{"sentence": "We examined the inducibility of drug resistance ( MDR1 , MRP1 , LRP ) and protein kinase C ( PKC ) isozyme ( alpha , epsilon , eta , theta , tau , zeta ) corresponding genes in A2780 ovarian cancer cells after a 24-hour treatment with adriamycin ( ADR ) , camptothecin ( CAM ) , etoposide ( ETO ) or vincristine ( VCR ) . Sublethal concentrations of drugs were used to exclude short-term effects caused by selection . Cell cycle analysis was performed to identify possible correlation between resistance factors , PKC isozymes and proliferation . We found a mostly combined induction of MDR1 , LRP , PKC tau and PKC zeta by CAM , ETO and VCR . PKC alpha , epsilon , eta and theta gene expression altered variably . Cell cycle analysis showed that A2780 cells responded with a marked G2/M arrest after a 24-hour treatment with CAM , ETO and VCR but an association between the induction of PKC isozymes corresponding genes and proliferation was not seen . Our analysis points to a possible link between atypical PKC tau/PKC zeta and MDR1/LRP in cytostatic stress response of cancer cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "12553062"}
{"sentence": "Manganese , an essential trace nutrient in human beings , has been widely used in the steel industry to improve hardness , stiffness , and strength . With the increased applications of manganese compounds , discharge into the environment has rapidly increased and may exert adverse effects on human health . In this study , manganese toxicity was investigated using cultured T98G cells , which are derived from human glioblasts with the ability to differentiate into several different types of neuroglia . Cytotoxicity was shown in manganese-treated groups ( 100 , 200 , 400 , and 800microM of MnCl(2) ) , and cell viability was decreased to 58.8% of the control group at 2days after treatment with 800microM of MnCl(2) . When cells were treated with manganese for 24h , ROS dose-dependently increased while antioxidant intracellular GSH decreased . With the generation of ROS , the increased activity of caspase-3 was shown , and was followed by chromatin condensation and breakage , which is an indication of the cellular apoptotic process . ROS also triggered pro-inflammatory responses in cultured T98G cells , which were demonstrated by the increased gene expression and protein levels of IL-6 and IL-8 .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "19815061"}
{"sentence": "The cellobiose- and cellulose-responsive induction of the FIII-avicelase ( cbhI ) , FII-carboxymethyl cellulase ( cmc2 ) , and FIa-xylanase ( xynIa ) genes is not regulated by XlnR in Aspergillus aculeatus , which suggests that this fungus possesses an unknown cellulase gene-activating pathway . To identify the regulatory factors involved in this pathway , we constructed a random insertional mutagenesis library using Agrobacterium tumefaciens-mediated transformation of A. aculeatus NCP2 , which harbors a transcriptional fusion between the cbhI promoter ( P ( CBHI ) ) and the orotidine 5'-phosphate decarboxylase gene ( pyrG ) . Of the transformants screened , one 5-FOA-resistant transformant , S4-22 , grew poorly on cellulose-containing media and exhibited reduced cellobiose-induced expression of cbhI . Southern blot analysis and nucleotide sequencing of the flanking regions of the T-DNA inserted in S4-22 indicated that the T-DNA was inserted within the coding region of a previously unreported Zn(II)(2)Cys(6)-transcription factor , which we designated the cellobiose response regulator ( ClbR ) . The disruption of the clbR gene resulted in a significant reduction in the expression of cbhI and cmc2 in response to cellobiose and cellulose . Interestingly , the cellulose-responsive induction of FI-carboxymethyl cellulase ( cmc1 ) and FIb-xylanase ( xynIb ) genes that are under the control of XlnR , was also reduced in the clbR-deficient mutant , but there was no effect on the induction of these genes in response to D-xylose or L-arabinose . These data demonstrate that ClbR participates in both XlnR-dependent and XlnR-independent cellobiose- and cellulose-responsive induction signaling pathways in A. aculeatus .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22851016"}
{"sentence": "The role of inflammatory cytokine interleukin-20 ( IL-20 ) has not yet been studied in cancer biology . Here , we demonstrated up-regulation of both IL-20 and IL-20R1 in muscle invasive bladder cancer ( MIBC ) patients . The expressions of IL-20 and IL-20R1 were observed in bladder cancer 5637 and T-24 cells . We found that IL-20 significantly increased the expression of matrix metalloproteinase ( MMP)-9 via binding activity of NF-\u03baB and AP-1 in bladder cancer cells and stimulated the activation of ERK1/2 , JNK , p38MAPK , and Jak-Stat signaling . Among the pathways examined , only ERK1/2 inhibitor U0126 significantly inhibited IL-20-induced migration and invasion . Moreover , siRNA knockdown of IL-20R1 suppressed migration , invasion , ERK1/2 activation , and NF-\u03baB-mediated MMP-9 expression induced by IL-20 . Unexpectedly , cell cycle inhibitor p21WAF1 was induced by IL-20 treatment without altering cell cycle progression . Blockade of p21WAF1 function by siRNA reversed migration , invasion , activation of ERK signaling , MMP-9 expression , and activation of NF-\u03baB in IL-20-treated cells . In addition , IL-20 induced the activation of IKK , the degradation and phosphorylation of I\u03baBa , and NF-\u03baB p65 nuclear translocation , which was regulated by ERK1/2 . IL-20 stimulated the recruitment of p65 to the MMP-9 promoter region . Finally , the IL-20-induced migration and invasion of cells was confirmed by IL-20 gene transfection and by addition of anti-IL-20 antibody . This is the first report that p21WAF1 is involved in ERK1/2-mediated MMP-9 expression via increased binding activity of NF-\u03baB , which resulted in the induction of migration in IL-20/IL-20R1 dyad-induced bladder cancer cells . These unexpected results might provide a critical new target for the treatment of bladder cancer .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23271730"}
{"sentence": "We analyzed the clinico-pathological features of the initial tumors in 205 patients with superficial bladder cancer , admitted to Kyoto University Hospital between 1974 and 1988 , to investigate the prognostic factors for progression to the muscle invasive disease or metastasis . Of 205 patients , 35 ( 17% ) exhibited muscular invasion alone ( 12 patients ) and/or metastasis ( 23 patients ) . Tumor multiplicity , higher grade and positive urinary cytology were the significant risk factors for later malignant progression . Expression of A , B , H-blood group isoantigens in the bladder tumor were significantly decreased from the onset in the patients with initially T1 tumor but not in those with Ta tumor . Significant loss of expression was also found at the time of progression in the initially Ta cases . Thus , loss of A , B , H-blood group antigen expression seems to be correlated with the malignant potential of superficial bladder cancer . However , more feasible and reliable diagnostic markers such as molecular genetical and biochemical markers remain to be developed to predict the malignant potential of the superficial bladder cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1524003"}
{"sentence": "We examined how well the human papillomavirus ( HPV ) E6 oncogene can function in the absence of the E7 oncogene during the carcinogenic process in human keratinocytes using a common HPV variant strongly associated with cervical cancer : the Asian-American E6 variant ( AAE6 ) . This E6 variant is 20 times more frequently detected in cervical cancer than the prototype European E6 variant , as evidenced by independent epidemiological data . Using cell culture and cell-based functional assays , we assessed how this variant can perform crucial carcinogenesis steps compared to the prototype E6 variant . The ability to immortalize and transform primary human foreskin keratinocytes ( PHFKs ) to acquire resilient phenotypes and the ability to promote cell migration were evaluated . The immortalization capability was assayed based on population doublings , number of passages , surpassing mortality stages 1 and 2 , human telomerase reverse transcriptase ( hTERT ) expression , and the ability to overcome G(1) arrest via p53 degradation . Transformation and migration efficiency were analyzed using a combination of functional cell-based assays . We observed that either AAE6 or prototype E6 proteins alone were sufficient to immortalize PHFKs , although AAE6 was more potent in doing so . The AAE6 variant protein alone pushed PHFKs through transformation and significantly increased their migration ability over that of the E6 prototype . Our findings are in line with epidemiological data that the AA variant of HPV16 confers an increased risk over the European prototype for cervical cancer , as evidenced by a superior immortalization , transformation , and metastatic potential .", "label": [1, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "22951839"}
{"sentence": "The omega-3 long chain polyunsaturated fatty acids , docosahexaenoic acid ( DHA ) and eicosapentaenoic acid ( EPA ) , elicit antiproliferative effects in cancer cell lines and in animal models . Dietary DHA and EPA can be converted to their ethanolamine derivatives , docosahexaenoyl ethanolamine ( DHEA ) and eicosapentaenoyl ethanolamine ( EPEA ) , respectively ; however , few studies are reported on their anticancer activities . Here , we demonstrated that DHEA and EPEA were able to reduce cell viability in MCF-7 breast cancer cells whereas they did not elicit any effects in MCF-10A non-tumorigenic breast epithelial cells . Since DHA and EPA are ligands of Peroxisome Proliferator-Activated Receptor ( PPAR ) \u03b3 , we sought to determine whether PPAR\u03b3 may also mediate DHEA and EPEA actions . In MCF-7 cells , both compounds enhanced PPAR\u03b3 expression , stimulated a PPAR response element-dependent transcription as confirmed by the increased expression of its target gene PTEN , resulting in the inhibition of AKT-mTOR pathways . Besides , DHEA and EPEA treatment induced phosphorylation of Bcl-2 promoting its dissociation from beclin-1 which resulted in autophagy induction . We also observed an increase of beclin-1 and microtubule-associated protein 1 light chain 3 expression along with an enhanced autophagosomes formation as revealed by mono-dansyl-cadaverine staining . Finally , we demonstrated the involvement of PPAR\u03b3 in DHEA- and EPEA-induced autophagy by using siRNA technology and a selective inhibitor . In summary , our data show that the two omega-3 ethanolamines exert antiproliferative effects by inducing autophagy in breast cancer cells highlighting their potential use as breast cancer preventive and/or therapeutic agents . J. Cell . Physiol. \u00a9 2012 Wiley Periodicals , Inc .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23168911"}
{"sentence": "Bioenergetic profiling of tumors is a new challenge of cancer research and medicine as therapies are currently being developed . Meanwhile , methodological means must be proposed to gather information on tumor metabolism in order to adapt these potential therapies to the bioenergetic specificities of tumors . Studies performed on tumors and cancer cell lines have shown that cancer cells bioenergetics is highly variable . This profile changes with microenvironmental conditions ( eg. substrate availability ) , the oncogenes activated ( and the tumor suppressors inactivated ) and the interaction with the stroma ( i.e. reverse Warburg effect ) . Here , we assessed the power of metabolic footprinting ( MFP ) to unravel the bioenergetics and associated anabolic changes induced by three oncogenes , c-Myc , KLF4 and Oct1 . The MFP approach provides a quantitative analysis of the metabolites secreted and consumed by cancer cells . We used ultra performance liquid chromatography for quantifying the amino acid uptake and secretion . To investigate the potential oncogene-mediated alterations in mitochondrial metabolism , we measured oxygen consumption rate and ATP production as well as the glucose uptake and lactate release . Our findings show that c-Myc deficiency initiates the Warburg effect along with a reduction of mitochondrial respiration . KLF4 deficiency also stimulated glycolysis , albeit without cellular respiration impairment . In contrast , Oct1 deficiency reduced glycolysis and enhanced oxidative phosphorylation efficiency . MFP revealed that c-Myc , KLF4 and Oct1 altered amino acid metabolism with specific patterns . We identified isoleucine , \u03b1-aminoadipic acid and GABA ( \u03b3-aminoisobutyric acid ) as biomarkers related . Our findings establish the impact of Oct1 , KLF4 and c-Myc on cancer bioenergetics and evidence a link between oncosecretomics and cellular bioenergetics profile .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "22842522"}
{"sentence": "The tumor suppressor gene p53 has been implicated in the regulation of epithelial-mesenchymal transition ( EMT ) and tumor metastasis by regulating microRNA ( miRNA ) expression . Here , we report that mutant p53 exerts oncogenic functions and promotes EMT in endometrial cancer ( EC ) by directly binding to the promoter of miR-130b ( a negative regulator of ZEB1 ) and inhibiting its transcription . We transduced p53 mutants into p53-null EC cells , profiled the miRNA expression by miRNA microarray and identified miR-130b as a potential target of mutant p53 . Ectopic expression of p53 mutants repressed the expression of miR-130b and triggered ZEB1-dependent EMT and cancer cell invasion . Loss of an endogenous p53 mutation increased the expression of miR-130b , which resulted in reduced ZEB1 expression and attenuation of the EMT phenotype . Furthermore , re-expression of miR-130b suppressed mutant p53-induced EMT and ZEB1 expression . Importantly , the expression of miR-130 was significantly reduced in EC tissues , and patients with higher expression levels of miR-130b survived longer . These data provide a novel understanding of the roles of p53 gain-of-function mutations in accelerating tumor progression and metastasis through modulation of the miR-130b-ZEB1 axis .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22847613"}
{"sentence": "Centrosome overduplication or amplification has been observed in many human cancers and in premalignant tissue , but the mechanisms leading to such centrosome aberrations are not fully understood . We previously showed that abnormal mitotic cells with supernumerary centrosomes increase with replicative senescence in human fibroblasts , especially in a polyploid subpopulation . This study examines localization of p53 protein at centrosomes in mitotic cells , which is often observed in association with DNA damage response , to investigate a possible association between p53 localization and numerical centrosome aberrations induced by cellular senescence . Cultures at later passages or the 4th day after exposure to H(2)O(2) showed increased frequencies of mitotic cells with supernumerary centrosomes , especially in a polyploid subpopulation . Immunohistochemical analysis frequently showed p53-positive foci in mitotic cells , and some were localized at centrosomes . The number of p53-positive foci in mitotic cells and its localization to centrosomes increased with replicative and premature senescence . Supernumerary centrosomes showed higher frequencies of p53 localization compared to normally duplicated centrosomes . Centrosome-associated p53 protein was phosphorylated at Ser15 . These data suggest a possible association between localization of p53 protein and numerical centrosome aberrations in replicatively or prematurely senescent cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23091651"}
{"sentence": "Metastatic breast tumors undergo epithelial-to-mesenchymal transition ( EMT ) , which renders them resistant to therapies targeted to the primary cancers . The mechanistic link between mtDNA ( mitochondrial DNA ) reduction , often seen in breast cancer patients , and EMT is unknown . We demonstrate that reducing mtDNA content in human mammary epithelial cells ( hMECs ) activates Calcineurin ( Cn)-dependent mitochondrial retrograde signaling pathway , which induces EMT-like reprogramming to fibroblastic morphology , loss of cell polarity , contact inhibition and acquired migratory and invasive phenotype . Notably , mtDNA reduction generates breast cancer stem cells . In addition to retrograde signaling markers , there is an induction of mesenchymal genes but loss of epithelial markers in these cells . The changes are reversed by either restoring the mtDNA content or knockdown of CnA\u03b1 mRNA , indicating the causal role of retrograde signaling in EMT . Our results point to a new therapeutic strategy for metastatic breast cancers targeted to the mitochondrial retrograde signaling pathway for abrogating EMT and attenuating cancer stem cells , which evade conventional therapies . We report a novel regulatory mechanism by which low mtDNA content generates EMT and cancer stem cells in hMECs.Oncogene advance online publication , 4 November 2013 ; doi:10.1038/onc.2013.467 .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "24186204"}
{"sentence": "A variety of reduced-intensity conditionings have been used in the reported studies of allogeneic hematopoietic stem cell transplantation ( HSCT ) for elderly patients with myeloid hematological malignancies . This study retrospectively analyzed the outcome of allogeneic HSCT for 10 patients aged 50 years or older with myeloid hematological malignancies after conditioning with fludarabine ( 125 mg/m(2) ) , melphalan ( 140 mg/m(2) ) and total body irradiation ( TBI ; 8 Gy ) . Median age of the patients was 56.5 years , and diagnoses included acute myelogenous leukemia , advance myelodysplastic syndrome , and secondary myelofibrosis . Sources of stem cells were bone marrow from sibling ( n=4 ) or unrelated donor ( n=6 ) . Both overall and disease-free survival rates were 40.0% ( 95% CI : 10.6 Causes of death were relapse ( n=2 ) , fungal infection ( n=2 ) , and secondary malignancies ( n=2 ) . Because of a high incidence of transplant-related mortality , further refinement of this conditioning is required .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22499048"}
{"sentence": "Progression to malignancy requires that cells overcome senescence and switch to an immortal phenotype . Thus , exploring the genetic and epigenetic changes that occur during senescence/immortalization may help elucidate crucial events that lead to cell transformation . In the present study , we have globally profiled DNA methylation in relation to gene expression in primary , senescent and immortalized mouse embryonic fibroblasts . Using a high-resolution genome-wide mapping technique , followed by extensive locus-specific validation assays , we have identified 24 CpG islands that display significantly higher levels of CpG methylation in immortalized cell lines as compared to primary murine fibroblasts . Several of these hypermethylated CpG islands are associated with genes involved in the MEK-ERK pathway , one of the most frequently disrupted pathways in cancer . Approximately half of the hypermethylated targets are developmental regulators , and bind to the repressive Polycomb group ( PcG ) proteins , often in the context of bivalent chromatin in mouse embryonic stem cells . Because PcG-associated aberrant DNA methylation is a hallmark of several human malignancies , our methylation data suggest that epigenetic reprogramming of pluripotency genes may initiate cell immortalization . Consistent with methylome alterations , global gene expression analysis reveals that the vast majority of genes dysregulated during cell immortalization belongs to gene families that converge into the MEK-ERK pathway . Additionally , several dysregulated members of the MAP kinase network show concomitant hypermethylation of CpG islands . Unlocking alternative epigenetic routes for cell immortalization will be paramount for understanding crucial events leading to cell transformation . Unlike genetic alterations , epigenetic changes are reversible events , and as such , can be amenable to pharmacological interventions , which makes them appealing targets for cancer therapy when genetic approaches prove inadequate .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23143272"}
{"sentence": "BACKGROUND Nephronophthisis ( NPHP ) as a cause of cystic kidney disease is the most common genetic cause of progressive renal failure in children and young adults . NPHP is characterized by abnormal and/or loss of function of proteins associated with primary cilia . Previously , we characterized an autosomal recessive phenotype of cystic kidney disease in the Lewis Polycystic Kidney ( LPK ) rat . RESULTS In this study , quantitative trait locus analysis was used to define a Mbp region on rat chromosome 10q25 harbouring the lpk mutation . Targeted genome capture and next-generation sequencing of this region identified a non-synonymous mutation R650C in the NIMA ( never in mitosis gene a)- related kinase 8 ( Nek8 ) gene . This is a novel Nek8 mutation that occurs within the regulator of chromosome condensation 1 ( RCC1)-like region of the protein . Specifically , the R650C substitution is located within a G[QRC]LG repeat motif of the predicted seven bladed beta-propeller structure of the RCC1 domain . The rat Nek8 gene is located in a region syntenic to portions of human chromosome 17 and mouse 11 . Scanning electron microscopy confirmed abnormally long cilia on LPK kidney epithelial cells , and fluorescence immunohistochemistry for Nek8 protein revealed altered cilia localisation . CONCLUSIONS When assessed relative to other Nek8 NPHP mutations , our results indicate the whole propeller structure of the RCC1 domain is important , as the different mutations cause comparable phenotypes . This study establishes the LPK rat as a novel model system for NPHP and further consolidates the link between cystic kidney disease and cilia proteins .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22899815"}
{"sentence": "Stable ectopic expression of Flt3 receptor tyrosine kinase is usually performed in interleukin 3 ( IL-3)-dependent murine cell lines like Ba/F3 , resulting in loss of IL-3 dependence . Such high-level Flt3 expression has to date not been reported in human acute myeloid leukemia ( AML ) cell lines , despite the fact that oncogenic Flt3 aberrancies are frequent in AML patients . We show here that ectopic Flt3 expression in different human cancer cell lines might reduce proliferation and induce apoptotic cell death , involving Bax/Bcl2 modulation . Selective depletion of Flt3-expressing cells occurred in human AML cell lines transduced with retroviral Flt3 constructs , shown here using the HL-60 leukemic cell line . Flt3 expression was investigated in two cellular model systems , the SAOS-2 osteosarcoma cell line and the human embryonic kidney HEK293 cell line , and proliferation was reduced in both systems . HEK293 cells underwent apoptosis upon ectopic Flt3 expression and cell death could be rescued by overexpression of Bcl-2 . Furthermore , we observed that the Flt3-induced inhibition of proliferation in HL-60 cells appeared to be Bax-dependent . Our results thus suggest that excessive Flt3 expression has growth-suppressive properties in several human cancer cell lines .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22422053"}
{"sentence": "MicroRNAs ( miRNAs ) are involved in cancer development and progression , acting as tumor suppressors or oncogenes . In this study , miRNA profiling was performed on 10 paired bladder cancer ( BC ) tissues using 20 GeneChipTM miRNA Array , and 10 differentially expressed miRNAs were identified in BC and adjacent noncancerous tissues of any disease stage/grade . After validated on expanded cohort of 67 paired BC tissues and 10 human BC cell lines by qRT-PCR , it was found that miR-100 was down-regulated most significantly in cancer tissues . Ectopic restoration of miR-100 expression in BC cells suppressed cell proliferation and motility , induced cell-cycle arrest in vitro , and inhibited tumorigenesis in vivo both in subcutaneous and intravesical passage . Bioinformatic analysis showed that mTOR gene was a direct target of miR-100. siRNA-mediated mTOR knockdown phenocopied the effect of miR-100 in BC cell lines . In addition , the cancerous metastatic nude mouse model established on the basis of primary BC cell lines suggested that miR-100/mTOR regulated cell motility and was associated with tumor metastasis . Both mTOR and p70S6K ( downstream messenger ) presented higher expression levels in distant metastatic foci such as in liver and kidney metastases than in primary tumor . Taken together , miR-100 may act as a tumor suppressor in BC , and reintroduction of this mature miRNA into tumor tissue may prove to be a therapeutic strategy by reducing the expression of target genes .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23270926"}
{"sentence": "BACKGROUND Colorectal cancer is one of the leading causes of cancer-related death throughout the world , and the risk to develop this malignant disease seems to be associated with long-term cigarette smoking . Nicotine , one of the major components of cigarette smoking , can stimulate cell proliferation and suppress apoptosis both in normal cells and in several human cancer cell lines derived from various organs . However , although nicotine appears to have a role in stimulating cell proliferation of colon cancer cells , there is no information on its role in inhibiting apoptosis in these cells . MATERIALS AND METHODS Human colorectal cancer cell lines Caco-2 and HCT-8 were treated with 1 \u03bcM nicotine alone or in combination with 1 \u03bcM \u03b1-BTX in complete or in serum free medium . Cell proliferation and apoptosis were determined by cell count performed with a cell counter and by cytofluorimetric assay respectively . PI3K/Akt and PKC/ERK1/2 pathways , survivin , and P-Bcl2 ( Ser70 ) were investigated by Western blot analysis . RESULTS Nicotine induced an increase in cell proliferation and a decrease of apoptosis in Caco-2 and HCT-8 cells . Both cell growth and apoptosis appear to be mediated by \u03b17-nicotinic acetylcholine receptors , since treatment with \u03b1-Bungarotoxin inhibited these processes . Nicotine induced a statistically significant increase in the expression of PI3K and in P-Akt/Akt ratio as well as in the expression of PKC , ERK1/2 , survivin , and P-Bcl2 ( Ser70 ) in both cell lines . CONCLUSIONS Nicotine , contained in cigarette smoking , could participate in colon cancer development and progression by stimulating cell proliferation and suppressing physiological apoptosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22520577"}
{"sentence": "The effect of quercetin , a flavonoid found in many plants , on the proliferation of human leukemic T-cells was analyzed . Quercetin reversibly blocked the cell cycle at a point 3-6 h before the start of DNA synthesis . Expression of the growth-related genes histone H4 , cyclin A and B , and p34cdc2 was suppressed in cells blocked with quercetin . Comparison of the quercetin arrest points with those of the cell cycle inhibitors aphidicolin and mimosine revealed a temporal order of arrest points in G1 of quercetin , mimosine , and aphidicolin . Mimosine and aphidicolin did not inhibit the expression of cyclin A or p34cdc2 , whereas all three reagents inhibited expression of cyclin B. Low concentrations of the protein inhibitor cycloheximide inhibited release of the quercetin but not the mimosine or aphidicolin block . A [ 35S]methionine-labeled M(r) 60,000 protein disappeared in quercetin-treated cells and was rapidly synthesized after removal of quercetin , suggesting the possibility that the M(r) 60,000 protein induces DNA synthesis after the cell is released from a quercetin block . These results suggest the usefulness of quercetin in studies of the regulation of late G1 phase .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "1423313"}
{"sentence": "The Ras association domain family 1 isoform A ( RASSF1A ) is a tumor suppressor whose inactivation is implicated in the development of many human cancers , including breast carcinomas . Little is known about the tumor-suppressive function of RASSF1A in breast tissue and whether its inactivation is mechanistically involved in the initiation and progression of breast tumors . Here , we show that RASSF1A inhibits breast cancer growth in vivo , and suppresses estrogen receptor ( ER\u03b1 ) expression and function . Reconstitution of RASSF1A in MCF7 cells led to decreased ER\u03b1 levels and reduced sensitivity to estrogen ( E2 ) . Concomitantly , we observed decreased expression of Id1 as well as the E2-responsive genes Bcl-2 and c-Myc that cooperatively contribute to the immortalization and transformation of breast epithelial cells . This downregulation was associated with induction of cell-cycle arrest and senescence that constitute early barriers to cancer initiation and progression . Knockdown of ER\u03b1 showed that downregulation of ER\u03b1 suffices to increase senescence and inhibit expression of Bcl-2 , c-Myc and Id1 . However , enforced expression of ER\u03b1 only partially rescued RASSF1A-mediated growth inhibition and senescence , suggesting that suppression of ER\u03b1 expression and activity is not the only mechanism by which RASSF1A inhibits growth and survival of breast cancer cells . Ectopic expression of Bcl-2 , c-Myc and Id1 had little or no effect on RASSF1A-mediated growth arrest , indicating that RASSF1A acts dominantly over these oncogenes . Mechanistically , RASSF1A was found to suppress ER\u03b1 expression through Akt1 . It also transiently inhibited ER\u03b1-induced Ras-MAPK activity after exposure of cells to E2 . Together , our data show that RASSF1A acts as a tumor suppressor in ER\u03b1+ mammary epithelial cells , in part through inhibiting ER\u03b1 expression and activity . These findings suggest that RASSF1A has a key role in suppressing the transformation of human breast epithelial cells and ER\u03b1+ breast cancer initiation .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "22266866"}
{"sentence": "Chronic inflammation is a critical component in breast cancer progression . Pro-inflammatory mediators along with growth/survival factors within the tumor microenvironment potentiate the expression of pro-inflammatory cytokines ( IL-1 , IL-6 , TNF-\u03b1 ) , chemotactic cytokines and their receptors ( CXCR4 , CXCL12 , CXCL8 ) and angiogenic factors ( VEGF ) that often overcome the effect of anti-inflammatory molecules ( IL-4 , IL-10 ) thus evading the host's antitumor immunity . Detailed knowledge , therefore , of the regulatory mechanisms determining cytokine levels is essential to understand the pathogenesis of breast cancer . HIF-1\u03b1 and NF-\u03baB transcription factors are important players for the establishment of a pro-inflammatory and potentially oncogenic environment . HIF-1\u03b1 is the key mediator of the cellular response to oxygen deprivation and induces the expression of genes involved in survival and angiogenesis within solid hypoxic tumors . The expression of these genes is often modulated by the p53 tumor suppressor protein that induces apoptosis or cell cycle arrest in neoplastic cells . Functional crosstalk between HIF-1\u03b1 and p53 pathways mediated by modulators shared between the two transcription factors such as SRC-1 and SIRT-1 differentially regulate the expression of distinct subsets of their target genes under variable stress conditions . In an attempt to shed light on the complex regulatory mechanisms involved in cancer-related inflammation , we investigated the role of the two common p53 and HIF-1\u03b1 co-regulators SRC-1 and SIRT-1 , in the expression of the highly potent metastatic chemokine receptor CXCR4 . Both SRC-1 and SIRT-1 overexpression in DSFX-treated MCF-7 cells reduced CXCR4 cellular levels implying that both co-regulators are crucial factors in the determination of the metastatic potential of breast cancer cells .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23023398"}
{"sentence": "BACKGROUND Chronic lymphocytic leukemia cells show prolonged survival in vivo , but rapidly die by spontaneous apoptosis in vitro , unless they are co-cultured with stromal cells or non-malignant leukocytes . The objective of this study was to characterize the survival-inducing cross-talk of chronic lymphocytic leukemia cells with their microenvironment to identify novel therapeutic targets . DESIGN AND METHODS We analyzed and compared microarray-based expression profiles of chronic lymphocytic leukemia cells before and after three different survival-inducing culture conditions : ( i ) stromal cell co-culture , ( ii ) stromal cell conditioned medium and ( iii ) high cell density cultures of unsorted peripheral blood mononuclear cells . Cytokine antibody arrays were applied to study the composition of soluble factors present in these cultures . RESULTS The different survival-supportive culture conditions induced distinct gene expression changes , the majority of which were common to all three conditions . Pathway analyses identified - in addition to known signaling networks in chronic lymphocytic leukemia - novel pathways , of which Toll-like receptor signaling , nuclear respiratory factor-2 ( NRF2)-mediated oxidative stress response , and signaling via triggering receptor expressed on myeloid cells-1 ( TREM1 ) were the most relevant . A high proportion of up-regulated genes were inflammatory cytokines , of which chemokine ( C-C motif ) ligand 2 ( CCL2 ) was shown to be induced in monocytes by the presence of chronic lymphocytic leukemia cells in vitro . In addition , increased serum levels of this chemokine were detected in patients with chronic lymphocytic leukemia . CONCLUSIONS Our data provide several lines of evidence that an inflammatory microenvironment is induced in survival-supportive cultures of chronic lymphocytic leukemia cells which might be directly or indirectly involved in the prolonged survival of the malignant cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21134984"}
{"sentence": "Recently , we identified the \" apoptotic ring, \" containing phosphorylated histone H2AX ( \u03b3-H2AX ) , as an early chromatin modification during apoptosis . Because \u03b3-H2AX initiates the DNA damage response ( DDR ) , we tested whether the apoptotic H2AX response leads to the full recruitment of the DDR factors that normally coordinate DNA repair and cell-cycle checkpoints . We show that the apoptotic H2AX response does not recruit the DDR factors because MDC1 ( mediator of DNA damage checkpoint protein 1 ) , which normally binds to \u03b3-H2AX in response to DNA damage and amplifies the DDR , is cleaved by caspase-3 . This cleavage separates the BRCT and FHA domains of MDC1 and constitutes a novel mechanism for the inactivation of DNA repair in apoptotic cells . Also , we show that downregulation of MDC1 increases the apoptotic response to TRAIL . Together , these results implicate MDC1 in the cellular apoptotic response .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "21148072"}
{"sentence": "DNA-protein cross-links ( DPCs ) are formed upon exposure to a variety of chemical and physical agents and pose a threat to genomic integrity . In particular , acrolein and related aldehydes produce DPCs , although the chemical linkages for such cross-links have not been identified . Here , we report that oligodeoxynucleotides containing 1,N(2)-deoxyguanosine adducts of acrolein , crotonaldehyde , and trans-4-hydroxynonenal can form cross-links with the tetrapeptide Lys-Trp-Lys-Lys . We concluded that complex formation is mediated by a Schiff base linkage because DNA-peptide complexes were covalently trapped following reduction with sodium cyanoborohydride , and pre-reduction of adducted DNAs inhibited complex formation . A previous NMR study demonstrated that duplex DNA catalyzes ring opening for the acrolein-derived gamma-hydroxy-1,N(2)-propanodeoxyguanosine adduct to yield an aldehydic function ( de los Santos , C. , Zaliznyak , T. , and Johnson , F . ( 2001 ) J. Biol . Chem. 276 , 9077-9082 ) . Consistent with this earlier observation , the adducts under investigation were more reactive in duplex DNA than in single-stranded DNA , and we concluded that the ring-open aldehydic moiety is the induced tautomer in duplex DNA for adducts exhibiting high relative reactivity . Adducted DNA cross-linked to Arg-Trp-Arg-Arg and Lys-Trp-Lys-Lys with comparable efficiency , and N(alpha)-acetylation of peptides dramatically inhibited trapping ; thus , the reactive nucleophile is located at the N-terminal alpha-amine of the peptide . These data suggest that Schiff base chemistry can mediate DPC formation in vivo following the formation of stable aldehyde-derived DNA adducts .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12502710"}
{"sentence": "UNLABELLED Oxygen free radicals and their reactive derivatives participate in formation of chronic inflammation states , which facilitate development of gastrointestinal tract tumors . Oxidative stress is one of the main causes of damage to cell membranes in result of exacerbated lipid peroxidation process . End products of lipid peroxidation ( aldehydes , organic peroxides ) react with important biological macromolecules such as DNA and proteins , cause changes in cell membrane structure and properties leading to loss of its integrity . Intensification of the lipid peroxidation process is a factor which may also lead to a malfunction in the antioxidant barrier , which further weakens the defense of cells against oxygen free radicals and promotes the onset and development of cancer . The aim of the study was the determination of lipid peroxidation level in gastrointestinal tract tumors ( stomach , liver , colon , and colorectal cancer to liver metastases ) . MATERIAL AND METHODS Materials for studies were obtained from 150 patients with gastrointestinal tract tumors : 10 with stomach cancer , 30 with malignant and benign liver cancers , 60 with primary colorectal cancer , and 50 with metachronous colorectal cancer liver metastases . We also investigated 25 patients with liver cirrhosis , which was treated as a pre-cancerous condition . In total , 175 patients were examined . Tumor specimens , and normal adjacent tissues ( 6-7 cm from the edge of the tumor ) , which served as control tissue in studies , were collected from patients ( with their consent ) during surgery . Additionally , liver specimens were collected from patients with liver cirrhosis . Lipid peroxidation level was determined spectrophotometrically as a concentration of final lipid peroxidation products , which in reaction with tiobarbituric acid ( TBA ) form colour complex ( thiobarbituric acid-reactive substances - TBARS ) . RESULTS The study showed the highest concentration of TBARS in benign , and the lowest in malignant liver tumors . Other types of gastrointestinal tumors studied , were characterized by similar levels of lipid peroxidation . TBARS concentration in these tumors was approximately 2-fold higher than in malignant liver tumors and much lower than in benign tumors . In all cancers of the digestive tract with the exception of malignant liver tumors increased level of TBARS was found , comparing with control tissue . The concentration of TBARS in cirrhotic liver was lower than in control . The level of lipid peroxidation in liver cirrhosis and malignant liver tumors was similar . There were no significant differences in TBARS concentration in the tumors of particular sections of the intestine and normal colon . The highest concentration of TBARS was found in G1 grade of colorectal cancer . In subsequent grades of cells differentiation ( G2 and G3 ) its concentration was lower . The highest level of lipid peroxidation , expressed as the concentration of TBARS was found in the I stage of colorectal cancer clinical advancement . The significantly lowest concentration of TBARS was shown for stage II ( UICC ) . CONCLUSIONS The level of lipid peroxidation in cancerous cells of gastrointestinal tract indicates increased oxidative stress . The changes of lipid peroxidation level--a marker of oxidative stress in gastrointestinal tumors appear to be closely associated with their development stages ( liver cirrhosis/malignant liver cancer ; colorectal cancer/colorectal cancer liver metastases ) and are likely to create such conditions , in which cancerous cells may proliferate , undergo gradual dedifferentiation and malignancy , and generate metastases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21268915"}
{"sentence": "Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects , including anti-inflammatory , cardio-protective , and cancer-protective activities . It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders . Ulcerative colitis is an idiopathic , chronic inflammatory disease of the colon associated with a high colon cancer risk . Here , we used a dextran sulfate sodium ( DSS ) mouse model of colitis , which resembles human ulcerative colitis pathology . Resveratrol mixed in food ameliorates DSS-induced colitis in mice in a dose-dependent manner . Resveratrol significantly improves inflammation score , downregulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propria , and modulates CD3(+) T cells that express tumor necrosis factor-alpha and IFN-gamma . Markers of inflammation and inflammatory stress ( p53 and p53-phospho-Ser(15) ) are also downregulated by resveratrol . Because chronic colitis drives colon cancer risk , we carried out experiments to determine the chemopreventive properties of resveratrol . Tumor incidence is reduced from 80% in mice treated with azoxymethane ( AOM ) + DSS to 20% in mice treated with AOM + DSS + resveratrol ( 300 ppm ) . Tumor multiplicity also decreased with resveratrol treatment . AOM + DSS-treated mice had 2.4 +/- 0.7 tumors per animal compared with AOM + DSS + 300 ppm resveratrol , which had 0.2 +/- 0.13 tumors per animal . The current study indicates that resveratrol is a useful , nontoxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20332304"}
{"sentence": "The epidermal growth factor receptor ( EGFR ) is a member of the HER family receptors and its activation induced by its natural ligand EGF results in colon cancer growth and progression . Panitumumab ( pmAb ) is a fully human IgG2 anti-EGFR antibody that blocks the EGFR actions . In the present study , we evaluated the effects of pmAb on the EGF-mediated cellular responses in a panel of colon cancer cells ( HCT-8 , HT-29 , DLD-1 and HCT-116 ) . HCT-1116 and DLD-1 cells showed no significant EGF-dependent cell proliferation ; HT-29 and HCT-8 exhibited an EGF-dependent proliferation , with HCT-8 cells to be the most responsive with significant EGFR phosphorylation upon treatment with EGF . The effects of pmAb were then evaluated in the most EGF-responsive cells , HCT-8 . In that respect , pmAb impedes the signaling cascade mediated by EGFR intracellular phosphorylation and activity of focal adhesion kinase ( FAK ) as well as the EGF-induced invasive and migratory potential of colon cancer cells . At the level of matrix effectors implicated in colon cancer progression we report that pmAb is a potent inhibitor of constitute and EGF-mediated gene expression of certain matrix effectors , such as membrane-type 1 metalloproteinase ( MT1-MMP ) , extracellular metalloproteinases inducer ( EMMPRIN ) , urokinase plasminogen activator ( uPA ) and syndecan-4 . The obtained data demonstrated that pmAb is a specific blocker of EGF-mediated EGFR activation , resulting in a significant inhibition of colon cancer cell proliferation in early stages of growth , migration and invasiveness as well as of matrix effector implicated in cancer progression .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22956286"}
{"sentence": "Exposure to benzo[a]pyrene ( BaP ) can induce inflammatory skin diseases and skin cancer , which are both associated to oxidative stress . BaP is known to bind with high specificity to the aryl hydrocarbon receptor ( AhR ) , modifying the expression of CYP1A1 , involved both in cancer and inflammation . While the current knowledge is based on murine skin and cell culture data , in this study human healthy skin has been treated with 5muM BaP in conditions simulating occupational and environmental exposure . AhR and CYP1A1 expression was evaluated by Western blotting , which revealed their presence even in control untreated skin ; both enzyme and receptor increased more than twofold after exposure to BaP . AhR expression level was lower than CYP1A1 in basal conditions and following induction . Oxidative stress was evaluated in terms of MTT reduction , protein peroxidation and reactive oxygen species ( ROS ) formation . A significant increase in ROS and carbonyl compound production , as well as reduced tissue viability have been determined by BaP . The results of this experiment indicate that BaP , an AhR agonist , can significantly increase receptor and CYP1A1 expression and induce oxidative stress in human skin , confirming the involvement of this pathway in the pathogenesis of tissue damage due to polycyclic aromatic hydrocarbons .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20307623"}
{"sentence": "Using an immunoradiometric assay , Cathepsin D ( Cath D ) levels were measured in the cytosol of 23 normal and 39 neoplastic human laryngeal tissues . Scattered Cath D levels ( from 2.2 to 17.8 pM/mg protein ; median = 7.6 ) were found in normal mucosa specimens . Cath D concentrations range from 2.0 to 29.3 pM/mg protein ( median = 8.5 ) in laryngeal tumors . When a comparison between Cath D levels in normal and neoplastic tissue specimens from the same patient was done , Cath D levels were significantly higher in laryngeal cancers than in their normal counterparts ( P = 0.03 ) . No correlation with clinico-pathological parameters and steroid hormone and epidermal growth factor receptor status was found . Further studies should investigate whether the production of Cath D by laryngeal tumors could have a clinical relevance for this neoplasia .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1483262"}
{"sentence": "A predictive mathematical model of the transition from the G2 phase in the cell cycle to mitosis ( M ) was constructed from the known interactions of the proteins that are thought to play significant roles in the G2 to M transition as well as the DNA damage- induced G2 checkpoint . The model simulates the accumulation of active cyclin B1/Cdk1 ( MPF ) complexes in the nucleus to activate mitosis , the inhibition of this process by DNA damage , and transport of component proteins between cytoplasm and nucleus . Interactions in the model are based on activities of individual phospho-epitopes and binding sites of proteins involved in G2/M . Because tracking phosphoforms leads to combinatorial explosion , we employ a rule-based approach using the BioNetGen software . The model was used to determine the effects of depletion or over-expression of selected proteins involved in the regulation of the G2 to M transition in the presence and absence of DNA damage . Depletion of Plk1 delayed mitotic entry and recovery from the DNA damage-induced G2 arrest and over-expression of MPF attenuated the DNA damage-induced G2 delay . The model recapitulates the G2 delay observed in the biological response to varying levels of a DNA damage signal . The model produced the novel prediction that depletion of pkMyt1 results in an abnormal biological state in which G2 cells with DNA damage accumulate inactive nuclear MPF . Such a detailed model may prove useful for predicting DNA damage G2 checkpoint function in cancer and , therefore , sensitivity to cancer therapy .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "23266715"}
{"sentence": "Many molecular mechanisms contribute to the development of doxorubicin resistance and different cancers can express wide and diverse arrays of drug-resistance genes . The aim of this study was to identify the changes in gene expression associated with the development of doxorubicin resistance in MCF7 breast cancer cell line . The doxorubicin resistant MCF7 cell line was developed by stepwise selection of MCF7 cells and was tested using the MTT assay . The alterations in gene expression were examined using the real-time based PCR array . The findings showed an up-regulation of many phase I/II metabolizing genes , specifically , the CYP1A1 and the CYP1A2 that were up-regulated by 206- and 96-fold respectively . Drug efflux pump genes were also up-regulated profoundly . TOP2A was strongly down-regulated by 202-fold . Many other changes were observed in genes crucial for cell cycle , apoptosis and DNA repair . The findings of this project imply that the development of doxorubicin resistance is a multi-factorial process .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 1, 0], "id": "23201559"}
{"sentence": "AIM To investigate the role of delta-like ligand 4 ( DLL4 ) in the angiogenesis of high-grade malignant glioma . MATERIALS AND METHODS DLL4 expression and microvessel density ( MVD ) were detected by immunohistochemistry in 51 human high-grade malignant glioma tissue samples . The vessel maturation index ( VMI ) was calculated as the percentage of a-smooth muscle actin ( a-SMA)-positive vessels in relation to the amount of CD31-positive vessels . Double fluorescent immunostaining for CD31 and EphrinB2 or EphB4 was performed to identify the arterial ( EphrinB2 ) or venous ( EphB4 ) origins of glioma microvessels . RESULTS Strong immunostaining of DLL4 and a positive correlation of DLL4 with the MVD were observed in high-grade malignant gliomas . The VMI of the DLL4-positive group was significantly higher than that of the DLL4-negative group . However , no significant association was found between DLL4 and EphrinB2 or EphB4 in high-grade gliomas . CONCLUSION DLL4 may be an important regulator for vessel proliferation and maturation in human high-grade malignant gliomas .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23207622"}
{"sentence": "The pancreatic stellate cells ( PSCs ) have complex roles in pancreas , including tissue repair and fibrosis . PSCs surround ATP releasing exocrine cells , but little is known about purinergic receptors and their function in PSCs . Our aim was to resolve whether PSCs express the multifunctional P2X7 receptor and elucidate how it regulates PSC viability . The number of PSCs isolated from wild type ( WT ) mice was 50% higher than those from the Pfizer P2X7 receptor knock out ( KO ) mice . The P2X7 receptor protein and mRNA of all known isoforms were expressed in WT PSCs , while KO PSCs only expressed truncated versions of the receptor . In culture , the proliferation rate of the KO PSCs was significantly lower . Inclusion of apyrase reduced the proliferation rate in both WT and KO PSCs , indicating importance of endogenous ATP . Exogenous ATP had a two-sided effect . Proliferation of both WT and KO cells was stimulated with ATP in a concentration-dependent manner with a maximum effect at 100 \u00b5M . At high ATP concentration ( 5 mM ) , WT PSCs , but not the KO PSCs died . The intracellular Ca(2+) signals and proliferation rate induced by micromolar ATP concentrations were inhibited by the allosteric P2X7 receptor inhibitor az10606120 . The P2X7 receptor-pore inhibitor A438079 partially prevented cell death induced by millimolar ATP concentrations . This study shows that ATP and P2X7 receptors are important regulators of PSC proliferation and death , and therefore might be potential targets for treatments of pancreatic fibrosis and cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23284663"}
{"sentence": "Nuclear factor kappa B ( NF-\u03baB ) is a key signaling molecule in the elaboration of the inflammatory response . Data indicate that curcumin , a natural ingredient of the curry spice turmeric , acts as a NF-\u03baB inhibitor and exhibits both anti-inflammatory and anti-cancer properties . Curcumin analogs with enhanced activity on NF-\u03baB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone ( EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone ( EF31 ) is a structurally-related curcumin analog whose potency for NF-\u03baB inhibition has yet to be determined . To examine the activity of EF31 compared to EF24 and curcumin , mouse RAW264.7 macrophages were treated with EF31 , EF24 , curcumin ( 1-100 \u03bcM ) or vehicle ( DMSO 1% ) for 1h . NF-\u03baB pathway activity was assessed following treatment with lipopolysaccharide ( LPS ) ( 1 \u03bcg/mL ) . EF31 ( IC(50) \u03bcM ) exhibited significantly more potent inhibition of LPS-induced NF-\u03baB DNA binding compared to both EF24 ( IC(50) \u03bcM ) and curcumin ( IC(50) >50 \u03bcM ) . In addition , EF31 exhibited greater inhibition of NF-\u03baB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein ( tumor necrosis factor-\u03b1 , interleukin-1\u03b2 , and interleukin-6 ) . Regarding the mechanism of these effects on NF-\u03baB , EF31 ( IC(50) \u03bcM ) exhibited significantly greater inhibition of I\u03baB kinase \u03b2 compared to EF24 ( IC(50) \u03bcM ) . Finally , EF31 demonstrated potent toxicity in NF-\u03baB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages . These data indicate that EF31 is a more potent inhibitor of NF-\u03baB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities . Thus , EF31 represents a promising curcumin analog for further therapeutic development .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22197802"}
{"sentence": "Most ovarian cancers are estrogen-positive and hormonal treatments using anti-estrogens or aromatase inhibitors are under investigation for treating the tumors that are resistant to conventional therapies . In this study , the long-term effects of two anti-estrogens , namely 4-hydroxytamoxifen and fulvestrant ( or ICI182,780 ) , were investigated in ER\u03b1-positive BG1 epithelial ovarian cancer cells . To this aim , cells were grown in the presence of anti-estrogen concentrations that were sufficient to saturate the estrogen receptors , but were neither cytotoxic nor cytostatic as indicated by the absence of inhibition of cell proliferation . In these conditions and despite the lack of cytostatic effect of the drugs , long-term treatment ( 3 months ) with the pure anti-estrogen fulvestrant induced a specific , reproducible and irreversible inhibition of ER\u03b1 expression . This inhibition was accompanied by loss of estrogen-induced cell proliferation and gene expression as indicated by the analysis of several estrogen-responsive genes . ER\u03b1 down-regulation was not linked to deregulated expression of transcription factors which drive ER\u03b1 transcription and did not involve DNA methylation or histone deacetylation . Altogether , these results demonstrate that non-cytotoxic concentrations of pure anti-estrogens affect estrogen signaling and might be relevant for the treatment for ovarian cancers .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22652558"}
{"sentence": "This study intended to investigate the expression of the ZEB1 and E-cadherin proteins in lung squamous cell carcinoma ( LSCC ) tissues and to examine the clinicopathological correlation between protein levels and LSCC . RT-PCR and Western blot were used to examine the expression of ZEB1 and E-cadherin mRNAs and proteins in LSCC tissues as well as in adjacent normal tissues , and then analyze the relationship between the clinicopathological characteristics and the expression changes of ZEB1 and E-cadherin mRNAs in LSCC . In addition , RNAi was used to knockdown the expression of the ZEB1 gene in Human HCC827 cells ; subsequently , changes in the invasive ability of the resultant cells were studied . The positive rates of ZEB1 and E-cadherin mRNAs in LSCC tissues were 69.2 and 38.5% , respectively . They differed significantly from the corresponding positive rates in the adjacent normal lung tissues ( 15.4 and 80.8% , p<0.05 ) . There was a negative correlation between the protein levels of ZEB1 and E-cadherin in LSCC tissues ( r=-0.714 , p<0.001 ) ; in addition , it was found that ZEB1 protein expression in LSCC tissues was significantly higher than that in the neighboring normal lung tissues ( p<0.05 ) , and its expression was also significantly higher in patients with lymph node metastases and distant metastases compared to those patients without metastatic disease ( p<0.05 ) . On the contrary , E-cadherin expression was significantly lower in LSCC tissues than that in the neighboring normal tissue ( p<0.05 ) . It was lower in patients with lymph node metastasis and distant metastasis compared to patients without metastatic disease ( p<0.05 ) . However , the expression of ZEB1 and E-cadherin was independent of gender , age , tumor size , or tumor differentiation level ( p>0.05 ) . Transfection of ZEB1 siRNA into HCC827 cells significantly reduced the ZEB1 protein level ( p<0.01 ) and significantly elevated E-cadherin levels ( p<0.01 ) . Moreover , significantly less ZEB1 siRNA-transfected cells migrated through Transwell chambers in the LSCC tissue than that in the control groups ( untransfected or transfected with control siRNA , p<0.01 ) . The expression of the ZEB1 gene in LSCC tissues is downregulated with the expression of E-cadherin . On the other hand , the expression of siRNA against ZEB1 promotes E-cadherin expression and suppresses the invasive ability conferred by E-cadherin . In conclusion , our data suggested that overexpression of the ZEB1 gene is possibly associated with the occurrence , development , invasion of LSCC .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23065281"}
{"sentence": "Tumor necrosis factor ( TNF ) is an important inflammatory cytokine and induces many cellular responses , including inflammation , cell proliferation , apoptosis , and necrosis . It is known that receptor interacting protein ( RIP ) kinases , RIP1 and RIP3 , are key effectors of TNF-induced necrosis , but little is known about how these two RIP kinases mediate this process , although reactive oxygen species ( ROS ) generation and JNK activation have been suggested to be two downstream events of RIP kinases . Here we report the identification of mixed lineage kinase domain-like , MLKL , as a key RIP3 downstream component of TNF-induced necrosis . Through screening a kinase/phosphatase shRNA library in human colon adenocarcinoma HT-29 cells , we found that knockdown of MLKL blocked TNF-induced necrosis . Our data suggest that MLKL functions downstream of RIP1 and RIP3 and is recruited to the necrosome through its interaction with RIP3 . Finally , we found that MLKL is required for the generation of ROS and the late-phase activation of JNK during TNF-induced necrosis . However , because these two events are not involved in TNF-induced necrosis in HT-29 cells , the target of MLKL during TNF-induced necrosis remains elusive . Taken together , our study suggests that MLKL is a key RIP3 downstream component of TNF-induced necrotic cell death .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22421439"}
{"sentence": "The Punica granatum L. var. granatum ( pomegranate ) has been demonstrated to exert antitumor effects on various types of cancer cells . The present study aimed to evaluate the medicinal herbs Punica granatum L. var. spinosa ( apple punice ) that are native to Iran . This study was determined to test the possible cytotoxic activity and induction of apoptosis on human prostate cell lines . The effect of ethanol extracts of the herbs on the inhibition of cell proliferation was assessed by MTT colorimetric assay . PC3 cell lines treated with the extracts were analyzed for the induction of apoptosis by cell death detection ( ELISA ) and TUNEL assay . Dye exclusion analysis was performed for viability rate . Our results demonstrated that the Punica granatum L. var. spinosa extract dose dependently suppressed the proliferation of PC3 cells ( IC(50)= 250.21\u2009\u03bcg/mL ) when compared with a chemotherapeutic anticancer drug ( Toxol ) ( Vesper Pharmaceuticals ) with increased nucleosome production from apoptotic cells . The Punica granatum L. var. spinosa extract attenuated the human prostate cell proliferation in vitro possibly by inducing apoptosis . The Punica granatum L. var. spinosa is likely to be valuable for the treatment of some forms of human prostate cell line .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23320197"}
{"sentence": "BACKGROUND Aerobic glycolysis , namely the Warburg effect , is the main hallmark of cancer cells . Mitochondrial respiratory dysfunction has been proposed to be one of the major causes for such glycolytic shift . This hypothesis has been revisited as tumors appear to undergo waves of gene regulation during progression , some of which rely on functional mitochondria . In this framework , the role of mitochondrial complex I is still debated , in particular with respect to the effect of mitochondrial DNA mutations in cancer metabolism . The aim of this work is to provide the proof of concept that functional complex I is necessary to sustain tumor progression . METHODS Complex I-null osteosarcoma cells were complemented with allotopically expressed complex I subunit 1 ( MT-ND1 ) . Complex I re-assembly and function recovery , also in terms of NADH consumption , were assessed . Clones were tested for their ability to grow in soft agar and to generate tumor masses in nude mice . Hypoxia levels were evaluated via pimonidazole staining and hypoxia-inducible factor-1\\u03b1 ( HIF-1\\u03b1 ) immunoblotting and histochemical staining. 454-pyrosequencing was implemented to obtain global transcriptomic profiling of allotopic and non-allotopic xenografts . RESULTS Complementation of a truncative mutation in the gene encoding MT-ND1 , showed that a functional enzyme was required to perform the glycolytic shift during the hypoxia response and to induce a Warburg profile in vitro and in vivo , fostering cancer progression . Such trigger was mediated by HIF-1\\u03b1 , whose stabilization was regulated after recovery of the balance between \\u03b1-ketoglutarate and succinate due to a recuperation of NADH consumption that followed complex I rescue . CONCLUSION Respiratory complex I is essential for the induction of Warburg effect and adaptation to hypoxia of cancer cells , allowing them to sustain tumor growth . Differently from other mitochondrial tumor suppressor genes , therefore , a complex I severe mutation such as the one here reported may confer anti-tumorigenic properties , highlighting the prognostic values of such genetic markers in cancer .", "label": [0, 0, 1, 0, 0, 1, 0, 0, 0, 0], "id": "24280190"}
{"sentence": "Radiotherapy is commonly used for cancer treatment . However , it often results in side effects due to radiation damage in normal tissue , such as bone marrow ( BM ) failure . Adult hematopoietic stem and progenitor cells ( HSPC ) reside in BM next to the endosteal bone surface , which is lined primarily by hematopoietic niche osteoblastic cells . Osteoblasts are relatively more radiation-resistant than HSPCs , but the mechanisms are not well understood . In the present study , we demonstrated that the stress response gene REDD1 ( regulated in development and DNA damage responses 1 ) was highly expressed in human osteoblast cell line ( hFOB ) cells after \\u03b3 irradiation . Knockdown of REDD1 with siRNA resulted in a decrease in hFOB cell numbers , whereas transfection of PCMV6-AC-GFP-REDD1 plasmid DNA into hFOB cells inhibited mammalian target of rapamycin ( mTOR ) and p21 expression and protected these cells from radiation-induced premature senescence ( PS ) . The PS in irradiated hFOB cells were characterized by significant inhibition of clonogenicity , activation of senescence biomarker SA-\\u03b2-gal , and the senescence-associated cytokine secretory phenotype ( SASP ) after 4 or 8 Gy irradiation . Immunoprecipitation assays demonstrated that the stress response proteins p53 and nuclear factor \\u03ba B ( NFkB ) interacted with REDD1 in hFOB cells . Knockdown of NFkB or p53 gene dramatically suppressed REDD1 protein expression in these cells , indicating that REDD1 was regulated by both factors . Our data demonstrated that REDD1 is a protective factor in radiation-induced osteoblast cell premature senescence .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "22629318"}
{"sentence": "The chemotherapeutic drug cis-diamminedichloroplatinum ( II ) covalently binds to DNA resulting in a variety of adducts and cross-links which are thought to be responsible for the toxicity of the drug . We have used the gel mobility shift assay to detect proteins which bind to DNA treated in vitro with cis-diamminedichloroplatinum ( II ) and have identified two complexes which bind with increased affinity to cis-diamminedichloroplatinum ( II)-damaged DNA . Using monoclonal antibodies we have shown that one complex , B1 , contains human single-stranded DNA binding protein , a protein known to be involved in the in vitro repair synthesis assay of mammalian excision repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1423284"}
{"sentence": "The phosphatidylinositol-3-kinase ( PI3K)/Akt oncogenic pathway is critical in glioblastomas . Loss of PTEN , a negative regulator of the PI3K pathway or activated PI3K/Akt pathway that drive increased proliferation , survival , neovascularization , glycolysis , and invasion is found in 70%-80% of malignant gliomas . Thus , PI3K is an attractive therapeutic target for malignant glioma . We report that a new irreversible PI3K inhibitor , PX-866 , shows potent inhibitory effects on the PI3K/Akt signaling pathway in glioblastoma . PX-866 did not induce any apoptosis in glioma cells ; however , an increase in autophagy was observed . PX-866 inhibited the invasive and angiogenic capabilities of cultured glioblastoma cells . In vivo , PX-866 inhibited subcutaneous tumor growth and increased the median survival time of animals with intracranial tumors . We also assessed the potential of proton magnetic resonance spectroscopy ( MRS ) as a noninvasive method to monitor response to PX-866 . Our findings show that PX-866 treatment causes a drop in the MRS-detectable choline-to-NAA , ratio and identify this partial normalization of the tumor metabolic profile as a biomarker of molecular drug action . Our studies affirm that the PI3K pathway is a highly specific molecular target for therapies for glioblastoma and other cancers with aberrant PI3K/PTEN expression .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20156803"}
