markov processes applied on Boolean network models. With this model, we aim to study the different modes of cell migration by considering both spatial information obtained from the agent-based simulation and intracellular regulation obtained from the Boolean model. Our multiscale model integrates the impact of gene mutations with the perturbation of the environmental conditions and allows the visualization of the results with 2D and 3D representations. The model successfully reproduces single and collective migration processes and is validated on published experiments on cell invasion. In silico experiments are suggested to search for possible targets that can block the more invasive tumoral phenotypes."
1783,Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression,"Madhura R. Pandkar, Sommya Sinha, Atul Samaiya, Sanjeev Shukla",https://www.biorxiv.org/content/10.1101/2023.05.14.540730v1,"Owing to the enhanced glycolytic rate, cancer cells generate lactate copiously, which in turn, promotes lactylation of histone. Even though histone lactylation has been explored to alter the expression of few genes, the role of this epigenetic modification in regulating the expression of oncogenes is largely unchartered. In this study, using breast cancer cell lines their mutants (which exhibit lactate-deficient metabolome), we have identified that intracellular lactate promotes histone lactylation-dependent c-Myc upregulation. Furthermore, we report that the c-Myc upregulates serine/arginine splicing factor 10 (SRSF10) to drive alternative splicing in breast cancer cells. Our findings provide novel mechanistic insights into the role assayed by aerobic glycolysis in orchestrating alternative splicing that collectively drive breast tumorigenesis. Moreover, we also envisage that chemotherapeutic interventions attenuating glycolytic rate can restrict breast cancer progression by impeding the c-Myc-SRSF10 axis."
1784,Single Cell lineage Tracing Identifies Cancer Testis Antigens as Mediators of Chemoresistance in Small Cell Lung Cancer,"Hannah Wollenzien, Yohannes Afeworki, Robert Szczepaniak-Sloane, Anthony Restaino, Michael S. Kareta",https://www.biorxiv.org/content/10.1101/2022.10.20.513051v1,"Small Cell Lung Cancer (SCLC) is often a heterogeneous tumor, where dynamic regulation of key transcription factors can drive multiple populations of phenotypically different cells which contribute differentially to tumor dynamics. This tumor is characterized by a very low 2-year survival rate, high rates of metastasis, and rapid acquisition of chemoresistance. The heterogeneous nature of this tumor makes it difficult to study and to treat, as it is not clear how or when this heterogeneity arises. Here we describe temporal, single-cell analysis of SCLC to investigate tumor initiation and chemoresistance in both SCLC xenografts and in situ SCLC mouse models. We identify an early population of tumor cells with high expression of AP-1 network genes that are critical for tumor growth. Furthermore, we have identified and validated the cancer testis antigens (CTAs) PAGE5 and GAGE2A as mediators of chemoresistance in human SCLC. CTAs have successfully been targeted in other tumor types and may be a promising avenue for targeted therapy in SCLC."
1786,3D organoid modeling identified that targeting IGF1R signaling may overcome drug resistance in breast cancer,"Ekansh Mittal, David Qian",https://www.biorxiv.org/content/10.1101/2023.05.14.540701v1,"Breast cancer is the most frequently diagnosed cancer and the second largest cause of cancer deaths in women. However, drug resistance and poor response to treatments are common. Thus, there is an unmet need to identify new treatments and effective lab-based drug testing methods. Here we established a novel 3-dimensional organoid method by co-culturing cancer cells with healthy endothelial cells for longer-term testing of new drug combinations that combat drug resistance. As a proof-of-concept we showed that paclitaxel efficacy can be improved by combining it with AKT inhibitors. In addition, we identified a new triple combination of paclitaxel, HER2 inhibitor, and IGF1R inhibitor, which is more effective in increasing cell death and reducing organoid growth. Interestingly, many IGF1R pathway members are upregulated in breast cancer patients, and high expression is associated with poor survival, indicating that IGF1R is an attractive therapeutic target. Overall, using this novel organoid method, we can mimic more accurate culture conditions and identify new targets to be tested in clinical trials. Our approach is applicable to various cancers to improve patients’ outcomes."
1787,"STimage:robust, confident and interpretable models for predicting gene markers from cancer histopathological images","Xiao Tan, Onkar Mulay, Samual MacDonald, Taehyun Kim, Jason Werry, Peter T Simpson, Fred Roosta, Maciej Trzaskowski, Quan Nguyen",https://www.biorxiv.org/content/10.1101/2023.05.14.540710v1,"Spatial transcriptomic (ST) data enables us to link tissue morphological features with thousands of unseen gene expression values, opening a horizon for breakthroughs in digital pathology. Models to predict the presence/absence, high/low, or continuous expression of a gene using images as the only input have a huge potential clinical applications, but such models require improvements in accuracy, interpretability, and robustness. We developed STimage models to estimate parameters of gene expression as distributions rather than fixed data points, thereby allowing for the essential quantification of uncertainty in the predicted results. We assessed aleatoric and epistemic uncertainty of the models across a diverse range of test cases and proposed an ensemble approach to improve the model performance and trust. STimage can train prediction models for one gene marker or a panel of markers and provides important interpretability analyses at a single-cell level, and in the histopathological annotation context. Through a comprehensive benchmarking with existing models, we found that STimage is more robust to technical variation in platforms, data types, and sample types. Using images from the cancer genome atlas, we showed that STimage can be applied to non-spatial omics data. STimage also performs better than other models when only a small training dataset is available. Overall, STimage contributes an important methodological advance needed for the potential application of spatial technology in cancer digital pathology."
1788,Live Cell Lineage Tracing of Dormant Cancer Cells,"Hyuna Kim, Anna Wirasaputra, Aritra Nath Kundu, Jennifer A.E. Esteves, Shelly R. Peyton",https://www.biorxiv.org/content/10.1101/2022.10.08.511405v1,"Breast cancer is a leading cause of global cancer-related deaths, and metastasis is the overwhelming culprit of poor patient prognosis. The most nefarious aspect of metastasis is dormancy, a prolonged period between primary tumor resection and relapse. Current therapies are insufficient at killing dormant cells; thus, they can remain quiescent in the body for decades until eventually undergoing a phenotypic switch, resulting in metastases that are more adaptable and more drug resistant. Unfortunately, dormancy has few in vitro models, largely because lab-derived cell lines are highly proliferative. Existing models address tumor dormancy, not cellular dormancy, because tracking individual cells is technically challenging. To combat this problem, we adapted a live cell lineage approach to find and track individual dormant cells, distinguishing them from proliferative and dying cells over multiple days. We applied this approach across a range of different in vitro microenvironments. Our approach revealed that the proportion of cells that exhibited long-term quiescence was regulated by both cell intrinsic and extrinsic factors, with the most dormant cells found in 3D collagen gels. We hope this approach will prove useful to biologists and bioengineers in the dormancy community to identify, quantify, and study dormant tumor cells."
1789,Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth,"Ying Zhang, Kaijing Chen, Seng Chuan Tang, Yichao Cai, Akiko Nambu, Yi Xiang See, Chaoyu Fu, Anandhkumar Raju, Benjamin Lebeau, Zixun Ling, Marek Mutwil, Manikandan Lakshmanan, Motomi Osato, Vinay Tergaonkar, Melissa Jane Fullwood",https://www.biorxiv.org/content/10.1101/2023.08.29.555291v1,"Human silencers have been shown to exist and regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form “super-silencers” and whether they are linked to cancer progression. Here, through interrogating two putative silencer components of FGF18 gene, we found that two nearby silencers can cooperate via compensatory chromatin interactions to form a “super-silencer”. Furthermore, double knockout of two silencers exhibited synergistic upregulation of FGF18 expression and changes of cell identity. To perturb the “super-silencers”, we applied combinational treatment of an EZH2 inhibitor GSK343, and a REST inhibitor, X5050 (“GR”). We found that GR led to severe loss of TADs and loops, while the use of one inhibitor by itself only showed mild changes. Such changes in TADs and loops were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GSK343 and X5050 synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects both in vitro and in vivo. Overall, our data demonstrated the first example of a “super-silencer” and showed that combinational usage of GSK343 and X5050 to disrupt “super-silencers” could potentially lead to cancer ablation."
1791,Hybrid computational modeling highlights reverse Warburg effect in breast cancer-associated fibroblasts,"Sahar Aghakhani, Sacha E Silva-Saffar, Sylvain Soliman, Anna Niarakis",https://www.biorxiv.org/content/10.1101/2023.05.11.540378v1,"Cancer-associated fibroblasts (CAFs) are key players of the tumor microenvironment (TME) involved in cancer initiation, progression, and resistance to therapy. These cells exhibit aggressive phenotypes affecting, among others, extracellular matrix remodeling, angiogenesis, immune system modulation, tumor growth, and proliferation. CAFs phenotypic changes appear to be associated with metabolic alterations, notably a reverse Warburg effect that may drive fibroblasts transformation. However, its precise molecular mechanisms and regulatory drivers are still under investigation. Deciphering the reverse Warburg effect in breast CAFs may contribute to a better understanding of the interplay between TME and tumor cells, leading to new treatment strategies. In this regard, dynamic modeling approaches able to span multiple biological layers are essential to capture the emergent properties of various biological entities when complex and intertwined pathways are involved. This work presents the first hybrid large-scale computational model for breast CAFs covering major cellular signaling, gene regulation, and metabolic processes. It was generated by combining an asynchronous cell- and disease-specific regulatory Boolean model with a generic core metabolic network leveraging both data-driven and manual curation approaches. This model reproduces the experimentally observed reverse Warburg effect in breast CAFs and further identifies Hypoxia-Inducible Factor 1 (HIF-1) as its key molecular driver. Targeting HIF-1 as part of a TME-centered therapeutic strategy may prove beneficial in the treatment of breast cancer by addressing the reverse Warburg effect. Such findings in CAFs, considering our previously published results in rheumatoid arthritis synovial fibroblasts, point to a common HIF-1-driven metabolic reprogramming of fibroblasts in breast cancer and rheumatoid arthritis."
1792,"A Gene Encoding an Architectural RNA, hsrω, is a Host Genetic Modifier of Cancer Progression in Drosophila","Anjali Bajpai, Sushmita Kundu, Ravi Kant Pandey, Bushra Ateeq, Subhash C. Lakhotia, Pradip Sinha",https://www.biorxiv.org/content/10.1101/2021.04.26.441543v2,"Genetic variations among individuals within a population, or host genetics, determine disease susceptibility or resistance. Here we show that heterozygosity of hsrω, a gene coding for a long noncoding architectural RNA (arcRNA), displays cancer susceptibility in Drosophila. Imaginal epithelia mutant for a null allele of hsrω, hsrω66 exhibits chronic stress, marked by loss of growth and proteostasis, besides cell death. Imaginal epithelia of larvae heterozygous for hsrω66 also show cellular stress, but conditionally: for instance, upon heat shock. Somatic clones displaying loss of Lgl tumor suppressor in such stress-sensitive imaginal epithelia of hsrω66 heterozygotes develop into metastatic tumors, unlike those induced in wild type epithelia wherein these are eliminated by intrinsic tumor suppression. Further, cell-autonomous gain or loss of hsrω in lgl mutant clones, too, results in their tumor progression. Finally, we note a transcriptional increase in human sat III arcRNA, a functional analog of Drosophila hsrω, in cancer cell lines. Loss of sat III decreases the viability of cancer cells under stress. Our findings suggest pervasive roles of arcRNA-coding genes as host genetic modifiers of cancer via their regulation of cell homeostasis."
1793,Deciphering of Somatic Mutational Signatures of Cancer,"Xiangwen Ji, Edwin Wang, Qinghua Cui",https://www.biorxiv.org/content/10.1101/2022.03.01.482591v2,"Somatic mutational signatures (MSs) identified by genome sequencing play important roles in exploring the cause and development of cancer. Thus far, many such signatures have been identified, and some of them do imply causes of cancer. However, a major bottleneck is that we do not know the potential meanings (i.e., cancer causal or biological functions) and contributing genes for most of them. Here we presented a computational framework, Gene Somatic Genome Pattern (GSGP), which can decipher the molecular mechanisms of the MSs. More importantly, it is the first time, GSGP is able to process MSs from RNA sequencing, which greatly extended the applications of both MS analysis and RNA sequencing. As a result, GSGP analysis matches consistently with previous reports and identify the aetiologies for a number of novel signatures. Notably, we applied GSGP to RNA sequencing data and revealed an RNA-derived MS involved in deficient DNA mismatch repair (dMMR) and microsatellite instability (MSI) in colorectal cancer (CRC)."
1794,Integrative Multi-Omics Approaches for Identifying Cervical Cancer Therapeutic Targets,"Santosh Kumari Duppala, Rajesh Yadala, Aayushi Velingkar, Prashanth Suravajhala, Smita C Pawar, Sugunakar Vuree",https://www.biorxiv.org/content/10.1101/2022.10.07.511244v1,"After breast cancer, cervical cancer (CC) is one of the most common malignancies in women globally. Over 90% of chronic infections are caused by human papillomavirus (HPV) and its subtypes. Extensive research efforts are required to identify the treatment targets and prognostic indicators for recurring and metastatic cancers. It may be possible because of omics methods, including genomes, epigenomics, transcriptomics, proteomics, and metabolomics. High throughput (HT) data on the differential mRNA and miRNA expression and their crucial interrelationships enable promising integration and interpretation of the results. Clinical data and multi-omics have risen to the top of the heap in delivering molecular and cellular activities. They aid in comparing data from different omics approaches and bridging the gap between genotype and phenotype. Therefore, multi-omic techniques may improve the knowledge of the molecular basis of the physiology and primary cause of disease, revealing a new route for the prognosis, diagnosis, prevention, and therapy of human diseases."
1797,KLIPP - a precision CRISPR approach to target structural variant junctions in cancer,"Huibin Yang, Radhika Suhas Hulbatte, Alan Kelleher, Natalie Gratsch, Yin Wang, Philip L. Palmbos, Mats Ljungman",https://www.biorxiv.org/content/10.1101/2023.05.10.540176v2,"Current cancer therapies typically give rise to dose-limiting normal tissue toxicity. We have developed KLIPP, a precision cancer approach that specifically kills cancer cells using CRISPR/Cas9 technology. The approach consists of guide RNAs that target cancer-specific structural variant junctions to nucleate two parts of a dCas9-conjugated endonuclease, Fok1, leading to its activation. We show that KLIPP causes induction of DNA double strand breaks (DSBs) at the targeted junctions and cell death. When cancer cells were grown orthotopically in mice, activation of Fok1 at only two junctions led to the disappearance of tumor cells in 7/11 mice. This therapeutic approach has high specificity for tumor cells and is independent of tumor-specific drivers. Individualized translation of KLIPP to patients would be transformative and lead to consistent and simplified cancer treatment decisions."
1798,Integrating current analyses of the breast cancer microbiome,"Sidra Sohail, Michael B. Burns",https://www.biorxiv.org/content/10.1101/2022.10.02.510553v1,"Breast cancer is the second leading cause of cancer death for women in the US (American Cancer Society: About Breast Cancer, n.d.). Many cancer types have significant associations with their resident microbial communities - emerging evidence suggests that breast cancers also interact with the local tissue-associated microbiota. Studies have examined the relationship between breast cancer and its microbiome, however, the studies varied in their approaches used to evaluate these relationships. Microbiome research advances rapidly and analysis pipelines and databases are updated frequently. This dynamic environment makes inter-study comparisons and superficial evaluations challenging as no two studies are using the same standards for evaluation."
1799,A high-throughput screening approach to discover potential colorectal cancer chemotherapeutics: Repurposing drugs to disrupt 14-3-3 protein-BAD interactions,"Siyi He, Luis Delgadillo Silva, Guy A. Rutter, Gareth E. Lim",https://www.biorxiv.org/content/10.1101/2023.12.14.571727v1,"Inducing apoptosis in different types of cancer cells is an effective therapeutic strategy. However, the success of existing chemotherapeutics can be compromised by tumor cell resistance and systemic off-target effects. Therefore, the discovery of pro-apoptotic compounds with minimal systemic side-effects is crucial. 14-3-3 proteins are molecular scaffolds that serve as important regulators of cell survival. Our previous study demonstrated that 14-3-3ζ can sequester BAD, a pro-apoptotic member of the BCL-2 protein family, in the cytoplasm and prevent its translocation to mitochondria to inhibit the induction of apoptosis. Despite being a critical mechanism of cell survival, it is unclear whether disrupting 14-3-3 protein:BAD interactions could be harnessed as a chemotherapeutic approach. Herein, we established a BRET-based high-throughput drug screening approach (Z’-score= 0.52) capable of identifying molecules that can disrupt 14-3-3ζBAD interactions. An FDA-approved drug library containing 1971 compounds was used for screening, and the capacity of identified hits to induce cell death was examined in NIH3T3-fibroblasts and colorectal cancer cell lines, HT-29 and Caco-2. Our in vitro results suggest that terfenadine, penfluridol, and lomitapide could be potentially repurposed for treating colorectal cancer. Moreover, our screening method demonstrates the feasibility of identifying pro-apoptotic agents that can be applied towards conditions where aberrant cell growth or function are key determinants of disease pathogenesis."
1800,Schisandrin B suppresses colon cancer growth by inducing cell cycle arrest and apoptosis via the CHOP signalling pathway,"Vanessa Anna Co, Hani El-Nezami, Yawen Liu, Bonsra Twum, Priyanka Dey, Paul A Cox, Shalu Joseph, Roland Agbodjan, Mehdi Sabzichi, Roger Draheim, Murphy Lam Yim Wan",https://www.biorxiv.org/content/10.1101/2023.08.27.554980v1,"Colon cancer is among the most lethal and prevalent malignant tumours in the world, and the lack of effective therapies highlights the need for novel therapeutic approaches. Schisandrin B (Sch B), a lignan extracted from the fruit Schisandra chinensis, has been reported for its anti-cancer properties. However, no studies to date have been done to characterise the exact molecular mechanisms regarding the anti-tumorigenic effect of Sch B in colon cancer. A comprehensive analysis of the molecular mechanism for the anti-tumorigenic effect of Sch B on human colon cancer cells was performed using combination of Raman spectroscopy, RNA-seq, computational docking and molecular biological experiments. The in vivo efficacy was evaluated by a mouse xenograft model. Sch B reduced cell proliferation and triggered apoptosis in human colon cancer cell lines. Raman spectroscopy, computational, RNA-seq, molecular and cellular studies revealed that Sch B activated unfolded protein responses by interacting with CHOP and upregulating CHOP, which thereby induced apoptosis. CHOP knockdown alleviated the Sch B-induced reduction in cell viability and apoptosis. Sch B reduced colon tumour growth in vivo. Our findings provide essential background for clinical trials examining the effects of Sch B in patients with colon cancer."
1801,Stromal signals dominate gene expression signature scores that aim to describe cancer-intrinsic stemness or mesenchymality characteristics,"Julian Kreis, Bogac Aybey, Felix Geist, Benedikt Brors, Eike Staub",https://www.biorxiv.org/content/10.1101/2023.08.25.554747v1,"Purpose Epithelial-to-mesenchymal transition (EMT) in cancer cells confers migratory ability, a crucial aspect of tumor metastasis that frequently leads to death. In multiple studies, authors proposed gene expression signatures for EMT, stemness, and mesenchymality (EMT-related) characteristics of tumors based on bulk tumor expression profiling. However, recent studies have suggested that non-cancerous cells in the tumor micro- or macroenvironment heavily influence individual signature profiles."
1802,Mammalian orthoreovirus infection in human epidermal growth factor receptor 2 positive (HER2+) breast cancer cells,"Nicole A. Jandick, Nicolette Kirner, Cathy L. Miller",https://www.biorxiv.org/content/10.1101/2023.05.10.540250v1,"Mammalian orthoreovirus (MRV) is a clinically benign oncolytic virus which has been investigated for use in multiple cancer types, including breast cancer (BC). In human clinical trials, MRV has been shown to be safe, and multiple BC patients have shown partial responses to intratumoral and intravenous virus delivery. Combination therapies inclusive of MRV and current FDA approved BC chemotherapies are being investigated to target metastatic, early BC, and triple negative BC. Though MRV is being tested clinically, we still do not fully understand the highly variable patient responses to MRV therapy. One of the most aggressive BC subtypes is HER2+ BC, in which human epidermal growth factor receptor 2 (HER2) is dysregulated, resulting in increased growth, survival, and metastasis of cancer cells. FDA approved therapies, trastuzumab and pertuzumab, target HER2 to prevent signaling of the phosphoinositide 3-kinase (PI3K) pathway. However, recent findings show that accumulation of hypoxia inducible factor-1 alpha (HIF-1α) in HER2+ BC cells contributes to trastuzumab resistance. In this work, we provide evidence that MRV infects, replicates in, and kills HER2 overexpressing cells. MRV infection is also found to have variable effects on signaling pathways that activate or are activated by HER2 expression. Finally, we show that MRV reduces HIF-1α accumulation in all the cell lines tested, including a HER2+ BC cell line. These studies provide further evidence that MRV holds promise for use in conjunction with trastuzumab to treat HER2+ BC patients."
1804,EvAM-Tools: tools for evolutionary accumulation and cancer progression models,"Ramon Diaz-Uriarte, Pablo Herrera-Nieto",https://www.biorxiv.org/content/10.1101/2022.07.05.498481v2,"EvAM-Tools is an R package and web application that provides a unified interface to state-of-the-art cancer progression models (CPMs) and, more generally, evolutionary models of event accumulation. The output includes, in addition to the fitted models, the transition (and transition rate) matrices between genotypes and the probabilities of evolutionary paths. Generation of random cancer progression models is also available. Using the GUI in the web application, users can easily construct models (modifying Directed Acyclic Graphs —DAGs— of restrictions, matrices of mutual hazards, or specifying genotype composition), generate data from them (with user-specified observational/genotyping error), and analyze the data."
1805,SeMOE allows for quantitative glycan perception and exhibits anti-cancer potentiality,"Xiao Tian, Lingna Zheng, Changjiang Wang, Yida Han, Yujie Li, Tongxiao Cui, Jialin Liu, Chuanming Liu, Guogeng Jia, Lujie Yang, Chen Zeng, Lijun Ding, Chu Wang, Bo Cheng, Meng Wang, Ran Xie",https://www.biorxiv.org/content/10.1101/2023.05.08.539922v1,"Metabolic oligosaccharide engineering (MOE) is a classical chemical approach to perturb, profile and perceive glycans in physiological systems, but probes upon bioorthogonal reaction require accessibility and background signal readout makes it challenging to achieve absolute glycan quantification. Here we develop SeMOE, a selenosugar-based metabolic oligosaccharide engineering strategy that combines elemental analysis and MOE to enable the absolute quantification and mass spectrometric imaging of glycome in a concise procedure. We demonstrate that SeMOE probes allow for perception, absolute quantification and visualization of glycans in diverse biological contexts. We demonstrate that chemical reporters on conventional MOE can be integrated into a bifunctional SeMOE probe to provide multimodality signal readouts. We further show the anti-cancer potentiality of SeMOE probes. SeMOE thus provides a convenient and simplified method to “see more” of the glyco-world."
1806,The impact of extracellular matrix on the precision medicine utility of pancreatic cancer patient-derived organoids,"Jan C. Lumibao, Shira R. Okhovat, Kristina L. Peck, Xiaoxue Lin, Kathryn Lande, Jingjing Zou, Dannielle D. Engle",https://www.biorxiv.org/content/10.1101/2023.01.26.525757v2,"The use of patient-derived organoids (PDOs) to characterize therapeutic sensitivity and resistance (pharmacotyping) is a promising precision medicine approach. The potential of this approach to inform clinical decisions is now being tested in several large multi-institutional clinical trials. PDOs are cultivated in extracellular matrix from basement membrane extracts (BMEs) that are most commonly acquired commercially. Each clinical site utilizes distinct BME lots and may be restricted due to the availability of commercial BME sources. However, the impact of different sources and lots of BMEs on organoid drug response is unknown. Here, we tested the impact of BME source and lot on proliferation, chemotherapy and targeted therapy drug response, and gene expression in mouse and human pancreatic ductal adenocarcinoma (PDA) organoids. Both human and mouse organoids displayed increased proliferation in Matrigel (Corning) compared to Cultrex (RnD) and UltiMatrix (RnD). However, we observed no substantial impact on drug response when oragnoids were cultured in Matrigel, Cultrex, or UltiMatrix. We also did not observe major shifts in gene expression across the different BME sources, and PDOs maintained their Classical or Basal-like designation. Overall, we find that BME source (Matrigel, Cultrex, UltiMatrix) does not shift PDO dose-response curves and drug testing results, indicating that PDO pharmacotyping is a robust approach for precision medicine."
1808,Auranofin Inhibition of Thioredoxin Reductase Sensitizes Lung Neuroendocrine Tumor Cells (NETs) and Small Cell Lung Cancer (SCLC) Cells to Sorafenib as well as Inhibiting SCLC Xenograft Growth,"Spenser S. Johnson, Dijie Liu, Jordan T. Ewald, Claudia Robles-Planells, Keegan A. Christensen, Khaliunaa Bayanbold, Brian R. Wels, Shane R. Solst, M. Sue O’Dorisio, Bryan G. Allen, Yusuf Menda, Douglas R. Spitz, Melissa A. Fath",https://www.biorxiv.org/content/10.1101/2023.05.07.539772v2,"Thioredoxin Reductase (TrxR) is a key enzyme in hydroperoxide detoxification through peroxiredoxin enzymes and in thiol-mediated redox regulation of cell signaling. Because cancer cells produce increased steady-state levels of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide), TrxR is currently being targeted in clinical trials using the anti-rheumatic drug, auranofin (AF). AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the lung atypical (neuroendocrine tumor) NET cell line H727. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, a multi-kinase inhibitor that was shown to decrease intracellular glutathione. The pharmacokinetic and pharmacodynamic properties of AF treatment in a mouse SCLC xenograft model was examined to maximize inhibition of TrxR activity without causing toxicity. AF was administered intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1 to 5 days in mice with DMS273 xenografts. Plasma levels of AF were 10-20 μM (determined by mass spectrometry of gold) and the optimal inhibition of TrxR (50 %) was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. When this daily AF treatment was extended for 14 days a significant prolongation of median survival from 19 to 23 days (p=0.04, N=30 controls, 28 AF) was observed without causing changes in animal bodyweight, CBCs, bone marrow toxicity, blood urea nitrogen, or creatinine. These results show that AF is an effective inhibitor of TrxR both in vitro and in vivo in SCLC, capable of sensitizing NETs and SCLC to sorafenib, and supports the hypothesis that AF could be used as an adjuvant therapy with agents known to induce disruptions in thiol metabolism to enhance therapeutic efficacy."
1809,Metastatic potentials classified with hypoxia-inducible factor 1 downstream gene in pan-cancer cell lines,"Kazuya Nakamichi, Kentaro Semba, Jun Nakayama",https://www.biorxiv.org/content/10.1101/2023.05.08.539810v1,"Hypoxia-inducible factor 1 (HIF1) gene codes a transcription factor that is stabilized under hypoxia conditions via post-translational modifications. HIF1 regulates tumor malignancy and metastasis by gene transcriptions, such as Warburg effect- and angiogenesis-related genes, in cancer cells. However, the HIF1 downstream genes show varied expressional patterns in different cancer types. Herein, we performed the hierarchical clustering based on the HIF1 downstream gene expression patterns using 1,406 cancer cell lines crossing 30 types of cancer to understand the relationship between HIF1 downstream genes and the metastatic potential of cancer cell lines. Four types of cancer were classified by HIF1 downstream genes with significantly altered metastatic potentials. Furthermore, different HIF1 downstream gene subsets were extracted to discriminate each subtype for the four cancer types. HIF1 downstream subtyping classification will help understand the novel insight into tumor malignancy and metastasis in each cancer type."
1810,TBX2 driven switch from Androgen Receptor to Glucocorticoid Receptor signaling confers therapeutic resistance in Prostate Cancer,"Sayanika Dutta, Girijesh Kumar Patel, Hamed Khedmatgozar, Daniel Latour, Manisha Tripathi, Srinivas Nandana",https://www.biorxiv.org/content/10.1101/2023.05.07.539754v1,"Recent studies have highlighted that androgen receptor (AR) signaling can be bypassed via activation of the glucocorticoid receptor (GR), and that this bypass drives enzalutamide resistance in advanced prostate cancer (PCa). However, the molecular mechanism(s) that drive the switch from AR to GR signaling remain unknown. We have previously reported that TBX2, a developmental T-box transcription factor (TF), is over-expressed in castrate resistant prostate cancer (CRPC) and that TBX2 drives the CRPC phenotype via cell-intrinsic and exosome-mediated paracrine modes. Our current study demonstrates that TBX2, a TF with known repressor and activator functions, may be the molecular switch that represses AR on one hand while activating GR expression on the other to drive CRPC. Mechanistically, our studies revealed a two-tiered mechanism of AR repression by TBX2 wherein TBX2 directly binds to the promoters of AR and GATA2, an AR coregulator, thereby resulting in the repression of AR as well as GATA2. Conversely, our results demonstrate that TBX2 mediates increased expression of GR via directly binding to the GR promoter, and through TBX2-GR functional protein-protein interaction. Our results demonstrate that the TBX2 driven switch from AR to GR signaling results in enzalutamide resistance since GR inhibition in the context of TBX2 over-expression attenuates enzalutamide resistance. Further, we present evidence that SP2509 based allosteric inhibition of Lysine Specific Demethylase 1 (LSD1), a protein that interacts with TBX2 as part of the Co-repressor of RE1-Silencing Transcription Factor (COREST) complex, is able to disrupt TBX2-GR interaction. Taken together, our study has identified TBX2 as the molecular switch that drives AR to GR signaling and thereby confers enzalutamide resistance in CRPC. Furthermore, our study provides key insights into a potential therapeutic strategy of targeting the AR to GR switch wherein SP2509-based allosteric inhibition of TBX2-LSD1 could be harnessed to target the TBX2-GR interaction, thereby resulting in the inhibition of enzalutamide resistance in CRPC."
1811,Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator POU2AF2,"V Rajasekaran, B. T Harris, R. T Osborn, C Smillie, K Donnelly, M Bacou, E Esiri-Bloom, L.Y Ooi, M Allan, M Walker, S Reid, A Meynert, G Grimes, J. P Blackmur, P. G Vaughan-Shaw, P. J Law, C Fernandez-Rozadilla, I. P Tomlinson, R Houlston, K. B Myant, F. V Din, M. G. Dunlop, S. M Farrington",https://www.biorxiv.org/content/10.1101/2023.08.24.554659v1,"Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, and exerts local (cis) expression quantitative trait locus (cis-eQTL) effects on POU2AF2, COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression at the 11q23.1 locus has thus far hindered elucidation of the mechanisms by which genetic variants impart CRC risk. Here, we establish that rs3087967 is the likely causal eQTL at this locus, co-localising with expression of POU2AF2 and CRC risk. Furthermore, we show trans-eQTL effects on 21 distant target genes, which are highly enriched for Tuft cell markers. Analysis of available scRNAseq, ChIPseq and scATACseq data implicates POU2AF2 as the primary controller of the tuft cell specific trans-genes through POU2F3-correlated genetic regulation. Immunofluorescence demonstrates that the rs3087967 risk genotype (T) is associated with lower tuft cell abundance in human colonic epithelium. CRISPR-mediated deletion of the 11q23.1 risk locus in the mouse germline exacerbated the ApcMin/+ mouse phenotype upon abrogation of Pou2af2 expression specifically. Taken together, we implicate a key protective role of tuft cells in the large bowel and the importance of mis-regulation of POU2AF2 as the prime tuft cell transcriptional activator at this locus."
1814,Weakly supervised contrastive learning infers molecular subtypes and recurrence of breast cancer from unannotated pathology images,"Hui Liu, Yang Zhang, Aichun Zhu, Zhiqiang Sun, Judong Luo",https://www.biorxiv.org/content/10.1101/2023.04.13.536813v3,"The deep learning-powered computational pathology has led to sig-nificant improvements in the speed and precise of tumor diagnosis,, while also exhibiting substantial potential to infer genetic mutations and gene expression levels. However,current studies remain limited in predicting molecular subtypes and recurrence risk in breast cancer. In this paper, we proposed a weakly supervised contrastive learning framework to address this challenge. Our framework first performed contrastive learning pretraining on large-scale unlabeled patches tiled from whole slide images (WSIs) to extract patch-level features. The gated attention mechanism was leveraged to aggregate patch-level features to produce slide feature that was then applied to various downstream tasks. To confirm the effectiveness of the proposed method, we have conducted extensive experiments on four independent cohorts of breast cancer. For gene expression prediction task, rather than one model per gene, we adopted multitask learning to infer the expression levels of 21 recurrence-related genes, and achieved remarkable performance and generalizability that were validated on an external cohort. Particularly, the predictive power to infer molecular subtypes and recurrence events was strongly validated by cross-cohort experiments. In addition, the learned patch-level attention scores enabled us to generate heatmaps that were highly consistent with pathologist annotations and spatial transcriptomic data. These findings demonstrated that our model effectively established the high-order genotype-phenotype associations, thereby enhances the potential of digital pathology in clinical applications."
1815,The Interplay between Mutagenesis and Extrachromosomal DNA Shapes Urothelial Cancer Evolution,"Duy D. Nguyen, William F. Hooper, Timothy R. Chu, Heather Geiger, Jennifer M. Shelton, Minita Shah, Zoe R. Goldstein, Lara Winterkorn, Michael Sigouros, Jyothi Manohar, Jenna Moyer, David Wilkes, Rahul R. Singh, Weisi Liu, Andrea Sboner, Scott T. Tagawa, David M. Nanus, Jones T. Nauseef, Cora N. Sternberg, Ana M. Molina, Douglas Scherr, Giorgio Inghirami, Juan Miguel Mosquera, Olivier Elemento, Nicolas Robine, Bishoy M. Faltas",https://www.biorxiv.org/content/10.1101/2023.05.07.538753v1,"Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity. In this study, we investigate the evolution of the genomic signatures caused by endogenous and external mutagenic stimuli and their interplay with complex structural variants. We superimposed mutational signatures and phylogenetic analyses of matched serial tumors from patients with urothelial cancer to define the evolutionary patterns of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas mutational bursts comprising hundreds of late subclonal mutations are induced by chemotherapy. Using a novel genome graph computational paradigm, we observed frequent circular high copy-number amplicons characteristic of extrachromosomal DNA (ecDNA) involving double-minutes, breakage-fusion-bridge, and tyfonas events. We characterized the distinct temporal patterns of APOBEC3 mutations and chemotherapy-induced mutations within ecDNA, gaining new insights into the timing of these events relative to ecDNA biogenesis. Finally, we discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA amplicons. These CCND1 ecDNA amplification events persisted and increased in complexity incorporating additional DNA segments potentially contributing selective fitness advantage to the evolution of treatment resistance. Our findings define fundamental mechanisms driving urothelial cancer evolution and have therapeutic implications for treating this disease."
1816,Kinome focused CRISPR-Cas9 screens in African ancestry patient-derived breast cancer organoids identifies essential kinases and synergy of EGFR and FGFR1 inhibition,"Florencia P. Madorsky Rowdo, Rachel Martini, Sarah Ackermann, Colin Tang, Marvel Tranquille, Adriana Irizarry, Ilkay Us, Omar Alawa, Jenna Moyer, Michael Sigouros, John Nguyen, Majd Al Assaad, Esther Cheng, Paula S. Ginter, Jyothi Manohar, Brian Stonaker, Richard Boateng, Joseph K. Oppong, Ernest K. Adjei, Baffour Awuah, Ishmael Kyei, Frances S. Aitpillah, Michael O. Adinku, Kwasi Ankomah, Ernest B. Osei-Bonsu, Kofi K. Gyan, Syed Hoda, Lisa Newman, Juan Miguel Mosquera, Andrea Sboner, Olivier Elemento, Lukas E. Dow, Melissa B. Davis, M. Laura Martin",https://www.biorxiv.org/content/10.1101/2023.12.11.570465v1,"Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapy strategies. These alterations are usually revealed via next generation sequencing of the tumor tissue. Yet, it is clear that some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. This is especially important in under-represented populations, whose mutational landscape and determinants of response to existing therapies are poorly characterized due to limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture in non-physiological conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in 3D-grown patient-derived tumor organoid (PDTO) models. We focused on identifying essential kinases that may translate to options for targeted therapies, including combination therapies. We first established a breast cancer PDTO biobank focused on underrepresented populations, including West African patients. We then performed a negative selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. We identified several previously unidentified kinase targets and showed that combination of FGFR1 and EGFR inhibitors synergizes to block organoids proliferation. Together these data demonstrate feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from under-represented cancer patients, and identify new targets for cancer therapy."
1818,Protein interactome homeostasis through an N-recognin E3 ligase is a vulnerability in aneuploid cancer,"Meena Kathiresan, Sambhavi Animesh, Robert Morris, Johannes Kreuzer, Krushna C. Patra, Lei Shi, Joshua Merritt, Xunqin Yin, Cyril H. Benes, Nabeel Bardeesy, Wilhelm Haas",https://www.biorxiv.org/content/10.1101/2023.05.04.539299v1,"Aneuploidy and resulting gene copy number alterations (CNAs) are important hallmarks of human cancers. Since CNAs are not associated with dosage compensation in mRNA expression, cancer cells with a high CNA burden must harbor mechanisms to mitigate proteotoxic stress resulting from stoichiometric imbalance and accumulation of unfolded proteins (1). Here, we show that aneuploid human cancer cells exhibit discordance between CNAs and protein levels due to compensation at the proteome level, mainly concerning multi-protein complexes. Moreover, we identify the N-recognin ubiquitin ligase UBR4 as a critical mediator of protein interactome homeostasis that is essential for viability, specifically in highly aneuploid cancers in vitro and in vivo. UBR4 prunes the proteome to ensure the balanced expression of protein complex members. Inactivation of UBR4 in highly aneuploid cancer cells causes a convergence of copy number and protein levels and induces proteotoxic stress pathways. UBR4 inhibition may present a broadly applicable therapeutic strategy for cancer and other diseases driven by aneuploidy."
1819,Inhibition of the serine/threonine kinase BUB1 reverses taxane resistance in prostate cancer,"Martinez Maria Julia, Lyles Rolando DZ, Peinetti Nahuel, Grunfeld Alex Michael, Burnstein Kerry L",https://www.biorxiv.org/content/10.1101/2023.05.05.539598v1,"Background: Men with incurable castration resistant prostate cancer (CRPC) are typically treated with taxanes; however, drug resistance rapidly develops. Thus, overcoming taxane resistant PC is a major clinical need. We previously identified a seven gene network in aggressive CRPC, which includes the mitotic serine threonine kinase BUB1, a major regulator of the spindle assembly checkpoint (SAC). Alterations in mitotic kinases (and SAC malfunction) are associated with advanced PC and taxane resistance development and thereby represent potential vulnerabilities."
1820,The transcriptional landscape of glycosylation-related genes in cancer,"Ernesto Rodriguez, Dimitri Lindijer, Sandra J. van Vliet, Juan J. Garcia Vallejo, Yvette van Kooyk",https://www.biorxiv.org/content/10.1101/2022.09.28.509853v1,"Changes in glycosylation patterns have been associated with malignant transformation and clinical outcome in several types of cancer, although no comprehensive analysis has been performed in a pan-cancer setting. Here, we performed an extensive transcriptomic analysis of glycosylation related genes (such as enzymes involved in synthesis and degradation of glycoconjugates, transporters, mucins and galectins), using publicly available bulk and single cell transcriptomic data sets from tumor samples and cancer cell lines. We identified genes and pathways associated with different tumor types, which may represent novel diagnostic biomarkers as α2-3 sialylation for Melanoma, MUC21 for Lung adenocarcinoma and Galectin-7 for Squamous cell carcinomas (SCC). Accordingly, serum levels of Galectin-7 in patients with lung cancer were elevated in SCC respect to adenocarcinomas, supporting its biomarker potential. Moreover, we characterized the contribution of different cell types to the overall glycosylation profiles observed by performing the integration and analysis of 14 single cell RNA-seq datasets. This led us to identify that cancer cells are responsible for the specific tumor glyco-codes identified in bulk transcriptomics, while stromal and immune cells contribute in a conserved manner across various malignancies. Furthermore, our results suggest that the glycosylation-related genes and pathways expressed by cancer cells are influenced by the cell of origin and the oncogenic pathways that led to malignant transformation. Lastly, we described the association of different glycosylation-related genes and pathways with the clinical outcome of patients. Interestingly, while the expression of genes associated to some pathways (as proteoglycan biosynthesis) are consistently associated with a more aggressive disease, the correlation of others pathways with the survival of patients depends on the particular tumor type. Remarkably, the expression of genes associated with the synthesis of CMP-sialic acid was correlated with lower survival of patients in Uveal Melanoma and PDAC, while the opposite was observed for colorectal cancer. The extensive transcriptomic analysis of glycosylation pathways in cancer that we report here can serve as a resource for future research aimed to unravel the glyco-code in cancer related to clinical outcome or biomarker development."
1821,Alendronate Conjugate for Targeted Delivery to Bone-Forming Prostate Cancer,"Jossana A. Damasco, Guoyu Yu, Ajay Kumar, Joy Perez, Rio Carlo M. Lirag, Elizabeth M. Whitley, Sue-Hwa Lin, Marites P. Melancon",https://www.biorxiv.org/content/10.1101/2022.09.26.508175v1,"Bone is the primary metastasis site for lethal prostate cancer, often resulting in poor prognosis, crippling pain, and diminished functioning that drastically reduce both quality of life and survivability. Uniquely, prostate cancer bone metastasis induces aberrant bone overgrowth, due to an increase of osteoblasts induced by tumor-secreted bone morphogenetic protein 4 (BMP4). Conjugating drugs to substances that target the tumor-induced bone area within the metastatic tumor foci would be a promising strategy for drug delivery. To develop such a strategy, we conjugated a near infrared (NIR) fluorescent probe, the dye Cy5.5, to serve as a surrogate for drugs, with alendronate, which targets bone. Characterization, such as infrared spectroscopy, confirmed the synthesis of the Cy5.5-ALN conjugate. The maximum absorbance of free Cy5.5, which was at 675 nm, did not change upon conjugation. Alendronate targeted the bone component hydroxyapatite in a dose-dependent manner up to 2.5 μM, with a maximum of 85% of Cy5.5-ALN bound to hydroxyapatite, while free Cy5.5 alone had 6% binding. In in vitro cell binding studies, Cy5.5-ALN bound specifically with mineralized bone matrix of differentiated MC3T3-E1 cells or 2H11 endothelial cells that were induced to become osteoblasts through endothelial-to-osteoblast transition, the underlying mechanism of prostate-cancer-induced bone formation. Neither Cy5.5-ALN nor free Cy5.5 bound to undifferentiated MC3T3-E1 or 2H11 cells. Bone-targeting efficiency studies in non-tumor-bearing mice revealed accumulation over time in the spine, jaw, knees, and paws injected with Cy5.5-ALN, and quantification showed higher accumulation in femurs than in muscle at up to 28 days, while the free Cy5.5 dye was observed circulating without preferential accumulation and decreased over time. There was a linear relationship with fluorescence when the injected concentration of Cy5.5-ALN was between 0.313 and 1.25 nmol/27 g of mouse, as quantified in mouse femurs both in vivo and ex vivo. Ex vivo evaluation of bone-targeting efficiency in nude mice was 3 times higher for bone-forming C4-2b-BMP4 tumors compared to non-bone-forming C4-2b tumors (p-value < 0.001). Fluorescence microscopy imaging of the tumors showed that Cy5.5-ALN co-localized with the bone matrix surrounding tumor-induced bone, but not with the viable tumor cells. Together, these results suggest that a drug-ALN conjugate is a promising approach for targeted delivery of drug to the tumor-induced bone area in the metastatic foci of prostate cancer."
1822,AI identifies potent inducers of breast cancer stem cell differentiation based on adversarial learning from gene expression data,"Zhongxiao Li, Antonella Napolitano, Monica Fedele, Xin Gao, Francesco Napolitano",https://www.biorxiv.org/content/10.1101/2023.08.21.554075v1,"Cancer stem cells (CSCs) are a subpopulation of cancer cells within tumors that exhibit stem-like properties, and represent a potentially effective therapeutic target towards long-term remission by means of differentiation induction. By leveraging an Artificial Intelligence (AI) approach solely based on transcriptomics data, this study scored a large library of small molecules based on their predicted ability to induce differentiation in stem-like cells. In particular, a deep neural network model was trained using publicly available single-cell RNA-Seq data obtained from untreated human induced pluripotent stem cells at various differentiation stages and subsequently utilized to screen drug-induced gene expression profiles from the LINCS database. The challenge of adapting such different data domains was tackled by devising an adversarial learning approach that was able to effectively identify and remove domain-specific bias during the training phase. Experimental validation in MDA-MB-231 and MCF7 cells demonstrated the efficacy of 5 out of 6 tested molecules among those scored highest by the model. In particular, the efficacy of triptolide, OTS-167, quinacrine, granisetron, and A-443654 offer a potential avenue for targeted therapies against breast CSCs."
1823,Shared requirement for MYC upstream super-enhancer region in tissue regeneration and cancer,"Inderpreet Sur, Wenshuo Zhao, Jilin Zhang, Margareta Kling Pilström, Björn Rozell, Anna T. Webb, Huaitao Cheng, Ari Ristimäki, Pekka Katajisto, Martin Enge, Helena Rannikmae, Marc de la Roche, Jussi Taipale",https://www.biorxiv.org/content/10.1101/2022.11.04.515076v2,"Cancer has been characterized as a wound that does not heal. Malignant cells are morphologically distinct from normal proliferating cells, but have extensive similarities to tissues undergoing wound healing and/or regeneration. The mechanistic basis of this similarity has, however, remained enigmatic. Here we show that the genomic region upstream of Myc, which is required for intestinal tumorigenesis, is also required for intestinal regeneration after radiation damage. The region is also critical for growth of adult intestinal cells in 3D organoid culture, indicating that culture conditions that recapitulate most aspects of normal tissue architecture still reprogram normal cells to proliferate using a mechanism similar to that employed by cancer cells. Our results uncover a genetic link between tissue regeneration and tumorigenesis, and establish that normal tissue renewal and regeneration of tissues after severe damage are mechanistically distinct."
1824,Long-read single-cell sequencing reveals expressions of hypermutation clusters of isoforms in human liver cancer cells,"Silvia Liu, Yan-Ping Yu, Bao-Guo Ren, Tuval Ben-Yehezkel, Caroline Obert, Mat Smith, Wenjia Wang, Alina Ostrowska, Alejandro Soto-Gutierrez, Jian-Hua Luo",https://www.biorxiv.org/content/10.1101/2023.03.16.532991v2,"The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Genetic mutation is essential in species evolution and cancer development. Accurate Long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthetic long-read single-cell sequencing technology based on LOOPseq technique. We applied this technology to analyze 447 transcriptomes of hepatocellular carcinoma (HCC) and benign liver from an individual. Through Uniform Manifold Approximation and Projection (UMAP) analysis, we identified a panel of mutation mRNA isoforms highly specific to HCC cells. The evolution pathways that led to the hyper-mutation clusters in single human leukocyte antigen (HLA) molecules were identified. Novel fusion transcripts were detected. The combination of gene expressions, fusion gene transcripts, and mutation gene expressions significantly improved the classification of liver cancer cells versus benign hepatocytes. In conclusion, LOOPseq single-cell technology may hold promise to provide a new level of precision analysis on the mammalian transcriptome."
1825,Combined Mek inhibition and Pparg activation Eradicates Muscle Invasive Bladder cancer in a Mouse Model of BBN-induced Carcinogenesis,"Tiffany Tate, Sakina A Plumber, Hikmat Al-Ahmadie, Xiao Chen, Woonyoung Choi, Chao Lu, Aaron Viny, Ekatherina Batourina, Krisjian Gartensson, Besmira Alija, Andrei Molotkov, Gregory Wiessner, James McKiernan, David McConkey, Colin Dinney, Bogdan Czerniak, Cathy Lee Mendelsohn",https://www.biorxiv.org/content/10.1101/2023.08.19.553961v1,"Bladder cancers (BCs) can be divided into 2 major subgroups displaying distinct clinical behaviors and mutational profiles: basal/squamous (BASQ) tumors that tend to be muscle invasive, and luminal/papillary (LP) tumors that are exophytic and tend to be non-invasive. Pparg is a likely driver of LP BC and has been suggested to act as a tumor suppressor in BASQ tumors, where it is likely suppressed by MEK-dependent phosphorylation. Here we tested the effects of rosiglitazone, a Pparg agonist, in a mouse model of BBN-induced muscle invasive BC. Rosiglitazone activated Pparg signaling in suprabasal epithelial layers of tumors but not in basal-most layers containing highly proliferative invasive cells, reducing proliferation but not affecting tumor survival. Addition of trametinib, a MEK inhibitor, induced Pparg signaling throughout all tumor layers, and eradicated 91% of tumors within 7-days of treatment. The 2-drug combination also activated a luminal differentiation program, reversing squamous metaplasia in the urothelium of tumor-bearing mice. Paired ATAC-RNA-seq analysis revealed that tumor apoptosis was most likely linked to down-regulation of Bcl-2 and other pro-survival genes, while the shift from BASQ to luminal differentiation was associated with activation of the retinoic acid pathway and upregulation of Kdm6a, a lysine demethylase that facilitates retinoid-signaling. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients. That muscle invasive tumors are populated by basal and suprabasal cell types with different responsiveness to PPARG agonists will be an important consideration when designing new treatments."
1826,"Systematic Pan-cancer Functional Inference and Validation of Hyper, Hypo and Neomorphic Mutations","Somnath Tagore, Samuel Tsang, Gordon B. Mills, Andrea Califano",https://www.biorxiv.org/content/10.1101/2023.04.29.538640v2,"While the functional effects of many recurrent cancer mutations have been characterized, the TCGA repository comprises more than 10M non-recurrent events, whose function is unknown. We propose that the context specific activity of transcription factor (TF) proteins—as measured by expression of their transcriptional targets—provides a sensitive and accurate reporter assay to assess the functional role of oncoprotein mutations. Analysis of differentially active TFs in samples harboring mutations of unknown significance—compared to established gain (GOF/hypermorph) or loss (LOF/hypomorph) of function—helped functionally characterize 577,866 individual mutational events across TCGA cohorts, including identification of mutations that are either neomorphic (gain of novel function) or phenocopy other mutations (mutational mimicry). Validation using mutation knock-in assays confirmed 15 out of 15 predicted gain and loss of function mutations and 15 of 20 predicted neomorphic mutations. This could help determine targeted therapy in patients with mutations of unknown significance in established oncoproteins."
1827,Cell-state transitions and frequency-dependent interactions among subpopulations together explain the dynamics of spontaneous epithelial-mesenchymal heterogeneity in breast cancer,"Paras Jain, Ramanarayanan Kizhuttil, Madhav B Nair, Sugandha Bhatia, Erik W Thompson, Jason T. George, Mohit Kumar Jolly",https://www.biorxiv.org/content/10.1101/2023.12.07.567986v1,"Individual cells in a tumour can be distributed among Epithelial (E) and Mesenchymal (M) cell-states, as characterised by the levels of canonical E and M markers. Even after E and M (E-M) subpopulations are isolated and then cultured independently, E-M heterogeneity can re-equilibrate in each population over time, sometimes regaining the initial distribution of the parental cell population. However, it remains unclear which population-level processes give rise to the dynamical changes in E-M heterogeneity observed experimentally, including 1) differential growth, 2) cell-state switching, and 3) frequency-dependent growth or state-transition rates. Here, we analyse the necessity of these three processes in explaining the dynamics of E-M population distributions as observed in PMC42-LA and HCC38 breast cancer cells. We find that growth differences among E and M subpopulations, with and without any frequency-dependent interactions (cooperation or suppression) among E-M sub-populations, are insufficient to explain the observed population dynamics. This insufficiency is ameliorated by including cell-state transitions, albeit at slow rates, in explaining both PMC42-LA and HCC38 cells data. Further, our models predict that treatment of HCC38 cells with TGFβ signalling and JAK2/3 inhibitors could significantly enhance the transition rates from M state to E state, but does not prevent transitions from E to M. Finally, we devise a selection criterion to identify the next most informative time points for which future experimental data can optimally improve the identifiability of our estimated best fit model parameters. Overall, our study identifies the necessary population-level processes shaping the dynamics of E-M heterogeneity in breast cancer cells."
1828,"A novel, RAS-independent role for NF1 in microtubular dynamics and damage repair dictates sensitivity to T-DM1 in HER2-positive breast cancer","Bruno A. Duso, Eleonora Messuti, Giulia Tini, Emanuele Bonetti, Alessia Castiglioni, Gianmaria Frigè, Giuseppe Ciossani, Silvia Monzani, Chiara Soriani, Daria Khuntsariya, Nicolò Roda, Andrea Polazzi, Marica R. Ippolito, Elena G. Doronzoro, Eltjona Mane, Alessia Farfalla, Costantino Jemos, Elena Guerini-Rocco, Simona Rodighiero, Daniela Tosoni, Stefano Santaguida, Marcus Braun, Zdeněk Lánský, Luigi Scietti, Pier Giuseppe Pelicci, Luca Mazzarella",https://www.biorxiv.org/content/10.1101/2023.12.06.569572v1,"The gene neurofibromatosis 1 (NF1) is increasingly recognized as a key somatic driver of cancerogenesis, in addition to its well-known role as the germline determinant of the onco-developmental syndrome Neurofibromatosis. NF1 is best characterized as a negative regulator of RAS activation, but several lines of evidence suggest that it may have additional, poorly characterized functions."
1832,Learning to Adapt - Deep Reinforcement Learning in Treatment-Resistant Prostate Cancer,"Kit Gallagher, Maximillian Strobl, Robert Gatenby, Philip Maini, Alexander Anderson",https://www.biorxiv.org/content/10.1101/2023.04.28.538766v1,"Standard-of-care treatment regimes have long been designed to for maximal cell kill, yet these strategies often fail when applied to treatment–resistant tumors, resulting in patient relapse. Adaptive treatment strategies have been developed as an alternative approach, harnessing intra-tumoral competition to suppress the growth of treatment resistant populations, to delay or even prevent tumor progression. Following recent clinical implementations of adaptive therapy, it is of significant interest to optimise adaptive treatment protocols. We propose the application of deep reinforcement learning models to provide generalised solutions within adaptive drug scheduling, and demonstrate this framework can outperform the current adaptive protocols, extending time to progression by up to a quarter. This strategy is robust to varying model parameterisations, and the underlying tumor model. We demonstrate the deep learning framework can produce interpretable, adaptive strategies based on a single tumor burden threshold, replicating and informing a novel, analytically–derived optimal treatment strategy with no knowledge of the underlying mathematical tumor model. This approach is highly relevant beyond the simple, analytically–tractable tumor model considered here, demonstrating the capability of deep learning frameworks to help inform and develop treatment strategies in complex settings. Finally, we propose a pathway to integrate mechanistic modelling with DRL to tailor generalist treatment strategies to individual patients in the clinic, generating personalised treatment schedules that consistently outperform clinical standard-of-care protocols."
1833,Exosomal microRNA signature from plasma-derived extracellular vesicles in gastric cancer,"Andrés Rincón-Riveros, Victoria E. Villegas, Nicolle Stefania Quintero Motta, Liliana López-Kleine, Josefa Antonia Rodríguezand",https://www.biorxiv.org/content/10.1101/2023.04.28.538562v1,"Background Gastric cancer is a heterogeneous pathology that represents the fifth most frequent malignancy in the world, with more than 750,000 deaths by 2020. With significant repercussions in public health, this pathology lacks biomarkers for early diagnosis, with endoscopy biopsy being the golden test for its detection. In the exploration of new strategies to control gastric cancer in recent years, liquid biopsy appears as a potential source of biomarkers using non-invasive procedures."
1834,Integrated microRNA and proteome analysis of cancer datasets with MoPC,"Marta Lovino, Elisa Ficarra, Loredana Martignetti",https://www.biorxiv.org/content/10.1101/2022.09.20.508638v1,"MicroRNAs (miRNAs) are small molecules that play an essential role in regulating gene expression by post-transcriptional gene silencing. Their study is crucial in revealing the fundamental processes underlying pathologies and, in particular, cancer. To date, most studies on miRNA regulation consider the effect of specific miRNAs on specific target mRNAs, providing wet-lab validation. However, few tools have been developed to explain the miRNA-mediated regulation at the protein level. In this paper, the MoPc computational tool is presented, that relies on the partial correlation between mRNAs and proteins conditioned on the miRNA expression to predict miRNA-target interactions in multi-omic datasets. MoPc returns the list of significant miRNA-target interactions and plot the significant correlations on the heatmap in which the miRNAs and targets are ordered by the chromosomal location. The software was applied on three TCGA/CPTAC datasets (breast, glioblastoma, and lung cancer), returning enriched results in three independent targets databases."
1835,Chemogenetic silencing of NaV1.8 positive sensory neurons reverses chronic neuropathic and bone cancer pain in FLEx PSAM4-GlyR mice,"Rayan Haroun, Samuel J Gossage, Ana Paula Luiz, Manuel Arcangeletti, Shafaq Sikandar, James J Cox, Jing Zhao, John N Wood",https://www.biorxiv.org/content/10.1101/2023.08.15.553398v1,"Drive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically-activated chloride channel PSAM4 -GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity using in vitro and in vivo GCaMP imaging upon activation of PSAM4 -GlyR with varenicline. A significant reduction in inflammatory heat hyperalgesia and oxaliplatin-induced cold allodynia was also observed. Importantly, there was no impairment of motor coordination, but innocuous von Frey sensation was inhibited. We generated a transgenic mouse that expresses a CAG-driven FLExed PSAM4 -GlyR downstream of the Rosa26 locus that requires Cre recombinase to enable the expression of PSAM4 -GlyR and tdTomato. We used NaV1.8 Cre to examine the role of predominantly nociceptive NaV1.8+ neurons in cancer-induced bone pain (CIBP) and neuropathic pain caused by chronic constriction injury (CCI). Varenicline activation of PSAM4 -GlyR in NaV1.8-positive neurons reversed CCI-driven mechanical, thermal, and cold sensitivity. Additionally, varenicline treatment of mice with CIBP expressing PSAM4 -GlyR in NaV1.8+ sensory neurons reversed cancer pain as assessed by weight-bearing. Moreover, when these mice were subjected to acute pain assays, an elevation in withdrawal thresholds to noxious mechanical and thermal stimuli was detected, but innocuous mechanical sensations remained unaffected. These studies confirm the utility of PSAM4 -GlyR chemogenetic silencing in chronic pain states for mechanistic analysis and potential future therapeutic use."
1837,A genetic mosaic mouse model illuminates the pre-malignant progression of basal-like breast cancer,"Jianhao Zeng, Shambhavi Singh, Ying Jiang, Eli Casarez, Kristen A. Atkins, Kevin A. Janes, Hui Zong",https://www.biorxiv.org/content/10.1101/2023.04.25.538333v1,"Basal-like breast cancer is an aggressive breast cancer subtype, often characterized by a deficiency in BRCA1 function and concomitant loss of p53. While conventional mouse models enable the investigation of its malignant stages, one that reveals its initiation and pre-malignant progression is lacking. Here, we leveraged a mouse genetic system known as Mosaic Analysis with Double Markers (MADM) to generate rare GFP-labeled Brca1, p53-deficient cells alongside RFP+ wildtype sibling cells in the mammary gland. The mosaicism resembles the sporadic initiation of human cancer and enables spatially resolved analysis of mutant cells in comparison to paired wildtype sibling cells. Mammary tumors arising in the model show transcriptomic and genomic characteristics similar to human basal-like breast cancer. Analysis of GFP+ mutant cells at interval time points before malignancy revealed a stepwise progression of lesions from focal expansion to hyper-alveolarization and then to micro-invasion. These stereotyped morphologies indicate the pre-malignant stage irrespective of the time point at which it is observed. Paired analysis of GFP-RFP siblings during focal expansion suggested that hyper-alveolarized structures originate from ductal rather than alveolar cells, despite their morphological similarities to alveoli. Evidence for luminal-to-basal transition at the pre-malignant stages was restricted to cells that had escaped hyper-alveoli and progressed to micro-invasive lesions. Our MADM-based mouse model presents a useful tool for studying the pre-malignancy of basal-like breast cancer."
1838,"The potential of Senicapoc, a KCNN4 inhibitor, for the prevention and treatment of breast cancer","Christos Xiao, Mariska Miranda, Wei Shi, Jonathan Beesley, Jodi M. Saunus, Andrew Civitarese, Debra M. Black, Meagan Ruppert, Melrine Pereira, Susan Jackson, Zachary Teale, Dylan Carter-Cusack, Lauren Kalinowski, Jamie R. Kutasovic, Amy E. McCart Reed, Herlina Y. Handoko, XiaoQing Chen, Darrell Bessette, Kelli MacDonald, Sunil R. Lakhani, Georgia Chenevix-Trench, Kara Britt, Fares Al-Ejeh",https://www.biorxiv.org/content/10.1101/2023.04.25.538345v1,"Background Genome-wide association studies have identified a breast cancer risk locus at 19q13.31. The candidate causal variants at this locus are located in the first exon of KCNN4. KCNN4, which regulates membrane potential and Ca2+ signaling, is a good candidate for drug repositioning because its inhibitor, Senicapoc, has been shown to be well tolerated in Phase-II and -III clinical trials for asthma and sickle cell anemia."
1839,ELISL: Early-Late Integrated Synthetic Lethality Prediction in Cancer,"Yasin Tepeli, Colm Seale, Joana Gonçalves",https://www.biorxiv.org/content/10.1101/2022.09.19.508413v1,"Anti-cancer therapies based on synthetic lethality (SL) exploit tumor vulnerabilities for treatment with reduced side effects. Since simultaneous loss-of-function of SL genes causes cell death, tumors with known gene disruptions can be treated by targeting SL partners. Computational selection of promising SL candidates amongst all gene combinations is key to expedite experimental screening. However, current SL prediction models: (i) only use tissue type-specific molecular data, which can be scarce/noisy, limiting performance for some cancers; and (ii) often rely on shared SL patterns across genes, showing sensitivity to prevalent gene selection bias. We propose ELISL, Early-Late Integrated models for SL prediction using forest ensembles. ELISL models ignore shared SL patterns, and integrate context-specific data from cancer cell lines or tumor tissue with context-free functional associations derived from protein sequence. ELISL outperformed existing methods and was more robust to selection bias in 8 cancer types, with prominent contribution from sequence. We found better survival for patients whose tumors carried simultaneous mutations in a BRCA gene together with an ELISL-predicted SL gene from the HH, FGF, or WNT families. ELISL thus arises as a promising strategy to discover SL interactions with therapeutic potential."
1840,A SREBF2-dependent gene program drives an immunotolerant dendritic cell population during cancer progression,"Michael P. Plebanek, Yue Xue, Y-Van Nguyen, Nicholas C. DeVito, Xueying Wang, Alisha Holtzhausen, Georgia M. Beasley, Nagendra Yarla, Bala Thievanthiran, Brent A. Hanks",https://www.biorxiv.org/content/10.1101/2023.04.26.538456v1,"Dendritic cells (cDCs) are essential mediators of anti-tumor immunity. Cancers have developed mechanisms to render DCs dysfunctional within the tumor microenvironment. Utilizing CD63 as a unique surface marker, we demonstrate that mature regulatory DCs (mregDCs) suppress DC antigen cross-presentation while driving TH2 and regulatory T cell differentiation within tumor-draining lymph node tissues. Transcriptional and metabolic studies show that mregDC functionality is dependent upon the mevalonate biosynthetic pathway and the master transcription factor, SREBP2. Melanoma-derived lactate activates DC SREBP2 in the tumor microenvironment (TME) and drives mregDC development from conventional DCs. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promotes anti-tumor CD8+ T cell activation and suppresses melanoma progression. CD63+ mregDCs reside within the sentinel lymph nodes of melanoma patients. Collectively, this work describes a tumor-driven SREBP2-dependent program that promotes CD63+ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME."
1841,Spatial transcriptomics reveal pitfalls and opportunities for the detection of rare high-plasticity breast cancer subtypes,"Angèle Coutant, Vincent Cockenpot, Lauriane Muller, Cyril Degletagne, Roxane Pommier, Laurie Tonon, Maude Ardin, Marie-Cécile Michallet, Christophe Caux, Marie Laurent, Anne-Pierre Morel, Pierre Saintigny, Alain Puisieux, Maria Ouzounova, Pierre Martinez",https://www.biorxiv.org/content/10.1101/2023.04.24.538061v1,"Breast cancer is one of the most prominent types of cancers, in which therapeutic resistance is still a major clinical hurdle. Specific subtypes like Claudin-low (CL) and metaplastic breast cancers (MpBC) have been associated with high non-genetic plasticity, which can facilitate resistance. The overlaps and differences between these orthogonal subtypes, respectively identified by molecular and histopathological analyses, are however still insufficiently characterised. Adequate methods to identify high-plasticity tumours to better anticipate resistance are furthermore still lacking. Here we analysed 11 triple negative breast tumours, including 3 CL and 4 MpBC samples, via high-resolution spatial transcriptomics. We combined pathological annotations and deconvolution approaches to precisely identify tumour spots, on which we performed signature enrichment, differential expression and copy-number analyses. We used the TCGA and CCLE public databases for external validation of expression markers. By levying spatial transcriptomics to focus analyses only to tumour cells in MpBC samples, and therefore bypassing the negative impact of stromal contamination, we could identify specific markers that are not expressed in other subtypes nor stromal cells. Three markers (BMPER, POPDC3 and SH3RF3) could furthermore be validated in external expression databases encompassing bulk tumour material and stroma-free cell lines. We find that existing bulk expression signatures of high-plasticity breast cancers are relevant in mesenchymal transdifferentiated compartments but can be hindered by stromal cell prevalence in tumour samples, negatively impacting their clinical applicability. Spatial transcriptomics analyses can however help identify more specific expression markers, and could thus enhance diagnosis and clinical care of rare high-plasticity breast cancers."
1842,A Bacterial Living Therapeutics with Engineered Protein Secretion Circuits To Eliminate Breast Cancer Cells,"Gozeel Binte Shahid, Recep Erdem Ahan, Julian Ostaku, Urartu Ozgur Safak Seker",https://www.biorxiv.org/content/10.1101/2023.04.27.538589v1,"Cancer therapy can be limited by potential side effects, and bacteria-based living cancer therapeutics have gained scientific interest in recent years. However, the full potential of bacteria as therapeutics has yet to be explored due to engineering challenges. n this study, we present a bacterial device designed to specifically target and eliminate breast cancer cells. We have engineered Escherichia coli (E. coli) to secrete a Shiga toxin, HlyE, which is a pore-forming protein that binds to HER2 receptors on breast cancer cells. This binding is facilitated by a nanobody expressed on the bacteria’s surface via the Ag43 autotransporter protein system. Our findings demonstrate that the nanobody efficiently binds to HER2+ cells in vitro, and we have utilized the YebF secretion system to secrete HlyE and kill the target cancer cells. Overall, our results highlight the potential of our engineered bacteria as an innovative strategy for breast cancer treatment."
1843,R-loops and Topoisomerase 1 facilitate formation of transcriptional DSBs at gene bodies of hypertranscribed cancer genes,"Osama Hidmi, Sara Oster, Jonathan Monin, Rami I. Aqeilan",https://www.biorxiv.org/content/10.1101/2022.12.12.520103v3,"DNA double-stranded breaks (DSBs) pose a significant threat to genomic integrity, and their generation during essential cellular processes like transcription remains poorly understood. In this study, we employed advanced techniques to map DSBs, R-loops, and Topoisomerase 1 cleavage complex (TOP1cc) and re-analyzed ChIP-seq and DRIP-seq data to comprehensively investigate the interplay between transcription, DSBs, Topoisomerase 1 (TOP1), and R-loops. Our findings revealed the presence of DSBs at highly expressed genes enriched with TOP1 and R-loops, indicating their crucial involvement in transcription-associated genomic instability. Depletion of R-loops and TOP1 specifically reduced DSBs at highly expressed genes, uncovering their pivotal roles in transcriptional DSB formation. By elucidating the intricate interplay between TOP1cc trapping, R-loops, and DSBs, our study provides novel insights into the mechanisms underlying transcription-associated genomic instability. Moreover, we establish a link between transcriptional DSBs and early molecular changes driving cancer development. Notably, our study highlights the distinct etiology and molecular characteristics of driver mutations compared to passenger mutations, shedding light on the potential for targeted therapeutic strategies. Overall, these findings deepen our understanding of the regulatory mechanisms governing DSBs in hypertranscribed genes associated with carcinogenesis, opening avenues for future research and therapeutic interventions."
1844,Seq2Neo: a comprehensive pipeline for cancer neoantigen immunogenicity prediction,"Kaixuan Diao, Jing Chen, Tao Wu, Xuan Wang, Guangshuai Wang, Xiaoqin Sun, Xiangyu Zhao, Chenxu Wu, Jinyu Wang, Huizi Yao, Casimiro Gerarduzzi, Xue-Song Liu",https://www.biorxiv.org/content/10.1101/2022.09.14.507872v1,"Neoantigens derived from somatic DNA alterations are ideal cancer-specific targets. In recent years, the combination therapy of PD-1/PD-L1 blockers and neoantigen vaccines shows clinical efficacy in original PD-1/PD-L1 blocker non-responders. However, not all somatic DNA mutations can result in immunogenicity in cancer cells, and efficient tools for predicting the immunogenicity of neoepitope are still urgently needed. Here we present the Seq2Neo pipeline, which provides a one-stop solution for neoepitope features prediction from raw sequencing data, and neoantigens derived from different types of genome DNA alterations, including point mutations, insertion deletions, and gene fusions are supported. Importantly a convolutional neural networks (CNN) based model has been trained to predict the immunogenicity of neoepitope. And this model shows improved performance compared with currently available tools in immunogenicity prediction in independent datasets. We anticipate that the Seq2Neo pipeline will become a useful tool in prediction of neoantigen immunogenicity and cancer immunotherapy. Seq2Neo is an open-source software under an academic free license (AFL) v3.0 and it is freely available at https://github.com/XSLiuLab/Seq2Neo."
1846,Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression,"Hashni Epa Vidana Gamage, Sayyed Hamed Shahoei, Samuel T. Albright, Yu Wang, Amanda J. Smith, Rachel Farmer, Emma C. Fink, Elise Jacquin, Erin Weisser, Rafael O. Bautista, Madeline A. Henn, Claire P. Schane, Adam T. Nelczyk, Liqian Ma, Anasuya Das Gupta, Shruti V. Bendre, Tiffany Nguyen, Srishti Tiwari, Natalia Krawczynska, Sisi He, Evelyn Tjoanda, Hong Chen, Maria Sverdlov, Peter H. Gann, Romain Boidot, Frederique Vegran, Sean W. Fanning, Lionel Apetoh, Paul J. Hergenrother, Erik R. Nelson",https://www.biorxiv.org/content/10.1101/2023.08.14.553229v1,"Immune checkpoint blockade (ICB) has revolutionized cancer therapy but has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. We demonstrate that NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the NLRP3 inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Loss of NR0B2 increased mammary tumor growth and metastasis. Small molecule agonists, including one developed here, reduced Treg expansion, reduced metastatic growth and improved the efficacy of ICB. This work identifies NR0B2 as a target to re-educate myeloid immune cells providing proof-of-principle that this cholesterol-homeostasis axis may have utility in enhancing ICB."
1847,Differential expression and function of SVIP in breast cancer cell lines and in silico analysis of its expression and prognostic potential in human breast cancer,"Esra Atalay Şahar, Petek Ballar Kirmizibayrak",https://www.biorxiv.org/content/10.1101/2023.03.03.530947v1,"The heterogeneity of cancer strongly suggests the need to explore additional pathways to target. As cancer cells have increased proteotoxic stress, targeting proteotoxic stress-related pathways such as endoplasmic reticulum stress is attracting attention as new anticancer treatments. One of the downstream responses to endoplasmic reticulum stress is endoplasmic reticulum-associated degradation (ERAD), a major degradation pathway that facilitates proteasome-dependent degradation of unfolded or misfolded proteins. Recently, SVIP, an endogenous ERAD inhibitor, has been implicated in cancer progression, especially in glioma, prostate, and head and neck cancers. Here, the data of several RNA-seq and gene array studies were combined to evaluate the SVIP gene expression analysis on a variety of cancers, with a particular focus on breast cancer. SVIP was found to be overexpressed in primary breast tumors compared to normal tissues correlated well with its promoter methylation status and genetic alterations. Similarly, immunoblotting analysis showed that SVIP was expressed significantly higher in breast cancer cell lines compared to non-tumorigenic epithelial cell line. On the other hand, the expression of the key proteins of gp78-mediated ERAD did not exhibit such a pattern. Interestingly, silencing of SVIP enhanced the proliferation of p53 wt MCF7 cells but not p53 mutant T47D cells, however increased migration ability of both cell lines. Interestingly, SVIP expression is high in primary breast tumors but low in breast metastatic tumors. This correlates well with a lower probability of survival of breast cancer patients with lower SVIP expression compared to the patients with overexpressed SVIP. Overall, our data revealing the differential expression and function of SVIP on breast cancer cell lines together with in silico data analysis suggest that SVIP may have complex functions in breast cancer progression and has the potential to be a therapeutic target for breast cancer."
1849,Identification of HPV oncogene and host cell differentiation associated cellular heterogeneity in cervical cancer via single-cell transcriptomic analysis,"Yingjie Li, Cankun Wang, Anjun Ma, Abdul Qawee Rani, Mingjue Luo, Jenny Li, Xuefeng Liu, Qin Ma",https://www.biorxiv.org/content/10.1101/2023.08.10.552878v1,"Human Papillomaviruses (HPVs) are associated with around 5-10% of human cancer, notably nearly 99% of cervical cancer. The mechanisms HPV interacts with stratified epithelium (differentiated layers) during the viral life cycle, and oncogenesis remain unclear. In this study, we used single-cell transcriptome analysis to study viral gene and host cell differentiation-associated heterogeneity of HPV-positive cervical cancer tissue. We examined the HPV16 genes - E1, E6, and E7, and found they expressed differently across nine epithelial clusters. We found that three epithelial clusters had the highest proportion of HPV-positive cells (33.6%, 37.5%, and 32.4%, respectively), while two exhibited the lowest proportions (7.21% and 5.63%, respectively). Notably, the cluster with the most HPV-positive cells deviated significantly from normal epithelial layer markers, exhibiting functional heterogeneity and altered epithelial structuring, indicating that significant molecular heterogeneity existed in cancer tissues and that these cells exhibited unique/different gene signatures compared with normal epithelial cells. These HPV-positive cells, compared to HPV-negative, showed different gene expressions related to the extracellular matrix, cell adhesion, proliferation, and apoptosis. Further, the viral oncogenes E6 and E7 appeared to modify epithelial function via distinct pathways, thus contributing to cervical cancer progression. We investigated the HPV and host transcripts from a novel viewpoint focusing on layer heterogeneity. Our results indicated varied HPV expression across epithelial clusters and epithelial heterogeneity associated with viral oncogenes, contributing biological insights to this critical field of study."
1850,Saracatinib synergizes with enzalutamide to downregulate androgen receptor activity in castration resistant prostate cancer,"Ralph E. White III, Maxwell Bannister, Abderrahman Day, Hannah E. Bergom, Victor M. Tan, Justin Hwang, Hai Dang Nguyen, Justin M. Drake",https://www.biorxiv.org/content/10.1101/2023.04.22.537922v1,"Prostate cancer (PCa) remains the most diagnosed non-skin cancer amongst the American male population. Treatment for localized prostate cancer consists of androgen deprivation therapies (ADTs), which typically inhibit androgen production and the androgen receptor (AR). Though initially effective, a subset of patients will develop resistance to ADTs and the tumors will transition to castration-resistant prostate cancer (CRPC). Second generation hormonal therapies such as abiraterone acetate and enzalutamide are typically given to men with CRPC. However, these treatments are not curative and typically prolong survival only by a few months. Several resistance mechanisms contribute to this lack of efficacy such as the emergence of AR mutations, AR amplification, lineage plasticity, AR splice variants (AR-Vs) and increased kinase signaling. Having identified SRC kinase as a key tyrosine kinase enriched in CRPC patient tumors from our previous work, we evaluated whether inhibition of SRC kinase synergizes with enzalutamide or chemotherapy in several prostate cancer cell lines expressing variable AR isoforms. We observed robust synergy between the SRC kinase inhibitor, saracatinib, and enzalutamide, in the AR-FL+/AR-V+ CRPC cell lines, LNCaP95 and 22Rv1. We also observed that saracatinib significantly decreases AR Y534 phosphorylation, a key SRC kinase substrate residue, on AR-FL and AR-Vs, along with the AR regulome, supporting key mechanisms of synergy with enzalutamide. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs."
1852,TRAIL pathway suppression of cancer cell growth and immune cell-mediated tumor cell-killing in a senescent fibroblast-constructed tumor microenvironment,"Shengliang Zhang, Kelsey E. Huntington, Lanlan Zhou, Attila A. Seyhan, Bianca Kun, Benedito A. Carneiro, Jill Kreiling, John M. Sedivy, Wafik S. El-Deiry",https://www.biorxiv.org/content/10.1101/2023.11.30.569479v1,"Cellular senescence and the associated secretory phenotype (SASP) promote cancer in the aging population. During aging or upon chemotherapy exposure, cellular and molecular changes occur in non-cancerous cells and alter responses to cancer therapy, primarily via modifications in the tumor microenvironment (TME) and immune response. Targeting senescent cells through removal, modulation of the SASP, or cellular reprogramming represent promising therapeutic avenues for treating cancer. We elucidate an interplay between cancer cells, immune cells, and senescent fibroblasts and describe the impact of fibroblast senescence on tumor growth and response to cancer therapy. Cytokine profiling reveals dynamic changes in SASP production during etoposide-induced senescence in IMR90 fibroblasts. We show that SASP is partially regulated by p21 (WAF1; CDKN1A), leading to the downregulation of anti-tumorigenic cytokines and upregulation of pro-tumorigenic cytokines. Senescent fibroblasts promote bystander cancer cell growth via a p21-driven SASP. These results provide strategies to target the p21-driven SASP in the TME during cancer therapy. Treatment with TRAIL or TRAIL-inducing Dordaviprone (TIC10/ONC201) reduces cell viability of tumor cells co-cultured with senescent or proliferating fibroblasts and promotes immune-mediated tumor cell-killing in co-culture with senescent IMR90 fibroblasts. ONC201 combined with senolytic drugs (e.g., Navitoclax, Lamivudine) synergizes towards tumor suppression. These results indicate that senolytic therapies may be combined with cancer therapies to target senescence-associated changes in the TME including for modulation of the senescent cytokine landscape."
1855,Effect of Lantana camara ethanolic leaf extract on survival and migration of MDA-MB-231 triple negative breast cancer cell line,"Arundhaty Pal, Sourav Sanyal, Sayantani Das, Tapas Kumar Sengupta",https://www.biorxiv.org/content/10.1101/2023.02.04.527114v2,"Introduction Breast cancer is a leading cause of cancer-related death worldwide. Lantana camara has been reported to cure a number of ailments, with few studies showing its cytotoxic effects on breast cancer cells. However, the impact of Lantana camara on triple negative breast cancer cells is largely obscure to date. The present study investigated the effect of ethanolic extract of Lantana camara leaves on the triple negative breast cancer cell line, MDA-MB-231."
1856,Mutational Landscape of Cancer-Driver Genes Across Human Cancers,Musalula Sinkala,https://www.biorxiv.org/content/10.1101/2022.09.11.507448v1,"The cancer driver genes are involved in transforming healthy cells into cancerous cells. The molecular aberrations which lead to cancer involve gain and loss of function mutations in various cancer driver genes. Here, we examine the genome sequences of 20,066 primary tumours representing 43 distinct human cancers to identify and catalogue driver mutations in 729 known cancer genes. We show that the frequency of driver mutations in these genes varies significantly between cancer types. We find that the class of cancer driver genes most frequently mutated are the tumour suppressor genes (94%), followed by oncogenes (93%), transcription factors (72%), kinases (64%), cell surface receptors (63%), and phosphatases (22%). Furthermore, we identify the subset of these genes within which mutations exhibit a co-occurrence or mutually exclusive pattern. Interestingly, we find that patients with tumours with different combinations of driver gene mutation patterns tend to exhibit variable survival outcomes. Here, among the well-studied cancer genes, we showed that patients with tumours with KRAS and TP53 mutations are associated with the worst disease outcomes, and those with PI3KCA and BRAF mutations are associated with favourable survival outcomes. Besides providing new insights into cancer driver mutations, we unearth mutation patterns associated with disease outcomes and various hallmarks of cancer that bring us closer to fully understanding various forms of cancer."
1857,Intracellular biotransformation and disposal mechanisms of magnetosomes in macrophages and cancer cells,"L. Gandarias, A.G. Gubieda, G. Gorni, O. Mathon, L. Olivi, Ana Abad-Díaz-de-Cerio, M.L. Fdez-Gubieda, A. Muela, A. García-Prieto",https://www.biorxiv.org/content/10.1101/2023.03.15.532722v3,"Magnetosomes are magnetite nanoparticles biosynthesized by magnetotactic bacteria. Given their potential clinical applications for the diagnosis and treatment of cancer, it is essential to understand what becomes of them once they are within the body. With this aim, here we have followed the intracellular long-term fate of magnetosomes in two cell types: cancer cells (A549 cell line), because they are the actual target for the therapeutic activity of the magnetosomes, and macrophages (RAW 264.7 cell line), because of their role at capturing foreign agents. We show that cells dispose of magnetosomes using three mechanisms: splitting them into daughter cells, excreting them to the surrounding environment, and degrading them yielding less or non-magnetic iron products. A deeper insight into the degradation mechanisms by means of time-resolved X-ray absorption near-edge structure (XANES) spectroscopy has allowed us to follow the intracellular biotransformation of magnetosomes by identifying and quantifying the iron species occurring during the process. In both cell types there is a first oxidation of magnetite to maghemite and then, earlier in macrophages than in cancer cells, ferrihydrite starts to appear. Given that ferrihydrite is the iron mineral phase stored in the cores of ferritin proteins, this suggests that cells use the iron released from the degradation of magnetosomes to load ferritin. Comparison of both cellular types evidences that macrophages are more efficient at disposing of magnetosomes than cancer cells, attributed to their role in degrading external debris and in iron homeostasis."
1858,Pharmacological Induction of mesenchymal-epithelial transition chemosensitizes breast cancer cells and prevents metastatic progression,"Meisam Bagheri, Gadisti Aisha Mohamed, Mohammed Ashick, Mohamed Saleem, Nevena B. Ognjenovic, Hanxu Lu, Fred W. Kolling 4th, Owen M. Wilkins, Subhadeep Das, Ian S. La Croix, Shivashankar H. Nagaraj, Kristen E. Muller, Scott A. Gerber, Todd W. Miller, Diwakar R. Pattabiraman",https://www.biorxiv.org/content/10.1101/2023.04.19.537586v1,"The epithelial-mesenchymal transition (EMT) is a developmental program co-opted by tumor cells that aids the initiation of the metastatic cascade. Tumor cells that undergo EMT are relatively chemoresistant, and there are currently no therapeutic avenues specifically targeting cells that have acquired mesenchymal traits. We show that treatment of mesenchymal-like triple-negative breast cancer (TNBC) cells with the microtubule-destabilizing chemotherapeutic eribulin, which is FDA-approved for the treatment of advanced breast cancer, leads to a mesenchymal-epithelial transition (MET). This MET is accompanied by loss of metastatic propensity and sensitization to subsequent treatment with other FDA-approved chemotherapeutics. We uncover a novel epigenetic mechanism of action that supports eribulin pretreatment as a path to MET induction that curtails metastatic progression and the evolution of therapy resistance."
1861,Predicting neoadjuvant treatment response in triple-negative breast cancer using machine learning,"Shristi Bhattarai, Geetanjali Saini, Hongxiao Li, Hongyi Duanmu, Gaurav Seth, Timothy B. Fisher, Emiel A.M. Janssen, Umay Kiraz, Jun Kong, Ritu Aneja",https://www.biorxiv.org/content/10.1101/2023.04.17.536459v1,"Background Neoadjuvant chemotherapy (NAC) is the standard treatment for early-stage triple negative breast cancer (TNBC). The primary endpoint of NAC is a pathological complete response (pCR). NAC results in pCR in only 30%–40% of TNBC patients. Tumor-infiltrating lymphocytes (TILs), Ki67 and phosphohistone H3 (pH3) are a few known biomarkers to predict NAC response. Currently, systematic evaluation of the combined value of these biomarkers in predicting NAC response is lacking. In this study, the predictive value of markers derived from H&E and IHC stained biopsy tissue was comprehensively evaluated using a supervised machine learning (ML)-based approach. Identifying predictive biomarkers could help guide therapeutic decisions by enabling precise stratification of TNBC patients into responders and partial or non-responders."
1863,Colocalization of Protein and microRNA Markers Reveals Unique Extracellular Vesicle Sub-Populations for Early Cancer Detection,"Zongbo Li, Kaizhu Guo, Ziting Gao, Junyi Chen, Zuyang Ye, Shizhen Emily Wang, Yadong Yin, Wenwan Zhong",https://www.biorxiv.org/content/10.1101/2023.04.17.536958v1,"Extracellular vesicles (EVs) play important roles in cell-cell communication but they are highly heterogeneous, and each vesicle has dimensions smaller than 200 nm thus encapsulates very limited amounts of cargos. We report the technique of NanOstirBar (NOB)-EnabLed Single Particle Analysis (NOBEL-SPA) that utilizes NOBs, which are superparamagnetic nanorods easily handled by a magnet or a rotating magnetic field, to act as isolated “islands” for EV immobilization and cargo confinement. NOBEL-SPA permits rapid inspection of single EV with high confidence by confocal fluorescence microscopy, and can assess the colocalization of selected protein/microRNA (miRNA) pairs in the EVs produced by various cell lines or present in clinical sera samples. Specific EV sub-populations marked by the colocalization of unique protein and miRNA combinations have been revealed by the present work, which can differentiate the EVs by their cells or origin, as well as to detect early-stage breast cancer (BC). We believe NOBEL-SPA can be expanded to analyze the co-localization of other types of cargo molecules, and will be a powerful tool to study EV cargo loading and functions under different physiological conditions, and help discover distinct EV subgroups valuable in clinical examination and therapeutics development."
1865,Oncolytic Newcastle disease virus enhanced apoptosis in colorectal cancer cell lines,"Teridah Ernala Ginting, Nur Rahmaniah Hidayat, Vina Cornelia, Young Othiwi Larasati, Kamaluddin Zarkasie, Irawan Yusuf",https://www.biorxiv.org/content/10.1101/2023.04.16.537098v1,"Colorectal cancer (CRC) is a deadly disease with a high prevalence and mortality rate worldwide. Previous investigations have shown that Newcastle disease virus (NDV) exhibits oncolytic activity and antitumor immunostimulation properties on several types of tumor cells but not normal cells. This study aims to examine NDV oncolytic activity against two kinds of human CRC cell lines, i.e., HCT116 and SW620, as well as its ability to induce apoptosis. The results showed that CRC cell lines were susceptible to NDV LaSota strain and the mechanism of death was due to caspase-dependent pathways apoptosis, followed by interferon signaling competence. NDV-induced proinflammatory cytokines in CRC cells might have contributed to apoptosis mechanism. Therefore, further investigation is recommended, using the findings obtained in this study as a basis for an animal CRC model."
1867,Analytical validation of the PROphet test for treatment decision-making guidance in metastatic non-small cell lung cancer,"Ben Yellin, Coren Lahav, Itamar Sela, Galit Yahalom, Shani Raveh Shoval, Yehonatan Elon, James Fuller, Michal Harel",https://www.biorxiv.org/content/10.1101/2023.04.20.537648v2,"The blood proteome, consisting of thousands of proteins engaged in various biological processes, acts as a valuable source of potential biomarkers for various medical applications. PROphet is a plasma proteomics-based test that serves as a decision-support tool for non-small cell lung cancer (NSCLC) patients. PROphet combines proteomic profiling using the SomaScan technology and subsequent computational algorithm. PROphet was implemented as a laboratory developed test (LDT). Under the Clinical Laboratory Improvement Amendments (CLIA) and Commission on Office Laboratory Accreditation (COLA) regulations, prior to releasing patient test results, a clinical laboratory located in the United States that employs an LDT must examine the performance characteristics concerning analytical validity. This study describes the experimental and computational analytical validity of the PROphet test, as required by CLIA/COLA. Experimental precision analysis displayed a median coefficient of variation (CV) of 3.9% and 4.7% for intra-plate and inter-plate examination, respectively, and the median accuracy rate between sites was 88%. Computational precision exhibited a high accuracy rate, with 93% of samples displaying complete concordance in results. A cross-platform comparison between SomaScan and other proteomics platforms yielded a median Spearman correlation coefficient of 0.51, affirming the consistency and reliability of the SomaScan platform. Our study presents a robust framework for evaluating the analytical validity of a platform that combines an experimental assay with subsequent computational algorithms. When applied to the PROphet test, strong analytical performance of the test was demonstrated."
1868,A Multithreaded Model for Cancer Tissue Heterogeneity: An Application,"Anik Chaudhuri, Shabnam Choudhury, Anwoy Kumar Mohanty, Manoranjan Satpathy, M. Shell, J. Doe",https://www.biorxiv.org/content/10.1101/2022.09.05.505544v1,"Studying the heterogeneity in cancerous tissue is challenging in cancer research. It is vital to process the real-world data efficiently to understand the heterogeneous nature of cancer tissue. GPU compatible models, which can estimate the subpopulation of cancerous tissue, are fast if the size of input data, i.e., the number of qPCR (quantitative polymerase chain reaction) gene expression reading is extensive. In the real world, we rarely get that much data to reap the benefits of a GPU’s parallelism. Real experimental data from fibroblasts are much less, and models using those data on a GPU are slower than the CPU multithreaded application. This paper will show a method to run GPU-compatible models for cancer tissue heterogeneity on a multithreaded CPU. Further, we also show that the model running on a multithreaded CPU is faster than the model running on a GPU with real experimental data."
1869,Atypical B cells mediate poor response to Bacillus Calmette Guérin immunotherapy in non-muscle invasive bladder cancer,"Priyanka Yolmo, Sadaf Rahimi, Stephen Chenard, Gwenaëlle Conseil, Danielle Jenkins, Kartik Sachdeva, Isaac Emon, Jake Hamilton, Minqi Xu, Manu Rangachari, Eva Michaud, Jose Mansure, Wassim Kassouf, David M. Berman, D. Robert Siemens, Madhuri Koti",https://www.biorxiv.org/content/10.1101/2022.12.30.522127v4,"Poor response to Bacillus Calmette-Guérin (BCG) immunotherapy remains a major barrier in the management of patients with non-muscle-invasive bladder cancer (NMIBC). Among the multiple factors contributing to poor outcomes, a B cell infiltrated pre-treatment immune microenvironment of NMIBC tumors has emerged as a key determinant of response to BCG. The mechanisms underlying the paradoxical roles of B cells in NMIBC are poorly understood. Here, we show that B cell dominant tertiary lymphoid structures (TLSs), a hallmark feature of chronic mucosal immune response, are abundant and located close to the epithelial compartment in pre-treatment tumors from BCG non-responders. Digital spatial proteomic profiling of whole tumor sections revealed higher expression of immune exhaustion-associated proteins within the TLSs from both responders and non-responders. Chronic local inflammation, induced by the N-butyl- N-(4-hydroxybutyl) nitrosamine (BBN) carcinogen, led to TLS formation with recruitment and differentiation of the immunosuppressive atypical B cell (ABCs) subset within the bladder microenvironment, predominantly in aging female mice compared to their male counterparts. Depletion of ABCs simultaneous to BCG treatment delayed cancer progression in female mice. Our findings provide the first evidence indicating the role of ABCs in BCG response and will inform future development of therapies targeting the B cell exhaustion axis."
1870,Multiplexed inhibition of immunosuppressive genes with Cas13d for on-demand combinatorial cancer immunotherapy,"Feifei Zhang, Wang Guangchuan, Ryan Chow, Emily He, Medha Majety, Yueqi Zhang, Sidi Chen",https://www.biorxiv.org/content/10.1101/2023.03.14.532668v2,"Checkpoint blockade immunotherapy is a potent class of cancer treatment, however, the complex immunosuppressive tumor microenvironment (TME) often requires multi-agent combinations to be effective. Current cancer immunotherapy combination approaches are cumbersome, usually involving one-drug-at-a-time scheme. Here, we devise Multiplex Universal Combinatorial Immunotherapy via Gene-silencing (MUCIG), as a versatile approach for combinatorial cancer immunotherapy. We harness CRISPR-Cas13d to efficiently target multiple endogenous immunosuppressive genes on demand, allowing us to silence various combinations of multiple immunosuppressive factors in the TME. Intratumoral AAV-mediated administration of MUCIG (AAV-MUCIG) elicits significant anti-tumor activity with several Cas13d gRNA compositions. TME target expression analysis driven optimization led to a simplified off-the-shelf MUCIG targeting a four gene combination (PGGC: Pdl1, Galectin9, Galectin3 and Cd47). AAV-PGGC shows significant in vivo efficacy in syngeneic tumor models. Single cell and flow profiling revealed that AAV-PGGC remodeled the TME by increasing CD8+ T cell infiltration and reducing myeloid-derived immunosuppressive cells (MDSCs). MUCIG thus serves as a universal method to silence multiple immune genes in vivo, and can be delivered via AAV as a therapeutic approach."
1874,Characterizing heterogeneity along EMT and metabolic axes in colorectal cancer reveals underlying consensus molecular subtype-specific trends,"Manas Sehgal, Soundharya R, Joel Markus Vaz, Raja G Yogeshwar, Srinath Muralidharan, Sankalpa Venkatraghavan, Mohit Kumar Jolly",https://www.biorxiv.org/content/10.1101/2023.08.06.551165v1,"Colorectal cancer (CRC) is highly heterogenous with variable survival outcomes and therapeutic vulnerabilities. A commonly used classification system in CRC is the Consensus Molecular Subtypes (CMS) based on gene expression patterns. However, how these CMS categories connect to axes of phenotypic plasticity and heterogeneity remains unclear. Here, we analyze 101 bulk transcriptomic datasets, along with patient tumor samples from TCGA and single-cell RNA sequencing data, to evaluate the extent of variation among CMS subtypes across metabolic plasticity and EMT axes. Our results show that CMS2 and CMS3 samples were relatively more epithelial as compared to CMS1 and CMS4. Single-cell RNA-seq analysis of CMS1 revealed two subpopulations: one close to CMS4 (more mesenchymal) and the other closer to CMS2 or CMS3 (more epithelial), indicating a partial EMT-like behavior. Further, in our meta-analysis and in TCGA data, epithelial phenotype score was positively correlated with scores of glycolysis, OXPHOS and FAO pathways, while mesenchymal scores showed CMS subtype-specific associations with metabolic axes. PD-L1 activity scores, however, consistently correlated positively with mesenchymal signature ones and negatively with epithelial signature ones, across the four CMS categories. Together, our results quantify the patterns of two interconnected axes of phenotypic heterogeneity - EMT and metabolic reprogramming - at a CMS subtype level in CRC."
1875,LARP1 regulates metabolism and mTORC1 activity in cancer,"James Chettle, Zinaida Dedeic, Roman Fischer, Iolanda Vendrell, Leticia Campo, Alistair Easton, Molly Browne, Josephine Morris, Hagen Schwenzer, Pauline Lascaux, Rik Gijsbers, Elisabete Pires, Daniel J. Royston, David J. P. Ferguson, An Coosemans, Benedikt Kessler, James McCullagh, Ahmed A. Ahmed, Kristijan Ramadan, Martin Bushell, Adrian L. Harris, Colin R. Goding, Sarah P. Blagden",https://www.biorxiv.org/content/10.1101/2022.09.04.506559v1,"The protein mammalian target of rapamycin (mTOR) is a master regulator of cell homeostasis. Although mTOR is aberrantly overactivated in 70% ovarian cancers, mTOR cascade inhibitors (such as those blocking the kinase activity of mTOR itself or upstream kinases PI3K/AKT) have demonstrated disappointing activity in ovarian cancer clinical trials. These findings indicate that, despite its pivotal role in normal cells, hyperactivated mTOR does not act as a master regulator of metabolism in this cancer context. Surprisingly, we have identified that the RNA binding protein LARP1, a known phospho-target of mTORC1 and activator of ribosomal biogenesis, is responsible for metabolic reprogramming in mTOR-dysregulated cancers. LARP1 post-transcriptionally regulates the expression of several hundred rate-limiting enzymes involved in multiple aspects of metabolism, including glycolysis and oxidative phosphorylation. Through this mechanism LARP1 sustains ATP production and mTORC1 localisation on the lysosome, thereby activating cell proliferation despite the scarcity of extracellular nutrients. Our findings show that, by sustaining global cellular metabolism in response to growth factor signalling, LARP1 has a central post-transcriptional role in controlling mTORC1 localisation and driving cancer progression, a key cancer hallmark."
1876,"Neurodevelopmental disorders and cancer networks share pathways; but differ in mechanisms, signaling strength, and outcome","Bengi Ruken Yavuz, M Kaan Arici, Habibe Cansu Demirel, Chung-Jung Tsai, Hyunbum Jang, Ruth Nussinov, Nurcan Tuncbag",https://www.biorxiv.org/content/10.1101/2023.04.16.536718v1,"Neurodevelopmental disorders (NDDs) and cancer are connected, with immunity as their common factor. Their clinical presentations differ; however, individuals with NDDs are more likely to acquire cancer. Schizophrenia patients have ∼50% increased risk; autistic individuals also face an increased cancer likelihood. NDDs are associated with specific brain cell types at specific locations, emerging at certain developmental time windows during brain evolution. Their related mutations are germline; cancer mutations are sporadic, emerging during life. At the same time, NDDs and cancer share proteins, pathways, and mutations. Here we ask exactly which features they share, and how despite their commonality, they differ in outcomes. Our pioneering bioinformatics exploration of the mutations, reconstructed disease-specific networks, pathways, and transcriptome profiles of autism spectrum disorder (ASD) and cancers, points to elevated signal strength in pathways related to proliferation in cancer, and differentiation in ASD. Signaling strength, not the activating mutation, is the key factor in deciding cancer versus NDDs."
1877,Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer,"Anna J. Wiecek, Stephen J. Cutty, Daniel Kornai, Mario Parreno-Centeno, Lucie E. Gourmet, Guidantonio Malagoli Tagliazucchi, Daniel H. Jacobson, Ping Zhang, Lingyun Xiong, Gareth L. Bond, Alexis R. Barr, Maria Secrier",https://www.biorxiv.org/content/10.1101/2021.11.12.468410v4,"Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative G0 state, which is difficult to capture and whose mutational drivers remain largely unknown. We developed methodology to robustly identify this state from transcriptomic signals and characterised its prevalence and genomic constraints in solid primary tumours. We show that G0 arrest preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We employ machine learning to uncover novel genomic dependencies of this process and validate the role of the centrosomal gene CEP89 as a modulator of proliferation/G0 arrest capacity. Lastly, we demonstrate that G0 arrest underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single cell data, and propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state."
1879,Pan-cancer analysis reveals tumor microbiome associations with host molecular aberrations,"Chenchen Ma, Changxing Su, Jiaxuan Li, Jiuxin Qu, Shimin Shuai",https://www.biorxiv.org/content/10.1101/2023.04.13.536730v2,"Host-microbiome interaction is known to play a pivotal role in the cancer ecosystem, yet the associations have not been systematically investigated at the pan-cancer and the multi-omics level. Here, we evaluated nearly 10,000 samples across 32 cancer types collected from The Cancer Genome Atlas (TCGA), to investigate the association between the tumor microbiome (taxa, n=1,630) and tumor microenvironment composition (cell types, n=20), epigenome (CpG island methylation, n=30,716), transcriptome (gene expression, n=10,216) and proteome (protein expression, n=193). We identified 836,738 candidate associations between the tumor microbiome and host molecular aberrations across multiple cancers. Besides cancer-specific associations, we also revealed recurrent pan-cancer associations between microbes (Lachnoclostridium, Flammeovirga, Terrabacter and Campylobacter) and immune cells, as well as between microbes (Collimonas and Sutterella) and fibroblasts, which were further validated by cell type estimations derived from pathological images and methylation data. We also identified several potential microbe and gene/protein expression associations mediated by DNA methylation using the sequential mediation analysis. Furthermore, our survival analysis demonstrated that tumor microbes may affect the patient’s overall survival and progression-free survival. Finally, a user-friendly web portal, Multi-Omics and Microbiome Associations in Cancer (MOMAC) was constructed for users to explore potential host-microbe interactions in cancer."
1881,Ensembles for improved detection of invasive breast cancer in histological images,"Leslie Solorzano, Stephanie Robertson, Johan Hartman, Mattias Rantalainen",https://www.biorxiv.org/content/10.1101/2023.04.13.536542v1,"Accurate detection of invasive breast cancer (IC) can provide decision support to pathologists as well as improve downstream computational analyses, where detection of IC is a first step. Tissue containing IC is characterized by the presence of specific morphological features, which can be learned by convolutional neural networks (CNN). Here, we compare the use of a single CNN model versus an ensemble of several base models with the same CNN architecture, and we evaluate prediction performance as well as variability across ensemble based model predictions."
1882,Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution,"Irene Casanova-Salas, Sarai Cordoba-Terreros, Daniel Aguilar, Laura Agundez, Julian Brandariz, Nicolas Herranz, Macarena Gonzalez, Rafael Morales-Barrera, Alexandre Sierra, Mario Soriano-Navarro, Pablo Cresta, Sara Simonetti, Gonçalo Rodrigues, Sara Arce-Gallego, Luisa Delgado-Soriano, Irene Agustí, Elena Castellano-Sanz, Richard Mast, Matias de Albert, Ana Celma, Anna Santamaria, Lucila Gonzalez, Natalia Castro, Maria del Mar Suanes, Javier Hernández-Losa, Lara Nonell, Hector Peinado, Joan Carles, Joaquin Mateo",https://www.biorxiv.org/content/10.1101/2023.04.14.536404v1,"Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of tumors through multi-omic profiling remains widely unexplored. Genomic and transcriptomic profiling of circulating EV-DNA and EV-RNA isolated from a range of in-vitro and in-vivo models of metastatic prostate cancer (mPC) revealed a high contribution of tumor material to EV-loaded DNA/RNA. Findings were validated in a cohort of longitudinal plasma samples collected from mPC patients during androgen receptor signaling inhibitor (ARSI) therapy. EV-DNA genomic features recapitulated matched-patient biopsies and associated with clinical progression. We developed a novel approach to enable the transcriptomic profiling of EV-RNA (RExCuE). We report how the transcriptomic profile in mPC EV-RNA is enriched for tumor-associated transcripts when compared to same patient blood RNA and healthy individuals EV-RNA, and reflect early on-therapy tumor adaptation changes. Altogether, we show that EV profiling enables longitudinal transcriptomic and genomic profiling of mPC in liquid biopsy."
1883,LGR5 targeting molecules as therapeutic agents for multiple cancer types,"Hung-Chang Chen, Nico Mueller, Katherine Stott, Eilidh Rivers, Chrysa Kapeni, Carolin M Sauer, Flavio Beke, Stephen Walsh, Nicola Ashman, Louise O’Brien, Amir Rafati Fard, Arman Godsinia, Fadwa Joud, Olivier Giger, Inti Zlobec, Ioana Olan, Sarah J. Aitken, Matthew Hoare, Richard Mair, Eva Serrao, James D Brenton, Alicia Garcia-Gimenez, Simon E. Richardson, Brian Huntly, David R. Spring, Mikkel-Ole Skjødt, Karsten Skjødt, Marc de la Roche, Maike de la Roche",https://www.biorxiv.org/content/10.1101/2022.09.01.506182v1,Leucine-rich repeat-containing G-protein receptor 5 (LGR5) has been characterised as a stem cell and cancer stem cell marker. Previous analyses of LGR5 transcript levels indicate high level expression discriminates malignancies such as colorectal cancer (CRC) and pre-B acute lymphoblastic leukaemia (pre-B ALL) from healthy tissues suggesting LGR5 protein expression may provide a molecular handle for prognosis and treatment.
1884,Combinatorial genetic strategy accelerates the discovery of cancer genotype-phenotype associations,"Shan Li, Alicia Wong, Huiyun Sun, Vipul Bhatia, Gerardo Javier, Sujata Jana, Robert B. Montgomery, Jonathan L. Wright, Hung-Ming Lam, Andrew C. Hsieh, Bishoy M. Faltas, Michael C. Haffner, John K. Lee",https://www.biorxiv.org/content/10.1101/2023.04.12.536652v1,"Available genetically-defined cancer models are limited in genotypic and phenotypic complexity and underrepresent the heterogeneity of human cancer. Herein, we describe a combinatorial genetic strategy applied to an organoid transformation assay to rapidly generate diverse, clinically relevant bladder and prostate cancer models. Importantly, the clonal architecture of the resultant tumors can be resolved using single-cell or spatially resolved next-generation sequencing to uncover polygenic drivers of cancer phenotypes."
1885,Expressional Diversity and Cancer-prone Phenotypes in Cigarette-smoking Lungs at Single Cell Resolution,"Jun Nakayama, Yusuke Yamamoto",https://www.biorxiv.org/content/10.1101/2021.12.09.472029v2,"Single-cell RNA-seq (scRNA-seq) technologies have been broadly utilized to reveal molecular mechanisms of respiratory pathology and physiology at single-cell resolution. Here, we established single-cell meta-analysis (scMeta-analysis) by integrating data from 8 public datasets, including 104 lung scRNA-seq samples with clinicopathological information and designated a cigarette smoking lung atlas. The atlas revealed early carcinogenesis events and defined the alterations of single-cell transcriptomics, cell population, and fundamental properties of biological pathways induced by smoking. In addition, we developed two novel scMeta-analysis methods: VARIED (Visualized Algorithms of Relationships In Expressional Diversity) and AGED (Aging-related Gene Expressional Differences). VARIED analysis revealed expressional diversity associated with smoking carcinogenesis. AGED analysis revealed differences in gene expression related to both aging and smoking states. The scMeta-analysis pave the way to utilize publicly -available scRNA-seq data and provide new insights into the effects of smoking and into cellular diversity in human lungs, at single-cell resolution."
1886,MutSigCVsyn: Identification of Thirty Synonymous Cancer Drivers,"Yiyun Rao, Nabeel Ahmed, Justin Pritchard, Edward O’Brien",https://www.biorxiv.org/content/10.1101/2022.01.16.476507v2,"Synonymous mutations, which change only the DNA sequence but not the encoded protein sequence, can affect protein structure and function, mRNA maturation, and mRNA half-lives. The possibility that synonymous mutations can act as cancer drivers has been explored in several recent studies. However, none of these studies control for all three levels (patient, histology, and gene) of mutational heterogeneity that are known to affect the accurate identification of non-synonymous cancer drivers. Here, we create an algorithm, MutSigCVsyn, an adaptation of MutSigCV, to identify synonymous cancer drivers based on a novel non-coding background model that takes into account the mutational heterogeneity across these levels. Examining 2,572 PCAWG cancer whole-genome sequences, MutSigCVsyn identifies 30 novel synonymous drivers that include mutations in promising candidates like BCL-2. By bringing the best practices in non-synonymous driver identification to the analysis of synonymous drivers, these are promising candidates for future experimental study."
1887,The anti-cancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3′ processing machinery,"Liang Liu, Angela M Yu, Xiuye Wang, Lindsey V. Soles, Yiling Chen, Yoseop Yoon, Kristianna S.K. Sarkan, Marielle Cárdenas Valdez, Johannes Linder, Ivan Marazzi, Zhaoxia Yu, Feng Qiao, Wei Li, Georg Seelig, Yongsheng Shi",https://www.biorxiv.org/content/10.1101/2023.04.11.536453v1,"JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3′ processing. Although CPSF73 is universally required for mRNA 3′ end formation, we have unexpectedly found that Compound 2- mediated inhibition of pre-mRNA 3′ processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity. By using massively parallel in vitro assays, we have measured the Compound 2 sensitivities of over 260,000 sequence variants and identified key sequence features that determine drug sensitivity. A machine learning model trained on these data can predict the impact of JTE-607 on poly(A) site (PAS) selection and transcription termination genome-wide. We propose a biochemical model in which CPSF73 and other mRNA 3′ processing factors bind to RNA of the CS region in a sequence-specific manner and the affinity of such interaction determines the Compound 2 sensitivity of a PAS. As the Compound 2-resistant CS sequences, characterized by U/A-rich motifs, are prevalent in PASs from yeast to human, the CS region sequence may have more fundamental functions beyond determining drug resistance. Together, our study not only characterized the mechanism of action of a compound with clinical implications, but also revealed a previously unknown and evolutionarily conserved sequence-specificity of the mRNA 3′ processing machinery."
1888,Minute virus of mice is oncolytic for pancreatic cancer cells with mesenchymal phenotype,"P. Garcin, H. Lulka, N. Dusetti, M. Vienne, L. Buscail, P. Cordelier",https://www.biorxiv.org/content/10.1101/2023.04.11.536425v2,"Pancreatic cancer will soon become the second cause of death by cancer in Western countries. The main barrier to increase the survival of patients with this disease requires the development of novel and efficient therapeutic strategies, that better consider tumor biology. Oncolytic viruses are quickly moving toward the forefront of medicines for the management of cancer. Among them, the fibrotropic minute virus of mice prototype (MVMp) preferentially infects migrating and undifferentiated cells, that highly resemble poorly differentiated, basal-like, pancreatic tumors showing the worst clinical outcome. Thus, we hypothesized that MVMp may specifically target the most aggressive subtype of pancreatic cancer cells. We report here that MVMp specifically infects, replicates in and kills pancreatic cancer cells from murine and human origin with a mesenchymal, basal-like profile, while sparing cancer cells with an epithelial phenotype. In vivo, MVMp shows oncolytic activity in experimental tumors with mesenchymal phenotype only, and shows increased antitumoral efficacy in immune competent models. Collectively, we demonstrate herein for the first time that MVMp is specific and oncolytic for pancreatic tumors with mesenchymal, basal-like profile, paving the way for precision medicine opportunities for the management of the most aggressive and lethal form of this disease."
1890,Predicting anti-cancer drug synergy using extended drug similarity profiles,"Sayed-Rzgar Hosseini, Xiaobo Zhou",https://www.biorxiv.org/content/10.1101/2022.08.28.505568v1,"Combination therapy is a promising strategy for confronting the complexity of cancer. However, experimental exploration of the vast space of potential drug combinations is costly and unfeasible. Therefore, computational methods for predicting drug synergy are much-needed for narrowing down this space, especially when examining new cellular contexts. Here, we thus introduce CCSynergy, a flexible, context-aware and integrative deep learning framework that we have established to unleash the potential of the Chemical Checker extended drug similarity profiles for the purpose of drug synergy prediction. We have shown that CCSynergy enables predictions of superior accuracy, remarkable robustness and improved context-generalizability as compared to the state-of-the-art methods in the field. Having established the potential of CCSynergy for generating experimentally validated predictions, we exhaustively explored the untested drug combination space. This resulted in a compendium of potentially synergistic drug combinations on hundreds of cancer cell lines, which can guide future experimental screens."
1891,Spatial transcriptomics reveals ovarian cancer subclones with distinct tumour microenvironments,"Elena Denisenko, Leanne de Kock, Adeline Tan, Aaron B. Beasley, Maria Beilin, Matthew E. Jones, Rui Hou, Dáithí Ó Muirí, Sanela Bilic, G. Raj K. A. Mohan, Stuart Salfinger, Simon Fox, Khaing Hmon, Yen Yeow, Elin S. Gray, Paul A. Cohen, Yu Yu, Alistair R. R. Forrest",https://www.biorxiv.org/content/10.1101/2022.08.29.505206v1,"High-grade serous ovarian carcinoma (HGSOC) is characterised by recurrence, chemotherapy resistance and overall poor prognosis. Genetic heterogeneity of tumour cells and the microenvironment of the tumour have been hypothesised as key determinants of treatment resistance and relapse. Here, using a combination of spatial and single cell transcriptomics (10x Visium and Chromium platforms), we examine tumour genetic heterogeneity and infiltrating populations of HGSOC samples from eight patients with variable response to neoadjuvant chemotherapy. By inferring gross copy number alterations (CNAs), we identified distinct tumour subclones co-existing within individual tumour sections. These tumour subclones have unique CNA profiles and spatial locations within each tumour section, which were further validated by ultra-low-pass whole genome sequencing. Differential expression analysis between subclones within the same section identified both tumour cell intrinsic expression differences and markers indicative of different infiltrating cell populations. The gene sets differentially expressed between subclones were significantly enriched for genes encoding plasma membrane and secreted proteins, indicative of subclone-specific microenvironments. Furthermore, we identified tumour derived ligands with variable expression levels between subclones that correlated or anticorrelated with various non-malignant cell infiltration patterns. We highlight several of these that are potentially direct tumour-stroma/immune cell relationships as the non-malignant cell type expresses a cognate receptor for the tumour derived ligand. These include predictions of CXCL10-CXCR3 mediated recruitment of T and B cells to associate with the subclones of one patient and CD47-SIRPA mediated exclusion of macrophages from association with subclones of another. Finally, we show that published HGSOC molecular subtype signatures associated with prognosis are heterogeneously expressed across tumour sections and that areas containing different tumour subclones with different infiltration patterns can match different subtypes. Our study highlights the high degree of intratumoural subclonal and infiltrative heterogeneity in HGSOC which will be critical to better understand resistance and relapse."
1893,Discovery and Validation of RUNX1 DNA Methylation in Differentiating Papillary Thyroid Cancer from Benign Nodules,"Junjie Li, Yifei Yin, Haixia Huang, Mengxia Li, Hong Li, Minmin Zhang, Chenxia Jiang, Rongxi Yang",https://www.biorxiv.org/content/10.1101/2023.04.10.536270v1,"Although most thyroid nodules can be diagnosed preoperatively by thyroid ultrasonography and fine-needle aspiration biopsy, it remains a challenge to accurately identify malignancy of thyroid nodules when the biopsy is indeterminate. This study aims to explore a novel biomarker to distinguish benign and malignant thyroid nodules. Tissue samples from patients with Stage I&II papillary thyroid carcinoma (PTC) and benign thyroid nodules (BTN) were collected for genome profiling by methylation EPIC 850K array and RNA-Sequencing. Genes with significantly differential DNA methylation and inverse mRNA expression were filtered out. The altered methylation of RUNX1 gene was validated in two independent case-control studies with a total of 699 formalin fixed paraffin-embedded (FFPE) samples using mass spectrometry and calculated by binary logistic regression analysis. Hypomethylation of RUNX1 gene in PTC patients compared to BTN subjects was verified in Validation Ⅰ (140 PTC vs. 189 BTN, ORs ≥ 1.50 per-10% methylation, P ≤ 4.40E-05, for all measurable CpG sites) and Validation Ⅱ (184 PTC vs. 186 BTN, ORs ≥ 1.72 per-10% methylation, P ≤ 2.38E-11, for all measurable CpG sites). Besides, RUNX1 methylation achieved good accuracy in differentiating early-stage PTC from BTN in Validation Ⅰ (AUC: 0.74) and Validation Ⅱ (AUC: 0.79). Gender- and age-stratified analysis revealed RUNX1 hypomethylation as an important risk factor for thyroid disease in younger women. We disclosed a significant association between RUNX1 hypomethylation and PTC, suggesting RUNX1 methylation based on FFPE tissue samples as a potential biomarker for predicting malignancy of thyroid nodules."
1894,Transcriptomics of mussel transmissible cancer MtrBTN2 suggests accumulation of multiple cancerous traits and oncogenic pathways shared among bilaterians,"E.A.V. Burioli, M. Hammel, E. Vignal, J. Vidal-Dupiol, G. Mitta, F. Thomas, N. Bierne, D. Destoumieux-Garzón, G.M. Charrière",https://www.biorxiv.org/content/10.1101/2023.01.03.522559v2,"Transmissible cancer cell lines are rare biological entities giving rise to diseases at the crossroads of cancer and parasitic diseases. These malignant cells have acquired the amazing capacity to spread from host to host. They have been described only in dogs, Tasmanian devils and marine bivalves. The Mytilus trossulus Bivalve Transmissible Neoplasia 2 (MtrBTN2) lineage has even acquired the capacity to spread inter-specifically between marine mussels of the Mytilus edulis complex worldwide. To identify the oncogenic processes underpinning the biology of these atypical cancers we performed transcriptomics of MtrBTN2 cells. Differential expression, enrichment, protein-protein interaction network, and targeted analyses were used. Overall, our results suggest the accumulation of multiple cancerous traits that way be linked to the long-term evolution of MtrBTN2. We also highlight that vertebrate and lophotrochozoan cancers could share a large panel of common drivers, which supports the hypothesis of an ancient origin of oncogenic processes in bilaterians."
1895,Spatiotemporal Genomic Profiling of Intestinal Metaplasia Reveals Clonal Dynamics of Gastric Cancer Progression,"Kie Kyon Huang, Haoran Ma, Tomoyuki Uchihara, Taotao Sheng, Roxanne Hui Heng Chong, Feng Zhu, Supriya Srivastava, Su Ting Tay, Raghav Sundar, Angie Lay Keng Tan, Xuewen Ong, Minghui Lee, Shamaine Wei Ting Ho, Tom Lesluyes, Peter Van Loo, Joy Shijia Chua, Kalpana Ramnarayanan, Tiing Leong Ang, Christopher Khor, Jonathan Wei Jie Lee, Stephen Kin Kwok Tsao, Ming Teh, Hyunsoo Chung, Jimmy Bok Yan So, Khay Guan Yeoh, Patrick Tan, Singapore Gastric Cancer Consortium",https://www.biorxiv.org/content/10.1101/2023.04.10.536195v1,"Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We analyzed 1256 gastric samples (1152 IMs) from 692 subjects through a prospective 10-year study. We identified 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9), largely occurring as small clonal events. Analysis of clonal dynamics between and within subjects, and also longitudinally across time, revealed that IM clones are likely transient but increase in size upon progression to dysplasia, with eventual transmission of somatic events to paired GCs. Single-cell and spatial profiling highlighted changes in tissue ecology and lineage heterogeneity in IM, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling revealed expression-based molecular subtypes of IM, including a body-resident “pseudoantralized” subtype associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical- genomic models outperform clinical-only models in predicting IMs likely to progress. Our results raise opportunities for GC precision prevention and interception by highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression."
1896,Disassembly of embryonic keratin filaments promotes pancreatic cancer metastases,"Ryan R. Kawalerski, Mariana Torrente Gonçalves, Chun-Hao Pan, Robert Tseng, Lucia Roa-Peña, Cindy V. Leiton, Luke A. Torre-Healy, Taryn Boyle, Sumedha Chowdhury, Natasha T. Snider, Kenneth R. Shroyer, Luisa F. Escobar-Hoyos",https://www.biorxiv.org/content/10.1101/2022.08.27.504988v1,"Keratin 17 (K17), an oncofetal intermediate filament protein, is one of the most abundantly expressed proteins in pancreatic ductal adenocarcinomas (PDACs) of the most aggressive molecular subtype. The mechanistic roles of this protein in malignancy, however, are largely unexplored. Here we show that K17 expression and disassembly enhances tumor growth and metastatic potential and shortens survival. Using mass spectrometry in K17 isolated from patient’s tumors, we identified a hotspot phosphorylation site in serines 10-13. Site-mutagenesis revealed that phosphorylation of this hotspot is sufficient to disassemble K17 and promote its nuclear translocation. In silico and pharmacologic inhibition studies uncovered the role of the PKC/MEK/RSK pathway in the phosphorylation and disassembly of K17. Murine models bearing tumors expressing phosphomimetic mutations at the serine hotspot displayed enhanced metastases, compared to mice bearing tumors expressing wild-type K17 or phosphorylation-resistant K17. Lastly, we found that detergent-soluble nuclear K17 promotes the expression of metastasis promoting genes in both patient and murine tumors. These results suggest that phosphorylation at specific serines is sufficient to promote pancreatic cancer metastasis and shorter survival, and that these sites could provide novel, druggable therapeutic domains to enhance PDAC patient survival."
1897,The pregnancy-associated protein glycodelin as a potential sex-specific target for resistance to immunotherapy in non-small cell lung cancer,"Sarah Richtmann, Sebastian Marwitz, Thomas Muley, Hannu Koistinen, Petros Christopoulos, Michael Thomas, Daniel Kazdal, Michael Allgäuer, Hauke Winter, Torsten Goldmann, Michael Meister, Ursula Klingmüller, Marc A. Schneider",https://www.biorxiv.org/content/10.1101/2023.03.02.530822v2,"Lung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, treatment failure and resistance to these therapies is common. Consideration of sex as a factor influencing therapy resistance is still rare. We hypothesize that the success of the treatment is impaired by the presence of the immunosuppressive pregnancy-associated glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. NSCLC-derived glycodelin interacts with immune cells in vitro and regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. In tumor microarray samples of patients, high glycodelin staining in tumor areas results in an impaired overall survival of female patients. Moreover, glycodelin colocalizes to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. High serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. In summary, our findings suggest that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer."
1899,"Darapladib, an inhibitor of Lp-PLA2, sensitizes cancer cells to ferroptosis by remodeling lipid metabolism","Mihee Oh, Seo Young Jang, Ji-Yoon Lee, Jong Woo Kim, Youngae Jung, Jinho Seo, Tae-Su Han, Eunji Jang, Hye Young Son, Dain Kim, Min Wook Kim, Kwon-Ho Song, Kyoung-Jin Oh, Won Kon Kim, Kwang-Hee Bae, Yong-Min Huh, Baek-Soo Han, Sang Chul Lee, Geum-Sook Hwang, Eun-Woo Lee",https://www.biorxiv.org/content/10.1101/2023.04.08.536136v1,"Arachidonic and adrenic acids in the membrane play key roles in ferroptosis, but how these fatty acids are manipulated in cells is largely unknown. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen identified that darapladib (SB-480848), an inhibitor of Lp-PLA2, synergistically induced ferroptosis with GPX4 inhibitors. Notably, darapladib was able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, Lp-PLA2 was located in the membrane and cytoplasm and suppressed ferroptosis, suggesting the critical role of intracellular Lp-PLA2. Lipidomic analysis showed that phosphatidylethanolamine (PE) species were generally enriched, while lysophosphatidylethanolamine (lysoPE) and free fatty acid levels were reduced, upon darapladib treatment. Finally, combination treatment with darapladib and PACMA31, a GPX4 inhibitor, efficiently inhibited tumor growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment."
1901,Comprehensive mapping of cell fates in microsatellite unstable cancer cells support dual targeting of WRN and ATR,"Dali Zong, Natasha C. Koussa, James A. Cornwell, Ajith V. Pankajam, Michael J. Kruhlak, Nancy Wong, Raj Chari, Steven D. Cappell, André Nussenzweig",https://www.biorxiv.org/content/10.1101/2023.07.28.550976v1,"Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN, knowledge that would be helpful for informing clinical development of WRN-targeting therapy, predicting possible resistance mechanisms, and identifying useful biomarkers of successful WRN inhibition. Here, we report the construction of an inducible ligand-mediated degradation system wherein the stability of endogenous WRN protein can be rapidly and specifically tuned, enabling us to track the complete sequence of cellular events elicited by acute loss of WRN function. We find that WRN degradation leads to immediate accrual of DNA damage in a replication-dependent manner that curiously did not robustly engage checkpoint mechanisms to halt DNA synthesis. As a result, WRN-degraded MSI-H cancer cells accumulate DNA damage across multiple replicative cycles and undergo successive rounds of increasingly aberrant mitoses, ultimately triggering cell death. Of potential therapeutic importance, we find no evidence of any generalized mechanism by which MSI-H cancers could adapt to near-complete loss of WRN. However, under conditions of partial WRN degradation, addition of low dose ATR inhibitor significantly increased their combined efficacy to levels approaching full inactivation of WRN. Overall, our results provided the first comprehensive view of molecular events linking upstream inhibition of WRN to subsequent cell death and suggested a potential therapeutical rationale for dual targeting of WRN and ATR."
1903,Senescence triggers intracellular acidification and lysosomal alkalinization via ATP6AP2 attenuation in breast cancer cells,"Wei Li, Kosuke Kawaguchi, Sunao Tanaka, Chenfeng He, Yurina Maeshima, Eiji Suzuki, Masakazu Toi",https://www.biorxiv.org/content/10.1101/2023.04.08.536098v1,"Several chemotherapy drugs induce the senescence of cancer cells; however, the mechanism underlying intracellular pH dysregulation in senescent cells remains unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. We here report a new function of ATP6AP2 in senescent breast cancer cells induced by doxorubicin and abemaciclib treatment. ATP6AP2 expression was significantly downregulated in senescent cells, leading to aberrant pH levels that impaired lysosome function and caused immune response changes. The drugs caused cell cycle arrest and proliferation suppression through the upregulation of senescence-related genes. Additionally, senescent cells showed altered inflammatory and immune transcriptional profiles by reprogramming the senescence-associated secretory phenotype. These findings suggest that ATP6AP2-mediated pH regulation during therapy-induced senescence may be linked to immune changes in senescent cancer cells. These findings provide novel insights into understanding the cellular mechanisms underlying the response to anti-cancer drugs."
1905,Magnetically Controlled Cyclic Microscale Deformation of In Vitro Cancer Invasion Models,"D.O. Asgeirsson, A. Mehta, N. Hesse, A. Scheeder, R. Ward, F. Li, M. G. Christiansen, A. J. De Micheli, E. S. Ildic, N. Aceto, S. Schuerle",https://www.biorxiv.org/content/10.1101/2023.03.30.534990v2,"Mechanical cues play an important role in the metastatic cascade of cancer. Three-dimensional (3D) tissue matrices with tunable stiffness have been extensively used as model systems of the tumor microenvironment for physiologically relevant studies. Tumor-associated cells actively deform these matrices, providing mechanical cues to other cancer cells residing in the tissue. Mimicking such dynamic deformation in the surrounding tumor matrix may help clarify the effect of local strain on cancer cell invasion. Remotely controlled microscale magnetic actuation of such 3D in vitro systems is a promising approach, offering a non-invasive means for in situ interrogation. Here, we investigate the influence of cyclic deformation on tumor spheroids embedded in matrices, continuously exerted for days by cell-sized anisotropic magnetic probes, referred to as µRods. Particle velocimetry analysis revealed the spatial extent of matrix deformation produced in response to a magnetic field, which was found to be on the order of 200 µm, resembling strain fields reported to originate from contracting cells. Intracellular calcium influx was observed in response to cyclic actuation, as well as an influence on cancer cell invasion from 3D spheroids, as compared to unactuated controls. Localized actuation at one side of a tumor spheroid tended to result in anisotropic invasion toward the µRods causing the deformation. In summary, our approach offers a strategy to test and control the influence of non-invasive micromechanical cues on cancer cell invasion and metastasis."
1906,Multi-omic study of genome-edited human colonoid models of colorectal cancer reveal genotype-specific patterns of microRNA regulation,"Jonathan W. Villanueva, Fong Cheng Pan, Edward J. Rice, Yu-Han Hung, Mary Winnicki, Shuibing Chen, Charles G. Danko, Praveen Sethupathy",https://www.biorxiv.org/content/10.1101/2023.07.28.551007v1,"Combinations of oncogenic mutations drive inter-tumor heterogeneity in colorectal cancer (CRC), which promotes distinct phenotypes and affects therapeutic efficacy. We recently demonstrated that combinations of mutations in mouse small intestinal organoids lead to unique changes in microRNA (miRNA) expression profiles. However, it remains unknown how different mutational backgrounds shape miRNA profiles in the human colon. We leveraged human colonic organoid models, termed colonoids, with gene edits targeting genes commonly mutated in CRC to profile genotype-specific changes in miRNA expression. By small RNA-sequencing we characterized genotype-specific miRNA profiles. We identified one group of miRNAs, including mir-34a-5p and mir-10a-5p, that is strongly downregulated in APC/KRAS/TP53 mutant (AKP-mutant) colonoids. Using chromatin run-on sequencing, we showed that most miRNA alterations in AKP-mutant colonoids are concordant with transcriptional changes. Transcription factor (TF) motif enrichment analysis using transcriptional regulatory elements with increased activity in AKP-mutant colonoids revealed an enrichment of binding sites for multiple oncogenic TFs. Several of these harbor predicted binding sites for mir-10a-5p and/or mir-34a-5p, suggesting these miRNAs may play a role in regulating transcriptional programs in AKP-mutant contexts. Ultimately, our study offers a glimpse into regulatory mechanisms that drive inter-tumor heterogeneity, and we highlight candidate therapeutic targets for the advancement of precision medicine."
1907,Is evolutionary conservation a useful predictor for cancer long noncoding RNAs? Insights from the Cancer lncRNA Census 3,"Adrienne Vancura, Alejandro H. Gutierrez, Thorben Hennig, Carlos Pulido-Quetglas, Frank Slack, Rory Johnson, Simon Häfliger",https://www.biorxiv.org/content/10.1101/2022.09.01.506261v1,"Evolutionary conservation is a measure of gene functionality that is widely used to prioritise long noncoding RNAs (lncRNA) in cancer research. Intriguingly, while updating our Cancer LncRNA Census, we observed an inverse relationship between year of discovery and evolutionary conservation. This observation is specific to cancer over other diseases, implying a sampling bias in selection of lncRNA candidates and casting doubt on the value of evolutionary metrics for prioritisation of cancer-related lncRNAs."
1909,An experimental comparison of the Digital Spatial Profiling and Visium spatial transcriptomics technologies for cancer research,"Taopeng Wang, Kate Harvey, John Reeves, Daniel L. Roden, Nenad Bartonicek, Jessica Yang, Ghamdan Al-Eryani, Dominik Kaczorowski, Chia-Ling Chan, Joseph Powell, Sandra O’Toole, Elgene Lim, Alexander Swarbrick",https://www.biorxiv.org/content/10.1101/2023.04.06.535805v1,"Background Spatial transcriptomic technologies are powerful tools for resolving the spatial heterogeneity of gene expression in tissue samples. However, little evidence exists on relative strengths and weaknesses of the various available technologies for profiling human tumour tissue. In this study, we aimed to provide an objective assessment of two common spatial transcriptomics platforms, 10X Genomics’ Visium and Nanostring’s GeoMx DSP."
1910,TGF-β induces matrisome pathological alterations and EMT in patient-derived prostate cancer tumoroids,"Soraia Fernandes, Jorge Oliver-De La Cruz, Marco Cassani, Sofia Morazzo, Helena Ďuríková, Alessio Caravella, Piergiuseppe Fiore, Giulia Azzato, Giuseppe De Marco, Agostino Lauria, Valerio Izzi, Veronika Bosáková, Jan Fric, Petr Filipensky, Giancarlo Forte",https://www.biorxiv.org/content/10.1101/2023.04.03.534859v1,"Extracellular matrix (ECM) tumorigenic alterations resulting in high matrix deposition and stiffening are hallmarks of adenocarcinomas and are collectively defined as desmoplasia. Here, we thoroughly analysed primary prostate cancer tissues obtained from numerous patients undergoing radical prostatectomy to highlight reproducible structural changes in the ECM leading to the loss of the glandular architecture. Starting from patient cells, we established prostate cancer tumoroids (PCTs) and demonstrated they require TGF-β signalling pathway activity to preserve phenotypical and structural similarities with the tissue of origin. By modulating TGF-β signalling pathway in PCTs, we unveiled its role in ECM accumulation and remodelling in prostate cancer. We also found that TGF-β-induced ECM remodelling is responsible for the initiation of prostate cell epithelial-to-mesenchymal transition (EMT) and the acquisition of a migratory, invasive phenotype. Our findings highlight the cooperative role of TGF-β signalling and ECM desmoplasia in prompting prostate cell EMT and promoting tumour progression and dissemination"
1911,Polyamine transport inhibition and cisplatin synergistically enhance tumor control through oxidative stress in murine head and neck cancer models,"Abdulkader Yassin-Kassab, Nathaniel Wang, Jackson Foley, Tracy Murray Stewart, Mark R. Burns, Robert A. Casero Jr, R. Alex Harbison, Umamaheswar Duvvuri",https://www.biorxiv.org/content/10.1101/2023.07.25.550524v1,"Background Surgery and/or platinum-based chemoradiation remain standard of care for patients with head and neck squamous cell carcinoma (HNSCC). While these therapies are effective in a subset of patients, a substantial proportion experience recurrence or treatment resistance. As cisplatin mediates cytotoxicity through oxidative stress while polyamines play a role in redox regulation, we posited that combining cisplatin with polyamine transport inhibitor, AMXT-1501, would increase oxidative stress and tumor cell death in HNSCC cells."
1912,ST3Gal1 synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer,"Rebecca Garnham, Daniel Geh, Ryan Nelson, Erik Ramon-Gill, Laura Wilson, Edward N Schmidt, Laura Walker, Beth Adamson, Adriana Buskin, Anastasia Hepburn, Kirsty Hodgson, Hannah Kendall, Fiona M Frame, Norman Maitland, Kelly Coffey, Craig N Robson, David J Elliott, Rakesh Heer, Matthew Macauley, Jennifer Munkley, Luke Gaughan, Jack Leslie, Emma Scott",https://www.biorxiv.org/content/10.1101/2023.04.03.535346v1,"Immune checkpoint blockade trials have yet to produce a robust anti-cancer response in prostate cancer patients as a monotherapy due to the immunosuppressed prostate cancer tumour immune microenvironment. ST3Gal1 and other sialyltransferases are implicated in cancer and immune suppression by synthesizing sialoglycans, which act as ligands for Siglec receptors. These checkpoints are important for the immune response. However, it’s unclear how the synthesis of Siglec ligands is regulated, and little is known about the role of sialoglycan-Siglec-axis in prostate cancer’s evasion of anti-tumour immunity. We report that ST3Gal1 levels negatively correlate with androgen signalling in prostate tumours. Utilising syngeneic mouse models, we demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion. Using mouse models, patient samples and in vitro models we show that ST3Gal1 synthesises sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. For the first time we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. Importantly, we show that these interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer."
1913,"Divergent outcomes of SAK3, a T-type calcium channel enhancer, in two luminal-A type breast cancer cell lines: T-47D and MCF7","Yashashwini Subbamanda Dinesh, Tharunika Subramanian, Aarushi K Zinzuvadia, Andres D Maturana, Anamika Bhargava",https://www.biorxiv.org/content/10.1101/2023.11.16.567333v1,"Voltage-gated calcium channels have emerged as promising targets in breast cancer. Breast cancer cell lines are widely used as experimental models. In our pursuit to explore the potential of augmenting T-type voltage-gated calcium channels as a therapeutic approach for breast cancer, we made an unexpected discovery: similar breast cancer subtype cell lines exhibited varying responses to SAK3, a T-type voltage-gated calcium channel enhancer, in terms of proliferation and intracellular calcium levels. In presenting these contrasting findings here, we aim to underscore the importance of exercising caution and validating results obtained from cell lines by cross-referencing them with other cell lines or models."
1915,A novel antagonist of the CCL5/CCR5 axis suppresses the tumor growth and metastasis of triple-negative breast cancer by CCR5-YAP1 regulation,"Ling Chen, Guiying Xu, Xiaoxu Song, Lianbo Zhang, Chuyu Chen, Gang Xiang, Shuxuan Wang, Zijian Zhang, Fang Wu, Xuanming Yang, Lei Zhang, Xiaojing Ma, Jing Yu",https://www.biorxiv.org/content/10.1101/2023.11.15.567291v1,"Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with a high mortality rate, and few effective therapeutic strategies are available. CCL5/CCR5 is an appealing immunotherapeutic target for TNBC. However, its signaling mechanism is poorly understood and its direct antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a more selective and potent antagonist than the known CCR5 antagonist maraviroc. Without photodynamic therapy, verteporfin demonstrated significant inhibition on TNBC tumor growth through immune regulation, remarkable suppression of lung metastasis by cell-intrinsic mechanism, and a significant extension of overall survival in vivo. Mechanistically, CCR5 was found to be essential for expression of the key hippo effector YAP1. It promoted YAP1 transcription via HIF-1α and exerted further control over the migration of CD8+ T, NK, and MDSC immune cells through chemokines CXCL16 and CXCL8 which were identified from RNA-seq. Moreover, the CCR5-YAP1 axis played a vital role in promoting metastasis by modulating β-catenin and core epithelial-mesenchymal transition transcription factors ZEB1 and ZEB2. It is noteworthy that the regulatory relationship between CCR5 and YAP1 was observed across various BC subtypes, TNBC patients, and showed potential relevance in fifteen additional cancer types. Overall, this study introduced an easy-to-use HTS assay that streamlines the discovery of CCL5/CCR5 axis antagonists. Verteporfin was identified as a specific molecular probe of this axis with great potentials as a therapeutic agent for treating sixteen malignant diseases characterized by heightened CCR5 and YAP1 levels."
1916,ATP13A4 upregulation drives the elevated polyamine transport system in the breast cancer cell line MCF7,"Sarah van Veen, Antria Kourti, Elke Ausloos, Joris Van Asselberghs, Chris Van den Haute, Veerle Baekelandt, Jan Eggermont, Peter Vangheluwe",https://www.biorxiv.org/content/10.1101/2023.03.31.534207v1,"Polyamine homeostasis is disturbed in several human diseases, including cancer, which is hallmarked by increased intracellular polyamine levels and an upregulated polyamine transport system (PTS). So far, the polyamine transporters contributing to the elevated levels of polyamines in cancer cells have not yet been described, despite the fact that polyamine transport inhibitors are considered for cancer therapy. Here, we tested whether upregulation of candidate polyamine transporters of the P5B- transport ATPase family is responsible for the increased PTS in the well-studied breast cancer cell line MCF7 compared to the non-tumorigenic epithelial breast cell line MCF10A. We found that MCF7 cells present elevated expression of a previously uncharacterized P5B-ATPase ATP13A4, which is responsible for the elevated polyamine uptake activity. Furthermore, MCF7 cells are more sensitive to polyamine cytotoxicity, as demonstrated by cell viability, cell death and clonogenic assays. Importantly, overexpression of ATP13A4 WT in MCF10A cells induces a MCF7 polyamine phenotype, with significantly higher uptake of BODIPY-labelled polyamines and increased sensitivity to polyamine toxicity. In conclusion, we establish ATP13A4 as a new polyamine transporter in the human PTS and show that ATP13A4 may play a major role in the increased polyamine uptake of breast cancer cells. ATP13A4 therefore emerges as a candidate therapeutic target for anticancer drugs that block the PTS."
1918,An integrative proteomics approach identifies tyrosine kinase KIT as a novel therapeutic target for SPINK1-positive prostate cancer,"Nishat Manzar, Umar Khalid Khan, Ayush Goel, Shannon Carskadon, Nilesh Gupta, Nallasivam Palanisamy, Bushra Ateeq",https://www.biorxiv.org/content/10.1101/2023.07.24.550265v1,"Elevated Serine Peptidase Inhibitor, Kazal type 1 (SPINK1) levels in ∼10-25% of prostate cancer (PCa) patients associate with aggressive phenotype, for which there are limited treatment choices and dismal clinical outcomes. Using an integrative proteomics approach involving label-free phosphoproteome and proteome profiling, we delineated the downstream signaling pathways involved in SPINK1-mediated tumorigenesis in PCa, and identified tyrosine kinase KIT as a highly enriched kinase. Furthermore, high to moderate levels of KIT expression was detected in ∼85% of SPINK1-positive PCa specimens. KIT signaling regulates SPINK1-associated oncogenesis, and treatment with KIT inhibitor reduces tumor growth and distant metastases in preclinical mice models. Mechanistically, KIT signaling modulates WNT/β-catenin pathway and confers stemness-related features in PCa. Notably, inhibiting KIT signaling restores AR/REST levels, forming a feedback loop enabling SPINK1 repression. Overall, we uncover the role of KIT signaling downstream of SPINK1 in maintaining lineage plasticity and provide new treatment modalities for advanced-stage SPINK1-positive subtype."
1919,Activation of the mevalonate pathway in response to anti-cancer treatments drives glioblastoma recurrences through activation of Rac-1,"Ling He, Angeliki Ioannidis, Evelyn Arambula, Carter J. Hoffman, Purva Joshi, Anoushka Kathiravan, Julian Whitelegge, Linda M. Liau, Harley I. Kornblum, Frank Pajonk",https://www.biorxiv.org/content/10.1101/2023.07.23.550205v1,Glioblastoma is the deadliest adult brain cancer. Under the current standard of care almost all patients succumb to the disease and novel treatments are urgently needed. Dopamine receptor antagonists have been shown to target cancer cell plasticity in GBM and repurposing these FDA-approved drugs in combination with radiation improves the efficacy of radiotherapy in glioma models. In cells surviving this combination treatment the mevalonate pathway is upregulated at the transcriptional and functional level.
1920,"Novel microRNAs downregulated in breast cancer tumors bind to the 3’UTR of SNAIL, SLUG, ZEB1 and/or TWIST and decrease metastatic behavior in breast cancer cells","Elisa Pérez-Moreno, Victoria Ortega-Hernández, Valentina A Zavala, Jorge Gamboa, Wanda Fernández, Pilar Carvallo",https://www.biorxiv.org/content/10.1101/2023.02.03.526978v1,"Metastasis, the leading cause of cancer-associated deaths, is promoted by transcription factors SNAIL, SLUG, ZEB1 and TWIST through the activation of epithelial-mesenchymal transition (EMT). MicroRNAs can suppress EMT, emerging as candidate molecular biomarkers and novel therapeutic targets. Herein, we evaluated microRNAs downregulated in breast cancer tissues expressing EMT transcription factors, to find new potential regulators of EMT. MiR-30a, miR-1271, miR-196a, miR-202, miR-210, miR-22, miR-331 and miR-34b were validated. Seven microRNAs downregulated luciferase activity through EMT transcription factors 3’UTR, and all microRNAs decreased cell migration, invasion and/or proliferation. In MDA-MB-231 cells, miR-196a and miR-22 decreased endogenous ZEB1 levels, and miR-30a endogenous CCR7 levels. These results suggest that microRNAs studied are novel regulators of EMT through the control of SNAIL, SLUG, ZEB1 and TWIST. They also regulate the metastatic behavior of cancer cells, and may control the development of lymph node metastasis through the regulation of CCR7."
1921,SERPINB3 induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer,"Yuuki Ohara, Wei Tang, Huaitian Liu, Shouhui Yang, Tiffany H. Dorsey, Helen Cawley, Paloma Moreno, Azadeh Azizian, Jochen Gaedcke, B. Michael Ghadimi, Nader Hanna, Stefan Ambs, S. Perwez Hussain",https://www.biorxiv.org/content/10.1101/2023.03.29.534766v1,"Pancreatic cancer is a heterogeneous disease with distinct subtypes. Here, we investigated candidate driver genes of the highly aggressive basal-like/squamous molecular subtype of pancreatic ductal adenocarcinoma (PDAC). Integrative transcriptomic analyses identified the upregulated serine/cysteine protease inhibitor, SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) in basal-like/squamous PDAC using discovery and validation approaches. Upregulation of SERPINB3 associated with decreased patient survival and a transcriptome profile indicative of the basal-like/squamous subtype. In human PDAC cell lines, SERPINB3 transgene expression enhanced their invasion capability. Moreover, upregulated expression of SERPINB3 in AsPC-1 cells resulted in enhanced lung metastasis in an orthotopic xenograft model. Molecular analysis of the primary tumor xenografts indicated activation of pathways related to metastasis, increased oxidative damage, and angiogenesis when SERPINB3 was upregulated. Furthermore, metabolomic analysis, using patient cohorts and PDAC cell lines showed a distinct metabolic pattern closely associated with both SERPINB3 and the basal-like/squamous subtype, which included upregulation of carnitine/acylcarnitine, amino acid, glutathione, and purine metabolic pathways, and glycolysis. Further RNA-seq and metabolomic analyses indicated that SERPINB3 may potentially induce the basal-like/squamous subtype and metabolic reprogramming through MYC activation. Taken together, our findings identified SERPINB3 as a candidate marker gene for the basal-like/squamous subtype, which may contribute to the disease aggressiveness in this subtype of PDAC."
1922,Regulation of VEGFR2 and AKT signaling by Musashi-2 in lung cancer,"Igor Bychkov, Iuliia Topchu, Petr Makhov, Alexander Kudinov, Jyoti D. Patel, Yanis Boumber",https://www.biorxiv.org/content/10.1101/2023.03.29.534783v1,"Lung cancer is the most frequently diagnosed cancer type and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents most of the lung cancer. Vascular endothelial growth factor receptor-2 (VEGFR2) is a member of the VEGF family of receptor tyrosine kinase proteins, expressed on both endothelial and tumor cells which is one of the key proteins contributing to cancer development and involved in drug resistance. We previously showed that Musashi-2 (MSI2) RNA-binding protein is associated with NSCLC progression by regulating several signaling pathways relevant to NSCLC. In this study, we performed Reverse Protein Phase Array (RPPA) analysis of murine lung cancer which nominated VEGFR2 protein as strongly positively regulated by MSI2. Next, we validated VEGFR2 protein regulation by MSI2 in several human NSCLC cell line models. Additionally, we found that MSI2 affected AKT signaling via negative PTEN mRNA translation regulation. In silico prediction analysis suggested that both VEGFR2 and PTEN mRNAs have predicted binding sites for MSI2. We next performed RNA immunoprecipitation coupled with quantitative PCR which confirmed that MSI2 directly binds to VEGFR2 and PTEN mRNAs, suggesting direct regulation mechanism. Finally, MSI2 expression positively correlated with VEGFR2 and VEGF-A protein levels in human NSCLC samples. We conclude that MSI2/VEGFR2 axis contributes to NSCLC progression and is worth further investigations and therapeutic targeting."
1924,Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer,"Amir Hosseini, Håvard T. Lindholm, Raymond Chen, Parinaz Mehdipour, Sajid A. Marhon, Charles A. Ishak, Daniel D. De Carvalho",https://www.biorxiv.org/content/10.1101/2023.03.30.531699v1,"Viral mimicry describes the immune response induced by endogenous stimuli such as dsRNA formed by endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune response. Paradoxically, cancer cells frequently present a dysregulated epigenome, leading to increased expression of retroelements. We previously found that ADAR1 p150 upregulation is an adaptation mechanism to tolerate high retroelement-derived dsRNA levels, leading to a druggable dependency. Here, we systematically identified novel mechanisms of viral mimicry adaptation associated with cancer cell dependencies. We correlated the gene knockout sensitivity from the DepMap dataset and interferon stimulated gene (ISG) expression in the Cancer Cell Line Encyclopedia (CCLE) dataset of 1005 human cell lines and identified pathways such as RNA modification and nucleic acid metabolism. Among the top hits was the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1-sensitive cancer cell lines have a high level of cytosolic dsRNA and high ISG expression. Furthermore, sensitivity to XRN1 knockout was mediated by MAVS and PKR activation, indicating that the cells die due to XRN1-dependent induction of viral mimicry. XRN1-resistant cell lines had low basal dsRNA levels, but became synthetically dependent on XRN1 upon treatment with viral mimicry inducing drugs such as 5-AZA-CdR or palbociclib. Finally, XRN1-dependency is partly independent of ADAR1 activity. These results confirm the potential for our ISG correlation analysis to discover novel regulators of viral mimicry and show that XRN1 activation is an adaptive mechanism to control high dsRNA stress induced by dysregulated retroelements in cancer cells and creates a dependency that can be explored for novel cancer therapies."
1927,Widespread perturbation of ETS factor binding sites in cancer,"S Carrasco Pro, H Hook, D Bray, D Berenzy, D Moyer, M Yin, AT Labadorf, R Tewhey, T Siggers, JI Fuxman Bass",https://www.biorxiv.org/content/10.1101/2022.08.10.503516v1,"Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted."
1928,Sorcin-STAT3-Serpin E1/CCL5 axis can be the trigger of pancreatic cancer-associated new-onset diabetes,"Jiali Gong, Xiawei Li, Zengyu Feng, Jianyao Lou, Kaiyue Pu, Yongji Sun, Sien Hu, Jian Wu, Yulian Wu",https://www.biorxiv.org/content/10.1101/2023.07.20.549805v1,"A rise in blood glucose is the early warning signs of underlying pancreatic cancer (PC), which could be the externalization of genetic events in PC progression. But there is still a vacancy in the field of mechanism research on pancreatic cancer-associated new-onset diabetes (PCAND). Using siRNA-mediated gene knockdown in vitro, we made MIN6 cells incubated with conditioned media from transfected PC cells, and detected its response. Immunological techniques were used to explore the interaction between sorcin and STAT3. Human cytokine array was performed to explore the inflammatory cytokines downstream of sorcin. In the present study, we have identified a PCAND driver gene SRI. In PC cells, sorcin and STAT3 form a positive feedback loop to enhance the transcription of serpin E1 and CCL5, which can impair nearby islet β-cells, likely by activating the p38 pathway. In 88 biopsies, expression of sorcin was elevated in PC tissues, especially so in PCAND patient samples. Furthermore, clinical-SRI gene combination model can better distinguish PCAND from T2DM, and serpin E1 level is higher in the peripheral blood samples from PCAND than T2DM. Thus, Sorcin could be the key driver in PCAND, and figuring out sorcin-STAT3-serpin E1/CCL5 signaling axis can help us better understand the pathogenesis of PCAND and identify potential biomarkers."
1931,ZEB1-dependent modulation of fibroblast polarization governs inflammation and immune checkpoint blockade sensitivity in colorectal cancer,"Harald Schuhwerk, Constantin Menche, Isabell Armstark, Pooja Gupta, Kathrin Fuchs, Ruthger van Roey, Mohammed H. Mosa, Carol I. Geppert, Stefanie Bärthel, Dieter Saur, Florian R. Greten, Simone Brabletz, Thomas Brabletz, Henner F. Farin, Marc P. Stemmler",https://www.biorxiv.org/content/10.1101/2023.03.28.534565v1,"The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers is reduced upon fibroblast-specific loss of Zeb1. Single-cell transcriptomics, histological and in vitro characterization reveal a crucial role in CAF polarization, promoting myofibroblastic features whilst restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, pointing to a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis."
1932,Integrative multi-omic sequencing reveals the MMTV-Myc mouse model mimics human breast cancer heterogeneity,"Carson D. Broeker, Mylena M. O. Ortiz, Michael S. Murillo, Eran R. Andrechek",https://www.biorxiv.org/content/10.1101/2023.03.28.534611v1,"Background Breast cancer is a complex and heterogeneous disease with distinct subtypes and molecular profiles corresponding to different clinical outcomes. Mouse models of breast cancer are widely used, but their relevance in capturing the heterogeneity of human disease is unclear. Previous studies have shown the heterogeneity at the gene expression level for the MMTV-Myc model, but have only speculated on the underlying genetics."
1933,Learning transcriptional and regulatory dynamics driving cancer cell plasticity using neural ODE-based optimal transport,"Alexander Tong, Manik Kuchroo, Shabarni Gupta, Aarthi Venkat, Beatriz P. San Juan, Laura Rangel, Brandon Zhu, John G. Lock, Christine L. Chaffer, Smita Krishnaswamy",https://www.biorxiv.org/content/10.1101/2023.03.28.534644v1,"While single-cell technologies have allowed scientists to characterize cell states that emerge during cancer progression through temporal sampling, connecting these samples over time and inferring gene-gene relationships that promote cancer plasticity remains a challenge. To address these challenges, we developed TrajectoryNet, a neural ordinary differential equation network that learns continuous dynamics via interpolation of population flows between sampled timepoints. By running causality analysis on the output of TrajectoryNet, we compute rich and complex gene-gene networks that drive pathogenic trajectories forward. Applying this pipeline to scRNAseq data generated from in vitro models of breast cancer, we identify and validate a refined CD44hiEPCAM+CAV1 + marker profile that improves the identification and isolation of cancer stem cells (CSCs) from bulk cell populations. Studying the cell plasticity trajectories emerging from this population, we identify comprehensive temporal regulatory networks that drive cell fate decisions between an epithelial-to-mesenchymal (EMT) trajectory, and a mesenchymal-to-epithelial (MET) trajectory. Through these studies, we identify and validate estrogen related receptor alpha as a critical mediator of CSC plasticity. We further apply TrajectoryNet to an in vivo xenograft model and demonstrate it’s ability to elucidate trajectories governing primary tumor metastasis to the lung, identifying a dominant EMT trajectory that includes elements of our newly-defined temporal EMT regulatory network. Demonstrated here in cancer, the TrajectoryNet pipeline is a transformative approach to uncovering temporal molecular programs operating in dynamic cell systems from static single-cell data."
1934,Implantation of engineered adipocytes that outcompete tumors for resources suppresses cancer progression,"Hai P. Nguyen, Rory Sheng, Elizabeth Murray, Yusuke Ito, Michael Bruck, Cassidy Biellak, Kelly An, Filipa Lynce, Deborah A. Dillon, Mark Jesus M. Magbanua, Laura A. Huppert, Heinz Hammerlindl, Laura Esserman, Jennifer M. Rosenbluth, Nadav Ahituv",https://www.biorxiv.org/content/10.1101/2023.03.28.534564v1,"Tumors acquire an increased ability to obtain and metabolize nutrients. Here, we engineered and implanted adipocytes to outcompete tumors for nutrients and show that they can substantially reduce cancer progression. Growing cells or xenografts from several cancers (breast, colon, pancreas, prostate) alongside engineered human adipocytes or adipose organoids significantly suppresses cancer progression and reduces hypoxia and angiogenesis. Transplanting modulated adipocyte organoids in pancreatic or breast cancer mouse models nearby or distal from the tumor significantly suppresses its growth. To further showcase therapeutic potential, we demonstrate that co-culturing tumor organoids derived from human breast cancers with engineered patient-derived adipocytes significantly reduces cancer growth. Combined, our results introduce a novel cancer therapeutic approach, termed adipose modulation transplantation (AMT), that can be utilized for a broad range of cancers."
1935,Structural modification of naturally-occurring phenolics as a strategy for developing cytotoxic molecules towards cancer cells,"Pedro Olim, Renato B. Pereira, Maria José G. Fernandes, Carolina M. Natal, José R. A. Coelho, A. Gil Fortes, M. Sameiro, T. Gonçalves, David M. Pereira",https://www.biorxiv.org/content/10.1101/2023.03.26.534257v1,"Natural products belonging to different chemical classes have been established as a promising source of novel anticancer drugs. Several low molecular weight compounds from the classes of monoterpenes, phenylpropanoids and flavonoids were shown to possess anticancer activities in previous studies. In this work, over 20 semisynthetic derivatives of molecules belonging to these classes, namely thymol, eugenol and 6-hydroxyflavanone were synthesized and tested for their cytotoxicity against two human cancer cell lines, namely gastric adenocarcinoma (AGS cells) and human lung carcinoma (A549 cells). An initial screening based on viability assessment was performed in order to identify the most cytotoxic compounds at 100 μM. The results evidenced that two 6-hydroxyflavanone derivatives were the most cytotoxic among the compounds tested, being selected for further studies. Noteworthy, in a general way some of the derivatives synthesized displayed enhanced toxicity when compared with their natural counterparts. Moreover, LDH assay showed that the loss of cell viability was not accompanied by a loss of membrane integrity, thus ruling out a necrotic process. Morphological studies with AGS cells demonstrated chromatin condensation compatible with apoptosis, confirmed by the activation of caspase 3/7. Furthermore, a viability assay on non-cancer human embryonic lung fibroblast cell line (MRC-5) confirmed these two derivatives possess selective anticancer activity."
1936,The ecology of cancer prevalence across species: Cancer prevalence is highest in desert species and high trophic levels,"Stefania E. Kapsetaki, Zachary Compton, Shawn M. Rupp, Michael M. Garner, Elizabeth G. Duke, Amy M. Boddy, Tara M. Harrison, Athena Aktipis, Carlo C. Maley",https://www.biorxiv.org/content/10.1101/2022.08.23.504890v1,"The ecology in which species live and evolve likely affects their health and vulnerability to diseases including cancer. Using 14,267 necropsy records across 244 vertebrate species, we tested if animals in low productivity habitats, with large habitat range, high body temperature and weight-inferred estimates of metabolic rates, and in high trophic levels (from lowest to highest: herbivores, invertivores, primary carnivores, and secondary carnivores) are linked with having increased prevalence of neoplasia. This study found that: (1) habitat productivity negatively correlated with the prevalence of malignancy and neoplasia across tissues, and malignancy and neoplasia in gastrointestinal tissues; (2) inferred metabolic rates negatively correlated with the prevalence of neoplasia; and (3) trophic levels positively correlated with malignancy and neoplasia prevalence in both mammals and non-mammals. However, only the correlations with trophic levels remained significant after Bonferroni corrections for multiple testing. There are several mechanisms that might explain these findings, including the biomagnification of carcinogens in higher trophic levels, as well as tradeoffs between cancer suppression versus reproduction and survival in low productivity environments."
1937,A systematic study of HIF1A cofactors in hypoxic cancer cells,"Yuxiang Zhang, Saidi Wang, Haiyan Hu, Xiaoman Li",https://www.biorxiv.org/content/10.1101/2022.08.09.503416v1,"Hypoxia inducible factor 1 alpha (HIF1A) is a transcription factor (TF) that forms highly structural and functional protein-protein interactions with other TFs to promote gene expression in hypoxic cancer cells. Despite the importance of these TF-TF interactions, we still lack a comprehensive view of many of the TF cofactors involved and how they cooperate in hypoxic cancer cells. In this study, we systematically studied HIF1A cofactors in eight cancer cell lines and discovered 201 potential HIF1A cofactors. These cofactors were statistically and biologically significant, with 30 of the top 37 cofactors validated or supported in the literature. Moreover, these predicted cofactors include 21 of the 29 known HIF1A TF cofactors in public databases. These discovered cofactors can be essential to HIF1A’s regulatory functions and may lead to the discovery of new therapeutic targets in cancer treatment."
1938,EPIGENOMIC VARIABILITY AND TRANSCRIPTOMICS AS A NOVEL MULTIOMIC COMPLEMENTARY APPROACH FOR PERSONALIZED NUTRITION IN COLORECTAL CANCER PATIENTS,"Teresa Laguna, Oscar Piette-Gómez, Marco Garranzo, Marta Gómez de Cedrón, Ana Ramírez de Molina, Enrique Carrillo de Santa Pau",https://www.biorxiv.org/content/10.1101/2023.07.19.549686v1,"Food natural compounds are of interest as modulators of cancer progression and prognosis, as they participate in cellular processes such as growth and differentiation, DNA repair, programmed cell death and oxidative stress. Here we select dietary biocompounds for specific subgroups of 285 colorectal adenocarcinoma (COAD) samples by finding bioactives with opposite transcriptomic profiles to the subgroup-specific tumoral transcriptomes, hypothesizing they may counteract the cancer gene-expression profiles. To establish a CRC classification based on epigenetic variability, we selected 2,189 CpGs based on their differentially variable methylation between tumor and normal samples by a combination of linear and Bartlett tests. Samples were meta-clustered by 1) classifying each sample by 8 different methods (including k-means and hierarchical clustering), 2) building a network and 3) meta-clustering it by the edge-betweenness method. We extracted 6 main subgroups, 2 of them with immune-affected transcriptomes. We compared the transcriptomes of the 6 subgroups with the ones of 56 in vitro bioactive studies from GEO by Gene Set Enrichment Analysis (GSEA), resulting in a potential positive effect of resveratrol, japonicone A and vitamin D. In summary, we present a promising in silico strategy to suggest specific bioactives as co-adjuvants in cancer treatment."
1939,"Clustering of colon, lung, and other cancer susceptibility genes with protein tyrosine phosphatases and protein kinases in multiple short genomic regions","Lei Quan, Peter Demant",https://www.biorxiv.org/content/10.1101/2023.11.07.566108v1,"Interactions of large gene families are poorly understood. We found that human, mouse, and rat colon and lung cancer susceptibility genes, presently considered as separate gene families, were frequently pairwise linked. The orthologous mouse map positions of 142 of 159 early discovered colon and lung cancer susceptibility genes formed 41 genomic clusters conserved >70 million years. These linked gene pairs concordantly affected both tumors and their majority was linked with two other gene families - protein tyrosine phosphatases and cancer driver protein kinases. 25% of both protein tyrosine phosphatases and protein kinases mapped <1 cM from a colon or lung cancer susceptibility gene, and 50% in <3 cM. Similar linkage was detected with most other human susceptibility genes that controlled 29 different cancer types. This concentration of tumor susceptibility genes with protein tyrosine phosphatases and driver protein kinases in multiple relatively short genomic regions suggests their possible functional diversity."
1940,"EHMT2/G9a-Inhibition Reprograms Cancer-Associated Fibroblasts (CAFs) to a More Differentiated, Less Proliferative and Invasive State","Nila C Wu, Rene Quevedo, Michelle Nurse, Kebria Hezaveh, Haijiao Liu, Fumao Sun, Julien Muffat, Yu Sun, Craig A Simmons, Tracy L McGaha, Panagiotis Prinos, Cheryl H Arrowsmith, Laurie Ailles, Elisa D’Arcangelo, Alison P McGuigan",https://www.biorxiv.org/content/10.1101/2023.07.17.549300v1,"Cancer-associated fibroblasts (CAFs) have previously been shown to play a pivotal role in multiple cancer dynamics, including mediating tumor cell invasion: their pro-invasive secretory profile and ability to remodel the extracellular matrix (ECM) architecture particularly promote tumor progression through tumor cell invasion into surrounding tissue areas and beyond. Given that reduced CAF abundance in tumors correlates with improved outcomes in various cancers, we set out to identify epigenetic targets involved in CAF activation in the tumor-stromal margin to reduce overall tumor aggressiveness. Using the GLAnCE (Gels for Live Analysis of Compartmentalized Environments) co-culture platform, we performed an image-based, phenotypic screen and identified EHMT2 (also known as G9a), an epigenetic enzyme that targets the methylation of histone 3 lysine 9 (H3K9), as the most potent modulator of CAF abundance and CAF-mediated tumor cell invasion. Transcriptomic and functional analysis of EHMT2-inhibited CAFs revealed the involvement of EHMT2 in driving CAFs towards a pro-invasive phenotype. Further, EHMT2 signaling mediated CAF hyperproliferation, a feature that is typically associated with activated fibroblasts present in tumors, but the molecular basis for which has not thus far been identified. This study suggests a role for EHMT2 as a regulator of CAF hyperproliferation within the tumor mass, which in turn magnifies CAF-induced pro-invasive effects on tumor cells."
1941,The Potential of Low Press and Hypoxia Environment in Assisting Pan-cancer Treatment,"Xiaoxi Hu, Xinrui Chen, Mengzhen Sun, Xilu Wang, Zixin Hu, Shixuan Zhang",https://www.biorxiv.org/content/10.1101/2023.03.23.534056v1,"Objective A low incidence and mortality rate of cancer has been observed in high-altitude regions, suggesting a potential positive effect of low press and hypoxia (LPH) environment on cancer. Based on this finding, our study aimed to construct a pan-cancer prognosis risk model using a series of ADME genes intervened by low oxygen, to explore the impact of LPH environment on the overall survival (OS) of various kinds of cancers, and to provide new ideas and approaches for cancer prevention and treatment."
1942,Normal and cancer tissues are accurately characterised by intergenic transcription at RNA polymerase 2 binding sites,"Pierre de Langen, Fayrouz Hammal, Elise Guéret, Lionel Spinelli, Benoit Ballester",https://www.biorxiv.org/content/10.1101/2023.03.24.534112v1,"Intergenic transcription in normal and cancerous tissue is pervasive and incompletely understood. To investigate this activity at a global level, we constructed an atlas of over 180,000 consensus RNA Polymerase II (RNAP2) bound intergenic regions from more than 900 RNAP2 ChIP-seq experiments across normal and cancer samples. Using unsupervised analysis, we identified 51 RNAP2 consensus clusters, many of which map to specific biotypes and identify tissue-specific regulatory signatures. We developed a meta-clustering methodology to integrate our RNAP2 atlas with active transcription across 28,797 RNA-seq samples from TCGA, GTEx and ENCODE, which revealed strong tissue- and disease-specific interconnections between RNAP2 occupancy and transcription. We demonstrate that intergenic transcription at RNAP2 bound regions are novel per-cancer and pan-cancer biomarkers showing genomic and clinically relevant characteristics including the ability to differentiate cancer subtypes and are associated with overall survival. Our results demonstrate the effectiveness of coherent data integration to uncover and characterise intergenic transcriptional activity in both normal and cancer tissues."
1943,Anti-cancer compound screening identifies Aurora Kinase A inhibition as a means to favor CRISPR/Cas9 gene correction over knock-out,"Danny Wilbie, Selma Eising, Vicky Amo-Addae, Johanna Walther, Esmeralda Bosman, Olivier G de Jong, Jan J Molenaar, Enrico Mastrobattista",https://www.biorxiv.org/content/10.1101/2023.11.09.566375v1,"CRISPR gene therapy holds the potential to cure a variety of genetic diseases by targeting causative mutations and introducing double stranded DNA breaks, subsequently allowing the host DNA repair mechanisms to introduce mutations. One option to introduce precise gene corrections is via the homology-directed repair (HDR) pathway. HDR can introduce a range of desired mutations dictated by a DNA template which holds a corrected DNA sequence which is written into the targeted gene. The problem in utilizing this pathway is that CRISPR-induced double stranded DNA breaks are repaired more often through the non-homologous end joining (NHEJ) pathway, which does not use a designed template and introduces random DNA damage in the form of insertions and deletions at the cut site. Since HDR activation depends on many interconnected processes in the cell, we aimed to screen a small library of drug compounds in clinical use or clinical development for cancer, to steer the DNA repair process towards preferential HDR activation."
1944,Uncovering Hidden Cancer Self-Dependencies through Analysis of shRNA-Level Dependency Scores,"Zohreh Toghrayee, Hesam Montazeri",https://www.biorxiv.org/content/10.1101/2023.03.23.533901v2,"Large-scale short hairpin RNA (shRNA) screens on well-characterized human cancer cell lines have been widely used to identify novel cancer dependencies. However, the off-target effects of shRNA reagents pose a significant challenge in the analysis of these screens. To mitigate these off-target effects, various approaches have been proposed that aggregate different shRNA viability scores targeting a gene into a single gene-level viability score. Most computational methods for discovering cancer dependencies rely on these gene-level scores. In this paper, we propose a computational method, named NBDep, to find cancer self-dependencies by directly analyzing shRNA-level dependency scores instead of gene-level scores. The NBDep algorithm begins by removing known batch effects of the shRNAs and selecting a subset of concordant shRNAs for each gene. It then uses negative binomial random effects models to statistically assess the dependency between genetic alterations and the viabilities of cell lines by incorporating all shRNA dependency scores of each gene into the model. We applied NBDep to the shRNA dependency scores available at Project DRIVE, which covers 26 different types of cancer. The proposed method identified more well-known and putative cancer genes compared to alternative gene-level approaches in pan-cancer and cancer-specific analyses. Additionally, we demonstrated that NBDep controls type-I error and outperforms statistical tests based on gene-level scores in simulation studies."
1945,Adaptive therapy for ovarian cancer: An integrated approach to PARP inhibitor scheduling,"Maximilian Strobl, Alexandra L. Martin, Jeffrey West, Jill Gallaher, Mark Robertson-Tessi, Robert Gatenby, Robert Wenham, Philip Maini, Mehdi Damaghi, Alexander Anderson",https://www.biorxiv.org/content/10.1101/2023.03.22.533721v1,"Toxicity and emerging drug resistance are important challenges in PARP inhibitor (PARPi) treatment of ovarian cancer. Recent research has shown that evolutionary-inspired treatment algorithms which adapt treatment to the tumor’s treatment response (adaptive therapy) can help to mitigate both. Here, we present a first step in developing an adaptive therapy protocol for PARPi treatment by combining mathematical modelling and wet-lab experiments to characterize the cell population dynamics under different PARPi schedules. Using data from in vitro Incucyte Zoom time-lapse microscopy experiments and a step-wise model selection process we derive a calibrated and validated ordinary differential equation model, which we then use to test different plausible adaptive treatment schedules. Our model can accurately predict the in vitro treatment dynamics, even to new schedules, and suggests that treatment modifications need to be carefully timed, or one risks losing control over tumour growth, even in the absence of any resistance. This is because our model predicts that multiple rounds of cell division are required for cells to acquire sufficient DNA damage to induce apoptosis. As a result, adaptive therapy algorithms that modulate treatment but never completely withdraw it are predicted to perform better in this setting than strategies based on treatment interruptions. Pilot experiments in vivo confirm this conclusion. Overall, this study contributes to a better understanding of the impact of scheduling on treatment outcome for PARPis and showcases some of the challenges involved in developing adaptive therapies for new treatment settings."
1946,Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer,"Jérôme Levallet, Tiphaine Biojout, Céline Bazille, Manon Douyère, Fatéméh Dubois, Dimitri Leite Ferreira, Jasmine Taylor, Sylvain Teulier, Jérôme Toutain, Myriam Bernaudin, Samuel Valable, Emmanuel Bergot, Guénaëlle Levallet",https://www.biorxiv.org/content/10.1101/2023.03.20.533395v1,"The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship."
1947,Optimal Cancer Evasion in a Dynamic Immune Microenvironment,"Jason T. George, Herbert Levine",https://www.biorxiv.org/content/10.1101/2022.08.03.502723v1,"The failure of cancer treatments, including immunotherapy, continues to be a major obstacle in preventing durable remission. This failure often results from tumor evolution, both genotypic and phenotypic, away from sensitive cell states. Here, we propose a mathematical framework for studying the dynamics of adaptive immune evasion that tracks the number of tumor-associated antigens available for immune targeting. We solve for the unique optimal cancer evasion strategy using stochastic dynamic programming and demonstrate that this policy results in increased cancer evasion rates when compared to a passive, fixed strategy. Our foundational model relates the likelihood and temporal dynamics of cancer evasion to features of the immune microenvironment, where tumor immunogenicity reflects a balance between cancer adaptation and host recognition. In contrast with a passive strategy, optimally adaptive evaders navigating varying selective environments result in substantially heterogeneous post-escape tumor antigenicity, giving rise to immunogenically hot and cold tumors."
1948,Amorphous calcium phosphate-coated surfaces as a model for bone microenvironment in prostate cancer,"Rebeca San Martin, Priyojit Das, Tianchun Xue, Morgan Rose Brown, Renata Dos Reis Marques, Michael Essington, Adrian Gonzalez, Rachel Patton McCord",https://www.biorxiv.org/content/10.1101/2023.03.20.533462v1,"Bone metastasis remains one of the biggest challenges in the treatment of prostate cancer, and other solid tumors such as breast, lung, and colon. Modeling a complex microenvironment in-vitro, such as the bone niche, requires interrogation of cell-cell interactions, specific extracellular matrix proteins and a high calcium environment. Here, we present a fast and cost-effective system in which commercially available, non-adhesive, cell culture vessels are coated with amorphous calcium phosphate (ACP) as a surrogate for bone matrix. We further present modified protocols for subculturing cells, as well as nucleic acid and protein collection in high calcium samples. We find that prostate epithelial cell lines show increased adhesion and proliferation when cultured in these surfaces, as well as independence from androgen starvation. We observe gene expression changes on ACP surfaces in early adenocarcinoma cell lines which may reflect alterations relevant to prostate cancer progression."
1949,PARP inhibition and pharmacological ascorbate demonstrate synergy in castration-resistant prostate cancer,"Nicolas Gordon, Peter T. Gallagher, Neermala Poudel Neupane, Amy C. Mandigo, Jennifer K. McCann, Emanuela Dylgjeri, Irina Vasilevskaya, Christopher McNair, Channing J. Paller, Wm. Kevin Kelly, Karen E. Knudsen, Ayesha A. Shafi, Matthew J. Schiewer",https://www.biorxiv.org/content/10.1101/2023.03.23.533944v1,"Prostate cancer (PCa) is the second leading cause of cancer death for men in the United States. While organ-confined disease has reasonable expectation of cure, metastatic PCa is universally fatal upon recurrence during hormone therapy, a stage termed castration-resistant prostate cancer (CRPC). Until such time as molecularly defined subtypes can be identified and targeted using precision medicine, it is necessary to investigate new therapies that may apply to the CRPC population as a whole."
1950,mRNA challenge predicts brain cancer immunogenicity and response to checkpoint inhibitors,"Paul Castillo, Elizabeth Ogando-Rivas, Hilary Geffrard, Alfonso Pepe, Ruixuan Liu, Duy T Nguyen, Diego I Pedro, Dingpeng Zhang, Anna DeVries, Sadeem Qdaisat, Aida Karachi, Maryam Rahman, Frances Weidert, Rowan Milner, Jianping Huang, Natalie L. Silver, John Ligon, Derek Li, Ji-Hyun Lee, Sheila Carrera-Justiz, Duane A Mitchell, Hector Mendez-Gomez, W Gregory Sawyer, Elias J Sayour",https://www.biorxiv.org/content/10.1101/2023.03.18.532056v1,"To prospectively determine whether brain tumors will respond to immune checkpoint inhibitors (ICIs), we developed a novel mRNA vaccine as a viral mimic to elucidate cytokine release from brain cancer cells in vitro. Our results indicate that cytokine signatures following mRNA challenge differ substantially from ICI responsive versus non-responsive murine tumors. These findings allow for creation of a diagnostic assay to quickly assess brain tumor immunogenicity, allowing for informed treatment with ICI or lack thereof in poorly immunogenic settings."
1952,Recurring EPHB1 mutations in human cancers alter receptor signalling and compartmentalisation of colorectal cancer cells,"Snehangshu Kundu, Luís Nunes, Jeremy Adler, Lucy Mathot, Ivaylo Stoimenov, Tobias Sjöblom",https://www.biorxiv.org/content/10.1101/2023.03.18.533270v1,"Ephrin (EPH) receptors have been implicated in tumorigenesis and metastasis, but the functional understanding of mutations observed in human cancers is limited. We previously demonstrated reduced cell compartmentalisation for somatic EPHB1 mutations found in metastatic colorectal cancer cases. We, therefore, integrated pan-cancer and pan-EPH mutational data to prioritise recurrent EPHB1 mutations for functional studies to understand their contribution to cancer development and metastasis. Here, 79,151 somatic mutations in 9,898 samples of 33 different tumour types were analysed to find 3D-mutated cluster pairs and recurring hotspot mutations in EPH receptors. From these, 15 recurring EPHB1 mutations were stably expressed in colorectal cancer cells. Whereas the ligand-binding domain mutations C61Y, R90C, and R170W, the fibronectin domain mutation R351L, and the kinase domain mutation D762N displayed reduced to strongly compromised cell compartmentalisation, the kinase domain mutations R743W and G821R enhanced this phenotype. While mutants with reduced compartmentalisation also had reduced ligand induced receptor phosphorylation, the enhanced compartmentalisation was not linked to receptor phosphorylation level. Phosphoproteome mapping pinpointed the PI3K pathway and PIK3C2B phosphorylation in cells harbouring mutants with reduced compartmentalisation. This is the first integrative study of pan-cancer EPH receptor mutations followed by in vitro validation, a robust way to identify cancer-causing mutations."
1953,YAP antagonizes TEAD-mediated AR signaling and prostate cancer growth,"Shu Zhuo, Xu Li, Yong Suk Cho, Yuchen Liu, Yingzi Yang, Jian Zhu, Jin Jiang",https://www.biorxiv.org/content/10.1101/2022.08.01.502314v1,"Hippo signaling restricts tumor growth by inhibiting the oncogenic potential of YAP/TAZ-TEAD transcriptional complex. Here we uncover a context-dependent tumor suppressor function of YAP in androgen receptor (AR) positive prostate cancer (PCa) and show that YAP impedes AR+ PCa growth by antagonizing TEAD-mediated AR signaling. TEAD forms a complex with AR to enhance its promoter/enhancer occupancy and transcriptional activity. YAP and AR compete for TEAD binding and consequently, elevated YAP in the nucleus disrupts AR-TEAD interaction and prevents TEAD from promoting AR signaling. Pharmacological inhibition of Hippo/MST1/2 kinase or transgenic activation of YAP suppressed the growth of PCa expressing therapy resistant AR splicing variants. Our study uncovers an unanticipated crosstalk between Hippo and AR signaling pathways, reveals an antagonistic relationship between YAP and TEAD in AR+ PCa, and suggests that targeting the Hippo signaling pathway may provide a therapeutical opportunity to treat PCa driven by therapy resistant AR variants."
1954,An integrated RNA-proteomic landscape of drug induced senescence in a cancer cell line,"Thomas Stevenson, Maha Al-Roshdi, Franziska Görtler, Sushma Nagaraja Grellscheid",https://www.biorxiv.org/content/10.1101/2023.03.21.533605v1,"Senescent cells are characterized by an arrest in proliferation. In addition to replicative senescence resulting from telomere exhaustion, sub-lethal genotoxic stress resulting from DNA damage, oncogene activation, mitochondrial dysfunction or reactive metabolites also elicits a senescence phenotype. Senescence is a controlled programme affecting a wide variety of biological processes with some core hallmarks of senescence as well as tissue specific changes. This study presents an integrative multi-omic analysis of proteomic and RNA-seq from proliferating and senescent osteosarcoma cells. This study demonstrates senescence induction in a widely used cell line which can be used as a model system for characterising cancer cell responses to sub-lethal doses of chemotherapeutic agents, and makes available both RNA-seq and proteomic data from proliferating and senescent cells in open access repositories to aid reuse by the community."
1955,A phase-field model for non-small cell lung cancer under the effects of immunotherapy,"Andreas Wagner, Pirmin Schlicke, Marvin Fritz, Christina Kuttler, J. Tinsley Oden, Christian Schumann, Barbara Wohlmuth",https://www.biorxiv.org/content/10.1101/2023.03.20.533400v1,"Formulating tumor models that predict growth under therapy is vital for improving patient-specific treatment plans. In this context, we present our recent work on simulating non-small-scale cell lung cancer (NSCLC) in a simple, deterministic setting for two different patients receiving an immunotherapeutic treatment."
1956,Multiple cancer types rapidly escape from multiple MAPK inhibitors to generate mutagenesis-prone subpopulations,"Timothy E. Hoffman, Chen Yang, Varuna Nangia, C. Ryland Ill, Sabrina L. Spencer",https://www.biorxiv.org/content/10.1101/2023.03.17.533211v1,"Many cancers harbor pro-proliferative mutations of the mitogen-activated protein kinase (MAPK) pathway and many targeted inhibitors now exist for clinical use, but drug resistance remains a major issue. We recently showed that BRAF-driven melanoma cells treated with BRAF inhibitors can non-genetically adapt to drug within 3-4 days to escape quiescence and resume slow proliferation. Here we show that this phenomenon is not unique to melanomas treated with BRAF inhibitors but rather is widespread across many clinical MAPK inhibitors and cancer types driven by EGFR, KRAS, and BRAF mutations. In all treatment contexts examined, a subset of cells can escape drug-induced quiescence within four days to resume proliferation. These escapee cells broadly experience aberrant DNA replication, accumulate DNA lesions, spend longer in G2-M cell cycle phases, and mount an ATR-dependent stress response. We further identify the Fanconi anemia (FA) DNA repair pathway as critical for successful mitotic completion in escapees. Long-term cultures, patient samples, and clinical data demonstrate a broad dependency on ATR- and FA-mediated stress tolerance. Together, these results highlight the pervasiveness with which MAPK-mutant cancers are able to rapidly escape drug and the importance of suppressing early stress tolerance pathways to potentially achieve more durable clinical responses to targeted MAPK pathway inhibitors."
1957,Absence of CD47 in the tumor microenvironment modulates tumor metabolism and immunosuppressive signatures limiting breast cancer progression,"Elizabeth R. Stirling, Yu-Ting Tsai, Steven M. Bronson, Adam Wilson, Brian Westwood, Alexandra Thomas, Pierre L. Triozzi, Cristina M. Furdui, Glenn J. Lesser, Katherine L. Cook, David R. Soto-Pantoja",https://www.biorxiv.org/content/10.1101/2023.07.12.548766v1,"The majority of breast cancers are generally considered immune-deprived tumors. This lack of immunogenicity severely hinders effectiveness of current immunotherapy approaches limiting therapeutic options to control disease. Therefore, we need new biomarkers to determine and enhance immune responses to improve the outcome of cancer patients experiencing invasive disease. Our data in matched human patient biopsies show that CD47 expression increases from primary to metastatic tumors. CD47 is an integral membrane protein that impairs antitumor immunosurveillance and influences normal tissue metabolism. However, whether CD47 plays a role in regulating tumor bioenergetics is unknown. A carcinogen-induced mouse mammary carcinogenesis model demonstrates that the absence of CD47 reduces tumor burden, which is associated with a distinct metabolic signature compared to WT tumors. Depletion of several lipid metabolites was observed in the absence of CD47, and metabolic dependency experiments suggest that anti-sense blockade of CD47 limits reliance on fatty acid oxidation as a fuel supporting cellular respiration on cancer cells. Our global metabolomics analysis also implicated the absence of CD47 in downregulation of immunosuppressive metabolites of the tryptophan and prostaglandin pathways. Spatial proteomic analysis revealed increased immune infiltrate and substantial reduction in immunosuppressive immune checkpoint proteins in the absence of CD47 with the highest reduction in intra-tumoral PD-L1 expression. Since anti-PD-L1 therapy is used in the current strategy to treat triple-negative breast cancer (TNBC), we targeted CD47 in an EMT-6 syngeneic TNBC model. The in vivo knockdown of CD47 sensitized tumors to anti-PD-L1 therapy to decrease tumor burden and increase intratumoral cytotoxic T cells. Therefore, targeting CD47 may be a suitable immunotherapeutic option to limit immunosuppression and enhance the efficacy of immune checkpoint blockade."
1958,The small cell lung cancer neuroendocrine transdifferentiation explorer,"Ling Cai, Varun Sondhi, Mingrui Zhu, Esra Akbay, Ralph J. DeBerardinis, Yang Xie, John D. Minna, Guanghua Xiao, Adi Gazdar",https://www.biorxiv.org/content/10.1101/2022.08.01.502252v2,"SCLC is a high-grade neuroendocrine (NE) cancer that exhibits cellular plasticity. Transdifferention into non-NE cells creates considerable intra-tumoral heterogeneity, enhanced metastasis, greater tumor burden, and treatment resistance. Similar NE transdifferentiation has been observed in neuroblastoma (NBL). Targeting NE plasticity and cooperation between NE and non-NE cells in the tumor microenvironment may provide an avenue to enhance and restore sensitivity to available treatments. Although substantial transcriptomic changes take place upon NE transdifferentiation, conservation of these changes has not been investigated. In this study, we extensively curated genes associated with NE transdifferentiation in SCLC. We collected 35 datasets and compared the NE score-associated transcriptome across studies, for SCLC vs. NBL human tumors, human NBL tumors vs. cell lines, SCLC human tumors vs. tumors from genetically engineered mouse models (GEMMs), and SCLC GEMM uncultured cancer cells vs. cultured cancer cells. We have also created a user-friendly web application for researchers to explore these results. This work establishes a useful resource for researchers to understand the NE transdifferentiation landscape and explore context-dependent NE associations in SCLC and NBL."
1961,Engineered immunomodulatory extracellular vesicles derived from epithelial cells acquire capacity for positive and negative T cell co-stimulation in cancer and autoimmunity,"Fernanda G. Kugeratski, Valerie S. LeBleu, Dara P. Dowlatshahi, Hikaru Sugimoto, Kent A. Arian, Yibo Fan, Li Huang, Danielle Wells, Sergio Lilla, Kelly Hodge, Sara Zanivan, Kathleen M. McAndrews, Raghu Kalluri",https://www.biorxiv.org/content/10.1101/2023.11.02.565371v1,"Extracellular vesicles (EVs) are generated by all cells and systemic administration of allogenic EVs derived from epithelial and mesenchymal cells have been shown to be safe, despite carrying an array of functional molecules, including thousands of proteins. To address whether epithelial cells derived EVs can be modified to acquire the capacity to induce immune response, we engineered 293T EVs to harbor the immunomodulatory CD80, OX40L and PD-L1 molecules. We demonstrated abundant levels of these proteins on the engineered cells and EVs. Functionally, the engineered EVs efficiently elicit positive and negative co-stimulation in human and murine T cells. In the setting of cancer and auto-immune hepatitis, the engineered EVs modulate T cell functions and alter disease progression. Moreover, OX40L EVs provide additional benefit to anti-CTLA-4 treatment in melanoma-bearing mice. Our work provides evidence that epithelial cell derived EVs can be engineered to induce immune responses with translational potential to modulate T cell functions in distinct pathological settings."
1963,HPV and p53 status as precision determinants of head and neck cancer response to DNA-PKcs inhibition in combination with irradiation,"Liana Hayrapetyan, Selina M. Roth, Lusine Hovhannisyan, Matúš Medo, Aurélie Quintin, Julien Ott, Joachim Albers, Daniel M. Aebersold, Yitzhak Zimmer, Michaela Medová",https://www.biorxiv.org/content/10.1101/2023.11.02.565300v1,"Major risk factors of head and neck squamous cell carcinoma (HNSCC) are tobacco use and human papillomavirus (HPV). HPV E6 oncoprotein leads to the degradation of the p53 protein, whereas HPV-negative cancers are frequently associated with TP53 mutations. Peposertib is a potent and selective, orally administered small-molecule inhibitor of the catalytic subunit of the DNA-dependent kinase (DNA-PKcs), a key regulator of non-homologous end joining (NHEJ). NHEJ inhibition along with irradiation (IR)-induced DNA double-strand breaks has the potential to increase antitumor treatment efficacy. Here, we investigated the responses of HNSCC models with distinct HPV and p53 status to treatments with IR, DNA-PKcs inhibition, and their combination."
1964,Combining cancer chemotherapeutics with bacterial DNA repair inhibitors to develop novel antimicrobials,"Lorenzo Bernacchia, Arya Gupta, Antoine Paris, Alexandra A. Moores, Neil M Kad",https://www.biorxiv.org/content/10.1101/2023.03.17.532951v1,"Cancer chemotherapeutics kill rapidly dividing cells, which includes cells of the immune system. The resulting neutropenia predisposes patients to infection, which delays treatment and is a major cause of morbidity and mortality. Here we have exploited the cytotoxicity of the anti-cancer compound cisplatin to screen for FDA-approved drugs that impair bacterial nucleotide excision DNA repair (NER), the primary mechanism bacteria use to repair cisplatin lesions. Five compounds have emerged of which three possess ideal antimicrobial properties including cell penetrance, specific activity for NER, and the ability to kill a multi-drug resistant clinically relevant E. coli strain. Targeting NER offers a new therapeutic approach for infections in cancer patients by combining antimicrobial activity with cancer chemotherapy."
1965,Cancer-associated fibroblasts actively compress cancer cells and modulate mechanotransduction,"Jorge Barbazan, Carlos Pérez-González, Manuel Gómez-González, Mathieu Dedenon, Sophie Richon, Ernest Latorre, Marco Serra, Pascale Mariani, Stéphanie Descroix, Pierre Sens, Xavier Trepat, Danijela Matic Vignjevic",https://www.biorxiv.org/content/10.1101/2021.04.05.438443v1,"During tumor progression, cancer-associated fibroblasts (CAFs) accumulate in tumors and produce excessive extracellular matrix (ECM), forming a capsule that enwraps cancer cells. This capsule is a barrier that restricts tumor growth leading to the buildup of intratumoral pressure. Combining genetic and physical manipulations in vivo with microfabrication and force measurements in vitro, we found that the CAFs capsule is not a passive barrier but instead actively compresses cancer cells using actomyosin contractility. Cancer cells mechanosense CAF compression, resulting in an altered localization of the transcriptional regulator YAP. Abrogation of CAFs contractility in vivo leads to the dissipation of compressive forces and impairment of capsule formation. By mapping CAF force patterns in 3D, we show that compression is a CAF-intrinsic property independent of cancer cell growth. Supracellular coordination of CAFs is achieved through fibronectin cables that serve as scaffolds allowing force transmission. Our study unveils that the contractile capsule actively compresses cancer cells, modulates their mechanical signaling, and reorganizes tumor morphology."
1967,Estrogen therapy induces receptor-dependent DNA damage enhanced by PARP inhibition in ER+ breast cancer,"Nicole A. Traphagen, Gary N. Schwartz, Steven Tau, Amanda Jiang, Sarah R. Hosford, Abigail E. Goen, Alyssa M. Roberts, Bianca A. Romo, Anneka L. Johnson, Emily-Claire K. Duffy, Eugene Demidenko, Paul Heverly, Yaron Mosesson, Shannon M. Soucy, Fred Kolling, Todd W. Miller",https://www.biorxiv.org/content/10.1101/2023.03.16.532956v1,"Purpose Clinical evidence indicates that treatment with estrogens elicits anti-cancer effects in ∼30% of patients with advanced endocrine-resistant estrogen receptor alpha (ER)-positive breast cancer. Despite the proven efficacy of estrogen therapy, its mechanism of action is unclear and this treatment remains under-utilized. Mechanistic understanding may offer strategies to enhance therapeutic efficacy."
1969,Single-residue mutation in protein kinase C toggles between cancer and neurodegeneration,"Alexander C. Jones, Alexandr P. Kornev, Jui-Hung Weng, Gerard Manning, Susan S. Taylor, Alexandra C. Newton",https://www.biorxiv.org/content/10.1101/2023.03.16.532226v1,"Conventional protein kinase C (PKC) isozymes tune the signaling output of cells, with loss-of-function somatic mutations associated with cancer and gain-of-function germline mutations identified in neurodegeneration. PKC with impaired autoinhibition is removed from the cell by quality-control mechanisms to prevent accumulation of aberrantly active enzyme. Here, we examine how a single residue in the C1A domain of PKCβ, arginine 42 (R42), permits quality-control degradation when mutated to histidine in cancer (R42H) and blocks downregulation when mutated to proline in the neurodegenerative disease spinocerebellar ataxia (R42P). Using FRET-based biosensors, we determined that mutation of R42 to any residue, including lysine, resulted in reduced autoinhibition as indicated by higher basal activity and faster agonist-induced plasma membrane translocation. R42 is predicted to form a stabilizing salt bridge with E655 in the C-tail and mutation of E655, but not neighboring E657, also reduced autoinhibition. Western blot analysis revealed that whereas R42H had reduced stability, the R42P mutant was stable and insensitive to activator-induced ubiquitination and downregulation, an effect previously observed by deletion of the entire C1A domain. Molecular dynamics (MD) simulations and analysis of stable regions of the domain using local spatial pattern (LSP) alignment suggested that P42 interacts with Q66 to impair mobility and conformation of one of the ligand-binding loops. Additional mutation of Q66 to the smaller asparagine (R42P/Q66N), to remove conformational constraints, restored degradation sensitivity to that of WT. Our results unveil how disease-associated mutations of the same residue in the C1A domain can toggle between gain- or loss-of-function of PKC."
1970,A mathematical model of the disruption of glucose homeostasis in cancer patients,"Noah Salentine, Jonathan Doria, Chinh Nguyen, Gabriella Pinter, Shizhen Emily Wang, Peter Hinow",https://www.biorxiv.org/content/10.1101/2023.03.15.532725v1,"In this paper we investigate the disruption of the glucose homeostasis at the whole-body level by the presence of cancer disease. Of particular interest are the potentially different responses of patients with or without hyperglycemia (including Diabetes Mellitus) to the cancer challenge, and how tumor growth, in turn, responds to hyperglycemia and its medical management. We propose a mathematical model that describes the competition between cancer cells and glucosedependent healthy cells for a shared glucose resource. We also include the metabolic reprogramming of healthy cells by cancer-cell-initiated mechanism to reflect the interplay between the two cell populations. We parametrize this model and carry out numerical simulations of various scenarios, with growth of tumor mass and loss of healthy body mass as endpoints. We report sets of cancer characteristics that show plausible disease histories. We investigate parameters that change cancer cells’ aggressiveness, and we exhibit differing responses in diabetic and non-diabetic, in the absence or presence of glycemic control. Our model predictions are in line with observations of weight loss in cancer patients and the increased growth (or earlier onset) of tumor in diabetic individuals. The model will also aid future studies on countermeasures such as the reduction of circulating glucose in cancer patients."
1971,LMO3 is a suppressor of the basal-like/squamous PDAC subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism,"Yuuki Ohara, Amanda J. Craig, Huaitian Liu, Shouhui Yang, Paloma Moreno, Tiffany H. Dorsey, Helen Cawley, Azadeh Azizian, Jochen Gaedcke, Michael Ghadimi, Nader Hanna, Stefan Ambs, S. Perwez Hussain",https://www.biorxiv.org/content/10.1101/2023.11.01.564448v1,"Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptomic and metabolomic analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype, and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolomic analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 expression and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptomic and metabolomic characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC."
1974,A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity,"Sai Shyam, R Soundharya, Manas Sehgal, Mohit Kumar Jolly",https://www.biorxiv.org/content/10.1101/2023.07.08.547338v1,"Phenotypic plasticity is a hallmark of cancer metastasis. Epithelial-mesenchymal transition (EMT) is an important axis of phenotypic plasticity. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are two proteins reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their roles in mediating EMT and associated other axes of plasticity remains unclear. Here, analysing transcriptomic data, we reveal their antagonistic trends in a pan-cancer manner, in terms of association with EMT, metabolic reprogramming and immune evasion via PD-L1. Next, we developed and simulated a mechanism-based gene regulatory network that captures how RKIP and BACH1 engage in feedback loops with drivers of EMT and stemness. We found that RKIP and BACH1 belong to two separate “teams” of players – while BACH1 belonged to the one that drove pro-EMT, stem-like and therapy-resistant cell-states, RKIP is a member of a team that enables pro-epithelial, less stem-like and therapy-sensitive phenotypes. Finally, we observed that low RKIP levels and concomitant upregulated BACH1 levels associated with worse clinical outcomes in many cancer types. Together, our systems-level analysis indicates that the emergent dynamics of underlying regulatory network underlie the antagonistic patterns of RKIP and BACH1 with various axes of cancer cell plasticity, as well as with patient survival data."
1975,Chromatin Remodeling in Patient-Derived Colorectal Cancer Models,"Kun Xiang, Ergang Wang, Gabrielle Rupprecht, John Mantyh, Marcos Negrete, Golshid Sanati, Carolyn Hsu, Peggy Randon, Anders Dohlman, Kai Kretzschmar, Nicholas Giroux, Shengli Ding, Lihua Wang, Jorge Prado Balcazar, Qiang Huang, Pasupathi Sundaramoorthy, Rui Xi, Shannon Jones McCall, Zhaohui Wang, Yubin Kang, Scott Kopetz, Gregory E. Crawford, Hans Clevers, David Hsu, Xiling Shen",https://www.biorxiv.org/content/10.1101/2022.07.24.501300v1,"Patient-Derived Organoids (PDO) and Xenografts (PDX) are the current gold standards for patient derived models of cancer (PDMC). Nevertheless, how patient tumor cells evolve in these models and the impact on drug response remains unclear. Herein, we compared the transcriptomic and chromatin accessibility landscapes of six matched sets of colorectal cancer (CRC) PDO, PDX, PDO-derived PDX (PDOX), and original patient tumors (PT) and discovered two major remodeling axes. The first axis delineates PDX and PDO from PT, and the second axis distinguishes PDX and PDO. PDOX were more similar to PDX than they were to PDO, indicating that the growth environment is a driving force for chromatin adaptation. Using bivariate genomic footprinting analysis, we identified transcription factors (TF) that differentially bind to open chromatins between matched PDO and PDOX. Among them, KLF14 and EGR2 footprints were enriched in all six PDOX relative to matched PDO, and silencing of KLF14 or EGR2 promoted tumor growth. Furthermore, EPHA4, a shared downstream target gene of KLF14 and EGR2, altered tumor sensitivity to MEK inhibitor treatment. Altogether, patient-derived CRC cells undergo both common and distinct chromatin remodeling in PDO and PDX/PDOX, driven largely by their respective microenvironments, which results in differences in growth and drug sensitivity and needs to be taken into consideration when interpreting their ability to predict clinical outcome."
1976,The T1150A cancer mutant of the protein lysine dimethyltransferase NSD2 can introduce H3K36 trimethylation,"Mina S. Khella, Philipp Schnee, Sara Weirich, Tan Bui, Alexander Bröhm, Pavel Bashtrykov, Jürgen Pleiss, Albert Jeltsch",https://www.biorxiv.org/content/10.1101/2023.03.13.532367v2,"Somatic mutations in protein lysine methyltransferases are frequently observed in cancer cells. We show here that the NSD1 mutations Y1971C, R2017Q and R2017L observed mostly in solid cancers are catalytically inactive suggesting that NSD1 acts as tumor suppressor gene in these tumors. In contrast, the frequent T1150A in NSD2 and its T2029A counterpart in NSD1, both observed in leukemia, are hyperactive and introduce up to H3K36me3 in biochemical and cellular assays, while wildtype NSD2 and NSD1 only generate up to H3K36me2. MD simulations with NSD2 revealed that H3K36me3 formation is possible due to an enlarged active site pocket of T1150A and loss of direct contacts of T1150 to critical residues which regulate the product specificity of NSD2. Bioinformatic analyses of published data suggest that the NSD2 T1150A mutation in lymphocytic leukemia could alter gene regulation by antagonizing H3K27me3 finally leading to the upregulation of oncogenes."
1977,"The efficacy of CB-103, a first-in-class transcriptional Notch inhibitor, in preclinical models of breast cancer","Michele Vigolo, Charlotte Urech, Sebastien Lamy, Giulia Monticone, Jovanny Zabaleta, Fokhrul Hossain, Dorota Wyczechowska, Luis Del Valle, Ruth O’Regan, Lucio Miele, Rajwinder Lehal, Samarpan Majumder",https://www.biorxiv.org/content/10.1101/2023.07.06.547830v1,"Background Notch signaling has been shown to mediate treatment resistance and support cancer stem cells (CSCs) in endocrine-resistant estrogen receptor positive (ER+) and triple negative breast cancers (TNBCs). The clinical development of GSIs, first generation Notch inhibitors, has been hindered by lack of Notch specificity and dose-limiting toxicity. Here we describe the safety and efficacy of a first-in-class, clinical stage, orally available small molecule pan-Notch inhibitor, CB-103. Due to its unique mode of action, CB-103 doesn’t induce GI toxicities noted with GSIs. There is a critical need for effective, safe, targeted therapies for patients with endocrine-refractory metastatic breast cancer. Recently approved targeted therapies for TNBC are only effective for a subset of patients. Moreover, GSI-resistant, constitutively activating Notch1 or Notch2 mutations are observed in ∼10% of TNBC. Our study elucidating the synergy of CB-103 with fulvestrant and paclitaxel in preclinical models of both hormone-refractory ER+ BC and TNBC respectively provides a novel and unique opportunity to address major unmet therapeutic needs."
1978,Calcimycin mediates apoptosis in Breast and Cervical cancer cells by inducing intracellular calcium levels in a P2RX4-dependent manner,"Neha, Prashant Ranjan, Parimal Das",https://www.biorxiv.org/content/10.1101/2023.07.06.548052v1,"Calcimycin (A23187) is a polyether antibiotic and divalent cation ionophore, extracted from Streptomyces chartrecensis. With wide variety of antimicrobial activities, it also exhibits cytotoxicity of tumor cells. Calcimycin exhibit therapeutic potential against tumor cell growth; however, the molecular mechanism remains to be fully elucidated. Present study explores the mechanism of calcimycin-induced apoptosis cancer cell lines. Calcimycin induces apoptosis accompanied by increased intracellular calcium-level and increased expression of purinergic receptor-P2RX4, a ligand-gated ion channel. The percentage of apoptotic cancer cells in a dose-dependent manner quickly rose as recorded with MTT assays, Phase contrast imaging, wound healing assay, fluorescence imaging by DAPI and AO/EB staining and FACS. Mitochondrial potential was analyzed by TMRM assay as Ca2+ signaling is well known to be influenced and synchronized by mitochondria also. Calcimycin treatment tends to increase the intracellular calcium level, mRNA expression of ATP receptor P2RX4, and phosphorylation of p38. Blocking of either intracellular calcium by BAPTA-AM, P2RX4 expression by antagonist 5-BDBD, and phospho-p38 by SB203580, abrogated the apoptotic activity of calcimycin. Taken together, these results show that calcimycin induces apoptosis in P2RX4 dependent ATP mediated intracellular Ca2+ and p38 MAPK mediated pathway in both the cancer cell lines."
1979,Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target,"Johan Vande Voorde, Arafath K. Najumudeen, Rory T. Steven, Chelsea J. Nikula, Alex Dexter, Lucas B. Zeiger, Efstathios A. Elia, Ammar Nasif, Ariadna Gonzalez-Fernandez, Teresa Murta, Michael Gillespie, Catriona A. Ford, Tamsin R.M. Lannagan, Nikola Vlahov, Rachel A. Ridgway, Colin Nixon, Kathryn Gilroy, David M. Gay, Amy Burton, Bin Yan, Katherine Sellers, Vincen Wu, Yuchen Xiang, Engy Shokry, William Clark, Vivian S.W. Li, Simon T. Barry, Richard J.A. Goodwin, Zoltan Takats, Oliver D.K. Maddocks, David Sumpton, Mariia O. Yuneva, Andrew D. Campbell, Josephine Bunch, Owen J. Sansom",https://www.biorxiv.org/content/10.1101/2023.03.12.531945v1,"With colorectal cancer (CRC) being the second most common cause of cancer-related deaths worldwide1, there is an urgent need for better diagnostic tools and new, more targeted therapies. Here we used genetically engineered mouse models (GEMMs), and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that unsupervised metabolic profiling can stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging (MSI) to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-mutant CRC, and propose one of its enzymes, i.e. adenosylhomocysteinase (AHCY), as a new therapeutic target. Collectively, we show that the profound genotype-dependent alterations in both lipid and small molecule metabolism in CRC may be exploited for tissue classification with no need for ion identification, and we applied further data analysis to expose a novel metabolic vulnerability of CRC."
1980,Unraveling dynamically-encoded latent transcriptomic patterns in pancreatic cancer cells by topic modelling,"Yichen Zhang, Mohammadali (Sam) Khalilitousi, Yongjin P Park",https://www.biorxiv.org/content/10.1101/2023.03.11.532182v1,"Building a comprehensive topic model has become an important research tool in single-cell genomics. With a topic model, we can decompose and ascertain distinctive cell topics shared across multiple cells, and the gene programs implicated by each topic can later serve as a predictive model in translational studies. Here, we present a Bayesian topic model that can uncover short-term RNA velocity patterns from a plethora of spliced and unspliced single-cell RNA-seq counts. We showed that modelling both types of RNA counts can improve robustness in statistical estimation and reveal new aspects of dynamic changes that can be missed in static analysis. We showcase that our modelling framework can be used to identify statistically-significant dynamic gene programs in pancreatic cancer data. Our results discovered that seven dynamic gene programs (topics) are highly correlated with cancer prognosis and generally enrich immune cell types and pathways."
1981,Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells,"Atikul Islam, Yu-Chun Chang, Xiao-Chi Chen, Chia-Wei Weng, Chien-Yu Chen, Che-Wei Wang, Mu-Kuan Chen, Alexander S. Tikhomirov, Andrey E. Shchekotikhin, Pin Ju Chueh",https://www.biorxiv.org/content/10.1101/2023.03.29.534690v2,"The antibiotic heliomycin (resistomycin), which is generated from Streptomyces resistomycificus, has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives of heliomycin were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, but the drug targets remained unknown. In this study, we conducted cellular thermal shift assays (CETSA) and molecular docking simulations to identify and validate that heliomycin and its water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH) engaged and targeted with sirtuin-1 (SIRT1) in p53-functional SAS and p53-mutated HSC-3 oral cancer cells. We further addressed the cellular outcome of SIRT1 inhibition by these compounds and found that, in addition to SIRT1, the water-soluble 4-dmH preferentially targeted a tumor-associated NADH oxidase (tNOX, ENOX2). The direct binding of 4-dmH to tNOX decreased the oxidation of NADH to NAD+ which diminished NAD+-dependent SIRT1 deacetylase activity, ultimately inducing apoptosis and significant cytotoxicity in both cell types, as opposed to the parental heliomycin-induced autophagy. We also observed that tNOX and SIRT1 were both upregulated in tumor tissues of oral cancer patients compared to adjacent normal tissues, suggesting their clinical relevance. Finally, the better therapeutic efficacy of 4-dmH was confirmed in tumor-bearing mice, which showed greater tNOX and SIRT1 downregulation and tumor volume reduction when treated with 4-dmH compared to heliomycin. Taken together, our in vitro and in vivo findings suggest that the multifaceted properties of water-soluble 4-dmH enable it to offer superior antitumor value compared to parental heliomycin, and indicated that it functions through targeting the tNOX-NAD+-SIRT1 axis to induce apoptosis in oral cancer cells."
1984,Constraint-based modeling predicts metabolic signatures of low- and high-grade serous ovarian cancer,"Kate E. Meeson, Jean-Marc Schwartz",https://www.biorxiv.org/content/10.1101/2023.03.09.531870v1,"Ovarian cancer is an aggressive, heterogeneous disease, burdened with late diagnosis and resistance to chemotherapy. Clinical features of ovarian cancer could be explained by investigating its metabolism, and how the regulation of specific pathways link to individual phenotypes. Ovarian cancer is of particular interest for metabolic research due to its heterogeneous nature, with five distinct subtypes having been identified, each of which may display a unique metabolic signature. To elucidate metabolic differences, constraint-based modeling (CBM) represents a powerful technology, inviting the integration of ‘omics’ data, such as transcriptomics. However, many CBM methods have not prioritised accurate growth rate predictions, and there are very few ovarian cancer genome-scale studies, thus highlighting a niche in disease research. Here, a novel method for constraint-based modeling has been developed, employing the genome-scale model Human1 and flux balance analysis (FBA), enabling the integration of in vitro growth rates, transcriptomics data and media conditions to predict the metabolic behaviour of cells. Using low- and high-grade ovarian cancer as a case study, subtype-specific metabolic differences have been predicted, which have been supported with CRISPR-Cas9 data and an extensive literature review. Metabolic drivers of aggressive phenotypes, as well as pathways responsible for increased proliferation and chemoresistance in low-grade cell lines have been suggested. Experimental gene dependency data has been used to validate fatty acid biosynthesis and the pentose phosphate pathway as essential for low-grade cellular growth, highlighting potential vulnerabilities for this ovarian cancer subtype."
1985,Machine-learning analysis of factors that shape cancer aneuploidy landscapes reveals an important role for negative selection,"Juman Jubran, Rachel Slutsky, Nir Rozenblum, Lior Rokach, Uri Ben-David, Esti Yeger-Lotem",https://www.biorxiv.org/content/10.1101/2023.07.05.547626v1,"Aneuploidy, an abnormal number of chromosomes within a cell, is considered a hallmark of cancer. Patterns of aneuploidy differ across cancers, yet are similar in cancers affecting closely-related tissues. The selection pressures underlying aneuploidy patterns are not fully understood, hindering our understanding of cancer development and progression. Here, we applied interpretable machine learning (ML) methods to study tissue-selective aneuploidy patterns. We defined 20 types of features of normal and cancer tissues, and used them to model gains and losses of chromosome-arms in 24 cancer types. In order to reveal the factors that shape the tissue-specific cancer aneuploidy landscapes, we interpreted the ML models by estimating the relative contribution of each feature to the models. While confirming known drivers of positive selection, our quantitative analysis highlighted the importance of negative selection for shaping the aneuploidy landscapes of human cancer. Tumor-suppressor gene density was a better predictor of gain patterns than oncogene density, and vice-versa for loss patterns. We identified the contribution of tissue-selective features and demonstrated them experimentally for chr13q gain in colon cancer. In line with an important role for negative selection in shaping the aneuploidy landscapes, we found compensation by paralogs to be a top predictor of chromosome-arm loss prevalence, and demonstrated this relationship for one such paralog interaction. Similar factors were found to shape aneuploidy patterns in human cancer cell lines, demonstrating their relevance for aneuploidy research. Overall, our quantitative, interpretable ML models improve the understanding of the genomic properties that shape cancer aneuploidy landscapes."
1987,"Robust prediction of patient outcomes with immune checkpoint blockade therapy for cancer using common clinical, pathologic, and genomic features","Tia-Gen Chang, Yingying Cao, Hannah J. Sfreddo, Saugato Rahman Dhruba, Se-Hoon Lee, Cristina Valero, Seong-Keun Yoo, Diego Chowell, Luc G. T. Morris, Eytan Ruppin",https://www.biorxiv.org/content/10.1101/2023.07.04.547697v1,"Despite the revolutionary impact of immune checkpoint blockade (ICB) in cancer treatment, accurately predicting patients’ responses remains elusive. We analyzed eight cohorts of 2881 ICB-treated patients across 18 solid tumor types, the largest dataset to date, examining diverse clinical, pathologic, and genomic features. We developed the LOgistic Regression-based Immunotherapy-response Score (LORIS) using a transparent, compact 6-feature logistic regression model. LORIS outperforms previous signatures in ICB response prediction and can identify responsive patients, even those with low tumor mutational burden or tumor PD-L1 expression. Importantly, LORIS consistently predicts both objective responses and short-term and long-term survival across most cancer types. Moreover, LORIS showcases a near-monotonic relationship with ICB response probability and patient survival, enabling more precise patient stratification across the board. As our method is accurate, interpretable, and only utilizes a few readily measurable features, we anticipate it will help improve clinical decision-making practices in precision medicine to maximize patient benefit."
1988,"The defined TLR3 agonist, Nexavant, exhibits anti-cancer efficacy and potentiates anti-PD-1 antibody therapy by enhancing immune cell infiltration","Seung-Hwan Lee, Young-Ho Choi, Soon-Myung Kang, Min-Gyu Lee, Arnaud Debin, Eric Perouzel, Seung-Beom Hong, Dong-Ho Kim",https://www.biorxiv.org/content/10.1101/2023.10.25.564097v1,"Nexavant has been reported as an alternative to the TLR3 agonist of Poly(I:C) and its derivatives. The physicochemical properties, signaling pathways, anti-cancer effects, and mechanisms of Nexavant were investigated. Nexavant’s distinct nature, compared to Poly(I:C), was evident through precise quantification, thermostability, and resistance to RNase A. Unlike Poly (I: C) which activates TLR3, RIG-I and MDA5, Nexavant stimulates the signaling through TLR3 and RIG-I but not MDA5. Intratumoral Nexavant treatment led to a unique immune response compared to Poly(I:C), immune cell infiltration, and suppression of tumor growth in various animal cancer models. Nexavant therapy outperformed anti-PD-1 antibody treatment in all tested models and showed a synergistic effect in combinational therapy, especially in well-defined cold tumor models. The effect was similar to Nivolumab in a humanized mouse model. Intranasal instillation of Nexavant recruited immune cells (NK, CD4+ T, CD8+ T) to the lungs, suppressing lung metastasis and improving animal survival. Our study highlighted Nexavant’s defined nature for clinical use, unique signaling pathways, and its potential as a standalone anti-cancer agent or in combination with anti-PD-1 antibody."
1989,Comparative analysis of syngeneic mouse models of high-grade serous ovarian cancer,"David P Cook, Kristianne JC Galpin, Galaxia M Rodriguez, Noor Shakfa, Juliette Wilson-Sanchez, Madison Pereira, Kathy Matuszewska, Jacob Haagsma, Humaira Murshed, Alison O Cudmore, Elizabeth MacDonald, Alicia Tone, Trevor G. Shepherd, James J Petrik, Madhuri Koti, Barbara C. Vanderhyden",https://www.biorxiv.org/content/10.1101/2023.03.09.531888v2,"Ovarian cancers often exhibit high rates of recurrence and poor treatment response. Preclinical models that recapitulate the heterogeneity of human disease are critical to develop new therapeutic approaches. While patient-derived models are a powerful tool for testing various therapeutics, their dependence on immune-compromised mice is severely limiting. Syngeneic mouse models, however, allow for the generation of tumours comprising the full repertoire of non-malignant cell types. Here we have performed a comparative analysis of diverse models of high-grade serous ovarian cancer based on transcriptomic profiling of 22 cell line models, and intrabursal and intraperitoneal tumours from 12 models. Among cell lines, we identify distinct features in signalling activity, such as elevated inflammatory signalling in STOSE and OVE16 models, and MAPK/ERK signalling in ID8 and OVE4 models; metabolic features, such as predicted reduction in glycolysis associated with subsets of engineered ID8 subclones; and relevant functional properties, including differences in EMT activation, PD-L1 and MHC class I expression, and predicted chemosensitivity. Finally, we evaluate variability in properties of the tumour microenvironment among models. We anticipate that this work will serve as a valuable resource, providing new insight to help in the selection of models for specific experimental objectives."
1990,BIRC5 Regulates IGFBP-3-Induced Autocrine Loop in Cancer Stem Cells,"Yeon-Jee Kahm, Uhee Jung, Rae-Kwon Kim",https://www.biorxiv.org/content/10.1101/2023.03.09.531969v1,"Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) is also known as survivin. BIRC5 is overexpressed in various carcinomas and is involved in cell growth and apoptosis. BIRC5, a member of the apoptosis inhibitor (IAP) family, negatively regulates apoptosis or programmed cell death by inhibiting caspase activation. Due to these properties, overexpression of BIRC5 enables specific survival and division associated with cancer malignancies. In addition, BIRC5 is highly expressed in stem cells, but not present at all in terminally differentiated cells. On this basis, there is speculation that BIRC5 may be involved in the regulation of cancer stem cells (CSCs), but few study results have been reported. In addition, the molecular mechanisms of BIRC5 regulation are not yet well understood. Through the present study, it was confirmed that BIRC5 is a key factor regulating CSCs and epithelial to mesenchymal transition (EMT) phenomena. BIRC5 was simultaneously overexpressed in lung cancer stem cells (LCSCs) and glioma stem cells (GSCs), and when the expression was suppressed, the characteristics of CSCs disappeared. In addition, IGFBP-3, a secreted factor regulated by BIRC5, is involved in signaling mechanisms that regulate cancer stem cells and EMT, and IGFBP-3 forms an autocrine chain. Based on these results, BIRC5 is proposed as a novel therapeutic target protein for LCSCs and GSCs."
1991,The lncRNA TRG-AS1 promotes the growth of colorectal cancer cells through the regulation of P2RY10/GNA13,"Lin Zhuang, Baoyang Luo, Linghui Deng, Qi Zhang, Yuanjiu Li, Donglin Sun, Hua Zhang, Qiutao Zhang",https://www.biorxiv.org/content/10.1101/2023.07.04.547664v1,Purpose The lncRNA TRG-AS1 and its co-expressed gene P2RY10 are important for colorectal cancer (CRC) occurrence and development. The purpose of our research was to explore the roles of TRG-AS1 and P2RY10 in CRC progression.
1992,Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells,"Flor A. Gowans, Danny Q. Thach, Yangzhi Wang, Belen E. Altamirano Poblano, Dustin Dovala, John A. Tallarico, Jeffrey M. McKenna, Markus Schirle, Thomas J. Maimone, Daniel K. Nomura",https://www.biorxiv.org/content/10.1101/2023.03.09.531918v1,"Summary Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anti-cancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many contexts. In this study, we used covalent chemoproteomic platforms to map the proteome-wide reactivity of OPA in a highly sensitive lung cancer cell line. Among several proteins that OPA engaged, we focused on two targets—cysteine C53 of HIG2DA and lysine K72 of COX5A—that are part of complex IV of the electron transport chain and contributed significantly to the anti-proliferative activity. OPA activated mitochondrial respiration in a HIG2DA and COX5A-dependent manner, led to an initial spike in mitochondrial ATP, but then compromised mitochondrial membrane potential leading to ATP depletion. We have used chemoproteomic strategies to discover a unique anti-cancer mechanism of OPA through activation of complex IV leading to compromised mitochondrial energetics and rapid cell death."
1993,Evolutionary history of MEK1 illuminates the nature of cancer and RASopathy mutations,"Ekaterina P. Andrianova, Robert A. Marmion, Stanislav Y. Shvartsman, Igor B. Zhulin",https://www.biorxiv.org/content/10.1101/2023.03.09.531944v1,"Mutations in signal transduction pathways lead to various diseases including cancers. MEK1 kinase, encoded by the human MAP2K1 gene, is one of the central components of the MAPK pathway and more than a hundred somatic mutations in MAP2K1 gene were identified in various tumors. Germline mutations deregulating MEK1 also lead to congenital abnormalities, such as the Cardiofaciocutaneous Syndrome and Arteriovenous Malformation. Evaluating variants associated with a disease is a challenge and computational genomic approaches aid in this process. Establishing evolutionary history of a gene improves computational prediction of disease-causing mutations; however, the evolutionary history of MEK1 is not well understood. Here, by revealing a precise evolutionary history of MEK1 we construct a well-defined dataset of MEK1 metazoan orthologs, which provides sufficient depth to distinguish between conserved and variable amino acid positions. We used this dataset to match known and predicted disease-causing and benign mutations to evolutionary changes observed in corresponding amino acid positions. We found that all known and the vast majority of suspected disease-causing mutations are evolutionarily intolerable. We selected several MEK1 mutations that cannot be unambiguously assessed by automated variant prediction tools, but that are confidently identified as evolutionary intolerant and thus “damaging” by our approach, for experimental validation in Drosophila. In all cases, evolutionary intolerant variants caused increased mortality and severe defects in fruit fly embryos confirming their damaging nature predicted by out computational strategy. We anticipate that our analysis will serve as a blueprint to help evaluate known and novel missense variants in MEK1 and that our approach will contribute to improving automated tools for disease-associated variant interpretation."
1995,Genomic characteristics and clinical significance of CD56+ Circulating Tumor Cells in Small Cell Lung Cancer,"C. Ricordel, L. Chaillot, E. I. Vlachavas, M. Logotheti, A. Jouannic, T. Desvallees, G. Lecuyer, M. Aubry, G. Kontogianni, C. Mastrokalou, F. Jouan, U. Jarry, R. Corre, Y. Le Guen, T. Guillaudeux, H. Lena, A. Chatziioannou, R. Pedeux",https://www.biorxiv.org/content/10.1101/2022.04.30.487775v3,Introduction Circulating Tumor Cells (CTC) have been studied in various solid tumors but clinical utility of CTC in Small Cell Lung Cancer (SCLC) remains unclear. The aim of the CTC-CPC study was to develop an EpCAM-independent CTC isolation method allowing isolation of a broader range of living CTC from SCLC and decipher their genomic and biological characteristics.
1996,TRPS1 modulates chromatin accessibility to regulate estrogen receptor (ER) binding and ER target gene expression in luminal breast cancer cells,"Thomas G. Scott, Kizhakke Mattada Sathyan, Daniel Gioeli, Michael J. Guertin",https://www.biorxiv.org/content/10.1101/2023.07.03.547524v1,"Breast cancer is the most frequently diagnosed cancer in women. The most common subtype is luminal breast cancer, which is typically driven by the estrogen receptor α (ER), a transcription factor (TF) that activates many genes required for proliferation. Multiple effective therapies target this path-way, but individuals often develop resistance. Thus, there is a need to identify additional targets that regulate ER activity and contribute to breast tumor progression. TRPS1 is a repressive GATA-family TF that is overexpressed in breast tumors. Common genetic variants in the TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. However, we do not know how TRPS1 regulates target genes to mediate these breast cancer patient and cellular outcomes. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over eighty percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes ER to redistribute in the genome. ER redistribution leads to both repression and activation of dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the activity of other TFs, both activating and repressing transcription of genes related to cancer cell fitness."
1999,Antigen-presenting type-I conventional dendritic cells facilitate curative checkpoint blockade immunotherapy in pancreatic cancer,"Krishnan K. Mahadevan, Allison M. Dyevoich, Yang Chen, Bingrui Li, Hikaru Sugimoto, Amari M. Sockwell, Kathleen M. McAndrews, Huamin Wang, Shabnam Shalapour, Stephanie S. Watowich, Raghu Kalluri",https://www.biorxiv.org/content/10.1101/2023.03.05.531191v1,"Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type-I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+ T cell activation and eradication of ptPDAC with restoration of lifespan even upon PDAC re-challenge. Such eradication of ptPDAC was reversed following specific depletion of dendritic cells. Employing PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with a curative outcome. Analysis of the T-cell receptor (TCR) sequences in the tumor infiltrating CD8+ T cells following cDC1 vaccination coupled with iCBT identified unique CDR3 sequences with potential therapeutic significance. Our findings identify a fundamental difference in the immune microenvironment and adaptive immune response in PDAC concurrent with, or without pancreatitis, and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option."
0,The Role of Telomerase in Breast Cancer's Response to Therapy.,"Judasz E, Lisiak N, Kopczyński P, Taube M, Rubiś B.",https://pubmed.ncbi.nlm.nih.gov/36361634/,"Currently, breast cancer appears to be the most widespread cancer in the world and the most common cause of cancer deaths. This specific type of cancer affects women in both developed and developing countries. Prevention and early diagnosis are very important factors for good prognosis. A characteristic feature of cancer cells is the ability of unlimited cell division, which makes them immortal. Telomeres, which are shortened with each cell division in normal cells, are rebuilt in cancer cells by the enzyme telomerase, which is expressed in more than 85% of cancers (up to 100% of adenocarcinomas, including breast cancer). Telomerase may have different functions that are related to telomeres or unrelated. It has been shown that high activity of the enzyme in cancer cells is associated with poor cell sensitivity to therapies. Therefore, telomerase has become a potential target for cancer therapies. The low efficacy of therapies has "
1,Cancer and cure: A critical analysis.,"Roy PS, Saikia BJ.",https://pubmed.ncbi.nlm.nih.gov/28244479/,"Cancer is one of the most dreaded diseases of the 20th century and spreading further with continuance and increasing incidence in the 21st century. The situation is so alarming that every fourth person is having a lifetime risk of cancer. India registers more than 11 lakh new cases of cancer every year, whereas, this figure is above 14 million worldwide. Is cancer curable? The short answer to this question is ""Yes."" In fact, all cancers are curable if they are caught early enough. Cancer cells continue to grow unless one of four things occur: (1) The cancerous mass is removed surgically; (2) using chemotherapy or another type of cancer-specific medication, such as hormonal therapy; (3) using radiation therapy; or (4) the cancer cells shrink and disappear on their own."
2,Measuring cancer evolution from the genome.,"Graham TA, Sottoriva A.",https://pubmed.ncbi.nlm.nih.gov/27741350/,"The temporal dynamics of cancer evolution remain elusive, because it is impractical to longitudinally observe cancers unperturbed by treatment. Consequently, our knowledge of how cancers grow largely derives from inferences made from a single point in time - the endpoint in the cancer's evolution, when it is removed from the body and studied in the laboratory. Fortuitously however, the cancer genome, by virtue of ongoing mutations that uniquely mark clonal lineages within the tumour, provides a rich, yet surreptitious, record of cancer development. In this review, we describe how a cancer's genome can be analysed to reveal the temporal history of mutation and selection, and discuss why both selective and neutral evolution feature prominently in carcinogenesis. We argue that selection in cancer can only be properly studied once we have some understanding of what the absence of selection looks like. We review the data describing punctuated evolution in cancer, and reason that punctuated phenotype evolution is consistent with both gradual and punctuated genome evolution. We conclude that, to map and predict evolutionary trajectories during carcinogenesis, it is critical to better understand the relationship between genotype change and phenotype change. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd."
3,Field cancerization in breast cancer.,"Gadaleta E, Thorn GJ, Ross-Adams H, Jones LJ, Chelala C.",https://pubmed.ncbi.nlm.nih.gov/35362092/,"Breast cancer affects one in seven women worldwide during their lifetime. Widespread mammographic screening programs and education campaigns allow for early detection of the disease, often during its asymptomatic phase. Current practice in treatment and recurrence monitoring is based primarily on pathological evaluations but can also encompass genomic evaluations, both of which focus on the primary tumor. Although breast cancer is one of the most studied cancers, patients still recur at a rate of up to 15% within the first 10 years post-surgery. Local recurrence was originally attributed to tumor cells contaminating histologically normal (HN) tissues beyond the surgical margin, but advances in technology have allowed for the identification of distinct aberrations that exist in the peri-tumoral tissues themselves. One leading theory to explain this phenomenon is the field cancerization theory. Under this hypothesis, tumors arise from a field of molecularly altered cells that create a permissive environment for malignant evolution, which can occur with or without morphological changes. The traditional histopathology paradigm dictates that molecular alterations are reflected in the tissue phenotype. However, the spectrum of inter-patient variability of normal breast tissue may obfuscate recognition of a cancerized field during routine diagnostics. In this review, we explore the concept of field cancerization focusing on HN peri-tumoral tissues: we present the pathological and molecular features of field cancerization within these tissues and discuss how the use of peri-tumoral tissues can affect research. Our observations suggest that pathological and molecular evaluations could be used synergistically to assess risk and guide the therapeutic management of patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland."
4,Tumor cell metabolism: cancer's Achilles' heel.,"Kroemer G, Pouyssegur J.",https://pubmed.ncbi.nlm.nih.gov/18538731/,"The essential hallmarks of cancer are intertwined with an altered cancer cell-intrinsic metabolism, either as a consequence or as a cause. As an example, the resistance of cancer mitochondria against apoptosis-associated permeabilization and the altered contribution of these organelles to metabolism are closely related. Similarly, the constitutive activation of signaling cascades that stimulate cell growth has a profound impact on anabolic metabolism. Here, we review the peculiarities of tumor cell metabolism that might be taken advantage of for cancer treatment. Specifically, we discuss the alterations in signal transduction pathways and/or enzymatic machineries that account for metabolic reprogramming of transformed cells."
5,Mapping cancer origins.,Gilbertson RJ.,https://pubmed.ncbi.nlm.nih.gov/21458665/,"Cancer comprises a bewildering assortment of diseases that kill 7.5 million people each year. Poor understanding of cancer's diversity currently thwarts our goal of a cure for every patient, but recent integration of genomic and stem cell technologies promises a route through this impasse."
6,What Is Cancer?,Hausman DM.,https://pubmed.ncbi.nlm.nih.gov/31761807/,"This essay focuses on themes in Explaining Cancer: Finding Order in Disorder (2018) by Anya Plutynski, a monograph that has important things to say about both the peculiarities of cancers and our theories about them. Cancer's agents of destruction are human cells that have been recruited and to some extent transformed into pathological organisms or the building blocks of tumors. Cancers both undermine and exploit mechanisms of multicellular organization, and understanding them gives rise to difficult philosophical problems. In addition to sketching Plutynski's discussion of these problems, this essay defends Christopher Boorse's account of disease from Plutynski's criticisms, and it expresses some qualms about her treatment of scientific explanation."
7,New methods in the diagnosis of cancer and gene therapy of cancer based on nanoparticles.,"Zaimy MA, Saffarzadeh N, Mohammadi A, Pourghadamyari H, Izadi P, Sarli A, Moghaddam LK, Paschepari SR, Azizi H, Torkamandi S, Tavakkoly-Bazzaz J.",https://pubmed.ncbi.nlm.nih.gov/28574057/,"Cancer is one of the leading cause of death in the world with the prevalence of >10 million mortalities annually. Current cancer treatments include surgical intervention, radiation, and taking chemotherapeutic drugs, which often kill the healthy cells and  Therefore, researchers are looking for ways to be able to eliminate just cancerous cells. Intra-tumor heterogeneity of cancerous cells is the main obstacle on the way of an effective cancer treatment. However, better comprehension of molecular basis of tumor and the advent of new diagnostic technologies can help to improve the treatment of various cancers. Therefore, study of epigenetic changes, gene expression of cancerous cells and employing  In this paper, we will review the recent advanced strategies being used in the field of cancer research."
8,[Lucy's cancer(s): A prehistorical origin?].,"Chene G, Lamblin G, Le Bail-Carval K, Beaufils E, Chabert P, Gaucherand P, Mellier G, Coppens Y.",https://pubmed.ncbi.nlm.nih.gov/27839715/,"7-million-year-old osteosarcoma from South Africa has raised the question of the origin of cancer and its determinants. We aimed to determine whether malignant and benign tumors exist in the past societies.
    


           Only cases with morphological and paraclinical analysis were included. The following keywords were used: cancer; paleopathology; malignant neoplasia; benign tumor; leiomyoma; myoma; breast cancer; mummies; soft tissue tumor; Antiquity.
    


          
    


          Conclusions:
        
      
      The fact that there were some malignant tumors, even few tumors and probably underdiagnosed, in the past may be evidence that cancer is not only a disease of the modern world. Cancer may be indeed a moving target: we have likely predisposing genes to cancer inherited from our ancestors. The malignant disease could therefore appear because of our modern lifestyle (carcinogens and risk factors related to the modern industrial society)."
9,"Signaling, metabolism, and cancer: An important relationship for therapeutic intervention.","Vaghari-Tabari M, Ferns GA, Qujeq D, Andevari AN, Sabahi Z, Moein S.",https://pubmed.ncbi.nlm.nih.gov/33580511/,"In cancerous cells, significant changes occur in the activity of signaling pathways affecting a wide range of cellular activities ranging from growth and proliferation to apoptosis, invasiveness, and metastasis. Extensive changes also happen with respect to the metabolism of a cancerous cell encompassing a wide range of functions that include: nutrient acquisition, biosynthesis of macromolecules, and energy generation. These changes are important and some therapeutic approaches for treating cancers have focused on targeting the metabolism of cancerous cells. Oncogenes and tumor suppressor genes have a significant effect on the metabolism of cells. There appears to be a close interaction between metabolism and the signaling pathways in a cancerous cell, in which the interaction provides the metabolic needs of a cancerous cell for uncontrolled proliferation, resistance to apoptosis, and metastasis. In this review, we have reviewed the latest findings in this regard and briefly review the most recent research findings regarding targeting the metabolism of cancer cells as a therapeutic approach for treatment of cancer."
10,Tertiary lymphoid structures are critical for cancer prognosis and therapeutic response.,"Zhang Q, Wu S.",https://pubmed.ncbi.nlm.nih.gov/36713409/,"Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregates that form at sites of chronic inflammation, including cancers, in non-lymphoid tissues. Although the formation of TLSs is similar to that of secondary lymphoid organs, the pathogenic factors leading to TLS formation in cancerous tissues and the mechanisms underlying the role of these structures in the intra-tumoral adaptive antitumor immune response are not fully understood. The presence of TLSs may impact patient prognosis and treatment outcomes. This review examines the current understanding of TLSs in cancers, including their composition and formation as well as their potential to predict prognosis and therapeutic efficacy. We also summarize strategies to induce TLS formation for cancer treatment."
11,Cancer prevention: from 1727 to milestones of the past 100 years.,"Lippman SM, Hawk ET.",https://pubmed.ncbi.nlm.nih.gov/19491253/,"The rich, multidisciplinary history of cancer prevention recounted here begins with surgical and workplace recommendations of the 1700s and ends with 2009  This history comprises a fascinating array of chemopreventive, vaccine, surgical, and behavioral science research, both preclinical and clinical. Preclinical milestones of cancer prevention include the 1913 and 1916 mouse studies by Lathrop and Loeb of cancer development associated with pregnancy or cancer prevention through castration (oophorectomy), preventing chemically induced mouse carcinogenesis as early as 1929, energy restriction studies in the 1940s, the 1950s discoveries and later molecular characterizations of field cancerization and multistep carcinogenesis, and the effects of angiogenesis inhibition in genetically engineered mice reported in 2009. The extraordinary panoply of clinical research includes numerous large and smaller chemoprevention studies of nutritional supplements, other dietary approaches, a Bacillus Calmette-Guérin trial in 1976, molecular-targeted agents, and agents to prevent infection-related cancers such as hepatitis B virus vaccine to prevent liver cancer in 1984. Clinical surgical prevention includes removal of intraepithelial neoplasia detected by screening (including Pap testing developed in 1929 and culposcopy for cervical premalignancy and colonoscopy and polypectomy to prevent colorectal cancer begun in the 1960s) and prophylactic surgeries, such as in Lynch syndrome patients begun in 1977. Behavioral studies include smoking cessation and control beginning in the 1950s, obesity control rooted in studies of 1841, and genetic-counseling and cancer-survivorship studies. This history of pioneering events may help in better understanding who we are and what we want to achieve as cancer prevention researchers and practitioners."
12,Detection of Cancer DNA in Early Stage and Metastatic Breast Cancer Patients.,"Medford AJ, Gillani RN, Park BH.",https://pubmed.ncbi.nlm.nih.gov/29717446/,"Breast cancer is the leading cause of cancer in women and the second leading cause of cancer-related death. There are many subtypes of breast cancer, which can be identified through the process of molecular and genetic profiling. While the current standard of care utilizes tumor tissue biopsy to subclassify breast cancer, plasma tumor DNA (ptDNA) can be detected through droplet digital PCR (ddPCR) of plasma obtained from a simple blood draw. Tissue biopsy is not only more invasive but because tumors exhibit heterogeneity it can be less accurate. Blood collects DNA shed from normal and cancerous cells alike, thus ddPCR of plasma offers a broader picture of a cancer's genetic makeup. This chapter summarizes how patients with breast cancer can be screened for specific cancerous mutations in both tissue and plasma through the use of ddPCR."
13,Exploiting cancer's drinking problem: regulation and therapeutic potential of macropinocytosis.,"Puccini J, Badgley MA, Bar-Sagi D.",https://pubmed.ncbi.nlm.nih.gov/34649835/,"Macropinocytosis, an evolutionarily conserved endocytic mechanism that mediates non-specific fluid-phase uptake, is potently upregulated by various oncogenic pathways. It is now well appreciated that high macropinocytic activity is a hallmark of many human tumors, which use this adaptation to scavenge extracellular nutrients for fueling cell growth. In the context of the nutrient-scarce tumor microenvironment, this process provides tumor cells with metabolic flexibility. However, dependence on this scavenging mechanism also illuminates a potential metabolic vulnerability. As such, there is a great deal of interest in understanding the molecular underpinnings of macropinocytosis. In this review, we will discuss the most recent advances in characterizing macropinocytosis: the pathways that regulate it, its contribution to the metabolic fitness of cancer cells, and its therapeutic potential."
14,Measuring Clonal Evolution in Cancer with Genomics.,"Williams MJ, Sottoriva A, Graham TA.",https://pubmed.ncbi.nlm.nih.gov/31059289/,"Cancers originate from somatic cells in the human body that have accumulated genetic alterations. These mutations modify the phenotype of the cells, allowing them to escape the homeostatic regulation that maintains normal cell number. Viewed through the lens of evolutionary biology, the transformation of normal cells into malignant cells is evolution in action. Evolution continues throughout cancer growth, progression, treatment resistance, and disease relapse, driven by adaptation to changes in the cancer's environment, and intratumor heterogeneity is an inevitable consequence of this evolutionary process. Genomics provides a powerful means to characterize tumor evolution, enabling quantitative measurement of evolving clones across space and time. In this review, we discuss concepts and approaches to quantify and measure this evolutionary process in cancer using genomics."
15,Sex differences in cancer risk and outcomes after kidney transplantation.,"Buxeda A, Redondo-Pachón D, Pérez-Sáez MJ, Crespo M, Pascual J.",https://pubmed.ncbi.nlm.nih.gov/34020178/,"Kidney transplant recipients (KTRs) experience a two- to four-fold increased risk of developing and dying from cancer compared with the general population. High cancer risk  This mapping review explores the impact of sex disparity on cancer's increased incidence and mortality after kidney transplantation (KT). In terms of age, population-based studies indicate that younger recipients of both sexes experience a higher risk of cancer, but this is more pronounced in young women. On the contrary, older men are more likely to be diagnosed with cancer, although their increased risk is not statistically significant compared with the general population. Regarding cancer type, studies show an increased risk of Kaposi sarcoma, gynecologic and lung cancer in women, and bladder and kidney cancer in men. Immune-related cancers such as pos-transplant lymphoproliferative disorders and melanoma are increased in both sexes. Mortality also shows differences between sexes. Although cancer is the second cause of death in both male and female KTRs, studies show higher overall mortality in men and elderly recipients. However, the relative risk of cancer mortality compared with the general population is higher at a younger age, with disparate  Female KTRs appear to die at a younger age than males when compared with the general population. Differences in cancer rates by sex after renal transplantation need further studies. A better understanding of sex-specific differences in cancer epidemiology after KT could help nephrologists to better address pre-transplant counseling, to establish early surveillance programs, and to plan modifiable risk factors such as immunosuppression."
16,"Signaling, cancer cell plasticity, and intratumor heterogeneity.","Cordani M, Dando I, Ambrosini G, González-Menéndez P.",https://pubmed.ncbi.nlm.nih.gov/38702718/,"Cancer's complexity is in part due to the presence of intratumor heterogeneity and the dynamic nature of cancer cell plasticity, which create substantial obstacles in effective cancer management. Variability within a tumor arises from the existence of diverse populations of cancer cells, impacting the progression, spread, and resistance to treatments. At the core of this variability is the concept of cellular plasticity - the intrinsic ability of cancer cells to alter their molecular and cellular identity in reaction to environmental and genetic changes. This adaptability is a cornerstone of cancer's persistence and progression, making it a formidable target for treatments. Emerging studies have emphasized the critical role of such plasticity in fostering tumor diversity, which in turn influences the course of the disease and the effectiveness of therapeutic strategies. The transformative nature of cancer involves a network of signal transduction pathways, notably those that drive the epithelial-to-mesenchymal transition and metabolic remodeling, shaping the evolutionary path of cancer cells. Despite advancements, our understanding of the precise molecular machinations and signaling networks driving these changes is still evolving, underscoring the necessity for further research. This editorial presents a series entitled ""Signaling Cancer Cell Plasticity and Intratumor Heterogeneity"" in Cell Communication and Signaling, dedicated to unraveling these complex processes and proposing new avenues for therapeutic intervention."
17,Uncovering cancer's secrets: could liquid biopsies and artificial intelligence hold the answers?,Parker J.,https://pubmed.ncbi.nlm.nih.gov/37317873/,"Tweetable abstract How are #liquidbiopsies and #AI pushing us closer to the goal of early cancer detection for all? Plus, what more needs to be done to truly deciphers cancer's secrets? Find out in this editorial by @JadeParkerB."
18,Cancer's sweet spot: techniques to harness saccharides in tumor biology.,Parker J.,https://pubmed.ncbi.nlm.nih.gov/38047326/,"All of the cells in our bodies are enveloped in sugar, this sweet coating plays a particularly interesting and crucial role in tumor biology. Here, we review the techniques being used to detect and exploit cancer's sweet spot. including click chemistry, glycoproteomic profiling and bioorthogonal chemistry."
19,Gastric adenocarcinoma: A review of the TNM classification system and ways of spreading.,"López Sala P, Leturia Etxeberria M, Inchausti Iguíñiz E, Astiazaran Rodríguez A, Aguirre Oteiza MI, Zubizarreta Etxaniz M.",https://pubmed.ncbi.nlm.nih.gov/36842787/,"Gastric cancer is the fifth most common cancer in the world. The most common histologic subtype is adenocarcinoma. Gastric adenocarcinomas are staged using the American Joint Committee on Cancer's 8th TNM classification. The perigastric ligaments, mesentery, omentum, and potential spaces between the parietal and visceral peritoneal linings play are important structures for staging. The spread of disease is influenced by the location of the tumor within the stomach, as well as by the anatomy related to the ligaments and lymph vessels. CT is the imaging modality of choice for the preoperative clinical staging of gastric cancer, and it is essential for planning treatment. To be able to do an adequate imaging workup, radiologists need to know the different pathways through which gastric cancer can spread: lymphatic, subperitoneal, direct invasion, transperitoneal, hematogenous, and extramural venous invasion."
20,The Intratumoral Heterogeneity of Cancer Metabolism.,"Nabi K, Le A.",https://pubmed.ncbi.nlm.nih.gov/29946781/,"Cancer is one of the deadliest diseases in the world, especially within the past few decades, causing over half a million deaths a year in the USA only [1]. Despite recent advances made in the field of cancer biology and the therapies that have been developed, it is clear that more advances are necessary for us to classify cancer as curable. The logical question that arises is simple: Why, despite all the technologies and medical innovations of our time, has a cure eluded us? This chapter will shed light on one of cancer’s most impactful attributes: its heterogeneity and, more specifically, the intratumoral heterogeneity of cancer metabolism. Simply put, what makes cancer one of the deadliest known diseases is its ability to change and adapt. Cancer cells’ rapid evolution, coupled with their irrepressible ability to divide, gives them the advantage over our immune systems. In this chapter, we will delve into the complexities of this adaptability and the vital role that metabolism plays in the rise and progression of this heterogeneity."
21,Targeting cancer's metabolic co-dependencies: A landscape shaped by genotype and tissue context.,"Bi J, Wu S, Zhang W, Mischel PS.",https://pubmed.ncbi.nlm.nih.gov/29775654/,"Tumors cells reprogram their metabolism to fuel rapid growth. The ability to trace nutrient fluxes in the context of specific alterations has provided new mechanistic insight into the process of oncogenic transformation. A broad array of complementary genetic, epigenetic, transcriptional and translational mechanisms has been identified, revealing a metabolic landscape of cancer. However, cancer metabolism is not a static or uniform process, including within a single tumor. Tumor cells adapt to changing environmental conditions, profoundly shaping the enzymatic dependencies of individual cells. The underlying molecular mechanisms of adaptation, and the specific interactions between tumor genotype, oncogenic signaling, and tissue/biochemical context, remain incompletely understood. In this review, we examine dynamic aspects of how metabolic dependencies develop in cancer, shaped both by genotype and biochemical environment, and review how these interlaced processes generate targetable metabolic vulnerabilities. This article is part of a Special Issue entitled: Cancer Metabolism edited by Dr. Chi Van Dang."
22,Decoding human cancer with whole genome sequencing: a review of PCAWG Project studies published in February 2020.,Giunta S.,https://pubmed.ncbi.nlm.nih.gov/34097189/,"Cancer is underlined by genetic changes. In an unprecedented international effort, the Pan-Cancer Analysis of Whole Genomes (PCAWG) of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) sequenced the tumors of over two thousand five hundred patients across 38 different cancer types, as well as the corresponding healthy tissue, with the aim of identifying genome-wide mutations exclusively found in cancer and uncovering new genetic changes that drive tumor formation. What set this project apart from earlier efforts is the use of whole genome sequencing (WGS) that enabled to explore alterations beyond the coding DNA, into cancer's non-coding genome. WGS of the entire cohort allowed to tease apart driving mutations that initiate and support carcinogenesis from passenger mutations that do not play an overt role in the disease. At least one causative mutation was found in 95% of all cancers, with many tumors showing an average of 5 driver mutations. The PCAWG Project also assessed the transcriptional output altered in cancer and rebuilt the evolutionary history of each tumor showing that initial driver mutations can occur years if not decades prior to a diagnosis. Here, I provide a concise review of the Pan-Cancer Project papers published on February 2020, along with key computational tools and the digital framework generated as part of the project. This represents an historic effort by hundreds of international collaborators, which provides a comprehensive understanding of cancer genetics, with publicly available data and resources representing a treasure trove of information to advance cancer research for years to come."
23,Adaptive Cancer Therapy in the Age of Generative Artificial Intelligence.,Derbal Y.,https://pubmed.ncbi.nlm.nih.gov/38897721/,"Therapeutic resistance is a major challenge facing the design of effective cancer treatments. Adaptive cancer therapy is in principle the most viable approach to manage cancer's adaptive dynamics through drug combinations with dose timing and modulation. However, there are numerous open issues facing the clinical success of adaptive therapy. Chief among these issues is the feasibility of real-time predictions of treatment response which represent a bedrock requirement of adaptive therapy. Generative artificial intelligence has the potential to learn prediction models of treatment response from clinical, molecular, and radiomics data about patients and their treatments. The article explores this potential through a proposed integration model of Generative Pre-Trained Transformers (GPTs) in a closed loop with adaptive treatments to predict the trajectories of disease progression. The conceptual model and the challenges facing its realization are discussed in the broader context of artificial intelligence integration in oncology."
24,Advancing preclinical cancer models to assess clinically relevant outcomes.,"Golebiewska A, Fields RC.",https://pubmed.ncbi.nlm.nih.gov/36899363/,"Cancer models are indispensable research tools for elucidating the mechanisms involved in tumor onset, progression and treatment resistance. They are key in evaluating therapeutics prior clinical trials. In this editorial, we invite contributions for a BMC Cancer's Collection of articles addressing 'Advances in pre-clinical cancer models' towards relivable outcomes at the preclinical stage."
25,Recent progress in single-cell cancer genomics.,"Tsoucas D, Yuan GC.",https://pubmed.ncbi.nlm.nih.gov/28126650/,"The advent of single-cell sequencing has been revolutionary to the field of cancer genomics. Perfectly suited to capture cancer's heterogeneous nature, single-cell analyses provide information bulk sequencing could never hope to uncover. Many mechanisms of cancer have yet to be fully understood, and single-cell approaches are showing promise in their abilities to uncover these mysteries. Here we focus on the most recent single-cell "
26,Evolution-Informed Strategies for Combating Drug Resistance in Cancer.,"Lin-Rahardja K, Weaver DT, Scarborough JA, Scott JG.",https://pubmed.ncbi.nlm.nih.gov/37047714/,"The ever-changing nature of cancer poses the most difficult challenge oncologists face today. Cancer's remarkable adaptability has inspired many to work toward understanding the evolutionary dynamics that underlie this disease in hopes of learning new ways to fight it. Eco-evolutionary dynamics of a tumor are not accounted for in most standard treatment regimens, but exploiting them would help us combat treatment-resistant effectively. Here, we outline several notable efforts to exploit these dynamics and circumvent drug resistance in cancer."
27,Cancer's Lasting Financial Burden: Evidence From a Longitudinal Assessment.,"Shih YT, Owsley KM, Nicholas LH, Yabroff KR, Bradley CJ.",https://pubmed.ncbi.nlm.nih.gov/35325197/,"
    


           Outcomes included monthly OOPE for prescription drugs (RX-OOPE_MONTHLY) and OOPE for medical services other than drugs in the past 2 years (non-RX-OOPE_2YR), consumer debt, and new individual retirement account (IRA) withdrawals. Generalized linear models were used to compare OOPEs between cancer and matched control groups. Logistic regressions were used to compare household-level consumer debt or early IRA withdrawal. Subgroup analysis stratified patients by age, health status, and household income, with the low-income group stratified by Medicaid coverage. All statistical tests were 2-sided.
    


           Mean non-RX-OOPE_2YR of cancer patients was similar to that of participants in the matched control group before diagnosis but statistically significantly higher at diagnosis ($1157, P < .001), 2 ($511, P < .001) years, 4 ($360, P = .006) years, and 6 ($430, P = .01) years after diagnosis. A similar pattern was observed in RX-OOPE_MONTHLY. A statistically significantly higher proportion of cancer patients incurred consumer debt at diagnosis (34.5% vs 29.9%; P < .001) and 2 years after (32.5% vs 28.2%; P = .002). There was no statistically significant difference in new IRA withdrawals. Patients experienced lasting financial consequences following cancer diagnosis that were most pronounced among patients aged 65 years and older, in good-to-excellent health at baseline, and with low income, but without Medicaid coverage.
    


          Conclusions:
        
      
      Policies to reduce costs and expand insurance coverage options while reducing cost-sharing are needed."
28,Cancer's Achilles' Heel: Apoptosis and Necroptosis to the Rescue.,"Dasgupta A, Nomura M, Shuck R, Yustein J.",https://pubmed.ncbi.nlm.nih.gov/28025559/,"Apoptosis, and the more recently discovered necroptosis, are two avenues of programmed cell death. Cancer cells survive by evading these two programs, driven by oncogenes and tumor suppressor genes. While traditional therapy using small molecular inhibitors and chemotherapy are continuously being utilized, a new and exciting approach is actively underway by identifying and using synergistic relationship between driver and rescue genes in a cancer cell. Through these synthetic lethal relationships, we are gaining tremendous insights into tumor vulnerabilities and specific molecular avenues for induction of programmed cell death. In this review, we briefly discuss the two cell death processes and cite examples of such synergistic manipulations for therapeutic purposes."
29,Cancer's Fuel Choice: New Flavors for a Picky Eater.,"DeNicola GM, Cantley LC.",https://pubmed.ncbi.nlm.nih.gov/26590711/,"Otto Warburg discovered that cancer cells exhibit a high rate of glycolysis in the presence of ample oxygen, a process termed aerobic glycolysis, in 1924 (Warburg et al., 1924). Since then we have significantly advanced our understanding of cancers' fuel choice to meet their demands for energy and for the production of biosynthetic precursors. In this review, we will discuss the preferred nutrients of cancer cells and how they are utilized to satisfy their bioenergetic and biosynthetic needs. In addition, we will describe how cell intrinsic and extrinsic factors such as oncogene mutations, nutrient and oxygen availability, and other microenvironmental factors influence fuel choice."
30,Cancer clusters in the USA: what do the last twenty years of state and federal investigations tell us?,"Goodman M, Naiman JS, Goodman D, LaKind JS.",https://pubmed.ncbi.nlm.nih.gov/22519802/," At a 1989 national conference on disease clusters, it was reported that cluster studies conducted in the 1970s and 1980s rarely, if ever, produced important findings. We seek to answer the question: Have cancer cluster investigations conducted by US health agencies in the past 20 years improved our understanding of cancer etiology, or informed cancer prevention and control?
    


           Investigations were categorized with respect to cancer type(s), hypothesized exposure, whether perceived clusters were confirmed (e.g. by elevated incidence), and conclusions about a link between cancer(s) of concern and hypothesized environmental exposure(s).
    


           An increase in incidence was confirmed for 72 (13%) cancer categories (including the category ""all sites""). Three of those were linked (with variable degree of certainty) to hypothesized exposures, but only one investigation revealed a clear cause.
    


          Conclusions:
        
      
      It is fair to state that extensive efforts to find causes of community cancer clusters have not been successful. There are fundamental shortcomings to our current  We recommend a multidisciplinary national dialogue on creative, innovative approaches to understanding when and why cancer and other chronic diseases cluster in space and time."
31,Rare Ovarian Cancer's First Positive Trial.,[No authors listed],https://pubmed.ncbi.nlm.nih.gov/35373274/,The MEK1/2 inhibitor trametinib increases progression-free survival from 7.2 months to 13 months in women with recurrent low-grade serous ovarian cancer. The drug also boosts the overall response rate from 6% to 26%.
32,"Cancer Diagnosis, Treatment Linked to Suicide Risk.",[No authors listed],https://pubmed.ncbi.nlm.nih.gov/35475895/,Two recent studies pull data from millions of patient records to provide a comprehensive picture of cancer's psychologic burden on patients with different tumor types and treatment regimens. The findings underscore the elevated risk of suicide and self-harm among patients with cancer and can help oncologists identify those in need of psychiatric care.
33,Innate sensing of cancer's non-immunologic hallmarks.,"Seelige R, Searles S, Bui JD.",https://pubmed.ncbi.nlm.nih.gov/29032295/,"A cancer mass consists of a complex composition of cancer cells, stromal cells, endothelial cells and also immune cells, which can represent more than half of the cellularity of a solid cancer. These immune cells become activated when they sense cancer antigens and stress ligands. Innate immune cells also detect various aspects of cellular stress that characterize a growing tumor mass. These key hallmarks of cellular stress are also detected by the cancer cell itself. In this review, we highlight studies that show that the cancer cell itself could be considered an 'innate cell' that senses and reacts to non-immunologic hallmarks of cancer, including displaced nucleic acids, proteotoxic stress, oxidative stress, and metabolic alterations."
34,[Intratumoral heterogeneity of gastric cancer-impact on biomarker evaluation].,Halske C.,https://pubmed.ncbi.nlm.nih.gov/33427920/," Predictive biomarker testing is usually carried out on tissue biopsies, which do not represent the entire tumor biology and intratumoral heterogeneity.
    


          
    


          Materials and  The following biomarkers were determined: HER2, MET, Ki67, PD-L1/PD‑1, VISTA, EBV-status, and PIK3CA.
    


           Tissue biopsies might carry the risk of sampling errors, which may significantly hamper adequate tumor classification in a clinical setting.
    


          Conclusions:
        
      
      Our findings unravel issues of tumor heterogeneity in gastric cancer. Biomarker diagnostics on tissue biopsies should be carried out on at least five biopsies of different tumor areas. If possible, biomarker diagnostics should be repeated on resection specimens. Tissue microarrays should no longer be used for research studies of gastric cancer."
35,Finding cancer's weakest link.,"Sodir NM, Evan GI.",https://pubmed.ncbi.nlm.nih.gov/22202195/,"The biological programs of vertebrates exhibit a remarkable degree of functional degeneracy, adaptive compensation and robustness, to preserve homeostasis and generate reproducible phenotypic outputs irrespective of variations in signal strength, noise and quality. Cancers are difficult to treat not only because they are so mechanistically diverse but also because they adapt or evolve in response to any pharmacological elective pressure we impose upon them. Hence, an ideal cancer drug target would exert a function both necessary for cancer cell survival and functionally non-redundant, rendering it impossible for tumor cells to compensate for, or evolve independence from, the inhibitory effect of any drug aimed at that target. In this review, we discuss the unique, non-degenerate and highly pleiotropic role played by Myc in coordinating, engaging and maintaining the diverse intracellular and extracellular programs required for cell proliferation in vivo. These properties make Myc a compelling candidate cancer drug target, at least in principle: an assertion recently reinforced by new in vivo genetic data."
36,The Intratumoral Heterogeneity of Cancer Metabolism.,"Nabi K, Le A.",https://pubmed.ncbi.nlm.nih.gov/34014541/,"Cancer is one of the deadliest diseases in the world, causing over half a million deaths a year in the USA alone. Despite recent advances made in the field of cancer biology and the therapies that have been developed [1, 2], it is clear that more advances are necessary for us to classify cancer as curable. The logical question that arises is simple: Why, despite all the technologies and medical innovations of our time, has a complete cure eluded us? This chapter sheds light on one of cancer's most impactful attributes: its heterogeneity and, more specifically, the intratumoral heterogeneity of cancer metabolism. Simply put, what makes cancer one of the deadliest diseases is its ability to change and adapt. Cancer cells' rapid evolution, coupled with their irrepressible ability to divide, gives most of them the advantage over our immune systems. In this chapter, we delve into the complexities of this adaptability and the vital role that metabolism plays in the rise and progression of this heterogeneity."
37,Cancer in Jews: introduction and overview.,"Lynch HT, Rubinstein WS, Locker GY.",https://pubmed.ncbi.nlm.nih.gov/15516840/,"This article is based upon a literature overview of cancer in Jews. It involves a comparison of variation in incidence and prevalence rates between Jews and non-Jews. However, the reader must exercise a certain amount of skepticism when considering secular changes in cancer incidence and prevalence and the public health implications of such cancer variation. Ashkenazi Jews have a lifetime CRC risk of 9--15%. This elevated CRC risk is similar to that of individuals in the ""familial risk'' category, and differs strikingly from the 5-6% CRC risk for non-Ashkenazi members of general Western populations. A MedLine search tested the hypothesis that site-specific and/or all-cancer incidence and mortality rates are either higher or lower than expected in Ashkenazi Jews worldwide, when compared with reference populations.  Indeed, rates for some cancers, such as carcinoma of the lung in Ashkenazi males, are low; this example is likely attributable in large part to decreased tobacco use. Carcinoma of the ovary, pancreas, stomach, and non-Hodgkin's lymphoma have a higher incidence rate in Ashkenazi. Even though BRCA1 and BRCA2 founder mutations which predispose to carcinoma of the breast and ovary appear increased in Ashkenazi breast cancer affected women, there was no evidence supporting an elevated risk of breast cancer among Ashkenazi women. Our primary concern, however, is that Ashkenazi Jews may have one of the highest lifetime CRC risks of any ethnic group in the world, a risk that diverges significantly from that of the general population; therein, it logically calls for more intensive CRC screening guidelines. We have emphasized that the reader use caution in the interpretation of statistics which portray variation in incidence and prevalence figures for cancer in any racial, ethnic, or religious group, inclusive, of course, of Jews. Clearly, more research will be required in the interest of accuracy in the understanding of these cancer variations, since they portend the need for special cancer control strategies. A lesser degree of attention can then be given to carcinoma of the penis and uterine cervix, which occur very infrequently in Jews. We urge our colleagues to continue to probe further into these statistical differences in cancer's incidence and prevalence in order to garner a better understanding of cancer's etiology and pathogenesis."
38,Autophagy: cancer's friend or foe?,"Bhutia SK, Mukhopadhyay S, Sinha N, Das DN, Panda PK, Patra SK, Maiti TK, Mandal M, Dent P, Wang XY, Das SK, Sarkar D, Fisher PB.",https://pubmed.ncbi.nlm.nih.gov/23768510/,"The functional relevance of autophagy in tumor formation and progression remains controversial. Autophagy can promote tumor suppression during cancer initiation and protect tumors during progression. Autophagy-associated cell death may act as a tumor suppressor, with several autophagy-related genes deleted in cancers. Loss of autophagy induces genomic instability and necrosis with inflammation in mouse tumor models. Conversely, autophagy enhances survival of tumor cells subjected to metabolic stress and may promote metastasis by enhancing tumor cell survival under environmental stress. Unraveling the complex molecular regulation and multiple diverse roles of autophagy is pivotal in guiding development of rational and novel cancer therapies."
39,Aneuploidy: cancer's fatal flaw?,"Williams BR, Amon A.",https://pubmed.ncbi.nlm.nih.gov/19549887/,"Aneuploidy is a characteristic of cancer, with greater than 90% of all solid tumors in humans carrying an aberrant karyotype. Yet, whether or how this condition contributes to tumorigenesis is not understood. Here we summarize our recent findings on the effects of aneuploidy on cell physiology and proliferation. These studies suggest that aneuploidy puts significant stress on the cell, which responds to this condition in what can be viewed as an aneuploidy stress response. We will discuss how our "
40,Cancer's molecular sweet tooth and the Warburg effect.,"Kim JW, Dang CV.",https://pubmed.ncbi.nlm.nih.gov/16982728/,"More than 80 years ago, the renowned biochemist Otto Warburg described how cancer cells avidly consume glucose and produce lactic acid under aerobic conditions. Recent studies arguing that cancer cells benefit from this phenomenon, termed the Warburg effect, have renewed discussions about its exact role as cause, correlate, or facilitator of cancer. Molecular advances in this area may reveal tactics to exploit the cancer cell's ""sweet tooth"" for cancer therapy."
41,Therapeutic potential of cancer stem cells.,"Yang C, Jin K, Tong Y, Cho WC.",https://pubmed.ncbi.nlm.nih.gov/25920610/,"Cancer stem cells (CSCs) play an important role in cancer growth, self-renewal, metastasis, recurrence and radio/chemotherapy. However, the underlying mechanisms remain elusive. In this review, we explore the roles of CSCs in cancer's relapse and progression and discuss the biomarkers of CSCs to predict clinical outcome and their diagnostic potential. The different approaches of CSC therapies are also reviewed, including cytotoxic, radiation, differentiation and targeting signaling pathways. We also discuss the challenge of targeting CSCs in cancer therapy. In addition, non-coding RNAs in CSC therapies are also discussed."
42,Pathophysiology of lung cancer.,"Seale DD, Beaver BM.",https://pubmed.ncbi.nlm.nih.gov/1508734/,"Cigarette smoking is responsible for approximately 30% of all cancer deaths. Smoking accounts for 85% of lung cancer cases in men and 75% in women. There are about 38 million former cigarette smokers and about 50 million smokers in the United States today. Smoking rates are higher among blacks, blue collar workers, and less educated people. More than 140,000 lives will be lost to cancer each year because of tobacco smoking. All cancers caused by cigarette smoking could be prevented. It is hoped that public education, smoking cessation programs, and efforts to eliminate carcinogens in the work environment will impact the future incidence of new lung cancer cases. As preventive measures continue, refinement in the diagnosis and treatment of cancer must continue to advance. The recognition of any one of cancer's seven warning signals and prompt subsequent action could lead to earlier detection and a chance for 3- and 5-year survival rates to improve. With medical and research progress, clinical concerns have grown beyond addressing only the patient's physical needs to include important issues such as employment and insurance needs and the psychosocial needs of both the patient and the family as they learn to live with cancer."
43,"Cancer survivorship research: state of knowledge, challenges and opportunities.",Aziz NM.,https://pubmed.ncbi.nlm.nih.gov/17497308/," While most therapeutic modalities for cancer are beneficial and lifesaving, they are associated with adverse long-term and late sequelae.
    


          Materials and  Emerging concepts in survivorship research such as definitional issues, research paradigms and 
    


           Follow-up care relevant to survivorship outcomes is neither standardized nor guideline or evidence based for most adult cancers, and optimal practices have yet to be defined.
    


          Discussion:
        
      
      Adverse sequelae contribute to burden of illness, health care costs, and decreased length and quality of survival. To-date, very few studies have compared survivor outcomes pre-and post diagnosis. It is critical to examine under-researched questions and understudied survivor groups. Regular follow-up care and monitoring of health status post cancer treatment should 1) permit the timely diagnosis and treatment of adverse outcomes; 2) enable timely diagnosis and treatment of recurrences; 3) facilitate screening and early detection of second cancer(s); 4) allow for detection and management of co-morbidities; and 5) provide the opportunity for preventive strategies such as lifestyle changes. Research findings to-date underscore the need for continued cancer survivorship research that will: inform our understanding of the mechanisms underlying adverse sequelae; lead to the design of less toxic treatments; test the effectiveness of interventions - medical, pharmacologic, and behavioral - that reduce adverse outcomes; test models of post-treatment follow-up care; develop an evidence base for optimal follow-up care practices; and inform survivor and provider decision making."
44,Keeping Abreast of Developments in the Cancer Wars: A View From the Front.,Baenziger NL.,https://pubmed.ncbi.nlm.nih.gov/29141730/,"Cancer somehow lends itself to military analogies, perhaps because of its status as a threat to life itself. We've declared war on cancer over several decades, viewing cancer as a cell going rogue, dividing uncontrollably, and ultimately breaking through local boundaries to spread. Less well known, but critically relevant to the health care impact of questioning authority, is the war within the breast cancer management community, among those studying molecular and cellular targets in breast cancer biology and those managing the human targets that represent cancer's toll. This article outlines current concepts and controversies about breast cancer, presenting a bio/sociological basis and a mental toolkit for thinking about and coping with this conflict."
45,"Personalized Assessment for Cancer Prevention, Detection, and Treatment.",Paleari L.,https://pubmed.ncbi.nlm.nih.gov/39125710/,The intention of this Special Issue is to highlight research that aims to recognize cancer's complexity to better prevent or treat its occurrence [...].
46,Cancer is a propagandist.,Fantuzzi G.,https://pubmed.ncbi.nlm.nih.gov/28410500/,"Communication among cells (also known as cross-talk) plays a prominent role in the current knowledge of the pathophysiology of cancer and of cancer-associated conditions such as paraneoplastic syndromes and cachexia that are responsible for much of cancer's morbidity and mortality. Yet, biomedical scientists lack an explicit unifying frame that places this exchange of molecular information at the core of their understanding of cancer as a systemic disease. Propaganda is a type of information that aims at misleading, a form of communication intended primarily to serve the messenger. The biased molecular cross-talk between cancer and non-cancer cells can be considered as a form of biological propaganda. I here propose cancer is a propagandist as a metaphor that may serve as a unifying frame to interpret both cancer and cancer-associated syndromes under the same communication-based concept and may thus serve to bring together research that is currently compartmentalized under separate disciplines."
47,Role of miR-193a in Cancer: Complexity and Factors Control the Pattern of its Expression.,"Mamoori A, Gopalan V, Lam AK.",https://pubmed.ncbi.nlm.nih.gov/29521232/,"
    


          
    


          
    


           Also, miR-193a can be used to differentiate some types of cancer. In cancer, miR-193a can act as a tumour suppressor gene or as an oncogene. Till now, several genetic factors (MAX, RXR α, XB130, P63, P73, AEG-1, HIFs, EGFR, Drosha, DGCR8, Dicer) and epigenetic factors (DNA methylation and long non-coding RNAs) were predicted to control miR-193a expression. They have fundamental effects on its biological behaviour in different types of cancers.
    


          Conclusion:
        
      
      miR-193a has significant roles in cancer and can be targeted in the future for cancer therapy by better understanding of the factors that control its biological behaviour."
48,Evolving Strategies for Therapeutically Targeting Cancer Stem Cells.,"Talukdar S, Emdad L, Das SK, Sarkar D, Fisher PB.",https://pubmed.ncbi.nlm.nih.gov/27451127/,"Cancer is a multifactor and multistep process that is affected intrinsically by the genetic and epigenetic makeup of tumor cells and extrinsically by the host microenvironment and immune system. A key component of cancer involves a unique subpopulation of highly malignant cancerous cells referred to as cancer stem cells (CSCs). CSCs are positioned at the apex of the tumor hierarchy with an ability to both self-renew and also generate non-CSC/differentiated progeny, which contribute to the majority of the tumor mass. CSCs undergo functional changes and show plasticity that is stimulated by specific microenvironmental cues and interactions in the tumor niche, which contribute to the complexity and heterogeneity of the CSC population. The prognostic value of CSCs in the clinic is evident since there are many examples in which CSCs serve as markers for poor patient prognosis. CSCs are innately resistant to many standard therapies and they display anoikis resistance, immune evasion, tumor dormancy, and field cancerization, which may  Many academic laboratories and biotechnology companies are currently focusing on strategies that target CSCs. Combination therapies, epigenetic modifiers, stemness inhibitors, CSC surface marker-based therapies, and immunotherapy-based CSC-targeting drugs are currently undergoing clinical trials. Potential new targets/strategies in CSC-targeted therapy include MDA-9/Syntenin (SDCBP), Patched (PTCH), epigenetic targets, noncoding RNAs, and differentiation induction. Defining ways of targeting and destroying CSCs holds potential to impact significantly on cancer therapy, including prevention of metastasis and cancer recurrence."
49,Early breast cancer.,"Suzuki T, Toi M, Saji S, Horiguchi K, Aruga T, Suzuki E, Horiguchi S, Funata N, Karasawa K, Kamata N.",https://pubmed.ncbi.nlm.nih.gov/16622745/,"Breast cancer remains a common disease throughout the world. Here we review new knowledge about early breast cancer obtained during the past 5 years. The prognosis of early breast cancer is generally favorable. Especially, ductal carcinoma in situ has been regarded as a non-life-threatening disease. Therefore, early diagnosis and early onset of the treatment has been important. Early age at menarche, late age at first birth, and late age at menopause are related to breast cancer risk. Examination by mammography and ultrasonography is still the most effective means of detection for premenopausal and postmenopausal women, respectively. Additionally, there have been important advances in MRI, sentinel lymph node biopsy, breast-conserving surgery, partial breast irradiation, neoadjuvant systemic therapy, and adjuvant systemic therapy. Another approach to keeping the disease under control is the elucidation of breast cancer's molecular biological features. Assessment of potential molecular targets can lead to early diagnosis and molecular targeted treatment."
50,Transposable Elements (Human Endogenous Retroviruses) in Cancer.,"Qadir MI, Usman M, Akash MSH.",https://pubmed.ncbi.nlm.nih.gov/29199607/,"Transposable elements (TEs) have shown a great significance in regulatory elements research, being responsible for different types of cancers. They are divided into three classes on the basis of their mode of transposition, structural properties, and their homology with DNA sequence. In evaluating their role in cancers and other pathologies, researchers have found extensive evidence of their involvement. TEs can also be used as genetic markers for cancers and help in identifying potential therapeutic targets. There have been advancements in the management of hepatocellular carcinoma using TEs as regulatory components involved in the cancer's pathogenesis."
51,Metabolic targets for cancer therapy.,"Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G.",https://pubmed.ncbi.nlm.nih.gov/24113830/,"Malignant cells exhibit metabolic changes, when compared to their normal counterparts, owing to both genetic and epigenetic alterations. Although such a metabolic rewiring has recently been indicated as yet another general hallmark of cancer, accumulating evidence suggests that the metabolic alterations of each neoplasm represent a molecular signature that intimately accompanies and allows for different facets of malignant transformation. During the past decade, targeting cancer metabolism has emerged as a promising strategy for the development of selective antineoplastic agents. Here, we discuss the intimate relationship between metabolism and malignancy, focusing on strategies through which this central aspect of tumour biology might be turned into cancer's Achilles heel."
52,Signalling architectures can prevent cancer evolution.,"Oña L, Lachmann M.",https://pubmed.ncbi.nlm.nih.gov/31959809/,"Cooperation between cells in multicellular organisms is preserved by an active regulation of growth through the control of cell division. Molecular signals used by cells for tissue growth are usually present during developmental stages, angiogenesis, wound healing and other processes. In this context, the use of molecular signals triggering cell division is a puzzle, because any molecule inducing and aiding growth can be exploited by a cancer cell, disrupting cellular cooperation. A significant difference is that normal cells in a multicellular organism have evolved in competition between high-level organisms to be altruistic, being able to send signals even if it is to their detriment. Conversely, cancer cells evolve their abuse over the cancer's lifespan by out-competing their neighbours. A successful mutation leading to cancer must evolve to be adaptive, enabling a cancer cell to send a signal that  Using a mathematical model of such molecular signalling mechanism, this paper argues that a signal mechanism would be effective against abuse by cancer if it affects the cell that generates the signal as well as neighbouring cells that would receive a benefit without any cost,  We find that such molecular signalling mechanisms normally operate in cells as exemplified by growth factors. In scenarios of global and local competition between cells, we calculate how this process affects the fixation probability of a mutant cell generating such a signal, and find that this process can play a key role in limiting the emergence of cancer."
53,"Cancer's second genome: Microbial cancer diagnostics and redefining clonal evolution as a multispecies process: Humans and their tumors are not aseptic, and the multispecies nature of cancer modulates clinical care and clonal evolution: Humans and their tumors are not aseptic, and the multispecies nature of cancer modulates clinical care and clonal evolution.","Sepich-Poore GD, Guccione C, Laplane L, Pradeu T, Curtius K, Knight R.",https://pubmed.ncbi.nlm.nih.gov/35253252/,"The presence and role of microbes in human cancers has come full circle in the last century. Tumors are no longer considered aseptic, but implications for cancer biology and oncology remain underappreciated. Opportunities to identify and build translational diagnostics, prognostics, and therapeutics that exploit cancer's second genome-the metagenome-are manifold, but require careful consideration of microbial  Furthermore, the discoveries of intracellular and intra-metastatic cancer bacteria necessitate fundamental changes in describing clonal evolution and selection, reflecting bidirectional interactions with non-human residents. Reconsidering cancer clonality as a multispecies process similarly holds key implications for understanding metastasis and prognosing therapeutic resistance while providing rational guidance for the next generation of bacterial cancer therapies. Guided by these new findings and challenges, this Review describes opportunities to exploit cancer's metagenome in oncology and proposes an evolutionary framework as a first step towards modeling multispecies cancer clonality. Also see the video abstract here: https://youtu.be/-WDtIRJYZSs."
54,"Impact of cancer on income, wealth and economic outcomes of adult cancer survivors: a scoping review.","Bentley C, Teckle P, McQuarrie L, Peacock S, El Adam S.",https://pubmed.ncbi.nlm.nih.gov/36691144/,"
    


          Design:
        
      
      A scoping review following the Joanna Briggs Institute's 
    


          Data sources:
        
      
      Ovid MEDLINE, PsycINFO, CINAHL, EMBASE, Econ-Lit and Evidence-based Medicine Reviews, and reference lists of evidence syntheses. Published literature of any study type in English was searched from January 2000 to December 2020.
    


          Eligibility and criteria:
        
      
      Study participants were individuals diagnosed with cancer during adulthood (age ≥18 years). Studies from any country and/or healthcare system were included. Primary outcomes were employment income (eg, individual or household); investment income (eg, stocks/bonds, properties, savings); government transfer payments (eg, disability income/pension); debt and bankruptcy.
    


          Data extraction and synthesis:
        
      
      Findings are summarised descriptively and in tabular form.
    


           Most (51%) were published in 2016-2020; 65% were published in the USA or Scandinavia. Survivors incurred debt (24 studies), depleted savings (13 studies) and liquidated stocks/bonds (7 studies) in response to a cancer diagnosis. 41 studies reported changes to employment income; of these, 12 case-control studies reported varying  Initial declines in income tended to lessen over time.
    


          Conclusions:
        
      
      Cancer's impact on survivors' income is complex and time-varying. Longitudinal studies are needed to document the trend of initial declines in income, with declines lessening over time, and its variations. Study designs using standardised income measures and capturing treatment type and follow-up time will improve our understanding of cancer's impact on survivors' income."
55,Metastatic prostate cancer mimicking a subdural hematoma: A case report and literature review.,"Nunno A, Johnson MD, Wu G, Li YM.",https://pubmed.ncbi.nlm.nih.gov/29980476/,"Occurrences of metastatic prostate cancer imitating a subdural hematoma are limited to a small number of case reports, even though prostate cancer spreads to the dura more than other types of cancer. Here, we present the case of a 64 year-old male whose prostate carcinoma's metastasis mimicked a subdural hematoma, and he suffered a middle cerebral artery stroke. Prostate cancer's high rate of progression to the dura is disproportionate to its relatively low rate of brain metastasis. Furthermore, we explore the potential molecular implications of prostate cancer's propensity to spread to the dura."
56,The life history of 21 breast cancers.,"Nik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW, Raine K, Jones D, Marshall J, Ramakrishna M, Shlien A, Cooke SL, Hinton J, Menzies A, Stebbings LA, Leroy C, Jia M, Rance R, Mudie LJ, Gamble SJ, Stephens PJ, McLaren S, Tarpey PS, Papaemmanuil E, Davies HR, Varela I, McBride DJ, Bignell GR, Leung K, Butler AP, Teague JW, Martin S, Jönsson G, Mariani O, Boyault S, Miron P, Fatima A, Langerød A, Aparicio SA, Tutt A, Sieuwerts AM, Borg Å, Thomas G, Salomon AV, Richardson AL, Børresen-Dale AL, Futreal PA, Stratton MR, Campbell PJ; Breast Cancer Working Group of the International Cancer Genome Consortium.",https://pubmed.ncbi.nlm.nih.gov/22608083/,"Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis."
57,Is there an increased risk of cancer among spouses of patients with an HPV-related cancer: A systematic review.,"Mirghani H, Sturgis EM, Aupérin A, Monsonego J, Blanchard P.",https://pubmed.ncbi.nlm.nih.gov/28351568/," As these malignancies occur as a  Few studies have addressed this issue and whether the HPV-related cancer risk of partners of patients with HPV-related cancers is comparable to or greater than that of the general population.
    


           Out of 1055 references screened, 53 articles were found eligible for inclusion.
    


           Four of these registry studies showed an increased risk of cervical cancer in the partner while four did not. Among the four positive studies, odds ratios for the development of HPV-related cancer among spouses were between 2.6 and 6.7. One study showed an increased risk of tongue or tonsil cancer among husbands of women with cervical dysplasia or cancer. Overall the absolute risk increase in all these studies was small, on the order of 1-3%, although potentially underestimated. Indeed, all these studies have assessed partner's cancer risk at only one anatomical site whereas HPV- related malignancies can affect different locations.
    


          Conclusion:
        
      
      This systematic review suggests a small trend of increase risk in HPV-associated cancers among spouses of patients with HPV-related cancer."
58,Cancer's craving for sugar: an opportunity for clinical exploitation.,"Yeluri S, Madhok B, Prasad KR, Quirke P, Jayne DG.",https://pubmed.ncbi.nlm.nih.gov/19415328/,"More than 80 years ago, Otto Warburg described the phenomenon whereby cancer cells avidly take up glucose and produce lactic acid under aerobic conditions, a process subsequently referred to as the Warburg effect or aerobic glycolysis. The exact molecular mechanisms underlying cancers reliance on glycolysis remains unclear, but is likely a combination of an epigenetic response to the hypoxic tumour environment in combination with direct oncogenic stimulation. The aim of the current manuscript is to review the normal process of glycolysis and highlight the alterations that occur with malignant transformation, to consider the potential advantages of glycolytic respiration for cancer cell survival, and finally to explore areas where altered glucose metabolism can be exploited for clinical benefit."
59,Cancer's insatiable appetite.,"Locasale JW, Cantley LC, Vander Heiden MG.",https://pubmed.ncbi.nlm.nih.gov/19816448/,Seemingly unrelated mutations that drive cancer share the ability to promote nutrient uptake and metabolism conducive to cell growth.
60,Cancer outlook: an African perspective.,Walker AR.,https://pubmed.ncbi.nlm.nih.gov/7884774/,"In all western populations, mortality rates from cancer are high and even increasing: moreover, incidence rates of some cancers are also rising. As to propitiousness of preventive factors, genetic, gender, and age are beyond alteration: much the same applies to certain protective factors, e.g. late menarche, teenage pregnancy, high parity, long lactation, and greater physical activity. Influential dietary factors, i.e. intakes of energy, fat and fibre, often do not lend themselves to major alteration. Although reductions in smoking have occurred, the practice remains widespread and the intake of alcohol remains high. In developing countries, such as Africa, life-style changes are occurring and the population is incurring all risk factors mentioned. Whereas cancer is relatively uncommon in rural dwellers in developing countries, it is increasing in the huge peri-urban and urban populations due to changes in diet and way of life. Although knowledge should enable us to halve cancer's burden, hopes for meaningful changes are meagre. Survival time can be lengthened by more effective screening, especially of the very susceptible, and by further advances in treatment. Since known risk factors account for only half or less of occurrences of cancer, further rises, or, hopefully, welcome falls, could conceivably occur in the future. We must continue to try to educate the public regarding cancer avoidance: compliance by even a small proportion of those at risk could benefit huge numbers."
61,CYP1B1: A Promising Target in Cancer Drug Discovery.,"Fabris M, Luiza Silva M, de Santiago-Silva KM, de Lima Ferreira Bispo M, Goes Camargo P.",https://pubmed.ncbi.nlm.nih.gov/36655529/,"CYP1B1 plays an essential role in cancer's pathogenesis since it activates procarcinogens. Significantly, this enzyme catalyzes the hydroxylation of 17β-estradiol, leading to carcinogenic metabolites involved in carcinogenesis and cancer progression. Therefore, the inhibition of CYP1B1 activity is considered a therapeutic target for chemotherapy. In addition, CYP1B1 is overexpressed in hormone-dependent cancer cells and could be related to resistance to anticancer drugs. However, the activity of CYP1B1 in the tumor microenvironment can metabolize and activate prodrugs in cancer cells, providing more selectivity and being useful for chemoprevention or chemotherapy strategies. Furthermore, due to its importance in anticancer drug design, recent studies have reported using computational  Therefore, in this perspective, we highlight recent findings in developing CYP1B1 inhibitors (flavonoids, trans-stilbenes, estradiol derivatives, and carbazoles) and CYP1B1-activated prodrugs (a chalcone DMU-135 and an oxime DMAKO-20). Finally, we have analyzed their possible molecular interactions with this enzymatic target by molecular docking, which can help to design new active substances."
62,Sphingolipid metabolism in the development and progression of cancer: one cancer's help is another's hindrance.,"Piazzesi A, Afsar SY, van Echten-Deckert G.",https://pubmed.ncbi.nlm.nih.gov/34289244/,"Cancer development is a multistep process in which cells must overcome a series of obstacles before they can become fully developed tumors. First, cells must develop the ability to proliferate unchecked. Once this is accomplished, they must be able to invade the neighboring tissue, as well as provide themselves with oxygen and nutrients. Finally, they must acquire the ability to detach from the newly formed mass in order to spread to other tissues, all the while evading an immune system that is primed for their destruction. Furthermore, increased levels of inflammation have been shown to be linked to the development of cancer, with sites of chronic inflammation being a common component of tumorigenic microenvironments. In this Review, we give an overview of the impact of sphingolipid metabolism in cancers, from initiation to metastatic dissemination, as well as discussing immune responses and resistance to treatments. We explore how sphingolipids can either help or hinder the progression of cells from a healthy phenotype to a cancerous one."
63,Unveiling the potential of proteomic and genetic signatures for precision therapeutics in lung cancer management.,"Srivastava S, Jayaswal N, Kumar S, Sharma PK, Behl T, Khalid A, Mohan S, Najmi A, Zoghebi K, Alhazmi HA.",https://pubmed.ncbi.nlm.nih.gov/37866667/,"Lung cancer's enduring global significance necessitates ongoing advancements in diagnostics and therapeutics. Recent spotlight on proteomic and genetic biomarker research offers a promising avenue for understanding lung cancer biology and guiding treatments. This review elucidates genetic and proteomic lung cancer biomarker progress and their treatment implications. Technological strides in mass spectrometry-based proteomics and next-generation sequencing enable pinpointing of genetic abnormalities and abnormal protein expressions, furnishing vital data for precise diagnosis, patient classification, and customized treatments. Biomarker-driven personalized medicine yields substantial treatment improvements, elevating survival rates and minimizing adverse effects. Integrating omics data (genomics, proteomics, etc.) enhances understanding of lung cancer's intricate biological milieu, identifying novel treatment targets and biomarkers, fostering precision medicine. Liquid biopsies, non-invasive tools for real-time treatment monitoring and early resistance detection, gain popularity, promising enhanced management and personalized therapy. Despite advancements, biomarker repeatability and validation challenges persist, necessitating interdisciplinary efforts and large-scale clinical trials. Integrating artificial intelligence and machine learning aids analyzing vast omics datasets and predicting treatment responses. Single-cell omics reveal cellular connections and intratumoral heterogeneity, valuable for combination treatments. Biomarkers enable accurate diagnosis, tailored medicines, and treatment response tracking, significantly impacting personalized lung cancer care. This approach spurs patient-centered trials, empowering active patient engagement. Lung cancer proteomic and genetic biomarkers illuminate disease biology and treatment prospects. Progressing towards individualized efficient therapies is imminent, alleviating lung cancer's burden through ongoing research, omics integration, and technological strides."
64,Commentary: Role and communications of cancer hazard determinations.,"Samet JM, Berrington de Gonzalez A, Lunn RM, Schubauer-Berigan MK.",https://pubmed.ncbi.nlm.nih.gov/35016221/,"This commentary is written in response to a recent commentary in Carcinogenesis that provides several viewpoints on the International Agency for Research on Cancer's (IARC) Monographs program on cancer hazard identification. This commentary offers an alternative viewpoint of the role of cancer hazard identification derived from cancer epidemiology studies in risk characterization, as well as clarification on the previous commentary's interpretation of the purpose of the Monographs and other programs of cancer hazard identification and how IARC communicates the findings of the Monographs."
65,What do people fear about cancer? A systematic review and meta-synthesis of cancer fears in the general population.,"Vrinten C, McGregor LM, Heinrich M, von Wagner C, Waller J, Wardle J, Black GB.",https://pubmed.ncbi.nlm.nih.gov/27643482/," To elucidate fear's behavioural effects, we systematically reviewed and synthesised qualitative literature to explore what people fear about cancer.
    


          
    


          
    


          Conclusions:
        
      
      This view of cancer as 'an enemy' reprises the media's 'war on cancer' theme and may affect the acceptance of cancer early detection and prevention messages, since cancer's characteristics influenced whether 'fight' or 'flight' was considered appropriate."
66,Cancer screening in the elderly.,"Heflin MT, Cohen HJ.",https://pubmed.ncbi.nlm.nih.gov/11263800/,"A number of disease- and patient-specific factors need to be taken into account when cancer screening is considered in an older patient. They include the impact of aging on the cancer's biology and screening test performance, the patient's remaining years of life and candidacy for further diagnostic testing and available therapies, potential barriers to compliance with screening, and the patient's values and preferences about the screening."
67,Finding the perfect match between nanoparticles and microfluidics to respond to cancer challenges.,"Maia FR, Reis RL, Oliveira JM.",https://pubmed.ncbi.nlm.nih.gov/31843662/,"The clinical translation of new cancer theranostic has been delayed by inherent cancer's heterogeneity. Additionally, this delay has been enhanced by the lack of an appropriate in vitro model, capable to produce accurate data. Nanoparticles and microfluidic devices have been used to obtain new and more efficient strategies to tackle cancer challenges. On one hand, nanoparticles-based therapeutics can be modified to target specific cells, and/or molecules, and/or modified with drugs, releasing them over time. On the other hand, microfluidic devices allow the exhibition of physiologically complex systems, incorporation of controlled flow, and control of the chemical environment. Herein, we review the use of nanoparticles and microfluidic devices to address different cancer challenges, such as detection of CTCs and biomarkers, point-of-care devices for early diagnosis and improvement of therapies. The future perspectives of cancer challenges are also addressed herein."
68,Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype.,"Rodic S, Vincent MD.",https://pubmed.ncbi.nlm.nih.gov/28940517/,"Cancer cells exhibit a wide range of metabolic phenotypes, ranging from strict aerobic glycolysis to increased mitochondrial respiration. The cause and utility of this metabolic variation is poorly understood. Given that cancer cells experience heavy selection within their microenvironment, survival requires metabolic adaptation to both extracellular and intracellular conditions. Herein, we suggest that reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype. Intracellular ROS levels can be modified by an assortment of critical parameters including oxygenation, glucose availability and growth factors. ROS act as integrators of environmental information as well as downstream effectors of signaling pathways. Maintaining ROS within a narrow range allows malignant cells to enhance growth and invasion while limiting their apoptotic susceptibility. Cancer cells actively modify their metabolism to optimize intracellular ROS levels and thereby improve survival. Furthermore, we highlight distinct metabolic phenotypes in response to oxidative stress and their tumorigenic drivers."
69,Tumor Evolutionary Principles: How Intratumor Heterogeneity Influences Cancer Treatment and Outcome.,"Venkatesan S, Swanton C.",https://pubmed.ncbi.nlm.nih.gov/27249716/,"Recent studies have shown that intratumor heterogeneity contributes to drug resistance in advanced disease. Intratumor heterogeneity may foster the selection of a resistant subclone, sometimes detectable prior to treatment. Next-generation sequencing is enabling the phylogenetic reconstruction of a cancer's life history and has revealed different modes of cancer evolution. These studies have shown that cancer evolution is not always stochastic and has certain constraints. Consideration of cancer evolution may enable the better design of clinical trials and cancer therapeutics. In this review, we summarize the different modes of cancer evolution and how this might impact clinical outcomes. Furthermore, we will discuss several therapeutic strategies for managing emergent intratumor heterogeneity."
70,Knocking off cancer's HAT: CSS1477 disrupts oncogenic programs.,"Xu LK, Ntziachristos P.",https://pubmed.ncbi.nlm.nih.gov/38134880/,"EP300/CBP are histone acetyltransferases recruited onto chromatin by oncogenic transcription factors and control the transcriptional program via their activity in enhancer areas. In the December issue of Cancer Cell, Nicosia et al.1 offer new promise in targeting EP300/CBP using the small-molecule inhibitor CSS1477 in patients with blood tumors and no other therapeutic options."
71,European Journal of Cancer's Biennial report on soft tissue and visceral sarcomas or the rapid evolution of treatment concepts in sarcomas.,"Blay JY, Brahmi M, Ray-Coquard I.",https://pubmed.ncbi.nlm.nih.gov/27889671/,"Soft tissue and visceral sarcoma gather a large group of rare to very rare cancers and locally aggressive connective tissue tumours. Novel concepts on histological and molecular classification, optimal management of patients, systemic adjuvant and neoadjuvant treatment have been emerging in the last 5 years. In the present publication, we review and summarise significant changes which impact on disease management in this group of rare cancers."
72,Cancer in pregnancy: a review of the literature. Part I.,"Antonelli NM, Dotters DJ, Katz VL, Kuller JA.",https://pubmed.ncbi.nlm.nih.gov/8622836/,"Cancer is an important cause of death in the United States in women of childbearing age. Approximately 1 per 1000 pregnant women will develop cancer. This review (Part II follows in this issue) examines the diagnosis, prognosis, and management of cancer during pregnancy; both in terms of the cancer's effect on the pregnancy, and the pregnancy's effect on the cancer. Some diagnostic modalities and some therapies are problematic to the fetus and placenta. However, in most cases and the pregnancy can be managed concurrently with a good outcome for the baby and without compromising the mother's prognosis."
73,Inflammatory chemokines in cancer growth and progression.,Rollins BJ.,https://pubmed.ncbi.nlm.nih.gov/16510278/,"Leukocyte infiltration is a cardinal feature of almost all cancers. Chemokines are generally responsible for eliciting local accumulation of inflammatory cells and they appear to play the same role in the formation of peri- and intra-tumoural infiltrates. Chronic inflammation predisposes to cancer formation and progression, and it is likely that the chemokine system contributes to this process. In part, this may be a consequence of its ability to attract mononuclear cells to cancer sites, where they provide growth or angiogenic factors that enhance cancer development. However, accumulating evidence also points to a direct effect of chemokines on cancer cells that express chemokine receptors. In particular, some chemokines can activate anti-apoptotic pathways in these cells. By either mechanism, tumour cells that secrete and/or respond to chemokines would have a selective advantage. This provides another example of cancer's ability to co-opt host systems in order to promote tumour progression."
74,The Metabolism of Renal Cell Carcinomas and Liver Cancer.,"Nguyen T, Le A.",https://pubmed.ncbi.nlm.nih.gov/29946779/,"According to data from the American Cancer Society, cancer is one of the deadliest health problems globally. Annually, renal cell carcinoma (RCC) and liver cancer cause more than 100,000 and 800,000 deaths worldwide, respectively [1–4], creating an urgent need to develop effective therapeutic treatments to increase patient survival outcomes. New therapeutic treatments are expected to address a major factor contributing to cancer’s resistance to standard therapies: oncogenic heterogeneity. Because gene expression can vary tremendously among different types of cancers, different patients of the same tumor type, and even within individual tumors, various metabolic phenotypes can emerge, making single-therapy approaches insufficient. This heterogeneity translates into changes in the landscape of metabolic enzymes and biomolecules within both the cancer cell and tumor microenvironment. Novel strategies targeting the diverse metabolism of cancers aim to overcome this obstacle, and though some have yielded positive  Nonetheless, the metabolic-oriented research focusing on these cancers has offered different, fresh new perspectives, which are expected to contribute heavily to the development of new therapeutic treatments."
75,Cancer is an adaptation that selects in animals against energy dissipation.,Muller AWJ.,https://pubmed.ncbi.nlm.nih.gov/28673566/,"As cancer usually follows reproduction, it is generally assumed that cancer does not select. Graham has however argued that juvenile cancer, which precedes reproduction, could during evolution have implemented a ""cancer selection"" that  We modify the cancer selection mechanism to the posited ""cancer adaptation"" mechanism, in which juvenile mortality is enhanced through the diminished care received by juveniles from their (grand) parents when these suffer from cancer in old age. Moreover, it is posited that the cancer adaptation selects against germline ""dissipative genes"", genes that  Cancer's progression is interpreted as a cascade at increasing scale of repeated amplification of energy dissipation, a cascade involving heat shock, the Warburg effect, the cytokine IL-6, tumours, and hypermetabolism. Disturbance of any physiological process must enhance energy dissipation if the animal remains functioning normally, what explains multicausality, why ""everything gives you cancer"". The hypothesis thus comprises two newly invoked partial processes-diminished (grand) parental care and dissipation amplification-and  Due to this benefit, cancer would essentially be an adaptation, and not a genetic disease, as assumed in the ""somatic mutation theory"". Cancer by somatic mutations is only a side process. The cancer adaptation hypothesis is substantiated by (1) cancer's extancy, (2) the failure of the somatic mutation theory, (3) cancer's initiation by a high temperature, (4) the interpretation of cancer's progression as a thermal process, and (5) the interpretation of tumours as organs that implement thermogenesis. The hypothesis could in principle be verified by monitoring in a population over several generations (1) the presence of dissipative genes, (2) the incidence of cancer, and (3) the beneficial effect of dissipative gene removal by cancer on starvation/famine survival."
76,The cancer's nervous tooth: Considering the neuronal crosstalk within tumors.,"Entschladen F, Palm D, Niggemann B, Zaenker KS.",https://pubmed.ncbi.nlm.nih.gov/18249004/,"The nervous system is a superordinate organ in the body that controls the function of virtually all other organs and tissues. In the past, the role of the nervous system in cancer development and progression has largely been ascribed to an immunosuppressive function, which saps the immune system's ability to respond to a tumor. However, it is now clear that direct interactions of tumor cells with nerve cells occur, too. We herein provide arguments for the hypothesis that tumors initiate their own innervation by the release of neurotrophic factors including the nerve growth factor, the brain-derived growth factor, and the vascular endothelial growth factor. By this process, which we have termed neoneurogenesis, the tumor cells get in close contact to the nerve cells, forming a neuro-neoplastic synapse. Through these synapses, neurotransmitters are directly supplied to the tumors, which has impact on tumor growth and metastasis formation."
77,Targeting cancer metabolism--aiming at a tumour's sweet-spot.,"Jones NP, Schulze A.",https://pubmed.ncbi.nlm.nih.gov/22207221/,"Targeting cancer metabolism has emerged as a hot topic for drug discovery. Most cancers have a high demand for metabolic inputs (i.e. glucose/glutamine), which aid proliferation and survival. Interest in targeting cancer metabolism has been renewed in recent years with the discovery that many cancer-related (e.g. oncogenic and tumour suppressor) pathways have a profound effect on metabolism and that many tumours become dependent on specific metabolic processes. Considering the recent increase in our understanding of cancer metabolism and the increasing knowledge of the enzymes and pathways involved, the question arises: could metabolism be cancer's Achilles heel? During recent years, interest into the possible therapeutic benefit of targeting metabolic pathways in cancer has increased dramatically with academic and pharmaceutical groups actively pursuing this aspect of tumour physiology. Therefore, what has fuelled this revived interest in targeting cancer metabolism and what are the major advances and potential challenges faced in the race to develop new therapeutics in this area? This review will attempt to answer these questions by summarising recent developments in this field. We aim to illustrate why we, and others, believe that targeting metabolism in cancer presents such a promising therapeutic rationale."
78,"Nutrition and Dietary Intervention in Cancer: Gaps, Challenges, and Future Perspectives.","Zeb F, Mehreen A, Naqeeb H, Ullah M, Waleed A, Awan UA, Haider A, Naeem M.",https://pubmed.ncbi.nlm.nih.gov/39133412/,"The term ""cancer"" refers to the state in which cells in the body develop mutations and lose control over their replication. Malignant cancerous cells invade in various other tissue sites of the body. Chemotherapy, radiation, and surgery are the first-line modalities for the majority of solid cancers. These treatments work by mitigating the DNA damage of cancerous cells, but they can also cause harm to healthy cells. These side effects might be immediate or delayed, and they can cause a high rate of morbidity and mortality. Dietary interventions have a profound impact on whole-body metabolism, including immunometabolism and oncometabolism which have been shown to reduce cancer growth, progression, and metastasis in many different solid tumor models with promising outcomes in early phase clinical studies. Dietary interventions can improve oncologic or quality-of-life outcomes for patients that are undergoing chemotherapy or radiotherapy. In this chapter, we will focus on the impact of nutritional deficiencies, several dietary interventions and their proposed mechanisms which are used as a novel therapy in controlling and managing cancers."
79,"Neoplastic ""Black Ops"": cancer's subversive tactics in overcoming host defenses.","Biragyn A, Longo DL.",https://pubmed.ncbi.nlm.nih.gov/22257681/,"Metastatic cancer is usually an incurable disease. Cancers have a broad repertoire of subversive tactics to defeat the immune system. They mimic self, they down-regulate MHC molecules so that T cells are blind to their presence, they interfere with antigen presentation, and they produce factors that can kill T cells or paralyze their response to antigens. Furthermore, the same powerful machinery designed to prevent harmful autoimmune responses is also acting to protect cancers. In particular, cancer is protected with the help of so-called regulatory immune cells. These unique subsets of cells, represented by almost every immune cell type, function to control responses of effector immune cells. In this review, we will discuss the evidence that cancer actively promotes cross-talk of regulatory immune cells to evade immunosurveillance. We will also discuss the role of a newly described cell type, regulatory B cells, by emphasizing their importance in suppression of antitumor immune responses. Thus, cancer not only directly suppresses immune function, but also recruits components of the immune system to become traitors and protect the tumor from immune attack."
80,Genome sequencing and cancer.,Mardis ER.,https://pubmed.ncbi.nlm.nih.gov/22534183/,"New technologies for DNA sequencing, coupled with advanced analytical approaches, are now providing unprecedented speed and precision in decoding human genomes. This combination of technology and analysis, when applied to the study of cancer genomes, is revealing specific and novel information about the fundamental genetic mechanisms that underlie cancer's development and progression. This review outlines the history of the past several years of development in this realm, and discusses the current and future applications that will further elucidate cancer's genomic causes."
81,Improving the International Agency for Research on Cancer's consideration of mechanistic evidence.,"Goodman J, Lynch H.",https://pubmed.ncbi.nlm.nih.gov/28162991/," This framework is useful for identifying and organizing large bodies of literature on carcinogenic mechanisms, but it lacks sufficient guidance for conducting evaluations that fully integrate mechanistic evidence into hazard assessments.
    


