doi stringlengths 13 36 | title stringlengths 37 233 | abstract stringlengths 0 9.8k | fulltext_sections listlengths 1 127 | fulltext_additional listlengths 0 19 |
|---|---|---|---|---|
10.5114/aoms.2015.53289 | Systematic review/Meta-analysis The role of gender in patients with diffuse large B cell lymphoma treated with rituximab-containing regimens: a meta-analysis | Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). Although gender has not been included in prognostic systems, male gender has been found as a bad prognostic indicator in Hodgkin lymphoma, follicular lymphoma and chronic lymphocytic leukemia. The relationship between gender and prognosis is not clear in patients with DLBCL treated with rituximab-containing regimens. The aim of this meta-analysis is to determine the prognostic/predictive role of gender in patients with DLBCL treated with rituximab-containing regimens.We systematically searched for studies investigating the relationships between gender and prognosis in DLBCL treated with rituximab-containing regimens. After careful review, survival data were extracted from eligible studies. A meta-analysis was performed to generate combined hazard ratios for overall survival, disease-free survival (DFS) and event-free survival (EFS).A total of 5635 patients from 20 studies were included in the analysis. Our results showed that male gender was associated with poor prognosis in terms of overall survival (OS) (hazard ratio (HR) = 1.155; 95% confidence interval (CI): 1.037-1.286; p < 0.009). The pooled hazard ratio for DFS and EFS showed that male gender was not statistically significant (HR = 1.219; 95% CI: 0.782-1.899; p = 0.382, HR = 0.809; 95% CI: 0.577-1.133; p = 0.217).The present meta-analysis indicated male gender to be associated with a poor prognosis in patients with DLBCL treated with rituximab-containing regimens. | [
{
"section_content": "age, performance score, stage, proliferation fraction and gene expression profiles [3, 4]. Today, the International Prognostic Index (IPI) and age-adjusted International Prognostic Index (aaIPI) are the most important scores used in daily practice to determine the prognosis and treatment s... | [
{
"section_content": "",
"section_name": "Conflict of interest",
"section_num": null
},
{
"section_content": "The authors declare no conflict of interest.",
"section_name": "Conflict of interest",
"section_num": null
},
{
"section_content": "",
"section_name": "R e f e r e n ... |
10.31557/apjcp.2022.23.9.3229 | Interleukin-10-1082A>G (rs1800896) Single Nucleotide Polymorphism is Not a Risk Factor of Chronic Lymphocytic Leukemia in Sudanese Population | Objectif : La présente étude a été menée pour examiner l'association entre le polymorphismeIL-10-1082A >G (rs 1800896) et le risque de leucémie lymphoïde chronique et pour évaluer la corrélation entre ce polymorphisme et les caractères clinicopathologiques. Méthodes : Une étude cas-témoins a été menée dans l'État de Khartoum, au Soudan, entre avril 2017 et avril 2018, auprès de 110 patients atteints de LLC et de 80 volontaires sains en tant que groupe témoin. Un examen physique, une numération formule sanguine complète et un immunophénotype ont été effectués chez tous les patients pour confirmer le diagnostic. La stadification clinique telle que Rai et Binet a été étudiée. CD38 et ZAP70 ont été réalisés par cytométrie de flux. Des échantillons de sang ont été prélevés chez tous les participants ; l'ADN a été extrait à l'aide du kit d'extraction d'ADN sanguin ANALYTIKJENA et analysé le polymorphisme IL-10-1082A >G à l'aide de la réaction en chaîne de la polymérase spécifique de l'allèle. L'analyse statistique a été réalisée à l'aide d'un progiciel statistique pour la version 23.0 du logiciel des sciences sociales. Résultats : La fréquence des génotypes AA, AG et GG était de 32,7 %, 55,5 % et 11,8 % pour le groupe de patients et de 31,25 %, 51,25 % et 17,5 % dans le groupe témoin, respectivement. Le génotype de l'IL-10 (-1082A>G) n'était pas associé à la sensibilité de la LLC dans notre population. L'étude a montré que l'allèle G du gène IL-10 (-1082A >G) est associé au sexe masculin. Cependant, aucune association significative n'a été trouvée entre le génotype -1082A >G et les caractères clinicopathologiques. Conclusion : Nos résultats ne supportent pas l'implication du polymorphisme du gène promoteur IL-10 − 1082A >G dans la susceptibilité accrue à la LLC. L'allèle IL-10-1082G (IL-10-1082AG ou IL-10-1082GG) a été trouvé plus fréquemment chez les hommes. De plus, aucune association n'a été observée entre le polymorphisme IL-10-1082A >G et les systèmes de stades cliniques ainsi que les marqueurs de mauvais pronostic établis. Enfin, au sein du groupe de patients atteints de LLC, il n'y avait pas de différence entre l'âge au diagnostic et les paramètres hématologiques en fonction des distributions génotypiques. | [
{
"section_content": "Chronic lymphocytic leukemia is characterized by the progressive accumulation of monoclonal, small, mature-appearing CD5 + B-cells in the peripheral blood, bone marrow, and secondary lymphoid tissue (Caligaris-Cappio and Hamblin, 1999). Genetic variation of some immunomodulatory cytokine m... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "We would like to thank the staff of the Hematology Department at Al Neelain University for facilities and supporting and we are grateful to the staff of Flow Cytometry Laboratory for Leukemia... |
10.3892/ijo.2012.1528 | Epimutation and cancer: A new carcinogenic mechanism of Lynch syndrome | Epimutation is defined as abnormal transcriptional repression of active genes and/or abnormal activation of usually repressed genes caused by errors in epigenetic gene repression. Epimutation arises in somatic cells and the germline, and constitutional epimutation may also occur. Epimutation is the first step of tumorigenesis and can be a direct cause of carcinogenesis. Cancers associated with epimutation include Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC), chronic lymphocytic leukemia, breast cancer and ovarian cancer. Epimutation has been shown for many tumor suppressor genes, including RB, VHL, hMLH1, APC and BRCA1, in sporadic cancers. Methylation has recently been shown in DNA from normal tissues and peripheral blood in cases of sporadic colorectal cancer and many studies show constitutive epimutation in cancers. Epimutation of DNA mismatch repair (MMR) genes (BRCA1, hMLH1 and hMSH2) involved in development familial cancers has also been found. These results have led to a focus on epimutation as a novel oncogenic mechanism. | [
{
"section_content": "",
"section_name": "Recommendation",
"section_num": null
},
{
"section_content": "",
"section_name": "Reasons for Recommendation",
"section_num": null
}
] | [
{
"section_content": "",
"section_name": "Additional Comments",
"section_num": null
},
{
"section_content": "Submission of this form allows Spandidos Publications to contact your institution regarding this recommendation. If you do not want Spandidos Publications to contact your institution, thi... |
10.7554/elife.98747.3 | The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation | <jats:p>The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.</jats:p> | [
{
"section_content": "The skin is a vital organ that acts as a protective barrier against the external environment, and safeguards against fluid loss. An important component of this barrier function is the presence of a complex mixture of oils, known as sebum, which is produced by the SGs. SGs are part of the e... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We are grateful to C Cottonham, S Hankeova, and G Hernandez for their helpful discussions. We thank the Genentech Research Pathology, Necropsy, and Histology laboratories for their experimen... |
10.1186/s13000-017-0634-3 | Detection of 22 common leukemic fusion genes using a single-step multiplex qRT-PCR-based assay | Fusion genes generated from chromosomal translocation play an important role in hematological malignancies. Detection of fusion genes currently employ use of either conventional RT-PCR methods or fluorescent in situ hybridization (FISH), where both methods involve tedious methodologies and require prior characterization of chromosomal translocation events as determined by cytogenetic analysis. In this study, we describe a real-time quantitative reverse transcription PCR (qRT-PCR)-based multi-fusion gene screening method with the capacity to detect 22 fusion genes commonly found in leukemia. This method does not require pre-characterization of gene translocation events, thereby facilitating immediate diagnosis and therapeutic management.We performed fluorescent qRT-PCR (F-qRT-PCR) using a commercially-available multi-fusion gene detection kit on a patient cohort of 345 individuals comprising 108 cases diagnosed with acute myeloid leukemia (AML) for initial evaluation; remaining patients within the cohort were assayed for confirmatory diagnosis. Results obtained by F-qRT-PCR were compared alongside patient analysis by cytogenetic characterization.Gene translocations detected by F-qRT-PCR in AML cases were diagnosed in 69.4% of the patient cohort, which was comparatively similar to 68.5% as diagnosed by cytogenetic analysis, thereby demonstrating 99.1% concordance. Overall gene fusion was detected in 53.7% of the overall patient population by F-qRT-PCR, 52.9% by cytogenetic prediction in leukemia, and 9.1% in non-leukemia patients by both methods. The overall concordance rate was calculated to be 99.0%. Fusion genes were detected by F-qRT-PCR in 97.3% of patients with CML, followed by 69.4% with AML, 33.3% with acute lymphoblastic leukemia (ALL), 9.1% with myelodysplastic syndromes (MDS), and 0% with chronic lymphocytic leukemia (CLL).We describe the use of a F-qRT-PCR-based multi-fusion gene screening method as an efficient one-step diagnostic procedure as an effective alternative to lengthy conventional diagnostic procedures requiring both cytogenetic analysis followed by targeted quantitative reverse transcription (qRT-PCR) methods, thus allowing timely patient management. | [
{
"section_content": "Fusion genes are genetic chromosomal aberrations formed by the juxtaposition of two disparate gene loci through chromosomal translocation, interstitial deletion, or inversion and is most frequently detected through cytogenetic abnormalities. Although hundreds of fusion genes have been asso... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "Not applicable.",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "",
"section_name": "Funding",
"section_num": null
},
{
"sec... |
10.1038/s41467-024-46547-7 | Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation | <jats:title>Abstract</jats:title><jats:p>Myelodysplastic syndromes (MDS) with mutated <jats:italic>SF3B1</jats:italic> gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes <jats:italic>SRSF2</jats:italic> or <jats:italic>U2AF1</jats:italic>. Molecular bases of these divergences are poorly understood. Here we find that <jats:italic>SF3B1</jats:italic>-mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in <jats:italic>U2AF1</jats:italic>- or <jats:italic>SRSF2</jats:italic>-mutated MDS. Compared to erythroblasts from <jats:italic>SRSF2-</jats:italic> or <jats:italic>U2AF1</jats:italic>-mutated patients, <jats:italic>SF3B1</jats:italic>-mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves <jats:italic>SF3B1</jats:italic>-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of <jats:italic>SF3B1</jats:italic>-mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.</jats:p> | [
{
"section_content": "term treatment [6] [7] [8]. Deciphering the mechanisms of anemia is needed to generate treatments. \n\nSF3B1 mutation causes multiple alterations in mRNA processing. The use of alternative 3′ or 5′ splice site produces transcripts containing short intronic sequences that are degraded by th... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "The authors dedicate this work to the memory of their colleague Dr Angelos Constantinou whose discoveries inspired this work. The authors acknowledge Pr Seishi Ogawa ( Kyoto University, Japa... |
10.1186/2045-824x-3-17 | Therapeutic promise and challenges of targeting DLL4/NOTCH1 | DLL4-mediated NOTCH1 signaling represents an essential pathway for vascular development and has emerged as an attractive target for angiogenesis-based cancer therapies. However, newly reported toxicity findings raise safety concerns of chronic pathway blockade. Lessons learned from the development of γ-secretase inhibitors (GSIs) might offer insights into how to safely harness this important signaling pathway. | [
{
"section_content": "In metazoans, the evolutionarily conserved NOTCH pathway functions as an essential mechanism to regulate numerous cell fate/lineage decisions during embryogenesis, postnatal development, and in the maintenance of adult tissue homeostasis. NOTCH receptors are normally constrained in a dorma... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "The author would like to thank Weilan Ye, Jessica Couch and Kevin Leong for valuable suggestions and critical reading of the manuscript.",
"section_name": "Acknowledgements",
"sectio... |
10.18632/oncotarget.13712 | Humoral immune responses toward tumor-derived antigens in previously untreated patients with chronic lymphocytic leukemia | In chronic lymphocytic leukemia (CLL) the occurrence and the impact of antibody responses toward tumor-derived antigens are largely unexplored. Our serological proteomic data show that antibodies toward 47 identified antigens are detectable in 29 out of 35 patients (83%) with untreated CLL. The glycolytic enzyme alpha-enolase (ENO1) is the most frequently recognized antigen (i.e. 54% of CLL sera). We show that ENO1 is upregulated in the proliferating B-cell fraction of CLL lymph nodes. In CLL cells of the peripheral blood, ENO1 is exclusively expressed at the intracellular level, whereas it is exposed on the surface of apoptotic leukemic cells.From the clinical standpoint, patients with progressive CLL show a higher number of antigen recognitions compared to patients with stable disease. Consistently, the anti-ENO1 antibodies are prevalent in sera from patients with progressive disease and their presence is predictive of a shorter time to first treatment. This clinical inefficacy associates with the inability of patients' sera to trigger complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity against leukemic cells.Together, these results indicate that antibody responses toward tumor-derived antigens are frequently detectable in sera from patients with CLL, but they are expression of a disrupted immune system and unable to hamper disease progression. | [
{
"section_content": "Immune dysfunctions are a key feature of chronic lymphocytic leukemia (CLL) and frequently result in clinically manifest complications contributing to patients' morbidity and mortality, such as opportunistic infections and autoimmune conditions. The impairment of the host immune system als... | [
{
"section_content": "",
"section_name": "CONFLICTS OF INTEREST",
"section_num": null
},
{
"section_content": "",
"section_name": "Authorship contributions",
"section_num": null
}
] |
10.1371/journal.pone.0004434 | Tumorigenic Potential of Olfactory Bulb-Derived Human Adult Neural Stem Cells Associates with Activation of TERT and NOTCH1 | Multipotent neural stem cells (NSCs) have been isolated from neurogenic regions of the adult brain. Reportedly, these cells can be expanded in vitro under prolonged mitogen stimulation without propensity to transform. However, the constitutive activation of the cellular machinery required to bypass apoptosis and senescence places these cells at risk for malignant transformation.Using serum-free medium supplemented with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), we established clonally derived NS/progenitor cell (NS/PC) cultures from the olfactory bulb (OB) of five adult patients. The NS/PC cultures obtained from one OB specimen lost growth factor dependence and neuronal differentiation at early passage. These cells developed glioblastoma tumors upon xenografting in immunosuppressed mice. The remaining NS/PC cultures were propagated either as floating neurospheres or as adherent monolayers with maintenance of growth factor dependence and multipotentiality at late passage. These cells were engrafted onto the CNS of immunosuppressed rodents. Overall, the grafted NS/PCs homed in the host parenchyma showing ramified morphology and neuronal marker expression. However, a group of animals transplanted with NS/PCs obtained from an adherent culture developed fast growing tumors histologically resembling neuroesthesioblastoma. Cytogenetic and molecular analyses showed that the NS/PC undergo chromosomal changes with repeated in vitro passages under mitogen stimulation, and that up-regulation of hTERT and NOTCH1 associates with in vivo tumorigenicity.Using culturing techniques described in current literature, NS/PCs arise from the OB of adult patients which in vivo either integrate in the CNS parenchyma showing neuron-like features or initiate tumor formation. Extensive xenografting studies on each human derived NS cell line appear mandatory before any use of these cells in the clinical setting. | [
{
"section_content": "Due to their ability to self-renew and to differentiate towards the neuronal phenoype, human adult neural stem cells (NSCs) provide an attractive tool for transplantation-based therapy of neurodegenerative diseases that avoids the ethical issues raised by the use of human embryos. However,... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "We thank Teresa M. Natale for her contribution in karyotype analysis.",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "This work was supported... |
10.1038/s41467-018-04283-9 | NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence | <jats:title>Abstract</jats:title><jats:p>Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes. We have recently identified that NOTCH1 can drive ‘lateral induction’ of a unique senescence phenotype in adjacent cells by specifically upregulating the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells exhibit a massive increase in chromatin accessibility. NOTCH signalling suppresses SAHF and increased chromatin accessibility in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, drive similar chromatin architectural changes in adjacent cells through cell–cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in multiple human cancers. Thus, HMGA1 is involved not only in SAHFs but also in RIS-driven chromatin accessibility. In conclusion, this study identifies that the JAG1–NOTCH–HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.</jats:p> | [
{
"section_content": "ellular senescence is an autonomous tumour-suppressor mechanism that can be triggered by pathophysiological stimuli including replicative exhaustion, exposure to chemotherapeutic drugs and hyper-activation of oncogenes, such as RAS 1. Persistent cell cycle arrest is accompanied by diverse ... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We thank all members of the Narita laboratory for helpful discussions, M. de la Roche for reagents and staff of the Cancer Research UK Cambridge Institute core facilities for technical suppo... |
10.1186/s40164-016-0036-3 | New CD20 alternative splice variants: molecular identification and differential expression within hematological B cell malignancies | CD20 is a B cell lineage-specific marker expressed by normal and leukemic B cells and targeted by several antibody immunotherapies. We have previously shown that the protein from a CD20 mRNA splice variant (D393-CD20) is expressed at various levels in leukemic B cells or lymphoma B cells but not in resting, sorted B cells from the peripheral blood of healthy donors.Western blot (WB) analysis of B malignancy primary samples showed additional CD20 signals. Deep molecular PCR analysis revealed four new sequences corresponding to in-frame CD20 splice variants (D657-CD20, D618-CD20, D480-CD20, and D177-CD20) matching the length of WB signals. We demonstrated that the cell spliceosome machinery can process ex vivo D480-, D657-, and D618-CD20 transcript variants by involving canonical sites associated with cryptic splice sites. Results of specific and quantitative RT-PCR assays showed that these CD20 splice variants are differentially expressed in B malignancies. Moreover, Epstein-Barr virus (EBV) transformation modified the CD20 splicing profile and mainly increased the D393-CD20 variant transcripts. Finally, investigation of three cohorts of chronic lymphocytic leukemia (CLL) patients showed that the total CD20 splice variant expression was higher in a stage B and C sample collection compared to routinely collected CLL samples or relapsed refractory stage A, B, or C CLL.The involvement of these newly discovered alternative CD20 transcript variants in EBV transformation makes them interesting molecular indicators, as does their association with oncogenesis rather than non-oncogenic B cell diseases, differential expression in B cell malignancies, and correlation with CLL stage and some predictive CLL markers. This potential should be investigated in further studies. | [
{
"section_content": "CD20 protein was highlighted in 1980 as a B lymphocyte-specific cell-surface antigen expressed in all stages of B cell ontogenesis except for early pro-B cells and plasma cells [1]. Despite no identified ligands, CD20 functions were investigated, and studies assigned it a role in cell diff... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "The authors thank Dr. Alain Coaquette ( Service de virology, CHU Besançon, France ) for providing post-transplant EBV samples, Dr. Bernard Royer ( INSERM UMR1098 ) for assistance with statis... |
10.21203/rs.3.rs-2175987/v1 | The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma | <jats:title>Abstract</jats:title> <jats:p>Background Cancer associated fibroblasts (CAFs), an important component of the tumor microenvironment (TME), play crucial roles in tumor stemness. Stanniocalcin-1 (STC1) was found secreted by CAFs in various cancers, but its main source and its role in hepatocellular carcinoma (HCC) was still unclear. Methods The serum and intracellular expression levels of STC1 were detected by ELISA and western blot. The role of CAFs-derived STC1 in HCC stemness was probed by sphere formation, sorafenib resistance, colony formation, and transwell migration and invasion assays in vitro and orthotopic liver xenograft tumor model in vivo. An HCC tissue microarray containing 72 samples was used to identify the STC1 and the Notch1 in HCC tissues. Co-immunoprecipitation (CoIP) and dual-luciferase reporter assay were performed to further explore the underlying mechanisms. ELISA assays were used to detect the serum concentration of STC1 in HCC patients. Results We demonstrated that CAFs were the main source of STC1 in HCC and that CAFs-derived STC1 promoted HCC stemness through the activation of the Notch signaling pathway. In HCC patients, the expression of STC1 was positively correlated with poor prognosis and the Nocth1 expression. Co-IP assay showed that STC1 directly bound to Notch1 receptors to activate the Notch signaling pathway, thereby promoting the stemness of HCC. Our data further demonstrated that STC1 was a direct transcriptional target of CSL in HCC cells. Furthermore, ELISA revealed that the serum STC1 concentration was higher in patients with advanced liver cancer than patients with early liver cancer. Conclusions CAFs-derived STC1 promoted HCC stemness via the Notch signaling pathway. STC1 might serve as a potential biomarker for the prognostic assessment of HCC, and the stromal-tumor amplifying STC1-Notch1 feedforward signal could provide an effective therapeutic target for HCC patients.</jats:p> | [
{
"section_content": "As the fourth leading cause of cancer death, liver cancer causes a great burden on global health [1]. Hepatocellular carcinoma (HCC), which accounts for about 80% of all primary liver cancer, is a highly heterogeneous disease caused by multiple etiologies and has a low long-term survival r... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "We sincerely thank Menghan Sha and Mengjia Jing from the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology for their help of animal experiments and mechan... |
10.5334/jbsr.2475 | Neurotoxoplasmosis in a Patient with Chronic Lymphocytic Leukemia | Teaching Point: Neurotoxoplasmosis should be part of the differential diagnosis for single or multiple cerebral lesions in hematologic patients. | [
{
"section_content": "Neurotoxoplasmosis is the most aggressive presentation of toxoplasmosis and is associated with high mortality. It usually occurs in immunocompromised patients, with hematologic patients representing an emerging group at risk. We describe a case of neurotoxoplasmosis in a HIV-negative patie... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGEMENTS",
"section_num": null
},
{
"section_content": "We thank Delrée Paul ( Department of Pathology, Institute of Pathology and Genetics, Gosselies ) who provided histopathological illustration.",
"section_name": "ACKNOWLEDGEMENTS",
"s... |
10.1038/s41467-020-16276-8 | Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours | <jats:title>Abstract</jats:title><jats:p>Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline <jats:italic>MBD4</jats:italic> mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (<jats:italic>GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX</jats:italic>). We identify three other significantly mutated genes (<jats:italic>TP53</jats:italic>, <jats:italic>RPL5</jats:italic> and <jats:italic>CENPE</jats:italic>).</jats:p> | [
{
"section_content": "veal melanoma (UM) arises from melanocytes in the uveal tract, and though less common than cutaneous melanoma, a higher proportion of UM patients die from the disease [1] [2] [3]. Risk determination of metastatic spread can be obtained through assessment of specific chromosome copy number ... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We are indebted to the patients and their families for their participation and support of this study, and the many clinicians and allied health professionals involved in their management. We... |
10.1007/s12471-015-0649-x | Bicuspid aortic valve; optimal diagnosis and latest interventional treatment | Bicuspid aortic valve (BAV) is one of the most common congenital heart defects with a population prevalence of 0.5 to 1.3 % [1]. The defect is considered to be a heritable disorder with a family recurrence rate of approximately 35 %. Recent studies show that mutations in the NOTCH1 gene are associated with BAV [2]. BAV progresses more rapidly into regurgitation or stenosis of the valve [3]. This results in a higher occurrence of aortic valve replacement, especially at younger age. Additionally, BAV is more susceptible than a tricuspid aortic valve (TAV) to nest bacteria or other organisms, leading to endocarditis. BAV is not only a peculiar valve morphology leading to specific valve pathology, it is also frequently associated with (asymptomatic) ascending aorta dilatation which leads to an increased susceptibility to ascending aortic aneurysms and aortic dissection [4]. Aortic elasticity measurements of BAV patients suggest that diminished aortic elasticity is at least part of its causation. | [
{
"section_content": "in BAV patients more frequently than echocardiography (96 versus 73 %); CMR appeared to be more sensitive for detecting of BAV whereas echocardiography appeared to be more specific. Among unselected patients with severe aortic valve stenosis, a high percentage of patients with BAV was foun... | [] |
10.12669/pjms.36.3.541 | Prognostic markers in Chronic Lymphocytic Leukaemia - A flow cytometric analysis | <jats:p>Objective: To find out the frequency of ZAP-70, CD38 and CD49d in patients diagnosed with CLL in our population.