{"sentence": "2,3,7,8-tetrachlorodibenzo-p-dioxin ( TCDD ) is the most potent tumor promoter ever tested in rodents . Although it is known that most of TCDD actions are mediated by binding to the aryl hydrocarbon receptor ( AhR ) , the mechanisms leading to tumor promotion still remain to be elucidated . Loss of contact inhibition is one characteristic hallmark in tumorigenesis . In rat liver epithelial WB-F344 cells , TCDD induces a release from contact inhibition , which is manifested by a twofold increase in cell number when TCDD ( 1 nM for 48 h ) is added to confluent cells in the presence of serum , but not when given to exponentially growing or subconfluent , serum-deprived WB-F344 cells . Loss of G1 arrest was also shown by flow cytometric analysis . We demonstrate that TCDD treatment significantly increases cyclin D2 and cyclin A protein levels and show by immunofluorescence that these proteins accumulate in the nucleus . Although TCDD treatment leads to a strong increase in cyclin D2/cdk4 and cyclin A/cdk2 complex formation , we could only detect an elevation of cyclin A/cdk2 activity . In accordance with a lack of elevated cdk4 activity , no decrease in the amount of hypophosphorylated retinoblastoma protein could be shown after TCDD treatment . The importance of increased cyclin A/cdk2 activity for TCDD-dependent release from contact inhibition was shown by the fact that the cdk2/cdc2-specific inhibitor olomoucine ( 25 microM ) abolished TCDD response . These data indicate cyclin A-dependent loss of G1 arrest after TCDD treatment mainly downstream of the retinoblastoma protein .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "12387751"}
{"sentence": "OBJECTIVE To study the effects of angiostatin(AS) gene mediated by liposome on human pancreatic cancer cell line SW1990 . METHODS Angiostatin gene was cloned into the eukaryotic expression vector pRC/CMV . The recombinant of pRC/CMV-AS was introduced into the pancreatic cancer cell line , SW1990 . The mechanism of anti-tumor was studied and tested . RESULTS The eukaryotic expression vector pRC/CMV-AS was identified by the restriction digest. pRC/CMV-AS was stably integrated into the target cells and expressed by Western blot and drug-sensitivity tests , and inhibited the vascular endothelial cells proliferation in vitro . In addition , the effects of the angiostatin vector on reducing the volume of tumors implanted in nude mouse models were also noted . CONCLUSION This study demonstrated that the recombinant pRC/CMV-AS mediated by liposome may play a potential role in the treatment of pancreatic cancer in the future .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "14607726"}
{"sentence": "PURPOSE Anthracyclines have been widely used as antitumor agents , playing a crucial role in the successful treatment of many types of cancer , despite some side effects related to cardiotoxicity . New anthracyclines have been designed and tested , but the first ones discovered , doxorubicin and daunorubicin , continue to be the drugs of choice . Despite their extensive use in chemotherapy , little is known about the DNA repair mechanisms involved in the removal of lesions caused by anthracyclines . The anthracycline cosmomycin D is the main product isolated from Streptomyces olindensis , characterized by a peculiar pattern of glycosylation with two trisaccharide rings attached to the A ring of the tetrahydrotetracene . METHODS We assessed the induction of apoptosis ( Sub-G1 ) by cosmomycin D in nucleotide excision repair-deficient fibroblasts ( XP-A and XP-C ) as well as the levels of DNA damage ( alkaline comet assay ) . RESULTS Treatment of XP-A and XP-C cells with cosmomycin D resulted in apoptosis in a time-dependent manner , with highest apoptosis levels observed 96 h after treatment . The effects of cosmomycin D were equivalent to those obtained with doxorubicin . The broad caspase inhibitor Z-VAD-FMK strongly inhibited apoptosis in these cells , and DNA damage induced by cosmomycin D was confirmed by alkaline comet assay . CONCLUSIONS Cosmomycin D induced time-dependent apoptosis in nucleotide excision repair-deficient fibroblasts . Despite similar apoptosis levels , cosmomycin D caused considerably lower levels of DNA damage compared to doxorubicin . This may be related to differences in structure between cosmomycin D and doxorubicin .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "20107801"}
{"sentence": "PURPOSE This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras ( KRAS ) gene on treatment efficacy in patients with metastatic colorectal cancer ( mCRC ) . PATIENTS Overall , 119 patients bearing a KRAS mutation in codon 12 were evaluated . All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group ( CECOG ) , AIO KRK-0104 or AIO KRK-0306 trials . RESULTS Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens . Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations ( overall survival 23.3 vs. 14-18 months ; hazard ratio 0.66 , range 0.43-1.03 ) . An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab . CONCLUSION The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22948721"}
{"sentence": "OBJECTIVES Epiphyseal cartilage is a barrier to osteosarcoma invasion , however the mechanisms behind this resistance remain unclear . The aim of this study was to examine the chronological and spatial patterns of osteosarcoma growth and invasion of local tissue structures including epiphyseal cartilage . METHODS We used an in vivomouse model of osteosarcoma to histologically examine tumors at different stages of disease progression . We compared the pattern of osteosarcoma penetration of epiphyseal cartilage with the expression pattern of two potent mediators of angiogenesis ; proangiogenic vascular endothelial growth factor ( VEGF ) and antiangiogenic pigment epithelium-derived factor ( PEDF ) . RESULTS Epiphyseal cartilage remained intact across its entire length in all sections examined , despite increasing tumor size as well as intra- and extraosseous destruction . In the most advanced cases , only the proangiogenic lowermost layers of the hypertrophic zone of the growth plate were eroded . This corresponded with the growth plate layers which highly expressed the angiogenic factor VEGF . In contrast , the resting , proliferative and upper hypertrophic layers were resistant to osteosarcoma invasion in all cases . This corresponded to the layers with the highest expression of the potent antiangiogenic factor PEDF . CONCLUSION Epiphyseal cartilage is resistant to local invasion by osteosarcoma . The balance of angiogenesis , influenced by pro- and antiangiogenic factors , is likely to play an important role in this resistance .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12865633"}
{"sentence": "OBJECTIVE To observe the anti-tumor recurrent and metastatic efficacy of Ru'ai Shuhou Recipe ( RSR ) on HER2 positive breast cancer , to evaluate the effects of RSR on the expressions of matrix metalloproteinases ( MMPs ) and the tissue inhibitor of metalloproteinases ( TIMPs ) in the recurrence and metastasis of HER2 positive breast cancer , thus revealing its anti-tumor recurrent and metastatic mechanisms . METHODS Selected were 30-week-old HER2/neu transgenic spontaneous breast cancer mice FVB/neu . The primary tumor resection was carried out . After surgery they were randomly divided into the blank control group , the RSR group , the Herceptin group , and the combination group ( RSR + Herceptin group ) . The treatment lasted for 4 months . The inhibition rate of the recurrent tumor volume and the inhibition rate of the lung metastasis were evaluated . The expressions of matrix metalloproteinase-2 ( MMP-2 ) , matrix metalloproteinase-9 ( MMP-9 ) , tissue inhibitor of metalloproteinase ( TIMP-1 ) , and TIMP-2 in the recurrent tumor tissue were detected using Western blot . RESULTS By the end of the treatment the average recurrent tumor volume was 11.11 +/- 8.71 cm3 in the blank control group and 5.56 +/- 5.55 cm3 of the RSR group , showing statistical difference between the two groups ( P = 0.037 ) . The average lung metastatic nodule was 16 in the blank control group and 10 in the RSR group . The inhibition rate of lung metastasis was 37. 85% in the RSR group , but with no statistical significance . The expression level of activated MMP-2 in the RSR group was down-regulated when compared with the blank control group , the Herceptin group , and the combination group ( P < 0.05 ) . The expression of MMP-9 of the RSR group , the Herceptin group , and the combination group was significantly down-regulated when compared with the blank control group ( P < 0.05 ) . The expression of MMP-9 of the RSR group and the combination group was further down-regulated when compared with the Herceptin group ( P < 0.05 ) . The expressions of both TIMP-1 and TIMP-2 of the RSR group , the Herceptin group , and the combination group were all up-regulated when compared with the blank control group ( P < 0.05 ) . The increased expression of TIMP-1 was more significantly in the RSR group and the combination group when compared with the Herceptin group ( P < 0.05 ) . It was higher in the combination group than in the RSR group ( P < 0.05 ) . CONCLUSIONS RSR could inhibit the tumor recurrence of FVB/neu mice . It could reduce the degradation of extracellular matrix and increase the protective effects of extracellular matrix . It might achieve its anti-tumor effect through effecting the invasive and metastatic capabilities of breast tumor cells .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23359979"}
{"sentence": "It was proved that nuclear factor-kappa B play an important role in the activation of immune cell , anti-virus , various stress reaction , and regulation of apoptosis , etc . The objective of this study was to investigate the effect of NF-kappa B signal-transduction pathway on apoptosis of hepatic carcinoma cell line-7721 induced by TNF-alpha .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12508545"}
{"sentence": "BACKGROUND It has been proven that metastasis-associated in colon cancer 1 ( MACC1 ) is a new gene that is related to the invasion and metastasis of tumors . MACC1 also regulates c-met expression . The aim of this study is to explore the expressions of MACC1 and hepatocyte growth factor receptor ( c-met ) , and its relationship with invasion , metastasis , and prognosis of non-small cell lung cancer ( NSCLC ) . METHODS MACC1 and c-met expressions were detected in 103 cases of NSCLC and 40 cases of neighboring normal lung cancer tissue using immunohistochemistry . RESULTS MACC1 and c-met expressions were significantly higher in lung cancer tissues than that in neighboring normal tissue ( P<0.001 ) . MACC1 and c-met expressions were associated with poor differentiation , advanced T stages , lymph node metastasis , and advanced TNM stages ( P<0.05 ) of NSCLC , but not with sex , age , smoking , and histological classification ( P>0.05 ) . In addition , a positive correlation between MACC1 and c-met expressions was observed ( r=0.403 , P<0.001 ) . The result from the Kaplan-Meier survival analysis showed that the five-year survival rate in patients with positive MACC1 and c-met expressions was remarkanly lower than that in patients with negative expressions ( P<0.05 ) . The result from the Cox regression analysis showed that MACC1 expression was an independent prognostic factor for NSCLC ( P=0.026 ) . CONCLUSIONS MACC1 and c-met have an important function in the differentiation , invasion , and metastasis of NSCLC . MACC1 and c-met have poor prognosis in patients with NSCLC . Moreover , MACC1 expression is an independent prognostic factor for NSCLC .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22814258"}
{"sentence": "The effects of human interferon ( IFN)-alpha , -beta , and -gamma on the immortalization of human and rabbit lymphocytes by human T-lymphotropic virus type-I ( HTLV-I ) have been investigated . The immortalization of human peripheral-blood lymphocytes co-cultured with lethally X-ray-irradiated HTLV-I-producer cells , MT-2 , was blocked in the presence of more than 40 u/ml human recombinant IFN-alpha or more than 200 u/ml human natural type IFN-beta . However , rhIFN-gamma did not block immortalization by HTLV-I even at higher doses . On the other hand , the presence of high doses of hIFN-alpha , -beta , or -gamma did not exhibit any biological effect on the immortalization of rabbit peripheral-blood lymphocytes co-cultured with lethally X-ray-irradiated MT-2 cells . Integration of the full length of HTLV-I genome was detected in every transformant by Southern blot analysis . All cell lines established were CD4+/CD8 divided by T-lymphocytes , except for one cell line of CD4+/CD8+ . Morphologically intact HTLV-I production was observed by electron microscopy in these cells . Our results indicate that HTLV-I released under the strongly suppressed condition in the presence of IFNs remains active and able to immortalize T lymphocytes . It is also suggested that immortalization of human T lymphocytes by HTLV-I can be inhibited by the antiviral state induced by the treatment with low doses of hIFN-alpha and -beta , whereas immortalization of rabbit T lymphocytes is not inhibited because of the species specificity of hIFNs .", "label": [0, 1, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1639539"}
{"sentence": "PURPOSE : Acid ceramidase ( AC ) occupies an important place in the control of cancer cell proliferation . We tested the influence of AC inhibition on the effects of PSC 833 , a P-glycoprotein antagonist with potent ceramide-generating capacity , to determine whether AC could be a therapeutic target in pancreatic cancer . METHODS : Ceramide metabolism was followed using ( 3)H-palmitate , and molecular species were determined by mass spectroscopy . Apoptosis was measured by DNA fragmentation , autophagy by acridine orange staining , and cell cycle was assessed by flow cytometry and RB phosphorylation . AC was measured in intact cells using fluorescent substrate . RESULTS : Exposure of human PANC-1 or MIA-PaCa-2 cells to PSC 833 promoted increases in de novo ( dihydro)ceramides , ( dihydro)glucosylceramides , and ( dihydro)sphingomyelins , demarking ceramide generation and robust metabolism . Despite the multifold increases in ( dihydro)ceramide levels , cells were refractory to PSC 833 . However , PSC 833 produced a dose-dependent decrease in DNA synthesis and dose- and time-dependent decreases in RB phosphorylation , consistent with cell cycle arrest as demonstrated at G1 . Cytostatic effects of PSC 833 were converted to cytotoxic end-point by acid ceramidase inhibition . Cytotoxicity was accompanied by formation of acridine orange-stained acidic vesicles and an increase in LC3 expression , indicative of autophagic response . Cell death was not reversed by preexposure to myriocin , which blocks PSC 833-induced ceramide generation . CONCLUSION : Although the role of ceramide in end-point cytotoxicity is unclear , our results suggest that acid ceramidase is a viable target in pancreatic cancer . We propose that AC inhibition will be effective in concert with other anticancer therapies .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23263160"}
{"sentence": "BACKGROUND Angiogenesis plays an important role in the progression of colorectal cancer ( CRC ) . Studies have indicated vascular endothelial growth factor ( VEGF ) is the predominant angiogenic factor . Cyclin D1 ( CCND1 ) induces production of VEGF and is required for migration of blood vessels . Our aim was to determine the roles of CCND1 and VEGF overexpression in CRC patients . METHODS We analyzed clinicopathological features , VEGF and CCND1 expressions by immunohistochemical ( IHC ) staining in 100 stage I-III CRC patients ( 44 were postoperative relapsed ; 56 were postoperative non-relapsed ) to determine the correlation between clinicopathologic features and co-existence of CCND1 and VEGF . Furthermore , the clinical outcomes of co-existence of CCND1 and VEGF were investigated . RESULTS Multivariate analysis showed vascular invasion ( P = 0.019 ) , VEGF overexpression ( P = 0.033 ) , and high postoperative serum carcinoembryonic antigen ( CEA ) levels ( P = 0.022 ) were independent predictors of postoperative relapse . Co-existence of CCND1 and VEGF overexpression had significantly poorer disease-free survival rates ( P \u2009= 0.004 ) and overall survival rates ( P = 0.001 ) than other phenotypes . CONCLUSIONS Co-existence of CCND1 and VEGF overexpression would potentially assist in TNM staging systems to predict the prognosis of these patients who would benefit from intensive follow-up and therapeutic programs .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22926658"}
{"sentence": "Leishmaniasis is one of the major tropical parasitic diseases , and the condition ranges in severity from self-healing cutaneous lesions to fatal visceral manifestations . There is no vaccine available against visceral leishmaniasis ( VL ) ( also known as kala-azar in India ) , and current antileishmanial drugs face major drawbacks , including drug resistance , variable efficacy , toxicity and parenteral administration . We report here that n-hexane fractions of Artemisia annua leaves ( AAL ) and seeds ( AAS ) possess significant antileishmanial activity against Leishmania donovani promastigotes , with GI(50) of 14.4 and 14.6 \u00b5g ml(-1) , respectively , and the IC(50) against intracellular amastigotes was found to be 6.6 and 5.05 \u00b5g ml(-1) , respectively . Changes in the morphology of promastigotes and growth reversibility analysis following treatment confirmed the leishmanicidal effect of the active fractions , which presented no cytotoxic effect on mammalian cells . The antileishmanial activity was mediated via apoptosis , as evidenced by externalization of phosphatidylserine , in situ labelling of DNA fragments by terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling ( TUNEL ) and cell-cycle arrest at the sub-G(0)/G(1) phase . High-performance thin-layer chromatography ( HPTLC ) fingerprinting showed that the content of artemisinin in crude bioactive extracts ( \u00b5g per 100 \u00b5g n-hexane fraction ) was too low to account for the observed antileishmanial activity . Characterization of the active constituents by GC-MS showed that \\u03b1-amyrinyl acetate , \\u03b2-amyrine and derivatives of artemisinin were the major constituents in AAL and cetin , EINECS 211-126-2 and artemisinin derivatives in AAS . Our findings indicate the presence of antileishmanial compounds besides artemisinin in the n-hexane fractions of A. annua leaves and seeds .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22956747"}
{"sentence": "BACKGROUND Prostate cancer is the second leading cause of cancer mortality among US men . Epidemiological evidence suggests that high vitamin D status protects men from prostate cancer and the active form of vitamin D , 1alpha,25 dihydroxyvitamin D3 ( 1,25(OH)2D ) has anti-cancer effects in cultured prostate cells . Still , the molecular mechanisms and the gene targets for vitamin D-mediated prostate cancer prevention are unknown . RESULTS We examined the effect of 1,25(OH)2D ( +/- 100 nM , 6 , 24 , 48 h ) on the transcript profile of proliferating RWPE1 cells , an immortalized , non-tumorigenic prostate epithelial cell line that is growth arrested by 1,25(OH)2D ( Affymetrix U133 Plus 2.0 , n = 4/treatment per time and dose ) . Our analysis revealed many transcript level changes at a 5% false detection rate : 6 h , 1571 ( 61% up ) , 24 h , 1816 ( 60% up ) , 48 h , 3566 ( 38% up). 288 transcripts were regulated similarly at all time points ( 182 up , 80 down ) and many of the promoters for these transcripts contained putative vitamin D response elements . Functional analysis by pathway or Gene Set Analysis revealed early suppression of WNT , Notch , NF-kB , and IGF1 signaling . Transcripts related to inflammation were suppressed at 6 h ( e.g . IL-1 pathway ) and suppression of proinflammatory pathways continued at later time points ( e.g . IL-17 and IL-6 pathways ) . There was also evidence for induction of anti-angiogenic pathways and induction of transcripts for protection from oxidative stress or maintenance of cell redox homeostasis at 6 h . CONCLUSIONS Our data reveal of large number of potential new , direct vitamin D target genes relevant to prostate cancer prevention . In addition , our data suggests that rather than having a single strong regulatory effect , vitamin D orchestrates a pattern of changes within prostate epithelial cells that limit or slow carcinogenesis .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "20070897"}
{"sentence": "Double-strand DNA breaks are a serious threat to cellular viability and yeast systems have proved invaluable in helping to understand how these potentially toxic lesions are sensed and repaired . An important method to study the processing of DNA breaks in the budding yeast Saccharomyces cerevisiae is to introduce a unique double-strand break into the genome by regulating the expression of the site-specific HO endonuclease with a galactose inducible promoter . Variations of the HO site-specific DSB assay have been adapted to many organisms , but the methodology has seen only limited use in the fission yeast Schizosaccharomyces pombe because of the lack of a promoter capable of inducing endonuclease expression on a relatively short time scale ( We have overcome this limitation by developing a new assay in which expression of the homing endonuclease I-PpoI is tightly regulated with a tetracycline-inducible promoter . We show that induction of the I-PpoI endonuclease produces rapid cutting of a defined cleavage site ( > 80% after 1\u2009h ) , efficient cell cycle arrest and significant accumulation of the checkpoint protein Crb2 at break-adjacent regions in a manner that is analogous to published findings with DSBs produced by an acute exposure to ionizing irradiation . This assay provides an important new tool for the fission yeast community and , because many aspects of mammalian chromatin organization have been well-conserved in Sz. pombe but not in S. cerevisiae , also offers an attractive system to decipher the role of chromatin structure in modulating the repair of double-stranded DNA breaks .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22674789"}
{"sentence": "Abstract Purpose : Cell death is one of the most important endpoints of radiosensitivity . The tumor suppressor p53 participates not only in regulation of apoptosis , but also in autophagy mechanism . In this study , H1299-P53 ( with wild-type p53 ) and H1299-175H ( with mutant 175H ) were used , and the effects of p53 on radiosensitivity were analyzed . Methods : Cell models with different p53 status were established by gene engineering , and cell viability was examined by colony formation assay , and cell counting kit-8 ( CCK-8 ) , 3-Methyladenine , and Z-VAD were used to block autophagy and apoptosis , respectively . Western blot was used to detect protein expression ; monodansylcadaverine ( MDC ) staining was used to analyze autophagy rate ; DAPI/Propidium Iodide ( PI ) staining and flow cytometry were used to assess apoptosis and necrosis . Results : In parental H1299 , H1299-P53 , and H1299-175H cells , radiosensitivity exhibited different by colony formation and CCK-8 assay ( D0 : 1.764 Gy , 1.407 Gy and 1.695 Gy ; Dq : 2.977 Gy , 1.199 Gy and 2.312 Gy in turn ) . The radiosensitization of p53 was associated with the increase of MDM2 and P21 expression . The ionizing radiation ( IR)-induced apoptosis was significant in H1299-P53 compared with in H1299 and H199-175H ( p<0.05 ) by flow cytometry , and the expression of cleaved-caspase3 was increased in H1299-P53 cells . While the IR-induced autophagy was significant in H1299 cells ( p<0.01 ) and decreased in H1299-P53 and H1299-175H cells ( p<0.01 ) by MDC staining , the expression of MAPLC3II and Beclin-1 increased in H1299 , but not in H1299-p53 and H199-175H cells . The IR-induced cell survival was significantly increased by Z-VAD-FMK and decreased by 3MA in H1299-P53 cells ; IR- induced autophagy was significantly increased by Z-VAD-FMK in H1299-P53 cells ( p<0.01 ) , but not changed in H1299 cells . Conclusion : p53 could regulate radiosensitivity by inhibiting autophagy and activating apoptosis ; autophagy provides a prosurvival mechanism , and p53 potently abrogated the IR-induced autophagy , while mutant 175H shown no effect on radiosensitivity , suggesting that individual treatment strategies should be based on p53 status in patients .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23268708"}
{"sentence": "A recurrent mutation affecting codon 132 of the isocitrate dehydrogenase 1 ( IDH1 ) gene has been found in of primary glioblastomas ( GBMs ) , but in >70% of secondary GBMs or oligodendroglial and astrocytic tumors . We investigated IDH1 mutations in a series of 134 brain tumors to determine the prevalence and prognostic impact of IDH1 mutations . We also examined the correlations among histology , p53 and PTEN immunoexpression , MGMT methylation status , 1p 19q co-deletion and EGFR gene amplification . The 134 brain tumors included 41 low-grade oligodendrogliomas ( LOs ) , 47 anaplastic oligodendrogliomas ( AOs ) and 46 primary GBMs . Data showed that 53.7% ( 72/134 ) of cases showed mutations affecting codon 132 of IDH1 , including 73.2% of LOs , 82.9% of AOs and three primary GBMs ( 6.5% ) . All IDH1 mutations were Arg132His . In a survival analysis , patients with IDH1 mutations had better survival compared to those with wild-type IDH1 ( p<0.05 ) in LOs and AOs , but not in primary GBMs ( p=0.587 ) . In addition , in patients with both IDH1 mutation and MGMT methylation , p53 overexpression was a significant poor prognostic factor both in LOs and AOs . However , IDH1 mutation was not correlated with common genetic profiles that affect patient prognosis , including MGMT methylation , 1p 19q co-deletion , PTEN loss and EGFR amplification in LOs , AOs and GBMs . From our results , IDH1 mutation was an independent positive prognostic factor in LOs and AOs , especially in the absence of p53 overexpression .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22922798"}
{"sentence": "Kinins and their receptors have been recently implicated in cancer . Using functional and molecular approaches , we investigated the relevance of kinin B(1) and B(2) receptors in bladder cancer . Functional studies were conducted using bladder cancer cell lines , and human biopsies were employed for molecular studies . Both B(1) des-Arg(9)-BK and B(2) BK receptor agonists stimulated the proliferation of grade 3-derived T24 bladder cancer cells . Furthermore , treatment with B(1) and B(2) receptor antagonists ( SSR240612 and HOE140 ) markedly inhibited the proliferation of T24 cells . Only higher concentrations of BK increased the proliferation of the grade 1 bladder cancer cell line RT4 , while des-Arg(9)-BK completely failed to induce its proliferation . Real-time PCR revealed that the mRNA expression of kinin receptors , particularly B(1) receptors , was increased in T24 cells relative to RT4 cells . Data from bladder cancer human biopsies revealed that B(1) receptor expression was increased in all tumor samples and under conditions of chronic inflammation . We also show novel evidence demonstrating that the pharmacological inhibition of PI3K\u03b3 ( phosphatidylinositol 3-kinase ) with AS252424 , concentration-dependently reduced T24 cell proliferation induced by BK or des-Arg(9)-BK . Finally , the incubation of T24 cells with kinin agonists led to a marked activation of the PI3K/AKT and ERK 1/2 signaling pathways , whereas p38 MAP kinase remained unaffected . Kinin receptors , especially B(1) receptors , appear to be implicated in bladder cancer progression . It is tempting to suggest that selective kinin antagonists might represent potential alternative therapies for bladder cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "23224295"}
{"sentence": "Background : Green tea catechins possess a wide range of pharmacological properties , including antiviral , anti-infective , and immunostimulatory properties . They also have demonstrated inhibitory effects on a variety of enzymatic and metabolic pathways involved in cancer development . Catechins have been shown to have antiproliferative properties in various cell lines and may have direct virucidal effect . The United States Food and Drug Administration has approved a topical ointment formulation of sinecatechins , derived from green tea catechins and other tea components , for the treatment of external genital and perianal warts . The exact mechanism of action of sinecatechins in eradication of human papillomavirus-induced external genital and perianal warts is unknown , but may be due to one or more of the mechanisms mentioned . Objective : This study was conducted to investigate the growth inhibitory potential of the sinecatechins in human cervical carcinoma cell lines infected with human papillomavirus . Methods : The viability of tumor cell lines ( CaSki and SiHa infected with human papillomavirus-16 ; HeLa and C4-I infected with human papillomavirus-18 ) was investigated as one parameter in a short-term viability assay ( 48 hours ) . This was followed by a long-term clonogenic assay ( 12-23 days ) to determine the cytotoxic potential of sinecatechins as a parameter for cell viability and proliferation . This assay determined if the effect observed in the viability assay was due to retardation in cell proliferation or to a reduction of total cell number , leading to cell death . Results : Based on the data collected , sinecatechins inhibited cell growth in all four tumor cell lines by 50 percent ( GI(50) ) at concentrations ranging from 160 to 360\ufffdM . C4-I cells were the most sensitive to treatment with sinecatechins , with a lower GI(50) ( Total GI was achieved in a 48-hour assay at 625\ufffdM sinecatechins ( 40\ufffdM for C4-I ) , with growth inhibitory potential detectable after one hour . Clonogenic assays confirmed the cytotoxic potential of sinecatechins with a reduction in clone numbers in a concentration-dependent fashion . Sinecatechins substantially reduced the number of surviving HeLa cells at a concentration of 200\ufffdM , while surviving SiHa cells were almost totally eradicated with a concentration of 600\ufffdM . Conclusion : Sinecatechins demonstrated growth inhibitory potential in all four human papillomavirus-infected tumor cell lines , which may be attributed to the induction of apoptosis , mediated by cell cycle deregulation . In addition , this antiproliferative effect may contribute to the overall cancer-preventative function and possible direct antiviral activity of sinecatechins that may contribute to external genital and perianal warts clearance .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22468171"}
{"sentence": "The HOX11 gene encodes a homeodomain transcription factor that is essential for spleen development during embryogenesis . HOX11 is also leukaemogenic , both through its clinical association with childhood T-cell acute lymphoblastic leukaemia , and its ability to immortalize other haematopoietic cell lineages experimentally . To examine the pathological role of HOX11 in tumorigenesis , we constitutively expressed HOX11 cDNA in J2E murine erythroleukaemic cells , which are capable of terminal differentiation . Enforced HOX11 expression was found to induce a profound alteration in J2E cellular morphology and differentiation status . Our analyses revealed that HOX11 produced clones with a preponderance of less differentiated cells that were highly adherent to plastic . Morphologically , the cells overexpressing HOX11 were larger and had decreased globin levels , as well as a reduction in haemoglobin synthesis in response to erythropoietin ( EPO ) . Immunocytochemical analysis confirmed the immature erythroid phenotype imposed by HOX11 , with clones transfected with HOX11 demonstrating expression of the c-Kit stem cell marker , while retaining EPO receptor expression . Taken together , these results show that HOX11 alters erythroid differentiation , favouring a less mature progenitor-like stage . This supports the notion that disrupted haematopoietic cell differentiation is responsible for pre-leukaemic immortalization by the HOX11 oncoprotein .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12181065"}
{"sentence": "New molecularly targeted therapies are needed for childhood ependymoma . Angiogenesis and the PDGFR pathway could be potential therapeutic targets . This study aimed to screen ependymomas for the expression and clinicopathological correlates of angiogenic factors and potential therapeutic targets including VEGFR , endoglin ( CD105 ) , CD34 , CD31 , c-Kit , PDGFR-\u03b1 and PDGFR-\u03b2 . Immunohistochemistry for angiogenesis factors and PDGFR-\u03b1 and \u03b2 was performed in 24 archival tumor samples from children and adults treated for ependymoma at our institution . CD31 density , CD105 density and pericyte coverage index ( PCI ) were calculated . These findings were correlated with clinical outcome . VEGFR2 was overexpressed in tumor cells in only one out of 24 cases , but was found overexpressed in the vessels in 6 cases . PDGFR-\u03b1 and \u03b2 were found to be over-expressed in the ependymoma tumor cells in seven out of 24 cases ( 29.2 % ) . CD31 density , CD105 density and PCI did not correlate with expression of PDGFRs . Overexpression of PDGFR-\u03b1 and \u03b2 in tumor cells and overexpression of PDGFR-\u03b1 in tumor endothelium had prognostic significance and this was maintained in multivariate analysis for overexpression of PDGFR-\u03b1 in tumor cells ( 2 year progression free survival was 16.7 \u00b1 15.2 for cases with overexpression of PDGFR-\u03b1 in the tumor vs. 74.5 \u00b1 15.2 for those with low/no expression , hazard ratio = 5.78 , p = 0.04 ) . A number of angiogenic factors are expressed in ependymoma tumor cells and tumor endothelium . Preliminary evidence suggests that the expression of PDGFRs could have a prognostic significance in ependymoma . This data suggests that PDGFRs should be further evaluated as targets using novel PDGFR inhibitors .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23135775"}
{"sentence": "To elucidate the mechanism of the synergistic cytotoxicity of 5-fluorouracil ( 5-FU ) and cis-diamminedichloroplatinum(II) ( CDDP ) , we studied the interaction of these agents using a human squamous carcinoma cell line ( HST-1 ) . Exposure to 5-FU for 24 h and to CDDP for 1 h produced a 50% inhibitory concentration of 1.0 micrograms/ml ( 7.7 microM ) and 2.5 micrograms/ml ( 8.3 microM ) , respectively . The cytotoxic action of CDDP was augmented , and a greater than additive effect was observed when the cells were exposed to 5-FU ( 1.0 micrograms/ml ; 7.7 microM ) for 24 h before the CDDP treatment . This synergistic activity was maximal when the interval between 5-FU and CDDP exceeded 24 h . In contrast , the cytotoxicity of CDDP was attenuated when it preceded the exposure to 5-FU . Thymidine did not alter the 5-FU-CDDP interaction . Evaluation of the kinetics of the removal of DNA interstrand cross-links , measured by alkaline elution , showed a significant reduction of this removal in the cells exposed to 5-FU followed by CDDP with a drug-free interval of 48 h , as compared with cells exposed to CDDP alone , or to 5-FU immediately followed by CDDP , although no differences were found in the formation of DNA interstrand cross-links by CDDP among these cells . No significant differences in the accumulation of intracellular platinum were detected by atomic absorption spectrophotometry . These findings suggest that 5-FU modulates the repair of platinum-DNA adducts , thereby potentiating the antitumor activity of CDDP .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1423296"}
{"sentence": "Several studies have indicated that the cell-surface expressed nucleolin is implicated in tumorigenesis and angiogenesis , and represents an important target for cancer therapy . Here we show that treatment of rhabdoid tumor derived G401 cells with a nucleolin antagonist , the HB-19 pseudopeptide , could restore contact inhibition , impair anchorage-independent growth , and suppress tumor development in nude mice . G401 cells grow without contact inhibition , which is an in vitro characteristic property of malignant tumor cells . At concentrations of HB-19 that does not affect cell viability and multiplication index , there is restoration of contact inhibition thus suggesting that HB-19 treatment causes reversion of the malignant phenotype . Accordingly , HB-19 pretreated G401 cells lose the capacity to form colonies in soft agar . When assayed for tumorigenicity in nude mice , only 50% of mice injected with HB-19 pretreated G401 cells developed tumors with the mean tumor weight of 0.32 g , compared to 100% of mice injected with control G401 cells with the mean tumor weight of 2.36 g . Interestingly , the restoration of contact inhibition in HB-19 treated G401 cells is concomitant with marked reduction of transcripts coding the Wilms ' tumor 1 gene , matrix metalloproteinase-2 , epithelial isoform of CD44 , and vascular endothelial growth factor , whereas no apparent modification is detected for transcripts coding the proto-oncogene c-Myc , anti-apoptotic Bcl-2 , pro-apoptotic Bax , tissue inhibitor of metalloproteinase TIMP-1 , angiogenesis inhibitor TSP-1 , and growth factor Midkine . These findings indicate that the molecular mechanism of action of HB-19 on such highly malignant rhabdoid tumor cells is associated with a selective inhibitory effect on the expression of genes implicated in tumorigenesis and angiogenesis .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21040752"}
{"sentence": "Epidermal growth factor ( EGF ) and transforming growth factor alpha ( TGF alpha ) content was measured in normal ovaries and benign ovarian tumours . Epidermal growth factor was present in 12.7% of normal ovaries , with a range 0.030-0.533 ng/mg DNA , and in 31.8% of benign ovarian tumours , with a range 0.1335-2.080 ng/ml DNA . TGF alpha was present in 84.5% of normal ovaries , with a range of values from 0.037-18.2 ng/mg DNA , and in 84.1% of benign ovarian tumours , with a range of 0.083-195 ng/mg DNA . The TGF alpha content in post menopausal benign ovarian tumours was significantly higher ( P < 0.0001 ) than TGF alpha in the pre-menopausal normal ovarian group . The frequency of detection and levels of TGF alpha measured were significantly higher than those of EGF in the normal ovary group ( P < 0.001 ) and also in the benign ovarian group ( P < 0.005 ) . We conclude that TGF alpha is the predominant growth factor present in normal ovaries and benign ovarian tumours .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1294409"}
{"sentence": "PURPOSE Mitotic cells are hypersensitive to ionizing radiation , exhibiting single-hit inactivation coefficients near to those of repair deficient cell lines and lymphocytes . To elucidate possible mechanisms for this hypersensitivity , the kinetics of oxygen radiosensitization , the proportion of indirect effect by OH radicals and the kinetics of radiation-induced DNA strand breakage in the chromatin of mitotic cells were investigated . MATERIALS AND METHODS Synchronized populations of >90% mitotic HT-29 cells were obtained by the mitotic shake-off method . Cells were irradiated at < or =4 degrees C with ( 137)Cs gamma-rays . Cellular oxygen concentration was varied by gassing cell suspensions prior to and during irradiation with mixtures of pure N(2) that contained 5% CO(2) and measured quantities of O(2) . The indirect effect of OH radicals was investigated with the radical scavenger , DMSO . DNA strand breakage was measured by the comet assay . RESULTS Mitotic HT-29 cell inactivation is well described by a single-hit inactivation coefficient ( alpha ) of 1.14 +/- 0.06 Gy(-1) . The oxygen enhancement ratio of mitotic cells ( at 10% survival ) was found to be approximately 2.0 , significantly lower than the value of 2.8 measured for interphase ( asynchronous ) cells . More than 60% of mitotic cell killing was eliminated when the media contained 2 M DMSO , indicating that indirect effect is as important in the killing of mitotic cells as it is for interphase cells . The chromatin in mitotic cells was found to be times more sensitive to radiation-induced DNA single-strand breakage than the chromatin of interphase cells . CONCLUSIONS The alpha-inactivation coefficient of mitotic HT-29 cells was times larger than that of interphase cells . Mitotic cell chromatin appears to contain intrinsic DNA breaks that are not lethal . In addition , chromatin in mitotic cells was found to be more susceptible to radiation-induced DNA strand-breakage than the dispersed chromatin of interphase cells . How the enhanced production of these simple DNA lesions ( that are usually reparable ) translates into the lethal ( non-reparable ) events associated with alpha-inactivation is not known . The compaction/dispersion status of DNA throughout the cell cycle appears to be an important factor for determining intrinsic cell radiosensitivity and might be manipulated for radiotherapeutic advantage .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12556342"}
{"sentence": "The RuvABC and RecBCD proteins promote rescue of stalled or broken DNA replication forks in Escherichia coli . Strains lacking these proteins cope poorly with DNA damage and have problems with chromosome segregation and cell division . We show how these difficulties are overcome to varying degrees by a sub-class of RNA polymerase mutations selected for their stringent phenotype . Thirty-five mutations were sequenced . All but one change single amino acids in RpoB or RpoC that lie on or near the path taken by DNA through the enzyme , indicating they may affect the stability of transcription complexes . Four mutant enzymes are shown to form unstable open complexes at the lambdacro promoter . At least one may also release stalled complexes or limit their formation , as it reduces the need for reactivation of transcription by GreA or GreB , and for transcription-coupled DNA repair of UV damage by Mfd . The results shed light on the interplay between DNA replication and transcription and suggest ways in which conflicts between these two vital cellular processes are avoided or resolved .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12486015"}
{"sentence": "Prostate cancer is the most common cancer in men in Europe and the United States , and the third leading cause of death from cancer in Europe . Survival of prostate cancer cells is dependent on the activation of androgen receptors ( AR ) , that are overexpressed in this tumor . Furthermore , of prostate cancer patients that respond to first-line androgen deprivation therapy ( ADT ) undergo rapid progression . This condition is defined as castration-resistant prostate cancer ( CRPC ) . Docetaxel-based regimens significantly improve overall survival ( OS ) in patients with CRPC and represent the only treatment strategy approved by the Food and Drug Administration ( FDA ) . Recently , abiraterone ( second hormonal therapy ) and cabazitaxel ( new taxane ) have been shown to improve survival in patients with CRPC who progressed following docetaxel-based chemotherapy . Vaccine therapy has also been demonstrated to improve OS in patients with asymptomatic or minimally symptomatic metastatic CRPC . Additional therapeutic targets have been analyzed in prostate cancer , including apoptosis , angiogenic receptors , vitamin D and Src pathways . Several phase II studies are ongoing . The high frequency of prostate cancer-related metastatic bone disease has led to consider this pathway as a therapeutic target . To this end , several bone-targeted agents have been investigated , most notably zoledronic acid , which is highly effective at stabilizing the bone and preventing skeletal complications . More recently , a nuclear factor-\u03b2 ligand ( RANKL ) inhibitor , denosumab , has been developed for the treatment of bone metastases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22322981"}
{"sentence": "Notch signaling controls cell fate decisions of hematopoietic progenitors by inhibiting certain steps of differentiation and inducing either self-renewal or differentiation toward lymphoid or myeloid lineages . In addition , truncated Notch1 alleles could be associated with 10% of all cases of human T lymphoblastic leukemia and , when introduced into mouse bone marrow stem cells , cause T-cell neoplasms . However , functional links between the abundant expression of intact Notch1 and oncogenesis are still lacking . Here we show that Notch1 is highly expressed in B- and T-cell-derived tumor cells of Hodgkin and anaplastic large cell lymphoma . We demonstrate a novel mechanism for the oncogenic capacity of Notch1 by showing that the interaction between intact Notch1 on tumor cells and its ligand Jagged1 dramatically induces proliferation and inhibition of apoptosis in vitro . We further provide evidence that in Hodgkin and anaplastic large cell lymphoma , Jagged1 is expressed in malignant and in bystander cells colocalizing with Notch1-positive tumor cells . Notch1 signaling may therefore be activated in tumor cells by Jagged1 through homotypic or heterotypic cell-cell interactions , and it seems likely that these interactions contribute to lymphomagenesis in vivo . Thus , our data suggest that activated Notch1 signaling plays an important role in the pathobiology of Hodgkin and anaplastic large cell lymphoma and that it might be a potential new target for treatment .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "11964309"}
{"sentence": "DNA repair is essential in maintaining genome integrity and defects in different steps of the process have been linked to cancer and aging . It is a long lasting question how DNA repair is spatially and temporarily organized in the highly compartmentalized nucleus and whether the diverse nuclear compartments regulate differently the efficiency of repair . Increasing evidence suggest the involvement of nuclear pore complexes in repair of double-strand breaks ( DSBs ) in yeast . Here , we show that the human nucleoporin 153 ( NUP153 ) has a role in repair of DSBs and in the activation of DNA damage checkpoints . We explore the mechanism of action of NUP153 and we propose its potential as a novel therapeutic target in cancers .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22249246"}
{"sentence": "BACKGROUND Patients with invasive breast ductal carcinoma ( IBDC ) with metastasis have a very poor prognosis . Little is known about the synergistic action of growth and inflammatory factors in IBDC metastases . METHODS The expression of activated extracellular signal-regulated kinase1/2 ( phosphorylated or p-ERK1/2 ) was analyzed by immunohistochemistry in IBDC tissue samples from 80 cases . BT474 IBDC cell migration and invasion were quantified using the Transwell assay . Matrix metalloproteinase ( MMP)-9 expression and activity were analyzed by RT-PCR , Western blotting and zymography . Activator protein ( AP)-1 activity was measured with a luciferase reporter gene assay . The Wilcoxon signed-rank test , Chi-square test , the partition of Chi-square test , independent t-test , and Spearman's method were used for the statistical analysis . RESULTS Phosphorylated ERK1/2 was detected in 58/80 ( 72.5% ) IBDC tissues , and was associated with higher TNM stage and lymph node metastasis , but not patient age or tumor size . Individually , epidermal growth factor ( EGF ) , and interleukin ( IL)-1\u03b2 activated ERK1/2 , increased cell migration and invasion , MMP-9 expression and activity , AP-1 activation in vitro and the expression of p-ERK1/2 was positively correlated with EGF expression levels , as well as IL-1\u03b2 , MMP-9 and c-fos in IBDC tissue samples . Co-stimulation with EGF and IL-1\u03b2 synergistically increased ERK1/2 and AP-1 activation , cell migration and invasion , and MMP-9 expression and activity . Inhibition of ERK1/2 using U0126 or siRNA abolished EGF and/or IL-1\u03b2-induced cell migration and invasion in a dose-dependent manner . CONCLUSION Activated ERK1/2 was associated with higher TNM stage and lymph node metastasis in IBDC . Both in vitro and in vivo studies indicated that ERK-1/2 activation may increase the metastatic ability of IBDC cells . Growth and inflammatory factors synergistically induced IBDC cell migration and invasion via ERK1/2 signaling , AP-1 activation and MMP-9 upregulation .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "23083134"}
{"sentence": "Base analogs are powerful antimetabolites and dangerous mutagens generated endogenously by oxidative stress , inflammation , and aberrant nucleotide biosynthesis . Human inosine triphosphate pyrophosphatase ( ITPA ) hydrolyzes triphosphates of noncanonical purine bases ( i.e. , ITP , dITP , XTP , dXTP , or their mimic : 6-hydroxyaminopurine ( HAP ) deoxynucleoside triphosphate ) and thus regulates nucleotide pools and protects cells from DNA damage . We demonstrate that the model purine base analog HAP induces DNA breaks in human cells and leads to elevation of levels of ITPA . A human polymorphic allele of the ITPA , 94C->A encodes for the enzyme with a P32T amino-acid change and leads to accumulation of nonhydrolyzed ITP . The polymorphism has been associated with adverse reaction to purine base-analog drugs . The level of both spontaneous and HAP-induced DNA breaks is elevated in the cell line with the ITPA P32T variant . The results suggested that human ITPA plays a pivotal role in the protection of DNA from noncanonical purine base analogs .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20936128"}
{"sentence": "Common use of antimutagens and anticarcinogens in everyday life is an effective measure for preventing human cancer and genetic diseases . Antioxidant properties of tea have vast potential as protective agents against diverse toxic effects . The present study was aimed to evaluate the role of aqueous clonal tea extracts ( green tea , oolong tea and black tea ) in modulating the genotoxic damage induced by cyclophosphamide ( CP ) , a commonly used chemotherapeutic drug and a well-known mutagen and clastogen . All the three tea extracts at 1 and 2% concentration did not increase the frequency of micronucleated polychromatic erythrocytes ( MPE ) in bone marrow cells of mice when administered individually . The tea extracts decreased the micronuclei ( MN ) induced by CP . Therefore , regular intake of tea may improve the antioxidant status in in vivo and thereby reduce the risk of cancer and coronary heart disease .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12674376"}
{"sentence": "This research aims to give a new insight to the relationship between host local immune response and the biological behaviour of the tumor by evaluating of intratumoral natural killer ( NK ) cells and tumor necrosis factor-alpha ( TNFalpha ) expressions in oral squamous cell carcinomas . New paraffin sections of the deepest parts of the 46 cases of oral squamous cell carcinomas were immunohistochemically treated by CD57 , selected as NK cell indicator , and TNFalpha monoclonal antibodies . The tumors were graded according to histopathologic grading scores of invasive margins and categorized into 2 groups as \" good \" and \" poor \" prognostic groups . Fifteen cases , from which could be obtained full clinical data , were clinically staged and because of the scarcity of the cases in each group were divided , again , two groups as group 1 : stage I+stage II and group 2 : stage III+stage IV . The expression levels of CD57 and TNFalpha were evaluated according to histopathologic grading groups and clinical staging groups . The results showed that the density of CD57+cells ( NK cells ) was statistically lower in tumors graded as poor prognostic group compared to the cases in good prognostic group . On the contrary , expression level of TNFalpha was statistically higher in poor prognostic group . These findings suggested that increased secretion of TNFalpha in the tumors , which show high invasive potential , may be one of the facilitating factors for tumor invasion and be responsible from suppression of NK cells . Withdrawal of NK cells in the high invasive tumor areas also reminds the necessity of certain shared genetic rearrangements in tumor cells for getting protected from NK cell attacks and moving ahead within the extracellular matrix .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "20347380"}
{"sentence": "UNLABELLED Activation of beta-catenin , the central effector of the canonical Wnt pathway and a recognized oncogene , has been implicated in hepatocellular carcinoma . We examined N-nitrosodiethylamine ( DEN)-induced tumorigenesis in hepatic beta-catenin conditional knockout mice ( beta-cat KO ) . Male beta-cat KO and age- and sex-matched littermate controls were given a single intraperitoneal DEN injection and followed for 6-12 months for hepatic tumors . Hepatic tumors were characterized for histology , proliferation , apoptosis , oxidative stress , and specific proteins by way of western blot , immunohistochemistry , and coprecipitation studies . For in vivo tumor intervention studies , specific inhibitors were administered intraperitoneally or through drinking water . Intriguingly , beta-cat KO mice showed a paradoxical increase in susceptibility to DEN-induced tumorigenesis . This accelerated tumorigenesis is due to increased injury and inflammation , unrestricted oxidative stress , fibrosis , and compensatory increase in hepatocyte proliferation secondary to platelet-derived growth factor receptor alpha ( PDGFRalpha)/phosphoinositide 3-kinase ( PIK3CA)/Akt activation and c-Myc overexpression . In vitro suppression of beta-catenin expression in hepatoma cells led to enhanced PDGFRalpha expression , which was abrogated in the presence of nuclear factor kappaB ( NF-kappaB ) inhibitor . Daily treatment of 6-month-old DEN-exposed beta-cat KO with PDGFRalpha inhibitor dramatically reduced tumor numbers and size . Inclusion of N-acetyl-L-cysteine , a known antioxidant and NF-kappaB inhibitor , in the drinking water led to complete abolition of tumorigenesis in DEN-exposed beta-cat KO . CONCLUSION Loss of beta-catenin impairs the liver's ability to counteract DEN-induced oxidative stress and enhances tumorigenesis through PDGFRalpha/PIK3CA/Akt signaling . Blockade of PDGFRalpha or oxidative stress dramatically affects beta-catenin-deficient tumorigenesis . Also , hepatoma cells use PDGFRalpha/PIK3CA signaling as an escape mechanism following beta-catenin suppression , and their sequential suppression profoundly impedes tumor proliferation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20583210"}
{"sentence": "Cancer cells universally increase glucose and glutamine consumption , leading to the altered metabolic state known as the Warburg effect ; one metabolic pathway , highly dependent on glucose and glutamine , is the hexosamine biosynthetic pathway . Increased flux through the hexosamine biosynthetic pathway leads to increases in the post-translational addition of O-linked \u03b2-N-acetylglucosamine ( O-GlcNAc ) to various nuclear and cytosolic proteins . A number of these target proteins are implicated in cancer , and recently , O-GlcNAcylation was shown to play a role in breast cancer ; however , O-GlcNAcylation in other cancers remains poorly defined . Here , we show that O-GlcNAc transferase ( OGT ) is overexpressed in prostate cancer compared with normal prostate epithelium and that OGT protein and O-GlcNAc levels are elevated in prostate carcinoma cell lines . Reducing O-GlcNAcylation in PC3-ML cells was associated with reduced expression of matrix metalloproteinase ( MMP)-2 , MMP-9 , and VEGF , resulting in inhibition of invasion and angiogenesis . OGT-mediated regulation of invasion and angiogenesis was dependent upon regulation of the oncogenic transcription factor FoxM1 , a key regulator of invasion and angiogenesis , as reducing OGT expression led to increased FoxM1 protein degradation . Conversely , overexpression of a degradation-resistant FoxM1 mutant abrogated OGT RNAi-mediated effects on invasion , MMP levels , angiogenesis , and VEGF expression . Using a mouse model of metastasis , we found that reduction of OGT expression blocked bone metastasis . Altogether , these data suggest that as prostate cancer cells alter glucose and glutamine levels , O-GlcNAc modifications and OGT levels become elevated and are required for regulation of malignant properties , implicating OGT as a novel therapeutic target in the treatment of cancer .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22275356"}
{"sentence": "Retinoic acid ( RA ) and its derivatives inhibit the proliferation of normal human mammary epithelial cells ( HMEC ) and some breast carcinoma lines by mechanisms which are not fully understood . To identify genes that mediate RA-induced cell growth arrest , an HMEC cDNA library was synthesized and subtractive screening was performed . We identified the interleukin-1beta ( IL-1beta ) gene as an RA induced gene in HMEC . Northern blot analyses showed that the IL-1beta gene was up-regulated as early as 2 h after RA treatment . Results from the treatment of HMEC with cycloheximide and actinomycin D indicated that the regulation of the IL-1beta gene by RA occurred at the transcriptional level and that the IL-1beta gene is a direct , downstream target gene of RA . To evaluate the effects of IL-1beta on cell proliferation , the proliferation of HMEC was measured in the presence of RA or IL-1beta , or both . Either RA or IL-1beta could significantly inhibit the proliferation of HMEC . However , the addition of soluble IL-1 receptor antagonist ( sIL-1ra ) to the cell culture medium did not block RA-induced HMEC growth inhibition , whereas sIL-1ra did block the growth inhibition of HMEC by IL-1beta . IL-1beta expression was not observed in the three carcinoma cell lines , MCF-7 , MDA-MB-231 , and MDA-MB-468 , as compared to the HMEC . Growth curves of the breast carcinoma cell lines showed strong inhibitory effects of RA and IL-1beta on the growth of the estrogen receptor ( ER ) positive MCF-7 cell line , but only a small effect on the ER negative MDA-MB-231 cells . The expression of the IL-1beta gene was also transcriptionally activated by RA in normal epithelial cells of prostate and oral cavity . Our results suggest that : ( a ) the IL-1beta gene is a primary target of RA receptors in HMEC ; ( b ) the enhanced expression of the IL-1beta gene does not mediate the RA-induced growth arrest of HMEC ; and ( c ) the expression of the IL-1beta gene is low or absent in all three human breast carcinoma cell lines examined , but the defect in the IL-1beta signaling pathway may be different in ER positive versus ER negative carcinoma cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12385002"}
{"sentence": "OBJECTIVE To study the clinicopathologic features , immunophenotype and ultrastructural features of sinonasal inflammatory myofibroblastic tumors ( IMT ) . METHODS The clinical and histologic features of 5 cases of sinonasal IMT were reviewed . Immunohistochemical study for vimentin , MSA , SMA , calponin , h-caldesmon , desmin , ALK , fibronectin , CK , S-100 and Ki-67 was carried out . Ultrastructural examination was also performed in two of the cases . RESULTS The patients age ranged from 28 to 62 years ( mean = 43 years ) . The male-to-female ratio was 2:3 . The clinical presentation included nasal obstruction , nasal discharge , nasal bleeding , facial pain , facial swelling , toothache and tear overflow . All of the 5 patients suffered from disease relapses ; and 4 of them had recurrences for more than 5 times . One patient had lymph node metastasis and 3 patients died of the disease . Histologically , the tumor cells were arranged in interlacing fascicles and sometimes haphazard in fashion . They were spindly in shape , cytoplasm eosinophilic with mild nuclear atypia and a low mitotic activity . The intervening stroma was myxoid in appearance accompanied by lymphocyte and plasma cell infiltration , abundant blood vessels and focal collagenized areas . In 3 of the recurrent cases , the tumor cells displayed increased nuclear atypia and mitotic activity ( average about 5 to 6 per 10 high-power fields ) , accompanied by patchy necrosis , less inflammatory cell infiltration and focal sarcomatous changes . Immunohistochemical study showed that the tumor cells were diffusely positive for vimentin . SMA , MSA , calponin and fibronectin were variably expressed . Desmin was weakly positive in 1 case . The staining for h-caldesmon , ALK , S-100 and CK was negative . The Ki-67 proliferation index increased with tumor recurrences . Electron microscopy revealed abundant rough endoplasmic reticulum and dense body formation in the cytoplasm . There were an increased amount of collagen fibers in the stroma . CONCLUSIONS IMT rarely occurs in nasal cavity and paranasal sinuses . The tumor is prone to local invasion and recurrences , with subsequent progression to frank malignancy and distant metastasis , resulting in high mortality and poor prognosis . Complete surgical resection remains the main modality of treatment .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 1], "id": "20450762"}
{"sentence": "Heparanase is a mammalian endoglycosidase that degrades heparan sulfate at the cell surface and in the extracellular matrix . The expression of heparanase was detected in a wide variety of human malignant tumors and closely associated with tumor invasion , metastasis , and angiogenesis . However , the specific roles of heparanase and its mechanisms of regulating the malignant potential of non-small cell lung cancer ( NSCLC ) cells still remain unclear . In the present study , the expression of heparanase was down-regulated in NSCLC cell line by antisense oligodeoxynucleotide . Results showed that down-regulation of heparanase led to significant inhibition of invasive and proliferative potentials of A549 cells in vitro and in vivo . Further research demonstrated that down-regulation of heparanase significantly inhibited the angiogenic potential of A549 cells , which might be the mechanism responsible for the inhibition of A549 cell proliferation in BALB/c nude mice in vivo . These findings demonstrate that heparanase plays essential roles in regulating the invasion , proliferation , and angiogenesis of A549 cells .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "23241438"}
{"sentence": "The effects of genomic changes in hepatitis B virus ( HBV ) on the occurrence of hepatocellular carcinoma ( HCC ) are still unclear , especially in relation to the genotype of HBV . In this study , we examined the effects of genomic changes in HBV of genotype C2 on the development of HCC . A total of 318 patients with HBV-associated HCC and 234 patients with chronic hepatitis B ( CHB ) were studied . All of HCC cases were diagnosed histologically and treated with surgical resection . The whole of the X , S , basal core promoter ( BCP ) and precore regions of the viral genome from sera or liver tissues were sequenced . All subjects had HBV of genotype C2 . The prevalence of the T1653 mutation in the X region and the A1896 mutation in the precore region of HBV was significantly higher in the HCC group than in the control CHB group ( 22% vs 11% , P = 0.003 ; 50% vs 23% , P < 0.001 , respectively ) . Moreover , the T1762/A1764 mutations in the BCP region in combination with either T1653 or A1896 were more common in the HCC compared with the CHB group ( BCP+X1653 : 18% vs 11% , P = 0.05 ; BCP+PC , 40% vs 15% , P < 0.001 , respectively ) . In multivariate analysis , T1653 and A1896 were revealed to be independent risk factors for HCC development . G1896A in the precore region and C1653T mutation in the X region of genotype C2 HBV are important risk factors for HCC development . Also , the A1762T/G1764A double mutation may act in synergy with C1653T to increase the risk of HCC in patients chronically infected with HBV genotype C2 .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23383661"}
{"sentence": "Cell proliferation is known to be accompanied by activation of glycolysis . We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase , isoform 3 ( PFKFB3 ) , is degraded by the E3 ubiquitin ligase APC/C-Cdh1 , which also degrades cell-cycle proteins . We now show in two different cell types ( neoplastic and nonneoplastic ) that both proliferation and aerobic glycolysis are prevented by overexpression of Cdh1 and enhanced by its silencing . Furthermore , we have coexpressed Cdh1 with PFKFB3--either wild-type or a mutant form resistant to ubiquitylation by APC/C-Cdh1--or with the glycolytic enzyme 6-phosphofructo-1-kinase and demonstrated that whereas glycolysis is essential for cell proliferation , its initiation in the presence of active Cdh1 does not result in proliferation . Our experiments indicate that the proliferative response , regardless of whether it occurs in normal or neoplastic cells , is dependent on a decrease in the activity of APC/C-Cdh1 , which activates both proliferation and glycolysis . These observations have implications for cell proliferation , neoplastic transformation , and the prevention and treatment of cancer .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20080744"}
{"sentence": "Variable number tandem repeats ( VNTRs ) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them . Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms . Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 ( DOCK5 ) gene . The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion , all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects . We have developed a novel VNTR association method named VNTRtest , suitable for association analysis of multi-allelic loci with binary and quantitative outcomes , and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity ( P(empirical)= 8.9 \u00d7 10(-8) and P= 3.1 \u00d7 10(-3) , respectively ) which we estimate explains of the phenotypic variance . We also identified an independent association between the 3975 base pair ( bp ) deletion and obesity , explaining a further 0.46% of the variance ( P(combined)= 1.6 \u00d7 10(-3) ) . Evidence for association between DOCK5 transcript levels and the 3975 bp deletion ( P= 0.027 ) and both VNTRs ( P(empirical)= 0.015 ) was also identified in adipose tissue from a Swedish family sample , providing support for a functional effect of the DOCK5 deletion and VNTRs . These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22595969"}