          
    


          Discussion:
        
      
      While the framework is useful for organizing mechanistic evidence, its lack of guidance for implementation limits its utility for understanding human carcinogenic potential. Specifically, it does not include explicit guidance for evaluating the biological significance of mechanistic endpoints, inter- and intra-individual variability, or study quality and relevance. It also does not explicitly address how mechanistic evidence should be integrated with other realms of evidence. Because mechanistic evidence is critical to understanding human cancer hazards, we recommend that IARC develop transparent and systematic guidelines for the use of this framework so that mechanistic evidence will be evaluated and integrated in a robust manner, and concurrently with other realms of evidence, to reach a final human cancer hazard conclusion.
    


          Conclusions:
        
      
      IARC does not currently provide a standardized approach to evaluating mechanistic evidence. Incorporating the recommendations discussed here will make IARC analyses of mechanistic evidence more transparent, and lead to assessments of cancer hazards that reflect the weight of the scientific evidence and allow for scientifically defensible decision-making."
82,Metabolic modulation of cancer: a new frontier with great translational potential.,"Kinnaird A, Michelakis ED.",https://pubmed.ncbi.nlm.nih.gov/25586106/,"Metabolic oncology is an exciting new field in cancer research, offering a new window to cancer's molecular plasticity and promise for the development of effective, cancer-selective therapies and novel biomarkers. It is based on the realization that cancer's unique metabolism (known since Warburg's report in 1923) with suppression of mitochondrial glucose oxidation and upregulation of cytoplasmic glycolysis is not a secondary but a primary event, offering many growth advantages to cancer cells. Many mechanisms have been revealed, including growth factors, oncogenes, and mutations, all contributing to a suppression of mitochondria, similar to what takes place in hypoxia. This suppression leads to inhibition of mitochondria-driven apoptosis, promotes proliferation, and enhances angiogenesis and metastatic potential. A number of molecular tools and small molecules targeting metabolic enzymes, including pyruvate kinase, pyruvate dehydrogenase kinase, isocitrate dehydrogenase, and lactate dehydrogenase, have been developed, inhibiting cancer growth in vitro and in vivo in several cancer types. Several have already entered early-phase trials, a great translational success considering the young age of the field (less than 10 years). Here we review the mechanisms and effects of these metabolic modulators and the rationale for further development. This rapidly accumulating knowledge allows some optimism that this may prove to be a paradigm shift in the way we understand and treat cancer."
83,A combined biological and clinical rationale for evaluating metastasis directed therapy in the management of oligometastatic prostate cancer.,"Kucharczyk MJ, So J, Gravis G, Sweeney C, Saad F, Niazi T.",https://pubmed.ncbi.nlm.nih.gov/32858066/,"The initial management of potentially oligometastatic hormone sensitive prostate cancer has been complicated by rapid advances in the field. Clinically, subgroup analyses of two randomized control trials have suggested that a specific synchronous oligometastatic prostate cancer state may be predictive for benefit from radiation to the primary. Further exploration of metastasis-directed therapy has been supported for various prostate cancer populations among three phase II clinical trials. There are numerous caveats in applying this evidence, a dilemma being addressed by present and upcoming clinical trials. Despite existing clinical equipoise and an avenue to address this uncertainty, the temptation to combine this evidence off-trial exists. Matters have become more complex as our ability to evaluate metastatic disease and tumour biology have also matured. This paper synthesizes our understanding of prostate cancer's natural history into a model which rationalizes both the theoretical benefits and limitations of metastasis directed therapy. We postulate that a metastatic prostate cancer's total disease activity is primarily driven by the combination of its burden of disease and underlying biology, namely genomic instability, then highlight the numerous remaining questions that challenge this hypothesis. This review focuses on harmonizing the language used to describe the disease, the current efforts exploring this hypothesis, and the need for clinical trial participation to appropriately advance patient care."
84,Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis.,Lin PP.,https://pubmed.ncbi.nlm.nih.gov/32599893/,"Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from ""cancerization of stromal endothelial cells"" and ""endothelialization of carcinoma cells"" in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy."
85,Cellular and molecular mechanisms in cancer immune escape: a comprehensive review.,"Bhatia A, Kumar Y.",https://pubmed.ncbi.nlm.nih.gov/24325346/,"Immune escape is the final phase of cancer immunoediting process wherein cancer modulates our immune system to escape from being destroyed by it. Many cellular and molecular events govern the cancer's evasion of host immune response. The tumor undergoes continuous remodeling at the genetic, epigenetic and metabolic level to acquire resistance to apoptosis. At the same time, it effectively modifies all the components of the host's immunome so as to escape from its antitumor effects. Moreover, it induces accumulation of suppressive cells like Treg and myeloid derived suppressor cells and factors which also enable it to elude the immune system. Recent research in this area helps in defining the role of newer players like miRNAs and exosomes in immune escape. The immunotherapeutic approaches developed to target the escape phase appear quite promising; however, the quest for a perfect therapeutic agent that can achieve maximum cure with minimal toxicity continues."
86,Open questions and novel concepts in oral cancer surgery.,"Tirelli G, Zacchigna S, Biasotto M, Piovesana M.",https://pubmed.ncbi.nlm.nih.gov/26003319/,"The persistence of cancerous cells after surgery in oral squamous cell carcinoma (OSCC) represents a major challenge, as it often leads to local recurrences and secondary primary tumors, which are eventually responsible for a large proportion of deaths. This persistence is currently evaluated by histological analyses. In this review we discuss some important pitfalls of the histopathological analysis, such as margin evaluation, specimen shrinkage and T staging. In addition, we critically analyze the appropriateness of current surgical techniques in relation to the concept of field cancerization. Finally, we describe some novel imaging and molecular approaches, which might be useful in tailoring surgical resections and encourage the use of OSCC animal models to explore and provide proof of concept of the feasibility and potential clinical utility of innovative surgical protocols."
87,Bioclinical markers in breast cancer: updates and perspectives.,"Di Vita M, Berretta M, Zanghi A, Cacopardo B, Cavallaro A, Lombardi D, Lo Menzo E, Cappellani A.",https://pubmed.ncbi.nlm.nih.gov/20036952/,"Molecular studies have definitely changed our knowledge of the biology of cancers, and breast cancer's tremendous social impact has stimulated a large mass of research. Classic markers have opened a road, but their usefulness appears limited to prognosis or follow up, while several new markers, both genetic and molecular, are assuming different, yet still controversial, importance: they may play a major role in the surveillance of subjects at risk, in detecting primary or recurrent cancers, and in predicting the need of adjuvant therapy, or the response to therapy. ."
88,Diagnosing and exploiting cancer's addiction to blocks in apoptosis.,Letai AG.,https://pubmed.ncbi.nlm.nih.gov/18202696/,"Cancer cells survive despite violating rules of normal cellular behaviour that ordinarily provoke apoptosis. The blocks in apoptosis that keep cancer cells alive are therefore attractive candidates for targeted therapies. Recent studies have significantly increased our understanding of how interactions among proteins in the BCL2 family determine cell survival or death. It is now possible to systematically determine how individual cancers escape apoptosis. Such a determination can help predict not only whether cells are likely to be killed by antagonism of BCL2, but also whether they are likely to be sensitive to chemotherapy that kills by the intrinsic apoptotic pathway."
89,[Breast cancer and pregnancy. Review of the literature].,"Dequanter D, Hertens D, Veys I, Nogaret JM.",https://pubmed.ncbi.nlm.nih.gov/11217201/,"
    


          Materials and 
    


           No histological difference, between patients with pregnancy-associated breast cancer and patients with non-pregnancy-associated breast cancer, was diagnosed.
    


          Conclusion:
        
      
      The treatment is linked to the effects of adjuvant therapy on the fetus."
90,Introducing Five New Cancer Grand Challenges Teams.,"Scott D, Singer DS.",https://pubmed.ncbi.nlm.nih.gov/38446429/,"Cancer Grand Challenges is an international funding initiative that aims to unite the world's best scientists to tackle some of cancer's toughest problems by funding team science on a global scale. Here, we discuss the five newly funded teams and the challenges they will address over the coming years."
91,Biology of lung cancer with implications for new therapies.,"Aberle MF, McLeskey SW.",https://pubmed.ncbi.nlm.nih.gov/12692661/,"Purpose/
    


          Data sources:
        
      
      Published articles, abstracts, book chapters, lectures, and personal experiences with 
    


          Data synthesis:
        
      
      Lung cancer is the number one cause of cancer deaths for men and women in the United States, with minimal changes in the five-year survival rate during the past decade. New understanding of the biologic process of lung cancer is providing potential new therapies that many hope will lead to increased survival for patients with lung cancer.
    


          Conclusions:
        
      
      Exciting new therapies for lung cancer are being developed that target specific biologic processes of lung cancer.
    


          Implications for nursing:
        
      
      When nurses are familiar with the rationale behind biologic therapies, they can understand the drugs, assess toxicities, and help patients make educated decisions about therapeutic alternatives."
92,Clinical symptoms and comorbidity: significance for the prognostic classification of cancer.,"Piccirillo JF, Feinstein AR.",https://pubmed.ncbi.nlm.nih.gov/8608472/," Because the cornerstone of cancer staging is the Tumor, Node, Metastasis (TNM) system, this article is devoted to a brief history of the system, to important concepts of clinical biology that should be included in classification systems for cancer, and to sources and potential solutions for current problems.
    


          
    


           Important prognostic information can be determined by a patient's symptoms, which reflect some of a tumor's biologic behavior, and by comorbidity that is not a feature of the cancer itself. Five reasons were identified for the adherence to a strictly morphologic staging system.
    


          Conclusions:
        
      
      Widespread use of the TNM system during the past 30 years has unquestionably helped to standardize the classification of cancer and to improve prognostic estimates. Nevertheless, the estimates remain relatively imprecise, impairing the evaluation of treatment effectiveness. A prime scientific challenge in current cancer staging is to incorporate the omitted patient-based variables to produce an improved clinical system of classification."
93,We need to talk about lung cancer's cholesterol-hoarding problem.,Fessler MB.,https://pubmed.ncbi.nlm.nih.gov/37267910/,"Proliferative cells require excess cholesterol to support rapid membrane biogenesis. Using a mutant KRAS mouse model of non-small cell lung cancer, Guilbaud et al. show that lung cancers accumulate cholesterol by locally and distally reprogramming lipid trafficking and that cholesterol-removing interventions may hold promise as a therapeutic strategy."
94,Neutrophils fan cancer's flames.,"Wculek SK, Malanchi I.",https://pubmed.ncbi.nlm.nih.gov/26194723/,"A new study published in this issue of The EMBO Journal looks into the crosstalk between inflammation and cancer (Antonio et al, 2015). By using a zebrafish melanoma model, the authors reveal that neutrophils recruited at the wound site directly interact with cells undergoing oncogenic transformation and provide them with a paracrine proliferative support. Importantly, the authors demonstrate the clinical relevance of this association, showing that neutrophil infiltration has an independent prognostic value for human melanoma. This study reinforces the notion that inflammation flames carcinogenesis, which might have important implications for the improvement of antitumour therapies."
95,CancerNet: a unified deep learning network for pan-cancer diagnostics.,"Gore S, Azad RK.",https://pubmed.ncbi.nlm.nih.gov/35698059/," Early detection of cancer and localization of the tissue of its origin are key to effective treatment. Here, we leverage technological advances in machine learning or artificial intelligence to design a novel framework for cancer diagnostics. Our proposed framework detects cancers and their tissues of origin using a unified model of cancers encompassing 33 cancers represented in The Cancer Genome Atlas (TCGA). Our model exploits the learned features of different cancers reflected in the respective dysregulated epigenomes, which arise early in carcinogenesis and differ remarkably between different cancer types or subtypes, thus holding a great promise in early cancer detection.
    


           Furthermore, our model distinguishes cancers from pre-cancerous lesions to metastatic tumors and discriminates between hypomethylation changes due to age related epigenetic drift and true cancer.
    


          Conclusions:
        
      
      Beyond detection of primary cancers, our proposed computational model also robustly detects tissues of origin of secondary cancers, including metastatic cancers, second primary cancers, and cancers of unknown primaries. Our assessment revealed the ability of this model to characterize pre-cancer samples, a significant step forward in early cancer detection. Deployed broadly this model can deliver accurate diagnosis for a greatly expanded target patient population."
96,Treatment options for localized prostate cancer.,"Mohan R, Schellhammer PF.",https://pubmed.ncbi.nlm.nih.gov/21842788/,"In the United States, more than 90 percent of prostate cancers are detected by serum prostate-specific antigen testing. Most patients are found to have localized prostate cancer, and most of these patients undergo surgery or radiotherapy. However, many patients have low-risk cancer and can follow an active surveillance protocol instead of undergoing invasive treatments. Active surveillance is a new concept in which low-risk patients are closely followed and proceed to intervention only if their cancer progresses. Clinical guidelines can help in selecting between treatment or active surveillance based on the cancer's stage and grade, the patient's prostate-specific antigen level, and the comorbidity-adjusted life expectancy. Radical prostatectomy or external beam radiation therapy is recommended for higher-risk patients. These treatments are almost equivalent in effectiveness, but have different adverse effect profiles. Brachytherapy is an option for low- and moderate-risk patients. Evidence is insufficient to determine whether laparoscopic or robotic surgery or cryotherapy is superior to open radical prostatectomy."
97,Multifocal Primary Prostate Cancer Exhibits High Degree of Genomic Heterogeneity.,"Løvf M, Zhao S, Axcrona U, Johannessen B, Bakken AC, Carm KT, Hoff AM, Myklebost O, Meza-Zepeda LA, Lie AK, Axcrona K, Lothe RA, Skotheim RI.",https://pubmed.ncbi.nlm.nih.gov/30181068/,"
    


          
    


          Design, setting, and participants:
        
      
      High-coverage whole-exome sequencing of 153 frozen tissue samples, taken from two to three distinct tumor foci and one non-cancerous area from each of 41 patients, covering a total of 89 tumor foci.
    


          Outcome measurements and statistical analysis:
        
      
      State-of-the-art bioinformatics tools for mutation calling and copy number determination from whole-exome sequencing data.
    


           The few point mutations shared across tumor foci were seldom in cancer-critical genes.
    


          Conclusions:
        
      
      In this first large genomic heterogeneity study of primary prostate cancer, we observe that different tumor foci within the same patient are genetically distinct, only rarely sharing any somatic gene mutations, including those in cancer driver genes. This heterogeneity affects how genomics-based management of prostate cancer can be implemented, as information from all tumor foci is necessary to draw valid conclusions about the cancer's genomic alterations.
    


          Patient summary:
        
      
      Most primary prostate cancers consist of multiple tumors within the same organ, but little is known about their relationships. We have compared the sets of gene mutations among such tumors and found that they only exceptionally have any in common. This will influence treatment decisions in the future as each tumor's mutations will render it unique and have to be considered to gain the best treatment "
98,Management of non-melanoma skin cancer in immunocompromised solid organ transplant recipients.,"Bangash HK, Colegio OR.",https://pubmed.ncbi.nlm.nih.gov/22592596/,"The management of non-melanoma skin cancers (NMSCs) in solid organ transplant recipients (OTRs) presents a variety of clinical challenges for physicians. OTRs are at a 65-fold increased risk for developing cutaneous squamous cell carcinomas (SCC), the most common NMSC that develops after transplantation. Risk factors contributing to the development of NMSCs in OTRs include a past medical history of any previous skin cancer, a personal history of significant sun exposure and a fair skin complexion or phototype. Further, greater immunosuppressive medication levels lead to an increased risk of NMSCs. Among immunosuppressants, specific older agents such as azathioprine and cyclosporine may increase the risk of developing NMSCs in contrast to newer agents such as sirolimus. Early skin biopsy and treatment of premalignant and malignant lesions are essential for treating these patients successfully. In this regard, the concept of field cancerization has been instructive in broadening treatments to include entire affected areas rather than individual lesions given that the areas with significant ultraviolet irradiation will continue to develop numerous individual precancerous and cancerous lesions. Field therapy with photodynamic therapy or topical 5-fluorouracil, imiquimod or diclofenac is often used in OTRs according to individual patient tolerability. Prompt excision or Mohs micrographic surgery is the standard of care of primary, uncomplicated squamous cell and basal cell carcinomas. For patients with in-transit or metastatic squamous cell carcinomas, adjuvant radiation, chemotherapy, and staging by sentinel lymph node dissection may be employed. For patients who develop numerous SCC per year, chemoprophylaxis can be effective in limiting the burden of disease. In consultation with the multidisciplinary transplant team, the immunosuppressive regimen can be revised to lower overall immunosuppression or altered to include newer drugs that have decreased oncogenic potential in OTRs. The greatest impact may be made by the prevention of NMSCs through simple, but rigorous, patient education on the benefits of UV protection, periodic self-skin examinations, and regular follow-ups. Accordingly, vitamin D and calcium supplementation should also be incorporated in transplant recipients. Management of OTRs requires patient education, frequent motivation for vigilance, regular follow-up, and interdisciplinary collaboration between transplant surgeons, nephrologists, hepatologists, cardiologists, transplant nurses, dermatologists, oncologists, pharmacists, and other relevant physicians ideally orchestrated by the essential transplant coordinators."
99,The role of the microscopic world: Exploring the role and potential of intratumoral microbiota in cancer immunotherapy.,"Zhang L, Yu L.",https://pubmed.ncbi.nlm.nih.gov/38758914/,"Microorganisms, including bacteria, viruses, and fungi, coexist in the human body, forming a symbiotic microbiota that plays a vital role in human health and disease. Intratumoral microbial components have been discovered in various tumor tissues and are closely linked to the occurrence, progression, and treatment  The intratumoral microbiota can enhance antitumor immunity through mechanisms such as activating the stimulator of interferon genes signaling pathway, stimulating T and NK cells, promoting the formation of TLS, and facilitating antigen presentation. Conversely, the intratumoral microbiota might suppress antitumor immune responses by increasing reactive oxygen species levels, creating an anti-inflammatory environment, inducing T cell inactivation, and enhancing immune suppression, thereby promoting cancer progression. The impact of intratumoral microbiota on antitumor immunity varies based on microbial composition, interactions with cancer cells, and the cancer's current state. A deep understanding of the complex interactions between intratumoral microbiota and antitumor immunity holds the potential to bring new therapeutic strategies and targets to cancer immunotherapy."
100,The molecular and cellular basis of human lung cancer.,Gazdar AF.,https://pubmed.ncbi.nlm.nih.gov/8166465/,"Lung cancer arises after a series of morphological changes, which take several years to progress from normal epithelium to invasive cancer. The morphological changes progress from hyperplasia, to metaplasia, to dysplasia, to carcinoma in situ, to invasive cancer and finally to metastatic cancer. Multiple molecular changes have been documented in lung cancers, both small cell (SCLC) and non-small cell (NSCLC) types. The number of changes has been estimated to be in double digits. How can so many changes develop in one cell? One possible explanation is the ""field cancerization"" theory, that states that all or much of the aerodigestive tract epithelium has been mutagenized, perhaps as the  The molecular changes include activation of dominant oncogenes (myc family, K-ras and HER/2/neu genes), as well as loss of recessive growth regulatory genes or anti-oncogenes (p53, and rb as well as unidentified gene or genes on chromosome 3). However, cytogenetic and molecular genetic studies indicate that multiple other specific sites of actual or potential DNA loss may be present in lung cancers. Many of the well characterized molecular changes may function as negative prognostic factors for survival in subsets of lung cancers. Other changes may include development of drug resistance, and production of growth factors and their receptors. It is tempting to associate specific molecular changes with specific morphological changes, as has been attempted in the colon. However, because of the difficulties in serially sampling the respiratory tract, only a modest amount of data has been collected to date. It appears that deletions of chromosome 3p, hyperproliferation and aneuploidy are early changes, while p53 mutations appear later in the preneoplastic cascade. Documentation of intermediate markers for lung cancer and prospective studies of their prognostic effects will be necessary for the design of rational chemoprevention trials."
101,Lipid Metabolism Fuels Cancer's Spread.,"Li Z, Kang Y.",https://pubmed.ncbi.nlm.nih.gov/28178563/,"The ability to prospectively identify metastasis-initiating cells is essential for developing new anti-metastasis therapeutics. In a recent issue of Nature, Pascual et al. (2017) demonstrate that the fatty acid receptor CD36 marks a subpopulation of cancer cells with unique metastasis-initiating potential, highlighting a key role of lipid metabolism in metastatic colonization."
102,Biology and chemoprevention of lung cancer.,Siegfried JM.,https://pubmed.ncbi.nlm.nih.gov/9438689/,"Advances in cell and molecular biology have increased our understanding of the multiple events that lead to the development of lung cancer. The field cancerization theory suggests that multiple genetic abnormalities occur throughout the respiratory epithelium as a  Because of this diffuse injury throughout the lung, systemic therapy that could halt or reverse the development of cancerous changes may be effective in preventing lung cancer. This article summarizes the chemoprevention agents that have been used in clinical trials to prevent lung cancer of the head and neck. Biomarkers that have been suggested as intermediate end points in evaluating the effectiveness of chemoprevention agents are also discussed."
103,Field cancerization in mammary carcinogenesis - Implications for prevention and treatment of breast cancer.,"Rivenbark AG, Coleman WB.",https://pubmed.ncbi.nlm.nih.gov/23142414/,"The natural history of breast cancer unfolds with the development of ductal carcinoma in situ (DCIS) in normal breast tissue, and evolution of this pre-invasive neoplasm into invasive cancer. The mechanisms that drive these processes are poorly understood, but evidence from the literature suggests that mammary carcinogenesis may occur through the process of field cancerization. Clinical observations are consistent with the idea that (i) DCIS may arise in a field of altered breast epithelium, (ii) narrow surgical margins do not remove the entire altered field (contributing to recurrence and/or disease progression), and (iii) whole-breast radiation therapy is effective in elimination of the residual field of altered cells adjacent to the resected DCIS. Molecular studies suggest that the field of altered breast epithelial cells may carry cancer-promoting genetic mutations (or other molecular alterations) or cancer promoting epimutations (oncogenic alterations in the epigenome). In fact, most breast cancers develop through a succession of molecular events involving both genetic mutations and epimutations. Hence, in hereditary forms of breast cancer, the altered field reflects the entire breast tissue which is composed of cells with a predisposing molecular lesion (such as a BRCA1 mutation). In the example of a BRCA1-mutant patient, it is evident that local resection of a DCIS lesion or localized but invasive cancer will not  In sporadic breast cancer patients, the mechanistic basis for the altered field may not be so easily recognized. Nonetheless, identification of the nature of field cancerization in a given patient may guide clinical intervention. Thus, patients with DCIS that develops in response to an epigenetic lesion (such as a hypermethylation defect affecting the expression of tumor suppressor genes) might be treated with epigenetic therapy to normalize the altered field and reduce the risk of secondary occurrence of DCIS or progression to invasive cancer."
104,Forkhead box-O transcription factor: critical conductors of cancer's fate.,"Weidinger C, Krause K, Klagge A, Karger S, Fuhrer D.",https://pubmed.ncbi.nlm.nih.gov/18775975/,"Cells have evolved elaborated mechanisms to coordinate the cellular answer of either survival or apoptosis. Recent concepts of human carcinogenesis have suggested disturbances in these cellular relays as a potential link to cellular dedifferentiation and uncontrolled proliferation. Forkhead box-O transcription factors (FOXOs) play an important role in tumour suppression by regulating the expression of genes involved in stress resistance, DNA damage repair, cell cycle arrest and apoptosis. The specific regulation of FOXO function is tightly controlled by posttranslational modifications such as phosphorylation, acetylation and ubiquitination. Loss of FOXO function has recently been identified in several human cancers. In this review, we will give an overview about recent progress in the understanding of function and regulation of FOXOs, as well as their role in carcinogenesis. Furthermore, we will discuss a potential clinical use of FOXOs by therapeutically restoring their tumour suppressive properties."
105,Mapping cutaneous field carcinogenesis of nonmelanoma skin cancer using mesoscopic imaging of pro-inflammation cues.,"Shugar AL, Konger RL, Rohan CA, Travers JB, Kim YL.",https://pubmed.ncbi.nlm.nih.gov/38610095/,"Nonmelanoma skin cancers remain the most widely diagnosed types of cancers globally. Thus, for optimal patient management, it has become imperative that we focus our efforts on the detection and monitoring of cutaneous field carcinogenesis. The concept of field cancerization (or field carcinogenesis), introduced by Slaughter in 1953 in the context of oral cancer, suggests that invasive cancer may emerge from a molecularly and genetically altered field affecting a substantial area of underlying tissue including the skin. A carcinogenic field alteration, present in precancerous tissue over a relatively large area, is not easily detected by routine visualization. Conventional dermoscopy and microscopy imaging are often limited in assessing the entire carcinogenic landscape. Recent efforts have suggested the use of noninvasive mesoscopic (between microscopic and macroscopic) optical imaging  This concise review covers major types of mesoscopic optical imaging modalities capable of assessing pro-inflammatory cues by quantifying blood haemoglobin parameters and hemodynamics. Importantly, these imaging modalities demonstrate the ability to detect angiogenesis and inflammation associated with actinically damaged skin. Representative  Overall, mesoscopic optical imaging modalities assessing chronic inflammatory hyperemia can enhance the understanding of cutaneous field carcinogenesis, offer a window of intervention and monitoring for actinic keratoses and nonmelanoma skin cancers and maximise currently available treatment options."
106,Stem cells and lung cancer: future therapeutic targets?,"Alison MR, Lebrenne AC, Islam S.",https://pubmed.ncbi.nlm.nih.gov/19653862/,"In both the UK and USA more people die of lung cancer than any other type of cancer. Lung cancer's high mortality rate is also reflected on a global scale, with lung cancer accounting for more than 1 million deaths per year. In tissues with ordered structure such a lung epithelia, it is likely that the cancers have their origins in normal adult stem cells, and then the tumours themselves are maintained by a population of malignant stem cells - so-called cancer stem cells. This review examines both these postulates in animal models and in the clinical setting, noting that stem cell niches appear to foster tumour development, and that drug resistance can often be attributed to malignant cells with stem cell properties."
107,Cancer's impact on employment and earnings--a population-based study from Norway.,"Syse A, Tretli S, Kravdal Ø.",https://pubmed.ncbi.nlm.nih.gov/18792789/," Of particular concern is cancer's effect on productivity and work ability, which in turn is important for persons' financial situation, life satisfaction, and social relationships. We explored the extent to which Norwegian cancer survivors stay affiliated to working life compared to the cancer-free population, and quantified cancer-associated earning declines.
    


           These analyses revealed that a cancer diagnosis was strongly associated with not being employed. Log-linear regression models were used to estimate the effect of cancer on labor earnings in 2001 for those employed. Cancer was associated with a 12% decline in earnings overall. Leukemia, lymphomas, lung, brain, bone, colorectal, and head-and-neck cancer  Earning declines were strongly associated with educational level. In addition, linear regression models were used to estimate differentials in earnings before and after cancer. These 
    


          Conclusion and implications for cancer survivors:
        
      
      Cancer survivors are less likely to be employed than the cancer-free population, and undertake modifications in their employment, e.g. reduce work-hours or hold lower-wage jobs, which  A social class gradient is present and must be addressed to accommodate appropriate intervention from welfare societies."
108,Critical care of the patient with lung cancer.,Nally AT.,https://pubmed.ncbi.nlm.nih.gov/8697117/,"Critical care of patients with lung cancer requires a knowledge of the behavior of this malignancy and the implications of several prognostic variables. Lung cancer's location, cellular characteristics, and metastatic patterns predispose patients to many emergencies that may require critical care intervention. In this article, the author presents important  Included is a discussion of complications such as spinal cord compression, superior vena cava syndrome, airway obstruction, pleural effusions, and neoplastic cardiac tamponade, with an overview of common paraneoplastic syndromes. A case study exemplifies a possible presentation and management of a patient with lung cancer and some of these complications."
109,Cancer's Enemy.,Conde C.,https://pubmed.ncbi.nlm.nih.gov/21732250/,"The Cancer Prevention and Research Institute of Texas (CPRIT) supports cancer prevention and control programs, as well as research and commercialization projects. CPRIT funds public and professional education, clinical services, and policy and systems change. It is interested in supporting projects that will encourage real change in how physicians deliver cancer care and show a measurable difference at the patient level."
110,"[Prevention of cervical cancer (II): prophylactic HPV vaccination, current knowledge, practical procedures and new issues].",Monsonego J.,https://pubmed.ncbi.nlm.nih.gov/17350792/,"Despite the considerable success of early screening for prevention of cervical cancer, Pap smears have not fulfilled the hopes that it would lead to a large-scale reduction of this cancer's incidence. Screening appears to be useful for a tiny portion of the world population, although a relatively large portion must put up with its limitations and disadvantages. Human papilloma viruses (HPV) 16 and 18 are responsible for two thirds of all cervical cancers worldwide. The condylomata (condyloma acuminatum), or genital warts, induced by HPV 6 and 11 are frequent among the young and difficult to manage. The extent and burden of HPV infection are considerable, as is the psychological and emotional impact of the diseases associated with it. Because cancer of the cervix is the final consequence of chronic HPV infection, it can be prevented by vaccination. A prophylactic vaccine to protect against the precancerous and cancerous lesions associated with HPV should save lives, reduce expensive diagnostic and therapeutic interventions, and have substantial individual and collective benefits. Clinical trials of anti-HPV vaccines for the prevention of cervical cancer and condyloma have shown remarkable  Vaccine efficacy has been shown only in young girls never exposed to the virus and only for the lesions associated with the specific viral types in the vaccine. Preliminary data indicate that the vaccination is effective in women who have previously eliminated naturally the virus. It has no therapeutic effects on existing lesions or in healthy virus carriers. Practical questions remain to be resolved. If the vaccination is left to individual initiative and vaccination coverage is insufficient, there will be no perceptible reduction in the frequency of cervical cancer. Vaccination policies will not be identical in poor countries, where the disease represents one of the leading causes of mortality among women, and in the rich countries, where screening programs have considerably reduced the frequency of this cancer. Current planning calls for the  Nonetheless mathematical models and immunogenicity  This approach must still be assessed in the clinical trials underway. Because the vaccine does not protect against all types of HPV associated with cervical cancer, screening must be continued according to the conditions currently set. Vaccination and screening, which are complementary and synergistic, now constitute the new standards for prevention of this disease."
111,A new chink in cancer's armor: Unleashing cell death by selective PP5 inhibition.,van Oosten-Hawle P.,https://pubmed.ncbi.nlm.nih.gov/37863031/,"Serine/threonine protein phosphatases play a significant role in the survival and propagation of multiple cancers. In this issue of Cell Chemical Biology, Ahanin et al.1 demonstrate that protein phosphatase 5 (PP5) dephosphorylates and inactivates the cell death effector protein FADD independently of Hsp90, and they identify a selective PP5 inhibitor as a new therapeutic strategy for renal cancer."
112,Targeting cancer's weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model.,"Lineweaver CH, Davies PC, Vincent MD.",https://pubmed.ncbi.nlm.nih.gov/25043755/,"In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation."
113,[Cancer prevention by stopping smoking].,Tominaga S.,https://pubmed.ncbi.nlm.nih.gov/9617314/,"Many epidemiological studies have revealed that cigarette smoking is associated with lung cancer and several other cancers and that the risk of lung cancer decreased after smoking cessation. The risk attributable to smoking from cancer can be calculated from the relative risk for smokers and the proportion of smokers in a given population. In Japan 26.7% of cancer of all sites was attributable to smoking among males, whereas only 4.4% was attributable to smoking in females, mainly because of their lower smoking frequency. It was also estimated that if the smoking rate was decreased from the present level of 56.1% to 40% and 20%, 7.7% and 17.2% of cancers of all sites could be prevented in males. The preventable fraction of cancer in females was small (1.4% and 2.9%) even if the smoking rate was decreased from the present level of 14.5% to 10% and 5%. Among males, 65.9% of lung cancer was considered attributable to smoking, and were the smoking rate decreased from the present level of 56.1% to 40% and 20%, up to 18.9% and 42.4% of lung cancer could be prevented. In view of the recent remarkable increase of lung cancer in Japan and the relatively low mortality reducing efficacy of lung cancer screening, it is necessary to promote primary prevention of lung cancer and of other smoking-related cancerous and non-cancerous diseases by extensive smoking control."
114,Generalizing Few-Shot Classification of Whole-Genome Doubling Across Cancer Types.,"Chao S, Belanger D.",https://pubmed.ncbi.nlm.nih.gov/34890144/,"The study and treatment of cancer is traditionally specialized to the cancer's site of origin. However, certain phenotypes are shared across cancer types and have important implications for clinical care. To date, automating the identification of these characteristics from routine clinical data - irrespective of the type of cancer - is impaired by tissue-specific variability and limited labeled data. Whole-genome doubling is one such phenotype; whole-genome doubling events occur in nearly every type of cancer and have significant prognostic implications. Using digitized histopathology slide images of primary tumor biopsies, we train a deep neural network end-to-end to accurately generalize few-shot classification of whole-genome doubling across 17 cancer types. By taking a meta-learning approach, cancer types are treated as separate but jointly-learned tasks. This approach outperforms a traditional neural network classifier and quickly generalizes to both held-out cancer types and batch effects. These "
115,Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics.,"Chu X, Wang J.",https://pubmed.ncbi.nlm.nih.gov/34752443/,"Cancer reflects the dysregulation of the underlying gene network, which is strongly related to the 3D genome organization. Numerous efforts have been spent on  However, there is still a lack of genomic structural-level understanding of the temporal dynamics for cancer initiation and progression. Here, we use a landscape-switching model to investigate the chromosome structural transition during the cancerization and reversion processes. We find that the chromosome undergoes a non-monotonic structural shape-changing pathway with initial expansion followed by compaction during both of these processes. Furthermore, our analysis reveals that the chromosome with a more expanding structure than those at both the normal and cancer cell during cancerization exhibits a sparse contact pattern, which shows significant structural similarity to the one at the embryonic stem cell in many aspects, including the trend of contact probability declining with the genomic distance, the global structural shape geometry and the spatial distribution of loci on the chromosome. In light of the intimate structure-function relationship at the chromosomal level, we further describe the cell state transition processes by the chromosome structural changes, suggesting an elevated cell stemness during the formation of the cancer cells. We show that cell cancerization and reversion are highly irreversible processes in terms of the chromosome structural transition pathways, spatial repositioning of chromosomal loci and hysteresis loop of contact evolution analysis. Our model draws a molecular-scale picture of cell cancerization from the chromosome structural perspective. The process contains initial reprogramming towards the stem cell followed by the differentiation towards the cancer cell, accompanied by an initial increase and subsequent decrease of the cell stemness."
116,Proteomic analysis of cancer tissues: shedding light on carcinogenesis and possible biomarkers.,"Kuramitsu Y, Nakamura K.",https://pubmed.ncbi.nlm.nih.gov/16972299/,"Lung, gastric, colorectal, pancreatic, and esophageal cancers, as well as hepatocellular carcinoma (HCC), were the six most common and highly fatal cancers for Japanese men in Japan in 2003, while for women uterine cervical cancer could also be added to this list. To identify diagnostic or therapeutic biomarkers for these cancers, investigators are nowadays performing proteomic analyses of cancer tissues and cells, and revealing a large number of molecules which are diagnostic, prognostic and informative of carcinogenesis. From reports of proteomic analyses of cancerous tissues and noncancerous tissues sampled from HCC, and pancreatic, esophageal, gastric, colorectal, lung and uterine cervical cancers, we classified the proteins into digestive enzymes, growth factors, cell adhesion molecules, calcium-binding proteins, proteases, protease inhibitors, transporter proteins, structural molecules, apoptosis inhibitor, molecular chaperone, as well as proteins related to cell growth, cell differentiation, cell transformation, tumor invasion, carcinogen metabolism, and others. The aim of this study was to understand carcinogenesis of major cancers from a proteomics perspective using samples from cancer patients, and to elucidate their tumor biomarkers."
117,Strategies for stalling malignancy: targeting cancer's addiction to Hsp90.,Prodromou C.,https://pubmed.ncbi.nlm.nih.gov/19860736/,"Hsp90 is involved in the maturation and activation of client proteins. Often these are key proteins involved in signal transduction and regulatory pathways that in a mutated and/or deregulated form sustain an oncogenic cellular state. Consequently, the malignancy is maintained with the aid of Hsp90 upon which the mutated proteins have become particularly dependent for their activity. The requirement for the Hsp90 chaperone machine to drive the malignancy makes Hsp90 a prime anticancer target, an 'axle in a wheel' that when disrupted has been shown to be effective in killing cancerous cells. This review aims to identify potential drug targets, based on the current structural knowledge of the Hsp90-chaperone machine, that could be targeted with the aim of disrupting its functioning and promoting an anti-cancer activity."
118,Treating the incurables: Cancer asylums in 18th and 19th century.,"Karamanou M, Psaltopoulou T, Markatos K, Karaoglanis G, Androutsos G.",https://pubmed.ncbi.nlm.nih.gov/29135134/,"For centuries several hypotheses were formulated on cancer's pathogenesis such as contagiousness, melancholy, heredity and sexuality. In the 18th and 19th century, despite the advent of medical thought and practice, cancer was considered an incurable and contagious disease. Hospitals were refusing to treat cancer patients while the social stigma which followed the disease made primordial the need for the establishment of special institutions. In our article we will present the cancer asylums which counterbalanced the prejudices of the time and contributed to the establishment of modern cancer hospitals."
119,Clinical approaches to osseous metastases in prostate cancer.,"Morris MJ, Scher HI.",https://pubmed.ncbi.nlm.nih.gov/12697941/," Osseous metastases pose a formidable health threat to patients with metastatic disease, putting them at risk for pain, marrow crowding, fracture, and other sequelae. Treatments directed against bone disease have the potential both to palliate pain and to increase survival.
    


          Conclusions:
        
      
      A number of agents exist that have the potential to palliate the effects of osseous metastases and should be routinely applied in the clinical care of the patient with advanced prostate cancer. These include hormones, bone-seeking radiopharmaceuticals, chemotherapy, and bisphosphonates. Strategies under investigation aim to eradicate bone disease, and not merely palliate symptoms. These approaches combine those listed above with tumor-directed targeting of osseous disease and manipulation of the biology that underlies the cancer's relationship to bone."
120,Epistemology of the origin of cancer: a new paradigm.,"Brücher BL, Jamall IS.",https://pubmed.ncbi.nlm.nih.gov/24885752/," Fewer than 10% of all cancers are hereditary; the ratio in gastric (1%), colorectal (3-5%) and breast (8%) cancers is even less. Cancers caused by infection are thought to constitute some 15% of the non-hereditary cancers. Those remaining, 70 to 80%, are called ""sporadic,"" because they are essentially of unknown etiology. We propose a new paradigm for the origin of the majority of cancers.
    


          Presentation of hypothesis:
        
      
      Our paradigm postulates that cancer originates following a sequence of events that include (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. If we are correct, this paradigm would suggest that the majority of the findings in cancer genetics so far reported are either late events or are epiphenomena that occur after the appearance of the pre-cancerous niche.
    


          Testing the hypothesis:
        
      
      If, based on  Our model would make clear the need to establish preventive measures long before a cancer becomes clinically apparent. Future research should focus on the intermediate steps of our proposed sequence of events, which will enhance our understanding of the nature of carcinogenesis. Findings on inflammation and fibrosis would be given their warranted importance, with research in anticancer therapies focusing on suppressing the PCN state with very early intervention to detect and quantify any subclinical inflammatory change and to treat all levels of chronic inflammation and prevent fibrotic changes, and so avoid the transition from a normal cell to a cancer cell.
    


          Implication of the hypothesis:
        
      
      The paradigm proposed here, if proven, spells out a sequence of steps, one or more of which could be interdicted or modulated early in carcinogenesis to prevent or, at a minimum, slow down the progression of many cancers."
121,Glycosylation and Antitumor Immunity.,"Cadena AP, Cushman TR, Welsh JW.",https://pubmed.ncbi.nlm.nih.gov/30712671/,"Glycosylation and its by-product, the glycan, play a crucial role in many cellular processes. Aberrant glycan structures and mutations of the glycosylation pathway have been intricately linked with the development of cancer and more recently with cancer's ability to escape the innate immune system. This chapter aims to elucidate how glycosylation interacts with the immune system to promote tumor deviation through endogenous lectins, mutated glycosphingolipids, sialic acid domains, and more. This chapter also explores the mechanisms of glycosylation that may lead to powerful translational therapeutic tools, such as glycotransferase inhibitors, glycan/glycopeptide-based vaccines, and antibody-based immunotherapies, all of which have shown great promise clinically in the field of immuno-oncology."
122,An Entropy-Based Method for Identifying Mutual Exclusive Driver Genes in Cancer.,"Song J, Peng W, Wang F.",https://pubmed.ncbi.nlm.nih.gov/30763245/,"Cancer in essence is a complex genomic alteration disease which is caused by the somatic mutations during the lifetime. According to previous researches, the first step to overcome cancer is to identify driver genes which can promote carcinogenesis. However, it is still a big challenge to precisely and efficiently extract the cancer related driver genes because the nature of cancer is heterogeneous and there exists tremendously irrelevant passenger mutations which have no function impact on the cancer's development. In this work, we proposed a novel entropy-based  EntroRank can take into full consideration different properties of driver genes. Considering the modularity of driver genes, the mutated genes in the network were first clustered into different subgroups according to their located compartments. After that, the structural entropy of the gene in the subgroup was employed to measure its indispensability. Considering mutual exclusive property between driver genes in the modules, relative entropy was utilized to measure the degree of mutual exclusive between two mutated genes in terms of their variation frequency. We applied our  The  Besides, EntroRank can identify driver genes having mutual exclusive property. Compared with other existing "
123,Does cancer affect marriage rates?,Syse A.,https://pubmed.ncbi.nlm.nih.gov/18663582/," Cancer's impact on marriage formation rates was therefore explored.
    


          2 million) come from the Cancer Registry and the Central Population Register. Marriage rates for 12,100 persons diagnosed with cancer were compared to marriage rates for otherwise similar persons using discrete-time hazard regression models.
    


          05, CI 1.01-1.11) than cancer-free men. No cancer forms reduced men's marriage rates, and significantly elevated rates were seen after skin and testicular cancer (OR 1.16 and 1.11). Cancer did not impact significantly on women's overall marriage rate (OR 0.95, CI 0.90-1.00), but pronounced deficiencies were seen after brain and breast cancer (OR 0.62 and 0.74). Skin cancer elevated women's marriage rate (OR 1.27). Male cancer survivors with children were more likely to marry than their female counterparts. Significant increases in cancer survivors' marriage rates were observed over time.
    


          Conclusion:
        
      
      Marrying after cancer is more common today than previously, and only slight overall differences were observed in cancer survivors' marriage rates relative to those of the cancer-free population. However, while brain and breast cancer in women is associated with reduced marriage rates, testicular cancer is associated with increased rates. The differences observed between common cancer forms in young adults deserve further exploration.
    


          Implications for cancer survivors:
        
      
      In general, marriage rates in survivors of most types of cancer are very similar to those in the population as a whole. Women with brain and breast cancer have lower marriage rates than their cancer-free counterparts. While it is necessary to identify exactly why this was observed, the information can alert those with these cancers to the potential impact on marriage and thus work to reduce the possible effect, if desired."
124,In situ research and diagnosis of breast cancer by using HOF-ATR-FTIR spectroscopy.,"Lu Y, Zhao Y, Zhu Y, Xu X, Yin J.",https://pubmed.ncbi.nlm.nih.gov/32247254/,"To accurately investigate in situ breast cancer would be very significant for real-time information and in situ diagnosis. In this in situ study, home-made hollow optical fiber attenuated total reflection (HOF-ATR) probe was integrated into Fourier transform infrared (FTIR) spectroscopic system to perform breast cancer research at molecular level. Based on the FTIR spectral analysis on band shifts and absorbance ratios, it's disclosed that the molecular structure, conformation and content of main components change with cancerization of breast tissue. Fisher's discriminant analysis on HOF-ATR-FTIR spectra was applied to identify the healthy and cancerous breast tissues for the first time. The identification accuracy was 96.67% for training group and 93.33% for cross-validation, respectively, as well as 95% for the prediction group. This paper provides much in situ information of tissue cancerization at molecular level, which can be used as fingerprint biomarkers of tissue cancerization for in situ diagnosis. HOF-ATR-FTIR spectroscopy with discriminant analysis has potential to be an effective and promising "
125,Anti-tumor pharmacology of natural products targeting mitosis.,"Huang M, Liu C, Shao Y, Zhou S, Hu G, Yin S, Pu W, Yu H.",https://pubmed.ncbi.nlm.nih.gov/35699421/,"Cancer has been an insurmountable problem in the history of medical science. The uncontrollable proliferation of cancer cells is one of cancer's main characteristics, which is closely associated with abnormal mitosis. Targeting mitosis is an effective  This review summarizes several natural products with anti-tumor effects related to mitosis, focusing on targeting microtubulin, inducing DNA damage, and modulating mitosis-associated kinases. Furthermore, the main disadvantages of several typical compounds, including drug resistance, toxicity to non-tumor tissues, and poor aqueous solubility and pharmacokinetic properties, are also discussed, together with strategies to address them. Improved understanding of cancer cell mitosis and natural products may pave the way to drug development for the treatment of cancer."
126,Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells.,"Wu CH, Silvers CR, Messing EM, Lee YF.",https://pubmed.ncbi.nlm.nih.gov/30593508/,"The field cancerization effect has been proposed to explain bladder cancer's multifocal and recurrent nature, yet the mechanisms of this effect remain unknown. In this work, using cell biology, flow cytometry, and qPCR analyses, along with a xenograft mouse tumor model, we show that chronic exposure to tumor-derived extracellular vesicles (TEVs)  Inhibition of EV uptake prevented this transformation. Transformed cells not only possessed several oncogenic properties, such as increased genome instability, loss of cell-cell contact inhibition, and invasiveness, but also displayed altered morphology and cell structures, such as an enlarged cytoplasm with disrupted endoplasmic reticulum (ER) alignment and the accumulation of smaller mitochondria. Exposure of SV-HUC cells to TEVs provoked the unfolded protein response in the endoplasmic reticulum (UPRER). Prolonged induction of UPRER signaling activated the survival branch of the UPRER pathway, in which cells had elevated expression of inositol-requiring enzyme 1 (IRE1), NF-κB, and the inflammatory cytokine leptin, and incurred loss of the pro-apoptotic protein C/EBP homologous protein (CHOP). More importantly, inhibition of ER stress by docosahexaenoic acid prevented TEV-induced transformation. We propose that TEVs promote malignant transformation of predisposed cells by inhibiting pro-apoptotic signals and activating tumor-promoting ER stress-induced unfolded protein response and inflammation. This study provides detailed insight into the mechanisms underlying the bladder cancer field effect and tumor recurrence."
127,Epigenetic field cancerization in gastrointestinal cancers.,"Baba Y, Ishimoto T, Kurashige J, Iwatsuki M, Sakamoto Y, Yoshida N, Watanabe M, Baba H.",https://pubmed.ncbi.nlm.nih.gov/26971491/,"Epigenetic alterations, including aberrant DNA methylation, play an important role in human cancer development. Importantly, epigenetic alterations are reversible and can be targets for therapy or chemoprevention for various types of human cancers. A field for cancerization, or a field defect, is formed by the accumulation of genetic and/or epigenetic alterations in normal-appearing tissues and can correlate with risk of cancer development. Thus, a better understanding of epigenetic field cancerization may represent a useful translational opportunity for cancer risk assessment, including previous history and exposure to carcinogenic factors, and for cancer prevention. In this article, we summarize current knowledge regarding epigenetic field cancerization and its clinical implications in gastrointestinal cancers, including colorectal cancer, gastric cancer and esophageal cancer."
128,Melancholy as a risk factor for cancer: a historical overview.,"Karamanou M, Tzavellas E, Laios K, Koutsilieris M, Androutsos G.",https://pubmed.ncbi.nlm.nih.gov/27569105/,"In antiquity, physicians related depression or melancholic humour to cancer's pathogenesis. Galen (130-201 AD), sustained that melancholy could give rise to a tumour and his theory was repeated by the Byzantine and Arab physicians. In the 19th century, malignancy and depression became synonymous and people attributed their cancer to sadness. In 1893, the London surgeon Hebert Snow (1847-1930), performed an epidemiological study in order to clarify that link. The  His work was followed by several large scale prospective studies some of which identified depression as a risk factor for cancer where others found no association. However, a possible explanation could be given by our current knowledge in immunology: inflammation and nonspecific immune activation play a role in the pathophysiology of depression and cancer growth."
129,Neurofibromatosis and lessons for the war on cancer.,Reilly KM.,https://pubmed.ncbi.nlm.nih.gov/20049721/,"In the war on cancer, a great deal of attention is being paid to knowing the 'enemy'. It is widely believed that by understanding the driving forces underlying cancer, researchers can develop better ways to target the disease. Currently, large-scale efforts have been under taken to completely characterize molecular changes in common human cancers (http://cancergenome.nih.gov/) (Collins & Barker, 2007). However, as more is learned about cancer, the debate increases on what exactly the enemy is: cells making up the bulk of the tumour, rare tumour stem cells that can regrow the tumour, tumour microenvironment, the subset of cancer cells with metastatic potential, etc. Studies of the cancers associated with Neurofibromatosis type 1 (NF1) are helping to define the relationship between many of these different cell types. It is still unclear how these different enemies are related to each other and how they interact to wage cancer's war on the patient. 'If you know the enemy and know yourself you need not fear the ' - Sun Tzu, The Art of War, c. 500 B.C."
130,The role of integrated computed tomography positron-emission tomography in esophageal cancer: staging and assessment of therapeutic response.,"Erasmus JJ, Munden RF.",https://pubmed.ncbi.nlm.nih.gov/17185195/,"Computed tomography (CT) and endoscopy/endoscopic ultrasonography are usually performed to initially stage patients with esophageal cancer, to determine primary tumor response, and to detect nodal and distant metastases after preoperative therapy. Positron-emission tomography (PET) with [18F]-fluoro-2-deoxy-D-glucose and integrated CT-PET are useful in the initial staging of patients with esophageal cancer as well as in the prediction of pathologic response, disease-free interval, and overall survival after preoperative therapy. Importantly, integrated CT-PET imaging decreases the number of futile attempts at surgical resection, mainly because of the detection of occult distant metastases. The following sections review the use of integrated CT-PET imaging in determining the T, N, and M descriptors of the American Joint Commission on Cancer's 2002 guidelines for pathologic and clinical staging at initial diagnosis and after chemoradiation therapy in those patients being considered for surgical resection."
131,Mechanisms and Potential Clinical Implications of Oral Microbiome in Oral Squamous Cell Carcinoma.,"Wang J, Gao B.",https://pubmed.ncbi.nlm.nih.gov/38248096/,"Microorganisms in the oral cavity are abundant in the human body. At present, more than 700 species of oral microorganisms have been identified. Recently, a lot of literature has indicated that the oral microbiota plays an important role in the occurrence, development, and prognosis of oral squamous cell carcinoma (OSCC) through various mechanisms. And researchers are now trying to utilize oral microbiota in cancer diagnosis and treatment. However, few articles systematically summarize the effects of oral microbes in the diagnosis, treatment, and disease outcomes of oral cancer. Herein, we made a summary of the microbial changes at cancerous sites and placed more emphasis on the mechanisms by which the oral microbiome promotes cancerization. Moreover, we aimed to find out the clinical value of the oral microbiome in OSCC."
132,An evolutionary perspective on field cancerization.,"Curtius K, Wright NA, Graham TA.",https://pubmed.ncbi.nlm.nih.gov/29217838/,"Tumorigenesis begins long before the growth of a clinically detectable lesion and, indeed, even before any of the usual morphological correlates of pre-malignancy are recognizable. Field cancerization, which is the replacement of the normal cell population by a cancer-primed cell population that may show no morphological change, is now recognized to underlie the development of many types of cancer, including the common carcinomas of the lung, colon, skin, prostate and bladder. Field cancerization is the consequence of the evolution of somatic cells in the body that  Here, we review the evidence of field cancerization across organs and examine the biological mechanisms that drive the evolutionary process that  We discuss the clinical implications, principally, how measurements of the cancerized field could improve cancer risk prediction in patients with pre-malignant disease."
133,Cancer patient education in Iran: a descriptive study.,"Montazeri A, Vahdani M, Haji-Mahmoodi M, Jarvandi S, Ebrahimi M.",https://pubmed.ncbi.nlm.nih.gov/11862507/,"Abstract. This study was carried out to examine the status of cancer patient education in Iran. Using the Multinational Association of Supportive Care in Cancer's (MASCC) patient education questionnaire, 310 individuals - a sample of heterogeneous cancer patients ( n=167) and their relatives ( n=143) - were enrolled in the study. The pooled  In contrast, 30% of respondents thought less than 20% of patients knew their cancer diagnosis. When asked, ""Were you given written materials about (i) cancer, (ii) treatment, and (iii) symptom management"", the vast majority of respondents said ""No"" (91%, 87%, and 87%, respectively). When respondents were asked, ""Would you like to learn more about cancer and treatments"", 97% said ""Yes"". Most respondents indicated the need for information on the treatments available (27%) and general information about cancer (20%); most had sought information from health professionals (31%), other cancer patients and friends (29%), and television (22%). Finally, it was found that concern about patients' depression (17%), lack of printed materials (13%), the idea that it was better for patients not to know (12%), and families' requests not to tell the patient (11%) were the most frequently stated barriers to or reasons for restricted cancer patient education. The findings of the study suggest that cancer patient education in Iran is very poor and there is an urgent need to develop policy guidelines on disclosure of cancer diagnoses and patient education."
134,Impact of molecular surgical margin analysis on the prediction of pancreatic cancer recurrences after pancreaticoduodenectomy.,"Sunagawa Y, Hayashi M, Yamada S, Tanabe H, Kurimoto K, Tanaka N, Sonohara F, Inokawa Y, Takami H, Kanda M, Tanaka C, Nakayama G, Koike M, Kodera Y.",https://pubmed.ncbi.nlm.nih.gov/34530906/," Pathological diagnosis of surgical margins is sometimes unreliable due to tissue shrinkage, invisible field cancerization and skipped lesions like tumor budding. As a 
    


           Surgical specimens were collected from 45 pancreatic cancer cases who received subtotal stomach preserving pancreatoduodenectomy at Nagoya University Hospital during 2017-2019. Quantitative methylation-specific PCR (QMSP) of the original methylation marker panel (CD1D, KCNK12, PAX5) were performed and analyzed with postoperative survival outcomes.
    


           Among the 38 tumors in which at least one of the three markers was positive, CD1D-positive cancer cells, KCNK12-positive cancer cells, and PAX5-positive cancer cells were detected at the surgical margin in 8 cases, 7 cases and 10 cases, respectively. Consequently, a total of 17 patients had at least one marker detected at the surgical margin by QMSP, and these patients were defined as MSM-positive. They were associated with significantly poor recurrence-free survival (p = 0.002) and overall survival (p = 0.005) than MSM-negative patients. Multivariable analysis showed that MSM-positive was the only significant independent factor for worse recurrence-free survival (hazard ratio: 3.522, 95% confidence interval: 1.352-9.179, p = 0.010). On the other hand, a significant proportion of MSM-negative cases were found to have received neoadjuvant chemotherapy (p = 0.019).
    


          Conclusion:
        
      
      Pancreatic cancer-specific methylation marker panel was established to perform MSM analysis. MSM-positive status might represent microscopically undetectable cancer cells on the surgical margin and might influence the postoperative long-term outcomes."
135,"Hepatobiliary Cancers: Progress in Diagnosis, Pathogenesis, and Treatment.","Pant K, Gradilone SA.",https://pubmed.ncbi.nlm.nih.gov/35546130/,"Hepatobiliary cancers comprise a wide range of malignancies such as hepatocellular carcinoma and cholangiocarcinoma, and they are some of the most challenging to treat human neoplasms. Due to the rarity of the illnesses, the development of treatment measures for malignancies of the gastrointestinal system is far behind. The number of patients eligible for curative treatment is limited due to cancer's aggressive nature and the difficulties of early identification. Furthermore, surgery is frequently intrusive and linked with a significant level of risk. The therapy "
136,How carcinogens cause cancer.,"Chaambers MS, Jacob RJ.",https://pubmed.ncbi.nlm.nih.gov/8633289/,"Several concepts have been formed regarding the origin of primary malignancies, but only recently has a theory on second primary cancers evolved. The aim of this report is to review the literature regarding current concepts associated with carcinogenesis, tobacco and alcohol, oral premalignancy, field cancerization and cancer prevention."
137,"The 'cause' of my cancer, beliefs about cause among breast cancer patients and survivors who do and do not seek IO care.","Andersen MR, Afdem K, Hager S, Gaul M, Sweet E, Standish LJ.",https://pubmed.ncbi.nlm.nih.gov/26552994/,"
    


           Of these, 245 women had sought treatment from complementary and alternative integrative oncology (IO) clinics, and 307 women did not.
    


           Self-reported beliefs about cancer's cause differed among women in association with their use of IO. IO users were somewhat more likely to describe stress and poor coping as causes of their cancer and less likely to describe random chance as a cause of cancer (p < 0.05).
    


          Conclusions:
        
      
      Beliefs about the cause of cancer change over time and may predict decisions to use specific treatment including complementary and alternative medicine and IO. Copyright © 2015 John Wiley & Sons, Ltd."
138,Tumor Hypoxia and Circulating Tumor Cells.,"Tinganelli W, Durante M.",https://pubmed.ncbi.nlm.nih.gov/33339353/,"Circulating tumor cells (CTCs) are a rare tumor cell subpopulation induced and selected by the tumor microenvironment's extreme conditions. Under hypoxia and starvation, these aggressive and invasive cells are able to invade the lymphatic and circulatory systems. Escaping from the primary tumor, CTCs enter into the bloodstream to form metastatic deposits or re-establish themselves in cancer's primary site. Although radiotherapy is widely used to cure solid malignancies, it can promote metastasis. Radiation can disrupt the primary tumor vasculature, increasing the dissemination of CTCs. Radiation also induces epithelial-mesenchymal transition (EMT) and eliminates suppressive signaling, causing the proliferation of existent, but previously dormant, disseminated tumor cells (DTCs). In this review, we collect the "
139,The presence of cancer-associated fibroblast in breast cavity side margins is in correlation with the expression of oncoproteins by adjacent epithelial cells: a new era in cancerous potential.,"Miripour ZS, Aminifar M, Hoseinpour P, Abbasvandi F, Karimi K, Ghahremani A, Parniani M, Ghaderinia M, Makiyan F, Aghaee P, Akbari ME, Abdolahad M.",https://pubmed.ncbi.nlm.nih.gov/39287633/,"Purpose:
        
      
      Cancer-associated fibroblasts (CAFs) are one of the most critical cells in the tumor environment, with crucial roles in cancer progression and metastasis. Due to Field-Effect phenomena (also called field cancerization), the adjacent cavity side area of the margin is histologically normal, but it has been entered into neoplastic transformation due to MCT4 and MCT1 pathways activated by H2O2/ROS oxidative stress agents secreted by CAF in adjacent tumor bed microenvironment. This paper specifically focused on the role of cancer-associated fibroblast in breast tumor beds and its correlation with the presence of scattered cancer cells or onco-protein-activated cells (may be high risk but not completely transformed cancer cells) in the cavity side margins.
    


           This  Subsequently, RT-PCR, fluorescent, histopathological, and invasion assays were conducted on hyperglycolytic lesions to explore any correlation between the abundance of CAFs and the electrochemical responses of the non-cancerous tissues surrounding the tumor, as well as their neoplastic potential.
    


           At mean 70.4%, 66.7%, 70.4%, and 44.5% increments were observed in GLUT-1, MMP-2, N-cadherin, and MMP-9 transcriptomes by highly glycolytic but histologically cancer-free expression samples in comparison with negative controls (histologically non-cancer lesions with low glycolytic behavior).
    


          Conclusion:
        
      
      The presence of CAFs is correlated with the presence of high glycolytic metabolism in the cavity margin lesion, high ROS level in the lesion, and finally aggressive cancer-associated proteins (such as MMP2, …) in the margin while these metabolomes, molecules, and proteins are absent in the margins with negatively scored CDP response and low ROS level. So, it seems that when we observe CAFs in glycolytic lesions with high ROS levels, some high-risk epithelial breast cells may exist while no histological trace of cancer cells was observed. Further research on CAFs could provide valuable insights into the local recurrence of malignant breast diseases. Hence, real-time sensors can be used to detect and investigate CAFs in the non-tumoral regions surrounding tumors in cancer patients, potentially aiding in the prevention of cancer recurrence."
140,Clonal analysis of early-stage bilateral papillary thyroid cancer identifies field cancerization.,"Su X, Chen S, He K, Mao Z, Ruan J, Zhou J, Teng X, Jin J, Fahey TJ 3rd, Wang W, Teng L.",https://pubmed.ncbi.nlm.nih.gov/30806961/," However, the clonal origin of these bilateral tumors remains unclear.
    


           Genomic DNA was extracted from paraffin-embedded tissues after microdissection and analyzed for BRAF mutation and X-chromosome inactivation.
    


          1%) harbored different BRAF status in bilateral tumors. Fourteen patients were available for X-chromosome inactivation assay and 10 of them achieved informative  Bilateral tumors from four cases had distinct patterns of X-chromosome inactivation. Combining the 3% (18/28) cases harbored discordant X-chromosome inactivation or BRAF status, indicating their independent clonal origin in bilateral tumors.
    


          Conclusions:
        
      
      The present study confirms ""field cancerization"" in early-stage bilateral thyroid cancers, suggesting that these subtype papillary thyroid cancers should be treated as independent and localized tumors."
141,Novel Antineoplastic Inducers of Mitochondrial Apoptosis in Human Cancer Cells.,Kesel AJ.,https://pubmed.ncbi.nlm.nih.gov/38398665/,"I propose a new strategy to suppress human cancer completely with two entirely new drug compounds exploiting cancer's Warburg effect characterized by a defective mitochondrial aerobic respiration, substituted by cytosolic aerobic fermentation/glycolysis of D-(+)-glucose into L-(+)-lactic acid. The two essentially new drugs, compound 1 [P(op)T(est)162] and compound 3 (PT167), represent new highly symmetric, four-bladed propeller-shaped polyammonium cations. The in vitro antineoplastic highly efficacious drug compound 3 represents a covalent combination of compound 1 and compound 2 (PT166). The intermediate drug compound 2 is an entirely new colchic(in)oid derivative synthesized from colchicine. Compound 2's structure was determined using X-ray crystallography. Compound 1 and compound 3 were active in vitro versus 60 human cancer cell lines of the National Cancer Institute (NCI) Developmental Therapeutics Program (DTP) 60-cancer cell testing. Compound 1 and compound 3 not only stop the growth of cancer cells to ±0% (cancerostatic effect) but completely kill nearly all 60 cancer cells to a level of almost -100% (tumoricidal effect). Compound 1 and compound 3 induce mitochondrial apoptosis (under cytochrome c release) in all cancer cells tested by (re)activating (in most cancers impaired) p53 function, which "
142,Atomic force microscopy-based assessment of multimechanical cellular properties for classification of graded bladder cancer cells and cancer early diagnosis using machine learning analysis.,"Zhu X, Qin R, Qu K, Wang Z, Zhao X, Xu W.",https://pubmed.ncbi.nlm.nih.gov/36581006/,"Cellular mechanical properties (CMPs) have been frequently reported as biomarkers for cell cancerization to assist  In this work, we extract 4 CMPs of four different graded bladder cancer (BC) cell lines by AFM (atomic force microscopy)-based nanoindentation to generate a CMP database, which is used to train a cancerization-grade classifier by machine learning. The classifier is tested on 4 categories of BC cells at different cancer grades. The classification shows split-independent robustness and an accuracy of 91.25% with an AUC-ROC (ROC stands for receiver operating characteristic, and ROC curve is a graphical plot which illustrates the performance of a binary classifier system as its discrimination threshold is varied) value of 97.98%. Finally, we also compare our proposed  Unlike former studies focusing on the discrimination between normal and cancerous cells, our study fulfills the classification of 4 graded cell lines at different cancerization stages, and thus provides a potential  STATEMENT OF SIGNIFICANCE: We measured four cellular mechanical properties (CMPs) of 4 graded bladder cancer (BC) cell lines using AFM (atomic force microscopy). We found that single or dual CMPs cannot fulfill the task of BC cell classification. Instead, we employ MLA (Machine Learning Algorithm)-based analysis whose inputs are BC CMPs. Compared with traditional cytomorphology-based prognoses, the non-invasive  The proposed non-invasive prognosis is characterized with high sensitivity and specificity, and thus provides a potential tumor-grading means to identify cancer cells with different metastatic potential. Moreover, our study proposes an "
143,Turning cancer's metabolic plasticity into fragility- an evolving paradigm.,Ganapathy-Kanniappan S.,https://pubmed.ncbi.nlm.nih.gov/29723104/,"In an elegant report, Corbet et al 1 recently demonstrated the much needed insight to exploit cancer's metabolic reprogramming for potential therapeutic intervention. In brief, the findings underscore the principle that abrogation of mitochondrial pyruvate metabolism upregulates glycolysis, and sensitizes cancer cells to radiation. Distinctive from the conventional approach of inhibition/ down-regulation of glycolysis, this emerging paradigm of forced-upregulation of glycolysis (i.e., a ""hyperglycolytic"" phenotype) concomitant with a reduced mitochondrial capacity turns the metabolic plasticity into vulnerability that may have implications in therapeutic targeting. Nevertheless, this commendable report 1 also provokes scientific curiosity and future directions of research on the opportunities and challenges of such forced upregulation of glycolysis in cancer."
144,Engineering cancer's end: An interdisciplinary approach to confront the complexities of cancer.,"Flores ER, Sawyer WG.",https://pubmed.ncbi.nlm.nih.gov/38848721/,"Cancer engineering is an interdisciplinary approach that promises to confront the complexities of cancer and accelerate transformative discoveries by integrating innovative fields across engineering and the physical sciences with a focus on cancer. We offer a conceptual framework for the hallmarks of cancer engineering, integrating 12 fields: system dynamics; imaging, radiation, and spectroscopy; robotics and controls; solid mechanics; fluid mechanics; chemistry and nanomaterials; mathematics and simulation; cellular and protein engineering; kinetics and thermodynamics; materials science; manufacturing and biofabrication; and microsystems."
145,Losing control: cancer's catastrophic transition.,"Rajapakse I, Scalzo D, Groudine M.",https://pubmed.ncbi.nlm.nih.gov/21941112/,"Adaptability and ""emergent"" properties are the dominant characteristics of complex systems, whether naturally occurring or engineered. Structurally, a complex system might be made up of a large number of simpler components, or it might be formed from hierarchies of smaller numbers of interacting subsystems and work together to produce a defined function. The nucleus of a cell has all of these features, many of which may become disrupted in cancer and other disease states. The general view is that cancer progresses gradually over time; cells become premalignant, then increasingly abnormal before they become cancerous. However, recent work by Stephens et al. (2011) has revealed that cancer can emerge much more rapidly. Based on DNA sequences from multiple cancer samples of various types, they show that cancer can arise suddenly from a single catastrophic event that causes massive genomic rearrangement."
146,Enhancing identification of cancer types via lowly-expressed microRNAs.,"Rasnic R, Linial N, Linial M.",https://pubmed.ncbi.nlm.nih.gov/28379430/,"The primary function of microRNAs (miRNAs) is to maintain cell homeostasis. In cancerous tissues miRNAs' expression undergo drastic alterations. In this study, we use miRNA expression profiles from The Cancer Genome Atlas of 24 cancer types and 3 healthy tissues, collected from >8500 samples. We seek to classify the cancer's origin and tissue identification using the expression from 1046 reported miRNAs. Despite an apparent uniform appearance of miRNAs among cancerous samples, we recover indispensable information from lowly expressed miRNAs regarding the cancer/tissue types. Multiclass support vector machine classification yields an average recall of 58% in identifying the correct tissue and tumor types. Data discretization had led to substantial improvement, reaching an average recall of 91% (95% median). We propose a straightforward protocol as a crucial step in classifying tumors of unknown primary origin. Our counter-intuitive conclusion is that in almost all cancer types, highly expressing miRNAs mask the significant signal that lower expressed miRNAs provide."
147,Is cancer a genetic program with an unknown function?,Garcia-Garcia A.,https://pubmed.ncbi.nlm.nih.gov/19136220/,"Cancer is a tissue that requires a genetic program, possibly involving hundreds of genes, as indicated by studies of differential gene expression performed with microarrays in various types of cancer. Cancer is thus a biological process of considerable precision as described by Schrödinger's equation, and it is not simply the random expression of hundreds of genes, but rather a program that gives neoplastic tissue characteristics that are independent of the originating tissue: invasion capacity and destruction of neighbouring tissues, metastasis, and capacity to progressively disengage from the genetic program of the original tissue. This program is common to all types of cancer, and does not appear to be related to the genetic program of any known differentiated tissue. In other words, cancer's genetic program appears to be universal in all tissues, since cancer behaves similarly in all tissues; though depending on the tissue in which it originates it will show certain specific characteristics, reflecting the extent to which the neoplastic cells are able to escape from the characteristics of the original tissue."
148,Establishment of permutation for cancer risk estimation in the urothelium based on genome-wide DNA methylation analysis.,"Tsumura K, Arai E, Tian Y, Shibuya A, Nishihara H, Yotani T, Yamada Y, Takahashi Y, Maeshima AM, Fujimoto H, Nakagawa T, Kume H, Homma Y, Yoshida T, Kanai Y.",https://pubmed.ncbi.nlm.nih.gov/31241739/,"The aim of this study was to establish permutation for cancer risk estimation in the urothelium. Twenty-six samples of normal control urothelium obtained from patients without urothelial carcinomas (C), 47 samples of non-cancerous urothelium without noticeable morphological changes obtained from patients with urothelial carcinomas (N), and 46 samples of the corresponding cancerous tissue (T) in the learning cohort and 64 N samples in the validation cohort, i.e. 183 tissue samples in total, were analyzed. Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation 450K BeadChip, and DNA methylation levels were verified using pyrosequencing and MassARRAY. Amplicon sequencing was performed using the GeneRead DNAseq Targeted Panels V2. Although N samples rarely showed genetic mutations or copy number alterations, they showed DNA methylation alterations at 2502 CpG sites compared to C samples, and such alterations were inherited by or strengthened in T samples, indicating that DNA methylation alterations may participate in field cancerization in the urothelium. Receiver operating characteristic curve analysis confirmed the feasibility of cancer risk estimation to identify urothelium at the precancerous stage by DNA methylation quantification. Cancer risk estimation permutation was established using a combination of two marker CpG loci on the HOXC4, TENM3 and TLR1 genes (sensitivity and specificity 96-100%). Among them, the diagnostic impact of 10 patterns of permutation was successfully validated in the validation cohort (sensitivity and specificity 94-98%). These data suggest that cancer risk estimation using procedures such as urine tests during health checkups might become applicable for clinical use."
149,[Clinical characteristics of multiple primary cancer associated with esophageal squamous carcinoma].,"He S, Liu Y, Liu X, Dou L, Zhang Y, Ni X, Lai S, Yu X, Zhang L, Wang G.",https://pubmed.ncbi.nlm.nih.gov/26815192/,"
    


           The patients were divided into two groups according to whether they had multiple primary cancer.
    


          9%) patients were found multiple primary cancer in the other organs. Among these patients, 72.4% was found synchronously, another primary cancer was found in the head and neck region in 211 (6.8%), in the stomach in 140 (4.2%), and in the lung, colon, breast, and other locations in the remaining patients. Of the 211 patients with another primary cancer in the head and neck region, 156 (73.2%) had hypopharyngeal cancer. Furthermore, the incidence of intraesophageal multiple cancerous lesion in the patients with primary cancer in the head and neck region was significantly higher than that in those whose other primary cancers were gastric cancer or in those with non-multiple primary cancer (P<0.01).
    


          Conclusion:
        
      
      There is a high incidence of multiple primary cancers in patients with esophageal squamous carcinoma, mostly found synchronously. The leading multiple primary cancers were head and neck cancer and stomach cancer. Intraesophageal multiple cancerous lesion is an indicator for a second primary cancer in head and neck. A better knowledge of the relationships between esophageal carcinoma and cancers in other organs may lead to earlier detection of other primary cancers and improved therapeutic "
150,Barriers and facilitators to implementing the commission on cancer's distress screening program standard.,"Knies AK, Jutagir DR, Ercolano E, Pasacreta N, Lazenby M, McCorkle R.",https://pubmed.ncbi.nlm.nih.gov/29880068/," This paper presents outcomes for the first cohort of participants (n = 36) of a Screening for Psychosocial Distress Program (SPDP), a 2-year training program designed to assist clinicians in implementing routine distress screening as mandated by the American College of Surgeons Commission on Cancer. Specifically, participants' success with distress screening implementation, institutional barriers and facilitators to implementation, and the role of the SPDP are described.
    


           An investigator-developed questionnaire collected qualitative (distress screening goals, institutional barriers and facilitators, facilitators associated with participation in the SPDP) and quantitative (level of goal achievement) data at 6, 12, and 24 months of participation in the SPDP. Conventional content analysis was applied to qualitative data. Mixed  Most common institutional barriers to distress screening implementation were ""lack of staff,"" ""competing demands,"" and ""staff turn-over."" Most common institutional facilitators were ""buy-in,"" ""institutional support,"" and ""recognition of participants' expertise."" The number of reported facilitators associated with SPDP participation was higher than the number associated with any institutional factor, and increased over time of participation.Significance of  Training programs are needed to promote facilitators and overcome barriers to distress screening."
151,Mitochondrial Flexibility of Breast Cancers: A Growth Advantage and a Therapeutic Opportunity.,"Avagliano A, Ruocco MR, Aliotta F, Belviso I, Accurso A, Masone S, Montagnani S, Arcucci A.",https://pubmed.ncbi.nlm.nih.gov/31052256/,"Breast cancers are very heterogeneous tissues with several cell types and metabolic pathways together sustaining the initiation and progression of disease and contributing to evasion from cancer therapies. Furthermore, breast cancer cells have an impressive metabolic plasticity that is regulated by the heterogeneous tumour microenvironment through bidirectional interactions. The structure and accessibility of nutrients within this unstable microenvironment influence the metabolism of cancer cells that shift between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to produce adenosine triphosphate (ATP). In this scenario, the mitochondrial energetic pathways of cancer cells can be reprogrammed to modulate breast cancer's progression and aggressiveness. Moreover, mitochondrial alterations can lead to crosstalk between the mitochondria and the nucleus, and subsequently affect cancer tissue properties. This article reviewed the metabolic plasticity of breast cancer cells, focussing mainly on breast cancer mitochondrial metabolic reprogramming and the mitochondrial alterations influencing nuclear pathways. Finally, the therapeutic strategies targeting molecules and pathways regulating cancer mitochondrial alterations are highlighted."
152,Racial variation and cancer: a historical approach.,"Karamanou M, Tekiner H, Papaioannou TG, Konstantopoulos K, Androutsos G.",https://pubmed.ncbi.nlm.nih.gov/28039729/,"At the end of the 19th century, in an attempt to define cancer's etiology, scientists considered that cancer was mainly affecting the white race and the temperate zone countries. In their turn, epidemiological studies held in the early 20th century sustained the dogma of cancer's racial distribution, targeting and stigmatizing ethnic groups."
153,Fatty acid metabolites in rapidly proliferating breast cancer.,"O'Flaherty JT, Wooten RE, Samuel MP, Thomas MJ, Levine EA, Case LD, Akman SA, Edwards IJ.",https://pubmed.ncbi.nlm.nih.gov/23658799/,"Purpose:
        
      
      Breast cancers that over-express a lipoxygenase or cyclooxygenase are associated with poor survival possibly because they overproduce metabolites that alter the cancer's malignant behaviors. However, these metabolites and behaviors have not been identified. We here identify which metabolites among those that stimulate breast cancer cell proliferation in vitro are associated with rapidly proliferating breast cancer.
    


           We then related their levels to each cancer's proliferation rate as defined by its Mib1 score.
    


           It was similarly associated with aggressive grade and a key component of grade, mitosis, and also trended to be associated with lymph node metastasis. PGE2 and PGD2 trended to be negatively associated with these markers. No other metabolite in cancer and no metabolite in normal tissue had this profile of associations.
    


          Conclusions:
        
      
      Our data fit a model wherein the overproduction of 13-HODE by 15-lipoxygenase-1 shortens breast cancer survival by stimulating its cells to proliferate and possibly metastasize; no other oxygenase-metabolite pathway, including cyclooxygenase-PGE2/D2 pathways, uses this specific mechanism to shorten survival."
154,Risk of skin cancer development in 672 patients affected by actinic keratosis.,"Dika E, Fanti PA, Misciali C, Vaccari S, Crisman G, Barisani A, Baraldi C, Ribero S, Patrizi A.",https://pubmed.ncbi.nlm.nih.gov/26381460/," The skin areas affected by the so-called ""field cancerization"" harbor mutagenetic risks for the development of squamous cell carcinoma (SCC).
    


           The frequency of non-melanoma skin cancers (NMSC, namely SCC and basal cell carcinoma [BCC]) and malignant melanomas (MMs) in patients affected by multiple AKs were analyzed.
    


           The risk of developing another skin malignancy appeared to be higher in the age range between 61 and 80 years. The relative risk of developing a BCC and/or an MM in patients with a previous AK diagnosis was found to be 4.52.
    


          Conclusions:
        
      
      The presence of multiple AKs and ""field cancerization"" seems to be associated with a high risk not only of NMSC such as SCC and BCC, but also of MM. An adequate follow-up is required in these groups of patients."
155,Field cancerization in the understanding of parenchymal analysis of mammograms for breast cancer risk assessment.,"Miranda DA, Pertuz S.",https://pubmed.ncbi.nlm.nih.gov/31837523/,"In recent years, mammographic image analysis has shown great potential for breast cancer risk assessment. The aim of risk assessment is to predict how likely a woman is to develop breast cancer in the future. Several studies suggest that computerized parenchymal analysis of mammograms can be utilized as an independent imaging biomarker of breast cancer. Parenchymal analysis consists of the quantitative assessment of visual texture patterns in mammograms to infer the level of risk. In spite of substantial evidence of the association between parenchymal patterns and breast cancer risk, its biological foundations remain poorly understood. In this work, we draw a hypothesis that links the field cancerization (FC) with breast cancer risk assessment based on the parenchymal analysis. In the literature, the FC is interpreted as a biochemical anomaly amplification in otherwise healthy cells due to the effect of pre-cancerous transformed cells in surrounding regions. Our hypothesis is that these biochemical anomaly amplifications change the cellular micro-environment which, in turn, alter tissue responses to X-ray radiation. As a  We believe that our hypothesis provides an actionable explanation as to how computerized parenchymal analysis of apparently normal mammograms can be successfully utilized for the stratification of breast cancer risk."
156,"""They Did Not Understand"": Exploring Adult Survivors of Childhood Cancer's Memories of Their Experiences With Peers.","Hinton T, Burns-Nader S.",https://pubmed.ncbi.nlm.nih.gov/39169722/," Children with cancer can feel isolation, such as bullying and lack of engagement, from their peers. As the rates of survival increase, one way to further learn about the experiences of childhood cancer is to reflect on the memories of adult survivors. This study examines adult survivors of childhood cancer's memories of their experiences with peers during their cancer.  Using inductive thematic analysis, open-ended survey questions were analyzed.  Participants' memories included peers' lack of understanding about their diagnosis, prognosis, and treatment, positive and negative responses to their cancer diagnosis, acts of services and gifts from peers, and feelings of isolation during the cancer experience. Discussion: In the current study, adult survivors of childhood cancer had specific memories about how cancer impacted peer relationships. Such findings contribute to the evidence that children with cancer could benefit from psychosocial interventions, including education to peers about the diagnosis and the impact of diagnosis on peer relationships, peer engagement activities, and peer support groups."
157,Exhaustive Review on Lung Cancers: Novel Technologies.,"Khan S, Ali S, Muhammad.",https://pubmed.ncbi.nlm.nih.gov/32013812/," Lung cancers consisting of two substantial forms based on the microscopic appearance of tumor cells are: Non-Small-Cell-Lung-Cancer (NSCLC) (80 to 85%) and Small-Cell-Lung-Cancer (SCLC) (15 to 20%).
    


          Discussion:
        
      
      Lung cancers are existing luxuriantly across the globe and the most prominent cause of death in advanced countries (USA & UK). There are many causes of lung cancers in which the utmost imperative aspect is the cigarette smoking. During the early stage, there is no perspicuous sign/symptoms but later many symptoms emerge in the infected individual such as insomnia, headache, pain, loss of appetite, fatigue, coughing etc. Lung cancers can be diagnosed in many ways, such as history, physical examination, chest X-rays and biopsy. However, after the diagnosis and confirmation of lung carcinoma, various treatment approaches are existing for curing of cancer in different stages such as surgery, radiation therapy, chemotherapy, and immune therapy. Currently, novel techniques merged that revealed advancements in detection and curing of lung cancer in which mainly includes: microarray analysis, gene expression profiling.
    


          Conclusion:
        
      
      Consequently, the purpose of the current analysis is to specify and epitomize the novel literature pertaining to the development of cancerous cells in different parts of the lung, various preeminent approaches of prevention, efficient diagnostic procedure, and treatments along with novel technologies for inhibition of cancerous cell growth in advance stages."
158,"Cancer control through principles of systems science, complexity, and chaos theory: a model.",Janecka IP.,https://pubmed.ncbi.nlm.nih.gov/17589568/,"Cancer is a significant medical and societal problem. This reality arises from the fact that an exponential and an unrestricted cellular growth destabilizes human body as a system. From this perspective, cancer is a manifestation of a system-in-failing.A model of normal and abnormal cell cycle oscillations has been developed incorporating systems science, complexity, and chaos theories. Using this model, cancer expresses a failing subsystem and is characterized by a positive exponential growth taking place in the outer edge of chaos. The overall survival of human body as a system is threatened. This model suggests, however, that cancer's exponential cellular growth and disorganized complexity could be controlled through the process of induction of differentiation of cancer stem cells into cells of low and basic functionality. This concept would imply reorientation of current treatment principles from cellular killing (cyto-toxic therapies) to cellular retraining (cyto-education)."
159,Marriage after cancer in older adulthood.,"Syse A, Aas GB.",https://pubmed.ncbi.nlm.nih.gov/19148756/," Marriage rates among older adults were therefore explored.
    


           Marriage rates for 27,600 persons diagnosed with cancer were compared to those of the general population by means of discrete-time hazard regression models.
    


           This deficit was most pronounced after ovarian (OR 0.48) and breast (OR 0.69) cancer. Marriage rates decreased with time from diagnosis. No cancer forms elevated marriage rates.
    


          Conclusion:
        
      
      Marriage rates among older male cancer survivors are similar to those of the general population. Ovarian and breast cancer in older women was associated with pronounced marriage deficits. A possible explanation is that these gender-specific cancers relate to aspects of persons' psychological well-being, body image, and sense of femininity. Long-term adverse treatment effects are also common for the cancers in question. To explore explanations further, more details on treatment and illness progression are needed.
    


          Implications for cancer survivors:
        
      
      Increased awareness of how ovarian and breast cancer may affect (prospects of) interpersonal relationships is valuable for cancer survivors and clinicians, and may facilitate communication of relevant, related issues during consultations. Our findings may suggest a need for more extensive psychosocial follow-up after these gender-specific cancer forms in older women, but further research is clearly warranted."
160,"Penile cancer: clinical presentation, diagnosis, and staging.","Barocas DA, Chang SS.",https://pubmed.ncbi.nlm.nih.gov/20674691/,"Penile cancer is an uncommon malignancy in developed countries, with an estimated 1290 new cases of invasive penile cancer and 290 deaths among men in the United States in 2009, but is much more common in the developing countries of Asia, Africa, and South America. This disease can  Thus, recognizing penile cancer early in the clinical setting and accurately diagnosing the patients is critical. Because the management and prognosis varies by the extent of local disease, lymph node status, and other factors, accurate staging of penile cancer is of utmost importance. This article focuses on the presentation, diagnosis, and staging of invasive squamous cell carcinoma of the penis. The authors highlight the recent changes to the American Joint Committee on Cancer's staging system for penile carcinoma and discuss other prognostic factors and predictive models."
161,High incidence of head and neck cancers after endoscopic resection for esophageal cancer in younger patients.,"Maekawa A, Ishihara R, Iwatsubo T, Nakagawa K, Ohmori M, Iwagami H, Matsuno K, Inoue S, Arao M, Nakahira H, Matsuura N, Schichijo S, Kanesaka T, Yamamoto S, Takeuchi Y, Higashino K, Uedo N, Fujii T, Morishima T, Miyashiro I.",https://pubmed.ncbi.nlm.nih.gov/31813008/," We evaluated the incidence of second cancers at different sites by patients' ages when their index ECs were diagnosed.
    


           Patients' data, including sex, age at diagnosis, sequence of cancer incidence, cancer histology, and cancer site, were extracted from the cancer registry.
    


           Simultaneous head and neck cancers (HNCs) and other organ cancers (OCs) were, respectively, present in 15% (80/544) and 9.6% (52/544) of patients; and 30% (162/544) developed metachronous second cancers over a median follow-up period of 79.5 months (range 2-120), including 44 metachronous HNCs and 70 OCs. The cumulative incidence of metachronous HNCs was significantly higher in younger patients (< 60 years) than in older patients (≥ 60 years; P = 0.001), whereas the cumulative incidence of OCs was significantly higher in older patients than in younger patients (P = 0.03).
    


          Conclusions:
        
      
      The incidence of second HNC after index EC was higher in younger-onset patients than in older-onset patients. We suggest that younger patients with EC should be carefully monitored for early detection of second HNC."
162,Refining the Classification of Field Cancerization.,"Kitrell B, Crew A, Wysong A, Sutton A.",https://pubmed.ncbi.nlm.nih.gov/36728040/," Lack of a consensus definition makes characterizing and studying this condition difficult.
    


          
    


          
    


           They have started to recruit and study the highest risk cohort (Category 4 or 5) and have recruited 57 patients with 5 or more lifetime keratinocyte carcinomas for a prospective study evaluating chemoprevention strategies and disease burden. In these cohorts, the average number of skin cancers was greater than 12; however, less than 39% of these patients had used any chemoprevention in the prior 6 months.
    


          Conclusion:
        
      
      A meaningful and clinically relevant disease stratification framework with chemoprevention guidance has the potential to highly impact the specialty and patients."
163,Reactive oxygen species: a volatile driver of field cancerization and metastasis.,"Liao Z, Chua D, Tan NS.",https://pubmed.ncbi.nlm.nih.gov/30927919/,"Field cancerization and metastasis are the leading causes for cancer recurrence and mortality in cancer patients. The formation of primary, secondary tumors or metastasis is greatly influenced by multifaceted tumor-stroma interactions, in which stromal components of the tumor microenvironment (TME) can affect the behavior of the cancer cells. Many studies have identified cytokines and growth factors as cell signaling molecules that aid cell to cell communication. However, the functional contribution of reactive oxygen species (ROS), a family of volatile chemicals, as communication molecules are less understood. Cancer cells and various tumor-associated stromal cells produce and secrete a copious amount of ROS into the TME. Intracellular ROS modulate cell signaling cascades that aid in the acquisition of several hallmarks of cancers. Extracellular ROS help to propagate, amplify, and effectively create a mutagenic and oncogenic field which facilitate the formation of multifoci tumors and act as a springboard for metastatic tumor cells. In this review, we summarize our current knowledge of ROS as atypical paracrine signaling molecules for field cancerization and metastasis. Field cancerization and metastasis are often discussed separately; we offer a model that placed these events with ROS as the focal instigating agent in a broader ""seed-soil"" hypothesis."
164,Genetics and oncology nursing.,"Calzone KA, Masny A.",https://pubmed.ncbi.nlm.nih.gov/15491027/,"
    


          Data sources:
        
      
      Published articles.
    


          Conclusion:
        
      
      Genetic information in oncology health care is used not only to predict risk but to elucidate disease biology, explain individual variation in vulnerability to environmental carcinogens, diagnose and characterize malignancies, design treatment regimens specific to a cancer's genetic fingerprint, develop new, therapeutic modalities, and clarify modulators of drug metabolism, efficacy, and interactions.
    


          Implications for nursing practice:
        
      
      With current and emerging genetic discoveries, all oncology nurses will use genetic information in their practice."
165,Field Cancerization in NSCLC: A New Perspective on MicroRNAs in Macrophage Polarization.,"Pirlog R, Cismaru A, Nutu A, Berindan-Neagoe I.",https://pubmed.ncbi.nlm.nih.gov/33451052/,"Lung cancer is currently the first cause of cancer-related death. The major lung cancer subtype is non-small cell lung cancers (NSCLC), which accounts for approximatively 85% of cases. The major carcinogenic associated with lung cancer is tobacco smoke, which produces long-lasting and progressive damage to the respiratory tract. The progressive and diffuse alterations that occur in the respiratory tract of patients with cancer and premalignant lesions have been described as field cancerization. At the level of tumor cells, adjacent tumor microenvironment (TME) and cancerized field are taking place dynamic interactions through direct cell-to-cell communication or through extracellular vesicles. These molecular messages exchanged between tumor and nontumor cells are represented by proteins, noncoding RNAs (ncRNAs) and microRNAs (miRNAs). In this paper, we analyze the miRNA roles in the macrophage polarization at the level of TME and cancerized field in NSCLC. Identifying molecular players that can influence the phenotypic states at the level of malignant cells, tumor microenvironment and cancerized field can provide us new insights into tumor regulatory mechanisms that can be further modulated to restore the immunogenic capacity of the TME. This approach could revert alterations in the cancerized field and could enhance currently available therapy approaches."
166,"Field cancerization: why late ""recurrent"" ovarian cancer is not recurrent.","Buller RE, Skilling JS, Sood AK, Plaxe S, Baergen RN, Lager DJ.",https://pubmed.ncbi.nlm.nih.gov/9579425/," We hypothesize that recurrent ovarian cancers are distinguishable on the basis of a molecular genetic fingerprint and that some are actually new primary cancers of the peritoneum rather than recurrent ovarian cancer.
    


          Study design:
        
      
      We constructed molecular genetic fingerprints of 13 paired primary and late recurrent ovarian cancers to study their clonal relationships. The tumor pairs were analyzed for p53 mutations and allelotypes, patterns of X-chromosome inactivation, loss of heterozygosity, and microsatellite instability at 12 different loci on 6 different chromosomes. Techniques used included single-strand conformational polymorphism mutation screening and polymerase chain reaction-based sequence analysis of the p53 locus, restriction digestion of the androgen receptor locus to determine X-chromosome inactivation, and polyacrylamide gel electrophoresis of highly polymorphic dinucleotide, trinucleotide, and tetranucleotide repeats.
    


          7 years (range 45.3 to 65.5). Mean interval to recurrence was 42.7 months (range 28 to 62). Molecular fingerprints were characterized for 4 to 8 informative loci per tumor pair. The fingerprints of 10 (77%) differed significantly, strongly suggesting that a second primary cancer had developed. The remaining 3 tumor pairs demonstrated identical allelotypes consistent with regrowth of dormant tumor cells.
    


          Conclusion:
        
      
      Our  Late development of a new primary cancer may herald the proband as a member of a familial cancer phenotype. These studies provide a molecular genetic rationale that both explains and prognosticates the clinical course of recurrent ovarian cancer."
167,Busting robustness: using cancer's greatest strength to our advantage.,Westin JR.,https://pubmed.ncbi.nlm.nih.gov/24673642/,"What do complex networks, such as those found in cancer cells, airplane flight patterns and the Internet have in common? A remarkable robustness with a surprising vulnerability. Complex networks follow remarkably similar patterns across seemingly unconnected fields, and it is possible that cancer researchers could thus learn from the advances in complex network theory. Very limited, yet coordinated, specific targeting of the most critical parts of a network can have dramatically outsized effects. ""At times, our strengths propel us so far forward we can no longer endure our weaknesses and perish from them."" Nietzsche."
168,Cancerization of ducts in hilar cholangiocarcinoma.,"Lee JW, Zhang Y, Yoshizawa T, Argani P, Wood LD, Oshima K.",https://pubmed.ncbi.nlm.nih.gov/35527321/,"Invasive cancers that arise from ductal structures can infiltrate and colonize pre-existing ducts in a process referred to as cancerization of ducts (COD). COD in cholangiocarcinoma is an under-studied process whose clinical significance remains poorly understood. Even though both cancerized ducts and biliary intraepithelial neoplasias (BilINs) show dysplastic changes, hallmarks of COD are (i) an abrupt transition from the normal/reactive epithelium to severe dysplasia and (ii) close proximity to invasive carcinoma with similar cytologic features. We investigated 113 cases of surgically resected hilar cholangiocarcinoma and identified COD in 37 cases (33%). Using immunohistochemistry, we found that COD and adjacent invasive carcinoma had a concordant pattern of p53 and SMAD4 staining in 95% (21/22) and 100% (21/21) of cases, respectively. In contrast, BilINs and cancerized ducts showed significantly lower levels of concordance in p53 and SMAD4 staining at 44% (8/18) and 47% (8/17) of cases, respectively (P = 0.0007 and 0.0001, respectively). By univariate analysis, positive lymph node metastasis (P = 0.027), positive final bile duct margin (P = 0.021), and the presence of COD (P = 0.020) were associated with decreased overall survival. We further performed multivariate analysis to demonstrate that positive lymph node metastasis (P = 0.031), positive final bile duct margin (P = 0.035), and COD (P = 0.0051) were correlated with decreased overall survival. Together, our study highlights that COD is a clinically significant process in hilar cholangiocarcinoma that can be identified using morphological criteria in conjunction with p53 and SMAD4 immunolabeling."
169,Skin cancer: preventive photodynamic therapy in patients with face and scalp cancerization. A randomized placebo-controlled study.,"Apalla Z, Sotiriou E, Chovarda E, Lefaki I, Devliotou-Panagiotidou D, Ioannides D.",https://pubmed.ncbi.nlm.nih.gov/19863513/," This finding led to the field cancerization theory, which suggests that the entire epithelial surface of the regional skin has an increased risk for the development of malignant lesions. Management of field change is challenging, taking into account the high impact of NMSCs on public health and healthcare costs.   During the next 12-month period of follow up, patients were clinically evaluated for new NMSCs.  Conclusions The "
170,A pathology of progress? Locating the historiography of cancer.,Arnold-Forster A.,https://pubmed.ncbi.nlm.nih.gov/27935474/,"Despite its prominent position in today's medical research, popular culture and everyday life, cancer's history is relatively unwritten. Compared to the other great 'plagues' - cholera, tuberculosis or tropical fevers, to name but a scant handful - cancer has few dedicated pages in the general surveys, and its specialists have largely failed to convince the broader community of medical historians - or indeed historians of anything at all - that histories of the disease can tell us fundamental things about the science and practice of medicine, both past and present. Moreover, cancer has a remarkably stable profile over time, at least in terms of its definition, language and terminology - a detail that only makes the disease's absence from historical literature more surprising."
171,"Differential expression of hsa-miR-221, hsa-miR-21, hsa-miR-135b, and hsa-miR-29c suggests a field effect in oral cancer.","Lopes CB, Magalhães LL, Teófilo CR, Alves APNN, Montenegro RC, Negrini M, Ribeiro-Dos-Santos Â.",https://pubmed.ncbi.nlm.nih.gov/29976158/," One of the many molecular changes described in cancer are microRNAs (miRNAs), which regulates the expression of important genes during carcinogenesis. Thus, the aim of this study was to investigate the field effect in oral cancer.
    


          
    


           No significant difference was found when comparing the expression profile of cancerous and tissue-adjacent tissue groups. We found a negative correlation between the expression of hsa-miR-21 expression and STAT3 in oral squamous cell carcinoma.
    


          Conclusion:
        
      
      These  Our data corroborates the hypothesis of field cancerization."
172,Predicting MicroRNA Biomarkers for Cancer Using Phylogenetic Tree and Microarray Analysis.,Wang H.,https://pubmed.ncbi.nlm.nih.gov/27213352/,"MicroRNAs (miRNAs) are shown to be involved in the initiation and progression of cancers in the literature, and the expression of miRNAs is used as an important cancer prognostic tool. The aim of this study is to predict high-confidence miRNA biomarkers for cancer. We adopt a  There are 53 miRNAs selected through this  These miRNAs can be used as high-confidence miRNA biomarkers of these seven investigated cancers for further  miR-17, miR-20, miR-106a, miR-106b, miR-92, miR-25, miR-16, miR-195 and miR-143 are selected to involve a single cancer's development in these seven cancers. They have the potential to be useful miRNA biomarkers when the "
173,[Application and development of purification in cancer genomics research].,"Liu ZQ, Tian YQ.",https://pubmed.ncbi.nlm.nih.gov/15522191/,"In the study of cancer genomics, a series of purification  Tissue microdissection  Each "
174,"Bottom up design of nanoparticles for anti-cancer diapeutics: ""put the drug in the cancer's food"".","Needham D, Arslanagic A, Glud K, Hervella P, Karimi L, Høeilund-Carlsen PF, Kinoshita K, Mollenhauer J, Parra E, Utoft A, Walke P.",https://pubmed.ncbi.nlm.nih.gov/27646195/,"The story starts in Basel at CLINAM in 2013, when I asked Pieter about making nanoparticles and he advised me to ""try this solvent-exchange  We are particularly interested in what are ""limit size materials"" because we want to test the feasibility of an idea: could we design, make, develop, and test the concept for treating metastatic cancer by, ""Putting the Drug in the Cancer's Food? ""Limit size"" is the size of the cancer's food, ? the common Low Density Lipoprotein, (LDL) ~20 nm diameter. In this contribution to Pieter's LTAA we focus on the ""bottom"" (nucleation) and the ""up"" (growth) of ""bottom-up design"" as it applies to homogeneous nucleation of especially, hydrophobic drugs and the 8 physico-chemical stages and associated parameters that determine the initial size, and any subsequent coarsening, of a nanoparticle suspension. We show that, when made by the rapid solvent-exchange  Furthermore, the obtained size follows the predictions of classic nucleation theory when the appropriate values for the parameters (surface tension and supersaturation) at nucleation are included. Calculations on dissolution time for nanoparticles reveal that a typical fewmicromolar-solubility, hydrophobic, anti-cancer drug (like Lapatinib, Niclosamide, Abiraterone, and Fulvestrant) of 500 nm diameter would take between 3?7 s to dissolve in an infinite sink like the blood stream; and a 50 nm particle would dissolve in less than a second! And so the nanoparticle design requires a highly water-insoluble drug, and a tight, encapsulating, impermeable lipid:cholesterol monolayer. While the ""Y"" junction can be used to mix an ethanolic solution with anti-solvent, we find that a ""no-junction"" can give equally good  A series of nanoparticles (DiI-fluorescently labeled Triolein-cored and drug-cored nanoparticles of Orlistat) were then tested in well-characterized cell lines for uptake and efficacy as well as a PET-imageable nanoparticle in initial PET-imaging studies in animals for EPR uptake and tumor detection. We show that, while free-drug cannot be optimally administered in vivo, a nanoparticle formulation of orlistat could in principle represent a stable parenteral delivery system. The article ends with a brief discussion of what we see as the way forward in Individualized Medicine from the Diagnostic-Therapeutic (""Diapeutic"") side, requiring 18FDG detection of metastatic lesions, functional imaging of a protein target (e.g. Fatty Acid Synthase) using 11C acetate, then a PET (or other)-imageable nanoparticle to demonstrate EPR accumulation, and then the administration of the pure-drug nanoparticle taken in by the most aggressive cancer cells in the perivascular space, as they would their ""food""."
175,Targeting cancer stem cells for more effective therapies: Taking out cancer's locomotive engine.,"Winquist RJ, Boucher DM, Wood M, Furey BF.",https://pubmed.ncbi.nlm.nih.gov/19539800/,"Novel therapies for the treatment of solid tumors have generally failed to improve patient overall survival. These therapeutic approaches are typically focused on targeting signaling pathways implicated in cell growth and/or survival in order to shrink the malignant mass and achieve an  This clinical conundrum could be explained by the existence of a tumorigenic cell population that is relatively resistant to these therapies and retains pluripotent status in order to repopulate the original tumor and/or contribute to distant metastasis following treatment. Compelling data from liquid tumors, and more recently from studies focused on solid tumors, now support the existence of such tumorigenic cells (i.e., cancer stem cells) as a distinct subpopulation within the total tumor cell mass. These cancer stem cells (CSCs), as compared to the non-CSC population, have the ability to reconstitute the primary tumor phenotype when transplanted into recipient animals. In addition, data are beginning to emerge demonstrating that many standard-of-care chemotherapeutics are less effective in promoting cell death or cytostasis in these putative cancer stem cells as compared to effects in the non-stem cell cancerous cells. Therefore, targeting these locomotive drivers of tumors, the cancer stem cell population, should be considered a high priority in the continued pursuit of more effective cancer therapies."
176,Similar survival after endoscopic submucosal dissection and esophagectomy in early esophageal cancer and synchronous or metachronous head and neck cancer.,"Ke RT, Hsiao YH, Tai WC, Li SH, Yao CC, Chuang KH, Lai HH, Chen Y, Chen LC, Lu HI, Chen YH, Lo CM.",https://pubmed.ncbi.nlm.nih.gov/38311758/," Field cancerization in patients with early-stage esophageal cancer affects treatment outcomes and causes synchronous or metachronous head and neck cancers. We hypothesized that esophagectomy could provide better overall and relapse-free survivals in patients with esophageal cancer and synchronous or metachronous head and neck cancer.
    


           We separated the patients into endoscopic submucosal dissection and esophagectomy groups to compare overall and relapse-free survivals.
    


           Overall and relapse-free survivals did not show significant differences between the two groups for both synchronous and metachronous head and neck cancers.
    


          Conclusions:
        
      
      Endoscopic submucosal dissection could provide similar overall and relapse-free survivals in patients with esophageal cancer and synchronous or metachronous head and neck cancer."
177,Field cancerization in non-small cell lung cancer: implications in disease pathogenesis.,"Kadara H, Wistuba II.",https://pubmed.ncbi.nlm.nih.gov/22550239/,"Lung cancer, of which non-small cell lung cancer (NSCLC) composes the majority, is the leading cause of cancer-related deaths in the United States and worldwide. NSCLCs are tumors with complex biology that we have recently started to understand with the advent of various histological, transcriptomic, genomic, and proteomic technologies. However, the histological and molecular pathogenesis of this malignancy, in particular of adenocarcinomas, is still largely unknown. Earlier studies have highlighted a field cancerization phenomenon in which histologically normal-appearing tissue adjacent to neoplastic and pre-neoplastic lesions display molecular abnormalities, some of which are in common with those in the tumors. This review will summarize advances in understanding the field cancerization phenomenon and the potential relevance of this knowledge to gain important and novel insights into the molecular pathogenesis of NSCLC as well as to subsequent development of biomarkers for early detection of lung cancers and possibly personalized prevention."
178,Epigenetic field for cancerization.,Ushijima T.,https://pubmed.ncbi.nlm.nih.gov/17394762/,"Epigenetic alterations, represented by aberrant DNA methylation, are deeply involved in human cancers. In gastric cancers, tumor-suppressor genes are inactivated more frequently by promoter methylation than by mutations. We recently showed that H. pylori infection, a potent gastric carcinogenic factor, induces methylation of specific genes in the gastric mucosae. When the methylation levels were analyzed in the gastric mucosae of healthy volunteers, cases with a single gastric cancer, and cases with multiple gastric cancers, who have increasing levels of risks for gastric cancers, there was a significant increasing trend in the methylation levels among the individuals without current H. pylori infection. This finding unequivocally showed the presence of an epigenetic field for cancerization. The degree of the field defect was measured more conveniently using methylation levels of marker genes than using those of tumor-suppressor genes. The presence of an epigenetic field for cancerization has been indicated for liver, colon, Barrett's esophageal, lung, breast, and renal cancers. Since decreased transcription is involved in the specificity of methylated genes, it is likely that specific genes are methylated according to carcinogenic factors. These findings emphasize the usefulness of DNA methylation as a marker for past exposure to carcinogens and future risk of cancer development."
179,Communication dilemmas in the context of cancer: survivors' and partners' strategies for communicating throughout survivorship.,Miller LE.,https://pubmed.ncbi.nlm.nih.gov/25426747/,"More people are now living longer beyond cancer treatment and are facing the complexities associated with survivorship. Communicating amid a cancer experience, for example, can be difficult for couples, and survivors must face these challenges for extended periods of time. The current study employed a communication perspective to explore couples' conversations throughout cancer survivorship. In-depth interviews with 35 cancer survivors and 25 partners yielded insight into the specific communicative challenges couples face after completing cancer treatment. The data highlight cancer's lingering uncertainties and are discussed in terms of the dyadic challenges inherent in couples' communicative efforts."
180,"Lymphadenectomy for testicular, penile, upper tract urothelial and urethral cancers.","Hu B, Djaladat H.",https://pubmed.ncbi.nlm.nih.gov/25581543/,"Purpose of review:
        
      
      The lymph node dissection (LND) is an integral component of many oncologic surgeries. Better understanding of each cancer's behaviour and improvements in surgical techniques necessitate a critical analysis of lymph node disease and the optimal LND template. This review will focus on updates in managing lymph node disease in testicular, penile, upper tract urothelial and urethral cancer.
    


          Recent findings:
        
      
      For testicular and penile cancer, advances have focused on reducing the morbidity associated with the standard templates of dissection while maintaining oncologic efficacy. For upper tract urothelial carcinoma, data continue to be mixed regarding the need for a LND, though it does seem to benefit patients with advanced tumours. Little is known regarding the optimal LND template for urethral cancer.
    


          Summary:
        
      
      A thorough LND has an established diagnostic and therapeutic role in testicular and penile cancer. For upper tract urothelial carcinoma, the role of an LND remains controversial, though emerging evidence points to an association with improved outcomes. Due to the rarity of urethral cancer, there are no standard LND templates, though excising clinically positive nodes is recommended. For all these cancers, more sophisticated risk stratification based upon clinical and pathologic factors has helped determine which patients require an LND and how to best manage these patients after surgery."
181,"Insulin, chemotherapy, and the mechanisms of malignancy: the design and the demise of cancer.","Ayre SG, Garcia y Bellon DP, Garcia DP Jr.",https://pubmed.ncbi.nlm.nih.gov/11000062/,"The endogenous molecular biology of cancer cells involves autocrine and paracrine secretion of insulin and insulin-like growth-factors I and II, which subserve energy production and growth stimulation, respectively, in these cells. These activities confer on cancer its malignant potential, working as they do autonomously, free from higher levels of integrated control. Taking advantage of cancer's mechanisms of malignancy by employing exogenous insulin as a biologic response modifier, it is possible to potentiate the cytotoxic effects of chemotherapeutic agents for improved treatment of cancer. A synergy between certain membrane and metabolic effects of insulin on cancer cell molecular biology increases anticancer drug efficacy, and it does so with reduced doses of the drugs, enhancing their safety. This treatment strategy has been applied abroad over the last five decades with very promising clinical "
182,Metastatic cancer involving pancreatic duct epithelium and its mimicry of primary pancreatic cancer.,"Matsukuma S, Suda K, Abe H, Ogata S, Wada R.",https://pubmed.ncbi.nlm.nih.gov/9088948/,"We investigated 47 autopsy cases of metastatic cancer involving the pancreas. Metastatic disease in nine cases involved the pancreatic duct epithelium. In two cases, metastatic cancer cells showed Pagetoid features. In three cases, pancreatic metastatic disease showed solitary proliferation with focal in situ carcinoma-like lesions mimicking primary pancreatic cancers. Each of these three cases had primary lung adenocarcinomas. Serial sections revealed abrupt borders between the in situ carcinoma-like lesions and the non-cancerous epithelium. Primary pancreatic cancers did not show Pagetoid features or abrupt borders between the cancerous and non-cancerous epithelium. We conclude that the possible diagnosis of pancreatic metastasis should be carefully ruled out in the histological detection of latent primary pancreatic cancer."
183,The hamster cheek pouch model for field cancerization studies.,"Monti-Hughes A, Aromando RF, Pérez MA, Schwint AE, Itoiz ME.",https://pubmed.ncbi.nlm.nih.gov/25494606/,"External carcinogens, such as tobacco and alcohol, induce molecular changes in large areas of oral mucosa, which increase the risk of malignant transformation. This condition, known as 'field cancerization', can be detected in biopsy specimens using histochemical techniques, even before histological alterations are identified. The efficacy of these histochemical techniques as biomarkers of early cancerization must be demonstrated in appropriate models. The hamster cheek pouch oral cancer model, universally employed in biological studies and in studies for the prevention and treatment of oral cancer, is also an excellent model of field cancerization. The carcinogen is applied in solution to the surface of the mucosa and induces alterations that recapitulate the stages of cancerization in human oral mucosa. We have demonstrated that the following can be used for the early detection of cancerized tissue: silver staining of nucleolar organizer regions; the Feulgen reaction to stain DNA followed by ploidy analysis; immunohistochemical analysis of fibroblast growth factor-2, immunohistochemical labeling of proliferating cells to demonstrate an increase of epithelial cell proliferation in the absence of inflammation; and changes in markers of angiogenesis (i.e. those indicating vascular endothelial growth factor activity, endothelial cell proliferation and vascular density). The hamster cheek pouch model of oral cancer was also proposed and validated by our group for boron neutron capture therapy studies for the treatment of oral cancer. Clinical trials of this novel treatment modality have been performed and are underway for certain tumor types and localizations. Having demonstrated the efficacy of boron neutron capture therapy to control tumors in the hamster cheek pouch oral cancer model, we adapted the model for the long-term study of field cancerized tissue. We demonstrated the inhibitory effect of boron neutron capture therapy on tumor development in field cancerized tissue with acceptable levels of mucositis, a dose-limiting side-effect."
184,"Cancer's conceptions of Marie Francois Xavier Bichat (1771-1802), founder of histology.","Androutsos G, Diamantis A, Vladimiros L.",https://pubmed.ncbi.nlm.nih.gov/17600889/,"The French doctor Bichat had a brief but outstanding career. Although the training of Bichat was exclusively that of a surgeon, his scientific interests embraced all of medicine, especially descriptive anatomy, histology, pathological anatomy and histopathology. His important contribution was to point out that organs were not homogeneous structures but were composed of different tissues."
185,Are macrophages in tumors good targets for novel therapeutic approaches?,"Alahari SV, Dong S, Alahari SK.",https://pubmed.ncbi.nlm.nih.gov/25518927/,"The development of cancer has been an extensively researched topic over the past few decades. Although great strides have been made in cancer prevention, diagnosis, and treatment, there is still much to be learned about cancer's micro-environmental mechanisms that contribute to cancer formation and aggressiveness. Macrophages, lymphocytes which originate from monocytes, are involved in the inflammatory response and often dispersed to areas of infection to fight harmful antigens and mutated cells in tissues. Macrophages have a plethora of roles including tissue development and repair, immune system functions, and inflammation. We discuss various pathways by which macrophages get activated, various approaches that can regulate the function of macrophages, and how these approaches can be helpful in developing new cancer therapies."
186,Circulating Tumor DNA Allele Fraction: A Candidate Biological Signal for Multicancer Early Detection Tests to Assess the Clinical Significance of Cancers.,"Bredno J, Venn O, Chen X, Freese P, Ofman JJ.",https://pubmed.ncbi.nlm.nih.gov/35948080/,"Current imaging-based cancer screening approaches provide useful but limited prognostic information. Complementary to existing screening tests, cell-free DNA-based multicancer early detection (MCED) tests account for cancer biology [manifested through circulating tumor allele fraction (cTAF)], which could inform prognosis and help assess the cancer's clinical significance. This review discusses the factors affecting circulating tumor DNA (ctDNA) levels and cTAF, and their correlation with the cancer's clinical significance. Furthermore, it discusses the influence of cTAF on MCED test performance, which could help inform prognosis. Clinically significant cancers show higher ctDNA levels quantified by cTAF than indolent phenotype cancers within each stage. This is because more frequent mitosis and cell death combined with increased trafficking of cell-free DNA into circulation leads to greater vascularization and depth of tumor invasion. cTAF has been correlated with biomarkers for cancer aggressiveness and overall survival; cancers with lower cTAF had better survival when compared with cancers as determined by the higher cTAF and Surveillance, Epidemiology, and End  MCED-detected cancers in case-control studies had comparable survival to Surveillance, Epidemiology, and End  Because many MCED tests use ctDNA as an analyte, cTAF could provide a common metric to compare performance. The prognostic value of cTAF may allow MCED tests to preferentially detect clinically significant cancers at early stages when outcomes are favorable and this may avoid overdiagnosis."
187,Personalized therapy in oncology: melanoma as a paradigm for molecular-targeted treatment approaches.,Kim KB.,https://pubmed.ncbi.nlm.nih.gov/38935186/,"In recent decades, the field of systemic cancer treatment has seen remarkable changes due to advancements in the understanding of cancer's biology, immunology, and genetic makeup. As a  The goal of personalized cancer therapy is to enhance clinical outcomes by customizing drug treatments to suit the unique genetic and/or epigenetic profiles of each patient's tumor. This approach aims to reduce the side effects commonly associated with ineffective treatments. Advances in genetic sequencing and molecular cytogenetics have been instrumental in identifying cancer-driving mutations and epigenetic irregularities, leading to the development of specific molecular therapies. This review article highlights the progress and success of targeted molecular therapies in treating malignant melanoma, illustrating the concept of personalized cancer treatment."
188,Integration of pain management into comprehensive cancer care.,Levy MH.,https://pubmed.ncbi.nlm.nih.gov/2470492/,"Pain management is an integral component of comprehensive cancer care. Designing an effective pain control strategy for the individual patient requires knowledge of the ways in which a patient's cancer, cancer therapy, and pain therapy can interact. Two important aspects of cancer that affect the way in which pain is managed are the cancer's treatability and components of its pathophysiology that themselves do not cause pain (the cancer's ""nonpain"" pathophysiology). Cancer treatability modifies the need for pain management and the appropriateness of invasive pain procedures. Cancer nonpain pathophysiology can interfere with the oral administration of medications, narrow the patient's therapeutic window for analgesic drugs, limit the effectiveness of psychologic pain therapies, and complicate or preclude invasive pain-relieving procedures. In addition, cancer therapy can interfere with or enhance pain therapy and vice versa. Cancer therapy can interfere with pain therapy by causing pain or by producing other adverse effects. Cancer therapy can enhance pain therapy by reducing the extent of cancer, by acting as a coanalgesic, and by providing intravenous access for parenteral drug administration to patients who require it. Pain therapy can interfere with cancer therapy by increasing or complicating the adverse effects of cancer therapy. Pain therapy can enhance cancer therapy by improving patient performance, and certain palliative surgical procedures may have the ancillary effect of improving organ function. Five case descriptions are presented as illustrations of effective integration of pain management into comprehensive cancer care."
189,Automated tumor segmentation in thermographic breast images.,"Trongtirakul T, Agaian S, Oulefki A.",https://pubmed.ncbi.nlm.nih.gov/37920034/,"Identifying and delineating suspicious regions in thermal breast images poses significant challenges for radiologists during the examination and interpretation of thermogram images. This paper aims to tackle concerns related to enhancing the differentiation between cancerous regions and the  Furthermore, it aims to effectively segment tumors that exhibit limited contrast with the  A new cancer segmentation scheme comprised of two primary stages is proposed to tackle these challenges. In the first stage, an innovative image enhancement technique based on local image enhancement with a hyperbolization function is employed to significantly improve the quality and contrast of breast imagery. This technique enhances the local details and edges of the images while preserving global brightness and contrast. In the second stage, a dedicated algorithm based on an image-dependent weighting strategy is employed to accurately segment tumor regions within the given images. This algorithm assigns different weights to different pixels based on their similarity to the tumor region and uses a thresholding  The proposed enhancement and segmentation  The  These findings convincingly establish the superiority of the proposed  The obtained "
190,A paradoxical idea of cancer's resolution.,"Gogichadze GK, Gedenidze AV.",https://pubmed.ncbi.nlm.nih.gov/11000055/,"Polykaryocytes arising by means of fusion represent genetic deadlock. They cannot enter the S-phase of mitosis and they die quickly. A concept of cancer treatment proposes the conversion of tumor cells synchronously into the stage of unviable polykaryocytes, which leads to dissociation of the tumor substrate, reduction of the mass of tumor, and even to its resolution. Under echoscopic control, it is proposed to introduce into the tumor a solution ofwell-known fusogenic agents, such as polyethylene glycol (PEG) with the 15% dimethylsulfoxide (DMSO)."
191,"A note from history: landmarks in history of cancer, part 3.",Hajdu SI.,https://pubmed.ncbi.nlm.nih.gov/21751192/,"In the early 19th century, microscopy in pathology replaced gross descriptive pathology of the 18th century. Cells became known as the most important and distinct elements of benign and cancerous tissues. Thus, by the mid-1800s, a solid foundation had been laid for microscopy, and surgeons recognized that microscopic diagnosis by pathologists merited attention. In due course, preoperative microscopic diagnoses and classification of cancers in biopsy specimens were incorporated into choosing the most fitting surgical operation."
192,The value of genomics in dissecting the RAS-network and in guiding therapeutics for RAS-driven cancers.,"Shrestha G, MacNeil SM, McQuerry JA, Jenkins DF, Sharma S, Bild AH.",https://pubmed.ncbi.nlm.nih.gov/27338857/,"The rise in genomic knowledge over the past decade has revealed the molecular etiology of many diseases, and has identified intricate signaling network activity in human cancers. Genomics provides the opportunity to determine genome structure and capture the activity of thousands of molecular events concurrently, which is important for deciphering highly complex genetic diseases such as cancer. In this review, we focus on genomic efforts directed towards one of cancer's most frequently mutated networks, the RAS pathway. Genomic tools such as gene expression signatures and assessment of mutations across the RAS network enable the capture of RAS signaling complexity. Due to this high level of interaction and cross-talk within the network, efforts to target RAS signaling in the clinic have generally failed, and we currently lack the ability to directly inhibit the RAS protein with high efficacy. We propose that the use of gene expression data can identify effective treatments that broadly inhibit the RAS network as this approach measures pathway activity independent of mutation status or any single mechanism of activation. Here, we review the genomic studies that map the complexity of the RAS network in cancer, and that show how genomic measurements of RAS pathway activation can identify effective RAS inhibition strategies. We also address the challenges and future directions for treating RAS-driven tumors. In summary, genomic assessment of RAS signaling provides a level of complexity necessary to accurately map the network that matches the intricacy of RAS pathway interactions in cancer."
193,Multiple primary cancers in patients with gastric cancer.,"Wu CW, Lo SS, Chen JH, Hsieh MC, Li AF, Lui WY.",https://pubmed.ncbi.nlm.nih.gov/16795993/," We evaluate the current status of MPC with gastric cancer.
    


          
    


          7%). Second cancer (77.8%) was discovered within 5 years before and after the onset of gastric cancer. 34.3% of patients were discovered within 1 year (synchronous tumor). In the 77 male patients, prostate cancer was the most common occurrence (19.5%), followed by cancers of the colon (18.2%) and liver (14.3%). In the 22 female patients, colon cancer was the most common (31.9%) followed by breast and cervix cancers (22.7%). These cancers were the most common diseases in Taiwan in the same period. Gastric cancer patients with MPC had less stromal reaction and better survival than those without. Patients with metachronous secondary tumors had more peritoneal dissemination and worse survival than those with synchronous primary cancer.
    


          Conclusions:
        
      
      Gastric cancer patients may develop second cancer(s), which is often a current prevalent malignancy. Knowledge of time to development and mode of organ association may allow clinicians to detect potentially curable subsequent cancer(s)."
194,Retrospective studies of gastric subserosal (ss) cancer--in comparison to pm- and se-cancers.,"Takeda J, Koufuji K, Tanaka T, Kodama I, Hashimoto K, Kakegawa T.",https://pubmed.ncbi.nlm.nih.gov/1405436/,"The deepest gastric cancer invasion into the tela subserosa is expressed as the ss-cancer. Subserosal gastric cancers (ss) can be divided into 4 subtypes; ss alpha, ss beta, (ss gamma) and ss gamma, pathologically. These four subtypes were compared to cancerous invasion into the muscularis propria (pm-cancer) and cancerous invasion with serosal exposure (se-cancer). During the 10 years from 1979 to 1988, a total of 938 cases with gastric cancer were resected in the First Department of Surgery, Kurume University Hospital. Of these, 104 (11.1%) cases were ss-cancers, consisting of 28 (27%) cases of ss alpha, 33 (32%) cases of ss beta, 4 (3%) cases of (ss gamma) and 39 (38%) cases of ss gamma. Pm-cancers and ss-cancers were most frequently observed in Borrmann type 2, macroscopically, and in the differentiated type, histologically. On the other hand, se-cancers were frequently observed in Borrmann type 3 and in an undifferentiated type. Positive lymph node metastases were found in 49.1% of pm-cancers, in 50.0% of ss-cancers and in 79.9% of se-cancers (p < 0.01), with no statistical difference in the positive lymph node metastasis rates for the subdivisions of ss-cancer. In ss-cancer, however, there was a statistical difference in prognosis according to the tumor size, and according to the degree of subserosal infiltration. The 5-year survival rate was 82.3% for pm-cancer, 75.0% for ss-cancer and 34.7% for se-cancer (p < 0.01)."
195,A clinical and radiologic study of primary liver cancer associated with extrahepatic primary cancer.,"Takayasu K, Kasugai H, Ikeya S, Muramatsu Y, Moriyama N, Makuuchi M, Yamazaki S, Hirohashi S.",https://pubmed.ncbi.nlm.nih.gov/1309309/,"In a consecutive series of 393 patients with excised and pathologically proven primary liver cancer (PLC)--including 374 hepatocellular carcinomas (HCC), nine cholangiocellular carcinomas (CCC), and ten mixed type of HCC and CCC--33 patients (8.4%) had one or two other malignancies in the extrahepatic organ(s). Of these, 29 had double cancers and four, triple cancers. This was synchronous in 11 patients, metachronous in 20 (including 18 with double cancers and two with triple cancers) and synchronous and metachronous in two with triple cancers. Metachronous cancer was found in 21 patients 1 year before hepatectomy for PLC and in three patients, 1 year after hepatectomy. The median age of PLC patients with multiple primary cancer (MPC) was 63.6 +/- 6.9 years; this was significantly greater than that of PLC patients without MPC (P less than 0.01). The associated cancer was gastric cancer in 11 patients (29.7%), colorectal cancer in six, pharyngeal cancer in four, and other cancers in ten different organs in 16. Thirteen of 22 patients had a history of blood transfusion. The incidence of liver cirrhosis in PLC associated with MPC (57.6%) was significantly lower than that without MPC (82.8%, P less than 0.01). The differential diagnosis of PLC from liver metastasis was possible retrospectively in 78.6% using sonograms, 79.3% using computed tomograms, and 91.3% using angiograms. The survival rates of patients with PLC with (n = 33) and without (n = 299) MPC who had undergone hepatectomy were 97.0% and 85.4% at 1 year, 55.5% and 59.5% at 3 years, and 40.5% and 40.1% at 5 years, respectively. There was no significant difference between the survival rates of those who underwent operations for PLC and extrahepatic primary cancer(s) synchronously and metachronously."
196,[Clinical analysis of multiple primary carcinomas in colorectal cancer patients].,"Zhang CH, He YL, Zhan WH, Cai SR, Huang MJ, Wang JP, Peng JJ.",https://pubmed.ncbi.nlm.nih.gov/16148997/,"
    


           Patients were divided into multiple-cancer group (MCG) and single- cancer group (SCG). Clinical features and prognosis were compared between two groups.
    


          4 % (83/ 1125). Forty- seven patients had multiple colorectal cancers metachronous CRC(S) in 12 and synchronous CRC(S) in 35. Thirty- six patients 5 patients with synchronous cancers had malignant tumors outside colorectal tract,12 of whom were gastric carcinomas. No significant differences were found between MCG and SCG regarding gender, onset age, Dukes stage and differentiation of index CRC. Cancer family history (P=0.002) and colorectal adenoma (P=0.036) were significantly more common in MCG than those in SCG. The local recurrence or distant metastasis in MCG was significantly higher than that in SCG (P=0.047), though there was no significant difference in survival between the two groups. Forty- one percent of index tumors were located in right colon in MCG, significantly higher than that in SCG (P=0.048). The secondary tumors were mainly adenoma cancerization in MCG.
    


          Conclusion:
        
      
      Cancer family history and colorectal adenoma seems to be at high risk for developing multiple cancers in CRC patients. Gastric cancer and colorectal adenoma cancerization were common secondary tumors of multiple primary neoplasms in patients with colorectal carcinoma."
197,Effective integration of pain management into comprehensive cancer care.,Levy MH.,https://pubmed.ncbi.nlm.nih.gov/1722037/,"Pain management is an integral component of comprehensive cancer care. The combined goals of optimal comfort and optimal function require a working understanding of how pain therapy interacts with cancer and cancer therapy. The two main aspects of cancer which affect pain management are the cancer's treatability and its non-pain pathophysiology. Cancer treatability determines the importance of pain management and the appropriateness of invasive pain-blocking procedures. Cancer non-pain pathophysiology often hinders pain control by preventing oral administration of medications, narrowing a patient's therapeutic window for opioid analgesics, limiting psychological therapies, and interfering with invasive pain relieving procedures. Cancer therapy can impair or enhance pain therapy and vice versa. Cancer therapy can impair pain therapy by its production of adverse effects or by its direct causation of pain. Cancer therapy can enhance pain therapy by reducing the amount of cancer, by including drugs which act as coanalgesics, and by providing intravenous access devices for parenteral opioid administration. Pain therapy can impair cancer therapy by augmenting or complicating cancer therapy's adverse effects. Pain therapy can enhance cancer therapy by improving organ function and patient performance status permitting previously limited or contraindicated cancer therapies to be given. Five case studies are presented to illustrate how effective integration of pain management into comprehensive cancer care is mandatory for optimal care of cancer patients and their families."
198,Oral field cancerization: current evidence and future perspectives.,"Angadi PV, Savitha JK, Rao SS, Sivaranjini Y.",https://pubmed.ncbi.nlm.nih.gov/22354325/,"
    


          Discussion:
        
      
      This review deals in detail with the origin, principle, various theories used to explain this effect and molecular, genetic, as well as cytogenetic findings related to oral field cancerization. Further, the clinical implications and future research directives are also discussed."
199,"[Breast cancer pathogenesis of stagnation of phlegm, poison and blood stasis: rationale and clinical application in traditional Chinese medicine].","Liu S, Hua YQ, Sun ZP, Tan S, Lu DM.",https://pubmed.ncbi.nlm.nih.gov/17352863/,"Breast cancer is called ""Ruyan"" in literature of traditional Chinese medicine. We synthesized the ancient and contemporary discussions and raised the theory that ""Duxie"" (poisonous pathogenic factor) is the etiological factor and pathologic product through the whole course of breast cancer. ""Liuyin Fudu"" (latent poison of six exogenous pathogenic factors) and ""Qiqing Yudu"" (stagnant poison of seven emotions) are the main etiological factors affecting the breast cancer occurrence. ""Aidu Neisheng"" (internal product of cancer poison) is the essential change in breast cancer occurrence. ""Tandu Yujie"" (stagnation of phlegm, poison and blood stasis) is the essential pathogenesis of the breast cancer's development. ""Yudu Weiqing"" (vestigial poison) is the main pathogenesis of breast cancer after operation. ""Yudu Pangcuan"" (vestigial poison invasion elsewhere) is the key pathogenesis of recurrence and metastasis after operation. ""Sanjie Jiedu"" (dispersing accumulation and detoxification) is an important therapeutic principle in breast cancer's treatment after operation. The ""Tandu Yujie"" pathogenesis theory and ""Sanjie Jiedu"" therapeutic principle developed the theory about breast cancer in traditional Chinese medicine, and have some clinical application value."
200,The hydra phenomenon of cancer: why tumors recur locally after microscopically complete resection.,"Höckel M, Dornhöfer N.",https://pubmed.ncbi.nlm.nih.gov/15833823/,"After surgical resection with microscopically clear margins, solid malignant tumors recur locally in up to 50%. Although the effect of a local tumor recurrence on the overall survival may be low in common cancers such as carcinoma of the breast or prostate, the affected patients suffer from exacerbated fear and the burden of the secondary treatment. With some tumor entities such as carcinoma of the uterine cervix or carcinoma of the head and neck, a local recurrence indicates incurability in the majority of cases. The pathomechanisms of local tumor spread and relapse formation are still unclear and comparatively little research has been devoted to their elucidation. Through the analysis of clinical and molecular data, we propose the concept of two pathogenetically and prognostically different local relapse types (i) in situ recurrences that arise in the residual organ/organ system not involved in the surgery for the primary tumor and (ii) scar recurrences that develop at the site of previous tumor resection. Whereas field cancerization, the monoclonal or multiclonal displacement of normal epithelium by a genetically altered but microscopically undistinguishable homologue, may explain the origin of in situ recurrences, most scar recurrences are regarded as the  The therapeutic implications derived from these concepts and areas of future research aimed to reduce local relapses are discussed in this perspective."
201,Ploidy analysis of field cancerization and cancer development in the hamster cheek pouch carcinogenesis model.,"Raimondi A, Cabrini R, Itoiz ME.",https://pubmed.ncbi.nlm.nih.gov/15752258/," Our aim was to numerically characterize the premalignant and malignant lesions and expressions of field cancerization in this model using ploidy as the end-point.
    


          
    


           The aneuploidy index was higher in NUMF areas than in control and differed significantly from control in preneoplastic areas and carcinoma.
    


          Conclusions:
        
      
      The unexpected alteration in DNA content observed in NUMF epithelia is of great relevance as a biomarker of field cancerized areas."
202,"Gendered Hormonal Binaries and the Development of the Category of ""Hormone-Dependent Cancers,"" 1940-1980.",Surita G.,https://pubmed.ncbi.nlm.nih.gov/38588195/,"This article considers the establishment of the category of ""hormone-dependent cancers,"" identified around the middle of the twentieth century as cancers sustained by particular hormones. A comparison of hormonal treatments for prostate cancer and those for breast cancer reveals that the genesis of ""hormone-dependent cancer"" as a biomedical category relied upon assumptions that cast androgens and estrogens as opposing ends of a gendered hormonal binary of health and disease. In the 1930s, cancer researchers claimed ""female sex hormones"" (estrogens) exacerbated breast cancer and ""male sex hormones"" (androgens) prevented it. In the early 1940s, Dr. Charles Huggins applied the opposite logic to the treatment of human prostate cancer, which he determined to be ""hormone-dependent."" As ""hormone dependency"" was also recognized in human breast cancer over the subsequent decades, estrogen claimed a prominent place in discussions of breast cancer's causation, diagnosis, and treatment. This close association between estrogen and breast cancer contributed to reinterpretations of both biomedical categories."
203,Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development.,"Schoultz E, Johansson E, Moccia C, Jakubikova I, Ravi N, Liang S, Carlsson T, Montelius M, Patyra K, Kero J, Paulsson K, Fagman H, Bergo MO, Nilsson M.",https://pubmed.ncbi.nlm.nih.gov/34379110/,"Cancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAF-mutant lineage becomes a cancerized lineage. The TgCreERT2;BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution."
204,"Determinants of enrollment in cancer clinical trials: the relationship between the current state of knowledge, societal disease burden, and randomized clinical trial enrollment.","Lloyd S, Buscariollo DL, Gross CP, Makarov DV, Yu JB.",https://pubmed.ncbi.nlm.nih.gov/23946172/,"Whether clinical cancer research currently focuses on gaps in the evidentiary basis for clinical guidelines and/or on cancers that impose greater societal burden is unclear. This study assessed the relationship between cancer research efforts in terms of planned randomized controlled trial (RCT) enrollment,  The authors calculated the planned RCT enrollment listed on ClinicalTrials.gov for the 17 most prevalent solid cancers. Using cancer type as the unit of analysis, linear regression was used to examine the association between planned enrollment in RCTs and 1) evidence quality, as measured by the absolute number and percent of highest quality category (category 1 [C1]) recommendations in the NCCN Clinical Practice Guidelines in Oncology for each cancer, and 2) measures of burden on society, including prevalence, incidence, person-years of life lost (PYLL), and disability-adjusted life years (DALY). Non-normal distributions were log transformed when appropriate. Overall, 15% of the NCCN recommendations were based on the highest quality evidence.  Planned RCT enrollment ranged from 2270 (testis) to 492,876 (breast) and was correlated neither with absolute number nor percent of C1 recommendations for that cancer. Planned RCT enrollment was positively correlated with a cancer's prevalence (P=.01), incidence (P<.01), PYLL (P<.01), and DALY (P<0.01). In multivariate analysis, prevalence (P<.01) and PYLL (P<.01) had the strongest association with planned RCT enrollment. Findings showed, therefore, that planned cancer RCT enrollment is associated with higher societal disease burden, not the quality of a cancer's clinical guidelines."
205,"Cutaneous field cancerization: clinical, histopathological and therapeutic aspects.","Torezan LA, Festa-Neto C.",https://pubmed.ncbi.nlm.nih.gov/24173184/,"The concept of ""field cancerization"" was first introduced by Slaughter in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. Organ systems in which field cancerization has been described since then are: head and neck (oral cavity, oropharynx, and larynx), lung, vulva, esophagus, cervix, breast, skin, colon, and bladder. Recent molecular studies support the carcinogenesis model in which the development of a field with genetically altered cells plays a central role. An important clinical implication is that fields often remain after the surgery for the primary tumor and may lead to new cancers, designated presently as ""a second primary tumor"" or ""local recurrence,"" depending on the exact site and time interval. In conclusion, the development of an expanding pre-neoplastic field appears to be a critical step in epithelial carcinogenesis with important clinical consequences. Diagnosis and treatment of epithelial cancers should not only be focused on the tumor but also on the field from which it developed. The most important etiopathogenetic, clinical, histopathological and therapeutic aspects of field cancerization are reviewed in this article."
206,The role of the acute care nurse practitioner in the implementation of the commission on cancer's standards on palliative care.,Fox K.,https://pubmed.ncbi.nlm.nih.gov/24480663/,"As valuable members of the oncology team, acute care nurse practitioners (ACNPs) are in the perfect position to deliver high-quality palliative care. They are instrumental in coordinating the palliative care needs of their patients. Through proper training, ACNPs are able to assess, plan, implement, and evaluate palliative care interventions. Along with oncology-certified nurses, ACNPs help their patients navigate the complexities of the healthcare system. The skills that the American College of Surgeons Commission on Cancer identified in its standard for palliative care are skills possessed by ACNPs, making them the perfect fit to carry out these standards in healthcare institutions around the United States."
207,Valerie Weaver: overcoming cancer's stiff resistance. Interview by Caitlin Sedwick.,Weaver V.,https://pubmed.ncbi.nlm.nih.gov/21624950/,Weaver investigates the mechanical properties of tumors and how changes in the tumor microenvironment influence cancer cell behavior.
208,Chemoprevention of aerodigestive tract cancers.,"Kim ES, Hong WK, Khuri FR.",https://pubmed.ncbi.nlm.nih.gov/11818472/,"Epithelial cancers are a major worldwide health problem. Since the mid-1970s, advances in multidisciplinary cancer therapeutics have only slightly improved the mortality rate from epithelial malignancies. Chemoprevention is the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent progression to invasive cancer. Chemopreventive medicine is based on translating basic biologic research into clinical chemical interventions, thus attempting to impede carcinogenesis. Its principles build on the concepts of field cancerization (diffuse epithelial injury that  Chemoprevention targets the carcinogenic process at earlier and potentially more reversible stages, focusing on the inhibition of one or many steps in the progression towards cancer. Strategies of chemoprevention include primary prevention in groups at high risk, reversal of premalignant lesions, and prevention of second primary tumors."
209,Human papillomavirus infection on initiating synchronous esophageal neoplasia in patients with head and neck cancer.,"Wang WL, Wang YC, Chang CY, Lo JL, Kuo YH, Hwang TZ, Wang CC, Mo LR, Lin JT, Lee CT.",https://pubmed.ncbi.nlm.nih.gov/27107411/," We aimed to investigate whether HPV infection underlies the field cancerization phenomenon over upper aerodigestive tract to develop synchronous multiple cancers.
    


          Study design:
        
      
      A case control study.
    


           The clinicopathologic characteristics were further analyzed according to the presence of HPV.
    


           The prevalence of HPV infection were not different between the synchronous and HNSCC alone groups (P = 0.357). Testing for HPV in paired HNSCC and ESCC tissues from the same patient revealed that none were concomitantly HPV-positive. Multivariate logistic regression showed drinking alcohol (odds ratio [OR], 18.75; P = 0.030), alcohol flushing (OR, 2.53; P = 0.041), and body mass index (OR, 0.77; P = 0.001) but not HPV infection were independent risk factors for synchronous phenotype. The patients with synchronous ESCCs had significantly poorer survival than those with HNSCC alone (5-year overall survival: 30% vs. 70%; log-rank P < 0.001). However, patients with HPV-positive HNSCC tend to have favorable outcome than those with HPV-negative HNSCC.
    


          Conclusions:
        
      
      HPV infection plays little role in field cancerization phenomenon to initiate synchronous SCC. The synchronous HNSCC and ESCC from the same patients had no clonal relationship. Routine endoscopic examination of the esophagus should be recommended for patients with risk factors identified.
    


          Levels of evidence:
        
      
      NA. Laryngoscope, 126:1097-1102, 2016."
210,Recent advances in field cancerization and management of multiple cutaneous squamous cell carcinomas.,Christensen SR.,https://pubmed.ncbi.nlm.nih.gov/29904586/,"Cutaneous squamous cell carcinoma (SCC) is among the most common cancers in humans, and many patients with SCC will develop multiple tumors within their lifetime. The field cancerization concept, originally proposed over 60 years ago, hypothesized that multiple primary cancers may arise simultaneously and coexist with subclinical precursor lesions within a defined field. Genetic sequencing of SCC and precursor lesions has identified what may be the earliest clonal proliferations in SCC development and confirmed that field cancerization in the skin is mediated by ultraviolet radiation. For patients with multiple SCCs and severe actinic damage, treatment of precursor lesions within a cancerized field can decrease the risk of subsequent cancer development. Sunblock is an effective intervention for field cancerization, even in patients with established disease. There is now direct evidence that field therapy with topical 5-fluorouracil is effective in reducing the incidence of subsequent SCC, and there is indirect evidence suggesting that topical imiquimod, topical ingenol mebutate, and photodynamic therapy are similarly effective. There is limited direct evidence to show that systemic acitretin or nicotinamide can decrease incident SCC in patients with field cancerization. In this review, an approach to the management of patients with multiple SCCs and field cancerization is presented along with the rationale to support field-directed therapy."
211,Angiotensin-converting enzyme and its association with outcome in lung cancer.,Rømer FK.,https://pubmed.ncbi.nlm.nih.gov/6258623/,"Serum angiotensin-converting enzyme (SACE) in 141 patients with newly detected primary lung cincer was 22.1 +/- 6.1 nmol/ml/min (mean +/- s.d.); lower than in healthy controls (24.4 +/- 6.2 nmol/ml/min, P less than 0.02). No correlation was found between SACE and sex, age, site of cancer, histological type, or lung function. After subdivision of the patients according to increasing SACE levels: less than 16.0 (mean SACE of lung cancer--s.d.), 16.0-22.0, 22.1-28.2 and greater than 28.2 nmol/ml/min (mean SACE of lung cancer + s.d.) there was a strong association (P less than 0.001) between SACE level and the proportion of patients who were radically operated without relapse during 8-22 months follow-up. None of 23 patients within the lowest SACE range were cured, even though 7 were referred for operation after preoperative examination. In contrast, 10/25 patients (40%) within the highest SACE range were cured. The "
212,Actinic keratosis and squamous cell carcinoma: clinical and pathological features.,"Filosa A, Filosa G.",https://pubmed.ncbi.nlm.nih.gov/26099352/,"Actinic keratoses (AKs) are the most common keratinocytederived precancerous lesion in humans; they can be observed predominantly in fair-skinned individuals on sun-exposed surfaces. The primary risk factor for AKs is cumulative UV exposure from sunlight and/or tanning salons. AKs may present on a patient as a few detectable lesions. In addition to these, there are subclinical (invisible) AKs that are estimated to occur up to 10 times more often than visible AKs, since unprotected skin receives UV radiation from the sun. Clinical and subclinical AK lesions occurring in photo-damaged skin are called field cancerization. A field of change can be up to 7 cm around the primary lesions,  AKs are defined at the histologic level by dysplasia and consist of keratinocytes manifesting atypical nuclei that are enlarged, irregular, and hyperchromatic. The histopathologic changes noted in keratinocytic proliferative lesions involve disturbance of normal surface maturation. The degree and extent of keratinocytic atypia vary in these lesions. The atypical keratinocytes show enlarged nuclei with hyperchromasia, dyskeratosis and mitoses in any layer of the epidermis. In lesions of epidermal dysplasias, surface keratinocytic maturation is present, and a granular cell layer is usually noted. In intraepidermal carcinomas, there is full-thickness involvement of the epidermis by the atypical keratinocytes. While molecular techniques have improved our ability to distinguish squamous cell carcinomas (SCCs) from AKs, they have also reinforced the concept that non-melanoma skin cancers arise through a complex series of aberrations at the molecular level. AKs represent a spectrum along the continuum to invasive cancer. They are the most visible manifestation of field cancerization which creates a population of atypical cells with the potential to progress to invasive malignancy capable of metastasis. As the perilesional epithelium also has abnormalities due to photo exposure, understanding the existence of a ""cancerization field"" should be explained to the patients, reinforcing the importance of preventive clinical follow-up. The aim of the present review was to emphasize the histopathological aspect of the morphological spectrum in AK, and SCCs, also elucidating the clinicopathology of field canceriziation."
213,Narrow band imaging in the intra-operative definition of resection margins in oral cavity and oropharyngeal cancer.,"Tirelli G, Piovesana M, Gatto A, Tofanelli M, Biasotto M, Boscolo Nata F.",https://pubmed.ncbi.nlm.nih.gov/26216339/,"5-2 cm from the gross tumour edge is currently considered appropriate, and the status of resection margins is the most reliable indicator of radicality. Awareness of ""field cancerization"" calls for a re-evaluation of the benchmarks of tumour resection; however, its identification is not simple because the dysplastic areas may be far from the main lesion and difficult to recognize macroscopically. New technologies such as narrow band imaging (NBI) could improve the detection of neoplastic and pre-neoplastic areas, ensuring more precise resections. The main purpose of this study was to investigate the value of NBI in detecting pre-cancerous areas and/or cancer around the tumour bulk intra-operatively, to achieve adequate resection of the tumour.
    


          Materials and  Resections were performed following the NBI-drawing if extemporaneous histological examinations of the NBI-defined enlargements were positive for dysplasia or cancer. The number of clear margins was evaluated.
    


           Among the NBI-defined enlargements, 25% were positive for dysplasia and 75% for cancer. The sensitivity, specificity, positive and negative predictive values were 100%, 88.9%, 100% and 87.5%, respectively.
    


          Conclusion:
        
      
      The "
214,The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment.,"Wagner JS, Adson MA, Van Heerden JA, Adson MH, Ilstrup DM.",https://pubmed.ncbi.nlm.nih.gov/6721600/,"Five-year survival after resection of hepatic metastases from colorectal cancer is 25%. Although resection palliates some patients who do not live that long, 50% of patients so treated are not helped at all. Until ignorance of a cancer's real stage is resolved by improved techniques, the evaluation and choice of therapy can be based only upon knowledge of the natural history of untreated metastases and determinants of prognosis derived from treated patients. Analysis of the survival rates of 252 patients who had biopsy proven, unresected hepatic metastases that were the only evidence of residual disease shows the extent to which natural history, rather than resection, may determine length of survival-- and indicates the need for critical analysis of 2- and 3-year survival rates reported after any therapy. Study of 141 patients who had hepatic metastases resected shows that the stage of the primary lesion, being female, and the absence of extrahepatic metastases are significant determinants of favorable prognosis after resection of hepatic metastases."
215,"Gene expression subtraction of non-cancerous lung from smokers and non-smokers with adenocarcinoma, as a predictor for smokers developing lung cancer.","Stav D, Bar I, Sandbank J.",https://pubmed.ncbi.nlm.nih.gov/18811983/," Adenocarcinoma is becoming the most common form of lung cancer. Cigarette smoking is the main risk factor for lung cancer. Long-term cigarettes smoking may be characterized by genetic alteration and diffuse injury of the airways surface, named field cancerization, while cancer in non-smokers is usually clonally derived. Detecting specific genes expression changes in non-cancerous lung in smokers with adenocarcinoma may give us instrument for predicting smokers who are going to develop this malignancy.
    


          
    


           The cDNA was hybridized to the U133A GeneChip array. Hierarchical clustering analysis on genes obtained from smokers and non-smokers, after subtracting were exported to the Ingenuity Pathway Analysis software for further analysis.
    


           They were subsequently mapped and sorted based on location, cellular components, and biochemical activity. The gene functional analysis disclosed 20 genes, which are involved in cancer process (P = 7.05E-5 to 2.92E-2).
    


          Conclusion:
        
      
      Detected genes may serve as a predictor for smokers who may be at high risk of developing lung cancer. In addition, since these genes originating from non-cancerous lung, which is the major area of the lungs, a sample from an induced sputum may represent it."
216,Understanding the Lymphatics: Review of the N Category in the Updated TNM Staging of Cancers of the Digestive System.,"Pedersen CK, Babu AS.",https://pubmed.ncbi.nlm.nih.gov/32432907/," The N category has been significantly updated in the 8th edition of the American Joint Committee on Cancer's TNM classification. To ensure correct tumor staging, prognosis, and management, it is critical to be aware of these changes. This article reviews the updated N category, organ-specific regional lymph nodes, and lymphatic drainage pathways for cancers of the digestive system from the esophagus to the anal canal. CONCLUSION. Detection of lymph node involvement may be challenging, and knowledge of nodal characteristics, lymphatic drainage pathways, and imaging modalities is essential to optimize detection rate to ensure accurate staging, prognosis estimation, and streamlined management."
217,A biocompatible and magnetic nanocarrier with a safe UV-initiated docetaxel release and cancer secretion removal properties increases therapeutic potential for skin cancer.,"Kong F, Huang X, Yue D, Pan J.",https://pubmed.ncbi.nlm.nih.gov/28482566/,"Cancer is a leading fatal disease worldwide. To increase its therapeutic efficiency, more effective with less side effect and patient acceptable administration approach is expected. Moreover, modification of tumor microenvironment is proved to be operative recently. In this paper, a nanocarrier named LDEDDS was developed for intelligent tropical administration of skin cancer, along with removal of hydrophobic cancerous secretion to change tumor microenvironment. It was made by coating of amphipathic polymer P(BA-co-HBA) on docetaxel (TXT, a model hydrophobic anticancer drug) loaded Fe3O4@ZnO. 75±0.15%, corresponding to loading capacity of 17.95±2.97% when the mass ratio of Fe3O4@ZnO to TXT was 1:20. The LDEDDS had a narrow distribution size of 115.8nm in average and was superparamagnetic. Without UV radiation, it had low TXT release (<7% in 48h) and cytotoxicity (<14% in 96h) to both the normal and carcinoma skin cells. While under a UV with a dose much lower than physiological dose of normal sunlight, LDEDDS released around 60% and 90% of TXT in 1 and 48h. 1h UV treated LDEDDS removed up to 62% of cancer secreted epidermal growth factor (EGF), a model hydrophobic secretion in 96h. Consequently, 1h UV treated LDEDDS inhibited up to 60% of the growth of skin cancer cells in 96h, overriding those effects of the same concentration of TXT in in vitro cellular  This is the first study to change tumor microenvironment by removal of cancerous secretion and is proved to be effective. Along with the superparamagnetic property, which provides potential for concentrating, increasing penetration and internalization into cancerated cells as well as removing from body under an external magnetic field, we predict LDEDDS will have potential applications in clinic skin cancer therapy."
218,The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions.,"Bouyahya A, Mechchate H, Oumeslakht L, Zeouk I, Aboulaghras S, Balahbib A, Zengin G, Kamal MA, Gallo M, Montesano D, El Omari N.",https://pubmed.ncbi.nlm.nih.gov/35327559/,"Cancer is a complex disease  The mechanistic understanding of the pathways involved in tumor transformation has implicated a priori predominance of epigenetic perturbations and a posteriori genetic instability. In this work, we aimed to explain the mechanistic involvement of epigenetic pathways in the cancer process, as well as the abilities of natural bioactive compounds isolated from medicinal plants (flavonoids, phenolic acids, stilbenes, and ketones) to specifically target the epigenome of tumor cells. The molecular events leading to transformation, angiogenesis, and dissemination are often complex, stochastic, and take turns. On the other hand, the decisive advances in genomics, epigenomics, transcriptomics, and proteomics have allowed, in recent years, for the mechanistic decryption of the molecular pathways of the cancerization process. This could explain the possibility of specifically targeting this or that mechanism leading to cancerization. With the plasticity and flexibility of epigenetic modifications, some studies have started the pharmacological screening of natural substances against different epigenetic pathways (DNA methylation, histone acetylation, histone methylation, and chromatin remodeling) to restore the cellular memory lost during tumor transformation. These substances can inhibit DNMTs, modify chromatin remodeling, and adjust histone modifications in favor of pre-established cell identity by the differentiation program. Epidrugs are molecules that target the epigenome program and can therefore restore cell memory in cancerous diseases. Natural products isolated from medicinal plants such as flavonoids and phenolic acids have shown their ability to exhibit several actions on epigenetic modifiers, such as the inhibition of DNMT, HMT, and HAT. The mechanisms of these substances are specific and pleiotropic and can sometimes be stochastic, and their use as anticancer epidrugs is currently a remarkable avenue in the fight against human cancers."
219,Cognitive determinants of quality of life after onset of cancer.,"Wagner MK, Armstrong D, Laughlin JE.",https://pubmed.ncbi.nlm.nih.gov/7501754/,"To investigate cognitive coping styles and how they might relate to perceived quality of life for individuals seriously ill with cancer 41 mostly elderly, male patients with a wide variety of cancers were administered the Illness Effects Questionnaire, a quality of life measure, the COPE Questionnaire, which samples different coping strategies, and questions regarding beliefs about illness behaviors, expectations about cancer's effects, comparisons of the participants' lives with those of others, feelings since having cancer, and motivation to resist lifestyle disruptions. Six of the belief factors and two of the coping strategies were related to perceived quality of life. If the effects of cancer were less than expected, quality of life was better; with an expectation of a negative effect from the disease, lowered quality of life was perceived. Two coping strategies were related to quality of life, suppression of competing activities and using religious practices. Other relationships were also discussed."
220,Field cancerization: concept and clinical implications in head and neck squamous cell carcinoma.,"Jaiswal G, Jaiswal S, Kumar R, Sharma A.",https://pubmed.ncbi.nlm.nih.gov/24416996/,"Cancer begins with multiple cumulative epigenetic and genetic alterations that sequentially transform a cell or a group of cells in a particular organ. The early genetic events might lead to clonal expansion of pre-neoplastic daughter cells in a particular tumor field. Subsequent genomic changes in some of these cells drive them towards the malignant phenotype. These transformed cells are diagnosed histopathologically as cancers owing to changes in cell morphology. Conceivably, a population of daughter cells with early genetic changes (without histopathology) remains in the organ, demonstrating the concept of field cancerization. The concept of ""field cancerization"" was first introduced by Slaughter et al in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. With present technological advancement and carefully designed studies using appropriate control tissue will enable identification of important molecular signatures in these genetically transformed but histologically normal cells. Such tumor-specific biomarkers should have excellent clinical utility. This review examines the concept of field cancerization in head and neck cancer and its possible utility in early detection, tumor progression and clinical significance."
221,Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer.,"Müller MW, Giese NA, Swiercz JM, Ceyhan GO, Esposito I, Hinz U, Büchler P, Giese T, Büchler MW, Offermanns S, Friess H.",https://pubmed.ncbi.nlm.nih.gov/17631638/,"Neural alterations and aberrantly expressed nerve-specific factors promoting tumor progression are known to contribute to pancreatic cancer's extremely poor prognosis. Despite hints that axon guidance factor semaphorin 3A (SEMA3A) may function as a tumor inhibitor, its clinical importance and therapeutic potential have not yet been explored. The present study investigated the role of SEMA3A and its receptors-plexins A1-A4 (PLXNA1-A4) and neuropilin-1 (NRP1)-in pancreatic cancer. QRT-PCR and immunohistochemical analyses revealed overexpression of SEMA3A, NRP1 and PLXNA1 in metaplastic ducts, malignant cells and nerves of cancerous specimens, and showed that elevated levels of corresponding mRNA (6.8-fold, 2.0-fold and 1.5-fold, respectively) clearly correlated with negative clinicopathological manifestations such as shorter survival (SEMA3A and PLXNA1) and a lesser degree of tumor differentiation (NRP1) in Stages I-III patients. High SEMA3A expression in pancreata of Stage IV M1 patients and in peritoneal metastases, and consequent functional studies indicated that poor clinical outcome might be related to the ability of SEMA3A to promote dissemination and invasiveness of pancreatic cancer cells through activation of multiple pathways involving Rac1, GSK3b or p42/p44 MAPK, but not E- to N-cadherin switch, MMP-9 or VEGF induction. Thus, this study is the first to quantify expression of the SEMA3A system in human malignancy and to show that overexpression of SEMA3A by nerves and transformed cells leads to a SEMA3A-rich environment which may favor malignant activities of tumor cells. Furthermore, negative clinicopathological correlations suggest that SEMA3A might represent a novel intervention target but not a treatment option for pancreatic cancer patients."
222,Craig Thompson: the method to cancer's madness. Interview by Caitlin Sedwick.,Thompson C.,https://pubmed.ncbi.nlm.nih.gov/21079241/,Thompson studies the metabolic requirements of dividing immune and cancer cells.
223,Prognostic value of NOB1 expression levels in various cancers: a systematic review and meta-analysis.,"Zhang Y, Li Z, Chen X, Huang Y, Zou B, Xu Y.",https://pubmed.ncbi.nlm.nih.gov/38881528/,"Aim: This study evaluates the prognostic significance of NOB1 expression levels in various cancers.Patients & 12, 95% CI: 1.82-2.48) and PFS (HR: 2.23, 95% CI: 1.62-3.07) and was associated with adverse tumor characteristics such as stage and metastasis.Conclusion: Elevated NOB1 expression in various tumors signifies a poor prognosis, serving as a predictive marker for malignancy outcomes.PROSPERO Register Number: CRD42023394051."
224,"[Coincidental squamous cell cancers of the esophagus, head, and neck: risk and screening].","Scherübl H, Steinberg J, Schwertner C, Mir-Salim P, Stölzel U, de Villiers EM.",https://pubmed.ncbi.nlm.nih.gov/17928979/,"The term ""field cancerization"" was coined by Slaughter in1953 when describing multifocal synchronous and metachronous carcinogenesis in the upper aerodigestive system. Patients suffering from head and neck cancer (HNC) have or develop a second esophageal squamous cell cancer (ESCC) or bronchial cancer (BC) in 5-14% of cases. When a second esophageal cancer occurs in a patient with HNC, the prognosis is generally determined by the ESCC, and, unfortunately, it is poor. Screening and surveillance by Lugol chromoesophagoscopy enable early detection and curative treatment of second esophageal neoplasias. Surveillance appears to  Vice versa, patients with ESCC or BC have a risk of about 10% for developing HNC. Periodic pharyngolaryngoscopy is recommended for curatively treated ESCC or BC patients. Patients with field cancerization should be surveilled by a multidisciplinary approach."
225,Theranostic Platforms Proposed for Cancerous Stem Cells: A Review.,"Zarrintaj P, Mostafapoor F, Milan PB, Saeb MR.",https://pubmed.ncbi.nlm.nih.gov/30280678/,"It is next-to-impossible not to accept that cancer takes a position as the main cause of the global burden of disease, for it is hard to ignore the outnumbered people dying from cancer. Looking at the statistics proves that progress in cancer therapy is always beyond cancer in a race of pessimism about the future; for various kinds of cancers yearly cause death in the world, whereas the conventional and even modern therapies often exhibit lack of reliability in the treatment of cancer. In principle, various reasons are identified for cancer resistance and recurrence. Recognizing the cells/tissue from which cancer takes origin enables its early detection, and optimistically saying, protection of patients against death. It has been recognized that cancer stem cells are responsible for cancer cell proliferation and metastasis. Conventional therapies cannot eradicate the cancer stem cell; therefore, cancer recurrence is unavoidable. In this regards, designing smart platforms with specific properties is an essential step in cancer treatment. Theranostic platforms have facilitated the cancer diagnosis and treatment, simultaneously. In this respect, several types of smart materials have been designed to detect and cure cancer. Cancer stem cell as a root of the cancerous tumor should be eradicated to achieve the complete treatment; hence, cancer stem cell mechanism must be known precisely to design an appropriate platform making possible to encounter with cancer stem cell. In this review paper, various therapeutic and diagnostic techniques of cancerous stem cell are discussed to pave a way for designing proper platforms for cancer eradication."
226,Exact analytical solution of the peristaltic nanofluids flow in an asymmetric channel with flexible walls and slip condition: application to the cancer treatment.,"Ebaid A, Aly EH.",https://pubmed.ncbi.nlm.nih.gov/24151526/,"In the cancer treatment, magnetic nanoparticles are injected into the blood vessel nearest to the cancer's tissues. The dynamic of these nanoparticles occurs under the action of the peristaltic waves generated on the flexible walls of the blood vessel. Studying such nanofluid flow under this action is therefore useful in treating tissues of the cancer. In this paper, the mathematical model describing the slip peristaltic flow of nanofluid was analytically investigated. Exact expressions were deduced for the temperature distribution and nano-particle concentration. In addition, the effects of the slip, thermophoresis, and Brownian motion parameters on the temperature and nano-particle concentration profiles were discussed and further compared with other approximate  In particular, these , ""Peristaltic flow of a nanofluid with slip effects,"" 2012. The  Accordingly, the current analysis and "
227,Mechanism and its regulation of tumor-induced angiogenesis.,"Gupta MK, Qin RY.",https://pubmed.ncbi.nlm.nih.gov/12800214/,"Tumor angiogenesis is the proliferation of a network of blood vessels that penetrates into cancerous growths, supplying nutrients and oxygen and removing waste products. The process of angiogenesis plays an important role in many physiological and pathological conditions. Solid tumors depend on angiogenesis for growth and metastasis in a hostile environment. In the prevascular phase, the tumor is rarely larger than 2 to 3 mm(3) and may contain a million or more cells. Up to this size, tumor cells can obtain the necessary oxygen and nutrient supplies required for growth and survival by simple passive diffusion. The properties of tumors to release and induce several angiogenic and anti-angiogenic factors which play crucial roles in regulating endothelial cell (EC) proliferation, migration, apoptosis or survival, cell-cell and cell-matrix adhesion through different intracellular signaling are thought to be the essential mechanisms during tumor-induced angiogenesis. Tumor angiogenesis actually starts with tumor cells releasing molecules that send signals to surrounding normal host tissue. This signaling activates certain genes in the host tissue that, in turn, make proteins to encourage growth of new blood vessels. In this review, we focus the mechanisms of tumor-induced angiogenesis, with an emphasis on the regulatory role of several angiogenic and anti-angiogenic agents during the angiogenic process in tumors. Advances in understanding the mechanisms of tumor angiogenesis have led to the development of several most effective anti-angiogenic and anti-metastatic therapeutic agents and also have provided several techniques for the regulation of cancer's angiogenic switch. The suggestion is made that standard cytotoxic chemotherapy and angiogenesis inhibitors used in combination may produce complementary therapeutic benefits in the treatment of cancer."
228,[Breast cancer on a scar of excision of ectopic breast tissue: a case report].,"Guèye M, Guèye SM, Rault S, Ronzino V, Gharbi M, Renard C, Croce S, Mathelin C.",https://pubmed.ncbi.nlm.nih.gov/21354849/,"The cancerization of supernumerary breast is uncommon. So when this situation occurs, the diagnosis is often late. Cancers of ectopic breast tissue have been reported in the international literature, but to our knowledge, no cancer after excision of accessory breast gland has been published. This article describes a case of ectopic breast tissue cancer in axillary situation occurring several years after excision and details its specific diagnostic, therapeutic and prognosis."
229,"Secondary prevention of esophageal squamous cell carcinoma in areas where smoking, alcohol, and betel quid chewing are prevalent.","Chung CS, Lee YC, Wang CP, Ko JY, Wang WL, Wu MS, Wang HP.",https://pubmed.ncbi.nlm.nih.gov/20610142/,"Esophageal cancer is ranked as the sixth most common cause of cancer death worldwide and has a substantial effect on public health. In contrast to adenocarcinoma arising from Barrett's esophagus in Western countries, the major disease phenotype in the Asia-Pacific region is esophageal squamous cell carcinoma which is attributed to the prevalence of smoking, alcohol, and betel quid chewing. Despite a multidisciplinary approach to treating esophageal cancer, the outcome remains poor. Moreover, field cancerization reveals that esophageal squamous cell carcinoma is closely linked with the development of head and neck cancers that further sub-optimize the treatment of patients. Therefore, preventive strategies are of paramount importance to improve the prognosis of this dismal disease. Since obstacles exist for primary prevention via risk factor elimination, the current rationale for esophageal cancer prevention is to identify high-risk groups at earlier stages of the disease, and encourage them to get a confirmatory diagnosis, prompt treatment, and intensive surveillance for secondary prevention. Novel biomarkers for identifying specific at-risk populations are under extensive investigation. Advances in image-enhanced endoscopy do not just substantially improve our ability to identify small precancerous or cancerous foci, but can also accurately predict their invasiveness. Research input from the basic sciences should be translated into preventive measures in order to decrease the disease burden of esophageal cancer."
230,[Mechanism of cancer induction by radiation].,Tanooka H.,https://pubmed.ncbi.nlm.nih.gov/6512997/,"The mechanism of radiation carcinogenesis was reviewed on the basis of recent knowledge on cancer-related mutation, oncogene-activation, and monoclonal origin of cancer. Evidence for the systemic suppression of cancerized cells in situ was presented from  partial-body irradiation, and single vs. repeated irradiation."
231,Molecular and cellular biomarkers for field cancerization and multistep process in head and neck tumorigenesis.,"Papadimitrakopoulou VA, Shin DM, Hong WK.",https://pubmed.ncbi.nlm.nih.gov/8842479/,"One way to explain the development of head and neck cancer is through the theories of field cancerization, i.e., the exposure of an entire field of tissue to repeated carcinogenic insult, and multistep process, i.e., development of multiple cancers in a predisposed filed through a series of recognizable stages. Recent molecular genetic studies of histologically normal and premalignant epithelia of high-risk subjects and studies of malignant tumors in aerodigestive tract epithelia have identified a continuum of accumulated specific genetic alterations that possibly occur during the clonal evolution of tumors, namely, during the multistep process. Second primary or multiple primary tumors arise in the same fields as independent clones, with similar but unique molecular genetic and/or cellular alterations. Consequently, the assessment of these genetic and phenotypic alterations has been integrated into clinical chemoprevention trials in an effort to identify biomarkers that are also risk predictors and intermediate end points. This review covers candidate biomarkers of the processes of field cancerization and multistep tumor development in aerodigestive tract epithelia, including general and specific genetic markers, proliferation markers, and squamous differentiation markers."
232,[Current state and future perspectives of oncology care in Hungary based on epidemiologic data].,Kásler M.,https://pubmed.ncbi.nlm.nih.gov/16136773/,"The cancer mortality and morbidity data over the period of 1999-2003 in Hungary has been analyzed. The attempts for the harmonization of cancer care's organization between European Cancer Centers and Hungarian Cancer Centers will also be reviewed. Total cancer mortality of Hungary was found to be 33 530 persons in 2003. According to the cancer mortality data of 36 European countries the highest mortality rate were in Hungary for male in 1999. Hungary had the second place in the female cancer mortality in Europe. It has also been found that the Hungarian men had the highest rate tobacco related cancers (lung, oral cancers) in Europe. The trends of the cancer mortality for women is changed during the period 1999-2003. In 1999 breast cancer was the leading cause of cancer's death for women followed by colorectal and lung cancers. The lung cancer rates have been rising in Hungarian women and became the main cause of cancer death in 2002. The unfavorable cancer mortality trends in Hungary might be attributed to the high consumption of tobacco and alcohol, moreover the unsatisfactory care of cancer patients. The cancer mortality in Hungary could be reduced by the improvement of prevention, diagnosis and treatment of cancer patients. The European accreditation of the cancer control activities should be based on the network of Cancer Centers in Hungary. This accreditation of the Hungarian Cancer Centers is indispensable for the high quality of the care of cancer patients."
233,"""A quiet still voice that just touches"": music's relevance for adults living with life-threatening cancer diagnoses.","O'Callaghan CC, McDermott F, Michael N, Daveson BA, Hudson PL, Zalcberg JR.",https://pubmed.ncbi.nlm.nih.gov/24287507/,"Purpose:
        
      
      Music has historically aided health and loss-adaptation, however, cancer patients' experience of music for self-care is not well understood. This study examines adult cancer patients' views about music's role before and after diagnosis.
    


           Patients from Australian metropolitan cancer and hospice settings completed demographic questionnaires and participated in semi-structured interviews. Qualitative inter-rater reliability was applied.
    


           Music may remain incidental; however, many patients adapt music usage to ameliorate cancer's aversive effects. Patients often draw from their musical lives and explore unfamiliar music to: remain connected with pre-illness identities; strengthen capacity for enduring treatment, ongoing survival (even when knowing ""you're going to die""), or facing death; reframe upended worlds; and live enriched lives. Patients can ascribe human or physical properties to music when describing its transformative effects. Familiar lyrics maybe reinterpreted, and patients' intensified emotional reactions to music can reflect their threatened mortality. Sometimes music becomes inaccessible, elusive, and/or intensifies distress and is avoided. Families', friends' and professionals' recognition of patients' altered musical lives and music-based suggestions can extend patients' use of music for self-care.
    


          Conclusion:
        
      
      Health professionals can support patients by inquiring about their music behaviours and recognising that altered music usage may signify vulnerability. Although commonly recommended, hospital concerts and music broadcasts need sensitive delivery. Patients' preferred music should be available in diagnostic, treatment and palliative settings because it can promote endurance and life enrichment."
234,Cancer's Risky Business. Educating Your Patients About Cancer Risk Factors.,Pirschel C.,https://pubmed.ncbi.nlm.nih.gov/30399236/,"ALTHOUGH IT'S IMPOSSIBLE TO PREDICT what can lead to cancer in any individual, researchers look at data compiled over many years to make confident decisions that certain behaviors, characteristics, and factors increase the risk of developing cancer. By discussing these factors with patients, oncology nurses can potentially reduce or identify their chances of developing future cancers."
235,A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications.,"Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH.",https://pubmed.ncbi.nlm.nih.gov/12702551/,"The concept of ""field cancerization"" was first introduced by Slaughter et al. [D. P, Slaughter et al., Cancer (Phila.), 6: 963-968, 1953] in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. Organ systems in which field cancerization has been described since then are: head and neck (oral cavity, oropharynx, and larynx), lung, vulva, esophagus, cervix, breast, skin, colon, and bladder. Recent molecular findings support the carcinogenesis model in which the development of a field with genetically altered cells plays a central role. In the initial phase, a stem cell acquires genetic alterations and forms a ""patch,"" a clonal unit of altered daughter cells. These patches can be recognized on the basis of mutations in TP53, and have been reported for head and neck, lung, skin, and breast cancer. The conversion of a patch into an expanding field is the next logical and critical step in epithelial carcinogenesis. Additional genetic alterations are required for this step, and by virtue of its growth advantage, a proliferating field gradually displaces the normal mucosa. In the mucosa of the head and neck, as well as the esophagus, such fields have been detected with dimensions of >7 cm in diameter, whereas they are usually not detected by routine diagnostic techniques. Ultimately, clonal divergence leads to the development of one or more tumors within a contiguous field of preneoplastic cells. An important clinical implication is that fields often remain after surgery of the primary tumor and may lead to new cancers, designated presently by clinicians as ""a second primary tumor"" or ""local recurrence,"" depending on the exact site and time interval. In conclusion, the development of an expanding preneoplastic field appears to be a critical step in epithelial carcinogenesis with important clinical consequences. Diagnosis and treatment of epithelial cancers should not only be focused on the tumor but also on the field from which it developed."
236,Photodynamic therapy for skin field cancerization: an international consensus. International Society for Photodynamic Therapy in Dermatology.,"Braathen LR, Morton CA, Basset-Seguin N, Bissonnette R, Gerritsen MJ, Gilaberte Y, Calzavara-Pinton P, Sidoroff A, Wulf HC, Szeimies RM.",https://pubmed.ncbi.nlm.nih.gov/22220503/,"Field cancerization is a term that describes the presence of genetic abnormalities in a tissue chronically exposed to a carcinogen. These abnormalities are responsible for the presence of multilocular clinical and sub-clinical cancerous lesions that explains the increased risks of multiple cancers in this area. With respect to the skin, this term is used to define the presence of multiple non-melanoma skin cancer, its precursors, actinic keratoses and dysplastic keratinocytes in sun exposed areas. The multiplicity of the lesions and the extent of the area influence the treatment decision. Providing at least equivalent efficacy and tolerability, field directed therapies are therefore often more worthwhile than lesion targeted approaches. Photodynamic therapy (PDT) with its selective sensitization and destruction of diseased tissue is one ideal form of therapy for this indication. In the following paper the use of PDT for the treatment of field cancerized skin is reviewed and recommendations are given for its use."
237,Leucocyte-migration-inhibition test in patients with colorectal cancer: clinicopathological correlations.,"Burtin P, Pinset C, Chany E, Fondaneche MC, Chavanel G.",https://pubmed.ncbi.nlm.nih.gov/743487/,"Leucocyte-migration-inhibition test was used to study the immune reactions of leucocytes from 136 colorectal cancer patients, 43 patients with non-cancerous chronic colorectal diseases and 82 controls, with saline extracts of HT29 line. A positive inhibition was found in only 43% of colorectal cancer patients. It was higher in carcinomas of limited extension than in invasive ones (64% against 39%). Furthermore, operation by itself had a depressive effect on the reaction, as the positivity in 25 patients tested twice was 64% before operation and 32% after. Leucocytes from patients with non-cancerous chronic colorectal diseases gave many positive reactions (65%). The percentage of positivity was about the same for diseases with high, low or no risk of cancerization. Hence the antigen(s) of tumour extracts that react with patient's leucocytes are, at least partially, unrelated to cancer."
238,RX for social death: the cancer patient as counselor.,"Kleiman MA, Mantell JE, Alexander ES.",https://pubmed.ncbi.nlm.nih.gov/891133/,"Cancer patients frequently encounter psychological problems distinct from those with other serious illnesses. Cancer's deadly nature and its drastic treatment often alienate patients from relatives and caregivers. The CanCervive program trained cancer patients to counsel other patients. They functioned as role models and provided opportunities for catharsis. Yet their own unresolved conflicts often led them to overidentify with patients. Volunteers lacked insight into their own feelings of stress at seeing dying patients and their own guilt over their relatively advantaged medical status. Despite this, they helped patients cope with their insecurities and dependency needs, and assisted with professional education."
239,Screening and prevention of colorectal cancer in Haining County.,Zhang SQ.,https://pubmed.ncbi.nlm.nih.gov/2581744/,"From September 15, 1977, to April 15, 1978, 450, 477 persons over the age of 7 years were screened for schistosomiasis; a subgroup of 198,950 over 30 years were screened for colorectal cancer. Seventy-five malignant colorectal tumors were discovered in the latter group, a positive rate of 37.69 per 100,000 (seven were colonic cancers, 14 rectal cancers, 20 polyps with cancerous change, and 34 carcinoids). Of this group, 2701 had various types of polyps and 5242 had definitive diagnostic schistosomiasis. History, physical examination, and an occult blood test are simple, useful  While digital rectal examination is an important, effective  It cannot be used for mass screening because the examining finger cannot tolerate such constant use and is too short to discover higher tumors. The sequence of colorectal cancerous change found in our center was from normal intestinal epithelium to tumorigenic polyps or colorectal ulcer, to polyps with anaplastic change, to polyps with local cancerous change, to adenocarcinoma. Cancer was seen more frequently in villous and adenomatous polyps; these are called precancerous stages of colorectal cancer. No relationship between schistosomiasis and colorectal cancer was found."
240,Diagnostic ultrasound in breast cancer: analysis of retrotumorous echo patterns correlated with sonic attenuation by cancerous connective tissue.,Kobayashi T.,https://pubmed.ncbi.nlm.nih.gov/230202/,"Echocardiographic diagnosis of breast cancer has been used in clinical medicine for the past several years. Echographic findings and characteristics suggesting differentiation between malignant and benign tumors have been reported by various investigators. These signs are analysed in correlation with histological findings, especially cancerous connective tissue and nonconnective tissue and retrotumorous shadow patterns in clinical echograms of various breast cancers. Special reference is made to ultrasound attenuation related to bioacoustical tissue characteristics. This casual mechanism provides a stepping-stone for further improvements in ultrasound apparatus designed for clinical diagnosis of breast cancer. Furthermore, it may stimulate basic research on the bioacoustical properties of ultrasound reflection, absorption, and velocity."
241,[Epidemiology and management of rare paediatric tumours within the framework of the French Society for Children Cancer].,"Réguerre Y, Lacour B, André N, Claude L, Hameury F, Lavrand F, Kalfa N, Peuchmaur M, Orbach D.",https://pubmed.ncbi.nlm.nih.gov/20813657/,"Less than 1% of cancer occurs in children. With the progress made by national and international cooperative groups 75% of them are actually cured. However some entities have an incidence so weak that we can't actually establish standardized therapeutics guidelines. To improve our knowledge on these rare tumours a national organisation become necessary as well as an international collaboration. A French rare tumour committee was created within the French Society for Children Cancer (SFCE). Others European countries have such organisation. The  This article focuses on the specific French organization for rare tumours treatment. It also describes the draft for the creation of a new data base for prospective registry of clinical, therapeutics and follow up data. To provide a better understanding of these pathologies, the ""Bulletin du Cancer's"" editorial board decided to regularly publish an update on a rare paediatric tumour in a specific section."
242,Could stroma contribute to field cancerization?,"Ge L, Meng W, Zhou H, Bhowmick N.",https://pubmed.ncbi.nlm.nih.gov/20149555/,"The common oral diseases as well as oral cancer have the characteristic of field cancerization or field effect. Field cancerization, characterized by phenotypic and genetic changes in the neighboring cells of the frank cancer cells, is a clinical phenomenon first found in head and neck cancers. Field cancerization of the epithelia is currently a widely-accepted model in cancer biology as a manifestation of cancer progression. The concomitant changes in the tumor microenvironment have drawn more attention recently. Could the changes in the tumor microenvironment and the epithelial field cancerization concepts be linked? In view of the importance of stroma in the development of epithelium and evidence in carcinoma-associated stroma, we propose the question if stroma not only reciprocates the neoplastic changes of the epithelia, but also contributes to field cancerization. Actually one perspective paper pointed out that healing wound can influence the recurrence of field cancerization. In another words, the microenvironment of healing wound determines the prognosis of field cancerization. Based on the literatures published and our own work, we hypothesize a new model of field cancerization focusing on the co-evolution of the tumor microenvironment. We suggest that the microenvironment cannot be neglected when treating diseases with characteristics of field cancerization."
243,A case report of secondary parathyroid adenomatous hyperplasia with carcinoma.,"Chen S, Sui X, Zhao B, Liu Z, Dai X, Ding Y.",https://pubmed.ncbi.nlm.nih.gov/36401397/," However, secondary parathyroid hyperplasia still has the possibility of canceration, and it is still important to be alert to its occurrence when performing ultrasound examinations and clinical treatment.
    


          Patient concerns:
        
      
      A 49-years-old man visited our outpatient department with generalized weakness and pain in both lower extremities a month ago.
    


          Diagnosis:
        
      
      Hyperparathyroidism secondary to chronic renal failure.
    


          Interventions:
        
      
      The patient underwent ultrasound and other preoperative examinations. The preoperative ultrasound showed 3 parathyroid enlargements, 2 on the left and 1 on the right. The patient then underwent surgical treatment.
    


          Outcomes:
        
      
      Ultrasonography suggested the presence of 3 parathyroid hyperplasias, and ectopic right inferior parathyroid gland was visible during intraoperative examination. 10 days after surgery, the patient's Parathyroid Hormone returned to the normal range.
    


          Conclusion:
        
      
      Secondary parathyroid hyperplasia has the potential to become cancerous, so doctors should be alert to its occurrence when conducting ultrasound examinations. Ultrasound examination is the key to its diagnosis and subsequent treatment."
244,[Breast cancer's causality analyzed through the Health Belief Model].,"Fugita RM, Gualda DM.",https://pubmed.ncbi.nlm.nih.gov/17310566/,The  Cultural Anthropology was the theoretical framework and Oral History the  Interviews were performed with nine women who had been submitted to a mastectomy. The Health Beliefs Model was used as conceptual reference for a better understanding and explanation of these women's health behavior. The 
245,Various manifestations of early and minimally advanced gastric cancer in gastrointestinal series (GIS).,"Saitoh H, Okuno Y, Suzuki M, Takasu K, Kim YC, Mukaihara S, Kataoka M, Hayakawa K, Nishimura K.",https://pubmed.ncbi.nlm.nih.gov/9445146/,"Preoperative gastrointestinal series (GIS) have been used to assess the precise localization and extent of early and minimally advanced gastric cancers, which are sometimes difficult to define en face by endoscopy. The purpose of this study was to relate various GIS manifestations of gastric cancer with the pathological condition. We reviewed 99 gastric cancer cases (107 lesions), which were treated between 1992 and 1995, in which the lesions were depicted by GIS assisted by a nasogastric tube. The pathological conditions were determined from the resected specimens. Differences in anatomic location and in some morphological characteristics contribute to differences in histological classification. We conclude that lesion depiction by GIS assisted by nasogastric tube reflects the cancer's pathological characteristics, including histological type, malignant cycle, and modification by desmoplastic reaction."
246,[The expression of MG7 corresponding antigen in gastrointestinal polyps and its relation with cancer].,Chen SZ.,https://pubmed.ncbi.nlm.nih.gov/1339741/,"We studied 112 patients with polyps of the stomach, gallbladder and colorectum by immunohistochemical staining with monoclonal antibody (MG7) against gastric cancer and avidin-biotin complex (ABC) technique. The positive expression of the MG7-corresponding antigen (MG7-Ag) was 100%, 100%, and 60.0% respectively in villous, mixed and tubular polyps. A close correlation was shown between dysplasia of grade II and the positive expression of MG7-Ag (p < 0.05). The positive expression was significantly related to canceration (P < 0.025). No malignancy was found in 45 patients with negative expression. But 12 of 67 patients with positive expression developed cancers in 3 to 38 months. The patients with positive expression of MG7-Ag were high risk group developing cancer."
247,Reconstruction with cutaneous flap after resection for breast cancer's skin metastases in a chemoresistant patient.,"Varricchio A, Di Libero L, Iannace C.",https://pubmed.ncbi.nlm.nih.gov/23685463/,"We reported a case of a breast cancer's skin metastases in a patient that had sustained 3 lines of chemotherapy. At first she received surgical treatment with Madden's mastectomy with dissection of axillary limphnodes and positioning of an expander. After that she underwent to chemo- and radiotherapy. The schedules we performed were: FEC, TC,Vinorelbine and Capecitabine. Only after the FEC there was a clinical remission just for 1 year. After that she underwent to surgery for the removal of a lozenge of skin on the right hemithorax, including also the subcutaneous tissue, a strip of muscular tissue, and a residue of the breast implant. The histology showed a multiple-nodules infiltration involving the dermis, the hypodermis, and the muscle. This pattern was valuated as a G3 breast cancer recurrence with ER 70%, PgR<5%, Ki67 50% Her2neu-. During the second line chemotherapy with TC she developed an high grade LCIS with lymphovascular infiltration on the left breast; on the right hemithorax there were cutaneous metastases with dermis' infiltration. Surgery with local excision was performed, and a cutaneous flap was realized."
248,Super competition as a possible mechanism to pioneer precancerous fields.,"Rhiner C, Moreno E.",https://pubmed.ncbi.nlm.nih.gov/19126656/,"Cancer is the  The insight that cancerous cells arise from a series of mutations in oncogenes and tumor suppressors, commonly known as multistep carcinogenesis, has been conceptually elaborated and proven in the last 20 years. Although knowledge about late steps of cancerogenesis and disease progression has greatly advanced, the initial molecular events remain largely unknown. Basic research in Drosophila has started the quest to find early markers that detect initial clonal expansion of precancerous cells. These efforts were spurred by novel findings demonstrating that certain mutations transform cells into super-competitors that expand at the expense of the surrounding epithelial cells without inducing histological changes. This mechanism, discovered as super competition in the fly, might also lie at the heart of a clinical observation termed 'field cancerization'. This review aims to bring together current understanding from basic research on cell competition and clinical studies that have analyzed field characteristics to highlight parallels and possible connections."
249,Gene mutation analysis of oral submucous fibrosis cancerization in Hainan Island.,"Li B, Chen X, Xian H, Wen Q, Wang T.",https://pubmed.ncbi.nlm.nih.gov/38050610/,"
    


           DNA was extracted, and targeted gene panel sequencing technology was used to analyze the gene frequency of pathogenic mutation sites in clinical samples.
    


           The  According to the frequency of gene mutations from high to low, they were TP53, FLT4, PIK3CA, CDKN2A, FGFR4, HRAS, BRCA1, PTPN11, NF1, KMT2A, RB1, PTEN, MSH2, MLH1, KMT2D, FLCN, BRCA2, APC. The mutation frequency of FLT4 gene was significantly higher than that of OSCC group (P < 0.05).
    


          Conclusion:
        
      
      FLT4 gene may be related to OSF cancerization and is expected to be an early diagnostic biomarker for OSF cancerization."
250,The glutathione cycle is the creative reaction of life and cancer. Cancer causes oncogenes and not vice versa.,Holt JA.,https://pubmed.ncbi.nlm.nih.gov/8350775/,"Life is definable as a chemical reaction which obeys exponential growth and dies if reversed. Such a reaction must be the commencement of all life so that every evolved form of it inherits these characteristics. As no single reaction known has these two features, life must be a combination of two or more reactions which whilst obeying all the classical laws of physics and chemistry assume an exponential form and effectively act as being irreversible. The reactions of glutathione--oxidation and reduction--when combined in sequence as a cyclical process fulfill these criteria. The cyclic changes of glutathione from reduced to oxidised to reduced forms must therefore be the reaction which creates life and is responsible for cancer's growth. 434 mHz electromagnetic radiation stimulates cancer growth rate by forcing this cycle into activity. Proof of this hypothesis is the long-term control of cancer in 11 patients treated with oxidised glutathione and 434 mHz radiation. Genetic material does not contain any energy system with exponential form, neither is it self-replicating. Genetic material will only reproduce if placed within an immortal cell in which all controls of the glutathione system have been lost, as in a cancer cell. Oncogenes must be the product of cancer and not the reverse."
251,Frequent involvement of chromatin remodeler alterations in gastric field cancerization.,"Takeshima H, Niwa T, Takahashi T, Wakabayashi M, Yamashita S, Ando T, Inagawa Y, Taniguchi H, Katai H, Sugiyama T, Kiyono T, Ushijima T.",https://pubmed.ncbi.nlm.nih.gov/25462860/,"A field for cancerization, or a field defect, is formed by the accumulation of genetic and epigenetic alterations in normal-appearing tissues, and is involved in various cancers, especially multiple cancers. Epigenetic alterations are frequently present in chronic inflammation-exposed tissues, but information on individual genes involved in the formation of a field defect is still fragmental. Here, using non-cancerous gastric tissues of cancer patients, we isolated 16 aberrantly methylated genes, and identified chromatin remodelers ACTL6B and SMARCA1 as novel genes frequently methylated in non-cancerous tissues. SMARCA1 was expressed at high levels in normal gastric tissues, but was frequently silenced by aberrant methylation in gastric cancer cells. Moreover, somatic mutations of additional chromatin remodelers, such as ARID1A, SMARCA2, and SMARCA4, were found in 30% of gastric cancers. Mutant allele frequency suggested that the majority of cancer cells harbored a mutation when present. Depletion of a chromatin remodeler, SMARCA1 or SMARCA2, in cancer cell lines promoted their growth. These "
252,[Pain related to head and neck cancers during disease progression].,Bertrand-Deligne J.,https://pubmed.ncbi.nlm.nih.gov/18047862/,"Head and neck cancers can be revealed by pain symptoms caused by an excess of nociception. Other pain sometimes occurs during the cancer's progression such as neuropathic or mixed pain. These should incite the clinician to be watchful so as not to miss recurrence of the cancer. Treatment is complex, requiring management by a multidisciplinary team."
253,Mueller matrix polarimetry for differentiating characteristic features of cancerous tissues.,"Du E, He H, Zeng N, Sun M, Guo Y, Wu J, Liu S, Ma H.",https://pubmed.ncbi.nlm.nih.gov/25027001/,"Polarization measurements allow one to enhance the imaging contrast of superficial tissues and obtain new polarization sensitive parameters for better descriptions of the micro- and macro- structural and optical properties of complex tissues. Since the majority of cancers originate in the epithelial layer, probing the morphological and pathological changes in the superficial tissues using an expended parameter set with improved contrast will assist in early clinical detection of cancers. We carry out Mueller matrix imaging on different cancerous tissues to look for cancer specific features. Using proper scattering models and Monte Carlo simulations, we examine the relationship between the microstructures of the samples, which are represented by the parameters of the scattering model and the characteristic features of the Mueller matrix. This study gives new clues on the contrast mechanisms of polarization sensitive measurements for different cancers and may provide new diagnostic techniques for clinical applications."
254,Field cancerization in oral lichen planus.,"Mignogna MD, Fedele S, Lo Russo L, Mignogna C, de Rosa G, Porter SR.",https://pubmed.ncbi.nlm.nih.gov/17084578/," Here we address whether this concept should be extended also to patients affected by oral lichen planus (OLP), an inflammatory disorder associated with an increased risk of cancer development.
    


           Patients who presented more than one oral neoplastic event were considered for further data analysis as regards incidence, localization, management and prognosis.
    


          4%) patients were affected by one single neoplastic event while 25 (55.6%) developed multiple and often multifocal oral dysplastic and/or malignant events. In most cases, a careful surveillance programme led to diagnosis and effective treatment of oral neoplasias at an early intraepithelial and microinvasive stage, leading to long-term survival. In some patients, however, additional primary tumours occurred suddenly with rapid invasion, leading to advanced stage diagnosis and poor prognosis. Overall, three patients (12%) died due to malignant oral disease.
    


          Conclusions:
        
      
      Patients with OLP and subsequent development of dysplasia/ oral squamous cell carcinoma are at risk of having multiple and multifocal neoplastic events of the oral cavity, a phenomenon which parallels the concept of field cancerization of traditional head and neck cancers. If detected at an early stage, these neoplasias can be managed with superficial and complete resection. However a small number of patients have loco-regional tumour spread despite a standard surveillance protocol."
255,[Classification and pathogenesis of lung carcinoma].,"Brambilla E, Lantuejoul S, Sturm N.",https://pubmed.ncbi.nlm.nih.gov/12879793/,"The international standard for histologic classification of lung tumours is that proposed by the WHO/IASLC (1999). Ninety percent of these cancers are distributed in squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and large cell carcinoma, all related to tobacco smoke carcinogens, responsible for 90% of tumours. As a consequence of their derivation from totipotential stem cells, heterogeneity is common. They arise from multifocal preinvasive lesions reflecting the ""field cancerization"" process of the entire bronchial tree. All together 1999 WHO classification offers a valuable hallmark for clinical, biological, and epidemiological studies, and a solid basis for inclusion of patients in randomized therapeutical trials as well as for interpretation of sensibility or resistance to new therapeutic agents."
256,Synchronous triple primary cancers of the pharynx and esophagus.,"Kataoka S, Omae M, Horiuchi Y, Ishiyama A, Yoshio T, Hirasawa T, Yamamoto Y, Tsuchida T, Fujisaki J, Yamada K, Igarashi M.",https://pubmed.ncbi.nlm.nih.gov/28315155/,"A 72-year-old male with nausea and heartburn was found to have early pharyngeal squamous cell carcinoma, superficial and advanced esophageal squamous cell carcinoma and early esophageal adenocarcinoma by esophagogastroduodenoscopy. Computerized tomography demonstrated left cardiac lymph node swellings. We prioritized the treatment for esophageal squamous cell carcinoma, as this was the most advanced cancer among the triple primaries. The patient underwent neoadjuvant chemotherapy for esophageal squamous cell carcinoma followed by esophagectomy. Four months after esophagectomy, endoscopic submucosal dissection for pharyngeal squamous cell carcinoma was performed. This is a first report of pharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma and esophageal adenocarcinoma occurring as triple primary cancers in a single patient. Smoking-induced tumor formation through DNA methylation is a common risk factor for patients with triple primary malignancies, being an example of epigenetic field cancerization induced by exposure to carcinogenic factors."
257,[Primary and secondary prevention of skin cancer in organ transplant recipients].,"Lonsdorf AS, Becker MR, Stockfleth E, Schäkel K, Ulrich C.",https://pubmed.ncbi.nlm.nih.gov/20177652/,"Skin cancer constitutes the most frequently reported post-transplant malignancy in solid organ transplant recipients (OTR) worldwide. Whereas the risk for malignant melanoma is only moderately increased, non-melanoma skin cancers (NMSC) seem to thrive on chronic immunosuppression and account for up to 95% of post-transplant cutaneous malignancies. Compared to the general population cutaneous squamous cell carcinoma (SCC) and actinic keratoses (AK) characteristically show even higher incidences than basal cell carcinoma (BCC) and act as an indicator for the development of multiple primary cutaneous neoplasias and locally recurrent cancers (field cancerization). Early diagnosis and therapy of pre-malignant cutaneous lesions is crucial for the secondary prophylaxis of further invasive and highly aggressive skin cancers. High quality interdisciplinary care and prophylactic modalities, including consistent and sufficient UV protection, topical immunmodulatory therapies of UV-damaged skin areas, retinoid chemoprevention as well as tapering immunosuppressive treatment or the selection of immunosuppressants with proposed antiangiogenic properties like mTor-inhibitors may help to reduce the multiplicity of subsequent primary skin cancers in high-risk patients. Apart from the continuous need for educational intervention of OTR in the primary prophylaxis of post-transplant skin cancers, dermatologic care occupies a central position within the field of transplantation medicine in terms of pre- and post-transplantation dermatologic evaluation and therapy as well as the implication of timely and effective secondary preventive approaches in the management of this high-risk patient population."
258,Clinicopathologic study of minute and small early gastric cancer. Histogenesis of gastric cancer.,"Hirota T, Itabashi M, Suzuki K, Yoshida S.",https://pubmed.ncbi.nlm.nih.gov/6256703/,"According to the report by Sano, and our previous study of 900 cases of early gastric cancer, multiple gastric cancers were seen in 73 patients (8 percent). The remaining 827 had solitary cancers. In comparison with solitary cancers, multiple gastric cancers were seen more often in males, with the predominant histologic type being well-differentiated adenocarcinoma. A higher incidence (28 percent) of elevated types (I and IIa) was noticed in multiple gastric cancer cases than in solitary cancers (19 percent). The incidence of ulceration within the cancerous lesion was low (35 percent) in multiple cancers but high (69 percent) in solitary cancers. These differences between solitary and multiple cancers observed in 900 early gastric cancer cases were also noted between solitary and multiple cancers in the present series, regardless of the size of lesions."
259,Clonality analysis of multifocal papillary thyroid carcinoma by using genetic profiles.,"Lu Z, Sheng J, Zhang Y, Deng J, Li Y, Lu A, Zhang J, Yu H, Zhang M, Xiong Z, Yan H, Diplas BH, Lu Y, Liu B.",https://pubmed.ncbi.nlm.nih.gov/27071483/,"Papillary thyroid carcinoma (PTC) is the most common adult thyroid malignancy and often presents with multiple anatomically distinct foci within the thyroid, known as multifocal papillary thyroid carcinoma (MPTC). The widespread application of the next-generation sequencing technologies in cancer genomics research provides novel insights into determining the clonal relationship between multiple tumours within the same thyroid gland. For eight MPTC patients, we performed whole-exome sequencing and targeted region sequencing to identify the non-synonymous point mutations and gene rearrangements of distinct and spatially separated tumour foci. Among these eight MPTCs, completely discordant mutational spectra were observed in the distinct cancerous nodules of patients MPTC1 and 5, suggesting that these nodules originated from independent precursors. In another three cases (MPTC2, 6, and 8), the distinct MPTC foci of these patients had no other shared mutations except BRAF V600E, also indicating likely independent origins. Two patients (MPTC3 and 4) shared almost identical mutational spectra amongst their separate tumour nodules, suggesting a common clonal origin. MPTC patient 7 had seven cancer foci, of which two foci shared 66.7% of mutations, while the remaining cancer foci displayed no common non-synonymous mutations, indicating that MPTC7 has multiple independent origins accompanied by intraglandular disease dissemination. In this study, we found that 75% of MPTC cases arose as independent tumours, which supports the field cancerization hypothesis describing multiple malignant lesions. MPTC may also arise from intrathyroidal metastases from a single malignant clone, as well as multiple independent origins accompanied by intrathyroidal metastasis."
260,Spindle cell carcinoma in the trail of radiotherapy for oral squamous cell carcinoma: A quest for rationale.,"Rajalekshmi MP, Thankappan P, Joseph TI, Girish KL.",https://pubmed.ncbi.nlm.nih.gov/37787328/,"Spindle cell carcinoma (SpCC) is a rare variant of oral squamous cell carcinoma (SCC) with unique clinicopathological characteristics, a high recurrence rate, and metastatic potential. It will be truly devastating when it occurs as a second wave in a cancer survivor. Despite the multidisciplinary approach in the management of oral SCC, the incidence of second malignancies or multiple carcinomas has been constantly reporting in the literature. Although radiotherapy has saved the lives of countless cancer patients, its several serious late effects are well-documented in the literature, making it a double-edged sword. Radiation epidemiology studies revealed an increased risk of developing radiogenic second cancers after 5 or more years. The purpose of this article is to document a case of SpCC arising in a patient after a span of 5 years who was previously diagnosed and treated with radiotherapy for well-differentiated SCC."
261,[Cancerization of first branchial cleft cyst in the parotid gland: one case report].,"Zhuo L, Chen Z, Li W, Xue L, Shou Z.",https://pubmed.ncbi.nlm.nih.gov/34886611/,A rare case of branchiogenic carcinoma from first cleft branchial cyst in the parotid gland is reported. An elderly male patient was admitted to the hospital presented with a mass accompanying with swelling and pain in the right parotid area for 5 days. Total right parotidectomy including the tumor resection and selective neck dissection were performed under general anesthesia. A thick-walled cyst containing necrotic tissue in the parotid gland was found. Postoperative histopathology showed that the tumor contained squamous epithelium and pseudostratified columnar epithelium. The cyst epithelium had atypical hyperplasia with necrosis. Some areas were cancerous with the formation of well-differentiated squamous cell carcinoma and cancer infiltration. No metastasis was found in the cervical lymph nodes. This case was in accordance with the diagnostic criteria of cancerization of the first branchial cleft cyst.
262,Could field cancerization be interpreted as a biochemical anomaly amplification due to transformed cells?,"Fernández P J, Méndez-Sánchez SC, Gonzalez-Correa CA, Miranda DA.",https://pubmed.ncbi.nlm.nih.gov/27876116/,"Field cancerization is a concept used to explain cellular and molecular alterations in tissue associated to neoplasia and cancer. This effect was proposed by Slaughter in order to explain the development of multiple primary tumors and locally recurrent cancer. The particular changes associated with this effect, in each type of cancer, have been detected even at distances greater than 10cm off the tumor, in areas classified as normal by histopathological studies. Early detection of lung, colon, and ovary cancer has been reported by the use of Partial Wave Microscopy Spectroscopy (PWS) and has been explained in terms of the field cancerization effect. Until now, field cancerization has been studied as a field effect and we hypothesize that it can be understood as an amplifying effect of biochemical abnormalities in cells, which leads us to ask the question: Could field cancerization be interpreted as a biochemical anomaly amplification due to transformed cells? We propose this question because the biochemical changes due to field cancerization alter the dynamics of molecules and cells in abnormal tissues in comparison to normal ones, these alterations modify the interaction of intracellular and extracellular medium, as well as cellular movement. We hypothesize that field cancerization when interpreted as an amplification effect can be used for the early detection of cancer by measuring the change of cell dynamics."
263,An enzymatic effect for cancer prevention and eradication.,Hirata Y.,https://pubmed.ncbi.nlm.nih.gov/8748088/,"As previously described in a series of hypotheses, cancer development depends on an unconvertable duplication mitosis caused by some abnormal supplement of the mitotic maturation promoting system which is paralyzed in the cancerous cell's cytoplasm. This abnormal supplement, which may be responsible for the cancer's development, must be a biochemical compound that could be eliminated by exposure to the action of certain enzymes. Accordingly, in order to prevent and eradicate cancer development in general, an enzyme which would destroy and eliminate the biochemical supplement needs to be identified, and a specific "
264,[Radiological findings of cancerous invasion in colorectal cancer less than 3 cm in diameter].,"Matsukawa M, Usui Y, Negoro T, Kan T, Kondou K, Yamada S.",https://pubmed.ncbi.nlm.nih.gov/2746951/,"131 colorectal cancers, less than 3 cm in diameter, experienced at Juntendo University Hospital in Oct. 1977 through Dec. 1988 were studied with respect to their radiological and macroscopic features. Macroscopic features of the cancers were classified into type a (a lesion with a long stalk), type b (a subpedunculated or sessile lesion), type c (a plaque-like lesion) and type d (a lesion with a depression). Type a is early cancer. An early cancer of type b was mostly demonstrated as a lobular pattern of tumor surface, and an advanced cancer as a nodular pattern. Type c less than 1 cm in diameter was seen a sm cancer. A sm cancer of type d was mostly demonstrated as a faint barium fleck of the depression, an advanced cancer as a mild barium fleck. By deformed colonic wall in profile view, an early cancer was mostly demonstrated as a thorn shape deformity, sm or pm cancer as an arch shaped deformity and a cancer with deeper cancerous invasion than pm as a trapezoid deformity."
265,Treating Field Cancerization by Ablative Fractional Laser and Indoor Daylight: Assessment of Efficacy and Tolerability.,"Paasch U, Said T.",https://pubmed.ncbi.nlm.nih.gov/32272521/,"  LAAD was applied using a CO2 ablative fractional laser (AFXL) and aminolevulonic acid. Thereafter, IDL-PDT was administered using a novel device that mimics the sun radiation with a total dose of 48 J/cm². 7%, partial: 28.3%). Pain scores using a visual analog scare immediately following treatments were 9.0 ± 2.0. Conclusions: AFXL-LAAD combined with IDL-PDT is extremely effective for the treatment of skin field cancerization associated with AK. Nevertheless, the high pain scores associated with this combined approach may prove to be a limiting factor. Thus, further protocol modifications in larger scale studies are still warranted. J Drugs Dermatol. 2020;19(3):425-427. doi:10.36849/JDD.2020.4589."
266,Covert operations: cancer's many subversive tactics in overcoming host defenses.,Longo DL.,https://pubmed.ncbi.nlm.nih.gov/23874020/,"In an effort to use the patient's T cells to fight his or her own cancer, we inadvertently discovered a distinctive form of tumor-induced immune suppression. T cells from tumor-bearing patients are often defective in signaling. They lack the zeta chain of the T-cell receptor and the src kinases crucial for its downstream effects including lck. They truncate the carboxy terminal of the p50 NF-kappaB transcription factor. At the population level, CD4 T cells are polarized toward the Th2 subtype and inhibitory Tregs expand. These T cells can recover after several days of culture outside of the tumor-bearing host environment. The effect is mediated by one or more factors made by the tumor given that the same T-cell defects occur in mice with tumors implanted in hollow fibers that never directly contact cells of the host. Several promising strategies may overcome these immunosuppressive effects."
267,"[Screening and early diagnosis of other cancers (non-small cell lung carcinoma, urologic cancers, liver cancer and melanoma)].","Ducreux M, Mateus C, Planchard D, Fizazi K.",https://pubmed.ncbi.nlm.nih.gov/20225562/,"Apart from ideal models such as breast cancer, colon cancer and cervical cancer, other cancers particularly broncho-pulmonary cancer, urological (outside the case of the prostate), liver and melanoma do not lend themselves to actions of screening and early diagnosis. This assertion must be qualified because even in these cancers, targeted actions on certain populations may lead to cost-effective actions. The best example is monitoring of cirrhotic patients by ultrasonography and determination of alpha-feto-protein every 6 months which has proved effective in reducing mortality due to primary liver cancer. The monitoring of certain populations of patients with many naevi or a history of melanoma also allows early diagnosis and effective melanoma price, however, the excision of many non-cancerous lesions. Some cancers did not follow this rule because, for instance, the screening and early diagnosis of lung cancer among smokers is still a failure even when using the scanner."
268,Taking stock: A systematic review of archaeological evidence of cancers in human and early hominin remains.,"Hunt KJ, Roberts C, Kirkpatrick C.",https://pubmed.ncbi.nlm.nih.gov/29773338/,"This study summarizes data from 154 paleopathological studies documenting 272 archaeologically recovered individuals exhibiting skeletal or soft tissue evidence of cancer (malignant neoplastic disease) between 1.8 million years ago and 1900 CE. The paper reviews and summarizes the temporal, spatial and demographic distribution of the evidence and the  Metastasis to bone is the most widely reported evidence (n = 161), followed by multiple myeloma (n = 55). In the dataset, males were represented more than females (M = 127, F = 94), and middle-adults (35-49) and old-adults (50+) were represented most among age groups (MA = 77, OA = 66). The majority of the evidence comes from Northern Europe (n = 51) and Northern Africa (n = 46). The data are summarized in the Cancer Research in Ancient Bodies (CRAB) Database, a growing online resource for future paleo-oncological research. This systematic review contributes to broader studies of malignant neoplastic disease in antiquity; it provides an overview of paleo-oncological data, discusses the many practical and "
269,Raman exfoliative cytology for prognosis prediction in oral cancers: A proof of concept study.,"Sahu A, Gera P, Malik A, Nair S, Chaturvedi P, Murali Krishna C.",https://pubmed.ncbi.nlm.nih.gov/30719849/,"Oral cancer is associated with high rates of recurrence, attributable to field cancerization. Early detection of advanced field changes that can potentially progress to carcinoma can facilitate timely intervention and can lead to improved prognosis. Previous in vivo studies have successfully detected advanced field effects in oral cancers. Raman exfoliative cytology has previously shown to differentiate normal, oral pre-cancer and cancers. The present study explores Raman-exfoliative-cytology-based detection of field effects. Exfoliated cells were collected from tumor (n = 16) and contralateral-normal appearing mucosa (n = 16) of oral cancer patients, and healthy tobacco habitués (n = 20). After spectral acquisition, specimens were Pap-stained for cytological evaluation. Data analysis, by Principal Component Analysis and Principal Component-Linear Discriminant Analysis, indicate several spectral-misclassifications between contralateral normal and tumor, which were investigated and correlated with spectral, cytological and clinical outcomes. A qualitative analysis by grouping patients with number of misclassifications with tumor (Group 1: 0, Group 2: 1 and Group 3: >1) was explored. Group 3 with highest misclassifications showed spectral and cytological similarity to tumor group - one patient was a case of early inoperable residual disease, despite clear margins on histopathology. Thus, these misclassifications could be indicative of cancer field changes, and can prospectively help to identify patients susceptible to recurrences ."
270,Colonoscopy Combined with Me-Nbi to Observe the Canceration Characteristics of Colon Polyps and the Correlation of RHOC Protein Expression.,"Shuqi Xu, Weimin Chen, Yiming Chen, Xuanfu Xu, Ying Dai, Jianqing Chen, Wenhui Mo, Meng Ji, Yueyue Li, Wenjing Liu.",https://pubmed.ncbi.nlm.nih.gov/37715435/,"The current study was carried out to analyze the characteristics of colon polyps canceration observed by colonoscopy combined with ME-NBI (Magnifying Endoscopy combined with Narrow-Band Imaging) and its correlation with RhoC (Ras homolog gene family, member C) protein expression. For this purpose, A total of 300 patients with colorectal polyps and cancerous lesions (192 colorectal polyps and 200 cancerous lesions) who were treated in the digestive endoscopy room of the hospital and underwent colonoscopy were selected, and they were divided into polyp group and malignant lesion according to the diagnosis  groups, 150 cases in each group. There were 75 patients with non-adenomatous polyps and 75 patients with adenomatous polyps in the polyp group; 75 patients with high-grade neoplasia and cancerous changes in the malignant group. The microvascular structure and surface structure of the lesions were observed by colonoscopy, and the correlation between microvascular morphological characteristics and RhoC protein expression was analyzed. 05). In the malignant transformation group, the positive rate of RhoC expression in mucosal and submucosal superficial infiltration of 150 patients with colon polyp carcinoma was lower than that in submucosal deep infiltration, and the difference was statistically significant (P<0.05). NICE (National Institute for Clinical Excellence) type 2 was diagnosed as colorectal superficial submucosal The sensitivity, specificity, and accuracy of colorectal submucosal invasion were 73.1%, 84.6%, and 83.2%, respectively; the sensitivity, specificity, and accuracy of NICE type 3 in diagnosing colorectal submucosal invasion were 74.6%, 96.8%, and 92.7%, respectively. . Type 2 and type 3 lesions with cancerous features in NICE classification were correlated with the expression of RhoC protein (P<0.05). In conclusion, NICE classification under colonoscopy combined with magnifying colonoscopy has a good effect on colorectal lesions. Differential diagnostic value, RhoC protein is highly expressed in colon cancer and is closely related to the occurrence of colon cancer and the depth of lesion invasion. With the progression of colorectal adenomas, the expression of RhoC protein in the lesions gradually increased."
271,In vivo Raman spectroscopy-assisted early identification of potential second primary/recurrences in oral cancers: An exploratory study.,"Malik A, Sahu A, Singh SP, Deshmukh A, Chaturvedi P, Nair D, Nair S, Murali Krishna C.",https://pubmed.ncbi.nlm.nih.gov/28736959/," The present study explored utility of identification of potential recurrences by Raman spectroscopy, which has been shown to identify oral precancers, cancers, and field cancerization in humans and micro-sized mechanical irritation-induced tumors in animals.
    


           Misclassifications observed in subsequent multivariate statistical analysis between contralateral normal and tumor spectra were correlated with appearance of new malignant lesions.
    


          5 times higher chances of developing local recurrence. The sensitivity of Raman spectroscopy in predicting the recurrences was 80% and the specificity was 29.7%.
    


          Conclusion:
        
      
      Findings provide proof-of-concept for Raman spectroscopy-based identification of sites that have higher propensity to progress to carcinomas before becoming clinically apparent. Prospective validation of Raman spectroscopy by including additional oral cavity subsites and use of multifiber bundles may improve rate of identification of recurrence-prone subjects."
272,[Vernes/Augusti cancer assessment. Documentation 17].,Jallut O.,https://pubmed.ncbi.nlm.nih.gov/2799155/,"The principles are: Determination of mucopolysaccharides, expressed as weight of mannose-galactose per liter of serum. Because of the non-specificity of this test in cancers, it is combined with other ""more specific tests of the inflammatory condition"" (orosomucoids and seromucoids). The floculation reaction of proteins through acidified copper acetate provokes the formation in the serum of a precipitate containing mainly beta and gamma globulins, frequently found in the blood of cancer patients, not specific to that condition but nevertheless ""providing information on the development of cancers"". Originally this test was used as a  The set of tests amounts to sFr. 150.-, to be repeated every six weeks. The cancerometry has been developed in the thirties by Dr. Alfred Vernes and was used as  The main promoter is at present Dr. Augusti in Paris. Augusti, in a study on the "" Up to now no clinical trials have been published."
273,"[Epidemiology of cancers in Niger, 1992 to 2009].","Garba SM, Zaki HM, Arfaoui A, Hami H, Soulaymani A, Nouhou H, Quyou A.",https://pubmed.ncbi.nlm.nih.gov/23420007/,"The present study aims to determine the various epidemiological characteristics of cancers in Niger from 1992 to 2009. It is a retrospective and descriptive study led from the data of the National cancers Register of Niger country between 1992 and 2009. During that period, 7,031 cases of cancers were collected. The number of registered patients suffering from cancers significantly increased, from 186 cases in 1992 to 646 cases in 2009. The ascendancy was feminine with a sex-ratio of 1.40. The average age was of 43 ± 17.53 years. The majority of the patients (70.2%) lived from the Niamey area. The breast cancer (27.36%) was the most frequent feminine cancer, followed by the cervical cancer (13.41%) and ovary cancer (8.83%). The main localizations in the man were the liver (19%), the skin (8.04%) and the bladder (4.92%). Approximately 7% of the registered cases are due to the child's cancers. The cancer's diagnosis of confirmation represented 42%; the carcinomas constituted (27.03%) the most frequent histological type. The Burkitt lymphoma (15.1%) was the most histological entity met in the child."
274,Differentiation of lung cancer and radiation fibrosis using magnetic resonance images: a case study.,"Shioya S, Haida M, Ono Y, Ohta T, Hayashi Y, Kurata T.",https://pubmed.ncbi.nlm.nih.gov/2130536/,"We used magnetic resonance imaging to differentiate residual and recurrent lung cancer from the surrounding radiation pulmonary fibrosis in a 62-year-old patient. The cancer's signal intensity was greater than the fibrotic lung tissue's intensity in an ECG-gated image with relatively short repetition and echo times and, also, in images with long repetition and echo times."
275,DNA demethylation in normal colon tissue predicts predisposition to multiple cancers.,"Kamiyama H, Suzuki K, Maeda T, Koizumi K, Miyaki Y, Okada S, Kawamura YJ, Samuelsson JK, Alonso S, Konishi F, Perucho M.",https://pubmed.ncbi.nlm.nih.gov/22310288/,"Some colon cancer (CC) patients present synchronous cancers at diagnosis and others develop metachronous neoplasms, but the risk factors are unclear for non-hereditary CC. We showed previously that global DNA demethylation increased with aging and correlated with genomic damage in CC, and we show now that preferentially associates to CCs with wild-type p53. This study aimed to elucidate the extent of DNA hypomethylation in patients with single and multiple CC, its relationship with aging, and its potential as predictive tool. We compared by real-time methylation-specific PCR the relative demethylation level (RDL) of long interspersed nucleotide element-1 (LINE-1) sequences in matched cancer tissues and non-cancerous colonic mucosa (NCM) from patients with single and multiple right-sided CCs. Although no RDL difference was found in NCM from single CC patients and healthy volunteers (P=0.5), there was more demethylation (higher RDL) in NCM from synchronous cancer patients (P=1.1 × 10(-5)) multiple CCs also were more demethylated than single CCs (P=0.0014). High NCM demethylation was predictive for metachronous neoplasms (P=0.003). In multivariate logistic regression analyses RDL was the only independent predictor for metachronous (P=0.02) and multiple (P=4.9 × 10(-5)) tumors. The higher LINE-1 demethylation in NCM from patients with multiple (synchronous and metachronous) tumors (P=9.6 × 10(-7)) was also very significant in patients with tumors without (P=3.8 × 10(-6)), but not with (P=0.16) microsatellite instability. NCM demethylation increased with aging in patients with single tumors, but decreased in those with multiple tumors. Moreover, the demethylation difference between patients with single vs multiple tumors appeared higher in younger (P=3.6 × 10(-4)) than in older (P=0.0016) patients. These  The stronger association of demethylation in NCM with multiple CC risk from younger patients also suggests an inherited predisposition for the apparent field cancerization effect of somatic demethylation."
276,Boron neutron capture therapy for oral precancer: proof of principle in an experimental animal model.,"Monti Hughes AM, Pozzi EC, Thorp S, Garabalino MA, Farías RO, González SJ, Heber EM, Itoiz ME, Aromando RF, Molinari AJ, Miller M, Nigg DW, Curotto P, Trivillin VA, Schwint AE.",https://pubmed.ncbi.nlm.nih.gov/23410091/," Boron neutron capture therapy (BNCT) is based on biological targeting and would serve to treat undetectable foci of malignant transformation. The aim of this study was to optimize BNCT for the integral treatment for oral cancer, with particular emphasis on the inhibitory effect on tumour development originating in precancerous conditions, and radiotoxicity of different BNCT protocols in a hamster cheek pouch oral precancer model.
    


          Materials and  Cancerized, sham-irradiated hamsters served as controls. Clinical status, tumour development from field-cancerized tissue and mucositis were followed for 8 months.
    


          
    


          Conclusion:
        
      
      BNCT can be optimized for the integral treatment for head and neck cancer, considering the implications for field-cancerized tissue."
277,Bilateral breast cancer: the frequency of undiagnosed cancers.,"Beller FK, Nienhaus H, Niedner W, Holzgreve W.",https://pubmed.ncbi.nlm.nih.gov/3017110/,"The risk of developing cancer in the contralateral breast is five to seven times the risk of cancer occurrence for the normal female population. In patients in 365 consecutive operations, 15 frankly invasive cancers and four metastatic lesions were found in the contralateral breast as well as an additional 28 lesions in situ, totaling 13%. An additional 30% of the patients had severe dysplasia with an unknown potential for becoming cancerous. Only less than one third of the cancers in the contralateral breast were symptomatic (by palpation or mammography or both) but not recognized at the time of primary treatment. The majority of lesions in the contralateral breast are due to a second primary growth, and only a minority is metastatic. The "
278,"Field cancerization in the aerodigestive tract--its etiology, manifestation, and significance.","Strong MS, Incze J, Vaughan CW.",https://pubmed.ncbi.nlm.nih.gov/6716542/,"Field cancerization of the mucous membranes of the aerodigestive tract frequently develops in response to tobacco and alcohol usage; it is characterized by a variety of premalignant and frankly malignant epithelial changes that may lead to the development of multiple primary cancers of the aerodigestive tract. Field cancerization can be demonstrated by supravital staining with toluidine blue or by electron microscopic study of random biopsies taken from apparently normal mucosa. Field cancerization should be taken into account in treatment planning of a patient with cancer so that all treatment options, including the use of radiation therapy, be kept open for as long as possible in the event that the patient may develop multiple primary tumors."
279,[Detection of MG7 antigen expression in predicting high-risk in gastric cancer by automatic image analysis].,"Liu J, Lin Y, Zhang L.",https://pubmed.ncbi.nlm.nih.gov/9388888/,"To study the predictive value of gastric cancer monoclonal antigen (MG7-Ag) in detecting atypical hyperplasia of gastric mucosa, its expression in 72 cases of the illness with follow-up was determined quantitatively by computer-aided image analysis system with immunohistochemical stain for MG7 antibody. Critical value of MG7-Ag expression for high-risk in gastric cancer was explored preliminarily by Youden index and receiver operator characteristic curve. 6%) in 34 cancerous cases, and only seven in 38 non-cancerous cases (18.4%), with a significant difference. Image analysis showed an average MG7-Ag density equal to or greater than 0.19 was regarded as the critical value for high-risk in gastric cancer, which could be used to discriminate atypical hyperplasia from canceration, with a sensitivity of 82.4%, a specificity of 78.9%, and an accuracy of 80.6%. Thus, it could be concluded that MG7-Ag expression correlated closely with canceration of gastric atypical hyperplasia, positive MG7-Ag expression in gastric mucosa of patients with atypical hyperplasia, especially in cases with a density of equal to or greater than 0.19, was an indicator for high risk in canceration. If they are put under strict follow-up, early detection of gastric cancer will be improved."
280,[Predicting cancerization of condyloma acuminatum by testing expression of p16].,"Su XY, Lai W, Zhu HL, Su ZL, Guo SZ, Lin SX.",https://pubmed.ncbi.nlm.nih.gov/15522188/," Some studies indicated that homologous deletion of p16 gene is a major factor that causes cancerization of CA. This study was to detect expression of P16 protein in CA tissues and its cancerization tissues, and to investigate relationship of abnormal expression of P16 and cancerization of CA.
    


           Expression of P16 was tested by LSAB immunohistochemistry, and relationship of P16 and cancerization of CA was statistically analyzed.
    


          05). Cancerized CA tissues showed positive or strongly positive expression of P16, significantly stronger than CA and normal skin tissues (P< 0.05).
    


          Conclusions:
        
      
      Positive and strongly positive expression of P16 in CA tissue implied risk of cancerization of CA. P16 may be a useful predictor for cancerization of CA."
281,Differential gene expression in tumor adjacent histologically normal prostatic tissue indicates field cancerization.,"Haaland CM, Heaphy CM, Butler KS, Fischer EG, Griffith JK, Bisoffi M.",https://pubmed.ncbi.nlm.nih.gov/19639174/,"Field cancerization denotes the occurrence of aberrant cells in tumor adjacent histologically normal tissues (TAHN). To characterize field cancerization in prostate cancer, we used RNA from paired patient tumor and TAHN tissues excised at 1 cm from the tumor margin and subjected them to microarray expression analysis comparative to RNA from normal cancer-free prostatic tissues. Eleven novel transcripts were significantly up-regulated in TAHN tissues and also in tumors. Expression of early growth response protein 1, tristetraprolin, testican, and fatty acid synthase, mutually up-regulated at different levels in tumors and TAHN tissues was confirmed by quantitative reverse transcriptase PCR in the  This study offers proof of expressional changes in field cancerized prostatic TAHN tissues at defined distances from tumor margins. Markers of field cancerized prostatic tissues could be early diagnostic indicators in biopsies after abnormal prostate-specific antigen and digital rectal examination and independent of cancerous histology and/or early targets for chemo-preventive intervention in pre-malignant disease."
282,"Prostate field cancerization and exosomes: Association between CD9, early growth response 1 and fatty acid synthase.","Amirrad F, Pytak PA, Sadeghiani-Pelar N, Nguyen JPT, Cauble EL, Jones AC, Bisoffi M.",https://pubmed.ncbi.nlm.nih.gov/32319557/,"Intracapsular and well‑defined adenocarcinomas of the prostate are often surrounded by tissue areas that harbor molecular aberrations, including those of genetic, epigenetic and biochemical nature. This is known as field cancerization, or a field effect and denotes a state of pre‑malignancy. Such alterations in histologically normal tumor‑adjacent prostatic tissues have been recognized as clinically important and are potentially exploitable as biomarkers of disease and/or targets for preventative/therapeutic intervention. The authors have previously identified and validated two protein markers of field cancerization: The expressional upregulation of the transcription factor early growth response 1 (EGR‑1) and the lipogenic enzyme fatty acid synthase (FASN). However, the molecular etiology of prostate field cancerization, including EGR‑1 and FASN upregulation, remains largely unknown. It was thus hypothesized that extracellular vesicles, notably exosomes, released by tumor lesions may induce molecular alterations in the surrounding tissues,  Towards testing this hypothesis, the current study, to the best of our knowledge, for the first time, presents correlative protein expression data, generated in disease‑free, tumor‑adjacent and cancerous human prostate tissues by quantitative immunofluorescence, between the exosomal marker CD9, and EGR‑1 and FASN. Despite the pilot character of the present study, and the static nature and heterogeneity of human tissues, the data suggest that CD9 expression itself is part of a field effect. In support of this hypothesis, the  These findings were corroborated in established cell models of cancerous (LNCaP) and non‑cancerous (RWPE‑1) human prostate epithelial cells. The findings of this study warrant further investigation into the functional interface between exosomes and field cancerization, as a detailed understanding of this characterization may lead to the development of clinical applications related to diagnosis and/or prognosis and targeted intervention to prevent progression from pre‑malignancy to cancer."
283,Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma.,"Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S, Schwartz M, Fiel I, Thung S, Mazzaferro V, Bruix J, Bottinger E, Friedman S, Waxman S, Llovet JM.",https://pubmed.ncbi.nlm.nih.gov/17393520/,"Although HCC is the third-leading cause of cancer-related deaths worldwide, there is only an elemental understanding of its molecular pathogenesis. In western countries, HCV infection is the main etiology underlying this cancer's accelerating incidence. To characterize the molecular events of the hepatocarcinogenic process, and to identify new biomarkers for early HCC, the gene expression profiles of 75 tissue samples were analyzed representing the stepwise carcinogenic process from preneoplastic lesions (cirrhosis and dysplasia) to HCC, including 4 neoplastic stages (very early HCC to metastatic tumors) from patients with HCV infection. We identified gene signatures that accurately reflect the pathological progression of disease at each stage. Eight genes distinguish between control and cirrhosis, 24 between cirrhosis and dysplasia, 93 between dysplasia and early HCC, and 9 between early and advanced HCC. Using quantitative real-time reverse-transcription PCR, we validated several novel molecular tissue markers for early HCC diagnosis, specifically induction of abnormal spindle-like, microcephaly-associated protein, hyaluronan-mediated motility receptor, primase 1, erythropoietin, and neuregulin 1. In addition, pathway analysis revealed dysregulation of the Notch and Toll-like receptor pathways in cirrhosis, followed by deregulation of several components of the Jak/STAT pathway in early carcinogenesis, then upregulation of genes involved in DNA replication and repair and cell cycle in late cancerous stages.
    


          Conclusion:
        
      
      These findings provide a comprehensive molecular portrait of genomic changes in progressive HCV-related HCC."
284,Therapies for advanced cancers pose a special challenge for health technology assessment organizations in many countries.,"Neumann PJ, Bliss SK, Chambers JD.",https://pubmed.ncbi.nlm.nih.gov/22492886/,"Health technology assessment organizations evaluate medical therapies and technologies to help inform coverage and reimbursement decisions for payers around the globe. Even as they establish strict review processes, these organizations--and the reimbursement authorities that use their assessments--have sometimes handled cancer interventions with special care. We found that some countries have created separate health technology assessment pathways for cancer treatment, while others have eased access to cancer treatments through end-of-life or disease-severity exceptions within health technology assessment policies. In the United States, although no separate evaluation pathways exist for cancer, cancer drugs receive special status by virtue of unique Medicare rules covering off-label indications. Worldwide, we demonstrate that health technology assessment organizations are struggling with cancer's ""exceptionalism."""
285,Selection of patients with non-small-cell lung carcinoma for surgical resection.,Rizk NW.,https://pubmed.ncbi.nlm.nih.gov/3909642/,"Cancer of the lung is rapidly increasing in incidence in both sexes and soon will overtake breast cancer as the most deadly cancer in women. Selection of patients with non-small-cell carcinoma for surgical resection is largely based on preoperative clinical staging, using the American Joint Committee on Cancer's TNM-based group staging protocol. Determining the presence or absence of mediastinal nodal metastasis is paramount and is currently best achieved by computed tomographic scanning of the chest and biopsy of enlarged nodes via mediastinoscopy. Certain types of stage III lesions, previously excluded from surgical treatment, are now recognized as operable."
286,"One patient--three head and neck primaries: nasopharyngeal, tongue and thyroid cancers.","Fareed MM, Al Amro A, Bayoumi Y, AlQahtani KH, Fatani HA, Tunio MA, Khalid F.",https://pubmed.ncbi.nlm.nih.gov/24164964/," Squamous cell carcinoma of tongue and papillary thyroid carcinoma occurred as metachronous cancers in a patient with primary nasopharyngeal carcinoma. These three pathologically distinct malignancies of head and neck region in one patient is a rare phenomenon and is not reported so far.
    


          Case presentation:
        
      
      A 60 year old Saudi female patient presented in March 2011 with locally advanced nasopharyngeal carcinoma. After completion of concurrent chemoradiation in June 2011, she developed two new primaries i-e thyroid cancer and tongue cancer in May 2012 along with recurrent nasopharyngeal carcinoma. We discuss histopathologic features, diagnostic tools and treatment modalities for this rarely existing case.
    


          Conclusion:
        
      
      High index of suspicion and thorough work up is essential in follow up of patients with head and neck primary cancers. The effect of field cancerization and environmental factors need to be explored in greater depths in such selected cases. However, which patients are at increased risk of triplet primaries, is still unknown."
287,[Pathological study of 16 cases of lung cancer with long-term exposure to dusts in coal mine].,Wang BS.,https://pubmed.ncbi.nlm.nih.gov/1819381/,"16 cases of lung cancer with long-term exposed to dusts in coal mine were studied by autopsies. This group of lung cancer's pathologic characteristics were: The mean of the age of death of the patients were 51.3 yrs, 10 years younger than that of the general population. In addition to the main tumor, multiple origin of bronchial mucosa with epithelial hyperplasia, metaplasia, and carcinoma in situ were seen. Dusts smear were seen under polar-microscope and identification by EDAX in H-800 electronic microscope. According to EDAX analysis, on the surface of some particles, Co, Cr, ions were detected."
288,"Personalized therapy of sarcomas: integration of biomarkers for improved diagnosis, prognosis, and therapy selection.",Ludwig JA.,https://pubmed.ncbi.nlm.nih.gov/18778559/,"An improved understanding of cancer's molecular diversity at the genetic, proteomic, and epigenetic levels has made it evident that ""sarcoma"" comprises more than 50 different types, each as unique as, for example, breast carcinoma is from colon carcinoma. Sarcomas exhibit characteristic differences in cell of origin, disease site, likelihood and site of metastasis, growth propensity, and chemosensitivity. Additionally, as many as one third of sarcomas harbor specific chromosomal translocations that can be used to discriminate one subtype from another. Although biomarkers can be integrated into clinical practice to improve diagnostic accuracy and predict treatment response, a number of challenges hinder their widespread use. This review addresses the current use of biomarkers for clinical oncology, with special emphasis on diagnosis, staging, and grading. It also discusses types of biomarkers that are emerging to aid selection of therapy for patients with sarcoma. Finally, we consider practical factors that appear to limit biomarker integration into clinical practice."
289,[Treatment options of non-melanoma skin tumors in organ transplant recipients in relation to a case report].,"Gellén E, Péter Z, Emri G, Asztalos L, Remenyik É.",https://pubmed.ncbi.nlm.nih.gov/27263436/,"The authors present the case of a 59-year-old male patient, whose first kidney transplantation was in 1983 and the second in 2000. The first squamous cell carcinoma appeared on the skin 2 years after the first transplantation. Since 2003, at least two precancerous lesions or non-melanoma skin tumors have been removed surgically yearly. These cancers appeared predominantly on the sun-exposed skin, and were multiple. As these tumors could behave aggressively and prone to recurrence, complex treatment was applied, which included a switch in immunosuppressive drugs and the application of field therapies. The authors give an overview of these treatment options in relation to the case presentation, emphasizing that not only early detection and active treatment of the precancerous lesions and skin cancers are essential, but education of proper sun-protection "
290,[Telomerase activity in colorectal cancer--a semi-quantitative procedure].,"Ohki S, Satoh H, Watanabe F, Andoh Y, Nomizu T, Yoshida T, Tsuchiya A, Abe R, Yamaki Y.",https://pubmed.ncbi.nlm.nih.gov/9589055/,"Telomerase maintains telomere at the end of chromosome and stabilizes chromosome. It is thought to have important roles in cancer progression and cell immortality. We evaluated the role of telomerase expression in colorectal carcinogenesis. Materials included 13 colonic adenomas, 9 early colorectal cancers, 32 advanced colorectal cancers, 5 metastatic tumors, and 30 non-cancerous colon mucosas. The telomerase activity was analyzed using TRAP-eze (Oncor Inc.) for a semi-quantitative  The positive rate of telomerase activity was 13.3% in non-cancerous colonic mucosa, 15.4% in colonic adenomas, 77.8% in early colorectal cancers, 93.8% in advanced colorectal cancers, and 100% in metastatic tumors; the mean value was 18.0, 29.9, 65.8, 97.0 and 161.3. The correlation between telomerase activity and tumor size, histologic type, or depth of invasion was noted. Sensitivity, specificity and accuracy were on the order of 89%, 98% and 93% at the cut-off level as two times the mean value of non-cancerous mucosa. Telomerase had an important role in carcinogenesis, and progression of colorectal cancer, and it was suggested to be useful for a tumor marker."
291,[Recognition of occupational cancers: review of existing methods and perspectives].,"Vandentorren S, Salmi LR, Brochard P.",https://pubmed.ncbi.nlm.nih.gov/16203270/,"Occupational risk factors represent a significant part of cancer causes and are involved in all type of cancers. Nonetheless, the frequency of these cancers is largely under-estimated. Parallel to the epidemiological approach (collective), the concept of occupational cancer is often linked (at the individual level) to the compensation of occupational diseases. To give rise to a financial compensation, the occupational origin of the exposition has to be established for a given cancer. Whatever the  The aim of this work is to synthesize and describe the main principles of recognition of occupational cancers, to discuss the limits of available  In France, the recognition of a cancer's occupational origin consists in tables of occupational diseases that are based on presumption of causality. These tables consist in medical, technical and administrative conditions that are necessary and sufficient for the recognition of an occupational disease and its financial compensation. Whenever causality presumption does not apply, imputation is based on case analyses run by experts within regional committees of occupational diseases recognition that lack reproducibility. They do not allow statistical quantization and do not always take into account the weight of associated factors. Nonetheless, reliability and validity of the expertise could be reinforced by the use of formal consensus techniques. This process could ideally lead to the generation of decision-making algorithms that could guide the user towards the decision of imputing or not the cancer to an occupational exposure. This would be adapted to the build-up of new tables. The imputation process would be better represented by statistical  The application of these  Acquiring these data and diffusing these "
292,"Clinical, histopathological and immunohistochemical assessment of human skin field cancerization before and after photodynamic therapy.","Szeimies RM, Torezan L, Niwa A, Valente N, Unger P, Kohl E, Schreml S, Babilas P, Karrer S, Festa-Neto C.",https://pubmed.ncbi.nlm.nih.gov/22329784/," Topical photodynamic therapy (PDT) is a noninvasive therapeutic 
    


          
    


           Biopsies before and 3 months after the last treatment session were taken from normal-appearing skin on the field-cancerized area. Immunohistochemical stainings were performed for TP-53, procollagen-I, metalloproteinase-1 (MMP-1) and tenascin-C (Tn-C).
    


           The global score for photodamage improved considerably in all patients (P < 0·001). The AK clearance rate was 89·5% at the end of the study. Two treatment sessions were as effective as three MAL-PDT sessions. A significant decrease in atypia grade and extent of keratinocyte atypia was observed histologically (P < 0·001). Also, a significant increase in collagen deposition (P = 0·001) and improvement of solar elastosis (P = 0·002) were noticed after PDT. However, immunohistochemistry showed only a trend for decreased TP-53 expression (not significant), increased procollagen-I and MMP-1 expressions (not significant) and an increased expression of Tn-C (P = 0·024).
    


          Conclusions:
        
      
      Clinical and histological improvement in field cancerization after multiple sessions of MAL-PDT is proven. The decrease in severity and extent of keratinocyte atypia associated with a decreased expression of TP-53 suggest a reduced carcinogenic potential of the sun-damaged area. The significant increase of new collagen deposition and the reduction of solar elastosis explain the clinical improvement of photodamaged skin."
293,Occurrence of metachronous multiple primary cancers occurred in different parts of the stomach with 2 pathologic features: A case report.,"Song Y, Zhao N, Jiang K, Zheng Z, Wang B, Kong D, Li S.",https://pubmed.ncbi.nlm.nih.gov/29768377/,"Rationale:
        
      
      With the increasing survival rate of gastric cancer, more multiple primary cancers (MPC) have been reported. However, few cases involve metachronous multiple primary cancers which both occurred in the stomach.
    


          Patient concerns:
        
      
      An 83-year-old Chinese male had been diagnosed with gastric cardia cancer and underwent proximal gastrectomy. The pathological  13 years later the patient's gastroscope  The biopsy of the antrum revealed dysplasia with doubtful focal cancerization.
    


          Diagnoses:
        
      
      Metachronous multiple primary cancers in the stomach.
    


          Interventions:
        
      
      Endoscopic submucosal dissection (ESD) was performed. The pathological 
    


          Outcomes:
        
      
      After treatment, the patient is alive with good condition until now.
    


          Lessons:
        
      
      This is an unusual case of MPC with different pathological features in different parts of the same organ in an interval of more than ten years and undergoing different operations."
294,Laser-assisted MAL-PDT associated with acoustic pressure wave ultrasound with short incubation time for field cancerization treatment: A left-right comparison.,"Pires MTF, Pereira AD, Durães SMB, Issa MCA, Pires M.",https://pubmed.ncbi.nlm.nih.gov/31479804/," Nonetheless, clinical effects of this association when reducing MAL incubation time is poorly discussed. Furthermore, the association of acoustic pressure wave ultrasound with laser-assisted MAL-PDT with short incubation time for field cancerization had not been reported before.
    


          
    


           Two protocols were randomly chosen. One side was treated with conventional MAL-PDT, whereas the other with laser-assisted MAL-PDT associated with acoustic pressure wave ultrasound with 1-hour incubation time. Actinic keratoses were quantitively measured, and the other signs of sun-damaged skin, like pigmentation and texture, in field cancerized skin were qualitatively evaluated before and after six months. Side effects were assessed subjectively during the procedure and one week after.
    


           At six months after treatment, both protocols reduced the number of AK (72%; CO2 + PDT, and 65%; MAL-PDT). The difference between these two protocols was not statistically significant (p = 0.77). The improvement of pigmentation and texture of field cancerized skin was more significant on the side treated with laser-assisted MAL-PDT associated with acoustic pressure wave ultrasound. Both protocols were well tolerated and without significant difference in adverse events.
    


          Conclusion:
        
      
      Laser-assisted MAL-PDT using CO2 laser and acoustic pressure wave ultrasound with short incubation time of 1 h was as effective as conventional MAL-PDT for field-cancerized skin with actinic keratosis in forearms with better cosmetic outcome."
295,Successful multidisciplinary treatment for synchronous advanced esophageal and cecal cancers after total gastrectomy with reconstruction by jejunal interposition.,"Sato Y, Tanaka Y, Yamamoto K, Horaguchi T, Fukada M, Sengoku Y, Yasufuku I, Asai R, Tajima JY, Kiyama S, Kato T, Murase K, Matsuhashi N.",https://pubmed.ncbi.nlm.nih.gov/38486303/," Synchronous esophageal and colorectal cancers are also encountered with a certain frequency. A good prognosis can be expected if the tumors in both locations can be safely and completely removed. For patients with multiple cancers that occur simultaneously with esophageal cancer, it is necessary to perform a staged operation, taking into consideration the associated surgical invasiveness. It is also necessary to select multidisciplinary treatment depending on the degree of progression of the multiple lesions. We report our rare experience with a staged operation for a patient with synchronous advanced cancers of the esophagus and cecum who had previously undergone total gastrectomy with reconstruction by jejunal interposition for gastric cancer.
    


          Case presentation:
        
      
      A 71-year-old man with a history of reconstruction by jejunal interposition after total gastrectomy was diagnosed as having multiple synchronous esophageal and cecal cancers. After neoadjuvant chemotherapy, we performed a planned two-stage operation, with esophagectomy and jejunostomy in the first stage and ileocecal resection and jejunal reconstruction with vascular anastomosis in the second. Postoperatively, the patient was relieved without major complications, and both tumors were amenable to curative pathologic resection.
    


          Conclusions:
        
      
      Our procedure reported here may be recommended as an option for staged resection and reconstruction in patients with simultaneous advanced esophageal and cecal cancer after total gastrectomy."
296,[5-Fluorouracil level and pyrimidine nucleoside phosphorylase activity in cancer patients after oral administration of doxifluridine (5'-DFUR)].,"Maeda H, Miyamoto T, Mochinaga N, Tsunoda T.",https://pubmed.ncbi.nlm.nih.gov/1827573/,"For the purpose to evaluate the distribution of 5'-DFUR in the cancerous tissues and non-cancerous tissues of 64 cancer patients (21 gastric, 25 colo-rectal and 18 breast cancers), pyrimidine nucleoside phosphorylase (PyNPase) activity and 5-FU level were determined by bioassay and GC-MS  5-FU levels in the plasma were also measured in all patients. Four hundred mg of 5'-DFUR was orally administrated three times a day for 3 to 7 days and just 3 hours before surgical operations. PyNPase activity and 5-FU level were significantly higher in the cancerous tissues than non-cancerous ones. 5-FU levels in the plasma were significantly lower than those in both cancerous and non-cancerous tissues. In conclusion, 5'-DFUR is expected to be an useful anticancer drug because of the selective accumulation of converted 5-FU in cancerous tissues."
297,Short incubation fractional CO(2) laser-assisted photodynamic therapy vs. conventional photodynamic therapy in field-cancerized skin: 12-month follow-up results of a randomized intraindividual comparison study.,"Vrani F, Sotiriou E, Lazaridou E, Vakirlis E, Sideris N, Kirmanidou E, Apalla Z, Lallas A, Ioannides D.",https://pubmed.ncbi.nlm.nih.gov/29869444/," Skin pretreatment with ablative CO2 fractional laser (AFXL) prior to MAL-PDT enhances drug penetration and could minimize incubation time.
    


          
    


           All patients underwent two treatment sessions 1 week apart. Irradiation was performed using a red light-emitting diode lamp at 37 J/cm2 . Patients were followed up at 3, 6, 9 and 12 months for the evaluation of development of new NMSCs lesions.
    


           There was no statistically significant difference with respect to the total number of new actinic keratoses at any point of follow-up as well as to the mean time of occurrence of new lesions between treatment fields. Both treatment regimens were safe and well tolerated.
    


          Conclusion:
        
      
      Ablative CO2 fractional laser pretreatment may be considered as an option for reducing photosensitizer occlusion time while providing the same preventative efficacy as CPDT in patients with field-cancerized skin."
298,Changes in the 7th edition of the AJCC TNM classification and recommendations for pathologic analysis of lacrimal gland tumors.,"Rootman J, White VA.",https://pubmed.ncbi.nlm.nih.gov/19653723/,"In our recent work to update the American Joint Committee on Cancer's AJCC Cancer Staging Manual, we brought the staging system in line with that of salivary gland malignancies to better describe the range of these tumors. In addition, we have suggested that information be collected on biomarkers and clinical and histologic data points. This revised staging, along with careful histologic analysis and patient follow-up, may provide information that helps develop more targeted management for these lesions."
299,[Expression of CD10 in tumor-associated fibroblast of cancerized or recurrent colorectal adenomas].,"Zheng J, Zhu Y, Li C, Li Y, Nie Q, Zhu Z, Deng H.",https://pubmed.ncbi.nlm.nih.gov/27868405/,"  The expression of CD10 in the stromal TAFs, and the expressions of β-catenin, Ki-67, p53 and CyclinD1 in tumor cells were detected by immunohistochemistry (Envision). The correlation of CD10 expression in stromal TAFs with the expressions of β-catenin, Ki-67, p53 and CyclinD1 in tumor cells was analyzed by Spearmen. One hundred samples of low-grade colorectal adenoma were collected, including 57 non-recurrent cases and 43 recurrent cases (16 cases of recurrent adenoma and 27 cases of recurrent adenocarcinoma); the expression of stromal TAF CD10 were determined and compared among groups.  The expression rates of TAF CD10 in low-grade adenoma, high-grade adenoma and colorectal adenocarcinoma were 22%, 50% and 78%, respectively (all P<0.05). The expression of Ki-67 and β-catenin in low-grade adenoma, high-grade adenoma, colorectal adenocarcinoma was on a rising trend (all P<0.01). The expression of CyclinD1 in high-grade adenoma was higher than that in colorectal adenocarcinoma and low-grade adenoma (all P>0.05). The expression of p53 in colorectal adenocarcinoma and high-grade adenoma was higher than that in low grade adenoma (all P<0.01). The expression of TAF CD10 was correlated with the expression of p53, Ki-67 and β-catenin-nucleus(r=0.264、0.307、0.320, all P<0.01),but not correlated with CyclinD1 and β-catenin-membrane (r=0.012、-0.073, all P>0.05). The TAF CD10 level was significantly higher in low-grade adenoma with recurrence than that in those without recurrence (P<0.05).The expression of CD10 in recurrent colorectal adenocarcinoma was higher than that in recurrent adenoma (P<0.05). Conclusion: The expression of TAF CD10 is increased gradually in the process of adenoma-cancer, indicating that it may play an important role in the canceration of adenoma. Adenomas with high expression of CD10 TAF are likely to be recurrent and cancerized, and detection of TAF CD10 combined with p53, Ki-67 and β-catenin may be of value in predicting canceration or recurrence of colorectal adenoma."
300,"Multiple skin cancers in a single patient: Multiple pigmented Bowen's disease, giant basal cell carcinoma, squamous cell carcinoma.","Saini R, Sharma N, Pandey K, Puri KJ.",https://pubmed.ncbi.nlm.nih.gov/26458715/,"Basal cell carcinoma (BCC) and squamous cell carcinoma are the most common type of nonmelanoma skin cancers (NMSCs). Bowen's disease (BD), a premalignant condition, has a marginal potential (3-5%) to progress to invasive carcinoma. We report here a rarest of a rare case of multiple pigmented BD with overlying squamous cell cancer along with a giant neglected BCC on the scalp of a 76-year-old man. The occurrence of multiple BD and NMSC in a single patient compelled us to explore the following hypothesis: (1) The multiple precancerous and cancerous lesions can be due to common etiopathogenesis. Chronic ultraviolet exposure, immunosupresssion, human papillomavirus infection, dietary factors, and environmental factors including arsenic exposure were probed in to. (2) There is evolution of precancerous lesions into a different type of cancers in different time frame. (3) The new cancerous lesions are subsequent cancers that developed after neglected untreated primary cancer."
301,[Surgical treatment of squamous cell carcinoma of the thoracic esophagus].,"Dabrowski A, Ciechański A, Abramowicz K.",https://pubmed.ncbi.nlm.nih.gov/10522409/,The authors present modern approach of the squamous cell esophageal cancer's therapy. They emphasize the role of the surgical treatment with Akiyama 
302,Genetic sequence variants and the development of secondary primary cancers in patients with head and neck cancers.,"Azad AK, Bairati I, Samson E, Cheng D, Cheng L, Mirshams M, Savas S, Waldron J, Wang C, Goldstein D, Xu W, Meyer F, Liu G.",https://pubmed.ncbi.nlm.nih.gov/22009713/," We comprehensively evaluated 23 germline sequence variants (from published literature) in 17 genes from 7 biological pathways associated with the HNC survival. Because cancer prognosis correlates with disease aggressiveness, the factors that determine aggressive disease may influence field cancerization process to favor SPC development. We thus hypothesized that the same sequence variants associated with HNC survival can also be associated with SPC.
    


          
    


           Median follow-up time was 5 years. SPCs were diagnosed in 21% of patients. The 5-year SPC-free survival was 79%. All but 1 evaluated sequence variant were not associated with SPC. There was a strong association of the DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) sequence variant, DNMT3B:C149T (rs2424913) with SPC: the adjusted hazard ratio (aHR) for TT versus CC was 2.23 (1.32-3.78; P = .003), whereas each variant T allele was associated with an aHR of 1.49 (1.15-1.95; P = .003).
    


          Conclusions:
        
      
      A functional sequence variant in DNMT3B is associated with the development of SPCs in HNC early stage patients treated with radiation. Aberrant DNA methylation may be an important modulator of SPC development in at-risk individuals with HNCs."
303,Photodynamic therapy of malignant and premalignant lesions in patients with 'field cancerization' of the oral cavity.,"Grant WE, Hopper C, Speight PM, Macrobert AJ, Bown SG.",https://pubmed.ncbi.nlm.nih.gov/8289004/,"The management of patients with 'field cancerization' of the oral mucosa, with multicentric foci of invasion, presents a considerable problem for the head and neck surgeon. Surgical resection of synchronous or metachronous primary squamous cell carcinomas, along with adjacent premalignant lesions, is likely to be associated with considerable mutilation. Photodynamic therapy (PDT) has been shown to be of value in the treatment of superficial tumours in the upper aerodigestive tract, with excellent healing of treated areas. This study reports the use of PDT to treat 11 patients with 'field cancerization' occurring in the oral cavity. Six patients had multiple primary cancers and five had single primary tumours. All had associated areas of leukoplakia. Each received Photofrin 2 mg/kg 48 hours prior to photoirradiation with 50-100 J/cm2 red laser light by surface illumination. Six to eight weeks later treated areas in 10 of the 11 patients showed a complete response to PDT; one patient had areas of residual leukoplakia. Two patients developed further areas of leukoplakia or erythroplakia within 12 months but no patient has had evidence of recurrent invasive carcinoma in the treated areas. Longer term follow-up will be necessary to exclude further recurrence. It is concluded that PDT offers an effective repeatable treatment option, whether on its own or as an adjunct to local excision, for patients with 'field cancerization' of the oral cavity."
304,Biphasic co-detection of melanoma aneuploid tumor cells and tumor endothelial cells in guidance of specifying the field cancerized surgical excision margin and administering immunotherapy.,"Fu Z, Zhang L, Chen R, Zhan J, Zhong J, Zheng W, Zou J, Wang P, Deng X, Lin AY, Wang DD, Lin PP, He R.",https://pubmed.ncbi.nlm.nih.gov/38971491/,"An optimum safety excision margin (EM) delineated by precise demarcation of field cancerization along with reliable biomarkers that enable predicting and timely evaluating patients' response to immunotherapy significantly impact effective management of melanoma. In this study, optimized biphasic ""immunofluorescence staining integrated with fluorescence insitu hybridization"" (iFISH) was conducted along the diagnosis-metastasis-treatment-cellular MRD axis to longitudinally co-detect a full spectrum of intact CD31- aneuploid tumor cells (TCs), CD31+ aneuploid tumor endothelial cells (TECs), viable and necrotic circulating TCs (CTCs) and circulating TECs (CTECs) expressing PD-L1, Ki67, p16 and Vimentin in unsliced specimens of the resected primary tumor, EM, dissected sentinel lymph nodes (SLNs) and peripheral blood in an early-stage melanoma patient. Numerous PD-L1+ aneuploid TCs and TECs were detected at the conventional safety EM (2 cm), quantitatively indicating the existence of a field cancerized EM for the first time. Contrary to highly heterogeneous PD-L1 expression and degrees of Chr8 aneuploidy in TCs and TECs in the primary lesions as well as CTCs and CTECs in peripheral blood, almost all TCs and TECs in SLNs and EM were homogeneously PD-L1+ haploid cells. Dynamic monitoring and cellular MRD assessment revealed that, in contrast to PD-L1+ CTCs being responsive to the immune checkpoint inhibitor (ICI-anti-PD-1), multiploid (≥pentasomy 8) PD-L1+ and Ki67+ CTECs were respectively resistant to ICI-sensitized T cells. In therapeutically stressed lymphatic and hematogenous metastatic cascades, stratified phenotypic and karyotypic profiling of iFISH tissue and liquid biopsied TCs, TECs, CTCs and CTECs in future large-cohort studies will enable appropriate re-specification of the optimal safety EM and distribution mapping of in-depth characterized, subcategorized target cells to help illustrate their metastatic relevance, ultimately improving risk stratification and clinical intervention of tumor progression, metastases, therapy resistance and cancer relapse."
305,Revisit of field cancerization in squamous cell carcinoma of upper aerodigestive tract: better risk assessment with epigenetic markers.,"Lee YC, Wang HP, Wang CP, Ko JY, Lee JM, Chiu HM, Lin JT, Yamashita S, Oka D, Watanabe N, Matsuda Y, Ushijima T, Wu MS.",https://pubmed.ncbi.nlm.nih.gov/21952583/,"We quantified field cancerization of squamous cell carcinoma in the upper aerodigestive tract with epigenetic markers and evaluated their performance for risk assessment. Methylation levels were analyzed by quantitative methylation-specific PCR of biopsied specimens from a training set of 255 patients and a validation set of 224 patients. We also measured traditional risk factors based on demographics, lifestyle, serology, genetic polymorphisms, and endoscopy. The methylation levels of four markers increased stepwise, with the lowest levels in normal esophageal mucosae from healthy subjects without carcinogen exposure, then normal mucosae from healthy subjects with carcinogen exposure, then normal mucosae from cancer patients, and the highest levels were in cancerous mucosae (P < 0.05). Cumulative exposure to alcohol increased methylation of homeobox A9 in normal mucosae (P < 0.01). Drinkers had higher methylation of ubiquitin carboxyl-terminal esterase L1 and metallothionein 1M (P < 0.05), and users of betel quid had higher methylation of homeobox A9 (P = 0.01). Smokers had increased methylation of all four markers (P < 0.05). Traditional risk factors allowed us to discriminate between patients with and without cancers with 74% sensitivity (95% CI: 67%-81%), 74% specificity (66%-82%), and 80% area under the curve (67%-91%); epigenetic markers in normal esophageal mucosa had values of 74% (69%-79%), 75% (67%-83%), and 83% (79%-87%); and both together had values of 82% (76%-88%), 81% (74%-88%), and 91% (88%-94%). Epigenetic markers done well in the validation set with 80% area under the curve (73%-85%). We concluded that epigenetics could improve the accuracies of risk assessment."
306,Early growth response 1 and fatty acid synthase expression is altered in tumor adjacent prostate tissue and indicates field cancerization.,"Jones AC, Trujillo KA, Phillips GK, Fleet TM, Murton JK, Severns V, Shah SK, Davis MS, Smith AY, Griffith JK, Fischer EG, Bisoffi M.",https://pubmed.ncbi.nlm.nih.gov/22127986/," In prostate cancer, identification of field cancerization has several potential clinical applications. However, prostate field cancerization remains ill defined. Our previous work has shown up-regulated mRNA of the transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS) in tissues adjacent to prostate cancer.
    


          
    


          6× on average) and in tumor (3.0× on average) tissues compared to disease-free tissues. In addition, the ratio of cytoplasmic versus nuclear EGR-1 expression was elevated in both tumor adjacent and tumor tissues. Similarly, FAS expression was elevated in both tumor adjacent (2.7× on average) and in tumor (2.5× on average) compared to disease-free tissues.
    


          Conclusions:
        
      
      EGR-1 and FAS expression is similarly deregulated in tumor and structurally intact adjacent prostate tissues and defines field cancerization. In cases with high suspicion of prostate cancer but negative biopsy, identification of field cancerization could help clinicians target areas for repeat biopsy. Field cancerization at surgical margins on prostatectomy specimen should also be looked at as a predictor of cancer recurrence. EGR-1 and FAS could also serve as molecular targets for chemoprevention."
307,[Histological study of urinary bladder tumor: DNA of rat urinary bladder tumor caused by N-butyl-N-(4-hydroxybutyl) nitrosamine and that of human bladder tumor].,"Murase T, Kobayashi O, Aota Y, Mitsuta H, Koshikawa T.",https://pubmed.ncbi.nlm.nih.gov/6677123/,"Male Fisher rats were treated with 0.5% BBN, and the appearance of cancer in the rat's bladder was observed successively. The quantities of DNA in the normal and tumorous tissues were compared with those in the bladder cancer excised from man; and, the bladder cancer produced in the rat and that occurring in man were compared. 96 rats were divided into 4 groups, and given 8, 16, 24 or 32 weeks of treatment with BBN. Papillomas appeared after administration for 8 weeks, and with subsequent increase in the period of administration the rate of canceration increased. The cancerous tissue proliferated papillarily , the malignancy was grade 1 to 2, no case showed infiltration into the muscle layer, and the quantity of DNA scarcely changed with time, always showing a peak near 2c. In the papillary type of bladder cancer in man, the quantity of DNA showed little change at any stage, and little tendency of infiltration; and, the growth pattern was similar to that of the BBN-induced cancer in rats. On the other hand, non-papillary cancer in man showed a flat histogram of DNA, had a strong tendency of infiltration, and showed a growth pattern different from that of the BBN-induced cancer in rats, thus the BBN-induced cancer in the rat cannot be used as a model of non-papillary infiltrative cancer."
308,Sclerosing adenosis cancerized by intraductal carcinoma.,"Chan JK, Ng WF.",https://pubmed.ncbi.nlm.nih.gov/2832807/,"Sclerosing adenosis is a common proliferative lesion of the mammary lobule which is not associated with an increased risk of developing breast cancer. An unusual case of florid sclerosing adenosis showing extensive cancerization by intraductal carcinoma is reported. The neoplastic nature of the sclerosing lesion can be recognized by the unusual distension of the tubules by cells and the subtle cytological changes, and further confirmed by finding foci of classical intraductal carcinoma."
309,"Hypomethylation of Alu repetitive elements in esophageal mucosa, and its potential contribution to the epigenetic field for cancerization.","Matsuda Y, Yamashita S, Lee YC, Niwa T, Yoshida T, Gyobu K, Igaki H, Kushima R, Lee S, Wu MS, Osugi H, Suehiro S, Ushijima T.",https://pubmed.ncbi.nlm.nih.gov/22527164/," Such hypermethylation is also present in normal-appearing esophageal mucosae of ESCC patients and is considered to contribute to the formation of a field for cancerization. On the other hand, the presence of global hypomethylation in ESCCs or in their 
    


           Methylation levels of repetitive elements (Alu, LINE1) and cancer/testis antigen genes (NY-ESO-1, MAGE-C1) were measured by bisulfite pyrosequencing and quantitative methylation-specific PCR, respectively.
    


           Also, in the  In ESCCs, methylation levels of the two repetitive elements and the two cancer/testis antigen genes were correlated with each other.
    


          Conclusion:
        
      
      This is the first study to show the presence of global hypomethylation in ESCCs, and even in their non-cancerous  Alu hypomethylation might reflect the severity of an epigenetic field for cancerization."
310,Surveillance and management of patients at high genetic risk for ovarian carcinoma.,"Lynch HT, Albano WA, Lynch JF, Lynch PM, Campbell A.",https://pubmed.ncbi.nlm.nih.gov/7070730/,"The present study is concerned with surveillance/management programs for hereditary ovarian cancer syndromes. These syndromes lack distinguishing premonitory physical signs or biomarkers; therefore, in these genotypic settings, ovarian cancer risk must be assessed by analysis of the patient's pedigree. The authors describe 10 families showing a hereditary proclivity to ovarian carcinoma and/or associated cancer(s) in accord with their respective cancer-prone genotypes. Cancer education, genetic counseling, and surveillance should be instituted early. In addition to bimanual pelvic examination, ultrasound should be tested for its possible efficacy as a screening technique. The option of prophylactic bilateral oophorectomy and hysterectomy is thoroughly discussed with highly selected candidates. The authors believe that the aggressive management approach proposed for ovarian carcinoma is warranted for high-risk members of cancer-prone families, wherein the risk for ovarian cancer may approach 50%."
311,Microsatellite instability in squamous cell carcinomas of the head and neck related to field cancerization phenomena.,"Piccinin S, Gasparotto D, Vukosavljevic T, Barzan L, Sulfaro S, Maestro R, Boiocchi M.",https://pubmed.ncbi.nlm.nih.gov/9820170/,"Patients affected by squamous cell carcinoma of the head and neck (HNSCC) show frequent occurrence of multiple cancers and widespread precancerous lesions in the mucosa of the upper respiratory tract, a phenomenon known as field cancerization. In this study, we investigated the role of genetic instability in the development of HNSCC and in particular in tumour multiplicity phenomena of the upper respiratory tract. For this purpose, we analysed microsatellite instability (MI) and loss of heterozygosity (LOH) at 20 loci mapping on five chromosomal arms in 67 HNSCC patients, 45 of whom had a single cancer and 22 had multiple primary tumours. The possible involvement of the hMLH1 gene in genetic instability and as a potential target of 3p21 deletion phenomena in head and neck cancers was also investigated. Our data indicate that mismatch repair-related genetic instability plays a minor role in the carcinogenesis of HNSCC and in tumour multiplicity of the head and neck region. Moreover, our  We conclude that presumably other genetic mechanisms, such as those hypothesized for MI-negative hereditary non-polyposis colorectal cancer patients, may play a major role in the carcinogenesis of the mucosa of the upper respiratory tract."
312,[Clinical studies on endoscopic electromyogram of gastric cancer (author's transl)].,"Akasaka Y, Sugawara K, Niki I, Kawai K.",https://pubmed.ncbi.nlm.nih.gov/916438/,"Endoscopic gastroelectromyograms were obtained from 8 patients with gastric cancer, which was located at the gastric antrum. These cancers include 6 cases of advanced cancers and 2 cases of early cancers with mucosal invasion. On healthy volunteers, the gastroelectromyograms from the gastric antrum showed spike bursts with equal intervals. On the other hand, in the patients with advanced cancers on which muscular layer was completely destroyed by the cancerous invasion, the gastroelectromyograms from the cancerous lesion showed no spike bursts. However, in the patients with mucosal cancers in which the cancerous invasion destroyed neither muscular membrane nor muscular layer, the gastroelectromyogram from the cancerous lesion showed spike bursts similar to those of healthy volunteers. From these  In future, endoscopic lead of gastroelectromyogram will become useful for the diagnosis of the degree of cancerous invasion and infiltration."
313,Oxidative DNA base modifications and polycyclic aromatic hydrocarbon DNA adducts in squamous cell carcinoma of larynx.,"Jałoszyński P, Jaruga P, Oliński R, Biczysko W, Szyfter W, Nagy E, Möller L, Szyfter K.",https://pubmed.ncbi.nlm.nih.gov/12688418/,"Tobacco smoke, recognized as a major etiological factor for cancers of the upper aerodigestive tract, represents an abundant source of reactive oxygen species (ROS), which are believed to play a significant role in mutagenesis and carcinogenesis. An additional source of ROS in tissues exposed to tobacco smoke may be metabolic oxidation of polycyclic aromatic hydrocarbons (PAH). To investigate the relationships between oxidative DNA lesions and aromatic DNA adducts, six modified DNA bases 5-hydroxyuracil, 5-hydroxycytosine, 7,8-dihydro-8-oxoguanine, 7,8-dihydro-8-oxoadenine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine and 4,6-diamino-5-formamidopyrimidine and the total level of PAH-related DNA adducts were measured in cancerous and the surrounding normal larynx tissues (68 subjects), using gas chromatography/isotope-dilution mass spectroscopy with selected ion monitoring and the 32P-postlabeling-HPLC assay, respectively. The levels of oxidative DNA lesions in cancerous and adjacent tissue were comparable; the differences between the two types of tissue were significant only for 5-hydroxypyrimidines (slightly higher levels were observed in the adjacent tissue). Comparable levels of DNA lesions in cancerous and the surrounding normal tissues observed in the larynx tumors support a field cancerization theory. The surrounding tissues may still be recognized as normal by histological criteria. However, molecular alterations  Thus, a demonstration of similar levels of DNA damage in cancerous and the adjacent tissue could explain a frequent formation of secondary tumors in the larynx and the frequent recurrence in this type of cancer. A weak, but distinct effect of tumor grading and metastatic status was observed in both kinds of tissue in the case of 5-hydroxyuracil, 5-hydroxycytosine, 7,8-dihydro-8-oxoguanine, 7,8-dihydro-8-oxoadenine. This effect was displayed as a gradual shift in the data distribution toward high values from G1 through G2-G3 and from non-metastatic to metastatic tumors. Since the levels of oxidative DNA base modifications tended to increase with the tumor aggressiveness, we postulate that the oxidative DNA lesions increase genetic instability and thus contribute to tumor progression in laryngeal cancer. No associations between aromatic adduct levels and oxidative DNA lesions were present, suggesting that the metabolism of PAH does not contribute significantly to the oxidative stress in larynx tissues, remaining the tobacco smoke ROS as a major source of oxidative DNA damage in the exposed tissue."
314,Excision of oral leukoplakias by CO2 laser on an out-patient basis: a useful procedure for prevention and early detection of oral carcinomas.,"Chiesa F, Sala L, Costa L, Moglia D, Mauri M, Podrecca S, Andreola S, Marchesini R, Bandieramonte G, Bartoli C, et al.",https://pubmed.ncbi.nlm.nih.gov/3739009/,"Several epidemiologic studies have shown that oral cancer develops among individuals with a prior diagnosis of an oral premalignant lesion. Canceration chance in these patients is 17%, with the greatest rate occurring in the second year of observation. Based on this data, since 1981, 92 leukoplakias have been treated by out-patient laser surgery at the Istituto Nazionale Tumori of Milano. The therapeutic technique was laser excision to obtain a specimen for histology. Two groups were distinguished according to the diagnostic procedure. Thirty-three lesions (December 1981 to December 1982) were operated on without preliminary histologic examination, on the basis of a simple clinical diagnosis. Since January 1983 all leukoplakias have been biopsied in a systematic way and those negative for cancer treated with laser. Histology of the specimen showed 5 squamous cell carcinomas (15%) in the group of patients who did not undergo preoperative biopsy. Postoperative histology showed malignancy in 6 of 59 (10.2%) cases in spite of negative preoperative biopsies. Speckled and erosive leukoplakias had the highest canceration rate. Three of 11 patients with cancer were treated by knife excision or interstitial needle implantation because of margins in tumoral tissue or because they were not evaluable for injury by heat. "
315,Paget's disease of the oesophagus associated with mucous gland carcinoma of the lower oesophagus.,"Haleem A, Kfoury H, Al Juboury M, Al Husseini H.",https://pubmed.ncbi.nlm.nih.gov/12493026/,"Aim:
        
      
      To report a rare case of oesophageal Paget's disease and its rarer combination with submucosal gland carcinoma of the lower oesophagus.
    


           Endoscopic examination showed an ulcerated tumour at the gastro-oesophageal junction. Initial biopsy showed an undifferentiated carcinoma with pagetoid spread in the oesophageal stratified squamous epithelium. Oesophago-gastrectomy specimen showed a lobulated, poorly differentiated mucous gland carcinoma at the gastro-oesophageal junction. The tumour showed focal acinar differentiation and obvious cancerization of the submucosal glands, somewhat similar to the breast lobular carcinoma in situ. One of the isolated and cancerized submucosal glands also showed carcinoma in situ of its duct. Oesophageal surface epithelium showed extensive pagetoid spread, both over and away from the main tumour. The pagetoid tumour cells showed selective positivity for cytokeratin 7, cytokeratin Cam 5.2, BerEP4 and to a lesser extent for CEA.
    


          Conclusions:
        
      
      As far as we know, this is the fifth case report of oesophageal Paget's disease and the first report of its association with the underlying mucous gland carcinoma."
316,Boron neutron capture therapy (BNCT) inhibits tumor development from precancerous tissue: an experimental study that supports a potential new application of BNCT.,"Monti Hughes A, Heber EM, Pozzi E, Nigg DW, Calzetta O, Blaumann H, Longhino J, Nievas SI, Aromando RF, Itoiz ME, Trivillin VA, Schwint AE.",https://pubmed.ncbi.nlm.nih.gov/19376711/,"We previously demonstrated the efficacy of boron neutron capture therapy (BNCT) mediated by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and (GB-10+BPA) to control tumors, with no normal tissue radiotoxicity, in the hamster cheek pouch oral cancer model. Herein we developed a novel  Clinically, second primary tumor recurrences occur in field-cancerized tissue, causing therapeutic failure. We performed boron biodistribution studies followed by in vivo BNCT studies, with 8 months follow-up. All 3 BNCT protocols induced a statistically significant reduction in tumor development from precancerous tissue, reaching a maximum inhibition of 77-100%. The inhibitory effect of BPA-BNCT and (GB-10+BPA)-BNCT persisted at 51% at the end of follow-up (8 months), whereas for GB-10-BNCT it faded after 2 months. Likewise, beam-only elicited a significant but transient reduction in tumor development. No normal tissue radiotoxicity was observed. At 8 months post-treatment with BPA-BNCT or (GB-10+BPA)-BNCT, the precancerous pouches that did not develop tumors had regained the macroscopic and histological appearance of normal (non-cancerized) pouches. A potential new clinical application of BNCT would lie in its capacity to inhibit local regional recurrences."
317,[Expressions of Livin and PTEN in Cancerous Tissues of Ovary Endometriosis].,"Liu XY, Wang HJ, Xu P, Chen J, Pan HY, Liu Y.",https://pubmed.ncbi.nlm.nih.gov/28591952/,"
    


          
    


          05). The positive expression rate of PTEN in ovary endometriosis cancerous tissues (16%) was obviously lower than that in ovary endometriosis tissues (65%) and benign tumor tissues (80%)( P<0.01). There was no correlations between positive expressions of Livin and age, clinical stage, grading, histological type and lymphatic metastasis of ovary endometriosis cancer ( P>0.05), the same  Livin and PTEN expression presented an obviously negative correlation in ovary endometriosis cancer ( r=-0.559, P=0.001).
    


          Conclusions:
        
      
      Up-regulation of Livin expression and down-regulation of PTEN may be involved in the occurrence and development of ovary endometriosis cancerization."
318,The dielectric properties of cancerous tissues in a nude mouse xenograft model.,Yoo DS.,https://pubmed.ncbi.nlm.nih.gov/15376246/,"The dielectric properties of various cancers, namely brain tumor, breast cancer, gastric carcinoma, and colon cancer, were measured in the frequency range of 500 MHz to 5 GHz. Cancers were cultivated applying the xenograft model of growing human cancerous tissues using the specific pathogen free, homo inbred mouse (a nude mouse). The complex permittivity was measured using an open-ended coaxial probe (HP85070B) and a computer controlled network analyzer (HP8510C). For the measurement of the dielectric properties, a total of 58 xenografted specimens was used. The  It might be agreed that components and characteristics of different cancerous tissues would be similar despite their different occurrences in the human body. It is necessary to investigate this "
319,Three synchronous HPV-associated squamous cell carcinomas of Waldeyer's ring: case report and comparison with Slaughter's model of field cancerization.,"McGovern SL, Williams MD, Weber RS, Sabichi A, Chambers MS, Martin JW, Chao KS.",https://pubmed.ncbi.nlm.nih.gov/19572386/," The rate of synchronous lesions in human papillomavirus (HPV)-positive oropharyngeal cancers is unknown.
    


          
    


          
    


          Conclusion:
        
      
      Comparison with the Slaughter model of field cancerization suggests that HPV-positive SCC of the head and neck may have a distinct mechanism for the development of multifocal disease. Therefore, the emerging population of young patients with head and neck SCC with HPV-positive cancers presents a new opportunity for understanding the molecular origins of synchronous tumors."
320,A non-Darwinian role for mutagenesis in stem cell-derived cancers.,Bergstein I.,https://pubmed.ncbi.nlm.nih.gov/12503073/,"It is clear that mutations cause cancer. The implicated mechanism is Darwinism. That is, a stochastic series of mutations is purported to effect the cellular variability upon which natural selection acts to yield increasingly cancer-like intermediates leading ultimately to malignant clones. It is no wonder then that the neoplastic phenotype is considered ""alien,"" having evolved via random unrehearsed events. Neoplasia, however, has also been depicted as something less than foreign, bordering on familiar. This is because cancer shares proliferative and invasive qualities with the native developmental processes of embryogenesis and adult tissue renewal/repair. A question then arises: If key features of malignancy already naturally exist within well-choreographed programs, why reinvent this phenotype via stochastic multistep schemes rather than reactivate it largely en bloc? Indeed, as will be shown, tissues do harbor a malignant potential capable of reactivation. Specifically, this capability is maintained by stem cells (having inherited such from embryonic precursors)-a phenotype controlled by a microenvironment favoring perpetual rearing by (quiescent) stem cells of proliferative progeny for orderly renewal over neoplasia. Accordingly, normally well-sequestered stem cells, when amid carcinogen/mutagen-induced disruption to local surroundings, produce progeny tending by default toward disorderliness (neoplasia) over renewal. Because such tumor-causing mutations act non-cell autonomously, this cancerous state is potentially reversible but subsequent cell-autonomous mutations can impair particular clonal progeny, already cancerous, from regressing. Thus, a scenario wherein mutations (1) de-repress malignancy non-cell autonomously and then (2) slow its reversion cell autonomously, commonly misinterpreted as Darwinian, may constitute a non-Darwinian mechanism for the genesis of cancers that are stem cell derived."
321,Elevated expression of nuclear protein kinase CK2alpha as a poor prognosis indicator in lymph node cancerous metastases of human thyroid cancers.,"Guo M, Liu C, Qi FJ, Zhang XM, Ren LL, Liu YM, Meng ZC, Zhu ZT, Xiao JY.",https://pubmed.ncbi.nlm.nih.gov/25227853/,"Aim:
        
      
      To investigate the expression of protein kinase CK2α (CK2α) in human thyroid disease and its relationship with thyroid cancer metastasis.
    


          Materials and 
    


           These findings were also confirmed by RT-PCR and Western blotting. More strikingly, elevated expression of CK2α in thyroid papillary carcinoma tissues was not only significantly associated with lymph node cancerous metastasis and clinical stage of thyroid cancers; but also correlated with epithelial-mesenchymal transition (EMT) and high tenascin C (TNC) expression. In addition, EMT and high TNC expression in thyroid carcinoma tissues was significantly associated with lymph node cancerous metastasis.
    


          Conclusions:
        
      
      Elevated expression of nuclear CK2α is a poor prognosis indicator in lymph node cancerous metastasis of human thyroid cancers."
322,[Expression of cytokeratin 19 in the development and progression of oral squamous cell carcinoma].,"Tan D, Li CH, Nie MH.",https://pubmed.ncbi.nlm.nih.gov/28116435/,"Purpose:
        
      
      To investigate the expression of cytokeratin 19 (CK19) in various stages of oral squamous cell carcinoma (OSCC), and to explore the relation between CK19 and OSCC.
    


           The expression of CK19 was detected by immunohistochemistry and Western blot. The serum of OSCC patients and healthy people was collected and CYFRA21-1 level was determined by ELISA. SPSS17.0 software package was used for data elevated.
    


           With epithelia dysplasia becoming worse, the positive rate and the intensity of CKI9 raised significantly. CYKA21-1 in OSCC was significantly higher than that in normal control group(P<0.01).
    


          Conclusions:
        
      
      CK19 overexpression is an early event in the process of oral mucosal canceration. Its abnormal expression can be used as one of the reliable indexes of early diagnosis of OSCC."
323,Donor-derived human bone marrow cells contribute to solid organ cancers developing after bone marrow transplantation.,"Avital I, Moreira AL, Klimstra DS, Leversha M, Papadopoulos EB, Brennan M, Downey RJ.",https://pubmed.ncbi.nlm.nih.gov/17690178/,"Bone marrow-derived stem cells have been shown to participate in solid organ repair after tissue injury. Animal models suggest that epithelial malignancies may arise as aberrant stem cell differentiation during tissue repair. We hypothesized that if bone marrow stem cells participate in human neoplasia, then solid organ cancers developing after allogeneic bone marrow transplantation (ABMT) might include malignant cells of donor origin. We identified four male patients who developed solid organ cancers (lung adenocarcinoma, laryngeal squamous cell carcinoma, glioblastoma, and Kaposi sarcoma) after myeloablation, total body irradiation, and ABMT from female donors. Donor-derived malignant cells comprised 2.5%-6% of the tumor cellularity The presence of donor-derived malignant cells in solid organ cancers suggests that human bone marrow-derived stem cells have a role in solid organ cancer's carcinogenesis. However, the nature of this role is yet to be defined."
324,Association of the recurrence and canceration rate of vocal leukoplakia with interleukin-10 promoter variants over a 2-year period.,"Zhou J, Zhang D, Zhou L, Yang Y, Liu F, Tao L, Lu LM.",https://pubmed.ncbi.nlm.nih.gov/27299734/,"Conclusion This study indicates that IL-10 promoter polymorphism variants, smoking, and alcohol consumption increase the risk of recurrence and canceration in vocal leukoplakia.  Participants and  Recurrence and canceration rates were used to evaluate the association between the genotype variants and the clinical outcome. 4% vs 0%, p-value = 0.038). Compared with the non-smoker group, the smoker group had a higher recurrence rate of vocal leukoplakia (29.3% vs 5%, p-value =0.044). Likewise, the recurrence rate in the alcohol consumption group was also higher (30.6% vs 8%, p-value =0.034). The percentage of cancerization in the alcohol consumption group was significantly higher than that in the non-alcohol consumption group (19.4% vs 0%, p-value =0.035)."
325,Mutations of the P53 tumor suppressor gene as clonal marker for multiple primary lung cancers.,"Mitsudomi T, Yatabe Y, Koshikawa T, Hatooka S, Shinoda M, Suyama M, Sugiura T, Ogawa M, Takahashi T.",https://pubmed.ncbi.nlm.nih.gov/9305187/," The 
    


           We examined 16 of these patients for mutations of the p53 gene occurring in exons 5 through 8 by the polymerase chain reaction/single strand conformation polymorphism  Differential diagnosis was also made on a morphologic basis, considering the degree of cellular differentiation and cytologic subtypes.
    


           We were thus able to make molecular diagnoses for these patients. The mutational status of the p53 gene was discordant in all nine patients, suggesting a different clonal origin despite the fact that six of them had almost identical histologic features.
    


          Conclusions:
        
      
      Analysis of p53 gene mutations was thus useful in distinguishing second primary lung cancers from recurrent tumors. The observed heterogeneity of p53 status was also in line with the ""field cancerization"" concept."
326,Tubular adenosis of the breast. A distinctive benign lesion mimicking invasive carcinoma.,"Lee KC, Chan JK, Gwi E.",https://pubmed.ncbi.nlm.nih.gov/8540608/,"Tubular adenosis, a term first coined by Oberman, is an uncommon benign lesion of the breast that may mimic invasive carcinoma. There is no formal description of this condition in the literature. We report the findings on six specimens from five patients (one with bilateral disease), including three that showed cancerization by intraductal carcinoma (DCIS). The ages of the patients ranged from 40 to 82 years. One patient presented with a 3-cm breast mass, and the others were found in specimens resected for infiltrating ductal carcinoma (two specimens) or DCIS (three specimens). The histologic hallmark of tubular adenosis was haphazard proliferation of elongated tubules that were noncrowded, narrow, and sometimes branching. There was no lobular arrangement or, at most, vague lobular grouping, with some tubules often extending into the fat. The tubules contained basophilic or granular eosinophilic secretion. The stroma was sclerotic to edematous. The tubules were lined by bland-looking ductal cells and were surrounded by an intact myoepithelial layer, a phenomenon well highlighted by immunostaining for muscle-specific actin (HHF-35) or S-100 protein. In three specimens, the tubular adenosis was cancerized by noncomedo DCIS, producing a pattern strongly mimicking infiltrating carcinoma; the in situ nature of the carcinoma was confirmed by actin immunoreactivity in the residual myoepithelium as well as by the presence of architecturally similar tubular adenosis in the vicinity. Tubular adenosis shows an infiltrative growth similar to microglandular adenosis and adenomyoepithelial adenosis, but it differs from them by the interdigitating tubular configuration and also differs from microglandular adenosis by the presence of myoepithelium. Tubular adenosis can be distinguished from sclerosing adenosis by the lack of obvious lobular architecture or whorled arrangement and wider separation of the tubules. Tubular adenosis appears to be a benign lesion per se, but whether it has premalignant potential remains to be determined. The importance of recognizing this entity lies in its being potentially mistaken for invasive carcinoma, especially at intraoperative frozen section or when the lesion is cancerized by DCIS."
327,When is precancerous actually postcancerous?,Bergstein I.,https://pubmed.ncbi.nlm.nih.gov/11108657/,"Demonstration that certain rare cancer-related mutations can (i) be shared by adjoining benign and cancerous tumor regions or (ii) be present solely in a cancerous but not in an adjoining benign tumor region are data often cited in strong support of the conventional idea that benign tumor regions consist of precancerous cells. However, considering the well-documented evidence that many malignant cell types are still capable of regression through differentiation, one can envisage an alternative (or coincident) scenario whereby (i) mutations are shared by adjoining benign and cancerous tumor regions because a cancer cell with a non-differentiation-impairing mutation differentiates into a benign (postcancerous) cell or (ii) mutations are present solely in a cancerous tumor region because a cancer cell acquires a differentiation-impairing mutation that prevents its regression into a benign cell. Only with higher-resolution lineage analyses of a type not yet performed but  Accordingly, it is quite possible that common cancers regularly differentiate, such that a benign tumor region may actually harbor not only precancerous but also postcancerous cells. Demonstration of this phenomenon and elucidation of its mechanism could lead to novel therapeutics designed to effect reversion of the more common cancers that, when in advanced stages, are notoriously inadequately treated by current cytotoxic regimens."
328,Clonal analysis of a case of multifocal oesophageal (Barrett's) adenocarcinoma by comparative genomic hybridization.,"van Dekken H, Vissers CJ, Tilanus HW, Tanke HJ, Rosenberg C.",https://pubmed.ncbi.nlm.nih.gov/10419593/,"Oesophageal adenocarcinomas arising in Barrett's epithelium occasionally present as multiple lesions. This could be due to either a multifocal presentation of the same tumour, or different neoplasms arising simultaneously in a dysplastic Barrett's oesophagus ('field cancerization'). This is a report of the genetic analysis of multiple neoplastic sites in a Barrett's oesophagus with an extensive area of dysplasia. In addition, the dysplastic Barrett's epithelium was evaluated. For the genetic screening, comparative genomic hybridization (CGH) allowed evaluation of the whole genome of each specimen. Five cancerous regions were selected and subsequently dissected from paraffin-embedded tissue blocks. The use of archival materials enabled a targeted collection of representative tumour locations. Multiple genetic aberrations were detected by CGH in all cancer sites. Losses on 3p, 4, 7q, 18q, and Y, as well as gains on 8q, 9q, 12p, 13q, 17q, 20p and X, were found in each specimen. In four out of the five lesions, simultaneous losses on 9p, 15q, and 16q, with concomitant gains on 5p, 7q, and 10p, were disclosed by CGH. Adjacent high-grade dysplastic Barrett's mucosa shared the losses on 3p, 4, 7q, 9p, 18, and Y, as well as the gains on 5p, 7q, 13q, 17q, and X, thereby confirming its precursor status. Within this single and rare case of multifocal Barrett's adenocarcinoma, a monoclonal genotype was present. This must have been caused by an extensive outgrowth of a single tumour."
329,FURTHER EXPERIMENTS ON THE CAUSE OF SEQUENTIAL NEOPLASTIC CHANGES. THE EFFECTS OF 20-METHYLCHOLANTHRENE ON TRANSPLANTED EPIDERMAL MOUSE PAPILLOMAS AND THE DERIVATIVE CARCINOMAS.,"HENDERSON JS, ROUS P.",https://pubmed.ncbi.nlm.nih.gov/14208248/,"When crystalline 20-methylcholanthrene (MC) and the cells of tar-induced mouse papillomas (paps.) are injected together into the thigh muscles of mice the carcinogen exerts a marked promoting and chemotactic influence upon the cells while it is dissolving in the tissue fluid. Under such circumstances it strongly stimulates and attracts them, with  Because of these findings intramuscular tests were made to learn whether MC would hasten the occurrence or increase the number of cancers that now and again derive from paps.; but the tests were repeatedly marred by the extraordinary behavior of such cancerous cells as happened to be already present in the implanted material. They responded far more actively to MC than did the pap. cells and soon took over the growths. Some carcinomas which failed to grow when transplanted alone, or only gradually formed small, regressing nodules, gave rise rapidly to huge growths of similar sort when exposed to MC. To exclude cancerous cells so far as possible from the later tests small grafts of pap. tissue with MC crystals adhering to them were implanted subcutaneously. The pap. cells promptly lined the graft pockets, encysting the crystals incidentally, and formed tumors that enlarged progressively by keratinizing inwards. While they did this their living layer of pap. tissue was continually bathed in dissolved MC throughout many weeks. Despite these apparently favorable conditions the carcinogen neither hastened the occurrence nor increased the number of visible epidermal cancers deriving from the paps. It also failed to bring about sequential malignant changes in the carcinomas. These negative  They accord also with another previous finding, namely that MC fails to bring on the malignant changes of discontinuous, sequential sort that mammary mouse carcinomas often undergo ""spontaneously."" Taken together these facts indicate that the change or changes whereby normal cells are converted into benign tumor cells differ in nature from those taking place when they become cancer cells, as also from those occurring when cancer cells undergo further, step-like, malignant changes. A study has been begun to learn whether the widely various carcinomas deriving from benign papillomas differ from these latter and from one and other in their chromosomal content."
330,[The expression of nm23-H1 in the investing papilloma and it's cancerated tissue of nasal cavity and parasinuses].,"Li T, Xia L, Meng Q, Chen J.",https://pubmed.ncbi.nlm.nih.gov/15362683/,"
    


          
    


          05. The expression of nm23-H1 in the investing papilloma was higher than in the chronic sinusitis, the positive rate of the latter was 14.3%, P < 0.05.
    


          Conclusion:
        
      
      The lower expression the nm23-H1 protein in the cancerated tissue of investing papilloma was related to the infiltration and canceration."
331,Discordant p53 gene mutations in primary head and neck cancers and corresponding second primary cancers of the upper aerodigestive tract.,"Chung KY, Mukhopadhyay T, Kim J, Casson A, Ro JY, Goepfert H, Hong WK, Roth JA.",https://pubmed.ncbi.nlm.nih.gov/8453641/,"Patients with primary head and neck malignancies have a 3-7% yearly incidence of second primary cancers. It is thought that these second primary cancers arise independently following exposure to a common carcinogen by a process that has been called field cancerization. Since mutations in the p53 tumor suppressor gene represent a genetic alteration occurring during the evolution of premalignant lesions to malignancies of the upper aerodigestive tract, we analyzed mutations in the p53 gene of patients with cancer of the head and neck who developed second primary tumors of the upper aerodigestive tract epithelium to test the field cancerization hypothesis. DNA was extracted from primary head and neck cancers and second primary cancers of 31 patients. DNA from exons 5-8 of the p53 gene was analyzed by the single strand conformation polymorphism technique to identify the locations of the mutations in different regions of the gene. DNA from 6 patients was also sequenced by the chain termination  Twenty-one of the 31 patients had 1 or more p53 mutations. In all 21 cases the genetic lesions were discordant such that the presence or location of the mutations in the initial primary cancer differed from those of the second and third primary cancers. In each of the five patients with mutations in both primary tumors, the mutations occurred in different regions of the p53 gene. Of the other 16 patients, 8 had a p53 mutation in the first primary but not the subsequent primary cancer and the other 8 had no mutation in the initial primary but did have a mutation in subsequent primary cancers. Sequencing confirmed the single strand conformation polymorphism analysis and showed that 73% of the mutations were transitions. The discordant p53 mutations in second primary cancers arising in patients with primary epithelial cancer of the upper aerodigestive tract suggest that these cancers arise as independent events. These observations provide the first demonstration of a molecular basis for field cancerization effects in cancers of the upper aerodigestive tract."
332,The integration of irradiation and surgery as the treatment for selected cancers.,Moss WT.,https://pubmed.ncbi.nlm.nih.gov/7141917/,"Combinations of radiation therapy with surgery originated when the surgeon thought he had transected cancer. Unrealistic expectations, however, plagued these combinations until it was appreciated that the dose required to eradicate a given cancerous mass varied primarily with its volume and the associated oxygen tension of its cells. This helped to establish the rationale for combining irradiation and surgery and enabled the radiation therapist to more closely tailor dose needs to each specific clinical problem. Tailoring of dose remains crude. Our greatest errors continue to be attributable to poor definition of tumor extent and the underestimation of residual tumor volume. We need more precise information from the surgeon and pathologist along with greater knowledge of patterns of spread. To the degree that such added information becomes available, we have the means to increase loco-regional control rates."
333,Metallothionein stroma reaction in tumor adjacent healthy tissue in head and neck squamous cell carcinoma and breast adenocarcinoma.,"Dutsch-Wicherek M, Popiela TJ, Klimek M, Rudnicka-Sosin L, Wicherek L, Oudinet JP, Skladzien J, Tomaszewska R.",https://pubmed.ncbi.nlm.nih.gov/16264399/," Histopathologically healthy tumor adjacent tissue might be considered as a cancerization field which is typified by genetic changes required for the development of cancer. Metallothionein (MT) is considered to be a protective and anti-apoptotic protein. The aim of our study was to evaluate the MT expression in head and neck squamous cells carcinoma and breast adenocarcinoma and their histologically healthy adjacent tissue.
    


          Materials and  Antibody recognizing MT-1 was used for immunohistochemical analysis.
    


           It was found in all tumor adjacent tissue. MT expression was statistically significantly higher in tumor adjacent tissue than in cancer tissue in cases with the presence of lymph node metastases in both, breast adenocarcinoma and head and neck squamous cell carcinoma. Generally stroma seems to respond to the presence of cancer by the expression of MT, even in tissues which normally do not express MT.
    


          Conclusions:
        
      
      MT might be a normal or protective reaction of healthy adjacent tissue to the presence of tumor."
334,Radiotherapy and cellular infiltration of tumor nests.,"Mikuriya S, Oh'ami H.",https://pubmed.ncbi.nlm.nih.gov/6680201/,"There are several opinions which deny the therapeutic effects of preoperative irradiation. However, we have obtained favorable  We adapted this kind of radiation  After preoperative irradiation, we examined the resected specimen histopathologically. Remarkable cellular infiltrations, such as neutrocytes, lymphocytes, macrophages and plasma cells of the tumor nests were observed; and these cellular infiltrations, after preoperative irradiation, were more remarkable than the cases without radiotherapy or with conventional fractionated radiotherapy. These cellular infiltrations suggest participation of immunoreaction and we are convinced that this kind of preoperative irradiation could enhance positive immunoreactions. The indications are that this kind of preoperative irradiation of advanced breast and stomach cancer significantly improve the cancer's resectability and curability."
335,[Clonality of the peripheral papilloma and cancerous cells of breast].,"Niu Y, Yu Q, Yu Y, Ding XM, Shi YR.",https://pubmed.ncbi.nlm.nih.gov/17459204/,"
    


           DNA was extracted and amplified via nested-PCR with or without previous digestion by the methylation-sensitive restriction endonuclease Hha I. The products were resolved on denaturing polyacrylamide gels and visualized through silver staining. The clonality of these samples was analyzed by showing the lanes.
    


          0%) of peri-PM with ADH, indicating the monoclonality of the tumor. Twenty-four cases (92.3%) of the 26 cases with peri-PM and the 20 specimens of normal tissue were shown to be polyclonal. In the 16 cases of developed canceration identical X chromosome inactivation (monoclonal alterations) was observed in the cancer focus, parts of peri-PM with ADH, and the part of DCIS.
    