 Methods: This is a cross sectional study conducted in Army Medical College in collaboration with Armed Forces Institute of Pathology and Military Hospital Rawalpindi from 1st January 2018 to 30th November 2018. Permission from Institutional Ethical Committee was obtained. Blood samples were collected by non-probability consecutive sampling technique and analyzed for blood counts and flow cytometry was done for ZAP-70, CD38 and CD49d. Manufacturer’s instructions for the kits were strictly followed.
 Results: Fifty-one newly diagnosed patients with CLL were studied for the prognostic markers in CLL. CD 38 was expressed in 25(49%) and CD49d in 21(41.2%). ZAP-70 expression was not detected in our series of patients.
 Conclusion: We conclude that CD38 and CD49d expression was detected in almost half of the patients of CLL in our series. CD49d showed statistically positive correlation with CD38, showing that it is a more pragmatic choice for reliable prognostication of CLL along with CD38.
 doi: https://doi.org/10.12669/pjms.36.3.541
 How to cite this:Haq H, Uddin N, Khan SA, Sunia Ghaffar4. Prognostic markers in Chronic Lymphocytic Leukaemia - A flow cytometric analysis. Pak J Med Sci. 2020;36(3):338-343. doi: https://doi.org/10.12669/pjms.36.3.541
 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</jats:p> | [
{
"section_content": "Chronic Lymphocytic Leukemia (CLL) is characterized by accumulation of small mature looking, ineffectual, CD5+ B-cells in the peripheral blood, bone marrow and secondary lymphoid tissues. 1 These cells have a characteristic immunophenotype i. e. CD19+, CD20+ and CD23+ with relatively low e... | [
{
"section_content": "",
"section_name": "Conflict of interest:",
"section_num": null
},
{
"section_content": "There is no conflict of interest among the authors.",
"section_name": "Conflict of interest:",
"section_num": null
},
{
"section_content": "",
"section_name": "Sourc... |
10.1186/1742-6405-11-38 | Expression of activating receptors on natural killer cells from AIDS-related lymphoma patients | Abnormal NK phenotype and cytotoxic functions have been described in acute myeloid leukemia, chronic lymphocytic leukemia, myeloma and myelodysplastic syndromes. Defective NK cytotoxicity is due to decreased expression of the Natural Cytotoxicity Receptors (NCRs), 2B4/CD244/p38, or NKG2D. This prompted us to test the expression of these molecules on circulating NK cells from patients with AIDS-related lymphomas (RL) in comparison with HIV + patients without lymphoma, healthy subjects and HIV-negative patients with lymphoma.Blood samples were analyzed by flow cytometry for NCRs, 2B4/CD244/p38 and NKG2D expression on NK cells defined as CD3-/CD56+ lymphocytes. We also analyzed by quantitative PCR specific RNA for NKp30/NCR3 and NKp46/NCR1.We could not detect any defect in NKp46/NCR1 expression between all groups. NKp44/NCR2, NKp30/NCR3 and NKG2D had lower expression in AIDS-RL in comparison with HIV + patients without lymphoma when compared to patients with similar (>0.3 G/L) CD4+ lymphocyte levels. Expression of 2B4/CD244/p38 was lower in AIDS-RL than in HIV-negative lymphoma. Comparison of specific NKp30/NCR3 and NKp46/NCR1 RNA showed increased steady state levels, despite decreased surface expression for NKp30/NCR3, suggesting abnormal post-transcriptional regulatory mechanisms.We show a more pronounced defect in NK activating molecule when HIV infection is associated with lymphoma than when only one condition (HIV positivity or lymphoma) is present. Defective NK phenotype, in addition to CD4+ depletion and dysfunction, may participate to the increased incidence of lymphoma in HIV patients. | [
{
"section_content": "Advances in lymphoma treatment prolong progressionfree survival. Nonetheless, many patients relapse. Deficient cytotoxic functions of natural killer (NK) cells [1], which can be infected by HIV [2], may participate in the failure to cure AIDS-related lymphomas (AIDS-RL). Engagement of inhi... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "Special thanks to Bernadette Barbarat for kind help for qRT-PCR, and special thanks to Marta Garcia-Granero for additional help in statistical analysis. Special thanks to Jean Gabarre for he... |
10.3390/molecules24132367 | The Metabolomic Profile of Lymphoma Subtypes: A Pilot Study | <jats:p>Lymphoma defines a group of different diseases. This study examined pre-treatment plasma samples from 66 adult patients (aged 20–74) newly diagnosed with any lymphoma subtype, and 96 frequency matched population controls. We used gas chromatography-mass spectrometry (GC-MS) to compare the metabolic profile by case/control status and across the major lymphoma subtypes. We conducted univariate and multivariate analyses, and partial least square discriminant analysis (PLS-DA). When compared to the controls, statistically validated models were obtained for diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and Hodgkin lymphoma (HL), but not follicular lymphoma (FL). The metabolomic analysis highlighted interesting differences between lymphoma patients and population controls, allowing the discrimination between pathologic and healthy subjects: Important metabolites, such as hypoxanthine and elaidic acid, were more abundant in all lymphoma subtypes. The small sample size of the individual lymphoma subtypes prevented obtaining PLS-DA validated models, although specific peculiar features of each subtype were observed; for instance, fatty acids were most represented in MM and HL patients, while 2-aminoadipic acid, 2-aminoheptanedioic acid, erythritol, and threitol characterized DLBCL and CLL. Metabolomic analysis was able to highlight interesting differences between lymphoma patients and population controls, allowing the discrimination between pathologic and healthy subjects. Further studies are warranted to understand whether the peculiar metabolic patterns observed might serve as early biomarkers of lymphoma.</jats:p> | [
{
"section_content": "Lymphomas represent a heterogeneous group of lymphoid malignancies with varied patterns of clinical behavior and responses to treatment. Lymphomas rank the fifth most common cancer in the developed world [1]. Prognosis depends on the histologic type, clinical factors, and molecular charact... | [
{
"section_content": "",
"section_name": "Acknowledgments:",
"section_num": null
},
{
"section_content": "The authors are thankful to the patients and the population controls who participated in the study.",
"section_name": "Acknowledgments:",
"section_num": null
},
{
"section_co... |
10.1186/s13073-015-0252-1 | Landscape of gene fusions in epithelial cancers: seq and ye shall find | Enabled by high-throughput sequencing approaches, epithelial cancers across a range of tissue types are seen to harbor gene fusions as integral to their landscape of somatic aberrations. Although many gene fusions are found at high frequency in several rare solid cancers, apart from fusions involving the ETS family of transcription factors which have been seen in approximately 50% of prostate cancers, several other common solid cancers have been shown to harbor recurrent gene fusions at low frequencies. On the other hand, many gene fusions involving oncogenes, such as those encoding ALK, RAF or FGFR kinase families, have been detected across multiple different epithelial carcinomas. Tumor-specific gene fusions can serve as diagnostic biomarkers or help define molecular subtypes of tumors; for example, gene fusions involving oncogenes such as ERG, ETV1, TFE3, NUT, POU5F1, NFIB, PLAG1, and PAX8 are diagnostically useful. Tumors with fusions involving therapeutically targetable genes such as ALK, RET, BRAF, RAF1, FGFR1-4, and NOTCH1-3 have immediate implications for precision medicine across tissue types. Thus, ongoing cancer genomic and transcriptomic analyses for clinical sequencing need to delineate the landscape of gene fusions. Prioritization of potential oncogenic "drivers" from "passenger" fusions, and functional characterization of potentially actionable gene fusions across diverse tissue types, will help translate these findings into clinical applications. Here, we review recent advances in gene fusion discovery and the prospects for medicine. | [
{
"section_content": "Recurrent chromosomal rearrangements in cancers have been described for over half a century [1, 2]. The characterization of the oncogenic fusion BCR-ABL1 at t (9, 22) translocation loci in chronic myeloid leukemia, which culminated in the development of a molecularly targeted therapy, prov... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We thank Robin Kunkel for help with the artwork for the figures. AMC is supported by the Doris Duke Charitable Foundation Clinical Scientist Award and the Prostate Cancer Foundation. AMC is ... |
10.3389/fmed.2018.00335 | From Vascular Smooth Muscle Cells to Folliculogenesis: What About Vasorin? | First described in 1988, vasorin (VASN) is a transmembrane glycoprotein expressed during early mouse development, and with a less extent, in various organs and tissues (e.g., kidney, aorta, and brain) postnatally. Vasn KO mice die after 3 weeks of life from unknown cause(s). No human disease has been associated with variants of this gene so far, but VASN seems to be a potential biomarker for nephropathies and tumorigenesis. Its interactions with the TGF-β and Notch1 pathways offer the most serious assumptions regarding VASN functions. In this review, we will describe current knowledge about this glycoprotein and discuss its implication in various organ pathophysiology. | [
{
"section_content": "Vasorin (VASN), a cell surface glycoprotein of 673 amino acids (aa), is encoded by the VASN gene also named Slit-like 2 (Slitl2) due to its strong homologies with the slit family of important signaling molecules. Vasorin was identified by various screens in several vertebrates including ro... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGMENTS",
"section_num": null
},
{
"section_content": "Mia Krautzberger whom Ph. D. thesis work has supported this review.",
"section_name": "ACKNOWLEDGMENTS",
"section_num": null
},
{
"section_content": "",
"section_name": "A... |
10.1371/journal.pcbi.1002724 | MOSAIC: A Multiscale Model of Osteogenesis and Sprouting Angiogenesis with Lateral Inhibition of Endothelial Cells | The healing of a fracture depends largely on the development of a new blood vessel network (angiogenesis) in the callus. During angiogenesis tip cells lead the developing sprout in response to extracellular signals, amongst which vascular endothelial growth factor (VEGF) is critical. In order to ensure a correct development of the vasculature, the balance between stalk and tip cell phenotypes must be tightly controlled, which is primarily achieved by the Dll4-Notch1 signaling pathway. This study presents a novel multiscale model of osteogenesis and sprouting angiogenesis, incorporating lateral inhibition of endothelial cells (further denoted MOSAIC model) through Dll4-Notch1 signaling, and applies it to fracture healing. The MOSAIC model correctly predicted the bone regeneration process and recapitulated many experimentally observed aspects of tip cell selection: the salt and pepper pattern seen for cell fates, an increased tip cell density due to the loss of Dll4 and an excessive number of tip cells in high VEGF environments. When VEGF concentration was even further increased, the MOSAIC model predicted the absence of a vascular network and fracture healing, thereby leading to a non-union, which is a direct consequence of the mutual inhibition of neighboring cells through Dll4-Notch1 signaling. This result was not retrieved for a more phenomenological model that only considers extracellular signals for tip cell migration, which illustrates the importance of implementing the actual signaling pathway rather than phenomenological rules. Finally, the MOSAIC model demonstrated the importance of a proper criterion for tip cell selection and the need for experimental data to further explore this. In conclusion, this study demonstrates that the MOSAIC model creates enhanced capabilities for investigating the influence of molecular mechanisms on angiogenesis and its relation to bone formation in a more mechanistic way and across different time and spatial scales. | [
{
"section_content": "The process of angiogenesis during fracture healing\n\nThe biological process of fracture healing comprises three main stages: (i) the ''inflammation phase'', where the trauma site becomes hypoxic and is invaded by inflammatory cells, fibroblasts, endothelial cells and mesenchymal stem cel... | [
{
"section_content": "These authors were supported by the following funding: AC: PhD fellow of the Research Foundation Flanders, LG: Funded by the Special Research Fund of the University of Lie `ge ( FRS. D-10/20 ), KB: Funded by the Artemis network grant, Foundation Leducq, PC: This work of PC is supported by ... |
10.1038/s41408-023-00784-z | Risk of second primary malignancies in patients with chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989-2019 | <jats:title>Abstract</jats:title><jats:p>The longevity of patients with chronic lymphocytic leukemia (CLL) has improved progressively over the past decades, making it essential to understand long-term health outcomes, such as second primary malignancies (SPMs). Therefore, this nationwide, population-based study assessed the risk of SPM development in CLL patients diagnosed during 1989-2019 in the Netherlands compared to the expected number of malignancies in an age-, sex-, and period-matched group from the general Dutch population. In 24,815 CLL patients followed for 162,698.49 person-years, 4369 SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.63 (95% confidence interval [CI] 1.59–1.68). This elevated risk was observed for solid (SIR, 1.67; 95% CI, 1.65–1.75) and hematological SPMs (SIR 1.42; 95% CI, 1.24–1.62). The highest risk for SPMs was noted beyond five years post-diagnosis (SIR, 1.70; 95% CI, 1.62–1.77), for male individuals (SIR, 1.70; 95% CI, 1.64–1.77), and patients aged 18–69 years (SIR, 1.92; 95% CI, 1.79–2.05). The risk of SPMs was higher in CLL patients who received anti-neoplastic therapy (SIR, 2.12; 95% CI, 1.96–2.28), as compared with those who did not (SIR, 1.58; 95% CI, 1.53–1.63). Routine surveillance activities and tailored interventions to counteract the increased morbidity and excess mortality associated with SPMs are essential for improving long-term outcomes in CLL patients.</jats:p> | [
{
"section_content": "Chronic lymphocytic leukemia (CLL) is the most frequently diagnosed leukemia among adults in the Western world, with an age-standardized incidence rate ranging from 3. 8 to 5. 0 per 100,000 person-years as of the 2000s [1] [2] [3] [4] [5]. The clinical behavior of CLL is heterogeneous, ran... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGEMENTS",
"section_num": null
},
{
"section_content": "The authors would like to thank the registration clerks of the Netherlands Cancer Registry (NCR) for their dedicated data collection. The nationwide population-based NCR is maintained and ho... |
10.3324/haematol.10317 | APRIL but not BLyS serum levels are increased in chronic lymphocytic leukemia: prognostic relevance of APRIL for survival | APRIL (a proliferation-inducing ligand) and BLyS (B lymphocyte stimulator) expression have been reported in chronic lymphocytic leukemia (CLL) cells. We examined APRIL and BLyS serum levels in CLL patients and evaluated the prognostic significance of APRIL expression on survival. | [
{
"section_content": "BLyS is a fundamental survival factor for transitional and mature B cells, whereas APRIL mainly affects B-1 cell activity, humoral responses and immunoglobulin class switching. 1 We recently reported that aging APRIL transgenic mice develop B-1 cell-associated tumors that are highly remini... | [
{
"section_content": "+ These authors share senior authorship *Institut de Génétique Moléculaire de Montpellier, UMR5535, Montpellier, France; °Department of Statistics and Operation Research, University of Jaén, Spain; # Laboratory for Experimental Oncology and Radiobiology, Amsterdam Medical Center, Amsterdam... |
10.1186/bcr2347 | The cytotoxicity of γ-secretase inhibitor I to breast cancer cells is mediated by proteasome inhibition, not by γ-secretase inhibition | <jats:title>Abstract</jats:title><jats:sec> <jats:title>Introduction</jats:title> <jats:p>Notch is a family of transmembrane protein receptors whose activation requires proteolytic cleavage by γ-secretase. Since aberrant Notch signaling can induce mammary carcinomas in transgenic mice and high expression levels of Notch receptors and ligands correlates with overall poor clinical outcomes, inhibiting γ-secretase with small molecules may be a promising approach for breast cancer treatment. Consistent with this hypothesis, two recent papers reported that γ-secretase inhibitor I (GSI I), Z-LLNle-CHO, is toxic to breast cancer cells both in vitro and in vivo. In this study, we compared the activity and cytotoxicity of Z-LLNle-CHO to that of two highly specific GSIs, DAPT and L-685,458 and three structurally unrelated proteasome inhibitors, MG132, lactacystin, and bortezomib in order to study the mechanism underlying the cytotoxicity of Z-LLNle-CHO in breast cancer cells.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Three estrogen receptor (ER) positive cell lines, MCF-7, BT474, and T47D, and three ER negative cell lines, SKBR3, MDA-MB-231, and MDA-MB-468, were used in this study. Both SKBR3 and BT474 cells also overexpress HER2/neu. Cytotoxicity was measured by using an MTS cell viability/proliferation assay. Inhibition of γ-secretase activity was measured by both immunoblotting and immunofluorescent microscopy in order to detect active Notch1 intracellular domain. Proteasome inhibition was determined by using a cell-based proteasome activity assay kit, by immunoblotting to detect accumulation of polyubiquitylated protein, and by immunofluorescent microscopy to detect redistribution of cellular ubiquitin.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We found that blocking γ-secretase activity by DAPT and L-685,458 had no effect on the survival and proliferation of a panel of six breast cancer cell lines while Z-LLNle-CHO could cause cell death even at concentrations that inhibited γ-secretase activity less efficiently. Furthermore, we observed that Z-LLNle-CHO could inhibit proteasome activity and the relative cellular sensitivity of these six breast cancer cell lines to Z-LLNle-CHO was the same as observed for three proteasome inhibitors. Finally, we found that the cell killing effect of Z-LLNle-CHO could be reversed by a chemical that restored the proteasome activity.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>We conclude that the cytotoxicity of Z-LLNle-CHO in breast cancer cells is mediated by proteasome inhibition, not by γ-secretase inhibition.</jats:p> </jats:sec> | [
{
"section_content": "Notch is a family of single-pass type I transmembrane protein receptors that, in mammals, includes four homologs, Notch1 to 4 [1]. Ligand-induced Notch receptor activation requires at least two cleavages that release the intracellular domain from the cytomembrane and allow it to translocat... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "This project has been made possible through a grant from the Alberta Cancer Research Institute (ACRI) and the Alberta Cancer Foundation. Jianxun Han is supported by an ACRI Graduate Students... |
10.18632/oncotarget.6769 | Combination therapy of RY10-4 with the γ-secretase inhibitor DAPT shows promise in treating HER2-amplified breast cancer | RY10-4, a novel protoapigenone analog, shows potent cytotoxicity against human breast cancer cells. However, breast cancer cell lines overexpressing human epidermal growth factor receptor 2 (HER2), SKBR3 and BT474, showed less sensitivity to RY10-4 when compared to breast cancer cells lines expressing lower levels of HER2, such as MDA-MB-231 and MCF-7 cells. This was associated with aberrant hyperactivity in Notch signaling in cells treated with RY10-4, since treatment with RY10-4 causes an increase in Notch activity by 2-to3.5-fold in SKBR3 and BT474 cell lines. The increase in activity was abrogated with a γ-secretase inhibitor, DAPT, or with Notch1 small-interfering RNA (si-Notch1). Cell proliferation was inhibited more effectively by RY10-4 plus DAPT or si-Notch1 than either agent alone. RY10-4 plus DAPT increases apoptosis in both HER2-overexpressing cell lines by two-fold compared to RY10-4 alone, while DAPT alone has no significant effects on apoptosis. In addition, we previously found RY10-4 could inhibit tumor growth through the PI3K/AKT pathway. Here we report that the combination of RY10-4 and DAPT exhibit additive suppression on AKT phosphorylation, contributing to the anti-cancer effects. In an animal model, this combination therapy inhibits the growth of SKBR3 tumor xenografts in nude mice to a greater extent than treatment with either reagent alone. These results indicate that the aberrant activation of Notch signaling impedes the inhibitory effect of RY10-4 on HER2-amplified cell proliferation. Furthermore, these adverse effects can be prevented by treatment combining RY10-4 with a Notch pathway inhibitor. | [
{
"section_content": "Breast cancer is the most commonly diagnosed malignancy among women, and it is a leading cause of cancer death in females from western countries [1]. Novel strategies for prevention and treatment of breast cancer are needed to minimize off-target drug-related toxicities and to ultimately e... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGMENTS",
"section_num": null
},
{
"section_content": "We would like to sincerely thank professor Yung-Chi Cheng of Yale University for providing us with a good environment and facilities to perform this project. Also, we want to especially thank... |
10.1186/s12885-021-07864-y | A novel scoring system integrating molecular abnormalities with IPSS-R can improve the risk stratification in patients with MDS | <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>The treatment strategies for Myelodysplastic Syndromes (MDS) are usually based on the risk stratification system. However, few risk signatures which integrate the revised international prognostic scoring system (IPSS-R) with gene mutations can be easily applied in the real world.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>The training cohort of 63 MDS patients was conducted at Zhongda Hospital of Southeast University from January 2013 to April 2020. The validation cohort of 141 MDS patients was obtained from GSE129828. The mutation scoring system was based on the number of mutations and a unique favorable prognostic factor, which is <jats:italic>SF3B1</jats:italic> mutation. Univariate Cox, multivariate Cox, and LASSO regression analyses were used to determine the significant factors that influenced the overall survival. The receiver operating characteristic curve (ROC) was used to evaluate the efficiency of the prognostic model.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>A novel risk scoring system we named “mutation combined with revised international prognostic scoring system (MIPSS-R)” was developed based on the results derived from multivariate analysis which assigned points to the IPSS-R and the mutation scores according to their relative statistical weight. Based on the quintile of the new scores, patients were divided into five risk levels. The Kaplan-Meier curves showed the superiority of MIPSS-R in separating patients from different groups, comparing with IPSS-R both in the training cohort (<jats:italic>p</jats:italic> = 1.71e-08 vs. <jats:italic>p</jats:italic> = 1.363e-04) and validation cohort (<jats:italic>p</jats:italic> = 1.788e-04 vs. <jats:italic>p</jats:italic> = 2.757e-03). The area under the ROC of MIPSS-R was 0.79 in the training cohort and 0.62 in the validation cohort. The retrospective analysis of our house patients showed that the risk levels of 57.41% of patients would adjust according to MIPSS-R. After changing risk levels, 38.71% of patients would benefit from treatment strategies that MIPSS-R recommends.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>A mutation scoring system was conducted based on the number of mutations and a unique favorable prognostic factor. MIPSS-R, the novel integral risk stratification system was developed by integrating IPSS-R and the mutation scores, which is more effective on prognosis and treatment guidance for MDS patients.</jats:p> </jats:sec> | [
{
"section_content": "Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by ineffective and dysplastic hematopoiesis that causes cytopenia, which are also likely to progress to the development of acute myeloid leukemia (AML) [1, 2]. MDS is predominantly diagnos... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "Not Applicable.",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "",
"section_name": "Funding",
"section_num": null
},
{
"sec... |
10.1186/s12263-016-0537-z | Fatty acid extract from CLA-enriched egg yolks can mediate transcriptome reprogramming of MCF-7 cancer cells to prevent their growth and proliferation | Our previous study showed that fatty acids extract obtained from CLA-enriched egg yolks (EFA-CLA) suppressed the viability of MCF-7 cancer cell line more effectively than extract from non-enriched egg yolks (EFA). In this study, we analysed the effect of EFA-CLA and EFA on transcriptome profile of MCF-7 cells by applying the whole Human Genome Microarray technology.We found that EFA-CLA and EFA treated cells differentially regulated genes involved in cancer development and progression. EFA-CLA, compared to EFA, positively increased the mRNA expression of TSC2 and PTEN tumor suppressors as well as decreased the expression of NOTCH1, AGPS, GNA12, STAT3, UCP2, HIGD2A, HIF1A, PPKAR1A oncogenes.We show for the first time that EFA-CLA can regulate genes engaged in AKT/mTOR pathway and inhibiting cell cycle progression. The observed results are most likely achieved by the combined effect of both: incorporated CLA isomers and other fatty acids in eggs organically modified through hens' diet. Our results suggest that CLA-enriched eggs could be easily available food products with a potential of a cancer chemopreventive agent. | [