{"sentence": "INTRODUCTION Natural herbal compounds with novel actions different from existing breast cancer ( BCa ) treatment modalities are attractive for improving therapeutic efficacy and safety . We have recently shown that penta-1,2,3,4,6-O-galloyl-\u03b2-D-glucose ( PGG ) induced S-phase arrest in prostate cancer ( PCa ) cells through inhibiting DNA replicative synthesis and G(1) arrest , in addition to inducing cell death at higher levels of exposure . We and others have shown that PGG through intraperitoneal ( i.p. ) injection exerts a strong in vivo growth suppression of human PCa xenograft models in athymic nude mice . This study aims to test the hypothesis that the novel targeting actions of PGG are applicable to BCa cells , especially those lacking proven druggable targets . METHODS Mono-layer cell culture models of p53-wild type estrogen receptor ( ER)-dependent MCF-7 BCa cells and p53-mutant ER-/progesterone receptor ( PR)- and Her2-regular ( triple-negative ) MDA-MB-231 BCa were exposed to PGG for a comprehensive investigation of cellular consequences and molecular targets/mediators . To test the in vivo efficacy , female athymic mice inoculated with MDA-MB-231 xenograft were treated with 20mg PGG/kg body weight by daily gavage starting 4 days after cancer cell inoculation . RESULTS Exposure to PGG induced S-phase arrest in both cell lines as indicated by the lack of 5-bromo2'-deoxy-uridine ( BrdU ) incorporation into S-phase cells as well as G(1) arrest . Higher levels of PGG induced more caspase-mediated apoptosis in MCF-7 , in strong association with induction of P53 Ser(15) phosphorylation , than in MDA-MB-231 cells . The cell cycle arrests were achieved without an induction of cyclin dependent kinase ( CDK ) inhibitory proteins P21(Cip1) and P27(Kip1) . PGG treatment led to decreased cyclin D1 in both cell lines and over-expressing cyclin D1 attenuated G(1) arrest and hastened S arrest . In serum-starvation synchronized MCF-7 cells , down-regulation of cyclin D1 was associated with de-phosphorylation of retinoblastoma ( Rb ) protein by PGG shortly before G(1)-S transition . In vivo , oral administration of PGG led to a greater than 60% inhibition of MDA-MB231 xenograft growth without adverse effect on host body weight . CONCLUSIONS Our in vitro and in vivo data support PGG as a potential drug candidate for breast cancer with novel targeting actions , especially for a triple negative BCa xenograft model .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20809980"}
{"sentence": "Sustained release of copper ( Cu ) ions from Cu-containing intrauterine devices ( CuIUD ) is quite efficient for contraception . However , the tissue surrounding the CuIUD is exposed to toxic Cu ion levels . The objective for this study was to quantify the concentration dependent cytotoxic effects of Cu ions and correlate the toxicity due to Cu ion burst release for two popular T-shaped IUDs - TCu380A and TCu220C on L929 mouse fibroblasts . Fibroblasts were cultured in 98 well tissue culture plates and 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphehyltetrazolium bromide ( MTT ) assay was used to determine their viability and proliferation as a function of time . For cell seeding numbers ranging from 10,000 to 100,000 , a maximum culture time of 48 h was identified for fibroblasts without significant reduction in cell proliferation due to contact inhibition . Thus , for Cu cytotoxicity assays , a cell seeding density of 50,000 and a maximum culture time of 48 h in 96 well plates were used. 24 h after cell seeding , culture media were replaced with Cu ion containing media solutions of different concentrations , including 24 and 72 h extracts from TCuIUDs and incubated for a further 24 h . Cell viability decreased with increasing Cu ion concentration , with 30 % and 100 % reduction for 40 \\u03bcg/ml and 100 \\u03bcg/ml respectively at 24 h . The cytotoxic effects were further evaluated using light microscopy , apoptosis and cell cycle analysis assays . Fibroblasts became rounded and eventually detached from TCP surface due to Cu ion toxicity . A linear increase in apoptotic cell population with increasing Cu ion concentration was observed in the tested range of 0 to 50 \\u03bcg/ml . Cell cycle analysis indicated the arrest of cell division for the tested 25 to 50 \\u03bcg/ml Cu ion treatments . Among the TCuIUDs , TCu220C having 265 mm(2) Cu surface area released 9.08 \u00b1 0.16 and 26.02 \u00b1 0.25 \\u03bcg/ml , while TCu380A having 400 mm(2) released 96.7 \u00b1 0.11 and 159.3 \u00b1 0.15 \\u03bcg/ml respectively following 24 and 72 h extractions . The effects of TCuIUD extracts on viability , morphology , apoptosis and cell cycle assay on L929 mouse fibroblasts cells , were appropriate for their respective Cu ion concentrations . Thus , a concentration of about 46 \\u03bcg/ml ( \\u03bcM ) was identified as the LD50 dose for L929 mouse fibroblasts when exposed for 24 h based on our MTT cell viability assay . The burst release of lethal concentration of Cu ions from TCu380A , especially at the implant site , is a cause of concern , and it is advisable to use TCuIUD designs that release Cu ions within cytotoxic limits yet therapeutic , similar to TCu220C .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22526680"}
{"sentence": "BACKGROUND Young age is a favorable prognostic factor for patients with glioblastoma multiforme ( GBM ) . We reviewed the outcomes and molecular tumor characteristics of adolescent and young adult patients with GBM treated in 2 Austrian centers . PATIENTS AND METHODS Data on patients with histologically proven primary GBM diagnosed from 18 through 40 years of age were retrospectively analyzed . All patients were treated with standard first-line therapy . The primary end points were overall survival ( OS ) and time to progression ( TTP ) . IDH1-R132H mutation status was analyzed using immunohistochemistry , and MGMT promoter methylation was assessed using methylation-specific polymerase chain reaction . RESULTS We included 70 patients ( 36 men and 34 women ) with a median age of 33 years . IDH1-R132H mutations were detected in 22 ( 39.3% ) of 56 cases and MGMT promoter methylation in 33 ( 61.1% ) of 54 cases with available tissue samples . In patients with wild-type IDH , median TTP was 8.2 months and median OS was 24 months , compared with 18 months and 44 months , respectively , observed in patients with mutated IDH . Neither IDH1 nor MGMT status showed a statistically significant association with TTP or OS . Of note , the social and economical situation of the young patients with GBM was alarming , because only 17% succeeded in staying employed after receiving the diagnosis . CONCLUSIONS We found a high frequency of IDH1 mutations and MGMT promoter methylation among young adult patients with primary GBM that may contribute to the generally favorable outcome associated with young age . The social and economic coverage of patients with glioma remains an unsolved socio-ethical problem .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23223340"}
{"sentence": "We assayed the estrogen and progesterone cytosolic receptors by using the enzyme immunoassay method , the epidermal growth factor ( EGF ) cell surface receptors by using 125I-labeled hormone , and the levels of polyamines ( putrescine , spermine , and spermidine ) by using a high-pressure liquid chromatography ( HPLC ) procedure in neoplastic and surrounding normal tissues of patients with colorectal cancer . Our findings show that mean polyamine levels in neoplastic tissue were approximately two-fold greater than the levels in normal colonic mucosa . Estrogen and progesterone receptorial content in normal mucosa were twofold greater than those in neoplastic tissue . No significant differences in EGF receptors were found between colonic cancer tissue and the surrounding normal tissues . The correlations we found between 1 ) estrogen and polyamine levels and 2 ) estrogen and EGF binding suggest the existence of a modulation of the estrogens on colonic mucosa cell proliferation . Furthermore , there was no significant dependency of polyamine and receptor concentrations from the tumor site , the histologic differentiation , or the age and sex of patients .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1582349"}
{"sentence": "DNA mismatch repair ( MMR ) of simple base mismatches and small insertion-deletion loops in eukaryotes is initiated by the binding of the MutS homolog 2 ( MSH2)-MSH6 heterodimer to mismatched DNA . Cadmium ( Cd ) is a genotoxic heavy metal that has been recognized as a human carcinogen . Oxidant stress and inhibition of DNA repair have been proposed as major factors underlying Cd genotoxicity . Our previous studies indicated the ability of Cd to disturb the gene expression of MSH6 in zebrafish ( Danio rerio ) embryos . This study was undertaken to explore if Cd-induced oxidative stress down-regulated MSH gene activities . Following the exposure of zebrafish embryos at 1 h post fertilization ( hpf ) to sublethal concentrations of Cd at 3-5 \\u03bcM for 4 or 9 h , a parallel down-regulation of MSH2 , MSH6 and Cu/Zn superoxide dismutase ( Cu/Zn-SOD ) gene expression was detected by real-time RT-PCR and the expression levels were 40-50% of control after a 9-h exposure . Cd exposure also induced oxidative stress , yet no inhibition of catalase gene activity was observed . Whole mount in situ hybridization revealed a wide distribution of msh6 mRNA in the head regions of 10 hpf embryos and pretreatment of embryos with antioxidants butylhydroxytoluene ( BHT ) , d-mannitol or N-acetylcysteine ( NAC ) at 1-10 \\u03bcM restored Cd-suppressed msh6 expression . QPCR confirmed the protective effects of antioxidants on Cd-suppressed msh2/msh6 mRNA production . Down-regulated MSH gene activities reaching about 50% of control were also induced in embryos exposed to paraquat , a reactive oxygen species ( ROS)-generating herbicide , or hydrogen peroxide at 200 \\u03bcM . Hence , Cd at sublethal levels down-regulates msh2/msh6 expression primarily via ROS as signaling molecules . The transcriptional activation of human msh6 is known to be fully dependent on the specificity factor 1 ( Sp1 ) . Cd failed to inhibit the DNA binding activity of zebrafish Sp1 unless at lethal concentrations based on band shift assay , therefore excluding the involvement of Sp1 inactivation in Cd-induced MSH gene inhibition in zebrafish embryos .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23143036"}
{"sentence": "Chinese medicinal herbs are traditionally used to prevent and treat a variety of diseases , including cancer . These herbal preparations are purported to have many biological effects including direct antiproliferative effects on cancer cells , anti-mutagenic activity , and stimulatory or suppressive effects on immune responses . The present study investigates the effects of aqueous extracts from seventy-one Chinese medicinal herbs on the growth of five breast cancer cell lines ( SK-BR-3 , MCF7 , MDA-MB-231 , BT-474 and MCNeuA ) . Twenty-one percent ( 15 out of 71 ) of the extracts demonstrated greater than 50% growth inhibition on at least 4 of the 5 cell lines . Dose-response curves were obtained for several of the most potent crude extracts and demonstrated IC50 values ranging from < 10 micrograms/ml to > 1 mg/ml . Six of seven herbs tested induced high molecular weight DNA fragmentation , an early marker of apoptosis , while one of these also induced low molecular weight DNA fragmentation . Flow cytometric analysis of breast cancer cells exposed to one of these herbs ( Rheum palmatum ) suggested that it arrests cells in the G2/M phase of the cell cycle . These results indicate that many of the herbs used in traditional Chinese medicine for the treatment of cancer have significant growth inhibitory effects on breast cancer cells in vitro .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "12553004"}
{"sentence": "We studied the effect of the immune system on two differentially aggressive melanomas developing in mice on conditional deletion of the INK4A/ARF tumor suppressor gene , with concomitant expression of oncogene H-Ras(G12V) and a natural cancer-germline tumor antigen ( TA ) . \" Slow progressor \" melanomas contained no activated T lymphocytes ( TL ) . In contrast , \" aggressive \" melanomas were infiltrated by activated TLs lacking effector molecules and expressing high levels of PD-1 , indicating an exhausted phenotype . Aggressive melanomas were also infiltrated by immature myeloid cells ( IMC ) . Infiltration was associated with local inflammation and systemic Th2/Th17-oriented chronic inflammation that seemed to impair further activation of TLs , as tumor-specific T cells adoptively transferred into mice bearing aggressive melanomas were poorly activated and failed to infiltrate the melanoma . This immunosuppression also led to the incapacity of these mice to reject inoculated TA-positive tumors , in contrast to slow-progressing melanoma-bearing mice , which were responsive . To test the role of adaptive immunity in tumor progression , we induced melanomas in immunodeficient RagKO compound mice . These mice developed aggressive but not slow-progressing melanomas at a higher frequency and with a shorter latency than immunocompetent mice . Immunodeficient mice also developed abnormal inflammation and infiltration of IMCs in a manner similar to immunocompetent mice , indicating that this phenotype was not dependent on adaptive immunity . Therefore , tumor-intrinsic factors distinguishing the two melanoma types control the initiation of inflammation , which was independent of adaptive immunity . The latter delayed development of aggressive melanomas but was overridden by inflammation .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20406967"}
{"sentence": "RASSF2 has recently been identified as a potential tumor suppressor that serves as a Ras effector in various types of human cancers . However , there have been few reports detailing this in gastric cancer . Samples of gastric adenocarcinoma from 276 Chinese patients with follow-up were analyzed for RASSF2 protein expression by immunohistochemistry . RASSF2 was expressed in up to 31.2% ( 86/276 ) of this group of gastric carcinoma . The expression of RASSF2 was significantly lower in carcinomas than in normal mucosas ( P<0.05 ) . RASSF2 corresponded positively with patient age , histological differentiation , depth of tumor invasion , regional lymph node and distant metastasis , and TNM stage ( all P<0.05 ) . Further multivariate analysis revealed that patient gender , depth of tumor invasion , distant metastasis , TNM stage and the expression of RASSF2 were independent prognostic factors for patients with gastric cancer . The Kaplan-Meier plot showed that the overall mean survival time of the patients with RASSF2-negative expression was shorter than that of patients with positive expression ( \u03c7(2)=156.874 , P<0.0001 ) . Moreover , RASSF2-negative expression had a much more significant effect on the survival of those patients with early stage tumors ( \u03c7(2)=127.167 , P<0.0001 ) , highlighted by a >50.9% reduction in 3-year survival compared to that of patients with RASSF2-positive expression . In late stages , the difference was also significant ( \u03c7(2)=6.246 , P=0.019 ) , with a 35.5% reduction in 3-year survival . It is suggested that RASSF2 plays an important role in the evolution of gastric adenocarcinoma and should be considered as a potential marker for its prognosis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22969901"}
{"sentence": "Many human cellular and tissue compartments are supersaturated with respect to calcium oxyanion salts . In order to prevent the formation of injurious crystals efficient anti-crystallization protective mechanisms must be necessary . We suggest that depletion of such systems , particularly in ageing organisms and under conditions of oxidative stress , plays an important role in degenerative and inflammatory diseases , including cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "1614357"}
{"sentence": "INTRODUCTION During selective segregation of DNA , a cell asymmetrically divides and retains its template DNA . Asymmetric division yields daughter cells whose genome reflects that of the parents ' , simultaneously protecting the parental cell from genetic errors that may occur during DNA replication . We hypothesized that long-lived epithelial cells are present in immortal , premalignant cell populations , undergo asymmetric division , retain their template DNA strands , and cycle both during allometric growth and during pregnancy . METHODS The glands of 3-week old immune competent Balb/C female mice were utilized intact or cleared of host epithelium and implanted with ductal-limited , lobule-limited , or alveolar-ductal progenitor cells derived from COMMA-D1 pre-malignant epithelial cells. 5-bromo-2-deoxyuridine ( 5-BrdU ) was administered to identify those cells which retain their template DNA . Nulliparous mice were then either injected with [ (3)H]-thymidine ( (3)H-TdR ) to distinguish 5-BrdU-label retaining cells that enter the cell cycle and euthanized , or mated , injected with ( 3)H-TdR , and euthanized at various days post-coitus . Sections were stained for estrogen receptor-\u03b1(ER-\u03b1) or progesterone receptor ( PR ) via immunohistochemistry . Cells labelled with both 5-BrdU and ( 3)H-TdR were indicative of label-retaining epithelial cells ( LREC ) . RESULTS Cells that retained a 5-BrdU label and cells labelled with [ (3)H]-thymidine were found in all mice and were typically detected along the branching epithelium of mature mouse mammary glands . Cells containing double-labelled nuclei ( LREC ) were found in the intact mammary gland of both pregnant and nulliparous mice , and in mammary glands implanted with pre-malignant cells . Double-labelled cells ( (3)H-TdR/5-BrdU ) represent a small portion of cells in the mammary gland that cycle and retain their template DNA ( 5-BrdU ) . Some label-retaining cells were also ER-\u03b1 or PR positive . LRECs distributed their second label ( (3)H-TdR ) to daughter cells ; and this effect persisted during pregnancy . LRECs , and small focal hyperplasia , were found in all immortalized premalignant mammary implant groups . CONCLUSIONS The results indicate that a subpopulation of long-lived , label-retaining epithelial cells ( LRECs ) is present in immortal premalignant cell populations . These LRECs persist during pregnancy , retain their original DNA , and a small percentage express ER-\u03b1 and PR . We speculate that LRECs in premalignant hyperplasia represent the long-lived ( memory ) cells that maintain these populations indefinitely .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20964820"}
{"sentence": "Tumor aerobic glycolysis , or the Warburg effect , plays important roles in tumor survival , growth , and metastasis . Pyruvate kinase isoenzyme M2 ( PKM2 ) is a key enzyme that regulates aerobic glycolysis in tumor cells . Recent research has shown that PKM2 can be used as a tumor marker for diagnosis and , in particular , as a potential target for cancer therapy . We investigated the effects of combining shRNA targeting PKM2 and docetaxel on human A549 lung carcinoma cells both in vivo and in vitro . We observed that the shRNA can significantly downregulate the expression level of PKM2 . The decrease of PKM2 resulted in a decrease in ATP synthesis , which caused intracellular accumulation of docetaxel . Furthermore , the combination of pshRNA-pkm2 and docetaxel inhibited tumor growth and promoted more cancer cell apoptosis both in vivo and in vitro . Our findings suggest that targeting tumor glycolysis can increase the efficacy of chemotherapy . In particular , the targeting of PKM2 could , to some extent , be a new way of reversing chemotherapy resistance to cancer therapy .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20507318"}
{"sentence": "AIMS Three-month chronic systemic-to-pulmonary shunting in growing piglets has been reported as an early pulmonary arterial hypertension ( PAH ) model with preserved right ventricular ( RV ) function . We sought to determine whether prolonged shunting might be associated with more severe PAH and RV failure . METHODS AND RESULTS Fourteen growing piglets were randomized to a sham operation or the anastomosis of the left innominate artery to the pulmonary arterial trunk . Six months later , the shunt was closed and the animals underwent haemodynamic evaluation followed by tissue sampling for pathobiological assessment . Prolonged shunting had resulted in increased mean pulmonary artery pressure ( 22 \u00b1 2 versus 17 \u00b1 1 mmHg ) and pulmonary arteriolar medial thickness , while cardiac output was decreased . However , RV-arterial coupling was markedly deteriorated , with a decrease in the ratio of end-systolic to pulmonary arterial elastances ( Ees/Ea ) . Lung tissue expressions of endothelin-1 , angiopoietin-1 , and bone morphogenetic protein receptor-2 were similarly altered compared with previously observed after 3-month shunting . At the RV tissue level , pro-apoptotic ratio of Bax-to-Bcl-2 expressions and caspase-3 activation were increased , along with an increase in cardiomyocyte size , while expressions in voltage-gated potassium channels ( Kv1.5 and Kv2.1 ) and angiogenic factors ( angiopoietin-2 and vascular endothelial growth factor ) were decreased . Right ventricular expressions of pro-inflammatory cytokines [ interleukin ( IL)-1\u03b1 , IL-1\u03b2 , tumour necrosis factor-\u03b1 ( TNF-\u03b1) ] and natriuretic peptide precursors ( NPPA and NPPB ) were increased . There was an inverse correlation between RV Ees/Ea and pro-apoptotic Bax/Bcl-2 ratios . CONCLUSIONS Prolonged left-to-right shunting in piglets does not further aggravate pulmonary vasculopathy , but is a cause of RV failure , which appears related to an activation of apoptosis and inflammation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21606077"}
{"sentence": "The cadherins are a family of cell surface glycoproteins responsible for cell adhesion which play an important role in cell morphology , contact inhibition and signal transduction during tumorigenesis . Protocadherin 8 ( PCDH8 ) , a member of the cadherin family , has been reported to act as a tumor suppressor involved in oncogenesis in breast cancer . In this study , we aimed to investigate the epigenetic inactivation of PCDH8 and its tumor suppressor function in gastric cancer . The expression of PCDH8 was markedly reduced or silenced in gastric cancer cell lines compared with normal gastric cells or tissues . Methylation of the PCDH8 gene promoter was observed in 100% ( 4/4 ) of cell lines and 55.38% ( 36/65 ) of the primary gastric cancer by methylation-specific PCR , but not in normal gastric mucosa ( 0/10 ) . Methylated PCDH8 was significantly associated with lymph node metastasis in a logistic regression analysis . The demethylation reagent 5-aza-2'-deoxycytidine was able to restore or upregulate PCDH8 expression in gastric cancer cell lines . Ectopic expression of PCDH8 in silenced gastric cancer cells significantly inhibited cell migration and induced apoptosis . For the first time , our study demonstrates the epigenetic inactivation of PCDH8 by promoter methylation and its tumor suppressor function in human gastric cancer . Thus , PCDH8 could be identified as a candidate tumor suppressor in human gastric cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22941331"}
{"sentence": "Mouse models can be useful for increasing the understanding of lung tumorigenesis and assessing the potential of chemopreventive agents . We explored the role of inflammation in lung tumor development in mice with knockout of the tumor suppressor Gprc5a . Examination of normal lung tissue and tumors from 51 Gprc5a(+/+) ( adenoma incidence , 9.8% ; adenocarcinoma , 0% ) and 38 Gprc5a(-/-) mice ( adenoma , 63% ; adenocarcinoma , 21% ) revealed macrophage infiltration into lungs of 45% of the Gprc5a(-/-) mice and 8% of Gprc5a(+/+) mice and the direct association of macrophages with 42% of adenomas and 88% of adenocarcinomas in the knockout mice . Gprc5a(-/-) mouse lungs contained higher constitutive levels of proinflammatory cytokines and chemokines and were more sensitive than lungs of Gprc5a(+/+) mice to stimulation of NF-kappaB activation by lipopolysaccharide in vivo . Studies with epithelial cells cultured from tracheas of Gprc5a(-/-) and Gprc5a(+/+) mice revealed that Gprc5a loss is associated with increased cell proliferation , resistance to cell death in suspension , and increased basal , tumor necrosis factor alpha-induced , and lipopolysaccharide-induced NF-kappaB activation , which were reversed partially in Gprc5a(-/-) adenocarcinoma cells by reexpression of Gprc5a . Compared with Gprc5a(+/+) cells , the Gprc5a(-/-) cells produced higher levels of chemokines and cytokines and their conditioned medium induced more extensive macrophage migration . Silencing Gprc5a and the p65 subunit of NF-kappaB in Gprc5a(+/+) and Gprc5a(-/-) cells , respectively , reversed these effects . Thus , Gprc5a loss enhances NF-kappaB activation in lung epithelial cells , leading to increased autocrine and paracrine interactions , cell autonomy , and enhanced inflammation , which may synergize in the creation of a tumor-promoting microenvironment .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20354164"}
{"sentence": "The ATM kinase and p53 are key tumor suppressor factors that control the genotoxic stress response pathway . The ATM substrate Mdm2 controls p53 activity by either targeting p53 for degradation or promoting its synthesis by binding the p53 mRNA . The physiological role and regulation of Mdm2's dual function toward p53 is not known . Here we show that ATM-dependent phosphorylation of Mdm2 at Ser395 is required for the p53 mRNA-Mdm2 interaction . This event also promotes SUMO-conjugation of Mdm2 and its nucleoli accumulation . Interfering with the p53 mRNA-Mdm2 interaction prevents p53 stabilization and activation following DNA damage . These results demonstrate how ATM activity switches Mdm2 from a negative to a positive regulator of p53 via the p53 mRNA .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22264786"}
{"sentence": "In Saccharomyces cerevisiae , Mre11p , Rad50p , and Xrs2p function as a multiprotein complex that has a central role in several DNA repair mechanisms . Though Mre11p has both single-stranded and double-stranded 3'-5 ' exonuclease activity in vitro , null mutants of MRE11 , RAD50 , and XRS2 exhibit reduced 5'-3 ' resection of HO-induced double-strand breaks ( DSBs ) in vivo . In this study , we analyzed four mre11 mutants harboring changes in the N-terminus of Mre11p where the four phosphoesterase motifs specify the in vitro nuclease activities of Mre11p and its homologues . We find that the 5'-3 ' resection defects in vivo do not correlate with several mitotic phenotypes : non-homologous end-joining ( NHEJ ) , telomere length maintenance , and adaptation to the DNA damage-inducible G2/M checkpoint . Overexpression of the 5'-3 ' exonuclease Exo1p in a mre11Delta strain partially increased 5'-3 ' resection and partially suppressed both methyl methanesulfonate ( MMS ) hypersensitivity and adaptation phenotypes , but did not affect telomere length or NHEJ . Surprisingly , the co-expression of two alleles , mre11-58S and mre11-N113S , each of which confers MMS hypersensitivity and short telomeres , can fully complement the MMS sensitivity and shortened telomere length of mre11Delta cells . We propose that at least two separate activities associated with the N-terminus of Mre11p are required for its mitotic function .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "12509295"}
{"sentence": "Since tumor cells are more dependent on glycolysis for energy supply than other cells , we tested whether its inhibition by 2-deoxy-D-glucose ( 2-DG ) affects tumor growth . Male Wistar rats were inoculated in the liver with tumor cells from a chemically induced colonic adenocarcinoma . From day 5 after inoculation 2-DG ( 400 mg/kg/24 h ) was continuously infused into the hepatic artery for 5 days ; controls received saline in the same fashion . Seven days after the end of infusion , the animals were sacrificed . A second experimental group of rats was treated with isolated liver perfusion for 30 min with oxygenated blood through the portal vein and hepatic artery simultaneously . In the perfusate , 400 mg/kg 2-DG were added , and the rats were sacrificed at 10 days after perfusion . A first control group underwent perfusion without 2-DG , and a second control group received i.v. infusion of 2-DG ( 400 mg/kg/30 min ) for 30 min over 5 days . A nontreated control group was also added . All animals survived the procedures . The concentration of blood glucose increased in the rats receiving 2-DG i.v. and intraarterially but was unchanged in the other groups . The tumor growth was significantly reduced by 2-DG in all experimental groups , with no difference between the groups . It is therefore concluded that 2-DG is of potential interest in the treatment of malignancies . Since local application of 2-DG avoids the risk for systemic side effects , this approach should be explored further .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "1394204"}
{"sentence": "AIM To investigate the progressive transformation of immortal cells of human fetal esophageal epithelium induced by human papillomavirus , and to examine biological criteria of sequential passage of cells , including cellular phenotype , proliferative rate , telomerase , chromosome and tumorigenicity . METHODS The SHEE cell series consisted of immortalized embryonic esophageal epithelium which was in malignant transformation when cultivated over sixty passages without co-carcinogens . Cells of the 10th , 31st , 60th and 85th passages were present in progressive development after being transfected with HPV . Cells were cultivated in a culture flask and 24-hole cultural plates . Progressive changes of morphology , cell growth , contact-inhibition , and anchorage-dependent growth characteristics were examined by phase contrast microscopy . The cell proliferation rate was assayed by flow cytometry . The modal number of chromosomes was analyzed . HPV18E(6)E(7) was detected by Western blot methods and activities of telomerase were analyzed by TRAP . Tumorigenicity of cells was detected with soft agar plates cultivated and with tumor formation in SCID mice . RESULTS In morphological examination the 10th passage cells were in good differentiation , the 60th and 85th passages cells were in relatively poor differentiation , and the 31st passage cells had two distinct differentiations . The characteristics of the 85th and 60th passage cells were weakened at contact-inhibition and anchorage-dependent growth . Karyotypes of four stages of cells belonged to hyperdiploid or hypotriploid , and bimodal distribution of chromosomes appeared in the 31st and 60th passage cells . All of these characteristics combined with a increasing trend . The activities of telomerase were expressed in the latter three passages . Four fourths of SCID mice in the 85th passage cells and one fourth of SCID mice in the 60th passage cells developed tumors , but the cells in the 10th and 31st passage displayed no tumor formation . CONCLUSION In continual cultivation of fetal esophageal epithelial cells with transduction of HPV18E(6)E(7) , cells from the 10th to the 85th passage were changed gradually from preimmortal , immortal , precancerous to malignantly transformed stages . All of these changes were in a dynamic progressive process . The establishment of a continuous line of esophageal epithelium may provide a in vitro model of carcinogenesis induced by HPV .", "label": [0, 0, 0, 1, 1, 0, 0, 0, 0, 0], "id": "12439909"}
{"sentence": "PURPOSE To investigate the in vitro release of octreotide acetate , a somatostatin agonist , from microspheres based on a hydrophilic polyester , poly(D,L-lactide-co-hydroxymethyl glycolide ) ( PLHMGA ) . METHODS Spherical and non-porous octreotide-loaded PLHMGA microspheres ( 12 to 16\\u03bcm ) and loading efficiency of 60-70% were prepared by a solvent evaporation . Octreotide release profiles were compared with commercial PLGA formulation ( Sandostatin LAR(\u00ae) ) ; possible peptide modification with lactic , glycolic and hydroxymethyl glycolic acid units was monitored . RESULTS PLHMGA microspheres showed burst release ( followed by sustained release for 20-60days , depending on the hydrophilicity of the polymer . Percentage of released loaded peptide was high ( 70-90% ) ; >\\u200960% of released peptide was native octreotide . PLGA microspheres did not show peptide release for the first 10days , after which it was released in a sustained manner over the next 90days ; >\\u200975% of released peptides were acylated adducts . CONCLUSIONS PLHMGA microspheres are promising controlled systems for peptides with excellent control over release kinetics . Moreover , substantially less peptide modification occurred in PLHMGA than in PLGA microspheres .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21744173"}
{"sentence": "The purpose of this study was to use the proteomics approach , which is based on high resolution two-dimensional electrophoresis coupled with multivariate correspondence analysis and mass spectrometry , to classify objectively the biochemical basis of the anti-cancer activity of the synthetic cyclin-dependent kinase inhibitor , bohemine ( BOH ) . The changes in the cell cycle and corresponding protein composition of the A549 human lung adenocarcinoma cell line after treatment with BOH were evaluated and proteins differentially expressed in the BOH treated A549 cells , compared to the untreated A549 counterparts , were selected . Thirteen of these candidate proteins associated with the drug effects in vitro were identified by mass spectrometry . Many of these proteins fall into one of three functional categories : i ) metabolic pathways ( glycolysis , nucleic acid synthesis and NADPH production ) , ii ) stress response and protein folding , and iii ) cytoskeleton and exocytosis . Changes in protein expression patterns corresponded to a higher resistance of A549 lung carcinoma cells to BOH when compared to the CEM leukaemia cell line . These protein changes reflect a fine balance of the resistant versus the susceptible phenotype in response to the drug . Since BOH is a selective cyclin-dependent kinase inhibitor , changes in the protein expression pattern can be more generally associated with cell cycle regulation as evidenced by inhibition of cell cycling in A549 cells . Our conclusions further underline the importance of cell cycle control in both the cellular signalling and metabolic pathways .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "12625783"}
{"sentence": "TGF-\u03b2 derived from bone fuels melanoma bone metastases by inducing tumor secretion of prometastatic factors that act on bone cells to change the skeletal microenvironment . Halofuginone is a plant alkaloid derivative that blocks TGF-\u03b2 signaling with antiangiogenic and antiproliferative properties . Here , we show for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through the inhibition of TGF-\u03b2 signaling . Halofuginone treatment of human melanoma cells inhibited cell proliferation , phosphorylation of SMAD proteins in response to TGF-\u03b2 , and TGF-\u03b2-induced SMAD-driven transcription . In addition , halofuginone reduced expression of TGF-\u03b2 target genes that enhance bone metastases , including PTHrP , CTGF , CXCR4 , and IL11 . Also , cell apoptosis was increased in response to halofuginone . In nude mice inoculated with 1205Lu melanoma cells , a preventive protocol with halofuginone inhibited bone metastasis . The beneficial effects of halofuginone treatment were comparable with those observed with other anti-TGF-\u03b2 strategies , including systemic administration of SD208 , a small-molecule inhibitor of TGF-\u03b2 receptor I kinase , or forced overexpression of Smad7 , a negative regulator of TGF-\u03b2 signaling . Furthermore , mice with established bone metastases treated with halofuginone had significantly less osteolysis than mice receiving placebo assessed by radiography . Thus , halofuginone is also effective in reducing the progression of melanoma bone metastases . Moreover , halofuginone treatment reduced melanoma metastasis to the brain , showing the potential of this novel treatment against cancer metastasis . Cancer Res ; 72(23) ; 6247-56. \ufffd2012 AACR .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23002206"}
{"sentence": "Metastasis is the most lethal attribute of human malignancy . High-level expression of survivin is involved in both carcinogenesis and angiogenesis in cancer . Previous studies indicate that a mutation of the threonine residue at position 34 ( Thr34Ala ) of survivin generates a dominant-negative mutant that induces apoptosis , inhibits angiogenesis , and suppresses highly metastatic breast carcinoma in mouse models . We investigated the efficacy of gene therapy with a survivin dominant-negative mutant and possible factors related to lymph node metastasis . The metastasis rate was compared between each group in order to find a survivin-targeted therapy against lymphangiogenesis in its earliest stages . We established lymph node metastasis models and treated animals with H22 tumors with Lip-mSurvivinT34A ( Lip-mS ) , Lip-plasmid ( Lip-P ) , or normal saline ( NS ) . Eight days after the last dose , five randomly chosen mice from each group were sacrificed . We detected the apoptotic index , microvessel density ( MVD ) , lymphatic microvessel density ( LMVD ) , and the expression of VEGF-D with immunohistochemistry . After the remaining animals were sacrificed , we compared the tumor-infiltrated lymph nodes in each group . Administration of mSurvivinT34A plasmid complexed with cationic liposome ( DOTAP/chol ) resulted in the efficacious inhibition of tumor growth and lymph node metastasis within the mouse H22 tumor model . These responses were associated with tumor cell apoptosis , and angiogenesis and lymphangiogenesis inhibition . Our results suggested that Lip-mSurvivinT34A induced apoptosis and inhibited tumor angiogenesis and lymphangiogenesis , thus suppressing tumor growth and lymphatic metastasis . The mSurvivinT34A survivin mutant is a promising strategy of gene therapy to inhibit lymphatic metastasis .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "24139416"}
{"sentence": "BACKGROUND Inherited malabsorption of cobalamin ( Cbl ) causes hematological and neurological abnormalities that can be fatal . Three genes have been implicated in Cbl malabsorption ; yet , only about 10% of reported cases have been molecularly studied to date . Recessive mutations in CUBN or AMN cause Imerslund-Gr\u00e4sbeck Syndrome ( IGS ) , while recessive mutations in GIF cause Intrinsic Factor Deficiency ( IFD ) . IGS and IFD differ in that IGS usually presents with proteinuria , which is not observed in IFD . The genetic heterogeneity and numerous differential diagnoses make clinical assessment difficult . METHODS We present a large genetic screening study of 154 families or patients with suspected hereditary Cbl malabsorption . Patients and their families have been accrued over a period spanning >12\\u2009 years . Systematic genetic testing of the three genes CUBN , AMN , and GIF was accomplished using a combination of single strand conformation polymorphism and DNA and RNA sequencing . In addition , six genes that were contenders for a role in inherited Cbl malabsorption were studied in a subset of these patients . RESULTS Our results revealed population-specific mutations , mutational hotspots , and functionally distinct regions in the three causal genes . We identified mutations in 126/154 unrelated cases ( 82% ) . Fifty-three of 126 cases ( 42% ) were mutated in CUBN , 45/126 ( 36% ) were mutated in AMN , and 28/126 ( 22% ) had mutations in GIF . We found 26 undescribed mutations in CUBN , 19 in AMN , and 7 in GIF for a total of 52 novel defects described herein . We excluded six other candidate genes as culprits and concluded that additional genes might be involved . CONCLUSIONS Cbl malabsorption is found worldwide and genetically complex . However , our results indicate that population-specific founder mutations are quite common . Consequently , targeted genetic testing has become feasible if ethnic ancestry is considered . These results will facilitate clinical and molecular genetic testing of Cbl malabsorption . Early diagnosis improves the lifelong care required by these patients and prevents potential neurological long-term complications . This study provides the first comprehensive overview of the genetics that underlies the inherited Cbl malabsorption phenotype .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22929189"}
{"sentence": "As part of our program to develop breast cancer specific therapeutic agents , we have synthesized a conjugate agent that is a conjugate of the steroidal anti-estrogen and the potent cytotoxin doxorubicin . In this effort , we employed a modular assembly approach to prepare a novel 11\u03b2-substituted steroidal anti-estrogen functionalized with an azido-tetraethylene glycol moiety , which could be coupled to a complementary doxorubicin benzoyl hydrazone functionalized with a propargyl tetraethylene glycol moiety . Huisgen [ 3 + 2 ] cycloaddition chemistry gave the final hybrid that was evaluated for selective uptake and cytotoxicity in ER(+)-MCF-7 and ER(-)-MDA-MB-231 breast cancer cell lines . The results demonstrated that the presence of the anti-estrogenic component in the hybrid compound was critical for selectivity and cytotoxicity in ER(+)-MCF-7 human breast cancer cells as the hybrid was more potent than doxorubicin in inhibition of cell proliferation and promoting cell death .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22404783"}
{"sentence": "Cellular senescence has emerged as a critical tumor suppressive mechanism in recent years , but relatively little is known about how senescence occurs . Here , we report that secreted Frizzled-related protein 1 ( SFRP1 ) , a secreted antagonist of Wnt signaling , is oversecreted upon cellular senescence caused by DNA damage or oxidative stress . SFRP1 is necessary for stress-induced senescence caused by these factors and is sufficient for the induction of senescence phenotypes . We present evidence suggesting that SFRP1 functions as a secreted mediator of senescence through inhibition of Wnt signaling and activation of the retinoblastoma ( Rb ) pathway and that cancer-associated SFRP1 mutants are defective for senescence induction .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 1], "id": "22927647"}
{"sentence": "BACKGROUND The receptor tyrosine kinase family includes many transmembrane proteins with diverse physiological and pathophysiological functions . The involvement of tyrosine kinase signaling in promoting a more aggressive tumor phenotype within the context of chemotherapeutic evasion is gaining recognition . The Ron receptor is a tyrosine kinase receptor that has been implicated in the progression of breast cancer and evasion of tamoxifen therapy . RESULTS Here , we report that Ron expression is correlated with in situ , estrogen receptor alpha ( ER\u03b1)-positive tumors , and is higher in breast tumors following neoadjuvant tamoxifen therapy . We also demonstrate that the majority of mammary tumors isolated from transgenic mice with mammary specific-Ron overexpression ( MMTV-Ron mice ) , exhibit appreciable ER expression . Moreover , genetic-ablation of ER\u03b1 , in the context of Ron overexpression , leads to delayed mammary tumor initiation and growth , but also results in an increased metastasis . CONCLUSIONS Ron receptor overexpression is associated with ER\u03b1-positive human and murine breast tumors . In addition , loss of ER\u03b1 on a Ron overexpressing background in mice leads to the development of breast tumors which grow slower but which exhibit more metastasis and suggests that targeting of ER\u03b1 , as in the case of tamoxifen therapy , may reduce the growth of Ron overexpressing breast cancers but may cause these tumors to be more metastatic .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22226043"}
{"sentence": "Trabecular meshwork ( TM ) cells have widely been used as an invitro model for glaucoma research . However , primary TM cells suffer the disadvantages of limited cell numbers and slow rates of proliferation . We discovered a spontaneously transformed bovine TM ( BTM ) cell line , BTM-28T . This cell line proliferated rapidly in low-glucose culture medium but also demonstrated contact inhibition in high-glucose culture medium . BTM-28T cells expressed key TM cell markers including \\u03b1-smooth muscle actin ( \\u03b1-SMA ) , laminin and collagen IV ( col IV ) . Also , 100nM dexamethasone ( DEX ) enhanced the formation of cross-linked actin networks ( CLANs ) in confluent BTM-28T cell cultures . Transforming growth factor beta 2 ( TGF\\u03b22 ) induced the expression of fibronectin ( FN ) , plasminogen activator inhibitor-1 ( PAI-1 ) , and connective tissue growth factor ( CTGF ) in our cell cultures . This cell line will be helpful to better understand the aqueous humor outflow pathway as related to the pathophysiology of glaucoma .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23116564"}
{"sentence": "We report that all-trans retinoic acid ( ATRA ) in combination with zoledronic acid has strong synergistic cytotoxic and apoptotic effects against human hormone- and drug-refractory prostate cancer cells , PC-3 and DU-145 , in a time- and dose-dependent manner . We further investigated the effect of the combination treatment on the apoptotic process by both oligoarray and protein array analysis in DU-145 cells , in which the drug combination shows much more strong synergistic effects , as compared to PC-3 cells . Moreover , we have also performed real time-PCR array analysis to validate oligoarray results . We demonstrated that the combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in human androgen-and drug refractory prostate cancer cells DU-145 , at either transcriptional or translational levels . While expression of proapoptotic genes such as tumor necrosis factor receptor superfamily ( TNFRSF ) , Bad , Bax , Fas , FADD are induced with the exposure of the combination , expression of antiapoptotic genes or proteins such as members of inhibitor apoptosis family ( IAPs ) , MCL-1 , LTBR , p53 and bcl-2 are reduced . Because this novel combination treatment has fewer side effects than is generally the case with conventional cytotoxic agents , this regimen may be a good option for treatment of elderly prostate cancer patients .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20349282"}
{"sentence": "To elucidate the function of MAS-related GPCR , member D ( MRGD ) in cancers , we investigated the in vitro and in vivo oncogenic function of MRGD using murine fibroblast cell line NIH3T3 in which MRGD is stably expressed . The expression pattern of MRGD in clinical samples was also analyzed . We found that overexpression of MRGD in NIH3T3 induced focus formation and multi-cellular spheroid formation , and promoted tumors in nude mice . In other words , overexpression of MRGD in NIH3T3 induced the loss of contact inhibition , anchorage-independent growth and in vivo tumorigenesis . Furthermore , it was found that the ligand of MRGD , beta-alanine , enhanced spheroid formation in MRGD-expressing NIH3T3 cells . From investigation of clinical cancer tissues , we found high expression of MRGD in several lung cancers by immunohistochemistry as well as real time PCR . Based on these results , MRGD could be involved in tumorigenesis and could also be a novel anticancer drug target .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "22715397"}
{"sentence": "Prolactin ( PRL ) promotes the proliferation and survival of breast cancer cells in part via the transactivation of human epidermal growth factor receptor 2 ( HER2 ) , also known as Neu in rodents . A PRL receptor ( PRLR ) antagonist , G129R , has been developed , which indirectly inhibits the tyrosine phosphorylation of HER2 ( p-HER2 ) in human breast cancer cell lines . In this study , we investigate the effects of cancer-associated fibroblasts ( CAFs ) upon this molecular cross-talk using tumor cells and CAFs derived from spontaneous mammary tumors of female MMTV-neu transgenic mice . Tumors were resected and cultured as small tumor chunks ( mm3 ) or were cultured in monolayer . G129R reduced tyrosine phosphorylation of Neu ( p-Neu ) in a dose-dependent manner ( IC50 \u03bcg/ml ) in tumor chunks , but had no effect on primary tumor epithelial cells grown in monolayer . Direct co-culture of mouse or human tumor epithelial cell lines with CAFs restored the epithelial cells ' response to G129R , similar to that observed in mouse tumor chunks . The addition of PRL , as expected , induced p-Neu in both the tumor chunk and co-culture models . The inhibitory effect of G129R was absent when CAFs were physically separated from mouse tumor epithelial cells using a transwell system , or when CAFs were replaced with normal fibroblasts in direct co-culture with human or mouse tumor epithelial cells . In vivo , G129R reduced p-Neu levels in primary mammary tumors of mice in a time- and dose-dependent manner . In conclusion , CAFs play a critical role in bridging the cross-talk between PRL and HER2/Neu in both mouse and human models of breast cancer . The inhibitory effects of G129R on p-Neu and on tumor growth are dependent upon interactions of tumor epithelial cells with CAFs .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22270933"}
{"sentence": "The main objective of the present investigation was to study the urinary neopterin excretion in the context of the activation of the adaptive cellular immune system at the tumor site . For this purpose , we compared pre-treatment urinary neopterin levels measured in 92 ovarian cancer patients , with intratumoral levels of mRNA transcripts from factors either involved in the adaptive antitumor immune defense ( CD3 , IFN-\u03b3 , IRF-1 , IRF-2 , SOCS1 and iNOS ) or immune tolerance ( FoxP3 ) . This study did not reveal an association between urinary neopterin and one of these investigated \" on tumor site transcripts \" . From all the factors reflecting the magnitude of the local adaptive antitumor response , intratumoral IRF-1 expression above the edge of the 25th percentile was found to predict most reliably favorable progression-free ( median 34 months vs. 10 months ; p < 0.001 ) and overall ( median 52 months vs. 16 months ; p < 0.001 ) survival . In contrast , pre-treatment urinary neopterin excretion above 275 \u03bcmol/mol creatinine , which indicates an unspecific activation of the innate immune system , was associated with a very poor overall survival with a median of only 11 months when compared with a median overall survival of 40 months in patients with lower urinary neopterin excretion ( p = 0.021 ) . Interestingly , the considerable survival benefit in patients with high IRF-1-expressing cancers was completely abrogated as well for progression-free as for overall survival when urinary neopterin concentrations were found to be concomitantly elevated . These findings demonstrate that in ovarian carcinomas the unspecific \" cancer-related inflammation \" contributes to a significant subversion of the adaptive antitumor immune defense mounted at the tumor site .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20717669"}
{"sentence": "BACKGROUND Paclitaxel and pirarubicin exhibit cytotoxic and antitumor activities . However , little is known about the apoptosis-inducing effects of paclitaxel and pirarubicin on human osteosarcoma MG-63 cells . METHODS The effects of paclitaxel and pirarubicin on cell cycle arrest and apoptosis were studied in MG-63 cells using flow cytometry . PCNA , Bcl-2 , Bax , cyclin D1 and cyclin E expression was assessed by Western blotting . RESULTS Paclitaxel and pirarubicin caused G2/M and G0/G1 cell cycle arrest in MG-63 cells , respectively . Apoptosis of MG-63 cells mediated by paclitaxel was dependent on treatment duration . Interestingly , in cells treated with pirarubicin , apoptosis was related to treatment duration at concentrations of 10(2)-10(3) nM , whereas the effect of treatment duration was less marked at concentrations >10(4)-10(5) nM . Furthermore , paclitaxel and pirarubicin suppressed the expression of PCNA , cyclin D1 , cyclin E and Bcl-2 , and increased Bax expression . CONCLUSION These results suggest that the G2/M or G0/G1 cell cycle arrest and apoptosis induced by paclitaxel and pirarubicin are Bcl-2/Bax dependent , suggesting favorable effects of combination therapy with paclitaxel and pirarubicin in the treatment of osteosarcoma .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20357441"}
{"sentence": "BACKGROUND Methyl sulfone is a small molecule that reverses cancerous phenotypes of a melanoma cell line . Here , we sought to determine whether methyl sulfone was effective against human breast cancer tissue . METHODS We studied normal and cancerous breast tissue obtained from 17 patients . RESULTS Methyl sulfone introduced structural order , with cancer tissue taking on the morphology of normal in vivo breast tissue ; this structural order was sustainable over long-term culture . Methyl sulfone promoted proper wound healing , including migration of cells into wounded areas and establishment of stable contact inhibition once wounds were covered . Methyl sulfone decreased expression of two breast stem cell marker proteins , HCAM and OCT3/4 , which are associated with aberrantly rapid migration of metastatic cells . Finally , normal and cancerous primary breast cells remained viable and healthy in methyl sulfone culture for at least 90 days . CONCLUSION Methyl sulfone reintroduced a normal structural phenotype to human breast cancer tissues .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23816712"}
{"sentence": "INTRODUCTION Anterior-gradient 2 ( AGR2 ) is an estrogen-responsive secreted protein . Its upregulation has been well documented in a number of cancers , particularly breast cancer , for which mixed data exist on the prognostic implications of AGR2 expression . Although emerging evidence indicates that AGR2 is associated with poor prognosis , its function and impact on cancer-relevant pathways have not been elucidated in breast cancer . METHODS To investigate the biologic role of AGR2 in breast cancer , AGR2 was transiently knocked down , by using siRNA , in T47 D and ZR-75-1 ( estrogen receptor-alpha ( ER)-positive ) and MDA-MB-231 and SK-BR-3 ( ER-negative ) human breast cancer cell lines . The impact of silencing AGR2 was evaluated in both anchorage-dependent and anchorage-independent growth ( soft agar , spheroid ) assays . Cell-cycle profiles in ER-positive cell lines were determined with BrdU incorporation , and cell death was measured with Annexin V , JC-1 , and F7-26 staining . After transiently silencing AGR2 or stimulating with recombinant AGR2 , modulation of key regulators of growth and survival pathways was assessed with Western blot . Combination studies of AGR2 knockdown with the antiestrogens tamoxifen and fulvestrant were carried out and assessed at the level of anchorage-dependent growth inhibition and target modulation ( cyclin D1 , ER ) . RESULTS AGR2 knockdown inhibited growth in anchorage-dependent and anchorage-independent assays , with a more-pronounced effect in ER-positive cell lines . Cyclin D1 levels and BrdU incorporation were reduced with AGR2 knockdown . Conversely , cyclin D1 was induced with recombinant AGR2 . AGR2 knockdown induced cell death in ZR-75-1 and T47 D cells , and also downregulated survivin and c-Myc . Evidence of AGR2-ER crosstalk was demonstrated by a reduction of ER at the protein level after transiently silencing AGR2 . AGR2 knockdown in combination with fulvestrant or tamoxifen did not preclude the efficacy of the antiestrogens , but enhanced it . In addition , p-Src , implicated in tamoxifen resistance , was downregulated with AGR2 knockdown . CONCLUSIONS Transiently silencing AGR2 in ER-positive breast cancer cell lines inhibited cell growth and cell-cycle progression and induced cell death . Breast cancer drivers ( ER and cyclin D1 ) as well as cancer-signaling nodes ( pSrc , c-Myc , and survivin ) were demonstrated to be downstream of AGR2 . Collectively , the data presented support the utility of anti-AGR2 therapy in ER-positive breast cancers because of its impact on cancer-relevant pathways .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20525379"}
{"sentence": "Autophagy is an evolutionarily conserved , multi-step lysosomal degradation process in which a cell degrades its own long-lived proteins and damaged organelles . Ataxia telangiectasia mutated ( ATM ) has recently been shown to upregulate the process of autophagy . Previous studies showed that certain microRNAs , including miR-18a , potentially regulate ATM in cancer cells . However , the mechanisms behind the modulation of ATM by miR-18a remain to be elucidated in colon cancer cells . In the present study , we explored the impact of miR-18a on the autophagy process and ATM expression in HCT116 colon cancer cells . To determine whether a preliminary link exists between autophagy and miR-18a , HCT116 cells were irradiated and quantitative ( q ) PCR was performed to measure miR-18a expression . HCT116 cells were transfected with an miR-18a mimic to study its impact on indicators of autophagy . Western blotting and luciferase assays were implemented to explore the impact of miR-18a on ATM gene expression in HCT116 cells . The results showed that miR-18a expression was strongly stimulated by radiation . Ectopic overexpression of miR-18a in HCT116 cell lines potently enhanced autophagy and ionizing radiation-induced autophagy . Moreover , miR-18a overexpression led to the upregulation of ATM expression and suppression of mTORC1 activity . Results of the present study pertaining to the role of miR-18a in regulating autophagy and ATM gene expression in colon cancer cells revealed a novel function for miR-18a in a critical cellular event and on a crucial gene with significant impacts in cancer development , progression , treatment and in other diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23229340"}
{"sentence": "BACKGROUND & OBJECTIVE Hereditary non-polyposis colorectal cancer ( HNPCC or Lynch syndrome ) , is a genetically heterogeneous disorder that is believed to account for 2-10 per cent of all the colorectal cancer cases . The disease follows autosomal dominant inheritance pattern with high penetrance ( 85% ) and younger age of onset when compared to patients with sporadic tumours . HNPCC is associated with germ-line mutations in the DNA mismatch repair ( MMR ) genes namely MLH1 , MSH2 , MSH6 , and PMS2 . The present study was aimed at analyzing mismatch repair gene(s) in an extended Indian family satisfying the Amsterdam criteria , and extending the analysis to general population to estimate frequency of the mutations/polymorphisms observed . METHODS A total 12 members of the HNPCC family were studied for genetic investigation . Ethnically matched 250 normal individuals were also included as controls to study the observed mutations/polymorphisms at population level . RESULTS The analysis resulted in identification of a 1975C>T mutation in exon 17 , resulting in substitution of arginine residue with stop codon at codon 659. 655A>G substitution was also observed , resulting in replacement of isoleucine with valine at codon 219 . Similar analysis on 250 ethnically matched control subjects revealed complete absence of R659X mutation , while I219V variant was found in 9.8 per cent of the controls . INTERPRETATION & CONCLUSION R659X mutation correlates with disease phenotype , and 655A>G locus is highly polymorphic . Our study suggested that R659X substitution was prime cause for the disease phenotype in this family . I219V substitution is a polymorphism having no association with the disease onset or segregation . The family members harbouring this mutation were advised to be under regular medical surveillance .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20167975"}
{"sentence": "Overexpression of cyclin D1 is believed to endow mammary epithelial cells ( MEC ) with a proliferative advantage by virtue of its contribution to pRB inactivation . Accordingly , abrogation of the kinase-dependent function of cyclin D1 is sufficient to render mice resistant to breast cancer initiated by ErbB2 . Here , we report that mouse cyclin D1(KE/KE) MECs ( deficient in cyclin D1 activity ) upregulate an autophagy-like process but fail to implement ErbB2-induced senescence in vivo . In addition , immortalized cyclin D1(KE/KE) MECs retain high rates of autophagy and reduced ErbB2-mediated transformation in vitro . However , highlighting its dual role during tumorigenesis , downregulation of autophagy led to an increase in senescence in cyclin D1(KE/KE) MECs . Autophagy upregulation was also confirmed in human mammary epithelial cells ( HMEC ) subjected to genetic and pharmacologic inhibition of cyclin D1 activity and , similar to our murine system , simultaneous inhibition of Cdk4/6 and autophagy in HMECs enhanced the senescence response . Collectively , our findings suggest a previously unrecognized function of cyclin D1 in suppressing autophagy in the mammary epithelium . Cancer Res ; 72(24) ; 6477-89. \ufffd2012 AACR .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 0], "id": "23041550"}
{"sentence": "BACKGROUND Coronins are a family of highly evolutionary conserved proteins reportedly involved in the regulation of actin cytoskeletal dynamics , although only coronin 3 has been shown to be related to cancer cell migration . In glioblastoma cells , the knockdown of coronin 3 inhibits cell proliferation and invasion . Coronin 3 is also associated with the aggression and metastasis of hepatocellular carcinoma . In this paper , we analyze the migration , invasion and metastasis abilities of gastric cancer cells after up- or down-regulation of coronin 3 , and explore the mechanism of coronin 3 in the process of gastric cancer metastasis . RESULTS The expression of coronin 3 was higher in the highly metastatic sub-cell line MKN28-M , which we established in our laboratory . We also demonstrated that the expression of coronin 3 was remarkably higher in lymph lode metastases than in primary gastric cancer tissues , and over-expression of coronin 3 was correlated with the increased clinical stage and lymph lode metastasis . Recombinant lentiviral vectors encoding shRNAs were designed to down-regulate coronin 3 expression in gastric cancer cell lines . Stable knockdown of coronin 3 by this lentiviral vector could efficiently inhibit the migration and invasion of MKN45 gastric cancer cells . In contrast , up-regulation of coronin 3 significantly enhanced migration and invasion of MKN28-NM cells . In addition , knockdown of coronin 3 significantly reduced liver metastasis in mice after tail vein injection of gastric cancer cells . The Human Tumor Metastasis PCR Array was used to screen the metastasis-associated genes identified by the down-regulation of coronin 3 , and the results suggested that , following the knockdown of coronin 3 , the tumor cell migration and invasion were inhibited by the reduced expression of MMP-9 and cathepsin K. CONCLUSION Coronin 3 is highly expressed in gastric cancer metastases and can promote the metastatic behaviors of gastric cancer cells , including their migration and invasion .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22974233"}
{"sentence": "Breast cancer is the second most common cancer with a high incidence rate worldwide . One of the promising therapeutic approaches on breast cancer is to use the drugs that target the estrogen receptor ( ER ) . In the present investigation , marmorin , a type I ribosome inactivating protein from the mushroom Hypsizigus marmoreus , inhibited the survival of breast cancer in vitro and in vivo . It evinced more potent cytotoxicity toward estrogen receptor ( ER)-positive MCF7 breast cancer cells than ER-negative MDA-MB-231 cells . Further study disclosed that marmorin undermined the expression level of estrogen receptor \u03b1 ( ER\u03b1 ) and significantly inhibited the proliferation of MCF7 cells induced by 17\u03b2-estradiol . Knockdown of ER\u03b1 in MCF7 cells significantly attenuated the inhibitory effect of marmorin on proliferation , suggesting that the ER\u03b1-mediated pathway was implicated in the suppressive action of marmorin on ER-positive breast cancer cells . Moreover , marmorin induced time-dependent apoptosis in both MCF7 and MDA-MB-231 cells . It brought about G2/M-phase arrest , mitochondrial membrane potential depolarization and caspase-9 activation in MCF7 cells , and to a lesser extent in MDA-MB-231 cells . Marmorin triggered the death receptor apoptotic pathway ( e.g. caspase-8 activation ) and endoplasmic reticulum stress ( ERS , as evidenced by phosphorylation of PERK and IRE1\u03b1 , cleavage of caspase-12 , and up-regulation of CHOP expression ) in both MCF7 and MDA-MB-231 cells . In summary , marmorin exhibited inhibitory effect on breast cancer partially via diminution of ER\u03b1 and apoptotic pathways mediated by mitochondrial , death receptor and ERS . The results advocate that marmorin is a potential candidate for breast cancer therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23274857"}