          Conclusion:
        
      
      Normal breast tissue and peri-PM show polyclonality and the peri-PM with ADH shows monoclonality. Clonality analysis may be a useful modality to screen high-risk cases from precancerous lesions or to distinguish between the benign hyperplasia and early carcinoma."
336,[p53 expression in colorectal adenoma and early carcinoma].,"Takagi S, Kiyohashi A, Motohashi O, Sano H, Shimizu A.",https://pubmed.ncbi.nlm.nih.gov/8089914/,"Expression of p53 was studied immunohistologically in 25 adenomas, 46 cancers in adenoma, and 18 cancers without adenoma, which were obtained by endoscopic polypectomy or mucosal resection. Positive ratio of p53 expression was 100% in cancer without adenoma, 78.3% in cancer in adenoma, and 48% in adenoma. We divided the positive case of p53 expression to three staining patterns, poorly stained type, focal type and diffuse type. The diffuse type was most of cancer without adenoma. In each diagnostic group there was no significant colleration between sex, age, and shape of polyp and the staining pattern. But in cancer without adenoma, there was significant colleration between size of polyp and the staining pattern, and number of the diffuse type increased as the polyp size was larger. Consequently, it was suggested that p53 takes a role of cancerization from adenomas at every step."
337,[Multiple primary cancers of the head and neck].,"Aibara R, Yumoto E, Okamura H, Yanagihara N.",https://pubmed.ncbi.nlm.nih.gov/2352045/,"Multiple primary cancers of the head and neck are not always rare. We have experienced 30 cases of multiple primary cancers in the Department of Otolaryngology, Ehime University School of Medicine from 1976 to 1989. The incidence ranged from 3.6% to 8.9% with flexible criteria. The minimum was 14 of 393 cases of all index cancers, strictly conformed with Warren's definition. The maximum was 29 of 327 cases of index cancers on the mucosal surfaces, including a combination of both head and neck cancers. In view of organic specificity of the index cancers, the incidence was high in the larynx and oral cavity, low in the nasopharynx and maxillary sinus. The concept of ""multicentric cancerization"" was verified by the  During following-up studies of oropharyngeal, hypopharyngeal and laryngeal cancers, we have to examine the esophagus periodically due to high risk of occurrence of cancer. To compare the data of multiple primary cancers of the head and neck between institutions, adequate and detailed criteria should be established."
338,[Clinicopathological study on 3441 cases of benign and malignant ulcers. The National Cooperative Group for Pathological Study on the Canceration of Gastric Ulcer].,[No authors listed],https://pubmed.ncbi.nlm.nih.gov/1617745/,"Resected specimens of benign and malignant gastric ulcers from 3441 cases were studied and compared clinically and pathologically. Among them, 421 cases of malignant ulcer were found. The malignant ulcers differed notably from the ulcerating gastric carcinoma and showed many similarities to the benign chronic gastric ulcer (CGU). The most distinct feature of malignant ulcer was the lack of cancerous infiltration and muscular residue in the scar tissue of ulcer base. The existence of this type of ulcer clinically and pathomorphologically supports the viewpoint that CGU can undergo malignant change. The rate of malignant change of CGU in this study was 3.48%."
339,[A clinicopathological study of multiple thyroid carcinomas].,"Ishikita T, Ishida T, Ogawa T, Nakamura T, Sato K, Kurosumi M, Kawai T, Izuo M.",https://pubmed.ncbi.nlm.nih.gov/3204661/,"Thyroid cancers associated with multiple cancerous lesions that were detected by clinical and/or histological examination, namely, multiple thyroid carcinomas have been studied clinicopathologically. Of 443 cases of primary thyroid cancers, 111 (25%) had multiple cancerous lesions. Histologically, most multiple cancers consisted of papillary carcinomas. In 66% of the cases, the size of the second cancer was 1.0 cm or less. Fifty-three percent of multiple cancers were located in both the right and left thyroid lobes. Therefore, it is important to examine the contralateral lobe at operation to be certain that there are no other nodular lesions. Since lymph node metastasis was positive in 83% of the cases, it is necessary to perform bilateral neck dissection in multiple cancer cases of not only the bilateral but also of the unilateral type."
340,"Case report of a patient with multiple lesions of the stomach, including multiple cancers and an adenomatous polyp.","Kimura H, Kanno M, Takamura H, Arakawa H, Maeda K, Uogishi M, Sodani H, Kawashima A.",https://pubmed.ncbi.nlm.nih.gov/7719403/,"This paper describes an unusual case of an 80-year-old man followed up for multifocal gastric cancers. There were three separate polypoid carcinomas and one adenomatous polyp with no sign of malignancy. We measured the DNA content of the gastric cancer and adenomatous cells obtained from endoscopically biopsied specimens. The adenomatous polyp and one of the cancerous lesions showed DNA diploidy. The other two cancerous lesions showed DNA aneuploidy, with different DNA index (DI) values (1.12 and 1.64, respectively). It is considered that the three cancers arose from different stem lines. However, an operation was not performed because the patient refused gastrectomy, and therefore only conservative follow up has been continued. Presentation of this case is followed by a detailed discussion focusing on the possible development of carcinoma in gastric adenomatous polyps in view of the data from the literature."
341,[Clinical impact of gamma-glutamyl transpeptidase messenger RNA subtypes on early diagnosis of hepatocellular carcinoma].,"Han GQ, Qin CY, Ren WH, Shi J, Wang YJ, Liu HL.",https://pubmed.ncbi.nlm.nih.gov/12479075/," However, the genomic changes in GGT relating to the development of HCC are not known. This study was designed to explore the relationship between alteration in GGTmRNA subtypes and the development of HCC, and to seek a new 
    


          
    


           The prevalence of subtype H was significantly higher in cancerous tissues, adjacent paracancerous and distal cancerous tissues from the livers with HCC than that in tissues from normal livers and noncancerous liver diseases (P < 0.05). The prevalence of subtype F in cancerous tissues was significantly lower than that in tissues from normal livers and noncancerous liver diseases (P < 0.05). Among 26 patients with HCC, GGTmRNA-H in peripheral blood was found in 12 cases. In 10 HCC patients with negative AFP, GGTmRNA-H in peripheral blood was found in 5 cases.
    


          Conclusions:
        
      
      The changes of GGTmRNA subtypes are closely related to the development of HCC, and the analysis of GGT genes might be a sensitive assay to monitor the hepatic cell canceration."
342,[9 years of systematic cytologic examinations of expressed galactophorous discharge. Detection of cancerous and precancerous conditions].,"Jahier J, Feldman JP, Mavel A, Kamp A, Halfon D, Barthelet J, Michiels R, Mottot C.",https://pubmed.ncbi.nlm.nih.gov/3983528/,"Nine years of experience performing cytologic examinations on expressed breast discharge has enabled the identification of precancerous and cancerous conditions of the breast. Three thousand women were monitored. The only abnormal findings were cytologic (clinical and radiological examinations were normal). One case of atypical hyperplasia, 3 cases of cancer in situ, and 2 invasive cancers were identified upon histologic examination. Three women were lost to follow-up and subsequently developed invasive cancer."
343,"[Cancerized phagedenic ulcers. A study about 19 cases observed in Dakar ""Hopital Principal"" from 1961 to 1976 (author's transl)].",Lariviere JY.,https://pubmed.ncbi.nlm.nih.gov/481182/,"Cancerization is the main complication of phagedenic ulcers which are frequent in tropical areas. The detection of the turn towards cancer is generally too late because of social and psychological conditions. Patients of this study were civil servants and had beneficial of a comparatively early detection. The clinical, radiological and pathological features are described and the importance of the control of lymph nodes is emphasized. The surgical tactic is discussed according to each situation but it must be as conservative as possible, even if the amputation is only delayed since lymphatic dissemination is late and amputation eminently dramatic in the african context."
344,"[Routine endoscopy of the esophagus in buccal, pharyngeal and laryngeal cancers].","Andrieu-Guitancourt J, Brossard-Legrand M, Happich JL, Lamy JM.",https://pubmed.ncbi.nlm.nih.gov/1225106/,"We practiced a systematic endoscopy of the upper part of the aero-digestive tract on 160 patients suffering from a cancer in the mouth, the pharynx and the upper part of the larynx. This unit, going from the mouth to the cardia does really exist: it has the same epithelial coating, the same function and is liable to suffer the same damages. It is the seat of many well-known cancerous localizations that always need to be searched for on principle when face to face with any cancer. The endoscopic examination so conceived allowed the authors to find a cancerous association on the very level of the upper sero-digestive tract among 14 per cent of the patients; 4 out of these 14 per cent having oesophageal damages impossible to detect clinically on one hand, and often radiologically on the other hand. Morever, 3 out of 7 of lesions were tiny: from 1 to 3 millimetres, extending the limits of the diagnosis of the cancer of the aesophagus and perhaps leaving better therapeutic possibilities."
345,Lesions preceding squamous cell carcinoma of the bronchus and multicentricity of canceration--serial slicing of minute lung cancers smaller than 1 mm.,"Nagamoto N, Saito Y, Sato M, Sagawa M, Kanma K, Takahashi S, Usuda K, Endo C, Fujimura S, Nakada T.",https://pubmed.ncbi.nlm.nih.gov/8278985/,"A total of ten minute squamous cell carcinomas smaller than 1 mm were found in surgical lung specimens from 108 patients who had roentgenographically occult lung cancer. These minute lesions were detected by submitting, in all the 108 specimens, the whole bronchial tree to 2-mm-thick sequential transverse slicing which was then followed by microscopic examination of each slice on an H-E stained section. When a focus of minute carcinoma was found, the slice was further serially sectioned to study whether there were such carcinoma-related lesions as dysplasia or other atypical changes of epithelia, and when there were, the spatial relation of these with the carcinoma. It was demonstrated that all the minute carcinomas were closely associated with either dysplasia or what we call ""basal cells with marked atypia"", cells with markedly enlarged nuclei arranged in linear fashion on the basement membrane. The contiguity of these changes with minute carcinoma strongly suggested that they are lesions preceding overt carcinoma. Also, there were some minute foci of carcinoma, which, though not involving the entire epithelial thickness, proved to have already begun microinvasion."
346,Genetics and biology of pancreatic ductal adenocarcinoma.,"Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA.",https://pubmed.ncbi.nlm.nih.gov/16702400/,"Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%-5%. The cancer's lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biology and resistance to conventional and targeted therapeutic agents leads to a typical clinical presentation of incurable disease at the time of diagnosis. The well-defined serial histopathologic picture and accompanying molecular profiles of PDAC and its precursor lesions have provided the framework for emerging basic and translational research. Recent advances include insights into the cancer's cellular origins, high-resolution genomic profiles pointing to potential new therapeutic targets, and refined mouse models reflecting both the genetics and histopathologic evolution of human PDAC. This confluence of developments offers the opportunity for accelerated discovery and the future promise of improved treatment."
347,Review of recent advances in fluorescence bronchoscopy in early localization of central airway lung cancer.,"Kennedy TC, Lam S, Hirsch FR.",https://pubmed.ncbi.nlm.nih.gov/11423672/,"Centrally located lung cancers are radiologically occult until so far advanced as to have a low cure rate or require extensive resection for cure, but at a cost of high morbidity. These cancers represent about one-fifth of new lung cancers. Autofluorescence bronchoscopy appears to be an important tool in localizing premalignant and early malignant lesions in the large central airways, particularly when applied to high-risk patients. Applications include studies of molecular biology of premalignancy and early malignancy, chemoprevention studies, endobronchial therapy studies, localization of synchronous tumors, estimation of the extent of field cancerization, and better estimation of resection margins. Autofluorescence bronchoscopy appears to be significantly more sensitive than white light examination but has low specificity. This technology is likely to gain widespread use when evaluation of sputum for malignant changes is both more sensitive and specific, and when its application is demonstrated to reduce mortality in this important subgroup of non-small cell lung cancer patients."
348,ALEX1 may be a novel biomarker for human cervical squamous cell carcinoma.,"Zeng F, Liao K, Wu J, Gao Y, Li H, Fan J, Zhang H, Li Y, Bai X, Liu G, Song F.",https://pubmed.ncbi.nlm.nih.gov/26464700/,"The armadillo repeat proteins were first found in armadillo gene of Drosophila. Since then a number of proteins containing armadillo repeats have been noticed and studied. These proteins that consist of 6 to 13 armadillo repeat domains are classified as family of armadillo repeat proteins. Recently, several studies indicated that armadillo repeat family of proteins play an important role in the tumorigenesis and maintenance of tissue integrity. ALEX1 (Arm protein lost in epithelial cancers, on chromosome X), contains two armadillo repeats domains, is expressed different in normal and carcinomas tissues. Several studies have found that ALEX1 protein lost in tumors that originated in epithelial tissues. We evaluated the ALEX1 protein expression in 53 cervical cancers and in 53 non-cancerous cervical tissues from patients and adjacent non-cancerous tissues using immunohistochemistry
    


           We found, for the first time, that ALEX1 protein expression in cervical cancers tissues is higher than non-cancerous tissues. It is suggested that the ALEX1 protein is associated with tumorigenesis in cervical cancer and we speculate that the ALEX1 may plays a role as an oncogene in cervical cancer. Moreover, ALEX1 may serve as a novel potential diagnostic biomarker in identifying cervical cancer."
349,"Causes, consequences, and therapy of tumors acidosis.","Pillai SR, Damaghi M, Marunaka Y, Spugnini EP, Fais S, Gillies RJ.",https://pubmed.ncbi.nlm.nih.gov/30911978/,"While cancer is commonly described as ""a disease of the genes,"" it is also associated with massive metabolic reprogramming that is now accepted as a disease ""Hallmark."" This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer's metabolic program can improve patients' outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as ""aerobic glycolysis"" or the ""Warburg Effect."" Much has been written about the mechanisms of the Warburg effect, and this remains a topic of great debate. However, herein, we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: (1) neutralizing acid directly with buffers, (2) targeting metabolic vulnerabilities revealed by acidosis, (3) developing acid-activatable drugs and nanomedicines, and (4) inhibiting metabolic processes responsible for generating acids in the first place."
350,The Heterogeneity Metabolism of Renal Cell Carcinomas.,"Zarisfi M, Nguyen T, Nedrow JR, Le A.",https://pubmed.ncbi.nlm.nih.gov/34014538/,"According to data from the American Cancer Society, cancer is one of the deadliest health problems globally. Annually, renal cell carcinoma (RCC) causes more than 100,000 deaths worldwide [1-4], posing an urgent need to develop effective treatments to increase patient survival outcomes. New therapies are expected to address a major factor contributing to cancer's resistance to standard therapies: oncogenic heterogeneity. Gene expression can vary tremendously among different types of cancers, different patients of the same tumor type, and even within individual tumors; various metabolic phenotypes can emerge, making singletherapy approaches insufficient. Novel strategies targeting the diverse metabolism of cancers aim to overcome this obstacle. Though some have yielded positive  In the quest to overcome this obstacle, the metabolic oriented research focusing on these cancers has offered freshly new perspectives, which are expected to contribute heavily to the development of new treatments."
351,Complementary and alternative medicine therapies as symptom management strategies for the late effects of breast cancer treatment.,"Henneghan AM, Harrison T.",https://pubmed.ncbi.nlm.nih.gov/24935277/,"Advancements in breast cancer treatment continue to improve the likelihood of survival. The increase in survival has come at a cost, however; the late effects of breast cancer treatment have remained a constant reminder to women of what they have endured and require holistic nursing's attention. One area of nursing practice that might improve the condition of breast cancer survivors once their treatment has ended is complementary and alternative medicine (CAM) therapies. To provide guidance to nurses working with breast cancer survivors, a focused review of the literature exploring the symptomatology and prevalence of breast cancer's late effects as well as the use of CAM therapies to improve those effects is presented. Evidence suggests that CAM therapies have sometimes been incorporated into symptom management strategies currently employed; however, the evidential claims as a whole have been generally inconclusive, especially for complete resolution of the late effects. Regardless, a number of studies demonstrate a reduction of negative symptoms experienced with few to no side effects of CAM therapies."
352,Review: Warburg effect and renal cancer caused by errs in fumarate hydratase encoding gene.,"Qureshi AS, Ali S.",https://pubmed.ncbi.nlm.nih.gov/31081789/,"The several types of heterogeneous kidney cancers are interrelated by their primary sites of pathology. Despite its origin in the kidney, renal cell carcinoma (RCC) is associated with its varying genetic basis. Von Hippel-Lindau (VHL) syndrome is the earliest and, thus the most highly, characterized of genetic forms of kidney cancer, which is associated with alterations in the Von Hippel-Lindau (VHL) gene. As a  But this theory was disdained because of the discovery of tumor suppressor genes and oncogenes. Lately, the breakthrough finding about the tumor suppressing role of gene coding for enzymes involved in Krebs cycle has revived the interest in Warburg's hypothesis. This effect has led to the uncovering of the links between metabolic alterations, mitochondrial dysfunction and cancer. One such metastatic cancer characterized by the germ-line inactivating mutation of the gene coding for fumarate hydratase (FH), a Krebs cycle's enzyme, is hereditary leiomyomatosis and renal cell carcinoma (HLRCC). In this review paper, we have discussed the "
353,Mucin histochemical analysis of minute gastric differentiated adenocarcinoma.,"Egashira Y, Shimoda T, Ikegami M.",https://pubmed.ncbi.nlm.nih.gov/10227725/,"Fifty-six surgically resected intramucosal differentiated adenocarcinomas (DA) of the stomach with a maximum diameter of less than 5 mm were analyzed by mucin histochemistry. Gastric type phenotypic expression was observed in 41.1% of cases, intestinal type in 28.6% and gastric-intestinal type in 28.6% of all cancers. Gastric type phenotypic expression was the most frequent. As the tumor diameter increased, the incidence of DA with gastric phenotype tended to decrease. Intestinal metaplasia of the cancer's surrounding mucosa was absent or slight in DA with gastric phenotype, but moderate to severe in DA with gastric-intestinal phenotype and intestinal phenotype. Morphologically and mucin histochemically, intestinal metaplasia surrounding DA with gastric phenotype was immature and incomplete compared with DA with gastric-intestinal phenotype or intestinal phenotype. It is suggested that a large amount of DA with gastric phenotype is histogenetically derived from the gastric gland proper without intestinal metaplasia. However, as the tumor grows and intestinal metaplasia progresses, intestinal type phenotypic expression appears and then DA with gastric phenotype changes into DA with gastric-intestinal phenotype or intestinal phenotype."
354,A systems biology road map for the discovery of drugs targeting cancer cell metabolism.,"Alberghina L, Gaglio D, Moresco RM, Gilardi MC, Messa C, Vanoni M.",https://pubmed.ncbi.nlm.nih.gov/23859611/,"Despite their different histological and molecular properties, different types of cancers share few essential functional alterations. Some of these cancer hallmarks may easily be studied in in vitro cultures, while others are related to the way in which tumors grow in vivo. According to the systems biology paradigm, complex cellular functions arise as system-level properties from the dynamic interaction of a large number of biomolecules. We previously newly defined four basic cancer cell properties derived from known cancer hallmarks amenable to system-level investigation in cell cultures: enhanced growth, altered response to apoptotic cues, genomic instability and inability to enter senescence following oncogenic signaling. Here we summarize the major properties of enhanced growth that is dependent on metabolism rewiring - in which glucose is mostly used by fermentation while glutamine provides nitrogen and carbon atoms for biosyntheses - and controlled by oncogene signaling. We then briefly review the major drugs used to target signaling pathways in preclinical and clinical studies, whose clinical efficacy is unfortunately severely limited by tumor resistance, substantially due to signaling cross-talk. We present a systems biology roadmap that integrates different types of mathematical models with conventional and post-genomic biomolecular analyses that will provide a deeper mechanistic understanding of the links between metabolism and uncontrolled cancer cell growth. This approach is taken to be instrumental both in unraveling cancer's first principles and in designing novel drugs able to target one or more control or execution steps of the cancer rewired metabolism, in order to achieve permanent arrest of tumor development."
355,Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers.,"Tsvetkov P, Sokol E, Jin D, Brune Z, Thiru P, Ghandi M, Garraway LA, Gupta PB, Santagata S, Whitesell L, Lindquist S.",https://pubmed.ncbi.nlm.nih.gov/28028240/,"The use of proteasome inhibitors to target cancer's dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers."
356,Clinical and Prognostic Features of Patients With Esophageal Cancer and Multiple Primary Cancers: A Retrospective Single-institution Study.,"Baba Y, Yoshida N, Kinoshita K, Iwatsuki M, Yamashita YI, Chikamoto A, Watanabe M, Baba H.",https://pubmed.ncbi.nlm.nih.gov/28151796/,"
    


          Summary 
    


           The Cox proportional hazard model was used to compute the hazard ratio (HR) for mortality.
    


           Multiple primary cancers were significantly associated with alcohol use and tobacco smoking (Brinkman index). Patients with synchronous cancers had significantly shorter overall survival than those without multiple primary cancers (log-rank P = 0.032; univariate HR = 1.53, 95% confidence interval 1.02-2.17, P = 0.040; multivariate HR: 1.61; 95% confidence interval: 1.08-2.36; P = 0.020). Patients with metachronous cancers had similar prognoses to those without multiple primary cancers. The prognostic effect of synchronous cancers on overall survival was particularly prominent in patients with Stage I esophageal cancer (log-rank P = 0.0002).
    


          Conclusions:
        
      
      Multiple primary cancers are associated with a history of tobacco and alcohol use, supporting the concept of field cancerization. Synchronous multiple primary cancers may be an independent predictor of poorer long-term survival in patients undergoing resection of esophageal cancers."
357,Fibrosis and cancer: shared features and mechanisms suggest common targeted therapeutic approaches.,"Landolt L, Spagnoli GC, Hertig A, Brocheriou I, Marti HP.",https://pubmed.ncbi.nlm.nih.gov/33280031/,"Epidemiological studies support a strong link between organ fibrosis and epithelial cancers. Moreover, clinical and  As a deregulated response to injury occurring in all body tissues, fibrosis is characterized by activation of fibroblasts and immune cells, contributing to progressive deposition of extracellular matrix (ECM) and inflammation. Cancers are driven by genetic alterations  However, non-cancerous components of tumour tissues including fibroblasts, inflammatory cells and ECM play key roles in oncogenesis and cancer progression by providing a pro-mutagenic environment where cancer cells can develop, favouring their survival, expansion and invasiveness. Additional commonalities of fibrosis and cancer are also represented by overproduction of growth factors, like transforming growth factor β, epithelial-to-mesenchymal transition, high oxidative stress, Hippo pathway dysfunctions and enhanced cellular senescence. Here, we review advances in the analysis of cellular and molecular mechanisms involved in the pathogenesis of both organ fibrosis and cancer, with particular reference to chronic kidney diseases and renal cell cancers. Most importantly, improved understanding of common features is contributing to the development of innovative treatment strategies targeting shared mechanisms."
358,[News treatments and survival in lung cancer].,"Lamkhioued M, Pierret T.",https://pubmed.ncbi.nlm.nih.gov/36820443/,"NEW TREATMENTS AND SURVIVAL IN LUNG CANCER. Treatment paradigm for non-squamous cell lung cancer (NSCLC) has evolved dramatically in the early 2000s, mainly because of the identification of targetable oncogenes such as EGFR (epidermal growth factor receptor) and ALK (anaplasic lymphome kinase). Incidence and mortality have both declined thanks to the development of novel therapies. Since major diagnosis and therapeutics were made, and immune-based therapies are the new corner stone of non-small cell lung cancer's treatment. Systemic drugs are no longer limited to advanced stages, as they are now standing alongside surgery and radiotherapy. Recent major therapeutic advances have improved survival and quality of life among lung cancer patients."
359,Understanding and intervening in breast cancer's emotional and sexual side effects.,Rabinowitz B.,https://pubmed.ncbi.nlm.nih.gov/12116604/,"There is an evolving body of research and clinical literature that illuminates the variety of psychological and sexual sequelae of a breast cancer diagnosis and treatment, and the interventions that may aid in recovery. This article presents findings that highlight the impact on both patients and their family members. Recommendations are offered regarding the helpful role that physicians may play in mitigating the effects of some of the consequences of diagnosis and treatment."
360,[A novel transforming gene from human stomach cancers].,"Sakamoto H, Yoshida T, Miyagawa K, Terada M.",https://pubmed.ncbi.nlm.nih.gov/3606143/,"We have identified a novel transforming gene, hst, from a human stomach cancer, and the  From a total of 26 patients with stomach cancer, DNAs from 21 of their stomach cancers, 16 metastatic lymph node tumors from stomach cancers and 21 non-cancerous stomach mucosae, were assayed for their transforming activity to NIH3T3 cells. Three samples of DNA were positive; one was from a primary stomach cancer, the second from a non-cancerous portion of the same patient's stomach mucosa, and the third from a lymph node metastasis stomach cancer from a different patient. A portion of the transforming gene and near full-length cDNA for this gene was cloned. From the  We applied the term, hst (human stomach cancer), to this novel transforming gene. The hst gene was found to be responsible for acquisition of transforming activity of all the three different samples of DNAs."
361,Cancer stem cells and field cancerization of oral squamous cell carcinoma.,"Simple M, Suresh A, Das D, Kuriakose MA.",https://pubmed.ncbi.nlm.nih.gov/25920765/,"Oral squamous cell carcinoma (OSCC) has a high propensity for local failure, which is attributed to recurrence at the primary site or the development of second primary tumors (SPT). Field cancerization that refers to the existence of transformed cells in areas adjacent to the primary tumor, has been attributed to be one of the probable reasons underlying disease relapse. The carcinogenic process necessitates multiple molecular events for the transformation of a normal cell into a cancer cell. This implies that only the long-time residents of the epithelium, such as the stem cells, might be the candidates capable of accumulating these genetic hits. These transformed stem cells- the 'Cancer stem cells' (CSCs), are further known to be equipped with the properties of tumor initiation and migration, both of which are essential for orchestrating field cancerization. The concept that the CSCs might be responsible for field cancerization in OSCC has not been explored extensively. If the role of CSCs as the primary units of field cancerization process is established, their presence in the mucosa adjacent to the tumor may be an indicator for local recurrence and/or development of second primary tumors. In this review, we examine the available evidence in literature exploring the possibilities of CSCs driving the process of field cancerization and thereby being the underlying mechanism for disease recurrence and development of SPT."
362,Toxicity of Saffron Extracts on Cancer and Normal Cells: A Review Article.,"Shakeri M, Hashemi Tayer A, Shakeri H, Sotoodeh Jahromi A, Moradzadeh M, Hojjat-Farsangi M.",https://pubmed.ncbi.nlm.nih.gov/32711409/," According to WHO, 80% of Asian and African people rely on traditional medicine and medicinal plants to conserve their health. Saffron has received much attention among the herbal compounds related to cancer treatment.
    


           The review is based on the available data accessible in PubMed, Science Direct, Google Scholar, Magiran.ir, and SID.ir databases.
    


           Saffron appears to reduce the toxic effects of anticancer drugs. Saffron has toxicity effects when used in high amounts, which are far greater than those are used in human food culture.
    


          Conclusions:
        
      
      Considering the observed effects of saffron on the removal of cancer cells, saffron extract can be used in the treatment and prevention of cancer after confirmation in human clinical trials. According to the high IC50 of saffron extracts in normal cells, its toxicity against non-cancerous cells is low and its use is safe. Besides, the studies suggested the cytotoxic effects of saffron on some of the more cancers, including nervous system cancer and common cancers. Further studies are required to determine the effective dose and influence of mechanism of saffron in various animal type of cancers."
363,Sexuality and intimacy issues facing women with breast cancer.,"Huber C, Ramnarace T, McCaffrey R.",https://pubmed.ncbi.nlm.nih.gov/17149399/,"Purpose/
    


          Data sources:
        
      
      Published articles; OVID, PsycINFO, and Florida Atlantic University databases; Web sites; and books.
    


          Data synthesis:
        
      
      Patient perceptions and knowledge of mastectomy and chemotherapy-induced menopause in regard to lifelong sexual experiences are lacking. Healthcare providers must institute much-needed education and open lines of communication.
    


          Conclusions:
        
      
      The physical and psychological  Breast cancer's survival rate is at an all-time high, increasing the number of people who will be living with such issues on a daily basis and shifting the focus from acute care concerns to chronic disease concerns.
    


          Implications for nursing:
        
      
      Healthcare providers should assess individual patients for potential issues they may face. By identifying problems, they can challenge health care to focus on the long-term problems associated with sexuality and intimacy issues facing patients."
364,Therapeutic effect of boron neutron capture therapy (BNCT) on field cancerized tissue: inhibition of DNA synthesis and lag in the development of second primary tumors in precancerous tissue around treated tumors in DMBA-induced carcinogenesis in the hamster cheek pouch oral cancer model.,"Heber EM, Aromando RF, Trivillin VA, Itoiz ME, Nigg DW, Kreimann EL, Schwint AE.",https://pubmed.ncbi.nlm.nih.gov/17137553/," The aim of the present study was to evaluate the effect of these BNCT protocols on DNA synthesis in precancerous and normal tissue in this model and assess the potential lag in the development of second primary tumors in precancerous tissue. The data are relevant to potential control of field cancerized tissue and tolerance of normal tissue.
    


          Materials and  The BNCT-induced potential lag in the development of second primary tumors from precancerous tissue was monitored.
    


           The histological categories evaluated individually within precancerous tissue (dysplasia, hyperplasia and NUMF [no unusual microscopic features]) responded similarly. DNA synthesis in normal tissue treated with BNCT oscillated around the very low pre-treatment values. A BNCT-induced lag in the development of second primary tumors was observed.
    


          Conclusions:
        
      
      BNCT induced a drastic fall in DNA synthesis in precancerous tissue that would be associated to the observed lag in the development of second primary tumors. The minimum variations in DNA synthesis in BNCT-treated normal tissue would correlate with the absence of normal tissue radiotoxicity. The present data would support the control of field-cancerized areas by BNCT."
365,Thymidylate synthase and dihydropyrimidine dehydrogenase are upregulated in pancreatic and biliary tract cancers.,"Shimoda M, Sawada T, Kubota K.",https://pubmed.ncbi.nlm.nih.gov/19571608/,"Purpose:
        
      
      To investigate a rationale of pancreatobiliary cancers, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) concentrations in cancer tissues were evaluated.
    


          Patients and  ELISA was used to assess the concentrations of TS and DPD in cancerous and noncancerous tissues. All 82 patients were followed up at least 12 months after surgery. We compared patient survivals between the 2 groups, taking TS and DPD cutoff as median values, high versus low DPD and high versus low TS in the cancerous tissue of PC and BTC patients.
    


          016 vs. 0.036). In BTC, TS concentration was higher in cancerous than in noncancerous tissue (p = 0.0001). Patients with low TS and DPD concentrations had a tendency to have a better disease-free survival than those with high TS and DPD concentrations in PC groups; especially, BTC patients' disease-free survival with high TS was significantly longer than that with low TS (p = 0.0083).
    


          Discussion:
        
      
      TS and DPD levels had a tendency to be high in PC and BTC cancerous tissues. High TS in the cancerous tissue was associated with better disease-free survival in BTC."
366,[Radiation exposure and thyroid cancer].,"Cannizzaro MA, Veroux M, Costanzo M, Buffone A, Okatyeva V.",https://pubmed.ncbi.nlm.nih.gov/23064295/,"Thyroid cancer is the most common malignant tumor of the endocrine system. The most frequent type of thyroid malignancy is papillary carcinoma. Thyroid cancer's incidence rates have increased over the last three decades throughout the world. Numerous studies have documented that radiation exposure is a well-established risk factor for the thyroid cancer. It has been reported that exposure to external medical radiation or to external and internal radiation from atomic bomb explosions, nuclear tests or nuclear accidents leads to an increased risk for thyroid cancer. The risk of thyroid cancer is maximal during the first years of life and decreases with increasing age at exposure due to morphologic and functional heterogeneity in the thyroid tissue of children and adults. Also it has been indicated that iodine deficiency increases the risk of the thyroid cancer related to radioactive iodines in case of exposure to radioactive iodines in childhood and the stable iodine supplementation reduces this risk. Ionizing radiation produces a range of mutations in irradiated cells of the thyroid. The prevalence of RET/PTC mutations is significantly higher in papillary carcinomas from childhood patients with the precedent history of radiation."
367,Do New pN Subclassifications Proposed by IASLC's Lung Cancer Staging Project Agree with ypN Categories after Trimodality Therapy for Initial N2 Disease?,"Kim H, Ahn YC, Pyo H, Oh D, Noh JM, Sun JM, Ahn JS, Ahn MJ, Park K, Choi YS, Kim J, Zo JI, Shim YM, Lee M, Han J.",https://pubmed.ncbi.nlm.nih.gov/27423392/," The authors investigated whether this new subclassification agrees with the ypN categories after trimodality therapy for initially N2 disease.
    


           Data on 481 patients were analyzed and compared with special focus on the current and new pN classification.
    


          8%: 62.6% in ypN0; 45.5% in ypN1; 37.6% in ypN2; and 0% in ypN3. Comparisons between neighboring ypN categories showed significant difference between ypN0 and ypN1 (p = 0.028) but not between other categories. The 5-year OS rates according to new ypN subclassification were 48.2% in ypN1a, 39.0% in ypN1b, 52.8% in ypN2a1, 37.9% in ypN2a2, and 32.1% in ypN2b. Although the OS rate of ypN2a1 was numerically higher than those of ypN1b and ypN2b, comparisons between neighboring ypN categories revealed no significant difference.
    


          Conclusions:
        
      
      The current study was specifically intended to investigate whether ypN categories after trimodality therapy agree with International Association for the Study of Lung Cancer's new pN subclassification. Through the current study, the authors have confirmed that ypN downstaging to ypN0-1 from initial N2 stage is a favorable factor with respect to OS and raised the need for refinement of ypN subcategorization after trimodality therapy."
368,A new clinical index of growth rate in the staging of breast cancer.,"Charlson ME, Feinstein AR.",https://pubmed.ncbi.nlm.nih.gov/7424942/,"The clinical rate of growth in patients with breast cancer can be auxometrically classified by identifying the first clinical manifestation observed by the patient (or physician) and by then noting the progression interval that elapsed before treatment and the occurrence of prognostically unfavorable transition events during that interval. These two features can be used to demarcate slow, intermediate and rapid auxometric stages, which approximate the cancer's rate of progression. A fourth stage consists of patients who have systemic or metastatic symptoms before treatment. Within any TNM (tumor-nodes-metastases) stage, degree of nodal involvement or treatment, these four auxometric stages delineate patients with distinctly different prognoses. In particular, the slow auxometric stage can be used to identify a subgroup of patients with excellent 10 year survival and other patients who have good outcomes despite an anatomically unfavorable status. Conversely, the rapid and systemic-metastatic stages identify patients with relatively poor prognoses despite an apparently favorable anatomic status. The auxometric classification is easily used, readily available and involves no technologic expense or risk. By improving the accuracy of anatomic staging, auxometry adds an important refinement to the estimation of prognosis and the evaluation of therapy for patients with breast cancer."
369,[Laryngostroboscopy in the monitoring of precancerous lesion of vocal cord and in canceration tracing].,"Song F, Zhang Q, Wang J, Zhao H, Niu Y, Liu X, Yuan R.",https://pubmed.ncbi.nlm.nih.gov/12768676/,"
    


           The modifications of mucosal wave and amplitude of vocal cord vibration were observed. All cases were monitored for 1-6 years.
    


          3%) and the amplitude of vocal cord vibration was weak in 4 of 52 cases (9.6%) with precancerous lesions. However, the mucosal wave disappeared and the amplitude of vocal cord vibration weakened in all 14 cases with early glottic cancer.
    


          Conclusion:
        
      
      Laryngostroboscopy can be used in diagnosis of glottic precancerous lesion and distinguishing it from the early glottic cancer. It is also an effective means of canceration tracing."
370,[Follow up after potential curative surgery of colorectal cancer. Guidelines from the Norwegian Gastrointestinal Cancer Group].,"Norum J, Gerner T, Bergan A, Lange O.",https://pubmed.ncbi.nlm.nih.gov/9340857/,"In Norway, about 2,800 cases of colorectal cancer are diagnosed every year. Two-thirds of the patients undergo potentially curative surgery and almost half of them develop local or distant metastases. The follow-up of colorectal cancer patients involves four strategies: Educating the patients about the disease, symptoms of relapse, and risk of hereditariness; Early diagnosis of relapse, to make curative re-surgery possible; Diagnosis of metachronous/synchronous cancer(s); Recording the  The Norwegian Gastrointestinal Cancer Group recommend a four-year follow-up programme (every third month for two years and then twice a year) of colorectal cancer patients. It is suggested that patients treated with low anterior resection are followed regularly by means of rectoscopy and local examination (digital or by ultrasound) undertaken by specialist (surgeon or gastroenterologist). The others should be followed up mainly by general practitioners. Carcinoembryonic antigen (CEA)-monitoring is suggested every third month for two years, and then every sixth month. Colonoscopy is recommended at one and four year follow-up. Patients with normal CEA levels prior to surgery should be evaluated by ultrasound of the liver every sixth month for four years."
371,Hereditary pancreatic adenocarcinoma. A clinical perspective.,"Brand RE, Lynch HT.",https://pubmed.ncbi.nlm.nih.gov/10872423/,"Although the total number of patients in these various high-risk groups is relatively small, they nevertheless provide excellent models for studying the cause, natural history, pathogenesis, and treatment of pancreatic cancer. These patients would also benefit greatly from procedures capable of detecting cancer at an early stage. This knowledge would be useful for the much commoner sporadic form of pancreatic cancer, in which diagnosis is almost always late and prognosis fatal. With early diagnosis, surgical resection before the cancer's extension beyond the organ's anatomic confines could be curative. The establishment of a National Familial Pancreatic Cancer Registry is essential and would increase the availability of these invaluable families for medical research."
372,Cell-to-cell fusion as a link between viruses and cancer.,"Duelli D, Lazebnik Y.",https://pubmed.ncbi.nlm.nih.gov/18034186/,"The ability to fuse cells is shared by many viruses, including common human pathogens and several endogenous viruses. Here we will discuss how cell fusion can link viruses to cancer, what types of cancers it can affect, how the existence of this link can be tested and how the hypotheses that we propose might affect the search for human oncogenic viruses. In particular, we will focus on the ability of cell fusion that is caused by viruses to induce chromosomal instability, a common affliction of cancer cells that has been thought to underlie the malignant properties of cancerous tumours."
373,Cancer driver mutations in protein kinase genes.,"Torkamani A, Verkhivker G, Schork NJ.",https://pubmed.ncbi.nlm.nih.gov/19081671/,"Recent studies investigating the genetic determinants of cancer suggest that some of the genetic alterations contributing to tumorigenesis may be inherited, but the vast majority is somatically acquired during the transition of a normal cell to a cancer cell. A systematic understanding of the genetic and molecular determinants of cancers has already begun to have a transformative effect on the study and treatment of cancer, particularly through the identification of a range of genetic alterations in protein kinase genes, which are highly associated with the disease. Since kinases are prominent therapeutic targets for intervention within the cancer cell, studying the impact that genomic alterations within them have on cancer initiation, progression, and treatment is both logical and timely. In fact, recent sequencing and resequencing (i.e., polymorphism identification) efforts have catalyzed the quest for protein kinase 'driver' mutations (i.e., those genetic alterations which contribute to the transformation of a normal cell to a proliferating cancerous cell) in distinction to kinase 'passenger' mutations which reflect mutations that merely build up in course of normal and unchecked (i.e., cancerous) somatic cell replication and proliferation. In this review, we discuss the recent progress in the discovery and functional characterization of protein kinase cancer driver mutations and the implications of this progress for understanding tumorigenesis as well as the design of 'personalized' cancer therapeutics that target an individual's unique mutational profile."
374,Psychosocial support of the pediatric cancer patient: lessons learned over the past 50 years.,"Askins MA, Moore BD 3rd.",https://pubmed.ncbi.nlm.nih.gov/18928661/,"Advances in pediatric cancer treatment over the past 50 years have dramatically improved survival rates. Once considered almost uniformly fatal, pediatric cancer's overall survival rates now approach 85%. Formerly, little psychosocial support existed for the child with cancer other than that provided by nurses and family. The prospect for long-term survival was so remote that plans for the future (eg, school, social relationships, late effects of treatment, and emotional adjustment) were abandoned. As the survival rate for children with cancer improved, so did the need for and quality of psychosocial care, largely because of hope for a cure. Today children with cancer benefit from comprehensive behavioral pediatric psychosocial support programs in psychiatry, psychology, neuropsychology, child life, education (school), creative arts, chaplaincy, social work, and career and vocational counseling. Pediatric psycho-oncology research has provided insights into clinical care and the psychosocial adaptation of children and families to cancer treatment and survivorship."
375,Cancer-associated fibroblasts in tumor microenvironment - Accomplices in tumor malignancy.,"Liao Z, Tan ZW, Zhu P, Tan NS.",https://pubmed.ncbi.nlm.nih.gov/29397066/,"There is much cellular heterogeneity in the tumor microenvironment. The tumor epithelia and stromal cells co-evolve, and this reciprocal relationship dictates almost every step of cancer development and progression. Despite this, many anticancer therapies are designed around druggable features of tumor epithelia, ignoring the supportive role of stromal cells. Cancer-associated fibroblasts (CAFs) are the dominant cell type within the reactive stroma of many tumor types. Numerous previous studies have highlighted a pro-tumorigenic role for CAFs via secretion of various growth factors, cytokines, chemokines, and the degradation of extracellular matrix. Recent works showed that CAFs secrete H2O2 to effect stromal-mediated field cancerization, transform primary epithelial cells, and aggravate cancer cell aggressiveness, in addition to inflammatory and mitogenic factors. Molecular characterization of CAFs also underscores the importance of Notch and specific nuclear receptor signaling in the activation of CAFs. This review consolidates recent findings of CAFs and highlights areas for future investigations."
376,Flavin-dependent enzymes in cancer prevention.,"Wojcieszyńska D, Hupert-Kocurek K, Guzik U.",https://pubmed.ncbi.nlm.nih.gov/23222680/,"Statistical studies have demonstrated that various agents may reduce the risk of cancer's development. One of them is activity of flavin-dependent enzymes such as flavin-containing monooxygenase (FMO)(GS-OX1), FAD-dependent 5,10-methylenetetrahydrofolate reductase and flavin-dependent monoamine oxidase. In the last decade, many papers concerning their structure, reaction mechanism and role in the cancer prevention were published. In our work, we provide a more in-depth analysis of flavin-dependent enzymes and their contribution to the cancer prevention. We present the actual knowledge about the glucosinolate synthesized by flavin-containing monooxygenase (FMO)(GS-OX1) and its role in cancer prevention, discuss the influence of mutations in FAD-dependent 5,10-methylenetetrahydrofolate reductase on the cancer risk, and describe FAD as an important cofactor for the demethylation of histons. We also present our views on the role of riboflavin supplements in the prevention against cancer."
377,"Boveri at 100: cancer evolution, from preneoplasia to malignancy.",Wright NA.,https://pubmed.ncbi.nlm.nih.gov/25043632/,"In the 100 years since the publication of Boveri's manuscript, 'Concerning the origin of human tumours', we have seen many advances in our understanding of how tumours originate, develop and progress. However, reading this article now, it is possible to find conclusions, or more often predictions, of what we now consider basic tenets of tumour biology. These include predicting the stochastic nature of the malignant change and that all tumours are necessarily of clonal origin, perhaps the basis of the modern concepts of field cancerization, of tumour heterogeneity and the clonal evolution of tumours. Modern researchers rarely refer to this paper, yet as a source of ideas it must rank amongst the landmarks in tumour biology of the last 100 years."
378,Field change and oral cancer: new evidence for widespread carcinogenesis?,Thomson PJ.,https://pubmed.ncbi.nlm.nih.gov/12190131/,"Patients with oral squamous cell carcinoma (OSCC) are at risk of developing second or multiple primary cancers as a  In order to quantify the incidence of field change observable in oral mucosa, 26 consecutive new (untreated) patients presenting with a unilateral OSCC (18) or a premaligant lesion (eight) underwent 'mirror image' biopsies from clinically normal-looking mucosa at corresponding anatomical sites. A total of 15 patients (58%) demonstrated histologically abnormal tissue upon microscopic examination: six showed reactive change/cellular atypia associated with chronic irritation, seven exhibited frank dysplasia, whilst two displayed carcinoma-in-situ (CIS) or microinvasive SCC. Although not statistically significant, there was an observable trend for the lateral/ventral tongue and floor of mouth to display increased vulnerability to dysplastic change."
379,[Lung cancer and women].,"Teixeira E, Conde S, Alves P, Ferreira L, Figueiredo A, Parente B.",https://pubmed.ncbi.nlm.nih.gov/14685633/,"The epidemiology of lung cancer has changed in the last years in several countries all over the world. In the 19th century, the lung cancer was rare but it incidence increase drastically during the 20th century, and the tendency is to continue in the 20th century. Actually the lung cancer's incidence and mortality are higher in the developed countries, especially in Europe and Unites States of America, with a increasing in the women incidence. These geographic differences and gender differences are related with smoking habits. Women begin to smoke earlier and have more difficulty to stop, because of problems related with obesity; they have more sensibility to the carcinogens and the risk of lung cancer is 1.5 times higher than the men with the same habits. Adenocarcinoma is the more frequent histological type in young people, in the total of the women and in non-smokers. Many factors since tobacco, home and professional pollution, nutritional, associated diseases even genetic and hormonal factors have been investigated to define its influence in development in women lung cancer. It specificity in women with lung cancer is the common problem for the medical people to treat this disease (pathology).The literature about this problem is not clear, and is necessary to advance with many studies in this area with the "
380,Laser-induced fluorescence imaging in localization of head and neck cancers.,"Kulapaditharom B, Boonkitticharoen V.",https://pubmed.ncbi.nlm.nih.gov/9525247/,"Laser-induced fluorescence tumor imaging exploits the difference in tissue autofluorescence properties between normal and cancerous tissues. The effectiveness and reliability of fluorescence imaging with a lung imaging fluorescence endoscopy (LIFE) system for cancers in the head and neck were compared to those of white light endoscopy (WLE). Examinations by WLE and LIFE were conducted on 25 patients suspected for malignancy. Histologic diagnosis was confirmed by biopsy. Posttreatment evaluations were performed on 6 cancer patients identified by this study. By LIFE, all 16 cancerous lesions, including 2 occult cancers, were identified (100%), while WLE achieved only an 87.5% detection rate. LIFE (specificity 87.5%) was greatly helpful to WLE (specificity 50%) in differentiating inflammation from malignancy, though it failed to exclude granuloma. The "
381,Cancer immunotherapy: an embarrassment of riches?,"Whelan M, Whelan J, Russell N, Dalgleish A.",https://pubmed.ncbi.nlm.nih.gov/12623239/,"There is clear evidence that certain forms of immunotherapy can be successful against certain cancers. However, it would appear that cancerous cells of various origin are exceptionally adept at subverting the immune response. Consequently, it is probable that the most efficacious therapy will be one in which multiple responses of the immune system are activated. There is currently an embarrassment of riches with regard to multiple vaccine strategies in the clinic, although no single  Here, we draw together several of the humoral- and cellular-activating strategies currently under clinical investigation."
382,Direct ChIP-bisulfite sequencing reveals a role of H3K27me3 mediating aberrant hypermethylation of promoter CpG islands in cancer cells.,"Gao F, Ji G, Gao Z, Han X, Ye M, Yuan Z, Luo H, Huang X, Natarajan K, Wang J, Yang H, Zhang X.",https://pubmed.ncbi.nlm.nih.gov/24407023/,"The model describing that aberrant CpG island (CGI) methylation leads to repression of tumour suppressor genes in cancers has been influential, but it remains unclear how such aberrancy is induced. Recent studies provided clues indicating that promoter hypermethylation in cancers might be associated with PRC target genes. Here, we used ChIP-BS-seq to examine methylation of the DNA fragments precipitated by the antibodies to both H3K27me3 and H3K4me3 histone modifications. We showed that, for a set of genes highly enriched with H3K27me3 both in cancer and normal cells, CGI promoters were aberrantly hypermethylated only in cancer cells in comparison with normal cells. In contrast, such aberrant CGI hypermethylation in cancer promoters that were deficient of H3K27me3 was not notable. Furthermore, we confirmed that these genes were consistently hypermethylated in TCGA primary cancer cells. These works support the association between H3K27me3 and DNA methylation marks for specific cancer genes and will spur future work on combined histone and DNA methylation that could define cancer's epigenetic abnormalities."
383,"Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors.","Peng G, Hakim M, Broza YY, Billan S, Abdah-Bortnyak R, Kuten A, Tisch U, Haick H.",https://pubmed.ncbi.nlm.nih.gov/20648015/," In this study, we investigated the ability of a nanosensor array to discriminate between breath VOCs that characterise healthy states and the most widespread cancer states in the developed world: lung, breast, colorectal, and prostate cancers.
    


           Breath from cancerous subjects was collected before any treatment. The healthy population was healthy according to subjective patient's data. The breath of volunteers was examined by a tailor-made array of cross-reactive nanosensors based on organically functionalised gold nanoparticles and gas chromatography linked to the mass spectrometry technique (GC-MS).
    


           Moreover, the nanosensor array could distinguish between the breath patterns of different cancers in the same statistical analysis, irrespective of age, gender, lifestyle, and other confounding factors. The GC-MS 
    


          Conclusions:
        
      
      The reported "
384,Folate deficiency and aberrant expression of DNA methyltransferase 1 were associated with cervical cancerization.,"Wang JT, Ding L, Jiang SW, Hao J, Zhao WM, Zhou Q, Yang ZK, Zhang L.",https://pubmed.ncbi.nlm.nih.gov/23888945/,"DNA methyltransferase 1 (DNMT1) plays a significant role in maintaining DNA methylation. Aberrant DNA methylation is a recognized feature of human cancers and folate is directly involved in DNA methylation via one-carbon metabolism. Previous reports also have suggested that folate deficiency was associated with many cancers. The aim of the present study was to evaluate the effect of folate deficiency and aberrant expression of DNA methyltransferase 1 (DNMT1) on cervical cancerization. The expression of DNMT1 protein and mRNA and levels of serum folate were detected in 238 women with a diagnosis of normal cervix (NC，n = 53), cervical intraepithelial neoplasia (CIN I, n = 52; CIN II/III, n = 53), and squamous cell carcinoma of the cervix (SCC; n = 80). In addition, the expression of DNMT1 protein and mRNA was measured in cervical cancer cells (Caski and C33A) treated by different concentration of folate. Serum folate levels decreased and expression levels of DNMT1 protein and mRNA increased gradually with progressive severity of the cervix lesions (P<0.001). It was found that folate was able to reduce the viability of Caski or C33A cell (r=0.978, P=0.002; r=0.984, P<0.001) and regulated aberrant expression of DNMT1 protein (r=-0.859, P=0.01; r=-0.914, P<0.001) and mRNA (r=-0.297, P=0.159; r=0.433, P=0.034) in vitro. Our findings indicated that the low-level of serum folate and high-expression of DNMT1 protein or mRNA was significantly associated with cervical carcinogenesis. Folate deficiency and aberrant expression of DNA methyltransferase 1 had additive effect on cervical cancerization. Folate supplement and recovery of aberrant DNA methylation status may offer a new strategy for prevention and therapy of cancers."
385,"Focusing on the Abnormal Events of NPC1, NPC2, and NPC1L1 in Pan-Cancer and Further Constructing LUAD and KICH Prediction Models.","Chen K, Zhang X, Sun G, Fang Z, Liao L, Zhong Y, Huang F, Dong M, Luo S.",https://pubmed.ncbi.nlm.nih.gov/38109854/,"Cancer's high incidence and death rate jeopardize human health and life, and it has become a global public health issue. Some members of NPCs have been studied in a few cancers, but comprehensive and prognostic analysis is lacking in most cancers. In this study, we used the Cancer Genome Atlas (TCGA) data genomics and transcriptome technology to examine the differential expression and prognosis of NPCs in 33 cancer samples, as well as to investigate NPCs mutations and their effect on patient prognosis and to evaluate the methylation level of NPCs in cancer. The linked mechanisms and medication resistance were subsequently investigated in order to investigate prospective tumor therapy approaches. The relationships between NPCs and immune infiltration, immune cells, immunological regulatory substances, and immune pathways were also investigated. Finally, the LUAD and KICH prognostic prediction models were built using univariate and multivariate COX regression analysis. Additionally, the mRNA and protein levels of NPCs were also identified."
386,Intraoperative colonoscopy for the diagnosis of multiple cancers of the large intestine.,"Kaibara N, Kimura O, Nishidoi H, Miyano Y, Koga S.",https://pubmed.ncbi.nlm.nih.gov/7109357/,"Seventeen patients with multiple simultaneous cancers of the large intestine were investigated. Three out of 4 patients with multiple advanced cancers were correctly diagnosed preoperatively. Multiple cancerous lesions of early and advanced stages coexisted in 13 patients, and it was possible to diagnose the existence of multiple cancers in only 5 preoperatively. A study on the preoperative detectability of coexisting early cancers showed that early lesions located distally to the advanced ones were frequently detected, however, subsidiary lesions located proximally tended to be overlooked. Hence, intraoperative colonoscopy was performed in patients with cancer of the large intestine whenever there was a portion that had not been adequately inspected prior to surgery. Of 31 patients subjected to this examination, 5 had a total of 7 polypoid lesions, in one case we found evidence of a small advanced cancer which was not detected preoperatively."
387,"Cancer incidence in adolescents and young adults in the United States, 1992-1997.","Wu XC, Chen VW, Steele B, Roffers S, Klotz JB, Correa CN, Carozza SE.",https://pubmed.ncbi.nlm.nih.gov/12782451/,"Purpose:
        
      
      To examine cancer incidence patterns among adolescents and young adults in the United States.
    


           Individual cancers were grouped into specific diagnostic groups and subgroups using an integrated classification scheme. The integrated scheme was developed for this study and was based on the most commonly used schemes in population-based epidemiologic studies: Surveillance, Epidemiology, and End  Percent distributions and age-specific incidence rates per million population were computed for adolescents (aged 15-19 years) and young adults (aged 20-24 years) by gender.
    


           Among 15-19-year-olds, the five most common cancers were Hodgkin's disease, leukemia, cancer in the brain and other nervous system, bone cancer, and non-Hodgkin's disease. Among 20-24-year-olds, the five most common cancers were Hodgkin's disease, testicular cancer, thyroid cancer, melanoma of the skin, and leukemia. The proportions and rates of the histologic subtypes for most of the common cancers changed with advancing age. For example, among 15-19-year-olds, acute lymphocytic leukemia accounted for approximately 60% of leukemias in males and 50% in females. Among 20-24-year-olds, however, the corresponding percentages of acute lymphocytic leukemia were 37% in males and 31% in females. For ovarian cancer, the germ cell tumor was the most common subtype (54.6% of all ovarian cancers) among 15-19-year-olds. In contrast, ovarian carcinoma was the predominant subtype (70.4%) among 20-24-year-olds. For both age groups, the incidence rates of nodular Hodgkin's disease, melanoma of the skin, and thyroid cancer were significantly greater in females than in males.
    


          Conclusions:
        
      
      Cancer incidence patterns among adolescents and young adults are distinctive. In these age groups, a transition from predominantly pediatric histologic subtypes to adult subtypes was observed for Hodgkin's disease, leukemia, ovarian cancer, and soft tissue sarcoma. Gender differences were found for Hodgkin's disease, melanoma of the skin, and thyroid cancer."
388,[THE GIFT OF THE APPLICATION OF REIKI THERAPY IN CANCER PATIENTS].,Sánchez Domínguez J.,https://pubmed.ncbi.nlm.nih.gov/27548991/,"Pain is one of the most feared symptoms of cancer. Bad pain not properly relieved contributes to the suffering of the patient and family. This may encourage them to seek additional complementary and alternative therapies, such as the one in our literature review. Reiki is understood as a healing  Reiki is a relatively new the rapyin relation to the relief of the symptoms of cancer. In fact, there are still a few articles in this field. Currently, the authors explore the evidence on the effectiveness of Reiki in relation to cancer pain and symptom control. Due to the increased interest deposited in Reiki by the health professionals--especially for oncology professionals--to relieve the symptoms of cancer, there has been a synthesis of recent studies to provide the evidence so far. After our literature review, we can conclude that there is insufficient evidence on the effectiveness of Reiki in relieving the cancer's symptoms due to the small sample size used, the paucity of studies and the abandonment of the study participants and others."
389,Multiple oral cancer development-Clinico-pathological features in the Hong Kong population.,"Choi SW, Thomson P.",https://pubmed.ncbi.nlm.nih.gov/31544259/," We have previously profiled contemporaneous demographics and confirmed a rising incidence of oral cancer within the Hong Kong population. In this further study, we sought to characterize the presenting clinico-pathological features and clinical outcome consequent upon multiple primary tumour (PT) development.
    


          
    


          5%) developed multiple PTs, most commonly 2 (663) but 3 (91), 4 (12), 5 (2) and 6 (1) were also observed. The male to female ratio was 2.25 to 1 (P = .004), with female patients significantly older at first tumour presentation (P = .002), demonstrating longer periods before second PT development (P = .001) and better long-term survival than males (P = .001). Buccal mucosa (143), oropharynx (134) and tongue (112) were the sites most frequently affected by second tumours. Whilst buccal SCC showed a propensity for subsequent buccal tumour development (60), oropharynx primaries developed second PTs most frequently on the tonsil (28) and tongue (27). Tongue primaries were associated with second PTs on the floor of mouth (61) and oropharynx (57).
    


          Conclusion:
        
      
      Development of multiple oral cancers is a significant risk in Hong Kong, particularly for male patients. Following initial tumour management, regular and careful patient follow-up is important for early recognition of multiple SCC development."
390,Anterior gradient 2: a new target to treat colorectal cancer.,"Gao H, Xu X, Chen B, Wang F, Zhang W, Geng H, Wang Y.",https://pubmed.ncbi.nlm.nih.gov/23528333/,"Colorectal cancer is one of the leading causes of cancer-associated morbidity and mortality across the world. Every year many patients died from the advanced colorectal cancer. We had tried our best to stop the progress by the chemotherapy and radiotherapy, but the process has not stopped. And we just can use the target drug to extend the survival time of the patient who is in advanced stage. It is said that the circulating tumor cells, distributed in the peripheral blood, is the initial material leading to metastases formation. And Anterior gradient 2 is a biomarker of these cells. It shows an enormous role in the process of cancer's occurrence, development and metastasis. It may be a useful target for us to prevent colorectal cancer from progress. And it may be a new way to treat the colorectal cancer."
391,Present and future of personalized medicine in adult genitourinary tumors.,"Ciccarese C, Santoni M, Massari F, Cheng L, Lopez-Beltran A, Scarpelli M, Conti A, Tortora G, Cascinu S, Montironi R.",https://pubmed.ncbi.nlm.nih.gov/25952784/,"The development of targeted agents has completely revolutionized the therapeutic scenario of genitourinary tumors. However, no biomarkers of tumor response or patient tolerability have been validated so far, and the selection of patients who may benefit from these approaches is still empirical. Significant advances in genomic sequencing and molecular characterization of these tumors have allowed identification of complex genomic abnormalities, thus increasing our knowledge on cancer biological landscapes and paving the way to the development of personalized strategies based on the patient's genomic and cancer's molecular profiles. This review is an overview of recent findings and emerging individualized therapies in patients with prostate, renal and bladder cancer, focusing on the promises and limitations of this approach in this setting."
392,An overview of the risk factors associated with multiple oral premalignant lesions with a case report of extensive field cancerization in a female patient.,"Sreedhar G, Narayanappa Sumalatha M, Shukla D.",https://pubmed.ncbi.nlm.nih.gov/24401899/," in 1953. Tobacco chewing was associated with the greatest increase in the risk of multiple oral premalignant lesions and may be the major source of field cancerization of the oral cavity in the Indian population. The field cancerization will probably help clinicians in complementing evaluation of pathologic biopsy specimens.
    


          Material and  She presented with an intra-oral generalized hyperkeratotic verruciform type white lesions involving right and left buccal mucosa, lower labial mucosa, upper and lower vestibule, dorsal, ventral and right lateral border of the tongue, hard and soft palate. Microscopic examination revealed features of verrucous carcinoma in one area, squamous cell carcinoma in another and carcinoma in situ in other areas. Based on the overall features in various areas of the oral cavity, the lesion was diagnosed as field cancerization.
    


          Conclusion:
        
      
      Reviewing the literature revealed the presence of a field with genetically altered cells appear to be induced by tobacco (smoking/smokeless form). The large number of premalignant cells in the fields may increase cancer risk considerably. Thus screening and monitoring of the field may have serious implications for oral cancer prevention."
393,[A case of five cancerous lesions of the colon diagnosed by preoperative examination].,"Ebihara T, Koyama S, Fukutomi H, Osuga T, Nakamura K.",https://pubmed.ncbi.nlm.nih.gov/3613107/,"A rare case of five synchronous colon cancers has been reported. A 52-year-old woman was admitted to our hospital complaining of pain at the right lower quadrant. roentgenographic and endoscopic studies of the colon revealed three cancerous lesions in the cecum the ascending colon, and two lesions at the sigmoid and rectosigmoid colon. Histopathological findings of the respective specimens showed one advanced cancer which had invaded into the muscuralis propria on the upper part of the Bauhin's valve, and four early type carcinomas invaded into the mucosa or submucosa. There were metastatic lesions at the regional lymph nodes in sigma, but distant metastatic lesions were not observed. These histologic findings suggest that these carcinomas had not arisen in preexisting benign adenomas, but had arose from normal mucosa (de novo cancer)."
394,Focal photodynamic intracellular acidification as a cancer therapeutic.,"Gdovin MJ, Kadri N, Rios L, Holliday S, Jordan Z.",https://pubmed.ncbi.nlm.nih.gov/28215969/,"Cancer cells utilize an array of proton transporters to regulate intra- and extracellular pH to thrive in hypoxic conditions, and to increase tumor growth and metastasis. Efforts to target many of the transporters involved in cancer cell pH regulation have yielded promising  Following a review of the status of photodynamic cancer therapy, a novel light-activated process is presented which creates very focal, rapid, and significant decreases in only intracellular pH (pHi), leading to cell death. The light-activation of the H+ carrier, nitrobenzaldehyde, has been effective at initiating pH-induced apoptosis in non-cancerous and numerous cancerous cell lines in vitro, to include breast, prostate, and pancreatic cancers. Also, this intracellular acidification technique caused significant reductions in tumor growth rate and enhanced survival in mice bearing triple negative breast cancer tumors. The efficacy of an NBA-upconverting nanoparticle to kill breast cancer cells in vitro is described, as well as a discussion of the potential intracellular mechanisms underlying the pH-induced apoptosis."
395,[The role of medicinal herbs with anti-inflammatory properties in prevention and treatment of cancer].,"Berkovich L, Ron I, Earon G, Abu-Ghanem S, Rimmon A, Lev-Ari S.",https://pubmed.ncbi.nlm.nih.gov/23367734/,"The association between chronic inflammation and carcinogenesis, as well as neoplastic progression, has been researched and is well-established. Being a central coordinator of immune responses, nuclear factor-kappa B (NFkappaB) signaling plays a critical role in cancer development and progression. The activation of the NFkappaB signaling pathway is highly monitored under normal conditions, and is mainly known as a key pathway in activation of immune responses. Constitutively active NFkappaB has been identified in most tumor cell lines, as well as in a wide variety of tumor tissues derived from cancer patients. Such activation may also affect the cancer's response to therapy, making it less susceptive to radio and chemo treatment. Hence, NFkappaB has become a target for inhibition by chemotherapeutic agents. Traditionally, medicinal herbs have been used to prevent and treat a variety of diseases, including cancer. In this article, we review several natural, herbal-derived compounds shown to have anti-inflammatory and anticancer activities mediated, at least in part, by NFkappaB signaling inhibition. Compounds of this sort may potentially serve as clinically effective anticancer treatments."
396,Organ-specific endoglin (CD105) expression in the angiogenesis of human cancers.,"Minhajat R, Mori D, Yamasaki F, Sugita Y, Satoh T, Tokunaga O.",https://pubmed.ncbi.nlm.nih.gov/17096728/,"Some markers of angiogenic endothelial cells are emerging as targets for cancer therapy. The present study compared the expression of CD105 with that of other endothelial markers in cancers from various organs. Surgically resected cancer tissues from 188 patients comprising brain (n = 17), lung (n = 38), breast (n = 30), stomach (n = 30), colon (n = 31), liver (n = 32), and kidney (n = 10) cancers were immunohistochemically analyzed on tissue microarrays using a panel of eight endothelial markers. CD31 was expressed in vascular endothelial cells in cancer lesions as well as in non-cancerous areas (30-100%) in all core tissue samples. CD105 expression was intense and restricted to capillary endothelial cells in cancer lesions (>73%). In contrast, positive expression of CD105 was seen in <20% of non-cancerous areas in the same organs. However, no significant difference in CD105 expression in vascular endothelial cells between cancer lesions and non-cancerous areas from liver and renal cancer samples was found. Vascular endothelial growth factor (VEGF), Flt1, and Flk1 were also expressed, but only sporadically and in few samples (<30%), and transforming growth factor (TGF)-beta1 and TGF-betaRII were negative in vascular endothelial cells but generally positive in cancer cells. CD44 was strongly expressed in sinusoidal endothelial cells of the liver (90-100%). These "
397,Epidemiology of Cancer.,Schwartz SM.,https://pubmed.ncbi.nlm.nih.gov/38175589/," A large amount of knowledge has accumulated regarding the epidemiology of most cancer types, including their causes.
    


          Content:
        
      
      The cancer types most frequently diagnosed among adults in most high-income countries are lung, colorectal, female breast, cutaneous melanoma, and prostate. In general cancer incidence and mortality is very low in children and adolescents, rising exponentially with increasing age during adulthood. There is marked international variation in the incidence of most cancers. The most important causes of cancer are tobacco use (primarily cigarette use), excess alcohol consumption, obesity, lack of physical activity, diets low in fruits and vegetables, infectious agents, and sun exposure. Early detection can reduce the chances that a person will die of cancers of the female breast, uterine cervix, colon and rectum, lung, and prostate.
    


          Summary:
        
      
      Although the most common cancers in the United States continue to have a substantial impact on public health, they are caused in whole or part by factors over which people and governments have control through choices they make. Among these are tobacco and alcohol use, obesity, diets low in fruits and vegetables and lack of physical activity, and sun exposure. Thus, a very large proportion of cancer's impact could be ameliorated if more people avoided these exposures."
398,Impact of COVID-19 Pandemic on Non-Melanoma Skin Cancer's Tumor Burden and Care: a Multi-Center Study Based in Northern Italy.,"Silvia C, Denis C, Mario C, Luigi V, Federico T, Marcello C.",https://pubmed.ncbi.nlm.nih.gov/35918285/,"The brisk remodeling in healthcare delivery observed after the COVID-19 outbreak led us to evaluate how the pandemic affected non-melanoma skin cancer's (NMSC) care and tumor burden. To address this topic, we set up a retrospective real-life multi-center study based on the cities of Bergamo and Varese, whose provinces were the worst hit in Italy by the pandemic. We analyzed medical and pathological data from patients that underwent surgery in the two months preceding the outbreak in Italy and compared them to those who did in the corresponding bimester of the following year, reaching 214 patients and 274 lesions. We observed a considerable and significant increase in NMSC's diameter, as well as in the proportion of squamous cell carcinomas. Both the average waiting time to obtain an evaluation visit and the average time in the surgical waiting list was shorter after the COVID-19 outbreak: the reason is that we evaluated and operated near-exclusive patients affected by high-priority lesions, who benefited from ""fast-track"" referrals. Conversely, less-concerning lesions were, and still are, left on hold, until they will become advanced enough to be labeled as ""urgent"". Plastic surgery departments should evade as soon as possible from this downward spiral, in order to provide our patients with timely cancer care and to be able to treat all plastic surgery-requiring pathologies."
399,[Experimental stomach cancerization in the rat].,"Santini R, Dumas J, Penaud J, Thouvenot J.",https://pubmed.ncbi.nlm.nih.gov/140741/,Simulated gastric cancers in rats have been realised by implantation of walker tumour with three different  The best  With this 
400,History of Japan Clinical Oncology Group (JCOG) Lung Cancer Study Group.,"Horinouchi H, Ohe Y.",https://pubmed.ncbi.nlm.nih.gov/32115625/,"The Japan Clinical Oncology Group Lung Cancer Study Group has been carrying out clinical studies, exploring new strategies of treatment, supportive therapies (antiemetics, etc.), etc., for a variety of cancers, including not only small cell lung cancer and non-small cell lung cancer but also rare chest tumours (represented by thymoma) and cancer-associated conditions (cancerous pericarditis, cancerous pleuritis, etc.). In this review, an overview of all studies conducted from 1985 to 2019 is provided."
401,Molecular biology and the staging of prostate cancer.,"Marandola P, Bonghi A, Jallous H, Bombardelli E, Morazzoni P, Gerardini M, Tiscione D, Albergati F.",https://pubmed.ncbi.nlm.nih.gov/15650255/,"Cancer of the prostate is still controlled or cured by surgery, radiotherapy, and hormone therapy. The present criteria of complication and prediction are criticized more and more for not being sufficiently reliable, due to the high heterogeneity of prostatic cells. The continuing discoveries of intra- and extracellular mechanisms of the molecular informational network, which allow the continuity or discontinuity of the cell's life, are also related to prostate cancer. The role of androgen receptors is now under close scrutiny, in the light of the knowledge of regulatory genes and their molecular expression. In the near future, a complete study of prostate cancer's DNA is certainly envisaged. Looking forward to the extraordinary applications of molecular biology in this field, this article is aimed at establishing a clear link between the conventional ways of interpreting the clinical expression of prostate cancer and the oncoming applications of genomics and proteomics."
402,Field cancerization in the GI tract.,"Graham TA, McDonald SA, Wright NA.",https://pubmed.ncbi.nlm.nih.gov/21823893/,"The widely accepted paradigm for tumorigenesis begins with rate-limiting mutations in a key growth control gene  Tumor progression occurs as cells within the tumor acquire additional carcinogenic mutations. However, there is clear evidence that the road to cancer can begin long before the growth of a clinically detectable lesion - indeed, long before any of the usual morphological correlates of preneoplasia are recognizable. Field cancerization, the replacement of the normal cell population by a histologically nondysplastic but protumorigenic mutant cell clone, underlies the development of many cancer types, and in this article we review field cancerization in the GI tract. We present the evidence that field cancerization can underpin tumorigenesis in all gastrointestinal compartments, discuss the homeostatic mechanisms that could permit clone spread and highlight how an understanding of the mechanisms driving field cancerization is a means to study human stem cell biology. Finally, we discuss how appropriate recognition of the role of field cancerization in tumorigenesis could impact patient care."
403,Phytocompounds from the Medicinal and Dietary Plants: Multi-target Agents for Cervical Cancer Prevention and Therapy.,"Shoaib S, Islam N, Yusuf N.",https://pubmed.ncbi.nlm.nih.gov/35232338/,"Cervical cancer is the fourth leading cause of cancer death among women worldwide. Due to cervical cancer's high incidence and mortality, there is an unmet demand for effective diagnostic, therapeutic, and preventive agents. At present, the preferred treatment strategies for advanced metastatic cervical cancer include surgery, radiotherapy, and chemotherapy. However, cervical cancer is gradually developing resistance to chemotherapy, thereby reducing its efficacy. Over the last several decades, phytochemicals, a general term for compounds produced from plants, have gained attention for their role in preventing cervical cancer. This role in cervical cancer prevention has garnered attention on the medicinal properties of fruits and vegetables. Phytochemicals are currently being evaluated for their ability to block proteins involved in carcinogenesis and chemoresistance against cervical cancer. Chemoresistance to cancer drugs like cisplatin, doxorubicin, and 5-fluorouracil has become a significant limitation of drug-based chemotherapy. However, the combination of cisplatin with other phytochemicals has been identified as a promising alternative to subjugate cisplatin resistance. Phytochemicals are promising chemo-preventive and chemotherapeutic agents as they possess antioxidant, anti-inflammatory, and anti-proliferative potential against many cancers, including cervical cancer. Furthermore, the ability of the phytochemicals to modulate cellular signaling pathways through up and down regulation of various proteins has been claimed for their therapeutic potential. Phytochemicals also display a wide range of biological functions, including cell cycle arrest, apoptosis induction, inhibition of invasion, and migration in cervical cancer cells. Numerous studies have revealed the critical role of different signaling proteins and their signaling pathways in the pathogenesis of cervical cancer. Here, we review the ability of several dietary phytochemicals to alter carcinogenesis by modulating various molecular targets."
404,Does cancer in a child affect parents' employment and earnings? A population-based study.,"Syse A, Larsen IK, Tretli S.",https://pubmed.ncbi.nlm.nih.gov/20822964/,"Purpose:
        
      
      Cancer in a child may adversely affect parents' work opportunities due to enlarged care burdens and/or altered priorities. Few studies exist, and possible effects on parental employment and earnings were therefore explored.
    


          Materials and 2 million) was retrieved from national registries. Employment rates for parents of 3263 children with cancer were compared to those of parents with children without cancer by means of logistic regression models. Log-linear regression models were used to explore childhood cancer's effect on parental earnings for the large majority of parents who remained employed.
    


           For employed mothers, CNS cancers, germinal cell cancers, and unspecified leukemia were associated with significant reductions in earnings (10%, 21%, and 60%, respectively). Reductions were particularly pronounced for mothers with a young and alive child, and became more pronounced with time elapsed from diagnosis. Fathers' earnings were not affected significantly.
    


          Discussion and conclusion:
        
      
      Parents' employment is not adversely affected by a child's cancer in Norway. Earnings are reduced in certain instances, but the overall effects are minor. Generous welfare options and flexible labor markets typical for Nordic welfare states may account for this. In line with traditional caregiving responsibilities, reductions in earnings were most pronounced for mothers."
405,Modeling nanophotothermal therapy: kinetics of thermal ablation of healthy and cancerous cell organelles and gold nanoparticles.,"Letfullin RR, Iversen CB, George TF.",https://pubmed.ncbi.nlm.nih.gov/20732456/,"Nanoparticles are being researched as a noninvasive  With particular antibody coatings on nanoparticles, they attach to the abnormal cells of interest (cancer or otherwise). Once attached, nanoparticles can be heated with ultraviolet-visible/infrared or radiofrequency pulses, heating the surrounding area of the cell to its point of death. Researchers often use single-pulse or multi-pulse modes of laser heating when conducting nanoparticle ablation research. In this article, time-dependent simulations and detailed analyses are carried out for different nonstationary pulsed laser-nanoparticle interaction modes, and the advantages and disadvantages of single-pulse and multi-pulse (set of short pulses) laser heating of nanoparticles are shown. Simulations are performed for the metal nanoparticles in the biological surrounding medium as well as for healthy and cancerous cell organelles.
    


          From the clinical editor:
        
      
      External laser pulses can be used to generate heating of targeted metal nanoparticles for thermal ablation therapy of cancers, however the approach used in individual studies is idiosyncratic. In this manuscript, time-dependent simulations and analyses are used to determine the pros and cons of single versus multiple laser pulses for differential impact of healthy versus cancerous cell organelles."
406,Metastatic pancreatic cancer: the dilemma of quality vs. quantity of life.,"Shahrokni A, Saif MW.",https://pubmed.ncbi.nlm.nih.gov/23846935/,"Due to pancreatic cancer's dismal prognosis, much of management is focused upon palliation and symptom management, and the decision to treat a patient with more aggressive maneuvers must always take into account the impact upon a patient's quality of life. In addition, majority of the patients with advanced pancreatic cancer are elderly. Oncologists are challenged to make tough treatment decisions. Many elderly patients cannot tolerate side effects of chemotherapy, especially the combination regimens. Despite that many patients continue to receive chemotherapy even in the last month of their lives. The effect of referral to palliative care on health-related outcome especially for patients with poor quality of life is still not very clear. The authors will review abstracts that have focused on these fields that were presented at the Annual Meeting of ASCO 2013 (Abstracts #4009, #4053, #6607, #9518, #9538, #9539, #9546, and #9638)."
407,"Tissue transglutaminase, inflammation, and cancer: how intimate is the relationship?","Kumar S, Mehta K.",https://pubmed.ncbi.nlm.nih.gov/22083892/,"Despite significant advances in surgery and biology, cancer remains a major health problem. It is now well accepted that metastasis and cancer cells' acquired or inherent resistance to conventional therapies are major roadblocks to successful treatment. Chronic inflammation is an important driving force that provides a favorable platform for cancer's progression and development and suggests a link between inflammation and metastatic transformation. However, how chronic inflammation contributes to metastatic cell transformation is not well understood. According to the current theory of cancer progression, a small subpopulation of cancer stem cells (CSCs) in tumors is responsible for their metastasis, resistance, and sustenance. Whether CSCs originate from normal stem cells or from dedifferentiation of terminally differentiated cells remains unknown. Recent evidence indicates that stem cells are not unique; malignant or nonmalignant cells can reprogram and de-differentiate to acquire a stemness phenotype. Thus, phenotypic plasticity may exist between stem cells and non-stem cells, and a dynamic equilibrium may exist between the two phenotypes. Moreover, this equilibrium may shift in one direction or another on the basis of contextual signals in the microenvironment that influence the interconversion between stem and non-stem cell compartments. Whether the inflammatory microenvironment influences this interconversion and shifts the dynamic equilibrium towards stem cell compartments remains unknown. We recently found that aberrant tissue transglutaminase (TG2) expression induces the mesenchymal transition (EMT) and stem cell characteristics in epithelial cells. This finding, in conjunction with the observation that inflammatory signals (e.g., TGFβ, TNFα, and NF-κB) which induce EMT, also induce TG2 expression, suggests a possible link between TG2, inflammation, and cancer progression. In this review, we summarize TG2-driven processes in inflammation and their implications in cancer progression."
408,In silico and In vitro Investigation of a Likely Pathway for Anti-Cancerous Effect of Thrombocidin-1 as a Novel Anticancer Peptide.,"Tanhaian A, Mohammadi E, Vakili-Ghartavol R, Saberi MR, Mirzayi M, Jaafari MR.",https://pubmed.ncbi.nlm.nih.gov/32072885/,"the anti-cancerous feature of this peptide is still uncovered.
    


          
    


           In addition, the coding sequence of TC-1+6xhistidine (rTC-1) was inserted into the pET22b(+) vector and cloned and expressed by E. coli BL21 and finally purified through nickel affinity column. Afterward, the retrieved rTC-1 was used in MTT assay against mouse colon adenocarcinoma, hepatocellular carcinoma, chondrosarcoma, mouse melanoma, and breast adenocarcinoma cell lines to investigate its probable anticancer application.
    


           Besides, the stability of the rTC-1_CXCR11-38 complex was shown during 100ns MD simulation. In addition, the successful expression and purification of rTC-1 depict an 8kD peptide. The IC50 
    


          Conclusion:
        
      
      Therefore, apart from probable anti-cancerous effect of rTC-1 on C26-A and SW1353 cell lines, this peptide may be able to mimic the anti-cancerous pathway of IL-8."
409,Cancer's sweet tooth.,"Bui T, Thompson CB.",https://pubmed.ncbi.nlm.nih.gov/16766260/,"Even in the presence of an adequate oxygen supply, many tumors metabolize the majority of the glucose they take up through glycolysis. It has been a long-held belief that this glycolytic phenotype is due to cancer-specific defects in mitochondrial oxidative phosphorylation. In this issue of Cancer Cell, Fantin et al. now report that most tumor cells have a substantial reserve capacity to produce ATP by oxidative phosphorylation when glycolysis is suppressed. These new data add to mounting evidence that the high rate of glycolysis exhibited by most tumors is required to support cell growth rather than to compensate for defect(s) in mitochondrial function."
410,Retinoids as chemoprevention for head and neck cancer: where do we go from here?,"Smith W, Saba N.",https://pubmed.ncbi.nlm.nih.gov/15886010/,"The retinoids, natural and synthetic derivatives of vitamin A, have a promising role in the chemoprevention of head and neck squamous cell carcinoma despite facing the limitations of toxicity as well as innate and acquired resistance. Adhering to the concept of field cancerization and following multi-step carcinogenesis, premalignant lesions of the head and neck have long been the focus of intervention with retinoids. Similarly, these agents have been applied towards preventing second primary malignancies from developing following curative therapy for upper aerodigestive cancers. Despite encouraging response rates, the need for overcoming innate and acquired retinoid resistance as well as minimizing retinoid-related toxicity will likely be relegated to the new generation of receptor-selective, synthetic retinoids. In the interim, retinoid-non-retinoid combinations as well as other classes of chemopreventive agents seem to provide promise in curtailing the incidence of aerodigestive malignancies."
411,Hypoxia-induced genetic instability--a calculated mechanism underlying tumor progression.,"Huang LE, Bindra RS, Glazer PM, Harris AL.",https://pubmed.ncbi.nlm.nih.gov/17180667/,"The cause of human cancers is imputed to the genetic alterations at nucleotide and chromosomal levels of ill-fated cells. It has long been recognized that genetic instability-the hallmark of human cancers-is responsible for the cellular changes that confer progressive transformation on cancerous cells. How cancer cells acquire genetic instability, however, is unclear. We propose that tumor development is a  In this article, we review the recent literature regarding how hypoxia functionally impairs various DNA repair pathways "
412,Financial Burden and Employment Support for Patients with Cancer in Japan: A Review.,Onishi K.,https://pubmed.ncbi.nlm.nih.gov/30226962/,"Aim and 
    


           Over 80% of patients with cancer wished to remain employed (nearly 70% among patients who had resigned following incidence of cancer) in order to maintain their households and quality of life and cover cancer treatment costs. Approximately half of the Japanese companies surveyed did not grasp the employees' cancer incidence, considering it to be a private injury. Additionally, 74% of companies had not recorded one month or more of absences due to cancer- related sickness. Nonetheless, among large companies, around 70% of regular employees with cancer were able to return to work (RTW) within one year of the start of cancer-related sickness absence (81% returned working shorter hours; 62% returned to full-time work).
    


          Conclusions:
        
      
      A year of sickness absence and shorter working hours enables employees with cancer to RTW. Employment continuation support should principally promote RTW from the initial announcement of cancer. The author proposes a modified health promotion management strategy that aims to ensure a safe RTW through employers' systematic initiatives and with employees' collaborative effort to improve wellness in the corporate community. Collaboration between hospitals, companies' industrial medical staff, and company staff will facilitate RTW. Policy aimed at reducing hospital stays requires that ambulatory nurses in hospitals plan long-term individual nursing care and provide high-quality nursing care tailored to the various needs of patients, according to the Information Prescription. However, this service's medical fee valuation is low. Improving ambulatory nursing therefore requires increasing this fee."
413,Polarized Micro-Raman Spectroscopy and 2D Convolutional Neural Network Applied to Structural Analysis and Discrimination of Breast Cancer.,"Shang L, Tang J, Wu J, Shang H, Huang X, Bao Y, Xu Z, Wang H, Yin J.",https://pubmed.ncbi.nlm.nih.gov/36671896/,"Raman spectroscopy has been efficiently used to recognize breast cancer tissue by detecting the characteristic changes in tissue composition in cancerization. In addition to chemical composition, the change in bio-structure may be easily obtained via polarized micro-Raman spectroscopy, aiding in identifying the cancerization process and diagnosis. In this study, a polarized Raman spectral technique is employed to obtain rich structural features and, combined with deep learning technology, to achieve discrimination of breast cancer tissue. The  Optical anisotropy of collagen fibers weakens in cancer tissue, which is closely related with the tumor's progression. To distinguish breast cancer tissue, a discrimination model is established based on a two-dimensional convolutional neural network (2D-CNN), where the input is a matrix containing the Raman spectra acquired at a set of linear polarization angles varying from 0° to 360°. As a 01% for test samples is achieved, better than that of the KNN classifier and 1D-CNN that are based on non-polarized Raman spectra. This study implies that polarized Raman spectroscopy combined with 2D-CNN can effectively detect changes in the structure and components of tissues, innovatively improving the identification and automatic diagnosis of breast cancer with label-free probing and analysis."
414,Early epigenetic cancer decisions.,"Martín-Lorenzo A, Gonzalez-Herrero I, Rodríguez-Hernández G, García-Ramírez I, Vicente-Dueñas C, Sánchez-García I.",https://pubmed.ncbi.nlm.nih.gov/25205718/,"Abstract A cancer dogma states that inactivation of oncogene(s) can cause cancer remission, implying that oncogenes are the Achilles' heel of cancers. This current model of cancer has kept oncogenes firmly in focus as therapeutic targets and is in agreement with the fact that in human cancers all cancerous cells, with independence of the cellular heterogeneity existing within the tumour, carry the same oncogenic genetic lesions. However, recent studies of the interactions between an oncogene and its target cell have shown that oncogenes contribute to cancer development via developmental reprogramming of the epigenome within the target cell. These  Here we analyse these evidences and discuss how this vision offers new avenues for developing novel anti-cancer interventions."
415,Immune biomarkers for chronic inflammation related complications in non-cancerous and cancerous diseases.,"Meirow Y, Baniyash M.",https://pubmed.ncbi.nlm.nih.gov/28674756/,"Chronic inflammation arising in a diverse range of non-cancerous and cancerous diseases, dysregulates immunity and exposes patients to a variety of complications. These include immunosuppression, tissue damage, cardiovascular diseases and more. In cancer, chronic inflammation and related immunosuppression can directly support tumor growth and dramatically reduce the efficacies of traditional treatments, as well as novel immune-based therapies, which require a functional immune system. Nowadays, none of the immune biomarkers, regularly used by clinicians can sense a developing chronic inflammation, thus complications can only be detected upon their appearance. This review focuses on the necessity for such immune status biomarkers, which could predict complications prior to their appearance. Herein we bring examples for the use of cellular and molecular biomarkers in diagnosis, prognosis and follow-up of patients suffering from various cancers, for prediction of response to immune-based anti-cancer therapy and for prediction of cardiovascular disease in type 2 diabetes patients. Monitoring such biomarkers is expected to have a major clinical impact in addition to unraveling of the entangled complexity underlying dysregulated immunity in chronic inflammation. Thus, newly discovered biomarkers and those that are under investigation are projected to open a new era towards combating the silent damage induced by chronic inflammation."
416,"From skid row to Main Street: the Bowery series and the transformation of prostate cancer, 1951-1966.",Aronowitz R.,https://pubmed.ncbi.nlm.nih.gov/24976163/,"Between 1951 and 1966, more than twelve hundred homeless, alcoholic men from New York's skid row were subjected to invasive medical procedures, including open perineal biopsy of the prostate gland. If positive for cancer, men typically underwent prostatectomy, surgical castration, and estrogen treatments. The Bowery series was meant to answer important questions about prostate cancer's diagnosis, natural history, prevention, and treatment. While the Bowery series had little ultimate impact on practice, in part due to ethical problems, its means and goals were prescient. In the ensuing decades, technological tinkering catalyzed the transformation of prostate cancer attitudes and interventions in directions that the Bowery series' promoters had anticipated. These largely forgotten set of practices are a window into how we have come to believe that the screen and radical treatment paradigm in prostate cancer is efficacious and the underlying logic of the twentieth-century American quest to control cancer and our fears of cancer."
417,Scientific basis for cancer prevention. Intermediate cancer markers.,"Mulshine JL, Jett M, Cuttitta F, Treston AM, Quinn K, Scott F, Iwai N, Avis I, Linnoila RI, Shaw GL.",https://pubmed.ncbi.nlm.nih.gov/8334673/,"Promising cancer clinical trials  Key to the efficient progress in this field is a clear understanding of the complex biology of the early stages of cancerization that proceed on the epithelial surface. Systematic analysis of the biology of strategic targets such as growth factors is one approach to this problem. Gastrin-releasing peptide is an autocrine growth factor for certain types of lung cancer cells. Mechanisms involved in the production and activation of this peptide are discussed as an example of how rational approaches to neutralization of cancer promotion biology can be achieved. The tools to monitor the success of this type of intervention also emerge from the understanding of the biology of growth factors, and intermediate end point markers that determine the presence or effects of a growth factor are attractive candidates for evaluation. Additional biologic tools reflecting the early stages of the cancer process need to be validated for use in serially evaluating the status of the relevant epithelium so that the ongoing success of a cancer intervention procedure can be established. Through this type of translational research, important applications of molecular biology may greatly improve the success of preventative strategies for cancer control."
418,The impact and outcomes of cancer-macrophage fusion.,"Li M, Basile JR, Mallya S, Lin YL.",https://pubmed.ncbi.nlm.nih.gov/37264310/," Although genetic mutations and epigenetic changes have been implicated, they don't fully explain the leukocytic traits that many cancers develop. Cell fusion between cancer and somatic cells, particularly macrophages, has been suggested as an alternative pathway for cancer cells to obtain new traits by acquiring exogenous genetic material.
    


           Two clones with markedly different tumorigenicity were selected, and RNA-seq was used to compare their RNA expressions with that of the control cells. Based on the 
    


           Notably, while one clone was highly tumorigenic, the other showed little tumorigenicity. Despite these differences, both hybrid clones were potent environmental modifiers, exhibiting significant abilities to recruit stromal and immune cells and establish angiogenesis.
    


          Conclusions:
        
      
      The study revealed that tumor-somatic cell fusion is a potent environmental modifier that can modulate tumor survival and evolution, despite its relatively low occurrence. These findings suggest that tumor-somatic cell fusion could be a promising target for developing new cancer therapies. Furthermore, this study provides an "
419,Mammary field cancerization: molecular evidence and clinical importance.,"Heaphy CM, Griffith JK, Bisoffi M.",https://pubmed.ncbi.nlm.nih.gov/19685287/,"The term ""field cancerization"" originally denoted the presence of histologically abnormal tissue/cells surrounding primary tumors of the head and neck. Similar concepts with different and continuously changing definitions have been used for other types of tumors including breast adenocarcinoma, where field cancerization presently denotes the occurrence of molecular alterations in histologically normal tissues surrounding areas of overt cancer. Human mammary tissue morphology lends itself to the proposed concepts of field cancerization, which may include the gradual accumulation of genetic and other aberrations in stationary epithelial cells with intact morphology, or the spread of histologically normal yet genetically aberrant epithelial cells within mammary tissue. In this report, we review published molecular genetic, epigenetic, and gene expressional data in support of field cancerization in human mammary tissues. We then discuss the clinical implications of mammary field cancerization, including its source for potential biomarkers with diagnostic/prognostic potential, and its relationship to surgical margins and disease recurrence. We conclude with a future outlook on further research on mammary field cancerization addressing "
420,[A case of bronchioloalveolar carcinoma diagnosed by a segmental resection].,"Umemori Y, Kotani K, Makihara S.",https://pubmed.ncbi.nlm.nih.gov/11889819/,"A 66-year-old man who underwent an extirpation of thymoma in stage I on September 16 1997 was followed in the outpatient clinic. In October 1998, a chest CT scan revealed a 2.0 x 1.0 cm faint frosted glass like shadow in the right S9. On September 13 1999, the patient was admitted to the hospital for close examination. Two times of transbronchial lung biopsy could not offer any clear diagnosis because the lesion was present so as to encircle the central segment of the B9 gronchus. A segmental resection (S9 + 10) under thoracotomy was performed. Intraoperative frozen section diagnosis was bronchioloalveolar carcinoma (type A according to Noguchi's classification), and a resection of the remnant lower lobe and mediastinal lymph nodes dissection (ND 2 a) were added. With expected increase in frequency of detecting early pulmonary cancer's through CT, clinical cases for which we are obliged to diagnosed the disease by segmental resection may increase, if the lesion develops in the vicinity of the hilum of lung like this case."
421,Current understanding of cancer stem cells: Review of their radiobiology and role in head and neck cancers.,"Reid PA, Wilson P, Li Y, Marcu LG, Bezak E.",https://pubmed.ncbi.nlm.nih.gov/28644558/,"Evidence of cancer cells that bear attributes analogous to those of normal stem cells has developed a hierarchical model of cancer's architecture and progression. This subset of cancer stem cells (CSCs) drives the progression and therapy resistance of cancers. Research to identify the phenotypes of these CSCs presents evidence of a subpopulation that is more resistant to therapy and may proliferate in response. Literature shows that CSCs typically represent around 1%-10% of cell populations in head and neck cancer but this proportion may increase in response to a therapeutic radiation dose. This is shown to be not just as a  The CSCs represent the apex of a hierarchy in the heterogeneity of cancer cells and may be seen as the agents of treatment failure, metastasis, and tumor recurrence, the principal cause of mortality in head and neck cancers. Greater than 90% of head and neck cancers are squamous cell carcinomas (HNSCCs), and among these an increasing incidence of the involvement of the human papillomavirus (HPV) is reported. Chemoradiotherapy along with surgical resection are the interventions of choice for control and cure of HNSCC, but given CSCs therapy resistance and proliferative responses to radiation, the identification and understanding of the radiobiology of this subpopulation is critical to their targeted elimination. This article reviews the current evidence on CSC generally and in HNSCC specifically to identify their phenotype, evaluate their responses to radiotherapy, and evaluate the defensive mechanisms used to resist therapeutic control."
422,Ductal carcinoma in situ develops within clonal fields of mutant cells in morphologically normal ducts.,"Hutten SJ, Messal HA, Lips EH, Sheinman M, Ciwinska M, Braams E, van der Borden C, Kristel P, Stoffers S, Wessels LF; Grand Challenge PRECISION Consortium; Jonkers J, van Rheenen J, Wesseling J, Scheele CL.",https://pubmed.ncbi.nlm.nih.gov/38779852/,"Mutations are abundantly present in tissues of healthy individuals, including the breast epithelium. Yet it remains unknown whether mutant cells directly induce lesion formation or first spread, leading to a field of mutant cells that is predisposed towards lesion formation. To study the clonal and spatial relationships between morphologically normal breast epithelium adjacent to pre-cancerous lesions, we developed a three-dimensional (3D) imaging pipeline combined with spatially resolved genomics on archival, formalin-fixed breast tissue with the non-obligate breast cancer precursor ductal carcinoma in situ (DCIS). Using this 3D image-guided characterization  We show that the local heterogeneity within a DCIS lesion is limited. However, by mapping the CNA profiles back onto the 3D reconstructed ductal subtree, we find that in eight out of 16 cases the healthy epithelium adjacent to the DCIS lesions has overlapping structural variations with the CNA profile of the DCIS. Together, our study indicates that pre-malignant breast transformations frequently develop within mutant clonal fields of morphologically normal-looking ducts. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland."
423,Cancer--an ayurvedic perspective.,"Balachandran P, Govindarajan R.",https://pubmed.ncbi.nlm.nih.gov/15519531/,"An integrated approach is needed to manage cancer using the growing body of knowledge gained through scientific developments. Thousands of herbal and traditional compounds are being screened worldwide to validate their use as anti-cancerous drugs. The science of Ayurveda is supposed to add a step on to the curative aspects of cancers that have resemblance with clinical entities of arbuda and granthi mentioned in Sushrutha samhita. Hence, an attempt is made in this review to discuss about the pathology and therapeutic management of various cancers described in Ayurveda. Review of literature on anticancer drugs of plant origin revealed identification of newer ayurvedic drugs that are not mentioned in the ancient texts. These new findings add up to ayurvedic science that has been developed through ages. In addition, details of "
424,[A case of adult intussusception in the transverse colon with an advanced ileal Peutz-Jeghers type polyp associated with cancer].,"Matsui T, Oryu M, Kobara H, Komatsu A, Chiyo T, Kobayashi N, Fujihara S, Nishiyama N, Yachida T, Masaki T.",https://pubmed.ncbi.nlm.nih.gov/34629346/,"A man in his thirties was admitted to the hospital because of upper abdominal pain. Computed tomography showed intussusception in the ascending and transverse colon. After spontaneous discontinuation, endoscopy revealed a 25-mm 0-I tumor in the ileum. An emergency operation was performed the next day due to intussusception recurrence. The tumor was hyperplastic intestinal epithelium with dendritic smooth muscle fascicles and partly cancerous. The patient had no clinical features of Peutz-Jeghers syndrome. Therefore, the patient was diagnosed with Peutz-Jeghers type polyps based on pathological findings. This case is considered to be a rare case of intussusception in the transverse colon due to Peutz-Jeghers type polyp with canceration."
425,Non-invasive scoring of cellular atypia in keratinocyte cancers in 3D LC-OCT images using Deep Learning.,"Fischman S, Pérez-Anker J, Tognetti L, Di Naro A, Suppa M, Cinotti E, Viel T, Monnier J, Rubegni P, Del Marmol V, Malvehy J, Puig S, Dubois A, Perrot JL.",https://pubmed.ncbi.nlm.nih.gov/35013485/,"Diagnosis based on histopathology for skin cancer detection is today's gold standard and relies on the presence or absence of biomarkers and cellular atypia. However it suffers drawbacks: it requires a strong expertise and is time-consuming. Moreover the notion of atypia or dysplasia of the visible cells used for diagnosis is very subjective, with poor inter-rater agreement reported in the literature. Lastly, histology requires a biopsy which is an invasive procedure and only captures a small sample of the lesion, which is insufficient in the context of large fields of cancerization. Here we demonstrate that the notion of cellular atypia can be  A Deep Learning (DL) algorithm is trained to segment keratinocyte (KC) nuclei from Line-field Confocal Optical Coherence Tomography (LC-OCT) 3D images. Based on these segmentations, a series of quantitative, reproducible and biologically relevant metrics is derived to describe KC nuclei individually. We show that, using those metrics, simple and more complex definitions of atypia can be derived to discriminate between healthy and pathological skins, achieving Area Under the ROC Curve (AUC) scores superior than 0.965, largely outperforming medical experts on the same task with an AUC of 0.766. All together, our approach and findings open the door to a precise quantitative monitoring of skin lesions and treatments, offering a promising non-invasive tool for clinical studies to demonstrate the effects of a treatment and for clinicians to assess the severity of a lesion and follow the evolution of pre-cancerous lesions over time."
426,Distribution of epithelial dysplasia in the cancerous esophagus.,"Ohta H, Nakazawa S, Segawa K, Yoshino J.",https://pubmed.ncbi.nlm.nih.gov/3726448/,"A total of 114 cases, consisting of 20 non-cancerous esophagi, 48 non-irradiated cancerous esophagi, and 46 irradiated cancerous esophagi, were investigated with semiserial sections to evaluate the role of epithelial dysplasia as a precursor of esophageal cancer. The incidence of dysplasia was higher in cancerous esophagi than in non-cancerous esophagi and in non-irradiated cancerous esophagi than in irradiated cancerous esophagi. The difference in distribution pattern of dysplasia made it possible to classify the esophagi into three types: extensive, multifocal, and scanty. In the extensive type the main tumor tended to have an ill-defined margin and large diameter. In the multifocal type it tended to be superficial and small, and in the scanty type it usually had a well-defined margin. A possible relationship of epithelial dysplasia to the origin of esophageal cancer and its growth was shown by at least two thirds of the esophageal cancers."
427,Tumor registry audit of mammography in community practice.,"Moseson D, Meharg K.",https://pubmed.ncbi.nlm.nih.gov/8185037/,"The 395 analytic breast cancers logged into a community hospital tumor registry from 1988 to 1992 included information as to (1) the mode of detection and (2) the time interval since prior mammography. Mammography alone detected 44% of the cancers in women under 50 years of age and 47% of the cancers in women over 50 years of age. The American Joint Committee on Cancer's 1988 ""Manual for Staging of Cancer"" TNM staging of mammographically detected cancers in both age groups was similar, ie, there were 89% stage 0/1 in women aged under 50 and 86% in women over age 50. Twenty-one percent of the mammographically detected cancers were in women under age 50, whereas a disproportionate 36% of the ""interval cancers"" occurred in this group. A ratio of the number of mammographically detected cancers to the number of interval cancers was 5.8 in women over age 50 and 2.7 in women under age 50. This ratio fell to 1.7 when the time interval following prior mammography was 2 years. Correctable errors accounted for 21% of the interval cancers."
428,"Overview: cellular plasticity, cancer stem cells and metastasis.","Elshamy WM, Duhé RJ.",https://pubmed.ncbi.nlm.nih.gov/23796691/,"Recently, a number of hypotheses have converged into a unified theoretical framework which addresses the most vexing aspects of cancer: metastasis, relapse and therapeutic resistance. The central component of this framework is the new paradigm of cellular differentiation, once viewed as a unidirectional process, but now recognized as a plastic process in which cancer cells can dedifferentiate into more primitive, stem-like phenotypes. This plasticity is controlled by both intrinsic biochemical processes and bi-directional environmental cues involving cancer-associated non-cancerous cells. Such plastic phenotypic shifts may influence the discontinuous behavior of cancers, in which some cancers remain dormant for months or years after therapy, only to relapse and wreak havoc. This Special Issue of Cancer Letters assembles a collection of mini-reviews describing the current knowledge of cellular plasticity and its relationship to cancer ""stemness"" and progression, illuminating how progress in this field may yield major benefits in overcoming resistance and thwarting metastasis."
429,[Clinicopathological study of early cancer-like advanced gastric cancer].,"Tei H, Shimoda T, Ikegami M, Ohshiba S.",https://pubmed.ncbi.nlm.nih.gov/2384981/,"We had clinicopathologically studied early cancer-like advanced gastric cancer in relation to peptic ulcer (UI). Early cancer-like advanced cancers with the difficulty to distinguish from early gastric cancer were selected for materials. 2%) had peptic ulcer in cancerous lesion (73 lesions were active stage and 55 lesions were scarring stage). 2) Early cancer-like advanced cancers were 17.0% in all advanced gastric cancers. Proper muscle cancer (in which depth of cancerous invasion is up to proper muscle coat) was more common in early cancer-like advanced cancers than in Borrmann type advanced cancers. 3) Early cancer-like advanced cancers with peptic ulcer showed wide intramucosal cancerous infiltration. Thus, average of maximum diameter was 51.8 mm. 4) Those ulcer were commonly reaching to proper muscle coat or subserosa. Submucosal fibrosis was prominent and scattered proliferation of tumor cells were often seen within fibrosis. 5) Extent of cancerous infiltration in mucosa was more wide than that in submucosa. The above findings have led us to consider that early cancer-like advanced cancers have grown because of high degree submucosal fibrosis by the deep ulcerations due to ""malignant cycle""."
430,"Anatomical, Physiological, and Molecular Imaging for Pancreatic Cancer: Current Clinical Use and Future Implications.","Chang J, Schomer D, Dragovich T.",https://pubmed.ncbi.nlm.nih.gov/26146615/,"Pancreatic adenocarcinoma is one of the deadliest human malignancies. Early detection is difficult and effective treatment is limited. Verifying the presence of micrometastatic dissemination and vessel invasion remains elusive, limiting radiological staging once this diagnosis is made. Diagnostic imaging provides independent tools to evaluate and characterize the biologic behavior of pancreatic cancer. Conventional anatomic imaging alone with either CT or MRI yields useful information on organ involvement but is limited in providing molecular and physiological information. Molecular imaging techniques such as PET or MRS provide information on metabolic and signaling pathways. Advanced MR sequences that target physiological parameters expand imaging options to characterize these tumors. By considering the parametric data from these three imaging approaches (anatomic, molecular, and physiological) we can better define specific tumor signatures. Such parametric characterization can provide insight into tumor metabolism, cellular density, protein expression, focal perfusion, and vascular permeability of these tumors. Radiogenomics research has already demonstrated ability to obtain information about cancer's genotype and phenotype; this is without invasive procedures or surgery. Further advances in these areas of "
431,Recent advances in osteosarcoma.,"Botter SM, Neri D, Fuchs B.",https://pubmed.ncbi.nlm.nih.gov/24632219/,"Although osteosarcoma (OS) is a rare malignancy, it is ranked among the leading causes of cancer-related death in the pediatric age group. The cancer's low prevalence and its large tumor heterogeneity make it difficult to obtain meaningful progress in patient survival. In this review we present an overview of current clinical trials which largely focus on stimulation of the immune system or rely on the inhibition of kinases such as Src and mTOR. The potential efficacy of tumor-targeted TNFalpha is discussed, as well as the importance of preclinical validation of new targets. To improve the success of future clinical trials, clinicians and basic researchers need to intensify their exchange. Finally, a case is made for individualized treatment of OS patients, based on interdisciplinary cooperation in dedicated Sarcoma Centers."
432,[Compressive dyspnea and dysphagia caused by sclerous cervical cutaneous metastasis disclosing breast carcinoma].,"Audeguy P, Leclech C, Lortholary A, Mège M, Berrut G, Croué A, Fressinaud P.",https://pubmed.ncbi.nlm.nih.gov/9686057/," They usually appear as cutaneous thoracic nodules. We report the case of a cutaneous sclerous metastasis from breast carcinoma revealed by acute compressive dyspnea and dysphagia.
    


          Case report:
        
      
      A 65 years old woman was admitted for compressive acute dyspnea and dysphagia attributed to the growth of a sclerous cervical isolated metastasis. Investigations revealed rapidly growing low-differentiated primitive breast carcinoma. Chemotherapy induced good clinical response allowing a 27 months survival, in spite of a strong chemodependance.
    


          Discussion:
        
      
      This case-report of a breast carcinoma's metastasis is notable because of its clinical revealing signs (acute compressive dyspnea and dysphagia), clinical aspect, cervical location preceding primitive cancer's clinical expression, and long term survival with treatment. The initial submaxillary location suggest the possibility of a metastasis to submaxillary salivary glands with secondary extension to the skin."
433,Expression profile of class I histone deacetylases in human cancer tissues.,"Nakagawa M, Oda Y, Eguchi T, Aishima S, Yao T, Hosoi F, Basaki Y, Ono M, Kuwano M, Tanaka M, Tsuneyoshi M.",https://pubmed.ncbi.nlm.nih.gov/17786334/,"Histone deacetylase (HDAC) activity is one of the widely used and well-established mechanisms for regulation of various genes in cancer. To identify which subtype of class I HDACs are overexpressed in cancers, we analyzed the expression of class I HDAC isotypes composed of HDAC1, 2, 3 and 8 in several cell lines and human cancer tissues, including cancer of the stomach, esophagus, colon, prostate, breast, ovary, lung, pancreas and thyroid. The  However, the immunoreactivity of HDAC8 in both prostatic cancer tissue and non-cancerous prostate glands was lower than that in other cancer tissues. Furthermore, 5-40% of cancer tissues overexpressed class I HDACs, when compared with normal epithelium. The "
434,Telomerase activity in gynecological tumors.,"Sakamoto M, Toyoizumi T, Kikuchi Y, Okamoto A, Nakayama H, Aoki D, Yamamoto K, Hata H, Sugishita T, Tenjin Y.",https://pubmed.ncbi.nlm.nih.gov/10948330/,"The aim of this study was to define the clinical implications of semi-quantitative telomerase activity in gynecological tumors by comparing the telomerase activity of cancerous lesion and the adjacent non-cancerous lesion. In 118 cases of gynecologic tumors, including 41 uterine cervical tumors, 43 uterine body tumors and 34 ovarian tumors, telomerase activities were determined using TRAPeze telomerase detection kit for the extension reaction of the telomere sequence and the PCR reaction for amplification of the sequence, and using fluorecence-based telomere repeat amplification protocol (F-TRAP)  In all gynecologic cancers examined, telomerase activity of the cancerous lesion was significantly higher than that of the non-cancerous lesion. Telomerase activity in the uterine cervix increased in the following order of the normal uterine cervix, cervical dysplasia and cervical cancer. Regarding the endometrial cancer, telomerase activity at the primary lesion in patients with lymph node metastases was significantly higher than that in patients without lymph node metastases. When telomerase activity was compared by histologic subtypes of the ovarian cancer, clear cell adenocarcinoma showed significantly lower telomerase activity than the other subtypes, especially endometrioid adenocarcinoma. In all gynecologic cancers examined, there was no clear correlation between the telomerase activity and age at diagnosis or age of menopause. Although all tumors with 100 units or more telomerase activity were cancerous, the sensitivity was 39% in cervical cancer, 41% in endometrial cancer and 21% in ovarian cancer, respectively. Cervical intraepithelial neoplasia (CIN) had already increased telomerase activity and endometrial cancer with lymph node metastases had also greater activity than that without lymph node metastases. Although telomerase activity in ovarian cancer tended to increase as stage advances, it is noteworthy that clear cell adenocarcinoma showed significantly lower telomerase activity than endometrioid adenocarcinoma."
435,"Molecular pathways: involvement of Helicobacter pylori-triggered inflammation in the formation of an epigenetic field defect, and its usefulness as cancer risk and exposure markers.","Ushijima T, Hattori N.",https://pubmed.ncbi.nlm.nih.gov/22205689/,"Infection-associated cancers account for a large proportion of human cancers, and gastric cancer, the vast majority of which is associated with Helicobacter pylori infection, is a typical example of such cancers. Epigenetic alterations are known to occur frequently in gastric cancers, and H. pylori infection has now been shown to induce aberrant DNA methylation in gastric mucosae. Accumulation of aberrant methylation in gastric mucosae produces a field for cancerization, and methylation levels correlate with gastric cancer risk. H. pylori infection induces methylation of specific genes, and such specificity is determined by the epigenetic status in normal cells, including the presence of H3K27me3 and RNA polymerase II (active or stalled). Specific types of inflammation, such as that induced by H. pylori infection, are important for methylation induction, and infiltration of monocytes appears to be involved. The presence of an epigenetic field defect is not limited to gastric cancers and is observed in various types of cancers. It provides translational opportunities for cancer risk diagnosis incorporating life history, assessment of past exposure to carcinogenic factors, and cancer prevention."
436,Gastric cancer exosomes contribute to the field cancerization of gastric epithelial cells surrounding gastric cancer.,"Yoon JH, Choi BJ, Nam SW, Park WS.",https://pubmed.ncbi.nlm.nih.gov/34993738/," We investigated whether exosomes derived from gastric cancer cells affected the fate of the surrounding gastric epithelial cells.
    


           pylori CagA. Cell proliferation and apoptosis were analyzed by BrdU incorporation, flow-cytometry, and colony formation assays. We examined telomere length, expression and activity of telomerase, and expression of telomere-related genes in PNSECs treated with cancer exosomes, and in 60 gastric cancer and corresponding mucosal tissues. The differentially expressed genes and transcriptional regulation of telomere-related genes were verified using real-time qPCR and ChIP analyses, respectively.
    


           The internalization of cancer exosomes in PNSECs dramatically increased the number of surviving colonies and induced a multilayer growth and invasion into the scaffold. Treatment of PNSECs with cancer exosomes markedly increased the expression and activity of telomerase and the T/S ratio and regulated the expression of the telomere-associated genes, heat-shock genes, and hedgehog genes. Compared to gastric mucosae, gastric cancer showed increased hTERT expression, which was positively correlated with telomere length. Interestingly, seven (46.7%) of 15 non-cancerous gastric mucosae demonstrated strong telomerase activity.
    


          Conclusion:
        
      
      These "
437,Effect of synthetic protease inhibitor on histologic changes and free radical activity in hamsters with pancreatic cancer.,"Manabe T, Asano N, Yoshimura T, Suwa H, Imamura T, Ohshio G.",https://pubmed.ncbi.nlm.nih.gov/8210989/,"To investigate the effects of synthetic trypsin inhibitors on pancreatic cancer, camostat (FOY-305) was administered orally to hamsters with  The effect of free radicals on carcinogenesis was examined by measuring the tissue levels of the scavengers superoxide dismutase (SOD) and glutathione peroxidase (GSX-Px), and pancreatic tissues were examined histologically. Cancers developed in all hamsters that survived 24 weeks in the DIPN group and the FOY group, but 80% of the cancers in the DIPN group were tubular adenocarcinomas, and 91% of those in the FOY group papillary adenocarcinomas. The SOD activity in the DIPN group was significantly lower in the cancerous area and the borderline region than in the non-cancerous region and normal tissue. SOD activity in the cancerous and borderline regions was higher in the FOY groups than in the DIPN group. GSH-Px levels in the borderline and non-cancerous regions were significantly higher in the FOY group than in the DIPN group. These "
438,International cooperation to fight cancer's late-stage presentation in low- and middle-income countries.,"Henke O, Qader AQ, Malle GL, Kuiate JR, Hennig L, Demeke T, Stroetmann C, Henke AA, Alaric TT, Rushanyan M, Enssle C, Bussmann H.",https://pubmed.ncbi.nlm.nih.gov/36646888/,"Cancer is becoming a massive public health burden in low- and middle-income countries (LMIC). 70% of all cancer deaths globally are attributed to LMIC while the incidence proportion is below 60%. The main reason for the higher mortality rate is ""late-stage presentation"" of patients with stage III or IV diseases when being diagnosed. Main reasons for this are limited (financial) resources, poor knowledge of health service provider about cancer, misbelieves and fear among patients as well as low health literacy rate. During the 1st International Conference on Hospital Partnerships, conducted by the German Agency for International Cooperation (GIZ), cancer specialists from seven LMIC and Germany discussed opportunities, challenges and solutions of the development of cancer services. Two days of in-depths discussion identified five topics to be playing a key role in the effort to reduce the cancer burden in LMIC: Health Policy & Financing, Barriers to Access, Capacity Building, Cancer Registries and Adapted Treatment Guidelines. By using mind-mapping technique, stakeholders, core topics, main and important topics were visualized and interconnections displayed. Many topics can be addressed through international cooperations but political willingness and commitment in the respective countries plays the crucial role. An essential contribution will be to assist policy makers in formulating and endorsing affordable and effective health policies. Another lesson learned from this workshop is the similarity of challenges among the participating representatives from different LMIC. The authors of this letter emphasize on the importance of building international long-term cooperations to advance oncology care on a global scale."
439,A Graph Convolution Network-Based Model for Prioritizing Personalized Cancer Driver Genes of Individual Patients.,"Peng W, Yu P, Dai W, Fu X, Liu L, Pan Y.",https://pubmed.ncbi.nlm.nih.gov/37195839/,"Cancer driver genes are mutated genes that play a key role in the growth of cancer cells. Accurately identifying the cancer driver genes helps us understand cancer's pathogenesis and develop effective treatment strategies. However, cancers are highly heterogeneous diseases; patients with the same cancer type may have different genomic characteristics and clinical symptoms. Hence, it is urgent to devise effective  This work presents a  NIGCNDriver first constructs a gene-sample association matrix using the associations between a sample and its known driver genes. Then, it employs graph convolution models on the gene-sample network to aggregate neighbor node features, and themself features, and then combines with the element-wise level interactions between neighbors to learn new feature representations for the samples and gene nodes. Finally, a linear correlation coefficient decoder is used to reconstruct the association between the sample and the mutant gene, enabling the prediction of a personalized driver gene for the individual sample. We applied the NIGCNDriver  The "
440,Detection of hTERT mRNA in gastrointestinal tract cancer specimens.,"Udomchaiprasertkul W, Narong S, Kongsema M, Leelawat K.",https://pubmed.ncbi.nlm.nih.gov/18564721/,"Human telomerase consisting of telomerase RNA template (hTR) and telomerase reverse transcriptase (hTERT) provides a mechanism for synthesis of telomere repeats that prolongs life span of cells. Telomerase activity is present in germ-line and malignant tumor cells but not in most normal human somatic cells. This study determined hTERT mRNA level in tissue samples from patients with gastrointestinal tract (GI) cancers. Tissue samples were obtained from 22 GI cancer patients, 3 gastrointestinal stomal tumors (GIST) and 25 corresponding non-cancerous tissues. hTERT expression was determined by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) using Taqman probe, hTERT mRNA was detected in 12 of 22 cancerous tissue samples. Six of 8 tissue samples obtained from patients with hepatocellular carcinoma and cholangiocarcinoma were positive for hTERT. However, hTERT mRNA was not detected in GIST and non-cancerous tissues. These "
441,[Initial changes in the development of gastric cancer].,"Yokoyama H, Nagayo T.",https://pubmed.ncbi.nlm.nih.gov/3712765/,"Among 123 cases of surgically resected stomachs bearing minute cancerous foci, which comprised 9.5% of all the early gastric cancers obtained, six cancerous foci with either intestinal type of diffuse-type histology showing the earliest changes of development were selected and the macroscopic and histological features of the foci were presented. Foci of the former type were found in the deepest layer of the gastric foveolae in severely metaplastic mucosa in a budding-like growth pattern and tended to enlarge the area toward the surface of the mucosa, which  On the other hand, lesions of the latter type were found in the neck zone of the mucosa with little or no intestinal metaplasia and spread laterally into the surrounding mucosa by infiltrative growth as groups of signet-ring type cancer cells, which "
442,Cancerous residue in breast-conserving surgery.,"Morimoto T, Okazaki K, Komaki K, Sasa M, Mori T, Tsuzuki H, Kamamura Y, Miki H, Monden Y.",https://pubmed.ncbi.nlm.nih.gov/8385722/,"Local tumor extension was studied using a continuous series of multiple blocks of mastectomy specimens to assess malignancy remaining after breast-conserving surgery for early-stage breast cancer. In this study, 183 cases were chosen, consisting of 6 noninvasive ductal carcinoma cases and 177 invasive ductal carcinoma cases. The histopathology in 59 (32%) of the 183 cases corresponded to that showing extensions of more than 2.6 cm from the tumor margin. These wide extensions were also seen in 17% of breast cancers with a tumor size of less than 2 cm. The incidence of wide extension was higher in younger patients with cases of noninvasive ductal carcinoma. Extension to the nipple-areola was seen in 14% of cases with a tumor size of less than 2 cm. Breast cancers with multicentric development accounted for 3% of those with a tumor size under 2 cm. These findings suggest that if lumpectomy is performed with a margin of 2 cm for tumors with a size of 2 cm or less, a cancerous residue would be found in the surgical margin of 15-20% of the cases. The actual incidence was 23% of cases after breast-conserving treatment in our study. On the basis of the data, breast-conserving treatment with only local resection of the primary lesion showed cancerous residue such as intraductal cancerous extension in about 20% of cases. Therefore, it was concluded that, as part of breast-conserving therapy of early-stage breast cancer, radiation therapy of the whole breast should be performed after surgery with clear margins to control local recurrence."
443,The emerging clinical relevance of genomics in cancer medicine.,"Berger MF, Mardis ER.",https://pubmed.ncbi.nlm.nih.gov/29599476/,"The combination of next-generation sequencing and advanced computational data analysis approaches has revolutionized our understanding of the genomic underpinnings of cancer development and progression. The coincident development of targeted small molecule and antibody-based therapies that target a cancer's genomic dependencies has fuelled the transition of genomic assays into clinical use in patients with cancer. Beyond the identification of individual targetable alterations, genomic  Emerging clinical applications of cancer genomics include monitoring treatment responses and characterizing mechanisms of resistance. The increasing relevance of genomics to clinical cancer care also highlights several considerable challenges, including the need to promote equal access to genomic testing."
444,Usefulness of esophagogastroduodenoscopy and (18)F-fluorodeoxyglucose positron-emission tomography in detecting synchronous multiple primary cancers with oral cancer.,"Ishibashi-Kanno N, Yamagata K, Uchida F, Hasegawa S, Yanagawa T, Bukawa H.",https://pubmed.ncbi.nlm.nih.gov/28856516/,"Purpose:
        
      
      The purpose of this study is to compare the value of screening for synchronous multiple primary cancers in other organs by esophagogastroduodenoscopy (EGD) or 18F-fluorodeoxyglucose positron-emission tomography (PET-CT) in patients newly diagnosed with oral cancer.
    


           The study included 190 patients (106 males and 84 females) from 36 to 93 years of age (median age 68.8 years). The patients were screened by EGD, PET-CT, or both before beginning treatment for OSCC.
    


           The sites of the 17 multiple primary cancers were gastric (6), esophageal (4), and lung (3), and ovarian, colon, liver, and thyroid (1 each). All of the gastric and esophageal cancers were found by EGD and were not detected by PET-CT. For three patients, the detection of multiple cancers affected the treatment modality or order of treatment selected for the OSCC. In two cases, the oral cancer and multiple primary cancer(s) in another organ were resected simultaneously by joint surgical teams.
    


          Conclusions:
        
      
      PET-CT for oral cancer patients is an effective supporting diagnostic tool. However, the ability of PET-CT has some limitations. Especially for early detection of the upper gastrointestinal cancers, it is necessary to be supplemented by EGD."
445,Psychiatric considerations in the oncology setting.,"Mehta RD, Roth AJ.",https://pubmed.ncbi.nlm.nih.gov/26012508/,"An aging population and advances in diagnostics and treatment have  People live longer after a cancer diagnosis and tolerate more aggressive treatments than in the past. Younger patients struggle with diversions from the normal developmental milestones in career and relationships, while older patients deal with the dual challenges of aging and cancer. Cancer's transition from likely death to survival has increased interest in its impact on psychosocial issues and quality of life, rather than just longevity. In this article, the authors review the psychiatric diagnosis and management of the mental health issues most often encountered in oncology. Oncology treatment teams, including oncologists, nurses, social workers, and other ancillary staff, are often on the front lines of addressing psychiatric distress and clinical syndromes when psychiatrists are not easily available. The purpose of this review article is to highlight opportunities for nonpsychiatrists to improve identification and treatment of psychosocial distress and psychiatric syndromes and to request formal psychiatric consultation in appropriate situations. Psychotherapeutic, psychopharmacologic, cognitive, and behavioral-oriented interventions, as well as supportive interventions, are discussed for treating patients who are facing challenges during active cancer treatment, survivorship, and at the end of life. This review is not exhaustive but highlights the more common psychosomatic medicine and palliative care scenarios that impact cancer patient care. The importance of recognizing and addressing burnout and compassion fatigue in multidisciplinary professionals who care for those treated for cancer is also discussed given the secondary impact this can have on patient care."
446,Potential therapeutic applications of microRNAs in cancer diagnosis and treatment: Sharpening a double-edged sword?,"Abdel Rhman M, Pmo O.",https://pubmed.ncbi.nlm.nih.gov/35981607/,"Cancer is a leading cause of increased morbidity and mortality worldwide despite advancements in diagnosis and treatment. Lack of early detection and diagnosis of different cancers and adverse effects and toxicity associated with conventional cancer treatments, such as chemotherapy and radiation, remains a problem. MicroRNAs can act as oncogenes or tumour suppressors in different types of cancers. Their distinct gene expression in various stages and types of cancerous cells make them attractive targets for cancer diagnosis and therapy. The growing research and clinical interests in gene therapy and nano-drug delivery systems have led to the development of potential miRNA-targeted treatments encompassing miRNA mimics, antagonists, and their use in cancer chemotherapy sensitization. In this review, we discuss the recent advancements in understanding the role of miRNAs in cancer development and their potential use as biomarkers in clinical diagnostics and as targets in chemotherapy of cancer."
447,"Pathological characteristics of gastric cancer that develop hematogenous recurrence, with special reference to the site of recurrence.","Koga S, Takebayashi M, Kaibara N, Nishidoi H, Kimura O, Kawasumi H, Makino M.",https://pubmed.ncbi.nlm.nih.gov/3695528/,"The pathologic characteristics of gastric cancer in 57 patients with hematogenous recurrence were pathologically analyzed by the site of recurrence. In recurrence of gastric cancer that developed in the liver, macroscopic observation revealed that cancers of Borrmann type 2 and 3 were most frequent. Microscopic examination revealed that the rate of occurrence of the medullary type of differentiated or poorly differentiated adenocarcinoma were high and that there were relatively frequent invasion by cancerous cells of the blood vessel that were closely related to the hematogenous metastasis. On the other hand, with respect to recurrence of gastric cancer that had developed in the lung or bone, Borrmann type 3 and 4, respectively, were more frequently observed. In these cases, microscopic analysis revealed that these cancers were poorly differentiated adenocarcinomas. In gastric cancer with bone recurrence, the rate of recurrence of the scirrhous type of tumor were higher than that of other types. It is important, for the management of patients after gastric cancer surgery, to predict possible hematogenous recurrence and its site by evaluation of the pathologic characteristics of the gastric cancer."
448,Arginine dependence of tumor cells: targeting a chink in cancer's armor.,"Patil MD, Bhaumik J, Babykutty S, Banerjee UC, Fukumura D.",https://pubmed.ncbi.nlm.nih.gov/27109103/,"Arginine, one among the 20 most common natural amino acids, has a pivotal role in cellular physiology as it is being involved in numerous cellular metabolic and signaling pathways. Dependence on arginine is diverse for both tumor and normal cells. Because of decreased expression of argininosuccinate synthetase and/or ornithine transcarbamoylase, several types of tumor are auxotrophic for arginine. Deprivation of arginine exploits a significant vulnerability of these tumor cells and leads to their rapid demise. Hence, enzyme-mediated arginine depletion is a potential strategy for the selective destruction of tumor cells. Arginase, arginine deiminase and arginine decarboxylase are potential enzymes that may be used for arginine deprivation therapy. These arginine catabolizing enzymes not only reduce tumor growth but also make them susceptible to concomitantly administered anti-cancer therapeutics. Most of these enzymes are currently under clinical investigations and if successful will potentially be advanced as anti-cancer modalities."
449,Global Cancer Incidence and Mortality Rates and Trends--An Update.,"Torre LA, Siegel RL, Ward EM, Jemal A.",https://pubmed.ncbi.nlm.nih.gov/26667886/,"There are limited published data on recent cancer incidence and mortality trends worldwide. We used the International Agency for Research on Cancer's CANCERMondial clearinghouse to present age-standardized cancer incidence and death rates for 2003-2007. We also present trends in incidence through 2007 and mortality through 2012 for select countries from five continents. High-income countries (HIC) continue to have the highest incidence rates for all sites, as well as for lung, colorectal, breast, and prostate cancer, although some low- and middle-income countries (LMIC) now count among those with the highest rates. Mortality rates from these cancers are declining in many HICs while they are increasing in LMICs. LMICs have the highest rates of stomach, liver, esophageal, and cervical cancer. Although rates remain high in HICs, they are plateauing or decreasing for the most common cancers due to decreases in known risk factors, screening and early detection, and improved treatment (mortality only). In contrast, rates in several LMICs are increasing for these cancers due to increases in smoking, excess body weight, and physical inactivity. LMICs also have a disproportionate burden of infection-related cancers. Applied cancer control measures are needed to reduce rates in HICs and arrest the growing burden in LMICs."
450,"Spatial epidemiology of cancer: a review of data sources, methods and risk factors.","Roquette R, Painho M, Nunes B.",https://pubmed.ncbi.nlm.nih.gov/28555468/,"Cancer is a major concern among chronic diseases today. Spatial epidemiology plays a relevant role in this matter and we present here a review of this subject, including a discussion of the literature in terms of the level of geographic data aggregation, risk factors and  For this purpose, we performed a websearch in the Pubmed and Web of Science databases including studies published between 1979 and 2015. We found 180 papers from 63 journals and noted that spatial epidemiology of cancer has been addressed with more emphasis during the last decade with research based on data mostly extracted from cancer registries and official mortality statistics. In general, the research questions present in the reviewed papers can be classified into three different sets: i) analysis of spatial distribution of cancer and/or its temporal evolution; ii) risk factors; iii) development of data analysis  This review is expected to help promote research in this area through the identification of relevant knowledge gaps. Cancer's spatial epidemiology represents an important concern, mainly for public health policies design aimed to minimise the impact of chronic disease in specific populations."
451,Role of major lifetime stressors in patients' and spouses' reactions to cancer.,"Silver-Aylaian M, Cohen LH.",https://pubmed.ncbi.nlm.nih.gov/11469165/,"This study examined the role of number of major lifetime stressors (e.g., rape, abuse), and the perceived resolution of those stressors, in cancer patients' (n = 54) and spouses' (n = 30) appraisals and current mood. We hypothesized that a high number of lifetime stressors, and low resolution ratings, would be associated with more distress and more negative appraisals of the cancer. Hierarchical regression analyses showed that number of lifetime stressors was a positive predictor of patients' ratings of the cancer's threat, and a positive predictor of their spouses' anger. Mean resolution ratings were a significant positive predictor of spouses' positive affect. The findings suggest that experience with previous stressors affects an individual's reactions to cancer."
452,"Amplification of c-erbB-2 proto-oncogene in cancer foci, adjacent normal, metastatic and normal tissues of human primary gastric adenocarcinomas.","Kim JS, Choi CW, Kim BS, Shin SW, Kim YH, Mok YJ, Kim JS, Koo BH.",https://pubmed.ncbi.nlm.nih.gov/9288630/,"Genetic damages are frequently found in both tumor and normal cells at carcinogen exposed areas in the patients with upper aerodigestive tract cancer. These phenomena are explained by the multistage process and/or field cancerization theories. The c-erbB-2 proto-oncogene has been amplified in many human tumors including breast, stomach, kidney and lung cancers. To study the possible evidence of multistage process and/or field cancerization in the development of gastric adenocarcinoma, the amplification statuses of c-erbB-2 proto-oncogene using the Southern hybridization technique were evaluated at the 45 gastric adenocarcinoma specimen sets consisting of tumor tissue, adjacent normal tissue (within 2 cm of the primary tumor), metastatic tissue and normal stomach tissue (at least 5 cm away from primary tumor). As a 4%) was amplified 2- to 4-fold to normal control status. In these 2 cases, c-erbB-2 proto-oncogene at histologically normal tissue adjacent to tumor tissue was amplified. And, the metastatic tissue of 1 case also exhibited c-erbB-2 proto-oncogene amplification of which the degree was less than that of tumor tissue. From these  And, this "
453,"A novel transforming gene, hst, from human stomach cancers and a non-cancerous portion of stomach mucosa.","Terada M, Sakamoto H, Yoshida T, Miyagawa K, Sugimura T.",https://pubmed.ncbi.nlm.nih.gov/3455413/,"DNAs from 21 human stomach cancers, 16 metastatic stomach cancers to lymph nodes, and 21 non-cancerous mucosae of the stomach from a total number of 26 patients with stomach cancer were assayed for their transforming activity to NIH3T3 cells. Three samples of DNA were positive in transfection assay; one was from a primary stomach cancer of one patient (No. 361), the second was from a non-cancerous portion of stomach mucosa of the same patient (No. 363) and the third was from a lymph node metastasis of stomach cancer from another patient (No. 51). A portion of the transforming gene was cloned and a cDNA clone for this gene was isolated. The reading frame essential for the transforming activity was identified. From the  We applied the term, hst (human stomach cancer), to this novel transforming gene. This hst gene was not only responsible for acquisition of transforming activity of No. 361 DNA, but also for that of No. 363 and No. 51 DNAs; all the transformants induced by Nos. 361, 363, and 51 DNAs contained hst gene."
454,Oral cancer. The importance of early diagnosis and treatment.,Sciubba JJ.,https://pubmed.ncbi.nlm.nih.gov/11705251/,"Oral cancer is an important health issue. The WHO predicts a continuing worldwide increase in the number of patients with oral cancer, extending this trend well into the next several decades. In the US the projected number of new cases of oral and oropharyngeal cancer will exceed 31,000 per year. Mortality due to cancers in this region exceeds the annual death rate is the US caused by either cutaneous melanoma or cervical cancer. Significant agents involved in the etiology of oral cancer in Western countries include sunlight exposure, smoking and alcohol consumption. Use of the areca or betel nut in many cultures is a major etiological factor outside of the USA. Other etiologic factors associated with oral squamous cell carcinoma, but far less significant statistically, include syphilis and sideropenic dysphagia. Recently, strong evidence for an etiological relationship between human papilloma virus and a subset of head and neck cancers has been noted. It is generally accepted that most sporadic tumors are the  These alterations affect epithelial cell behavior by way of loss of chromosomal heterozygosity which in turn leads to a series of events progressing to the ultimate stage of invasive squamous cell carcinoma. The corresponding genetic alterations are reflected in clinical and microscopic pathology from hyperplasia through invasiveness. A wide range of mucosal alternations fall within the rubric of leukoplakia. Proliferative verrucous leukoplakia represents a relatively new type of leukoplakia that is separate from the more common or less innocuous form of this condition. Erythroplakia is particularly relevant considering its almost certain relationship with dysplasia or invasive carcinoma. Squamous cell carcinoma will develop from antecedent dysplastic oral mucosal lesions if an early diagnosis has not been made and treatment given. Early diagnosis within stages I and II correspond to a vastly improved 5-year survival rate when compared with more advanced stage III and IV lesions. Surgical management of this disease remains the mainstay of treatment. Other therapies include radiation and chemotherapy options that may be used adjunctively and palliatively. Following treatment, it is important to understand the significant risks of second primary cancers developing within the upper aerodigestive tract as a  The most important message is that early detection of the asymptomatic early stage oral cancer translates in general terms to satisfactory clinical outcome and cure in most patients."
455,"Cancer and social justice: a demographic, economic, historic, sociocultural, and ethical perspective.",Bal DG.,https://pubmed.ncbi.nlm.nih.gov/16270311/,"In the current presentation, as a first-generation Asian-American immigrant, the author discussed the dire inequities of the current cancer prevention and control systems in the U.S. and attempted to analyze the root causes of the problem. The universal concern is that the occurrence of cancer, cancer's behavioral antecedents, (diet, physical activity, and tobacco use), the early detection of cancer, and cancer survivorship all relate inversely to education, income, social class, and white race. In other words, not only are cancer rates higher among lesser educated, poorer, and socially deprived individuals, but the availability and benefits of primary, secondary, and tertiary cancer prevention also are rationed, consciously or sub-consciously, by current society within and outside the borders of the U.S. Asian Americans are one of the unrecognized populations among these deprived groups. The  Because of the audience at the Asian American Network for Cancer Awareness, Research, and Training meeting, where the current report was presented, the author tried to avoid a treatise on Asian philosophy and values but could not resist the comment that, in archaic Chinese terms, the public health and health care systems in the U.S. today lack balance and harmony."
456,Associations Between Amplification (1q) and Prior Cancer in a Real-World De Novo Myeloma Cohort.,"Lamont EB, Yee AJ, Goldberg SL, Siegel DS, Norden AD.",https://pubmed.ncbi.nlm.nih.gov/33442665/,"Genomic biomarkers inform treatment in multiple myeloma (MM), making patient clinical data a potential window into MM biology. We evaluated de novo MM patients for associations between specific MM cytogenetic patterns and prior cancer history. Analyzing a MM real-world dataset, we identified a cohort of 1769 patients with fluorescent in situ hybridization cytogenetic testing at diagnosis. Of the patients, 241 (0.14) had histories of prior cancer(s). Amplification of the long arm of chromosome 1 [amp(1q)] varied by prior cancer history (0.31 with prior cancer vs 0.24 without; 2-sided P = .02). No other MM translocations, amplifications, or deletions were associated with prior cancers. Amp(1q) and cancer history remained strongly associated in a logistic regression adjusting for patient demographic and disease attributes. The  Broadly, the findings suggest that analyses of patient-level phenotypic-genomic real-world dataset may accelerate cancer research through hypothesis-generating studies."
457,"Esophageal Cancer: Overview, Risk Factors, and Reasons for the Rise.","Lander S, Lander E, Gibson MK.",https://pubmed.ncbi.nlm.nih.gov/37812328/,"Purpose of review:
        
      
      Esophageal cancer (EC) is a common cancer affecting many regions of the world and carries significant morbidity and mortality. In this article, we review the key risk factors and their associated impact on the changing incidence and prevalence of EC subtypes within different global regions. We also highlight potential reasons for the ever-changing epidemiology of this prevalent cancer type.
    


          Recent findings:
        
      
      There has been a shift in incidence of Esophageal Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) within certain populations primarily due to an increase prevalence of primary risk factors. In Western nations, more often the United States, there has been a shift from SCC predominance to the majority of new cases of EC being adenocarcinoma. This shift within the United States has largely correlated with a rise in obesity. The prevalence of AC in Asia is also starting to rise as more countries adopt a western diet. The pathophysiology, associated risk factors, and presentation of ESCC and AC are different. This difference is seen in varying lifestyles, population health, and certain genetic risks. With further development closer analysis of primary risk factors and implementation of policies and programs that promote public health literacy, there is a potential to decrease esophageal cancer's global disease burden."
458,The expression and clinical significance of circulating microRNA-21 in serum of five solid tumors.,"Wang B, Zhang Q.",https://pubmed.ncbi.nlm.nih.gov/22638884/,"Purpose:
        
      
      MicroRNA-21 (miR-21) was reported as being overexpressed in various human cancerous tissues, but its expression in cancerous serum was not unanimous in different laboratories. On the base of optimizing 
    


           Furthermore, we analyzed the associations between miR-21 expression and clinical features of patients.
    


          001), and its sensitivity and specificity were significantly higher than the currently used tumor markers. High miR-21 expression was not correlated with gender, age, clinical stage, and lymph node metastasis status.
    


          Conclusion:
        
      
      Circulating miR-21 could serve as a potential broad-spectrum serum-based biomarker for the detection of some solid cancers."
459,Skin cancer in elderly patients.,"Dewberry C, Norman RA.",https://pubmed.ncbi.nlm.nih.gov/15018013/,The role of the dermatologist who provides care to the geriatric patient assumes the care for the integument system. The ability to diagnose and treat cancerous lesions effectively with special care given to the needs of the geriatric patient is considered indispensable. The clinician should accept the responsibility of skin cancers and obtain biopsies with empathy and care.
460,Animal Models of Chemical Carcinogenesis: Driving Breakthroughs in Cancer Research for 100 Years.,Kemp CJ.,https://pubmed.ncbi.nlm.nih.gov/26430259/,"The identification of carcinogens in the workplace, diet, and environment through chemical carcinogenesis studies in animals has directly contributed to a reduction of cancer burden in the human population. Reduced exposure to these carcinogens through lifestyle changes, government regulation, or change in industry practices has reduced cancer incidence in exposed populations. In addition to providing the first  More recently, combining chemical carcinogens with genetically engineered mouse models has emerged as an invaluable approach to study the complex interaction between genotype and environment that contributes to cancer development. In the future, animal models of environmentally induced cancer are likely to provide insight into areas such as the epigenetic basis of cancer, genetic modifiers of cancer susceptibility, the systems biology of cancer, inflammation and cancer, and cancer prevention."
461,How aneuploidy may cause cancer and genetic instability.,"Duesberg P, Rasnick D, Li R, Winters L, Rausch C, Hehlmann R.",https://pubmed.ncbi.nlm.nih.gov/10697602/,"It has been difficult to find a common cause for the many and complex phenotypes of cancer such as dedifferentiation, invasiveness, abnormal morphology, growth rate and metabolism, genetic instability, progression to malignancy, cellular heterogeneity of phenotypes and karyotypes, and clonal origin despite heterogeneity. Over 100 years ago aneuploidy, an abnormal balance of chromosomes, was proposed to cause cancer. However, the aneuploidy hypothesis has since been abandoned, in favor of the gene mutation hypothesis, because it could not offer conventional explanations for cancer-specific phenotypes. For example, the aneuploidy hypothesis seemed unable to (i) explain the genesis of abnormal, cancer-specific phenotypes, (ii) reconcile the heterogeneous karyotypes with the clonal origin of cancers, (iii) explain aneuploidy in non-cancerous cells, and (iv) explain how carcinogens would cause aneuploidy. Here we introduce new evidence that aneuploidy offers a simple, coherent explanation of all cancer-specific phenotypes: (i) Congenital and  (ii) Based on metabolic control analysis, we have derived equations that correlate degrees of aneuploidy with the  These equations suggest that aneuploidy must exceed a certain threshold to generate cancer-specific phenotypes. Therefore, we propose that multistep carcinogenesis corresponds to multiple steps of aneuploidization. (iii) Aneuploidy is also sufficient to explain cancer-specific, karyotypic instability. Since aneuploidy imbalances the highly balance-sensitive components of the spindle apparatus it destabilizes symmetrical chromosome segregation. This autocatalytic instability is the reason why cancers have heterogeneous karyotypes, but are clonal for aneuploidy. Progression to malignancy corresponds to selection of ever more aggressive karyotypic variants. (iv) Both non-genotoxic and genotoxic carcinogens can cause aneuploidy by physical or chemical interaction with mitosis proteins. We conclude that aneuploidy offers a mechanism of phenotype alteration which--above a certain threshold--is sufficient to cause all cancer-specific phenotypes, and is independent of gene mutation."
462,Phenotypic and genetic alterations in pre-cancerous cells in the colon.,"Lundy J, Chen J, Wang P, Fromowitz F, Schuss A, Lynch S, Brugge J, Viola MV.",https://pubmed.ncbi.nlm.nih.gov/3052255/,"Cell dysplasia in polyps and in ulcerative colitis are thought to be the pre-cancerous lesion leading to invasive colon cancer. Many polyps and dysplastic lesions in ulcerative colitis have phenotypic changes (blood group antigen, cytokeratins, CEA, TAG-72.3 antigen expression) and genetic changes (c-K-ras mutation, enhanced c-myc expression and pp60c-src activity) which are characteristic of invasive cancers. Thus, these early pre-cancerous lesions may be a late stage in the genetic evolution of colon cancer."
463,[CARIMS (Cancer Risk In Multiple Sclerosis) project: impact of long-term treatment].,"Lebrun C, Debouverie M, Vermersch P, Clavelou P, Rumbach L, de Seze J, Defer G, Berthier F; Club Francophone de la Sclérose en Plaques.",https://pubmed.ncbi.nlm.nih.gov/17304171/,"Controversial  Multiple sclerosis has been linked to reduced rates of cancer prior to the era of immunomodulating or immunosuppressive treatments and until today, only 9 studies can be found in the literature. New strategies and early use of IM or IS drugs in MS justify to study and follow patients to detect a potential increase of cancer's incidence in treated patients. It is important to follow and collect prospectively in MS centers, patients with history of cancer, to document histologies, and potential relations with repeated IM or IS treatments. A prospective study is in progress in French MS centers on behalf the Club Francophone de la SEP (CARIMS Project)."
464,Possible role of accessibility of protein-SH groups to the cancer state.,Knock FE.,https://pubmed.ncbi.nlm.nih.gov/6266365/,"From out histochemical studies, protein-sulfhydryl (SH) groups are found mainly concentrated in the nucleus and in cell nuclear membranes. Both clinically and in sensitivity tests, selected SH inhibitors have been found to be more active than other commonly used anticancer agents, against an array of cancers, than against normal tissues. The same SH inhibitors can induce immunity against some cancers in animals, while causing blunting of microvilli and alterations in cell surface of the cancer cells. From recent electron spin resonance data (ESR), selected SH inhibitors and glyoxal derivatives can raise the low ESR signal of cancers towards or above normal. The variety of important roles of protein-SH groups to the cancerous state underscores the possible role of accessibility of protein-SH groups to cancer. This very importance of protein-SH groups to cancer, with their highly variable chemical reactivity, underscores also the lack of validity of randomized protocols for clinical cancer therapy. None of these take into account any measure of the chemical sensitivity of each patient's own cancer."
465,[Topical therapy of squamous cell carcinoma].,Hengge UR.,https://pubmed.ncbi.nlm.nih.gov/17429585/,Many forms of topical chemo- and immunotherapy are employed to treat skin cancers. Topical treatment is particularly attractive for field cancerization involving multiple non-melanoma skin cancers. The dermatologist must identify such patients and lesions and provide the most suited therapy.
466,"[Second carcinomas in cancers of the mouth cavity, pharynx and larynx. Clinical, histopathologic and cell kinetic findings].","Esser D, Anke S, Roessner A, Freigang B.",https://pubmed.ncbi.nlm.nih.gov/11006912/," The prognosis not only shows a high ratio of recidivations and formation of metastases, but also a typical field canceration. There is a high rate of incidence of multiple primary, resp. secondary tumours that may occur synchronously or metachronously. Up to now we have learnt only little about the mechanisms concerning the development of tumours and their spread on the cellular molecular level.
    


           The control group were patients suffering from primary tumours of the same location and subsequent recidivation or metachronous metastasis. By determination of the degree of malignity and keratinisation of the DNA ploidy, of the immunohistological expression of p53 and the immunohistological proliferation marker MIB1 conclusions had to be drawn with regard to the biological behaviour of tumours.
    


           Surprisingly, most common were secondary tumours in case of larynx carcinomatas. Patients suffering from secondary tumours show a bad prognosis, however, their maximum survival does not differ considerably from that of patients suffering from recidivations, resp. metastases. Because of the early diagnosis of the secondary carcinomatas the prognosis will depend on the primary carcinoma in most of the cases. The prognosis data indicate that independently from the fact whether there is a primary or a subsequent tumour, the therapy to be applied can only be a combined therapy consisting of operation and ray-therapy. The present examinations confirm reports with regard to disturbance of the p53 regulation that also play an important role in case of the head-neck area. The parallel analysis of MIB1 as a proliferation marker showed in case of the primary carcinomatas a correlation of positive p53-immunocolour with moderate and strong proliferation. Tumours in the hypopharynx and larynx showed a significantly smaller proliferation than that of the oral cavity and oropharynx. In case of the primary and secondary tumours the proliferation is more common in case of the G3-tumours.
    


          Conclusions:
        
      
      The in total modest differences between the primary and secondary carcinoma with regard to the DNA-ploidy; the proliferation and the p53-expression presumably originate in their formation within the scope of a so-called field canceration. Because of the field canceration supposed for the mucous membranes of the upper aerodigestive tract, the check-ups of these patients performed in regular intervals must not be limited in any case to the area of the primary tumour. They will have to consider the entire visible area of the upper respiratory and esophageal tract."
467,Targeting acidity in cancer and diabetes.,"Gillies RJ, Pilot C, Marunaka Y, Fais S.",https://pubmed.ncbi.nlm.nih.gov/30708040/,"While cancer is commonly described as ""a disease of the genes"", it is also a disease of metabolism. Indeed, carcinogenesis and malignancy are highly associated with metabolic re-programming, and there is clinical evidence that interrupting a cancer's metabolic program can improve patients' outcomes. Notably, many of the metabolic adaptations observed in cancer are similar to the same perturbations observed in diabetic patients. For example, metformin is commonly used to reduce hyperglycemia in diabetic patients, and has been demonstrated to reduce cancer incidence. Treatment with PI3K inhibitors can induce hyperinsulinemia, which can blunt therapeutic efficacy if unchecked. While commonalities between metabolism in cancer and diabetes have been extensively reviewed, here we examine a less explored and emergent convergence between diabetic and cancer metabolism: the generation of lactic acid and subsequent acidification of the surrounding microenvironment. Extracellular lactic acidosis is integral in disease manifestation and is a negative prognostic in both disease states. In tumors, this  In diabetes, acidosis impacts the ability of insulin to bind to its receptor, leading to peripheral resistance and an exacerbation of symptoms. Thus, acidosis may be a relevant therapeutic target, and we describe three approaches for targeting: buffers, nanomedicine, and proton pump inhibitors."
468,[A case of familial breast cancer].,"Nomizu T, Sekikawa K, Watanabe I, Endo S.",https://pubmed.ncbi.nlm.nih.gov/6090724/,"The occurrence of breast cancer in 5 members of a family is reported. No specificity of the location, staging or histological typing of the lesions was observed in these cancers. But the characteristics of ""hereditary breast cancer"", early onset and the occurrence of metachronous double cancers, were observed. As for heredity, it is suspected to be autosomal dominant trait; on the other hand it is more appropriate to assume a poly genic pattern. Recognizing the importance of familial cancer occurrence, it may be possible to detect early cancerous lesions in family members."
469,Curbing cancer's sweet tooth: is there a role for MnSOD in regulation of the Warburg effect?,"Holley AK, Dhar SK, St Clair DK.",https://pubmed.ncbi.nlm.nih.gov/22820117/,"Reactive oxygen species (ROS), while vital for normal cellular function, can have harmful effects on cells, leading to the development of diseases such as cancer. The Warburg effect, the shift from oxidative phosphorylation to glycolysis, even in the presence of adequate oxygen, is an important metabolic change that confers many growth and survival advantages to cancer cells. Reactive oxygen species are important regulators of the Warburg effect. The mitochondria-localized antioxidant enzyme manganese superoxide dismutase (MnSOD) is vital to survival in our oxygen-rich atmosphere because it scavenges mitochondrial ROS. MnSOD is important in cancer development and progression. However, the significance of MnSOD in the regulation of the Warburg effect is just now being revealed, and it may significantly impact the treatment of cancer in the future."
470,Salivary diagnostics for oral cancer.,Wong DT.,https://pubmed.ncbi.nlm.nih.gov/16900988/,"Oral cancers annually strike 38,000 individuals in the United States and hundreds of thousands of others around the globe. Despite treatment advances, the disease's overall five-year survival rate has not improved in the past three decades and remains among the worst of all cancers. One factor behind oral cancer's high mortality is the challenge detecting it at its early stages. The use of saliva for the detection of oral cancer has been a historical goal that has yet to come to fruition. This review highlights translational research efforts in alignment with initiatives sparked by the National Institute of Dental and Craniofacial Research toward bringing saliva diagnostics to fruition and, in particular, for saliva-based oral cancer detection."
471,"Hypothyroidism after a cancer diagnosis: etiology, diagnosis, complications, and management.","Carter Y, Sippel RS, Chen H.",https://pubmed.ncbi.nlm.nih.gov/24309982/,"Hypothyroidism is a common disease that is easily treated in the majority of cases, when readily diagnosed; however, presentation of an aggregate of its symptoms is often clinically overlooked or attributed to another disease and can potentially be lethal. Already prevalent in older women, its occurrence in younger patients is rising as a  The presence of nonspecific constitutional symptoms and neuropsychiatric complaints in cancer patients can be attributed to a myriad of other diagnoses and therapies. Thyroid dysfunction can be easily overlooked in cancer patients because of the complexity of cancer's clinical picture, particularly in the pediatric population. Underdiagnosis can have important consequences for the management of both hypothyroidism and the malignancy. At minimum, quality of life is adversely affected. Untreated hypothyroidism can lead to heart failure, psychosis, and coma and can reduce the effectiveness of potentially life-saving cancer therapies, whereas iatrogenic causes can provoke atrial fibrillation and osteoporosis. Consequently, the diagnosis and treatment of hypothyroidism in cancer patients are pertinent. We summarize the history, epidemiology, pathophysiology, clinical diagnosis, and management of hypothyroidism in cancer patients."
472,Genetic evidence for the multicentric origin of synchronous multiple gastric carcinoma.,"Kang GH, Kim CJ, Kim WH, Kang YK, Kim HO, Kim YI.",https://pubmed.ncbi.nlm.nih.gov/9121123/,"Multiple gastric cancers, which constitute 4% to 10% of all gastric cancers, occur in older people and are associated with more extensive intestinal metaplasia. With regard to the genesis of multiple gastric cancers, multicentricity (independent origin) rather than multifocality (local or lateral spread of one cancer) has been the favored theory. Conventional morphologic study, however, has not been able to provide convincing evidence in support of multicentricity. The purpose of this study was to verify the multicentric origin of multiple gastric cancers at a genetic level. For this purpose, immunohistochemical and molecular techniques were used to define the mutation pattern of APC, MCC and p53 in multiple lesions of synchronous multiple gastric cancers. The study was based on a total of 30 gastric tumors from 13 patients, including 10 double tumors, 2 triple tumors, and 1 quadruple tumor. Single-strand conformation polymorphism and polymerase chain reaction direct sequencing were carried out for exons 5 to 8 of p53, and loss of heterozygosity was detected on the basis of polymerase chain reaction amplification of polymorphism in exon 10 of MCC and in exon 11 of APC. Twelve of 13 cases showed alteration in one or more genetic markers. Of these, three demonstrated a discordant mutation pattern of p53 in individual lesions, and another two revealed allelic loss of MCC in one lesion and p53 mutation in the other. In six other cases, only one lesion showed alteration of APC, MCC, or p53, and in the remaining case, one lesion carried p53 and MCC mutations and the other carried MCC loss of heterozygosity only. The  Collectively, these findings supported the theory of field cancerization in gastric carcinogenesis."
473,Combinatory low methylation statuses of SAT-alpha and L1 are associated with shortened survival time in patients with advanced gastric cancer.,"Kim Y, Wen X, Jeong S, Cho NY, Kim WH, Kang GH.",https://pubmed.ncbi.nlm.nih.gov/29926315/," Unlike L1 hypomethaylation, nothing is known regarding the prognostic implication of SAT-α hypomethylation alongside L1 hypomethaylaton in gastric cancers.
    


          
    


           L1 or SAT-α methylation levels were lower in gastric cancers with venous invasion or nodal metastasis than those without. L1 methylation was lower in gastric cancers with lymphatic emboli than in those with no lymphatic emboli, but was higher in gastric cancers with perineural invasion than in those with no perineural invasion. Multivariate survival analysis revealed that both tumoral L1 and SAT-α hypomethylations were found to correlate independently with OS (HR = 1.477; 95% CI 1.079-2.021 and HR = 1.394; 95% CI 1.011-1.922, respectively) and RFS (HR = 1.477; 95% CI 1.090-2.001 and HR = 1.516; 95% CI 1.106-2.078, respectively). Combined L1 and SAT-α hypomethylation turned out to correlate independently with OS (HR = 2.003; 95% CI 1.268-3.164) and RFS (HR = 2.226; 95% CI 1.411-3.510).
    


          Conclusion:
        
      
      Not only tumoral L1 hypomethylation, but also tumoral SAT-α hypomethylation was found to be independent prognostic parameters in patients with advanced gastric cancer. SAT-α methylation status can be used to further divide gastric cancers with L1 hypomethylation into subsets of gastric cancers with better and worse prognosis."
474,Adaptive Control of Tumor Growth.,Derbal Y.,https://pubmed.ncbi.nlm.nih.gov/38294947/,"Cancer treatment optimizations select the most optimum combinations of drugs, sequencing schedules, and appropriate doses that would limit toxicity and yield an improved patient quality of life. However, these optimizations often lack an adequate consideration of cancer's near-infinite potential for evolutionary adaptation to therapeutic interventions. Adapting cancer therapy based on monitored tumor burden and clonal composition is an intuitively sound approach to the treatment of cancer as an inherently complex and adaptive system. The adaptation would be driven by clinical outcome setpoints embodying the aims to thwart therapeutic resistance and maintain a long-term management of the disease or even a cure. However, given the nonlinear, stochastic dynamics of tumor response to therapeutic interventions, adaptive therapeutic strategies may at least need a one-step-ahead prediction of tumor burden to maintain their control over tumor growth dynamics. The article explores the feasibility of adaptive cancer treatment driven by tumor state feedback assuming cell adaptive fitness to be the underlying source of phenotypic plasticity and pathway entropy as a biomarker of tumor growth trajectory. The exploration is undertaken using deterministic and stochastic models of tumor growth dynamics."
475,"A Critical Overview of the Construct of Supportive Care Need in the Cancer Literature: Definitions, Measures, Interventions and Future Directions for Research.","Miniotti M, Botto R, Soro G, Olivero A, Leombruni P.",https://pubmed.ncbi.nlm.nih.gov/38397704/,"The growing amount of evidence about the role of supportive care in enhancing cancer patients' outcomes has made healthcare providers more sensitive to the need for support that they experience during cancer's trajectory. However, the lack of a consensus in the definition of supportive care and lack of uniformity in the theoretical paradigm and measurement tools for unmet needs does not allow for defined guidelines for evidence-based best practices that are universally accepted. Contemporary cancer literature confirms that patients continue to report high levels of unmet supportive care needs and documents the low effectiveness of most of the interventions proposed to date. The aim of this critical review is to consolidate the conceptual understanding of the need for supportive care, providing definitions, areas of expertise and a careful overview of the measurement tools and intervention proposals developed to date. The possible reasons why the currently developed interventions do not seem to be able to meet the needs, and the issues for future research were discussed."
476,Deep learning ensemble approach with explainable AI for lung and colon cancer classification using advanced hyperparameter tuning.,"Vanitha K, R MT, Sree SS, Guluwadi S.",https://pubmed.ncbi.nlm.nih.gov/39112991/,"Lung and colon cancers are leading contributors to cancer-related fatalities globally, distinguished by unique histopathological traits discernible through medical imaging. Effective classification of these cancers is critical for accurate diagnosis and treatment. This study addresses critical challenges in the diagnostic imaging of lung and colon cancers, which are among the leading causes of cancer-related deaths worldwide. Recognizing the limitations of existing diagnostic  This innovative ensemble model aims to enhance feature extraction, improve model robustness, and reduce overfitting.Our  The 44%, with perfect precision and recall in identifying certain cancerous and non-cancerous tissues, marking a significant improvement over traditional approach.The practical implications of these findings are profound. By integrating Gradient-weighted Class Activation Mapping (Grad-CAM), the model offers enhanced interpretability, allowing clinicians to visualize the diagnostic reasoning process. This transparency is vital for clinical acceptance and enables more personalized, accurate treatment planning. Our study not only pushes the boundaries of medical imaging technology but also sets the stage for future research aimed at expanding these techniques to other types of cancer diagnostics."
477,Recurrence of ovarian cancer-living in limbo.,"Ekwall E, Ternestedt BM, Sorbe B.",https://pubmed.ncbi.nlm.nih.gov/17666975/,"Few studies have shed light on women's life situation after being informed of having recurrent ovarian cancer. The present study aimed to elucidate women's experiences of living with this knowledge. Interviews were conducted with 12 women who were undergoing or had just completed chemotherapy, 5 to 10 months after learning of the recurrence. Data were collected and analyzed based on a life world perspective using a descriptive phenomenological  The women's experiences are described via 3 key constituents: being denied one's future while simultaneously hoping to be able to delay the cancer's advancement, feeling alienated from both oneself and one's surroundings, and being responsible. The key constituents were integrated into the structure ""living in limbo."" The women lived on the threshold to the unknown. They were preparing themselves both for a continued life and for death. ""Living in limbo"" can be described as a phase of a health-illness transition characterized by loneliness. The vulnerable position and existential struggle of these women should be focused upon in nursing. The sensitive dialogue is essential in these cases."
478,Psychological referral and consultation for adolescents and young adults with cancer treated at pediatric oncology unit.,"Clerici CA, Massimino M, Casanova M, Cefalo G, Terenziani M, Vasquez R, Meazza C, Ferrari A.",https://pubmed.ncbi.nlm.nih.gov/18253959/,"Purpose:
        
      
      Managing older adolescents and young adults with cancer is a challenge, both medically and psychosocially: it is important to assess these patients' psychological issues and the type of services they need when deciding who should treat these patients, and where.
    


          
    


           The number of interviews per patient was 2.8 for patients under fifteen and 7.8 for older patients. Younger patients were referred by all members of staff, while most older patients were referred by doctors, mainly because they had trouble adapting to the cancer's diagnosis and treatment. An ongoing, weekly, long-term psychotherapy was needed for 1% of patients <15 and 10% of those >/=15 years old.
    


          Conclusions:
        
      
      Adolescents and young adults with cancer have specific psychological needs. While awaiting the full development of programs dedicated to these patients, they would seem to benefit from being treated in a multidisciplinary setting of the kind usually developed at pediatric units, fully integrating the psychological operators with the other staff members."
479,Ubiquitin ligases in cancer: ushers for degradation.,"Newton K, Vucic D.",https://pubmed.ncbi.nlm.nih.gov/17882664/,"The regulated degradation of cellular proteins by the ubiquitin-proteasome system impacts a range of vital cellular processes in both normal and cancerous cells. An ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) catalyzes the conjugation of the protein ubiquitin to a target protein and, thereby, tags that protein for recognition and destruction by the proteasome. Ubiquitin ligases are particularly interesting because they determine substrate selection. This review examines the role of dysregulated ubiquitin ligase activity in the development and progression of various cancers, and highlights why ubiquitin ligases have emerged as extremely attractive targets for therapeutic intervention in a number of human malignancies."
480,Immunotherapy and Prevention of Pancreatic Cancer.,"Morrison AH, Byrne KT, Vonderheide RH.",https://pubmed.ncbi.nlm.nih.gov/29860986/,"Pancreatic cancer is the third-leading cause of cancer mortality in the USA, recently surpassing breast cancer. A key component of pancreatic cancer's lethality is its acquired immune privilege, which is driven by an immunosuppressive microenvironment, poor T cell infiltration, and a low mutational burden. Although immunotherapies such as checkpoint blockade or engineered T cells have yet to demonstrate efficacy, a growing body of evidence suggests that orthogonal combinations of these and other strategies could unlock immunotherapy in pancreatic cancer. In this Review article, we discuss promising immunotherapies currently under investigation in pancreatic cancer and provide a roadmap for the development of prevention vaccines for this and other cancers."
481,The Variation of Peripheral Inflammatory Markers in Vocal Leukoplakia before and after Recurrence and Canceration.,"Fang Y, Chen M, Yang Y, Chen J, Cheng L, He P, Wu H.",https://pubmed.ncbi.nlm.nih.gov/32831972/,"
    


           The clinical data were collected, and neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocytes-to-lymphocyte ratio (MLR) before and after recurrence and canceration were calculated. Related comparison with two-grade pathological classification was made to evaluate their potential connection with postsurgical histopathology and clinical events.
    


           The NLR, PLR, and MLR were significantly increased in canceration event compared to the first (P = 0.009, 0.004, 0.007, respectively) and penultimate (P = 0.013, 0.041, 0.006, respectively) time when the previous pathologies were leukoplakia. When redividing the Group A according to the two-grade pathological classification, the high-risk groups showed statistically higher NLR and PLR values than low-risk groups in the subgroups with grade changing (P = 0.016, 0.005, 0.007, 0.005, respectively) and subgroups without grade changing (P = 0.020, 0.027, 0.030, 0.029, respectively).
    


          Conclusions:
        
      
      NLR, PLR, and MLR are reliable biomarkers in the circulation system which show significantly interrelation with the pathological progression of vocal fold leukoplakia. Presurgical evaluation of NLR, PLR, and MLR may have potential values to indicate the following treatment in clinical practice."
482,Recent Updates on the Relationship between Cancer and Autoimmune Pancreatitis.,"Okamoto A, Watanabe T, Kamata K, Minaga K, Kudo M.",https://pubmed.ncbi.nlm.nih.gov/30713326/,"Autoimmune pancreatitis (AIP) is now considered a pancreatic manifestation of a newly proposed disease condition, IgG4-related disease (IgG4-RD). IgG4-RD is characterized by enhanced IgG4 antibody responses and multiple organ involvements. Recent epidemiological studies have addressed the incidence of cancer in patients with AIP and/or IgG4-RD. Surprisingly, a significant number of AIP patients were detected with cancer at or within one year of the diagnosis of AIP. Furthermore, around 50% of all cancers detected in AIP patients comprised mainly 3 types (gastric, lung, and prostate cancer). Thus, AIP appears to be associated with cancer of other organs rather than the pancreas itself, which suggests that AIP is not a pre-cancerous condition of the pancreas. Moreover, the simultaneous occurrence of cancer and AIP in many patients has led to the establishment of an attractive concept that AIP might sometimes arise from co-existing cancers as a paraneoplastic syndrome."
483,[A study on effect of mechanical irritation in development and progression of tongue cancer].,Sato T.,https://pubmed.ncbi.nlm.nih.gov/8583164/,"It is considered that the mechanical irritation acts as an inducer in the canceration process of tongue cancer. The purpose of this study was to clarify the effect of mechanical irritation on the development and progression of tongue cancer. Leukoplakia and cancer were produced on the hamster tongue by paratripsis and applying 1% DMBA acetone solution 3 times per week for 8 or 10 weeks, and there after only paratripsis was continued. The effect of mechanical irritation was examined histopathologically. The intensity of DNA damage caused by mechanical irritation was investigated by measuring the activity of Poly (ADP-ribose) polymerase (PADPRP), which is an enzyme associated with DNA damage. After carcinogenic treatment, canceration of leukoplakia and early carcinoma progressed into become advanced carcinoma histopathologically by mechanical irritation only. In the precancerous condition, active oxygen was found in part of the subepitherial inflammatory cell infiltration and in part of the cancer cells of carcinoma. The activity of PADPRP increased during the scratching period. These "
484,Molecular signatures of noncancerous liver tissue can predict the risk for late recurrence of hepatocellular carcinoma.,"Utsunomiya T, Shimada M, Imura S, Morine Y, Ikemoto T, Mori M.",https://pubmed.ncbi.nlm.nih.gov/19997856/,"Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to tumor metastases or recurrence even after undergoing potentially curative treatment. There are two types of HCC recurrence. The early and late tumor recurrences appear in distinct biological contexts, and their clinical courses are quite different. Therefore, it is important to precisely and distinctly discriminate the risk of each type of HCC recurrence. Many researchers have used DNA microarray technology to reclassify HCC with respect to its malignant potential. Some of these studies successfully identified specific gene-expression signatures derived from the cancerous tissues of HCC for predicting the early recurrence due to intrahepatic metastasis. However, there are no well-defined predictors for late recurrence. Recently, a few studies have focused on the nontumorous portion of liver tissues to predict late recurrence, possibly due to de novo hepatocarcinogenesis based on the idea of ""field cancerization."" This study reviewed the possible value of a gene-expression analysis of noncancerous liver tissue to clarify the risk for multicentric late recurrence of HCC. These findings may have important implications for chemopreventive strategies and tailored surveillance programs. Furthermore, this approach may also be applicable to other multifocal tumors, such as head and neck carcinoma."
485,Particle Radiation Therapy for Gastrointestinal Cancers.,"Shinoto M, Ebner DK, Yamada S.",https://pubmed.ncbi.nlm.nih.gov/26849660/,"Particle irradiation of cancerous disease has gained great traction in recent years. The ability for particle therapy centers to deliver radiation with a highly conformal dose distribution while maintaining minimal exit or excess dose delivered to normal tissue, coupled with various biological advantages particularly found with heavy-ion beams, enables treatment of diseases inapproachable with conventional radiotherapy. Here, we present a review of the current status of particle therapy with regard to cancers of the gastrointestinal tract, including esophagus, liver, pancreas, and recurrent rectal cancer."
486,Pancreatic cancer's initial presentation: back pain due to osteoblastic bone metastasis.,"Pneumaticos SG, Savidou C, Korres DS, Chatziioannou SN.",https://pubmed.ncbi.nlm.nih.gov/19708936/,"Pancreatic cancer may cause osteolytic metastases, but the osteoblastic ones are extremely rare. In addition, it almost always presents with symptoms related to the invasion of the structures in the abdomen. Symptoms from bone metastases are rare and, if seen, are in the late phase of the course. We present a case of cancer of the body of the pancreas, which presented with severe back pain due to an osteoblastic lesion to L3 vertebra. Biopsy of the vertebra led to the diagnosis. Radiographs, computed tomography, magnetic resonance and scintigraphic images as well as pathology slices are shown. The present case raises the issue that pancreatic cancer, as a cause of an osteolytic bone lesion, should not be overlooked in an unknown primary investigation."
487,Screening for a cancer: thinking before rethinking.,Miettinen OS.,https://pubmed.ncbi.nlm.nih.gov/20458523/,"A recent article (by Esserman et al.) called to serious question the diagnostic and prognostic premises of screening for breast and prostate cancers, and it proceeded to adduce, also, other radical rethinking of these screenings. That questioning was 'evidence-based' in the contemporary epidemiological meaning of this--use was made of cancer-registry data as well as of evidence from such randomized trials as epidemiologists now take to be essential in actual research on screening for a cancer--and, evidence-based as it was, that questioning has been left unquestioned. But that questioning, as to the interpretation of the evidence, was not adequately thinking-based. It was, instead, rife with the misunderstandings that permeate contemporary epidemiological thinking about screening for a cancer and about research for the scientific knowledge-base of this. In the truly called-for rethinking, the point of departure would be the recognition that the premises of screening for a cancer are clinical in nature, as obviously also are both the entire process potentially leading to a cancer's early, preclinical diagnosis and the individual counselling about submitting oneself to this. Epidemiologists should focus on epidemiology--practice of and research for community medicine, community-level preventive medicine, that is--and to have no presumptions of understanding, better than clinicians, the (clinical) issues surrounding the pursuit of early diagnosis of a cancer, whether matters of practice, research, or public policy. Clinicians and clinical researchers, in turn, should disregard epidemiologists'--and other public-health professionals'--ideas about screening for a cancer, the practice of and research on this. The need for this aprioristic rethinking is manifest, very eminently, in the fresh recommendations about screening for breast cancer, issued by the US Preventive Services Task Force, and in the public uproar provoked by these."
488,Lysosomes in cancer-living on the edge (of the cell).,"Hämälistö S, Jäättelä M.",https://pubmed.ncbi.nlm.nih.gov/26921697/,"The lysosomes have definitely polished their status inside the cell. Being discovered as the last resort of discarded cellular biomass, the steady rising of this versatile signaling organelle is currently ongoing. This review discusses the recent data on the unconventional functions of lysosomes, focusing mainly on the less studied lysosomes residing in the cellular periphery. We emphasize our discussion on the emerging paths the lysosomes have taken in promoting cancer progression to metastatic disease. Finally, we address how the altered cancerous lysosomes in metastatic cancers may be specifically targeted and what are the pending questions awaiting for elucidation."
489,The risk of second cancer (SC) in patients treated for testicular seminoma.,"Hellbardt A, Mirimanoff RO, Obradovic M, Mermillod B, Paunier JP.",https://pubmed.ncbi.nlm.nih.gov/2115033/,"The exact risk of second cancer (S.C.) following treatment of testicular seminoma is not well determined in most series. At our institution, 122 patients with pure seminoma were treated by orchidectomy followed by radiation therapy from 1951 to 1986. Six were lost to follow-up. For the 116 remaining patients, the overall 5-, 10-, 15- and 20-year survival probability was 95%, 90%, 87%, and 84%, respectively. Eleven patients developed 12 second cancers, with a cumulative risk of 7%, 16%, and 16% at 10, 15, and 20 years, respectively. Overall, the risk of second cancer was increased (O/E = 1.97, p = 0.023). There were 3 controlateral seminoma (O/E = 50, p = 0.001), 2 transitional carcinoma of the bladder (O/E = 6.9, p = 0.035), 2 non-Hodgkin's lymphoma (N.S.), 1 acute myeloblastic leukemia, 1 chronic lymphocytic leukemia, 1 intracranial dysgerminoma, 1 rectal and 1 lung adenocarcinoma. Four tumors developed within the previously irradiated field (O/E = 2.2, N.S.). Excluding second seminoma, the overall risk of second cancer was not significant (O/E = 1.33). Five of the 11 patients with second cancer are currently alive without recurrent cancer. We conclude that patients treated for seminoma have an increased risk of second cancer but the overall prognosis remains excellent. The potential factors responsible for second cancer, including irradiation, are discussed."
490,Splenectomy for treatment of gastric cancer: Japanese experience.,"Okajima K, Isozaki H.",https://pubmed.ncbi.nlm.nih.gov/7676696/,"Surgery for gastric cancer in Japan has frequently been combined with resection of the spleen (splenectomy) or of the pancreatic body and tail and spleen (pancreatosplenectomy, PS). Splenectomy in patients with gastric cancer has been performed with two major purposes in mind: (1) curability of the cancer and (2) immunologic reasons. Direct cancerous invasion to the pancreas requires PS, although examination of these cases revealed that in 34.3% of such macroscopic invasions only fibrous adhesion to pancreas existed. Metastases to lymph nodes at the splenic hilus (no. 10) or along the splenic artery (no. 11) also required splenectomy. The incidences of no. 10 or no. 11 lymph node metastasis were as high as 26.7% and 22.2% respectively, for cancers of whole stomach, and 15.5% and 12.1% for cancers of the upper portion of stomach. Concerning the immunologic aspect of splenectomy for gastric cancer, the reports of fundamental research and clinical studies suggest that the spleen plays sometimes acts as a suppressor and at other times as a helper to the tumor activity, according to the number of tumor cells. From these data, we concluded that the spleen should be preserved in stage I, II, and III patients with curative operation; for stage IV patients the spleen should be resected. The immunologic significance of splenectomy should be clarified precisely in the near future."
491,An analysis of Social Work Oncology Network Listserv Postings on the Commission of Cancer's distress screening guidelines.,"Burg MA, Adorno G, Hidalgo J.",https://pubmed.ncbi.nlm.nih.gov/23101548/,"This is a qualitative study of listserv postings by members of the Social Work Oncology Network (SWON) in response to the Commission on Cancer's 2011 guidelines for distress screening of cancer patients. Archived listserv postings for the period of December 2010 to November 2011 were deidentified and a sample was derived by a list of keywords for the analysis. Aims of the study included describing the general categories and themes of the postings devoted to the new distress screening standard and examining the process of facilitation of mutual support and information exchange by oncology social workers in response to the new screening standards. During the 12-month timeframe there were 242 unique listserv postings sampled for the analysis. Oncology social worker (OSW) discussion of the distress screening guidelines remained a constant topic over the 12 months, and major themes that emerged from the data included processes of implementation of distress screening in cancer centers, screening policies and protocols, screening tool choice, and oncology social worker professional identity. The SWON listserv members used the listserv as a mechanism to post their requests for information on screening, to share their experiences in the beginning stages of implementing the guidelines, and to build support for legitimizing oncology social workers as the lead profession in the implementation of the guidelines in member cancer centers."
492,"siRNA therapeutics for breast cancer: recent efforts in targeting metastasis, drug resistance, and immune evasion.","Ngamcherdtrakul W, Yantasee W.",https://pubmed.ncbi.nlm.nih.gov/31487500/,"Small interfering RNA (siRNA) has an established and precise mode of action to achieve protein knockdown. With the ability to target any protein, it is very attractive as a potential therapeutic for a plethora of diseases driven by the (over)expression of certain proteins. Utilizing siRNA to understand and treat cancer, a disease largely driven by genetic aberration, is thus actively investigated. However, the main hurdle for the clinical translation of siRNA therapeutics is to achieve effective delivery of siRNA molecules to tumors and the site of action, the cytosol, within cancer cells. Several nanoparticle delivery platforms for siRNA have been developed. In this Review, we describe recent efforts in developing siRNA therapeutics for the treatment of cancer, with particular emphasis on breast cancer. Instead of conventionally targeting proliferation and apoptosis aspects of tumorigenesis, we focus on recent attempts in targeting cancer's metastasis, drug resistance, and immune evasion, which are considered more challenging and less manageable in clinics with current therapeutic molecules. siRNA can target all proteins, including traditionally undruggable proteins, and is thus poised to address these clinical challenges. Evidence also suggests that siRNA can be superior to antibodies or small molecule inhibitors when inhibiting the same druggable pathway. In addition to cancer cells, the role of the tumor microenvironment has been increasingly appreciated. Components in the tumor microenvironment, particularly immune cells, and thus siRNA-based immunotherapy, are under extensive investigation. Lastly, multiple siRNAs with or without additional drugs can be codelivered on the same nanoparticle to the same target site of action, maximizing their potential synergy while limiting off-target toxicity."
493,Detection of K-ras gene mutations in non-neoplastic lung tissue and lung cancers.,"Nelson MA, Wymer J, Clements N Jr.",https://pubmed.ncbi.nlm.nih.gov/8616804/,"Oncogene and tumor suppressor gene mutations are candidate biomarkers for cancer risk assessment and lesion detection. The K-ras oncogene has previously been associated with non-small cell lung cancer (NSCLC), particularly adenocarcinomas in which reported rates of mutation have approached 30-40%. We have analyzed non-malignant lung tissue from patients with lung cancer and primary lung cancers for K-ras gene mutations. Mutations were detected in 32% cancers and 29% non-malignant lung tissue from patients with cancer. The majority of tumors testing positive were adenocarcinoma of the lung. Normal DNA controls, including peripheral blood lymphocytes and normal lung from non-smokers, were negative. The ability to detect genetic alterations in non-malignant lung tissues is consistent with the concept that genetic alterations are involved in field cancerization of the aerodigestive tract."
494,Exploring animal models in oral cancer research and clinical intervention: A critical review.,"Khayatan D, Hussain A, Tebyaniyan H.",https://pubmed.ncbi.nlm.nih.gov/37196179/,"Cancer is a leading cause of death worldwide, but advances in treatment, early detection, and prevention have helped to reduce its impact. To translate cancer research findings into clinical interventions for patients, appropriate animal  In vitro  This review discusses the various animal models used in recent years for research and clinical intervention in oral cancer, along with their advantages and disadvantages. We highlight the advantages and limitations of the used animal models in oral cancer research and therapy by searching the terms of animal models, oral cancer, oral cancer therapy, oral cancer research, and animals to find all relevant publications during 2010-2023. Mouse models, widely used in cancer research, can help us understand protein and gene functions in vivo and molecular pathways more deeply. To induce cancer in rodents, xenografts are often used, but companion animals with spontaneous tumours are underutilized for rapid advancement in human and veterinary cancer treatments. Like humans with cancer, companion animals exhibit biological behaviour, treatment responses, and cytotoxic agent responses similar to humans. In companion animal models, disease progression is more rapid, and the animals have a shorter lifespan. Animal models allow researchers to study how immune cells interact with cancer cells and how they can be targeted specifically. Additionally, animal models have been extensively used in research on oral cancers, so researchers can use existing knowledge and tools to better understand oral cancers using animal models."
495,Cancer 'chemotherapia specifica' ninety years after Paul Ehrlich.,"Shukla SK, Petrucci F, Caimi S, Alimonti A, Cusumano R.",https://pubmed.ncbi.nlm.nih.gov/17728538/,"From his student days throughout his whole life, Paul Ehrlich tried hard to obtain 'chemotherapia specifica' for the harmless systemic therapy of infectious diseases. Given the poor therapeutic benefit obtained with cytotoxic therapeutic agents and empirical radiopharmaceuticals, so far used only for neoadjuvant and adjuvant treatments of cancer, we have tried to develop Paul Ehrlich's 'chemotherapia specifica' for safe and effective therapy of cancers in cigarette smokers. With the help of sector-field inductively coupled plasma mass spectrometry, we have tried to find the metabolic action of cigarette smoke constituents in the cancerous organ. On the basis of these  The purity, stability and chemical nature of the pharmaceuticals and radiopharmaceuticals required for therapy have been studied by chromatography and electrophoresis. The cancer specificity of the therapeutic agent has been examined by the total body distribution of its gamma- and beta-labelled species in solution. At present, a bladder cancer-specific therapeutic agent is being developed."
496,The cancer stem cell hypothesis: failures and pitfalls.,"Rahman M, Deleyrolle L, Vedam-Mai V, Azari H, Abd-El-Barr M, Reynolds BA.",https://pubmed.ncbi.nlm.nih.gov/21135745/,"Based on the clonal evolution model and the assumption that the vast majority of tumor cells are able to propagate and drive tumor growth, the goal of cancer treatment has traditionally been to kill all cancerous cells. This theory has been challenged recently by the cancer stem cell (CSC) hypothesis, that a rare population of tumor cells, with stem cell characteristics, is responsible for tumor growth, resistance, and recurrence. Evidence for putative CSCs has been described in blood, breast, lung, prostate, colon, liver, pancreas, and brain. This new hypothesis would propose that indiscriminate killing of cancer cells would not be as effective as selective targeting of the cells that are driving long-term growth (ie, the CSCs) and that treatment failure is often the The CSC hypothesis has gained a great deal of attention because of the identification of a new target that may be responsible for poor outcomes of many aggressive cancers, including malignant glioma. As attractive as this hypothesis sounds, especially when applied to tumors that respond poorly to current treatments, we will argue in this article that the proposal of a stemlike cell that initiates and drives solid tissue cancer growth and is responsible for therapeutic failure is far from proven. We will present the point of view that for most advanced solid tissue cancers such as glioblastoma multiforme, targeting a putative rare CSC population will have little effect on patient outcomes. This review will cover problems with the CSC hypothesis, including applicability of the hierarchical model, inconsistencies with xenotransplantation data, and nonspecificity of CSC markers."
497,Pretumor microenvironment of hepatocellular carcinoma: Cancerization or anticancerization?,"Li G, Ni A, Yu M.",https://pubmed.ncbi.nlm.nih.gov/30902783/," However, the pretumor microenvironment (PTM) was poorly understood. The purpose in this study was to explore the possible pathophysiological features of PTM before hepatocellular carcinoma (HCC) appearance.
    


           The transcriptomes of samples were generated using RNA-seq and validated using RT-qPCR.
    


           Among those 194 DEGs, 104 displayed upregulation and 90 downregulation. Some of these DEGs could promote the ability to resist cancerization or facilitate cancer metastasis, while others indicated liver impairment. The DEGs were involved in 16 relevant pathways. Additionally, the frequency of alternative splicing (AS) in the DEGs in various samples was positively related to the expression of those DEGs.
    


          Conclusions:
        
      
      The PTM initiatively armed itself to combat cancerization when its indications appeared although the PTM did not manifest any tissue swelling. However, the cancer cells were negatively influencing immunity to prevent clearance and positively promoting transformation to construct a suitable environment. During transformation by cancer cells, some genes with acquired AS participated in the construction of the PTM. This alteration created an invadable space and an appropriate environment for cancer cells."
498,Optimizing target selection and development strategy in cancer treatment: the next wave.,Sausville EA.,https://pubmed.ncbi.nlm.nih.gov/15379701/,"Successful cancer treatments of the future are being developed with a focus on the molecular targets underlying the pathophysiology of neoplasia. Prominent targets which have emerged are those which are mutated in the course of a cancer's development, and mediate activation or release from suppression of pathways mediating proliferation or apoptosis. These arguably are ""pathogenic"" targets. However, equally important are targets which can be defined on the basis of ""large scale"" analysis techniques of gene or protein expression in tumors which define targets expressed as a  Irrespective of the nature of the molecular target which is the focus of new therapeutic efforts, target definition in susceptible tumors or patients ideally would be part of the development plan. In addition, an understanding of the therapeutic index which might be achieved in host vs tumor tissues using a surrogate or actual marker of drug effect ideally would be available from animal models and inform the development strategy in humans."
499,"Field Cancerization Is Associated with Tumor Development, T-cell Exhaustion, and Clinical Outcomes in Bladder Cancer.","Strandgaard T, Nordentoft I, Birkenkamp-Demtröder K, Salminen L, Prip F, Rasmussen J, Andreasen TG, Lindskrog SV, Christensen E, Lamy P, Knudsen M, Steiniche T, Jensen JB, Dyrskjøt L.",https://pubmed.ncbi.nlm.nih.gov/37718188/," Bladder field cancerization may explain the development and recurrence of bladder cancer and may be associated with treatment outcomes.
    


          
    


          Design, setting, and participants:
        
      
      We conducted comprehensive genomic and proteomic analyses for 751 bladder biopsies and 234 urine samples from 136 patients with NMIBC. The samples were collected at multiple time points during the disease course. Field cancerization in normal-appearing bladder biopsies was measured using deep-targeted sequencing and error correction models.
    


          Outcome measurements and statistical analysis:
        
      
      Endpoints included the rates of recurrence and progression. Cox regression and Wilcoxon rank-sum and Fisher's exact tests were used.
    


          007), high tumor neoantigen load (p = 0.029), and high tumor-associated CD8 T-cell exhaustion (p = 0.017). In addition, high field cancerization was associated with worse short-term outcomes (p = 0.029). Nonsynonymous mutations in bladder cancer-associated genes such as KDM6A, ARID1A, and TP53 were identified as early disease drivers already found in normal-appearing bladder biopsies. Urinary tumor DNA (utDNA) levels reflected the bladder tumor burden and originated from tumors and field cancerization. High levels of utDNA after BCG were associated with worse clinical outcomes (p = 0.027) and with disease progression (p = 0.003). High field cancerization  Limitations include variation in the number of biopsies and time points analyzed.
    


          Conclusions:
        
      
      Field cancerization levels are associated with tumor development, immune responses, and clinical outcomes. utDNA measurements can be used to monitor disease status and treatment response.
    


          Patient summary:
        
      
      Molecular changes in the tissue lining the bladder  Urinary measurements may be used to monitor bladder cancer status and treatment responses."
500,Phenotypic variation in hereditary breast cancer. Cancer control implications.,"Lynch HT, Conway TA, Lynch JF.",https://pubmed.ncbi.nlm.nih.gov/8048849/,"
    


          Setting:
        
      
      Oncology clinic and hereditary cancer institute.
    


          Patients and other participants:
        
      
      Physician- or self-referral probands.
    


          Interventions:
        
      
      None.
    


          Main outcome measure:
        
      
      Greater understanding of the diagnosis, surveillance, and treatment of hereditary breast cancer.
    


          
    


          Conclusion:
        
      
      Hereditary breast cancer is an important public health problem accounting for about 9% of breast cancer cases. The recent identification of a molecular basis for the identification of a subset of hereditary breast cancer, and thereby the likelihood of the sequencing and cloning of the susceptibility gene(s), will enable targeting of surveillance and treatment measures toward patients at an inordinately high risk of developing cancer. Central to this entire process will be the identification of families with hereditary breast cancer."
501,Chemical heterogeneity of structural proteins of cancers with a common low electron spin resonance signal.,"Knock FE, Gascoyne PR.",https://pubmed.ncbi.nlm.nih.gov/6280219/,"Electron spin resonance measurements are presented for the separated structural and soluble components of a variety of both normal and cancerous tissues. The signal at g = 2 from the structural part of the normal tissues was at least an order of magnitude stronger than the corresponding signal from the structural part of the cancers. In contrast, no significant difference in radical concentration was found between the soluble fractions of normal and cancerous tissues. Despite their common low signal at g = 2, the structural cancer fractions displayed a remarkable chemical heterogeneity. An important finding was that even cancers of the same histology reacted differently from one another when treated with a variety of chemical probes."
502,Ageing and cancer: the telomere and telomerase connection.,"Shay JW, Wright WE.",https://pubmed.ncbi.nlm.nih.gov/11280022/,"Telomeres are repetitive DNA sequences at the ends of linear chromosomes. Telomerase, a cellular reverse transcriptase, helps stabilize telomere length in human stem, reproductive and cancer cells by adding TTAGGG repeats onto the telomeres. Each time a telomerase-negative cell divides some telomeric sequences are lost. When telomeres are short, cells enter an irreversible growth arrest state called replicative senescence. In most instances cells become senescent before they can become cancerous, thus the growth arrest induced by short telomeres may be a potent anti-cancer mechanism. Since most cancers express telomerase, maintenance of telomere stability is likely to be required for the long-term viability of tumours. Inhibition of telomerase   However, cells with introduced telomerase are not cancer cells since they have not accumulated the other changes needed to become cancerous. This indicates that telomerase-induced telomere length manipulations may have utility for tissue engineering and for dissecting the molecular mechanisms underlying genetic diseases including cancer."
503,Lessons from applied ecology: cancer control using an evolutionary double bind.,"Gatenby RA, Brown J, Vincent T.",https://pubmed.ncbi.nlm.nih.gov/19752088/,"Because the metastatic cascade is largely governed by the ability of malignant cells to adapt and proliferate at the distant tissue site, we propose that disseminated cancers are analogous in many important ways to the evolutionary and ecological dynamics of exotic species. Although pests can be decimated through the application of chemical toxins, this strategy virtually never achieves robust control as evolution of resistant phenotypes typically permits population recovery to pretreatment levels. In general, biological strategies that introduce predators, parasitoids, or pathogens have achieved more durable control of pest populations even after emergence of resistant phenotypes. From this we propose that long term outcome from any treatment strategy for invasive pests, including cancer, is not limited by evolution of resistance, but rather by the phenotypic cost of that resistance. If a cancerous cell's adaptation to therapy is achieved by upregulating xenobiotic metabolism or a redundant signaling pathway, the required investment in resources is small, and the original malignant phenotype remains essentially intact. As a  Robust population control is possible if resistance to therapy requires a substantial and costly phenotypic adaptation that also significantly reduces the organism's fitness in its original niche: an evolutionary double bind."
504,PASuite: a preprocessing algorithm suite for cellular and molecular image classification in cancer diagnosis and treatment.,"Sharma Y, Raza SH, Kong KY, Chaudry Q, Muller S, Young AN, Chen ZG, Wang MD.",https://pubmed.ncbi.nlm.nih.gov/19163366/,"We present a generalized tool to mark and preprocess cancerous regions in an image. Currently, tissue biopsies are analyzed and graded manually by expert pathologists and thus can be time consuming and challenging due to variations in tissue morphology, inconsistencies in preparation of tissue specimen and errors in the image acquisition process. Our tool is designed to automatically standardize the variations in different images due to changing illumination and  Segregating cancerous regions from non-cancerous areas is a mandatory step before extracting relevant information from cancer images such as the number and size of nuclei and subsequently using it for classification and quantitative analysis. We tested our tool for two completely different cancers: Head and Neck Cancer (HNC) and Renal Cell Carcinoma (RCC). The tool enables the user to successfully segment the cancerous areas for both types of cancers and our "
505,Awkward Choreographies from Cancer's Margins: Incommensurabilities of Biographical and Biomedical Knowledge in Sexual and/or Gender Minority Cancer Patients' Treatment.,"Bryson MK, Taylor ET, Boschman L, Hart TL, Gahagan J, Rail G, Ristock J.",https://pubmed.ncbi.nlm.nih.gov/30488328/,"Canadian and American population-based research concerning sexual and/or gender minority populations provides evidence of persistent breast and gynecologic cancer-related health disparities and knowledge divides. The Cancer's Margins research investigates the complex intersections of sexual and/or gender marginality and incommensurabilities and improvisation in engagements with biographical and biomedical cancer knowledge. The study examines how sexuality and gender are intersectionally constitutive of complex biopolitical mappings of cancer health knowledge that shape knowledge access and its mobilization in health and treatment decision-making. Interviews were conducted with a diverse group (n=81) of sexual and/or gender minority breast or gynecologic cancer patients. The LGBQ//T2 cancer patient narratives we have analyzed document in fine grain detail how it is that sexual and/or gender minority cancer patients punctuate the otherwise lockstep assemblage of their cancer treatment decision-making with a persistent engagement in creative attempts to resist, thwart and otherwise manage the possibility of discrimination and likewise, the probability of institutional erasure in care settings. Our findings illustrate the demands that cancer places on LGBQ//T2 patients to choreograph access to, and mobilization of knowledge and care, across significantly distinct and sometimes incommensurable systems of knowledge."
506,"ClearCell® FX, a label-free microfluidics technology for enrichment of viable circulating tumor cells.","Lee Y, Guan G, Bhagat AA.",https://pubmed.ncbi.nlm.nih.gov/30080307/,"Circulating tumor cells (CTCs) dissociate from primary tumor into the bloodstream, and carry with them cancer's fingerprints as well as the potential to turn aggressive and metastasize. In order to understand CTCs and develop clinical utility, different  Here, we report the use of a label-free platform, ClearCell® FX which isolates CTCs by their mechanical features and its advantages. The technology utilizes Dean Flow Fractionation (DFF) principle in a spiral microfluidics system to separate the larger CTCs from smaller blood cells. The gentle and fast workflow allows for a range of downstream assays to be performed on the intact CTCs, particularly studies that examine an epithelial cell adhesion molecular (EpCAM)-independent population. Viable, intact cells are also retrievable for development of culture or in vivo models. © 2018 International Society for Advancement of Cytometry."
507,Genomic analysis of a case of multifocal adenocarcinoma in ulcerative colitis.,"van Dekken H, Wink JC, Vissers KJ, van Marion R, Franken PF, Hoogmans MM, Dinjens WN, Schouten WR, Kuipers EJ, van der Woude CJ.",https://pubmed.ncbi.nlm.nih.gov/17091253/,"Long-standing ulcerative colitis is associated with an elevated risk of developing colonic adenocarcinoma. A very limited group of patients present with multiple synchronous cancers. This could be due to either a multifocal presentation of the same neoplastic clone or different tumors arising in a large area of polyclonal dysplastic colonic mucosa (""field cancerization""). Here, we describe a patient with long-standing colitis and three different tumors in the rectosigmoid part of the large bowel. Clonal evaluation of the lesions was performed by array-based comparative genomic hybridization. These three neoplasms showed a comparable pattern of genomic alterations characterized by gains of chromosomes 12, 13, and 20. Noteworthy, dysplastic mucosa distal to the three cancers displayed a completely different pattern of genomic changes indicating that different cell lineages were present. In addition, all three carcinomas were microsatellite stable and revealed identical immunoprofiles for several cancer-associated genes. We conclude that these three multifocal tumors must have originated from the same preneoplastic lineage."
508,Bioinformatics analysis of prognostic value and immunological role of MeCP2 in pan-cancer.,"Wang Y, Zhang Y, Wang F, Li T, Song X, Shi H, Du J, Zhang H, Jing H, Han J, Tong D, Zhang J.",https://pubmed.ncbi.nlm.nih.gov/36323715/,"Methyl-CpG-binding protein 2(MeCP2) is an important epigenetic regulatory factor that promotes many tumor developments, such as liver cancer, breast cancer, and colorectal cancer. So far, no pan-cancer analysis has been reported. Therefore, this study aims to explore pan-cancer's prognostic value, immune infiltration pattern, and biological function. We used bioinformatics  The  The promoter methylation level of MeCP2 DNA was decreased in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), liver hepatocellular carcinoma (LIHC), prostate adenocarcinoma (PRAD), uterine corpus endometrial carcinoma (UCEC), testicular germ cell tumors (TGCT), and stomach adenocarcinoma (STAD);decreased phosphorylation of S25, S90, S92, S241, S286, S325 and S435 was found in MeCP2, such as UCEC, lung adenocarcinoma (LUAD), ovarian serous cystadenocarcinoma (OV), colon adenocarcinoma (COAD), and kidney renal clear cell carcinoma (KIRC). Furthermore, MeCP2 expression was significantly associated with multiple immunomodulators and immune cell infiltration levels across most tumors. Therefore, our pan-cancer explored the prognostic markers and immunotherapeutic value of MeCP2 in different cancers."
509,Actinic Keratoses: Reconciling the Biology of Field Cancerization with Treatment Paradigms.,Gilchrest BA.,https://pubmed.ncbi.nlm.nih.gov/32956650/,"This Perspective briefly reviews the relationship between UV-induced mutations in habitually sun-exposed human skin and subsequent development of actinic keratoses (AKs) and skin cancers. It argues that field therapy rather than AK-selective therapy is the more logical approach to cancer prevention and hypothesizes that treatment early in the process of field cancerization, even prior to the appearance of AKs, may be more effective in preventing cancer as well as more beneficial for and better tolerated by at-risk individuals. Finally, the Perspective encourages use of rapidly advancing DNA analysis techniques to quantify mutational burden in sun-damaged skin and its reduction by various therapies."
510,PET/CT in oncology: a major technology for cancer care.,Ell PJ.,https://pubmed.ncbi.nlm.nih.gov/16086542/,"PET-CT can image tumor metabolism, proliferation, hypoxia, and apoptosis with precise anatomic image fusion and will become an essential tool in the management of patients with cancer by its ability to assess the extent and severity of disease and treatment response. F-18 fluoro-2-deoxy-D-glucose (FDG) is the most frequently used radiopharmaceautical today and new F-18 labeled ligands are under development. It has changed dramatically the management of numerous cancers such brain tumors, head and neck cancers, thyroid cancer, parathyroid cancer, lung cancer, esophageal cancer, lymphoma, pancreatic cancer, colorectal cancer, and many others. Its utility for non-cancerous conditions is also gradually established. In this article the basic technology, the ligands available for routine clinical applications, and expected developments in the near future will be addressed. PET-CT will be used with increasing frequency and will become progressively used as a surrogate marker for disease response. Novel ligands, labeled with F-18, will further increase the clinical utility of this technology."
511,[Breast cancer prevention: from chemoprevention to prophylactic surgery].,"Morcel K, Rouquette S, Dugast C, Bendavid C, Audrain O, Levêque J.",https://pubmed.ncbi.nlm.nih.gov/18653291/,"
    


          Material and 
    


           The benefit seems continue in time. Raloxifene and tamoxifene effects are comparable with bone benefits and a less risk of endometrial cancer for raloxifene, but the risk of venous thrombosis is still persisting. The breast prophylactic surgery is effective mainly in case of genetic elevated risk when it is practiced in the young age, and requires a patient agreement (the decision needs to follow the patient advice after complete information). The prophylactic ovariectomy has a positive impact on the mammal risk even in the high genetic risk women.
    


          Conclusion:
        
      
      The breast cancer prevention requires a better selection of the patients, an adaptation of the type of prevention taking account of the balance risks and benefits (mammals and extramammals) before a clinical use in routine."
512,Tumor microenvironment: recent advances in various cancer treatments.,"Wang JJ, Lei KF, Han F.",https://pubmed.ncbi.nlm.nih.gov/29949179/,"This is a review regarding different types of cancer treatments. We aimed at analyzing the tumor microenvironment and the recent trends for the therapeutic applications and effectiveness for several kinds of cancers. Traditionally the cancer treatment was based on the neoplastic cells.  The tumor microenvironment describes the non-cancerous cells in the tumor and has enabled to investigate the behavior and response of the cancer cells to a treatment process; it consists in a tissue that may have a predictive significance for tumor behavior and response to therapy. These include fibroblasts, immune cells and cells that comprise the blood vessels. It also includes the proteins produced by all of the cells present in the tumor that support the growth of the cancer cells. By monitoring changes in the tumor microenvironment using its molecular and cellular profiles as the tumor progresses will be vital for identifying cell or protein targets for the cancer prevention and its therapeutic purposes."
513,The betaII isotype of tubulin is present in the cell nuclei of a variety of cancers.,"Yeh IT, Ludueña RF.",https://pubmed.ncbi.nlm.nih.gov/14691949/,"Tubulin, the subunit protein of microtubules, has generally been thought to be exclusively a cytoplasmic protein in higher eukaryotes. We have previously shown that cultured rat kidney mesangial cells contain the betaII isotype of tubulin in their nuclei in the form of an alphabetaII dimer [Walss et al., 1999: Cell Motil. Cytoskeleton 42:274-284, 1999]. More recently, we examined a variety of cancerous and non-cancerous cell lines and found betaII in the nuclei of all of the former and only a few of the latter (Walss-Bass et al., 2002: Cell Tissue Res. 308:215-223]. In order to determine if betaII-tubulin occurs in the nuclei of actual cancers as well as in cancer cell lines, we used the immunoperoxidase  We found that 75% of these tumors contain betaII in their nuclei. Distribution of nuclear betaII was highly dependent on the type of cancer, with 100% of the colon and prostate cancers, but only 19% of the skin tumors, having nuclear betaII. Nuclear betaII was particularly marked in tumors of epithelial origin, of which 83% showed nuclear betaII, in contrast to 54% in tumors of non-epithelial origin. In many cases, betaII staining occurred very strongly in the nuclei and not in the cytoplasm; in other cases, betaII was present in both. In many cases, particularly metastases, otherwise normal cells adjacent to the tumor also showed nuclear betaII, suggesting that cancer cells may influence nearby cells to synthesize betaII and localize it to their nuclei. Our "
514,Light scattering from normal and cervical cancer cells.,"Lin X, Wan N, Weng L, Zhou Y.",https://pubmed.ncbi.nlm.nih.gov/28430229/,"The light scattering characteristic plays a very important role in optic imaging and diagnostic applications. For optical detection of the cell, cell scattering characteristics have an extremely vital role. In this paper, we use the finite-difference time-domain (FDTD) algorithm to simulate the propagation and scattering of light in biological cells. The two-dimensional scattering cell models were set up based on the FDTD algorithm. The cell models of normal cells and cancerous cells were established, and the shapes of organelles, such as mitochondria, were elliptical. Based on these models, three aspects of the scattering characteristics were studied. First, the radar cross section (RCS) distribution curves of the corresponding cell models were calculated, then corresponding relationships between the size and the refractive index of the nucleus and light scattering information were analyzed in the three periods of cell canceration. The values of RCS increase positively with the increase of the nucleo-cytoplasmic ratio in the cancerous process when the scattering angle ranges from 0° to 20°. Second, the effect of organelles in the scattering was analyzed. The peak value of the RCS of cells with mitochondria is higher than the cells without mitochondria when the scattering angle ranges from 20° to 180°. Third, we demonstrated that the influence of cell shape is important, and the impact was revealed by the two typical ideal cells: round cells and oval cells. When the scattering angle ranges from 0° to 80°, the peak values and the frequencies of the appearance of the peaks from the two models are roughly similar. It can be concluded that: (1) the size of the nuclei and the change of the refractive index of cells have a certain impact on light scattering information of the whole cell; (2) mitochondria and other small organelles contribute to the cell light scattering characteristics in the larger scattering angle area; and (3) the change of the cell shape significantly influences the value of scattering peak and the deviation of scattering peak position. The "
515,"Traditional medicines, collective negotiation, and representations of risk in Indian cancer care.","Broom AF, Doron A.",https://pubmed.ncbi.nlm.nih.gov/23044983/,"Cancer is emerging as a key disease in India, but there has been virtually no research exploring understandings of cancer and practices of communication within oncology settings. This is despite the fact that the Indian context presents clinicians, patients, and family members with a range of unique challenges, including those related to disease awareness, interpersonal dynamics, and the use of traditional, complementary, and alternative medicines (TCAM). Drawing on a series of qualitative interviews with 22 Delhi-based oncology clinicians, in this article we examine clinicians' accounts of communication with their cancer patients. The interviews reveal the challenges of communication given cancer's relative novelty, cultural practices around collective negotiation, and rhetorical practices evident in advice-giving regarding TCAM. We conclude that with cancer set to become a major burden in India, research exploring competing forms of expertise, the politics of representation, and the nexus between traditional beliefs and techno-scientific development is urgently needed."
516,Characteristics of Epstein-Barr virus-associated gastric carcinoma with lymphoid stroma in Japan.,"Matsunou H, Konishi F, Hori H, Ikeda T, Sasaki K, Hirose Y, Yamamichi N.",https://pubmed.ncbi.nlm.nih.gov/8640662/," However, there are many clinicopathologic problems that remain unsolved.
    


           In addition, nine patients who had advanced gastric carcinoma with massive liver metastases, who showed good response to chemotherapy and had prolonged survival, were examined for the presence or absence of EBV-associated GCLS.
    


          6%) of 26 GCLS. Hybridization signals were also noted in all four non-GCLS adenocarcinomas accompanying GCLS. As a  Long term survivors with liver metastases included two patients with EBV-associated GCLS.
    


          Conclusion:
        
      
      Approximately 84.6% of GCLS were related to EBV. EBV-associated GCLS constitutes one-half of the EBV-infected stomach cancers in our institution. The complete response and long term survival after conventional chemotherapy of two patients with Stage IV GCLS suggests that this form of gastric carcinoma may be especially sensitive to this treatment. The identification of EBV-associated synchronous multicentric cancers of both GCLS and non-GCLS type suggests that EBV infection may be an early event in the induction process of these tumors."
517,"The potential role of miR-29 in health and cancer diagnosis, prognosis, and therapy.","Alizadeh M, Safarzadeh A, Beyranvand F, Ahmadpour F, Hajiasgharzadeh K, Baghbanzadeh A, Baradaran B.",https://pubmed.ncbi.nlm.nih.gov/30950056/,"miR-29 family is one of the small noncoding RNAs and has a very important role in many physiologic and pathologic functions through regulating the target genes that play roles in various bioprocesses such as proliferation, survival, apoptosis, and angiogenesis. Thus, we aim to survey the potential of the miR-29 family in normal model and development and progression of malignancy in this study. In addition, the potential role of miR-29 family has been studied as the clinical marker for the diagnosis and prognosis of many cancers as the potential targets to treat cancer. Moreover, it was stated in summary that the herbal compounds can regulate miR-29 family in cancers. Therefore, regulating the expression of the miR-29 family in a variety of cancers can be a new strategy to obtain better "
518,Macrophages hold the key to cancer's inner sanctum.,Wolf GL.,https://pubmed.ncbi.nlm.nih.gov/30593391/,"All malignancies contain tumor-associated macrophages (TAMs) that facilitate cancer growth by secreting chemicals to elicit angiogenesis and shield the cancer from the immune system. The abundance of TAMs is a reflection of invasiveness and metastatic potential. TAMs will actively ingest ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles following intravenous administration and will store them as large lysosomal aggregates which can be imaged with MRI and ultrasound and visualized or quantitated in tissue biopsies. Since the USPIO also enhances regional lymph nodes, it is possible to include this information for more accurate cancer staging. The USPIO aggregates surprisingly also serve as heat sinks and can enhance hyperthermic regimens with focal laser, focused microwaves, or high-intensity focused ultrasound (HIFU). The hyperthermic intervention can be chosen based upon accessibility for the selected energy source. By sustaining an intratumoral elevation of temperature for an effective period of time, ablation of a small or large fraction of the TAMs and cancer cells can be achieved. Thus, for aggressive cancer, USPIO is a theragnostic agent. Following USPIO-enhanced hyperthermia, the  An effective vaccine or adjuvant could be injected peritumorally to improve immunorecognition of that patient's cancer. The field of immunotherapy is being intensely explored at present. Using the theragnostic properties of USPIOs that are accumulated in the TAMs may prove useful in further attempts to make immunotherapy successful. This intervention could be utilized at any stage of cancer therapy. Should immunological recognition occur, an abscopal response may be achieved for that patient and for his/her cancer. This would truly be personalized cancer therapy."
519,Clinical experience with autofluorescence imaging system in patients with lung cancers and precancerous lesions.,"Ueno K, Kusunoki Y, Imamura F, Yoshimura M, Yamamoto S, Uchida J, Tsukamoto Y.",https://pubmed.ncbi.nlm.nih.gov/16679756/," Autofluorescence bronchoscopy is a useful device in the detection of preinvasive and cancerous lesions. Recently, a new autofluorescence bronchoscopic system, autofluorescence imaging (AFI) system, has been developed.
    


          
    


           We evaluated autofluorescence findings using a four-point scale: AFI-I, II, III, and B. The findings in WLB were evaluated on a three-point scale: WLB-I, II, and III. Abnormal areas by WLB and AFI were biopsied for histopathological examinations.
    


           When the AFI-III finding was regarded as positive in AFI and WLB-III as positive in WLB, sensitivity for severe dysplasia or worse was 94.7% with AFI and 73.7% with WLB, respectively.
    


          Conclusions:
        
      
      AFI is an effective system for the detection of precancerous and cancerous lesions."
520,"Machine Learning Approach to Facilitate Knowledge Synthesis at the Intersection of Liver Cancer, Epidemiology, and Health Disparities Research.","Hyams TC, Luo L, Hair B, Lee K, Lu Z, Seminara D.",https://pubmed.ncbi.nlm.nih.gov/35623021/,"Purpose:
        
      
      Liver cancer is a global challenge, and disparities exist across multiple domains and throughout the disease continuum. However, liver cancer's global epidemiology and etiology are shifting, and the literature is rapidly evolving, presenting a challenge to the synthesis of knowledge needed to identify areas of research needs and to develop research agendas focusing on disparities. Machine learning (ML) techniques can be used to semiautomate the literature review process and improve efficiency. In this study, we detail our approach and provide practical benchmarks for the development of a ML approach to classify literature and extract data at the intersection of three fields: liver cancer, health disparities, and epidemiology.
    


           We then developed an extraction model (V) and applied it (VI) to the liver cancer literature identified through PubMed. We present precision, recall, F1, and accuracy metrics for the classifier and extraction models as appropriate for each phase of the process. We also provide the 
    


           The disparities concept was the most challenging to accurately classify, and concepts that appeared infrequently in our data set were the most difficult to extract.
    


          Conclusion:
        
      
      We provide a roadmap for using ML to classify and extract comprehensive information on multidisciplinary literature. Our technique can be adapted and modified for other cancers or diseases where disparities persist."
521,[Feelings and experiences in women with breast cancer's life].,"Vieira CP, Lopes MH, Shimo AK.",https://pubmed.ncbi.nlm.nih.gov/17722400/,"Identifying feelings and experiences related to breast cancer becomes important to enable those who are part of a woman's social circle to grasp this stage of her life. For this study, a literature review was carried out in order to identify what are the most common thoughts and feelings women experience after a breast cancer diagnosis. The review was conducted through bibliographical research in LILACS and MEDLINE databases using the key words breast, cancer, feeling, female, and representation. Contents related to cancer were searched, such as the meaning of the disease and its implication to the woman's emotional and social life. The conclusion was that experiences related to breast cancer have an individual scope, and that their representations are different for each woman."
522,Cellular signaling modulated by miRNA-3652 in ovarian cancer: unveiling mechanistic pathways for future therapeutic strategies.,"Imran K, Iqbal MJ, Abid R, Ahmad MM, Calina D, Sharifi-Rad J, Cho WC.",https://pubmed.ncbi.nlm.nih.gov/37845675/,"MicroRNAs (miRNAs) are small non-coding RNA molecules that play pivotal roles in regulating gene expression and have been implicated in the pathogenesis of numerous cancers. miRNA-3652, though relatively less explored, has recently emerged as a potential key player in ovarian cancer's molecular landscape. This review aims to delineate the functional significance and tumor progression role of miRNA-3652 in ovarian cancer, shedding light on its potential as both a diagnostic biomarker and therapeutic target. A comprehensive literature search was carried out using established databases, the focus was on articles that reported the role of miRNA-3652 in ovarian cancer, encompassing mechanistic insights, functional studies, and its association with clinical outcomes. This updated review highlighted that miRNA-3652 is intricately involved in ovarian cancer cell proliferation, migration, and invasion, its dysregulation was linked to altered expression of critical genes involved in tumor growth and metastasis; furthermore, miRNA-3652 expression levels were found to correlate with clinical stages, prognosis, and response to therapy in ovarian cancer patients. miRNA-3652 holds significant promise as a vital molecular player in ovarian cancer's pathophysiology. Its functional role and impact on tumor progression make it a potential candidate for diagnostic and therapeutic applications in ovarian cancer. Given the pivotal role of miRNA-3652 in ovarian cancer, future studies should emphasize in-depth mechanistic explorations, utilizing advanced genomic and proteomic tools. Collaboration between basic scientists and clinicians will be vital to translating these findings into innovative diagnostic and therapeutic strategies, ultimately benefiting ovarian cancer patients. Video Abstract."
523,The diagnosis of lung cancer using 1064-nm excited near-infrared multichannel Raman spectroscopy.,"Yamazaki H, Kaminaka S, Kohda E, Mukai M, Hamaguchi HO.",https://pubmed.ncbi.nlm.nih.gov/12801137/,"Purpose:
        
      
      Raman spectroscopy is based on Raman scattering of light from molecules. Because the wavelength of Raman scattered light depends on molecular composition, Raman spectra provide highly useful information about molecular composition. It has already been shown that Raman spectroscopy is potentially useful for the clinical diagnosis of malignant tumors. However, this technique had never been applied to the diagnosis of lung cancers, primarily because of interference from the strong fluorescence emitted from lung tissues. Our purpose was to examine the effectiveness of near-infrared Raman spectroscopy for the diagnosis of lung cancers.
    


           Using this system, we collected a total of 210 Raman spectra from cancerous and non-cancerous lung tissues and analyzed these spectra by a least-squares fitting procedure for cancer diagnosis.
    


          0001 according to Fisher's exact test.
    


          Conclusions:
        
      
      A "
524,State-level cancer quality assessment and research: building and sustaining the data infrastructure.,"Lipscomb J, Gillespie TW.",https://pubmed.ncbi.nlm.nih.gov/21799333/,"Over a decade ago, the Institute of Medicine called for a national cancer data system in the United States to support quality-of-care assessment and improvement, including research on effective interventions. Although considerable progress has been achieved in cancer quality measurement and effectiveness research, the nation still lacks a population-based data infrastructure for accurately identifying cancer patients and tracking services and outcomes over time. For compelling reasons, the most effective pathway forward may be the development of state-level cancer data systems, in which central registry data are linked to multiple public and private secondary sources. These would include administrative/claims files from Medicare, Medicaid, and private insurers. Moreover, such a state-level system would promote rapid learning by encouraging adoption of near-real-time reporting and feedback systems, such as the Commission on Cancer's new Rapid Quality Reporting System. The groundwork for such a system is being laid in the state of Georgia, and similar work is advancing in other states. The pace of progress depends on the successful resolution of issues related to the application of information technology, financing, and governance."
525,Genitourinary cancers: molecular determinants for personalized therapies.,"Mazzucchelli R, Gasparrini S, Galosi AB, Massari F, Raspollini MR, Scarpelli M, Lopez-Beltran A, Cheng L, Montironi R.",https://pubmed.ncbi.nlm.nih.gov/27338983/,"Recent insights and emerging strategies for individualized therapeutic approaches in patients with genitourinary (GU) cancers are based on patient's genomic and cancer's molecular profiles. This depends on the significant advances made in molecular biology technologies, such as next-generation sequencing and whole-exome sequencing. The rise of such novel techniques has grayly increased our knowledge on cancer cell biology and development, thus allowing to identify complex abnormalities at the genomic level. These findings have paved the way toward what is called precision medicine, thus providing healthcare from an individual perspective in patients with GU tumors."
526,[Diagnosing intramucosal cancers of the esophagus].,Nishizawa M.,https://pubmed.ncbi.nlm.nih.gov/2431169/,"We have come to the following conclusions based on 11 cases of resected mucosal cancers of the esophagus. X-ray findings of esophageal mucosal cancer can be characterized by; concerning marginal changes, limited extension with irregularities. concerning mucosal changes, slightly elevated plateau and shallow erosions. Endoscopic findings can be characterized by reddening, discoloration, shallow depression, coarse mucosal appearance, and plateau showing whitish hue. Lugol dye-scattering turned out to be extremely effective in defining location, size, shape, and spread of cancerous invasion. 8 out of 11 cases were intraepithelial cancers, mostly showing superficial flat type. Mucosal cancers of the esophagus can be detected very effectively, males over 50 being of a high risk and panendoscope being employed."
527,"Proliferative verrucous leukoplakia: unusual locations of oral squamous cell carcinomas, and field cancerization as shown by the appearance of multiple OSCCs.","Bagán JV, Murillo J, Poveda R, Gavaldá C, Jiménez Y, Scully C.",https://pubmed.ncbi.nlm.nih.gov/14969824/,"Proliferative verrucous leukoplakia (PVL) is an uncommon entity with a high tendency to develop oral squamous cell carcinomas (OSCCs). The  We studied 19 patients with PVL who had developed at least one OSCC. We analysed how many of these developed more than one OSCC over a period between 24 and a maximum of 130 months, indicating the location of their OSCC, clinical type and the time lapse between the appearance of each of the different OSCCs in the same patient. Of the 19 patients, 10 presented more than one of these cancers, one of whom even went on to develop five different cancers. The most frequent location of OSCC was the gingiva and the palate; the least common was the tongue/floor of mouth. Ninety percent were women and 20% were smokers. The average time elapsed between the detection of the first tumour and the appearance of the second was 19.20 months (SD 13.41). Our patients with PVL developed a high frequency of OSCCs, on many occasions manifesting several cancers at different oral locations, thus demonstrating the field cancerization of this entity. The OSCC in PVL patients were at sites quite uncommonly affected in patients who develop OSCC in the absence of PVL."
528,Comparative molecular subtypes of index and metachronous gastric adenocarcinomas: a study of 42 Korean patients.,"Kim BH, Kővári B, Kim H, Boulware DC, Pimiento J, Lauwers GY.",https://pubmed.ncbi.nlm.nih.gov/34193964/,"To date, there have been no studies comparing the molecular subtypes of Index gastric cancers (IGCs) and metachronous gastric cancers (MGCs). We evaluated a cohort of 42 patients with 43 IGCs and 45 MGCs. Molecular subtyping was performed by immunohistochemistry of mismatch repair (MMR) proteins, E-cadherin, p53, and Epstein-Barr virus- (EBV-) in situ hybridization (ISH). Gastric adenocarcinomas were classified into 5 subtypes: EBV-associated, MMR deficient (MMRD), E-cadherin aberrant, p53-aberrant [p53(+)], and p53 non-aberrant [p53(neg)]. All IGCs had been successfully treated by either surgery (19%) or endoscopic resection (81%). The mean interval between IGCs and MGCs was 85 months. Among the IGCs, EBV-associated, MMRD, E-cadherin-aberrant, p53(+), and p53(neg) molecular subtypes represented 2 (5%), 4 (9%), 2 (5%), 21 (49%), and 14 (32%) of the cases, respectively. Two cases had concomitant p53(+) and aberrant E-cadherin molecular subtypes. Among metachronous cancers, EBV-associated, MMRD, E-cadherin-aberrant, p53(+), and p53(neg) molecular subtypes represented 3 (7%), 11 (24%), 0 (0%), 22 (49%), and 9 (20%) cases. Concomitant p53(+) was observed in 1 EBV-associated and 2 MMRD MGCs. Although, there was no significant difference in the frequency of most molecular subtypes in IGCs and MGCs, the number of MMRD gastric cancers more than doubled in the MGC group. Half of the MGCs had a divergent molecular subtype compared to that of the IGCs. Notably, the interval between the development of IGCs and MGCs was significantly longer in patients with divergent molecular subtypes (P = 0.010). All 4 patients with MMRD IGC developed MMRD MGCs. Although the concept of mucosal field cancerization may explain the matching molecular subtypes in early-developing MGCs, the presence of divergent subtypes in late-occurring MGCs suggests a shift in the carcinogenic mechanism affecting the residual mucosa possibly related to Helicobacter pylori eradication."
529,"Iron, Copper, and Selenium: Cancer's Thing for Redox Bling.","Terzi EM, Possemato R.",https://pubmed.ncbi.nlm.nih.gov/37932129/,"Cells require micronutrients for numerous basic functions. Among these, iron, copper, and selenium are particularly critical for redox metabolism, and their importance is heightened during oncogene-driven perturbations in cancer. In this review, which particularly focuses on iron, we describe how these micronutrients are carefully chaperoned about the body and made available to tissues, a process that is designed to limit the toxicity of free iron and copper or by-products of selenium metabolism. We delineate perturbations in iron metabolism and iron-dependent proteins that are observed in cancer, and describe the current approaches being used to target iron metabolism and iron-dependent processes."
530,[Field cancerization and field therapy - the therapy of actinic keratosis by imiquimod].,Idezuki T.,https://pubmed.ncbi.nlm.nih.gov/23306911/,"Field cancerization is a phenomenon in which multiple cancers easily occur on a specific area by carcinogens such as alcohol or ultraviolet rays. Deficiency of aldehyde dehydrogenase-2 increases the level of formaldehyde when drinking, and is considered an important factor for causing middle or lower pharyngeal cancer and esophageal cancer. Multiple actinic keratoses frequently occur both in synchronism or asynchronism on elderly people as a consequence of cumulative ultraviolet exposure. Field therapy, the regional overall treatment of actinic keratosis which takes place on the same field, is made possible by external use of imiquimod cream. Imiquimod is a topical immune response modifier which is effective through toll-like receptor 7, and it has fewer recurrences of actinic keratoses than the existing treatment."
531,Research and Patents Status of Selected Phytochemicals Against Cancer: How Close and How Far?,"Fatma H, Siddique HR.",https://pubmed.ncbi.nlm.nih.gov/36345243/," Over the years, the underlying molecular mechanism of cancers was thoroughly researched, leading to multiple drugs' development. Unfortunately, most drugs have some serious drawbacks, such as therapy resistance and toxicity. Epidemiological studies have shown that a diet rich in fruits and vegetables has cancer prevention properties, which shifted the attention to the potential role of phytochemicals in anti-carcinogenic activity.
    


          
    


          
    


           Thus, phytochemicals might be an excellent chemosensitizing agent against chemoresistant cells and possibly one of the safest and most effective options for cancer therapy. However, one of the limitations of phytochemicals is their poor bioavailability and rapid excretion. Several analogs have been introduced to increase bioavailability, better biological efficacy, absorption, and retention. In fact, various phytochemicals and their analogs have been patented for their anti-cancerous properties.
    


          Conclusion:
        
      
      This mini-review discusses various phytochemicals and their anti-cancerous and chemosensitizing roles. Due to their clinical relevance, recent trends in phytochemical extraction and exploration have shown that more and more phytochemicals are being patented."
532,Un-FASN-ing cancer's seat belt: Linking lipid metabolism and antigen presentation.,"Corey Z, Schechter E, Nemenoff RA.",https://pubmed.ncbi.nlm.nih.gov/37738950/,"MHC-II expression on cancer cells is associated with improved treatment outcome. In this issue, Huang et al.1 report a panel of small molecules that selectively upregulate MHC-II on cancer cells through suppression of fatty acid synthase (FASN),  Targeting this link between lipid metabolism and antigen presentation may improve response to immunotherapy."
533,Metabolic adaptation in hypoxia and cancer.,"Paredes F, Williams HC, San Martin A.",https://pubmed.ncbi.nlm.nih.gov/33444690/,"The ability of tumor cells to adapt to changes in oxygen tension is essential for tumor development. Low oxygen concentration influences cellular metabolism and, thus, affects proliferation, migration, and invasion. A focal point of the cell's adaptation to hypoxia is the transcription factor HIF1α (hypoxia-inducible factor 1 alpha), which affects the expression of specific gene networks involved in cellular energetics and metabolism. This review illustrates the mechanisms by which HIF1α-induced metabolic adaptation promotes angiogenesis, participates in the escape from immune recognition, and increases cancer cell antioxidant capacity. In addition to hypoxia, metabolic inhibition of 2-oxoglutarate-dependent dioxygenases regulates HIF1α stability and transcriptional activity. This phenomenon, known as pseudohypoxia, is frequently used by cancer cells to promote glycolytic metabolism to support biomass synthesis for cell growth and proliferation. In this review, we highlight the role of the most important metabolic intermediaries that are at the center of cancer's biology, and in particular, the participation of these metabolites in HIF1α retrograde signaling during the establishment of pseudohypoxia. Finally, we will discuss how these changes affect both the development of cancers and their resistance to treatment."
534,Decreased expression of S100A6 in oral squamous cell carcinoma.,"Yang X, Wei KJ, Zhang L, Pan HY, Ye DX, Zhong LP, Zhang ZY.",https://pubmed.ncbi.nlm.nih.gov/20596636/,"We previously established an in vitro cellular carcinogenesis model of oral squamous cell carcinoma (OSCC) with a line of human immortalized oral epithelia cells (HIOECs), a line of cancerous HB96 cells, and other cells (HB56 cells) at the early stage of carcinogenesis. In this study, comparative proteomic analysis identified a panel of differentially expressed proteins among these cells, and S100A6 was shown as one of the significantly down-regulated proteins accompanying cellular transformation. S100A6 was further validated for its expression in the three cell lines and in the clinical samples of cancerous and paracancerous tissues from 30 primary OSCC patients. Western blot analysis and real-time PCR revealed the decreased S100A6 protein and mRNA levels in the cancerous HB56 and HB96 cells over HIOECs. Immunohistochemistry and real-time PCR also showed decreased S100A6 protein and mRNA levels in the cancerous tissues compared to the paracancerous tissues from OSCC patients. The "
535,The coming decade in precision oncology: six riddles.,"Wahida A, Buschhorn L, Fröhling S, Jost PJ, Schneeweiss A, Lichter P, Kurzrock R.",https://pubmed.ncbi.nlm.nih.gov/36434139/,"High-throughput  The singular lesson of precision oncology might be that, for it to be precise, treatment must be personalized, as each cancer's complex molecular and immune landscape differs from patient to patient. Transformative therapies include those that are targeted at the sequelae of molecular abnormalities or at immune mechanisms, and, increasingly, pathways previously thought to be undruggable have become druggable. Critical to applying precision medicine is the concept that the right combination of drugs must be chosen for each patient and used at the right stage of the disease. Multiple puzzles remain that complicate therapy choice, including evidence that deleterious mutations are common in normal tissues and non-malignant conditions. The host's role is also likely to be key in determining treatment response, especially for immunotherapy. Indeed, maximizing the impact of immunotherapy will require omic analyses to match the right immune-targeted drugs to the individualized patient and tumour setting. In this Perspective, we discuss six key riddles that must be solved to optimize the application of precision oncology to otherwise lethal malignancies."
536,[Relation between aging and cancer].,"Sato T, Miyaishi O.",https://pubmed.ncbi.nlm.nih.gov/1987890/,"Relationship between aging and cancerization is a very interesting problem to be clarified in future. As the most important finding in the aged, Tauchi previously proposed a decrease in number of the parenchymal cells due mainly to ""inhibitory factors for cell division"", which increase with growth, differentiation, maturation and aging of the cells, and for the cancerization he suggested a loss of the ""inhibitory factors"" due to dedifferentiation of the cells. On the growth promoting and/or inhibitory factors, some discussions have been made, in relation to the immortalization, and cancerization of the cells and also to the aging process of them."
537,Micronutrients Importance in Cancer Prevention-Minerals.,"Saeed RF, Awan UA, Aslam S, Qazi AS, Bhatti MZ, Akhtar N.",https://pubmed.ncbi.nlm.nih.gov/39133407/,"Cancer, a non-communicable disease with diverse kinds is one of the major global problems with high incidence and no proven  Minerals including trace elements are significant micronutrients for preserving the body's typical physiological function. In contrast to extremely processed industrial food, they are rich in natural sources of food and frequently included in nutritional supplements. The daily intake, storage capacities, and homeostasis of micronutrients depend on specific dietary practices in contemporary civilization and can be disturbed by various malignancies. Varied minerals have different effects on the status of cancer depending on how they affect these pathways. The outcomes could differ depending on the mineral such as calcium's supply and the cancer's location. A mineral called zinc helps the immune system function better and aids in wound healing. On the other hand, selenium exhibits anti-oxidant functions and has a dose-response relationship with many cancer types. However, this component can make the patient's condition worse. Although the body produces free radicals when iron is deficient, anaemia affects a patient's quality of life and ability to receive therapy. This chapter compiles the knowledge of minerals connected to unusual accumulation or depletion states in various malignancies."
538,CAR T treatment beyond cancer: Hope for immunomodulatory therapy of non-cancerous diseases.,"Yang Z, Liu Y, Zhao H.",https://pubmed.ncbi.nlm.nih.gov/38471620/,"Engineering a patient's own T cells to accurately identify and eliminate cancer cells has effectively cured individuals afflicted with previously incurable hematologic cancers. These findings have stimulated research into employing chimeric antigen receptor (CAR) T therapy across various areas within the field of oncology. However, evidence from both clinical and preclinical investigations emphasize the broader potential of CAR T therapy, extending beyond oncology to address autoimmune disorders, persistent infections, cardiac fibrosis, age-related ailments and other conditions. Concurrently, the advent of novel technologies and platforms presents additional avenues for utilizing CAR T therapy in non-cancerous contexts. This review provides an overview of the rationale behind CAR T therapy, delineates ongoing challenges in its application to cancer treatment, summarizes recent findings in non-cancerous diseases, and engages in discourse regarding emerging technologies that bear relevance. The review delves into prospective applications of this therapeutic approach across a diverse range of scenarios. Lastly, the review underscores concerns related to precision and safety, while also outlining the envisioned trajectory for extending CAR T therapy beyond cancer treatment."
539,Evidence for field effect cancerization in colorectal cancer.,"Hawthorn L, Lan L, Mojica W.",https://pubmed.ncbi.nlm.nih.gov/24316131/,"We compared transcript expression, and chromosomal changes on a series of tumors and surrounding tissues to determine if there is evidence of field cancerization in colorectal cancer. Epithelial cells were isolated from tumors and areas adjacent to the tumors ranging from 1 to 10cm. Tumor abnormalities mirrored those previously reported for colon cancer and while the number and size of the chromosomal abnormalities were greatly reduced in cells from surrounding regions, many chromosome abnormalities were discernable. Interestingly, these abnormalities were not consistent across the field in the same patient samples suggesting a field of chromosomal instability surrounding the tumor. A mutator phenotype has been proposed to account for this instability which states that the genotypes of cells within a tumor would not be identical, but would share at least a single mutation in any number of genes, or a selection of genes affecting a specific pathway which provide a proliferative advantage."
540,"A systematic review of photodynamic therapy in the treatment of pre-cancerous skin conditions, Barrett's oesophagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin.","Fayter D, Corbett M, Heirs M, Fox D, Eastwood A.",https://pubmed.ncbi.nlm.nih.gov/20663420/," PDT is used either as a primary treatment or as an adjunctive treatment. It is fairly well accepted in clinical practice for some types of skin cancer but has yet to be fully explored as a treatment for other forms of cancer.
    


          
    


          Data sources:
        
      
      The search strategy included searching electronic databases (between August and October 2008), followed by update searches in May 2009, along with relevant bibliographies, existing reviews, conference abstracts and contact with experts in the field.
    


          Study designs:
        
      
      Randomised controlled trials (RCTs) in skin conditions and Barrett's oesophagus, non-randomised trials for all other sites.
    


          Participants:
        
      
      People with Barrett's oesophagus, pre-cancerous skin conditions or primary cancer in the following sites: biliary tract, brain, head and neck, lung, oesophageal and skin.
    


          Intervention:
        
      
      Any type of PDT for either curative or palliative treatment.
    


          Comparators:
        
      
      Any comparator including differing applications of PDT treatments (relevant comparators varied according to the condition).
    


          Main outcomes:
        
      
      The outcomes measured were mortality, morbidity, quality of life, adverse events and resource use.
    


          Review  The quality of RCTs and non-randomised controlled studies was assessed using standard checklists. Data extracted from the studies were tabulated and discussed in a narrative synthesis, and the influence of study quality on  Meta-analysis was used to estimate a summary measure of effect on relevant outcomes, with assessment of both clinical and statistical heterogeneity. Two reviewers independently screened all titles and abstracts, and data extracted and quality assessed the trials, with discrepancies resolved by discussion or referral to a third reviewer. A scoping review was also undertaken.
    


           For actinic keratosis (AK), the only clear evidence of effectiveness was that PDT appeared to be superior to placebo. For Bowen's disease, better outcomes with PDT were suggested when compared with cryotherapy or fluorouracil. For basal cell carcinoma (BCC), PDT may  For nodular lesions, PDT appeared to be superior to placebo and less effective than surgery but suggestive of better cosmetic outcome. For Barrett's oesophagus, PDT in addition to omeprazole appeared to be more effective than omeprazole alone at long-term ablation of high-grade dysplasia and slowing/preventing progression to cancer. No firm conclusions could be drawn for PDT in oesophageal cancer. Further research into the role of PDT in lung cancer is needed. For cholangiocarcinoma, PDT may improve survival when compared with stenting alone. There was limited evidence on PDT for brain cancer and cancers of the head and neck. A wide variety of photosensitisers were used and, overall, no serious adverse effects were linked to PDT.
    


          Limitations:
        
      
      There were few well-conducted, adequately powered RCTs, and quality of life (QoL) and resource outcomes were under-reported. Problems were identified with reporting of key study features and quality parameters, making the reliability of some studies uncertain. 
    


          Conclusions:
        
      
      Evidence of effectiveness was found for PDT in the treatment of AK and nodular BCC in relation to placebo, and possibly for treating Barrett's oesophagus. However, the effectiveness of PDT in relation to other treatments is not yet apparent. High-quality trials are needed to compare PDT with relevant comparators for all meaningful outcomes, including QoL and adverse effects. Further research is also needed on patient experience of PDT, as well as on the cost-effectiveness of PDT."
541,"Protocol of mixed-methods assessment of demographic, epidemiological and clinical profile of decentralised patients with cancer at Nelson Mandela Academic Hospital and Rob Ferreira Hospital, South Africa.","Chitha W, Jafta Z, Mnyaka OR, Hongoro D, Godlimpi L, Swartbooi B, Williams N, Zungu C, Buthi L, Kuseni S, Nasila J, Sibulawa S, Giwu O, Mavimbela A, Essel V, Mabunda SA.",https://pubmed.ncbi.nlm.nih.gov/35450901/," However, cancer care services are often concentrated in urban centres. Two of South Africa's hospitals have decentralised cancer care delivery since February 2018 and August 2019, respectively. This study aims to describe the demographic, epidemiological and clinical profile of various cancers at Nelson Mandela Academic Hospital (NMAH) and Rob Ferreira Hospital (RFH), in South Africa's Eastern Cape and Mpumalanga provinces, respectively.
    


           A mixed- A validated, researcher-administered survey questionnaire will be used to assess demographic characteristics, and prevalence of different cancers among patients. Concurrently, a document review will be undertaken on patients with cancer using a patient registry to ascertain the duration of diagnosis, type of cancer(s), management plan and patient survival time. STATA V.17 will be used for data analysis. The Shapiro-Wilk test will be used to explore the distribution of numerical variables. The χ2 or Fisher's exact tests will be used depending on the value of the expected frequencies to compare categorical variables. Kaplan-Meier survival estimates will be used to determine the survival time. Hazard ratios will be used to determine the predictors of death. The level of statistical significance will be set at p value ≤0.05. The 95% CI will be used for the precision of estimates.
    


          Ethics and dissemination:
        
      
      Ethics approval was obtained from the Human Research Ethics Committees of the University of the Witwatersrand (M210211) and Walter Sisulu University, South Africa (Ref: 040/2020). Findings will be reported through peer-reviewed journal(s), presentations at conferences and at partner meetings."
542,Revisiting the transcriptional analysis of primary tumours and associated nodal metastases with enhanced biological and statistical controls: application to thyroid cancer.,"Tarabichi M, Saiselet M, Trésallet C, Hoang C, Larsimont D, Andry G, Maenhaut C, Detours V.",https://pubmed.ncbi.nlm.nih.gov/25965298/," The interpretation of these data, however, is not without ambiguities.
    


           We also included patient-matched non-cancerous thyroid and lymph node samples as controls to address some limits of previous studies.
    


           This similarity partly reflected patient  Lymphoid tissues in the metastases confounded the comparison of patient-matched primary tumours and metastases. We circumvented this with an original data adjustment, revealing a differential expression of stroma-related gene signatures also regulated in other organs. The comparison of N0 vs N+ primary tumours uncovered a signal irreproducible across independent data sets. This signal was also detectable when comparing the non-cancerous thyroid tissues adjacent to N0 and N+ tumours, suggesting a cohort-specific bias also likely present in previous similarly sized studies. Classification of N0 vs N+ yielded an accuracy of 63%, but additional statistical controls absent in previous studies revealed that this is explainable by chance alone. We used large data sets from The Cancer Genome Atlas: N0 vs N+ classification was not better than random for most cancers. Yet, it was significant, but of limited accuracy (<70%) for thyroid, breast and head and neck cancers.
    


          Conclusions:
        
      
      The clinical potential of gene expression to predict nodal metastases seems limited for most cancers."
543,"Defeating Cancers' Adaptive Defensive Strategies Using Thermal Therapies: Examining Cancer's Therapeutic Resistance, Ablative, and Computational Modeling Strategies as a means for Improving Therapeutic Outcome.","Baust JM, Rabin Y, Polascik TJ, Santucci KL, Snyder KK, Van Buskirk RG, Baust JG.",https://pubmed.ncbi.nlm.nih.gov/29566612/," Commonly applied with the intent to cure, these ablative therapies are providing promising success rates similar to and often exceeding ""gold standard"" approaches. Cancer-curing prospects may be enhanced by deeper understanding of thermal effects on cancer cells and the hosting tissue, including the molecular mechanisms of cancer cell mutations, which enable resistance to therapy. Furthermore, thermal ablative therapies may benefit from recent developments in computer hardware and computation tools for planning, monitoring, visualization, and education.
    


           Further, these discoveries are now providing insight into the success of the diverse types of ablative therapies utilized in the clinical arena today and into how they directly and indirectly overcome many of the cancers' defensive strategies. Additionally, the manner in which minimally invasive thermal therapy is enabled by imaging, which facilitates anatomical features reconstruction, insertion guidance of thermal probes, and strategic placement of thermal sensors, plays a critical role in the delivery of effective ablative treatment.
    


           Also discussed is the development of thermal adjunctive therapies-the combination of drug and thermal treatments-which provide new and more effective combinatorial physical and molecular-based approaches for treating various cancers. Finally, advanced computational and planning tools are also discussed.
    


          Conclusion:
        
      
      This review lays out the various molecular adaptive mechanisms-the hallmarks of cancer-responsible for therapeutic resistance, on one hand, and how various ablative therapies, including both heating- and freezing-based strategies, overcome many of cancer's defenses, on the other hand, thereby enhancing the potential for curative approaches for various cancers."
544,Direct measurement of human lung cancerous and noncancerous tissues by fourier transform infrared microscopy: can an infrared microscope be used as a clinical tool?,"Yano K, Ohoshima S, Gotou Y, Kumaido K, Moriguchi T, Katayama H.",https://pubmed.ncbi.nlm.nih.gov/11112267/,"We have analyzed very small amounts of human lung cancerous tissues directly by a Fourier transform infrared microscopy (FT-IR-MC). The corrected peak heights (H1045 and H1467) obtained from the bands at 1045 and 1467 cm(-1) due to glycogen and cholesterol were chosen for a quantitative evaluation of the malignancy. We found that the H1045/H1467 ratio is an exceptionally useful factor for discrimination of the cancerous tissues from the noncancerous tissues. If the H1045/H1467 ratio from the measured spectrum is larger than 1.4, we can say with confidence that the tissue contains squamous cell carcinoma or adenocarcinoma at least partially. Furthermore, we carried out the microscopic mapping of the tissues containing both cancerous and noncancerous sections, demonstrating that the color map reflects small changes in the spatial distribution of cancer cells in the tissues. The present  In addition, since FT-IR-MC costs relatively little and does not require a special operator training for collecting and analyzing the spectra, it seems to be perhaps the apparatus best suited to clinical usage, especially in rather small hospitals."
545,Relationship between TP73 polymorphism (G4C14-A4T14) and cancer risk: a meta-analysis based on literatures.,"Yu XJ, Fang F, Xie J.",https://pubmed.ncbi.nlm.nih.gov/21672615/,"The tumor protein p73 (TP73) gene belongs to the TP53 gene family and functions in the induction of apoptosis or cell-cycle arrest. The TP73 polymorphism (G4C14-A4T14) has been reported and many studies have focused on the role of this polymorphism in various cancers. However, the data reported for most individual cancer types were limited and not able to support a convincible conclusion. Hence, in this study, we explored the relationship between TP73 polymorphism (G4C14-A4T14) and cancer risk by carrying out a comprehensive meta-analysis. Performing both the overall and subgroup meta-analyses with a total of 23 eligible studies (6635 cases and 7378 controls in all), we detected significant cancer risk variations in the overall analysis, as well as the subgroup analysis based on ethnicity for both Asians and Caucasians. In the subgroup analysis based on source of controls, significant associations were also observed in the hospital-based controls' subgroup yet not in the population-based controls' subgroup. Furthermore, in the subgroup analysis based on cancer types, significant associations were found in colorectal cancer's subgroup but not in other cancer types' subgroups. In summary, according to the "
546,Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer.,"Johnson JM, Lai SY, Cotzia P, Cognetti D, Luginbuhl A, Pribitkin EA, Zhan T, Mollaee M, Domingo-Vidal M, Chen Y, Campling B, Bar-Ad V, Birbe R, Tuluc M, Martinez Outschoorn U, Curry J.",https://pubmed.ncbi.nlm.nih.gov/26615136/,"Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non-cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target."
547,p53 mutation in nonmelanoma skin cancers occurring in psoralen ultraviolet a-treated patients: evidence for heterogeneity and field cancerization.,"Stern RS, Bolshakov S, Nataraj AJ, Ananthaswamy HN.",https://pubmed.ncbi.nlm.nih.gov/12190879/,"A combination of psoralens and ultraviolet A radiation is widely used to treat psoriasis. Long-term, high-dose exposure to psoralen + ultraviolet A is associated with an increased risk of nonmelanoma skin cancer, particularly squamous cell carcinoma. In this study, we used p53 mutations as a molecular marker to determine the separate contributions of psoralen + ultraviolet A and other ultraviolet exposures, such as ultraviolet B for skin cancer development in psoralen + ultraviolet A-treated psoriasis patients. The  Of 37 tumors with mutations, 17 (46%) tumors had only ultraviolet-type mutations, two (5%) tumors had only psoralen + ultraviolet A-type mutations, and 18 (49%) tumors had both types of mutations. Interestingly, psoralen + ultraviolet A-type p53 mutations were more frequent than ultraviolet type in tumors arising in patients with high-dose exposure to psoralen + ultraviolet A. Field cancerization and tumor heterogeneity appeared to occur frequently in the same patient and even in the same tumor. This study's data suggest that psoralen + ultraviolet A-induced p53 mutations may play an important part in the development of nonmelanoma skin cancer in psoralen + ultraviolet A-treated patients, but these mutations are likely to act in concert with the effects of other carcinogenic exposures, particularly ultraviolet B, in the development of skin cancer."
548,"European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Europeenne des Medecins Specialistes).","Kandolf L, Peris K, Malvehy J, Mosterd K, Heppt MV, Fargnoli MC, Berking C, Arenberger P, Bylaite-Bučinskiene M, Del Marmol V, Dirschka T, Dreno B, Forsea AM, Harwood CA, Hauschild A, Heerfordt IM, Kauffman R, Kelleners-Smeets N, Lallas A, Lebbe C, Leiter U, Longo C, Mijušković Ž, Pellacani G, Puig S, Saiag P, Šitum M, Stockfleth E, Salavastru C, Stratigos A, Zalaudek I, Garbe C; European Association of Dermato‐Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).",https://pubmed.ncbi.nlm.nih.gov/38451047/,"A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC in situ and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised."
549,CO2 laser ablative fractional resurfacing photodynamic therapy for actinic keratosis and nonmelanoma skin cancer: a randomized split-side study.,"Miller MB, Padilla A.",https://pubmed.ncbi.nlm.nih.gov/32603389/,"Aminolevulinic acid (ALA) photodynamic therapy (PDT) is a preferred  Pretreatment with CO2 laser ablative fractional resurfacing (AFR) may increase the efficacy of PDT. This study compared the effect and durability of CO2 laser AFR-assisted ALA-PDT vs ALA-PDT alone in the treatment of AKs and nonmelanoma skin cancers (NMSCs) at various body locations. In this randomized, split-side study, 19 patients had 1 side pretreated with AFR before treatment of both sides with ALA-PDT. "
550,Unraveling cancer lineage drivers in squamous cell carcinomas.,"Guan Y, Wang G, Fails D, Nagarajan P, Ge Y.",https://pubmed.ncbi.nlm.nih.gov/31836455/,"Cancer hijacks embryonic development and adult wound repair mechanisms to fuel malignancy. Cancer frequently originates from de-regulated adult stem cells or progenitors, which are otherwise essential units for postnatal tissue remodeling and repair. Cancer genomics studies have revealed convergence of multiple cancers across organ sites, including squamous cell carcinomas (SCCs), a common group of cancers arising from the head and neck, esophagus, lung, cervix and skin. In this review, we summarize our current knowledge on the molecular drivers of SCCs, including these five major organ sites. We especially focus our discussion on lineage dependent driver genes and pathways, in the context of squamous development and stratification. We then use skin as a model to discuss the notion of field cancerization during SCC carcinogenesis, and cancer as a wound that never heals. Finally, we turn to the idea of context dependency widely observed in cancer driver genes, and outline literature support and possible explanations for their lineage specific functions. Through these discussions, we aim to provide an up-to-date summary of molecular mechanisms driving tumor plasticity in squamous cancers. Such basic knowledge will be helpful to inform the clinics for better stratifying cancer patients, revealing novel drug targets and providing effective treatment options."
551,Reviewing cancer's biology: an eclectic approach.,"Diori Karidio I, Sanlier SH.",https://pubmed.ncbi.nlm.nih.gov/34719756/,"
    


          Main body:
        
      
      The disease conditions are commonly characterized by unrestricted cell proliferation and dysfunctional replicative senescence pathways. In fact, the cell cycle operates under the rigorous control of complex signaling pathways involving cyclins and cyclin-dependent kinases assumed to be specific to each phase of the cycle. At each of these checkpoints, the cell is checked essentially for its DNA integrity. Genetic defects observed in these molecules (i.e., cyclins, cyclin-dependent kinases) are common features of cancer cells. Nevertheless, each cancer is different concerning its molecular and cellular etiology. These could range from the genetic defects mechanisms and/or the environmental conditions favoring epigenetically harbored homeostasis driving tumorigenesis alongside with the intratumoral heterogeneity with respect to the model that the tumor follows.
    


          Conclusions:
        
      
      This review is not meant to be an exhaustive interpretation of carcinogenesis but to summarize some basic features of the molecular etiology of cancer and the intratumoral heterogeneity models that eventually bolster anticancer drug resistance for a more efficient design of drug targeting the pitfalls of the models."
552,Genetic progression model for head and neck cancer: implications for field cancerization.,"Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, Corio R, Lee D, Greenberg B, Koch W, Sidransky D.",https://pubmed.ncbi.nlm.nih.gov/8653682/,"A genetic progression model of head and neck squamous cell carcinoma has not yet been elucidated, and the genetic basis for ""field cancerization"" of the aerodigestive tract has also remained obscure. Eighty-seven lesions of the head and neck, including preinvasive lesions and benign lesions associated with carcinogen exposure, were tested using microsatellite analysis for allelic loss at 10 major chromosomal loci which have been defined previously. The spectrum of chromosomal loss progressively increased at each histopathological step from benign hyperplasia to dysplasia to carcinoma in situ to invasive cancer. Adjacent areas of tissue with different histopathological appearance shared common genetic changes, but the more histopathologically advanced areas exhibited additional genetic alterations. Abnormal mucosal cells surrounding preinvasive and microinvasive lesions shared common genetic alterations with those lesions and thus appear to arise from a single progenitor clone. Based on these findings, the local clinical phenomenon of field cancerization seems to involve the expansion and migration of clonally related preneoplastic cells."
553,Assessment of the specificity of a new folate-targeted photosensitizer for peritoneal metastasis of epithelial ovarian cancer to enable intraperitoneal photodynamic therapy. A preclinical study.,"Azaïs H, Schmitt C, Tardivel M, Kerdraon O, Stallivieri A, Frochot C, Betrouni N, Collinet P, Mordon S.",https://pubmed.ncbi.nlm.nih.gov/26200606/," Recurrence rate is disappointingly high as 60% of women with epithelial ovarian cancer considered in remission will develop recurrent disease within 5 years. Special attention to undetected peritoneal metastasis during surgery is necessary as they are the main predictive factors of recurrences. Folate Receptor α (FRα) shows promising prospects in targeting ovarian cancerous cells and intraperitoneal photodynamic therapy (PDT) could be a solution in addition to macroscopic cytoreductive surgery to treat peritoneal micrometastasis. The aim of this preclinical study is to assess the specificity of a folate-targeted photosensitizer for ovarian peritoneal micrometastasis.
    


           Three groups of 6 rats were studied (Control (no photosensitizer)/Non-conjugated photosensitizer (Porph)/Folate-conjugated photosensitizer (Porph-s-FA)). Four hours after the administration of the photosensitizer, animals were sacrificed and intraperitoneal organs tissues were sampled. FRα tissue expression was evaluated by immunohistochemistry. Tissue incorporation of photosensitizers was assessed by confocal microscopy and tissue quantification.
    


           Cytoplasmic red endocytosis vesicles observed by confocal microscopy are well correlated to FRα tissue expression. Photosensitizer tissue quantification shows a mean tumor-to-normal tissue ratio of 9.6.
    


          Conclusion:
        
      
      We demonstrated that this new generation folate-targeted photosensitizer is specific of epithelial ovarian peritoneal metastasis and may allow the development of efficient and safe intraperitoneal PDT procedure."
554,[Case Report of Long-Term Survival for Stage IV Advanced Sigmoid Colon Cancer with Para-Aortic Nodes by R0 Resection and Chemotherapy].,"Akai M, Otsuka S, Yasui Y, Isoda K, Hamano R, Tokunaga N, Takahashi K, Miyaso H, Tsunemitsu Y, Iwakawa K, Inagaki M, Iwagaki H.",https://pubmed.ncbi.nlm.nih.gov/29394654/,"The patient was a man in his early 30s. He underwent sigmoidectomy with D3+ #216 for advanced sigmoid colon cancer with metastatic para-aortic lymph nodes. The pathological diagnosis was colon cancer(S), type 2, moderately differentiated, pT4a(SE), pN3(19/33), pM1a(LYM), pStage IV , KRAS wild-type, EGFR(+). He received FOLFOX plus bevacizumab(Bmab) as adjuvant chemotherapy. One year postoperatively, he experienced recurrence as multiple lung metastases. FOLFIRI plus panitumumab, SOX plus Bmab, CapeOX, nivolumab and FOLFIRI plus ramucirumab were then administered. The patient has survived for 4 years and 11 months from operation."
555,Chemiluminescence: a diagnostic adjunct in oral precancer and cancer: a review.,"Shashidara R, Sreeshyla HS, Sudheendra US.",https://pubmed.ncbi.nlm.nih.gov/25313726/,"Oral cancer is one of the most common cancers in India. It's also associated with poor survival rate. Early diagnosis is the only way of reducing the high morbidity and mortality associated with it. However, most often there is delay in its diagnosis. Several adjuncts have been developed to aid in the diagnosis of cancer in its pre-cancerous and early stage. Chemiluminescence is one of the newly developed adjuncts, which is still in its infancy. This article reviews chemiluminescence technique and its applications in oral cancer diagnosis."
556,Noncoding RNAs Serve as the Deadliest Universal Regulators of all Cancers.,"Wang A, Hai R.",https://pubmed.ncbi.nlm.nih.gov/33419895/,"Numerous cancer drivers have been identified, but they are specific to a given cancer type and condition; universal cancer drivers and universal cancer mechanisms still remain largely unclear. Here, we identified the deadliest universal drivers for all cancers via developing algorithms to analyze massive RNAseqs and clinical data from The Cancer Genome Atlas (TCGA). In general, noncoding RNAs primarily serve as the most important inducers and suppressors for all types of cancers. In particular, pseudogenes are primary inducers, and specifically the antisense RNA RP11-335K5.2 serves as the most universal cancerous driver, independently of the cancer type and condition. Therefore, noncoding RNAs, instead of proteins as conventionally thought, primarily drive cancer, which establishes a novel field for future cancer research and therapy."
557,A data-driven approach to modeling cancer cell mechanics during microcirculatory transport.,"Balogh P, Gounley J, Roychowdhury S, Randles A.",https://pubmed.ncbi.nlm.nih.gov/34315934/,"In order to understand the effect of cellular level features on the transport of circulating cancer cells in the microcirculation, there has been an increasing reliance on high-resolution in silico models. Accurate simulation of cancer cells flowing with blood cells requires resolving cellular-scale interactions in 3D, which is a significant computational undertaking warranting a cancer cell model that is both computationally efficient yet sufficiently complex to capture relevant behavior. Given that the characteristics of metastatic spread are known to depend on cancer type, it is crucial to account for mechanistic behavior representative of a specific cancer's cells. To address this gap, in the present work we develop and validate a means by which an efficient and popular membrane model-based approach can be used to simulate deformable cancer cells and reproduce  Here, cells are modeled using the immersed boundary  Through detailed comparisons with  non-nucleated cell models and their ability to match  While many works have used the membrane-model based  Here, we describe a phenomenological, data-driven approach that can not only yield good agreement for large deformations, but explicitly detail how it can be used to represent different cancer cell lines. This model is readily incorporated into cell-resolved hemodynamic transport simulations, and thus offers significant potential to complement "
558,Cancer related fatigue and cancer cachexia are the consequence of endocrine failure caused by persistent stress.,Lai S.,https://pubmed.ncbi.nlm.nih.gov/30696594/,"This study researches the cause of tumor, cancer related fatigue (CRF) and cancer cachexia (CC), and the relationship among tumor and CRF and CC. Carcinogenesis is consequence of failure of tissue development. Tumor originates from tissue regeneration. The tumor cell is normal incomplete differentiated cell that stop in different phases of differentiation. Tumor promoter stimulates stem cell to proliferate. Carcinogen obstructs stem cell to differentiate. With tumor promoter and carcinogen, the tissue stem cells proliferate but cannot differentiate into mature cell, and form tumors. The disorder of biological signals cell proliferation and differentiation facilitates tumor development. CRF and CC are consequence of endocrine hypofunction and failure caused by persistent stress. Nature factors and psychological factors stimulate organic stress. The significant change of stress is the activation of endocrine system. The persistent stress exhausts the capacity of endocrine glands or hormone receptors of target cells, and leads to endocrine hypofunction even failure. CRF and CC are clinical manifestation of endocrine hypofunction and failure. Cancer is a local lesion, also is a systemic disease. As a local lesion, carcinogen obstructed stem cell to differentiate, developmental failure of local tissue forms tumor. As a systemic disease, cancer is related to natural physical, chemical, and biological factors, as well as negative spiritual factors. The material and spiritual factors induce persistent stress which eventually leads to endocrine hypofunction even failure and unbalance of homeostasis. The disorder of biological signals of cell proliferation and differentiation facilitates tumor development. CRF and CC, as clinical manifestation of endocrine hypofunction and failure, have nothing to do with tumor size and type, but facilitate tumor development. CRF and CC are through all the course of systemic cancerous disease, and commonly precede tumorigenesis. Many patients have been found tumors because of symptoms of CRF and CC. Even if no tumor be found at that time, various tumors would be found in the follow-up. For systemic cancerous disease, cachexia is the cause of death. Most cancer patients do not die of tumor, but of cancer cachexia. Eradicating tumor cell cannot cure systemic cancerous disease; on the contrary, the poisonous side effect of therapies usually speeds up the progress of CC and death. It is important for curing cancer cachexia and restoring the patient's constitution to prevent systemic cancer and improve the quality of life and prolong the survival."
559,Clinical significance of cancerous inhibitor of protein phosphatase 2A in human cancers.,"Khanna A, Pimanda JE.",https://pubmed.ncbi.nlm.nih.gov/25628223/,"Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A), a recently identified oncogene, has emerged as a potential drug target for a range of different tumor types. High CIP2A expression has been reported in almost all solid organ cancers and in some hematological tumors and is associated with high grade and poor prognosis. Notably, high CIP2A expression is determined in over 70% of tumor patient samples in the majority of human cancers. High expression of CIP2A has also been proposed as a useful biomarker that predicts therapeutic response to chemotherapeutics such as Bortezomib, Erlotinib, Checkpoint Kinase 1 inhibitors and pro-senescence based therapies. In this review, we highlight, critically evaluate and discuss the ambiguity in CIP2A's prognostic role in different human cancers and its role in modulating response and resistance to chemotherapeutics."
560,Surveying Breast Cancer's Genomic Landscape.,[No authors listed],https://pubmed.ncbi.nlm.nih.gov/27225883/,"An in-depth analysis has produced the most comprehensive portrait to date of the myriad genomic alterations involved in breast cancer. In sequencing the whole genomes of 560 breast cancers and combining this information with published data from another 772 breast tumors, the research team uncovered several new genes and mutational signatures that potentially influence this disease."
561,Protocol for establishing organoids from human ovarian cancer biopsies.,"Maenhoudt N, Vankelecom H.",https://pubmed.ncbi.nlm.nih.gov/33870230/,"Ovarian cancer (OC) is the most lethal gynecological cancer. Faithful research models are indispensable to the progression of understanding OC etiology and therapy. Here, we provide a detailed protocol for establishing organoid cultures from patient OC biopsies. The organoids reproduce primary tumor- and patient-specific characteristics including phenotypic properties and genomic aberrations and exhibit patient-dependent responsiveness to drugs. OC-derived organoids provide powerful tools to gain deep insight into the cancer's pathobiology and to screen patient-tumor drug sensitivity to progress toward personalized medicine. For complete details on the use and execution of this protocol, please refer to Maenhoudt et al. (2020)."
562,Preliminary efficacy and safety analysis: 12-month results in 83 patients using a novel approach of widefield radiation therapy for extensive skin field cancerization with or without keratinocyte cancers.,"Potter AE, Baker C, Shumack S, Sinclair R, Curran WJ Jr, Christie D, Wong B, Foley P, O'Brien P, Spelman L; National Dermatology Radiation Oncology Registry (NDROR) investigators and sites..",https://pubmed.ncbi.nlm.nih.gov/35603502/,"Purpose:
        
      
      Evaluate the use of widefield radiation therapy (RT) in the management of extensive skin field cancerization (ESFC) with/without keratinocyte cancer (KC).
    


           It captures disease description, prior therapies, radiation prescription, clinical effect, skin cosmesis scores, and toxicity data. This analysis included 12-month follow-up data on 89 treated fields from a subset of 83 patients.
    


           Complete lesion response was seen in 96% of evaluable (n = 25) ESFC with KC. Recurrence (4/89 [5%]) and appearance of new lesions (10/89 [11%]) were minimal. Cosmetic outcome was excellent/good in 98% ESFC and 96% ESFC with KC. Grade 1-2 acute radiation dermatitis occurred in up to 80% of treated fields. The frequency of Grade 3 acute skin toxicities was low.
    


          Conclusions:
        
      
      Registry data demonstrate the potential for widefield RT to treat patients with significant skin pathology who have exhausted other therapies and require durable, minimally invasive treatment options. At 12 months, observed clinical success rates were higher than those reported for topical interventions for ESFC. Ongoing follow-up is required to determine longer term outcomes."
563,"""Fingerprinting"" Benign and Cancerous Skin Lesions Using Vibrational Optical Coherence Tomography: Differentiation among Cancerous Lesion Types Based on the Presence of New Cells, Blood Vessels, and Fibrosis.","Silver FH, Deshmukh T, Ryan N, Romm A, Nadiminti H.",https://pubmed.ncbi.nlm.nih.gov/36291542/,"In this study, we use vibrational optical coherence tomography (VOCT) to examine the morphology and stiffness of benign and cancerous lesions. Lesion images and 3D plots of weighted displacement versus frequency and depth were used to compare the cellular, dermal collagen, new blood vessels, and fibrotic composition of normal skin, actinic keratoses (AK), nodular and superficial basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs), and melanomas. The 8 MPa), new blood vessel peaks (130 Hz, 4.10 MPa) that appear to be less stiff than normal blood vessels, and new fibrous tissue peaks (260 Hz, 15-17 MPa) that are present in carcinomas but not in normal skin and only partially present (80 Hz and 130 Hz only) in AKs.  The  The invasiveness and metastatic potential of melanomas may be a  The new cancer-associated blood vessels in the vicinity of the new cancer-associated cells may promote this migration and eventual metastasis. The ratios of peak heights 50/130 Hz and 80/130 Hz of normal cells, new lesion cells, new lesion blood vessels, and fibrotic tissue may be used as a ""fingerprint"" for detecting melanoma and to differentiate it from other skin cancers non-invasively using VOCT."
564,Cancer's sweet tooth for serine.,Luo J.,https://pubmed.ncbi.nlm.nih.gov/22189202/,"Exemplified by the cancer cell's preference for glycolysis (the Warburg effect), altered metabolism has taken centerstage as an emerging hallmark of cancer. Charting the landscape of cancer metabolic addictions should reveal new avenues for therapeutic attack. Two recent studies found subsets of human melanoma and breast cancers to have high levels of phosphoglycerate dehydrogenase (PHGDH), a key enzyme for serine biosynthesis, and these cancer cells are dependent on PHGDH for their growth and survival. Tumors may thus harbor distinct metabolic alterations to support their malignancy, and targeting enzymes such as PHGDH might prove a viable therapeutic strategy in this scenario."
565,Oncogenic nexus of cancerous inhibitor of protein phosphatase 2A (CIP2A): an oncoprotein with many hands.,"De P, Carlson J, Leyland-Jones B, Dey N.",https://pubmed.ncbi.nlm.nih.gov/25015035/,"Oncoprotein CIP2A a Cancerous Inhibitor of PP2A forms an ""oncogenic nexus"" by virtue of its control on PP2A and MYC stabilization in cancer cells. The expression and prognostic function of CIP2A in different solid tumors including colorectal carcinoma, head and neck cancers, gastric cancers, lung carcinoma, cholangiocarcinoma, esophageal cancers, pancreatic carcinoma, brain cancers, breast carcinoma, bladder cancers, ovarian carcinoma, renal cell carcinomas, tongue cancers, cervical carcinoma, prostate cancers, and oral carcinoma as well as a number of hematological malignancies are just beginning to emerge. Herein, we reviewed the recent progress in our understanding of (1) how an ""oncogenic nexus"" of CIP2A participates in the tumorigenic transformation of cells and (2) how we can prospect/view the clinical relevance of CIP2A in the context of cancer therapy. The review will try to understand the role of CIP2A (a) as a biomarker in cancers and evaluate the prognostic value of CIP2A in different cancers (b) as a therapeutic target in cancers and (c) in drug response and developing chemo-resistance in cancers."
566,Reducing HPV-associated cancer globally.,"Lowy DR, Schiller JT.",https://pubmed.ncbi.nlm.nih.gov/22219162/,"Human papillomavirus (HPV)-related cancers are a major worldwide public health concern. Virtually all cervical cancer is HPV related, with 70% caused by HPV16 and -18. Variable proportions of certain noncervical cancers (e.g., anal, vulvar, and oropharyngeal) are HPV related; more than 90% of the HPV-related ones are caused by HPV16, -18. The HPV-related cancers are dominated by cervical cancer in the developing world, where cervical cancer screening is limited. In this setting, widespread uptake of current HPV vaccines by adolescent girls could reduce this cancer's incidence and mortality by approximately two-thirds, with cost-effective screening programs of adult women having the potential to reduce mortality more rapidly. In the industrialized world, some noncervical HPV-related cancers, especially oropharyngeal, are rapidly increasing, and now rival the incidence of cervical cancer, whose rates continue to decline thanks to established cervical screening programs. Therefore, reducing HPV-associated noncervical cancers with HPV vaccination has greater importance in the industrialized world, especially because there are no approved screening programs for these cancers. Preventing the substantial number of noncervical HPV cancers in men will require either ""herd"" immunity through high-vaccination rates in females or male vaccination. Current HPV vaccination can complement cervical screening in protecting against cervical cancer and may permit the safe reduction of screening intensity in industrialized countries. Second-generation HPV vaccines (active against a broader array of cervical cancer-related HPV types) could prevent an even higher proportion of cervical precancer and cancer and might permit further reductions in screening intensity."
567,Telomerase activity in cervical cancer is quantitatively distinct from that in its precursor lesions.,"Kyo S, Takakura M, Tanaka M, Kanaya T, Inoue M.",https://pubmed.ncbi.nlm.nih.gov/9495361/,"Studies using the telomeric repeat amplification protocol (TRAP) assay have demonstrated telomerase activity not only in cancers but also in non-cancerous lesions. However, quantitative differences in activity between both lesions have not been examined. In the present study, using a stretch PCR assay, telomerase activity was analyzed quantitatively in cervical cancer, its precursor squamous intra-epithelial lesions (SILs) and normal cervix. In stretch PCR assay, telomerase activity was expressed in relative units vs. control activity from C33A cells (100 units). Mean telomerase activities in cervical cancer, SIL and normal cervix were 72+/-35 units, 18+/-17 units and 7+/-4 units, respectively, suggesting that telomerase activity in cancer lesions was quantitatively distinct from that in pre-malignant lesions, which may mean a much more pronounced activation of telomerase in cancers than in SIL. Our findings also suggest that stretch PCR assay can distinguish telomerase activity in cancer from that in non-cancerous lesions and may be useful for the differential diagnosis of cancer lesions."
568,Expressional variations of Kaiso: an association with pathological characteristics and field cancerization of OSCC.,"Ahmed S, Khan S, Qureshi MA, Bukhari U, Anis M, Mughal MN.",https://pubmed.ncbi.nlm.nih.gov/36115941/," Numerous molecules are being investigated for their significance in the development of this phenomenon. One such protein of this family is Kaiso also known as ZBTB33 (Zinc Finger and BTB Domain containing 33). This protein belongs to the POZ-ZF family of transcription factors and may have functional tasks similar to its other siblings such as the growth and development of vertebrates and the pathogenesis of neoplastic diseases. Nevertheless, its role in the pathogenesis, progression, epithelial mesenchyal transition and field cancerization in case of oral cancer still needs exploration. Hence, this study was designed to explore the expressional differences between the mucosa of controls and those diagnosed with oral squamous cell carcinoma (OSCC).
    


           The acquired samples were subjected to Immunohistochemical exploration for expression of Kaiso and E-Cadherin. The expression was measured using Image-J IHC profiler and summed as Optical density. The Optical density values were then subjected to statistical analysis.
    


          0001), showing almost 50% down-regulation of Kaiso in all three tissue samples taken from oral cancer patients as compared to normal mucosa.
    


          Conclusion:
        
      
      Kaiso has a significant difference of expression in the mucosa of oral cancer patients as compared to the mucosa of normal patients, making it a probable contributor to disease pathogenesis and field cancerization."
569,Nanoparticle drug delivery to target breast cancer brain metastasis: Current and future trends.,"Kannan S, Cheng VWT.",https://pubmed.ncbi.nlm.nih.gov/37096795/,"Breast cancer brain metastasis (BCBM) is rapidly becoming an impediment to continuing survival gains seen in breast cancer patients. Drug delivery across the blood-brain barrier is the main issue hindering systemic therapy against BCBM. This review details recent advances in nanoparticle (NP) drug delivery systems to target BCBM. Their primary benefits are: enhanced circulating and intra-BCBM drug biodistribution, BCBM targeting through NP functionalization, opportunities for gene manipulation and their theragnostic applications. Multiple NPs have been synthesized to deliver therapeutic HER2 blockade, which is particularly important given HER2-positive breast cancer's tendency to form BCBM. Finally, we review the clinical context in which NP-based therapeutics have been investigated in BCBM patients. While a breakthrough in improving patient outcomes remain awaited, these clinical trials represent positive steps in the changing attitude towards BCBM as a treatable illness. Although multiple challenges remain in the clinical translation of BCBM-directed NP therapies, ongoing research in the field offers promising avenues for novel targeting of this devastating disease."
570,Cancer stem cell immunology and immunotherapy: Harnessing the immune system against cancer's source.,"Ruiu R, Tarone L, Rolih V, Barutello G, Bolli E, Riccardo F, Cavallo F, Conti L.",https://pubmed.ncbi.nlm.nih.gov/31383404/,"Despite recent advances in diagnosis and therapy having improved cancer outcome, many patients still do not respond to treatments,  The limited efficacy of therapy is often attributable to its inability to affect cancer stem cells (CSCs), a small population of cells resistant to current radio- and chemo-therapies. CSCs are characterized by self-renewal and tumor-initiating capabilities, and function as a reservoir for the local and distant recurrence of the disease. Therefore, new therapeutic approaches able to effectively target and deplete CSCs are urgently needed. Immunotherapy is facing a renewed interest for its potential in cancer treatment, and the possibility of harnessing the immune system to target CSCs is being addressed by a new exciting research field. In this chapter, we discuss the cancer stem cell model and illustrate CSC biological and molecular properties, critically addressing theoretical and practical issues linked with their definition and study. We then review the existing literature regarding the immunological properties of CSCs and the complex interplay occurring between CSCs and immune cells. Finally, we present up-to-date studies on CSC immunotargeting and its potential future perspective. In conclusion, understanding the interplay between CSC biology and tumor immunology will provide a deeper understanding of the mechanisms that regulate CSC immunological properties. This will contribute to the design of new CSC-directed immunotherapeutic strategies with the potential of strongly improving cancer outcomes."
571,Gene expression correlation for cancer diagnosis: a pilot study.,"Ling B, Chen L, Liu Q, Yang J.",https://pubmed.ncbi.nlm.nih.gov/24818135/,"Poor prognosis for late-stage, high-grade, and recurrent cancers has been motivating cancer researchers to search for more efficient biomarkers to identify the onset of cancer. Recent advances in constructing and dynamically analyzing biomolecular networks for different types of cancer have provided a promising novel strategy to detect tumorigenesis and metastasis. The observation of different biomolecular networks associated with normal and cancerous states led us to hypothesize that correlations for gene expressions could serve as valid indicators of early cancer development. In this pilot study, we tested our hypothesis by examining whether the mRNA expressions of three randomly selected cancer-related genes PIK3C3, PIM3, and PTEN were correlated during cancer progression and the correlation coefficients could be used for cancer diagnosis. Strong correlations (0.68 ≤ r ≤ 1.0) were observed between PIK3C3 and PIM3 in breast cancer, between PIK3C3 and PTEN in breast and ovary cancers, and between PIM3 and PTEN in breast, kidney, liver, and thyroid cancers during disease progression, implicating that the correlations for cancer network gene expressions could serve as a supplement to current clinical biomarkers, such as cancer antigens, for early cancer diagnosis."
572,Cancer's epigenetic drugs: where are they in the cancer medicines?,Ghasemi S.,https://pubmed.ncbi.nlm.nih.gov/31819161/,"Epigenetic modulation can affect the characteristics of cancers. Because it is likely to manipulate epigenetic genes, they can be considered as potential targets for cancer treatment. In this comprehensive study, epigenetic drugs are categorized according to anticancer mechanisms and phase of therapy. The relevant articles or databases were searched for epigenetic approaches to cancer therapy. Epigenetic drugs are divided according to their mechanisms and clinical phases that have been approved by the FDA or are undergoing evaluation phases. DNA methylation agents, chromatin remodelers specially HDACs, and noncoding RNAs especially microRNAs are the main epi-drugs for cancer. Despite many challenges, combination therapy using epi-drugs and routine therapies such as chemotherapy in various approaches have exhibited beneficial effects compared with each treatment alone. Cancer stem cell targeting and epigenetic editing have been confirmed as definitive pathways for cancer treatment. This paper reviewed the available epigenetic approaches to cancer therapy."
573,The impact of heterogeneity in phosphoinositide 3-kinase pathway in human cancer and possible therapeutic treatments.,"Wang W, Lv J, Wang L, Wang X, Ye L.",https://pubmed.ncbi.nlm.nih.gov/27582428/,"Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) plays a crucial role in the initiation and progress of cancerous tumors through the overexpression of the PI3K pathway promoting uncontrollable levels of cell proliferation. In addition only Class I PI3K has been discovered to be involved in human cancer due to its unique ability to produce phosphoinositide 3,4,5 trisphosphate (PIP3), which has been discovered to play a crucial role in human oncogenesis. The role of PIK3CA is lucubrated in breast cancer and gastric cancer, but is not well characterized in lung diseases. In this review, we summarized the common biology and mutations in PIK3CA with its related signaling pathways. Furthermore, we elucidated the PIK3CA heterogeneity in different domains, between various cancers and in different lung cancers. We also take a look at current inhibitors such as KP-372-1 (KP-1), KP-372-2 (KP-2), GSK690693, etc. in order to highlight potential treatment of PIK3CA mutations in human cancer and what directions future research should focus on."
574,Lack of Correlation between Stem-Cell Proliferation and Radiation- or Smoking-Associated Cancer Risk.,"Little MP, Hendry JH, Puskin JS.",https://pubmed.ncbi.nlm.nih.gov/27031507/," They proposed an extra-risk score as way of distinguishing the effects of the stochastic, replicative component of cancer risk from other causative factors, specifically those due to the external environment and inherited mutations.
    


          
    


          
    


           Analysis of the extra-risk score and various other measures (number of stem cell divisions per year, cumulative number of stem cell divisions over life) considered by Tomasetti and Vogelstein suggests that these are poorly predictive of currently available estimates of radiation- or smoking-associated cancer risk-for only one out of 37 measures or logarithmic transformations thereof is there a statistically significant correlation (p<0.05) with radiation- or smoking-associated risk.
    


          Conclusions:
        
      
      The data used by Tomasetti and Vogelstein are in conflict with predictions of a multistage model of carcinogenesis, under the assumption of homogeneity of numbers of driver mutations across most cancer sites. Their hypothesis that if the extra-risk score for a tissue type is high then one would expect that environmental factors would play a relatively more important role in that cancer's risk is in conflict with the lack of correlation between the extra-risk score and other stem-cell proliferation indices and radiation- or smoking-related cancer risk."
575,Calcium signaling and T-type calcium channels in cancer cell cycling.,"Taylor JT, Zeng XB, Pottle JE, Lee K, Wang AR, Yi SG, Scruggs JA, Sikka SS, Li M.",https://pubmed.ncbi.nlm.nih.gov/18763278/,"Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca(2+) channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca(2+) channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel is minimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca(2+) channels are not expressed in epithelial cells, selective T-type Ca(2+) channel blockers may be useful in the treatment of certain types of cancers."
576,Employers' role in cancer prevention and treatment-developing success metrics for use by the CEO Roundtable on Cancer.,"Henke R, Goetzel RZ, McHugh J, Gorhan D, Reynolds M, Davenport J, Rasmussen K, Isaac F.",https://pubmed.ncbi.nlm.nih.gov/23672234/,"As evidence accumulates on the risk factors for cancer, it is becoming clearer that employers can play a significant role in the fight against the disease by creating a workplace conducive to lowering health risks. The CEO Roundtable on Cancer's CEO Cancer Gold Standard Program defines what companies can do to prevent cancer, detect it early, and ensure access to the best available treatments for those who are afflicted with the disease. This article describes how Johnson & Johnson incorporated the Cancer Gold Standard Program into its existing health promotion initiatives. Then, a framework is proposed that employers can use to monitor progress in cancer prevention and treatment enhancement efforts. Finally, health care eligibility, claims, and health risk assessment data are analyzed to quantify Johnson & Johnson's progress since implementation of the Cancer Gold Standard Program. Companies interested in initiating or furthering their health promotion efforts should consider joining groups such as the CEO Cancer Gold Standard. Collectively, companies have the ability to influence policy makers, payers, and the industry at large in changing behaviors and creating a culture of health and wellness in the fight against cancer."
577,Raman spectroscopy to discriminate laryngeal squamous cell carcinoma from non-cancerous surrounding tissue.,"van Lanschot C, Schut TB, Barroso E, Sewnaik A, Hardillo J, Monserez D, Meeuwis C, Keereweer S, de Jong RB, Puppels G, Koljenović S.",https://pubmed.ncbi.nlm.nih.gov/37624524/,"As for many solid cancers, laryngeal cancer is treated surgically, and adequate resection margins are critical for survival. Raman spectroscopy has the capacity to accurately differentiate between cancer and non-cancerous tissue based on their molecular composition, which has been proven in previous work. The aim of this study is to investigate whether Raman spectroscopy can be used to discriminate laryngeal cancer from surrounding non-cancerous tissue. Patients surgically treated for laryngeal cancer were included. Raman mapping  Water concentration analysis and CH-stretching region analysis were performed in the high wavenumber range of 2500-4000 cm-1. Thirty-four mapping  Both laryngeal cancer and all non-cancerous tissue structures showed high water concentrations of around 75%. Discriminative information was only found to be present in the CH-stretching region of the Raman spectra of the larynx (discriminative power of 0.87). High wavenumber region Raman spectroscopy can discriminate laryngeal cancer from non-cancerous tissue structures. Contrary to the findings for oral cavity cancer, water concentration is not a discriminating factor for laryngeal cancer."
578,Carcinoma of the urinary bladder in a tertiary care setting in a developing country.,"Badar F, Sattar A, Meerza F, Irfan N, Siddiqui N.",https://pubmed.ncbi.nlm.nih.gov/19640189/," Most bladder cancers are transitional cell carcinomas.
    


           1994 through Dec. 2004.
    


           Gender, age, histologic types, grade, stage, symptoms, risk factors, and patient follow-up were studied. Staging was done through the American Joint Commission on Cancer's criteria. Class of Case was established using the Facility Oncology Registry Data Standards, 2004.
    


          5 years; men: 83%. Transitional cell- in 86%, squamous cell- in 4%, adeno- in 3%, and undifferentiated carcinoma in 7% of the cases. Stage: II in 18.3%, I in 17.3%, III in 14.2%, IV in 26%, 0 in 6.3%, and not evaluable in 17.8% of the cases. Grades: G3 in 37.9%, G2 in 25.2%, G1 in 9.7%, G4 in 2.8%, and undetermined in 24.4% of the subjects. Commonest presenting symptom: hematuria in 54.7% men and 52.9% women; risk factor: positive smoking history in nearly 35% males and 2% females. Average interval between diagnosis and last contact: 26.5 months; for analytic cases, 34.9 months.
    


          Conclusion:
        
      
      Urinary bladder cancer was seen primarily in males; transitional cell type was dominant. The majority of the patients were symptomatic; smoking history was recorded mostly in men. Further, improving in staging could be useful in addressing the concerns about data reproducibility over time and use for surveillance purposes."
579,Long-Term Survivorship Care After Cancer Treatment - Summary of a 2017 National Cancer Policy Forum Workshop.,"Kline RM, Arora NK, Bradley CJ, Brauer ER, Graves DL, Lunsford NB, McCabe MS, Nasso SF, Nekhlyudov L, Rowland JH, Schear RM, Ganz PA.",https://pubmed.ncbi.nlm.nih.gov/30496448/,"The National Cancer Policy Forum of the National Academies of Sciences, Engineering and Medicine sponsored a workshop on July 24 and 25, 2017 on Long-Term Survivorship after Cancer Treatment. The workshop brought together diverse stakeholders (patients, advocates, academicians, clinicians, research funders, and policymakers) to review progress and ongoing challenges since the Institute of Medicine (IOM)'s seminal report on the subject of adult cancer survivors published in 2006. This commentary profiles the content of the meeting sessions and concludes with recommendations that stem from the workshop discussions. Although there has been progress over the past decade, many of the recommendations from the 2006 report have not been fully implemented. Obstacles related to the routine delivery of standardized physical and psychosocial care services to cancer survivors are substantial, with important gaps in care for patients and caregivers. Innovative care models for cancer survivors have emerged, and changes in accreditation requirements such as the Commission on Cancer's (CoC) requirement for survivorship care planning have put cancer survivorship on the radar. The Center for Medicare & Medicaid Innovation's Oncology Care Model (OCM), which requires psychosocial services and the creation of survivorship care plans for its beneficiary participants, has placed increased emphasis on this service. The OCM, in conjunction with the CoC requirement, is encouraging electronic health record vendors to incorporate survivorship care planning functionality into updated versions of their products. As new models of care emerge, coordination and communication among survivors and their clinicians will be required to implement patient- and community-centered strategies."
580,Multiplexed fluorescence imaging of tumor biomarkers in gene expression and protein levels for personalized and predictive medicine.,"Smith MQ, Staley CA, Kooby DA, Styblo T, Wood WC, Yang L.",https://pubmed.ncbi.nlm.nih.gov/19747113/,"Combining groundbreaking research and developments in cancer biomarkers, nanotechnology and molecular targeted medicine, a new realm of therapy is possible: personalized and predictive medicine. Developing a  Theoretically, a cancer's unique molecular profile can be used to predict its invasive and metastatic potential, its ability to evade immune surveillance, and its potential response to treatment. Fluorescent probes have been developed to detect the levels of expression of various biomarkers in tumor cells and tissues. Expression of biomarker messenger RNAs (mRNAs) or the presence of a specific mutation in an oncogene in cancer cells can be detected using molecular beacons (MBs) that only emit fluorescent signals after binding to its specific target mRNAs. Antibodies or ligands labeled with fluorophores or fluorescent quantum dots (QDs) have been successfully used to identify specific proteins expressed in cells. Furthermore, multiplex imaging using both MBs and antibodies labeled with a fluorescent probe on the same sample may provide important information correlating the level of mRNA expression and the subsequent level of protein production for a given biomarker. This technology will be useful in research investigating cancer biology, molecular imaging and molecular profiling. With the identification of biomarkers that are related to aggressive tumor types, we may be able to predict within certain patient populations who will develop invasive cancers, and what their prognosis will be given different treatment modalities, ultimately delivering medical care and treatment strategies that are specifically tailored to each individual patient, making personalized and predictive medicine a reality."
581,[Persistence of social representation regarding breast cancer].,Giraldo-Mora CV.,https://pubmed.ncbi.nlm.nih.gov/20169208/,"
    


           The analysis was orientated by grounded theory.
    


           They identified its causes with personal and emotional problems and certain daily habits such as inadequate food (""a bodily payback for the abuses which we subject ourselves to"").
    


          Discussion:
        
      
      The word ""breast cancer"" was associated with inevitable death, terror, suffering, incurability, devastation, powerlessness and pain. This cancer has strong social representation due to its severe implications for females, their attractiveness and self-image.
    


          Conclusions:
        
      
      The persistence of breast cancer's negative image is associated with ""the life-style myth"" (1) for which people tend to blame the patient. Our biological reductionism hides environmental, social and political factors. We are obsessed by the dangers and their control (2) and powerful images are added to these messages such as those in which ""one out of nine women will develop breast cancer"" to foster self-responsibility (2). However, the ghost of cancer in developing societies in which many people are still trapped is magnified and has also yet to be overcome."
582,"Inhibiting the ""Undruggable"" RAS/Farnesyltransferase (FTase) Cancer Target by Manumycin-related Natural Products.","Silva LR, da Silva-Júnior EF.",https://pubmed.ncbi.nlm.nih.gov/33719954/,"Cancer is an uncontrolled cell growth that can generate diverse types of cancer, in which these will also present a different behavior in the face of pharmacological treatment. These cancers' types are found in one of the three categories, leukemias (also named lymphomas), carcinomas, and sarcomas. In general, cancer's pathogenesis is associated with three genetic mutations, where could emerge from oncogenes, tumor suppressor genes, and/or genes responsible for regulating DNA replication. The term ""undruggable"" is frequently related to the difficulty to design drugs to specific targets, such as MYC, MYB, NF-κB, and RAS family of proteins. This last comprises more than 140 proteins, and these are responsible for 30% of mutations in human cancers. Also, there are three ras genes transcribed in human cells, called H-, K-, and N-ras oncogenes. Still, the RAS proteins (farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) enzymes) perform essential steps in post-translational modification of eukaryotes cells, such as (1) the farnesylation of the cysteine residue at the C-terminal tetrapeptide CAAX; (2) proteolytic cleavage of the three C-terminal AAX oligopeptide; and (3) carboxymethylation of the new C-terminal prenylated cysteine. Thus, the inhibition of this undruggable RAS family of proteins has been considered a promising alternative to design new anticancer agents since they are responsible for many types of human cancers. Then, the manumycin A (obtained from the Streptomyces parvulus Tü64) and its analogs (epoxyquinol core with or without their southern and eastern side chains; and dihydroxycyclohexenones core) have been described as promising FTase inhibitors, which have demonstrated their benefits against several types of cancer. In this review, a complete  Posteriorly, studies involving manumycin-related compounds are described, showing some synthetic routes for obtaining them and utilizing these natural products in monotherapies or combined therapies with other anticancer drugs."
583,Beyond the C18 frontier: Androgen and glucocorticoid metabolism in breast cancer tissues: The role of non-typical steroid hormones in breast cancer development and progression.,"McNamara KM, Sasano H.",https://pubmed.ncbi.nlm.nih.gov/26057662/,"Breast cancer's hormonal dependence is well known and has been so for a long time. However in the last two decades great advances have been made in understanding the local metabolism of steroids within tissue. In the form of aromatase inhibition this is already one of the mainstays of breast cancer therapy. This review aims to summarise briefly what is known in terms of the metabolism of C18 steroids but perhaps more importantly to touch on the new developments regarding the importance of the metabolism of androgens and glucocorticoids in breast tissue. It is our hope that this review should provide the reader with a ""birds eye view"" of the current state of knowledge regarding localised steroid metabolism in the breast."
584,[Natural history of human cancer].,Sugano H.,https://pubmed.ncbi.nlm.nih.gov/6876413/,"Two important subjects in natural history of human cancer were reviewed and discussed. It is noted high incidence of latent cancer or microcancer in the thyroid, prostate and stomach. From these  We proposed the concept of the basic cancer and the variable cancer. The basic cancer is a proper cancer of a certain organ and stable in its incidence, while the variable cancer is a cancer whose incidence varies by environmental conditions."
585,Which Metrics Are Appropriate to Describe the Value of New Cancer Therapies?,"Johnson P, Greiner W, Al-Dakkak I, Wagner S.",https://pubmed.ncbi.nlm.nih.gov/26161418/,"Patients with certain cancers are treated with curative intent, but for others the  Early data suggest that new therapies, which modulate immune responses to cancers, may have potential for long-term survival in a proportion of cases. Therefore, it is timely to consider whether metrics generally used to describe the medical value of therapies for patients with common solid tumors remain appropriate for therapies with curative potential. Literature reviews were conducted to define how various stakeholders describe cure in oncology and to identify the endpoints used in clinical trials for selected solid tumors. The  The review of trial endpoints showed frequent use of median overall survival (OS) and progression- and response-related endpoints. Because these endpoints were mainly described in the context of chemotherapies that are not generally curative, they may not adequately capture outcomes of new therapeutic modalities with potential for long-term survival. More appropriate endpoints may include mean OS, cure fraction, and OS rate at landmark time points."
586,Study on breast cancerization and isolated diagnosis in situ by HOF-ATR-MIR spectroscopy with deep learning.,"Shang H, Wu Q, Wu J, Zhou S, Wang Z, Wang H, Yin J.",https://pubmed.ncbi.nlm.nih.gov/38824755/,"Mid-infrared (MIR) spectroscopy can characterize the content and structural changes of macromolecular components in different breast tissues, which can be used for feature extraction and model training by machine learning to achieve accurate classification and recognition of different breast tissues. In parallel, the one-dimensional convolutional neural network (1D-CNN) stands out in the field of deep learning for its ability to efficiently process sequential data, such as spectroscopic signals. In this study, MIR spectra of breast tissue were collected in situ by coupling the self-developed MIR hollow optical fiber attenuated total reflection (HOF-ATR) probe with a Fourier transform infrared spectroscopy (FTIR) spectrometer. Staging analysis was conducted on the changes in macromolecular content and structure in breast cancer tissues. For the first time, a trinary classification model was established based on 1D-CNN for recognizing normal, paracancerous and cancerous tissues. The final predication 09%, exhibiting superior discrimination ability than machine learning models of SVM-DA (90.00%), SVR (88.89%), PCA-FDA (67.78%) and PCA-KNN (70.00%). The "
587,[Whole abdominal irradiation for peritoneal dissemination of alimentary tract cancers].,"Sugahara S, Ohara K, Todoroki T, Tatsuzaki H, Fuji H, Kawashima M, Fukao K, Itai Y.",https://pubmed.ncbi.nlm.nih.gov/8532507/,"Between January 1986 and August 1991, 19 patients with alimentary tract cancers complicated by peritoneal dissemination received whole abdominal irradiation combined with intraperitoneal chemotherapy postoperatively. Using a moving-strip technique of irradiation, 12.0 Gy was delivered in three fractions to the entire abdominal contents with partial liver and kidney shielding. The primary tumor sites were the stomach in 12 patients, the colorectum in five, and the gall bladder in two. Nine patients with gross residual disease also received a limited field boost of 30.6 Gy in 17 fractions after completion of treatment to the whole abdomen. None of the patients failed to complete the planned dose despite acute gastrointestinal toxicity (nausea and vomiting, 84%, diarrhea and cramping, 78%) and acute hematologic toxicity (leukocytopenia, 84%, thrombocytopenia, 68%). Our follow-up study revealed that the actuarial one-year survival rate was 28.4% and the median survival time was 9.0 months. Survival rates at one-year for patients with colorectal and gastric cancer were 75.0% and 16.7%, respectively. Patients with gastric cancer (n = 12) had a poorer outcome than those with colorectal cancer (n = 5) in the present study. One reason for this difference may have been the presence of cancerous pleuritis, which was frequently observed in patients with gastric cancer. Therefore, more intensive treatment to prevent cancerous pleuritis seems to be necessary to improve the efficacy of whole abdominal irradiation."
588,Cancer-associated fibroblasts enact field cancerization by promoting extratumoral oxidative stress.,"Chan JS, Tan MJ, Sng MK, Teo Z, Phua T, Choo CC, Li L, Zhu P, Tan NS.",https://pubmed.ncbi.nlm.nih.gov/28102840/,"Histological inspection of visually normal tissue adjacent to neoplastic lesions often reveals multiple foci of cellular abnormalities. This suggests the presence of a regional carcinogenic signal that spreads oncogenic transformation and field cancerization. We observed an abundance of mutagenic reactive oxygen species in the stroma of cryosectioned patient tumor biopsies, indicative of extratumoral oxidative stress. Diffusible hydrogen peroxide (H2O2) was elevated in the conditioned medium of cultured skin epithelia at various stages of oncogenic transformation, and H2O2 production increased with greater tumor-forming and metastatic capacity of the studied cell lines. Explanted cancer-associated fibroblasts (CAFs) also had higher levels of H2O2 secretion compared with normal fibroblasts (FIBs). These  Indeed, H2O2-treated keratinocytes displayed decreased phosphatase and tensin homolog (PTEN) and increased Src activities because of oxidative modification. Furthermore, treating FIBs with CAF-conditioned medium or exogenous H2O2  In vivo, the proliferative potential and invasiveness of composite tumor xenografts comprising cancerous or non-tumor-forming epithelia with CAFs and FIBs could be attenuated by the presence of catalase. Importantly, we showed that oxidatively transformed FIBs isolated from composite tumor xenografts retained their ability to promote tumor growth and aggressiveness when adoptively transferred into new xenografts. Higher H2O2 production by CAFs was contingent on impaired TGFβ signaling leading to the suppression of the antioxidant enzyme glutathione peroxidase 1 (GPX1). Finally, we detected a reduction in Smad3, TAK1 and TGFβRII expression in a cohort of 197 clinical squamous cell carcinoma (SCC) CAFs, suggesting that impaired stromal TGFβ signaling may be a clinical feature of SCC. Our study indicated that CAFs and cancer cells engage redox signaling circuitries and mitogenic signaling to reinforce their reciprocal relationship, suggesting that future anticancer approaches should simultaneously target ligand receptor and redox-mediated pathways."
589,Policies and Practices to Address Cancer's Long-Term Adverse Consequences.,"Bradley CJ, Kitchen S, Bhatia S, Bynum J, Darien G, Lichtenfeld JL, Oyer R, Shulman LN, Sheldon LK.",https://pubmed.ncbi.nlm.nih.gov/35438165/,"As cancer detection and treatment improve, the number of long-term survivors will continue to grow, as will the need to improve their survivorship experience and health outcomes. We need to better understand cancer and its treatment's short- and long-term adverse consequences and to prevent, detect, and treat these consequences effectively. Delivering care through a collaborative care model; standardizing information offered to and collected from patients; standardizing approaches to documenting, treating, and reducing adverse effects; and creating a data infrastructure to make population-based information widely available are all actions that can improve survivors' outcomes. National policies that address gaps in insurance coverage, the cost and value of treatment and survivorship care, and worker benefits such as paid sick leave can also concurrently reduce cancer burden. The National Cancer Policy Forum and the Forum on Aging, Disability, and Independence at the National Academies of Sciences, Engineering, and Medicine sponsored a virtual workshop on ""Addressing the Adverse Consequences of Cancer Treatment,"" November 9-10, 2020, to examine long-term adverse consequences of cancer treatment and to identify practices and policies to reduce treatment's negative impact on survivors. This commentary discusses high-priority issues raised during the workshop and offers a path forward."
590,Carcinoma associated mucins: molecular biology and clinical applications.,Verma M.,https://pubmed.ncbi.nlm.nih.gov/7728736/,Mucin is a viscous secretion of glycoproteins secreted by epithelial cells of normal and cancerous tissues. Excessive and abnormal mucin synthesis has been observed in a number of cancers. The conformation and configuration of the surface carbohydrates play a key role in generating multiple forms of mucins in different cancers. The epitopes on the surface of mucin are recognized by antibodies present in different cancer cells. The primary structure of some of the cancer-associated mucins has been determined by molecular cloning of their complementary DNAs. The detection 
591,Endothelin-1 inhibition by ambrisentan as a potential treatment adjunct after debulking surgery in epithelial ovarian cancer.,Kast RE.,https://pubmed.ncbi.nlm.nih.gov/19544975/,"The 21 amino acid signaling peptide endothelin-1 is commonly elevated in epithelial ovarian cancer, and it mediates or facilitates much of this cancer's aggressive behavior. Ambrisentan (Letairis; Gilead Sciences Inc.) is an antagonist of endothelin-1 at its cognate receptor that has just been approved to treat pulmonary hypertension. Ambrisentan is a well-tolerated pill taken once daily. In theory, it should retard and inhibit lodgement and establishment of disseminated peritoneal micrometastases after debulking surgery."
592,The Many Faces of MTA3 Protein in Normal Development and Cancers.,"Ma L, Yao Z, Deng W, Zhang D, Zhang H.",https://pubmed.ncbi.nlm.nih.gov/27033852/,"As a family of chromatin remodeling proteins, metastasis-associated proteins (MTAs) have shown to be the master regulators in both physiological and pathological contexts. Although MTA3 is the latest being identified in MTA family, it has started to draw as much attention as the other family members. MTA3 is expressed in various tissues and is associated with different physiological functions. In cancerous context, both MTA1 and MTA2 are generally considered as oncogenes because they are capable of enhancing metastasis. However, MTA3 appears to play more complicated roles in cancers depending on the contexts. As a tumor suppressor, MTA3 usually down-regulates Snail, the master regulator of epithelium-mesenchymal transition, and subsequently represses cancer cell invasion and migration. Additionally, MTA3 may function by enhancing cancer cell differentiation without affecting proliferation in certain cancers. On the other hand, MTA3 might function in oncogene - related properties similarly as MTA1 and MTA2. In this review, we summarize our current understanding about MTA3 in normal development, cancers as well as other human diseases by comparing the similarities and differences between MTA3 and the other members of the MTA family."
593,Diagnostic relevance of overexpressed mRNA of novel oncogene with kinase-domain (NOK) in lung cancers.,"Amachika T, Kobayashi D, Moriai R, Tsuji N, Watanabe N.",https://pubmed.ncbi.nlm.nih.gov/17298854/,"There have been no target molecules that have enabled us to diagnose lung cancer with high sensitivity and specificity even in its early clinical stages. A molecule termed novel oncogene with kinase-domain (NOK) was recently reported as a receptor protein tyrosine kinase that is expressed in some cancer cell lines and causes the transformation and progressive proliferation of normal cells. Therefore, NOK could be a possible candidate for a diagnostic marker for human cancers. We examined here, the degree of NOK mRNA expression in lung cancer tissues and compared it to that in non-cancerous tissues. More than 60% of non-cancerous samples (8/13) showed undetectable levels of mRNA. In contrast, NOK mRNA was detected in 97.6% (40/41) of lung cancer tissues, 5% and a specificity of 92.3% that was estimated using the cutoff obtained from receiver operating characteristic curve analysis. Further, NOK mRNA expression was found to be elevated in 92.3% (12/13) of cancerous tissues when paired cancerous and non-cancerous tissues from identical patients were compared. There were no obvious correlations between clinicopathological factors and NOK mRNA expression; however, NOK mRNA was highly expressed even at the early clinical stages of the cancer. These "
594,Tumor M2-pyruvate kinase as tumor marker in exocrine pancreatic cancer a meta-analysis.,"Kumar Y, Gurusamy K, Pamecha V, Davidson BR.",https://pubmed.ncbi.nlm.nih.gov/17632316/," This meta-analysis aimed to evaluate its diagnostic utility in comparison to carbohydrate antigen 19-9 (CA19-9) in pancreatic cancer.
    


           A total of 258 references were retrieved. Of these, 118 duplicates were removed and 132 references were excluded. All studies comparing TuM2-PK with CA19-9 in pancreatic cancer were included. Full text was obtained for 8 references of 7 included studies. Diagnostic odds ratio (DOR) and 95% confidence interval (CI) was calculated from the available specificity and sensitivity for each study and were pooled to give overall DOR and 95% CI for TuM2-PK and CA19-9. Receiver operator characteristic curve was calculated to give overall specificity and sensitivity for TuM2-PK.
    


          7-62.3) was similar to those of CA19-9 (DOR, 44; 95% CI, 26.5-73.1). The overall specificity for TuM2-PK was 60% with corresponding sensitivity of 95%.
    


          Conclusion:
        
      
      Efficacy of TuM2-PK as a tumor marker is similar to that of CA19-9. Further trials are needed to use it alone or in combination with CA19-9 in patients with suspected pancreatic cancer."
595,Serum Raman spectroscopy: Prognostic applications in oral cancers.,"Saha P, Sawant S, Deshmukh A, Hole A, Murali Krishna C.",https://pubmed.ncbi.nlm.nih.gov/36919570/," The current study evaluates potential of serum Raman spectroscopy (SRS) to identify recurrence-prone OC subjects.
    


           OC subjects were followed-up for 7-years.
    


           4-, 3-, and 2-model multivariate analyses were used to stratify BS and AS groups. H spectra were 100% distinguishable from all other groups. AS, R and NR were distinguished with high accuracy (84%) in all models. No stratification (~50%) was observed BS.
    