{
"section_content": "Conjugated linoleic acid (CLA) term includes several isomers of linoleic acid (18:2), naturally present in ruminant and dairy products, due to the activity of the rumen microflora [25, 30]. In numerous studies, CLA was shown to have several beneficial properties on human health. Researcher... | [
{
"section_content": "",
"section_name": "Funding",
"section_num": null
},
{
"section_content": "This work was supported by the Polish National Science Center (grant number 2011/03/B/NZ9/01423 ) \"Conjugated linoleic acid (CLA)-induced transcriptional activation of PPAR-an investigation of molec... |
10.3390/curroncol30100643 | Next-Generation Sequencing Analysis of Mutations in Circulating Tumor DNA from the Plasma of Patients with Head–Neck Cancer Undergoing Chemo-Radiotherapy Using a Pan-Cancer Cell-Free Assay | <jats:p>Using next-generation sequencing (NGS), we investigated DNA mutations in the plasma tumor cell-free circulating DNA (ctDNA) of 38 patients with inoperable squamous cell head neck cancer (SCHNC) before and after the completion of chemoradiotherapy (CRT). Baseline mutations of the TP53 were recorded in 10/38 (26.3%) and persisted in 4/10 patients after CRT. ΤP53 mutations were further detected post CRT in 7/38 additional patients with undetectable mutations at baseline (overall rate 44.7%). Furthermore, 4/38 patients exhibited baseline mutations of the EGFR, AR, FGFR3, and FBXW3, and four new gene mutations were detected after CRT (MTOR, EGFR3, ALK, and SF3B1). Τ4 stage was related with a significantly higher rate of mutations (TP53 and overall). Mutations were observed in 8/30 (26.6%) responders (complete/partial response) vs. in 6/8 (75%) of the rest of the patients (p = 0.03). Significant poorer LRFS was noted for patients with mutations detected before and after CRT (p = 0.02). Patients who had detectable mutations either before or after CRT had significantly worse DMFS (p = 0.04 overall, and p = 0.02 for TP53 mutations). It was concluded that assessment of mutations before and after the end of CRT is essential to characterize patients with a high risk of locoregional recurrence or metastatic progression.</jats:p> | [
{
"section_content": "During disease progression, cancer cells and especially stem cells acquire genetic mutations that define clinical aggressiveness, invasion, metastasis, and resistance to radiotherapy (RT) and chemotherapy [1, 2]. Such mutations can appear even during therapy, either as a result of direct D... | [
{
"section_content": "Data Availability Statement: All data are available in the files of the Department of Radiotherapy. and Oncology, Democritus University of Thrace. The data presented in this study are available on reasonable request from the corresponding author.",
"section_name": "",
"section_num"... |
10.3390/jcm11082076 | Old and New Drugs for Chronic Lymphocytic Leukemia: Lights and Shadows of Real-World Evidence | <jats:p>Several novel treatments for chronic lymphocytic leukemia (CLL) have been recently approved based on the results of randomized clinical trials. However, real-world evidence (RWE) is also requested before and after drug authorization in order to confirm safety and to provide data for health technology assessments. We conducted a scoping review of the available RWE for targeted treatments of CLL, namely ibrutinib, acalabrutinib, idelalisib, and venetoclax, as well as for chemoimmunotherapy (CIT). In particular, we searched studies published since 1 January 2010 and reported outcomes of the above treatments based on health databases, registries, or phase IV studies, including named-patient programs. We included both full papers and abstracts of studies presented at major meetings. Overall, 110 studies were selected and analyzed: 28,880 patients were treated with ibrutinib, 1424 with idelalisib, 751 with venetoclax, 496 with acalabrutinib, and 14,896 with CIT. Reported discontinuation rates were higher than in clinical trials, while effectiveness could not be indirectly compared with clinical trials since a detailed case mix, including cytogenetic risk factors, was partially available and propensity scores rarely applied. RWE on CLL can help to set realistic outcomes with novel treatments, however, real-world studies should be fostered, and available data shared.</jats:p> | [
{
"section_content": "Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative neoplasm harbored by 5. 6 in 10,000 inhabitants (https://seer. cancer. gov/statfacts/html/clyl. html accessed on 30 December 2021). Clinical practice guidelines formerly recommended frontline chemoimmunotherapy (CIT) for... | [
{
"section_content": "",
"section_name": "Conflicts of Interest:",
"section_num": null
},
{
"section_content": "Funding: This research received no external funding. \n\nInstitutional Review Board Statement: Not applicable. \n\nInformed Consent Statement: Not applicable.",
"section_name": "",... |
10.3324/haematol.2009.010173 | Differential diagnosis of cyclin D2+ mantle cell lymphoma based on fluorescence in situ hybridization and quantitative real-time-PCR | Mantle cell lymphoma is characterized by the t(11;14) chromosomal translocation, resulting in the overexpression of cyclin D1 (CycD1). Recently, cases of mantle cell lymphoma negative for cycD1 but positive for cycD2 or cycD3 were identified by gene expression profiling and confirmed by immunohistochemistry. We analyzed 4 cases of cycD2(+) mantle cell lymphoma with a translocation involving the CCND2 locus, and its differential diagnosis from 35 mature B-cell non-Hodgkin's lymphomas based on immunohistochemistry, quantitative RT-PCR and FISH analysis. Bona fide cycD2(+) mantle cell lymphoma carried translocations involving the CCND2 gene, and IGH and IGK loci were identified as partners. As a result of this translocation, cycD2 mRNA was highly over-expressed when compared with normal lymphoid tissue and other B-cell non-Hodgkin's lymphomas, including chronic lymphocytic leukemia, making this technique ideally suited to identify cycD2(+)mantle cell lymphoma. In contrast, positive immunostaining for cycD2 was found in most B-cell non-Hodgkin's lymphomas, and therefore, it is not specific for a diagnosis of cycD2(+)mantle cell lymphoma. | [
{
"section_content": "Mantle cell lymphoma (MCL) is a distinct subtype of aggressive B-cell non-Hodgkin's lymphoma (NHL) with specific clinical and pathological features that accounts for approximately 6% of all lymphomas. 1 The genetic hallmark of mantle cell lymphoma (MCL) is the t(11;14) (q13;q32) chromosoma... | [
{
"section_content": "",
"section_name": "Authorship and Disclosures",
"section_num": null
},
{
"section_content": "LQ-M was the principal investigator and takes primary responsibility for the paper; LQ-M and FF designed research, coordinated the research, analyzed and interpreted data and draft... |
10.3324/haematol.2009.005561 | Predictive value of 2-microglobulin ( 2-m) levels in chronic lymphocytic leukemia since Binet A stages | We read with interest the study by Rossi and coworkers, reporting CD49d expression as risk factor of treatment free survival (TFS) in Binet A CLL patients.[1][1] In this paper, a close association between CD49d and CD38, LDH and β2-m is also described. We would like to add further information about | [
{
"section_content": "We read with interest the study by Rossi and coworkers, reporting CD49d expression as risk factor of treatment free survival (TFS) in Binet A CLL patients. 1 In this paper, a close association between CD49d and CD38, LDH and β2-m is also described. We would like to add further information ... | [
{
"section_content": "Funding: supported from Associazione Italiana Ricerca sul Cancro (AIRC) (to FM and MF) and Fondazione 'Amelia Scorza' Onlus, Cosenza, Italy. Acknowledgments: we would like to acknowledge Dr. Vincenzo Callea, Prof Luca Baldini, Dr Ugo Consoli and Dr Serena Matis for their contribution and u... |
10.3390/math8040564 | Sensitivity Analysis of Mathematical Model to Study the Effect of T Cells Infusion in Treatment of CLL | <jats:p>In this paper, we considered a mathematical model concerned with the treatment of Chronic Lymphocytic Leukemia (CLL) taking into account the effect of superficially infused T cells in this particular type of tumor. The model is described thoroughly by the system of non-linear differential equations explaining the interaction of naïve, infected, cancer and immune cell population. The detailed sensitivity analysis with the application is the major part of this paper. The basic objective is to provide insight to how parameters’ behavior varies model results by elaborating the results obtained from the application of sensitivity analysis. The sensitivity of the model was evaluated not only theoretically, but also with the help of a numerical approach, producing graphs providing better imminent of results. We argue that the application of the sensitivity analysis method endows an insight into how and which parameters are of primary significance in controlling the spread of leukemia.</jats:p> | [
{
"section_content": "The inherited concept of irrelevance of mathematics and biology has been changed to a great extent, somewhat because of the realization of the scientific world [1] of the undeniable services of mathematics in helping to gain a better understanding of various biological phenomena occurring ... | [
{
"section_content": "Funding: This research received no external funding. \n\nAcknowledgments: Authors acknowledge the support given by their respective universities.",
"section_name": "",
"section_num": ""
},
{
"section_content": "",
"section_name": "Conflicts of Interest:",
"section_n... |
10.7150/jca.30690 | Effects of Notch Signaling Pathway in Cervical Cancer by Curcumin Mediated Photodynamic Therapy and Its Possible Mechanisms in Vitro and in Vivo | Curcumin, as a high effect and low toxicity anti-cancer drug and photosensitiser, has synergistic and complementary effects with photodynamic therapy (PDT). However, due to its unclear mechanism, PDT's application and efficacy were limited. Notch signaling pathway, which is highly correlates with carcinogenesis and development of cervical cancer, could be a potential therapeutic targets to improve the effectiveness of PDT. Therefore, in this study, we explored the effects of Notch signaling pathway in cervical cancer by curcumin mediated PDT with/without Notch receptor blocker (DAPT), and hope to elucidate its mechanism. Firstly, the effect on the proliferation of cervical cancer Me180 cells were detected with MTT assay, and apoptosis were detected with Annexin V-FITC/PI combined with flow cytometry. Secondly, after establishment of nude mice model, dividing the experimental animals into model group, curcumin PDT group, simple DAPT group, and curcumin-PDT+DAPT group, and analyzing tumor volume changes as well as HE staining in each group. mRNA and protein expression of gene Notch-1 and its downstream NF-κB and VEGF were observed with RT-PCR, immunohistochemical staining and Western-blot with/without inhibition of Notch signaling pathway by DAPT, both in vivo and in vitro experiments. We found both DAPT and curcumin-PDT can inhibit the proliferation and induce apoptosis of cervical cancer cell. The two have synergistic effect in vitro and in vivo. This effect can effectively block the conduction of Notch signaling pathway, which is associated with down-regulation of the expression of Notch1 and NF-κB. Notch signaling pathway could be one of the targets of curcumin-PDT photodynamic therapy. | [
{
"section_content": "Cervical cancer is the third most common cancer in women worldwide and the fourth leading cause of tumor-induced death. China is a country with high incidence of cervical cancer in the world. About 150,000 women are infected every year, accounting for one-third of new cases globally and th... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "This work was supported by the National Nature Science Foundation of China (Foundation No. 81202966 )",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_... |
10.4322/acr.2021.278 | De novo double-hit B-cell precursor leukemia/lymphoma - an unusual presentation as peritoneal lymphomatosis | Peritoneal lymphomatosis (PL) is a rare presentation of extranodal precursor leukemia/lymphoma.The presentation is often non-specific, leading to delayed diagnosis and treatment.In this case, though the preliminary diagnosis was established on ascitic fluid cytology, the disease progressed rapidly, leading to demise before initiating chemotherapy.Immunophenotyping and molecular studies, performed later, established a diagnosis of de novo B-cell precursor leukemia/ lymphoma with MYC, BCL2 rearrangements (Double-hit lymphoma).MYC, BCL2 rearrangements are rarely reported in precursor B-lymphoma/leukemia which carry dismal prognosis.In this report, we illustrate autopsy findings of PL in an elderly gentleman who presented with ascites for evaluation. | [
{
"section_content": "Peritoneal lymphomatosis (PL) is a rare presentation of extranodal Non-Hodgkin lymphoma (NHL). Since the clinical presentation of PL is non-specific, the diagnosis is often delayed. Peritoneal carcinomatosis accompanied by malignant ascites is relatively common; however, 'peritoneal lympho... | [
{
"section_content": "Autops Case Rep (São Paulo). 2021;11:e2021278 This work was carried out at the Post Graduate Institute of Medical Education and Research (PGIMER). Chandigarh, India.",
"section_name": "",
"section_num": ""
},
{
"section_content": "",
"section_name": "CONCLUSIONS",
"... |
10.1038/cddis.2014.391 | Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling | <jats:title>Abstract</jats:title><jats:p>Chronic lymphocytic leukemia (CLL) can be divided into groups based on biomarkers of poor prognosis. The expression of the tyrosine kinase ZAP-70 (member of the Syk tyrosine kinase family) in CLL cells is associated with shorter overall survival in CLL patients. Currently, there is a lack of targeted therapies for patients with ZAP-70 expression in CLL cells. The tyrosine kinase inhibitor gefitinib has been shown to be effective at induce apoptosis in acute myeloid leukemia through inhibition of Syk. In this study, we sought to test the efficacy of gefitinib in primary human ZAP-70+ CLL cells. We demonstrate that gefitinib preferentially induces cell death in ZAP-70-expressing CLL cells with a median IC<jats:sub>50</jats:sub> of 4.5 <jats:italic>μ</jats:italic>M. In addition, gefitinib decreases the viability of ZAP-70+ Jurkat T leukemia cells but fails to affect T cells from CLL patients. Western blot analysis shows gefitinib reduces both basal and B-cell receptor (BCR)-stimulated phosphorylation of Syk/ZAP-70, ERK, and Akt in ZAP-70+ CLL cells. Moreover, gefitinib inhibits the pro-survival response from BCR stimulation and decreases pro-survival proteins such as Mcl-1. Finally, ZAP-70 expression sensitizes Raji cells to gefitinib treatment. These results demonstrate that gefitinib specifically targets ZAP-70+ CLL cells and inhibits the BCR cell survival pathway leading to apoptosis. This represents the likelihood of tyrosine kinase inhibitors being effective targeted treatments for ZAP-70+ CLL cells.</jats:p> | [
{
"section_content": "The clinical course of chronic lymphocytic leukemia (CLL) is highly variable, and although some patients are treated at diagnosis, others may not require therapy for years. 1 Biomarkers can help stratify these patients into indolent and aggressive disease categories. The aggressiveness of ... | [
{
"section_content": "Acknowledgements. We thank the Manitoba CLL Tumor Bank for organization of patient samples, Michelle Brown for the mutational analysis of patient samples, and Dr. Aaron Marshall and Hongzhao Li for the transduced Raji cell lines. This research is supported by the CancerCare Manitoba Founda... |
10.1186/1471-2164-14-s7-s1 | Automatic B cell lymphoma detection using flow cytometry data | Flow cytometry has been widely used for the diagnosis of various hematopoietic diseases. Although there have been advances in the number of biomarkers that can be analyzed simultaneously and technologies that enable fast performance, the diagnostic data are still interpreted by a manual gating strategy. The process is labor-intensive, time-consuming, and subject to human error.We used 80 sets of flow cytometry data from 44 healthy donors, 21 patients with chronic lymphocytic leukemia (CLL), and 15 patients with follicular lymphoma (FL). Approximately 15% of data from each group were used to build the profiles. Our approach was able to successfully identify 36/37 healthy donor cases, 18/18 CLL cases, and 12/13 FL cases.This proof-of-concept study demonstrated that an automated diagnosis of CLL and FL can be obtained by examining the cell capture rates of a test case using the computational method based on the multi-profile detection algorithm. The testing phase of our system is efficient and can facilitate diagnosis of B-lymphocyte neoplasms. | [
{
"section_content": "Flow cytometry (FC) involves conjugating fluorochromes to antibodies, allowing them to bind different cell biomarkers, and passing the stained cells through the path of a laser where the fluorochromes are excited and fluorescence emission is measured. Forward and side scatter of cells give... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "This project was supported in part by NIH grants R01CA151955 (YZ) and R33CA173382 (YZ).",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "",
... |
10.3390/cells9071600 | Loss of ZC4H2 and RNF220 Inhibits Neural Stem Cell Proliferation and Promotes Neuronal Differentiation | <jats:p>The ubiquitin E3 ligase RNF220 and its co-factor ZC4H2 are required for multiple neural developmental processes through different targets, including spinal cord patterning and the development of the cerebellum and the locus coeruleus. Here, we explored the effects of loss of ZC4H2 and RNF220 on the proliferation and differentiation of neural stem cells (NSCs) derived from mouse embryonic cortex. We showed that loss of either ZC4H2 or RNF220 inhibits the proliferation and promotes the differentiation abilities of NSCs in vitro. RNA-Seq profiling revealed 132 and 433 differentially expressed genes in the ZC4H2−/− and RNF220−/− NSCs, compared to wild type (WT) NSCs, respectively. Specifically, Cend1, a key regulator of cell cycle exit and differentiation of neuronal precursors, was found to be upregulated in both ZC4H2−/− and RNF220−/− NSCs at the mRNA and protein levels. The targets of Cend1, such as CyclinD1, Notch1 and Hes1, were downregulated both in ZC4H2−/− and RNF220−/− NSCs, whereas p53 and p21 were elevated. ZC4H2−/− and RNF220−/− NSCs showed G0/G1 phase arrest compared to WT NSCs in cell cycle analysis. These results suggested that ZC4H2 and RNF220 are likely involved in the regulation of neural stem cell proliferation and differentiation through Cend1.</jats:p> | [
{
"section_content": "During mammalian embryonic development, the multipotent neural stem/precursor cells (NSCs/NPCs) undergo sequential differentiation to form the nervous system. The NSCs may self-renew, differentiate, or remain quiescent [1], depending on the intrinsic and external signaling environment. In ... | [
{
"section_content": "Funding: This work was supported by grants from the Chinese National Science foundation ( 31671521 and 31871483 to B. M) and the Bureau of Frontier Sciences and Education of Chinese Academy of Sciences ( QYZDJ-SSW-SMC005 to Y. G. Y. ).",
"section_name": "",
"section_num": ""
},
... |
10.1590/fst.90721 | Role of oleanolic acid in relieving psoriasis and its underlying mechanism of action | Abstract The present study aimed to determine whether oleanolic acid (Ole) could be used to treat psoriasis and its related underlying mechanism of action via in vitro analysis. HaCaT cells were stimulated with IL-22 to established an in vitro psoriasis cell model. MTT, flow cytometry and TUNEL assays, respectively. Transmission electron microscopy was used to observe the cell ultrastructure. LC3B protein expression levels were analyzed using immunofluorescence, other protein expression levels were determined using western blotting. Cell viability was significantly increased, while the apoptotic rate was significantly decreased in the model group (P < 0.001). In addition, Notch1, Hes1, beclin 1 and LC3B protein expression levels were significantly downregulated, while P62 protein expression levels were significantly upregulated in the model group compared with the control group (P < 0.001). Supplementation of Ole, the increased levels of proliferation were significantly suppressed, while cell apoptosis was significantly increased (P < 0.05) in a dose-dependent manner, which was discovered to occur via Notch1 upregulation. Notably, the transfection with small interfering RNA-Notch1 significantly reversed the effect of Ole treatment (P < 0.001) and the levels of autophagy were also decreased. In conclusion, the findings of the current study suggested that Ole may relieve psoriasis via upregulating Notch1, which subsequently regulates cell autophagy. | [
{
"section_content": "Psoriasis is a common and recurring chronic inflammatory skin condition, and its prevalence among adults ranges from 0. 91 to 8. 5% in different Please clarify, are you referring to different countries and ethnic (Griffiths et al. 2017). However, the exact pathogenesis of psoriasis remains... | [
{
"section_content": "",
"section_name": "Supplementary Material",
"section_num": null
},
{
"section_content": "Supplementary material accompanies this paper. Supplementary Figure 1. Notch1 mRNA expression in difference groups NC: HaCaT cells were treated with normal medium; si-NC: HaCaT cells w... |
10.1038/s41408-021-00556-7 | Survival of patients with chronic lymphocytic leukemia before and after the introduction of chemoimmunotherapy in Germany | <jats:title>Abstract</jats:title><jats:p>Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in western countries. Therapy is indicated in symptomatic and advanced stages and has changed fundamentally since 2010 when rituximab, an anti-CD20 antibody, has been approved for treatment of CLL. Until then therapy had been based on chemotherapy drugs. This study investigates whether survival in CLL patients improved at the population level after the introduction of combined chemoimmunotherapy. Data from the cancer registry North-Rhine Westphalia was used to calculate relative survival (RS) by applying period analyses. Age-standardized 5-year RS increased from 79% in 1998–2002 (75% in 2003–2007) to 81% in the calendar period 2008–2012 and 88% in 2013–2016 for men and continuously from 71% in 1998–2002 to 92% in 2013–2016 for women. In CLL patients aged 15–69 years 5-year RS increased from 83% to 90% for men and from 82% to 94% for women after adding an anti-CD20-antibody to chemotherapy while in the older age group of 70–79-year-old CLL patients an increase by 20 percentage points was observed. These findings show marked improvements in the survival of CLL patients at the population level subsequently to the approval of anti-CD 20 antibodies like rituximab, ofatumumab or obinutuzumab for CLL treatment.</jats:p> | [
{
"section_content": "Chronic lymphocytic leukemia (CLL) is the most common leukemic disease in western countries. The age-standardized incidence rate is four to five cases per 100,000 person-years [1, 2] and about 5500 patients in Germany are newly diagnosed with CLL annually. Men are more often affected than ... | [
{
"section_content": "",
"section_name": "Reporting summary",
"section_num": null
},
{
"section_content": "Further information on experimental design is available in the Nature Research Reporting Summary linked to this article.",
"section_name": "Reporting summary",
"section_num": null
... |
10.1186/s12885-024-12063-6 | Integrated analysis of transcriptome and genome variations in pediatric T cell acute lymphoblastic leukemia: data from north Indian tertiary care center | <jats:title>Abstract</jats:title><jats:sec> <jats:title>Introduction</jats:title> <jats:p>T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease with poor prognosis and inferior outcome. Although multiple studies have been perform on genomics of T-ALL, data from Indian sub-continent is scarce.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>In the current study we aimed to identify the genetic variability of T-ALL in an Indian cohort of pediatric (age ≤ 12 years) T-ALL patients (<jats:italic>n</jats:italic> = 25) by whole transcriptome sequencing along with whole exome sequencing and correlated the findings with clinical characteristics and disease outcome.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>The median age was 7 years (range 3 -12 years). RNA sequencing revealed a definitive fusion event in 14 cases (56%) (including a novel fusions) with <jats:italic>STIL::TAL1</jats:italic> in 4 (16%), followed by <jats:italic>NUP21::ABL1, TCF7::SPI1, ETV6::HDAC8, LMO1::RIC3, DIAPH1::JAK2, SETD2::CCDC12</jats:italic> and <jats:italic>RCBTB2::LPAR6</jats:italic> in 1 (4%) case each. Significant aberrant expression was noted in <jats:italic>RAG1</jats:italic> (64%), <jats:italic>RAG2</jats:italic> (80%), <jats:italic>MYCN</jats:italic> (52%), <jats:italic>NKX3-1</jats:italic> (52%),<jats:italic> NKX3-2</jats:italic> (32%), <jats:italic>TLX3 </jats:italic>(28%), <jats:italic>LMO1</jats:italic> (20%) and <jats:italic>MYB</jats:italic> (16%) genes. WES data showed frequent mutations in <jats:italic>NOTCH1</jats:italic> (35%) followed by <jats:italic>WT1</jats:italic> (23%), <jats:italic>FBXW7</jats:italic> (12%), <jats:italic>KRAS</jats:italic> (12%), <jats:italic>PHF6</jats:italic> (12%) and <jats:italic>JAK3</jats:italic> (12%). Nearly 88.2% of cases showed a deletion of <jats:italic>CDKN2A/CDKN2B/MTAP</jats:italic> genes. Clinically significant association of a better EFS and OS (<jats:italic>p</jats:italic>=0.01) was noted with <jats:italic>RAG2</jats:italic> over-expression at a median follow up of 22 months, while a poor EFS (<jats:italic>p</jats:italic>=0.041) and high relapse rate (<jats:italic>p</jats:italic>=0.045) was observed with <jats:italic>MYB</jats:italic> over-expression.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Overall, the present study demonstrates the frequencies of transcriptomic and genetic alterations from Indian cohort of pediatric T-ALL and is a salient addition to current genomics data sets available in T-ALL.</jats:p> </jats:sec> | [