{"sentence": "BACKGROUND : The p38\u03b1 MAP kinase pathway is involved in inflammation , cell differentiation , growth , apoptosis and production of pro-inflammatory cytokines TNF-\u03b1 and IL-1\u03b2 . The overproduction of these cytokines plays an important role in cancer . The aim of this work was to design a peptide inhibitor on the basis of structural information of the active site of p38\u03b1 . METHODS : A tetrapeptide , VWCS as p38\u03b1 inhibitor was designed on the basis of structural information of the ATP binding site by molecular modeling . The inhibition study of peptide with p38\u03b1 was performed by ELISA , binding study by Surface Plasmon Resonance and anti-proliferative assays by MTT and flow cytometry . RESULTS : The percentage inhibition of designed VWCS against pure p38\u03b1 protein and serum of HNSCC patients was 70.30 and 71.5% , respectively . The biochemical assay demonstrated the K(D) and IC(50) of the selective peptide as 7.22\ufffd10(-9)M and 20.08nM , respectively . The VWCS as inhibitor significantly reduced viability of oral cancer KB cell line with an IC(50) value of 10\u03bcM and induced apoptosis by activating Caspase 3 and 7 . CONCLUSIONS : VWCS efficiently interacted at the ATP binding pocket of p38\u03b1 with high potency and can be used as a potent inhibitor in case of HNSCC . GENERAL SIGNIFICANCE : VWCS can act as an anticancer agent as it potentially inhibits the cell growth and induces apoptosis in oral cancer cell-line in a dose as well as time dependent manner . Hence , p38\u03b1 MAP kinase inhibitor can be a potential therapeutic agent for human oral cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23238519"}
{"sentence": "Given the important role of CXCR4 in cancer metastasis , microenvironmental factors that modulate CXCR4 may have an impact on the process of tumor expansion . Hypoxia is a common feature of solid tumors and a significant microenvironmental factor that drives aggressive behavior . CXCR4 is upregulated in several cancer cells under hypoxic conditions , suggesting a relationship between tumor hypoxia and CXCR4 . However , the role of hypoxia in regulating CXCR4 in gastric cancer remains poorly understood . KATO III gastric cancer cells were exposed to hypoxia or normoxia . CXCR4 expression in cells transfected with shRNA specific for HIF-1\u03b1 was investigated by western blotting and flow cytometry . Wound healing , migration and invasion assays were used to assess cell motility and the chemotactic response to CXCL12 , a major CXCR4 ligand . CXCR4 expression at the protein level and in the cell membrane was significantly increased in KATOIII cells following exposure to hypoxia . This upregulation of CXCR4 was implicated in increased cell motility and enhanced chemotactic responses ( migration and invasion ) to CXCL12 treatment in vitro . The increases in CXCR4 expression and metastatic potential in gastric cancer cells exposed to hypoxia were blocked by HIF-1\u03b1-specific shRNA . Our results indicate that hypoxia upregulates CXCR4 in gastric cancer cells in a HIF-1\u03b1-dependent manner , and that upregulation of CXCR4 plays a role in cancer cell migration and invasion . Thus , disrupting the hypoxia-HIF-1\u03b1-CXCR4 axis could be an attractive therapeutic strategy for the treatment of gastric cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23023480"}
{"sentence": "Depleted uranium ( DU ) is commonly used in military armor and munitions , and thus , exposure of soldiers and noncombatants is frequent and widespread . Previous studies have shown that DU has both chemical and radiological toxicity and that the primary route of exposure of DU to humans is through inhalation and ingestion . However , there is limited research information on the potential carcinogenicity of DU in human bronchial cells . Accordingly , we determined the neoplastic transforming ability of particulate DU to human bronchial epithelial cells ( BEP2D ) . We observed the loss of contact inhibition and anchorage independent growth in cells exposed to DU after 24 h . We also characterized these DU-induced transformed cell lines and found that 40% of the cell lines exhibit alterations in plating efficiency and no significant changes in the cytotoxic response to DU . Cytogenetic analyses showed that 53% of the DU-transformed cell lines possess a hypodiploid phenotype . These data indicate that human bronchial cells are transformed by DU and exhibit significant chromosome instability consistent with a neoplastic phenotype .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20000475"}
{"sentence": "Previous studies have demonstrated that mesenchymal stromal cells ( MSCs ) enhance cell survival through upregulation and secretion of stanniocalcin-1 ( STC1 ) . This study shows that MSC-derived STC1 promotes survival of lung cancer cells by uncoupling oxidative phosphorylation , reducing intracellular reactive oxygen species ( ROS ) , and shifting metabolism towards a more glycolytic metabolic profile . MSC-derived STC1 upregulated uncoupling protein 2 ( UCP2 ) in injured A549 cells in an STC1-dependent manner . Knockdown of UCP2 reduced the ability of MSCs and recombinant STC1 ( rSTC1 ) to reduce cell death in the A549 population. rSTC1-treated A549 cells displayed decreased levels of ROS , mitochondrial membrane potential ( MMP ) , and increased lactate production , all of which were dependent on the upregulation of UCP2 . Our data suggest that MSCs can promote cell survival by regulating mitochondrial respiration via STC1 .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "22146344"}
{"sentence": "Periplocin is one of cardenolides isolated from cortex periplocae which is used for treatment of rheumatoid arthritis and reinforcement of bones and tendons in traditional medicine . Here , we investigated the anti-tumor activity of periplocin against lung cancer cells bothin vitro and in vivo , and explored its anti-cancer mechanism . Periplocin inhibited the growth of lung cancer cells and induced their apoptosis in time- and dose-dependent manners by cell cycle arrest in G0/G1 phase . Periplocin exhibited anti-tumor activity both in human ( A549 ) and mouse ( LL/2 ) lung cancer xenograft models . Immunohistochemical analysis revealed that intratumoral angiogenesis was significantly suppressed . Furthermore , anti-cancer activity mediated by periplocin was associated with decreased level of phosphorylated AKT and ERK both in vitro and in vivo , which were important for cell growth and survival . Moreover , periplocin induced apoptosis by downregulating Bcl-2 and upregulating Bax , leading to activation of caspase-3 and caspase-9 . These findings suggested that periplocin could inhibit the growth of lung cancer both in vitro and in vivo , which could be attributed to the inhibition of proliferation and the induction of apoptosis signaling pathway , such as AKT and ERK . These observations provide further evidence on the anti-tumor effect of periplocin , and it may be of importance to further explore its potential role as a therapeutic agent for cancer .", "label": [0, 0, 0, 0, 1, 0, 1, 1, 1, 0], "id": "21063098"}
{"sentence": "The effects of high and low dietary fat ( 20% vs. 0.5% corn oil ) , and of the prostaglandin synthetase inhibitor indomethacin ( 0.005% w/w ) , on tumour incidence , tumour growth , hormone-receptor status and growth-factor expression were examined in dimethylbenzanthracene ( DMBA)-induced rat breast cancer . The high dietary-fat group showed a significantly higher tumour incidence , larger tumour size and larger number of bromodeoxyuridine(BrdU)-positive cells of tumours as compared with those in the low dietary-fat group . Indomethacin reduced tumour incidence significantly , but conversely increased the tumour size and the number of BrdU-positive cells in both the high and the low dietary-fat groups . No significant difference was noted in the hormone-receptor status of the tumours . Growth factors ( TGF-alpha and IGF-II ) were somewhat highly expressed in the high dietary-fat group as compared with the low dietary-fat group , but indomethacin rather reduced the growth-factor expression . It is concluded that high dietary fat stimulates tumour incidence and tumour proliferation , while indomethacin has dual effects : a stimulating effect on tumour proliferation , but an inhibiting effect on tumour incidence . It is also suggested that hormone-receptor status and growth-factor expression do not play an important role in their stimulating effects on tumour proliferation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1306527"}
{"sentence": "The knowledge of alterations in regulation of autophagy during tumorigenesis may also help our understanding of its normal control . We established an experimental system and reported recently that autophagic capacity , measured as the cell's capability of increasing segregation ( formation of autophagosomes ) and subsequent degradation of cytoplasmic quanta were highly increased in premalignant nodule cells 6 months after initiation by azaserine in the rat pancreas in vivo . In the present study , we followed changes of these autophagic functions throughout the tumour progression . We carried out electron-microscopic morphometrical analysis of the expansion of autophagic vacuole compartment and subcompartments induced by vinblastine ( an in vivo segregation enhancer ) , as well as their regression upon segregation-inhibitor cycloheximide post-treatment . Premalignant tumour samples were taken at month 5 , month 8 ( nodules ) , month 10 and month 15 ( adenomas ) after initiation . In all these stages , a highly increased and varying autophagic capacity was found compared with the host tissue . The basal ( non-stimulated ) autophagic compartment was measurable only at month 5 and month 15 , and its regression upon cycloheximide was consistent with increased basal autophagic activity . Compared with the host tissue , autophagic capacity profoundly decreased in the differentiated and anaplastic adenocarcinomas at month 20 , when , surprisingly , cycloheximide was unable to inhibit segregation . Our conclusion is that down-regulation of the cycloheximide sensitive segregation and a partly compensatory up-regulation of an alternative pathway of segregation might occur along with malignant transformation .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12195297"}
{"sentence": "Most cancer cells exhibit increased glycolysis for generation of their energy supply . This specificity could be used to preferentially kill these cells . In this study , we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor ( DR)-induced apoptosis . We showed , in several human cancer cell lines ( such as Jurkat , HeLa , U937 ) , that glucose removal or the use of nonmetabolizable form of glucose ( 2-deoxyglucose ) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand . This sensitization is controlled through the adenosine monophosphate ( AMP)-activated protein kinase ( AMPK ) , which is the central energy-sensing system of the cell . We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin ( mTOR ) inhibition leading to Mcl-1 decrease , but no other Bcl-2 anti-apoptotic members . Interestingly , we determined that , upon glycolysis inhibition , the AMPK-mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation . Therefore , our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression . In addition , this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "19966861"}
{"sentence": "Elevated androgen receptor ( AR ) activity in castration-resistant prostate cancer ( CRPC ) may occur through increased levels of AR coactivator proteins . Vav3 , a guanine nucleotide exchange factor ( GEF ) , is upregulated following progression to castration-resistance in preclinical models and is overexpressed in a significant number of human prostate cancers . Vav3 is a novel coactivator of the AR . We sought to identify Vav3 binding partners in an effort to understand the molecular mechanisms underlying Vav3 enhancement of AR activity and to identify new therapeutic targets . The cell division cycle 37 homolog ( Cdc37 ) , a protein kinase-specific co-chaperone for Hsp90 , was identified as a Vav3 interacting protein by yeast two hybrid screening . Vav3-Cdc37 interaction was confirmed by GST pulldown and , for native proteins , by coimmunoprecipitation experiments in prostate cancer cells . Cdc37 potentiated Vav3 coactivation of AR transcriptional activity and Vav3 enhancement of AR amino-carboxyl terminal ( N-C ) interaction , which is essential for optimal receptor transcriptional activity . Cdc37 increased prostate cancer cell proliferation selectively in Vav3 expressing cells . Cdc37 did not affect Vav3 nucleotide exchange activity , Vav3 protein levels or subcellular localization . Disruption of Vav3-Cdc37 interaction inhibited Vav3 enhancement of AR transcriptional activity and AR N-C interaction . Diminished Vav3-Cdc37 interaction also caused decreased prostate cancer cell proliferation selectively in Vav3 expressing cells . Taken together , we identified a novel Vav3 interacting protein that enhances Vav3 coactivation of AR and prostate cancer cell proliferation . Vav3-Cdc37 interaction may provide a new therapeutic target in prostate cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23281476"}
{"sentence": "This study aimed to investigate the mechanism by which the human lung cancer drug resistance-related gene BC006151 regulates chemosensitivity by down-regulating BC006151 expression via antisense gene transfer in H446/(C)DDP cells . A retroviral vector containing the antisense BC006151 sequence was constructed and transfected into H446/(C)DDP cells . Transfection of the empty vector served as a negative control . The two groups of transfected cells were treated with various chemotherapeutic agents , after which morphological changes in cell ultrastructure were compared by transmission electron microscopy , cell proliferation and chemosensitivity to particular chemotherapeutic agents were compared by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method , the effects of chemotherapy on cell cycle and apoptosis were compared by flow cytometry , and Bcl-2 was evaluated by immunohistochemistry and Western blot analysis . Results showed that apoptotic body-like structures were identified by transmission electron microscopy in the antisense gene-transfected cells . MTT founded that these cells exhibited a significantly lower level of proliferation than the control cells ( p<0.01 ) , together with a markedly increased sensitivity to various chemotherapeutic agents ( p<0.01 ) . Flow cytometry analysis revealed that a G1 phase arrest accounted for the reduction in proliferation in the antisense gene-transfected cells ; increased apoptosis was also detected ( p<0.01 ) . Both immunohistochemistry and western blot analysis confirmed that Bcl-2 expression was significantly down-regulated in the antisense gene-transfected cells compared to controls . In a word , down-regulation of BC006151 can significantly inhibit proliferation and increase apoptosis of H446/(C)DDP cells after chemotherapy , and this gene may play an important role in the development of multidrug resistance in lung cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "20686220"}
{"sentence": "Mas oncogene has been shown to have focus-inducing ability in NIH 3T3 cells which are tumorigenic in vivo in nude mice . Its stable expression in a variety of cell lines conferred some angiotensin responsiveness . To understand why mas-transfected cells exhibit a transformed phenotype and if angiotensin responsiveness plays any role in this process , we studied the growth characteristics of mas-transfected 3T3 cells and demonstrated that they lose contact inhibition , exhibit foci formation , and increased DNA synthesis even in absence of serum . Our results suggest that the transformed phenotype is due to the production of a mas receptor ligand distinct from angiotensin .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "1327543"}
{"sentence": "The mechanisms of formation of sister chromatid exchanges ( SCEs ) and chromosome aberrations following inhibition of poly(ADP-ribose) polymerase by 3-aminobenzamide were studied in Chinese hamster ovary cell lines deficient in different repair pathways . The results confirm earlier findings that ( a ) the ' spontaneous ' SCEs are formed due to the incorporated BrdU in the DNA , ( b ) ' spontaneous ' and induced SCEs originate from different mechanisms , and ( c ) SCEs and chromatid exchanges are formed by different pathways .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20389038"}
{"sentence": "Congenital cataract is a leading cause of visual impairment in children and brings approximately 10% of childhood blindness worldwide . Molecular analysis revealed loci to be associated with several phenotypes of childhood cataracts . Until now , more than 30 loci and 18 genes on different chromosomes have been associated with autosomal dominant congenital cataract ( ADCC ) . Here , we present a three-generation Italian family with a non syndromic ADCC . A linkage analysis carried out using HumanCytoSNP-12 DNA Analysis BeadChip led us to identify ten genomic regions virtually involved in the disease . All the genes located in these regions were scored for possible relationship with ADCC and , according to a strict clinical and genetic selection , 4 genes have been analyzed . A novel sequence variant was found in the CRYBB2 gene ( p.Ser143Phe ) . This variant affects a conserved aminoacid in the third Greek key motif of the protein , cosegregates with the disease phenotype in all affected individuals and is not present both in the unaffected family members and 100 healthy control subjects . Finally , we identified the first CRYBB2 mutation in an Italian family causing a clinical picture of ADCC .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22846113"}
{"sentence": "Colorectal cancer ( CRC ) is one of the leading causes of cancer deaths in Western countries . A significant number of CRC patients undergoing curatively intended surgery subsequently develop recurrence and die from the disease . MicroRNAs ( miRNAs ) are aberrantly expressed in cancers and appear to have both diagnostic and prognostic significance . In this study , we identified novel miRNAs associated with recurrence of CRC , and their possible mechanism of action . TaqMan\ufffd Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosas and 46 microsatellite stable CRC tumors . Four miRNAs ( miR-362-3p , miR-570 , miR-148a* and miR-944 ) were expressed at a higher level in tumors from patients with no recurrence ( p < 0.015 ) , compared to tumors from patients with recurrence . A significant association with increased disease free survival was confirmed for miR-362-3p in a second independent cohort of 43 CRC patients , using single TaqMan\ufffd microRNA assays . In vitro functional analysis showed that over-expression of miR-362-3p in colon cancer cell lines reduced cell viability , and proliferation mainly due to cell cycle arrest . E2F1 , USF2 and PTPN1 were identified as potential miR-362-3p targets by mRNA profiling of HCT116 cells over-expressing miR-362-3p . Subsequently , these genes were confirmed as direct targets by Luciferase reporter assays . Their knockdown in vitro phenocopied the effects of miR-362-3p over-expression . We conclude that miR-362-3p may be a novel prognostic marker in CRC , and hypothesize that the positive effects of augmented miR-362-3p expression may in part be mediated through the targets E2F1 , USF2 and PTPN1. \ufffd 2012 Wiley Periodicals , Inc .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23280316"}
{"sentence": "Oncogene-induced senescence can provide a protective mechanism against tumour progression . However , production of cytokines and growth factors by senescent cells may contribute to tumour development . Thus , it is unclear whether induction of senescence represents a viable therapeutic approach . Here , using a mouse model with orthotopic implantation of metastatic melanoma tumours taken from 19 patients , we observed that targeting aurora kinases with MLN8054/MLN8237 impaired mitosis , induced senescence and markedly blocked proliferation in patient tumour implants . Importantly , when a subset of tumour-bearing mice were monitored for tumour progression after pausing MLN8054 treatment , 50% of the tumours did not progress over a 12-month period . Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response , which mediated senescence and a NF-\u03baB-related , senescence-associated secretory phenotype ( SASP ) . Blockade of IKK\u03b2/NF-\u03baB led to reversal of MLN8237-induced senescence and SASP . Results demonstrate that removal of senescent tumour cells by infiltrating myeloid cells is crucial for inhibition of tumour re-growth . Altogether , these data demonstrate that induction of senescence , coupled with immune surveillance , can limit melanoma growth .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "23180582"}
{"sentence": "Currently there is no good hepatocyte model for studying growth hormone ( GH ) function that reflects its normal physiological roles . Here we report the establishment of a functional hepatocyte cell line , SDRL-1 , from the liver of young male spontaneous dwarf rats ( SDR ) , with isolated GH deficiency . This line has been maintained in Dulbecco's Modified Eagle Medium ( DMEM)/F12 medium supplemented with 10% fetal bovine serum ( FBS ) with retention of a near diploid karyotype for extended periods of time . When grown as a monolayer sheet , it displayed a pavement-like appearance and contact inhibition . These cells have a poorly developed rough endoplasmic reticulum ( r-ER ) , few mitochondria and glycogen granules , and produce a small amount of albumin and \u03b1-fetoprotein , that is enhanced when grown on a collagen gel sponge . Human recombinant GH stimulated JAK2 and STAT5b tyrosine phosphorylation and IGF-I production in a concentration-dependent manner . When the cells were cultured with GH-supplemented medium , the number of mitochondria and glycogen granules increased together with the r-ER and Golgi apparatus . A number of microvilli were observed on the surface of the cultured cells , further suggesting that this cell line is composed of normally functioning hepatocytes . In summary , we established a novel hepatocyte cell line ( SDRL-1 ) , that appears to display normal function , which we propose can serve as a good in vitro model for studying GH-target organ interactions .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21166888"}
{"sentence": "Like all cancers , breast cancer is considered to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss . More recently , CpG island hypermethylation is known to be associated with gene silencing in cancer , and these silenced genes can be reactivated by 5-aza-2'-deoxycytidine ( 5-Aza-CdR ) . Retionoic acid receptor beta 2 gene is a tumor suppressor gene and the chemopreventive effects of retinoids are due to induction of RAR beta 2 . In this study , the effect of 5-Aza-CdR RAR beta 2 restoration was investigated in the MRK-nu-1 human female breast cancer cell line . Changes of the RAR beta 2 methylation status were assessed by methylation-specific PCR . Reverse transcription PCR was used to evaluate RARb beta 2 restoration . Cell cycling and growth inhibition were studied using flow cytometric analysis of DNA content and CellTiter 96 AQueous non-radioactive cell proliferation assay , respectively. 5-Aza-CdR treatment resulted in complete demethylation of the RAR beta 2 gene . RAR beta 2 restoration was accompanied by cell cycle arrest ( increase in the G0/G1- and decrease in the S- and G2/M-phases ) and time-dependent growth inhibition . In conclusion , RAR beta 2 can be activated in vitro by 5-Aza-CdR , which may be one of the mechanisms for the tumor cell growth inhibition by 5-Aza-CdR .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "12529992"}
{"sentence": "Capsaicin , one of the major pungent ingredients found in red peppers , has been recently demonstrated to induce apoptosis in various malignant cell lines through an unclear mechanism . In this study , the effect of capsaicin on proliferation and apoptosis in the human pancreatic cancer cell line PANC-1 and its possible mechanism(s) of action were investigated . The results of a Cell Counting Kit-8 ( CCK-8 ) assay revealed that capsaicin significantly decreased the viability of PANC-1 cells in a dose-dependent manner . Capsaicin induced G0/G1 phase cell cycle arrest and apoptosis in PANC-1 cells as demonstrated by a flow cytometric assessment . Caspase-3 expression at both the protein and mRNA level was promoted following capsaicin treatment . Furthermore , we revealed that phospho-PI3 Kinase p85 ( Tyr458 ) and phospho-Akt ( Ser473 ) in PANC-1 cells were downregulated in response to capsaicin . Moreover , capsaicin gavage significantly inhibited the growth of pancreatic cancer PANC-1 cell xenografts in athymic nude mice . An increased number of TUNEL-positive cells and cleaved caspase-3 were observed in capsaicin-treated mice . In vivo , capsaicin downregulated the expression of phospho-PI3 Kinase p85 ( Tyr458 ) and phospho-Akt ( Ser473 ) . In conclusion , we have demonstrated that capsaicin is an inhibitor of growth of PANC-1 cells , and downregulation of the phosphoinositide 3-kinase/Akt pathway may be involved in capsaicin-induced apoptosis in vitro and in vivo .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23255891"}
{"sentence": "BACKGROUND/AIMS Mesenchymal stem cells ( MSCs ) have been implicated in antitumor therapy for hematopoietic and non-hematopoietic tumors . Cell-contact and soluble factors are demonstrated to play a role in the growth inhibition of tumor cells mediated by MSCs in vitro , while there is little clue about signaling pathways involved in the process . P38 MAPK has been implicated as a suppressor of cell proliferation and tumorigenesis . We here investigate whether p38 MAPK is involved in MSC-induced growth inhibition of leukemic tumor cells . Methods : We characterized the effect of human umbilical cord mesenchymal stem cells ( UC-MSCs ) on proliferation , cell cycle and phosphorylation pattern of p38 MAPK in HL60 and K562 cells . SB203580 , a specific inhibitor of p38 MAPK , or p38 MAPK-small interfering RNA ( siRNA ) , were used to identify the role of p38 in growth suppression by UC-MSCs . We also investigated the expression of cell cycle regulators . RESULTS Treatment with UC-MSCs led to potent proliferation-inhibition of HL60 and K562 cells without inducing apoptosis . Growth inhibition by UC-MSCs was due to G0/G1 arrest . UC-MSCs increased phosphorylation of p38 MAPK in HL60 and K562 cells . Pharmacological inhibition or genetic silencing ( through siRNA ) of p38 MAPK partially abrogated the proliferation-suppression and cell cycle arrest caused by UC-MSCs . UC-MSCs also modulated the expression of cell cycle regulatory proteins in HL60 and K562 cells while SB203580 reversed the effect . CONCLUSION Taken together , our findings indicate that p38 MAPK is critical for the growth inhibitory effect of UC-MSCs on leukemic tumor cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "21220911"}
{"sentence": "Arginine deprivation is a promising strategy for treating ASS-negative malignant tumors including melanoma . However , autophagy can potentially counteract the effectiveness of this treatment by acting as a pro-survival pathway . By combining tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL ) with arginine deprivation using ADI-PEG20 ( pegylated arginine deiminase ) , we achieved enhanced apoptosis and accelerated cell death in melanoma cell lines . This implies a switch from autophagy to apoptosis . In our current investigation , we found that TRAIL could induce the cleavage of two key autophagic proteins , Beclin-1 and Atg5 , in the combination treatment . Using specific inhibitors for individual caspases , we found that caspase-8 inhibitor could completely abolish the cleavage . Furthermore , caspase-8 inhibitor was able to fully reverse the enhanced cytotoxicity induced by TRAIL . Inhibitors for caspase-3 , 6 , 9 , and 10 were able to block the cleavage of these two autophagic proteins to some extent and correspondingly rescue cells from the cytotoxicity of the combination of TRAIL and arginine deprivation . In contrast , calpain inhibitor could not prevent the cleavage of either Beclin-1 or Atg5 , and was unable to prevent cell death . Overall , our data indicate that the cleavage of Beclin-1 and Atg5 by TRAIL-initiated caspase activation is one of the mechanisms that lead to the enhancement of the cytotoxicity in the combination treatment .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23180246"}
{"sentence": "Proliferator-activated receptor gamma ( PPARgamma ) is a nuclear receptor , which mainly associates with adipogenesis , but also appears to facilitate cell differentiation or apoptosis in certain malignant cells . This apoptosis induction by PPARgamma is increased by co-stimulation with tumor necrosis factor ( TNF)-alpha-related apoptosis-inducing ligand ( TRAIL ) , a member of the TNF family . In this study , we investigated the effect of PPARgamma on Fas-mediated apoptosis in hepatocellular carcinoma ( HCC ) cell lines . PPARgamma was expressed on all seven HCC cell lines and located in their nuclei. 15-Deoxy-Delta-12,14-prostaglandin J2 ( 15d- PGJ2 ) , a PPARgamma ligand , inhibited cellular proliferation in HepG2 , SK-Hep1 or HLE cells , unlike pioglitazone , another PPARgamma ligand , which did not have a significant influence on proliferation of these cells . However , 15d-PGJ2 facilitated Fas-mediated HCC apoptosis that could not be induced by Fas alone . These results suggest that PPARgamma can augment TNF-family-induced apoptosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "11914642"}
{"sentence": "Ophiopogonin B ( OP-B ) is a bioactive component of Radix Ophiopogon Japonicus , which is often used in Chinese traditional medicine to treat pulmonary disease . However , whether or not OP-B has any potential antitumor activity has not been reported . Here , we show that the non-small cell lung cancer ( NSCLC ) cell lines NCI-H157 and NCI-H460 treated with OP-B grow more slowly and accumulate vacuoles in their cytoplasm compared to untreated control cells . Flow cytometric analysis showed that the cells were arrested in G0/G1 phase . Nuclear morphology , Annexin-V/PI staining , and expression of cleaved caspase-3 all confirm that OP-B does not induce apoptosis . Instead , based on results from both transmission electron microscopy ( TEM ) and the expression of microtubule-associated protein 1 light chain 3-II ( LC3-II ) , we determined that OP-B treatment induced autophagy in both cell lines . Next , we examined the PI3K/Akt/mTOR signaling pathway and found that OP-B inhibited phosphorylation of Akt(Ser473 , Thr308 ) in NCI-H157 cells and also inhibited several key components of the pathway in NCI-H460 cells , such as p-Akt(Ser473 , Thr308 ) , p-p70S6K ( Thr389 ) . Additionally , insulin-mediated activation of the PI3K/Akt/mTOR pathway provides evidence that activation of this pathway may correlate with induction of autophagy in H460 cells . Therefore , OP-B is a prospective inhibitor of PI3K/Akt and may be used as an alternative compound to treat NSCLC .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23151908"}
{"sentence": "PURPOSE Current antibody-based immunotherapeutic approaches under evaluation for breast carcinoma are limited in target scope . For example , administration of the human epidermal growth factor receptor ( EGFR ) antibody , alone or in combination with a chemotherapeutic drug , is thought to primarily inhibit tumor cell proliferation . The aim of this study was to assess the effects of a combined blockade designed to inhibit tumor growth by inhibition of proliferation rate and the proinflammatory effects of interleukin ( IL ) 8 . EXPERIMENTAL DESIGN A human breast carcinoma cell line that produces high levels of IL-8 was injected s.c. into severe combined immunodeficient mice . IL-8 has been reported to augment the progression of some human tumors ; thus , we used a human IL-8 antibody , ABXIL8 , in combination with anti-EGFR , ABXEGFR , to inhibit the metastasis of MDA231 tumors . RESULTS Whereas anti-IL-8 alone had no appreciable antimetastatic effect , the combination of ABXIL8 significantly enhanced the antitumor effects of ABXEGFR , resulting in greater survival of SCID tumor-bearing mice . This effect on survival was correlated with decreased metastatic spread and decreased tumor size in mice receiving both antibodies . Intriguingly , in vitro studies indicate that this antibody combination markedly inhibited matrix metalloproteinase activity associated with MDA-231 cells to a greater degree than either antibody alone . CONCLUSION Combined administration of these two human antibodies using growth factor blockade in conjunction with chemokine blockade may thus provide a more effective approach for treatment of metastatic human breast carcinoma .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12171898"}
{"sentence": "BACKGROUND Matrix metalloproteinases ( MMP ) are a gene family of zinc enzymes capable of degrading almost all of the extracellular matrix macromolecules in vivo . Their enzymic activities are believed to be responsible for tumor invasion and metastasis . METHODS In this study , using peroxidase-antiperoxidase method , monospecific antisera against MMP-1 ( tissue collagenase ) , MMP-2 ( type IV collagenase/72-kilodalton [ KD ] gelatinase ) , and MMP-3 ( stromelysin ) were applied to 29 squamous cell carcinomas and normal epithelium of the esophagus to identify cells synthesizing and secreting these enzymes . RESULTS Immunoreactivity of MMP-1 , -2 , and -3 was observed in small cancer nests of the deeply invasive or marginal portion of the tumor . Among the 29 patients studied , the presence of at least one MMP was observed in 17 ( 58.6% ) . All three enzymes were observed in six ( 20.6% ) patients , MMP-2 and -3 in five ( 17.2% ) patients , only MMP-2 in three ( 10.3% ) patients , and MMP-3 alone in three ( 10.3% ) patients . There was a good correlation among histologic stage and tumor invasion , lymph node metastasis , and MMP expression . In particular , expression of MMP-2 and -3 was closely related to lymph node metastasis and vascular invasion . CONCLUSIONS These results suggest that MMP , especially MMP-2 and -3 , play an important role in tumor invasion and metastasis and that analysis of MMP-2 and -3 production is useful for evaluation of malignant potential in esophageal carcinoma .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1451050"}
{"sentence": "OBJECTIVE Mutations in GJB2 , encoding connexin 26 ( CX26 ) , are causally related to autosomal recessive form of non-syndromic hearing loss ( NSHL ) at the DFNB1 locus and autosomal dominant NSHL at the DFNA3 locus . In this study , we investigated the prevalence of GJB2 mutations in the Iranian deaf population . METHODS A total of 2322 deaf probands presenting the ethnically diverse Iranian population were screened for variants in GJB2 . All persons were first screened for the c.35delG mutation , as this variant is the most prevalent GJB2-deafness causing mutation in the Iranian population . In all persons carrying zero or one c.35delG allele , exons 1 and 2 were then sequenced . RESULTS In total , 374 ( families segregated GJB2-related deafness caused by 45 different mutations and 5 novel variants . The c.35delG mutation was most commonly identified and accounts for of the GJB2 mutations found in population studied . CONCLUSION Our data also show that there is a gradual decrease in the frequency of the c.35delG mutation and of GJB2-related deafness in general in a cline across Iran extending from the northwest to southeast .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22695344"}
{"sentence": "Calcium ( Ca(2+) ) signals are involved in important checkpoints in cell death pathways and promote both apoptosis and autophagy . However , the relationship between autophagy and apoptosis in response to Ca(2+) level elevation is poorly understood . Here , we provided evidence that the influx of extracellular Ca(2+) triggered by Trichokonin VI ( TK VI ) , an antimicrobial peptide , induced calpain-dependent apoptosis and autophagy in hepatocellular carcinoma ( HCC ) cells . Remarkably , TK VI preferentially induced apoptosis that was associated with calpain-mediated Bax and Atg5 cleavage , which resulted in the collapse of the mitochondrial membrane potential and cytochrome c release . Interestingly , truncated , but not full-length Atg5 , associated with Bcl-xL and promoted the intrinsic pathway . Moreover , TK VI treatment induced reactive oxygen species ( ROS ) accumulation , an effect in which Bak might play a major role . This accumulation of ROS resulted in the subsequent disposal of damaged mitochondria within autophagosomes via Atg5-mediated and mitochondria-selective autophagy . Both the inhibition of calpain activity and Bax deficiency activated a switch that promoted an enhancement of autophagy . The inhibition of both apoptosis and autophagy significantly attenuated the TK VI cytotoxicity , indicating that the two processes had stimulatory effects during TK VI-meditated cell death . These results suggested that calpain , Bak and Atg5 were molecular links between autophagy and apoptosis and revealed novel aspects of the crosstalk between these two processes . The potential of TK VI is proposed as a promising anticancer agent for its well-characterized activity of Ca(2+) agonist and as a possible novel therapeutic strategy that acts on cancer cell mitochondria .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23242420"}
{"sentence": "In Salmonella enterica , the protein acetyltransferase ( Pat ) enzyme is part of the sirtuin-dependent acylation/deacylation system ( SDPADS ) that modulates the activity of several proteins via the acylation of lysine residues critical to their activities . Pat is a kDa protein with two distinct domains , an N-terminal acyl-CoA synthetase ( NDP-forming ) domain ( aa ) and a C-terminal acetyltransferase domain ( aa ) , with homology to proteins of the Gcn5-related N-acetyltransferase ( GNAT ) superfamily . Although the role of the GNAT-like domain is likely responsible for the catalytic activity of Pat , the role of the N-terminal domain remains unclear . Here we report the use of positive selection for identification of residues critical for Pat enzyme activity . This approach revealed seven residues that , when changed , resulted in drastic loss of Pat activity in vitro which caused a discernable loss-of-function phenotype . Five of the seven residues were located in the N-terminal region of Pat and two were located in the GNAT-like domain . Each single-amino-acid variant had a circular dichroism spectrum that differed from that of the wild-type Pat protein , suggesting that loss of enzymatic activity in the mutant proteins was likely due to an inability to acquire its biologically active fold .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22677774"}
{"sentence": "The functions of Rap-1A in oral carcinogenesis are largely unexplored . In this study , we examined the expression of Rap-1A at different malignant stages of oral cavity squamous cell carcinoma ( OCSCC ) . Semiquantitative RT-PCR , quantitative RT-PCR , and Western blotting were used to evaluate Rap-1A mRNA and protein expressions , respectively , in paired OCSCC patient specimens . To determine the possible correlation between Rap-1A expression and various clinical characteristics , 256 samples from patients with OCSCC were evaluated by immunohistochemical staining . Strong Rap-1A expression was a significant prognostic marker and predictor of aggressive OCSCC . The overall and disease-specific 5-year survival rates were significantly correlated with strong expression of Rap-1A ( P < 0.001 ) . Functionally , overexpressed Rap-1A could promote oral cancer cell migration and invasion by Transwell chambers and wound healing assay . Conversely , the suppression of Rap-1A expression using Rap-1A-mediated siRNA was sufficient to decrease cell motility . Furthermore , our data also illustrated that Aurora-A could not only induce mRNA and protein expressions of Rap-1A for enhancing cancer cell motility but also co-localize and form a complex with Rap-1A in the oral cancer cell line . Finally , immunohistochemical staining , indirect immunofluorescence , and Western blotting analysis of human aggressive OCSCC specimens revealed a significantly positive correlation between Rap-1A and Aurora-A expression . Taken together , our results suggest that the Aurora-A/Rap-1A pathway is associated with survival , tumor progression , and metastasis of OCSCC patients .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23219753"}
{"sentence": "Mitochondrial dysfunction and oxidative stress have been implicated in cellular senescence , apoptosis , aging and aging-associated pathologies . Telomere shortening and genomic instability have also been associated with replicative senescence , aging and cancer . Here we show that mitochondrial dysfunction leads to telomere attrition , telomere loss , and chromosome fusion and breakage , accompanied by apoptosis . An antioxidant prevented telomere loss and genomic instability in cells with dysfunctional mitochondria , suggesting that reactive oxygen species are mediators linking mitochondrial dysfunction and genomic instability . Further , nuclear transfer protected genomes from telomere dysfunction and promoted cell survival by reconstitution with functional mitochondria . This work links mitochondrial dysfunction and genomic instability and may provide new therapeutic strategies to combat certain mitochondrial and aging-associated pathologies .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 1], "id": "12882352"}
{"sentence": "Zinc dyshomeostasis can induce cell death . However , the mechanisms involved have not been fully elucidated in prostate cancer ( PCa ) cells , which differ dramatically from normal cells in their zinc handling ability . Here , we studied the effects of the ionophore Zn-pyrithione ( ZP ) and the chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine ( TPEN ) . Both compounds induced cell death at micromolar concentrations when incubated with androgen-dependent ( LNCaP ) , androgen-independent ( PC3 , DU145 ) and androgen-sensitive ( C4-2 ) PCa cell-lines . Compared to PCa cells , RWPE1 prostate epithelial cells were less sensitive to ZP and more sensitive to TPEN , but total cellular zinc levels were changed similarly . ZnSO4 enhanced the toxicity of ZP , but inhibited the effects of TPEN as expected . The morphological/biochemical responses to ZP and TPEN differed . ZP decreased ATP levels and stimulated ERK , AKT and PKC phosphorylation . DNA laddering was observed only at low doses of ZP but all doses of TPEN . TPEN activated caspase 3/7 and induced PARP-cleavage , DNA-fragmentation , ROS-formation and apoptotic bodies . PKC and ERK-pathway inhibitors , and antioxidants protected against ZP-induced but not TPEN-induced death . Inhibitors of MPTP-opening protected both . Cell death in response to TPEN ( but not ZP ) was diminished by a calpain inhibitor and largely prevented by a caspase 3 inhibitor . Overall , the results indicated primarily a necrotic cell death for ZP and an apoptotic cell death for TPEN . The enhanced sensitivity of PCa cells to ZP and the apparent ability of ZP and TPEN to kill quiescent and rapidly dividing cells in a p53-independent manner suggest that ZP/TPEN might be used to develop adjunct treatments for PCa .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22027089"}
{"sentence": "The purpose of the study was to evaluate Sorafenib ( BAY 43-9006 ) derived receptor tyrosine kinase inhibition on tumor progression in murine islet cell tumors . Sorafenib is considered to be a potent inhibitor of tumor angiogenesis and neovascularization in various solid tumors . Rip1Tag2 mice were treated in two different groups according to the model of tumor progression : the early treatment group received vehicle or Sorafenib from 10 to 14 weeks of age and the late treatment group from week 12 until death . Tumor surface , tumor cell proliferation , and apoptosis were measured in both treatment groups to assess the in vivo effects of Sorafenib . Survival was recorded for the late treatment group . In the early treatment group Sorafenib led to a dramatic decrease in tumor volume compared to the control group . Apoptosis was significantly augmented and cell proliferation was inhibited . As a single therapy Sorafenib significantly improved survival in the late treatment group . Conclusion . Sorafenib may provide a new paradigm for the therapy of islet cell tumors .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23346016"}
{"sentence": "OBJECTIVE To evaluate the risk factors for sentinel lymph node metastasis and validate the value of the Memorial Sloan-Kettering Cancer Center nomogram for the prediction of sentinel lymph node metastasis in breast cancer patients . METHODS A sentinel lymph node biopsy database containing 1227 consecutive breast cancer patients ( 416 patients with at least one positive sentinel lymph node ) was retrospectively analyzed . The predictive value of the Memorial Sloan-Kettering Cancer Center nomogram was calculated by the trend line and the area under the receiver-operator characteristic curve . Meanwhile , predictors for sentinel lymph node metastasis were also evaluated . RESULTS Tumor size , histological grade , lymphovascular invasion , mulifocality , estrogen receptor and progesterone receptor status were significant independent predictors for sentinel lymph node metastasis ( all P<0.01 ) . The Memorial Sloan-Kettering Cancer Center nomogram presented an area under the receiver-operator characteristic curve value of 0.730 . Patients with predictive value<16% had a frequency of sentinel lymph node metastasis of 0.9% . Those with values larger than 70% had a frequency of 96.2% . CONCLUSIONS The risk factors for sentinel lymph node metastasis in our study were consistent with those in the Memorial Sloan-Kettering Cancer Center nomogram . The Memorial Sloan-Kettering Cancer Center nomogram is a useful tool that could accurately predict the probability of sentinel lymph node metastasis in our breast cancer patients . Axillary surgical staging might be avoided in patients with a predictive value of <16% and axillary lymph node dissection might be done directly in those with a predictive value >70% , while other patients should still accept sentinel lymph node biopsy .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23100610"}
{"sentence": "Adhesion molecules play an important role in the functioning of the immune system , particularly with regard to cell-cell interactions and antigen presentation . Several adhesion molecules are expressed on Hodgkin's disease-derived cell lines and these are important in their molecular interactions as antigen presenting cells ( APC ) . There are no data regarding the expression of many of these adhesion molecules on Reed-Sternberg cells and its mononuclear variant ( Hodgkin's cells ( HC) ) present in pathological material . To obtain this information we undertook an immunohistological study on material from 18 cases of Hodgkin's disease using a panel of MoAbs to examine the expression of adhesion molecules on HC . The HC were shown to express the integrin beta 1 subfamily molecules , LFA-1 ( CD11a ) and p150,95 ( CD11c ) in high density but lacked CR3 ( CD11b ) . All of the immunoglobulin gene superfamily adhesion molecules studied were present to some degree on HC , with ICAM-2 , in particular , showing moderate to strong expression in most cases . The Hermes antigen CD44 was present in high density but leukosialin ( CD43 ) , another molecule present on diverse leucocyte types , was , in general , not detected on HC . These new data showing that ICAM-1 , ICAM-2 and LFA-3 are , like LFA-1 , expressed on HC emphasize the ability of HC to act as APC . The known adhesion molecule phenotype of the recently defined haematopoietic lineage of human dendritic cells ( DC ) is broadly similar to that of HC , perhaps supporting the hypothesis that some HC represent a malignancy of an APC ( DC ) lineage .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1395091"}
{"sentence": "BACKGROUND DNA-damaging compounds ( e.g. , alkylating agents , cytotoxic antibiotics and DNA topoisomerase poisons ) are the most widely used anticancer drugs . The inability of tumor cells to properly repair some types of DNA damage may explain why specific DNA-damaging drugs can selectively kill tumor cells . Phenylglyoxal is a dicarbonyl compound known to react with guanidine groups such as that of the DNA base guanine , therefore suggesting that phenylglyoxal could induce DNA damage and have anticancer activity . METHODS Cellular DNA damage was measured by the alkaline comet assay and the \\u03b3H2AX focus assay . Formation of topoisomerase I- and topoisomerase II-DNA complexes was assessed by the TARDIS assay , an immunofluorescence technique that employs specific antibodies to DNA topo I or topo II to detect the protein covalently bound to the DNA in individual cells . Cell growth inhibition and cytotoxicity were determined by XTT , MTT and clonogenic assays . Apoptosis was assessed by the Annexin V flow cytometry assay . RESULTS Phenylglyoxal induced cellular DNA damage and formation of high levels of topoisomerase I- and topoisomerase II-DNA complexes in cells . These topoisomerase-DNA complexes were abolished by catalase pretreatment and correlated well with the induction of apoptosis . Phenylglyoxal-induced cell death was partially prevented by catalase pretreatment and was higher in lung cancer cells ( A549 ) than in normal lung fibroblasts ( MRC5 ) . Mammalian cell lines defective in nucleotide excision repair ( NER ) , homologous recombination ( HR ) and non-homologous end joining ( NHEJ ) were more sensitive to phenylglyoxal than parental cells ; this suggests that phenylglyoxal may induce bulky distortions in the shape of the DNA double helix ( which are repaired by the NER pathway ) and DNA double-strand breaks ( which are repaired by HR and NHEJ ) . CONCLUSION This report shows that phenylglyoxal is a new DNA-damaging agent with anticancer activity , and suggests that tumor cells with defects in NER , HR and NHEJ may be hypersensitive to the cytotoxic activity of phenylglyoxal .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "23406762"}
{"sentence": "FMS-like tyrosine kinase 3 ( FLT3 ) normally functions in the survival/proliferation of hematopoietic stem/progenitor cells , but its constitutive activation by internal tandem duplication ( ITD ) mutations correlates with a poor prognosis in AML . The development of FLT3 tyrosine kinase inhibitors ( TKI ) is a promising strategy , but resistance that arises during the course of treatment caused by secondary mutations within the mutated gene itself poses a significant challenge . In an effort to predict FLT3 resistance mutations that might develop in patients , we used saturation mutagenesis of FLT3/ITD followed by selection of transfected cells in FLT3 TKI . We identified F621L , A627P , F691L and Y842C mutations in FLT3/ITD that confer varying levels of resistance to FLT3 TKI . Western blotting confirmed that some FLT3 TKI were ineffective at inhibiting FLT3 autophosphorylation and signaling through MAP kinase , STAT5 and AKT in some mutants . Balb/c mice transplanted with the FLT3/ITD Y842C mutation confirmed resistance to sorafenib in vivo but not to lestaurtinib . These results indicate a growing number of FLT3 mutations that are likely to be encountered in patients . Such knowledge , combined with known remaining sensitivity to other FLT3 TKI , will be important to establish as secondary drug treatments that can be substituted when these mutants are encountered .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "22858906"}
{"sentence": "BACKGROUND Epstein-Barr virus ( EBV ) encodes six nuclear transformation-associated proteins that induce extensive changes in cellular gene expression and signaling and induce B-cell transformation . The role of HIF1A in EBV-induced B-cell immortalization has not been previously studied . METHODS AND FINDINGS Using Western blotting and Q-PCR , we found that HIF1A protein is stabilized in EBV-transformed lymphoblastoid cells . Western blotting , GST pulldown assays , and immunoprecipitation showed that EBV-encoded nuclear antigens EBNA-5 and EBNA-3 bind to prolylhydroxylases 1 and 2 , respectively , thus inhibiting HIF1A hydroxylation and degradation . Immunostaining and Q-PCR showed that the stabilized HIF1A translocates to the nucleus , forms a heterodimer with ARNT , and transactivates several genes involved in aerobic glycolysis . Using biochemical assays and Q-PCR , we also found that lymphoblastoid cells produce high levels of lactate , lactate dehydrogenase and pyruvate . CONCLUSIONS Our data suggest that activation of the aerobic glycolytic pathway , corresponding to the Warburg effect , occurs in EBV-transformed lymphoblastoid cells , in contrast to mitogen-activated B-cells .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "22848707"}
{"sentence": "Focal adhesion kinase ( FAK ) is an important mediator of extracellular matrix integrin signaling , cell motility , cell proliferation and cell survival . Increased FAK expression is observed in a variety of solid human tumors and increased FAK expression and activity frequently correlate with metastatic disease and poor prognosis . Herein we identify miR-7 as a direct regulator of FAK expression. miR-7 expression is decreased in malignant versus normal breast tissue and its expression correlates inversely with metastasis in human breast cancer patients . Forced expression of miR-7 produced increased E-CADHERIN and decreased FIBRONECTIN and VIMENTIN expression in breast cancer cells . The levels of miR-7 expression was positively correlated with E-CADHERIN mRNA and negatively correlated with VIMENTIN mRNA levels in breast cancer samples . Forced expression of miR-7 in aggressive breast cancer cell lines suppressed tumor cell monolayer proliferation , anchorage independent growth , three-dimensional growth in Matrigel , migration and invasion . Conversely , inhibition of miR-7 in the HBL-100 mammary epithelial cell line promoted cell proliferation and anchorage independent growth . Rescue of FAK expression reversed miR-7 suppression of migration and invasion. miR-7 also inhibited primary breast tumor development , local invasion and metastatic colonization of breast cancer xenografts . Thus , miR-7 expression is decreased in metastatic breast cancer , correlates with the level of epithelial differentiation of the tumor and inhibits metastatic progression .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22876288"}
{"sentence": "Background . Multiple myeloma ( MM ) , an almost incurable disease , is the second most common blood cancer . Initial chemotherapeutic treatment could be successful ; however , resistance development urges the use of higher toxic doses accompanied by hematopoietic stem cell transplantation . The establishment of more effective treatments that can overcome or circumvent chemoresistance has become a priority . We recently demonstrated that venom extracted from Walterinnesia aegyptia ( WEV ) either alone or in combination with silica nanoparticles ( WEV+NPs ) mediated the growth arrest and apoptosis of prostate cancer cells . In the present study , we evaluated the impact of WEV alone and WEV+NP on proliferation and apoptosis of MM cells . Methods . The impacts of WEV alone and WEV+NP were monitored in MM cells from 70 diagnosed patients . The influences of WEV and WEV+NP were assessed with flow cytometry analysis . Results . WEV alone and WEV+NP decreased the viability of MM cells . Using a CFSE proliferation assay , we found that WEV+NP strongly inhibited MM cell proliferation . Furthermore , analysis of the cell cycle using the propidium iodide ( PI ) staining method indicated that WEV+NP strongly altered the cell cycle of MM cells and enhanced the induction of apoptosis . Conclusions . Our data reveal the biological effects of WEV and WEV+NP on MM cells that enable these compounds to function as effective treatments for MM .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23304253"}
{"sentence": "During tumorigenesis , cells acquire immortality in association with the development of genomic instability . However , it is still elusive how genomic instability spontaneously generates during the process of tumorigenesis . Here , we show that precancerous DNA lesions induced by oncogene acceleration , which induce situations identical to the initial stages of cancer development , trigger tetraploidy/aneuploidy generation in association with mitotic aberration . Although oncogene acceleration primarily induces DNA replication stress and the resulting lesions in the S phase , these lesions are carried over into the M phase and cause cytokinesis failure and genomic instability . Unlike directly induced DNA double-strand breaks , DNA replication stress-associated lesions are cryptogenic and pass through cell-cycle checkpoints due to limited and ineffective activation of checkpoint factors . Furthermore , since damaged M-phase cells still progress in mitotic steps , these cells result in chromosomal mis-segregation , cytokinesis failure and the resulting tetraploidy generation . Thus , our results reveal a process of genomic instability generation triggered by precancerous DNA replication stress .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "20098673"}
{"sentence": "Fagonia indica is a small spiny shrub of great ethnopharmacological importance in folk medicine . The aqueous decoction of aerial parts is a popular remedy against various skin lesions , including cancer . We used a biological activity-guided fractionation approach to isolate the most potent fraction of the crude extract on three cancer cell lines : MCF-7 oestrogen-dependent breast cancer , MDA-MB-468 oestrogen-independent breast cancer , and Caco-2 colon cancer cells . A series of chromatographic and spectroscopic procedures were utilised on the EtOAc fraction , which resulted in the isolation of a new steroidal saponin glycoside . The cytotoxic activity of the saponin glycoside was determined in cancer cells using the MTT and neutral red uptake assays . After 24h treatment , the observed IC(50) values of the saponin glycoside were 12.5 \u03bcM on MDA-MB-468 and Caco-2 cells , but 100 \u03bcM on MCF-7 cells . Several lines of evidence : PARP cleavage , caspase-3 cleavage , DNA ladder assays , and reversal of growth inhibition with the pan-caspase inhibitor Z-VAD-fmk , suggested stimulation of apoptosis in MDA-MB-468 and Caco-2 cells , but not in MCF-7 cells , which do not express caspase-3 . The haemolytic activity of the saponin glycoside was confirmed in sheep red blood cells , with cell lysis observed at >100 \u03bcM , suggesting that , at this concentration , the saponin glycoside caused necrosis through cell lysis in MCF-7 cells . Using the DNA ladder assay , the saponin glycoside ( 12.5 \u03bcM ) was not toxic to HUVEC ( human umbilical vein endothelial cells ) or U937 cells , indicating some selectivity between malignant and normal cells . We conclude that the steroidal saponin glycoside isolated from F. indica is able to induce apoptosis or necrosis in cancer cells depending on the cell type .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22800968"}
{"sentence": "Although the etiology of primary brain tumors is largely unknown , prior studies suggest that DNA repair polymorphisms may influence risk of glioma . Altered DNA repair is also likely to affect the risk of meningioma and acoustic neuroma , but these tumors have not been well studied . We estimated the risk of glioma ( n = 362 ) , meningioma ( n = 134 ) , and acoustic neuroma ( n = 69 ) in non-Hispanic whites with respect to 36 single nucleotide polymorphisms from 26 genes involved in DNA repair in a hospital-based , case-control study conducted by the National Cancer Institute . We observed significantly increased risk of meningioma with the T variant of GLTSCR1 rs1035938 ( OR(CT/TT) = 3.5 ; 95% confidence interval : 1.8-6.9 ; P(trend) .0006 ) , which persisted after controlling for multiple comparisons ( P = .019 ) . Significantly increased meningioma risk was also observed for the minor allele variants of ERCC4 rs1800067 ( P(trend) .01 ) ; MUTYH rs3219466 ( P(trend) .02 ) , and PCNA rs25406 ( P(trend) .03 ) . The NBN rs1805794 minor allele variant was associated with decreased meningioma risk ( P(trend) .006 ) . Risk of acoustic neuroma was increased for the ERCC2 rs1799793 ( P(trend) .03 ) and ERCC5 rs17655 ( P(trend) .05 ) variants and decreased for the PARP1 rs1136410 ( P(trend) .03 ) . Decreased glioma risk was observed with the XRCC1 rs1799782 variant ( P(trend) .04 ) . Our results suggest that common DNA repair variants may affect the risk of adult brain tumors , especially meningioma .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20150366"}
{"sentence": "We have discovered that 3,3',5-triiodothyronine ( T3 ) inhibits binding of a PIP-box sequence peptide to proliferating cell nuclear antigen ( PCNA ) protein by competing for the same binding site , as evidenced by the co-crystal structure of the PCNA-T3 complex at 2.1 \u212b resolution . Based on this observation , we have designed a novel , non-peptide small molecule PCNA inhibitor , T2 amino alcohol ( T2AA ) , a T3 derivative that lacks thyroid hormone activity . T2AA inhibited interaction of PCNA/PIP-box peptide with an IC(50) of \u03bcm and also PCNA and full-length p21 protein , the tightest PCNA ligand protein known to date . T2AA abolished interaction of PCNA and DNA polymerase \u03b4 in cellular chromatin . De novo DNA synthesis was inhibited by T2AA , and the cells were arrested in S-phase . T2AA inhibited growth of cancer cells with induction of early apoptosis . Concurrently , Chk1 and RPA32 in the chromatin are phosphorylated , suggesting that T2AA causes DNA replication stress by stalling DNA replication forks . T2AA significantly inhibited translesion DNA synthesis on a cisplatin-cross-linked template in cells . When cells were treated with a combination of cisplatin and T2AA , a significant increase in phospho(Ser(139))histone H2AX induction and cell growth inhibition was observed .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22383522"}
{"sentence": "Binding of erythropoietin ( EPO ) to its receptor ( EPOR ) on erythroid cells induces the activation of numerous signal transduction pathways , including the mitogen-activated protein kinase Jun-N-terminal kinase ( JNK ) . In an effort to understand the regulation of EPO-induced proliferation and JNK activation , we have examined the role of potential autocrine factors in the proliferation of the murine erythroleukemia cell line HCD57 . We report here that treatment of these cells with EPO induced the expression and secretion of tumor necrosis factor alpha ( TNF-alpha ) . EPO-dependent proliferation was reduced by the addition of neutralizing antibodies to TNF-alpha , and exogenously added TNF-alpha induced proliferation of HCD57 cells . EPO also could induce TNF-alpha expression in BAF3 and DA3 myeloid cells ectopically expressing EPOR . Addition of TNF-alpha activated JNK in HCD57 cells , and the activity of JNK was partially inhibited by addition of a TNF-alpha neutralizing antibody . Primary human and murine erythroid progenitors expressed TNF-alpha in either an EPO-dependent or constitutive manner . However , TNF-alpha had an inhibitory effect on both immature primary human and murine cells , suggestive that the proliferative effects of TNF-alpha may be limited to erythroleukemic cells . This study suggests a novel role for autocrine TNF-alpha expression in the proliferation of erythroleukemia cells that is distinct from the effect of TNF-alpha in normal erythropoiesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12393629"}
{"sentence": "The tumor suppressor p27(Kip1) is an inhibitor of cyclin/cyclin-dependent kinase ( CDK ) complexes and plays a crucial role in cell cycle regulation . Nevertheless , p27 function in the tumorigenesis of the uterine cervix has been poorly defined . Some phenomenon hints that HPV E7 protein can enhance p27 expression , which is contradictory to HPV E7's property of increasing cell proliferation rate . So , in the present study , we have examined the effect of E7 on p27 expression . Though the levels of p27 are increased after HPV E7 expression , most of the p27 protein localized in the cytoplasm and have no function on cell cycle arrest and contact inhibition . The cell migration rate is elevated when p27 is high expression and located in cytoplasm . The results indicated that E7-p27 interaction not only abolished the p27's cell cycle inhibitory function by sequestering it to the cytoplasm , but also endow the cell with invasive property which is the feature of malignant cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20200484"}
{"sentence": "We describe a severe form of congenital myasthenic syndrome ( CMS ) caused by two heteroallelic mutations : a nonsense and a missense mutation in the gene encoding agrin ( AGRN ) . The identified mutations , Q353X and V1727F , are located at the N-terminal and at the second laminin G-like ( LG2 ) domain of agrin , respectively . A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction ( NMJ ) , including : dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase ; simplification of postsynaptic membranes ; pronounced reduction of the axon terminal size ; widening of the primary synaptic cleft ; and , collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm . Expression studies in heterologous cells revealed that the Q353X mutation abolished expression of full-length agrin . Moreover , the V1727F mutation decreased agrin-induced clustering of the acetylcholine receptor ( AChR ) in cultured C2 muscle cells by >100-fold , and phosphorylation of the MuSK receptor and AChR beta subunit by Surprisingly , the V1727F mutant also displayed increased binding to \\u03b1-dystroglycan but decreased binding to a neural ( z+ ) agrin-specific antibody . Our findings demonstrate that agrin mutations can associate with a severe form of CMS and cause profound distortion of the architecture and function of the NMJ . The impaired ability of V1727F agrin to activate MuSK and cluster AChRs , together with its increased affinity to \\u03b1-dystroglycan , mimics non-neural ( z- ) agrin and are important determinants of the pathogenesis of the disease .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22205389"}