          Conclusion:
        
      
      SRS shows potential to identify recurrence prone subjects, post-surgery, using serum collected as early as 1 week after surgery."
596,Screening for cancer and pre-cancer.,Mera SL.,https://pubmed.ncbi.nlm.nih.gov/8520249/,"In some countries cervical screening has been established for many years and has had a considerable impact on mortality from invasive cervical cancer. Because of this success, and in view of the continued high incidence and mortality from cancers generally, there is much interest in extending screening for other types of cancer. One example is the more recent  For other cancers, such as those of the colon, rectum, prostate and ovary, screening is currently confined to demonstration projects. Much of the success of cervical screening is attributable to the fact that abnormalities are detectable at a pre-cancerous stage, and treatment is effective in halting progression to invasive cancer. This is not always the case for most other forms of cancer screening."
597,Molecular medicine: a primer for clinicians. Part V: Cancer.,[No authors listed],https://pubmed.ncbi.nlm.nih.gov/8023129/,"Cancer is among the most common human diseases. However, with few exceptions, the etiology of the human cancers is not apparent. The tools of modern molecular biology have begun to elucidate the steps involved as a normal cell becomes cancerous. The  The ability to identify and manipulate these genes suggests possible molecular medicine-based diagnostic and prognostic tests as well as potential gene-based treatments or cures. The paper discusses recent advances in cancer molecular biology. The application of this information to patient care is also described. Finally, some of the ethical issues raised by the potential application of molecular medicine to cancer are discussed."
598,Nasopharyngeal cancer in North--Eastern Nigeria: clinical trends.,"Garandawa HI, Ahmad BM, Nggada HA.",https://pubmed.ncbi.nlm.nih.gov/20329676/," It is one of the most difficult diseases to diagnose at an early stage.
    


          Aim:
        
      
      To determine prevalence, clinical trends and histopathological types of Nasopharyngeal cancer in Maiduguri, North Eastern Nigeria.
    


          Patients and 
    


          1% of all malignancies of ear, nose, throat during the study period. The M:F was 2.1-1, the mean age was 39(+/- 16.5) years and a peak age group and its occurrence of 40-49 years. The commonest symptom at presentation were cervical lymphadenopathy (72.5%), rhinorrhoea (55%), epistaxis(45%). The commonest histological type was squamous cell carcinoma(92.5%). Patients who received chemotherapy in addition to radiotherapy and higher symptom free period.
    


          Conclusion:
        
      
      Cancer is a difficult disease to diagnose at an stage. A meticulous ear, nose and throat examination and thorough evaluation of nasal symptoms with associated cervical lymphadenopathy may lead to an early diagnosis of nasopharyngeal cancer's."
599,p53 mutations associated with aging-related rise in cancer incidence rates.,Richardson RB.,https://pubmed.ncbi.nlm.nih.gov/23839036/,"TP53's role as guardian of the genome diminishes with age, as the probability of mutation increases. Previous studies have shown an association between p53 gene mutations and cancer. However, the role of somatic TP53 mutations in the steep rise in cancer rates with aging has not been investigated at a population level. This relationship was quantified using the International Agency for Research on Cancer (IARC) TP53 and GLOBOCAN cancer databases. The power function exponent of the cancer rate was calculated for 5-y age-standardized incidence or mortality rates for up to 25 cancer sites occurring in adults of median age 42 to 72 y. Linear regression analysis of the mean percentage of a cancer's TP53 mutations and the corresponding cancer exponent was conducted for four populations: worldwide, Japan, Western Europe, and the United States. Significant associations (P ≤ 0.05) were found for incidence rates but not mortality rates. Regardless of the population studied, positive associations were found for all cancer sites, with more significant associations for solid tumors, excluding the outlier prostate cancer or sex-related tumors. Worldwide and Japanese populations yielded P values as low as 0.002 and 0.005, respectively. For the United States, a significant association was apparent only when analysis utilized the Surveillance, Epidemiology, and End  This study found that TP53 mutations accounts for approximately one-quarter and one-third of the aging-related rise in the worldwide and Japanese incidence of all cancers, respectively. These significant associations between TP53 mutations and the rapid rise in cancer incidence with aging, considered with previously published literature, support a causal role for TP53 according to the Bradford-Hill criteria. However, questions remain concerning the contribution of TP53 mutations to neoplastic development and the role of factors such as genetic instability, obesity, and gene deficiencies other than TP53 that reduce p53 activity."
600,Identification of Gene-Expression Signatures and Protein Markers for Breast Cancer Grading and Staging.,"Yao F, Zhang C, Du W, Liu C, Xu Y.",https://pubmed.ncbi.nlm.nih.gov/26375396/,"The grade of a cancer is a measure of the cancer's malignancy level, and the stage of a cancer refers to the size and the extent that the cancer has spread. Here we present a computational  By applying a differential expression and an SVM-based classification approach, we found that 324 and 227 genes in cancer have their expression levels consistently up-regulated vs. their matching controls in a grade- and stage-dependent manner, respectively. By using these genes, we predicted a 9-gene panel as a gene signature for distinguishing poorly differentiated from moderately and well differentiated breast cancers, and a 19-gene panel as a gene signature for discriminating between the moderately and well differentiated breast cancers. Similarly, a 30-gene panel and a 21-gene panel are predicted as gene signatures for distinguishing advanced stage (stages III-IV) from early stage (stages I-II) cancer samples and for distinguishing stage II from stage I samples, respectively. We expect these gene panels can be used as gene-expression signatures for cancer grade and stage classification. In addition, of the 324 grade-dependent genes, 188 and 66 encode proteins that are predicted to be blood-secretory and urine-excretory, respectively; and of the 227 stage-dependent genes, 123 and 51 encode proteins predicted to be blood-secretory and urine-excretory, respectively. We anticipate that some combinations of these blood and urine proteins could serve as markers for monitoring breast cancer at specific grades and stages through blood and urine tests."
601,Cachexia and anorexia: cancer's covert killer.,"Davis MP, Dickerson D.",https://pubmed.ncbi.nlm.nih.gov/10789957/,"Cachexia and anorexia are often not observed at the time of diagnosis of cancer. While the initial medical intervention for cancer patients includes antitumor therapy and pain management, the consequences of cachexia and anorexia may be ignored, to the detriment of the patient's quality of life and his or her potential response to chemotherapy. The importance of a well-defined therapeutic strategy to treat cachexia is in order if the patient's overall wellbeing is to improve. Presented is a review of the pharmacological management of anorexia and cachexia, including a four-step ladder approach to medical management."
602,Genetics of nonmelanoma skin cancer.,Tsao H.,https://pubmed.ncbi.nlm.nih.gov/11708952/,"Cancer is in essence a genetic disease characterized by genomic instability. Unlike classic genetic syndromes in which a single inherited mutation is often sufficient to determine the perturbed phenotype, most cancers, especially solid tumors, develop after an accumulation of multiple genetic lesions. Inherited mutations that predispose individuals to cancer formation are termed germline, while acquired mutations that contribute to tumor development are designated somatic. Bona fide hereditary cancers account for only a small proportion of all documented cancers. Most tumors  When mutations occur in critical growth regulatory genes, variations in cellular proliferation and survival contribute to the selection of dominant tumor population(s). Furthermore, these mutations may alter the antigenic properties of the cancerous cell and encourage escape from the host response. Thus, cancer is evolution at the microscopic level."
603,"Clinical and prognostic factors for melanoma of the skin using SEER registries: collaborative stage data collection system, version 1 and version 2.","Kosary CL, Altekruse SF, Ruhl J, Lee R, Dickie L.",https://pubmed.ncbi.nlm.nih.gov/25412392/,"
    


           Percentages of unknown cases for 7 SSFs were examined, along with staging trends from 2004 to 2010 and differences in AJCC 6th and 7th edition stage distributions for 2010 cases.
    


           For the remaining SSFs, 36-81% of cases were coded as unknown. Stage distributions were relatively consistent across time and between the AJCC 6th and 7th editions, with the exception of stage IA and stage INOS (not otherwise specified), for which a shift in cases was observed between the AJCC 6th and 7th edition guidelines fOR 2010 cases.
    


          Conclusions:
        
      
      A shift of cases out of stage IA and into stage INOS was observed between the AJCC 6th and 7th edition guidelines for 2010 cases. This was attributed to the high number of cases coded as unknown for SSF7 (primary tumor mitotic count/rate). The percentage of cases coded as unknown varied by SSF. Data completeness presents an issue for SSFs introduced in CS version 2."
604,Multiple cancers associated with esophageal and oropharyngolaryngeal squamous cell carcinoma and the aldehyde dehydrogenase-2 genotype in male Japanese drinkers.,"Yokoyama A, Watanabe H, Fukuda H, Haneda T, Kato H, Yokoyama T, Muramatsu T, Igaki H, Tachimori Y.",https://pubmed.ncbi.nlm.nih.gov/12223435/,"Aldehyde dehydrogenase-2 (ALDH2) is a key enzyme for the elimination of acetaldehyde, an established animal carcinogen generated by alcohol metabolism. In the presence of ALDH2*2, a mutant allele that is prevalent in East Asians, this enzyme is inactive, leading to excessive accumulation of acetaldehyde. Only among Japanese alcoholic patients has the positive association between this inactive form of ALDH2 and multiple-field cancerization in the upper aerodigestive tract been demonstrated. Whether this finding could be extended to multiple-cancer patients in general is of great interest, because the prevalence of esophageal cancer with other organ cancers has increased dramatically during recent decades in Japan. This study compared the ALDH2 genotypes of groups of male Japanese drinkers who had either esophageal squamous cell carcinomas (SCCs) with (n = 26) or without (n = 48) multiplicity or oropharyngolaryngeal SCCs with (n = 17) or without (n = 29) multiplicity. After adjustments for age and drinking and smoking habits, logistic regression analysis showed significantly increased risk for each multiplicity associated with either esophageal or oropharyngolaryngeal SCCs in the presence of the ALDH2*2 allele (odds ratio, 5.26; 95% confidence interval, 1.08-51.06 and odds ratio, 7.36; 95% confidence interval, 1.29-80.70, respectively). This study is the first to strongly link inactive ALDH2 with the multiple cancer susceptibility of male Japanese drinkers with either esophageal or oropharyngolaryngeal cancers. A simple questionnaire about both current and past facial flushing after drinking a glass of beer was highly sensitive (95.6%) in detecting inactive ALDH2 in these patients and may be useful for identifying high-risk patients."
605,Radiotherapy for oral cancer as a risk factor for second primary cancers.,"Hashibe M, Ritz B, Le AD, Li G, Sankaranarayanan R, Zhang ZF.",https://pubmed.ncbi.nlm.nih.gov/15766594/,"Radiation exposure, known to cause DNA damage, may be a potential source of field cancerization of the upper aerodigestive tract. Radiotherapy for head and neck cancers has been examined as a possible risk factor for second primary cancers, but the  We evaluated the impact of therapeutic radiation for oral cancer on the risk of second primary cancers with data from the Surveillance, Epidemiology, and End  Among 30,221 first primary oral squamous cell carcinoma patients, 6163 (20.4%) patients developed a second primary cancer, 5042 of which were metachronous. Patients treated with radiation only (RR=1.64, 95%CI=1.18-2.29) or radiation with surgery (RR=1.49, 95%CI=1.07, 2.06) had elevated risks of developing a second primary tumor, whereas patients treated with surgery only did not appear to be at increased risk (RR=1.28, 95%CI=0.93, 1.76). Consistent with an expected latent period between radiation exposure and tumor occurrence, radiation became a risk factor after 10 years of follow-up for solid cancers of the oral cavity (RR=2.8, 95%CI=1.5, 5.2), pharynx (RR=5.9, 95%CI=1.7, 20.7), esophagus (RR=3.9, 95%CI=1.1, 13.4) and lung (RR=1.5, 95%CI=1.0, 2.4), and after 1-5 years of follow-up for second primary leukemia (RR=2.5, 95%CI=1.0, 6.7). Radiotherapy for oral cancer appears to be a risk factor for second primary tumors. Further studies that account for chemotherapy and examine frequency and duration of radiotherapy would be of interest in confirming the observed association."
606,"Comparison of long non‑coding RNAs, microRNAs and messenger RNAs involved in initiation and progression of esophageal squamous cell carcinoma.","Li SQ, Li F, Xiao Y, Wang CM, Tuo L, Hu J, Yang XB, Wang JS, Shi WH, Li X, Cao XF.",https://pubmed.ncbi.nlm.nih.gov/24888564/,"Traditionally, cancer research has focused on protein‑coding genes, which are considered the principal effectors and regulators of tumorigenesis. Non‑coding RNAs, in particular microRNAs (miRNAs) and long non‑coding RNAs (lncRNAs), have been widely reported to be important in the regulation of tumorigenesis and cancer development. However, to the best of our knowledge, investigation of the expression profiles of lncRNAs and a comparison of the involvement of lncRNAs, miRNAs and messenger RNAs (mRNAs) in esophageal tumorigenesis and development have not previously been performed. In the current study, intrinsic associations among the expression profiles of lncRNAs, miRNAs and mRNAs from normal esophageal tissues and those from cancer tissues were investigated. Oligonucleotide microarrays were used to detect the expression profiles of the three types of RNA in the canceration processes of human esophageal squamous cell carcinoma (ESCC) tissues. It was demonstrated that the different RNAs exhibit associated patterns of expression among normal esophageal epithelium, low‑grade intraepithelial neoplasia (LGIN), high‑grade intraepithelial neoplasia (HGIN), and carcinoma tissues, particularly in the critical period of canceration (HGIN to ESCC). Furthermore, the  In the current study, a first generation atlas of lncRNA profiling and its association with miRNAs and mRNAs in the canceration processes of ESCC were presented."
607,"Clinical, Prognostic and Therapeutic Significance of Heat Shock Proteins in Cancer.","Saini J, Sharma PK.",https://pubmed.ncbi.nlm.nih.gov/28831912/," HSPs are also known to modulate a number of key apoptotic factors. High expression of these proteins is reported in an array of cancers, such as breast, prostate, colorectal, lung, ovarian, gastric, oral and esophageal cancer. Ample amount of investigations were carried out on a variety of cancers suggesting HSPs as a promising hallmark in cancers. Their expression profile in several tumors elucidates that they help in proliferation, invasion, metastasis and death of cancerous cells. Detection of the levels of heat shock proteins and their specific antibodies in the sera of diseased individuals can play an important role in cancer diagnosis.
    


           It will also highlight the clinical and prognostic features of HSP27, HSP60, HSP70, HSP90 and HSP110, and will discuss future implications of HSPs in the diagnosis and prognosis of cancer. Furthermore, the role of heat shock proteins as a therapeutic target in cancer will be discussed. In addition, the review article will report various studies, where HSPs have been targeted for their therapeutic potential.
    


          Conclusion:
        
      
      In summary, multiple  HSPs are associated with a number of cancer hallmarks such as cell proliferation, invasion and metastasis. Inhibition of HSPs has  It has served as a novel anti-cancer therapy for the treatment of several cancer forms. However, more  Novel and effective interventions through HSP inhibition are expected to decrease the burden of cancer in the near future."
608,Cancer knowledge and acceptance of children with cancer.,"Mabe PA, Riley WT, Treiber FA.",https://pubmed.ncbi.nlm.nih.gov/3644085/,"In this study, a Cancer Knowledge Questionnaire (CKQ) for elementary schoolchildren was developed and the relationship of cancer knowledge to attitudinal predispositions to accept and interact with children with cancer was assessed. CKQ includes 21 yes-no items that assess general cancer knowledge and knowledge of cancer's effects on social and emotional functioning. A sample of 478 children, ages six-12, completed CKQ, and a separate sample of 41 children completed it on two occasions separated by a one-week interval. Adequate internal consistency and test-retest reliability were obtained. Children's knowledge of cancer increased with age but generally was limited across all age groups. Knowledge of cancer was associated positively with previous experiences with cancer, lower fear of cancer, less worry about children with cancer, and attitudinal predispositions to accept and interact with children having cancer."
609,The emerging roles of histone demethylases in cancers.,"Tong D, Tang Y, Zhong P.",https://pubmed.ncbi.nlm.nih.gov/38227150/,"Modulation of histone methylation status is regarded as an important mechanism of epigenetic regulation and has substantial clinical potential for the therapy of diseases, including cancer and other disorders. The present study aimed to provide a comprehensive  A series of clinical trials have been performed to explore potential roles of histone demethylases in several cancer types. Numerous targeted inhibitors associated with immunotherapy, chemotherapy, radiotherapy, and targeted therapy have been used to exert anticancer functions. Future studies should evaluate the dynamic transformation of histone demethylases leading to carcinogenesis and explore individual therapy."
610,Estimating the prevalence of cancer in the United States.,Polednak AP.,https://pubmed.ncbi.nlm.nih.gov/9210719/,"S. ever diagnosed with invasive cancer.
    


           Estimated prevalence rates for Connecticut were compared with those for 1982, and were applied to the total U.S. population for selected years.
    


           The age-standardized prevalence rate had increased by 40% in males and 13% in females since 1982, due in part to large increases for breast, prostate, and (in females) lung carcinoma. Using the data for Connecticut, an estimated 7.1 million Americans in 1995 had ever been diagnosed with invasive cancer; projected numbers were 7.7 million for 2000 and 13.2 million for 2030.
    


          Conclusions:
        
      
      The prevalence of persons ever diagnosed with invasive cancer could increase considerably in the coming decades, and numbers for elderly males could surpass those for elderly females by 2020. Although projections must be interpreted with caution, these data emphasize the need for primary prevention of cancer and for studies of cancer survivors."
611,Over-expression of the overexpressed in lung cancer 1 is associated with poor prognosis in epithelial ovarian cancer.,"Jia C, Li X, Sun H, Sui L.",https://pubmed.ncbi.nlm.nih.gov/23609236/," The purpose of this study was to determine whether increased expression of OLC1 is associated with epithelial ovarian carcinoma (EOC) that diagnosed in patients.
    


           Univariate and multivariate analysis were performed to determine the association between OLC1 expression and prognosis.
    


           The 5-year overall survival (OS) rates of patients with high OLC1 expression and low OLC1 expression were 24.8% and 75.2%, respectively (hazard ratio: 21.43, 95% CI: 2.54, 7.12, P < 0.0001). The 5-year progression-free survival (PFS) rates were 30.1% for patients in the high-expression group and 69.9% for patients in the low OLC1 expression group (hazard ratio: 17.04, 95% CI: 0.33, 5.96, P < 0.0001).
    


          Conclusions:
        
      
      OLC1 over-expression is an important factor in epithelial ovarian carcinoma prognosis and can be a potential biomarker for ovarian carcinoma."
612,"Critical regulatory levels in tumor differentiation: Signaling pathways, epigenetics and non-coding transcripts.","Zolghadr F, Bakhshinejad B, Davuchbabny S, Sarrafpour B, Seyedasli N.",https://pubmed.ncbi.nlm.nih.gov/33644880/,"Approaches to induce tumor differentiation often  This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non-coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely "
613,Cancer-related attitudes: A comparative study in Japan and the US.,"Gotay CC, Shimizu H, Muraoka M, Ishihara Y, Tsuboi K, Ogawa H.",https://pubmed.ncbi.nlm.nih.gov/15334534/,"The cancer-related attitudes and beliefs of adults living in central Japan (N = 357) were compared to those of respondents in a US state (Hawaii) (N = 223) consisting of both Japanese (n = 106) and Caucasian (n = 117) individuals. Almost all US subjects endorsed doctors disclosing cancer diagnoses to their patients, while a minority of the Japan sample supported cancer disclosure as a general practice. However, the majority of Japan respondents expressed a personal preference to be told if they themselves were diagnosed with cancer, as did virtually all US respondents. US subjects were more optimistic than Japanese subjects about cancer's curability, both at the present time and in the future; Japanese Americans scored intermediate between Japanese and Caucasian Americans. Word-association data indicated that cancer was most likely to be associated with death by Japanese respondents. The data support the continued international differences in views about cancer and suggest that some of these differences persist over many generations of US residence."
614,Expression of high-mobility group-1 mRNA in human gastrointestinal adenocarcinoma and corresponding non-cancerous mucosa.,"Xiang YY, Wang DY, Tanaka M, Suzuki M, Kiyokawa E, Igarashi H, Naito Y, Shen Q, Sugimura H.",https://pubmed.ncbi.nlm.nih.gov/9036861/,"An 1194-nucleotide complementary DNA clone, FM1, encoding a human high-mobility group-1 protein (HMG-1) was isolated from a well-differentiated human gastric-carcinoma cell line complementary DNA library by a differential screening  FM1 is similar to the published human HMG-1 in mature protein, with only 3 different codons at positions 11, 149, and 190. We analyzed 33 gastric and colorectal adenocarcinomas for expression of the FM1 gene. Northern-blot analysis revealed that all of the cancers expressed FM1 at a higher level than in corresponding non-cancerous mucosa, with 2 transcripts of approximately 1.4 and 2.4 kilobases. The FM1 expression level in the non-cancerous tissues increased with the depth of accompanying cancer invasion. Only 18.2% of well-differentiated cancers showed a higher expression level in corresponding non-cancerous tissues, whereas the expression in corresponding non-cancerous tissues was significantly higher in moderately (60%) and poorly differentiated (83.3%) cancers. In situ hybridization demonstrated the location of FM1 mRNA in well- and poorly differentiated gastric-cancer cells as well as in non-cancerous tissue adjacent to poorly differentiated gastric cancer, but no hybridization was detected in normal epithelial cells adjacent to well-differentiated gastric cancer. These findings may provide new information on HMG-1 mRNA expression in human gastrointestinal cancer and suggest a correlation between FM1 mRNA expression to the differentiation and the stage of human gastrointestinal adenocarcinomas."
615,Proteome analysis of prostate cancer.,"Kuruma H, Egawa S, Oh-Ishi M, Kodera Y, Maeda T.",https://pubmed.ncbi.nlm.nih.gov/15477873/,"In this paper, we briefly review cancer proteomics in general, with particular attention to our proteome analyses of prostate cancer. Our efforts include development of new tools and novel approaches to discovering proteins potentially useful as cancer diagnostic and/or prognostic biomarkers or as therapeutic targets. To this end, we analyzed prostate cancer proteomes using two-dimensional gel electrophoresis employing agarose gels for the initial isoelectric focusing step (agarose 2-DE), with mass spectrometry used for protein identification. Agarose 2-DE offers advantages over the more widely used immobilized pH gradient 2-DE for separating high molecular mass proteins (15-500 kDa), thereby increasing its power to detect changes in the cancer's high-molecular mass proteomes."
616,Ligand-based active targeting strategies for cancer theranostics.,"Bandyopadhyay A, Das T, Nandy S, Sahib S, Preetam S, Gopalakrishnan AV, Dey A.",https://pubmed.ncbi.nlm.nih.gov/37466702/,"In the past decades, for the intermediate or advanced cancerous stages, preclinical and clinical applications of nanomedicines in cancer theranostics have been extensively studied. Nevertheless, decreased specificity and poor targeting efficiency with low target concentration of theranostic are the major drawbacks of nanomedicine in employing clinical substitution over conventional systemic therapy. Consequently, ligand decorated nanocarrier-mediated targeted drug delivery system can transcend the obstructions through their enhanced retention activity and increased permeability with effective targeting. The highly efficient and specific nanocarrier-mediated ligand-based active therapy is one of the novel and promising approaches for delivery of the therapeutics for different cancers in recent years to restrict various cancer growth in vivo without harming healthy cells. The article encapsulates the features of nanocarrier-mediated ligands in augmentation of active targeting approaches of various cancers and summarizes ligand-based targeted delivery systems in treatment of cancer as plausible theranostics."
617,[Precancerous and early invasive carcinomas: non-surgical treatment of head and facial skin].,Haneke E.,https://pubmed.ncbi.nlm.nih.gov/19322549/,"Chronic exposure to sunlight with its high proportion of high energy ultraviolet light is the main cause of the common cutaneous precancerous lesions and carcinomas of the head and neck. This causes a field cancerization effect frequently with multiple actinic keratoses (AKs), basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). Although demonstrating the best cure rates and lowest recurrence rates, surgical excision rapidly progresses to its limits. Field cancerization requires field therapy. Non-specific caustic agents may remove superficial lesions, however, the modern therapeutic modalities such as topical cytotoxic treatment with 5-fluorouracil, photodynamic therapy with 5-aminolevulinic acid (ALA) or its methyl ester (MeALA), the topical immune response modifier imiquimod or the local application of the cyclooxygenase inhibitor diclofenac are more specific and effective. Intralesional and perilesional injections of cytotoxic agents and interferons as well as the new targeted anti-cancer drugs are further alternatives. The most important aspect, however, is the prophylaxis of chronic photodamage."
618,Renovating the Commission on Cancer's Quality Measure Portfolio.,"Boffa DJ, Lum SS, Palis B, McCabe R, Park KU, Siddiqui MM, Facktor M, Mullet T, Nelson H.",https://pubmed.ncbi.nlm.nih.gov/38545786/,"Importance:
        
      
      Nearly 75% of newly diagnosed cancer patients in the United States will receive care from a hospital that is accredited by the Commission on Cancer (CoC). To support hospitals in their quality assurance efforts, the CoC maintains a portfolio of quality measures to give hospitals compliance data with select best practices for cancer care. As the CoC quality measures have evolved over recent years, many clinicians may lack awareness of the intent and content of the measure portfolio, as well as the mechanism by which new measures originate.
    


          Observations:
        
      
      The CoC quality measures are based on data that hospitals submit to the National Cancer Database, allowing the CoC to track compliance with a subset of consensus best practices. Each year, new measures are designed by diverse teams of specialists in the different treatment modalities for the tumor types covered by the portfolio. These proposed measures are then subjected to a range of vetting, refinement, and prioritization steps before being voted into the portfolio by the Quality Assurance and Data Committee of the CoC. Over the past 4 years, the CoC has worked to renovate not only the portfolio but also the process used to create and launch new measures, revise existing measures, and retire obsolete measures.
    


          Conclusion and relevance:
        
      
      In the following overview, we outline the current measure process, highlight important changes to the portfolio, and share opportunities to further increase the impact."
619,Isochromosome 17 in prostatic cancer.,"Oshimura M, Sandberg AA.",https://pubmed.ncbi.nlm.nih.gov/1159920/,In a continuing search for karyotypic changes characterizing various human cancers we have examined in detail with Q and G banding techniques the chromosomal constitution of a metastatic cancer of the prostate. The  Only further studies on the precise identification of individual chromosomes in other cancers will reveal the significance of this marker in human cancer.
620,Natural Products and Altered Metabolism in Cancer: Therapeutic Targets and Mechanisms of Action.,"Talib WH, Baban MM, Bulbul MF, Al-Zaidaneen E, Allan A, Al-Rousan EW, Ahmad RHY, Alshaeri HK, Alasmari MM, Law D.",https://pubmed.ncbi.nlm.nih.gov/39273552/,"Cancer is characterized by uncontrolled cell proliferation and the dysregulation of numerous biological functions, including metabolism. Because of the potential implications of targeted therapies, the metabolic alterations seen in cancer cells, such as the Warburg effect and disruptions in lipid and amino acid metabolism, have gained attention in cancer research. In this review, we delve into recent research examining the influence of natural products on altered cancer metabolism. Natural products were selected based on their ability to target cancer's altered metabolism. We identified the targets and explored the mechanisms of action of these natural products in influencing cellular energetics. Studies discussed in this review provide a solid ground for researchers to consider natural products in cancer treatment alone and in combination with conventional anticancer therapies."
621,[Screening of cervical cancer--theoretical background].,"Ondrus J, Dvorák V.",https://pubmed.ncbi.nlm.nih.gov/20437840/,"
    


          Design:
        
      
      Review article.
    


          Setting:
        
      
      Centrum of gyneco-oncology prevention, Havírov.
    


          
    


          Conclusion:
        
      
      Screening programme should be set up economic possibilities of state. It must cover all risk group. It should have high specificity and sensitivity. This test should be connected with diagnostic "
622,Levels of tissue polypeptide antigen in serum and the progression of gastric cancer.,"Hamazoe R, Koga S, Maeta M, Shimizu N, Inoue Y, Ishiguro M, Murakami A.",https://pubmed.ncbi.nlm.nih.gov/2724980/,"Correlations between levels of tissue polypeptide antigen (TPA) in serum and histologic stage or progression of cancer were studied in 94 patients with gastric cancer. Levels of TPA in serum from patients with cancerous invasion into the vein of the stomach wall (v-invasion) were elevated in parallel to the progression of cancer by stage, and were significantly higher in each positive case than in each negative case of lymph node metastasis or of cancerous invasion into lymph vessels of the stomach wall (P less than 0.05 and P less than 0.01, respectively). There were no differences in levels of TPA in serum from patients without v-invasion when these cancers were classified by stage, progression, or histologic type. It appears that elevation of levels of TPA in serum is associated with v-invasion, and that a determination of the level of TPA in serum is useful for the prediction of hematogenic metastasis in cases of gastric cancer."
623,A meta-analysis of the association between adjuvant chemoradiotherapy and disease-free survival in gastric cancer according to the histology.,"Yildirim HC, Guven DC, Akyildiz A, Yalcin S, Dizdar O.",https://pubmed.ncbi.nlm.nih.gov/36867373/," Perioperative chemotherapy, adjuvant chemotherapy, and adjuvant chemoradiotherapy (CRT) have all been demonstrated to be effective in the treatment of gastric cancer. The goal of this study was to do a meta-analysis of published studies that were eligible to see if adjuvant chemoradiotherapy was helpful for gastric cancer based on the cancer's histology.
    


          
    


           Adjuvant CRT was found to have no effect on disease-free survival (DFS) in gastric cancer patients treated with D2 surgery (HR: 0.70 (0.62-1.02), p: 0.07). However, patients with intestinal-type gastric cancers exhibited significantly longer DFS (HR: 0.58 (0.37-0.92), p = 0.02).
    


          Discussion:
        
      
      After D2 dissection, adjuvant CRT improved DFS in patients with intestinal-type gastric cancers but not in those with diffuse-type gastric cancers."
624,Can the molecules carried by extracellular vesicles help to diagnose pancreatic cancer early?,"Malhotra P, Casari I, Falasca M.",https://pubmed.ncbi.nlm.nih.gov/37236324/," Early-detection of this cancer in its initial stage would represent a game changer in the fight against this disease. The few currently available biomarkers detectable in patients' body fluids lack sensitivity and specificity.
    


          Scope of review:
        
      
      The recent discovery of extracellular vesicles and their role in promoting cancer's advancement has boosted interest in researching their cargo, to find reliable early detection biological markers. This review examines the most recent discoveries in the analysis of potential extra vesicle-carried biological markers for the early detection of pancreatic cancer.
    


          Major conclusions:
        
      
      Despite the advantages of using extracellular vesicles for early diagnosis, and the promising findings of extracellular vesicle-carried molecules possibly functional as biomarkers, until now there are no validated markers derived from extracellular vesicles available to be used in the clinic.
    


          General significance:
        
      
      Further studies in this direction are urgently required to provide what would be a major asset for defeating pancreatic cancer."
625,CiRS-7/CDR1as; An oncogenic circular RNA as a potential cancer biomarker.,"Rahmati Y, Asemani Y, Aghamiri S, Ezzatifar F, Najafi S.",https://pubmed.ncbi.nlm.nih.gov/34649055/,"Circular RNAs (circRNAs) as a new class of non-coding RNAs (ncRNAs) play role in gene regulation in multicellular organisms via various interactions with nucleic acids, proteins and particularly microRNAs. They have been found to be involved in a number of biological functions particularly in regulation of cell cycle, and extracellular interactions. Thus, dysregulation of circRNAs is found to be associated with several human diseases and especially numerous types of cancers. ciRS-7 is an example of circRNAs which have been studied in a number of human diseases like neurological diseases, diabetes mellitus, and importantly different malignancies. It has been found to regulate cell proliferation and malignant features in cancer cells. CiRS-7 is upregulated in several cancers and its overexpression promoted malignant phenotype of cancer cells via enhancing cell proliferation, migration, and invasion in vitro and in vivo. As a competing endogenous RNA (ceRNA), ciRS-7 is found to sponge miR-7 as the most common miRNA target in interaction together. Functional analyses show role of ciRS-7 in downregulation of miR-7 and involvement of a series of signaling pathways in turn through them it is believed that ciRS-7 regulates malignant behaviors of cancer cells. Clinical studies demonstrate upregulation of ciRS-7 in cancer tissues compared to their non-cancerous adjacent tissues, correlation with worse clinicopathological features in cancerous patients and an independent prognostic factor. In this review, we have an overview to the role of ciRS-7 in development and progression of cancer and also assess its potentials as a diagnostic and prognostic biomarker in human cancers."
626,Prognostic value of Zinc-finger protein X-linked in patients with solid tumors.,"Dai C, Dong Q, Lu Q, Liu FT, Zhu ZM.",https://pubmed.ncbi.nlm.nih.gov/27733754/," It was frequently overexpressed in cancerous tissues and the high expression of ZFX may have important clinical value. This meta-analysis aims to investigate the prognostic value of ZFX as a biomarker of solid cancers.
    


          Evidence acquisition:
        
      
      We search for multiple databases, including Pubmed, Springer, Web of Science, CNKI from 1996 to Sep. 1, 2016. Eligible articles were collected to explore the association between the expression levels of ZFX and overall survival (OS).
    


          Evidence synthesis:
        
      
      There were totally 933 cancer patients from eight studies. The pooled 26, 95%CI:1.77-2.75, P=0.000) than those with low ZFX expression. Statistical significance was also observed in subgroup meta-analysis stratified in the sampling object and cancer type.
    


          Conclusions:
        
      
      High expression of ZFX correlated with poor clinical outcome, ZFX might be sever as a potential prognostic biomarker in various cancers, especially for colorectal cancer."
627,Public perceptions of cancer: a qualitative study of the balance of positive and negative beliefs.,"Robb KA, Simon AE, Miles A, Wardle J.",https://pubmed.ncbi.nlm.nih.gov/25011992/," However, advances in early diagnosis and treatment mean that death rates are declining, and there are more than 30 million cancer survivors worldwide. This might be expected to  The present study used a qualitative 
    


          Design:
        
      
      A qualitative study using semistructured interviews with thematic analysis.
    


          Setting:
        
      
      A university in London, UK.
    


          Participants:
        
      
      30 participants (23-73 years), never themselves diagnosed with cancer.
    


           In almost all respondents, the first response identified fear, trauma or death. However, this was followed-sometimes within the same sentence-by acknowledgement that improvements in treatment mean that many patients can survive cancer and may even resume a normal life. Some respondents spontaneously reflected on the contradictions, describing their first response as a 'gut feeling' and the second as a more rational appraisal-albeit one they struggled to believe. Others switched perspective without apparent awareness.
    


          Conclusions:
        
      
      People appear to be 'in two minds' about cancer. A rapid, intuitive sense of dread and imminent death coexists with a deliberative, rational recognition that cancer can be a manageable, or even curable, disease. Recognising cancer's public image could help in the design of effective cancer control messages."
628,The anti-tumor activity of pineal melatonin and cancer enhancing life styles in industrialized societies.,"Bartsch C, Bartsch H.",https://pubmed.ncbi.nlm.nih.gov/16596311/,"This review discusses the potential role of the anti-tumor activity of pineal melatonin for the aetiology and prevention of cancers related to life-styles in industrialized societies, e.g. frequent long-distance flights as well as chronic night shift work leading to circadian disturbances of neuroendocrine parameters including melatonin.  Therefore, it is plausible that disturbances of circadian melatonin rhythmicity could be functionally involved in elevated cancer risks among aircrew members and nurses frequently working on night shifts. Due to the suppression of melatonin by light it can be assumed that too much artificial light at night could, at least in part, be responsible for generally increasing rates of e.g. breast cancer in industrialized countries. It is discussed under which conditions a transient substitutional therapy with melatonin could be justified or which forms of living could help to physiologically foster melatonin secretion to optimise control over cancerous growth and development."
629,"Gold nanoparticles, radiations and the immune system: Current insights into the physical mechanisms and the biological interactions of this new alliance towards cancer therapy.","Dimitriou NM, Tsekenis G, Balanikas EC, Pavlopoulou A, Mitsiogianni M, Mantso T, Pashos G, Boudouvis AG, Lykakis IN, Tsigaridas G, Panayiotidis MI, Yannopapas V, Georgakilas AG.",https://pubmed.ncbi.nlm.nih.gov/28322970/,"Considering both cancer's serious impact on public health and the side effects of cancer treatments, strategies towards targeted cancer therapy have lately gained considerable interest. Employment of gold nanoparticles (GNPs), in combination with ionizing and non-ionizing radiations, has been shown to improve the effect of radiation treatment significantly. GNPs, as high-Z particles, possess the ability to absorb ionizing radiation and enhance the deposited dose within the targeted tumors. Furthermore, they can convert non-ionizing radiation into heat, due to plasmon resonance, leading to hyperthermic damage to cancer cells. These observations, also supported by  In addition, they can be chemically modified to selectively target tumors, which renders them suitable for future cancer treatment therapies. Herein, a current review of the latest data on the physical properties of GNPs and their effects on GNP circulation time, biodistribution and clearance, as well as their interactions with plasma proteins and the immune system, is presented. Emphasis is also given with an in depth discussion on the underlying physical and biological mechanisms of radiosensitization. Furthermore, simulation data are provided on the use of GNPs in photothermal therapy upon non-ionizing laser irradiation treatment. Finally, the "
630,Post-traumatic stress disorder in cancer: a review.,"Smith MY, Redd WH, Peyser C, Vogl D.",https://pubmed.ncbi.nlm.nih.gov/10607985/,"The stressor criterion for Post-Traumatic Stress Disorder (PTSD) has been recently modified to include life-threatening illnesses, such as cancer, as precipitating traumatic events. We sought to examine the empiric evidence for cancer's inclusion as a traumatic stressor. Nine published studies assessing PTSD in cancer survivors and/or family members were identified in the literature. The studies were predominantly small (n<100) and cross-sectional. Study target groups included one or more of the following: children cancer survivors, parents of pediatric survivors and adult cancer survivors. There was considerable inter- and intra-study variability in the type and stage of cancer diagnosed and in the type of treatment regimens participants had undergone. Only three studies utilized a validated PTSD diagnostic tool to evaluate the disorder. Evidence of full-blown PTSD was found for adults and parents, and for children in all but one instance. These "
631,"Fields and field cancerization: the preneoplastic origins of cancer: asymptomatic hyperplastic fields are precursors of neoplasia, and their progression to tumors can be tracked by saturation density in culture.",Rubin H.,https://pubmed.ncbi.nlm.nih.gov/21254148/,"Most basic research on cancer concerns genetic changes in benign and malignant tumors. Yet evidence indicates that the majority of the mutations in tumors occur in the preneoplastic field stage of their development. That early stage is represented by grossly invisible, broad regions of ""field cancerization"" which have not, heretofore, been operationally analyzed in cell culture. Conditions are described for quantitating preneoplasia by increased saturation density followed by progression to transformation. These parameters are driven by Darwinian selection of spontaneously occurring, cumulative mutations, in accordance with recent genomic analyses of human cancer, just as it is in the evolution of species. The cell culture model will allow correlation of the preneoplastic increases in saturation density with genetic changes, and development of "
632,Viruses and human cancers: challenges for preventive strategies.,de The G.,https://pubmed.ncbi.nlm.nih.gov/8741797/,"Virus-associated human cancers provide unique opportunities for preventive strategies. The role of human papilloma viruses (HPV 16 and 18), hepatitis B virus (HBV), Epstein-Barr herpes virus (EBV), and retroviruses (human immunodeficiency virus [HIV] and human T-cell leukemia/lymphoma virus [HTLV]) in the development of common carcinomas and lymphomas represents a major cancer threat, particularly among individuals residing in developing countries, which account for 80% of the world's population. Even though these viruses are not the sole etiological agents of these cancers (as would be the case for infectious diseases), different approaches can be implemented to significantly decrease the incidence of virus-associated malignancies. The first approach is vaccination, which is available for HBV and possibly soon for EBV. The long delay between primary viral infection and development of associated tumors as well as the cost involved with administering vaccinations detracts from the feasibility of such an approach within developing countries. The second approach is to increase efforts to detect pre-cancerous lesions or early tumors using immunovirological means. This would allow early diagnosis and better treatment. The third strategy is linked to the existence of disease susceptibility genes, and suggests that counseling be provided for individuals carrying these genes to encourage them to modify their lifestyles and other conditions associated with increased cancer risks (predictive oncology). Specific recommendations include: a) increase international studies that explore the causes of the large variations in prevalence of common cancers throughout the world; b) conduct interdisciplinary studies involving laboratory investigation and social sciences, which may suggest hypotheses that may then be tested "
633,Saliva--a pivotal player in the pathogenesis of oropharyngeal cancer.,"Reznick AZ, Hershkovich O, Nagler RM.",https://pubmed.ncbi.nlm.nih.gov/15162153/,"Oropharyngeal (OP) cancer, which is usually squamous cell carcinoma, is the most common head and neck malignancy and accounts for 2-4% of all new cancers. It is primarily induced by exposure to tobacco. The paradigm of cigarette smoke (CS)-induced OP cancer's pathogenesis is based on the assumption that a constant direct attack of various CS carcinogens causes widespread accumulating cellular and DNA aberrations in the OP mucosal cells, in turn eventually  However, there is never a direct contact between CS and the OP mucosa. Saliva, bathing the mucosa from the oral cavity to the larynx, always intervenes, and CS must first interact with saliva before it reaches the mucosa. The current study investigated the role of saliva in the pathogenesis of OP cancer. A synergistic effect of CS and saliva on oral cancer cells was demonstrated. This synergism is based on the reaction between redox active metals in saliva and low reactive free radicals in CS, which  Thus, when exposed to CS, salivary behavior is reversed and the saliva loses its antioxidant capacity and becomes a potent pro-oxidant milieu. The devastating role of CS-borne aldehydes was demonstrated as well. Based on these "
634,[Site-specific incidence of benign and precancerous leukoplakias and cancers of the oral cavity].,"Schell H, Schönberger A.",https://pubmed.ncbi.nlm.nih.gov/3617851/,"The distribution patterns of benign and precancerous oral leukoplakias as well as oral cancer were investigated in 547 patients. The most frequently affected site was the buccal mucosa, the rarest localization was the floor of mouth. 96% of buccal lesions were benign, 4% were precancerous or cancerous. In contrast, 68% of the lesions on the floor of the mouth were precancerous or cancerous. Our "
635,Esophageal cancer: the role of integrated CT-PET in initial staging and response assessment after preoperative therapy.,"Munden RF, Macapinlac HA, Erasmus JJ.",https://pubmed.ncbi.nlm.nih.gov/16770230/,"Esophageal cancer, an uncommon neoplasm, has been increasing in incidence over the past few decades. Optimal management of patients is determined by the stage of disease at presentation, patient performance status, and location of the primary cancer. Recently, there has been increasing use of multimodality therapy in suitable candidates that employs preoperative chemotherapy and/or radiation followed by surgical resection. This evolving treatment strategy together with the substantial morbidity and mortality associated with esophagectomy makes appropriate patient selection critical. Computed tomography (CT) and endoscopy/endoscopic ultrasonography are usually carried out to initially stage patients with esophageal cancer, to determine primary tumor response, and to detect nodal and distant metastases after preoperative therapy. Positron emission tomography (PET) with [18F]-fluoro-2-deoxy-D-glucose and integrated CT-PET are useful in the initial staging of patients with esophageal cancer and in the prediction of pathologic response, disease-free interval, and overall survival after preoperative therapy. Importantly, integrated CT-PET imaging decreases the number of futile attempts at surgical resection, mainly because of the detection of occult distant metastases. The following sections review the use of integrated CT-PET imaging in determining the T, N, and M descriptors of the American Joint Commission on Cancer's 2002 guidelines for pathologic and clinical staging at initial diagnosis and after chemoradiation therapy in those patients being considered for surgical resection."
636,[Development of molecular targeting drugs for the treatment of cancer-therapeutic potential and issues to be addressed in global development].,"Akaza H, Aiba K, Isonishi S, Ogawa O, Shibuya M, Sone S, Tsuruo T, Noguchi S, Hinotsu S, Kono S, Mikami O, Blackledge G, Vose B, Stribling D.",https://pubmed.ncbi.nlm.nih.gov/11057319/,"A survey of cancer treatment in a sample of hospitals > 100 beds conducted in 1998 compared with experience in the US showed that good progress has been achieved in Japan in the screening and early treatment of gastric cancer, and that the prognosis for breast cancer is better than in the West. Although in the past, the cytotoxic therapies available to physicians in Japan vs the West have been different, recent acceleration of regulatory review will  However, world wide there is a need for new improved therapies in all cancers evaluated. Particular needs are in the management of NSCLC, advanced disease and cancers which form micrometastases. The eventual hope is that cancer can be turned from a lethal disease into a chronic disease where patients maintain a good QOL. Apart from anti hormonal therapies, the usual approach has been to kill the cancerous cells. However, the new approaches to intervening in the growth and migration of cancerous cells or the host tissue response by molecular targeting offer the promise of achieving a step change in therapy. Although EGF tyrosine Kinase inhibitors such as ZD 1839 have been shown to cause a conventional tumour response in NSCLC, many of these new approaches are unlikely to show a short term response even if they have the capacity to affect tumour development and increase disease free survival. Some compounds will require combination therapy with a conventional cytotoxic or radiotherapy to show their full benefit. For conventional cytotoxics, the usual approach to development has been to select the maximum tolerated dose and then evaluate the efficacy in advanced disease. However, for the new approaches which will not have such severe dose limiting toxicities, it will be necessary to select a surrogate marker of the intended biological effect to select the optimal biological dose (OBD) and dose regimen in phase I/II studies for further evaluation in phase II or III studies which are designed to show the expected patient benefit. The tumour target, the stage of the disease and the possible need for concomitant therapy will also have to be considered according to the mechanism of action of the product."
637,[Carcinoma of the gastric stump].,"Voboril Z, Pavlata J.",https://pubmed.ncbi.nlm.nih.gov/2263905/,"The problems related to the postgastrectomy cancers occurrence are studied in the present work. A total of 65 subjects with postgastrectomy stump's cancer has been managed at Clinic of surgery in Hradec Králové starting from 1955 to 1984. An interval averaged as 26.4 years followed from the gastrectomy up to the cancer' occurrence in postgastrectomy stump. Such an interval was stated to be longer in gastrectomized younger patients. Postgastrectomies of II. type  Authors preclude the postgastrectomy patients (II. type especially) are a group of cancer's risk in stomach stump, and are recommended to be covered with the out-patient care. The appropriate findings are compared to those of worldwide literary sources."
638,UTRN as a potential biomarker in breast cancer: a comprehensive bioinformatics and in vitro study.,"Li H, Zhang W, Liu Y, Cai Z, Lan A, Shu D, Shen M, Li K, Pu D, Tan W, Liu S, Peng Y.",https://pubmed.ncbi.nlm.nih.gov/38565593/,"Utrophin (UTRN), known as a tumor suppressor, potentially regulates tumor development and the immune microenvironment. However, its impact on breast cancer's development and treatment remains unstudied. We conducted a thorough examination of UTRN using both bioinformatic and in vitro  We discovered UTRN expression decreased in breast cancer compared to standard samples. High UTRN expression correlated with better prognosis. Drug sensitivity tests and RT-qPCR assays revealed UTRN's pivotal role in tamoxifen resistance. Furthermore, the Kruskal-Wallis rank test indicated UTRN's potential as a valuable diagnostic biomarker for breast cancer and its utility in detecting T stage of breast cancer. Additionally, our  This research provides a novel perspective on UTRN's role in breast cancer's prognostic and therapeutic value. Low UTRN expression may contribute to tamoxifen resistance and a poor prognosis. Specifically, UTRN can improve clinical decision-making and raise the diagnosis accuracy of breast cancer."
639,Epidemiology of cancers: I. Cancerous diseases of the large bowel.,"Schwarz K, McDonald M, Malpress W.",https://pubmed.ncbi.nlm.nih.gov/277800/,"A pilot study of cancerous diseases of the large bowel in Canterbury is described. The experience of 346 patients derived from the Cancer Registry for 1970-72 is presented. The feasibility of the  The preliminary  While demographic characteristics do not appear to help in defining persons at high risk from cancerous diseases of the large bowel, nevertheless other features of the natural history of this disorder indicate that it might be feasible to define high risk profiles."
640,Allelic imbalance of 8p indicates poor survival in gastric cancer.,"French AJ, Petroni G, Thibideau SN, Smolkin M, Bissonette E, Roviello F, Harper JC, Koch BR, Anderson SA, Hebbring SJ, Powell SM.",https://pubmed.ncbi.nlm.nih.gov/15269302/,"Gastric cancer is a common tumor worldwide and a tremendous health burden. However, the underlying mechanisms of tumorigenesis in this cancer's development are primarily undefined. Allelic imbalance (AI) of 8p has been reported in many cancers, yet, the target(s) of alteration and the importance of allelic imbalance on this chromosomal arm in gastric carcinoma development remained to be characterized. Our findings confirmed a high rate of AI on 8p in gastric cancers. Moreover, we demonstrated that AI on 8p, either overall or at marker D8S560, was associated with poorer survival in patients with gastric cancer. Finally, gastric cancers with a high rate of microsatellite instability were significantly associated with noncardia tumors and with female gender."
641,Lysine demethylase 5B (KDM5B): A key regulator of cancer drug resistance.,"Cao Y, Wu C, Ma L.",https://pubmed.ncbi.nlm.nih.gov/38014925/,"Chemoresistance, a roadblock in the chemotherapy process, has been impeding its effective treatment. KDM5B, a member of the histone demethylase family, has been crucial in the emergence and growth of malignancies. More significantly, KDM5B has recently been linked closely to cancer's resistance to chemotherapy. In this review, we explain the biological properties of KDM5B, its function in the emergence and evolution of cancer treatment resistance, and our hopes for future drug resistance-busting combinations involving KDM5B and related targets or medications."
642,Importance of volumetric measurement processes in oncology imaging trials for screening and evaluation of tumors as per response evaluation criteria in solid tumors.,"Vemuri RC, Jarecha R, Hwi KK, Gundamaraju R, Maruthikanth A, Kulkarni A, Reddy S.",https://pubmed.ncbi.nlm.nih.gov/24716987/,"Cancer, like any disease, is a pathologic biological process. Drugs are designed to interfere with the pathologic process and should therefore also be validated using a functional screening  Screening for cancers at an appropriate time and also evaluating  Volumetric measurement helps in better screening and evaluation of tumors. Volumetry is a process of quantification of the tumors by identification (pre-cancerous or target lesion) and measurement. Volumetric image analysis allows an accurate, precise, sensitive, and medically valuable assessment of tumor response. It also helps in identifying possible outcomes such disease progression (PD) or complete response as per Response Evaluation Criteria in Solid Tumors (RECIST)."
643,An indicator of cancer: downregulation of monoamine oxidase-A in multiple organs and species.,"Rybaczyk LA, Bashaw MJ, Pathak DR, Huang K.",https://pubmed.ncbi.nlm.nih.gov/18366702/," Previous work has produced promising  Recently drugs that affect serotonin reuptake were shown to reduce the risk of colon cancer in man. Here, we analyze an ensemble of cancer datasets focusing on genes involved in the serotonergic pathway. Genechip datasets consisting of cancerous tissue from human, mouse, rat, or zebrafish were extracted from the GEO database. We first compared gene expression between cancerous tissues and normal tissues for each type of cancer and then identified changes that were common to a variety of cancer types.
    


           MAO-A expression was decreased in 95.4% of human cancer patients and 94.2% of animal cancer cases compared to the non-cancerous controls.
    


          Conclusion:
        
      
      These are the first findings that identify a single reliable change in so many different cancers. Future studies should investigate links between MAO-A suppression and the development of cancer to determine the extent that MAO-A suppression contributes to increased cancer risk."
644,Mammographically non-calcified ductal carcinoma in situ: sonographic features with pathological correlation in 35 patients.,"Mesurolle B, El-Khoury M, Khetani K, Abdullah N, Joseph L, Kao E.",https://pubmed.ncbi.nlm.nih.gov/19414087/,"Aim:
        
      
      To present the sonographic findings of mammographically non-calcified ductal carcinoma in situ (DCIS) with histopathologic correlation.
    


          Materials and  Histological characteristics (architectural appearance, nuclear grade, percent of involved lobules, and presence of necrosis) were reviewed.
    


           Ultrasonographically, these lesions showed an irregular shape (28/47, 60%), microlobulated margins (34/47, 72%) and abrupt interfaces (42/47, 90%). Only 11% (5/47) displayed posterior shadowing. The echotexture of these lesions was most frequently complex (29/47, 62%); therefore, they were divided into two types: type I (24 cases), which were predominantly solid with cystic components, and type II (five cases), which were predominantly cystic with a solid intra-cystic component. A trend to have greater than 50% DCIS cells in cancerous lobules was observed in masses displaying type I echotexture (difference=36%, 95% confidence interval 10.6-62.5) and microlobulated margins (difference=32%, 95% confidence interval 5.1-58.7).
    


          Conclusion:
        
      
      Ultrasonographically detected radiographically non-calcified DCIS commonly displays an irregular shape, microlobulated margins, and complex echotexture, giving a ""pseudomicrocystic"" appearance. Microlobulated margins and ""pseudomicrocystic"" echotexture seem to be associated with a cancerization of the lobules."
645,Field cancerization: are multiple primary cancers monoclonal or polyclonal?,Carey TE.,https://pubmed.ncbi.nlm.nih.gov/8811160/,"Second primary cancers are a difficult problem in the upper aerodigestive tract and in several other organ sites. Among patients with early stage head and neck cancers, second primary tumours are a primary cause of death. It has been postulated that such second cancers represent new tumours developing from carcinogen-damaged cells in the same epithelial surface as the original tumour. An alternative hypothesis is that second primary tumours are the  New   There are contradictions in the data obtained by different assays, but there are also alternative interpretations for some of the  The strongest evidence shows that second primary cancers contain genetic markers identical to the original tumour. If additional study confirms that many or most second primary cancers are really metastases then a major shift in how we treat patients with epithelial carcinogen-induced cancers is indicated."
646,Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots.,"Korkaya H, Liu S, Wicha MS.",https://pubmed.ncbi.nlm.nih.gov/21685479/,"There is substantial evidence that many human cancers are driven by a subpopulation of cells that display stem cell properties. These cancer stem cells (CSC) may also contribute to metastasis and treatment resistance. Furthermore, just as normal stem cells are regulated by their microenvironment, or niche, CSCs interact with and in turn are regulated by cells in the tumor microenvironment. These interactions involve inflammatory cytokines, such as interleukin (IL)-1, IL-6, and IL-8, which in turn activate Stat3/NF-κB pathways in both tumor and stromal cells. Activation of these pathways stimulates further cytokine production, generating positive feedback loops that in turn drive CSC self-renewal. These cytokine loops and the pathways they regulate resemble those activated during chronic inflammation and wound healing, and may contribute to the known link between inflammation and cancer. Inhibitors of these cytokines and their receptors have been developed as anti-inflammatory agents. By blocking signals from the tumor microenvironment, these agents have the potential to target CSCs. Future clinical trials using these compounds will be needed to determine whether targeting the CSC population has clinical benefit."
647,Potential role of beta-carotene in prevention of oral cancer.,Garewal HS.,https://pubmed.ncbi.nlm.nih.gov/1985401/,"Recent data suggests that retinoids and carotenoids may be effective in reversing a putative ""field cancerization"" defect in the epithelium at risk for oral cancer. Animal  Several clinical trials have demonstrated the ability of retinoids to reverse oral leukoplakia. However, toxicities associated with retinoids at the doses used in these studies limits their potential for chemoprevention. Because of its lack of toxicity, beta-carotene is a very attractive agent for chemoprevention. It suppresses micronuclei in exfoliated oral mucosal cells from subjects at risk for oral cancer and recently has been shown to be active in reversing leukoplakia. Another area under investigation is the possibility of preventing second primary tumors in patients cured of their initial cancer who have an increased risk of developing new cancers of the upper acrodigestive tract."
648,[Adenoma of the gallbladder and its canceration: an analysis of 88 cases].,"Zhang ZX, Yin WH, Zhu ZY.",https://pubmed.ncbi.nlm.nih.gov/7842974/,"In this report, 88 cases of gallbladder adenoma collected from Chinese medical literature including the author's own 12 cases were analysed. Canceration was found in 17 (19.3%) cases. Risk factors included multiple and sessile adenoma, tubular adenoma, adenoma of more than 1 cm in diameter, and adenoma coexistent with gallstones. It is the authors' believe that any polypoid neoplasms of the gallbladder of more than 0.5 cm in diameter found by B-mode ultrasonography justify surgical exploration in order not to overlook a possible canceration."
649,Metal- and redox homeostasis in prostate cancer with vitamin D(3) supplementation.,"Süle K, Szentmihályi K, Szabó G, Kleiner D, Varga I, Egresi A, May Z, Nyirády P, Mohai M Jr, Blázovics A.",https://pubmed.ncbi.nlm.nih.gov/29886377/,"Vitamin D3 supplementation has a beneficial effect on cancerous patients, although it can influence the redox- and metal homeostasis. The aim of our investigation was to demonstrate the effect of vitamin D3 consumption on the redox- and metal homeostasis in prostate cancer, because of the recommended daily dose increased from 200 IU to 2000 IU in recent years in Hungary. Forty-three volunteers were involved in the study. The grouping was applied according to the clinical routine laboratory parameters (vitamin D3) and the tumor markers (PSA, fPFA). Patients were divided into 5 groups: (A) patient control (N = 8), (B) patient control with vitamin D3 treatment (N = 9), (C) high-risk prostate cancer group (N = 6), (D) high-risk prostate cancer group with vitamin D3 treatment (N = 8) and (E) vitamin D3 treated cancerous group with androgen deprivation therapy (N = 11). The element concentrations were determined with ICP-OES. Among the redox parameters, free radical scavenging capacity and H-donating ability were determined with luminometry and spectrometry. Vitamin D3 treatment caused differences in the metal- and redox homeostasis in either patient control and cancerous groups. The concentration of Fe, Cr, and Pb significantly increased in the erythrocytes of prostate cancer patients. According to the higher scavenging capacity by vitamin D3 treatment, it seems that vitamin D3 helps to equilibrate the redox homeostasis that could affect the outcome of cancer positively. However, the tendency in the metal element status does not give a clear explanation of cancer's outcome, but the accumulation of Pb by vitamin D3 supplementation needs to be taken into more serious consideration in set terms of occupational diseases."
650,"MicroRNA-221 and MicroRNA-222 in Common Human Cancers: Expression, Function, and Triggering of Tumor Progression as a Key Modulator.","Amini S, Abak A, Sakhinia E, Abhari A.",https://pubmed.ncbi.nlm.nih.gov/31049571/,"MicroRNAs (miRNAs) are a class of short (~22 nucleotides [nt]), single-stranded RNA oligonucleotides that are regulatory in nature and are often dysregulated in various diseases, including cancer. miRNAs can act as oncomiRs (miRNAs associated with cancer) or tumor suppressor miRNAs and have the potential to be a diagnostic, prognostic, noninvasive biomarker for these diseases. MicroRNA-221 (miR-221) and microRNA-222 (miR-222) are homologous miRNAs, located on the human chromosome Xp11.3, which factored significantly in impairment in the regulation of a wide range of cancers. In this review, we have highlighted the most consistently reported dysregulated miRNAs that trigger human tissues to express cancerous features and surveyed the role of those miRNAs in metastasis, apoptosis, angiogenesis, and tumor prognosis. Also, we applied the causes of drug resistance and the role of coordinated actions of these miRNAs to epigenetic changes and selected miRNAs as a potential type of cancer treatment."
651,Metaplastic breast cancer.,"Greenberg D, McIntyre H, Bierre T.",https://pubmed.ncbi.nlm.nih.gov/15230766/,Metaplastic breast carcinoma is uncommon and constitutes less than 5% of all breast cancers. The cancerous epithelium becomes non-glandular through metaplastic differentiation. There are various subtypes and the extent to which this process occurs varies. A case of a 52-year-old female patient is reported and the published literature is reviewed.
652,SIX1 amplification modulates stemness and tumorigenesis in breast cancer.,"Guo L, Li F, Liu H, Kong D, Chen C, Sun S.",https://pubmed.ncbi.nlm.nih.gov/38031089/," SIX1 is upregulated in different types of tumors, including breast cancer. However, the role and mechanism of SIX1 upregulation in breast cancer carcinogenesis remains uncertain.
    


           We also conducted both in vitro and in vivo 
    


           Besides, SIX1 participates in the rewiring of several cancer signaling pathways, including estrogen, WNT, MAPK, and other pathways, and interacts with cancer stem cells. SIX1 showed a significant positive correlation with breast cancer stem cell markers such as ALDH1A1, EPCAM, ITGB1, and SOX2. Moreover, our in vitro and in vivo 
    


          Conclusions:
        
      
      Altogether, our  The interaction between SIX1 and cancer stem cells may play a critical role in regulating breast cancer's initiation and metastasis."
653,New insights into pharmacological tools to TR(i)P cancer up.,"Gautier M, Dhennin-Duthille I, Ay AS, Rybarczyk P, Korichneva I, Ouadid-Ahidouch H.",https://pubmed.ncbi.nlm.nih.gov/24345078/,"The aim of this review is to address the recent advances regarding the use of pharmacological agents to target transient receptor potential (TRP) channels in cancer and their potential application in therapeutics. Physiologically, TRP channels are responsible for cation entry (Ca(2+) , Na(+) , Mg(2+) ) in many mammalian cells and regulate a large number of cellular functions. However, dysfunction in channel expression and/or activity can be linked to human diseases like cancer. Indeed, there is growing evidence that TRP channel expression is altered in cancer tissues in comparison with normal ones. Moreover, these proteins are involved in many cancerous processes, including cell proliferation, apoptosis, migration and invasion, as well as resistance to chemotherapy. Among the TRP superfamily, TRPC, TRPV, TRPM and TRPA1 have been shown to play a role in many cancer types, including breast, digestive, gliomal, head and neck, lung and prostate cancers. Pharmacological modulators are used to characterize the functional implications of TRP channels in whole-cell membrane currents, resting membrane potential regulation and intracellular Ca(2+) signalling. Moreover, pharmacological modulation of TRP activity in cancer cells is systematically linked to the effect on cancerous processes (proliferation, survival, migration, invasion, sensitivity to chemotherapeutic drugs). Here we describe the effects of such TRP modulators on TRP activity and cancer cell phenotype. Furthermore, the potency and specificity of these agents will be discussed, as well as the development of new strategies for targeting TRP channels in cancer."
654,[Relationship between tumor suppressor gene p16 and Rb and early diagnosis of lung cancers].,"Ye Y, Su C, Wang D, Liu S, Liu Y, Liu B, Cao X, Shan X, Wu M.",https://pubmed.ncbi.nlm.nih.gov/11832104/,"
    


          
    


           In stage I and II lung cancers, the obvious inactivation of tumor suppressor gene p16 or Rb was examined (32.6% or 28.3%); p16 inactivation was detected mainly in non-small cell lung cancers, and Rb inactivation mainly in small cell lung cancers. There were three mechanisms of homozygous deletions, methylations and mutations for p16 gene inactivation. The deletion rate of p16 exon1 and/or exon2 was 25.8%, mainly took place in p16 protein negative cases of non-small cell lung cancers. 15 cases (16.9%) took part in methylations on SmaI sites of CpG island of p16 gene. PCR-SSCP and sequencing showed that 9 cases had p16 gene mutations.
    


          Conclusions:
        
      
      p16 and Rb genes may play important roles in genesis and progression of lung cancers. Inactivation of p16 or Rb gene may be is an early link of lung canceration, that is very important for early diagnosis of lung cancers. A new gene classification model for lung cancer diagnosis would be set up based on the research of p16 and Rb genes."
655,Detection of small hepatocellular carcinomas in cirrhotic livers using iodised oil computed tomography.,"Saada J, Bhattacharya S, Dhillon AP, Dick R, Burroughs AK, Rolles K, Davidson BR.",https://pubmed.ncbi.nlm.nih.gov/9378400/,"
    


          Aims:
        
      
      To assess the sensitivity of iodised oil computed tomography (IOCT).
    


          Patients and  Following transplantation the explant liver was serially sectioned for pathological evaluation. Soft tissue radiographs of the liver slices were used to match histological lesions with CT findings.
    


           Of the remaining 39, histological evaluation revealed no cancers in 33 explant livers, in keeping with negative preoperative imaging. Six explant livers contained 55 HCCs, 84% of which were less than 1 cm in diameter. Pretransplant IOCT detected 3/6 patients with cancer (50%) but only 7% of cancerous lesions. Ultrasound, contrast CT, and angiography each detected 2/6 patients with cancer and 4% of cancerous lesions.
    


          Conclusion:
        
      
      IOCT is an insensitive "
656,[The progression of lung cancer incidence in France (1978-2000)].,"Molinié F, Velten M, Remontet L, Bercelli P, Réseau Francim.",https://pubmed.ncbi.nlm.nih.gov/16788436/," Our 
    


           These registries also provided information about histological type.
    


          0% of all incident cancers and was responsible for 18.1% of deaths from cancer. From 1980 to 2000, the incidence rose from 47.4 to 52.2 per hundred thousand in men and from 3.7 to 8.6 per hundred thousand in women. The risk of developing lung cancer, which remained constant in men, has increased considerably (+451%) between the generation of women born in 1953 and those born in 1913. The proportion of epidermoid cancers has dropped whilst that of adenocarcinomas has risen sharply.
    


          Conclusions:
        
      
      The last few years have seen a large increase in the incidence of lung cancer in women and an increasing incidence of adenocarcinoma in both men and women."
657,The status of ultrasound and color Doppler imaging for the early detection of ovarian carcinoma.,Karlan BY.,https://pubmed.ncbi.nlm.nih.gov/9171861/,"Noninvasive imaging techniques such as ultrasound and color doppler imaging have been evaluated during the last decade for their ability to detect organ-confined curable ovarian cancer. While sensitivities approaching 100% can be achieved by these techniques, their specificities and the frequent invasive procedures required to confirm the abnormal sonographic findings have led to caution regarding the widespread use of ultrasound screening for ovarian cancer. These data are reviewed, as well as the NIH Consensus Panel on ovarian cancer's recommendation that routine screening for ovarian carcinoma should not be carried out at this time. Hereditary ovarian cancer syndromes account for approximately 5-10% of the cases. Many of the genes responsible for these syndromes have recently been elucidated. Due to the significant increase in the risk of ovarian cancer in these families, many screening studies have focused on this patient population. Findings from these trials, as well as studies on the psychological impact of screening are presented."
658,[Loss of fragile histidine triad expression and metastasis in breast cancer].,"Zhao P, Li XY, Chen LZ.",https://pubmed.ncbi.nlm.nih.gov/12452072/," The aim of this study was to investigate the expression of FHIT protein, Fhit and the possible relationship between Fhit expression and clinicopathological indices in breast cancer.
    


          
    


          6%) cases of carcinomas showed a marked loss or absence of Fhit expression compared with the adjacent non-cancerous breast tissues, in which 22 cases were negative. The remain 18 (27.3%) showed stronger than, and 10 (15.2%) equal to the Fhit expression of the adjacent non-cancerous tissue. The lower expression of Fhit was found in 20/24(83.3%) cases with local or axillary lymphatic metastasis, and in 18/36 (50%) cases without metastasis in the invasive ductal carcinoma. Fhit expression was determined in all 6 cases of in situ ductal carcinoma did not show lower than non-cancerous tissue. There was a significant difference in the expression of Fhit between the breast cancers with and without lymphatic metastasis, both in ductal carcinoma (P < 0.01) and in invasive ductal carcinoma(P < 0.01).
    


          Conclusions:
        
      
      The expression of Fhit is associated with invasion and metastasis of tumor in breast cancer. It is suggested that decreased Fhit expression may play an important role in the development and progression of the tumor, and thus may become a new prognostic marker for breast cancer."
659,[Update on oral cancer--awareness equals survival?].,"Czerninski R, Markitziu A.",https://pubmed.ncbi.nlm.nih.gov/11905094/,"There is a trend towards higher prevalence of oral cancer and no progress has been achieved concerning survival rates during the last few decades. Despite the simplicity of the oral examination most of oral cancers are discovered at advanced stages bearing severe prognosis. Improved awareness of both the attendant medical team and the target population may improve the chances of prevention by earlier detection thus enhancing the survival rate. We present current diagnostic procedures for early detection of oral cancerous lesions together with a short review of epidemiology, clinical aspects, risk factors and treatment modalities."
660,Proteomic approaches for cancer epigenetics research.,"Marchione DM, Garcia BA, Wojcik J.",https://pubmed.ncbi.nlm.nih.gov/30482069/," The chromatin landscape in cancer cells is often marked by abnormal histone post-translational modification (PTM) patterns and by aberrant assembly and recruitment of protein complexes to specific genomic loci. Mass spectrometry-based proteomic analyses can support the discovery and characterization of both phenomena. Areas covered: We broadly divide this literature into two parts: 'modification-centric' analyses that link histone PTMs to cancer biology; and 'complex-centric' analyses that examine protein-protein interactions that occur de novo as a  We also discuss proteomic studies of oncohistones. We highlight relevant examples, discuss limitations, and speculate about forthcoming innovations regarding each application. Expert commentary: 'Modification-centric' analyses have been used to further understanding of cancer's histone code and to identify associated therapeutic vulnerabilities. 'Complex-centric' analyses have likewise revealed insights into mechanisms of oncogenesis and suggested potential therapeutic targets, particularly in MLL-associated leukemia. Proteomic  Additional applications of proteomics that may benefit cancer epigenetics research include middle-down and top-down histone PTM analysis, chromatin reader profiling, and genomic locus-specific protein identification. In the coming years, proteomic approaches will remain powerful ways to interrogate the biology of cancer."
661,[Expression of hedgehog proteins in periampullary cancer].,"Lee SY, Lee KT, Jang KT, Choi SH, Heo JS, Kim DH, Lee JK, Paik SW, Rhee JC.",https://pubmed.ncbi.nlm.nih.gov/16247273/," Here, we performed hedgehog immunostaining in periampullary cancer to evaluate the differences according to the location type of cancer and the differentiation of adenocarcinoma.
    


           Immunohistochemical stain was performed in both normal and cancerous tissue portions of each case using Sonic hedgehog (H-160) rabbit polyclonal antibody. Immunohistochemical stain 
    


          3% (41/43 cases). Strongly stained cases were more frequently seen in ampulla of Vater cancers (13/15) and in combined ampulla of Vater/bile duct cancers (3/3) than in distal common bile duct cancers (4/12) and in pancreatic head cancers (3/13) (p=0.002). In addition, strongly stained cases were more frequently seen in well-differentiated adenocarcinoma than the others (p<0.001).
    


          Conclusions:
        
      
      Most of the periampullary cancers show hedgehog protein expression. In addition, hedgehog protein immunostainings shows stronger expression in ampulla of Vater cancers and in well-differentiated adenocarcinoma."
662,"CT, positron emission tomography, and MRI in staging lung cancer.","Erasmus JJ, Sabloff BS.",https://pubmed.ncbi.nlm.nih.gov/18267183/,"Lung cancer is a common malignancy and remains the leading cause of cancer-related deaths in both men and women in the United States. Imaging plays an important role in the detection, diagnosis, and staging of the disease as well as in assessing response to therapy and monitoring for tumor recurrence after treatment. This article reviews the staging of the two major histologic categories of lung cancer-non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma-and emphasizes the appropriate use of CT, MRI, and positron emission tomography imaging in patient management. Also discussed are proposed revisions of the International Association for the Study of Lung Cancer's terms used to describe the extent of NSCLC in terms of the primary tumor, lymph nodes, and metastases descriptors."
663,Exploring the role of psychosocial care in value-based oncology: Results from a survey of 3000 cancer patients and survivors.,"Doherty M, Miller-Sonet E, Gardner D, Epstein I.",https://pubmed.ncbi.nlm.nih.gov/30451102/,"Purpose:
        
      
      To explore the psychosocial needs of cancer patients and survivors across the United States and their implications for value-based oncology.
    


          Design:
        
      
      A secondary analysis of findings from a cross-sectional national online survey.
    


          Sample:
        
      
      Respondents were sampled and stratified by cancer type and geographic region to approximate the cancer-affected population of the United States. Breast, prostate, and colorectal were the most common cancers reported. Across surveys, the majority of respondents were female (57%), over 55 (60%), and white (70%) and had at least some college (36%).
    


           Survey topics included: (1) diagnosis, (2) treatment planning, (3) communication with providers, (4) insurance and financial concerns, (5) quality of life, side effects, and symptoms, and (6) survivorship and end-of-life. Descriptive analyses were used to explore psychosocial needs and experiences across three domains of patient-centered value in oncology.
    


          Findings:
        
      
      Each survey received 500-527 responses. Respondents most commonly reported needing more information regarding their insurance coverage and out-of-pocket costs (65%), access to clinical trials (89%), and support organizations (45%). Forty-one percent were very or extremely distressed about cancer's impact on their ability to work and over 25% reported high-levels of cancer-related financial hardship.
    


          Conclusions:
        
      
      Patients and survivors reported significant unmet informational needs, financial hardship, distress, and symptoms or treatment side effects that interfered with daily life. Implications for Psychosocial Providers or Policy: Providers and payment reform advocates can improve value in oncology by ensuring access to comprehensive psychosocial care and informational support."
664,Breast cancer in men.,Mattarella A.,https://pubmed.ncbi.nlm.nih.gov/20207793/,"Less than 1% of all breast cancers occur in men, and although the disease is rare, the incidence appears to be increasing. Because men usually do not suspect breast cancer when they feel a lump in the breast, diagnosis frequently is delayed. Although screening for breast cancer is not recommended for men, radiographic imaging plays an important role in distinguishing benign conditions from malignant disease, and mammography usually is recommended as the first radiographic assessment. Ultrasonography is useful in differentiating between noncancerous cysts and solid malignant tumors, especially if coexisting gynecomastia masks a cancerous lesion on mammography. Sonography also is useful to guide breast biopsy."
665,The correlation of epidermal growth factor with invasion and metastasis in human gastric cancer.,"Onda M, Tokunaga A, Nishi K, Yoshiyuki T, Shimizu Y, Kiyama T, Mizutani T, Matsukura N, Tanaka N, Yamashita K, et al.",https://pubmed.ncbi.nlm.nih.gov/2193178/,"We examined the localization of epidermal growth factor (EGF) in 185 specimens of primary human gastric cancer using the avidin-biotin peroxidase complex immunohistochemical  Thirty-four per cent of the gastric cancer specimens were positive for EGF, which was mainly located in the cytoplasm of the cancer cells and occasionally in the stromal cells, but was not detected in non-cancerous gastric epithelium. Moreover, the presence of EGF in gastric cancer was correlated with gastric wall invasion and lymph node metastasis. EGF was found more often in advanced cancers than in early ones (p less than 0.01), and also more often in cancers with lymph node metastasis than in those without (p less than 0.05). The five-year survival of patients with EGF-positive tumors was worse than that of patients with EGF-negative tumors (p less than 0.05). The presence of EGF in human gastric cancer may thus represent higher malignant potential."
666,Advances in research on the relationship between the gut microbiome and cancer.,"Song P, Wang QB, Liang B, Jiang SJ.",https://pubmed.ncbi.nlm.nih.gov/34486684/,"
    


          Materials and  By reviewing and analyzing the literature, we analyzed how the bacterial microbiome influences the immune system and cancer, as well as how changes in symbiotic flora may be applied to improve the efficacy of cancer immunotherapy.
    


           In recent years, a number of studies have confirmed the influence of intestinal flora on immune checkpoint inhibitors in cancer patients, and studies have also shown the link between the intestinal microbiome and treatment-related immune toxicity. Antibiotics, proton pump inhibitors, and hormones affect the composition of the gut microbiota.
    


          Conclusions:
        
      
      Intestinal flora is closely related to cancer. Intestinal flora has a certain impact on cancer occurrence, cancer treatment, cancer immunotherapy efficacy, and side effects."
667,Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria.,"Mathupala SP, Ko YH, Pedersen PL.",https://pubmed.ncbi.nlm.nih.gov/16892090/,"A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals."
668,An epidemiological study to identify the risk factors with two different types of controls in high-grade cervical lesions including invasive cancer.,"Sardana S, Sharma S, Sodhani P, Sehgal A, DAS BC.",https://pubmed.ncbi.nlm.nih.gov/19549283/,"A multidisciplinary study on pre-cancerous and early cancerous lesions of uterine cervix was carried out at our Institute from which the subjects (cases and one group of control) for the present study were selected with the  One group of control was women with negative Pap smear and second group of control was the women with breast cancer but negative Pap smear. A total of 100 biopsy-proven cases of high-grade cervical intraepithelial lesions and Invasive cancer were recruited. The  So it is concluded that in order to remove any bias, normal hospital controls or controls selected from multiple cancers should be taken to study the risk factors involved in cervical carcinogenesis."
669,"Cancer Statistics over Time in Northwestern Sao Paulo State, Brazil: Incidence and Mortality.","Mafra da Costa A, Hernandes ICP, Weiderpass E, Soerjomataram I, Fregnani JHTG.",https://pubmed.ncbi.nlm.nih.gov/35131883/," This study aimed to provide statistics over time on cancer incidence and mortality in the Barretos Region, Brazil.
    


           Age-standardized rates for incidence and mortality were calculated. Joinpoint Regression software was used to estimate the average annual percentage changes (AAPC).
    


          2), rectum and rectosigmoid (AAPC: 2.4), liver (AAPC: 4.7), female breast (AAPC: 2.2), and thyroid cancer (AAPC: 3.8) but decreased for esophageal (AAPC: -3.2), stomach (AAPC: -4.2), lung (AAPC: -2.0), and ovarian cancer (AAPC: -5.6). The mortality increased for liver cancer (AAPC: 2.3) and decreased for pharyngeal cancer (AAPC: -5.8), stomach cancer (AAPC: -6.6), cervical uterine cancer (AAPC: -5.9), prostate cancer (AAPC: -2.4), and ovarian cancer (AAPC: -3.3).
    


          Conclusions:
        
      
      We observed decreases in some cancers related to tobacco smoking and cervical and stomach cancers related to infectious agents, showing strong regional and national prevention programs' successes. But, we also observed rises in many cancer sites linked to lifestyle factors, such as breast or colorectal cancer, without a sign of declining mortality.
    


          Impact:
        
      
      These "
670,Long Noncoding RNA PVT1 as a Potent Predictor of Prognosis in Cancers: a Meta-Analysis.,"Pan X, Li B, Fan N, Li J, Cai F, Zhao G, Zheng G, Gao C.",https://pubmed.ncbi.nlm.nih.gov/29035442/," Many studies have found that high expression of PVT1 was correlated with poor prognosis.
    


           The hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CI) were computed to estimate the pooled effect of PVT1 on prognosis of cancers using Stata 12.0 version software.
    


           The pooled 91, 95% CI: 1.61 - 2.26, p < 0.001) and disease-free survival (HR = 1.90, 95% CI: 1.46 - 2.48, p < 0.001) or recurrencefree survival (HR = 1.77, 95% CI: 1.24 - 2.52, p = 0.002) or progression-free survival (HR = 2.84, 95% CI: 1.67 - 4.82, p < 0.001). High expression of PVT1 was closely associated with tumor-node-metastasis (TNM) stage (III/IV vs. I/II: OR = 3.19, 95% CI: 2.43 - 4.18, p < 0.001), and the significant correlation between PVT1 expression and TNM stage is found in T classification (T3/4 vs. T1/2: OR = 6.48, 95% CI: 2.93 - 14.31, p < 0.001) and lymph node metastasis (present vs. absent: OR = 2.56, 95% CI:1.36 - 4.80, p = 0.003), but not in distant metastasis of patients with cancers (yes vs. no: OR = 2.50, 95% CI: 0.72 - 8.66, p = 0.15). Furthermore, the cancerous patients with high PVT1 expression had a worse histological differentiation than those with low PVT1 expression (undifferentiated/poorly vs. moderately/well: OR = 1.48, 95% CI: 1.02 - 2.14, p = 0.039).
    


          Conclusions:
        
      
      PVT1 could serve as a potent predicator of prognosis in different types of cancers."
671,Drug Resistance in Cancers: A Free Pass for Bullying.,"Li J, Li X, Guo Q.",https://pubmed.ncbi.nlm.nih.gov/36359776/,"The cancer burden continues to grow globally, and drug resistance remains a substantial challenge in cancer therapy. It is well established that cancerous cells with clonal dysplasia generate the same carcinogenic lesions. Tumor cells pass on genetic templates to subsequent generations in evolutionary terms and exhibit drug resistance simply by accumulating genetic alterations. However, recent evidence has implied that tumor cells accumulate genetic alterations by progressively adapting. As a  The genetic adaptive mechanisms of action of ITH include activating ""cellular plasticity"", through which tumor cells create a tumor-supportive microenvironment in which they can proliferate and cause increased damage. These highly plastic cells are located in the tumor microenvironment (TME) and undergo extreme changes to resist therapeutic drugs. Accordingly, the underlying mechanisms involved in drug resistance have been re-evaluated. Herein, we will reveal new themes emerging from initial studies of drug resistance and outline the findings regarding drug resistance from the perspective of the TME; the themes include exosomes, metabolic reprogramming, protein glycosylation and autophagy, and the relates studies aim to provide new targets and strategies for reversing drug resistance in cancers."
672,A critical investigation of the Oxford tumour marker Ca1 in the histological diagnosis of breast cancer and pre-cancer.,"Simpson HW, Candlish W, Liddle C, McGregor M, Mutch F, Tinkler B.",https://pubmed.ncbi.nlm.nih.gov/6376326/,"Ca1 antibody reacted focally with all of the 20 cancers examined, but also with 12 out of 13 fibroadenomata and with each of 20 normal breasts. These observations indicate that there are severe limitations to the use of Ca1 antibody for defining benign versus malignant processes. Ca1 is most specific in terms of the cytoplasmic staining of tumours versus normal tissues. If a hierarchy of maximal staining is drawn up, cancers and fibroadenomata appear at the top, with normal tissue found in various types of breast in the middle, and non-neoplastic lesion such as epitheliosis, hyperplasia and apocrine change at the bottom of the hierarchy. There is a growing list of non-cancerous tissues which show reactivity to Ca1. In July 1983 this list numbered about 15. The designation 'Ca' is inappropriate."
673,Correlation of level of gangliosides in plasma with cancer in human patients.,"Mondal S, Saha S.",https://pubmed.ncbi.nlm.nih.gov/11144525/,"Levels of gangliosides in the plasma of human patients with cancers of the breast, cheek, oesophagus, rectum, penis, bladder and skin, as analysed by thin layer chromatography and quantitative densitometric scanning, were found to increase many fold (ranging from 3.5 to 5.96 folds), compared to that of normal individuals. The ganglioside levels in the plasma of patients with benign tumors were comparable to that of normal individuals, thus suggesting correlation between increased ganglioside levels in the plasma and malignant growth in cancer patients. These increased levels of gangliosides in the plasma of Ca-breast, Ca-cheek and Ca-penis gradually increased with the advancement of the disease and showed some correlation with the increase in stage of the disease. The levels of gangliosides in the plasma of patients with Ca-breast and Ca-cheek were found to decrease significantly after surgical removal of the primary cancerous growth. The "
674,A functional perspective of nitazoxanide as a potential anticancer drug.,"Di Santo N, Ehrisman J.",https://pubmed.ncbi.nlm.nih.gov/25847384/,"Cancer is a group of diseases characterized by uncontrolled cell proliferation, evasion of cell death and the ability to invade and disrupt vital tissue function. The classic model of carcinogenesis describes successive clonal expansion driven by the accumulation of mutations that eliminate restraints on proliferation and cell survival. It has been proposed that during cancer's development, the loose-knit colonies of only partially differentiated cells display some unicellular/prokaryotic behavior reminiscent of robust ancient life forms. The seeming ""regression"" of cancer cells involves changes within metabolic machinery and survival strategies. This atavist change in physiology enables cancer cells to behave as selfish ""neo-endo-parasites"" that exploit the tumor stromal cells in order to extract nutrients from the surrounding microenvironment. In this framework, it is conceivable that anti-parasitic compounds might serve as promising anticancer drugs. Nitazoxanide (NTZ), a thiazolide compound, has shown antimicrobial properties against anaerobic bacteria, as well as against helminths and protozoa. NTZ has also been successfully used to promote Hepatitis C virus (HCV) elimination by improving interferon signaling and promoting autophagy. More compelling however are the potential anti-cancer properties that have been observed. NTZ seems to be able to interfere with crucial metabolic and pro-death signaling such as drug detoxification, unfolded protein response (UPR), autophagy, anti-cytokine activities and c-Myc inhibition. In this article, we review the ability of NTZ to interfere with integrated survival mechanisms of cancer cells and propose that this compound might be a potent addition to the current chemotherapeutic strategy against cancer."
675,Quantitative estimates of preventable and treatable deaths from 36 cancers worldwide: a population-based study.,"Frick C, Rumgay H, Vignat J, Ginsburg O, Nolte E, Bray F, Soerjomataram I.",https://pubmed.ncbi.nlm.nih.gov/37774721/," This study estimates premature deaths at ages 30-69 years and distinguishes these as deaths that are preventable (avertable through primary or secondary prevention) or treatable (avertable through curative treatment) in 185 countries worldwide.
    


           Crude and age-adjusted cancer-specific years of life lost (YLLs) were calculated for 36 cancer types.
    


          Findings:
        
      
      Of the estimated all-ages cancer burden of 265·6 million YLLs, 182·8 million (68·8%) YLLs were due to premature deaths from cancer globally in 2020, with 124·3 million (68·0%) preventable and 58·5 million (32·0%) treatable. Countries with low, medium, or high human development index (HDI) levels all had greater proportions of YLLs at premature ages than very high HDI countries (68·9%, 77·0%, and 72·2% vs 57·7%, respectively). Lung cancer was the leading contributor to preventable premature YLLs in medium to very high HDI countries (17·4% of all cancers, or 29·7 million of 171·3 million YLLs), whereas cervical cancer led in low HDI countries (26·3% of all preventable cancers, or 1·83 million of 6·93 million YLLs). Colorectal and breast cancers were major treatable cancers across all four tiers of HDI (25·5% of all treatable cancers in combination, or 14·9 million of 58·5 million YLLs).
    


          Interpretation:
        
      
      Alongside tailored programmes of early diagnosis and screening linked to timely and comprehensive treatment, greater investments in risk factor reduction and vaccination are needed to address premature cancer inequalities.
    


          Funding:
        
      
      Erasmus Mundus Exchange Programme and the International Agency for Research on Cancer.
    


          Translations:
        
      
      For the German, French, Spanish and Chinese translations of the abstract see Supplementary Materials section."
676,"[Thermogenesis of mammary epitheliomas. III. Study, by means of fluvography, of the termal conductivity of mammary tissue and of the influence of tumor vascularization].","Gautherie M, Qenneville Y, Gros CH.",https://pubmed.ncbi.nlm.nih.gov/1174632/,"The effective thermal conductivity of different ""in vivo"" and excised breast tissues and the specific heat power of a series of 24 breast carcinomas have been measured ""in situ"" by means of intratissular thermometric and fluvographic needle probes, and using a mathematical model operated with a computer. The thermal conductivity which depends directly on the capillary blood flow is higher within irrigated tissues than in the excised ones and demonstrates significant changes according to the adipose, fibrous or glandular structure of the breast; furthermore, it is much higher within cancerous tissues, more especially in the surroundings of the tumour. The heat power changes largely from one cancer to another and may reach values higher than those measured on the most thermogenic normal tissues. At hand of comparison with thermography, radiography and arteriography, these "
677,"Hexokinase-2 bound to mitochondria: cancer's stygian link to the ""Warburg Effect"" and a pivotal target for effective therapy.","Mathupala SP, Ko YH, Pedersen PL.",https://pubmed.ncbi.nlm.nih.gov/19101634/,"The most common metabolic hallmark of malignant tumors, i.e., the ""Warburg effect"" is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen. The pivotal player in this frequent cancer phenotype is mitochondrial-bound hexokinase [Bustamante E, Pedersen PL. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 1977;74(9):3735-9; Bustamante E, Morris HP, Pedersen PL. Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J Biol Chem 1981;256(16):8699-704]. Now, in clinics worldwide this prominent phenotype forms the basis of one of the most common detection systems for cancer, i.e., positron emission tomography (PET). Significantly, HK-2 is the major bound hexokinase isoform expressed in cancers that exhibit a ""Warburg effect"". This includes most cancers that metastasize and kill their human host. By stationing itself on the outer mitochondrial membrane, HK-2 also helps immortalize cancer cells, escapes product inhibition and gains preferential access to newly synthesized ATP for phosphorylating glucose. The latter event traps this essential nutrient inside the tumor cells as glucose-6-P, some of which is funneled off to serve as carbon precursors to help promote the production of new cancer cells while much is converted to lactic acid that exits the cells. The  With the re-emergence and acceptance of both the ""Warburg effect"" as a prominent phenotype of most clinical cancers, and ""metabolic targeting"" as a rational therapeutic strategy, a number of laboratories are focusing on metabolite entry or exit steps. One remarkable success story [Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 2004;324(1):269-75] is the use of the small molecule 3-bromopyruvate (3-BP) that selectively enters and destroys the cells of large tumors in animals by targeting both HK-2 and the mitochondrial ATP synthasome. This leads to very rapid ATP depletion and tumor destruction without harm to the animals. This review focuses on the multiple roles played by HK-2 in cancer and its potential as a metabolic target for complete cancer destruction."
678,Gastric Cancer: Advances in Carcinogenesis Research and New Therapeutic Strategies.,"Seeneevassen L, Bessède E, Mégraud F, Lehours P, Dubus P, Varon C.",https://pubmed.ncbi.nlm.nih.gov/33810350/,"Gastric cancer's bad incidence, prognosis, cellular and molecular heterogeneity amongst others make this disease a major health issue worldwide. Understanding this affliction is a priority for proper patients' management and for the development of efficient therapeutical strategies. This review gives an overview of major scientific advances, made during the past 5-years, to improve the comprehension of gastric adenocarcinoma. A focus was made on the different actors of gastric carcinogenesis, including, Helicobacter pylori cancer stem cells, tumour microenvironment and microbiota. New and recent potential biomarkers were assessed as well as emerging therapeutical strategies involving cancer stem cells targeting as well as immunotherapy. Finally, recent "
679,Transcriptomics of mussel transmissible cancer MtrBTN2 suggests accumulation of multiple cancer traits and oncogenic pathways shared among bilaterians.,"Burioli EAV, Hammel M, Vignal E, Vidal-Dupiol J, Mitta G, Thomas F, Bierne N, Destoumieux-Garzón D, Charrière GM.",https://pubmed.ncbi.nlm.nih.gov/37816387/,"Transmissible cancer cell lines are rare biological entities giving rise to diseases at the crossroads of cancer and parasitic diseases. These malignant cells have acquired the amazing capacity to spread from host to host. They have been described only in dogs, Tasmanian devils and marine bivalves. The Mytilus trossulus bivalve transmissible neoplasia 2 (MtrBTN2) lineage has even acquired the capacity to spread inter-specifically between marine mussels of the Mytilus edulis complex worldwide. To identify the oncogenic processes underpinning the biology of these atypical cancers we performed transcriptomics of MtrBTN2 cells. Differential expression, enrichment, protein-protein interaction network, and targeted analyses were used. Overall, our  We also highlight that vertebrate and lophotrochozoan cancers could share a large panel of common drivers, which supports the hypothesis of an ancient origin of oncogenic processes in bilaterians."
680,Potential pitfalls in MitoChip detected tumor-specific somatic mutations: a call for caution when interpreting patient data.,"Palanichamy MG, Zhang YP.",https://pubmed.ncbi.nlm.nih.gov/21034508/," In consequence, a host of somatic mtDNA mutations have been identified as linked to different types of cancers. However, closer examination of these data show that there are a number of potential pitfalls in the detection tumor-specific somatic mutations in clinical case studies, thus urging caution in the interpretation of mtDNA data to the patients. This study examined mitochondrial sequence variants demonstrated in cancer patients, and assessed the reliability of using detected patterns of polymorphisms in the early diagnosis of cancer.
    


          
    


           Our phylogenetic analysis of these tumor and control leukocyte mtDNA haplotype sequences shows clear cut evidence of mixed ancestries found in single individuals.
    


          Conclusions:
        
      
      Our study makes two prescriptions: both in the clinical situation and in research 1. more care should be taken in maintaining sample identity and 2. analysis should always be undertaken with respect to all the data available and within an evolutionary framework to eliminate artifacts and mix-ups."
681,Long non-coding RNAs and microorganism-associated cancers.,"Ranjbar R, Behjatfar M, Teimouri A, Aghaie Fard A, Maniati M, Taheri-Anganeh M.",https://pubmed.ncbi.nlm.nih.gov/34227160/,"Cancerous cells are abnormal cells characterized by aberrant growth and proliferation, which can involve various types of cells and tissues. Through numerous signalling pathways, many mechanisms are involved in cells that keep them normal. These signalling pathways are tightly set by different proteins whose expression is regulated by a large number of factors. In other words, when a regulating factor does not act properly or undergoes a change in its function or expression, the  This leads to disordered signalling pathways which bring about uncontrolled proliferation in cells. One of the most significant factors in adjusting the expression of genes is noncoding RNAs. It should be noted that all underlying causes initiating malignancy try to alter the main regulatory factors in cellular processes and gene expression and direct the cell to an unregulated state. Microorganisms have been identified as one of the important elements to direct normal cells to abnormality. That is, they probably agitate the malignant traits through manipulating significant factors such as ncRNAs in given cells using their own or host-related factors. The present study is aimed at examining how the long noncoding RNAs are involved in microorganism-mediated cancers."
682,Study on canceration law of gastric mucosal dysplasia based on syndromes of Chinese medicine.,"Shen SW, Hui JP, Yuwen Y, Wang JH, Chen LY, Niu Y, Peng N, Yang ZH, Zhao Y.",https://pubmed.ncbi.nlm.nih.gov/21611897/,"
    


          
    


          0%. The three syndromes with higher canceration rate were the damp-heat accumulating Wei syndrome concurring or combining with asthenia-cold in Pi and Wei syndrome for 16.7%; stagnation in Wei collaterals syndrome concurring or combining with asthenia of both qi and yin syndrome for 13.2%; stagnation of Gan and Wei qi syndrome concurring or combining with asthenia-cold in Pi and Wei syndrome for 8.0%, respectively. Among the three syndromes, the highest level of TSGF occurred in the former two syndromes. In the half year before carcinogenesis, the syndromes of the patients took on deficiency and excess concurrent syndromes, and the deficiency syndromes involving the qi and blood deficiency syndrome and the Shen deficiency syndrome accounting for 48.0%.
    


          Conclusions:
        
      
      Gastric mucosal dyspalsia canceration syndromes took on the polymorphism of excess and deficiency concurrent syndromes and had the characteristics of deficiency syndromes involving qi and blood deficiency syndrome and Shen-yin-yang deficiency syndrome."
683,Cell plasticity and heterogeneity in cancer.,"Marjanovic ND, Weinberg RA, Chaffer CL.",https://pubmed.ncbi.nlm.nih.gov/23220226/," These factors conspire to create a disease with various phenotypes. There are 2 established models of cancer development and progression to metastatic disease. These are the clonal evolution and cancer stem cell models.
    


          Content:
        
      
      The clonal evolution theory suggests that successive mutations accumulating in a given cell generate clonal outgrowths that thrive in response to microenvironmental selection pressures, dictating the phenotype of the tumor. The alternative cancer stem cell (CSC) model suggests that cancer cells with similar genetic  Accordingly, CSCs reside at the apex of the hierarchy and are thought to possess the majority of a cancer's tumor-initiating and metastatic ability. A defining feature of this model is its apparent unidirectional nature, whereby CSCs undergo symmetric division to replenish the CSC pool and irreversible asymmetric division to generate daughter cells (non-CSCs) with low tumorigenic potential. However, evolving evidence supports a new model of tumorigenicity, in which considerable plasticity exists between the non-CSC and CSC compartments, such that non-CSCs can reacquire a CSC phenotype. These findings suggest that some tumors may adhere to a plastic CSC model, in which bidirectional conversions are common and essential components of tumorigenicity.
    


          Summary:
        
      
      Accumulating evidence surrounding the plasticity of cancer cells, in particular, suggests that aggressive CSCs can be created de novo within a tumor. Given the current focus on therapeutic targeting of CSCs, we discuss the implications of non-CSC-to-CSC conversions on the development of future therapies."
684,Linking tumor glycolysis and immune evasion in cancer: Emerging concepts and therapeutic opportunities.,Ganapathy-Kanniappan S.,https://pubmed.ncbi.nlm.nih.gov/28400131/,"Metabolic reprogramming and immune evasion are two hallmarks of cancer. Metabolic reprogramming is exemplified by cancer's propensity to utilize glucose at an exponential rate which in turn is linked with ""aerobic glycolysis"", popularly known as the ""Warburg effect"". Tumor glycolysis is pivotal for the efficient management of cellular bioenergetics and uninterrupted cancer growth. Mounting evidence suggests that tumor glycolysis also plays a key role in instigating immunosuppressive networks that are critical for cancer cells to escape immune surveillance (""immune evasion""). Recent data show that induction of cellular stress or metabolic dysregulation sensitize cancer cells to antitumor immune cells implying that metabolic reprogramming and immune evasion harmonize during cancer progression. However, the molecular link between these two hallmarks of cancer remains obscure. In this review the molecular intricacies of tumor glycolysis that facilitate immune evasion has been discussed in the light of recent research to explore immunotherapeutic potential of targeting cancer metabolism."
685,Prognostic role of microRNA-100 in various carcinomas: evidence from six studies.,"Chen J, Zheng B, Wang C, Chen Y, Du C, Zhao G, Zhou Y, Shi Y.",https://pubmed.ncbi.nlm.nih.gov/24258109/,"Recent studies have shown that microRNAs (miRNA) exhibit altered expression levels in cancers, and they may be considered as valuable prognostic biomarkers for patients with cancers. We performed this meta-analysis to provide a comprehensive evaluation of the role of miRNA-100 expression on the overall survival rate by calculating the pooled hazard ratio (HR) for overall survival (OS), which compared the high and low expression levels of miR-100 in patients of the available studies. Finally, a total of six studies dealing with various carcinomas were involved for this meta-analysis. The 19 (95% CI 1.49-3.24, P = 0.0007). In conclusion, the findings from this present meta-analysis suggest that miR-100 expression is associated with OS in cancer patients and could be a useful clinical prognostic factor for those patients."
686,Synchronous cancers in patients with head and neck cancer: risks in the era of human papillomavirus-associated oropharyngeal cancer.,"Jain KS, Sikora AG, Baxi SS, Morris LG.",https://pubmed.ncbi.nlm.nih.gov/23423883/," Synchronous SPMs are of significant clinical interest because they potentially can be identified by screening procedures at the time of diagnosis of the index cancer. Recently, human papillomavirus (HPV) has emerged as a distinct risk factor for oropharyngeal head and neck squamous cell carcinoma (HNSCC), differing from classic tobacco/alcohol-associated HNSCC, suggesting that there also may be distinct patterns of synchronous SPMs.
    


           Excess risk was calculated using standardized incidence ratios (SIR) and excess absolute risk per 100 patients.
    


          0, corresponding to 2.62 excess cases per 100 patients. The site with the highest excess risk of a second cancer was the head and neck (SIR, 41.4), followed by the esophagus (SIR, 21.8), and lung (SIR, 7.4). The risk of synchronous SPM changed markedly over time for patients with oropharyngeal HNSCC. In the 1970s and 1980s, oropharyngeal cancers carried the highest risk of SPM. Risk began to dramatically decline in the 1990s; and currently, oropharyngeal cancers carry the lowest risk of synchronous SPM.
    


          Conclusions:
        
      
      The current data are consistent with the etiologic shift of oropharyngeal HNSCC, from a primarily tobacco-associated malignancy associated with significant field cancerization of the upper aerodigestive mucosa, to a malignancy primarily caused by oncogenic human papillomavirus."
687,Expression of OATP family members in hormone-related cancers: potential markers of progression.,"Pressler H, Sissung TM, Venzon D, Price DK, Figg WD.",https://pubmed.ncbi.nlm.nih.gov/21625523/,"The organic anion transporting polypeptide (OATP) family of transporters has been implicated in prostate cancer disease progression probably by transporting hormones or drugs. In this study, we aimed to elucidate the expression, frequency, and relevance of OATPs as a biomarker in hormone-dependent cancers. We completed a study examining SLCO1B3, SLCO1B1 and SLCO2B1 mRNA expression in 381 primary, independent patient samples representing 21 cancers and normal tissues. From a separate cohort, protein expression of OATP1B3 was examined in prostate, colon, and bladder tissue. Based on expression frequency, SLCO2B1 was lower in liver cancer (P = 0.04) which also trended lower with decreasing differentiation (P = 0.004) and lower magnitude in pancreatic cancer (P = 0.05). SLCO2B1 also had a higher frequency in thyroid cancer (67%) than normal (0%) and expression increased with stage (P = 0.04). SLCO1B3 was expressed in 52% of cancerous prostate samples and increased SLCO1B3 expression trended with higher Gleason score (P = 0.03). SLCO1B3 expression was also higher in testicular cancer (P = 0.02). SLCO1B1 expression was lower in liver cancer (P = 0.04) which trended lower with liver cancer grade (P = 0.0004) and higher with colon cancer grade (P = 0.05). Protein expression of OATP1B3 was examined in normal and cancerous prostate, colon, and bladder tissue samples from an independent cohort. The  OATPs correlate to differentiation in certain hormone-dependent cancers, thus may be useful as biomarkers for assessing clinical treatment and stage of disease."
688,Feature selection algorithm based on dual correlation filters for cancer-associated somatic variants.,"Seo H, Cho DH.",https://pubmed.ncbi.nlm.nih.gov/33121438/," As the effects of variants on human cancer become known, it is important to find cancer-associated variants among countless variants.
    


           Both variants associated with the activation and deactivation of cancer's characteristics are analyzed using dual correlation filters. The multi To overcome high computational complexity problem, we calculate the correlation-based weight to select significant variants instead of directly searching for the optimal subset of variants. The proposed algorithm is applied to the identification of melanoma metastasis or breast cancer stage, and the classification 
    


          Conclusions:
        
      
      We verified that the proposed dual correlation filter-based "
689,The predictive value of tumor classification compared with results of the British Institute of Radiology fractionation trial in the treatment of laryngopharyngeal carcinoma.,"Wiernik G, Alcock CJ, Fowler JF, Haybittle JL, Hopewell JW, Rezvani M.",https://pubmed.ncbi.nlm.nih.gov/2199740/,"Data from a clinical trial involving 734 patients have shown the value and the deficiencies of the current Union Internationale Contre le Cancer's tumor, node, and metastasis classification system for prognostic purposes. The tumor-category classification provides a good discriminant for both nodal involvement and survival; however, the previous node classification system only discriminated between node-negative and node-positive patients, as nodal fixity was not found to be a discriminator. The current anatomical site classification is ambiguous for some laryngeal and pharyngeal subsites, and modifications to the present system based on prognostic values are proposed. A difference in patient age between tumor categories has been shown, and various differences in incidence and survival data for the sexes have been demonstrated. Differences in observed and expected survival rates are related to continued late deaths from tumor. Multivariate analyses have shown that stage grouping is the most powerful prognostic discriminator, followed by anatomical site and age."
690,The emerging role of circRNAs and their clinical significance in human cancers.,"Qian L, Yu S, Chen Z, Meng Z, Huang S, Wang P.",https://pubmed.ncbi.nlm.nih.gov/29928954/,"Circular RNA (circRNA), a recently discovered subclass of non-coding RNAs (ncRNAs), forms a covalently closed loop with neither a 5' cap structure nor a 3' polyadenylated tail. Generated from precursor mRNA (pre-mRNA) through ""backsplicing"" (a type of alternative RNA splicing), the majority of circRNAs are located in the cytoplasm and are widespread among living organisms. They are stable and conserved and exhibit spatiotemporal-specific expression. CircRNAs are known to be involved in the development and progression of multiple diseases, including cancer, by acting as microRNA (miRNA) sponges and by regulating processes such as transcription and translation. The extensively aberrant expression profiles of circRNAs in multiple cancerous tissues make these molecules promising diagnostic biomarkers and therapeutic targets for cancer. Here, we briefly review the characteristics, biogenesis, classification, and functions of circRNAs, with a particular focus on the role of circRNAs in various cancers."
691,The Effect of Resveratrol on Cellular Senescence in Normal and Cancer Cells: Focusing on Cancer and Age-Related Diseases.,"Farhadnejad H, Emamat H, Zand H.",https://pubmed.ncbi.nlm.nih.gov/30955382/,"Cellular senescence is generally defined as irreversible cell-cycle arrest and loss of replicative capacity in virtually all cell types which can have effects on tissues and possibly play a significant role in promoting age-related chronic diseases and cancers. Recently, use of natural bioactive substances such as resveratrol to modify the process of cellular senescence in tissue cells based on specific context has opened an interesting therapeutic perspective in aging and chronic diseases such as cancers. This natural polyphenol is currently being evaluated as a promising anticancer and anti-age-related disease agent. Resveratrol modulates cell cycles and multiple pathways involved in cell growth, apoptosis, senescence, and inflammation, which has mostly observed in laboratory models. In vitro studies indicate that biological effects of resveratrol on cellular senescence or other cell processes may vary depending on cell types and certain contexts. This review aims to discuss the current body of knowledge on the effects of resveratrol on cellular senescence in cancerous and normal cells and its possible effect on prevention of cancers and aging based on in vitro and in vivo studies. It also deals with the putative mechanisms underlying these effects of resveratrol and propounds the controversy on this topic."
692,"[Chemical forms and ecological effect of soil Mn in liver cancer's high incidence area in Zhu-jiang River Delta, China].","Dou L, Zhou YZ, Li Y, Ma J, An YF, Du HY, Li ZQ.",https://pubmed.ncbi.nlm.nih.gov/18808033/,"The samples of surface soil, deep soil, and vegetables were collected from the liver cancer's high- and low incidence areas in Zhujiang River Delta to study the relationships between soil Mn forms and vegetables' Mn enrichment. The  The average soil Mn content in liver cancer's high incidence area was 577.65 mg x kg(-1), being significantly lower than that of liver cancer's low incidence area (718.04 mg x kg(-1)) and whole country (710 mg x kg(-1)). The Mn forms in high incidence area were mainly of residual Mn and Fe-Mn oxide, and less of water soluble Mn and exchangeable Mn, with the sum of the latter two's distribution coefficients being not higher than 4%. In low incidence area, the distribution pattern of soil Mn forms was similar to that in high incidence area, but the absolute contents of the Mn forms were significantly higher. Soil total Mn and soil pH had significant effects on soil Mn forms. There existed significant positive correlations between soil total Mn and the Mn forms of Fe-Mn bound, humic acid bound, carbonate bound, and residual, and negative correlations between soil pH and soil water soluble and organic bound Mn forms. Among the test five kinds of vegetables, Youmai lettuce and Chinese cabbage in liver cancer' s high incidence area had a significantly lower Mn content than in low incidence area, while the other three had less difference. The Mn enrichment in test vegetables was positively correlated with to the content of soil available Mn (sum of water soluble Mn and exchangeable Mn), but had no correlations with the contents of soil total Mn and other Mn forms."
693,International Validation of the American Joint Committee on Cancer's 7th Edition Classification of Uveal Melanoma.,AJCC Ophthalmic Oncology Task Force.,https://pubmed.ncbi.nlm.nih.gov/25555246/,"Importance:
        
      
      Although an accurate uveal melanoma staging system is needed to improve research and patient care, the evaluation of eye cancer staging systems requires international multicenter data sharing to acquire a statistically significant analysis.
    


          
    


          Design, setting, participants:
        
      
      A committee was formed to create patient-specific data fields for patients with uveal melanoma. Ten subspecialty ophthalmic oncology centers from 4 continents shared data. Patient selection criteria included diagnosis of uveal melanoma from April 1, 2001, to April 1, 2011, adequate records to allow tumor staging by the AJCC criteria, and follow-up for metastatic melanoma.
    


          Interventions:
        
      
      Primary treatments included local resection, radiation therapy, and enucleation.
    


          Main outcomes and measures:
        
      
      Metastasis after initial tumor staging with 5- and 10-year Kaplan-Meier metastasis-free point estimates, depending on AJCC prognostic stages I through IV, tumor size category, and subclassification (defined by the presence of ciliary body involvement and/or extrascleral extension).
    


           Of these, 3377 records (88.7%) were complete. Primary ciliary body and choroidal melanoma was the diagnosis for 3217, and 160 had primary iris melanoma. Tumor size categories were T1 in 1115 (34.7%) of the 3217 patients, T2 in 1128 patients (35.1%), T3 in 789 patients (24.5%), and T4 in 185 patients (5.8%). The 5- and 10-year Kaplan-Meier metastasis-free point estimates by tumor size categories were 97% (95% CI, 95%-98%) and 94% (95% CI, 91%-96%) for T1 tumors, 85% (95% CI, 82%-88%) and 80% (95% CI, 75%-84%) for T2 tumors, 77% (95% CI, 73%-80%) and 68% (95% CI, 60%-74%) for T3 tumors, and 61% (95% CI, 49%-71%) (5-year only) for T4 tumors, respectively. Increasing tumor size was consistent with increased metastasis risk (P < .001). Subclassifications were significantly associated with increased risk of metastasis (P < .001). The AJCC prognostic and anatomical groupings were as follows: stage I, 1030 (32.0%); stage IIA, 1095 (34.0%); stage IIB, 710 (22.1%); stage IIIA, 282 (8.8%); stage IIIB, 79 (2.5%); and stage IIIC, 21 (0.7%). The 5- and 10-year Kaplan-Meier metastasis-free estimates for prognostic stages were 97% (95% CI, 95%-98%) and 94% (95% CI, 91%-96%) for stage I, 89% (95% CI, 86%-91%) and 84% (95% CI, 80%-88%) for stage IIA, 79% (95% CI, 75%-83%) and 70% (95% CI, 62%-76%) for stage IIB, 67% (95% CI, 59%-73%) and 60% (95% CI, 51%-68%) for stage IIIA, 50% (95% CI, 33%-65%) and 50% (95% CI, 33%-65%) for stage IIIB, and 25% (95% CI, 4%-53%) (5-year only) for stage IIIC, respectively. The 160 iris melanomas were too few for subgroup analysis.
    


          Conclusions and relevance:
        
      
      Multicenter, worldwide, Internet-based data sharing was used to study a heterogenous patient population in ophthalmic oncology. Our "
694,Survival analysis of Sudanese oral squamous cell carcinoma patients with field of cancerization.,"Eltohami Y, Suleiman A.",https://pubmed.ncbi.nlm.nih.gov/38622532/," In Sudan, cases with delayed presentation, particularly those with risk factors such as Toombak dipping and alcohol consumption, frequently present with extensive lesions and a wide area of Field cancerization which characterized by the presence of genetic and epigenetic changes in histologically normal-appearing tissues, and have increased risk for recurrent and second primary tumors. This necessitates more aggressive treatment and is usually associated with poorer outcomes. The present study aims to investigate the survival of oral squamous cell carcinoma patients with a wide field of cancerization.
    


           These patients were regularly assessed for clinical changes such as recurrence, the development of second primary tumours, and overall survival over a period of one year.
    


          3%) were males, and 36 (38.7%) were females. The majority of the patients (82%) had stage IV tumours, and 62.3% had nodal metastasis. Twenty-eight (30%) patients developed recurrences, and 14 (15%) developed second primary tumours. The overall one-year survival rate was 89%, and all deceased patients passed away within 12 months. The survival rate for patients with different types of recurrences varied, with patients who had regional, local, and locoregional recurrences having survival rates of 87%, 74%, and 72%, respectively. Patients who did not experience a recurrence had a one-year survival rate of 92%. Patients who developed second primary tumours had an 86% survival rate. The survival rates for OSCC patients at stages III, IVa, and IVb were 90%, 90%, and 71%, respectively.
    


          Conclusion:
        
      
      In this study, 62% of patients had nodal metastasis, 30% developed recurrence, and 15% developed second primary tumours. The overall one-year survival rate was 89%, although the development of recurrences and second primary tumours had a negative impact on the survival rate."
695,Cyclin D1 overexpression in esophageal dysplasia: a possible biomarker for carcinogenesis of esophageal squamous cell carcinoma.,"Shamma A, Doki Y, Shiozaki H, Tsujinaka T, Yamamoto M, Inoue M, Yano M, Monden M.",https://pubmed.ncbi.nlm.nih.gov/10639568/,"There is controversy as to whether esophageal squamous dysplasia is a pre-cancerous lesion or a non-cancerous lesion. In this study, we conducted an immunohistochemical investigation of cyclin D1, retinoblastoma (Rb), p16INK4 and p27KIP1 expression in 36 squamous dysplasias and 34 early squamous cell carcinomas of the esophagus. The frequency of cyclin D1 overexpression was similar in dysplasias and early cancers (30% vs. 35%). Loss of p16INK4 and p27KIP1 expression was less frequent in dysplasias than in early cancers (p=0.005 and 0.001, respectively). Loss of Rb protein expression was not detected in dysplasia and rarely observed in early cancer (7%). The proliferation cell nuclear antigen index increased from moderate dysplasia to mucosal invasive carcinoma and was correlated significantly with the expression of cyclin D1, p16INK4 and p27KIP1 (p=0.0001, 0.003, and 0.007, respectively). Thus, this study found that cyclin D1 overexpression starts early in dysplasia and could be a useful marker for its malignant potentiality while reduction of p16INK4 and p27KIP1 occurs during the transformation from dysplasia to cancer. These findings suggest that esophageal dysplasia should be treated as a precancerous lesion."
696,[The value of a study of the microvascularization and the cellular immunosurveillance of precancerous states and micro-cancers of the oral cavity].,"Chomette G, Auriol M, Labrousse F.",https://pubmed.ncbi.nlm.nih.gov/1695019/,"In 35 patients with leukoplakia or erythroplastic lesions of oral mucosa, the immunohistochemical study of Langerhans cells and various types of lymphocytes demonstrated increasing changes in cellular immunoreactivity in benign leukokeratosis, dysplasia and in situ or microinvasive carcinoma. Besides, the study of alkaline phosphatase activity by means of histoenzymological "
697,"New prospective for non-invasive detection, grading, size evaluation, and tumor location of prostate cancer.","Cortesi M, Fridman E, Volkov A, Shilstein SSh, Chechik R, Breskin A, Vartsky D, Raviv G, Ramon J.",https://pubmed.ncbi.nlm.nih.gov/20564321/," Thus alternative approaches are highly desired. We present and assess a novel 
    


           They were used to generate computer simulated zinc-concentration maps, further analyzed with image-processing tools. The tumor detection performances versus Gleason grade were assessed.
    


           Tumor detection performance in zinc-concentration maps progressively improves with the cancer's first component score. Reliable information on the location, size and Gleason-grade combination of the lesion can be extracted for clinically relevant volumes.
    


          Conclusions:
        
      
      Zinc depletion in the prostate peripheral zone is the basis for a novel, non-invasive PCa detection, localization, volume evaluation and grading  Its realization and application as a pre-biopsy and pre-treatment examination, or a follow-up tool, relies on the development of a dedicated transrectal probe. It should have significant impact on biopsy effectiveness, point at a possible extraprostatic extension and provide critical data for focal treatment. The information on tumor grade and distribution may have an important impact on disease management."
698,[Analysis of endoscopic and pathological features of gastric adenomatous polyps and risk factors for canceration].,"Niu ZY, Xue Y, Zhang J, Zhang HJ, Ding SG.",https://pubmed.ncbi.nlm.nih.gov/34916692/,"
    


          
    


          20% of whom were females. The average age was (66.7±12.3) years. 64.80% of patients with gastric adenomatous polyps equal or more than 65 years old, and only 5.60% of the patients less than 45 years old. Adenomatous polyps were mostly distributed in the corpus and antrum with 40.80% and 32.80%, respectively. The majority of them were single (90.40%) and sessile (76.81%). 65.4% of adenomatous polyps were no more than 1.0 cm in diameter, and 23.20% of patients with adenomatous polyps were combined with hyperplastic polyps and/or fundus glandular polyps, and 1.60% had both pathological types of polyps. 58.62% (17/29) patients with hyperplastic polyps and/or fundus glandular polyps had multiple polyps. 1.60% (2/125) of the patients had gastric neuroendocrine tumor of G1 stage. Synchronous gastric cancer was detected in 13.60% (17/125) of the patients with adenomatous polyps, and the proportion of low-grade intraepithelial neoplasia was 18.40% (23/125). The main types of synchronous gastric cancer were progressive (70.59%) and undifferentiated (66.67%). Chronic atrophic gastritis with intestinal metaplasia was found in 52.80% of the patients, and autoimmune gastritis accounted for 11.20%. The positive rate of Helicobacter pylori was 21.60%. The canceration rate of gastric adenomatous polyps was 20.80%. The cancer was mainly differentiated, but there was sigmoid ring cell carcinoma as well. Diameter of >1.0 cm (OR=5.092, 95%CI: 1.447-17.923, P=0.011), uneven surface morphology and erosion (OR=13.749, 95%CI: 1.072-176.339, P=0.044) were independent risk factors of adenomatous polyps.
    


          Conclusion:
        
      
      The synchronous gastric cancer is common and the canceration of gastric adenomatous polyps is high with diameter and surface morphology as independent risk factors. We should pay attention to the identification of the pathological types of polyps and the evaluation of the whole gastric mucosa during the endoscopic examination."
699,Development of chemopreventive agents for lung and upper aerodigestive tract cancers.,"Kelloff GJ, Boone CW, Steele VK, Perloff M, Crowell J, Doody LA.",https://pubmed.ncbi.nlm.nih.gov/8412195/,"The lung and upper aerodigestive tract (oral cavity, larynx, pharynx, upper esophagus) will harbor the greatest proportion (approximately 20%) of estimated new cancer cases in 1992. The estimated mortality rate is even higher (32%), which is reflected in a 5-year survival rate of only 7% and 12% for esophageal and lung cancer, respectively. Tobacco use appears to remain the major cause of aerodigestive cancers despite efforts at primary prevention--cessation of exposure. Another strategy to decrease this public health problem is secondary prevention or chemoprevention. Cancer chemoprevention is defined as intervention with chemical agents before invasion to halt or slow the carcinogenic process; potential agents may include minor dietary constituents and pharmaceuticals. The main  The testing of cancer chemopreventives for efficacy in the clinic differs from that of cancer treatment drugs. Chemopreventive drug trials involve healthy target populations, and the endpoints are reduced cancer incidence or mortality, or increased latency, with no to minimal toxicity. The lung and upper aerodigestive tract represent a unique opportunity for intervention in this setting. Even with cessation of tobacco exposure, the risk of cancer in the entire epithelium remains high for years due to the ""field cancerization"" effect. Some of the first chemopreventive trials made use of this system due to the availability of a study population with a tissue at demonstrably high risk for malignant progression. Much of the evidence for chemopreventive efficacy is in the oral cavity because of the well-defined epithelial neoplastic progression, the existence of well-established preclinical models, and relative ease of tissue monitoring and sampling. In one of the first randomized trials, Hong and co-workers demonstrated that 13-cis-retinoic acid prevents the appearance of second primary tumors in patients previously treated for squamous cell carcinomas of the oral cavity and upper respiratory tract. Even using a high risk population, chemoprevention trials involve large sample sizes, lengthy duration and follow-up, and high cost. To circumvent these problems, the use of intermediate biomarkers as surrogate endpoints is being explored. Intermediate biomarkers are defined as biological alterations in tissue (histological, genetic, biochemical, proliferative, differentiation-related) occurring prior to cancer development. In the oral cavity, studies using modulation of a histological intermediate biomarker, dysplastic leukoplakia, as the endpoint have demonstrated response to a retinoid.(ABSTRACT TRUNCATED AT 400 WORDS)"
700,"Identification, genetic testing, and management of hereditary melanoma.","Leachman SA, Lucero OM, Sampson JE, Cassidy P, Bruno W, Queirolo P, Ghiorzo P.",https://pubmed.ncbi.nlm.nih.gov/28283772/,"Several distinct melanoma syndromes have been defined, and genetic tests are available for the associated causative genes. Guidelines for melanoma genetic testing have been published as an informal ""rule of twos and threes,"" but these guidelines apply to CDKN2A testing and are not intended for the more recently described non-CDKN2A melanoma syndromes. In order to develop an approach for the full spectrum of hereditary melanoma patients, we have separated melanoma syndromes into two types: ""melanoma dominant"" and ""melanoma subordinate."" Syndromes in which melanoma is a predominant cancer type are considered melanoma dominant, although other cancers, such as mesothelioma or pancreatic cancers, may also be observed. These syndromes are associated with defects in CDKN2A, CDK4, BAP1, MITF, and POT1. Melanoma-subordinate syndromes have an increased but lower risk of melanoma than that of other cancer(s) seen in the syndrome, such as breast and ovarian cancer or Cowden syndrome. Many of these melanoma-subordinate syndromes are associated with well-established predisposition genes (e.g., BRCA1/2, PTEN). It is likely that these predisposition genes are responsible for the increased susceptibility to melanoma as well but with lower penetrance than that observed for the dominant cancer(s) in those syndromes. In this review, we describe our extension of the ""rule of twos and threes"" for melanoma genetic testing. This algorithm incorporates an understanding of the spectrum of cancers and genes seen in association with melanoma to create a more comprehensive and tailored approach to genetic testing."
701,Managing Colorectal Cancer from Ethology to Interdisciplinary Treatment: The Gains and Challenges of Modern Medicine.,"Berbecka M, Berbecki M, Gliwa AM, Szewc M, Sitarz R.",https://pubmed.ncbi.nlm.nih.gov/38396715/,"Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract, which has become a serious threat to human health worldwide. This article exhaustively reviews colorectal cancer's incidence and relevance, carcinogenesis molecular pathways, up-to-date treatment opportunities, prophylaxis, and screening program achievements, with attention paid to its regional variations and changes over time. This paper provides a concise overview of known CRC risk factors, including familial, hereditary, and environmental lifestyle-related risk factors. The authors take a closer look into CRC's molecular genetic pathways and the role of specific enzymes involved in carcinogenesis. Moreover, the role of the general practitioner and multidisciplinary approach in CRC treatment is summarized and highlighted based on recent recommendations and experience. This article gives a clear understanding and review of the gains and challenges of modern medicine towards CRC. The authors believe that understanding the current patterns of CRC and its revolution is imperative to the prospects of reducing its burden through cancer prevention and cancer-adjusted treatment."
702,Clinical Significance of Factor XIII Activity and Monocyte-Derived Microparticles in Cancer Patients.,"Sawai Y, Yamanaka Y, Nomura S.",https://pubmed.ncbi.nlm.nih.gov/32280233/,"
    


           We measured various biomarkers including FXIIIa and MDMPs.
    


           MCP-1, sCD14, and MDMPs were significantly correlated with FXIIIa in multivariate analysis in cancer patients. In addition, MCP-1, sCD14, and MDMP levels were significantly increased in the high FXIIIa group of patients. Finally, the survival rate of the high FXIIIa group was significantly poor in the Kaplan-Meier analysis.
    


          Conclusion:
        
      
      These "
703,Personalized Oncology Meets Immunology: The Path toward Precision Immunotherapy.,"Mandal R, Chan TA.",https://pubmed.ncbi.nlm.nih.gov/27107038/,"Personalized oncology aims to tailor therapy by targeting the unique genetic characteristics of a patient's tumor, whereas cancer immunotherapy focuses on activating the patient's immune system to control the tumor. The fusion of these ostensibly separate strategies has created a new dimension for personalized cancer immunotherapy. This entails the development of next-generation cancer vaccines that target neoantigens as well as the use of mutational signatures as predictive biomarkers for clinical response. The optimal use of immunotherapeutic agents will hinge on a robust understanding of the mutational profile of a cancer's genome that significantly dictates antitumor immunity and immunotherapeutic response.
    


          Significance:
        
      
      Cancer immunotherapy has provided substantial clinical benefit in a significant number of patients with advanced disease. However, the need for more precise immunotherapies and predictive biomarkers remains pressing. Recent progress in these areas has been promising and has created a framework for precision immune-oncology. Cancer Discov; 6(7); 703-13. ©2016 AACR."
704,[Current strategy to cure pancreatic cancer].,Tanaka M.,https://pubmed.ncbi.nlm.nih.gov/11968759/,"For more than a decade extensive retroperitoneal dissection, chemotherapy, or radiotherapy has not prolonged the survival of patients with pancreatic cancer. Two prospective randomized studies addressing the clinical significance of extensive dissection or pancreatic resection for advanced cancer are now in progress. Nonetheless, at present, resection offers the patient the only possibility of cure. Although the diagnosis of curable pancreatic cancer is difficult, recent evidences have given a few hints. The first is pancreatic duct dilatation caused by cancerous stricture. The second is diabetes as a sign of pancreatic cancer. Our prospective pancreatographic screening of diabetic patients selected by our criteria(Table 1) revealed 7 cancers in 98 patients(7.1%). Within 3 years from diagnosis, the prevalence was 15%. Although the 7 cancers were advanced, this suggests that earlier examinations in diabetic patients may possibly lead to earlier diagnosis. The third is a small cystic lesion as a sentinel of pancreatic cancer. Endoscopic retrograde cholangiopancreatography with cytology of the pancreatic juice may show the presence of in situ cancer in patients with a pancreatic cyst. At the moment, careful checks for the presence of these hints seem to be the only strategy to offer a chance for cure to patients with pancreatic cancer."
705,[Human Papillomavirus: screening of cervical and anal cancers].,"Pache B, Jacot-Guillarmod M, Hübner M, Mathevet P.",https://pubmed.ncbi.nlm.nih.gov/36259700/,"Cervical cancer is preventable through primary and secondary prevention. Vaccination against the human papillomavirus (HPV), the virus necessary for the development of precancerous lesions, can prevent most of them. Screening by cytology for these precancerous (or cancerous) lesions can be replaced by screening for certain types of HPV, high risk (HR-HPV), causing cervical cancer. The presence of HR-HPV on the cervix should raise suspicion of concomitant infection in the anus, as both epithelia are highly susceptible. This attitude is dictated by the increase incidence in anal cancer in the population, which is also HPV-dependent and therefore also potentially preventable through vaccination and screening."
706,Microbes in Tumoral In Situ Tissues and in Tumorigenesis.,"Feng X, Han L, Ma S, Zhao L, Wang L, Zhang K, Yin P, Guo L, Jing W, Li Q.",https://pubmed.ncbi.nlm.nih.gov/33330121/,"Cancerous tumors are severe diseases affecting human health that have a complicated etiology and pathogenesis. Microbes have been considered to be related to the development and progression of numerous tumors through various pathogenic mechanisms in recent studies. Bacteria, which have so far remained the most studied microbes worldwide, have four major possible special pathogenic mechanisms (modulation of inflammation, immunity, DNA damage, and metabolism) that are related to carcinogenesis. This review aims to macroscopically summarize and verify the relationships between microbes and tumoral in situ tissues from cancers of four major different systems (urinary, respiratory, digestive, and reproductive); the abovementioned four microbial pathogenic mechanisms, as well as some synergistic pathogenic mechanisms, are also discussed. Once the etiologic role of microbes and their precise pathogenic mechanisms in carcinogenesis are known, the early prevention, diagnosis, and treatment of cancers would progress significantly."
707,[Clinicopathological study of esophageal cancer in the early stage and its later development].,Ide H.,https://pubmed.ncbi.nlm.nih.gov/3985640/,"Ninety-five specimens taken from 82 cases of superficial esophageal cancer limited within the submucosal layer were studied to clarify the developmental changes of early esophageal cancer. Esophageal epithelium was also open to cancerous or dysplastic changes. Cancers limited to the mucosal layer were grossly classified as follows. 1) those progressing to carcinoma in situ of several millimeters to 2-5 cm in size, then invading deep beyond the mucosa, and 2) those invading beyond the mucosal layer to proliferate before reaching several millimeters in extent. Most of the resected cases belonged to type 1. which was flat in form with redness, erosive appearance or sclerohypertrophic appearance of the mucosa. These findings depended on the degree of cellular atypism and histological differentiation. Almost all submucosal cancer lesions less than 2 cm in size were of macroscopically protruding or depressed type. Many cases were simple type without intraepithelial spreading around the primary lesion and seemed to develop with in micro-cancer nests. Superficial circularly spreading cancer was one of the complex types observed with intraepithelial cancer around the primary lesion. Most superficial spreading cancers originating as large flat epithelial lesions, and the protrusions or depressions found in the lesions were considered to have developed as secondary changes occurring during the course of change. Vessel-invasion of superficial esophageal cancer was also discussed."
708,Is neonatal phototherapy associated with a greater risk of childhood cancers?,"Sabzevari F, Sinaei R, Bahmanbijari B, Dehghan Krooki S, Dehghani A.",https://pubmed.ncbi.nlm.nih.gov/35729528/,"
    


           Moreover, 116 pediatric patients without cancer hospitalized at the same Center were included after sex and age matching as the control group. The history of phototherapy and its duration were evaluated in these two groups.
    


           However, high intensive phototherapy was higher historically among affected cancerous patients than in non-cancerous cases without any statistically significant difference (25% vs 19%; P = 0.26). Maternal educational level and history of maternal infection during pregnancy, which initially appeared to be two factors associated with malignancy in single variable regression analyses, were not significant based on the adjusted models.
    


          Conclusions:
        
      
      The  However, some other evidence is worrisome enough that NNPT should not be considered risk-free. Additional multi-centric studies should be undertaken to specify that phototherapy is really safe."
709,Positron emission tomography molecular imaging-based cancer phenotyping.,"Jin C, Luo X, Li X, Zhou R, Zhong Y, Xu Z, Cui C, Xing X, Zhang H, Tian M.",https://pubmed.ncbi.nlm.nih.gov/35417604/,"During the past several decades, numerous studies have provided insights into biological characteristics of cancer cells and identified various hallmarks of cancer acquired in the tumorigenic processes. However, it is still challenging to image these distinctive traits of cancer to facilitate the management of patients in clinical settings. The rapidly evolving field of positron emission tomography (PET) imaging has provided opportunities to investigate cancer's biological characteristics in vivo. This article reviews the current status of PET imaging on characterizing hallmarks of cancer and discusses the future directions of PET imaging strategies facilitating in vivo cancer phenotyping."
710,Programmed cell death 4 protein in esophageal cancer.,"Fassan M, Cagol M, Pennelli G, Rizzetto C, Giacomelli L, Battaglia G, Zaninotto G, Ancona E, Ruol A, Rugge M.",https://pubmed.ncbi.nlm.nih.gov/20514454/,"Screening for genes down-regulated in esophageal cancers (Oncomine database) pinpointed programmed cell death 4 (PDCD4) as one of the most consistently involved. PDCD4 is a new putative tumor suppressor gene implicated in cell transformation, tumorigenesis, and invasiveness. Based on such a biological rationale, the aim of the present study was to evaluate the prognostic value of PDCD4 in esophageal cancers. The immunohistochemical expression of PDCD4 protein was assessed in 111 consecutive esophageal cancers (63 adenocarcinomas and 48 squamous cell carcinomas) and paired non-cancerous samples. PDCD4 immunostaining was significantly lower in cancer samples than in non-cancerous mucosa (p<0.001). In all cases, the native esophageal epithelium consistently expressed nuclear PDCD4, which was significantly less expressed (37/111 cases) or completely lacking (31/111 cases) in the cancer samples. A significant inverse correlation emerged between nuclear PDCD4 expression and tumor stage (p=0.002), pT (p<0.001), nodal metastasis (p=0.038), and with both vascular (p=0.005) and perineural invasion (p=0.004). Nuclear PDCD4 expression was associated with a longer disease-free (p=0.011) and overall (p=0.021) survival. PDCD4 expression predicts the patient outcome in esophageal cancers. Additional functional studies should look into the role of PDCD4 in the multistep process of esophageal oncogenesis also inquiring on the clinical usefulness of the protein expression as prognostic marker in esophageal precancerous lesions."
711,Advances made in the treatment of testicular cancer in the U.S. Military: 1946 to the present.,"Hawksworth DJ, McLeod DG, Brassell SA.",https://pubmed.ncbi.nlm.nih.gov/19720302/,"Testicular cancer is presently one of the most curable solid tumors, and thanks to diagnostic, surgical, and medical advances over the last several decades, the treatment of this tumor serves as a paradigm for multimodal treatment of solid malignancies. Due to testicular cancer's predilection for younger patients, many of the seminal improvements and discoveries were made possible as a  This article reviews historical contributions of the United States Military Medical Departments in the arena of testicular cancer treatment in the post-World War II era."
712,The evolution of cancer of the colon and rectum.,"Muto T, Bussey HJ, Morson BC.",https://pubmed.ncbi.nlm.nih.gov/1203876/,"The malignant potential of adenomas of the colon and rectum varies with size, histological type and grade of epithelial atypia. The adenomatous polyp is usually small and has a low malignant potential, whereas tumors with a villous structure are usually larger and have a much higher cancer rate. Severe atypia is more common in villous adenomas than in adenomatous polyps. Evidence is presented which suggests that most cancers of the colon and rectum have evolved through the polyp-cancer sequence although the majority of adenomas do not becoma cancerous during a normal adult life span. The slow evolution of the polyp-cancer sequence is stressed. The implications of the polyp-cancer sequence for the design of cancer prevention programmes and the study of the aetiology of large bowel cancer are discussed."
713,Hematoporphyrin photodynamic therapy: is there truly a future in head and neck oncology? Reflections on a 5-year experience.,Gluckman JL.,https://pubmed.ncbi.nlm.nih.gov/1701843/,"Photodynamic therapy, which consists of the selective destruction of tumors using a combination of a photosensitizer administered systemically (dihematoporphyrin ether) and an argon dye-pumped laser, has provoked profound interest amongst oncologists and has particularly titillated head and neck oncologists with its potential. Unfortunately, no multi-institutional trials for head and neck tumors have been introduced, and the literature is replete with anecdotal reports from individual researchers on the management of advanced cancers for palliation, superficial early cancers, and field cancerization of the mucosa (""condemned mucosa""). A personal 5-year experience with 41 head and neck cancers was reviewed, as was the current literature. An attempt was made to place in perspective the true role and future direction of this technology."
714,Epidemiology of basal cell carcinoma: scholarly review.,"Verkouteren JAC, Ramdas KHR, Wakkee M, Nijsten T.",https://pubmed.ncbi.nlm.nih.gov/28220485/,"Basal cell carcinoma (BCC) is the most common cancer in white-skinned individuals with increasing incidence rates worldwide. Patients with BCC place a large burden on healthcare systems, because of the high incidence and the increased risk of synchronous and metachronous BCCs and other ultraviolet radiation (UVR) related skin cancers (i.e. field cancerization). As a  BCC is a complex disease, in which the interplay between UVR, phenotype (UVR-sensitive) and genotype (somatic mutations and germline mutations/polymorphisms) fulfils a key role in the aetiopathogenesis. Prevention programmes with continual refinements and improvements could be of major importance in tackling the growing skin cancer problem. To provide the most appropriate BCC care, physicians should engage in shared decision-making and choose their treatments wisely."
715,"piRNA, the new non-coding RNA, is aberrantly expressed in human cancer cells.","Cheng J, Guo JM, Xiao BX, Miao Y, Jiang Z, Zhou H, Li QN.",https://pubmed.ncbi.nlm.nih.gov/21616063/," They are involved in germline development, in silencing of selfish DNA elements, and in maintaining germline DNA integrity. The relationship between piRNAs and carcinogenesis has not been shown yet.
    


           The piR-651 inhibitor was transfected into gastric cancer cells to assess its influence on cell growth. Cell cycle analysis was used to reveal the cellular mechanisms of piR-651 in the genesis of gastric cancer.
    


           The levels of piR-651 were associated with TNM stage (P=0.032). The expression of piR-651 in gastric, colon, lung, and breast cancer tissues was higher than that in paired non-cancerous tissues. The upregulated expression of piR-651 was confirmed in several cancer cell lines including gastric, lung, mesothelium, breast, liver, and cervical cancer cell lines. The growth of gastric cancer cells was inhibited by a piR-651 inhibitor and arrested at the G(2)/M phase.
    


          Conclusion:
        
      
      piR-651 might be involved in the development of gastric cancer and other cancers, and is a potential marker for cancer diagnosis."
716,Accurate molecular classification of cancer using simple rules.,"Wang X, Gotoh O.",https://pubmed.ncbi.nlm.nih.gov/19874631/," Feature selection is often used to address this problem by selecting informative genes from among thousands or tens of thousands of genes. However, most of the existing  For a better understanding of the classification 
    


           Applying the decision rules induced by the selected genes or gene pairs, we constructed cancer classifiers. We tested the efficacy of the classifiers by leave-one-out cross-validation (LOOCV) of training sets and classification of independent test sets.
    


           acute myeloid leukemia [AML]), lung cancer, prostate cancer, breast cancer, and leukemia (ALL vs. mixed-lineage leukemia [MLL] vs. AML). Accurate classification outcomes were obtained by utilizing just one or two genes. Some genes that correlated closely with the pathogenesis of relevant cancers were identified. In terms of both classification performance and algorithm simplicity, our approach outperformed or at least matched existing 
    


          Conclusion:
        
      
      In cancerous gene expression datasets, a small number of genes, even one or two if selected correctly, is capable of achieving an ideal cancer classification effect. This finding also means that very simple rules may perform well for cancerous class prediction."
717,[Treatment of colorectal cancer].,Hojo K.,https://pubmed.ncbi.nlm.nih.gov/3947103/,"The large majority of colorectal cancers are well or moderately differentiated adenocarcinomas. Their biological behavior is not as malignant as that of stomach cancer, with a tendency of slow growth and limited spread. Surgery is therefore the first choice for management of these cancers even in cases where complete removal of the tumor is not expected, surgery is useful for the prolongation or improvement of the quality of life. However, the correct choice of operation for such cases is very important. The extent of resection and dissection must be decided based upon the degree of cancer spread. Both must be sufficient, but not excessive. In cases in the early stage where cancerous growth has not spread beyond the submucosal layer, local or segmental excision may be a good enough treatment. On the other hand, for far advanced rectal cancer involving adjacent organs, combined resection and pelvic evisceration is curatively effective. Several pathological findings of resected specimens influencing prognosis were investigated in the present study. In cases which appeared to be diffuse infiltrative spreading type in macroscopic appearance or poorly differentiated, undifferentiated, or mucinous types of cancer in their histological features, survival rates were low. However, these were uncommon and over half of them were much too far advanced to receive curative resection. Irradiation combined with hyperthermia or heavy chemotherapy were applied, but were mostly ineffective. For these uncommon types of cases as well as far advanced cases, we have no effective treatment other than surgery at this time."
718,Expression of multidrug resistance gene (mdr-1) mRNA in gastric and colorectal cancers.,"Motoo Y, Su SB, Nakatani MT, Sawabu N.",https://pubmed.ncbi.nlm.nih.gov/9677442/,"Fresh surgical specimens of 52 gastric cancers and 25 colorectal cancers were analyzed for the expression of multidrug resistance (mdr-1) gene mRNA with non-isotopic in situ hybridization (ISH) using a biotin-labeled oligonucleotide probe. The mdr-1 mRNA was expressed in 15.4% in cancerous portions and 1.9% in non-cancerous portions of gastric cancers (p < 0.02). In colorectal cancers, the mdr-1 mRNA was positive in 36% in cancerous portions and 28% in non-cancerous portions. In gastric cancers, the well-differentiated type showed a significantly higher positive rate than the poorly differentiated type (p < 0.01). These "
719,Characteristics of gastric and intestinal mucin phenotypes of gastric carcinoma.,"Mabuchi N, Niwa Y, Hirooka Y, Ohmiya N, Itoh A, Maeda O, Ando T, Goto H.",https://pubmed.ncbi.nlm.nih.gov/19260522/,"
    


           Sections from representative paraffin blocks of each case were immunostained with human gastric mucin, MUC2, CD10, and paradoxical concanavalin A class III. Gastric cancers were divided into three phenotypes; gastric phenotype (G-type), intestinal phenotype (I-type), and the Null phenotype (N-type). Surrounding non-cancerous mucosa was also phenotyped as G- or I-type.
    


          004). As for surrounding non-cancerous mucosa, the G-type mucosa was more frequently seen than the I-type mucosa in incomplete intestinal metaplasia (p<0.001). I-type gastric cancers were more frequent in non-cancerous surrounding mucosa with incomplete intestinal metaplasia, and G-type cancers were more frequent in non-cancerous surrounding mucosa with no intestinal metaplasia (p=0.03).
    


          Conclusions:
        
      
      G-type gastric cancers may develop in G-type gastric mucosa with incomplete intestinal metaplasia and progress to the G-type undifferentiated carcinomas or the I-type differentiated carcinomas."
720,Absence of evidence or evidence of absence? A discussion on paleoepidemiology of neoplasms with contributions from two Portuguese human skeletal reference collections (19th-20th century).,"Marques C, Matos V, Costa T, Zink A, Cunha E.",https://pubmed.ncbi.nlm.nih.gov/29776881/,"Biological, sociocultural, demographic and environmental factors are major contributors to the contemporary burden of oncological diseases. Although cancer's current epidemiological landscape is fairly well known, its past occurrence and history seem more obscure. In order to test the hypothesis that paleopathological diagnosis is an adequate measure of the prevalence of malignant neoplasms in human remains, 131 skeletons (78 females, 53 males, age-at-death range: 15-93 years) from Coimbra and Lisbon Identified Skeletal Collections, 19th/20th century (Portugal), were examined. The cause of death for all of the selected skeletons was a malignant neoplasm, as recorded in the collection's documental files. Through the application of standard paleopathological protocols, it was determined that 17.6% (n = 23) of the skeletons had unequivocal osseous signs of metastatic and/or neoplastic lesions. Forty-five percent (n = 59) had manifest osseous lesions, however the lesional patterns were not clearly pathognomonic. Although all of the analyzed individuals were documented as having succumbed to malignant neoplastic disease, a total of 37.4% (n = 49) of the individuals did not exhibit osseous abnormalities. Individuals with breast cancer often exhibited lesions. This study presents a quantitative estimate of the accuracy of paleopathological diagnosis; as well as a theoretical reflection on the burden of cancer in the past. We emphasize the need for a paradigm shift while thinking about the future of paleo-oncology."
721,Pruning Cancer's Evolutionary Tree with Lesion-Directed Therapy.,"Hiley CT, Swanton C.",https://pubmed.ncbi.nlm.nih.gov/26851181/,Next-generation sequencing of spatially and temporally separated biopsies and circulating tumor DNA directs therapy in response to tumor evolution and acquired resistance in colorectal cancer.
722,Skin cancer in organ transplant recipients--where do we stand today?,"Ulrich C, Kanitakis J, Stockfleth E, Euvrard S.",https://pubmed.ncbi.nlm.nih.gov/18782290/,"Skin cancers are the most frequent malignancies in organ transplant recipients (OTR), with 95% being nonmelanoma skin cancers (NMSC), especially squamous (SCC) and basal cell carcinomas. Most OTR with a first SCC subsequently develop multiple NMSC within 5 years, highlighting the concept of 'field cancerization', and are also at high risk for noncutaneous cancers. In order to reduce the tumor burden in these patients, their management requires an interdisciplinary approach including revision of immunosuppression, new dermatological treatments and adequate education about photoprotection in specialized dermatology clinics for OTR. Whereas surgery remains the gold-standard therapy for NMSC, noninvasive  Although the threshold of skin cancer necessitating revision of immunosuppression is debated, this measure should be envisaged at the occurrence of the first SCC, or in case of multiple non-SCC NMSC. While the role of immunosuppressants in the occurrence of NMSC is widely recognized, the best immunosuppressive strategies remain to be defined. Presently, randomized prospective studies assess the burden of new skin tumors, as well as graft and patient survival, in patients with one or several NMSC after the "
723,Uterine metastasis from invasive ductal breast carcinoma: A case report with literature review.,"Bouvier AS, Panchbhaya N, Brochard C, Marchand E, Mezzadri M, Leveau-Vallier AS, Cornelis F, Benifla JL, Mimoun C.",https://pubmed.ncbi.nlm.nih.gov/33217599/,"Breast cancer is the leading cause of cancer death in women, and most breast cancer related deaths are due to metastases. Uterine metastases from breast cancer are uncommon and rarely reported in the literature. We described the case of a 50 years-old-woman who developed a uterine metastasis, 6 years after the diagnosis of an invasive ductal breast carcinoma. Indeed, although the patient was asymptomatic, the monitoring imaging examinations, particularly the computed tomography (CT) and the positron emission tomography/computed tomography (PET/CT), showed a myometrial lesion. Non-conservative total hysterectomy was performed. The anatomo-pathological examination revealed a myometrial metastasis from an invasive ductal breast carcinoma. Seventeen months after surgery, the patient had no pelvic recurrence, but lungs and bones metastases progressed despite chemotherapy. In the lack of guidelines of uterine metastases from breast cancer's management, we reviewed the existing literature with the aim to provide a rational framework for clinical presentation, diagnostic approach, histological findings and treatment of this rare and heterogeneous pathology. Uterine metastases of breast cancer are frequently revealed with metrorrhagia. They occur preferentially in tumours with initial lobular carcinoma, initial lymph node involvement and positive hormonal receptors."
724,Toll-like receptor-induced cytokines as immunotherapeutic targets in cancers and autoimmune diseases.,"Patra MC, Shah M, Choi S.",https://pubmed.ncbi.nlm.nih.gov/31054927/,"Immune cells of the myeloid and lymphoid lineages express Toll-like receptors (TLRs) to recognize pathogenic components or cellular debris and activate the immune system through the secretion of cytokines. Cytokines are signaling molecules that are structurally and functionally distinct from one another, although their secretion profiles and signaling cascades often overlap. This situation gives rise to pleiotropic cell-to-cell communication pathways essential for protection from infections as well as cancers. Nonetheless, deregulated signaling can have detrimental effects on the host, in the form of inflammatory or autoimmune diseases. Because cytokines are associated with numerous autoimmune and cancerous conditions, therapeutic strategies to modulate these molecules or their biological responses have been immensely beneficial over the years. There are still challenges in the regulation of cytokine function in patients, even in those who take approved biological therapeutics. In this review, our purpose is to discuss the differential expression patterns of TLR-regulated cytokines and their cell type specificity that is associated with cancers and immune-system-related diseases. In addition, we highlight key structural features and molecular recognition of cytokines by receptors; these data have facilitated the development and approval of several biologics for the treatment of autoimmune diseases and cancers."
725,Functional genomic studies: insights into the pathogenesis of liver cancer.,Han ZG.,https://pubmed.ncbi.nlm.nih.gov/22703171/,"Liver cancer is the sixth-most-common cancer overall but the third-most-frequent cause of cancer death. Among primary liver cancers, hepatocellular carcinoma (HCC), the major histological subtype, is associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Although previous studies have revealed that certain genetic and epigenetic changes, such as TP53 and β-catenin mutations, occur in HCC cells, the pathogenesis of this cancer remains obscure. Functional genomic approaches-including genome-wide association studies, whole-genome and whole-exome sequencing, array-based comparative genomic hybridization, global DNA methylome mapping, and gene or noncoding RNA expression profiling-have recently been applied to HCC patients with different clinical features to uncover the genetic risk factors and underlying molecular mechanisms involved in this cancer's initiation and progression. The genome-wide analysis of germline and somatic genetic and epigenetic events facilitates understanding of the pathogenesis and molecular classification of liver cancer as well as the identification of novel diagnostic biomarkers and therapeutic targets for cancer."
726,[Features of home care for patients with advanced breast cancer].,"Ashino Y, Sato M.",https://pubmed.ncbi.nlm.nih.gov/11787277/,"We examined the features of home care for patients with noncurable breast cancer. The patients were 21 women with advanced breast cancer who entered the home care program between April 1987 and May 2001. The first feature was that their young age: six of them were in their forties, five were in their fifties, and the mean age was 57.4 years old. The second feature was that the period home care was provided was long. The mean duration of home care from the beginning to their death was 143 days. This was because the period of sickness and the period until the breast cancer's relapsing were both long. The mean period until the relapse was 2.3 years, and the mean period of sickness was 4.1 years. The third feature was the great variety of symptoms. It is this cause that there are a lot of metastasis organs. The fourth feature was that no special treatment, such as infusion therapy, was really necessary to alleviate the symptoms. Pain control was important because there were a lot of patients whose main complaint was pain. However, pain could be controlled with morphine. In conclusion, if it is excluded not to have the nursing power because the age is generally young, home care can be comparatively offered to the person who has an advanced breast cancer for a long term."
727,Diagnostic relevance of overexpressed Nanog gene in early lung cancers.,"Nirasawa S, Kobayashi D, Tsuji N, Kuribayashi K, Watanabe N.",https://pubmed.ncbi.nlm.nih.gov/19639208/,"Currently, no target molecules have been identified that enable the diagnosis of lung cancer with high sensitivity and specificity, especially in the early clinical stages of cancer. Recently, Nanog has been reported to play an important role in the self-renewal and regeneration of ES cells by maintaining these cells in the undifferentiated state and by accelerating cell proliferation. Here, we compared the degree of Nanog mRNA expression in lung cancer tissues with that in non-cancerous tissues. Nanog mRNA was detected in 84.8% (39/46) of lung cancer tissues. The sensitivity and specificity of this diagnostic technique was 80.4 and 93.3%, respectively, as estimated using the cut-off obtained from the analysis of the receiver operating characteristic curve. Further, comparison of paired cancerous and non-cancerous tissues from the same patient revealed elevated Nanog mRNA levels in all patients. No obvious correlations were detected between the clinicopathological factors and Nanog mRNA expression; however, Nanog mRNA was expressed at high levels even in the early clinical stages of the cancer. In addition, the transduction of Nanog siRNA in lung carcinoma cells  These "
728,[The place of scintigraphy in the lung cancer diagnosis].,"Boldeanu D, Sfrângeu C, Răducanu G, Precup D, Adrieş G.",https://pubmed.ncbi.nlm.nih.gov/11374375/,"The incidence of lung cancer has had a significant increase during the last years, belonging today, along with the cardiovascular disease and accidents, to the top three places in mortality. The current article presents the importance of the pulmonary perfusion scintigraphy during the algorithm of the bronchopulmonary cancer's diagnosis, clinical staging and resection, in correlation with other imagistic (Rx, CT, NMR) and non-imagistic  Based on the cases of the Nuclear Medicine Dept. of the County's Clinical Hospital of Cluj-Napoca, the study was made on 130 cases, investigated between 01.01.1998 and 15.06.1999. The initial diagnosis of the patients which needed pulmonary perfusion scintigraphy was diverse, most of them being period being suspected of lung embolism, followed by those suspected of bronchopulmonary cancer. We've taken into account a number of 34 cases of lung cancer. Out of them, 20 patients (58.82%) presented minor peripheral perfusion deficit and had surgical procedures, and 14 patients (41.17%) presented centrohilar carcinoma with major perfusion deficit. The pulmonary perfusion scintigraphy is an "
729,"Revolutionizing cancer care strategies: immunotherapy, gene therapy, and molecular targeted therapy.","Zafar A, Khan MJ, Abu J, Naeem A.",https://pubmed.ncbi.nlm.nih.gov/38281269/,"Despite the availability of technological advances in traditional anti-cancer therapies, there is a need for more precise and targeted cancer treatment strategies. The wide-ranging shortfalls of conventional anticancer therapies such as systematic toxicity, compromised life quality, and limited to severe side effects are major areas of concern of conventional cancer treatment approaches. Owing to the expansion of knowledge and technological advancements in the field of cancer biology, more innovative and safe anti-cancerous approaches such as immune therapy, gene therapy and targeted therapy are rapidly evolving with the aim to address the limitations of conventional therapies. The concept of immunotherapy began with the capability of coley toxins to stimulate toll-like receptors of immune cells to provoke an immune response against cancers. With an in-depth understating of the molecular mechanisms of carcinogenesis and their relationship to disease prognosis, molecular targeted therapy approaches, that inhibit or stimulate specific cancer-promoting or cancer-inhibitory molecules respectively, have offered promising outcomes. In this review, we evaluate the achievement and challenges of these technically advanced therapies with the aim of presenting the overall progress and perspective of each approach."
730,Somatic mutations and genetic polymorphisms of the PPP1R3 gene in patients with several types of cancers.,"Takakura S, Kohno T, Shimizu K, Ohwada S, Okamoto A, Yokota J.",https://pubmed.ncbi.nlm.nih.gov/10698503/,"Recently, we found nonsense and missense mutations of the PPP1R3 (protein phosphatase 1, regulatory subunit 3) gene in diverse human cancer cell lines and primary lung carcinomas, indicating that PPP1R3 functions as a tumor suppressor in human carcinogenesis. In this study, to assess the prevalence of PPP1R3 mutations in human primary cancers and the genetic diversity of the PPP1R3 gene in the human population, somatic mutations and genetic polymorphisms in the PPP1R3 gene were examined in 137 pairs of cancerous and non-cancerous tissues of patients with cancers of colon, ovary, and liver. Five somatic mutations including two missense mutations were detected in three cancerous tissues consisting of two colorectal carcinomas and one ovarian carcinoma. Five novel single nucleotide polymorphisms (SNPs) associated with the substitution of amino acids were also identified in cancer patients, in addition to five known nonsynonymous SNPs, including three previously reported ones as having an impact on the susceptibility to insulin resistant disorders. Differences in the activities and properties of multiple PPP1R3 proteins, which are produced in human cells due to variable somatic mutations and genetic polymorphisms in the PPP1R3 gene, can be involved in human carcinogenesis and susceptibility to diseases."
731,Traits of a mussel transmissible cancer are reminiscent of a parasitic life style.,"Burioli EAV, Hammel M, Bierne N, Thomas F, Houssin M, Destoumieux-Garzón D, Charrière GM.",https://pubmed.ncbi.nlm.nih.gov/34916573/,"Some cancers have evolved the ability to spread from host to host by transmission of cancerous cells. These rare biological entities can be considered parasites with a host-related genome. Still, we know little about their specific adaptation to a parasitic lifestyle. MtrBTN2 is one of the few lineages of transmissible cancers known in the animal kingdom. Reported worldwide, MtrBTN2 infects marine mussels. We isolated MtrBTN2 cells circulating in the hemolymph of cancerous mussels and investigated their phenotypic traits. We found that MtrBTN2 cells had remarkable survival capacities in seawater, much higher than normal hemocytes. With almost 100% cell survival over three days, they increase significantly their chances to infect neighboring hosts. MtrBTN2 also triggered an aggressive cancerous process: proliferation in mussels was ~ 17 times higher than normal hemocytes (mean doubling time of ~ 3 days), thereby favoring a rapid increase of intra-host population size. MtrBTN2 appears to induce host castration, thereby favoring resources re-allocation to the parasites and increasing the host carrying capacity. Altogether, our "
732,"[Lymphocytes subpopulation in cancer's patients. Relationship with primitive anatomical location, histological type and clinical stage (author's transl)].","Saiz Garcia F, Rodriguez Valverde V.",https://pubmed.ncbi.nlm.nih.gov/6971668/,"Several markers of humoral and cellular immunity were studied in 49 untreated patients with malignancies of different anatomical locations, histological types and clinical stages. The proportion of EAC rosettes, levels of immunoglobulins as well as levels of the C3 and C4 components of the complement system were within the normal range (p.n.s.). The proportion of T lymphocytes, measured by the classical E rosette 0005), regardless of the anatomical origin of the tumor. In patients with lung cancer (45,52 +/- 10,37), those with the epidermoid type (51 +/- 9,45) had a reduced number of E rosettes when compared with controls (58,87 +/- 5,53 p less than 0.005) but they were still greater in number than in the other histological types (43,16 +/ 9,97 p less than 0.025). We found no relationship between the proportion of E rosettes and the clinical stage. The number of T lymphocytes with E rosettes after incubation at 30 degrees C was within normal limits in most patients, except in those cases with lung cancer at an early clinical stage (23,94 +/- 5,85 p less than 0.005). Our findings would support the hypothesis of a deficiency in cellular immunity in patients with malignancies, which could favour the progression of the disease."
733,Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer.,"Zhan C, Shi Y, Lu C, Wang Q.",https://pubmed.ncbi.nlm.nih.gov/23317289/,"It's frequently stated that the pyruvate kinase M2 (PKM2) and Warburg effect are important for cancer development by accumulating more raw materials for macromolecule biosynthesis. However, the correlation between PKM2 and cancer is poorly reported. Here, we investigated the PKM2 expression in esophageal squamous cell cancer (ESCC). We observed that the expression of PKM2 was much higher in ESCC than in control normal tissue, and it is highly associated with many clinical features and prognosis. Specially, we found that the expression of PKM2 was closely related to the differentiation state of ESCC, and we further confirmed this discovery in vitro. As a  Considering previous researches on the link among PKM2, Warburg effect, and differentiation, our study inferred the direct roles of PKM2 and Warburg effect in the differentiation of cancer cells rather than only providing synthetic intermediates for the promotion of cancer's progression."
734,"Expression of PI3Kp110alpha and PI3Kp110beta in the colorectal conventional adenoma, serrated lesions and adenoma with canceration and their significance.","Wu S, Li T, Mu Q, Li Y, Gao X, He S, Sun C.",https://pubmed.ncbi.nlm.nih.gov/26884879/,"Aims:
        
      
      To evaluate the expression and clinical significance of PI3Kp110α and PI3Kp110β in colorectal conventional adenoma, serrated lesions and adenoma with canceration.
    


           05). But there was no significant difference between the adenoma canceration and the high grade adenoma of conventional adenoma, all grade of villous adenoma and serrated adenoma (P>0.05). The expression of p110α and p110β was correlated with different clinicopathologic factors in conventional adenoma, serrated adenoma and adenoma canceration (P<0.05).
    


          Conclusions:
        
      
      p110α and p110β were highly expressed in villous adenoma, serrated adenoma and adenoma with canceration. Its high expression may be the risk factor of the progress of adenoma to adenocarcinoma, and may be an important cause of what canceration rate of villous adenoma and serrated adenoma was higher than that of other adenomas. Combined detection of p110α and p110β is helpful to determine the canceration potential of colorectal villous adenoma and serrated adenoma."
735,Optical properties of normal and cancerous human skin in the visible and near-infrared spectral range.,"Salomatina E, Jiang B, Novak J, Yaroslavsky AN.",https://pubmed.ncbi.nlm.nih.gov/17212549/,"Differences in absorption and/or scattering of cancerous and normal skin have the potential to provide a basis for noninvasive cancer detection. In this study, we have determined and compared the in vitro optical properties of human epidermis, dermis, and subcutaneous fat with those of nonmelanoma skin cancers in the spectral range from 370 to 1600 nm. Fresh specimens of normal and cancerous human skin were obtained from surgeries. The samples were rinsed in saline solution and sectioned. Diffuse reflectance and total transmittance were measured using an integrating sphere spectrophotometer. Absorption and reduced scattering coefficients were calculated from the measured quantities using an inverse Monte Carlo technique. The differences between optical properties of each normal tissue-cancer pair were statistically analyzed. The  In this spectral region, the scattering of cancerous lesions is consistently lower than that of normal tissues, whereas absorption does not differ significantly, with the exception of nodular basal cell carcinomas (BCC). Nodular BCCs exhibit significantly lower absorption as compared to normal skin. Therefore, the spectral range between 1050 and 1400 nm appears to be optimal for nonmelanoma skin cancer detection."
736,Resveratrol nanoformulation for cancer prevention and therapy.,"Siddiqui IA, Sanna V, Ahmad N, Sechi M, Mukhtar H.",https://pubmed.ncbi.nlm.nih.gov/26109073/,"Chemoprevention of human cancer(s) is a viable option for cancer control, especially when chemopreventive intervention is involved during the early stages of the carcinogenesis process. Naturally occurring bioactive food components, such as dietary polyphenols, have shown good antioxidant activity and other beneficial activities. In addition, compounds belonging to the polyphenolic chemical class may play promising roles in cancer prevention. Among them, the phytoalexin resveratrol has demonstrated antiproliferative effects, as well as the ability to inhibit initiation and promotion of induced cancer progression in a wide variety of tumor models. However, resveratrol, like other natural polyphenols, is an extremely photosensitive compound with low chemical stability and limited bioavailibility, which limit the therapeutic application of its beneficial effects. In this context, the development of innovative formulation strategies able to overcome physicochemical and pharmacokinetic limitations of this compound could be beneficial. This may be achieved via nanotechnology approaches utilizing suitable carriers that allow slow, sustained, and controlled release of the encapsulated agent. This review focuses on the recent developments of novel nanoformulations used to deliver sustained levels of resveratrol."
737,Marijuana smoking and head and neck cancer.,"Hashibe M, Ford DE, Zhang ZF.",https://pubmed.ncbi.nlm.nih.gov/12412843/,"A recent epidemiological study showed that marijuana smoking was associated with an increased risk of head and neck cancer. Among high school students and young adults, the prevalence of marijuana use was on the rise in the 1990s, with a simultaneous decline in the perception that marijuana use is harmful. It will be a major public health challenge to make people aware of the harmful effects of marijuana smoking, when some people view it as the illicit drug with the least risk. The carcinogenicity of delta9-tetrahydrocannabinol (THC) is not clear, but according to laboratory studies, it appears to have antitumor properties such as apoptosis as well as tumor-promoting properties such as limiting immune function and increasing reactive oxygen species. Marijuana tar contains similar carcinogens to tar from tobacco cigarettes, but each marijuana cigarette maybe more harmful than a tobacco cigarette since more tar is inhaled and retained when smoking marijuana. More molecular alterations have been observed in bronchial mucosa specimens of marijuana smokers compared to nonsmokers. Field cancerization may be occurring on the bronchial epithelium due to marijuana smoking exposure. Several case studies were suggestive of an association of marijuana smoking with head and neck cancers and oral lesions. However, in a cohort study with 8 years of follow-up, marijuana use was not associated with increased risks of all cancers or smoking-related cancers. Further epidemiological studies are necessary to confirm the association of marijuana smoking with head and neck cancers and to examine marijuana smoking as a risk factor for lung cancer. It will also be of interest to examine potential field cancerization of the upper aerodigestive tract by marijuana and to explore marijuana as a risk factor for oral premalignant lesions."
738,Clinico-pathological peculiarities of human papilloma virus driven head and neck squamous cell carcinoma: A comprehensive update.,"Devaraja K, Aggarwal S, Verma SS, Gupta SC.",https://pubmed.ncbi.nlm.nih.gov/32007572/,"Aims:
        
      
      The current article provides a detailed account of the current understanding of molecular and clinico-pathological aspects of Human papilloma virus (HPV) driven head and neck squamous cell carcinoma (HNSCC).
    


          Materials and 
    


          Key findings:
        
      
      HPV positive HNSCC differ distinctly from HPV negative tobacco-related HNSCC, especially in oropharyngeal region. Therefore, the American joint committee on cancer`s latest manual for classification and staging of cancer suggests a separate staging system for HPV positive oropharyngeal cancers. Despite the younger patients being affected and the high propensity for cervical metastasis, the HPV positive oropharyngeal cancers respond much better to the treatment. The association with wild type TP53 and low EGFR expression confers the favorable prognosis in HPV driven HNSCC. Since the association is not universal, we suggest checking for p53 and EGFR expression status before considering de-intensification of therapy. In addition, the presence of matted lymph nodes and five or more nodes could mean relatively poorer prognosis, and are not suitable for de-intensification of therapy. The same is also true probably with higher T stage and co-existing tobacco use. The 
    


          Significance:
        
      
      This article provides latest developments on the HPV driven HNSCC. 'Diagnosis of transcriptionally active HPV infection,' 'Modalities for surveillance,' 'Implication of de-escalation of therapy' are some of the critical issues that could serve the medical, the research as well as the patient communities."
739,Cellular and Molecular Signaling as Targets for Cancer Vaccine Therapeutics.,"Wei WC, Shyur LF, Yang NS.",https://pubmed.ncbi.nlm.nih.gov/35563896/,"Plenty of evidence has recently shown that various inflammatory activities at the local tissue, organ, or even the whole body (systemic) level are strongly linked to many life-threatening chronic diseases, most notably various cancers. However, only very limited information is available for making good use of our supporting immune-modulatory therapeutics for the treatment of cancers. This may  Our group and laboratories were fortunate to have initiated and consistently pursued an integrated team-work program project, aimed at investigating selected medicinal herbs and the derived, purified phytochemical compounds. We focused on the study of key and specific immune-signaling mechanisms at the cellular and molecular levels. We were fortunate to obtain a series of fruitful research  We believe that our key findings reported herein may be helpful for proposing future thematic and integrated research projects that aim to develop future phytochemical drugs against cancers. The mechanisms of the cellular and molecular systems involved in inflammation are becoming increasingly recognized as keystones for the development of future therapeutic approaches for many chronic and cancerous diseases. Recently, the immune checkpoint inhibitors such as antibodies against PD-1 and/or PD-L1 have been shown to be too expensive for general clinical use, and their effects far from optimal, often showing little or no effect or only short-term efficacy. These "
740,Frequent translocalization of beta-catenin in gastric cancers and its relevance to tumor progression.,"Cheng XX, Sun Y, Chen XY, Zhang KL, Kong QY, Liu J, Li H.",https://pubmed.ncbi.nlm.nih.gov/15138556/,"Altered distribution of beta-catenin has been found in many human malignancies including gastric cancer, but its reason(s) and biological implications have not yet been fully clarified. By the  Membranous beta-catenin was detected constantly in non-cancerous mucosa but became reduced or absent in cancer tissues. The cytoplasmic and nuclear accumulation of beta-catenin could be observed in premalignant (atrophic gastritis and intestinal metaplasia) and cancer tissues, particularly in those infiltrated into deep muscular region. beta-catenin mutation was not detected in all of tissue samples with and without translocalized beta-catenin. These  The loss of membranous and the gain of cytoplasmic and nuclear beta-catenin in gastric cancers checked in this study are not due to the mutational event. beta-catenin molecules translocalized in the nuclei are closely correlated with tumor invasion."
741,The systemic effect of cancers on human sera proton NMR relaxation times.,"Beall PT, Narayana PA, Amtey SR, Spiga L, Intra E, Ridella S, Mela GS.",https://pubmed.ncbi.nlm.nih.gov/6085132/,"In animal models of cancer, an elevation of T1 and T2 in uninvolved tissues and in the blood of tumor bearing animals has been termed ""the systemic effect."" This study reports T1 values in sera of human patients from Genoa, Italy, with several types of cancer and non-cancerous diseases. T1 values were significantly elevated over normal controls (1628 +/- 113 ms) in colorectal cancers (1725 +/- 149 ms) and stomach cancers (1817 +/- 219 ms). However a systemic effect was not demonstrated in acute myeloid leukemia, chronic lymphatic leukemia, chronic myeloid leukemia, or plasma cell myeloma, or in pancreatic and lung cancers. Noncancerous states of cirrhosis, chronic hepatitis, and monoclonal gammapathies did not show a T1 elevation. In general, T1 values of sera correlated with protein content of the sera; however, a disproportionate contribution of gamma-globulin protein on water proton relaxation times was observed in several cases."
742,"Gene therapy for cancer treatment: past, present and future.","Cross D, Burmester JK.",https://pubmed.ncbi.nlm.nih.gov/16988102/,"The broad field of gene therapy promises a number of innovative treatments that are likely to become important in preventing deaths from cancer. In this review, we discuss the history, highlights and future of three different gene therapy treatment approaches: immunotherapy, oncolytic virotherapy and gene transfer. Immunotherapy uses genetically modified cells and viral particles to stimulate the immune system to destroy cancer cells. Recent clinical trials of second and third generation vaccines have shown encouraging  Oncolytic virotherapy, which uses viral particles that replicate within the cancer cell to cause cell death, is an emerging treatment modality that shows great promise, particularly with metastatic cancers. Initial phase I trials for several vectors have generated excitement over the potential power of this technique. Gene transfer is a new treatment modality that introduces new genes into a cancerous cell or the surrounding tissue to cause cell death or slow the growth of the cancer. This treatment technique is very flexible, and a wide range of genes and vectors are being used in clinical trials with successful outcomes. As these therapies mature, they may be used alone or in combination with current treatments to help make cancer a manageable disease."
743,[Detection of estrogen receptors (ER) in gastric cancer].,Zhu B.,https://pubmed.ncbi.nlm.nih.gov/1315669/,"Using Avidn-biotin-peroxidase complex (ABC) immunohistochemical  In 38 of 68 gastric cancer specimens, ER concentrations were also biochemically determined by Dextran-coated charcoal (DCC) assay. The  ER was present in 21 (30.9%) of gastric cancers. The ER positive cases were chiefly poorly differentiated gastric cancers. There were no significant statistical differences in the patient's age or sex, size of primary tumor and the ER positive rates. The "
744,"Results of second-stage screening for skin cancers in Oita Prefecture, Japan.","Kai Y, Ishikawa K, Goto M, Sakai T, Ito A, Shono T, Shimada H, Shimizu F, Goto M, Hatano Y, Okamoto O, Katagiri K, Aono H, Eshima N, Fujiwara S.",https://pubmed.ncbi.nlm.nih.gov/26177589/,"We performed skin cancer screenings for 2 or 3 days annually from 2006 through 2013 in Oita Prefecture, Japan. Screening of approximately 3000 people in total allowed us to identify and treat several skin cancers, including five cases of malignant melanoma, four of squamous cell carcinoma, 16 of basal cell carcinoma, 11 of Bowen's disease, 17 of actinic keratosis, one of extramammary Paget's disease and one of metastatic breast carcinoma. The sensitivity and specificity for the category defined by an identified lesion associated with risk of cancer and requiring further examination (category C) were 92.7% and 95%, respectively. We cannot estimate the outcome of our skin cancer screenings in terms of cancer mortality because of the small number of subjects examined and the brief follow-up period. However, we did estimate the effectiveness of these screenings in terms of stages or sizes of cancerous lesions. The relative numbers of subjects with malignant melanoma at various clinical stages, identified during skin cancer screenings and during a routine visit to our hospital, were significantly different. We also compared, statistically, the sizes of lesions in Bowen's disease that were found during cancer screenings and during a direct visit to our hospital. The former lesions were smaller than the latter. Our data suggest the benefits of our skin cancer screenings and the importance of campaigns and education to encourage people to visit dermatologists for the detection of skin cancers at an early stage."
745,The Association between Charlson Comorbidity Index and the Medical Care Cost of Cancer: A Retrospective Study.,"Yoon SJ, Kim EJ, Seo HJ, Oh IH.",https://pubmed.ncbi.nlm.nih.gov/26347086/,"
    


           The effect of comorbidity on the medical care cost was investigated using multiple regression and logistic regression models and controlling for demographic characteristics and cancer stage.
    


          05- and 1.01-fold higher, respectively, in patients with higher CCI determined. For breast cancer, the highest costs were seen in those with chronic obstructive pulmonary disease (COPD), but the increase in cost reduced as CCI increased. Colon cancer patients with diabetes mellitus and a CCI = 1 score had the highest medical costs. The lowest medical costs were incurred by lung cancer patients with COPD and a CCI = 2 score.
    


          Conclusion:
        
      
      The comorbidities had a major impact on the use of medical resources, with chronic comorbidities incurring the highest medical costs. The "
746,Serum alkaline phosphatase (Al-Pase) isozyme in gastric and colonic cancer (using a simple thin layer polyacrylamide gel electrophoresis).,"Yamaguchi K, Fujimoto S, Misaki F, Kawai K.",https://pubmed.ncbi.nlm.nih.gov/213341/,"Using the simple thin layer polyacrylamide gel electrophoresis, serum alkaline phosphatase could be separated 5 isozyme bands in various digestive diseases, consisting of 54 cases of gastric cancer, 11 of colonic cancer, 12 of hepatoma, 4 of cholangioma, 14 of pancreatic cancer, 81 of benign hepatobilliary diseases, 13 of cancers of other organs and 61 of control. The obtained  On the contrary, alkaline phosphatase O was never found in gastric and colonic cancer without cholelithiasis. On the contrary, alkaline phosphatase O was never found in gastric and colonic cancer without cancerous metastasis to the liver, and it was also inclined to be positive with the progress of liver metastasis among them. 2) Intestinal alkaline phosphatase was usually found in higher frequency in blood group B and O than in the others, and it was apt to disappear in gastric or colonic cancer with an exacerbation of its cancerous lesions. 3) Heat-stable alkaline phosphatase was found in 10% of gastric or colonic cancer, all of which were histologically proved to be well differentiated adenocarcinoma."
747,Immunohistochemical evaluation of the HER-2 protein in the infiltrative lobular breast cancer.,"Radovic S, Babic M, Doric M, Secic S, Beslić S, Balta E, Kapetanovic E.",https://pubmed.ncbi.nlm.nih.gov/16761510/,"Aim of the study:
        
      
      To investigate the correlation between the expression of HER-2 membrane protein and basic pathohistological parameters in cases of infiltrative breast cancer.
    


          Material and  Mastectomy with a dissection of axillary's lymph nodes was performed in all cases. Upon standard procedure of formalin fixation, embedding in paraffin and examination of slides stained with hematoxillin-eosin, a semiquantitaive 
    


           In the majority of cases (44,9 %) cancer's diameter ranged from 20-50 mm (pT2), with a moderate degree of differentiation (46,4 %), no signs of vascular invasion (50,7 %) and no metastases in axillary's lymph nodes (65,2 %). Evaluation of immunohistochemical expression of the HER-2 protein revealed that only the degree of tumor differentiation has been in statistically significant (p=0, 037) correlation with the intensity of the HER-2 protein expression.
    


          Conclusion:
        
      
      In cases of lobular infiltrative breast cancer, oncogenic effect of the HER-2 protein was associated with the degree of cellular differentiation, while it was not in correlation with other pathological parameters of poorer prognosis, such as the size of tumor, presence of vascular invasion and occurrence of metastases in regional lymph nodes."
748,Early detection of central airway lung cancer in smokers with silicosis.,"Lo AI, Huang Y, Lam SY, Cheung AH, Au R, Leung CC, Lam WK, Ip MS, Chan-Yeung M, Lam B.",https://pubmed.ncbi.nlm.nih.gov/21396213/,"
    


          
    


           Sputum specimens were collected for cytology/cytometry examination and autofluorescence bronchoscopy was performed in subjects with an abnormal sputum 
    


           The mean age and smoking history were respectively 63 ± 10 years and 51 ± 30 pack-years. Intraepithelial lung cancers and pre-neoplastic lesions (squamous metaplasia or above) were detected in respectively 2 (4.2%) and 14 (29.2%) subjects. The proportions of current smokers (75.0% vs. 40.6%, P = 0.03) and asbestos exposure (37.5% vs. 9.4%, P = 0.04) were significantly higher in subjects with the above lesions compared with those without.
    


          Conclusions:
        
      
      Sputum examination followed by autofluorescence bronchoscopy may be a useful way of identifying cancerous/pre-cancerous lesions among silicotic smokers. Current smoking and asbestos exposure were associated with these lesions."
749,HPV status and second primary tumours in oropharyngeal squamous cell carcinoma.,"Xu CC, Biron VL, Puttagunta L, Seikaly H.",https://pubmed.ncbi.nlm.nih.gov/23718873/," Studies have shown that these virally mediated tumours are epidemiologically, clinically, and biologically different than other head and neck squamous cell carcinomas and traditional concepts of field cancerization may not apply to HPV-related oropharyngeal cancer.
    


          
    


          Design:
        
      
      Retrospective review.
    


          Setting:
        
      
      Tertiary cancer care centers in Alberta.
    


           HPV-status of tumours was determined by tissue microarray using immunohistochemistry staining for p16.
    


          Primary outcome:
        
      
      incidence of upper aerodigestive tract second primary tumours in p16-positive versus p16-negative OPSCC.
    


          Secondary outcomes:
        
      
      diagnostic yield of traditional field cancerization work-up in p16-positive versus negative patients.
    


          4% (30/406). The incidence rate of SPTs was significantly lower in p16-positive patients (0.7 per 100 patient-yrs vs. 8.5 in p16-negative, p < 0.0001). Field cancerization work-up for synchronous lesions in the upper aerodigestive tract, including panendoscopy and whole-body PET-CT, had decreased diagnostic yield in p16-positive patients (2.8% vs. 10.2% in HPV-negative patients, p=0.02).
    


          Conclusions:
        
      
      Patients with HPV-related OPSCC, who are non-smokers have decreased risk of developing second primary tumours in the upper aerodigestive tract and have low yield on field cancerization work-up. This study provides further evidence that virally mediated OPSCC are distinct and may benefit from alternate diagnostic pathways."
750,Constructal approach to cell membranes transport: Amending the 'Norton-Simon' hypothesis for cancer treatment.,"Lucia U, Ponzetto A, Deisboeck TS.",https://pubmed.ncbi.nlm.nih.gov/26822208/,"To investigate biosystems, we propose a new thermodynamic concept that analyses ion, mass and energy flows across the cell membrane. This paradigm-shifting approach has a wide applicability to medically relevant topics including advancing cancer treatment. To support this claim, we revisit 'Norton-Simon' and evolving it from an already important anti-cancer hypothesis to a thermodynamic theorem in medicine. We confirm that an increase in proliferation and a reduction in apoptosis trigger a maximum of ATP consumption by the tumor cell. Moreover, we find that positive, membrane-crossing ions lead to a decrease in the energy used by the tumor, supporting the notion of their growth inhibitory effect while negative ions apparently increase the cancer's consumption of energy hence reflecting a growth promoting impact. Our  We conclude with providing theoretical evidence that applying electromagnetic field therapy early on in the treatment cycle may maximize its anti-cancer efficacy."
751,Cancer as biographical disruption: constructions of living with cancer.,"Hubbard G, Forbat L.",https://pubmed.ncbi.nlm.nih.gov/22076620/,"Purpose:
        
      
      From a cancer survivor perspective, the purpose of this paper is to explore what has changed in their lives that they attribute to the disease. The rationale for the study is that evidence of the extent to which cancer disrupts people's lives in the longer term is contradictory.
    


           The researchers drew on the concept of biographical disruption as a framework for analysis.
    


           Cancer is constructed as a permanent threat to life which is responsible for increasing their awareness of their own mortality and invoking positive changes to self. These formulations of living with cancer were found across a range of participants, including those who defined themselves as currently free of cancer, those who had recurrence, those who had been diagnosed 5 years ago and those who had been free of cancer for a long time.
    


          Conclusions:
        
      
      This study adds to the body of literature exploring how to enhance supportive care for cancer survivors by reflecting on biographical disruption and continuity, and the complexities within individual constructions of changes in life that they attribute to cancer. Cancer survivors should be given opportunities to articulate the impact of cancer, thus giving legitimate space to talk about cancer's ongoing resonance on life so that problems and difficulties are not dismissed or trivialised."
752,Curcuminoids as Cell Signaling Pathway Modulators: A Potential Strategy for Cancer Prevention.,"Noor A, Shafi S, Sehar N, Qadir I, Bilquees, Rashid S, Arafah A, Rasool S, Dar NJ, Masoodi MH, Rehman MU.",https://pubmed.ncbi.nlm.nih.gov/37559247/,"Despite substantial advancements in curative modern medicine in the last few decades, cancer risk and casualty rates have continued to mount globally. The exact reason for cancer's onset and progression is still unknown. However, skeletal and functional abnormalities in the genetic code are assumed to be the primary cause of cancer. Many lines of evidence reported that some medicinal plants can be utilized to curb cancer cell proliferation with a safe, fruitful, and cost-efficient perspective. Curcuminoid, isolated from Curcuma longa, have gotten a lot of focus due to their anticancer potential as they reduce tumor progression, invasion, and dissemination. Further, they modulated signal transduction routes like MAPK, PI3K/Akt/mTOR, JAK/STAT, and Wnt/β-catenin, etc., and triggered apoptosis as well as actuated autophagy in malignant cells without altering the normal cells, thus preventing cancer progression. Besides, Curcuminoid also regulate the function and expression of anti-tumor and carcinogenic miRNAs. Clinical studies also reported the therapeutic effect of Curcuminoid against various cancer through decreasing specific biomarkers like TNF-α, Bcl-2, COX-2, PGE2, VEGF, IκKβ, and various cytokines like IL-12p70, IL-10, IL-2, IFN-γ levels and increasing in p53 and Bax levels. Thus, in the present review, we abridged the modulation of several signal transduction routes by Curcuminoids in various malignancies, and its modulatory role in the initiation of tumor-suppressive miRNAs and suppression of the oncogenic miRNAs are explored. Additionally, various pharmacokinetic approaches have been projected to address the Curcuminoids bioavailability like the use of piperine as an adjuvant; nanotechnology- based Curcuminoids preparations utilizing Curcuminoids analogues are also discussed."
753,[Tumour genomics: an unstable landscape].,"Moyret-Lalle C, Falette N, Grelier G, Puisieux A.",https://pubmed.ncbi.nlm.nih.gov/19004721/,"Oncogenesis and tumour progression are caused by the progressive accumulation of genetic and epigenetic abnormalities in pre-cancerous and cancerous cells, conferring increased capabilities of proliferation and survival. Recent technological advances, including the development of CGH arrays and high-throughput sequencing, have made it possible to map the genetic landscape of human cancers. Molecular characterisation studies have provided key insights into the disease mechanisms that can be used for the design of tailored therapies and have led to the identification of specific biomarkers for guiding patient management. Nevertheless, the genetic instability of cancer cells and the consecutive intra-tumoral heterogeneity remain critical constraints in the context of the emergence of targeted therapies."
754,Tumor-associated carbohydrate antigens of MUC1 - Implication in cancer development.,Radziejewska I.,https://pubmed.ncbi.nlm.nih.gov/38643541/,"Glycosylation of cancerous epithelial MUC1 protein is specifically altered in comparison to that which is presented by healthy cells. One of such changes is appearing tumor-associated carbohydrate antigens (TACAs) which are rare in normal tissues and are highly correlated with poor clinical outcomes and cancer progression. This review summarizes and describes the role of Tn, T antigens, their sialylated forms as well as fucosylated Lewis epitopes in different aspects of tumor development, progression, and metastasis. Finally, applications of MUC1 glycan epitopes as potential targets for therapeutic strategy of cancers are notified. One of the novelties of this review is presentation of TACAs as inherently connected with MUC1 mucin."
755,Carcinogenic potential of the noncancerous epithelium in patients with oesophageal cancer.,"Maeta M, Koga S, Shimizu N, Inoue Y, Ishiguro M, Sawada T.",https://pubmed.ncbi.nlm.nih.gov/3395816/,"Detailed histopathological examination of serial blocks and subserial sections of the entire resected oesophagus in 63 patients operated upon for oesophageal cancer revealed 11 associated minute superficial cancers, independent and apart from the main tumours, in 10 patients (15.9 per cent). Only one of these eleven lesions was diagnosed preoperatively, and only three of the eleven lesions were detected macroscopically on the resected specimens. The high incidence of such coexisting independent lesions may indicate a possible increased multicentric carcinogenic potential in the non-cancerous epithelium of patients who have had an antecedent oesophageal cancer. These "
756,"[Clinical evaluation of endoscopic therapy for early gastric cancer by diathermic polypectomy, Nd; YAG laser irradiation and heater probe].","Takahashi H, Fujita Y, Seki M, Kousen K, Fujita R, Sugata F, Namatame K, Suzuki K.",https://pubmed.ncbi.nlm.nih.gov/3382217/,"Forty early gastric cancers (37 cases) were treated endoscopically by diathermic polypectomy and Nd; YAG laser irradiation. In 23 cases of protruded early gastric cancer, 16 cases were treated by diathermic polypectomy only, 2 cases by Nd; YAG laser only and 5 cases underwent combination therapy with both procedures. Endoscopic treatment was successful in 20 cases, but surgery was performed in two cases with cancerous invasion or lymph vessel infiltration at their cut ends after polypectomy. Local recurrence occurred in a case of submucosal involvement 6 months after combination therapy. In excavated early gastric cancers, 17 lesions of 14 cases were treated by Nd; YAG laser irradiation. Although 13 lesions disappeared successfully after laser treatment, cancers remained in 3 lesions with submucosal involvement after several irradiations. Local recurrence was experienced in a lesion of poorly differentiated adenocarcinoma three months after treatment. In addition, a heat probe unit for hemostasis was applied for endoscopic treatment of early gastric cancer and found to be effective for cancer of the mucosal layer. Among other early gastric cancers, endoscopic treatment is indicated for differentiated adenocarcinomas which are less than 2 cm in size and confined within the mucosal layer."
757,Expression of MicroRNA in Locoregional Recurrent Rectal Cancer.,"Kotnik N, El-Sourani N, Raap U, Raab HR, Bockhorn M, Meyer H, Troja A.",https://pubmed.ncbi.nlm.nih.gov/32366447/," It is unknown, however, if these regulatory changes also play a role in local recurrent rectal cancers. In this study, the expression of various angiogenetic small non-coding ribonucleic acids, namely miRNA-21, miRNA-215, miRNA-221, and miRNA-222 were analysed in cancerous and healthy rectal tissues.
    


          Patients and  Samples were obtained from 20 patients who were treated for local recurrent rectal cancer at the Department for general and visceral surgery, Klinikum Oldenburg, Germany.
    


           However, a significant differential expression was detected for miRNA-21.
    


          Conclusion:
        
      
      miRNA-21 is differentially expressed in recurrent rectal cancer tissue and healthy tissues. However, miRNA-215, miRNA-221 and miRNA-222 are not significantly differentially expressed."
758,[Advanced therapeutic procedures for head and neck cancer and relation to quality of life].,Sawaki S.,https://pubmed.ncbi.nlm.nih.gov/3415264/,"The advanced therapeutic procedures of the head and neck cancer, which trend the quality of life, were discussed. Among these cancers, those of the maxillary, laryngeal and hypopharyngeal carcinoma were adopted, because more cases suffer from these carcinomas. The laryngectomized person loses his or her voice, because of the deficit of the phoniatric organ, and has many troubles for life. The rehabilitation of speech should be considered important. In order to avoid the troubles for the patient's life, after the primary treatment of the head and neck cancer, it is ideal that the cancer cases can be treated completely with the anti-cancerous chemotherapeutic drugs."
759,"Ductal carcinoma in situ: terminology, classification, and natural history.",Allred DC.,https://pubmed.ncbi.nlm.nih.gov/20956817/,"Ductal carcinoma in situ (DCIS) refers to breast epithelial cells that have become ""cancerous"" but still reside in their normal place in the ducts and lobules. In this setting, cancerous means that there is an abnormal increase in the growth of the epithelial cells, which accumulate within and greatly expand the ducts and lobules. DCIS is a nonlethal type of cancer because it stays in its normal place. However, DCIS is very important because it is the immediate precursor of invasive breast cancers, which are potentially lethal. This article provides a general overview of DCIS, including historical perspective, "
760,"Quadruple cancer, including triple cancers in the head and neck region.","Németh Z, Czigner J, Iván L, Ujpál M, Barabás J, Szabó G.",https://pubmed.ncbi.nlm.nih.gov/12584590/,"Multiple primary tumors are not rare: they are encountered in 3-5% of malignant tumors. They are particularly frequent in the head and neck [20]. They are most often met with secondary malignant tumors; triple tumors occur in only 0.5%, quadruple tumors in 0.3% of malignant tumors. The possibility of developing a second metachronous cancer 5 years after undergoing treatment of the initial head and neck cancer is approximately 22%. Multiple metachronous tumors often appear 3-4 years after the observation of the primary tumor, or even after 5-10 years in the case of laryngeal tumors. The frequency of multiple primary tumors in the head and neck region supports the ""field cancerization"" theory, according to which the inducing agents (primarily smoking and alcohol consumption) can initiate the tumorous degeneration at a number of sites in the oropharyngeal region. The authors report on a case in whom surgery for bladder tumor was followed 101 months later by tumor development in the region of the head and neck: 3 such tumors were treated within a period of 21 months. The histologic  Three of the tumors were treated effectively (no local recurrence or metastasis developed), but the fourth led to the death of the patient. The literature on multiple tumors of the head and neck is reviewed, and possible etiologic factors are discussed. It is pointed out that, besides primary and secondary prevention, close observation of these patients is required, repeated panendoscopy of the upper aerodigestive tract and genetic examinations are recommended."
761,The association of HOTAIR expression with clinicopathological features and prognosis in gastric cancer patients.,"Liu FT, Qiu C, Luo HL, Zhang Y, Xia GF, Hao TF, Zhu PQ.",https://pubmed.ncbi.nlm.nih.gov/26964077/," Overexpression of HOTAIR is associated with the development in gastric cancer.
    


          Evidence acquisition:
        
      
      We collected all relevant articles and explored the association of HOTAIR expression with clinicopathological features and prognosis in patients with gastric cancer. Literature collections were conducted by searching a number of electronic databases (up to November 15, 2015). The meta-analysis was conducted by using RevMan v.5.3 software and Stata SE 12.0.
    


          Evidence synthesis:
        
      
      A total of 832 patients with gastric cancer based on 10 studies were included. The Meta-analysis  In addition, aberrant HOTAIR expression is also significantly associated with the prognosis in gastric cancer patients.
    


          Conclusions:
        
      
      There is an association between HOTAIR expression and clinicopathological features and prognosis in gastric cancer patients. High expression of HOTAIR in cancerous tissue could predict poor clinical outcome in gastric cancer, suggesting HOTAIR abundance may serve as a novel candidate biomarker for the clinical outcome in gastric cancers."
762,Psychosocial issues associated with genetic testing for breast and ovarian cancer risk: an integrative review.,Pasacreta JV.,https://pubmed.ncbi.nlm.nih.gov/14533449/,"The identification of the BRCA1/2 genes, and their possible etiologic relationship with various forms of inherited cancer, has been recognized universally as a cornerstone in the search for cancer's genetic link and has made it possible to identify specific individuals and families who harbor a mutation in one of these predisposition genes. Genetic testing for breast and ovarian cancer susceptibility may pose unanticipated psychological and social problems. Because of the recent availability of predisposition genetic testing, research efforts have begun to investigate factors that may influence an individual's intention to undergo testing and the psychosocial sequelae associated with testing. The purpose of this article is to provide an integrative review of the literature that will delineate what is currently known about the psychosocial issues associated with genetic testing for breast and ovarian cancer risk. Important generalizations from the literature include: (a) a positive test for breast cancer susceptibility may ignite a psychological response similar to the diagnosis of breast cancer itself; (b) there is likely a subset of individuals at increased risk for hereditary breast and ovarian cancer who are also at risk for sustained psychosocial problems; (c) available literature challenges a common notion that only individuals with a positive test  Clinical issues and directions for future research were highlighted."
763,[Reporting of resected colonic carcinomas. Assessment of practices in 8 French counties in 1995].,"Papin F, Maurel J, Grosclaude P, Faivre J, Schaffer P, Arveux P, Dubreuil A, Daurès JP, Menegoz F, Herbert C, Monges G, Launoy G.",https://pubmed.ncbi.nlm.nih.gov/10642621/,"
    


           For each report, the presence of the information requested by the Guidelines was looked for. Three synthetic variables were built: 2 scores and one qualitative at 2 classes. The influence of patients, tumour and health care system's characteristics was analysed on the 3 dependent variables.
    


           In monovariate analysis, scores were significantly influenced by cancer's sub-location, area of patient's residence, surgical center, type of laboratories and pathologist case volume. In multivariate analysis, significant heterogeneity in practices remained between geographical areas. Types of laboratories and pathologist case volume affected differently dependent variables.
    


          Conclusion:
        
      
      This study shows the necessity to assess the practices before consensus because of the impact of pathological forms in therapeutic decisions and variations observed."
764,To screen or not to screen: ongoing debate in the early detection of prostate cancer.,Marroquin JM.,https://pubmed.ncbi.nlm.nih.gov/21278045/,"Debate about the use of prostate-specific antigen (PSA) tests to screen prostate cancer in men is ongoing. Prostate cancer is the most common cancer after skin cancer in men and the second most deadly after lung cancer. An elevated PSA level can lead to this cancer's diagnosis and treatment even before the onset of symptoms. However, other causes also can create a high PSA level, which may lead to men being unnecessarily treated for prostate cancer. This article will shed some light on the issue and discuss prostate cancer screening."
765,Identification of differentially expressed genes in hepatocellular carcinoma and metastatic liver tumors by oligonucleotide expression profiling.,"Tackels-Horne D, Goodman MD, Williams AJ, Wilson DJ, Eskandari T, Vogt LM, Boland JF, Scherf U, Vockley JG.",https://pubmed.ncbi.nlm.nih.gov/11466695/," Global gene expression profiling with microarrays has now offered a powerful tool to measure the changes of thousands of genes in any carcinoma tissues in an effort to identify these key disease-related genes. To compare the gene expression of a primary liver carcinoma, metastatic carcinoma to the liver, and normal liver, the authors analyzed tissue from six primary hepatocellular carcinomas (HCCs), five colorectal adenocarcinoma metastases to the liver, and eight normal livers.
    


           Analyses were performed to determine the consensus pattern of gene expression for primary liver carcinoma, metastatic liver carcinoma, and normal liver tissue and their changes in expression level.
    


           Of note, 7 of the 20 most increased identified known genes previously have been associated with liver carcinoma or other types of cancers. The 13 additional identified genes until now have not previously shown strong association with cancers. Furthermore, the authors identified 42 genes and 24 expressed sequence tags that are expressed at a significant level in both HCC and metastastic tumors, presenting a list of marker genes indicative of cancerous liver tissue.
    


          Conclusions:
        
      
      In this study, genes that can be involved in the production of and maintenance of hepatic carcinomas were identified. These data offer new insight into genes that are potentially important in the pathogenesis of liver carcinoma, as well as additional targets for new strategies for cancer therapy and treatment."
766,Cytokine-mediated crosstalk between cancer stem cells and their inflammatory niche from the colorectal precancerous adenoma stage to the cancerous stage: Mechanisms and clinical implications.,"Cui G, Wang Z, Liu H, Pang Z.",https://pubmed.ncbi.nlm.nih.gov/36466926/,"The majority of colorectal cancers (CRCs) are thought to arise from precancerous adenomas. Upon exposure to diverse microenvironmental factors, precancerous stem cells (pCSCs) undergo complex genetic/molecular changes and gradually progress to form cancer stem cells (CSCs). Accumulative evidence suggests that the pCSC/CSC niche is an inflammatory dominated milieu that contains different cytokines that function as the key communicators between pCSCs/CSCs and their niche and have a decisive role in promoting CRC development, progression, and metastasis. In view of the importance and increasing data about cytokines in modulating pCSCs/CSC stemness properties and their significance in CRC, this review summarizes current new insights of cytokines, such as interleukin (IL)-4, IL-6, IL-8, IL-17A, IL-22, IL-23, IL-33 and interferon (IFN)-γ, involving in the modulation of pCSC/CSC properties and features in precancerous and cancerous lesions and discusses the possible mechanisms of adenoma progression to CRCs and their therapeutic potential."
767,Anticancer drugs: How to select small molecule combinations?,"Nussinov R, Yavuz BR, Jang H.",https://pubmed.ncbi.nlm.nih.gov/38782689/,"Small molecules are at the forefront of anticancer therapies. Successive treatments with single molecules incur drug resistance, calling for combination. Here, we explore the tough choices oncologists face - not just which drugs to use but also the best treatment plans, based on factors such as target proteins, pathways, and gene expression. We consider the reality of cancer's disruption of normal cellular processes, highlighting why it's crucial to understand the ins and outs of current treatment  The discussion on using combination drug therapies to target multiple pathways sheds light on a promising approach while also acknowledging the hurdles that come with it, such as dealing with pathway crosstalk. We review options and provide examples and the mechanistic basis, altogether providing the first comprehensive guide to combinatorial therapy selection."
768,"Cytologic, histologic and clinical correlations of precancerous and cancerous oral lesions in 57,518 industrial workers of Gujarat, India.","Silverman Sol, Bilimoria KF, Bhargava K, Mani NJ, Shah RA.",https://pubmed.ncbi.nlm.nih.gov/266329/,"A group of 57,518 industrial workers of Gujarat, India were screened for oral cancerous and precancerous oral lesions between 1967 and 1971. All subjects were 35 years of age or older and 95 per cent were males. The 27,841 oral lesions found were examined by cytologic scrapings and 13,230 were biopsied. Also, all lesions were followed clinically to assure a malignancy was not overlooked. There were 51 oral cancers diagnosed (.18% of the lesions and .09% of the entire study group). Computing all the cytologic smears, there was an overall accuracy exceeding 99 per cent. When assessing just the malignancies, the accuracy decreased to 80.4 per cent. Since there was a high degree of clinical suspicion on the part of the screeners, only one unsuspected cancer was discovered by cytology. There were four false positive interpretations; and 53 other specimens classified as ""suspicious"" subsequently were shown to be benign. Although exfoliative cytology has proved useful in assessing oral lesions as an adjunct to biopsy, the low frequency of oral cancer limits the value of this technique as a screening modality. Most false negatives have been associated with leukoplakic (hyperkeratotic) lesions. Therefore, in a persistent oral lesion, even though a cytologic scraping may not be suspicious or characteristic of malignancy, a biopsy should still be strongly considered."
769,Clinicopathologic implications of genetic instability in intestinal-type gastric cancer and intestinal metaplasia as a precancerous lesion: proof of field cancerization in the stomach.,"Zaky AH, Watari J, Tanabe H, Sato R, Moriichi K, Tanaka A, Maemoto A, Fujiya M, Ashida T, Kohgo Y.",https://pubmed.ncbi.nlm.nih.gov/18343789/,"To clarify field cancerization in the stomach by genetic alterations, we studied 83 cases of intestinal-type gastric cancer (GC) and paired intestinal metaplasia (IM) distant from GC and 39 cases of chronic gastritis with IM (CG-IM) for genetic instability (GIN). Microsatellite instability (MSI) and loss of heterozygosity (LOH) were evaluated at 5 microsatellite loci. The incidence of GIN was 21% (8/39) in CG-IM, 48% (40/83) in GC-IM, and 65% (54/83) in GC and showed a significant difference among these 3 categories. By tumor location, MSI showed the highest incidence in GC and GC-IM with the tumor located in the upper third of the stomach. GIN in GC and GC-IM significantly increased with the progression of tumor invasion from mucosal to advanced cancer. GIN, especially LOH, was more frequently detected in cases with vs without lymphatic or vascular invasion and lymph node involvement in GC and GC-IM. The GIN of GC and GC-IM was significantly similar in relation to clinicopathologic features. Biologic detection of GIN in IM may be a surrogate marker for GC risk and for clinical evaluation of malignant potential. The condition is consistent with the hypothesis of field cancerization in the stomach."
770,Common cancer biomarkers.,"Basil CF, Zhao Y, Zavaglia K, Jin P, Panelli MC, Voiculescu S, Mandruzzato S, Lee HM, Seliger B, Freedman RS, Taylor PR, Hu N, Zanovello P, Marincola FM, Wang E.",https://pubmed.ncbi.nlm.nih.gov/16540643/,"There is an increasing interest in complementing conventional histopathologic evaluation with molecular tools that could increase the sensitivity and specificity of cancer staging for diagnostic and prognostic purposes. This study strove to identify cancer-specific markers for the molecular detection of a broad range of cancer types. We used 373 archival samples inclusive of normal tissues of various lineages and benign or malignant tumors (predominantly colon, melanoma, ovarian, and esophageal cancers). All samples were processed identically and cohybridized with an identical reference RNA source to a custom-made cDNA array platform. The database was split into training (n = 201) and comparable prediction (n = 172) sets. Leave-one-out cross-validation and gene pairing analysis identified putative cancer biomarkers overexpressed by malignant lesions independent of tissue of derivation. In particular, seven gene pairs were identified with high predictive power (87%) in segregating malignant from benign lesions. Receiver operator characteristic curves based on the same genes could segregate malignant from benign tissues with 94% accuracy. The relevance of this study rests on the identification of a restricted number of biomarkers ubiquitously expressed by cancers of distinct histology. This has not been done before. These biomarkers could be used broadly to increase the sensitivity and accuracy of cancer staging and early detection of locoregional or systemic recurrence. Their selective expression by cancerous compared with paired normal tissues suggests an association with the oncogenic process "
771,mda-7/IL-24: exploiting cancer's Achilles' heel.,"Lebedeva IV, Sauane M, Gopalkrishnan RV, Sarkar D, Su ZZ, Gupta P, Nemunaitis J, Cunningham C, Yacoub A, Dent P, Fisher PB.",https://pubmed.ncbi.nlm.nih.gov/15585401/,"The mda-7/IL-24 cDNA was isolated almost a decade ago in a screen for genes differentially upregulated following growth arrest and terminal differentiation of a human melanoma cell line employed as an in vitro cell differentiation model. The underlying rationale for the screen was that oncogenesis arises from a cellular dedifferentiation process culminating in uncontrolled proliferation and acquisition of invasive and metastatic potential. Identification of genes upregulated during the process of reactivation of faulty or inoperational differentiation maintenance programs was postulated to have cancer gene therapeutic potential. In this context, it is heartening to note that mda-7/IL-24 has made a  Extensive in vitro and in vivo human tumor xenograft studies have established its transformed cell apoptosis-inducing capacity in various model systems. It has recently taken an important step for a candidate cancer gene therapeutic molecule, in the ultimate goal of benchtop to clinic, by being currently utilized in human Phase I/II clinical trials. This review provides a current perspective of our understanding of mda-7/IL-24, including established and more recent information about the molecular properties, specificity of anti-tumor-cell apoptosis-inducing activity, and underlying mechanisms of this action relative to its cancer gene therapeutic potential."
772,Roles of the Exosomes Derived From Myeloid-Derived Suppressor Cells in Tumor Immunity and Cancer Progression.,"Chen Z, Yuan R, Hu S, Yuan W, Sun Z.",https://pubmed.ncbi.nlm.nih.gov/35154134/,"Tumor immunity is involved in malignant tumor progression. Myeloid-derived suppressor cells (MDSCs) play an irreplaceable role in tumor immunity. MDSCs are composed of immature myeloid cells and exhibit obvious immunomodulatory functions. Exosomes released by MDSCs (MDSCs-Exos) have similar effects to parental MDSCs in regulating tumor immunity. In this review, we provided a comprehensive description of the characteristics, functions and mechanisms of exosomes. We analyzed the immunosuppressive, angiogenesis and metastatic effects of MDSCs-Exos in different tumors through multiple perspectives. Immunotherapy targeting MDSCs-Exos has demonstrated great potential in cancers and non-cancerous diseases."
773,Upregulation of URI/RMP gene expression in cervical cancer by high-throughput tissue microarray analysis.,"Gu J, Li X, Liang Y, Qiao L, Ran D, Lu Y, Li X, Wei W, Zheng Q.",https://pubmed.ncbi.nlm.nih.gov/23573313/,"URI, or RMP, is a RNA polymerase II subunit RPB5-associated protein known to play essential roles in ubiquitination and transcription. Recently, we and others have shown that URI/RMP is also important for progression of hepatocellular carcinoma, ovarian, and prostate cancers. To identify the mechanistic basis of URI/RMP during multiple cellular processes, we investigated URI/RMP expression in a tissue microarray (TMA) containing multiple normal human tissues. The  To elucidate the role of URI/RMP during oncogenesis of multiple malignancies, especially the tumors of reproductive system, we analyzed URI/RMP expression in a TMA containing multiple reproductive system tumors. We did not observe significant difference of URI/RMP expression between cancerous and adjacent tissues of the prostate, breast, ovarian, and endometrial cancers. However, increased URI/RMP expression was observed in two of the three cases of cervical SCC (squamous cell carcinoma) cells compared to their adjacent epithelial cells. Moreover, we detected significantly upregulated URI/RMP expression not only in cervical cancers but also in pre-cancerous CINs (cervical intra-epithelial neoplasias) in a TMA that covers the whole spectrum of normal cervix, CINs, and cervical cancers. No difference of URI/RMP expression was observed between CINs and cervical cancers. Given the high risk of CINs (especially CIN3) turning into cervical cancer if left untreated, the increased URI/RMP expression in CINs as well as in cervical cancers suggest a clinical relevance of URI/RMP upon cervical cancer tumorigenesis and worth further investigation."
774,"Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century.","Williams SA, Anderson WC, Santaguida MT, Dylla SJ.",https://pubmed.ncbi.nlm.nih.gov/23917877/,"Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer's secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer."
775,LINC00958 regulated miR-627-5p/YBX2 axis to facilitate cell proliferation and migration in oral squamous cell carcinoma.,"Chen F, Liu M, Yu Y, Sun Y, Li J, Hu W, Wang X, Tong D.",https://pubmed.ncbi.nlm.nih.gov/31161900/,"Oral squamous cell carcinoma (OSCC), the subtype of head and neck cancers, is notorious for its high incidence and death rate. The role of long non-coding RNAs (lncRNAs) is discovered to be significant for the canceration and cancer progression. Long intergenic non-protein coding RNA 958 (LINC00958) is discovered as a carcinogene in multiple cancers, such as gastric cancer, pancreatic cancer, and glioma, but there has been no report about how LINC00958 functions in OSCC. The  First, TCGA database showed the upregulation and prognostic significance of LINC00958 in head and neck squamous carcinoma. Then, we discovered in OSCC clinical samples that LINC00958 presented high expression and predicted poor prognosis. Also, LINC00958 was elevated in OSCC cells. In vitro gain- and loss-function  Mechanistically, we confirmed the cytoplasmic expression of LINC00958 in OSCC cells, and revealed that LINC00958 sequestered miR-627-5p to upregulate YBX2 expression. Rescue assays indicated that LINC00958 regulated OSCC cell proliferation, motility and EMT through YBX2. Together, we showed that LINC00958 promoted OSCC progression through miR-627-5p/YBX2 axis, indicating LINC00958 as a new prognostic marker, and provided new perspectives for molecular targeted treatment for OSCC."
776,Spotlight on the relevance of mtDNA in cancer.,"Cruz-Bermúdez A, Vicente-Blanco RJ, Gonzalez-Vioque E, Provencio M, Fernández-Moreno MÁ, Garesse R.",https://pubmed.ncbi.nlm.nih.gov/27778302/,"The potential role of the mitochondrial genome has recently attracted interest because of its high mutation frequency in tumors. Different aspects of mtDNA make it relevant for cancer's biology, such as it encodes a limited but essential number of genes for OXPHOS biogenesis, it is particularly susceptible to mutations, and its copy number can vary. Moreover, most ROS in mitochondria are produced by the electron transport chain. These characteristics place the mtDNA in the center of multiple signaling pathways, known as mitochondrial retrograde signaling, which modifies numerous key processes in cancer. Cybrid studies support that mtDNA mutations are relevant and exert their effect through a modification of OXPHOS function and ROS production. However, there is still much controversy regarding the clinical relevance of mtDNA mutations. New studies should focus more on OXPHOS dysfunction associated with a specific mutational signature rather than the presence of mutations in the mtDNA."
777,Clinical performance indicators for monitoring the management of cutaneous melanoma: a population-based perspective.,"Buja A, Rugge M, De Luca G, Zorzi M, Cozzolino C, Vecchiato A, Del Fiore P, Tropea S, Bortolami A, Benini P, Rossi CR, Mocellin S.",https://pubmed.ncbi.nlm.nih.gov/35855661/,"The prognosis of cutaneous malignant melanoma (CMM) is based on disease progression. The highly heterogeneous clinical-pathological characteristics of CMM necessitate standardized diagnostic and therapeutic interventions tailored to cancer's stage. This study utilizes clinical performance indicators to assess the quality of CMM care in Veneto (Northeast Italy). This population-based study focuses on all incidences of CMMs registered by the Veneto Cancer Registry in 2015 (1279 patients) and 2017 (1368 patients). An interdisciplinary panel of experts formulated a set of quality-monitoring indicators for diagnostic, therapeutic, and end-of-life clinical interventions for CMM. The quality of clinical care for patients was assessed by comparing the reference thresholds established by experts to the actual values obtained in clinical practice. The prevalence of stage I-CMM decreased significantly from 2015 to 2017 (from 71.8 to 62.4%; P < 0.001), and almost all the pathology reports mentioned the number of nodes dissected during a lymphadenectomy. More than 90% of advanced CMMs were promptly tested for molecular BRAF status, but the proportion of patients given targeted therapies fell short of the desired threshold (61.1%). The proportion of stage I-IIA CMM patients who inappropriately underwent computerized tomography/MRI/PET dropped from 17.4 to 3.3% ( P < 0.001). Less than 2% of patients received medical or surgical anticancer therapies in the month preceding their death. In the investigated regional context, CMM care exhibited both strengths and weaknesses. The evaluated clinical indicators shed essential insight on the clinical procedures requiring corrective action. It is crucial to monitor clinical care indicators to improve care for cancer patients and promote the sustainability of the healthcare system."
778,Molecular Processes Exploited as Drug Targets for Cancer Chemotherapy.,"Gupta SP, Sharma A, Patil VM.",https://pubmed.ncbi.nlm.nih.gov/33208079/,"Cancer is an uncontrolled malignant tumor growth taking place in any tissue of the body and attains complex diversity which makes it difficult for oncologists to choose therapeutics. The changes leading to formation of cancerous cells occur due to a series of molecular events. Now scientists are trying to understand the various molecular processes that are involved in the growth of cancers. This article presents a brief account of epigenetics with reference to DNA methylation and histone modification as an important contributor to the formation of cancer cells. Drug targeting the epigenetic regulators has been considered for various types of cancer. The enzymes in DNA methylation and histone modification, FDA approved clinical drugs along with the challenges associated with the development of anti-cancer target based therapeutics are summarized."
779,Metabolic Codependencies in the Tumor Microenvironment.,"Dey P, Kimmelman AC, DePinho RA.",https://pubmed.ncbi.nlm.nih.gov/33504580/,"Metabolic reprogramming enables cancer cell growth, proliferation, and survival. This reprogramming is driven by the combined actions of oncogenic alterations in cancer cells and host cell factors acting on cancer cells in the tumor microenvironment. Cancer cell-intrinsic mechanisms activate signal transduction components that either directly enhance metabolic enzyme activity or upregulate transcription factors that in turn increase expression of metabolic regulators. Extrinsic signaling mechanisms involve host-derived factors that further promote and amplify metabolic reprogramming in cancer cells. This review describes intrinsic and extrinsic mechanisms driving cancer metabolism in the tumor microenvironment and how such mechanisms may be targeted therapeutically. SIGNIFICANCE: Cancer cell metabolic reprogramming is a consequence of the converging signals originating from both intrinsic and extrinsic factors. Intrinsic signaling maintains the baseline metabolic state, whereas extrinsic signals fine-tune the metabolic processes based on the availability of metabolites and the requirements of the cells. Therefore, successful targeting of metabolic pathways will require a nuanced approach based on the cancer's genotype, tumor microenvironment composition, and tissue location."
781,[Changes in bone marrow cellularity close to cancer metastases. Cyto-histologic study].,"Henon P, Marsan C, Gerota I, Zitouna M, Palacios S.",https://pubmed.ncbi.nlm.nih.gov/188149/,"Before starting any therapy, we systematically studied by biopsy the bone marrow of 66 patients suffering from various cancers and suspect of marrow metastasis. Metastatic cells were thus found in 45 patients. Bone marrow composition was examined on histologic sections by granulometric  It then appeared that any important metastatic invasion goes together with deep alterations of the surrounding hematopoietic tissue, with frequent peri-metastatic collagenic fibrosis and hypoplasia of the various cell-lines; when metastatic growth is still moderate, hematopoietic tissue is, on the contrary, often hyperplastic, ""irritative"". These marrow alterations are not to be found far from the metastasis, and thus seem to be directly linked to the actual presence of cancerous cells."
782,"Illness appraisal, religious coping, and psychological responses in men with advanced cancer.","Rand KL, Cripe LD, Monahan PO, Tong Y, Schmidt K, Rawl SM.",https://pubmed.ncbi.nlm.nih.gov/21927993/,"Purpose:
        
      
      Patients experience diverse psychological responses to cancer. Appraisals and coping have been shown to predict psychological responses to stressors. For men with advanced cancer, appraisal of cancer's impact on their lives (illness appraisal) and religious coping may be particularly important predictors of psychological responses. We examined the relationships among illness appraisal, religious coping, and positive and negative psychological responses while controlling for disease and patient characteristics.
    


           Treating oncologists completed questions about disease status and estimated the chances of the patient surviving 6 months.
    


          20), illness appraisal (β = -0.48), and negative religious coping (β = 0.24). Negative mental adjustment was predicted by prognosis (β = -0.23) and illness appraisal (β = -0.57). Positive mental adjustment was predicted by illness appraisal (β = 0.46) and positive religious coping (β = 0.29). Posttraumatic growth was predicted by positive religious coping (β = 0.49).
    


          Conclusions:
        
      
      Illness appraisal was more consistently associated with psychological responses to advanced cancer than patient or disease characteristics. Consequently, helping patients with their illness appraisals may be effective for improving patient psychological well-being."
783,Epigenetic perspective into head and neck cancer through in silico gene expression profiling of histone lysine methyltransferases.,"Biron VL, Dort JC.",https://pubmed.ncbi.nlm.nih.gov/19128641/,"
    


          Design:
        
      
      Gene expression profiles from histone lysine methyltransferases (HKMTases) were obtained from UniGene expressed sequence tags (ESTs). HKMTase expression levels in respective tissues were analyzed for elevated expression or altered levels of normal versus human cancers.
    


          Setting:
        
      
      UniGene EST data were derived from normal and cancerous human tissues submitted to UniGene.
    


           An analysis of expression levels was carried out to identify HKMTases with tissue-specific expression and alteration in head and neck cancer.
    


          Main outcome measures:
        
      
      Expression levels of HKMTases in normal and cancerous tissues of the head and neck in comparison with other anatomic sites.
    


           In all five head and neck cancers, we identified HKMTases specifically elevated in these tumours. In addition, we identitified HKMTases with altered expression in tumour versus normal head and neck tissues.
    


          Conclusions:
        
      
      Normal head and neck tissues have unique epigenetic profiles demarcated by distinct HKMTase gene expression. We identified HKMTases as potentially tissue-specific epigenetic regulators of the head and neck, which could behave as oncogenes or tumour suppressor genes important in malignant transformation of these tissues."
784,The psychological impact of a cancer diagnosed during pregnancy: determinants of long-term distress.,"Henry M, Huang LN, Sproule BJ, Cardonick EH.",https://pubmed.ncbi.nlm.nih.gov/21370310/," Although a newly diagnosed cancer is associated with substantial distress, little is known about cancer's emotional impact on women when diagnosed during pregnancy, and no studies have been conducted on the subject.
    


           Cardonick MD, specialist in Maternal and Fetal Medicine and Associate Professor of Obstetrics and Gynecology at Robert Wood Johnson Medical School, to examine the consequences of maternal cancer diagnosis and treatment during pregnancy on maternal, fetal, and neonatal outcomes, including the impact of in utero exposure to chemotherapy.
    


          
    


          8 years (SD 2.5) following their cancer diagnosis. Potential variables related to distress included information on: sociodemographics, disease, pregnancy, birth, cancer treatment, and health status. Multiple regression analyses revealed that women were at higher risk of long-term distress if they had not received fertility assistance, had been advised to terminate the pregnancy, had had a preterm baby, had had a cesarean delivery, had not produced sufficient milk to breastfeed, had been experiencing a recurrence, and/or had undergone surgery post-pregnancy.
    


          Conclusion:
        
      
      "
785,Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract.,"Takahashi T, Habuchi T, Kakehi Y, Mitsumori K, Akao T, Terachi T, Yoshida O.",https://pubmed.ncbi.nlm.nih.gov/9865743/,"Recent molecular genetic studies have suggested that multifocal urothelial cancers are derived from an identical progenitor cell. However, the clonal origin of multifocal urothelial cancers of a low-grade superficial type has not been fully defined. Using microsatellite markers, we examined genetic alterations at 20 loci on eight chromosomal arms (2q, 4p, 4q, 8p, 9p, 9q, 11p, and 17p) in 87 metachronous and/or synchronous multifocal urothelial cancers, which included 84 low-grade superficial papillary tumors from 29 patients. Judging from the patterns of loss of heterozygosity, microsatellite shifts, and the subchromosomal partial deletion, multifocal tumors in at least 20 (80%) of the 25 evaluable patients were considered to be derived from a single progenitor cell, although the possibility remained that multifocal tumors in a small subset of patients might develop from distinct progenitor cells due to field cancerization. In 13 of the 20 patients, a chronological genetic analysis was available: genetic heterogeneity was detected in 3 (23%) patients, and an apparent accumulated pattern of genetic alterations was detected in only 1 (8%) patient. In the 20 patients with multifocal tumors of an identical clonal origin, discordant microsatellite alterations were observed, with significantly lower frequencies on chromosome 9 compared to those on the other chromosomes tested. The  This heterotopic spread and genetic divergence may occur long before the clinical manifestation of multiplicity from a single transformed cell. These data support the previous view that heterotopic spread of transformed progenitor cells and genetic divergence occur after chromosome 9 alterations in most of low-grade superficial urothelial cancers."
786,N-acetylgalactosaminyltransferases in cancer.,"Hussain MR, Hoessli DC, Fang M.",https://pubmed.ncbi.nlm.nih.gov/27322213/,"Aberrant mucin-type O-glycosylation by glycosyltransferases is a well-described hallmark of many cancers and is also associated with additional non-cancerous developmental and metabolic disorders. The current review focuses on N-acetylgalactosaminyltransferase genes (GALNTs) and proteins (GalNAcTs) to illustrate their importance in cancer biology. Aberrant O-glycosylation by GalNAcTs activates a wide range of proteins that carry out interactions of sessile and motile cells affecting organogenesis, responses to agonists and stimulating hyperproliferation and metastatisation of neoplastic cells. As genome-wide analyses have provided abundant clues regarding under- or over-expressed genes that characterize different types of cancers, GALNTs and their transferase products have attracted attention by being unexpected actors in neoplastic contexts. We intend to review the current knowledge on GALNTs and their encoded transferases in cancer and suggest what could be the significance of such information in cancer pathogenesis and management."
787,Magnetic fluid-modeled microgravity: a novel way to treat tumor.,"Chen J, Yan Z, Liu R, Wang N, Li J, Wang Z.",https://pubmed.ncbi.nlm.nih.gov/21996162/,"With the advances of nanotechnology in recent years, our understanding of the therapy of cancers has deepened and the development of new technologies for cancer diseases has emerged. Here, with the recent discoveries of nanomagnetic fluids as well as microgravity effects upon cancerous cells, we suggest an innovative  Magnetic fluids are delivered by outside magnetic field to tumor issue either intravenously or through direct injection, and this is followed by application of an uniform external magnetic field that causes microgravity. The modeled microgravity is to inhibit cancerous cells growth and invasion."
788,A Review of Cell-Based Computational Modeling in Cancer Biology.,"Metzcar J, Wang Y, Heiland R, Macklin P.",https://pubmed.ncbi.nlm.nih.gov/30715927/,"Cancer biology involves complex, dynamic interactions between cancer cells and their tissue microenvironments. Single-cell effects are critical drivers of clinical progression. Chemical and mechanical communication between tumor and stromal cells can co-opt normal physiologic processes to promote growth and invasion. Cancer cell heterogeneity increases cancer's ability to test strategies to adapt to microenvironmental stresses. Hypoxia and treatment can select for cancer stem cells and drive invasion and resistance. Cell-based computational models (also known as discrete models, agent-based models, or individual-based models) simulate individual cells as they interact in virtual tissues, which allows us to explore how single-cell behaviors lead to the dynamics we observe and work to control in cancer systems. In this review, we introduce the broad range of techniques available for cell-based computational modeling. The approaches can range from highly detailed models of just a few cells and their morphologies to millions of simpler cells in three-dimensional tissues. Modeling individual cells allows us to directly translate biologic observations into simulation rules. In many cases, individual cell agents include molecular-scale models. Most models also simulate the transport of oxygen, drugs, and growth factors, which allow us to link cancer development to microenvironmental conditions. We illustrate these  An ecosystem of interoperable cell-based simulation tools is emerging at a time when cloud computing resources make software easier to access and supercomputing resources make large-scale simulation studies possible. As the field develops, we anticipate that high-throughput simulation studies will allow us to rapidly explore the space of biologic possibilities, prescreen new therapeutic strategies, and even re-engineer tumor and stromal cells to bring cancer systems under control."
789,Aneuploidy in pluripotent stem cells and implications for cancerous transformation.,"Na J, Baker D, Zhang J, Andrews PW, Barbaric I.",https://pubmed.ncbi.nlm.nih.gov/24899134/,"Owing to a unique set of attributes, human pluripotent stem cells (hPSCs) have emerged as a promising cell source for regenerative medicine, disease modeling and drug discovery. Assurance of genetic stability over long term maintenance of hPSCs is pivotal in this endeavor, but hPSCs can adapt to life in culture by acquiring non-random genetic changes that render them more robust and easier to grow. In separate studies between 12.5% and 34% of hPSC lines were found to acquire chromosome abnormalities over time, with the incidence increasing with passage number. The predominant genetic changes found in hPSC lines involve changes in chromosome number and structure (particularly of chromosomes 1, 12, 17 and 20), reminiscent of the changes observed in cancer cells. In this review, we summarize current knowledge on the causes and consequences of aneuploidy in hPSCs and highlight the potential links with genetic changes observed in human cancers and early embryos. We point to the need for comprehensive characterization of mechanisms underpinning both the acquisition of chromosomal abnormalities and selection pressures, which allow mutations to persist in hPSC cultures. Elucidation of these mechanisms will help to design culture conditions that minimize the appearance of aneuploid hPSCs. Moreover, aneuploidy in hPSCs may provide a unique platform to analyse the driving forces behind the genome evolution that may eventually lead to cancerous transformation."
790,[Descriptive epidemiology of cancers in Cote d'Ivoire].,"Effi AB, Koffi KE, Aman NA, Doukouré B, N'dah KJ, Koffi KD, Kouyaté M, Koui BB, Hondé M, Diomandé MI.",https://pubmed.ncbi.nlm.nih.gov/23406565/,"The cancerous disease is a real pain in developed countries due to the ageing of the population. According to the World Report Cancer in 2000, cancer tends to be a major problem of public health in the developing nations. This study research aimed at describing the epidemiological features of cancers in Cote d'Ivoire. It is a 26-year retrospective and descriptive study focusing on all cancers confirmed histologically by using the data from the registers of Anatomic Pathology laboratory of Abidjan teaching hospitals. The parameters of the study were frequency, age, sex, site and histological type. We obtained 12,841 cancers within patients aged from 2 months to 107 years old along with 51.26-year median age and 0.9 as sex-ratio. The most important cancer locations are cervix (17.41%) followed by skin (15.81%), prostate (7.73%), breast (6.88%), and stomach (6.09%). With women, the median age was 49.23 years, and the most common cancers were cervical cancer (33.25%) followed by breast cancer (12.44%) and skin cancer (10.50%). With men, the median age was 53.95 years, and the most frequent cancers were skin cancer (21.29%) followed by prostate cancer (15.69%) and stomach cancer (8.71%). Burkitt lymphoma (33.95%), retinoblastoma (10.92%) and nephroblastoma (5.88%) are the most important cancers in children. Cancers are frequent in Cote d'Ivoire. Cervical cancer, skin cancer, and prostate are updated problems with a worse prognosis. Therefore, the screening and the early diagnosis remain the best conditions to improve the prognosis of cancer."
791,"Causal attributions, coping strategies, and adjustment to breast cancer.","Lavery JF, Clarke VA.",https://pubmed.ncbi.nlm.nih.gov/8904383/,"In this retrospective questionnaire study of a convenience sample of 244 Australian women, type of causal attributions and their impact on coping strategies adopted by women with breast cancer were studied in relation to women's adjustment to their illness. Although 70% of the women made attributions about their cancer's origins, these women were not significantly better adjusted than women who had not make an attribution. Of those women who had made a causal attribution, type of attribution, whether controllable or uncontrollable (based on perceptions as to the controllability/uncontrollability of the cause of the disease), determined the extent to which exhibited information-seeking behavior. In the present study, women who perceived the cause of their cancer as emanating from uncontrollable circumstances were more active in seeking information about breast cancer than women who perceived the cause of their cancer as emanating from controllable circumstances. Different types of coping strategies adopted by women were associated with adjustment. Women who rated their adjustment as excellent displayed lower levels of helplessness, made fewer changes to their social behavior, were more anxiously preoccupied with their illness, sought more alternatives to medical therapy, and exhibited more information-seeking behavior than did their less-well-adjusted counterparts. The theoretical and practical implications of these "
792,Multiplexed imaging and effluent analysis to monitor cancer cell intravasation using a colorectal cancer-on-chip.,"Strelez C, Ghaffarian K, Mumenthaler SM.",https://pubmed.ncbi.nlm.nih.gov/34927093/,"Despite colorectal cancer's (CRC) prevalence, its progression is not well understood. The microfluidic organ-on-chip (OOC) model described herein recreates the epithelial-endothelial tissue-tissue interface, fluid flow, and mechanical forces that exist in vivo , making it an attractive model to understand and ultimately disrupt CRC intravasation. This protocol provides step-by-step details for tumor cell seeding to create a CRC-on-chip model, chip effluent collection and analysis, and on-chip imaging to monitor tumor cell invasion within a more physiologically relevant microenvironment. For complete details on the use and execution of this protocol, please refer to Strelez et al. (2021)."
793,Molecular imaging of cancer: MR spectroscopy and beyond.,"Pinker K, Stadlbauer A, Bogner W, Gruber S, Helbich TH.",https://pubmed.ncbi.nlm.nih.gov/20554145/,"Proton magnetic resonance spectroscopic imaging is a non-invasive diagnostic tool for the investigation of cancer metabolism. As an adjunct to morphologic and dynamic magnetic resonance imaging, it is routinely used for the staging, assessment of treatment response, and therapy monitoring in brain, breast, and prostate cancer. Recently, its application was extended to other cancerous diseases, such as malignant soft-tissue tumours, gastrointestinal and gynecological cancers, as well as nodal metastasis. In this review, we discuss the current and evolving clinical applications of proton magnetic resonance spectroscopic imaging. In addition, we will briefly discuss other evolving techniques, such as phosphorus magnetic resonance spectroscopic imaging, sodium imaging and diffusion-weighted imaging in cancer assessment."
794,Comprehensive prognostic and immunological analysis of Cullin2 in pan-cancer and its identification in hepatocellular carcinoma.,"Jia L, Zhang X, Zhou T, Xie J, Jin J, Zhang D, Zhu C, Wan R.",https://pubmed.ncbi.nlm.nih.gov/38787355/," However, the precise role of CUL2 in human cancer remains largely elusive.
    


           Kaplan-Meier and Spearman correlation analyses were employed to investigate the potential links between CUL2 level, patient prognosis, and the infiltration of immune cells. In addition, the association between CUL2 and the efficacy of immunotherapy in an immunotherapy cohort was investigated. Moreover, the expression and distribution of CUL2 in cells were observed using the Human Protein Atlas (THPA) database. Finally, clinical tissue specimens and in vitro function assays were conducted to validate the expressions and effects of CUL2 on the biological functions in hepatocellular carcinoma (HCC) cells.
    


           In addition, CUL2 gene mutations are common in multiple cancers with low mutation rates and CUL2 is closely related to the prognosis of some cancer's patients, some immune regulatory factors, TMB, MSI, MMR genes, and DNA methylation. Further, our 
    


          Conclusions:
        
      
      The expression of CUL2 has an impact on the prognosis of various tumors, and this correlation is particularly noteworthy due to its significant association with the infiltration of immune cells within tumors. CUL2 was an oncogene contributing to the progression of HCC."
795,"European guidelines for topical photodynamic therapy part 2: emerging indications--field cancerization, photorejuvenation and inflammatory/infective dermatoses.","Morton CA, Szeimies RM, Sidoroff A, Braathen LR.",https://pubmed.ncbi.nlm.nih.gov/23181556/,"In addition to established indications in non-melanoma skin cancer in immunocompetent patients, photodynamic therapy (PDT) has been studied for the treatment, and possible prevention, of superficial skin cancers in immunosuppressed patients. As a topical photosensitizer can be applied over large areas, PDT is also increasingly used for field cancerization in photodamaged skin, with evidence of potential to delay the development of actinic keratoses and basal cell carcinoma, although direct evidence of prevention of invasive squamous cell carcinoma remains limited. PDT has been studied in patch/plaque-stage cutaneous T-cell lymphoma, with efficacy more likely in unilesional disease. Accumulating evidence supports the use of PDT in acne and several other inflammatory/infective dermatoses including cutaneous leishmaniasis, although protocols are still to be refined. Despite proven efficacy, PDT is not widely used in viral/genital warts, where pain during treatment can be intense. PDT is a therapeutic option for photorejuvenation, with improvement in fine wrinkles, mottled hyperpigmentation, roughness and sallowness reported."
796,Maximum tolerated dose versus metronomic scheduling in the treatment of metastatic cancers.,"Benzekry S, Hahnfeldt P.",https://pubmed.ncbi.nlm.nih.gov/23850479/,"Although optimal control theory has been used for the theoretical study of anti-cancerous drugs scheduling optimization, with the aim of reducing the primary tumor volume, the effect on metastases is often ignored. Here, we use a previously published model for metastatic development to define an optimal control problem at the scale of the entire organism of the patient. In silico study of the impact of different scheduling strategies for anti-angiogenic and cytotoxic agents (either in monotherapy or in combination) is performed to compare a low-dose, continuous, metronomic administration scheme with a more classical maximum tolerated dose schedule. Simulation "
797,Cancer proteomics by quantitative shotgun proteomics.,"Chen EI, Yates JR 3rd.",https://pubmed.ncbi.nlm.nih.gov/18443658/,"A major scientific challenge at the present time for cancer research is the determination of the underlying biological basis for cancer development. It is further complicated by the heterogeneity of cancer's origin. Understanding the molecular basis of cancer requires studying the dynamic and spatial interactions among proteins in cells, signaling events among cancer cells, and interactions between the cancer cells and the tumor microenvironment. Recently, it has been proposed that large-scale protein expression analysis of cancer cell proteomes promises to be valuable for investigating mechanisms of cancer transformation. Advances in mass spectrometry technologies and bioinformatics tools provide a tremendous opportunity to qualitatively and quantitatively interrogate dynamic protein-protein interactions and differential regulation of cellular signaling pathways associated with tumor development. In this review, progress in shotgun proteomics technologies for examining the molecular basis of cancer development will be presented and discussed."
798,The implications of cancer survivorship for spousal employment.,"Hollenbeak CS, Short PF, Moran J.",https://pubmed.ncbi.nlm.nih.gov/21369843/,"
    


           Comparable spouses of individuals without cancer were drawn from the Panel Survey of Income Dynamics. The final sample included 827 spouses of cancer survivors (542 husbands, 285 wives) and 2,766 spouses of individuals without cancer (1,459 husbands, 1,307 wives). Three employment outcomes were studied 2-6 years after diagnosis: whether working, whether working full time (35+ hours per week), and usual hours per week. We used propensity scores to match cases to controls 3:1.
    


          5 percentage points) of being employed 2-6 years after diagnosis (p = 0.036). They were slightly more likely to be working full time, while averaging 1.1 fewer hours per week overall, but these effects were not statistically significant. Cancer's effect on husbands was not significant for any of the employment outcomes. However, if survivor wives and husbands were working at follow-up, they had more than twice the odds of working full-time (wives OR = 2.18, p = 0.0004; husbands OR = 2.65, p = 0.012) and worked more hours per week than other spouses (wives 1.9, p = 0.041; husbands 1.5, p = 0.04).
    


          Conclusions:
        
      
      The implications to cancer survivors and their spouses of these  However, there is little or no effect on aggregate hours worked by spouses who were employed at diagnosis."
799,Cancer's sweet tooth: the Janus effect of glucose metabolism in tumorigenesis.,Ashrafian H.,https://pubmed.ncbi.nlm.nih.gov/16488806/,"Despite Otto Warburg's 1931 Nobel Prize for his work affirming the role of metabolism in carcinogenesis, there has been little further interest in this association between metabolism and cancer. Disinterest has, in part, been attributable to the notion that Warburg's description of a relation between a shift to glycolysis in carcinogenesis may be an epiphenomenon rather than a mechanistic determinant. By studying the critical cellular energy sensor AMP-activated protein kinase (AMPK), I postulate that the association between intermediary metabolism and tumours varies over time. Through accumulation of carbohydrates and pan-inhibition of AMPK, premalignant tumours may gain a replicative advantage through the repression of senescence. Conversely, malignant tumours, with a defective tumour suppressor contingent, undergo a ""glycolytic switch"", in part by tolerating a degree of AMPK activation, to mitigate substrate limitation. I contend that this Janus-faced relation with intermediary metabolism contributes to carcinogenesis; if proven, this finding would have important implications for public health, in that it would lend support to the idea that prevention of obesity, and caloric restriction and exercise could reduce the predisposition to cancer."
800,Natural HSP90 inhibitors as a potential therapeutic intervention in treating cancers: A comprehensive review.,"Liew HY, Tan XY, Chan HH, Khaw KY, Ong YS.",https://pubmed.ncbi.nlm.nih.gov/35577308/,"Heat shock protein 90 (Hsp90) has evolved as a cancerous cell growth regulator by stabilising various oncogenic kinases. Upon the Hsp90 inhibition, the expression of its client proteins is downregulated and thus leads to denaturation of cellular proteins and cancer cell death. Hsp90 inhibitors, particularly those naturally derived from plants, fungi and bacteria, have gained substantial interest as a feasible therapeutic approach for cancer treatment due to their diverse pharmacological properties. In order to gain insights into the potential development of more efficacious Hsp90 inhibitors for cancer treatment, this review is conducted to analyse both in vitro and in vivo data on the chemical and biological activities of natural Hsp90 inhibitors. The systematic search was conducted in databases (PubMed, Scopus and Web of Science) with terms ""Hsp90 inhibitor"" and ""cancer"", prompting a total of 61 articles after screening with inclusion criteria. This comprehensive review systematically summarised the efficacy of 14 different classes of naturally derived Hsp90 inhibitors in cancerous cell and animal tumour models by consolidating the primary outcomes in terms of IC50, reduction of tumour size and physicochemical properties. The detailed pharmacodynamic (the structure-activity relationship, mechanism of action) and pharmacokinetics (toxicity, oral bioavailability) of these Hsp90 inhibitors together with the study limitations were discussed. Collectively, these findings emphasise the necessity of comprehending the molecular mechanisms as well as the correlation of Hsp90 and its relative client proteins to drive the generation of viable Hsp90 inhibitors with improved pharmacodynamic and pharmacokinetic profiles."
801,Cancer's unequal impact on incomes in Norway.,"Syse A, Tønnessen M.",https://pubmed.ncbi.nlm.nih.gov/22150076/," Norwegian cancer survivors' incomes, including both labor earnings and compensatory welfare benefits, were compared to those of the cancer-free population to assess potential welfare consequences of cancer. Possible modifying effects of parental and marital status, education, prior earnings and age were assessed in depth.
    


          Material and 
    


           The decline was, however, significantly associated with sociodemographic factors, marital status exempted. Childless men with low education and low prior earnings were most adversely affected. Lymphomas and lung cancer accounted largely for these unfavorable effects.
    


          Conclusions:
        
      
      Declines in earnings after cancer are to a large degree compensated by the Norwegian welfare state, and incomes overall are only modestly decreased among cancer survivors compared to the general population. Persons with multiple unfavorable sociodemographic characteristics experience particularly low incomes after cancer. This is of concern in a supposedly egalitarian society with public health care and antidiscrimination acts in place. Welfare state interventions, i.e. work reintegration efforts and/or compensations for labor earning drops, directed specifically towards these subgroups might be warranted."
802,Haralick texture analysis of prostate MRI: utility for differentiating non-cancerous prostate from prostate cancer and differentiating prostate cancers with different Gleason scores.,"Wibmer A, Hricak H, Gondo T, Matsumoto K, Veeraraghavan H, Fehr D, Zheng J, Goldman D, Moskowitz C, Fine SW, Reuter VE, Eastham J, Sala E, Vargas HA.",https://pubmed.ncbi.nlm.nih.gov/25991476/,"
    


           Cancers ≥0.5 ml and non-cancerous peripheral (PZ) and transition (TZ) zone tissue were identified on T2WI and apparent diffusion coefficient (ADC) maps, using whole-mount pathology as reference. Texture features (Energy, Entropy, Correlation, Homogeneity, Inertia) were extracted and analysed using generalized estimating equations.
    


          0001-0.008). In TZ cancers (n = 43) we observed significant differences for all five texture features on the ADC map (all p-values: <.0001) and for Correlation (p = 0.041) and Inertia (p = 0.001) on T2WI. On ADC maps, GS was associated with higher Entropy (GS 6 vs. 7: p = 0.0225; 6 vs. >7: p = 0.0069) and lower Energy (GS 6 vs. 7: p = 0.0116, 6 vs. >7: p = 0.0039). ADC map Energy (p = 0.0102) and Entropy (p = 0.0019) were significantly different in GS ≤3 + 4 versus ≥4 + 3 cancers; ADC map Entropy remained significant after controlling for the median ADC (p = 0.0291).
    


          Conclusion:
        
      
      Several Haralick-based texture features appear useful for prostate cancer detection and GS assessment.
    


          Key points:
        
      
      • Several Haralick texture features may differentiate non-cancerous and cancerous prostate tissue. • Tumour Energy and Entropy on ADC maps correlate with Gleason score. • T2w-image-derived texture features are not associated with the Gleason score."
803,The microcosmos of intratumor heterogeneity: the space-time of cancer evolution.,Janiszewska M.,https://pubmed.ncbi.nlm.nih.gov/31784650/,"The Cancer Genome Atlas consortium brought us terabytes of information about genetic alterations in different types of human tumors. While many cancer-driver genes have been identified through these efforts, interrogating cancer genomes has also shed new light on tumor complexity. Mutations were found to vary tremendously in their allelic frequencies within the same tumor. Based on those variant allelic frequencies grouping, an estimate of genetically distinct ""clones"" of cancer cells can be determined for each tumor. It was estimated that 4-8 clones are present in every human tumor. Presence of distinct clones, cells that differ in their genotype and/or phenotype, is one of the roots for the major challenge of effectively curing cancer patients. Any given treatment applied to a heterogeneous mixture of cancer cells will yield distinct responses in different cells and may be ineffective in killing particular clones. Moreover, in highly heterogeneous tumors, stochastically, there is a higher chance of presence of traits, such as point mutations in key receptor tyrosine kinases, that drive drug resistance. Thus, intratumor heterogeneity is like an arsenal, providing a variety of weapons for self-defense against cancer-targeted therapy. However, in this arsenal the supplies are constantly changing, as cancer cells are accumulating new mutations. What is also changing is the battlefield-the tumor microenvironment including all noncancerous cells within the tumor and surrounding tissue, which also contribute to the diversification of cancer's forces. In order to design more effective therapies that would target this ever-changing landscape, we need to learn more about the two elusive variables that shape the tumor ecosystem: the space-how could we exploit the organization of tumor microenvironment? and the time-how could we predict the changes in heterogeneous tumors?"
804,"""RIPping"" off Pancreas Cancer's Blockage of Immune Surveillance.","Liu X, Sells BE, DeNardo DG.",https://pubmed.ncbi.nlm.nih.gov/38327192/,"MHC-I downregulation is correlated with immunotherapy resistance in PDAC, but efficient strategies to increase cell-surface MHC-I are still lacking. This study by Sang, Zhou, Chen, Yu, and colleagues identified inhibition of tumor-intrinsic RIPK2 as a pharmacologic target to block the degradation of MHC-I on tumor cells and improved PDAC responses to anti-PD-1 immunotherapy. See related article by Sang et al., p. 326 (1) ."
805,An in silico study on the detectability of field cancerization through parenchymal analysis of digital mammograms.,"Hernández A, Miranda DA, Pertuz S.",https://pubmed.ncbi.nlm.nih.gov/36994613/," However, the working principles behind this practice are yet not well understood. Field cancerization is a phenomenon associated with genetic and epigenetic alterations in large volumes of cells, putting them on a path of malignancy before the appearance of recognizable cancer signs. Evidence suggests that it can induce changes in the biochemical and optical properties of the tissue.
    


          Purpose:
        
      
      The aim of this work was to study whether the extended genetic mutations and epigenetic changes due to field cancerization, and the impact they have on the biochemistry of breast tissues are detectable in the radiological patterns of mammography images.
    


           Mammography images from these phantoms were generated and compared with images obtained from their non-modified counterparts, that is, without field cancerization. We extracted 33 texture features from the breast area to quantitatively assess the impact of the field cancerization model. We analyzed the similarity and statistical equivalence of texture features with and without field cancerization using the t-test, Wilcoxon sign rank test and Kolmogorov-Smirnov test, and performed a discrimination test using multinomial logistic regression analysis with lasso regularization.
    


          9% of the breast volume, some texture features started to fail to show equivalence (p < 0.05). At 7.9% volume modification, a high percent of texture features showed statistically significant differences (p < 0.05) and non-equivalence. At this level, multinomial logistic regression analysis of texture features showed a statistically significant performance in the discrimination of mammograms from breasts with and without field cancerization (AUC = 0.89, 95% CI: 0.75-1.00).
    


          Conclusions:
        
      
      These "
806,Cross detection for odor of metabolic waste between breast and colorectal cancer using canine olfaction.,"Seo IS, Lee HG, Koo B, Koh CS, Park HY, Im C, Shin HC.",https://pubmed.ncbi.nlm.nih.gov/29438432/,"Although several studies have been performed to detect cancer using canine olfaction, none have investigated whether canine olfaction trained to the specific odor of one cancer is able to detect odor related to other unfamiliar cancers. To resolve this issue, we employed breast and colorectal cancer in vitro, and investigated whether trained dogs to odor related to metabolic waste from breast cancer are able to detect it from colorectal cancer, and vice versa. The culture liquid samples used in the cultivation of cancerous cells (4T1 and CT26) were employed as an  Two different breeds of dogs were trained for the different cancer odor each other. The dogs were then tested using a double-blind  For two cancers, both dogs regardless of whether training or non-training showed that accuracy was over 90%, and sensitivity and specificity were over 0.9, respectively. Through these  That is, it testifies that metabolic waste between breast and colorectal cancer have the common specific odor in vitro. Accordingly, a trained dogs for detecting odor for metabolic waste of breast cancer can perceive it of colorectal cancer, and vice versa. In order to the future work, we will plan in vivo  Furthermore, the relationship between breast and colorectal cancer should be investigated using other research "
807,The role of CIP2A in cancer: A review and update.,"Soofiyani SR, Hejazi MS, Baradaran B.",https://pubmed.ncbi.nlm.nih.gov/29035828/,"Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a characterized human oncoprotein that is able to promote cancer cells proliferation, anchorage-independent cell growth and resistance to apoptosis. CIP2A inactivates protein phosphatase 2A (PP2A) which down-regulates Akt (Protein Kinase B) phosphorylation and stabilizes c-Myc (c-Myc oncogene product) in cancer cells. CIP2A has been studied in the most of human malignancies. Here we discuss the role of CIP2A in cancer and give a summary of CIP2A expression in malignancies. Also, where available we indicated the association of CIP2A with the stage of cancers and patients prognosis, explain its localization and the possibility of targeting CIP2A in different cancers."
808,Long-term trend of future Cancer onset: A model-based prediction of Cancer incidence and onset age by region and gender.,"Xie C, Huang X, Lin D, Huang X, Lin S, Luo S, Xu X, Weng X.",https://pubmed.ncbi.nlm.nih.gov/37951546/,"
    


           Using the average annual percentage change (AAPC) to quantify the trends of ASIR and the onset age. In addition, the incidences in 2019 were fixed to distinguish the age onset changes caused by demographic and incidence from 2020 to 2040.
    


           In five SDI regions, the proportion of weighted average onset age above 60 years old will rise above 10% in the next 20 years and increase sequentially with the rise of the SDI level. Preclude sex-specific cancers, the onset age is younger in men than in women in 2040. Rule out the influence of changing demographics, half of cancer's morbidity has a youth-oriented tendency globally, which is concentrated in hormone-related and digestive tract cancer.
    


          Conclusion:
        
      
      From 2020 to 2040, the incidence and onset age changes demonstrate marked geographic and gender variations in the cancer spectrum. Cancer incidence and onset age are predicted to continuously increase worldwide in the future."
809,Is cancer really a 'local' cellular clonal disease?,Bronchud MH.,https://pubmed.ncbi.nlm.nih.gov/12376079/,"Cancer is not simply the  To accumulate three, or often as many as seven, specific mutations in a single cell without incurring a significant number of additional mutations that might lead to cell lethality requires a large number of target cells, some mutagenic activity acting on those target cells for a variable period of time, and efficient selection strategies, which may be to some extent tissue-specific. A number of 'protective' intracellular regulatory circuits might be present in proliferating cells deliberately to protect against carcinogenesis. If it does require some seven sequential carcinogenic 'genetic hits' in a single cellular clone for a malignant tumor to develop, it is mathematically more likely to occur in a tissue with a high  In this context, the old 'field cancerization' theory by Slaughter and the more recent 'multistep carcinogenesis' model by Fearon and Vogelstein can come together in a single model: 'multistep field cancerization'. This simple conclusion, and our ability to measure ' Molecular technologies are just beginning to be sufficiently sensitive to start testing the hypothesis."
810,The Role of Polyphenol (Flavonoids) Compounds in the Treatment of Cancer Cells.,"Hazafa A, Rehman KU, Jahan N, Jabeen Z.",https://pubmed.ncbi.nlm.nih.gov/31287738/,"Cancer remains a second leading cause of deaths and major public health problem. It occurs due to extensive DNA damage caused by ultraviolet radiations, ionizing radiations, environmental agents, therapeutic agents, etc. Among all cancers, the most frequently diagnosed cancers are lung (12.7%), breast (10.9%), colorectal (9.7%), and gastric cancer (7.81%). Natural compounds are most favorable against cancer on the count of their anti-cancerous ability, easy to avail and efficient. Among natural compounds, polyphenols (flavonoids, catechin, hesperetin, flavones, quercetin, phenolic acids, ellagic acid, lignans, stilbenes, etc.) represent a large and diverse group used in the prevention and treatment of cancer. Natural flavonoids are derived from different plant sources and from various medicinal plants including Petroselinum crispum, Apium graveolens, Flemingia vestita, Phyllanthus emblica, etc. Natural flavonoids possess antioxidant, anti-inflammation, as well as anti-cancerous activities through multiple pathways, they induce apoptosis in breast, colorectal, and prostate cancers, lower the nucleoside diphosphate kinase-B activity in lung, bladder and colon cancers, inhibit cell-proliferation and cell cycle arrest by suppressing the NF-kB pathway in various cancers, etc. The current review summarized the anticancer activities of natural polyphenols and their mechanisms of action."
811,Disseminated epithelial cancers-An autopsy analysis.,"Vaideeswar P, Patil S, Chaudhari J.",https://pubmed.ncbi.nlm.nih.gov/35074969/," Despite increasing public awareness and availability of sophisticated imaging techniques, some cancers evade clinical diagnosis and/or are incidentally encountered at autopsies, often with dissemination.
    


          Aims:
        
      
      The present study evaluated the disseminated epithelial cancers at autopsy.
    


          Materials and  The cases were categorized as (1) clinically diagnosed malignancy, known primary; (2) clinically diagnosed malignancy, unknown primary; and (3) clinically undiagnosed malignancy.
    


          Statistical analysis:
        
      
      Nil.
    


          9%) of the 114 patients with epithelial malignancies. There were 29 patients (43.9%) in category 1, 26 patients (39.4%) in category 2, and 11 patients (16.7%) in category 3, majority of whom were women (38 patients, 57.6%). When all categories were considered together, lung and colorectal carcinomas were the commonest cancers seen in 13 (19.7%) and 8 (12.1%) patients, respectively, in both men and women. Majority of the patients (43 cases, 65.2%) had symptoms produced by metastases, which were the sole manifestations in 13 patients (19.7%). Lungs and liver were the common metastatic sites.
    


          Conclusions:
        
      
      Cancerous dissemination continues to be a major cause of morbidity and mortality even after considerable improvements in the surgical or nonsurgical treatment modalities. An autopsy study can provide important clinical insights in retrospect."
812,Daylight photodynamic therapy vs. Conventional photodynamic therapy as skin cancer preventive treatment in patients with face and scalp cancerization: an intra-individual comparison study.,"Sotiriou E, Apalla Z, Vrani F, Lazaridou E, Vakirlis E, Lallas A, Ioannides D.",https://pubmed.ncbi.nlm.nih.gov/28222225/," The latter represents the clinical expression of the 'field cancerization' theory; supporting the presence of multiple malignant clones of dysplastic keratinocytes over the entire epithelium that potentially can progress into clinical lesions. Taking into consideration that the burden of NMSCs on public health and health-care cost is high, adequate control of recurrences and management of field change is challenging.
    


           conventional photodynamic therapy (C-PDT) in the prevention of occurrence of new NMSCs in patients with clinical and histological signs of actinic field damage.
    


           For a 12-month period, individuals were clinically evaluated for development of new NMSCs.
    


           Local adverse events were more intense with C-PDT, and patients' preference was more for DL-PDT compared to C-PDT.
    


          Conclusions:
        
      
      The current findings suggest equal preventive potential of DL-PDT vs. C-PDT against the formation of new NMSCs in patients exhibiting actinic field damage."
813,Enzyme trafficking and coclustering precede and accurately predict human breast cancer recurrences: an interdisciplinary review.,Petty HR.,https://pubmed.ncbi.nlm.nih.gov/35385324/,"Although great effort has been expended to understand cancer's origins, less attention has been given to the primary cause of cancer deaths-cancer recurrences and their sequelae. This interdisciplinary review addresses mechanistic features of aggressive cancer by studying metabolic enzyme patterns within ductal carcinoma in situ (DCIS) of the breast lesions. DCIS lesions from patients who did or did not experience a breast cancer recurrence were compared. Several proteins, including phospho-Ser226-glucose transporter type 1, phosphofructokinase type L and phosphofructokinase/fructose 2,6-bisphosphatase type 4 are found in nucleoli of ductal epithelial cells in samples from patients who will not subsequently recur, but traffic to the cell periphery in samples from patients who will experience a cancer recurrence. Large coclusters of enzymes near plasmalemmata will enhance product formation because enzyme concentrations in clusters are very high while solvent molecules and solutes diffuse through small channels. These structural changes will accelerate aerobic glycolysis. Agglomerations of pentose phosphate pathway and glutathione synthesis enzymes enhance GSH formation. As aggressive cancer lesions are incomplete at early stages, they may be unrecognizable. We have found that machine learning provides superior analyses of tissue images and may be used to identify biomarker patterns associated with recurrent and nonrecurrent patients with high accuracy. This suggests a new prognostic test to predict patients with DCIS who are likely to recur and those who are at low risk for recurrence. Mechanistic interpretations provide a deeper understanding of anticancer drug action and suggest that aggressive metastatic cancer cells are sensitive to reductive chemotherapy."
814,Oral field cancerization: carcinogen-induced independent events or micrometastatic deposits?,"van Oijen MG, Slootweg PJ.",https://pubmed.ncbi.nlm.nih.gov/10750662/,"Patients with a head and neck squamous cell carcinoma (HNSCC) often develop multiple (pre)malignant lesions. This finding led to the field cancerization theory, which hypothesizes that the entire epithelial surface of the upper aerodigestive tract has an increased risk for the development of (pre)malignant lesions because of multiple genetic abnormalities in the whole tissue region. Demonstration of alterations in histologically normal tumor-adjacent mucosa from HNSCC patients supported this hypothesis. Currently, the question has been raised whether multiple lesions develop independently from each other or from migrated malignant or progenitor cells. The majority of the mucosal alterations appear to be related to the exposure to alcohol and/or tobacco. Moreover, almost all primary remote tumors from HNSCC patients appear to be clonally unrelated. Therefore, there is more evidence that field cancerization is due to multiple independent events than to migration of genetically altered cells."
815,Multiple primary esophageal and concurrent upper aerodigestive tract cancer and the aldehyde dehydrogenase-2 genotype of Japanese alcoholics.,"Yokoyama A, Muramatsu T, Ohmori T, Makuuchi H, Higuchi S, Matsushita S, Yoshino K, Maruyama K, Nakano M, Ishii H.",https://pubmed.ncbi.nlm.nih.gov/8640660/," They are often explained by the concept of field cancerization, which suggests a similar etiology. However, little is known about the nature of the hypothesized etiology.
    


           The multiplicity of their esophageal carcinoma and their concurrent UADT cancer was compared with their genotype for aldehyde dehydrogenase-2 (ALDH2), the major determinant of blood acetaldehyde concentration after drinking.
    


          5%) had multiple primary carcinoma of the esophagus, whereas 5 of 16 (31.3%) with active ALDH2 had multiple carcinomas (P < 0.01). The prevalence of concurrent UADT cancer was 29.4% in those patients with inactive ALDH2, compared with 6.3% in those patients with active ALDH2.
    


          Conclusions:
        
      
      Inactive ALDH2 is a risk factor for multiple carcinoma of the esophagus in alcoholics. Acetaldehyde, a recognized animal carcinogen, appears to play a critical role in field cancerization."
816,Pharmacotherapeutic approaches for transportation of anticancer agents via skin.,"Shende P, Vaidya J, Gaud RS.",https://pubmed.ncbi.nlm.nih.gov/30095010/,"Cancer is the largest family of diseases that involve abnormal uncontrolled cell growth which metastasizes to other parts of the body. The most common type of cancers includes lung, liver, colorectal, prostate, stomach, breast and cervical cancer with skin cancer excluding melanoma (contribute up to 40% of the cases). The conventional treatment approaches like surgery, chemotherapy, etc., have several side effects such as severe inflammation and pain. Hence, pharmacotherapeutic approaches of antineoplastic agents can be advantageous for treating various forms of cancer through the skin. Novel transdermal techniques and preparations have been emerged to overcome the limitations of skin and to penetrate inside the cancerous cells by transporting through the deeper tissues of the skin. The transdermal penetration of drugs using different formulations such as nanocarriers, physical penetration enhancement techniques, chemical penetration enhancers and newer technologies such as gels, dendrimers, needle-free injection jet etc., show improved patient compliance, abolition of scars and economic value. The topical delivery of antineoplastic agents is an attractive choice for increasing site-specific delivery, reducing side effects and improving therapeutic effects. The "
817,Heteroplasmic mutation of mitochondrial DNA D-loop and 4977-bp deletion in human cancer cells during mitochondrial DNA depletion.,"Lee HC, Hsu LS, Yin PH, Lee LM, Chi CW.",https://pubmed.ncbi.nlm.nih.gov/17280876/,"Somatic mutations in mitochondrial DNA (mtDNA) have been demonstrated in various human cancers. Many cancers have high frequently of mtDNA with homoplasmic point mutations, and carry less frequently of mtDNA with large-scale deletions as compared with corresponding non-cancerous tissue. Moreover, most cancers harbor a decreased copy number of mtDNA than their corresponding non-cancerous tissue. However, it is unclear whether the process of decreasing in mtDNA content would be involved in an increase in the heteroplasmic level of somatic mtDNA point mutation, and/or involved in a decrease in the proportion of mtDNA with large-scale deletion in cancer cells. In this study, we provided evidence that the heteroplasmic levels of variations in cytidine number in np 303-309 poly C tract of mtDNA in three colon cancer cells were not changed during an ethidium bromide-induced mtDNA depleting process. In the mtDNA depleting process, the proportions of mtDNA with 4977-bp deletion in cybrid cells were not significantly altered. These  Mitochondrial genome instability and reduced mtDNA copy number may independently occur in human cancer."
818,Frequent and increased expression of human METCAM/MUC18 in cancer tissues and metastatic lesions is associated with the clinical progression of human ovarian carcinoma.,"Wu GJ, Dickerson EB.",https://pubmed.ncbi.nlm.nih.gov/25510693/," To initiate the study we determined expression of this protein in normal and cancerous ovarian tissues, cystadenomas, metastatic lesions, and ovarian cancer cell lines.
    


          Materials and  We also determined expression levels of several downstream effectors of METCAM/MUC18 in these tissues.
    


           IHC  In higher pathological grades of ovarian cancer and metastatic lesions, the percentage of cells stained in IHC was increased. Thirty percent of normal tissues weakly expressed the huMETCAM/MUC18 antigen, but 70% of cancer tissues and 100% of metastatic lesions expressed the antigen. Expression levels of several downstream effectors of huMETCAM/MUC18, Bcl2, PCNA and VEGF, were elevated in cancerous tissues, however, not that of Bax. The phospho-AKT/AKT ratio was elevated in metastatic lesions.
    


          Conclusion:
        
      
      Upexpression of huMETCAM/MUC18 may be a marker for the malignant potential of ovarian carcinomas. Progression of ovarian cancer may involve increased signaling in anti-apoptosis, proliferation, survival/proliferation pathway, and angiogenesis."
819,The expression profile of apoptosis-related genes in the chicken as a human epithelial ovarian cancer model.,"Seo HW, Rengaraj D, Choi JW, Park KJ, Song G, Han JY.",https://pubmed.ncbi.nlm.nih.gov/21109956/,"The purpose of our study was to examine the expression pattern of apoptosis-related genes in normal and cancerous ovaries of the hen. Localization of apoptosis-related gene mRNA was investigated in cancerous ovaries using in situ hybridization. The expression patterns of apoptosis-related genes were confirmed with RT-PCR in normal and cancerous ovaries. Differences of expression level between normal ovaries and ovarian cancers were analyzed using quantitative RT-PCR. In both normal and cancerous chicken ovaries, the expression of CASP1, CASP2, CASP3, CASP6, CASP8 and CASP9 were detected through RT-PCR analysis. The expression of BCL2, BCL2L1 and BID were confirmed in normal and cancerous ovaries of the hen. Quantitative RT-PCR showed that CASP1 expression was significantly increased in cancerous ovaries compared with normal ovaries, whereas BID expression was decreased. Our  Collectively, this phenomenon is closely associated with the dysregulation of CASP1 and BID expression in chicken ovarian cancer."
820,Obesity and cancer risk: Emerging biological mechanisms and perspectives.,"Avgerinos KI, Spyrou N, Mantzoros CS, Dalamaga M.",https://pubmed.ncbi.nlm.nih.gov/30445141/,"Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype."
821,Immunotherapies and Combination Strategies for Immuno-Oncology.,"Barbari C, Fontaine T, Parajuli P, Lamichhane N, Jakubski S, Lamichhane P, Deshmukh RR.",https://pubmed.ncbi.nlm.nih.gov/32679922/,"The advent of novel immunotherapies in the treatment of cancers has dramatically changed the landscape of the oncology field. Recent developments in checkpoint inhibition therapies, tumor-infiltrating lymphocyte therapies, chimeric antigen receptor T cell therapies, and cancer vaccines have shown immense promise for significant advancements in cancer treatments. Immunotherapies act on distinct steps of immune response to augment the body's natural ability to recognize, target, and destroy cancerous cells. Combination treatments with immunotherapies and other modalities intend to activate immune response, decrease immunosuppression, and target signaling and resistance pathways to offer a more durable, long-lasting treatment compared to traditional therapies and immunotherapies as monotherapies for cancers. This review aims to briefly describe the rationale, mechanisms of action, and clinical efficacy of common immunotherapies and highlight promising combination strategies currently approved or under clinical development. Additionally, we will discuss the benefits and limitations of these immunotherapy approaches as monotherapies as well as in combination with other treatments."
822,Changes in serum levels of Forssman-like antibody in patients with gastric cancer.,"Hirayama R, Hirokawa K, Takagi Y, Utsuyama M, Maejima S, Takemura K, Mishima Y, Makinodan T.",https://pubmed.ncbi.nlm.nih.gov/2924260/,"Because Forssman antigen, one of the most well-known heteroantigens, has been noted in certain cancerous tissues, it would seem that the serum levels of the Forssman antibody of patients with these cancers would be low, owing to the absorption of the naturally occurring antibody by the Forssman antigen-containing cancerous tissues. This hypothesis was tested by researchers assessing the serum hemolysin titers of 174 patients with cancer (gastric cancer, 100; colonic cancer, 40; and other cancers, 45) and of 856 age-matched, sex-matched, and blood type-matched healthy individuals against the serum levels of sheep red blood cells. Serum levels of the hemolysin of patients with gastric cancer tend to be lower than those of patients with other types of cancer and also lower than those of age-matched and sex-matched controls. The decrease was especially prominent in patients with moderately differentiated adenocarcinoma of the stomach. Preoperative and postoperative serum samples of 40 patients with gastric cancer were analyzed therefore to determine the effect of surgically removing the cancer on the serum level of the hemolysin. The  However, in patients with recurrence of the cancer, the serum levels of hemolysin decreased again in 11 of 11 patients. These "
823,The association between trace metals in both cancerous and non-cancerous tissues with the risk of liver and gastric cancer progression in northwest China.,"Yan J, Zhang H, Zhang M, Tian M, Nie G, Xie D, Zhu X, Li X.",https://pubmed.ncbi.nlm.nih.gov/38359492/,"Liver cancer and gastric cancer have extremely high morbidity and mortality rates worldwide. It is well known that an increase or decrease in trace metals may be associated with the formation and development of a variety of diseases, including cancer. Therefore, this study aimed to evaluate the contents of aluminium (Al), arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), selenium (Se), and zinc (Zn) in cancerous liver and gastric tissues, compared to adjacent healthy tissues, and to investigate the relationship between trace metals and cancer progression. During surgery, multiple samples were taken from the cancerous and adjacent healthy tissues of patients with liver and gastric cancer, and trace metal levels within these samples were analysed using inductively coupled plasma mass spectrometry (ICP-MS). We found that concentrations of As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Se, and Zn in tissues from patients with liver cancer were significantly lower than those in healthy controls (P < 0.05). Similarly, patients with gastric cancer also showed lower levels of Cd, Co, Cr, Mn, Ni, and Zn-but higher levels of Cu and Se-compared to the controls (P < 0.05). In addition, patients with liver and gastric cancers who had poorly differentiated tumours and positive lymph node metastases showed lower levels of trace metals (P < 0.05), although no significant changes in their concentrations were observed to correlate with sex, age, or body mass index (BMI). Logistic regression, principal component analysis (PCA), Bayesian kernel regression (BKMR), weighted quantile sum (WQS) regression, and quantile-based g computing (qgcomp) models were used to analyse the relationships between trace metal concentrations in liver and gastric cancer tissues and the progression of these cancers. We found that single or mixed trace metal levels were negatively associated with poor differentiation and lymph node metastasis in both liver and gastric cancer, and the posterior inclusion probability (PIP) of each metal showed that Cd contributed the most to poor differentiation and lymph node metastasis in both liver and gastric cancer (all PIP = 1.000). These data help to clarify the relationship between changes in trace metal levels in cancerous liver and gastric tissues and the progression of these cancers. Further research is warranted, however, to fully elucidate the mechanisms and causations underlying these findings."
824,Characteristics of DNA macro-alterations in breast cancer with liver metastasis before treatment.,"Fan Y, Zou L, Zhong X, Wang Z, Wang Y, Luo C, Zheng H, Wang Y.",https://pubmed.ncbi.nlm.nih.gov/37434117/," However, the macro-alterations that characterise liver metastasis in breast cancer(BC) are poorly understood. Here, we conducted a whole-genome sequencing analysis of liver metastases to explore the status and the time frame model of these macro-alterations in pre-treatment patients with metastatic breast cancer.
    


           We also chose five postoperative frozen specimens from patients with early-stage breast cancer before any treatment as control. Surprisingly, all four liver metastasis samples were classified as WGD + . However, the previous study reported that WGD happened in 30% of cancers and 2/5 in our early-stage samples. WGD was not observed in the two separate primary tumours and one lymph node metastasis of one patient with metastatic BC, but her liver metastasis showed an early burst of bi-allelic copy number gain. The phylogenetic tree proves her 4 tumour samples were the polyclonal origin and only one WGD + clone metastasis to the liver. Another 3 metastatic BC patients' primary tumour and lymph node metastasis experienced WGD as well as liver metastasis, and they all showed similar molecular time-frame of copy number(CN) gain across locations within the same patient. These patients' tumours were of monoclonal origin, and WGD happened in a founding clone before metastasis, explaining that all samples share the CN-gain time frame. After WGD, the genomes usually face instability to evolve other macro-alterations. For example, a greater quantity and variety of complex structural variations (SVs) were detected in WGD + samples. The breakpoints were enriched in the chr17: 39 Mb-40 Mb tile, which contained the HER2 gene,  These complex SVs may be involved in the evolutionary mechanisms of the dramatic increase of HER2 copy number.
    


          Conclusion:
        
      
      Our work revealed that the WGD + clone might be a critical evolution step for liver metastasis and favoured following complex SV of breast cancer."
825,"Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment.","Pai SI, Westra WH.",https://pubmed.ncbi.nlm.nih.gov/18729723/,"The prototypic head and neck squamous cell carcinoma (HNSCC) arises from the mucosal lining of the upper aerodigestive tract, demonstrates squamous differentiation microscopically, involves older men with a long history of cigarette smoking and alcohol consumption, and is treated by multimodality therapy. HNSCC has long been regarded as a uniform disease process requiring a  Divergence in epidemiologic trends among HNSCCs arising from different anatomic sites has introduced a view that, morphologic repetition aside, head and neck cancers form a heterogeneous group. This view has been supported at the molecular genetic level. A more complete understanding of the molecular genetics of head and neck cancer is providing new insights into long-held but poorly comprehended concepts such as field cancerization and is introducing various biomarkers with potential application for diagnosing, staging, monitoring, and prognosticating HNSCC."
826,Vision 20/20: the role of Raman spectroscopy in early stage cancer detection and feasibility for application in radiation therapy response assessment.,"Devpura S, Barton KN, Brown SL, Palyvoda O, Kalkanis S, Naik VM, Siddiqui F, Naik R, Chetty IJ.",https://pubmed.ncbi.nlm.nih.gov/24784365/,"Raman spectroscopy is an optical technique capable of identifying chemical constituents of a sample by their unique set of molecular vibrations. Research on the applicability of Raman spectroscopy in the differentiation of cancerous versus normal tissues has been ongoing for many years, and has yielded successful  Recently, much effort has been invested on developing noninvasive ""Raman"" probes to provide real-time diagnosis of potentially cancerous tumors. In this regard, it is feasible that the Raman technique might one day be used to provide rapid, minimally invasive real-time diagnosis of tumors in patients. Raman spectroscopy is relatively new to the field of radiation therapy. Recent work involving cell lines has shown that the Raman technique is able to identify proteins and other markers affected by radiation therapy. Although this work is preliminary, one could ask whether or not the Raman technique might be used to identify molecular markers that predict radiation response. This paper provides a brief review of Raman spectroscopic investigations in cancer detection, benefits and limitations of this "
827,[Histogenesis of gallbladder cancer with special reference to metaplastic changes and distribution of various mucins and CEA].,"Inada A, Konishi F, Yamamichi N, Ito H.",https://pubmed.ncbi.nlm.nih.gov/2796960/,"In order to study the histogenesis of gallbladder cancer, metaplastic changes and dysplasia in the mucosal epithelium were investigated in 30 cases of gallbladder cancer and 300 cases of chronic cholecystitis. Intestinal metaplasia was observed more frequently in the cases of cancer, both in cancerous and non-cancerous tissues, than those of chronic cholecystitis. In addition, CPS III type of mucin, which is preferably demonstrated in the pyloric glands, was observed in the tumor cells of 50% of cancers. Thus, gastric metaplasia as well as intestinal metaplasia seems to be important as a predisposing lesion to gallbladder cancer. By means of reconstruction  As for mucin secretion, the rate of sialomucin-containing cells was notably high in the lesions of dysplasia and cancer, increasing in intensity in this order, accompanied with positive CEA. The "
828,Quantitative determination of N-glycolylneuraminic acid expression in human cancerous tissues and avian lymphoma cell lines as a tumor-associated sialic acid by gas chromatography-mass spectrometry.,"Kawai T, Kato A, Higashi H, Kato S, Naiki M.",https://pubmed.ncbi.nlm.nih.gov/1997165/,"N-Glycolylneuraminic acid (NeuGc) is distributed in most animals except humans and chickens. However, human and chicken cancerous tissues often synthesize this heterophilic sialic acid as a tumor-associated Hanganutziu-Deicher antigen [M. Naiki and H. Higashi, Adv. Exp. Med. Biol., 152: 445-456, 1982; H. Higashi et al., Cancer Res., 45: 3796-3802, 1985]. In this paper, NeuGc in human cancerous tissues and chicken Marek's disease lymphoma cell lines was determined quantitatively with gas chromatography-mass spectrometry analysis using mass fragmentography. The detectable limit of NeuGc was 40 pg (0.12 pmol) in each injection using 5 ng of trideuteriomethyl ester trideuteriomethyl glycoside of the sialic acid as an internal standard sample when a pair of ions at m/e 386 and 389 was chosen for ion monitoring. NeuGc was detected in ganglioside-rich fractions of various human cancerous tissues from 5 of 8 patients examined but was not detected in glycosphingolipids of normal human tissues. The contents of NeuGc in these cancerous tissues ranged from 0.02 to 0.5% of the total sialic acid content. NeuGc was also detected in freeze-dried samples of 5 different cell lines from chicken Marek's disease lymphomas but was not detected in a cell line from chicken lymphoid leukosis lymphoma and normal chicken skeletal muscle tissue. The contents of NeuGc in the positive cell lines ranged from 0.03 to 0.11% of the total sialic acid content. These "
829,"Menopausal status, adipose tissue, and breast cancer risk: impact of estrogen replacement therapy.",Eden JA.,https://pubmed.ncbi.nlm.nih.gov/25436720/,"The seeds of breast cancer are likely sown in the first two or three decades of life. Rapid weight gain and height in infancy predict breast cancer risk in later life. The age at first pregnancy is also a strong predictor for breast cancer; the earlier the first full-term pregnancy, then the lower the risk of breast cancer in later life. It has been postulated that the breast stem cell number may be the factor linking these observations together. Menopause, per se, is associated with an increase in central adiposity, which is reversed by hormone replacement usage. Breast and nonbreast fat both produce estrogens and cytokines that may promote the growth of small breast cancers making them appear earlier. Obesity also is associated with metabolic syndrome, which is a risk factor for breast cancer. The breast cancer stem cells make up only around 1%-2% of the tumor mass and, yet, are the likely driver for much of a breast cancer's behavior. Future research into breast cancer biology, especially into the cancer stem cells is likely to translate into novel "
830,Exploring alternative ovarian cancer biomarkers using innovative nanotechnology strategies.,"Castro CM, Im H, Le C, Lee H, Weissleder R, Birrer MJ.",https://pubmed.ncbi.nlm.nih.gov/25543192/,"Our increased understanding of ovarian cancer's blueprints (mediated by DNA and RNA) and behavior (mediated by proteins) points to wide differences across patients that cannot be depicted by histology alone. Conventional diagnosis usually entails an adequate tissue biopsy, which limits serial testing. There is thus a motivation to shift towards easier to obtain clinical samples (e.g., ascites or blood). In response, investigators are increasingly leveraging alternative circulating biomarkers in blood or proximal fluids and harnessing novel profiling platforms to help explore treatment-related effects on such biomarkers in serial fashion. In this review, we discuss how new nanotechnologies we developed intersect with alternative ovarian cancer biomarkers for improved understanding of metastases and therapeutic response."
831,Noniatrogenic Meningitis Caused by Streptococcus salivarius Associated with Early Esophageal Cancer and Early Gastric Cancer.,"Yanagida M, Hosoi Y, Kawano T, Otake Y, Yamanaka Y, Baba T, Ito M.",https://pubmed.ncbi.nlm.nih.gov/37344440/,"Streptococcus salivarius is part of the normal oral cavity and gastrointestinal tract microflora and an unusual cause of acute bacterial meningitis. We herein report an 81-year-old man with S. salivarius meningitis, which led to a diagnosis of early esophageal cancer and early gastric cancer. S. salivarius infection may occur through the gastrointestinal mucosa when it is disrupted in association with early gastrointestinal cancer. To our knowledge, this is the first report describing S. salivarius meningitis associated with multiple early gastrointestinal cancers in the absence of other sources of infection."
832,Detection of minimal residual cancer to investigate why oral tumors recur despite seemingly adequate treatment.,"Partridge M, Li SR, Pateromichelakis S, Francis R, Phillips E, Huang XH, Tesfa-Selase F, Langdon JD.",https://pubmed.ncbi.nlm.nih.gov/10914716/,"Improvements in surgery and radiotherapy techniques have led to only a modest increase in the 5-year survival rate for patients with head and neck cancer. This is because the pattern of clinical disease is changing, such that locoregional recurrence now accounts for fewer treatment failures, but more patients develop a second primary cancer or distant metastatic disease. In this study, we have used the p53 phage plaque assay, immunocytochemistry, and mutational analysis to assess the contribution of minimal residual cancer and genetic aberrations in clinically normal upper aerodigestive tract mucosa to treatment failure. Eighteen consecutive patients with oral tumors, with conventional clear margins, have been followed for a minimum of 36 months. Molecular assessment identified tumor-positive surgical margins for 6 of 11 assessable patients and additional tumor-positive lymph nodes for three cases. Disseminated malignant cells were detected in the hematopoietic cell compartment for six cases, and one patient had molecular evidence of field cancerization. Locoregional recurrence developed in five patients with tumors harboring a p53 gene mutation; four of these were associated with tumor-positive surgical margins, and one was associated with molecular evidence of field cancerization. Radiotherapy to the primary site did not prevent development of local recurrence when the residual tumor harbored a p53 gene mutation. Three of six cases with a tumor-positive bone marrow aspirate developed distant metastases. These findings reveal that molecular and immunocytochemical detection of minimal residual cancer and field cancerization can help identify patients who may develop locoregional or distant recurrence and justify further studies to evaluate the contribution of these remaining malignant cells to treatment failure."
833,DNA helicases and their roles in cancer.,"Dhar S, Datta A, Brosh RM Jr.",https://pubmed.ncbi.nlm.nih.gov/33137625/,"DNA helicases, known for their fundamentally important roles in genomic stability, are high profile players in cancer. Not only are there monogenic helicase disorders with a strong disposition to cancer, it is well appreciated that helicase variants are associated with specific cancers (e.g., breast cancer). Flipping the coin, DNA helicases are frequently overexpressed in cancerous tissues and reduction in helicase gene expression  The seminal roles of helicases in the DNA damage and replication stress responses, as well as DNA repair pathways, validate their vital importance in cancer biology and suggest their potential values as targets in anti-cancer therapy. In recent years, many laboratories have characterized the specialized roles of helicase to resolve transcription-replication conflicts, maintain telomeres, mediate cell cycle checkpoints, remodel stalled replication forks, and regulate transcription. In vivo models, particularly mice, have been used to interrogate helicase function and serve as a bridge for preclinical studies that may lead to novel therapeutic approaches. In this review, we will summarize our current knowledge of DNA helicases and their roles in cancer, emphasizing the latest developments."
834,A colorimetric nano-biosensor for simultaneous detection of prevalent cancers using unamplified cell-free ribonucleic acid biomarkers.,"Mollasalehi H, Shajari E.",https://pubmed.ncbi.nlm.nih.gov/33421955/,"Early detection of cancer increases the chance of effective treatment and survival rates. The aim of this study is to develop a rapid and non-invasive nano-biosensing  In that regard, two circulating microRNA (miR-21, miR-155) biomarkers, which are upregulated in plasma in prevalent cancers, were targeted by a rapid and colorimetric nano-biosensor based on non-crosslinking Au-nanoprobes without amplification requirement. Multiple cancerous cell lines, including A549, MCF7, HT-29, A2780, AGS, MKN-45, and SW-1736 and the primary fibroblast were examined with naked eyes after the hybridization assay using exogenous biomarkers. The  The upregulated miRNAs in cancerous cell lines caused a significant blue shift in the Au-nanoprobe absorbance spectrum while the samples isolated from normal cells remained intact red. The limit of detection (LOD) of the  The developed geno-sensing "
835,Total gastrectomy for early gastric cancer.,"Kitamura K, Yamaguchi T, Okamoto K, Taniguchi H, Hagiwara A, Sawai K, Takahashi T.",https://pubmed.ncbi.nlm.nih.gov/7564386/,"A total gastrectomy was performed in 49 patients with early gastric cancer, and the effectiveness of this procedure was evaluated by reviewing the hospital files of the patients. The reasons for this total gastrectomy were as follows: (1) lymph node dissection for 22 patients, (2) surgeon's choice in reconstruction for 10 patients, (3) modification of the surgery from subtotal to total gastrectomy for seven patients, (4) synchronous multiple cancers for seven patients, and (5) cancer in a stomach remnant for three patients. Of 49 patients, 42 had the cancerous lesions in the upper portion of their stomachs. Lymph node involvement occurred in 5 patients, but not in the supra- or infrapyloric lymph nodes. Postoperative complications such as anastomotic leakage, reflux esophagitis and pancreatic fistula occurred in five, four, and two patients, respectively. Postoperative death, including two patients who died within 30 days after the surgery, occurred in 5 patients. Our study showed that total gastrectomy 6%). We conclude that a total gastrectomy should not be performed on patients with early gastric cancer except for synchronous multiple cancers and for cancers in a stomach remnant."
836,Tumor cell- and microenvironment-specific roles of cysteine cathepsins in mouse models of human cancers.,"Hölzen L, Parigiani MA, Reinheckel T.",https://pubmed.ncbi.nlm.nih.gov/32247787/,"The human genome encodes for 11 papain-like endolysosomal cysteine peptidases, collectively known as the cysteine cathepsins. Based on their biochemical properties and with the help of  However, tumors are known to be complex tissues in which non-cancerous cells are also critical for tumorigenesis. Here we discuss the  We focus on models in immunocompetent mice, because only such models allow for analysis of cathepsins in a fully functional tumor microenvironment. An important outcome of those studies was the identification of cancer-promoting cathepsins in tumor-associated macrophages. Another interesting outcome of these animal studies was the identification of a homeostatic tumor-suppressive role for cathepsin L in skin and intestinal cancers. Taken together, these in vivo findings provide a basis for the use of cysteine cathepsins as therapeutic targets, prodrug activators, or as proteases for imaging tumors."
837,Selective Visualization of Tumor Cell Membranes and Tumors with a Viscosity-Sensitive Plasma Membrane Probe.,"Li Q, Zhu W, Gong S, Jiang S, Feng G.",https://pubmed.ncbi.nlm.nih.gov/37125920/,"Cancer is a worldwide health problem. Revealing the changes in the microenvironment after cell carcinogenesis is helpful to understand cancer and develop sensitive  We developed herein a viscosity-responsive plasma membrane probe (TPA-S) that was successfully used to probe the viscosity difference between normal and tumor cell plasma membranes for the first time. The probe shows AIE properties with good water solubility, significant near-infrared (NIR) fluorescence responses to viscosity with high sensitivity, and excellent cell membrane location performance. With these features, our  In addition, TPA-S was successfully applied to specifically light up tumors. Altogether, this work explored the changes of cell membrane viscosity after canceration, provided a new "
838,Association between continuous cessation or reduction of drinking alcohol and improvement of multiple dysplastic lesions in patients with esophageal squamous cell carcinoma after endoscopic resection.,"Hori K, Katada C, Okada H, Katagiri A, Matsuo Y, Yokoyama T, Yano T, Suzuki H, Shimizu Y, Furue Y, Nakanishi H, Koike T, Takizawa K, Hirao M, Yoshii T, Yamanouchi T, Kawakubo H, Kobayashi N, Shimoda T, Ochiai A, Ishikawa H, Yokoyama A, Muto M.",https://pubmed.ncbi.nlm.nih.gov/38070099/," Squamous dysplastic lesion is clinically visualised as a Lugol-voiding lesion (LVL) by chromoendoscopy. Whether cessation or reduction of alcohol drinking improves multiple LVL and reduces the risk of field cancerization has not been elucidated.
    


           The grade of LVL was assessed in all patients every 6 months. We instructed the patients to stop smoking and drinking and recorded their drinking and smoking status every 6 months.
    


           Of the remaining 232 patients, 158 continuously ceased or reduced their drinking habit. Patients who ceased or reduced their drinking habit significantly showed improvement in the grade of LVL. Multivariate analysis showed that continuous cessation or reduction of drinking habit improved the grade of LVL (hazard ratio [HR] = 8.5, 95% confidence interval [CI] 1.7-153.8, p = 0.0053). Higher grade of LVL carried a high risk of multiple ESCC and head and neck SCC (HNSCC) (HR = 3.7, 95% CI 2.2-6.4, p < 0.0001). Improvement in LVL significantly decreased the risk of multiple ESCC and HNSCC (HR = 0.2, 95% CI 0.04-0.7, p = 0.009).
    


          Conclusions:
        
      
      This is the first report indicating that field cancerization was reversible and cessation or reduction of drinking alcohol could prevent multiple squamous dysplastic lesion and multiple ESCC and HNSCC development.
    


          Clinical trials registry number:
        
      
      UMIN000001676."
839,MAL-PDT for difficult to treat nonmelanoma skin cancer.,"Stebbins WG, Hanke CW.",https://pubmed.ncbi.nlm.nih.gov/21276161/,"With an incidence of over 3.5 million nonmelanoma skin cancers (NMSCs) per year in the United States, there is an increasing need for effective, cost-effective treatments for NMSC. When surgical excision is impractical or not feasible, methyl aminolevulinate photodynamic therapy (MAL-PDT) has demonstrated consistently high long-term cure rates ranging from 70-90%, with superior cosmetic outcomes compared with other treatment modalities. With the exception of invasive squamous cell carcinoma, MAL-PDT has been successful in treating all types of NMSC, especially in patients with multiple comorbidities, field cancerization, and lesions in cosmetically sensitive locations. Herein, a step-by-step description of the procedure for MAL-PDT is provided, followed by a review of outcomes from large clinical trials performed over the past 15 years for each variant of NMSC. After reading this review, clinicians should have a thorough understanding of the benefits and limits of MAL-PDT, and should be able to add this valuable procedure to their armamentarium of therapies for NMSC."
840,Influence of age on colorectal cancer's 5-year survival.,"Kemppainen M, Räihä I, Sourander L.",https://pubmed.ncbi.nlm.nih.gov/7601366/,"The aim of this study was to ascertain the 5-year survival figures of 171 consecutive colorectal cancer patients in southwestern Finland, the differences between various age groups, and which clinical variables predict poor outcome. The mean age at the time of diagnosis was 67 years in men and 69 years in women. The 5-year survival was lower in older patients, especially in those over 80 years with concomitant diseases. However, the colorectal cancer mortality did not differ between the three age groups: < 65, 65-80, > 80 years. Employing univariate analysis, a poor 5-year outcome was associated with metastases, and the outcome was excellent if the cancer was confined locally (p = 0.0001). As many as 26% of the patients in whom the cancer was confined to the bowel wall (Dukes B) at the time of operation died within 5 years. A poor survival rate was also found if the patients had emergency operations (p = 0.021). The postoperative mortality was 6%. Using logistic regression analysis, the poor 5-year survival rate was correlated strongly with metastasized cancer (p = 0.000) but less so with age (p = 0.040)."
841,Recent changes in the morphology of gastric cancer in Japan.,"Nagayo T, Yokoyama H.",https://pubmed.ncbi.nlm.nih.gov/669846/,"The macroscopical and histological features of 4,428 cases of gastric cancer resected stomachs was noted.d surgically between 1953 and 1974 were studied. Of these cases, 81.9% were in an advanced stage and 18.1% in an early stage. The following changes were observed. (1) In the group of advanced cancers, a gradual decrease in the frequency of Borrmann II type was noted. Most of these tumors were well-differentiated adenocarcinomas. (2) In the group of early cancers, a gradual increase in the proportion of ""cancerous erosion"" was detected. The majority of these tumors were poorly differentiated adenocarcinomas or infiltrating signet-ring cell cancers. (3) At intervals of 10 years, 5-10% decrease in the frequency of intestinal metaplasia in resected stomachs was noted."
842,[Robo1 expression in non-small cell lung cancer and its brain metastasis].,"Li XX, Jin L, Sun ZF, Gu F, Li WL, Ma YJ.",https://pubmed.ncbi.nlm.nih.gov/23880000/,"
    


           The Robo1 expression was further examined in 17 self control cases with lung cancer tissues and their brain metastasis tissues. The 
    


          9% (1/52), 13.8% (11/80) and 40.3% (29/72), respectively, and significant differences were detected among them (P < 0.05). During the 17 self control cases, the positive expression rate of Robo1 in lung cancer tissue and their brain metastasis tissues were 17.6% and 64.7%, respectively, with a significant difference between them (P < 0.01). Among the 72 cases of lung cancer brain metastasis, the median survival time of cases with positive Robo1 expression was 10 months, significantly shorter than that of cases with negative expression of Robo1 (17 months, P < 0.05).
    


          Conclusions:
        
      
      The positive expression rate of Robo1 was increased in sequence from the lowest in adjacent non-cancerous tissues, intermediate in the lung cancer tissues to highest in the lung cancer brain metastasis tissues. The expression of Robo1 in lung cancer brain metastasis is negatively correlated with the prognosis of patients with lung cancer brain metastasis. Robo1 may promote the genesis and progression of lung cancer and lung cancer brain metastasis as a cancer-promoting oncogene."
843,A longitudinal analysis of phenotypic and symptom characteristics associated with inter-individual variability in employment interference in patients with breast cancer.,"Chan RJ, Cooper B, Koczwara B, Chan A, Tan CJ, Paul SM, Dunn LB, Conley YP, Kober KM, Levine JD, Miaskowski C.",https://pubmed.ncbi.nlm.nih.gov/31955276/,"Purpose:
        
      
      A breast cancer diagnosis has a substantial economic impact. Study aims were to evaluate for inter-individual differences in cancer's level of interference with employment and identify phenotypic and symptom characteristics associated with higher levels of interference.
    


           Interference with employment was measured using a 0 (no problem) to 10 (severe problem) numeric rating scale. Hierarchical linear modeling (HLM) was used to evaluate for inter-individual differences in trajectories of employment interference and characteristics associated with employment interference at enrollment and over 12 months.
    


          0 (±11.7) years and the majority underwent breast conservation surgery (80.6%). Mean employment interference score was 3.2 (±3.7). Unconditional model for employment interference demonstrated a decreasing linear trend (-.076/month). Younger age, lower income, higher pain intensity, and having an axillary lymph node dissection were associated with higher pre-surgical interference scores. Having a sentinel lymph node biopsy was associated with ongoing employment interference scores. Higher sleep disturbance scores were associated with both initial and ongoing employment interference scores. Receipt of chemotherapy, use of complementary or alternative therapies, and re-excision or mastectomy following surgery were significant time varying covariates.
    


          Conclusion:
        
      
      This study is the first to use HLM to describe inter-individual differences in the trajectories of cancer's interference with employment and associated factors prior to and for 12 months following breast cancer surgery. Patients with the identified risk factors warrant ongoing assessments of employment interference and appropriate referrals."
844,Intravoxel incoherent motion DWI with different mathematical models in predicting rectal adenoma with and without canceration.,"Jia Y, Song G, Wu R, Hong Y, Dou W, Li A.",https://pubmed.ncbi.nlm.nih.gov/36030659/,"Purpose:
        
      
      To evaluate the clinical value of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) with mono-exponential (ME), bi-exponential (BE), and stretched-exponential (SE) models for predicting rectal adenomas with canceration.
    


          Material and  The ME-derived apparent diffusion coefficient (ADC), BE-derived true diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), SE-derived distributed diffusion coefficient (DDC), and water molecular diffusion heterogeneity index (α) were measured. The differences in each parameter between adenoma and canceration were compared. Multivariate binary logistic regression analysis was used to establish models for predicting rectal adenomas with canceration. Receiver operating characteristic curve analysis was applied to evaluate diagnostic performances of each model in terms of sensitivity, specificity, accuracy, and area under the curve (AUC).
    


          851 (95 % confidence interval, CI, 0.735-0.930), 0.895 (95 % CI, 0.789-0.960), 0.720 (95 % CI, 0.589-0.828), 0.791 (95 % CI, 0.667-0.886), 0.841 (95 % CI, 0.724-0.923) and 0.738 (95 % CI, 0.608-0.834), respectively. The AUCs of BE and SE models were 0.927 (95 % CI, 0.829-0.978) and 0.874 (95 % CI, 0.763-0.946), respectively. The AUC, sensitivity, specificity, and accuracy of the derived four values (ADC, D, f, and DDC) from the combination of three models were 0.950, 96.6 % (95 % CI, 95.3-97.6 %), 80.6 % (95 % CI, 78.0-82.9 %), and 88.3 % (95 % CI, 86.2-90.2 %), respectively.
    


          Conclusion:
        
      
      ADC can easily and effectively predict rectal adenomas with canceration. The BE model has a better combination of sensitivity and specificity for the diagnosis of rectal adenoma canceration."
845,Epigenetic inactivation of FAT4 contributes to gastric field cancerization.,"Yoshida S, Yamashita S, Niwa T, Mori A, Ito S, Ichinose M, Ushijima T.",https://pubmed.ncbi.nlm.nih.gov/26792292/," Nevertheless, the individual driver genes involved in such field cancerization are still unclear. Here, we aimed to demonstrate that FAT4, a novel tumor suppressor identified by exome sequencing of GC, is methylation-silenced and that such methylation is involved in epigenetic field cancerization for GC.
    


           DNA methylation was analyzed by bisulfite sequencing with use of a next-generation sequencer or quantitative methylation-specific PCR. Gene expression was analyzed by quantitative reverse transcription PCR.
    


           FAT4 was highly methylated in two of 13 GC cell lines and was not expressed in them. Removal of FAT4 methylation by a DNA demethylating agent (5-aza-2'-deoxycytidine) restored its expression in the two cell lines. In primary GC samples, FAT4 was methylated in 12 of 82 GCs (14.6 %). FAT4 methylation was associated with the presence of the CpG island methylator phenotype but not with prognosis, tumor invasion, lymph node metastasis, or histological types. In noncancerous gastric mucosae, high FAT4 methylation levels were associated with the presence of GC and Helicobacter pylori infection.
    


          Conclusions:
        
      
      FAT4 was methylation-silenced in GCs. Its methylation in gastric mucosae was associated with H. pylori infection and likely contributed to epigenetic field cancerization."
846,Paired ductal carcinoma in situ and invasive breast cancer lesions in the D-loop of the mitochondrial genome indicate a cancerization field effect.,"Maggrah A, Robinson K, Creed J, Wittock R, Gehman K, Gehman T, Brown H, Harbottle A, Froberg MK, Klein D, Reguly B, Parr R.",https://pubmed.ncbi.nlm.nih.gov/23509716/,"Alterations in the mitochondrial genome have been chronicled in most solid tumors, including breast cancer. The intent of this paper is to compare and document somatic mitochondrial D-loop mutations in paired samples of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC) indicating a potential breast ductal epithelial cancerization field effect. Paired samples of these histopathologies were laser-captured microdissected (LCM) from biopsy, lumpectomy, and mastectomy tissues. Blood samples were collected as germplasm control references. For each patient, hypervariable region 1 (HV1) in the D-loop portion of the mitochondrial genome (mtGenome) was sequenced for all 3 clinical samples. Specific parallel somatic heteroplasmic alterations between these histopathologies, particularly at sites 16189, 16223, 16224, 16270, and 16291, suggest the presence of an epithelial, mitochondrial cancerization field effect. These  Moreover, this paper indicates that biofluids with low cellularity, such as nipple aspirate fluid and/or ductal lavage, warrant further investigation as early and minimally invasive detection mediums of a cancerization field effect within breast tissue."
847,p53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect.,"Abukwaik R, Vera-Siguenza E, Tennant D, Spill F.",https://pubmed.ncbi.nlm.nih.gov/39207627/,"Cancer cells exhibit significant alterations in their metabolism, characterised by a reduction in oxidative phosphorylation (OXPHOS) and an increased reliance on glycolysis, even in the presence of oxygen. This metabolic shift, known as the Warburg effect, is pivotal in fuelling cancer's uncontrolled growth, invasion, and therapeutic resistance. While dysregulation of many genes contributes to this metabolic shift, the tumour suppressor gene p53 emerges as a master player. Yet, the molecular mechanisms remain elusive. This study introduces a comprehensive mathematical model, integrating essential p53 targets, offering insights into how p53 orchestrates its targets to redirect cancer metabolism towards an OXPHOS-dominant state. Simulation outcomes align closely with  Additionally, our findings reveal the dynamic capability of elevated p53 activation to fully reverse the Warburg effect, highlighting the significance of its activity levels not just in triggering apoptosis (programmed cell death) post-chemotherapy but also in modifying the metabolic pathways implicated in treatment resistance. In scenarios of p53 mutations, our analysis suggests targeting glycolysis-instigating signalling pathways as an alternative strategy, whereas targeting solely synthesis of cytochrome c oxidase 2 (SCO2) does support mitochondrial respiration but may not effectively suppress the glycolysis pathway, potentially boosting the energy production and cancer cell viability."
848,ARID1A gene mutation in ovarian and endometrial cancers (Review).,"Takeda T, Banno K, Okawa R, Yanokura M, Iijima M, Irie-Kunitomi H, Nakamura K, Iida M, Adachi M, Umene K, Nogami Y, Masuda K, Kobayashi Y, Tominaga E, Aoki D.",https://pubmed.ncbi.nlm.nih.gov/26572704/,"The AT-rich interacting domain‑containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome‑wide analyses with next‑generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis‑associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis‑associated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening  Important  Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular‑targeted drug can inhibit proliferation of ARID1A‑mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop "
849,[Lipid peroxidation level in gastrointestinal tract tumors].,"Czeczot H, Scibior-Bentkowska D, Skrzycki M, Majewska M, Podsiad M.",https://pubmed.ncbi.nlm.nih.gov/21268915/,"Oxygen free radicals and their reactive derivatives participate in formation of chronic inflammation states, which facilitate development of gastrointestinal tract tumors. Oxidative stress is one of the main causes of damage to cell membranes in  End products of lipid peroxidation (aldehydes, organic peroxides) react with important biological macromolecules such as DNA and proteins, cause changes in cell membrane structure and properties leading to loss of its integrity. Intensification of the lipid peroxidation process is a factor which may also lead to a malfunction in the antioxidant barrier, which further weakens the defense of cells against oxygen free radicals and promotes the onset and development of cancer. The aim of the study was the determination of lipid peroxidation level in gastrointestinal tract tumors (stomach, liver, colon, and colorectal cancer to liver metastases).
    