{
"section_content": "T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive form of ALL and represents 15-20% of pediatric ALL cases [1]. Even with highly intensified therapy, 25% of T-ALL patients experience relapse and have lower post-relapse survival compared to the B-lineage ALL [1]. The geneti... | [
{
"section_content": "",
"section_name": "Supplementary Information",
"section_num": null
},
{
"section_content": "The online version contains supplementary material available at https://doi. org/10. 1186/s12885-024-12063-6.",
"section_name": "Supplementary Information",
"section_num": n... |
10.1038/s41598-021-92412-8 | Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia | <jats:title>Abstract</jats:title><jats:p>Hypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.</jats:p> | [
{
"section_content": "have been identified, for example: direct and indirect inhibition of T-cell activation 5, induction of anergy and impairment of BCR-and TLR-signalling on B cells 6, 7, and inhibition of the mononuclear phagocytic system 8, 9. \n\nThe immunomodulatory capacity of Ig preparations on CLL cell... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "The authors would like to thank to María Tejeda and Romina Mariel Pagano from CONICET for their technical assistance, and Guillermo Atenza from Microsules Argentina for the support on the pr... |
10.1186/s12890-019-0977-5 | miR-34a in serum is involved in mild-to-moderate COPD in women exposed to biomass smoke | <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities. The main causes of COPD are Gene-environment interactions associated with tobacco smoking (COPD-TS) and biomass smoke (COPD-BS). It is well know that microRNAs (miRNAs) participate in the control of post-transcriptional regulation and are involved in COPD-TS; nevertheless, those miRNAS are participating in the COPD-BS are unidentified. Thus, we studied which miRNAs are involved in COPD-BS (GOLD stages I–II).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In the screening phase, the profile of the miRNAs was analyzed in serum samples (<jats:italic>n</jats:italic> = 3) by means of a PCR array. Subsequently, the miRNAs were validated with RT-qPCR (<jats:italic>n</jats:italic> = 25) in the corresponding study groups. Additionally, the serum concentration of Notch1 was measured comparing COPD-BS vs COPD-TS.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>miR-34a was down-regulated in COPD- BS vs COPD-TS. In the other study groups, three miRNAs were differentially expressed: miR-374a was down-regulated in COPD-BS vs C, miR-191-5p was up-regulated in COPD-BS vs H-BS, and miR-21-5p was down-regulated in COPD-TS compared to the C group. Moreover, the serum concentration of Notch1, one of the targets of miR-34a, was increased in COPD-BS compared to women with COPD-TS.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>This is the first study in patients with COPD due to biomass that demonstrates miRNA expression differences between patients. The observations support the concept that COPD by biomass has a different phenotype than COPD due to tobacco smoking, which could have important implications for the treatment of these diseases.</jats:p></jats:sec> | [
{
"section_content": "Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable disease, characterized by persistent respiratory symptoms and airflow limitation. COPD is caused by exposure to noxious particles or gases [1] ; tobacco smoke inhalation is a fundamental cause of COPD and a... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We are grateful to PhD. Eduardo Montes Martinez at Clinica of Asthma ), and to MSc. Christian Adolfo Trejo Jasso for his valuable advice and help in the development of RT-qPCR and ELISA tech... |
10.1186/s12938-021-00973-6 | The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019 | <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Chronic lymphocytic leukemia (CLL) is the most prevalent subtype of leukemia in Western countries, causing a substantial health burden on patients and society. Comprehensive evaluation of the epidemiological characteristics of CLL is warranted, especially in the current context of global population aging. The main objective of this study is evaluating the disease burden of CLL at global, regional, and national levels from 1990 to 2019. As secondary objectives, we studied the influence of demographic factors and performed risk factor analysis. We hope this study could provide evidence for the evaluation of the effectiveness of previous prevention strategies and the formulation of future global health policies.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Based on data of CLL between 1990 to 2019 from the Global Burden of Disease (GBD) study 2019, we depicted the age, gender, and regional structure of the CLL burden population and described the impact of social development on the disease burden of CLL. The distribution and changing trends of attributable risk factors were also investigated. The global burden of CLL has increased dramatically. A high incidence has been achieved in males and elder people. Countries and territories with high social-demographic index (SDI) tended to have higher global burden than low-SDI region. Of risk factors, high body mass index and smoking were the major contributors for CLL-related mortality and disability adjusted life-years (DALYs).</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>In summary, the global CLL burden continues to rise over the past 30 years. The relocation of medical resource should be considered on a global scale.</jats:p> </jats:sec><jats:sec> <jats:title>Graphical Abstract</jats:title> </jats:sec> | [
{
"section_content": "",
"section_name": "Graphical Abstract",
"section_num": null
},
{
"section_content": "Chronic lymphocytic leukemia (CLL) represents a prevalent adult leukemia, which is characterized by abnormal accumulation of immunologically incompetent lymphocytes in blood, bone marrow, ... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "Not applicable.",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "",
"section_name": "Funding",
"section_num": null
},
{
"sec... |
10.1371/journal.pone.0233672 | An exon skipping screen identifies antitumor drugs that are potent modulators of pre-mRNA splicing, suggesting new therapeutic applications | <jats:title>ABSTRACT</jats:title><jats:p>Agents that modulate pre-mRNA splicing are of interest in multiple therapeutic areas, including cancer. We report our recent screening results with the application of a cell-based Triple Exon Skipping Luciferase Reporter (TESLR) using a library that is composed of FDA approved drugs, clinical compounds, and mechanistically characterized tool compounds. Confirmatory assays showed that three clinical antitumor therapeutic candidates (milciclib, PF-3758309 and PF-030871) are potent splicing modulators and that these drugs are, in fact, nanomolar inhibitors of multiple kinases involved in the regulation the spliceosome. We also report the identification of new SF3B1 antagonists (sudemycinol C and E) and show that these antagonists can be used to develop a displacement assay for SF3B1 small molecule ligands. These results further supports the broad potential for the development of agents that target the spliceosome for the treatment of cancer and other diseases, as well as new avenues for chemotherapeutic discovery.</jats:p> | [
{
"section_content": "The use of targeted high-throughput screening (HTS) of recently available compound libraries composed of drugs, clinical compounds and advanced tool compounds offers the biomedical research community the opportunity to elucidate the mechanism of action (MOA), on-target specificity and pote... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "The authors wish to thank Karen Tenney of the Department of Chemistry and Biochemistry at UCSC for her contributions to the administration and organization of this project. We also gratefully... |
10.1007/s12032-019-1300-2 | Examination of clonal evolution in chronic lymphocytic leukemia | Chronic lymphocytic leukemia (CLL) is one of the most frequent lymphoproliferative diseases. CLL is characterized by unusual heterogeneity, which probably reflects its biological and genetic lack of homogeneity. Clonal chromosome aberrations belong to the most important prognostic and predictive factors in CLL. This research was aimed at observing clonal evolution in CLL at the chromosomal level, and assessing its clinical significance in relation to selected prognostic factors. The study involved 72 untreated patients with CLL. The preliminary investigations using cytogenetic banding analysis (CBA) and FISH were performed at the time of diagnosis, and again after about 24 months to observe clonal changes (clonal evolution). In addition, other parameters were evaluated, i.e., the expression of ZAP-70 kinase, CD38 antigen, and the mutation statuses of IGVH and NOTCH1 genes. Classic prognostic factors, i.e., categorized ZAP70 and CD38 expressions as well as mutations in IGVH and NOTCH1 genes did not influence the course of clonal evolution in the examined group of patients. Clonal evolution was detected in 45.8% of patients by means of CBA, and in 19.4% patients with FISH. Analysis of chromosomal aberrations in the examined group of patients showed that the incidence of 17p deletions and translocations in karyotypes has a negative impact on overall survival. CE was found to be a risk factor for the occurrence of disease progression (OR = 2.22). Our observations indicate that combined CBA and FISH are the most optimal techniques for monitoring clonal evolution in the course of CLL. | [
{
"section_content": "Chronic lymphocytic leukemia (CLL) is one of the most common lymphoproliferative diseases that occur in elderly people in Europe and North America. It is a monoclonal disease, characterized by accumulation of small, morphologically mature, resting lymphocytes B in peripheral blood, bone ma... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "The authors would like to thank M. Luterek, I. Pilecka, MSc, and M. Wojcierowska-Litwin, MSc for help in performed chromosome banding and genes sequencing.",
"section_name": "Acknowledge... |
10.3389/fphar.2021.772576 | Danzhi Xiaoyao Powder Promotes Neuronal Regeneration by Downregulating Notch Signaling Pathway in the Treatment of Generalized Anxiety Disorder | <jats:p><jats:bold>Background:</jats:bold> Generalized anxiety disorder (GAD) is one of the most common types of anxiety disorders with unclear pathogenesis. Our team’s previous research found that extensive neuronal apoptosis and neuronal regeneration disorders occur in the hippocampus of GAD rats. Danzhi Xiaoyao (DZXYS) Powder can improve the anxiety behavior of rats, but its molecular mechanism is not well understood.</jats:p><jats:p><jats:bold>Objective:</jats:bold> This paper discusses whether the pathogenesis of GAD is related to the abnormal expression of Notch signal pathway, and whether the anti-anxiety effect of DZXYS promotes nerve regeneration in the hippocampus by regulating the Notch signaling pathway.</jats:p><jats:p><jats:bold>Methods:</jats:bold> The animal model of GAD was developed by the chronic restraint stress and uncertain empty bottle stimulation method. After the model was successfully established, the rats in the model preparation group were divided into the buspirone, DZXYS, DZXYS + DAPT, and model groups, and were administered the corresponding drug intervention. The changes in body weight and food intake of rats were continuously monitored throughout the process. The changes in anxiety behavior of rats were measured by open field experiment and elevated plus-maze test, and morphological changes and regeneration of neurons in the rat hippocampus were observed by HE staining and double immunofluorescence staining. Changes in the expression of key targets of the Notch signaling pathway in the hippocampus were monitored by real-time fluorescence quantitative PCR and western blotting.</jats:p><jats:p><jats:bold>Results:</jats:bold> In this study, we verified that the GAD model was stable and reliable, and found that the key targets of the Notch signaling pathway (Notch1, Hes1, Hes5, etc.) in the hippocampus of GAD rats were significantly upregulated, leading to the increased proliferation of neural stem cells in the hippocampus and increased differentiation into astrocytes, resulting in neuronal regeneration. DZXYS intervention in GAD rats can improve appetite, promote weight growth, and significantly reverse the anxiety behavior of GAD rats, which can inhibit the upregulation of key targets of the Notch signaling pathway, promote the differentiation of neural stem cells in the hippocampus into neurons, and inhibit their differentiation into astrocytes, thus alleviating anxiety behavior.</jats:p><jats:p><jats:bold>Conclusion:</jats:bold> The occurrence of GAD is closely related to the upregulation of the Notch signaling pathway, which hinders the regeneration of normal neurons in the hippocampus, while DZXYS can downregulate the Notch signaling pathway and promote neuronal regeneration in the hippocampus, thereby relieving anxiety behavior.</jats:p> | [
{
"section_content": "Generalized anxiety disorder (GAD) is a chronic anxiety disorder characterized by persistent significant tension, accompanied by autonomic nervous function excitement and over alertness. According to the World Health Organization (WHO) World Mental Health Survey, anxiety disorder is the mo... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGMENTS",
"section_num": null
},
{
"section_content": "Thank Servicebio Technology Co., Ltd. for its help in the immunofluorescence experiment in this experiment. Thank Ran Xue for his guidance in the production of this picture.",
"section_na... |
10.1101/2021.06.03.446738 | The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins | <jats:title>Abstract</jats:title><jats:p>CD8<jats:sup>+</jats:sup> T cell differentiation into effector cells is initiated early after antigen encounter by signals from the T cell antigen receptor and costimulatory molecules. The molecular mechanisms that establish the timing and rate of differentiation however are not defined. Here we show that the RNA binding proteins (RBP) ZFP36 and ZFP36L1 limit the rate of differentiation of activated naïve CD8<jats:sup>+</jats:sup> T cells and the potency of the resulting cytotoxic lymphocytes. The RBP function in an early and short temporal window to enforce dependency on costimulation via CD28 for full T cell activation and effector differentiation by directly binding mRNA of <jats:italic>NF-κB</jats:italic>, <jats:italic>Irf8</jats:italic> and <jats:italic>Notch1</jats:italic> transcription factors and cytokines, including <jats:italic>Il2</jats:italic>. Their absence in T cells, or the adoptive transfer of small numbers of CD8<jats:sup>+</jats:sup> T cells lacking the RBP, promotes resilience to influenza A virus infection without immunopathology. These findings highlight ZFP36 and ZFP36L1 as nodes for the integration of the early T cell activation signals controlling the speed and quality of the CD8<jats:sup>+</jats:sup> T cell response.</jats:p> | [
{
"section_content": "CD8 + T cells are instrumental for the clearance of pathogen infected or malignant cells and the provision of immune memory. \n\nUpon T cell receptor (TCR) sensing of peptide presented by MHC-I, naive CD8 + T cells exit quiescence and engage a differentiation program to form cytotoxic T-ly... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "We thank the Babraham Institute Biological Support Unit, Flow Cytometry and Kirsty Bates, Anne Segonds-Pichon and the Bioinformatics Facilities for assistance; Elisa Monzon-Casanova, Adrian L... |
10.1186/s13075-023-03039-1 | Notch signaling is activated in knee-innervating dorsal root ganglia in experimental models of osteoarthritis joint pain | <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>We aimed to explore activation of the Notch signaling pathway in knee-innervating lumbar dorsal root ganglia (DRG) in the course of experimental osteoarthritis (OA) in mice, and its role in knee hyperalgesia.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Cultured DRG cells were stimulated with the TLR4 agonist, lipopolysaccharide (LPS). Notch signaling in the cells was either inhibited with the γ-secretase inhibitor, DAPT, or with soluble Jagged1, or activated through immobilized Jagged1. CCL2 production was analyzed at mRNA and protein levels. In in vivo experiments, knee hyperalgesia was induced in naïve mice through intra-articular (IA) injection of LPS. The effect of inhibiting Notch signaling was examined by pre-injecting DAPT one hour before LPS. OA was induced through surgical destabilization of the medial meniscus (DMM) in male C57BL/6 mice. Gene expression in DRG was analyzed by qRT-PCR and RNAscope in situ hybridization. Activated Notch protein (NICD) expression in DRG was evaluated by ELISA and immunofluorescence staining. DAPT was injected IA 12 weeks <jats:italic>post</jats:italic> DMM to inhibit Notch signaling, followed by assessing knee hyperalgesia and CCL2 expression in the DRG.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>In DRG cell cultures, LPS increased NICD in neuronal cells. Inhibition of Notch signaling with either DAPT or soluble Jagged1 attenuated LPS-induced increases of <jats:italic>Ccl2</jats:italic> mRNA and CCL2 protein. Conversely, activating Notch signaling with immobilized Jagged1 enhanced these LPS effects. In vivo, IA injection of LPS increased expression of Notch genes and NICD in the DRG. Pre-injection of DAPT prior to LPS alleviated LPS-induced knee hyperalgesia, and decreased LPS-induced CCL2 expression in the DRG. Notch signaling genes were differentially expressed in the DRG from late-stage experimental OA. <jats:italic>Notch1</jats:italic>, <jats:italic>Hes1</jats:italic>, and NICD were increased in the neuronal cell bodies in DRG after DMM surgery. IA administration of DAPT alleviated knee hyperalgesia <jats:italic>post</jats:italic> DMM, and decreased CCL2 expression in the DRG.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These findings suggest a synergistic effect of Notch signaling with TLR4 in promoting CCL2 production and mediating knee hyperalgesia. Notch signaling is activated in knee-innervating lumbar DRG in mice with experimental OA, and is involved in mediating knee hyperalgesia. The pathway may therefore be explored as a target for alleviating OA pain.</jats:p> </jats:sec> | [
{
"section_content": "Keywords Notch signaling, Dorsal root ganglia, Osteoarthritis, Pain, Mouse model",
"section_name": "",
"section_num": ""
},
{
"section_content": "Our incomplete understanding of the mechanisms underlying joint pain in osteoarthritis (OA) accounts for the general ineffective... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "Not applicable.",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "",
"section_name": "Funding",
"section_num": null
},
{
"sec... |
10.18632/oncotarget.24927 | Assessment of micro RNAs expression in leukemic cells as prognostic markers in chronic lymphocytic leukemia: micro RNAs can predict survival in a course of the disease | Numerous genetic alterations predicting prognosis and clinical outcome are revealed recently in chronic lymphocytic leukemia (CLL). Among them the deregulated expression of micro RNAs that can induce tumor growth, or act as tumor suppressors seem to be of great importance. This study aimed to analyze the possible role of chosen micro RNAs as markers of prognosis in patients with CLL. We assessed the expression of miR-21, miR-34a, miR-181a, miR-199a/b and miR-221 in previously separated leukemic cells with the use of qRQ-PCR technique at the moment of diagnosis. The results were then analyzed in regards to presence of prognostic factors, clinical data and the end points like progression free survival (PFS), time to progression (TP) and overall survival time (OS). We detected significant correlations between expression of the analyzed micro RNAs and CLL prognostic markers particularly as far as miR-221 and miR-181a were concerned. The subsequent analysis revealed that high expression of miR-34a and miR-181a as well as low miR-21 expression indicated longer TTP, while miR-221 was predictor of OS. The obtained results prove the role of micro RNAs as CLL prognostic markers, particularly as factors predicting survival in a course of the disease. | [
{
"section_content": "Chronic lymphocytic leukemia (CLL), one of the most frequently diagnosed leukemias, is characterized by the accumulation of leukemic CD19+/CD5+/CD23+ B cells in the blood, bone marrow, lymph nodes and spleen [1, 2]. Clinical course and prognosis of this type of leukemia are highly variable... | [
{
"section_content": "",
"section_name": "FUNDING",
"section_num": null
},
{
"section_content": "This study was funded by the research grant of Medical University of Lublin [ DS176 ].",
"section_name": "FUNDING",
"section_num": null
},
{
"section_content": "",
"section_name":... |
10.3390/toxins16090394 | Proteome and Phosphoproteome Profiling Reveal the Toxic Mechanism of Clostridium perfringens Epsilon Toxin in MDCK Cells | <jats:p>Epsilon toxin (ETX), a potential agent of biological and toxic warfare, causes the death of many ruminants and threatens human health. It is crucial to understand the toxic mechanism of such a highly lethal and rapid course toxin. In this study, we detected the effects of ETX on the proteome and phosphoproteome of MDCK cells after 10 min and 30 min. A total of 44 differentially expressed proteins (DEPs) and 588 differentially phosphorylated proteins (DPPs) were screened in the 10 min group, while 73 DEPs and 489 DPPs were screened in the 30 min group. ETX-induced proteins and phosphorylated proteins were mainly located in the nucleus, cytoplasm, and mitochondria, and their enrichment pathways were related to transcription and translation, virus infection, and intercellular junction. Meanwhile, the protein–protein interaction network screened out several hub proteins, including SRSF1/2/6/7/11, SF3B1/2, NOP14/56, ANLN, GTPBP4, THOC2, and RRP1B. Almost all of these proteins were present in the spliceosome pathway, indicating that the spliceosome pathway is involved in ETX-induced cell death. Next, we used RNAi lentiviruses and inhibitors of several key proteins to verify whether these proteins play a critical role. The results confirmed that SRSF1, SF3B2, and THOC2 were the key proteins involved in the cytotoxic effect of ETX. In addition, we found that the common upstream kinase of these key proteins was SRPK1, and a reduction in the level of SRPK1 could also reduce ETX-induced cell death. This result was consistent with the phosphorylated proteomics analysis. In summary, our study demonstrated that ETX induces phosphorylation of SRSF1, SF3B2, THOC2, and SRPK1 proteins on the spliceosome pathway, which inhibits normal splicing of mRNA and leads to cell death.</jats:p> | [
{
"section_content": "Epsilon toxin (ε-toxin, ETX), produced by Clostridium perfringens types B and D [1], is the causative agent of enterotoxaemia in animals [2, 3] and is also considered to be related to multiple sclerosis in humans, causing human health threats and economic losses to the global livestock ind... | [
{
"section_content": "",
"section_name": "Data Availability Statement:",
"section_num": null
},
{
"section_content": "The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.",
"section_name": "Data Availabili... |
10.1186/s12935-017-0496-5 | A novel Notch1 missense mutation (C1133Y) in the Abruptex domain exhibits enhanced proliferation and invasion in oral squamous cell carcinoma | Notch1 has been regarded as a fundamental regulator in tissue differentiation and stem cell properties. Recently, Notch1 mutations have been reported intensively both in solid tumors and in hematopoietic malignancies. However, little is known about the biological effect and the clinical implication of these reported mutations. Previously, we discovered several missense mutations in the Notch1 receptor in a Chinese population with oral squamous cell carcinoma (OSCC).We selected a 'hotspot' mutation in the Abruptex domain (C1133Y). The expression of Notch1 was determined by western blot and real-time qPCR in OSCC cell lines transfected with pcDNA3.1-Notch1WT, pcDNA3.1-Notch1C1133Y, or pcDNA3.1 empty vector. CCK-8 assays were used to assess cell proliferation. Flow cytometry and western blot were used to confirm the alteration of cell cycle after transfection. Transwell assays and the detection of Epithelial-to-mesenchymal transition (EMT) markers were used to determine the invasive ability. The effects of Notch1 C1133Y mutation were analyzed by Immunofluorescence staining and the expression of EGFR-PI3K/AKT signaling.We demonstrated that Notch1C1133Y mutation inactivated the canonical Notch1 signaling. We identified an oncogenic phenotype of this mutation by promoting cell proliferation, invasion and by inducing EMT in OSCC cell lines. We found that the Notch1C1133Y mutation exhibited a decreased S1-cleavage due to the impaired transport of Notch1 protein from the endoplasmic reticulum (ER) to the Golgi complex, which was consistent with the observation of the failure of the Notch1C1133Y mutated receptor to present at the cell surface. Importantly, the mutated Notch1 activated the EGFR-PI3K/AKT signaling pathway, which has been confirmed as an overwhelming modulator in OSCC.Taken together, our findings revealed for the first time a novel Notch1 mutation that enhances proliferation and invasion in OSCC cell lines. The Notch1 C1133Y mutation impairs the processing of notch1 protein and the critical links between the mutated Notch1 and the activated EGFR-PI3K/AKT signaling pathway. | [
{