{"sentence": "The androgen receptor ( AR ) plays a central role in prostate cancer progression to the castration-resistant ( CR ) lethal state . L-Dopa decarboxylase ( DDC ) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells , where it may enhance AR activity . Here , we hypothesize that the DDC enzymatic inhibitor , carbidopa , can suppress DDC-coactivation of AR and retard prostate tumor growth . Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen ( PSA ) mRNA levels . Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays . The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells ( stably expressing AR ) . In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated \u223c2-fold in LNCaP xenografts , inducibly overexpressing DDC , were reverted to control levels with carbidopa administration . In castrated mice , treating LNCaP tumors , expressing endogenous DDC , with carbidopa delayed progression to the CR state from 6 to 10 weeks , while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold , respectively . Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors , decrease serum PSA , reduce tumor growth and delay CR progression . Since carbidopa is clinically approved , it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "21780103"}
{"sentence": "Profound disruptions of circadian rhythms and sleep/wake cycles constitute a major cause of institutionalization of AD patients . This study investigated whether a rodent model of AD , APP(NLH/NLH)/PS-1(P264L/264L) ( APPxPS1 ) mice , exhibits circadian alterations . The APPxPS1 mice were generated using CD-1/129 mice and Cre-lox knock-in technology to \" humanize \" the mouse amyloid ( A)\\u03b2 sequence and create a presenilin-1 mutation identified in familial early-onset AD patients . APPxPS1 and WT mice of several ages ( 11 , and 15 months ) were monitored for circadian rhythms in wheel running , cage activity , and sleep:wake behavior . After rhythm assessment , the mice were euthanized at zeitgeber time ( ZT ) 2 or 10 ( i.e. , 2 or 10 h after lights-on ) and brains were dissected . Amyloid\\u03b2 levels were measured in cortical samples and brain sections of the hypothalamus and hippocampus were prepared and used for in situ hybridization of circadian or neuropeptide genes . The most significant effects of the APPxPS1 transgenes were phase delays of h in the onset of daytime wakefulness bouts ( P<0.005 ) and peak wakefulness ( P<0.02 ) , potentially relevant to phase delays previously reported in AD patients . However , genotype did not affect the major activity peaks or phases of wheel running , wake , or general movement , which were bimodal with dominant dawn and dusk activity . Expression of Period 2 in the suprachiasmatic nucleus was affected by ZT ( P<0.0001 ) with a marginal interaction effect of age , genotype , and ZT ( P<0.08 ) . A separate analysis of the old animals indicated a robust interaction between ZT and genotype , as well as main effects of these parameters . Aging also altered sleep ( e.g. , bout length and amount of daytime sleep ) and the amount of wheel running and cage activity . In conclusion , the APPxPS1 knock-in mice exhibit some alterations in their sleep:wake rhythm and clock gene expression , but do not show robust , genotype-related changes in activity rhythms . The prominent daytime activity peaks shown by the background strain complicate the use of these APPxPS1 knock-in mice for investigations of circadian activity rhythms in AD . In addition to this unusual activity pattern , lack of hyperactivity differentiates the APPxPS1 knock-in mice from other transgenic AD models .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22634208"}
{"sentence": "Piceatannol has potent anti-inflammatory , immunomodulatory , anticancer and antiproliferative effects . However , little is known about the mechanism by which piceatannol inhibits invasion and metastasis . The aim of the current study was to investigate the effects of piceatannol on the expression of matrix metalloproteinase-9 ( MMP-9 ) in DU145 human prostate cancer cells . The results revealed that MMP-9 activity was significantly increased in response to tumor necrosis factor-\\u03b1 ( TNF-\\u03b1 ) . However , treatment with piceatannol reversed TNF-\\u03b1- and MMP-9-induced gelatin zymography and its gene expression . In addition , a Matrigel invasion assay determined that piceatannol reduces the TNF-\\u03b1-induced invasion of DU145 cells . Nuclear factor-\\u03ba B ( NF-\\u03baB ) is a significant transcription factor that regulates numerous genes involved in tumor cell invasion and metastasis . Therefore , whether piceatannol acts on NF-\\u03baB to regulate MMP-9 gene expression was analyzed . The results revealed that piceatannol attenuates MMP-9 gene expression via the suppression of NF-\\u03baB activity . Using a specific NF-\\u03baB inhibitor , pyrrolidine dithiocarbamate , it was confirmed that TNF-\\u03b1-induced MMP-9 gene expression is primarily regulated by NF-\\u03baB activation . Piceatannol inhibited NF-\\u03baB activity by suppressing nuclear translocation of the NF-\\u03baB p65 and p50 subunits . Furthermore , TNF-\\u03b1-induced Akt phosphorylation was significantly downregulated in the presence of piceatannol . The Akt inhibitor LY294002 caused a significant decrease in TNF-\\u03b1-induced NF-\\u03baB activity and MMP-9 gene expression . Overall , these data suggest that piceatannol inhibits TNF-\\u03b1-induced invasion by suppression of MMP-9 activation via the Akt-mediated NF-\\u03baB pathway in DU145 prostate cancer cells .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23255946"}
{"sentence": "Regulation of poly(ADP-ribose) ( PAR ) synthesis and turnover is critical to determining cell fate after genotoxic stress . Hyperactivation of PAR synthesis by poly(ADP-ribose) polymerase-1 ( PARP-1 ) occurs when cells deficient in DNA repair are exposed to genotoxic agents ; however , the function of this hyperactivation has not been adequately explained . Here , we examine PAR synthesis in mouse fibroblasts deficient in the base excision repair enzyme DNA polymerase \\u03b2 ( pol \\u03b2 ) . The extent and duration of PARP-1 activation was measured after exposure to either the DNA alkylating agent , methyl methanesulfonate ( MMS ) , or to low energy laser-induced DNA damage . There was strong DNA damage-induced hyperactivation of PARP-1 in pol \\u03b2 nullcells , but not in wild-type cells . In the case of MMS treatment , PAR synthesis did not lead to cell death in the pol \\u03b2 null cells , but instead resulted in increased PARylation of the nonhomologous end-joining ( NHEJ ) protein Ku70 and increased association of Ku70 with PARP-1 . Inhibition of the NHEJ factor DNA-PK , under conditions of MMS-induced PARP-1 hyperactivation , enhanced necrotic cell death . These data suggest that PARP-1 hyperactivation is a protective mechanism triggering the classical-NHEJ DNA repair pathway when the primary alkylated base damage repair pathway is compromised .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "23145148"}
{"sentence": "To investigate the molecular mechanisms underlying altered T cell response in renal cell carcinoma ( RCC ) patients , we compared autologous and allogeneic CD8(+) T cell responses against RCC line from RCC patients and their HLA-matched donors , using mixed lymphocyte/tumor cell cultures ( MLTCs ) . In addition , we analyzed the expression of molecules associated with cell cycle regulation . Autologous MLTC responder CD8(+) T cells showed cytotoxic activity against RCC cell lines ; however the analysis of the distribution of CD8(+) T-cell subsets revealed that allogenic counterparts mediate superior antitumor efficacy . In RCC patients , a decreased proliferative response to tumor , associated with defects in JAK3/STAT5/6 expression that led to increased p27KIP1 expression and alterations in the cell cycle , was observed . These data define a molecular pathway involved in cell cycle regulation that is associated with the dysfunction of tumor-specific CD8(+) effector cells . If validated , this may define a therapeutic target in the setting of patients with RCC .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20339477"}
{"sentence": "INTRODUCTION Astrocytic gliomas are the most common intracranial central nervous system neoplasias , accounting for about 60% of all primary central nervous system tumors . Despite advances in the treatment of gliomas , no effective therapeutic approach is yet available ; hence , the search for a more realistic model to generate more effective therapies is essential . OBJECTIVE To develop an experimental malignant astrocytoma model with the characteristics of the human tumor . METHOD Primary cells from subcutaneous xenograft tumors produced with malignant astrocytoma U87MG cells were inoculated intracerebrally by stereotaxis into immunosuppressed ( athymic ) Rowett rats . RESULTS All four injected animals developed non-infiltrative tumors , although other glioblastoma characteristics , such as necrosis , pseudopalisading cells and intense mitotic activity , were observed . CONCLUSION A malignant astrocytoma intracerebral xenograft model with poorly invasive behavior was achieved in athymic Rowett rats . Tumor invasiveness in an experimental animal model may depend on a combination of several factors , including the cell line used to induce tumor formation , the rat strains and the status of the animal's immune system .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20360922"}
{"sentence": "Cell kinetics and activity of ornithine decarboxylase ( ODC ) were studied during the process of 1-hydroxyanthraquinone ( 1-HA)-induced intestinal carcinogenesis in rats . Starting at 6 weeks of age , a total of 37 male ACI/N rats were divided into two groups and treated as follows : group I ( 18 rats ) received diet containing 1% 1-HA for 12 months ; group II ( 19 rats ) was given the basal diet alone . Sub-groups of 5-7 rats were sequentially killed at 4 , 8 and 12 months for evaluation of the length , cell numbers and 5-bromo-2'-deoxyuridine ( BrDU ) labeling indices of large bowel crypts together with ODC activity . All kinetic and ODC data indicated increased DNA synthesis and proliferation at all time points . Morphological observation of the intestines also revealed melanosis , crypt abscesses and erosion , becoming more pronounced with length of exposure to the anthraquinone . The data thus suggest that cell proliferation in the crypts of the cecum or colon is important for 1-HA-induced intestinal carcinogenesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1473227"}
{"sentence": "Caveolin-1 ( -/- ) null stromal cells are a novel genetic model for cancer-associated fibroblasts and myofibroblasts . Here , we used an unbiased informatics analysis of transcriptional gene profiling to show that Cav-1 ( -/- ) bone-marrow derived stromal cells bear a striking resemblance to the activated tumor stroma of human breast cancers . More specifically , the transcriptional profiles of Cav-1 ( -/- ) stromal cells were most closely related to the primary tumor stroma of breast cancer patients that had undergone lymph-node ( LN ) metastasis . This is consistent with previous morphological data demonstrating that a loss of stromal Cav-1 protein ( by immuno-histochemical staining in the fibroblast compartment ) is significantly associated with increased LN-metastasis . We also provide evidence that the tumor stroma of human breast cancers shows a transcriptional shift towards oxidative stress , DNA damage/repair , inflammation , hypoxia , and aerobic glycolysis , consistent with the \" Reverse Warburg Effect \" . Finally , the tumor stroma of \" metastasis-prone \" breast cancer patients was most closely related to the transcriptional profiles derived from the brains of patients with Alzheimer's disease . This suggests that certain fundamental biological processes are common to both an activated tumor stroma and neuro-degenerative stress . These processes may include oxidative stress , NO over-production ( peroxynitrite formation ) , inflammation , hypoxia , and mitochondrial dysfunction , which are thought to occur in Alzheimer?s disease pathology . Thus , a loss of Cav-1 expression in cancer-associated myofibroblasts may be a protein biomarker for oxidative stress , aerobic glycolysis , and inflammation , driving the \" Reverse Warburg Effect \" in the tumor micro-environment and cancer cell metastasis .", "label": [0, 0, 1, 0, 0, 1, 0, 0, 0, 1], "id": "20442453"}
{"sentence": "The ALKBH family of proteins are highly expressed in various types of human cancer where they are involved in tumor growth and progression . However , multiple isoforms of ALKBH exist and the effect of individual isoforms on the development of urinary bladder cancer is unknown , particularly the molecular mechanisms involved in the progression from a noninvasive to invasive phenotype . We examined the role and function of ALKBH2 in human bladder cancer development in vitro and provide the first report that suppression of ALKBH2 in a human urothelial carcinoma cell line , KU7 , reduced the expression of the transmembrane mucin protein , MUC1 , and induced G1 cell cycle arrest . Moreover , reduction of ALKBH2 suppressed epithelial to mesenchymal transition ( EMT ) via increasing E-cadherin and decreasing vimentin expression . Transfection of MUC1 siRNA inhibited cell proliferation and EMT to the same extent as ALKBH2 gene silencing in vitro . ALKBH2 knockdown significantly suppressed MUC1 expression and tumor volume of bladder cancers in vivo as assessed in an orthotopic mouse model using ALKBH2 shRNA transfected KU7 cells . Immunohistochemical examination showed high expression levels of ALKBH2 in human urothelial carcinoma samples , especially in high-grade , superficially and deeply invasive carcinomas ( pT(1) and >pT(2) ) , and in carcinoma in situ but not in normal urothelium . This study demonstrates that ALKBH2 is an upstream molecule of the oncoprotein , MUC1 , and regulates cell cycle and EMT , resulting in progression of urothelial carcinomas .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23279696"}
{"sentence": "Twelve postmenopausal women ( 54-93 years ) with primary breast carcinoma were treated with tamoxifen due to infirmity or refusal to undergo surgery . Seven premenopausal patients ( 32-50 years ) were given preoperative chemotherapy because of large tumors or inflammatory carcinoma . Fine-needle aspiration biopsy was used to procure tumor cells for diagnosis , hormone receptor determination and analysis of proliferation fraction . Aspirations were repeated every 3 months in the tamoxifen group and each month in patients receiving chemotherapy . Two patients who responded to tamoxifen had tumors with more than 75% estrogen receptor positive cells . A decreased proliferation fraction was observed in two tumors responding to tamoxifen . Eight patients , all with estrogen receptor positive tumors , had stable disease . Progressive disease was observed in two patients with less than 25% receptor positive cells . In these tumors the percentage of proliferating cells remained high during therapy . Objective response was recorded for six patients treated with chemotherapy . The clinical response was reflected in a decreased proliferation fraction . No correlation was observed between response and percentage of proliferating cells in the untreated tumor . The results suggest that analysis of tumor cell characteristics such as hormone receptor content and proliferation fraction can be used to predict and monitor response to endocrine treatment and chemotherapy in breast carcinomas .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1622628"}
{"sentence": "Angiogenesis is increased in hematologic malignancies , including non-Hodgkin lymphoma ( NHL ) . Elevated serum levels of two important angiogenic factors , vascular endothelial growth factor ( VEGF ) and basic fibroblast growth factor ( bFGF ) , are associated with a poor prognosis . Immunohistochemistry was used to evaluate 27 patients with NHL and bone marrow involvement ( 17 with low-grade B-cell NHL , including 7 with higher grade transformation ; 6 with intermediate-grade B-cell NHL ; and 4 with T-cell lymphoma ) . Among the 17 patients with low-grade B-cell NHL , results for 7 were positive for VEGF stain ( 41.2% ) , and results were negative for all other stains for VEGF receptors , bFGF , and bFGF receptors . In the 10 patients with intermediate-grade B-cell NHL and T-cell lymphoma , all VEGF staining was positive ( 100% ) , but bFGF staining was only weakly positive in 2 . Staining results for seven patients who had low-grade B-cell NHL with higher grade transformation showed that VEGF staining was positive in large lymphoid cells of 5 patients and in small lymphoid cells of one patient . Staining for the receptors VEGFR-1 and VEGFR-2 was positive in large lymphoid cells in four and two cases , respectively . Staining for bFGF was positive in two cases of large lymphoid cells . We concluded that VEGF , but not bFGF , was associated with higher tumor grading of NHL and high-grade transformation of low-grade lymphoma .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12607599"}
{"sentence": "Recently , our group reported the discovery of three new withanolides , physangulidines A-C , from Physalis angulata . In this study , the biological effects of physangulidine A ( 1 ) , which was the most active and abundant of the three new constituents , are described . It was found that 1 significantly reduces survival in clonogenic assays for two hormone-independent prostate cancer cell lines . Flow cytometry and confocal microscopy studies in DU145 human prostate cancer cells indicated that 1 induces cell cycle arrest in the G(2)/M phase and causes defective mitosis . It was determined also that 1 produces programed cell death by apoptosis , as evidenced by biochemical markers and distinct changes in cell morphology . These results imply that the antimitotic and proapoptotic effects of 1 may contribute significantly to the biological activities and potential medicinal properties of its plant of origin .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23270478"}
{"sentence": "Cancer cells preferentially metabolize glucose by aerobic glycolysis , characterized by increased lactate production . This distinctive metabolism involves expression of the embryonic M2 isozyme of pyruvate kinase , in contrast to the M1 isozyme normally expressed in differentiated cells , and it confers a proliferative advantage to tumor cells . The M1 and M2 pyruvate-kinase isozymes are expressed from a single gene through alternative splicing of a pair of mutually exclusive exons . We measured the expression of M1 and M2 mRNA and protein isoforms in mouse tissues , tumor cell lines , and during terminal differentiation of muscle cells , and show that alternative splicing regulation is sufficient to account for the levels of expressed protein isoforms . We further show that the M1-specific exon is actively repressed in cancer-cell lines--although some M1 mRNA is expressed in cell lines derived from brain tumors--and demonstrate that the related splicing repressors hnRNP A1 and A2 , as well as the polypyrimidine-tract-binding protein PTB , contribute to this control . Downregulation of these splicing repressors in cancer-cell lines using shRNAs rescues M1 isoform expression and decreases the extent of lactate production . These findings extend the links between alternative splicing and cancer , and begin to define some of the factors responsible for the switch to aerobic glycolysis .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20133837"}
{"sentence": "AIMS Treatment decisions are difficult in clinically localised prostate cancer and further biomarkers of aggressive behaviour are required . We investigated the hypothesis that the tissue expression of three cell cycle markers , Rb , p21 and p16 , would provide helpful prognostic information in a well characterised series of prostate cancers which were clinically localised and treated conservatively . METHODS The immunohistochemical staining expression of these markers was assessed in tissue microarrays and correlated with 10 year prostate cancer survival and overall survival and then compared with pathological data including contemporary Gleason score , age , measures of tumour extent and initial serum prostate specific antigen ( PSA ) level . RESULTS Rb overexpression did not show any significant association with Gleason score or prostate cancer survival. p21 protein expression showed a significant association with prostate cancer survival ( p\u2009=\u20090.02 ) and overall survival ( p\u2009=\u20090.01 ) in a univariate model but not in a multivariate model with pathological and serum PSA data . There was a significant association between p16 cytoplasmic expression and prostate cancer survival ( HR\u2009=\u20092.52 , 95%CI\u2009= 1.79-3.55 , p\u2009<\u20090.001 ) and overall survival ( HR\u2009= 1.54 , 95% CI\u2009=\u20091.20-1.98 , p\u2009=\u20090.001 ) in a univariate model. p16 expression remained an independent prognostic factor for prostate cancer survival ( HR\u2009=\u20091.50 , 95%CI\u2009=\u20091.05-2.14 , p\u2009=\u20090.03 ) . CONCLUSION We conclude that p16 cytoplasmic expression can be used as a predictor of outcome in conservatively treated prostate cancer . Rb and p21 show no independent association with outcome and therefore further research is not warranted .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20854069"}
{"sentence": "The in vitro immortalization of primary human mammary epithelial ( HME ) cells solely by the exogenous introduction of the catalytic subunit of human telomerase ( hTERT ) has been achieved . Early passage hTERT-transfected HME ( T-HME ) cells continuously decreased the length and density of telomeres even in the presence of telomerase activity , with a significant number of cells staining positive for senescence-associated beta-galactosidase ( SA-beta-gal ) . Subsequently , with the increase in cell passages , the copy number of the exogenously transfected hTERT gene and the percentage of SA-beta-gal positive cells were found to decrease . Eventually , a single copy of the exogenous hTERT gene was observed in the relatively later passage T-HME cells in which telomere length was elongated and stabilized without obvious activation of endogenous hTERT and c-Myc expression . In T-HME cells , the expression of two p53 regulated genes p21(WAF) and HDM2 increased ( as in primary senescent HME cells ) , and was found to be further elevated as the function of p53 was activated by treatment with DNA-damaging agents. p16(INK4a) was shown to be significantly higher in the primary senescent HME and the early passage T-HME cells when compared with the primary presenescent HME cells , with a dramatic repression of p16(INK4a) observed in the later passage T-HME cells . In addition , the expression of E2F1 and its transcription factor activity were found to be significantly higher in the later passage T-HME cells when compared with the earlier passage T-HME cells . Together , our results indicate that in vitro immortalization in HME cells may require the activation of the function of telomerase and other genetic alterations such as the spontaneous loss of p16(INK4a) expression .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "11978176"}
{"sentence": "Cancer cells require glucose to support their rapid growth through a process known as aerobic glycolysis , or the Warburg effect . As in ovarian cancer cells , increased metabolic activity and glucose concentration has been linked to aggressiveness of cancer . However , it is unclear as to whether targeting the glycolytic pathway may kill the malignant cells and likely have broad therapeutic implications against ovarian cancer metastasis . In the present research , we found that EF24 , a HIF-1\\u03b1 inhibitor , could significantly block glucose uptake , the rate of glycolysis , and lactate production compared with vehicle treatment in SKOV-3 , A2780 and OVCAR-3 cells . These results might possibly contribute to the further observation that EF24 could inhibit ovarian cancer cell migration and invasion from wound healing and Transwell assays . Furthermore , as an important mediator of glucose metabolism , glucose transporter 1 ( Glut1 ) was found to contribute to the function of EF24 in both energy metabolism and metastasis . To examine the effect of EF24 and the mediated role of Glut1 in vivo in a xenograph subcutaneous tumor model , intraperitoneal metastasis and lung metastasis model were introduced . Our results indicated that EF24 treatment could inhibit tumor growth , intraperitoneal metastasis and lung metastasis of SKOV-3 cells , and Glut1 is a possible mediator for the role of EF24 . In conclusion , our results highlight that an anti-cancer reagent with an inhibiting effect on energy metabolism could inhibit metastasis , and EF24 is a possible candidate for anti-metastasis therapeutic applications for ovarian cancer .", "label": [1, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "24112101"}
{"sentence": "Androgen deprivation is currently a standard-of-care , first-line therapy for prostate cancer in the United States . Although this regimen effectively regresses androgen-dependent disease , relapse often occurs in an androgen-independent manner and is associated with poor prognosis . Such castration-resistant prostate cancer represents a major clinical challenge , and the mechanisms underlying castration resistance are not fully understood . Epithelial-mesenchymal transition ( EMT ) is a key developmental process and has also been implicated in cancer metastasis and therapeutic resistance in recent years . However , the factors contributing to EMT in human cancers remain unclear . Here , we show that both normal mouse prostate tissue and human LuCaP35 prostate tumor explants display an EMT as well as increased stem cell-like features following androgen deprivation . Importantly , we observed similar changes in mesenchymal features in prostate tumors from patients treated with androgen-deprivation therapy . In addition , we have delineated a feedback loop involving the androgen receptor and the Zeb1 transcription factor that seems to mediate this transition . In summary , we show for the first time that androgen deprivation induces EMT in both normal prostate and prostate cancer , revealing a potentially important consequence of a standard-of-care treatment for prostate cancer . This finding could have significant implications for second-line treatment strategies in this clinical setting .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22108827"}
{"sentence": "Cancer cells have elevated aerobic glycolysis that is termed the Warburg effect . But several tumor cells , including leukemic cells , also increase glutamine metabolism , which is initiated by glutaminase ( GLS ) . The microRNA ( miRNA ) miR-23 targets GLS mRNA and inhibits expression of GLS protein . Here we show that in human leukemic Jurkat cells the NF-\u03baB p65 subunit binds to miR-23a promoter and inhibits miR-23a expression . Histone deacetylase ( HDAC ) inhibitors release p65-induced inhibition . Jurkat cells growing in glutamine decrease proliferation due to cell accumulation in G0/G1 phase . Nevertheless , cells get used to this new source of energy by increasing GLS expression , which correlates with an increase in p65 expression and its translocation to the nucleus , leading to a higher basal NF-\u03baB activity . Jurkat cells overexpressing p65 show increase basal GLS expression and proliferate faster than control cells in glutamine medium . Overexpressing miR-23a in leukemic cells impaired glutamine use and induces mitochondrial dysfunction leading to cell death . Therefore , p65 activation decreases miR-23a expression , which facilitates glutamine consumption allowing leukemic cells to use this alternative source of carbon and favoring their adaptation to the metabolic environment .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 1, 0], "id": "22634383"}
{"sentence": "During papillomavirus infection , the E5 protein localizes in the cell Golgi apparatus and other endomembrane compartments . Cells transformed by E5 do not express major histocompatibility class I complex ( MHC I ) on the cell surface , while cells transformed by the other transforming proteins E6 and E7 do . In addition , the total amount of both MHC I protein and mRNA is reduced in E5-transformed cells . Here we show that expression of bovine papillomavirus E5 causes the retention of MHC I in the Golgi apparatus , thus preventing its transport to the cell surface . We ascribe this effect to a failure of acidification of the Golgi apparatus , as similar effects are observed in control cells treated with the ionophore monensin . Treatment of E5-transformed cells with either beta- or gamma-interferon increases the synthesis of MHC I , showing that inhibition of MHC I expression by E5 is not irreversible . However , even after interferon treatment , MHC I , although increased in quantity , is not transported to the cell surface . E5 therefore affects MHC I at several levels , but prevention of MHC I transport to the cell surface appears to be the dominant effect . Lack of surface MHC I would have profound consequences for presentation of viral peptides to the immune system .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12420217"}
{"sentence": "Human carcinomas are defined by recurrent chromosomal aneuploidies , which result in a tissue-specific distribution of genomic imbalances . In order to develop models for these genome mutations and to determine their role in tumorigenesis , we generated 45 spontaneously transformed murine cell lines from normal epithelial cells derived from bladder , cervix , colon , kidney , lung , and mammary gland . Phenotypic changes , chromosomal aberrations , centrosome number , and telomerase activity were assayed in control uncultured cells and in three subsequent stages of transformation . Supernumerary centrosomes , binucleate cells , and tetraploidy were observed as early as 48 hr after explantation . In addition , telomerase activity increased throughout progression . Live-cell imaging revealed that failure of cytokinesis , not cell fusion , promoted genome duplication . Spectral karyotyping demonstrated that aneuploidy preceded immortalization , consisting predominantly of whole chromosome losses ( 4 , 9 , 12 , 13 , 16 , and Y ) and gains ( 1 , 10 , 15 , and 19 ) . After transformation , focal amplifications of the oncogenes Myc and Mdm2 were frequently detected . Fifty percent of the transformed lines resulted in tumors on injection into immunocompromised mice . The phenotypic and genomic alterations observed in spontaneously transformed murine epithelial cells recapitulated the aberration pattern observed during human carcinogenesis . The dominant aberration of these cell lines was the presence of specific chromosomal aneuploidies . We propose that our newly derived cancer models will be useful tools to dissect the sequential steps of genome mutations during malignant transformation , and also to identify cancer-specific genes , signaling pathways , and the role of chromosomal instability in this process .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "22161874"}
{"sentence": "The ability of p53 to alter , at the transcriptional level , the gene expression of downstream targets is critical for its role as a tumor suppressor . Most models of p53 activation postulate the stepwise recruitment by p53 of coactivators , histone acetyltransferases , and/or chromatin remodeling factors to a promoter region to facilitate the subsequent access of the general transcriptional machinery required for transcriptional induction . We demonstrate here , however , that the promoter regions for the p53 target genes , p21 , 14-3-3sigma , and KARP-1 , exist in a constitutively open conformation that is readily accessible to DNase I. This conformation was not altered by DNA damage or by whether p53 was present or absent in the cell . In contrast , p53 response elements , which resided outside the immediate promoter regions , existed within DNase I-resistant chromatin domains . Thus , p53 activation of downstream target genes occurs without p53 inducing chromatin alterations detectable by DNase I accessibility at either the promoter or the response element . As such , these data support models of p53 activation that do not require extensive chromatin alterations to support cognate gene expression .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12475992"}
{"sentence": "Diets rich in fruits and vegetables are associated with lower risk of cancer which may be conferred in part by the antioxidant properties of these foods . However , antioxidant supplementation or increased consumption of antioxidant-rich foods has been reported to have inconsistent effects on DNA damage . The present work ( the DART study ) investigated the extent of inter-individual variation in DNA damage , the capacity for base excision repair ( BER ) and the responses of both variables to supplementation with an antioxidant supplement for 6 weeks . There was a wide inter-individual variation in endogenous lymphocyte DNA strand breaks ( 8-fold variation ) , in damage after a challenge with H2O2 ( 16-fold variation ) and in DNA repair ( 41-fold variation ) measured using the comet assay . When stratified into tertiles according to the pre-supplementation level of endogenous DNA damage , there was a statistically significant decrease in DNA damage after supplementation in the tertile with the highest pre-supplementation level of damage . There was no effect of supplementation on BER . Endogenous DNA damage level before supplementation was significantly different ( P = 0.037 ) between the three genotypes for the Val16Ala single nucleotide polymorphism in manganese superoxide dismutase ( rs4880 ) with individuals homozygous/wild type showing less damage than those carrying the alanine variant .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20082738"}
{"sentence": "Hypoxia\u2013reoxygenation ( HR ) is a primary driver of angiogenesis in both atherogenesis and tumorigenesis . The main target of hypoxia-driven proangiogenic signaling is adherens junctions responsible for contact inhibition of endothelial cells . We analyzed the effects of hypoxia ( 8\u201312 hours ) followed by a brief period of reoxygenation ( 2 hours ) ( HR ) on angiogenesis and integrity of adherens junction in cultured human umbilical vein endothelial cells as well as the effects of aspirin on modulation of human umbilical vein endothelial cells ' response to HR . Cells exposed to HR displayed considerable enhancement of tube formation ( angiogenesis ) on matrigel . Immunocytostaining of near-confluent cells revealed that HR caused disruption of adherens junctions and internalization of their components VE-cadherin , p120 catenin , and b-catenin . Additionally , HR resulted in the appearance of binucleated cells , and VE-cadherin in colocalization with b-catenin was found to be positioned between the separating nuclei . Presence of aspirin ( acetylsalicylic acid , 1 mM ) resulted in preservation of adherens junctions on the cellular membrane and prevented angiogenesis as well as mitosis . HR caused upregulation LOX-1 , the p47(phox) subunit of NADPH , while reducing transcription of endothelial nitric oxide synthase . Aspirin had no effect on endothelial nitric oxide synthase and canceled the transcriptional activation of the LOX-1 and p47(phox) subunit of NADPH oxidase . Based on these data , we hypothesize that aspirin preserves the integrity of adherens junctions and thus blunts angiogenic response to HR through downregulation of LOX-1 and the LOX-1-mediated p47(phox) component of NADPH oxidase transcription , thus preventing NADPH oxidase assembly and function .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "20881612"}
{"sentence": "The glycolytic phenotype is a widespread phenomenon in solid cancer forms , including breast cancer . Dichloroacetate ( DCA ) has recently been proposed as a novel and relatively non-toxic anti-cancer agent that can reverse the glycolytic phenotype in cancer cells through the inhibition of pyruvate dehydrogenase kinase . We have examined the effect of DCA against breast cancer cells , including in a highly metastatic in vivo model . The growth of several breast cancer cell lines was found to be inhibited by DCA in vitro . Further examination of 13762 MAT rat mammary adenocarcinoma cells found that reversal of the glycolytic phenotype by DCA correlated with the inhibition of proliferation without any increase in cell death . This was despite a small but significant increase in caspase 3/7 activity , which may sensitize cancer cells to other apoptotic triggers . In vivo , DCA caused a 58% reduction in the number of lung metastases observed macroscopically after injection of 13762 MAT cells into the tail vein of rats ( P = 0.0001 , n > or = 9 per group ) . These results demonstrate that DCA has anti-proliferative properties in addition to pro-apoptotic properties , and can be effective against highly metastatic disease in vivo , highlighting its potential for clinical use .", "label": [1, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "19543830"}
{"sentence": "We have modelled multiple stages of malignant transformation of human endothelial cells ( ECs ) by overexpressing the catalytic subunit of human telomerase ( hTERT ) , together with SV40 T antigen ( SV40T ) and oncogenic N-ras . Transfection with hTERT alone , led to the immortalization of two out of three cultures of bone marrow-derived ECs ( BMECs ) . One hTERT transduced BMEC culture underwent a long proliferative lag before resuming proliferation . BMECs transfected with hTERT alone were functionally and phenotypically normal . BMECs transfected with SV40T ( BMSVTs ) had an extended lifespan , but eventually succumbed to crisis . BMSVTs exhibited a partially transformed phenotype , demonstrating growth factor independence , altered antigen expression and forming tiny , infrequent colonies in vitro . Transduction of BMSVTs with hTERT resulted in immortalization of 4 out of 4 cultures . BMSVTs immortalized with hTERT formed large colonies in vitro and small transient tumours in vivo . BMECs co-expressing SV40T , hTERT and N-ras exhibited an overtly transformed phenotype ; forming very large colonies with an altered morphology and generating rapidly growing tumours in vivo . These investigations demonstrate transformation of human ECs to an overtly malignant phenotype . This model will be useful for understanding mechanisms underlying vascular and angiogenic neoplasias , as well as for testing drugs designed to curtail aberrant EC growth .", "label": [0, 0, 0, 1, 0, 0, 1, 0, 1, 0], "id": "12082607"}
{"sentence": "OBJECTIVE Although downregulation of neural cell adhesion molecule ( NCAM ) has been correlated with poor prognosis in colorectal cancer ( CRC ) , it is also possible that colon cancer spreading comes from reducing tumor cell adhesion through NCAM polysialylation , as occurs in lung carcinoma or Wilms ' tumor . METHODS To prove this hypothesis , we have performed a prospective study on tumor and control specimens from 39 CRC patients , which were immunostained for NCAM and PSA ( polysialic acid ) expression . RESULTS Tumor versus control expression of NCAM and PSA epitopes in tissue specimens , as well as correlation between tumor expression and clinicopathological features , were statistically analyzed . Results showed a low constitutive expression of NCAM and PSA ( PSA-NCAM ) in control tissue , which reached a statistically significant increase in the tumor tissue . Likewise , the presence and number of lymph node metastases at surgery were correlated with NCAM expression and PSA/NCAM coexpression . CONCLUSIONS These data highlight the importance of taking into account PSA-associated epitopes when dealing with NCAM cell expression studies in tumor development and progression . The analysis of PSA and NCAM expression in CRC suggests a new way , other than downregulation of NCAM , in order to escape contact inhibition and promote cell tumor spreading in colorectal cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20414008"}
{"sentence": "Manipulating acetylation status of key gene targets is likely to be crucial for effective cancer therapy . In this study , we utilized green tea catechins , epicatechin ( EC ) , epigallocatechin ( EGC ) and epigallocatechin-3-gallate ( EGCG ) to examine the regulation of androgen receptor acetylation in androgen-dependent prostate cancer cells by histone acetyl-transferase ( HAT ) activity . EC , EGC and EGCG induced prostate cancer cell death , suppressed agonist-dependent androgen receptor ( AR ) activation and AR-regulated gene transcription . These results demonstrated a similar tendency to HAT inhibitory activities ; EGCG>EGC>EC . The strongest HAT inhibitor among them , EGCG ( 50 \ufffdM ) , downregulated AR acetylation and finally , AR protein translocation to nucleus from the cytoplasmic compartment was effectively inhibited in the presence of the agonist . These results suggest another mechanism to develop effective therapeutics based on green tea catechins .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22505206"}
{"sentence": "The aim of this study was to address whether there is a fundamental difference in regulation of histone gene expression in cells that have become quiescent but retain the ability to proliferate , compared with those cells that have differentiated . We compared multiple levels of regulation of histone gene expression during 3T3-L1 pre-adipocyte differentiation . Confluent cells induced to differentiate by treatment with insulin , dexamethasone , and isobutylmethylxanthine initially exhibited an increased proliferative response compared with cells given serum alone . This initial differentiation response was associated with a twofold increase in both histone gene transcription and cellular histone mRNA levels , as well as with enhanced sequence-specific binding of nuclear factors to the proximal cell-cycle-regulatory element of the H4 histone promoter . Transforming growth factor beta 1 , an inhibitor of 3T3-L1 differentiation , increased both the percentage of proliferating cells and the cellular levels of histone mRNA when given in addition to serum stimulation , but no enhancement of these parameters was observed upon addition of TGF beta 1 to the differentiation treatment . Interestingly , although TGF beta 1 enhanced binding of nuclear factors to the proximal cell cycle regulatory element of the histone promoter , these protein/DNA interactions were not associated with an increase in histone transcription . Our results are consistent with the down-regulation of histone gene expression at confluency being controlled primarily at the post-transcriptional level , in contrast to an increased involvement of transcriptional down-regulation at the onset of differentiation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1429875"}
{"sentence": "BACKGROUND Breast cancer is less common in China than in the United States and perinatal characteristics predict breast cancer risk in the offspring . We determined levels of pregnancy hormones in Boston and Shanghai to identify those possibly involved in the intrauterine origin of breast cancer . Participants and methods : We compared maternal and cord blood levels of estradiol , estriol , testosterone , progesterone , prolactin , insulin-like growth factors ( IGF ) 1 and 2 , insulin-like growth factor-binding protein 3 , adiponectin and sex hormone-binding globulin ( SHBG ) in 241 Caucasian and 295 Chinese women . RESULTS In both centers , hormone levels at the 16th were predictive of those at the 27th gestational week , but there was little correlation between maternal and cord blood levels . In cord blood , we found significantly ( P < 0.01 ) higher levels of estradiol ( 44.2% ) , testosterone ( 54.5% ) , IGF-2 ( 22.7% ) and strikingly SHBG ( 104.6% ) in Shanghai women , whereas the opposite was true for IGF-1 ( -36.8% ) . CONCLUSIONS Taking into account the current understanding of the plausible biological role of the examined endocrine factors , those likely to be involved in the intrauterine origin of breast cancer are SHBG and IGF-2 , with higher cord blood levels among Chinese , and IGF-1 , with higher cord blood levels among Caucasian women .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20943596"}
{"sentence": "Placental Growth Factor ( PGF ) is a key molecule in angiogenesis . Several studies have revealed an important role of PGF primarily in pathological conditions ( e.g. : ischaemia , tumour formation , cardiovascular diseases and inflammatory processes ) suggesting its use as a potential therapeutic agent . However , to date , no information is available regarding the genetics of PGF variability . Furthermore , even though the effect of environmental factors ( e.g. : cigarette smoking ) on angiogenesis has been explored , no data on the influence of these factors on PGF levels have been reported so far . Here we have first investigated PGF variability in two cohorts focusing on non-genetic risk factors : a study sample from two isolated villages in the Cilento region , South Italy ( N=871 ) and a replication sample from the general Danish population ( N=1,812 ) . A significant difference in PGF mean levels was found between the two cohorts . However , in both samples , we observed a strong correlation of PGF levels with ageing and sex , men displaying PGF levels significantly higher than women . Interestingly , smoking was also found to influence the trait in the two populations , although differently . We have then focused on genetic risk factors . The association between five single nucleotide polymorphisms ( SNPs ) located in the PGF gene and the plasma levels of the protein was investigated . Two polymorphisms ( rs11850328 and rs2268614 ) were associated with the PGF plasma levels in the Cilento sample and these associations were strongly replicated in the Danish sample . These results , for the first time , support the hypothesis of the presence of genetic and environmental factors influencing PGF plasma variability .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22916133"}
{"sentence": "Repetitive DNA sequences with the potential to form alternative DNA conformations , such as slipped structures and cruciforms , can induce genetic instability by promoting replication errors and by serving as a substrate for DNA repair proteins , which may lead to DNA double-strand breaks ( DSBs ) . However , the contribution of each of the DSB repair pathways , homologous recombination ( HR ) , non-homologous end-joining ( NHEJ ) and single-strand annealing ( SSA ) , to this sort of genetic instability is not fully understood . Herein , we assessed the genome-wide distribution of repetitive DNA sequences in the Mycobacterium smegmatis , Mycobacterium tuberculosis and Escherichia coli genomes , and determined the types and frequencies of genetic instability induced by direct and inverted repeats , both in the presence and in the absence of HR , NHEJ , and SSA . All three genomes are strongly enriched in direct repeats and modestly enriched in inverted repeats . When using chromosomally integrated constructs in M. smegmatis , direct repeats induced the perfect deletion of their intervening sequences above background . Absence of HR further enhanced these perfect deletions , whereas absence of NHEJ or SSA had no influence , suggesting compromised replication fidelity . In contrast , inverted repeats induced perfect deletions only in the absence of SSA . Both direct and inverted repeats stimulated excision of the constructs from the attB integration sites independently of HR , NHEJ , or SSA . With episomal constructs , direct and inverted repeats triggered DNA instability by activating nucleolytic activity , and absence of the DSB repair pathways ( in the order NHEJ>HR>SSA ) exacerbated this instability . Thus , direct and inverted repeats may elicit genetic instability in mycobacteria by 1 ) directly interfering with replication fidelity , 2 ) stimulating the three main DSB repair pathways , and 3 ) enticing L5 site-specific recombination .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23251422"}
{"sentence": "High-altitude long-term hypoxia ( LTH ) is known to induce pulmonary arterial smooth muscle cell ( PASMC ) proliferation in the fetus , leading to pulmonary arterial remodeling and pulmonary hypertension of the newborn . The mechanisms underlying these conditions remain enigmatic however . We hypothesized that epigenetic alterations in fetal PASMC induced by high-altitude LTH may play an important role in modulating their proliferation during pulmonary arterial remodeling . To test this hypothesis , we have analyzed epigenetic alterations in the pulmonary vasculature of fetal lambs exposed to high-altitude LTH [ pregnant ewes were kept at 3,801 m altitude from to 145 days gestation ] or to sea level atmosphere . Intrapulmonary arteries were isolated , and fetal PASMC were cultured from both control and LTH fetuses . Compared with controls , in LTH fetus pulmonary arteries measurements of histone acetylation and global DNA methylation demonstrated reduced levels of global histone 4 acetylation and DNA methylation , accompanied by the loss of the cyclin-dependent kinase inhibitor p21 . Treatment of LTH fetal PASMCs with histone deacetylase ( HDAC ) inhibitor trichostatin A decreased their proliferation rate , in part because of altered expression of p21 at both RNA and protein level . In PASMC of LTH fetuses , HDAC inhibition also decreased PDGF-induced cell migration and ERK1/2 activation and modulated global DNA methylation . On the basis of these observations , we propose that epigenetic alterations ( reduced histone acetylation and DNA methylation ) caused by chronic hypoxia leads to fetal PASMC proliferation and vessel remodeling associated with vascular proliferative disease and that this process is regulated by p21 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23043075"}
{"sentence": "Angiogenesis is defined as the formation of new blood vessels form existing vessels surrounding a tumor . The process of angiogenesis is an important step for tumor growth and metastasis , as is inflammation . Thus , angiogenesis inhibitors that suppress inflammation have been studied as an anticancer treatment . Recently , many research groups have investigated the anti-angiogenic activity of natural compounds since some have been demonstrated to have anticancer properties . Among many natural compounds , we focused on betaine , which is known to suppress inflammation . Betaine , trimethylglycine ( TMG ) , was first discovered in the juice of sugar beets and was later shown to be present in wheat , shellfish and spinach . In Southeast Asia , betaine is used in traditional oriental medicine for the treatment of hepatic disorders . Here , we report the anti-angiogenic action of betaine . Betaine inhibited invitro angiogenic cascade , tube formation , migration and invasion of human umbilical vein endothelial cells ( HUVECs ) . Betaine also inhibited invivo angiogenesis in the mouse Matrigel plug assay . The mRNA expression levels of basic fibroblast growth factor ( bFGF ) , matrix metalloproteinase-2 ( MMP-2 ) and matrix metalloproteinase-9 ( MMP-9 ) in HUVECs were decreased by betaine treatment . In addition , betaine suppressed NF-\u03baB and Akt activation .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "22940742"}
{"sentence": "OBJECTIVE To evaluate the difference of angiogenic factors PDGF/dThdPase,VEGF expression and microvessel density ( MVD ) in primary hypopharyngeal tumor and metastasis lymph nodes . METHOD The author studied immunohistochemically a series of 48 primary hypopharyngeal carcinoma patients and metastasis lymph nodes were calculated . RESULT The percentage of VEGF was 25.38% in primary tumor and 21.52% in lymph nodes . No significant difference was found . The percentage of PDGF/dThdPase was 29.59% in primary tumor and and 21.2% in lymph nodes . This showed significent difference . VEGF showed significent difference between live and death group(P < 0.05 ) and among differentiation group ( P < 0.05 ) . MVD showed significant difference between live and death group , early and late stage group , and T1-2 and T3-4 group ( P < 0.05 ) . There were statistically significant correlations between the score of PDGF/ dThdPase , or VEGF and the score of MVD respectively . CONCLUSION The present study suggests that there was a correlation between VEGF or PDGF and MVD . VEGF and MVD were possible to be prognostic discriminators in hypopharyngeal carcinoma . PDGF expression in lymph nodes was significant higher than in primary tumors , and MVD expression in primary tumor was significant higher than in lymph nodes .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "15515527"}
{"sentence": "DNA polymerases beta ( pol beta ) and eta ( pol eta ) are the only two eukaryotic polymerases known to efficiently bypass cisplatin and oxaliplatin adducts in vitro . Frameshift errors are an important aspect of mutagenesis . We have compared the types of frameshifts that occur during translesion synthesis past cisplatin and oxaliplatin adducts in vitro by pol beta and pol eta on a template containing multiple runs of nucleotides flanking a single platinum-GG adduct . Translesion synthesis past platinum adducts by pol beta resulted in approximately 50% replication products containing single-base deletions . For both adducts the majority of -1 frameshifts occurred in a TTT sequence 3-5 bp upstream of the DNA lesion . For pol eta , all of the bypass products for both cisplatin and oxaliplatin adducts contained -1 frameshifts in the upstream TTT sequence and most of the products of replication on oxaliplatin-damaged templates had multiple replication errors , both frameshifts and misinsertions . In addition , on platinated templates both polymerases generated replication products 4-8 bp shorter than the full-length products . The majority of short cisplatin-induced products contained an internal deletion which included the adduct . In contrast , the majority of oxaliplatin-induced short products contained a 3 ' terminal deletion . The implications of these in vitro results for in vivo mutagenesis are discussed .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12531010"}
{"sentence": "The expression of \" growth arrest and DNA damage inducible genes 45 and 153 \" is related to apoptotic induction of cells . GADD45 is an effector gene of the tumor suppressor p53 , and GADD153 is associated with cellular function of cancer prevention . Curcumin , isolated from the plant Curcuma longa ( LINN ) , has been investigated as a promising cancer preventive in food because curcumin , a phenolic and coloring compound , is widely ingested in the Indian subcontinent . However , the exact mechanisms of action of curcumin have not yet been clearly elucidated . Based on our successful results with green tea catechins as cancer preventive , we studied the relationship between the expression of GADD45 and 153 and apoptotic induction in human lung cancer cell line PC-9 . In our study curcumin increased the expression of GADD45 and 153 in a p53-independent manner . Curcumin also inhibited the growth of PC-9 cells and induced G(1)/S arrest of the cell-cycle followed by strong induction of apoptosis . Treatment with GADD45 and 153 small interfering RNAs ( siRNAs ) inhibited the apoptotic induction in PC-9 cells by curcumin . Moreover , curcumin induced the expression of cyclin dependent kinase inhibitor genes p21 and p27 , while it inhibited the expression of numerous genes , including Bcl-2 , cyclin D1 , CDK2 , CDK4 and CDK6 . All the results with PC-9 cells suggest that the up-regulation of GADD45 and 153 by curcumin is a prime mechanism in the anticancer activity of curcumin .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20686221"}
{"sentence": "Although the immense efforts have been made for cancer prevention , early diagnosis , and treatment , cancer morbidity and mortality has not been decreased during last forty years . Especially , lung cancer is top-ranked in cancer-associated human death . Therefore , effective strategy is strongly required for the management of lung cancer . In the present study , we found that novel daphnane diterpenoids , yuanhualine ( YL ) , yuanhuahine ( YH ) and yuanhuagine ( YG ) isolated from the flower of Daphne genkwa ( Thymelaeaceae ) , exhibited potent anti-proliferative activities against human lung A549 cells with the IC50 values of 7.0 , 15.2 and 24.7 nM , respectively . Flow cytometric analysis revealed that the daphnane diterpenoids induced cell-cycle arrest in the G0/G1 as well as G2/M phase in A549 cells . The cell-cycle arrests were well correlated with the expression of checkpoint proteins including the up-regulation of cyclin-dependent kinase inhibitor p21 and p53 and down-regulation of cyclin A , cyclin B1 , cyclin E , cyclin dependent kinase 4 , cdc2 , phosphorylation of Rb and cMyc expression . In the analysis of signal transduction molecules , the daphnane diterpenoids suppressed the activation of Akt , STAT3 and Src in human lung cancer cells . The daphnane diterpenoids also exerted the potent anti-proliferative activity against anticancer-drug resistant cancer cells including gemcitabine-resistant A549 , gefitinib- , erlotinib-resistant H292 cells . Synergistic effects in the growth inhibition were also observed when yuanhualine was combined with gemcitabine , gefitinib or erlotinib in A549 cells . Taken together , these findings suggest that the novel daphnane diterpenoids might provide lead candidates for the development of therapeutic agents for human lung cancers .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "24009843"}
{"sentence": "AIM To elucidate the roles of receptor tyrosine kinases RET and VEGFR2 and the RAF/MEK/ERK signaling cascade in cancer treatment with sorafenib . METHODS The cell lines A549 , HeLa , and HepG2 were tested . The enzyme activity was examined under cell-free conditions using 384-well microplate assays . Cell proliferation was evaluated using the Invitrogen Alarmar Blue assay . Gene expression was analyzed using the Invitrogen SYBR Green expression assays with a sequence detection system . Protein expression analysis was performed using Western blotting . RESULTS Sorafenib potently suppressed the activities of cRAF , VEGFR2 , and RET with IC(50) values of 20.9 , 4 and 0.4 nmol/L , respectively . Sorafenib inhibited cRAF , VEGFR2 , and RET via non-ATP-competitive , ATP-competitive and mixed-type modes , respectively . In contrast , sorafenib exerted only moderate cytotoxic effects on the proliferation of the 3 cell lines . The IC(50) values for inhibition of A549 , HeLa , and HepG2 cells were 8572 , 4163 , and 8338 nmol/L , respectively . In the 3 cell lines , sorafenib suppressed the cell proliferation mainly by blocking the MEK/ERK downstream pathway at the posttranscriptional level , which in turn regulated related gene expression via a feed-back mechanism . CONCLUSION This study provides novel evidence that protein kinases RET and VEGFR2 play crucial roles in cancer treatment with sorafenib .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22941289"}
{"sentence": "Recent evidence indicates that the estrogen receptor-\u03b1-negative , androgen receptor ( AR)-positive molecular apocrine subtype of breast cancer is driven by AR signaling . The MDA-MB-453 cell line is the prototypical model of this breast cancer subtype ; its proliferation is stimulated by androgens such as 5\u03b1-dihydrotestosterone ( DHT ) but inhibited by the progestin medroxyprogesterone acetate ( MPA ) via AR-mediated mechanisms . We report here that the AR gene in MDA-MB-453 cells contains a G-T transversion in exon 7 , resulting in a receptor variant with a glutamine to histidine substitution at amino acid 865 ( Q865H ) in the ligand binding domain . Compared with wild-type AR , the Q865H variant exhibited reduced sensitivity to DHT and MPA in transactivation assays in MDA-MB-453 and PC-3 cells but did not respond to non-androgenic ligands or receptor antagonists . Ligand binding , molecular modeling , mammalian two-hybrid and immunoblot assays revealed effects of the Q865H mutation on ligand dissociation , AR intramolecular interactions , and receptor stability . Microarray expression profiling demonstrated that DHT and MPA regulate distinct transcriptional programs in MDA-MB-453 cells . Gene Set Enrichment Analysis revealed that DHT- but not MPA-regulated genes were associated with estrogen-responsive transcriptomes from MCF-7 cells and the Wnt signaling pathway . These findings suggest that the divergent proliferative responses of MDA-MB-453 cells to DHT and MPA result from the different genetic programs elicited by these two ligands through the AR-Q865H variant . This work highlights the necessity to characterize additional models of molecular apocrine breast cancer to determine the precise role of AR signaling in this breast cancer subtype .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22719059"}
{"sentence": "Cellular senescence , an irreversible cell cycle arrest induced by a diversity of stimuli , has been considered as an innate tumor suppressing mechanism with implications and applications in cancer therapy . Using a targeted proteomics approach , we show that fibroblasts induced into senescence by expression of oncogenic Ras exhibit a decrease of global acetylation on all core histones , consistent with formation of senescence-associated heterochromatic foci . We also detected clear increases in repressive markers ( e.g. >50% elevation of H3K27me2/3 ) along with decreases in histone marks associated with increased transcriptional expression/elongation ( e.g . H3K36me2/3 ) . Despite the increases in repressive marks of chromatin , 179 loci ( of 2206 total ) were found to be upregulated by global quantitative proteomics . The changes in the cytosolic proteome indicated an upregulation of mitochondrial proteins and downregulation of proteins involved in glycolysis . These alterations in primary metabolism are opposite to the well-known Warburg effect observed in cancer cells . This study significantly improves our understanding of stress-induced senescence and provides a potential application for triggering it in antiproliferative strategies that target the primary metabolism in cancer cells .", "label": [0, 0, 1, 1, 0, 0, 0, 0, 0, 0], "id": "23798001"}
{"sentence": "BACKGROUND Dendritic cells ( DCs ) isolated from tumor bearing animals or from individuals with solid tumors display functional abnormalities and the DC impairment has emerged as one mechanism for tumor evasion from the control of the immune system . Ductal pancreatic adenocarcinoma ( PDAC ) , the most common pancreatic cancer , is recognized as a very aggressive cancer type with a mortality that almost matches the rate of incidence . METHODS We examined the systemic influence ductal pancreatic adenocarcinoma ( PDAC ) exerted on levels of peripheral blood DCs and inflammatory mediators in comparison to the effects exerted by other pancreatic tumors , chronic pancreatitis , and age-matched controls . RESULTS All groups examined , including PDAC , had decreased levels of myeloid DCs ( MDC ) and plasmacytoid DCs ( PDC ) and enhanced apoptosis in these cells as compared to controls . We found elevated levels of PGE2 and CXCL8 in subjects with PDAC , and chronic pancreatitis . Levels of these inflammatory factors were in part restored in PDAC after tumor resection , whereas the levels of DCs were impaired in the majority of these patients approximately 12 weeks after tumor removal . Our results prove that solid pancreatic tumors , including PDAC , systemically affect blood DCs . The impairments do not seem to be tumor-specific , since similar results were obtained in subjects with chronic pancreatitis . Furthermore , we found that PDAC patients with a survival over 2 years had significant higher levels of blood DCs compared to patients with less than one year survival . CONCLUSIONS Our findings points to the involvement of inflammation in the destruction of the blood MDCs and PDCs . Furthermore , the preservation of the blood DCs compartment in PDAC patients seems to benefit their ability to control the disease and survival .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20214814"}
{"sentence": "PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands ( PD-L ) and is suggested to play a role in the maintenance of self-tolerance . In the present study , we examined possible roles of the PD-1/PD-L system in tumor immunity . Transgenic expression of PD-L1 , one of the PD-L , in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro , and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L . Both effects could be reversed by anti-PD-L1 Ab . Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1 . Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice . These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12218188"}
{"sentence": "Epidemiological studies have indicated that females may be at greater risk of smoking associated lung cancer compared with males . Several lines of biochemical evidence support these observations . A possible role of circulating steroid hormones in the etiology of lung cancer has been hypothesized . In the present paper , we have studied the expression of the estrogen receptors ( ER)-alpha and ER beta in histologically normal human lung tissue and lung tumor cell lines . Relative ER mRNA levels were measured by reverse transcriptase-PCR and normalized to the level of expression of the glyceraldehyde 3-phosphate dehydrogenase gene ( GAPDH ) . In lung tissue , an ER alpha transcript was found at various levels in 38 out of 46 cases ( 83% ) . ER beta was expressed in all cases . The ERs were expressed at similar levels in females and males , and the levels of ER alpha and ER beta mRNA were significantly related ( P<0.0001 ) . Compared with the lung tissue , ER expression levels were lower in 16 human lung tumor cell lines and two immortalized human bronchial epithelial cell lines . Five of the tumor cell lines ( 31% ) expressed detectable levels of ER alpha and both of the immortalized cell lines showed a weak ER alpha expression level . All cell lines expressed the ER beta . The lung cell lines BEAS-2B and DB354 showed significantly reduced cell proliferation in response to tamoxifen and a minor increased growth in response to 17 beta-estradiol . In conclusion , ER genes are abundantly expressed in both histologically normal human lung and lung tumor cell lines . This indicates a possible role of ERs in lung carcinogenesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12140138"}