          Material and  We also investigated 25 patients with liver cirrhosis, which was treated as a pre-cancerous condition. In total, 175 patients were examined. Tumor specimens, and normal adjacent tissues (6-7 cm from the edge of the tumor), which served as control tissue in studies, were collected from patients (with their consent) during surgery. Additionally, liver specimens were collected from patients with liver cirrhosis. Lipid peroxidation level was determined spectrophotometrically as a concentration of final lipid peroxidation products, which in reaction with tiobarbituric acid (TBA) form colour complex (thiobarbituric acid-reactive substances - TBARS).
    


           Other types of gastrointestinal tumors studied, were characterized by similar levels of lipid peroxidation. TBARS concentration in these tumors was approximately 2-fold higher than in malignant liver tumors and much lower than in benign tumors. In all cancers of the digestive tract with the exception of malignant liver tumors increased level of TBARS was found, comparing with control tissue. The concentration of TBARS in cirrhotic liver was lower than in control. The level of lipid peroxidation in liver cirrhosis and malignant liver tumors was similar. There were no significant differences in TBARS concentration in the tumors of particular sections of the intestine and normal colon. The highest concentration of TBARS was found in G1 grade of colorectal cancer. In subsequent grades of cells differentiation (G2 and G3) its concentration was lower. The highest level of lipid peroxidation, expressed as the concentration of TBARS was found in the I stage of colorectal cancer clinical advancement. The significantly lowest concentration of TBARS was shown for stage II (UICC).
    


          Conclusions:
        
      
      The level of lipid peroxidation in cancerous cells of gastrointestinal tract indicates increased oxidative stress. The changes of lipid peroxidation level--a marker of oxidative stress in gastrointestinal tumors appear to be closely associated with their development stages (liver cirrhosis/malignant liver cancer; colorectal cancer/colorectal cancer liver metastases) and are likely to create such conditions, in which cancerous cells may proliferate, undergo gradual dedifferentiation and malignancy, and generate metastases."
850,Consistency in Distribution of Facial Skin Cancers Treated With Mohs Micrographic Surgery.,"Horeczko J, Hendi A.",https://pubmed.ncbi.nlm.nih.gov/35533023/,"Mohs micrographic surgery (MMS) has become the standard of treatment for skin malignancies of the head and neck. However, there is a paucity of literature describing facial distributions of MMS. Anatomical location of skin cancer is an important feature to study as it can affect prognosis as well as pathogenesis of skin cancers. This study aims to analyze consistency in head and neck MMS anatomical distributions and compare differences between multiple centers. The study retrospectively reviews 5871 MMS cases performed at a single center in Chevy Chase, Maryland from January 2014 through December 2019.  This knowledge of consistency provides a foundation for future studies because it allows for comparison. Comparing and contrasting data across multiple centers can elucidate regional characteristics that may impact the pathogenesis and distribution of facial skin tumors. Many regional or demographical factors may be important in the development of cutaneous malignancies. This information should be considered when assessing risk factors for cancerous skin lesions.J Drugs Dermatol. 2022;21(5):506-509. doi:10.36849/JDD.6143."
851,Specific molecular signatures of non-tumor liver tissue may predict a risk of hepatocarcinogenesis.,"Utsunomiya T, Shimada M, Morine Y, Tajima A, Imoto I.",https://pubmed.ncbi.nlm.nih.gov/24766251/,"Hepatocellular carcinoma (HCC) is one of the most common human cancers and a major cause of cancer-related death worldwide. The bleak outcomes of HCC patients even after curative treatment have been, at least partially, attributed to its multicentric origin. Therefore, it is necessary to examine not only tumor tissue but also non-tumor liver tissue to investigate the molecular mechanisms operating during hepatocarcinogenesis based on the concept of ""field cancerization"". Several studies previously investigated the association of molecular alterations in non-tumor liver tissue with clinical features and prognosis in HCC patients on a genome-wide scale. In particular, specific alterations of DNA methylation profiles have been confirmed in non-tumor liver tissue. This review focuses on the possible clinical value of array-based comprehensive analyses of molecular alterations, especially aberrant DNA methylation, in non-tumor liver tissue to clarify the risk of hepatocarcinogenesis. Carcinogenetic risk estimation based on specific methylation signatures may be advantageous for close follow-up of patients who are at high risk of HCC development. Furthermore, epigenetic therapies for patients with chronic liver diseases may be helpful to reduce the risk of HCC development because epigenetic alterations are potentially reversible, and thus provide promising molecular targets for therapeutic intervention."
852,Value of the dynamic and delayed MR sequence with Gd-DTPA in the T-staging of stomach cancer: correlation with the histopathology.,"Kang BC, Kim JH, Kim KW, Lee DY, Baek SY, Lee SW, Jung WH.",https://pubmed.ncbi.nlm.nih.gov/10652915/,"
    


           Axial, sagittal, or coronal two-dimensional fast low-angle shot) MR images for the water-distended stomach were obtained with dynamic protocol, including precontrast images and images obtained 30, 60, 90, and 240-300 s after intravenous injection of the 0.1 mM Gd-DTPA/kg solution. We evaluated the thickness, interruption (or not) of the low signal intensity bands, and enhancement pattern of the cancerous wall and normal gastric wall. We prospectively evaluated the depth of cancer invasion, perigastric infiltration (extraserosal invasion), perigastric organ invasion, and regional lymph nodes and determined tumor staging on MR images. These MR evaluations including MR-determined staging were correlated with the surgicopathologic findings.
    


           The mucosa (and/or submucosa) affected by stomach cancer showed an early enhancement pattern (30-90 s after Gd-DTPA administration) in 43 of 46 patients (93%). The normal gastric mucosa demonstrated a delayed peak enhancement pattern (> 90 s after Gd-DTPA administration) in 29 of 46 patients (63%) and variable enhancement pattern in 17 of 46 patients (37%). An interrupted low signal intensity band or highly enhanced tumorous lesion penetrating through the gastric wall was seen in 17 of 19 pT3 patients (90%). Consistency between MR-determined staging and surgicopathologic staging occurred in three of four pT1 tumors (75%), 10 of 13 pT2 tumors (77%), 17 of 19 pT3 tumors (90%), and eight of 10 pT4 tumors (80%); overall accuracy was 83%. Overall accuracy of regional lymph node involvement, as determined by enhanced MR, was 52%; 24 of 46 node groups were positive.
    


          Conclusions:
        
      
      Dynamic and delayed MR imaging can be useful for predicting depth of cancer invasion, perigastric infiltration (extraserosal invasion), and perigastric organ invasion by gastric cancer."
853,Pathways and molecules for overcoming immunotolerance in metastatic gastrointestinal tumors.,"Gan Q, Li Y, Li Y, Liu H, Chen D, Liu L, Peng C.",https://pubmed.ncbi.nlm.nih.gov/38646539/,"Worldwide, gastrointestinal (GI) cancer is recognized as one of the leading malignancies diagnosed in both genders, with mortality largely attributed to metastatic dissemination. It has been identified that in GI cancer, a variety of signaling pathways and key molecules are modified, leading to the emergence of an immunotolerance phenotype. Such modifications are pivotal in the malignancy's evasion of immune detection. Thus, a thorough analysis of the pathways and molecules contributing to GI cancer's immunotolerance is vital for advancing our comprehension and propelling the creation of efficacious pharmacological treatments. In response to this necessity, our review illuminates a selection of groundbreaking cellular signaling pathways associated with immunotolerance in GI cancer, including the Phosphoinositide 3-kinases/Akt, Janus kinase/Signal Transducer and Activator of Transcription 3, Nuclear Factor kappa-light-chain-enhancer of activated B cells, Transforming Growth Factor-beta/Smad, Notch, Programmed Death-1/Programmed Death-Ligand 1, and Wingless and INT-1/beta-catenin-Interleukin 10. Additionally, we examine an array of pertinent molecules like Indoleamine-pyrrole 2,3-dioxygenase, Human Leukocyte Antigen G/E, Glycoprotein A Repetitions Predominant, Clever-1, Interferon regulatory factor 8/Osteopontin, T-cell immunoglobulin and mucin-domain containing-3, Carcinoembryonic antigen-related cell adhesion molecule 1, Cell division control protein 42 homolog, and caspases-1 and -12."
854,Endoscopic and histological features of gastric cancers after successful Helicobacter pylori eradication therapy.,"Saka A, Yagi K, Nimura S.",https://pubmed.ncbi.nlm.nih.gov/25752268/," Furthermore, it has become evident that non-neoplastic epithelium covers cancerous areas in gastric cancer after eradication. Here, we investigated these endoscopic features and their relationship to histological findings.
    


           pylori eradication, respectively. A gastritis-like appearance revealed by conventional endoscopy was defined as a mucosal pattern with no marked difference from the surrounding non-cancerous area and that revealed by narrow-band imaging (NBI)-magnifying endoscopy (ME) as the mucosal pattern observed in H. pylori-associated atrophic gastritis. We investigated a gastritis-like appearance revealed by conventional endoscopy (A), a gastritis-like appearance at the margin (B) and within (C) the cancerous area revealed by NBI-ME, and the histological characteristics of the overlying non-neoplastic epithelium. We also evaluated the relationship between endoscopic and histological findings in the eradication group.
    


          031, P < 0.001, P < 0.001, respectively). Non-neoplastic epithelium covered more than 10 % of the cancerous area more frequently in the eradication group. In the eradication group, more than 90 % of cancers showing a gastritis-like appearance had non-neoplastic epithelium extending over 10 % of the cancerous area.
    


          Conclusion:
        
      
      Gastric cancer after successful H. pylori eradication tends to have gastritis-like features due to non-neoplastic epithelium covering the cancerous tissue."
855,The Key microRNAs Regulated the Development of Non-small Cell Lung Cancer by Targeting TGF-beta-induced epithelial-mesenchymal Transition.,"Chen G, Ye B.",https://pubmed.ncbi.nlm.nih.gov/30968775/,"Purpose:
        
      
      Epithelial-to-Mesenchymal Transition (EMT) was reported to play a key role in the development of Non-Small Cell Lung Cancer (NSCLC). The process of EMT is regulated by the changes of miRNAs expression. However, it is still unknown which miRNA changed the most in the process of canceration and whether these changes played a role in tumor development.
    


           The samples of cancer tissues and paracancer tissues of patients were collected and analyzed. Then, the miRNAs in normal lung cells and NSCLC cells were also analyzed. In the presence of TGF-β, we transfected the miRNA mimics or inhibitor into NSCLC cells to investigate the role of the significantly altered miRNAs in cell migration and invasion and in the process of EMT.
    


           Transfected miRNA-205 mimics or miRMA-330-3p inhibitor inhibited the migration and invasion of NCIH1975 cell and restrained TGF-β-induced EMT in NSCLC cells.
    


          Conclusion:
        
      
      miRNA-330-3p and miRNA-205 changed the most in the process of canceration in NSCLC. Furthermore, miR-330-3p promoted cell invasion and metastasis in NSCLC probably by promoting EMT and miR-205 could restrain NSCLC likely by suppressing EMT."
856,"Aneuploidy, the somatic mutation that makes cancer a species of its own.","Duesberg P, Rasnick D.",https://pubmed.ncbi.nlm.nih.gov/11013390/,"The many complex phenotypes of cancer have all been attributed to ""somatic mutation."" These phenotypes include anaplasia, autonomous growth, metastasis, abnormal cell morphology, DNA indices ranging from 0.5 to over 2, clonal origin but unstable and non-clonal karyotypes and phenotypes, abnormal centrosome numbers, immortality in vitro and in transplantation, spontaneous progression of malignancy, as well as the exceedingly slow kinetics from carcinogen to carcinogenesis of many months to decades. However, it has yet to be determined whether this mutation is aneuploidy, an abnormal number of chromosomes, or gene mutation. A century ago, Boveri proposed cancer is caused by aneuploidy, because it correlates with cancer and because it generates ""pathological"" phenotypes in sea urchins. But half a century later, when cancers were found to be non-clonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a  Intrigued by the enormous mutagenic potential of aneuploidy, we undertook biochemical and biological analyses of aneuploidy and gene mutation, which show that aneuploidy is probably the only mutation that can explain all aspects of carcinogenesis. On this basis we can now offer a coherent two-stage mechanism of carcinogenesis. In stage one, carcinogens cause aneuploidy, either by fragmenting chromosomes or by damaging the spindle apparatus. In stage two, ever new and eventually tumorigenic karyotypes evolve autocatalytically because aneuploidy destabilizes the karyotype, ie. causes genetic instability. Thus, cancer cells derive their unique and complex phenotypes from random chromosome number mutation, a process that is similar to regrouping assembly lines of a car factory and is analogous to speciation. The slow kinetics of carcinogenesis reflects the low probability of generating by random chromosome reassortments a karyotype that surpasses the viability of a normal cell, similar again to natural speciation. There is correlative and functional proof of principle: (1) solid cancers are aneuploid; (2) genotoxic and non-genotoxic carcinogens cause aneuploidy; (3) the biochemical phenotypes of cells are severely altered by aneuploidy affecting the dosage of thousands of genes, but are virtually un-altered by mutations of known hypothetical oncogenes and tumor suppressor genes; (4) aneuploidy immortalizes cells; (5) non-cancerous aneuploidy generates abnormal phenotypes in all species tested, e.g., Down syndrome; (6) the degrees of aneuploidies are proportional to the degrees of abnormalities in non-cancerous and cancerous cells; (7) polyploidy also varies biological phenotypes; (8) variation of the numbers of chromosomes is the basis of speciation. Thus, aneuploidy falls within the definition of speciation, and cancer is a species of its own. The aneuploidy hypothesis offers new prospects of cancer prevention and therapy."
857,"Differences in Patient Outcomes of Prevalence, Interval, and Screen-Detected Lung Cancers in the CT Arm of the National Lung Screening Trial.","Schabath MB, Massion PP, Thompson ZJ, Eschrich SA, Balagurunathan Y, Goldof D, Aberle DR, Gillies RJ.",https://pubmed.ncbi.nlm.nih.gov/27509046/,"Lung cancer screening identifies cancers with heterogeneous behaviors. Some lung cancers will be identified among patients who had prior negative CT screens and upon follow-up scans develop a de novo nodule that was determined to be cancerous. Other lung cancers will be identified among patients who had one or more prior stable positive scans that were not determined to be lung cancer (indeterminate pulmonary nodules), but in follow-up scans was diagnosed with an incidence lung cancer. Using data from the CT arm of the National Lung Screening Trial, this analysis investigated differences in patient characteristics and survival endpoints between prevalence-, interval-, and screen-detected lung cancers, characterized based on sequence of screening  Lung cancers immediately following a positive baseline (T0), and prior to the T1 screen, formed the prevalence cohort. Interval cancers were diagnosed following a negative screen at any time point prior to the next screening round. Two cohorts of screen-detected lung cancers (SDLC) were identified that had a baseline positive screen that was that was not determined to be lung cancer (i.e., an indeterminate pulmonary nodule), but in follow-up scans was diagnosed with an incidence lung cancer 12 (SDLC1) or 24 (SDLC2) months later. Two other incidence cohorts had screen-detected lung cancers that had baseline negative screen and upon follow-up scans developed a de novo nodule determined to be cancerous at 12 (SDLC3) or 24 (SDLC4) months later. Differences in patient characteristics, progression-free survival (PFS), and overall survival (OS) were assessed. The lung cancer-specific death rate was higher for SDLC3/SDLC4 compared to SDLC1/SDLC2 lung cancers (136.6/1,000 person-years vs. 71.3/1,000 person-years, P < 0.001). Moreover, PFS and OS were significantly lower for SDLC3/SDLC4 compared to SDLC1/SDLC2 (P < 0.004; P < 0.002, respectively). The findings were consistent when stratified by stage and histology. Multivariable Cox proportional models revealed that the SDLC3/SDLC4 case groups were associated with significantly poorer PFS (HR = 1.89; 95% CI 1.31-2.74) and OS (HR = 1.80; 95% CI 1.21-2.67) compared to SDLC1/SDLC2 lung cancers (HR = 1.00). Lung cancer patients who develop a de novo nodule that determined to be cancerous (i.e., at least one negative CT screen prior to cancer diagnosis) had poorer survival outcomes compared to patients who had at least one positive screen prior to cancer diagnosis. As such, the observation that de novo screen-detected are associated with poorer survival could be attributed to faster growing, more aggressive cancers that arose from a lung environment previously lacking focal abnormalities."
858,Peutz-Jeghers syndrome with small intestinal malignancy and cervical carcinoma.,"Li LJ, Wang ZQ, Wu BP.",https://pubmed.ncbi.nlm.nih.gov/19109876/,"We report a case of 30-year-old woman with Peutz-Jeghers syndrome (PJS). Because of small intestinal obstruction, she received the small intestinal polypectomy in 2001, and the pathological diagnosis was Peutz-Jeghers polyp canceration (mucinous adenocarcinoma, infiltrating full-thickness of the intestine). The patient did not feel uncomfortable after 6 mo of chemotherapy and other management. We kept a follow-up study on her and found that she suffered from cervical cancer in 2007, with a pathological diagnosis of cervical adenosquamous carcinoma.The patient presented with typical features of PJS, but without a family history. The PJS accompanied with both small intestinal and cervical malignancies has not been reported so far in the world."
859,"Palladin is overexpressed in the non-neoplastic stroma of infiltrating ductal adenocarcinomas of the pancreas, but is only rarely overexpressed in neoplastic cells.","Salaria SN, Illei P, Sharma R, Walter KM, Klein AP, Eshleman JR, Maitra A, Schulick R, Winter J, Ouellette MM, Goggins M, Hruban R.",https://pubmed.ncbi.nlm.nih.gov/17404500/," This hypothesis was based on reverse transcriptase-polymerase chain reaction analyses of bulk pancreatic tissue, yet pancreatic cancer is a complex admixture of neoplastic epithelial cells and desmoplastic stroma.
    


          Design:
        
      
      Immunohistochemical labeling of tissue microarrays was used to define the patterns of palladin protein expression in 177 ductal adenocarcinomas of the pancreas. Western blot analysis was used to determine the epitope(s) of palladin recognized by the antibody as well as the relative levels of palladin expression in short-term cultures of stromal fibroblasts, non-neoplastic ductal cells and pancreatic cancer cell lines.
    


          6%) of the 177 evaluable pancreatic cancers. By contrast, the overexpression of palladin protein by the neoplastic epithelial cells relative to normal pancreatic epithelium was observed in only 22 (12.4%) of the 177 cancers. Western blot analysis confirmed that the antibody recognizes the -90 kDa isoform of palladin, and demonstrated that fibroblast cell lines had higher expression of palladin than pancreatic cancer cell lines.
    


          Conclusions:
        
      
      The overexpression of palladin relative to normal pancreas in the majority of pancreatic cancers is limited to non-neoplastic stromal cells. This observation highlights the limitations of relying on bulk tissues when analyzing gene expression. Since palladin is not overexpressed in most pancreatic cancer cells, the overexpression of palladin is not likely to be responsible for pancreatic cancer cells invasive and migratory abilities."
860,Clinicopathological and Prognostic Significance of PRMT5 in Cancers: A System Review and Meta-Analysis.,"Liang Z, Liu L, Wen C, Jiang H, Ye T, Ma S, Liu X.",https://pubmed.ncbi.nlm.nih.gov/34758643/,"Purpose:
        
      
      Since protein arginine methyltransferase 5 (PRMT5) is abnormally expressed in various tumors, in this study we aim to assess the association between PRMT5 and clinicopathological and prognostic features.
    


           The critical appraisal of the eligible studies was performed using the Newcastle-Ottawa Quality Assessment Scale. Pooled hazard ratios (HR) and pooled odds ratios (OR) were calculated to assess the effect. Engauge Digitizer version 12.1, STATA version 15.1, and R version 4.0.5 were used to obtain and analysis the data.
    


           In our data, it indicated that high level of PRMT5 was significantly correlated with advanced tumor stage (OR = 2.12, 95% CI: 1.22-3.70, P =.008; I2 = 80.7%) and positively correlated with poor overall survival (HR = 1.59, 95% CI: 1.46-1.73, P < .001; I2 = 50%) and progression-free survival (HR = 1.53, 95% CI: 1.24-1.88, P < .001; I2 = 0%). In addition, sub-group analysis showed that high level of PRMT5 was associated with poor overall survival for such 5 kinds of cancers as hepatocellular carcinoma, pancreatic cancer, breast cancer, gastric cancer, and lung cancer.
    


          Conclusion:
        
      
      For the first time we found PRMT5 was pan-cancerous as a prognostic biomarker and high level of PRMT5 was associated with poor prognosis for certain cancers."
861,A short account of cancer--specifically in relation to squamous cell carcinoma.,"Feller L, Bouckaert M, Chikte UM, Wood NH, Khammissa RA, Meyerov R, Lenner J.",https://pubmed.ncbi.nlm.nih.gov/21133236/,"Cancer is the outcome of a complex multifactorial process of cytogenetic and epigenetic changes that affect cell cycle progression, apoptosis, DNA repair mechanisms and cell differentiation. Cancer cells have the capacity to evade the immune system, to invade tissues and to metastasize. Cancer is treated by surgery, chemotherapy and radiotherapy, each as single treatment modalities or more often in combination. Failure of treatment to cure a patient of cancer may be owing to the fact that radiotherapy and chemotherapy can eradicate transit-amplifying cells which are characterized by uncontrolled proliferation and prolonged survival; but cannot eradicate all cancer stem cells that divide slowly, have a relatively unlimited self-renewal capacity and express anti-apoptotic genes; and also owing to the fact that surgery cannot always eliminate occult fields of pre-cancerization."
862,"Cancerous inhibitor of protein phosphatase 2A, an emerging human oncoprotein and a potential cancer therapy target.","Khanna A, Pimanda JE, Westermarck J.",https://pubmed.ncbi.nlm.nih.gov/24204027/,"Protein phosphatase 2A (PP2A) complexes function as tumor suppressors by inhibiting the activity of several critical oncogenic signaling pathways. Consequently, inhibition of the PP2A phosphatase activity is one of many prerequisites for the transformation of normal human cells into cancerous cells. However, mechanisms for PP2A inactivation in human cancers are poorly understood. The aberrant expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), a recently identified endogenous PP2A inhibitor in malignant cells, is one such mechanism. Various independent studies have validated CIP2A's role in promoting tumor growth and resistance to apoptosis and senescence-inducing therapies. Notably, high CIP2A expression predicts poor patient prognosis in several human cancer types. Among the oncogenic proteins dephosphorylated by PP2A, the MYC oncoprotein, which is phosphorylated at serine 62, has surfaced as a marker for the oncogenic activity of CIP2A. The positive-feedback loop between CIP2A and MYC augments the activity of MYC in cancer cells. In addition, CIP2A promotes the phosphorylation and activity of additional oncoproteins, including E2F1 and AKT. However, CIP2A is not essential for normal mouse growth and development. These findings indicate that CIP2A is a novel anticancer target based on PP2A reactivation and inhibition of the oncogenic activity of its downstream effectors. The potential approaches and feasibility of targeting CIP2A are discussed here."
863,"[Current etiological problems, in France, related to primary liver cancer in cirrhosis (personal observation of 130 cases)].",Darnis F.,https://pubmed.ncbi.nlm.nih.gov/1657322/,"The etiological problems concerning, in France, hepatocellular carcinoma (H C C) developed on liver cirrhosis, are studied in this work through 130 personal cases followed up during the last decade. These 130 cases of H C C are divided in five groups according to apparent etiology: alcoholic (63%), B virus (15.3%), cryptogenetic (11,5%), hemochromatic (7.6%), autoimmune (2.3%). A review of these cases according to recent publications shows an evidence underestimated for years: we mean the important role played in France by H B V (and probably H C V) not only in chronic cirrhotic hepatitis, but even more in cancerization of cirrhosis in general whatever is the apparent etiology. This role, unsuspected when biological investigations are limited to serological markers of H B V, is demonstrated by implementing more sophisticated+ technics (molecular hybridization+ and gene amplification). But it is very unlikely that this role is exclusive++ and one must recognize that viral ""focalization"" of recent publications has a tendency to hide other causes of H C C and primarily the toxicological etiology in a wide sense. This etiology is in fact indubitable, already in tropical areas, where the role of mycotoxins and particularly of aflatoxin B l is very well demonstrated, even in areas of very high incidence of H B V. In low incidence areas, such as France, the specific carcinogenic role of alcohol cannot be excluded, neither the role of numerous  If the accidents of research lead to privilege temporarily one or the other factor, one must not forget that the genesis of H C C is most probably multifactorial, as for the majority of human cancers."
864,Intercellular communication and tissue growth. I. Cancerous growth.,"Loewenstein WR, Kanno Y.",https://pubmed.ncbi.nlm.nih.gov/6039367/,Intercellular communication was examined with intracellular electrical techniques in primary and transplanted rat liver cancers. Normal liver cells communicate rather freely with each other through permeable junctional membranes. Cancer liver cells show no communication at all; their surface membrane is a strong barrier to diffusion all around the cell. Cancer cells induce alterations in membrane permeability in normal liver cells; communication among the latter is markedly reduced when cancer cells grow near them.
865,Fibroblasts as architects of cancer pathogenesis.,"Marsh T, Pietras K, McAllister SS.",https://pubmed.ncbi.nlm.nih.gov/23123598/,"Studies of epithelial cancers (i.e., carcinomas) traditionally focused on transformation of the epithelium (i.e., the cancer cells) and how aberrant signaling within the cancer cells modulates the surrounding tissue of origin. In more recent decades, the normal cells, blood vessels, molecules, and extracellular components that surround the tumor cells, collectively known as the ""tumor microenvironment"" or ""stroma"", have received increasing attention and are now thought to be key regulators of tumor initiation and progression. Of particular relevance to the work reviewed herein are the fibroblasts, which make up the major cell type within the microenvironment of most carcinomas. Due to their inherent heterogeneity, plasticity, and function, it is perhaps not surprising that fibroblasts are ideal modulators of normal and cancerous epithelium; however, these aspects also present challenges if we are to interrupt their tumor-supportive functions. Here, we review the current body of knowledge and the many questions that still remain about the special entity known as the cancer-associated fibroblast. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease."
866,Patients with oesophageal cancer report elevated distress and problems yet do not have an explicit wish for referral prior to receiving their medical treatment plan.,"Jacobs M, Anderegg MC, Schoorlemmer A, Nieboer D, Steyerberg EW, Smets EM, Sprangers MA, van Berge Henegouwen MI, de Haes JC, Klinkenbijl JH.",https://pubmed.ncbi.nlm.nih.gov/27246192/," To identify the clinical relevance of patients with oesophageal cancer's level of distress and type of problems, we build models to predict elevated distress, wish for referral, and overall survival.
    


           A score of ≥5 on the Distress Thermometer reflected elevated distress. We first created an initial model including predictors based on the literature. We then added predictors to the initial model to create an extended model based on the sample data. We used the 'least absolute shrinkage and selection operator' to define our final model.
    


          9%, of 390 eligible patients with oesophageal cancer) which were similar to non-respondents in their demographic and clinical characteristics. One-hundred thirteen (60%) patients reported elevated distress. The five most frequently reported problems were as follows: eating, tension, weight change, fatigue, and pain. Most patients did not have a wish for referral. Predictors for elevated distress were as follows: being female, total number of practical, emotional, and physical problems, pain, and fatigue. For referral, we identified age, the total number of emotional problems, the level of distress, and fear. The level of distress added prognostic information in a model to predict overall survival.
    


          Conclusions:
        
      
      Patients with oesophageal cancer report elevated distress and a myriad of problems yet do not have an explicit wish for referral prior to receiving their medical treatment plan. Copyright © 2016 John Wiley & Sons, Ltd."
867,The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients.,"Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD.",https://pubmed.ncbi.nlm.nih.gov/8326560/,"The incidence of clinically detected prostate cancer is increasing with more frequent diagnosis in younger male patients. Whether this represents a genuine increase in incidence or earlier detection is not clear. To understand better the evolution and early changes of prostate cancer we evaluated 152 prostate glands from young male patients 10 to 49 years old. Of the prostates 98 were from African-Americans and 54 were from white patients. Prostatic intraepithelial neoplasia was identified in 0%, 9%, 20 and 44%, and small foci of histological cancer in 0%, 0%, 27% and 34% of the male patients in the second, third, fourth and fifth decades of age, respectively. The majority of the cases of prostatic intraepithelial neoplasia were of low grade. High grade prostatic intraepithelial neoplasia, found in 5 prostates, was first identified in the fifth decade. All 5 cases occurred in prostates containing histological carcinoma. Incidental carcinoma was detected with a similar frequency in white and black patients. The cancerous foci were of similar size with a tendency for cancer in black patients to be multifocal, particularly in those in the fifth decade. We conclude that prostatic intraepithelial neoplasia and histological cancers are surprisingly common in young male patients of both races. The evolution of prostatic intraepithelial neoplasia and focal histological cancers is not clear but it appears to present several decades earlier than clinically detected carcinoma. The natural history of prostate cancer must encompass many more years (decades) than has been previously realized. In addition, the initiating events leading to clinically relevant prostate cancers likely occur at a remarkably young age."
868,Comparison of tumor and two types of paratumoral tissues highlighted epigenetic regulation of transcription during field cancerization in non-small cell lung cancer.,"Wang Q, Wu L, Yu J, Li G, Zhang P, Wang H, Shao L, Liu J, Shen W.",https://pubmed.ncbi.nlm.nih.gov/35313869/," Aberrant DNA methylation has been implicated in early cancer development in non-small cell lung cancer (NSCLC); however, studies on its role in field cancerization (FC) are limited. This study aims to identify FC-specific methylation patterns that could distinguish between pre-malignant lesions and tumor tissues in NSCLC.
    


           Methylation levels were profiled by bisulfite sequencing using a custom lung-cancer methylation panel.
    


           Comparison of TUM and DIS profiles led to identification of 1740 tumor-specific differential methylated regions (DMRs), including 1675 hypermethylated and 65 hypomethylated (adjusted P < 0.05). Six of the top 10 tumor-specific hypermethylated regions were associated with cancer development. We then compared the TUM, ADJ, and DIS to further identify the progressively aggravating aberrant methylations during cancer initiation and early development. A total of 332 DMRs were identified, including a predominant proportion of 312 regions showing stepwise increase in methylation levels as the sample drew nearer to the tumor (i.e. DIS < ADJ < TUM) and 20 regions showing a stepwise decrease pattern. Gene set enrichment analysis (GSEA) for KEGG and GO terms consistently suggested enrichment of DMRs located in transcription factor genes, suggesting a central role of epigenetic regulation of transcription factors in FC and tumorigenesis.
    


          Conclusion:
        
      
      We revealed distinct methylation patterns between pre-malignant lesions and malignant tumors, suggesting the essential role of DNA methylation as an early step in pre-malignant field defects. Moreover, our study also identified differentially methylated genes, especially transcription factors, that could potentially be used as markers for lung cancer screening and for mechanistic studies of FC and early cancer development."
869,Tertiary lymphoid structures in cancer: maturation and induction.,"Chen Y, Wu Y, Yan G, Zhang G.",https://pubmed.ncbi.nlm.nih.gov/38690273/,"Tertiary lymphoid structure (TLS) is an ectopic lymphocyte aggregate formed in peripheral non-lymphoid tissues, including inflamed or cancerous tissue. Tumor-associated TLS serves as a prominent center of antigen presentation and adaptive immune activation within the periphery, which has exhibited positive prognostic value in various cancers. In recent years, the concept of maturity regarding TLS has been proposed and mature TLS, characterized by well-developed germinal centers, exhibits a more potent tumor-suppressive capacity with stronger significance. Meanwhile, more and more evidence showed that TLS can be induced by therapeutic interventions during cancer treatments. Thus, the evaluation of TLS maturity and the therapeutic interventions that induce its formation are critical issues in current TLS research. In this review, we aim to provide a comprehensive summary of the existing classifications for TLS maturity and therapeutic strategies capable of inducing its formation in tumors."
870,Modelling the impact of detecting and treating ductal carcinoma in situ in a breast screening programme.,"McCann J, Treasure P, Duffy S.",https://pubmed.ncbi.nlm.nih.gov/15333269/," Opinions vary as to whether this constitutes over-diagnosis or an opportunity to interrupt breast cancer's natural history. In England, incidence of invasive cancer and CIS increased in women of screening age (50-64 years), leading to a subsequent deficit in invasive incidence in women aged 65-69 years immediately beyond the invited age range. We aimed to model underlying incidence of invasive cancer and CIS expected in the absence of screening, and to quantify the likely relative contributions of their early detection to the observed reduction in invasive cancer in women of postscreening age.
    


          Setting:
        
      
      UK NHS breast screening programme in England.
    


           We then estimated age- and year-specific excess detection rates attributable to screening. Applying these to population figures we estimated conservatively the relative contributions of early diagnosis of CIS and invasive cancer at 50-64 years of age to the subsequent deficit in invasive cancer in women beyond invitation age (65-69 years), for screening early in the programme and at steady state.
    


          6% annual increase in incidence, giving an estimated deficit of 4.22 invasive cancers per 10,000 women aged 65-69 years in 1996. Carcinoma in situ contributed 13-17% to the deficit, assuming a mean six year lead time and 75-100% progression to invasive cancer. At steady state, with current screening performance and with lead times of 3-4 years (invasive cancer) and 6-9 years (CIS), invasive incidence might be reduced by 5-6 cancers per 10,000 women aged 65-69 years in 2010 (15-20% of underlying incidence), CIS contributing 20-40%.
    


          Discussion:
        
      
      The longer lead time associated with CIS attenuates the impact its early detection has on subsequent invasive incidence. At steady state screening, its detection contributes significantly to the deficit in invasive incidence. Our "
871,Primary lung cancer after treatment of head and neck cancer without lymph node metastasis: is there a role for autofluorescence bronchoscopy?,"Lee P, de Bree R, Brokx HA, Leemans CR, Postmus PE, Sutedja TG.",https://pubmed.ncbi.nlm.nih.gov/18486989/," As good locoregional tumor control can be achieved with current treatment strategies, patients who develop second primary tumors from field cancerization have poorer prognosis.
    


          
    


           Data on patient demographics, smoking, cancer characteristics, and outcome were prospectively collected.
    


           Median age was 70 years, all were current or former smokers of 35 pack years, and 25 had chronic obstructive lung disease. Over a median follow up of 60 months, 8 patients were diagnosed with synchronous and 26 with metachronous SPLC. Forty-two SPLC were found; 12 (29%) affected the tracheobronchial tree and 30 (71%) involved the lung parenchyma. Median time to metachronous SPLC was 22 months. Most of SPLC were surgically resectable. Five radiographically occult lung cancers detected by AF were successfully treated with endobronchial therapy. Lung cancer mortality was 24%. HNC patients who developed synchronous and metachronous SPLCs had significantly shorter survival (51 and 144 months) compared to those without (240 months) (p=0.0005).
    


          Conclusion:
        
      
      SPLC impacted negatively on the survival of patients with HNC. Close surveillance with AF and CT for SPLC combined with aggressive treatment of early stage lung cancer might be a strategy to improve outcome."
872,Computer-assisted three-dimensional analysis of multifocal/multicentric prostate cancer.,"Fujii T, Ishida E, Shimada K, Hirao K, Tanaka N, Fujimoto K, Konishi N.",https://pubmed.ncbi.nlm.nih.gov/24827595/,"In order to study multiple contiguous prostate cancer lesions, we constructed computer-assisted, three-dimensional models of multifocal prostate cancer specimens obtained by radical prostatectomy. We then examined the genetic heterogeneity among the specimens by DNA microarray analysis. Cancer foci with high Gleason patterns were found to occur de novo, whereas those with low Gleason patterns occurred contiguously with cancers of low Gleason patterns. Three-dimensional analysis showed that distinct, noncontiguous cancerous foci were genetically independent and multicentric. In contrast some contiguous multifocal lesions had the same genetic origin."
873,Tug-of-war between driver and passenger mutations in cancer and other adaptive processes.,"McFarland CD, Mirny LA, Korolev KS.",https://pubmed.ncbi.nlm.nih.gov/25277973/,"Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations--a natural consequence of cancer's elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies."
874,Urban environment and cancer in wildlife: available evidence and future research avenues.,"Sepp T, Ujvari B, Ewald PW, Thomas F, Giraudeau M.",https://pubmed.ncbi.nlm.nih.gov/30963883/,"While it is generally known that the risk of several cancers in humans is higher in urban areas compared with rural areas, cancer is often deemed a problem of human societies with modern lifestyles. At the same time, more and more wild animals are affected by urbanization processes and are faced with the need to adapt or acclimate to urban conditions. These include, among other things, increased exposure to an assortment of pollutants (e.g. chemicals, light and noise), novel types of food and new infections. According to the abundant literature available for humans, all of these factors are associated with an increased probability of developing cancerous neoplasias; however, the link between the urban environment and cancer in wildlife has not been discussed in the scientific literature. Here, we describe the available evidence linking environmental changes  We identify the knowledge gaps in this field and suggest future research avenues, with the ultimate aim of understanding how our modern lifestyle affects cancer prevalence in urbanizing wild populations. In addition, we consider the possibilities of using urban wild animal populations as models to study the association between environmental factors and cancer epidemics in humans, as well as to understand the evolution of cancer and defence mechanisms against it."
875,Prognostic impact of CD168 expression in gastric cancer.,"Ishigami S, Ueno S, Nishizono Y, Matsumoto M, Kurahara H, Arigami T, Uchikado Y, Setoyama T, Arima H, Yoshiaki K, Kijima Y, Kitazono M, Natsugoe S.",https://pubmed.ncbi.nlm.nih.gov/21435222/," Cancerous CD168 expression is correlated with aggressive biological features in several cancers. However, the clinical implications of CD168 positivity in gastric cancer have remained unclear.
    


           According to CD168 positivity, the 196 gastric cancer patients were divided into two groups (57 CD168-positive and 139 CD168-negative patients). The correlation between CD168 expression and clinicopathological factors (age, sex, histology, tumor depth, lymph node status, and vessel invasion) was evaluated according to the Japanese Classification of Gastric Carcinoma.
    


           CD168 positivity was significantly correlated with the depth of invasion, nodal involvement, and vessel invasion (p < 0.01). Survival analysis of the 196 gastric cancer patients showed that the CD168-positive group had a significantly higher mortality than the CD168-negative group (p < 0.01). In terms of a correlation with CD168 positivity at separate clinical stages, a significance difference was only found in stages II and III. Multivariate analysis revealed that CD168 expression was a significant independent prognostic marker (p = 0.013) after depth of invasion (p < 0.005) and nodal involvement (p < 0.01).
    


          Conclusion:
        
      
      Our  These "
876,Correlated and Coupled Trajectories of Cancer-Related Worries and Depressive Symptoms among Long-Term Cancer Survivors.,"Kypriotakis G, Deimling GT, Piccinin AM, Hofer SM.",https://pubmed.ncbi.nlm.nih.gov/25085102/,"The quality of life over time of long-term survivors has become an important part of both cancer and aging research. This paper examines individual differences in trajectories of cancer-related worries and depressive symptoms of 179 participants who completed four waves of annual interviews. Cancer-related worries were significantly associated with both initial level and trajectories of depressive symptoms. In a parallel process growth curve model, the initial level of depressive symptoms was significantly correlated with both the initial level and rate of change in cancer-related worry over time. Our findings indicate that cancer survivors are never completely removed from cancer's threats to quality of life, even as they survive into later life. These findings also suggest that older adults face the dual vulnerability of aging with its growing number of comorbidities and related symptoms along with the vulnerability conferred by cancer-related sequelae and the possibility of recurrence or new cancers."
877,Educational and vocational goal disruption in adolescent and young adult cancer survivors.,"Vetsch J, Wakefield CE, McGill BC, Cohn RJ, Ellis SJ, Stefanic N, Sawyer SM, Zebrack B, Sansom-Daly UM.",https://pubmed.ncbi.nlm.nih.gov/28778113/," Absence from school and time lost from work, together with the physical impacts of treatment on energy and cognition, can disrupt educational and vocational goals. The purpose of this paper is to report on AYA cancer survivors' experiences of reintegration into school and/or work and to describe perceived changes in their educational and vocational goals.
    


           Responses were analysed to determine the extent of, and explanations for, cancer's effect on school/work.
    


           Compared with their previous vocational functioning, 12 (28.6%) were scored as experiencing mild impairment, 14 (33.3%) moderate impairment, and 3 (7.1%) marked impairment. Adolescents and young adults described difficulties reintegrating to school/work as a  Despite these reported difficulties, the majority indicated that their vocation goals were of equal or greater importance than before diagnosis (26/42; 62%), and most AYAs did not see their performance as compromised (23/42; 55%). Many survivors described a positive shift in life goals and priorities. The theme of goal conflict emerged where AYAs reported compromised abilities to achieve their goals.
    


          Conclusions:
        
      
      The physical and cognitive impacts of treatment can make returning to school/work challenging for AYA cancer survivors. Adolescents and young adults experiencing difficulties may benefit from additional supports to facilitate meaningful engagement with their chosen educational/vocational goals."
878,Redirecting the focus of cancer immunotherapy to premalignant conditions.,Young MRI.,https://pubmed.ncbi.nlm.nih.gov/28130162/,"Much progress has been made in introducing immunological treatment approaches for cancer, with lessons learned from both the successes and failures of immunotherapy. Among the challenges of immunotherapeutic approaches for cancer are the multitudes of mechanisms by which cancers are known to subvert the immune defenses. This has led to the incorporation into the immunotherapeutic arsenal strategies by which to overcome the cancer's immunological blockades. What has been only superficially explored is the immunological milieu of premalignant lesions and the possibility of immunological approaches for the treatment of premalignant lesions so as to prevent secondary premalignant lesions and their progression to cancer. This review discusses the immunological environment associated with premalignant lesions, and the possible missed opportunity of utilizing immunological treatment strategies in the less hostile environment of premalignant lesions as compared to the immune subversive cancer environment."
879,"Down-regulation of DNA polymerases kappa, eta, iota, and zeta in human lung, stomach, and colorectal cancers.","Pan Q, Fang Y, Xu Y, Zhang K, Hu X.",https://pubmed.ncbi.nlm.nih.gov/15617831/,"Human DNA polymerases kappa, eta, iota, and zeta are responsible for the translesion DNA synthesis. Numerous in vitro studies indicated that these enzymes may contribute to DNA lesion-triggered and spontaneous mutation. We measured the transcripts of these 4 enzymes in 131 self-paired cancerous and non-tumor samples, including 23 lung cancers, 49 stomach cancers, and 59 colorectal cancers. Our "
880,Focus on skin cancer association and progression under TNF antagonist therapy.,"Piérard-Franchimont C, Piérard GE, Quatresooz P.",https://pubmed.ncbi.nlm.nih.gov/21762036/," Their prevalence is higher in immunocompromized patients. 
    


          Areas covered:
        
      
      Peer-reviewed articles about human skin cancers possibly related to TNF antagonists. The occurrence and growth kinetics of NMSC are possibly increased in some patients under TNF antagonist therapy. Other issues of such biological treatment suggested include the activation of other distinct skin malignancies, including malignant melanoma. Benign melanocytic tumours appear to be boosted as well. At present, most of the reported findings only represent anecdotal case reports. The influence of cumulative co-factors must not be neglected, particularly the effect of other therapies administered to the patients. The occurrence of antibodies to some TNF antagonists may decrease both the treatment efficacy and the risk of skin cancer progression.
    


          Expert opinion:
        
      
      More research needs to be performed in order to firmly establish and understand the risk of anti-TNF biologicals in the area of human skin cancers. At present, NMSC progression appears to be boosted on areas of skin field cancerization. Benign melanocytic naevi may develop as well."
881,Optimization of the classical oral cancerization protocol in hamster to study oral cancer therapy.,"Santa Cruz IS, Garabalino MA, Trivillin VA, Itoiz ME, Pozzi ECC, Thorp S, Curotto P, Guidobono JS, Heber EM, Nigg DW, Schwint AE, Monti Hughes A.",https://pubmed.ncbi.nlm.nih.gov/32297432/," Dimethylbenz[a]anthracene (DMBA) cancerization induces early severe mucositis, affecting animal's welfare and causing tissue loss and pouch shortening. ""Short"" pouches cannot be everted for local irradiation for boron neutron capture therapy (BNCT). Our aim was to optimize the DMBA classical cancerization protocol to avoid severe mucositis, without affecting tumor development. We evaluated BNCT in animals cancerized with this novel protocol.
    


          Materials and  BNCT mediated by boronophenylalanine (BPA) was performed in both groups.
    


           Tumor development and the histologic characteristics of tumor and precancerous tissue were not affected by the interruptions. For both groups, overall tumor response was more than 80%, with a similar incidence of BNCT-induced severe mucositis.
    


          Conclusion(s):
        
      
      The twice-interrupted protocol reduced severe mucositis during cancerization without affecting tumor development. This favored the animal's welfare and reduced the number of animals to be cancerized for our studies, without affecting BNCT response."
882,Unexpected guests in the tumor microenvironment: microbiome in cancer.,"Wong-Rolle A, Wei HK, Zhao C, Jin C.",https://pubmed.ncbi.nlm.nih.gov/33296049/,"Although intestinal microbiome have been established as an important biomarker and regulator of cancer development and therapeutic response, less is known about the role of microbiome at other body sites in cancer. Emerging evidence has revealed that the local microbiota make up an important part of the tumor microenvironment across many types of cancer, especially in cancers arising from mucosal sites, including the lung, skin and gastrointestinal tract. The populations of bacteria that reside specifically within tumors have been found to be tumor-type specific, and mechanistic studies have demonstrated that tumor-associated microbiota may directly regulate cancer initiation, progression and responses to chemo- or immuno-therapies. This review aims to provide a comprehensive review of the important literature on the microbiota in the cancerous tissue, and their function and mechanism of action in cancer development and treatment."
883,Application of a Neural Network Whole Transcriptome-Based Pan-Cancer Method for Diagnosis of Primary and Metastatic Cancers.,"Grewal JK, Tessier-Cloutier B, Jones M, Gakkhar S, Ma Y, Moore R, Mungall AJ, Zhao Y, Taylor MD, Gelmon K, Lim H, Renouf D, Laskin J, Marra M, Yip S, Jones SJM.",https://pubmed.ncbi.nlm.nih.gov/31026023/,"Importance:
        
      
      A molecular diagnostic 
    


           Testing was performed retrospectively on untreated primary cancers and treated metastases from volunteer adult patients at BC Cancer in Vancouver, British Columbia, from January 1, 2013, to March 31, 2016, and testing spanned 10 822 samples and 66 output classes representing untreated primary cancers (n = 40) and adjacent normal tissues (n = 26). SCOPE's performance was demonstrated on 211 untreated primary mesothelioma cancers and 201 treatment-resistant metastatic cancers. Finally, SCOPE was used to identify the putative site of origin in 15 cases with initial presentation as cancers with unknown primary of origin.
    


           Demographic data were not available for all data sets. Among the training data set, 5157 of 10 244 (50.3%) were male and the mean (SD) age was 58.9 (14.5) years. Testing was performed on 211 patients with untreated primary mesothelioma (173 [82.0%] male; mean [SD] age, 64.5 [11.3] years); 201 patients with treatment-resistant cancers (141 [70.1%] female; mean [SD] age, 55.6 [12.9] years); and 15 patients with cancers of unknown primary of origin; among the treatment-resistant cancers, 168 were metastatic, and 33 were the primary presentation. An accuracy rate of 99% was obtained for primary epithelioid mesotheliomas tested (125 of 126). The remaining 85 mesotheliomas had a mixed etiology (sarcomatoid mesotheliomas) and were correctly identified as a mixture of their primary components, with potential implications in resolving subtypes and incidences of mixed histology. SCOPE achieved an overall mean (SD) accuracy rate of 86% (11%) and F1 score of 0.79 (0.12) on the 201 treatment-resistant cancers and matched 12 of 15 of the putative diagnoses for cancers with indeterminate diagnosis from conventional pathology.
    


          Conclusions and relevance:
        
      
      These  SCOPE uses the whole transcriptomes from normal and tumor tissues, and  Genes most relevant in SCOPE's decision making were examined, and several are known biological markers of respective cancers. SCOPE may be applied as an orthogonal diagnostic "
884,[Field cancerization in the face of a 44-year-old female welder].,"Kristensen RN, Sørensen JA.",https://pubmed.ncbi.nlm.nih.gov/26099185/,"Welding generates ultraviolet radiation and has been suggested to cause skin cancer. However, it remains questionable whether welding is in fact causally associated with the development of skin cancer. We report on a 44-year-old female with ten years occupational experience as a welder, who developed multiple squamous cell carcinomas located exclusively on the right side of her face. During welding she had experienced numerous facial burns limited to the right side. This marked anatomical relationship between exposure and illness supports a causal association between welding and skin cancer."
885,Vascular density of superficial esophageal squamous cell carcinoma determined by direct observation of resected specimen using narrow band imaging with magnifying endoscopy.,"Kikuchi D, Iizuka T, Hoteya S, Nomura K, Kuribayashi Y, Toba T, Tanaka M, Yamashita S, Furuhata T, Matsui A, Mitani T, Inoshita N, Kaise M.",https://pubmed.ncbi.nlm.nih.gov/28881911/,"Observation of the microvasculature using narrow band imaging (NBI) with magnifying endoscopy is useful for diagnosing superficial squamous cell carcinoma. Increased vascular density is indicative of cancer, but not many studies have reported differences between cancerous and noncancerous areas based on an  We observed specimens of endoscopic submucosal dissection (ESD) using NBI magnification, and determined the vascular density of cancerous and noncancerous areas. A total of 25 lesions of esophageal squamous cell carcinoma that were dissected en bloc by ESD between July 2013 and December 2013 were subjected to NBI magnification. We constructed a device that holds an endoscope and precisely controls the movement along the vertical axis in order to observe submerged specimens by NBI magnification. NBI image files of both cancerous (pathologically determined invasion depth, m1/2) and surrounding noncancerous areas were created and subjected to vascular density assessment by two endoscopists who were blinded to clinical information. The invasion depth was m1/2 in 20, m3/sm1 in four and sm2 in one esophageal cancer lesion. Mean vascular density was significantly increased in cancerous areas (37.6 ± 16.3 vessels/mm2) compared with noncancerous areas (17.6 ± 10.0 vessels/mm2) (P < 0.05). The correlation coefficients between vascular density determined by two endoscopists were 0.86 and 0.81 in cancerous and noncancerous areas, respectively. Receiver operating curve (ROC) analysis revealed that the area under the curve (AUC) of vascular density was 0.895 (95% CI, 0.804-0.986). For this ROC curve, sensitivity was 78.3% and specificity was 87.0% when the cutoff value of vascular density was 26 vessels/mm2. NBI magnification confirmed significant increases in vascular density in cancerous areas compared with noncancerous areas in esophageal squamous cell carcinoma. The rates of agreement between vascular density values determined by two independent operators were high."
886,Embodied decisions unfolding over time: a meta-ethnography systematic review of people with cancer's reasons for delaying or declining end-of-life care.,"Young J, Lyons A, Egan R, Dew K.",https://pubmed.ncbi.nlm.nih.gov/38369452/," An important yet less researched area is why people approaching the end-of-life decline a referral when they are offered services. This review focused on synthesising literature on patients in the last months of life due to a cancer diagnosis who have declined a referral to end-of-life care.
    


           Two researchers independently reviewed and critically appraised the studies. Using meta-ethnographic 
    


           The included studies can be reconceptualised with the key concept of 'embodied decisions unfolding over time'. It emphasises the iterative, dynamic, situational, contextual and relational nature of decisions about end-of-life care that are grounded in people's physical experiences. The primary influences on how that decision unfolded for patients were (1) the communication they received about end-of-life care; (2) uncertainty around their prognosis, and (3) the evolving situations in which the patient and family found themselves. Our review identified contextual, person and medical factors that helped to shape the decision-making process.
    


          Conclusions:
        
      
      Decisions about when (and for some, whether at all) to accept end-of-life care are made in a complex system with preferences shifting over time, in relation to the embodied experience of life-limiting cancer. Time is central to patients' end-of-life care decision-making, in particular estimating how much time one has left and patients' embodied knowing about when the right time for end-of-life care is. The multiple and intersecting domains of health that inform decision-making, namely physical, mental, social, and existential/spiritual as well as emotions/affect need further exploration. The integration of palliative care across the cancer care trajectory and earlier "
887,Overexpression of aldose reductase in human cancer tissues.,"Saraswat M, Mrudula T, Kumar PU, Suneetha A, Rao Rao TS, Srinivasulu M, Reddy B.",https://pubmed.ncbi.nlm.nih.gov/17136009/," Some recent studies have shown overexpression of AR and AR-like proteins in human liver cancers and some cancer cell lines such as HepG2 and HeLa cells. However, apart from hepatic cancer tissue, the status of AR expression has not been reported in other human cancer tissues. Therefore, in this preliminary report, the expression of AR in a few other commonly occurring cancer tissues was investigated.
    


          Material/ Tumor area and tumor characteristics were determined by histopathological analysis. The expression and activity of AR in tumor and non-tumor areas was carried out by immunohistochemical, immunoblotting, and enzyme activity studies.
    


           Furthermore, biochemical data revealed that the specific activity of AR was higher in tumor areas than in non-tumor regions of these tissues. The overexpression of AR in tumor tissue was further validated by immunohistochemistry in the case of breast tissue.
    


          Conclusions:
        
      
      These preliminary  However, the incidence of AR overexpression and its role in drug resistance needs to be established with a large number of samples of various cancers."
888,Mucinous adenocarcinoma caused by cancerization from a ciliated multinodular papilloma tumor: A case report.,"Chen F, Ren F, Zhao H, Xu X, Chen J.",https://pubmed.ncbi.nlm.nih.gov/33811447/,"Ciliated multinodular papilloma tumor (CMPT), a subtype of proximal bronchiolar adenoma (BA), is a rare mucin-producing papillary tumor arising in the peripheral lung. The nature of CMPT is so far controversial. The hypothesis that CMPT is a precancerous lesion that can lead to mucinous adenocarcinoma requires further research. A 61-year-old man with a ground-glass opacity (GGO) suspected to be lung adenocarcinoma in the right lower lobe of his lung underwent surgical treatment. Postoperative pathology suggested that the patient had mucinous adenocarcinoma caused by cancerization from CMPT. Targeted next-generation sequencing (NGS) was utilized to detect driver mutations in tumor DNA. Among the identified mutated genes, there were regrettably no high frequency mutations. This report describes a case of mucinous adenocarcinoma caused by cancerization from CMPT, indicating that CMPT may be a neoplasm rather than a metaplastic process and provides histological evidence for the hypothesis that CMPT is a precancerous lesion of mucinous adenocarcinoma."
889,SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.,"Hu-Lieskovan S, Bhaumik S, Dhodapkar K, Grivel JJB, Gupta S, Hanks BA, Janetzki S, Kleen TO, Koguchi Y, Lund AW, Maccalli C, Mahnke YD, Novosiadly RD, Selvan SR, Sims T, Zhao Y, Maecker HT.",https://pubmed.ncbi.nlm.nih.gov/33268350/,"Since the publication of the Society for Immunotherapy of Cancer's (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients."
890,Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases.,"Kumar R, Paul AM, Amjesh R, George B, Pillai MR.",https://pubmed.ncbi.nlm.nih.gov/32820388/,"Most epithelial cancer types are polygenic in nature and are driven by coordinated dysregulation of multiple regulatory pathways, genes, and protein modifications. The process of coordinated regulation of cancer promoting pathways in response to extrinsic and intrinsic signals facilitates the dysregulation of several pathways with complementary functions, contributing to the hallmarks of cancer. Dysregulation and hyperactivation of cell surface human epidermal growth factor receptors (HERs) and cytoskeleton remodeling by p21-activated kinases (PAKs) are two prominent interconnected aspects of oncogenesis. We briefly discuss the discoveries and significant advances in the area of coordinated regulation of HERs and PAKs in the development and progression of breast and other epithelial cancers. We also discuss how initial studies involving heregulin signaling via HER3-HER2 axis and HER2-overexpressing breast cancer cells not only discovered a mechanistic role of PAK1 in breast cancer pathobiology but also acted as a bridge in generating a broader cancer research interest in other PAK family members and cancer types and catalyzed establishing the role of PAKs in human cancer, at-large. In addition, growth factor stimulation of the PAK pathway also helped to recognize new facets of PAKs, connecting the PAK pathway to oncogenesis, nuclear signaling, gene expression, mitotic progression, DNA damage response, among other phenotypic responses, and shaped the field of PAK cancer research. Finally, we recount some of the current limitations of HER- and PAK-directed therapeutics in counteracting acquired therapeutic resistance and discuss how cancer's as a polygenic disease may be best targeted with a polygenic approach."
891,[Multiple primary malignant neoplasms. Report of a rare case with 5 metachronous tumors].,"Mosca F, Stracqualursi A, Lipari G, Persi A, Latteri S.",https://pubmed.ncbi.nlm.nih.gov/11280822/,"The Authors report on a patient admitted several times for the occurrence of five multiple metachronous primary malignancies (laryngeal carcinoma, endometrial adenocarcinoma, rectal cancerous polyp, ampulla of Vater carcinoma and transverse colon cancer). All five carcinomas were independent primary cancers, and the lengthy time intervals between the onsets of the individual tumours supports their independent non-metastatic origin. Classification, pathogenesis, genetic and environmental interactions of multiple tumours are discussed. In the case reported, a family history of colon cancer was present, while no genetic marker abnormalities or chronic exposure to carcinogens were found. The case report shows that an aggressive, appropriate surgical approach together with thorough follow-up monitoring offers a chance of long-term survival for patients with metachronous malignant primary tumours."
892,The natural history of colorectal adenomas and early cancer.,Risio M.,https://pubmed.ncbi.nlm.nih.gov/22945585/,"Adenomas represent the morphological precursors of the vast majority of colorectal cancers: although every adenoma has the capacity of malignant evolution, most adenomas stabilize their progression or even regress. Pathological factors are predictive of the natural history of adenomas in terms of potential and time interval for becoming malignant. Regression of adenomas is histologically well established, but it is thought to be a dynamic process, with cycling phases of regression and growth. Colorectal carcinoma invading the submucosa but not the muscular layer represents the earliest form of clinically relevant colorectal cancer. Grade of differentiation of carcinoma, lymphovascular invasion, and state of the resection margin predict the risk of metastasis. Microstaging of invasive cancer together with tumuor budding allow the metastatic risk to be further stratified into minimal, low, and high. Two distinct profiles are identifiable in the natural history of cancerous adenomas: blocking the growth of early cancer and allowing its progression towards advanced cancer. Thus, biomarkers to distinguish between progressive and non-progressive pT1 neoplasia are needed."
893,Cadherin 13 in cancer.,"Andreeva AV, Kutuzov MA.",https://pubmed.ncbi.nlm.nih.gov/20607704/,"We review the evidence suggesting the involvement of Cadherin 13 (CDH13, T-cadherin, H-cadherin) in various cancers. CDH13 is an atypical member of the cadherin family, devoid of a transmembrane domain and anchored to the exterior surface of the plasma membrane via a glycosylphosphatidylinositol anchor. CDH13 is thought to affect cellular behavior largely through its signaling properties. It is often down-regulated in cancerous cells. CDH13 down-regulation has been associated with poorer prognosis in various carcinomas, such as lung, ovarian, cervical and prostate cancer. CDH13 re-expression in most cancer cell lines inhibits cell proliferation and invasiveness, increases susceptibility to apoptosis, and reduces tumor growth in in vivo models. These properties suggest that CDH13 may represent a possible target for therapy in some cancers. At the same time, CDH13 is up-regulated in blood vessels growing through tumors and promotes tumor neovascularization. In contrast to most cancer cell lines, CDH13 overexpression in endothelial cells promotes their proliferation and migration, and has a pro-survival effect. We also discuss molecular mechanisms that may regulate CDH13 expression and underlie its roles in cancer."
894,Testicular metastasis from adenocarcinoma of the esophagus.,"Gillen S, Feith M, Gertler R, Langer R, Massmann J, Sarbia M, Friess H.",https://pubmed.ncbi.nlm.nih.gov/19231438/,"We report the case of a 61-year-old patient, operated on for adenocarcinoma of the esophagus in 2002, who presented in 2007 with a hydrocele and palpable mass of the right testis. Operative exploration and orchiectomy were performed. Histopathology revealed a testicular and epididymidal metastasis from the esophageal adenocarcinoma. Only a few testicular metastases have been reported from gastrointestinal cancers. No case of testicular metastasis from esophageal cancer, including Barrett's carcinoma has been reported. In most cases, the testicular tumor was accompanied by a hydrocele. Therefore, cancerous and metastatic lesions should be considered in the management of hydrocele and testicular masses."
895,Potential tumor-suppressive role of monoglyceride lipase in human colorectal cancer.,"Sun H, Jiang L, Luo X, Jin W, He Q, An J, Lui K, Shi J, Rong R, Su W, Lucchesi C, Liu Y, Sheikh MS, Huang Y.",https://pubmed.ncbi.nlm.nih.gov/22349814/,"Human monoglyceride lipase (MGL) is a recently identified lipase and very little is known about its regulation and function in cellular regulatory processes, particularly in context to human malignancy. In this study, we investigated the regulation and function of MGL in human cancer(s) and report that MGL expression was either absent or reduced in the majority of primary colorectal cancers. Immunohistochemical studies showed that reduction of MGL expression in the colorectal tumor tissues predominantly occurred in the cancerous epithelial cells. MGL was found to reside in the core surface of a cellular organelle named 'lipid body'. Furthermore, it was found to interact selectively with a number of phospholipids, including phosphatidic acid and phosphoinositol(3,4,5)P3, phosphoinositol(3,5)P2, phosphoinositol(3,4)P2 and several other phosphoinositides, and among all phosphoinositides analyzed, its interaction with PI(3,4,5)P3 was found to be the strongest. In addition, overexpression of MGL suppressed colony formation in tumor cell lines and knockdown of MGL  Taken together, our "
896,"The collagenase activities, interstitial collagenase and type IV collagenase, in human stomach cancer: with special reference to local spreading and lymph node metastasis.",Otani Y.,https://pubmed.ncbi.nlm.nih.gov/2175001/,"In order to investigate the role of collagenase in cancer invasion and metastasis, two collagenase activities of interstitial collagenase and type IV collagen degrading enzyme (type IV collagenase) were determined in 40 cases of human stomach cancer tissue. Elevated cancers which are known to have a propensity to cause blood-borne metastases showed higher activities of both interstitial collagenase and type IV collagenase than flat or ulcerous type of cancer. Using the parameters of lymph node metastasis vs tumor size or vs depth of cancerous invasion into the stomach wall, classification of the cases was attempted according to the degree of malignancy. In the cases with marked lymph node metastases in spite of small tumor size and/or shallow cancerous invasion into the stomach wall, type IV collagenase activity was higher than that in the cases with lower malignancy (p less than 0.025, p less than 0.05, respectively). These  Type IV collagenase activity in stomach cancer tissue could be one of the useful biological markers for the degree of malignancy."
897,The National Cancer Data Base report on gastric carcinoma.,"Hundahl SA, Menck HR, Mansour EG, Winchester DP.",https://pubmed.ncbi.nlm.nih.gov/9404711/," In combination with other programs of the American College of Surgeons Commission on Cancer, the NCDB offers a working example of voluntary, accurate, and cost-effective ""outcomes management"" on a both a local and a national scale.
    


          6% of total NCDB cases). In addition to describing trends, this report focuses on 5-year relative survival for a cohort of 1987-1988 cases staged according to the third edition of the American Joint Committee on Cancer's TNM classification, as well as patterns of care for a cohort of 1992-1993 cases.
    


           Without noteworthy changes in stage distribution, demographics, or other factors, the proportion of patients treated by total gastrectomy is increasing slightly, but proximal gastrectomy for proximal cancers remains surprisingly popular. The proportion of cases receiving postoperative adjuvant treatment has declined slightly. Presumably because of advanced age and/or medical infirmity, a substantial proportion of U.S. patients with disease at every stage receive no treatment for cancer.
    


          Conclusions:
        
      
      This analysis of patterns of care has revealed unexplained variations in treatment and opportunities for improvement. Treatment of the elderly, infirm patient with gastric carcinoma appears problematic."
898,Overexpression of insulin-like growth factor binding protein 3 in oral squamous cell carcinoma.,"Zhong LP, Yang X, Zhang L, Wei KJ, Pan HY, Zhou XJ, Li J, Chen WT, Zhang ZY.",https://pubmed.ncbi.nlm.nih.gov/19020726/,"Previously, we established an in vitro cellular carcinogenesis model of oral squamous cell carcinoma (OSCC), including a human immortalized oral epithelial cell (HIOEC) line and its derived cancerous HB96 cell line. Further cDNA microarray analysis showed a significant up-regulated gene, insulin-like growth factor binding protein 3 (IGFBP3), accompanying with in vitro cancerization from HIOEC to HB96. In order to investigate IGFBP3 up-regulation and its potential usefulness as a molecular marker in OSCC, we detected the IGFBP3 expression with a panel of OSCC lines, and clinical samples of cancerous tissues and paired adjacent non-malignant epithelia from primary OSCC patients. Western blotting and real-time PCR showed increased IGFBP3 mRNA level and protein expression in OSCC cell lines compared with HIOEC in vitro; immunohistochemistry and real-time PCR also showed increased IGFBP3 mRNA level and protein expression in cancerous tissues compared with adjacent non-malignant epithelia from OSCC patients. Positive correlations were found between the IGFBP3 protein-positive grade in cancerous tissue and the tumor size as well as lymph node metastasis, a larger tumor size and positive lymph node metastasis indicating a higher level of IGFBP3 protein-positive grade. Based on these "
899,Deciphering the genetic and epigenetic architecture of prostate cancer.,"Nazir SU, Mishra J, Maurya SK, Ziamiavaghi N, Bodas S, Teply BA, Dutta S, Datta K.",https://pubmed.ncbi.nlm.nih.gov/39032950/,"Prostate cancer, one of the most frequently diagnosed cancers in men, leads to significant mortality worldwide. Its study is important due to the complexity and diversity in its progression, highlighting the urgent need for improved therapeutic strategies. This chapter probes into the genetic and epigenetic factors influencing prostate cancer progression, underscoring the importance of understanding the disease's molecular fundamentals for the development of targeted therapies. It specifically reviews the role of key genetic mutations in genes such as Androgen Receptor, TP53, SPOP, FOXA1 and PTEN which are crucial for the disease onset and a progression. Furthermore, it examines the impact of epigenetic modifications, including DNA methylation and histone modification, which contribute to the cancer's progression by affecting gene expression and cellular behavior. Further, in this chapter we delve into the underlying signaling mechanism, the advancements in targeting genetic and epigenetic alterations in prostate cancer. These findings have revealed promising targets for therapeutic advancements, aiming to understand and identify promising avenues for future therapies. This chapter improves our current understanding of prostate cancer genetic and epigenetic landscape, emphasizing the necessity of advancing our knowledge to refine and expand treatment options for prostate cancer patients."
900,Microfluidics and circulating tumor cells.,"Dong Y, Skelley AM, Merdek KD, Sprott KM, Jiang C, Pierceall WE, Lin J, Stocum M, Carney WP, Smirnov DA.",https://pubmed.ncbi.nlm.nih.gov/23266318/,"Circulating tumor cells (CTCs) are shed from cancerous tumors, enter the circulatory system, and migrate to distant organs to form metastases that ultimately lead to the death of most patients with cancer. Identification and characterization of CTCs provides a means to study, monitor, and potentially interfere with the metastatic process. Isolation of CTCs from blood is challenging because CTCs are rare and possess characteristics that reflect the heterogeneity of cancers. Various  Microfluidics offers an opportunity to create a next generation of superior CTC enrichment devices. This review focuses on various microfluidic approaches that have been applied to date to capture CTCs from the blood of patients with cancer."
901,"Breast cancer in young women in Latin America: an unmet, growing burden.","Villarreal-Garza C, Aguila C, Magallanes-Hoyos MC, Mohar A, Bargalló E, Meneses A, Cazap E, Gomez H, López-Carrillo L, Chávarri-Guerra Y, Murillo R, Barrios C.",https://pubmed.ncbi.nlm.nih.gov/24277771/,"Breast cancer (BC) is the leading cause of malignancy-related deaths among women aged ≤45 years. There are unexplored and uncertain issues for BC in this particular group in Latin America. The aim of this study is to evaluate BC incidence and mortality among young women and related clinicopathological and survivorship aspects in this region.
    


          Materials and  We requested collaboration from the 12 different national cancer institutes in Latin America through SLACOM, the Latin American and Caribbean Society of Medical Oncology, and conducted a systematic literature review to obtain local data regarding the prevalence of BC among young women and their characteristics, outcomes, and survivorship-related issues.
    


           12% and 14% vs. 7%, respectively). We found only a few Latin American series addressing this topic, and prevalence varied between 8% and 14%. Stage II and III disease, high histological grade, and triple-negative and HER2 BC were features frequently observed among young Latin American BC patients.
    


          Conclusion:
        
      
      The rising incidence and mortality of BC in young Latin American women is a call to action in the region. It is necessary to monitor the epidemiological and clinical data through reliable cancer registries and to consider the implementation of protocols for education of patients and health professionals. This unmet, growing burden must be considered as a top priority of the national programs in the fight against BC, and models of specialized units should be implemented for this particular group of patients to provide better care for this emergent challenge."
902,Cytogenetic analysis of epithelial ovarian cancer's stem cells: an overview on new diagnostic and therapeutic perspectives.,"Laganà AS, Colonese F, Colonese E, Sofo V, Salmeri FM, Granese R, Chiofalo B, Ciancimino L, Triolo O.",https://pubmed.ncbi.nlm.nih.gov/26513872/,"Ovarian cancer is one of the most frequent solid tumor that shows clearly biphasic behaviour in response to chemotherapy, with the majority of patients who achieved complete remission after the first cycle of chemotherapy, and subsequently present a relapse which, in most cases, leads to death. Epithelial ovarian cancer (EOC) arises as a consequence of genetic alterations that affect the cells of the ovarian surface, which leads to changes that occur through the activation of oncogenes and inactivation of tumor suppressor genes. The progression of EOC is characterized by a series of combined epigenetic aberrations, including the most important of those determined by the loss of methylation of certain regions of DNA encoding genes such as Ras-association domain-containing family 1 [(RASSF1A) tumor suppressor], death-associated protein kinase [(DAPK) protein kinase associated with the regulation of apoptosis], human sulfa- tase-I [(hSulf-1) sulfatase, which plays a key role in the regulation of apoptosis], breast cancer 1 gene [(BRCA1) tumor suppressor gene, involved in the processes of DNA repair], and HOXAI0 (gene required to promote many transcription factors). To date, accumulating evidence suggests that the initial clinical response is due primarily to the therapeutic efficacy of chemotherapy against differentiated can- cer cells that constitute the bulk of the tumor, whereas the high rate of recurrence is thought to be due to remaining drug-resistant cells, biologically distinct, identified as cancer stem cells (CSC). Current efforts are focusing on genetic and cytological definition of CSC, to guide the development of new diagnostic, and therapeutic perspectives."
903,Integrating ensemble systems biology feature selection and bimodal deep neural network for breast cancer prognosis prediction.,"Cheng LH, Hsu TC, Lin C.",https://pubmed.ncbi.nlm.nih.gov/34290286/,"Breast cancer is a heterogeneous disease. To guide proper treatment decisions for each patient, robust prognostic biomarkers, which allow reliable prognosis prediction, are necessary. Gene feature selection based on microarray data is an approach to discover potential biomarkers systematically. However, standard pure-statistical feature selection approaches often fail to incorporate prior biological knowledge and select genes that lack biological insights. Besides, due to the high dimensionality and low sample size properties of microarray data, selecting robust gene features is an intrinsically challenging problem. We hence combined systems biology feature selection with ensemble learning in this study, aiming to select genes with biological insights and robust prognostic predictive power. Moreover, to capture breast cancer's complex molecular processes, we adopted a multi-gene approach to predict the prognosis status using deep learning classifiers. We found that all ensemble approaches could improve feature selection robustness, wherein the hybrid ensemble approach led to the most robust  Among all prognosis prediction models, the bimodal deep neural network (DNN) achieved the highest test performance, further verified by survival analysis. In summary, this study demonstrated the potential of combining ensemble learning and bimodal DNN in guiding precision medicine."
904,Strategic disruption of cancer's powerhouse: precise nanomedicine targeting of mitochondrial metabolism.,"Lin P, Lu Y, Zheng J, Lin Y, Zhao X, Cui L.",https://pubmed.ncbi.nlm.nih.gov/38849914/,"Mitochondria occupy a central role in the biology of most eukaryotic cells, functioning as the hub of oxidative metabolism where sugars, fats, and amino acids are ultimately oxidized to release energy. This crucial function fuels a variety of cellular activities. Disruption in mitochondrial metabolism is a common feature in many diseases, including cancer, neurodegenerative conditions and cardiovascular diseases. Targeting tumor cell mitochondrial metabolism with multifunctional nanosystems emerges as a promising strategy for enhancing therapeutic efficacy against cancer. This review comprehensively outlines the pathways of mitochondrial metabolism, emphasizing their critical roles in cellular energy production and metabolic regulation. The associations between aberrant mitochondrial metabolism and the initiation and progression of cancer are highlighted, illustrating how these metabolic disruptions contribute to oncogenesis and tumor sustainability. More importantly, innovative strategies employing nanomedicines to precisely target mitochondrial metabolic pathways in cancer therapy are fully explored. Furthermore, key challenges and future directions in this field are identified and discussed. Collectively, this review provides a comprehensive understanding of the current state and future potential of nanomedicine in targeting mitochondrial metabolism, offering insights for developing more effective cancer therapies."
905,Targeting the genetic landscape of oral potentially malignant disorders has the potential as a preventative strategy in oral cancer.,"Prime SS, Cirillo N, Cheong SC, Prime MS, Parkinson EK.",https://pubmed.ncbi.nlm.nih.gov/34139286/,"This study reviews the molecular landscape of oral potentially malignant disorders (OPMD). We examine the impact of tumour heterogeneity, the spectrum of driver mutations (TP53, CDKN2A, TERT, NOTCH1, AJUBA, PIK3CA, CASP8) and gene transcription on tumour progression. We comment on how some of these mutations impact cellular senescence, field cancerization and cancer stem cells. We propose that OPMD can be monitored more closely and more dynamically through the use of liquid biopsies using an appropriate biomarker of transformation. We describe new gene interactions through the use of a systems biology approach and we highlight some of the first studies to identify functional genes using CRISPR-Cas9 technology. We believe that this information has translational implications for the use of re-purposed existing drugs and/or new drug development. Further, we argue that the use of digital technology encompassing clinical and laboratory-based data will create relevant datasets for machine learning/artificial intelligence. We believe that therapeutic intervention at an early molecular premalignant stage should be an important preventative strategy to inhibit the development of oral squamous cell carcinoma and that this approach is applicable to other aerodigestive tract cancers."
906,CD9 expression in gastric cancer and its significance.,"Hori H, Yano S, Koufuji K, Takeda J, Shirouzu K.",https://pubmed.ncbi.nlm.nih.gov/15047125/," Previous studies have reported that reduced expression of CD9 is related to aggressive behavior of cancer cells. However, the cause-and-effect relationship between the CD9 expression level and the state of malignancy remains unclear. Here, we investigated the connection between the CD9 expression level and the state of malignancy in gastric cancers.
    


          Materials and  In total, specimens from 78 patients were used for immunohistological staining and specimens from 57 patients were subjected to Northern blotting. Paired samples of tumor/normal tissues obtained from five cases of gastric cancer were used for Western blotting.
    


           Contrary to previous reports for other cancers, CD9 expression was intensified in cancerous areas of gastric cancers in comparison with noncancerous areas in the same patient. When analyzed by the malignancy status based on the clinicopathological diagnosis, there was a tendency that CD9 expression was observed in severe vessel invasion, active lymph node metastasis, and advanced stage.
    


          Conclusions:
        
      
      CD9 expression was rather intensified in gastric cancer tissue in comparison with normal tissues. CD9 expression was more prominent in advanced gastric cancer."
907,Methods of active immunotherapy and viral oncolysis in some forms of cancer.,"Neagoe G, Stoian M.",https://pubmed.ncbi.nlm.nih.gov/3014637/,"In some cancers with a high antigenicity (gastric, intestinal, mammary, laryngeal, etc.) the authors associated to the classical treatment an autovaccine prepared by combining the tumoral extract (obtained by trituration, sonication and centrifugation, and stored at -80 degrees C) with some mitogens (phytohemagglutinin) and adjuvants (ovalbumin, tuberculin, lymphocyte promotion factor, etc.) obtaining a greater survival (4-6 years). The association of viruses with an oncolytic action (mumps virus) to the active unspecific immunotherapy in some cancerous structures (peritoneal, pleuropulmonary and synovial malignant mesothelioma, malignant cholangioma of the liver, hepatic metastases of some adenocarcinomas of the colon, gastric cirrhous, clearly differentiated macrocellular carcinomas of the lung, pulmonary mucoid adenocarcinomas, traditional recurrent carcinomas of the urinary bladder), in which all other oncotherapeutic resources have been exhausted, induced slow involution up to disappearance of the tumor and a favourable evolution of the patients without signs-of recurrence after 5-7 years in 73% of cases. To obtain the expected "
908,Electronic Cigarette Use among Survivors of Smoking-Related Cancers in the United States.,"Akinboro O, Nwabudike S, Elias R, Balasire O, Ola O, Ostroff JS.",https://pubmed.ncbi.nlm.nih.gov/31501150/," We sought to estimate the prevalence of e-cigarette use and examine its associations with cigarette smoking and smoking quit attempts among smoking-related cancer survivors in the United States.
    


           We calculated the prevalence of current e-cigarette use and utilized multinomial logistic regression in examining the independent association between e-cigarette use and cigarette smoking. Appropriate survey weights were applied in estimating the prevalence rates, relative risk ratios (RRR), ORs, and confidence intervals (CI).
    


           The prevalence of current e-cigarette use was 3.18% (95% CI, 2.40-3.96). Current e-cigarette users were 83 times as likely as never users to be current cigarette smokers (RRR, 82.89; 95% CI, 16.54-415.37). Among those with a history of cigarette smoking, current e-cigarette users were 90% less likely to be former smokers (OR, 0.10; 95% CI, 0.05-0.18). No association was seen between current e-cigarette use and a smoking quit attempt in the prior year.
    


          Conclusions:
        
      
      E-cigarette use among cigarette ever smokers was associated with a lower likelihood of being a former smoker/having quit smoking, and e-cigarette use was not associated with smoking quit attempts.
    


          Impact:
        
      
      Our findings do not provide evidence that e-cigarette use facilitates smoking cessation among smoking-related cancer survivors."
909,A Data Mining Approach to Diagnose Cancer for Therapeutic Decision Making.,"Rajan JR, Chelvan AC.",https://pubmed.ncbi.nlm.nih.gov/30626737/," The uncommon cancers are generally sporadic and there are no pre-defined techniques/tools for the diagnosis. Identifying the diseases at an early stage can avoid the cancerous cells from metastasis to different body parts through tissue, lymph system and blood. It is very difficult for the parents to know that the child is suffering from cancer until the cancer has reached to Stage 4. The duration it takes the cancer to reach Stage 4 can depend on many factors but the fact about childhood cancer is that it is curable to some extent. Diagnoses of the cancer at an early stage, i.e. at Stage 1, from childhood to old age can increase the survival rate of the patients by 85% and also helps to come up with certain therapy.
    


          Materials and  Two approached are being implemented in this paper: Modified version of the Support Vector Machine and Kohonen' s Self Organizing Map to identify the disease during its Stage 1. Annova 
    


          1% and the Kohonen's map has produced an accuracy of 89% with the same set of samples.
    


          Conclusions:
        
      
      Support Vector Machine has yielded a good accuracy  A combination of both the tools can be used based on the type of patients visiting the practitioner. The approaches can assist the medical practitioners as pre-diagnoses tool for the early diagnoses of pediatric cancer."
910,Update on Oral and Oropharyngeal Cancers: A guide for oral health care providers.,"Johnson LB, Reznik AS, Villa A.",https://pubmed.ncbi.nlm.nih.gov/38649286/,"Oral squamous cell carcinomas (OSCC) signs and symptoms may be first identified by dental hygienists during routine extra and intra-oral examinations. A comprehensive extra-oral and intra-oral examination during regular dental hygiene assessment is paramount to identifying oral potentially malignant disorders (OPMD) and cancerous lesions for timely referral and treatment. Integrating a systematic list of questions during the medical and dental assessment along with careful visual and tactile examinations is critical to identifying OPMDs and cancerous lesions. Understanding the relationship between oropharyngeal squamous cell carcinomas (OPSCC) and Human Papilloma Virus (HPV) and how vaccination can prevent HPV-related OPSCC is critical to providing evidence-based recommendations and care. The purpose of this report is to provide an update on current epidemiological trends of OSCC and OPSCC rates in the United States (US) and provide the latest evidence on what dental hygienists must know to improve health outcomes and mitigate the consequences of undiagnosed cancer. This report considers enduring challenges with the annual rise in OPSCC rates and the public health burden of HPV-related cancers in the US. Emphasis on regular, quality continuing education about OSCC and OPSCC is emphasized along with recommendations for evidence-based training."
911,"Autophagy, stress, and cancer metabolism: what doesn't kill you makes you stronger.","Mathew R, White E.",https://pubmed.ncbi.nlm.nih.gov/22442109/,"Altered metabolism is a hallmark of cancer. Oncogenic events that lead to cancerous states reorganize metabolic pathways to increase nutrient uptake, which promotes biosynthetic capabilities and cell-autonomous behavior. Increased biosynthesis dictates metabolic demand for ATP, building blocks, and reducing equivalents, rendering cancer cells metabolically in a perpetually hungry state. Moreover, most chemotherapy agents induce acute metabolic stress that cancer cells must overcome for their survival. These metabolic stress cues in cancer cells can activate and cause dependence on the self-cannibalization mechanism of macroautophagy (autophagy hereafter) for the lysosomal turnover and recycling of organelles and proteins for energy and stress survival. For example, activating mutations in Ras or Ras-effector pathways induce autophagy, and cancer cell lines with Ras activation show elevated levels of basal autophagy that is essential for starvation survival and tumor growth. The metabolic implications of this are profound and multifaceted. First, autophagy-mediated degradation and recycling of cellular substrates can support metabolism and promote survival and tumor growth. Second, acute autophagy activation in response to cancer therapy can potentially lead to refractory tumors resistant to conventional chemotherapy. For example, a specific form of autophagy that targets mitochondria (mitophagy) may also function to promote cell survival by the clearance of damaged mitochondria that are potential sources of reactive oxygen species (ROS). These point to the possibility that autophagy is a unique metabolic need, important for survival as well as therapy resistance in cancer cells. Targeting autophagy in single-agent therapy to sensitize aggressive cancers that are dependent on autophagy for survival or in combination with therapeutic agents that induce autophagy as a resistance mechanism may be an effective therapeutic strategy to treat cancer."
912,Surgical pathology stage by American Joint Commission on Cancer criteria predicts patient survival after preoperative chemoradiation for localized gastric carcinoma.,"Rohatgi PR, Mansfield PF, Crane CH, Wu TT, Sunder PK, Ross WA, Morris JS, Pisters PW, Feig BW, Gunderson LL, Ajani JA.",https://pubmed.ncbi.nlm.nih.gov/16944539/," Therefore, the authors hypothesized that surgical pathology stage would be a better prognosticator of overall survival (OS) than baseline stage.
    


           Patients must have had localized gastric adenocarcinoma and were staged extensively, including endoscopic ultrasonography and laparoscopy. Patients had to be fit for surgery medically with a technically resectable cancer. All patients provided written informed consent. Patients first received induction chemotherapy for up to 2 months followed by chemoradiation (45 grays) and an attempted surgery. OS was correlated with pretreatment and posttreatment parameters, including surgical pathology stage according to American Joint Commission on Cancer criteria.
    


           Nineteen patients (26%) had a pathologic complete response (pathCR), and 55 patients (81%) had a curative (R0) resection. None of the pretreatment parameters correlated with OS; however, longer OS correlated with lower pathologic stage (P < .0001), R0 resection (P < .001), clinical response noted prior to surgery (P = .002), pathCR (P = .004), lower pathologic lymph node classification (P = .006), and lower pathologic tumor classification (P = .03). Pathologic stage and R0 resection were independent prognostic factors for OS (multivariate Cox model; both P = .05).
    


          Conclusions:
        
      
      When preoperative chemoradiation strategy was employed for gastric cancer, the surgical pathology stage, a reflection of cancer's biologic heterogeneity, was a better prognosticator of OS than the baseline clinical stage. Surgical pathology stage, in this setting, may serve as an intermediate endpoint for Phase II/III trials."
913,Ras GTPase-Activating-Like Protein IQGAP1 (IQGAP1) Promotes Breast Cancer Proliferation and Invasion and Correlates with Poor Clinical Outcomes.,"Zeng F, Jiang W, Zhao W, Fan Y, Zhu Y, Zhang H.",https://pubmed.ncbi.nlm.nih.gov/29779034/," As a key integrator of cell signaling pathways, IQGAP1 contributes to the development and progression of several cancers. However, the exact effects and molecular mechanisms of IQGAP1 in breast cancer progression remain poorly understood. MATERIAL AND  To further explore the biological function of IQGAP1 in breast cancer cells, we knocked down IQGAP1 expression in MCF-7 cells and overexpressed it in SK-BR-3 cells.  Moreover, IQGAP1 expression was positively correlated with breast cancer survival rate. IQGAP1 also promoted breast cancer cell proliferation and cell cycle progression and suppressed apoptosis. CONCLUSIONS In conclusion, our "
914,Optimal band imaging system can facilitate detection of changes in depressed-type early gastric cancer.,"Osawa H, Yoshizawa M, Yamamoto H, Kita H, Satoh K, Ohnishi H, Nakano H, Wada M, Arashiro M, Tsukui M, Ido K, Sugano K.",https://pubmed.ncbi.nlm.nih.gov/18061596/," The newly developed optimal band imaging (OBI) system can reconstruct the best spectral images derived from ordinary endoscopic images and enhances the mucosal surface without the use of dyes. This imaging technique is based on narrowing the bandwidth of conventional image arithmetically by using spectral estimation technology.
    


          
    


          Design:
        
      
      Prospective study.
    


          Setting:
        
      
      Jichi Medical University in Japan.
    


          Patients:
        
      
      Twenty-seven cases with depressed-type early gastric cancer.
    


          Main outcome measurement:
        
      
      Comparative study for the success rate of identifying the demarcation line of depressed-type early gastric cancer by using optimal band images and conventional endoscopic images.
    


           With 40-fold magnification of optimal band images, the demarcation was also clearly recognized in all cases. Medical students could point out the demarcation line with significantly greater accuracy by observing the new nonmagnified optimal band images than by the conventional images (P< .0001).
    


          Limitation:
        
      
      Small sample size.
    


          Conclusions:
        
      
      The new contrasting images of the OBI system can delineate the depressed-type early gastric cancer more easily than conventional endoscopy."
915,Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression.,"Lochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, Ogino S.",https://pubmed.ncbi.nlm.nih.gov/24925058/,"The term 'field effect' (also known as field defect, field cancerization, or field carcinogenesis) has been used to describe a field of cellular and molecular alteration, which predisposes to the development of neoplasms within that territory. We explore an expanded, integrative concept, 'etiologic field effect', which asserts that various etiologic factors (the exposome including dietary, lifestyle, environmental, microbial, hormonal, and genetic factors) and their interactions (the interactome) contribute to a tissue microenvironmental milieu that constitutes a 'field of susceptibility' to neoplasia initiation, evolution, and progression. Importantly, etiological fields predate the acquisition of molecular aberrations commonly considered to indicate presence of filed effect. Inspired by molecular pathological epidemiology (MPE) research, which examines the influence of etiologic factors on cellular and molecular alterations during disease course, an etiologically focused approach to field effect can: (1) broaden the horizons of our inquiry into cancer susceptibility and progression at molecular, cellular, and environmental levels, during all stages of tumor evolution; (2) embrace host-environment-tumor interactions (including gene-environment interactions) occurring in the tumor microenvironment; and, (3) help explain intriguing observations, such as shared molecular features between bilateral primary breast carcinomas, and between synchronous colorectal cancers, where similar molecular changes are absent from intervening normal colon. MPE research has identified a number of endogenous and environmental exposures which can influence not only molecular signatures in the genome, epigenome, transcriptome, proteome, metabolome and interactome, but also host immunity and tumor behavior. We anticipate that future technological advances will allow the development of in vivo biosensors capable of detecting and quantifying 'etiologic field effect' as abnormal network pathology patterns of cellular and microenvironmental responses to endogenous and exogenous exposures. Through an 'etiologic field effect' paradigm, and holistic systems pathology (systems biology) approaches to cancer biology, we can improve personalized prevention and treatment strategies for precision medicine."
916,Radioimmunoguided surgery challenges traditional decision making in patients with primary colorectal cancer.,"Arnold MW, Schneebaum S, Berens A, Mojzisik C, Hinkle G, Martin EW Jr.",https://pubmed.ncbi.nlm.nih.gov/1411932/," Reported here is experience with RIGS-influenced therapeutic decisions in patients with primary colorectal cancer.
    


           Pharmacokinetic determination and precordial counts were obtained after injection and weekly until levels were less than 20 counts/2 sec. At surgery abdominal and pelvic explorations were performed, first traditionally by inspection and palpation and then with the hand-held, gamma-detecting probe. RIGS-positive tissue was considered cancerous and removed if possible.
    


           Of those patients with localization, in 24 (80%) additional information was obtained at the time of surgery. In 11 patients (34%) staging changes were made as a  New findings  Eleven (30%) of the original 36 patients became eligible for adjuvant chemotherapy based on current recommendations because of RIGS findings.
    


          Conclusions:
        
      
      In conclusion, the RIGS system provides immediate staging information that impacts on therapeutic interventions, challenging the adequacy of traditional procedures alone for primary colorectal cancer exploration."
917,Impact of homeobox genes in gastrointestinal cancer.,"Joo MK, Park JJ, Chun HJ.",https://pubmed.ncbi.nlm.nih.gov/27729732/,"Homeobox genes, including HOX and non-HOX genes, have been identified to be expressed aberrantly in solid tumors. In gastrointestinal (GI) cancers, most studies have focused on the function of non-HOX genes including caudal-related homeobox transcription factor 1 (CDX1) and CDX2. CDX2 is a crucial factor in the development of pre-cancerous lesions such as Barrett's esophagus or intestinal metaplasia in the stomach, and its tumor suppressive role has been investigated in colorectal cancers. Recently, several HOX genes were reported to have specific roles in GI cancers; for example, HOXA13 in esophageal squamous cell cancer and HOXB7 in stomach and colorectal cancers. HOXD10 is upregulated in colorectal cancer while it is silenced epigenetically in gastric cancer. Thus, it is essential to examine the differential expression pattern of various homeobox genes in specific tumor types or cell lineages, and understand their underlying mechanisms. In this review, we summarize the available research on homeobox genes and present their potential value for the prediction of prognosis in GI cancers."
918,Elf5 - breast cancer's little helper.,"Frend HT, Watson CJ.",https://pubmed.ncbi.nlm.nih.gov/23534926/,"A variety of transcription factors has been shown to regulate lineage commitment in the mammary gland and to be associated with different molecular subtypes of breast cancer. E74-like factor 5 (Elf5) has now been identified as a marker of oestrogen receptor status, and high expression correlates with more aggressive basal cancers and resistance to anti-oestrogens. Manipulation of Elf5 transcript levels perturbs the molecular profiles of luminal and basal subtypes, highlighting the possibility that targeting Elf5 could provide a new approach for the treatment of basal cancers."
919,Pathogenesis sequences in Gejiu miners with lung cancer: an introduction.,"Li B, Ruan Y, Ma L, Hua H, Li Z, Tuo X, Zhou Z, Li T, Liu S, Jin K.",https://pubmed.ncbi.nlm.nih.gov/26163268/,"Tin miners in Gejiu, Yunnan Province, China are at high risk of developing lung cancer with significant occupational characteristics. Tissue samples from these miners presented pathological characteristics, such as fibroplasia in carcinomas, peri-cancerous tissue in lung cancers, and hyperplasia and dysplasia of epithelial cells in peri-cancerous tissue. Carcinomas induced by Yunnan tin mine dust in the animal  A correlated and synergistic relationship was observed between bronchial epithelial cell transformation and fibroblast activation in vitro induced by mine dust. Fibroblast hyperplasia and activation are important factors that promote the transformation and carcinogenesis of epithelial cells. Our findings suggested that pulmonary fibrosis may increase the risk and promote the occurrence of lung cancer, which can lead to lung fiber hyperplasia."
920,Phosphorylation of STAT3 at Tyr705 regulates MMP-9 production in epithelial ovarian cancer.,"Jia ZH, Jia Y, Guo FJ, Chen J, Zhang XW, Cui MH.",https://pubmed.ncbi.nlm.nih.gov/28859117/,"Ovarian cancer's poor progression is closely associated with overexpression of matrix metalloproteinase 9 (MMP-9), which belongs to the class of enzymes believed to be involved in the degradation of extracellular matrix. However, the mechanisms underlying regulation of MMP-9 are not completely understood. STAT (signal transducer and activator of transcription) family of transcription factors is well known to be engaged in diverse cellular functions. Activation of STAT3 has been observed in a number of cancers, promoting tumorigenesis and metastasis via transcriptional activation of its target genes. In this study, we tested our hypothesis that STAT3 regulates MMP-9 gene expression in epithelial ovarian cancer. Using epithelial ovarian cancer cell lines as in vitro model, we show an abundance of phosphorylated STAT3 at Tyr705 (p-STAT3) in SKOV3 cell line. We further show that MMP-9 gene promoter was significantly enriched by p-STAT3, and IL-6 treatment led to a significant increase of MMP-9 at mRNA and protein levels, in addition to an association of p-STAT3 with MMP-9 gene. By using luciferase reporter assay, we determined that the STAT3 DNA responsive element of MMP-9 was sufficient to regulate transcriptional activity of a heterologous promoter. These "
921,Prevalence and characteristics of HPV-driven oropharyngeal cancer in France.,"Mirghani H, Bellera C, Delaye J, Dolivet G, Fakhry N, Bozec A, Garrel R, Malard O, Jegoux F, Maingon P, Sarini J, Noel G, Duflo S, Temam S, Lefebvre JL, Costes-Martineau V.",https://pubmed.ncbi.nlm.nih.gov/31158796/," Despite this, the epidemiological impact of high-risk human papilloma virus (HR-HPV) remains poorly investigated.
    


           HPV-status was determined by p16-immunohistochemistry, and by detection of HPV-DNA using in situ hybridization. Cancers were classified as HPV-driven if both p16-immunohistochemistry and HPV-DNA assays were positive. Demographical and clinical features were recorded.
    


           Of these, 43.1% of samples were p16-positive and 37.7% were positive for both p16 and HPV-DNA. Prognosis was significantly better in patients with HPV-driven cancers, with smoking negatively impacting patients' oncological outcomes.
    


          Conclusion:
        
      
      In France, more than a third of tonsillar and tongue base cancers are HPV-driven. More research concerning the evolution of HPV-driven cancers over time is needed."
922,Early detection markers in Pancreas Cancer.,"Farrell JJ, van Rijnsoever M, Elsaleh H.",https://pubmed.ncbi.nlm.nih.gov/17192037/,"The role of early detection in cancer has shown improved survival for certain cancers, including colon cancer, cervical cancer and breast cancer. The possibility for early detection of pancreatic cancer may be realized by an improved understanding of the histology and molecular genetics of precursor lesions and cancerous lesions in pancreatic cancer and the development of sensitive and specific screening tests (both invasive and non-invasive) to detect early pancreatic cancer. The NIH-NCI Early Detection Research Network (EDRN) in Pancreatic Cancer has been focussed on the development and validation of new biomarkers for the detection of early pancreatic cancer. This review will focus on our understanding of the histologic and molecular model of pancreatic carcinogenesis, current strategies and limitations of screening for pancreatic cancer and the development and validation of new biomarkers for the early detection of pancreatic cancer."
923,[Organ transplant recipients need intensive control and treatment of skin cancer].,"Togsverd-Bo K, Sørensen SS, Hædersdal M.",https://pubmed.ncbi.nlm.nih.gov/23663395/,"The risk of non-melanoma skin cancer (NMSC) and in particular squamous cell carcinoma is significantly increased in organ transplant recipients due to long-term treatment with immunosuppressives. Dermatologic management in the form of a multidisciplinary approach, including patient education, skin surveillance and early treatment of premalignant and malignant lesions is recommended. Field-directed rather than lesional therapy is preferred for actinic keratosis in field-cancerized skin; and high-efficacy therapies are recommended in NMSC due to an increased risk of recurrences and metastases."
924,"Perspectives of African American, Amish, Appalachian And Latina women on breast and cervical cancer screening: implications for cultural competence.","Documét PI, Green HH, Adams J, Weil LA, Stockdale J, Hyseni Y.",https://pubmed.ncbi.nlm.nih.gov/18263986/,"Low-income and minority women are less likely to be screened for breast and cervical cancer and less likely than others to be diagnosed at an early stage in the cancer's growth. We consulted women and providers to understand how social, economic, and health care environments affect screening among African American, Amish, Appalachian, and Latina women, and to outline possible solutions. Women participated in 31 focus groups. Providers completed a mail survey (n=168) and follow-up interviews (n=12). We identified barriers women face: not always following recommendations; feeling intimidated during appointments; having incorrect information about risks, screening guidelines, and programs; and receiving information in ways they cannot understand or accept. Women indicated a strong desire for accurate information and, like the providers, identified strategies for reducing barriers to screening. In the terms of a social ecological model, our "
925,Frequency of multiple primary cancers in the lung and other organs in hemodialysis patients.,"Obuchi T, Saito T, Iwasaki A.",https://pubmed.ncbi.nlm.nih.gov/22566268/,"
    


          0 years successfully underwent pulmonary resection at our institution. We investigated the 5-year survival rate and causes of death. The occurrence of multiple primary cancers in our patients and other lung-cancer patients reported in the articles were statistically compared by Chi-square test. A p value <0.05 was considered to be statistically significant.
    


          3 %, and six patients had died before our investigation. Four of the six had died of non-cancerous diseases related to hemodialysis. Five of 14 patients had a history of other primary cancers in other organs, and this incidence rate of multiple primary cancers was significantly higher than in other lung-cancer patients (p = 0.0071).
    


          Conclusion:
        
      
      The frequency of cancer in hemodialysis patients can be underestimated because of their early deaths by non-cancerous diseases. However, the incidence rate of multiple primary cancers may represent a unique characteristic of such patients."
926,A follow-up study of resected stomach cancer patients with special emphasis on the incidence of second primary cancers.,"Tominaga K, Koyama Y, Sasagawa M, Yamaguchi E, Yoshinari M, Nagai M.",https://pubmed.ncbi.nlm.nih.gov/8283786/,"The causes of death in long-term survivors of stomach cancer after a gastrectomy have been investigated in a follow-up study of 320 such patients, with special focus on the postoperative development of a second primary cancer. The five- and 10-year overall survival rates of early stomach cancer patients were 87.5 and 75.8%, respectively, and of advanced stomach cancer patients, 44.2 and 37.5%, respectively. A multivariate analysis identified the patient's age and stage of cancer at the time of diagnosis as separate prognostic factors for overall survival. During the observation period, 15 (4.7%) patients developed a second primary cancer, so that no significantly elevated risk of developing a second primary cancer was demonstrated. During the same observation period, however, 48 (15%) of the patients died of a non-cancerous disease, 12 succumbing to an acute myocardial infarction and/or heart failure. Given these "
927,[Is cancer a hereditary or a degenerative disease?].,Cassiman JJ.,https://pubmed.ncbi.nlm.nih.gov/11436418/,"All malignancies, whether they are solid tumors or leukemias, always originate from modifications of the genetic information of the cells. In most cases these changes occur in a single cell, which will then generate a whole series of malignant cells through cell division. In these cases the cancer is sporadic and therefore not hereditary. In a small percentage of the cases the DNA defects are inherited from one of the parents. All cells of the body will then carry this defect, but only a few tissues will become cancerous later in life based on this defect. These forms of cancer, such as some forms of breastca, colonca, thyroidca a.o. are hereditary. Nevertheless the malignant process will not be initiated in all individuals who carry these defects and the age at onset cannot be predicted with precision. In some malignancies, whether sporadic or hereditary, the first gene that carries a defect will be essential for normal cellular function. As a  Gradually, additional defects will accumulate in other genes in these cells leading to an increasing malignant behavior of the cancer. In other cases the consequences of the first defect remain limited but the accumulation of additional defects in other genes is facilitated  The environmental factors that cause or facilitate the occurrence of the first DNA defect in the cells, or that facilitate the initiation of hereditary cancers remain largely unknown. Chance plays of course an important role since we accumulate continuously defects in our DNA. Nevertheless evidence exists for the presence of components in our atmosphere, our food or beverages that facilitate the accumulation of defects in our DNA. The identification of these components provides an important starting point for improved prevention. In the mean time, making genetic tests available to individuals at risk for hereditary cancers remains an important, be it delicate task, since they can potentially influence their chances of survival. The improving insights into the mechanisms involved in the pathogenesis of cancers guarantees a better and more efficient treatment in the future."
928,Patient-derived tumour xenografts for breast cancer drug discovery.,"Cassidy JW, Batra AS, Greenwood W, Bruna A.",https://pubmed.ncbi.nlm.nih.gov/27702751/,"Despite remarkable advances in our understanding of the drivers of human malignancies, new targeted therapies often fail to show sufficient efficacy in clinical trials. Indeed, the cost of bringing a new agent to market has risen substantially in the last several decades, in part fuelled by extensive reliance on preclinical models that fail to accurately reflect tumour heterogeneity. To halt unsustainable rates of attrition in the drug discovery process, we must develop a new generation of preclinical models capable of reflecting the heterogeneity of varying degrees of complexity found in human cancers. Patient-derived tumour xenograft (PDTX) models prevail as arguably the most powerful in this regard because they capture cancer's heterogeneous nature. Herein, we review current breast cancer models and their use in the drug discovery process, before discussing best practices for developing a highly annotated cohort of PDTX models. We describe the importance of extensive multidimensional molecular and functional characterisation of models and combination drug-drug screens to identify complex biomarkers of drug resistance and response. We reflect on our own experiences and propose the use of a cost-effective intermediate pharmacogenomic platform (the PDTX-PDTC platform) for breast cancer drug and biomarker discovery. We discuss the limitations and unanswered questions of PDTX models; yet, still strongly envision that their use in basic and translational research will dramatically change our understanding of breast cancer biology and how to more effectively treat it."
929,Targeting apoptosis in clear cell renal cell carcinoma.,"Kowalewski A, Borowczak J, Maniewski M, Gostomczyk K, Grzanka D, Szylberg Ł.",https://pubmed.ncbi.nlm.nih.gov/38781868/,"Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cancer, accounting for approximately 80% of all renal cell cancers. Due to its exceptional inter- and intratumor heterogeneity, it is highly resistant to conventional systemic therapies. Targeting the evasion of cell death, one of cancer's hallmarks, is currently emerging as an alternative strategy for ccRCC. In this article, we review the current state of apoptosis-inducing therapies against ccRCC, including antisense oligonucleotides, BH3 mimetics, histone deacetylase inhibitors, cyclin-kinase inhibitors, inhibitors of apoptosis protein antagonists, and monoclonal antibodies. Although preclinical studies have shown encouraging  Current evidence suggests that inducing apoptosis in ccRCC may promote tumor progression through apoptosis-induced proliferation, anastasis, and apoptosis-induced nuclear expulsion. Therefore, re-evaluating this approach is expected to enable successful preclinical-to-clinical translation."
930,Leiomyosarcoma of the vulva: a case report.,"Dewdney S, Kennedy CM, Galask RP.",https://pubmed.ncbi.nlm.nih.gov/16220773/,"
    


          Case:
        
      
      A 36-year-old woman was referred for a slowly growing painless vulvar mass that was initially thought to be a Bartholin's duct cyst but was cancerous upon biopsy. A modified radical vulvectomy was performed, and pathology revealed a grade 1 leiomyosarcoma. Thirteen months later, the tumor had not recurred.
    


          Conclusion:
        
      
      Vulvar cancer must be considered in patients with a suspected Bartholin duct cyst that demonstrates atypical features. A biopsy should be obtained if the mass appears firm or solid on palpation, is ulcerated or presents in a slightly different location from the usual area of the Bartholin gland."
931,[Breast cancer's impact on work life. Survey among women of the ELIPPSE cohort].,"Gallardo L, Rey D, Peretti-Watel P.",https://pubmed.ncbi.nlm.nih.gov/22736710/,"Working people who are diagnosed with cancer must generally stop working, and returning to work after treatment is a very important issue for them. This article investigates the impact of cancer on professional trajectory among working women after a breast cancer diagnosis. We conducted in-depth interviews with 21 women from the ELIPPSE cohort. They were aged under 40 at cancer diagnosis, and they were interviewed from 16 months to 3 years after diagnosis. Several participants reported a deterioration of their professional situation even before they stopped working, with long-lasting consequences on their daily allowance. Others reported such deterioration during their sick leave. For all of them, returning to work after cancer treatment was very important, but they faced several obstacles. For example, some of them had to give up their former profession because of treatment side-effects. Moreover, the cancer experience frequently changed their attitude and expectations toward their working career. Finally, in order to find a new job these women were prone to hide their cancer experience and to resort to their social network (this network was also helpful to face the financial consequences of their sick leave)."
932,CT colonography for detection and characterisation of synchronous proximal colonic lesions in patients with stenosing colorectal cancer.,"Park SH, Lee JH, Lee SS, Kim JC, Yu CS, Kim HC, Ye BD, Kim MJ, Kim AY, Ha HK.",https://pubmed.ncbi.nlm.nih.gov/22115824/,"
    


           Pathological examination of colectomy specimen and/or postsurgical colonoscopy with pathological confirmation of the proximal synchronous lesions to serve as reference standards existed in 284 patients. Per-patient and per-lesion diagnostic performance measures of CTC for diagnosing proximal synchronous lesions ≥6 mm analysed by histopathological categories were obtained for the 284 patients. Per-lesion sensitivity and positive predictive value (PPV) of various CTC lesion size criteria and lesion size combined with other CTC findings for diagnosing cancer in the proximal colon were determined.
    


          3% to 100% and 70.7% to 100%, respectively) with the corresponding per-patient negative predictive value (NPV) of a negative CTC of 100% (194/194 patients; 95% CI 98.3% to 100%). Per-patient NPV of a negative CTC for advanced neoplasia (ie, advanced adenomas and colorectal cancers) was 97.4% (189/194 patients; 95% CI 93.9% to 99.1%). A lesion size ≥15 mm on CTC as the criterion to specifically diagnose proximal cancer yielded 87.5% (7/8 lesions; 95% CI 50.8% to 99.9%) per-lesion sensitivity, rendering one 8-mm submucosal cancer mischaracterised as a non-cancerous lesion, and 70% (7/10 lesions; 95% CI 39.2% to 89.7%) per-lesion PPV. Additional CTC findings did not improve the sensitivity.
    


          Conclusion:
        
      
      CTC is highly sensitive in detecting synchronous cancers proximal to a stenosing colorectal cancer. CTC has limited capability in differentiating advanced adenomas from colorectal cancer and this compromises the PPV of CTC for the presence of proximal cancer."
933,Application of monoclonal antibody KH2 against lactosyl and neolactotetraosyl ceramide to immunohistochemical study of human cancers.,"Hinoda Y, Imai K, Itoh F, Nakagawa N, Naiki M, Yachi A.",https://pubmed.ncbi.nlm.nih.gov/2554480/,"Monoclonal antibody KH2 (IgM) reactive with lactosyl ceramide and neolactotetraosyl ceramide was applied for the first time to the staining of human cancerous and noncancerous tissues which were fixed with formalin and embedded in paraffin. Digestive-tract cancers originating from stomach, colon, pancreas, gallbladder and bile duct were clearly stained. The staining intensity was especially strong in the apical portion and the intraluminal content of adenocarcinomas. In noncancerous tissues, it was of interest that gastric intestinal metaplasia and certain fetal tissues were stained. A part of the tubules of the kidney, pancreatic ductal cells, lung alveolar epithelial cells and polymorphonuclear leukocytes were stained in normal adult tissues in our study. Enhancement of the intensity of immunostaining by neuraminidase treatment indicated that most of the antigenic determinants should be sialylated and the antigenicity exposed after neuraminidase treatment in several kinds of cancerous and noncancerous tissues. These data suggest that the monoclonal antibody KH2 may be useful in the immunohistologic diagnosis of formalin-fixed human cancerous tissues."
934,Cancer stem cells (CSCs): key player of radiotherapy resistance and its clinical significance.,"Hoque S, Dhar R, Kar R, Mukherjee S, Mukherjee D, Mukerjee N, Nag S, Tomar N, Mallik S.",https://pubmed.ncbi.nlm.nih.gov/36503350/,"Cancer stem cells (CSCs) are self-renewing and slow-multiplying micro subpopulations in tumour microenvironments. CSCs contribute to cancer's resistance to radiation (including radiation) and other treatments. CSCs control the heterogeneity of the tumour. It alters the tumour's microenvironment cellular singling and promotes epithelial-to-mesenchymal transition (EMT). Current research decodes the role of extracellular vesicles (EVs) and CSCs interlink in radiation resistance. Exosome is a subpopulation of EVs and originated from plasma membrane. It is secreted by several active cells. It involed in cellular communication and messenger of healthly and multiple pathological complications. Exosomal biological active cargos (DNA, RNA, protein, lipid and glycan), are capable to transform recipient cells' nature. The molecular signatures of CSCs and CSC-derived exosomes are potential source of cancer theranostics development. This review discusse cancer stem cells, radiation-mediated CSCs development, EMT associated with CSCs, the role of exosomes in radioresistance development, the current state of radiation therapy and the use of CSCs and CSCs-derived exosomes biomolecules as a clinical screening biomarker for cancer. This review gives new researchers a reason to keep an eye on the next phase of scientific research into cancer theranostics that will help mankind."
935,"Effect of Nicotinamide in Skin Cancer and Actinic Keratoses Chemoprophylaxis, and Adverse Effects Related to Nicotinamide: A Systematic Review and Meta-Analysis.","Mainville L, Smilga AS, Fortin PR.",https://pubmed.ncbi.nlm.nih.gov/35134311/,"
    


          
    


           We used Medline, EMBASE, CENTRAL, and Web of Science databases from their inception to October 2020 to search the following concepts: ""nicotinamide""; ""randomized controlled trial"" (validated filters). Two independent reviewers screened titles and abstracts for intervention and study design before searching full texts for eligibility criteria. To be eligible, ≥1 outcome had to be covered. We used a standardized collection grid to complete data extraction in duplicate. The primary outcome was skin cancers (all types). Secondary outcomes were basal cell carcinomas (BCCs); cSCCs; actinic keratoses; melanomas; digestive, cutaneous, and biochemical adverse effects (AEs). Subgroup analyses were planned a priori.
    


           Nicotinamide was associated with a significant reduction in skin cancers compared to control (rate ratio 0.50 (95% CI, 0.29-0.85; I 2 = 64%; 552 patients; 5 trials); moderate strength of the evidence). Heterogeneity was explained by risk of bias. Nicotinamide was associated with a significant reduction in BCCs and cSCCs, and increased risk of digestive AEs.
    


          Conclusion:
        
      
      Oral nicotinamide should be considered in healthy patients or organ transplant recipients with history of skin cancer (GRADE: weak recommendation; moderate-quality evidence), in particular of BCC and cSCC."
936,[Clinical usefulness of urinary diacetylpolyamines as novel tumor markers].,"Kawakita M, Hiramatsu K, Sugimoto M, Takahashi K, Toi M.",https://pubmed.ncbi.nlm.nih.gov/15164599/,"N1,N12-Diacetylspermine(DiAcSpm) and N1,N8-diacetylspermidine(DiAcSpd) are excreted in the urine of healthy persons as minor components of urinary polyamine, with small individual variations in amount. They are promising tumor markers, since their excretion is frequently elevated in patients with various types of cancers. DiAcSpm is sensitive in cancer detection, while DiAcSpd is highly specific for cancer. Diacetylpolyamines were initially characterized and determined by HPLC fractionation, followed by enzymatic detection. More recently, antibodies highly specific for DiAcSpm and DiAcSpd were developed, and an ELISA system applicable to the determination of urinary DiAcSpm was established. Measurement of urinary DiAcSpm using this ELISA system revealed that DiAcSpm is a more sensitive tumor marker than CEA, CA19-9 and CA15-3 for colon and breast cancers. More importantly, DiAcSpm efficiently detects patients at early stages. On the other hand, CEA, CA19-9 and CA15-3 are quite insensitive for early stage cancers. The urinary DiAcSpm level tends to remain low even in tumor-bearing individuals when their cancerous lesions remain static, while it rises rapidly concomitant with recurrence. DiAcSpm may serve as a prognostic indicator and marker for recurrence of prostate and colon cancers. Diacetylpolyamines may turn out to be general tumor markers, since active proliferation of any cancer tissues would likely be accompanied by activation of polyamine metabolism."
937,Increased expression of galectin-3 in primary gastric cancer and the metastatic lymph nodes.,"Miyazaki J, Hokari R, Kato S, Tsuzuki Y, Kawaguchi A, Nagao S, Itoh K, Miura S.",https://pubmed.ncbi.nlm.nih.gov/12375039/,"Galectin-3, a multifunctional beta-galactocide binding lectin possibly participates in a variety of biological events including cell proliferation, differentiation, and apoptosis. The implication of galectin-3 during malignancy progression has been suggested in several cancers, including colon, prostate, thyroid, and breast cancer, however, scarce data are available in gastric cancer. We examined the expression of galectin-3 in 86 primary gastric cancers and the 40 metastatic lymph nodes by immunohistochemistry to explore whether it is related to the malignant progression. Positive galectin-3 expression was observed in 84% of the gastric cancer cases. In enhanced cells of cancerous lesions, 48% showed stronger nuclear immunoreactivity than cytoplasmic one, whereas adjacent epithelial cells showed little or weak nuclear immunoreactivity. When galectin-3 expression in gastric carcinoma was compared with that in gastric tissues adjacent to the cancers, there was a significant difference. The degree of enhancement of immunoreactivity was different corresponding to various histopathological subtypes in cancer tissues. A significantly stronger expression of galectin-3 in cancer tissues was only observed in papillary and poorly differentiated adenocarcinoma. When galectin-3 expression and tumor progression (TNM staging) was compared, a significant correlation was observed in overall cases, and only in poorly differentiated adenocarcinoma the galectin-3 expression correlated with tumor progression among various subtypes. Galectin-3 expression was observed significantly stronger in metastatic lymph nodes than in the primary gastric cancers, and also in these cases among histological subtypes, only in poorly differentiated adenocarcinoma, the expression of galectin-3 in metastatic lymph nodes was stronger than the primary cancer. In conclusion galectin-3 might be a useful tumor marker for gastric cancers with respects to tumor progression and potentiality of lymph node metastasis especially in certain histological types of gastric cancer."
938,Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumors.,"Fukushima M, Morita M, Ikeda K, Nagayama S.",https://pubmed.ncbi.nlm.nih.gov/14612954/,"Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) has been suggested to be sensitivity-limiting factors of 5-fluorouracil therapy in cancer patients. We conducted a large-scale population study on the activity of TS and DPD in patients with various solid tumors. A total of 2590 clinically removed tumors, consisting of 1112 colon, 724 gastric, 520 breast, and 236 non-small cell lung cancers, were provided to measure TS and DPD activity. TS activity in the gastric, colon, and non-small cell lung cancers was significantly higher than in matched non-cancerous tissue (P<0.0002), but there was no difference in TS expression between tumor and non-cancerous tissue from breast cancer patients. Gastric, breast, and non-small cell lung cancers showed significantly higher DPD activity than their corresponding non-cancerous tissues, but colon cancers did not. There was no correlation between TS activity and DPD activity, and thus each enzyme was considered to be an independent sensitivity-limiting factor for 5-fluorouracil therapy. The median TS activity and median DPD activity in all specimens including gastric, colorectal, breast, and non-small cell lung cancers tested were 0.041 and 110.1 pmol/mg protein, respectively. We classified each of the type of carcinoma into 4 groups by using the median activity of TS and DPD as the cutoff values: a low TS/low DPD group, high TS/low DPD group, low TS/high DPD group, and high TS/high DPD group. About 50% of the gastric, 47% of the colon, 70% of the breast and 30% of the non-small cell lung cancers had high TS activity, and 60% of the gastric, 40% of the colon, 48% of the breast, and 87% of the lung cancers had high DPD activity. Moreover, breast cancer was characterized by high TS activity and lung cancer by high DPD activity as compared with gastric and colon cancers, and their high activity levels may influence to the effectiveness of 5-fluorouracil against cancers of these organs. The "
939,Midkine expression in human breast cancers: expression of truncated form.,"Miyashiro I, Kaname T, Shin E, Wakasugi E, Monden T, Takatsuka Y, Kikkawa N, Muramatsu T, Monden M, Akiyama T.",https://pubmed.ncbi.nlm.nih.gov/9065593/,"The expression of midkine (MK), a growth/differentiation factor, was assessed in 34 surgically resected specimens of primary breast cancer or mastopathy. Using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, all of the non-cancerous and cancerous tissues were found to express MK except for one breast cancer specimen. Northern blot analysis revealed that MK mRNA was also expressed in the normal breast tissues examined. Immunohistochemical analysis of the MK protein was performed on a limited number of the specimens, showing that some cancerous tissues were immunoreactive with anti-MK antibodies. Furthermore, using RT-PCR analysis, expression of not only the wild-type but also a truncated form of MK, which was recently found in various human tumor cell lines, was detected in 6 of 26 cancerous tissues but not in non-cancerous tissues."
940,"Glucose transporters: expression, regulation and cancer.","Medina RA, Owen GI.",https://pubmed.ncbi.nlm.nih.gov/12125211/,"Mammalian cells depend on glucose as a major substrate for energy production. Glucose is transported into the cell via facilitative glucose transporters (GLUT) present in all cell types. Many GLUT isoforms have been described and their expression is cell-specific and subject to hormonal and environmental control. The kinetic properties and substrate specificities of the different isoforms are specifically suited to the energy requirements of the particular cell types. Due to the ubiquitousness of these transporters, their differential expression is involved in various disease states such as diabetes, ischemia and cancer. The majority of cancers and isolated cancer cell lines over-express the GLUT family members which are present in the respective tissue of origin under non-cancerous conditions. Moreover, due to the requirement of energy to feed uncontrolled proliferation, cancer cells often express GLUTs which under normal conditions would not be present in these tissues. This over-expression is predominantly associated with the likelihood of metastasis and hence poor patient prognosis. This article presents a review of the current literature on the regulation and expression of GLUT family members and has compiled clinical and research data on GLUT expression in human cancers and in isolated human cancer cell lines."
941,Evidence for the association of synaptotagmin with glutathione S-transferases: implications for a novel function in human breast cancer.,"Sreenath AS, Kumar KR, Reddy GV, Sreedevi B, Praveen D, Monika S, Sudha S, Reddy MG, Reddanna P.",https://pubmed.ncbi.nlm.nih.gov/15820774/,"
    


          Design and 
    


          26 U/mg protein) was significantly higher (P < 0.05) as compared to those from adjacent non-cancerous tissues (0.14 U/mg protein) of breast cancer patients. Further analysis of GST subunits on SDS-PAGE and Western blots using class-specific GST antibodies revealed significant elevation in GST-pi levels in cancer tissues with no appreciable changes in GST-alpha and GST-mu. Along with the elevation of GST-pi levels, high molecular weight proteins (approximately 70 kDa) cross reacting with GST antibodies were detected only in surgically resected tumor biopsies but not in the non-cancerous tissues adjacent to the tumor. Based on MALDI-TOF analysis, the high molecular weight band was identified as synaptotagmin V bound to GST-M1 with 47% sequence coverage after processing on an MS-FIT search engine.
    


          Conclusions:
        
      
      Our  As this association of GST M1-synaptotagmin was not seen in adjacent non-cancerous tissues, this can be used as a marker for breast cancers."
942,Electrospun nanofibers: a promising horizon toward the detection and treatment of cancer.,"Asghari S , Rezaei Z , Mahmoudifard M .",https://pubmed.ncbi.nlm.nih.gov/32096500/,"Due to the increase in the number of cancer patients, because of environmental parameters, high stress, low immunity, etc., there is an urgent need to develop cost-effective sensors for early targeted detection of cancerous cells with adequate selectivity and efficiency. Early disease diagnosis is important, as it is necessary to start treatments before disease progression. On the other hand, we need new, more efficient cancer treatment approaches with minimized side effects, more biocompatibility, and easy disposal. Nanobiotechnology is a field that can assist in developing new diagnostic and treatment approaches, specifically in fatal cancers. Herein, a study on the different applications of nanofibers in cancer detection as well as its treatment has been done. Here, a very brief survey on the main structure of biosensors and their different categories has been conducted and will precede the discussion of the study to serve as a reference and guide the reader's understanding."
943,Pancreatic cancer.,"Li D, Xie K, Wolff R, Abbruzzese JL.",https://pubmed.ncbi.nlm.nih.gov/15051286/,"Pancreatic cancer remains a major unsolved health problem, with conventional cancer treatments having little impact on disease course. Almost all patients who have pancreatic cancer develop metastases and die. The main risk factors are smoking, age, and some genetic disorders, although the primary causes are poorly understood. Advances in molecular biology have, however, greatly improved understanding of the pathogenesis of pancreatic cancer. Many patients have mutations of the K-ras oncogene, and various tumour-suppressor genes are also inactivated. Growth factors also play an important part. However, disease prognosis is extremely poor. Around 15-20% of patients have resectable disease, but only around 20% of these survive to 5 years. For locally advanced, unresectable, and metastatic disease, treatment is palliative, although fluorouracil chemoradiation for locally advanced and gemcitabine chemotherapy for metastatic disease can provide palliative benefits. Despite pancreatic cancer's resistance to currently available treatments, new  Preoperative chemoradiation is being advocated, with seemingly sound reasoning, and a wider role for gemcitabine is being explored. However, new therapeutic strategies based on the molecular biology of pancreatic cancer seem to hold the greatest promise."
944,[Clinical features of patients with head and neck malignant tumor concurrent with multiple primary carcinoma].,"Zhang XX, Yan F, Liu MB, Wang JL, Wu WM, Ma L, Huang DL.",https://pubmed.ncbi.nlm.nih.gov/27480296/,"
    


          4%) patients were field cancerization of head neck (FCHN) and 26 (36.6%) patients were non-field cancerization of head neck (NFCHN). For the synchronous MPC patients with an interval of 0 month, the lesion sites of FCHN were treated with combined chemotherapy and radiotherapy, the site of severe lesion of NFCHN received firstly a standard treatment. Other types of MPC were treated according to international guide lines or experts consensus.
    


          4 months, the 3-year and 5-year overall survival (OS) were 84.6% and 75.7% respectively. The 3-year and 5-year OS were 56.4% and 37.6% respectively in patients with synchronous MPC, and were 92.2% and 84.2% respectively in patients with metachronous MPC. There was significant difference in the OS between patients with metachronous MPC and patients with synchronous MPC (P=0.0002). The 3-year and 5-year OS were 85.7% and 77.9% respectively in patients with FCHN, and were 82.9% and 72.8% respectively in patients with NFCHN, with no significant difference between the two groups (P=0.297).
    


          Conclusion:
        
      
      With correct diagnosis and effective curative treatment, some of patients with MPC can get long-term survival, showing the better prognosis in metachronous MPC compared to synchronous MPC."
945,"Cancer, pre-cancer and normal oral cells distinguished by dielectrophoresis.","Mulhall HJ, Labeed FH, Kazmi B, Costea DE, Hughes MP, Lewis MP.",https://pubmed.ncbi.nlm.nih.gov/21877186/,"Most oral cancers are oral squamous cell carcinomas (OSCC) that arise from the epithelial lining of the oral mucosa. Given that the oral cavity is easily accessible, the disease lends itself to early detection; however, most oral cancers are diagnosed at a late stage, and approximately half of oral cancer sufferers do not survive beyond five years, post-diagnosis. The low survival rate has been attributed to late detection, but there is no accepted, reliable and convenient  Dielectrophoresis (DEP) is a label-free technique which can be used to obtain multi-parametric measurements of cell electrical properties. Parameters such as cytoplasmic conductivity and effective membrane capacitance (C(Eff)) can be non-invasively determined by the technique. In this study, a novel lab-on-a-chip device was used to determine the cytoplasmic conductivity and C(Eff) of primary normal oral keratinocytes, and pre-cancerous and cancerous oral keratinocyte cell lines. Our  Furthermore, increasing C (Eff) and decreasing cytoplasmic conductivity correlate with disease progression which could prove significant for diagnostic and prognostic applications. DEP has the potential to be used as a non-invasive technique to detect oral cancer and oral pre-cancer. Clinical investigation is needed to establish the reliability and temporal relationship of the correlation between oncologic disease progression and the electrical parameters identified in this study. To use this technique as an OSCC detection tool in a clinical setting, further characterisation and refinement is warranted."
946,Laparoscopic cholecystectomy with full-thickness dissection for potentially cancerous lesions: comparison with standard technique.,"Kubota K, Toyoda H, Noie T, Abe H, Watanabe M, Makuuchi M.",https://pubmed.ncbi.nlm.nih.gov/10626164/," Since September 1991, we employed LC with full-thickness dissection (LC-F) for polypoid lesions of the gallbladder. In the present study, the utility of the procedure was investigated.
    


          
    


           The mean operation times for S-LC and LC-F were 157 and 120 min, respectively, (p < 0.05). Gallbladder perforation occurred in 29 S-LCs, whereas there was none in 30 LC-Fs (p < 0.05). Bleeding from the gallbladder bed occurred in 1 patient in each of the 2 groups, but was stopped easily. There was neither post-operative bleeding nor bile leakage in either group. Mucosal cancer was diagnosed in 3 gallbladders resected by S-LC and 1 resected by LC-F. One patient of the LC-F group with advanced cancer underwent laparotomy. All the patients have no signs of recurrence.
    


          Conclusions:
        
      
      LC-F allows the complete removal of the connective tissue of the gallbladder bed without perforation and, therefore, is considered as a safe and useful procedure for resecting gallbladders with potentially cancerous lesions."
947,Specific 8-oxo-dGTPase activity of MTH1 (NUDT1) protein as a quantitative marker and prognostic factor in human colorectal cancer.,"Bialkowski K, Szpila A.",https://pubmed.ncbi.nlm.nih.gov/34624481/,"The MTH1 (NUDT1) gene, because it is frequently upregulated in many types of human cancers, has been considered a general marker of carcinogenesis for over two decades. The MTH1 protein hydrolyzes the oxidized mutagenic DNA precursor, 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP), to the corresponding 5'-monophosphate and inorganic pyrophosphate. This prevents its incorporation into DNA by DNA polymerases and protects cells from the accumulation of 8-oxo-dGTP-induced point mutations. Elevated MTH1 mRNA and protein in many types of human cancer indicate a worse prognosis. However, the enzymatic activity of MTH1 has remained largely uninvestigated in this context. Therefore, we have set out to determine the specific 8-oxo-dGTPase activity of MTH1 in 57 pairs of human colorectal cancers (CRC) and adjacent cancer-free tissues (CFCF). The goal was to ascertain the potential for measuring this enzymatic activity as a way to differentiate cancerous from non-cancerous specimens of the intestine, as well as defining its capabilities as a prognostic value for disease-free survival. We found that 79% of CRC tumors exhibited a higher MTH1 activity than did CFCF, with a significant 1.6-fold increase in overall median value (p < 1E-6). The 8-oxo-dGTPase in both tissues was proportional to the corresponding levels of MTH1 protein, as assayed by Western blotting. Activity higher than the ROC-optimized threshold (AUC = 0.71) indicated cancerous tissue, with a 54% sensitivity and an 83% specificity. Postoperative fate followed for up to 100 months showed that higher 8-oxo-dGTPase, in either the CFCF or the CRC tumor, clearly lowered the probability of a relapse-free survival, although borderline statistical significance (p < 0.05) was crossed only for the CFCF."
948,[Comparative proteomic analysis of cancerous and adjacent normal lung tissues].,"Lee KB, Pi KB.",https://pubmed.ncbi.nlm.nih.gov/21395069/,"Lung cancer is the leading cause of cancer-related mortality in industrialized countries. Unfortunately, most lung cancers are found too late for a cure, therefore early detection and treatment is very important. We have applied proteomic analysis by using two-dimensional gel electrophoresis and peptide mass fingerprinting techniques for examination of cancerous and adjacent non-cancerous lung tissues from the same patient. The aim of the study was to find proteins, which could be used as biomarkers for diagnosis and monitoring of this disease. Indeed, we found differences in expression of several proteins, related to various cellular activities, such as, chaperoning (e.g., GRP96, GRP78, HSP27), metabolism and oxidation stress (e.g., L-fucose, GST), cytoskeleton (e.g., tubulin beta 2/3, beta actin), cell adhesion (e.g., annexin A5/3), binding proteins (e.g., 14-3-3 theta) and signal transduction. These changes may be important for progression of carcinogenesis; they may be used as the molecular-support for future diagnostic markers."
949,Evaluation of Raman probe for oesophageal cancer diagnostics.,"Kendall C, Day J, Hutchings J, Smith B, Shepherd N, Barr H, Stone N.",https://pubmed.ncbi.nlm.nih.gov/20949209/,"Early detection of (pre-)cancerous changes improves prognosis, therefore in the UK patients at high risk of developing gastrointestinal cancers are enrolled on endoscopic surveillance programmes or the Bowel Cancer Screening Programme. The current gold standard technique for the detection of pre-cancerous changes in the gastrointestinal tract is histopathological analysis of biopsy tissue collected at endoscopy. This relies upon subjective assessment of morphological changes within the excised tissue samples and poor targeting of pre-malignant lesions. Raman spectroscopy offers a number of potential advantages for in vivo assessment of tissue at endoscopy. The performance of a custom built Raman probe as a biopsy targeting tool has been evaluated using excised biopsy material. Multivariate classification models have been used to demonstrate the likely ability of a miniature, confocal, fibre optic Raman probe to be used as an optical biopsy tool at endoscopy to provide spectral information in clinically practicable timescales. This technique could facilitate improved targeting of excisional biopsy with associated clinical benefits."
950,Association of Quantitative Metastatic Lymph Node Burden With Survival in Hypopharyngeal and Laryngeal Cancer.,"Ho AS, Kim S, Tighiouart M, Gudino C, Mita A, Scher KS, Laury A, Prasad R, Shiao SL, Ali N, Patio C, Mallen-St Clair J, Van Eyk JE, Zumsteg ZS.",https://pubmed.ncbi.nlm.nih.gov/29192305/,"Importance:
        
      
      Nodal staging for laryngohypopharyngeal cancers is based primarily on size and laterality, with less value placed on absolute number of metastatic lymph nodes (LNs). We are aware of no studies to date that have specifically addressed the prognostic effect of quantitative nodal burden in larynx or hypopharynx malignancies.
    


          
    


          Design, setting, and participants:
        
      
      Univariate and multivariable models were constructed to evaluate the association between patients' number of metastatic LNs and their survival, adjusting for factors such as nodal size, laterality, extranodal extension, margin status, and adjuvant treatment. Participants were patients with squamous cell carcinoma of the larynx or hypopharynx undergoing upfront surgical resection for curative intent at a US hospital between 2004 and 2013, as identified in the National Cancer Database. A neck dissection of a minimum of 10 LNs was required.
    


          Main outcomes and measures:
        
      
      Overall survival.
    


          1] years; 6499 men [77.8%]; 4710 patients with metastatic LNs and 3641 with no metastatic LNs). Mortality risk escalated continuously without plateau as number of metastatic nodes increased, with the hazard per node (hazard ratio [HR], 1.19; 95% CI, 1.16-1.23; P < .001) most pronounced up to 5 positive LNs. Extranodal extension was also associated with increased mortality (HR, 1.34; 95% CI, 1.13-1.59; P < .001). Increasing number of nodes examined was associated with improved survival, albeit to a lesser degree (per 10 LNs: HR, 0.97; 95% CI, 0.96-0.98; P < .001) and without a detectable change point. Other nodal factors, including nodal size, contralateral LN involvement (TNM stage N2c), and lower LN involvement (levels 4-5), were not associated with mortality in multivariable models when accounting for number of positive LNs. A novel, parsimonious nodal staging system derived by recursive partitioning analysis exhibited greater concordance with survival than the TNM staging system outlined in the American Joint Committee on Cancer's AJCC Staging Manual, 8th edition.
    


          Conclusions and relevance:
        
      
      The number of metastatic nodes is a predominant independent factor associated with mortality in hypopharyngeal and laryngeal cancers. Moreover, standard nodal staging factors like LN size and contralaterality have no independent prognostic value when accounting for positive LN number. Deeper integration of quantitative metastatic nodal disease may simplify staging and better triage the need for adjuvant therapy."
951,LINE-1 methylation patterns of different loci in normal and cancerous cells.,"Phokaew C, Kowudtitham S, Subbalekha K, Shuangshoti S, Mutirangura A.",https://pubmed.ncbi.nlm.nih.gov/18776216/,"This study evaluated methylation patterns of long interspersed nuclear element-1 (LINE-1) sequences from 17 loci in several cell types, including squamous cell cancer cell lines, normal oral epithelium (NOE), white blood cells and head and neck squamous cell cancers (HNSCC). Although sequences of each LINE-1 are homologous, LINE-1 methylation levels at each locus are different. Moreover, some loci demonstrate the different methylation levels between normal tissue types. Interestingly, in some chromosomal regions, wider ranges of LINE-1 methylation levels were observed. In cancerous cells, the methylation levels of most LINE-1 loci demonstrated a positive correlation with each other and with the genome-wide levels. Therefore, the loss of genome-wide methylation in cancerous cells occurs as a generalized process. However, different LINE-1 loci showed different incidences of HNSCC hypomethylation, which is a lower methylation level than NOE. Additionally, we report a closer direct association between two LINE-1s in different EPHA3 introns. Finally, hypermethylation of some LINE-1s can be found sporadically in cancer. In conclusion, even though the global hypomethylation process that occurs in cancerous cells can generally deplete LINE-1 methylation levels, LINE-1 methylation can be influenced differentially depending on where the particular sequences are located in the genome."
952,"American Joint Committee on Cancer's Staging System for Breast Cancer, Eighth Edition: What the Radiologist Needs to Know.","Kalli S, Semine A, Cohen S, Naber SP, Makim SS, Bahl M.",https://pubmed.ncbi.nlm.nih.gov/30265613/,"The TNM staging system for cancer was developed by Pierre Denoix in France in the 1940s and 1950s. The North American effort to standardize the TNM system for cancer staging was first organized in 1959 as the American Joint Committee for Cancer Staging and End- The most recent edition of the AJCC Cancer Staging Manual, the eighth edition, was globally adopted on January 1, 2018. Previous editions of the manual have relied on anatomic  In the era of precision medicine, the major change in the eighth edition is the incorporation of prognostic biomarkers to more accurately predict clinical outcomes and treatment response on an individual basis, without relying solely on the anatomic extent of disease. Factors such as tumor grade, hormone receptor and oncogene expression, and multigene panel recurrence scores are now integrated with anatomic information to yield a final prognostic stage group, which will provide better stratification of patient prognosis. The purpose of this article is to review the major changes in the AJCC eighth edition for breast cancer staging, review anatomic TNM staging, familiarize the radiologist with prognostic biomarkers and prognostic staging, and identify key sites of disease that may alter clinical management. ©RSNA, 2018."
953,Negative Lymph Node Count is an Independent Impact Factor for Predicting the Specific Survival of Primary Duodenal Neoplasms under Surgical Procedures.,Zheng L.,https://pubmed.ncbi.nlm.nih.gov/32538047/,"
    


           First, the important factors were screened by the Kaplan-Meier (Log-rank) in R and the Cox's proportional hazards regression model. Subsequently, a nomogram was established based on key proportional hazards including the negative lymph node count. Finally, the analysis of the specific survival by Kaplan-Meier (Log-rank) and X-Tile was performed to identify the cutoff values of negative lymph node numbers.
    


           Five impact factors were screened including the negative lymph node count (between 10 and 32), age (< 73), differentiation of cancers (well or moderate), primary tumors' invasion to tissues' superficial parts, no distant metastasis. The C-index of the nomogram in this paper was 0.74.
    


          Conclusions:
        
      
      The negative lymph node count and the other four factors were used for predicting the specific survival of primary duodenal neoplasms under surgical treatment, and the highest 2-year cancer's specific survival occurred when the negative lymph node numbers were 10 - 32. Besides, the nomogram in this paper proved to be more useful in predicting the survival effects than the traditional American Joint Committee on Cancer classifica-tion "
954,Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women.,"Bartlett TE, Evans I, Jones A, Barrett JE, Haran S, Reisel D, Papaikonomou K, Jones L, Herzog C, Pashayan N, Simões BM, Clarke RB, Evans DG, Ghezelayagh TS, Ponandai-Srinivasan S, Boggavarapu NR, Lalitkumar PG, Howell SJ, Risques RA, Rådestad AF, Dubeau L, Gemzell-Danielsson K, Widschwendter M.",https://pubmed.ncbi.nlm.nih.gov/35701800/," Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation.
    


          
    


           Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar  Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders.
    


          Conclusions:
        
      
      These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers.
    


          Trial registration:
        
      
      Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control - a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40 ; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312 ; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19 ; registered on 15 July 2015."
955,Analytical studies on growth of human gastric cancer.,"Kohli Y, Kawai K, Fujita S.",https://pubmed.ncbi.nlm.nih.gov/7240688/,"Doubling times of early and advanced gastric cancers were determined on serial double-contrast roentgenographs, and those of tumor metastatic to the abdominal wall from the stomach were calculated from direct measurement. Doubling times of early gastric cancer ranged from 577 to 3462 days, while advanced gastric cancer had doubling times from 69 to 305 days. Doubling times of tumors metastatic to the abdominal wall were shorter, that is, from 17.7 to 60.2 days. The difference of growth rates in these three situations may  Equally important, the peptic ulceration which accompanies early gastric cancer seemed to have a dual significance; that is, in many cases of early gastric cancer it had an important role as a factor in cell loss, but in some cases it was likely to accelerate to a deeper cancerous invasion. From the retrospective or prospective follow-up study, early gastric cancer, type IIb, was likely to show abnormal redness or discoloration on the mucosal surface, which could be more easily recognized at endoscopy with the dye-spraying "
956,"[""Field cancerization""--an additional phenomenon in development of colon tumors? K-ras codon 12 mutations in normal colonic mucosa of patients with colorectal neoplasms].","Aivado M, Gynes M, Gorelov V, Schmidt WU, Röher HD, Goretzki PE.",https://pubmed.ncbi.nlm.nih.gov/11077584/," About 40-50% of colorectal cancers bear a point mutation of the K-ras codon 12 within exon I, leading to activation of the K-ras oncogene.
    


          
    


           Using this very sensitive 2sRFLP technique (detection level = 0.2% of mutated cells), we were able to find K-ras codon 12 mutations in normal mucosa in 4 out of 18 (22.2%) patients with colorectal neoplasia.
    


          Conclusions:
        
      
      This "
957,Elevated expression of cyclooxygenase-2 in breast cancer and ductal carcinoma in situ has no correlation with established prognostic markers.,"Ranger GS, Jewell A, Thomas V, Mokbel K.",https://pubmed.ncbi.nlm.nih.gov/15499599/," There has been inconsistency in the literature regarding the precise significance of this-some studies have found no clinicopathological relevance at all, whilst others have concluded COX-2 expression is an important biomarker in invasive disease and pre-cancerous lesions, correlating with poor prognostic features. We studied COX-2 expression in invasive ductal cancer (IDC) specimens and ductal carcinoma in situ (DCIS) in order to clarify these issues.
    


           
    


          7% of IDCs and 54.5% of DCIS lesions. There was no correlation between increased expression and any clinicopathological features. COX-2 expression did not occur in adjacent non-cancerous tissue (ANCT).
    


          Conclusion:
        
      
      We have confirmed that COX-2 expression does occur in invasive cancers, in DCIS, and is not associated with established prognostic markers. The presence of COX-2 expression in DCIS and invasive cancers has positive implications for the future prevention and treatment of breast cancer with COX-2 inhibitors. A large proportion of tumours are, however, COX-2 negative and may be poor candidates for COX-2 suppression."
958,Hope in cancer patients: the relational domain as a crucial factor.,"Proserpio T, Ferrari A, Lo Vullo S, Massimino M, Clerici CA, Veneroni L, Bresciani C, Casali PG, Ferrari M, Bossi P, Galmozzi G, Pierantozzi A, Licitra L, Marceglia S, Mariani L.",https://pubmed.ncbi.nlm.nih.gov/26045106/,"Aims and  We explored the determinants of hope in patients with cancer using a questionnaire administered over the course of 1 day to an unselected sample of patients at an Italian cancer center.
    


           A cross-sectional study was conducted on 320 patients who answered the questionnaire.
    


          8% had a religious belief. Women, patients with limited formal education, and believers were more hopeful. Patients placed trust in God, their partners and children, scientific research, and doctors. On univariate and multivariate analysis, hope was found sensitive to patients' sharing their experiences with others (including family and friends), their positive perception of the people around them, and their relationship with doctors and nurses.
    


          Conclusions:
        
      
      If validated in further studies, these  This may be important to health care organization and resource allocation."
959,Multilocular Cyst of Type 1 Autoimmune Pancreatitis Masquerading as Cancerization of Intraductal Papillary Mucinous Neoplasm.,"Kaneko J, Matsubayashi H, Satoh T, Sato J, Takinami M, Ishiwatari H, Uesaka K, Abe M, Sasaki K, Ono H.",https://pubmed.ncbi.nlm.nih.gov/31484912/,"A small proportion of intraductal papillary mucinous neoplasms (IPMNs) are accompanied by type 1 autoimmune pancreatitis (AIP); however their clinical courses and image characteristics have not been fully reported. A 65-year-old woman was referred to our hospital for the examination of a pancreatic head cyst that had shown exacerbation for two years. Several images demonstrated a multilocular cyst with a symmetrically thickened, enhanced, cyst wall. Cancerization of IPMN was suspected, and pancreatoduodenectomy was performed. The resected specimens showed a multilocular cyst with solid areas. The solid areas demonstrated pathological findings that corresponded with type 1 AIP. Papillary epithelia suggestive of IPMN was recognized in some parts of the cystic wall."
960,[Histology of precancerous lesions of the breast].,"Contesso G, Rouëssé J, Jacquemier J.",https://pubmed.ncbi.nlm.nih.gov/1194641/,"The authors are dealing with the problem of pre-cancerous lesions from data contained in the pathological archives of the Institut Gustave-Roussy. One series consists of 320 cases operated upon for benign lesions or tumors of the breast (Fibroadenomas appearing at a relatively advanced age) of which 4 developed cancers. The past histories of another series of 730 patients having had mastectomies for cancer are examined; 24 of these had been operated upon previously for benign tumours or lesions of the breast. Attention is drawn to a number of histological signs the presence of which in an ""a priori"" benign lesion should evoke caution: multilayered epithelium of the galactophores glands with an ""en flammèche"" appearance, tubular adenomatous hyperplasia, irregular lobular hyperplasia, microcalcifications... Despite careful examination of multiple sections, the pathologists decision between benign and malignant lesion continue to be difficult."
961,[The handling of anti-cancer drugs in elderly patients].,"Gaujard S, Albrand G, Bonnefoy M, Courpron P, Freyer G.",https://pubmed.ncbi.nlm.nih.gov/15988347/,"The management of elderly patients with cancer is not established. The use of antineoplastic agents (particularly of chemotherapy) raises a lot of questions. Efficiency and toxicity. Data come from subgroups of clinical trials and from selected populations. Chronological age itself does not contra-indicate chemotherapy. Pharmacokinetics. Physiologic and functional changes occur with aging but there is great inter-patient variability. Oral chemotherapy. Oral treatments underline the problem of compliance. Under-treatment. Elderly patients are under-represented in clinical trials. Relevant issues have to be defined individually and cancer's real place in patient's general situation has to be specified. Geriatric assessment. This tool has proved its usefulness in many domains for global management of elderly patients. A multidisciplinary team is necessary, under geriatrician coordination. The aim is to elaborate an individualized medico-social intervention program. Geriatric assessment in oncology. Its interest for cancer patients is shown by emerging reports but its routine use by oncologists is impossible. Treatment strategies. They are not validated.
    


          Future:
        
      
      New clinical and pharmacokinetic studies are necessary in order to specify the place of the various tools and to enhance the handling of such molecules."
962,Recent Radiomics Advancements in Breast Cancer: Lessons and Pitfalls for the Next Future.,"Pesapane F, Rotili A, Agazzi GM, Botta F, Raimondi S, Penco S, Dominelli V, Cremonesi M, Jereczek-Fossa BA, Carrafiello G, Cassano E.",https://pubmed.ncbi.nlm.nih.gov/34202321/,"Radiomics is an emerging translational field of medicine based on the extraction of high-dimensional data from radiological images, with the purpose to reach reliable models to be applied into clinical practice for the purposes of diagnosis, prognosis and evaluation of disease response to treatment. We aim to provide the basic information on radiomics to radiologists and clinicians who are focused on breast cancer care, encouraging cooperation with scientists to mine data for a better application in clinical practice. We investigate the workflow and clinical application of radiomics in breast cancer care, as well as the outlook and challenges based on recent studies. Currently, radiomics has the potential ability to distinguish between benign and malignant breast lesions, to predict breast cancer's molecular subtypes, the response to neoadjuvant chemotherapy and the lymph node metastases. Even though radiomics has been used in tumor diagnosis and prognosis, it is still in the research phase and some challenges need to be faced to obtain a clinical translation. In this review, we discuss the current limitations and promises of radiomics for improvement in further research."
963,Cancer breath testing: a patent review.,"Kabir KMM, Donald WA.",https://pubmed.ncbi.nlm.nih.gov/29297703/," The presence of cancer cells can affect the identity and abundances of chemicals in breath when compared to those in healthy control subjects, which can be used to indicate the likelihood of a patient having cancer. Recently, the chemical analysis of exhaled breath from patients has been shown to be promising for diagnosing many different types of cancers, including lung, breast, colon, head, neck, and prostate, along with pre-cancerous conditions (dysplasia).
    


          Areas covered:
        
      
      Here, we reviewed the sampling, analytical and data analysis  In addition, the different types of cancer biomarkers that were disclosed are discussed.
    


          Expert opinion:
        
      
      The major advantages of breath testing compared to conventional X-ray and imaging based  Such  However, the establishment of standard sampling, detection and quantification "
964,Targeting pyruvate dehydrogenase kinase signaling in the development of effective cancer therapy.,"Anwar S, Shamsi A, Mohammad T, Islam A, Hassan MI.",https://pubmed.ncbi.nlm.nih.gov/34023419/,"Pyruvate is irreversibly decarboxylated to acetyl coenzyme A by mitochondrial pyruvate dehydrogenase complex (PDC). Decarboxylation of pyruvate is considered a crucial step in cell metabolism and energetics. The cancer cells prefer aerobic glycolysis rather than mitochondrial oxidation of pyruvate. This attribute of cancer cells allows them to sustain under indefinite proliferation and growth. Pyruvate dehydrogenase kinases (PDKs) play critical roles in many diseases because they regulate PDC activity. Recent findings suggest an altered metabolism of cancer cells is associated with impaired mitochondrial function due to PDC inhibition. PDKs inhibit the PDC activity via phosphorylation of the E1a subunit and subsequently cause a glycolytic shift. Thus, inhibition of PDK is an attractive strategy in anticancer therapy. This review highlights that PDC/PDK axis could be implicated in cancer's therapeutic management by developing potential small-molecule PDK inhibitors. In recent years, a dramatic increase in the targeting of the PDC/PDK axis for cancer treatment gained an attention from the scientific community. We further discuss breakthrough findings in the PDC-PDK axis. In addition, structural features, functional significance, mechanism of activation, involvement in various human pathologies, and expression of different forms of PDKs (PDK1-4) in different types of cancers are discussed in detail. We further emphasized the gene expression profiling of PDKs in cancer patients to prognosis and therapeutic manifestations. Additionally, inhibition of the PDK/PDC axis by small molecule inhibitors and natural compounds at different clinical evaluation stages has also been discussed comprehensively."
965,The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy.,"Shukla A, Cloutier M, Appiya Santharam M, Ramanathan S, Ilangumaran S.",https://pubmed.ncbi.nlm.nih.gov/33671123/,"The immune system constantly monitors the emergence of cancerous cells and eliminates them. CD8+ cytotoxic T lymphocytes (CTLs), which kill tumor cells and provide antitumor immunity, select their targets by recognizing tumor antigenic peptides presented by MHC class-I (MHC-I) molecules. Cancer cells circumvent immune surveillance using diverse strategies. A key mechanism of cancer immune evasion is downregulation of MHC-I and key proteins of the antigen processing and presentation machinery (APM). Even though impaired MHC-I expression in cancers is well-known, reversing the MHC-I defects remains the least advanced area of tumor immunology. The discoveries that NLRC5 is the key transcriptional activator of MHC-I and APM genes, and genetic lesions and epigenetic modifications of NLRC5 are the most common cause of MHC-I defects in cancers, have raised the hopes for restoring MHC-I expression. Here, we provide an overview of cancer immunity mediated by CD8+ T cells and the functions of NLRC5 in MHC-I antigen presentation pathways. We describe the impressive advances made in understanding the regulation of NLRC5 expression, the data supporting the antitumor functions of NLRC5 and a few reports that argue for a pro-tumorigenic role. Finally, we explore the possible avenues of exploiting NLRC5 for cancer immunotherapy."
966,Natural Killer Cell Defects in Breast Cancer: A Key Pathway for Tumor Evasion.,"Arianfar E, Shahgordi S, Memarian A.",https://pubmed.ncbi.nlm.nih.gov/33258393/,"As the most important innate immune component cancers invader, natural killer (NK) cells have a magnificent role in antitumor immunity without any prior sensitization. Different subsets of NK cells have distinct responses during tumor cell exposure, according to their phenotypes and environments. Their function is induced mainly by the activity of both inhibitory and activating receptors against cancerous cells. Since the immunosuppression in the tumor microenvironment of breast cancer patients has directly deteriorated the phenotype and disturbed the function of NK cells, recruiting compensatory mechanisms indicate promising outcomes for immunotherapeutic approaches. These evidences accentuate the importance of NK cell distinct features in protection against breast tumors. In this review, we discuss the several mechanisms involved in NK cells suppression which consequently promote tumor progression and disease recurrence in patients with breast cancer."
967,Overexpression of p53 in tumor-distant epithelia of head and neck cancer patients is associated with an increased incidence of second primary carcinoma.,"Homann N, Nees M, Conradt C, Dietz A, Weidauer H, Maier H, Bosch FX.",https://pubmed.ncbi.nlm.nih.gov/11234882/,"Second primary carcinoma is a peculiar feature of head and neck cancer and represents a form of treatment failure distinct from the recurrence of the primary tumor. Whether altered p53 expression in tumor-distant epithelia at the time of diagnosis is of clinical value as a biomarker for second primary carcinoma development has not been rigorously answered because of the lack of long-term follow-up studies involving a sufficiently large patient cohort. In this prospective study, we have investigated p53 expression in tumor-distant epithelia and in the corresponding primary tumors of 105 head and neck cancer patients by immunohistochemistry on frozen sections. After a median follow-up of 55 months, the clinical course of disease parameters, i.e., local recurrences, lymph node and distant metastasis, incidence of second primary carcinoma, and survival, was evaluated. Overexpression of p53 in tumor-distant epithelia was found in 49 patients (46.7%), and it was independent of the p53 protein status of the primary tumor and of the tumor site, size, stage, and grading. Mucosal p53 overexpression was not associated with local primary recurrences, lymph node or distant metastases, or overall survival. Importantly, mucosal p53 overexpression, but not overexpression in the primary tumors, was significantly associated with an increased incidence of second primary carcinomas (P = 0.0001; Fisher's exact test). When the times to second primary tumor occurrence were analyzed by the Kaplan-Meier 005; log rank test). We conclude that IHC staining for p53 overexpression in tumor-distant epithelia provides a simple and rapid tool to identify head and neck cancer patients at increased risk of developing second primary tumors. Because p53 overexpression in these epithelia in our patient cohort was specifically associated with second primary cancer but not with recurrences, at least a fraction of the second primary cancers appears to have "
968,Urinary Volatiles and Chemical Characterisation for the Non-Invasive Detection of Prostate and Bladder Cancers.,"Tyagi H, Daulton E, Bannaga AS, Arasaradnam RP, Covington JA.",https://pubmed.ncbi.nlm.nih.gov/34821653/,"Bladder cancer (BCa) and prostate cancer (PCa) are some of the most common cancers in the world. In both BCa and PCa, the diagnosis is often confirmed with an invasive technique that carries a risk to the patient. Consequently, a non-invasive diagnostic approach would be medically desirable and beneficial to the patient. The use of volatile organic compounds (VOCs) for disease diagnosis, including cancer, is a promising research area that could support the diagnosis process. In this study, we investigated the urinary VOC profiles in BCa, PCa patients and non-cancerous controls by using gas chromatography-ion mobility spectrometry (GC-IMS) and gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) to analyse patient samples. GC-IMS separated BCa from PCa (area under the curve: AUC: 0.97 (0.93-1.00)), BCa vs. non-cancerous (AUC: 0.95 (0.90-0.99)) and PCa vs. non-cancerous (AUC: 0.89 (0.83-0.94)) whereas GC-TOF-MS differentiated BCa from PCa (AUC: 0.84 (0.73-0.93)), BCa vs. non-cancerous (AUC: 0.81 (0.70-0.90)) and PCa vs. non-cancerous (AUC: 0.94 (0.90-0.97)). According to our study, a total of 34 biomarkers were found using GC-TOF-MS data, of which 13 VOCs were associated with BCa, seven were associated with PCa, and 14 VOCs were found in the comparison of BCa and PCa."
969,L1CAM in human cancer.,"Altevogt P, Doberstein K, Fogel M.",https://pubmed.ncbi.nlm.nih.gov/26111503/,"L1 cell adhesion molecule (L1CAM) is one of the first neural adhesion molecules described with important functions in the development of the nervous system. Subsequent work discovered that L1CAM is expressed in many human cancers and is often associated with bad prognosis. This is most likely due to the motility and invasion promoting function of L1CAM. Here, we describe the path L1CAM has taken from a neural adhesion molecule to a recognized tumor antigen. We summarize the literature on L1CAM expression in cancers and pre-cancerous lesions. We focus on the genetic elements required for its re-expression and highlight preclinical studies for targeted therapy. The data suggest that L1CAM is a valuable diagnostic/prognostic marker and an attractive target for the therapy of several human cancers."
970,Establishment of an integrated management model for the secondary prevention of cervical cancer - an experience in taiwan hospital.,"Yan YH, Hsu S, Fang SC, Kung CM.",https://pubmed.ncbi.nlm.nih.gov/19469646/,"In the present study, secondary data analysis was utilized to evaluate the efficiency of the integrated management model (IMM) on the Pap smear test for screening of women's uterine cervical cancer. The data of female patients receiving a Pap smear test were collected both before (from July to December, 2006) and after (from January to June, 2007) introducing the IMM in a regional hospital in Tainan. The 1% to 15.4% (p < 0.001) among the female patients in the OPD (out-patient department), although the post-IMM participation rate was still much lower than that of general hospital data in Taiwan. Since IMM has proved efficacious for the management of various diseases, improvement in our IMM for the female uterine cervical cancer's prevention and management is conceivable. Studies on influencing factors should be carried out to allow strategies for resolution of problems to be designed, documented and implemented."
971,Cancer knowledge and misconceptions: a survey of immigrant Salvadorean women.,"Shankar S, Figueroa-Valles N.",https://pubmed.ncbi.nlm.nih.gov/10421082/,"This study assessed cancer knowledge, beliefs, and awareness of signs, symptoms, and early detection C. metropolitan area (DCMA). A face-to-face survey sampled 843 females aged 20 and above. Descriptive statistics were used to compute frequency of response for sociodemographic characteristics, beliefs, and awareness of signs, symptoms, and early detection  The sample's mean age was 34.5 years; 10% had no schooling, and 7.4% had more than a high school education. Sixty-six percent of the women worked full- or part-time; 16% had an annual income of $20,000 or more; and 26% reported having medical insurance. Thirty percent of the sample lacked knowledge of the etiology and spread of cancer. The statement, ""Bumps on your body can cause cancer"" was endorsed by 61.6%. Beliefs that ""destiny cannot be changed"" or ""just about anything can cause cancer"" were prevalent among 18.5%. ""Cancer is a punishment from God"" was believed by 10.9%. A general physical examination was the most frequent (82%) early detection  The Pap test was identified by 24.2%, and mammography by 14%; 5.6% mentioned breast self examination. Similar to other Hispanics, immigrant Salvadorean women in DCMA demonstrated a lack of knowledge of cancer's signs and symptoms, and early detection  Educational programs designed specifically for immigrant Salvadorean women to increase their knowledge of cancer and prevention "
972,[Recurrent epithelial ovarian cancer].,"Ding X, Lang J, Shen K.",https://pubmed.ncbi.nlm.nih.gov/11263170/,"
    


           All of these cases had postoperative pathological diagnosis.
    


           According to FIGO criteria, stage I, II 4 cases (12.9%), III, IV 27 cases (87.1%). The mean recurrent time of no-residual disease was 17.2 months, while that of residual disease < or = 2 cm was 10.1 months (P < 0.01). The mean recurrent time of those having chemotherapy > or = 6 cycles was 13.1 months, while that of those having chemotherapy < 6 cycles was 10.1 months (P > 0.05). The five-year survival rate of 18 cases having secondary cytoreductive surgery was 27.3%, while that of 4 cases having chemotherapy only was 7.1% (P < 0.01). The five-year survival rate of 7 cases abandoning any therapy was 4.8% (P < 0.01). 2 cases had only irradiation therapy.
    


          Conclusions:
        
      
      Histology, stage, degree of tumor differentiation, chemotherapy and the residual disease of cytoreductive surgery all influence recurrence of epithelial ovarian cancer. Secondary cytoreductive surgery along with chemotherapy can raise recurrent epithelial ovarian cancer's five-year survival rate."
973,Evaluation of miR-22 and miR-20a as diagnostic biomarkers for gastric cancer.,"Jafarzadeh-Samani Z, Sohrabi S, Shirmohammadi K, Effatpanah H, Yadegarazari R, Saidijam M.",https://pubmed.ncbi.nlm.nih.gov/28482669/," Diagnosing GC in its early stages is followed by more successful treatment. Unfortunately, there is no accurate  Recently, miRNAs have been investigated in the most cancer researches which have demonstrated that they have been dysregulated in many cancers.
    


           Quantitative reverse transcriptase PCR (q-RT PCR) was used for investigating the expression rate of these miRNAs.
    


          9 times) in comparison with their healthy tissues (P<0.001), while the expression rate of miR-22 in cancerous tissues was significantly decreased (1.9 times) (P<0.05).
    


          Conclusions:
        
      
      The obtained  However more research is needed to investigate their efficacy."
974,"Breast cancer in young women in Latin America: an unmet, growing burden.","Villarreal-Garza C, Aguila C, Magallanes-Hoyos MC, Mohar A, Bargalló E, Meneses A, Cazap E, Gomez H, López-Carrillo L, Chávarri-Guerra Y, Murillo R, Barrios C.",https://pubmed.ncbi.nlm.nih.gov/24334479/," There are unexplored and uncertain issues for BC in this particular group in Latin America. The aim of this study is to evaluate BC incidence and mortality among young women and related clinicopathological and survivorship aspects in this region.
    


          Materials and  We requested collaboration from the 12 different national cancer institutes in Latin America through SLACOM, the Latin American and Caribbean Society of Medical Oncology, and conducted a systematic literature review to obtain local data regarding the prevalence of BC among young women and their characteristics, outcomes, and survivorship-related issues.
    


           12% and 14% vs. 7%, respectively). We found only a few Latin American series addressing this topic, and prevalence varied between 8% and 14%. Stage II and III disease, high histological grade, and triple-negative and HER2 BC were features frequently observed among young Latin American BC patients.
    


          Conclusion:
        
      
      The rising incidence and mortality of BC in young Latin American women is a call to action in the region. It is necessary to monitor the epidemiological and clinical data through reliable cancer registries and to consider the implementation of protocols for education of patients and health professionals. This unmet, growing burden must be considered as a top priority of the national programs in the fight against BC, and models of specialized units should be implemented for this particular group of patients to provide better care for this emergent challenge."
975,Unfolding of Imminent Bio-Signatures in the Prognosis of Thyroid Cancer; The Emergence of Estrogen Related Receptor Gamma (ERRgamma) as a Hurricane.,"Gulwani D, Upadhyay P, Goel R, Sarangthem V, Debraj Singh T.",https://pubmed.ncbi.nlm.nih.gov/36853284/,"Thyroid cancer's incidence has increased by leaps and bounds over the last years and accounts for 2.8% of new cases of cancers. This increasing bar is partially assisted by enormous screening to understand the sub-clinical status. Advanced tumor growth is the leading cause of thyroid cancer-associated death. However, the complete understanding of the underlying cause is still to be disclosed. The updated clinical assessment evidenced a few major oncogenes viz. RAS, BRAF, and RET as key drivers in the development and progression of thyroid cancer. The BRAF mutation, a major cause of aggressive tumor type in papillary thyroid carcinoma, is frequently reported. The characteristic oncogenic changes imply thyroid cancer to be clinically an ideal model for targeted therapy against RET, RAS, and BRAF mutation. Though the sensitive biochemical marker assay has been improvised, the diagnosis of thyroid follicular neoplasms is still a big challenge as the biopsy aspiration cannot define the nature of the tumor in 30% of the cases. The main hurdle is assisted distinction between follicular thyroid lesions. The discrimination between follicular thyroid adenomas and carcinomas is histologically accomplished. This strictly necessitates the identification of sensitive diagnostic/prognostic markers to mitigate the risk of thyroid cancer and to avoid the unnecessary hurdles of biopsy and surgery. An array of prognostic biomarkers is being used for the diagnosis of thyroid cancer. However, Estrogen Related Receptor Gamma (ERRγ) is setting a new benchmark among the clinical biomarkers. The dramatic expression of ERRγ in thyroid cancer enables itself not only to serve as a characteristic diagnostic marker but also as a therapeutic target. Recently, we have reported that ERRγ is upregulated in 96 papillary thyroid cancer (PTC) and 26 poorly differentiated/ anaplastic thyroid cancer (ATC) samples. Various synthetic ERRγ inverse agonists viz. GSK5182, DN200434, and 24e are fully proved to modulate ERRγ expression in ATC to attain partial cure. If this finding can be assayed on a larger scale the evaluation of this marker may be warranted and informative. This review article highlights the ascending sheds of clinical biomarkers of thyroid cancer. This also reveals the clinical importance of ERRγ as an evolving diagnostic and therapeutic target in thyroid cancer."
976,"Specific overexpression of OLFM4(GW112/HGC-1) mRNA in colon, breast and lung cancer tissues detected using quantitative analysis.","Koshida S, Kobayashi D, Moriai R, Tsuji N, Watanabe N.",https://pubmed.ncbi.nlm.nih.gov/17270020/,"Overexpression of the olfactomedin 4 (OLFM4(GW112,/hGC-1)) gene was recently reported to inhibit various apoptotic pathways and promote proliferation of cancer cells, suggesting that OLFM4 might serve as a diagnostic marker for human cancers. Therefore, we examined cancer-specific OLFM4 overexpression. OLFM4 mRNA was highly expressed in cancerous tissues obtained from the colon, breast and lung. Positivity for OLFM4 mRNA, defined as the mean + 2 SD in non-cancerous colon and breast tissues, was observed in 68 and 50% of the studied colon and breast cancer tissues. OLFM4 mRNA expression was not detected in non-cancerous lung tissues but was evident in 62% of the lung cancer tissues. On comparing paired samples, the expression of OLFM4 mRNA was observed to be elevated in 90, 69 and 85% of colon, breast and lung cancer tissues, respectively. OLFM4 mRNA expression was observed even in the early stages of each cancer type. The expression of OLFM4 mRNA did not correlate with that of the antiapoptotic molecule survivin, indicating that it can be used independently in cancer diagnosis. Combining OLFM4 and survivin  Thus, OLFM4 mRNA might be a useful tool to support the diagnosis of cancer, irrespective of the clinical stages."
977,The emerging roles of Jab1/CSN5 in cancer.,"Wang L, Zheng JN, Pei DS.",https://pubmed.ncbi.nlm.nih.gov/27412572/,"C-Jun activation domain-binding protein-1 (Jab1) not only is full but also a subunit (CSN5) of the constitutive photomorphogenesis 9 signalosome (CSN), which is an evolutionarily conserved and multifunctional protein that involves in controlling cellular proliferation and apoptosis, affecting a series of pathways, as well as regulating genomic instability and DNA damage and repair. The CSN is a highly conservative protein from yeast to human and interacts with the cullin-RING family of ubiquitin ligases so that it could be execute a process of removing NEDD8, a ubiquitin-like polypeptide (deneddylase activity). The role of Jab1/CSN5's multi-function has been proved as being oncogenic in nature, what is more, Jab1/CSN5 has been confirmed by much evidence that it participates in the carcinogenesis progression and is tightly associated with poor prognosis. However, the biologic implication of Jab1/CSN5 activity during the cancer's development is unclear. We performed a systematic literature review and assessment from PubMed and Medline databases in this article. Jab1/CSN5 is participate in a lot of biologic responses, including cell proliferation, apoptosis, cell cycle regulation, DNA metabolism, invasion, DNA damage and repair, and recurrence. It also promotes cell transformation and tumorigenesis. In this review, we mainly expound the progress in the function and research advances of Jab1/CSN5 and in untangling the Jab1/CSN5 signaling pathway. Based on these bases, its potential as a therapeutic target for cancer can play a greater role in future cancer treatment."
978,"The relationship among the polymorphisms of SULT1A1, 1A2 and different types of cancers in Taiwanese.","Peng CT, Chen JC, Yeh KT, Wang YF, Hou MF, Lee TP, Shih MC, Chang JY, Chang JG.",https://pubmed.ncbi.nlm.nih.gov/12469224/,"Sulfotransferase (SULT) enzymes play an important role in the detoxification, metabolism and bioactivation of numerous xenobiotics, many dietary and environmental mutagens, drugs, neurotransmitters and hormones. The genes for SULT1A1 and SULT1A2 contain common genetic polymorphisms that are associated with individual variations in the level of enzyme activities as well as variations of biochemical and physical properties. We developed a PCR-RFLP  The  Neither SULT1A1*3 nor SULT1A2*3 were found in this study. The frequencies of SULT1A1*2 and SULT1A2*2 for hepatic, colon, lung, oral, gastric, renal and cervical cancerous patients were 3.95, 5.56, 4.92, 3.84, 2.70, 7.41 and 4.50%, respectively. No statistical significance was found for these cancer patients after comparison with normal controls (4.0%) for the allelic frequencies of SULT1A1*2 and SULT1A2*2."
979,[Detection of telomerase activity in gastric cancer and adjacent tissues].,"Gao F, Zhang W, Jing S, Liu Y, Zhang B.",https://pubmed.ncbi.nlm.nih.gov/12567454/,"
    


          
    


          1% (37/42) gastric cancerous specimens displayed telomerase activity. However, only 2 of 42 tissue samples adjacent to the gastric cancer showed telomerase activity. However our 
    


          Conclusions:
        
      
      The "
980,"Targets and mechanisms of berberine, a natural drug with potential to treat cancer with special focus on breast cancer.","Jabbarzadeh Kaboli P, Rahmat A, Ismail P, Ling KH.",https://pubmed.ncbi.nlm.nih.gov/24973693/,"Breast cancer is the most common cancer among women worldwide and novel therapeutic agents are needed to treat this disease. The plant-based alkaloid berberine has potential therapeutic applications for breast cancer, although a better understanding of the genes and cellular pathways regulated by this compound is needed to define the mechanism of its action in cancer treatment. In this review, the molecular targets of berberine in various cancers, particularly breast cancer, are discussed. Berberine was shown to be effective in inhibiting cell proliferation and promoting apoptosis in various cancerous cells. Some signaling pathways affected by berberine, including the MAP (mitogen-activated protein) kinase and Wnt/β-catenin pathways, are critical for reducing cellular migration and sensitivity to various growth factors. This review will discuss recent studies and consider the application of new prospective approaches based on microRNAs and other crucial regulators for use in future studies to define the action of berberine in cancer. The effects of berberine on cancer cell survival and proliferation are also outlined."
981,"Neoplastic lymphangiosis of the upper aerodigestive tract simulating field cancerization: histopathological analysis, surgical limits and literature review.","Mattavelli F, Pizzi N, Pennacchioli E, Radaelli S, Quattrone P, Mattavelli D, Fior A, Pilotti S.",https://pubmed.ncbi.nlm.nih.gov/23052176/,"Neoplastic lymphangiosis is defined as extensive embolic spread of cancer cells in the lymphatic vessels often without any evidence of a mass. Instead, field cancerization is defined by the presence of multifocal neoplastic lesions in a mucosal field previously exposed to mutagenic factors. In this case report, this oncological entity was suggested by the wide extent and multifocality of the disease and by the patient's exposure to risk factors. Instead, the pathological slides revealed the integrity of the mucosa and the presence of widespread embolic metastasis to lymphatic vessels. Thus, the diagnosis was changed to neoplastic lymphangiosis. This clinical presentation is a negative prognostic factor, and surgical treatment is ineffective because of the impossibility to obtain adequate free margins. The present case underlines the poor prognosis of such locally advanced cancer and the importance of recognizing it early so that the treatment approach can be adapted."
982,Sonographic appearance of thyroid cancer in patients with Hashimoto thyroiditis.,"Durfee SM, Benson CB, Arthaud DM, Alexander EK, Frates MC.",https://pubmed.ncbi.nlm.nih.gov/25792586/,"
    


           We evaluated each nodule for size, echogenicity, composition, margins, halo, and vascularity and evaluated the 
    


           Forty-two patients (29.0%) had Hashimoto thyroiditis with positive TPO antibodies, and 103 patients (71.0%) had negative TPO antibodies. The 1% versus 26.2%; P= .0005). Comparing cancers in TPO antibody-positive to TPO antibody-negative patients, there was no significant difference in the size, echogenicity, composition, margins, halo presence, calcification presence and type, or vascularity of the cancerous nodule (P > .05). Among TPO antibody-positive patients, comparing thyroid cancerous nodules in patients with heterogeneous glands to those with homogeneous glands, there was no significant difference in any sonographic characteristic except the margin of the nodule, which was more often irregular or poorly defined in heterogeneous glands and more often smooth in homogeneous glands (P< .05).
    


          Conclusions:
        
      
      Sonographic features of thyroid cancer are similar in patients with and without Hashimoto thyroiditis. Among patients with Hashimoto thyroiditis and thyroid cancer, the sonographic appearance of the cancerous nodule is similar, except that cancerous nodule margins are more likely to be irregular or poorly defined when the gland is heterogeneous."
983,Treating sex and gender differences as a continuous variable can improve precision cancer treatments.,"Yang W, Rubin JB.",https://pubmed.ncbi.nlm.nih.gov/38622740/," One barrier to translation is that cancer phenotypes cannot be segregated into distinct male versus female categories. Instead, within this convenient but contrived dichotomy, male and female cancer phenotypes are highly overlapping and vary between female- and male- skewed extremes. Thus, sex and gender-specific treatments are unrealistic, and our translational goal should be adaptation of treatment to the variable effects of sex and gender on targetable pathways.
    


           We calculated the posterior probabilities of predicting patient sex and gender based on the observed sexes of similar samples in this map of transcriptome similarity.
    


           TI supported deconvolution of transcriptomes into measures of patient-specific activity in sex and gender-biased, targetable pathways. It identified sex and gender-skewed extremes in mechanistic phenotypes like cell cycle signaling and immunity, and precisely positioned each patient's whole transcriptome on an axis of continuously varying sex and gender phenotypes.
    


          Conclusions:
        
      
      Cancer type, patient sex and gender, and TI value provides a novel and patient- specific mechanistic identifier that can be used for realistic sex and gender-adaptations of precision cancer treatment planning."
984,Telomere shortening in mucosa surrounding the tumor: biosensor of field cancerization and prognostic marker of mucosal failure in head and neck squamous cell carcinoma.,"Boscolo-Rizzo P, Rampazzo E, Perissinotto E, Piano MA, Giunco S, Baboci L, Spinato G, Spinato R, Tirelli G, Da Mosto MC, Del Mistro A, De Rossi A.",https://pubmed.ncbi.nlm.nih.gov/25771075/,"
    


          Materials and  Telomere length and levels of telomerase reverse transcriptase (TERT) transcripts were quantified by real-time PCR in cancer tissues and SM from 139 and 90 patients with HNSCC, respectively.
    


           Patients with short telomeres in SM had a higher risk of mucosal failure (adjusted HR=4.29). Patients with high TERT levels in cancer tissues had a higher risk of regional failure (HR=2.88), distant failure (HR=7.27), worse disease-specific survival (HR for related death=2.62) but not mucosal failure. High-risk patients having both short telomeres in SM and high levels of TERT in cancer showed a significantly lower overall survival (HR=2.46).
    


          Conclusions:
        
      
      Overall these findings suggest that telomere shortening in SM is a marker of field cancerization and may precede reactivation of TERT. Short telomeres in SM are strongly prognostic of mucosal failure, whereas TERT levels in cancer tissues increase with the aggressiveness of the disease and are prognostic of tumor spread."
985,Lung Cancer Deaths in the National Lung Screening Trial Attributed to Nonsolid Nodules.,"Yip R, Yankelevitz DF, Hu M, Li K, Xu DM, Jirapatnakul A, Henschke CI.",https://pubmed.ncbi.nlm.nih.gov/27378239/,"Purpose To validate the recommendation of performing annual follow-up of nonsolid nodules (NSNs) identified by computed tomographic (CT) screening for lung cancer, all cases of lung cancer manifesting as NSN in the National Lung Screening Trial (NLST) were reviewed. Materials and  The NLST database was searched to identify all participants with at least one NSN on CT scan with lung cancer as the cause of death (COD) documented by the NLST endpoint verification process. Among the 26 722 participants, 2534 (9.4%) had one or more NSNs, and lung cancer as the COD occurred for 48 participants. On review, 21 of the 48 patients had no NSN in the cancerous lobe, which left 27 patients whose CT scans were reviewed by four radiologists: Group A (n = 12) were cases of lung cancer as the COD because of adenocarcinoma, and group B (n = 15) were cases of lung cancer as the COD because of other cell types. Frequency of lung cancer as the COD because of NSN and the time from randomization to diagnosis within these groups was determined.  Five of the 15 patients in group B had no NSN, and for the remaining 10 patients, lung cancer as the COD was not because of NSN. Conclusion It seems unlikely that patients with lung cancer as the COD occurred with solitary or dominant NSN as long as annual follow-up was performed. This lends further support that lung cancers that manifest as NSNs have an indolent course and can be managed with annual follow-up. © RSNA, 2016."
986,Delineating the extent of esophageal squamous cell carcinoma.,"Kono M, Kanesaka T, Ishihara R, Kitamura M, Shoji A, Inoue T, Matsueda K, Miyake M, Waki K, Shimamoto Y, Fukuda H, Iwagami H, Matsuura N, Nakahira H, Shichijo S, Maekawa A, Yamamoto S, Takeuchi Y, Higashino K, Uedo N, Michida T, Nakatsuka SI, Fujiwara Y.",https://pubmed.ncbi.nlm.nih.gov/34052934/," However, the boundaries of some lesions are unclear even with Lugol chromoendoscopy, and there is a risk of residual lesions or over-excision. This study aimed to evaluate the utility of narrow-band imaging (NBI) for the delineation of esophageal SCC in endoscopic resection.
    


           The proportion of residual cancer, which was defined as histologically proven cancer confirmed adjacent to the scar within 1 year after endoscopic resection, was evaluated. To evaluate whether the marks added by Lugol chromoendoscopy after NBI marking were more reliable, we evaluated the presence of cancer in the iodine-unstained area outside the NBI-determined marks, i.e., the cancerous area missed by NBI. The presence of cancer in the iodine-stained areas inside the NBI-determined marks, i.e., the cancerous area missed by Lugol, was also evaluated. These were compared to assess the risk of residual cancer in endoscopic resection with NBI and Lugol chromoendoscopy.
    


          7%) residual cancers were detected. The cancerous area missed by NBI and the cancerous area missed by Lugol were identified in 18 (6%) and 43 (14%) lesions, respectively (P = 0.001).
    


          Conclusions:
        
      
      NBI might be acceptable for delineating the extent of esophageal SCCs that are difficult to delineate with Lugol chromoendoscopy."
987,Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy.,"Crees Z, Girard J, Rios Z, Botting GM, Harrington K, Shearrow C, Wojdyla L, Stone AL, Uppada SB, Devito JT, Puri N.",https://pubmed.ncbi.nlm.nih.gov/24975605/,"Cancer is a leading cause of death worldwide and an estimated 1 in 4 deaths in the United States is due to cancer. Despite recent advances in cancer treatment, adverse effects related to cancer therapy remain a limiting factor for many patients. The ideal cancer treatment would selectively target cancerous cells while sparing normal, healthy cells to offer maximal therapeutic benefit while minimizing toxicity. Telomeres are structurally unique DNA sequences at the end of human chromosomes, which play an integral role in the cellular mortality of normal cells. As telomeres shorten with successive cellular divisions, cells develop chromosomal instability and undergo either apoptosis or senescence. In many cancers, this apoptosis or senescence is avoided as normal telomere length is maintained by a ribonucleoprotein reverse transcriptase called telomerase. Telomerase is expressed in more than 85% of all cancers and confers cancerous cells with a replicative immortality, which is a hallmark of malignant tumors. In contrast, telomerase activity is not detectable in the majority of normal somatic cell populations. Therefore, the targeting of telomerase and telomere maintenance mechanisms represent a potentially promising therapeutic approach for various types of cancer. This review evaluates the roles of GRN163L, T-oligo and small molecule G-quadruplex stabilizers as potential anticancer therapies by targeting telomerase and other telomere maintenance mechanisms."
988,Quantitative analysis of free ubiquitin and multi-ubiquitin chain in colorectal cancer.,"Ishibashi Y, Hanyu N, Suzuki Y, Yanai S, Tashiro K, Usuba T, Iwabuchi S, Takahashi T, Takada K, Ohkawa K, Urashima M, Yanaga K.",https://pubmed.ncbi.nlm.nih.gov/15194223/,"Accumulation of ubiquitin (Ub) has been documented in various cancers. The levels of the two forms of Ub, i.e. free ubiquitin (FUb) and multi-ubiquitin chain (MUC) were measured in colorectal cancers and in matched normal colonic tissues in 43 patients. When compared to normal colonic tissues, the levels of both FUb and MUC were significantly higher in the cancerous tissues (P < 0.01, respectively). The level of FUb was related to the depth of invasion (P < 0.05). The level of MUC was related to blood vessel invasion and lymphatic vessel invasion (P < 0.05). The levels of FUb and MUC had no correlation with histological grade, lymph node metastasis, liver metastasis or relapse-free survival. We conclude that the levels of FUb and MUC were up-regulated in colorectal cancer and were correlated with the pathological findings."
989,The impact of symptoms and comorbidity on prognosis in stage IB cervical cancer.,"Peipert JF, Wells CK, Schwartz PE, Feinstein AR.",https://pubmed.ncbi.nlm.nih.gov/8372869/," Because clinical variables such as patients' symptoms, symptom severity, and comorbidity may indicate a cancer's biologic virulence and the host-tumor interaction, this study was performed to test the hypothesis that clinical variables will also affect survival of patients with stage IB cervical cancer.
    


          Study design:
        
      
      From medical records of 251 cases of invasive cervical cancer treated at Yale-New Haven Hospital between 1984 and 1988, information was extracted for patients' demographic characteristics, symptoms, symptom severity, comorbidity, physical findings, laboratory data, treatment, and subsequent course.
    


           For a composite clinical predictive system on the basis of symptom status and comorbidity, the 3-year survival rates were as follows: symptomatic patients with comorbidity 58% (seven of 12), either symptomatic or comorbid but not both 77% (46/60), and asymptomatic patients without comorbidity 86% (43/50) (p = 0.02 for linear trend chi 2). When entered into a Cox proportional-hazard model along with other variables that might have an impact on prognosis, the composite symptom-comorbidity stage was the only variable that remained statistically significant.
    


          Conclusion:
        
      
      These findings demonstrate the importance of clinical variables in estimating prognosis in stage IB cervical cancer. Unless these variables are suitably analyzed, prognostic estimates based only on morphologic studies will be imprecise and therapeutic evaluations may be misleading."
990,Primary Liver Cancers: Connecting the Dots of Cellular Studies and Epidemiology with Metabolomics.,Berkemeyer S.,https://pubmed.ncbi.nlm.nih.gov/36768732/,"Liver cancers are rising worldwide. Between molecular and epidemiological studies, a research gap has emerged which might be amenable to the technique of metabolomics. This review investigates the current understanding of liver cancer's trends, etiology and its correlates with existing literature for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and hepatoblastoma (HB). Among additional factors, the literature reports dysfunction in the tricarboxylic acid metabolism, primarily for HB and HCC, and point mutations and signaling for CCA. All cases require further investigation of upstream and downstream events. All liver cancers reported dysfunction in the WNT/β-catenin and P13K/AKT/mTOR pathways as well as changes in FGFR. Metabolites of IHD1, IDH2, miRNA, purine, Q10, lipids, phosphatidylcholine, phosphatidylethanolamine, acylcarnitine, 2-HG and propionyl-CoA emerged as crucial and there was an attempt to elucidate the WNT/β-catenin and P13K/AKT/mTOR pathways metabolomically."
991,Risk of lung cancer in pre- and post-menopausal women with ano-genital malignancies.,"Frisch M, Melbye M.",https://pubmed.ncbi.nlm.nih.gov/7665218/,"Women diagnosed during the period 1943-1990 and reported to the Danish Cancer Registry with invasive squamous-cell carcinomas of the uterine cervix, vulva, vagina or anus, together with those having pre-cancerous lesions (CIN III or carcinoma in situ) of the uterine cervix diagnosed in the period 1958-1990, were followed for the occurrence of subsequent lung cancer over 762,000 person-years. Overall, these patients developed 2 to 2 1/2 times more lung cancers than women in the general Danish population. Women in whom cervical cancer was diagnosed recently, and before the age of 45 years, had a 4.6 times elevated risk of developing lung cancer, while young women with vulvar or vaginal cancer were at a 4.0-fold elevated risk. Similarly, women in whom anal cancer was diagnosed before the age of 60 years were at a 3.5-fold increased risk of developing lung cancer. The present study supports the hypothesis that smoking is involved in the aetiology of ano-genital malignancies. The particularly high risk of developing subsequent lung cancers seen in women who were pre-menopausal (< 45 years) at the time of the ano-genital cancer diagnosis suggests that the effect of smoking in ano-genital carcinogenesis might be partly mediated through alterations in oestrogen metabolism. Alternatively, patients who developed their initial ano-genital cancer at a young age might harbour some genetic susceptibility which could explain their excess lung-cancer risk."
992,[Androgens and laryngeal cancer].,"Medraś M, Jóźków P, Krecicki T, Zalesska-Krecicka M.",https://pubmed.ncbi.nlm.nih.gov/11202336/,The article concerns relations between larynx cancer and androgenic activity in men. Up till now the role of androgens in laryngeal carcinogenesis has not been established. Authors point out to andropenia (gonadal and supracortical) in elderly males and its influence on larynx cancer occurrence in the course of aging.  There is presented data on serum androgen concentrations in healthy men and patients with laryngeal neoplasms. The necessity of further studies of the larynx cancer's hormone-dependence is underlined.
993,"History, pathogenesis, and management of familial gastric cancer: original study of John XXIII's family.","Corso G, Roncalli F, Marrelli D, Carneiro F, Roviello F.",https://pubmed.ncbi.nlm.nih.gov/23484115/," The guidelines for hereditary diffuse gastric cancer are clearly established; however, there are no defined recommendations for the management of familial intestinal gastric carcinoma.
    


           Family history was analysed according to the International Gastric Cancer Linkage Consortium criteria, and gastric tumours were classified in accord with the last Japanese guidelines.
    


           John XXIII's clinical tumour (cTN) was classified as cT4bN3a (IV stage). In two other cases, gastric carcinomas were classified as intestinal histotype and staged as pT1bN0 and pT2N2, respectively.
    


          Conclusions:
        
      
      Pope John XXIII's family presents a strong aggregation for gastric cancer affecting almost seven members; it spreads through two consecutive generations. In absence of defined genetic causes and considering the increased risk of gastric cancer's development in these families, as well as the high mortality rates and advanced stages, we propose an intensive surveillance protocol for asymptomatic members."
995,Evidence based demonstration of the concept of 'field cancerization' by p53 expression in mirror image biopsies of patients with oral squamous cell carcinoma - an immunohistochemical study.,"Hande AH, Mohite DP, Chaudhary MS, Patel M, Agarwal P, Bohra S.",https://pubmed.ncbi.nlm.nih.gov/26662135/," Identification of patients at high risk for development of SPT is an important part of research for cancer management. This study was designed keeping this aspect in mind and utilizing the increased expression of p53 as an indicator of existence of altered fields in mirror image biopsies of OSCC patients.
    


          Design:
        
      
      Forty clinically diagnosed oral cancer patients were included in the study. Biopsy tissue samples from clinically diagnosed oral cancer patients (Group A) and the mirror image, clinically normal looking mucosa at corresponding contralateral anatomical site (Group B) were studied for histopathological evaluation and p53 immunoexpression.
    


           There was statistically significant (chi-square value - 126.6, p=0.0001) difference in grades of epithelial dysplasia and p53 immunoexpression in Group B. Spearman's Rank Correlation Coefficient shows non-significant positive correlation between epithelial dysplasia and p53 (r=0.28, p=0.05) in Group B.
    


          Conclusions:
        
      
      Evidence of presence of field cancerization, evaluated by histopathological alterations and enhanced p53 expression was observed in mirror image biopsies of OSCC patients. This could predict the altered state of oral mucosa secondary to carcinogen exposure. The realization of a genetically altered field as a cancer risk factor provides a new paradigm. It would be prudent to keep these patients under close observation and to advice them chemotherapeutic regimes."
996,Induction of tumor immunity by photodynamic therapy.,Korbelik M.,https://pubmed.ncbi.nlm.nih.gov/9612200/,"The mechanism of tumor destruction by photodynamic therapy (PDT) incorporates a variety of events leading to inactivation of tumor cells. The unique feature of PDT is the mobilization of the host to participate in the eradication of treated cancer. A critical element is the induced inflammation at the treated site associated with massive invasion of activated myeloid cells. In addition to further destruction of cancer cells, conditions are created for the presentation of tumor antigens with subsequent activation of lymphoid cells, leading to tumor-specific immunity. This inflammation-primed immune development process  Once generated by PDT, it is conceivable that these immune cells (especially if further expanded and activated by adjuvant immunotherapy) can be engaged in additional eradication of disseminated and/or metastatic lesions of the same cancer. A number of immunotherapy regimens have already been proven effective in enhancing the curative effect of PDT with various animal tumor models. Inflamed cancerous tissue at the PDT-treated site appears to exert powerful attracting signals for immune cells activated by different immunotherapy regimens."
997,p53 and Bcl-2 expression in pneumoconiosis-related pre-cancerous lesions and lung cancers: frequent and preferential p53 expression in pneumoconiotic bronchiolar dysplasias.,"Katabami M, Dosaka-Akita H, Honma K, Kimura K, Fujino M, Uchida Y, Mikami H, Ohsaki Y, Kawakami Y, Kikuchi K.",https://pubmed.ncbi.nlm.nih.gov/9466648/,"To explore the mechanism by which lung cancers excessively arise from pneumoconiosis, we determined the altered expression of p53 and Bcl-2 by immunohistochemistry (IHC) in lung cancers, dysplasias and non-cancerous pulmonary epithelia in pneumoconiotics in comparison with those from non-pneumoconiotic patients. We examined p53 expression in squamous cell carcinomas (SCCs) and dysplasias separately in the central and peripheral zones of bronchial trees, based on observations that SCCs from pneumoconiotic patients occurr more frequently in peripheral epithelia than those from non-pneumoconiotic patients (55 of 72 SCCs with pneumoconiosis vs. 33 of 72 SCCs without pneumoconiosis). Forty-one of 72 patients with pneumoconiosis-related lung cancers had altered p53 expression, which was comparable to the positivity of p53 expression in lung cancers without pneumoconiosis. p53 expression was observed significantly more frequently in bronchiolar dysplasias with pneumoconiosis than in those from non-pneumoconiotic patients (13 of 23 vs. 4 of 22), while p53 expression was found in bronchial dysplasias with pneumoconiosis as frequently as those without pneumoconiosis. Moreover, in patients with pneumoconiosis, bronchiolar dysplasias exhibited p53 expression more frequently than bronchial dysplasias (13 of 23 vs. 4 of 19). When comparison was restricted to bronchiolar dysplasias from patients without lung cancer, p53 expression had a strikingly higher frequency in the dysplasias with pneumoconiosis than in those from non-pneumoconiotic patients (8 of 15 vs. 0 of 14). Bcl-2 occasionally was expressed in squamous metaplasias and basal cell hyperplasias, in contrast to p53, for which immunostaining was negative in these lesions. Altogether, our "
998,Carcinogens and cancers in freshwater fishes.,"Black JJ, Baumann PC.",https://pubmed.ncbi.nlm.nih.gov/2050071/,"Epizootics of neoplasms in freshwater fish species are considered in relation to circumstantial and  Although there is concern for the safety of consuming fish affected with neoplasms, this concern may be misdirected as direct transmission of cancer by ingesting cancerous tissue would seem unlikely. Of greater concern is the matter of toxic and cancer-causing chemicals present in edible fish that exhibit neoplasia as a symptom of past exposure via residence in a polluted waterway. There is ample evidence to suggest that contaminant chemicals ingested via contaminated Great Lakes fish may already be affecting both human and ecosystem health, but these effects are subtle and may require new approaches to the study of the affected systems."
999,Peroral video cholangioscopy to evaluate indeterminate bile duct lesions and preoperative mucosal cancerous extension: a prospective multicenter study.,"Osanai M, Itoi T, Igarashi Y, Tanaka K, Kida M, Maguchi H, Yasuda K, Okano N, Imaizumi H, Itokawa F.",https://pubmed.ncbi.nlm.nih.gov/23807803/," Therefore, the aim of this study was to clarify the accuracy of PVCS in evaluating biliary tract lesions.
    


          Patients and  The study evaluated the ability of PVCS to diagnose indeterminate biliary tract diseases, detect mucosal cancerous extension preoperatively in extrahepatic bile duct cancers, and predict adverse events.
    


          1 % of patients whereas biopsy alone was accurate in 85.7 %. In extrahepatic bile duct cancer, mucosal cancer extended histologically at least 20 mm in 34.7 % (17/49) of patients. The accuracy rate of PVCS to evaluate the presence or absence of mucosal cancerous extension by endoscopic retrograde cholangiography (ERC) alone, ERC with PVCS, and ERC with PVCS + biopsy were 73.5 %, 83.7 %, and 92.9 %, respectively. Adverse events were seen in 6.9 % of PVCS patients, but no serious complications were observed.
    


          Conclusion:
        
      
      PVCS enhanced the accurate diagnosis of biliary tract lesions by providing excellent resolution in combination with biopsy."
1000,Clonality and prognostic implications of p53 and epidermal growth factor receptor somatic aberrations in multiple primary lung cancers.,"Chang YL, Wu CT, Lin SC, Hsiao CF, Jou YS, Lee YC.",https://pubmed.ncbi.nlm.nih.gov/17200338/,"Purpose:
        
      
      For treatment decision and prognostic applications, we evaluated p53/epidermal growth factor receptor (EGFR) somatic aberrations in multiple primary lung cancers to differentiate multifocal tumors from intrapulmonary metastasis.
    


           Genomic DNA was extracted from microdissected cells of paraffin-embedded multiple primary lung cancer tissues. Overexpression and somatic mutations in exons of p53 (exons 5-8) and tyrosine kinase domain of EGFR (exons 18-22) were examined by immunohistochemical staining and DNA sequencing, respectively.
    


          9%) and/or EGFR (44 of 58, 75.9%) 2%) of multiple primary lung cancers. Twenty-two cases (37.9%) were assessed as having the same clonality and 28 cases (48.3%) were determined as having different clonality, which further supported the carcinogenic theory of field cancerization. Notably, the occurrence of lymph node metastasis was more commonly observed in tumors with the same clonality (P = 0.045) and was associated with poor patient 5-year survival rate (P = 0.001). However, no correlation was found between tumor clonality and patient survival (P = 0.630). The EGFR somatic aberrations in 58 multiple primary lung cancers, including vascular invasion associated with EGFR overexpression (P = 0.012) and mutation (P = 0.025), further suggested the potential benefits of target therapy of inoperable multiple primary lung cancers.
    


          Conclusions:
        
      
      Our "
1001,[Magnesium content of laryngeal precancerous conditions and laryngeal cancers].,"Szmeja Z, Kończewska H.",https://pubmed.ncbi.nlm.nih.gov/3957730/,"The content of magnesium in tissues, erythrocytes and serum was analysed by atomic absorption spectrometry. A higher concentration of magnesium was found in malignant laryngeal tissue and in lymph nodes of the neck compared to homologous pre-cancerous tissue. In pre-cancerous lesions of the larynx the magnesium concentration of the erythrocytes and serum lay at the lower limit of normal. In patients with cancer of the larynx, the magnesium concentration was considerably below the normal levels and continued to decline as the disease progressed."
1002,Expression and function of gastrin-releasing peptide (GRP) in normal and cancerous urological tissues.,"Ischia J, Patel O, Bolton D, Shulkes A, Baldwin GS.",https://pubmed.ncbi.nlm.nih.gov/24894852/,"Gastrin-releasing peptide (GRP) acts as an important regulatory peptide in several normal physiological processes and as a growth factor in certain cancers. In this review we provide a comprehensive overview of the current state of knowledge of GRP in urological tissues under both normal and cancerous conditions. GRP and its receptor, GRP-R, are expressed in the normal kidney and renal cancers. GRP can stimulate the growth of renal cancer cells. GRP and GRP-R are expressed in prostate cancer and GRP can stimulate the growth of prostate cancer cell lines. Importantly, GRP is a key neuroendocrine peptide, which may be involved in the progression of advanced prostate cancer and in the neuroendocrine differentiation of prostate cancer. Recent animal studies have shown that GRP and GRP-R are an integral part of male sexual function and play a crucial role in spinal control of erections and ejaculation."
1003,The integration of multi-omics analysis and machine learning for the identification of prognostic assessment and immunotherapy efficacy through aging-associated genes in lung cancer.,"Lu W, Zhou Y, Zhao R, Liu Q, Yang W, Zhu T.",https://pubmed.ncbi.nlm.nih.gov/38261733/," Lung cancer's heterogeneity complicates prognosis prediction. This study integrates pivotal molecules to evaluate patient prognosis and immunotherapy efficacy.
    


           The Lasso-Cox  GO and KEGG analyses explored gene pathways. ssGSEA quantified immune cell types and functions. The riskScore predicts the effectiveness of immunotherapy based on its correlation with DNA repair and immune checkpoint genes. Single-cell sequencing examined key gene expression across cell types.
    


           Lasso-Cox selected ""BLK,"" ""ITGB4,"" ""PRKCH,"" and ""SNAI1"" for the prognostic model. MF analysis revealed enriched functions including antigen binding, GTPase regulator activity. In terms of BP, processes like immune signaling and mitotic division were enriched. CC enrichment included immunoglobulin complexes and chromosomal regions. Enriched pathways encompassed Cell cycle, Focal adhesion, Cellular senescence, and p53 signaling. ssGSEA evaluated immune cell abundance. RiskScore correlated with CTLA4 and PD1 through MMR and immune checkpoint analysis. Single-cell analysis indicated gene expression across cell types for BLK, ITGB4, PRKCH, and SNAI1.
    


          Conclusion:
        
      
      In summary, our developed prognostic model utilizing age-related genes effectively predicts lung cancer prognosis and the efficacy of immune therapy."
1004,Retroperitoneal follicular dendritic cell sarcoma in a young woman: Diagnosis and treatment challenges.,"Bouriga R, Abdessaied N, Hochlef M, Mallat N, Mahjoub M, Sriha B, Ahmed SB.",https://pubmed.ncbi.nlm.nih.gov/29395417/," Few cases have been reported in English literature so far. The scarcity may be partially due to under-recognition of this entity. Through this case report we analyzed the difficulties of clinical and pathological diagnosis of this rare tumor with its unusual location mistaken it with gynecological cancer's iliac lymph nodes metastases. We also discussed its systemic treatment options.
    


          Case report:
        
      
      A 48-year-old woman presented with a loss of weight and epigastralgia. Computed tomography (CT) showed a mass of 5cm of diameter, located close to iliac vessels. Investigation for gynecologic cancers was negative and a partial tumor resection was performed. Pathological examination readdressed the diagnosis of FDCS. Microscopically, the tumor was composed of a proliferation of spindle to ovoid cells arranged in fascicles, whorls and storiform pattern, accompanied by sprinkling of small lymphocytes. The nuclei of the tumor cells were elongated spindled or ovoid shape with vesicular chromatin and distinct small nuclei. Immunohistochemically, the tumor cells were positive for CD21, CD23 but negative for any type of cytokeratin. Even pathological diagnosis was misleading, therapeutic management was more challenging with this unusual location particularly associated with an aggressive clinical course. Two lines of chemotherapy gave different responses.
    


          Conclusion:
        
      
      Clinical and pathological diagnosis of retroperitoneal FDCS needs vigilance. Both lymphoma and sarcoma chemotherapy regimens are effective. Due to this pathology's rareness we highlighted a lack of treatment consensus and proposed options."
1005,DNA ploidy patterns of minute carcinomas in the stomach.,"Hattori T, Sugihara H, Fukuda M, Hamada S, Fujita S.",https://pubmed.ncbi.nlm.nih.gov/3084417/,"DNA ploidy patterns of minute carcinomas in the stomach were determined by cytofluorometric measurement, using paraffin sections which had been prepared for histological examination. The examples studied were 19 minute carcinomas less than 5 mm in diameter, of which 12 were adenocarcinomas, and 7 were signet ring cell carcinomas. By measuring the fluorescence intensity of more than 30 mitotic nuclei, the DNA ploidy pattern of each tumor was determined. The control diploid DNA content was obtained by measuring the fluorescence intensity of non-cancerous mitoses in the gastric mucosa. In the present study, heteroploidy was seen in 5 carcinomas; 4 adenocarcinomas and one signet ring cell carcinoma. The remaining 14 carcinomas were composed of a diploid stem cell line. In 3 adenocarcinomas, polyploid cells were seen. The occurrence of heteroploidy in the minute cancers was similar to that found in advanced cancers, whereas polyploid cells appeared to occur less frequently in the minute cancers than in the advanced cancers."
1006,MicroRNAs as biomarkers in colorectal cancer.,"Schee K, Fodstad Ø, Flatmark K.",https://pubmed.ncbi.nlm.nih.gov/20829435/,"Colorectal cancer is a leading cause of cancer-related morbidity and mortality in the Western world. While improved diagnostic surveillance and treatment strategies involving surgery, chemo-, and radiotherapy have all contributed to earlier detection and improved survival, treatment decisions are still made almost exclusively based on the cancer's clinicopathological stage at diagnosis. Therefore, the search for new biomarkers to facilitate early diagnosis and individualized treatment is particularly warranted. MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression through posttranscriptional interactions with mRNA, thereby potentially leading to a vast range of downstream effects that depend on the target proteins affected. The discovery that miRNAs may act as either oncogenes or tumor suppressors has initiated extensive research in the cancer field, leading to the identification of numerous miRNAs implicated in carcinogenesis and tumor progression. MiRNAs are chemically stable and can thus be detected in a broad range of clinical samples, making these molecules particularly attractive as potential biomarkers in cancer. While the knowledge of miRNA involvement in colorectal cancer biology is less extensive than for other cancer types and several targets with potential biological and clinical relevance have been identified, a significant amount of research is still needed. In this review, we explore the literature regarding the relevance of miRNAs in colorectal cancer, focusing in particular on miRNAs as potential diagnostic, prognostic, and predictive biomarkers."
1007,GIDB: a knowledge database for the automated curation and multidimensional analysis of molecular signatures in gastrointestinal cancer.,"Wang Y, Wang Y, Wang S, Tong Y, Jin L, Zong H, Zheng R, Yang J, Zhang Z, Ouyang E, Zhou M, Zhang X.",https://pubmed.ncbi.nlm.nih.gov/31089686/,"Gastrointestinal (GI) cancer is common, characterized by high mortality, and includes oesophagus, gastric, liver, bile duct, pancreas, rectal and colon cancers. The insufficient specificity and sensitivity of biomarkers is still a key clinical hindrance for GI cancer diagnosis and successful treatment. The emergence of `precision medicine', `basket trial' and `field cancerization' concepts calls for an urgent need and importance for the understanding of how organ system cancers occur at the molecular levels. Knowledge from both the literature and data available in public databases is informative in elucidating the molecular alterations underlying GI cancer. Currently, most available cancer databases have not offered a comprehensive discovery of gene-disease associations, molecular alterations and clinical information by integrated text mining and data mining in GI cancer. We develop GIDB, a panoptic knowledge database that attempts to automate the curation of molecular signatures using natural language processing approaches and multidimensional analyses. GIDB covers information on 8730 genes with both literature and data supporting evidence, 248 miRNAs, 58 lncRNAs, 320 copy number variations, 49 fusion genes and 2381 semantic networks. It presents a comprehensive database, not only in parallelizing supporting evidence and data integration for signatures associated with GI cancer but also in providing the timeline feature of major molecular discoveries. It highlights the most comprehensive overview, research hotspots and the development of historical knowledge of genes in GI cancer. Furthermore, GIDB characterizes genomic abnormalities in multilevel analysis, including simple somatic mutations, gene expression, DNA methylation and prognosis. GIDB offers a user-friendly interface and two customizable online tools (Heatmap and Network) for  More importantly, GIDB is an ongoing research project that will continue to be updated and improve the automated "
1008,Thyroid Autoimmunity and Thyroid Cancer - The Pathogenic Connection: A 2018 Update.,Nagayama Y.,https://pubmed.ncbi.nlm.nih.gov/30081426/,"The association between thyroid cancer and thyroid autoimmunity has long been suggested, but remains to be elucidated for several decades. Here the data on this issue are updated by summarizing relevant papers published between 2012 and early 2018. Although numerous papers demonstrated the significant increase in the prevalence of thyroid autoimmunity (positive intrathyroidal lymphocyte infiltration and/or anti-thyroglobulin/thyroid peroxidase antibodies) in patients with thyroid cancers as compared to those with benign nodules, and also the significant increase in the prevalence of papillary thyroid cancer (PTC) in patients with thyroid autoimmunity as compared to those without, there are some crucial biases that should be taken into account for their interpretation. However, a difference in the incidence of thyroid autoimmunity in patients with PTCs and those with other types of thyroid cancers appears to support the significant association of two conditions. Thyroid autoimmunity is, at least partly, likely to be elicited against antigens shared by normal and cancerous thyroid tissues, thereby inducing autoimmunity. At the same time, elevated TSH levels (even within the normal reference ranges), which often accompany Hashimoto's patients are a risk factor for thyroid cancer. However, it is still unclear whether or not the co-existence of thyroid autoimmunity impacts on cancer characteristics and prognosis. This issue needs to be further investigated with large-scale prospective studies."
1009,Moonshot to Cancer Cure: Recruiting Policy to Break Down Silos.,"Simon M, Cordova E, McKoy JM.",https://pubmed.ncbi.nlm.nih.gov/30552661/,"Funded by the 21st Century Cures Act, The Beau Biden Cancer Moonshot Initiative is broad, deep, integrative, and intended to expediently address cancer's most vexing problems. Launched in 2015, it is an effort to accelerate the pace of cancer research with a focus on breaking down silos through cross-pollination of research, recruitment of multidisciplinary clinical and basic science research teams, sharing of complex scientific databases, and the creation of public-private research partnerships. This audacious approach to cancer treatment is intended to alleviate the current burden of cancer within countries and across borders. At its core is the rapid development of safe drug therapies across different disciplines through the employment of genomics, targeted proteomics with predictive analytics, and other emerging drug therapies. It will use expansive patient registries and increase early access to clinical trials. The initiative is cocooned in forward-thinking drug policies that consider the specific needs of all oncology stakeholder groups both nationally and internationally."
1010,Music's relevance for adolescents and young adults with cancer: a constructivist research approach.,"O'Callaghan C, Barry P, Thompson K.",https://pubmed.ncbi.nlm.nih.gov/21311914/,"Purpose:
        
      
      Music is one of the most widely used activities amongst young people, significant in personal and group identity, motivation, physical release, and emotional support. Adolescents and young adults with cancer (AYA) require specialized care because of intensified challenges related to developmental vulnerability, treatment toxicity effects, and slower improvements in survival rates compared to other age groups. To advance effective supportive care for AYA, understanding their thoughts about music is necessary. This study examines AYAs' perspectives about music's role in their lives.
    


           Twelve people, 15 to 25 years old, known to onTrac@PeterMac Victorian Adolescent & Young Adult Cancer Service, participated. Respondents completed a brief music demographic questionnaire and participated in a semi-structured interview. Qualitative inter-rater reliability was integrated.
    


           Themes encompassed: music  Music provided supportive messages, enabled personal and shared understandings about cancer's effects, and elicited helpful physical, emotional, and imagery states. Music therapy could also promote normalized and supportive connections with others. A musician, however, struggled to get music ""back"" post-treatment. Supportive music-based strategies were recommended for other AYA and their health care providers.
    


          Conclusions:
        
      
      Music can signify and creatively enable AYAs' hope, endurance, identity development, and adjustment through cancer treatment and post-treatment phases. Health professionals are encouraged to support AYAs' music-based self-care and ""normalized"" activities."
1011,[OEstradiol and progesterone steroid hormone receptors in cancer of the endometrium. The significance of the progesterone receptor (author's transl)].,"Martin PM, Rolland PH, Gammerre M, Serment H.",https://pubmed.ncbi.nlm.nih.gov/553927/,It would seem that the satisfactory way for the clinician to orientate the treatment by hormones in cancers of the endometrium lies in the presence at the same time of oestrogen and progesterone receptors and in particular of the latter. This applies when treating cancers of the endometrium with hormones in a way that is directed by chemical determination of hormone susceptibility.
1012,The adolescent's experience when a parent has advanced cancer: A qualitative inquiry.,"Phillips F, Lewis FM.",https://pubmed.ncbi.nlm.nih.gov/25855631/," Currently, there is insufficient information describing the sources and nature of this distress during advanced parental cancer, especially concerning families with adolescent children.
    


          Aim:
        
      
      To address the significant gap in the literature by providing the adolescent's perspective on the impact of their parent's advanced cancer on their lives.
    


          Design:
        
      
      This qualitative study involved single-occasion, semi-structured elicitation interviews with adolescents whose parents were diagnosed with advanced stage cancer.
    


          Setting/participants:
        
      
      The study sample consisted of seven adolescents from six families, five females and two males ranging in age from 11 to 15 years (mean = 13.6 years, standard deviation = 1.4 years). The ill parents consisted of four females and two males diagnosed with Stage IV cancer.
    


          
    


          Conclusion:
        
      
      Study findings shed light on how adolescents self-manage their parent's advanced cancer and work to delimit the illness even as they are aware of its constant presence. Future research and intervention studies are needed to support and add to the adolescents' self-management strategies to weave a normal life for themselves while in the throes of the cancer's uncertainty and challenges with family communication."
1013,Integrative pan-cancer analysis of cuproplasia-associated genes for the genomic and clinical characterization of 33 tumors.,"Li X, Ma W, Liu H, Wang D, Su L, Yang X.",https://pubmed.ncbi.nlm.nih.gov/37027423/," Cuproplasia is defined as copper-dependent cell growth and proliferation, including its primary and secondary roles in tumor formation and proliferation through signaling pathways. In this study, we analyzed the differences in the expression of cuproplasia-associated genes (CAGs) in pan-cancerous tissues and investigated their role in immune-regulation and tumor prognostication.
    


           Pan-cancer analysis was conducted to analyze the CAG expression, single-nucleotide variants, copy number variants, methylation signatures, and genomic signatures of micro RNA (miRNA)-messenger RNA (mRNA) interactions. The Genomics of Drug Sensitivity in Cancer and the Cancer Therapeutics Response Portal databases were used to evaluate drug sensitivity and resistance against CAGs. Using single-sample Gene Set Enrichment Analysis (ssGSEA) and Immune Cell Abundance Identifier database, immune cell infiltration was analyzed with the ssGSEA score as the standard.
    


           The frequency of single-nucleotide variations in CAGs ranged from 1% to 54% among different cancers. Furthermore, the correlation between CAG expression in the tumor microenvironment and immune cell infiltration varied among different cancers. ATP7A and ATP7B were negatively correlated with macrophages in 16 tumors including breast invasive carcinoma and esophageal carcinoma, while the converse was true for MT1A and MT2A . In addition, we established cuproplasia scores and demonstrated their strong correlation with patient prognosis, immunotherapy responsiveness, and disease progression ( P <0.05). Finally, we identified potential candidate drugs by matching gene targets with existing drugs.
    


          Conclusions:
        
      
      This study reports the genomic characterization and clinical features of CAGs in pan-cancers. It helps clarify the relationship between CAGs and tumorigenesis, and may be helpful in the development of biomarkers and new therapeutic agents."
1014,Decreased expression of DICER1 in gastric cancer.,"Zheng ZH, Sun XJ, Fu WN, Guan Y, Gao F, Wang Y, Sun KL.",https://pubmed.ncbi.nlm.nih.gov/18167183/," All the tumor related genes may be the target of epigenetical or genetic regulation. We selected some epigenetically regulated genes for cDNA array analysis and observed variability in the expression of the DICER1 gene in distinct stages of gastric cancer. The aim of this study was to assess the correlation between the expression of DICER1, an epigenetically regulated gene, and gastric cancer.
    


           DICER1 mRNA expression and DICER1 protein expression were further analyzed by Real-time PCR and Western blot in 32 cases of progressive gastric cancer. DICER1 protein expression was also detected in 33 early and 30 progressive gastric cancers by the immunohistochemistry (IHC) 
    


           Real-time PCR 05). The IHC assay also showed that the expression of DICER1 was significantly decreased in progressive gastric cancer. Among the 63 cases of gastric cancers, 13/33 early (39.4%) and 19/30 (63.3%) progressive cancers showed negative expression of DICER1 (50.8%). The difference in expression of DICER1 between early and progressive gastric cancers was significant (P < 0.01). The 05).
    


          Conclusions:
        
      
      DICER1 expression is decreased during the progression of gastric cancer, especially in progressive gastric cancers, which indicating DICER1 may play an important role in the development of cancer and the epigenetical regulation involved."
1015,A very rare presentation of lung cancer: Metastases to the distal phalanx of index-case report.,"Afrăsânie VA, Adavidoaiei AM, Zamisnicu IH, Funingănă IG, Marinca MV, Gafton B, Clement DE, Păduraru MI, Demşa I, Miron L, Alexa-Stratulat T.",https://pubmed.ncbi.nlm.nih.gov/31804306/,"Rationale:
        
      
      Acrometastases of the hand are an unusual sign of lung cancer onset and may often be mistaken for other benign disorders, thus delaying diagnosis and treatment.
    


          Patient concerns:
        
      
      A 58-year-old man presented at the Rheumatology Clinic with a lump in the distal phalanx of the right index finger associated with intense pain, swelling, rib pain, and hemoptysis.
    


          Diagnoses:
        
      
      Given the clinical manifestations, an x-ray of the right hand was performed, and it revealed an osteolytic lesion in the distal phalanx of the right index finger. The subsequent CT of the thorax and abdomen showed a lung tumor, osteolytic lesions in the ribs, sternum, and the thoracic spine.
    


          Interventions:
        
      
      Amputation of the phalanx was decided on account of intense pain refractory to NSAIDs and opioids. Pathology assessment established the diagnosis of bone metastases secondary to lung adenocarcinoma. The patient underwent 6 cycles of first-line palliative chemotherapy with cisplatin and gemcitabine with partial response according to the RECIST 1.1. criteria. EGFR and ALK testing were not available at the time. A year later, the patient presented with progressive disease, which lead to 6 more cycles of chemotherapy with docetaxel. The disease progressed during chemotherapy and the patient was switched to erlotinib.
    


          Outcomes:
        
      
      After 7 months of anti-EGFR treatment, the patient passed away due to disease progression, thus having an overall survival of 25 months.
    


          Lessons:
        
      
      On rare occasions, acrometastases of the hand may be the first manifestation of a lung cancer and, as such, they must be taken into consideration in the differential diagnosis of rheumatologic disorders. They are a poor prognosis marker, but some cases like this one can have a better survival than reported in the literature, most likely due to that particular cancer's biology."
1016,Inflammation in the context of oral cancer.,"Feller L, Altini M, Lemmer J.",https://pubmed.ncbi.nlm.nih.gov/23910564/,"The link between cancer and inflammation is specific transcription factors that once activated have the capacity to enhance expression of genes that are common to both the regulation and the production of mediators of inflammation, and also to the regulation of the survival and proliferation of cancer cells. Cellular pathways activated by chronic inflammation brought about by chronic infections, by immune-mediated diseases, or by dysregulated wound healing at sites of repetitive tissue injury, constitute risk factors for initial cell transformation and for cancer progression. In established cancers, the cancer cells induce development of an exaggerated inflammatory state in the stroma, which in turn promotes cancer growth, invasion and metastasis. Inflammatory cells of myeloid origin in the tumour-associated stroma, mediate suppression of immune responses against cancer cells, which suppression favours tumour growth. Oral submucous fibrosis, and to a lesser extent oral lichen planus are precancerous conditions in which immuno-inflammatory processes are implicated in their pathogenesis, and in their cancerous transformation, if it occurs. Although there is some evidence for an association between oral squamous cell carcinoma on the one hand and dento-gingival bacterial plaques and chronic periodontitis on the other hand, the role of inflammation as the sole cause of cancerous transformation in such cases is not proven. The purpose of this article is to elaborate on some of the more important relationships between oral cancer and inflammation, and to comment on the role of inflammation in the pathogenesis of oral squamous cell carcinoma."
1017,Effect of tumor size on prognosis in colorectal cancer.,"Yirgin H, Sibiç O, Tatlidil YE, Bozdağ E, Bozkurt MA, Devecioğlu EG, Aziret M, Ercan M.",https://pubmed.ncbi.nlm.nih.gov/37464790/,"Aim:
        
      
      This study aimed to reveal the effect of tumor size on overall survival and disease-free survival.
    


          Material and  The patients were divided into two groups based on their tumor size; those with a tumor size <5 cm were grouped as group 1 and those with a tumor size ≥ 5 cm were grouped as group 2.
    


           The median follow-up period of the patients was 36.0 (1.4-107.4) months, mean tumor size was 5.1±2.3 cm, and number of patients with a tumor size of ≥5 cm was 117 (52.7%). There were statistically significant differences between the groups in terms of overall survival (Log-Rank = 12.559, p<0.001).
    


          Discussion:
        
      
      According to the American Joint Committee on Cancer's Cancer Staging Manual (8th edition), the CRC staging system considers the tumor's depth of invasion of the intestinal wall but not the tumor's size. Moreover, it considers the size of the tumors developing in the parenchymal organs (breasts and lungs) but not tumors developing in luminal organs (stomach, colon, etc.).
    


          Conclusions:
        
      
      Tumor size ≥5 cm was found to be a risk factor for poor prognosis. To a certain extent, we believe that this study will aid in elucidating the link between tumor size in and prognosis of patients with CRC.
    


          Key words:
        
      
      Colorectal cancer, Prognosis, Tumor size."
1018,A systems approach to clinical oncology uses deep phenotyping to deliver personalized care.,"Yurkovich JT, Tian Q, Price ND, Hood L.",https://pubmed.ncbi.nlm.nih.gov/31619755/,"Cancer encompasses a complex, heterogeneous and dynamic group of diseases that arise from perturbations to multiple biological networks within the body. A systems biology-based approach would help to decipher this complexity, to deeply characterize the pathophysiology of the disease and to stratify cancers into appropriate molecular subtypes to facilitate the development of personalized therapies. Technological advances made over the past decade have enabled multiscale, longitudinal measurements ('snapshots') of human biology, from single-cell analyses to whole-body monitoring. In this Perspective, we discuss some of these technologies and how they have (and will) contributed to our understanding of cancer biology as well as to the development of early diagnostics and personalized therapies. We argue that the integration of molecular profiling of cancerous tissues with deep, longitudinal profiling of the physiological state of an individual ('deep phenotyping') is key to understanding the prevention, initiation, progression and response to treatment of cancers. Systems biology-based approaches can provide an unprecedented trove of data for early detection of disease transitions, prediction of therapeutic responses and clinical outcomes, and for the design of personalized treatments."
1019,Neutrons applications in cancer treatment and in specific diagnostics.,"Shahri KK, Motavalli LR, Hakimabad HM.",https://pubmed.ncbi.nlm.nih.gov/21761010/,"The major effect of ionizing radiation in cells is to destroy the ability of cells to divide by damaging their DNA strands. Extensive researches are leading to an understanding that the characteristics of high LET radiations such as fast neutrons and low LET radiations like protons, photons and electrons are different; because of different types of their interactions with tissue. Low LET radiations mostly damage tissue by producing free radicals. Oxygen has an effect of enhancing free radical formation in cells. Indeed hypoxic cells, which exist in malignant tumors, are radio resistant under irradiation with low LET radiations. In contrast, neutron interacts with tissue primarily via nuclear interactions, so its biological effectiveness is not affected on the presence of oxygen. The required dose to kill the same number of cancerous cells by neutrons is about one third in comparison with photons. Clinical reports show that a full course of treatment with neutrons consists of 12 treatment sessions, compared to 30-40 treatments with photons or electrons. In conclusion, in this review we describe which cancers or tumors could be better treated with neutrons. We also refer to whether neutrons could be used for diagnosis."
1020,Selective expression of S100A11 in lung cancer and its role in regulating proliferation of adenocarcinomas cells.,"Hao J, Wang K, Yue Y, Tian T, Xu A, Hao J, Xiao X, He D.",https://pubmed.ncbi.nlm.nih.gov/21861103/,"S100A11, one secreted protein, is overexpressed in certain cancers. We investigated S100A11 expression in various subtypes of lung cancer and explored its role in cell proliferation. S100A11 mRNA level was examined in 45 pairs of frozen lung cancer tissues by reverse transcriptase PCR (RT-PCR). The specific expression and subcellular distribution of S100A11 were examined in 78 paraffin-embedded lung cancers, 2 benign lung diseases as well as 22 healthy lung tissues by immunohistochemistry. S100A11 protein level was further analyzed in the sera of 86 lung cancer patients and 50 healthy individuals by enzyme-linked immunosorbent assay. We found that both mRNA and protein levels of S100A11 were overexpressed in adenocarcinomas (ADC) and squamous cell carcinomas (SCC) compared with paired non-cancerous lung tissues, while S100A11 was detected downregulated in small cell lung cancers (SCLC). Further immunohistochemistry staining was positive for S100A11 only in non-small cell lung cancer (NSCLC) (ADC, SCC, large cell carcinomas, et al.), but not SCLC. Conclusively, we found S100A11 protein level increased in the sera of NSCLC patients. Furthermore, when S100A11 expression was knocked down in lung adenocarcinoma cells A549 and LTEP-a-2, the cell proliferation was significantly inhibited in vitro and in vivo."
1021,Histological verification of the usefulness of magnifying endoscopy with narrow-band imaging for horizontal margin diagnosis of differentiated-type early gastric cancers.,"Makazu M, Hirasawa K, Sato C, Ikeda R, Fukuchi T, Ishii Y, Kobayashi R, Kaneko H, Taguri M, Tateishi Y, Inayama Y, Maeda S.",https://pubmed.ncbi.nlm.nih.gov/28639135/," We aimed to characterize the pathological features of lesions in which the HM was identified using ME-NBI.
    


           The number and width of the intervening parts (IP) and the number, width, and depth of the subepithelial capillaries (SEC) in cancerous and noncancerous areas were measured.
    


          0%), more than 90% of the HM was not recognized with conventional endoscopy, but 11 of these lesions were detectable with ME-NBI (NBI group). The HMs of the other 626 lesions were mostly recognized using conventional endoscopy (WLI/CE group). In the NBI group, the IP width, standard deviation (SD), and number of IPs did not significantly differ between the cancerous and noncancerous areas. However, the SEC number was significantly larger and the depth was shallower in cancerous areas. In the WLI/CE group, the IP width and SD were significantly larger, but the IP number was significantly smaller in cancerous areas. The SEC depth was significantly shallower in cancerous areas.
    


          Conclusions:
        
      
      Differences of IP width, SD, and IP number may be factors for identifying HMs with conventional endoscopy. Because NBI can better visualize vessel structures, the increased SEC number and shallow SECs may clarify the HM."
1022,The Association between Survivorship Care Plans and Patient-Reported Satisfaction and Confidence with Follow-Up Cancer Care Provided by Primary Care Providers.,"Chu AK, Mutsaers B, Lebel S.",https://pubmed.ncbi.nlm.nih.gov/36290854/,"Survivorship care plans aim to facilitate a smooth transition from tertiary to primary care settings after primary cancer treatment is completed. This study sought to identify the sociodemographic factors associated with receiving a survivorship care plan and examine the relationship between receiving a plan and confidence in follow-up care delivered by primary care providers. A cross-sectional analysis of the Canadian Partnership Against Cancer's Experiences of Cancer Patients in Transition Study was conducted (n = 9970). Separate adjusted multinomial logistic regression models assessed the relationship between survivorship care plans and follow-up care outcomes. Proportion of survivors more likely to receive a survivorship care plan varied by numerous sociodemographic and medical factors, such as cancer type (colorectal and prostate), gender (male), and education (high school or less). In unadjusted and adjusted models, individuals who received a Survivorship Care Plan had significantly higher odds of: having felt their primary care providers were involved; agreeing that their primary care providers understood their needs, knew where to find supports and services, and were able to refer them directly to services; and were confident that their primary care provider could meet their follow-up care needs."
1023,"Use of Traditional Indigenous Medicine and Complementary Medicine Among Indigenous Cancer Patients in Queensland, Australia.","Adams J, Valery PC, Sibbritt D, Bernardes CM, Broom A, Garvey G.",https://pubmed.ncbi.nlm.nih.gov/25953415/," Meanwhile, a range of approaches to health and illness-including both complementary and alternative medicine (CAM) and traditional Indigenous medicine (TM)-are used by cancer patients. Little work has focused on Indigenous cancer patients with regard to CAM/TM use. This article reports findings from the first examination of the prevalence and profile of TM/CAM use and users among Indigenous Australians with cancer.
    


           All received treatment and were recruited from 1 of 4 large hospitals located in Queensland, Australia.
    


          7%) of Indigenous cancer patients use at least one TM/CAM for support with their care, including traditional Indigenous therapy use (2.8%), visiting a traditional Indigenous practitioner (2.8%), CAM use (10.7%), visiting a CAM practitioner (2.4%), and attending relaxation/meditation classes (4.0%). Having a higher level of educational attainment was positively associated with CAM practitioner consultations (P = .015). Women with breast cancer were more likely to attend relaxation/meditation classes (P = .019). Men with genital organ cancer were more likely to use traditional Indigenous therapies (P = .017) and/or CAM (P = .002).
    


          Conclusion:
        
      
      A substantial percentage of Indigenous Australians reported using TM/CAM for their cancer care, and there is a need to expand examination of this area of health care using large-scale studies focusing on in-depth specific cancer(s)."
1024,BRAF genetic heterogeneity in papillary thyroid carcinoma and its metastasis.,"Walts AE, Pao A, Sacks W, Bose S.",https://pubmed.ncbi.nlm.nih.gov/24746198/,"Intratumoral heterogeneity is widely recognized as an important determinant of a cancer's initial response and its subsequent resistance to targeted therapy. BRAF V600E mutation, common in papillary thyroid carcinoma (PTC), is helpful in fine needle aspiration diagnosis of thyroid nodules and is being evaluated for targeted therapies. This study was designed to assess the presence of BRAF mutation heterogeneity within primary PTCs and between paired primary and metastatic lesions. Genetic heterogeneity was evaluated in 47 PTCs (38 differentiated papillary thyroid carcinomas and 9 poorly differentiated PTCs with anaplastic areas). The differentiated papillary thyroid carcinomas included 16 cases with regional lymph node metastases at thyroidectomy and 9 cases with recurrent metastases to regional lymph nodes more than 5 years post thyroidectomy. Genetic heterogeneity of BRAF was studied by comparing the mutation status in different samples of tumor as follows: (a) 2 separate areas (each >1.5 cm in diameter) within the primary tumor, (b) a more than 1.5 cm area of primary carcinoma and a second 5 mm area simulating a fine needle aspiration sample from a different portion of the primary tumor, (c) primary carcinoma and its lymph node metastasis at thyroidectomy, (d) primary carcinoma and the recurrent metastasis, and (e) differentiated and anaplastic areas in the primary carcinoma. BRAF mutation status was concordant in 95.2% of the 62 paired samples. Discordant BRAF status was detected in only 4.8% of the pairs studied and most frequently involved cases with recurrent metastasis thus suggesting a need for additional testing of these lesions before instituting therapy."
1025,"Oral fluorescence imaging using 405-nm excitation, aiding the discrimination of cancers and precancers by identifying changes in collagen and elastic breakdown and neovascularization in the underlying stroma.","Lane P, Lam S, Follen M, MacAulay C.",https://pubmed.ncbi.nlm.nih.gov/22340643/,"
    


          
    


          
    


           Higher wavelengths may be necessary to differentiate potential confounding lesions, such as abrasions, burns, viral infections, inflammation, and gingivitis.
    


          Conclusions:
        
      
      Imaging at 405 nm could help doctors detect precancerous and cancerous oral lesions. Such imaging could be used by dentists, family practitioners, otorhinolaryngologists, general surgeons, obstetrician gynecologists, and internists, and could greatly increase the number of patients who have lesions detected in the precancerous phase."
1026,[Histological localization of mucin core polypeptide MUC-2 in application to the differential diagnosis of adenocarcinoma].,Yuan M.,https://pubmed.ncbi.nlm.nih.gov/1477935/,"Human mucin core cDNA-MUC-2 has been cloned and sequenced. Its major portion consists of amino acids tandem in arrangement with repetition in its sequence, locating at the 11th chromosome. Antibody against polypeptide MUC-2 was used for immunohistochemical SABC staining in order to investigate the expression of MUC-2 in human normal and cancerous tissues. The  If used in combining with monoclonal antibody against MUC-1, which is known to be expressed in normal and cancer tissues of pancreas, lung and breast, it is considered to be valuable for the differential diagnosis in detecting the origin of metastatic adenocarcinoma."
1027,Microenvironment-induced CREPT expression by cancer-derived small extracellular vesicles primes field cancerization.,"Lin Y, Jiang H, Li J, Ren F, Wang Y, Qiu Y, Li J, Li M, Wang Y, Yang L, Song Y, Jia H, Zhai W, Kuang Y, Yu H, Zhu W, Liu S, Morii E, Ensinger C, David C, Zheng H, Ji J, Wang H, Chang Z.",https://pubmed.ncbi.nlm.nih.gov/38169511/,"Rationale: Cancer local recurrence increases the mortality of patients, and might be caused by field cancerization, a pre-malignant alteration of normal epithelial cells. It has been suggested that cancer-derived small extracellular vesicles (CDEs) may contribute to field cancerization, but the underlying mechanisms remain poorly understood. In this study, we aim to identify the key regulatory factors within recipient cells under the instigation of CDEs.  TMT-based quantitative mass spectrometry was employed to investigate the proteomic differences between normal cells and tumor cells. Loss-of-function approaches by CRISPR-Cas9 system were used to assess the role of CREPT in CDEs-induced field cancerization. RNA-seq was performed to explore the genes regulated by CREPT during field cancerization.  Intriguingly, CDEs failed to induce field cancerization when CREPT was deleted, highlighting the importance of CREPT. Transcriptomic analyses revealed that CDEs elicited inflammatory responses, primarily through activation of the TNF signaling pathway. CREPT, in turn, regulates the transduction of downstream signals of TNF by modulating the expression of TNFR2 and PI3K, thereby promoting inflammation-to-cancer transition. Conclusion: CREPT not only serves as a biomarker for field cancerization, but also emerges as a target for preventing the cancer local recurrence."
1028,Cancer incidence and mortality among young adults aged 20-39 years worldwide in 2012: a population-based study.,"Fidler MM, Gupta S, Soerjomataram I, Ferlay J, Steliarova-Foucher E, Bray F.",https://pubmed.ncbi.nlm.nih.gov/29111259/," Our aim was to describe the scale and profile of cancer incidence and mortality worldwide among 20-39 year-olds, highlighting major patterns by age, sex, development level, and geographical region.
    


           We defined young adult cancers as those occurring between the ages of 20 and 39 years because these individuals will have passed puberty and adolescence, but not yet experienced the effects of hormonal decline, immune response deterioration, or organ dysfunction associated with chronic health conditions. Global, regional, and country-specific (n=184) data estimates of the number of new cancer cases and cancer-associated deaths that occurred in 2012 among young adults were extracted in four 5-year bands from the International Agency for Research on Cancer's GLOBOCAN 2012 for all cancers combined and for 27 major types as defined by the International Classification of Disease, tenth revision. We report the number of new cancer cases and cancer-associated deaths overall and by sex alongside corresponding age-standardised rates (ASR) per 100 000 people per year. We also present 
    


          Findings:
        
      
      975 396 new cancer cases and 358 392 cancer-associated deaths occurred among young adults worldwide in 2012, which equated to an ASR of 43·3 new cancer cases per 100 000 people per year and 15·9 cancer-associated deaths per 100 000 people per year. The burden was disproportionally greater among women and the most common cancer types overall in terms of new cases were female breast cancer, cervical cancer, thyroid cancer, leukaemia, and colorectal cancer; in terms of deaths, female breast cancer, liver cancer, leukaemia, and cervical cancer were the main contributors. When assessed by development level and geographical region, the cancer profile varied substantially; generally, the burden of infection-associated cancers was greater in regions under transition. Cancer incidence was elevated in very high-HDI regions compared with low-HDI regions (ASR 64·5 vs 46·2 cancer cases per 100 000 people per year); however, the mortality burden was 3 times higher in low-HDI regions (ASR 25·4 vs 9·2 cancer-associated deaths per 100 000 people per year), reflecting differences in cancer profiles and inferior outcomes.
    


          Interpretation:
        
      
      The global cancer burden among 20-39 year-olds differs from that seen in younger or older ages and varies substantially by age, sex, development level, and geographical region. Although the cancer burden is lower in this age group than that observed in older ages, the societal and economic effects remain great given the major effects of premature morbidity and mortality. Targeted surveillance, prevention, and treatment are needed to reduce the cancer burden in this underserved age group.
    


          Funding:
        
      
      International Agency for Research on Cancer (IARC) and European Commission's FP-7 Marie Curie Actions-People-COFUND."
1029,Irreversible Electroporation for Locally Advanced Pancreatic Cancer: Where Do We Stand in 2017?,"Tasu JP, Vesselle G, Herpe G, Richer JP, Boucecbi S, Vélasco S, Debeane B, Carretier M, Tougeron D.",https://pubmed.ncbi.nlm.nih.gov/28187107/,"Pancreatic adenocarcinoma has a very poor prognosis. Complete surgical resection remains the only current curative treatment. Locally advanced pancreatic cancers are considered as unresectable because of involvement of celiac and/or mesenteric vessels. Irreversible electroporation has recently been introduced to induce permanent cell death by apoptosis. Irreversible electroporation is a nonthermal cell-destruction technique that was claimed to allow destruction of cancerous cells with less damage to surrounding supporting connective tissues with collagenic structure (such as nearby blood vessels, biliary ducts, and nerves) than other types of treatment. Applications on pancreatic adenocarcinoma seem promising, and this article is an up-to-date review of the first "
1030,The unconventional role of Akt1 in the advanced cancers and in diabetes-promoted carcinogenesis.,"Alwhaibi A, Verma A, Adil MS, Somanath PR.",https://pubmed.ncbi.nlm.nih.gov/31078742/,"Decades of research have elucidated the critical role of Akt isoforms in cancer as pro-tumorigenic and metastatic regulators through their specific effects on the cancer cells, tumor endothelial cells and the stromal cells. The pro-cancerous role of Akt isoforms through enhanced cell proliferation and suppression of apoptosis in cancer cells and the cells in the tumor microenvironment is considered a dogma. Intriguingly, studies also indicate that the Akt pathway is essential to protect the endothelial-barrier and prevent aberrant vascular permeability, which is also integral to tumor perfusion and metastasis. To complicate this further, a flurry of recent reports strongly indicates the metastasis suppressive role of Akt, Akt1 in particular in various cancer types. These reports emanated from different laboratories have elegantly demonstrated the paradoxical effect of Akt1 on cancer cell epithelial-to-mesenchymal transition, invasion, tumor endothelial-barrier disruption, and cancer metastasis. Here, we emphasize on the specific role of Akt1 in mediating tumor cell-vasculature reciprocity during the advanced stages of cancers and discuss how Akt1 differentially regulates cancer metastasis through mechanisms distinct from its pro-tumorigenic effects. Since Akt is integral for insulin signaling, endothelial function, and metabolic regulation, we also attempt to shed some light on the specific effects of diabetes in modulating Akt pathway in the promotion of tumor growth and metastasis."
1031,The role of regional anesthesia in the propagation of cancer: A comprehensive review.,"Sen S, Koyyalamudi V, Smith DD, Weis RA, Molloy M, Spence AL, Kaye AJ, Labrie-Brown CC, Morgan Hall O, Cornett EM, Kaye AD.",https://pubmed.ncbi.nlm.nih.gov/31791567/,"New cancer incidences worldwide will eclipse 18 million in 2019, with nearly 10 million cancer-related deaths. It is estimated that in the United States, almost 40% of individuals will be diagnosed with cancer in their lifetime. Surgical resection of primary tumors remains a cornerstone of cancer treatment; however, the surgical process can trigger an immune-suppressing sympathetic response, which promotes tumor growth of any residual cancerous cells post surgery. Regional and local anesthesia have become staples of anesthesia and analgesia during and after surgery. Recently, much evidence in the form of retrospective and prospective studies has come to light regarding the protective, antitumor properties of anesthetic and analgesic agents across a wide variety of cancers and patient demographics. It is believed that by blocking afferent pain signals, the body does not mount the sympathetic response that contributes to the perpetuation of disease after surgical treatment. This review, therefore, investigates these studies as they pertain to the treatment and outcomes of cancers treated surgically to elucidate the role of regional anesthesia in the propagation of cancer."
1032,Carcinoma following gastric surgery: a national survey.,"Forestieri P, Formisano C, Meucci E, Falasconi C, Mazzeo F.",https://pubmed.ncbi.nlm.nih.gov/2753688/,"Definitive  Data concern 8427 cases of surgically treated gastric cancer. 558 were affected by carcinoma following gastric surgery and 471 of them were operated on, representing 5.59% of all gastric cancers (8427) submitted to surgery. The statistical analysis of "
1033,Preliminary studies of serum glycoconjugates in patients with cancer using the enzyme-linked lectin assay.,"Zhang SL, Liang YR, Li JL, Dai YR, Huang D.",https://pubmed.ncbi.nlm.nih.gov/2268850/,"After primary analyses on the serum glycoconjugates of lung cancer and normal individual using the enzyme-linked lectin assay (ELLA) with 12 kinds of lectins, PHA and LCA were selected for further study in the sera of 8 kinds of cancers, 4 kinds of non-malignant diseases and a kind of postoperative cancer. It was found that the test values of 7 kinds of cancers with PHA or LCA were significantly higher than those of the normal (P less than 0.01); the values of 4 kinds of non-malignant diseases with PHA were not higher (P greater than 0.05); the values of the postoperative cancer with PHA were obviously lower than those of the preoperative (P less than 0.02). The  The significance of the findings was discussed."
1034,"Carcinoma of the larynx. Growth, p-classification and grading of squamous cell carcinoma of the vocal cords.",Glanz HK.,https://pubmed.ncbi.nlm.nih.gov/6369947/,"For this investigation on growth, p-classification and grading of squamous cell carcinomas of the vocal cord serial sectioning was applied to 108 specimens (58 partially and 50 totally extirpated larynges) of vocal cord cancers that had not previously been treated otherwise. The evaluation of these serial sections showed that frequently recurring patterns of the spread of carcinomas can be recognized which may be subdivided as follows: (1) Carcinoma in situ and early carcinomas of the vocal cord (microinvasive or minimal invasive carcinomas) originate from the strip of squamous cell epithelium covering the vocal cord mostly on its subglottic part. There are circumscribed as well as diffuse types, the latter mostly spreading subglottically, too. (2) Similar to the early vocal cord carcinomas the larger ones mostly expand in the subglottic direction. These glotto-subglottic tumours also follow the metaplastic areas of squamous cell epithelium caudally; they often infiltrate deeply, affect the cricoid and the thyroid cartilage and leave finally the larynx dorsolaterally. They metastasize to the deep cervical and paratracheal lymph nodes. (3) Less frequently larger carcinomas develop in the upper half of the vocal cord epithelium at the floor of the ventricle and extend cranially. These 'ventricle carcinomas' do not spread widely on the surface, but at once infiltrate deeply lateralcaudally into the paraglottic space and - in extreme cases - grow intramurally circularly. They often penetrate the laryngeal framework and metastasize mainly to the deep cervical lymph nodes. (4) Transglottic tumours ('multiregional' vocal cord carcinomas) represent a kind of 'pool' for advanced vocal cord carcinomas having expanded in different directions (sub- and supraglottically). In extensive cancerized fields they can also arise multicentrically. They frequently penetrate the laryngeal framework and metastasize to the deep cervical and paratracheal lymph nodes. The investigation of the growth of vocal cord carcinomas proved different modes of invasion of the various anatomical structures of the larynx. The submucosa or the so-called compartments do not resist the tumour growth, muscles are destroyed with increasing infiltration; tumours quickly spread in the relatively loose tissue and use vessels and nerves as pathways. The ossified parts of the hyaline laryngeal framework are infiltrated comparatively easily whereas non-ossified parts, together with ciliated epithelium, and mucous glands represent a kind of barrier against tumour growth.(ABSTRACT TRUNCATED AT 400 WORDS)"
1035,Historical survey of carcinoma of the pancreas.,"Tsuchiya R, Fujisawa N.",https://pubmed.ncbi.nlm.nih.gov/10398904/,"The ancient Egyptians probably recognized cancerous lesions on the surface of the body. Hippocrates described cancers of the skin, larynx, breast, inguinal region, uterus, and vagina. For centuries, the treatments were excision, cauterization, ointment application, and fomentation. The development of anesthesia, antisepsis, and disinfection, and the discoveries of X-rays and radium in the nineteenth century, have greatly promoted advances in surgery in the twentieth century. At the beginning of this century, it became possible for surgeons to extirpate tumors from previously inaccessible body interiors, and today surgeons are able to remove affected organ systems and even entire regions of the body with safety because of advances in physiology, anesthesia, transfusion, and anti-infective agents. The surgical  Drastic extensive surgery has not led to better  A small carcinoma less than 1 cm in diameter may not always be an early carcinoma. Early cancer in duct cell carcinoma may be one localized in the mucous membrane of the pancreatic duct. There is now an expectation that early diagnosis will be possible by using magnetic resonance cholangiopancreatography and cytological diagnosis of the pancreatic juice."
1036,[Cell proliferation in a triple gastric cancer--a study using the isolated organ perfusion system].,"Tokita K, Tsuchihashi Y, Mitsufuji S, Isetani K, Hosokawa Y, Tani T, Maruyama K, Yorioka S, Suzuki G, Takanashi T, et al.",https://pubmed.ncbi.nlm.nih.gov/2355465/,"So as to study the cell proliferation in a case with triple gastric cancers, we labeled an operated whole stomach with bromodeoxyuridine (BrdU) by the isolated organ perfusion system using artificial blood. Anti-BrdU immunohistochemical staining of sections from every part of the stomach was performed, and 3 separated cancerous lesions were all diagnosed as well differentiated adenocarcinomas. The labeling index (L.I.) of the cancerous lesions were found to differ from part to part. However, the L.I. tended to be higher in the superficial mucosal areas and in the cell-dense areas of the submucosa. In the almost normal fundic glands, the labeled zone was localized in the neck of the glands. The more metaplastic gastritis was advanced, the more the labeled zone shifted irregularly toward the bottom of the glands. Whenever the interstinal metaplasia was completed, the labeled zone was localized in the bottom of the glands. This "
1037,"Radiotherapy for Patients With Resected Tumor Deposit-Positive Colorectal Cancer: A Surveillance, Epidemiology, and End Results-Based Population Study.","Chavali LB, Llanos AAM, Yun JP, Hill SM, Tan XL, Zhang L.",https://pubmed.ncbi.nlm.nih.gov/29048218/,"Context:
        
      
      - According to the American Joint Committee on Cancer's Cancer Staging Manual, 7th edition, TNM classification, tumor deposit (TD)-positive colorectal cancers (CRCs) are classified as N1c. The effects of radiotherapy and the effects of the updated American Joint Committee on Cancer 7th edition TNM N1c classification for patients with TD-positive CRC are unclear.
    


          
    


          Design:
        
      
      - Resected TD-positive CRCs diagnosed from 2010 to 2014 were identified in the Surveillance, Epidemiology, and End  Factors associated with overall survival (OS) and cancer-specific survival (CSS) were investigated using Kaplan-Meier and Cox proportional hazards models.
    


          9%) or received no radiotherapy (n = 2525; 93.1%). Univariate Cox proportional models showed improved CSS among all CRC patients who underwent adjuvant radiotherapy (CSS hazard ratio, 0.73; 95% CI, 0.57-0.95) and among rectal cancer patients when separated by location (hazard ratio, 0.57; 95% CI, 0.40-0.83), although these associations were attenuated in multivariable-adjusted models. There was improved OS among rectal cancer patients (hazard ratio, 0.77; 95% CI, 0.59-0.99). In subgroup analyses, radiotherapy was not associated with OS or CSS in either metastatic or nonmetastatic CRC patients. Instead, N1c category (versus N0) was associated with a worse OS (hazard ratio, 1.43; 95% CI, 1.31-1.57) but was not associated with CSS.
    


          Conclusions:
        
      
      - Radiotherapy did not independently improve OS among TD-positive CRC patients. In this study, classifying TD positivity as N1c was associated with worse OS than classifying TD positivity as N0. The findings seem to challenge the benefits of radiotherapy and the new N1c classification of TD for TD-positive CRC patients."
1038,RCAS1 as a tumour progression marker: an independent negative prognostic factor in gallbladder cancer.,"Oshikiri T, Hida Y, Miyamoto M, Hashida H, Katoh K, Suzuoki M, Nakakubo Y, Hiraoka K, Shinohara T, Itoh T, Kondo S, Katoh H.",https://pubmed.ncbi.nlm.nih.gov/11747335/,"Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) induces apoptosis in immune cells bearing the RCAS1 receptor. We sought to determine RCAS1 involvement in the origin and progression of gallbladder cancer, and also implications of RCAS1 for patient survival. RCAS1 expression was examined immunohistochemically in 110 surgically resected gallbladder specimens. The gallbladders represented 20 cases of cholecystitis with no associated pancreaticobiliary maljunction; 23 cases of cholecystitis with pancreaticobiliary maljunction; 14 cases of adenomyomatosis; 7 adenomas; and 46 cancers. High expression of RCAS1 (immunoreactivity in over 25% of cells) was observed in 32 of the 46 cancers (70%), but not in other diseases, including pre-cancerous conditions. RCAS1 immunoreactivity was associated with depth of tumour invasion (P = 0.0180), lymph node metastasis (P = 0.0033), lymphatic involvement (P = 0.0104), venous involvement (P = 0.0224), perineural involvement (P = 0.0351) and stage by the tumour, nodes and metastases (TNM) classification (P = 0.0026). Thus, RCAS1 expression may be a relatively late event in gallbladder carcinogenesis, possibly promoting tumour progression. Cox regression multivariate analysis demonstrated RCAS1 positivity to be an independent negative predictor for survival (P = 0.0337; risk ratio, 12.690; 95% confidence interval, 1.216-132.423). High expression of RCAS1 significantly correlated with tumour progression and predicted poor outcome in gallbladder cancer."
1039,MRNA expression of genes altered by 5-azacytidine treatment in cancer cell lines is associated with clinicopathological parameters of human cancers.,"Kanai Y, Ushijima S, Saito Y, Nakanishi Y, Sakamoto M, Hirohashi S.",https://pubmed.ncbi.nlm.nih.gov/11768609/,"
    


           Time-dependent induction of mRNA expression of Wip1, TROP2, B4-2 protein, BRCA-2 region transcription unit CG005, cofilin, ROCK, CD44. and interferon-inducible protein 6-16 was observed during 5-azacytidine treatment. We then evaluated the mRNA expression of these genes in 26 stomach and 32 colorectal cancers and 44 hepatocellular carcinomas (HCCs) and in the corresponding non-cancerous tissues.
    


           Reduced expression of Wip1 and BRCA-2 region transcription unit CG005 was significantly correlated with poorer differentiation of HCCs, and mRNA expression of these genes was significantly reduced in HCCs associated with portal vein involvement compared with HCCs without such involvement. Expression of TROP2 mRNA was significantly higher in chronically diseased liver from HCC patients compared with histologically normal liver, but was reduced in progressed HCCs. Reduced expression of B4-2 protein was observed in association with hepatitis B virus infection of HCC patients.
    


          Conclusions:
        
      
      These data suggest that DNA methylation may play a role in human multistage carcinogenesis through direct or indirect regulation of multiple tumor-related genes."
1040,Prostate field cancerization: deregulated expression of macrophage inhibitory cytokine 1 (MIC-1) and platelet derived growth factor A (PDGF-A) in tumor adjacent tissue.,"Jones AC, Antillon KS, Jenkins SM, Janos SN, Overton HN, Shoshan DS, Fischer EG, Trujillo KA, Bisoffi M.",https://pubmed.ncbi.nlm.nih.gov/25767870/,"Prostate field cancerization denotes molecular alterations in histologically normal tissues adjacent to tumors. Such alterations include deregulated protein expression, as we have previously shown for the key transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS). Here we add the two secreted factors macrophage inhibitory cytokine 1 (MIC-1) and platelet derived growth factor A (PDGF-A) to the growing list of protein markers of prostate field cancerization. Expression of MIC-1 and PDGF-A was measured quantitatively by immunofluorescence and comprehensively analyzed using two  A total of 208 digitized images were analyzed. MIC-1 and PDGF-A expression in tumor tissues were elevated 7.1x to 23.4x and 1.7x to 3.7x compared to disease-free tissues, respectively (p<0.0001 to p = 0.08 and p<0.01 to p = 0.23, respectively). In support of field cancerization, MIC-1 and PDGF-A expression in adjacent tissues were elevated 7.4x to 38.4x and 1.4x to 2.7x, respectively (p<0.0001 to p<0.05 and p<0.05 to p = 0.51, respectively). Also, MIC-1 and PDGF-A expression were similar in tumor and adjacent tissues (0.3x to 1.0x; p<0.001 to p = 0.98 for MIC-1; 0.9x to 2.6x; p<0.01 to p = 1.00 for PDGF-A). All analyses indicated a high level of inter- and intra-tissue heterogeneity across all types of tissues (mean coefficient of variation of 86.0%). Our data shows that MIC-1 and PDGF-A expression is elevated in both prostate tumors and structurally intact adjacent tissues when compared to disease-free specimens, defining field cancerization. These secreted factors could promote tumorigenesis in histologically normal tissues and lead to tumor multifocality. Among several clinical applications, they could also be exploited as indicators of disease in false negative biopsies, identify areas of repeat biopsy, and add molecular information to surgical margins."
1041,[Clinicopathological characteristics and prognostic factor analysis of carcinoma in remnant stomach cancer at Peking University Cancer Hospital].,"Wang Y, Li Z, Jin C, Ying X, Gao C, Wang Y, Xiao Q, Zhang Y, Chen Y, Zhang L, Ji J.",https://pubmed.ncbi.nlm.nih.gov/29774933/,"
    


           Between patients with primary benign diseases (CBS-B group) and primary malignant tumors (CBS-M group), continuous variables were compared using the Student's t-test or the Mann-Whitney U test; categorical variables were compared using the chi-square test or Fisher's exact test. Spearmen-Rho was used to examine correlation. Survival was estimated and compared using Kaplan-Meier  Cox proportional hazards regression was applied to identify independent prognostic factors. Area under ROC curve(AUC) was used to evaluate and compare prediction accuracy.
    


          4 to 1.0. The male: female ratio in CRS-B (n=46) and CRS-M (n=43) group was 14.3 to 1.0 and 2.9 to 1.0 respectively with significant difference (χ2=6.091, P=0.019). The interval time to canceration in CRS-B and CRS-M group was 342(36-576) months and 47(12-360) months respectively with significant difference (t=8.887, P=0.000). The interval time to canceration was correlated with the first operative procedure in CRS-B group (r=0.398, P=0.006), while interval time to canceration was correlated with the age at the first operation in CRS-M group (r=0.337, P=0.027). After differentiating the pathological findings of the first operative sample and the second operative sample, 27 patients presented recurrence and 15 patients had new cancer, and the corresponding interval time to canceration was 46(12-132) months and 60(12-360) months respectively with significant difference (t=5.652, P=0.023). In CRS-B group, location of stump carcinoma in gastric intestinal anastomosis, gastric anastomosis, and non-anastomosis area was found in 60.9%(28/46), 23.9%(11/46) and 15.2%(7/46) respectively, and the corresponding percentage in CRS-M group was 39.5%(17/43), 16.3%(7/43) and 44.2%(19/43) respectively without significant difference (χ2=4.726, P=0.096). Among 77 patients with radical gastrectomy, the overall surgical complication rate was 20.8%(16/77), including 8 cases of infection and 7 cases of respiratory system diseases. The 3-year survival rate was 78.4% and 62.6% in CRS-B and CRS-M group respectively with significant difference (χ2=3.969, P=0.046), indicating better prognosis of CRS-B patients. The AUC for the lymph nodes ratio and N staging was 0.725 and 0.639 respectively. Multivariate analysis showed the pathological T staging was an independent risk factor of prognosis (HR=1.192, 95%CI:1.032-1.376, P=0.017).
    


          Conclusions:
        
      
      Men have more CRS than women. The interval time to canceration is correlated to the first operative procedure for CRS-B patients, while it is correlated to the age at the first operation for CRS-M patients. The major location of CRS is in the gastrointestinal anastomosis for CRS-B patients and in non-anastomosis area for CRS-M patients. Main postoperative complications include respiratory and infectious complications. Pathological T staging is an independent prognostic risk factor for CRS patients."
1042,Prognostic role and immune infiltration characteristics of EI24 in multiple cancer types.,"Yang W, Zhou W, Zhao X, Duan L, Niu L, Zhang Y, Li Y, Wang X, Chen J, Fan A, Xie Q, Liu J, Han Y, Fan D, Hong L.",https://pubmed.ncbi.nlm.nih.gov/37086389/," We aimed to explore the prognostic role and immune infiltration characteristics of EI24 at a pan-cancer level.
    


           Correlations between EI24 expression and DNA methylation, RNA modification, tumor mutation burden (TMB), microsatellite instability (MSI), immune moderator, immune checkpoint-related genes, the tumor immune microenvironment, and clinicopathological characteristics were analyzed. Finally, immunohistochemistry and western blotting were performed to validate the protein levels of EI24 in different tumors.
    


           EI24 showed a significant association with prognosis and may represent a new indicator of prognosis in patients with cancer. In most cancers, EI24 is closely associated with tumor immunity and interacts with various immune cells. Moreover, significant correlations were observed between EI24 expression and RNA modification, TMB, MSI, immune moderators, and immune checkpoint-related genes.
    


          Conclusion:
        
      
      This study provides new insights into the functions and clinical value of EI24 in different tumors and suggests that EI24 may serve as a promising biomarker or therapeutic target for cancer management."
1043,Different expression of cyclooxygenase-2 in biliary epithelia of bile duct cancer with or without pancreaticobiliary maljunction.,"Watanabe O, Yoshimatsu K, Shiozawa S, Tsuchiya A, Oshibe N, Aiba M, Ogawa K.",https://pubmed.ncbi.nlm.nih.gov/15161010/," Little is known about the relationship between bile duct cancer associated with pancreaticobiliary maljunction (PBM) and COX-2.
    


          Materials and 
    


          9% for cancerous lesions and 7.1% for noncancerous lesions in cases of bile duct cancer without PBM. On the other hand, no positive expression of COX-2 was observed in cancerous lesion of bile duct cancer with PBM. Twenty % of the noncancerous bile duct mucosa with PBM was positive for COX-2.
    


          Conclusion:
        
      
      COX-2 is expressed in bile duct cancer while it is not expressed in bile duct cancer accompanied by PBM."
1044,[MRI and prostatic cancer: measurements of kinetic perfusion parameters of gadolinium with a computerized-aided diagnostic tool (CAD)].,"Sauvain JL, Palascak P, Gomez W, Nader N, Bremon JM, Bloqueau P, Jung L, Maniere P, Papavero R, Rhomer P.",https://pubmed.ncbi.nlm.nih.gov/20142053/,"
    


          9 ng/ml) with a prostatic cancer proved after a set of 12 biopsies underwent, before radical prostatectomy, a dynamic MRI (1.5T) with a surface coil after injection of gadolinium. We look with a CAD for foci of voxels with an abnormal Kep in ZP and/or in ZT. Foci of abnormal voxels computerized were compared with histological  The links between prostatic capsule and foci of voxels with elevated Kep were systematically evaluated. The location and the local extension of the various cancerous foci were estimated. A comparison with the 
    


           Hundred and seventy-eight of the 504 investigated prostatic sectors revealed a cancerous lesion after radical prostatectomy (RP) and 116 a focus of voxels with a pathological Kep being linked to 71 isolated lesions, some of them filling several sectors (47 peripheral and 24 transitional). The automatic research with the software of foci of voxels with a parameter Kep more than 2,2 per minute to detect a cancerous lesion had a sensitivity by sector less than the reading without CAD (69% in ZP and 58% in ZT against respectively, 85 and 66% (p<0.01) but seemed more specific: 98% in PZ and 95% in ZT against respectively, 80 and 82% (p<0.01). After RP, 16 cancers were classified Pt2, 10 Pt2R+ and 16 Pt3. The CAD had a better accuracy (74%) than T2W MRI (60%) to look for an extracapsular extension (EPE) or a risk of positive margins: 86% of extraprostatic extension and 60% of positive margins were near a focus of pathological voxels.
    


          Conclusions:
        
      
      CAD allowed a computerized qualitative and quantitative study of DCE MRI. It identified and localized with a good specificity the significant foci. A focus of voxels with elevated Kep against the capsule increased significantly the risk of an extraprostatic extension or a positive margin after radical prostatectomy."
1045,Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer.,"Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H.",https://pubmed.ncbi.nlm.nih.gov/16734726/,"Overexpression of the enhancer of zeste homolog 2 (EZH2) protein, a known repressor of gene transcription, has been reported to be associated with biological malignancy of prostate cancer and several other cancers. The purpose of this study was to examine the expression of EZH2 and analyze its relationship with the clinicopathological features of human gastric cancers. Expression levels of EZH2 mRNA and protein were examined in 13 gastric cancer cell lines and in 83 surgically removed human gastric cancer tissues. Immunohistochemical analysis of the 83 tissue samples and corresponding non-cancerous gastric mucosa showed that EZH2 was more highly expressed in the cancerous than in the non-cancerous tissues, and the expression levels of EZH2 were highly correlated with tumor size, depth of invasion, vessel invasion, lymph node metastasis and clinical stages. Univariate analysis of survival rate calculated by the Kaplan-Meier 0271). These findings suggest that overexpression of EZH2 may contribute to the progression and oncogenesis of human gastric cancers, and thus immunohistochemical study of EZH2 expression may serve as a new biomarker for predicting the prognosis of gastric cancers."
1046,The solitary pulmonary nodule in patients with previous cancer history: results of surgical treatment.,"Rena O, Davoli F, Boldorini R, Roncon A, Baietto G, Papalia E, Turello D, Massera F, Casadio C.",https://pubmed.ncbi.nlm.nih.gov/24035503/,"
    


          
    


           Primary lung cancers were significantly larger, had higher maxSUV at CT-PET scanning, occurred after a longer disease-free interval in patients older and with worse lung function when compared with metastatic lesions. Overall survival at 5-year was 67% for benign lesions, 62% for primary lung cancer, 48% for metastatic disease. Histological subtype, SPN diameter less than 2 cm and DFI >36 months were factors influencing long-term prognosis of metastatic patients. Histological subtype and pathological staging were factors influencing long-term outcome of primary lung cancer patients.
    


          Discussion:
        
      
      Surgical resection of solitary pulmonary nodule is essential in patients with history of previous cancer to rule out benign lesions, to offer diagnostic confirmation and local control of the disease in metastatic tumours and to correctly stage and treat primary lung cancer."
1047,Primary breast cancer of the vulva: a case report and review of the literature.,"Gorisek B, Zegura B, Kavalar R, But I, Krajnc I.",https://pubmed.ncbi.nlm.nih.gov/11098538/,"Since 1872, 40 cases of ectopic mammary gland tissue in the vulva have been reported in the literature. Out of these, 12 had a primary cancer in the ectopic breast tissue. Seven metastases of an orthotopic breast cancer have been found in this location. We are presenting the 20th case of cancerous breast tissue in the vulva whom we classified as the 13th case of primary cancer based on clinical and histopathological criteria of primary and metastatic malignant disease. Because of the advanced age of the patient, wide local excision followed by adjuvant hormonal therapy was opted for. Nineteen months after surgery, there is no evidence of recurrent disease. Due to the rarity of this entity, its management presents therapeutic dilemmas, and variable treatment strategies are being found in the literature. In our opinion, the same basic principles used for treatment of cancers of the orthotopic breast should be applied in ectopic breast carcinoma."
1048,[Studies on DNA content in ploidy patterns of esophageal cancer].,Rikitake H.,https://pubmed.ncbi.nlm.nih.gov/2385220/,"The present study was undertaken to evaluate the nuclear DNA content of esophageal cancer cells consequent on the process of growth and progression of the cancer. In  The study was also carried out to determine the DNA content in the ploidy patterns in man. Primary tumors associated 421 metastatic lymph nodes in the 62 patients with thoracic esophageal cancer were subjected for the study of ploidy patterns. The nuclear DNA content was determined by means of flow cytometry. In the study of the  Clinically in man, the incidence of DNA diploidy and aneuploidy in the 62 primary cancers was 56% and 44%, respectively. In the 421 metastatic lymph nodes, diploid was found in 73% and aneuploid in 11%, while the combination of diploid and aneuploid was observed in 16%. Difference in the DNA index (DI) between the primary cancers and metastatic lymph nodes was found in 29 cases (46.8%), and the difference increased with progression of the cancer. Two hundred and ninety seven metastatic lymph nodes of 29 cases were subdivided into 4 groups based on the extent of the cancerous nests, and the DI value was found to be increased in proportion to the extension. With the "
1049,[GASTRIC CANCER IN THE PRACTICE OF FAMILY PHYSICIAN].,Kranjčević K; Health Center Zagreb West; Family Physician Office.,https://pubmed.ncbi.nlm.nih.gov/29083846/,"Gastric cancer is the second most common cause of cancer-related death in the world. Gastric cancer mostly affects older people. The incidence increases with age and more than 75% of people are older than 50 years. Due to the relatively late detection, long-term survival is poor, except for patients with localized disease and it remains difficult to cure. There are many known risk factors for stomach cancer, but it is not known exactly how these factors cause cells of the stomach lining to become cancerous. But it is known that a certain kind of diet can contribute to its development such as a diet high in salty and smoked foods and low in fruits and vegetables. Long-term infection with H. pylori increases the risk of gastric cancer and the World Health Organization declared H. pylori as carcinogenic for some types of the gastric cancers. About 90% to 95% of cancers of the stomach are adenocarcinomas, the others are Lymphomas, Gastrointestinal stromal tumor (GIST) and MALT lymphoma. Early gastric cancer has no associated symptoms; however, some patients complain of indigestion, nausea or vomiting, dysphagia or postprandial fullness. When there is a suspicion of the gastric it is necessary to do an endoscopy with multiple biopsies. Many treatments may be used such as surgery, radiation therapy, chemotherapy, targeted drugs or a combination of these  Family physician should determine all patients who are at increased risk and regularly control them."
1050,Evidence for etiologic field changes in tongue distant from tumor in patients with squamous cell carcinoma of the oral tongue.,"Gu X, Wang L, Coates PJ, Gnanasundram SV, Sgaramella N, Sörlin J, Erdogan B, Magan M, Nylander K.",https://pubmed.ncbi.nlm.nih.gov/36314576/,"Oral cancer is a paradigm of Slaughter's concept of field cancerization, where tumors are thought to originate within an area of cells containing genetic alterations that predispose to cancer development. The field size is unclear but may represent a large area of tissue, and the origin of mutations is also unclear. Here, we analyzed whole exome and transcriptome features in contralateral tumor-distal tongue (i.e. distant from the tumor, not tumor-adjacent) and corresponding tumor tissues of 15 patients with squamous cell carcinoma of the oral tongue. The number of point mutations ranged from 41 to 237 in tumors and from one to 78 in tumor-distal samples. Tumor-distal samples showed mainly clock-like (associated with aging) or tobacco smoking mutational signatures. Tumors additionally showed mutations that associate with cytidine deaminase AID/APOBEC enzyme activities or a UV-like signature. Importantly, no point mutations were shared between a tumor and the matched tumor-distal sample in any patient. TP53 was the most frequently mutated gene in tumors (67%), whereas a TP53 mutation was detected in only one tumor-distal sample, and this mutation was not shared with the matched tumor. Arm-level copy number variation (CNV) was found in 12 tumors, with loss of chromosome (Chr) 8p or gain of 8q being the most frequent events. Two tumor-distal samples showed a gain of Chr8, which was associated with increased expression of Chr8-located genes in these samples, although gene ontology did not show a role for these genes in oncogenic processes. In situ hybridization revealed a mixed pattern of Chr8 gain and neutral copy number in both tumor cells and adjacent nontumor epithelium in one patient. We conclude that distant field cancerization exists but does not present as tumor-related mutational events. The data are compatible with etiologic field effects, rather than classical monoclonal field cancerization theory. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland."
1051,Genomic investigation of innate sensing pathways in the tumor microenvironment.,"Quinn G, Maggiore G, Li B.",https://pubmed.ncbi.nlm.nih.gov/39289651/,"The innate immune system is the first responder to infectious agents, cellular debris, and cancerous growths. This system plays critical roles in the antitumor immune responses by boosting and priming T cell-mediated cytotoxicity but is understudied due to the complexity and redundancy of its various downstream signaling cascades. We utilized a mathematical tool to holistically quantify innate immune signaling cascades and immunophenotype over 8,000 tumors from The Cancer Genome Atlas (TCGA). We found that innate immune activation was predictive of patient mortality in a subset of cancers. Further analysis identified PHF genes as transcripts that were associated with genomic stability and innate activation. Knockdown of PHF gene transcripts in vitro led to an increase in cell death and IFNB1 expression in a cGAS-dependent manner, validating PHF genes as potential anti-tumor targets. We also found an association between innate immune activation and both tumor immunogenicity and intratumor microbes, which highlights the versatility of this model. In conclusion, interrogating activation of innate immune signaling cascades demonstrated the importance of studying innate signaling in cancer and broadened the search for new therapeutic adjuvants."
1052,[Early invasive mucinous carcinoma of the breast].,"Komaki K, Sakamoto G, Sugano H, Kasumi F, Nishi M.",https://pubmed.ncbi.nlm.nih.gov/2837594/,"Cases of early invasive mucinous carcinoma of the breast have been reviewed. Microscopically, a typical lesion exhibits leakage of cancerous mucus into the stromal tissue from an intraductal carcinomatous component which were shown to be mucus-producing and to be lower papillary projection. Among 5,360 primary breast cancers that had been mastectomized at the C.I.H., 11 or 0.21% were determined as being ""early"" cases. All of these cases exhibited ""pure type"" mucinous carcinomas which were found to be highly mucus. The average age of these patients was 41 years (range: 34-51 yrs.), and no cases showed a nodal involvement. During an average follow-up of 8 years, no recurrent case were found. Thus, we have found that these ""early"" cases revealed an early invasion of a mucinous carcinoma that is highly mucus-producing but without an invasive ductal carcinomatous pattern."
1053,Stem cells in gastrointestinal cancers: a matter of choice in cell fate determination.,"Wei B, Chen L, Li R, Tian J.",https://pubmed.ncbi.nlm.nih.gov/20942633/,"Cancerous stem cells share the same properties of self-renewal and differentiation as normal stem cells, and have a similar phenotype to adult stem cells isolated from the same tissue. Some believe that cancer stem cells are derived from mutation of normal stem cells, whereas others suspect them to have different origins. Although complicated and controversial, the stem cell as the progenitor of cancer has found support in leukemia research, and subsequently in some solid tumors. It was first accepted that both stem and progenitor cells could acquire genetic abnormalities that would lead to uncontrolled replication and dysregulated differentiation, causing them to transform into cancerous stem cells that might then initiate and maintain a tumor. In this article, we discuss recent progress in the studies of stomach and intestinal cancer stem cells, while focusing on the complex molecular pathways underlying stem cell transformation and gastrointestinal tumorigenesis. This understanding provides a basis for promising new therapies that may specifically target gastrointestinal cancer stem cells."
1054,Lobular cancerization: incidence and differential diagnosis with lobular carcinoma in situ of breast.,"Kerner H, Lichtig C.",https://pubmed.ncbi.nlm.nih.gov/3733006/,"A series of 120 breast biopsies and mastectomy specimens originally diagnosed as carcinoma was reviewed in order to emphasize the differences between lobular carcinoma in situ and cancerization of lobules. Criteria for differential diagnosis between the two types of lobular lesion are proposed. In the reviewed material 15 (12.5%) cases of lobular carcinoma in situ and 64 (53.3%) of lobular cancerization were found. The carcinoma in situ usually co-existed with other types of breast carcinoma, such as intraductal carcinoma, cancerization and invasive carcinoma of different types."
1055,"Clinical and prognostic factors for renal parenchymal, pelvis, and ureter cancers in SEER registries: collaborative stage data collection system, version 2.","Altekruse SF, Dickie L, Wu XC, Hsieh MC, Wu M, Lee R, Delacroix S Jr.",https://pubmed.ncbi.nlm.nih.gov/25412394/," This report assesses changes from the AJCC 6th to the AJCC 7th edition stage distributions and the quality of site-specific factors (SSFs).
    


          
    


           During this period, the percentage of stage 0a renal pelvis and ureter cancers increased from 21% to 25%, and stage IV and unknown stage tumors decreased (20% to 18%, and 7% to 5%, respectively). Stage distributions under the AJCC 6th and 7th editions were about the same. For renal parenchymal cancers, 71%-90% of cases had known values for 6 required SSFs. For renal pelvis and ureter cancers, 74% of cases were coded as known for SSF1 (WHO/ISUP grade) and 47% as known for SSF2 (depth of renal parenchymal invasion). SSF values were known for larger proportions of cases with reported resections.
    


          Conclusions:
        
      
      Stage distributions between the AJCC 6th and 7th editions were similar. SSFs were known for more than two-thirds of cases, providing more detail in the SEER database relevant to prognosis."
1056,Heterogeneity and interplay: the multifaceted role of cancer-associated fibroblasts in the tumor and therapeutic strategies.,"Liu Q, Yao F, Wu L, Xu T, Na J, Shen Z, Liu X, Shi W, Zhao Y, Liao Y.",https://pubmed.ncbi.nlm.nih.gov/38602644/,"The journey of cancer development is a multifaceted and staged process. The array of treatments available for cancer varies significantly, dictated by the disease's type and stage. Cancer-associated fibroblasts (CAFs), prevalent across various cancer types and stages, play a pivotal role in tumor genesis, progression, metastasis, and drug resistance. The strategy of concurrently targeting cancer cells and CAFs holds great promise in cancer therapy. In this review, we focus intently on CAFs, delving into their critical role in cancer's progression. We begin by exploring the origins, classification, and surface markers of CAFs. Following this, we emphasize the key cytokines and signaling pathways involved in the interplay between cancer cells and CAFs and their influence on the tumor immune microenvironment. Additionally, we examine current therapeutic approaches targeting CAFs. This article underscores the multifarious roles of CAFs within the tumor microenvironment and their potential applications in cancer treatment, highlighting their importance as key targets in overcoming drug resistance and enhancing the efficacy of tumor therapies."
1057,Hospital-level compliance with the commission on cancer's quality of care measures and the association with patient survival.,"Nussbaum DP, Rushing CN, Sun Z, Yerokun BA, Worni M, Saunders RS, McClellan MB, Niedzwiecki D, Greenup RA, Blazer DG 3rd.",https://pubmed.ncbi.nlm.nih.gov/33943026/," The Commission on Cancer (CoC) is the largest cancer-specific accreditor of hospital quality in the United States and has implemented Quality of Care Measures to evaluate cancer care delivery. However, none has been formally tested as a valid metric for assessing hospital performance based on actual patient outcomes.
    


           Hospital-level compliance was calculated for the core measures, and the association with patient survival was tested using Cox regression.
    


           Increasing hospital-level compliance was associated with improved survival for only two measures, including a 35% reduced risk of mortality for the gastric cancer measure G15RLN (HR 0.65, 95% CI 0.58-0.72) and a 19% reduced risk of mortality for the colon cancer measure 12RLN (HR 0.81, 95% CI 0.77-0.85). For the lung cancer measure LNoSurg, increasing compliance was paradoxically associated with an increased risk of mortality (HR 1.14, 95% CI 1.08-1.20). For the remaining measures, hospital-level compliance demonstrated no consistent association with patient survival.
    


          Conclusion:
        
      
      Hospital-level compliance with the CoC's Quality of Care Measures is not uniformly aligned with patient survival. In their current form, these measures do not reliably discriminate hospital performance and are limited as a tool for value-based healthcare delivery."
1058,Peptides to Target Tumor Vasculature and Lymphatics for Improved Anti-Angiogenesis Therapy.,"Sivashankari PR, Prabaharan M.",https://pubmed.ncbi.nlm.nih.gov/26632433/,"Cancer has become one of the leading causes of increased mortality. The currently employed diagnostic and therapeutic modality offers only minimal specificity towards cancerous cells and affects normal healthy cells. Targeted drug delivery systems have shown an improved efficiency in the diagnosis and treatment of various cancers, as the targeted molecules specifically reach the tumor cells without exerting any undesirable effects on the normal healthy cells. Recent findings have shown that disruption of blood vasculature and lymphatics is efficient in treating various cancers. As these vessels supply nutrient and oxygen, remove wastes and help in the metastasis; therapeutic agents targeting them will be highly useful. Of the various ligands used for targeting blood vasculature and lymphatics, peptides possess great advantage over other molecules. This review article is aimed at focusing the recent findings and developments on the peptides as targeting ligands for the improved anti-angiogenesis therapy."
1059,The huge clinical potential of microbiota in the treatment of pancreatic cancer: The next frontier.,"Zhang Z, Tang D.",https://pubmed.ncbi.nlm.nih.gov/35483491/,"Microbes and their metabolites are found in all body organs; their interaction with body organs can influence inflammation, immunity, and cancer development. Pancreatic cancer development is closely related to intestinal, intrapancreatic, and oral flora. The microbiota plays a regulatory role in pancreatic cancer's malignant progression and treatment resistance. Thus, the study of microbiota-host interactions has emerged as a new hot topic in pancreatic cancer treatment, with microbiota control demonstrating significant clinical potential. This review summarizes recent advances in the clinical diagnosis and treatment of pancreatic cancer, emphasizing the enormous potential for operating microbiota in pancreatic cancer treatment."
1060,Renal cell carcinoma for the nephrologist.,"Perazella MA, Dreicer R, Rosner MH.",https://pubmed.ncbi.nlm.nih.gov/29661544/,"Renal cell carcinoma (RCC), a malignancy whose incidence is increasing, is frequently encountered in general nephrology practice when acute and chronic kidney disease occurs in the course of disease. Importantly, when kidney disease develops in the setting of RCC, mortality is significantly increased with patients often dying of a non-cancer-related complication of kidney disease. As such, practicing nephrologists need to have a working knowledge of this cancer's biology, treatment, and complications. Nephrologists should be involved in all aspects of the care of patients with RCC including in the acute setting prior to nephrectomy and in the chronic setting for patients with post-nephrectomy chronic kidney disease and those receiving potentially nephrotoxic anti-cancer agents. This collaborative approach to RCC care will hopefully improve patient outcomes."
1061,Population-based assessment of sentinel lymph node biopsy in the management of cutaneous melanoma.,"Ollek S, Minkova S, Taqi K, Chen L, Martinka M, Davis N, Hamilton T, Stuart H.",https://pubmed.ncbi.nlm.nih.gov/35701006/," Despite widely published guidelines for SLNB, variation exists in its use. We aimed to determine the frequency of and predictive factors for SLNB in patients with clinically node-negative melanoma in British Columbia.
    


           Patients included had a Breslow depth greater than 0.75 mm or a Breslow depth less than or equal to 0.75 mm with ulceration, or a mitotic rate greater than or equal to 1/mm2. SLNB was considered to be indicated for clinical stages IB to IIC (American Joint Committee on Cancer's AJCC Cancer Staging Manual, seventh edition).
    


           SLNB was performed in 54.8% (363/662) of patients when indicated. SLNB was more likely to be performed for tumours with a Breslow depth greater than 1.0 mm or a mitotic rate greater than or equal to 1/mm2. SLNB was less likely to be performed in patients older than 75 years and with a nonextremity tumour location. Compliance with SLNB guidelines decreased distant recurrence but did not significantly affect regional recurrence, nor did it have a significant impact on overall survival among patients aged 75 years and younger.
    


          Conclusion:
        
      
      SLNB is being underutilized in British Columbia. These  Efforts should be made to increase the use of SLNB in appropriate patients."
1062,Germline p53 mutation in a patient with multiple primary cancers.,"Kimura K, Shinmura K, Hasegawa T, Beppu Y, Yokoyama R, Yokota J.",https://pubmed.ncbi.nlm.nih.gov/11518751/,"We report a case of multiple primary cancers having a germline missense mutation of the p53 gene. The patient was a Japanese female and had a history of five different types of cancers. PCR/direct sequencing analysis revealed the presence of a nucleotide substitution, AGC (Ser) to AGG (Arg), at codon 106 of the p53 gene in DNA from non-cancerous breast tissue. This is the first case of germline p53 mutation at codon 106, and could contribute to establishing correlations between the types and locations of germline p53 mutations and their phenotypical consequences."
1063,Novel approach for detecting global epigenetic alterations associated with tumor cell aneuploidy.,"Habano W, Sugai T, Jiao YF, Nakamura S.",https://pubmed.ncbi.nlm.nih.gov/17546590/,"Although aneuploidy is commonly observed in human cancers, the molecular mechanism underlying aneuploidization remains unclear. We used multiploid cancer model that had diploid and aneuploid cancer cells within the same cancerous tissue and attempted to detect specific epigenetic alterations associated with tumor cell aneuploidy. Thirty-four multiploid colorectal cancers were subjected to crypt isolation and cell sorting, and paired diploid and aneuploid cancer cells were separated from each cancerous tissue. A methylated CpG island amplification provided a considerable number of CpG sequences that showed different methylation status between the above 2 cell populations. BLAST homology search revealed 24 different candidates (11 hypermethylated and 13 hypomethylated) from these sequences. The putative promoter sequence of the SALL4 (sal-like 4, a human homolog to Drosophila spalt) gene was particularly more frequently hypermethylated in aneuploid cells (62%) than diploid ones (35%) in the 34 multiploid cancers. Moreover, such hypermethylation occurred more often in aneuploid cancers (8 of 16, 50%) than diploid cancers (3 of 18, 17%). In combination with demethylation study on cultured cells, these  SALL4 may be one of important key players that act as ""caretakers"" for chromosomal stability. Our new approach is a powerful tool for the global identification of such key players."
1064,The Microbiome and Cancer: Creating Friendly Neighborhoods and Removing the Foes Within.,"Parida S, Sharma D.",https://pubmed.ncbi.nlm.nih.gov/33148661/,"The human body is colonized by the microbial cells that are estimated to be as abundant as human cells, yet their genome is roughly 100 times the human genome, providing significantly more genetic diversity. The past decade has observed an explosion of interest in examining the existence of microbiota in the human body and understanding its role in various diseases including inflammatory bowel disease, neurologic diseases, cardiovascular disorders, and cancer. Many studies have demonstrated differential community composition between normal tissue and cancerous tissue, paving the way for investigations focused on deciphering the cause-and-effect relationships between specific microbes and initiation and progression of various cancers. Also, evolving are the strategies to alter tumor-associated dysbiosis and move it toward eubiosis with holistic approaches to change the entire neighborhood or to neutralize pathogenic strains. In this review, we discuss important pathogenic bacteria and the underlying mechanisms by which they affect cancer progression. We summarize key microbiota alterations observed in multiple tumor niches, their association with clinical stages, and their potential use in cancer diagnosis and management. Finally, we discuss microbiota-based therapeutic approaches."
1065,"Low Dose CT for Lung Cancer Screening: The Background, the Guidelines, and a Tailored Approach to Patient Care.","Tylski E, Goyal M.",https://pubmed.ncbi.nlm.nih.gov/31645796/,"Despite lung cancer's prevalence and high burden of mortality, a useful screening program has taken a long time to develop. Now, most of the associated national organizations recommend low dose CT screening in the appropriate population. However, since the USPSTF guidelines were published, implementation has been slow. This article outlines the current evidence and provides additional resources to help physicians tailor a screening program for their patients."
1066,An S100P-positive biliary epithelial field is a preinvasive intraepithelial neoplasm in nodular-sclerosing cholangiocarcinoma.,"Nakanuma Y, Uchida T, Sato Y, Uesaka K.",https://pubmed.ncbi.nlm.nih.gov/27984121/,"Nodular-sclerosing cholangiocarcinoma (NS-CCA) is a common CCA of the intrahepatic large, perihilar, and distal bile ducts. Intraepithelial biliary neoplasms, such as the mucosal extension of carcinoma and preinvasive neoplastic lesions (ie, biliary intraepithelial neoplasia) reportedly occur in the bile ducts around CCA. In the present study, we collectively refer to these intraepithelial lesions as ""intraepithelial neoplasms of the bile duct (IENBs)"". We examined the IENBs in 57 surgically resected cases of NS-CCA. S100P immunostaining was used to help detect IENBs. The IENBs formed field(s) of continuous neoplastic biliary epithelial cells and showed a flat, micropapillary, or papillotubular configuration. IENBs could be classified into 3 categories based on their atypia: group A (neoplastic but not enough for malignancy), B (neoplastic and sufficiently well differentiated for high-grade dysplasia), and C (overtly malignant and variably differentiated). IENB was found in 31 of 57 cases, with group C the most common (26 cases) followed by group B (22 cases) and group A (16 cases). The expression of cancer-related molecules and MIB-1 index of groups A and B differed from those of invasive CCA, whereas these features of group C were relatively similar to those of invasive CCA. In conclusion, IENB was not infrequently found in NS-CCA and could be classified into 3 grades. Preinvasive lesions (biliary intraepithelial neoplasias) are likely to be found in groups A and B, whereas cancerization would be included in group C. The classification of IENB may be useful for future studies of the preinvasive intraepithelial neoplastic lesions of NS-CCAs."
1067,Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome.,"Yamanoi K, Arai E, Tian Y, Takahashi Y, Miyata S, Sasaki H, Chiwaki F, Ichikawa H, Sakamoto H, Kushima R, Katai H, Yoshida T, Sakamoto M, Kanai Y.",https://pubmed.ncbi.nlm.nih.gov/25740824/,"The aim of this study was to clarify the significance of DNA methylation alterations during gastric carcinogenesis. Single-CpG resolution genome-wide DNA methylation analysis using the Infinium assay was performed on 109 samples of non-cancerous gastric mucosa (N) and 105 samples of tumorous tissue (T). DNA methylation alterations in T samples relative to N samples were evident for 3861 probes. Since N can be at the precancerous stage according to the field cancerization concept, unsupervised hierarchical clustering based on DNA methylation levels was performed on N samples (βN) using the 3861 probes. This divided the 109 patients into three clusters: A (n = 20), B1 (n = 20), and B2 (n = 69). Gastric carcinomas belonging to Cluster B1 showed tumor aggressiveness more frequently than those belonging to Clusters A and B2. The recurrence-free and overall survival rates of patients in Cluster B1 were lower than those of patients in Clusters A and B2. Sixty hallmark genes for which βN characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (βT) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, βT was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that βT was a significant prognostic factor, being independent of clinicopathological parameters. These data indicate that DNA methylation profiles at the precancerous stage may be inherited by gastric carcinomas themselves, thus determining tumor aggressiveness and patient outcome."
1068,Epidemiological correlates between consumption of Indian chewing tobacco and oral cancer.,"Goud ML, Mohapatra SC, Mohapatra P, Gaur SD, Pant GC, Knanna MN.",https://pubmed.ncbi.nlm.nih.gov/2361546/,"The problem of cancer is universal; the only variation occurs in the type, site or other clinicoepidemiological parameters. Peculiarly enough, oral cancers caused by chewing tobacco are common in India and some parts of the Indian sub-continent. Oral cancers caused by other carcinogens are not common in these areas. The present study shows a significant association (P less than 0.001) between the use of Indian chewing tobacco and oral cancer. Number of quids, mean quantity of tobacco and mean duration of keeping the quids in the mouth had direct dose and effect relationships in causation of oral cancer. A dose of 10 gms of chewing tobacco for about 26 years was observed to have produced cancerous lesions in the buccal cavity."
1069,Cancer screening of upper aerodigestive tract in Japanese alcoholics with reference to drinking and smoking habits and aldehyde dehydrogenase-2 genotype.,"Yokoyama A, Ohmori T, Muramatsu T, Higuchi S, Yokoyama T, Matsushita S, Matsumoto M, Maruyama K, Hayashida M, Ishii H.",https://pubmed.ncbi.nlm.nih.gov/8903472/,"In this study, 1,000 Japanese male alcoholics were consecutively screened by upper gastrointestinal endoscopy with esophageal iodine staining. Associations among cancer-detection rates, drinking and smoking habits, and aldehyde dehydrogenase-2 (ALDH2) genotypes were evaluated. A total of 53 patients (5.3%) had histologically confirmed cancer. Esophageal cancer was diagnosed in 36, gastric cancer in 17, and oropharyngolaryngeal cancer in 9 patients: 8 of the esophageal-cancer patients were multiple-cancer patients, with additional cancer(s) in the stomach and/or oropharyngolaryngeal region. Multiple logistic regression revealed that use of stronger alcoholic beverages (whisky or shochu) in contrast with lighter beverages (sake or beer) and smoking of 50 pack-years or more increased the risks for esophageal (odds ratio 3.2 and 2.8 respectively), oropharyngolaryngeal (4.8 and 5.1 respectively) and multiple cancer (10.5 and 11.8 respectively). The inactive form of ALDH2, encoded by the gene ALDH2*1/2*2 prevalent in Orientals, exposes them to higher blood levels of acetaldehyde, a recognized animal carcinogen, after drinking. This inactive ALDH2 was detected in 19/36 (52.8%) patients with esophageal cancer, in 5/9 (55.6%) patients with oropharyngolaryngeal cancer, and in 7/8 (87.5%) patients with multiple cancer. All of these gene frequencies far exceeded that in a large alcoholic cohort (80/655, 12.2%). The triple combination of the risk factors of the inactive ALDH2, stronger alcoholic beverages and heavy smoking was more commonly associated with multiple-cancer patients than with patients with esophageal cancer alone (62.5% vs. 7.1%). These  For these high-risk drinkers, regimented screening appears to be indicated."
1070,"Employing nano-enabled artificial intelligence (AI)-based smart technologies for prediction, screening, and detection of cancer.","Chugh V, Basu A, Kaushik A, Manshu, Bhansali S, Basu AK.",https://pubmed.ncbi.nlm.nih.gov/38391246/,"Cancer has been classified as a diverse illness with a wide range of subgroups. Its early identification and prognosis, which have become a requirement of cancer research, are essential for clinical treatment. Patients have already benefited greatly from the use of artificial intelligence (AI), machine learning (ML), and deep learning (DL) algorithms in the field of healthcare. AI simulates and combines data, pre-programmed rules, and knowledge to produce predictions. Data are used to improve efficiency across several pursuits and tasks through the art of ML. DL is a larger family of ML  Support vector machines, convulsion neural networks, and artificial neural networks, among others, have been widely used in cancer research to construct prediction models that enable precise and effective decision-making. Although using these innovative  We cover contemporary  The presented prediction models are built using a variety of guided ML approaches, as well as numerous input attributes and data collections. Early identification and cost-effective detection of cancer's progression are equally necessary for successful treatment of the disease. Smart material-based detection techniques can give end consumers a portable, affordable instrument to easily detect and monitor their health issues without the need for specialized knowledge. Owing to their cost-effectiveness, excellent sensitivity, multimodal detection capacity, and miniaturization aptitude, two-dimensional (2D) materials have a lot of prospects for clinical examination of various compounds as well as cancer biomarkers. The effectiveness of traditional devices is moving faster towards more useful techniques thanks to developments in 2D material-based biosensors/sensors. The most current developments in the design of 2D material-based biosensors/sensors-the next wave of cancer screening instruments-are also outlined in this article."
1071,Factors Associated With Depression in Breast Cancer Patients in Saudi Arabia.,"Dewan MF, Lyons KS, Song M, Hassouneh D.",https://pubmed.ncbi.nlm.nih.gov/34380962/," Understanding the role of these factors can raise awareness and help create policies to improve care for breast cancer patients. Yet, there is limited research addressing the impact of these factors on depressive symptoms in AWBC.
    


          
    


           Participants completed an online survey or paper-based survey including questions on sociodemographics, social support, spirituality, religiosity, depressive symptoms, and breast cancer's stigma. Pearson correlation and multiple regression analysis were used to examine the influence of numerous factors on depressive symptoms in AWBC; Student t test statistic was used to distinguish the depressive symptom scores between online and paper-based survey.
    


          31). The mean (SD) of depressive symptoms was 20.52 (12.36). Pearson correlation analyses indicated that cancer patients with high levels of depressive symptoms were associated with low levels of spiritualty and religiosity, and high levels of breast cancer stigma.
    


          Conclusions:
        
      
      Religiosity and spirituality work as protective factors against depressive symptoms in AWBC.
    


          Implications for practice:
        
      
      Including religiosity and spirituality in the intervention plan should be considered when caring for AWBC."
1072,"Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth.","Martinez-Outschoorn UE, Lisanti MP, Sotgia F.",https://pubmed.ncbi.nlm.nih.gov/24486645/,"Fibroblasts are the most abundant ""non-cancerous"" cells in tumors. However, it remains largely unknown how these cancer-associated fibroblasts (CAFs) promote tumor growth and metastasis, driving chemotherapy resistance and poor clinical outcome. This review summarizes new findings on CAF signaling pathways and their emerging metabolic phenotypes that promote tumor growth. Although it is well established that altered cancer metabolism enhances tumor growth, little is known about the role of fibroblast metabolism in tumor growth. New studies reveal that metabolic coupling occurs between catabolic fibroblasts and anabolic cancer cells, in many types of human tumors, including breast, prostate, and head & neck cancers, as well as lymphomas. These catabolic phenotypes observed in CAFs are secondary to a ROS-induced metabolic stress response. Mechanistically, this occurs via HIF1-alpha and NFκB signaling, driving oxidative stress, autophagy, glycolysis and senescence in stromal fibroblasts. These catabolic CAFs then create a nutrient-rich microenvironment, to metabolically support tumor growth, via the local stromal generation of mitochondrial fuels (lactate, ketone bodies, fatty acids, glutamine, and other amino acids). New biomarkers of this catabolic CAF phenotype (such as caveolin-1 (Cav-1) and MCT4), which are reversible upon treatment with anti-oxidants, are strong predictors of poor clinical outcome in various types of human cancers. How cancer cells metabolically reprogram fibroblasts can also help us to understand the effects of cancer cells at an organismal level, explaining para-neoplastic phenomena, such as cancer cachexia. In conclusion, cancer should be viewed more as a systemic disease, that engages the host-organism in various forms of energy-transfer and metabolic co-operation, across a whole-body ""ecosystem""."
1073,"Vaccinal chronicity: immunotherapy, primary care, and the temporal remaking of lung cancer's patienthood in Cuba.",Graber N.,https://pubmed.ncbi.nlm.nih.gov/35306938/,"The Cuban biotechnology industry is producing cancer immunotherapy, in particular, therapeutic vaccines that actively stimulate the immune system to stabilise the tumour. These products aim to transform metastatic malignancies into a chronic disease. Since 2010, this therapeutic concept has been integrated within a public health  Such  Combining interviews with ethnographic observations focusing on care performed by professionals, patients, and their relatives, this paper analyses the experience of lung cancer chronicity under this type of immunotherapy in Cuba. It shows how a certain form of continuity is made between prophylactic and therapeutic vaccination to shape a new temporality of cancer care, through the integration within primary care, constant access to biotechnology, and multiple care practices directed to strengthen the immunotherapy's efficacy. If vaccinal chronicity remains fragile due to its "
1074,[Early gastric cancer associated with ectopic gastric mucosa (submucosal cysts)].,"Nakano H, Nakahara Y, Mizumoto K, Yoshioka Y, Tamura Y, Tanabe M, Ogino T.",https://pubmed.ncbi.nlm.nih.gov/2826987/,"A 72 year-old man visited our hospital complaining of anorexia and hungry epigastric pain. Gastroscopy and upper G-I series examination established the diagnosis of double gastric cancers. Total gastrectomy, R2 lymphadenectomy and beta anastomosis were performed. The type IIc early cancer lesion at the pyloric vestibule was sm in depth and revealed a histological pattern of tubular adenocarcinoma. The multiple lesions on the anterior and posterior walls of the lesser curvature were a cluster of submucosal cysts, and were partially accompanied by signet-ring cell carcinoma having the depth m. The two lesions were histologically isolated without continuity, and the histology progress was PoHoeta (-) ps(-), Stage I, aw(-), ow(-). Postoperative course was uneventful. Though multiple diffuse ectopic gastric mucosa is seemed to be benign submucosal tumor of the stomach, occasional co-existence of cancer has been frequently reported. Even if the  On detecting ectopic gastric mucosa, immediate and thorough resection seems desirable, especially when accompanied by cancer. The pathogenesis of multiple diffuse ectopic gastric mucosa has remained controversial and has been explained by the theory of either congenital or acquired aberration. From the histological findings, the pathogenesis of this case could not be determined."
1075,"The National Cancer Data Base report on carcinoma of the gallbladder, 1989-1995.","Donohue JH, Stewart AK, Menck HR.",https://pubmed.ncbi.nlm.nih.gov/9874470/," Data collected from 1989, 1990, 1994, and 1995 for carcinoma of the gallbladder are presented herein.
    


          S. Seven calls for data yielded a total of 5,850,000 cases for the years 1985-1995, including 2574 gallbladder carcinoma cases from 1989-1990 and 2914 cases from 1994-1995 from hospital cancer registries across the U.S. These data represent approximately 8.8% and 8.4% of the estimated cases of liver and biliary track cancers diagnosed in the U.S. during the two respective time periods.
    