"section_content": "Oral squamous cell carcinoma (OSCC) is a locally aggressive epithelial neoplasm, having a propensity of lymph-node metastasis and a poor prognosis [1] [2] [3]. Although the etiology and mechanisms of OSCC malignant progression, such as tumor proliferation, invasion, metastasis and stem cel... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "Not applicable.",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "",
"section_name": "Funding",
"section_num": null
},
{
"sec... |
10.1186/1755-8166-6-5 | Atypical rearrangement involving 3′-IGH@ and a breakpoint at least 400 Kb upstream of an intact MYC in a CLL patient with an apparently balanced t(8;14)(q24.1;q32) and negative MYC expression | <jats:title>Abstract</jats:title> <jats:p>The t(8;14)(q24.1;q32), the cytogenetic hallmark of Burkitt’s lymphoma, is also found, but rarely, in cases of chronic lymphocytic leukemia (CLL). Such translocation typically results in a <jats:italic>MYC</jats:italic>-<jats:italic>IGH@</jats:italic> fusion subsequently deregulating and overexpressing <jats:italic>MYC</jats:italic> on der 14q32. In CLL, atypical rearrangements resulting in its gain or loss, within or outside of <jats:italic>IGH@</jats:italic> or <jats:italic>MYC</jats:italic> locus, have been reported, but their clinical significance remains uncertain. Herein, we report a 67 year-old male with complex cytogenetic findings of apparently balanced t(8;14) and unreported complex rearrangements of <jats:italic>IGH@</jats:italic> and <jats:italic>MYC</jats:italic> loci. His clinical, morphological and immunophenotypic features were consistent with the diagnosis of CLL.</jats:p> <jats:p>Interphase FISH studies revealed deletions of 11q22.3 and 13q14.3, and an extra copy of <jats:italic>IGH@,</jats:italic> indicative of rearrangement. Karyotype analysis showed an apparently balanced t(8;14)(q24.1;q32). Sequential GPG-metaphase FISH studies revealed abnormal signal patterns: rearrangement of IGH break apart probe with the 5’-IGH@ on derivative 8q24.1 and the 3’-IGH@ retained on der 14q; absence of MYC break apart-specific signal on der 8q; and, the presence of unsplit 5’-<jats:italic>MYC</jats:italic>-3’ break apart probe signals on der 14q. The breakpoint on 8q24.1 was found to be at least 400 Kb upstream of 5’ of <jats:italic>MYC</jats:italic>. In addition, FISH studies revealed two abnormal clones; one with 13q14.3 deletion, and the other, with concurrent 11q deletion and atypical rearrangements. Chromosome microarray analysis (CMA) detected a 7.1 Mb deletion on 11q22.3-q23.3 including <jats:italic>ATM</jats:italic>, a finding consistent with FISH results. While no significant copy number gain or loss observed on chromosomes 8, 12 and 13, a 455 Kb microdeletion of uncertain clinical significance was detected on 14q32.33. Immunohistochemistry showed co-expression of CD19, CD5, and CD23, positive ZAP-70 expression and absence of <jats:italic>MYC</jats:italic> expression. Overall findings reveal an apparently balanced t(8;14) and atypical complex rearrangements involving 3’-<jats:italic>IGH@</jats:italic> and a breakpoint at least 400 Kb upstream of <jats:italic>MYC</jats:italic>, resulting in the relocation of the intact 5’-<jats:italic>MYC</jats:italic>-3’ from der 8q, and apposition to 3’-<jats:italic>IGH@</jats:italic> at der 14q. This case report provides unique and additional cytogenetic data that may be of clinical significance in such a rare finding in CLL. It also highlights the utility of conventional and sequential metaphase FISH in understanding complex chromosome anomalies and their association with other clinical findings in patients with CLL. To the best of our knowledge, this is the first CLL reported case with such an atypical rearrangement in a patient with a negative <jats:italic>MYC</jats:italic> expression.</jats:p> | [
{
"section_content": "Chronic lymphocyctic leukemia (CLL) is the most common leukemia in the elderly with clinical presentation of lymphocytosis, bone marrow involvement, lymphadenopathy, hepatosplenomegaly, complex cytogenetics and heterogeneous clinical course [1]. Immunophenotypically, aberrant expression of... | [
{
"section_content": "",
"section_name": "Acknowledgement",
"section_num": null
},
{
"section_content": "We would like to thank the assistance of the following UCLA Cytogenetics Lab Staff : Lynn Yang for her technical assistance and her willingness to help and make this project possible. We woul... |
10.1007/s10067-015-3014-y | Education for patients with rheumatoid arthritis in Latin America and the Caribbean | La educación del paciente es muy recomendable en la artritis reumatoide (AR) para apoyar el manejo del paciente. El desafío es cumplir con las recomendaciones para brindar educación sanitaria a los pacientes con AR en los países de América Latina y el Caribe (ALC) teniendo en cuenta factores como el analfabetismo en la salud de los pacientes, la falta de reumatólogos y la falta de recursos, incluido el acceso a medicamentos antirreumáticos modificadores de la enfermedad (FARME). Dado que el material educativo existente en los idiomas regionales no está fácilmente disponible y es inadecuado, proponemos desarrollar un programa educativo basado en la web que cumpla con los requisitos de la mayoría de los pacientes con AR en los países de ALC con énfasis en el uso correcto y seguro del metotrexato. | [
{
"section_content": "Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 0. 5-1 % of the adult population. RA produces pain, fatigue, and work incapacity, is potentially disabling, and shortens life expectancy. Much progress has been made in RA treatment in the last decades with... | [] |
10.3389/fonc.2022.841630 | Impact of Low-Burden TP53 Mutations in the Management of CLL | <jats:p>In chronic lymphocytic leukemia (CLL), <jats:italic>TP53</jats:italic> abnormalities are associated with reduced survival and resistance to chemoimmunotherapy (CIT). The recommended threshold to clinically report <jats:italic>TP53</jats:italic> mutations is a matter of debate given that next-generation sequencing technologies can detect mutations with a limit of detection of approximately 1% with high confidence. However, the clinical impact of low-burden <jats:italic>TP53</jats:italic> mutations with a variant allele frequency (VAF) of less than 10% remains unclear. Longitudinal analysis before and after fludarabine based on NGS sequencing demonstrated that low-burden <jats:italic>TP53</jats:italic> mutations were present before the onset of treatment and expanded at relapse to become the predominant clone. Most studies evaluating the prognostic or predictive impact of low-burden <jats:italic>TP53</jats:italic> mutations in untreated patients show that low-burden <jats:italic>TP53</jats:italic> mutations have the same unfavorable prognostic impact as clonal defects. Moreover, studies designed to assess the predictive impact of low-burden <jats:italic>TP53</jats:italic> mutations showed that <jats:italic>TP53</jats:italic> mutations, irrespective of mutation burden, have an inferior impact on overall survival for CIT-treated patients. As low-burden and high-burden <jats:italic>TP53</jats:italic> mutations have comparable clinical impacts, redefining the VAF threshold may have important implications for the clinical management of CLL.</jats:p> | [
{
"section_content": "The heterogeneous clinical course of chronic lymphocytic leukemia has highlighted the need to define prognostic and predictive markers to improve the management of patients (1). On one hand, prognostic markers reflect the underlying biology and natural history of CLL and are informative fo... | [
{
"section_content": "",
"section_name": "AUTHOR CONTRIBUTIONS",
"section_num": null
},
{
"section_content": "All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.",
"section_name": "AUTHOR CONTRIBUTIONS",
"section_... |
10.1371/journal.pone.0119723 | Epidermal Growth Factor Receptor Inhibition Reduces Angiogenesis via Hypoxia-Inducible Factor-1α and Notch1 in Head Neck Squamous Cell Carcinoma | Angiogenesis, a marker of cancer development, affects response to radiotherapy sensibility. This preclinical study aims to understand the receptor tyrosine kinase-mediated angiogenesis in head neck squamous cell carcinoma (HNSCC). The receptor tyrosine kinase activity in a transgenic mouse model of HNSCC was assessed. The anti-tumorigenetic and anti-angiogenetic effects of cetuximab-induced epidermal growth factor receptor (EGFR) inhibition were investigated in xenograft and transgenic mouse models of HNSCC. The signaling transduction of Notch1 and hypoxia-inducible factor-1α (HIF-1α) was also analyzed. EGFR was overexpressed and activated in the Tgfbr1/Pten deletion (2cKO) mouse model of HNSCC. Cetuximab significantly delayed tumor onset by reducing tumor angiogenesis. This drug exerted similar effects on heterotopic xenograft tumors. In the human HNSCC tissue array, increased EGFR expression correlated with increased HIF-1α and micro vessel density. Cetuximab inhibited tumor-induced angiogenesis in vitro and in vivo by significantly downregulating HIF-1α and Notch1. EGFR is involved in the tumor angiogenesis of HNSCC via the HIF-1α and Notch1 pathways. Therefore, targeting EGFR by suppressing hypoxia- and Notch-induced angiogenesis may benefit HNSCC therapy. | [
{
"section_content": "Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most frequent cancer worldwide with approximately 500,000 new cases per year worldwide [1]. Previous studies have established that risk factors, such as alcohol drinking, smoking, and human papilloma virus infection, contribu... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "We thank Dr. Ashok B. Kulkarni of LCDB, National Institute of Dental and Craniofacial Research, NIH, USA for gift Tgfbr1/Pten 2cKO mice. We thank EssayStar for its linguistic assistance durin... |
10.1371/journal.pone.0247717 | Subcutaneous immunoglobulins replacement therapy in secondary antibody deficiencies: Real life evidence as compared to primary antibody deficiencies | <jats:p>Secondary antibody deficiencies (SAD) may require immunoglobulin replacement therapy (IgRT). While the intravenous route (IVIG) is broadly considered effective in SAD, the use of subcutaneous immunoglobulins (SCIG) is mainly adopted from the experience in primary antibody deficiencies (PAD), where SCIG have been shown to perform as effective as IVIG. However, evidence-based data on SCIG administration in SAD patients are still insufficient. Herein we retrospectively evaluated the efficacy and safety profile of SCIG treatment in 131 SAD patients as compared to a group of 102 PAD patients. We found SCIG being equally effective in reducing annual infectious rate both in SAD and PAD patients. However, SAD patients required lower SCIG dosage and lower IgG through level to achieve similar biological effect in terms of infection burden, at the steady state. SAD patients also showed better correlation between SCIG dose and serum IgG achieved value. Furthermore, within SAD, SCIG were found to work irrespective of the underlying disease. Especially in Non-Hodgkin Lymphoma patients, whose indication to IgRT is still not included in all guidelines and for whom evidence-based data are still lacking, SCIG were as effective as in Chronic Lymphocytic Leukemia or Multiple Myeloma patients, and SCIG discontinuation, without evidence of B cell recovery, led to IgG decline and relapsed infections. Finally, treatment tolerance in SAD patients was comparable to the PAD cohort. Globally, our data suggest that SCIG, as already appreciated in PAD, represent a valuable option in SAD patients, independent on the disease leading to antibody deficiency.</jats:p> | [
{
"section_content": "The purpose of this core SmPC is to provide applicants and regulators with harmonised guidance on the information to be included in the summary of product characteristics (SmPC) for a human normal immunoglobulin for intravenous administration (IVIg). This guideline should be read in conjun... | [
{
"section_content": "EMA/CHMP/BPWP/94038/2007 replaced guideline on core SmPC for human normal immunoglobulin for intravenous administration (IVIg) with reference number CPMP/BPWP/859/95.",
"section_name": "",
"section_num": ""
},
{
"section_content": "",
"section_name": "Breast-feeding",
... |
10.1007/s12185-022-03414-9 | ASXL1 mutations with serum EPO levels predict poor response to darbepoetin alfa in lower-risk MDS: W-JHS MDS01 trial | <jats:title>Abstract</jats:title><jats:p>Darbepoetin alfa (DA) is used to treat anemia in lower-risk (IPSS low or int-1) myelodysplastic syndromes (MDS). However, whether mutations can predict the effectiveness of DA has not been examined. The present study aimed to determine predictive gene mutations. The primary endpoint was a correlation between the presence of highly frequent (≥ 10%) mutations and hematological improvement-erythroid according to IWG criteria 2006 by DA (240 μg/week) until week 16. The study included 79 patients (age 29–90, median 77.0 years; 52 [65.8%] male). Frequently (≥ 10%) mutated genes were <jats:italic>SF3B1</jats:italic> (24 cases, 30.4%), <jats:italic>TET2</jats:italic> (20, 25.3%), <jats:italic>SRSF2</jats:italic> (10, 12.7%), <jats:italic>ASXL1</jats:italic> (9, 11.4%), and <jats:italic>DNMT3A</jats:italic> (8, 10.1%). Overall response rate to DA was 70.9%. Multivariable analysis including baseline erythropoietin levels and red blood cell transfusion volumes as variables revealed that erythropoietin levels and mutations of <jats:italic>ASXL1</jats:italic> gene were significantly associated with worse response (odds ratio 0.146, 95% confidence interval 0.042–0.503; <jats:italic>p</jats:italic> = 0.0023, odds ratio 0.175, 95% confidence interval 0.033–0.928; <jats:italic>p</jats:italic> = 0.0406, respectively). This study indicated that anemic patients who have higher erythropoietin levels and harbor <jats:italic>ASXL1</jats:italic> gene mutations may respond poorly to DA. Alternative strategies are needed for the treatment of anemia in this population. Trial registration number and date of registration: UMIN000022185 and 09/05/2016.</jats:p> | [
{
"section_content": "Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis, and occasionally progress to acute myelogenous leukemia (AML) [1, 2]. The pathogenesis of MDS is thought to be a multistep process involving two or more genetic alterations that cause... | [
{
"section_content": "Acknowledgements This study was funded by Kyowa Kirin Co., Ltd., and was supported by the Ministry of Education, Culture, Sports, Science and Technology under Grant number hp160219 and hp200138 and by AMED under Grand number JP20cm0106501h0005 to SO. We would like to thank all of the parti... |
10.1038/s41598-024-59882-y | Targeting the ZMIZ1-Notch1 signaling axis for the treatment of tongue squamous cell carcinoma | <jats:title>Abstract</jats:title><jats:p>Zinc finger MIZ-type containing 1 (ZMIZ1) is a transcriptional coactivator related to the protein inhibitors of activated STATs (PIAS) family. Mounting evidence suggests that ZMIZ1 plays a crucial role in the occurrence and development of cancers. The function of ZMIZ1 in tongue squamous cell carcinoma (TSCC) and the mechanisms underpinning its role in this disease have not been fully clarified. We performed qualitative ZMIZ1 protein expression analyses using immunohistochemistry in 20 patient-derived, paraffin-embedded TSCC tissue sections. We used RNAi to knock down ZMIZ1 expression in the CAL-27 TSCC cell line and quantified the impact of ZMIZ1 knock down on proliferation, migration and apoptosis via CCK-8, scratch assay and flow cytometry, respectively. We used qRT-PCR and western blotting to investigate the role of ZMIZ1 in this cell line. Finally, we established a model of lung metastasis in nude mice to replicate the in vitro results. ZMIZ1 protein was significantly more abundant in TSCC case tissue samples. ZMIZ1 knockdown reduced the invasion and metastases of TSCC tumor cells and promoted apoptosis. ZMIZ1 knockdown was associated with the down-regulation of Notch signaling pathway related factors Jagged1 and Notch1, and invasion and metastasis related factors MKP-1, SSBP2 and MMP7 in vitro and in vivo, at the mRNA level. In vitro and in vivo data suggest that knock down of ZMIZ1 may inhibit TSCC invasion and metastasis by modulating Notch signaling. ZMIZ1 inhibition may therefore represent a new therapeutic target for TSCC.</jats:p> | [
{
"section_content": "www. nature. com/scientificreports/ Notch1 exhibited elevated expression and promotes TSCC invasion and metastasis by modulating the expression of matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition 14. Moreover, Notch1 expression can be used as a primary biomarker to ai... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "This study was supported by the National Natural Science Foundation of China ( 81773942 ), the Scientific and Technological Foundation of Gansu Province ( 21JR1RA112, 20JR10FA670 ), and the ... |
10.1038/s41375-023-01845-9 | Clinical impact of TP53 disruption in chronic lymphocytic leukemia patients treated with ibrutinib: a campus CLL study | NA | [
{
"section_content": "TO THE EDITOR Disruption of the TP53 gene, either by deletion at chromosome 17p13. 1 (del17p) or mutations, is the most important prognostic/ predictive biomarker in chronic lymphocytic leukemia (CLL), also in the context of the novel target therapies including ibrutinib [1] [2] [3] [4]. A... | [
{
"section_content": "",
"section_name": "DATA AVAILABILITY",
"section_num": null
},
{
"section_content": "The data that support the findings of this study are available from the corresponding author upon request.",
"section_name": "DATA AVAILABILITY",
"section_num": null
},
{
"s... |
10.1371/journal.pone.0039725 | NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches | Leukemia initiating cells (LIC) contribute to therapeutic resistance through acquisition of mutations in signaling pathways, such as NOTCH1, that promote self-renewal and survival within supportive niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in therapeutic resistance. However, the cell type and context specific consequences of NOTCH1 activation, its role in human LIC regeneration, and sensitivity to NOTCH1 inhibition in hematopoietic microenvironments had not been elucidated.We established humanized bioluminescent T-ALL LIC mouse models transplanted with pediatric T-ALL samples that were sequenced for NOTCH1 and other common T-ALL mutations. In this study, CD34(+) cells from NOTCH1(Mutated) T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1(Wild-type) CD34(+) cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1(Mutated) CD34(+) fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1(Mutated) T-ALL LIC-engrafted mice and resulted in depletion of CD34(+)CD2(+)CD7(+) cells that harbor serial transplantation capacity.These results reveal a functional hierarchy within the LIC population based on NOTCH1 activation, which renders LIC susceptible to targeted NOTCH1 inhibition and highlights the utility of NOTCH1 antibody targeting as a key component of malignant stem cell eradication strategies. | [
{
"section_content": "Seminal research suggests that leukemia relapse occurs because standard chemotherapy fails to eradicate self-renewing leukemia initiating cells (LIC) [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]. While human myeloid leukemia xenograft studies demonstrate that LIC resid... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "We are grateful to Dennis Young of the University of California at San Diego Moores Cancer Center FACS facility for his expert assistance with FACS Aria analysis and sorting; Drs Mitchell B. ... |
10.1016/j.hoc.2013.01.006 | Ibrutinib (PCI-32765) in Chronic Lymphocytic Leukemia | B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy. | [
{
"section_content": "Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world with approximately 16,060 men and women expected to be diagnosed with CLL in year 2012 in the United States. 1 Most patients with CLL do not need treatment at diagnosis; however, the majority of p... | [
{
"section_content": "",
"section_name": "KEY POINTS",
"section_num": null
},
{
"section_content": "• B-cell receptor (BCR) signaling plays a crucial role in pathogenesis of chronic lymphocytic leukemia (CLL). \n\n• Many kinases in the BCR signaling pathway are being explored as therapeutic targ... |
10.3324/haematol.2011.049155 | The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC- II depletion | In spite of potent first-line therapies for chronic lymphocytic leukemia, treatment remains palliative and all patients frequently relapse. Treatment options for these patients are more limited. BL22 is a recombinant protein composed of the variable region of a monoclonal antibody that binds to CD22 and of PE38, a truncated Pseudomonas exotoxin. BL22 is a very potent drug already used in patients with hairy cell leukemia, whereas in chronic lymphocytic leukemia its cytotoxicity is limited by a lower expression of CD22. Here we demonstrate that this limitation can be overcome by pre-activation of chronic lymphocytic leukemia cells with bryostatin 1.Primary malignant B cells from chronic lymphocytic leukemia and mantle cell lymphoma patients were used in vitro to assess the therapeutic impact of drug combinations using BL22 and bryostatin 1.We demonstrate that bryostatin 1 sensitizes chronic lymphocytic leukemia cells for the cytotoxic effects of BL22 through activation of protein kinase C and subsequently increased CD22 surface expression. Dose and time response analysis reveals that activation of protein kinase C further activates an autocrine feedback loop degrading protein kinase C-βII protein. Depletion of protein kinase C-βII and upregulation of CD22 persist for several days following pre-stimulation with bryostatin 1. Therefore, our data provide a rationale for the sequential administration of BL22 following bryostatin 1 treatment. In addition to primary chronic lymphocytic leukemia cells, bryostatin 1 also sensitizes diffuse large B-cell lymphoma and mantle cell lymphoma cells to BL22 induced apoptosis.Our data suggest that the combination of bryostatin 1 with antibodies directed against CD22 is a potent drug combination for the treatment of low- and high-grade B-cell lymphoma. | [
{
"section_content": "2] [3] The combination of the monoclonal antibody rituximab and fludarabine-based chemotherapies has now become the standard first-line therapy for young and fit CLL patients. However, in spite of excellent overall response rates, the disease still remains incurable with increasing shorter... | [
{
"section_content": "for helping to capture the images. Funding: this research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA to RJK and IP. This work was also supported by a grant from the Deutsche Forschungsgemeinschaft, Germany... |
10.1038/s41416-020-0887-6 | UGT2B17 modifies drug response in chronic lymphocytic leukaemia | <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>High UGT2B17 is associated with poor prognosis in untreated chronic lymphocytic leukaemia (CLL) patients and its expression is induced in non-responders to fludarabine-containing regimens. We examined whether UGT2B17, the predominant lymphoid glucuronosyltransferase, affects leukaemic drug response and is involved in the metabolic inactivation of anti-leukaemic agents.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Functional enzymatic assays and patients’ plasma samples were analysed by mass-spectrometry to evaluate drug inactivation by UGT2B17. Cytotoxicity assays and RNA sequencing were used to assess drug response and transcriptome changes associated with high UGT2B17 levels.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>High UGT2B17 in B-cell models led to reduced sensitivity to fludarabine, ibrutinib and idelalisib. UGT2B17 expression in leukaemic cells involved a non-canonical promoter and was induced by short-term treatment with these anti-leukaemics. Glucuronides of both fludarabine and ibrutinib were detected in CLL patients on respective treatment, however UGT2B17 conjugated fludarabine but not ibrutinib. AMP-activated protein kinase emerges as a pathway associated with high UGT2B17 in fludarabine-treated patients and drug-treated cell models. The expression changes linked to UGT2B17 exposed nuclear factor kappa B as a key regulatory hub.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Data imply that UGT2B17 represents a mechanism altering drug response in CLL through direct inactivation but would also involve additional mechanisms for drugs not inactivated by UGT2B17.</jats:p> </jats:sec> | [
{
"section_content": "Chronic lymphocytic leukaemia (CLL) is the most frequent adult leukaemia in the western world. Cancer growth varies widely with indolent and aggressive forms of CLL. In recent years, there has been substantial progress in the clinical management of CLL patients supported by a better risk s... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGEMENTS",
"section_num": null
},
{
"section_content": "We would like to thank Isabelle Laverdière and Dominic Bastien for their help with the FACS analysis of leukaemic cells, and Etienne Audet-Walsh for his helpful advices with expression analy... |