{"sentence": "BACKGROUND Modern allotetraploid cotton contains an \" A \" and \" D \" genome from an ancestral polyploidy event that occurred approximately 1-2 million years ago . Diploid A- and D-genome species can be compared to the A- and D-genomes found within these allotetraploids to make evolutionary inferences about polyploidy . In this paper we present a comprehensive EST assembly derived from diploid and model allotetraploid cottons and demonstrate several evolutionary inferences regarding genic evolution that can be drawn from these data . RESULTS We generated a set of cotton expressed sequence tags ( ESTs ) , comprising approximately 4.4 million Sanger and next-generation ( 454 ) transcripts supplemented by approximately 152 million Illumina reads from diploid and allotetraploid cottons . From the EST alignments we inferred 259,192 genome-specific single nucleotide polymorphisms ( SNPs ) . Molecular evolutionary analyses of protein-coding regions demonstrate that the rate of nucleotide substitution has increased among both allotetraploid genomes relative to the diploids , and that the ratio of nonsynonymous to synonymous substitutions has increased in one of the two polyploid lineages we sampled . We also use these SNPs to show that a surprisingly high percentage of duplicate genes ( show a signature of non-independent evolution in the allotetraploid nucleus , having experienced one or more episodes of nonreciprocal homoeologous recombination ( NRHR ) . CONCLUSIONS In this study we characterize the functional and mutational properties of the cotton transcriptome , produce a large genome-specific SNP database , and detect illegitimate genetic exchanges between duplicate genomes sharing a common allotetraploid nucleus . Our findings have important implications for our understanding of the consequences of polyploidy and duplicate gene evolution . We demonstrate that cotton genes have experienced an increased rate of molecular evolution following duplication by polyploidy , and that polyploidy has enabled considerable levels of nonreciprocal exchange between homoeologous genes .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22768919"}
{"sentence": "Results generated by the immunohistochemical staining with PC10 , a new monoclonal antibody recognizing PCNA ( a nuclear protein associated with cell proliferation ) in formalin-fixed and paraffin-embedded tissue were compared with those of Ki-67 labeling and DNA flow cytometry in 47 consecutive non-small cell lung cancer ( NSCLC ) . PCNA reactivity was observed in all samples and confined to the nuclei of cancer cells . Its frequency ranged from 0 to 80% ( 37.7 +/- 23.6 ) and larger sized , early-staged and DNA aneuploid tumors expressed a significant higher number of PCNA-reactive cells . The PCNA and Ki-67 labeling rates were closely correlated ( r = 0.383 , P = 0.009 ) . By flow cytometry , we observed a good correlation among PCNA labeling and S-phase fraction ( r = 0.422 , P = .0093 ) and G1 phase ( r = 0.303 , P = .051 ) of the cell cycle . Results indicate that PCNA labeling with PC10 is a simple method for assessing the proliferative activity in formalin-fixed , paraffin-embedded tissue of NSCLC and correlates well with Ki-67 labeling and S-phase fraction of the cell cycle .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1361306"}
{"sentence": "Mutations in the Nf2 tumor suppressor gene lead to tumor formation in humans and mice and cellular overproliferation phenotypes in Drosophila . The Nf2 encoded protein , merlin , shares close sequence similarity in its amino terminus to members of the band 4.1 family of membrane-cytoskeletal linkers . Similarities between merlin and this family suggest a role for merlin in regulating cytoskeletal function . However , the mechanism of the tumor suppressing activity of merlin is not yet understood . Mutational analysis of Nf2 in flies has led to the identification of a dominant-negative allele , which harbors mutations in the amino terminus of the protein . Here , we report that expression of a murine analog of this amino-terminal mutant of Nf2 leads to complete transformation of NIH3T3 fibroblasts in culture . Cells that express this Nf2 mutant allele display disruptions of the actin cytoskeleton , lack of contact inhibition of growth , and anchorage-independent growth . Finally , fibroblasts that express this mutant Nf2 allele form tumors when injected into nude mice .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "12203111"}
{"sentence": "The down-regulation of dominant oncogenes , including C-MYC , in tumor cells often leads to the induction of senescence via mechanisms that are not completely identified . In the current study , we demonstrate that MYC-depleted melanoma cells undergo extensive DNA damage that is caused by the underexpression of thymidylate synthase ( TS ) and ribonucleotide reductase ( RR ) and subsequent depletion of deoxyribonucleoside triphosphate pools . Simultaneous genetic inhibition of TS and RR in melanoma cells induced DNA damage and senescence phenotypes very similar to the ones caused by MYC-depletion . Reciprocally , overexpression of TS and RR in melanoma cells or addition of deoxyribo-nucleosides to culture media substantially inhibited DNA damage and senescence-associated phenotypes caused by C-MYC depletion . Our data demonstrate the essential role of TS and RR in C-MYC-dependent suppression of senescence in melanoma cells .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "23249808"}
{"sentence": "The effects of tea polyphenols and tea pigments on cell cycle of hepatic cancer cells were studied . HepG2 cells were incubated with 50 and 100 mg/L tea polyphenols and tea pigments for 48 h respectively . Flow cytometry , Western blot and RT-PCR analysis were used . Flow cytometry analysis showed that tea polyphenols and tea pigments induced G1 arrest . Western blot analysis showed tea polyphenols and tea pigments significantly inhibited the expression of cyclin D1 protein and induced higher expression of P21WAFI/CIPI protein . The result of RT-PCR analysis demonstrated that Cdk4 was significantly inhibited by tea polyphenols and tea pigments . It is concluded that the induction of cell cycle arrest may be an important mechanism of tea on cancer prevention .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "12572356"}
{"sentence": "DNA mismatch repair ( MMR ) is the process by which incorrectly paired DNA nucleotides are recognized and repaired . A germline mutation in one of the genes involved in the process may be responsible for a dominantly inherited cancer syndrome , hereditary nonpolyposis colon cancer . Cancer progression in predisposed individuals results from the somatic inactivation of the normal copy of the MMR gene , leading to a mutator phenotype affecting preferentially repeat sequences ( microsatellite instability , MSI ) . Recently , we identified children with a constitutional deficiency of MMR activity attributable to a mutation in the h MLH1 gene . These children exhibited a constitutional genetic instability associated with clinical features of de novo neurofibromatosis type 1 ( NF1 ) and early onset of extracolonic cancer . Based on these observations , we hypothesized that somatic NF1 gene mutation was a frequent and possibly early event in MMR-deficient cells . To test this hypothesis , we screened for NF1 mutations in cancer cells . Genetic alterations were identified in five out of ten tumor cell lines with MSI , whereas five MMR-proficient tumor cell lines expressed a wild-type NF1 gene . Somatic NF1 mutations were also detected in two primary tumors exhibiting an MSI phenotype . Finally , a 35-bp deletion in the murine Nf1 coding region was identified in mlh1-/- mouse embryonic fibroblasts . These observations demonstrate that the NF1 gene is a mutational target of MMR deficiency and suggest that its inactivation is an important step of the malignant progression of MMR-deficient cells .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12522551"}
{"sentence": "Immunosuppression has been related to the incidence of tumor apparition , including endocrine tumors . The intrasplenic ovarian tumor ( luteoma ) is a typical benign endocrine tumor that develops under high gonadotropin stimulation and , from the immunological perspective , is located in a critical organ involved in immune response . To establish if immunosuppression could alter the development of this experimental tumor , the effects of cyclosporin A ( CsA ) and dexamethasone ( Dex ) were evaluated . After surgery , tumor-bearing and sham animals were kept without treatment for 4 weeks ; thereafter , they were distributed into CsA ( 25 mg/kg ) , Dex ( 0.1 mg/kg ) , or vehicle ( 75:25 castor oil:ethanol ) groups and were injected on alternate days for 50 days . Body weight was evaluated weekly . Animals were sacrificed after a jugular vein blood sample was obtained . Thymi were weighed . Tumors were measured and placed in formaline for histological studies . Serum luteinizing hormone ( LH ) , follicle-stimulating hormone ( FSH ) , prolactin ( PRL ) , and estradiol were measured by radioimmunoassay . Hematological parameters were determined . CsA induced a significant decrease in survival rates both in tumor-bearing and sham animals ( P < 0.01 ) . Dex significantly impaired weight increase in both groups of animals . CsA induced a significant weight loss in sham animals , not observed in tumor-bearing animals . Dex induced thymus weight loss in both groups , whereas CsA induced thymus weight loss only in sham animals . Only Dex induced a decrease in lymphocyte number in both groups . CsA induced an increase in monocyte number only in sham animals . Treatments did not alter LH , FSH , or estradiol , whereas PRL was increased by CsA only in sham rats . Neither Dex nor CsA induced any significant variations in tumor volume , nor did they alter tumor histology . In addition , no visible metastases or alterations in other organs were observed . We conclude that , though immunological parameters were altered by the treatments , immunosuppressor drugs did not condition tumor development . In addition , tumors secrete one or more factor/s that counteract CsA effect .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12192110"}
{"sentence": "Transfected linear DNA molecules are substrates for double-strand break ( DSB ) repair in mammalian cells . The DSB repair process can involve recombination between the transfected DNA molecules , between the transfected molecules and chromosomal DNA , or both . In order to determine whether these different types of repair events are linked , we devised assays enabling us to follow the fate of linear extrachromosomal DNA molecules involved in both interplasmid and chromosome-plasmid recombination , in the presence or absence of a pre-defined chromosomal DSB . Plasmid-based vectors were designed that could either recombine via interplasmid recombination or chromosome-plasmid recombination to produce a functional beta-galactosidase ( betagal ) fusion gene . By measuring the frequency of betagal+ cells at 36 h post-transfection versus the frequency of betagal+ clones after 14 days , we found that the number of cells containing extrachromosomal recombinant DNA molecules at 36 h ( i.e. , betagal+ ) , either through interplasmid or chromosome-plasmid recombination , was nearly the same as the number of cells integrating these recombinant molecules . Furthermore , when a predefined DSB was created at a chromosomal site , the extrachromosomal recombinant DNA molecules were shown to integrate preferentially at that site by Southern and fiber-FISH ( fluorescence in situ hybridization ) analysis . Together these data indicate that the initial recombination event can potentiate or commit extrachromosomal DNA to integration in the genome at the site of a chromosomal DSB . The efficiency at which extrachromosomal recombinant molecules are used as substrates in chromosomal DSB repair suggests extrachromosomal DSB repair can be coupled to the repair of chromosomal DSBs in mammalian cells .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12474059"}
{"sentence": "Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis . This glycolytic shift , called the Warburg effect , provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents ( ERMA ) . We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition . The lead ERMA in this class , OSU-CG5 , decreases the production of ATP and NADH in LNCaP prostate cancer cells . In this study , we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate ( TRAMP ) mice . Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal , lateral , and anterior prostatic lobes relative to vehicle controls . The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen ( PCNA ) expression in the prostate . OSU-CG5 treatment was not associated with evidence of systemic toxicity . Microarray analysis indicated a central role for Akt , and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt , Src , androgen receptor , and insulin-like growth factor-1 receptor in prostate lobes . These findings support further investigation of OSU-CG5 as a potential chemopreventive agent .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23275006"}
{"sentence": "Lung cancer is one of the leading cancer malignancies , with a five-year survival rate of only We have developed a lentiviral-vector-mediated mouse model , which enables generation of non-small-cell lung cancer from less than 100 alveolar epithelial cells , and investigated the role of IKK2 and NF-\u03baB in lung-cancer development . IKK2 depletion in tumour cells significantly attenuated tumour proliferation and significantly prolonged mouse survival . We identified Timp1 , one of the NF-\u03baB target genes , as a key mediator for tumour growth . Activation of the Erk signalling pathway and cell proliferation requires Timp-1 and its receptor CD63 . Knockdown of either Ikbkb or Timp1 by short hairpin RNAs reduced tumour growth in both xenograft and lentiviral models . Our results thus suggest the possible application of IKK2 and Timp-1 inhibitors in treating lung cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22327365"}
{"sentence": "Immunosenescence , the progressive decline of adaptive immunity and chronic inflammation with ageing has been demonstrated to be the main factor responsible for infections , cancer and autoimmune conditions in the elderly . Senescence-accelerated mouse ( SAM ) was used to study the protective effects of Pu-erh tea in the elderly . The senile-prone sub-strain , SAM-P8 mice were administered individually with ripened or crude Pu-erh tea at 125 , 250 or 500mg/kg . The results showed that Pu-erh tea significantly increased the fractions of na\ufffdve T lymphocytes , CD8(+)CD28(+) T lymphocytes and NK cells in the peripheral blood , but decreased the levels of IL-6 in aged mice . These data suggested that the Pu-erh tea reversed the immunosenescence by restoring the immune deficiency and decreasing pro-inflammatory cytokine . Thus , long term drinking of Pu-erh tea may be beneficial for the aged population in terms of increasing the body's resistance to infection and cancer .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22980794"}
{"sentence": "The identification of molecular markers related to critical biological processes during carcinogenesis may aid in the evaluation of carcinogenic potentials of chemicals and chemical mixtures . Work from our laboratory demonstrated that a single treatment with N-methyl-N'-nitro-N-nitrosoguanidine ( MNNG ) enhanced spontaneous malignant transformation of the human keratinocyte cell line RHEK-1 . In contrast , chronic low-level exposure of cells to arsenic alone or in a mixture containing arsenic , cadmium , chromium , and lead inhibited malignant conversion . To identify changes in gene expression that influence these different outcomes , cDNA microarray technology was used . Analysis of multiple human arrays in MNNG-transformed RHEK-1 cells , designated OM3 , and those treated with arsenic or the arsenic-containing metal mixture showed unique patterns of gene expression . Genes that were overexpressed in OM3 included oncogenes , cell cycle regulators , and those involved in signal transduction , whereas genes for DNA repair enzymes and inhibitors of transformation and metastasis were suppressed . In arsenic-treated cells , multiple DNA repair proteins were overexpressed . Mixture-treated cells showed increased expression of a variety of genes including metallothioneins and integrin 4 . These cells showed decreased expression of oncogenes , DNA repair proteins , and genes involved in the mitogen-activated protein kinase pathway . For comparison we are currently analyzing gene expression changes in RHEK-1 cells transformed by other means . The goal of these studies is to identify common batteries of genes affected by chemical modulators of the carcinogenic process . Mechanistic studies may allow us to correlate alterations in their expression with sequential stages in the carcinogenic process and may aid in the risk assessment of other xenobiotics .", "label": [1, 0, 0, 0, 1, 1, 0, 0, 1, 0], "id": "12634122"}
{"sentence": "Perlecan Domain V ( DV ) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells ( BECs ) following stroke . In this study , we define the specific mechanism of DV interaction with the \u03b1(5)\u03b2(1) integrin , identify the downstream signal transduction pathway , and further investigate the functional significance of resultant VEGF release . Interestingly , we found that the LG3 portion of DV , which has been suggested to possess most of DV's angio-modulatory activity outside of the brain , binds poorly to \u03b1(5)\u03b2(1) and induces less BEC proliferation compared to full length DV . Additionally , we implicate DV's DGR sequence as an important element for the interaction of DV with \u03b1(5)\u03b2(1) . Furthermore , we investigated the importance of AKT and ERK signaling in DV-induced VEGF expression and secretion . We show that DV increases the phosphorylation of ERK , which leads to subsequent activation and stabilization of eIF4E and HIF-1\u03b1 . Inhibition of ERK activity by U0126 suppressed DV-induced expression and secretion of VEGR in BECs . While DV was capable of phosphorylating AKT we show that AKT phosphorylation does not play a role in DV's induction of VEGF expression or secretion using two separate inhibitors , LY294002 and Akt IV . Lastly , we demonstrate that VEGF activity is critical for DV increases in BEC proliferation , as well as angiogenesis in a BEC-neuronal co-culture system . Collectively , our findings expand our understanding of DV's mechanism of action on BECs , and further support its potential as a novel stroke therapy .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "23028886"}
{"sentence": "BACKGROUND AND AIMS Hepatitis C virus ( HCV)-induced chronic inflammation may induce oxidative stress which could compromise the repair of damaged DNA , rendering cells more susceptible to spontaneous or mutagen-induced alterations , the underlying cause of liver cirrhosis and hepatocellular carcinoma . In the current study we examined the induction of reactive oxygen species ( ROS ) resulting from HCV infection and evaluated its effect on the host DNA damage and repair machinery . METHODS HCV infected human hepatoma cells were analyzed to determine ( i ) ROS , ( ii ) 8-oxoG and ( iii ) DNA glycosylases NEIL1 , NEIL2 , OGG1 . Liver biopsies were analyzed for NEIL1 . RESULTS Human hepatoma cells infected with HCV JFH-1 showed 30-60-fold increases in ROS levels compared to uninfected cells . Levels of the oxidatively modified guanosine base 8-oxoguanine ( 8-oxoG ) were significantly increased sixfold in the HCV-infected cells . Because DNA glycosylases are the enzymes that remove oxidized nucleotides , their expression in HCV-infected cells was analyzed . NEIL1 but not OGG1 or NEIL2 gene expression was impaired in HCV-infected cells . In accordance , we found reduced glycosylase ( NEIL1-specific ) activity in HCV-infected cells . The antioxidant N-acetyl cystein ( NAC ) efficiently reversed the NEIL1 repression by inhibiting ROS induction by HCV . NEIL1 expression was also partly restored when virus-infected cells were treated with interferon ( IFN ) . HCV core and to a lesser extent NS3-4a and NS5A induced ROS , and downregulated NEIL1 expression . Liver biopsy specimens showed significant impairment of NEIL1 levels in HCV-infected patients with advanced liver disease compared to patients with no disease . CONCLUSION Collectively , the data indicate that HCV induction of ROS and perturbation of NEIL1 expression may be mechanistically involved in progression of liver disease and suggest that antioxidant and antiviral therapies can reverse these deleterious effects of HCV in part by restoring function of the DNA repair enzyme/s .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "20074151"}
{"sentence": "Within the family of protein kinase C ( PKC ) molecules , the novel isoform PRKCE ( PKC\u025b ) acts as a bona fide oncogene in in vitro and in vivo models of tumorigenesis . Previous studies have reported expression of PKC\u025b in breast , prostate and lung tumors above that of normal adjacent tissue . Data from the cancer genome atlas suggest increased copy number of PRKCE in triple negative breast cancer ( TNBC ) . We find that overexpression of PKC\u025b in a non-tumorigenic breast epithelial cell line is sufficient to overcome contact inhibition and results in the formation of cellular foci . Correspondingly , inhibition of PKC\u025b in a TNBC cell model results in growth defects in two-dimensional ( 2D ) and three-dimensional ( 3D ) culture conditions and orthotopic xenografts . Using stable isotope labeling of amino acids in a cell culture phosphoproteomic approach , we find that CTNND1/p120ctn phosphorylation at serine 268 ( P-S268 ) occurs in a strictly PKC\u025b-dependent manner , and that loss of PKC\u025b signaling in TNBC cells leads to reversal of mesenchymal morphology and signaling . In a model of Ras activation , inhibition of PKC\u025b is sufficient to block mesenchymal cell morphology . Finally , treatment with a PKC\u025b ATP mimetic inhibitor , PF-5263555 , recapitulates genetic loss of function experiments impairing p120ctn phosphorylation as well as compromising TNBC cell growth in vitro and in vivo . We demonstrate PKC\u025b as a tractable therapeutic target for TNBC , where p120ctn phosphorylation may serve as a readout for monitoring patient response.Oncogene advance online publication , 1 April 2013 ; doi:10.1038/onc.2013.91 .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23542175"}
{"sentence": "The PML protein and PML nuclear bodies ( PML-NB ) are implicated in multiple cellular functions relevant to tumor suppression , including DNA damage response . In most cases of acute promyelocytic leukemia , the PML and retinoic acid receptor alpha ( RARA ) genes are translocated , resulting in expression of oncogenic PML-RAR\\u03b1 fusion proteins . PML-NB fail to form normally , and promyelocytes remain in an undifferentiated , abnormally proliferative state . We examined the involvement of PML protein and PML-NB in homologous recombinational repair ( HRR ) of chromosomal DNA double-strand breaks . Transient overexpression of wild-type PML protein isoforms produced hugely enlarged or aggregated PML-NB and reduced HRR by suggesting that HRR depends to some extent upon normal PML-NB structure . Knockdown of PML by RNA interference sharply attenuated formation of PML-NB and reduced HRR by up to 20-fold . However , PML-knockdown cells showed apparently normal induction of H2AX phosphorylation and RAD51 foci after DNA damage by ionizing radiation . These findings indicate that early steps in HRR , including recognition of DNA double-strand breaks , initial processing of ends , and assembly of single-stranded DNA/RAD51 nucleoprotein filaments , do not depend upon PML-NB . The HRR deficit in PML-depleted cells thus reflects inhibition of later steps in the repair pathway . Expression of PML-RAR\\u03b1 fusion proteins disrupted PML-NB structure and reduced HRR by up to 10-fold , raising the possibility that defective HRR and resulting genomic instability may figure in the pathogenesis , progression and relapse of acute promyelocytic leukemia .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22213200"}
{"sentence": "Protein kinase B ( AKT)/mammalian target of rapamycin ( mTOR ) signaling pathway plays a crucial role in the tumorigenesis and progression of multiple tumors , and has been shown to be important therapeutic targets for cancer . The present study aimed to explore the role and molecular mechanisms of AKT/mTOR pathway in human hemangioma ( HA ) . Twenty-five cases of human HA tissues were collected . The expression of AKT , mTOR and proliferating cell nuclear antigen ( PCNA ) proteins was evaluated using semi-quantitative immunohistochemistry in biopsy samples in different phases of HA . AKT/mTOR pathway was blocked by recombinant small hairpin RNA adenovirus vector rAd5-AKT+mTOR ( rAd5-Am ) , used for infecting proliferating phase HA-derived endothelial cells ( HDEC ) . The expression of AKT , mTOR and PCNA was detected by Real-time PCR and Western blot assays . Cell proliferative activities were determined by MTT assay , and cell cycle distribution and apoptosis were analyzed by flow cytometry . As a consequence , the expression of AKT , mTOR and PCNA was significantly increased in proliferative phase HA , while that was decreased in involutive phase . Combined blockade of AKT/mTOR pathway by rAd5-Am diminished cell proliferative activities , and induced cell apoptosis and cycle arrest with the decreased expression of AKT , mTOR and PCNA in proliferative phase HDEC . In conclusion , the activity of AKT/mTOR pathway was increased in proliferative phase HA , while it was decreased in involutive phase . Combined blockade of AKT/mTOR pathway might suppress cell proliferation via down-regulation of PCNA expression , and induce apoptosis and cycle arrest in proliferative phase HDEC , suggesting that AKT/mTOR pathway might represent the important therapeutic targets for human HA .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23298485"}
{"sentence": "Gastrin stimulates the growth of pancreatic cancer cells through the activation of the cholecystokinin-B receptor ( CCK-BR ) , which has been found to be overexpressed in pancreatic cancer . In this study , we proposed that the CCK-BR drives growth of pancreatic cancer ; hence , interruption of CCK-BR activity could potentially be an ideal target for cancer therapeutics . The effect of CCK-BR downregulation in the human pancreatic adenocarcinoma cells was examined by utilizing specific CCK-BR-targeted RNA interference reagents . The CCK-BR receptor expression was both transiently and stably downregulated by transfection with selective CCK-BR small-interfering RNA or short-hairpin RNA , respectively , and the effects on cell growth and apoptosis were assessed . CCK-BR downregulation resulted in reduced cancer cell proliferation , decreased DNA synthesis , and cell cycle arrest as demonstrated by an inhibition of G(1) to S phase progression . Furthermore , CCK-BR downregulation increased caspase-3 activity , TUNEL-positive cells , and decreased X-linked inhibitor of apoptosis protein expression , suggesting apoptotic activity . Pancreatic cancer cell mobility was decreased when the CCK-BR was downregulated , as assessed by a migration assay . These results show the importance of the CCK-BR in regulation of growth and apoptosis in pancreatic cancer . Strategies to decrease the CCK-BR expression and activity may be beneficial for the development of new methods to improve the treatment for patients with pancreatic cancer .", "label": [1, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "22442157"}
{"sentence": "That a knock-in mouse harboring a dominant-negative thyroid hormone receptor ( TR)-\u03b2 ( Thrb ) mutation develops metastatic thyroid cancer strongly suggests the involvement of TR\u03b2 in carcinogenesis . Epigenetic silencing of the THRB gene is common in human cancers . The aim of the present study was to determine how DNA methylation affected the expression of the THRB gene in differentiated thyroid cancer ( DTC ) and how reexpression of the THRB gene attenuated the cancer phenotypes . We used methylation-specific PCR to examine the expression and promoter methylation of the THRB gene in DTC tissues . Thyroid cancer cells with hypermethylated THRB were treated with the demethylating agents 5'-aza-2'-deoxycytidine ( 5'-aza-CdR ) and zebularine to evaluate their impact on the cancer cell phenotypes . THRB mRNA expression in DTC was 90% lower than in normal controls , and this decrease was associated with a higher tumor/lymph node staging . The promoter methylation level of the THRB gene had a significant negative correlation with the expression level of the THRB gene . Treatment of FTC-236 cells with 5'-aza-CdR or zebularine induced reexpression of the THRB gene and inhibited cell proliferation and migration . FTC-236 cells stably expressing TR\u03b2 exhibited lower cell proliferation and migration through inhibition of \u03b2-catenin signaling pathways compared with FTC-236 without TR\u03b2. 5'-Aza-CdR also led to suppression of tumor growth in an in vivo xenograft model using FTC-236 cells consistent with the cell-based studies . These finding indicate that TR\u03b2 is a tumor suppressor and could be tested as a potential therapeutic target .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23183175"}
{"sentence": "Cell lines of human T-cell acute lymphoblastic leukemias ( T-ALL ) have gained high interest for study of mechanisms of cytostatic drug resistance . However , they should also be suited to examine the validity and reliability of molecular cytogenetic techniques in detecting genomic alterations in neoplastic cells . Therefore , comparative genomic hybridization ( CGH ) and 24-color-fluorescence-in-situ-hybridization ( M-FISH ) were applied to eight sublines of CCRF-CEM leukemia cells selected in vitro for drug resistance and to their drug-sensitive parental counterparts . All cell lines were characterized by altered chromosome numbers and by a variety of chromosomal structural aberrations as shown by M-FISH . The great majority of anomalies detected by this technique were confirmed by CGH . Interestingly , a considerable number of the rearrangements found were imbalanced . Amplifications of 5q13 in the six methotrexate-resistant cell lines , a del(9)(p21pter) in all lines examined , and a gain of chromosome 20 in 9 of the 10 lines examined were readily detected by both techniques . The same held true for losses of chromosomes 17 and 18 in the near tetraploid cell lines which could also be confirmed by CGH . Some imbalances of genomic material detected by CGH were , however , not observed by means of M-FISH , possibly due to the limited extension of the corresponding chromosomal segment involved or the small subpopulation of cells affected . On the other hand , reciprocal translocations , balanced isochromosomes , and small deletions remained mainly undetected by CGH . A comparison of chromosomal alterations in drug-resistant and parental cell lines showed not only amplifications of chromosomal segments harboring well-known drug resistance genes , e.g. , the dihydrofolate reductase gene , but also chromosomal changes which may involve novel genes associated with drug resistance . Thus , the present study has clearly unveiled the strengths and weaknesses of both techniques which can excellently complement each other . Their combination allowed a distinct improvement of the definition of the complex karyotypes of drug-resistant cell lines .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12697993"}
{"sentence": "Common fragile sites ( CFSs ) are hot spots of chromosomal breakage , and CFS breakage models involve perturbations of DNA replication . Here , we analyzed the contribution of specific repetitive DNA sequence elements within CFSs to the inhibition of DNA synthesis by replicative and specialized DNA polymerases ( Pols ) . The efficiency of in vitro DNA synthesis was quantitated using templates corresponding to regions within FRA16D and FRA3B harboring AT-rich microsatellite and quasi-palindrome ( QP ) sequences . QPs were predicted to form stems of self-homology , separated by 3-9 bases of intervening sequences . Analysis of DNA synthesis progression by human Pol \\u03b4 demonstrated significant synthesis perturbation both at [ A](n) and [ TA](n) repeats in a length-dependent manner and at short ( <40 base pairs ) QP sequences . DNA synthesis by the Y-family polymerase \\u03ba was significantly more efficient than Pol \\u03b4 through both types of repetitive elements . Using DNA trap experiments , we show that Pol \\u03b4 pauses within CFS sequences are sites of enzyme dissociation , and dissociation was observed in the presence of RFC-loaded PCNA . We propose that enrichment of microsatellite and QP elements at CFS regions contributes to fragility by perturbing replication through multiple mechanisms , including replicative Pol pausing and dissociation . Our finding that Pol \\u03b4 dissociates at specific CFS sequences is significant , since dissociation of the replication machinery and inability to efficiently recover the replication fork can lead to fork collapse and/or formation of double-strand breaks in vivo . Our biochemical studies also extend the potential involvement of Y-family polymerases in CFS maintenance to include polymerase \\u03ba .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23174185"}
{"sentence": "Urokinase-type plasminogen activator ( u-PA ) plays an important role in tumor growth and metastasis . The aim of this work was to study the u-PA production , in vitro and in vivo , in a transplantable murine mammary adenocarcinoma ( M3 ) , moderately metastatic to lung , and in a related tumor variant ( MM3 ) , highly metastatic to the same organ , during tumor development . At different times post-transplantation , tumors were employed to prepare either primary cell cultures or homogenates . PA activity from conditioned media ( CM ) , cell lysates ( CLs ) and tumor homogenates ( THs ) was quantitated by means of a fibrinolytic assay . Immunoneutralization and zymographic assays were performed to identify the PA present in both tumors . PA activity in CM , CLs and THs , that was undetectable at early stages , increased significantly along the growth of M3 adenocarcinoma . Secreted PA activity in MM3 CM was measurable at early stages and consistently increased up to 37 days post-transplantation , but a marked fall of activity was found at 48 days . PA activity in MM3 THs exhibited the same enhancement and late fall found in vitro . A positive correlation was observed between tumor size and THs PA values in both tumors . The PA present in cell cultures and THs was identified as of the u-PA type . These results support the hypothesis that high u-PA levels are important for tumor invasion and that the stage of tumor development is a critical factor in their PA activity .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1451349"}
{"sentence": "The effect of acute intense intermittent exercise compared with moderate-intensity exercise on angiogenic factors and the effect of 4 weeks of intense intermittent training on capillary growth were examined in nine healthy young men , preconditioned by moderate-intensity endurance training . The intense training consisted of 24 bouts of 1 min cycling at an initial work rate of 316 \u00b1 19 W ( of pretraining maximal oxygen uptake ) , performed three times per week . Skeletal muscle biopsies and muscle microdialysates were obtained from the vastus lateralis before , during and after acute exercise performed at either moderate or high intensity . Comparison of the response in angiogenic factors to acute moderate- versus high-intensity exercise , performed prior to the intense training intervention , revealed that intense exercise resulted in a markedly lower ( P < 0.05 ) increase in interstitial vascular endothelial growth factor than did moderate-intensity exercise . Muscle interstitial fluid obtained during moderate-intensity exercise increased endothelial cell proliferation in vitro more than interstitial fluid obtained during intense exercise ( sixfold versus 2.5-fold , respectively ; P < 0.05 ) . The 4 weeks of high-intensity training did not lead to an increased capillarization in the muscle but abolished the exercise-induced increase in mRNA for several angiogenic factors , increased the protein levels of endothelial nitric oxide synthase , lowered the protein levels of thrombospondin-1 in muscle but increased the interstitial protein levels of thrombospondin-1 . We conclude that intense intermittent exercise provides a weak stimulus for vascular endothelial growth factor secretion and endothelial cell proliferation and that intense intermittent training does not induce a sufficient angiogenic stimulus to induce capillary growth in muscle previously conditioned by moderate-intensity exercise .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22962287"}
{"sentence": "We have made xeroderma pigmentosum group A gene ( XPA)-knockout mice ( XPA(-/-) mice ) . The XPA(-/-) mice had no detectable activity for nucleotide excision repair ( NER ) and showed a high incidence of UVB-induced skin tumorigenesis . We have also found that cell lines derived from skin cancers in UVB-irradiated XPA(-/-) mice become tolerant to UV-irradiation and showed abnormal UV-induced cell cycle checkpoints and decreased mismatch repair ( MMR ) activity . These results suggested that the MMR-downregulation may help cells escape killing by UV-irradiation and thus MMR-deficient clones are selected for during the tumorigenic transformation of XPA(-/-) cells . In this report , we examined whether the incidence of UVB-induced skin tumorigenesis is enhanced in XPA(-/-)MSH2(-/-) , XPA(-/-) and MSH2(-/-) mice when compared with that in wild-type mice . Our results indicate that the MSH2-deficiency caused a high incidence of spontaneous and UVB-induced skin tumorigenesis and the XPA and MSH2 genes have additive roles in the UV-induced skin tumorigenesis .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "12531021"}
{"sentence": "Malignant mesothelioma ( MM ) still remains a therapeutic and diagnostic problem to which new therapeutic perspectives are being continuously tried and tested . Three different primary cultures ( MMGe-1 , MES MM 98 , and MES 1 ) and one immortalized cell line ( MSTO 211 H ) of human MM were studied in order to evaluate the HER-2/neu expression . Three out of four cell lines showed a different level of c-erbB-2 expression , the highest being detected on the MSTO 211 H cell line ( fibroblastic phenotype ) , whereas MMGe-1 resulted negative . The effect of the anti-HER-2/neu antibody ( Trastuzumab ) alone , and in combination with cisplatin ( CDDP ) at different doses ( ranging from 0.1 to 100 microg/ml ) , was studied on all the c-erB-2 positive cell lines . Trastuzumab was able to inhibit cell proliferation in a time-dependent manner , with growth inhibition also obtained at low concentrations ( 0.1-1 microg/ml ) . Combined treatment with Trastuzumab ( 10 microg/ml ) and CDDP ( 1 microg/ml ) showed synergism . Our results were encouraging , and suggest a rationale for further investigations in a clinical setting .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12209878"}
{"sentence": "OBJECTIVE The aim of this retrospective study is to analyze the clinical and pathological factors related to the prognosis of Chinese patients with stage Ib to IIb cervical cancer . METHODS AND RESULTS 13 clinical pathological factors in 255 patients with stage Ib to IIb cervical cancer undergoing radical hysterectomy and systematic lymphadenectomy were analyzed to screen for factors related to prognosis . The cumulative 5-year survival of the 255 patients was 75.7% . The result of the univariate analysis suggested that clinical stage , cell differentiation , depth of cervical stromal invasion , parametrial tissue involvement , and lymph node metastasis were prognostic factors for patients with stage Ib to IIb cervical cancer ( P<0.05 ) . Compared with cases with involvement of iliac nodes , obturator nodes , or inguinal lymph nodes , cases with metastasis to the common iliac lymph nodes had a poorer prognosis ( P<0.05 ) . Cases with involvement of four or more lymph nodes had a poorer prognosis than those with involvement of three or fewer lymph nodes ( P<0.05 ) . Using multivariate Cox proportional hazards model regression analysis , non-squamous histological type , poor differentiation , parametrial tissue involvement , and outer 1/3 stromal invasion were found to be independently related to patients poor prognosis ( P<0.05 ) . CONCLUSION Non-squamous histological type , poor cell differentiation , parametrial tissue involvement , and outer 1/3 stromal invasion are the independent poor prognostic factors for patients with stage Ib to IIb cervical cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23317208"}
{"sentence": "Gastrointestinal stromal tumor ( GIST ) is a prototype of mutant KIT oncogene-driven tumor . Prolonged tyrosine kinase inhibitor ( TKI ) treatment may result in a resistant phenotype through acquired secondary KIT mutation . Heat shock protein 90 ( HSP90AA1 ) is a chaperone protein responsible for protein maturation and stability , and KIT is a known client protein of HSP90AA1 . Inhibition of HSP90AA1 has been shown to destabilize KIT protein by enhancing its degradation via the proteasome-dependent pathway . In this study , we demonstrated that NVP-AUY922 ( AUY922 ) , a new class of HSP90AA1 inhibitor , is effective in inhibiting the growth of GIST cells expressing mutant KIT protein , the imatinib-sensitive GIST882 and imatinib-resistant GIST48 cells . The growth inhibition was accompanied with a sustained reduction of both total and phosphorylated KIT proteins and the induction of apoptosis in both cell lines . Surprisingly , AUY922-induced KIT reduction could be partially reversed by pharmacological inhibition of either autophagy or proteasome degradation pathway . The blockade of autophagy alone led to the accumulation of the KIT protein , highlighting the role of autophagy in endogenous KIT turnover . The involvement of autophagy in endogenous and AUY922-induced KIT protein turnover was further confirmed by the colocalization of KIT with MAP1LC3B- , acridine orange- or SQSTM1-labeled autophagosome , and by the accumulation of KIT in GIST cells by silencing either BECN1 or ATG5 to disrupt autophagosome activity . Therefore , the results not only highlight the potential application of AUY922 for the treatment of KIT-expressing GISTs , but also provide the first evidence for the involvement of autophagy in endogenous and HSP90AA1 inhibitor-induced KIT degradation .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23196876"}
{"sentence": "Antithymocyte globulin is widely used before haematopoietic transplantation with HLA-matched unrelated donors or mismatched relatives to prevent rejection and graft-versus-host disease ( GVHD ) . However , optimal dosage is still under debate . Thirty-one consecutive children , mainly with haematological malignancies , were transplanted in a single institution with such donors , selected by HLA-A -B compatibility by serology and DRB1* by DNA typing . Antithymocyte globulin ( Thymoglobuline ; Sangstat ) was infused at days -3 , -2 , -1 . Total dosage varied : 16 patients received a median of 7.5 mg/kg ( 2.5 to 10.5 : low-dose group ) , and 15 a median of 15.5 mg/kg ( 14.4 to 19.4 : high-dose group ) . Post-transplant GVHD prophylaxis consisted of cyclosporine , short-course methotrexate and steroids . CD3(+) , CD4(+) and CD19(+) cell reconstitution was slower in the high-dose group . Median time to reach 100 CD4(+) cells was 8 months vs 4 months ( P = 0.03 ) . Median time to normal CD19(+) cells was 16 months vs 8 months ( P = 0.01 ) . CD16(+)CD56(+) and CD8(+) cell reconstitution was similar . Nine patients in the high-dose group and two in the low-dose group experienced life-threatening opportunistic infections ( P = 0.009 ) . Although obtained from a limited number of patients , our data suggest that a higher pre-graft dose of antithymocyte globulin may negatively influence immune reconstitution .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12368953"}
{"sentence": "BACKGROUND Ovarian surface epithelial cells undergo several rounds of division to repair the wound created by follicular rupture at the time of ovulation . This cyclical requirement for cell division , when not interrupted by the long anovulatory rest periods that occur during pregnancy and lactation , may contribute to the development of ovarian cancer . PURPOSE AND METHODS To test this hypothesis , we isolated rat ovarian surface epithelial cells from 10 adult female Fisher rats , initiated two mixed-population and seven clonal cell lines , and repeatedly subcultured these cells in vitro for more than 20 passages . We then tested them for the acquisition of the following four features associated with transformation : 1 ) the loss of contact inhibition , 2 ) the capacity for substrate-independent growth , 3 ) the ability to form tumors when injected subcutaneously and/or intraperitoneally into athymic mice , and 4 ) cytogenetic abnormalities . RESULTS Loss of contact inhibition was observed in all nine late-passage cell lines . Six of the nine late-passage , but none of the early-passage , cell lines tested exhibited a capacity for substrate-independent growth that was augmented in a dose-dependent manner by epidermal growth factor . Two late-passage cell lines ( clone 2 and mixed-population 2 ) generated tumors in athymic BALB/c mice within 3 weeks following subcutaneous injection of 5 x 10(6) cells , whereas similar numbers of early-passage cells from the same cell lines failed to generate palpable tumors . Late-passage clone 7 cells were tumorigenic when 5 x 10(7) cells were injected intraperitoneally . Two of the cell lines analyzed exhibited alterations involving losses of part or all of one member of the chromosome 5 pair . Clone 2 possessed an interstitial deletion , del(5)(q21.3q24) , consistent with the loss of an uncloned putative tumor suppressor gene at 5q22q23 previously reported to reside near the loci for the interferon alpha , interferon beta , and c-jun genes . Early-passage clone 7 cells exhibited chromosome 5 monosomy , while late-passage cells contained one normal chromosome 5 and a derivative ( 5q12q ) . Southern analysis of the three cell lines revealed no consistent loss of loci for the interferon and c-jun genes , although early-passage clone 7 cells had one half the gene copy number for the interferon beta and c-jun genes and both early- and late-passage clone 7 cells lacked DNA sequences hybridizing with the probe for interferon alpha . CONCLUSION This pattern of passage-dependent spontaneous transformation of rat ovarian surface epithelial cells in vitro supports the hypothesis that repetitious ovulation contributes to the etiology of human ovarian cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "1556770"}
{"sentence": "Epidermal growth factor ( EGF ) receptor is inversely related to expression of estrogen receptor ( ER ) and progesterone receptor in primary breast tumors and is a negative predictor for response to endocrine therapy . To investigate a possible causal role of EGF receptor expression in breast cancer progression to hormone independence , we have created an experimental cell system . Epidermal growth factor receptor complementary DNA was introduced in estrogen-dependent ZR-75-1 breast cancer cells , and the resulting ZR/HERc cells exhibited a mitogenic response to epidermal growth factor , thus bypassing estrogen dependence . This EGF-induced proliferation could not be inhibited by antiestrogens . In addition , we noted changes in cell morphology and keratin expression of EGF-stimulated ZR/HERc cells , suggestive of an altered differentiation state . Furthermore , intolerance of functional ER and EGF receptor signal transduction pathways in ZR/HERc cells was observed during simultaneous activation , which possibly explains the inverse relationship of ER and EGF receptor expression in primary tumors . In contrast to the parental cells , ZR/HERc cells rapidly progressed to a stable ER-negative phenotype when cultured in the presence of the antiestrogen hydroxy-tamoxifen . These results suggest a possible role for EGF receptor in progression of breast cancer to hormone independence .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1516065"}
{"sentence": "Ruthenium complexes hold great potential as alternatives to cisplatin in cancer chemotherapy . We present results on the in vitro antitumor activity of an organometallic ' Ru(II)Cp ' complex , [ Ru(II)Cp(bipy)(PPh(3))][CF(3)SO(3) ] , designated as TM34 ( PPh(3) = triphenylphosphine ; bipy = 2,2'-bipyridine ) , against a panel of human tumor cell lines with different responses to cisplatin treatment , namely ovarian ( A2780/A2780cisR , cisplatin sensitive and resistant , respectively ) , breast ( MCF7 ) and prostate ( PC3 ) adenocarcinomas . TM34 is very active against all tumorigenic cell lines , its efficacy largely surpassing that of cisplatin ( CisPt ) . The high activity of TM34 towards CisPt resistant cell lines possibly suggests a mechanism of action distinct from that of CisPt . The effect of TM34 on the activity of the enzyme poly(ADP-ribose) polymerase 1 ( PARP-1 ) involved in DNA repair mechanisms and apoptotic pathways was also evaluated , and it was found to be a strong PARP-1 ruthenium inhibitor in the low micromolar range ( IC(50)=1.0 \u00b1 0.3 \\u03bcM ) . TM34 quickly binds to human serum albumin forming a 1:1 complex with a conditional stability constant ( log K ' comparable to that of the Ru(III) complex in clinical trial KP1019 . This indicates that TM34 can be efficiently transported by this protein , possibly being involved in its distribution and delivery if the complex is introduced in the blood stream . Albumin binding does not affect TM34 activity , yielding an adduct that maintains cytotoxic properties ( against A2780 and A2780cisR cells ) . Altogether , the properties herein evaluated suggest that TM34 could be an anticancer agent of highly relevant therapeutic value .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22877927"}
{"sentence": "The vascular endothelial growth factor ( VEGF ) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers . However , the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance . By screening a panel of candidate growth factors we identified fibroblast growth factor 2 ( FGF2 ) as a potent regulator of endothelial cell sensitivity to sunitinib . We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules . Importantly , these effects of FGF2 were ablated by PD173074 , a small molecule inhibitor of FGF receptor signalling . We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib . Finally , analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2 . We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21057538"}
{"sentence": "Emergence of vancomycin-intermediate Staphylococcus aureus ( VISA ) and vancomycin-resistant S. aureus ( VRSA ) strains has led to global concerns about treatments for staphylococcal infections . These strains are currently rare even though there is an upward trend in their reported incidence . Therefore , appropriate screening and epidemiological evaluation of VRSA strains can affect future global health care policies . Isolates of Staphylococcus aureus were obtained from various clinical samples and were then evaluated with agar screening , disk diffusion , and MIC methods to determine resistance to vancomycin and methicillin . After confirmation of the isolated VRSA strain , genetic analysis was performed by evaluating mecA and vanA gene presence , SCCmec , agr , and spa types , and toxin profiles . Multilocus sequence typing ( MLST ) and plasmid analysis were also performed . The VRSA strain was resistant to oxacillin ( MIC of 128 \\u03bcg/ml ) and vancomycin ( MIC of 512 \\u03bcg/ml ) . Disk diffusion antimicrobial susceptibility tests showed resistance to oxacillin , vancomycin , levofloxacin , ciprofloxacin , trimethoprim-sulfamethoxazole , clindamycin , rifampin , and tetracycline . The isolate was susceptible to minocycline and gentamicin . PCRs were positive for the mecA and vanA genes . Other genetic characteristics include SCCmec type III , agr I , spa type t037 , and sequence type ( ST ) 1283 . The plasmid profile shows five plasmids with a size of kb to >10 kb . The isolated VRSA strain was obtained from a critically ill hospitalized patient . Genetic analysis of this strain suggested that the strain was a methicillin-resistant S. aureus ( MRSA ) clone endemic in Asia that underwent some genetic changes , such as mutation in the gmk gene and acquisition of the vanA gene .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22933598"}
{"sentence": "It has been shown that regulation of EGFR expression in prostate cancer cells is mostly at the transcriptional level. microRNA-133 ( miR-133 ) has long been recognized as a muscle-specific miRNA which may regulate myoblast differentiation and participate in many myogenic diseases . Recently , it has been reported that miR-133 is also involved in other tumors , such as bladder cancer , esophageal cancer and may regulate cell motility in these cancer cells . In the present study , we examined the expression and effects of miR-133 in two hormone-insensitive prostate cancer cell lines . The expression of miR-133a and miR-133b were analyzed by quantitative RT-PCR . After transfection of miR-133a and miR-133b , cell viability assay , luciferase assay , western blot analysis , cell migration and invasion assay were conducted in Du145 and PC3 cells . In this study , we showed that miR\u2011133a and miR-133b are expressed at the detection limit in two hormone-insensitive prostate cancer cell lines , PC3 and DU145 . Ectopic expression of miR-133 inhibited cell proliferation , migration and invasion in these cells . We also provide the first evidence that miR-133 may target EGFR . Our study provided the first glimpse of the functional role of miR-133 in two hormone-independent prostate cancer cell lines . These results may add to our knowledge on the molecular basis of prostate cancer progression .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22407299"}
{"sentence": "The effects of an anti-CD3 mAb on induction of non-MHC restricted cytolysis was investigated . Peripheral blood mononuclear cells ( PBMC ) from normal donors ( 29 ) and cancer patients ( 18 ) were cultured in 100 U/ml of interleukin-2 ( rIL-2 ) with and without anti-CD3 mAb ( OKT3 , 10 ng/ml ) for the first 48 hours of incubation . Thereafter , both PBMC cultures were maintained on rIL-2 up to 20 days . PBMC proliferation was enhanced 17-fold in number by day 20 when anti-CD3 mAb and rIL-2 was present during the first 48 hours but only 3-fold by day 20 when rIL-2 alone was present . Concomitantly anti-CD3 mAb but not Lym-1 , an isotype matched control , inhibited the induction of lytic activity against both NK sensitive ( K562 ) and NK resistant ( Raji ) target cell lines . Thus the inhibitory effect is dependent on anti-CD3 mAb stimulating the CD3/TCR T-cell receptor complex . While lytic activity was dependent on the concentration of rIL-2 , inhibition of the induction phase of non-MHC restricted lytic activity was independent of the concentration of rIL-2 . Flow cytometry analysis indicated that treatment with the anti-CD3 mAb increased the percentage of CD3 positive cells , CD4 positive cells and especially CD25 positive cells , but decreased th percentage of CD56 positive cells . Supernatants from anti-CD3 mAb stimulated cultures also inhibited the induction of non-MHC restricted lytic activity . Lymphokine analysis showed that supernatants of anti-CD3 mAb stimulated cultures had higher levels of TNF-alpha and IFN-gamma . However , TNF-alpha and IFN-gamma alone or in combination could not mediate the inhibitory effect . The inhibitory factor(s) was partially purified by sequential chromatography on matrices of controlled pore glass and Sepharose CL-6B . The molecular weight of the inhibitory factor(s) was less than 67K . These studies have identified a novel regulatory pathway controlling non-MHC restricted cytolysis . Perturbation of the T-cell CD3/TCR complex with the anti-CD3 mAb results in the secretion of a soluble mediator that down-regulates the induction of rIL-2 dependent non-MHC restricted cytolysis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1295440"}
{"sentence": "Neurofibromatosis type 2 patients develop schwannomas , meningiomas and ependymomas resulting from mutations in the tumor suppressor gene , NF2 , encoding a membrane-cytoskeleton adapter protein called merlin . Merlin regulates contact inhibition of growth and controls the availability of growth factor receptors at the cell surface . We tested if microtubule-based vesicular trafficking might be a mechanism by which merlin acts . We found that schwannoma cells , containing merlin mutations and constitutive activation of the Rho/Rac family of GTPases , had decreased intracellular vesicular trafficking relative to normal human Schwann cells . In Nf2-/- mouse Schwann ( SC4 ) cells , re-expression of merlin as well as inhibition of Rac or its effector kinases , MLK and p38(SAPK) , each increased the velocity of Rab6 positive exocytic vesicles . Conversely , an activated Rac mutant decreased Rab6 vesicle velocity . Vesicle motility assays in isolated squid axoplasm further demonstrated that both mutant merlin and active Rac specifically reduce anterograde microtubule-based transport of vesicles dependent upon the activity of p38(SAPK) kinase . Taken together , our data suggest loss of merlin results in the Rac-dependent decrease of anterograde trafficking of exocytic vesicles , representing a possible mechanism controlling the concentration of growth factor receptors at the cell surface .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "22525268"}
{"sentence": "Intracellular pH ( pHi ) plays a critical role in the entry of cells into the DNA-synthesis phase of the cell cycle . Alterations in pHi may contribute to abnormal proliferative responses such as those seen in tumorigenic cells . We observed that alkaline stress leads to genomic transformation of Madin-Darby canine kidney ( MDCK ) cells . Transformed cells ( F cells ) form \" foci \" in culture , lack contact inhibition , and are able to migrate , typical characteristics of dedifferentiated tumorigenic cells . F cells exhibit spontaneous biorhythmicity . Rhythmic transmembrane Ca2+ flux activates plasma membrane K+ channels and Na+/H+ exchange . This leads to periodic changes of membrane voltage and pHi at about one cycle per minute . We conclude that endogenous oscillatory activity could be a trigger mechanism for DNA synthesis , proliferation , and abnormal growth of renal epithelial cells in culture .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "1450637"}
{"sentence": "Progression of breast cancer is associated with remodeling of the extracellular matrix , often involving a switch from estrogen dependence to a dependence on EGF receptor ( EGFR)/HER-2 and is accompanied by increased expression of the main binding protein for insulin-like growth factors ( IGFBP-3 ) . We have examined the effects of IGFBP-3 on EGF responses of breast epithelial cells in the context of changes in the extracellular matrix . On plastic and laminin with MCF-10A normal breast epithelial cells , EGF and IGFBP-3 each increased cell growth and together produced a synergistic response , whereas with T47D breast cancer cells IGFBP-3 alone had no effect , but the ability of EGF to increase cell proliferation was markedly inhibited in the presence of IGFBP-3 . In contrast on fibronectin with MCF-10A cells , IGFBP-3 alone inhibited cell growth and blocked EGF-induced proliferation . With the cancer cells , IGFBP-3 alone had no effect but enhanced the EGF-induced increase in cell growth . The insulin-like growth factor-independent effects of IGFBP-3 alone on cell proliferation were completely abrogated in the presence of an EGFR , tyrosine kinase inhibitor , Iressa . Although IGFBP-3 did not affect EGFR phosphorylation [ Tyr(1068) ] , it was found to modulate receptor internalization and was associated with activation of Rho and subsequent changes in MAPK phosphorylation . The levels of fibronectin and IGFBP-3 within breast tumors may determine their dependence on EGFR and their response to therapies targeting this receptor .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20851879"}
{"sentence": "The active involvement of physical exercise in the evolution of a variety of cancers is well documented . However , its role in solid leukemia tumor development is essentially unknown . Solid leukemia tumor cells were transplanted into 21 hybrid BDF1 control mice , exercise-trained mice that did not exercise during leukemia and exercise-trained mice that exercised during leukemia . The tumor size of the continuously exercising group was of that of control and exercise-terminated animals 18 days after the transplantation . The activity of antioxidant enzymes and the levels of lipid peroxidation and 8-hydroxy-2'-deoxyguanosine were not different in the tumors of the three groups . The level of carbonylated proteins was smaller in tumors of continuously exercising animals . The mutant form of cell regulatory protein p53 and vascular endothelial growth factor were present in similar amounts in the tumor cells of each group . On the other hand , the protooncogene Ras and I-kappaB proteins were present in higher concentrations in tumors of continuously exercising rats . The present data suggest that exercise during leukemia attenuates the development of tumors in mice . The selective alteration of regulatory proteins might play a role in the beneficial effects of exercise during leukemia .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "11970855"}
{"sentence": "High-throughput screening of a small-molecule library identified a 5-triazolo-2-arylpyridazinone as a novel inhibitor of the important glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 ( PFKFB3 ) . Such inhibitors are of interest due to PFKFB3's control of the important glycolytic pathway used by cancer cells to generate ATP . A series of analogues was synthesized to study structure-activity relationships key to enzyme inhibition . Changes to the triazolo or pyridazinone rings were not favoured , but limited-size substitutions on the aryl ring provided modest increases in potency against the enzyme . Selected analogues and literature-described inhibitors were evaluated for their ability to suppress the glycolytic pathway , as detected by a decrease in lactate production , but none of these compounds demonstrated such suppression at non-cytotoxic concentrations .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "24398380"}
{"sentence": "Cigarette smoking is implicated in numerous diseases , including emphysema and lung cancer . The clinical expression of lung disease in smokers is not well explained by currently defined variations in gene expression or simple differences in smoking exposure . Alveolar macrophages play a critical role in the inflammation and remodeling of the lung parenchyma in smoking-related lung disease . Significant gene expression changes in alveolar macrophages from smokers have been identified . However , the mechanism for these changes remains unknown . One potential mechanism for smoking-altered gene expression is via changes in cytosine methylation in DNA regions proximal to gene-coding sequences . In this study , alveolar macrophage DNA from heavy smokers and never smokers was isolated and methylation status at 25,000 loci determined . We found differential methylation in genes from immune-system and inflammatory pathways . Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune-system and inflammatory pathways . A significant number of genes with smoking-altered mRNA expression had inverse changes in methylation status . One gene highlighted by this data was the FLT1 , and further studies found particular up-regulation of a splice variant encoding a soluble inhibitory form of the receptor . In conclusion , chronic cigarette smoke exposure altered DNA methylation in specific gene promoter regions in human alveolar macrophages .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22427682"}
{"sentence": "Focal inflammation causes systemic fever . Cancer hyperthermia therapy results in shrinkage of tumors by various mechanisms , including induction of adaptive immune response . However , the physiological meaning of systemic fever and mechanisms of tumor shrinkage by hyperthermia have not been completely understood . In this study , we investigated how heat shock influences the adaptive immune system . We established a cytotoxic T lymphocyte ( CTL ) clone ( #IM29 ) specific for survivin , one of the tumor-associated antigens ( TAAs ) , from survivin peptide-immunized cancer patients ' peripheral blood , and the CTL activities were investigated in several temperature conditions ( 37-41\ufffdC ) . Cytotoxicity and IFN-\u03b3 secretion of CTL were greatest under 39\ufffdC condition , whereas they were minimum under 41\ufffdC . To address the molecular mechanisms of this phenomenon , we investigated the apoptosis status of CTLs , expression of CD3 , CD8 , and TCR\u03b1\u03b2 by flow cytometry , and expression of perforin , granzyme B , and Fas ligand by western blot analysis . The expression of perforin and granzyme B were upregulated under temperature conditions of 39 and 41\ufffdC . On the other hand , CTL cell death was induced under 41\ufffdC condition with highest Caspase-3 activity . Therefore , the greatest cytotoxicity activity at 39\ufffdC might depend on upregulation of cytotoxic granule proteins including perforin and granzyme B. These results suggest that heat shock enhances effector phase of the adaptive immune system and promotes eradication of microbe and tumor cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22777894"}