           Most gallbladder carcinoma patients were white women. The documentation of tumor stage improved noticeably between the two study periods. There was no increased frequency in the occurrence of early stage tumors between the two reporting times, an era that saw the development and widespread application of laparoscopic cholecystectomy. Treatment differed according to stage of disease. Surgery alone, particularly nonradical surgery, was performed more frequently in the initial treatment of gallbladder carcinoma. A large percentage of gallbladder carcinoma patients received no definitive therapeutic intervention because of the advanced stage of disease at presentation and the lack of effective treatments for these cancers. Multimodality treatment was utilized more often for young patients. Survival was closely related to tumor stage, with 60% 5-year survival for Stage 0 patients, 39% for Stage I patients, and 15% for Stage II patients, but only 5% for Stage III patients and 1% for Stage IV patients. Patient outcome was not demonstrably affected by more aggressive therapy, nor was an adverse effect in 
    


          Conclusions:
        
      
      The NCDB data are valuable in the evaluation of trends in malignant diseases, treatments, and patient survival. No substantial differences were apparent in the diagnosis, treatment, and survival of patients during this 7-year study period. The data do not support any adverse effect on outcome S."
1076,TP53 cancerous mutations exhibit selection for translation efficiency.,"Waldman YY, Tuller T, Sharan R, Ruppin E.",https://pubmed.ncbi.nlm.nih.gov/19887606/,"The tumor suppressor gene TP53 is known to be a key regulator in cancer, and more than half of human cancers exhibit mutations in this gene. Recent evidence shows that point mutations in TP53 not only disrupt its function but also possess gain-of-function and dominant-negative effects on wild-type copies, thus making the mutated gene an oncogene. Hence, this brings about the possibility that TP53 mutations may be under selection for increasing the overall translation efficiency (TE) of defected TP53 in cancerous cells. Here, we perform the first large-scale analysis of TE in human cancer mutated TP53 variants, identifying a significant increase in TE that is correlated with the frequency of TP53 mutations. Furthermore, mutations with a known oncogenic effect significantly increase their TE compared with the other TP53 mutations. Further analysis shows that TE may have influence both on selecting the location of the mutation and on its outcome: codons with lower TE show stronger selection toward nonsynonymous mutations and, for each codon, frequent mutations show stronger increase in TE compared with less frequent mutations. Additionally, we find that TP53 mutations have significantly higher TE increase in progressive versus primary tumors. Finally, an analysis of TP53 NCI-60 cell lines points to a coadaptation between the mutations and the tRNA pool, increasing the overall TP53 TE. Taken together, these "
1077,IGF-IEc Expression Is Associated With Advanced Differentiated Thyroid Cancer.,"Karagiannis AK, Philippou A, Tseleni-Balafouta S, Zevolis E, Nakouti T, Tsopanomichalou-Gklotsou M, Psarras V, Koutsilieris M.",https://pubmed.ncbi.nlm.nih.gov/31177118/,"e., IGF-IEa, IGF-IEb and IGF-IEc) in cancerous tissues, implying possible specific roles of the encoded IGF-I protein isoforms in cancer biology. In particular, there is growing evidence that the IGF-IEc isoform may play a distinct biological role in various types of cancers. The present study investigated whether IGF-IEc expression is associated with a particular type of thyroid cancer.
    


          Materials and  In addition, thyroid cancer biopsies of different TNM staging histological types were evaluated for mRNA expression of the IGF-IEc transcript by real-time polymerase chain reaction (PCR).
    


           The age of cancer diagnosis or tumor size did not significantly affect the IGF-IEc expression. Among all types of cancers, IGF-IEc was expressed in papillary differentiated thyroid cancer. Its expression/localization was mainly cytoplasmic and significantly associated with TNM staging and the presence of muscular and capsule cancerous invasion (p<0.05). Similarly, a differential profile was revealed regarding the mRNA expression of the IGF-IEc transcript, that exhibited a higher expression in aggressive compared to the non-aggressive papillary cancers.
    


          Conclusion:
        
      
      IGF-IEc isoform expression in thyroid cancer is positively associated with more advanced stages of papillary thyroid cancer."
1078,Early diagnosis of esophageal cancer. Analysis of 11 cases of esophageal mucosal cancer.,"Misumi A, Harada K, Murakami A, Arima K, Kondo H, Akagi M, Yagi Y, Ikeda T, Kobori Y, Matsukane H, et al.",https://pubmed.ncbi.nlm.nih.gov/2589886/,"We reviewed 11 patients with esophageal mucosal carcinoma in various aspects to improve the early diagnosis of the disease. Eighteen lesions measuring 0.5 to 5.0 cm were confirmed histologically in the 11 cases. Histologically 10 of the 18 lesions were carcinomas in situ (ep cancer), and the other 8 lesions were carcinomas confined to the mucosa other than ep cancer (mm cancer); all 18 lesions were squamous cell carcinomas. Six (85.7%) of the seven mm cancers showed abnormal radiographic findings regardless of the size. Similarly these findings were noted on four of five (80%) ep carcinomas 2 cm or larger in size. All 15 lesions diagnosed before operation showed abnormal findings on conventional endoscopy regardless of the size and depth of transmural invasion. Morphologic change was observed in 9 lesions (53.3%), while 13 (86.7%) showed color change; most of the lesions (80%) were manifested as redness. Dyeing of the resected specimen with Lugol solution (Katayama Chemical Industries, Osaka, Japan) showed all 18 cancerous lesions as unstained areas. Among the 18 lesions, two lesions were unstained areas, which agreed with the areas determined histologically. An additional lesion was visible with dye endoscopy as an unstained area but it was not visible with radiography or conventional endoscopy. Dye endoscopy using Lugol solution is very important because it allows detection and evaluation of the extent of esophageal mucosal cancer."
1079,Collagen: a possible prediction mark for gastric cancer.,"Yin Y, Zhao Y, Li AQ, Si JM.",https://pubmed.ncbi.nlm.nih.gov/18951724/,"Considering the high mortality rates and the unfavorable prognosis of gastric cancer (GC), it is important to predict early GC canceration and the metastasis. Unfortunately, it has not been any clinical prediction mark sufficiently sensitive to GC yet. It is therefore important to investigate new sensitive and specific marks for GC prediction. Here, we review the evidence on gastric cancer and collagen, and discuss the sensitivity and the feasibility of collagens as potential prediction marks.  As outlined above, we hypothesize that collagens may be independent prediction marks of GC canceration and metastasis."
1080,Clinical implication of CD166 expression in gastric cancer.,"Ishigami S, Ueno S, Arigami T, Arima H, Uchikado Y, Kita Y, Sasaki K, Nishizono Y, Omoto I, Kurahara H, Matsumoto M, Kijima Y, Natsugoe S.",https://pubmed.ncbi.nlm.nih.gov/20886585/," Its expression is associated with aggressive tumor behavior. CD166 expression is a prognostic marker in several cancers, but the predictive value of CD166 expression in gastric cancer has not been clarified yet.
    


          Patients and  The patients were composed of 99 men and 43 women, ranging in age from 42 to 84 years (mean 63 years). Cancerous CD166 expression was evaluated immunohistochemically.
    


           The rates of membranous and cytoplasmic CD166 positivities were 25.4% and 34.4%, respectively. Cytoplasmic and membranous CD166 positivities were significantly correlated with nodal involvement and vascular invasion. Survival analysis of the 142 gastric cancer patients revealed that membranous CD166-positive group (median survival 18.6 months, range 0.3-104.5 months) had a significantly poorer outcome than CD166-negative group (median 25.7 months range 1.4-106 months) (P < 0.05).
    


          Conclusions:
        
      
      Membranous CD166-positivity may contribute to one of the promising prognostic markers in gastric cancer."
1081,"Eurycoma longifolia, A Potential Phytomedicine for the Treatment of Cancer: Evidence of p53-mediated Apoptosis in Cancerous Cells.","Thu HE, Hussain Z, Mohamed IN, Shuid AN.",https://pubmed.ncbi.nlm.nih.gov/28721818/," Plethora of in vitro and in vivo studies evidenced their excellent antiproliferative and anticancer efficacy against various types of human cancers.
    


          
    


           Eurycomanone, one of the most active medicinal compounds of Eurycoma longifolia, displayed a strong dose-dependent anticancer efficacy against lung carcinoma (A-549 cells) and breast cancer (MCF-7 cells); however, showed moderate efficacy against gastric (MGC-803 cells) and intestinal carcinomas (HT-29 cells). The prime mode of cytotoxicity of Eurycoma longifolia and its medicinal compounds is the induction of apoptosis (programmed cell death) via the up-regulation of the expression of p53 (tumor suppressor protein) and pro-apoptotic protein (Bax) and downregulation of the expression of anti-apoptotic protein (Bcl-2). A remarkable alleviation in the mRNA expression of various cancer-associated biomarkers including heterogeneous nuclear ribonucleoprotein (hnRNP), prohibitin (PHB), annexin-1 (ANX1) and endoplasmic reticulum protein-28 (ERp28) has also been evidenced.
    


          Conclusion:
        
      
      Eurycoma longifolia and its medicinal constituents exhibit promising anticancer efficacy and thus can be considered as potential complementary therapy for the treatment of various types of human cancers."
1082,Pre-cancerous lesions for colorectal cancers in rodents: a new concept.,"Yamada Y, Mori H.",https://pubmed.ncbi.nlm.nih.gov/12807742/,"It is widely believed that colorectal carcinogenesis is a representative multi-step tumorigenesis with events of genetic alterations. Aberrant crypt foci (ACF) recognized on the surface of cancer-predisposed colons of rodents have been regarded as early-appearing pre-neoplastic lesions. However, it is not clear if such lesions are truly pre-cancerous lesions for colorectal cancers in rodents. Recently, beta-catenin-accumulated crypts (BCAC) were identified in colonic mucosa at the early stages of colon carcinogenesis. Accumulating evidence indicates that they are independent small dysplastic lesions of ACF. Here we discuss the importance of BCAC as pre-cancerous lesions in colon carcinogenesis."
1083,Carcinoma of the oropharynx.,"Hughes CJ, Spiro RH.",https://pubmed.ncbi.nlm.nih.gov/8179523/,"Carcinoma of the oropharynx poses particular challenges and problems to head and neck clinicians. These include relative anatomic inaccessibility, field cancerization and the need to minimize speech and swallowing dysfunction. The aim of this review is to bring together an appreciation of the issues involved in the management of this disease and the more recent "
1084,[Systematic screening for uterine cancer by exfoliative cytology: an account of 8 years activity in the cytology laboratory of the Jules Bordet Institute].,"Gompel C, Spetchinsky A.",https://pubmed.ncbi.nlm.nih.gov/17436510/,"After 8 years experience of systematic screening for asymptomatic uterine cancer in 115 604 cases, the authors report the following conclusions: The cytological 2 per cent of cancerous lesions in an asymptomatic population. The percentage of false positives or false negatives is negligible in a laboratory with well trained staff. The disparity between the number of no invasive and invasive cervical epitheliomas indicates that a certain percentage of non invasive forms do not evolve into the invasive form. The number of cancers discovered has remained constant over the years; this could be explained in several ways : insufficient effort has been made to organize mass screening; the populations effected by the screening campaigns do not represent the high-risk groups (older women and the poorer social classes); slowly evolving cervical lesions are more likely to be detected than those that develop rapidly and have a less favourable prognosis. The efficiency of screening campaigns could be improved by providing better information to the public and to the medical profession on the advantages of the technique. In the absence of a precise biological definition of the intraepithelial cancerous lesion, systematic screening for the so-called dysplasic or intraepithelial lesions should be continued and adequate conservative treatment must be provided."
1085,[Serum selenium contents and the risk of cancer].,"Ujiie S, Itoh Y, Kikuchi H.",https://pubmed.ncbi.nlm.nih.gov/9797811/,"To investigate the relationship between serum Se contents and the risk of cancer, 4857 serum samples were obtained from cancerous (2730) and non-cancerous patients (2127). In this cohort, the incidence of cancer in the non-cancerous patients was followed for the subsequent 3 years. The serum Se level of non-cancerous patients who later developed cancer during the 3 years was determined and compared with that of the non-cancerous patients. A high incidence of cancer was observed in the lower serum Se patients of the non-cancerous group. The serum Se levels of cancerous patients were significantly lower than in non-cancerous patients. These  To calculate the odds ratio, cancerous and non-cancerous patients were divided into group of less than 110 ppb and more than 111 ppb group in serum Se. The odds ratio was estimated to be 1.95, suggesting the high risk of cancer in the low serum Se group."
1086,The continuum model of selection in human tumors: general paradigm or niche product?,"Leedham S, Tomlinson I.",https://pubmed.ncbi.nlm.nih.gov/22552286/,"Berger and colleagues recently proposed a continuum model of how somatic mutations cause tumors to grow, thus supplementing the established binary models, such as oncogene activation and ""two hits"" at tumor suppressor loci. In the basic continuum model, decreases or increases in gene function, short of full inactivation or activation, impact linearly on cancer development. An extension, called the fail-safe model, envisaged an optimum level of gene derangement for tumor growth, but proposed that the cell gained protection from tumorigenesis because additional mutations caused excessive derangement. Most of the evidence in support of the continuum model came from Pten mutant mice rather than humans. In this article, we assess the validity and applicability of the continuum and fail-safe models. We suggest that the latter is of limited use: In part, it restates the existing ""just right"" of optimum intermediate gene derangement in tumorigenesis, and in part it is inherently implausible that a cell should avoid becoming cancerous only when it is some way down the road to that state. In contrast, the basic continuum model is a very useful addition to the other genetic models of tumorigenesis, especially in certain scenarios. Fittingly for a quantitative model, we propose that the continuum model is most likely to apply where multiple, cancer-promoting mutations have relatively small, additive effects, either through the well-established case of additive germline predisposition alleles or in a largely hypothetical situation where cancers may have acquired several somatic ""mini-driver"" mutations, each with weaker effects than classical tumor suppressors or fully activated oncogenes."
1087,S100A11 gene identified by in-house cDNA microarray as an accurate predictor of lymph node metastases of gastric cancer.,"Mori M, Shimada H, Gunji Y, Matsubara H, Hayashi H, Nimura Y, Kato M, Takiguchi M, Ochiai T, Seki N.",https://pubmed.ncbi.nlm.nih.gov/15138568/,"Gastric cancer is one of the most common malignancies in the world, and in Asian countries its incidence and mortality rates are very high. Worldwide, Japan ranks first in the incidence of this type of cancer for both sexes. To shed light on the mechanisms underlying the development and/or progression of gastric cancer, we compared the expression profiles in gastric cancer cells obtained from surgical dissection of 20 gastric adenocarcinoma specimens with those in the corresponding non-cancerous mucosa, by cDNA microarray analysis. In total, 8,000 cDNA clones were randomly picked up and their 5'-end nucleotide sequences were determined. On the basis of sequence information, 4,608 independent clones were selected and used to produce the cDNA microarray. We identified 26 genes that were commonly up-regulated and 44 genes that were commonly down-regulated in cancerous tissues. To validate the cDNA microarray analysis, real-time PCR was performed. We found that gene S100A11 expression was associated with the development of lymph node metastases. S100A11 gene expression was clearly up-regulated in specimens from patients with lymph node metastases relative to those from patients without lymph node metastases. S100A11 gene expression status was useful to distinguish gastric cancers with lymph node metastases from those without lymph node metastasis. This genome-wide information contributes to an improved understanding of molecular changes during the development of gastric cancers. It may also help clinicians predict the development of lymph node metastases and assist researchers in identifying novel therapeutic targets for patients with gastric cancer."
1088,Chemoprevention of asbestos-linked cancers: a systematic review.,"Neri M, Ugolini D, Boccia S, Canessa PA, Cesario A, Leoncini G, Mutti L, Bonassi S.",https://pubmed.ncbi.nlm.nih.gov/22399624/,"Asbestos has been used extensively and, in spite of many countries having banned most of its uses, professional, domestic and environmental exposure has not ceased worldwide. Inhaled asbestos fibers can lead to malignant mesothelioma, lung cancer and non-cancerous conditions, while the substance persists indefinitely in the lung and pleural tissue,  Exposed individuals may be offered medical surveillance or compensation, but nothing is currently being done to lower their specific cancer risk: chemoprevention seems a promising approach. A web search and a PubMed review of the literature on chemoprevention trials in individuals exposed to asbestos have been conducted. Forty-six articles on five projects were found and newly reviewed but, surprisingly, no novel trials have been set up for twenty years, although considerable advances have been gained in cancer chemoprevention. A re-consideration of possibilities offered by chemoprevention should be encouraged. New trials based on the most recently characterized molecules should be planned, taking into account specific issues such as the need for a very large number of participants and a long follow up or, alternatively, the use of biomarkers as surrogate endpoints. The long latency of asbestos related diseases may offer delayed intervention opportunities. The lack of chemoprevention trials for asbestos exposure highlights the urgent need for research in this field."
1089,Corrupted devolution: How normal cells are reborn as cancer precursors.,"Lord A, Ficz G.",https://pubmed.ncbi.nlm.nih.gov/35798274/,"Cancers are genetically divergent but intriguingly display similar patterns of epigenetic deregulation, including global DNA hypomethylation and hypermethylation of promoter CpG islands. Early developmental programmes mirror this cancer epigenome suggesting that reactivation of embryonic programmes is essential to the initiation of cancer. We propose a scenario where two waves of dedifferentiation underlie key cell transitions: the first from normal to cancer, and the second driving malignancy. The possibility that early developmental programmes underpin both normal development and the switch to cancer has huge therapeutic implications. The reignition of embryonic programmes and pluripotency networks in seemingly healthy tissues could provide unique cellular targets, to eliminate pre-cancerous or cancer promoting cells before they have the opportunity to form tumours. We conclude that focusing on epigenetic gatekeepers, and peri-implantation cellular identities, could transform the diagnosis and prevention of cancer, especially if these programmes crosscut many cancer types, solid and haematological."
1090,Hypermethylation of the hMLH1 gene promoter in solitary and multiple gastric cancers with microsatellite instability.,"Sakata K, Tamura G, Endoh Y, Ohmura K, Ogata S, Motoyama T.",https://pubmed.ncbi.nlm.nih.gov/11870538/,"Human cancers with a high frequency microsatellite instability phenotype develop due to defects in DNA mismatch repair genes. Silencing of a DNA mismatch repair gene, hMLH1 gene, by promoter hypermethylation is a frequent cause of the microsatellite instability-H phenotype. Using methylation specific PCR we investigated the methylation status of the hMLH1 gene promoter in 17 solitary gastric cancers (12 microsatellite instability-H and five microsatellite stable tumours from 17 patients), and 13 multiple gastric cancers (eight microsatellite instability-H, one low frequency microsatellite instability-L and four microsatellite stable tumours from five patients) and also examined non-cancerous gastric mucosa both adjacent to and distant from each tumour. Expression of hMLH1 protein was evaluated by immunohistochemistry. All microsatellite instability-H tumours (20 out of 20) had evidence of methylation of hMLH1 promoter, whereas only one out of 10 microsatellite instability-L and microsatellite stable tumours did (P<0.0000005), and the methylation status correlated with hMLH1 protein expression (P<0.000003). Furthermore, methylation of the hMLH1 promoter was detected in 50% (6 out of 12) and 63% (5 out of 8) of non-cancerous gastric mucosa samples adjacent to, and in 33% (4 out of 12) and 40% (2 out of 5) of those obtained from distant portion of, solitary and multiple cancers with microsatellite instability-H. Thus both solitary and multiple gastric cancers with microsatellite instability-H have evidence of similar high levels of hMLH1 promoter hypermethylation in the surrounding non-cancerous tissue. Hypermethylation of the hMLH1 promoter occurs in non-cancerous gastric mucosa of microsatellite instability-H tumours and may increase the risk of subsequent neoplasia."
1091,"Associations of multimorbidity with breast, cervical, and colorectal cancer screening delivery: a cross-sectional study of a nationally representative Japanese sample.","Yamashita H, Takahashi Y, Ishizaki T, Imura H, Nakayama T.",https://pubmed.ncbi.nlm.nih.gov/32980753/," Previous studies have indicated that multimorbidity tends to be associated with not receiving cancer screening, although this association remains unclear. This study aimed to investigate the associations between multimorbidity and the delivery of breast, cervical, and colorectal cancer screening in Japan, and to identify subgroups that did not receive cancer screening.
    


           Multivariable logistic regression models were used to evaluate the associations between the number of chronic conditions and each cancer's screening proportion. The relevant covariates included age, marital status, education level, occupation, and household income.
    


          42, 95% confidence interval [CI]: 2.80-10.5; cervical cancer, aOR: 4.59, 95% CI: 2.03-10.4; male colorectal cancer, aOR: 3.26, 95% CI: 1.29-8.24; female colorectal cancer, aOR: 1.05, 95% CI: 0.39-2.81). Low socioeconomic status was associated with not receiving any type of cancer screening consistently.
    


          Conclusion:
        
      
      Multimorbidity and high socioeconomic status were associated with higher proportions of screening for breast, cervical, and colorectal cancers in the Japanese population. More aggressive strategies may be needed to promote screening among Japanese individuals with no chronic conditions and individuals with low socioeconomic status."
1092,[Expert consensus on multidisciplinary diagnosis and treatment of precancerous lesions of hepatocellular carcinoma (2020 edition)].,[No authors listed],https://pubmed.ncbi.nlm.nih.gov/32023692/,"Hepatocellular carcinoma (HCC) currently holds the second position for cause of cancer-related deaths in China. Most of the pathogenic characteristics of HCC in China follow the tri-step model of hepatitis B-cirrhosis-liver cancer. The screening of precancerous lesions of stomach cancer, colorectal cancer and cervical cancer has achieved remarkable  Dysplastic nodules in the state of cirrhosis have strong potential for malignant changes, especially high-grade dysplastic nodules, have extremely high canceration rate. This expert consensus is based on the research  Furthermore, this consensus summarizes and defines high-grade dysplastic nodules of the liver as precancerous lesions of HCC through multidisciplinary collaboration in terms of conception, screening, diagnosis, treatment and follow-up, with the aim to reduce the HCC incidence and improve the overall therapeutic effect of HCC in China."
1093,[Diagnosis and treatment of primary ectopic thyroid carcinoma: report of 3 cases and literature review].,"Zhou Y, Qian M, Zhou Z, Gong T, Wang J.",https://pubmed.ncbi.nlm.nih.gov/24826448/,"
    


          
    


           The pathology  All cases had followed up till now and no relapse signs occurred.
    


          Conclusion:
        
      
      Ectopic thyroid tissue is  They can cancerization, the treatment of ectopic thyroid carcinoma is also controversial. Here,we report 3 cases of primary ectopic thyroid papillary carcinoma, all of which were removed by surgery, take thyroxin orally after surgery and have a great prognosis."
1094,p53 immunostaining and image cytometry DNA analysis in precancerous and cancerous squamous epithelial lesions of the larynx.,"Munck-Wikland E, Kuylenstierna R, Lindholm J, Auer G.",https://pubmed.ncbi.nlm.nih.gov/9059867/," Histopathologic evaluation/grading of these lesions is difficult and gives poor information concerning the risk for progression to cancer. Squamous cell carcinoma of the head and neck (SCCHN) frequently show p53 alteration and DNA-ploidy aberration. Could these markers be used as indicators for malignancy risk in the larynx?
    


          
    


           All but one of the invasive cancer lesions, and 77% of the precancerous lesions, showed aberrant DNA-ploidy  When DNA and p53 analysis were combined, only one of the lesions preceding cis or invasive cancer was negative.
    


          Conclusions:
        
      
      Both p53 immunoreactivity and DNA-ploidy aberration appear to be early events in the multistep process of squamous epithelial carcinogenesis. Immunohistochemical staining p53 analysis and ICM DNA analysis does increase the diagnostic sensitivity for cancerous and true precancerous lesions in the larynx."
1095,Pan-tissue mitochondrial phenotyping reveals lower OXPHOS expression and function across cancer types.,"Boykov IN, Montgomery MM, Hagen JT, Aruleba RT, McLaughlin KL, Coalson HS, Nelson MA, Pereyra AS, Ellis JM, Zeczycki TN, Vohra NA, Tan SF, Cabot MC, Fisher-Wellman KH.",https://pubmed.ncbi.nlm.nih.gov/37798427/,"Targeting mitochondrial oxidative phosphorylation (OXPHOS) to treat cancer has been hampered due to serious side-effects potentially arising from the inability to discriminate between non-cancerous and cancerous mitochondria. Herein, comprehensive mitochondrial phenotyping was leveraged to define both the composition and function of OXPHOS across various murine cancers and compared to both matched normal tissues and other organs. When compared to both matched normal tissues, as well as high OXPHOS reliant organs like heart, intrinsic expression of the OXPHOS complexes, as well as OXPHOS flux were discovered to be consistently lower across distinct cancer types. Assuming intrinsic OXPHOS expression/function predicts OXPHOS reliance in vivo, these data suggest that pharmacologic blockade of mitochondrial OXPHOS likely compromises bioenergetic homeostasis in healthy oxidative organs prior to impacting tumor mitochondrial flux in a clinically meaningful way. Although these data caution against the use of indiscriminate mitochondrial inhibitors for cancer treatment, considerable heterogeneity was observed across cancer types with respect to both mitochondrial proteome composition and substrate-specific flux, highlighting the possibility for targeting discrete mitochondrial proteins or pathways unique to a given cancer type."
1096,Targeting the Wnt pathway in cancer: the emerging role of Dickkopf-3.,"Veeck J, Dahl E.",https://pubmed.ncbi.nlm.nih.gov/21982838/,"Aberrant activation of the Wnt signaling pathway is a major trait of many human cancers. Due to its vast implications in tumorigenesis and progression, the Wnt pathway has attracted considerable attention at several molecular levels, also with respect to developing novel cancer therapeutics. Indeed, research in Wnt biology has recently provided numerous clues, and evidence is accumulating that the secreted Wnt antagonist Dickkopf-related protein 3 (Dkk-3) and its regulators may constitute interesting therapeutic targets in the most important human cancers. Based on the currently available literature, we here review the knowledge on the biological role of Dkk-3 as an antagonist of the Wnt signaling pathway, the involvement of Dkk-3 in several stages of tumor development, the genetic and epigenetic mechanisms disrupting DKK3 gene function in cancerous cells, and the potential clinical value of Dkk-3 expression/DKK3 promoter methylation as a biomarker and molecular target in cancer diseases. In conclusion, Dkk-3 rapidly emerges as a key player in human cancer with auspicious tumor suppressive capacities, most of all affecting apoptosis and proliferation. Its gene expression is frequently downregulated by promoter methylation in almost any solid and hematological tumor entity. Clinically, evidence is accumulating of Dkk-3 being both a potential tumor biomarker and effective anti-cancer agent. Although further research is needed, re-establishing Dkk-3 expression in cancer cells holds promise as novel targeted molecular tumor therapy."
1097,[A Case of Laparoscopically Resected Sigmoid Colon Cancer and Transverse Colon Mesentery Primary Solitary Fibrous Tumor].,"Tokunou K, Kawaoka T, Sato T, Umeno H, Sakai B, Suzuki A, Sudou Y, Iwamoto R, Ikeshita T, Tamesa T, Fujita Y, Miyahara M, Akiyama N, Yamamoto S.",https://pubmed.ncbi.nlm.nih.gov/36733003/,"The patient is a 52-year-old woman who visited the general practitioner because of positive fecal occult blood test by medical examination. The patient underwent colonoscopy at the hospital, which revealed sigmoid colon cancer. Therefore, the patient was referred to our hospital for surgery. Preoperative CT scan revealed a well-defined and lobulated 54 mm tumor on the caudal side of the duodenal third portion. On MRI, the tumor showed low T1-weighted image signal and high T2-weighted and diffusion-weighted images signal, with low ADC. For preoperative diagnosis, we diagnosed sigmoid colon cancer and transverse colon mesenteric and performed laparoscopic sigmoid colon and transverse colon mesenteric tumor resections. The histopathological tumor diagnoses were sigmoid colon cancer(S, type 2, 30×30 mm, 1/2 circumference, moderately differentiated adenocarcinoma, pT3[SS], INF b, Ly1a, V1a, pN1b[#252: 2/4], sM0, fStage Ⅲb)and transverse colon mesentery primary solitary fibrous tumor. The patient was treated with XELOX as the adjuvant chemotherapy and survived without recurrence until present."
1098,Beyond DNA-targeting in Cancer Chemotherapy. Emerging Frontiers - A Review.,"Mbugua SN, Njenga LW, Odhiambo RA, Wandiga SO, Onani MO.",https://pubmed.ncbi.nlm.nih.gov/32814532/,"Modern anti-cancer drugs target DNA specifically for rapid division of malignant cells. One downside of this approach is that they also target other rapidly dividing healthy cells, such as those involved in hair growth leading to serious toxic side effects and hair loss. Therefore, it would be better to develop novel agents that address cellular signaling mechanisms unique to cancerous cells, and new research is now focussing on such approaches. Although the classical chemotherapy area involving DNA as the set target continues to produce important findings, nevertheless, a distinctly discernible emerging trend is the divergence from the cisplatin operation model that uses the metal as the primary active center of the drug. Many successful anti-cancer drugs present are associated with elevated toxicity levels. Cancers also develop immunity against most therapies and the area of cancer research can, therefore, be seen as an area with a high unaddressed need. Hence, ongoing work into cancer pathogenesis is important to create accurate preclinical tests that can contribute to the development of innovative drugs to manage and treat cancer. Some of the emergent frontiers utilizing different approaches include nanoparticles delivery, use of quantum dots, metal complexes, tumor ablation, magnetic hypothermia and hyperthermia by use of Superparamagnetic Iron oxide Nanostructures, pathomics and radiomics, laser surgery and exosomes. This review summarizes these new approaches in good detail, giving critical views with necessary comparisons. It also delves into what they carry for the future, including their advantages and disadvantages."
1099,The complex relationship between infertility and female genital tract cancer: A review.,"Alessandra F, Vitalba G, Antonella B, Giulia DM, Carmine C, Marco D, Rachel S, Giacomo C, Anna F, Valerio G, Giovanni S.",https://pubmed.ncbi.nlm.nih.gov/34338095/," Although cervical cancer has the worst impact on female fertility, as it is usually diagnosed in patients of reproductive age, endometrial and ovarian cancer are also diagnosed and treated often in relatively younger patients in which fertility preservation is a relevant issue. The aim of this review is to highlight the correlation between therapy for female infertility and the developing cancer's risk and to describe the fertility sparing treatments in gynecological oncology.
    


          Material and  We selected the most relevant articles based on the largest case series and the latest updates. All selected documents have been listed in the references.
    


          In young patients diagnosed with gynecological cancer, preservation of fertility is a personalized choice depending on several factors (type, stage, age and desire to conceive, safety of the treatment, and feasibility of fertility sparing surgery). For ovarian cancer FIGO stage IA G1, IA G2 (grade), and IC G1; for endometrial adenocarcinoma grade 1 with no lymphovascular space invasion (LVSI) or myometrial invasion and for early-stage cervical cancer (FIGO stage 2018: IA1-IB1), fertility sparing treatment is possible. The role of fertility sparing treatment with the increase of personalization of therapies therapy is always a theme of discussion and research.
    


          Conclusion:
        
      
      At present data regarding the risk of gynecological cancers after infertility treatments are reassuring. Careful evaluation of female fertility-sparing options in young women interested by ovarian, endometrial, or cervical tumors should be carried out involving a multidisciplinary team and ensuring safety and efficacy."
1100,LHRH-Targeted Drug Delivery Systems for Cancer Therapy.,"Li X, Taratula O, Taratula O, Schumann C, Minko T.",https://pubmed.ncbi.nlm.nih.gov/27739358/,"Targeted delivery of therapeutic and diagnostic agents to cancer sites has significant potential to improve the therapeutic outcome of treatment while minimizing severe side effects. It is widely accepted that decoration of the drug delivery systems with targeting ligands that bind specifically to the receptors on the cancer cells is a promising strategy that may substantially enhance accumulation of anticancer agents in the tumors. Due to the transformed cellular nature, cancer cells exhibit a variety of overexpressed cell surface receptors for peptides, hormones, and essential nutrients, providing a significant number of target candidates for selective drug delivery. Among others, luteinizing hormonereleasing hormone (LHRH) receptors are overexpressed in the majority of cancers, while their expression in healthy tissues, apart from pituitary cells, is limited. The recent studies indicate that LHRH peptides can be employed to efficiently guide anticancer and imaging agents directly to cancerous cells, thereby increasing the amount of these substances in tumor tissue and preventing normal cells from unnecessary exposure. This manuscript provides an overview of the targeted drug delivery platforms that take advantage of the LHRH receptors overexpression by cancer cells."
1101,Expression of early lung cancer detection marker p31 in neoplastic and non-neoplastic respiratory epithelium.,"Zhou J, Jensen SM, Steinberg SM, Mulshine JL, Linnoila RI.",https://pubmed.ncbi.nlm.nih.gov/8696723/,"In an immunocytochemical study of sputum, two antibodies, including a mouse monoclonal antibody (703D4) to a 31 kDa protein (p31) antigen, have been previously shown to detect lung cancer earlier than routine cytomorphology or chest X-ray. To understand the basis of p31 expression, the distribution of this antigen in the respiratory epithelium of individuals known to have lung cancer was mapped. These individuals are likely to demonstrate extensive changes throughout the epithelium due to field cancerization. p31 immunoreactivity was examined in primary tumors and surrounding non-neoplastic lungs containing both histologically normal and abnormal areas obtained from 28 Stage I non-small cell lung cancer (NSCLC) patients. Distribution and intensity of p31 expression was scored in three lung compartments (bronchi, bronchioli, alveoli). While p31 was present in histologically unremarkable bronchial and bronchiolar epithelium, no expression was detected in bronchi or bronchioli containing histologic abnormalities. Furthermore, in the peripheral lung p31 staining was frequently observed in alveolar type II cells and was most commonly detected in reactive, hyperplastic type II cells. When p31 immunoreactivity was correlated with clinicopathological features, a statistically significant increase in p31 expression was found both in bronchioli and alveoli of older individuals a well as in bronchioli of patients with most extensive smoking exposure. We conclude that p31 expression occurs in both non-neoplastic and neoplastic epithelium of the human respiratory tract. The increased expression of p31 in the peripheral lung may be potentially informative as to what critical cell populations are involved in the development of invasive cancers. Moreover, this study provides a model approach for analysis of the nature of early epithelial changes leading to the development of lung cancer."
1102,Ultrasensitive Surface Plasmon Resonance Sensor with a Feature of Dynamically Tunable Sensitivity and High Figure of Merit for Cancer Detection.,"Gollapalli R, Phillips J, Paul P.",https://pubmed.ncbi.nlm.nih.gov/37420756/,"Cancer is one of the leading causes of death worldwide, and it is well known that an early detection of cancer in a human body will provide an opportunity to cure the cancer. Early detection of cancer depends on the sensitivity of the measuring device and  Recently, Surface Plasmon Resonance (SPR) has proven to be a promising  The SPR  There exist many techniques where different combinations of metals, metal alloys and different configurations have been shown to lead to high sensitivities of the SPR sensors. Based on the difference in the refractive index between a normal healthy cell and a cancerous cell, recently, SPR  In this work, we propose a new sensor surface configuration that comprises of gold-silver-graphene-black phosphorus to detect different cancerous cells based on the SPR  Additionally, recently we proposed that the application of electric field across gold-graphene layers that form the SPR sensor surface can provide enhanced sensitivity than that is possible without the application of electrical bias. We utilized the same concept and numerically studied the impact of electrical bias across the gold-graphene layers combined with silver and black Phosphorus layers which forms the SPR sensor surface. Our numerical  Not only that, our  Such dependence of sensitivity on the applied bias provides a dynamic tunability of the sensitivity and figure-of-merit (FOM) of the sensor to detect different types of cancer. In this work, we used the proposed heterostructure to detect six different types of cancers: Basal, Hela, Jurkat, PC12, MDA-MB-231, and MCF-7. Comparing our 2 to 1851.4 (deg/RIU) and FOM values ranging from 62.13 to 89.81 far above the values presented recently by other researchers."
1103,Prognostic significances of systemic inflammatory response markers in patients with synchronous esophageal and head and neck cancers.,"Wang CC, Hsu MH, Lee CT, Chen CJ, Hwang TZ, Wang HP, Lin JT, Wang WL.",https://pubmed.ncbi.nlm.nih.gov/38344911/," The neutrophil to lymphocyte (NLR), platelet to lymphocyte (PLR), and lymphocyte to monocyte ratios (LMRs), reflect the balance between pro-cancer inflammation and anti-cancer immune responses, but their role in HNSCC and synchronous cancer remain uncertain.
    


           The pretreatment NLR, LMR and PLRs were calculated and analyzed in comparison with the clinical factors.
    


          4%) were found to have synchronous ESCCs, and were associated with a significantly lower absolute lymphocyte count (p < 0.001), higher NLRs (p = 0.044) and lower LMRs (p = 0.001), but not PLRs (p = 0.49). The ROC curve for the presence of synchronous ESCC verified the optimal cutoff value as 2.5 for NLRs and 4.0 for LMRs. Multivariable logistic regression revealed that a LMR <4 (OR 2.22; 95% CI 1.27-3.88, p = 0.005), alcohol consumption (OR 4.19; 95% CI 1.47-11.91, p = 0.007), tumor location over the pharynx (OR 1.68; 95% CI 1.07-2.64, p = 0.025), and low body mass index (OR 0.94; 95% CI 0.88-0.99, p = 0.039) were risk factors for developing synchronous ESCC. A low-LMR was significantly associated with decreases in overall survival (p < 0.0001), in both synchronous and non-synchronous groups. Multivariate analysis demonstrated that LMR <4 (HR 1.97; 95% CI 1.38-2.81, p < 0.001), a low-BMI (HR 0.96; 95% CI 0.93-0.99, p = 0.044) and presence of synchronous ESCC (HR 1.56; 95% CI 1.10-2.22, p = 0.013) were independent prognostic factors for HNSCC patients.
    


          Conclusion:
        
      
      Incorporation of LMR into other identified risk factors, such as alcohol consumption, tumor location over pharynx, and low-BMI, may establish a more efficient screening program for esophageal exploration in HNSCC patients. The significances of LMR also suggest that anti-cancer immunity may play a role in the filed cancerization to initiate multiple cancers, and the immunotherapy may have potentials for prevention or as an adjuvant treatment for synchronous SCC in the future."
1104,New imaging approaches for understanding lung cancer response to treatment.,"de Ryk J, Namati E, Weydert J, Thiesse J, McLennan G.",https://pubmed.ncbi.nlm.nih.gov/18769370/,"The survival rate for lung cancer patients has barely improved over the past 30 years. New evaluation benchmarks for cancer response are needed to test therapy agents in a cost-effective and timely manner. From recent work, it is evident that primary lung cancers are very complex structures containing not only cancerous cells but also fibrotic and inflammatory cells and necrotic tissue. A greater understanding of the three-dimensional structure of primary lung cancer is emerging, allowing for the first time an appreciation of how this biomass is represented in medical imaging data. It is only through a greater understanding of the lung cancer biomass that we can define rational and early-response measures, including specific cellular responses such as cancer cell death or growth inhibition. In doing so, we can define response metrics that will shorten new drug discovery times and reduce costs, allowing for the evaluation of many more agents with therapeutic potential."
1105,USP28 is a potential prognostic marker for bladder cancer.,"Guo G, Xu Y, Gong M, Cao Y, An R.",https://pubmed.ncbi.nlm.nih.gov/24347490/,"This study was conducted to analyze the expression of the ubiquitin-specific protease Usp28 and assess its clinical significance in human bladder cancer. mRNA and protein expression levels of Usp28 were determined by real-time polymerase chain reaction (PCR) and Western blot in 24 paired bladder cancers and the adjacent non-cancerous tissues. In addition, the expression of Usp28 protein in 186 bladder cancers was also determined by immunohistochemistry. The relationship between expression of Usp28 and clinico-pathologic features and prognosis was finally evaluated. Usp28 was expressed at a higher level in bladder cancers compared to adjacent non-cancerous tissues at both the mRNA and protein levels in 24 paired samples (all P < 0.01). In immunohistochemical examination, 78 (41.9%) of 186 cases displayed low Usp28 expression in cancerous tissues, whereas 108 (58.1%) cases displayed high Usp28 expression. In the universal analysis, Usp28 correlated strongly with histopathological grade, clinical stage, tumor number and recurrence rate (P = 0.0001, 0.0001, 0.0001 and 0.0051, respectively), but did not correlate with gender or age (P = 0.5588 and 0.6574). After multiple analysis of the above factors and consideration of confounding factors, tumor number, histological grade, clinical stage, and recurrence were related to Usp28 expression (P = 0.001, 0.001, 0.001 and 0.001, respectively). Finally, Usp28 expression was indentified as a independent predictors of survival (P = 0.001). Usp28 protein expression is potentially valuable in prognostic evaluation of bladder cancer."
1106,Emerging technologies for salivaomics in cancer detection.,"Kaczor-Urbanowicz KE, Martín Carreras-Presas C, Kaczor T, Tu M, Wei F, Garcia-Godoy F, Wong DT.",https://pubmed.ncbi.nlm.nih.gov/27862926/,"Salivary diagnostics has great potential to be used in the early detection and prevention of many cancerous diseases. If implemented with rigour and efficiency, it can  Recently, extraordinary efforts have been taken to develop non-invasive technologies that can be applied without complicated and expensive procedures. Saliva is a biofluid that has demonstrated excellent properties and can be used as a diagnostic fluid, since many of the biomarkers suggested for cancers can also be found in whole saliva, apart from blood or other body fluids. The currently accepted gold standard  However, salivary diagnostics is a flourishing field with the rapid development of novel technologies associated with point-of-care diagnostics, RNA sequencing, electrochemical detection and liquid biopsy. Those technologies will help introduce population-based screening programs, thus enabling early detection, prognosis assessment and disease monitoring. The purpose of this review is to give a comprehensive update on the emerging diagnostic technologies and tools for the early detection of cancerous diseases based on saliva."
1107,The perceived impact of cancer on quality of life for post-treatment survivors of childhood cancer.,"Zebrack BJ, Landier W.",https://pubmed.ncbi.nlm.nih.gov/21452086/,"Purpose:
        
      
      To examine whether childhood cancer survivors' perceptions of the impact of cancer are related to quality of life (QOL) and psychological distress.
    


           Hierarchical linear regression models analyzed the independent effects of perceived impacts of cancer on distress and QOL and the extent to which positive and negative perceptions attenuated the effects of covariates on outcomes.
    


           Psychological distress and the mental health component of QOL appeared to be less influenced by sociodemographic status and health problems and more a function of how survivors perceive cancer as impacting their lives.
    


          Conclusions:
        
      
       Future research is needed to examine combinations of pharmacological, psychological and/or social interventions that are likely to "
1108,Tumor matrix protein collagen XIalpha1 in cancer.,"Raglow Z, Thomas SM.",https://pubmed.ncbi.nlm.nih.gov/25511741/,"The extracellular matrix is increasingly recognized as an essential player in cancer development and progression. Collagens are one of the most important components of the extracellular matrix, and have themselves been implicated in many aspects of neoplastic transformation. Collagen XI is a minor collagen whose main physiologic function is to regulate the diameter of major collagen fibrils. The α1 chain of collagen XI (colXIα1) has known pathogenic roles in several musculoskeletal disorders. Recent research has highlighted the importance of colXIα1 in many types of cancer, including its roles in metastasis, angiogenesis, and drug resistance, as well as its potential utility in screening tests and as a therapeutic target. High levels of colXIα1 overexpression have been reported in multiple expression profile studies examining differences between cancerous and normal tissue, and between beginning and advanced stage cancer. Its expression has been linked to poor progression-free and overall survival. The consistency of these data across cancer types is particularly striking, including colorectal, ovarian, breast, head and neck, lung, and brain cancers. This review discusses the role of collagen XIα1 in cancer and its potential as a target for cancer therapy."
1109,"Familial atypical multiple mole melanoma (FAMMM) syndrome: history, genetics, and heterogeneity.","Lynch HT, Shaw TG.",https://pubmed.ncbi.nlm.nih.gov/26892865/,"Approximately 5-10 % of cutaneous melanoma occurs in kindreds with a hereditary predisposition. Mutations in the CDKN2A gene are found to occur in approximately 20-40 % of these kindreds. The first historical mention of what is now called the familial atypical multiple mole melanoma syndrome appears to be from 1820, with more reports throughout the 1950s, 1960s, and later years. In 1991, Lynch and Fusaro described an association between familial multiple mole melanoma and pancreatic cancer and work continues to elucidate the syndrome's genotypic and phenotypic heterogeneity. Individuals at risk for familial melanoma need periodic screenings. Unfortunately, adequate screening for pancreatic cancer does not currently exist, but pancreatic cancer's prominence in the hereditary setting will hopefully act as a stimulus for development of novel screening measures."
1110,"Genetics, biomarkers, hereditary cancer syndrome diagnosis, heterogeneity and treatment: a review.","Lynch HT, Drescher K, Knezetic J, Lanspa S.",https://pubmed.ncbi.nlm.nih.gov/24827900/,"Molecular genetic pathways that drive the phenotypic and genotypic heterogeneity of hereditary colorectal cancer also can affect response to chemotherapy and chemoprevention. These mutations also can alter patients' response to therapy. Environmental differences can affect this highly complex conundrum. We will use Lynch syndrome as a model to explore this issue. However, to begin with, after more than a century of documentation, we must ask what is meant by the eponym ""Lynch syndrome"". Germline mutations may act as drivers of chemoprevention and chemotherapy and therein may act positively or conversely they may have a negative effect in terms of inhibiting the inactivation of cancer-causing germline mutations. A relatively new field of hereditary cancer therapeutics has significantly impacted cancer care, from the standpoint of the sensitivity or resistance to a particular form of chemotherapy and/or chemoprevention. The question for the diagnostician and therapist must always concern what is the best possible management approach for the patient, particularly when he or she harbors a cancer-causing germline mutation, which, in this case, causes Lynch syndrome. Continued molecular genetic research might yield a more tailored effective treatment for Lynch syndrome. The ultimate goal of such hereditary oncologic research is to better understand the mutation's therapeutic task, namely, its potential to benefit the patient in terms of its treatment goal, thereby fulfilling the essence of personalized medicine. However, this goal may be exceedingly complicated. For example, in the natural clinical and molecular genetic history of hereditary forms of cancer, there will be a predominance of early-onset cancers of multiple anatomic sites. In our Lynch syndrome model, these will be most commonly colorectal, endometrial, and ovarian cancer. Attention must initially be focused upon cancer's early age of onset coupled with the tendency to multiple primary cancers so that, in the case of CRC, colonoscopic screening must be initiated by age 20-25 years and repeated every other year until age 40 years and then annually thereafter. However, screening will be of limited efficacy in the gynecologic cancers (endometrial and ovarian) so that once the family is completed, particularly by age 35-40 years, careful attention must be given to the option of prophylactic hysterectomy and bilateral salpingo-oophorectomy. Given issues of tumor heterogeneity, selected Lynch syndrome families may show an excess of urologic cancers or cancers of the small bowel, and highly targeted screening should be given serious consideration for these as well as cancers of other anatomic sites in such high-risk, cancer-prone patients."
1111,"Expression of Lewis y antigen and integrin alphav, beta3 in ovarian cancer and their relationship with chemotherapeutic drug resistance.","Gao J, Hu Z, Liu D, Liu J, Liu C, Hou R, Gao S, Zhang D, Zhang S, Lin B.",https://pubmed.ncbi.nlm.nih.gov/23725446/," We further evaluate the relationship between their expression and chemotherapy resistance of ovarian cancer and its possible clinical significance.
    


           The expression and relationship of Lewis y antigen and integrin αv, β3 are assessed in paraffin sections using immunohistochemistry and double-labeling immunofluorescence  Multivariate logistic regression analysis was used to investigate the relationship between age, clinical stage, differentiation, histologic subtype, Lewis y antigen and integrin αv, β3 expression in ovarian cancer patients.
    


          05). Multivariate analysis showed that the expression of Lewis y antigen, integrin αv and ovarian cancer's clinical stage were independent, drug resistance-related risk factors. The expression levels of Lewis y antigen and integrin αv, β3 were positively correlated with each other.
    


          Conclusions:
        
      
      A close correlation between Lewis y antigen, integrin αv, β3 and ovarian cancer was observed. Lewis y antigen can influence the biological behavior of a tumor cell as an important composition of integrin αv, β3 by some signal pathway. And the expression of Lewis y antigen, integrin αv and ovarian cancer's clinical stage are both independent, drug resistance-related risk factors."
1112,Early identification of esophageal squamous neoplasm by hyperspectral endoscopic imaging.,"Wu IC, Syu HY, Jen CP, Lu MY, Chen YT, Wu MT, Kuo CT, Tsai YY, Wang HC.",https://pubmed.ncbi.nlm.nih.gov/30218087/,"Esophageal squamous neoplasm presents a spectrum of different diatheses. A precise assessment for individualized treatment depends on the accuracy of the initial diagnosis. Detection relies on comprehensive and accurate white-light, iodine staining, and narrow-band imaging endoscopy. These  These limitations include difficulties in precise tumor delineation to enable complete resection, inflammation and malignancy differentiation, and stage determination. The resolution of these problems depends on the surgeon's ability and experience with available technology for visualization and resection. We proposed a   The narrow-band imaging (NBI) image shows remarkable spectral characteristic distribution, and the sensitivity and specificity of the proposed 8 and ~0.88, respectively. The proposed "
1113,Multifocal epithelial tumors and field cancerization: stroma as a primary determinant.,Dotto GP.,https://pubmed.ncbi.nlm.nih.gov/24691479/,"It is increasingly evident that cancer  This applies especially to epithelial cancer, the most common form of human solid tumors and a major cause of cancer lethality. In the vast majority of cases, in situ epithelial cancer lesions do not progress into malignancy, even if they harbor many of the genetic changes found in invasive and metastatic tumors. While changes in tumor stroma are frequently viewed as secondary to changes in the epithelium, recent evidence indicates that they can play a primary role in both cancer progression and initiation. These processes may explain the phenomenon of field cancerization, i.e., the occurrence of multifocal and recurrent epithelial tumors that are preceded by and associated with widespread changes of surrounding tissue or organ ""fields."""
1114,Expression of CDC25 phosphatases in human gastric cancer.,"Xing X, Chen J, Chen M.",https://pubmed.ncbi.nlm.nih.gov/17934831/," CDC25 phosphatases comprise a multigene family, including CDC25A and CDC25B, that plays a crucial role in the control of cell cycle progression and has been linked to the development of human cancers. The role of CDC25 phosphatases in the pathogenesis of gastric cancers is, however, still largely unknown.
    


          Material and 
    


           In gastric cancer tissues, the enhanced immunoreactivity of CDC25 phosphatases was independent of intestinal or diffuse type of gastric cancer. However, the intensity of immunostaining was related to the grade of differentiation of the tumors. Interestingly, c-myc expression was directly correlated with CDC25A and B expression.
    


          Conclusions:
        
      
      The overexpression of CDC25A and B seems to be a common and very early event in the development of both intestinal and diffuse types of gastric cancer and may play an important role in gastric carcinogenesis."
1115,Contralateral lymph node metastases in patients with vulvar cancer and unilateral sentinel lymph node metastases.,"Ignatov T, Gaßner J, Bozukova M, Ivros S, Mészáros J, Ortmann O, Eggemann H, Ignatov A.",https://pubmed.ncbi.nlm.nih.gov/33811323/,"
    


          Material and  The primary outcome measure was the rate of contralateral non-SLN metastases in the case of positive unilateral SLN.
    


           Out of 66 patients with unilateral metastatic SLN, 62 (93.9%) received contralateral lymphadenectomy-18 after unilateral and 44 after bilateral SLN biopsy. In the study group, 132 SLN were assessed with a median number of 2 (range 1-4) per patient and 76 of these were positive. Lymph node-positivity was associated with advanced tumor stage, as well as lymph and vascular space invasion. In the group of patients with bilateral inguino-femoral lymphadenectomy, 1004 lymph nodes were resected with a median number of 15 (range 10-29) per patient. After full dissection of the inguino-femoral lymph nodes, no contralateral non-SLN metastases were found.
    


          Conclusions:
        
      
      The risk of contralateral non-SLN metastases in patients with unilateral SLN metastases was low. Therefore, the impact of contralateral lymphadenectomy on patient survival should be investigated in further studies."
1116,Exosomal hsa-miR-151a-3p and hsa-miR-877-5p are potential novel biomarkers for predicting bone metastasis in lung cancer.,"Zhao K, Jia C, Wang J, Shi W, Wang X, Song Y, Peng C.",https://pubmed.ncbi.nlm.nih.gov/38180107/,"Exosomal miRNAs (exo-miRNAs) have arisen as novel diagnostic biomarkers for various cancers. However, few reports on exo-miRNAs related to bone metastasis (BM) in lung cancer exist. This study aims to screen out key exo-miRNAs and estimate their prognostic values for predicting BM in lung cancer. The differentially expressed exo-miRNAs between the highly-metastatic (95D) and lowly-metastatic (A549) human lung cancer cell lines were comprehensively analyzed using high-throughput sequencing followed by bioinformatic analyses. 29 candidate exo-miRNAs were identified, and 101 BM-related target genes were predicted. Enrichment analysis revealed that these target genes were mainly involved in regulating transcription and pathways in cancer. An exosomal miRNA-mRNA regulatory network consisting of 7 key miRNAs and 10 hub genes was constructed. Further function analysis indicated that these 10 hub genes were mainly enriched in regulating cancer's apoptosis and central carbon metabolism. The survival analysis indicated that 7 of 10 hub genes were closely related to prognosis. Mutation analysis showed that lung cancer patients presented certain genetic alterations in the 7 real hub genes. GSEA for a single hub gene suggested that 6 of 7 real hub genes had close associations with lung cancer development. Finally, ROC analysis revealed that hsa-miR-151a-3p and hsa-miR-877-5p provided high diagnostic accuracy in discriminating patients with bone metastasis (BM+) from patients without bone metastasis (BM-). These findings provided a comprehensive analysis of exo-miRNAs and target genes in the regulatory network of BM in lung cancer. In particular, hsa-miR-151a-3p and hsa-miR-877-5p may be novel biomarkers for predicting BM in lung cancer."
1117,Custom designing therapeutic cancer vaccines: delivery of immunostimulatory molecule adjuvants by protein transfer.,"Selvaraj P, Yerra A, Tien L, Shashidharamurthy R.",https://pubmed.ncbi.nlm.nih.gov/18382145/,"Attempts to create vaccines for humans against invading pathogens such as viruses and bacteria have met with tremendous success. The process of developing vaccines against these pathogens is greatly aided by the fact that they contain antigens that are entirely foreign to humans. Although the knowledge and strategies developed for designing vaccines against these microbes may be of use in developing cancer vaccines, the poor antigenicity and immunosuppressive ability of cancers pose major hurdles to vaccine development. Established tumors have not only withstood immune screening and selection pressure, making them poor stimulators of an immune response, but have also adapted mechanisms to continue evading immune surveillance by creating an immunosuppressive environment. Also, genetic differences in immune responses to an antigen among individuals  Cancers bear such great similarities to normal cells in the body that, on a molecular level, the differences between cancerous and non-cancerous cells are minor. Therefore, developing vaccines which use the host's own tumor tissues carries the risk of breaking tolerance to self-antigens that are present in the tumor tissue. Vaccination strategies that will optimally stimulate the immune system against tumor specific antigens under immunosuppressive conditions need to be developed. In practical terms, this calls for a  Ex vivo manipulation of dendritic cells and gene transfer of immunostimulatory molecules in ex vivo expanded tumors are being tested in both  Some of them have met with limited success. Emerging technologies such as protein transfer, which make it possible to express immunostimulatory molecules on tumor cell membranes, offer the means to develop efficient tumor vaccines that are simple and fast, while being easy to store and administer in human patients. Progress in these techniques will move the cancer vaccine field a step closer towards realizing custom designed cancer vaccines in human clinical settings."
1118,"Evolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients.","Fontana D, Crespiatico I, Crippa V, Malighetti F, Villa M, Angaroni F, De Sano L, Aroldi A, Antoniotti M, Caravagna G, Piazza R, Graudenzi A, Mologni L, Ramazzotti D.",https://pubmed.ncbi.nlm.nih.gov/37749078/,"Recurring sequences of genomic alterations occurring across patients can highlight repeated evolutionary processes with significant implications for predicting cancer progression. Leveraging the ever-increasing availability of cancer omics data, here we unveil cancer's evolutionary signatures tied to distinct disease outcomes, representing ""favored trajectories"" of acquisition of driver mutations detected in patients with similar prognosis. We present a framework named ASCETIC (Agony-baSed Cancer EvoluTion InferenCe) to extract such signatures from sequencing  We apply ASCETIC to (i) single-cell data from 146 myeloid malignancy patients and bulk sequencing from 366 acute myeloid leukemia patients, (ii) multi-region sequencing from 100 early-stage lung cancer patients, (iii) exome/genome data from 10,000+ Pan-Cancer Atlas samples, and (iv) targeted sequencing from 25,000+ MSK-MET metastatic patients, revealing subtype-specific single-nucleotide variant signatures associated with distinct prognostic clusters. Validations on several datasets underscore the robustness and generalizability of the extracted signatures."
1119,Sulindac induces apoptosis and protects against colon carcinoma in mice.,"Sun BC, Zhao XL, Zhang SW, Liu YX, Wang L, Wang X.",https://pubmed.ncbi.nlm.nih.gov/15884131/,"Aim:
        
      
      To study the effect of sulindac on colon cancer induction in mice.
    


           Using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) technique and PCNA immunohistochemical staining, we observed the apoptotic and proliferative cell density changes at different carcinogenic stages and the effect of sulindac on these two phenomena.
    


           Compared with the control group, feeding sulindac during initiation and post-initiation stages inhibited the incidence by 46.7-50.4%, and feeding sulindac during progressive stages inhibited the incidence by 41.1%. Animals that were fed sulindac showed less serious pathological changes than those that were fed the control diet (P<0.01, H = 33.35). There was no difference in the density of proliferating cells among those groups which were or were not fed sulindac. In the same period, feeding sulindac 
    


          Conclusion:
        
      
      Sulindac has an anti-carcinogenic function in mice. Its effect on preventing colon carcinogenesis is better than its effect on treating established tumors. By inducing apoptosis, sulindac inhibited the development of colon cancer and delayed canceration. Sulindac has no effect on proliferation. The anti-carcinogenic properties of sulindac are most effective in the moderate and severe stages of dysplasia and canceration."
1120,Natural Compound Allicin Containing Thiosulfinate Moieties as Transmembrane Protein 16A (TMEM16A) Ion Channel Inhibitor for Food Adjuvant Therapy of Lung Cancer.,"Bai X, Cheng Y, Wan H, Li S, Kang X, Guo S.",https://pubmed.ncbi.nlm.nih.gov/36574498/,"Cancer is one of the most serious malignant diseases, and chemotherapy is cancer's main clinical treatment  However, chemotherapy inevitably produces drug resistance, and side effects accompany them. Adjuvant therapy is an effective way to enhance chemotherapeutic drug sensitivity and reduce side effects. This study found allicin, garlic's active ingredient, is an inhibitor of transmembrane protein 16A (TMEM16A), a novel drug target of lung adenocarcinoma. Allicin concentration-dependently inhibited TMEM16A currents with an IC50 of 24.35 ± 4.14 μM. Allicin thiosulfinate moieties bound with R535A/E624A/E633A residues of TMEM16A blocked the ion transport function and downregulated TMEM16A protein expression affecting the mitogen-activated protein kinase signal transduction. Then, allicin reduced the viability and migration of LA795 cells, and induced cell apoptosis. Moreover, multitarget combination administration 56 mg/kg allicin and 3 mg/kg cisplatin combined administration was superior to the superposition of the two drugs alone, demonstrating that the anticancer effects of allicin and cisplatin were synergistic. In addition, low-concentration combined administration also avoided the side effects of cisplatin in mice. Based on the good tumor suppressor effect and high biosafety of allicin and cisplatin combination in vivo, allicin can be used for food adjuvant therapy of cisplatin chemotherapy."
1121,"Diagnostic and prognostic impact of cytokeratin 18 expression in human tumors: a tissue microarray study on 11,952 tumors.","Menz A, Weitbrecht T, Gorbokon N, Büscheck F, Luebke AM, Kluth M, Hube-Magg C, Hinsch A, Höflmayer D, Weidemann S, Fraune C, Möller K, Bernreuther C, Lebok P, Clauditz T, Sauter G, Uhlig R, Wilczak W, Steurer S, Minner S, Burandt E, Krech R, Dum D, Krech T, Marx A, Simon R.",https://pubmed.ncbi.nlm.nih.gov/33588765/,"
    


          
    


           At least an occasional weak CK18 positivity was seen in 90 of 115 (78.3%) tumor types. Wide-spread CK18 positivity was seen in 37 (31.9%) of tumor entities, including adenocarcinomas of the lung, prostate, colon and pancreas as well as ovarian cancer. Tumor categories with variable CK18 immunostaining included cancer types arising from CK18 positive precursor cells but show CK18 downregulation in a fraction of cases, tumor types arising from CK18 negative precursor cells occasionally exhibiting CK18 neo-expression, tumors derived from normal tissues with variable CK18 expression, and tumors with a mixed differentiation. CK18 downregulation was for example seen in renal cell cancers and breast cancers, whereas CK18 neo-expression was found in squamous cell carcinomas of various origins. Down-regulation of CK18 in invasive breast carcinomas of no special type and clear cell renal cell carcinomas (ccRCC) was related to adverse tumor features in both tumors (p ≤ 0.0001) and poor patient prognosis in ccRCC (p = 0.0088). Up-regulation of CK18 in squamous cell carcinomas was linked to high grade and lymph node metastasis (p < 0.05). In summary, CK18 is consistently expressed in various epithelial cancers, especially adenocarcinomas.
    


          Conclusions:
        
      
      Down-regulation or loss of CK18 expression in cancers arising from CK18 positive tissues as well as CK18 neo-expression in cancers originating from CK18 negative tissues is linked to cancer progression and may reflect tumor dedifferentiation."
1122,Restoring cancer's death sentence.,Letai A.,https://pubmed.ncbi.nlm.nih.gov/17097553/,"In this issue of Cancer Cell, two groups present data on the function of an antagonist of BCL-2, ABT-737. Both groups find that expression of MCL-1, an antiapoptotic protein related to BCL-2, is a key determinant of resistance to ABT-737. Lowering MCL-1 levels is an effective adjunct to BCL-2 antagonism, and both groups suggest ways that this might be accomplished practically in a clinical setting. The mechanism by which ABT-737 selectively kills cancer cells is discussed below in the context of these and prior reports of ABT-737's function. Antagonism of BCL-2 is an exciting anticancer strategy that may soon become a clinical reality."
1123,The intrapersonal and interpersonal processes of fear of recurrence among cervical cancer survivors: a qualitative study.,"Hamama-Raz Y, Shinan-Altman S, Levkovich I.",https://pubmed.ncbi.nlm.nih.gov/34817691/," Fear of cancer recurrence has been identified as prominent in patients and survivors, yet there is a paucity of studies regarding this population. The present study sought to explore and expand the understanding of the meaning of fear of cancer recurrence among cervical cancer survivors.
    


           The interviewees' mean age was 41.33 years (range 34-47 years), and the mean time since diagnosis was 3.1 years (ranged from 0.5 to 7 years).
    


           The second, ""To be afraid in a dyad,"" relates to the interpersonal level that included mutual fears shared by the interviewee and her partner. The third ""And what if the disease comes back and I die?"" represents a combination of intrapersonal and interpersonal processes manifested by the greatest fear - death - expressed by both the interviewee and her partner.
    


          Conclusions:
        
      
      The present findings revealed that the fear of cancer recurrence represents intrapersonal and interpersonal processes encompassing three factors - uncertainty, social-cognitive processing, and death anxiety. Accordingly, potential psycho-social treatment options could be tailored to specifically address the prominence of these factors for cervical cancer survivors."
1124,Oropharyngeal squamous cell carcinoma and human papillomavirus-associated cancers in women: epidemiologic evaluation of association.,"Biron VL, Côté DW, Seikaly H.",https://pubmed.ncbi.nlm.nih.gov/21453664/," The 
    


           A review of pathology reports in these patients was undertaken to identify HPV-related cancerous lesions of the cervix. Standardized incidence ratios (SIRs) of cervical cancer in oropharyngeal cancer patients were calculated using control data obtained from provincial cancer surveillance. Overall and disease-specific survival of patients with OPSCC only versus patients with OPSCC and cervical cancer was calculated using Kaplan-Meier and Cox regression models.
    


          4, 95% CI 12.05-74.98). Patients with OPSCC and cervical cancer also had a significantly improved disease-specific survival in comparison to patients with no history of cervical cancer.
    


          Conclusions:
        
      
      Women with OPSCC have a significantly elevated risk of developing HPV-related genital cancers, which suggests frequent HPV coinfection of oropharyngeal and genital tissues in this patient population. Women with OPSCC with cervical cancer also have an improved disease-specific survival, as previously shown with HPV-associated OPSCC."
1125,Cancer chemoprevention.,"Hong WK, Lippman SM.",https://pubmed.ncbi.nlm.nih.gov/8573453/,"A new direction for cancer prevention and control is chemoprevention, defined as the use of specific natural and synthetic chemical agents to reverse or suppress carcinogenesis and prevent the development of invasive cancer. The chemopreventive approach depends on the ability of certain chemical agents to block mutagenesis and control cellular differentiation and proliferation in epithelial tissues. Support for the chemopreventive approach is based on the biologic concepts of field cancerization and multistep carcinogenesis, as well as the clinical efficacy already shown by agents such as retinoids and tamoxifen in reversing premalignancy and preventing second primary tumors. Although chemoprevention is not yet established as a standard therapy, the  The development of more effective, less toxic chemopreventive agents remains a high priority in furthering the use of this clinically valuable approach to the prevention and control of cancer."
1126,"Heat-stable alkaline phosphatase in uterine cancer, with special reference to its histochemical heat-stability and the L-phenylalanine inhibition test.","Nozawa S, Ohta H, Izumi S, Hayashi S, Tsutsui F, Kurihara S, Watanabe K.",https://pubmed.ncbi.nlm.nih.gov/7338483/,"We report a histochemical study of alkaline phosphatase (ALP) in normal cells of the female reproductive system, in pre-cancerous and cancerous lesions of the uterine cervix and in endometrial cancer to ascertain the incidence of ALP and its isoenzyme type. For this purpose, serial sections were subjected to heat stability and L-phenylalanine (LP) inhibition tests. The Regan-like isoenzyme, a heat-stable and LP-sensitive ALP, which has been thought to derive only from cancer or the placenta, was found in uterine cervical reserve cells and endometrial luminal surface lining cells. In contrast, ALP activity in endometrial glandular cells was found to be heat and LP sensitive. Of 183 cases of cervical neoplasia, 60 (33%) manifested non-specific ALP activity. One dysplasia and two invasive cancer cases manifested the Regan-like isoenzyme. The other 36 classifiable lesions had small-intestine ALP-like activity (marked heat and LP sensitivity) or a liver ALP-like isoenzyme (marked heat and slight LP sensitivity). Of 42 cases of endometrial cancer, all cases manifested non-specific ALP activity. Seven endometrial cancers exhibited the Regan-like isoenzyme. The other 19 cases manifested either small intestine or liver ALP-like isoenzyme. Our findings indicate that in the course of uterine carinogenesis, the ALP isoenzyme of reserve cell and endometrial glandular cells undergo a change and that enzyme deviation occurs."
1127,"EPA, DHA, and resolvin effects on cancer risk: The underexplored mechanisms.","Kiyasu Y, Zuo X, Liu Y, Yao JC, Shureiqi I.",https://pubmed.ncbi.nlm.nih.gov/38825147/,"Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplements have exhibited inconsistent effects on cancer risk, and their potential efficacy as cancer preventive agents has been increasingly questioned, especially in recent large randomized clinical trials. The role of host factors that govern EPA and DHA metabolism in relation to their impact on carcinogenesis remains understudied. Resolvins, the products of EPA and DHA oxidative metabolism, demonstrate intriguing antitumorigenic effects through mechanisms such as promoting macrophage phagocytosis of cell debris and inhibiting the production of proinflammatory chemokines and cytokines by tumor-associated macrophages (TAMs), which are crucial for cancer progression. However, clinical studies have not yet shown a significant increase in target tissue levels of resolvins with EPA and DHA supplementation. 15-Lipoxygenase-1 (ALOX15), a key enzyme in EPA and DHA oxidative metabolism, is often lost in various major human cancers, including precancerous and advanced colorectal cancers. Further research is needed to elucidate whether the loss of ALOX15 expression in colorectal precancerous and cancerous cells affects EPA and DHA oxidative metabolism, the formation of resolvins, and subsequently carcinogenesis. The findings from these studies could aid in the development of novel and effective chemoprevention interventions to reduce cancer risk."
1128,Risk assessment of oral cancer in patients with pre-cancerous states of the oral cavity using micronucleus test and challenge assay.,"Saran R, Tiwari RK, Reddy PP, Ahuja YR.",https://pubmed.ncbi.nlm.nih.gov/17936677/,"Oral cancer is a common malignancy, ranking first among all cancers in Western and Asian countries. Use of tobacco is regarded as a major risk factor, along with age and gender. Oral cancer is preceded by some benign lesions or conditions, which are termed pre-cancerous. Only one-third of people at the pre-cancerous stage of disease succumb to cancer. No biomarker is available to identify people with pre-cancerous lesions or conditions at high risk of developing cancer. The focus of this study was to explore such biomarkers. The study included 129 untreated people with cancer, 138 untreated people at the pre-cancerous stage and 176 control participants. For statistical analysis of this data, analysis of variance and t-test were used. Three biomarkers (i.e. micronucleus test [MNT], comet assay and challenge comet assay were used. MNT and comet assay were carried out on buccal epithelial cells. In addition, challenge comet assay was carried out on peripheral blood leucocytes by using mutagen MNNG sensitivity of DNA after DNA repair. A significant stepwise increase in the DNA damage (basal/MNNG-treated/post-repair) was observed in buccal epithelial cells and peripheral blood leucocytes from control to pre-cancer patients and from pre-cancer to cancer patients. Micronucleus frequency also increased in the same way. Considerable inter-individual and inter-cellular variability in DNA damage was observed, which increased from control to pre-cancer patients and from pre-cancer to cancer patients. The outliers among patients with pre-cancerous states were identified on the basis of more than mean +2 SD limits for comet tail length, as well as mean percentage of micronuclei. Hence, those participants whose cells showed high basal DNA damage, extreme sensitivity to MNNG and reduced repair were identified as high-risk individuals."
1129,"Concurrent expression of aryl hydrocarbon receptor and CYP1A1 but not CYP1A1 MspI polymorphism is correlated with gastric cancers raised in Dalian, China.","Ma JX, Zhang KL, Liu X, Ma YL, Pei LN, Zhu YF, Zhou L, Chen XY, Kong QY, Li H, Liu J.",https://pubmed.ncbi.nlm.nih.gov/16337337/,"The frequency of cancer-associated m2m2- (C-) genotype of CYP1A1 and the factors contributing to the increased CYP1A1 expression in gastric cancers (GCs) are largely unknown. To address theses issues, PCR-restriction fragment length polymorphism (PCR-RFLP) was performed to elucidate the MspI polymorphism in 60 GC cases and 57 normal donor samples. The frequencies of m1m1-, m1m2- and m2m2-genotype were 43.3, 45 and 11.7% among GC patients and 45.6, 49.1 and 5.3% among the normal donors respectively, demonstrating no significant difference of them between cancer and control groups (chi(2)=0.343, P=0.558). The correlation of Aryl hydrocarbon receptor (AhR) with the frequent CYP1A1 expression in stepwise gastrocarcinogenesis was determined by RT-PCR, immunohistochemical staining (IHC) and Western blotting, using GC samples as well as their pre-malignant and non-cancerous counterparts. RT-PCR revealed that the AhR detection rates were 100, 94.12 and 85.17% in GC, pre-malignant and non-cancerous mucosa (P>0.05) respectively but the level of AhR expression in GCs was much higher than that of non-cancerous tissues. IHC showed that the frequencies of AhR detection were 94.87% (37/39) in GCs, 94.12% (16/17) in pre-malignant lesions and 50% (3/6) in non-cancerous mucosa, revealing significant difference in frequencies of AhR detection and levels of AhR expression between GC or pre-malignant group and non-cancerous one (P<0.05). The frequency of AhR nucleus translocation was significantly high in GCs (94.87%; 37/39) than that in pre-malignant (70.59%; 12/17) and especially in non-cancerous group (16.67%; 1/6). Co-existence of AhR nuclear translocation and CYP1A1 expressions were found in 82.70% (43/52) of GCs (r(s)=0.437, P<0.01). Our "
1130,"A qualitative exploration of the meaning of the term ""survivor"" to young women living with a history of breast cancer.",Rees S.,https://pubmed.ncbi.nlm.nih.gov/29630750/,"There has been a recent increase in research considering the perceptions of the term ""cancer survivor"" held by individuals who have or have had cancer. This article explores the meaning of the term to young women living with a history of breast cancer. Twenty women participated in semi-structured interviews about their experience of breast cancer. The  Three of the women interviewed said they would use the term survivor to describe themselves, but most of the women felt it did not fit with their experiences. The accounts of those who accepted and rejected the survivor identity are explored, and subthemes in the latter are ""survivor as somebody else"" and ""cancer's ongoing presence."" This article calls into question the basing of intervention strategies on the notion of the ""cancer survivor,"" and the assumption that younger women favour the survivor identity. Participants struggled with the demand to live up to the ideal of the survivor, which implied a high degree of agency where in reality, cancer was a disempowering experience. Being labelled a survivor obscured ongoing impacts of cancer on the young women's lives."
1131,Immunometabolism at the Nexus of Cancer Therapeutic Efficacy and Resistance.,"Traba J, Sack MN, Waldmann TA, Anton OM.",https://pubmed.ncbi.nlm.nih.gov/34079545/,"Constitutive activity of the immune surveillance system detects and kills cancerous cells, although many cancers have developed strategies to avoid detection and to resist their destruction. Cancer immunotherapy entails the manipulation of components of the endogenous immune system as targeted approaches to control and destroy cancer cells. Since one of the major limitations for the antitumor activity of immune cells is the immunosuppressive tumor microenvironment (TME), boosting the immune system to overcome the inhibition provided by the TME is a critical component of oncotherapeutics. In this article, we discuss the main effects of the TME on the metabolism and function of immune cells, and review emerging strategies to potentiate immune cell metabolism to promote antitumor effects either as monotherapeutics or in combination with conventional chemotherapy to optimize cancer management."
1132,MCMs in Cancer: Prognostic Potential and Mechanisms.,"Yu S, Wang G, Shi Y, Xu H, Zheng Y, Chen Y.",https://pubmed.ncbi.nlm.nih.gov/32089988/,"Enabling replicative immortality and uncontrolled cell cycle are hallmarks of cancer cells. Minichromosome maintenance proteins (MCMs) exhibit helicase activity in replication initiation and play vital roles in controlling replication times within a cell cycle. Overexpressed MCMs are detected in various cancerous tissues and cancer cell lines. Previous studies have proposed MCMs as promising proliferation markers in cancers, while the prognostic values remain controversial and the underlying mechanisms remain unascertained. This review provides an overview of the significant findings regarding the cellular and tumorigenic functions of the MCM family. Besides, current evidence of the prognostic roles of MCMs is retrospectively reviewed. This work also offers insight into the mechanisms of MCMs prompting carcinogenesis and adverse prognosis, providing information for future research. Finally, MCMs in liver cancer are specifically discussed, and future perspectives are provided."
1133,The levels and trends of cancer incidence in the elderly population at national and sub-national scales in Iran from 1990 to 2016.,"Shokri Varniab Z, Saeedi Moghaddam S, Pourabhari Langroudi A, Azadnajafabad S, Mortazavi SS, Sheidaei A, Gohari K, Farzi Y, Shirzad Moghaddam Z, Sohrabi H, Shati M.",https://pubmed.ncbi.nlm.nih.gov/38049962/," It is necessary to gain a better understanding of cancer's trend and distribution among elderlies and provide comprehensive cancer care for this population.
    


          Aims:
        
      
      The aim of the current study was to show the trends in cancer incidence focusing on the population aged 60+ from 1990 to 2016 in Iran.
    


          Material and  In order to account for incomplete data we used a two-stage spatiotemporal model along with random intercept mixed effect models. We calculated annual age-standardized incidence rates (ASIRs) for age groups 60+ and 5-interval age groups. There was an increasing trend of 25.3% to 936.9% (95% uncertainty interval: 769.6-1141.8) in ASIR in the elderly in 2016. ASIR of all cancers were 889.7 (731.3-1083.6) in women and 988.1 (811.1-1205) in men in 2016, per 100 000 respectively, which had an increasing trend comparing 1990. Skin, breast, and stomach cancers in women and prostate, skin, and stomach cancers in men were the most common types in 2016. All the most incident cancer subtypes underwent an increasing trend in both sexes, except for the bladder, esophageal, and skin cancers which almost had a similar level in 1990 and 2016. Most provinces had an increasing trend in ASIR in all cancers combined from 1990 to 2016 except Zanjan with a decreasing trend.
    


          Conclusion:
        
      
      Regarding the persistent increasing trend of most elderly cancers' incidence, this is crucial for policymakers to establish preventive plans, determine proper resource allocation, and develop specific treatments for elderly cancer patients."
1134,MicroRNA-based therapeutics for cancer.,"Wang V, Wu W.",https://pubmed.ncbi.nlm.nih.gov/19344188/,"MicroRNAs (miRNAs) are non-protein-coding small RNA molecules that negatively regulate target messenger RNA through degradation or suppression of protein translation. MiRNAs play important roles in the control of many biologic processes, such as development, differentiation, proliferation, and apoptosis. Increasing evidence shows that aberrant miRNA expression profiles and unique miRNA signaling pathways are present in a variety of cancers. MiRNAs function as oncogenes or tumor suppressors during tumor development and progression.  MiRNA-based gene therapy provides an attractive anti-tumor approach for integrated cancer therapy. In this review, we focus on miRNA-based treatment for cancers, summarize the delivery systems used in "
1135,Prenatal X-ray Exposure and the Risk of Developing Pediatric Cancer-A Systematic Review of Risk Markers and a Comparison of International Guidelines.,"Wit F, Vroonland CCJJ, Bijwaard H.",https://pubmed.ncbi.nlm.nih.gov/34261894/,"Since the first Oxford Survey of Childhood Cancer's  As a  In this review, the  The current international guidelines for diagnostic x-ray examinations were compared to the review. All epidemiological studies starting from 2007 and all relevant international guidelines were included. Apart from one study that involved rhabdomyosarcoma, no statistically significant associations were found between prenatal exposure to x rays and the development of cancer during 2007-2020. Most of the studies were constrained in their design due to too small a cohort or number of cases, minimal x-ray exposure, and/or data obtained from the exposed mothers instead of medical reports. In one of the studies, computed tomography exposure was also included, and this requires more and longer follow-up in successive studies. Most international guidelines are comparable, provide risk coefficients that are quite conservative, and discourage abdominal examinations of pregnant women."
1136,Gene expression in inherited breast cancer.,"Hedenfalk IA, Ringnér M, Trent JM, Borg A.",https://pubmed.ncbi.nlm.nih.gov/11883525/,"Large proportions of hereditary breast cancers are due to mutations in the two breast cancer susceptibility genes BRCA1 and BRCA2. Considerable effort has gone into studying the function(s) of these tumor suppressor genes, both in attempts to better understand why individuals with these inherited mutations acquire breast (and ovarian) cancer and to potentially develop better treatment strategies. The advent of tools such as cDNA microarrays has enabled researchers to study global gene expression patterns in, for example, primary tumors, thus providing more comprehensive overviews of tumor development and progression. Our recent study (Hedenfalk et al., 2001) strongly supports the principle that genomic approaches to classification of hereditary breast cancers are possible, and that further studies will likely identify the most significant genes that discriminate between subgroups and may influence prognosis and treatment. A large number of hereditary breast cancer cases cannot be accounted for by mutations in these two genes and are believed to be due to as yet unidentified breast cancer predisposition genes (BRCAx). Subclassification of these non-BRCA1/2 breast cancers using cDNA microarray-based gene expression profiling, followed by linkage analysis and/or investigation of genomic alterations, may help in the recognition of novel breast cancer predisposition loci. To summarize, gene expression-based analysis of hereditary breast cancer can potentially be used for classification purposes, as well as to expand upon our knowledge of differences between different forms of hereditary breast cancer. Initial studies indicate that a patient's genotype does in fact leave an identifiable trace on her/his cancer's gene expression profile."
1137,NMR in cancer. VII. Sodium-23 magnetic resonance of normal and cancerous tissues.,"Goldsmith M, Damadian R.",https://pubmed.ncbi.nlm.nih.gov/171689/,"Sodium-23 magnetic resonance was performed on four types of cancers and six types of normal tissues of rats and mice. The spin-lattice relaxation time of the tumors was generally longer than that of the normal tissues, with the most marked difference occurring between rat liver (T1 = 6.5 msec) and Novikoff hepatoma (T1 =23.7 msec). Estimation of tissue sodium from the signal intensity of the resonance indicated that all four types of tumors contained more sodium than any of the normal tissues."
1138,[Cancer trends in hospital morbidity and lethality].,"Guanche Garcell H, García Arzola E, González Isla J, Salomón Zaldivar E, Pérez Montero P.",https://pubmed.ncbi.nlm.nih.gov/17373862/,"
    


           We obtain information about admission, total and for cancer, deceased patients and lethality rates (deceased for cancer/admission for cancer x 100). From the 2005 admission we obtain age, sex, cause of admission, and if the diagnostic of cancer was doing during this admission or before.
    


          99% in 2005. Lethality rates have an irregular behavior with smaller rate in 1999 (12.7%) and bigger in 2001 (27.86%). Internal Medicine service gave care to 60.71% of cancer admission, with less frequency in general surgery service (26.81%). 44% of patients were diagnosed during this admission, and 56% the diagnosis was doing in previous admission, of which 42.1% were admitted to treatment (surgical and drugs) and 53.5% for cancer complications.
    


          Conclusions:
        
      
      We show a continuous increased trend in hospital cancer morbidity. It is a commit to modify healthcare's strategies of cancer patient addressed to guarantee the quality of services in front of the increased demand."
1139,Mutational landscape of cancer-driver genes across human cancers.,Sinkala M.,https://pubmed.ncbi.nlm.nih.gov/37550388/,"The genetic mutations that contribute to the transformation of healthy cells into cancerous cells have been the subject of extensive research. The molecular aberrations that lead to cancer development are often characterised by gain-of-function or loss-of-function mutations in a variety of oncogenes and tumour suppressor genes. In this study, we investigate the genomic sequences of 20,331 primary tumours representing 41 distinct human cancer types to identify and catalogue the driver mutations present in 727 known cancer genes. Our findings reveal significant variations in the frequency of cancer gene mutations across different cancer types and highlight the frequent involvement of tumour suppressor genes (94%), oncogenes (93%), transcription factors (72%), kinases (64%), cell surface receptors (63%), and phosphatases (22%), in cancer. Additionally, our analysis reveals that cancer gene mutations are predominantly co-occurring rather than exclusive in all types of cancer. Notably, we discover that patients with tumours displaying different combinations of gene mutation patterns tend to exhibit variable survival outcomes. These findings provide new insights into the genetic landscape of cancer and bring us closer to a comprehensive understanding of the underlying mechanisms driving the development of various forms of cancer."
1140,Double face of cytochrome c in cancers by Raman imaging.,"Abramczyk H, Brozek-Pluska B, Kopeć M.",https://pubmed.ncbi.nlm.nih.gov/35136078/,"Cytochrome c (Cyt c) is a key protein that is needed to maintain life (respiration) and cell death (apoptosis). The dual-function of Cyt c comes from its capability to act as mitochondrial redox carrier that transfers electrons between the membrane-embedded complexes III and IV and to serve as a cytoplasmic apoptosis-triggering agent, activating the caspase cascade. However, the precise roles of Cyt c in mitochondria, cytoplasm and extracellular matrix under normal and pathological conditions are not completely understood. To date, no pathway of Cyt c release that  The significance of mitochondrial dysfunctionality has not been studied in ductal carcinoma to the best of our knowledge. We used Raman spectroscopy and imaging to monitor changes in the redox state of the mitochondrial cytochromes in ex vivo surgically resected specimens of human breast tissues, and in vitro human breast cells of normal cells (MCF 10A), slightly malignant cells (MCF7) and highly aggressive cells (MDA-MB-231). We showed that Raman imaging provides insight into the biology of human breast ductal cancer. Here we show that proper concentration of monounsaturated fatty acids, saturated fatty acids, cardiolipin and Cyt c is critical in the correct breast ductal functioning and constitutes an important parameter to assess breast epithelial cells integrity and homeostasis. We look inside human breast ducts by Raman imaging answering fundamental questions about location and distribution of various biochemical components inside the lumen, epithelial cells of the duct and the extracellular matrix around the cancer duct during cancer development in situ. Our  The reduced cytochrome c is upregulated in all stages of cancers development. The  We found in histopathologically controlled breast cancer duct that Cyt c, cardiolipin, and palmitic acid are the main components inside the lumen of cancerous duct in situ. The presented  In contrast the lumen in normal duct is empty and free of Cyt c. Our  We anticipate our  For example, the correlation between concentration of Cyt c and cancer grade could be tested in various types of cancer. Furthermore, Cyt c is a target of anti-cancer drug development and a well-defined and quantitative Raman based assay for oxidative phosphorylation and apoptosis will be relevant for such developments."
1141,The role of non-coding RNAs in extracellular vesicles in breast cancer and their diagnostic implications.,"Samuels M, Jones W, Towler B, Turner C, Robinson S, Giamas G.",https://pubmed.ncbi.nlm.nih.gov/37670020/,"Breast Cancer (BC) is the most common form of cancer worldwide, responsible for 25% of cancers in women. Whilst treatment is effective and often curative in early BC, metastatic disease is incurable, highlighting the need for early detection. Currently, early detection relies on invasive procedures, however recent studies have shown extracellular vesicles (EVs) obtained from liquid biopsies may have clinical utility. EVs transport diverse bioactive cargos throughout the body, play major roles in intercellular communication and, importantly, mirror their cell of origin. In cancer cells, EVs alter the behaviour of the tumour microenvironment (TME), forming a bridge of communication between cancerous and non-cancerous cells to alter all aspects of cancer progression, including the formation of a pre-metastatic niche. Through gene regulatory frameworks, non-coding RNAs (ncRNAs) modulate vital molecular and cellular processes and can act as both tumour suppressors and oncogenic drivers in various cancer types. EVs transport and protect ncRNAs, facilitating their use clinically as liquid biopsies for early BC detection. This review summarises current research surrounding ncRNAs and EVs within BC, focusing on their roles in cancer progression through bi-directional communication with the microenvironment and their diagnostic implications. The role of EV ncRNAs in breast cancer. A representation of the different EV ncRNAs involved in tumourigenic processes in breast cancer. Pro-tumourigenic ncRNAs displayed in green and ncRNAs which inhibit oncogenic processes are shown in red."
1142,Genetic Analysis of Multiple Primary Malignant Tumors in Women with Breast and Ovarian Cancer.,"Savkova A, Gulyaeva L, Gerasimov A, Krasil'nikov S.",https://pubmed.ncbi.nlm.nih.gov/37047678/,"Familial cancer syndromes, which are commonly caused by germline mutations in oncogenes and tumor suppressor genes, are generally considered to be the cause of primary multiple malignant neoplasias (PMMNs). Using targeted genomic sequencing, we screened for eight germline mutations: BRCA1 185delAG, BRCA1 T300G, BRCA1 2080delA, BRCA1 4153delA, BRCA1 5382insC, BRCA2 6174delT, CHEK2 1100delC, and BLM C1642T, which provoke the majority of cases of hereditary breast and ovary cancer syndrome (HBOC), in genomic (blood) DNA from 60 women with PMMNs, including breast (BC) and/or ovarian cancer(s) (OC). Pathogenic allelic forms were discovered in nine samples: in seven instances, it was BRCA1 5382insC, and in the following two, BRCA1 4153delA and BRCA1 T300G. The age of onset in these patients (46.8 years) was younger than in the general Russian population (61.0) for BC but was not for OC: 58.3 and 59.4, correspondingly. There were invasive breast carcinomas of no special type and invasive serous ovarian carcinomas in all cases. Two or more tumors of HBOC-spectrum were only in five out of nine families of mutation carriers. Nevertheless, every mutation carrier has relatives who have developed malignant tumors."
1143,Case-control study of male cancer patients exposed to arsenic-contaminated drinking water and tobacco smoke with relation to non-exposed cancer patients.,"Wadhwa SK, Kazi TG, Kolachi NF, Afridi HI, Khan S, Chandio AA, Shah AQ, Kandhro GA, Nasreen S.",https://pubmed.ncbi.nlm.nih.gov/21558145/,"The investigated data indicated that inorganic arsenic in drinking water is associated with increased mortality from different types of cancers. In the present study, biological samples (blood and scalp hair) of male subjects having lung and bladder cancers and non-cancerous subjects belonging to arsenic (As)-exposed area of southern parts of Pakistan were analysed for As contents. The As levels in drinking water of understudy area showed that sections of understudy population are exposed to arsenic concentrations, which was 3-15-fold higher than the permissible level (<10 μg/L). For comparative purposes the biological samples of matched male cancer patient, as referent patients belonging to big city (Hyderabad) who had used municipal treated water with low arsenic levels <10 μg/L, were also collected. The exposed cancer patients have 2-3-fold higher level of As in both biological samples compared to non-exposed case-matched cancerous male subjects. This study is compelling evidence in support of positive associations between arsenic-contaminated water, food and cigarette with different types of risks of cancer."
1144,Phosphorylation of focal adhesion kinase at Tyr397 in gastric carcinomas and its clinical significance.,"Lai IR, Chu PY, Lin HS, Liou JY, Jan YJ, Lee JC, Shen TL.",https://pubmed.ncbi.nlm.nih.gov/20724588/,"Focal adhesion kinase (FAK) has been implicated in tumorigenesis in various cancers; however, it remains unclear how FAK participates in tumor malignancy in vivo. This study seeks to understand the role of FAK activation in gastric cancer progression. Using immunohistochemical staining and Western blotting, we found that pY397 FAK, an autophosphorylation site on FAK activation, was abundant in the cancerous tissues of 21 of 59 patients with gastric carcinomas. We attempted to correlate clinicopathological parameters, including histological types, TNM staging, and cancer recurrence, with the expression of FAK and pY397 FAK in cancerous tissues. Intriguingly, patients with higher levels of pY397 FAK displayed higher incidences of gastric cancer recurrence after surgery and poor 5-year recurrence-free survival. Furthermore, multivariate analyses showed that pY397 FAK was an independent predictor of gastric cancer recurrence. As a  Additionally, in vitro studies showed that overexpression of Y397F, a dominant-negative mutant of FAK, in AGS human gastric carcinoma cells impaired cell migration, invasion, and proliferation compared with cells overexpressing wild-type FAK. Thus, activation of FAK through autophosphorylation at Tyr397 leads to the progression of gastric carcinomas by promoting cell migration, invasion, and proliferation. Collectively, our "
1145,Differentiating Between Cancer and Inflammation: A Metabolic-Based Method for Functional Computed Tomography Imaging.,"Motiei M, Dreifuss T, Betzer O, Panet H, Popovtzer A, Santana J, Abourbeh G, Mishani E, Popovtzer R.",https://pubmed.ncbi.nlm.nih.gov/26886076/,"One of the main limitations of the highly used cancer imaging technique, PET-CT, is its inability to distinguish between cancerous lesions and post treatment inflammatory conditions. The reason for this lack of specificity is that [(18)F]FDG-PET is based on increased glucose metabolic activity, which characterizes both cancerous tissues and inflammatory cells. To overcome this limitation, we developed a nanoparticle-based approach, utilizing glucose-functionalized gold nanoparticles (GF-GNPs) as a metabolically targeted CT contrast agent. Our approach demonstrates specific tumor targeting and has successfully distinguished between cancer and inflammatory processes in a combined tumor-inflammation mouse model, due to dissimilarities in angiogenesis occurring under different pathologic conditions. This study provides a set of capabilities in cancer detection, staging and follow-up, and can be applicable to a wide range of cancers that exhibit high metabolic activity."
1146,"Synthesis, In Silico and In Vitro Assessment of New Quinazolinones as Anticancer Agents via Potential AKT Inhibition.","Noser AA, El-Naggar M, Donia T, Abdelmonsef AH.",https://pubmed.ncbi.nlm.nih.gov/33080996/,"A series of novel quinazolinone derivatives (2-13) was synthesized and examined for their cytotoxicity to HepG2, MCF-7, and Caco-2 in an MTT assay. Among these derivatives, compounds 4 and 9 exhibited significant cytotoxic activity against Caco-2, HepG2, and MCF-7 cancer cells. Compound 4 had more significant inhibitory effects than compound 9 on Caco-2, HepG2, and MCF-7 cell lines, with IC50 values of 23.31 ± 0.09, 53.29 ± 0.25, and 72.22 ± 0.14µM, respectively. The AKT pathway is one of human cancer's most often deregulated signals. AKT is also overexpressed in human cancers such as glioma, lung, breast, ovarian, gastric, and pancreas. A molecular docking study was performed to analyze the inhibitory action of newly synthetic quinazolinone derivatives against Homo sapiens AKT1 protein. Molecular docking simulations were found to be in accordance with in vitro studies, and hence supported the biological activity. The "
1147,Targeting Mutant-p53 for Cancer Treatment: Are We There Yet?,"Lim DV, Woo WH, Lim JX, Loh XY, Soh HT, Lim SYA, Lee ZY, Yow HY, Hamzah SB, Sellappans R, Foo JB.",https://pubmed.ncbi.nlm.nih.gov/37711005/," Not only does the initiation of oncogenesis ensue due to mutp53, but resistance towards chemotherapy and radiotherapy in cancer cells also occurs. This review aims to summarise and discuss the oncogenesis of mutant p53 in cancer cells and introduce the various mutant p53 inhibitors currently being evaluated at the pre-clinical and clinical stages. Compounds that induce the wild-type conformation on the targeted p53 missense mutation, restore or enhance the DNA binding of mutant p53, and inhibit cancer cells' growth are highlighted. In addition, the progression and development of the mutant p53 inhibitors in clinical trials are updated.
    


          Conclusion:
        
      
      The progress of developing a cancer treatment that may successfully and efficiently target mutant p53 is on the verge of development. Mutant p53 proteins not only initiate oncogenesis but also cause resistance in cancer cells to certain chemo or radiotherapies, further endorse cancer cell survival and promote migration as well as metastasis of cancerous cells. With this regard, many mutant p53 inhibitors have been developed, some of which are currently being evaluated at the pre-clinical level and have been identified and discussed. To date, APR-246 is the most prominent one that has progressed to the Phase III clinical trial."
1148,Role of Helicobacter pylori in gastric carcinogenesis: the origin of gastric cancers and heterotopic proliferative glands in Mongolian gerbils.,"Tatematsu M, Tsukamoto T, Mizoshita T.",https://pubmed.ncbi.nlm.nih.gov/15810939/,"Helicobacter pylori infection is well accepted to be a very important factor for the development of gastric carcinogenesis in the human stomach. In Mongolian gerbils treated with chemical carcinogens, H. pylori infection enhances glandular stomach carcinogenesis, and eradication of infection and  A high-salt diet exacerbates the effects of H. pylori infection on gastric carcinogenesis, and these two factors act synergistically to promote the development of gastric cancers in this animal model. However, the bacterium exerts the greater effects. Early acquisition significantly increases gastric chemical carcinogenesis in Mongolian gerbils, as compared to later infection. While heterotopic proliferative glands, hyperplastic and dilated glands localized beneath the muscularis mucosae, frequently develop with H. pylori infection alone in this animal model, they obviously regress on eradication, suggesting a relation to severe gastritis, rather than a malignant character. Furthermore, endocrine cells, positive for chromogranin A, are observed in the heterotopic proliferative glands, in contrast to cancerous lesions which lack endocrine elements. In conclusion, H. pylori is not an initiator, but rather a strong promoter of gastric carcinogenesis, whose eradication, together with reduction in salt intake, might effectively prevent gastric cancer development."
1149,"Boron neutron capture therapy (BNCT) translational studies in the hamster cheek pouch model of oral cancer at the new ""B2"" configuration of the RA-6 nuclear reactor.","Monti Hughes A, Longhino J, Boggio E, Medina VA, Martinel Lamas DJ, Garabalino MA, Heber EM, Pozzi ECC, Itoiz ME, Aromando RF, Nigg DW, Trivillin VA, Schwint AE.",https://pubmed.ncbi.nlm.nih.gov/28871389/,"Boron neutron capture therapy (BNCT) is based on selective accumulation of B-10 carriers in tumor followed by neutron irradiation. We demonstrated, in 2001, the therapeutic effect of BNCT mediated by BPA (boronophenylalanine) in the hamster cheek pouch model of oral cancer, at the RA-6 nuclear reactor. Between 2007 and 2011, the RA-6 was upgraded, leading to an improvement in the performance of the BNCT beam (B2 configuration). Our aim was to evaluate BPA-BNCT radiotoxicity and tumor control in the hamster cheek pouch model of oral cancer at the new ""B2"" configuration. We also evaluated, for the first time in the oral cancer model, the radioprotective effect of histamine against mucositis in precancerous tissue as the dose-limiting tissue. Cancerized pouches were exposed to: BPA-BNCT; BPA-BNCT + histamine; BO: Beam only; BO + histamine; CONTROL: cancerized, no-treatment. BNCT induced severe mucositis, with an incidence that was slightly higher than in ""B1""  BO induced low/moderate mucositis. Histamine slightly reduced the incidence of severe mucositis induced by BPA-BNCT (75 vs 86%) and prevented mucositis altogether in BO animals. Tumor overall response was significantly higher in BNCT (94-96%) than in control (16%) and BO groups (9-38%), and did not differ significantly from the ""B1""  Histamine did not compromise BNCT therapeutic efficacy. BNCT radiotoxicity and therapeutic effect at the B1 and B2 configurations of RA-6 were consistent. Histamine slightly reduced mucositis in precancerous tissue even in this overly aggressive oral cancer model, without compromising tumor control."
1150,Pathology of early hepatocellular carcinoma: progression from early to advanced.,Kojiro M.,https://pubmed.ncbi.nlm.nih.gov/9730375/,"Small, early stage hepatocellular carcinoma (HCC) can be divided into 2 types; small nodular HCC with distinct margins and small HCC with indistinct margins. The latter consists of well-differentiated cancerous tissue with replacing growth at the boundary and with many portal tracts retained in the tumor. When these tumors reach approximately 1.5-2.0 cm in diameter, moderately or poorly differentiated cancer tissues develop within the well-differentiated cancer tissue and well-differentiated cancer tissues are replaced by less differentiated cancer tissues. This dedifferentiation seems to be closely related to tumor proliferation. When less differentiated cancer tissues within the well-differentiated cancer nodules proliferate in an expansive fashion, a ""nodule in nodule"" appearance is frequently identified. On the other hand, small nodular HCCs with distinct margins are well-defined, with more than half of them encapsulated by a thin fibrous capsule, and about 60% moderately differentiated. Tumor invasion into the portal vein and intrahepatic metastasis are found in 27% and 10%, respectively. Thus, although the size of the tumor may be small, some distinctly nodular small HCCs can already be interpreted as advanced cancers."
1151,Proliferative verrucous leukoplakia and field cancerization: report of a case.,"Feller L, Wood NH, Raubenheimer EJ.",https://pubmed.ncbi.nlm.nih.gov/16623182/,"Proliferative verrucous leukoplakia (PVL) is a multi-focal oral pre-malignant lesion, proliferative in nature, with a tendency to recur despite adequate therapy, and a high rate of malignant transformation. The field cancerization phenomenon may explain the characteristic behaviour of PVL. A case of PVL is presented and the field cancerization concept is discussed."
1152,Comparison of methylation profiling in cancerous and their corresponding normal tissues from korean patients with breast cancer.,"Jung EJ, Kim IS, Lee EY, Kang JE, Lee SM, Kim DC, Kim JY, Park ST.",https://pubmed.ncbi.nlm.nih.gov/24205493/," We evaluated the gene hypermethylation profiles of primary breast tumors and their corresponding normal tissues and investigated the association between major clinicopathological features and gene hypermethylation.
    


          
    


           The most frequently methylated genes included RASSF1 (43.3%), APC (31.7%), CDKN2B (25.0%), CDH13 (23.3%), GSTP1 (16.7%), and BRCA1 (10%). APC was associated with lymph node metastasis, and BRCA1 was associated with negative estrogen receptor and negative progesterone receptor expression. In normal breast tissues, 8 of 24 tumor suppressor genes displayed promoter hypermethylation; CDKN2B (28.3%) and RASSF1 (8.3%) hypermethylation were most frequently observed.
    


          Conclusions:
        
      
      RASSF1 and CDKN2B hypermethylation in Korean breast cancer patients were the most frequent in cancerous tissue and corresponding normal tissue, respectively. Our data indicates that methylation of specific genes is a frequent event in morphologically normal breast tissues adjacent to breast tumors as well as the corresponding breast cancers. This study also suggests that gene methylation is linked to various pathological features of breast cancer; however, this requires confirmation in a larger study."
1153,Impact of the coxsackievirus and adenovirus receptor on the adenoma-carcinoma sequence of colon cancer.,"Stecker K, Vieth M, Koschel A, Wiedenmann B, Röcken C, Anders M.",https://pubmed.ncbi.nlm.nih.gov/21468049/," Its impact on the adenoma-carcinoma sequence of the colon, however, is unclear.
    


           The function of CAR in colon cancer cell lines was determined following application of CAR siRNA or ectopic expression of a human full-length CAR cDNA.
    


           At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001). Cytoplasmic CAR immunopositivity increased from normal mucosa (22%), to adenomas (73%, P=0.0006), primary cancers (83%, P<0.0001), and metastases (67%, P=0.0019). In cancer cell lines, CAR inhibition  Blocking the extracellular portion of CAR increased cell invasion in vitro. In mice, xenotransplants of colon cancer cells with enforced CAR expression formed significantly smaller tumours, whereas CAR inhibition increased the formation of liver metastases.
    


          Conclusion:
        
      
      We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases."
1154,Overview of SLC22A and SLCO families of drug uptake transporters in the context of cancer treatments.,"Cutler MJ, Choo EF.",https://pubmed.ncbi.nlm.nih.gov/21787263/,"The effectiveness of many anticancer agents is dependent on their disposition to the intracellular space of cancerous tissue. Accumulation of anticancer drugs at their sites of action can be altered by both uptake and efflux transport proteins, however the majority of research on the disposition of anticancer drugs has focused on drug efflux transporters and their ability to confer multidrug resistance. Here we review the roles of uptake transporters of the SLC22A and SLCO families in the context of cancer therapy. The many first-line anticancer drugs that are substrates of organic cation transporters (OCTs) organic cation/carnitine transporters (OCTNs) and organic anion- transporting polypeptides (OATPs) are summarized. In addition, where data is available a comparison of the localization of drug uptake transporters in healthy and cancerous tissues is provided. Expression of drug uptake transporters increases the sensitivity of cancer cell lines to anticancer substrates. Furthermore, early observational studies have suggested a causal link between drug uptake transporter expression and positive outcome in some cancers. Quantification of drug transporters by mass spectrometry will provide an essential technique for generation of expression data during future observational clinical studies. Screening of drug uptake transporter expression in primary tumors may help differentiate between susceptible and resistant cancers prior to therapy."
1155,Increased midkine gene expression in human gastrointestinal cancers.,"Aridome K, Tsutsui J, Takao S, Kadomatsu K, Ozawa M, Aikou T, Muramatsu T.",https://pubmed.ncbi.nlm.nih.gov/7559083/,"Midkine (MK) is a product of a retinoic acid-responsive gene, and is a novel growth differentiation factor. We examined the expression of the MK gene in specimens of 47 surgically removed human carcinomas of the gastrointestinal organs, namely, gastric, colorectal, hepatocellular, pancreatic, esophageal, ampullary duodenal and bile duct carcinomas. In most cases, the MK mRNA level was higher in cancer specimens than in the corresponding non-cancerous tissues. Furthermore, MK mRNA was more highly expressed in the colon adenocarcinoma lesion than in the adenoma lesions, in the two familial polyposis cases. While MK mRNA was not detected in the normal liver, it became detectable in cirrhotic tissues in 2 of 4 cases, and its expression was increased in the cancerous tissues. Thus, the increase of MK mRNA level is a phenomenon seen in many human gastrointestinal carcinomas. The increased expression of the MK gene in gastric carcinoma was significantly more prominent in well and moderately differentiated adenocarcinomas than in poorly differentiated adenocarcinomas and signet ring cell carcinomas."
1156,Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.,"Pereira B, Chen CT, Goyal L, Walmsley C, Pinto CJ, Baiev I, Allen R, Henderson L, Saha S, Reyes S, Taylor MS, Fitzgerald DM, Broudo MW, Sahu A, Gao X, Winckler W, Brannon AR, Engelman JA, Leary R, Stone JR, Campbell CD, Juric D.",https://pubmed.ncbi.nlm.nih.gov/34045463/,"In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this  In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our "
1157,The clinical meaning of a nonstructural pattern in early gastric cancer on magnifying endoscopy.,"Yoshida T, Kawachi H, Sasajima K, Shiokawa A, Kudo SE.",https://pubmed.ncbi.nlm.nih.gov/15990819/," Since en bloc EMR was developed, differentiation between mucosal and submucosal cancer is a critical issue in the management of gastric cancer. In this study, we evaluated the clinical meaning of a nonstructural pattern in magnifying gastroscopy.
    


           A cancerous lesion was subclassified into a differentiated-type group or a undifferentiated-type group according to histologic type. Before treatment, magnifying endoscopic observation was performed. After EMR or surgical intervention, resected specimens were observed by using stereomicroscopy. In both in vivo magnifying endoscopic and in vitro stereomicroscopic observations, the presence of a nonstructural pattern on the lesion was investigated. Compared with histologic findings, the clinical meaning of the presence of a nonstructural pattern on the gastric neoplastic lesion was evaluated.
    


           However, in 9 of 11 submucosal cancers, a nonstructural pattern could be identified.
    


          Conclusions:
        
      
      The presence of a nonstructural pattern appeared to be a useful marker to not proceed with EMR of gastric cancer."
1158,Cancer metabolism: current perspectives and future directions.,"Muñoz-Pinedo C, El Mjiyad N, Ricci JE.",https://pubmed.ncbi.nlm.nih.gov/22237205/,"Cellular metabolism influences life and death decisions. An emerging theme in cancer biology is that metabolic regulation is intricately linked to cancer progression. In part, this is due to the fact that proliferation is tightly regulated by availability of nutrients. Mitogenic signals promote nutrient uptake and synthesis of DNA, RNA, proteins and lipids. Therefore, it seems straight-forward that oncogenes, that often promote proliferation, also promote metabolic changes. In this review we summarize our current understanding of how 'metabolic transformation' is linked to oncogenic transformation, and why inhibition of metabolism may prove a cancer's 'Achilles' heel'. On one hand, mutation of metabolic enzymes and metabolic stress sensors confers synthetic lethality with inhibitors of metabolism. On the other hand, hyperactivation of oncogenic pathways makes tumors more susceptible to metabolic inhibition. Conversely, an adequate nutrient supply and active metabolism regulates Bcl-2 family proteins and inhibits susceptibility to apoptosis. Here, we provide an overview of the metabolic pathways that represent anti-cancer targets and the cell death pathways engaged by metabolic inhibitors. Additionally, we will detail the similarities between metabolism of cancer cells and metabolism of proliferating cells."
1159,A novel cross-communication of HIF-1alpha and HIF-2alpha with Wnt signaling in TNBC and influence of hypoxic microenvironment in the formation of an organ-on-chip model of breast cancer.,"Banerjee M, Devi Rajeswari V.",https://pubmed.ncbi.nlm.nih.gov/37454033/,"The microenvironment role is very important in cancer development. The epithelial-mesenchymal transition of the cancer cells depends upon specific signaling and microenvironmental conditions, such as hypoxic conditions. The crosstalk between hypoxia and Wnt signaling through some molecular mechanism in TNBC is related. Cross-communication between hypoxia and Wnt signaling in cancer cells is known, but the detailed mechanism in TNBC is unknown. This review includes the role of the hypoxia microenvironment in TNBC and the novel crosstalk of the Wnt signaling and hypoxia. When targeted, the new pathway and crosstalk link may be a solution for metastatic TNBC and chemoresistance. The microenvironment influences cancer's metastasis, which changes from person to person. Therefore, organ-on-a-chip is a very novel model to test the drugs clinically before going for human trials, focusing on personalized medications can be done. The effect of the hypoxia microenvironment on breast cancer stem cells is still unknown. Apart from all the published papers, this paper mainly focuses only on the hypoxic microenvironment and its association with the growth of TNBC. The medicines or small proteins, drugs, mimics, and inhibitors targeting wnt and hypoxia genes are consolidated in this review paper."
1160,Potential for peritoneal cancer cell seeding in endoscopic full-thickness resection for early gastric cancer.,"Goto O, Shimoda M, Sasaki M, Kiguchi Y, Mitsunaga Y, Akimoto T, Ochiai Y, Fujimoto A, Maehata T, Nishizawa T, Takeuchi H, Kitagawa Y, Kameyama K, Yahagi N.",https://pubmed.ncbi.nlm.nih.gov/28890117/," To assess the possibility of transplantation as a 
    


           Samples were obtained from cancerous and noncancerous areas, constituting the study and control groups, respectively. The detection rate of malignant class IV or V (C-IV/C-V) samples was investigated with Papanicolaou staining. The rate of CD44v9-positive cases, a cancer stem cell marker, was assessed in C-IV/C-V samples with immunohistochemical staining.
    


          6%) differed significantly from those of the C-IV/C-V samples in the noncancerous group (0/96 slides, 0%). Among the 53 slides of C-IV/C-V samples in the cancerous group, CD44v9 cells were expressed in 18 slides (34.0%).
    


          Conclusions:
        
      
      These data suggest that cancer cells, including cancer stem cells, in early gastric cancers are easily detached via contact with the tumor surface. In EFTR, a nonexposure approach is recommended to avoid the risk of iatrogenic cancer cell seeding via contact with and transplantation of cancer cells."
1161,"[Case of heterochronous triple urogenital cancer (renal cell carcinoma, bladder cancer, prostatic cancer)].","Okumura A, Tsuritani S, Takagawa K, Fuse H.",https://pubmed.ncbi.nlm.nih.gov/24564077/,"We report a case of a 73-year-old male with heterochronous triple urogenital cancer. The patient was referred to our hospital because serum PSA was elevated (7.0 ng/ml) in 1998. Prostatic needle biopsy revealed prostatic cancer in the right lobe, and total prostatectomy was performed. The histopathological diagnosis was moderately differentiated adenocarcinoma (TlcNOMO). Non-muscle invasive bladder cancer (NMIBC) was detected during an examination for microhematuria in 2002. Transurethral resection of the bladder tumor (TURBT) procedure was performed, and the histopathological diagnosis was grade 2 urothelial carcinoma (pTa). A right renal mass was detected incidentally on follow-up CT for bladder cancer in 2008. Renal enucleation was performed in 2009. The histopathological diagnosis was grade 2 clear cell renal cell carcinoma (pTlaNXMO). NMIBC was detected on follow-up urethrocystoscopy in 2011. The TURBT procedure was performed, and the histopathological diagnosis was grade 2 urothelial carcinoma (pTa). On follow-up for urogenital cancer patients, it is important to investigate recurrence of the primary cancer and also heterochronous canceration of other urogenital organs."
1162,Validation and evaluation of a common biomarker in human cancers sera protein detected by a monoclonal antibody UNIVmAb.,"Manjunath D, Kumaraswamy SB, Venkatakrishniah SA, Appaiah HN, Thomas A, Banerjee SD.",https://pubmed.ncbi.nlm.nih.gov/31727145/," In this manuscript we have evaluated the use of monoclonal antibody UNIVmAb, to detect the protein (H11) as a common biomarker for all cancers irrespective of the grade and origin. We have shown by both ELISA and Western Blot that the H11 protein, is a unique hyaluronan binding protein that has not been detected earlier. H11 protein was fractionated in an anion exchange column followed by cibacron blue gel exclusion chromatography. Hyaluronan binding H11 protein reacted with Monoclonal antibody UNIVmAb and b-HA inspite of b-Hyaluronan (biotinylated Hyaluronan) interaction and HA-Oligo (Hyaluronan oligosaccharides) competition from various grades of Human cancers sera.
    


           UNIVmAb reactive H11 protein can be used as a common biomarker. We believe, UNIVmAb detected H11 protein, is a unique hyaluronan binding protein, that can be used as a common biomarker for all cancers."
1163,The promise and obstacle of p53 as a cancer therapeutic agent.,"Willis AC, Chen X.",https://pubmed.ncbi.nlm.nih.gov/12108946/,"p53 is a tumor suppressor gene that is mutated in greater than 50% of human cancers. The action of p53 as a tumor suppressor involves inhibition of cell proliferation through cell cycle arrest and/or apoptosis. Loss of p53 function therefore allows the uncontrolled proliferation associated with cancerous cells. While design of most anti-cancer agents has focused on targeting and inactivating cancer promoting targets, such as oncogenes, recent attention has been given to restoring the lost activity of tumor suppressor genes. Because the loss of p53 function is so prevalent in human cancer, this protein is an ideal candidate for such therapy. Several gene therapeutic strategies have been employed in the attempt to restore p53 function to cancerous cells. These approaches include  In addition, because mutant p53 has oncogenic gain of function activity, several approaches have been investigated to selectively target and kill cells harboring mutant p53. These include the  Many obstacles remain to optimize these strategies for use in humans, but, despite these, restoration of p53 function is a promising anti-cancer therapeutic approach."
1164,From actinic keratosis to squamous cell carcinoma: pathophysiology revisited.,Fernandez Figueras MT.,https://pubmed.ncbi.nlm.nih.gov/28263020/,"The precursor of most cutaneous invasive squamous cell carcinomas (iSCCs) is intraepithelial UV-induced damage, known as field cancerization, which can eventually transform into actinic keratosis (AK). Although AK is the most common precursor of iSCC, many AKs will either persist in the same stage or regress, while only a few will progress into iSCC. Nevertheless, because the progression of individual AKs cannot be predicted, it has been proposed that all AKs, regardless of the grade, should be carefully monitored and appropriately treated in clinical practice. Modern imaging techniques such as dermatoscopy, reflectance confocal microscopy (RCM) and high-definition optical coherence tomography (HD-OCT) may have potential to monitor the evolution of actinic field damage. Dermatoscopy can be used to differentiate between AK, intraepidermal carcinoma (IEC) and SCC which may help clinicians to diagnose in situ or invasive lesions at an earlier stage. HD-OCT and RCM can be used to detect cellular and histological changes characteristic of subclinical lesions, allowing visualization of previously invisible lesions. As development of invasive AK directly from the cancer field cannot be ruled out, the ideal treatment should be able to eradicate AK lesions and reverse the underlying field cancerization."
1165,"Spontaneous apoptosis in gallbladder carcinoma. Relationships with clinicopathologic factors, expression of E-cadherin, bcl-2 protooncogene, and p53 oncosuppressor gene.","Sasatomi E, Tokunaga O, Miyazaki K.",https://pubmed.ncbi.nlm.nih.gov/8918403/,"
    


           The relationships between frequency of apoptosis, which was expressed as the maximal apoptotic index (MAI), and clinicopathologic factors, immunoreactivity of E-cadherin (E-CD), bcl-2 protooncogene, and p53 oncosuppressor gene were investigated.
    


          020) and high T category (P = 0.034). A closer correlation between high MAI and high T category was observed in E-CD positive cases (P = 0.0035), whereas no such correlation was evident in E-CD negative cases (P = 0.536). No relationship was observed between MAI and age, sex, histology, grading, stromal volume, venous or lymphatic permeation, and lymph node status. Overexpression of bcl-2 and p53 was observed in 18.4% (9 of 49) and 34.7% (17 of 49) of the cases, respectively, and there was a positive correlation between bcl-2 and p53 (P = 0.035). No notable relationship was observed between apoptosis and overexpression of bcl-2 or p53.
    


          Conclusions:
        
      
      These  Oncogenic changes of bcl-2 and p53 may play a role in tumorigenesis of gallbladder carcinoma, but such changes were not correlated with spontaneous apoptosis."
1166,"Identification of a Novel Gene Signature with DDR and EMT Difunctionalities for Predicting Prognosis, Immune Activity, and Drug Response in Breast Cancer.","Zhang P, Li Q, Zhang Y, Wang Q, Yan J, Shen A, Hu B.",https://pubmed.ncbi.nlm.nih.gov/36673982/,"Breast cancer, with an overall poor clinical prognosis, is one of the most heterogeneous cancers. DNA damage repair (DDR) and epithelial-mesenchymal transition (EMT) have been identified to be associated with cancer's progression. Our study aimed to explore whether genes with both functions play a more crucial role in the prognosis, immune, and therapy response of breast cancer patients. Based on the Cancer Genome Atlas (TCGA) cancer database, we used LASSO regression analysis to identify the six prognostic-related genes with both DDR and EMT functions, including TP63, YWHAZ, BRCA1, CCND2, YWHAG, and HIPK2. Based on the six genes, we defined the risk scores of the patients and reasonably analyzed the overall survival rate between the patients with the different risk scores. We found that overall survival in higher-risk-score patients was lower than in lower-risk-score patients. Subsequently, further GO and KEGG analyses for patients revealed that the levels of immune infiltration varied for patients with high and low risk scores, and the high-risk-score patients had lower immune infiltration's levels and were insensitive to treatment with chemotherapeutic agents. Furthermore, the Gene Expression Omnibus (GEO) database validated our findings. Our data suggest that TP63, YWHAZ, BRCA1, CCND2, YWHAG, and HIPK2 can be potential genetic markers of prognostic assessment, immune infiltration and chemotherapeutic drug sensitivity in breast cancer patients."
1167,Characterization of healthy and nonmelanoma-induced mouse utilizing the Stokes-Mueller decomposition.,"Le DL, Huynh TN, Nguyen DT, Vo TV, Pham TT.",https://pubmed.ncbi.nlm.nih.gov/30554502/,"Skin cancer is one of the most common cancers, including melanoma and nonmelanoma cancer. Melanoma can be easily detected by the observation of abnormal moles, but nonmelanoma signs and symptoms are not apparent in the early stages. We use the Stokes-Mueller matrix decomposition  With this decomposition  The healthy skin and the induced nonmelanoma skin cancer of mice are analyzed and compared based on their optical parameters. We find distinctive ranges of values for normal skin tissue and nonmelanoma skin cancer, in which β and D in cancerous tissue are larger and nonmelanoma skin becomes less depolarized. This research creates an innovative solid foundation for the diagnosis of skin cancer in the future."
1168,Benign ovarian cysts and ovarian cancer: a cohort study with implications for screening.,"Crayford TJ, Campbell S, Bourne TH, Rawson HJ, Collins WP.",https://pubmed.ncbi.nlm.nih.gov/10744092/," If a large proportion of ovarian cancers arose in this way, it might be possible to remove the benign cysts in a screening programme before they became malignant. We used follow-up data from a cohort of 5479 self-referred women without symptoms, who participated in a ultrasonographic-screening trial for early ovarian cancer between June, 1981, and August, 1987. We assessed whether the removal of persistent ovarian cysts from these women was associated with a reduction in the expected number of deaths from ovarian cancer in the cohort as a whole.
    


           The actual number of deaths and each cause were obtained and the proportional mortality ratio was calculated for each cause of death.
    


          Findings:
        
      
      5135 (95%) of the participants in the original trial were traced. During the screening, five of these women were found to have stage I epithelial ovarian cancer and 88 had benign epithelial ovarian tumours. The number of reported deaths from all causes (387 [50% of expected]), all cancers (221 [71%]), and ovarian cancer (22 [90%]) was lower than expected because of the ""healthy-volunteer effect"". Proportional mortality ratios were 100% (by definition) for all cancers, 141% for breast cancer, 128% for ovarian cancer (95% CI 87.7-187.6, p=0.19), 84% for colorectal cancer, and 48% for lung cancer.
    


          Interpretation:
        
      
      The removal of persistent ovarian cysts was not associated with a decrease in the proportion of expected deaths from ovarian cancer relative to other cancers during follow-up. For population-based screening of healthy women without a family history of ovarian cancer, a screening test is required that is specific and sensitive to early malignant disease, and inexpensive."
1169,Whole-volume apparent diffusion coefficient-based entropy parameters for assessment of gastric cancer aggressiveness.,"Liu S, Zheng H, Zhang Y, Chen L, Guan W, Guan Y, Ge Y, He J, Zhou Z.",https://pubmed.ncbi.nlm.nih.gov/28471511/,"Purpose:
        
      
      To explore the role of whole-volume apparent diffusion coefficient (ADC)-based entropy parameters in the preoperative assessment of gastric cancer's aggressiveness.
    


          Materials and 0T magnetic resonance imaging (MRI) were retrospectively included. Regions of interest were drawn manually using in-house software, around gastric cancer lesions on each slice of the diffusion-weighted images and ADC maps. Entropy-related parameters based on ADC maps were calculated automatically: (1) first-order entropy; (2-5) second-order entropies, including entropy(H)0 , entropy(H)45 , entropy(H)90 , and entropy(H)135 ; (6) entropy(H)mean ; and (7) entropy(H)range . Correlations between entropy-related parameters and pathological characteristics were analyzed with the Spearman correlation test. The parameters were compared among different pathological characteristics with independent-samples Kruskal-Wallis or Mann-Whitney U-test. Additionally, diagnostic performances of parameters in differentiating different pathological characteristics were analyzed by receiver operating characteristic (ROC) curve analysis.
    


          588, 0.585, and 0.677, respectively, all P < 0.05). All the entropy-related parameters showed significant differences in gastric cancers at different T, N, and overall stages, as well as at different status of vascular invasion (P < 0.001-0.027). And four parameters, including entropy, entropy(H)0 , entropy(H)45 , and entropy(H)90 , showed significant differences between gastric cancers with and without perineural invasion (P 0.006-0.040).
    


          Conclusion:
        
      
      Entropy-related parameters derived from whole-volume ADC texture analysis could help assess the aggressiveness of gastric cancers via analyzing intratumoral heterogeneity quantitatively, especially the first-order entropy.
    


          Level of evidence:
        
      
      2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:168-175."
1170,CDC20 overexpression predicts a poor prognosis for patients with colorectal cancer.,"Wu WJ, Hu KS, Wang DS, Zeng ZL, Zhang DS, Chen DL, Bai L, Xu RH.",https://pubmed.ncbi.nlm.nih.gov/23758705/," CDC20 overexpression has been detected in many types of human cancers; however, its clinical role in colorectal cancer remains unknown.
    


           Additionally, the correlation of CDC20 expression with patient clinical parameters and its diagnostic value were statistically analyzed.
    


           Interestingly, CDC20 expression was further increased in metastatic liver tissues. CDC20 protein expression was significantly correlated with clinical stage (P = 0.008), N classification (P = 0.020), M classification (P = 0.013) and pathologic differentiation (P = 0.008). Patients with higher CDC20 expression had a shorter overall survival than those with lower CDC20 expression. Univariate and multivariate analyses indicated that CDC20 expression was an independent prognostic factor (P < 0.001).
    


          Conclusion:
        
      
      CDC20 may serve as a potential prognostic biomarker of human colorectal cancer."
1171,Cathepsin D in the Tumor Microenvironment of Breast and Ovarian Cancers.,"Pranjol ZI, Whatmore JL.",https://pubmed.ncbi.nlm.nih.gov/32578168/,"Cancer remains a major and leading health problem worldwide. Lack of early diagnosis, chemoresistance, and recurrence of cancer means vast research and development are required in this area. The complexity of the tumor microenvironment in the biological milieu poses greater challenges in having safer, selective, and targeted therapies. Existing strategies such as chemotherapy, radiotherapy, and antiangiogenic therapies moderately improve progression-free survival; however, they come with side effects that reduce quality of life. Thus, targeting potential candidates in the microenvironment, such as extracellular cathepsin D (CathD) which has been known to play major pro-tumorigenic roles in breast and ovarian cancers, could be a breakthrough in cancer treatment, specially using novel treatment modalities such as immunotherapy and nanotechnology-based therapy. This chapter discusses CathD as a pro-cancerous, more specifically a proangiogenic factor, that acts bi-functionally in the tumor microenvironment, and possible ways of targeting the protein therapeutically."
1172,"Radiological approach for the newly incorporated T staging factor, depth of invasion (DOI), of the oral tongue cancer in the 8th edition of American Joint Committee on Cancer (AJCC) staging manual: assessment of the necessity for elective neck dissection.","Baba A, Hashimoto K, Kayama R, Yamauchi H, Ikeda K, Ojiri H.",https://pubmed.ncbi.nlm.nih.gov/32356237/,"The 8th edition of American Joint Committee on Cancer's (AJCC) Cancer Staging Manual was modified by incorporating depth of invasion (DOI) in the T categorization of oral cavity cancer. This is because DOI is strongly associated with cervical lymph node metastasis, which is the most important negative prognostic factor of oral cavity cancer. This major change in the AJCC Cancer Staging Manual caused re-staging of T category in several cases. Although, the DOI on MRI and CT (radiological DOI; r-DOI) strongly correlated with pathological DOI (p-DOI), it is often 2-3 mm larger than p-DOI. Due to this variance, estimation of p-DOI based on r-DOI may not be accurate. However, when a lesion is undetectable on MRI, p-DOI was often smaller than 4 mm. On the other hand, when MRI depicts lesions with styloglossus and hyoglossus muscle invasion, p-DOI was always larger than 4 mm. These correlations between MRI findings and p-DOI are important when assessing the need for elective neck dissection, as the National Comprehensive Cancer Network (NCCN) recommends elective neck dissection in cases with DOI greater than 4 mm."
1173,The origin of endometriosis-associated ovarian cancer from uterine neoplastic lesions.,"Garavaglia E, Sigismondi C, Ferrari S, Candiani M.",https://pubmed.ncbi.nlm.nih.gov/29317075/,"Endometriosis is a risk factor for type I epithelial ovarian cancer but an issue to be clarified is the site of origin of endometriosis associated ovarian cancer. Here we proposed that the uterus may be the organ of origin of ovarian endometrioid cancer associated with endometriosis. Thus, the first neoplastic transformation would characterize the uterine cells migrating in the pelvis via retrograde menstruation and they would implant secondarily on the ovary. Supporting this hypothesis, an higher incidence of synchronous precancerous and cancerous endometrial pathology in patients affected by ovarian endometrioid cancer associated with endometriosis was showed. Moreover, uterine endometrial type I carcinoma resembles endometriosis associated endometrioid ovarian cancer in behavior and prognosis. This hypothesis is also supported by epidemiologic evidence showing a protective effect for tubal ligation and oral contraceptive use for endometriosis associated endometrioid ovarian cancer. Endometriosis and endometrioid ovarian carcinoma might represent two distinct biological entities characterized by the same organ of origin (the uterus), the same pathogenetic mechanism (transtubal reflux) and the same target organ (the ovary). By shifting the early events of ovarian carcinogenesis to the endometrium, prevention approaches as salpingectomy/tubal ligation and intervention at uterine corpus level may play an important role."
1174,[Anal epidermoid carcinoma: a rare incidence or a rare diagnosis?].,"Prieto Reyes M, Vázquez Márquez L.",https://pubmed.ncbi.nlm.nih.gov/9115820/,"Epidermoid cancer of the anus is a rare entity which represents 1-2% of all gastrointestinal tract cancers. Possible predisposing causes include smoking and sexual behaviour, particularly homosexual anal intercourse, chronic inflammation (Crohn, anal fistula, fissure, sepsis, hydradenitis suppurativa), and transmissible agents (human papillomavirus type 16 y 18, condylomata acuminata). Another factor is the genetic, which may be related to changes in chromosome 11 and the sort arm of chromosome 3. The aetiology of anal carcinoma is a multifactorial interaction between environmental factors. HPV infection, immune status and suppressor genes. We report on three cases of squamous cell carcinoma of the anus seen in our Unit of Proctology. One patient with widespread perianal hydradenitis suppurativa. Another one in a patient VIH+ with anal human papillomavirus infection, in situ cervix cancer and condylomata acuminata of the vulva and anus. A third case, a man with haemorrhoids. Is addition, constant irritation, chronic inflammatory changes, and repeated epithelial regeneration that accompany noninfectious conditions may be related to risk of anal epidermoid cancer. It is important that this cancer is kept in mind. It is unforgivable that a cancerous lesion that can be suspected in a simple inspection or rectal digital examination be attributed, to a benign anal condition."
1175,'We are survivors too': African-American youths' experiences of coping with parental breast cancer.,"Davey MP, Tubbs CY, Kissil K, Niño A.",https://pubmed.ncbi.nlm.nih.gov/20198717/,"
    


           Interviews were audio-taped and transcribed verbatim, and analyzed using content analysis.
    


           Four primary themes emerged which were coping with cancer, it affects us too, changes in family functioning, and growth through pain. African-American youth described feeling overlooked by their families and oncology staff treating their parents, often being in the role of protecting their parents physically and emotionally.
    


          Conclusions:
        
      
      This study suggests that clinicians can improve the care of African-American breast cancer patients and their adolescent children by being more family-centered. Adolescents need more developmentally appropriate preparation for the family changes likely to occur when a parent is diagnosed and treated for breast cancer. Developing a support group comprised of other youth coping with parental breast cancer from diagnosis throughout treatment was described as a preferred intervention to promote a shared understanding in order to overcome feelings of isolation, worry, and fear."
1176,Colorectal cancer screening: the old and the new.,Ziebert JJ.,https://pubmed.ncbi.nlm.nih.gov/11233058/,"As the second leading cancer killer of Americans, colorectal cancer represents a serious health threat to all Americans. All health care providers and patients should demand colorectal cancer screening, which has been shown to decrease the incidence and mortality of the disease through the detection and removal of the cancer's precursor lesion, the adenomatous polyp. Colonoscopy is the most effective screening tool because it identifies and treats more polyps than any other screening tool available today. However, cost issues have led to considerable controversy regarding its universal application as a screening tool."
1177,Atorvastatin lowers breast cancer risk by reversing an early tumorigenic signature.,"Foda MY, Salem ML, AlAkwaa FM, El-Khawaga OY.",https://pubmed.ncbi.nlm.nih.gov/39090164/,"Breast cancer remains a significant health challenge with complex molecular mechanisms. While many studies have explored genetic markers in breast carcinogenesis, few have studied the potential impact of pharmacological interventions such as Atorvastatin on its genetic landscape. This study aimed to elucidate the molecular distinctions between normal and tumor-adjacent tissues in breast cancer and to investigate the potential protective role of atorvastatin, primarily known for its lipid-lowering effects, against breast cancer. Searching the Gene Expression Omnibus database identified two datasets, GSE9574 and GSE20437, comparing normal breast tissues with tumor-adjacent samples, which were merged, and one dataset, GSE63427, comparing paired pre- and post-treated patients with atorvastatin. Post-ComBat application showed merged datasets' consistency, revealing 116 DEGs between normal and tumor-adjacent tissues. Although initial GSE63427 data analysis suggested a minimal impact of atorvastatin, 105 DEGs post-treatment were discovered. Thirteen genes emerged as key players, both affected by Atorvastatin and dysregulated in tumor-adjacent tissues. Pathway analysis spotlighted the significance of these genes in processes like inflammation, oxidative stress, apoptosis, and cell cycle control. Moreover, there was a noticeable interaction between these genes and the immunological microenvironment in tumor-adjacent tissues, with Atorvastatin potentially altering the suppressive immune landscape to favor anti-tumor immunity. Survival analysis further highlighted the prognostic potential of the 13-gene panel, with 12 genes associated with improved survival outcomes. The 13-gene signature offers promising insights into breast cancer's molecular mechanisms and atorvastatin's potential therapeutic role. The preliminary findings advocate for an in-depth exploration of atorvastatin's impact on."
1178,[Surface electrogastrography (EGG) in cancer: influence of the localization and tumor characteristics on the spectral components of the signal].,"Lemaire MC, Pezzola F, Abbattista N, Giorgio I, Thouvenot J.",https://pubmed.ncbi.nlm.nih.gov/2648266/,"1) The present paper concerns the relationship between localization and extension of gastric cancers and the spectral characteristics of the EGG in 73 subjects (32 women and 41 men). 2) The recordings were made in the morning (during 1 h) on fastened patients. Three sets of bipolar cutaneous electrodes were placed on the abdomen around the pyloric radiological projection taken for axis (radius 7 cm; angle 60 degrees); sampling period for analysis is 1 per sec. The spectrum is computed (FFT) for 256 samples in each channel. 3) In the control subjects (n = 72: 24 women and 48 men), the ""normal characteristics"" of the peak EGG are the following: frequency: 2.89 +/- 0.2 c/min; amplitude 40 +/- 20 microV (2-5 derivation), whatever the age. 4) In the cancerous subjects significative increase of the mean spectral component amplitude of the gastric frequency was always found in all different localizations. However, this criterion of amplitude was missing for the corpus localization. 5) The process of infiltration of the wall was accompanied by a significative decrease of the mean frequency. But in ulcerous, vegetant or stenosant cases the frequency was not affected in contrast with the amplitude. 6) In extensive cases the decrease of the frequency was more important. If in several cases (early cancers, mucous cancers of the lesser or greater curvature), no significative abnormality of the spectrum was observed, abnormalities are frequent in cardiac, fundic and antral neoplasies."
1179,Atrazine and breast cancer: a framework assessment of the toxicological and epidemiological evidence.,"Simpkins JW, Swenberg JA, Weiss N, Brusick D, Eldridge JC, Stevens JT, Handa RJ, Hovey RC, Plant TM, Pastoor TP, Breckenridge CB.",https://pubmed.ncbi.nlm.nih.gov/21768606/,"The causal relationship between atrazine exposure and the occurrence of breast cancer in women was evaluated using the framework developed by Adami et al. (2011) wherein biological plausibility and epidemiological evidence were combined to conclude that a causal relationship between atrazine exposure and breast cancer is ""unlikely"". Carcinogenicity studies in female Sprague-Dawley (SD) but not Fischer-344 rats indicate that high doses of atrazine caused a decreased latency and an increased incidence of combined adenocarcinoma and fibroadenoma mammary tumors. There were no effects of atrazine on any other tumor type in male or female SD or Fischer-344 rats or in three strains of mice. Seven key events that precede tumor expression in female SD rats were identified. Atrazine induces mammary tumors in aging female SD rats by suppressing the luteinizing hormone surge, thereby supporting a state of persistent estrus and prolonged exposure to endogenous estrogen and prolactin. This endocrine mode of action has low biological plausibility for women because women who undergo reproductive senescence have low rather than elevated levels of estrogen and prolactin. Four alternative modes of action (genotoxicity, estrogenicity, upregulation of aromatase gene expression or delayed mammary gland development) were considered and none could account for the tumor response in SD rats. Epidemiological studies provide no support for a causal relationship between atrazine exposure and breast cancer. This conclusion is consistent with International Agency for Research on Cancer's classification of atrazine as ""unclassifiable as to carcinogenicity"" and the United States Environmental Protection Agency's classification of atrazine as ""not likely to be carcinogenic."""
1180,Current perspectives in prostate cancer vaccines.,"Arlen PM, Gulley JL.",https://pubmed.ncbi.nlm.nih.gov/19719454/,"The use of vaccines as a potential therapeutic modality for the treatment of cancer has been extensively studied. Recent advances include identification and characterization of tumor-associated antigens, novel vaccine delivery systems, and the combination of vaccines with immune stimulants and other therapeutic modalities. Immunotherapy as a modality for treatment of prostate cancer has received significant attention. There are several characteristics of prostate cancer that make it an ideal target for immunotherapy. Prostate cancer's relative indolence allows sufficient time to generate immune responses, which may take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal vital tissue. This review focuses on promising new vaccines and novel perspectives in the treatment of prostate cancer."
1181,Practical guide to bone health in the spectrum of advanced prostate cancer.,"Butoescu V, Tombal B.",https://pubmed.ncbi.nlm.nih.gov/24775729/," Bone metastases account for most of prostate cancer's morbidity.
    


          Materials and 
    


           This may  SREs negatively impact quality-of-life and survival and represent a major cost for the healthcare system. The bone metastases conundrum is further aggravated by the fact that androgen deprivation therapy (ADT), the reference systemic treatment of advanced prostate cancer, profoundly affects the skeletal integrity as well. ADT accelerates the physiological bone resorption, leading to osteoporosis and fragility fractures.
    


          Conclusion:
        
      
      The concept of ""bone health"" or ""skeletal heath"" refers to the diagnostic, prevention, and treatment of cancer treatment induced bone loss (CTIBL) and metastasis, and their respective complications, osteoporotic fractures and SREs."
1182,Metastatic ER+ Breast Cancer's Genomic Landscape.,[No authors listed],https://pubmed.ncbi.nlm.nih.gov/27974416/,"Whole-exome and transcriptome sequencing have yielded a clearer picture of the molecular differences between ER-positive primary and metastatic breast cancer. Comparing metastatic breast tumor samples with matched primary tumor tissue, researchers found clinically relevant mutations in various genes, including ESR1 and RB1, that were acquired during metastasis. Their findings may better guide the selection of therapies for patients no longer benefiting from ER-targeted agents."
1183,[Pulmonary cancerization in juvenile laryngeal papillomatosis].,"Swoboda H, Braun P, Schratter M.",https://pubmed.ncbi.nlm.nih.gov/3695767/,"A case of early onset type of juvenile laryngeal papillomatosis (JLP) is reported, where pulmonary involvement developed in typical aspiration site evidenced by tuberculosis of the right lung, and which stimulated after years a squamous epithelial carcinoma. After comparison of this case with similar cases reported in the literature, the clinical feature of cancerization in JLP is discussed in the context of recent virological, immunohistochemical and pathohistological findings. The infectious nature of this disease and the reparative character of the pathologically accelerated proliferation of the papilloma epithelium are stressed, which latter is thus particularly susceptible to additional noxae: irradiation, cigarette smoke, infection and necrosis. These noxae are considered to be the ultimate cause of cancerization in JLP, especially long-standing necrosis. These noxae are considered to be the ultimate cause of cancerization in JLP, especially long-standing necrotisation of lung structures in pulmonary involvement. Surgical treatment of JLP, eradication being unconceivable, should therefore be rather conservative, and any therapeutic attendance should take utmost care to avoid intrapulmonary seeding."
1184,[High risk indication of postoperative chemotherapy in early stage non-small cell lung cancer].,"Mao F, Pan Y, Li Z, Cai M, Shen-Tu Y.",https://pubmed.ncbi.nlm.nih.gov/24854559/," There're much controversy over the necessity of adjuvant chemotherapy to them. This aim of this study is investigated the clinical and pathological characters influencing prognosis of the stage Ib non-small cell lung cancer (NSCLC) and to explore the indication of postoperative chemotherapy.
    


           Cox proportional-hazards ratios were used to identify independent prognostic factors for survival. Kaplan-Meier survival curves were calculated to estimate survival rates.
    


          05). The poor histologic grade and cancerous embolus in the blood vessel were closely associated with increased mortality risk on multivariate analysis in stage Ib NSCLC.
    


          Conclusions:
        
      
      The low histologic grade and cancerous embolus in the blood vessel or lymphatic vessel are closely correlated with survival in the stage Ib NSCLC and can be an index for the postoperative chemotherapy."
1185,Up-regulated expression of the uridine phosphorylase gene in human gastric tumors is correlated with a favorable prognosis.,"Kawamura K, Takiguchi N, Wada A, Takenobu H, Kimura H, Soda H, Nagata M, Asano T, Tagawa M.",https://pubmed.ncbi.nlm.nih.gov/17214321/,"Uridine phosphorylase (UP) is one of the enzymes involved in 5-fluorouracil (5-FU) activation. The expression was compared in paired specimens from cancerous and non-cancerous regions of gastric, colon and lung cancer patients. Among 28 paired gastric samples, 20 cases showed greater expression in tumors than in normal surrounding tissues and 8 cases showed equal or lower expression levels in tumors. All the gastric patients received 5-FU before and/or after the surgical resection and the prognosis of the patients, whose UP tumor expression increased, was relatively better than that of the patients with equal or less UP gene tumor expression. In contrast, most of the colon (22 cases in total) and all the lung cancer patients (14 in total) did not receive 5-FU and the majority of the colon (12 cases) and lung (10 cases) specimens showed lower expression in the cancerous region. The differential expression between cancerous and non-cancerous regions in colon and lung cancers was not linked with the prognosis. These data suggest that the paired expression level of the UP gene in gastric cancer is a possible prognostic marker for the patients who received 5-FU."
1186,Clinical evidence of field cancerization in patients with oral cavity cancer in a betel quid chewing area.,"Liao CT, Wallace CG, Lee LY, Hsueh C, Lin CY, Fan KH, Wang HM, Ng SH, Lin CH, Tsao CK, Chen IH, Huang SF, Kang CJ, Yen TC.",https://pubmed.ncbi.nlm.nih.gov/24882501/," We also assessed whether betel quid chewing is an independent risk factor for field cancerization in OSCC patients.
    


           A total of 1243 study participants (79%) had a positive history of betel quid chewing before surgery. Of the 767 patients treated with surgery alone, 599 (78%) were preoperative chewers, whereas a history of preoperative betel quid chewing was identified in 644 (80%) of the 803 patients who received adjuvant therapy. The 5-year control, survival, and second primary tumors (SPTs) rates served as the main outcome measures.
    


           Despite a similar risk profile in terms of tumor depth, lymph node metastasis, and pathological margin status, preoperative chewers showed a significantly higher incidence of 5-year SPTs and local recurrences compared with non-chewers. Moreover, multivariate analysis demonstrated that preoperative betel quid chewing was an independent prognostic factor for 5-year local control and SPTs occurrence rates.
    


          Conclusions:
        
      
      Our "
1187,Endogenous network states predict gain or loss of functions for genetic mutations in hepatocellular carcinoma.,"Wang G, Su H, Yu H, Yuan R, Zhu X, Ao P.",https://pubmed.ncbi.nlm.nih.gov/26911487/,"Cancers have been typically characterized by genetic mutations. Patterns of such mutations have traditionally been analysed by posteriori statistical association approaches. One may ponder the possibility of a priori determination of any mutation regularity. Here by exploring biological processes implied in a mechanistic theory recently developed (the endogenous molecular-cellular network theory), we found that the features of genetic mutations in cancers may be predicted without any prior knowledge of mutation propensities. With hepatocellular carcinoma (HCC) as an example, we found that the normal hepatocyte and cancerous hepatocyte can be represented by robust stable states of one single endogenous network. These stable states, specified by distinct patterns of expressions or activities of proteins in the network, provide means to directly identify a set of most probable genetic mutations and their effects in HCC. As the key proteins and main interactions in the network are conserved through cell types in an organism, similar mutational features may also be found in other cancers. This analysis yielded straightforward and testable predictions on accumulated and preferred mutation spectra in normal tissue. The validation of predicted cancer state mutation patterns demonstrates the usefulness and potential of a causal dynamical framework to understand and predict genetic mutations in cancer."
1188,Accurate genotyping from paraffin-embedded normal tissue adjacent to breast cancer.,"Xie B, Freudenheim JL, Cummings SS, Singh B, He H, McCann SE, Moysich KB, Shields PG.",https://pubmed.ncbi.nlm.nih.gov/16113052/,"Genetic polymorphism analysis for disease risk is widely used in epidemiology studies; blood or oral cavity cells are the most widely used source of DNA. However, these types of samples are not always available, particularly for studies that were conducted years ago. An alternative potential source of patient DNA exists in the form of paraffin-embedded normal tissue adjacent to tumor samples, which are collected and stored routinely for clinical use. The use of such samples can be conceptually problematic, however, due to the presence of field cancerization in the surrounding normal tissue, with the possible presence of chromosomal loss. Specifically, loss of heterozygosity (LOH) might bias the genotyping  However, field cancerization and LOH might not be an issue because LOH is not easily found unless there is careful microdissection of only tumor cells (leaving stromal, inflammatory and fat cells), for example, laser-capture microdissection. In this study, we set out to determine the degree of genotype misclassification from normal tissues adjacent to tumors, if any, by comparing these  We examined samples from 106 subjects with breast cancer, analyzing five different genotypes selected from regions commonly known to have LOH in breast cancer. These genotypes were methylenetetrahydrofolate reductase (MTHFR), oxoguanosine glycosylase 1 (hOGG1), dopamine beta-hydroxylase (DBH), dopamine receptor D2 (DRD2) and NAD(P)H dehydrogenase quinone 1 (NQO1), conducted by using real-time PCR and TaqMan genotyping analyses. We found that among these five genotypes and 106 comparisons, there was a 100% concordance for genotyping from normal tissue adjacent to tumor and from blood. Our findings indicate that the use of adjacent normal tissues provides accurate genotyping  Although this study only used breast tumor samples, and may be applicable only to breast cancer studies, we expect the "
1189,Actinic keratosis as a marker of field cancerization in excision specimens of cutaneous malignancies.,"Lanoue J, Chen C, Goldenberg G.",https://pubmed.ncbi.nlm.nih.gov/27416085/,"Field cancerization is the process in which a singular cell accumulates genetic mutations following carcinogen exposure and then divides to create a ""field"" of monoclonal premalignant cells. In this study, microscopically identified actinic keratoses (AKs) were used as markers of field cancerization in all excision specimens of squamous cell carcinomas (SCCs), basal cell carcinomas (BCCs), and malignant melanomas (MMs) received by our institution's dermatopathology department over a 3- to 6-month period. Our findings provide additional evidence for the theory of field cancerization, its association with cutaneous malignancies, and the need to assess the extent of field damage when determining treatment strategies."
1190,[Development of novel immunotherapy targeting cancer immune evasion].,Tamada K.,https://pubmed.ncbi.nlm.nih.gov/25248888/,"Immunotherapy has been developed as an innovative medical intervention against advanced cancer that is refractory to conventional therapies. In recent years, there have been significant advances in our basic knowledge of tumor immunology and ample experience with the clinical application of novel cancer immunotherapies. Accordingly, many of the molecular and cellular mechanisms of the interaction between cancer cells and the immune system have been elucidated. At the initial stage of cancer occurrence, the immune system constantly surveys for the emergence of cancerous cells in order to eliminate them. For cancers that have evaded immune surveillance, the immune system generates anti-tumor responses by recognizing tumor- associated antigens. In response to such immunological pressure, cancer cells edit their immunogenicity and create immunosuppressive conditions in the tumor microenvironment,  Therefore, in order to achieve effective immunotherapy, it is imperative to inactivate mechanisms used by cancer cells to evade and suppress immune responses. In this article, immune checkpoint blockade, one of the most attractive approaches in cancer immunotherapy, will be discussed."
1191,"Serum levels of circulating miRNA-21, miRNA-10b and miRNA-200c in triple-negative breast cancer patients.","Niedźwiecki S, Piekarski J, Szymańska B, Pawłowska Z, Jeziorski A.",https://pubmed.ncbi.nlm.nih.gov/30215459/," These classifications influence the choice of therapies (either neoadjuvant or adjuvant), and the range of prognoses, from good (luminal A subtype) to poor (triple-negative cancers).
    


          
    


          Materials and  One group (TNBC) consisted of patients with triple-negative cancer, and the other group (ER(+)/PR(+)) was comprised of patients with positive ER and PR receptors.
    


          05). No statistically significant difference was found between the two groups with regard to the mean levels of miRNA-21 or miRNA-10b.
    


          Conclusion:
        
      
      The level of miRNA-200c was lower in triple-negative patients when compared with the levels in the study's ER/PR positive group."
1192,Diagnostic performance of a computer-assisted diagnosis system for bone scintigraphy of newly developed skeletal metastasis in prostate cancer patients: search for low-sensitivity subgroups.,"Koizumi M, Motegi K, Koyama M, Terauchi T, Yuasa T, Yonese J.",https://pubmed.ncbi.nlm.nih.gov/28456877/,"Purpose:
        
      
      The computer-assisted diagnostic system for bone scintigraphy (BS) BONENAVI is used to evaluate skeletal metastasis. We investigated its diagnostic performance in prostate cancer patients with and without skeletal metastasis and searched for the problems.
    


           Receiver operating characteristic curve analysis was performed and the sensitivity and specificity determined (cutoff ANN = 0.5). Patient's situation at the time of diagnosis of skeletal metastasis, computed tomography (CT) type, extent of disease (EOD), and BS uptake grade were analyzed. False-negative and false-positive 
    


           There were no significant differences among CT types, although low EOD and faint BS uptake were associated with low ANN values and low sensitivity. Patients showed lower sensitivity during the follow-up period than staging work-up. False-negative lesions were often located in the pelvis or adjacent to it. They comprised not only solitary, faint BS lesions but also overlaying to urinary excretion.
    


          Conclusions:
        
      
      BONENAVI with BS has good sensitivity and specificity for detecting prostate cancer's osseous metastasis. Low EOD and faint BS uptake are associated with low sensitivity but not the CT type. Prostate cancer patients likely to have false-negative "
1193,Improving cancer detection through combinations of cancer and immune biomarkers: a modelling approach.,"Eftimie R, Hassanein E.",https://pubmed.ncbi.nlm.nih.gov/29554938/," For epithelial ovarian cancer (which is the leading cause of death among gynaecologic malignancies) the classical detection approach is based on measurements of CA-125 biomarker. However, the poor sensitivity and specificity of this biomarker impacts the detection of early-stage cancers.
    


          g., CA-125 and IL-7), to improve early cancer detection.
    


           However, the immune response (which influences the level of secreted IL-7 biomarker) plays an important role in improving and/or delaying cancer detection. Moreover, the detection level of IL-7 immune biomarker could be in a range that would not allow to distinguish between a healthy state and a cancerous state. In this case, the construction of solution diagrams in the space generated by the IL-7 and CA-125 biomarkers could allow us predict the long-term evolution of cancer biomarkers, thus allowing us to make predictions on cancer detection times.
    


          Conclusions:
        
      
      Combining cancer and immune biomarkers could improve cancer detection times, and any predictions that could be made (at least through the use of CA-125/IL-7 biomarkers) are patient specific."
1194,What Children and Adolescents Know and Need to Learn about Cancer.,"Sigelman C, Jami I, D'Andria E.",https://pubmed.ncbi.nlm.nih.gov/35509191/,"Despite cancer's devastating effects on health and longevity, and the critical role of health habits formed during childhood and adolescence in its prevention, children's knowledge of contributors to cancer is understudied. In this paper, the first developmental analysis of the literature, we outline relevant theoretical perspectives and three early emerging intuitions about illness evident among preschool children-contagion/germ, contamination, and unhealthy lifestyle theories-and then review research on elementary and secondary school students' awareness of risk factors for cancer in light of these early intuitive theories. Our analysis centers on the 16 studies we could locate, done in seven countries, that allowed calculating the percentages of children of different age groups who mentioned various risk factors in response to open-ended questions or endorsed them in response to structured questions. Awareness of primary known risk factors (led by smoking), lifestyle contributors, and personal factors (genetics and old age) increased with age, while contact myths decreased with age until adolescents began to show awareness of sexual contact as a contributor to certain cancers. In addition, the analysis revealed higher levels of awareness in response to structured questions than in response to open-ended questions; a glaring need for research asking young school-aged children about key risk factors and exploring not only their knowledge but their causal understanding; a need for attention to sociocultural influences; and connections between preschool children's intuitive theories of disease and older children's patterns of belief about cancer that can help guide school-based cancer education."
1195,Update on immunotherapy in the management of gallbladder cancer.,"Kassab J, Saba L, Gebrael G, Kais S, Kassab R, Kourie HR.",https://pubmed.ncbi.nlm.nih.gov/36617963/,"Gallbladder cancer (GBC) is a relatively infrequent but highly lethal cancer with a poor prognosis. Management remains challenging and controversial, and most patients are diagnosed at an advanced stage. However, with the progressive advances in the use of immunotherapies, new treatment modalities are being implemented. In September 2022, the US FDA approved durvalumab (a PD-L1 inhibitor) in combination with chemotherapy for adult patients with locally advanced or metastatic GBC. This groundbreaking news is the first FDA approval for the use of immunotherapy in biliary tract cancers. This article reviews the newest advances and trials regarding immunotherapy for GBC."
1196,Pan-cancer analysis revealed the significance of the GTPBP family in cancer.,"Hu Y, Chen L, Tang Q, Wei W, Cao Y, Xie J, Ji J.",https://pubmed.ncbi.nlm.nih.gov/35320117/," Although research on the pathogenesis and treatment of cancer is progressing rapidly, the current knowledge on this topic is far from sufficient. Some tumors with poor prognoses lack effective prognostic biomarkers.
    


           Subsequently, we explored the expression of GTPBP1-10 in cancer by way of a paired t-test and plotted the survival curve using KM and univariate Cox regression analysis to explore the relationship between GTPBP1-10 and the prognosis of cancer. We then explored the significance of the GTPBP family in the tumor microenvironment.
    


           Members of the GTPBP family may serve as novel prognostic markers for these tumors. Moreover, members of the GTPBP family are correlated with the immune microenvironment of tumors, which is valuable in terms of adding to our understanding of the mechanisms of tumor genesis. Finally, we identified drugs showing a high correlation with GTPBP family members, which are therefore conducive to the development of GTPBP family member-based treatment regimens.
    


          Conclusions:
        
      
      The 10 members of the GTPBP family have prognostic value in multiple tumor types and are associated with the immune microenvironment. Our study may provide a reference for the diagnosis and treatment of tumors."
1197,Interrogating the precancerous evolution of pathway dysfunction in lung squamous cell carcinoma using XTABLE.,"Roberts M, Ogden J, Hossain ASM, Chaturvedi A, Kerr ARW, Dive C, Beane JE, Lopez-Garcia C.",https://pubmed.ncbi.nlm.nih.gov/36892933/,"Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low- and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new  To facilitate this research, we have designed XTABLE (Exploring Transcriptomes of Bronchial Lesions), an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two- and multiple-group comparisons, interrogation of genes of interests, and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages."
1198,Cerebellar degeneration-related proteins 2 and 2-like are present in ovarian cancer in patients with and without Yo antibodies.,"Raspotnig M, Haugen M, Thorsteinsdottir M, Stefansson I, Salvesen HB, Storstein A, Vedeler CA.",https://pubmed.ncbi.nlm.nih.gov/28710511/," Recent data show that Yo antibodies also target the CDR2-like protein (CDR2L). We, therefore, examined the expression of CDR2 and CDR2L in ovarian cancer tissue from patients with and without Yo antibodies and from various other cancerous and normal human tissues.
    


           Clinical data were available for all patients. The human tissues were examined by western blot and immunohistochemistry using rabbit CDR2 and CDR2L antibodies.
    


           Both proteins were also present in normal and cancer tissue from mammary tissue, kidney, ovary, prostate, and testis.
    


          Conclusion:
        
      
      CDR2L is present in ovarian cancers from patients with and without Yo antibodies as was shown previously for CDR2. In addition, both CDR2 and CDR2L proteins are more widely expressed than previously thought, both in normal and cancerous tissues."
1199,Incidence of precancerous foci of mammary glands and growth rate of transplantable mammary cancers in sialoadenectomized mice.,"Inui T, Tsubura A, Morii S.",https://pubmed.ncbi.nlm.nih.gov/2795695/,"Sialoadenectomies performed on 8-week-old female SHN and GR mice markedly reduced the numbers of precancerous and cancerous lesions in their mammary glands that had been mildly hypoplastic; the mice were necropsied when they were 30 weeks old. The success rate of the mammary cancer transplantation to isogenic male SHN or C3H mice was lower in the sialoadenectomized animals, and growth of the grafted tumors was delayed after gland removal. Some tumor development resumed in the hosts that received mouse epidermal growth factor after surgery. Therefore, we believe this growth factor may play a role in the multistage process of mouse mammary carcinogenesis."
1200,Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy.,"Maldonado LY, Arsene D, Mato JM, Lu SC.",https://pubmed.ncbi.nlm.nih.gov/29141455/,"Methionine adenosyltransferase genes encode enzymes responsible for the biosynthesis of S-adenosylmethionine, the principal biological methyl donor and precursor of polyamines and glutathione. Mammalian cells express three genes - MAT1A, MAT2A, and MAT2B - with distinct expression and functions. MAT1A is mainly expressed in the liver and maintains the differentiated states of both hepatocytes and bile duct epithelial cells. Conversely, MAT2A and MAT2B are widely distributed in non-parenchymal cells of the liver and extrahepatic tissues. Increasing evidence suggests that methionine adenosyltransferases play significant roles in the development of cancers. Liver cancers, namely hepatocellular carcinoma and cholangiocarcinoma, involve dysregulation of all three methionine adenosyltransferase genes. MAT1A reduction is associated with increased oxidative stress, progenitor cell expansion, genomic instability, and other mechanisms implicated in tumorigenesis. MAT2A/MAT2B induction confers growth and survival advantage to cancerous cells, enhancing tumor migration. Highlighted examples from colon, gastric, breast, pancreas and prostate cancer studies further underscore methionine adenosyltransferase genes' role beyond the liver in cancer development. In this subset of extra-hepatic cancers, MAT2A and MAT2B are induced via different regulatory mechanisms. Understanding the role of methionine adenosyltransferase genes in tumorigenesis helps identify attributes of these genes that may serve as valuable targets for therapy. While S-adenosylmethionine, and its metabolite, methylthioadenosine, have been largely explored as therapeutic interventions, targets aimed at regulation of MAT gene expression and methionine adenosyltransferase protein-protein interactions are now surfacing as potential effective strategies for treatment and chemoprevention of cancers. Impact statement This review examines the role of methionine adenosyltransferases (MATs) in human cancer development, with a particular focus on liver cancers in which all three MAT genes are implicated in tumorigenesis. An overview of MAT genes, isoenzymes and their regulation provide context for understanding consequences of dysregulation. Highlighting examples from liver, colon, gastric, breast, pancreas and prostate cancers underscore the importance of understanding MAT's tumorigenic role in identifying future targets for cancer therapy."
1201,Detection of deletions and/or amplifications of genes related with lung cancer by multiplex ligation-dependent probe amplification (MLPA) technique.,"Tepeli E, Muslumanoglu MH, Uludag A, Buyukpinarbasili N, Ozdemir M, Oznur M, Aslan H, Artan S.",https://pubmed.ncbi.nlm.nih.gov/20068387/,"The aim of the study was determining deleted and/or amplified regions of 64 different loci previously associated with lung cancer, by using Multiplex Ligation-dependent Probe Amplification (MLPA).
    


           We observed same deletions in the same regions in normal lung tissues as in cancerous tissues in lower frequencies. Deletions in 5q, 8p, 9q, 10p, 11p. 11q, 12p, 14q, 17q and 21q probe regions were seen especially in cancerous tissues.
    


          Materials/ DNA extracts of normal lung tissues from the same patients were used as control group in the study.
    


          Conclusions:
        
      
      As a conclusion, it was determined that MLPA is an alternative technique which can give cheap, fast and reliable  The findings obtained in the study are compatible with the literature. MLPA is one of the most important molecular techniques which have been developed recently and it can be used in cancer screening easily and reliably."
1202,Artificial intelligence for the detection of esophageal and esophagogastric junctional adenocarcinoma.,"Iwagami H, Ishihara R, Aoyama K, Fukuda H, Shimamoto Y, Kono M, Nakahira H, Matsuura N, Shichijo S, Kanesaka T, Kanzaki H, Ishii T, Nakatani Y, Tada T.",https://pubmed.ncbi.nlm.nih.gov/32511793/," There are no reports on artificial intelligence (AI) diagnosis for E/J cancer from Asian countries. Therefore, we aimed to develop a computerized image analysis system using deep learning for the detection of E/J cancers.
    


           A total of 232 images from 36 cancer cases and 43 non-cancerous cases were used as the validation test data. The same validation test data were diagnosed by 15 board-certified specialists (experts).
    


           The sensitivity of the AI system was favorable, while its specificity for non-cancerous lesions was similar to that of the experts. Interobserver agreement among the experts for detecting superficial E/J was fair (Fleiss' kappa = 0.26, z = 20.4, P < 0.001).
    


          Conclusions:
        
      
      Our AI system achieved high sensitivity and acceptable specificity for the detection of E/J cancers and may be a good supporting tool for the screening of E/J cancers."
1203,A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.,"Boone PG, Rochelle LK, Ginzel JD, Lubkov V, Roberts WL, Nicholls PJ, Bock C, Flowers ML, von Furstenberg RJ, Stripp BR, Agarwal P, Borowsky AD, Cardiff RD, Barak LS, Caron MG, Lyerly HK, Snyder JC.",https://pubmed.ncbi.nlm.nih.gov/31792216/,"Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell  In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers."
1204,Optical detection of field cancerization in the buccal mucosa of patients with esophageal cancer.,"Bugter O, Spaander MCW, Bruno MJ, Baatenburg de Jong RJ, Amelink A, Robinson DJ.",https://pubmed.ncbi.nlm.nih.gov/29712897/," This prognosis could improve with more early tumor detection. We have previously shown that we can use an optical spectroscopy to detect field cancerization in the buccal mucosa of patients with laryngeal cancer. The aim of this prospective study was to investigate whether we could detect field cancerization of buccal mucosa of patients with esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC).
    


           MDSFR spectra were acquired by a handheld probe incorporating three fiber diameters. Multiple absorption and scattering parameters that are related to the physiological and ultrastructural properties of the buccal mucosa were derived from these spectra. A linear discriminant analysis of the parameters was performed to create a combined biomarker σ to discriminate oncologic from non-oncologic patients.
    


           The median value of our biomarker σ was significantly higher in patients with ESCC (2.07 [1.93-2.10]) than control patients (1.86 [1.73-1.95], p = 0.022). After cross-validation σ was able to identify ESCC patients with a sensitivity of 66.7% and a specificity of 70.8%. There were no significant differences between the EAC group and the control group.
    


          Conclusion:
        
      
      Field cancerization in the buccal mucosa can be detected using optical spectroscopy in ESCC patients. This may be the first step towards non-invasive ESCC cancer screening."
1205,Salpingo-oophorectomy specimens for endometrial cancer staging: a comparative analysis of representative sampling versus whole tissue processing.,"Fadare O, Khabele D.",https://pubmed.ncbi.nlm.nih.gov/23084582/,"Involvement of the ovary and/or fallopian tube by an endometrial cancer is uncommon but clinically significant because this is one of the indications for adjuvant chemotherapy. The authors evaluated whether the routine microscopic evaluation of the adnexal organs in this setting should be of the entire specimen or of representative sections. Slides and reports were reviewed for 105 consecutive patients who underwent a staging salpingo-oophorectomy (205 ovaries, 210 tubes) for endometrial carcinoma/carcinosarcoma. The study period encompassed the periods before and after an institutional policy change from discretionary (predominantly representative) adnexal sampling to obligatory total processing. Ninety-four and 111 ovaries (and 92 and 118 tubes) were entirely and representatively processed, respectively. Even when using the most expansive definition of ovarian gross abnormality (definition with the highest sensitivity and lowest specificity for microscopically confirmed cancer), we still identified 4 (of 148; 2.7%) grossly normal ovaries and 3 (of 187; 1.6%) grossly normal tubes that were found to harbor microscopic cancers. There was no significant increase in the number of grossly occult cancers detected after the policy change, and 5 (71%) of the 7 grossly occult cancers were in the representatively sampled group. Approximately 3.76 more blocks per patient were required for total overrepresentative processing, and the total cost of these additional sections was estimated to be $25.57 per patient. In conclusion, the 1.6% to 2.7% of grossly normal adnexa that proved to be cancerous represents, at least theoretically, the risk for misdiagnosis and understaging that is associated with representative sampling, at relatively modest savings. However, the findings in this study do not provide direct evidentiary support for routine complete processing."
1206,Control of cancers by combining antiangiogenesis and cancer immunotherapy.,"Moniz M, Yeatermeyer J, Wu TC.",https://pubmed.ncbi.nlm.nih.gov/16193100/,"Ideally, cancer therapy would eliminate tumor growth at multiple sites in the body without damaging normal cells. In this regard, antiangiogenesis and immunotherapy may represent two potential approaches for control of cancers. Inhibition of tumor-specific angiogenesis restrains neoplastic growth by sequestering cancerous cells from an adequate blood supply, while activation of cancer-specific T cell-mediated immune responses can initiate attacks on tumors associated with a specific antigen. A novel approach that combines both strategies may potentially generate a better antitumor effect. In this review, we will outline the fields of cancer antiangiogenesis and cancer immunotherapy, including their advantages and limitations. In addition, we will discuss the feasibility of combining both mechanisms to generate a more powerful strategy for cancer therapy."
1207,International trends in anal cancer incidence rates.,"Islami F, Ferlay J, Lortet-Tieulent J, Bray F, Jemal A.",https://pubmed.ncbi.nlm.nih.gov/27789668/," There is very limited information on whether this pattern is replicated in other parts of the world. In this study, we examine recent trends in anal cancer incidence in 18 countries worldwide.
    


           We also conducted an extended analysis of the data from the USA through to 2012.
    


           The incidence of ASCC increased in both men and women in several high-income countries, including Australia, Canada, Denmark, France, Italy, Netherlands, the UK and the USA, whereas it increased only in women in Colombia, Estonia, the Russian Federation, Slovakia and Switzerland. Conversely, there was little change in the incidence of ASCC in either men or women in India, Israel, Japan, Singapore and Spain. The incidence rates of AAC decreased or were stable in most populations.
    


          Conclusions:
        
      
      The ASCC incidence rates increased in both men and women or in women in all countries included in this study, except Asian countries and Spain, where the rates remained unchanged. Population-based preventive measures, including human papillomavirus vaccination and advocacy for safe sexual behaviours, may contribute to curbing the surging burden of the disease."
1208,Cancer cell cycle control.,Funk JO.,https://pubmed.ncbi.nlm.nih.gov/10697591/,"The cell cycle is controlled by multiple mechanisms on which exogenous and endogenous stimuli converge. The pathways governing the different cell cycle phases are central for the cells' decisions when to commit to DNA synthesis and proliferation versus growth arrest, DNA repair or apoptosis. Consequently, these pathways incorporate various oncogenes and tumor suppressors and are therefore a central target for genetic alterations in human cancers. These events may ultimately lead to aberrant cell proliferation and increased genetic instability. Unraveling these regulatory networks provides an important insight into the balance of normal and cancerous cell proliferation and is pivotal for the design of novel anticancer strategies."
1209,Mutagenic assessment of chemotherapy and Smac mimetic drugs in cells with defective DNA damage response pathways.,"Miles MA, Hawkins CJ.",https://pubmed.ncbi.nlm.nih.gov/30258062/,"DNA damaging therapies can spur the formation of therapy-related cancers, due to mis-repair of lesions they create in non-cancerous cells. This risk may be amplified in patients with impaired DNA damage responses. We disabled key DNA damage response pathways using genetic and pharmacological approaches, and assessed the impact of these deficiencies on the mutagenicity of chemotherapy drugs or the ""Smac mimetic"" GDC-0152, which kills tumor cells by targeting XIAP, cIAP1 and 2. Doxorubicin and cisplatin provoked mutations in more surviving cells deficient in ATM, p53 or the homologous recombination effector RAD51 than in wild type cells, but suppressing non-homologous end joining (NHEJ) by disabling DNA-PKcs prevented chemotherapy-induced mutagenesis. Vincristine-induced mutagenesis required p53 and DNA-PKcs but was not affected by ATM status, consistent with it provoking ATM-independent p53-mediated activation of caspases and CAD, which creates DNA lesions in surviving cells that could be mis-repaired by NHEJ. Encouragingly, GDC-0152 failed to stimulate mutations in cells with proficient or defective DNA damage response pathways. This study highlights the elevated oncogenic risk associated with treating DNA repair-deficient patients with genotoxic anti-cancer therapies, and suggests a potential advantage for Smac mimetic drugs over traditional therapies: a reduced risk of therapy-related cancers."
1210,Novel therapies in the management of oral cancer: An update.,"Nandini DB, Rao RS, Hosmani J, Khan S, Patil S, Awan KH.",https://pubmed.ncbi.nlm.nih.gov/32594997/,"An estimated 4% of all cancers are of the oral cavity or oropharyngeal. Presently, management of the oral cancers mainly includes surgery, radiotherapy, and chemotherapy either alone or in combination depending on the individual case. Each of these techniques has their advantages and disadvantages. Surgery demands removal of cancerous tissue causing disfigurement and functional impairment. Radiotherapy has significant side effects like mucositis, myelosuppression, xerostomia and dental caries. With the advent of newer treatment  This has generally improved survival rates and quality of life of cancer patients."
1211,"Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy, Part I: Introduction and Indications.",Dunn D.,https://pubmed.ncbi.nlm.nih.gov/31660604/,"Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal carcinomatosis, which often is secondary to gastrointestinal and ovarian cancers. During CRS, the surgeon resects cancerous tumors from the peritoneal cavity. During HIPEC, a chemotherapy agent is introduced into a solution that flows in and out of catheters in the abdominal cavity for approximately 90 minutes. The chemoperfusate is heated to 42° C (107.6° F), which kills cancer cells but is nonthreatening to normal cells. A primary goal of combining CRS with HIPEC is to apply targeted regional chemotherapy directly to the peritoneum to destroy residual micrometastatic disease while the tumor burden is minimal and before cancer cells become entrapped by the body's wound-healing processes. Although HIPEC usually is not curative, it can extend a patient's life expectancy three to five years. This is the first article in a two-part discussion of CRS with HIPEC."
1212,Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient.,"Yoshida T, Kinoshita H, Segawa T, Nakamura E, Inoue T, Shimizu Y, Kamoto T, Ogawa O.",https://pubmed.ncbi.nlm.nih.gov/16266977/,"Androgen ablation therapies are effective in controlling prostate cancer. Although most cancers relapse and progress despite androgen ablation, some patients experience antiandrogen withdrawal syndrome, in which those treated with antiandrogen show clinical improvement when antiandrogen is discontinued. Although the androgen receptor (AR) is suggested to play an important role in prostate cancer progression even after the androgen ablation, limited tissue availability for molecular studies and small numbers of human prostate cancer cell lines have restricted prostate cancer research. Here, we describe KUCaP, a novel serially transplantable human prostate cancer xenograft model. We established KUCaP from liver metastatic tissue of a patient treated with antiandrogen bicalutamide. KUCaP expressed the AR with a point mutation at amino acid 741 (tryptophan to cysteine; W741C) in the ligand-binding domain. This mutation was also present in cancerous tissue used for generation of KUCaP. Although the growth of KUCaP in male mice was androgen dependent, bicalutamide aberrantly promoted the growth and prostate-specific antigen production of KUCaP. For the first time, we show the agonistic effect of bicalutamide to a xenograft with clinically induced AR mutation. This bicalutamide-responsive mutant AR will serve in the development of new therapies for androgen ablation-resistant prostate cancers."
1213,Advances of targeting the YAP/TAZ-TEAD complex in the hippo pathway for the treatment of cancers.,"Luo M, Xu Y, Chen H, Wu Y, Pang A, Hu J, Dong X, Che J, Yang H.",https://pubmed.ncbi.nlm.nih.gov/36265280/,"The Hippo pathway is an evolutionarily conserved signaling pathway that plays critical roles in the tumorigenesis and progression of breast cancer, oral cancer, rectal cancer, colloid cancer, and so on. YAP/TAZ-TEAD complex is a key knot in the Hippo pathway regulating cell proliferation and stem cell functions. Activation or overexpression of this complex has been proved to lead to cell transformation, proliferation and eventually cancerization. In this review, the association between the alterations of hippo pathway and tumorigenesis of various cancer had been elucidated. The structural basis of YAP/TAZ-TEAD complex is analyzed, and the targeting inhibitors are summarized within the medicinal chemistry classification. Moreover, we have also discussed the clinical status and current challenges of these drug candidates, and provide guidance for the future development of inhibitors targeting this pathway, especially YAP/TAZ-TEAD complex."
1214,Toward a Portable Cancer Diagnostic Tool Using a Disposable MEMS-Based Biochip.,"Pandya HJ, Park K, Chen W, Goodell LA, Foran DJ, Desai JP.",https://pubmed.ncbi.nlm.nih.gov/26930673/,"Goal:
        
      
      The 
    


           The sensor covers the area of 2 mm and the biochip is 10 mm in diameter. A portable tool capable of holding tissue and biochip is fabricated using 3-D printing. Invasive ductal carcinoma and normal tissue blocks are selected from cancer tissue bank in Biospecimen Repository Service at Rutgers Cancer Institute of New Jersey. The ETM properties of the normal and cancerous breast tissues (3-mm thickness and 2-mm diameter) are measured by indenting the tissue placed on the biochip integrated inside the 3-D printed tool.
    


           Using this device, we have shown a statistically significant difference between cancerous and normal breast tissues in mechanical stiffness, electrical resistivity, and thermal conductivity.
    


          Conclusion:
        
      
      The developed cancer diagnosis device is capable of simultaneous ETM measurements of breast tissue specimens and can be a potential candidate for delineating normal and cancerous breast tissue cores.
    


          Significance:
        
      
      The portable cancer diagnosis tool could potentially provide a deterministic and quantitative information about the breast tissue characteristics, as well as the onset and disease progression of the tissues. The tool can be potentially used for other tissue-related cancers."
1215,Predicting and Overcoming Chemotherapeutic Resistance in Breast Cancer.,"Chun KH, Park JH, Fan S.",https://pubmed.ncbi.nlm.nih.gov/29282680/,"Our understanding of breast cancer and its therapeutic approach has improved greatly due to the advancement of molecular biology in recent years. Clinically, breast cancers are characterized into three basic types based on their immunohistochemical properties. They are triple-negative breast cancer, estrogen receptor (ER) and progesterone receptor (PR)-positive-HR positive breast cancer, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Even though these subtypes have been characterized, assessment of a breast cancer's receptor status is still widely used to determine whether or not a targeted therapy could be applied. Moreover, drug resistance is common in all breast cancer types despite the different treatment modalities applied. The development of resistance to different therapeutics is not mutually exclusive. It seems that tumor could be resistant to multiple treatment strategies, such as being both chemoresistant and monoclonal antibody resistant. However, the underlying mechanisms are complicated and need further investigation. In this chapter, we aim to provide a brief review of the different types of breast cancer and their respective treatment strategies. We also review the possible mechanisms of potential drug resistance associated with each treatment type. We believe that a better understanding of the drug resistance mechanisms can lead to a more effective and efficient therapeutic success."
1216,High incidence of EGF receptor hyperproduction in esophageal squamous-cell carcinomas.,"Ozawa S, Ueda M, Ando N, Abe O, Shimizu N.",https://pubmed.ncbi.nlm.nih.gov/3493224/,"EGF receptor levels were investigated in esophageal squamous-cell carcinoma tissues from 31 patients. Twenty-two (71%) of these cancer tissues exhibited significantly higher 125I-EGF binding activity than normal mucosa in the adjacent non-cancerous tissues. These EGF receptor levels were then compared on the basis of pathological findings including lymph-node metastasis, depth of invasion, differentiation type, vascular invasion, infiltration and location of the lesion. Unlike previous reports on breast and bladder cancers, our study showed no obvious correlation between these pathological characteristics and the EGF receptor levels in esophageal carcinomas. Immunohistochemical staining with the anti-EGF receptor monoclonal antibody detected EGF receptors in squamous cells of the cancer tissues as well as in the basal cells of nearby normal epithelium. Since the basal cells have proliferative potential in the esophagus, the increase in EGF receptor levels in these cells may possibly be associated with the development of human esophageal squamous-cell cancer."
1217,A hidden translatome in tumors-the coding lncRNAs.,"Wang J, Wang W, Ma F, Qian H.",https://pubmed.ncbi.nlm.nih.gov/37154857/,"Long noncoding RNAs (lncRNAs) have been extensively identified in eukaryotic genomes and have been shown to play critical roles in the development of multiple cancers. Through the application and development of ribosome analysis and sequencing technologies, advanced studies have discovered the translation of lncRNAs. Although lncRNAs were originally defined as noncoding RNAs, many lncRNAs actually contain small open reading frames that are translated into peptides. This opens a broad area for the functional investigation of lncRNAs. Here, we introduce prospective  We also summarize the specific lncRNA-encoded proteins and their molecular mechanisms that promote or inhibit cancerous. Importantly, the role of lncRNA-encoded peptides/proteins holds promise in cancer research, but some potential challenges remain unresolved. This review includes reports on lncRNA-encoded peptides or proteins in cancer, aiming to provide theoretical basis and related references to facilitate the discovery of more functional peptides encoded by lncRNA, and to further develop new anti-cancer therapeutic targets as well as clinical biomarkers of diagnosis and prognosis."
1218,The multidimensional nature of the financial and economic burden of a cancer diagnosis on patients and their families: qualitative findings from a country with a mixed public-private healthcare system.,"Timmons A, Gooberman-Hill R, Sharp L.",https://pubmed.ncbi.nlm.nih.gov/22987093/,"Purpose:
        
      
      Although awareness is increasing that cancer can have an adverse financial and economic impact for patients, the overall burden remains poorly understood. To elucidate these issues, we used qualitative 
    


           Participants were asked about the (1) extra expenses incurred, (2) cancer's impact on work and income, and (3) accessing financial assistance/social welfare benefits. The two interview sets were analysed separately using thematic analysis.
    


          
    


          Conclusions:
        
      
      This study reveals the complex, multidimensional nature of the financial and economic burden cancer imposes on patients and the whole family unit. Changes in income post-cancer exacerbate the effects of cancer-related out-of-pocket expenses. These findings have implications for healthcare professionals, service providers and policy makers."
1219,Current concepts in oral cancer.,"Sugerman PB, Savage NW.",https://pubmed.ncbi.nlm.nih.gov/10592559/,"Over 750 new intra-oral squamous cell carcinomas are registered in Australia each year. In this article, the authors review the epidemiology, aetiology, genetics and spread of intra-oral squamous cell carcinoma. The mechanisms of field cancerization are discussed. The prevention of intra-oral squamous cell carcinoma is highlighted and future treatments are presented."
1220,Newly developed primary malignancies in long-term survivors who underwent curative esophagectomy for squamous cell carcinoma of the esophagus.,"Shimizu D, Koike M, Kanda M, Sonohara F, Hattori N, Hayashi M, Tanaka C, Yamada S, Kodera Y.",https://pubmed.ncbi.nlm.nih.gov/32638131/,"Purpose:
        
      
      We evaluated the efficacy of the long-term follow-up of patients who underwent radical esophagectomy for esophageal squamous cell carcinoma (ESCC) to screen for recurrence and new primary malignancies.
    


           Esophagogastroduodenoscopy, computed tomography, a stool test and the assessment of the serum concentration of squamous cell carcinoma antigen and carcinoembryonic antigen were performed annually, even over 5 years after esophagectomy. The incidence of ESCC recurrence and new primary malignancies was investigated.
    


           A total of 104 new primary malignancies occurred in 82 patients (36.9%) after esophagectomy. Twenty-one malignancies were in the head and neck region, 14 in the residual esophagus, 13 in the prostate and 11 in the gastric tube and lung. Patients who developed new primary malignancies after esophagectomy had a significantly higher Brinkman index than those without new malignancies. An endoscopic approach successfully treated 92.9% of carcinomas in the residual esophagus, 90.9% of cancers in the gastric tube and 42.9% of carcinomas in the head and neck region.
    


          Conclusion:
        
      
      The incidence of new primary malignancies was higher than the age-standardized incidence. Long-term follow-up and systemic screening may increase the probability of an early diagnosis and subsequent low-invasive treatment."
1221,Concentration of thymidine kinase 1 in serum (S-TK1) is a more sensitive proliferation marker in human solid tumors than its activity.,"He Q, Zhang P, Zou L, Li H, Wang X, Zhou S, Fornander T, Skog S.",https://pubmed.ncbi.nlm.nih.gov/16142366/,"Activity of thymidine kinase 1 in serum (STK) is a useful marker for leukaemia and lymphoma, but not for solid tumors. We investigate thymidine kinase 1 concentration in serum (S-TK1) as a potential tumor marker. S-TK1 concentration and STK activity levels were determined in 9 human malignant diseases (breast, gastric, rectal, colorectal, lung, brain cancer, hepatoma, lymphoma, leukaemia) and in benign and non-cancerous diseases, representing 850 preoperative cases. Healthy volunteers (n=43) were used as positive controls. S-TK1 concentration was determined by ECL dot blot assay and STK activity levels by an RIA assay. S-TK1 concentrations and STK activity levels in preoperative malignant patients were significantly higher than in healthy individuals, in patients with benign tumors and in those with non-cancerous diseases. Significant correlations between concentration and activity level were only found in healthy individuals, in patients with benign tumors, and in some patients with malignancies, i.e. leukaemia, and breast and gastric cancers. About 90-95 percent of the malignant patients showed S-TK1 concentrations above those of the healthy controls. The corresponding value for STK activity was about 75 percent. When sera from malignant patients were diluted with sera from healthy individuals, S-TK1 concentrations and STK activity levels decreased more than expected. This indicates the presence of a compound (or compounds) in the serum of healthy individuals that destabilises S-TK1. We conclude that S-TK1 concentration is a more sensitive tumor marker in solid malignancies than is STK activity."
1222,[Efficacy of local resection on lower rectal cancer of early stage: efficacy of report of 23 cases].,"Hong J, Tang YQ.",https://pubmed.ncbi.nlm.nih.gov/15642206/," This study was to evaluate efficacy of local resection for lower rectal cancer of early stage.
    


           1989 to Apr. 1999 in our hospital were analyzed retrospectively.
    


           Three patients had local recurrence, 2 of 3 were salvaged by trans-anal local excision, and 1 of 3 was treated by abdominoperineal resection. All patients were followed-up for more than 5 years with a 5-year survival rate of 95.65%.
    


          Conclusion:
        
      
      So long as carefully considering indications of trans-anal local excision in treating patients with lower rectal cancer of early stage, good efficacy may be achieved."
1223,Decreased DCC mRNA expression in human gastric cancers is clinicopathologically significant.,"Yoshida Y, Itoh F, Endo T, Hinoda Y, Imai K.",https://pubmed.ncbi.nlm.nih.gov/9842974/,"Loss of heterozygosity (LOH) or decreased expression of the deleted in colorectal cancer (DCC) gene, a candidate tumor suppressor gene, has been suggested to correlate with progression in several types of tumors. In human gastric cancers, although DCC LOH has been reported to be frequent in expanding-type tumors, the relation of decreased DCC mRNA expression with clinicopathological features, including metastatic events, remains to be investigated in detail. Therefore, expression levels of DCC mRNA were examined in 52 advanced gastric cancers by the reverse transcription-polymerase chain reaction  Overall, decreased DCC mRNA expression was observed in 27 of the tumors (52%). According to Ming's [Cancer 39, 2475-2485 (1977)] classification, the expanding type showed a significantly higher incidence (71%) than the infiltrative type (17%) (p = 0.0002). Immunohistochemical analysis demonstrated the presence of DCC expression in cancer but not non-cancerous cells in infiltrative-type lesions. An additional follow-up study of tumor recurrence in 42 patients undergoing curative resection implicated decreased DCC expression in metachronous liver metastasis. The  Assessment of this parameter in primary lesions may thus find predictive application."
1224,Novel responses of peripheral lymphocytes of cancer patients to chemical induction of sister chromatid exchanges.,"Oikawa A, Horaguchi K, Sugawara R, Kikuchi J, Tohda H, Takahashi K, Wakui A, Yamauchi A, Nakada T.",https://pubmed.ncbi.nlm.nih.gov/3079670/,"Sensitivities to sister chromatid exchange (SCE) induction by chemicals of peripheral lymphocytes from 26 cancer patients were estimated under conditions identical to those for healthy humans which had been reported (Cancer Res., 43: 439-442, 1983). The sensitive individual was defined as one whose cells give a mean induced SCE frequency more than 2 standard deviation units above the population mean of induced SCEs in cells from the healthy humans. When cells were treated with 3-amino-1-methyl-5H-pyrido[4, 3-b]indole in the presence of rat liver S9 mix, 8 in 10 stomach cancer patients, 4 in 4 colon cancer patients, 3 in 9 lung cancer patients, 0 in 3 patients bearing other cancers, and 0 in 9 non-cancerous individuals were sensitive. The corresponding frequency of individuals in the healthy population, reported previously, was 1 in 33 persons. Thus, the frequency of sensitive individuals in the combined group of stomach and colon cancer patients was very significantly higher than were frequencies in control groups. Three in 10 patients with stomach cancer and 4 in 16 patients with other cancers were sensitive to induction of SCE by methyl methanesulfonate. Six in these 7 methyl methanesulfonate-sensitive patients were also 3-amino-1-methyl-5H-pyrido[4,3-b]indole sensitive. The frequency of methyl methanesulfonate-sensitive individuals in the healthy populations was 2 in 50. There was no patient who was sensitive to SCE induction by 4-nitroquinoline 1-oxide. The frequency was not significantly different from the healthy population, in which 3 in 50 persons were sensitive. These "
1225,Unmet needs of black patients with cancer posthospitalization: a descriptive study.,"O'Hare PA, Malone D, Lusk E, McCorkle R.",https://pubmed.ncbi.nlm.nih.gov/8391685/,"This article describes self-reported unmet needs of black patients with cancer posthospitalization and suggests a plan of research. The study sample consisted of 63 black patients with solid cancerous tumors who were discharged from seven hospitals in the Philadelphia, PA, area. The investigators collected data using the Enforced Social Dependency Scale (ESDS) and the Symptom Distress Scale (SDS). They added a checklist to the end of the ESDS to collect self-reported needs areas. The patients reported demographic data such as race and income. The investigators abstracted other demographic data, along with medical factors and complex problems, from the patients' hospital or home health agency medical records. Descriptive statistics and t-tests were used to analyze the data. Personal care and home activity needs were not being met adequately for this sample of low-income, urban-dwelling, black patients with cancer. The SDS revealed that the patients had significantly greater symptom distress related to frequency of nausea, intensity of pain, and difficulty breathing. Overall, patients with breast and gynecologic cancers reported the highest levels of symptom distress. Women who were elderly, black, alone, poor, and chronically ill were likely to have unmet needs and high levels of symptom distress."
1226,[Rhinophyma and skin carcinoma: a case report and literature review].,"Qassemyar A, Corbisier N, Poiret G, Mortier L, Martinot-Duquennoy V, Guerreschi P.",https://pubmed.ncbi.nlm.nih.gov/22209650/,"Rhinophyma, final stage of rosacea is considered as benign pathology. We present the case of a patient with basal cell carcinoma diagnosed on rhinophyma. The removal of all cutaneous nasal unit and its analysis has diagnosed the presence of three basal cell carcinomas and two in situ squamous cell carcinomas. Reconstruction was performed by full-thickness skin graft. The literature reports a few cases of association between rhinophyma and skin cancers but none ever reported the simultaneous presence of basal cell carcinoma and squamous cell carcinomas. The low number of articles does not reveal statistically significant relationship between rhinophyma and skin cancer, which would consider the rhinophyma as a risk factor. Monitoring of these patients should be as rigorous as possible and surgical care requires histologic analysis not to omit the presence of cancerous lesions."
1227,IL-11 signaling as a therapeutic target for cancer.,"Putoczki TL, Ernst M.",https://pubmed.ncbi.nlm.nih.gov/25917632/,"IL-11 is a member of the IL-6 family of cytokines. While it was discovered over 20 years ago, we have very little understanding of the role of IL-11 during normal homeostasis and disease. Recently, IL-11 has gained interest for its newly recognized role in the pathogenesis of diseases that are attributed to deregulated mucosal homeostasis, including gastrointestinal cancers. IL-11 can increase the tumorigenic capacity of cells, including survival of the cell or origin, proliferation of cancerous cells and survival of metastatic cells at distant organs. Here we outline our current understanding of IL-11 biology and recent advances in our understanding of its role in cancer. We advocate that inhibition of IL-11 signaling may represent an emerging therapeutic opportunity for numerous cancers."
1228,Immunotherapy for Prostate Cancer: Where Do We Go From Here?-PART 1: Prostate Cancer Vaccines.,"Patel A, Fong L.",https://pubmed.ncbi.nlm.nih.gov/29548065/,"Immunotherapies have emerged as a revolutionary modality for cancer treatment, and a variety of immune-based approaches are currently being investigated in the field of prostate cancer. Despite the 2010 approval of sipuleucel-T, subsequent progress in prostate cancer immunotherapy development has been limited by disappointing  Nevertheless, there remains strong preclinical and clinical evidence to suggest that prostate cancer is a susceptible target for immune therapies. Innovative strategies for vaccine development, adoptive cell transfer, alleviation of immunosuppression in the tumor microenvironment, and combinatorial approaches using existing drugs and novel immune agents hold great promise for improving the treatment of prostate cancer. The first article in this two-part series will provide an overview of both past and present therapeutic vaccination strategies for the promotion of antitumor immunity against prostate cancer. Later, in Part 2, we will discuss novel areas of clinical development and identify the trends that may define the future of prostate cancer immunotherapy."
1229,Detection of (pre)cancerous colorectal lesions in Lynch syndrome patients by microsatellite instability liquid biopsy.,"Boeri M, Signoroni S, Ciniselli CM, Gariboldi M, Zanutto S, Rausa E, Segale M, Zanghì A, Ricci MT, Verderio P, Sozzi G, Vitellaro M.",https://pubmed.ncbi.nlm.nih.gov/38332046/,"Lynch syndrome (LS) is an inherited condition characterized by an increased risk of developing cancer, in particular colorectal cancer (CRC). Microsatellite instability (MSI) is the main feature of (pre)cancerous lesions occurring in LS patients. Close endoscopic surveillance is the only option available to reduce CRC morbidity and mortality. However, it may fail to intercept interval cancers and patients' compliance to such an invasive procedure may decrease over the years. The development of a minimally invasive test able to detect (pre)cancerous colorectal lesions, could thus help tailor surveillance programs in LS patients. Taking advantage of an endoscopic surveillance program, we retrospectively assessed the instability of five microsatellites (BAT26, BAT25, NR24, NR21, and Mono27) in liquid biopsies collected at baseline and possibly at two further endoscopic rounds. For this purpose, we tested a new multiplex drop-off digital polymerase chain reaction (dPCR) assay, reaching mutant allele frequencies (MAFs) as low as 0.01%. Overall, 78 plasma samples at the three time-points from 18 patients with baseline (pre)cancerous lesions and 18 controls were available for molecular analysis. At baseline, the MAFs of BAT26, BAT25 and NR24 were significantly higher in samples of patients with lesions but did not differ with respect to the grade of dysplasia or any other clinico-pathological characteristics. When all markers were combined to determine MSI in blood, this test was able to discriminate lesion-bearing patients with an AUC of 0.80 (95%CI: 0.66; 0.94)."
1230,PINCH-2 presents functional copy number variation and suppresses migration of colon cancer cells by paracrine activity.,"Park CH, Rha SY, Ahn JB, Shin SJ, Kwon WS, Kim TS, An S, Kim NK, Yang WI, Chung HC.",https://pubmed.ncbi.nlm.nih.gov/25346044/,"In recent years, characterization of cancer and its environment has become necessary. However, studies of the cancer microenvironment remain insufficient. Copy number variations (CNVs) occur in 40% of cancer-related genes, but few studies have reported the correlation between CNVs in morphologically normal tissues adjacent to cancer and cancer progression. In this study, we evaluated cancer cell migration and invasion according to the genetic differences between cancer tissues and their surrounding normal tissues. To study the field cancerization effect, we screened 89 systemic metastasis-related CNVs from morphologically normal tissues adjacent to colon cancers. Among these CNVs, LIM and senescent cell antigen-like domain 2 (PINCH-2) showed copy number amplification and upregulation of mRNA in the nonrelapsed group compared to the systemic relapse group. PINCH-2 expression in colon cancer cells was lower than that in normal epithelial colon cells at both the protein and mRNA levels. Suppression of PINCH-2  Although PINCH-2 expression of survival pathway-related proteins (Akt and phospho-Akt) did not change upon suppression of PINCH-2 expression, cell migration-related proteins [matrix-metalloproteinase (MMP)-9 and -11] were upregulated through autocrine and paracrine activation. Thus, PINCH-2 participates in decreased systemic recurrence by competitively regulating IPP complex formation with PINCH-1, thereby suppressing autocrine and paracrine effects on motility in colon cancer. This genetic change in morphologically normal tissue suggests a field cancerization effect of the tumor microenvironment in cancer progression."
1231,Microscopical cancer of the stomach--a study on histogenesis of gastric carcinoma.,Nagayo T.,https://pubmed.ncbi.nlm.nih.gov/1176195/,"In order to elucidate the histogenesis of gastric cancer preceded by ""chronic gastritis"", 67 foci (58 cases) of minute cancer less than 5 mn in largest diameter were examined histologically. The  They were more frequent in the lesser curvature than in other parts of the stomach. (2) Histologically, 18 foci were found in an area close to the main lesion, while 40 were far from the lesion. Seven foci were detected in the mucosa adjacent to ulcer scars. (3) In retrospective macroscopical examinations, 41 foci showed minimal erosion or tiny depressions on the affected mucosa, while in the other 26 no recognizable changes were observable. (4) Histologically, the gastric mucosa outside the cancer lesions was more or less atrophic with or without intestinal metaplasia. (5) Regardless of histological types, all the minute cancers were found in the transitional zone between foveolar epithelium and pyloric glands corresponding to ""generative cell layer"" in autoradiographic studies. (6) Poorly differentiated adenocarcinomas containing signet-ring cells occurred most often in combination with no or slight intestinal metaplasia of the mucosa, while well-differentiated adenocarcinomas were always found in ventricles with severe intestinal metaplasia."
1232,"Recent Updates on Oncogenic Signaling of Aurora Kinases in Chemosensitive, Chemoresistant Cancers: Novel Medicinal Chemistry Approaches for Targeting Aurora Kinases.","Kumari P, Beeraka NM, Tengli A, Bannimath G, Baath RK, Patil M.",https://pubmed.ncbi.nlm.nih.gov/37138483/,"The Aurora Kinase family (AKI) is composed of serine-threonine protein kinases involved in the modulation of the cell cycle and mitosis. These kinases are required for regulating the adherence of hereditary-related data. Members of this family can be categorized into aurora kinase A (Ark-A), aurora kinase B (Ark-B), and aurora kinase C (Ark-C), consisting of highly conserved threonine protein kinases. These kinases can modulate cell processes such as spindle assembly, checkpoint pathway, and cytokinesis during cell division. The main aim of this review is to explore recent updates on the oncogenic signaling of aurora kinases in chemosensitive/chemoresistant cancers and to explore the various medicinal chemistry approaches to target these kinases. We searched Pubmed, Scopus, NLM, Pubchem, and Relemed to obtain information pertinent to the updated signaling role of aurora kinases and medicinal chemistry approaches and discussed the recently updated roles of each aurora kinases and their downstream signaling cascades in the progression of several chemosensitive/chemoresistant cancers; subsequently, we discussed the natural products (scoulerine, Corynoline, Hesperidin Jadomycin-B, fisetin), and synthetic, medicinal chemistry molecules as aurora kinase inhibitors (AKIs). Several natural products' efficacy was explained as AKIs in chemosensitization and chemoresistant cancers. For instance, novel triazole molecules have been used against gastric cancer, whereas cyanopyridines are used against colorectal cancer and trifluoroacetate derivatives could be used for esophageal cancer. Furthermore, quinolone hydrazine derivatives can be used to target breast cancer and cervical cancer. In contrast, the indole derivatives can be preferred to target oral cancer whereas thiosemicarbazone-indole could be used against prostate cancer, as reported in an earlier investigation against cancerous cells. Moreover, these chemical derivatives can be examined as AKIs through preclinical studies. In addition, the synthesis of novel AKIs through these medicinal chemistry substrates in the laboratory using in silico and synthetic routes could be beneficial to develop prospective novel AKIs to target chemoresistant cancers. This study is beneficial to oncologists, chemists, and medicinal chemists to explore novel chemical moiety synthesis to target specifically the peptide sequences of aurora kinases in several chemoresistant cancer cell types."
1233,NY-ESO-1 Based Immunotherapy of Cancer: Current Perspectives.,"Thomas R, Al-Khadairi G, Roelands J, Hendrickx W, Dermime S, Bedognetti D, Decock J.",https://pubmed.ncbi.nlm.nih.gov/29770138/,"NY-ESO-1 or New York esophageal squamous cell carcinoma 1 is a well-known cancer-testis antigen (CTAs) with re-expression in numerous cancer types. Its ability to elicit spontaneous humoral and cellular immune responses, together with its restricted expression pattern, have rendered it a good candidate target for cancer immunotherapy. In this review, we provide  Furthermore, NY-ESO-1-specific immune responses have been observed in various cancer types; however, their utility as biomarkers are not well determined. Finally, we describe the immune-based therapeutic options targeting NY-ESO-1 that are currently in clinical trial. We will highlight the recent advancements made in NY-ESO-1 cancer vaccines, adoptive T cell therapy, and combinatorial treatment with checkpoint inhibitors and will discuss the current trends for future NY-ESO-1 based immunotherapy. Cancer treatment has been revolutionized over the last few decades with immunotherapy emerging at the forefront. Immune-based interventions have shown promising  The majority of successful immunotherapy studies have been reported in liquid cancers, whereas these approaches have met many challenges in solid cancers. Effective immunotherapy in solid cancers is hampered by the complex, dynamic tumor microenvironment that modulates the extent and phenotype of the antitumor immune response. Furthermore, many solid tumor-associated antigens are not private but can be found in normal somatic tissues,  Therefore, there is an ongoing effort to identify tumor-specific antigens to target using various immune-based modalities. CTAs are considered good candidate targets for immunotherapy as they are characterized by a restricted expression in normal somatic tissues concomitant with a re-expression in solid epithelial cancers. Moreover, several CTAs have been found to induce a spontaneous immune response, NY-ESO-1 being the most immunogenic among the family members. Hence, this review will focus on NY-ESO-1 and discuss the past and current NY-ESO-1 targeted immunotherapeutic strategies."
1234,[UV-irradiation-induced skin cancer as a new occupational disease].,"Diepgen TL, Drexler H, Elsner P, Schmitt J.",https://pubmed.ncbi.nlm.nih.gov/25737435/,"With the revision of the German Ordinance on Occupational Diseases, skin cancer due to UV irradiation was amended as a new occupational disease to the list of occupational diseases in Germany. The new occupational disease BK 5103 has the following wording: ""Squamous cell carcinoma or multiple actinic keratosis of the skin caused by natural UV irradiation"". Actinic keratoses are to be considered as multiple according to this new occupational diseases if they occur as single lesions of more than five annually, or are confluent in an area > 4 cm(2) (field cancerization). It is estimated that more than 2.5 million employees are exposed to natural UV irradiation due to their work (outdoor workers) in Germany and therefore have an increased risk of skin cancer. In this article the medical and technical prerequisites which have to be fulfilled for this new occupational disease in Germany are introduced."
1235,[Siblings of familial adenomatosis coli with gastric cancer--case report].,"Takano H, Oguchi Y, Yumiba T, Inoue Y, Ochi A, Oshita Y, Kobayashi S.",https://pubmed.ncbi.nlm.nih.gov/2826986/,"Adenomatosis coli is recently regarded as a systemic disease with a predisposition to multiple tumor formation. We report siblings of familial adenomatosis coli with gastric cancers. Case 1 was a 58 year-old elder brother. His diagnosis was familial adenomatosis coli accompanied with colon cancer and simultaneous early gastric cancer. Total colectomy and partial gastrectomy were carried out on Mar. 13, 1984 at our hospital. Numerous polyps over the whole colon and an ulcerative tumor in the hepatic flexure were found in the resected colon. Histologically tubular adenocarcinoma were demonstrated in the ulcerative tumor, and all other polyps were adenomas. In the resected gastric specimen, there were two shallow, depressed lesions on the each anterior and posterior wall of the antrum. Histologically both of them were adenocarcinoma confined within the mucosa. Postoperative course was satisfactory and he is quite healthy 2 and a half years after surgery. Case 2 was a 56 year-old younger brother. He received a partial gastrectomy for advanced gastric cancer at another hospital on May 20, 1982. In one and a half year from the surgery, a large lung tumor (probably metastasis of the gastric cancer) was found and he received chemotherapy. He also received radiation therapy in June, 1984 and during this admission barium enema study was performed. It revealed numerous polyps over the whole colon. No cancerous lesions were found. He died of lung tumor on Dec. 8, 1985. The similar siblings were first reported by Kokaji et al. in 1984, and our cases seem to be the second ones."
1236,In-silico analysis of kallikrein gene expression in pancreatic and colon cancers.,"Yousef GM, Borgoño CA, Popalis C, Yacoub GM, Polymeris ME, Soosaipillai A, Diamandis EP.",https://pubmed.ncbi.nlm.nih.gov/15015574/,"Human kallikreins are a cluster of 15 serine protease genes located in the chromosomal band 19q13.4, a non-randomly rearranged region in many solid tumors, including pancreatic cancer. We utilized the SAGE and EST databases of the Cancer Genome Anatomy Project to perform in-silico analysis of kallikrein gene expression in normal and cancerous pancreatic and colon tissues and cell lines using virtual Northern blotting (VNB), digital differential display (DDD) and X-profiler. At least two kallikreins, KLK6 and KLK10, are significantly up-regulated in pancreatic cancer. We probed 2 normal and 6 pancreatic cancer SAGE libraries with gene-specific tags for each of these kallikreins. KLK6 was found to be expressed in 5/6 cancer libraries and showed the most marked (5-fold) increase in average expression levels in cancer vs. normal. These data were verified by screening the EST databases, where all mRNA clones isolated were from cancerous libraries, with no clones detected in normal pancreatic tissues or cell lines. X-profiler comparison of two pools of normal and cancerous pancreatic libraries further verified the significant increase of KLK6 expression levels in pancreatic cancer. DDD data showed a 13-fold increase in KLK10 expression in pancreatic cancer. Three kallikrein genes, KLK6, 8 and 10 are overexpressed in colon cancer compared to normal colon, while one kallikrein, KLK1, is down-regulated. While no expression of KLK6 was detected in normal colon, KLK6-specific tags were detectable in 2 cancer libraries. Similar  KLK10 was not detectable in normal colon. Gene-specific tags were, however, detectable with high density in colon cancer and 7 EST clones were found to be expressed in colon Adenocarcinoma."
1237,A new trial in endoscopic diagnosis for stomach cancer:intra-arterial dye (IAD) method.,"Ikeda K, Sannohe Y, Araki S, Inutsuka S.",https://pubmed.ncbi.nlm.nih.gov/7358261/,"Forty gastric cancers were examined by endoscopy before and after the injection of Evans blue or indigo carmine dye into the celiac artery. Seventeen of these lesions were also examined after injection of vasomotor drugs. The authors conclude that these techniques permitted more precise endoscopic deliniation of the size and extent of cancerous lesions, particularly those otherwise obscured by overlying, intact epithelium."
1238,Music's Relevance for People Affected by Cancer: A Meta-Ethnography and Implications for Music Therapists.,"O'Callaghan CC, McDermott F, Reid P, Michael N, Hudson P, Zalcberg JR, Edwards J.",https://pubmed.ncbi.nlm.nih.gov/27980035/," By comparison, little is understood about music-based self-care. This meta-ethnography examined five published qualitative studies to extend understanding of music's relevance, including helpfulness, for people affected by cancer; including children, adolescents, and adults with cancer, carers, and the bereaved.
    


          
    


           Five studies were synthesized that included 138 participants: 26 children and 28 parents of children with cancer; 12 adolescents and young adults with cancer; 52 adults with cancer; 12 carers; and 8 bereaved. Studies' category and thematic findings were compared and integrated into third-order interpretations, and a line of argument. Perspectives from the five studies that illuminated the line of argument were developed.
    


           Music can be a lifeline, support biopsychosocial and spiritual well-being, or become elusive, that is, difficult to experience. Music helps or intrudes because it extends self-awareness and social connections, and prompts play, memories, imageries, and legacies. Music therapists may help patients and carers to recover or extend music's helpful effects.
    


          Conclusions:
        
      
      Cancer care can be improved through offering music-based resources/services, which give cancer patients and carers opportunities to extend music usage for personal support and, for carers, to support patients. Music therapists can advocate for such resources and educate health professionals about assessing/recognizing when patients' and carers' changed music behaviors signify additional support needs."
1239,Antioxidants: friends or foe in prevention or treatment of cancer: the debate of the century.,"Saeidnia S, Abdollahi M.",https://pubmed.ncbi.nlm.nih.gov/23680455/,"There are a number of intrinsic (e.g. oncogenes) and extrinsic (e.g. radiation and inflammation) factors, which may arise in reactive oxygen species (ROS),  In this situation, initial cancerous cells would balance the harmful effects of ROS by switching on the protective effects in a longstanding manner. In normal conditions, ROS have an important role in signal transduction and gene transcription, nevertheless, ROS may act as a trigger for carcinogenesis via persistent DNA injuries as well as mutations in p53 such as conditions observed in skin, hepatocellular, and colon cancers. Some compounds like paclitaxel are able to attack cancer cells through generation of ROS or interfering with ROS metabolism, while there are a few anti-angiogenesis compounds without toxicity such as endostatin, which act as anti-neoplastic only together with another chemotherapeutic drug. Furthermore, some anti-cancer agents like piperlongumine bind to the active sites of several key cellular antioxidants including glutathione S transferase and carbonyl reductase 1 only in the cancer cells. Although the natural antioxidants can alone or in combination with the diet provide some benefits for chemoprevention, their position in cancer therapy, especially initial stages of carcinogenesis is breaking down. On the other hand antioxidants can promote the survival of detached cells from extra cellular medium playing dual activities with respect to tumorigenesis through inhibition of tumorigenesis by preventing oxidative injuries to DNA and otherwise maintenance of tumor by promoting cell survival via metabolic rescue. Hopefully, more details of antioxidant and anti-neoplastic mechanisms become clear day by day, which have made researchers renew the strategy for designing cancer prevention or treatment."
1240,[Serum selenium contents in cancer patients].,"Ujiie S, Itoh Y, Kikuchi H, Wakui A.",https://pubmed.ncbi.nlm.nih.gov/9063475/,"The conclusions were confirmed by determining the serum Selenium levels in 2099 cancerous of non-cancerous patients as follows: 1) The mean serum Selenium levels of males is significantly higher than in females. 2) Serum Selenium levels tend to decrease with age. 3) The serum Selenium levels of cancerous patients is significantly lower than in non-cancerous patients. 4) No significant difference in the serum Selenium levels was observed between cancerous patients with and without metastasis. Most patients without metastasis are free from cancer after surgery, so the low serum Selenium level in cancerous patients may not be induced by the tumor but was present before the tumor."
1241,Preoperative predictors of cancerous involvement of the neurovascular bundles in patients with localized prostate cancer.,"Inoue T, Hioki T, Hayashi N, Takahashi S, Shirai T, Sugimura Y.",https://pubmed.ncbi.nlm.nih.gov/11972650/,"
    


           Preoperative prostate-specific antigen (PSA) and pathologic features in systematic biopsy specimens also were reviewed.
    


           The percentage of each biopsy specimen occupied by the cancer was scored from zero to four and defined as the positive biopsy score. Preoperative PSA (P = 0.046), mean positive biopsy score (total sum of positive biopsy score divided by number of biopsy specimens; P = 0.001), number of cores containing cancer (P = 0.011), percentage of cores involved (P = 0.036) and maximum positive biopsy score (P < 0.001) were significant for predicting cancerous involvement in the NVB region using univariate analysis. However, only the mean positive biopsy score was independently significant according to multivariate analysis. To predict cancerous involvement in the region of each NVB, we found that ipsilateral mean positive biopsy score (total sum of corresponding positive biopsy score divided by number of ipsilateral biopsy specimens), number of cores involved on the ipsilateral side, percentage of cores involved on the ipsilateral side and maximum positive biopsy score on the ipsilateral side were significant predictive variables: the ipsilateral mean positive biopsy score being most appropriate for clinical practice.
    


          Conclusion:
        
      
      Ipsilateral mean positive biopsy score in systematic biopsy specimens can be an appropriate variable for selecting patients with localized prostate cancer for nerve-sparing prostatectomy."
1242,Mammaglobin B gene as a novel marker for lymph node micrometastasis in patients with abdominal cancers.,"Aihara T, Fujiwara Y, Miyake Y, Okami J, Okada Y, Iwao K, Sugita Y, Tomita N, Sakon M, Shiozaki H, Monden M.",https://pubmed.ncbi.nlm.nih.gov/10755390/,"Mammaglobin B is a recently-isolated gene speculated to belong to the uteroglobin gene family and is overexpressed in primary breast cancers. We investigated mammaglobin B mRNA expression in various cancers of the digestive system. Given the absence of mammaglobin B expression in normal lymph nodes, we also assessed the usefulness of mammaglobin B as a marker for lymph node micrometastases in cancer patients. Mammaglobin B gene transcripts were frequently detected by reverse transcriptase-polymerase chain reaction (RT-PCR) assay in primary tumors of the esophagus (2/3), stomach (7/7), colon (15/15), pancreas (4/6), common bile duct (6/6), cholangioma (2/2) and gall bladder (1/1). Mammaglobin B overexpression was observed in three of 15 cases (20%) of colon cancer, suggesting its possible contribution to colon carcinogenesis. Down-regulated mammaglobin B expression was observed in hepatoma cells in comparison with corresponding non-cancerous livers (3/3). RT-PCR assay of mammaglobin B detected 14 of 15 histologically positive lymph nodes from patients with gastric cancer, colon cancer and cholangioma. Seven of 32 (22%), three of nine (33%), and three of seven (43%) histologically negative nodes from patients with gastric, colon and cholangiocellular carcinoma, respectively, were found to express mammaglobin B mRNA. Our "
1243,[Morphometric characteristics of the immunomorphological reactions in metastasizing and nonmetastasizing thyroid cancers].,"Kulaev IA, Kovalenko VL.",https://pubmed.ncbi.nlm.nih.gov/6971013/,"Morphometrically, immunomorphological reactions have been studied on the intraoperative material from 70 patients with thyroid cancer of various histological pattern. It was found that metastasization of cancerous tumors proceeds on the "
1244,Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer.,"Mitsudomi T, Yatabe Y.",https://pubmed.ncbi.nlm.nih.gov/19922469/,"Epidermal growth factor receptor (EGFR) and its three related proteins (the ERBB family) are receptor tyrosine kinases that play essential roles in both normal physiological conditions and cancerous conditions. Upon binding its ligands, dynamic conformational changes occur in both extracellular and intracellular domains of the receptor tyrosine kinases,  These provide docking sites for downstream molecules and lead to the evasion of apoptosis, to proliferation, to invasion and to metastases, all of which are important for the cancer phenotype. Mutation in the tyrosine kinase domain of the EGFR gene was found in a subset of lung cancers in 2002. Lung cancers with an EGFR mutation are highly sensitive to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib. Here, we review the discovery of EGFR, the EGFR signal transduction pathway and mutations of the EGFR gene in lung cancers and glioblastomas. The biological significance of such mutations and their relationship with other activated genes in lung cancers are also discussed."
1245,Efficacy of a photolyase-based device in the treatment of cancerization field in patients with actinic keratosis and non-melanoma skin cancer.,"Puviani M, Barcella A, Milani M.",https://pubmed.ncbi.nlm.nih.gov/24442053/,"Eryfotona AK-NMSC (ISDIN Spain) is a film-forming medical device in cream or fluid formulation containing the DNA-repair enzyme photolyase and high-protection UV filters in liposomes (repairsomes) indicated in the treatment of cancerization field in patients with actinic keratosis (AK) or non-melanoma skin cancer (NMSC). Photolyase is an enzyme that recognizes and directly repairs UV-induced DNA damage. The most common UV-induced DNA damage is the formation of cyclobutane pyrimidine dimers (CPD). Clinical studies evaluating the histological and cellular effects of Eryfotona AK-NMSC have shown a potential benefit in the treatment of the cancerization field in AK patients. In particular the use of Eryfotona AK-NMSC improves the confocal microscopic appearance of skin at the cancerization field level. In addition, Eryfotona AK-NMSC improves the p53 gene expression at keratinocyte level. In this study we reported a series of 6 cases of patients with AK or NMSC lesions treated with Eryfotona AK-NMSC fluid, both as coadjuvant and as single treatment, applied twice daily in the affected area with photograph documentation. Clinical photographs of the skin lesions at baseline and after Eryfotona AK-NMSC treatment were taken in all cases using a high-definition digital camera. Six patients with multiple AK lesions of the scalp or face with or without NMSC were treated for a mean of 1-3 months with Eryfotona AK-NMSC fluid formulation. Image documentations before and after treatment of this clinical series show a great improvement in AK lesions count and of cancerization field. This clinical series supports the clinical efficacy of the use of photolyase and high-protection UV filters in the treatment of cancerization field and AK lesions in patients with actinic damage."
1246,Moving Forward on Tumor Pathology Research Reporting: A Guide for Pathologists From the World Health Organization Classification of Tumors Living Evidence Gap Map by Tumour Type Group.,"Colling R, Indave I, Del Aguilla J, Cierco Jimenez R, Campbell F, Chechlinska M, Kowalewska M, Holdenrieder S, Trulson I, Worf K, Pollán M, Plans-Beriso E, Pérez-Gómez B, Craciun O, García-Ovejero E, Michalek IM, Maslova K, Rymkiewicz G, Didkowska J, Tan PH, Diyana Bte Md Nasir N, Myles N, Giesen C, Goldman-Lévy G, Lokuhetty D, Cree IA.",https://pubmed.ncbi.nlm.nih.gov/38763419/,"Evidence-based medicine (EBM) can be an unfamiliar territory for those working in tumor pathology research, and there is a great deal of uncertainty about how to undertake an EBM approach to planning and reporting histopathology-based studies. In this article, reviewed and endorsed by the Word Health Organization International Agency for Research on Cancer's International Collaboration for Cancer Classification and Research, we aim to help pathologists and researchers understand the basics of planning an evidence-based tumor pathology research study, as well as our recommendations on how to report the findings from these. We introduce some basic EBM concepts, a framework for research questions, and thoughts on study design and emphasize the concept of reporting standards. There are many study-specific reporting guidelines available, and we provide an overview of these. However, existing reporting guidelines perhaps do not always fit tumor pathology research papers, and hence, here, we collate the key reporting data set together into one generic checklist that we think will simplify the task for pathologists. The article aims to complement our recent hierarchy of evidence for tumor pathology and glossary of evidence (study) types in tumor pathology. Together, these articles should help any researcher get to grips with the basics of EBM for planning and publishing research in tumor pathology, as well as encourage an improved standard of the reports available to us all in the literature."
1247,Cancerous genetic peculiarities non-responsible for cancer development.,"Hirata Y, Hirata S.",https://pubmed.ncbi.nlm.nih.gov/12445502/,"Certain genetic peculiarities recently identified in cancer cells have generally been regarded as the abnormalities responsible for cancer development. However, these abnormalities may also be found in maturable cancer cells and are not limited only to the non-maturable type. As previously described by the authors, cancer tissue consists of two types of cancerous cells: maturable and non-maturable. The development of cancer may be dependent only on the non-maturable cancerous stem cells, not on the maturable type. Since the non-maturable cell may be solely responsible for carcinogenesis, the relevant genetic peculiarities that are also found in the maturable cancer cells should not be regarded as the abnormalities responsible for carcinogenesis."
1248,Transcriptional signals of transformation in human cancer.,"Kildisiute G, Kalyva M, Elmentaite R, van Dongen S, Thevanesan C, Piapi A, Ambridge K, Prigmore E, Haniffa M, Teichmann SA, Straathof K, Cortés-Ciriano I, Behjati S, Young MD.",https://pubmed.ncbi.nlm.nih.gov/38195504/," The transcriptomic profile of this final state may encode information about cancer's origin and how cancers relate to their normal cell counterparts.
    


           We utilised bulk transcriptomes across a wide spectrum of adult and childhood cancers, using a previously established  We extend and validate these findings using single-cell cancer transcriptomes and organ-specific atlases of colorectal and liver cancer.
    


           This finding was confirmed with single-cell cancer transcriptomes.
    


          Conclusions:
        
      
      Our findings provide a nuanced picture of transformation in human cancer, indicating cancer-specific rather than universal patterns of transformation pervade adult epithelial cancers."
1249,[Clinical observation of Ruyiping in preventing recidivation and metastasis of breast cancer].,"Liu S, Hua YQ, Sun ZP, Tan S, Lu DM.",https://pubmed.ncbi.nlm.nih.gov/17352869/,"
    


          
    


           The recidivation and metastasis rates were 5.41% and 7.89% respectively. The difference between the two groups was not statistically significant (P>0.05). The difference of disease-free survival time between the two groups was also not statistically significant.
    


          Conclusions:
        
      
      The effect of Ruyiping in preventing recidivation and metastasis is similar to that of Runing II. Ruyiping is the essential component of Runing II for preventing recidivation and metastasis. The "
1250,Increased expression of cysteine cathepsins in ovarian tissue from chickens with ovarian cancer.,"Ahn SE, Choi JW, Rengaraj D, Seo HW, Lim W, Han JY, Song G.",https://pubmed.ncbi.nlm.nih.gov/20727192/," These functions are also related to cancer cell invasion and metastasis. Chickens spontaneously develop epithelial ovarian cancer and are therefore a good animal model for human ovarian cancer. However, no studies have investigated the expression of CTSs in chickens with ovarian cancer.
    


           Ovarian cancers were evaluated with hematoxylin and eosin staining. Reverse transcriptase and quantitative PCR analyses, in situ hybridization analysis were performed to examine the mRNA expression pattern of three CTSs in detail, and protein expression of CTSB was evaluated.
    


           Messenger RNAs for the three CTSs were localized to a nodule area, a major characteristic of cancerous ovaries, but the three CTSs showed no specific localization in normal ovaries. Immunoreactive CTSB protein was present in the nodule area of cancerous ovaries.
    


          Conclusion:
        
      
      Our "
1251,MiRNA targets of prostate cancer.,"Deng JH, Deng Q, Kuo CH, Delaney SW, Ying SY.",https://pubmed.ncbi.nlm.nih.gov/23007521/,"Prostate cancer (PC) is the most prevalent strain of cancer in men, but it is often slow-acting or undetected. Common diagnostic tools for PC include prostate biopsy and consequent analysis by the Gleason scoring of the tissue samples, as well as tests for the presence and levels of prostate-specific antigens. Common treatments for androgen-dependent PC include prostatectomy or irradiation, which can be invasive and significantly lower the patient's quality of life. Alternative treatments exist, such as androgen ablation therapy, which, though effective, causes relapse into androgen-independent PC, which is far more invasive and likely to metastasize to other parts of the body. MicroRNAs (miRNA) are short nucleotide sequences (between 19 and 25 nucleotides long) that bind to various targeted messenger RNA (mRNA) sequences post-transcriptionally through complementary binding and control gene expression, often through silencing or leading to the degradation of targeted mRNA. Studies have shown that miRNAs are expressed abnormally in various cancers, suggesting that they play a pivotal role in cancer development and progression. Some miRNAs are oncogenes that incite cancerous growth, while others are involved in tumor suppression and cell cycle controls. MiRNA expression also differs in various types of cancers. Studies of PC-specific miRNAs show potential for their utilization in the prevention, diagnosis, and treatment of PC to more effectively target tumor growth and provide patients with better therapeutic options."
1252,Borderline and malignant serous tumor arising in pelvic lymph nodes: evidence of origin in benign glandular inclusions.,"Prade M, Spatz A, Bentley R, Duvillard P, Bognel C, Robboy SJ.",https://pubmed.ncbi.nlm.nih.gov/7883433/,"This report describes two cases of malignant serous cancers with areas of borderline malignancy, which appear to have arisen within benign glandular inclusions of coelomic origin in pelvic or para-aortic lymph nodes. The patients were 44 and 62 years of age. In both cases the nodes contained benign glandular inclusions lined by a single layer of epithelium which resembled that of tubal epithelium. The location of the glandular epithelium varied from within the fat near the node to intracapsular, subcapsular, or interfollicular positions. The number of glands ranged from few to extensive. In both cases the glandular inclusions disclosed epithelial proliferations, ranging from minor degrees of stratification with formation of small papillae of atypical cells (borderline serous tumor) to almost solid tumor typical of serous cancer. In both cases, the borderline and cancerous tumors exhibited areas of transition which appeared to arise from benign glands. Although benign glandular inclusions of coelomic origin are well documented to occur in pelvic or para-aortic lymph nodes of 5-20% of women and have been considered to be of significance only because of the possibility of the misdiagnosis of cancer, it should now be recognized that the glandular inclusion cysts themselves can become neoplastic."
1253,A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.,"Gentry SN, Jackson TL.",https://pubmed.ncbi.nlm.nih.gov/23990931/,"Hierarchical organized tissue structures, with stem cell driven cell differentiation, are critical to the homeostatic maintenance of most tissues, and this underlying cellular architecture is potentially a critical player in the development of a many cancers. Here, we develop a mathematical model of mutation acquisition to investigate how deregulation of the mechanisms preserving stem cell homeostasis contributes to tumor initiation. A novel feature of the model is the inclusion of both extrinsic and intrinsic chemical signaling and interaction with the niche to control stem cell self-renewal. We use the model to simulate the effects of a variety of types and sequences of mutations and then compare and contrast all mutation pathways in order to determine which ones generate cancer cells fastest. The model predicts that the sequence in which mutations occur significantly affects the pace of tumorigenesis. In addition, tumor composition varies for different mutation pathways, so that some sequences generate tumors that are dominated by cancerous cells with all possible mutations, while others are primarily comprised of cells that more closely resemble normal cells with only one or two mutations. We are also able to show that, under certain circumstances, healthy stem cells diminish due to the displacement by mutated cells that have a competitive advantage in the niche. Finally, in the event that all homeostatic regulation is lost, exponential growth of the cancer population occurs in addition to the depletion of normal cells. This model helps to advance our understanding of how mutation acquisition affects mechanisms that influence cell-fate decisions and leads to the initiation of cancers."
1254,[Beyond actinic keratoses: Field cancerization of the skin].,"Reygagne P, Rostain G.",https://pubmed.ncbi.nlm.nih.gov/30243819/,"Lesions occurring in actinic keratoses (AK) form erythematous, squamous, crusty and keratotic papules that appear on skin chronically exposed to the sun due to ultraviolet radiation. They are formed by the proliferation of atypical keratinocytes limited to the epidermis and may progress to squamous cell carcinoma in situ and to cutaneous squamous cell carcinoma (CEC). Although low, the metastatic risk associated with the CEC is not negligible. The concept of field cancerization was introduced in 1953 following studies of neoplastic lesions of the oral mucosa. A cancer field is a normal-looking pre-tumoral zone with subclinical, multifocal anomalies, which may constitute a base for new neoplastic lesions. Such fields are frequently seen in areas of photo-exposed skin and around the edges of AK and CEC. In this event, treatment should not be limited to visible or palpable AK lesions, and if a cancer field is suspected, treatment involving the physical destruction or elimination of atypical keratinocytes from the entire area should be considered. Such an approach may improve the long-term prognosis, reduce treatment costs and ensure optimal cosmetic outcome."
1255,Immunohistochemical and immunoblot analyses of ras-p21 expression in lung carcinomas.,"Koshiishi Y, Noguchi M, Nakajima T, Hirohashi S, Shimosato Y, Hayata Y.",https://pubmed.ncbi.nlm.nih.gov/2686349/,"Immunohistochemical and immunoblot analyses were performed on 49 cases of surgically resected primary lung carcinoma to examine the expression of ras oncogene product using monoclonal antibodies to ras-p21. Two different monoclonal antibodies, NCC-RAS-001 and RAP-5 were used for immunohistochemical study. Cancer cells of 16 cases (33%) and 15 cases (31%) were strongly positive for NCC-RAS-001 and RAP-5, respectively. The staining pattern of antibodies was heterogenous among cancer cells, even in the same case. Among various histologic type of lung cancers, squamous cell carcinomas and well-differentiated adenocarcinomas had a tendency to react more intensively than other histologic types of carcinoma. Immunoblot analysis using monoclonal antibody NCC-RAS-004 revealed the presence of ras-p21 not only in cancer tissues but also in non-cancerous tissues in all cases analysed. In 13 cases (27%), cancer tissue expressed more than twice as much ras-p21 as non-cancerous tissues. Our study showed that the over-expression of ras-p21 in lung carcinomas compared with non-cancerous tissues was a relatively common phenomenon, especially in squamous cell carcinomas and adenocarcinomas."
1256,Frequent CYP1A1 expression in gastric cancers and their related lesions.,"Zhang KL, Ma JX, Chen XY, Sun Y, Kong QY, Liu J, Li H.",https://pubmed.ncbi.nlm.nih.gov/15547760/,"CYP1A1 expression in various tissues of 43 gastric cancer cases was analyzed with frozen tissue array-based immunohistochemical staining (IHC), RT-PCR, Western blot analysis and EROD (7-ethoxyresourfin-O-deethylase) assay. CYP1A1 was detected immunohistochemically in 86% (37/43) of gastric cancers, in both 57% (4/7) of atrophic gastritis and intestinal metaplasia and in 7.7% (1/13) of non-cancerous mucosa. RT-PCR and Western blot analysis revealed coincident  EROD assay showed increased CYP1A1/1B1 activity in either cancer or premalignant tissues but not in non-cancerous ones. The frequencies of CYP1A1 expression are significantly different between non-cancerous and premalignant (P<0.025) or cancer groups (P<0.005), suggesting that CYP1A1 is expressed at relatively early stage of gastrocarcinogenesis and exerts its effects throughout the stepwise oncogenic processes."
1257,Effect of neoadjuvant chemotherapy on the immune microenvironment of gynaecological tumours.,"Xue J, Yan X, Ding Q, Li N, Wu M, Song J.",https://pubmed.ncbi.nlm.nih.gov/37983527/,"Purpose: To assess the impact of neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment (TIME) in gynaecological tumors, with a focus on understanding the potential for enhanced combination therapies. In cervical cancer, NACT boosts immune-promoting cells, enhancing tumor clearance. Ovarian cancer studies yield variable outcomes, influenced by patient-specific factors and treatment regimens. Limited research exists on NACT's impact on endometrial cancer's immune microenvironment, warranting further exploration. In summary, NACT-induced immune microenvironment changes display variability. Clinical trials highlight personalized immunotherapy's positive impact on gynaecological tumor prognosis, suggesting potential avenues for future cancer treatments. However, rigorous investigation is needed to determine the exact efficacy and safety of combining NACT with immunotherapy.Conclusion: This review provides a solid foundation for the development of late-stage immunotherapy and highlights the importance of therapeutic strategies targeting immune cells in TIME in anti-tumor therapy."
1258,Characterizing inhibited tumor growth in stem-cell-driven non-spatial cancers.,"Rodriguez-Brenes IA, Wodarz D, Komarova NL.",https://pubmed.ncbi.nlm.nih.gov/26344137/,"Healthy human tissue is highly regulated to maintain homeostasis. Secreted negative feedback factors that inhibit stem cell division and stem cell self-renewal play a fundamental role in establishing this control. The appearance of abnormal cancerous growth requires an escape from these regulatory mechanisms. In a previous study we found that for non-solid tumors if feedback inhibition on stem cell self-renewal is lost, but the feedback on the division rate is still intact, then the tumor dynamics are characterized by a relatively slow sub-exponential growth that we called inhibited growth. Here we characterize the cell dynamics of inhibited cancer growth by modeling feedback inhibition using Hill equations. We find asymptotic approximations for the growth rates of the stem cell and differentiated cell populations in terms of the strength of the inhibitory signal: stem cells grow as a power law t(1/k+1),and the differentiated cells grow as t(1/k), where k is the Hill coefficient in the feedback law regulating cell divisions. It follows that as the tumor grows, undifferentiated cells take up an increasingly large fraction of the population. Implications of these  Understanding how the regulatory mechanisms that continue to operate in cancer affect the rate of disease progression can provide important insights relevant to chronic or other slow progressing types of cancer."
1259,Simulating the healthcare workforce impact and capacity for pancreatic cancer care in Victoria: a model-based analysis.,"Gao L, Ugalde A, Livingston PM, White V, Watts JJ, Jongebloed H, McCaffrey N, Menzies D, Robinson S.",https://pubmed.ncbi.nlm.nih.gov/38395852/," With improvements in knowledge for screening and early detection, earlier detection of pancreatic cancer will continue to be more common. To support workforce planning, our aim is to perform a model-based analysis that simulates the potential impact on the healthcare workforce, assuming an earlier diagnosis of pancreatic cancer.
    


          e. new cases of pancreatic cancer) and supply (i.e. the healthcare workforce including general surgeons, medical oncologists, radiation oncologists, pain medicine physicians, and palliative care physicians) between 2023 and 2027 in Victoria, Australia. The model compares the current scenario to one in which pancreatic cancer is diagnosed at an earlier stage. The incidence of pancreatic cancer in Victoria, five-year survival rates, and Victoria's population size were obtained from Victorian Cancer Registry, Cancer Council NSW, and Australian Bureau of Statistics respectively. The healthcare workforce data were sourced from the Australian Government Department of Health and Aged Care's Health Workforce Data. The model was constructed at the remoteness level. We analysed the new cases and the number of healthcare workforce by profession together to assess the impact on the healthcare workforce.
    


           Assuming 20-70% of the shift towards pancreatic cancer's earlier diagnosis (shifting from stage IV to stages I-II pancreatic cancer within one year), the stages I-II cases could increase to 351 to 390 or 598 to 665 per year. The shift to early diagnosis led to substantial survival gains, translating into an additional 284 or 795 out of 5246 patients with pancreatic cancer remaining alive up to year 5 post-diagnosis. Workforce supply decreases significantly by the remoteness levels, and remote areas face a shortage of key medical professionals registered in delivering pancreatic cancer care, suggesting travel necessities by patients or clinicians.
    


          Conclusion:
        
      
      Improving the early detection and diagnosis of pancreatic cancer is expected to bring significant survival benefits, although there are workforce distribution imbalances in Victoria that may affect the ability to achieve the anticipated survival gain."
1260,Outcomes and Trends of Treatments in High-Risk Differentiated Thyroid Cancer.,"Abiri A, Goshtasbi K, Torabi SJ, Kuan EC, Armstrong WB, Tjoa T, Haidar YM.",https://pubmed.ncbi.nlm.nih.gov/35471863/,"
    


          Study design:
        
      
      Retrospective cohort study.
    


          Setting:
        
      
      National Cancer Database.
    


           Cox proportional hazards and Kaplan-Meier analyses assessed for treatment-associated survival.
    


          6 ± 17.1 years (71.3% female). When compared with surgery alone, S + RAI was associated with reduced mortality in papillary (hazard ratio [HR], 0.574; P < .001) and follicular (HR, 0.489; P = .004) thyroid cancer. S + RAI + THST was associated with reduced mortality in papillary (HR, 0.514; P < .001), follicular (HR, 0.602; P = .016), and Hurthle cell (HR, 0.504; P = .021) thyroid cancer. In papillary thyroid cancer, S + RAI (91.3%), S + THST (89.2%), and S + RAI + THST (92.7%) were associated with higher 5-year overall survival rates than surgery (85.4%, all P < .001). Papillary thyroid cancer treatments involving THST were associated with higher 5-year overall survival rates than corresponding regimens without THST (all P < .001). In follicular thyroid cancer, S + RAI (73.9%) and S + RAI + THST (78.7%) were associated with higher 5-year overall survival rates than surgery (65.6%, all P < .05). In Hurthle cell thyroid cancer, S + RAI (66.5%) and S + RAI + THST (73.4%) were associated with higher 5-year overall survival rates than surgery (53.7%, all P < .05). On linear regression, THST usage increased by 77.5% (R2 = 0.944, P < .001), while RAI usage declined by 11.3% (R2 = 0.320, P = .035).
    


          Conclusions:
        
      
      High-risk differentiated thyroid cancer exhibited varying susceptibilities to different treatment combinations depending on histology, with greatest responses to regimens that included RAI. Physician practices have trended toward decreased RAI and increased THST usage."
1261,Discriminating bladder cancer cells through rheological mechanomarkers at cell and spheroid levels.,"Gnanachandran K, Kędracka-Krok S, Pabijan J, Lekka M.",https://pubmed.ncbi.nlm.nih.gov/36252307/,"The stiffening or softening of cancers observed in nanoindentation  In bladder cancers, continuous stretching/destretching is observed due to its functionality, indicating that shear forces dominate the mechanical response of these cells. Thus, nanoindentation and microrheological measurements conducted in parallel allow for a fully reliable mechanomarker of cancer progression. Here, bladder cancer cell lines, i.e., non-malignant cell cancer of the ureter (HCV29), bladder carcinoma (HT1376), and transitional cell carcinoma (T24), were studied. Nanoindentation and microrheological  The  Applying microrheology recognizes the type of grade 3 bladder cancers (carcinoma HT1376 or transitional cell carcinoma T24 cells). We showed that actin filaments are a vital element defining the rheological properties of spheroids. Differences in mechanical properties of cell monolayers could be associated with thick actin bundles and intercellular connections, with some extracellular matrix (ECM) contributing to the stiffening of such monolayers. Our findings demonstrate that a complete image of how cancer cells respond to mechanical stress (compressive and shear forces) can only be obtained after microrheological measurements using the transition frequency separating elastic and viscous regimes as a non-labeled biomarker of bladder cancer progression."
1262,[New methods of urinary bladder cancer detection at the early stage of the disease in patients of various ages].,Kheĭfets VKh.,https://pubmed.ncbi.nlm.nih.gov/15559503/,"In the sickness rate's structure of the malignant neoplasms the urological localization take 6.8 per cent (%). Among them 70% is cancer of the urinary organs. The average age of the patients with cancer of the urinary bladder is from 65.2 to 69.7 years old. The use of fluorescent cystoscopy allows to improve the quality of the diagnostics of the urinary bladder's mucous' neoplastic changes. It is illustrated that the fluorescent cystoscopy's sensitivity is 96.9-98.7% and exeeds the sensitivity of simple cystoscopy research  Carcinoma in situ was found 2 times more often than with the help of traditional cystoscopy and ""blind"" biopsy. Carrying out urinary bladder's wall transuretral resection under the photodynamic control increases the radical character of the endoscopic operation and allows to reduce the quantity of cancer's relapses by decreasing the amount of residual tumors. The test examination (in a year after the operation) has shown that the tumor's recurrences were registered 2.2 times more seldom in those group of patients, which had the neoplasms extracted under the photodynamic control."
1263,Co-Expression of TWIST1 and ZEB2 in Oral Squamous Cell Carcinoma Is Associated with Poor Survival.,"Kong YH, Syed Zanaruddin SN, Lau SH, Ramanathan A, Kallarakkal TG, Vincent-Chong VK, Wan Mustafa WM, Abraham MT, Abdul Rahman ZA, Zain RB, Cheong SC.",https://pubmed.ncbi.nlm.nih.gov/26214683/,"Oral squamous cell carcinoma (OSCC) is an aggressive disease accounting for more than 260,000 cancer cases diagnosed and 128,000 deaths worldwide. A large majority of cancer deaths  The relationship between genetic changes and clinical outcome can reflect the biological events that promote cancer's aggressive behavior, and these can serve as molecular markers for improved patient management and survival. To this end, epithelial-mesenchymal transition (EMT) is a major process that promotes tumor invasion and metastasis, making EMT-related proteins attractive diagnostic biomarkers and therapeutic targets. In this study, we used immunohistochemistry to study the expression of a panel of transcription factors (TWIST1, SNAI1/2, ZEB1 and ZEB2) and other genes intimately related to EMT (CDH1 and LAMC2) at the invasive tumor front of OSCC tissues. The association between the expression of these proteins and clinico-pathological parameters were examined with Pearson Chi-square and correlation with survival was analyzed using Kaplan Meier analysis. Our  Specifically, CDH1 loss was significantly associated with Broder's grading, while diffused LAMC2 was similarly associated with non-cohesive pattern of invasion. Notably, co-expression of TWIST1 and ZEB2 in OSCC was significantly associated with poorer overall survival, particularly in patients without detectable lymph node metastasis. This study demonstrates that EMT-related proteins are differentially expressed in OSCC and that the co-expression of TWIST1 and ZEB2 could be of clinical value in identifying patients with poor survival for appropriate patient management."
1264,Expression analysis of URI/RMP gene in endometrioid adenocarcinoma by tissue microarray immunohistochemistry.,"Gu J, Liang Y, Qiao L, Li X, Li X, Lu Y, Zheng Q.",https://pubmed.ncbi.nlm.nih.gov/24228101/,"Multiple studies have recently demonstrated the oncogenic property of URI (or RMP, a member of the prefoldin family of molecular chaperones) during progression of hepatocellular carcinoma, ovarian cancer, and possibly prostate cancer. Most recently, we have shown that URI/RMP is up-regulated in cervical cancer, another reproductive system tumor beside ovarian and prostate cancers. To investigate if URI/RMP also plays a role in other reproductive system tumors, especially in endometrioid adenocarcinoma, we analyzed URI/RMP expression in a TMA (tissue microarray) containing tissues from 30 cases of endometrioid adenocarcinoma (which covers tumor tissues from Grade I through Grade III) and adjacent endometrium by immunohistochemistry (IHC) and densitometry analysis using image-pro plus 6.0 software. Our 05). There is no significant difference either between the mean density of Grade III cancerous tissue and that of Grade I and II cancers. Notably, we detected significantly higher signal intensity in cancerous tissue of all 7 Grade III cases than that of their adjacent endometrial tissue (p<0.05), suggesting a correlation of URI/RMP expression with the differentiation and pathological classification of endometrioid adenocarcinoma. Together, our  The higher level of URI/RMP expression in high-grade endometrioid adenocarcinomas compared to tissues of adjacent endometrium or gland suggests a diagnostic and possibly, a prognostic value of URI/RMP in endometrioid adenocarcinoma."
1265,Cell-specific frequency as a new hallmark to early detection of cancer and efficient therapy: Recording of cancer voice as a new horizon.,"Jafari M, Hasanzadeh M.",https://pubmed.ncbi.nlm.nih.gov/31918289/,"Early detection is the most important strategy for controlling and management of cancer, which can significantly increase the survival rate by detecting disease in the early stages and rapid treating and preventing the progression of the disease. There are a number of  The  Also, the  There are more evidences for the existence of specific cell frequencies in the form of the response of each cell to its own specific frequency and the difference between normal and tumor cell frequency levels. Based on these evidences, it can be introduced as a hallmark with the ability to the distinction between normal and tumor cells for cancer detection. Our suggestion is to hear the voice of cancer, by designing and developing a non-invasive, biocompatible, affordable and miniaturized tools, such as nano-antennas and implantable biosensors that able to detect and record cell-specific frequencies. Designing transducers to convert the cell-specific frequency to a sound or other measurable signal will accomplish the job. To the best of our knowledge, this is the first time that the cell-specific frequency measurement, which is derived from cell activity, is introduced as a biomarker for early detection of cancer. The development of studies aimed at expanding research and designing instruments for detection of the frequency with the goal of establishing a comparative library of cell-specific frequency for all cell types, especially non-communicable diseases such as cancer. The main goal of the project is to plan the idea of developing modern tools and hallmark for early detection of cancer as one of the most important global strategies for managing the disease by introducing new parameters with a high-accuracy and in proportion and direct relationship with the activity and functioning of the body, without any affecting exogenous interferer."
1266,Detection of squamous cell cancer and pre-cancerous lesions by imaging of tissue autofluorescence in the hamster cheek pouch model.,"Kluftinger AM, Davis NL, Quenville NF, Lam S, Hung J, Palcic B.",https://pubmed.ncbi.nlm.nih.gov/1341249/,"Early detection of invasive and pre-invasive neoplasms of the aerodigestive tract will ultimately improve the management of patients with these lesions. This paper describes the use of quantitative fluorescence imaging of early squamous cell carcinomas in an animal model. Dysplasia, carcinoma in situ and invasive cancers were imaged exploiting tumour autofluorescence. Mapped biopsies were obtained from areas imaged determining a sensitivity of 100% and specificity of 80%. Autofluorescence imaging is an excellent "
1267,Recurrent non-melanoma skin cancer: remission of field cancerization after conversion from calcineurin inhibitor- to proliferation signal inhibitor-based immunosuppression in a cardiac transplant recipient.,"Signorell J, Hunziker T, Martinelli M, Koestner SC, Mohacsi PJ.",https://pubmed.ncbi.nlm.nih.gov/21094874/,"Non-melanoma skin cancers (NMSCs) are the most common malignancies after solid organ transplantation. Their incidence increases with time after transplantation. Calcineurin-inhibitors (CNIs) and azathioprine are known as skin neoplasia-initiating and -enhancing immunosuppressants. In contrast, increasing clinical experience suggests a relevant antiproliferative effect of mammalian target of rapamycin inhibitors, also named proliferation signal inhibitors (PSIs). We report the case of a cardiac allograft recipient with an impressive and consolidated reduction of recurrent NMSC, observed after conversion from CNI-therapy to a PSI-based protocol."
1268,Primary Squamous Cell Carcinoma of the Stomach: A Case Report and Review of the Literature.,"Segura S, Pender J, Dodge J, Brandwein SL, El-Fanek H.",https://pubmed.ncbi.nlm.nih.gov/27265923/,"Primary gastric squamous cell carcinoma (PGSCC) is an exceedingly rare disease, accounting for 0.04% - 0.07% of all gastric cancers. First reported in 1895 by Rörig et al, less than 100 cases of PGSCC worldwide have been reported in the literature. These reports show PGSCC is more common in males (5:1 male to female ratio), and exhibits a peak incidence in the sixth decade of life. It may involve any portion of the stomach with predilection for the proximal stomach, especially along the lesser curvature. Although no clear pathogenesis of this tumor has been reported, several plausible theories have been proposed. These include squamous differentiation of preexisting gastric adenocarcinoma, cancerization of ectopic squamous epithelium, malignant transformation of squamous metaplasia of glandular epithelium, association with Helicobacter pylori or Epstein-Barr virus infection, and evolution in the setting of marked chronic gastritis with intestinal metaplasia. This report presents and discusses the case of a 64-year-old female who developed PGSCC arising in the gastric fundus."
1269,Immunological processes of enhancers and suppressors of long non-coding RNAs associated with brain tumors and inflammation.,"Tahmasebi Dehkordi H, Khaledi F, Ghasemi S.",https://pubmed.ncbi.nlm.nih.gov/37974420/,"Immunological processes, such as inflammation, can both cause tumor suppression and cancer progression. Moreover, deregulated levels of long non-coding RNA (lncRNA) expression in the brain may cause inflammation and lead to the growth of tumors. Like other biological processes, the immune system's role in cancer is complicated, varies, and can help or hurt the cancer's maintenance. According to research, inflammation and brain cancer are correlated via several signaling pathways. A variety of lncRNAs have recently been revealed to influence cancer by modulating inflammatory pathways. As a  Although the study and targeting of lncRNAs have made great progress in the treatment of cancer, there are definitely limitations and challenges. Using new technologies like nanocarriers and cell-penetrating peptides (CPPs) to target treatments without hurting healthy body tissues has shown to be very effective. In this review article, we have collected significantly related lncRNAs and their inhibitory or stimulating roles in inflammation and brain cancer for the first time. However, there are limitations, such as side effects and damage to normal tissues. With the advancement of new targeting technologies, these lncRNAs may be candidates for the specific targeting therapy of brain cancers by limiting inflammation or stimulating the immune system against them in the future."
1270,Intracellular pH-Regulating Nanoparticles to Improve Anticancer Drug Efficacy for Cancer Treatment.,"Lee T, Kim KS, Na K.",https://pubmed.ncbi.nlm.nih.gov/36223489/,"Here, we describe an intracellular pH-regulating nanoparticle (IPRN), coencapsulated with chemosensitizers and anticancer agents for effective and safe cancer treatment. IPRN contains a tubulysin derivative (TUB), a hydrophobic anticancer drug, and pantoprazole (PTZ), a hydrophilic proton-pump inhibitor. IPRN with a size of 62 nm has an anionic surface charge and is stable for at least two weeks under storage conditions, though PTZ and TUB encapsulated in IPRN showed different drug release patterns. PTZ was released before TUB, controlling the cancer's intracellular pH, maintaining a pH at which TUB can work well. The encapsulated PTZ increased the pH of endolysosomes and inhibited ion trapping, with TUB ionization, thereby exhibiting increased cytotoxicity compared with free TUB observed in various cancer cell lines, such as human liver adenocarcinoma, human glioblastoma, and human pancreatic carcinoma. IPRN exhibited a 1.9-fold improved tumor growth inhibitory effect in a human liver adenocarcinoma-bearing mouse model, while minimizing the hepatotoxicity of free TUB. Thus, nanomedicines that contain both a chemosensitizer and an anticancer agent, such as IPRN, are expected to be next-generation anticancer agents that reduce the side effects of anticancer drugs and increase the therapeutic effect."
1271,Development and assessment of morphologic criteria for diagnosing gastric cancer using confocal endomicroscopy: an ex vivo and in vivo study.,"Kakeji Y, Yamaguchi S, Yoshida D, Tanoue K, Ueda M, Masunari A, Utsunomiya T, Imamura M, Honda H, Maehara Y, Hashizume M.",https://pubmed.ncbi.nlm.nih.gov/16981104/," and Pentax Corp.) is a newly developed imaging tool that uses laser light and optical technology to visualize living tissue at the cellular level. Digital images of cells magnified 1000-fold appear in real time on a computer screen, which enables immediate detection of changes in cellular structure without the need for a biopsy. The aim of this study was to assess the features of the cellular architecture of cancerous tissue that can be used in the differential diagnosis of cancerous tissue and normal mucosa using this system's image-processing software.
    


          Patients and  A fluorescent contrast agent, acriflavine, was applied topically to normal and to cancerous mucosa. In vivo imaging of the gastric mucosa after intravenous injection of fluorescein sodium was also performed in nine patients with gastritis or gastric cancer.
    


           The mean nuclear area of cancer cells was found to be significantly larger than that of normal cells in 18/27 gastric cancers (67 %). The mean nuclear area of the cancers tended to be larger than that of normal mucosa, especially in cases of differentiated adenocarcinoma. In more than half the cases, it was possible to diagnose malignancy automatically using confocal endomicroscopy and image-processing software without the need for biopsy and pathological examination. In vivo imaging of cancerous lesions showed irregularity in cellularity and vascularity.
    


          Conclusion:
        
      
      The ability of this imaging device to differentiate between normal tissue and cancerous tissues gives it potential value as a new screening tool for early detection of malignancy."
1272,Radioimmunotherapy for peritoneal cancers.,"Seidl C, Essler M.",https://pubmed.ncbi.nlm.nih.gov/23557422/,"Peritoneal carcinomatosis is the most common secondary cancerous disease to affect the peritoneal cavity, implying poor prognosis. Standard therapy consists of cytoreductive surgery in combination with adjuvant chemotherapy. To improve the therapeutic outcome, targeted therapy using radionuclides such as α-, β- and Auger emitters coupled to antibodies seems a promising option. Although β-emitters have shown promising  Because α-particles very efficiently eradicate small tumor cell nodules, they represent a promising option for treatment of micrometastatic disease characteristic of peritoneal carcinomatosis. α-emitter radioimmunoconjugates have been successfully used in various  Although confirmation of these "
1273,PAK4 confers the malignance of cervical cancers and contributes to the cisplatin-resistance in cervical cancer cells via PI3K/AKT pathway.,"Shu XR, Wu J, Sun H, Chi LQ, Wang JH.",https://pubmed.ncbi.nlm.nih.gov/26411419/," Particular those, which are associated with the chemo- or radio-resistance of cervical cancers, have been proposed to be promising and to facilitate the definition for cervical cancer treatment options.
    


          
    


           The high PAK4 expression was also independently associated with poor prognosis to cervical cancer patients. Moreover, PAK4 confers cisplatin resistance in cervical cancer Hela or Caski cells. In addition, the PI3K/Akt pathway has been implicated in the PAK4-confered cisplatin resistance. And the PI3K/Akt inhibitor, LY294002, markedly deteriorated the cisplatin-mediated viability reduction of Hela or Caski cells, indicating the involvement of PI3K/Akt pathway in the cisplatin resistance in cervical cancer cells.
    


          Conclusion:
        
      
      This study has confirmed the significant prognostic role of PAK4 level in cervical cancer patients and has recognized the regulatory role in cervical cancer progression. Moreover, our study has indicated that PAK4 also confers the chemoresistance of cervical cancer cells in a PI3K/Akt-dependent way. Thus, our study indicates PAK4 as a promising marker for cervical cancer treatment."
1274,Immune Checkpoint Blockade in Advanced Cutaneous Squamous Cell Carcinoma: What Do We Currently Know in 2020?,"Wessely A, Steeb T, Leiter U, Garbe C, Berking C, Heppt MV.",https://pubmed.ncbi.nlm.nih.gov/33291277/,"Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer that predominantly arises in chronically sun-damaged skin. Immunosuppression, genetic disorders such as xeroderma pigmentosum (XP), exposure to certain drugs and environmental noxae have been identified as major risk factors. Surgical removal of cSCC is the therapy of choice and mostly curative in early stages. However, a minority of patients develop locally advanced tumors or distant metastases that are still challenging to treat. Immune checkpoint blockade (ICB) targeting CTLA-4, PD-L1 and PD-1 has tremendously changed the field of oncological therapy and especially the treatment of skin cancers as tumors with a high mutational burden. In this review, we focus on the differences between cSCC and cutaneous melanoma (CM) and their implications on therapy, summarize the current evidence on ICB for the treatment of advanced cSCC and discuss the chances and pitfalls of this therapy option for this cancer entity. Furthermore, we focus on special subgroups of interest such as organ transplant recipients, patients with hematologic malignancies, XP and field cancerization."
1275,Tracking the seed and tending the soil: evolving concepts in metastatic breast cancer.,Comen EA.,https://pubmed.ncbi.nlm.nih.gov/22935206/,"Metastasis, the process whereby cancer cells spread from their primary site of origin and grow in adjacent or distant sites, is the primary cause of death in cancer patients. The last 30 years has witnessed significant progress in decreasing cancer mortality rates--largely as a  Despite these improvements, metastasis relentlessly drives mortality. The pervasive mortality from metastasis highlights the shortcomings of traditionally accepted hypotheses on the metastatic process. Historically, metastasis has been described as a unidirectional process, whereby cancer cells leave a primary tumor and seed metastasis in regional lymph nodes or distant sites. This anatomically based hypothesis has dictated much of our medical, and in particular, surgical approach to treating cancers. Alternatively, recent research indicates that metastasis is a multidirectional process whereby cancer cells can seed distant sites as well as the primary tumor itself. The multidirectional pathway of cancer cells, termed ""self-seeding,"" has been corroborated in several  This review will evaluate the ""self-seeding"" hypothesis with attention both to the ""seed"" (cancer cells) as well as the ""soil"" (premetastatic niche). Increasingly, the role of the microenvironment surrounding metastases appears essential to the survival of metastatic colonies. The self-seeding model depends not only on the inherent mobility of cancer cells, but also on the supporting non-cancerous cells which enable circulating tumors cells to migrate to and survive in distant sites. The recognition that some of these non-cancerous cells include key components of the immune system has re-ignited the field of immunotherapy in cancer. One particular area of immunotherapy research, tumor entrained neutrophils, will be reviewed in more depth. Ultimately, understanding the dynamic interplay between cancer cells and the metastatic niche offers fertile ground for progress both in the treatment and prevention of metastasis."
1276,"Refute the conclusion made by Jie et al. in ""prognostic role of microRNA-100 in various carcinomas: evidence from six studies"".","Chen D, Zhou Y, Du H, Che G.",https://pubmed.ncbi.nlm.nih.gov/24903380/,"Recently, we had the honor of reading a meta-analysis article published in Tumor Biology which was completed by Jie et al. Because of our interest in the correlations between microRNAs (miRs) and human cancer prognosis, we carefully read the entire article. Jie et al. put forward a standpoint that deregulation of miR-100 in cancerous tissues could significantly predict poor survival in various carcinomas. The pooled hazard ratio (HR) with 95 % confidence interval (CI) was 2.19 (1.49-3.24, p = 0.0007). The reliability of the meta-analysis is reciprocally higher than traditional and narrative reviews. Furthermore, the reliability is exclusively dependent on reference retrieval, incorporating eligible articles as comprehensive as possible, and proper and accurate data extraction. We found several critical errors in their meta-analysis, and its conclusion was unbelievable and might misguide readers. According to their statistical strategies, we also conducted a meta-analysis to reevaluate the relationship between deregulation of miR-100 and human cancer prognosis for rectification. The present studies are not powerful enough to demonstrate the prognostic role of miR-100 in human cancers, and thus, much more works are needed in this field."
1277,Pilot study on confocal endomicroscopy for determination of the depth of squamous cell esophageal cancer in vivo.,"Iguchi Y, Niwa Y, Miyahara R, Nakamura M, Banno K, Nagaya T, Nagasaka T, Watanabe O, Ando T, Kawashima H, Ohmiya N, Itoh A, Hirooka Y, Goto H.",https://pubmed.ncbi.nlm.nih.gov/19780887/," We planned a pilot study of the diagnosis of the depth of esophageal cancer using confocal endomicroscopy for treatment strategies.
    


           The depth of neoplasms in 15 lesions was confirmed by endoscopic mucosal resection or surgery. We examined the rate of delineation and compared  We classified two cellular and three microvascular patterns on confocal endomicroscopic images: CP-N for normal squamous mucosa and CP-Ca for cancerous lesion; VP-type A for normal squamous mucosa; VP-type B for T1a-EP and T1a-LPM cancers; and VP-type C for T1a-MM or a more invasive cancer pattern. We measured diameters of microvessels for the three patterns of confocal endomicroscopic images and histological specimens.
    


          3% (11/15) for esophageal cancer. The  Two endoscopists blindly diagnosed the two types by cellular pattern and the three types by vascular pattern: their overall accuracies were 96% and 89% for the cellular pattern and 85% and 85% for the vascular pattern, respectively. The k value of the cellular pattern and the vascular pattern diagnosis was 0.84 and 0.75, respectively.
    


          Conclusion:
        
      
      Scoring and quantification of confocal endomicroscopic images may be useful for the differential diagnosis and diagnosis of superficial invasion by squamous cell carcinoma."
1278,Expression profiling of fecal colonocytes for RNA-based screening of colorectal cancer.,"Yajima S, Ishii M, Matsushita H, Aoyagi K, Yoshimatsu K, Kaneko H, Yamamoto N, Teramoto T, Yoshida T, Matsumura Y, Sasaki H.",https://pubmed.ncbi.nlm.nih.gov/17912428/,"The early detection of colorectal cancer originating from any part of the colorectum is desirable because this cancer can be cured surgically if diagnosed early. We searched for marker genes for a fecal RNA-based colorectal cancer screening  Of 14,564 genes, only 3 (PAP, REG1A, and DPEP1) were selectable as final candidates which were expressed frequently at any stage of this cancer and were suppressed in non-cancerous tissues and also in the peripheral blood and colonocytes of healthy volunteers. Next, we directly compared fecal RNA-expression profiles between colorectal cancer patients and healthy volunteers, and found that most of the genes (92%) expressed in the colonocytes of the cancer patients were not expressed in those of the healthy volunteers. Six genes (SEPP1, RPL27A, ATP1B1, EEF1A1, SFN, and RPS11) selected randomly from 85 cancer patient-derived colonocyte-specific genes were evaluated. In total, reverse transcription-polymerase chain reaction or focused microarray of all those 9 genes detected 18 (78%) of 23 curable colorectal cancers (Dukes stages A-C), 9 or 10 (64% or 71%) of 14 early cancers with no lymph node metastasis (Dukes stage A or B) and 4 (80%) of 5 right-sided cancers. Our extensive gene list provides other markers for fecal RNA-based colorectal cancer screening."
1279,Analysis of TSG101 tumour susceptibility gene transcripts in cervical and endometrial cancers.,"Chang JG, Su TH, Wei HJ, Wang JC, Chen YJ, Chang CP, Jeng CJ.",https://pubmed.ncbi.nlm.nih.gov/10027311/,"Carcinoma of the uterine cervix is a common malignancy among women that has been found to show loss of heterozygosity in the chromosome 11p. Recent studies have localized the TSG101 gene in this region, and also demonstrated a high frequency of abnormalities of this gene in human breast cancer. To determine the role of the TSG101 gene in the carcinogenesis of cervical and uterine carcinoma, 19 cases of cervical carcinoma and five cases of endometrial carcinoma, as well as nearby non-cancerous tissue from the same patients, and 16 blood samples from healthy persons as normal control were analysed by Southern blot analysis of genomic DNA, reverse transcription of the TSG101 mRNA followed by PCR amplification and sequencing of the products. We found that abnormal transcripts of the TSG101 gene were common both in cancerous or non-cancerous tissues of the uterus and cervix and in normal peripheral mononuclear cells. There was no genomic deletion or rearrangement in spite of the presence of abnormal transcripts, and no definite relationship between the abnormal transcripts and HPV infection was found. Although the frequency of abnormal transcripts was higher in cancerous than in non-cancerous tissue, normal peripheral mononuclear cells also had abnormal transcripts. Given these findings, the role of the TSG101 gene as a tumour-suppressor gene should be re-evaluated. Because some aberrant transcripts could be found at the first PCR reaction, we suggest that the aberrant transcripts might be the "
1280,Towards a personalized surgical margin for breast conserving surgery-Implications of field cancerization in local recurrence.,"Lebya K, Garcia-Smith R, Swaminathan R, Jones A, Russell J, Joste N, Bisoffi M, Trujillo K.",https://pubmed.ncbi.nlm.nih.gov/28054359/,"The amount of normal tissue that should be excised during breast conserving surgery is widely debated. Tissue adjacent to breast tumors, although histologically normal, possesses many of the molecular abnormalities found in tumor tissues. Here, we propose that the ideal physical distance for a surgical margin may not be universal. Rather, an adequate surgical margin likely varies from patient to patient, depending on the biology of the tissue that remains after surgery. J. Surg. Oncol. 2017;115:109-115. © 2017 Wiley Periodicals, Inc."
1281,[Significance of proliferative breast lesions around breast cancers].,"Moriya T, Manabe T, Sakurai T, Sakamoto K.",https://pubmed.ncbi.nlm.nih.gov/7747991/,"To clarify the relationships between benign proliferative diseases and cancers of the breast, 44 cases treated with breast conserving surgeries were analyzed histopathologically. Intraductal hyperplasia, sclerosing adenosis and adenosis were more frequently seen in cancerous than non-cancerous breasts, with a statistically significant difference. Additionally, histologies of some intraductal spread in carcinomas were identical to those of atypical hyperplasias. Further studies should be undertaken, and definitions of atypical hyperplasia, especially in cancerous breasts, should be critically redefined."
1282,A Novel Oncogenic Role of Disulfidptosis-related Gene SLC7A11 in Anti-tumor Immunotherapy Response to Human Cancers.,"Xu B, Liang J, Fu L, Wei J, Lin J.",https://pubmed.ncbi.nlm.nih.gov/38303526/," Yet, its relevance in prognosis, immunity, and cancer treatment efficacy is not well understood.
    


            The association between SLC7A11 expression, immune cell infiltration, and immune-related gene expression was also scrutinized.
    


           Increased SLC7A11 expression was linked to poor outcomes, particularly in liver hepatocellular carcinoma (LIHC). This protein's expression also showcased significant relationships with diverse molecular and immune subtypes. Additionally, a prognostic nomogram was devised, integrating SLC7A11 expression and clinical variables. High SLC7A11 levels corresponded with cell growth and senescence pathways in various cancers and with lipid and cholesterol metabolism in LIHC. Furthermore, potential therapeutic compounds for LIHC with high SLC7A11 were identified. Real-time PCR (qPCR) and Western blot were conducted to explore the expression of SLC7A11 in tumor tissues and cancer cell lines.
    


          Conclusion:
        
      
      In summation, this study emphasizes the prognostic and immunological importance of SLC7A11, spotlighting its potential as a therapeutic target in LIHC."
1283,Fertility cycle influence on surgical breast cancer cure.,"Bove K, Lincoln DW, Wood PA, Hrushesky WJ.",https://pubmed.ncbi.nlm.nih.gov/12500935/,"Cancer growth and spread is an intricate process dependent upon both tumor and host. This laboratory is interested in the role of the fertility cycle, specifically cyclic changes in steroid hormone levels, in tumor growth and metastases. Our previous studies, using a murine model, have documented that breast cancer growth rate and post-resection metastatic behavior each change reproducibly during the estrous cycle, and that post-resection cancer spread depends upon the time within the estrous cycle that an advanced transplanted cancer is resected. Twelve to thiry-two percent cure rates were seen in these studies. That early work described estrous cycle stages just prior and near to putative ovulation to be superior while those stages farther from ovulation were disadvantageous times for surgery. Data presented here confirm the role of the estrous cycle in post-resection metastatic spread. This current work validates vaginal smear determined estrous cycle stage with uterine weight. A primary, transplantable, mammary carcinoma, which metastasizes to the lungs, was resected for surgical cure in cycling C3HeB/FeJ female mice at each fertility cycle stage. A group of oophorectomized (ovx) animals was also used. In two large, independent studies resecting much earlier stage cancers than in prior studies, a 96% surgical cure frequency was documented when the tumor is resected during estrus. The second best surgical cure rate is achieved when tumors are resected during metestrus (79% overall cure rate). Cure frequency in ovx animals is intermediate. These  We conclude that the timing of surgical resection within the estrous cycle affects the cancer's metastatic potential and that the optimal timing of resection may also depend to some extent upon the size (stage) of the resected cancer."
1284,Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation.,"Wang J, Su W, Zhang T, Zhang S, Lei H, Ma F, Shi M, Shi W, Xie X, Di C.",https://pubmed.ncbi.nlm.nih.gov/37024471/,"Cyclin D1 (CCND1), a crucial mediator of cell cycle progression, possesses many mutation types with different mutation frequencies in human cancers. The G870A mutation is the most common mutation in CCND1, which produces two isoforms: full-length CCND1a and divergent C-terminal CCND1b. The dysregulation of the CCND1 isoforms is associated with multiple human cancers. Exploring the molecular mechanism of CCND1 isoforms has offer new insight for cancer treatment. On this basis, the alterations of CCND1 gene are described, including amplification, overexpression, and mutation, especially the G870A mutation. Subsequently, we review the characteristics of CCND1 isoforms caused by G870A mutation. Additionally, we summarize cis-regulatory elements, trans-acting factors, and the splice mutation involved in splicing regulation of CCND1. Furthermore, we highlight the function of CCND1 isoforms in cell cycle, invasion, and metastasis in cancers. Importantly, the clinical role of CCND1 isoforms is also discussed, particularly concerning prognosis, chemotherapy, and radiotherapy. Last, emphasis is given to the corrective strategies that modulate the cancerous CCND1 isoforms. Thus, it is highlighting significance of aberrant isoforms of CCND1 as targets for cancer therapy."
1285,"Literature review of imaging, pathological diagnosis, and outcomes of metachronous lung and pancreatic metastasis of cecal cancer.","Wu X, Zhou S, Zhou X, Xu X, Wang L, Ruan Y, Lu J, Li H, Xu H, Ma X, Li H.",https://pubmed.ncbi.nlm.nih.gov/36253824/," Here, we report a case of colorectal cancer with lung and pancreatic metastasis and analyze the histopathology, immunohistochemistry, and next-generation sequencing (NGS) to generate a differential diagnosis and treatment of metastatic colon cancer.
    


          Case presentation:
        
      
      AC1 A 78-year-old man was admitted because of a recently elevated carcinoembryonic antigen. This patient had undergone laparoscopic right hemicolectomy for cecal cancer IIA (T3N0M0) 5 years before admission, and thoracoscopic left upper lung wedge resection for primary colon cancer lung metastasis 2 years before admission. At that time, the patient was thought to have pancreatic metastasis from colon cancer. He underwent laparoscopic distal pancreatectomy (combined with splenectomy). Postoperative pathology revealed colon cancer metastasis. We performed NGS on tumor samples at three loci and found colon cancer's most common oncogenic driver genes (KRAS, APC, and TP53). One month after surgery, the patient was given capecitabine for six cycles of chemotherapy. At present, no high adverse reactions have been reported.
    


          Discussion:
        
      
      For patients with pancreatic space-occupying, such as a previous history of colorectal cancer, and recent carcinoembryonic antigen elevation, we should highly suspect pancreatic metastatic colorectal cancer. NGS is an essential auxiliary for identifying metastatic tumors. Surgery combined with postoperative chemotherapy is an effective treatment."
1286,Patterns of care for cancer of the larynx in the United States.,"Shah JP, Karnell LH, Hoffman HT, Ariyan S, Brown GS, Fee WE, Glass AG, Goepfert H, Ossoff RH, Fremgen A.",https://pubmed.ncbi.nlm.nih.gov/9158393/,"
    


          Design:
        
      
      Analyses performed on retrospectively collected survey data submitted by hospitals for diagnostic periods 1980 through 1985 and 1990 through 1992 (with a 9-year follow-up for the long-term group).
    


          Setting:
        
      
      Broad spectrum of US hospitals (N = 769).
    


          Patients:
        
      
      Consecutively accrued series of patients with laryngeal cancer (N = 16,936), with only squamous cell carcinomas (N = 16,213) analyzed.
    


          Interventions:
        
      
      Surgery, radiation therapy, and chemotherapy.
    


          Main outcome measures:
        
      
      Descriptive analyses of case-mix, diagnostic, and treatment characteristics plus recurrence and 5-year, disease-specific survival outcomes.
    


           Overall diversity of management of this disease (by site and stage) was apparent. Five-year survival rates indicated a large difference between modified groupings of the T and N classifications, separating stages III and IV cases into localized disease (87.5% for T1-T2; 76.0% for T3-T4 cases) and regional metastasis (46.2%).
    


          Conclusions:
        
      
      Regardless of improvements in entering data in hospital records (most commendably, staging), more rigorous standards are needed. Also, the small increase in advanced-stage patients indicates that efforts toward early detection have not been successful. The rise in radiation therapy perhaps reflected an increased use of nonsurgical treatment for early-stage patients and organ-sparing radiochemotherapy protocols for advanced-stage patients. Regrouping stages III and IV cases into localized disease vs regional metastasis appears to predict survival better. Ongoing refinements of the American Joint Committee on Cancer staging scheme will hopefully improve this cancer's classification."
1287,"Enriching the molecular definition of the airway ""field of cancerization:"" establishing new paradigms for the patient at risk for lung cancer.","Gomperts BN, Walser TC, Spira A, Dubinett SM.",https://pubmed.ncbi.nlm.nih.gov/23233734/,"The ""field of cancerization"" refers to histologically normal-appearing tissue adjacent to neoplastic tissue that displays molecular abnormalities, some of which are the same as those of the tumor. Improving our understanding of these molecular events is likely to increase our understanding of carcinogenesis. Kadara and colleagues attempt to characterize the molecular events occurring temporally and spatially within the field of cancerization of patients with early-stage non-small cell lung cancer (NSCLC) following definitive surgery. They followed patients with bronchoscopies annually after tumor resection and extracted RNA from the serial brushings from different endobronchial sites. They then conducted microarray analysis to identify gene expression differences over time and in different sites in the airway. Candidate genes were found that may have biologic relevance to the field of cancerization. For example, expression of phosphorylated AKT and ERK1/2 was found to increase in the airway epithelium with time. Although there are limitations in the study design, this investigation demonstrates the utility of identifying molecular changes in histologically normal airway epithelium in lung cancer. In addition to increasing our understanding of lung cancer biology, studying the field of cancerization has the potential to identify biomarkers from samples obtained in a minimally invasive manner."
1288,Somatic mutations and losses of expression of microRNA regulation-related genes AGO2 and TNRC6A in gastric and colorectal cancers.,"Kim MS, Oh JE, Kim YR, Park SW, Kang MR, Kim SS, Ahn CH, Yoo NJ, Lee SH.",https://pubmed.ncbi.nlm.nih.gov/20198652/,"Mounting evidence indicates that deregulation of microRNAs (miRNAs) are involved in development of many human diseases, including cancers. Regulation of miRNA is a complicated process and some components in the regulation are known to be altered in human cancers. Among the miRNA regulation-related genes, we found that AGO1, AGO2, TNRC6A, TNRC6C, TARBP2 and EXPORTIN5 genes have mononucleotide repeats in their coding sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analysed the mononucleotide repeats in 27 gastric cancers (GCs) with high MSI (MSI-H), 18 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 41 colorectal cancers (CRCs) with MSI-H, 14 CRCs with MSI-L and 45 CRCs with stable MSI (MSS) by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. We found AGO2, TNRC6A, TARBP2, TNRC6C and EXPORTIN5 mutations in 10, six, one, one and one cancer(s), respectively. They were detected in MSI-H but not in MSI-L or MSS cancers. The GCs and CRCs with MSI-H harboured one or more mutations of the genes in 22% and 27%, respectively. We also analysed Ago2 and TNRC6A protein expressions in GCs and CRCs with MSI-H. In cancers with MSI-H, loss of Ago2 expression was observed in 40% of GCs and 35% of CRCs, while loss of TNRC6A was observed in 52% of the GCs and 54% of the CRCs. Our data indicate that frameshift mutations in AGO2 and TNRC6A and their losses of expression are common in GCs and CRCs with MSI-H, and suggest that these alterations may contribute to the cancer development by deregulating miRNA regulation."
1289,Endoscopic laser therapy in the curative and palliative treatment of upper gastrointestinal cancer.,"Suzuki H, Miho O, Watanabe Y, Kohyama M, Nagao F.",https://pubmed.ncbi.nlm.nih.gov/2471365/,"Endoscopic laser treatment was initially applied for gastrointestinal bleeding, but has been actively extended, especially in Japan, to the curative treatment of early upper gastrointestinal cancers. We have treated 10 cases of early gastric cancer and 1 case of early esophageal cancer by Nd-YAG laser radiation, and 2 cases of early gastric cancer by photochemical therapy (PCT) with argon laser + hematoporphyrin derivative. Also, 62 cases of advanced cancer were treated, 10 of the esophagus and 52 of the stomach, for bleeding (18 cases) or stenosis (34 cases). The cases were nonresectable or they were patients who refused surgery. Satisfactory  In order to find indications for the possible extension of endoscopic laser therapy to operable cases of early gastric cancer, we studied lymph node metastases in 200 cases of early gastric cancer surgically treated by us. It was found that early gastric cancers (both mucosal and submucosal) measuring less than 2 cm in diameter, of type I, IIa, and IIc (without ulcer scar), had no lymph node metastases and such cases can be treated by local therapy--such as endoscopic laser therapy. In palliative endoscopic laser therapy for complications of advanced gastrointestinal cancers, there are no major problems with active performance. We obtained a high (90%) hemostatic rate in bleeding cases of upper gastrointestinal cancer and a satisfactory (65%) rate of dilating effect in cases of cancerous stenosis at the esophagus and cardia.(ABSTRACT TRUNCATED AT 250 WORDS)"
1290,Genomic landscapes of canine splenic angiosarcoma (hemangiosarcoma) contain extensive heterogeneity within and between patients.,"Wong S, Ehrhart EJ, Stewart S, Zismann V, Cawley J, Halperin R, Briones N, Richter K, Sivaprakasam K, Perdigones N, Contente-Cuomo T, Facista S, Trent JM, Murtaza M, Khanna C, Hendricks WPD.",https://pubmed.ncbi.nlm.nih.gov/35867969/,"Cancer genomic heterogeneity presents significant challenges for understanding oncogenic processes and for cancer's clinical management. Variation in driver mutation frequency between patients with the same tumor type as well as within an individual patients' cancer can shape the use of mutations as diagnostic, prognostic, and predictive biomarkers. We have characterized genomic heterogeneity between and within canine splenic hemangiosarcoma (HSA), a common naturally occurring cancer in pet dogs that is similar to human angiosarcoma (AS). HSA is a clinically, physiologically, and genomically complex canine cancer that may serve as a valuable model for understanding the origin and clinical impact of cancer heterogeneity. We conducted a prospective collection of 52 splenic masses from 43 dogs (27 HSA, 15 benign masses, and 1 stromal sarcoma) presenting for emergency care with hemoperitoneum secondary to a ruptured splenic mass. Multi-platform genomic analysis included matched tumor/normal targeted sequencing panel and exome sequencing. We found candidate somatic cancer driver mutations in 14/27 (52%) HSAs. Among recurrent candidate driver mutations, TP53 was most commonly mutated (30%) followed by PIK3CA (15%), AKT1 (11%), and CDKN2AIP (11%). We also identified significant intratumoral genomic heterogeneity, consistent with a branched evolution model, through multi-region exome sequencing of three distinct tumor regions from selected primary splenic tumors. These data provide new perspectives on the genomic landscape of this veterinary cancer and suggest a cross-species value for using HSA in pet dogs as a naturally occurring model of intratumoral heterogeneity."
1291,Feature-weight based measurement of cancerous transcriptome using cohort-wide and sample-specific information.,"Wang Q, Song JJ, Zhang F.",https://pubmed.ncbi.nlm.nih.gov/37814075/,"Identifying cancerous samples or cells using transcriptomic data is critical for cancer related basic research, early diagnosis, and targeted therapy. However, the high transcriptional heterogeneity of cancers still hinders people from accurately recognizing cancerous transcriptome using bulk, single-cell, or spatial RNA-seq data. Here, we present a novel  The workflow of FWP is, first, to calculate feature weights using the training dataset, and then, for each sample in the testing dataset, calculate the feature-weight based final score by combining the cohort-wide and sample-specific information. Those two types of information are utilized through conducting weighted principal component analysis and calculating correlation perturbations. The effectiveness and superiority of FWP over other  In addition, the high robustness and efficiency of FWP are also demonstrated by using different numbers of features and cells, respectively. FWP is available at https://github.com/jumphone/fwp ."
1292,TCTP as therapeutic target in cancers.,"Acunzo J, Baylot V, So A, Rocchi P.",https://pubmed.ncbi.nlm.nih.gov/24650927/,"The translationally controlled tumor protein (TCTP) is a highly conserved protein present in eukaryotic organisms. This protein, located both in the cytoplasmic and the nucleus, is expressed in various tissues and is regulated in response to a wide range of extracellular stimuli. TCTP interacts with itself and other protein including MCL1 and p53. TCTP has been shown to play an important role in physiological events, such as cell proliferation, cell death and immune responses but also in stress response and tumor reversion. Moreover, TCTP expression is associated with malignancy and chemoresistance. In this review, we will evaluate pathways regulated by TCTP and current inhibitory strategy to target TCTP in cancerous diseases."
1293,Surgical outcomes of patients with gastric carcinoma: the importance of primary tumor location and microvessel invasion.,"Talamonti MS, Kim SP, Yao KA, Wayne JD, Feinglass J, Bennett CL, Rao S.",https://pubmed.ncbi.nlm.nih.gov/14605635/,"
    


           There were 74 men and 36 women with a mean age of 65.2 years (range 27 to 87 years). Log-rank tests and Kaplan-Meier survival curves were generated to determine clinicopathologic factors influencing DFS and OS. Significant factors were then determined with Cox multivariate analysis.
    


          2 months and the estimated 5-year OS was 42.3%. There were no significant differences in DFS or OS for female sex, black race, or age>65. Symptoms associated with lower DFS were weight loss and palpable abdominal mass (P<.05), although none were predictive for OS. Median survival was markedly worse in patients undergoing esophagogastrectomy versus gastrectomy (26.8 vs 52.3 months; P<.05), although there were no significant differences between patients undergoing total gastrectomy versus subtotal gastrectomy. As expected, OS was inversely proportional to the American Joint Committee on Cancer's tumor stage. When compared with patients with partial-thickness tumors (T(1-2)), full-thickness (T(3-4)) tumors had a decreased median survival (63.8 vs 27.9 months; P<.01). Although N(2) stage was associated with decreased survival (20.6 months), patient outcomes were similar for N(0) and N(1) stages (52.5 and 48.8 months). Lymphatic and capillary invasion (21.4 vs 45.3 months; P<.02) and proximal location of primary tumors (28.5 vs 58.6 months; P<.02) were the only other factors adversely affecting survival. Lauren classification and histologic grade were not significant predictors of patient outcomes.
    


          Conclusions:
        
      
      In addition to the American Joint Committee on Cancer stage, microvessel involvement and tumor location are important predictors of DFS and OS in gastric cancer and should be included in risk stratification and selection criteria for patients entering novel adjuvant or neoadjuvant clinical trials."
1294,Clinically localized prostate cancer in 2017: A review of comparative effectiveness.,"Lavery HJ, Cooperberg MR.",https://pubmed.ncbi.nlm.nih.gov/27998677/,"Introducing the topic of comparative effectiveness for prostate cancer treatments with a reminder of the disease's heterogeneity risks tautology. However, the profound variation both in this cancer's biology and its clinical course is increasingly widely recognized, while management alternatives for clinically localized prostate cancer have exploded. Available options now include active surveillance, multiple surgical approaches to prostatectomy, various forms of external-beam and interstitial radiation, and a growing list of energy ablative technologies. Each treatment option has its own efficacy rate as well as its own set of complications, side effects and financial costs. Difficulties comparing these options, together with the high prevalence of the disease, led the Institute of Medicine to include localized prostate cancer among the top 25 priority conditions for future comparative effectiveness research. The sheer volume of possible treatment options, with their individual risks and benefits, can be confusing for patients and clinicians to research, understand and explain. To help clinicians navigate these treatment options, we have assembled this Urologic Oncology Seminar on the comparative effectiveness of treatments for clinically localized prostate cancer. The articles focus on high quality evidence-based medicine and most have included useful tables summarizing seminal trials and available resources."
1295,"GLI3: a mediator of genetic diseases, development and cancer.","Matissek SJ, Elsawa SF.",https://pubmed.ncbi.nlm.nih.gov/32245491/,"The transcription factor GLI3 is a member of the Hedgehog (Hh/HH) signaling pathway that can exist as a full length (Gli3-FL/GLI3-FL) or repressor (Gli3-R/GLI3-R) form. In response to HH activation, GLI3-FL regulates HH genes by targeting the GLI1 promoter. In the absence of HH signaling, GLI3 is phosphorylated leading to its partial degradation and the generation of GLI3-R which represses HH functions. GLI3 is also involved in tissue development, immune cell development and cancer. The absence of Gli3 in mice impaired brain and lung development and GLI3 mutations in humans are the cause of Greig cephalopolysyndactyly (GCPS) and Pallister Hall syndromes (PHS). In the immune system GLI3 regulates B, T and NK-cells and may be involved in LPS-TLR4 signaling. In addition, GLI3 was found to be upregulated in multiple cancers and was found to positively regulate cancerous behavior such as anchorage-independent growth, angiogenesis, proliferation and migration with the exception in acute myeloid leukemia (AML) and medulloblastoma where GLI plays an anti-cancerous role. Finally, GLI3 is a target of microRNA. Here, we will review the biological significance of GLI3 and discuss gaps in our understanding of this molecule. Video Abstract."
1296,[Cervical smears: towards an optimal screening for cervical cancer].,"Leroy JL, Boman F.",https://pubmed.ncbi.nlm.nih.gov/12610474/,"THE INTEREST OF CERVICO-UTERINE CYTOLOGY: Cytology is the most appropriate means of screening for cancers and pre-cancerous states of the cervix. It permits the prevention of invasive cancers by identifying the precursor lesions, which exist more than 10 years before the invasion, and their effective excision or destruction. The absence of screening represents the greatest risk factor for invasive cancer and explains its higher frequency in developing countries. The Bethesda system is a language shared by cytologists and clinicians for spotting situations at risk Histology is essential before any therapeutic decision. It is provided by biopsies during colposcopy or by diagnostic coning in ambiguous situations. The cytological diagnosis of a low grade lesion and atypia of undetermined significance sometimes corresponds, histologically, to a high grade lesion. ENHANCING THE  Conditions for optimising screening are wide coverage of women, good quality smears, competent cytologists and the appropriate follow-up of abnormal smears."
1297,Factors Associated with Adherence to Preventive Breast Cancer Screenings among Middle-aged African American Women.,"Guo Y, Cheng TC, Yun Lee H.",https://pubmed.ncbi.nlm.nih.gov/31411130/,"Medical and other health professionals recommend biyearly screening for breast cancer for women 40-74 years of age. However, the breast cancer screening rate of African American women aged 45 and up is lower than that of other ethnicities. The present study intended to identify factors impacting African American women's participation in breast cancer screening. This study is a longitudinal secondary data analysis of 3,911 African American participants of the Study of Women's Health Across the Nation. By using Systems Model of Clinical Preventive Care, multinomial logistic regression was applied to explore the likelihood of having breast cancer screenings (breast exam and/or mammogram) associating with predisposing factors, enabling factors, referencing factors, and situational factors. Participants with older age, with higher education, having a healthcare provider for female health, in far distance, and with a cancer(s) were significantly more likely to adhere to the recommendations of breast cancer screenings. However, participants who did not have time to visit doctors, did not trust the physicians, and who smoked regularly were significantly less likely to adhere to the recommendations of breast cancer screenings. Implications for policy and practice are discussed."
1298,The hypoxic core: a possible answer to the cancer paradox.,Guppy M.,https://pubmed.ncbi.nlm.nih.gov/12459193/,"There are many differences, at all levels of organization, between cancerous and normal cells. Two of these (oxygen delivery and glucose metabolism) are related and manifest as low intercellular oxygen tensions (pO(2)) and a glycolytic metabolic profile in tumours and/or cancer cells. It is becoming increasingly apparent that these characteristics of cancer combine to enhance both the survival and aggressiveness of cancer cells, and that they can adversely impact on some forms of treatment. But they are also exploited in current strategies of detection and monitoring of cancers. These are therefore characteristics with important implications for the crucial balance between the aggression and growth characteristics of a tumour, and our ability to detect and treat it. The interactions and the hierarchy of events leading to these manifestations are complex, not fully understood, and involve a pivotal and intriguing paradox. This paradox  This review is a synthesis of the available data into a feasible hypothesis which offers a possible resolution of this paradox and provides a testable paradigm for tumour behaviour."
1299,Biomarkers for early identification of recurrences in HPV-driven oropharyngeal cancer.,"Mirghani H, Lang Kuhs KA, Waterboer T.",https://pubmed.ncbi.nlm.nih.gov/29909884/,"One of the major concerns in oncology lies in the ability to detect recurrences at their earliest stage to increase the likelihood of cure following second line, or salvage, therapy. Although human papillomavirus (HPV)-driven oropharyngeal cancers have a good prognosis, 20-25% of patients will recur within 5 years of treatment and a significant portion will die from their disease. In recent years, great effort has been put toward evaluating the potential clinical utility of HPV-related biomarkers for early diagnosis of recurrent disease. Indeed, following completion of treatment, detection of HPV-DNA in oral rinses or blood and serologic assays against HPV oncoproteins could be helpful to track residual disease or recurrence. Several recent studies have reported promising findings, thus potentially paving the way for the use of biomarkers in the management of HPV-OPC. In this review, we evaluate and discuss the current knowledge on this topic and provide some directions for future research."
1300,[Inhibitory effect of siRNA on heparanase expression and invasion ability of gastric cancer cells: an in vitro experiment].,"Zhang Y, Wang ZN, Zhang X, Xu HM, Jiang L, Luo Y, Xing LL, Xu MD, Li J.",https://pubmed.ncbi.nlm.nih.gov/17825158/,"
    


           Human gastric cancer cells of the line SGC7901 were cultured and transfected with the siRNA of the concentrations of 5, 10, 20, and 40 nmol/L respectively. Forty-eight hours later RT-PCR and Western blotting were applied to detect the mRNA and protein expression of heparanase. Millicell chamber assay was performed to detect the invasion ability of the SGC7901 cells. Blank control group and negative control group were set.
    


          207 +/- 0.095 and 0.200 +/- 0.085 respectively, both significantly lower than that of the control group (0.60 +/- 0.09, both P < 0.05). Western blotting showed that the protein expression of heparanase of the different siRNA subgroups were all decreased dose-dependently; and no heparanase band was seen in the 40 nmol/L subgroup. The invasion rate of the siRNA group was significantly lower than that of the control group with a mean inhibition rate of (61 +/- 36)%.
    


          Conclusion:
        
      
      RNAi inhibits the expression of heparanase and the invasion ability of human gastric cancer cells. Heparanase may be a new target in treatment of gastric cancer's metastasis."
1301,"Actinic keratosis: precancer, squamous cell carcinoma, or marker of field cancerization?","Deltondo JA, Helm KF.",https://pubmed.ncbi.nlm.nih.gov/19755947/,"The early detection, recognition, and progression of the actinic keratosis (AK) and its relationship with squamous cell carcinoma have long been an area of debate. Recent advancements in medicine have examined the role of field cancerization in a variety of tumors. The role of AK as a marker for field cancerization will be here discussed."
1302,Relation of matrilysin messenger RNA expression with invasive activity in human gastric cancer.,"Senota A, Itoh F, Yamamoto H, Adachi Y, Hinoda Y, Imai K.",https://pubmed.ncbi.nlm.nih.gov/9626810/,"Matrilysin is a member of the matrix metalloproteinase gene family which is believed to play an important role in tumor progression. Expression of matrilysin mRNA was examined by reverse transcription-polymerase chain reaction combined with Southern blot analysis in 46 human primary gastric cancers. Overexpression of matrilysin was observed in 28 (61%) of gastric cancer tissues. The positive expression ratio of matrilysin was significantly higher in the gastric cancers of subserosa or beyond it than in those within the submucosal layer. Immunohistochemical study with anti-matrilysin monoclonal antibody revealed that matrilysin was mainly expressed on cancer cells but not or very weakly expressed on other cells. In addition, an activated form of matrilysin detected by zymographic analysis was observed in gastric cancer tissues whereas none was detected in non-cancerous tissues, suggesting that matrilysin may directly and powerfully contribute to the invasion step of human gastric cancer. In order to gain more insight into the relationship of this metalloproteinase to invasive activity, we also modulated the expression of matrilysin in gastric cancer cells by DNA transfection using gastric cancer cell lines. Overexpression of matrilysin rendered the gastric cancer cells more invasive in vitro. Concomitant with clinical investigations, matrilysin may be an important metalloproteinase in the progression of gastric cancer."
1303,PARP-1 activity in normal and cancerous human endometrium and its relationship with quantity of abasic sites (AP).,"Postawski K, Monist M, Keith G.",https://pubmed.ncbi.nlm.nih.gov/21469519/," Recent data suggest that polymerase is involved in the development of endometrial adenocarcinomas and more advanced tumors displaying lowest enzyme protein expression. Data on PARP-1 activity regarding carcinogenesis in human endometrium are scarce. That was the reason why the authors of the present work wished to investigate the enzyme activity in human uterine hormone-dependent cancer and to compare the  The next aim was to check whether enzyme activity in normal and cancerous endometrium depends on the number of AP sites, which are widely known as oxidative stress DNA damage markers and PARP-1 activity stimulators.
    


          Material and  Apurinic sites/105 base pairs (bp) were measured by Oxidative DNA Damage Kit Quantitative.  Finally the PARP-1 activity was analyzed for histological and some clinical features of neoplasms.
    


           no differences in PARP-1 activity were found in non-cancerous types of human endometrium; 2. mean enzyme activity was lower in sporadic endometrial cancers than in noncancerous endometrial specimens (2.89 +/- 0.55 vs 6.39 +/- 0.06; p < 0.005); 3. mean PARP-1 activity in lower grade neoplasms was higher than in G3 tumors and was lower in adenocarcinomas displaying deep uterine wall infiltration; 4. there was no relationship between PARP-1 activity and AP level."
1304,The Evaluation of Cancer Testis Gene PIWIL2 Expression Levels as a New Prognostic Biomarker for Breast Cancer.,"Sarvestani FM, Safaei A, Talei A, Dianatpour M.",https://pubmed.ncbi.nlm.nih.gov/28164625/," Likewise, it has been demonstrated that CTgs express aberrantly in various tumors and play essential roles in both initiation and development of cancers. In this study, PIWIL2, one member of CTgs, which has an indispensable role in spermatogenesis and tumorigenesis, was examined as an efficient prognostic and diagnostic biomarker in breast cancer. It is worth mentioning that the expression study of PIWIL2 by qPCR on breast cancer samples was performed for the first time, since this approach is much more sensitive than western blot, RT-PCR, and immunohistochemistry.
    


           None of the patients had received chemotherapy. The relationships between the PIWIL2 status and the clinicopathological parameters were ultimately determined.
    


          05).
    


          Conclusions:
        
      
      The PIWIL2 gene could be considered as an efficient prognostic biomarker in breast cancer."
1305,The costs of treating vaginal and vulval cancer in England (2009-2015).,"Stephens S, Chatterjee A, Coles V, Crawford R.",https://pubmed.ncbi.nlm.nih.gov/32252711/," A causal relationship also exists between HPV and cancer in other areas of the female reproductive system including the vagina and vulva. Whilst the incidence of vaginal cancer in the UK has remained relatively stable over the past 25 years, vulval cancer rates are increasing. A body of literature exists on the epidemiology and aetiology of vaginal and vulval cancer, but little is known about the economic burden. The 
    


           Health Resource Group (HRG) tariffs and National Reference Costs were used to estimate the cost of treating pre-cancerous and invasive vaginal and vulval lesions in England.
    


           Vulval cancer accounted for the largest proportion; an estimated 60% of the total cost (£8.82 million). On average 4316 patients per year in England were admitted to hospital and 912 patients attended outpatient settings for pre-cancerous and invasive disease of the vagina and vulva.
    


          Conclusion:
        
      
      The  Given the causal role of HPV in a proportion of these cancers, preventative measures such as the national HPV immunisation programme have the potential to reduce the economic burden. To ensure optimal use of NHS resources, it is important that future economic evaluations of such preventative measures consider the full burden of HPV related disease."
1306,Microsatellite instability is correlated with lymph node-positive breast cancer.,"De Marchis L, Contegiacomo A, D'Amico C, Palmirotta R, Pizzi C, Ottini L, Mastranzo P, Figliolini M, Petrella G, Amanti C, Battista P, Bianco AR, Frati L, Cama A, Mariani-Costantini R.",https://pubmed.ncbi.nlm.nih.gov/9815679/,"We analyzed 81 cases of primary breast carcinoma and 7 cases of fibroadenoma for microsatellite instability at eight loci. Twenty-seven cases (33.3%) manifested aberrant microsatellite alleles: 7 (8.6%) at one locus and 20 (24.7%) at two or more loci [tumors with replication error-positive (RER+) phenotype]. No evidence of microsatellite instability was observed in fibroadenomas. We investigated correlations between RER+ phenotype and clinicopathological characteristics of the carcinomas. The RER+ phenotype was statistically associated with large tumor diameter; of 19 RER+ tumors with measured size, 16 were > 2 cm, compared to 28 of 58 tumors with no evidence of microsatellite instability or with shifts in allele sizes limited to one locus (P </= 0.005, chi2 test). Consistently, there was also a strong statistical association between RER+ phenotype and lymph node metastasis; 14 of 19 RER+ tumors with known lymph node status were N+, compared to 15 of 59 tumors with no evidence of microsatellite instability or with allele shifts limited to one locus (P </= 0.0002, chi2 test). Correlations with age of patients, proliferative activity, histotype (ductal versus lobular), and grade of differentiation were not statistically significant, although the RER+ phenotype was more frequent in lobular and high-grade ductal carcinomas, in carcinomas with high proliferative activity, and in carcinomas from patients </=50 years. Data concerning cancer(s) in first and/or second degree relatives were available for 66 cases, including 33 positive and 33 negative for family history of cancer. No correlations were detected between RER+ phenotype and family history of cancer. In conclusion, our "
1307,Which putatively pre-malignant oral lesions become oral cancers? Clinical relevance of early targeting of high-risk individuals.,"Sudbø J, Reith A.",https://pubmed.ncbi.nlm.nih.gov/12542827/,"Oral squamous cell carcinomas continue to be a group of diseases with high mortality and increasing incidence rates, particularly among young individuals. This is a paradox finding, since most oral cancers are preceded - even by several years - by readily detectable mucosal changes, most often white or red patches (leukoplakias and erythroplakias, respectively). However, only a small fraction of leukoplakias or erythroplakias are related to cancer development, and the challenge has been to identify the high-risk lesions. From the vast literature on molecular markers in oral pre-cancer, no reliable prognostic marker for risk assessment in putatively pre-malignant lesions has emerged. For this reason, a wait-and-see approach has been adopted for this group of lesions. Recently published data point to gross genomic aberrations (DNA aneuploidy) as a tool for targeting patients at particular risk for future cancerous lesions in the oral cavity. Thus, DNA aneuploidy signalled a very high risk for subsequent development of carcinomas in a wide range of lesions from the oral mucous membrane, ranging from oral leukoplakias to oral erythroplakias and even including lesions that had been explicitly defined as being without a malignant potential by a group of trained pathologists. As an extension of research in oral pre-malignancies, the enzyme cyclooxygenase-2 (COX-2) seems to be enhanced specifically in high-risk oral lesions, as defined by the aberrant DNA content of their lesions. These data strongly indicate that COX-2 inhibitors (coxibs) should be investigated as chemopreventive agents in patients identified to be at high risk of developing oral cancer."
1308,PRMTs and Arginine Methylation: Cancer's Best-Kept Secret?,"Jarrold J, Davies CC.",https://pubmed.ncbi.nlm.nih.gov/31230909/,"Post-translational modification (PTM) of proteins is vital for increasing proteome diversity and maintaining cellular homeostasis. If the writing, reading, and removal of modifications are not controlled, cancer can develop. Arginine methylation is an understudied modification that is increasingly associated with cancer progression. Consequently protein arginine methyltransferases (PRMTs), the writers of arginine methylation, have rapidly gained interest as novel drug targets. However, for clinical success a deep mechanistic understanding of the biology of PRMTs is required. In this review we focus on advances made regarding the role of PRMTs in stem cell biology, epigenetics, splicing, immune surveillance and the DNA damage response, and highlight the rapid rise of specific inhibitors that are now in clinical trials for cancer therapy."
1309,High IGF2 expression is associated with poor clinical outcome in human ovarian cancer.,"Dong Y, Li J, Han F, Chen H, Zhao X, Qin Q, Shi R, Liu J.",https://pubmed.ncbi.nlm.nih.gov/26063585/,"Ovarian cancer is one of the most common types of cancer in females and is the leading cause of death among gynaecological cancers in women worldwide. In the present study, we identified insulin-like growth factor 2 (IGF2) as a differentially expressed gene between cancerous and non-cancerous ovarian tissues. IGF2 was frequently increased in the human ovarian cancers when compared to the frequency in the non-cancerous ovarian tissues both at the mRNA (30/35) and protein level (61/72). The mean level of IGF2 in the tumor tissues was markedly higher than that in the non-cancerous tissues (nearly 3-fold change) (P=0.000). There was a significant correlation of IGF2 expression with histological grade (P=0.047). Kaplan-Meier analysis indicated that the ovarian cancer patients with high IGF2 expression showed a poorer prognosis both in regards to overall survival (OS) and progression-free survival (PFS) (n=1,648, P=0.000). Further analysis revealed that high expression of IGF2 was an unfavorable factor for the prognosis of the ovarian cancer patients at clinical stage I + II, stage III, histological grade 2, grade 3 or those treated with chemotherapy containing platin and Taxol. Our data provide evidence that IGF2 expression is frequently increased in ovarian cancer tissues, and high expression of IGF2 may be a significant prognostic factor for poor survival in ovarian cancer patients."
1310,Method of Assessing Skin Cancerization and Keratoses(TM) (MASCK): development and photographic validation in multiple anatomical sites of a novel assessment tool intended for clinical evaluation of patients with extensive skin field cancerization.,"Baker C, James A, Supranowicz M, Spelman L, Shumack S, Cole J, Weightman W, Sinclair R, Foley P.",https://pubmed.ncbi.nlm.nih.gov/35150158/,"
    


          Aims:
        
      
      To develop a versatile quantitative instrument for 
    


           The study was noninterventional and used a convenience sample of de-identified patient photographs selected based on preset criteria. An expert panel developed the instrument and scoring system via a modified Delphi voting process. A sample of 16 healthcare professionals from multiple specialties undertook the pilot testing, and a panel of seven dermatologists were involved in validation testing. Validation was determined by assessment of overall inter-rater agreement using Gwet chance-corrected agreement coefficients (ACs).
    