10.18632/oncotarget.26043 | Fludarabine-resistance associates with ceramide metabolism and leukemia stem cell development in chronic lymphocytic leukemia | Fludarabine (flu) -containing regimens such as flu, cyclophosphamide and rituximab have been established as one of the standard first line therapy in medically-fit chronic lymphocytic leukemia (CLL) patients. Therefore, flu-refractory (primary flu-insensitivity or flu-caused relapse) remains a major problem causing treatment failure for CLL patients. We isolated the peripheral blood mononuclear cells (PBMCs) from CLL patients and treated with flu to find flu-refractory cases, and established flu-resistant clonal cells to study molecular mechanism of flu-resistance. By comparing parental MEC-2 cells, a human CLL cell line, we found that flu-resistant clonal cells were significantly increased lethal dose 50 of flu concentration, and up-regulated expression of P-glycoprotein, a drug-resistant marker, glucosylceramide synthase (GCS), an enzyme that can convert ceramide to glucosylceramide, and CD34, a leukemia stem cell marker. Overexpression of GCS leads to promptly elimination of cellular ceramide levels and accumulation of glucosylceramide, which reduces apoptosis and promotes survival and proliferation of flu-resistant clonal cells. Furthermore, we demonstrated that the accumulation of glucosylceramide can be blocked by PDMP to restore flu-sensitivity in flu-resistant clonal cells. We also found that elevating glucosylceramide levels in flu-resistant clonal cells was associated with up-regulation of GCS and CD34 expression. Importantly, overexpression of GCS or CD34 was also determined in flu-refractory PBMCs. Our results show that flu-resistance is associated with the alteration of ceramide metabolism and the development of leukemia stem cell-like cells. The flu-resistance can be reversed by GCS inhibition as a novel strategy for overcoming drug resistance. | [
{
"section_content": "Chronic lymphocytic leukemia (CLL) is classified as a lymphoproliferative disorder characterized by the accumulation of a clonally expanded lymphocytic population with resistance to apoptosis and coexpression of CD5, CD19, and CD23 in B lymphocytes in the peripheral blood, lymph nodes, bon... | [
{
"section_content": "",
"section_name": "FUNDING",
"section_num": null
},
{
"section_content": "This work was supported by the grants from the Elsa U. Pardee Foundation and Saint Louis University.",
"section_name": "FUNDING",
"section_num": null
},
{
"section_content": "",
"... |
10.1007/s00277-024-05627-w | Conditional survival to assess prognosis in patients with chronic lymphocytic leukemia | <jats:title>Abstract</jats:title><jats:p>Biomarkers in chronic lymphocytic leukemia (CLL) allow assessment of prognosis. However, the validity of current prognostic biomarkers based on a single assessment point remains unclear for patients who have survived one or more years. Conditional survival (CS) studies that address how prognosis may change over time, especially in prognostic subgroups, are still rare. We performed CS analyses to estimate 5-year survival in 1-year increments, stratified by baseline disease characteristics and known risk factors in two community-based cohorts of CLL patients (Freiburg University Hospital (<jats:italic>n</jats:italic> = 316) and Augsburg University Hospital (<jats:italic>n</jats:italic> = 564)) diagnosed between 1984 and 2021. We demonstrate that 5-year CS probability is stable (app. 75%) for the entire CLL patient cohort over 10 years. While age, sex, and stage have no significant impact on CS, patients with high-risk disease features such as non-mutated <jats:italic>IGHV</jats:italic>, deletion 17p, and high-risk CLL-IPI have a significantly worse prognosis at diagnosis, and 5-year CS steadily decreases with each additional year survived. Our results confirm that CLL patients have a stable survival probability with excess mortality and that the prognosis of high-risk CLL patients declines over time. We infer that CS-based prognostic information is relevant for disease management and counseling of CLL patients.</jats:p> | [
{
"section_content": "Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous hematologic malignancy with variable outcomes [1, 2]. While some patients may have a prolonged survival without needing treatment, others experience a rapidly fatal disease course despite receiving highly effective therapies ... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "The authors thank the staff of the cancer registries of the University Hospitals of Augsburg and Freiburg, especially Mrs. Vera Gumpp, for collecting and providing patient data. The authors ... |
10.3390/cancers12113142 | A Molecular Test for Quantifying Functional Notch Signaling Pathway Activity in Human Cancer | <jats:p>Background: The Notch signal transduction pathway is pivotal for various physiological processes, including immune responses, and has been implicated in the pathogenesis of many diseases. The effectiveness of various targeted Notch pathway inhibitors may vary due to variabilities in Notch pathway activity among individual patients. The quantitative measurement of Notch pathway activity is therefore essential to identify patients who could benefit from targeted treatment. Methods: We here describe a new assay that infers a quantitative Notch pathway activity score from the mRNA levels of generally conserved direct NOTCH target genes. Following the calibration and biological validation of our Notch pathway activity model over a wide spectrum of human cancer types, we assessed Notch pathway activity in a cohort of T-ALL patient samples and related it to biological and clinical parameters, including outcome. Results: We developed an assay using 18 select direct target genes and high-grade serous ovarian cancer for calibration. For validation, seven independent human datasets (mostly cancer series) were used to quantify Notch activity in agreement with expectations. For T-ALL, the median Notch pathway activity was highest for samples with strong NOTCH1-activating mutations, and T-ALL patients of the TLX subtype generally had the highest levels of Notch pathway activity. We observed a significant relationship between ICN1 levels and the absence/presence of NOTCH1-activating mutations with Notch pathway activity scores. Patients with the lowest Notch activity scores had the shortest event-free survival compared to other patients. Conclusions: High Notch pathway activity was not limited to T-ALL samples harboring strong NOTCH1 mutations, including juxtamembrane domain mutations or hetero-dimerization combined with PEST-domain or FBXW7 mutations, indicating that additional mechanisms may activate Notch signaling. The measured Notch pathway activity was related to intracellular NOTCH levels, indicating that the pathway activity score more accurately reflects Notch pathway activity than when it is predicted on the basis of NOTCH1 mutations. Importantly, patients with low Notch pathway activity had a significantly shorter event-free survival compared to patients showing higher activity.</jats:p> | [
{
"section_content": "An increasing number of precision drugs are becoming available for clinical medicine, and many more are in development. These targeted drugs are intended for personalized medicine and aim at targeting the pathophysiological defects underlying specific diseases in individual patients. For c... | [
{
"section_content": "Funding: K. C. -B and R. H. are funded by the Dutch 'Kinderen Kanker Vrij ' foundation grants KiKa-295 and KiKa-219, respectively. V. C. is funded by the Dutch Cancer Society grant KWF-10355.",
"section_name": "",
"section_num": ""
}
] |
10.3960/jslrt.22047 | Concurrent development of small lymphocytic lymphoma and lung cancer: A report of two cases and a review of the literature | Small lymphocytic lymphoma (SLL) is a rare disease subtype which has the same morphological and immunophenotypic features as chronic lymphocytic leukemia (CLL) but does not demonstrate lymphocytosis and grows mainly in the lymph nodes and spleen. As with CLL, SLL patients tend to present with immune abnormalities, and are associated with an increased risk for developing second primary malignancies. We report here two cases of SLL who developed lung cancer concurrently. The biological and clinical features of these two patients were very similar to each other; they both developed SLL with trisomy 12 and lacked lymphocytosis or cytopenia. SLL cells involved nodal areas adjacent to lung adenocarcinoma which expressed PD-L1. One patient received immunochemotherapy including nivolumab and ipilimumab against lung cancer, and notably, transient deterioration of SLL occurred after the second cycle of immunochemotherapy along with the development of immune related adverse events. Immunohistochemical analysis of the SLL samples of the patient revealed that the tumor cells were positive for CTLA-4, suggesting that ipilimumab might have potentially induced the activation of SLL cells by blocking the inhibitory signal mediated by CTLA-4. These clinical findings indicate the potential biological relationship between SLL and lung cancer. According to these observations, we would like to draw attention to the possibility of deterioration of SLL when immune checkpoint inhibitors are used for the treatment of malignancies developed in SLL patients. | [
{
"section_content": "Chronic lymphocytic leukemia (CLL) is a lymphoid malignancy that is characterized by monoclonal B-cell lymphocytosis in the blood and lymphoid organs. Small lymphocytic lymphoma (SLL) is a rare disease subtype which has the same morphological and immunophenotypic features as CLL but does n... | [
{
"section_content": "",
"section_name": "CONFLICT OF INTEREST",
"section_num": null
},
{
"section_content": "The authors declare no potential conflict of interest in this work.",
"section_name": "CONFLICT OF INTEREST",
"section_num": null
}
] |
10.21203/rs.3.rs-3186246/v1 | 5-Aza-4’-thio-2’-deoxycytidine induces C&gt;G transversions in a specific trinucleotide context and leads to acute lymphoid leukemia | <jats:title>Abstract</jats:title> <jats:p>DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that are used clinically to decrease 5’-cytosine methylation, with the aim of re-expression of tumor suppressor genes. We used a murine pre-clinical model of myelodysplastic syndrome based on transplantation of cells expressing a NUP98::HOXD13 transgene to investigate 5-Aza-4’-thio-2’-deoxycytidine (Aza TdCyd or ATC), a thiol substituted DNMTi, as a potential therapy. We found that ATC treatment led to lymphoid leukemia in wild-type recipient cells; further study revealed that healthy mice treated with ATC also developed lymphoid leukemia. Whole exome sequencing revealed thousands of acquired mutations, almost all of which were C > G transversions in a previously unrecognized, specific 5’-NCG-3’ context. These mutations involved dozens of genes well-known to be involved in human lymphoid leukemia, such as <jats:italic>Notch1, Pten, Pax5, Trp53</jats:italic>, and <jats:italic>Nf1</jats:italic>. Treatment of human cells <jats:italic>in vitro</jats:italic> showed thousands of acquired C > G transversions in a similar context. Deletion of <jats:italic>Dck</jats:italic>, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C > G transversions. Taken together, these findings demonstrate that DNMTi can be potent mutagens in human and mouse cells, both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>.</jats:p> | [
{
"section_content": "Myelodysplastic syndromes (MDS) are a diverse group of blood cancers characterized by peripheral blood cytopenias and dysplastic blood cell morphology 1, 2. Up to 40% of patients with high risk MDS will transform to acute myeloid leukemia (AML) 3, an aggressive blood cancer with signi cant... | [
{
"section_content": "",
"section_name": "Acknowledgments:",
"section_num": null
},
{
"section_content": "The authors thank current and former members of the Aplan lab, Andre Nussenzweig, and Michael Kuehl (deceased) for insightful discussions. We thank the NCI Sequencing Minicore for Sanger seq... |
10.1038/s41419-022-05052-9 | Hydroxylation of the NOTCH1 intracellular domain regulates Notch signaling dynamics | <jats:title>Abstract</jats:title><jats:p>Notch signaling plays a pivotal role in the development and, when dysregulated, it contributes to tumorigenesis. The amplitude and duration of the Notch response depend on the posttranslational modifications (PTMs) of the activated NOTCH receptor – the NOTCH intracellular domain (NICD). In normoxic conditions, the hydroxylase FIH (factor inhibiting HIF) catalyzes the hydroxylation of two asparagine residues of the NICD. Here, we investigate how Notch-dependent gene transcription is regulated by hypoxia in progenitor T cells. We show that the majority of Notch target genes are downregulated upon hypoxia. Using a hydroxyl-specific NOTCH1 antibody we demonstrate that FIH-mediated NICD1 hydroxylation is reduced upon hypoxia or treatment with the hydroxylase inhibitor dimethyloxalylglycine (DMOG). We find that a hydroxylation-resistant NICD1 mutant is functionally impaired and more ubiquitinated. Interestingly, we also observe that the NICD1-deubiquitinating enzyme USP10 is downregulated upon hypoxia. Moreover, the interaction between the hydroxylation-defective NICD1 mutant and USP10 is significantly reduced compared to the NICD1 wild-type counterpart. Together, our data suggest that FIH hydroxylates NICD1 in normoxic conditions, leading to the recruitment of USP10 and subsequent NICD1 deubiquitination and stabilization. In hypoxia, this regulatory loop is disrupted, causing a dampened Notch response.</jats:p> | [
{
"section_content": "The highly conserved Notch signaling pathway regulates a wide range of biological processes such as immune cell development and function [1] vascular morphogenesis [2, 3] and its deregulation is frequently observed in cancer [4] [5] [6]. Notch signaling is activated by the binding of a Not... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGEMENTS",
"section_num": null
},
{
"section_content": "We are grateful to T. Schmidt-Wöll for excellent technical assistance. The authors wish to acknowledge Centro de Análisis Genómico (CNAG-CRG), Spain, for sequencing the RNA-Seq samples. The ... |
10.1371/journal.pone.0046627 | A Novel Anticancer Therapy That Simultaneously Targets Aberrant p53 and Notch Activities in Tumors | Notch signaling pathway plays an important role in tumorigenesis by maintaining the activity of self-renewal of cancer stem cells, and therefore, it is hypothesized that interference of Notch signaling may inhibit tumor formation and progression. H101 is a recombinant oncolytic adenovirus that is cytolytic in cells lacking intact p53, but it is unable to eradicate caner stem cells. In this study, we tested a new strategy of tumor gene therapy by combining a Notch1-siRNA with H101 oncolytic adenovirus. In HeLa-S3 tumor cells, the combined therapy blocked the Notch pathway and induced apoptosis in tumors that are p53-inactive. In nude mice bearing xenograft tumors derived from HeLa-S3 cells, the combination of H101/Notch1-siRNA therapies inhibited tumor growth. Moreover, Notch1-siRNA increased Hexon gene expression at both the transcriptional and the translational levels, and promoted H101 replication in tumors, thereby enhancing the oncolytic activity of H101. These data demonstrate the feasibility to combine H101 p53-targted oncolysis and anti-Notch siRNA activities as a novel anti-cancer therapy. | [
{
"section_content": "Most forms of cancer chemotherapy are unable to eradicate all malignant cells, and they often are highly toxic because of their lack of selectivity to cancer cells. As a result, new efforts have focused on developing interventions that include tumor-specific replicating viruses and siRNA. ... | [
{
"section_content": "This study was supported by The National Key Program for Basic Research of China ( 2010CB529902 ), The National Natural Science Foundation of China ( 10979034 and 81001008 ) to G. Q. ; The Science and Technology Commission of Shanghai ( 10JC1409100 ), The Shanghai Leading Academic Discipli... |
10.3324/haematol.2012.069369 | Clinical implications of the molecular genetics of chronic lymphocytic leukemia | Genetics and molecular genetics have contributed to clarify the biological bases of the clinical heterogeneity of chronic lymphocytic leukemia. In recent years, our knowledge of the molecular genetics of chronic lymphocytic leukemia has significantly broadened, offering potential new clinical implications. Mutations of TP53 and ATM add prognostic information independently of fluorescence in situ hybridization cytogenetic stratification. In addition, next generation sequencing technologies have allowed previously unknown genomic alterations in chronic lymphocytic leukemia to be identified. Mutations of NOTCH1, SF3B1 and BIRC3 have been associated with short time to progression and survival. Each of these lesions recognizes a different distribution across different clinical phases and biological subgroups of the disease. The clinical implications of these molecular lesions are in some instances well established, such as in the case of patients with TP53 disruption, who should be considered for alternative therapies/allogeneic stem cell transplant upfront, or in patients with ATM disruption, who are candidates to rituximab-based immunochemotherapy. On the contrary, NOTCH1, SF3B1 and BIRC3 mutations appear to have a specific significance, the clinical value of which is currently being validated, i.e. association to Richter syndrome transformation for NOTCH1 mutations, and short progression-free survival after treatment for SF3B1 mutations. Certainly, these new lesions have helped clarify the molecular bases of chronic lymphocytic leukemia aggressiveness beside TP53 disruption. This review covers the recent advancements in our understanding of the molecular genetics of chronic lymphocytic leukemia and discusses how they are going to translate into clinical implications for patient management. | [
{
"section_content": "The clinical course of chronic lymphocytic leukemia (CLL) is extremely heterogeneous. [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] The Rai and Binet clinical staging systems still remain the cornerstone for identifying CLL patients with advanced disease stages for whom treatme... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "The work by the authors described in this review was supported by AIRC Special Program Molecular Clinical Oncology, 5 x 1000, n. 10007, Milan, Italy (to RF and to GG); Compagnia di San Paolo,... |
10.30977/at.2219-8342.2019.44.0.5 | Research and diagnostics of electric car BMW I3 electric systems | The problem. The article considers the problem of increasing the efficiency of the use of electric vehicles. This is done by studying and diagnosing electrical equipment of the BMW i3 electric car. Goal. The purpose of the work is to increase the efficiency of the use of electric vehicles by studying and diagnosing electrical equipment of BMW i3 elec-tric vehicle. Methodology. Systematic, theoretical analysis of the methods applied to an electric car. The methodology is based on the integrated approach to studying the BMW i3. The research of the main components of the electrical equipment of the electric vehicle was carried out, its technical characteristics and the principle of operation of the power system were analyzed, issues of charging a high-voltage battery were considered. System power control functions were investigated. The diagnostics of BMW i3 power system in the conditions of the service station was performed. Results. It is established that the purpose of the power control program is to provide sufficient level of the battery charge in different conditions of car operation. It is determined that for the BMW i3 you can use 4 different types of charging. It has been discovered that an emergency situation caused by a discharged battery or problems in the on-board power grid may have various causes, which in most cases do not relate to a high-voltage rechargeable battery. Originality. In the article a comprehensive study of the BMW i3 electric vehicle was conducted. Practical value. New original knowledge has been gained that will improve the performance of BMW i3 electric vehicle. | [
{
"section_content": "Для досягнення поставленої мети необхідно вирішити такі завдання:\n\n-проаналізувати технічні характеристики електромобіля BMW i3 та дослідити його основні компоненти електрообладнання. До таких компонентів належать: система електроживлення, тягова акумуляторна батарея (ТАБ) з контролером ... | [] |
10.3389/fgene.2022.1001364 | Super-Enhancer–Associated nine-gene prognostic score model for prediction of survival in chronic lymphocytic leukemia patients | <jats:p>Chronic lymphocytic leukemia (CLL) is a type of highly heterogeneous mature B-cell malignancy with various disease courses. Although a multitude of prognostic markers in CLL have been reported, insights into the role of super-enhancer (SE)–related risk indicators in the occurrence and development of CLL are still lacking. A super-enhancer (SE) is a cluster of enhancers involved in cell differentiation and tumorigenesis, and is one of the promising therapeutic targets for cancer therapy in recent years. In our study, the CLL-related super-enhancers in the training database were processed by LASSO-penalized Cox regression analysis to screen a nine-gene prognostic model including TCF7, VEGFA, MNT, GMIP, SLAMF1, TNFRSF25, GRWD1, SLC6AC, and LAG3. The SE-related risk score was further constructed and it was found that the predictive performance with overall survival and time-to-treatment (TTT) was satisfactory. Moreover, a high correlation was found between the risk score and already known prognostic markers of CLL. In the meantime, we noticed that the expressions of TCF7, GMIP, SLAMF1, TNFRSF25, and LAG3 in CLL were different from those of healthy donors (<jats:italic>p</jats:italic> &lt; 0.01). Moreover, the risk score and LAG3 level of matched pairs before and after treatment samples varied significantly. Finally, an interactive nomogram consisting of the nine-gene risk group and four clinical traits was established. The inhibitors of mTOR and cyclin-dependent kinases (CDKs) were considered effective in patients in the high-risk group according to the pRRophetic algorithm. Collectively, the SE-associated nine-gene prognostic model developed here may be used to predict the prognosis and assist in the risk stratification and treatment of CLL patients in the future.</jats:p> | [
{
"section_content": "Chronic lymphocytic leukemia (CLL), a mature and monoclonal CD5+ CD23+ B cell malignancy, proliferates and accumulates in the bone marrow, blood, and lymphoid nodes (Hallek et al., 2018). It is often asymptomatic in the early stage. It is often found that painless lymphadenopathy or the ab... | [
{
"section_content": "",
"section_name": "Funding",
"section_num": null
},
{
"section_content": "This work was supported by the major subject of science and technology of Anhui province: (Grant number 201903a07020030 ).",
"section_name": "Funding",
"section_num": null
},
{
"secti... |
10.1186/1471-213x-8-75 | Msx1 and Msx2are required for endothelial-mesenchymal transformation of the atrioventricular cushions and patterning of the atrioventricular myocardium | <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p> <jats:italic>Msx1</jats:italic> and <jats:italic>Msx2</jats:italic>, which belong to the highly conserved <jats:italic>Nk</jats:italic> family of homeobox genes, display overlapping expression patterns and redundant functions in multiple tissues and organs during vertebrate development. <jats:italic>Msx1</jats:italic> and <jats:italic>Msx2</jats:italic> have well-documented roles in mediating epithelial-mesenchymal interactions during organogenesis. Given that both <jats:italic>Msx1</jats:italic> and <jats:italic>Msx2</jats:italic> are crucial downstream effectors of Bmp signaling, we investigated whether <jats:italic>Msx1</jats:italic> and <jats:italic>Msx2</jats:italic> are required for the Bmp-induced endothelial-mesenchymal transformation (EMT) during atrioventricular (AV) valve formation.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>While both <jats:italic>Msx1-/-</jats:italic> and <jats:italic>Msx2-/-</jats:italic> single homozygous mutant mice exhibited normal valve formation, we observed hypoplastic AV cushions and malformed AV valves in <jats:italic>Msx1-/-; Msx2-/-</jats:italic> mutants, indicating redundant functions of <jats:italic>Msx1</jats:italic> and <jats:italic>Msx2</jats:italic> during AV valve morphogenesis. In <jats:italic>Msx1/2</jats:italic> null mutant AV cushions, we found decreased Bmp2/4 and <jats:italic>Notch1</jats:italic> signaling as well as reduced expression of <jats:italic>Has2</jats:italic>, <jats:italic>NFATc1</jats:italic> and <jats:italic>Notch1</jats:italic>, demonstrating impaired endocardial activation and EMT. Moreover, perturbed expression of chamber-specific genes <jats:italic>Anf</jats:italic>, <jats:italic>Tbx2</jats:italic>, <jats:italic>Hand1</jats:italic> and <jats:italic>Hand2</jats:italic> reveals mispatterning of the <jats:italic>Msx1/2</jats:italic> double mutant myocardium and suggests functions of <jats:italic>Msx1</jats:italic> and <jats:italic>Msx2</jats:italic> in regulating myocardial signals required for remodelling AV valves and maintaining an undifferentiated state of the AV myocardium.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Our findings demonstrate redundant roles of <jats:italic>Msx1</jats:italic> and <jats:italic>Msx2</jats:italic> in regulating signals required for development of the AV myocardium and formation of the AV valves.</jats:p> </jats:sec> | [
{
"section_content": "A complex series of morphogenetic events and hemodynamic influences are required for cardiogenesis [1] [2] [3]. Malformations of cardiac valves constitute the most prevalent form of human birth defects, appearing in nearly one percent of newborn infants [4, 5]. The formation of cardiac val... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We are grateful to Dr. Chrissa Kioussi for the kind gift of anti-Pitx2 antibody, Dr. Vesa Kaartinen for the kind gift of anti-NFATc1 antibody, and Drs. James F. Martin and Eric N. Olson for ... |