{"sentence": "OBJECTIVE To study the effect of necrostatin ( Nec-1 ) on apoptosis induced by aluminum ( Al ) , and approach the mechanism . METHODS Neural cell death model was made by 4 mmol/L Al treated neuroblastoma cells ( SH-SY5Y ) . Cell viabilities were detected at different concentrations of Al and/or Nec-1 . Hoechst 33342/PI double staining was used to observe apoptosis and ( or ) necrosis that were quantified by flow cytometry using Annexin V/PI double staining . Apoptotic pathway was tested by activities of Caspase-3 , Caspase-8 and Caspase-9 . In addition , the expression of NF-kappa B and Cyt-c was measured by immunocytochemistry . RESULTS Cell viabilities were significantly decreased with the increasing concentrations of Al ( P < 0.05 ) , which could be significantly upregulated by 60 micromol/L Nec-1 ( P < 0.05 ) and were correlated with the concentrations of Nec-1 ( P < 0.05 , P < 0.01 ) . Apoptosis and necrosis were observed under fluorescent microscope and quantified by flow cytometry , which suggested an increasing trend of apoptotic and necrotic rates ( P < 0.05 , P < 0.01 ) . Whereas , Nec-1 could not only decrease the necrotic rate but also apoptotic rate as well ( P < 0.05 , P < 0.01 ) . Data of Nec-1 on caspases activities showed that Nec-1 could not affect Caspase-9 activity ( P > 0.05 ) and Cty-c protein expression as well ( P > 0.05 ) . However , Nec-1 could reduce Caspase-8 activity significantly ( P < 0.05 , P < 0.01 ) and increase NF-kappa B protein expression ( P < 0.05 , P < 0.01 ) and finally decrease Caspase-3 activity ( P < 0.05 ) . CONCLUSION Nec-1 could reduce cell apoptosis induced by Al , through Caspase-8 pathway , and up-regulate the expression of NF-kappa B protein .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20635689"}
{"sentence": "When the cell cycle is arrested , even though growth-promoting pathways such as mTOR are still active , then cells senesce . For example , induction of either p21 or p16 arrests the cell cycle without inhibiting mTOR , which , in turn , converts p21/p16-induced arrest into senescence ( geroconversion ) . Here we show that geroconversion is accompanied by dramatic accumulation of cyclin D1 followed by cyclin E and replicative stress . When p21 was switched off , senescent cells ( despite their loss of proliferative potential ) progressed through S phase , and levels of cyclins D1 and E dropped . Most cells entered mitosis and then died , either during mitotic arrest or after mitotic slippage , or underwent endoreduplication . Next , we investigated whether inhibition of mTOR would prevent accumulation of cyclins and loss of mitotic competence in p21-arrested cells . Both nutlin-3 , which inhibits mTOR in these cells , and rapamycin suppressed geroconversion during p21-induced arrest , decelerated accumulation of cyclins D1 and E and decreased replicative stress . When p21 was switched off , cells successfully progressed through both S phase and mitosis . Also , senescent mouse embryonic fibroblasts ( MEFs ) overexpressed cyclin D1 . After release from cell cycle arrest , senescent MEFs entered S phase but could not undergo mitosis and did not proliferate . We conclude that cellular senescence is characterized by futile hyper-mitogenic drive associated with mTOR-dependent mitotic incompetence .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "23187803"}
{"sentence": "Single-nucleotide polymorphisms in genes involved in DNA-damage-induced responses are reported frequently to be a risk factor in various cancer types . Here we analysed polymorphisms in 5 genes involved in DNA repair ( XPD Asp312Asn and Lys751Gln , XRCC1 Arg399Gln , APE1 Asp148Glu , NBS1 Glu185Gln , and XPA G-4A ) and in a gene involved in regulation of the cell-cycle ( CCND1 A870G ) . We compared their frequencies in groups of colon , head and neck , and breast cancer patients , and 2 healthy control groups : ( 1 ) matched healthy Polish individuals and ( 2 ) a NCBI database control group . Highly significant differences in the distribution of genotypes of the APE1 , XRCC1 and CCND1 genes were found between colon cancer patients and healthy individuals . The 148Asp APE1 allele and the 399Gln XRCC1 allele apparently increased the risk of colon cancer ( OR = 1.9-2.3 and OR = 1.5-2.1 , respectively ) . Additionally , frequencies of XPD genotypes differed between healthy controls and patients with colon or head and neck cancer . Importantly , no differences in the distribution of these polymorphisms were found between healthy controls and breast cancer patients . The data clearly indicate that the risk of colon cancer is associated with single-nucleotide polymorphism in genes involved in base-excision repair and DNA-damage-induced responses .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20720310"}
{"sentence": "Findings of increased numbers of epidermal growth factor receptors ( EGF-R ) and increased expression of transforming growth factor alpha ( TGF-alpha ) in surgical specimens of human renal cell carcinoma have led to the proposal that growth of these tumors may be regulated by TGF-alpha in an autocrine manner . In the studies presented here , we have examined this hypothesis using two human renal carcinoma cell lines , SKRC-4 and SKRC-29 . We demonstrated that both SKRC-4 and SKRC-29 cells were growth stimulated by greater than 35% when cultured in the presence of TGF-alpha or EGF and were inhibited by 29% to 46% if cultured in the presence of anti-EGF-R monoclonal antibody 225 . Treatment of cells with TGF-alpha enhanced the levels of expression of EGF-R mRNA and TGF-alpha mRNA . In addition , incubation of cells with monoclonal antibody 225 significantly elevated the levels of excreted TGF-alpha species in the culture medium . Our findings suggest that proliferation of human renal carcinoma cells may be regulated by endogenously produced TGF-alpha and that this regulatory pathway can be interrupted using antibody to its receptor , EGF-R .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1596891"}
{"sentence": "Breast cancer is the most commonly diagnosed cancer in women in the world and is one of the leading causes of death due to cancer . Health benefits have been linked to additive and synergistic combinations of phytochemicals in fruits and vegetables . Nigella sativa has been shown to possess anti-carcinogenic activity , inhibiting growth of several cancer cell lines in vitro . However , the molecular mechanisms of the anti-cancer properties of Nigella sativa phytochemical extracts have not been completely understood . Our data showed that Nigella sativa extracts significantly inhibited human breast cancer MDA-MB-231 cell proliferation at doses of 2.5-5 \u03bcg/mL ( P<0.05 ) . Apoptotic induction in MDA-MB-231 cells was observed in a dose-dependent manner after exposure to Nigella sativa extracts for 48 h . Real time PCR and flow cytometry analyses suggested that Nigella sativa extracts possess the ability to suppress the proliferation of human breast cancer cells through induction of apoptosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23317266"}
{"sentence": "Kaposi sarcoma is the most common neoplasm caused by Kaposi sarcoma-associated herpesvirus ( KSHV ) . It is prevalent among the elderly in the Mediterranean , inhabitants of sub-Saharan Africa , and immunocompromised individuals such as organ transplant recipients and AIDS patients . Current treatments for Kaposi sarcoma can inhibit tumor growth but are not able to eliminate KSHV from the host . When the host's immune system weakens , KSHV begins to replicate again , and active tumor growth ensues . New therapeutic approaches are needed . Cannabidiol ( CBD ) , a plant-derived cannabinoid , exhibits promising antitumor effects without inducing psychoactive side effects . CBD is emerging as a novel therapeutic for various disorders , including cancer . In this study , we investigated the effects of CBD both on the infection of endothelial cells ( ECs ) by KSHV and on the growth and apoptosis of KSHV-infected ECs , an in vitro model for the transformation of normal endothelium to Kaposi sarcoma . While CBD did not affect the efficiency with which KSHV infected ECs , it reduced proliferation and induced apoptosis in those infected by the virus . CBD inhibited the expression of KSHV viral G protein-coupled receptor ( vGPCR ) , its agonist , the chemokine growth-regulated protein \u03b1 ( GRO-\u03b1 ) , vascular endothelial growth factor receptor 3 ( VEGFR-3 ) , and the VEGFR-3 ligand , vascular endothelial growth factor C ( VEGF-C ) . This suggests a potential mechanism by which CBD exerts its effects on KSHV-infected endothelium and supports the further examination of CBD as a novel targeted agent for the treatment of Kaposi sarcoma .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "23264851"}
{"sentence": "In cancer , glucose uptake and glycolysis are increased regardless of the oxygen concentration in the cell , a phenomenon known as the Warburg effect . Several ( but not all ) glycolytic enzymes have been investigated as potential therapeutic targets for cancer treatment using RNAi . Here , four previously untargeted glycolytic enzymes , aldolase A , glyceraldehyde 3-phosphate dehydrogenase , triose phosphate isomerase , and enolase 1 , are targeted using RNAi in Ras-transformed NIH-3T3 cells . Of these enzymes , knockdown of aldolase causes the greatest effect , inhibiting cell proliferation by 90% . This defect is rescued by expression of exogenous aldolase . However , aldolase knockdown does not affect glycolytic flux or intracellular ATP concentration , indicating a non-metabolic cause for the cell proliferation defect . Furthermore , this defect could be rescued with an enzymatically dead aldolase variant that retains the known F-actin binding ability of aldolase . One possible model for how aldolase knockdown may inhibit transformed cell proliferation is through its disruption of actin-cytoskeleton dynamics in cell division . Consistent with this hypothesis , aldolase knockdown cells show increased multinucleation . These results are compared with other studies targeting glycolytic enzymes with RNAi in the context of cancer cell proliferation and suggest that aldolase may be a useful target in the treatment of cancer .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23093405"}
{"sentence": "Chromosomal instability is the major form of genomic instability in cancer cells . Amongst various forms of chromosomal instability , pericentromeric or centromeric instability remains particularly poorly understood . In the present study , we found that pericentromeric instability , evidenced by dynamic formation of pericentromeric or centromeric rearrangements , breaks , deletions or iso-chromosomes , was a general phenomenon in human cells immortalized by expression of human papillomavirus type 16 E6 and E7 ( HPV16 E6E7 ) . In particular , for the first time , we surprisingly found a dramatic increase in the proportion of pericentromeric chromosomal aberrations relative to total aberrations in HPV16 E6E7-expressing cells 72 h after release from aphidicolin ( APH)-induced replication stress , with pericentromeric chromosomal aberrations becoming the predominant type of structural aberrations ( of total aberrations ) . In contrast , pericentromeric aberrations accounted for only about 20% of total aberrations in cells at the end of APH treatment . This increase in relative proportion of pericentromeric aberrations after release from APH treatment revealed that pericentromeric breaks induced by replication stress are refractory to prompt repair in HPV16 E6E7-expressing epithelial cells . Telomerase-immortalized epithelial cells without HPV16 E6E7 expression did not exhibit such preferential pericentromeric instability after release from APH treatment . Cancer development is often associated with replication stress . Since HPV16 E6 and E7 inactivate p53 and Rb , and p53 and Rb pathway defects are common in cancer , our finding that pericentromeric regions are refractory to prompt repair after replication stress-induced breakage in HPV16 E6E7-expressing cells may shed light on mechanism of general pericentromeric instability in cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23119062"}
{"sentence": "Curcumin ( CUR ; diferuloylmethane ) , a rhizome extract of Curcuma Longa L. is commonly used as a food coloring and flavoring agent . Although oriental and Ayurvedic medicines have traditionally used CUR in the treatment of diseases , conventional medicine has just begun to recognize its potential therapeutic value . Numerous recent studies have demonstrated the ability of CUR to halt or prevent certain types of cancer , decrease inflammation , and improve cardiovascular health . However , very few studies have examined its ability to protect against drug-induced organ injury . This study explored whether CUR pre-exposure has the potential to prevent acetaminophen ( APAP)-induced : ( i ) hepatotoxicity , ( ii ) genomic injury , ( iii ) oxidative stress in the liver , and ( iv ) apoptotic and necrotic cell deaths in the liver in vivo . Additional goals were to investigate the interplay of pro- and anti-apoptotic genes and their ultimate impact on various forms of cell death . In order to study the CUR-APAP interaction , male B6C3F1 mice were gavaged with CUR ( 17 mg/kg/day , p.o. ) for 12 days followed by a single APAP exposure ( 400 mg/kg , ip ) . Four groups of animals ( control , CUR , APAP , CUR+APAP ) were sacrificed 24 h after APAP exposure . The results indicated that APAP-induced liver injury associated events as serum ALT ( 80-fold ) , lipid peroxidation ( 357% ) and DNA fragmentation ( 469% ) were markedly reduced to 3-fold , 134% and 162% , respectively , in the CUR+APAP group . The APAP-induced increase in expression of pro-apoptotic genes ( Bax , caspase-3 ) decreased while expression of anti-apoptotic genes ( Bcl-XL ) increased in CUR preexposed mouse livers , and these changes were mirrored in the pattern of apoptotic and necrotic cell deaths . Levels of DNA damage sensor P\u2075\u00b3 and its counterpart Mdm2 were also analyzed during this interaction . Based on the available literature , and these results , it seems likely that CUR may impart global protection in vivo against drug-induced liver injury by opposing several crucial events instrumental to both apoptosis and necrosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "22272768"}
{"sentence": "The triterpene saponin ginsenoside Rh2 has been shown to have antiproliferative effects on various cancer cells . However , the effect of Rh2 on the cell cycle and its underlying molecular mechanism in human leukemia cells are not fully understood . In this study , we found that Rh2 inhibited the proliferation of human leukemia cells concentration- and time-dependently with an IC(50) of \ufffdM . DNA flow cytometric analysis indicated that Rh2 blocked cell cycle progression at the G(1) phase in HL-60 and U937 cells , and this was found to be accompanied by the downregulations of cyclin-dependent kinase ( CDK ) 4 , CDK6 , cyclin D1 , cyclin D2 , cyclin D3 and cyclin E at the protein level . However , CDK inhibitors ( CDKIs ) , such as p21(CIP1/WAF1) and p27(KIP1) , were gradually upregulated after Rh2 treatment at the protein and messenger RNA ( mRNA ) levels . In addition , Rh2 markedly enhanced the bindings of p21(CIP1/WAF1) and p27(KIP1) to CDK2 , CDK4 and CDK6 , and these bindings reduced CDK2 , CDK4 and CDK6 activities . Furthermore , Rh2 induced the differentiation of HL-60 cells as demonstrated by biochemical assays and the expression levels of cell surface antigens . In addition , treatment of HL-60 cells with Rh2 significantly increased transforming growth factor-\u03b2 ( TGF-\u03b2 ) production , and cotreatment with TGF-\u03b2 neutralizing antibody prevented the Rh2-induced downregulations of CDK4 and CDK6 , upregulations of p21(CIP1/WAF1) and p27(KIP1) levels and the induction of differentiation . These results demonstrate that the Rh2-mediated G(1) arrest and the differentiation are closely linked to the regulation of TGF-\u03b2 production in human leukemia cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23125221"}
{"sentence": "PURPOSE Astrocytoma arises in the central nervous system as a tumor of great lethality , in part because of the invasive potential of the neoplastic cells that are able to release extracellular matrix-degrading enzymes . Furin convertase activates several precursor matrix metalloproteases involved in the breakdown of the extracellular matrix . In the present study inhibition of furin was achieved by gene transfer of alpha(1)-antitrypsin Portland ( PDX ) cDNA . EXPERIMENTAL DESIGN This furin inhibitor was transfected into two tumorigenic astrocytoma cell lines . The inhibitory effect was evaluated using in vivo tumorigenicity , invasion , and proliferation assays , as well as by investigating impairment of furin substrate processing . RESULTS Expression of PDX prevented the s.c. growth of the transfected cells . Invasion assays demonstrated that PDX-transfected cells exhibited a reduced invasive ability in vitro and in vivo . Furthermore , s.c. growth of PDX transfectant xenotransplants showed a significant reduction in size that coincided with a significant decrease of the in vitro doubling time and of the in vivo cell proliferation ability . Additional studies showed that the furin substrates insulin-like growth factor IR , transforming growth factor beta and membrane type 1-matrix metalloprotease were not activated in PDX-expressing astrocytoma cells . CONCLUSIONS PDX expression in astrocytoma cells demonstrated a direct mechanistic link between furin inhibition , and decreased astrocytoma proliferation and invasive ability . Because furin inhibition inhibits both invasiveness and cell growth in astrocytoma , furin should be considered a promising target for glioblastoma therapy .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12060611"}
{"sentence": "Ovarian hormones have a pivotal role in the control of proliferation in the mammary gland , and cumulative life-time exposure to ovarian hormones is known to be a determinant of breast cancer risk . We have shown previously that a p.o.-active , long-acting butyrate analogue , sodium phenylbutyrate ( PB ) , reduced proliferation in normal and malignant human breast cells in culture and reduced expression of ovarian hormone receptors , suggesting that PB had cellular effects consistent with decreasing breast cancer risk . The aim of this study was to determine the in vivo effects of PB in the normal mammary gland on epithelial cell proliferation , estrogen receptor alpha ( ER alpha ) expression , and cyclin D1 expression . BALB/c mice were treated with PB , delivered by mini-osmotic pumps , for 7 days . Moderate ( 250 mg/kg/day ) and high ( 500 mg/kg/day ) PB treatment resulted in a decrease in proliferation in mammary epithelial cells ( P < 0.001 ) , determined by bromodeoxyuridine incorporation . Analysis of ER alpha immunostaining revealed a significant reduction in moderate- and high-treatment groups ( P = 0.01 and P = 0.02 ) , and expression of cyclin D1 was virtually ablated ( P < 0.001 ) . Histone deacetylase inhibition is a known mechanism of butyrate action , and consistent with this , PB increased levels of acetylated histone H3 in the mammary gland . In summary , PB decreased proliferation in the mammary gland in vivo at clinically achievable doses . Decreased proliferation was accompanied by changes in the levels of ER alpha and cyclin D1 . These data show that PB modulates parameters thought to be involved in the carcinogenic process in the normal mammary gland , and compounds in this class may therefore be useful candidates for breast cancer chemoprevention .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12481425"}
{"sentence": "AMP-activated protein kinase ( AMPK ) has been implicated in anti-proliferative actions in a range of cell systems . Recently , it was observed that Compound C , an inhibitor of AMPK , also reduced the cell viability in human diploid fibroblasts ( HDFs ) . Compound C-induced growth arrest was associated with a decrease in the cell cycle regulatory proteins , such as proliferating cell nuclear antigen , phosphorylated pRB , cyclin-dependent protein kinases ( Cdk 2 and 4 ) , cyclins ( D and E ) , and the Cdk inhibitors ( p21 , p16 , and p27 ) . Therefore , the present study examined the molecular mechanism of the antiproliferative effects of Compound C. Although Compound C inhibited serum-induced phosphorylation of Akt and its substrate , glycogen synthase kinase-3\u03b2 , it did not affect the Akt activity in vitro . Compound C significantly inhibited the receptor tyrosine phosphorylation and the activity of downstream signaling molecules , such as p85 phosphoinositide 3-kinase , phospholipase C-\u03b31 , and extracellular signal-regulated kinase 1/2 , induced by platelet-derived growth factor ( PDGF ) but not by epidermal growth factor- and insulin-like growth factor . In vitro growth factor receptor tyrosine kinase activity profiling revealed the IC(50) for PDGF receptor-\u03b2 ( PDGFR\u03b2 ) to be 5.07 \u03bcM , whereas the IC(50) for the epidermal growth factor receptor and insulin-like growth factor receptor was \u2265100 \u03bcM . The inhibitory effect of Compound C on PDGFR\u03b2 and Akt was also observed in AMPK\u03b1(1)/\u03b1(2)-knockout mouse embryonic fibroblasts , indicating that its inhibitory effect is independent of the AMPK activity . The inhibitory effect of Compound C on cell proliferation and PDGFR\u03b2 tyrosine phosphorylation was also demonstrated in various PDGFR-expressing cells , including MRC-5 , BEAS-2B , rat aortic vascular smooth muscle cells , and A172 glioblastoma cells . These results indicate that Compound C can be used as a potential antiproliferative agent for PDGF- or PDGFR-associated diseases , such as cancer , atherosclerosis , and fibrosis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23277201"}
{"sentence": "Transcriptional coactivator amplified in breast cancer 1 ( AIB1 ) plays important roles in the progression of several cancers such as prostate cancer , breast cancer , and hepatocellular carcinoma . However , its role in cholangiocarcinoma ( CCA ) , a chemoresistant bile duct carcinoma with a poor prognosis , remains unclear . In this study we found that AIB1 protein was frequently overexpressed in human CCA specimens and CCA cell lines . Down-regulation of AIB1 induced the G2/M arrest and decreased the expression of mitosis-promoting factors including Cyclin A , Cyclin B , and Cdk1 through suppressing the Akt pathway , which resulted in inhibiting CCA cell proliferation . In addition , AIB1 enhanced the chemoresistance of CCA cells at least in part through up-regulating the expression of antiapoptotic protein Bcl-2 . AIB1 regulated the expression of Bcl-2 in CCA cells through activating the Akt pathway as well as suppressing intracellular reactive oxygen species ( ROS ) . AIB1 suppressed ROS by up-regulating antioxidants such as glutathione synthetase and glutathione peroxidase , which are targets of the NF-E2-related factor 2 ( Nrf2 ) , a critical transcription factor that regulates antioxidants , detoxification enzymes , and drug efflux proteins . AIB1 also increased the expression of another two Nrf2 targets , ABCC2 and ABCG2 , to enhance drug efflux . AIB1 served as an essential coactivator for Nrf2 activation by physically interacting with Nrf2 to enhance its transcriptional activity . Conclusion : AIB1 plays an important role in proliferation and chemoresistance of CCA through simultaneous activation of Akt and Nrf2 pathways , suggesting that AIB1 is a potential molecular target for CCA treatment .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 1], "id": "22213475"}
{"sentence": "This study aimed to observe the effects of octreotide ( OCT ) on cisplatin resistance reversal of cancer cells in vitro and in nude mice in vivo . MTT method and flow cytometry were used to investigate the effect of cisplatin , OCT or the combination of these two compounds on the proliferation and apoptosis of SKOV3-DDP cells . The size and weight of xenograft tumors from the nude mice model were measured . Real-time PCR was used to detect the mRNA expression of SSTR2 , MDR1 , MRP2 , GST-pi and EGFR in SKOV3/DDP cells following the different treatment . At the concentration of 2.5-20 g/ml , OCT significantly reduced IC50 ( p < 0.05 ) and promoted apoptosis ( p < 0.05 ) of SKOV3-DDP cells ' response to cisplatin . Unchanged expression was found in SSTR2 on the SKOV3/DDP cell in vitro after OCT treatment , but increased expression in vivo ( p < 0.05 ) . OCT increased GST-pi expression ( p < 0.05 ) and reduced MRP2 and EGFR expression ( p < 0.05 ) in a dose-dependent manner . The similar results were obtained in mice in vivo experiment , except the reduced expression of GST-pi . It is suggested that OCT could inhibit ovarian cancer proliferation and promote apoptosis , via the cell surface SSTR2 , and reverse cisplatin resistance through inhibition of MRP2 , EGFR , and even GST-pi expressions .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23327050"}
{"sentence": "Medulloblastomas are the most common malignant brain tumors in children . Several large-scale genomic studies have detailed their heterogeneity , defining multiple subtypes with unique molecular profiles and clinical behavior . Increased expression of the miR-183 cluster of microRNAs has been noted in several subgroups , including the most clinically aggressive subgroup associated with genetic amplification of MYC . To understand the contribution of miR-183 to the pathogenesis of this aggressive subtype of medulloblastoma , we analyzed global gene expression and proteomic changes that occur upon modulation of miRNAs in this cluster individually and as a group in MYC-amplified medulloblastoma cells . Knockdown of the full miR-183 cluster results in enrichment of genes associated with apoptosis and dysregulation of the PI3K/AKT/mTOR signaling axis . Conversely , there is a relative enrichment of pathways associated with migration , metastasis and epithelial to mesenchymal transition , as well as pathways associated with dysfunction of DNA repair in cells with preserved miR-183 cluster expression . Immunocytochemistry and FACS analysis confirm induction of apoptosis upon knockdown of the miR-183 cluster . Importantly , cell-based migration and invasion assays verify the positive regulation of cell motility/migration by the miR-183 cluster , which is largely mediated by miR-182 . We show that the effects on cell migration induced by the miR-183 cluster are coupled to the PI3K/AKT/mTOR pathway through differential regulation of AKT1 and AKT2 isoforms . Furthermore , we show that rapamycin inhibits cell motility/migration in medulloblastoma cells and phenocopies miR-183 cluster knockdown . Thus , the miR-183 cluster regulates multiple biological programs that converge to support the maintenance and metastatic potential of medulloblastoma .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22402744"}
{"sentence": "Currently , there are no satisfactory biomarkers available to screen for nasopharyngeal carcinoma ( NPC ) . Nitric oxide ( NO ) , produced by inducible nitric oxide synthase ( iNOS ) , has been suggested to cause nitrative and oxidative stress , leading to the accumulation of 8-nitroguanine ( 8-NitroG ) and 8-hydroxy-2'-deoxyguanosine ( 8-OHdG ) and the subsequent transversion mutation of DNA . The aim of this study was to evaluate iNOS expression and the status of nitrative and oxidative stress in NPC . Fifty-nine cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine the expression of iNOS and the formation of 8-NitroG and 8-OHdG , using double-immunofluorescent staining . The statistical differences in immunoreactivities were analyzed using the Mann-Whitney test . Thirty-six patients from the 57 cases of NPC and 36 healthy controls were investigated to examine the level of serum 8-OHdG , using enzyme-linked immunosorbent assay ( ELISA ) . The statistical differences were analyzed using a t test . Strong DNA lesions were observed in the cancer cells of NPC patients . All cases of NPC were positive for 8-NitroG and 8-OHdG , and 54 ( 94.7% ) were positive for iNOS . NPC samples exhibited significantly more intense staining for 8-NitroG , 8-OHdG and iNOS than those of chronic nasopharyngitis ( P < 0.05 , respectively ) . The mean value of serum 8-OHdG in the 36 NPC patients was 0.538 \u00b1 0.336 ng/ml compared to 0.069 \u00b1 0.059 ng/ml for the healthy controls . The difference in the serum levels of 8-OHdG between the NPC patients and controls was statistically significant ( P < 0.05 ) . Our present findings suggest that pathological stimulation of nasopharyngeal tissue , caused by bacterial , viral or parasitic inflammation , may lead to nitrative and oxidative DNA lesions , caused by NO . This may contribute to the cause and development of NPC . Thus , 8-NitroG and 8-OHdG could be potential biomarkers for evaluating the risk of NPC . Better understanding of the molecular mechanisms underlying nitrative and oxidative DNA damage may provide clues to molecular targets for new approaches of NPC prevention .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "20339958"}
{"sentence": "Induction of the expression of the Mr 67,000 high-affinity laminin receptor gene has been postulated as playing a role in the progression of human tumors to invasive cancers . We tested this hypothesis by examining histopathological sections of a large number of epithelial lesions of the genital tract associated with human papillomaviruses . In situ hybridization was performed with a riboprobe generated from a laminin receptor complementary DNA . Laminin receptor mRNA was expressed primarily in the less differentiated cells in normal squamous tissues and in a spectrum of squamous neoplasms . There was no net induction of mRNA per cell in intraepithelial or invasive squamous neoplasms relative to normal tissue . In contrast , laminin receptor mRNA was not expressed at a detectable level in normal glands of the uterine cervix but was dramatically induced in morphologically abnormal , human papillomavirus-positive glands , irrespective of the genotype of human papillomaviruses present . The induction occurred before any evidence of invasion , and there was no further increase during the transition from adenocarcinoma in situ to invasive carcinoma . We conclude that induction of high-affinity laminin receptor gene expression is associated with the development of malignancies of cervical glandular epithelia , but the increased expression appears to correlate with the proliferative rather than the invasive properties of these cells .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1311633"}
{"sentence": "Semi-conservative replication of double-stranded DNA in eukaryotic cells is an asymmetric process involving leading and lagging strand synthesis and different DNA polymerases . We report a study to analyze the effect of these asymmetries when the replication machinery encounters alkylation-induced DNA adducts . The model system is an EBV-derived shuttle vector which replicates in synchrony with the host human cells and carries as marker gene the bacterial gpt gene . A preferential distribution of N-methyl-N-nitrosourea ( MNU)-induced mutations in the non transcribed DNA strand of the shuttle vector pF1-EBV was previously reported . The hypermutated strand was the leading strand . To test whether the different fidelity of DNA polymerases synthesizing the leading and the lagging strands might contribute to MNU-induced mutation distribution the mutagenesis study was repeated on the shuttle vector pTF-EBV which contains the gpt gene in the inverted orientation . We show that the base substitution error rates on an alkylated substrate are similar for the replication of the leading and lagging strands . Moreover , we present evidence that the fidelity of replication opposite O6-methylguanine adducts of both the leading and lagging strands is not affected by the 3 ' flanking base . The preferential targeting of mutations after replication of alkylated DNA is mainly driven by the base at the 5 ' side of the G residues .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1336179"}
{"sentence": "Targeting cancer cell metabolism is a new promising strategy to fight cancer . Metformin , a widely used antidiabetic agent , exerts antitumoral and antiproliferative action . In this study , the addition of metformin to 2-deoxyglucose ( 2DG ) inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a severe depletion in ATP . The combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone , leading to 96% inhibition of cell viability in LNCaP prostate cancer cells . In contrast , a moderate effect on cell viability was observed in normal prostate epithelial cells . At the cellular level , the combination of metformin and 2DG induced p53-dependent apoptosis via the energy sensor pathway AMP kinase , and the reexpression of a functional p53 in p53-deficient prostate cancer cells restored caspase-3 activity . In addition to apoptosis , the combination of metformin and 2DG arrested prostate cancer cells in G(2)-M . This G(2)-M arrest was independent of p53 and correlated with a stronger decrease in cell viability than obtained with either drug . Finally , metformin inhibited 2DG-induced autophagy , decreased beclin 1 expression , and triggered a switch from a survival process to cell death . Our study reinforces the growing interest of metabolic perturbators in cancer therapy and highlights the potential use of the combination of metformin and 2DG as an anticancerous treatment .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "20215500"}
{"sentence": "The epithelial-mesenchymal transition ( EMT ) is a fundamental process governing morphogenesis in multicellular organisms and has recently been implicated in promoting carcinoma invasion and metastasis . Besides their therapeutic effects , accumulating evidences suggest that chemotherapeutic agents also induced EMT and enhanced the malignancy of treated cancer cells ; however , the mechanism(s) still remains unclear . Here , we investigated the role of \u03b2-catenin signaling in doxorubicin ( Dox)-induced EMT in human gastric cancer cell line BGC-823 . We found that the transient treatment of Dox induced EMT and enhanced the in vitro migration ability of cancer cells . We also found that \u03b2-catenin signaling was activated upon Dox treatment . Inhibition of \u03b2-catenin by indomethacin ( Indo ) or siRNA suppressed Dox-induced EMT and decreased cancer cell migration ability . Our results showed that \u03b2-catenin signaling was critical to Dox-induced EMT . Indo and other \u03b2-catenin inhibitors may have a potential implication in prevention of gastric cancer metastasis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23055201"}
{"sentence": "Breast cancer is a heterogeneous disease at both the clinical and molecular levels . This heterogeneity may give rise to different therapy responses . Molecular profiling has facilitated identification of signatures for stratifying patients who would potentially benefit from given therapies . Previously , we reported on a subset of genes with the potential for predicting response of primary breast cancer to neoadjuvant chemotherapy . Herein , we report that patients with luminal ( estrogen receptor \u03b1 [ ER\u03b1]-expressing ) breast cancer were enriched for nonresponders . To identify novel factors that contribute to the survival of breast cancer cells , a loss-of-function screen was performed with a subset of genes overexpressed in patients with disease resistant to chemotherapy . This approach led us to identify protein phosphatase 1 , regulatory subunit 15B ( PPP1R15B ) as a factor with a potentially essential role in the survival of ER\u03b1-positive breast cancer cells . Functional analyses showed that PPP1R15B depletion results in impaired proliferation due to unsuccessful transition of cells from G1 to S phase of the cell cycle , and apoptosis induction . Moreover , our data revealed a regulatory role for PPP1R15B in activating ER\u03b1 . Furthermore , a high level of PPP1R15B mRNA expression was associated with poor outcome following tamoxifen-based therapy . Accordingly , knockdown of PPP1R15B expression sensitized tamoxifen-resistant MCF-7 breast cancer cells to tamoxifen while reducing ER\u03b1 abundance in these cells . Our findings reveal a novel role for PPP1R15B in the survival and therapy response of ER\u03b1-positive breast cancer and may open new avenues for tumor subtype-specific therapeutic strategies in the era of personalized medicine .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23169272"}
{"sentence": "Xanthone exhibits several medicinal activities and especially it inhibits the growth of cancer cells . However , the use of xanthone is limited because of its low aqueous solubility and systemic toxicity . In the present study xanthone was loaded into poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl ) methacrylamide-dilactate ] mPEG-b-p(HPMAm-Lac(2)) micelles in order to overcome these drawbacks . It was shown that xanthone could be loaded in these micelles up to 2 mg/mL with entrapment efficiency and loading capacity . The average particle diameter of the xanthone loaded mPEG-b-p(HPMAm-Lac(2)) micelles as determined by dynamic light scattering ranged from 84 to 112 nm . In vitro assays showed that xanthone in its free form as well as loaded in polymeric micelles had a high cytotoxicity towards both doxorubicin sensitive and , importantly , resistant cancer cells . On the other hand empty mPEG-b-p(HPMAm-Lac(2)) micelles did not show any cytotoxicity towards normal cells ( PBMCs ) . Interestingly , the cytostatic effect of xanthone towards normal cells was masked when loaded in the micelles . The mechanism of cell growth inhibition by xanthone-loaded polymeric micelles was mediated through induction of apoptosis , as evidenced from a subdiploid peak of propidium iodide stained cells using flow cytometric analysis . From the results of this study it can be concluded that xanthone has potent anticancer activity not only on sensitive but also on doxorubicin resistant cancer cell lines. mPEG-b-p(HPMAm-Lac(2)) micelles are therefore attractive delivery systems of xanthone for the treatment of cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22377215"}
{"sentence": "The Sonic hedgehog ( SHH ) pathway is implicated in the etiology of the most common human cancer in Caucasians , the basal cell carcinoma ( BCC ) . Mutations in the receptor of SHH , the patched gene , have been characterized in sporadic BCCs as well as those from patients with the rare genetic syndromes nevoid BCC and xeroderma pigmentosum ( XP ) . To elucidate the role of UV in the deregulation of the SHH pathway , we analyzed for alterations of smoothened , a transmembrane signaling component regulated by patched , in BCCs and squamous cell carcinomas from UV hypersensitive XP patients . We find UV-specific smoothened mutations in 30% of XP BCCs , three times higher than those in sporadic Caucasian BCCs , confirming the high rate of UV-induced mutations in DNA repair-deficient XP patients . No alteration was found in XP squamous cell carcinomas , indicating the involvement of smoothened specifically in the development of BCC .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12499255"}
{"sentence": "p53 is a crucial tumor suppressor that is mutated or deleted in a majority of cancers . Exactly how p53 prevents tumor progression has proved elusive for many years ; however , this information is crucial to define targets for chemotherapeutic development that can effectively restore p53 function . Bioactive sphingolipids have recently emerged as important regulators of proliferative , apoptotic and senescent cellular processes . In this study , we demonstrate that the enzyme sphingosine kinase 1 ( SK1 ) , a critical enzyme in the regulation of the key bioactive sphingolipids ceramide , sphingosine and sphingosine-1-phosphate ( S1P ) , serves as a key downstream target for p53 action . Our results show that SK1 is proteolysed in response to genotoxic stress in a p53-dependent manner. p53 null mice display elevation of SK1 levels and a tumor-promoting dysregulation of bioactive sphingolipids in which the anti-growth sphingolipid ceramide is decreased and the pro-growth sphingolipid S1P is increased . Importantly , deletion of SK1 in p53 null mice completely abrogated thymic lymphomas in these mice and prolonged their life span by Deletion of SK1 also significantly attenuated the formation of other cancers in p53 heterozygote mice . The mechanism of p53 tumor suppression by loss of SK1 is mediated by elevations of sphingosine and ceramide , which in turn were accompanied by increased expression of cell cycle inhibitors and tumor cell senescence . Thus , targeting SK1 may restore sphingolipid homeostasis in p53-dependent tumors and provide insights into novel therapeutic approaches to cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21765468"}
{"sentence": "To determine the threshold dose of \u03b2-Naphthoflavone ( BNF ) that induces hepatocellular tumor promoting effects , reactive oxygen species ( ROS ) generation and thiobarbituric acid-reactive substance ( TBARS ) formation , and drug-metabolizing enzymes that protect against ROS generation , two-stage liver carcinogenesis model was used . Partial hepatectomized rats ( n = 11 to 12 ) were fed diets containing 0 , 0.03 , 0.06 , 0.125 or 0.25% BNF for 6 weeks after an intraperitoneal injection of N-diethylnitrosamine ( DEN ) to initiate hepatocarcinogenesis . Histopathologically , glutathione S-transferase placental form ( GST-P)-positive foci significantly increased in rats given 0.25% BNF . No marked changes in ROS production and TBARS contents were observed between the BNF treated and DEN alone groups . Real-time RT-PCR showed that the expression of Cyp1a1 , Cyp1a2 , Cyp1b1 and Nqo1 significantly increased in the groups given 0.03% BNF or more , but Ugt1a6 , Akr7a3 and Gstm1 significantly increased in the groups given 0.125% BNF or more . Gpx2 and Yc2 significantly increased in the groups given 0.06% BNF or more and 0.25% BNF , respectively . Inflammation-related genes such as Ccl2 , Mmp12 , Serpine1 and Cox-2 significantly increased in the 0.25% BNF group . In immunohistochemistry , the number of cyclooxygenase-2 ( COX-2)-positive cells increased in rats given 0.25% BNF . These results suggest that 0.25% BNF is the threshold dose for liver tumor promotion , and the fact that inflammation-related genes and COX-2 protein increased in the 0.25% BNF group strongly suggests that inflammation is involved in the liver tumor promoting effect of BNF in rats .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22687991"}
{"sentence": "This article describes evaluation of plasma membrane fluidity and intracellular SOD with relation to apoptotic death of cervical carcinoma cells after radiation therapy . Cells from biopsies of cancer patients ( stage IIIB ) prior to and 24 h after radiation dose of 2 Gy were examined . Plasma membrane fluidity , measured by fluorescence polarization of DPH incorporated into lipid bilayer and superoxide dismutase ( SOD ) activity , determined by epinephrine method , showed significant decrease but per cent apoptotic cells , as determined by annexin-V and TUNEL methods , were found increased by two folds after radiotherapy . It is suggested that decrease in DPH polarization in membrane , reduction in SOD activity and increased apoptosis in cervical cells of cancer patients treated with radiation may be consequent to oxidative damage induced by reactive oxygen species ( ROS ) , which may have implications in developing predictive protocol in cancer radiotherapy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "12815293"}
{"sentence": "The AP-1 transcription factor c-Jun is essential for cellular proliferation in many cell types , but the molecular link between growth factors and c-Jun activation has been enigmatic . In this study we identify a previously uncharacterized RING-domain-containing protein , RACO-1 ( RING domain AP-1 co-activator-1 ) , as a c-Jun co-activator that is regulated by growth factor signalling . RACO-1 interacted with c-Jun independently of amino-terminal phosphorylation , and was both necessary and sufficient for c-Jun/AP-1 activation . Growth factor-mediated stimulation of AP-1 was attributable to MEK/ERK-dependent stabilization of RACO-1 protein . Stimulation of the MEK/ERK pathway strongly promoted Lys 63-linked ubiquitylation of RACO-1 , which antagonized Lys 48-linked degradative auto-ubiquitylation of the same Lys residues . RACO-1 depletion reduced cellular proliferation and decreased expression of several growth-associated AP-1 target genes , such as cdc2 , cyclinD1 and hb-egf . Moreover , transgenic overexpression of RACO-1 augmented intestinal tumour formation triggered by aberrant Wnt signalling and cooperated with oncogenic Ras in colonic hyperproliferation . Thus RACO-1 is a co-activator that links c-Jun to growth factor signalling and is essential for AP-1 function in proliferation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20852630"}
{"sentence": "BACKGROUND Acrylamide is a common dietary exposure that crosses the human placenta . It is classified as a probable human carcinogen , and developmental toxicity has been observed in rodents . OBJECTIVES We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother-child study . METHODS Hemoglobin ( Hb ) adducts of acrylamide and its metabolite glycidamide were measured in cord blood ( reflecting cumulated exposure in the last months of pregnancy ) from 1,101 singleton pregnant women recruited in Denmark , England , Greece , Norway , and Spain during 2006-2010 . Maternal diet was estimated through food-frequency questionnaires . RESULTS Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference . The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was -132 g ( 95% CI : -207 , -56 ) ; the corresponding difference for head circumference was -0.33 cm ( 95% CI : -0.61 , -0.06 ) . Findings were similar in infants of nonsmokers , were consistent across countries , and remained after adjustment for factors associated with reduced birth weight . Maternal consumption of foods rich in acrylamide , such as fried potatoes , was associated with cord blood acrylamide adduct levels and with reduced birth weight . CONCLUSIONS Dietary exposure to acrylamide was associated with reduced birth weight and head circumference . Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero . If confirmed , these findings suggest that dietary intake of acrylamide should be reduced among pregnant women .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23092936"}
{"sentence": "Hepatitis C virus ( HCV ) NS3 helicase couples adenosine triphosphate ( ATP ) binding and hydrolysis to polynucleotide unwinding . Understanding the regulation mechanism of ATP binding will facilitate targeting of the ATP-binding site for potential therapeutic development for hepatitis C. T324 , an amino acid residue connecting domains 1 and 2 of NS3 helicase , has been suggested as part of a flexible hinge for opening of the ATP-binding cleft , although the detailed mechanism remains largely unclear . We used computational simulation to examine the mutational effect of T324 on the dynamics of the ATP-binding site . A mutant model , T324A , of the NS3 helicase apo structure was created and energy was minimized . Molecular dynamics simulation was conducted for both wild type and the T324A mutant apo structures to compare their differences . For the mutant structure , histogram analysis of pairwise distances between residues in domains 1 and 2 ( E291-Q460 , K210-R464 and R467-T212 ) showed that separation between the two domains was reduced by and the standard deviation by Root mean square fluctuation ( RMSF ) analysis demonstrated that residues in close proximity to residue 324 have at least 30% RMSF value reductions in the mutant structure . Solvent RMSF analysis showed that more water molecules were trapped near D290 and H293 in domain 1 to form an extensive interaction network constraining cleft opening . We also demonstrated that the T324A mutation established a new atomic interaction with V331 , revealing that an atomic interaction cascade from T324 to residues in domains 1 and 2 controls the flexibility of the ATP-binding cleft .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22870946"}
{"sentence": "BACKGROUND MicroRNAs ( miRNAs ) are short , non-coding RNAs ( nt ) that play important roles in the pathogenesis of human diseases by negatively regulating gene expression . Although miR-196a has been implicated in several other cancers , its role in non-small cell lung cancer ( NSCLC ) is unknown . The aim of the present study was to examine the expression pattern of miR-196a in NSCLC and its clinical significance , as well as its biological role in tumor progression . METHODS Expression of miR-196a was analyzed in 34 NSCLC tissues and five NSCLC cell lines by quantitative reverse-transcription polymerase chain reaction ( qRT-PCR ) . The effect of DNA methylation on miR-196a expression was investigated by 5-aza-2-deoxy-cytidine treatment and bisulfite sequencing . The effect of miR-196a on proliferation was evaluated by MTT and colony formation assays , and cell migration and invasion were evaluated by transwell assays . Analysis of target protein expression was determined by western blotting . Luciferase reporter plasmids were constructed to confirm the action of miR-196a on downstream target genes , including HOXA5 . Differences between the results were tested for significance using Student's t-test ( two-tailed ) . RESULTS miR-196a was highly expressed both in NSCLC samples and cell lines compared with their corresponding normal counterparts , and the expression of miR-196a may be affected by DNA demethylation . Higher expression of miR-196a in NSCLC tissues was associated with a higher clinical stage , and also correlated with NSCLC lymph-node metastasis . In vitro functional assays demonstrated that modulation of miR-196a expression affected NSCLC cell proliferation , migration and invasion . Our analysis showed that miR-196a suppressed the expression of HOXA5 both at the mRNA and protein levels , and luciferase assays confirmed that miR-196a directly bound to the 3'untranslated region of HOXA5 . Knockdown of HOXA5 expression in A549 cells using RNAi was shown to promote NSCLC cell proliferation , migration and invasion . Finally , we observed an inverse correlation between HOXA5 and miR-196a expression in NSCLC tissues . CONCLUSIONS Our findings indicate that miR-196a is significantly up-regulated in NSCLC tissues , and regulates NSCLC cell proliferation , migration and invasion , partially via the down-regulation of HOXA5 . Thus , miR-196a may represent a potential therapeutic target for NSCLC intervention .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22876840"}
{"sentence": "Whole genome duplications ( WGDs ) are considered to have been a driving force in the generation of evolutionary diversity that is characteristic of higher eukaryotes . The ancestor of salmonids underwent two additional WGDs compared to mammals , one ( 3R ) at the base of the teleost radiation and another ( 4R ) in the common ancestor of extant salmonids . We have chosen the fatty acid binding protein ( fabp ) gene family as a model to study the fate of duplicated genes in teleosts following WGDs . As previously described for zebrafish , we identified two copies ( fabp7a and fabp7b ) of the brain-type fabp gene in several fish including rainbow smelt , but there was only a single transcript in northern pike , the closest relative of the salmonids , and two rather than the expected four fabp7 genes in Atlantic salmon , rainbow trout and grayling . A phylogenetic analysis revealed that a loss of the fabp7a gene occurred in the common ancestor of the northern pike and salmonids after it had diverged from the rainbow smelt , and that the 4R WGD then gave rise to the fabp7bI and fabp7bII observed in salmonids . This is supported by genetic mapping that placed the Atlantic salmon duplicated fabp7b genes on homeologous chromosomes . There was no evidence of neo-functionalization in the salmonid fabp7bI and fabp7bII genes based on dN/dS ratios and an examination of amino acid substitutions . Atlantic salmon fabp7bI and fabp7bII genes are both expressed broadly like fabp7b expression in northern pike . However , only Atlantic salmon fabp7bII , like its counterpart in northern pike and zebrafish , was expressed in the liver . A comparison of upstream of Atlantic salmon fabp7b gene duplicates revealed an insertion of 62bp in fabp7bI relative to fabp7bII . The presence of predicted transcription factor binding sites in this insertion sequence may explain the differential expression of the fabp7b gene duplicates in Atlantic salmon liver .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22575613"}
{"sentence": "Collagen triple helix repeat containing-1 ( CTHRC1 ) is a secreted protein involved in vascular remodeling , bone formation and developmental morphogenesis . CTHRC1 has recently been shown to be expressed in human cancers such as breast cancer and melanoma . In this study , we show that CTHRC1 is highly expressed in human pancreatic cancer tissues and plays a role in the progression and metastasis of the disease . CTHRC1 promoted primary tumor growth and metastatic spread of cancer cells to distant organs in orthotopic xenograft tumor mouse models . Overexpression of CTHRC1 in cancer cells resulted in increased motility and adhesiveness , whereas these cellular activities were diminished by down-regulation of the protein . CTHRC1 activated several key signaling molecules , including Src , focal adhesion kinase , paxillin , mitogen-activated protein kinase kinase ( MEK ) , extracellular signal-regulated kinase and Rac1 . Treatment with chemical inhibitors of Src , MEK or Rac1 and expression of dominant-negative Rac1 attenuated CTHRC1-induced cell migration and adhesion . Collectively , our results suggest that CTHRC1 has a role in pancreatic cancer progression and metastasis by regulating migration and adhesion activities of cancer cells .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23222813"}
{"sentence": "Thirty-five cases of clear cell sarcoma of soft tissues were studied to determine the clinical or morphologic features that are important in predicting prognosis . Tumors occurred most commonly in the extremities , and the majority of the patients were young women . Surgery was the elected treatment in every case . Five patients experienced local recurrences , and metastases developed in 22 . Fifty-four percent of the patients died of tumor , 11% are alive with disease , and the remaining 34% are alive and well ; the average survival for each group was 67 months , 113 months , and 103.5 months , respectively . This sarcoma is characterized by small clusters of polygonal to spindle cells featuring clear to slightly basophilic cytoplasm and vesicular nuclei with prominent nucleoli . The clusters are separated by delicate fibrous septa . In a deletion , clear cell sarcoma has low mitotic activity , little or no necrosis , and mild nuclear pleomorphism . Tumor size and the presence of necrosis are statistically significant predictors of prognosis . All 12 patients with tumors measuring > 5 cm died of disease or are alive with disease . Eleven of the 20 patients with tumors measuring < 5 cm are alive with no evidence of disease . Tumor necrosis was present in 10 cases ; eight of these patients died of disease and one is alive with disseminated metastases .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1463095"}
{"sentence": "Thrombospondin-1 is a matricellular protein with potent antitumour activities , the levels of which determine the fate of many different tumours , including renal carcinomas . However , the factors that regulate this protein remain unclear . In renal carcinomas , hypoxic conditions enhance the expression of angiogenic factors that help adapt tumour cells to their hostile environment . Therefore , we hypothesized that anti-angiogenic factors should correspondingly be dampened . Indeed , we found that hypoxia decreased the thrombospondin-1 protein in several clear cell renal carcinoma cell lines ( ccRCC ) , although no transcriptional regulation was observed . Furthermore , we proved that hypoxia stimulates multiple signals that independently contribute to diminish thrombospondin-1 in ccRCC , which include a decrease in the activity of oxygen-dependent prolylhydroxylases ( PHDs ) and activation of the PI3K/Akt signalling pathway . In addition , thrombospondin-1 regulation in hypoxia proved to be important for ccRCC cell migration and invasion .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23145312"}
{"sentence": "PURPOSE To investigate treatment of human pancreatic cancer cell lines and xenografts with combinations of Erbitux ( IMC-C225 ) anti-epidermal growth factor receptor ( EGFR ) antibody , gemcitabine , and radiation . METHODS AND MATERIALS BxPC-3 and MiaPaCa-2 human pancreatic carcinoma cells were treated in vitro for 24 h with IMC-C225 ( 5 microg/mL ) , then exposed to epidermal growth factor ( EGF ) ( 10 mM ) for 5 min . Immunoblots were screened for EGFR expression and the ability of IMC-C225 to block EGF-induced tyrosine phosphorylation of EGFR . Cells were treated with IMC-C225 ( 5 microg/mL ) on Day 0 , the IC(50) dose of gemcitabine on Day 1 for 24 h , followed by 3 Gy 60Co irradiation on Day 2 , or the combination of each agent . For cell proliferation , cells were counted on Day 4 , and for apoptosis , cells were stained with annexin V-FITC and propidium iodide , then analyzed by FACS . Cells were treated with the same single or multiple treatments and analyzed in a clonogenic cell survival assay . The effect of IMC-C225 , gemcitabine , and radiation on the growth of BxPC-3 and MiaPaCa-2 tumor xenografts was determined . Athymic nude mice bearing established s.c. tumor xenografts of 6-8 mm diameter received 6 weeks of treatment with IMC-C225 ( 1 mg every 3 days x 6 ) alone or in combination with gemcitabine ( 120 mg/kg i.v. every 6 days x 6 ) , and 6 weekly fractions of 3 Gy radiation on the days after gemcitabine administration . Tumor growth was measured with Vernier calipers . RESULTS BxPC-3 and MiaPaCa-2 cell lines expressed low levels of EGFR . IMC-C225 inhibited EGF-induced tyrosine phosphorylation of the EGF receptor on both cell lines . Treatment of cells with a combination of IMC-C225 + gemcitabine + radiation produced the highest induction of apoptosis and inhibition of proliferation in vitro . Combination treatment with IMC-C225 , gemcitabine , and radiation produced 100% complete regression of MiaPaCa-2 tumors for more than 250 days , and the greatest growth inhibition of BxPC-3 tumors compared to any single or dual treatments . CONCLUSIONS The IMC-C225 therapy in combination with gemcitabine chemotherapy and radiation therapy demonstrated statistically significantly greater efficacy over the single and double combination therapies . This form of multimodality treatment shows potential clinical application in the treatment of pancreatic cancer in humans .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12419447"}
{"sentence": "Chromatin , a complex of DNA and proteins in the eukaryotic cell nucleus governs various cellular processes including DNA replication , DNA repair and transcription . Chromatin architecture and dynamics dictates the timing of cellular events by regulating proteins ' accessibility to DNA as well as by acting as a scaffold for protein-protein interactions . Nucleosome , the basic unit of chromatin consists of a histone octamer comprised of ( H3-H4)2 tetramer and two H2A-H2B dimers on which 146 bp of DNA is wrapped around times . Chromatin changes brought about by histone modifications , histone-modifying enzymes , chromatin remodeling factors , histone chaperones , histone variants and chromatin dynamics influence the regulation and timing of gene expression . Similarly , the timing of DNA replication is dependent on the chromatin context that in turn dictates origin selection . Further , during the process of DNA replication , not only does an organism's DNA have to be accurately replicated but also the chromatin structure and the epigenetic marks have to be faithfully transmitted to the daughter cells . Active transcription has been shown to repress replication while at the same time it has been shown that when origins are located at promoters , because of enhanced chromatin accessibility , they fire efficiently . In this review , we focus on how chromatin modulates two fundamental processes , DNA replication and transcription .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22267489"}
{"sentence": "Hormone antagonist therapy for estrogen receptor positive ( ER+ ) breast cancer patients post radical surgery and radiation therapy has a poor prognosis and also causes bone loss. 1\u03b1,25-dihydroxyvitamin D(3) [ 1\u03b1,25(OH)(2)D(3) ] is a potent antitumor agent in pre-clinical studies , but caused hypercalcemia when its effective antitumor doses were used . Therefore , we investigated the effects of a less-calcemic 1\u03b1,25(OH)(2)D(3) analog , 19-nor-2\u03b1-(3-hydroxypropyl)-1\u03b1,25-dihydroxyvitamin D(3 )(MART-10 ) , on ER+MCF-7 cells . We demonstrate that MART-10 is 500- to 1000-fold more potent than 1\u03b1,25(OH)(2)D(3) in inhibiting cell growth in a dose- and time-dependent manner . MART-10 is also much more potent in arresting MCF-7cell cycle progression at G(0)/G(1) phase as compared to 1\u03b1,25(OH)(2)D(3) , possibly mediated by a greater induction of p21 and p27 expression . Moreover , MART-10 is more active than 1\u03b1,25(OH)(2)D(3) in causing cell apoptosis , likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol . Based on our in vitro findings , MART-10 could be a promising vitamin D analog for the potential treatment of breast cancer , for example , ER+ patients , to decrease the tumor relapse rate and the side effect on bone caused by antihormone regimens . Thus , further in vivo animal study is warranted .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23304196"}
{"sentence": "Reactive oxygen species ( ROS ) such as hydrogen peroxide ( H(2)O(2) ) , O(*-)(2) and OH(*) participate in the pathogenesis of ischemia/reperfusion injury , inflammation and atherosclerosis . Our previous studies have suggested that increased angiotensin II ( Ang II)-forming chymase may be involved in the development of atherosclerosis . However , the regulatory mechanism of chymase expression has not yet been clarified . In this study , we tested whether oxidative stress upregulates mouse mast cell proteinase chymase , mouse mast cell proteinase ( MMCP)-5 or MMCP-4 . We also examined the expression and activity of these proteins after treatment . Cultured mouse mastocytoma cells ( MMC ) displaying chymase-dependent Ang II-forming activity were treated with H(2)O(2) and several aminothiols with or without anti-oxidants . The levels of MMCP-5 and MMCP-4 expression were determined by quantitative RT-PCR ; the level of chymase-dependent Ang II-forming activity was measured by high performance liquid chromatography using Ang I as a substrate . Treatment of MMC with homocysteine ( 0.1-3 mmol l(-1) ) significantly increased MMCP-5 and MMCP-4 expression , as well as Ang II-forming activity . These effects were significantly inhibited by the addition of catalase and further suppressed by the combination of catalase and superoxide dismutase . Incubation with hydrogen peroxide alone caused a significant increase in Ang II-forming activity , which was completely suppressed by co-treatment with catalase . Furthermore , MMCP-5 and MMCP-4 expression levels were drastically suppressed and chymase induction by homocysteine was diminished under the GATA-inhibited condition . Homocysteine increased mast cell chymase expression and activity through the mechanism of oxidative stress . Our results suggest that there is a biochemical link between oxidative stress and the local Ang II-forming system .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "19960020"}
{"sentence": "BACKGROUND Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts . In the present study , we aimed to compare the mutation spectrum of 14 cancer genes , between these two phenotypes . METHODS A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in \" hot spot \" regions of KRAS , BRAF , PIK3CA and NRAS , as well as selected mutations in CTNNB1 ( \\u03b2-catenin ) , EGFR , FBXW7 ( CDC4 ) , PTEN , STK11 , MAP2K4 , SMAD4 , PIK3R1 and PDGFRA using a high-throughput genotyping technique . Additionally , APC was analyzed using direct sequencing . RESULTS APC mutations were more frequent in polypoid adenomas compared to flat adenomas ( 48.5% versus 30.3% , respectively , p\\u200a=\\u200a0.02 ) . Mutations in KRAS , BRAF , NRAS , FBXW7 and CTNNB1 showed similar frequencies in both phenotypes . Between the different subtypes of flat adenomas ( 0-IIa , LST-F and LST-G ) no differences were observed for any of the investigated genes . CONCLUSION The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes . Furthermore , in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22848674"}