           The SFCIndex is a composite score comprising the number and thickness of AKs multiplied by area of skin involvement. ACs for the SFCIndex components, the overall SFCIndex score and the global assessment score were > 0.80 (rated 'almost perfect') while the AC for the cancer-in-zone metric was lower (0.33, rated 'fair'). Internal consistency was demonstrated via positive correlation between the overall SFCIndex score and the global assessment score.
    


          Conclusions:
        
      
      Our study found near-perfect agreement in inter-rater reliability when using MASCK to assess the severity of ESFC in multiple anatomical sites. Further validation of this novel instrument is planned to specifically assess its reliability, utility and feasibility in clinical practice."
1311,p53 mutations in nonmelanoma skin cancer of the head and neck: molecular evidence for field cancerization.,"Kanjilal S, Strom SS, Clayman GL, Weber RS, el-Naggar AK, Kapur V, Cummings KK, Hill LA, Spitz MR, Kripke ML, et al.",https://pubmed.ncbi.nlm.nih.gov/7627969/,"Multiple and distinct p53 mutations were detected by DNA sequence analysis in tumor and adjacent nonmalignant skin samples from eight patients with nonmelanoma skin cancer of the head and neck, providing unambiguous evidence for field cancerization. The mutations consisted of C-->T transitions at dipyrimidine sequences (30% of all single base substitutions), T-->C transitions (47%), and G-->T transversions (12%), suggesting that other carcinogens may act along with UV radiation in the development of nonmelanoma skin cancer. Patient interviews revealed that, in addition to substantial exposure to solar UV radiation, most had a history of smoking and were exposed to carcinogens from industrial or agricultural sources. These data show that extensive molecular epidemiological investigations are necessary to elucidate risk factors associated with the disease in localities where patients often report substantial exposure to environmental carcinogens."
1312,Estrogen receptor-positive proliferating cells in the normal and precancerous breast.,"Shoker BS, Jarvis C, Clarke RB, Anderson E, Hewlett J, Davies MP, Sibson DR, Sloane JP.",https://pubmed.ncbi.nlm.nih.gov/10595909/,"Recently it has been shown that epithelial cell expression of the estrogen receptor (ER) and that of the proliferation-associated marker Ki-67 are almost mutually exclusive in the normal premenopausal human breast but that coexpression frequently occurs in estrogen receptor-positive (ER+) breast cancers. This coexpression may indicate disordered expression of ER in the cell cycle or failure to suppress division of ER+ cells and could be important in neoplastic transformation. The purpose of this study was to determine whether in situ proliferations known to be associated with different levels of risk for developing breast cancer contain these coexpressing cells and, if so, the stage at which they occur. We found that ER+ proliferating cells were rare in premenopausal lobules but increased with age in the normal breast. There was no difference in nonlesional tissue between cancerous and noncancerous breasts. The percentage of dual-expressing cells was significantly increased, however, in all of the in situ proliferations and correlated positively with the level of risk of developing breast cancer. We suggest that development of at least some human breast cancers is associated with increasing failure to down-regulate ER as cells enter the cycle or to suppress division of ER+ cells. The mechanism may involve the loss of a tumor suppressor gene."
1313,Florida adults' oral cancer knowledge and examination experiences.,"Tomar SL, Logan HL.",https://pubmed.ncbi.nlm.nih.gov/16468464/,"
    


           Data from 1,773 respondents were weighted to permit statewide estimates. Bivariate analyses were used to examine awareness and knowledge of oral cancer. Multiple logistic regression analysis was used to model past-year oral cancer examination experiences of Florida's adults.
    


          5% of adults aged 40 years and older had never heard of oral cancer and another 40.3% reportedly knew little or nothing about it. About one-half of adults did not think oral white or red patches or bleeding could indicate oral cancer and 27.6% correctly identified three of oral cancer's major risk factors. After hearing an oral cancer exam described, just 19.5% of adults reported receiving one within the preceding 12 months. Blacks and Hispanics were significantly less likely than non-Hispanic whites to have received a recent oral cancer examination. Persons with low levels of education, those who lacked a regular dentist or source of preventive medical care, and adults who knew few or none of the clinical signs of oral cancer also were less likely to have received a recent oral cancer exam.
    


          Conclusions:
        
      
      There is widespread lack of awareness and knowledge in Florida regarding oral cancer and low levels of reported examination, particularly among groups experiencing disproportionately high incidence and late stage diagnosis. Increasing awareness of this disease and promoting primary and secondary prevention may help lessen the disease burden in Florida and reduce racial disparities in its outcomes."
1314,A comparative analysis of factors influencing colorectal cancer's age standardized mortality ratio among Korean women in the hot and cold spots.,"Lee C, Kim S, Woo J.",https://pubmed.ncbi.nlm.nih.gov/36083985/,"The study aimed at exploring factors that most influence colorectal cancer (CRC) age standardized mortality ratio (ASMR) among Korean women, as reported in previous studies. The factors used the data of 250 municipalities from the Korean Statistical Information Service (KOSIS) from 2010 to 2018. In the exploratory survey, over 70% of women aged 65 and above died of colorectal cancer. After investigating the existing literature and theories, 250 regions were classified into hot and cold spots according to age standardized mortality ratio (ASMR). The Nearest Neighbor Index (NNI), Moran's I index and The Durbin-Watson test were also utilized. The ASMR's regional cluster analysis showed that the inland areas were the hot spots and the cold spots were in the southwest coastal areas. The  In addition, there was no significant difference in ASMR for breast cancer, CRC deaths, and agricultural product shipments between the two regions. In the multiple regression model, CRC mortality, diabetes, and CRC age standardized incidence ratio (ASIR) were analyzed as major influencing factors, demonstrated a significant 6% by examining the adjusted R-squared. However, this study showed that factors such as smoking, alcohol consumption, abdominal obesity, breast cancer, and food consumption indicated to have less influence on the occurrence of CRC. The aging rate, amount of food consumption, seafood production, livestock product shipments, and drinking rate were higher in the cold spot than in the hot spot."
1315,Genes involved in development and differentiation are commonly methylated in cancers derived from multiple organs: a single-institutional methylome analysis using 1007 tissue specimens.,"Ohara K, Arai E, Takahashi Y, Ito N, Shibuya A, Tsuta K, Kushima R, Tsuda H, Ojima H, Fujimoto H, Watanabe SI, Katai H, Kinoshita T, Shibata T, Kohno T, Kanai Y.",https://pubmed.ncbi.nlm.nih.gov/28069692/,"The aim of this study was to clarify the significance of DNA methylation alterations shared by cancers derived from multiple organs. We analyzed single-institutional methylome data by single-CpG-resolution Infinium assay for 1007 samples of non-cancerous tissue (N) and corresponding cancerous tissue (T) obtained from lung, stomach, kidney, breast and liver. Principal component analysis revealed that N samples of each organ showed distinct DNA methylation profiles, DNA methylation profiles of N samples of each organ being inherited by the corresponding T samples and DNA methylation profiles of T samples being more similar to those of N samples in the same organ than those of T samples in other organs. In contrast to such organ and/or carcinogenetic factor-specificity of DNA methylation profiles, when compared with the corresponding N samples, 231 genes commonly showed DNA hypermethylation in T samples in four or more organs. Gene ontology enrichment analysis showed that such commonly methylated genes were enriched among ""transcriptional factors"" participating in development and/or differentiation, which reportedly show bivalent histone modification in embryonic stem cells. Pyrosequencing and quantitative reverse transcription-PCR revealed an inverse correlation between DNA methylation levels and mRNA expression levels of representative commonly methylated genes, such as ALX1, ATP8A2, CR1 and EFCAB1, in tissue samples. These data suggest that disruption of the differentiated state of precancerous cells via alterations of expression, independent of differences in organs and/or carcinogenetic factors, may be a common feature of DNA methylation alterations during carcinogenesis in multiple organs."
1316,Human epidermal growth factor receptor-2 in oesophageal cancers: an observational study.,"Al-Momani H, Barnes R, El-Hadi A, Shah R, Lewis WG, Edwards P.",https://pubmed.ncbi.nlm.nih.gov/23197890/,"Aim:
        
      
      To determine the incidence of human epidermal growth factor receptor 2 (HER2) over expression in oesophageal cancers.
    


           Cancer cases were diagnosed between April 2007 and June 2010. HER2 over expression was assessed using immunohistochemistry, those that scored ""0"" and ""+1"" were considered ""negative"" for HER2; those that scored ""+3"" were considered ""Positive"". Cases that were scored ""+2"" on immunohistochemistry further went on to have HER2 gene analysis using the Ventana HER brightfield dual-colour in situ hybridisations (HER B DISH) assay and either came back to be positive or negative for HER2 over expression. Overall survival was measured from date of histological diagnosis until date of death. 93% of the cases were followed up till five years or death, and all were followed up till two years. Cases of gastro-oesophageal junctional tumours were excluded.
    


           Eighty one were male and 19 female. Ninety-one of the cases were adenocarcinoma of the oesophagus and the rest were cases of squamous cell carcinoma. The anatomical distribution of the tumours was; upper oesophagus 2, middle oesophagus 11, and 87 were in the lower oesophagus. Operative resection was completed in 15 cases; seven cases had attempted surgical resections, i.e., open and close, 33 patients received definitive chemo-radiation and 52 had palliative treatment. Twenty-five of the cancers showed evidence of HER2 over expression, all were adenocarcinomas. Of the 25 cases that showed evidence of HER2 over expression, 21 (84%) were located in the lower third of the oesophagus. On staging, 24 out of the 25 HER2 positive cases were at stage 3 or more (13 at stage 3 and 11 at stage 4), For HER2 negative cases 37 were at stage 3 and 32 were staged as stage 4. Seventeen out of twenty five cases (68%) with HER2 over expression received palliative therapy, in comparison to thirty five out of seventy five (46.7%) in tumours not expressing HER2. No significant difference in overall survival was demonstrated between patients whose cancers showed evidence of HER2 over expression and those who did not; median overall survival for HER2 positive tumours was 15 mo (95%CI, 11-19 mo) compared to 13 mo (95%CI, 9-17 mo) for HER2 negative ones. Two years cumulative survival for cases with HER2 over expression was 33.7% compared to 31.6% in cases without HER2 over expression (P = 0.576). Only cancer's stage significantly affected overall survival on both univariant and multivariable analysis (P = 0.034 and P = 0.009 respectively). None of the patients included in this study received Trastuzumab.
    


          Conclusion:
        
      
      Twenty-seven point five percent of oesophageal adenocarcinomas showed evidence of HER2 over expression. Routine testing for human HER2 in oesophageal adenocarcinomas can have significant implication on treatments offered to patients that may potentially affect their prognosis."
1317,ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of thyroid nodules and cancer.,"Vrachimis A, Iakovou I, Giannoula E, Giovanella L.",https://pubmed.ncbi.nlm.nih.gov/32438345/,"Most patients with thyroid nodules and thyroid cancer (TC) referred for diagnostic work-up and treatment are not considered at higher risk of infection from SARS-CoV-2 compared to the general population. On the other hand, healthcare resources should be spared to the maximum extent possible during a pandemic. Indeed, while thyroid nodules are very common, only a small percentage are cancerous and, in turn, most thyroid cancers are indolent in nature. Accordingly, diagnostic work-up of thyroid nodules, thyroid surgery for either benign or malignant thyroid nodules and radioiodine treatment for differentiated thyroid cancers may be safely postponed during SARS-CoV-2 pandemic. Appropriate patient counselling, however, is mandatory and red flags should be carefully identified prompting immediate evaluation and treatment as appropriate. For these selected cases diagnostic work-up (e.g. ultrasound, scintigraphy, fine-needle aspiration), surgery and radioiodine therapy may proceed despite the threat of SARS-CoV-2 infection and COVID-19, after an individual risk-benefit analysis."
1318,Cancer cell-targeted cisplatin prodrug delivery in vivo via metabolic labeling and bioorthogonal click reaction.,"Liu X, Wu F, Cai K, Zhao Z, Zhang Z, Chen Y, Liu Y, Cheng J, Yin L.",https://pubmed.ncbi.nlm.nih.gov/33350407/,"The discrepancy of surface receptors on cancerous and non-cancerous cells has been regarded as the mainstay of cancer-targeted therapy. However, due to the heterogeneity of tumor cells and the insufficient levels of receptors on the tumor cell surface, the success of cancer cell-targeted therapies is largely limited. Histone deacetylase/cathepsin l-responsive acetylated azidomannose (DCL-AAM) was previously developed to effectively and selectively label cancer cell surfaces with reactive azido groups via sugar metabolism. Herein, the labeling kinetics and generality of DCL-AAM were systematically investigated in varieties of tumor cells in vitro and in SKOV3 xenograft tumors in vivo. Based on this, dibenzocyclooctyne-cisplatin (DBCO-Pt) prodrug was developed, and DCL-AAM-mediated metabolic labeling of SKOV3 cells enhanced the tumor accumulation of DBCO-Pt ∼2 fold via bioorthogonal click chemistry, potentiating the anti-tumor efficacy of cisplatin yet alleviating the systemic toxicity. This work, therefore, provides the "
1319,In vivo study for the discrimination of cancerous and normal skin using fibre probe-based Raman spectroscopy.,"Schleusener J, Gluszczynska P, Reble C, Gersonde I, Helfmann J, Fluhr JW, Lademann J, Röwert-Huber J, Patzelt A, Meinke MC.",https://pubmed.ncbi.nlm.nih.gov/26010742/,"Raman spectroscopy has proved its capability as an  Most publications are based on a Raman microspectroscopic ex vivo approach. In this in vivo clinical evaluation, we apply Raman spectroscopy using a fibre-coupled probe that allows access to a multitude of affected body sites. The probe design is optimized for epithelial sensitivity, whereby a large part of the detected signal originates from within the epidermal layer's depth down to the basal membrane where early stages of skin cancer develop. Data analysis was performed on measurements of 104 subjects scheduled for excision of lesions suspected of being malignant melanoma (MM) (n = 36), basal cell carcinoma (BCC) (n = 39) and squamous cell carcinoma (SCC) (n = 29). NMSC were discriminated from normal skin with a balanced accuracy of 73% (BCC) and 85% (SCC) using partial least squares discriminant analysis (PLS-DA). Discriminating MM and pigmented nevi (PN)  These  Discrimination proved to be unsuccessful between cancerous lesions and suspicious lesions that had been histopathologically verified as benign by dermoscopy."
1320,Effectiveness of a surveillance program of upper endoscopy for upper gastrointestinal cancers in Lynch syndrome patients.,"Ceravolo AH, Yang JJ, Latham A, Markowitz AJ, Shia J, Mermelstein J, Calo D, Gerdes H, Ludwig E, Schattner MA, Stadler ZK, Kantor E, Du M, Mendelsohn RB.",https://pubmed.ncbi.nlm.nih.gov/34698909/,"
    


           Patients were included if they had at least two EGDs or an upper GI cancer detected on the first surveillance EGD. EGD and pathology reports were extracted manually.
    


          1 years (SD 12.6) at first EGD. Patients had a mean of 3.5 EGDs (range 1-16). Mean duration of follow-up was 5.7 years. Average interval between EGDs was 2.3 years. Surveillance EGD detected precursor lesions in 8 (3.2%) patients, two (0.8%) gastric cancers and two (0.8%) duodenal cancers. Two interval cancers were diagnosed: a duodenal adenocarcinoma was detected 2 years, 8 months after prior EGD and a jejunal adenocarcinoma was detected 1 year, 9 months after prior EGD.
    


          Conclusions:
        
      
      Our data suggest that surveillance EGD is a useful tool to help detect precancerous and cancerous upper GI lesions in LS patients. To our knowledge, this is the first study to examine a program of surveillance EGDs in LS patients. More data are needed to determine the appropriate surveillance interval."
1321,Use of tamoxifen for breast cancer: twenty-eight years later.,"Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN.",https://pubmed.ncbi.nlm.nih.gov/7844613/,"Purpose:
        
      
      The mechanisms of antitumor activity, clinical pharmacology, toxicity, and efficacy of tamoxifen in women with early and advanced breast cancer and the drug's potential role in prevention of breast cancer were reviewed.
    


          Design:
        
      
      A comprehensive review of the literature from 1966 to 1994 was conducted; reports were identified using the Cancerline and Medline data bases.
    


           Disease-free and overall survival rates have been increased in postmenopausal women with ER-positive tumors when tamoxifen has been used as adjuvant therapy (irrespective of nodal status). In premenopausal women, adjuvant therapy with tamoxifen has been associated with prolongation of disease-free survival, but its impact on survival remains to be defined. Tamoxifen is the initial hormonal treatment of choice in both premenopausal and postmenopausal women with ER-positive metastatic disease. Retrospective review of adjuvant therapy studies showed an approximately 39% reduction in the incidence of contralateral primary breast carcinoma in tamoxifen-treated women, which indicates that tamoxifen could have a role in breast cancer prevention.
    


          Conclusion:
        
      
      The use of tamoxifen has  Ongoing clinical trials will examine the effects of tamoxifen therapy on lipids, coagulation proteins, bone, and endometrium, and its effectiveness as an agent in the prevention of breast cancer."
1322,Is chimerism associated with cancer across the tree of life?,"Kapsetaki SE, Fortunato A, Compton Z, Rupp SM, Nour Z, Riggs-Davis S, Stephenson D, Duke EG, Boddy AM, Harrison TM, Maley CC, Aktipis A.",https://pubmed.ncbi.nlm.nih.gov/37384647/,"Chimerism is a widespread phenomenon across the tree of life. It is defined as a multicellular organism composed of cells from other genetically distinct entities. This ability to 'tolerate' non-self cells may be linked to susceptibility to diseases like cancer. Here we test whether chimerism is associated with cancers across obligately multicellular organisms in the tree of life. We classified 12 obligately multicellular taxa from lowest to highest chimerism levels based on the existing literature on the presence of chimerism in these species. We then tested for associations of chimerism with tumour invasiveness, neoplasia (benign or malignant) prevalence and malignancy prevalence in 11 terrestrial mammalian species. We found that taxa with higher levels of chimerism have higher tumour invasiveness, though there was no association between malignancy or neoplasia and chimerism among mammals. This suggests that there may be an important biological relationship between chimerism and susceptibility to tissue invasion by cancerous cells. Studying chimerism might help us identify mechanisms underlying invasive cancers and also could provide insights into the detection and management of emerging transmissible cancers."
1323,Diagnostic value of confocal laser endomicroscopy for gastric superficial cancerous lesions.,"Li WB, Zuo XL, Li CQ, Zuo F, Gu XM, Yu T, Chu CL, Zhang TG, Li YQ.",https://pubmed.ncbi.nlm.nih.gov/21193460/," Confocal laser endomicroscopy (CLE) can provide in vivo histological observation without the need for biopsy.
    


          
    


          Design:
        
      
      Prospective study.
    


          Setting:
        
      
      Qilu Hospital, Shandong University, Jinan, China.
    


          Patients:
        
      
      A total of 182 patients were enrolled into phase I and 1786 patients were enrolled into phase II.
    


          Interventions:
        
      
      CLE images were blindly evaluated after endoscopy in phase I, and real-time iCLE diagnosis during endoscopy was compared with WLE diagnosis by using histopathology as a gold standard in phase II.
    


          Main outcome measurements:
        
      
      The validity and reliability of the CLE diagnosis for identifying gastric superficial cancerous lesions.
    


          1%) and specificity (98.6%). When the two-tiered CLE classification of non-cancerous lesions and cancer/high-grade intraepithelial neoplasia (HGIN) lesions was introduced, CLE diagnosis led to a higher sensitivity (90.2%) and specificity (98.5%) (phase I). Real-time iCLE diagnosis had a higher sensitivity (88.9%), specificity (99.3%) and accuracy (98.8%) for gastric superficial cancer/HGIN lesions than WLE diagnosis (sensitivity, 72.2%; specificity, 95.1%; and accuracy, 94.1%) (p < 0.05) (phase II). Limitations This was a single-centre study.
    


          Conclusions:
        
      
      CLE can be used to identify gastric superficial cancer/HGIN lesions with high validity and reliability."
1324,The glycosaminoglycans of human bladder cancers of varying grade and stage.,De Klerk DP.,https://pubmed.ncbi.nlm.nih.gov/3932680/,"The glycosaminoglycans of four normal human bladders and fourteen bladder cancers were characterized and quantitated (after proteolytic extraction) by specific enzyme digestion, cellulose acetate electrophoresis and densitometry. Hyaluronic acid, heparan sulfate, dermatan sulfate and chondroitin sulfate were identified in both normal and cancerous bladders. Hyaluronic acid and dermatan sulfate were the major glycosaminoglycans of the normal epithelium/submucosa while heparan sulfate and dermatan sulfate were predominant in normal bladder muscle. Bladder cancer glycosaminoglycan content was influenced by the stage and grade of the neoplasm. Hyaluronic acid and dermatan sulfate tended to decrease and chondroitin sulfate to increase in infiltrating cancers, whereas a decrease in the percentage of heparan sulfate correlated closely with higher grade tumors. The bladder cancer glycosaminoglycan profile may be indicative of the tumor's invasive potential."
1325,Surgical approach to the management of field cancerization: Own experience.,"Wójcicka K, Szepietowski JC.",https://pubmed.ncbi.nlm.nih.gov/32430938/,"The term field cancerization was proposed by Slaughter in 1953 to describe multifocal neoplastic lesions in the oral mucosa. Currently, it is well known that field cancerization can occur also in the skin. There is no one, universal and generally accepted management for the patients with multiple actinic keratosis and field cancerization. We presented two cases with large field cancerization on the face and the scalp. In both patients, we performed one stage surgery with split thickness skin graft with good final esthetic and functional  Available literature on the role of classical surgical removal in treating field cancerization is very limited. We believe that surgery can be consider as an option for the treatment in some high risk patients with very large field cancerization, but further observation and evaluation of this "
1326,[Stimulation of adenyl cyclase and fixation of iodine in human cancerous thyroid cells in culture].,Thomas-Morvan C.,https://pubmed.ncbi.nlm.nih.gov/3004675/,"In primary cultures of cells from human thyroid cancer, functional activity was investigated by adenylate cyclase responsiveness and radioiodine uptake. In cells from well-differentiated follicular carcinomas (2 cases), TSH stimulation of cAMP accumulation is similar to that of normal thyroid cells. In contrast, in papillary carcinomas (11 cases), the mean dose-response curve is much lower than normal. In thyroid cancers, radioiodine uptake by the cells has been detected in some cases after 3 days of 125I incorporation. As previously observed, our "
1327,Insights into the Relationship between Pentraxin-3 and Cancer.,"Bogdan M, Meca AD, Turcu-Stiolica A, Oancea CN, Kostici R, Surlin MV, Florescu C.",https://pubmed.ncbi.nlm.nih.gov/36499628/,"Although cancer can be cured if detected early and treated effectively, it is still a leading cause of death worldwide. Tumor development can be limited by an appropiate immune response, but it can be promoted by chronic extensive inflammation through metabolic dysregulation and angiogenesis. In the past decade, numerous efforts have been made in order to identify novel candidates with predictive values in cancer diagnostics. In line with this, researchers have investigated the involvement of pentraxin-3 (PTX-3) in cellular proliferation and immune escape in various types of cancers, although it has not been clearly elucidated. PTX-3 is a member of the long pentraxin subfamily which plays an important role in regulating inflammation, innate immunity response, angiogenesis, and tissue remodeling. Increased synthesis of inflammatory biomarkers and activation of different cellular mechanisms can induce PTX-3 expression in various types of cells (neutrophils, monocytes, lymphocytes, myeloid dendritic cells, fibroblasts, and epithelial cells). PTX-3 has both pro- and anti-tumor functions, thus dual functions in oncogenesis. This review elucidates the potential usefulness of PTX-3 as a serum biomarker in cancer. While future investigations are needed, PTX-3 is emerging as a promising tool for cancer's diagnosis and prognosis, and also treatment monitoring."
1328,Recent advances in nanoparticle-based nuclear imaging of cancers.,"Srivatsan A, Chen X.",https://pubmed.ncbi.nlm.nih.gov/25287687/,"Nuclear imaging techniques that include positron emission tomography (PET) and single-photon computed tomography have found great success in the clinic because of their inherent high sensitivity. Radionuclide imaging is the most popular form of imaging to be used for molecular imaging in oncology. While many types of molecules have been used for radionuclide-based molecular imaging, there has been a great interest in developing newer nanomaterials for use in clinic, especially for cancer diagnosis and treatment. Nanomaterials have unique physical properties which allow them to be used as imaging probes to locate and identify cancerous lesions. Over the past decade, a great number of nanoparticles have been developed for radionuclide imaging of cancer. This chapter reviews the different kinds of nanomaterials, both organic and inorganic, which are currently being researched for as potential agents for nuclear imaging of variety of cancers. Several radiolabeled multifunctional nanocarriers have been extremely successful for the detection of cancer in preclinical models. So far, significant progress has been achieved in nanoparticle structure design, in vitro/in vivo trafficking, and in vivo fate mapping by using PET. There is a great need for the development of newer nanoparticles, which improve active targeting and quantify new biomarkers for early disease detection and possible prevention of cancer."
1329,"Quantitative Evaluation of Heavy Metals and Trace Elements in the Urinary Bladder: Comparison Between Cancerous, Adjacent Non-cancerous and Normal Cadaveric Tissue.","Abdel-Gawad M, Elsobky E, Shalaby MM, Abd-Elhameed M, Abdel-Rahim M, Ali-El-Dein B.",https://pubmed.ncbi.nlm.nih.gov/27147435/,"The role of heavy metals and trace elements (HMTE) in the development of some cancers has been previously reported. Bladder carcinoma is a frequent malignancy of the urinary tract. The most common risk factors for bladder cancer are exposure to industrial carcinogens, cigarette smoking, gender, and possibly diet. The aim of this study was to evaluate HTME concentrations in the cancerous and adjacent non-cancerous tissues and compare them with those of normal cadaveric bladder. This prospective study included 102 paired samples of full-thickness cancer and adjacent non-cancerous bladder tissues of radical cystectomy (RC) specimens that were histologically proven as invasive bladder cancer (MIBC). We used 17 matched controls of non-malignant bladder tissue samples from cadavers. All samples were processed and evaluated for the concentration of 22 HMTE by using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). Outcome analysis was made by the Mann-Whitney U, chi-square, Kruskal-Wallis, and Wilcoxon signed ranks tests. When compared with cadaveric control or cancerous, the adjacent non-cancerous tissue had higher levels of six elements (arsenic, lead, selenium, strontium, zinc, and aluminum), and when compared with the control alone, it had a higher concentration of calcium, cadmium, chromium, potassium, magnesium, and nickel. The cancerous tissue had a higher concentration of cadmium, lead, chromium, calcium, potassium, phosphorous, magnesium, nickel, selenium, strontium, and zinc than cadaveric control. Boron level was higher in cadaveric control than cancerous and adjacent non-cancerous tissue. Cadmium level was higher in cancerous tissue with node-positive than node-negative cases. The high concentrations of cadmium, lead, chromium, nickel, and zinc, in the cancerous together with arsenic in the adjacent non-cancerous tissues of RC specimens suggest a pathogenic role of these elements in BC. However, further work-up is needed to support this conclusion by the application of these HMTE on BC cell lines."
1330,Heterozygosity of p16 expression in an oral squamous cell carcinoma with associated loss of heterozygosity and copy number alterations.,"Ambele MA, Pepper MS, van Heerden MB, van Heerden WFP.",https://pubmed.ncbi.nlm.nih.gov/30552721/," This case demonstrated differential p16 expression in different sections of the same HPV negative tumor on the floor of mouth in a patient with history of prolonged smoking.
    


          
    


           OncoScan analysis showed genetic changes that define field cancerization of the p16 negative tumor as revealed by mosaicism in both loss of heterozygosity and copy number alterations in cancer-associated genes located on 3p, 7p, 9p 11q, and 17p.
    


          Conclusion:
        
      
      These changes were indicative of field cancerization in response to tobacco exposure."
1331,Cancer's positive flip side: posttraumatic growth after childhood cancer.,"Gianinazzi ME, Rueegg CS, Vetsch J, Lüer S, Kuehni CE, Michel G; Swiss Pediatric Oncology Group (SPOG).",https://pubmed.ncbi.nlm.nih.gov/26003421/," We aimed to (1) describe PTG in Swiss childhood cancer survivors including the most and the least common PTG phenomena on the subscale and item levels and (2) determine factors associated with PTG.
    


           Eligible survivors were diagnosed after 1990 at age ≤16 years, survived ≥5 years, and were aged ≥18 years at the time the second questionnaire was sent. We included the Posttraumatic Growth Inventory (PTGI) to assess five areas of PTG. We investigated the association of PTG with socio-demographic characteristics, self-reported late effects, and psychological distress, which were assessed in the SCCSS and clinical variables extracted from the SCCR. We used descriptive statistics to describe PTG and linear regressions to investigate factors associated with PTG.
    


           Most individuals reported to have experienced some PTG. The most endorsed change occurred in ""relation with others,"" the least in ""spiritual change."" PTG was significantly higher in survivors with older age at diagnosis (p = 0.001) and those with a longer duration of treatment (p = 0.042), while it was lower in male survivors (p = 0.003).
    


          Conclusions:
        
      
      Supporting experiences of PTG during follow-up may help survivors successfully return to daily life."
1332,Histological findings of thyroid cancer after lenvatinib therapy.,"Okubo Y, Toda S, Sato S, Yoshioka E, Ono K, Hasegawa C, Washimi K, Yokose T, Miyagi Y, Iwasaki H, Hayashi H.",https://pubmed.ncbi.nlm.nih.gov/37501641/,"Aims:
        
      
      Lenvatinib is a multikinase inhibitor used for treating unresectable or metastatic cancers, including thyroid cancer. As total thyroidectomy followed by radioactive iodine therapy is a commonly recommended initial treatment for thyroid cancer, histological findings of the thyroid after lenvatinib therapy remain unclear. Therefore, the aim of this study was to analyse in-vivo changes in patients who underwent thyroidectomy after lenvatinib therapy.
    


           Among these patients, six underwent thyroidectomy (lenvatinib-treated group: PTC, n = 3; FTC, n = 1; ATC, n = 2), and the specimens were examined. Five patients with PTC who did not receive lenvatinib therapy were included for comparison (untreated group). Microvessel density (MVD) was evaluated in both groups. The PTC and FTC specimens showed relatively more ischaemic changes than ATC specimens. Coagulative necrosis and ischaemic changes in cancer cells were frequently observed. ATC specimens showed fibrosis and mild cell damage. As hypothyroidism is a common side effect of lenvatinib therapy, non-cancerous thyroid tissues were also examined. Histological findings included mild lymphocytic infiltration, lymphoid follicular formation, histiocytic reaction and follicular epithelial destruction. The MVD in lenvatinib-treated tissues was significantly lower than that in untreated tissues.
    


          Conclusions:
        
      
      Lenvatinib therapy probably induces relatively specific ischaemic changes in thyroid cancer cells. Moreover, inflammatory cell infiltration and decreased MVD occur to varying degrees in non-cancerous thyroid tissue and may be related to hypothyroidism, a side effect of lenvatinib."
1333,Systematic analysis of breast cancer morphology uncovers stromal features associated with survival.,"Beck AH, Sangoi AR, Leung S, Marinelli RJ, Nielsen TO, van de Vijver MJ, West RB, van de Rijn M, Koller D.",https://pubmed.ncbi.nlm.nih.gov/22072638/,"The morphological interpretation of histologic sections forms the basis of diagnosis and prognostication for cancer. In the diagnosis of carcinomas, pathologists perform a semiquantitative analysis of a small set of morphological features to determine the cancer's histologic grade. Physicians use histologic grade to inform their assessment of a carcinoma's aggressiveness and a patient's prognosis. Nevertheless, the determination of grade in breast cancer examines only a small set of morphological features of breast cancer epithelial cells, which has been largely unchanged since the 1920s. A comprehensive analysis of automatically quantitated morphological features could identify characteristics of prognostic relevance and provide an accurate and reproducible means for assessing prognosis from microscopic image data. We developed the C-Path (Computational Pathologist) system to measure a rich quantitative feature set from the breast cancer epithelium and stroma (6642 features), including both standard morphometric descriptors of image objects and higher-level contextual, relational, and global image features. These measurements were used to construct a prognostic model. We applied the C-Path system to microscopic images from two independent cohorts of breast cancer patients [from the Netherlands Cancer Institute (NKI) cohort, n = 248, and the Vancouver General Hospital (VGH) cohort, n = 328]. The prognostic model score generated by our system was strongly associated with overall survival in both the NKI and the VGH cohorts (both log-rank P ≤ 0.001). This association was independent of clinical, pathological, and molecular factors. Three stromal features were significantly associated with survival, and this association was stronger than the association of survival with epithelial characteristics in the model. These findings implicate stromal morphologic structure as a previously unrecognized prognostic determinant for breast cancer."
1334,The molecular biology of mucosal field cancerization of the head and neck.,"Ha PK, Califano JA.",https://pubmed.ncbi.nlm.nih.gov/14530304/,"Field cancerization was first described in 1953 as histologically altered epithelium surrounding tumor samples taken from the upper aerodigestive tract. Since then, the term has been used to describe multiple patches of pre-malignant disease, a higher-than-expected prevalence of multiple local second primary tumors, and the presence of synchronous distant tumors within the upper aerodigestive tract. Molecular techniques such as karyotype analysis, microsatellite analysis, p53 mutation screening, and X-chromosome inactivation studies have further refined the relationship among these lesions. While there are differences in the techniques used to identify the clonal origins of the lesions, these studies indicate that there is often lateral clonal spread of pre-malignant or malignant disease, and a significant portion of local second primary tumors are in fact genetically related. Distant second primary tumors found in the esophagus are often not related to concurrent head and neck cancer, whereas synchronous squamous lung tumors with a head and neck primary are often, in fact, metastases, rather than independently arising malignancies. These observations help to explain the high incidence of recurrent disease, despite excision or other therapy--pre-malignant or malignant clones often have the ability to migrate and persist outside of the field of treatment. Therefore, alternative means of prevention or therapy that can affect the entire head and neck region may be of benefit to such patients. Future studies will further refine the relationship among these lesions and perhaps identify key molecular alterations to be used as targets for gene therapy."
1335,CCT3 suppression prompts apoptotic machinery through oxidative stress and energy deprivation in breast and prostate cancers.,"Temiz E, Koyuncu İ, Sahin E.",https://pubmed.ncbi.nlm.nih.gov/33508424/,"Mediated by chaperon proteins, protein misfolding plays a crucial role in cancer pathogenesis. Chaperonin Containing TCP1 Subunit 3 (CCT3) is one of eight subunits forming eukaryotic chaperons that catalyzes correct folding of the proteins employed in cell division, proliferation, and apoptosis pathway. Moreover, CCT3 expression increases responsively with carcinogenesis. However, how CCT3 drives the cancerous process has not been documented. Here we probed the mechanistic and functional interactions between CCT3 and apoptotic pathways and cell stressors. First, we profiled CCT3 expression levels of different 16 cell lines and found that CCT3 expression levels of CRL-2329 and PC3 were significantly increased. Then, we suppressed CCT3 levels in CRL-2329 and PC3 lines by miR-24-3p, miR-128-3p, and miR-149-5p mimics, and measured apoptotic response of the cell lines to the knockdown of CCT3 by acridine orange/ethidium bromide and Annexin V/PI staining, cell-cycle and mitochondria membrane potential (MMP) analyses, intracellular reactive oxygen species (ROS) measurement and analysis of expression levels of the apoptotic genes. After having suppressed CCT3, the cell cycle was arrested in the G0/G1 phase, MMP was impaired, and the intracellular ROS level was increased. These signs of apoptotic flux were corroborated by morphological images, statistically enhanced expression levels of the apoptotic pathway modulators and intracellular free amino acids profile. The free amino acid profile, which is heavily implicated in energy metabolism and cell division, is fluctuated in the progress of canceration. Strikingly, suppressed CCT3 shifted intracellular levels of glutamine, beta-alanine, glycine, serin, asparagine and sarcosine, which are employed in energy metabolism. Consequently, miRNA-mediated CCT3 suppression spur apoptosis by unbalancing the homeostasis in intracellular ROS and the profile of free amino acids in energy metabolism. Taken together, we anticipate that miRNA-mediated CCT3 suppression might provide a ""dual therapeutic strategy"" through conventional cellular toxicity as well as energy withdrawal."
1336,Frequent epigenetic inactivation of RSK4 by promoter methylation in cancerous and non-cancerous tissues of breast cancer.,"Li Q, Jiang Y, Wei W, Ji Y, Gao H, Liu J.",https://pubmed.ncbi.nlm.nih.gov/24338215/,"Breast cancer is one of the most common cancers and is the second leading cause of cancer-related death in women worldwide. Ribosomal s6 kinase4 (RSK4) is a potential tumor suppressor in multiple cancers, while its role in breast cancer is largely unknown. Our study here aimed to explore the relationship between RSK4 expression with the clinicopathologic characteristics and the promoter methylation status of RSK4. Real-time PCR and bisulfite sequencing PCR were, respectively, used to detect the expression difference of RSK4 mRNA and RSK4 methylation in the 49 breast cancer and paired non-cancerous samples. The associations of RSK4 expression and methylation status with the clinicopathologic characteristics were analyzed. In the 49 breast cancer patients' specimens, RSK4 mRNA expression was found to be significantly decreased in most of breast cancer tissues compared with paired non-cancerous tissues (p = 0.002), which was largely due to the promoter hypermethylation (p = 0.005). Frequency of RSK4 promoter methylation in breast cancers was significantly higher than paired non-cancerous tissues (p = 0.009); RSK4 methylation was not associated with all clinicopathological features. The silencing of RSK4 due to promoter hypermethylation is a frequent event in breast cancer. The majority of cancers have a higher level of methylation status when compared with non-cancerous tissues. RSK4 may be a valuable biomarker for the study of breast cancer carcinogenesis and progression."
1337,[The concept of field cancerization and its clinical application].,"Wei ZH, Gong W, Zhou M, Chen QM.",https://pubmed.ncbi.nlm.nih.gov/27596348/,"Head and neck squamous cell carcinoma(HNSCC) is among the most common malignances worldwide. Patients with HNSCC often develop primary tumors at multiple sites and have tendency for local recurrences following curative resectional surgery. Field cancerization theory presumes that, after repeated carcinogenic exposures, the entire superficialepitheliium of the upper aerodigestive tract has an increased risk for developing (pre)malignant lesions because of multiple genetic abnormalities. This theorywell explains the strong potential with malignant transformation and loco-regional recurrence in HNSCC, and helps to better understand the pathogenesis, and thus provides a new idea for prevention and treatment of this disease. This paper will give an overview of field cancerization, including the concept and its clinical application."
1338,"Paraneoplasia, cancer development and immunity: what are the connections?",Chesler L.,https://pubmed.ncbi.nlm.nih.gov/25093228/,"Paraneoplasia literally means conditions adjacent to, or associated with, abnormal cancerous tissue growth. In this Comment article, I discuss what the immune-mediated paraneoplasias teach us about the immune response and cancer development."
1339,The concerns of patients and spouses after the diagnosis of colon cancer: a qualitative analysis.,"Northouse LL, Schafer JA, Tipton J, Metivier L.",https://pubmed.ncbi.nlm.nih.gov/10036419/,"Purpose:
        
      
      The purposes of this study were to describe the concerns of patients and their spouses after a diagnosis of colon cancer and to identify ways in which health care professionals could assist both patients and their spouses to cope more effectively with this illness and its treatment.
    


          Design:
        
      
      Descriptive, cross-sectional study.
    


          Setting and subjects:
        
      
      Thirty patients with colon cancer and their spouses completed interviews in their homes. Most patients (83%) had undergone partial colon resection, and 77% had no evidence of cancer in adjacent lymph nodes. Twelve of the patients (40%) had a colostomy at the time the data were collected.
    


           Content analysis was used to analyze the interview data and to group data into inductively derived categories. Interrater reliability was obtained by having 2 researchers independently code the data.
    


           Both patients and spouses reported that fear of cancer's recurrence was their greatest concern. Most also reported lifestyle changes (80%) as a  Half of the patients and most of the spouses (75%) reported a favorable reaction to the colostomy. Approximately half of the couples expressed satisfaction with the information they received; they reported a need for more information about treatments and management of side effects. When asked how professionals could help them, most couples stated that they wanted more information about the expected course of recovery.
    


          Conclusion:
        
      
      Spouses should be included in health assessment and teaching because they regard the illness more negatively than do patients. Both patients and spouses desire information that will help them to understand the typical course of recovery, assist them to plan for lifestyle changes, and enable them to manage the side effects of treatment."
1340,Mechanical Signaling in the Mammary Microenvironment: From Homeostasis to Cancer.,"Boyle ST, Poltavets V, Samuel MS.",https://pubmed.ncbi.nlm.nih.gov/34664249/,"It is becoming increasingly appreciated that biophysical influences on tissues are at least as important as biochemical influences in regulating normal development and homeostasis. Furthermore, diseases of aberrant tissue homeostasis such as cancers are driven by the abnormal biophysics of cancerous tissues. The mammary gland, a mechanoresponsive tissue, is exquisitely sensitive to changes in its mechanical microenvironment. Forces play an important role in normal mammary development, lactation, and involution, as well as in mammary neoplasia. As such the mechanical influences on normal tissue homeostasis and neoplasia are easily studied in this tissue. Here, we discuss the role of mechanical forces in these developmental and homeostatic processes and highlight insights gained from new findings in the field of mammary mechanobiology. We also discuss the potential for harnessing these insights into novel anticancer therapy approaches that halt tumor progression, with opportunities to revolutionize cancer care and outcomes for patients."
1341,Continuous wave terahertz transmission imaging of nonmelanoma skin cancers.,"Joseph CS, Yaroslavsky AN, Neel VA, Goyette TM, Giles RH.",https://pubmed.ncbi.nlm.nih.gov/21761415/," Terahertz pulse imaging (TPI) has already shown that there is contrast between basal cell carcinoma and normal skin. Continuous-wave imaging offers a simpler, lower cost alternative to TPI. The goal of this study was to investigate the feasibility of continuous wave terahertz imaging for delineating skin cancers by demonstrating contrast between cancerous and normal tissue in transmission mode.
    


          Materials and 39 and 1.63 THz. The transmitted signals were detected using a liquid Helium cooled Silicon bolometer. Fresh skin cancer specimens were obtained from Mohs surgeries. The samples were processed and imaged within 24 hours after surgery. During the imaging  At both THz frequencies two-dimensional THz transmission images of nonmelanoma skin cancers were acquired with spatial resolution of 0.39 mm at 1.4 THz and 0.49 mm at 1.6 THz. For evaluation purposes, hematoxylin and eosin (H&E) histology was processed from the imaged tissue.
    


           Two negative controls were also imaged. The difference in transmission between normal and cancerous tissue was found to be approximately 60% at both frequencies, which suggests that contrast between normal and cancerous tissue at these frequencies is dominated by differences in water content.
    


          Conclusions:
        
      
      Our "
1342,Retrospective histological studies on biopsied gastric lesions of patients in whom cancer was diagnosed at follow-up examination.,"Nagayo T, Suzuki R, Sato T, Suchi T.",https://pubmed.ncbi.nlm.nih.gov/3117756/,"Serial biopsy specimens of gastric lesions of patients in whom cancer was diagnosed at follow-up examination were reexamined retrospectively; the source materials were 17,429 gastric biopsies carried out on 14,779 patients from 1971 to 1985 at Aichi Cancer Center Hospital. Among these cases, cancers were found at follow-up in 34 cases at locations distinct from the initially biopsied lesions, and in 41 cases, cancerous changes were detected at follow-up at the locations of the original lesions. These 41 cases amounted to 0.5% of the total biopsied cases with negative  The average interval from the first to the last endoscopic examination in these 41 cases was 52.1 months and the longest interval was 150 months in the case of a scarred lesion. Based on the reexamination of the histology of the biopsy specimens taken at the first examination, these 41 cases were classified into three subgroups: 1) no precancerous atypical changes were observed, 2) doubtful precancerous changes were observed and 3) minute or slight malignant changes did exist but had been overlooked. The number of cases in the first category was 33 (80.5%), among which ulcer or its scar was most common, the number in the second category was 6 (14.6%), most of them being polypoid lesions, and the number in the third category was 2 (4.9%). Histological features of some cases in each subgroup are presented and the "
1343,HMGA2 overexpression in non-small cell lung cancer.,"Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, Vollmer E, Bullerdiek J.",https://pubmed.ncbi.nlm.nih.gov/17477356/,"Lung cancer is still the leading cause of death from cancer worldwide primarily because of the fact that most lung cancers are diagnosed at advanced stages. Overexpression of the high mobility group protein HMGA2 has been observed in a variety of malignant tumors and often correlates with poor prognosis. Herein, HMGA2 expression levels were analyzed in matching cancerous and non-cancerous lung samples of 17 patients with adenocarcinoma (AC) and 17 patients with squamous cell carcinoma (SCC) with real-time quantitative RT-PCR (qRT-PCR). Transcript levels were compared to  HMGA2 expression was detectable by qRT-PCR in all samples tested and varied from 5422 to 16 991 545 copies per 250 ng total RNA in the carcinoma samples and from 289 to 525 947 copies in the non-cancerous tissue samples. In 33/34 non-small cell lung cancer (NSCLC) samples tested, an overexpression of HMGA2 was revealed with statistically highly significant differences between non-neoplastic and tumor samples for both AC (P < 0.0001) as well as for SCC (P < 0.0001). Expression varies strongly and is increased up to 911-fold for AC and up to 2504-fold for SCC, respectively, with statistically significant higher increase in SCC (P < 0.05). The "
1344,LncRNA-MALAT1: A Key Participant in the Occurrence and Development of Cancer.,"Hao L, Wu W, Xu Y, Chen Y, Meng C, Yun J, Wang X.",https://pubmed.ncbi.nlm.nih.gov/36903369/,"LncRNAs are a group of non-coding RNA transcripts with lengths of over 200 nucleotides and can interact with DNA, RNA, and proteins to regulate gene expression of malignant tumors in human tissues. LncRNAs participate in vital processes, such as chromosomal nuclear transport in the cancerous site of human tissue, activation, and the regulation of proto-oncogenes, the differentiation of immune cells, and the regulation of the cellular immune system. The lncRNA metastasis-associated lung cancer transcript 1 (MALAT1) is reportedly involved in the occurrence and development of many cancers and serves as a biomarker and therapeutic target. These findings highlight its promising role in cancer treatment. In this article, we comprehensively summarized the structure and functions of lncRNA, notably the discoveries of lncRNA-MALAT1 in different cancers, the action mechanisms, and the ongoing research on new drug development. We believe our review would serve as a basis for further research on the pathological mechanism of lncRNA-MALAT1 in cancer and provide evidence and novel insights into its application in clinical diagnoses and treatments."
1345,Aberrant FHIT transcripts in cancerous and corresponding non-cancerous lesions of the digestive tract.,"Chen YJ, Chen PH, Lee MD, Chang JG.",https://pubmed.ncbi.nlm.nih.gov/9378557/,"The FHIT gene was recently discovered and proposed as a tumor-suppressor gene. We examined the FHIT gene in a panel of digestive-tract cancers along with their corresponding non-tumorous tissues by reverse transcription of FHIT mRNA followed by PCR amplification and sequencing of the products. A normal FHIT transcript was found to be expressed at robust levels in 44 of 46 cancerous tissues and in all of 46 non-cancerous tissues tested. Of the 46 cancerous specimens, 21 (45.7%) revealed the occurrence of aberrant transcripts. In addition, of the 46 matched normal tissues, 14 (30.4%) showed the existence of aberrant transcripts. Sequence analysis confirmed that aberrant transcripts were missing in one or more exons of the FHIT cDNA, while 8 cases displayed aberrant transcripts of the FHIT gene both in cancerous and in non-cancerous tissues. However, sequence analysis revealed that the patterns of the aberrant transcripts were different between the corresponding paired samples. In addition, there were 6 cases displaying aberrant FHIT transcripts only in their normal-tissue counterparts. These studies indicate that abnormalities of the FHIT gene transcripts occur at a fairly high frequency in cancerous and corresponding non-cancerous lesions of the digestive tract. However, they might not be causally related to the tumorigenesis of the digestive tract."
1346,Elevated preoperative levels of CA 19-9 and CA 125 predicts overall survival time in the pancreatic adenocarcinoma. Single institution series.,"Hogendorf P, Skulimowski A, Durczyński A, Kumor A, Poznańska G, Poznańska A, Oleśna A, Rut J, Øvereng Juliebø S, Szmiel A, Strzelczyk J.",https://pubmed.ncbi.nlm.nih.gov/32759395/,"&lt;b&gt; Its aggressiveness is due to its specific biology and the late diagnosis of cancer. Therefore, the prognosis for patients suffering from this cancer is dismal, with 5-year overall survival rate of around 6-10%. Up to date, only a complete surgical resection of the cancerous entity warrants a significant improvement in patients' survival. Nevertheless, the pancreatic cancer's biology is still not fully elucidated, so that the accuracy of prognosis for certain patients is highly uncertain. Consequently, the importance of both clinical and basic research aiming to reveal the crucial molecular factors affecting long-term prognosis should be highlighted. There is a growing number of evidence that biomarkers of PC not only reflect the presence of tumor itself but also present a ""hint"" regarding its physiology. Thus the aim of this study was to assess the levels of commonly measured biomarkers and their influence on patients' overall survival. &lt;br&gt;&lt;b&gt;Materials and  On the day of admission all the patients had their levels of CA&lt;sub&gt;19-9&lt;/sub&gt;, CA&lt;sub&gt;125&lt;/sub&gt;, CEA and CA&lt;sub&gt;15-3&lt;/sub&gt; measured. The overall survival (OS) was defined as time elapsing from the day of admission to the day of death. The Kaplan- Meier curves were built for all potential factors, Cox regression model was applied to carry out a multivariate analysis. &lt;br&gt;&lt;b&gt; As many as 95 of them had an unresectable lesion and 34 underwent curative operation. In total, the analyzed patient group was characterized by a median survival of 7 months and 12 days. Cumulative 1-year, 2-year and 4-year survival rates were 35%, 16% and 15%, respectively. In univariate analysis, factors such as age &gt;= 60, inoperable lesion, CA&lt;sub&gt;19-9&lt;/sub&gt; &gt;= 200, CA&lt;sub&gt;125&lt;/sub&gt; &gt;= 20 and Neutrophile to Lymphocyte Ratio (NLR) &gt;= 5 were associated with a lower median OS. In multivariate analysis, three factors, CA&lt;sub&gt;19-9&lt;/sub&gt; &gt;= 200, CA&lt;sub&gt;125&lt;/sub&gt; &gt;= 20 and age &gt;= 60, were found to be statistically significant. Indeed, patients possessing all of them noted much poorer outcomes regarding OS factors: 89 days versus 235 days for the other patients (log rank test P = 0.02). &lt;br&gt;&lt;b&gt;Conclusions: &lt;/b&gt;Our study fortifies the evidence that preoperative levels of CA&lt;sub&gt;19-9&lt;/sub&gt; and CA&lt;sub&gt;125&lt;/sub&gt; have a direct influence on the longterm OS. Interestingly, in our patient group, the correlation of biomarkers with OS was higher than that of resectability. However, our study has some limitations regarding, for instance, the lack of data on chemotherapy, comorbidities etc. In the view of recent molecular studies on mucin involvement in PC development, it provides a strong clinical evidence to prove their importance."
1347,"Dermatologic sequelae of breast cancer: From disease, surgery, and radiation.","Milam EC, Rangel LK, Pomeranz MK.",https://pubmed.ncbi.nlm.nih.gov/33226140/,"The care of breast cancer patients is important to dermatologists. Breast cancer's initial presentation, clinical progression, and its associated treatments can  Dermatologists may be the first to identify a breast cancer diagnosis, as a subset of patients first present with direct extension of an underlying tumor or with a cutaneous metastasis. The surgical treatment of breast cancer also begets a variety of skin sequelae, including postoperative lymphedema, soft tissue infections, seromas, pyoderma gangrenosum, and scarring disorders. Moreover, breast cancer radiation treatment commonly  Radiation may also precipitate secondary malignancies, such as angiosarcoma, as well as rarer dermatologic diseases, such as radiation-induced morphea, lichen planus, and postirradiation pseudosclerodermatous panniculitis. Finally, breast cancer is also associated with an array of paraneoplastic phenomena, including Sweet's syndrome and the rarer intralymphatic histiocytosis. Herein, we review the dermatological manifestations of breast cancer, including conditions associated with its presentation, progression, and treatment sequelae. Chemotherapy-induced cutaneous side effects are beyond the scope of this review. This article provides a comprehensive review for dermatologist to be able to identify, diagnose, and manage breast cancer patients from initial presentation to treatment monitoring and subsequent follow-up."
1348,Circulating miRNA is a novel marker for head and neck squamous cell carcinoma.,"Hsu CM, Lin PM, Wang YM, Chen ZJ, Lin SF, Yang MY.",https://pubmed.ncbi.nlm.nih.gov/22811001/,"The aim of the study is to investigate the alteration of plasma miRNA in head and neck squamous cell carcinoma (HNSCC). Altered microRNAs (miRNAs) expression has been found in many cancers, including lung cancer, breast cancer, prostate cancer, bladder cancer and colorectal cancer. Many recent studies have demonstrated that aberrant plasma miRNAs were also found in various types of cancers. However the alteration of plasma expression in HNSCC remains unclear. In this present study, the expression profiles of ten miRNAs, let-7a, miR-21, miR26b, miR-34c, miR-99a, miR-133a, miR-137, miR-184, miR-194a, and miR-375, in plasma from 50 patients and 36 healthy subjects were evaluated using real-time quantitative polymerase chain reaction (PCR). Our 01) than those from healthy subjects, which were in consistent with our finding in HNSCC tissues. A 7.7-fold increase of miR-21 in cancerous parts when compared to their non-cancerous counterparts (p < 0.0001) was observed in HNSCC tissues. In addition, the expression levels of miR-21 and miR-26b were both reduced in post-operative HNSCC patients with good prognosis. In contrast, the concentration of plasma miR-21 and miR-26b stayed high after tumor removal in the expired cases. Our study suggests that detecting circulating miR-21 and miR-26b pre- and post-operatively might provide a novel tumor marker for HNSCC."
1349,Friend or foe: Multiple roles of adipose tissue in cancer formation and progression.,"Wang YX, Zhu N, Zhang CJ, Wang YK, Wu HT, Li Q, Du K, Liao DF, Qin L.",https://pubmed.ncbi.nlm.nih.gov/31054175/,"Obesity is well-known as the second factor for tumorigenesis after smoking and is bound up with the malignant progression of several kinds of cancers, including esophageal cancer, liver cancer, colorectal cancer, kidney cancer, and ovarian cancer. The increased morbidity and mortality of obesity-related cancer are mostly attributed to dysfunctional adipose tissue. The possible mechanisms connecting dysfunctional adipose tissue to high cancer risk mainly focus on chronic inflammation, obesity-related microenvironment, adipokine secretion disorder, and browning of adipose tissue, and so forth. The stromal vascular cells in adipose tissue trigger chronic inflammation through secreting inflammatory factors and promote cancer cell proliferation. Hypertrophic adipose tissues lead to metabolic disorders of adipocytes, such as abnormal levels of adipokines that mediate cancer progression and metastasis. Cancer patients often show adipose tissue browning and cancerous cachexia in an advanced stage, which lead to unsatisfied chemotherapy effect and poor prognosis. However, increasing evidence has shown that adipose tissue may display quite opposite effects in cancer development. Therefore, the interaction between cancers and adipose tissue exert a vital role in mediates adipose tissue dysfunction and further leads to cancer progression. In conclusion, targeting the dysfunction of adipose tissue provides a promising strategy for cancer prevention and therapy."
1350,Methylation profiles of 22 candidate genes in breast cancer using high-throughput MALDI-TOF mass array.,"Radpour R, Kohler C, Haghighi MM, Fan AX, Holzgreve W, Zhong XY.",https://pubmed.ncbi.nlm.nih.gov/19503099/,"Alterations of DNA methylation patterns have been suggested as biomarkers for diagnostics and therapy of cancers. Every novel discovery in the epigenetic landscape and every development of an improved approach for accurate analysis of the events may offer new opportunity for the management of patients. Using a novel high-throughput mass spectrometry on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) silico-chips, we determined semiquantitative methylation changes of 22 candidate genes in breast cancer tissues. For the first time we analysed the methylation status of a total of 42 528 CpG dinucleotides on 22 genes in 96 different paraffin-embedded tissues (48 breast cancerous tissues and 48 paired normal tissues). A two-way hierarchical cluster analysis was used to classify methylation profiles. In this study, 10 hypermethylated genes (APC, BIN1, BMP6, BRCA1, CST6, ESRb, GSTP1, P16, P21 and TIMP3) were identified to distinguish between cancerous and normal tissues according to the extent of methylation. Individual assessment of the methylation status for each CpG dinucleotide indicated that cytosine hypermethylation in the cancerous tissue samples was mostly located near the consensus sequences of the transcription factor binding sites. These hypermethylated genes may serve as biomarkers for clinical molecular diagnosis and targeted treatments of patients with breast cancer."
1351,Beyond Margin Status: Population-Based Validation of the Proposed International Association for the Study of Lung Cancer Residual Tumor Classification Recategorization.,"Osarogiagbon RU, Faris NR, Stevens W, Fehnel C, Houston-Harris C, Ojeabulu P, Akinbobola OA, Lee YS, Ray MA, Smeltzer MP.",https://pubmed.ncbi.nlm.nih.gov/31783180/,"
    


          
    


          3% were R0, 4.3% were R1, and 0.4% were R2 by UICC criteria; 33.3% were R0, 60.8% were R-uncertain, and 5.8% were R1/2 by IASLC criteria; 2044 patients (63.8%) migrated from UICC R0 to IASLC R-uncertain. Median survival was not reached, 69 (95% confidence interval [CI]: 64-77), and 25 (95% CI: 18-36) months, respectively, for patients with IASLC R0, R-uncertain, and R1 or R2 resections. Failure to achieve nodal dissection criteria caused 98% of migration to R-uncertainty, metastasis to the highest mediastinal node station, 5.8%. Compared with R0, R-uncertain resections with mediastinal nodes, no mediastinal nodes, and no nodes had adjusted hazard ratios of 1.28 (95% CI: 1.10-1.48), 1.47 (95% CI: 1.24-1.74), and 1.74 (95% CI: 1.37-2.21), respectively, suggesting a dose-response relationship between nodal R-uncertainty and survival. Accounting for mediastinal nodal involvement, the highest mediastinal station involvement was not independently prognostic. The incomplete resection variables were uniformly prognostic.
    


          Conclusions:
        
      
      The proposed R classification recategorization variables were mostly prognostic, except the highest mediastinal nodal station involvement. Further categorization of R-uncertainty by severity of nodal quality deficit should be considered."
1352,Smoking impact on HPV driven head and neck cancer's oncological outcomes?,"Mirghani H, Leroy C, Chekourry Y, Casiraghi O, Aupérin A, Tao Y, Nguyen F, Caroline E, Breuskin I, Plana AM, Hartl D, Janot F, Temam S, Gorphe P, Blanchard P.",https://pubmed.ncbi.nlm.nih.gov/29909887/," The aim of our study is to characterize the interplay between tobacco consumption, patient and disease characteristics, and disease control.
    


          Materials and  Demographic, clinical, morphological and tobacco consumption were correlated with oncologic outcomes.
    


          8% who were smoking at the time of diagnosis and 37.6% who had a tobacco consumption exceeding 20 pack-years. In multivariate analysis, the strongest prognostic factor for survival was smoking status at cancer diagnosis, with a hazard ratio (HR) for non-smokers compared to smokers of 0.25 ([0.12, 0.50], p = 0.0001). Smoking history, either more than 20 pack-years or smoking at diagnosis, was associated with local relapse and distant relapse. There was no difference in terms of comorbidity (p = 0.32) and radiotherapy duration (p = 0.93) according to tobacco consumption.
    


          Discussion:
        
      
      Smoking is frequent among patients with HPV-driven OPC and increases the risk of death and oncologic failure."
1353,New advances in focal therapy for early stage prostate cancer.,"Tay KJ, Schulman AA, Sze C, Tsivian E, Polascik TJ.",https://pubmed.ncbi.nlm.nih.gov/28635336/,"Prostate focal therapy offers men the opportunity to achieve oncological control while preserving sexual and urinary function. The prerequisites for successful focal therapy are to accurately identify, localize and completely ablate the clinically significant cancer(s) within the prostate. We aim to evaluate the evidence for current and upcoming technologies that could shape the future of prostate cancer focal therapy in the next five years. Areas covered: Current literature on advances in patient selection using imaging, biopsy and biomarkers, ablation techniques and adjuvant treatments for focal therapy are summarized. A literature search of major databases was performed using the search terms 'focal therapy', 'focal ablation', 'partial ablation', 'targeted ablation', 'image guided therapy' and 'prostate cancer'. Expert commentary: Advanced radiological tools such as multiparametric magnetic resonance imaging (mpMRI), multiparametric ultrasound (mpUS), prostate-specific-membrane-antigen positron emission tomography (PSMA-PET) represent a revolution in the ability to understand cancer function and biology. Advances in ablative technologies now provide a menu of modalities that can be rationalized based on lesion location, size and perhaps in the near future, pre-determined resistance to therapy. However, these need to be carefully studied to establish their safety and efficacy parameters. Adjuvant strategies to enhance focal ablation are under development."
1354,The Mutational Landscape of Cancer's Vulnerability to Ionizing Radiation.,"Gopal P, Yard BD, Petty A, Lal JC, Bera TK, Hoang TQ, Buhimschi AD, Abazeed ME.",https://pubmed.ncbi.nlm.nih.gov/36222846/,"Purpose:
        
      
      Large-scale sequencing efforts have established that cancer-associated genetic alterations are highly diverse, posing a challenge to the identification of variants that regulate complex phenotypes like radiation sensitivity. The impact of the vast majority of rare or common genetic variants on the sensitivity of cancers to radiotherapy remains largely unknown.
    


           Variants were prioritized on the basis of genotype-phenotype associations from a previously completed large-scale cancer cell line radiation profiling study. Altogether, 488 alleles (396 unique single-nucleotide variants) from 92 genes were generated and profiled in an immortalized lung cell line, BEAS-2B. We validated our 
    


           Some genes (e.g., KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g., CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. We combined 
    


          Conclusions:
        
      
      Our "
1355,Acid-base Homeostasis and Implications to the Phenotypic Behaviors of Cancer.,"Zhou Y, Chang W, Lu X, Wang J, Zhang C, Xu Y.",https://pubmed.ncbi.nlm.nih.gov/35787947/,"Acid-base homeostasis is a fundamental property of living cells, and its persistent disruption in human cells can lead to a wide range of diseases. In this study, we conducted a computational modeling analysis of transcriptomic data of 4750 human tissue samples of 9 cancer types in The Cancer Genome Atlas (TCGA) database. Built on our previous study, we quantitatively estimated the average production rate of OH- by cytosolic Fenton reactions, which continuously disrupt the intracellular pH (pHi) homeostasis. Our predictions indicate that all or at least a subset of 43 reprogrammed metabolisms (RMs) are induced to produce net protons (H+) at comparable rates of Fenton reactions to keep the pHi stable. We then discovered that a number of well-known phenotypes of cancers, including increased growth rate, metastasis rate, and local immune cell composition, can be naturally explained in terms of the Fenton reaction level and the induced RMs. This study strongly suggests the possibility to have a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors. In addition, strong evidence is provided to demonstrate that a popular view that Na+/H+ exchangers along with lactic acid exporters and carbonic anhydrases are responsible for the intracellular alkalization and extracellular acidification in cancer may not be justified."
1356,Correlation between survivin mRNA expression and lymph node metastasis in gastric cancer.,"Miyachi K, Sasaki K, Onodera S, Taguchi T, Nagamachi M, Kaneko H, Sunagawa M.",https://pubmed.ncbi.nlm.nih.gov/14716515/," Survivin is a member of the inhibiting apoptosis protein family that is abundant in embryonic and carcinoma tissues. We measured the expression of survivin mRNA in gastric cancer to determine whether levels of survivin mRNA expression could serve as an index of malignancy.
    


           Survivin mRNA was detected by the real-time polymerase chain reaction (PCR) 
    


           The Mean value of survivin mRNA expression in cancerous tissue was 5.18 +/- 1.30, significantly higher ( P < 0.01) than that in noncancerous tissue, at 4.21 +/- 1.48. No significant differences were found in the values of survivin mRNA expression according to histological classification or according to increasing depth of tumor invasion. However, survivin mRNA expression was significantly higher ( P < 0.01) in patients displaying lymph node metastasis (5.48 +/- 1.01) than in patients without the metastasis (4.70 +/- 1.55).
    


          Conclusions:
        
      
      These  Moreover, the level of survivin mRNA expression may indicate the potential for lymph node metastasis in patients with gastric cancer. Correlations between the malignant potential and prognosis of cancer and abnormal control mechanisms of apoptosis have been discovered in a variety of cancers. Survivin is a member of the inhibiting apoptosis protein family that is abundant in embryonic and carcinoma tissues. We measured the expression of survivin mRNA in gastric cancer to determine whether levels of survivin mRNA expression could serve as an index of malignancy."
1357,Systematic review of baseline low-dose CT lung cancer screening.,"Yau G, Lock M, Rodrigues G.",https://pubmed.ncbi.nlm.nih.gov/17723250/,"The purpose of this systematic review was to provide physicians and patients with a synthesis of the available data and an assessment of the operating characteristics associated with baseline LDCT screening for lung cancer. Various databases, meeting abstracts, clinical trials in progress, and major textbooks for relevant data from 1966 to 2006 were searched for relevant studies. The median value of sensitivity, specificity, positive predictive value and negative predictive value were 81%, 81%, 8% and 99%, respectively. Of the studies that compared LDCT with other lung cancer screening maneuvers, it was found that LDCT detected a greater number of cancerous nodules. On average, 80% of lung cancers detected by baseline LDCT screening were categorized as Stage I cancers. Current data demonstrate that both the operating characteristics of baseline LDCT screening and the relatively high proportion of Stage I cancers detected with LDCT may potentially lead to effective screening programs. However, evidence of reduced mortality and morbidity with the use of LDCT is not established. Therefore, LDCT for lung cancer screening should be considered as investigative and needs to be confirmed by well-designed randomized controlled trials prior to community and institutional implementation."
1358,Evaluation of prognostic impact of pre-treatment neutrophil to lymphocyte and lymphocyte to monocyte ratios in dogs with oral malignant melanoma treated with surgery and adjuvant CSPG4-antigen electrovaccination: an explorative study.,"Camerino M, Giacobino D, Iussich S, Ala U, Riccardo F, Cavallo F, Martano M, Morello E, Buracco P.",https://pubmed.ncbi.nlm.nih.gov/33443307/,"The role of systemic inflammation in cancer's progression has been widely investigated, especially in melanoma in humans. Pre-treatment leukocyte counts and ratios play a recognized prognostic role in several types of malignancies, but no information is available regarding canine oral malignant melanoma (COMM). The purpose of this explorative retrospective study was to investigate the prognostic impact of pre-treatment neutrophil to lymphocyte (NLR) and lymphocyte to monocyte (LMR) ratios in dogs with oral malignant melanoma that underwent surgical resection and immunotherapy with adjuvant CSPG4-antigen electrovaccination. Thirty-nine dogs with histologically confirmed oral melanoma and with available pre-treatment haematological analyses, performed at maximum 60 days before the first treatment, were retrospectively enrolled. Statistical analysis was performed to explore possible correlations among NLR and LMR with age, clinical stage, tumour pigmentation, tumour size, nuclear atypia, mitotic index, Ki67, CSPG4 expression, ulceration, bone invasion and excision margins status. The impact of NLR and LMR on overall survival time (OST) was explored among various ratio cut off and across different time points with Kaplan-Meier  No significant relationship was identified between leukocytes ratios and histological parameters, CSPG4 expression, excision margin status, age, tumour size and clinical stage. NLR and LMR did not display a prognostic impact on the survival time of the entire population. Pre-treatment leukocyte ratios may not represent a useful prognostic factor in dogs with oral melanoma, especially in absence of distant metastatic disease."
1359,Cancer's got nerve: Schwann cells drive perineural invasion.,"Azam SH, Pecot CV.",https://pubmed.ncbi.nlm.nih.gov/26999601/,"The invasion of cancer cells around and into nerves is associated with increased cancer aggression and poor patient outcome. As this perineural invasion increases disease severity, a better understanding of how the process is regulated may help in the development of therapeutics to target neuronal involvement in cancer. In this issue of the JCI, Deborde and colleagues show that direct contact between Schwann cells and cancer cells promotes cancer cell dissociation, migration, and invasion. Moreover, their data specifically suggest NCAM1 as an important molecular mediator of this Schwann cell-directed regulation of cancer cells in perineural invasion. The "
1360,Expression of adenomatous polyposis coli (APC) in tumorigenesis of human oral squamous cell carcinoma.,"Tsuchiya R, Yamamoto G, Nagoshi Y, Aida T, Irie T, Tachikawa T.",https://pubmed.ncbi.nlm.nih.gov/15380172/,"The product of the adenomatous polyposis coli (APC) tumor suppressor gene has been observed to regulate the Wnt signaling pathway through beta-catenin. In the present study, we attempted to clarify the relation between APC and the canceration of oral squamous epithelium. Each target tissue of normal squamous epithelium, epithelial dysplasia, and squamous cell carcinoma (SCC) was recovered the oral SCC case by laser microdissection. In recovered cells, we examined the change in expression of APC and beta-catenin gene transcription products, as well as the existence of mutations in APC gene. We analyzed the localization of each protein of APC and beta-catenin by immunohistochemical study. We found a clear change in the expression level of the gene transcription product of APC in canceration of oral squamous epithelium and the differentiation of oral SCC. In addition, there was some change in the localization of the APC protein in canceration. It was not clear, however, whether the APC was mutated. A change was also observed in the expression level of the beta-catenin gene transcription product during the differentiation of oral SCC. Our  Mutations of the APC gene might not be indispensable, however, in canceration of oral squamous epithelium."
1361,Comparing CISNET Breast Cancer Models Using the Maximum Clinical Incidence Reduction Methodology.,"van den Broek JJ, van Ravesteyn NT, Mandelblatt JS, Cevik M, Schechter CB, Lee SJ, Huang H, Li Y, Munoz DF, Plevritis SK, de Koning HJ, Stout NK, van Ballegooijen M.",https://pubmed.ncbi.nlm.nih.gov/29554471/," A necessary step in the interpretation of collaborative cancer screening model  In this study, we examined the relative contributions of the pre-clinical duration of breast cancer, the sensitivity of screening, and the improvement in prognosis associated with treatment of screen-detected cases to the breast cancer incidence and mortality predictions of 5 Cancer Intervention and Surveillance Modeling Network (CISNET) models.
    


          e., cure) of all screen-detected cancers; 3) one-time digital mammogram and perfect treatment of all screen-detected cancers; and 4) one-time digital mammogram and current guideline-concordant treatment of all screen-detected cancers.
    


           In this perfect scenario, the models with assumptions of tumor inception before it is first detectable by mammography predicted substantially higher incidence and mortality reductions than models with assumptions of tumor onset at the start of a cancer's screen-detectable phase. The range across models in breast cancer clinical incidence (11% to 24%) and mortality reduction (8% to 18%) from a one-time digital mammogram at age 62 y with observed sensitivity and current guideline-concordant treatment was considerably smaller than achievable under perfect conditions.
    


          Conclusions:
        
      
      The timing of tumor inception and its effect on the length of the pre-clinical phase of breast cancer had a substantial impact on the grouping of models based on their predictions for clinical incidence and breast cancer mortality reduction. This key finding about the timing of tumor inception will be included in future CISNET breast analyses to enhance model transparency. The MCLIR approach should aid in the interpretation of variations in model "
1362,Remodeling nanoDESI Platform with Ion Mobility Spectrometry to Expand Protein Coverage in Cancerous Tissue.,"Chen CL, Kuo TH, Chung HH, Huang P, Lin LE, Hsu CC.",https://pubmed.ncbi.nlm.nih.gov/33507077/,"Nanospray desorption electrospray ionization mass spectrometry is an ambient ionization technique that is capable of mapping proteins in tissue sections. However, high-abundant molecules or isobaric interference in biological samples hampers its broad applications in probing low-abundant proteins. To address this challenge, herein we demonstrated an integrated module that coupled pneumatic-assisted nanospray desorption electrospray ionization mass spectrometry with high-field asymmetric ion mobility spectrometry. Using this module to analyze mouse brain sections, the protein coverage was significantly increased. This improvement allowed the mapping of low-abundant proteins in tissue sections with a 5 μm spatial resolution enabled by computationally assisted fusion with optical microscopic images. Moreover, the module was successfully applied to characterize melanoma in skin tissues based on the enhanced protein profiles. The "
1363,Inflammasome: cancer's friend or foe?,"Terlizzi M, Casolaro V, Pinto A, Sorrentino R.",https://pubmed.ncbi.nlm.nih.gov/24518102/,"High serum concentrations of IL-1β and IL-18 are correlated to malignancies with low-rate survival from the time of diagnosis. The multimeric complex of the inflammasome is responsible for IL-1β/IL-18 synthesis/release. A number of endogenous (damage-associated molecular patterns) and exogenous (pathogen-associated molecular patterns) stimuli can provide signals for inflammasome activation in cancer. These stimuli can behave as tumor promoters via inducing chronic inflammation that, rather than providing a protective response to loss of tissue homeostasis, aberrantly facilitates tumor development. This view is contrasted in animal models of colon cancer in which the activation of some inflammasome complexes is associated with tumor protection. More studies are needed to understand the biology of the inflammasome in cancer and explore its therapeutic potential."
1364,Identification of immunoglobulin superfamily 11 (IGSF11) as a novel target for cancer immunotherapy of gastrointestinal and hepatocellular carcinomas.,"Watanabe T, Suda T, Tsunoda T, Uchida N, Ura K, Kato T, Hasegawa S, Satoh S, Ohgi S, Tahara H, Furukawa Y, Nakamura Y.",https://pubmed.ncbi.nlm.nih.gov/16108831/,"We previously performed gene expression profile analyses of 20 intestinal-type gastric cancers, and identified a set of genes whose expression levels were elevated in cancer tissues compared to their corresponding non-cancerous tissues. In the present study we focused on the immunoglobulin superfamily 11 gene (IGSF11). Its expression was also elevated in colorectal cancers and hepatocellular carcinomas as well as intestinal-type gastric cancers. Northern blot analysis showed that it was expressed abundantly in testis and ovary. These data suggest that IGSF11 is a good candidate of cancer-testis antigen. Furthermore, suppression of IGSF11 by siRNA retarded the growth of gastric cancer cells. To investigate the possibility of clinical application of peptide vaccine to IGSF11, we synthesized candidate epitope peptides for IGSF11 and tested whether the peptides elicit IGSF11-specific CTL. As a  In addition, we also established additional CTL using IGSF11-9V (ALSSGLYQV), anchor-modified peptides of IGSF11-9-207. These peptides showed IGSF11-specific cytotoxic activity in an HLA-A*0201-restricted fashion, suggesting that these peptides may be applicable for cancer immunotherapy. These findings have provided a novel insight into carcinogenesis of the stomach, colon and liver, and will be helpful for the development of novel therapeutic strategies to a wide range of human cancers."
1365,Right ventricle toxicity in cancer treatment: a focused review on cardiac imaging.,"Sanadgol G, Samimi S, Shirini D, Nakhaei P, Mohseni M, Alizadehasl A.",https://pubmed.ncbi.nlm.nih.gov/37830360/," Aim: We aimed to review the role that various cardiac imaging modalities play in RV assessment as part of the integrative management of patients undergoing cancer therapy. Discussion: RV assessment remains challenging by traditional 2D echocardiography. In this review we discuss other parameters such as right atrial strain, and other echocardiographic modalities such as 3D and stress echocardiography. We also elaborate on the specific role that cardiac magnetic resonance imaging and equilibrium radionuclide angiocardiography can play in assessing the RV. Conclusion: Biventricular function should be monitored following chemotherapy for early detection of subclinical CTRCD and possible solitary RV changes."
1366,Up regulation of Rho-associated coiled-coil containing kinase1 (ROCK1) is associated with genetic instability and poor prognosis in prostate cancer.,"Steurer S, Hager B, Büscheck F, Höflmayer D, Tsourlakis MC, Minner S, Clauditz TS, Hube-Magg C, Luebke AM, Simon R, Izbicki JR, Burandt E, Sauter G, Fraune C, Weidemann S, Schlomm T, Heinzer H, Haese A, Graefen M, Huland H, Heumann A.",https://pubmed.ncbi.nlm.nih.gov/31557128/,"
    


           In cancer, ROCK1 staining was considered weak, moderate, and strong in 22%, 53%, and 18% of cases respectively. Higher ROCK1 expression levels were associated with tumor stage, and Gleason grade, positive nodal stage, positive surgical margin, accelerated cell proliferation and early PSA recurrence in multivariable analysis. ROCK1 up regulation was associated with androgen receptor (AR) expression, TMPRSS2:ERG fusion, genomic deletions of the PTEN tumor suppressor, as well as recurrent deletions at chromosomes 3p, 5q, 6q. Strong ROCK1 staining was found in 3% of AR-negative, but in 27% of strongly AR positive cancers, in 13% of ERG-negative but in 25% of ERG positive cancers, and in 12% of PTEN normal but in 26% of PTEN deleted cancers.
    


          Conclusions:
        
      
      This study identifies ROCK1 expression associated with prognosis in prostate cancer.
    


          "
1367,Management of thyroid cancers diagnosed histologically after surgery.,"Liaw KY, Chien YC.",https://pubmed.ncbi.nlm.nih.gov/8104578/,"Thirty-three patients with thyroid cancer diagnosed histologically after surgery from 1960 to 1987 were reviewed to delineate an acceptable treatment policy. The first group of 17 patients did not undergo a second operation, and five of these patients (29%) experienced local recurrence, metastasis and death during follow-up (minimum of 15 years). A second group of 16 patients underwent a second operation, and all remained healthy during the mean follow-up period of eight years. In 56% of the specimens obtained during the second operation, a histologic examination revealed residual cancerous foci in the remnant thyroid tissue or lymph node. This present study indicates that age, tumor grade, extent and size (AGES score), and the operative strategy used in the initial procedure are important factors affecting the prognosis. We suggest that patients whose tumors lose capsular integrity, show evidence of intraglandular metastases or have an AGES score of 3.1 or more should be considered as candidates for a second operation."
1368,Intermittent androgen blockade in prostate cancer: rationale and clinical experience.,"Wolff JM, Tunn UW.",https://pubmed.ncbi.nlm.nih.gov/11025372/,"Cancer of the prostate continues to be one of the most common malignancies in men in Europe, with a large number of patients presenting with advanced disease. The current standard treatment for metastatic cancer of the prostate, permanent androgen withdrawal, is palliative. Patients treated with permanent androgen blockade usually relapse and die secondary to prostate cancer's ability to progress to an androgen-independent state of growth. Based on  Through the cycling of reversible androgen suppression, there appears to be recovery of apoptosis and subsequent slower progression to an androgen-independent state. In this paper  At present several prospective randomized trials are under way to test intermittent androgen blockade as an alternative treatment in various stages of cancer of the prostate. However, until the "
1369,[Interest of the prevention of uterine cervix cancer at prenuptial examination (author's transl)].,Millot MJ.,https://pubmed.ncbi.nlm.nih.gov/618029/,"The French obligatory prenuptial certificate is issued by a doctor in the light of certain examination  The medical consultation which it implies offers a special opportunity to obtain from women a cervical smear that would allow the finding of possible pre-cancerous lesions of the uterine cervix. Such smears, along with supervision or treatment of the lesions discovered would amount to genuine prevention of cervical cancer. The evaluation made in this article shows that, among 370,000 women, it would be possible to find 5,800 dysplasias and 2,400 in situ cancers each year. This form of prevention would give 165,000 extra years of life and would economise treatment costs amounts to 250 millions francs, whereas the smears taken at prenuptial examination would cost 30 millions francs."
1370,Role of Tyrosine Kinases and their Inhibitors in Cancer Therapy: A Comprehensive Review.,"Kumar V, Kaur N, Sahu S, Sharma V, Kumar D, Sharma A, Wadhwa P.",https://pubmed.ncbi.nlm.nih.gov/35894454/," Thus, there is non-stop search for novel targets and small molecules to improve the chemotherapeutic outcomes concerning potency, selectivity, efficiency, affinity, ADMET, etc. Among anticancer therapeutic targets, tyrosine kinase has been documented well and approved as an important target with the development of various clinically used drugs. There are several structurally diverse small molecules in different preclinical and clinical stages of development that act by affecting tyrosine kinases in cancerous cells. Here, we have summarized different potent molecules acting against tyrosine kinases that can be considered as anticancer agents.
    


          
    


           The review also highlighted the structural aspects of the interaction between inhibitors and amino acid residues of tyrosine kinases. Moreover, it also provided a summary of different types of cancers and the currently available options for treatment.
    


           Tyrosine kinases have been reported involving in routine cellular functions, growth, and division of cells through different pathways which depend on phosphorylation. The overexpression and uncontrolled activity of tyrosine kinases have been identified as an important feature of cancerous cells. Thus, various small molecules have been reported which inhibit tyrosine kinases to block the growth and division of cancer cells. Here, more than 30 highly potent inhibitors of tyrosine kinases are summarised, which consist of pyrimidine, pyrazole, triazine, quinazoline, quinoline, pyrazine, chromene, etc. rings as a basic skeleton with different substituents.
    


          Conclusion:
        
      
      Inhibition of tyrosine kinases by different small molecules is an approved strategy for the development of novel anticancer agents. Several published reports have mentioned the characteristics of the different binding sites and crucial residues in tyrosine kinases for the design of novel molecular inhibitors. However, selectivity is an important criterion for the development of chemotherapeutic agents due to the existence of approximately 30 families of tyrosine kinases."
1371,Collagen I dysregulation is pivotal for ovarian cancer progression.,"Sarwar M, Sykes PH, Chitcholtan K, Evans JJ.",https://pubmed.ncbi.nlm.nih.gov/34871826/,"As a principal matrisomal protein, collagen is involved in the regulation of the structural framework of extracellular matrix (ECM) and therefore is potentially crucial in determining the biophysical character of the ECM. It has been suggested that collagen architecture plays a role in ovarian cancer development, progression and therapeutic responses which led us to examine the collagen morphology in normal and cancerous ovarian tissue. Also, the behaviour of ovarian cancer cells cultured in four qualitatively different collagen gels was investigated. The  Tumour-associated collagen I showed streams or channels of thick elongated collagen I fibrils. Moreover, fibril alignment was significantly more prevalent in endometrioid and clear cell cancers than other ovarian cancer subtypes. In this work, for the first-time collagen I architecture profiling (CAP) was introduced using histochemical staining, which distinguished between the collagen I morphologies of ovarian cancer subtypes. Immunohistochemical examination of ovarian normal and cancerous tissues also supported the notion that focal adhesion and Rho signalling are upregulated in ovarian cancers, especially in the high-grade serous tumours, as indicated by higher expression of p-FAK and p190RhoGEF. The  The study provides evidence that modification of collagen I architecture integrity is associated with ovarian cancer development and therapeutic responses."
1372,Comparative promoter methylation analysis of p53 target genes in urogenital cancers.,"Christoph F, Hinz S, Weikert S, Kempkensteffen C, Schostak M, Miller K, Schrader M.",https://pubmed.ncbi.nlm.nih.gov/18587251/,"
    


          Material and  Included were 103 patients with bladder cancer, 85 patients with kidney cancer and 42 patients with testicular cancer in non-advanced and advanced tumor stages. Non-cancerous tissue from 49 patients was used as control.
    


           Highest APAF-1 and DAPK-1 levels of methylation were found in the advanced tumor groups. In normal tissue, methylation frequency and methylation levels were significantly lower. APAF-1 methylation was also frequent in normal testicular tissue but to lower methylation levels as in cancerous tissue. APAF-1 and IGFBP-3 methylation levels were significantly higher in recurrent superficial and muscle-invasive bladder tumors. Methylation levels of APAF-1 also correlated with higher risk for recurrent metastatic disease in non-advanced tumors of the kidney.
    


          Conclusions:
        
      
      The methylation profile observed demonstrates a substantial role of the APAF-1 gene in tumorigenesis. The different methylation pattern in testicular cancer might represent a different methylotype of this cancer. The extent of promoter methylation may be a promising target for application as a tumor marker in urogenital cancer disease."
1373,Analysis of FHIT transcripts in cervical and endometrial cancers.,"Su TH, Wang JC, Tseng HH, Chang CP, Chang TA, Wei HJ, Chang JG.",https://pubmed.ncbi.nlm.nih.gov/9537583/,"Carcinoma of the uterine cervix is a common malignancy, and many affected women, have been found to exhibit loss of heterozygosity (LOH) in the chromosome 3p region. Recent studies have localized the FHIT (fragile histidine triad) gene in this region and also demonstrated a high frequency of abnormalities of this gene in various cancers. To determine the role of the FHIT gene in cervical and uterine carcinomas, 16 cases of cervical carcinoma and 7 cases of endometrial carcinoma, as well as nearby non-cancerous tissues in these patients, were analyzed by reverse transcription of the FHIT mRNA followed by polymerase chain reaction amplification and sequencing of the products. In this study, 13 of 16 cervical cancers and 4 of 7 endometrial cancers displayed abnormal FHIT transcripts, including a lack of 2 or more exons of the FHIT gene, the insertion of several bases in the deletion junctions, and a 282 bp deletion from cDNA 171 to 452,  Moreover, 5 of 16 matched non-cancerous tissues from the cervical cancer patients and 4 of 7 non-cancerous tissues from endometrial cancer patients also showed the presence of abnormal transcripts lacking 3 or more exons of the FHIT gene. Only 1 of 23 paired samples exhibited LOH. Our  We also checked for HPV infection in these samples and found no definite relationship between the abnormal transcript and human papillomavirus infection."
1374,Fluorescence-based co-culture of normal and cancerous cells as an indicator of therapeutic effects in cancer.,"Tamura M, Matsui H, Hyodo I, Tanaka J, Miwa Y.",https://pubmed.ncbi.nlm.nih.gov/24995702/,"Comprehensive evaluation of the effects of cancer therapies in vitro is difficult because of the need to distinguish the main effects from the side effects within the data. This problem cannot be overcome by  In order to promote therapeutic development, therefore, we need a novel drug evaluation  Co-culture creates a more biomimetic condition in comparison to monoculture. The novel  We have previously established two cell lines: a rat gastric mucosal cell line (RGM) and its corresponding cancerous mutant cell line (RGK). In this study, we have developed a new evaluation procedure using a co-culture of green fluorescent protein-expressing RGM cells (RGM-GFP) and kusabira orange-expressing RGK cells (RGK-KO). These cell lines emit green and red fluorescence, respectively. We demonstrated the capability of the  These "
1375,The underlying mechanism of nuclear and mitochondrial DNA damages in triggering cancer incidences: Insights into proteomic and genomic sciences.,"Saadi S, Nacer NE, Saari N, Mohammed AS, Anwar F.",https://pubmed.ncbi.nlm.nih.gov/38309588/,"The attempt of this review article is to determine the impact of nuclear and mitochondrial damages on the propagation of cancer incidences. This review has advanced our understanding to altered genes and their relevant cancerous proteins. The progressive raising effects of free reactive oxygen species ROS and toxicogenic compounds contributed to significant mutation in nuclear and mitochondrial DNA where the incidence of gastric cancer is found to be linked with down regulation of some relevant genes and mutation in some important cellular proteins such as AMP-18 and CA-11. Thereby, the  Reduction of these apoptotic growth factors and nuclear damages is increasingly accepted by cell reactivation effect, enhanced cellular signaling and DNA repairs. Acetylation, glycation, pegylation and phosphorylation are among the molecular techniques used in DNA repair for rectifying mutation incidences. In addition, the molecular labeling based fluorescent materials are currently used along with the bioconjugating of signal molecules in targeting disease translocation site, particularly cancers and tumors. These strategies would help in determining relevant compounds capable in overcoming problems of down regulating genes responsible for repair mechanisms. These issues of course need interplay of both proteomic and genomic studies often in combination of molecular engineering to cible the exact expressed gene relevant to these cancerous proteins."
1376,Effect of tamoxifen on steroid hormone receptors and creatine kinase activity in human endometrial carcinoma.,"Iacobelli S, Scambia G, Atlante G, Landoni F, Sismondi P, Vecchio FM.",https://pubmed.ncbi.nlm.nih.gov/3956553/,"Estrogen receptor (ER), progesterone receptor (PR) and creatine kinase (CK) were measured in cancerous tissue from 29 post-menopausal patients with endometrial carcinoma under basal conditions and after a short course of tamoxifen treatment. ER and PR were detected in nearly all tumors. CK was detected in all of the tumors examined. After tamoxifen, PR and CK increased simultaneously in 26% of cases, while they were either enhanced, decreased or unmodified in the remainder. No correlation could be found between increase of PR and tumor differentiation. CK, however, was enhanced only in the more differentiated cancers. These  It is hypothesized that patients bearing these tumors are those likely to benefit from endocrine therapy."
1377,[Assessment of cancer incidence in Tunisia 1993-1997].,"Hsairi M, Fakhfakh R, Ben Abdallah M, Jlidi R, Sellami A, Zheni S, Hmissa S, Achour N, Nacef T.",https://pubmed.ncbi.nlm.nih.gov/12080555/,"The  The incidence rate of in all localizations are 100.11/100.000 for male and 86.4/100.000 for female. The main cancerous localizations for male are the lung (20.8/100.000) the bladder (10.7/100.000), the cutaneous cancers (7.2/100.000) and the prostate (6.1/100.000). For female the main localization are the breast (19.7/100.000), skin (5.8/100.000) and the cervix uteri (4.8,100.000). These "
1378,The Enhancing Connections-Telephone study: a pilot feasibility test of a cancer parenting program.,"Lewis FM, Griffith KA, Walker A, Lally RM, Loggers ET, Zahlis EH, Shands ME, Alzawad Z, Al Mulla H, Chi NC.",https://pubmed.ncbi.nlm.nih.gov/27770206/,"Purpose:
        
      
      The purposes of the study were to (1) test the short-term impact of a telephone-delivered cancer parenting education program, the Enhancing Connections-Telephone (EC-T) Program, on maternal anxiety, depressed mood, parenting competencies, and child behavioral-emotional adjustment and (2) compare those outcomes with outcomes achieved from an in-person delivery of the same program (EC).
    


           Mothers were eligible if they had one or more dependent children and were recently diagnosed with stages 0-III breast cancer. Mothers in both groups received five intervention sessions at 2-week intervals from a patient educator using a fully scripted intervention manual.
    


           Outcomes from the between-group analysis showed the EC-T did as well or better than EC in positively affecting maternal anxiety, depressed mood, parenting competencies, and the child's behavioral-emotional adjustment. Furthermore, the EC-T had a significantly greater impact than the EC on maternal confidence in helping their family and themselves manage the cancer's impact and in staying calm during emotionally charged conversations about the breast cancer with their child.
    


          Conclusions:
        
      
      Regardless of the channel of delivery, the Enhancing Connections Program has the potential to positively affect parenting competencies and behavioral-emotional adjustment in mothers and dependent children in the first year of stages 0-III maternal breast cancer. Its positive impact from telephone delivery holds promise for sustainability."
1379,Common expression of the tumor marker D-galactose-beta-[1-->3]-N-acetyl-D-galactosamine by different adenocarcinomas: evidence of field effect phenomenon.,"Shamsuddin AM, Tyner GT, Yang GY.",https://pubmed.ncbi.nlm.nih.gov/7805025/,"The simple carbohydrate tumor marker D-galactose-beta-[1-->3]-N-acetyl-D-galactosamine (Gal-GalNAc) can be easily identified by a sequential galactose oxidase (GO)-Schiff reaction either on tissues or on rectal mucus samples from patients with colorectal cancer. To check the usefulness of this marker and technology in identifying cancers and precancers of other organs, we have assessed the differential expression of Gal-GalNAc in various adenocarcinomas and their corresponding normal tissues. The expression of Gal-GalNAc determined by GO-Schiff sequence was examined in a total of 133 tissue samples from 81 cases of the adenocarcinomas of the breast, ovary, pancreas, stomach, and endometrium and 52 cases of respective normal controls. None of the 52 cases of normal tissues (except 15 cases of stomach) showed expression of Gal-GalNAc. In contrast, 100% of adenocarcinomas from the breast (19 of 19), ovary (15 of 15), and pancreas (6 of 6), 94.1% of stomach (16 of 17) cancers, and 91.7% (11 of 12) of uterine adenocarcinomas expressed Gal-GalNAc. The expression of Gal-GalNAc in cancerous tissues was mostly strong and widespread and was distributed in both secreted mucin and cytoplasmic mucin droplets. The normal epithelia and their secretions in the vicinity of the carcinoma (within the ""field"") in the breast, bronchus, endometrium, and pancreatic duct also expressed Gal-GalNAc in contrast to normal tissues obtained from noncancerous individuals, which were totally nonreactive. It is concluded that the tumor marker Gal-GalNAc recognized by GO-Schiff sequence was highly expressed not only by a variety of adenocarcinomas but also by the apparently normal-appearing epithelia and their secretions in the vicinity of carcinomas, strongly suggesting a field effect phenomenon of carcinogenic agent(s). Identification of the marker in these secretions may have great potential in our strategies for mass screening for those cancers."
1380,Breast cancer and thyroid diseases: analysis of 867 consecutive cases.,"Chiappa C, Rovera F, Rausei S, Del Ferraro S, Fachinetti A, Lavazza M, Marchionini V, Arlant V, Tanda ML, Piantanida E, Kim HY, Anuwong A, Dionigi G.",https://pubmed.ncbi.nlm.nih.gov/27624298/," Many authors have already studied the possible relationship between these two diseases, but the 
    


          Materials and  Statistical analyses were performed using SPSS software for Windows; we used nonparametric tests (Chi-square and Mann-Whitney), and the level of significance was set at p < 0.05.
    


          003). Moreover, we analyzed the role of thyroid autoimmunity identifying an association between chronic autoimmune thyroiditis and breast cancer diagnosed before menopause (p < 0.05). Regarding receptor profile of breast carcinoma, we have found an increased expression of estrogen receptors in patients with autoimmune thyroiditis compared to patients with any other thyroid diseases (p < 0.03). Contrariwise, we do not have found any difference between the group with every thyroid disease and the group without thyroid disease (p < 1.00). We did not find other statistically significant associations with breast cancer's parameters like family history, tumor size, lymph node metastasis, distant metastasis, cancer clinical and pathological stage, differentiation grade and expression of Ki67, p53 and Her2 in the two main groups with or without thyroid disease. Likewise, we did not found other statistically significant association between hypothyroidism or hyperthyroidism and breast cancer."
1381,[Acquired hemophilia as the initial manifestation of colorectal cancer's recurrence].,"Villalba NL, Zulfiqar AA, Alonso Ortiz MB, Jannot X, Syrovatkova A, Andres E.",https://pubmed.ncbi.nlm.nih.gov/33906149/,"We report the case of an 86-year-old man presenting with a spontaneous hematoma in the left iliac muscle and previous diagnosis of colon cancer in 1998 (stage pT3N0M0) treated with transverse colectomy and considered in complete remission. After a complete study, it was possible to identify the presence of Factor VIII inhibitors antibodies that confirmed the presence of acquired hemophilia. During hospitalization the patient presented a lower gastrointestinal bleeding leading to the diagnosis of recurrence of a previously treated colorectal adenocarcinoma. He responded to initial therapy with systemic corticoids and anti-inhibitory coagulant complex which includes activated VII Factor [FEIBA]."
1382,Assessment of the reliability of MSI status and dMMR proteins deficiency screening on endoscopic biopsy material in esophagus and gastric adenocarcinoma.,"Asesio N, Mhamdi Aloui N, Bonnereau J, Lehmann-Che J, Bouhidel F, Kaci R, Corte H, Svrcek M, Minh MLT, Gornet JM, Cattan P, Allez M, Bertheau P, Aparicio T.",https://pubmed.ncbi.nlm.nih.gov/37142454/," We aimed to evaluate reliability of dMMR/MSI status screening performed on preoperative endoscopic biopsies.
    


           We compared dMMR status obtained by immunohistochemistry (IHC) and MSI status by PCR. dMMR/MSI status on surgical specimen was considered as reference.
    


          4%) and 47 (85.5%) of the 55 patients enrolled. IHC was not contributive for 1 surgical specimen. A third reading of IHC was carried out for 3 biopsies. MSI status was observed in 7 (12.5%) surgical specimens. When analyses were contributive, sensitivity and specificity of biopsies for dMMR/MSI were respectively 85% and 98% for PCR vs. 86% and 98% for IHC. Concordance rate between biopsies and surgical specimen was 96.2% for PCR and 97.8% for IHC.
    


          Conclusions:
        
      
      Endoscopic biopsies are a suitable source of tissue for dMMR/MSI status determination in oesogastric adenocarcinoma which should be routinely performed at diagnosis to better adapt neoadjuvant treatment.
    


          Miniabstract:
        
      
      By comparison of dMMR phenotype obtained by immunohistochemistry and MSI status by PCR between match-paired samples of oesogastric cancer's endoscopic biopsies and surgical specimen, we observed that biopsies are a suitable source of tissue for dMMR/MSI status determination."
1383,Outcomes of surgical resection and loco-regional therapy in patients with stage 3A hepatocellular carcinoma: a retrospective review from the national cancer database.,"Seshadri RM, Baker EH, Templin M, Swan RZ, Martinie JB, Vrochides D, Iannitti DA.",https://pubmed.ncbi.nlm.nih.gov/26271743/," The aim of the present study was to analyse the role of surgical resection (SR) and loco-regional therapy (LRT) in these advanced stage patients to determine if there was a survival benefit.
    


           In total, 148,882 patients with liver cancer were identified, of which 126,984 had HCC. Of these, 64,264 patients (1998-2006) had 5-year survival data available and 8825 patients had Stage 3A disease based on AJCC classification. Of these patients, 884 had SR, 771 had LRT and 7170 patients had neither intervention. Kaplan-Meier curves and log-rank tests were used for statistical analysis.
    


           The mean age (years) in the SR, LRT and no intervention group were 62.5, 64.3 and 64.2, respectively. Most patients were males in all three groups (77.5%, 74.5% and 68.1%). The mean tumour size (cm) in the three groups was 9.8, 6.4 and 8.4, respectively. SR and LRT were primarily performed in major academic and comprehensive cancer programmes compared with community cancer programmes and other centres (SR: 93% versus 7%; LRT: 94.6% versus 5.4%). The median 5-year survival (months) was 26.6 in SR, 16.5 in LRT and 4.8 in the no intervention group (P < 0.0001).
    


          Conclusion:
        
      
      A SR and LRT offer a survival benefit in select patients diagnosed with Stage 3A HCC."
1384,Absence of correlation between serum CRP levels and mitochondrial D-loop DNA mutations in gastro-oesophageal adenocarcinoma.,"Tan BH, Skipworth RJ, Wheelhouse NM, Fearon KC, Ross JA.",https://pubmed.ncbi.nlm.nih.gov/24762507/," The aim of this study was to evaluate the relationship between inflammation and accumulation of mitochondrial DNA (mtDNA) mutations in the D-loop region in carcinogenesis of gastro-oesophageal adenocarcinomas.
    


          Materials and  Direct sequencing of mtDNA in the D-loop region was done in the 20 adenocarcinoma samples and their corresponding surrounding non-cancerous tissue. Sequences were compared with existing mtDNA databases to identify mutations.
    


          0 ± 1.6) and adenocarcinoma (3.1 ± 1.9) (P = 0.916, paired t-test). CRP levels are not predictive of the number of D-loop mutations in both adenocarcinoma (β: -0.131; 95% CI: -2.354-1.364; P = 0.583) and non-cancerous tissue samples (β: 0.130; 95% CI: -1.125-1.933; P = 0.586). Five new mutations were identified that were not recorded previously in mtDNA databases.
    


          Conclusion:
        
      
      D-loop mtDNA mutations are common in both gastro-oesophageal adenocarcinoma and surrounding non-cancerous tissue. However, the accumulation of such mutations appears to occur independent of systemic inflammation. The frequency of D-loop mutations is likely not useful as a marker for carcinogenesis in gastro-oesophageal adenocarcinoma."
1385,Four hundred seventeen squamous cell cancers in a heart transplant patient.,"Liu AS, Eriksson E.",https://pubmed.ncbi.nlm.nih.gov/22001423/,"Squamous cell carcinoma (SCC) is the most common malignancy in organ transplant recipients. In this patient population it pursues a much more aggressive course than in the general population: it occurs with higher frequency and displays a greater tendency to recur locally and metastasize, even after surgical excision. Hence, prophylactic measures assume a very important role in these patients. Patients should minimize their sun exposure and have their skin examined routinely. For those with large numbers of SCCs, systemic retinoids and reduction in immunosuppressive regimen may be of benefit. We present the case of a 70-year-old male heart transplant recipient who developed 334 SCCs, 83 SCCs in situ, and innumerable actinic keratoses during the course of 19 years posttransplant. His cancerous lesions were all excised surgically, but over the years, his cancer assumed a progressively more aggressive course. His immunosuppressive regimen was eventually reduced."
1386,Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study.,"Catto JW, Robinson MC, Albertsen PC, Goepel JR, Abbod MF, Linkens DA, Davis M, Rosario DJ, Warren AY, Varma M, Griffiths DF, Grigor KM, Mayer NJ, Oxley JD, Deshmukh NS, Lane JA, Metcalfe C, Donovan JL, Neal DE, Hamdy FC; ProtecT study group.",https://pubmed.ncbi.nlm.nih.gov/21863028/," Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial.
    


           These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately.
    


           In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38-66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and  Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions.
    


          Conclusion:
        
      
      Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression."
1387,Second cancers discovered by (18)FDG PET/CT imaging for choroidal melanoma.,"Chin K, Finger PT, Kurli M, Tena LB, Reddy S.",https://pubmed.ncbi.nlm.nih.gov/17662928/," It is currently and widely used for cancer staging (both initial and follow-up). Here we report our findings of second primary cancers incidentally discovered during PET/CT staging of patients with choroidal melanomas.
    


           In this series, 93 were scanned before treatment and 46 during the course of their follow-up systemic examinations. Their mean follow-up was 50.9 months.
    


          3%) had second primary cancers revealed by PET/CT imaging. Three patients (50%) were synchronous (found at initial staging), and the remaining 3 patients (50%) were metachronous (found at follow-up staging). Second primary cancers were found in the lung, breast, uterus, colon, and thyroid.
    


          Conclusions:
        
      
      Although whole-body PET/CT scans were ordered as part of the staging process of patients with diagnosed choroidal melanoma, both synchronous and metachronous second primary cancers were found. PET/CT has become an indispensable tool for staging, diagnosis, and treatment planning for choroidal melanoma. The possibility of detecting second primary cancers should also be considered valuable."
1388,Mitochondrial DNA mutations and 8-hydroxy-2'-deoxyguanosine Content in Japanese patients with urinary bladder and renal cancers.,"Wada T, Tanji N, Ozawa A, Wang J, Shimamoto K, Sakayama K, Yokoyama M.",https://pubmed.ncbi.nlm.nih.gov/17094459/," The origin of these mutations may be attributable to oxidative damage from reactive oxygen species (ROS). In order to investigate the relationship between mtDNA mutations and ROS in human cancers, urinary bladder and renal cancers were examined for mutations in the displacement-loop (D-loop) region of mtDNA and for 8-hydroxy-2'-deoxyguanosine (8-OHdG) content.
    


          Materials and  The level of 8-OHdG was measured in the patients who had undergone radical cystectomy or nephrectomy from excised specimens.
    


           The most frequent mutations were in the poly(C) mononucleotide repeat located at positions 303 to 309. The levels of 8-OHdG in cancer tissues were significantly higher than in the neighboring non-cancerous tissues, but many of the cancers with an elevated 8-OHdG level did not display D-loop mutations.
    


          Conclusion:
        
      
      These "
1389,Wnt pathway is involved in advanced gastric carcinoma.,"Zhang H, Xue Y.",https://pubmed.ncbi.nlm.nih.gov/18705344/," Deregulation of Wnt/beta-catenin signaling is frequently found in various human cancers. This study evaluated the relationship between the expression of Wnt-1, beta-catenin and E-cadherin in gastric cancer and gastric cancer clinicopathological characters.
    


           The immunohistochemical SP  The pathological stage of gastric cancer was evaluated in hematoxylin-eosin staining by the same pathologist.
    


          4%, 45.6%, 47.2%, respectively, which is significantly higher than the percentage expression of these genes in normal tissues (p<0.01). The expression levels of these three genes are significantly related to tumor size, tumor invasive depth, lymph node metastasis, pTNM stage, differentiation and five-year survival rate.
    


          Conclusions:
        
      
      Wnt-1, beta-catenin and E-cadherin play an important role in the differentiation, progression, invasion and metastasis in gastric cancer; they are good indicators for evaluating the biological behaviors of gastric cancer. And also, they will be promising targets for developing anti-cancer drug in gastric cancer."
1390,Acid-Induced Downregulation of ASS1 Contributes to the Maintenance of Intracellular pH in Cancer.,"Silberman A, Goldman O, Boukobza Assayag O, Jacob A, Rabinovich S, Adler L, Lee JS, Keshet R, Sarver A, Frug J, Stettner N, Galai S, Persi E, Halpern KB, Zaltsman-Amir Y, Pode-Shakked B, Eilam R, Anikster Y, Nagamani SCS, Ulitsky I, Ruppin E, Erez A.",https://pubmed.ncbi.nlm.nih.gov/30573518/,"Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) by either promoter methylation or by HIF1α is associated with increased metastasis and poor prognosis in multiple cancers. We have previously shown that in normoxic conditions, ASS1 downregulation facilitates cancer cell proliferation by increasing aspartate availability for pyrimidine synthesis by the enzyme complex CAD. Here we report that in hypoxia, ASS1 expression in cancerous cells is downregulated further by HIF1α-mediated induction of miR-224-5p, making the cells more invasive and dependent on upstream substrates of ASS1 for survival. ASS1 was downregulated under acidic conditions, and ASS1-depleted cancer cells maintained a higher intracellular pH (pHi), depended less on extracellular glutamine, and displayed higher glutathione levels. Depletion of substrates of urea cycle enzymes in ASS1-deficient cancers decreased cancer cell survival. Thus, ASS1 levels in cancer are differentially regulated in various environmental conditions to metabolically benefit cancer progression. Understanding these alterations may help uncover specific context-dependent cancer vulnerabilities that may be targeted for therapeutic purposes. SIGNIFICANCE: Cancer cells in an acidic or hypoxic environment downregulate the expression of the urea cycle enzyme ASS1, which provides them with a redox and pH advantage, Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/3/518/F1.large.jpg."
1391,DNA-methylation variability in normal mucosa: a field cancerization marker in patients with adenomatous polyps.,"Yates J, Schaufelberger H, Steinacher R, Schär P, Truninger K, Boeva V.",https://pubmed.ncbi.nlm.nih.gov/38273663/," Assessing the scope and intensity of this process in the colon may support risk prediction and colorectal cancer prevention.
    


           Methylation variations were evaluated for their discriminative capability, including in external cohorts, genomic localization, clinical correlations, and associated RNA expression patterns.
    


           Leveraging these adenoma-related differentially variable and methylated CpGs (aDVMCs), our classifier discerned between healthy and AP-adjacent tissues across SWEPIC datasets (cross-validated area under the receiver operating characteristic curve [ROC AUC] = 0.63-0.81), including within age-stratified cohorts. This discriminative capacity was validated in 3 external sets, differentiating healthy from cancer-adjacent tissue (ROC AUC = 0.82-0.88). Notably, aDVMC dysregulation correlated with polyp multiplicity. More than 50% of aDVMCs were significantly associated with age. These aDVMCs were enriched in active regions of the genome (P < .001), and associated genes exhibited altered expression in AP-adjacent tissues.
    


          Conclusions:
        
      
      Our findings underscore the early onset of field cancerization in the right colon during the neoplastic transformation process. A more extensive validation of aDVMC dysregulation as a stratification tool could pave the way for enhanced surveillance approaches, especially given its linkage to adenoma emergence."
1392,Development of a model to predict breast cancer survival using data from the National Cancer Data Base.,"Asare EA, Liu L, Hess KR, Gordon EJ, Paruch JL, Palis B, Dahlke AR, McCabe R, Cohen ME, Winchester DP, Bilimoria KY.",https://pubmed.ncbi.nlm.nih.gov/26365950/," However, no widely accepted survival calculator is available that uses national data and includes multiple prognostic factors. Our ""
    


          Patients and  A multivariable Cox proportional hazards regression model to predict overall survival was developed. Model discrimination by 10-fold internal cross-validation and calibration was assessed.
    


           The c-index for the 10-fold cross-validation ranged from 0.779 to 0.788 after inclusion of all available pertinent prognostic factors. A plot of the observed versus predicted 5 year overall survival showed minimal deviation from the reference line.
    


          Conclusion:
        
      
      This breast cancer survival prognostic model to be used as a prototype for building the Commission on Cancer's ""Cancer Survival Prognostic Calculator"" will offer patients and clinicians an "
1393,Psychological morbidity and autonomic reactivity to emotional stimulus in parental cancer: a study with adult children caregivers.,"Teixeira RJ, Pereira MG.",https://pubmed.ncbi.nlm.nih.gov/23889149/,"Literature suggests that parental cancer can provoke aversive emotional arousal in adult children, who may perceive caregiving as a traumatic experience. Limited research has been conducted on emotional and physiological impact of family caregiving for cancer patients undergoing chemotherapy. The aim of the present study was to examine psychological and physiological responses in parental cancer's caregivers. Two matched groups of adult children, with 78 participants each (parental cancer vs. control), completed psychological measures of distress, post-traumatic stress disorder (PTSD) symptoms, and burden. Additionally, each participant visualised standardised pictures with different emotional valences, while cardiovascular (heart rate) and electrodermal responses (skin conductance) were recorded. Between-group analysis showed significant differences on all psychological variables, and on skin conductance for all types of pictures. However, for the heart rate responses, differences were found only for pictures with unpleasant emotional arousal. In the parental cancer group, the heart rate peak response stood out as a predictor of PTSD symptoms, after controlling for distress and burden. This study highlights the important role of psychophysiological measures of family caregiving in oncology. Physiological responses may explain a higher prevalence of PTSD symptoms. Therefore, biofeedback combined with targeted psychosocial interventions for relaxation could be of great clinical value for this population."
1394,[Cancer of the testis in cryptorchidism. Apropos of 5 cases].,"Njeh M, Belhadj M, Mnif J, Bahloul A, Jlidi R, Krichen MS, Mhiri MN.",https://pubmed.ncbi.nlm.nih.gov/8558039/,"Five cases of cancer of the testicle in patients with cryptorchidism are presented. In one case the tumour occurred 16 years after cure for cryptorchidism at 15 years of age. In the other cases, the tumour developed on a testicle in an inguinal or intra-abdominal position. In two cases, it was impossible to remove the tumour which had developed on an intra-abdominal position. These patients died. These cases emphasize the importance of surgical cure in all cases of cryptorchidism, preferable before the age of 2 years, in order to improve functional prognosis and reduce the risk of cancerization. The gravity of cancer of the testicle in cases of cryptorchidism is often discovered too late."
1395,Hedgehog signaling: from the cuirass to the heart of pancreatic cancer.,"Di Marco M, Macchini M, Vecchiarelli S, Sina S, Biasco G.",https://pubmed.ncbi.nlm.nih.gov/22898642/,"Exocrine pancreatic cancer is the fifth cause of cancer-related death in Europe and carries a very poor prognosis for all disease stages. To date no medical treatment has significantly increased patients' survival. One of the reasons for pancreatic cancer's chemoresistence is the complex tumor architecture: cancer cells are surrounded by a dense desmoplastic stroma that blocks drug delivery. Moreover, pancreatic cancer is characterized by a marked heterogeneity of cells, including cancer stem cells (CSCs) that act as tumor-initiating cells and hierarchically control the differentiated cancer cells. In particular, this subpopulation is resistant to classic cytotoxic therapies, and seems to be responsible for disease renewal. Hedgehog signaling (HH) is implicated in pancreatic gland development during embryogenesis and is reactivated during tumorigenesis and the maintenance of pancreatic cancer. Some studies demonstrated that the Hedgehog-secreted signaling proteins are overexpressed in both the stromal and CSCs pools, implying an abnormal activation of HH in the main compartment of pancreatic cancer. For this reason, the Hedgehog pathway could be an interesting target for clinical trials to increase drug concentration in neoplastic cells and hence deplete the stroma and directly kill tumor-initiating cells."
1396,Association between aldehyde dehydrogenase gene polymorphisms and the phenomenon of field cancerization in patients with head and neck cancer.,"Muto M, Nakane M, Hitomi Y, Yoshida S, Sasaki S, Ohtsu A, Yoshida S, Ebihara S, Esumi H.",https://pubmed.ncbi.nlm.nih.gov/12376487/,"Patients with squamous-cell carcinoma in the head and neck (HNSCC) often develop second primary esophageal squamous-cell carcinomas (ESCC). In addition, widespread epithelial oncogenic alterations are also frequently observed in the esophagus and can be made visible as multiple Lugol-voiding lesions (multiple LVL) by Lugol chromoendoscopy. Multiple occurrences of neoplastic change in the upper aerodigestive tract have been explained by the concept of 'field cancerization', usually associated with repeated exposure to carcinogens such as alcohol and cigarette smoke. However, the etiology of second ESCC in HNSCC patients remains unclear and acetaldehyde, the first metabolite of ethanol, has been implicated as the ultimate carcinogen in alcohol-related carcinogenesis. We first investigated the relation between second ESCC and multiple LVL in 78 HNSCC patients. Multiple LVL and second ESCC were observed in 29 (37%) and 21 (27%) patients, respectively. All of the second ESCC were accompanied by multiple LVL. This may indicate that episodes of multiple LVL are precursors for second ESCC. We then examined the association of multiple LVL with the patients' characteristics, including genetic polymorphisms of the alcohol metabolizing enzymes, alcohol dehydrogenase type 3 (ADH3) and aldehyde dehydrogenase type 2 (ALDH2). We also investigated acetaldehyde concentrations in the breath of 52 of the 78 patients. All the patients with multiple LVL were both drinkers and smokers. Multivariable logistic analysis showed that the inactive ALDH2 allele (ALDH2-2) was the strongest contributing factor for the development of multiple LVL (odds ratio 17.6; 95% confidence intervals 4.7-65.3). After alcohol ingestion, acetaldehyde in the breath was elevated to a significantly higher level in all patients with the ALDH2-2 allele than in those without it. The high levels of breath acetaldehyde were significantly modified by the slow-metabolizing ADH3-2 allele. These  Ultimately, increased local acetaldehyde exposure thus appears to be a critical determinant of the phenomenon of 'field cancerization'."
1397,Log Odds of Positive Lymph Nodes (LODDS) as an Independent Predictor of Overall Survival Following Radical Cystectomy in Urothelial Bladder Cancer: Time to Rethink Conventional Node Staging.,"Salari A, Ghahari M, Nowroozi A, Ghahari P, Haddad M, Sahebi L, Ayati M, Momeni SA, Nowroozi MR, Amini E.",https://pubmed.ncbi.nlm.nih.gov/36567241/," The American Joint Committee on Cancer's (AJCC) node staging and lymph node ratio (LNR) systems are used in estimating prognosis; however, they do not directly factor in negative dissected nodes. In this study, we evaluated the log odds of positive lymph nodes (LODDS), a novel measure of nodal involvement, as a predictor of survival.
    


          Patients and  Kaplan-Meier curve and Cox regression were used for survival analyses.
    


           ROC curve analysis indicated -0.92 as the optimal LODDS cutoff. LODDS > -0.92 was associated with higher T stage, lymphovascular invasion, and significantly worse overall survival (OS) (mean OS 18.6 vs. 45.1 months, P-value < .001). Furthermore, we evaluated AJCC node staging, LNR, and LODDS in three separate multivariable Cox regression models. Among 3 different measures of nodal disease burden, only LODDS was an independent predictor of OS (HR 2.71, 95% CI 1.28-5.73, P = .009).
    


          Conclusions:
        
      
      Our "
1398,Squamous cell carcinoma of head and neck.,"Voravud N, Charuruks N, Mutirangura A.",https://pubmed.ncbi.nlm.nih.gov/9175390/,"Head and neck cancers are a major heath problem and common malignancies in Thailand. Up to 80 per cent of cases are caused by smoking and alcohol consumption. Epithelial mucosa of the aerodigestive tract exposed to carcinogens  Over 90 per cent of cases are squamous cell carcinoma. Prognostic factors depend on the patients, diseases and treatment. Currently, several molecular pathogenesis have been discovered such as abnormalities of c-myc, c-ras, c-erbB-1, bcl, int-2, hst1 oncogenes, p53 and p16 tumor suppressor genes. Common chromosomal abnormalities are 3p, 9p, 11q, 13q, 17p. Diagnosis requires symptoms and signs, radioimaging, and pathology. Stage I and II can be treated by surgery or radiotherapy. However, stage II requires and combination of surgery and radiotherapy, and studies of chemotherapy and local treatment to increase therapeutic efficacy by several approaches such as combination chemotherapy, new drugs, and biologic therapy."
1399,"Therapeutic potential of ethoxy mansonone G: A comprehensive exploration of its anticancer actions in breast cancer, colorectal cancer, and non-small cell lung carcinoma.","Fayyaz A, Basit M, Farooq A, Khan T, Ayub U, Khan S, Armaghan M, Mati-Ur-Rahman, Ammad M, Büsselberg D, Khan K, Habtemariam S, Sharifi-Rad J.",https://pubmed.ncbi.nlm.nih.gov/38924324/,"Mansonone G (MG), a 1,2-naphthoquinones with antiestrogenic, antimicrobial, and anti-adipogenic activities, is derived from the heartwood of Mansonia gagei Drumm. Ethoxy mansonone G (EMG), an essential derivative of MG, has anticancer and antioxidant agent. EMG also has antiestrogen activity and is demonstrated to lower estrogen receptor expression in endocrine-resistant cells. EMG significantly inhibits cell division, invasion, and anchorage-dependent growth in all cancer types. Through the stimulation of the tumor protein (p53) and extracellular signal-regulated kinase (ERK) signaling cascades, it also causes apoptosis. Moreover, it manifests its anti-cancerous effects in toll-like receptor pathways, c-Jun N-terminal kinase (c-JNK), and nuclear factor kappa B (NF-κB). EMG inhibits the phosphorylation of glycogen synthase kinase (GSK3), Erk, protein kinase B (Akt), and mammalian target of rapamycin (mTOR). By interfering with molecular cascades, EMG significantly reduces the metabolism of cancer cells. This paper focuses on the potential use of EMG in cancer treatment. Moreover, it states the  Breast cancer, non-small cell lung cancer, and colorectal cancer are only a few of the cancers for which EMG was shown to be effective. Through further research, EMG may be developed as a therapeutic solution to complications caused by cancer. This study presents EMG as a novel candidate for cancer therapy, offering a unique combination of pharmacological advantages and mechanistic insights that warrant further exploration and development toward addressing the complexities of cancer treatment."
1400,Gastric and intestinal phenotypic correlation between exocrine and endocrine components in human stomach tumors.,"Takenaka Y, Tsukamoto T, Mizoshita T, Ogasawara N, Hirano N, Otsuka T, Ban H, Nakamura T, Yamamura Y, Kaminishi M, Tatematsu M.",https://pubmed.ncbi.nlm.nih.gov/17163401/,"We have previously suggested that an origin of a stomach cancer is from a progenitor cell specializing toward exocrine cell (Exo-cell) lineages. To clarify whether our hypothesis is correct or not, we analyzed the expression of Exo-cell and endocrine cell (End-cell) markers in a series of lesions for comparison. We evaluated chromogranin A (CgA) expression in 37 early and 73 advanced stomach cancers, in 30 stomach adenomas, in 8 carcinoid tumors, and in 4 endocrine cell carcinomas (ECCs) with assessment of gastric and/or intestinal (G/I) phenotypes in both Exo-cell and End-cell by immunohistochemistry. CgA expression was observed in 10.8% of the early and 16.4% of the advanced stomach cancers, respectively. The End-cell G/I phenotypes were in line with the Exo-cell counterparts in the CgA-positive stomach cancerous areas, and there was strong association between Cdx2 expression and the intestinal End-cell markers. All of the adenoma cases had the intestinal Exo-cell phenotypic expression, with the positive link between Exo-cell and End-cell G/I phenotypes. All stomach carcinoids had CgA expression but no expression of Exo-cell markers. In conclusion, most stomach cancers might develop from a progenitor cell specializing towards Exo-cell lineages, but some cases possessed both Exo-cell and End-cell markers with maturely differentiated phenotypes. In such cases, Exo-cell and End-cell phenotypes were found to correlate strongly, suggesting the possibility of histogenesis from ""cancer stem cells""."
1401,[The expressions of alpha-enolase in the nasopharyngeal cancer tissue].,"Cheng C, Long X, Li X, Xie M, Guo M.",https://pubmed.ncbi.nlm.nih.gov/21950004/,"
    


          
    


          0% in the nasopharyngeal cancer tissues,significantly higher than that (27.5%, 11/40) of in inflammatory nasopharyngeal mucosa (P<0.05). The positive expression rate of ENO1 protein in stage T1 + T2 + T3 was higher than that of in patients with T4 (chi2 = 11.424, P<0.05). But there was no significant relationship between expression of ENO1 and lymph node metastasis and postradiotherapy distant metastasis (P>0.05).
    


          Conclusion:
        
      
      The "
1402,Telomerase reactivation is associated with hepatobiliary and pancreatic cancers.,"Sansone V, Le Grazie M, Roselli J, Polvani S, Galli A, Tovoli F, Tarocchi M.",https://pubmed.ncbi.nlm.nih.gov/32386990/,"
    


          Data sources:
        
      
      We performed a PubMed search with the following keywords: telomerase, hepatocellular carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma by December 2019. We reviewed the relevant publications that analyzed the correlation between telomerase activity and hepatobiliary and pancreatic diseases.
    


          
    


          Conclusions:
        
      
      Our review summarized the evidence about the critical role of hTERT in cancerous and precancerous lesions of the alteration and its activity in hepatobiliary and pancreatic diseases."
1403,Up-regulation of Flot-2 protein is related to lymph node metastasis and poor prognosis in human solid tumors.,"Liu FT, Qu QG, Zhu ZM.",https://pubmed.ncbi.nlm.nih.gov/27981826/," Increased expression of Flot-2 was correlated to a poor prognosis in cancer patients.
    


          Evidence acquisition:
        
      
      Eligible literatures were collected by retrieving multiple databases, including PubMed, Web of Science, Embase, CNKI and Wanfang database. With RevMan5.3 software and Stata SE12.0, the association of Flot-2 expression level with lymph node metastasis (LNM) and overall survival (OS) were explored in cancer patients.
    


          Evidence synthesis:
        
      
      A total of 1947 cancer patients from 13 eligible articles were included in this meta-analysis. The 58, 95% CI: 1.60-4.16, P=0.0001), as well as shorter OS (HR=1.59, 95% CI: 1.13-2.06, P=0.000), compared to those patients with lower expression of Flot-2 in tumor tissues.
    


          Conclusions:
        
      
      Flot-2 protein might be a novel biomarker; LNM and OS may be predicted by up-regulated expression of Flot-2 in various tumors."
1404,Efficacy of laser capture microdissection plus RT-PCR technique in analyzing gene expression levels in human gastric cancer and colon cancer.,"Makino H, Uetake H, Danenberg K, Danenberg PV, Sugihara K.",https://pubmed.ncbi.nlm.nih.gov/18652704/," For more reliable predictability, their expressions in cancer cells and stromal cells in the cancerous tissue (cancerous stroma) have been separately investigated using laser capture microdissection.
    


          
    


          0001, p <0.0001 respectively in gastric cancer and P = 0.0002, p < 0.0001 respectively in colon cancer) and dihydropyrimidine dehydrogenase mRNA expressions were lower in cancer cells than in cancerous stroma (P = 0.0136 in gastric cancer and p < 0.0001 in colon cancer). In contrast, thymidine phosphorylase mRNA was higher in cancer cells than in cancerous stroma in gastric cancer (p < 0.0001) and lower in cancer cells than in cancerous stroma in colon cancer (P = 0.0055).
    


          Conclusion:
        
      
      By using this  Our "
1405,Targeting of oncogenic signaling pathways by berberine for treatment of colorectal cancer.,"Hallajzadeh J, Maleki Dana P, Mobini M, Asemi Z, Mansournia MA, Sharifi M, Yousefi B.",https://pubmed.ncbi.nlm.nih.gov/32303850/,"Studies indicate that inhibiting a single signaling pathway or one single product of a gene is insufficient for the prevention and treatment of cancer. This is due to the fact that dysregulation must occur in more than 500 genes in order to produce a cancerous phenotype. Despite this evidence, available drugs used for cancer treatment focus on a single target. Meanwhile, berberine as a nutraceutical is capable of targeting various processes involved in tumor development including proliferation, invasion, angiogenesis, and metastasis. In comparison with synthetic agents, berberine is cheaper, safer, and more available. Berberine has shown anti-inflammatory properties which make it an ideal option in order to prevent inflammation-associated cancers. Colorectal cancer is one of the most common cancers all over the world and its incidence is increasing each day. Therefore, further investigations about berberine could be helpful in the discovery of novel agents for preventing and/or treating colorectal cancer. This review emphasizes the studies investigating the roles of berberine in colorectal cancer such as controlling cell signaling pathways, inducing apoptosis, regulating microRNAs, attenuating oxidative stress, and affecting inflammation."
1406,Cross-individual cancer transmission to children during the gestational and perinatal periods.,"Arakawa A, Tao K, Kohno T, Ogawa C.",https://pubmed.ncbi.nlm.nih.gov/38369705/,"Cancer transmission may rarely occur between individuals. Besides through allogenic transplantation, cancer transmission via the hemochorial placenta, which is permissive for cell traffic, has been described in a few reports. Three etiologies of transplacental cancer transmission include (1) maternofetal transmission of maternal cancer cells, (2) transmission of gestational choriocarcinoma to the fetus, and (3) transfer of preleukemic cells from one monozygotic twin to the other. Additionally, we recently reported two pediatric cases of lung tumors in which the lung-only distribution of tumors and genomic profiling of both the child's and mother's tumor samples suggested the airway/transbronchial transmission of maternal cervical cancer cells to the child by aspiration at birth. The immune system coordinates the hemostatic balance between effector and regulatory immunity, especially during fetal development. The immunoregulatory properties are shared in both physiological pregnancy-related and pathological cancer-related conditions. Mechanistically, the survival and colonization of transmitted cancer cells within a child are likely attributed to a combination of the child's immune tolerance and the cancer's immune escape. In this review, we summarize the current understanding of gestational/perinatal cancer transmission and discuss the possible mechanism-based immunotherapy for this rare form of pediatric cancer."
1407,Evaluation of the delivery of survivorship care plans for South Asian female breast cancer survivors residing in Canada.,"Singh-Carlson S, Wong F, Oshan G.",https://pubmed.ncbi.nlm.nih.gov/30111971/," Evaluating the utility of the scp was important to understand how sociocultural influences might affect uptake of the scp by sa bcss, especially as they transition from treatment to community care.
    


           A longitudinal study using a mixed-
    


           Most participants reported the discharge appointments to be extremely or very helpful with respect to post-treatment care questions. All have visited their family physicians for follow-up as recommended. The three major sources of support were family, faith, and family physician. Qualitative responses from the health care professionals who developed or implemented the scps identified two challenges in scp delivery: engaging patients or family members in relationship, and translating key information through interpreters.
    


          Conclusions:
        
      
      It is important to evaluate the utility of scps for sa female survivors, who might differ from the general bcs population because of a different understanding of the disease; language barriers; strong influence of family members; societal stigmas; and personal, social, cultural, and religious beliefs and values. A formal nurse-led discharge appointment with discussions about follow-up care and an individualized scp outlining the short- and long-term effects of treatment are recommended. Particular attention has to be paid to the practical and psychosocial needs of sa bcss and their supporting family members."
1408,Metabolic Pathway Inhibition in Liver Cancer.,Zarrinpar A.,https://pubmed.ncbi.nlm.nih.gov/28314110/,"Liver cancer is fundamentally physiologically different from the surrounding liver tissue. Despite multiple efforts to target the altered signaling pathways created by oncogenic mutations, not many have focused on targeting the altered metabolism that allows liver cancer to develop and grow. Still to be resolved is the question of whether the altered metabolic pathways in this cancer differ enough from the surrounding noncancerous cells to allow for the development of potent and specific compounds. Clinical studies of metabolic modulators would provide some more information with regard to the feasibility of this approach. Furthermore, as it appears that oncogenic signaling is essential to this cancer's altered metabolism, it stands to reason that targeting this altered signaling may allow the exploitation of specific metabolic vulnerabilities in combination with other drugs for enhanced efficacy. The identification of biomarkers of metabolic sensitivity will also be essential to determine whether these drugs will have the desired effect."
1409,Nanotheranostics for Diagnosis and Treatment of Breast Cancer.,"Patel P, Kumar K, Jain VK, Popli H, Yadav AK, Jain K.",https://pubmed.ncbi.nlm.nih.gov/36999427/,"Recently, breast cancer has reached the highest incident rate amongst all the reported cancers, and one of its variants, known as triple-negative breast cancer (TNBC), is deadlier compared to the other types of breast cancer due to a lack of feasible diagnostic techniques. Advancements in nanotechnology have paved the way to formulate several nanocarriers with the ability to deliver anticancer drugs effectively and selectively to cancer cells with minimum side effects to non-cancerous cells. Nanotheranostics is a novel approach that can be used in the diagnosis of disease along with therapeutic effects. Currently, various imaging agents, such as organic dyes, radioactive agents, upconversion nanoparticles, various contrasting agents, quantum dots, etc., are being explored for the imaging of internal organs or to examine drug distribution. Furthermore, ligand-targeted nanocarriers, which have the potential to target cancer sites, are being used as advanced agents for cancer theranostic applications, including the identification of various metastatic sites of the cancerous tumor. This review article discusses the need for theranostic application in breast cancer with various imaging techniques, the latest nanotheranostic carriers in breast cancer, and related safety and toxicity issues, as well as highlights the importance of nanotheranostics in breast cancer, which could be helpful in deciphering questions related to nanotheranostic systems."
1410,Current advances in microbial-based cancer therapies.,"Shahbaz A, Mahmood T, Javed MU, Abbasi BH.",https://pubmed.ncbi.nlm.nih.gov/37330997/,"Microbes have an immense metabolic capability and can adapt to a wide variety of environments; as a  The goal of microbial-based cancer therapy is to treat patients with cancers that are not easily treatable, by using tumor-specific infectious microorganisms. Nevertheless, a number of difficulties have been encountered as a  Due to these difficulties, there is now a larger need for designing alternative strategies that are more effective and selective when targeting tumor cells. The fight against cancer has advanced significantly owing to cancer immunotherapy. The researchers have greatly benefited from their understanding of tumor-invading immune cells as well as the immune responses that are specifically targeted against cancer. Application of bacterial and viral cancer therapeutics offers promising potential to be employed as cancer treatments among immunotherapies. As a novel therapeutic strategy, microbial targeting of tumors has been created to address the persisting hurdles of cancer treatment. This review outlines the mechanisms by which both bacteria and viruses target and inhibit the proliferation of tumor cells. Their ongoing clinical trials and possible modifications that can be made in the future have also been addressed in the following sections. These microbial-based cancer medicines have the ability to suppress cancer that builds up and multiplies in the tumor microenvironment and triggers antitumor immune responses, in contrast to other cancer medications."
1411,Feeding cancer's sweet tooth: specialized tumour vasculature shuttles glucose in pancreatic ductal adenocarcinoma.,"Dudley AC, Bautch VL.",https://pubmed.ncbi.nlm.nih.gov/25727340/,"Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal neoplasm characterized by a 'fortress' of thick collagen fibres, abundant myofibroblasts, and paradoxically reduced vascularization compared to normal pancreas. Despite these features, PDAC shows no reduction in the uptake of glucose that fuels tumour cell survival. In new work published in The Journal of Pathology, Saiyin and colleagues have identified a novel adaptation of PDAC tumour endothelium; namely, 'hairy-like' basal microvilli that increase the total vascular surface area and correlate with regions of highest glucose uptake. Since basal microvilli are not present on normal pancreatic blood vessels, their presence may add diagnostic value and blocking their function is a potential new treatment strategy for PDAC. This novel finding of basal microvilli on PDAC endothelium is a striking example of how phenotypic plasticity in tumour blood vessels contributes to tumour growth and progression, independent of conventional modes of angiogenesis."
1412,Hetero-duplication type of cancerous mitosis.,Hirata Y.,https://pubmed.ncbi.nlm.nih.gov/8183127/,"In normal mitosis, the two daughter cells are identical to each other. However, in the case of duplication mitosis of the non-matureable cancerous stem cell, the two daughter stem cells must be non-visually, but certainly different from each other in order to allow for the characteristic type of cancerous cell turnover development. One of these daughter stem cells is matureable and normally activated by the maturation factor, then undergoes maturation mitosis and finally passes through its lifespan. However, the other daughter stem cell is non-matureable and not activated by the maturation factor. It undergoes the original mitosis again, reproducing two daughter stem cells that differ from each other: te above matureable cell and the original non-matureable cell (Fig.). Such a hetero-duplication type of mitosis is peculiar to carcinoma and responsible for the oncogenesis. The origin of this mitosis is most probably an unequal division of a mitotic maturation promoting system (MMPS) at the mitotic phase, and may be dependent on some abnormal supplement of the MMPS. Thus, therapy aimed at the complete eradication of cancer should focus on removal of this supplement from the cancerous cell."
1413,Focal therapy for prostate cancer: possibilities and limitations.,"Eggener S, Salomon G, Scardino PT, De la Rosette J, Polascik TJ, Brewster S.",https://pubmed.ncbi.nlm.nih.gov/20378241/,"Context:
        
      
      A significant proportion of patients diagnosed with prostate cancer have well-differentiated, low-volume tumors at minimal risk of impacting their quality of life or longevity. The selection of a treatment strategy, among the multitude of options, has enormous implications for individuals and health care systems.
    


           We gave particular emphasis to the conceptual possibilities and limitations.
    


          Evidence acquisition:
        
      
      A National Center for Biotechnology Information PubMed search (www.pubmed.gov) was performed from 1995 to 2009 using medical subject headings ""focal therapy"" or ""ablative"" and ""prostate cancer."" Additional articles were extracted based on recommendations from an expert panel of authors.
    


          Evidence synthesis:
        
      
      Focal therapy of the prostate in patients with low-risk cancer characteristics is a proposed treatment approach in development that aims to eradicate all known foci of cancer while minimizing damage to adjacent structures necessary for the preservation of urinary, sexual, and bowel function. Conceptually, focal therapy has the potential to minimize treatment-related toxicity without compromising cancer-specific outcome. Limitations include the inability to stage or grade the cancer(s) accurately, suboptimal imaging capabilities, uncertainty regarding the natural history of untreated cancer foci, challenges with posttreatment monitoring, and the lack of quality-of-life data compared with alternative treatment strategies. Early clinical experiences with modest follow-up evaluating a variety of modalities are encouraging but hampered by study design limitations and small sample sizes.
    


          Conclusions:
        
      
      Prostate focal therapy is a promising and emerging treatment strategy for men with a low risk of cancer progression or metastasis. Evaluation in formal prospective clinical trials is essential before this new strategy is accepted in clinical practice. Adequate trials must include appropriate end points, whether absence of cancer on biopsy or reduction in progression of cancer, along with assessments of safety and longitudinal alterations in quality of life."
1414,[Cancer epidemiology and French medical data (author's transl)].,"Brunet M, Berlié J.",https://pubmed.ncbi.nlm.nih.gov/218258/,"The authors remind: cancerous disease's possibilities of description before any treatment through its topography, its morphology and its clinical medicine; the modalities for taking surgical, actinic, chemical, immunologic therapeutics in account; the technics of the cancerous disease supervision after treatment, from the vital points of view (study of observed and relative survival, and of recovery) and from the carcinologic and fonctionnal points of view. They insist on the possibilities of these languages that go from the simple notation of information to the taking of these sundries modalities in account. The disposable datums in France are schematicly described. They concern: the study of survival from hospitable series; mortality by cancer for the whole of the country. The authors consider that no entry must be undertaken without the purposes, in the same way as the considered modalities for analysis, being precisely fixed. They insist on the notion of information level, of which three levels are schematicly defined, according as descriptive epidemiology or epidemiologic research or clinical research is in question."
1415,Circulating tumor DNA analysis in breast cancer: Is it ready for prime-time?,"Buono G, Gerratana L, Bulfoni M, Provinciali N, Basile D, Giuliano M, Corvaja C, Arpino G, Del Mastro L, De Placido S, De Laurentiis M, Cristofanilli M, Puglisi F.",https://pubmed.ncbi.nlm.nih.gov/30682661/,"Precision Medicine is becoming the new paradigm in healthcare as it enables better resources allocation, treatment optimization with a potential side-effects reduction and consequent impact on quality of life and survival. This revolution is being catalyzed by liquid biopsy technologies, which provide prognostic and predictive information for advanced cancer patients, without the analytical and procedural drawbacks of tissue-biopsy. In particular, circulating tumor DNA (ctDNA) is gaining momentum as a clinically feasible option capable to capture both spatial and temporal tumor heterogeneity. Several techniques are currently available for ctDNA extraction and analysis, each with its preferential case scenarios and preanalytical implications which must be taken into consideration to effectively support clinical decision-making and to better highlight its clinical utility. Aim of this review is to summarize both analytical developments and clinical evidences to offer a comprehensive update on the deployment of ctDNA in breast cancer's (BC) characterization and treatment."
1416,The dark side of lipid metabolism in prostate and renal carcinoma: novel insights into molecular diagnostic and biomarker discovery.,"di Meo NA, Lasorsa F, Rutigliano M, Milella M, Ferro M, Battaglia M, Ditonno P, Lucarelli G.",https://pubmed.ncbi.nlm.nih.gov/36960789/," The increased intracellular accumulation of different classes of lipids in renal cell carcinoma (RCC) and prostate cancer (PCa) cells may be caused by elevated absorption or by increased de novo lipogenesis as a consequence of lipid metabolism reprogramming. The involvement of cholesterol metabolism in cancer's aberrant pathways has also been demonstrated.
    


          Areas covered:
        
      
      This review provides an update on the most important lipidomics studies and applications in RCC and PCa, with a particular focus on how knowledge of aberrant lipid pathways may be used to identify biomarkers and novel therapeutic targets. In addition, the application of this  Tracking tumor progression using specific biofluid metabolite profiles offers a huge translational opportunity for urological malignancies.
    


          Expert opinion:
        
      
      Lipidomics is a promising branch of 'omics' approach and should include in next decade new standardized analysis "
1417,Role of receptor for advanced glycation end products in the complication and progression of various types of cancers.,"Malik P, Chaudhry N, Mittal R, Mukherjee TK.",https://pubmed.ncbi.nlm.nih.gov/26028296/," Use of RAGE deficient mice (RAGE(-/-)) as well as established mouse models pertaining to inflammation-associated carcinogenesis such as that of chemically induced carcinogenesis and colitis associated cancer provides a direct genetic evidence for a likelihood novel role of RAGE in cancer, with respect to its ability to lead cancer cell proliferation and survival. Besides inflammation, interaction of RAGE with its various ligands enhances oxidative stress both in cancerous and noncancerous cells which further complicates the progression of cancers.
    


          Scope of review:
        
      
      Till date, no single review article has discussed the mechanism of RAGE dependent complication of cancers, particularly the role of RAGE in cancer cell proliferation, angiogenesis, survival and anti-apoptosis needs to be discussed.
    


          Major conclusion:
        
      
      RAGE enhances the number of cancer cells by activating the cell cycle proteins (e.g., cyclin D1), anti-apoptotic proteins (e.g., BCl2), prosurvival (AKT) and autophagic proteins. Role of RAGE has also been detected in formation of new blood vessels (angiogenesis) in the cancer cells and activation of myeloid derived suppressor cells (MDSCs).
    


          General significance:
        
      
      This review article describes the role of RAGE in the complication of various types of cancers and the possible usefulness of RAGE dependent therapy to confront cancers in a stronger magnitude."
1418,Mineral dusts in lungs with scar or scar cancer.,"Yao YT, Wang NS, Michel RP, Poulsen RS.",https://pubmed.ncbi.nlm.nih.gov/6478417/,"Five lungs with small scars and five lungs with small scar associated cancers, were studied by light and scanning electron microscopy and x-ray energy dispersive spectrometry. Six hundred particles were photographed and their physical and chemical properties analyzed from scar, cancer, or normal alveolar tissue on carbon planchet-mounted, deparaffinized and low temperature-ashed sections. Amosite/crocidolite fibers were accumulated only in one cancerous lung. All other lungs shared similar types of mineral particles. The lungs with noncancer scars, however, showed an increase in the ratio of aluminum and calcium salts (non-silicates), while the lungs with scar cancers had a higher ratio of silicates. These patterns of particle distribution were similar in different areas of the same lung, despite the fact mechanism is unclear, these "
1419,Field cancerization: from molecular basis to selective field-directed management of actinic keratosis.,Philipp-Dormston WG.,https://pubmed.ncbi.nlm.nih.gov/25561215/,"The incidence of non-melanoma skin cancer (NMSC), including actinic keratosis (AK), squamous cell carcinoma (SCC), Bowen's Disease (BD) and basal cell carcinoma (BCC), is increasing. UVA and UVB radiation lead to genetic alterations in keratinocytes, which eventually  In the concept of field cancerization of the skin, genetically altered keratinocytes accumulate over an area exposed to UV radiation. Field treatment not only clears clinically visible NMSC lesions but also potentially targets subclinical 'sleeping' cell patches and fields. Topical treatments are available for the field-directed management of NMSC. They are either self-administered by the patient (ingenol mebutate, diclofenac, imiquimod or 5-FU) or administered by the dermatologist (photodynamic therapy (PDT)). This article discusses the treatment options with respect to their efficacy, tolerability and selectivity. Selective treatment options for atypic keratinocytes include imiquimod, ingenol mebutate, diclofenac and PDT. PDT yields 100% treatment compliance because it is always administered by the treating dermatologist. The efficacy rates achieved with PDT significantly exceed those of the patient-administered topicals. The first clinical trials assessing the effects of PDT on field cancerization clinically, histologically and immunochemically have been conducted and have yielded promising  Preventive effects and a delay in the re-occurrence of NMSC have been observed in animal "
1420,[Canceration of inflammatory myofibroblastic tumor of the larynx:a case report].,"Wang YB, Shi SJ, Qiao ZH, Zhang XL, Liu CB.",https://pubmed.ncbi.nlm.nih.gov/31914279/,"Summary Inflammatory myofibroblastic tumor（IMT） is a rare spindle neoplasm with malignant potentials of local invasion, recurrence and metastasis. Here, we present an extremely unusual case of the larynx IMT that was recurred three times and transformed into laryngeal squamous cell carcinoma."
1421,Effect of imiquimod as compared with surgery on the cancerization field in basal cell carcinoma.,"Graells J, Ojeda RM, García-Cruz A.",https://pubmed.ncbi.nlm.nih.gov/24139468/," It is possible that imiquimod might reduce this risk by acting on the cancerization field.
    


          
    


           The patients were divided into 2 groups depending on whether they had been treated with surgery or with imiquimod. Comparing the 2 groups, we analyzed the development of new BCCs, the time that elapsed between first and subsequent tumors, and the site of occurrence of the second BCC with respect to the first one (local, same lymphatic drainage basin or anatomic region, or other). Survival 
    


           Of these, 550 had been treated with surgery (88.3%) and 71 with imiquimod (11.4%). Overall, a second BCC occurred in 36.4% of patients (n=227). The rate of occurrence was 38.2% in the surgery group and 23.9% in the imiquimod group (P=.02). The hazard ratio for the occurrence of a subsequent BCC was 2.13 (95% CI, 1.28-3.53) for patients treated with surgery compared with those treated with imiquimod. Imiquimod reduced the risk of a second BCC locally, regionally, and in the lymphatic drainage area. Our findings are limited by the retrospective nature of our study and the small number of patients treated with imiquimod.
    


          Conclusions:
        
      
      Imiquimod may reduce the risk of subsequent BCC in patients treated for BCC and its effect could last for up to 2 years in local, regional and lymphatic cancerization fields. We believe that the cancerization field concept should be expanded to include not only the local area, but also the pertinent anatomic region and the regional lymphatic drainage area."
1422,Long non-coding RNAs in gastrointestinal cancers: Implications for protein phosphorylation.,"Su T, Wang T, Zhang N, Shen Y, Li W, Xing H, Yang M.",https://pubmed.ncbi.nlm.nih.gov/35007523/,"Phosphorylation of proteins is one of the most extensively investigated post-translational protein modifications. Threonine, serine and tyrosine in proteins are the most commonly phosphorylated amino acids. Dysregulated cancer-related signaling pathways due to aberrant phosphorylation status of the key protein(s) in these pathways exist in most malignancies. Intensive studies in the recent decade have implicated long non-coding RNAs (lncRNAs) in the precise regulation of protein phosphorylation in cancers. In this review, we systematically delve into recent advance that underlines the multidimensional role of lncRNAs in modulating protein phosphorylation, regulating cancerous signaling and impacting prognosis of gastrointestinal (GI) cancers including hepatocellular carcinoma, colorectal cancer, gastric cancer, esophageal cancer, and pancreatic cancer. LncRNAs regulate protein phosphorylation via directly binding to the target protein(s), interacting with the partner protein(s) of the target protein(s) or lncRNAs-encoded small peptides. Although there are still extensive studies on disclosing the intricate interactions between lncRNAs and proteins and their impacts on protein phosphorylation, we believe that targeting lncRNAs controlling phosphorylation of key protein(s) in cancerous signaling pathways might provide novel paths for precision therapeutics of GI cancers in the future."
1423,Monitoring the effects of treatment in colon cancer cells using immunohistochemical and histoenzymatic techniques.,"Pallag A, Roşca E, ţiŢ DM, MuŢiu G, Bungău SG, Pop OL.",https://pubmed.ncbi.nlm.nih.gov/26662146/," Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics. The purpose of the present study is to evaluation and analysis of the colon cancer cells under anti-angiogenic treatment, to establish the changes in the cellular energy metabolism and apoptotic potential. Anti-angiogenic drugs block the vascular endothelial growth factors, preventing the formation of new vessels.
    


          Materials and  Colorectal tumor tissue samples were obtained by biopsy following the surgical procedures at the County Clinical Hospital of Oradea (Romania).
    


           Our 
    


          Conclusions:
        
      
      It was been demonstrated that the apoptotic potential of malignant cells increases significantly during anti-angiogenic treatment. There is growing evidence that cancer's ""Achilles' heel"" is tumor cell metabolism."
1424,Conventionally used reference genes are not outstanding for normalization of gene expression in human cancer research.,"Jo J, Choi S, Oh J, Lee SG, Choi SY, Kim KK, Park C.",https://pubmed.ncbi.nlm.nih.gov/31138119/," Theoretically they should be expressed stably and not regulated by  However, identification and validation of reference genes for human cancer research are still being regarded as a critical point, because cancerous tissues often represent genetic instability and heterogeneity. Recent pan-cancer studies have demonstrated the importance of the appropriate selection of reference genes for use as internal controls for the normalization of gene expression; however, no stably expressed, consensus reference genes valid for a range of different human cancers have yet been identified.
    


           Furthermore, we identified 38 novel candidate reference genes for the normalization of gene expression, independent of cancer type. These genes were found to be highly expressed and highly connected to relevant gene networks, and to be enriched in transcription-translation regulation processes. The expression stability of the newly identified reference genes across 29 cancerous and matched normal tissues were validated via quantitative reverse transcription PCR (RT-qPCR).
    


          Conclusions:
        
      
      We reveal that most commonly used reference genes in current cancer studies cannot be appropriate to serve as representative control genes for quantifying cancer-related gene expression levels, and propose in this study three potential reference genes (HNRNPL, PCBP1, and RER1) to be the most stably expressed across various cancerous and normal human tissues."
1425,Mechanisms of immune evasion in breast cancer.,"Bates JP, Derakhshandeh R, Jones L, Webb TJ.",https://pubmed.ncbi.nlm.nih.gov/29751789/,"Tumors develop multiple mechanisms of immune evasion as they progress, with some cancer types being inherently better at 'hiding' than others. With an increased understanding of tumor immune surveillance, immunotherapy has emerged as a promising treatment strategy for breast cancer, despite historically being thought of as an immunologically silent neoplasm. Some types of cancer, such as melanoma, bladder, and renal cell carcinoma, have demonstrated a durable response to immunotherapeutic intervention, however, breast neoplasms have not shown the same efficacy. The causes of breast cancer's immune silence derive from mechanisms that diminish immune recognition and others that promote strong immunosuppression. It is the mechanisms of immune evasion in breast cancers that are poorly defined. Thus, further characterization is critical for the development of better therapies. This brief review will seek to provide insight into the possible causes of weak immunogenicity and immune suppression mediated by breast cancers and highlight current immunotherapies being used to restore immune responses to breast cancer."
1426,Knowledge about Breast Cancer and Barriers to Screening among Saudi Women in Al-Baha Region.,"Alghamdi AG, Algharsan FA, Alzahrani RA, Alghamdi RH, Alzahrani AA, Alzahrani YK, Hussain MF.",https://pubmed.ncbi.nlm.nih.gov/38546080/," To achieve this, a cross-sectional study was conducted, involving 468 women, to assess their understanding of breast cancer and to explore the obstacles they face in accessing breast cancer screening services.
    


           Participants were interviewed by well-trained team members of the research, and their responses were subsequently entered into a Google Form. This process aimed to evaluate their awareness, knowledge, and barriers to breast cancer screening.
    


          9%) were in the 18-28 age group. The findings reveal a high level of awareness (96.4%) among participants regarding the significance of early breast cancer detection. For the effectiveness of breast cancer treatment, 59% believed there is an effective treatment, while 32.9% were uncertain or did not know. Knowledge about various risk factors for breast cancer varied. Smoking (73.5%), genetic factors (65.6%), and a family history of breast cancer (70.7%) were well-recognized as risk factors. Education and occupation significantly influenced knowledge about breast cancer (p-value of 0.000, and 0.035 respectively).
    


          Conclusion:
        
      
      this research highlights strong awareness of breast cancer's importance but gaps in knowledge regarding lesser-known factors. Education is crucial, requiring tailored campaigns and healthcare professional engagement."
1427,[Clinicopathological features of early gastric cancer after Helicobacter pylori eradication].,"Hou WH, Wang XZ, Shi ZY, Li FL, Fang ZH, Sun XL, Liu YF, Wang LN, Jin ML.",https://pubmed.ncbi.nlm.nih.gov/35922158/," pylori) eradication.  pylori eradication and 45 cases without H. pylori eradication in the 989 Hospital of the Joint Logistics Support Force of the People's Liberation Army (the former 152 Hospital), Pingdingshan, China from 2013 to 2021 were collected. The histological, immunophenotypic and clinical characteristics of the two groups were compared, and discussed with review of the related literature.  pylori eradication, there were 20 males and 6 females with a median age of 65 years (range 53 to 77 years). The cancer involved the upper part of the stomach in 12 cases, the middle part of the stomach in 4 cases, and the lower part of the stomach in 10 cases. The median diameter of the tumors was 12 mm (range 4-29 mm). According to the Paris Classification, 4 cases were 0-Ⅱa, 4 cases were 0-Ⅱb, 18 cases were 0-Ⅱc. White light endoscopy showed that the lesions were reddish to yellowish. The lesion boundary was clear in 12 cases and was unclear or gastritis-like changes in 14 cases, while the irregular microvascular structure and microsurface structure, as well as the relatively visible spinous boundary, were visible under narrow-band imaging. There were 20 cases of well-differentiated tubular adenocarcinoma, 4 cases of highly to moderately differentiated tubular adenocarcinoma, and 2 cases of well-differentiated tubular adenocarcinoma with papillary adenocarcinoma. Compared with gastric cancers without H. pylori eradication, gastric cancers diagnosed after H. pylori eradication was associated with lower nucleus-cytoplasm ratio (<50%), normal epithelial coverage on the cancer surface, mild atypical epithelial coverage on the cancer surface, elongation of non-cancerous glands in the cancer tissue and subepithelial progression of cancerous glands were higher (P<0.05). The cellular immunophenotypes were gastric type in 6 cases, intestinal type in 4 cases and gastrointestinal mixed type in 16 cases. Conclusions: The early gastric cancers diagnosed after H. pylori eradication are more subtle clinically and mostly well-differentiated tubular adenocarcinoma. The important morphological features of gastric cancer diagnosed after H. pylori eradication are decreased cytological atypia and overlying normal epithelium or mildly atypical epithelium of the cancer. Understanding and recognizing these morphological features are helpful to make correct endoscopic and pathological diagnoses."
1428,Long-Standing Ulcerative Colitis May Trigger a Multilineage Cancerization Field.,"Fassan M, Brignola S, Sarzo G, Cappellesso R, Rugge M.",https://pubmed.ncbi.nlm.nih.gov/29580126/,Longstanding/relapsing inflammation characterizing ulcerative colitis (UC) has been associated to an increased risk of colon mucosa neoplastic transformation. We describe the clinicopathological features of a UC-related poorly-differentiated neuroendocrine carcinoma coexisting with a conventional adenocarcinoma. This case supports UC as a multilineage cancerization field.
1429,Nodal Downstaging in Gastric Cancer Patients: Promising Survival if ypN0 is Achieved.,"Ikoma N, Estrella JS, Hofstetter W, Das P, Minsky BD, Ajani JA, Fournier KF, Mansfield P, Badgwell BD.",https://pubmed.ncbi.nlm.nih.gov/29748883/," Overall, ypN0 patients have better survival outcomes than ypN+ patients. However, whether patients with cN+/ypN0 disease (""downstaged N0"") and those with cN0/ypN0 disease (""natural N0"") have similar survival is unknown.
    


           Patients were categorized into three groups based on nodal status: cN0/ypN0, cN+/ypN0, and ypN+. Univariable and multivariable Cox regression models were used to identify clinicopathologic factors associated with overall survival (OS).
    


           Ninety-four patients (30%) had cN0/ypN0 disease, 93 (29%) had cN+/ypN0 disease, and 129 (41%) had ypN+ disease. The median OS was 7.7 years, and the 5-year OS was 60.3%. In the multivariate analysis, OS did not differ between the cN0/ypN0 and cN+/ypN0 patients (hazard ratio, 0.90 [95% CI 0.54-1.48]; p = 0.666), but it was shorter in ypN+ patients (hazard ratio, 1.82 [95% CI 1.15-2.87]; p = 0.01).
    


          Conclusions:
        
      
      In gastric cancer patients who underwent preoperative therapy, we found similar OS in cN0/ypN0 and cN+/ypN0 patients. Because ypN+ patients had poor OS, achieving ypN0 status is an important hallmark demonstrating the effectiveness of preoperative therapy for gastric cancer."
1430,Causal associations of histidine and 12 site-specific cancers: a bidirectional Mendelian randomization study.,"Kong X, Yu J, Zhu Z, Wang C, Zhang R, Qi J, Wang Y, Wang X, Pan S, Liu L, Feng R.",https://pubmed.ncbi.nlm.nih.gov/37498357/,"An increasing number of studies indicate that cancer patients' histidine (HIS) circulating levels have changed. However, the causality between HIS and cancer is still not well established. Thus, to ascertain the causal link between HIS and cancers, we performed a bidirectional Mendelian randomization (MR) analysis. Summary-level data are derived from publicly available genome-wide association studies (GWAS). The causal effects were mainly estimated using the inverse-variance weighted  The weighted-median (WM)  In the forward-MR, we found malignant neoplasm of respiratory system and intrathoracic organs (OR: 1.020; 95% CI: 1.006-1.035; pIVW = 0.007) genetically associated with circulating HIS. And there was no significant genetic correlation between HIS and another 11 site-specific cancers using IVW  In the reversed-MR, we did not observe the causal relationship between HIS and 12 site-specific cancers. Our findings help clarify that HIS, as a biomarker for malignant neoplasms of respiratory system and intrathoracic organs, is causal rather than a secondary biomarker of the cancerous progression. The mechanism between histidine and cancer progression deserves further investigation."
1431,Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability.,"Song SY, Kang MR, Yoo NJ, Lee SH.",https://pubmed.ncbi.nlm.nih.gov/20477815/,"Coordinated protein phosphorylation and dephosphorylation are crucial in the regulation of cell signaling, and disruption of the coordination is known to play important roles in cancer development. Recent reports revealed that classical protein tyrosine phosphatase (PTP)-encoded genes are somatically mutated in human colorectal cancer. However, data on dual specificity phosphatase (DPTP) gene mutations in human cancers are lacking. By analyzing a public genomic database, we found that five DPTP genes, CDC14A, MTM1, MTMR3, SSH1, and SSH2, have mononucleotide repeats in their coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analyzed the mononucleotide repeats in 26 gastric cancers (GC) with MSI (MSI-H), 12 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 33 colorectal cancers (CRC) with MSI-H, 14 CRC with MSI-L, and 45 CRC with MSS by single-strand conformation polymorphism (SSCP). We found CDC14A and MTMR3 mutations in five and one cancer (s), respectively. These mutations were detected in MSI-H cancers, but not in MSI-L or MSS cancers. The GC and CRC with MSI-H harbored the mutations in 15% and 6%, respectively. The CDC14A and MTMR3 mutations detected in the GC and CRC were deletion or duplication mutations of one base in the nucleotide repeats that would  Our data show that frameshift mutations of DPTP genes in MSI-H cancers occur at moderate frequencies. The data suggested that alterations in the CDC14A and MTMR3 genes may play a role in the development of GC and CRC with MSI-H by deregulating phosphatase functions possibly together with mutations of classical PTP genes."
1432,[Clinical study on tissue polypeptide antigen (TPA) as a tumor marker].,"Kanauchi M, Sawai F, Saito T, Yumura F, Kanauchi K, Hamaguchi T, Hara Y, Yoshimura K, Nishiura K, Dohi K.",https://pubmed.ncbi.nlm.nih.gov/6201629/,"We evaluated whether assay of tissue polypeptide antigen (TPA) in sera is valuable for the determination of cancer stages compared to other tumor markers such as CEA, AFP, beta2-microglobulin, ferritin, and elastase-1. The study population consisted of cancer patients (33 gastric cancers, 7 colo-rectal cancers and 15 hepatomas), 169 patients with benign gastro-enteric diseases and 72 healthy volunteers. The percentage of positive cases for TPA (higher than 200 u/l) was 61% in gastric cancer, 71% in colo-rectal cancer and 87% in hepatoma. In certain non-cancerous conditions, such as gastric ulcer (active stage), acute hepatitis and chronic hepatitis, the TPA levels were increased over the level of healthy volunteers. There was no significant correlation between TPA and the other tumor markers. Our study suggests that TPA may be useful in the identification and evaluation of cancer patients."
1433,Research Progress of Multiple Primary Malignancies Associated With Esophageal Cancer.,"Cui Y, Ren W, Du X, Yang L, Tan B.",https://pubmed.ncbi.nlm.nih.gov/37212379/,"With the improvement in survival of patients with tumors, and continuous advancement of diagnostic technology and treatment modalities, instances of multiple primary malignancies (MPMs) are becoming an increasingly common phenomenon. The occurrence of esophageal-relevant MPMs increases the difficulty of diagnosis and treatment, and the overall prognosis is poor. Esophageal cancer related-MPMs tend to occur in areas such as the head, neck, stomach, and lungs. ""Field cancerization"" is one theoretical basis for the disease, and chemoradiotherapy, environmental life factors, and gene polymorphism are etiological factors. However, the influence of new therapeutic  Additionally, there is a lack of unified standards for diagnosis and treatment. Therefore, this study aimed to review the causes, clinical features, and prognostic factors of MPMs related to esophageal cancer."
1434,"Enhanced expression of alpha 2,6-sialyltransferase ST6Gal I in cervical squamous cell carcinoma.","Wang PH, Lee WL, Lee YR, Juang CM, Chen YJ, Chao HT, Tsai YC, Yuan CC.",https://pubmed.ncbi.nlm.nih.gov/12798701/," In many tissues, ST6Gal I is transcriptionally regulated through the use of promoters that originate in the mRNA species that diverge in the 5'-untranslated regions. To clarify the roles of ST6Gal I mRNA species in cervical SCC, we investigated their expression, including a ""constitutive"" promoter (placental or Y + Z form), ""hepatic"" promoter (H form), and a specific lymphoblastic promoter (X form), in normal and SCC tissues of the cervix using real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR).
    


          
    


          004, Mann-Whitney U test; P < 0.001, paired t test). Expression of the Y + Z form did not appear to be affected by cancer transformation, since it was detected at comparable levels in normal and cancerous tissues (P = 0.986), but H form expression was significantly enhanced in cancerous tissues compared to that in normal tissues (P < 0.001, Mann-Whitney U test and paired t test). Surprisingly, the X form could be detected in some patients with and without cancer, but the detection rate was significantly higher in patients with cancer (86.8% vs 52.6%, respectively; P = 0.021, Fisher's exact test). Although the X transcript was detected at a low level compared to the H and Y + Z transcripts, its expression was also significantly enhanced in patients with cancers compared to those without cancers (P < 0.001, Mann-Whitney U test and paired t test).
    


          Conclusions:
        
      
      An increased level of hepatic transcripts may be important in cancer transformation because the transcripts contribute to enhance ST6Gal I expression in cancerous tissues."
1435,Matrix-assisted laser desorption/ionization mass spectrometry reveals decreased calcylcin expression in small cell lung cancer.,"Lee HS, Park JW, Chertov O, Colantonio S, Simpson JT, Fivash MJ, Yoo CW, Lee GK, Zo JI, Kim HT, Kim HK.",https://pubmed.ncbi.nlm.nih.gov/22192801/,"To date, most of the proteomic analyses on lung cancer tissue samples have been performed using surgical specimens, which are obtained after a diagnosis is made. To determine if a proteomic signature obtained from bronchoscopic biopsy samples could be found to assist with diagnosis, 50 lung cancer bronchoscopic biopsy samples and 13 adjacent normal lung tissue samples were analyzed using histology-directed, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). Lung tissue samples were cryosectioned, and sinapinic acid was robotically deposited on areas of each tissue section enriched in epithelial cells, either tumor or normal. Mass spectra were acquired using a MALDI-time of flight instrument. Small cell lung cancers (SCLCs) demonstrated clearly different protein profiles from normal lung tissue and from non-small cell lung cancers (NSCLCs). Calcyclin (m/z= 10,094.7) was identified to be underexpressed in small cell lung cancers, as compared with non-small cell lung cancers and normal lung tissue. An immunohistochemistry study using 152 NSCLCs and 21 SCLCs confirmed significantly reduced calcyclin stain in SCLCs. Thus, protein profiles obtained from bronchoscopic biopsy samples via MALDI MS distinguish cancerous epithelium from normal lung tissue and between NSCLCs and SCLCs."
1436,Changes in radiotherapy fractionation-breast cancer.,Yarnold J.,https://pubmed.ncbi.nlm.nih.gov/29345152/,"Conventional fractionation for half a century has been justified on the basis that 2.0 Gy fractions spare dose-limiting late-responding normal tissues to a greater degree than cancerous tissues. Early indications that breast cancer responds more strongly to fraction size than many other common cancers were followed several decades of investigation, but there is now reliable Level I evidence that this is the case. Four randomised trials testing fraction sizes in the range 2.7-3.3 Gy have reported 10-year follow up in almost 8000 patients, and they provide robust estimates of α/β in the range of 3 Gy. The implication is that there are no advantages in terms of safety or effectiveness of persisting with 2.0 Gy fractions in patients with breast cancer. 15- or 16-fraction schedules are replacing the conventional 25-fraction regimen as a standard of care for adjuvant therapy in an increasing number of countries. A number of concerns relating to the appropriateness of hypofractionation in patient subgroups, including those treated post-mastectomy, advanced local-regional disease and/or to lymphatic pathways are addressed. Meanwhile, hypofractionation can be exploited to modulate dose intensity across the breast according to relapse risk by varying fraction size across the treatment volume. The lower limits of hypofractionation are currently being explored, one approach testing a 5-fraction schedule of local-regional radiotherapy delivered in 1 week."
1437,Plasma DNA as a marker of cancerous cell death. Investigations in patients suffering from lung cancer and in nude mice bearing human tumours.,"Fournié GJ, Courtin JP, Laval F, Chalé JJ, Pourrat JP, Pujazon MC, Lauque D, Carles P.",https://pubmed.ncbi.nlm.nih.gov/7767913/,"Plasma DNA that circulates mainly as mononucleosomes is a cell death marker. Its significance and prognostic value in cancer as compared to other tumour markers was investigated in 68 patients hospitalised for lung cancers. Prognostic values of the various studied parameters were evaluated using the Cox's model. The cellular origin of plasma DNA was further investigated in nude mice transplanted with human lung adenocarcinoma. Plasma DNA concentrations were increased in cancer patients as compared to normal subjects (P < 0.01). They were higher in patients with extended (Stage 4) disease than in patients with limited stage disease (P < 0.05). Plasma DNA concentrations, serum lactate dehydrogenase activities and neuron-specific enolase concentrations were correlated all together in small cell lung carcinoma (SCLC) and in non-SCLC. Similar relationships were found between survival and each of these three cell death/tumour markers (P < 0.02-0.005). Plasma DNA from mice bearing human tumour hybridised with both mouse and human plasma DNA, while plasma DNA from endotoxin-injected mice hybridised only with mouse plasma DNA. In conclusion, in patients suffering from lung cancer, plasma DNA as well as LDH and NSE represent cell death markers that are correlated with survival. At a time when apoptosis pathways appear to be potential targets for cancer therapy, plasma DNA is a cell death/tumour marker that should be taken into account in studying the cancerous process in human diseases."
1438,Clinical Significance of Serum Interleukin-31 and Interleukin-33 Levels in Patients of Endometrial Cancer: A Case Control Study.,"Zeng X, Zhang Z, Gao QQ, Wang YY, Yu XZ, Zhou B, Xi MR.",https://pubmed.ncbi.nlm.nih.gov/27340318/,"Aims. Previous evidence has proved that interleukin-31 (IL-31) and interleukin-33 (IL-33) can be potential markers in some cancers' formulation. We aimed to determine the potential role of IL-31 and IL-33 in prognosis of endometrial cancer patients.  Serum samples were collected from 160 patients with endometrial cancer and 160 healthy controls. The ELISA kits (Raybio® Systems) specific for human IL-31 and human IL-33 were used. Serum levels of tumor markers (CEA, CA-125, and CA19-9) were measured by chemiluminescence immunoassay. A two-side P value < 0.05 was indicated to be significant.  Serum levels of IL-31 and IL-33 in patients were significantly elevated compared to those of healthy controls. The interleukin levels were also related to clinical characteristics, including tumor stages, depth of invasion, and existence of node metastases and distant metastases. The sensitivity and specificity of IL-31 and IL-33 were higher than the counterparts of tumor markers, both separately and in combination of IL-31, IL-33, and the clinical markers. Conclusions. This report is the first one mentioning the possible association between serum IL-31 and IL-33 and endometrial cancer. With their sensitivity and specificity, the interleukins may be useful biomarkers for endometrial cancer's prognosis."
1440,Label-free biosensor: a novel phage-modified Light Addressable Potentiometric Sensor system for cancer cell monitoring.,"Jia Y, Qin M, Zhang H, Niu W, Li X, Wang L, Li X, Bai Y, Cao Y, Feng X.",https://pubmed.ncbi.nlm.nih.gov/17329093/,"Early diagnosis has become the most important factor influencing the cancer's curing efficiency in clinical medicine. Here we present a new way for detection of cancer markers and cancer cells based on phage-modified Light Addressable Potentiometric Sensor (phage-LAPS). Phages were immobilized on the Si(3)N(4) chip surfaces covalently. Using the back-illuminating system, this phage-LAPS is tested to detect human phosphatase of regenerating liver-3 (hPRL-3) in the concentrations of 0.04-400 nM, and the mammary adenocarcinoma cell (MDAMB231) in the concentrations of 0-105 mL. The maximum responding signal is about 10 and 60 microV, respectively. The  This work might show potential application in clinic assays of cancer and the study of phage-cell interaction."
1441,Myxoma virus and oncolytic virotherapy: a new biologic weapon in the war against cancer.,"Stanford MM, McFadden G.",https://pubmed.ncbi.nlm.nih.gov/17727330/,"Oncolytic virotherapy is an innovative alternative to more conventional cancer therapies. The ability of some viruses to specifically target and kill malignant cancerous cells while leaving normal tissue unscathed has opened a large repertoire of new and selective cancer killing therapeutic candidates. Poxviruses, such as vaccinia virus, have a long history of use in humans as live vaccines and have more recently been studied as potential platforms for delivery of immunotherapeutics and attenuated variants of vaccinia have been explored as oncolytic candidates. In contrast, the poxvirus myxoma virus is a novel oncolytic candidate that has no history of use in humans directly, as it has a distinct and absolute host species tropism to lagomorphs (rabbits). Myxoma virus has been recently shown to be able to also selectively infect and kill human tumor cells, a unique tropism that is linked to dysregulated intracellular signalling pathways found in the majority of human cancers. This review outlines the existing knowledge on the tropism of myxoma virus for human cancer cells, as well as preclinical data exhibiting its ability to infect and clear tumors in animal models of cancer. This is an exciting new therapeutic option for treating cancer, and myxoma virus joins a growing group of oncolytic virus candidates that are being developed as a new class of cancer therapies in man."
1442,Targeting the Oxytocin Receptor for Breast Cancer Management: A Niche for Peptide Tracers.,"Kalaba P, Sanchez de la Rosa C, Möller A, Alewood PF, Muttenthaler M.",https://pubmed.ncbi.nlm.nih.gov/38235665/,"Breast cancer is a leading cause of death in women, and its management highly depends on early disease diagnosis and monitoring. This remains challenging due to breast cancer's heterogeneity and a scarcity of specific biomarkers that could predict responses to therapy and enable personalized treatment. This Perspective describes the diagnostic landscape for breast cancer management, molecular strategies targeting receptors overexpressed in tumors, the theranostic potential of the oxytocin receptor (OTR) as an emerging breast cancer target, and the development of OTR-specific optical and nuclear tracers to study, visualize, and treat tumors. A special focus is on the chemistry and pharmacology underpinning OTR tracer development, preclinical in vitro and in vivo studies, challenges, and future directions. The use of peptide-based tracers targeting upregulated receptors in cancer is a highly promising strategy complementing current diagnostics and therapies and providing new opportunities to improve cancer management and patient survival."
1443,"Distribution and secretory pathways of prostate specific antigen, alpha1-antichymotrypsin and prostate secretory granules in prostate cancers.","Ishida E, Nakamura M, Shimada K, Kishi M, Nakaoka S, Konishi N.",https://pubmed.ncbi.nlm.nih.gov/12828605/,"Using 19 radical prostatectomy specimens, we studied the histological distribution of free prostate specific antigen (PSA), total PSA, alpha1-antichymotrypsin (ACT) and prostate secretory granules (PSG) in both normal and cancerous cells of the prostate. After glutaraldehyde fixation, numerous fine eosinophilic droplets of PSG could be found mainly in the apical portions of normal acinous epithelial cells, but was markedly decreased in cancer cells. With antibodies against free PSA, normal acinous cells were granularly positive in the apical portion of the epithelium, which corresponded to the PSG, whereas cancer cells were diffusely positive. With antibodies against ACT, normal duct cells and cancer cells were often positive, but few normal acinous cells were positive. Presumably, these findings indicate that free PSA is secreted into the lumen as PSG in normal glands, but not by the same pathway in cancers where free PSA appears to accumulate due to a decrease of PSG, then leak into the blood producing complexed PSA to some extent in the cytoplasm. One factor analysis of variance (ANOVA) on the correlation of tumor differentiation or Gleason score with serum values of total PSA, free PSA and a free/total PSA ratio demonstrated no significant links. Elucidation of secretory mechanisms should provide better comprehension of various PSA indices for prostate cancer screening."
1444,Poly (ADP-ribose) polymerase inhibitors: on the horizon of tailored and personalized therapies for epithelial ovarian cancer.,"Ratner ES, Sartorelli AC, Lin ZP.",https://pubmed.ncbi.nlm.nih.gov/22759740/,"Purpose of review:
        
      
      Management of the epithelial ovarian cancer (EOC) remains a therapeutic challenge, with continued poor overall survival (OS). Given low chemotherapy response rates for recurrent disease and short survival times, new treatment options with improved therapeutic indices for targeting cancer's vulnerability are urgently needed in this patient population.
    


          Recent findings:
        
      
      In this review, we summarize the recent development and clinical evaluations of inhibitors of poly (ADP-ribose) polymerase (PARP) as novel targeting agents for EOC. PARP inhibitors exploit synthetic lethality to target DNA repair defects in hereditary breast and ovarian cancer.In recent clinical trials, EOC patients with BRCA mutations exhibited favorable responses to the PARP inhibitor olaparib compared with patients without BRCA mutations. Additionally, olaparib has been reported to augment the effects of cisplatin and carboplatin on recurrence-free survival and OS in mice bearing BRCA1/2-deficient tumors.Given that hereditary EOC with deleterious BRCA1/2 mutations and BRCAness sporadic EOC are profoundly susceptible to synthetic lethality with PARP inhibition, it is imperative to identify a population of EOC patients that is likely to respond to PARP inhibitors. Recent studies have identified the gene expression profiles of DNA repair defects and BRCAness that predict clinical outcomes and response to platinum-based chemotherapy in EOC patients.
    


          Summary:
        
      
      Ovarian cancer continues to carry the highest mortality among gynecologic cancers in the western world. Clinical development of PARP inhibitors that target DNA repair defects in cancer is a novel and imperative stride in individualized identification of molecular characteristics in management of ovarian cancer."
1445,Asbestos and ovarian cancer: examining the historical evidence.,"Slomovitz B, de Haydu C, Taub M, Coleman RL, Monk BJ.",https://pubmed.ncbi.nlm.nih.gov/33037108/,"Asbestos recently returned to the spotlight when Johnson & Johnson halted sales of baby powder due to lawsuits claiming that the talc in baby powder may have been contaminated with asbestos, which has been linked to the risk of ovarian cancer development. Although talc and asbestos have some structural similarities, only asbestos is considered causally associated with ovarian cancer by the WHO's International Agency for Research on Cancer. While it is useful to understand the types and properties of asbestos and its oncologic biology, the history of its association with ovarian cancer is largely based on retrospective observational studies in women working in high asbestos exposure environments. In reviewing the literature, it is critical to understand the distinction between associative risk and causality, and to examine the strength of association in the context of how the diagnosis of ovarian cancer is made and how the disease should be distinguished from a similar appearing but unrelated neoplasm, malignant mesothelioma. Based on contextual misinterpretation of these factors, it is imperative to question the International Agency for Research on Cancer's assertion that asbestos has a clear causal inference to ovarian cancer. This has important clinical implications in the way patients are conceivably counseled and provides motivation to continue research to improve the understanding of the association between asbestos and ovarian cancer."
1446,The association and prognostic relevance of cancerous inhibitor of protein phosphatase 2A and inflammation in tongue squamous cell carcinoma.,"Seppälä M, Tervo S, Pohjola K, Laranne J, Huhtala H, Toppila-Salmi S, Paavonen T.",https://pubmed.ncbi.nlm.nih.gov/26522733/,"Cancerous inhibitor of protein phosphatase 2A (CIP2A) prevents proteolytic degradation of a universal transcription factor, c-Myc. Strong CIP2A expression associates with poor prognosis in early-stage tongue cancer and in other cancers. The aim of this study was to evaluate CIP2A and mucosal inflammation in tongue hyperplasia, in tongue cancer, and in its metastasis. Retrospective tongue and lymph node specimens (n = 105) were stained immunohistochemically with polyclonal antibody anti-CIP2A. CIP2A staining intensity and inflammation were assessed semi-quantitatively with light microscopy. CIP2A was similarly detected in tongue cancer and tongue hyperplasia, whereas local inflammation was stronger in cancer (p = 0.000). CIP2A expression was increased in metastasized cancer compared to non-metastasized (p = 0.019). Markers for poorer survival were tumor size of ≥20 mm, presence of metastasis and nodal CIP2A (p = 0.031, p = 0.000, p = 0.042). Cancer patients aged ≥60 with increased inflammation predicted poor survival (p = 0.037). CIP2A and inflammation might play a role in progression of tongue cancer."
1447,Recent improvement in completeness of incidence data on acute myeloid leukemia in US cancer registries.,Polednak AP.,https://pubmed.ncbi.nlm.nih.gov/25153013/,"A limitation of data prior to 2010 on incidence of leukemia in US population-based cancer registries is that acute myeloid leukemia (AML) diagnosed as progression (transformation) from a previously diagnosed myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN, other than polycythemia vera), or chronic myeloid leukemia (CML) was not reportable. Data were used from a research database for the 18 cancer registries of the Surveillance, Epidemiology and End  Analyses compared the age-standardized incidence rate (ASIR) per 100,000 for AML before (ie, 2000-2009) vs after (ie, 2010) the new reportability rules for AML. The ASIR for all ages combined fluctuated until increasing from 3.60 (95 percent CI, 3.47-3.73; N = 3,068) in 2009 to 3.89 (95 percent CI, 3.76-4.03; N = 3,355) in 2010 in SEER, and from 3.64 (95 percent CI, 3.58-3.71; N = 11,488) in 2009 to 3.89 (95 percent CI, 3.82-3.96; N = 12,351) in 2010 in USCS. The increase from 2009 to 2010 was limited to ages 60+ years (from 13.87 to 15.59 in SEER and from 14.13 to 15.34 in USCS). The SEER research database allowed analysis by the number of cancers per person, which showed that the increase in AML cases and rates for age 60+ years from 2009 to 2010 was due to an increase in cases with a previous cancer(s) largely representing newly-reportable post-MDS, post-MPN and post-CML AML cases. Continued surveillance is needed to address the eventual impact of delayed reporting of diagnoses in 2010 on estimates and projections of AML incidence in the US population."
1448,[Simultaneous Laparoscopic Sigmoid Colectomy and Malignant Lymphoma Biopsy-A Case Report].,"Kobayashi N, Miyake M, Uemura M, Kato T, Kitakaze M, Kobayashi Y, Yamamoto K, Hamakawa T, Maeda S, Hama N, Nishikawa K, Miyamoto A, Hirao M, Takami K, Sekimoto M.",https://pubmed.ncbi.nlm.nih.gov/30914601/,"The patient, a woman in her 70s, was diagnosed with occlusive ileus caused by sigmoid colon cancer.She underwent transanal stent placement to release the occlusion.Subsequent detailed testing revealed a 70×60mm mass on the dorsal side of the pancreas and PET-CT indicated an SUVmax 18.2 FDG uptake. EUS-FNA was performed twice.However, the mass was unable to be definitively diagnosed.The patient was then referred to our hospital.She underwent laparoscopic sigmoid colectomy and laparoscopic biopsy of the mass for sigmoid colon cancer.The patient progressed well postoperatively and was discharged home on postoperative day 9.The postoperative diagnosis was colon cancer(S, Type 2, 58×50 mm, tub2, pT4a [SE], pN1, Stage Ⅲa)and the biopsied mass was found to be a nodal marginal zone B-cell lymphoma according to histopathological testing.After undergoing chemotherapy at our hematology department, she has experienced no recurrence."
1449,Promoter CpG methylation of tumor suppressor genes in colorectal cancer and its relationship to clinical features.,"Lin SY, Yeh KT, Chen WT, Chen HC, Chen ST, Chiou HY, Chang JG.",https://pubmed.ncbi.nlm.nih.gov/14719065/,"Aberrant promoter methylation of CpG islands of tumor suppressor genes inhibits expression of the genes and may lead to tumorigenesis. We investigated the aberrant methylation profile of potential tumor suppressor genes of p15, p16, SOCS-1, and Wnt signaling pathway in colorectal cancers and correlated the data with clinical findings. Cancerous and nearby non-cancerous tissues of 185 sporadic colorectal cancer samples were studied. Methylation specific PCR was performed to explore the mechanism of inactivation in p15, p16, SOCS-1, E-cadherin, APC, GSK-3beta, and Axin1 genes. Aberrant promoter methylation in p15, p16, SOCS-1, E-cadherin, APC, GSK-3beta, and Axin1 genes were 5.9, 7.0, 3.8, 5.9, 12.4, 2.2, and 0% for cancerous tissues, respectively, whereas the frequencies were 3.8, 0, 0, 7.0, 2.7, 0.5, and 0% for nearby non-cancerous tissues, respectively. The frequency of aberrant promoter methylation of cancerous tissues was significant higher than non-cancerous tissues in p16, SOCS-1, and APC genes (p<0.05) and methylation status of these genes had no clear relationship with clinical parameters. Of the 66 patients who showed at least one aberrant promoter methylation in the tumor-suppressor genes, 5 (7.6%) patients demonstrated multiple methylation phenotype (methylation > or =3) and associated with increased lymph node metastasis (p=0.036). Our findings suggest that inactivation of some tumor suppressor genes through aberrant promoter methylation of CpG islands may play a role in the development of colorectal cancer and methylation inactivation of these genes except p16 and SOCS1 may occur at the precancerous stage. Multiple methylation pathways may be involved in the tumorigenesis of colorectal cancer and associated with aggressiveness of clinical disease."
1450,Selenium Overcomes Doxorubicin Resistance in Their Nano-platforms Against Breast and Colon Cancers.,"Abd-Rabou AA, Ahmed HH, Shalby AB.",https://pubmed.ncbi.nlm.nih.gov/31066020/,"Colon cancer in men and breast cancer in women are regarded as major health burdens, accounting for majority of cancer diagnoses globally. Doxorubicin (DOX) resistance in breast and colon cancers represents the main reason of unsuccessful therapy. The rationale of this study is to explore whether selenium nanoparticles (nano-Se) can overcome this resistance obstacle of DOX nanoparticles (nano-DOX) in these cancerous cells. Nano-Se and nano-DOX were manufactured and characterized using electron microscopy and Malvern ZetaSizer, applied separately or in the form of combinatorial regimen against human breast cancer cells (MCF7 and MDA-MB-231) and human colorectal cancer cells (HCT 116 and Caco-2). Cytotoxicity, early/late apoptosis, necrosis, cellular zinc, glucose uptake, and redox status were assessed after applying different nano-treatments versus their free counterparts. Nano-DOX induces cytotoxicity in MCF7 and Caco-2 more than MDA-MB-231 and HCT 116 cancerous cells. In addition, nano-DOX plus nano-Se diminish MCF7 and Caco-2 chemoresistance higher than MDA-MB-231 and HCT 116 cancerous cells. Moreover, Se and DOX nano-platforms inhibit glucose uptake. Furthermore, nano-DOX increases nitric oxide (NO) and malondialdehyde (MDA) in cancer cells' media, while nano-DOX combination with nano-Se rebalances the redox status with zinc augmentation. We reported that Caco-2 cancer cells are more sensitive than HCT 116 cancer cells to nano-DOX and nano-Se. Nano-DOX plus nano-Se induces cytotoxicity-mediated late apoptosis in Caco-2 more than HCT 116 cell lines. This de novo strategy could have great power to overcome the problem of DOX resistance during colon cancer therapy."
1451,Environmental chemicals and breast cancer: An updated review of epidemiological literature informed by biological mechanisms.,"Rodgers KM, Udesky JO, Rudel RA, Brody JG.",https://pubmed.ncbi.nlm.nih.gov/28987728/," Breast cancer's long latency and multifactorial etiology make evaluation of these chemicals in humans challenging.
    


           We assessed whether study designs captured relevant exposures and disease features suggested by toxicological and biological evidence of genotoxicity, endocrine disruption, tumor promotion, or disruption of mammary gland development.
    


           We critically reviewed the articles.
    


           Consistent with 14 to 5.0), and for occupational exposure to solvents and other mammary carcinogens, such as gasoline components (risk estimates ranged from 1.42 to 3.31). Notably, one 50-year cohort study captured exposure to DDT during several critical windows for breast development (in utero, adolescence, pregnancy) and when this chemical was still in use. Most other studies did not assess exposure during a biologically relevant window or specify the timing of exposure. Few studies considered genetic variation, but the Long Island Breast Cancer Study Project reported higher breast cancer risk for polycyclic aromatic hydrocarbons (PAHs) in women with certain genetic variations, especially in DNA repair genes.
    


          Conclusions:
        
      
      New studies that targeted toxicologically relevant chemicals and captured biological hypotheses about genetic variants or windows of breast susceptibility added to evidence of links between environmental chemicals and breast cancer. However, many biologically relevant chemicals, including current-use consumer product chemicals, have not been adequately studied in humans. Studies are challenged to reconstruct exposures that occurred decades before diagnosis or access biological samples stored that long. Other problems include measuring rapidly metabolized chemicals and evaluating exposure to mixtures."
1452,[Indications and surgical technique of Appleby's operation for tumor invasion of the celiac trunk and its branches].,"Bonnet S, Kohneh-Shahri N, Goere D, Deshayes I, Ayadi S, Elias D.",https://pubmed.ncbi.nlm.nih.gov/19446687/,"Cancerous invasion of the celiac trunk is usually considered a contraindication to attempts at curative resection. Appleby was the first to propose an en bloc resection of the celiac trunk along with the celiac nervous plexus and lymph nodes for advanced gastric cancer. We describe a ""modified Appleby technique"" without gastrectomy for locally advanced cancer of the body of the pancreas. It accomplishes radical tumor resection, relieves pain, and improves the quality of life and overall prognosis. The principal complications are pancreatic fistula and gastric ischemia. Preoperative embolization of the common hepatic artery helps to develop favorable collateral blood flow and to avoid ischemia of the hepatobiliary system. A stomach-preserving"" Appleby resection"" may be appropriate treatment for selected nonaggressive cancers of the midpancreas; preoperative embolization of the common hepatic artery is an important adjunct of this technique."
1453,Association of expression of blood group-related carbohydrate antigens with prognosis in breast cancer.,"Narita T, Funahashi H, Satoh Y, Watanabe T, Sakamoto J, Takagi H.",https://pubmed.ncbi.nlm.nih.gov/8490832/,"
    


          
    


           No correlation was detected between the antigen expression and clinicopathologic factors. The prognosis of patients in whom type 2 carbohydrate antigens were increased in the cancerous portion, especially Lex (19.7% of patients) and sialyl Lex-i (20.3% of patients), was poorer than in patients in whom they were not increased (P < 0.01).
    


          Conclusions:
        
      
      The relative expression of type 2 carbohydrate antigens in breast cancer tissue seems capable of serving as a prognostic factor."
1454,[Cancer chemotherapy of unresectable primary gastric cancer].,"Kurihara M, Taguchi S.",https://pubmed.ncbi.nlm.nih.gov/2946880/,"The criteria for cancer chemotherapy of gastric cancers proposed by the Japanese Research Society for Gastric Cancer is introduced with several effective cases. Three subtypes of judgment  Measurable lesions in a case such as aPR should be recorded in metric notation, using a ruler or calipers on X-ray films. bPR is a case when chemotherapy of primary foci is markedly effective with a flattening of the randwall or polypoid part and a shrinkage of cancerous ulceration, but the size of a primary lesion is not decreased. cPR is a case when an expansion of affected site by more than 100% is proved by gastric radiogram or endoscopic image on primary focus in Borrman type 4, a synonym of gastric scirrhous clinically."
1455,Down-regulation of transcription elogation factor A (SII) like 4 (TCEAL4) in anaplastic thyroid cancer.,"Akaishi J, Onda M, Okamoto J, Miyamoto S, Nagahama M, Ito K, Yoshida A, Shimizu K.",https://pubmed.ncbi.nlm.nih.gov/17076909/," However, the carcinogenic mechanism of anaplastic transformation remains unclear. Previously, we investigated specific genes related to ATC based on gene expression profiling using cDNA microarray analysis. One of these genes, transcription elongation factor A (SII)-like 4 (TCEAL4), encodes a member of the transcription elongation factor A (SII)-like gene family. The detailed function of TCEAL4 has not been described nor has any association between this gene and human cancers been reported previously.
    


          
    


           TCEAL4 was expressed ubiquitously in all normal human tissues tested.
    


          Conclusion:
        
      
      To our knowledge, this is the first report of altered TCEAL4 expression in human cancers. We suggest that loss of TCEAL4 expression might be associated with development of ATC from DTC. Further functional studies are required."
1456,Circulating non-coding RNAs as a diagnostic and management biomarker for breast cancer: current insights.,"Hosseinalizadeh H, Mahmoodpour M, Ebrahimi A.",https://pubmed.ncbi.nlm.nih.gov/34677714/,"Cancer biomarkers can be used to determine the molecular status of a tumor or its metastases, which either release them directly into body fluids or indirectly through disruption of tumor/metastatic tissue. New minimally invasive and repeatable sample collection  Circulating non-coding RNAs, which include microRNAs, long non-coding RNAs, and PIWI-interacting RNAs, are increasingly being recognized as potential cancer biomarkers. The growing understanding of cancer's molecular pathogenesis, combined with the rapid development of new molecular techniques, encourages the study of early molecular alterations associated with cancer development in body fluids. Specific genetic and epigenetic changes in circulating free RNA (cf-RNA) in plasma, serum, and urine could be used as diagnostic biomarkers for a variety of cancers. Only a subset of these cf-RNAs have been studied in breast cancer, with the most extensive research focusing on cf-miRNA in plasma. These findings pave the way for immediate use of selected cf-RNAs as biomarkers in breast cancer liquid biopsy, as well as additional research into other cf-RNAs to advance."
1457,Outpatient surgical treatment with CO2 laser in oral cancer: immediate and long-term results.,"Tradati N, Zurrida S, Bartoli C, Boracchi P, Sala L, Contardi N, Rossi N, Chiesa F.",https://pubmed.ncbi.nlm.nih.gov/1862553/,"The immediate and long-term  From January 1982 to December 1989, 39 cases of T1 and 12 cases of small (less than 2.5 cm) non-infiltrating recurrences of squamous cell carcinoma were treated at the Istituto Nazionale Tumori in Milan. Complete removal was obtained in 44 instances, while in 7 cases cancerous margins were observed on the specimen; 5 of these underwent another wider treatment and 2 refused further therapy. Two of 39 T1 patients developed local relapses and 6/12 recurrent cancers relapsed again. Long term  Out-patient laser therapy is well accepted by patients and its use involves lowered direct and indirect health organisation and social costs."
1458,"Comparison of essential and toxic elements in esophagus, lung, mouth and urinary bladder male cancer patients with related to controls.","Kazi TG, Wadhwa SK, Afridi HI, Talpur FN, Tuzen M, Baig JA.",https://pubmed.ncbi.nlm.nih.gov/25548013/,"There is a compelling evidence in support of negative associations between essential trace and toxic elements in different types of cancer. The aim of the present study was to investigate the relationship between carcinogenic (As, Cd, Ni) and anti-carcinogenic (Se, Zn) trace elements in scalp hair samples of different male cancerous patients (esophagus, lung, mouth, and urinary bladder). For comparative purposes, the scalp hair samples of healthy males of the same age group (ranged 35-65 years) as controls were analyzed. Both controls and patients have the same socioeconomic status, localities, dietary habits, and smoking locally made cigarette. The scalp hair samples were oxidized by 65% nitric acid: 30% hydrogen peroxide (2:1) ratio in microwave oven followed by atomic absorption spectrometry. The validity and accuracy of the  The mean concentrations of As, Cd, and Ni were found to be significantly higher in scalp hair samples of patients having different cancers as compared to the controls, while reverse 01). The study revealed that the carcinogenic processes are significantly affecting the trace elements burden and mutual interaction of essential trace and toxic elements in the cancerous patients."
1459,Molecular characterization of the peripheral airway field of cancerization in lung adenocarcinoma.,"Tsay JC, Li Z, Yie TA, Wu F, Segal L, Greenberg AK, Leibert E, Weiden MD, Pass H, Munger J, Statnikov A, Tchou-Wong KM, Rom WN.",https://pubmed.ncbi.nlm.nih.gov/25705890/,"Field of cancerization in the airway epithelium has been increasingly examined to understand early pathogenesis of non-small cell lung cancer. However, the extent of field of cancerization throughout the lung airways is unclear. Here we sought to determine the differential gene and microRNA expressions associated with field of cancerization in the peripheral airway epithelial cells of patients with lung adenocarcinoma. We obtained peripheral airway brushings from smoker controls (n=13) and from the lung contralateral to the tumor in cancer patients (n=17). We performed gene and microRNA expression profiling on these peripheral airway epithelial cells using Affymetrix GeneChip and TaqMan Array. Integrated gene and microRNA analysis was performed to identify significant molecular pathways. We identified 26 mRNAs and 5 miRNAs that were significantly (FDR <0.1) up-regulated and 38 mRNAs and 12 miRNAs that were significantly down-regulated in the cancer patients when compared to smoker controls. Functional analysis identified differential transcriptomic expressions related to tumorigenesis. Integration of miRNA-mRNA data into interaction network analysis showed modulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in the contralateral lung field of cancerization. In conclusion, patients with lung adenocarcinoma have tumor related molecules and pathways in histologically normal appearing peripheral airway epithelial cells, a substantial distance from the tumor itself. This finding can potentially provide new biomarkers for early detection of lung cancer and novel therapeutic targets."
1460,The Importance of Cancer-Associated Fibroblasts in the Pathogenesis of Head and Neck Cancers.,"Raudenská M, Svobodová M, Gumulec J, Falk M, Masařík M.",https://pubmed.ncbi.nlm.nih.gov/32075388/," Recent studies have shown that tumour stroma may play an important role in the pathogenesis of this malignant disease. Fibroblasts are a major component of the tumour microenvironment and may significantly influence HNSCC progression as indicated by the contribution they make to important hallmarks of cancer, such as inflammation, non-restricted growth, angiogenesis, invasion, metastasis, and therapy resistance. It is well known that tumour cells can confer a cancer-associated fibroblast (CAF) phenotype that supports the growth and dissemination of cancer cells. CAFs can stimulate cancer progression through cell-cell contacts and communication, remodelling of extracellular matrix, and production of many signal molecules and matrix metalloproteinases. Consequently, genetic changes in epithelial cells are probably not the only factor that drives HNSCC carcinogenesis. Non-genetic changes in the tumour stroma can also be significantly involved. Stress-induced signals can induce a multicellular program, creating a field of tissue that is predisposed to malignant transformation. The &#8220;field cancerization&#8221; concept represents a process of active evolution of intercellular interactions and feedback loops between tumour and stromal cells. This model paves the way to study cancer from a new perspective and identify new therapeutic targets.
    


          Purpose:
        
      
      In this review, we discuss current knowledge about CAFs, such as their cellular origin, phenotypical plasticity and functional heterogeneity, and stress their contribution to HNSCC progression. This article was supported by the project AZV 16-29835A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 18. 6. 2019 Accepted: 9. 9. 2019."
1461,Relationships between UMPK and PGD activities and deletions of chromosome 1p in colorectal cancers.,"Bravard A, Luccioni C, Muleris M, Lefrancois D, Dutrillaux B.",https://pubmed.ncbi.nlm.nih.gov/1660788/,"A deletion involving a large segment of the short arm of chromosome 1(1p-) occurs in about 50% of colorectal cancers. It was previously noticed that, in these tumors, many deletions affect genes encoding for enzymes of the de novo pathway of nucleotide synthesis. The gene for uridine monophosphate kinase (UMPK), mapped on 1p32, is generally involved in del(1p). The activity of the corresponding enzyme was measured and compared to that of 6-phosphogluconate dehydrogenase (PGD), encoded by a gene also mapped on chromosome 1p and frequently deleted, but involved in another metabolism. It was found that a clear relationship exists between activity and the number of chromosome 1p for PGD but not for UMPK, both on primary tumors (PTs) and on tumors grafted into nude mice (GTs). By comparison to corresponding normal mucosae, the activity of PGD was high in PTs and GTs, but this increase was reduced in case of del(1p). The activity of UMPK being increased in PTs but not in GTs, it is assumed that the increase in PTs is due to non-cancerous cells, which are missing in GTs. The fact that no gene dosage effect exists, although the tendency for del(1p) coexists with the relative decrease of UMPK activity in cancerous by comparison to non-cancerous cells, suggests that either mutation or disregulation of UMPK gene occurred early."
1462,Immunohistochemical galectin-3 expression in non-melanoma skin cancers.,"Kapucuoglu N, Basak PY, Bircan S, Sert S, Akkaya VB.",https://pubmed.ncbi.nlm.nih.gov/18951731/,"Galectin-3 is a ss-galactoside-binding lectin. It participates in a variety of normal and pathologic processes, including cancer progression. In this study, we evaluated the pattern of expression of galectin-3 in cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and its correlation with the grade of differentiation in SCC and tumor size. Galectin-3 expression was evaluated by immunohistochemistry in 31 SCCs, 30 BCCs, and 29 non-tumoral skin samples. Galectin-3 expression was higher in normal epidermis than in non-melanoma skin cancers, except for cytoplasmic immunoreactivity in SCC. Cytoplasmic galectin-3 immunoreactivity was significantly higher than nuclear immunoreactivity in non-melanoma skin cancers. Cytoplasmic galectin-3 immunoreactivity was significantly higher in SCC than in both circumscribed and infiltrative BCCs, but no difference was detected between these two types of BCC. Cytoplasmic galectin-3 immunoreactivity predominated within SCCs (p=0.000), and a positive correlation was detected between tumor size and cytoplasmic immunoreactivity (r=0.385, p=0.043). There was no correlation between galectin-3 staining and tumor differentiation and lymph node metastasis. Decreased nuclear galectin-3 expression and cytoplasmic immunoreactivity in tumors are important factors in the progression from the normal to the cancerous state in non-melanoma skin cancers. We speculate that cytoplasmic galectin-3 expression may be one of the factors that contribute to tumor aggressiveness in SCC."
1463,"Relationship between PRRX1, circulating tumor cells, and clinicopathological parameter in patients with gastric cancer.","Zhang Y, Yao J, Feng J, Wang S, Yang Z, Huang W, Da M.",https://pubmed.ncbi.nlm.nih.gov/32862590/,"Purpose:
        
      
      Paired related homoeobox 1 (PRRX1) has been identified as a new epithelial-mesenchymal transition (EMT) inducer in gastric cancer and that PRRX1 upregulation is closely correlated with gastric cancer metastasis. In addition, circulating tumor cells (CTCs) play an important role in the process of gastric cancer's distant metastasis. Our study aimed to correlate Prrx1, CTCs and the clinicopathological parameters in primary gastric cancer patients.
    


           Then the integrated subtraction enrichment and immunostaining fluorescence in situ hybridization (SET-imFISH) platform were applied to detect and characterize CTCs in patients with gastric cancer. Finally, their correlations with clinicopathological parameters could be analyzed.
    


          84% and the rate was 36.84% in adjacent normal gastric mucosa, which was confirmed to be statistically significant. In the meantime, both the expression of PRRX1 and the positive rate of CTCs did not significantly correlate with age, gender or histologic type (p>0.05) but significantly related to tumor size, grade of differentiation, lymph node invasion, vascular invasion, metastasis status, depth of tumor invasion, lymph node metastasis and TNM stage (p<0.05). Besides, there was a close relationship between the PRRX1 of gastric cancer and the CTCs of peripheral blood specimens of cancer patients with the correlation coefficient 0.322.
    


          Conclusion:
        
      
      Gastric cancer tissues showed that the level of PRRX1 expression was higher compared to the adjacent normal gastric mucosa. Both the expression of PRRX1 and the positive rate of CTCs significantly correlated with clinicopathological parameters. In addition, there was a positive correlation relationship between the PRRX1 of gastric cancer and the CTCs of peripheral blood specimens of cancer patients. These findings demonstrate that higher-level expression of PRRX1 in gastric cancer tissues increased the amount of CTCs in peripheral blood and facilitated the invasion and metastasis in patients with gastric cancer. Meanwhile, it gave some clues to clinical treatment. CTCs may contribute to promotion in diagnosis, therapy monitoring and prognosis of gastric cancer."
1464,Immunotherapy for Gynecologic Cancer: Current Applications and Future Directions.,"Lynam S, Lugade AA, Odunsi K.",https://pubmed.ncbi.nlm.nih.gov/31833846/,"The role of the immune system in the development of cancer has been a subject of ongoing clinical investigation in recent years. Emerging data demonstrate that tumorigenesis  Leveraging the immune system through the use of immune checkpoint inhibitors, therapeutic vaccine therapy, and adoptive cell transfer presents a profound opportunity to revolutionize cancer treatment. This review will encompass the role of the immune system in development of gynecologic cancers and highlight recent data regarding immunotherapy applications in ovarian, uterine, and cervical cancers."
1465,Heterogeneous nuclear ribonucleoprotein B1 expressed in esophageal squamous cell carcinomas as a new biomarker for diagnosis.,"Matsuyama S, Goto Y, Sueoka N, Ohkura Y, Tanaka Y, Nakachi K, Sueoka E.",https://pubmed.ncbi.nlm.nih.gov/10874220/,"We recently reported that heterogeneous nuclear ribonucleoprotein (hnRNP) B1 was overexpressed in most human lung cancers, especially squamous cell carcinoma (SCC), as well as human oral SCC. To find the significance of hnRNP B1 in cancer diagnosis, we studied hnRNP B1 expression in 16 paraffinized sections of esophageal SCC, using immunohistochemical staining with anti-hnRNP B1 polyclonal antibody, raised in a rabbit. We compared the expression of hnRNP B1 in cancerous and noncancerous regions of the same specimen: enhanced expression was observed in 63% of cancerous regions (10 / 16), whereas none of the noncancerous regions showed enhanced expression. The enhanced expression of hnRNP B1 in cancerous regions was compared with that in noncancerous tissue in relation to histopathological grade: 83% for well differentiated (5 / 6), 83% for moderately differentiated (5 / 6) and 0% for poorly differentiated (0 / 4). Histologically, enhanced expression of hnRNP B1 was observed around cancer pearls, as well as in the cells of nests lacking keratinization in well and moderately differentiated SCC. Western blotting analysis revealed enhanced expression in three frozen specimens of moderately differentiated SCC. Using esophageal cancer cell lines, we further confirmed the decreased expression in poorly differentiated SCC cells, compared with other differentiation types. All our "
1466,Topoisomerase-I PS506 as a Dual Function Cancer Biomarker.,"Zhao M, Gjerset RA.",https://pubmed.ncbi.nlm.nih.gov/26248194/,"Novel biomarkers for cancer diagnosis and therapy selection are urgently needed to facilitate early detection and improve therapy outcomes. We have previously identified a novel phosphorylation site at serine 506 (PS506) on topoisomerase-I (topo-I) and have shown that it is widely expressed in cell lines derived from several cancers, including lung cancer, but is low in cell lines derived from non-cancerous tissues. Here we have investigated how PS506 expression in lung tissue specimens correlates with their malignant status. We find that PS506 expression is significantly elevated in malignant tumors of non-small cell lung cancer (NSCLC) compared to adjacent, non-cancerous lung tissue and benign lung tumors. PS506 expression was up to 6-fold higher in malignant specimens than in paired non-malignant tissue. Using the well-characterized NIH/NCI 60-cell line panel, we correlate the most elevated expression levels of PS506 in lung, ovarian, and colon cancer cells lines with increased sensitivity to camptothecin, a plant alkaloid that targets topo-I. This is consistent with our earlier studies in a smaller sampling of cell lines and with our finding that PS506 increases topo-I DNA binding. Two widely used chemotherapeutic drugs for ovarian and colon cancer, topotecan and irinotecan, respectively, are derived from camptothecin. Irinotecan has also displayed efficacy in clinical trials of NSCLC. Our  PS506 may therefore serve as a biomarker for diagnosis or therapy selection."
1467,Definitive proton beam radiation therapy for inoperable gastric cancer: a report of two cases.,"Shibuya S, Takase Y, Aoyagi H, Orii K, Sharma N, Tsujii H, Tsuji H, Iwasaki Y.",https://pubmed.ncbi.nlm.nih.gov/1649484/,"Proton beam radiation therapy using 250 MeV protons was carried out on two patients with early gastric cancer (T1, N0, M0). One patient was an 85-year-old man with early gastric cancer of type IIa + IIc. The other one was a 70 year old man with early gastric cancer of type IIc. In both cases histological examination of biopsy specimens showed differentiated adenocarcinoma; distant metastasis was not found by other examinations. Both patients were considered inoperable due to their poor cardiac and/or respiratory functions. Therefore, it was decided to treat them by definitive proton irradiation, delivering total doses of 86 Gy and 83 Gy, respectively. In both patients, skin erythema that did not require any special treatment was found in the irradiation field. Hematobiological examinations did not show any abnormality. Although endoscopic examination at two years after irradiation in the former case and at seven months in the latter case showed persistent gastric ulcer at the site of the cancerous lesions, cancer cells were not found histologically. Therefore, we concluded that proton irradiation therapy was useful for inoperable early gastric cancers."
1468,[Cancer of the mesopharynx].,"Sato T, Miyahara H.",https://pubmed.ncbi.nlm.nih.gov/3783940/,"The incidence of cancer of mesopharynx is not so high in Japan. Age-standardized incidence rates per 100,000 population of this tumor is 0.2 (0.4 in male, 0.1 in female) in Japan. The mesopharyngeal tumors contain three types: squamous cell carcinoma from squamous epithelium, malignant lymphoma from Waldeyer's tonsillar ring and adenocarcinoma from minor salivary glands. The squamous cell carcinoma is most frequent in patients between the ages of 50 and 70 years, males being affected 5-10 times as frequently as females. Epidermiologically, cancerization of mesopharynx is dependent on heavy smoking and drinking. Because of the high incidence of regional neck node metastases at initial examination, combined therapy with radiotherapy, adjuvant chemotherapy, composite operation and reconstructive surgery must be done in co-operation with surgeon and radiation therapist, working as a team. Survival rates of this tumor are 30-40%."
1469,Magnifying pharmacoendoscopy: response of microvessels to epinephrine stimulation in differentiated early gastric cancers.,"Fukui H, Shirakawa K, Nakamura T, Suzuki K, Masuyama H, Fujimori T, Hiraishi H, Terano A.",https://pubmed.ncbi.nlm.nih.gov/16813801/,"
    


          
    


          Design:
        
      
      This was a prospective pilot study.
    


          Setting:
        
      
      This study was conducted at an academic hospital.
    


          Patients:
        
      
      Twenty-nine patients with differentiated early gastric cancer were enrolled.
    


          Interventions:
        
      
      Microvessels in both the cancerous lesion and its adjacent non-neoplastic gastric mucosa were observed by magnifying endoscopy before and after focal spray with epinephrine solution (0.05 mg/mL).
    


          Main outcome measurements and  On the other hand, all the cancerous lesions examined clearly showed enhancement of tumor microvessels. The rate of detection of tumor microvessels by magnifying pharmacoendoscopy (100%) was significantly higher than that by magnifying endoscopy alone (41.3%).
    


          Limitations:
        
      
      This was small pilot study.
    


          Conclusions:
        
      
      Magnifying pharmacoendoscopy with epinephrine is a powerful tool for assessing tumor vascularity and may contribute to the histologic diagnosis of differentiated early gastric cancers before endoscopic treatment."
1470,[Age's influence in superficial bladder cancer's behaviour].,"Moyano Calvo JL, Gutiérrez González M, Pérez-Lanzac Llorca A, Molina Carranza A, Alvarez-Ossorio Fernández JL, Sánchez Sánchez E, Castiñeiras Fernández J.",https://pubmed.ncbi.nlm.nih.gov/15786768/," The tumor's aggressiveness in this population is subject of discussion. We present our experience.
    


          Material &  Group A (less than 41 years old), Group B (bigger than 40 years old). We compare, stage, grade, lymphatic permeation, multiplicity, recurrence, progression, sex, T.L.E. (time free of disease), volume. We do uni and multivariate analysis.
    


          1%). The recurrence rate is 11.8% in Group A and 36% in Group B (p .041). Progression rate: 0% in A and 4.1% in B (p .253). In Group A, T1 tumors (13.3% vs. 39%), G2 tumors (0% vs. 36.7%); withouts in lymphatic permeation (0% vs. 35%) and solitary tumors (13.3% vs. 35.3%) have statistically less recurrence. In univariate analysis we appreciate statistical differences in relation with grade (p .002) and sex (p .011). In multivariate analysis, stage, ""group of age"" and prophylactic treatment are independent variables for recurrence, and grade for progression.
    


          Conclusions:
        
      
      In younger than 41 years old: Less pathologic aggressivity (0% G3); Group of age is independent prognostic variable for recurrence, but not p for progression, despite a ""less aggressive behaviour"": 11.8% recurrence, 0% progression; T.L.E. bigger (one year more); Higher incidence in women (41% vs. 11%); Less recurrence in T1 tumors (13.3% vs. 39%), G2 tumors (0% vs. 36.7%) and solitary tumors (13.3% vs. 35.32%)."
1471,Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human cancer.,"Bielanska J, Hernández-Losa J, Pérez-Verdaguer M, Moline T, Somoza R, Ramón Y Cajal S, Condom E, Ferreres JC, Felipe A.",https://pubmed.ncbi.nlm.nih.gov/20025600/,"Membrane ion channels participate in cancerous processes such as proliferation, migration and invasion, which contribute to metastasis. Increasing evidence indicates that voltage-dependent K(+) (Kv) channels are involved in the proliferation of many types of cells, including tumor cells. Kv channels have generated immense interest as a promising tool for developing new anti-tumor therapies. Therefore, the identification of potential biomarkers and therapeutic targets in specific cancers is an important prerequisite for the treatment. Since Kv1.3 and Kv1.5 are involved in the proliferation of many mammalian cells, we aimed to study the expression of Kv1.3 and Kv1.5 in a plethora of human cancers. Thus, tissues from breast, stomach, kidney, bladder, lung, skin, colon, ovary, pancreas, brain, lymph node, skeletal muscle and some of their malignant counterparts have been analyzed. Whereas Kv1.3 expression was either decreased or did not change in most tumors, Kv1.5 was overexpressed. However, the presence of Kv1.3 was mostly associated with inflammatory lymphoplasmocytic cells. Independent of the suitability of individual channels as therapeutic targets, the identification of a Kv phenotype from tumor specimens could have a diagnostic value of its own. Our 5, and to some extent Kv1.3, are aberrantly expressed in a number of human cancers. These channels could serve both as novel markers of the metastatic phenotype and as potential new therapeutic targets. The concept of Kv channels as therapeutic targets or prognostic biomarkers attracts increasing interest and warrants further investigation."
1472,The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth.,"de Visser KE, Joyce JA.",https://pubmed.ncbi.nlm.nih.gov/36917948/,"Cancers represent complex ecosystems comprising tumor cells and a multitude of non-cancerous cells, embedded in an altered extracellular matrix. The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in the pathogenesis of cancer. The cellular composition and functional state of the TME can differ extensively depending on the organ in which the tumor arises, the intrinsic features of cancer cells, the tumor stage, and patient characteristics. Here, we review the importance of the TME in each stage of cancer progression, from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Understanding the complex interplay between tumor cell-intrinsic, cell-extrinsic, and systemic mediators of disease progression is critical for the rational development of effective anti-cancer treatments."
1473,Attitudes and Perceptions of Parenthood Among Young Adult Survivors of Childhood Cancer.,"Himelhoch AC, Datillo TM, Tuinman MA, Gerhardt CA, Lehmann V.",https://pubmed.ncbi.nlm.nih.gov/33999693/,"Purpose: Increasing numbers of childhood cancer survivors enter adulthood and encounter decisions surrounding parenthood. However, limited research has systematically examined how childhood cancer may influence parenthood attitudes among survivors. 2 years, range: 22-43; 91% White), rated their perceived impact of cancer at enrollment and parenthood attitudes using the ""Attitudes to Parenthood After Cancer Scale"" 2 years later. First, internal consistencies for the parenthood measure were examined, and modified subscales were proposed. Second, hierarchical stepwise regressions analyzed the contribution of  78): improved parenting due to cancer, no children due to cancer, concerns about a (potential) child's health, and parenthood desire irrespective of own health concerns. Already having children (n = 38) was related to more favorable ratings on most subscales. Older age was associated with perceiving improved parenting due to cancer (r = .24) and shorter time since diagnosis was related to considering having no children due to cancer (r = -.23). Hierarchical stepwise regressions reconfirmed parenthood status as related to more favorable parenting attitudes. Cancer preoccupation and perceiving cancer as a most difficult life experience predicted more concerns toward parenthood (R2 = .044-.216). Conclusions: Parenthood attitudes were more favorable among survivors with children, who were older, and/or further into survivorship. Survivors burdened by their cancer experience reported more concerns about parenthood. Childhood cancer may shape parenthood perceptions positively and negatively, warranting further research to inform interventions."
1474,Molecular mechanisms of silibinin-mediated cancer chemoprevention with major emphasis on prostate cancer.,"Ting H, Deep G, Agarwal R.",https://pubmed.ncbi.nlm.nih.gov/23588585/,"Despite advances in early detection, prostate cancer remains the second highest cancer mortality in American men, and even successful interventions are associated with enormous health care costs as well as prolonged deleterious effects on quality of patient life. Prostate cancer chemoprevention is one potential avenue to alleviate these burdens. It is a regime whereby long-term treatments are intended to prevent or arrest cancer development, in contrast to more direct intervention upon disease diagnosis. Based on this intention, cancer chemoprevention generally focuses on the use of nontoxic chemical agents which are well-tolerated for prolonged usage that is necessary to address prostate cancer's multistage and lengthy period of progression. One such nontoxic natural agent is the flavonoid silibinin, derived from the milk thistle plant (Silybum marianum), which has ancient medicinal usage and potent antioxidant activity. Based on these properties, silibinin has been investigated in a host of cancer models where it exhibits broad-spectrum efficacy against cancer progression both in vitro and in vivo without noticeable toxicity. Specifically in prostate cancer models, silibinin has shown the ability to modulate cell signaling, proliferation, apoptosis, epithelial to mesenchymal transition, invasion, metastasis, and angiogenesis, which taken together provides strong support for silibinin as a candidate prostate cancer chemopreventive agent."
1475,MDM2- an indispensable player in tumorigenesis.,"Zafar A, Khan MJ, Naeem A.",https://pubmed.ncbi.nlm.nih.gov/37314603/,"Murine double minute 2 (MDM2) is a well-recognized molecule for its oncogenic potential. Since its identification, various cancer-promoting roles of MDM2 such as growth stimulation, sustained angiogenesis, metabolic reprogramming, apoptosis evasion, metastasis, and immunosuppression have been established. Alterations in the expression levels of MDM2 occur in multiple types of cancers  The cellular processes are modulated by MDM2 through transcription, post-translational modifications, protein degradation, binding to cofactors, and subcellular localization. In this review, we discuss the precise role of deregulated MDM2 levels in modulating cellular functions to promote cancer growth. Moreover, we also briefly discuss the role of MDM2 in inducing resistance against anti-cancerous therapies thus limiting the benefits of cancerous treatment."
1476,Role of tissue trace elements in liver cancers and non-cancerous liver parenchyma.,"Maeda T, Shimada M, Harimoto N, Tsujita E, Maehara S, Rikimaru T, Tanaka S, Shirabe K, Maehara Y.",https://pubmed.ncbi.nlm.nih.gov/15783026/," The aim of this study is to analyze the characteristics of trace elements in liver cancers and non-cancerous liver and to discuss their role in hepatic fibrosis, hepatocarcinogenesis and progression of HCC.
    


          
    


           The amounts of Zn and Cu were higher in HCC than the amounts found in CCC and Meta. The amount of Zn in HCC tissue decreased, but the amount of Fe increased in tumors more than 4cm in diameter.
    


          Conclusions:
        
      
      These  Also that decreases in Zn and increases of Fe in HCC tissue correlates with HCC tumor progression."
1477,MicroRNAs and target molecules in bladder cancer.,"Parizi PK, Yarahmadi F, Tabar HM, Hosseini Z, Sarli A, Kia N, Tafazoli A, Esmaeili SA.",https://pubmed.ncbi.nlm.nih.gov/33216248/,"Bladder cancer (BC) is considered as one of the most common malignant tumors in humans with complex pathogenesis including gene expression variation, protein degradation, and changes in signaling pathways. Many studies on involved miRNAs in BC have demonstrated that they could be used as potential biomarkers in the prognosis, response to treatment, and screening before the cancerous phenotype onset. MicroRNAs (miRNAs) regulate many cellular processes through their different effects on special targets along with modifying signaling pathways, apoptosis, cell growth, and differentiation. The diverse expression of miRNAs in cancerous tissues could mediate procedures leading to the oncogenic or suppressor behavior of certain genes in cancer cells. Since a specific miRNA may have multiple targets, an mRNA could also be regulated by multiple miRNAs which further demonstrates the actual role of miRNAs in cancer. In addition, miRNAs can be utilized as biomarkers in some cancers that cannot be screened in the early stages. Hence, finding blood, urine, or tissue miRNA biomarkers by novel or routine gene expression  In the present review, we have thoroughly evaluated the recent findings on different miRNAs in BC which can provide comprehensive information on better understanding the role of diverse miRNAs and better decision making regarding the new approaches in the diagnosis, prognosis, prevention, and treatment of BC."
1478,Natural Killer Cell-Derived Extracellular Vesicles as a Promising Immunotherapeutic Strategy for Cancer: A Systematic Review.,"Chan AML, Cheah JM, Lokanathan Y, Ng MH, Law JX.",https://pubmed.ncbi.nlm.nih.gov/36835438/,"Cancer is the second leading contributor to global deaths caused by non-communicable diseases. The cancer cells are known to interact with the surrounding non-cancerous cells, including the immune cells and stromal cells, within the tumor microenvironment (TME) to modulate the tumor progression, metastasis and resistance. Currently, chemotherapy and radiotherapy are the standard treatments for cancers. However, these treatments cause a significant number of side effects, as they damage both the cancer cells and the actively dividing normal cells indiscriminately. Hence, a new generation of immunotherapy using natural killer (NK) cells, cytotoxic CD8+ T-lymphocytes or macrophages was developed to achieve tumor-specific targeting and circumvent the adverse effects. However, the progression of cell-based immunotherapy is hindered by the combined action of TME and TD-EVs, which render the cancer cells less immunogenic. Recently, there has been an increase in interest in using immune cell derivatives to treat cancers. One of the highly potential immune cell derivatives is the NK cell-derived EVs (NK-EVs). As an acellular product, NK-EVs are resistant to the influence of TME and TD-EVs, and can be designed for ""off-the-shelf"" use. In this systematic review, we examine the safety and efficacy of NK-EVs to treat various cancers in vitro and in vivo."
1479,Genetic determinants of aggressive breast cancer.,"Ventura AC, Merajver SD.",https://pubmed.ncbi.nlm.nih.gov/17914925/,"The development and spread of breast and other human cancers are caused by the overexpression, mutation, and/or deletion of specific genes that drive these events. Finding genetic and molecular differences between cancerous and healthy cells can reveal the genetic determinants of cancer. This knowledge  We review the concepts of biomarker, genetic marker, and genetic determinant in cancer, with particular focus on the most aggressive and lethal form of breast cancer, termed inflammatory breast cancer (IBC). Using IBC as an example, we describe in detail the approaches to identify the genes that are responsible for-and not merely associated with-this disease."
1480,Helicases as prospective targets for anti-cancer therapy.,"Gupta R, Brosh RM Jr.",https://pubmed.ncbi.nlm.nih.gov/18473724/,"It has been proposed that selective inactivation of a DNA repair pathway may enhance anti-cancer therapies that eliminate cancerous cells through the cytotoxic effects of DNA damaging agents or radiation. Given the unique and critically important roles of DNA helicases in the DNA damage response, DNA repair, and maintenance of genomic stability, a number of strategies currently being explored or in use to combat cancer may be either mediated or enhanced through the modulation of helicase function. The focus of this review will be to examine the roles of helicases in DNA repair that might be suitably targeted by cancer therapeutic approaches. Treatment of cancers with anti-cancer drugs such as small molecule compounds that modulate helicase expression or function is a viable approach to selectively kill cancer cells through the inactivation of helicase-dependent DNA repair pathways, particularly those associated with DNA recombination, replication restart, and cell cycle checkpoint."
1481,Bioimaging-based detection of mislocalized proteins in human cancers by semi-supervised learning.,"Xu YY, Yang F, Zhang Y, Shen HB.",https://pubmed.ncbi.nlm.nih.gov/25414362/,"Motivation:
        
      
      There is a long-term interest in the challenging task of finding translocated and mislocated cancer biomarker proteins. Bioimages of subcellular protein distribution are new data sources which have attracted much attention in recent years because of their intuitive and detailed descriptions of protein distribution. However, automated  The transfer prediction idea of applying models trained on normal tissue proteins to predict the subcellular locations of cancerous ones is arbitrary because the protein distribution patterns may differ in normal and cancerous states.
    


           Our approach enables us to selectively use the low-quality images in normal states to expand the training sample space and provides a general way for dealing with the small size of annotated images used together with large unannotated ones. 
    


          Availability and implementation:
        
      
      The data and code are available at: www.csbio.sjtu.edu.cn/bioinf/SemiBiomarker/.
    


          Supplementary information:
        
      
      Supplementary data are available at Bioinformatics online."
1482,Viruses for tumor therapy.,"Bell J, McFadden G.",https://pubmed.ncbi.nlm.nih.gov/24629333/,"Oncolytic virotherapy exploits live viruses with selective tropism for cancerous cells and tissues to treat cancer. As discussed here, the field has progressed considerably as a  These studies indicate that oncolytic viruses are remarkably safe and more efficacious when virus replication stimulates sustained antitumor immune responses. In the future, virotherapy should be combined with immunomodulatory reagents that target immune tolerance to established cancers."
1483,A case of simultaneous multiple gastric cancers with p53 gene mutation.,"Lin SY, Lee MD, Wang CK, Chen YJ, Chang JG.",https://pubmed.ncbi.nlm.nih.gov/8176766/,"Simultaneous multiple gastric cancers are rarely observed in clinical practice, and its association with p53 gene mutation has not been mentioned in any previous reports. We report a case of advanced gastric cancer with two primary lesions in the stomach who received total gastrectomy. Tumor and surrounding normal tissues from the surgical specimen were studied by using polymerase chain reaction-single strand conformation polymorphism analysis, restriction enzyme digestion  Point mutations of p53 gene at codon 248 (CGG-->TGG) were found in both primary tumor foci. The patient developed cancerous peritonitis eight months after the operation and expired six months later. This report suggests that p53 gene mutation can occur at an earlier stage in the tumorigenesis of gastric cancer than previously reported and it might be associated with an unusual clinical and pathological presentation."
1484,LncRNA SNHG6 role in clinicopathological parameters in cancers.,"Khan K, Irfan M, Sattar AA, Faiz MB, Rahman AU, Athar H, Calina D, Sharifi-Rad J, Cho WC.",https://pubmed.ncbi.nlm.nih.gov/37735423/,"RNA sequencing has revealed that a substantial portion of the human genome undergoes transcription, yet a minimal fraction of these transcripts translates into proteins. LncRNAs, RNA molecules less than 200 nt in length, once deemed as transcriptional noise, have now emerged as crucial regulators of numerous cellular processes. This review focuses on the lncRNA SNHG6, aiming to elucidate its biogenesis, the pivotal roles it plays, and its mechanisms in facilitating the hallmarks of cancer. A comprehensive literature review and analysis were undertaken to delve into the biogenesis of SNHG6, its roles in cellular processes, and the mechanisms through which it contributes to the hallmarks of cancer. SNHG6 is a notable lncRNA, observed to be overexpressed in various cancer types; its perturbation has been linked to tumor progression, emphasizing its significance in oncogenesis. This lncRNA contributes to a range of cellular aberrations, influencing transcriptional, post-transcriptional, and epigenetic processes of mRNA, ultimately driving cancerous transformations. LncRNA SNHG6 serves as a potential biomarker and therapeutic target due to its association with tumorigenesis. Understanding its mechanism and role in cancer can pave the way for novel diagnostic and therapeutic strategies."
1485,Expression of survivin mRNA and livin mRNA in non-small-cell lung cancer.,"Tanabe H, Yagihashi A, Tsuji N, Shijubo Y, Abe S, Watanabe N.",https://pubmed.ncbi.nlm.nih.gov/15541814/,"It has been suggested that suppression of apoptosis may contribute to the development and progression of cancer. Anti-apoptotic survivin and livin genes are highly expressed in cancer cells and transformed cells, but show little or no expression in normal differentiated tissues. However, there are no available data concerning livin expression in non-small-cell lung cancer (NSCLC). We therefore measured livin mRNA and survivin mRNA expression in 38 NSCLC cancer samples and 15 paired non-cancerous lung tissue samples using a quantitative reverse transcription-polymerase chain reaction (RT-PCR). While both mRNAs showed higher expression in cancers than non-cancerous tissues (P < 0.001), livin mRNA and survivin mRNA expression did not correlate with one another. When a cut-off value for positivity was set at the mean + S.D. for expression values in non-cancerous tissues, positivity rates for livin mRNA and survivin mRNA expression were 76.3% (29 of 38) and 36.8% (14 of 38) in lung cancers and 6.7% (1 of 15) and 0% (0 of 15), respectively, in paired non-cancerous lung tissue samples. Livin mRNA and survivin mRNA expression in tumors were up-regulated in 23 of 31 (74.2%) early-stage NSCLC patients and 11 of 31 (35.5%), respectively. Expression of both mRNAs in tumors varied independently of tumor histology. These "
1486,Expression of GOLPH2 is associated with the progression of and poor prognosis in gastric cancer.,"Liu G, Zhang Y, He F, Li J, Wei X, Li Y, Liao X, Sun J, Yi W, Niu D.",https://pubmed.ncbi.nlm.nih.gov/25119897/,"Golgi phosphoprotein 2 (GOLPH2) has been associated with the development and progression of various human cancers. The aims of this study were to investigate the relationship between GOLPH2 and gastric cancer (GC) progression and explore the clinical significance of GOLPH2 in GC. GOLPH2 expression was examined in four pairs of primary GC tissues and the adjacent non-cancerous tissues from the same patients, using immunohistochemistry (IHC), quantitative PCR and western blotting. Furthermore, GOLPH2 protein expression was analyzed in 10 normal gastric tissues and 385 clinicopathologically characterized cases of GC by IHC. Statistical analyses were performed to determine the prognostic and diagnostic associations. GOLPH2 mRNA and protein expression were both markedly upregulated in GC tissues, compared with the paired adjacent non-cancerous tissues. The Chi-square test and Spearman analysis revealed a significant correlation between GOLPH2 expression and clinical stage, T classification, lymph node metastasis, metastasis and venous invasion. Patients with a higher GOLPH2 expression had a shorter overall survival (OS), compared to patients with lower GOLPH2 expression. Notably, our  Therefore, additional studies focusing on the potential of GOLPH2 as a novel therapeutic target in GC are required."
1487,Antioxidant enzyme levels in cancer.,"Oberley TD, Oberley LW.",https://pubmed.ncbi.nlm.nih.gov/9151141/,"Normal cells are protected by antioxidant enzymes from the toxic effects of high concentrations of reactive oxygen species generated during cellular metabolism. Even though cancer cells generate reactive oxygen species, it has been demonstrated biochemically that antioxidant enzyme levels are low in most animal and human cancers. However, a few cancer types have been found to have elevated levels of antioxidant enzymes, particularly manganese superoxide dismutase. Morphologic studies of animal and human cancer have confirmed that although the majority of tumor cell types from several organ systems have low antioxidant enzymes, adenocarcinomas may have elevated manganese superoxide dismutase and catalase levels. However, all cancers examined to date have some imbalance in antioxidant enzyme levels compared with the cell of origin. Antioxidant enzyme importance in cancer genesis has been difficult to evaluate in early cancerous lesions using biochemical techniques because such lesions are small and therefore below the level of detection. Using immunohistochemical techniques, early lesions of human and animal cancers were demonstrated to have low antioxidant enzymes, thus suggesting a role for these enzymes both in the genesis of cancer and the malignant phenotype. All but one human cancer cell type (the granular cell variant of human renal adenocarcinoma) examined showed both low catalase and glutathione peroxidase levels, suggesting that most cancer cell types cannot detoxify hydrogen peroxide. Our "
1488,"E10A, an adenovirus carrying human endostatin gene, in combination with docetaxel treatment inhibits prostate cancer growth and metastases.","Zhao P, Luo R, Wu J, Xie F, Li H, Xiao X, Fu L, Zhu X, Liu R, Zhu Y, Liang Z, Huang W.",https://pubmed.ncbi.nlm.nih.gov/26065034/,"E10A, a replication-defective adenovirus carrying human endostatin gene, has finished Phase I clinical trials for solid cancers. We assessed whether the combination of E10A with docetaxel would enhance antiangiogenic activities and inhibit prostate cancer growth and metastases. Combination use of conditioned medium from prostate cancer cells infected by E10A and docetaxel exerted synergistic inhibition of HUVECs proliferation, migration and tube formation, compared with either agent alone. In prostate cancer s.c. xenograft models, combined therapy  The antitumoral effect was tightly correlated with a remarkable decrease in tumor cell proliferation, microvessel, especially immature vasculature and significant increase in apoptosis induction. Systemic administration of E10A and docetaxel also effectively inhibited orthotopic growth and metastases of prostate cancer and achieved better in vivo antiangiogenic effects than either agent alone. Our data indicate that E10A in combination with docetaxel exert enhanced antiangiogenic activities and inhibit prostate cancer growth and metastases. Therefore, this approach may be an effective treatment for advanced prostate cancer and deserves more extensive investigation."
1489,[Expression of thymidine phosphorylase in primary colorectal cancer and liver metastasis-relationship between mRNA levels in cancer cells and protein levels in cancerous tissue].,"Ishibashi K, Sobajima J, Ishiguro T, Okada N, Miyazaki T, Yokoyama M, Ishida H.",https://pubmed.ncbi.nlm.nih.gov/19295266/,"Purpose:
        
      
      To compare mRNA levels in cancer cells and protein levels in cancerous tissue in terms of the expression of thymidine phosphorylase(TP).
    


          Materials and  The expressions of TP mRNA in cancer cells was quantified by reverse-transcriptase polymerase chain reaction(RT-PCR)using cells obtained by microdissection of paraffinembedded specimens(Danenberg tumor profiling  The protein level of TP was determined by enzyme-linked immunosorbent assay(ELISA).
    


          04), but these factors did not correlate with each other in liver metastases. There was no relationship between primary colorectal lesions and synchronous liver metastases in terms of TP mRNA levels and TP protein levels. In relation to the efficacy of 5-fluorouracil(or UFT)/Leucovorin, the mRNA level of the primary lesion was marginally higher in the order of patients with PD(n=11), SD(n=3), and CR/PR(n=4)(p=0.05). However, the TP protein level did not correlate with therapeutic efficacy.
    


          Conclusions:
        
      
      The different "
1490,[Cancer of the breast at the time of diagnosis. A national CANAM study: analysis of 3007 cases].,"Marty M, Rossignol C, Serruys G, Petrissans JL, Baillet F, Netter-Pinon G, Romieux G, Saez S.",https://pubmed.ncbi.nlm.nih.gov/1387214/,"Between April 1988 and February 1990, 3,007 cases of female breast cancer were recorded among people insured by CANAM*; 118 cancers were bilateral from the start and 2,889 were unilateral. At the time of diagnosis the patients' age ranged from 24 to 101 years (median: 60 years), and 35.6 percent of the tumours were virtually subclinical. Lymph node involvement was clinically absent in 75 percent of the cases and histologically absent in 57 percent. In women under 50 the proportion of small TO-T1 tumours was greater than 40 percent, which pleaded for detection before the age of 50 years. Conversely, in economically weak populations and in women who were followed up for cancerous disease, breast cancer was diagnosed at a later stage. In older (retired) women (median age: 74), who accounted for 44 percent of the whole population, the proportion of advanced tumours was practically doubled (T4: 11 percent versus 6 percent), and the probability of metastases at the time of diagnosis had risen from 4.2 to 6.1 percent. In these patients, clinical examination once a year should contribute to an earlier diagnosis."
1491,Metabolic profiling detects field effects in nondysplastic tissue from esophageal cancer patients.,"Yakoub D, Keun HC, Goldin R, Hanna GB.",https://pubmed.ncbi.nlm.nih.gov/20884633/,"The variable rate of missed cancer in endoscopic biopsies and lack of other biomarkers reduce the effectiveness of surveillance programs in esophageal cancer. Based on the ""field cancerization"" hypothesis that tumors arise within a transformed field with an altered biochemical phenotype, we sought to test if metabolic profiling could differentiate between histologically normal tissue from individuals with and without esophageal cancer. Thirty-five patients with esophageal adenocarcinoma and 52 age-matched controls participated in the study. Using 1H magic angle spinning-nuclear magnetic resonance spectroscopy of intact tissue, we generated metabolic profiles of tumor tissue, proximal histologically normal mucosa from cancer patients (PHINOM), and proximal histologically normal mucosa from a control group. Using multivariate regression and receiver-operator characteristic analysis, we identified a panel of metabolites discriminating malignant and histologically normal tissues from cancer patients and from that of controls. Whereas 26% and 12% of the spectral profile regions were uniquely discriminating tumor or control tissue, respectively, 5% of the profile exhibited a significant progressive change in signal intensity from controls to PHINOM to tumor. Regions identified were assigned to phosphocholine (PC), glutamate (Glu), myo-inositol, adenosine-containing compounds, uridine-containing compounds, and inosine. In particular, the PC/Glu ratio in histologically normal tissue signified the presence of esophageal cancer (n=123; area under the curve, 0.84; P<0.001). In conclusion, our findings support the hypothesis of the presence of metabonomic field effects in esophageal cancer, even in non-Barrett's segments. This indicates that metabolic profiling of tissue can potentially play a role in the surveillance of cancer by reporting on the phenotypic consequences of field cancerization."
1492,[Blood and bone marrow abnormalities in primary lung cancers (author's transl)].,"Piéron R, Constans T, Roland J, Chatelet F.",https://pubmed.ncbi.nlm.nih.gov/6244639/,"Blood and bone marrow abnormalities accompanying cancers have been known for a while, without yet being understood. The study of 89 patients having lung cancers leads to the following observations: thrombocytosis is frequent and should be considered as a diagnostic criterion; anemia is often associated and we have noticed a correlation between the two. The bone marrow abnormalities shown on biopsy are also frequent, presenting mainly (54/104) as irritative type. This histological pattern becomes a criterion of prognosis, since one should interpret it as a bone marrow reaction to the implantation of cancerous cells. Lastly, no relationship has been found between the blood count and the bone marrow pattern."
1493,Prevalent overexpression of prolyl isomerase Pin1 in human cancers.,"Bao L, Kimzey A, Sauter G, Sowadski JM, Lu KP, Wang DG.",https://pubmed.ncbi.nlm.nih.gov/15111319/,"Phosphorylation of proteins on serine or threonine residues preceding proline (pSer/Thr-Pro) is a major regulatory mechanism in cell proliferation and transformation. Interestingly, the pSer/Thr-Pro motifs in proteins exist in two distinct cis and trans conformations, whose conversion rate is normally reduced on phosphorylation, but is catalyzed specifically by the prolyl isomerase Pin1. Pin1 can catalytically induce conformational changes in proteins after phosphorylation, thereby having profound effects on catalytic activity, dephosphorylation, protein-protein interactions, subcellular location, and/or turnover of certain phosphorylated proteins. Recently, it has been shown that Pin1 is overexpressed in human breast cancer cell lines and cancer tissues and plays a critical role in the transformation of mammary epithelial cells by activating multiple oncogenic pathways. Furthermore, Pin1 expression is an excellent independent prognostic marker in prostate cancer. However, little is known about Pin1 expression in other human normal and cancerous tissues. In the present study, we quantified Pin1 expression in 2041 human tumor samples and 609 normal tissue samples as well as normal and transformed human cell lines. We found that Pin1 was usually expressed at very low levels in most normal tissues and its expression was normally associated with cell proliferation, with high Pin1 levels being found only in a few cell types. However, Pin1 was strikingly overexpressed in many different human cancers. Most tumors (38 of 60 tumor types) have Pin1 overexpression in more than 10% of the cases, as compared with the corresponding normal controls, which included prostate, lung, ovary, cervical, brain tumors, and melanoma. Consistent with these findings, Pin1 expression in human cancer cell lines was also higher than that in the normal cell lines examined. These  Given previous findings that Pin1 expression is an excellent prognostic marker in prostate cancer and that inhibition of Pin1 can suppress transformed phenotypes and inhibit tumor cell growth, these findings may have important implications for the pathogenesis, diagnosis, and treatment of human cancers."
1494,Squamous cell carcinomas of the esophagus arise from a telomere-shortened epithelial field.,"Kammori M, Poon SS, Nakamura K, Izumiyama N, Ishikawa N, Kobayashi M, Naomoto Y, Takubo K.",https://pubmed.ncbi.nlm.nih.gov/17982685/,"Critically shortened telomeres make chromosomes susceptible to the instability and widespread cytogenetic alterations that characterize most human cancers. We hypothesized that the very rapid cell proliferation observed in esophageal squamous cell carcinomas might accelerate telomere shortening and chromosomal instability associated with carcinogenesis. We used a number of telomere measurement techniques including quantitative fluorescence in situ hybridization (Q-FISH) to compare chromosomal aberrations and telomere lengths of individual chromosomes in esophageal squamous cell carcinomas (ESCCs) and nearby non-neoplastic esophageal epithelium (NNEE) cells. Our  In addition, there was no evidence linking telomere shortening of a particular chromosome to field cancerization in ESCC. However, a mechanistic link between telomere shortening and chromosomal instability was supported by a higher frequency of anaphase/telophase bridges and an increase in the frequency of aneuploidy. This study furthers our understanding of the mechanism by which telomere shortening and chromosomal instability lead to carcinogenesis and field cancerization in the esophagus."
1495,"Sequential Curettage, 5-Fluorouracil, and Photodynamic Therapy for Field Cancerization of the Scalp and Face in Solid Organ Transplant Recipients.","Jambusaria-Pahlajani A, Ortman S, Schmults CD, Liang C.",https://pubmed.ncbi.nlm.nih.gov/26730976/," These patients often show inadequate responses to g., topical chemotherapy).
    


          
    


           Light curettage of hypertrophic lesions was followed by application of 5-fluorouracil 5% cream twice daily for 5 days and photodynamic therapy (PDT) with 1-hour incubation on day 6. Pain level during and after PDT was recorded. Photographs were obtained immediately before and after treatment and at follow-up appointments.
    


           Patients remained free of AK/SCCIS based on clinical examination 1 to 6 months after treatment.
    


          Conclusion:
        
      
      For SOTRs with field cancerization, sequential therapy represents a viable therapeutic regimen with good tolerability and durable clinical response. This approach warrants further investigation to determine which therapeutic combinations have optimal tolerability and efficacy."
1497,Methylation profiles of miR34 gene family in Vietnamese patients suffering from breast and lung cancers.,"Lan VTT, Son HV, Trang VL, Trang NT, Phuong NT, Toan NL, Duong PAT.",https://pubmed.ncbi.nlm.nih.gov/29916548/,"The three genes encoding small non‑coding microRNA (miR)34a, MIR34b and MIR34c act as tumor‑suppressor genes. Their aberrant expressions regulated by DNA methylation have been frequently found in various types of cancer. In the present study, the DNA promoter methylation profiles of the MIR34 gene family were analyzed using the methylation specific polymerase chain reaction in order to clarify their association with breast and lung cancer, non‑cancerous or normal adjacent tissues. The methylation frequency of MIR34a was significantly higher in breast cancer (49.37%) compared with normal adjacent tissues (30.38%). The methylation frequency of MIR34b/c was 59.49 and 62.03% in breast cancer and normal adjacent tissues, respectively. MIR34a methylation showed a significant concordance with that of MIR34b/c only in breast cancer tissue. MIR34a methylation was significantly associated with cancer and the invasive ductal carcinoma type of breast cancer (P=0.015 and P=0.02, respectively). Methylation frequency of MIR34a and MIR34b/c was 48.42 and 56.84% in lung cancer, and 47.22 and 51.39% in pulmonary diseases, respectively. No significant association was observed between the methylation status of MIR34a and MIR34b/c, and the clinicopathological features of lung cancer or with those of non‑cancerous pulmonary diseases. Promoter methylation of MIR34a and MIR34b/c occurs frequently and concomitantly in breast and lung cancer, as well as in pulmonary diseases tissues, but not in breast normal tissues adjacent to tumor. These  Furthermore, MIR34a methylation may be a promising marker for a subtype of breast cancer."
1498,[FHIT gene is abnormal in Chinese lung cancers].,"Zhang J, Fu W, Zhang X.",https://pubmed.ncbi.nlm.nih.gov/11715406/,"2 is abnormal in Chinese lung cancers.
    


           Total RNA was extracted and the FHIT gene was detected by RT-PCR and DNA sequencing technology.
    


           Aberrant transcripts were observed in 15 (48%) of 31 cases of cancerous tissues, 57% (12/21) in SQC and 33% (3/10) in ADC, respectively. All the abnormal transcripts observed lacked exon 5, the first coding exon. The sequence analyses of the aberrant cDNAs revealed deletions of various regions between exon 4 and 10. A synonymous mutation in E8, codon98CAT(H)-->CAC(H), was found in a SQC.
    


          Conclusion:
        
      
      The high deletion rate of the FHIT gene in Chinese lung cancer supports the hypothesis that the FHIT gene alteration is involved in tumorigenic development of human neoplasm."
1499,Common skin cancers and their precursors.,"Arora A, Attwood J.",https://pubmed.ncbi.nlm.nih.gov/19465206/,"This review of precancerous and cancerous skin lesions serves as an overview for the general surgeon in clinical practice. Because these lesions are common in the general population, it is likely that they will be encountered frequently, perhaps even during consultation for an unrelated issue. General surgeons have a unique role in caring for these common skin cancers both primarily and by understanding the basis for referral to a specialist. With these goals in mind, we discuss the pathophysiology of cutaneous malignancy as well as the diagnosis and treatment of the three most common cutaneous malignancies in the United States: basal cell, squamous cell, and melanoma skin cancers."
1500,"An Integrated Data Analysis of mRNA, miRNA and Signaling Pathways in Pancreatic Cancer.","Sohrabi E, Rezaie E, Heiat M, Sefidi-Heris Y.",https://pubmed.ncbi.nlm.nih.gov/33813720/,"Although many genes and miRNAs have been reported for various cancers, pancreatic cancer's specific genes or miRNAs have not been studied precisely yet. Therefore, we have analyzed the gene and miRNA expression profile of pancreatic cancer data in the gene expression omnibus (GEO) database. The microarray-derived miRNAs and mRNAs were annotated by gene ontology (GO) and signaling pathway analysis. We also recognized mRNAs that were targeted by miRNA through the mirDIP database. An integrated analysis of the microarray revealed that only 6 out of 43 common miRNAs had significant differences in their expression profiles between the tumor and normal groups (P value < 0.05 and |log Fold Changes (logFC)|> 1). The hsa-miR-210 had upregulation, whereas hsa-miR-375, hsa-miR-216a, hsa-miR-217, hsa-miR-216b and hsa-miR-634 had downregulation in pancreatic cancer (PC). The analysis 1 databases. Pathway analysis showed that amoebiasis, axon guidance, PI3K-Akt signaling pathway, absorption and focal adhesion, adherens junction, platelet activation, protein digestion, human papillomavirus infection, extracellular matrix (ECM) receptor interaction, and riboflavin metabolism played important roles in pancreatic cancer. GO analysis revealed the significant enrichment in the three terms of biological process, cellular component, and molecular function, which were identified as the most important processes associated strongly with pancreatic cancer. In conclusion, DTL, CDH11, COL5A1, ITGA2, KIF14, SMC4, VCAN, hsa-mir-210, hsa-mir-217, hsa-mir-216a, hsa-mir-216b, hsa-mir-375 and hsa-mir-634 can be reported as the novel diagnostic or even therapeutic markers for the future studies. Also, the hsa-mir-107 and hsa-mir-125a-5p with COL5A1, CDH11 and TGFBR1 genes can be introduced as major miRNA and genes on the miRNA-drug-mRNA network. The new regulatory network created in our study could give a deeper knowledge of the pancreatic cancer."
1501,Histamine reduces boron neutron capture therapy-induced mucositis in an oral precancer model.,"Monti Hughes A, Pozzi E, Thorp SI, Curotto P, Medina VA, Martinel Lamas DJ, Rivera ES, Garabalino MA, Farías RO, Gonzalez SJ, Heber EM, Itoiz ME, Aromando RF, Nigg DW, Trivillin VA, Schwint AE.",https://pubmed.ncbi.nlm.nih.gov/25926141/," However, BNCT-induced mucositis in field-cancerized tissue was dose limiting. In a clinical scenario, oral mucositis affects patients' treatment and quality of life. Our aim was to evaluate different radioprotectors, seeking to reduce the incidence of BNCT-induced severe mucositis in field-cancerized tissue.
    


          Materials and 
    


           Hislow was non-toxic and did not compromise the long-term therapeutic effect of BNCT or alter gross boron concentration.
    


          Conclusion:
        
      
      Histamine reduces BNCT-induced mucositis in  The fact that both histamine and boronophenylalanine are approved for use in humans bridges the gap between "
1502,Short-term effects of breast cancer on labor market attachment: results from a longitudinal study.,"Bradley CJ, Neumark D, Bednarek HL, Schenk M.",https://pubmed.ncbi.nlm.nih.gov/15617792/,"In this longitudinal study, we examine the consequences of breast cancer for women's labor market attachment for the 6-month period following diagnosis. Women with breast cancer, with the exception of those having in situ cancer, were less likely to work 6 months following diagnosis relative to a control sample of women drawn from the Current Population Survey. Breast cancer's non-employment effect appears to be twice as large for African-American women. Women with breast cancer who remained working worked fewer hours than women in the control group."
1503,3D in vitro cancerous tumor models: Using 3D printers.,"Zahedi-Tabar Z, Bagheri-Khoulenjani S, Mirzadeh H, Amanpour S.",https://pubmed.ncbi.nlm.nih.gov/30798926/,"Recently, magnetic Hyperthermia is one of the promising  In this  The degree and pattern of generated heat in cancerous and adjacent non-cancerous tissues plays an important role on the outcome of the treatment. it is mainly affected by diffusion and distribution pattern of magnetic nanoparticles within the cancerous and non-cancerous tissues. Study the diffusion and distribution patterns of magnetic nanoparticle in vivo is difficult and costly in many cases and in some cases evaluating the amount of generated heat at cancer site is almost impossible. In vitro models for cancer tissues are alternatives for in vivo models. However, usual in vitro models could not resembling all the characteristics of a cancer tumor. In this hypothesis we propose that using 3D printers can provide a platform to fabricate a personalized in vitro cancer model which could simulate the most important features of the cancerous tissues (including shape and vascular network) and can be used to study magnetic hyperthermia in a simulated media of compatible to in vivo conditions."
1504,[Magnifying endoscope and stereomicroscope in diagnosing colon tumor: experience with 139 cases].,"Han YJ, Lai ZS, Wang YD, Jiang B.",https://pubmed.ncbi.nlm.nih.gov/15447870/,"
    


          
    


           Five laterally spreading tumors (LST) ranging from 10 to 50 mm in diameter, including 1 of pit IIIL, and 4 of pit IV. were found. The findings of the pit patterns by magnifying endoscope were highly consistent with those by stereomicroscope in these patients.
    


          Conclusions:
        
      
      Pit patterns are crucial to distinguish the cancerous lesions form non-cancerous one and helpful for early detection of colorectal cancers. Pit V may serve as warning sign of early cancerous lesions."
1505,Associations of positive and negative life changes with well-being in young and middle-aged adult cancer survivors.,"Park CL, Blank TO.",https://pubmed.ncbi.nlm.nih.gov/21732906/,"Both positive and negative changes are commonly reported by cancer survivors, and both may impact quality of life. Yet few studies have directly compared the associations of positive and negative changes across multiple life domains with multiple aspects of well-being. This study examined positive and negative changes and their conjoint relation to a range of well-being indices. We used correlational and regression analyses of data from 237 young to middle aged (X = 45.3 years) cancer survivors, several years after treatment. Measures included demographic and medical variables, medical post-cancer positive and negative changes on multiple life domains, and a range of positive and negative adjustment indices. Demographic factors, especially income, related to both positive and negative outcomes. On average, participants reported no change on most life domains, although modest amounts of both positive and negative changes were reported. Negative change, rather than positive change, was closely associated with cancer survivors' adjustment. Detailed measurement of both positive and negative changes - as well as lack of change - is important to advance understanding of cancer's impact on survivors."
1506,Transmissible cancers and the evolution of sex under the Red Queen hypothesis.,"Aubier TG, Galipaud M, Erten EY, Kokko H.",https://pubmed.ncbi.nlm.nih.gov/33211684/,"The predominance of sexual reproduction in eukaryotes remains paradoxical in evolutionary theory. Of the hypotheses proposed to resolve this paradox, the 'Red Queen hypothesis' emphasises the potential of antagonistic interactions to cause fluctuating selection, which favours the evolution and maintenance of sex. Whereas empirical and theoretical developments have focused on host-parasite interactions, the premises of the Red Queen theory apply equally well to any type of antagonistic interactions. Recently, it has been suggested that early multicellular organisms with basic anticancer defences were presumably plagued by antagonistic interactions with transmissible cancers and that this could have played a pivotal role in the evolution of sex. Here, we dissect this argument using a population genetic model. One fundamental aspect distinguishing transmissible cancers from other parasites is the continual production of cancerous cell lines from hosts' own tissues. We show that this influx dampens fluctuating selection and therefore makes the evolution of sex more difficult than in standard Red Queen models. Although coevolutionary cycling can remain sufficient to select for sex under some parameter regions of our model, we show that the size of those regions shrinks once we account for epidemiological constraints. Altogether, our  Nonetheless, we confirm that vertical transmission of cancerous cells can promote the evolution of sex through a separate mechanism, known as similarity selection, that does not depend on coevolutionary fluctuations."
1507,"Transcriptome Analysis of Cisplatin, Cannabidiol, and Intermittent Serum Starvation Alone and in Various Combinations on Colorectal Cancer Cells.","Cherkasova V, Ilnytskyy Y, Kovalchuk O, Kovalchuk I.",https://pubmed.ncbi.nlm.nih.gov/37834191/,"Platinum-derived chemotherapy medications are often combined with other conventional therapies for treating different tumors, including colorectal cancer. However, the development of drug resistance and multiple adverse effects remain common in clinical settings. Thus, there is a necessity to find novel treatments and drug combinations that could effectively target colorectal cancer cells and lower the probability of disease relapse. To find potential synergistic interaction, we designed multiple different combinations between cisplatin, cannabidiol, and intermittent serum starvation on colorectal cancer cell lines. Based on the cell viability assay, we found that combinations between cannabidiol and intermittent serum starvation, cisplatin and intermittent serum starvation, as well as cisplatin, cannabidiol, and intermittent serum starvation can work in a synergistic fashion on different colorectal cancer cell lines. Furthermore, we analyzed differentially expressed genes and affected pathways in colorectal cancer cell lines to understand further the potential molecular mechanisms behind the treatments and their interactions. We found that synergistic interaction between cannabidiol and intermittent serum starvation can be related to changes in the transcription of genes responsible for cell metabolism and cancer's stress pathways. Moreover, when we added cisplatin to the treatments, there was a strong enrichment of genes taking part in G2/M cell cycle arrest and apoptosis."
1508,[Current perspectives in cervical cancer].,"Valdespino Gómez VM, Valdespino Castillo VE.",https://pubmed.ncbi.nlm.nih.gov/15239562/,"Cervical cancer is a Public Health problem among women worldwide, especially in the developing world. The understanding of the HPV association with the high-grade squamous intraepithelial lesions and cervical cancer and the knowledge of the pre-invasive lesions natural history have strengthened the justification of different means of cancer prevention and screening programs, the application of different pre-invasive lesion treatments and particularly advances in conventional treatments of cervical cancer. In the last thirty years, cervical cancer's incidence and mortality rates have decreased in more than 75% in developed nations due to efficient application of secondary prevention based on cytology and colposcopy screening programs plus to in-office implementation of precursor lesions treatment  In the developing nations, these achievements can be obtained using specific steps of primary prevention, massive participation of risk patients in screening programs and improving ambulatory application of pre-invasive cervical lesion treatments. In Mexico several indicators suggest that this condition has began. New knowledge paradigms of the local immune response to HPV-cervical cancer pre-invasive and invasive lesions are being added to the construction of new preventive and therapeutic anti-cancer strategies. The preventive vaccines anti-high risk oncogenic-HPVs offer a good perspective in short term, also the use of different cellular immunotherapy strategies anti-cervical cancer as adyuvant of conventional treatments offer an encouraging panorama in not long term. In the next years, the improving of specific genes determination and their correlation with biologic features of the specific tumor which are involved on pre-invasive and invasive stages of cervical cancer will raise the understanding and the treatment of these patients."
1509,Abdominal wall recurrence after laparoscopic colectomy for colon cancer.,"Cirocco WC, Schwartzman A, Golub RW.",https://pubmed.ncbi.nlm.nih.gov/7940187/," Overall, 13 case reports of abdominal wall cancer recurrence after laparoscopic surgery have been published.
    


           Recurrent cancer was located in the abdominal wall incision and also in all four port sites 9 months after surgery. These four cases have all involved patients with advanced cancers of the right side of the colon who underwent a laparoscopic-assisted right hemicolectomy. These cases of abdominal wall cancer recurrence carry ominous implications for the future of laparoscopic surgical procedures involving colorectal malignancy. Recurrent cancer in minilaparotomy incisions may simply be due to local spread of cancerous cells. However, remote port site recurrence may be due to the liberation of cancer cells throughout the abdomen from advanced colorectal cancer no longer confined to the bowel wall facilitated by intraperitoneal carbon dioxide insufflation during laparoscopy.
    


          Conclusions:
        
      
      Abdominal wall cancer recurrence is enhanced by the laparoscopic approach to colectomy for colorectal cancer. Except for controlled, clinical studies, laparoscopic colectomy for malignancy should be abandoned."
1510,Will knowledge of human genome variation result in changing cancer paradigms?,"Gottlieb B, Beitel LK, Trifiro M.",https://pubmed.ncbi.nlm.nih.gov/17563087/,"Our incomplete understanding of carcinogenesis may be a significant reason why some cancer mortality rates are still increasing. This lack of understanding is likely due to a research approach that relies heavily on genetic comparison between cancerous and non-cancerous tissues and cells, which has led to the identification of genes of cancer proliferation rather than differentiation. Recent observations showing that a tremendous degree of natural human genetic variation occurs are likely to lead to a shift in the basic paradigms of cancer genetics, in that there is a need to consider both the nature of the genes involved, and the idea that not every genetic variation identified in these genes may be associated with carcinogenesis. Based on studies using LCM and micro-genetic analyses, we propose that significant cancer initiating events may take place during the very early stages of development of cancer-susceptible tissues and that using such techniques might greatly help us in our understanding of carcinogenesis."
1511,Barrett's to oesophageal cancer sequence: a model of inflammatory-driven upper gastrointestinal cancer.,"Picardo SL, Maher SG, O'Sullivan JN, Reynolds JV.",https://pubmed.ncbi.nlm.nih.gov/22868386/,"Cancer-related inflammation is considered the 'seventh hallmark of cancer'; many studies show that tumours develop and progress within inflammatory diseases. This review focuses on Barrett's oesophagus, a common condition in which chronic inflammation and  Changes that occur in the tissue microenvironment during development of this disease are discussed. Infiltration of immune cells facilitates tumour development through production of factors that promote carcinogenesis and by enabling tumours to evade the host immune response. Small molecules including cytokines, chemokines and growth factors play key roles in both inflammation and cancer by promoting proliferation, angiogenesis and carcinogenesis and by recruiting immune cells. The extracellular matrix is altered in inflammation, and provides structural support to developing tumours. Hypoxia is a common state in cancers and inflamed tissues which causes DNA damage and induces tumourigenic factors. Finally, tissue vasculature is a vital part of its microenvironment, supplying oxygen, nutrients and growth factors to rapidly dividing cells, and providing a mechanism for metastatic spread. The cells and molecules outlined here represent potential targets for treatment of this cancer, especially in its pre-cancerous, inflammatory stage."
1512,Epidemiology and Inherited Predisposition for Sporadic Pancreatic Adenocarcinoma.,"Stolzenberg-Solomon RZ, Amundadottir LT.",https://pubmed.ncbi.nlm.nih.gov/26226901/,"Given the changing demographics of Western populations, the numbers of pancreatic cancer cases are projected to increase during the next decade. Diabetes, recent cigarette smoking, and excess body weight are the cancer's most consistent risk factors. The search for common and rare germline variants that influence risk of pancreatic cancer through genome-wide association studies and high-throughput-sequencing-based studies is underway and holds the promise of increasing the knowledge of variants and genes that play a role in inherited susceptibility of this disease. Research reported in this review has advanced the understanding of pancreatic cancer."
1513,The rationale for patient-reported outcomes surveillance in cancer and a reproducible method for achieving it.,"Smith TG, Castro KM, Troeschel AN, Arora NK, Lipscomb J, Jones SM, Treiman KA, Hobbs C, McCabe RM, Clauser SB.",https://pubmed.ncbi.nlm.nih.gov/26619031/,"Patient-reported outcomes (PROs) measure quality of life, symptoms, patient functioning, and patient perceptions of care; they are essential for gaining a full understanding of cancer care and the impact of cancer on people's lives. Repeatedly captured facility-level and/or population-level PROs (PRO surveillance) could play an important role in quality monitoring and improvement, benchmarking, advocacy, policy making, and research. This article describes the rationale for PRO surveillance and the  The American Cancer Society, the National Cancer Institute, the Commission on Cancer, and RTI International collaborated on PROSSES. PROSSES was conducted at 17 cancer programs that participated in the National Cancer Institute Community Cancer Centers Program among patients diagnosed with locoregional breast or colon cancer. The  Differences in clinical and demographic characteristics between respondents and nonrespondents were mostly negligible, with the exception that non-white individuals were somewhat less likely to respond. These  If repeated and expanded, they could provide PRO surveillance data from patients with cancer on a national scale."
1514,[Amplification and expression of oncogenes in human malignant tumors--organ or tissue specificity and prognosis].,"Ueda M, Shimizu N, Abe O.",https://pubmed.ncbi.nlm.nih.gov/2573817/,"We investigated the amplification and expression of oncogenes in human cancerous and noncancerous tissues, and clarified the correlation between the biological characteristics and them. Amplification of c-erb B oncogene is detected in 12% of squamous cancer tissues such as cancer of the lung and esophagus, but not others. That of c-erb A and c-erb B-2 oncogenes is, specifically, detected in 20-25% of breast cancers. On the other hand, amplification of c-myc is detected in 10-20% of various cancers. EGF receptors is highly and specifically, overexpressed in squamous cancers, and the prognosis of the patients with amplification and overexpression of c-erb B oncogenes is poor."
1515,Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management.,"Shah SC, Itzkowitz SH.",https://pubmed.ncbi.nlm.nih.gov/34757143/,"Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC), despite decreases in CRC incidence in recent years. Chronic inflammation is the driver of neoplastic progression,  Colitis-associated CRC shares many molecular similarities with sporadic CRC, and preclinical investigations have demonstrated a potential role for the microbiome in concert with the host immune system in the development of colitis-associated colorectal cancer (CAC). Some unique molecular differences occur in CAC, but their role in the pathogenesis and behavior of inflammation-associated cancers remains to be elucidated. Nonconventional types of dysplasia have been increasingly recognized, but their natural history is not well defined, and they have not been incorporated into surveillance algorithms. The concept of cumulative inflammatory burden highlights the importance of considering histologic inflammation over time as an important risk factor for CAC. Dysplasia is arguably the most important risk factor for developing CAC, and advances have been made in the endoscopic detection and removal of precancerous lesions, thereby deferring or avoiding surgical resection. Some of the agents used to treat IBD are chemopreventive. It is hoped that by gaining better control of the underlying inflammation with newer medications and better endoscopic detection and management, a more sophisticated appreciation of clinicopathologic risk factors, and growing awareness of the genetic, immunologic, and environmental causes of colitis- associated neoplasia, that colitis-associated colorectal neoplasia will become even more predictable and manageable in the coming years."
1516,Human sialidase as a cancer marker.,"Miyagi T, Wada T, Yamaguchi K, Shiozaki K, Sato I, Kakugawa Y, Yamanami H, Fujiya T.",https://pubmed.ncbi.nlm.nih.gov/18651674/,"Altered sialylation of cell surface glycoproteins and glycolipids is closely related to the malignant phenotype of cancer cells, including the metastatic potential and invasiveness. Many cancer-related antigens in clinical use contain sialic acids at the terminal position of sugar chains in the molecules. To elucidate the molecular mechanism, we focused our investigation on sialidase, which catalyzes the removal of sialic acid residues from the glycoconjugates. Four types of human sialidases identified to date behave in different manners during carcinogenesis. One of the sialidases, found in the lysosomes, showed downregulation in cancers, promoting anchorage-independent growth, and metastatic ability, while another, found in the plasma membrane, showed marked upregulation, causing apoptosis suppression. It was found that estimation of the mRNA levels of sialidases by real-time PCR allowed discrimination of cancerous from noncancerous tissues and even determination of the pathological stage in some cancers. Immunohistochemistry of cancer tissues using the antibody against the plasma membrane sialidase was useful for clinical diagnosis. This paper briefly summarizes our findings of the altered sialidase expression in cancers and the possibility of their clinical application as cancer markers. Human sialidases are indeed related to malignancy and may be potential targets for cancer diagnosis and therapy."
1517,DNA methylation: a marker for carcinogen exposure and cancer risk.,"Nakajima T, Enomoto S, Ushijima T.",https://pubmed.ncbi.nlm.nih.gov/19568874/,"Cancers arise as a consequence of multiple genetic and epigenetic alterations. Many genes aberrantly methylated in cancers have been identified in recent years, and their use in cancer diagnosis and therapy is currently under investigation. During our genome-wide screening for a novel tumor-suppressor gene in gastric cancers, we found that only a small amount of aberrant methylation was present, even in non-cancerous gastric mucosae. A subsequent large-scale analysis of the gastric mucosae of healthy individuals and gastric cancer patients using quantitative methylation-specific PCR (qMSP) revealed that Helicobacter pylori infection potently induced aberrant DNA methylation in non-cancerous gastric mucosae and that these high methylation levels can decrease following cessation of the H. pylori infection. Helicobacter pylori infection induced the methylation of specific genes among 48 genes that can be methylated in gastric cancer cell lines. Most importantly, the methylation levels in the gastric mucosae of individuals without H. pylori infection correlated with their risk of gastric cancer. These findings show that a field for cancerization is formed by H. pylori infection and that this field can be measured using DNA methylation as a marker. The concept of an ""epigenetic field for cancerization"" has been also demonstrated for colon and breast cancers, and it is possibly present for other cancers and other diseases. Applied knowledge of epigenetic changes in human diseases has now started to make an impact on the prevention, diagnostics, and therapeutics of these diseases."
1518,"Field cancerization: Definition, epidemiology, risk factors, and outcomes.","Willenbrink TJ, Ruiz ES, Cornejo CM, Schmults CD, Arron ST, Jambusaria-Pahlajani A.",https://pubmed.ncbi.nlm.nih.gov/32387665/,"Field cancerization was first described in 1953 when pathologic atypia was identified in clinically normal tissue surrounding oropharyngeal carcinomas. The discovery of mutated fields surrounding primary tumors raised the question of whether the development of subsequent tumors within the field represented recurrences or additional primary tumors. Since this initial study, field cancerization has been applied to numerous other epithelial tissues, including the skin. Cutaneous field cancerization occurs in areas exposed to chronic ultraviolet radiation, which leads to clonal proliferations of p53-mutated fields and is characterized by multifocal actinic keratoses, squamous cell carcinomas in situ, and cutaneous squamous cell carcinomas. In the first article in this continuing medical education series, we define field cancerization, review the available grading systems, and discuss the epidemiology, risk factors, and outcomes associated with this disease."
1519,Embracing the complexity: Older adults with cancer-related cognitive decline-A Young International Society of Geriatric Oncology position paper.,"Pergolotti M, Battisti NML, Padgett L, Sleight AG, Abdallah M, Newman R, Van Dyk K, Covington KR, Williams GR, van den Bos F, Pollock Y, Salerno EA, Magnuson A, Gattás-Vernaglia IF, Ahles TA.",https://pubmed.ncbi.nlm.nih.gov/31619372/,"Cancer-related cognitive decline (CRCD) may have particularly significant consequences for older adults, impacting their functional and physical abilities, level of independence, ability to make decisions, treatment adherence, overall quality of life, and ultimately survival. In honor of Dr. Hurria's work we explore and examine multiple types of screening, assessment and non-pharmacologic treatments for CRCD. We then suggest future research and clinical practice questions to holistically appreciate the complexity of older adults with cancer's experiences and fully integrate the team-based approach to best serve this population."
1520,Laser-induced fluorescence spectroscopy for in vivo diagnosis of non-melanoma skin cancers.,"Panjehpour M, Julius CE, Phan MN, Vo-Dinh T, Overholt S.",https://pubmed.ncbi.nlm.nih.gov/12430156/," The 
    


          Study design/materials and  Two hundred and seventy nine measurements were performed from normal and abnormal tissues in 49 patients. Patients were classified as having either skin types I, II, or III. Biopsy of the abnormal tissues were then performed. Each measurement was assigned as either normal, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), pre-cancerous, or benign. Total emission photon count was used as the discriminating index. A threshold value was calculated to separate normal tissue indices from indices of cancer tissues. The classification accuracy of each data point was determined using the threshold value.
    


           Normal tissues were classified 93, 88, and 50% correctly in patients with skin types I, II, and III, respectively. Using the same threshold, pre-cancerous spectra were classified 78 and 100% correctly in skin types I and III, respectively. Benign lesions were classified 100, 46, and 27% correctly in patient with skin types I, II, and III, respectively.
    


          Conclusions:
        
      
      In vivo laser induced fluorescence spectroscopy at 410 nm excitation and using the intensity of emission signal is effective for detection of BCC, SCC, and actinic keratosis, specially in patients with light colored skin."
1521,A cellular automaton model of cancerous growth.,"Qi AS, Zheng X, Du CY, An BS.",https://pubmed.ncbi.nlm.nih.gov/8501923/,"A cellular automaton model describing immune system surveillance against cancer is furnished. In formulating the model, we have taken into account the microscopic mechanisms of cancerous growth, such as the proliferation of cancer cells, the cytotoxic behaviors of the immune system, the mechanical pressure inside the tumor and so forth. The model may describe the Gompertz growth of a cancer. The  The influences of the proliferation rate of cancer cells, the cytotoxic rate and other relevant factors affecting the Gompertz growth are studied."
1522,"Proteomic profiling of cancer--opportunities, challenges, and context.","Arnott D, Emmert-Buck MR.",https://pubmed.ncbi.nlm.nih.gov/20623483/,"The article by Roesch-Ely and colleagues in a recent issue of The Journal of Pathology describes the use of proteomic techniques to examine mucosal biopsies in patients with head and neck squamous cell cancer (HNSCC) and in corresponding control samples. The authors were able to determine the anatomical site of origin of the biopsies based on modelling of multiplex protein datasets, and to use the information to analyse field cancerization as a means of predicting tumour recurrence. Although the study included only a relatively small number of cases, and will require future validation in a larger patient cohort, the "
1523,Tumorigenesis as the Paradigm of Quasi-neutral Molecular Evolution.,"Chen B, Shi Z, Chen Q, Shen X, Shibata D, Wen H, Wu CI.",https://pubmed.ncbi.nlm.nih.gov/30912799/,"In the absence of both positive and negative selections, coding sequences evolve at a neutral rate (R = 1). Such a high genomic rate is generally not achievable due to the prevalence of negative selection against codon substitutions. Remarkably, somatic evolution exhibits the seemingly neutral rate R ∼ 1 across normal and cancerous tissues. Nevertheless, R ∼ 1 may also mean that positive and negative selections are both strong, but equal in intensity. We refer to this regime as quasi-neutral. Indeed, individual genes in cancer cells often evolve at a much higher, or lower, rate than R ∼ 1. Here, we show that 1) quasi-neutrality is much more likely when populations are small (N < 50); 2) stem-cell populations in single normal tissue niches, from which tumors likely emerge, have a small N (usually <50) but selection at this stage is measurable and strong; 3) when N dips below 50, selection efficacy decreases precipitously; and 4) notably, N is smaller in the stem-cell niche of the small intestine than in the colon. Hence, the ∼70-fold higher rate of phenotypic evolution (observed as cancer risk) in the latter can be explained by the greater efficacy of selection, which then leads to the fixation of more advantageous and fewer deleterious mutations in colon cancers. In conclusion, quasi-neutral evolution sheds a new light on a general evolutionary principle that helps to explain aspects of cancer evolution."
1524,Breast cancer stem cells and tumor suppressor genes.,"Hwang-Verslues WW, Chang KJ, Lee EY, Lee WH.",https://pubmed.ncbi.nlm.nih.gov/18926942/,"Studies of breast cancer stem cells are in their infancy and many fundamental questions have yet to be fully addressed. The molecular distinction between normal and cancerous breast stem cells is not clear. While there have been recent breakthroughs in mouse mammary stem cells and lineage determination in mammary glands, little has been determined in human cells. Microarray analyses have provided molecular categorization of breast cancer. However, the cellular origin of different types of breast cancer is largely unknown. In addition, the relationship between breast cancer stem cells and mammary progenitor cells has yet to be clarified. One of the key questions is how a normal mammary stem cell becomes a breast cancer stem cell. Importantly, the existence of different types of human breast cancers with distinct pathologic and molecular signatures suggests the possibility that different types of breast cancer stem cells may exist. Here, we aim to review the current evidence for the existence of different subtypes of breast cancer stem cells and provide further insight into how tumor suppressors might be involved in the initiation of breast cancer stem cells."
1525,[A study on cancers in the gastric remnant -from standpoint of radiology (author's transl)].,Tajiri H.,https://pubmed.ncbi.nlm.nih.gov/7262817/,"A radiologic study was done retrospectively of 51 cases with carcinoma of the gastric remnant. In each case, the gastric remnant was resected in Cancer Institute Hospital from January 1952 to December 1978, 1) Descriptive breakdown of the cases: a. 8 cases had benign lesions at the initial gastrectomy. b. 13 cases were found to have recurrent of cancer in the stump or metastasis. c. 16 cases had multiple cancerous lesions. d. 2 cases showed cancer in the reconstructed stomach after excision of esophageal carcinomas. 3. 12 cases had uncertain  2) Chief complaints: Four out of the six cases of early cancer were asymptomatic. In the advanced carcinomas, 22 cases (60%) complained of dysphagia. 3) Period of time until re-resection and periodic examination: The period of time from the initial gastric resection until re-resection was less than 5 years in 22 cases (45%) and greater than 5 years in 29 cases (57%). Thus, periodic examinations employing both x-ray and endoscopy are very important even after 5 years have elapsed since gastrectomy. 4) Radiologic examination of gastric remnant carcinomas: After gastrectomy, particularly in the early period, careful attention should be paid to hyperplastic or granulomatous changes located at the suture line of the lesser curvature and the anastomosis. The sites of remnant carcinomas were found most frequently along the sutured portion of the lesser curvature or the anterior and posterior parts of the gastric remnant in 11 cases (27.5%). Seven cases (17.5%) were found in the cardia and five cases (12.5%) in the anastomosed portion. Therefore, it is very important to perform double contrast radiographs from the left anterior oblique projection which is close to the right lie projection, and to take pictures of the sites from the lower esophagus to the cardia of the stomach."
1526,DeeP4med: deep learning for P4 medicine to predict normal and cancer transcriptome in multiple human tissues.,"Mahdi-Esferizi R, Haji Molla Hoseyni B, Mehrpanah A, Golzade Y, Najafi A, Elahian F, Zadeh Shirazi A, Gomez GA, Tahmasebian S.",https://pubmed.ncbi.nlm.nih.gov/37403016/," For the prevention and treatment of diseases, prediction plays a fundamental role. One of the intelligent strategies is the design of deep learning models that can predict the state of the disease using gene expression data.
    


           The range of the F1 score of the model, depending on tissue type in the Classifier, is from 0.935 to 0.999 and in Transferor from 0.944 to 0.999. The accuracy of DeeP4med for tissue and disease classification was 0.986 and 0.992, respectively, which performed better compared to seven classic machine learning models (Support Vector Classifier, Logistic Regression, Linear Discriminant Analysis, Naive Bayes, Decision Tree, Random Forest, K Nearest Neighbors).
    


          Conclusions:
        
      
      Based on the idea of DeeP4med, by having the gene expression matrix of a normal tissue, we can predict its tumor gene expression matrix and, in this way, find effective genes in transforming a normal tissue into a tumor tissue.  This led that by using the gene expression matrix, to train the model with features of each person in a normal and cancer state, this model could predict diagnosis based on gene expression data from healthy tissue and be used to identify possible therapeutic interventions for those patients."
1527,Prevalence of BRCA1 and BRCA2 Mutations Among High-risk Bahraini Patients with Breast Cancer.,"Bukamal Z, AlRayes A.",https://pubmed.ncbi.nlm.nih.gov/37283256/,"
    


           Approximately 12% of women worldwide will develop carcinoma of the breast sometime during their life. Additionally, 72% of women with an inherited BRCA1 mutation and 69% of those with a mutated BRCA2 will develop breast cancer by 80 years of age. The incidence of breast cancer in Bahraini women have increased over the last decade. Still, the data on BRCA1 & BRCA2 mutations in relation to breast cancer patients is limited in the Arab region, not omitting Bahrain as a country with deficient BRCA prevalence data.
    


          
    


           Out of 271 patients, 35 were excluded. Out of the 236 breast cancer patients, 219 (93%) did not have the mutation. The BRCA gene was carried by a total of 17 (7%) patients; 13 (5%) BRCA1 and 4 (2%) BRCA2. Thirteen BRCA carrier patients had invasive ductal carcinoma (IDC) (76%), 2 had ductal carcinoma in situ (DCIS) (12%), while 2 patients' histopathology was not available. Molecular subtypes showed 4 triple negative basal sub-type (TNBC), 10 positive ER and PR hormonal status, 1 positive HER-2, while 2 patients' hormonal receptor status was not available. Two BRCA1 carriers had both breast and ovarian cancers. A total of 5 (2%) breast cancer male patients were among the tested population, out of which, 1 (0.4% of the total and 20% of the male patients) was a BRCA2 carrier. Out of the 236 patients, 76 (32%) were younger than 40 years of age at the time of diagnosis. Then again, out of the 17 BRCA carrier patients, 7 (41%) were younger than 40 years.
    


          Conclusion:
        
      
      The prevalence of BRCA mutation in high risk Bahraini breast cancer patients is 7%. Among those patients, BRCA1 mutation is the most prevalent (5%) and invasive ductal carcinoma (IDC) is the most common histopathological subtype. However, there was not enough data to conclude the most prevalent molecular subtype of breast cancer in BRCA carriers due to deficiency of overseas pathology reports for patients operated outside Bahrain. When developing treatment plans for younger patients with breast cancer, inherited syndromes and precisely BRCA mutations need to be considered. Bahrain is implementing genetic testing for breast cancer patients ≤ 50 years of age since 2018, according to NCCN guidelines. We will continue to build our database to better characterize breast cancer subtypes and determine their hereditary pattern for identification of high risk families in Bahrain and for future development of more specific therapeutic approaches.
    


          Key words:
        
      
      Breast cancer, BRCA1, BRCA2, BRCA mutation, Bahrain, Arab region."
1528,Oral field cancerization: history and future perspectives.,"Gabusi A, Morandi L, Asioli S, Foschini MP.",https://pubmed.ncbi.nlm.nih.gov/28635994/,"Notwithstanding extended surgical approaches or adjuvant chemoradiotherapy, the development of multiple neoplastic lesions arising in the oral cavity after treatment still represents a critical clinical challenge in the management of patients with oral squamous cell carcinoma. Such clinical behavior of oral squamous cell carcinoma is nowadays better known as ""field"" cancerization effect as suggested by Slaughter, the author that for the first time tried to describe it in a scientific paper. Field cancerization is now widely accepted not only in head and neck oncology but also in other anatomical districts as well as in different types of epithelial neoplasia. A brief history of the theory of field cancerization is here proposed and future perspectives deriving from new molecular techniques are discussed."
1529,Second primary tumors in laryngeal cancer: results of long-term follow-up.,"Narayana A, Vaughan AT, Fisher SG, Reddy SP.",https://pubmed.ncbi.nlm.nih.gov/9806515/,"Purpose:
        
      
      The development of second primary tumors (SPTs) is the most important factor determining the survival in early-stage head and neck cancer patients, whose first tumor has been successfully treated. New  The 
    


           The incidence, time to development, and survival of aerodigestive and other SPTs were noted. p53 overexpression indicating a mutated p53 gene was analyzed by immunohistochemistry.
    


           The actuarial incidence of developing a SPT at 5, 10, and 15 years was 23%, 44%, and 48.7% respectively. The median time interval for development of SPT in an upper aerodigestive tract was 21 months as opposed to 50 months for other sites (p = 0.02). The most common sites of SPTs included lung for upper aerodigestive tract; and prostate, followed by colon, for other sites. The actuarial risk of developing a nonaerodigestive SPT at 5 and 10 years was 35% and 55% respectively. p53 status affected neither the incidence of SPT nor the survival. SPTs were the leading cause of death in these early-stage laryngeal cancer patients.
    


          Conclusion:
        
      
      The origin of SPTs seems to be multifactorial, involving both the field cancerization effect and an increased baseline genetic predisposition. Until more reliable genetic markers are developed, chemoprevention remains the best treatment option at preventing SPTs in these early-stage patients."
1530,Epithelial ovarian cancer: role of pegylated liposomal Doxorubicin in prolonging the platinum-free interval and cancer antigen 125 trends during treatment.,"Tanguay JS, Ansari J, Buckley L, Fernando I.",https://pubmed.ncbi.nlm.nih.gov/19407560/," Platinum-free interval predicts subsequent platinum sensitivity and is a prognostic factor. Little has been published on the effect of pegylated liposomal doxorubicin (PLD) in the prolongation of treatment-free interval.
    


           All patients treated with PLD had progressed within 12 months of prior platinum therapy. Cancer antigen 125 fluctuations were categorized as the variances from the baseline (+/-10%, +/-10%-25%, and >25%). The response to chemotherapy was defined as Ca125 reduction from the baseline of more than 50%, clinical, or radiological response.
    


           The response rate (RR) to PLD was 28.9%, and the median overall survival from PLD initiation was 62 weeks. The number of women demonstrating more than 25% reduction in Ca125 from the baseline increased progressively with each cycle; at cycle 2, 11%; cycle 3, 18%; cycle 4, 22%; and cycle 5, 27% (trend significant between cycles 2 and 4, P = 0.004). Fifteen patients were re-treated with platinum after progression after PLD with 80% (12/15) of the patients responding. The RR to platinum retreatment after PLD compares favorably with the historical data on the response to second-line platinum retreatment.
    


          Conclusions:
        
      
      The sole use of early Ca125 trends in PLD treatment before cycle 4 may  Retreatment with platinum after PLD may yield a good RR in selected patients even those with disease progression within 12 months after prior platinum treatment."
1531,Gastric Cancer as Preventable Disease.,"Rugge M, Genta RM, Di Mario F, El-Omar EM, El-Serag HB, Fassan M, Hunt RH, Kuipers EJ, Malfertheiner P, Sugano K, Graham DY.",https://pubmed.ncbi.nlm.nih.gov/28532700/,"Gastric cancer, 1 of the 5 most common causes of cancer death, is associated with a 5-year overall survival rate less than 30%. A minority of cancers occurs as part of syndromic diseases; more than 90% of adenocarcinomas are considered as the ultimate consequence of a longstanding mucosal inflammation. Helicobacter pylori infection is the leading etiology of non-self-limiting gastritis, which may  Gastric atrophy establishes a field of cancerization prone to further molecular and phenotypic changes, possibly  This well-understood natural history provides the clinicopathologic rationale for primary and secondary cancer prevention strategies. A large body of evidence demonstrates that combined primary (H pylori eradication) and secondary (mainly endoscopy) prevention efforts may prevent or limit the progression of gastric oncogenesis. This approach, which is tailored to different country-specific gastric cancer incidence, socioeconomic, and cultural factors, requires that the complementary competences of gastroenterologists, oncologists, and pathologists be amalgamated into a common strategy of health policy."
1532,Advances in management of malignant diseases with the combination of radiation therapy and chemotherapy. Highlights from the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology.,Corn BW.,https://pubmed.ncbi.nlm.nih.gov/14988771/,"From October 19 through October 24, 2003, the American Society for Therapeutic Radiology and Oncology held its 45th Annual Meeting in Salt Lake City, Utah. The meeting was devoted to the presentation of advances in the management of malignant diseases with radiation modalities. The meeting brought together investigators, clinicians, policy makers and professionals interested in the science and impact of radiation on cancerous disease. This report examines the advances in combined modality approaches (i.e., the use of radiation therapy and chemotherapy) for the treatment of malignant disease. The American Society for Therapeutic Radiology and Oncology sponsors an annual meeting devoted to the presentation of radiation-related advances in malignant disorders. The educational elements of this program are targeted at oncologists of all disciplines (i.e., surgical oncologists, medical oncologists, radiation oncologists), physicists, biologists, nurses, and therapists as well as all health care workers who are involved in the treatment of patients with malignant diseases. The program includes presentations on standard, investigational and  Specific clinical areas include breast, central nervous system, gastrointestinal, genitourinary, gynecological, head and neck, and lung cancers. In addition, the program addresses quality of life, supportive care and socioeconomic issues. These topics are addressed by a combination of educational sessions, panel discussions, proffered papers and posters. Since a diminishing number of tumors can be managed solely by radiation therapy, among the most noteworthy developments this year were the combined modality approaches (i.e. radiation therapy combined with chemotherapy) in the treatment of malignant disease. In particular, a cluster of seminal papers was presented pertaining to colorectal and pulmonary (both small cell and non-small cell lung cancer) malignancies. This report focuses on the advances reported for those tumor types, which are among the most prevalent in the Western world."
1533,[ATM and Cancer].,Tang Y.,https://pubmed.ncbi.nlm.nih.gov/12513844/,"The mutation of AT gene (ATM) leads to the AT disease (ataxia telangiectasis), the cancer incidence of AT patients and its carriers are significantly higher than the normal persons. And they are easy to have lymphoid tumors, including the lymphoma and leukemia et al. These indicate the ATM play a important role in the cancers pathogenesis mechanism. The ATM gene locate in the human chromosome 11q22-23, and the ATM is a kind of nuclear protein, its major functional domain is P13K (phosphatidylinositol 3-kinase), locates on the carboxy terminus. ATM protein plays a critical role in the signal transduction of cell cycle checkpoint, the repair of damaged DNA and the apoptosis. The mutation of the ATM gene leads to the functional and structural change of ATM protein in the AT patient, then leads to the abnormality of cell cycle checkpoint and the DNA damage repair, the apoptosis sensitivity increase. So the AT patients and their cells are radiosensitive, the characteristic of AT patient suggests the ATM gene is valuable in the cancer's gene therapy"
1534,Evaluation of Malnutrition and Quality of Life in Patients Treated for Oral and Oropharyngeal Cancer.,"Pingili S, Ahmed J, Sujir N, Shenoy N, Ongole R.",https://pubmed.ncbi.nlm.nih.gov/34381320/," Depending on the site and extent of the involvement of the cancer and the type of treatment modality, these patients can develop pain, trismus, xerostomia, dysphagia, and taste disturbances, compromising them socially and nutritionally. The aim of the study was to evaluate malnutrition and quality of life in patients treated for oral and oropharyngeal cancer.  A cross-sectional study was conducted which included 97 patients treated for oral and oropharyngeal cancer. The quality of life of the selected patients was assessed by using a validated European Organization for the Research and Treatment of Cancer's Quality of Life Questionnaire, Head and Neck and Mandibular Function Impairment Questionnaire. Pre- and posttreatment weight of the patients were assessed, and weight loss of ≥10% of pretreatment weight was considered as malnutrition. The chi-square test was used to correlate the symptoms with the quality of life. A paired t test was used to assess the differences in weight before and after treatment, and a p value of <0.005 was considered as significant.
    


          81%), pain (81.44%), and dysphagia (76.3%). A total of 40.2% of the individuals in the study had malnutrition. Malnutrition was comparatively lower in the group who had nutritional supplements.
    


          Conclusion:
        
      
      The quality of life in patients treated for oral and oropharyngeal cancer deteriorates immediately after the treatment; however, it significantly improves over time."
1535,Implications of photodynamic cancer therapy: an overview of PDT mechanisms basically and practically.,"Sobhani N, Samadani AA.",https://pubmed.ncbi.nlm.nih.gov/34778919/," In this account, besides the molecular genetics  Photodynamic therapy (PDT) as a relatively noninvasive therapeutic  In this procedure, a series of events lead to the direct death of malignant cells such as damage to the microvasculature and also the induction of a local inflammatory function. PDT has participated with other treatment modalities especially in the early stage of malignant tumors and has  High spatial resolution of PDT has attracted considerable attention in the field of image-guided photodynamic therapy combined with chemotherapy of multidrug resistance cancers. Although PDT outcomes vary across the different tumor types, minimal natural tissue toxicity, minor systemic effects, significant reduction in long-term disease, lack of innate or acquired resistance mechanisms, and excellent cosmetic effects, as well as limb function, make it a valuable treatment option for combination therapies.
    