10.1186/s13046-019-1076-4 | Combination of Enzastaurin and Ibrutinib synergistically induces anti-tumor effects in diffuse large B cell lymphoma | Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma. Although durable remissions can be achieved in more than half of these patients, DLBCL remains a significant clinical challenge, with approximately 30% of patients not being cured. BCR-associated kinases (SYK, BTK, and PI3K) inhibitors have exhibited encouraging pre-clinical and clinical effects, as reported by many researchers. Early studies demonstrated that protein kinase C-β (PKCβ) inhibitors alter phosphorylation level the Bruton's tyrosine kinase (BTK), which leads to enhanced BTK signaling. Here, for the first time, we investigate whether the combination of PKCβ inhibitor enzastaurin and BTK inhibitor ibrutinib has synergistic anti-tumor effects in DLBCL.In vitro cell proliferation was analyzed using Cell Titer-Glo Luminescent Cell Viability Assay. Induction of apoptosis and cell cycle arrest were measured by flow cytometry. Western Blotting analysis was used to detect the essential regulatory enzymes in related signaling pathways. RNA-seq was conducted to evaluate the whole transcriptome changes brought by co-treatment with low doses of enzastaurin and ibrutinib. The synergistic anti-tumor effects of enzastaurin and ibrutinib were also evaluated in vivo.Combination of enzastaurin and ibrutinib produced a lasting synergistic effect on the survival and proliferation of DLBCL cells, including reduction of proliferation, promoting apoptosis, inducting G1 phase arrest, preventing cell invasion and migration, and down-regulating activation of downstream signaling. More importantly, whole-transcriptome changes results showed that combination therapy worked synergistically to regulate whole-transcriptome expression compared with enzastaurin and ibrutinib alone. Co-treatment with low doses of enzastaurin and ibrutinib could effectively downregulate BCR, NF-κB, JAK and MAPK related signaling pathway. Furthermore, the mRNA expression analysis further indicated that co-treatment significantly decreased the mRNA levels of NOTCH1. The combination effect in inhibiting proliferation of DLBCL cells probably was realized through suppression of NOTCH1 expression. Finally, the anti-tumor activity of co-treatment also was demonstrated in vivo.Combination of enzastaurin and ibrutinib had synergistic anti-tumor effects in DLBCL, independent of molecular subtype. These results provided a sound foundation for an attractive therapeutic treatment, and the simultaneous suppression of BTK and PKCβ might be a new treatment strategy for DLBCL. | [
{
"section_content": "Diffuse large B cell lymphoma (DLBCL), the most common form of lymphoma, is characterized by a heterogeneous tumor entity that can vary in morphologic, biological, immunophenotypic, and clinical presentation, as well as therapeutic outcome [1]. Gene expression profiling can be used to diff... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We thank Dr. Fu from the University of Nebraska Medical Center in USA for the kind gifts of the DLCBL cell lines. We also thank Dr. Luo Wen from Denovo Biopharma for provide guidance for exp... |
10.7892/boris.126363 | Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients | Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal samples; on average, we identified ≈930 exon-exon junctions ("neojunctions") in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor samples, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor sample that are also predicted major histocompatibility complex-I binders ("putative neoantigens"). | [
{
"section_content": "und für die Berichterstattung an die Fakultäten der Universität und den Kanton Bern verwendet. (if necessary after consultation with the submitters, cf. below, 6. 4). Members of the Editorial Board are appointed by the Open Science Team of the University Library of Bern. \n\n• Roles of res... | [] |
10.3389/fgene.2021.747344 | Sequence Divergence and Functional Specializations of the Ancient Spliceosomal SF3b: Implications in Flexibility and Adaptations of the Multi-Protein Complex | <jats:p>Multi-protein assemblies are complex molecular systems that perform highly sophisticated biochemical functions in an orchestrated manner. They are subject to changes that are governed by the evolution of individual components. We performed a comparative analysis of the ancient and functionally conserved spliceosomal SF3b complex, to recognize molecular signatures that contribute to sequence divergence and functional specializations. For this, we recognized homologous sequences of individual SF3b proteins distributed across 10 supergroups of eukaryotes and identified all seven protein components of the complex in 578 eukaryotic species. Using sequence and structural analysis, we establish that proteins occurring on the surface of the SF3b complex harbor more sequence variation than the proteins that lie in the core. Further, we show through protein interface conservation patterns that the extent of conservation varies considerably between interacting partners. When we analyze phylogenetic distributions of individual components of the complex, we find that protein partners that are known to form independent subcomplexes are observed to share similar profiles, reaffirming the link between differential conservation of interface regions and their inter-dependence. When we extend our analysis to individual protein components of the complex, we find taxa-specific variability in molecular signatures of the proteins. These trends are discussed in the context of proline-rich motifs of SF3b4, functional and drug binding sites of SF3b1. Further, we report key protein-protein interactions between SF3b1 and SF3b6 whose presence is observed to be lineage-specific across eukaryotes. Together, our studies show the association of protein location within the complex and subcomplex formation patterns with the sequence conservation of SF3b proteins. In addition, our study underscores evolutionarily flexible elements that appear to confer adaptive features in individual components of the multi-protein SF3b complexes and may contribute to its functional adaptability.</jats:p> | [
{
"section_content": "Several proteins in the cell perform vital functions as a component of specialized molecular complexes that are usually dedicated to carrying out sophisticated multistep biochemical events (Pieters et al., 2016). Like individual proteins, molecular complexes are also subject to evolutionar... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGMENTS",
"section_num": null
},
{
"section_content": "The authors thank Prof. R. Sowdhamini for her timely inputs in reviewing the revised manuscript. SS acknowledges MSRUAS for use of their facilities during final revisions of the manuscript.",... |
10.1186/s10020-021-00413-0 | Microfibrillar-associated protein 5 regulates osteogenic differentiation by modulating the Wnt/β-catenin and AMPK signaling pathways | <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Dysfunctional osteogenesis of bone marrow mesenchymal stem cells (BMSCs) plays an important role in osteoporosis occurrence and development. However, the molecular mechanisms of osteogenic differentiation remain unclear. This study explored whether microfibrillar-associated protein 5 (MFAP5) regulated BMSCs osteogenic differentiation.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>We used shRNA or cDNA to knock down or overexpress MFAP5 in C3H10 and MC3T3-E1 cells. AR-S- and ALP-staining were performed to quantify cellular osteogenic differentiation. The mRNA levels of the classical osteogenic differentiation biomarkers Runx2, Col1α1, and OCN were quantified by qRT-PCR. Finally, we employed Western blotting to measure the levels of Wnt/β-catenin and AMPK signaling proteins.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>At days 0, 3, 7, and 14 after osteogenic induction, AR-S- and ALP-staining was lighter in MFAP5 knockdown compared to control cells, as were the levels of Runx2, Col1α1 and OCN. During osteogenesis, the levels of β-catenin, p-GSK-3β, AMPK, and p-AMPK were upregulated, while that of GSK-3β was downregulated, indicating that Wnt/β-catenin and AMPK signaling were activated. The relevant molecules were expressed at lower levels in the knockdown than control group; the opposite was seen for overexpressing cell lines.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>MFAP5 regulates osteogenesis via Wnt/β‑catenin- and AMPK-signaling; MFAP5 may serve as a therapeutic target in patients with osteoporosis.</jats:p> </jats:sec> | [
{
"section_content": "Osteoporosis is very common worldwide, and is associated with bone fragility caused by osteopenia, reduced bone mass, and an increased fracture risk (Coughlan and Dockery 2014; Kanis 1994; Wang et al. 2009). \n\nOsteoporosis affects motor function and is also associated with secondary comp... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "Thanks to Zhenxu Wang from the Shanghai Children's Hospital for her enlightening advices of this research design.",
"section_name": "Acknowledgements",
"section_num": null
},
{
... |
10.3390/cancers15020507 | Characteristics and Clinical Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Receiving Ibrutinib for ≥5 Years in the RESONATE-2 Study | <jats:p>Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles (n = 133). Baseline characteristics in ibrutinib-randomized patients (n = 136) were generally similar between patients on ibrutinib treatment for ≥5 years (n = 79) versus those on treatment for <5 years (n = 57). In patients on ibrutinib treatment for ≥5 years, complete response rates improved over time, reaching 42% by 5 years. Estimated 7-year progression-free survival and overall survival rates were 82% and 94%, respectively. Adverse events (AEs) led to dose reductions in 16/79 patients (20%); these AEs were resolved for 13/16 patients (81%). AEs led to dose holds (≥7 days) in 45/79 patients (57%); these AEs were resolved for 43/45 patients (96%). More than half (58%) of ibrutinib-randomized patients benefitted from ibrutinib treatment for ≥5 years regardless of baseline characteristics. Dose modification resolved AEs for most patients, thereby facilitating continued treatment.</jats:p> | [
{
"section_content": "Ibrutinib is a once-daily oral Bruton tyrosine kinase (BTK) inhibitor that is approved as first-line treatment for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the United States, Europe, and other countries. Ibrutinib has the longest follow-up of any... | [
{
"section_content": "",
"section_name": "Acknowledgments:",
"section_num": null
},
{
"section_content": "We thank the patients who participated in the study and their supportive families, as well as the investigators and clinical research staff from the study centers. Editorial support was prov... |
10.7150/jca.51275 | Ethanol extracted from radix of Actinidia chinensis inhibits human colon tumor through inhibiting Notch-signaling pathway | <jats:title>Abstract</jats:title> <jats:p>Abstract: Background Colorectal cancer is one of the most common tumors, and its five-year survival is still very low despite of the advance of treatment strategies. The antitumor effect of ethanol extracted from radix of Actinidia chinensis (EERAC) were identified in human colon cancer cells, but the underlying mechanism remains unclear. Methods Cell proliferation, migration, and invasion were measured with CCK-8, wound healing, and transwell assays. Cell apoptosis and cycle were detected by flow cytometry. Western blotting and qRT-PCR were used to measure expression of target molecules. Xenograft tumor assay was applied to detect the influence of EERAC on tumor growth. Results In the present study, we found that EERAC inhibited the cell viability, migration, and invasion of SW480 cells in a concentration dependent manner, but promoted apoptosis and the cell percentage in S phase significantly. The suppression of notch-signaling pathway molecules (Notch1, Jagged1, and c-Myc) by EERAC was confirmed using western blotting and immunohistochemical staining. The significant inhibition of tumor growth by EERAC was also observed. Meanwhile, EERAC remarkably reversed the effects of MAML1 (activator of notch-signaling pathway) on cell survival of SW480. Conclusions Therefore, EERAC might be a promising chemotherapeutic agent for CRC treatment.</jats:p> | [
{
"section_content": "Colorectal cancer (CRC) is a common public health problem, being one of the most common gastrointestinal tumors in the world [1, 2]. The bad prognosis induced tumor metastases and invasion leads to the low five-year survival rate of CRC patients [3]. Although chemotherapy is accepted as st... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "The study was supported by National Natural Science Foundation of China (Grant NO. 81704076 ).",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content... |
10.17159/caj/2011/20/1.7180 | Air Quality and Human Health among a Low Income Community in the Highveld Priority Area | <jats:p>Human exposure to poor air quality is linked to adverse health effects. The largest burden of air pollution-related diseases is in developing countries where air pollution levels are also among the highest in the world. In South Africa, two geographic areas, the Vaal Triangle and the Highveld, have been identified for air quality managementinterventions to ensure compliance with National Air Quality Management Standards and to control potential harmful air pollution impacts on human health. The Highveld Priority Area (HPA) is characterised by intense mining, coal-fired power plants, industries, including iron and steel manufacturing, chemical plants, agricultural activity, motor vehicles and domestic fuel burning. Apart from two previous studies, no respiratory health studies have been carried out in the HPA. This paper describes the results of a recent, comprehensive study of ambient air quality, potential exposure to air pollution and air-related human health among a low income community living in the HPA in order to better understand the impact of air pollution on human health in South Africa.</jats:p> | [
{
"section_content": "Human exposure to poor air quality is linked to adverse health effects, ranging from acute symptoms, such as nose and throat irritation, to chronic and debilitating illness and disease. The World Health Organization (WHO) states that chronic respiratory diseases, (i. e. asthma, chronic obs... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "This project was supported by a CSIR Parliamentary Grant. The communities, clinics and local councillors are thanked for their support and cooperation. The NOVA Institute are acknowledged fo... |
10.18632/oncotarget.19534 | NOTCH1 activates the Wnt/β-catenin signaling pathway in colon cancer | The translocation of β-catenin/CTNNB1 to the nucleus activates Wnt signaling and cell proliferation; however, the precise mechanism underlying this phenomenon remains unknown. Previous reports have provided evidence that NOTCH1 is involved in the Wnt signaling pathway. Therefore, we sought to determine the mechanism by which NOTCH1 influences the Wnt/β-catenin pathway. We constructed a vector expressing the NOTCH1 intracellular domain (NICD1) and transfected the vector into HCT116 which has low expression of NICD1. Furthermore, inhibition of NOTCH signal pathway in SW480 which has abundant NICD1 expression, was performed by transfection of siNICD1 or DAPT, gamma secretase inhibitor, treatment. In addition, we evaluated NICD1 and β-catenin localization in colon cancer cell lines and in 189 colon cancer tissue samples and analyzed the correlation between the nuclear localization of NICD1 and the clinicopathological features of colon cancer patients.Immunohistochemical assays demonstrated that NICD1 and β-catenin exhibited a similar localization pattern in colon cancer tissues. In addition, we found that NICD1 induced the translocation of β-catenin to the nucleus and that NICD1 and β-catenin co-localized in the nucleus. Overexpression of NICD1 increased luciferase activity of Wnt signal pathway. On the other hand, reduction of NICD1 reduced luciferase activity of Wnt signaling pathway. In the 189 analyzed colon cancer cases, multivariate COX regression analysis demonstrated the independent prognostic impact of nuclear localization of NICD1(p=0.0376).NOTCH1 plays a key role in the Wnt pathway and activation of NOTCH1 is associated with the translocation of β-catenin to the nucleus. | [
{
"section_content": "Recent progress in cancer research has revealed that β-catenin/CTNNB1, which functions in cell-tocell adhesion and Wnt signaling, is a key contributor to carcinogenesis in various tissues, including the colon, liver, ovary, and skin [1] [2] [3] [4] [5] [6]. Cellular β-catenin is normally d... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGMENTS",
"section_num": null
},
{
"section_content": "The authors would like to thank Ms. Seiko Inumaru for her excellent technical assistance.",
"section_name": "ACKNOWLEDGMENTS",
"section_num": null
},
{
"section_content": "",
... |
10.1101/000992 | Mutated SF3B1 is associated with transcript isoform changes of the genes UQCC and RPL31 both in CLLs and uveal melanomas | <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Genome sequencing studies of chronic lympoid leukemia (CLL) have provided a comprehensive overview of recurrent somatic mutations in coding genes. One of the most intriguing discoveries has been the prevalence of mutations in the HEAT-repeat domain of the splicing factor<jats:italic>SF3B1</jats:italic>. A frequently observed variant is predicted to cause the substitution of a lysine with a glutamic acid at position 700 of the protein (K700E). However, the molecular consequences of the mutations are largely unknown.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>To start exploring this question, we sequenced the transcriptomes of six samples: four samples of CLL tumour cells, of which two contained the K700E mutation in<jats:italic>SF3B1</jats:italic>, and CD19 positive cells from two healthy donors. We identified 41 genes that showed differential usage of exons statistically associated with the mutated status of<jats:italic>SF3B1</jats:italic>(false discovery rate of 10%). These genes were enriched in pathways related to interferon signaling and mRNA splicing.</jats:p><jats:p>Among these genes, we found<jats:italic>UQCC</jats:italic>and<jats:italic>RPL31</jats:italic>; notably, a similar effect on these genes was described in a previously published study of uveal melanoma. In addition, while this manuscript was under revision, another study independently reported the common splicing signature of the gene<jats:italic>UQCC</jats:italic>in different tumour types with mutations in<jats:italic>SF3B1</jats:italic>.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our results suggest common effects of isoform deregulation in the genes<jats:italic>UQCC</jats:italic>and<jats:italic>RPL31</jats:italic>upon mutations in<jats:italic>SF3B1</jats:italic>. Additionally, our data provide a candidate list of potential isoform consequences of the SF3B1 (K700E) mutation in CLL, some of which might contribute to the tumourigenesis.</jats:p><jats:p>Validation studies on larger cohorts and model systems are required to extend these findings.</jats:p></jats:sec> | [
{
"section_content": "Several DNA sequencing studies of chronic lymphocytic leukemia (CLL) revealed that the splicing factor SF3B1 accumulated somatic point mutations in about 10% of patients [1] [2] [3]. In most cases the mutations were located in the genomic regions coding for the C-terminal HEAT-repeat domai... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We would like to thank EMBL's Genomics Core Facility for the RNA sequencing service and the Information Technology (IT) Core Facility for provision of computational infrastructure. WH and AR... |
10.1186/1749-8104-6-35 | Basal progenitor cells in the embryonic mouse thalamus - their molecular characterization and the role of neurogenins and Pax6 | <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>The size and cell number of each brain region are influenced by the organization and behavior of neural progenitor cells during embryonic development. Recent studies on developing neocortex have revealed the presence of neural progenitor cells that divide away from the ventricular surface and undergo symmetric divisions to generate either two neurons or two progenitor cells. These 'basal' progenitor cells form the subventricular zone and are responsible for generating the majority of neocortical neurons. However, not much has been studied on similar types of progenitor cells in other brain regions.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We have identified and characterized basal progenitor cells in the embryonic mouse thalamus. The progenitor domain that generates all of the cortex-projecting thalamic nuclei contained a remarkably high proportion of basally dividing cells. Fewer basal progenitor cells were found in other progenitor domains that generate non-cortex projecting nuclei. By using intracellular domain of Notch1 (NICD) as a marker for radial glial cells, we found that basally dividing cells extended outside the lateral limit of radial glial cells, indicating that, similar to the neocortex and ventral telencephalon, the thalamus has a distinct subventricular zone. Neocortical and thalamic basal progenitor cells shared expression of some molecular markers, including <jats:italic>Insm1</jats:italic>, Neurog1, Neurog2 and NeuroD1. Additionally, basal progenitor cells in each region also expressed exclusive markers, such as Tbr2 in the neocortex and Olig2 and Olig3 in the thalamus. In <jats:italic>Neurog1</jats:italic>/<jats:italic>Neurog2</jats:italic> double mutant mice, the number of basally dividing progenitor cells in the thalamus was significantly reduced, which demonstrates the roles of neurogenins in the generation and/or maintenance of basal progenitor cells. In <jats:italic>Pax6</jats:italic> mutant mice, the part of the thalamus that showed reduced Neurog1/2 expression also had reduced basal mitosis.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our current study establishes the existence of a unique and significant population of basal progenitor cells in the thalamus and their dependence on neurogenins and Pax6. These progenitor cells may have important roles in enhancing the generation of neurons within the thalamus and may also be critical for generating neuronal diversity in this complex brain region.</jats:p> </jats:sec> | [
{
"section_content": "The immense number of neurons in the mammalian neocortex is thought to be determined during development by a prominent progenitor cell population that shows a distinct pattern of migration and division. Unlike the predominant progenitor cell type in other brain regions, the radial glial ce... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We thank A Hanson and M Simon for their excellent technical assistance, J Johnson ( University of Texas Southwestern Medical Center ) for providing neurogenin knockout mouse embryos and comm... |
10.3390/molecules22122083 | Lipoprotein Lipase Expression in Chronic Lymphocytic Leukemia: New Insights into Leukemic Progression | <jats:p>Lipoprotein lipase (LPL) is a central enzyme in lipid metabolism. Due to its catalytic activity, LPL is involved in metabolic pathways exploited by various solid and hematologic malignancies to provide an extra energy source to the tumor cell. We and others described a link between the expression of LPL in the tumor cell and a poor clinical outcome of patients suffering Chronic Lymphocytic Leukemia (CLL). This leukemia is characterized by a slow accumulation of mainly quiescent clonal CD5 positive B cells that infiltrates secondary lymphoid organs, bone marrow and peripheral blood. Despite LPL being found to be a reliable molecular marker for CLL prognosis, its functional role and the molecular mechanisms regulating its expression are still matter of debate. Herein we address some of these questions reviewing the current state of the art of LPL research in CLL and providing some insights into where currently unexplored questions may lead to.</jats:p> | [
{
"section_content": "Lipoprotein lipase (LPL, EC 3. 1. 1. 34) is a N-glycosylated protein [1] that forms homodimers and is able to hydrolize triglycerides from chylomicrons [2] and very low-density lipoproteins [3]. The first evidence of its existence was serendipitously found when studying circulating red blo... | [
{
"section_content": "",
"section_name": "Acknowledgments:",
"section_num": null
},
{
"section_content": "The authors thank Uruguayan Agencia Nacional de Investigacion e Innovacion (ANII) for the graduate fellowship of DP and for the grants FMV_2_2011_1_7323 ; FMV_1_2014_1_104397 and FOCEM (MERC... |
10.1038/s41598-023-45893-8 | Evaluating anti-GPL-core IgA as a diagnostic tool for non-tuberculous mycobacterial infections in Thai patients with high antibody background | <jats:title>Abstract</jats:title><jats:p>Diagnosis of non-tuberculous mycobacterial (NTM) infection is difficult due to low sensitivity and time-consuming laboratory tests. Current serological assays fail in tropical countries due to high antibody background. This study aimed to investigate an appropriate method for detecting anti-glycopeptidolipid (GPL)-core antibodies to diagnose NTM infection in Thailand. Heparinized plasma samples were collected from 20 patients with NTM-pulmonary disease (NTM-PD) and 22 patients with disseminated NTM (dNTM) for antibody detection by ELISA. The results were compared with those from patients with tuberculosis, other bacterial pulmonary infections and healthy controls. Among the different antibody isotypes, anti-GPL-core IgA exhibited the highest suitability. Therefore, anti-GPL-core IgA and its subclass IgA2 were further investigated. A significant increase in antibody levels was observed during the active infection stage, whereas NTM-PD with culture conversion at the 6-month follow-up showed reduced IgA levels. The diagnostic cut-off for IgA and IgA2 was newly defined as 1.4 and 1.0 U/ml, respectively. Using our IgA cut-off, the sensitivity and specificity for diagnosing NTM-PD were 77.3% and 81.4%, respectively. The new IgA cut-off demonstrated significantly improved specificity compared to the manufacturer's cut-off. Thus, serological detection of anti-GPL-core IgA, with a cut-off of 1.4 U/ml, can be a valuable tool for supporting NTM diagnosis in Thailand.</jats:p> | [
{