          Short conclusion:
        
      
      In this review article, we tried to discuss the potential of PDT in the treatment of some dermatologic and solid tumors, particularly all its important mechanisms."
1536,Beneficial role of insect-derived bioactive components against inflammation and its associated complications (colitis and arthritis) and cancer.,"Dutta P, Sahu RK, Dey T, Lahkar MD, Manna P, Kalita J.",https://pubmed.ncbi.nlm.nih.gov/31542397/,"Insect-based bioactive components are emerging as novel sources of drugs, effective against various diseases. Inflammation is considered to be an innate immune response developed by different organisms against foreign pathogens and cellular stress. However, repetitive elevated inflammation is considered to be responsible for development of many other diseases including colitis and arthritis. Due to the limited activities and side effects of non-steroidal anti-inflammatory drugs, researchers are continuously looking for alternative sources of drug molecules to alleviate the inflammatory related complications. Recently, insect-based bioactive components, such as venoms, haemocytes, cecropin A, papiliocin, N-acetyldopamine dimers, cecropin-TY1 peptide, cop A3 peptide, glycosaminoglycan, coprisin peptide, silk fibroin microparticles, and silk fibroin nanoparticles have been found to be active against different inflammatory mechanisms and associated diseases. Cancers, are some of the deadliest diseases, which are mainly treated by chemotherapy, radiation therapy and surgery. However, such treatments, mainly chemotherapy, is associated with enormous side effects. Therefore, as an alternative, less hazardous option, compounds from insects with anti-cancerous activity are being explored. Insect-derived compounds, such as cantharidin, norcantharidin, isocoumarin, plancyols A, plancypyrazine A, pancratistatin, narciclasine, and ungeremine, show potential anti-cancerous activity. In this review, we will be discussing the role of different potential drug molecules of insect origin with special emphasis on anti-inflammation and their association with health disorders and cancer."
1537,Combining radiotherapy and immunotherapy in definitive treatment of head and neck squamous cell carcinoma: review of current clinical trials.,"Plavc G, Strojan P.",https://pubmed.ncbi.nlm.nih.gov/33064670/," Since immune checkpoint inhibitors (ICI) have shown clinically significant efficacy in patients with recurrent/metastatic HNSCC (R/M HNSCC), a plethora of trials are investigating their role in earlier stages of disease. At the same time, preclinical data showed the synergistic role of concurrently administered radiotherapy and ICIs (immunoradiotherapy) and explained several mechanisms behind it. Therefore, this approach is prospectively tested in a neoadjuvant, definitive, or adjuvant setting in non-R/M HNSCC patients. Due to the intricate relationship between host, immunotherapy, chemotherapy, and radiotherapy, each of these approaches has its advantages and disadvantages. In this narrative review we present the biological  Conclusions While immunotherapy with ICIs has already become a standard part of treatment in patients with R/M HNSCC, its efficacy in a non-R/M HNSCC setting is still the subject of extensive clinical testing. Irradiation can overcome some of the cancer's immune evasive manoeuvres and can lead to a synergistic effect with ICIs, with possible additional benefits of concurrent platinum-based chemotherapy. However, the efficacy of this combination is not robust and details in trial design and treatment delivery seem to be of unprecedented importance."
1538,Growth of diploid cells from breast cancers.,"Wolman SR, Smith HS, Stampfer M, Hackett AJ.",https://pubmed.ncbi.nlm.nih.gov/3971331/,Cell cultures were derived from normal and cancerous breast tissues and from metastases by  Karyotypic analyses of first or second passage cultures yielded predominantly normal diploid cells. Nonclonal aberrations were more common in tumor-derived than in normal cultures. Three of the cultures that originated from metastases were characterized by abnormal clones. These  They differ greatly from chromosomal findings in long-term cultures of tumor effusions and thus emphasize the karyotypic diversity that can be found in tumors from a single tissue of origin--the breast.
1539,Stellate Cells in the Tumor Microenvironment.,"Roife D, Sarcar B, Fleming JB.",https://pubmed.ncbi.nlm.nih.gov/32588324/,"As tumor microenvironments share many of the same qualities as chronic wounds, attention is turning to the wound-repair cells that support the growth of cancerous cells. Stellate cells are star-shaped cells that were first discovered in the perisinusoidal spaces in the liver and have been found to support wound healing by the secretion of growth factors and extracellular matrix. They have since been also found to serve a similar function in the pancreas. In both organs, the wound-healing process may become dysregulated and lead to pathological fibrosis (also known as cirrhosis in the liver). In recent years there has been increasing attention paid to the role of these cells in tumor formation and progression. They may be a factor in initiating the first steps of carcinogenesis such as with liver cirrhosis and hepatocellular carcinoma and also contribute to continued tumor growth, invasion, metastasis, evasion of the immune system, and resistance to chemotherapy, in cancers of both the liver and pancreas. In this chapter we aim to review the structure and function of hepatic and pancreatic stellate cells and their contributions to the tumor microenvironment in their respective cancers and also discuss potential new targets for cancer therapy based on our new understanding of these vital components of the tumor stroma."
1540,"Glycoconjugate with Ulex europaeus agglutinin-I-binding sites in normal mucosa, adenoma, and carcinoma of the human large bowel.","Yonezawa S, Nakamura T, Tanaka S, Sato E.",https://pubmed.ncbi.nlm.nih.gov/6181281/,"Cancerous lesions and nonneoplastic mucosa of surgically extirpated specimens from 94 patients with colorectal carcinoma (of the right colon, 31 patients; of the left colon, 29 patients; and of the rectum, 34 patients) and endoscopically polypectomized specimens from 18 patients with rectal adenoma were examined with fluorescein isothiocyanate-conjugated or horse-radish peroxidase-conjugated Ulex europaeus agglutinin-I (UEA-I) specific to a certain terminal alpha-L-fucosyl residue in glycoconjugates. Of the 31 patients with right colon cancers, 22 showed positive UEA-I binding in the neoplastic cell apexes, apical luminal borders, and luminal secretions. The adjacent nonneoplastic mucosa of all 31 patients, however, demonstrated positive UEA-I binding in the goblet cell mucus. UEA-I binding was positive for 23 of the 29 left colon cancers and for 28 of the 34 rectal cancers, although UEA-I binding was not revealed in the adjacent nonneoplastic mucosa for most of the cases. Of the 18 rectal adenomas, 12 specimens showed positive UEA-I binding in the apical secretions of their adenoma cells. Marked regional differences of UEA-I binding in the nonneoplastic mucosae indicated that the constituents of glycoprotein with UEA-I binding sites in goblet cell mucus differed significantly between the human right and left large bowels. Positive UEA-I binding in many rectal cancerous and adenomatous lesions suggested that a neoplastic glycoprotein with alpha-L-fucosyl residue was produced or that the terminal carbohydrate structure of glycoprotein present in the nonneoplastic mucosa was altered to bind easily with UEA-I after the neoplastic transformation had occurred. A possible relation of this UEA-I binding to blood group H(O) substance is discussed."
1541,"The lipid-chemical features of the metastatic tissues into the liver from the human gastric cancer, large intestinal cancer and malignant insulinoma.","Nakazawa I, Ohtsuki M, Goto Y.",https://pubmed.ncbi.nlm.nih.gov/212845/,"In order to clarify the biochemical features of metastatic tissues into the liver of human cancerous cells, 12 of primary cancerous tissues and 3 of metastatic tissues of the large intestinal cancer, 6 of primary cancerous tissues and 2 of metastatic tissues of the gastric cancer, and 3 of primary cancerous tissues and 3 of metastatic tissues of malignant insulinoma were studied lipid-chemically. Cancerous tissues and metastatic tissues into the liver were collected by biopsy or surgical operation. From each tissue, the total lipid was extracted and one part of the total lipid was separated into phospholipid and triglyceride by TLC. Then, the fatty acid composition and the fatty acid content of each lipid fraction were measured by GLC. The most remarkable findings were recognized in the phospholipid fatty acid composition of the tissues. Namely, the percentage values of C14:0 and C16:1 were larger and that of C20:4 was smaller in metastatic tissues than those of gastric primary lesions. As for the large intestinal cancer, the percentage value of C18:1 was smaller and that of C18:2 larger in metastatic tissues than those of primary lesions. In the malignant insulinoma, the percentage value of C18:0 was larger in metastatic tissues than that of the primary lesions."
1542,"Potential Therapeutic Targets of Quercetin, a Plant Flavonol, and Its Role in the Therapy of Various Types of Cancer through the Modulation of Various Cell Signaling Pathways.","Almatroodi SA, Alsahli MA, Almatroudi A, Verma AK, Aloliqi A, Allemailem KS, Khan AA, Rahmani AH.",https://pubmed.ncbi.nlm.nih.gov/33804548/,"Polyphenolic flavonoids are considered natural, non-toxic chemopreventers, which are most commonly derived from plants, fruits, and vegetables. Most of these polyphenolics exhibit remarkable antioxidant, anti-inflammatory, and anticancer properties. Quercetin (Qu) is a chief representative of these polyphenolic compounds, which exhibits excellent antioxidant and anticancer potential, and has attracted the attention of researchers working in the area of cancer biology. Qu can regulate numerous tumor-related activities, such as oxidative stress, angiogenesis, cell cycle, tumor necrosis factor, proliferation, apoptosis, and metastasis. The anticancer properties of Qu mainly occur through the modulation of vascular endothelial growth factor (VEGF), apoptosis, phosphatidyl inositol-3-kinase (P13K)/Akt (proteinase-kinase B)/mTOR (mammalian target of rapamycin), MAPK (mitogen activated protein kinase)/ERK1/2 (extracellular signal-regulated kinase 1/2), and Wnt/β-catenin signaling pathways. The anticancer potential of Qu is documented in numerous in vivo and in vitro studies, involving several animal models and cell lines. Remarkably, this phytochemical possesses toxic activities against cancerous cells only, with limited toxic effects on normal cells. In this review, we present extensive research investigations aimed to discuss the therapeutic potential of Qu in the management of different types of cancers. The anticancer potential of Qu is specifically discussed by focusing its ability to target specific molecular signaling, such as p53, epidermal growth factor receptor (EGFR), VEGF, signal transducer and activator of transcription (STAT), PI3K/Akt, and nuclear factor kappa B (NF-κB) pathways. The anticancer potential of Qu has gained remarkable interest, but the exact mechanism of its action remains unclear. However, this natural compound has great pharmacological potential; it is now believed to be a complementary-or alternative-medicine for the prevention and treatment of different cancers."
1543,Dysregulated expression of long noncoding RNAs in gynecologic cancers.,"Hosseini ES, Meryet-Figuiere M, Sabzalipoor H, Kashani HH, Nikzad H, Asemi Z.",https://pubmed.ncbi.nlm.nih.gov/28637507/,"Cancers of the female reproductive system include ovarian, uterine, vaginal, cervical and vulvar cancers, which are termed gynecologic cancer. The emergence of long noncoding RNAs (lncRNAs), which are believed to play a crucial role in several different biological processes, has made the regulation of gene expression more complex. Although the function of lncRNAs is still rather elusive, their broad involvement in the initiation and progression of various cancers is clear. They are also involved in the pathogenesis of cancers of the female reproductive system. LncRNAs play a critical physiological role in apoptosis, metastasis, invasion, migration and cell proliferation in these cancers. Different expression profiles of lncRNAs have been observed in various types of tumors compared with normal tissues and between malignant and benign tumors. These differential expression patterns may lead to the promotion or suppression of cancer development and tumorigenesis. In the current review, we present the lncRNAs that show a differential expression between cancerous and normal tissues in ovarian, cervical and endometrial cancers, and highlight the associations between lncRNAs and some of the molecular pathways involved in these cancers."
1544,DNA promoter hypermethylation in nipple fluid: a potential tool for early breast cancer detection.,"de Groot JS, Moelans CB, Elias SG, Jo Fackler M, van Domselaar R, Suijkerbuijk KP, Witkamp AJ, Sukumar S, van Diest PJ, van der Wall E.",https://pubmed.ncbi.nlm.nih.gov/27028854/," DNA promoter hypermethylation (""methylation"") occurs early and at high frequency in breast carcinogenesis, bearing the potential as a biomarker for cancer detection at its earliest stages. We assessed methylation in nipple fluid from breasts of healthy women, of women with sporadic breast cancer and of their contralateral breasts. Our goal was to investigate whether nipple fluid can be used as a reliable methylation biomarker source.
    


          Materials and 
    


           Despite the generally low methylation levels, cancerous and healthy breasts nipple fluid could be discriminated with an area under the receiver operating characteristic curve (AUC) of 0.64 (p<0.01) based on a multivariate model including AKR1B1, ALX1, RASSF1A and TM6SF1. Within-patient differences between cancerous and contralateral nipple fluid samples were less prominent.
    


          Conclusions:
        
      
      Cancerous nipple fluid contains increased levels of methylation of tumor suppressor genes that potentially could serve as a biomarker for early breast cancer detection."
1545,Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids.,"Zaidi N, Lupien L, Kuemmerle NB, Kinlaw WB, Swinnen JV, Smans K.",https://pubmed.ncbi.nlm.nih.gov/24001676/,"One of the most important metabolic hallmarks of cancer cells is enhanced lipogenesis. Depending on the tumor type, tumor cells synthesize up to 95% of saturated and mono-unsaturated fatty acids (FA) de novo in spite of sufficient dietary lipid supply. This lipogenic conversion starts early when cells become cancerous and further expands as the tumor cells become more malignant. It is suggested that activation of FA synthesis is required for carcinogenesis and for tumor cell survival. These observations suggest that the enzymes involved in FA synthesis would be rational therapeutic targets for cancer treatment. However, several recent reports have shown that the anti-tumor effects, following inhibition of endogenous FA synthesis in cancer cell lines may be obviated by adding exogenous FAs. Additionally, high intake of dietary fat is reported to be a potential risk factor for development and poor prognosis for certain cancers. Recently it was reported that breast and liposarcoma tumors are equipped for both de novo fatty acid synthesis pathway as well as LPL-mediated extracellular lipolysis. These observations indicate that lipolytically acquired FAs may provide an additional source of FAs for cancer. This review focuses on our current understanding of lipogenic and lipolytic pathways in cancer cell progression."
1546,TRAIL mediates apoptosis in cancerous but not normal primary cultured cells of the human reproductive tract.,"Sadarangani A, Kato S, Espinoza N, Lange S, Llados C, Espinosa M, Villalón M, Lipkowitz S, Cuello M, Owen GI.",https://pubmed.ncbi.nlm.nih.gov/17136491/,"Cancer of the reproductive tract encompasses malignancies of the uterine corpus, cervix, ovary, Fallopian tube, among others and accounts for 15% of female cancer mortalities. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates apoptosis by binding to death receptors and offers a promising cancer treatment. The goal of this study was to investigate and characterize the effect of TRAIL in endometrial cancer cell lines and normal (non-cancerous) epithelial cells of endometrial origin. We also examined the effect of TRAIL in other primary cultured cancers and normal cells of the human female reproductive tract and evaluated if TRAIL mediated apoptosis correlated with death receptors and decoy receptors 1 and 2.Herein, we demonstrate that TRAIL at concentrations which kill cancerous cells, does not mediate apoptosis or alter cell viability in normal human endometrium, ovary, cervix or Fallopian tube. The partial inhibition by a caspase 9 inhibitor and the total inhibition by a caspase 8 inhibitor demonstrates the dependency on the extrinsic apoptotic pathway. The selective mortality does not correlate with the presence of death or decoy receptors. These "
1547,Peptides as Potential Anticancer Agents.,"Aaghaz S, Gohel V, Kamal A.",https://pubmed.ncbi.nlm.nih.gov/30686254/,"Cancer consists of heterogeneous multiple cell subpopulation which at a later stage develop resistant phenotypes, which include resistance to pro-apoptotic stimuli and/or cytotoxic resistance to anticancer compounds. The property of cancerous cells to affect almost any part of the body categorizes cancer to many anatomic and molecular subtypes, each requiring a particular therapeutic intervention. As several modalities are hindered in a variety of cancers and as the cancer cells accrue varied types of oncogenic mutations during their progression the most likely benefit will be obtained by a combination of therapeutic agents that might address the diverse hallmarks of cancer. Natural compounds are the backbone of cancer therapeutics owing to their property of affecting the DNA impairment and restoration mechanisms and also the gene expression modulated via several epigenetic molecular mechanisms. Bioactive peptides isolated from flora and fauna have transformed the arena of antitumour therapy and prompt progress in preclinical studies is promising. The difficulties in creating ACP rest in improving its delivery to the tumour site and it also must maintain a low toxicity profile. The substantial production costs, low selectivity and proteolytic stability of some ACP are some of the factors hindering the progress of peptide drug development. Recently, several publications have tried to edify the field with the idea of using peptides as adjuvants with established drugs for antineoplastic use. This review focuses on peptides from natural sources that precisely target tumour cells and subsequently serve as anticancer agents that are less toxic to normal tissues."
1548,Endocrinology in cancer of the breast. Status and prospects.,Brennan MJ.,https://pubmed.ncbi.nlm.nih.gov/173180/,"Breast cancer is the  Initiation, promotion, dependency and autonomy make up a sequence of  Progression--the transition from dependency on hormonal support to autonomy--is demonstrable clinically. High-affinity saturatable estrogen binding by breast cancer cytosols distinguishes endocrine-responsive mammary neoplasms from autonomous breast cancers. Approximately 70% of neoplasms containing estrogen-recepor protein at a level of 2.5 femtomoles per mg. protein or higher regress after endocrine ablation (ovariectomy in premenopausal women; adrenalectomy or hypophysectomy in postmenopausal women). Only about 5% of neoplasms lacking the receptor will respond to these maneuvers. Estrogen-receptor content also predicts clinically for estrogen and androgen responsiveness, and  Fifty per cent of primary breast cancers in women are receptor-positive. Normal breast tissue and benign breast lesions characteristically lack receptor protein. The receptor proteins appear to be induced in neoplastic cells during mammary carcinogenesis in endocrinologic settings where non-cancerous breast cells do not contain free receptor in large amounts and fail to manifest endocrinologic growth stimulation. Implications of these findings for endocrinologic management of disseminated mammary cancer, adjuvant therapy, and breast cancer prevention are discussed."
1549,The role of molecular discreteness in normal and cancerous growth.,Michaelson J.,https://pubmed.ncbi.nlm.nih.gov/10697599/,"The physicochemical events that underlie biological processes are inevitably either/or events. Either a growth factor molecule binds to a cell, or it doesn't. Either a site on a cyclin molecule is phosphorylated, or it isn't. Either a regulatory molecule binds to a DNA sequence, or it doesn't. These molecular either/or events lead to cellular either/or events. Either a cell divides, or it doesn't. Either a cell dies, or it doesn't. Either a cell turns on a particular gene, or it doesn't. Either a tumor cell stays where it is, or it forms a distant metastasis. By considering biological processes as the macroscopic aggregate  In fact, as will be outlined here, such discrete modeling may allow us to see how the normal cellular populations of the body can grow to predictable sizes, at predictable times, and to predictable shapes. Such modeling can also allow us to gain insight into how normal cellular populations may become cancerous cellular populations. Indeed, such an approach allows us do a sufficiently good job of imitating the growth and spread of tumors as to be able to make estimates the most effective ways to both detect and treat cancer."
1550,Precancerous lesions in the stomach: from biology to clinical patient management.,"Rugge M, Capelle LG, Cappellesso R, Nitti D, Kuipers EJ.",https://pubmed.ncbi.nlm.nih.gov/23809241/,"Gastric cancer is the final step in a multi-stage cascade triggered by long-standing inflammatory conditions (particularly Helicobacter pylori infection)  Intraepithelial neoplasia is consistently recognized as the phenotypic bridge between atrophic/metaplastic lesions and invasive cancer. This paper addresses the epidemiology, pathology, molecular profiling, and clinical management of advanced precancerous gastric lesions."
1551,Five-year survival after surgical treatment for kidney cancer: a population-based competing risk analysis.,"Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK.",https://pubmed.ncbi.nlm.nih.gov/17351954/," Although surgery rates have paralleled this incidence trend, mortality continues to rise, calling into question the necessity of surgery for all patients with renal masses. Using a population-based cohort, a competing risk analysis was performed to estimate patient survival after surgery for kidney cancer, as a function of patient age and tumor size at diagnosis.
    


           Patients were sorted into 20 age-tumor size categories and the numbers of patients that were alive, dead from kidney cancer, and dead from other causes were tabulated. Poisson regression models were fitted to obtain estimates of cancer-specific and competing-cause mortality.
    


           Patients with the smallest tumors enjoyed the lowest cancer-specific mortality (5% for masses<or=4 cm). Competing-cause mortality rose with increasing patient age. The estimated 5-year competing-cause mortality for elderly subjects (>or=70 years) was 28.2% (95% confidence interval [CI]: 25.9%-30.8%), irrespective of tumor size.
    


          Conclusions:
        
      
      Despite surgical therapy, competing-cause mortality for patients with renal masses rises with increasing patient age. After 5 years, one-third of elderly patients (>or=70 years) will die from other causes, suggesting the need for prospective studies to evaluate the role of active surveillance as an initial therapeutic approach for some small renal masses."
1552,"[Long-term results after surgery for colorectal adenocarcinoma, stage I-III. Problems of prognosis].","Georgescu SO, Neacşu CN, Vintilă D, Popa P, Forţu L, Nistor A, Ferariu D, Târcoveanu E.",https://pubmed.ncbi.nlm.nih.gov/18389783/,"Colorectal cancer is one of the leading causes of cancer-related death worldwide.
    


          Study design:
        
      
      Prospective study on 142 consecutively cases with stage I to III colorectal adenocarcinomas (TNM AJCC/UICC) in which patients underwent potentially curative surgery in one single public health service (1st Surgical Clinic Iaşi, Romania) between 2004 and 2005.
    


          Material and 26 +/- 9.78 months (range 2 to 42 months). There were 85 men (59.9%) and 57 women (40.1%) with mean age 63.38 +/- 11.84 years (range 28 to 88 years). The surgical procedures performed were the following: right colectomy (n = 54; 30%); transverse colectomy (n = 2; 1.4%); left colectomy (n = 19; 13.4%); segmental colon resection with anastomosis (n = 5 ; 3.5%); Hartmann procedure (n = 18; 12.7%); anterior rectal resection (n = 11; 7.7%) and abdominoperineal resection (n = 33; 23.2%). With regard to postoperative adjuvant therapy most patients were given chemotherapeutic agents such as 5-fluorouracil and folinic acid. The mean overall survival (months) and 42-months survival rates were calculated. The patients were censored in the survival calculation (Kaplan-Meier  Some patients were censored because they were ""lost to follow-up"". Statistical significance is p < 0.05.
    


          
    


          Conclusion:
        
      
      Even with a radical surgical approach the advanced stage of colorectal adenocarcinoma has a low prognostic, but some other factors have also a high significance in postoperative outcome. Related to other prognostic factors we performed a review of literature."
1553,ImmCluster: an ensemble resource for immunology cell type clustering and annotations in normal and cancerous tissues.,"Jiang T, Zhou W, Sheng Q, Yu J, Xie Y, Ding N, Zhang Y, Xu J, Li Y.",https://pubmed.ncbi.nlm.nih.gov/36271790/,"Single-cell transcriptome has enabled the transcriptional profiling of thousands of immune cells in complex tissues and cancers. However, subtle transcriptomic differences in immune cell subpopulations and the high dimensionality of transcriptomic data make the clustering and annotation of immune cells challenging. Herein, we introduce ImmCluster (http://bio-bigdata.hrbmu.edu.cn/ImmCluster) for immunology cell type clustering and annotation. We manually curated 346 well-known marker genes from 1163 studies. ImmCluster integrates over 420 000 immune cells from nine healthy tissues and over 648 000 cells from different tumour samples of 17 cancer types to generate stable marker-gene sets and develop context-specific immunology references. In addition, ImmCluster provides cell clustering using seven reference-based and four marker gene-based computational  Five major analytic modules were provided for interactively exploring the annotations of immune cells, including clustering and annotating immune cell clusters, gene expression of markers, functional assignment in cancer hallmarks, cell states and immune pathways, cell-cell communications and the corresponding ligand-receptor interactions, as well as online tools. ImmCluster generates diverse plots and tables, enabling users to identify significant associations in immune cell clusters simultaneously. ImmCluster is a valuable resource for analysing cellular heterogeneity in cancer microenvironments."
1554,Molecular biology of lung cancer: clinical implications.,"Fong KM, Minna JD.",https://pubmed.ncbi.nlm.nih.gov/11901922/,"This review summarizes the rapidly expanding knowledge of the molecular pathogenesis of lung cancer. It is clear that respiratory epithelial cells require many genetic alterations to become invasive and metastatic cancer. Much more is to be learned, but with modern technology. Clinicians can detect ""field cancerized"" regions and preneoplastic and malignant cells, therefore offering the opportunity to intercede with biomarker-monitored prevention and early detection efforts. Such molecular screening and detection efforts will likely be coupled to advances in low-dose computed tomographic imaging, positron emission tomography scans, and other imaging modalities. Although this molecular marker approach has great potential, there is not yet a molecular marker validated in large prospective trials that has major independent predictive prognostic value. There is an urgent need for large, adequately powered, carefully designed prospective studies to identify clinically useful new biomarkers. Finally, new therapeutic strategies with genetic manipulation, small molecules, antibodies, vaccines, and, particularly, new drugs targeting specific biologic pathways found to be abnormal in lung provide for future optimism. Researchers need to define their individual value, especially when integrated with standard therapies."
1555,Sonic hedgehog expression in gastric cancer and gastric adenoma.,"Lee SY, Han HS, Lee KY, Hwang TS, Kim JH, Sung IK, Park HS, Jin CJ, Choi KW.",https://pubmed.ncbi.nlm.nih.gov/17390043/,"Hedgehog protein is essential to gastrointestinal tract development, and disruption of the hedgehog signaling pathway is associated with gastrointestinal tumorigenesis. Here, we analyzed the degree of hedgehog expression in gastric cancer and precancerous tissue. From August 2005 to May 2006, 52 gastric cancers and 16 gastric adenomas were obtained from surgically or endoscopically resected specimens. Immunohistochemical staining using sonic hedgehog (Shh) antibody was performed in cancerous and noncancerous tissue portions. Hedgehog expression was assessed based on the summed scores of the intensity and proportion of Shh staining. According to Lauren's classification, Shh expression was stronger in the intestinal type than in the diffuse type (p<0.001). Although Shh expression was not related to the location, size, metastatic status, or mucin phenotype of the gastric cancer, the expression was stronger in the tubular type of gastric cancer than in the mucinous and signet-ring cell types (p=0.001). Shh expression was stronger in gastric adenoma than in the diffuse-type gastric cancer (p<0.001), but revealed no difference with that of the intestinal-type gastric cancer (p=0.30). Shh expression was strongest in all types of intestinal metaplasia of noncancerous tissues. Shh expression is related to the intestinal type of gastric cancer. The stronger Shh expression in intestinal metaplasia and gastric adenoma indicates that hedgehog protein is involved at an early phase of gastric carcinogenesis."
1556,"Knowledge, attitude and practice of a Pakistani female cohort towards breast cancer.","Gilani SI, Khurram M, Mazhar T, Mir ST, Ali S, Tariq S, Malik AZ.",https://pubmed.ncbi.nlm.nih.gov/20225779/,"
    


           One thousand randomly selected adult females presenting as patients (excluding those with breast complaints) and their accompanying attendants were inducted and interviewed. Pre tested, structured questionnaire, containing 34 (open and closed ended) questions, along with demographic profile was used to gather data which was analyzed using SPSS version 13. Chi square test was applied at 5% level as test of significance.
    


          39 +/-10.47 years. Majority were married (88%), housewives (88%), and urban dwellers (75%) with average household income of Rupees 3000-6000 (33%). Majority (82.9%, n=829) had heard of breast cancer. Further questions were asked from these females. More than 50% participants were aware of cancer's relationship with increasing age, lack of breast feeding, painless lump, obesity, and smoking. Except for breast lump, over 50% participants had knowledge about breast cancer symptoms. >50% subjects had knowledge about diagnostic modalities, treatment and its relation with outcome. Majority (>90%) had positive attitude and intended to see a doctor immediately if they ever felt a breast lump, but had poor (28.3%) practices regarding breast self examination.
    


          Conclusion:
        
      
      Majority of study participants had limited knowledge, poor practices, but positive attitude towards breast cancer."
1557,Carcinoembryonic antigen (CEA) in human colorectal cancers growing subcutaneously in nude mice.,"Fiebig HH, von Kleist S.",https://pubmed.ncbi.nlm.nih.gov/6853586/,"Eleven human colorectal xenografts from 26 tumor lines established in nude mice in our laboratory were investigated for carcinoembryonic antigen (CEA) production. Serum levels of CEA in nude mice were markedly elevated in all cases but one, median values ranging from 3.7 to 42.8 ng/ml. Carcinoembryonic-antigen levels for ten nontumor-bearing nude mice ranged from 0.00 to 0.12 ng/ml (median value 0.07). A clear linear correlation could be demonstrated between log CEA serum levels and log tumor volumes in serial measurements. In one case, CEA was normal in the cancer patient's serum and gave the lowest value (3.7 ng/ml) in nude mice bearing the xenograft. By the indirect peroxidase technique, CEA was localized mainly on the apical cell membranes of the cancerous glands and in necrotic areas; only small amounts were detectable in the cytoplasm. Transplantation of human colorectal carcinomas into nude mice offers an excellent "
1558,Understanding the role of Cripto-1 in cancer progression and therapeutic strategies.,"Zeng Q, Gao Y, Zhou Y.",https://pubmed.ncbi.nlm.nih.gov/36456761/,"During the initial stages of gastrulation during embryonic differentiation and wound healing, Cripto-1 is a critical protein for human growth. The epithelial adhesion molecules' downregulation, the mesenchymal overexpression, and mobile proteins are important mechanisms by which Cripto-1 initiates epithelial to mesenchymal transition (EMT). As a  The majority of malignancies are reported to have elevated levels of Cripto-1. Cripto-1 can modify cancerous cells through its function in EMT, which enables these cells to migrate via the extracellular matrix, bloodstream, and lymphatic vessels, on their way for metastasizing to other organs. The goal of this review is to explain what role Cripto-1 plays in common cancers and to summarize how therapeutic strategies are used to interfere with this molecule to target cancers."
1559,Genetic and stochastic influences upon tumor formation and tumor types in Li-Fraumeni mouse models.,"Chan CS, Sun Y, Ke H, Zhao Y, Belete M, Zhang C, Feng Z, Levine AJ, Hu W.",https://pubmed.ncbi.nlm.nih.gov/33376133/,"p53 is the most frequently mutated gene in human cancers. Li-Fraumeni syndrome patients inheriting heterozygous p53 mutations often have a much-increased risk to develop cancer(s) at early ages. Recent studies suggest that some individuals inherited p53 mutations do not have the early onset or high frequency of cancers. These observations suggest that other genetic, environmental, immunological, epigenetic, or stochastic factors modify the penetrance of the cancerous mutant Tp53 phenotype. To test this possibility, this study explored dominant genetic modifiers of Tp53 mutations in heterozygous mice with different genetic  Both genetic and stochastic effects upon tumor formation were observed in these mice. The genetic  The onset age of a tumor is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. These observations help to explain the great diversity of cancers in different Li-Fraumeni patients over lifetimes."
1560,Systematic pan-cancer analysis of tumour purity.,"Aran D, Sirota M, Butte AJ.",https://pubmed.ncbi.nlm.nih.gov/26634437/,"The tumour microenvironment is the non-cancerous cells present in and around a tumour, including mainly immune cells, but also fibroblasts and cells that comprise supporting blood vessels. These non-cancerous components of the tumour may play an important role in cancer biology. They also have a strong influence on the genomic analysis of tumour samples, and may alter the biological interpretation of  Here we present a systematic analysis using different measurement modalities of tumour purity in >10,000 samples across 21 cancer types from the Cancer Genome Atlas. Patients are stratified according to clinical features in an attempt to detect clinical differences driven by purity levels. We demonstrate the confounding effect of tumour purity on correlating and clustering tumours with transcriptomics data. Finally, using a differential expression "
1561,Right trisectionectomy for primary liver cancer.,"Rui JA, Wang SB, Chen SG, Zhou L.",https://pubmed.ncbi.nlm.nih.gov/12679915/,"Aim:
        
      
      To evaluate the value of right trisectionectomy, previously named right trisegmentectomy, in the treatment of primary liver cancer by summarizing our 13-year experience for this procedure.
    


           1987 to Dec. 1999 were investigated retrospectively. The impacts in survival of patients by cancerous biological behavior, such as tumor thrombi and satellite nodules, were discussed respectively. All right trisectionectomies were performed under normothermic interruption of porta hepatis at single time. Ultrasonic dissector (CUSA system 200) was used in dissection of hepatic parenchyma from Nov. 1992, instead of finger fracture.
    


          9 %, 40.6 % and 34.4 %, respectively. The longest survival term with free cancer was 150 months (alive). There were no significant differences in survival curves between cases with and without tumor thrombi (right branch of portal vein) and satellite nodules. Operative mortality was 3.0 % (1/33). Main surgical complications occurred in 5 cases.
    


          Conclusion:
        
      
      Right trisectionectomy should be regarded as an effective and safe procedure for huge primary liver cancers and is worth using more widely."
1562,Current and future applications of magnetic resonance imaging (MRI) to breast and ovarian cancer patient management.,"Klostergaard J, Parga K, Raptis RG.",https://pubmed.ncbi.nlm.nih.gov/20799509/,"Magnetic resonance imaging (MRI) is occupying an increasing niche in the clinical diagnostic workup of several cancers, including breast cancers. Despite the high level of implementation of mammography, it has become apparent that MRI can play at least a complementary role in the imaging and diagnosis of primary breast cancers, including ductal carcinoma in situ, the earliest stage of breast cancer that is associated with an increased risk of invasive breast cancer. This can also be said of inflammatory breast cancer, of low incidence but with high impact on overall breast cancer mortality rates, and for which mammography is not ideal due to the typically diffused nature of this disease. Much of the value of breast MRI is dependent on its high sensitivity,  Interest has also increased in the application of diffusion-weighted MRI for early assessment of treatment response in this disease. Regarding ovarian and other gynecological cancers, MRI has already demonstrated value in the evaluation of patients with ovarian masses, uterine leiomyoma, endometrioma, and cervical cancer. Features on MRI suggestive of malignant ovarian tumors are varied, and span irregular or solid components to a cystic mass, prominent septations, evidence of peritoneal, hematogenous, or lymphatic spread, or local invasion. The majority of ovarian malignancies are diagnosed in advanced, incurable stages, where exploratory laparotomy provides the opportunity for maximal debulking. Although a role for MRI has yet to be established in this initial setting or in staging, some studies have shown that high sensitivity may be achieved with contrast agent-enhanced MRI for detection of recurrent disease, including demonstration of macroscopic intraabdominal dissemination and the hallmark omental ""cake"". Efforts in recent years have been focused on design of MRI contrast agents (MRI-CAs), which either target biomarkers, or take advantage of the different physiology of cancerous cells. MRI-CAs based on gadolinium complexes, ferrumoxides, or other metallic nanoparticles have been investigated. This review will focus on the recent progress in the application of MRI to the imaging of breast and ovarian cancers, and present a possible role for molecularly-targeted contrast agents in enriching the context for MRI-based diagnosis."
1563,Differential diagnosis of multielements in cancerous and non-cancerous esophageal tissues.,"Xie B, Lin J, Sui K, Huang Z, Chen Z, Hang W.",https://pubmed.ncbi.nlm.nih.gov/30683409/,"It is known that variations in the concentrations of certain elements in humans may be an indication of cancers. In this work, a  Based on the optimized platform combined with multivariate analysis, diagnostic models of ESCC were established using principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), showing excellent classification of cancerous and non-cancerous group by metallomic profiling. Elemental concentrations of 10 elements (Mn, Se, Cu, Ti, Mg, Fe, Co, Zn, Sr, Ca) showed significant difference (p < 0.001) in tumor and non-tumor tissues, in which Mn, Se, Cu and Ti are the top 4 elements of statistical significance and a shift towards higher concentration levels has also been observed in the tumor samples. These  To our knowledge, previous studies on elemental concentration in esophageal cancer were performed in serum or plasma levels; and this is the first study to evaluate the association of tissue elemental concentrations with ESCC."
1564,Screening peptide array library for the identification of cancer cell-binding peptides.,"Kaur K, Ahmed S, Soudy R, Azmi S.",https://pubmed.ncbi.nlm.nih.gov/25616337/,"The identification of cancer cell-specific ligands is a key requirement for the targeted delivery of chemotherapeutic agents. Usually phage display system is employed to discover cancer-specific peptides through a biopanning process. Synthetic peptide array libraries can be used as a complementary  Here, we describe a peptide array-whole cell binding assay to identify cancer cell-specific peptides. A peptide array library based on a lead dodecapeptide, p160, is synthesized on a functionalized cellulose membrane using solid phase chemistry and a robotic synthesizer. The relative binding affinity of the peptide library is evaluated by incubating the library with fluorescently labeled cancerous or non-cancerous cells. Thereby the assay allows picking peptides that show selective and high binding to cancerous cells. These peptides represent potential candidates for use in cancer-targeted drug delivery, imaging, and diagnosis."
1565,Long-read sequencing unveils novel somatic variants and methylation patterns in the genetic information system of early lung cancer.,"Cui X, Lin Q, Chen M, Wang Y, Wang Y, Wang Y, Tao J, Yin H, Zhao T.",https://pubmed.ncbi.nlm.nih.gov/38442557/,"Lung cancer poses a global health challenge, necessitating advanced diagnostics for improved outcomes. Intensive efforts are ongoing to pinpoint early detection biomarkers, such as genomic variations and DNA methylation, to elevate diagnostic precision. We conducted long-read sequencing on cancerous and adjacent non-cancerous tissues from a patient with lung adenocarcinoma. We identified somatic structural variations (SVs) specific to lung cancer by integrating data from various SV calling  This study discovered over 40,000 somatic SVs and over 180,000 DMRs linked to lung cancer. We identified approximately 700 genes of significant relevance through comprehensive analysis, including genes intricately associated with many lung cancers, such as NOTCH1, SMOC2, CSMD2, and others. Furthermore, we observed that somatic SVs and DMRs were substantially enriched in several pathways, such as axon guidance signaling pathways, which suggests a comprehensive multi-omics impact on lung cancer progression across various biological investigation levels. These datasets can potentially serve as biomarkers for early lung cancer detection and may hold significant value in clinical diagnosis and treatment applications."
1566,Microbial enzymes for deprivation of amino acid metabolism in malignant cells: biological strategy for cancer treatment.,"Dhankhar R, Gupta V, Kumar S, Kapoor RK, Gulati P.",https://pubmed.ncbi.nlm.nih.gov/32037468/,"Amino acid deprivation therapy (AADT) is emerging as a promising strategy for the development of novel therapeutics against cancer. This biological therapy relies upon the differences in the metabolism of cancer and normal cells. The rapid growth of tumors  These auxotrophic tumors are targeted by amino acid-depleting enzymes. The depletion of amino acid selectively inhibits tumor growth as the normal cells can synthesize amino acids by their usual machinery. The enzymes used in AADT are mostly obtained from microbes for their easy availability. Microbial L-asparaginase is already approved by FDA for the treatment of acute lymphoblastic leukemia. Arginine deiminase and methionase are under clinical trials and the therapeutic potential of lysine oxidase, glutaminase and phenylalanine ammonia lyase is also being explored. The present review provides an overview of microbial amino acid depriving enzymes. Various attributes of these enzymes like structure, mode of action, production, formulations, and targeted cancers are discussed. The challenges faced and the combat strategies to establish AADT in standard cancer armamentarium are also reviewed.Key Points • Amino acid deprivation therapy is a potential therapy for auxotrophic tumors. • Microbial enzymes are used due to their ease of manipulation and high productivity. • Enzyme properties are improved by PEGylation, encapsulation, and genetic engineering. • AADT can be employed as combinational therapy for better containment of cancer."
1567,Telomere dynamics in response to chemotherapy.,"Beeharry N, Broccoli D.",https://pubmed.ncbi.nlm.nih.gov/15974872/,"The use of chemotherapy provides an essential arm in the treatment of a number of cancers. The biological feature common to all cancerous cells that sensitizes them to chemotherapeutic agents is their elevated division rate. Rapidly dividing cells, such as tumor cells, are more sensitive to chemotherapeutic agents that act to initiate pathways leading to cell death, a process enhanced in cells with compromised DNA damage responses. The toxicity accompanying chemotherapy is due to side-effects induced in normal regenerative tissues which also have relatively high replication rates, such as hair follicles, the hematopoietic system, the gastrointestinal system, the germline and skin cells. While the side-effects of chemotherapy may be tolerated by the patient, the long term impact of the cytotoxic effects of chemotherapy on healthy tissues is only now becoming apparent. Chemotherapy-induced cytotoxicity in regenerative tissues requires multiple cell divisions in order to reconstitute the affected tissues. At least in part as a consequence of these extra divisions, telomeres in individuals treated with chemotherapy are shorter than age-matched control individuals who have never been exposed to these drugs. Given the essential role of telomeres in regulating cellular aging and chromosomal stability, it is possible that the prematurely shortened telomeres that arise following chemotherapy may impact the long-term replicative potential of these tissues. This review is focused on how telomeres may be modulated, directly or indirectly, by anticancer drugs and the potential long-term consequences of accelerated telomere shortening in healthy tissue as a "
1568,[Northern blot analysis of nm23 gene expression in human lung cancer].,"Liu L, Qin Y, Zhou Q.",https://pubmed.ncbi.nlm.nih.gov/10921026/,"
    


           Correlation of nm23 mRNA expression with clinical features of lung cancer was analyzed.
    


           The mRNA expression of nm23-H1 and nm23-H2 genes in small cell lung cancer was decreased compared to that in squamous-cell carcinoma. No significant difference in nm23 mRNA expression was observed in lung cancers with and without lymph node metastasis, nor was there significant difference in patients with lung cancers in different stages.
    


          Conclusion:
        
      
      The mRNA expression of nm23 gene is correlated with the degree of differentiation of lung cancer, but there is no evidence of metastasis suppression effect by nm23 gene."
1569,CIP2A with survivin protein expressions in human non-small-cell lung cancer correlates with prognosis.,"Xu P, Xu XL, Huang Q, Zhang ZH, Zhang YB.",https://pubmed.ncbi.nlm.nih.gov/21874565/,"Cancerous inhibitor of protein phosphatase 2A (CIP2A) and survivin are aberrantly expressed in a wide range of human cancers, including lung tumors. In order to assess the expressions of these two proteins in Chinese non-small-cell lung cancer (NSCLC) patients and determine their correlation with prognosis, NSCLC tissues and adjacent non-cancerous normal lung tissues were collected from 97 patients undergoing surgical treatment and evaluated by immunohistochemistry staining. CIP2A or survivin immunoreactivity was detected in significantly more NSCLC tissues than in adjacent non-cancerous lung tissues (P < 0.05). Moreover, CIP2A expression in NSCLC correlated with TNM stage, while survivin expression correlated with TNM stage and lymph node metastasis. Kaplan-Meier survival analysis showed that the overall survival times in patients expressing either CIP2A or survivin protein in NSCLC were shorter. COX regression analysis indicated that expression of CIP2A protein was an independent prognostic factor for NSCLC patients (HR = 3.631, P = 0.015). Therefore, CIP2A expression in Chinese NSCLC patients may be a useful biomarker of biological malignancy."
1570,Familial and personal history of cancer in bronchogenic carcinoma--frequency and clinical implications.,"Buccheri G, Ferrigno D.",https://pubmed.ncbi.nlm.nih.gov/15068322/,"A familial and personal history of cancer might be associated with a more aggressive cancerous disease. This study was carried out on 1277 consecutive lung cancer (LC) patients, seen from January 1989 to October 2002 in a single institution. A set of 31 clinical laboratory, radiological and pathological variables was recorded prospectively for all patients. In addition, both the number of first-degree blood-relatives with cancer (lung and non-lung cancers) and the personal history of previously cured cancers were noted. There were 368 patients (28.8% of the sample) who had one first-degree relative with cancer (112, 8.7% of the sample with LC), 100 (7.8%) had two first-degree relatives (six with LC) and 31 (2.4%) had three or more relatives affected (four with LC). In total, 1142 patients (89.4% of the sample) have never been treated for another cancer; the remaining 135 patients (10.6%) had already been diagnosed with a variety of tumours, including head and neck cancer (36 patients, 2.8%), bladder cancer (33 patients, 2.6%), colorectal cancer (24 patients, 1.9%), breast cancer (seven patients, 0.6%), melanoma (five patients, 0.4%), skin (five patients, 0.4%) and prostate cancer (five patients, 0.4%). Among the variables studied, none was found to be significantly associated with a personal and/or family history of cancer. Survival expectancy was similar among patients with or without a familial or personal history of cancer. A familial and a personal history of cancer are common features in LC, but are not of clinical significance."
1571,A national survey to assess breast cancer awareness among the female university students of Pakistan.,"Hussain I, Majeed A, Masood I, Ashraf W, Imran I, Saeed H, Ur Rehman A, Hashmi FK, Saleem F, Akbar M, Chaudhry MO, Ullah J, Rasool MF.",https://pubmed.ncbi.nlm.nih.gov/35061770/,"The incidence of breast cancer is increasing in Pakistan as well as globally. Awareness of women about breast cancer plays a cornerstone role in its early detection, better management, and prevention. Keeping this in mind, a cross-sectional study was carried out to assess the awareness of female university students about breast cancer's risk factors, signs and symptoms, and breast cancer examination. The data was collected from female university students studying in Pakistan. A total of 774 participants completed the survey and recorded their responses on an online pre-tested self-administered questionnaire. Only 29.8% of the participants have identified breast cancer history in their first-degree relatives as a risk factor. Moreover, 14.1% of the participant considered that the use of oral contraceptives for more than 5 years can increase the risk of developing breast cancer. In addition, inward pulled nipple, wounds around the nipple, and abrupt changes in the breast size were considered as the sign and symptoms of breast cancer by 25.2%, 25.7%, and 31.7% of the participants, respectively. Moreover, only 20.9% of the participants identified the correct year for starting breast cancer examination and 44.4% of the respondents marked that mammography should be initiated after 40 years. Overall, the university female students of Pakistan were poorly aware of breast cancer's risk factors, signs and symptoms, and breast examination. This study has highlighted the need for initiation of aggressive strategies regarding breast cancer awareness in both the literate and illiterate female population of Pakistan."
1572,Telomerase as an independent prognostic factor in head and neck squamous cell carcinoma.,"Liao CT, Tung-Chieh Chang J, Wang HM, Chen IH, Lin CY, Chen TM, Hsieh LL, Cheng AJ.",https://pubmed.ncbi.nlm.nih.gov/15162351/," We examined the association of telomerase activity with the clinical outcome of patients with HNSCC.
    


           Pearson chi-square test was used to analyze the correlation of telomerase activity with clinicopathologic parameters. Kaplan-Meier 
    


          1% of the normal and 63.3% of the cancer tissues had high levels of telomerase activity. Telomerase activity was shown to be statistically correlated with extracapsule spreading (ECS) of lymph nodes (p =.005) and overall survival (p =.003). On multivariant analysis, overall stage (p =.007), tumor depth (p =.045), and telomerase activity (p =.008) showed independent variables associated with poor survival.
    


          Conclusions:
        
      
      Telomerase activity has been shown to be an independent prognostic factor for survival in cases of HNSCC. Telomerase may be a potential molecular target for clinical use in prognostication and therapy in cases of the disease."
1573,Gene expression for suppressors of telomerase activity (telomeric-repeat binding factors) in breast cancer.,"Saito K, Yagihashi A, Nasu S, Izawa Y, Nakamura M, Kobayashi D, Tsuji N, Watanabe N.",https://pubmed.ncbi.nlm.nih.gov/11927006/,"Mechanisms regulating telomerase activity and telomere length remain incompletely understood in human breast cancer. We therefore studied gene expression for telomeric-repeat binding factors (TRFs) in relation to telomerase activity, telomere length, and clinicopathologic factors in human breast cancer. Telomerase activity was detected in 65.8% of 38 breast cancers, but none of 16 noncancerous samples. Terminal restriction fragments were longer in noncancerous than in cancerous tissues, but not significantly. Among 8 patients with both cancer and paired noncancerous tissue available for terminal restriction fragments length assay, terminal restriction fragments were shorter in cancers than in paired noncancerous samples in all but one. Significantly more mRNA encoding TRF1 and 2 was detected in noncancerous than in cancer tissues. Additionally, expression of TRF1 and 2 mRNA was significantly higher in cancers without detectable telomerase activity than in cancers showing activity. Expression of these genes tended to show a negative correlation with terminal restriction fragments length, but this was not statistically significant. No correlation was seen between TRF1 or 2 mRNA expression, and clinicopathologic factors except for TRF1 with respect to tumor size and progesterone receptor status. In addition to reactivation of telomerase activity, escape from negative regulation of this activity is needed to maintain telomere length during cell proliferation in breast cancer. Genes encoding telomerase inhibitors might be of value in gene therapy against human breast cancer."
1574,[Visible light reflectance spectrum for measurement of cancerous tissue].,"Wang C, Fan J, Ren QS.",https://pubmed.ncbi.nlm.nih.gov/18422114/,"A goal the authors always pursue is to realize diagnosis of precancer in vivo, real-time and non-invasive. In the present paper,  It was found that the main  The cancerous tissue has a lower reflectance in visible spectrum and has the strongest change in the absorption at 630 nm. Absorption peaks in the reflectance spectrum indicated that there are abundant of oxygenated hemoglobin and deoxygenated hemoglobin in the cancerous tissue. It is the same characteristics as in the cancerous tissue. It was fully indicated "
1575,Is there scope to do better? Clinical communication with adolescents and young adults with cancer-A scoping review.,"Critoph DJ, Cable M, Farmer J, Hatcher HM, Kuhn I, Taylor RM, Smith LAM.",https://pubmed.ncbi.nlm.nih.gov/38573227/," In a UK-wide survey of young people with cancer's research priorities, communication was a striking cross-cutting theme. It is increasingly recognised that AYACs have experiences and communication needs that differ significantly from those of younger children and older adults. The purpose of this review is to explore the features of effective clinical communication with AYACs.
    


           The searches yielded 5825 records, generating 4040 unique articles. These were screened and 71 full articles were read by four researchers with disagreements resolved by discussion leaving 29 included articles. Narrative synthesis was undertaken in relation to each of the research questions.
    


           AYACs need to feel that HCPs understand their unique perspective. They want to be involved, this changes over time and in different contexts. Supporters are a central tenet, are most often parents and undertake several roles which are not always universally supportive. HCPs enable involvement of AYACs, and this needs to be actively promoted. AYACs preference for their level of involvement requires continual assessment. The three themes are interlinked and exist within the wider scope of the triadic encounter and cancer experience.
    


          Conclusion:
        
      
      Supporters, most often parents were a key feature across the data and were seemingly paradoxical in nature. Triadic communication, the presence of a third person, is a central tenet of communication with AYACs and we propose a conceptual model to represent the nuances, components, and facets of this complex communication."
1576,Gene selection for classification of cancers using probabilistic model building genetic algorithm.,"Paul TK, Iba H.",https://pubmed.ncbi.nlm.nih.gov/16112804/,"Recently, DNA microarray-based gene expression profiles have been used to correlate the clinical behavior of cancers with the differential gene expression levels in cancerous and normal tissues. To this end, after selection of some predictive genes based on signal-to-noise (S2N) ratio, unsupervised learning like clustering and supervised learning like k-nearest neighbor (k NN) classifier are widely used. Instead of S2N ratio, adaptive searches like Probabilistic Model Building Genetic Algorithm (PMBGA) can be applied for selection of a smaller size gene subset that would classify patient samples more accurately. In this paper, we propose a new PMBGA-based  By applying our proposed "
1577,Intracellular localization of survivin determines biological behavior in colorectal cancer.,"Qi G, Tuncel H, Aoki E, Tanaka S, Oka S, Kaneko I, Okamoto M, Tatsuka M, Nakai S, Shimamoto F.",https://pubmed.ncbi.nlm.nih.gov/19639203/,"Survivin is a bifunctional protein that suppresses apoptosis and regulates cell division and is highly expressed in various human cancers. Recently, the intracellular localization of survivin in tumors has been suggested as a prognostic marker, but the molecular mechanisms are not understood. The aims of the present study were to investigate the different localization of survivin expression in colorectal carcinoma and expression of survivin relationships with clinicopathological factors and patient survival. Immunohistochemical analyses of 142 cases of advanced colorectal cancer showed that 109 (76.8%) cases expressed survivin in the nucleus and 29 cases (20.4%) in the cytoplasm. Cytoplasmic survivin overexpression was associated with a poor prognosis, but nuclear survivin overexpression was associated with a better prognosis. Subcellular distribution of survivin in five cases of cancerous or surrounding normal tissues derived from fresh biopsy of non-fixed samples of colorectal cancer patients was further demonstrated by Western blotting. Survivin was primarily found in the insoluble fraction. Interestingly, regardless of survivin protein levels in the insoluble fraction, patients who had cancerous tissue expressing cytoplasmic and nuclear soluble survivin suffered from lymph nodes metastases. These data suggest that the function of cytoplasmic survivin might be important for malignant progress and the levels of cytoplasmic and nuclear soluble survivin might be more relevant for prognostic factors for colorectal cancer than the total amount of survivin."
1578,Nanomechanical Analysis of Living Small Extracellular Vesicles to Identify Gastric Cancer Cell Malignancy Based on a Biomimetic Peritoneum.,"Ge Z, Dai S, Yu H, Zhao J, Yang W, Tan W, Sun J, Gan Q, Liu L, Wang Z.",https://pubmed.ncbi.nlm.nih.gov/38349890/,"Gastric cancer is one of the most prevalent digestive malignancies. The lack of effective in vitro peritoneal models has hindered the exploration of the potential mechanisms behind gastric cancer's peritoneal metastasis. An accumulating body of research indicates that small extracellular vesicles (sEVs) play an indispensable role in peritoneal metastasis of gastric cancer cells. In this study, a biomimetic peritoneum was constructed. The biomimetic model is similar to real peritoneum in internal microstructure, composition, and primary function, and it enables the recurrence of peritoneal metastasis process in vitro. Based on this model, the association between the mechanical properties of sEVs and the invasiveness of gastric cancer was identified. By performing nanomechanical analysis on sEVs, we found that the Young's modulus of sEVs can be utilized to differentiate between malignant clinical samples (ascites) and nonmalignant clinical samples (peritoneal lavage). Furthermore, patients' ascites-derived sEVs were verified to stimulate the mesothelial-to-mesenchymal transition, thereby promoting peritoneal metastasis. In summary, nanomechanical analysis of living sEVs could be utilized for the noninvasive diagnosis of malignant degree and peritoneal metastasis of gastric cancer. This finding is expected to contribute future treatments."
1579,CH-overtone regions as diagnostic markers for near-infrared spectroscopic diagnosis of primary cancers in human pancreas and colorectal tissue.,"Kondepati VR, Oszinda T, Heise HM, Luig K, Mueller R, Schroeder O, Keese M, Backhaus J.",https://pubmed.ncbi.nlm.nih.gov/17205263/,"We have investigated the application of near-infrared spectroscopy for detection of human primary pancreatic and colorectal cancers. Spectra from cancerous and normal tissue were collected from a total of 37 surgically resected pancreatic and colorectal patient tissue specimens using a fibre-optic probe. Major spectral differences were observed in the CH-stretching first (6,000-5,400 cm(-1)) and second overtone (9,000-7,900 cm(-1)) regions. By use of artificial neural networks, linear discriminant analysis, and cluster analysis as pattern-recognition  We also explored differences between the spectra obtained from colorectal and pancreatic tissue. Spectral data from cancerous and normal tissue were classified organ-specifically into four groups with accuracy between 80 and 83%. Our "
1580,A pilot study of new promising non-coding RNA diagnostic biomarkers for early-stage colorectal cancers.,"Liu H, Ye D, Chen A, Tan D, Zhang W, Jiang W, Wang M, Zhang X.",https://pubmed.ncbi.nlm.nih.gov/30978169/," Recent studies have demonstrated that circulating long non-coding RNAs have the potential to serve as biomarkers for the detection of cancers. We analyzed the significance of lncRNAs 91H, PVT-1 and MEG3 in the detection of CRC.  Then, we validated our findings by determining the expression levels of six promising lncRNAs in CRC tissues and normal colorectal tissues. Finally, we evaluated the clinical relevance of lncRNAs 91H, PVT-1 and MEG3 in the plasma of 58 CRC patients and 56 non-cancerous controls.  The combination of 91H, PVT-1 and MEG3 could discriminate CRC patients from non-cancerous controls with an area under the receiver-operating curve (AUC) of 0.877 at a cut-off value of 0.3816, with a sensitivity of 82.76% and 78.57% specificity. More importantly, the combination of lncRNAs shows more sensitivity in the detection of early-stage CRC than the combination of CEA and CA19-9, biomarkers currently used for CRC detection (p < 0.0001). Conclusions lncRNAs 91H, PVT-1 and MEG3 are promising diagnostic biomarkers for early-stage CRC."
1581,Chemoprevention strategies for lung and upper aerodigestive tract cancer.,"Benner SE, Lippman SM, Hong WK.",https://pubmed.ncbi.nlm.nih.gov/1563008/,"The field cancerization hypothesis suggests that carcinogen exposure affects the entire epithelial lining of the lungs and upper aerodigestive tract. The concept that common exposures place the entire epithelium at risk for the development of invasive cancer is supported both by the occurrence of premalignant lesions such as leukoplakia and squamous metaplasia, and by the development of multiple primary tumors within the field. Chemoprevention trials in lung and upper aerodigestive tract cancer have included studies to reverse premalignant lesions and to prevent second primary tumors. Promising  Several clinical trials are in progress which attempt both to reduce cancer incidence and to determine the mechanisms and biological markers of successful chemoprevention."
1582,Treatment-related experiences and preferences of patients with lung cancer: a qualitative analysis.,"Aumann I, Kreis K, Damm K, Golpon H, Welte T, Graf von der Schulenburg JM.",https://pubmed.ncbi.nlm.nih.gov/26468689/," Because of lung cancer's great burden, identification and use of the patients' preferences can help to improve patients' quality of life.
    


           Because chemotherapy is the common treatment option for lung cancer, we focused on this treatment. The interviews were audio-taped, verbally transcribed and evaluated via content analysis.
    


          Setting and participants:
        
      
      A total of 18 participants (11 men and 7 women) with small or non-small-cell lung cancer who were receiving chemotherapy in one clinic were interviewed between June and July 2013.
    


           One main aspect focused on organizational context, such as the treatment day process, or experiences with different stakeholders, such as with the health insurance company or physicians. The other category referred to experiences that influenced psychosocial factors, including physical and mental experiences.
    


          Discussion and conclusion:
        
      
      Patients reported different experiences concerning physical, psychological and organizational areas during chemotherapy. Nevertheless, some potential areas for improving care, and therefore the quality of life of patients with lung cancer, could be identified. These improvement measures highlighted that with small, non-time-consuming and inexpensive changes, the treatment for patients with lung cancer can be improved."
1583,Methylation Patterns of Lys9 and Lys27 on Histone H3 Correlate with Patient Outcome in Gastric Cancer.,"Li Y, Guo D, Sun R, Chen P, Qian Q, Fan H.",https://pubmed.ncbi.nlm.nih.gov/30350241/," Researches on the correlation between histone lysine methylation and gastric cancer (GC) will help in finding novel epigenetic biomarkers for monitoring cancers.
    


          Aims:
        
      
      The study detected the expression patterns of histone 3 lysine 9 dimethylation (H3K9me2), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3) in GC tissues and evaluated their clinical merit for GC patients.
    


           The relationship and clinicopathological significance of the three lysine methylations on histone H3 with GC were assessed by Paired t test, Chi-square test, Kaplan-Meier analysis with log-rank test, and Cox proportional hazard analyses.
    


           Higher expression patterns of H3K9me2, H3K9me3, and H3K27me3 significantly related to differentiation degree, lymph nodes metastases, and pathological TNM staging in GC. The GC patients with low scoring of the three markers implied long survival period and best prognosis. In contrast, the patients' survival time was significantly shorter if their cancerous tissues presented high expression of the three markers.
    


          Conclusions:
        
      
      H3K9me2, H3K9me3, and H3K27me3 expression patterns closely relate to clinicopathological features and may be the independent risk factors for the survival of GC patients. The combined pattern of the three markers rather than an individual marker is considered to more accurately evaluate the outcome of GC patients."
1584,[Clinicopathological features and prognosis of chronic gastric ulcer with early canceration].,"Shen ZB, Sun YH, Wang C, Fang Y, Wang HS, Wang XF, Chen WD, Liu FL, Shen KT, Qin XY.",https://pubmed.ncbi.nlm.nih.gov/23980050/,"
    


           These data were compared with those with primary intra-mucosa gastric cancer (type I and II 275 cases, type III 68 cases).
    


          8%) were male, 22 cases (51.2%) were younger than 60 years old. Lesions located in the body or antrum of the stomach in 39 cases (90.7%), were less than 2 cm in 26 cases (60.5%), were undifferentiated type in 23 cases (53.5%), and developed lymph node metastasis in 4 cases (9.3%). Lesions of 4 cases of chronic gastric ulcer with early canceration located in the upper third of the stomach, while those of type III primary intra-mucosal gastric cancer all located in the lower two thirds, and the difference was statistically significant (P<0.01). Compared to type III and type I and II primary intra-mucosal gastric cancer, chronic gastric ulcer with early canceration did not differ in clinicopathological characteristics such as histological type, vascular or lymphatic invasion, and lymph nodes metastasis (all P>0.05). The median follow-up time was 57 months (range 16 to 98 months). The 5-year overall survival was 95.3% in chronic gastric ulcer with early canceration group, similar to that of type I, II (97.4%) or type III (94.5%) primary intra-mucosal gastric cancer group (P>0.05).
    


          Conclusions:
        
      
      The clinicopathological features of chronic gastric ulcer with early canceration are similar to those of primary intra-mucosal gastric cancer. The prognosis is promising for those patients undergoing surgical treatment."
1585,Interplay Between Mitochondrial Peroxiredoxins and ROS in Cancer Development and Progression.,"Ismail T, Kim Y, Lee H, Lee DS, Lee HS.",https://pubmed.ncbi.nlm.nih.gov/31500275/,"Mitochondria are multifunctional cellular organelles that are major producers of reactive oxygen species (ROS) in eukaryotes; to maintain the redox balance, they are supplemented with different ROS scavengers, including mitochondrial peroxiredoxins (Prdxs). Mitochondrial Prdxs have physiological and pathological significance and are associated with the initiation and progression of various cancer types. In this review, we have focused on signaling involving ROS and mitochondrial Prdxs that is associated with cancer development and progression. An upregulated expression of Prdx3 and Prdx5 has been reported in different cancer types, such as breast, ovarian, endometrial, and lung cancers, as well as in Hodgkin's lymphoma and hepatocellular carcinoma. The expression of Prdx3 and Prdx5 in different types of malignancies involves their association with different factors, such as transcription factors, micro RNAs, tumor suppressors, response elements, and oncogenic genes. The microenvironment of mitochondrial Prdxs plays an important role in cancer development, as cancerous cells are equipped with a high level of antioxidants to overcome excessive ROS production. However, an increased production of Prdx3 and Prdx5 is associated with the development of chemoresistance in certain types of cancers and it leads to further complications in cancer treatment. Understanding the interplay between mitochondrial Prdxs and ROS in carcinogenesis can be useful in the development of anticancer drugs with better proficiency and decreased resistance. However, more targeted studies are required for exploring the tumor microenvironment in association with mitochondrial Prdxs to improve the existing cancer therapies and drug development."
1586,[Strontium 90 in the treatment of pre-cancerous lesions and of some superficial skin cancers (author's transl)].,"Stewart WM, Nouël-Midoux J, Lauret P, Thomine E, Boullie MC, Amice D.",https://pubmed.ncbi.nlm.nih.gov/613953/,"The use of strontium 90 has proved to be efficient and practical, because handy, and permitting short treatment, not only, to cure benign superficial tumors and, as reported in this study, of pre-cancerous lesions such as actinic keratosis, Bowen's disease of the skin but also some carefully chosen cases of superficial carcinomas. Hundred lesions have been so treated and followed for 3 years; two only have relapsed. The cosmetic  100."
1587,"Second primary tumors in head and neck cancer patients: The importance of a ""tailored"" surveillance.","Bertolini F, Trudu L, Banchelli F, Schipilliti F, Napolitano M, Alberici MP, Depenni R, D'Angelo E, Mattioli F, Rubino L, Presutti L.",https://pubmed.ncbi.nlm.nih.gov/33051941/," Because second primary represents a major cause of morbidity and mortality in this population, early detection is fundamental.
    


          Materials and  We included all patients with diagnosis of squamous cell carcinoma of the head and neck seen at the Modena University Hospital from 2008 to 2018.
    


          9%) developed second primary tumor; its survival probability at 5 years was 40.6%. Alcohol consumption (p = .0055) and index cancer in oropharynx (p = .0029), supraglottic larynx (p = .0000), glottic larynx (p = .0222) were associated with higher risk of second primary. The most common second primary sites were head and neck district and lung (70, 31.5%, and 67, 30.2%, respectively). Head and neck district were more common in oral cavity (18, 43%) and oropharynx index cancer (20, 31%); lung second primary in hypopharynx (4, 40%), supraglottic larynx (17, 43%), and glottic larynx index cancer (23, 35%).
    


          Conclusion:
        
      
      Head and neck cancer survivors developing a second primary tumor have dismal prognosis. Tailored surveillance is recommended."
1588,Temsirolimus induced structural transition of cancerous renal cystatin to normal form in rats: In vitro mechanistic approach underlying renal cancer prevention.,"Shamsi A, Ahmed A, Bano B.",https://pubmed.ncbi.nlm.nih.gov/27979728/,"Globally, renal cell carcinomas (RCCs) represent a major portion of patients suffering from cancer. Temsirolimus is an anti-renal cancer drug that has already been approved in poor-risk metastatic RCC (mRCC) patients. In our present study, we have evaluated the in vitro effect of varying concentrations of temsirolimus on cancerous rat kidney cystatin; renal cancer was induced in rats making use of dimethylnitrosamine (DMN). It has already been reported that cancerous rat kidney cystatin performs its activity in an efficacious manner as compared to normal rat kidney cystatin, so here an attempt was made to see the effect of temsirolimus on this increased activity of cystatin in renal cancers. Anti-papain activity assay was utilized to see this effect and it was found that temsirolimus reduces the increased activity of cancerous rat kidney cystatin similar to that of normal rat kidney cystatin. Further, to have an insight into temsirolimus induced structural alterations in cancerous rat kidney cystatin; various spectroscopic assays viz. UV, Fluorescence, Circular dichroism (CD) and FTIR spectroscopy were employed. UV and Fluorescence spectroscopy shows cancerous rat kidney cystatin transformation to normal form in the presence of temsirolimus. FTIR and CD spectroscopy confirmed the complete structural reversion of cancerous rat kidney cystatin to normal form in the presence of 40μM temsirolimus. Thus, it can said that temsirolimus causes renal cystatin to revert to normal form; the increased activity of renal cystatin observed in incidences of renal cancer is restored back to normal thereby halting the progression of renal cancer."
1589,Selenium status of cancer patients in Greece.,"Bratakos MS, Vouterakos TP, Ioannou PV.",https://pubmed.ncbi.nlm.nih.gov/2326622/,"The Se status of 177 Greek cancer patients has been assessed by fluorimetric analysis of the Se concentration in whole blood, urine (morning) and hair. Patients either with newly diagnosed cancers or with metastases or who are undergoing therapy have statistically significant less blood, urine and hair Se than age- and sex-matched healthy controls. There is a strong and significant correlation between blood and urine or hair Se in the newly diagnosed cancers. In cancers of systems involving absorption, metabolism and excretion of Se, and in female breast cancer, the Se levels in blood, urine and hair are significantly lower than in the controls. In cancers of the respiratory and haematologic systems, blood and urine Se are normal, while hair Se is significantly lower than in controls. The  Some cancerous tissues, such as those of the peptic system, accumulate Se compared with their adjacent, apparently healthy tissues, but others, of the urinary system for example, do not. The reason(s) for this behaviour, however, is not known."
1590,The impact of DAPK1 and mTORC1 signaling association on autophagy in cancer.,"Movahhed P, Saberiyan M, Safi A, Arshadi Z, Kazerouni F, Teimori H.",https://pubmed.ncbi.nlm.nih.gov/35083613/," Autophagy has two functions in cancerous cells which could inhibit tumorigenesis or lead to cancer progression by increasing cell survival and proliferation.
    


           Autophagy is managed through various proteins including the mTOR, which is two separated structural and functional complexes known as mTORC1 and mTORC2. MTORC1 is an important component of the regulatory pathway affecting numerous cellular functions including proliferation, migration, invasion, and survival. This protein plays a key role in human cancers. The activity level of mTORC1 is regulated by the death-associated protein kinases (DAPks) family, especially DAPK1. In many cancers, DAPK1 acts as a tumor suppressor which can be attributed to its ability to suppress cellular transformation and to inhibit metastasis.
    


          Conclusions:
        
      
      A deep investigation not only will reveal more about the function of DAPK1 but also might provide insights into novel therapies aimed to modulate the autophagy pathway in cancer and to achieve better cancer therapy."
1591,Chromosomes and causation of human cancer and leukemia. X. Banding patterns in cancerous effusions.,"Kakati S, Hayata I, Oshimura M, Sandberg AA.",https://pubmed.ncbi.nlm.nih.gov/1192362/,"Cells from five cancer effusions (two ovarian carcinomas, two lung cancers, and one carcinoma of the breast) were analyzed by G-, C-, and Q-banding techniques. The following observations were made: 1) The origin of some marker chromosomes could be traced accurately by these banding techniques. 2) Several chromosomes, which appeared normal with conventional staining techniques, were found to be re-arranged ones and, hence, abnormal. 3) Chromosomes No. 1, No. 3 and No. 11 were the most frequently involved in aberrations, whereas No. 12, No. 13, No. 17-20, and No. 22 Were least frequently involved. Only in one case each was the X chromosome or the Y chromosome involved in aberrations. The Y chromosome was found to be missing in all cancer cells of one lung cancer. 4) Each effusion had characteristic markers, invariably present in each cell, whether the cells were near diploid, or polyploid. 5) No common markers were observed in the two ovarian carcinomas studied, whereas the two lung cancers had a few common markers."
1592,High level of expression of alpha-fetoprotein receptor in gastric cancers.,"Tsuboi S, Taketa K, Nouso K, Fujikawa T, Manabe K, Ohmori H, Higashi T, Shiratori Y.",https://pubmed.ncbi.nlm.nih.gov/17028464/,"The expression of the receptor for alpha-fetoprotein (AFP-R) was examined immunohistochemically in 47 cancer and 14 benign human gastric tissues. Rabbit polyclonal antibody against human AFP-R was used for immunohistochemical staining. Thirty-four of the 47 cancer tissues expressed AFP-R showing granular or reticular staining on the cancer cell surface, while only 2 of 61 control cases (14 benign gastric tissues and 47 nonmalignant tissues adjacent to cancer) showed faint and homogeneous staining in the cytoplasm of noncancerous cells. There was a significant difference in staining intensity between the cancerous and noncancerous groups. However, no statistically significant difference in staining intensity was found among the groups of well-differentiated, moderately differentiated and poorly differentiated adenocarcinomas. On the other hand, the staining intensity of signet ring cell carcinoma was significantly weaker than that of the three adenocarcinoma groups. The high level of AFP-R expression in gastric cancers may allow the use of AFP-R as a new clinically useful marker of gastric cancer in the tissue level."
1593,[How to consider cancer: implications for the risk due to ionizing radiation].,Piechowski J.,https://pubmed.ncbi.nlm.nih.gov/16316836/,"Cancers induced by ionizing radiation have no particular specificity nor genetic remarkable signature, excepting numerous multideletions. They should therefore be studied in the general field of cancer biology in its broad sense. A gap remains between the initial events like the rather well identified genomic damage and the subsequent emerging cellular clone with cancer characteristics. Intermediate steps are generally described as accumulation of mutations and epigenetic modifications leading at one point to the malignant phenotype. However we have no clear nor understandable model on these steps of malignant transformation till now. It is quite possible that specific causes (tobacco, alcohol, radiations, chemical toxics) which produce different initial abnormalities then lead to (or accelerate the entry in) the common and same way as that  Genomic instability is certainly an important factor involved in the cellular drift leading to malignant transformation. We postulate that only cells having both a high telomerase activity and a low apoptotic activity may become cancerous. The hypothesis is that cancer  We propose to name anti-apoptosis, in contrast to apoptosis which is the programmed death, the ultimate process by which a cell loses its tissue-related properties. The oncogenic activation may propagate to primordial genes of development  Bio-molecular studies of embryonic development and of genome re-programming will probably allow us to better understand the mechanisms of cancer."
1594,"[Hereditary predisposition to cancers of the digestive tract, breast, gynecological and gonadal: focus on the Peutz-Jeghers].","Turpin A, Cattan S, Leclerc J, Wacrenier A, Manouvrier-Hanu S, Buisine MP, Lejeune-Dumoulin S.",https://pubmed.ncbi.nlm.nih.gov/25036236/,"Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disease due to mutations in the tumor suppressor gene STK11. PJS is characterized by periorificial hyperpigmented macules (lentiginosis) and hamartomatous polyposis. Polyps can be located anywhere in the gastrointestinal tract, but are preferably observed in the small bowel (70-90%), the colon (50%) and the stomach (25%). They tend to be cancerous in a particular sequence hamartoma-dysplasia-cancer. The diagnosis is often made in the first or second decade following the appearance of lentigines or upon the occurrence of complications due to polyps (obstruction, intussusception, occult bleeding responsible for anemia). Furthermore PJS is associated with a significant increase in cancer risk (relative risk of 89% over the life according to the most recent series). Digestive cancers are the more frequent with cumulative incidences of 55% for gastro-intestinal cancer (39% for colorectal cancer, 13% for small bowel cancer and between 11 and 36% for pancreatic cancer, respectively). There is also an increased risk of non digestive cancers. In particular the risk of breast cancer is similar to that of patients carrying deleterious BRCA1 or BRCA2 mutations (cumulative incidence of 45%). Gynecological and gonadal tumors are frequent as well and can be more (adenoma malignum) or less aggressive (ovarian sex cord tumors with annular tubules and testicular tumors with calcified Sertoli cells). Finally the frequency of lung cancer is moderately increased. Recommendations for screening and management based on retrospective series in the literature have led to various strategies. The aim of this paper is to summarize the clinical and molecular diagnostic criteria of PJS as well as recommendations on screening strategies, management and monitoring."
1595,Evaluation of CD47 in the Suppressive Tumor Microenvironment and Immunotherapy in Prostate Cancer.,"Wang Q, Feng C, Chen Y, Peng T, Li Y, Wu K, Pu X, Chen H, Liu J.",https://pubmed.ncbi.nlm.nih.gov/37719086/," Resistance to drugs and metastases are potential barriers for prostate cancer endocrine therapy. Although immunotherapy for tumors has developed rapidly in the last few decades, its effectiveness in treating prostate cancer is unsatisfactory. Prostate cancer has a high-expression level of CD47. Therefore, a novel approach for potential immunotherapy may be provided by investigating the relationship among CD47 and the infiltration of immune cells in the prostate carcinoma.
    


           Furthermore, the function of CD47 in prostate carcinoma was assessed by CancerSEA. The association among CD47 and the tumor microenvironment was assessed utilizing the TISCH single cell data database. By using TIMER, the connection among CD47 and immunological invasion of prostate cancer was explored. Moreover, macrophages were cocultured with mouse prostate cancer cell RM-1 blocked by CD47 antibody to observe the changes in phagocytosis efficiency in vitro.
    


           CD47 antibody blocking promotes macrophage phagocytosis of RM-1.
    


          Conclusion:
        
      
      Our research demonstrates a closely relationship among CD47 and the immunological microenvironment of prostate cancer, and blocking CD47 can promote macrophages to phagocytosis of prostate cancer cells. Therefore, CD47 may provide novel strategies for potential immunotherapy of prostate cancer."
1596,"Current status of endoscopic detection, characterization and staging of superficial esophageal squamous cell carcinoma.","Ishihara R, Muto M.",https://pubmed.ncbi.nlm.nih.gov/35452124/,"
    


          Detection:
        
      
      The diagnostic yield of white-light imaging is limited and narrow-band imaging has demonstrated a better performance for detecting oesophageal cancer. Narrow-band imaging has also shown similar sensitivity and superior specificity to iodine staining.
    


          Characterization:
        
      
      Accurate differentiation between cancerous and non-cancerous lesions can be achieved by magnifying narrow-band imaging or iodine staining with confirmation of a pink-colour sign. A per-patient analysis of a randomized study showed similar sensitivities, specificities and overall accuracies of magnifying narrow-band imaging and iodine staining of 82.2%, 95.1% and 91.2%, and 80.5%, 94.3% and 90.5%, respectively.
    


          Tumour-staging:
        
      
      The diagnostic capability of endoscopic ultrasonography after conventional and narrow-band imaging in terms of tumour depth was evaluated in a multicentre prospective study. Endoscopic ultrasonography did not significantly improve the accuracy for distinguishing between mucosal or submucosal microinvasive cancer and deeper cancers from 72.9 to 74.0%, suggesting that additional endoscopic ultrasonography did not improve the diagnostic accuracy. In addition, endoscopic ultrasonography increased the incidence of overdiagnosis, defined as a diagnosis of cancer depth greater than the actual depth, by 6.6%. The risk of overdiagnosis by endoscopic ultrasonography was reconfirmed in two systematic reviews.
    


          Conclusions:
        
      
      Narrow-band imaging is currently considered as the standard modality for the detection and characterization of oesophageal cancer. The risk of overdiagnosis should be considered when applying endoscopic ultrasonography for the evaluation of tumour invasion depth of superficial oesophageal squamous cell carcinoma."
1598,Effect of auto flash margin on superficial dose in breast conserving radiotherapy for breast cancer.,"Wang L, Qiu G, Yu J, Zhang Q, Man L, Chen L, Zhang X, Ren Q, Xu H, Hua X.",https://pubmed.ncbi.nlm.nih.gov/34028963/,"Purpose:
        
      
      To investigate the dose-effect of Auto Flash Margin (AFM) on breast cancer's superficial tissues based on the Treatment Planning System (TPS) in the breast-conserving radiotherapy plan.
    


           Then, every included case plan was designed using a 2 cm-AFM (the value of AFM is 2 cm) and N-AFM (without AFM). Under the condition of ensuring the same configuration of #MU and collimator, the absorbed dose after a simulated inspiratory motion was calculated again using the new plan center, which moved backward to the linac source. The dose difference between the measurement points between AFM and N-AFM groups was compared.
    


           Also, the dose  However, there was no significant difference between Lung_ContraV5Gy , HeartDmean , and Breast_ContraV10Gy in the two groups. In the collimator alignments at the same angle between groups, the AFM group formed an apparent air region outside the collimator compared with the N-AFM group. In the XVMC algorithm feature parameter, the AFM group had less #MU, higher QE, and slightly longer optimization time. The #segments of both groups were close to the 240 control points preset by the plan. The validation  The difference in film  4DCT was used to summarize the maximum and minimum inspiratory motion distances of 7.31 ± 0.45 and 3.42 ± 0.91 mm respectively.
    


          Conclusions:
        
      
      These "
1599,"""Deep Extrinsic Muscle Involvement"" Is a Fallacy in the American Joint Committee on Cancer's Seventh Edition of Tumor Staging of Oral Cavity Cancers.","Murthy SP, Thankappan K, Jayasankaran SC, Milind K, Prasad C, Balasubramanian D, Iyer S.",https://pubmed.ncbi.nlm.nih.gov/28683301/,"Purpose:
        
      
      The seventh edition of tumor staging by the American Joint Committee on Cancer (AJCC) includes extrinsic muscle involvement to define stage T4a tongue carcinomas. The anatomic location of extrinsic muscles predisposes them to early involvement even in superficial tumors. The purpose of this study was to expose a fallacy in this staging system for extrinsic muscle involvement.
    


          Materials and  Magnetic resonance imaging (MRI) parameters were 1) the distance of the extrinsic muscles from the surface measured on the normal side in millimeters (range, mean, and standard deviation); 2) maximum transverse, craniocaudal, and anteroposterior tumor dimensions (range, mean, and standard deviation); and 3) tumor involvement of the muscles recorded on the involved side for the number and percentage of each muscle involved. Histopathologic depth of invasion also was recorded.
    


           The mean distances of the most superficial part of the muscle to the normal surface at MRI for the genioglossus (anteroventral), hyoglossus, and styloglossus were 3.98, 2.13 and 0.66 mm, respectively. The patterns of extrinsic muscle involvement showed hyoglossus, styloglossus, and genioglossus involvement in 79 (90.8%), 58 (66.76%), and 31 (35.6%), respectively. In patients with a pathologic depth of invasion shallower than 10 mm, involvement of the hyoglossus, styloglossus, and genioglossus was seen in 80, 35, and 15%, respectively.
    


          Conclusion:
        
      
      The extrinsic muscles of the tongue are not deep. Even superficial thin tumors can involve these muscles. The eighth edition of tumor staging by the AJCC, which includes tumor thickness in the staging system, is in the process of being implemented. The present study justifies the removal of extrinsic muscle involvement in defining stage T4 of the oral cavity."
1600,Identification of type-specific anticancer histone deacetylase inhibitors: road to success.,"Noureen N, Rashid H, Kalsoom S.",https://pubmed.ncbi.nlm.nih.gov/20401613/,"Cancer is a serious and life-eliminating disease. Majority of anticancer agents are non-selective. Along with the cancerous cells they also target the normal ones. An important aspect is to hit the developing mechanism of the tumor, which is highlighted by in silico drug designing. On the basis of novel molecular targets, in silico (computational approach) drug discovery has emerged as today's need. Histone deacetylases are an important therapeutic target for many human cancers. The first and only approved (in 2006) histone deacetylase inhibitors (HDACIs) is Zolinza. Depending on the types of the histone deacetylase (HDAC) enzymes, discovery of type-specific inhibitors is important. With continued research and development, in near future HDACIs are likely to figure prominently in cancer treatment plans. This review presents the overview of HDACs, their role in cancer, their structural classes, activity, catalytic domain and the inhibitors of HDACs for cancer therapy. Also it helps in understanding the open directions in this area of research and highlights the importance of computational approaches in discovering specific drugs for cancer therapy."
1601,Preliminary report on local resection with lymphadenectomy for early gastric cancer.,"Seto Y, Nagawa H, Muto Y, Kaizaki S, Kitayama J, Muto T.",https://pubmed.ncbi.nlm.nih.gov/10215830/,"3 per cent) of 234) in patients treated in this unit between 1966 and 1995. This study was a prospective report on local resection with lymphadenectomy for early gastric cancer.
    


           The tumour was excised with a non-cancerous rim of approximately 2 cm. The extent of lymphadenectomy depended on tumour location. Intraoperative endoscopic examination and frozen-section analysis of the dissected nodes were used to determine the resection line and evaluate nodal status.
    


           There were no operative complications. Cancer invasion was confined to the mucosa in six tumours but two patients had minute submucosal invasion. The maximum diameter of the resected specimens was 10 cm and no nodal involvement was detected. No patient developed postgastrectomy syndrome.
    


          Conclusion:
        
      
      For selected patients with early gastric cancer, local resection with lymphadenectomy can provide a good quality of life without compromising cure rate."
1602,Dysregulated miRNAs in a canine model of haemangiosarcoma metastatic to the brain.,"Sabattini S, Baldassarro VA, Zaccone R, Calzà L, Giardino L, Vascellari M, Lorenzini L, Moretti M, Marconato L.",https://pubmed.ncbi.nlm.nih.gov/38112225/,"Haemangiosarcoma is a highly metastatic and lethal cancer of blood vessel-forming cells that commonly spreads to the brain in both humans and dogs. Dysregulations in phosphatase and tensin (PTEN) homologue have been identified in various types of cancers, including haemangiosarcoma. MicroRNAs (miRNAs) are short noncoding single-stranded RNA molecules that play a crucial role in regulating the gene expression. Some miRNAs can function as oncogenes or tumour suppressors, influencing important processes in cancer, such as angiogenesis. This study aimed to investigate whether miRNAs targeting PTEN were disrupted in canine haemangiosarcoma and its corresponding brain metastases (BM). The expression levels of miRNA-10b, miRNA-19b, miRNA-21, miRNA-141 and miRNA-494 were assessed in samples of primary canine cardiac haemangiosarcomas and their matched BM. Furthermore, the miRNA profile of the tumours was compared to samples of adjacent non-cancerous tissue and healthy control tissues. In primary cardiac haemangiosarcoma, miRNA-10b showed a significant increase in expression, while miRNA-494 and miRNA-141 exhibited downregulation. Moreover, the overexpression of miRNA-10b was retained in metastatic brain lesions. Healthy tissues demonstrated significantly different expression patterns compared to cancerous tissues. In particular, the expression of miRNA-10b was nearly undetectable in both control brain tissue and perimetastatic cerebral tissue. These findings can provide a rationale for the development of miRNA-based therapeutic strategies, aimed at selectively treating haemangiosarcoma."
1603,Gastric cancer: the correlation between the clinicopathological factors and patients' survival (I).,"Lazăr D, Tăban S, Dema A, Cornianu M, Goldiş A, Raţiu I, Sporea I.",https://pubmed.ncbi.nlm.nih.gov/19221644/," The purpose of this study consists in the identification of the clinicopathological parameters that influence the prognosis of the patients that underwent surgery for gastric cancer.
    


          Material and  A prospective study was conducted on this group, regarding the gastric cancer's evolution and aggressiveness, for a period of 5 years. The survival time was calculated starting with the month when the surgery took place, and up to the month of death or that of the survival confirmation, and the survival rate was represented by the percentage of survivals at the end of the tracked period (in years and months).
    


          34 years). Gastric cancer was encountered more frequently in males (70.5%) than in females (29.5%) (p<0.001 ES). The amount of gastric cancer cases grows with age, the highest percent being observed in patients from the 51-70 years age group. However, the incidence is significantly lower after the age of 71 - 8.2% (p<0.001 ES). Antral localization of the gastric cancer predominates in both males and females, for all the age groups (50.8%). The average 5 years survival rate, for the whole group has been of 16.4%. We remark the extremely low survival rate for the older patients. In our study, we have identified five early gastric carcinomas (8.2%), classified as being type I protrusive tumors of intestinal type and 56 advanced gastric carcinomas, 16 cases in females (28.6%) and 40 cases in males (71.4%). The average survival for the patients with advanced gastric cancers was of 13.9 months, significantly lower than the average survival value of the patients with early gastric cancers (57.2 months). According to Borrmann's classification, we have identified five type I carcinomas (8.9%), 20 type II carcinomas (35.7%), 22 type III carcinomas (39.3%), and nine type IV carcinomas (16.1%). We did not notice any significant differences between the survival values of the patients with tumors of types I, II and III (p>0.05 NS), but the patients with diffuse infiltrative gastric cancers had an average survival of only 4.9 months after the surgery.
    


          Conclusions:
        
      
      The prognosis for gastric cancer is reserved, the 5 years average survival rate is of 16.4%. We have noticed a significantly decrease of survival rate with age (p = 0.024688 S). The 5 years survival is of 10.7% for patients with advanced cancers, significantly lower than the 5 years survival of 80% for patients with early gastric cancers (p<0.001 ES).The ulcerative-infiltrative type of cancer is predominant (39.3%). The patients with diffuse infiltrative forms of gastric cancers survived for an average period of only 4.9 months after surgical intervention."
1604,Inferring Potential Cancer Driving Synonymous Variants.,"Zeng Z, Bromberg Y.",https://pubmed.ncbi.nlm.nih.gov/35627162/,"Synonymous single nucleotide variants (sSNVs) are often considered functionally silent, but a few cases of cancer-causing sSNVs have been reported. From available databases, we collected four categories of sSNVs: germline, somatic in normal tissues, somatic in cancerous tissues, and putative cancer drivers. We found that screening sSNVs for recurrence among patients, conservation of the affected genomic position, and synVep prediction (synVep is a machine learning-based sSNV effect predictor) recovers cancer driver variants (termed proposed drivers) and previously unknown putative cancer genes. Of the 2.9 million somatic sSNVs found in the COSMIC database, we identified 2111 proposed cancer driver sSNVs. Of these, 326 sSNVs could be further tagged for possible RNA splicing effects, RNA structural changes, and affected RBP motifs. This list of proposed cancer driver sSNVs provides computational guidance in prioritizing the  Furthermore, our list of novel potential cancer genes, galvanized by synonymous mutations, may highlight yet unexplored cancer mechanisms."
1605,Analysis of differentially expressed proteins in cancerous and normal colonic tissues.,"Gam LH, Leow CH, Man CN, Gooi BH, Singh M.",https://pubmed.ncbi.nlm.nih.gov/16937492/,"Aim:
        
      
      To identify and analyze the differentially expressed proteins in normal and cancerous tissues of four patients suffering from colon cancer.
    


           The extraction buffers were used in an orderly sequence of increasing extraction strength for proteins with hydrophobic properties. The protein extracts were separated using the SDS-PAGE  The target protein bands were subjected to in-gel digestion with trypsin and finally analyzed using an ESI-ion trap mass spectrometer.
    


          
    


          Conclusion:
        
      
      Many of the identified proteins have been reported to be involved in the progression of similar or other types of cancers. However, some of the identified proteins have not been reported before. In addition, a number of hypothetical proteins were also identified."
1606,Micronutrient Food Supplements in Patients with Gastro-Intestinal and Hepatic Cancers.,"Alam W, Ullah H, Santarcangelo C, Di Minno A, Khan H, Daglia M, Arciola CR.",https://pubmed.ncbi.nlm.nih.gov/34360782/,"Colorectal carcinogenesis is the second most common cause of mortality across all types of malignancies, followed by hepatic and stomach cancers. Chemotherapy and radiotherapy are key approaches to treating cancer patients, but these carry major concerns, such as a high risk of side effects, poor accessibility, and the non-selective nature of chemotherapeutics. A number of natural products have been identified as countering various forms of cancer with fewer side effects. The potential impact of vitamins and minerals on long-term health, cognition, healthy development, bone formation, and aging has been supported by  Successful treatment may thus be highly influenced by the nutritional status of patients. An insufficient diet could lead to detrimental effects on immune status and tolerance to treatment, affecting the ability of chemotherapy to destroy cancerous cells. In recent decades, most cancer patients have been taking vitamins and minerals to improve standard therapy and/or to decrease the undesirable side effects of the treatment together with the underlying disease. On the other hand, taking dietary supplements during cancer therapy may affect the effectiveness of chemotherapy. Thus, micronutrients in complementary oncology must be selected appropriately and should be taken at the right time. Here, the potential impact of micronutrients on gastro-intestinal and hepatic cancers is explored and their molecular targets are laid down."
1607,What's wrong with the theoretical research on molecular mechanisms of the chemical cancerization process.,Sung SS.,https://pubmed.ncbi.nlm.nih.gov/879980/,"The theoretical research on molecular mechanisms of chemical cancerization process is essentially a statistical problem in nature. Failing to have this notion in mind, many researchers in this field have engaged sterilizing controversies on the existence or the non existence of a correlation between the carcinogenic potency of a substance and some of its molecular properties. The following report is an example showing how the statistical concept and "
1608,Lung cancer risk and radiation dose among women treated for breast cancer.,"Inskip PD, Stovall M, Flannery JT.",https://pubmed.ncbi.nlm.nih.gov/8007020/,"
    


          Purpose:
        
      
      This study evaluated the long-term risk of lung cancer among women treated with radiation for breast cancer.
    


           Seventy-six cases of lung cancer were identified; however, 15 cases did not meet the criteria for inclusion. For the 61 remaining lung cancer case patients and 120 reference subjects (selected from the same registry and matched according to race, age at breast cancer diagnosis, year of breast cancer diagnosis, and survival without a second primary tumor), hospital charts were reviewed to collect medical history and radiotherapy information. A medical physicist estimated radiation dose to different segments of the lungs on the basis of radiotherapy reports and 
    


          8 (95% confidence interval [CI] = 0.8-3.8), and the RR increased with time following treatment. The RR for periods of 15 years or more after radiotherapy was 2.8 (95% CI = 1.0-8.2). Mean dose was 15.2 Gy to the ipsilateral lung, 4.6 Gy to the contralateral lung, and 9.8 Gy for both lungs combined. The excess RR was 0.08 per Gy, based on average dose to both lungs, and 0.20 per Gy to the affected (cancerous) lung.
    


          Conclusions:
        
      
      Breast cancer radiotherapy regimens in use before the 1970s were associated with an elevated lung cancer risk many years following treatment. The estimated risk coefficients are lower than those reported for atomic bomb survivors. The lower than expected risk might be attributable to high-dose cell killing or the fractionated nature of the exposure.
    


          Implications:
        
      
      Approximately nine cases of radiotherapy-induced lung cancer per year would be expected to occur among 10,000 women who received an average lung dose of 10 Gy and survived for at least 10 years. Current radiotherapy for breast cancer  Nonetheless, efforts to reduce unnecessary exposure of the lungs and heart should continue to further reduce possible adverse radiation effects."
1609,Pancreatic Cancer's PD1-Roadblock: When T-Cell Reinvigoration Is Not Enough.,"Lander VE, DeNardo DG.",https://pubmed.ncbi.nlm.nih.gov/38038687/,"PD1-blockade combinations in pancreatic ductal adenocarcinoma have been poorly effective, and the underlying reasons for this are unknown. A recent study revealed that chemoradiation plus PD1-blockade reinvigorates tumor-specific T cells; however, this T-cell activation is accompanied with exaggerated NFκB signaling, which may limit productive tumor-controlling immunity. See related article by Ali et al., p. 542."
1610,Role of Salivary Biomarkers in Oral Cancer Detection.,"Khurshid Z, Zafar MS, Khan RS, Najeeb S, Slowey PD, Rehman IU.",https://pubmed.ncbi.nlm.nih.gov/30144841/,"Oral cancers are the sixth most frequent cancer with a high mortality rate. Oral squamous cell carcinoma accounts for more than 90% of all oral cancers. Standard  The identification of biomarkers from biological fluids (blood, urine, saliva) has the potential of early diagnosis. The use of saliva for early cancer detection in the search for new clinical markers is a promising approach because of its noninvasive sampling and easy collection  Human whole-mouth saliva contains proteins, peptides, electrolytes, organic, and inorganic salts secreted by salivary glands and complimentary contributions from gingival crevicular fluids and mucosal transudates. This diagnostic modality in the field of molecular biology has led to the discovery and potential of salivary biomarkers for the detection of oral cancers. Biomarkers are the molecular signatures and indicators of normal biological, pathological process, and pharmacological response to treatment hence may provide useful information for detection, diagnosis, and prognosis of the disease. Saliva's direct contact with oral cancer lesions makes it more specific and potentially sensitive screening tool, whereas more than 100 salivary biomarkers (DNA, RNA, mRNA, protein markers) have already been identified, including cytokines (IL-8, IL-1b, TNF-α), defensin-1, P53, Cyfra 21-1, tissue polypeptide-specific antigen, dual specificity phosphatase, spermidine/spermineN1-acetyltransferase , profilin, cofilin-1, transferrin, and many more. However, further research is still required for the reliability and validation of salivary biomarkers for clinical applications. This chapter provides the latest up-to-date list of known and emerging potential salivary biomarkers for early diagnosis of oral premalignant and cancerous lesions and monitoring of disease activity."
1611,"Prognostic Significance of Size, Location, and Number of Lymph Node Metastases in Endometrial Carcinoma.","Tran L, Christensen P, Barroeta JE, Hunter K, Sookram J, McGregor SM, Wilkinson N, Orsi NM, Lastra RR.",https://pubmed.ncbi.nlm.nih.gov/36044323/,"Regional lymph node metastasis is a well-established negative predictive prognostic factor in endometrial carcinomas. Recently, our approach to the pathologic evaluation of lymph nodes in endometrial carcinomas has changed, mainly due to the utilization of immunohistochemical stains in the assessment of sentinel lymph nodes, which may  However, the clinical significance of this finding is not entirely clear. Following the experience in other organs systems such as breast, the Eight Edition of the American Joint Committee on Cancer's Cancer Staging Manual has recommended utilizing the N0(i+) terminology for this finding, without impact in the final tumor stage. We performed a comparative retrospective multi-institutional survival analysis of 247 patients with endometrial carcinoma with regional lymph node metastasis of various sizes identified in nonsentinel lymphadenectomy, demonstrating that the cumulative survival of patients with isolated tumor cells in regional lymph nodes is not statistically different from patient with negative lymph nodes, and is statistically different from those with lymph nodes showing micrometastasis or larger metastatic deposits. In addition, we evaluated the prognostic implications of the number of involved regional lymph nodes, demonstrating a worsening prognosis as the number of involved lymph nodes increases from none to one, and from one to more than one. Our data suggests that regional lymph nodes with isolated tumor cells in patients with endometrial carcinoma should likely be considered, for staging purposes, as negative lymph nodes, simply indicating their presence with the (i+) terminology."
1612,"""Buy one get one free"": armed viruses for the treatment of cancer cells and their microenvironment.","Kaur B, Cripe TP, Chiocca EA.",https://pubmed.ncbi.nlm.nih.gov/19860649/,"Oncolytic viral therapy is a promising biological therapy for the treatment of cancer. Recent advances in genetic engineering have facilitated the construction of custom-built oncolytic viruses that can be exquisitely targeted to tumors by exploiting each cancer's unique biology and their efficacy can be further enhanced by ""arming"" them with additional therapeutic genes. Such an approach allows the virus to unload its ""therapeutic cargo"" at the tumor site, thereby enhancing its anti-neoplastic properties. While several clever strategies have been recently described using genes that can induce cellular apoptosis/suicide and/or facilitate tumor/virus imaging, viruses armed with genes that also affect the tumor microenvironment present an exciting and promising approach to therapy. In this review we discuss recently developed oncolytic viruses armed with genes encoding for angiostatic factors, inflammatory cytokines, or proteases that modulate the extracellular matrix to regulate tumor vascularization, anti-tumor immune responses and viral spread throughout the solid tumor."
1613,How cancer cells attach to urinary bladder epithelium in vivo: study of the early stages of tumorigenesis in an orthotopic mouse bladder tumor model.,"Erman A, Kapun G, Novak S, Pavlin M, Dražić G, Drobne D, Veranič P.",https://pubmed.ncbi.nlm.nih.gov/30280243/,"The majority of bladder cancers in humans are non-muscle-invasive cancers that recur frequently after standard treatment procedures. Mouse models are widely used to develop anti-tumor treatments. The purpose of our work was to establish an orthotopic mouse bladder tumor model and to explore early stages of implantation of cancerous MB49 cells in vivo using various labeling and microscopic techniques. To distinguish cancer cells from normal urothelial cells in mouse urinary bladders, we performed molecular characterization of MB49 cells before intravesical injection  In this new approach we applied internalized metal nanoparticles to unequivocally discriminate cancer cells from normal cells. This  We found that cancer cells initially adhere to normal urothelial cells through filopodia and by focal contacts with basal lamina. This is the first in vivo characterization of intercellular contacts between cancerous and normal urothelial cells in the bladder. Our study yields new data about poorly known early events of tumorigenesis in vivo, which could be helpful for the translation into clinic."
1614,A New Questionnaire (QRFPC25) Regarding the Religiosity and Spirituality in People with Life-Threatening Disease: Reliability and Validity in a Population of Cancer Patients Undergoing Radiotherapy.,"Kouloulias V, Kokakis J, Kelekis N, Kouvaris J.",https://pubmed.ncbi.nlm.nih.gov/27659692/,"The development of a questionnaire (QRFPC25) assessing the religiosity of cancer patients. The  The questionnaire was completed on-site and a week after antineoplastic therapy. The final sample included 156 patients. The main topics of the QRFPC25 are the following: worship, relationship with the divine, spiritual discussion, hope, participation in holly communion, faith, life after death, love, bioethics and global quality of life (QoL). The average time of both times taken to complete the questionnaire was approximately 10 min. All multi-item scales met the minimal standards of reliability (Cronbach's alpha coefficient ≥.70) before or after treatment. Test-retest reliability in terms of the intraclass correlation coefficient was also satisfactory (p < 0.01). Validity was assured by inter-item correlations and correlations with the European Organisation for Research and Treatment of Cancer's Core Quality of Life Questionnaire (QLQ-C30, version 3.0), along with factor analysis which showed eight factors incorporated in the model. The QRFPC25 is a reliable and valid gauge for the assessment of religiosity in cancer patients undergoing radiotherapy."
1615,Multiscale modeling of tumor growth induced by circadian rhythm disruption in epithelial tissue.,"Bratsun DA, Merkuriev DV, Zakharov AP, Pismen LM.",https://pubmed.ncbi.nlm.nih.gov/26293211/,"We propose a multiscale chemo-mechanical model of cancer tumor development in epithelial tissue. The model is based on the transformation of normal cells into a cancerous state triggered by a local failure of spatial synchronization of the circadian rhythm. The model includes mechanical interactions and a chemical signal exchange between neighboring cells, as well as a division of cells and intercalation that allows for modification of the respective parameters following transformation into the cancerous state. The numerical simulations reproduce different dephasing patterns--spiral waves and quasistationary clustering, with the latter being conducive to cancer formation. Modification of mechanical properties reproduces a distinct behavior of invasive and localized carcinoma."
1616,Cytogenetic monitoring in human oral cancers and other oral pathology: the micronucleus test in exfoliated buccal cells.,"Chatterjee S, Dhar S, Sengupta B, Ghosh A, De M, Roy S, Raychowdhury R, Chakrabarti S.",https://pubmed.ncbi.nlm.nih.gov/19778244/,"Oral cancer is a lifestyle-related cancer, with tobacco as a primary factor. Progression of oral cancer develops over several years from the stage of leukoplakia, erythroplakia, etc. A micronucleus test was applied to oral mucosal cells, considering them as the target site for carcinogens and cytogenetic damage. The test has been established as a reliable biomarker for differential prevalence of MN indices among oral cancers, pre-cancers, non-malignant oral pathologies, and healthy controls for the first time. Buccal scrapings were collected from 63 patients with cancer and pre-cancerous lesions, 42 with non-malignant oral problems, and 100 healthy controls. The analysis revealed that MN frequencies in cancer and pre-cancerous cases were 4-fold elevated (p < 0.001) and 3.87-fold (p < 0.002) elevated for other non-malignant pathologies. Significant associations between use of tobacco in various forms and development of oral pathologies are also established. The relative cancer risk for smoking healthy controls with a definite MN frequency was also found to be significant. The "
1617,"Expression of the endothelial cell differentiation gene 7 (EDG-7), a lysophosphatidic acid receptor, in ovarian tumor.","Nakamoto T, Yasuda K, Yasuhara M, Yoshimura T, Kinoshita T, Nakajima T, Okada H, Ikuta A, Kanzaki H.",https://pubmed.ncbi.nlm.nih.gov/16018784/,"Aim:
        
      
      Lysophosphatidic acid (LPA) has received attention as a mitogen because the physiologically active lipid stimulates ovarian cancer cell growth by interacting with specific receptors, the endothelial cell differentiation gene (EDG) family. In the present study, we have investigated the expression of EDG-7 mRNA, part of the EDG family, in both human ovarian cancers and established human ovarian cancer cell lines.
    


           The expression of EDG-7 mRNA was measured using reverse transcription-polymerase chain reaction and northern blotting, using reduced glyceraldehyde-phosphate dehydrogenase and S26 as internal controls.
    


           The expression of EDG-7 mRNA was limited in MCAS, CRL-11730 and TYKnu. In the ovarian cancer tissues, EDG-7 mRNA was expressed most highly in endometrioid adenocarcinoma and serous cystadenocarcinoma. The expression of EDG-7 mRNA was limited in clear cell adenocarcinoma and undetectable in mucinous cystadenocarcinoma.
    


          Conclusions:
        
      
      The intense EDG-7 expression in ovarian cancers suggests that the relation between LPA and EDG-7 (an LPA receptor) is involved in cancer cell growth and proliferation in some histologic subtypes of ovarian cancer."
1618,Trends in end-of-life decision making in patients with and without cancer.,"Pardon K, Chambaere K, Pasman HR, Deschepper R, Rietjens J, Deliens L.",https://pubmed.ncbi.nlm.nih.gov/23478055/,"Purpose:
        
      
      Because of cancer's high symptom burden and specific disease course, patients with cancer are more likely than other patients to face end-of-life decisions that have possible or certain life-shortening effects (ELDs). This study examines the incidence of ELDs in patients with cancer compared with patients without cancer and the trends in ELD incidence from 1998-2007.
    


          Patients and  Physicians who had signed selected death certificates (n = 6,927) were sent a questionnaire.
    


          4%. Nonsudden deaths were studied. Intensified symptom alleviation occurred more in patients with cancer than in those without (53.8% v 31.7%; P < .001) as did euthanasia (6.8% v 0.9%; P < .001). There was no difference between groups in nontreatment decisions and life-ending acts without patient's explicit request. Patients with cancer were less involved in the end-of-life decision-making process than patients without cancer (69.7% v 83.5%; P = .001). From 1998 to 2007, ELD incidence has increased in patients with cancer (+6.7%) and even more in patients without cancer (+14.9%) because of an increase in intensified symptom alleviation. In patients with cancer, euthanasia rates increased strongly and life-ending acts without the patient's explicit request decreased.
    


          Conclusion:
        
      
      The higher ELD incidence in patients with cancer compared with those without is probably related to differences in disease trajectories and access to end-of-life care. During the period from 1998 to 2007, when euthanasia was legalized and palliative care intensified, overall ELDs increased, including those as a "
1619,Are carcinogens responsible for the superimposed neoplastic changes occurring in mouse tumor cells? The effect of methylcholanthrene and urethane on pulmonary adenomas and of methylcholanthrene on mammary carcinomas.,"DUMBELL K, ROUS P.",https://pubmed.ncbi.nlm.nih.gov/13271668/,"Three spontaneous pulmonary adenomas of C mice, morphologically resembling those induced by methylcholanthrene or urethane, were propagated in host after host under conditions such that the neoplastic cells were directly exposed, while proliferating, to one or the other of these agents. The successive periods of test lasted for more than a year in some instances, the total exposure to the carcinogens far exceeding that required to change normal pulmonary cells into adenoma cells. One of the adenomas remained unaltered, and the others underwent cancerous changes; but these took place with equal frequency in the control growths, and their occurrence was neither hastened nor delayed by the carcinogens. Two polymorphous mammary carcinomas of ""milk-factor"" type, with the characteristic tendency to form acini and tubules, were exposed to methylcholanthrene in the same way as the pulmonary adenomas and for periods quite as long. Their cells continued to differentiate, and in other respects underwent no significant change. Urethane had no influence on the rate of growth of the adenomas exposed to it; methylcholanthrene, on the other hand, markedly retarded the enlargement both of them and of the mammary tumors. Its inhibitory influence was not passed on from cell to cell however; when freed of the carcinogen by further transplantation, the retarded tumors grew as fast as the controls. Furthermore the retardation caused no evident delay in the occurrence of cancerous changes in the adenomas. One of the adenomas was maintained in twelve parallel lines while under test and new tumors arose in nine of them, the earliest appearing more than fifteen months after initial transfer of the growth. Always it was an adenoma solidum, this appearing almost concurrently in eight of the nine lines. In six of them it was soon followed by carcinomas, the sequence of events and the morphological findings both indicating that they had derived from it. Individually the cancers were widely various, but they were similar on the whole from line to line. Carcinomas of a wholly different aspect arose from the other adenoma undergoing cancerous change, and they were not preceded by adenoma solidum. In both instances the character of the superimposed neoplastic alterations seemed to have been determined by some inherent trait of the adenoma concerned."
1620,Receptor-binding cancer antigen expressed on SiSo cells can be detected in metastatic lymph nodes from gastrointestinal cancers.,"Leelawat K, Engprasert S, Tujinda S, Suthippintawong C, Enjoji M, Nakashima M, Watanabe T, Leardkamolkarn V.",https://pubmed.ncbi.nlm.nih.gov/16273616/,"Aim:
        
      
      To investigate the expression of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) in metastatic lymph nodes from gastrointestinal cancer.
    


          
    


           The immunoreactivity of RCAS1 was identified in 100% of metastatic lymph nodes. Both local and distant metastatic lymph nodes showed RCAS1 expression. On the contrary, specimens of non-cancerous lymph nodes were negative for RCAS1. The  RCAS1 mRNA was detected in all tumor cells that metastasized to lymph nodes.
    


          Conclusion:
        
      
      All metastatic lymph nodes express RCAS1 in tumor cells at both mRNA levels, and RCAS1 that should be used as a complementary factor for identification of metastatic lymph nodes from gastrointestinal cancers."
1621,Mesothelin is Commonly Expressed in Pancreatic Adenocarcinoma but Unrelated to Cancer Aggressiveness.,"Weidemann S, Perez D, Izbicki JR, Neipp M, Mofid H, Daniels T, Nahrstedt U, Jacobsen F, Bernreuther C, Simon R, Steurer S, Burandt E, Marx AH, Krech T, Clauditz TS, Jansen K.",https://pubmed.ncbi.nlm.nih.gov/34143695/,"Data on Mesothelin (MSLN) expression in human normal and cancerous tissues is controversial. We employed immunohistochemistry (IHC) on a tissue microarray (TMA) from 599 pancreatic cancers and 12 large tissue sections of pancreatitis. MSLN expression was highest in pancreatic adenocarcinomas (89%) and adenocarcinomas of the ampulla Vateri (79%), infrequent in pancreatitis and absent in 6 acinus cell carcinomas and normal pancreas. MSLN expression was unrelated to pathological tumor stage, grade, metastasis, and tumor-infiltrating CD8+ lymphocytes. In conclusion, pancreatic cancer may be ideally suited for putative anti- MSLN therapies, and MSLN may represent a suitable biomarker for pancreatic cancer diagnosis, especially on small biopsies."
1622,Find new channel for overcoming chemoresistance in cancers: Role of stem cells-derived exosomal microRNAs.,"Hussein GM, Mohammed SM, Faris M, Mohammed A, Kadhim MJ, Awadh SA, Ajam WH, Jalil AT.",https://pubmed.ncbi.nlm.nih.gov/35948201/,"Chemoresistance has remained a significant concern in tumor recurrence and elevated cancer-related mortalities. A deep insight into mechanisms by which cancerous cells resist administered drugs can pave the way to overcome chemotherapy-induced cell death and develop novel procedures to rescue patients. Regarding accumulated data, stem cell-derived exosomal microRNAs (miRNAs) can be deemed a novel and promising  It seems exosomal miRNAs play a dual role in the cancer microenvironment. On the one hand, as a messenger, they are transferred between donor and recipient cells contributing to cancer chemoresistance. On the other hand, stem cell-derived exosomal miRNA significantly restrains tumorigenesis and inhibits or alleviates drug resistance in the tumor niche. Hence, our purpose in this review evaluating the roles of stem cells-derived exosomal microRNAs in overcoming chemoresistance in tumors."
1623,Micrographic surgery for the microscopically controlled excision of eyelid cancer: history and development.,Mohs FE.,https://pubmed.ncbi.nlm.nih.gov/3331920/,The development of a  This  The reliability of the 1% for squamous cell carcinoma. The maximal conservation of normal tissues simplifies any needed repairs and permits some innovative ways of managing wounds with healing by granulation and by partial closures with guiding sutures.
1624,Quality of life and associated factors among adults living with cancer and their family caregivers.,"Gabriel I, Creedy D, Coyne E.",https://pubmed.ncbi.nlm.nih.gov/33605071/,"This study examined the association of needs, health literacy, and quality of life among adult Nigerians with cancer and family caregivers. A descriptive study was conducted involving 240 adults with cancer and family caregivers attending a tertiary hospital. More than two-thirds of participants reported moderate or high needs. Information (90.8%) and spiritual support (85%) were the domains of highest need among adults with cancer. Family/social support (85%) and spiritual support (81.7%) ranked the highest among family caregivers. A negative correlation was found between needs and quality of life. Stepwise regression analysis showed that needs and literacy explained 36% of the variance in adults with cancer's quality of life and 28% of the variance in family caregivers' quality of life. Spiritual need accounted l for 9.5% and 9.1% of variation for adults with cancer and family caregivers, respectively. Findings suggest that interventions with a focus on social/family and spiritual needs may improve wellbeing of adults with cancer and caregivers in Nigeria. This research are generalizable to other low-income countries where family values and spirituality are often a strong feature of daily life."
1625,Early detection of cervical cancer through acetic acid application--an aided visual inspection.,"Singh V, Sehgal A, Parashari A, Sodhani P, Satyanarayana L.",https://pubmed.ncbi.nlm.nih.gov/11764051/,"
    


          
    


           Seventy-three mild dysplasias, 50 moderate dysplasias, 45 severe dysplasias/Carcinoma in-situ and 40 early invasive cancerous cases were diagnosed histologically. The sensitivity of cytology (75.3%) was higher compared to that of acetic acid application (52.0%) for mild dysplasias. On the other hand, the sensitivity for detecting moderate dysplasias was 78% for cytology and 81.6% for acetic acid; for severe dysplasias/carcinoma in-situ it was 73.3% for cytology and 86.7% for acetic acid. For invasive cancers sensitivity for acetic acid application and cytology (95% for both modalities) was comparable. The specificity of cytology (99%) was higher compared to that of acetic acid application (94.3%). The false positive rate for cytology was 1.0% as against 5.7% for acetic acid application. The  It also reduced the false positive rates from 12% by unaided visual inspection to 5.7% by acetic acid application. Furthermore, cost of detection of one true lesion through acetic acid application (Rs.1689.00) was much lower as compared to the cost involved in cytology detected true lesions (Rs.2227.00). Visual inspection without acetic acid incurred Rs.6608.60 for detection of true lesion.
    


          Conclusion:
        
      
      Screening for cervical precancerous and cancerous lesions using visual inspection aided by acetic acid may be a suitable low-cost and a feasible alternative modality for control of cervical cancer in a resource poor setting."
1626,The anti-cancerous activity of adaptogenic herb Astragalus membranaceus.,"Sheik A, Kim K, Varaprasad GL, Lee H, Kim S, Kim E, Shin JY, Oh SY, Huh YS.",https://pubmed.ncbi.nlm.nih.gov/34479785/," A standardized chemotherapy regimen planned with curative intent weakens the immune system and damages healthy cells making the patient prone to infections and severe side effects with pain and fatigue.
    


          Purpose:
        
      
      Astragalus membranaceus (AM) has a long history of use in the treatment of severe adverse diseases. For thousands of years, it has been used in mixed herbal decoctions for the treatment of cancer. Due to growing interest in this plant root for its application to treat various types of cancers and tumors, has attracted researcher's interest.
    


          
    


          Outcome:
        
      
      Astragalus membranaceus has demonstrated the ability to modulate the immune system during drug therapy making the patient physically fit and prolonged life. It has become a buzzword of herbalists as it is one of the best of seven important adaptogenic herbs with a protective effect against chronic stress and cancer. It demonstrated significant amelioration of the perilous toxic effects induced by concurrently administered chemo onco-drugs.
    


          Conclusion:
        
      
      The natural phytoconstituents of this plant formononetin, astragalus polysaccharide, and astragalosides which show high potential anti-cancerous activity are studied and discussed in detail. One of them are used in clinical trials to overcome cancer related fatigue. Overall, this review aims to provide an insight into Astragalus membranaceus status in cancer therapy."
1627,Serum changes in trace elements during thyroid cancers.,"Al-Sayer H, Mathew TC, Asfar S, Khourshed M, Al-Bader A, Behbehani A, Dashti H.",https://pubmed.ncbi.nlm.nih.gov/15228079/,"The  Serum levels and tissue contents of trace elements (Zn, Cu, Mn, Mg, Fe and Se) were measured in 43 patients with thyroid cancer before and 4 days after surgery were compared to normal values. The serum levels of zinc in cancer patients were lower than those of normal subjects. Surgical removal of the cancer  Although serum Cu levels in patients were not different from normal, but post-operatively these levels rose significantly (p < 0.001). Levels of Fe, Mg and Mn were significantly lower (p < 0.001) post-operatively. There was no significant change in Serum Se levels. The thyroid tissue contents of these trace elements did not show a difference between the normal (Juxta-tumor) thyroid tissue and the cancerous lesion. Out of the six trace elements examined, the decrease of serum levels of zinc in cancer patients may be linked to the disease condition. It is suggested that this change: (a) may be used to demonstrate successful cancer surgery and (b) may have implications for a long-term follow-up of thyroid cancer patients."
1628,Immediate radical resection after local excision of rectal cancer: an oncologic compromise?,"Hahnloser D, Wolff BG, Larson DW, Ping J, Nivatvongs S.",https://pubmed.ncbi.nlm.nih.gov/15747069/,"Purpose:
        
      
      Local excision for early-staged rectal cancers is controversial. Preoperative understaging is not uncommon and radical resection after local resection may be needed for a curative treatment. The aim of this study was to determine the frequency and outcome of radical resection (within 30 days) after local excision for rectal adenocarcinoma.
    


           T2-3N0-1 stage cancers were each matched to three primary radical surgery controls for stage, age (+/- 5 years), gender, date (+/- 1 years), and type (abdominoperineal resection or low anterior resection) of operation. T1N0-1 cancers were compared with stage-matched rectal cancers treated by either primary radical surgery (n = 78) or local excision alone (n = 77).
    


           Radical surgery was performed because of a cancerous polyp (n = 42), positive margins (5), lymphovascular invasion (3), and T3-staged cancer (2). Twelve of 52 cancers (23 percent) were found to have nodal involvement and 15 of 52 (29 percent) showed residual cancer in the resected specimen. The T2-3N0-1 stage controls were well matched. No significant difference in tumor location, size, adjuvant therapy, or length of follow-up was noted. Local and distant recurrence occurred in 2 of 4 T2-3N1 tumors and in 2 of 11 T2-3N0 cancers and were comparable to the matched controls, as was survival, with the exception of shorter survival in T3N1 cases, but numbers were too small for a definitive conclusion. Length of follow-up was not different. For T1 cancers, the controls were also comparable regarding patient and tumor demographics and adjuvant therapy. Nodal involvement was 21 percent in T1 study cases and 15 percent in T1 primary radical-surgery controls, with a trend toward location in the lower third of the rectum in both groups (58 percent and 50 percent, respectively). Local recurrence rates were 3 percent in the study group, 5 percent for patients undergoing primary radical surgery, and 8 percent for local excision alone. Distant metastasis (11 percent, 12 percent, and 13 percent, respectively) and overall five-year survival were also not significantly different (78 percent, 89 percent, and 73 percent, respectively).
    


          Conclusions:
        
      
      Nodal involvement in attempted locally excised rectal cancers is not uncommon. Local excision of rectal tumors followed by radical surgery within 30 days in cancer patients does not compromise outcome compared with primary radical surgery. Even after radical surgery for superficial T1 rectal cancers, recurrence rates are not insignificant. Future improvements in preoperative staging may be helpful in selecting tumors for local excision only."
1629,Acute respiratory distress caused by esophageal duplication canceration in an adult.,"Liu JF, Liu G, Xu B.",https://pubmed.ncbi.nlm.nih.gov/22453545/,"Esophageal duplication (ED) in adults is rare, and ED canceration is very rare. We report a case of acute respiratory embarrassment caused by ED with squamous carcinoma in a 39-year-old man and a review of the literature."
1630,Adenocarcinoma of a neovagina constructed according to the Baldwin-Mori technique.,"Borruto F, Ferraro F.",https://pubmed.ncbi.nlm.nih.gov/2097157/,"The Authors describe a case of cancerization of a neovagina constructed according to the Baldwin-Mori technique, occurring 39 years after the initial operation. Description of the clinical case is followed by a number of anatomo-pathological considerations. The risk of cancerization and the adverse events associated with this type of neovagina militate against the use of autologous transplant operations in neovagina construction."
1631,Real-time Tracking and Classification of Tumor and Nontumor Tissue in Upper Gastrointestinal Cancers Using Diffuse Reflectance Spectroscopy for Resection Margin Assessment.,"Nazarian S, Gkouzionis I, Kawka M, Jamroziak M, Lloyd J, Darzi A, Patel N, Elson DS, Peters CJ.",https://pubmed.ncbi.nlm.nih.gov/36069888/,"Importance:
        
      
      Cancers of the upper gastrointestinal tract remain a major contributor to the global cancer burden. The accurate mapping of tumor margins is of particular importance for curative cancer resection and improvement in overall survival. Current mapping techniques preclude a full resection margin assessment in real time.
    


          
    


          Design, setting, and participants:
        
      
      This was a prospective ex vivo validation study. Patients undergoing esophageal or gastric cancer resection were prospectively recruited into the study between July 2020 and July 2021 at Hammersmith Hospital in London, United Kingdom. Tissue specimens were included for patients undergoing elective surgery for either esophageal carcinoma (adenocarcinoma or squamous cell carcinoma) or gastric adenocarcinoma.
    


          Exposures:
        
      
      A handheld DRS probe and tracking system was used on freshly resected ex vivo tissue to obtain spectral data. Binary classification, following histopathological validation, was performed using 4 supervised machine learning classifiers.
    


          Main outcomes and measures:
        
      
      Data were divided into training and testing sets using a stratified 5-fold cross-validation  Machine learning classifiers were evaluated in terms of sensitivity, specificity, overall accuracy, and the area under the curve.
    


           A total of 14 097 mean spectra for normal and cancerous tissue were collected. For normal vs cancer tissue, the machine learning classifier achieved a mean (SD) overall diagnostic accuracy of 93.86% (0.66) for stomach tissue and 96.22% (0.50) for esophageal tissue and achieved a mean (SD) sensitivity and specificity of 91.31% (1.5) and 95.13% (0.8), respectively, for stomach tissue and of 94.60% (0.9) and 97.28% (0.6) for esophagus tissue. Real-time tissue tracking and classification was achieved and presented live on screen.
    


          Conclusions and relevance:
        
      
      This study provides ex vivo validation of the DRS technology for real-time differentiation of gastric and esophageal cancer from healthy tissue using machine learning with high accuracy. As such, it is a step toward the development of a real-time in vivo tumor mapping tool for esophageal and gastric cancers that can aid decision-making of resection margins intraoperatively."
1632,Optical microsystem for analysis of diffuse reflectance and fluorescence signals applied to early gastrointestinal cancer detection.,"Pimenta S, Castanheira EM, Minas G.",https://pubmed.ncbi.nlm.nih.gov/25647742/,"The detection of cancer at its earliest stage is crucial in order to increase the probability of a successful treatment. Optical techniques, specifically diffuse reflectance and fluorescence, may considerably improve the ability to detect pre-cancerous lesions. These techniques have high sensitivity to some biomarkers present on the tissues, providing morphological and biochemical information of normal and diseased tissue. The development of a chip sized spectroscopy microsystem, based on these techniques, will greatly improve the early diagnosis of gastrointestinal cancers. The main innovation is the detection of the spectroscopic signals using only few, but representative, spectral bands allowing for miniaturization. This paper presents the mathematical models, its validation and analysis for retrieving data of the measured spectroscopic signals. These models were applied to a set of phantoms clearly representative of gastrointestinal tissues, leading to a more accurate diagnostic by a pathologist. Moreover, it was demonstrated that the models can use the reconstructed spectroscopic signals based only on its extraction on those specific spectral bands. As a "
1633,"miR-21, An Oncogenic Target miRNA for Cancer Therapy: Molecular Mechanisms and Recent Advancements in Chemo and Radio-resistance.","Javanmardi S, Aghamaali MR, Abolmaali SS, Mohammadi S, Tamaddon AM.",https://pubmed.ncbi.nlm.nih.gov/28042781/,"In the past decade, miRNAs have been extensively attracted the scientist's attentions as tumor suppressors or oncogenes that have been implicated in tumor progression, metastasis and intrinsic resistance to various cancer therapies. microRNA-21 (miR-21) demonstrates a potential oncogenic function and targets tumor inhibitor proteins in almost all types of cancer. miR-21 overexpression has been studied in terms of cell proliferation, migration, invasion, metastasis, and apoptosis regulation. Inhibition of miRNA expression using antisense technology by various nanovectors of different sizes, shapes and compositions has been evolved progressively to overcome the barriers confronted by miRNA delivery. Application of miR-21 antisense oligonucleotides for treating cancerous cells has become a promising achievement for cancer therapy. Moreover, miR-21 can mediate resistance to radiation and chemotherapy. The expanding role of miR-21 functions in human cancers with an emphasis on its regulatory targets and mechanisms, miR-21 related achievements against cancer promotion have been discussed."
1634,Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers.,"Li Y, Xiao K, Zhu W, Deng W, Lam KS.",https://pubmed.ncbi.nlm.nih.gov/24060922/,"Stimuli-responsive cross-linked micelles (SCMs) represent an ideal nanocarrier system for drug delivery against cancers. SCMs exhibit superior structural stability compared to their non-cross-linked counterpart. Therefore, these nanocarriers are able to minimize the premature drug release during blood circulation. The  In these instances, the payload drug is released almost exclusively in cancerous tissue or cancer cells upon accumulation via enhanced permeability and retention effect or receptor mediated endocytosis. In this review, we highlight recent advances in the development of SCMs for cancer therapy. We also introduce the latest biophysical techniques, such as electron paramagnetic resonance (EPR) spectroscopy and fluorescence resonance energy transfer (FRET), for the characterization of the interactions between SCMs and blood proteins."
1635,Pharmacoepigenetics and pharmacoepigenomics of gastrointestinal cancers.,"Lopomo A, Coppedè F.",https://pubmed.ncbi.nlm.nih.gov/28856927/,"Our understanding of the epigenetic changes occurring in gastrointestinal cancers has gained tremendous advancements in recent years, and some epigenetic biomarkers are already translated into the clinics for cancer diagnostics. In parallel, pharmacoepigenetics and pharmacoepigenomics of solid tumors are relevant novel, but emerging and promising fields. Areas covered: A comprehensive review of the literature to summarize and update the emerging field of pharmacoepigenetics and pharmacoepigenomics of gastrointestinal cancers. Expert commentary: Several epigenetic modifications have been proposed to account for interindividual variations in drug response in gastrointestinal cancers. Similarly, single-agent or combined strategies with high doses of drugs that target epigenetic modifications (epi-drugs) were scarcely tolerated by the patients, and current research has moved to their combination with standard therapies to achieve chemosensitization, radiosensitization, and immune modulation of cancerous cells. In parallel, recent genome-wide technologies are revealing the pathways that are epigenetically deregulated during cancer-acquired resistance, including those targeted by non-coding RNAs. Indeed, novel, less toxic, and more specific molecules are under investigation to specifically target those pathways. The field is rapidly expanding and gathering together information coming from these investigations has the potential to lead to clinical applications in the coming new years."
1636,"Are macrophages, myeloid derived suppressor cells and neutrophils mediators of local suppression in healthy and cancerous tissues in aging hosts?","Jackaman C, Nelson DJ.",https://pubmed.ncbi.nlm.nih.gov/24291067/,"Most cancers emerge in elderly and immune-comprised hosts implying an important role for cancer immune surveillance. Here, we focus on the role of tissue-associated innate immune cells including antigen presenting cells (i.e. dendritic cells and macrophages), myeloid derived suppressor cells and neutrophils in healthy and cancer-bearing elderly hosts. Most cancers, including the cancers that we are interested in, i.e. lung carcinomas and mesothelioma, emerge in aging populations at a time when naïve T cell function is declining. CD8(+) cytotoxic T lymphocytes are critical anti-tumor effector cells, and their diminished function may contribute to cancer escape mechanisms in the elderly. Therefore, we compare the likely consequences of innate immune cell interactions with T cells in young versus elderly hosts. We examine data showing that elderly-derived innate cells are highly immunosuppressive and may provide a more tumorigenic milieu than their younger counterparts. Standard chemotherapy often only provides these patients a few extra months survival time. Recent evidence has shown that standard chemotherapy is not as effective in hosts devoid of T cells. Therefore, T cell dysfunction in the elderly may contribute to poor treatment outcomes. However, there is also evidence that T cell immunity can be rejuvenated via activated dendritic cells and/or macrophages. Combining 'rejuvenation' immunotherapy with standard chemotherapy may offer an improved outcome for elderly cancer patients. We explore this potential herein."
1637,Recent Advances on PKM2 Inhibitors and Activators in Cancer Applications.,"Chen P, Lou L, Sharma B, Li M, Xie C, Yang F, Wu Y, Xiao Q, Gao L.",https://pubmed.ncbi.nlm.nih.gov/37455458/,"Metabolic reprogramming of cells, from the normal mode of glucose metabolism named glycolysis, is a pivotal characteristic of impending cancerous cells. Pyruvate kinase M2 (PKM2), an important enzyme that catalyzes the final rate-limiting stage during glycolysis, is highly expressed in numerous types of tumors and aids in development of favorable conditions for the survival of tumor cells. Increasing evidence has suggested that PKM2 is one of promising targets for innovative drug discovery, especially for the developments of antitumor therapeutics. Herein, we systematically summarize the recent advancement on PKM2 modulators including inhibitors and activators in cancer applications. We also discussed the classifications of pyruvate kinases in mammals and the biological functions of PKM2 in this review. We do hope that this review would provide a comprehensive understanding of the current research on PKM2 modulators, which may benefit the development of more potent PKM2-related drug candidates to treat PKM2-associated diseases including cancers in future."
1638,Experiences of Symptoms and Impact on Daily Life and Health in Hepatocellular Carcinoma Patients: A Meta-synthesis of Qualitative Research.,"Drott J, Björnsson B, Sandström P, Berterö C.",https://pubmed.ncbi.nlm.nih.gov/35025775/," To achieve optimal supportive cancer care for HCC patients, it is important to consider patients' experiences and preferences.
    


          
    


           In addition, searches were performed using Open Gray to identify relevant studies in the gray literature. The search was limited to studies published in English from 2009 to 2019. Five studies (124 participants) were identified, appraised, and ultimately interpreted and synthesized.
    


           Three themes were identified based on the meta-synthesis: (1) disrupted life, (2) living with uncertainty, and (3) a changed body. Patients with HCC experience disrupted lives because of the cancer's effect on health and multidimensional symptoms.
    


          Conclusion:
        
      
      Available research on the experiences of HCC patients is limited. This meta-synthesis of available studies shows that being given a diagnosis of HCC is an overwhelming event. Our study findings show that an HCC diagnosis affected the individual's entire life.
    


          Implications for practice:
        
      
      It is important to identify the patients' physical, psychological, social, and existential needs during the investigation of their condition, during any curative treatment, and at the palliative stage of the disease."
1639,"[The effects of localized therapy with postsurgical local recurrences of lung carcinoma and metastatic lung tumors--laser irradiation, IL-2+ LAK or ethanol injection].","Baba M, Yamaguchi Y, Fujisawa T, Kimura H.",https://pubmed.ncbi.nlm.nih.gov/3260090/,"Nd-YAG or Argon dye laser irradiations combined with radiotherapy were performed for lung cancer patients with central airway obstructions due to recurrences. Remarkable effects of immediate airway dilatation and reduction of symptoms were obtained after laser irradiations. IL-2 and LAK injections or ethanol injections into the peripheral recurrent or metastatic lung lesions. In one out of 5 patients after IL-2 and LAK injection, and in one out of 2 patients after ethanol injection, tumor size was reduced by 43% and 34%, respectively. IL-2 and/or LAK were injected into the pleural or pericardial spaces with malignant effusion, showing significant effects on a lung cancer patient with cancerous pericarditis who survived more than 9 months after this localized therapy. According to these "
1640,Recent advances in theranostic polymeric nanoparticles for cancer treatment: A review.,"Indoria S, Singh V, Hsieh MF.",https://pubmed.ncbi.nlm.nih.gov/32283197/,"Nanotheranostics is fast-growing pharmaceutical technology for simultaneously monitoring drug release and its distribution, and to evaluate the real time therapeutic efficacy through a single nanoscale for treatment and diagnosis of deadly disease such as cancers. In recent two decades, biodegradable polymers have been discovered as important carriers to accommodate therapeutic and medical imaging agents to facilitate construction of multi-modal formulations. In this review, we summarize various multifunctional polymeric nano-sized formulations such as polymer-based super paramagnetic nanoparticles, ultrasound-triggered polymeric nanoparticles, polymeric nanoparticles bearing radionuclides, and fluorescent polymeric nano-sized formulations for purpose of theranostics. The use of such multi-modal nano-sized formulations for near future clinical trials can assist clinicians to predict therapeutic properties (for instance, depending upon the quantity of drug accumulated at the cancerous site) and observed the progress of tumor growth in patients, thus improving tailored medicines."
1641,Procedure to estimate thermophysical and geometrical parameters of embedded cancerous lesions using thermography.,"Manuel Luna J, Romero-Mendez R, Hernandez-Guerrero A, Elizalde-Blancas F.",https://pubmed.ncbi.nlm.nih.gov/22482688/,"Based on the fact that malignant cancerous lesions (neoplasms) develop high metabolism and use more blood supply than normal tissue, infrared thermography (IR) has become a reliable clinical technique used to indicate noninvasively the presence of cancerous diseases, e.g., skin and breast cancer. However, to diagnose cancerous diseases by IR, the technique requires procedures that explore the relationship between the neoplasm characteristics (size, blood perfusion rate and heat generated) and the  In this research work the dual reciprocity boundary element  The  In addition, the DRBEM does not require any re-meshing at each proposed solution to solve the bioheat model. The inverse procedure has been tested considering input data for simulated neoplasms of different sizes and positions in relation to the skin surface. The successful estimation of unknown neoplasm parameters validates the idea of using the SA technique and the DRBEM in the estimation of parameters. Other estimation techniques, based on genetic algorithms or sensitivity coefficients, have not been capable of obtaining a solution because the skin surface temperature difference is very small."
1642,Cancer knowledge in the plural: queering the biopolitics of narrative and affective mobilities.,"Bryson MK, Stacey J.",https://pubmed.ncbi.nlm.nih.gov/23475453/,"In this age of DIY Health-a present that has been described as a time of ""ludic capitalism""-one is constantly confronted with the injunction to manage risk by means of making healthy choices and of informed participation in various self-surveillant technologies of bioinformatics. Neoliberal governmentality has been redacted by poststructuralist scholars of bioethics as defined by the two-fold emergence of, on the one hand, populations and on the other, the self-determining individual-as biopolitical entities. In this article, we provide a genealogical-phenomenological schematization (GPS analysis) of the narration of cancer in relation to ""sexual minority populations."" Canonical discourses concerning minority sexualities are articulated by means of a logic of ""inclusion and reification"" that organizes the interiorization of norms of embodied relationality, and a positive liaison with biomedical technologies and techniques in the taking up of a rhetorical style of biographical compliance. Neoliberal DIY Health logics conflate participation with agency, and institute norms of recognition that constrain visibility to: citizens who make healthy choices and manage risk, heroic cancer stories, stories of the reconstruction of states of normalcy, or of survival against all odds. Alternatively, we trace the performative articulations of queer narrative practices that constitute an ephemeral, nomadic praxiology-a doing of knowledge in cancer's queer narration. Queer cancer narrative practices represent a relationship to health and embodiment that is predicated, not on normalcy, but predicated on troubling norms, on artful failure, and on engaging in a kind of affective mapping that might be thought constitutive of a speculative bioethical relation to the self as other."
1643,The emerging roles of OSBP-related proteins in cancer: Impacts through phosphoinositide metabolism and protein-protein interactions.,Olkkonen VM.,https://pubmed.ncbi.nlm.nih.gov/33556339/,"Oxysterol-binding protein -related proteins (ORPs) form a large family of intracellular lipid binding/transfer proteins. A number of ORPs are implicated in inter-organelle lipid transfer over membrane contacts sites, their mode of action involving in several cases the transfer of two lipids in opposite directions, termed countercurrent lipid transfer. A unifying feature appears to be the capacity to bind phosphatidylinositol polyphosphates (PIPs). These lipids are in some cases transported by ORPs from one organelle to another to drive the transfer of another lipid against its concentration gradient, while they in other cases may act as allosteric regulators of ORPs, or an ORP may introduce a PIP to an enzyme for catalysis. Dysregulation of several ORP family members is implicated in cancers, ORP3, -4, -5 and -8 being thus far the most studied examples. The most likely mechanisms underlying their associations with malignant growth are (i) impacts on PIP-mediated signaling events  In this review I discuss the existing functional evidence for the involvement of ORPs in cancerous growth, discuss the findings in the light of the putative mechanisms outlined above and the possibility of employing ORPs as targets of anti-cancer therapy."
1644,Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma.,"Jardé T, Caldefie-Chézet F, Damez M, Mishellany F, Penault-Llorca F, Guillot J, Vasson MP.",https://pubmed.ncbi.nlm.nih.gov/18357374/,"Obesity is associated with an increased risk of breast cancer. Leptin, a hormone synthesised essentially by adipose tissue, may be involved in cancer development. We examined the expression of leptin and leptin receptor (Ob-R) in human primary breast cancer and adjacent non-cancerous tissue. We also analysed their relationships with histological variables such as the oestrogen and progesterone receptors, Ki67 proliferation factor and tumour size. The expressions of leptin and Ob-R were investigated by immunohistochemical staining in 35 primary breast cancers and 17 adjacent non-cancerous tissues. Samples and histological features were obtained from the Anti-Cancer Centre. Expressions of leptin and Ob-R were detected in, respectively, 85 and 75% of the primary breast cancer cases studied. The expression of leptin was significantly correlated with Ob-R detection (p=0.008). In addition, Ob-R expression in primary breast carcinoma was positively correlated with oestrogen receptor expression (p=0.028) and tumour size (p=0.045) but not with Ki67 or progesterone receptor expressions. However, the expression of leptin showed no statistical correlation with these variables. First, the co-expression of leptin and Ob-R in primary breast cancer shows that leptin acts on mammary tumour cells via an autocrine pathway. Second, the co-expression of Ob-R and oestrogen receptors suggests a possible interaction between leptin and oestrogen systems to promote breast carcinogenesis. Finally, the fact that Ob-R expression was positively correlated with tumour size may point to a potential role of leptin as a growth factor and of Ob-R as a new prognostic factor."
1645,Unveiling Prognostic RNA Biomarkers through a Multi-Cohort Study in Colorectal Cancer.,"Kim Z, Lee J, Yoon YE, Yun JW.",https://pubmed.ncbi.nlm.nih.gov/38542291/,"Because cancer is a leading cause of death and is thought to be caused by genetic errors or genomic instability in many circumstances, there have been studies exploring cancer's genetic basis using microarray and RNA-seq  This research introduces a  Heterogeneous gene expression data for colorectal cancer were collected from TCGA-COAD (RNA-seq), and GSE17536 and GSE39582 (microarray), and were integrated with Entrez Gene IDs. Using Cox regression analysis and random forest, genes with consistent hazard ratios and significantly affecting patient survivability were chosen. Predictive accuracy was evaluated using ROC curves. Pathway analysis identified potential RNA biomarkers. The authors identified 28 RNA biomarkers. Pathway analysis revealed enrichment in cancer-related pathways, notably EGFR downstream signaling and IGF1R signaling. Three RNA biomarkers (ZEB1-AS1, PI4K2A, and ITGB8-AS1) and two clinical biomarkers (stage and age) were chosen for a prognostic model, improving predictive performance compared to using clinical biomarkers alone. Despite biomarker identification challenges, this study underscores integration of heterogenous gene expression data for discovery."
1646,Identification of key proteins in the signaling crossroads between wound healing and cancer hallmark phenotypes.,"López-Cortés A, Abarca E, Silva L, Velastegui E, León-Sosa A, Karolys G, Cabrera F, Caicedo A.",https://pubmed.ncbi.nlm.nih.gov/34446793/,"Wound healing (WH) and cancer seem to share common cellular and molecular processes that could work in a tight balance to maintain tissue homeostasis or, when unregulated, drive tumor progression. The ""Cancer Hallmarks"" comprise crucial biological properties that mediate the advancement of the disease and affect patient prognosis. These hallmarks have been proposed to overlap with essential features of the WH process. However, common hallmarks and proteins actively participating in both processes have yet to be described. In this work we identify 21 WH proteins strongly linked with solid tumors by integrated TCGA Pan-Cancer and multi-omics analyses. These proteins were associated with eight of the ten described cancer hallmarks, especially avoiding immune destruction. These  This set of proteins, between WH and cancer, could represent key targets for developing therapies."
1647,Structured Population-based Prostate-specific Antigen Screening for Prostate Cancer: The European Association of Urology Position in 2019.,"Gandaglia G, Albers P, Abrahamsson PA, Briganti A, Catto JWF, Chapple CR, Montorsi F, Mottet N, Roobol MJ, Sønksen J, Wirth M, van Poppel H.",https://pubmed.ncbi.nlm.nih.gov/31092338/,"Prostate cancer (PCa) is one of the first three causes of cancer mortality in Europe. Screening in asymptomatic men (aged 55-69yr) using prostate-specific antigen (PSA) is associated with a migration toward lower staged disease and a reduction in cancer-specific mortality. By 20yr after testing, around 100 men need to be screened to prevent one PCa death. While this ratio is smaller than for breast and colon cancer, the long natural history of PCa means many men die from other causes. As such, the nonselective use of PSA testing and radical treatments can lead to overdiagnosis and overtreatment. The European Association of Urology (EAU) supports measures to encourage appropriate PCa detection through PSA testing, while reducing overdiagnosis and overtreatment. These goals may be achieved using personalized risk-stratified approaches. For diagnosis, the greatest benefit from early detection is likely to come in men assessed using baseline PSA levels at the age of 45yr to individualize screening intervals. Multiparametric magnetic resonance imaging as well as risk calculators based on family history, ethnicity, digital rectal examination, and prostate volume should be considered to triage the need for biopsy, thus reducing the risk of overdiagnosis. For treatment, the EAU advocates balancing patient's life expectancy and cancer's mortality risk when deciding an approach. Active surveillance is encouraged in well-informed patients with low-risk and some intermediate-risk cancers, as it decreases the risks of overtreatment without compromising oncological outcomes. Conversely, the EAU advocates radical treatment in suitable men with more aggressive PCa. Multimodal treatment should be considered in locally advanced or high-grade cancers. PATIENT SUMMARY: Implementation of prostate-specific antigen (PSA)-based screening should be considered at a population level. Men at risk of prostate cancer should have a baseline PSA blood test (eg, at 45yr). The level of this test, combined with family history, ethnicity, and other factors, can be used to determine subsequent follow-up. Magnetic resonance imaging scans and novel biomarkers should be used to determine which men need biopsy and how any cancers should be treated."
1648,Nonsense mutation at codon 63 of the BRCA1 gene in Japanese breast cancer patients.,"Kijima G, Murakami Y, Ohuchi N, Satomi S, Sekiya T.",https://pubmed.ncbi.nlm.nih.gov/9765620/,"The involvement of abnormalities of the BRCA1 gene in breast cancers in Japanese patients without any family history of this cancer was investigated by polymerase chain reaction-based single-strand conformation polymorphism analysis of the DNA sequences corresponding to the zinc finger domain (exons 2, 3 and 5) and the binding domain with Rad51 (exon 11) of the BRCA1 protein. An identical nonsense mutation at codon 63 (TTA to TAA) was found in 2 of 56 (3.5%) breast cancers from independent patients. The nucleotide change was also detected in the DNAs from non-cancerous tissues of both patients and therefore was a germline mutation. One of the patients was a member of a pedigree involving 3 ovarian cancer and 1 gastric cancer patients, while the other patient had no family history of malignancy. The same germline mutation at codon 63 was reported in four other independent Japanese pedigrees with frequent breast cancer, but not in such families in other countries. These observations suggest that the mutation commonly originated from a single Japanese ancestor. No other mutation of the BRCA1 gene was observed in the samples analyzed in this study. A low incidence of germline mutation and the absence of somatic mutation suggest that the aberration of the BRCA1 gene is involved only in a subset of Japanese breast cancers."
1649,Estrogen and progesterone receptors in gallbladder cancer.,"Nakamura S, Muro H, Suzuki S.",https://pubmed.ncbi.nlm.nih.gov/2657151/,"Cancerous tissues from 21 patients with primary gallbladder cancer were examined immuno-histochemically for the presence of receptors for estrogen (ER) and progesterone (PGR). ER and PGR, localized in the nucleus, were evident in 52.4 per cent and 0 per cent of the patients, respectively. Furthermore, ER and PGR were positive only in the cytoplasm of cancer cells in 28.6 per cent and 66.7 per cent, respectively. There was a higher tendency of moderately- and poorly-differentiated adenocarcinoma to have an ER-positive rate than well-differentiated adenocarcinoma. With respect to the relationship between ER and sex, ER-positive nuclei were observed in 8 of 14 women (57.1 per cent) and 3 of 7 men (42.9 per cent), but the difference between the two was not significant due to the small number of subjects. These "
1650,Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development.,"Baenke F, Peck B, Miess H, Schulze A.",https://pubmed.ncbi.nlm.nih.gov/24203995/,"An increased rate of lipid synthesis in cancerous tissues has long been recognised as an important aspect of the rewired metabolism of transformed cells. However, the contribution of lipids to cellular transformation, tumour development and tumour progression, as well as their potential role in facilitating the spread of cancerous cells to secondary sites, are not yet fully understood. In this article, we review the recent findings that support the importance of lipid synthesis and metabolism in tumorigenesis. Specifically, we explore the role of aberrant lipid biosynthesis in cancer cell migration and invasion, and in the induction of tumour angiogenesis. These processes are crucial for the dissemination of tumour cells and formation of metastases, which constitute the main cause of cancer mortality."
1651,"Achyrocline B (3,5 dihydroxy-6,7,8-trimethoxyflavone) synergizes with 5-fluorouracil allowing for dose reduction and reduced off-target toxicity in the treatment of colonic and pancreatic cancers.","Cartwright BM, Corso JN, Lightner J, Whitted C, Torrenegra RD, Krishnan K, Palau VE.",https://pubmed.ncbi.nlm.nih.gov/37741250/,"Surgically unresectable colorectal and pancreatic carcinomas have a high rate of mortality as current therapeutic options are limited. One common chemotherapeutic used to broadly treat both cancers is 5-flurouracil (5-Fu); however, treatment serves only to slow progression of the disease and comes with many side effects due to 5-Fu's intrinsic toxicity. Thus, strategies to decrease the dose of 5-Fu utilized therapeutically as well as reduce 5-Fu's off-target toxicity are paramount. Using cell models of colorectal and pancreatic cancers, we show that cotreatment with Achyrocline B (3,5 dihydroxy-6,7,8-trimethoxyflavone, AcB), a natural flavone from Achyrocline bogotensis, allows for four-fold reduction in 5-Fu dosage without loss of efficacy. We further show that the action of AcB is due to continued cell cycle progression despite 5-Fu pressure to synchronize at the G1/S threshold. In addition to AcB's effect on cancer cells, we found that AcB can directly reduce toxicity of 5-Fu in cells mimicking non-cancerous tissues. These in vitro  AcB was shown to increase apoptosis in tumors leading to degeneration of the outer tumoral boundary. Furthermore, in 5-Fu treated animals it was found that AcB provided protection to the intestinal tract as indicated by preserved histological and immunohistochemical features. These "
1652,Aberrant DNA methylation profile of hepatocellular carcinoma and surgically resected margin.,"Lou C, Du Z, Yang B, Gao Y, Wang Y, Fang S.",https://pubmed.ncbi.nlm.nih.gov/19385975/,"Field cancerization currently described the theory of tumorigenesis and, until now, has been described in almost all organ systems except in liver. For this reason, we explore the presence of field cancerization in liver and its underlying clinical implication in hepatocellular carcinoma (HCC). In our study, methylation profile of HCC and surgically resected margin (SRM) were established by methylation-specific PCR. Liver cirrhosis (LC), chronic hepatitis and normal liver were treated in the same way as the  The correlation analysis among the methylation profile of HCC, SRM and clinicopathological data of HCC patients was made respectively. Our  Monoclonal and polyclonal models may coexist in field cancerization in liver. Patients with RIZ1 methylation in SRM had a shorter disease free survival. The local recurrence trend of early and later recurrence in HCC is potentially related to a second field tumor. From these  The study of field cancerization in liver plays an important role in hepatocarcinogenesis. Second field tumor derived form field cancerization may have important implications in HCC prognosis assessment that is worthy of further study."
1653,Radiomics for Predicting Lung Cancer Outcomes Following Radiotherapy: A Systematic Review.,"Walls GM, Osman SOS, Brown KH, Butterworth KT, Hanna GG, Hounsell AR, McGarry CK, Leijenaar RTH, Lambin P, Cole AJ, Jain S.",https://pubmed.ncbi.nlm.nih.gov/34763965/,"Lung cancer's radiomic phenotype may potentially inform clinical decision-making with respect to radical radiotherapy. At present there are no validated biomarkers available for the individualisation of radical radiotherapy in lung cancer and the mortality rate of this disease remains the highest of all other solid tumours. MEDLINE was searched using the terms 'radiomics' and 'lung cancer' according to the Preferred Reporting Items for Systematic Reviews and Met-Analyses (PRISMA) guidance. Radiomics studies were defined as those manuscripts describing the extraction and analysis of at least 10 quantifiable imaging features. Only those studies assessing disease control, survival or toxicity outcomes for patients with lung cancer following radical radiotherapy ± chemotherapy were included. Study titles and abstracts were reviewed by two independent reviewers. The Radiomics Quality Score was applied to the full text of included papers. Of 244 returned  End points frequently reported were local (17%), regional (17%) and distant control (31%), overall survival (79%) and pulmonary toxicity (4%). Imaging features strongly associated with clinical outcomes include texture features belonging to the subclasses Gray level run length matrix, Gray level co-occurrence matrix and kurtosis. The median cohort size for model development was 100 (15-645); in the 11 studies with external validation in a separate independent population, the median cohort size was 84 (21-295). The median number of imaging features extracted was 184 (10-6538). The median Radiomics Quality Score was 11% (0-47). Patient-reported outcomes were not incorporated within any studies identified. No studies externally validated a radiomics signature in a registered prospective study. Imaging-derived indices attained through radiomic analyses could equip thoracic oncologists with biomarkers for treatment response, patterns of failure, normal tissue toxicity and survival in lung cancer. Based on routine scans, their non-invasive nature and cost-effectiveness are major advantages over conventional pathological assessment. Improved tools are required for the appraisal of radiomics studies, as significant barriers to clinical implementation remain, such as standardisation of input scan data, quality of reporting and external validation of signatures in randomised, interventional clinical trials."
1654,PAQR4 has a tumorigenic effect in human breast cancers in association with reduced CDK4 degradation.,"Zhang H, Han R, Ling ZQ, Zhang F, Hou Y, You X, Huang M, Zhao Z, Wang Z, Chen Y.",https://pubmed.ncbi.nlm.nih.gov/29228296/,"Progestin and adipoQ receptor 4 (PAQR4) is a member of the PAQR family, and the members within this family are involved in the regulation of a number of biological processes including metabolism and cancer development. The potential function of PAQR4 in human cancers is unknown. Analysis of ONCOMINE database reveals that PAQR4 is highly expressed in human breast cancers. We confirmed this finding by analyzing 82 human breast cancers samples. PAQR4 mRNA level was significantly upregulated in human breast cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The mRNA level of PAQR4 was negatively correlated with disease-free survival (P < 0.0001) and overall survival of the patients (P = 0.001). Knockdown of PAQR4 in human breast cancer cells SUM159 and MCF7 suppressed cell proliferation. In contrast, overexpression of PAQR4 in SUM159 cells enhanced cell proliferation and colony formation. In a tumor xenograft model, overexpression of PAQR4 promoted tumor growth of SUM159 cells in vivo, while PAQR4 knockdown suppressed the tumor growth. PAQR4 was able to negatively regulate cyclin-dependent kinases 4 (CDK4) protein level in the breast cancer cells. Knockdown of PAQR4 accelerated degradation of CDK4 together with upregulation of CDK4 polyubiquitination. On the other hand, overexpression of PAQR4 slowed down CDK4 protein degradation and reduced CDK4 polyubiquitination. Collectively, these data at the cellular, animal and human levels indicate that PAQR4 has a tumorigenic effect on human breast cancers, and such effect is associated with a modulatory activity of PAQR4 on protein degradation of CDK4."
1655,Cell and extracellular matrix growth theory and its implications for tumorigenesis.,"Sauer TJ, Samei E, Bejan A.",https://pubmed.ncbi.nlm.nih.gov/33358828/,"Cells associated with an abnormal (cancerous) growth exchange flows, morph freely and grow hand-in-glove with their immediate environment, the extracellular matrix (ECM). The cell structure experiences two mass flows in counterflow. Flowing into the structure are nutrients and flowing out is refuse from the metabolically active biomass within. The physical effect of the evolution of the cell and extracellular structure is more flow and mixing in that space, that is, more mixing than in the absence of a biological growth in that space. The  This amounts to predicting the timing and the main features of the transitions from single cell to clusters with two, four, eight and more cells, including larger clusters with cells organized on its outer surface. The predicted evolution of the size and configuration of the cell cluster is validated successfully by comparison with measurements from several independent studies of cancerous and non-cancerous growth patterns."
1656,High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis.,"Ren B, Yang J, Wang C, Yang G, Wang H, Chen Y, Xu R, Fan X, You L, Zhang T, Zhao Y.",https://pubmed.ncbi.nlm.nih.gov/34348759/," However, the role of the 3D epigenome in pancreatic cancer biology, especially its metastasis, remains unclear.
    


           Moreover, we found that upregulated genes, which were located in switched compartments, changed contact domains, and metastasis-specific enhancer-promoter loops, were related to cancer metastasis and poor prognosis of patients with pancreatic cancer. We also found that transcription factors in specific enhancer-promoter loop formation were also associated with metastasis. Finally we demonstrated that LIPC, looped to metastasis-specific enhancers, could promote pancreatic cancer metastasis.
    


          Conclusions:
        
      
      These "
1657,Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer.,"Kadara H, Sivakumar S, Jakubek Y, San Lucas FA, Lang W, McDowell T, Weber Z, Behrens C, Davies GE, Kalhor N, Moran C, El-Zein R, Mehran R, Swisher SG, Wang J, Zhang J, Fujimoto J, Fowler J, Heymach JV, Dubinett S, Spira AE, Ehli EA, Wistuba II, Scheet P.",https://pubmed.ncbi.nlm.nih.gov/30896962/,"Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non-small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown. Spatiotemporal relationships between the airway field and NSCLCs were assessed by phylogenetic analysis.Measurements and Main  The airway field epithelium exhibited a total of 269 somatic mutations in most patients (n = 36) including key drivers that were shared with the NSCLCs. Allele frequencies of these acquired variants were overall higher in NSCLCs. Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared ""two-hit"" alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1).Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment."
1658,Viral and Clinical Oncology of Head and Neck Cancers.,"Goon P, Schürmann M, Oppel F, Shao S, Schleyer S, Pfeiffer CJ, Todt I, Brasch F, Scholtz LU, Göerner M, Sudhoff H.",https://pubmed.ncbi.nlm.nih.gov/35347592/,"Purpose of review:
        
      
      This study assesses the current state of knowledge of head and neck squamous cell carcinomas (HNSCC), which are malignancies arising from the orifices and adjacent mucosae of the aerodigestive tracts. These contiguous anatomical areas are unique in that 2 important human oncoviruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), are causally associated with nasopharyngeal and oropharyngeal cancers, respectively. Mortality rates have remained high over the last 4 decades, and insufficient attention paid to the unique viral and clinical oncology of the different subgroups of HNSCC.
    


          Recent findings:
        
      
      We have compared and contrasted the 2 double-stranded DNA viruses and the relevant molecular oncogenesis of their respective cancers against other head and neck cancers. Tobacco and alcohol ingestion are also reviewed, as regard the genetic progression/mutation accumulation model of carcinogenesis. The importance of stringent stratification when searching for cancer mutations and biomarkers is discussed. Evidence is presented for a dysplastic/pre-invasive cancerous phase for HPV+ oropharyngeal cancers, and analogous with other HPV+ cancers. This raises the possibility of strategies for cancer screening as early diagnosis will undoubtedly save lives. Staging and prognostication have changed to take into account the distinct biological and prognostic pathways for viral+ and viral- cancers. Diagnosis of pre-cancers and early stage cancers will reduce mortality rates. Multi-modal treatment options for HNSCC are reviewed, especially recent developments with immunotherapies and precision medicine strategies. Knowledge integration of the viral and molecular oncogenic pathways with sound planning, hypothesis generation, and clinical trials will continue to provide therapeutic options in the future."
1659,Histamine and its metabolizing enzymes in tissues of primary ductal breast cancer.,"von Mach-Szczypiński J, Stanosz S, Sieja K, Stanosz M.",https://pubmed.ncbi.nlm.nih.gov/19899403/,"
    


          Material and  The 24-hour excretion of N-methylimidazolacetate acid was evaluated by the chromatography 
    


          
    


          Conclusions:
        
      
      1. Concentrations of histamine in plasma is dependent on the concentration of histamine in the tissues of ductal breast cancers. 2. Significant increases of histamine in cancerous tissues of ductal breast cancer could suggest the participation of this monoamine in the development of breast cancer. 3. The increase of histamine concentrations in ductal breast cancer tissues can be connected with disturbances in the balance between synthesis and enzymatic activation of this monoamine. 4. The concentration of histamine in plasma of women with ductal breast cancers is dependent on the number of lymph nodes and grade of histological malignancy."
1660,Helicobacter pylori infection in early gastric adenocarcinoma: relationship between histologic subtypes and ulcer-formation.,"Ono Y, Hirabayashi K, Ishida M, Sakuma K, Tomita S, Sano Y, Ichikawa K, Terano A, Ueda Y, Fujimori T.",https://pubmed.ncbi.nlm.nih.gov/9440063/,"Early stage of gastric cancers were divided into two subtypes; differentiated and undifferentiated adenocarcinomas, histologically. We examined the involvement of Helicobacter pylori (Hp) infection in the development and progression of cancer, and presence or absence of peptic ulcer (UL+/UL-). From the  2) Neither of gross features nor depth of the tumor did not correlate with Hp positive rates. 3) Hp positive rate of undifferentiated type carcinoma was significantly higher than that of differentiated type, contrarily to our expectation. These findings suggested that Hp infection might relate with ulcer formation in the cancerous lesion. The hypothesis which is ""gastritis-intestinal metaplasia-differentiated type carcinoma sequence"" was not supported by present study. Hence, Hp infection was suggested as an important factor of the gastric cancer development and progression, not only in differentiated type but also in undifferentiated type."
1661,Properties and clinical relevance of MTA1 protein in human cancer.,"Toh Y, Nicolson GL.",https://pubmed.ncbi.nlm.nih.gov/25359582/,"Among the genes that were found to be abundantly overexpressed in highly metastatic rat cell lines compared to poorly metastatic cell lines, we identified a completely novel complementary DNA (cDNA) without any homologous or related genes in the database in 1994. The full-length cDNA of this rat gene was cloned, sequenced, and named metastasis-associated gene 1 (mta1), and eventually, its human cDNA counterpart, MTA1, was also cloned and sequenced by our group. MTA1 has now been identified as one of the members of a gene family (MTA gene family) and the products of the MTA genes, the MTA proteins, are transcriptional co-regulators that function in histone deacetylation and nucleosome remodeling and have been found in nuclear histone remodeling complexes. Furthermore, MTA1 along with its protein product MTA1 has been repeatedly and independently reported to be overexpressed in a vast range of human cancers and cancer cell lines compared to non-cancerous tissues and cell lines. The expression levels of MTA1 correlate well with the malignant properties of human cancers, strongly suggesting that MTA1 and possibly other MTA proteins (and their genes) could be a new class of molecular targets for cancer diagnosis and therapy."
1662,Expectation-maximization method for reconstructing tumor phylogenies from single-cell data.,"Pennington G, Smith CA, Shackney S, Schwartz R.",https://pubmed.ncbi.nlm.nih.gov/17369656/,"Recent studies of gene expression in cancerous tumors have revealed that cancers presenting indistinguishable symptoms in the clinic can represent substantially different entities at the molecular level. The ability to distinguish between these different cancers makes possible more accurate prognoses and more finely targeted therapeutics. Making full use of this knowledge, however, requires characterizing commonly occurring cancer sub-types and the specific molecular abnormalities that produce them. Computational approaches to this problem to date have been hindered by the fact that tumors are highly heterogeneous masses typically containing cells at multiple stages of progression from healthy to aggressively malignant. We present a computational approach for taking advantage of tumor heterogeneity when characterizing tumor progression pathways by inferring those pathways from single-cell assays. Our approach uses phylogenetic algorithms to infer likely evolutionary sequences producing cell populations in single tumors, which are in turn used to create a profile of commonly used pathways across the patient population. This approach is combined with expectation maximization to infer unknown parameters used in the phylogeny construction. We demonstrate the approach on a set of fluorescent in situ hybridization (FISH) data measuring cell-by-cell gene and chromosome copy numbers in a large sample of breast cancers. The  They also provide novel insights into the mechanisms of tumor progression in these patients."
1663,Light gradient boosting-based prediction of quality of life among oral cancer-treated patients.,"Ramalingam K, Yadalam PK, Ramani P, Krishna M, Hafedh S, Badnjević A, Cervino G, Minervini G.",https://pubmed.ncbi.nlm.nih.gov/38504227/,"2%. Mouth opening and swallowing are challenging. Hence, most oral cancer patients only report later stages. They worry about surviving cancer and receiving therapy. Oral cancer severely affects QOL. QOL is affected by risk factors, disease site, and treatment. Using oral cancer patient questionnaires, we use light gradient Boost Tree classifiers to predict life quality.
    


           The European Organisation for Research and Treatment of Cancer's QLQ-C30 and QLQ-HN43 were used to document the findings. Anyone could enroll, regardless of gender or age. The IHEC/SDC/PhD/OPATH-1954/19/TH-001 Institutional Ethical Clearance Committee approved this work. After informed consent, patients received the EORTC QLQ-C30 and QLQ-HN43 questionnaires. Surveys were in Tamil and English. Overall, QOL ratings covered several domains. We obtained patient demographics, case history, and therapy information from our DIAS (Dental Information Archival Software). Enrolled patients were monitored for at least a year. After one year, the EORTC questionnaire was retaken, and scores were recorded. This prospective analytical exploratory study at Saveetha Dental College, Chennai, India, examined QOL at diagnosis and at least 12 months after primary therapy in patients with histopathologically diagnosed oral malignancies. We measured oral cancer patients' quality of life using data preprocessing, feature selection, and model construction. A confusion matrix was created using light gradient boosting to measure accuracy.
    


          20 log loss.
    


          Conclusion:
        
      
      Oral surgeons and oncologists can improve planning and therapy with this prediction model."
1664,Overexpression of cyclooxygenase-2 protein is less frequent in gastric cancers with microsatellite instability.,"Yamamoto H, Itoh F, Fukushima H, Hinoda Y, Imai K.",https://pubmed.ncbi.nlm.nih.gov/10404093/,"Overexpression of cyclooxygenase-2 (COX-2) has been reported in gastric cancers. However, the relationship between expression of COX-2 and clinico-pathological or genotypic features has not been elucidated. To address the issue, expression of COX-2 protein was analyzed in 100 gastric cancers as well as 7 gastric cancer cell lines by using immunoblot analysis. Overexpression of COX-2 in cancer tissues compared with matched non-cancerous tissues was found in 70% of cases and was significantly associated with lymphatic involvement, lymph node metastasis and advanced tumor stage. Interestingly, overexpression of COX-2 was less frequent in gastric cancers with microsatellite instability (MSI) than in those without MSI (8/20 vs. 62/80, p < 0.01). Expression of COX-2 protein was detected in some gastric cancer cell lines without MSI at various levels, but not in those with MSI. Our  We also observed a reduction of MSI phenotype after aspirin or sulindac treatment in a hMLH1-defective gastric cancer cell line SNU-1, which lacks COX-2 expression. Int. J. Cancer (Pred. Oncol.) 84:400-403, 1999."
1665,Diagnosis of skin cancer by correlation and complexity analyses of damaged DNA.,"Namazi H, Kulish VV, Delaviz F, Delaviz A.",https://pubmed.ncbi.nlm.nih.gov/26497203/,"Skin cancer is a common, low-grade cancerous (malignant) growth of the skin. It starts from cells that begin as normal skin cells and transform into those with the potential to reproduce in an out-of-control manner. Cancer develops when DNA, the molecule found in cells that encodes genetic information, becomes damaged and the body cannot repair the damage. A DNA walk of a genome represents how the frequency of each nucleotide of a pairing nucleotide couple changes locally. In this research in order to diagnose the skin cancer, first DNA walk plots of genomes of patients with skin cancer were generated. Then, the data so obtained was checked for complexity by computing the fractal dimension. Furthermore, the Hurst exponent has been employed in order to study the correlation of damaged DNA. By analysing different samples it has been found that the damaged DNA sequences are exhibiting higher degree of complexity and less correlation compared to normal DNA sequences. This investigation confirms that this  The "
1666,Molecular Imaging in Cancer Drug Development.,"Waaijer SJH, Kok IC, Eisses B, Schröder CP, Jalving M, Brouwers AH, Lub-de Hooge MN, de Vries EGE.",https://pubmed.ncbi.nlm.nih.gov/29371402/,"Development of new oncology drugs has increased since the improved understanding of cancer's complex biology. The oncology field has become the top therapeutic research area for new drugs. However, only a limited number of drugs entering clinical trials will be approved for use as the standard of care for cancer patients. Molecular imaging is increasingly perceived as a tool to support go/no-go decisions early during drug development. It encompasses a wide range of techniques that include radiolabeling a compound of interest followed by visualization with SPECT or PET. Radiolabeling can be performed using a variety of radionuclides, which are preferably matched to the compound on the basis of size and half-life. Imaging can provide information on drug behavior in vivo, whole-body drug target visualization, and heterogeneity in drug target expression. This review focuses on current applications of molecular imaging in the development of small molecules, antibodies, and antihormonal anticancer drugs."
1667,High expression of HSP60 and survivin predicts poor prognosis for oral squamous cell carcinoma patients.,"Zhou Y, Tang Y, Luo J, Yang Y, Zang H, Ma J, Fan S, Wen Q.",https://pubmed.ncbi.nlm.nih.gov/37661276/," Survivin is one of the inhibitors of apoptosis protein family member, which plays a significant part in cancer progression. They were capable of forming HSP60-survivin complexes and involved in the development of various tumors.
    


           Besides, expression of HSP60 and survivin proteins was studied utilizing immunohistochemistry in tissue microarrays (TMA) in OSCC and in adjacent non-cancerous squamous epithelium (Non-CCSE) tissues.
    


           HSP60 and survivin proved a significantly increased expression in OSCC samples compared to Non-CCSE both on mRNA and protein (both P < 0.05). Additionally, elevated HSP60 displayed a positive correlation with survivin in terms of mRNA and protein expression levels (all P < 0.001). Patients with OSCC who had advanced clinical stage or lymph node metastasis (LNM) showed higher HSP60 expression (P = 0.004, P = 0.006, respectively). Higher levels of the proteins HSP60 and survivin were significantly inversely correlated relationship with OSCC patients' overall survival rates in multivariate survival analysis (P = 0.018, P = 0.040). From the above 
    


          Conclusions:
        
      
      Elevated HSP60 and survivin might be served as novel poor prognosis biomarkers for surgically resected OSCC patients."
1668,Two dimensional multifractal detrended fluctuation analysis of low coherence images for diagnosis of cervical pre-cancer.,"Sahoo GR, Dey R, Das N, Ghosh N, Pradhan A.",https://pubmed.ncbi.nlm.nih.gov/33438637/,"We report detection of cervical pre-cancer through their low coherence images by applying two dimensional multifractal detrended fluctuation analysis. Low coherent backscattered images of pre-cancerous cervical tissue sections were captured using a common path interferometric setup. The captured images contain both depth and lateral information of the spatial variation in refractive index (RI) occurring with progression of cervical pre-cancer. A two-dimensional multifractal detrended fluctuation analysis (2D MFDFA) was applied on these low coherent images to study the variations occurring in their fractal nature. Long-range correlations were observed in the RI fluctuations and the strength of multifractality was found to be stronger for higher grades of cervical pre-cancer. A combination of derived multifractal parameters, namely, the generalized Hurst exponent and width of singularity spectrum showed clear differences among the different grades of pre-cancers. Normal, CIN-I and CIN-II were clearly discriminated by application of support vector machine (SVM) using radial Bessel function (RBF) kernel. The specificities and sensitivities between normal and CIN-I, CIN-I and CIN-II and normal and CIN-II were found to be 94%, 88% and 93%, 96% and 98%, 100% respectively."
1669,High expression of heparanase-2 is an independent prognostic parameter for favorable survival in gastric cancer patients.,"Zhang X, Xu S, Tan Q, Liu L.",https://pubmed.ncbi.nlm.nih.gov/24139593/,"Aim:
        
      
      Heparanase-2 expression has been suggested to up-regulate in several types of human cancers. However, the expression patterns of heparanase-2 in gastric cancer and its effect on prognosis of gastric cancer patients are unclear.
    


           Heparanase-2 expression was analyzed by immunohistochemistry in 95 clinicopathologically characterized gastric cancer cases. In addition Fisher's exact test, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the 
    


          5% (67/95) of gastric cancer, when compared with its normal counterpart. Overexpression of heparanase-2 was correlated with tumor size and differentiation (P<0.05). Further analysis showed that a significant correlation between high expression of heparanase-2 and favorable prognosis (P<0.05). In multivariate analysis, high expression of heparanase-2 was evaluated as an independent prognostic factor in gastric cancer (P<0.05).
    


          Conclusions:
        
      
      Our data suggest for the first time that the high expression of heparanase-2 is associated significantly with tumor growth and differentiation. Importantly, heparanase-2 may be a potential molecular marker for predicting prognosis of gastric cancer."
1670,[Tumorigenesis from a pathological perspective : Tumor spread and epigenetically regulated genes in bladder cancer].,Gaisa NT.,https://pubmed.ncbi.nlm.nih.gov/27613302/,"The article describes the tumorigenesis of bladder cancer from a pathological perspective in three dimensions: morphology, genetics and epigenetics. Field cancerization and tumor cell migration/seeding are the two main hypotheses used for explaining synchronous and metachronous tumors in the urinary tract. By detailed histological mapping of completely embedded cystectomy specimens we found a single tumor focus in nearly 2/3 of the bladders accompanied by surrounding preinvasive carcinoma in situ. We substantiated our findings by studies analyzing TP53 mutations and loss of heterozygosity in various tumor sites. Identical TP53 mutations suggested a clonal relationship of the tumor foci. In situ lineage tracing via cytochrome C oxidase and succinate dehydrogenase enzyme histochemistry and subsequent mitochondrial DNA mutation analysis for definitive evidence of a clonal relationship in bladder tumors remained inconclusive. We found indications for both theories but intraurothelial migration/seeding was more prominent.A further mechanism in tumorigenesis is gene inactivation by epigenetic DNA methylation. We analyzed DNA methylation of various genes, which had previously been found by RNA expression analysis to be downregulated in bladder cancer. Most importantly, epigenetically silenced ITIH5 was associated with early relapse in pT1 high grade tumors and functionally showed an enhanced invasive metastatic phenotype in tumor cells, suggesting a putative tumor suppressive role. Thus, epigenetic gene silencing is an additional mechanism of tumorigenesis especially in tumor progression."
1671,The scorpion venom peptide BmKn2 induces apoptosis in cancerous but not in normal human oral cells.,"Satitmanwiwat S, Changsangfa C, Khanuengthong A, Promthep K, Roytrakul S, Arpornsuwan T, Saikhun K, Sritanaudomchai H.",https://pubmed.ncbi.nlm.nih.gov/27780132/,"Aim:
        
      
      This study aimed to investigate the mechanism of the induction of apoptosis of human oral cancer cells by the scorpion venom peptide BmKn2.
    


           Cell viability was determined by the MTT assay. Apoptosis was assessed using phase contrast microscopy, by propidium iodide (PI) staining to assess nuclear morphology and by Annexin V staining. Apoptotic signaling pathways were investigated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting.
    


           The cells showed distinct morphological changes, nuclear disintegration and an increase in the number of Annexin V-positive cells. Interestingly, at concentrations which kill cancerous cells, BmKn-2 did not affect cell viability or mediate the induction of apoptosis in normal HGC or DPC. Induction of apoptosis by BmKn-2 in HSC4 and KB cells was associated with the activation of tumor suppress p53. Pro-apoptotic BAX expression was increased, whereas antiapoptotic BCL-2 expression was decreased in BmKn-2 exposed HSC4 and KB cells. BmKn-2 treated-oral cancer cells showed distinct upregulation of initiator caspase-9, with no effect on caspase-8 expression. Increased expression levels of executor caspases-3 and -7 were also found in treated cells for both oral cancers.
    


          Conclusion:
        
      
      This study has suggested for the first time that BmKn-2 exerts selective cytotoxic effects on human oral cancer cells by inducting apoptosis via a p53-dependent intrinsic apoptotic pathway. BmKn-2 peptide originally derived from a natural source shows great promise as a candidate treatment for oral cancer, with minimal effects on healthy tissue."
1672,Prognostic value of HMGB3 expression in patients with non-small cell lung cancer.,"Song N, Liu B, Wu JL, Zhang RF, Duan L, He WS, Zhang CM.",https://pubmed.ncbi.nlm.nih.gov/23609034/,"HMGB3 overexpression has been reported in a variety of human cancers. However, the role of HMGB3 in human non-small cell lung cancer (NSCLC) remains unclear. In this study, the HMGB3 expression was examined at mRNA and protein levels by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry in NSCLC tissues and adjacent non-cancerous tissues. Statistical analyses were applied to test the associations between HMGB3 expression, clinicopathologic factors, and prognosis. Western blotting and qRT-PCR showed that the expression levels of HMGB3 mRNA and protein were both significantly higher in NSCLC tissues than those in non-cancerous tissues. Immunohistochemistry analysis showed that HMGB3 expression was significantly correlated with tumor grade, tumor size, clinical stage, and lymph node metastases. The  Importantly, multivariate analysis showed that high HMGB3 expression was an independent prognostic factor for NSCLC patients. In sum, our data suggest that HMGB3 plays an important role in NSCLC progression, and that overexpression of HMGB3 in tumor tissues could be used as a potential prognostic marker for patients with NSCLC."
1673,Tackling Acute Lymphoblastic Leukemia-One Fish at a Time.,"Sinha AA, Park G, Frazer JK.",https://pubmed.ncbi.nlm.nih.gov/31731471/,"Despite advancements in the diagnosis and treatment of acute lymphoblastic leukemia (ALL), a need for improved strategies to decrease morbidity and improve cure rates in relapsed/refractory ALL still exists. Such approaches include the identification and implementation of novel targeted combination regimens, and more precise upfront patient risk stratification to guide therapy. New curative strategies rely on an understanding of the pathobiology that derives from systematically dissecting each cancer's genetic and molecular landscape. Zebrafish models provide a powerful system to simulate human diseases, including leukemias and ALL specifically. They are also an invaluable tool for genetic manipulation, in vivo studies, and drug discovery. Here, we highlight and summarize contributions made by several zebrafish T-ALL models and newer zebrafish B-ALL models in translating the underlying genetic and molecular mechanisms operative in ALL, and also highlight their potential utility for drug discovery. These models have laid the groundwork for increasing our understanding of the molecular basis of ALL to further translational and clinical research endeavors that seek to improve outcomes in this important cancer."
1674,Risk of melanocytic nevi and nonmelanoma skin cancer in children after allogeneic hematopoietic stem cell transplantation.,"Song JS, London WB, Hawryluk EB, Guo D, Sridharan M, Fisher DE, Lehmann LE, Duncan CN, Huang JT.",https://pubmed.ncbi.nlm.nih.gov/28368380/,"There is a known increased risk of skin cancer in the adult population after hematopoietic stem cell transplantation (HSCT). However, late dermatologic effects that children may experience after HSCT have not been well described. The primary  A cross-sectional cohort study of 85 pediatric HSCT recipients and 85 controls matched for age, sex and skin phototype was performed at a single institution. All participants underwent a full skin examination. Median age at study visit was 13.8 years in HSCT patients with median time post-HSCT of 3.6 years. HSCT patients had significantly more nevi than control patients (median (range): 44 (0-150) vs 11 (0-94), P<0.0001). HSCT patients also had significantly more nevi >5 mm in diameter and atypical nevi than controls. Factors associated with increased nevus count included malignant indication for HSCT, pretransplant chemotherapy, TBI exposure and myeloablative conditioning. A total of 16.5% of HSCT patients developed cancerous, precancerous lesions and/or lentigines. Our study suggests that pediatric HSCT recipients have an increased risk of benign and atypical melanocytic proliferations and nonmelanoma skin cancer that can manifest even during childhood."
1675,Glypican-3 expression is markedly decreased in human gastric cancer but not in esophageal cancer.,"Zhu Z, Friess H, Kleeff J, Wang L, Wirtz M, Zimmermann A, Korc M, Büchler MW.",https://pubmed.ncbi.nlm.nih.gov/12135726/,"
    


          
    


           Moderate to strong glypican-3 mRNA signals were found in the cytoplasm of squamous epithelial cells of the normal esophagus. In both squamous and adenocarcinomas of the esophagus glypican-3 mRNA signals were also moderately to strongly present in the cytoplasm of the cancer cells. In gastric tissues, glypican-3 mRNA was present in 53% of normal gastric tissue samples, but was below the detection level in all examined gastric cancer samples. Glypican-3 mRNA signals were moderately to strongly present in the cytoplasm of gastric mucosal epithelial cells, but were only very faintly present in some cancer cells.
    


          Conclusions:
        
      
      Glypican-3 may be involved in the growth control of normal esophageal and gastric epithelial cells. Furthermore, our "
1676,RJunBase: a database of RNA splice junctions in human normal and cancerous tissues.,"Li Q, Lai H, Li Y, Chen B, Chen S, Li Y, Huang Z, Meng Z, Wang P, Hu Z, Huang S.",https://pubmed.ncbi.nlm.nih.gov/33179749/,"Splicing is an essential step of RNA processing for multi-exon genes, in which introns are removed from a precursor RNA, thereby producing mature RNAs containing splice junctions. Here, we develope the RJunBase (www.RJunBase.org), a web-accessible database of three types of RNA splice junctions (linear, back-splice, and fusion junctions) that are derived from RNA-seq data of non-cancerous and cancerous tissues. The RJunBase aims to integrate and characterize all RNA splice junctions of both healthy or pathological human cells and tissues. This new database facilitates the visualization of the gene-level splicing pattern and the junction-level expression profile, as well as the demonstration of unannotated and tumor-specific junctions. The first release of RJunBase contains 682 017 linear junctions, 225 949 back-splice junctions and 34 733 fusion junctions across 18 084 non-cancerous and 11 540 cancerous samples. RJunBase can aid researchers in discovering new splicing-associated targets and provide insights into the identification and assessment of potential neoepitopes for cancer treatment."
1677,"Hypoxia induces copper stable isotope fractionation in hepatocellular carcinoma, in a HIF-independent manner.","Bondanese VP, Lamboux A, Simon M, Lafont JE, Albalat E, Pichat S, Vanacker JM, Telouk P, Balter V, Oger P, Albarède F.",https://pubmed.ncbi.nlm.nih.gov/27500357/,"Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, with increasing incidence worldwide. The unrestrained proliferation of tumour cells leads to tumour hypoxia which in turn promotes cancer aggressiveness. While changes in the concentration of copper (Cu) have long been observed upon cancerization, we have recently reported that the isotopic composition of copper is also altered in several types of cancer. In particular, we showed that in hepatocellular carcinoma, tumour tissue contains heavier copper compared to the surrounding parenchyma. However, the reasons behind such isotopic signature remained elusive. Here we show that hypoxia causes heavy copper enrichment in several human cell lines. We also demonstrate that this effect of hypoxia is pH, HIF-1 and -2 independent. Our data identify a previously unrecognized cellular process associated with hypoxia, and suggests that in vivo tumour hypoxia determines copper isotope fractionation in HCC and other solid cancers."
1678,"PKIB, a Novel Target for Cancer Therapy.","Musket A, Moorman JP, Zhang J, Jiang Y.",https://pubmed.ncbi.nlm.nih.gov/38731883/,"The serine-threonine kinase protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent intracellular protein with multiple roles in cellular biology including metabolic and transcription regulation functions. The cAMP-dependent protein kinase inhibitor β (PKIB) is one of three known endogenous protein kinase inhibitors of PKA. The role of PKIB is not yet fully understood. Hormonal signaling is correlated with increased PKIB expression through genetic regulation, and increasing PKIB expression is associated with decreased cancer patient prognosis. Additionally, PKIB impacts cancer cell behavior through two mechanisms; the first is the nuclear modulation of transcriptional activation and the second is the regulation of oncogenic AKT signaling. The limited research into PKIB indicates the oncogenic potential of PKIB in various cancers. However, some studies suggest a role of PKIB in non-cancerous disease states. This review aims to summarize the current literature and  In particular, we will focus on cancer development and therapeutic possibilities, which are of paramount interest in PKIB oncology research."
1679,Telomerase activity in primary prostate cancer.,"Lin Y, Uemura H, Fujinami K, Hosaka M, Harada M, Kubota Y.",https://pubmed.ncbi.nlm.nih.gov/9072562/,"Purpose:
        
      
      Telomerase activity has been detected in a wide variety of human tumor types. We analyzed the telomerase activity in association with the acquisition of prostate cancer.
    


          Materials and 
    


           The relative level of telomerase activity was associated with the pathological differentiation. High levels of telomerase activity were more frequently detected in poorly differentiated prostate cancer. None of the 10 samples taken from prostates with benign prostatic hyperplasia (BPH) or normal prostates expressed telomerase activity. In another 10 BPH samples obtained from prostate tissue adjacent to cancerous tissue, one of 10 samples (10%) showed weak telomerase activity. Furthermore, we investigated this activity in human prostate cancer cell lines (PC-3, LNCaP, and DU145) and all showed very high activity compared to normal human tissue samples. Four lymph nodes and one bone metastasis also exhibited extremely high telomerase activity.
    


          Conclusions:
        
      
      The present "
1680,The high frequency of de novo promoter methylation in synchronous primary endometrial and ovarian carcinomas.,"Furlan D, Carnevali I, Marcomini B, Cerutti R, Dainese E, Capella C, Riva C.",https://pubmed.ncbi.nlm.nih.gov/16740754/,"Purpose:
        
      
      The methylation status of hMLH1, CDKN2A, and MGMT was investigated in a panel of synchronous cancers of the ovary and endometrium, fulfilling the clinicopathologic criteria for independent primary tumors to define the possible role of epigenetic mechanisms in the development of these cancers.
    


           In all tumors, we also investigated the presence of microsatellite instability and hMLH1 immunohistochemical expression in relation to hMLH1 hypermethylation status.
    


           hMLH1 hypermethylation was observed in all tumors of five patients, and it was invariably associated with loss of hMLH1 protein and presence of microsatellite instability. CDKN2A and MGMT methylation was randomly detected among both endometrial (45% and 24% of cases, respectively) and ovarian carcinomas (39% and 39% of cases, respectively). Concordant methylation at two or three genes was observed in 35% of cases.
    


          Conclusions:
        
      
      Epigenetic inactivation of hMLH1, CDKN2A, and MGMT may be a common and early event in the development of synchronous primary endometrial and ovarian carcinomas and may qualify as a marker of a field cancerization encompassing the ovary and endometrium. Detection of MGMT hypermethylation may be useful to define a set of gynecologic malignancies with a specific sensitivity to alkylating chemotherapy."
1681,The atypical Rho GTPase RhoBTB2 is required for expression of the chemokine CXCL14 in normal and cancerous epithelial cells.,"McKinnon CM, Lygoe KA, Skelton L, Mitter R, Mellor H.",https://pubmed.ncbi.nlm.nih.gov/18762809/,"The Rho family of small GTPases control cell migration, cell invasion and cell cycle. Many of these processes are perturbed in cancer and several family members show altered expression in a number of tumor types. RhoBTB2/DBC2 is an atypical member of this family of signaling proteins, containing two BTB domains in addition to its conserved Rho GTPase domain. RhoBTB2 is mutated, deleted or silenced in a large percentage of breast and lung cancers; however, the functional consequences of this loss are unclear. Here we use RNA interference in primary human epithelial cells to mimic the loss of RhoBTB2 seen in cancer cells. Through microarray analysis of global gene expression, we show that loss of RhoBTB2  Loss of RhoBTB2 expression correlates with loss of CXCL14 secretion by head and neck squamous cell carcinoma cell lines, whereas re Our studies identify CXCL14 as a gene target of RhoBTB2 and support downregulation of CXCL14 as a functional outcome of RhoBTB2 loss in cancer."
1682,"""Cancer's a demon"": a qualitative study of fear and multilevel factors contributing to cancer treatment delays.","Frosch ZAK, Jacobs LM, O'Brien CS, Brecher AC, McKeown CJ, Lynch SM, Geynisman DM, Hall MJ, Edelman MJ, Bleicher RJ, Fang CY.",https://pubmed.ncbi.nlm.nih.gov/38060063/,"Purpose:
        
      
      Delays initiating cancer therapy are increasingly common, impact outcomes, and have implications for health equity. However, it remains unclear (1) whether patients' beliefs regarding acceptable diagnostic to treatment intervals align with current guidelines, and (2) to what degree psychological factors contribute to longer intervals. We conducted a qualitative study with patients and cancer care team members (""providers"").
    


           Interviews were analyzed using an interpretive approach, guided by modified grounded theory.
    


           Half of patients had breast cancer; 27% waited >60 days between diagnosis and treatment. Several themes emerged. (1) Patients felt treatment should begin immediately following diagnosis, while providers' opinion on the goal timeframe to start treatment varied. (2) Patients experienced psychological distress while waiting for treatment. (3) Participants identified logistical, social, and psychological sources of delay. Fear related to multiple aspects of cancer care was common. Emotion-driven barriers could manifest as not taking steps to move ahead, or as actions that delayed care. (4) Besides addressing logistical challenges, patients believed that education and anticipatory guidance, from their care team and from peers, may help overcome psychological barriers to treatment and facilitate the start of therapy.
    


          Conclusions:
        
      
      Patients feel an urgency to start cancer therapy, desiring time frames shorter than those included in guidelines. Psychological distress is frequently both a contributor to, and a consequence of, treatment delays. Addressing multilevel barriers, including psychological ones, may facilitate timely treatment and reduce distress."
1683,Regulation of miRNAs by herbal medicine: An emerging field in cancer therapies.,"Mohammadi A, Mansoori B, Baradaran B.",https://pubmed.ncbi.nlm.nih.gov/28006752/,"MicroRNAs' expression profiles have recently gained major attention as far as cancer research is concerned. MicroRNAs are able to inhibit target gene expression via binding to the 3' UTR of target mRNA,  MicroRNAs play significant parts in a myriad of biological processes; studies have proven, on the other hand, that aberrant microRNA expression is, more often than not, associated with the growth and progression of cancers. MicroRNAs could act as oncogenes (oncomir) or tumor suppressors and can also be utilized as biomarkers for diagnosis, prognosis, and cancer therapy. Recent studies have shown that such herbal extracts as Shikonin, Sinomenium acutum, curcumin, Olea europaea, ginseng, and Coptidis Rhizoma could alter microRNA expression profiles through inhibiting cancer cell development, activating the apoptosis pathway, or increasing the efficacy of conventional cancer therapeutics. Such findings patently suggest that the novel specific targeting of microRNAs by herbal extracts could complete the restriction of tumors by killing the cancerous cells so as to recover survival  In this review, we summarized the current research about microRNA biogenesis, microRNAs in cancer, herbal compounds with anti-cancer effects and novel strategies for employing herbal extracts in order to target microRNAs for a better treatment of patients diagnosed with cancer."
1684,Mathematical model identifies blood biomarker-based early cancer detection strategies and limitations.,"Hori SS, Gambhir SS.",https://pubmed.ncbi.nlm.nih.gov/22089452/,"Most clinical blood biomarkers lack the necessary sensitivity and specificity to reliably detect cancer at an early stage, when it is best treatable. It is not yet clear how early a clinical blood assay can be used to detect cancer or how biomarker-based strategies can be improved to enable earlier detection of smaller tumors. To address these issues, we developed a mathematical model describing dynamic plasma biomarker kinetics in relation to the growth of a tumor, beginning with a single cancer cell. To exemplify a realistic scenario in which biomarker is shed by both cancerous and noncancerous cells, we primed the model on ovarian tumor growth and CA125 shedding data, for which tumor growth parameters and shedding rates are readily available in published literature. We found that a tumor could grow unnoticed for more than 10.1 years and reach a volume of about π/6(25.36 mm)(3), corresponding to a spherical diameter of about 25.36 mm, before becoming detectable by current clinical blood assays. Model parameters were perturbed over log orders of magnitude to quantify ideal shedding rates and identify other blood-based strategies required for early submillimeter tumor detectability. The detection times we estimated are consistent with recently published tumor progression time lines based on clinical genomic sequencing data for several cancers. Here, we rigorously showed that shedding rates of current clinical blood biomarkers are likely 10(4)-fold too low to enable detection of a developing tumor within the first decade of tumor growth. The model presented here can be extended to virtually any solid cancer and associated biomarkers."
1685,Investigating a case of possible field cancerization in oral squamous cell carcinoma by the use of next-generation sequencing.,"Tabatabaeifar S, Larsen MJ, Larsen SR, Kruse TA, Thomassen M, Sørensen JA.",https://pubmed.ncbi.nlm.nih.gov/28438297/," We investigate the concept of field cancerization which proposes that normal tissue adjacent to the primary tumor harbor pre-neoplastic alterations that can lead to the development of local recurrence and SPTs.
    


          Materials and  Lastly, we sequenced one formalin-fixed paraffin-embedded recurrence biopsy that was collected approximately a year and half later located in the same area as before.
    


           We identified 24 mutations in the recurrence biopsy and 14 mutations are shared by the primary tumor.
    


          Conclusion:
        
      
      The low number of shared mutations indicates that either these mutations represent a very early clone in the primary tumor's evolution, or that these mutations represent a pre-neoplastic field, in which the primary tumor and recurrence are derived from. In both instances, the clinical recurrence is of a monoclonal origin which suggests either field cancerization by migration of mutated cells in the adjacent mucosa, or that the recurrence developed out of remaining tumor tissue."
1686,Surgical Delay Is Associated with Improved Survival in Hepatocellular Carcinoma: Results of the National Cancer Database.,"Xu K, Watanabe-Galloway S, Rochling FA, Farazi PA, Monirul Islam KM, Wang H, Luo J.",https://pubmed.ncbi.nlm.nih.gov/30328070/," Studies that investigated the impact of HCC therapeutic delays are limited to single centers, and no large-scale database research has been conducted. This study investigated the association of surgical delay and survival in HCC patients.
    


           Surgical delay was defined as > 60 days from the date of diagnosis to surgery. Generalized linear-mixed model assessed the demographic and clinical factors associated with delay, and frailty Cox proportional hazard analysis examined the prognostic factors for overall survival.
    


           Median wait time to surgery was 50 days (interquartile range, 29-86), and 4987 patients (41.2%) had surgical delay. Delayed patients demonstrated better 5-year survival for local tumor destruction (29.1 vs. 27.6%; P = .001) and resection (44.1 vs. 41.0%; P = .007). Risk-adjusted model indicated that delayed patients had a 7% decreased risk of death (HR, 0.93; 95% CI, 0.87-0.99; P = .027). Similar findings were also observed using other wait time cutoffs at 50, 70, 80, 90, and 100 days.
    


          Conclusions:
        
      
      A plausible explanation of this finding may be case prioritization, in which patients with more severe and advanced disease who were at higher risk of death received earlier surgery, while patients with less-aggressive tumors were operated on later and received more comprehensive preoperative evaluation."
1687,Hyperspectral Stimulated Raman Scattering Microscopy Unravels Aberrant Accumulation of Saturated Fat in Human Liver Cancer.,"Yan S, Cui S, Ke K, Zhao B, Liu X, Yue S, Wang P.",https://pubmed.ncbi.nlm.nih.gov/29757615/,"Lipid metabolism is dysregulated in human cancers. The analytical tools that could identify and quantitatively map metabolites in unprocessed human tissues with submicrometer resolution are highly desired. Here, we implemented analytical hyperspectral stimulated Raman scattering microscopy to map the lipid metabolites in situ in normal and cancerous liver tissues from 24 patients. In contrast to the conventional wisdom that unsaturated lipid accumulation enhances tumor cell survival and proliferation, we unexpectedly visualized substantial amount of saturated fat accumulated in cancerous liver tissues, which was not seen in majority of their adjacent normal tissues. Further analysis by mass spectrometry confirmed significant high levels of glyceryl tripalmitate specifically in cancerous liver. These findings suggest that the aberrantly accumulated saturated fat may have great potential to be a metabolic biomarker for liver cancer."
1688,Expression of hyaluronan receptors CD44 and RHAMM in stomach cancers: relevance with tumor progression.,"Li H, Guo L, Li JW, Liu N, Qi R, Liu J.",https://pubmed.ncbi.nlm.nih.gov/11029494/,"Interactions of hyaluronic acid (HA) with its binding proteins CD44 and RHAMM (receptor for HA-mediating motility) have been proposed to be important in promoting tumor progression and dissemination. However, a comparative study of their expression patterns in stomach cancer and its associated lesions is not yet available. To address this issue, the combined examinations of pathology, immunocytochemistry and Western blot hybridization were performed on advanced gastric cancer specimens as well as their preneoplastic and non-cancerous counterparts. Alternative CD44 expression was observed in the gastric mucosa with different lesions. CD44 proteins harboring variant exon 6 (CD44 v6) was detected only in cancer tissues with a total positive rate of 14% (10/74). Intracellular RHAMM molecules in Mr 93000 to 95000 were expressed in 3/31 non-cancerous mucosa. RHAMM detection rates increased along with tumor progression. Irrespective of the differences of gross and morphological pattern, majority (54/74) of cancer cases expressed multiple RHAMM isoforms in Mr 40000-45000, 64000, 70000-73000, 85000 and 93000-95000 with the appearance of cell surface immunocytochemical labeling. Among CD44 variant isoforms, v6 is more relevant with malignant transformation of gastric epithelium. Expression of RHAMM, especially the cell surface variants, is closely correlated with tumor progression (P<0.01). Expression of CD44 and RHAMM may benefit the invasion and metastasis of gastric cancer cells presumably in a reciprocal manner."
1689,Four major factors regulate phosphatidylinositol 3-kinase signaling pathway in cancers induced by infection of human papillomaviruses.,"Wu J, Chen J, Zhang L, Masci PP, Zhao KN.",https://pubmed.ncbi.nlm.nih.gov/24735365/,"Epidemiological surveys and molecular studies have indicated that infection of human papillomavirus (HPV)itself is necessary but insufficient for completing transformation of the human epithelial cells in vivo to lead to different cancers. Mounting evidence exists that HPV E6/E7 oncoproteins indeed alter the cellular and molecular events in their transformed cells to induce cancers through a phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. The PI3K/AKT/mTOR signaling pathway is, nonetheless, of the central importance, which tightly modulates many cellular events that occur in cells to lead them to be cancerous under the action of oncogenic factors. The cancinogenic roles of the PI3K/AKT/mTOR signaling in HPV-induced cancers are generally regulated by different upstream signaling molecules such as upstream receptor tyrosine kinases. In this article, we review that the four major upstream signaling molecules (growth factor receptor, notch receptor, Ras and PI3KCA genes) regulate PI3K/AKT/mTOR pathway to confer oncogenicity in HPV-immortalized epithelial cells and various transformed phenotypes."
1690,Promotion of cell proliferation and inhibition of ADCC by cancerous immunoglobulin expressed in cancer cell lines.,"Li M, Zheng H, Duan Z, Liu H, Hu D, Bode A, Dong Z, Cao Y.",https://pubmed.ncbi.nlm.nih.gov/22036905/,"To explore the significance of cancerous immunoglobulin (Ig) in cancer cell growth, HeLa cervical cancer cells were stably transfected with small interfering RNA (siRNA) that specifically, efficiently and consistently silences the expression of heavy chain genes of all immunoglobulin isotypes. This stable cell line was used to examine cell viability, colony formation and tumor growth in athymic nude mice. The  Similarly, this siRNA also inhibited the growth of MGC gastric cancer cells and MCF-7 breast cancer cells. Furthermore, the presence of cancerous Ig specifically reduced antibody-dependent cell-mediated cytotoxicity (ADCC) induced by an anti-human epithelial growth factor receptor (EGFR) antibody in a dose-dependent manner, suggesting that the cancerous Ig-Fc receptor interaction inhibits natural killer cell (or NK cell) effector function. The prevalent expression of Ig in human carcinomas and its capacity to promote growth and inhibit immunity might have important implications in growth regulation and targeted therapy for human cancers."
1691,"Autism and Cancer Share Risk Genes, Pathways, and Drug Targets.","Crawley JN, Heyer WD, LaSalle JM.",https://pubmed.ncbi.nlm.nih.gov/26830258/,"Autism is a neurodevelopmental disorder, diagnosed behaviorally by social and communication deficits, repetitive behaviors, and restricted interests. Recent genome-wide exome sequencing has revealed extensive overlap in risk genes for autism and for cancer. Understanding the genetic commonalities of autism(s) and cancer(s), with a focus on mechanistic pathways, could lead to repurposed therapeutics."
1692,[Cancer and pregnancy].,"Cappelaere P, Demaille A.",https://pubmed.ncbi.nlm.nih.gov/6229743/,"During the last decades, our ideas on the cancer-pregnancy association have been radically altered. Induced abortion, which has long been considered a prerequisite to successful treatment of cancer in such cases, is now performed only if requested by a fully informed mother or if embryotoxic chemotherapy is required. Many authors disagree that pregnancy has detrimental effects on cancer and believe that this only applies to breast cancers with axillary lymph mode involvement. Epidemiologists have shown that obstetrical factors are closely related to the risks of breast, endometrial and ovarian cancers. In some cancers, particularly in children and young adults, cure cannot be considered complete it has been obtained at the cost of infertility. To preserve fertility without reducing the prospects of cure is one of the major "
1693,Aptasensors for Cancerous Exosome Detection.,"Li J, Xie S, Qu F, Tan W.",https://pubmed.ncbi.nlm.nih.gov/35467275/,"Cancerous exosomes that carry multiple biomarkers are attractive targets for the early diagnosis and therapy of cancer. As one of the powerful molecular recognition tools, aptamers with excellent binding affinity and specificity toward biomarkers have been exploited to construct various aptamer-based biosensors (aptasensors) for exosome detection. Here, we review recent advances in aptasensors for the detection of cancerous exosomes. We first discuss the importance and potential of cancerous exosomes in cancer diagnosis and then summarize some conventional aptasensors from the perspective of biomarker recognition and signal collection strategies. Finally, we comment on the outlook for aptasensor research and new directions for cancerous exosome detection."
1694,Esophageal and laryngeal cancer incidentally found on [18F]fluorodeoxyglucose positron emission tomography/computed tomography during the staging workup for lung cancer.,"Jeon SY, Ahn SH, Kim CH, Lim SM, Koh JS, Lee JC.",https://pubmed.ncbi.nlm.nih.gov/18650172/,"During staging workup for lung cancer of a 74-year-old man, 2 more incidental tumors were found on [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). The 3 sites with cancer in this patient involved organs in which field cancerization has often been described, suggesting that triple primary tumors were more probable than metastasis. After treating them separately, complete response was achieved and sustained for > 2 years. The use of FDG-PET/CT seems necessary to evaluate patients with cancer, especially when there is a reasonable chance for cure. Incidentally identified lesions on FDG-PET/CT should be thoroughly explored to rule out the presence of hidden malignancy and the possibility of synchronous multiple primary tumors."
1695,Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis.,"Zhang H, Deng T, Liu R, Bai M, Zhou L, Wang X, Li S, Wang X, Yang H, Li J, Ning T, Huang D, Li H, Zhang L, Ying G, Ba Y.",https://pubmed.ncbi.nlm.nih.gov/28393839/,"The metastatic organotropism has been one of the cancer's greatest mysteries since the 'seed and soil' hypothesis. Although the role of EGFR in cancer cells is well studied, the effects of secreted EGFR transported by exosomes are less understood. Here we show that EGFR in exosomes secreted from gastric cancer cells can be delivered into the liver and is integrated on the plasma membrane of liver stromal cells. The translocated EGFR is proved to effectively activate hepatocyte growth factor (HGF) by suppressing miR-26a/b expression. Moreover, the upregulated paracrine HGF, which binds the c-MET receptor on the migrated cancer cells, provides fertile 'soil' for the 'seed', facilitating the landing and proliferation of metastatic cancer cells. Thus, we propose that EGFR-containing exosomes derived from cancer cells could favour the development of a liver-like microenvironment promoting liver-specific metastasis."
1696,Advancements in the identification of EV derived mRNA biomarkers for liquid biopsy of clear cell renal cell carcinomas.,"Kuczler MD, Zieren RC, Dong L, de Reijke TM, Pienta KJ, Amend SR.",https://pubmed.ncbi.nlm.nih.gov/34793840/," There is currently no kidney cancer specific screening or diagnostic technology. Therefore, one-third of kidney cancer diagnoses occur after the cancer has metastasized and is past curative measures MATERIALS AND  Extracellular vesicle (EV) isolation was performed on each sample, followed by mRNA extraction from isolated EVs. NanoString nCounter technology was utilized to count the mRNA transcripts present in matched plasma, urine, tumor tissue, and normal tumor adjacent tissue samples.
    


           Four EV derived mRNA transcripts (ALOX5, RBL2, VEGFA, TLK2) were found specific to urine and tumor tissue samples.
    


          Conclusion:
        
      
      Four candidate RCC-specific urine EV biomarkers were identified. However, due to the lack of a true negative control and urine collection techniques, further re-examination is necessary for validation. This study demonstrates the promise of defining disease-specific EV biomarkers in liquid biopsy patient samples."
1697,"A correlation study of fear of cancer recurrence, illness representation, self-regulation, and quality of life among gynecologic cancer survivors in Taiwan.","Tsai LY, Lee SC, Wang KL, Tsay SL, Tsai JM.",https://pubmed.ncbi.nlm.nih.gov/30545539/,"
    


          Materials and  Four questionnaires, the Assessment of Survivor Concerns (ASC), the Brief Illness Perception Questionnaire (BIPQ), the Self-Regulation Questionnaire (SRQ), and the European Organization for Research and Treatment of Cancer's Quality-of-Life Questionnaire-Core 30-item (EORTC QLQ-C30), were used to assess FCR, IR, SR, and QOL respectively. Data pertaining to socio-demographic characteristics and self-reported medical status was also collected from the participants. Stepwise regression analysis was performed to identify predictors of QOL.
    


          21, P < .01) and IR (r = -.44, P < .01) was negatively correlated with global QOL subscale of the EORTC QLQ-C30. SR, IR, and health status in the self-reported medical status explained 39% of the variance in global QOL, with SR of the largest.
    


          Conclusions:
        
      
      Our findings provided valuable information to healthcare professionals about the ability of SR to affect QOL and negative impacts of FCR and IR on gynecologic cancer survivors."
1698,Expression levels of 63 p53-related genes add up to similar values in 24 different tissues and are unified in cancer.,"Altenberg B, Rapp A, Schmitt E, Greulich KO.",https://pubmed.ncbi.nlm.nih.gov/17920238/,"The expression patterns of 62 genes interacting with p53 have been investigated in 24 normal and cancerous tissues using NIH's dbEST library. The expression levels of individual genes, such as the TTP53 gene itself, but also other genes, vary up to 33-fold among the 24 different tissues and no consistent pattern can be recognized. However, when expression levels for all 63 genes are summed, these ""cumulated levels"" are surprisingly constant over the 24 investigated normal tissues. In cancers, the variation is further reduced. Essentially, the cumulated expression levels in cancer are independent of those in normal tissue. We furthermore constructed a linear statistical classifier, i.e., a weighted sum of gene expression levels, which robustly distinguishes normal from cancer tissue independent of the particular kind of tissue. Thus, despite very large differences for individual genes and considerable changes during carcinogenesis, the cumulated expressions have narrowly defined levels."
1699,"Bladder cancer, a two phased disease?",Höglund M.,https://pubmed.ncbi.nlm.nih.gov/16574430/,"The processes of intraepithelial migration, intraluminal seeding, and field cancerization as models for initiation, spread, and recurrences of urothelial cell carcinoma (UCC) are reviewed in light of recent molecular investigations. The accumulated molecular data on synchronous and metachronous tumors indicate that the majority of recurrent and multiple tumors are monoclonal. Molecular data has also shown the presence of chromosomal and genetic changes in precursor lesions as well as in normal urothelial cells. Genetic-histological mapping of cystectomized bladders has shown that overt tumors occur as local events in areas of genetically altered urothelium. A model is put forward in which the tumor process is initiated by genetically altered but histologically normal cells that produce fields of altered cells by intraepithelial displacement. By the accumulation of further genetic changes the fields of altered urothelium reaches a state of criticality, which locally may produce frank tumors."
1700,Identification and validation that up-expression of HOXA13 is a novel independent prognostic marker of a worse outcome in gastric cancer based on immunohistochemistry.,"Han Y, Tu WW, Wen YG, Li DP, Qiu GQ, Tang HM, Peng ZH, Zhou CZ.",https://pubmed.ncbi.nlm.nih.gov/23592225/,"Homeobox (HOX) gene family is known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis. However, less is known about the involvement of HOX gene family with gastric cancerogenesis. Here, we screened the expression of HOX gene family in gastric cancers and explored the relationships between them by cDNA microarray. We found several differentially expressed HOX genes in gastric cancers, especially HOXA10 (11/12) and HOXA13 (11/12) with significantly higher expression in the cancerous tissues. Furthermore, we validated HOXA13 as a novel prognostic marker in gastric cancer based on immunohistochemistry and statistical analysis. HOXA13 expression was significantly up-regulated in cancerous tissues compared with the corresponding non-cancerous mucosa (P < 0.001). Up-expression of HOXA13 was significantly correlated with T stage (P = 0.002), M stage (P = 0.024), advanced UICC stage (P < 0.001), histological differentiation (P = 0.005), and relapse (P = 0.001). Patients with positive HOXA13 expression had a obviously lower overall survival (OS) and disease-free survival (DFS) rate than patients with negative HOXA13 expression (HR 3.331, 95 % CI 1.722-6.442, P < 0.001; HR 3.289, 95 % CI 1.703-6.351, P < 0.001, respectively). Univariate and multivariate Cox analysis confirmed that HOXA13 could serve as a significant independent prognostic factor for DFS and OS. Therefore, our  Furthermore, up-expression of HOXA13 might be associated with highly aggressive phenotype of gastric cancer. HOXA13 was a significant independent prognostic factor and could serve as a putative biomarker for diagnosis and prognosis of gastric cancer."
1701,An endoscopic staining method for detection and operation of early gastric cancer.,"Suzuki S, Murakami H, Suzuki H, Sakakibara N, Endo M, Nakayama K.",https://pubmed.ncbi.nlm.nih.gov/95454/,"The long term survival rate of gastric cancer has been much improved, and the 5-year survival rate in our institute was 42% with a significant difference between 29% in the advanced stage and 94% in the early stage. This  However, the diagnosis of early gastric cancer may remain extremely difficult even for an excellent endoscopist. Therefore, in order to clearly recognize early gastric cancer, an endoscopic staining  In this  Gastroscopy is performed routinely after this preparation. This procedure was performed on 153 gastric cancers and 137 of them (89.5%) have been successfully dyed in dark blue. In several cases, with this   Differential diagnosis of the dyed intestinal metaplasia and the dyed carcinoma seems to be very easy, because both gastric lesions have the characteristic dyed patterns. Mechanism of this phenomenon has been considered to be due to an absorption of the dye in the intestinal metaplasia, and in the gastric cancer, many factors may be involved, among which are the infiltration or diffusion of the dye into the cancerous tissue, the absorption from the abnormal epithelium, and the staining of the necrotic tissue."
1702,Odours of cancerous mouse congeners: detection and attractiveness.,"Gouzerh F, Buatois B, Hervé MR, Mancini M, Maraver A, Dormont L, Thomas F, Ganem G.",https://pubmed.ncbi.nlm.nih.gov/35403195/,"Chemical communication plays a major role in social interactions. Cancer, by inducing changes in body odours, may alter interactions between individuals. In the framework of research targeting non-invasive  If yes, were they able to detect cancer at an early developmental stage? Did it influence female preference? Did variations in volatile organic components of the odour source paralleled mice behavioural responses? We used transgenic mice strains developing or not lung cancer upon antibiotic ingestion. We sampled soiled bedding of cancerous mice (CC) and not cancerous mice (NC), at three  Habituation/generalisation and two-way preference tests were performed where soiled beddings of CC and NC mice were presented to wild-derived mice. The composition and relative concentration of volatile organic components (VOC) in the two stimuli types were analysed. Females did not show directional preference at any of the  Males did not discriminate between CC and NC stimuli at T0 but did so at T2 and T12, indicating that wild-derived mice could detect cancer at an early stage of development. Finally, although the VOC bouquet differed between CC and NC it did not seem to parallel the observed behavioural response suggesting that other types of odorant components might be involved in behavioural discrimination between CC and NC mice."
1703,New CT-based diagnoses of torso cancer is low in the emergency department setting.,"Goldman IA, Cunqueiro A, Scheinfeld MH.",https://pubmed.ncbi.nlm.nih.gov/31432349/,"Purpose:
        
      
      The incidence of new CT-based torso cancer diagnoses and the most commonly diagnosed cancer types in the emergency department (ED) setting are unknown. The purpose of our study was to determine the incidence and types of new CT-based torso cancer diagnoses in the ED.
    


           Each report and corresponding medical record was evaluated for presence of a new cancer. Cases were scored as no cancer, subcentimeter lung nodule, known cancer, new cancer, or suspicious, but unconfirmed for new cancer. Each mass was characterized as symptom-related or incidental.
    


           Of these 706, 126 and 905 were known cancer cases, subcentimeter lung nodules, and non-cancerous cases, respectively. There were 251 confirmed new cancers and 98 suspicious cases which lacked adequate diagnostic workup. Depending on whether only definite or definite and suspicious cases were included together, the number of new cancer cases per 100 torso CT exams was 1.3 or 1.8, respectively. Gastrointestinal, lung, pancreaticobiliary, urinary, and gynecologic cancers were most common. Only 58 of the confirmed cases (23%) were deemed as incidental findings.
    


          Conclusion:
        
      
      CT-diagnosis of new torso cancers was uncommon in our setting. Still, while extensive knowledge of cancer staging may not be necessary for ED radiologists, knowledge of the most common types of cancer including gastrointestinal, lung, pancreaticobiliary, urinary, and gynecologic cancers may improve sensitivity for these diagnoses and may expedite appropriate referrals for the newly diagnosed patients."
1704,[A clinicopathological study of advanced ovarian cancers without an enlargement of the ovaries].,"Kawagoe K, Kawana T, Mizuno M.",https://pubmed.ncbi.nlm.nih.gov/2921809/,"A clinicopathologic study of advanced ovarian carcinomas without an enlargement of the primary site has been performed. Cases studied were taken from 64 cases with a ""common"" epithelial tumor whose ovaries upon resection were directly measured for size. The ovaries of five cases (8%) were normal in size, and 3 (5%) of this number had been treated by chemotherapy prior to the resection of their ovaries. All three cases had been suspected to have an ovarian cancer at the start of treatment, one of these cases given a definite diagnosis of ovarian cancer, stage III, and the remaining two cases diagnosed as belonging to a special category. In these 3 cases, the ovaries had decreased in size and the primary cancerous site was difficult to determine, owing to the administered chemotherapy. A preoperative diagnosis of the remaining two of the 2 cases suspected an ovarian cancer in one, and a uterine corpus carcinoma, Ia in the other, associated with an ovarian cancer, stage III. These findings suggest that even though the enlargement of the ovaries was not to be remarkable, a laparotomy should be performed in cases strongly suspected of ovarian cancer, so as to ascertain the correct diagnosis by a careful inspection of the intraabdominal cavity, such as checking for the presence of ascites with malignant cells, or an elevated serum CA 125 without any other accountable primary foci."
1705,In vivo histological diagnosis for gastric cancer using endocytoscopy.,"Tsurudome I, Miyahara R, Funasaka K, Furukawa K, Matsushita M, Yamamura T, Ishikawa T, Ohno E, Nakamura M, Kawashima H, Watanabe O, Nakaguro M, Satou A, Hirooka Y, Goto H.",https://pubmed.ncbi.nlm.nih.gov/29085232/,"Aim:
        
      
      To examine usefulness of virtual biopsy using endocytoscopy by comparing the in vivo endocytoscopic and histopathological images of gastric cancers.
    


           Of these, 26 patients showed well differentiated adenocarcinomas, while 4 patients showed poorly differentiated adenocarcinomas (including one signet ring cell carcinoma). Cancerous and non-cancerous areas were observed after double staining with 0.05% crystal violet and 0.1% methylene blue. The endocytoscopic images obtained were evaluated by an expert endoscopist and an expert pathologist without knowledge of patient clinical data, and endocytoscopic and histopathological diagnoses were compared.
    


          3%) and 27 (90%) patients by endoscopist A and pathologist B, respectively, and those of the non-cancerous area as evaluable in 28 (93.3%) and 23 (76.7%) patients by the endoscopist and pathologist, respectively. The sensitivity, specificity, and diagnostic accuracy of gastric cancer diagnosis using evaluable endocytoscopic images were 88.0% and 92.9%, and 90.6% by endoscopist A, and 88.9% and 91.3%, and 90.0% by pathologist B, respectively. Evaluation of the diagnostic concordance rate between the endoscopist and the pathologist by inter-observer agreement calculation revealed no significant difference between the two observers. The inter-observer agreement (κ-value) for endocytoscopic diagnosis was 0.745.
    


          Conclusion:
        
      
      Endocytoscopy is useful for the differentiation of cancerous from non-cancerous gastric mucosa, making it a promising tool for virtual biopsy."
1706,Role of N-acetylgalactosaminyltransferase 6 in early tumorigenesis and formation of metastasis.,"Liesche F, Kölbl AC, Ilmer M, Hutter S, Jeschke U, Andergassen U.",https://pubmed.ncbi.nlm.nih.gov/27035742/,"Glycosylation is one of the most important posttranslational modifications of proteins and lipids that contributes to the structural diversity of cellular molecules. Enzymes of the glycosyltransferase class are responsible for altering glycosylation patterns by adding carbohydrate chains to the respective acceptor molecules. It is well known that glycosylation is commonly altered in cancerous tissue. Therefore, the present study aimed to determine the incidence of N‑acetylgalactosaminyltransferase 6 (GALNT6), a prominent member of the glycosyltransferase class, in breast cancer tissue of different developmental stages by immunohistochemistry. Although no correlation was identified between tumour characteristics and GALNT6 staining intensity, to the best of our knowledge, this is the first study to demonstrate that tissue from carcinoma in situ‑tumours and metastases were more heavily stained than late‑stage breast cancers. This may indicate an important role of glycosylation aberration in escaping the immune system at early phases of tumour development. The present study also hypothesised that nascent or early metastasizing tumours are normally recognized by the immune system of the patient, but glycosylation pattern changes may facilitate tumor escape from immune recognition. In follow‑up studies, our group will aim to confirm and consolidate these "
1707,The association between a mutated ras gene and cyclooxygenase-2 expression in human breast cancer cell lines.,"Gilhooly EM, Rose DP.",https://pubmed.ncbi.nlm.nih.gov/10402236/,"Cyclooxygenase (COX) is rate-limiting for arachidonic acid metabolism to the prostanoid family of eicosanoids. Some human breast cancers, notably those which are estrogen receptor (ER)-negative with high metastatic potential, produce high levels of prostaglandin E2 (PGE2). In some cell types, expression of the inducible COX-2 isoform occurred in association with a ras gene mutation. We determined COX-1 and COX-2 expression, and the corresponding PGE2 secretions, in 4 ER-negative human breast cancer cell lines, the MCF10A breast epithelial cell line, and the same non-cancerous line transfected with a mutated ras gene. The highly invasive MDA-MB-231 and Hs578T cancer cell lines, which possess a mutated Ki-ras and H-ras, respectively, expressed constitutive and inducible COX-2, and produced high PGE2 levels; the less invasive MDA-MB-435 and SK-BR-3 lines, without a mutated ras, possessed only low levels of COX-2, and secreted correspondingly low PGE2 levels. Similarly, the ras transfectant, but not parental MCF10A cells, expressed inducible COX-2. Chemosuppression with a selective COX-2 inhibitor may be effective only in that minority of breast cancers which have a mutated ras gene."
1708,Higher expression of topoisomerase II in lung cancers than normal lung tissues: different expression pattern from topoisomerase I.,"Hasegawa T, Isobe K, Nakashima I, Shimokata K.",https://pubmed.ncbi.nlm.nih.gov/8395833/,"To examine the expression of topoisomerase I and topoisomerase II in primary lung cancer specimens at mRNA level, we carried out Northern blot analysis. As for topoisomerase I expression, there was no remarkable difference between lung cancer specimens and non-cancerous lung tissues. On the other hand, we could detect topoisomerase II mRNA in almost all lung cancer specimens, but not in non-cancerous tissues. By Southern blot analysis, we could not detect large deletion nor rearrangement in DNA level. These "
1709,Human papillomavirus infection is not involved in esophageal verrucous carcinoma.,"Cappellesso R, Coati I, Barzon L, Peta E, Masi G, Scarpa M, Lanza C, Michelotto M, Ruol A, Cesaro S, Castoro C, Palù G, Nuovo GJ, Fassan M, Rugge M.",https://pubmed.ncbi.nlm.nih.gov/30423307/,"Verrucous carcinoma of the esophagus (VCE) is a rare variant of squamous cell cancer, with a puzzling clinical, etiological, and molecular profile. The etiological involvement of human papillomavirus (HPV) in the cancer's natural history is controversial. This study considers 9 cases of VCE, focusing on patients' clinical history before surgery, histologic phenotype, immunophenotype (epidermal growth factor receptor [EGFR], E-cadherin, cyclin D1, p16, and p53 expression), HPV infection, and TP53 gene mutational status (exons 5-8). Using 3 different molecular test  The only case with synchronous nodal metastasis was characterized by a TP53 missense point mutation in association with high EGFR and low E-cadherin expression levels. In conclusion, HPV infection is probably not involved with VCE, while TP53 gene mutation, EGFR overexpression, and E-cadherin loss might fuel the tumor's proliferation and lend it a metastatic potential."
1710,Inhibition of protein N-myristoylation: a therapeutic protocol in developing anticancer agents.,"Das U, Kumar S, Dimmock JR, Sharma RK.",https://pubmed.ncbi.nlm.nih.gov/22463587/,"N-myristoyltransferase (NMT) is an essential eukaryotic enzyme which catalyzes the transfer of the myristoyl group to the terminal glycine residue of a number of proteins including those involved in signal transduction and apoptotic pathways. Myristoylation is crucial for the cellular proliferation process and is required for the growth and development in a number of organisms including many human pathogens and viruses. Targeting the myristoylation process thus has emerged as a novel therapeutic strategy for anticancer drug design. The expression/activity of NMT is considerably elevated in a number of cancers originating in the colon, stomach, gallbladder, brain and breast and attenuation of NMT levels has been shown to induce apoptosis in cancerous cell lines and reduce tumor volume in murine xenograft models for cancer. A focus of current therapeutic interventions in novel cancer treatments is therefore directed at developing specific NMT inhibitors. The inhibition of the myristoyl lipidation process with respect to cancer drug development lies in the fact that many proteins involved in oncogenesis such as src and various kinases require myristoylation to perform their cellular functions. Inhibiting NMT functions to control malignancy is a novel approach in the area of anticancer drug design and there are rapidly expanding discoveries of synthetic NMT inhibitors as potential chemotherapeutic agents to be employed in the warfare against cancer. The current review focuses on developments of various chemical NMT inhibitors with potential roles as anticancer agents."
1711,"Incidence of colorectal cancer in West Virginia from 1993-1999: an update by gender, age, subsite and stage.","Jubelirer SJ, Wells JB, Emmett M, Broce M.",https://pubmed.ncbi.nlm.nih.gov/14959509/,"The sensitivities of different screening  Our  We studied the 7,895 cases of colorectal cancer reported to the West Virginia Cancer Registry between 1993 and 1999 and termed cancers proximal to, but not including the sigmoid colon as ""right-sided,"" and the remaining tumors as ""left-sided."" Multivariate analyses were used to differentiate the effects of age and gender on changes in tumor location over time. The impact of screening was shown by the increase in the percentage of localized disease from 30.5% among cancers in the proximal colon to 37.6% in the distal colorectum. In contrast, the percentage of regional disease decreased from 50% among cancers in the proximal colon to the distal colorectum. The male to female ratios also increased from the proximal colon to the distal colorectum. Incidence rates, regardless of time, increased with advancing age for cancers located in all anatomical subsite groups, but more substantially for proximal colon cancer than for descending and distal colorectal cancers. For males ages > 85 and for females who are > 75 years of age, the cancer rates arising in the proximal colon exceeded observed in groups but more substantially for proximal colon cancer than for descending and distal colorectal cancers. For males age > 85 and females > 75, the cancer rates arising in the proximal colon exceeded those arising in the distal colorectum. This shift occurred at a younger age among females than males. The apparent shift of colorectal cancers to more proximal locations with advancing age has important implications for screening strategies. A further decrease in the relative incidence of left-sided colon cancers may require modifying current practices to include more frequent use of screening colonoscopy, particularly in women ages 75 years or older."
1712,In vitro and in silico studies of holothurin A on androgen receptor in prostate cancer.,"Pranweerapaiboon K, Garon A, Seidel T, Janta S, Plubrukarn A, Chaithirayanon K, Langer T.",https://pubmed.ncbi.nlm.nih.gov/34514975/,"The androgen receptor (AR) plays a crucial role in the growth of prostate cancer, and has long been considered the cancer's primary strategic therapeutic target. However, despite the early susceptibility, patients receiving hormonal therapy targeting AR are likely to develops resistance to the treatment and progresses to the castration-resistant stage as a consequence of the mutation at the ligand binding pocket of AR. Interestingly, the surface pocket of the AR called binding function 3 (BF3) has been reported as a great benefit for treating a recurrent tumor. Herein, we investigate the potential of using a marine triterpenoid saponin, holothurin A, on targeting AR expression of prostate cancer using in vitro and in silico studies. Holothurin A reduced the PSA expression, leading to the growth inhibition of androgen sensitive prostate cancer cell line through a downregulation of AR activity. The molecular docking study demonstrated that holothurin A could bind strongly in the BF3 pocket by energetically favorable hydrogen acceptor and hydrophobic with a calculated binding affinity of -13.90 kcal/mol. Molecular dynamics simulations provided the additional evidence that holothurin A can form a stable complex with the BF3 pocket through the hydrophobic interactions with VAL676, ILE680, and ALA721. As a consequence, holothurin A modulates the activation function-2 (AF2) site of the AR through repositioning of the residues in the AF2 pocket. Targeting alternatives sites on the surface of AR via holothurin A will provide a potential candidate for future prostate cancer treatment.Communicated by Ramaswamy H. Sarma."
1713,Inferring parsimonious migration histories for metastatic cancers.,"El-Kebir M, Satas G, Raphael BJ.",https://pubmed.ncbi.nlm.nih.gov/29700472/,"Metastasis is the migration of cancerous cells from a primary tumor to other anatomical sites. Although metastasis was long thought to  However, accurate determination of migration patterns from somatic mutation data is complicated by intratumor heterogeneity and discordance between clonal lineage and cellular migration. We introduce MACHINA, a multi- MACHINA analysis of data from multiple cancers shows that migration patterns are often not uniquely determined from sequencing data alone and that complicated migration patterns among primary tumors and metastases may be less prevalent than previously reported. MACHINA's rigorous analysis of migration histories will aid in studies of the drivers of metastasis."
1714,[Prediction of treatment outcome after adjuvant loco-regional chemotherapy following liver resection for colorectal metastases--preliminary results].,"Strnad R, Ryska M, Belina F, Langer D, Novotný J, Ludvíková M.",https://pubmed.ncbi.nlm.nih.gov/16689143/," Colorectal liver metastases are detected in about a half of patients with colorectal cancer. Liver resection of colorectal metastases is currently the only potentially curative treatment with a chance for a long-term survival rate. Until now there has remained a question of whether adjuvant HAIC can improve the treatment  The aim of our study is to verify predictive efficiency of thymidylátsyntasis (TS), dihydropyrimidindehydrogenasis (DPD) and thymidinfosforylasis (TP) in patients undergoing adjuvant hepatic artery infusion chemotherapy (HAIC) following radical liver resection for colorectal metastases.
    


           R0 resection was achieved in 60 events. Ten patients who underwent R0 resection both for primary cancer and for colorectal liver metastases and who were given portcatheter for HAIC were included in this study. Adjuvant chemotherapy contained 5-fluorourycil (1200 mg/m2) combined with oxyliplatinum and leukovorin. Whole dose was administered via hepatic artery. The samples were procured both from healthy liver tissue and from metastases for imunohistochemical and molecular biological analysis.
    


           We detected neither occurrence of death nor serious complication in early postoperative course in none of ten patients. Low expression of TS was found in both events and very high expression of DPD in one event was detected.
    


          Discussion:
        
      
      High expression of DPD in one of these patients could contribute to lower outcome of adjuvant chemotherapy. Low expression of TS in both patients responds to the written statement regarding contribution of adjuvant chemotherapy only in patients with high TS level.
    


          Conclusion:
        
      
      The expression of TS and DPD responds to expected outcome of HAIC. Low number of patient does not permit statistic evaluation."
1715,Regular follow-up with cervical cytology is of questionable value following surgical treatment of microinvasive cervical cancer.,"Ashmore AA, Abdul S, Phillips A, Bali A, Tamizian O, Asher V.",https://pubmed.ncbi.nlm.nih.gov/38513505/," To evaluate whether intensive follow-up can detect pre-cancer early compared to the standard 3 yearly follow-up.
    


          Study design:
        
      
      Retrospective review.
    


           Patients who had initial hysterectomy were excluded from our analysis. Review conducted using electronic patient records for treatment, histology, and follow-up smears. Number of abnormal follow-up smears and number of recurrent cervical cancers were considered the main outcome measures.
    


           81 (82.65 %) were stage 1A1 and 17 (17.35 %) were stage 1A2. 74 (75.51 %) patients had squamous histology and 24 (24.49 %) had adenocarcinomas. Median follow-up was 11.08 years (4043 days). 510 follow-up smears were performed, of which 33 (6.47 %) were abnormal. 5 of these abnormal smears showed low grade dyskaryosis (0.98 %) and 2 smears showed high grade dyskaryosis (0.39 %). The positive predictive value of follow-up smears to detect pre-cancerous changes was 5.71 %. There were no recurrent cancers detected.
    


          Conclusions:
        
      
      Microinvasive cervical cancer is effectively managed with conservative surgery. There were no recurrent cancers detected in our cohort during follow-up and there were only 2 high grade dyskaryoses detected (n = 2/510, 0.39 %). We therefore believe that reducing the intensity of follow up of these patients should be considered."
1716,The Stem Cell Network model: clinical implications in cancer.,"Cabanillas R, Llorente JL.",https://pubmed.ncbi.nlm.nih.gov/18807062/,"This review will discuss the aspects of stem cell biology that can contribute to explain tumor development and why standard oncology treatments sometimes fail. We also propose an integrated model of tumor progression based on the putative occurrence of Stem Cell Networks (SCNs). In a SCN, the somatic stem cells are derived from a common embryonic stem cell, share a specific molecular profile and maintain a high degree of cell-cycle synchronization. In the study of cancer, the SCN model introduces an additional conceptual frame to the interpretation of both the cancer stem cell (CSC) hypothesis and the field cancerization concept. The CSC model may explain how the cancer fields develop, justifies their sizes and shapes, contribute to explain the local recurrences in patients with free margins, the second primary tumors, the success of organ preserving surgical approaches or the trend of different tumors to metastasize to certain locations. We propose that the SCN model of cancer provides some clues for further understanding tumor progression and raises promising "
1717,The survivin molecule as a double-edged sword in cellular physiologic and pathologic conditions and its role as a potential biomarker and therapeutic target in cancer.,"Rafatmanesh A, Behjati M, Mobasseri N, Sarvizadeh M, Mazoochi T, Karimian M.",https://pubmed.ncbi.nlm.nih.gov/31250439/,"Survivin is a member of the family of apoptosis inhibitory proteins with increased expression level in most cancerous tissues. Evidence shows that survivin plays regulatory roles in proliferation or survival of normal adult cells, principally vascular endothelial cells, T lymphocytes, primitive hematopoietic cells, and polymorphonuclear neutrophils. Survivin antiapoptotic role is, directly and indirectly, related to caspase proteins and shows its role in cell division through the chromosomal passenger complex. Survivin contains many genetic polymorphisms that the role of some variations has been proven in several cancers. The -31G/C polymorphism is one of the most important survivin mutations which is located in the promoter region on a CDE/CHR motif. This polymorphism can upregulate the survivin messenger RNA. In addition, its allele C can increase the risk of cancers in 1.27-fold than allele G. Considering the fundamental role of survivin in different cancers, this protein could be considered as a new therapeutic target in cancer treatment. For this purpose, various strategies have been designed including the prevention of survivin expression through inhibition of mRNA translation using antagonistic molecules, inhibition of survivin gene function through small inhibitory molecules, gene therapy, and immunotherapy. In this study, we describe the structure, played roles in physiological and pathological states and genetic polymorphisms of survivin. Finally, the role of survivin as a potential target in cancer therapy given challenges ahead has been discussed."
1718,Lipid profiles for intrahepatic cholangiocarcinoma identified using matrix-assisted laser desorption/ionization mass spectrometry.,"Park YS, Yoo CW, Lee SC, Park SJ, Oh JH, Yoo BC, Paik SS, Lee KG, Jin SY, Kim SC, Kim KP, Kim YH, Choi D, Kim HK.",https://pubmed.ncbi.nlm.nih.gov/21777572/,"
    


           2,5-dihydroxybenzoic acid / α-cyano-4-hydroxycinnamic acid were manually deposited on tumor-rich areas, and mass spectra were acquired using a MALDI-time of flight instrument.
    


          05 for the cross-validated misclassification rate. Cancer-associated lipid alteration was similar between cholangiocarcinomas and pancreatic cancers, but not between cholangiocarcinomas and colorectal cancers. Baseline lipid profiles were different between cholangiocarcinoma and colorectal cancers.
    


          Conclusions:
        
      
      MALDI MS analysis of lipid distinguishes cancerous epithelium of cholangiocarcinoma from adjacent normal tissue, and between cholangiocarcinomas and colorectal cancers."
1719,Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors.,"Heaphy CM, Bisoffi M, Fordyce CA, Haaland CM, Hines WC, Joste NE, Griffith JK.",https://pubmed.ncbi.nlm.nih.gov/16450377/,"Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our  The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery."
1720,"Assessment of genetic damage in inflammatory, precancerous, and cancerous pathologies of the esophagus using the comet assay.","Vasavi M, Vedicherala B, Vattam KK, Ahuja YR, Hasan Q.",https://pubmed.ncbi.nlm.nih.gov/20632893/,"The last few decades of cancer research indicate that DNA damage is a prerequisite for development of malignancies. An increase in damage points to reduced repair capacity and risk for progression. We have used the comet assay to assess DNA damage in individuals with various disorders of the upper gastrointestinal (GI) tract in a cohort of patients from South India. After thorough clinical, endoscopic, and histopathological evaluation, patients were categorized into cancers, precancers, inflammatory pathologies, and controls.  There was more DNA damage in cancers when compared with controls. A significant increase in damage in cancers (37%) and precancers (30.7%) when compared with the inflammatory pathologies (15.6%) and controls (10.03%) was noted. The interindividual variation observed was independent of confounding factors such as tobacco and alcohol. We suggest that the damage seen in the esophageal tissue is likely to be disease-related, whereas that seen in blood may be a reflection of disease. Individuals with greater damage may be prone to disease progression and the comet assay can be used as a cost-effective biomonitoring tool to assess damage and identify these individuals at risk for a progressive pathology, even to malignancy."
1721,Molecular Characterization of an Endometrial Endometrioid Adenocarcinoma Metastatic to a Thyroid Hurthle Cell Adenoma Showing Cancerization of Follicles.,"Afrogheh AH, Meserve E, Sadow PM, Stephen AE, Nosé V, Berlin S, Faquin WC.",https://pubmed.ncbi.nlm.nih.gov/26687112/,"Tumor-to-tumor metastasis is rare. Herein, we present a unique case of endometrial endometrioid adenocarcinoma metastatic to a thyroid Hürthle cell adenoma 9 years after initial diagnosis. On histologic examination of the thyroid, the malignant endometrioid glands and single cells (donor tumor) were dispersed within the Hürthle cell adenoma (recipient tumor). In several sections of the adenoma with still preserved microfollicular architecture, malignant endometrial adenocarcinoma cells were admixed within oncocytic adenomatous epithelium (so-called ""cancerization of the follicles""). This unusual phenomenon, to our knowledge, is a novel finding in the thyroid gland. Immunohistochemistry, subsequently elicited clinical history, and morphologic comparison of the tumor in the thyroid to the primary endometrial tumor confirmed the origin of the donor tumor cells. Molecular analysis of both the metastatic and primary endometrial tumors demonstrated PIK3CA and PTEN mutations in both tumors, as is characteristic of well-differentiated endometrioid tumors of the endometrium. Amplification of chromosome 1q was detected in both sites; however, only the metastatic tumor showed loss of chromosomes 2, 9, and 22. The morphologic differential diagnosis of metastatic endometrioid adenocarcinoma in the thyroid includes columnar cell variant of papillary thyroid carcinoma (CCVPTC) arising in a preexisting adenoma, endocrine glandular atypia within an adenoma, and metastasis from other anatomic sites. Histomorphologic differences among these entities may be subtle; therefore, knowledge of and morphologic comparison with prior malignancies and immunohistochemistry can be helpful in rendering the correct diagnosis."
1722,Promising new developments in the systemic treatment of ovarian cancer.,Reed E.,https://pubmed.ncbi.nlm.nih.gov/7513218/,"Advanced-stage cancer of the ovary is the most lethal of gynecologic malignancies, affecting African-American and white women with approximately equal frequency. In large part, ovarian cancer's lethality is due to the fact that most women are diagnosed with disease that is widespread throughout the abdomen and pelvis. This article reviews recent developments in the identification of new treatment approaches to ovarian cancer. Discussion focuses on current drug development activities of the Medical Ovarian Cancer Section of the National Cancer Institute, with reference to pertinent literature from other institutions. The drugs discussed are in clinical trials as of this writing. They include paclitaxel, an agent with a novel molecular mechanism of action; colony-stimulating factors, which enhance the therapeutic index of cytotoxic agents; and the antiproliferative agents suramin and carboxyamidotriazole."
1723,Fluorescence discrimination of cancer from inflammation by molecular response to COX-2 enzymes.,"Zhang H, Fan J, Wang J, Dou B, Zhou F, Cao J, Qu J, Cao Z, Zhao W, Peng X.",https://pubmed.ncbi.nlm.nih.gov/24200121/,"Accurate identification of cancer from inflammation and normal tissue in a rapid, sensitive, and quantitative fashion is important for cancer diagnosis and resection during surgery. Here we report the use of cyclooxygenase-2 as a marker for identification of cancer from inflammation and the design of a novel smart COX-2-specific fluorogenic probe (NANQ-IMC6). The probe's fluorescence is ""turned on"" in both inflammations and cancers where COX-2 is overexpressed. Intriguingly, the fluorescent emission is quite different at these two sites with different expression level of COX-2. Hence, NANQ-IMC6 can not only distinguish normal cells/tissues from cancer cells/tissues but also distinguish the latter from sites of inflammation lesions by the different fluorescence recognition of NANQ-IMC6 for COX-2 enzymes. Following spraying with the NANQ-IMC6 solution, cancerous tissue, inflamed tissues, and normal tissues can be accurately discriminated in vivo by the unaided eye using a hand-held ultraviolet lamp emitting at 365 nm. So the probe may have potential application varying from cancer inflammation diagnosis to guiding tumor resection during surgery."
1725,Characteristics of extracellular cyclic AMP-dependent protein kinase as a biomarker of cancer in dogs.,"Bhang DH, Choi US, Kim BG, Lee SN, Lee S, Roh HS, Chung WJ, Jeon KO, Song WJ, Youn HY, Baek KH.",https://pubmed.ncbi.nlm.nih.gov/28185388/," In this study, we evaluated extracellular cyclic AMP-dependent protein kinase A (ECPKA) level in serum as a useful cancer biomarker in dogs.
    


          
    


          1-, 8.8-, and 10.9-fold compared with those from dogs harbouring benign tumours, dogs with non-tumour diseases, and healthy control dogs, respectively (P < .0001). In addition, serum ECPKA level did not show statistically significant correlation with gender, breed, or age of dogs or their non-cancerous disease conditions.
    


          Conclusion:
        
      
      Our data strongly propose that detection of serum ECPKA level is a potential and specific diagnostic tool for cancer in dogs."
1726,Characterization of colorectal mucus using infrared spectroscopy: a potential target for bowel cancer screening and diagnosis.,"Nallala J, Jeynes C, Saunders S, Smart N, Lloyd G, Riley L, Salmon D, Stone N.",https://pubmed.ncbi.nlm.nih.gov/32203151/,"Biological materials presenting early signs of cancer would be beneficial for cancer screening/diagnosis. In this respect, the suitability of potentially exploiting mucus in colorectal cancer was tested using infrared spectroscopy in combination with statistical modeling. Twenty-six paraffinized colon tissue biopsy sections containing mucus regions from 20 individuals (10 normal and 16 cancerous) were measured using mid-infrared spectroscopic imaging. A digital de-paraffinization, followed by cluster analysis driven digital color-coded multi-staining segmented the infrared images into various histopathological features such as epithelium, connective tissue, stroma, and mucus regions within the tissue sections. Principal component analysis followed by supervised linear discriminant analysis was carried out on pure mucus and epithelial spectra from normal and cancerous regions of the tissue. For the mucus-based classification, a sensitivity of 96%, a specificity of 83%, and an area under the curve performance of 95% was obtained. For the epithelial tissue-based classification, a sensitivity of 72%, a specificity of 88%, and an area under the curve performance of 89% was obtained. The mucus spectral profiles further showed contributions indicative of glycans including that of sialic acid changes between these pathology groups. The study demonstrates that infrared spectroscopic analysis of mucus discriminates colorectal cancers with high sensitivity. This concept could be exploited to develop screening/diagnostic approaches complementary to histopathology."
1727,Epstein-Barr virus DNA is not increased in tonsillar carcinoma.,"Khabie N, Savva A, Kasperbauer JL, McGovern R, Gostout B, Strome SE.",https://pubmed.ncbi.nlm.nih.gov/11359160/,"Epstein-Barr virus (EBV) is a known oncogenic virus associated with a wide variety of cancers, including nasopharyngeal carcinoma. Waldeyer's ring, a collection of lymphoid tissues, includes the nasopharynx, pharyngeal, and lingual tonsils. To determine if EBV plays a causative role in carcinomas arising from other tissues in Waldeyer's ring, we examined pharyngeal tonsillar carcinomas for evidence of EBV infection. As previously reported, DNA was extracted from 53 consecutive tonsil cancers, as well as from age- and gender-matched non-cancerous tonsillectomy specimens. Three different sets of primers for discrete exons of EBV were then used to determine if active or latent EBV infection was expressed in the extracted DNA using the polymerase chain reaction (PCR). All positive bands were then sequenced to confirm the presence of amplified EBV fragments. None of the samples showed evidence for active EBV infection. In primers demonstrating latent infection, 1 of 53 (1.9%) of tumors were positive, versus 6 of 53 (11.3%) of the controls. These "
1728,LncRNA BLACAT1 May Serve as a Prognostic Predictor in Cancer: Evidence from a Meta-Analysis.,"Lu H, Liu H, Yang X, Ye T, Lv P, Wu X, Ye Z.",https://pubmed.ncbi.nlm.nih.gov/31061820/," This study aimed to evaluate its generalized predictive value for cancer prognosis.
    


          Materials and  The analyses were performed using Review Manager Version 5.3 and Stata SE 12.0. The primary endpoints included overall survival (OS), pathological characteristics (TNM stage and tumor grade), lymph node metastasis (LNM), and distant metastasis.
    


           The 82, 95% CI: 1.44-2.30, p < 0.00001) than patients with low lncRNA BLACAT1 expression. Moreover, elevated BLACAT1 expression was significantly associated with advanced TNM stage (OR: 2.29, 95% CI: 1.15-4.56, p = 0.005), high tumor grade (OR: 1.67, 95% CI: 1.11-2.53, p = 0.01), and lymph node metastasis (OR: 2.53, 95% CI: 1.80-3.57, p < 0.00001). Meanwhile, the expression of BLACAT1 had no significant association with age (p = 0.92), gender (p = 0.55), and smoking (p = 0.62).
    


          Conclusion:
        
      
      High expression of lncRNA BLACAT1 may predict a poor prognosis in OS, TNM stage, tumor grade, and LNM. Its predictive roles were not significantly affected by age, gender, or smoking. Therefore, lncRNA BLACAT1 may serve as a promising predictor in cancer prognosis."
1729,Sex-associated difference in estrogen receptor beta expression in N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric cancers in rats.,"Wakui S, Motohashi M, Muto T, Takahashi H, Hano H, Jutabha P, Anzai N, Wempe MF, Endou H.",https://pubmed.ncbi.nlm.nih.gov/22330348/,"Epidemiologic studies indicate that the incidence of gastric cancer is higher in males than in females. Although the mechanisms mediating this difference are unclear, a role for estrogens has been proposed. We used Western blotting to evaluate the role of estrogen receptor (ER) subtypes ERα and ERβ and proliferating cell nuclear antigen (PCNA) in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis in Wistar rats; ERα and ERβ mRNA levels also were analyzed by quantitative real-time RT-PCR analysis. The incidence of gastric cancer was significantly higher in male than female rats. In both sexes, ERα expression was similar in MNNG-treated cancerous and noncancerous tissues and normal gastric tissue. However, ERβ expression in MNNG-treated cancerous and noncancerous tissues was significantly lower in male rats and higher in female rats than that in normal gastric tissue; MNNG-induced cancerous tissue showed the highest ERβ expression. PCNA expression in MNNG-treated cancerous tissues was higher than that in noncancerous tissues, and was higher in male rats than female rats. Western blotting  The present study provides evidence of a sex-associated difference in ERβ and PCNA expression in MNNG-induced gastric cancers in Wistar rats."
1730,[Expression and clinical significance of apoptosis associated genes Livin and Smac/DIABLO in human gastric carcinomas].,"Zhao Y, Deng X, Wang Q.",https://pubmed.ncbi.nlm.nih.gov/19635196/," This study was to investigate the expression of Livin and Smac/DIABLO, and their correlations to the clinicopathological features in gastric adenocarcinomas.
    


           The protein expression and location of Livin and Smac/DIABLO were measured by western blot and immunohistochemistry (SP 
    


          374+/-4.759) compared with the control. The expression of Livin was higher in poorly differentiated gastric carcinomas and carcinomas with lymph node metastases than in highly differentiated gastric carcinomas and carcinomas without lymph node metastases. (Chi2=9.60, P<0.01; Chi2=5.51, P<0.05). The expression of Livin mRNA had no correlation to tumor site, and the invasion depth and TNM stage (P >0.05). In contrast, no expression of Livin was detected in normal and para-cancerous gastric tissues. The protein expression of Livin was consistent with that of its mRNA expression. The expression level of Smac/DIABLO mRNA was lower in gastric carcinomas (0.731+/-0.420) than in normal gastric tissues (1.104+/-0.276) and para-cancerous tissues (1.061+/-0.737), but there was no significant difference (P>0.05). The expression of Smac/DIABLO mRNA was not correlated to clinicopathological characters of gastric adenocarcinoma. The protein expression of Smac/DIABLO was not completely consistent with that of its mRNA expression. The expression of Smac/DIABLO was different between intestinal type gastric carcinoma (84.38%) and diffuse type gastric carcinoma (60.65%) (P<0.05).
    


          Conclusion:
        
      
      The expression and correlation of Livin and Smac/DIABLO vary in different stages and pathological types of gastric carcinoma. Overexpression of Livin is closely related to differentiation and metastases of gastric carcinoma."
1731,Targeting aldose reductase for the treatment of cancer.,"Tammali R, Srivastava SK, Ramana KV.",https://pubmed.ncbi.nlm.nih.gov/21486217/,"It is strongly established by numerous studies that oxidative stress-induced inflammation is one of the major causative agents in a variety of cancers. Various factors such as bacterial, viral, parasitic infections, chemical irritants, carcinogens are involved in the initiation of oxidative stress-mediated inflammation. Chronic and persistent inflammation promotes the formation of cancerous tumors. Recent investigations strongly suggest that aldose reductase [AR; AKR1B1], a member of aldo-keto reductase superfamily of proteins, is the mediator of inflammatory signals induced by growth factors, cytokines, chemokines, carcinogens etc. Further, AR reduced product(s) of lipid derived aldehydes and their metabolites such as glutathionyl 1,4-dihydroxynonanol (GS-DHN) have been shown to be involved in the activation of transcription factors such as NF-κB and AP-1 which transcribe the genes of inflammatory cytokines. The increased inflammatory cytokines and growth factors promote cell proliferation, a main feature involved in the tumorigenesis process. Inhibition of AR has been shown to prevent cancer cell growth in vitro and in vivo models. In this review, we have described the possible association between AR with oxidative stress- and inflammation- initiated carcinogenesis. A thorough understanding of the role of AR in the inflammation -associated cancers could lead to the use of AR inhibitors as novel chemotherapeutic agents against cancer."
1732,Improved indocyanine green retention after short-term lenvatinib withdrawal in three patients with hepatocellular carcinoma.,"Sugimoto R, Inada H, Tanaka Y, Senju T, Aratake Y, Nakanishi A, Miki M, Lee L, Hisano T, Matsumoto Y, Mano Y, Iguchi T, Sugimachi K, Okumura Y, Taguchi K, Furukawa M.",https://pubmed.ncbi.nlm.nih.gov/34176067/,"Use of lenvatinib, which has a high response rate in advanced hepatocellular carcinoma, sometimes  In Asia, including Japan, liver reserve, one of the determinants of resectability, is mainly determined by the indocyanine green (ICG) retention rate. Three patients with advanced liver cancer treated at our institution had very poor ICG retention rates during treatment with lenvatinib. Lenvatinib may reduce blood flow in both cancerous and non-cancerous regions by inhibiting vascular endothelial growth factor. Therefore, accurate determination of liver function likely requires withdrawal of this treatment several days before ICG retention testing."
1733,Multifocality and recurrence risk: a quantitative model of field cancerization.,"Foo J, Leder K, Ryser MD.",https://pubmed.ncbi.nlm.nih.gov/24735903/,"Primary tumors often emerge within genetically altered fields of premalignant cells that appear histologically normal but have a high chance of progression to malignancy. Clinical observations have suggested that these premalignant fields pose high risks for emergence of recurrent tumors if left behind after surgical removal of the primary tumor. In this work, we develop a spatio-temporal stochastic model of epithelial carcinogenesis, combining cellular dynamics with a general framework for multi-stage genetic progression to cancer. Using the model, we investigate how various properties of the premalignant fields depend on microscopic cellular properties of the tissue. In particular, we provide analytic  We also derive analytical  distant secondary tumors for different parameter regimes, a critical aspect for the optimal choice of post-operative therapy in carcinoma patients. This study contributes to a growing literature seeking to obtain a quantitative understanding of the spatial dynamics in cancer initiation."
1734,"BRCA1 methylation in breast duct carcinoma, a practical study in Duhok-Iraq.","Hasan NA, Pity IS.",https://pubmed.ncbi.nlm.nih.gov/38279496/,"Lacking protein functions of Breast cancer susceptibility gene1 (BRCA1) and Breast cancer susceptibility gene2 (BRCA2), by methylation, represents tissue-specific silent epigenetic regions that tolerate genomic instability and may end in different cancers, mainly breast and ovary. Promoter-CpG island hypermethylation is a common molecular defect in cancer cells. This has prompted us to use MSP for identification of BRCA1 methylation in these groups of women at Duhok, north of Iraq. Genomic DNA was isolated from 96 tumor samples from patients with primary breast cancer and normal tissues which include; 40 non-neoplastic breast tissues (considered as external control) and 40 distant non-cancerous tissues from the same cancerous women (internal control). The extracted DNA was subjected to methylation-specific PCR (MSP) to determine the promoter methylation status of BRCA1 and its correlation with study parameters including protein expression level of ER, PR, Her2/neu, and Ki67 receptors. The study revealed 10.4% complete BRCA1 methylation and 66.6% partial methylation (PM) among the cancerous samples. Partial methylation was observed in 95% of internal control and 20% of the external control. Complete methylation was negative in both control groups. Compared with negative methylation, positive BRCA1 promoter methylation was significantly high among triple negative (ER-, PR-, Her2-) cases with high proliferative index. There was also a methylation trend toward cases with T2 and higher staging status, although didn't reach the level of significance. BRCA1 promoter complete methylation was exclusive for cancerous tissues. With management of the above concerns, this line of research gains a strength point including the prevalence of DNA methylation changes among sporadic breast cancer (i.e. not restricted to the inherited type). Considering partial or focal BRCA1 methylation, caution has to be taken as this epigenetic alteration, which may progress to complete methylation status, was detected in non-neoplastic breast tissues adjacent to the cancerous ones and even normal breasts. This triggers application of extended screening programs, including BRCA1 methylation, for identification of women at risk, and can benefit from early intervention."
1735,Decreased expression of the FOXO3a gene is associated with poor prognosis in primary gastric adenocarcinoma patients.,"Yang XB, Zhao JJ, Huang CY, Wang QJ, Pan K, Wang DD, Pan QZ, Jiang SS, Lv L, Gao X, Chen HW, Yao JY, Zhi M, Xia JC.",https://pubmed.ncbi.nlm.nih.gov/24194912/," FOXO3a has been shown to be a tumor suppressor in various cancers. This study investigated the expression of FOXO3a in primary gastric adenocarcinomas and its prognostic value for primary gastric adenocarcinoma patients.
    


          
    


          03) and protein (p = 0.019) was lower in cancerous tissues compared with their adjacent non-tumorous tissues. In addition, the chi-square test revealed that low FOXO3a expression was significantly correlated with larger tumor size (p = 0.007), poor histopathological classification (p = 0.029), depth of invasion (p = 0.049), local lymph node metastasis (p = 0.013), distant metastasis (p = 0.013) and AJCC staging (p<0.001). Kaplan-Meier survival analysis demonstrated that low expression of FOXO3a was significantly correlated with a poor prognosis for gastric cancer patients (p<0.001). The multivariate analysis showed that FOXO3a expression was an independent prognostic factor of the overall survival rate of patients with primary gastric adenocarcinoma.
    


          Conclusion:
        
      
      Our study suggested that decreased FOXO3a expression may play an important role in the progression of gastric cancer. FOXO3a could be a valuable prognostic marker as well as a potential molecular therapy target for gastric cancer patients."
1736,Metabolomics-guided global pathway analysis reveals better insights into the metabolic alterations of breast cancer.,"Long NP, Heo D, Kim HY, Kim TH, Shin JG, Lee A, Kim DH.",https://pubmed.ncbi.nlm.nih.gov/34052553/,"Accurate metabolome measurements are critical for improved insights into breast cancer metabolic disturbances and enhanced exploration of novel therapeutic targets. Nevertheless, conventional functional interpretation is limited by metabolite identification capacity, which diminishes the scientific value of untargeted metabolomics analyses. In this study, we conducted a metabolomics-guided global pathway meta-analysis to investigate the metabolic alterations of breast cancer. Metabolic features were directly investigated in the pathway meta-analysis to identify breast cancer-associated metabolic processes. Conventional pathway analysis was also conducted involving identified metabolites alone. Comparison of the two strategies revealed that the global pathway meta-analysis approach could avoid the loss of functionally relevant information, relative to the conventional analysis findings. Furthermore, the pathway meta-analysis accurately captured alterations in the following components of the breast cancer metabolome: central carbon metabolism, oxidative glutamine metabolism, purine metabolism, nonessential amino acid metabolism, and glutathione metabolism. There were also substantial alterations of fatty acyl carnitine species and fatty acid β-oxidation processes. These pathways contribute to breast cancer initiation, progression, metastasis, and drug resistance. In conclusion, we suggest that global pathway analysis and the conventional approach with identified metabolites should be employed together to maximize the exploration of breast cancer's metabolic landscape."
1737,26S Proteasome Non-ATPase Regulatory Subunits 1 (PSMD1) and 3 (PSMD3) as Putative Targets for Cancer Prognosis and Therapy.,"Rubio AJ, Bencomo-Alvarez AE, Young JE, Velazquez VV, Lara JJ, Gonzalez MA, Eiring AM.",https://pubmed.ncbi.nlm.nih.gov/34572038/,"Ever since the ubiquitin proteasome system was characterized, efforts have been made to manipulate its function to abrogate the progression of cancer. As a  Despite success, adverse side effects and drug resistance are prominent, raising the need for alternative therapeutic options. We recently demonstrated that knockdown of the 19S regulatory components, 26S proteasome non-ATPase subunits 1 (PSMD1) and 3 (PSMD3),  Therefore, we hypothesized that PSMD1 and PSMD3 are potential targets for anti-cancer therapeutics and that their relevance stretches beyond CML to other types of cancers. In the present study, we analyzed PSMD1 and PSMD3 mRNA and protein expression in cancerous tissue versus normal controls using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), comparing expression with overall survival. Altogether, our data suggest that PSMD1 and PSMD3 may be novel putative targets for cancer prognosis and therapy that are worthy of future investigation."
1738,Matrix metalloproteinase matrilysin (MMP-7) participates in the progression of human gastric and esophageal cancers.,"Adachi Y, Itoh F, Yamamoto H, Matsuno K, Arimura Y, Kusano M, Endoh T, Hinoda Y, Oohara M, Hosokawa M, Imai K.",https://pubmed.ncbi.nlm.nih.gov/9772296/,"Matrilysin is one of matrix metalloproteinases, which is supposed to have a specific role in tumor progression. Expression of matrilysin was investigated in gastric and esophageal cancers by an immunohistochemical examination. Matrilysin was expressed in all esophageal squamous cell carcinomas (13/13) and in the majority of gastric adenocarcinomas (31/35, 89%). The positive staining was observed in tumor cells of cancerous tissues. In gastric cancers, there were significant statistical correlations between matrilysin expression at the invasive front and nodal metastasis or advanced stage. These "
1739,"Downregulation of TAP1 in Tumor-Free Tongue Contralateral to Squamous Cell Carcinoma of the Oral Tongue, an Indicator of Better Survival.","Attaran N, Gu X, Coates PJ, Fåhraeus R, Boldrup L, Wilms T, Wang L, Sgaramella N, Zborayova K, Nylander K.",https://pubmed.ncbi.nlm.nih.gov/32867395/,"Oral cancers are surrounded by epithelium that histologically might seem normal, but genetically has aberrations. In patients with squamous cell carcinoma of the oral tongue (SCCOT), it is therefore important to study not only the tumor but also the clinically tumor-free contralateral tongue tissue that remains in the patient after treatment to map changes of prognostic and/or diagnostic value. The transporter associated with antigen processing (TAP) dimer is a key factor in the process of activating cytotoxic T cells. By downregulating the expression of TAP, tumor cells can escape cytotoxic T cell recognition. Biopsies from tumor and clinically tumor-free contralateral tongue tissue in 21 patients with SCCOT were analyzed together with tongue biopsies from 14 healthy individuals, which served as the control group. Dividing patients into TAP1-high and TAP1-low groups according to the median TAP1 level in tumor-free samples showed that patients with lower TAP1 mRNA levels in tumor-free samples had better overall (p = 0.003) and disease-free survival (p = 0.002). The "
1740,Molecular mechanisms of tobacco induced oral and oropharyngeal cancer: Results of a tissue microarray and immunohistochemistry-based study from a tertiary cancer center in India.,"Agarwal A, Garg C, Ganesh MS, Reddy S.",https://pubmed.ncbi.nlm.nih.gov/32031115/," Though studies have shown expression of TIMP1, EPS8 and AXL in cancers, their role in tobacco-induced cancers is not known. We aimed this study to evaluate the role of these molecules in oral and oropharyngeal squamous cell cancers (SCC).
    


          Materials and  Smokers were excluded from the study. After informed consent biopsies were taken from affected and contralateral normal mucosa. Paraffin blocks were made and tissue microarray (TMA) were constructed using these blocks. Immunohistochemistry (IHC) for TIMP1, EPS8, AXL kinase was carried out on these tissue microarrays. The intensity of staining was scored from 0 to 3+, related to expression of each of the three molecules.
    


          000 in all three) in oral and oropharyngeal SCC exposed to chewing tobacco.
    


          Conclusion:
        
      
      Immunohistochemical expression of these molecular markers in oral and oropharyngeal SCC correlated with their molecular based studies. Significant IHC expression of TIMP1, EPS8 and AXL establishes their role in the pathogenesis of oral and oropharyngeal squamous cell carcinomas. Novel targeted therapies may be researched that can detect and target these molecules at an earlier stage of pathogenesis of these tumors."
1741,Applications of molecular diagnostics for personalized treatment of head and neck cancer: state of the art.,"Mes SW, Leemans CR, Brakenhoff RH.",https://pubmed.ncbi.nlm.nih.gov/26620464/,"Squamous cell carcinomas of the head and neck are the sixth most frequent tumors worldwide. Risk factors are carcinogenic exposure, infection with the human papillomavirus (HPV) and genetic predisposition. Lymph node metastasis in the neck and HPV status are major prognostic factors. There are several important clinical challenges that determine the research agenda in head and neck cancer. The first is more accurate staging, particularly of occult metastatic lymph nodes in the neck. A second challenge is the lack of biomarkers for personalized therapy. There are a number of treatment modalities that can be employed both single and in combination, but at present only site and stage of the tumor are used for treatment planning. Provided here is an overview of the successes and failures of molecular diagnostic approaches that have been and are being evaluated to address these clinical challenges."
1742,"Colposcopy in pre-malignant lesions and oral squamous cell carcinoma: Linking threads of clinical, histopathological and colposcopic inferences.","Ujwala N, Singh NA, Milind N, Prafulla P, Vidhya P, Bhushan B, Qahar QA, Abhijeet W.",https://pubmed.ncbi.nlm.nih.gov/27072254/,"Context:
        
      
      The single most important factor that is known to improve the end  Early diagnosis of cancer plays a lifesaving pivotal role in overall management. The technique of colposcopy enables evaluation of changes in surface topography and vascular patterns of the lining mucosa thus, aiding in selecting the most appropriate site of biopsy ruling out the possibility of taking biopsy from the most representative area supposed to reveal epithelial dysplasia. In view of the intra-oral application of micro-colposcopy, it was felt that colposcopy might provide a useful aid for the early enough diagnosis of oral precancerous and cancerous lesions and conditions affecting the oral mucosa to improve the prognosis.
    


          Aims:
        
      
      To clinicopathologically correlate cases of oral precancers; correlate the surface characteristics revealed by micro-colposcopy with the histopathological diagnoses of the sites under observation; and map out the areas of surface dysplasia to indicate the full extent of epithelial changes before taking the biopsy specimen to take specimen from areas most representative of dysplasic features (guided biopsies).
    


          Materials and 
    


           Positive predictive value was 91%.
    


          Conclusion:
        
      
      Although the degree of abnormality in colposcopic findings can be predicted by the vascular patterns of the lesion, the major advantage of colposcopy is to outline the most suspicious lesion for histologic diagnosis by directed biopsy, which is the mainstay in establishing the correct diagnosis. Colposcopy is valuable in the detection of early cancerous lesions. However the final diagnosis must rely on a meticulous histopathological examination by an expert pathologist."
1743,[The effect of FHIT gene on renal cell carcinomas].,"Chen X, Shen PF, Chen ZC.",https://pubmed.ncbi.nlm.nih.gov/12212117/,"
    


          
    


           The transcript in the renal-cell cancer cell line appeared a small-size one when cDNA was amplified with outside nest primer; absent expression of transcript was shown when amplified with inside nest primer. About twenty percent(5/24) cancerous tissues showed genomic rearrangement in FHIT gene locus.
    


          Conclusion:
        
      
      FHIT gene exhibited aberrant transcripts and genomics in some of renal cell cancers. Therefore change of FHIT gene may play a role in development of renal cell carcinomas."
1744,Decreased expression of eukaryotic initiation factor 3f is an adverse prognostic factor for stage I-III gastric cancer.,"Li G, Wang N, Sun C, Li B.",https://pubmed.ncbi.nlm.nih.gov/24678890/," However, the expression of eIF3f in gastric cancer (GC) is not well understood to date. Therefore, the aim of this study is to detect the expression of eIF3f in GC.
    


          
    


           eIF3f levels were correlated with more advanced tumor stages and likelihood of recurrence (all P<0.05). The Kaplan-Meier survival curves indicated that decreased expression of eIF3f could serve as a prognosis marker for poor outcome of GC patients (P=0.04).
    


          Conclusions:
        
      
      eIF3f may play an important role in recurrence, thus representing a promising predictive marker for the prognosis of GC."
1745,Early automated detection system for skin cancer diagnosis using artificial intelligent techniques.,"Mahmoud NM, Soliman AM.",https://pubmed.ncbi.nlm.nih.gov/38679633/,"Recently, skin cancer is one of the spread and dangerous cancers around the world. Early detection of skin cancer can reduce mortality. Traditional  Dermoscopy is used for noninvasive diagnosis of skin cancer. Artificial Intelligence (AI) plays a vital role in diseases' diagnosis especially in biomedical engineering field. The automated detection systems based on AI reduce the complications in the traditional  In this paper, automated early detection system for skin cancer dermoscopic images using artificial intelligent is presented. Adaptive snake (AS) and region growing (RG) algorithms are used for automated segmentation and compared with each other. The  Artificial Neural networks (ANN) and support vector machine (SVM) algorithms are used for automated classification compared with each other. The proposed system with ANN algorithm shows high accuracy (94%), precision (96%), specificity (95.83%), sensitivity (recall) (92.30%), and F1-score (0.94). The proposed system is easy to use, time consuming, enables patients to make early detection for skin cancer and has high efficiency."
1747,Bacterial delivery of therapeutic proteins to the nuclei of cancer cells.,"Bloom SMK, O'Hare N, Forbes NS.",https://pubmed.ncbi.nlm.nih.gov/36710503/,"Targeting nucleic targets with therapeutic proteins would enhance the treatment of hard-to-treat cancers. However, exogenous proteins are excluded from the nucleus by both the cellular and nuclear membranes. We have recently developed Salmonella that deliver active proteins into the cytoplasm of cancer cells. Here, we hypothesized that bacterially delivered proteins accumulate within nuclei, nuclear localization sequences (NLSs) increase delivery, and bacterially delivered proteins kill cancer cells. To test this hypothesis, we developed intranuclear delivering (IND) Salmonella and quantified the delivery of three model proteins. IND Salmonella delivered both ovalbumin and green fluorescent protein to nuclei of MCF7 cancer cells. The amount of protein in nuclei was linearly dependent on the amount delivered to the cytoplasm. The addition of a NLSs increased both the amount of protein in each nucleus and the number of nuclei that received protein. Delivery of Omomyc, a protein inhibitor of the nuclear transcript factor, Myc, altered cell physiology, and significantly induced cell death. These  Extending this "
1748,The Impact of Placement Errors on the Tumor Coverage in MRI-Guided Focal Cryoablation of Prostate Cancer.,"Moreira P, Tuncali K, Tempany CM, Tokuda J.",https://pubmed.ncbi.nlm.nih.gov/32863151/,"Rationale and  However, the impact of cryo-needle/probe placement accuracy within the tumor and gland has not been extensively studied. We analyzed how variations in the placement of the cryo-needles, specifically errors leading to incomplete ablation, may affect prostate cancer's 
    


          Materials and  We modeled the placement error as a Gaussian noise on the cryo-needle position. The analysis used retrospective MRI data of 15 patients with biopsy-proven, unifocal, and MRI visible prostate cancer to calculate the impact of placement error on the volume of the tumor encompassed by the -40°C and -20°C isotherms using one to four cryo-needles.
    


           The probability of positive margin was significantly lower considering the -20°C isotherm (0.04 for three needles) than using the -40°C isotherm (0.66 for three needles).
    


          Conclusion:
        
      
      The  The analysis shows that an admissible targeting error depends on the lethal temperature considered and the number of cryo-needles used."
1749,The 19th annual Prostate Cancer Foundation scientific retreat.,"Walia G, Pienta KJ, Simons JW, Soule HR.",https://pubmed.ncbi.nlm.nih.gov/23536559/,"Prostate Cancer Foundation (PCF) convened its 19th Annual Scientific Retreat October 25-27, 2012, in Carlsbad, CA. Each year, this event brings together diverse researchers in a collaborative forum to present and discuss new and largely unpublished findings for prostate cancer diagnosis, prognosis, and treatment and defines the challenges to ending this disease as a threat to life and well-being. Several themes resonated at the multidisciplinary meeting, notably (i) the roles of field cancerization, tumor microenvironment, epithelial plasticity, signal transduction pathways in cancer progression, and disease resistance; (ii) intratumoral heterogeneity and consequences for precision medicine; (iii) resistance mechanisms to androgen axis inhibitors; and (iv) advances in molecular imaging and therapeutics for better detection and treatment."
1750,An integrative analysis of the tumor suppressors and oncogenes from sexual dimorphism and gene expression alteration features in thyroid cancer.,"Huang Y, Wang Y, Liu S, Xu Z, Chen WX.",https://pubmed.ncbi.nlm.nih.gov/37355885/," Although mortality rates are relatively low compared to other cancers, the rate of new cases started to increase in the early 2000s. While tumor suppressors and oncogenes were recently identified in thyroid cancer, the potential roles of these genes in thyroid cancer remain unclear.
    


          
    


           The genes frequently associated with unfavorable thyroid cancer were examined and validated. The association of these target genes with thyroid tumorigenesis, stages, subtypes, and survival rates were analyzed. Additionally, the genes aberrantly expressed in thyroid cancer and significantly involved in thyroid tumorigenesis, stages, subtypes, and survival rates were identified.
    


           The expression of PAPSS2, PDLIM3, COPZ2, ALDH1B1, ANTXR1, GUF1, and SENP6 negatively correlated with thyroid cancer prognosis.
    


          Conclusion:
        
      
      Female sex was a risk factor for thyroid cancer. In addition, our analysis suggested that PAPSS2, PDLIM3, COPZ2, ALDH1B1, ANTXR1, GUF1, and SENP6 are negatively correlated with the prognosis of thyroid cancer. The expression of ANTXR1, GUF1, and PDLIM3 was weakly associated with thyroid cancer's immune and molecular subtypes."
1751,Progress in cancer biomarkers monitoring strategies using graphene modified support materials.,"Zaidi SA, Shahzad F, Batool S.",https://pubmed.ncbi.nlm.nih.gov/31987212/,"Cancer is the one of the fatal and dreaded disease responsible for huge number of morbidity and mortality across the globe. It is expected that the global burden will increase to 21.7 million fresh cancer cases as compared to present estimate of 18.1 million cancer cases in addition to nearly 9.6 million cancer deaths worldwide. In response to cancerous or certain benign conditions; specific type of tumor or cancer markers (biomarkers) are produced at much higher levels which are secreted into the urine, blood, stool, tumor or other tissues. Therefore, the efficient and early detection of cancer biomarkers is necessary which can offer a reliable way for cancer patient screening and diagnosis. This process not only helps in the evaluation of pathogenic processes but also the prognosis of different cancers and pharmacological responses to therapeutic interventions are secured. Over the past several years, electrochemical detection  Furthermore, the modifications of these electrochemical immunosensors by utilizing various types of nanomaterials enable these systems to detect trace amount of target tumor markers. Hence, herein, we intend to review the selective works on electrochemical detection of various biomarkers using wide range of nanomaterials with a particular focus on graphene."
1752,The long non-coding RNA BC200 (BCYRN1) is critical for cancer cell survival and proliferation.,"Booy EP, McRae EK, Koul A, Lin F, McKenna SA.",https://pubmed.ncbi.nlm.nih.gov/28651607/," BC200 has a hypothesized role in translational regulation; however, to date the functional role of BC200 in both normal and diseased states remains poorly characterized.
    


           Subcellular fractionation was performed to assess BC200 distribution and efficient knock-down of BC200 was established using both locked nucleic acid (LNA) GapmeRs and conventional siRNAs. Cell viability following BC200 knockdown and overexpression was assessed by MTT assay and induction of apoptosis was monitored by Annexin V/PI staining and flow cytometry. Cell cycle arrest and synchronization were performed using serum withdrawal as well as the specific inhibitors Lovastatin, Thymidine, RO3306 and Nocodazole. Synchronization was monitored by fluorescent analysis of cellular DNA content by flow cytometry  Expression in cultured tumour cells was dramatically higher than corresponding normal tissue; however, expression in cultured primary cells was similar to that in immortalized and cancer cell lines. BC200 knockdown  A substantial decrease in BC200 expression was observed upon cell confluence or serum deprivation, as well as drug induced cell cycle arrest in G1 or G2 but not S- or M-phases. Upon release from cell cycle arrest, BC200 expression was recovered as cells entered S-phase, but did not follow a periodic expression pattern during synchronized progression through the cell cycle. This elevated expression was critical for the survival of proliferating cancerous and non-cancerous cells, but is dispensable upon senescence or cell cycle arrest.
    


          Conclusions:
        
      
      BC200 expression is elevated in proliferating cultured cells regardless of origin. In primary cells, expression is dramatically reduced upon cell cycle arrest by confluence, serum deprivation or chemical inhibition. The lethality of BC200 knockdown is restricted to actively proliferating cells, making it a promising therapeutic target for a broad spectrum of cancers."
1753,Milk/colostrum exosomes: A nanoplatform advancing delivery of cancer therapeutics.,"Wallen M, Aqil F, Spencer W, Gupta RC.",https://pubmed.ncbi.nlm.nih.gov/36963459/,"Chemotherapeutics continue to play a central role in the treatment of a wide variety of cancers. Conventional chemotherapy involving bolus intravenous doses  Attempts to deliver small drug molecules using liposomes, polymeric nanoparticles, micelles, lipid nanoparticles, etc. have produced limited nanoformulations for clinical use, presumably due to a lack of biocompatibility of the material, costs, toxicity, scalability, and/or lack of effective administration. Naturally occurring small extracellular vesicles, or exosomes, may offer a solution and a viable system for delivering cancer therapeutics. Combined with their inherent trafficking ability and versatility of cargo capacity, exosomes can be engineered to specifically target cancerous cells, thereby minimizing off-target effects, and increasing the efficacy of cancer therapeutics. Exosomal formulations have mitigated the toxic effects of several drugs in murine cancer models. In this article, we review studies related to exosomal delivery of both small molecules and biologics, including siRNA to inhibit specific gene expression, in the pursuit of effective cancer therapeutics. We focus primarily on bovine milk and colostrum exosomes as the cancer therapeutic delivery vehicles based on their high abundance, cost effectiveness, scalability, high drug loading, functionalization of exosomes for targeted delivery, and lack of toxicity. While bovine milk exosomes may provide a new platform for drug delivery, extensive comparison to other nanoformulations and evaluation of long-term toxicity will be required to fully realize its potential."
1754,Vascular virtual endoluminal visualization of invasive colorectal cancer on MDCT colonography.,"Iinuma G, Moriyama N, Satake M, Miyakawa K, Tateishi U, Uchiyama N, Akasu T, Fujii T, Kobayashi T.",https://pubmed.ncbi.nlm.nih.gov/15788593/,"
    


          Conclusion:
        
      
      By means of Hounsfield-transparency settings, we obtained virtual endoluminal images that show vascular structures and delineate invasive cancers of the colorectal wall, and we call these images ""vascular views."" Using this technique for contrast-enhanced MDCT colonography, we found that the increase in flow and pooling of blood related to angiogenesis of cancerous lesions is easy to identify and that this finding is useful in the detection of invasive colorectal cancers."
1755,"""The development tumor model"" to study and monitor the entire progression of both primary and metastatic tumors.",Brognaro E.,https://pubmed.ncbi.nlm.nih.gov/24213851/,"Glioblastoma multiforme and other malignant cancers  In order to find more effective treatments, it is necessary to cultivate a better understanding of the dynamics of tumor development in relation to both primary and secondary tumors. Although hand-held or digital caliper  This is not enough. To improve our knowledge of the biological characteristics that take place during tumor progression at both primary and metastatic sites, it is indispensable to develop an in vivo model which enables us to reproduce, from the beginning to the end of the cancer's natural history, what really happens in a patient affected by a solid tumor. The ideal tumor model must allow us to monitor all the stages of the tumor's development, both in the primary bulk and in secondary locations, by obtaining cells, biopsies as well as performing stainings on sections. In this paper, ""the development tumor model"", already proposed by the author to monitor the whole progression of the glioblastoma, is also applied to the study of all solid malignancies. It is a xenogeneic orthotopic transplantation model using human tumor-derived cells from the pre-hypoxic phase as transplanted material, which will be cultured in a neurobasal serum-free medium. By transplanting the same material at the same time (time zero) into a number of immunodeficient and genetically identical mice or rats, the model can be used to create a pool of twin animal transplant candidates under the same testing conditions. By sacrificing one animal a week (or choosing other intervals as needed) and performing multiple biopsies and stainings on sections, we can monitor the entire development of both the primary and secondary tumors. This may shed light on which specific cells and particular markers need to be focused on in order to develop innovative, valid therapeutic strategies."
1756,MicroRNA-21 identified as predictor of cancer outcome: a meta-analysis.,"Zhu W, Xu B.",https://pubmed.ncbi.nlm.nih.gov/25098165/,"
    


          Materials and  Data was extracted from studies in terms of baseline characteristics and key statistics such as hazard ratio (HR), 95% confidence interval (CI) and P value, which were utilized to calculate pooled effect size.
    


           Elevated mir-21 level was demonstrated to moderately predict poor overall survival (OS) (HR = 1.903, 95% CI: 1.713-2.113, P = 0.000) and disease-free survival (DFS) (HR = 1.574, 95% CI: 1.139-2.175, P = 0.006) by the fixed and random effect model respectively. Importantly, subgroup analysis disclosed significant association between increased mir-21 level in cancerous tissue and worse survival status. Furthermore, over-expression of mir-21 was an independent prognostic factor for non-small cell lung cancer (NSCLC) and pancreatic cancer patients, with the pooled HR being 2.153 (95% CI: 1.693-2.739, P = 0.000) and 1.976 (95% CI: 1.639-2.384, P = 0.000).
    


          Conclusions:
        
      
      Over-expression of mir-21, especially in cancerous tissue, was effectively predictive of worse prognosis in various carcinomas. Non-invasive circulating mir-21, however, exhibited modest ability to discriminate outcomes. Major concerns about mir-21 assay standardization and selection of specimen need to be fully addressed before its practical implementation in management of cancer."
1757,Genuine eradication of cancer.,Hirata Y.,https://pubmed.ncbi.nlm.nih.gov/8321158/,"As described previously by the author in Duplication mitosis in carcinoma (2), the established organoid continuity of cancer depends on duplication mitosis that cannot be converted to a maturation type of mitosis. This unconverted mitosis is based on certain cell conditions that are peculiar to carcinoma and rejects the effect of a maturation factor, which converts the duplication type of mitosis immediately to the maturation type. This cell abnormality must be dependent on the paralysis of a mitotic maturation promoting system (MMPS). In short, therapy aimed at the complete eradication of cancer must focus on this paralysis, rather than on the destruction of the cancerous cell. In the past, this paralysis has been completely neglected, although it does not appear to be an insurmountable subject for study. If this paralysis could be completely recovered, the cancerous cell would lose its duplication mitotic activity and established organoid continuity, thus allowing the genuine eradication of cancer to be achieved in the future."
1758,Early genetic changes during upper aerodigestive tract tumorigenesis.,"Hittelman WN, Voravud N, Shin DM, Lee JS, Ro JY, Hong WK.",https://pubmed.ncbi.nlm.nih.gov/8412199/,"Upper aerodigestive tract tumorigenesis has been hypothesized to represent a field cancerization process with multistep events based on its association with known carcinogens, its frequent associated premalignant lesions, and its multifocal clinical manifestation. To further explore this working hypothesis, we have examined normal tissue and premalignant lesions in the field of tumors for evidence of genetic change. Paraffin sections of head and neck tumors harboring neighboring premalignant lesions were explored for the presence of chromosome polysomies using in situ hybridization and chromosome-specific centromeric probes. Cells exhibiting random polysomy were observed in the premalignant regions near the tumors. The frequency of polysomy in the tumor field increased as the tissue progressed from normal morphology (33%), to hyperplasia (67%), to dysplasia (95%), and to squamous cell carcinoma (96%). These  To determine whether the degree of accumulated genetic alterations might serve as a biomarker for risk of developing malignancy, a set of biopsies of oral premalignant lesions (leukoplakia, erythroplakia) were retrospectively chosen for polysomy analysis from two groups of individuals: one group who subsequently developed oral cancer and one group who did not develop oral cancer. Three of the five individuals who showed significant chromosome polysomies in their biopsies subsequently developed oral cancer, whereas only one of eight individuals with little evidence of polysomy subsequently progressed to oral cancer. These "
1759,FHL1 on chromosome X is a single-hit gastrointestinal tumor-suppressor gene and contributes to the formation of an epigenetic field defect.,"Asada K, Ando T, Niwa T, Nanjo S, Watanabe N, Okochi-Takada E, Yoshida T, Miyamoto K, Enomoto S, Ichinose M, Tsukamoto T, Ito S, Tatematsu M, Sugiyama T, Ushijima T.",https://pubmed.ncbi.nlm.nih.gov/22689052/,"Tumor-suppressor genes on chromosome X can be inactivated by a single hit, any of the point mutations, chromosomal loss and aberrant DNA methylation. As aberrant DNA methylation can be induced frequently, we here aimed to identify a tumor-suppressor gene on chromosome X inactivated by promoter DNA methylation. Of 69 genes on chromosome X upregulated by treatment of a gastric cancer cell line with a DNA-demethylating agent, 5-aza-2'-deoxycytidine, 11 genes had low or no expression in the cell line and abundant expression in normal gastric mucosae. Among them, FHL1 was frequently methylation-silenced in gastric and colon cancer cell lines, and methylated in primary gastric (21/80) and colon (5/50) cancers. Knockdown of the endogenous FHL1 in two cell lines by two kinds of shRNAs significantly increased cell growth in vitro and sizes of xenografts in nude mice. Expression of exogenous FHL1 in a non-expressing cell line significantly reduced its migration, invasion and growth. Notably, a somatic mutation (G642T; Lys214Asn) was identified in one of 144 colon cancer specimens, and the mutant FHL1 was shown to lack its inhibitory effects on migration, invasion and growth. FHL1 methylation was associated with Helicobacter pylori infection and accumulated in normal-appearing gastric mucosae of gastric cancer patients. These data showed that FHL1 is a methylation-silenced tumor-suppressor gene on chromosome X in gastrointestinal cancers, and that its silencing contributes to the formation of an epigenetic field for cancerization."
1760,Association between trace elements in cancerous and non-cancerous tissues with the risk of breast cancers in western Iran.,"Mansouri B, Ramezani Z, Yousefinejad V, Nakhaee S, Azadi N, Khaledi P, Nikkhoo B, Hassanzadeh K, Rahimi A.",https://pubmed.ncbi.nlm.nih.gov/34545524/,"This study aimed to assess the tissue content of essential and toxic metals including lead (Pb), cadmium (Cd), arsenic (As), silver (Ag), aluminum (Al), chromium (Cr), copper (Cu), iron (Fe), selenium (Se), and zinc (Zn) in the breast cancerous tissues compared to the non-cancerous tissue. The biopsy specimens of 63 breast cancers along with 63 adjacent healthy tissues in Kurdistan Province, Iran, were collected from 2019 to 2020 and assayed using ICP-MS (Agilent 7900). The 05), while Zn was the only trace element with higher levels in healthy subjects (p < 0.05). Moreover, weak to moderate correlations between elements were observed in the cancerous group including Al-Cr (r=0.60), As-Cu (r=0.52), and Cu-Se (r=0.56). In contrast, no correlation over 0.50 was found between trace elements in the non-cancerous group. Raw risk differences (RDs) accounted for a significant effect for Pb, Cd, As, Ag, Cr, Se, and Zn on the development of breast cancer. In conclusion, elevated levels of As, Cd, Cu, Pb, and Se may contribute to enhancing the risk of breast cancer."
1761,Aldehyde dehydrogenase 1B1 (ALDH1B1) is a potential biomarker for human colon cancer.,"Chen Y, Orlicky DJ, Matsumoto A, Singh S, Thompson DC, Vasiliou V.",https://pubmed.ncbi.nlm.nih.gov/21216231/,"Aldehyde dehydrogenases (ALDHs) belong to a superfamily of NAD(P)+-dependent enzymes, which catalyze the oxidation of endogenous and exogenous aldehydes to their corresponding acids. Increased expression and/or activity of ALDHs, particularly ALDH1A1, have been reported to occur in human cancers. It is proposed that the metabolic function of ALDH1A1 confers the ""stemness"" properties to normal and cancer stem cells. Nevertheless, the identity of ALDH isozymes that contribute to the enhanced ALDH activity in specific types of human cancers remains to be elucidated. ALDH1B1 is a mitochondrial ALDH that metabolizes a wide range of aldehyde substrates including acetaldehyde and products of lipid peroxidation (LPO). In this study, we immunohistochemically examined the expression profile of ALDH1A1 and ALDH1B1 in human adenocarcinomas of colon (N=40), lung (N=30), breast (N=33) and ovary (N=33) using an NIH tissue array. The immunohistochemical expression of ALDH1A1 or ALDH1B1 in tumor tissues was scored by their intensity (scale=1-3) and extensiveness (% of total cancer cells). Herein we report a 5.6-fold higher expression score for ALDH1B1 in cancerous tissues than that for ALDH1A1. Remarkably, 39 out of 40 colonic cancer specimens were positive for ALDH1B1 with a staining intensity of 2.8±0.5. Our study demonstrates that ALDH1B1 is more profoundly expressed in the adenocarcinomas examined in this study relative to ALDH1A1 and that ALDH1B1 is dramatically upregulated in human colonic adenocarcinoma, making it a potential biomarker for human colon cancer."
1762,Suppression of glucose utilization of murine peritoneal exudate macrophages by body fluids from cancer patients and identification of the susceptible enzyme.,"Nakamura K, Nakajima Y, Nakamura Y.",https://pubmed.ncbi.nlm.nih.gov/2945958/,"The glucose consumption of cultured murine (C57BL/6N) peritoneal exudate macrophages is suppressed by pleural effusions, ascitic fluids, and sera from patients with advanced primary lung and gastric cancers. Analysis for the generation of 14C-labeled CO2 after [14C]glucose metabolism revealed the glycolysis pathway to be more susceptible to cancerous body fluids than was the hexose monophosphate shunt. Enzymatic analysis showed that the enzyme susceptible to the cancerous body fluids was D-fructose-6-phosphate 1-phosphotransferase (PFK), the rate-limiting key enzyme in the glycolysis pathway. Other enzymes participating in glycolysis were insensitive to the cancerous body fluids. Suppression of PFK may represent a new tumor marker."
1763,Quality of life of patients more than 1 year after surgery for thyroid cancer.,"Büttner M, Hinz A, Singer S, Musholt TJ.",https://pubmed.ncbi.nlm.nih.gov/32201929/,"Purpose:
        
      
      Patients with thyroid cancer are often assumed to have no quality of life (QOL) impairments after treatment because of thyroid cancer's good prognosis. However, the QOL implications of surgical complications and the necessity to take lifelong medication are seldom assessed.
    


           QOL was assessed using the EORTC QLQ-C30 and the thyroid cancer module EORTC QLQ-THY34. Multiple logistic regression was used to determine factors associated with a worse QOL compared with a general population.
    


           Patients with persistent/prolonged calcium or vitamin D intake reported worse QOL in the domains of global health, physical functioning, role functioning, emotional functioning, and insomnia than patients without current intake. Current calcium and vitamin D intake, higher education, living with a partner, and age had an effect on the odds of having worse QOL than the age- and sex-adjusted general population.
    


          Conclusion:
        
      
      Prolonged calcium and/or vitamin D intake are negatively associated with certain domains of QOL in thyroid cancer patients who are at least 1 year post surgery. Assessment of calcium and vitamin D and diagnosis of hypoparathyroidism are therefore important for the follow-up of thyroid cancer survivors since it may affect their QOL."
1764,Generation of cancerous neural stem cells forming glial tumor by oncogenic stimulation.,"Lee JS, Lee HJ, Moon BH, Song SH, Lee MO, Shim SH, Kim HS, Lee MC, Kwon JT, Fornace AJ Jr, Kim SU, Cha HJ.",https://pubmed.ncbi.nlm.nih.gov/21755312/,"Neural stem cells in the brain have been shown to be 'cells of origin' of certain brain cancers, most notably astrocytomas and medulloblastoma. In particular, in a mouse model, the targeting of genetic modifications for astrocytoma-relevant tumor suppressors to neural stem cells causes malignant astrocytoma to arise, thereby suggesting that astrocytoma is derived from neural stem cells. However, it remains to be determined whether this important finding is reproducible in humans. Herein, we generated cancerous neural stem cells by introducing a set of oncogenes to human fetal neural stem cells (hfNSCs). Serial genetic modification with v-myc for immortalization and consequent H-Ras for oncogenic stimulation with viral gene delivery proved sufficient to induce the transformation of hfNSCs. The Ras cells evidenced a variety of the hallmarks of brain cancer stem cells and most importantly were tumorigenic, forming brain cancers consisting of both a large number of differentiated and a very few undifferentiated populations of cells in an in vivo mouse model. On the contrary, oligodendrocytes derived from the v-myc expressing parent neural stem cells were not transformed by H-Ras, which suggests that neural stem cells may be more susceptible to cancerous transformation by a combination of oncogenes. We also determined that v-myc expressing fetal neural stem cells were defective in p53 response upon the "
1765,p53 and the pathogenesis of skin cancer.,"Benjamin CL, Ananthaswamy HN.",https://pubmed.ncbi.nlm.nih.gov/17270229/,"The p53 tumor suppressor gene and gene product are among the most diverse and complex molecules involved in cellular functions. Genetic alterations within the p53 gene have been shown to have a direct correlation with cancer development and have been shown to occur in nearly 50% of all cancers. p53 mutations are particularly common in skin cancers and UV irradiation has been shown to be a primary cause of specific 'signature' mutations that can  There are certain 'hot-spots' in the p53 gene where mutations are commonly found that  This review discusses the role of p53 from normal function and its dysfunction in pre-cancerous lesions and non-melanoma skin cancers. Additionally, special situations are explored, such as Li-Fraumeni syndrome in which there is an inherited p53 mutation, and the consequences of immune suppression on p53 mutations and the "
1766,Expression of type I interferon receptor as a predictor of clinical response to interferon-alpha therapy of gastrointestinal cancers.,"Ota H, Nagano H, Doki Y, Sekimoto M, Kondo M, Wada H, Nakamura M, Noda T, Damdinsuren B, Marubashi S, Miyamoto A, Takeda Y, Dono K, Umeshita K, Nakamori S, Wakasa K, Sakon M, Monden M.",https://pubmed.ncbi.nlm.nih.gov/16820899/,"Interferon (IFN) is used in the treatment of many malignancies and viral disorders. We recently reported a significant correlation between the efficacy of IFN-alpha combined with chemotherapy in the treatment of advanced hepatocellular carcinoma (HCC) and IFN-alpha/type I IFN receptor (IFNAR2) expression. It is possible that the expression of IFNAR2 in gastrointestinal cancerous tissue, apart from HCC, may predict the efficacy of IFN-alpha combination therapy. We investigated the expression of IFNAR2 in 100 gastrointestinal cancerous tissues. IFNAR2 expression was examined using immunohistochemistry, in surgically resected tissue samples (20 esophageal, 20 gastric, 20 colorectal, 20 cholangiocarcinoma, and 20 pancreatic samples). The expression rate of IFNAR2 was 35.0% (7/20), 25.0% (5/20), 20.0% (4/20), 45.0% (9/20), and 25.0% (5/20) in esophageal, gastric cancer, colorectal, cholangiocarcinoma and pancreatic cancer samples, respectively. In our previous report, the expression rate of IFNAR2 in HCC samples was 64.8% (59/91). Thus, the expression rates of IFNAR2 in the five types of gastrointestinal cancers tested here were low, compared with HCC. The clinical efficacy of IFN-alpha mono- or combination therapies in patients with gastrointestinal neoplasms is expected to be lower than in patients with HCC based on the expression level of IFNAR2."
1767,Clinical characteristics of synchronous colorectal cancers in Japan.,"Kato T, Alonso S, Muto Y, Noda H, Miyakura Y, Suzuki K, Tsujinaka S, Saito M, Perucho M, Rikiyama T.",https://pubmed.ncbi.nlm.nih.gov/27776528/," We studied the incidence and clinicopathological characteristics of Japanese patients with sCRCs who underwent surgery for primary CRC and received exhaustive perioperative surveillance.
    


           The associations of clinical and pathological factors with sCRC development were assessed by univariate and multivariate logistic regression.
    


          4 %) developed sCRCs, 16 of them (19.0 %) harboring three or more cancers. Companion sCRCs were smaller and earlier stage than the index lesion (P < 0.0001). In multivariate analysis, advanced age (odds ratio (OR) 1.03 per year; P = 0.009) and left colon tumor location (OR 1.78; P = 0.013) are associated with higher risk of sCRCs, particularly in females. Overall survival did not differ between solitary CRC and sCRC (P = 0.62).
    


          Conclusions:
        
      
      Our  The incidence of sCRC, and notably of triple or more sCRCs, was higher than previously recognized. Because they are also significantly higher than expected by merely stochastic accumulation of individual cancerous lesions, we suggest that the occurrence of many sCRC reflects a hitherto uncharacterized predisposition condition."
1768,Lower connectivity of tumor coexpression networks is not specific to cancer.,"Dalgıç E, Konu Ö, Öz ZS, Chan C.",https://pubmed.ncbi.nlm.nih.gov/31156157/,"Global level network analysis of molecular links is necessary for systems level view of complex diseases like cancer. Using genome-wide expression datasets, we constructed and compared gene co-expression based specific networks of pre-cancerous tumors (adenoma) and cancerous tumors (carcinoma) with paired normal networks to assess for any possible changes in network connectivity. Previously, loss of connectivity was reported as a characteristics of cancer samples. Here, we observed that pre-cancerous conditions also had significantly less connections than paired normal samples. We observed a loss of connectivity trend for colorectal adenoma, aldosterone producing adenoma and uterine leiomyoma. We also showed that the loss of connectivity trend is not specific to positive or negative correlation based networks. Differential hub genes, which were the most highly differentially less connected genes in tumor, were mostly different between different datasets. No common gene list could be defined which underlies the lower connectivity of tumor specific networks. Connectivity of colorectal cancer methylation targets was different from other genes. Extracellular space related terms were enriched in negative correlation based differential hubs and common methylation targets of colorectal carcinoma. Our  This systems level behavior could not be attributed to a group of genes."
1769,"The cell surface glycoprotein CDCP1 in cancer--insights, opportunities, and challenges.","Wortmann A, He Y, Deryugina EI, Quigley JP, Hooper JD.",https://pubmed.ncbi.nlm.nih.gov/19514048/,"In the last few years dysregulated expression of the cell surface glycoprotein CUB domain-containing protein 1 (CDCP1) has been associated with several cancers and this cell surface molecule has been recognized both as a tumor marker and as a potential target to disrupt progression of cancer. Here we summarize what is known about CDCP1 including its structural features, expression in normal and cancerous tissues, and the in vitro  We conclude by highlighting opportunities and challenges in targeting CDCP1 in cancer."
1770,"RPS13, a potential universal reference gene for normalisation of gene expression in multiple human normal and cancer tissue samples.","Rashid M, Shah SG, Natu A, Verma T, Rauniyar S, Gera PB, Gupta S.",https://pubmed.ncbi.nlm.nih.gov/34657252/," However, these gene associates with different biological processes, and hence expression vary in different pathological conditions. Therefore, in the present study, eight different reference genes were used and compared to identify common reference gene usable for an array of different cell types and human cancers.
    


           Ribosomal protein S13 (RPS13) was found to be a common and stable reference gene across intra- and inter-comparison between various normal and tumor tissue types. Further, TCGA data analysis across and between normal and tumor tissue types also showed minimum deviation in expression of RPS13 gene out of eight routinely used reference genes.
    


          Conclusion:
        
      
      RPS13 is the common stable reference gene in normalization for gene expression based analysis in cancer research."
1771,Combining Raman spectroscopy and machine learning to assist early diagnosis of gastric cancer.,"Li C, Liu S, Zhang Q, Wan D, Shen R, Wang Z, Li Y, Hu B.",https://pubmed.ncbi.nlm.nih.gov/36368293/,"Gastric cancers, with gastric adenocarcinoma (GAC) as the most common histological type, cause quite a few of deaths. In order to improve the survival rate after GAC treatment, it is important to develop a  Raman spectroscopy is a potential tool for probing cancer cell due to its real-time and non-destructive measurements without any additional reagents. In this study, we use Raman spectroscopy to examine GAC samples, and distinguish cancerous gastric mucosa from normal gastric mucosa. Average Raman spectra of two groups show differences at 750 cm-1, 1004 cm-1, 1449 cm-1, 1089-1128 cm-1, 1311-1367 cm-1 and 1585-1665 cm-1, These peaks were assigned to cytochrome c, phenylalanine, phospholipid, collagen, lipid, and unsaturated fatty acid respectively. Furthermore, we build a SENet-LSTM model to realize the automatic classification of cancerous gastric mucosa and normal gastric mucosa, with all preprocessed Raman spectra in the range of 400-1800 cm-1 as input. An accuracy 96.20% was achieved. Besides, by using masking  The  All "
1772,Minimal residual disease in head and neck cancer.,"Gath HJ, Brakenhoff RH.",https://pubmed.ncbi.nlm.nih.gov/10505550/,"Squamous cell carcinoma of the head and neck (HNSCC) is a complex disease. Patients with more advanced stages are treated with curative intent by a combination of surgery and radiotherapy, but still about 50% develop a relapse: locally, regionally and at distant sites. This clinical outcome strongly indicates that small histologically undetectable tumor deposits remain at these sites: 'minimal residual disease'. In this article the different aspects related to minimal residual head and neck cancer will be reviewed shortly. The management of patients with head and neck cancer as well as the clinical problems in diagnosis and treatment will be described. The crucial role of minimal residual disease in head and neck cancer will be defined and diagnostic approaches to address the problem will be reviewed. We argue that the infiltration and dissemination of HNSCC takes place beyond the level of histopathological detection, and further that molecular staging will at least in part fill in the gap between anatomical TNM staging and the clinical outcome. However, it is not only the presence of infiltrated or disseminated tumor cells that will determine the prognosis. Also the biological characteristics of the tumor cells at the various sites are important for the clinical follow-up. Promising therapeutic approaches to deal with minimal residual disease will be discussed shortly. Finally the issues 'field cancerization' and second primary tumors in head and neck cancer are addressed as these are closely linked to local recurrence and distant metastases. Moreover, second primary tumors will gain more importance when the primary disease and the frequency of relapses are better controlled."
1773,Circular RNAs: epigenetic regulators in cancerous and noncancerous skin diseases.,"Abi A, Farahani N, Molavi G, Gheibi Hayat SM.",https://pubmed.ncbi.nlm.nih.gov/31477805/,"The most frequent kind of malignancy in the universe is skin cancer, which has been categorized into non-melanoma and melanoma skin cancer. There are no complete information of the skin carcinogenesis process. A variety of external and internal agents contribute to the non-melanoma and melanoma skin cancer pathogenesis. These factors are epigenetic changes, X-rays, genetic, arsenic compounds, UV rays, and additional chemical products. It was found that there could be a relationship between the appearing novel and more suitable therapies for participants in this class of diseases and detection of basic molecular paths. A covalently closed loop structure bond connecting the 5' and 3' ends characterizes a new group of extensively expressed endogenous regulatory RNAs, which are called circular RNAs (circRNAs). Mammals commonly express circRNAs. They are of high importance in tumorigenesis. Multiple lines evidence indicated that a variety of circular RNAs are associated with initiation and development of skin-related diseases such as skin cancers. Given that different circular RNAs (hsa_circ_0025039, hsa_circRNA006612, circRNA005537, and circANRIL) via targeting various cellular and molecular targets (e.g., CDK4, DAB2IP, ZEB1, miR-889, and let-7c-3p) exert their effects on skin cancers progression. Herein, for first time, we summarized different circular RNAs in skin cancers and noncancerous diseases. Moreover, we highlighted crosstalk between circular RNAs and ceRNAs in cancerous conditions."