"section_content": "Non-tuberculous mycobacteria (NTM) are commonly found in the environment, and their infections have become a global public health problem due to the increasing number of cases worldwide 1. NTM infections can occur in both immunocompetent and immunocompromised patients 2, 3. The most common... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "This research was funded by the National Research Council of Thailand (NRCT) (Contract No. N42A650205 ), Young Researcher Development Project of Khon Kaen University ( Year 2022 ), and Chian... |
10.3390/ijms22115784 | Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis | <jats:p>The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM.</jats:p> | [
{
"section_content": "Conjunctival melanoma (CM) comprises 5-10% of all ocular melanoma [1] [2] [3]. The majority derives from primary acquired melanosis with atypia (PAM), but infrequently, CM develops from a pre-existing nevus or de novo [1, [3] [4] [5] [6]. CM has an incidence of 0. 2-0. 8 per million [3, 6,... | [
{
"section_content": "",
"section_name": "Acknowledgments:",
"section_num": null
},
{
"section_content": "We would like to thank R. van Marion for his help performing next-generation sequencing.",
"section_name": "Acknowledgments:",
"section_num": null
},
{
"section_content": "Fu... |
10.1038/bcj.2016.9 | Lenalidomide treatment and prognostic markers in relapsed or refractory chronic lymphocytic leukemia: data from the prospective, multicenter phase-II CLL-009 trial | <jats:title>Abstract</jats:title><jats:p>Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified <jats:italic>TP53</jats:italic> mutations, unmutated <jats:italic>IGHV</jats:italic>, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of <jats:italic>TP53</jats:italic> mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or <jats:italic>IGHV</jats:italic> mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); <jats:italic>P</jats:italic>=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (⩾3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; <jats:italic>P</jats:italic>=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including <jats:italic>TP53</jats:italic> inactivation or unmutated <jats:italic>IGHV</jats:italic>. (ClinicalTrials.gov identifier: NCT00963105).</jats:p> | [
{
"section_content": "Single-agent lenalidomide has clinical activity in chronic lymphocytic leukemia (CLL), both in treatment-naive patients, 1, 2 and in those with relapsed and refractory disease [3] [4] [5] [6] or unfavorable characteristics. 2, 4, 5 8] [9] Multivariate analysis established del(17p), TP53 mu... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGEMENTS",
"section_num": null
},
{
"section_content": "We received editorial support from Excerpta Medica ( Ronald van Olffen, PhD, CMPP) in the preparation of this manuscript, funded by Celgene Corporation. We are fully responsible for all cont... |
10.1186/s13148-018-0476-1 | Dynamics of DNMT3A mutation and prognostic relevance in patients with primary myelodysplastic syndrome | DNMT3A gene mutation has been associated with poor prognosis in acute myeloid leukemia, but its clinical implications in myelodysplastic syndrome (MDS) and dynamic changes during disease progression remain controversial.In this study, DNMT3A mutation was identified in 7.9% of 469 de novo MDS patients. DNMT3A-mutated patients had higher platelet counts at diagnosis, and patients with ring sideroblasts had the highest incidence of DNMT3A mutations, whereas those with multilineage dysplasia had the lowest incidence. Thirty-one (83.8%) of 37 DNMT3A-mutated patients had additional molecular abnormalities at diagnosis, and DNMT3A mutation was highly associated with mutations of IDH2 and SF3B1. Patients with DNMT3A mutations had a higher risk of leukemia transformation and shorter overall survival. Further, DNMT3A mutation was an independent poor prognostic factor irrespective of age, IPSS-R, and genetic alterations. The sequential study demonstrated that the original DNMT3A mutations were retained during follow-ups unless allogeneic hematopoietic stem cell transplantation was performed, while DNMT3A mutation was rarely acquired during disease progression.DNMT3A mutation predicts unfavorable outcomes in MDS and was stable during disease evolutions. It may thus be a potential biomarker to predict prognosis and monitor the treatment response. | [
{
"section_content": "Alterations of epigenetic regulation may result in aberrations of gene expression and malignant transformation of cells [1, 2]. DNA methylation, one of the mechanisms for epigenetic control of gene expression, regulates important physiological development, such as gene imprint and Xchromos... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We would like to acknowledge the service provided by the DNA Sequencing Core of the First Core Laboratory, National Taiwan University College of Medicine.",
"section_name": "Acknowledgem... |
10.18632/oncotarget.12139 | Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia | The aim of this study was to investigate the anti-leukemic activity of the Bruton tyrosine kinase inhibitor Ibrutinib in combination with the small molecule MDM-2 inhibitor Nutlin-3 in preclinical models.The potential efficacy of the Ibrutinib/Nutlin-3 combination was evaluated in vitro in a panel of B leukemic cell lines (EHEB, JVM-2, JVM-3, MEC-1, MEC-2) and in primary B-chronic lymphocytic leukemia (B-CLL) patient samples, by assessing cell viability, cell cycle profile, apoptosis and intracellular pathway modulations. Validation of the combination therapy was assessed in a B leukemic xenograft mouse model.Ibrutinib exhibited variable anti-leukemic activity in vitro and the combination with Nutlin-3 synergistically enhanced the induction of apoptosis independently from the p53 status. Indeed, the Ibrutinib/Nutlin-3 combination was effective in promoting cytotoxicity also in primary B-CLL samples carrying 17p13 deletion and/or TP53 mutations, already in therapy with Ibrutinib. Molecular analyses performed on both B-leukemic cell lines as well as on primary B-CLL samples, while confirming the switch-off of the MAPK and PI3K pro-survival pathways by Ibrutinib, indicated that the synergism of action with Nutlin-3 was independent by p53 pathway and was accompanied by the activation of the DNA damage cascade signaling through the phosphorylation of the histone protein H2A.X. This observation was confirmed also in the JVM-2 B leukemic xenograft mouse model.Taken together, our data emphasize that the Ibrutinib/Nutlin-3 combination merits to be further evaluated as a therapeutic option for B-CLL. | [
{
"section_content": "Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase member of the Tec kinase family, plays a significant role in B-cell development. BTK is a key component of the B cell receptor (BCR) signaling that regulates B cell proliferation and survival and is involved in signaling pathways ... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGMENTS",
"section_num": null
},
{
"section_content": "Authors would like to thank Matteo Carantoni for his excellent technical work.",
"section_name": "ACKNOWLEDGMENTS",
"section_num": null
},
{
"section_content": "",
"sectio... |
10.1158/0008-5472.22395708 | Supplementary Methods from miRNA-130a Targets <i>ATG2B</i> and <i>DICER1</i> to Inhibit Autophagy and Trigger Killing of Chronic Lymphocytic Leukemia Cells | <jats:p><p>PDF file - 69K</p></jats:p> | [
{
"section_content": "(TO-PRO-3) and 520 nm (GFP) for each sample. The acquired images were analyzed with IDEAS software (Amnis). First, a scatter plot of aspect ratio/area was used to gate for single cells. Second, a gradient RMS (root mean square for image sharpness) histogram was used to gate for cells in fo... | [] |
10.3390/ijms23116260 | Venetoclax Induces Cardiotoxicity through Modulation of Oxidative-Stress-Mediated Cardiac Inflammation and Apoptosis via NF-κB and BCL-2 Pathway | <jats:p>Cardiovascular damage induced by anticancer therapy has become the main health problem after tumor elimination. Venetoclax (VTX) is a promising novel agent that has been proven to have a high efficacy in multiple hematological diseases, especially acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Considering its mechanism of action, the possibility that VTX may cause cardiotoxicity cannot be ruled out. Therefore, this study was designed to investigate the toxic effect of VTX on the heart. Male Sprague-Dawley rats were randomly divided into three groups: control, low-dose VTX (50 mg/kg via oral gavage), and high-dose VTX (100 mg/kg via oral gavage). After 21 days, blood and tissue samples were collected for histopathological, biochemical, gene, and protein analyses. We demonstrated that VTX treatment resulted in cardiac damages as evidenced by major changes in histopathology and markedly elevated cardiac enzymes and hypertrophic genes markers. Moreover, we observed a drastic increase in oxidative stress, as well as inflammatory and apoptotic markers, with a remarkable decline in the levels of Bcl-2. To the best of our knowledge, this study is the first to report the cardiotoxic effect of VTX. Further experiments and future studies are strongly needed to comprehensively understand the cardiotoxic effect of VTX.</jats:p> | [
{
"section_content": "Drug-induced toxicity effects on cardiovascular function or tissues are not only a serious health issue, but they are often detected after the introduction of the drug in clinical practice [1]. This reflects that these high-risk cardiovascular events are either not detected in earlier clin... | [
{
"section_content": "",
"section_name": "Acknowledgments:",
"section_num": null
},
{
"section_content": "The authors are thankful to the Researchers Supporting Project (number RSP-2021/335 ), King Saud University, Riyadh, Saudi Arabia.",
"section_name": "Acknowledgments:",
"section_num"... |
10.1186/1472-6750-8-6 | Negative selection of chronic lymphocytic leukaemia cells using a bifunctional rosette-based antibody cocktail | <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>High purity of tumour samples is a necessity for accurate genetic and expression analysis and is usually achieved by positive selection in chronic lymphocytic leukaemia (CLL).</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We adapted a bifunctional rosette-based antibody cocktail for negative selection of B-cells for isolating CLL cells from peripheral blood (PB). PB samples from CLL patients were split into aliquots. One aliquot of each sample was enriched by density gradient centrifugation (DGC), while the other aliquot of each sample was incubated with an antibody cocktail for B-cell enrichment prior to DGC (RS+DGC). The purity of CLL cells after DGC averaged 74.1% (range: 15.9 – 97.4%). Using RS+DGC, the purity averaged 93.8% (range: 80.4 – 99.4%) with 23 of 29 (79%) samples showing CLL purities above 90%. RNA extracted from enriched CLL cells was of appropriately high quality for microarray analysis.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>This study confirms the use of a bifunctional rosette-based antibody cocktail as an effective method for the purification of CLL cells from peripheral blood.</jats:p> </jats:sec> | [
{
"section_content": "Enrichment of tumour cells to a purity of more than 90% is highly desirable for accurate results in many applications, especially for RT-PCR and microarray based expression analysis [1, 2]. In B-cell chronic lymphocytic leukaemia (CLL), such purities have usually been achieved by density g... | [
{
"section_content": "",
"section_name": "Acknowledgements",
"section_num": null
},
{
"section_content": "We thank Nancy Messino for assisting with the immunophenotyping and Sophia Halley, Ida Candiloro, Angela Tan, Lasse Kristensen, Michael Krypuy and Chelsee Hewitt for critical reading of the ... |
10.3389/fonc.2022.809772 | Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations | <jats:sec><jats:title>Background</jats:title><jats:p>Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC) ,and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiation toxicity. However, the mechanism of the protective effect of NaB against RILI has not yet been clarified. This study aimed to explore the underlying protective mechanisms of NaB against RILI in NSCLC through network pharmacology, molecular docking, molecular dynamic simulations and <jats:italic>in vivo</jats:italic> experiments.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The predictive target genes of NaB were obtained from the PharmMapper database and the literature review. The involved genes of RILI and NSCLC were predicted using OMIM and GeneCards database. The intersectional genes of drug and disease were identified using the Venny tool and uploaded to the Cytoscape software to identify 5 core target genes of NaB associated with RILI. The correlations between the 5 core target genes and EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors were analyzed using TIMER 2.0, TIMER and TISIDB databases. We constructed the mechanism maps of the 3 key signaling pathways using the KEGG database based on the results of GO and KEGG analyses from Metascape database. The 5 core target genes and drug were docked using the AutoDock Vina tool and visualized using PyMOL software. GROMACS software was used to perform 100 ns molecular dynamics simulation. Irradiation-induced lung injury model in mice were established to assess the therapeutic effects of NaB.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 51 intersectional genes involved in NaB against RILI in NSCLC were identified. The 5 core target genes were AKT1, TP53, NOTCH1, SIRT1, and PTEN. The expressions of the 5 core target genes were significantly associated with EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors, respectively. The results from GO analysis of the 51 intersectional genes revealed that the biological processes were focused on the regulation of smooth muscle cell proliferation, oxidative stress and cell death, while the three key KEGG pathways were enriched in PI3K-Akt signal pathway, p53 signal pathway, and FOXO signal pathway. The docking of NaB with the 5 core target genes showed affinity and stability, especially AKT1. <jats:italic>In vivo</jats:italic> experiments showed that NaB treatment significantly protected mice from RILI, with reduced lung histological damage. In addition, NaB treatment significantly inhibited the PI3K/Akt signaling pathway.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>NaB may protect patients from RILI in NSCLC through multiple target genes including AKT1, TP53, NOTCH1, SIRT1 and PTEN, with multiple signaling pathways involving, including PI3K-Akt pathway, p53 pathway, and FOXO pathways. Our findings effectively provide a feasible theoretical basis to further elucidate the mechanism of NaB in the treatment of RILI.</jats:p></jats:sec> | [
{
"section_content": "Background: Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC),and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiatio... | [
{
"section_content": "",
"section_name": "FUNDING",
"section_num": null
},
{
"section_content": "The work was funded by Beijing Xisike Clinical Oncology Research Foundation ( Y-2019AZQN-04532 ), and the Key Program of Science and Technology of Guangxi, China ( AB20159024 ).",
"section_name":... |
10.1371/journal.pone.0034347 | Epigenetic Silencing of the Circadian Clock Gene CRY1 is Associated with an Indolent Clinical Course in Chronic Lymphocytic Leukemia | Disruption of circadian rhythm is believed to play a critical role in cancer development. Cryptochrome 1 (CRY1) is a core component of the mammalian circadian clock and we have previously shown its deregulated expression in a subgroup of patients with chronic lymphocytic leukemia (CLL). Using real-time RT-PCR in a cohort of 76 CLL patients and 35 normal blood donors we now demonstrate that differential CRY1 mRNA expression in high-risk (HR) CD38+/immunoglobulin variable heavy chain gene (IgVH) unmutated patients as compared to low-risk (LR) CD38-/IgVH mutated patients can be attributed to down-modulation of CRY1 in LR CLL cases. Analysis of the DNA methylation profile of the CRY1 promoter in a subgroup of 57 patients revealed that CRY1 expression in LR CLL cells is silenced by aberrant promoter CpG island hypermethylation. The methylation pattern of the CRY1 promoter proved to have high prognostic impact in CLL where aberrant promoter methylation predicted a favourable outcome. CRY1 mRNA transcript levels did not change over time in the majority of patients where sequential samples were available for analysis. We also compared the CRY1 expression in CLL with other lymphoid malignancies and observed epigenetic silencing of CRY1 in a patient with B cell acute lymphoblastic leukemia (B-ALL). | [
{
"section_content": "Accumulating epidemiological and genetic evidence indicates that disruption of circadian rhythms may increase the susceptibility for developing cancer including non-Hodgkin lymphoma (NHL) and also adversely affects tumor progression [1] [2] [3] [4] [5]. At the molecular level, several gene... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "We thank Sima Vagaie, Michael Mo ¨llmann, Sana Mohamad and Olga Rempel for excellent technical assistance, Anja Fu ¨hrer and Sabrina Kieruzel for maintaining the CLL biobank and Ute Schmu ¨ck... |
10.3390/cancers12103041 | Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies | <jats:p>Monoclonal antibody (mAb) therapy has rapidly changed the field of cancer therapy. In 1997, the CD20-targeting mAb rituximab was the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer. Within two decades, dozens of mAbs entered the clinic for treatment of several hematological cancers and solid tumors, and numerous more are under clinical investigation. The success of mAbs as cancer therapeutics lies in their ability to induce various cytotoxic machineries against specific targets. These cytotoxic machineries include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), which are all mediated via the fragment crystallizable (Fc) domain of mAbs. In this review article, we will outline the novel approaches of engineering these Fc domains of mAbs to enhance their Fc-effector function and thereby their anti-tumor potency, with specific focus to summarize their (pre-) clinical status for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM).</jats:p> | [
{
"section_content": "Naturally, antibodies (Abs) are produced by B-cells as a polyclonal population, with high specificity for their distinct target antigen and epitope. Antibodies thereby play various important roles in our immune system. The field of therapeutic Abs commenced in 1975, when the development of... | [
{
"section_content": "This research received no external funding.",
"section_name": "",
"section_num": ""
}
] |
10.1038/s41375-018-0342-3 | Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia | Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0-4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P < 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy. | [
{
"section_content": "Eosinophilia, defined as an elevation of the peripheral blood (PB) eosinophil count above 0. 5 × 10 9 /L, is conventionally divided into three main categories: primary, secondary (reactive) and idiopathic. Primary eosinophilia is a clonal hematologic disorder in which the eosinophils form ... | [
{
"section_content": "",
"section_name": "Compliance with ethical standards",
"section_num": null
},
{
"section_content": "Acknowledgements This study was funded by Bloodwise Specialist Programme Grant no. 13002 to NCPC, WJT and AC. We thank Professor Satu Mustjoki, Helsinki for providing contro... |
10.1371/journal.pone.0116791 | A Comparison of Assays for Accurate Copy Number Measurement of the Low-Affinity Fc Gamma Receptor Genes FCGR3A and FCGR3B | Le locus FCGR3 codant pour le récepteur d'activation de faible affinité FcγRIII, joue un rôle vital dans l'immunité déclenchée par les fonctions effectrices et régulatrices cellulaires. Il a déjà été rapporté que le numéro de copie des gènes FCGR3A et FCGR3B affecte la sensibilité à plusieurs maladies auto-immunes et affections inflammatoires chroniques. Cependant, de telles études d'association génétique donnent souvent des résultats incohérents ; elles nécessitent donc des tests robustes avec un faible taux d'erreur. Nous avons étudié la précision et l'efficacité de l'estimation de FCGR3 CNV en comparant Sequenom MassARRAY et le rapport paralogue test-restriction enzyme digest variant ratio (PRT-REDVR). De plus, étant donné que de nombreuses études d'association génétique de FCGR3B CNV ont été réalisées en utilisant la PCR quantitative en temps réel, nous avons également inclus l'évaluation de la performance de cette méthode dans l'estimation de la CNV multi-allélique de FCGR3B. Le test qPCR a montré une distribution considérablement plus large de l'intensité du signal, introduisant potentiellement une erreur dans l'estimation du nombre de copies et des taux de faux positifs plus élevés. Sequenom et PRT-REDVR ont tous deux montré un biais systématique moindre, mais Sequenom a biaisé vers un nombre de copies normal (CN = 2). L'écart entre Sequenom et PRT-REDVR pourrait être attribué soit au bruit des effets de lot dans les mesures individuelles. Notre étude suggère que PRT-REDVR est plus robuste et précis dans le génotypage du CNV de FCGR3, mais met en évidence les besoins de plusieurs tests indépendants pour une validation approfondie lors de la réalisation d'une étude d'association génétique avec des CNV multi-alléliques. | [
{
"section_content": "Copy number variation (CNV) is defined as genetic variation involving a loss or gain of large segments of DNA (typically over 1 kb), a definition that includes simple deletions and duplications [1]. CNV can affect phenotype by altering gene dosage, disrupting coding sequences, or perturbin... | [
{
"section_content": "",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "The authors thank all medical officers and staff nurses from Hospital Kota Bharu, Hospital USM and Hospital Sungai Buloh for assisting in sample recruitment.",
"section_name": "Acknowledg... |
10.3389/fimmu.2021.784691 | Bone Marrow Lymphoid Niche Adaptation to Mature B Cell Neoplasms | <jats:p>B-cell non-Hodgkin lymphoma (B-NHL) evolution and treatment are complicated by a high prevalence of relapses primarily due to the ability of malignant B cells to interact with tumor-supportive lymph node (LN) and bone marrow (BM) microenvironments. In particular, progressive alterations of BM stromal cells sustain the survival, proliferation, and drug resistance of tumor B cells during diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). The current review describes how the crosstalk between BM stromal cells and lymphoma tumor cells triggers the establishment of the tumor supportive niche. DLBCL, FL, and CLL display distinct patterns of BM involvement, but in each case tumor-infiltrating stromal cells, corresponding to cancer-associated fibroblasts, exhibit specific phenotypic and functional features promoting the recruitment, adhesion, and survival of tumor cells. Tumor cell-derived extracellular vesicles have been recently proposed as playing a central role in triggering initial induction of tumor-supportive niches, notably within the BM. Finally, the disruption of the BM stroma reprogramming emerges as a promising therapeutic option in B-cell lymphomas. Targeting the crosstalk between BM stromal cells and malignant B cells, either through the inhibition of stroma-derived B-cell growth factors or through the mobilization of clonal B cells outside their supportive BM niche, should in particular be further evaluated as a way to avoid relapses by abrogating resistance niches.</jats:p> | [
{
"section_content": "B-cell non-Hodgkin lymphomas (B-NHL) are a heterogeneous group of hematological malignancies that emerge from different stages of normal mature B-cell differentiation (1). Lymphoma evolution and treatment are complicated by a high prevalence of relapses (2) primarily due to the ability of ... | [
{
"section_content": "",
"section_name": "FUNDING",
"section_num": null
},
{
"section_content": "This work was supported by research grants from Fondation ARC ( PGA1 RF20170205386 ) and the Institut National du cancer (INCA AAP PNP19-009 ).",
"section_name": "FUNDING",
"section_num": nul... |
10.1038/bcj.2015.39 | A novel antibody–drug conjugate targeting SAIL for the treatment of hematologic malignancies | <jats:title>Abstract</jats:title><jats:p>Although several new therapeutic approaches have improved outcomes in the treatment of hematologic malignancies, unmet need persists in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin’s lymphoma. Here we describe the proteomic identification of a novel cancer target, SAIL (Surface Antigen In Leukemia), whose expression is observed in AML, MM, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). While SAIL is widely expressed in CLL, AML, MM, DLBCL and FL patient samples, expression in cancer cell lines is mostly limited to cells of AML origin. We evaluated the antitumor activity of anti-SAIL monoclonal antibodies, 7-1C and 67-7A, conjugated to monomethyl auristatin F. Following internalization, anti-SAIL antibody–drug conjugates (ADCs) exhibited subnanomolar IC<jats:sub>50</jats:sub> values against AML cell lines <jats:italic>in vitro</jats:italic>. In pharmacology studies employing AML cell line xenografts, anti-SAIL ADCs resulted in significant tumor growth inhibition. The restricted expression profile of this target in normal tissues, the high prevalence in different types of hematologic cancers and the observed preclinical activity support the clinical development of SAIL-targeted ADCs.</jats:p> | [
{
"section_content": "5] [6] There are currently more than 35 ADCs in clinical development, 7, 8 and even though some promising results have been reported, the available data suggest that developing highly efficacious therapeutics through this modality may be more complex than initially expected. 9 ne of the ma... | [
{
"section_content": "",
"section_name": "ACKNOWLEDGEMENTS",
"section_num": null
},
{
"section_content": "We are grateful to Jason Damiano and Sally Bolmer for critical reading of the manuscript. We thank Joseph Zachwieja, Steven Gomez and John Lippincott for their contribution to antibody gener... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.