{"sentence": "The new concept of keeping primary tumor under control in situ to suppress distant foci sheds light on the novel treatment of metastatic tumor . Hyperthermia is considered as one of the means for controlling tumor growth . In this study , a novel thermal modality was built to introduce hyperthermia effect on tumor to suppress its growth and progression using 4T1 murine mammary carcinoma , a common animal model of metastatic breast cancer . A mildly raised temperature ( i.e.39\ufffdC ) was imposed on the skin surface of the implanted tumor using a thermal heating pad . Periodic heating ( 12 hours per day ) was carried out for 3 days , 7 days , 14 days , and 21 days , respectively . The tumor growth rate was found significantly decreased in comparison to the control without hyperthermia . Biological evidences associated with tumor angiogenesis and metastasis were examined using histological analyses . Accordingly , the effect of mild hyperthermia on immune cell infiltration into tumors was also investigated . It was demonstrated that a delayed tumor growth and malignancy progression was achieved by mediating tumor cell apoptosis , vascular injury , degrading metastasis potential and as well as inhibiting the immunosuppressive cell myeloid derived suppressor cells ( MDSCs ) recruitment . Further mechanistic studies will be performed to explore the quantitative relationship between tumor progression and thermal dose in the near future .", "label": [1, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23367225"}
{"sentence": "In the present study , we investigated if the intracellular Cl(-) affects cell growth and cell cycle progression of androgen-independent prostate cancer PC3 cells . PC3 cells cultured in a medium containing 113 mM Cl(-) for 96 h grew up 9-fold in cell number , while PC3 cells cultured in an 8 mM-Cl(-)-containing culture medium showed complete arrest of cell growth even after culture for 96 h . Exposure of cells to the 8 mM-Cl(-) culture medium diminished phosphorylation levels of Rb and cdc2 , which are respectively key accelerators of transition from G(1) to S phase and G(2) to M phase in cell cycle progression . Culturing cells in the 8 mM-Cl(-)-containing culture medium upregulated the protein expression level of p21 ( a CDK inhibitor ) inhibiting transition of G(1) to S phase , and diminished the incorporation of 5-ethynyl-2'-deoxyuridine ( EdU ; a thymidine analogue ) into DNA . These results suggest that cells cultured in the low Cl(-) medium prolonged the duration of all phases of the cell cycle ( G(1) , S , and G(2)/M ) , thereby abolishing overall cell cycle progression . Effects of culturing cells in the low Cl(-) culture medium on cell cycle progression would be mediated via a change in the intracellular Cl(-) concentration ( [ Cl(-)](i) ) , since [ Cl(-)](i) was decreased under a low Cl(-) culture medium . To clarify this possibility , we studied effects of furosemide and bumetanide , Na+/K+/2Cl(-) cotransporter ( NKCC ) inhibitors , on proliferation of PC3 cells . Furosemide and bumetanide decreased [ Cl(-)](i) and cell growth of PC3 cells . These results suggest that a change in [ Cl(-)](i) would play a critical role in this growth mechanism .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20332618"}
{"sentence": "The therapeutic principle of allogeneic haematopoietic cell transplantation ( allo-HCT ) is based on an active donor immune system that eliminates host-derived tumour cells . We hypothesized that in addition to the alloantigen-driven anti-tumour response , disruption of the immunological microenvironment within the tumour is responsible for its elimination after allo-HCT . We observed that induction of graft-versus-host disease ( GvHD ) significantly reduced the abundance of luc(+) FoxP3(+) regulatory T ( Treg ) cells in the tumour tissue , which is indicative of impaired or over-ridden tumour recruitment signals towards Treg cells . Analysis of the intestines and liver revealed chemokines and purine nucleotides as candidates for attracting Treg to these sites of inflammation . Despite its expression on tissue-residing Treg cells , the chemokine receptor CCR3 was not critical for Treg-cell function following allo-HCT . Extracellular ATP can attract immune cells via P2Y2 . P2Y2 was found to be expressed on Treg cells , and we found a partial reduction of GvHD prevention when P2Y2(-/-) rather than P2Y2(+/+) Treg cells were given . Exogenous local inflammation reduced Treg-cell accumulation in the tumour , suggesting a potential clinical approach to prevent Treg-cell-mediated tumour escape . In conclusion , we demonstrate that GvHD-related inflammation reduced Treg-cell numbers at the tumour sites , which may in turn help to explain the observation that patients with GvHD have a lower risk of tumour relapse .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22681312"}
{"sentence": "To examine the association of cell cycle regulatory gene inactivation with human cell immortalization , we determined the expression status of INK4a , Rb , and WAF1/ CIP1 , in eleven in vitro immortalized human cell lines , including fibroblasts and keratinocytes . Two human papillomavirus type 16 E6 expressing cell lines with telomerase activity , including a fibroblast cell line and a keratinocyte cell line , expressed no detectable p16(INK4a) . These cell lines had a hyperphosphorylated pRb and reduced expression of p21(WAF1/CIP1) . All of seven fibroblast cell lines immortalized either spontaneously or by ( 60)Co , X-rays , 4-nitroquinoline 1-oxide or aflatoxin B(1) , maintaining their telomeres by the ALT ( alternative lengthening of telomeres ) pathway , displayed loss of expression of p16(INK4a) and hyperphosphorylation of pRb . Levels of p21(WAF1/CIP1) expression varied among the cell lines . Two fibroblast cell lines that became immortalized following infection with a retrovirus vector encoding human telomerase catalytic subunit ( hTERT ) cDNA were also accompanied by inactivation of p16(INK4a) and pRb pathways . Acquisition of telomerase activity alone was not sufficient for immortalization of these cell lines . Taken together , all the cell lines including fibroblasts and keratinocytes , with either telomerase activity or the ALT pathway for telomere maintenance showed loss of expression of p16(INK4a) and hyperphosphorylation of pRb . These demonstrate the association of inactivation of both p16(INK4a) and pRb with immortalization of human cells including fibroblasts and epithelial cells and telomerase-positive cells and ALT-positive cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12507935"}
{"sentence": "Although the expression of extracellular matrix protein-1 ( ECM1 ) has been documented in several tumor models , the function of ECM1 has remained unclear . In this study , expression of ECM1 was detected by real time PCR and immunohistochemistry . The role and mechanism of ECM1 overexpression in cholangiocarcinoma ( CCA ) cells were assessed by wound-healing , matrigel invasion assay and Western blotting . Expression of ECM1 was significantly elevated in CCA tissues than that in adjacent noncancerous , cholangitis and normal bile duct tissues . Its overexpression was associated with poor differentiation , lymph node metastasis , poor prognosis , and the level of CA199 , MMP-9 , estrogen receptor . Knockdown of ECM1 suppressed migration and invasion of CCA cells . Using PI3K or IKK inhibitor reduced the level of phospho-Akt or phospho-I\u03baB\u03b1 as well as ECM1 . Taken together , overexpression of ECM1 may contribute to CCA initiation and progression through promoting migration and invasion of CCA cells , its overexpression was associated with Akt/NF-\u03baB signaling axis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22489696"}
{"sentence": "The growth-inhibitory effects of ketoconazole , an antifungal agent which inhibits arachidonic acid lipoxygenases and cytochrome P-450 enzymes , were tested in human colon and breast cancer cell lines . In the serum independent HT29-S-B6 colon cell clone , ketoconazole reduced cell proliferation and [ 3H]thymidine incorporation in a dose-dependent fashion , with a 50% inhibitory concentration of approximately 2.5 microM . Flow cytometry showed an accumulation of cells in the G0-G1 phase of the cell cycle and a concomitant decrease of the percentage of cells in S phase . Ketoconazole also inhibited [ 3H]thymidine incorporation in the hormone-independent breast cancer cells MDA-MB-231 and Evsa-T , with respective 50% inhibitory concentration of approximately 13 and 2 microM . The mechanism of action of ketoconazole is unknown . However , another lipoxygenase inhibitor , BW755C , inhibited only weakly [ 3H]-thymidine incorporation and accumulated the cells in S and G2 . Conversely , clotrimazole and SKF525A , inhibitors of cytochrome P-450 enzymes , had effects similar to those of ketoconazole on HT29-S-B6 cells whereas metronidazole and secnidazole , other azole derivatives which do not inhibit cytochrome P-450 enzymes , had no effect . The results suggest that cytochrome P-450 enzyme(s) activity(ies) could be implicated in the antiproliferative effects of ketoconazole .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1458471"}
{"sentence": "UNLABELLED ABSTRACT : BACKGROUND Tamoxifen is used in hormone therapy for estrogen-receptor ( ER)-positive breast cancer , but also has chemopreventative effects against ER-negative breast cancers . This study sought to investigate whether oral iron-saturated bovine lactoferrin ( Fe-Lf ) , a natural product which enhances chemotherapy , could improve the chemotherapeutic effects of tamoxifen in the treatment of ER-negative breast cancers . METHODS In a model of breast cancer prevention , female Balb/c mice treated with tamoxifen ( 5\u2009mg/Kg ) were fed an Fe-Lf supplemented diet ( 5\u2009g/Kg diet ) or the base diet . At week 2 , 4T1 mammary carcinoma cells were injected into an inguinal mammary fat pad . In a model of breast cancer treatment , tamoxifen treatment was not started until two weeks following tumor cell injection . Tumor growth , metastasis , body weight , and levels of interleukin 18 ( IL-18 ) and interferon \u03b3 ( IFN-\u03b3 ) were analyzed . RESULTS Tamoxifen weakly ( IC50\u2009 inhibited the proliferation of 4T1 cells at pharmacological concentrations in vitro . In the tumor prevention study , a Fe-Lf diet in combination with tamoxifen caused a 4\u2009day delay in tumor formation , and significantly inhibited tumor growth and metastasis to the liver and lung by 48 , 58 , and 66% ( all P\u2009<\u20090.001 ) , respectively , compared to untreated controls . The combination therapy was significantly ( all P\u2009<\u20090.05 ) more effective than the respective monotherapies . Oral Fe-Lf attenuated the loss of body weight caused by tamoxifen and cancer cachexia . It prevented tamoxifen-induced reductions in serum levels of IL-18 and IFN-\u03b3 , and intestinal cells expressing IL-18 and IFN-\u03b3 . It increased the levels of Lf in leukocytes residing in gut-associated lymphoid tissues . B , T and Natural killer ( NK ) cells containing high levels of Lf were identified in 4T1 tumors , suggesting they had migrated from the intestine . Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors . CONCLUSIONS The results indicate that Fe-Lf is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen . It could have application in delaying relapse in tamoxifen-treated breast cancer patients who are at risk of developing ER-negative tumors .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23231648"}
{"sentence": "MDC1 ( NFBD1 ) and 53BP1 are critical mediators of the mammalian DNA damage response ( DDR ) at nuclear foci . Here we show by quantitative imaging assays that MDC1 and 53BP1 are similar in total copy number ( copies per focus ) , but differ substantially in dynamics at both replication-associated nuclear bodies in normal cells and DNA repair foci in ionizing radiation ( IR)-damaged cells . The majority of MDC1 ( is extremely mobile and under continuous exchange , with only a small fraction ( remaining immobile at foci irrespective of IR treatment . By contrast , 53BP1 has a smaller mobile fraction ( and a larger immobile fraction ( at nuclear bodies , and becomes more dynamic ( increase in mobile pool ) upon IR-induced DNA damage . More specifically , the dynamics of 53BP1 is dependent on a minimal foci-targeting region ( 1231-1709 ) , and differentially regulated by its N-terminus ( 1-1231 ) and C-terminal tBRCT domain ( 1709-1972 ) . Furthermore , MDC1 knockdown , or disruption of 53BP1-MDC1 interaction , reduced the number of 53BP1 molecules at foci by but only modestly affected 53BP1 retention . This novel in vivo evidence reveals distinct dynamics of MDC1 and 53BP1 at different types of nuclear structures , and shows that MDC1 directly recruits and retains a subset of 53BP1 for DNA repair .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22677490"}
{"sentence": "In the course of a medicinal chemistry program aimed at discovering novel tumour-active rebeccamycin derivatives targeting DNA and/or topoisomerase I , a series of analogues with the sugar residue linked to the two indole nitrogens was recently developed . Two promising drug candidates in this staurosporine-rebeccamycin hybrid series were selected for a DNA-binding study reported here . The DNA interaction of the cationic indolocarbazole glycosides MP059 bearing a N,N-diethylaminoethyl side chain and MP072 containing a sugar bearing an amino group was compared with that of the uncharged analogue MP024 . The results show that the addition of a cationic substituent , either directly on the indolocarbazole chromophore or on the carbohydrate residue , significantly reinforces the interaction of the drugs with nucleic acids . The two cationic molecules MP059 and MP072 recognise preferentially sequences containing GpT.ApC and TpG.CpA steps but they do not inhibit topoisomerase I , in contrast to the parent uncharged derivative MP024 which stimulates DNA single strand breaks by topoisomerase I. The cytotoxic activity of the indolocarbazole derivatives bearing positively charged groups is one order of magnitude higher than that of the neutral compound MP024 . The high cytotoxic potential can be attributed to the enhanced DNA binding and sequence recognition capacity of the cationic compounds . The study provides useful information for further structure-activity relationship studies in the indolocarbazole series .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12660017"}
{"sentence": "PURPOSE : Previous studies have shown that the novel microtubule poison , JG-03-14 , which binds to the colchicine binding site of tubulin , has the capacity to kill breast tumor cells primarily through the promotion of autophagy . The current work was designed to determine whether autophagy was , in fact , the primary mode of action as well as susceptibility to JG-03-14 in two additional tumor cell models , the B16/F10 murine melanoma cell line and the HCT-116 human colon cancer cell line . METHODS : Drug cytotoxicity was monitored based on viable cell number and clonogenic survival . Apoptosis was assessed by DAPI staining , the TUNEL assay and/or FACS analysis . Autophagy was monitored based on staining with acridine orange , redistribution and punctuation of RFP-LC3 and electron microscopy as well as p62 degradation . Senescence was evaluated based on \u03b2-galactosidase staining and alterations in cell morphology . Drug effects were also evaluated in a murine model of B16/F10 cells that localizes to the lungs while peripheral neuropathy was assessed by three complementary behavioral assays . RESULTS : Both HCT-116 colon cancer cells and B16/F10 melanoma cells were sensitive to JG-03-14 in that the drug demonstrated tumor cell killing . However , there was minimal induction of apoptosis . In contrast , there was clear evidence for autophagy and autophagic flux while the residual surviving cells appeared to be in a state of irreversible senescence . Inhibition of drug-induced autophagy in either the melanoma cells or the colon carcinoma cells was only slightly protective as the cells instead died by apoptosis . JG-03-14 reduced the size of tumor nodules in mice lungs ; furthermore , the drug did not promote peripheral neuropathy . CONCLUSIONS : Taken together with evidence for its actions as a vascular disrupting agent , these observations support the potential utility of JG-03-14 to effectively treat malignancies that might be resistant to conventional chemotherapy through evasion of apoptosis .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 0], "id": "23178952"}
{"sentence": "The vast majority of breast cancers are carcinomas that arise from mammary epithelial cells ( MECs ) . One of the key early events in tumorigenic transformation is the ability of cells to overcome replicative senescence . However , the precise genetic changes that are responsible for this event in MECs is largely unknown . Here , we report that Bmi-1 , originally identified as a c-Myc cooperating oncoprotein , can bypass senescence , extend the replicative life span , and immortalize MECs . Furthermore , Bmi-1 was overexpressed in immortal MECs and several breast cancer cell lines . Overexpression of Bmi-1 in MECs led to activation of human telomerase reverse transcriptase ( hTERT ) transcription and induction of telomerase activity . Telomerase induction by Bmi-1 was an early event in the extension of the replicative life span and immortalization . Bmi-1 was not overexpressed in hTERT-immortalized MECs , suggesting that Bmi-1 functions upstream of hTERT . Although , c-Myc has been reported to induce telomerase in MECs , Bmi-1 appeared to act independently of c-Myc binding sequences in the hTERT promoter . Deletion analysis of the Bmi-1 protein suggested that the RING finger , as well as a conserved helix-turn-helix-turn domain , were required for its ability to induce telomerase and immortalize MECs . These data suggest that Bmi-1 regulates telomerase expression in MECs and plays a role in the development of human breast cancer .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12183433"}
{"sentence": "MicroRNAs ( miRNAs or miR ) have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes . The miR-124 was reported to be attenuated in several tumors , such as glioma , medulloblastoma and hepatocellular carcinoma . However , its role in cancer remains greatly elusive . In this study , we show that the miR-124 expression is significantly suppressed in human breast cancer specimens , which is reversely correlated to histological grade of the cancer . More intriguingly , ectopic expression of miR-124 in aggressive breast cancer cell lines MDA-MB-231 and BT-549 strongly inhibits cell motility and invasive capacity , as well as the epithelial-mesenchymal transition process . Also , lentivirus-delivered miR-124 endows MDA-MB-231 cells with the ability to suppress cell colony formation in vitro and pulmonary metastasis in vivo . Further studies have identified the E-cadherin transcription repressor Slug as a direct target gene of miR-124 ; its downregulation by miR-124 increases the expression of E-cadherin , a hallmark of epithelial cells and a repressor of cell invasion and metastasis . Moreover , knockdown of Slug notably impairs the motility of MDA-MB-231 cells , whereas re-expression of Slug abrogates the reduction of motility and invasion ability induced by miR-124 in MDA-MB-231 cells . These findings highlight an important role for miR-124 in the regulation of invasive and metastatic potential of breast cancer and suggest a potential application of miR-124 in cancer treatment .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23250910"}
{"sentence": "Amplification of the epidermal growth factor receptor ( EGFR ) , frequently expressed as a constitutively active deletion mutant ( EGFRvIII ) , occurs commonly in glioblastoma multiformes ( GBM ) . However , blockade of EGFR is therapeutically disappointing for gliomas with PTEN deletion . To search for small molecules treating this aggressive cancer , we have established a cell-based screening and successfully identified acridine yellow G that preferentially blocks cell proliferation of the most malignant U87MG/EGFRvIII cells over the less malignant U87MG/PTEN cells . Oral administration of this compound markedly diminishes the brain tumor volumes in both subcutaneous and intracranial models . It directly inhibits EGFR and PKCs with IC(50) values of and 5 \u03bcM , respectively . It dually inhibits EGFR and PKCs , resulting in a blockade of mammalian target of rapamycin signaling and cell cycle arrest in the G(1) phase , which leads to activation of apoptosis in the tumors . Hence , combinatorial inhibition of EGFR and PKCs might provide proof of concept in developing therapeutic agents for treating malignant glioma and other human cancers .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22215664"}
{"sentence": "The androgen receptor ( AR ) has a critical role in the growth and progression of androgen-dependent and castration-resistant prostate cancers . To identify novel inhibitors of AR transactivation that block growth of prostate cancer cells , a luciferase-based high-throughput screen of small molecules was performed in cells stably expressing AR and a prostate-specific antigen ( PSA)-luciferase reporter . CPIC ( 1-(3-(2-chlorophenoxy) propyl)-1H-indole-3-carbonitrile ) was identified as a small molecule that blocks AR transactivation to a greater extent than other steroid receptors . CPIC inhibited AR-mediated proliferation of androgen-sensitive prostate cancer cell lines , with minimal toxicity in AR-negative cell lines . CPIC treatment also reduced the anchorage-independent growth of LAPC-4 prostate cancer cells . CPIC functioned as a pure antagonist by inhibiting the expression of AR-regulated genes in LAPC-4 cells that express wild-type AR and exhibited weak agonist activity in LNCaP cells that express the mutant AR-T877A . CPIC treatment did not reduce AR levels or alter its nuclear localization . We used chromatin immunoprecipitation to identify the site of action of CPIC . CPIC inhibited recruitment of androgen-bound AR to the PSA promoter and enhancer sites to a greater extent than bicalutamide . CPIC is a new therapeutic inhibitor that targets AR-mediated gene activation with potential to arrest the growth of prostate cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22589544"}
{"sentence": "AIM Colorectal cancer is the third most common form of cancer in the industrial countries . Due to advances regarding the treatments , primarily development of improved surgical methods and the ability to make the earlier diagnosis , the mortality has remained constant during the past decades even though the incidence in fact has increased . To improve chemotherapy and enable personalised treatment , the need of biomarkers is of great significance . In this study , we evaluated the gene expression profiles of the colon cancer cell lines treated with SN-38 , the active metabolite of topoisomerase-1 inhibitor irinotecan which leads to cell cycle arrest and apoptosis . MATERIAL AND METHODS The study included 3 colon cancer cell lines : KM12C , KM12SM and KM12l4a . The 3 cell lines were treated with SN-38 , and samples were obtained after 24 and 48 hour treatments . The gene expression analyses were performed using oligonucleotide microarrays comprising of approximately 27,000 spots where the untreated controls were compared to the SN-38-treated samples . RESULTS Unsupervised clustering clearly distinguished the treated cell lines from the untreated . Supervised analysis identified 3,974 significant genes ( p = 0.05 ) differentiating the treated samples from the untreated , majority of which were down-regulated after treatment . The top-ranked down-regulated genes in the treated cell lines included those related to receptor and kinase activity , signal transduction , apoptosis , RNA processing , protein metabolism and transport , cell cycle and transcription . A smaller number of genes were up-regulated in the cell lines after treatment and included genes involved in apoptosis , transcription , development and differentiation . CONCLUSIONS These results demonstrate that the expression of the genes involved in cell proliferation and apoptosis as well as RNA , DNA and protein metabolism were affected by SN-38 . The impact of certain genes on colorectal cancer development needs to be further evaluated ; however , these results could serve as a basis for further studies in order to find targets for irinotecan treatment .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20185912"}
{"sentence": "Adoptive T cell therapy uses the specificity of the adaptive immune system to target cancer and virally infected cells . Yet the mechanism and means by which to enhance T cell function are incompletely described , especially in the skin . In this study , we use a murine model of immunotherapy to optimize cell-mediated immunity in the skin . We show that in vitro-derived central but not effector memory-like T cells bring about rapid regression of skin-expressing cognate Ag as a transgene in keratinocytes . Local inflammation induced by the TLR7 receptor agonist imiquimod subtly yet reproducibly decreases time to skin graft rejection elicited by central but not effector memory T cells in an immunodeficient mouse model . Local CCL4 , a chemokine liberated by TLR7 agonism , similarly enhances central memory T cell function . In this model , IL-2 facilitates the development in vivo of effector function from central memory but not effector memory T cells . In a model of T cell tolerogenesis , we further show that adoptively transferred central but not effector memory T cells can give rise to successful cutaneous immunity , which is dependent on a local inflammatory cue in the target tissue at the time of adoptive T cell transfer . Thus , adoptive T cell therapy efficacy can be enhanced if CD8(+) T cells with a central memory T cell phenotype are transferred , and IL-2 is present with contemporaneous local inflammation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23144496"}
{"sentence": "The effect of transforming growth factor-beta 1 ( TGF-beta 1 ) and interleukin-1 beta ( IL-1 beta ) on LDL receptor in Hep G2 cells was investigated . A greater than two-fold stimulation of the binding and internalisation of [ 125I]-labelled LDL at 37 degrees C was observed after an 18-h incubation of the cells with TGF-beta 1 at 50 ng/ml and IL-1 beta at 11,700 units/ml compared with control cells . Scatchard analysis of the binding of [ 125I]-labelled LDL at 4 degrees C after an 18-h incubation of the cells with 1170 units/ml IL-1 beta and 5 ng/ml TGF-beta 1 showed that they were both acting primarily by increasing LDL receptor number . The increase in LDL receptor activity could not be attributed to an increase in cell proliferation as TGF-beta 1 at concentrations from 0.05 ng/ml to 50 ng/ml had no significant effect on either cell number or [ 3H]thymidine incorporation into DNA whilst IL-1 beta inhibited DNA synthesis by more than 80% at a concentration of 11,700 units/ml but had significant effect on cell number . Cholesterol biosynthesis from [ 14C]acetate , in contrast to the stimulation of LDL receptor activity , was inhibited by approximately two-fold by incubation with TGF-beta 1 at 50 ng/ml and IL-1 beta at 11,700 units/ml .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1445491"}
{"sentence": "Polyphenols are widely distributed in plants and known for antioxidant and anti-inflammatory properties . Areca nut , rich in polyphenols , is the major component of betel quid and we have previously shown that the extract of areca nut can induce oxidative stress in vitro . In this study , we have further pinpointed that areca nut extract ( ANE ) contains catechin based procyanidins which range from dimers to decamers and polymers ; this was carried out by HPLC and electrospray ionization/mass spectrometry ( ESI/MS ) . To quantify their antioxidant potential , oligomeric and polymeric procyanidins of ANE were separated and evaluated using the Trolox equivalent antioxidant capacity ( TEAC ) assay . The results clearly demonstrated that the antioxidant capacity of the ANE procyanidins increased with the degree of polymerization . The anti-inflammatory potential of ANE was also tested using 12-O-tetradecanoylphorbol-13-acetate ( TPA)-treated human oral cancer SAS cells . ANE inhibited TPA-induced cyclooxygenase-2 ( COX-2 ) protein expression at low doses , which correlated with the inhibition of ERK phosphorylation in the SAS cells . Furthermore , feeding rats with ANE at 1 and 10mg/kg/day for 5days significantly repressed carrageenan-induced inflammatory exudates and PGE(2) formation . In conclusion , ANE , which contains catechins based oligomeric and polymeric procyanidins , regulates COX-2 expression in vitro and possess anti-inflammatory potential in vivo .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "19840828"}
{"sentence": "Bisphenol A ( BPA ) is one of the most prevalent chemicals in daily-use materials , therefore , human exposure to BPA is ubiquitous . We found that low concentrations of BPA stimulate the spermatogonial GC-1 cells proliferation by G protein-coupled receptor 30 ( GPR30)-mediated epidermal growth factor receptor ( EGFR)-extracellular regulated kinase ( ERK)-c-Fos pathway . However , through the same pathway GPR30 expression has been shown to be induced by EGF , an EGFR ligand . Thus , we want to know if low concentrations of BPA are able to induce the GPR30 expression and the possible mechanism(s) in GC-1 cells . By transient transfection with expression plasmids , 10(-9)M BPA significantly transactivates the Gpr30-5'-flanking region through activating the GPR30 , cGMP-dependent protein kinase ( PKG ) , estrogen receptor-\u03b1 ( ER-\u03b1 ) , and EFGR-ERK pathways . Furthermore , an activator protein-1 ( AP-1 ) site located within this region is found to be responsible for the transactivation of BPA . Expectedly , through the same pathways , BPA significantly induces the gene and protein expression of GPR30. c-Fos is further observed to be strongly recruited to the AP-1 site in a chromatin immunoprecipitation assay and its dysfunction on the AP-1 site markedly suppresses the expression of GPR30 , p-ERK1/2 , p-Ser118-ER-\u03b1 and cell proliferation by BPA . Our results demonstrate that a low-concentration BPA induces GPR30 expression through the GPR30-EFGR-ERK-c-Fos , ER-\u03b1 , and PKG pathways , presumably boosting the cells proliferation via a regulatory loop . The present study provides a novel insight into the potential role of GPR30 in the initiation and progression of male germ cell cancer induced by environmentally relevant BPA .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23274518"}
{"sentence": "BACKGROUND Lung cancer often develops in association with chronic pulmonary inflammatory diseases with an influx of neutrophils . More detailed information on inflammatory pathways and the role of neutrophils herein is a prerequisite for understanding the mechanism of inflammation associated cancer . METHODS In the present study , we used microarrays in order to obtain a global view of the transcriptional responses of the lung to LPS in mice , which mimics an acute lung inflammation . To investigate the influence of neutrophils in this process , we depleted mice from circulating neutrophils by treatment with anti-PMN antibodies prior to LPS exposure . RESULTS A total of 514 genes was greater than 1.5-fold differentially expressed in the LPS induced lung inflammation model. 394 of the 514 were up regulated genes mostly involved in cell cycle and immune/inflammation related processes , such as cytokine/chemokine activity and signalling . Down regulated genes represented nonimmune processes , such as development , metabolism and transport . Notably , the number of genes and pathways that were differentially expressed , was reduced when animals were depleted from circulating neutrophils , confirming the central role of neutrophils in the inflammatory response . Furthermore , there was a significant correlation between the differentially expressed gene list and the promutagenic DNA lesion M1dG , suggesting that it is the extent of the immune response which drives genetic instability in the inflamed lung . Several genes that were specifically regulated by the presence of activated neutrophils could be identified and these were mostly involved in interferon signalling , oxidative stress response and cell cycle progression . The latter possibly refers to a higher rate of cell turnover in the inflamed lung with neutrophils , suggesting that the neutrophil influx is associated with a higher risk for the accumulation and fixation of mutations . CONCLUSION Gene expression profiling identified specific genes and pathways that are related to neutrophilic inflammation and could be associated to cancer development and indicate an active role of neutrophils in mediating the LPS induced inflammatory response in the mouse lung .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "20184723"}
{"sentence": "Genipin is a metabolite of geniposide isolated from an extract of Gardenia fructus . Some observations suggested that genipin could induce cell apoptosis in hepatoma cells and PC3 human prostate cancer cells . However , the effects of genipin on HeLa human cervical carcinoma cells are still unknown . In this study , we provided evidences that genipin induced the death of HeLa cells through apoptotic pathway in a dose-dependent manner . Genipin could remarkably induce cytotoxicity in HeLa cells and inhibit its proliferation . Induction of the apoptosis by genipin was confirmed by analysis of DNA fragmentation and induction of sub-G(1) peak through flow cytometry . The results also showed that genipin-treated HeLa cells cycle was arrested at G(1) phase . Western blot analysis revealed that the phosphorylated c-Jun NH(2)-terminal kinase ( JNK ) protein , phospho-Jun protein , p53 protein and bax protein significantly increased in a dose-dependent manner after treatment of genipin for 24 h , and to our knowledge , the activation of JNK maybe result in the increase of the p53 protein level , and the increase of the p53 protein led to the accumulation of bax protein , bax protein further induced cell apoptotic death eventually . Taken all these together , it is possible to develop genipin as an anti-cancer drug .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "20686229"}
{"sentence": "Overexpression of the Candida albicans ATP-binding cassette transporter CaCdr1p causes clinically significant resistance to azole drugs including fluconazole ( FLC ) . Screening of a \u00d7 10(6) member D-octapeptide combinatorial library that concentrates library members at the yeast cell surface identified RC21v3 , a 4-methoxy-2,3,6-trimethylbenzenesulphonyl derivative of the D-octapeptide D-NH(2) -FFKWQRRR-CONH(2) , as a potent and stereospecific inhibitor of CaCdr1p . RC21v3 chemosensitized Saccharomyces cerevisiae strains overexpressing CaCdr1p but not other fungal ABC transporters , the C. albicans MFS transporter CaMdr1p or the azole target enzyme CaErg11p , to FLC . RC21v3 also chemosensitized clinical C. albicans isolates overexpressing CaCDR1 to FLC , even when CaCDR2 was overexpressed . Specific targeting of CaCdr1p by RC21v3 was confirmed by spontaneous RC21v3 chemosensitization-resistant suppressor mutants of S. cerevisiae expressing CaCdr1p . The suppressor mutations introduced a positive charge beside , or within , extracellular loops 1 , 3 , 4 and 6 of CaCdr1p or an aromatic residue near the extracytoplasmic end of transmembrane segment 5 . The mutations did not affect CaCdr1p localization or CaCdr1p ATPase activity but some increased susceptibility to the CaCdr1p substrates FLC , rhodamine 6G , rhodamine 123 and cycloheximide . The suppressor mutations showed that the drug-like CaCdr1p inhibitors FK506 , enniatin , milbemycin \\u03b111 and milbemycin \\u03b29 have modes of action similar to RC21v3 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22788839"}
{"sentence": "The involvement of signal transduction systems in the initial attachment of two murine B16 melanoma clones of differing metastatic potential to extracellular matrix components was examined to learn more of the early events in cell-matrix interaction . Clones of high and low metastatic capacity attached similarly in the absence of any stimulators , exhibiting a two phase time course of attachment with 100% attachment by 60 min . A slight difference in attachment characteristics between the clones was seen in response to phorbol ester stimulation , which significantly inhibited attachment of the low metastatic clone but which had no effect on the highly metastatic clone . Total protein kinase C activity and distribution was similar for both clones . Attachment of both clones was severely reduced , however , if intracellular calcium was elevated or intracellular calmodulin inhibited . This study suggests that signal transduction mechanisms are involved in melanoma cell attachment to matrix proteins and offers an approach to pharmacological manipulation of these cell-matrix interactions which may be relevant to reducing metastatic spread .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1337999"}
{"sentence": "5-methylcytosine ( 5-mC ) constitutes of the total cytosines in human genomic DNA and impacts a broad range of biological functions , including gene expression , maintenance of genome integrity , parental imprinting , X-chromosome inactivation , regulation of development , aging , and cancer(1) . Recently , the presence of an oxidized 5-mC , 5-hydroxymethylcytosine ( 5-hmC ) , was discovered in mammalian cells , in particular in embryonic stem ( ES ) cells and neuronal cells(2-4). 5-hmC is generated by oxidation of 5-mC catalyzed by TET family iron ( II)/\u03b1-ketoglutarate-dependent dioxygenases(2 , 3). 5-hmC is proposed to be involved in the maintenance of embryonic stem ( mES ) cell , normal hematopoiesis and malignancies , and zygote development(2 , 5-10 ) . To better understand the function of 5-hmC , a reliable and straightforward sequencing system is essential . Traditional bisulfite sequencing cannot distinguish 5-hmC from 5-mC(11) . To unravel the biology of 5-hmC , we have developed a highly efficient and selective chemical approach to label and capture 5-hmC , taking advantage of a bacteriophage enzyme that adds a glucose moiety to 5-hmC specifically(12) . Here we describe a straightforward two-step procedure for selective chemical labeling of 5-hmC . In the first labeling step , 5-hmC in genomic DNA is labeled with a 6-azide-glucose catalyzed by \u03b2-GT , a glucosyltransferase from T4 bacteriophage , in a way that transfers the 6-azide-glucose to 5-hmC from the modified cofactor , UDP-6-N3-Glc ( 6-N3UDPG ) . In the second step , biotinylation , a disulfide biotin linker is attached to the azide group by click chemistry . Both steps are highly specific and efficient , leading to complete labeling regardless of the abundance of 5-hmC in genomic regions and giving extremely low background . Following biotinylation of 5-hmC , the 5-hmC-containing DNA fragments are then selectively captured using streptavidin beads in a density-independent manner . The resulting 5-hmC-enriched DNA fragments could be used for downstream analyses , including next-generation sequencing . Our selective labeling and capture protocol confers high sensitivity , applicable to any source of genomic DNA with variable/diverse 5-hmC abundances . Although the main purpose of this protocol is its downstream application ( i.e. , next-generation sequencing to map out the 5-hmC distribution in genome ) , it is compatible with single-molecule , real-time SMRT ( DNA ) sequencing , which is capable of delivering single-base resolution sequencing of 5-hmC .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23070273"}
{"sentence": "LewisY ( LeY ) antigen is an oligosaccharide that is highly expressed at the cell surface in various human cancers . Increased LeY expression activates epidermal growth factor receptor ( EGFR ) and human epidermal growth factor receptor 2 ( HER2 ) and promotes cell proliferation in EGFR-overexpressing cells . However , the effect of downregulation of LeY expression on cell proliferation in HER2-overexpressing cells remains unknown . FUT1 encodes \u03b11,2-fucosyltransferase , a key enzyme for LeY synthesis . We knocked down FUT1 by short interfering RNA ( siRNA ) in four HER2-overexpressing human cancer cell lines , including NCI-N87 , MKN7 , SKBr3 and BT474 . We investigated whether downregulation of LeY and alteration in the glycosylation status of these cells affect cell proliferation and HER2 activation . Knocking down FUT1 expression markedly inhibited proliferation of NCI-N87 , which highly expressed EGFR and was sensitive to EGFR deprivation . Furthermore , FUT1 siRNA downregulated the total amount of HER2 protein , phosphorylation of HER2 and EGFR , and phosphorylation of extracellular signal-regulated kinase ( ERK ) in this cell line . Moreover , the marked downregulation of phosphorylation of HER2 and ERK was observed following short-time EGF-stimulation . These effects were not observed in the other three cell lines . Our results suggest that knockdown of FUT1 downregulates HER2 signaling via EGFR downregulation . FUT1 may serve as a new molecular target for HER2-overexpressing human cancers with activated EGFR signaling .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23128605"}
{"sentence": "Ursolic acid ( UA ) is a pentacyclic triterpenoid with promising cancer chemopreventive properties . A better understanding of the mechanisms underlying anticancer activity of UA is needed for further development as a clinically useful chemopreventive agent . Here , we found that both endoplasmic reticulum ( ER ) stress and autophagy were induced by UA in MCF-7 human breast cancer cells . Surprisingly , ER stress was identified as an effect rather than a cause of UA-induced autophagy . Autophagy-dependent ER stress protected the cells from UA-induced apoptosis through EIF2AK3-mediated upregulation of MCL1 . Activation of MAPK1/3 but not inhibition of MTOR pathway contributed to UA-induced cytoprotective autophagy in MCF-7 cells . Our findings uncovered a novel cellular mechanism involved in the anticancer activity of UA , and also provided a useful model to study biological significance and mechanisms of autophagy-mediated ER stress .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23182854"}
{"sentence": "The role of regulatory T cells ( T(regs) ) in human colon cancer ( CC ) remains controversial : high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study . In mouse models of cancer , T(regs) have been reported to suppress inflammation and protect the host , suppress T cells and protect the tumor , or even have direct cancer-promoting attributes . These different effects may result from the presence of different T(reg) subsets . We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive , but compromised anti-inflammatory , properties ; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and ROR\u03b3t . T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis . Indeed , ablation of the ROR\u03b3t gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions , suppressed inflammation , improved polyp-specific immune surveillance , and severely attenuated polyposis . Ablation of interleukin-6 ( IL-6 ) , IL-23 , IL-17 , or tumor necrosis factor-\u03b1 in polyp-prone mice reduced polyp number but not to the same extent as loss of ROR\u03b3t . Surprisingly , loss of IL-17A had a dual effect : IL-17A-deficient mice had fewer polyps but continued to have ROR\u03b3t(+) T(regs) and developed invasive cancer . Thus , we conclude that ROR\u03b3t has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation , potency of immune surveillance , and severity of disease outcome .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23241743"}
{"sentence": "The hypothesis that rodent cells can be immortalized by the direct induction of a single mutation-like event was tested by initiating cultures of benzo(a)pyrene treated Syrian hamster embryo cells with low inocula and expanding these few cells maximally until senescence prevented further culturing or immortalization took place . According to the mutation hypothesis immortalization is hardly to be expected under these conditions . However , immortalization was frequently observed . Therefore the induction of immortalization appears indirect . The progeny of benzo(a)pyrene treated cells immortalized with a rate of 3.9 x 10(-8)/cell/generation , which is 64 times higher than the spontaneous rate . The results are in line with the probabilistic theory developed in 1980 by both Fernandez et al . ( Proc . Natl . Acad . Sci . USA , 77 : 7272-7276 , 1980 ) and Kennedy et al . ( Proc . Natl . Acad . Sci . USA , 77 : 7262-7266 , 1980 ) , which states that treatment of cells with a carcinogen can result in a so-called activated state of the treated cells which is transmitted to the progeny and which results in an enhanced rate of transforming events .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1559229"}
{"sentence": "Epidermal growth factor receptor-tyrosine kinase inhibitors ( EGFR-TKIs ) show dramatic antitumor activity in a subset of patients with non-small cell lung cancer who have an active mutation in the epidermal growth factor receptor ( EGFR ) gene . On the other hand , some lung cancer patients with wild type EGFR also respond to EGFR-TKIs , suggesting that EGFR-TKIs have an effect on host cells as well as tumor cells . However , the effect of EGFR-TKIs on host microenvironments is largely unknown . A multiple organ metastasis model was previously established in natural killer cell-depleted severe combined immunodeficient mice using human lung cancer cells . This model was used to investigate the therapeutic efficacy of erlotinib , an EGFR-TKI , on multiple organ metastases induced by human small cell lung cancer cells ( SBC-5 cells ) that did not express EGFR . Although erlotinib did not have any effect on the proliferation of SBC-5 cells in vitro , it significantly suppressed bone and lung metastases in vivo , but not liver metastases . An immunohistochemical analysis revealed that , erlotinib significantly suppressed the number of osteoclasts in bone metastases , whereas no difference was seen in microvessel density . Moreover , erlotinib inhibited EGF-induced receptor activator of nuclear factor kappa-B expression in an osteoblastic cell line ( MC3T3-E1 cells ) . These results strongly suggested that erlotinib prevented bone metastases by affecting host microenvironments irrespective of its direct effect on tumor cells .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "22170031"}
{"sentence": "Although regulatory T cells ( T(regs) ) are known to suppress self-reactive autoimmune responses , their role during T cell responses to nonself antigens is not well understood . We show that T(regs) play a critical role during the priming of immune responses in mice . T(reg) depletion induced the activation and expansion of a population of low-avidity CD8(+) T cells because of overproduction of CCL-3/4/5 chemokines , which stabilized the interactions between antigen-presenting dendritic cells and low-avidity T cells . In the absence of T(regs) , the avidity of the primary immune response was impaired , which resulted in reduced memory to Listeria monocytogenes . These results suggest that T(regs) are important regulators of the homeostasis of CD8(+) T cell priming and play a critical role in the induction of high-avidity primary responses and effective memory .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23112334"}
{"sentence": "PURPOSE Germline mutations in BRCA1 result in a strong predisposition to breast cancer , with frequent loss of heterozygosity of the remaining wild-type allele . The development of BRCA1 tumors is likely to depend on additional genetic alterations and gene expression changes which follow growth and DNA repair defects associated with BRCA1 deficiency . The identification of these modifications offers an opportunity to find surrogate markers of BRCA1 tumors . Here , we sought to identify differentially expressed proteins related to BRCA1 depletion . EXPERIMENTAL DESIGN We used isogenic HeLa cells either stably knocked-down or not for BRCA1 ( BRCA1(KD) ) and compared protein profiles of these cells by DIGE . RESULTS We detected increased levels of Replication protein A2 ( RPA2 ) in BRCA1(KD) cells as compared to control cells . RPA2 is an essential protein required for DNA replication and repair . We further demonstrated that depletion of RPA2 subunit delays growth of BRCA1(KD) respect to isogenic control cells . Strikingly , elevated levels of RPA2 were more frequently observed in BRCA1 tumors when triple-negative tumors from BRCA1 mutation carriers ( n=13 ) and non-carriers ( n=36 ) were stained in situ for RPA2 . CONCLUSIONS AND CLINICAL RELEVANCE RPA2 up-regulation may thus be involved in the growth and/or survival of BRCA1 tumor cells and useful in immunohistochemical discrimination of triple-negative BRCA1 tumors .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21137066"}
{"sentence": "Innate immunity in corals is of special interest not only in the context of self-defense but also in relation to the establishment and collapse of their obligate symbiosis with dinoflagellates of the genus Symbiodinium . In innate immunity system of vertebrates , approximately 20 tripartite nucleotide oligomerization domain ( NOD)-like receptor proteins that are defined by the presence of a NAIP , CIIA , HET-E and TP1 ( NACHT ) domain , a C-terminal leucine-rich repeat ( LRR ) domain , and one of three types of N-terminal effector domain , are known to function as the primary intracellular pattern recognition molecules . Surveying the coral genome revealed not only a larger number of NACHT- and related domain nucleotide-binding adaptor shared by APAF-1 , R proteins , and CED-4 ( NB-ARC)-encoding loci ( than in other metazoans but also surprising diversity of domain combinations among the coral NACHT/NB-ARC-containing proteins ; N-terminal effector domains included the apoptosis-related domains caspase recruitment domain ( CARD ) , death effector domain ( DED ) , and Death , and C-terminal repeat domains included LRRs , tetratricopeptide repeats , ankyrin repeats , and WD40 repeats . Many of the predicted coral proteins that contain a NACHT/NB-ARC domain also contain a glycosyl transferase group 1 domain , a novel domain combination first found in metazoans . Phylogenetic analyses suggest that the NACHT/NB-ARC domain inventories of various metazoan lineages , including corals , are largely products of lineage-specific expansions . Many of the NACHT/NB-ARC loci are organized in pairs or triplets in the Acropora genome , suggesting that the large coral NACHT/NB-ARC repertoire has been generated at least in part by tandem duplication . In addition , shuffling of N-terminal effector domains may have occurred after expansions of specific NACHT/NB-ARC-repeat domain types . These results illustrate the extraordinary complexity of the innate immune repertoire of corals , which may in part reflect adaptive evolution to a symbiotic lifestyle in a uniquely complex and challenging environment .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22936719"}
{"sentence": "BACKGROUND Angiogenesis is of crucial importance for tumor growth and development of metastases . Vascular endothelial growth factor ( VEGF ) has a potent angiogenic activity and mutations of the p53 gene has been thought to upregulate VEGF . The purpose of our study was to evaluate the prognostic significance of these tumor biomarkers for angiogenesis relative to the information derived from established clinicopathological parameters in gastric cancer . METHODS In this study , we conducted an immunohistochemical investigation of VEGF and p53 expression in 145 tissue samples obtained from gastric cancer patients undergoing curative surgical treatment . To evaluate angiogenesis , microvessel density ( MVD ) was counted by staining endothelial cells immunohistochemically using anti-CD34 monoclonal antibody . RESULTS High MVD was significantly associated with depth of tumor invasion and distant metastasis ( p = 0.004 , 0.021 , respectively ) . Moreover , overall survival for patients with high MVD were significantly lower than that of low MVD ( p = 0.048 ) . Positive expression of VEGF correlated significantly with lymph node and distant metastasis ( p = 0.040 , 0.048 , respectively ) . However , no significant correlation was found between p53 expression and various clinicopathological parameters . VEGF positive tumors showed a higher MVD than VEGF negative tumors ( p = 0.028 ) . The expression of p53 did not correlate with VEGF expression . Also , the relationship between the status of p53 expression and MVD had not statistically significant differences . In the multivariate analysis , status of VEGF , p53 expression and MVD were not an independent prognostic factor . CONCLUSION VEGF seems to be an important , clinically relevant inducer of angiogenesis and angiogenesis assessed by the MVD may be a useful marker for predicting metastasis in gastric cancer . However , further studies are warranted to clarify the impact of p53 on the angiogenesis and the prognostic significance of angiogenesis in gastric cancer .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12647634"}
{"sentence": "BACKGROUND Polymorphisms in DNA repair genes are associated with ability to remove DNA lesions , and therefore may contribute to an individual's susceptibility to different types of cancer . Base excision repair ( BER ) , and nucleotide excision repair ( NER ) are the main DNA repair pathways . The present study was conducted to determine the frequency distribution of single nucleotide polymorphisms ( SNPs ) selected for genes in these two pathways i.e . OGG1 Exon 7 ( C1245G ) , XPC Intron 9 ( PAT ) , and Exon 15 ( A33512C ) in a North Indian population in comparison with global populations . METHODS Genotyping was achieved by PCR-based analysis in 224 normal healthy , unrelated individuals of similar ethnicity . RESULTS Allelic frequencies in wild type of OGG1 Exon 7 C>G were 73% ( C ) ; XPC PAT D>I 75% ( D ) ; and XPC Exon 15 A>C 60.71.9% A. On the other hand , the variant allele frequency were 27% ( G ) in OGG1 Exon 7 C>G ; 25% ( I ) in XPC PAT ; and 28.1% ( C ) in XPC Exon 15 A>C . Major differences from other ethnic populations were observed . CONCLUSIONS Our results suggest that frequency distribution in these DNA repair genes exhibited a distinctive pattern in our population which could be attributed to ethnic variation . This could assist in high-risk screening of humans exposed to environmental carcinogens and cancer predisposition in different ethnic groups .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21338203"}
{"sentence": "A clinicopathological study of 41 cases of pituitary apoplexy in a series of 324 surgically treated pituitary adenomas is presented . In 23 patients , the predominant operative finding was hemorrhage with or without necrosis . However , there were 15 ( 37.7% ) cases where pale , necrotic tissue with no evidence of hemorrhage was found at surgery . Pale , necrotic material was particularly found when there was a long interval between the acute clinical event and surgery . It is concluded that the pale , necrotic debris represents one stage in the resorption process of blood after hemorrhagic necrosis of pituitary adenomas . This entity needs to be kept in mind especially since the material closely resemble the pultaceous material seen in craniopharyngiomas and epidermoid cysts .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12577104"}
{"sentence": "BACKGROUND Cisplatin chemotherapy often causes acute kidney injury in cancer patients . The causative mechanisms of cisplatin-induced acute kidney injury include renal inflammation , activation of p53 tumour suppressor protein and tubular apoptosis . Luteolin , a flavone found in medicinal herbs and plants , has been reported to exhibit anti-inflammatory , antioxidant and anticarcinogenic activities . The purpose of this study was to investigate the anti-apoptotic effect of luteolin on cisplatin-induced acute kidney injury and the molecular mechanism . METHODS C57BL/6 mice were treated with cisplatin ( 20 mg/kg ) with or without treatment with luteolin ( 50 mg/kg for 3 days ) . Renal function , histological changes , degree of oxidative stress and tubular apoptosis were examined . The effects of luteolin on cisplatin-induced expression of renal p53 , PUMA-\u03b1 and Bcl-2 family proteins were evaluated . RESULTS Treatment of mice with cisplatin resulted in renal damage , showing an increase in blood urea nitrogen and creatinine levels , tubular damage , oxidative stress and apoptosis . Treatment of cisplatin-treated mice with luteolin significantly improved renal dysfunction , reducing tubular cell damage , oxidative stress and apoptosis . Examination of molecules involving apoptosis of the kidney revealed that treatment of cisplatin increased the levels of p53 and its phosphorylation , PUMA-\u03b1 , Bax and caspase-3 activity that were significantly decreased by treatment with luteolin . CONCLUSION These results indicate that cisplatin induces acute kidney injury by regulation of p53-dependent renal tubular apoptosis and that luteolin ameliorates the cisplatin-mediated nephrotoxicity through down-regulation of p53-dependent apoptotic pathway in the kidney .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "20817674"}
{"sentence": "Previously , we reported that Helicobacter pylori-associated gastritis and gastric cancer are closely associated with increased levels of hydrogen sulfide ( H2S ) and that Korean red ginseng significantly reduced the severity of H. pylori-associated gastric diseases by attenuating H2S generation . Because the incubation of endothelial cells with H2S has been known to enhance their angiogenic activities , we hypothesized that the amelioration of H2S-induced gastric inflammation or angiogenesis in human umbilical vascular endothelial cells ( HUVECs ) might explain the preventive effect of Korean red ginseng on H. pylori-associated carcinogenesis . The expression of inflammatory mediators , angiogenic growth factors , and angiogenic activities in the absence or presence of Korean red ginseng extracts ( KRGE ) were evaluated in HUVECs stimulated with the H2S generator sodium hydrogen sulfide ( NaHS ) . KRGE efficiently decreased the expression of cystathionine \u03b2-synthase and cystathionine \u03b3-lyase , enzymes that are essential for H2S synthesis . Concomitantly , a significant decrease in the expression of inflammatory mediators , including cyclooxygenase-2 and inducible nitric oxide synthase , and several angiogenic factors , including interleukin ( IL)-8 , hypoxia inducible factor-1a , vascular endothelial growth factor , IL-6 , and matrix metalloproteinases , was observed ; all of these factors are normally induced after NaHS . An in vitro angiogenesis assay demonstrated that NaHS significantly increased tube formation in endothelial cells , whereas KRGE pretreatment significantly attenuated tube formation . NaHS activated p38 and Akt , increasing the expression of angiogenic factors and the proliferation of HUVECs , whereas KRGE effectively abrogated this H2S-activated angiogenesis and the increase in inflammatory mediators in vascular endothelial cells . In conclusion , KRGE was able to mitigate H2S-induced angiogenesis , implying that antagonistic action against H2S-induced angiogenesis may be the mechanism underlying the gastric cancer preventive effects of KRGE in H. pylori infection .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "23717113"}
{"sentence": "The involvement of iron and inflammation parameters on overall survival in non-small-cell lung cancer ( NSCLC ) patients was studied . Furthermore , transferrin receptors 1 ( TfR1 ) and ferritin expression in tumor tissue , tumor stroma , and normal lung tissue were analyzed . Iron metabolism and inflammation parameters were determined by automated laboratory measurements at the time of diagnosis . TfR1 and ferritin expression were determined by immuno-histochemical methods . About 50% of patients survived 12 months only . At the time of diagnosis more than half of the patients had anemia and significantly elevated serum ferritin . Iron content of serum ferritin ( ICF ) was below the reference values in 90% of patients . Furthermore , ICF showed positive correlation with iron metabolic parameters and survival but negative correlation with serum ferritin and ESR . The expression of TfR1 and ferritin in tumor cells was observed in 88% or 62% of patients , respectively . Tumor stroma was TfR1 negative and sporadically ferritin positive . Tumor tissue ferritin expression showed negative correlation with serum iron and hematokrit ( Ht ) , and positive correlation with ferritin , erythrocyte sedimentation rate ( ESR ) , alpha-1 globulin , and alpha-2 globulin . Positive correlation was found between TfR1 expression in tumor tissue and alpha-globulin . The correlation between TfR1/ferritin expression in tumor tissue and ICF or survival was not observed . Therefore , we conclude that elevated serum ferritin in sera of NSCLC patients is the result of inflammation and oxidative stress rather than body iron overload . Higher expression of ferritin in tumor tissue may be the consequence of iron deficiency or local toxicity induced by environmental factors .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "19308738"}
{"sentence": "The main feedback loop driving circadian rhythm in mice is controlled , in part , by the genes encoding the cryptochromes Cry1 and Cry2 . Targeted mutation of both Cry1 and Cry2 delay the early onset of tumor formation in p53-null mutant mice . Furthermore , Ras-transformed p53- and Cry-null mouse skin fibroblasts are more sensitive than p53 mutants to apoptotic cell death initiated by agents that activate either the intrinsic or the extrinsic apoptosis pathways . Here , we investigated the effect of Cry1 and Cry2 mutations on cell death by other genotoxic agents that generate alkylated bases , interstrand crosslinks , DNA-protein crosslinks , and double-strand breaks . Both ultraviolet ( UV ) and the UV mimetic compound oxaliplatin and the radiomimetic compound doxorubicin promoted apoptosis by upregulating the tumor suppressor p73 . However , only the UV and oxaliplatin-induced upregulation of p73 mediated by the transcription factor Egr1 , but not the doxorubicin-induced upregulation mediated by the transcription factor E2F1 , was enhanced by Cry1/Cry2 double mutation . Accordingly , Egr1 downregulation reduced oxaliplatin-induced apoptosis , whereas E2F1 downregulation reduced doxorubicin-induced apoptosis . Our findings establish distinct roles for cryptochromes in intrinsic apoptosis induced by UV mimetic and radiomimetic agents .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "23149912"}
{"sentence": "Endothelin plays important roles in various physiological functions including vascular constriction . Recent studies reported that the endothelin receptors ETA and ETB are highly expressed in lung and skin tumor tissues . In contrast , there are few reports on endothelin signalling in the proliferation of head and neck cancer . We found that both ETA and ETB endothelin receptors were overexpressed in tumor cells of tongue cancer samples by immunohistochemistry . ETA and ETB were expressed in cultured lingual and esophageal squamous cell carcinoma ( SCCs ) cell lines . When both cultured cell lines were treated with an ETA selective antagonist ( BQ123 ) or an ETB selective antagonist ( BQ788 ) , inhibition of cell growth was observed . Similar results were observed when SCCs were treated with specific siRNA for the suppression of ETA or ETB . Furthermore , inhibition of the mitogen-activated protein ( MAP ) kinase pathway by the treatments with ET receptor antagonists and siRNA was also observed . These results indicate that endothelin signalling may , in part , play important roles in cell growth in SCCs through the MAP kinase pathway .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22075705"}
{"sentence": "Homologous recombination ( HR ) is essential for repair of meiotic DNA double-strand breaks ( DSBs ) . Although the mechanisms of RAD-51-DNA filament assembly and strand exchange are well characterized , the subsequent steps of HR are less well defined . Here , we describe a synthetic lethal interaction between the C. elegans helicase helq-1 and RAD-51 paralog rfs-1 , which results in a block to meiotic DSB repair after strand invasion . Whereas RAD-51-ssDNA filaments assemble at meiotic DSBs with normal kinetics in helq-1 , rfs-1 double mutants , persistence of RAD-51 foci and genetic interactions with rtel-1 suggest a failure to disassemble RAD-51 from strand invasion intermediates . Indeed , purified HELQ-1 and RFS-1 independently bind to and promote the disassembly of RAD-51 from double-stranded , but not single-stranded , DNA filaments via distinct mechanisms in vitro . These results indicate that two compensating activities are required to promote postsynaptic RAD-51 filament disassembly , which are collectively essential for completion of meiotic DSB repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20122407"}
{"sentence": "We have previously shown that the antiprogestin and antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells . In this work , we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided as a consequence of the persistent activity of the PI3K/Akt survival pathway.To investigate the role of this pathway in mifepristone-induced growth inhibition , human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor , LY294002 . The activation of Akt in ovarian cancer cells , as marked by its phosphorylation on Ser473 , was not modified by cytostatic concentrations of mifepristone , but it was blocked upon treatment with LY294002 . The combination mifepristone/LY294002 , but not the individual drugs , killed ovarian cancer cells via apoptosis , as attested by genomic DNA fragmentation and cleavage of caspase-3 , and the concomitant down-regulation of anti-apoptotic proteins Bcl-2 and XIAP . From a pharmacological standpoint , when assessing cell growth inhibition using a median-dose analysis algorithm , the interaction between mifepristone and LY294002 was synergistic . The lethality caused by the combination mifepristone/LY294004 in two dimensional cell cultures was recapitulated in organized , tri-dimensional spheroids . This study demonstrates that mifepristone and LY294002 , when used individually , cause cell growth arrest , yet when combined , they cause lethality .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23420486"}
{"sentence": "DNA double strand breaks ( DSBs ) occur constantly in eukaryotes . These potentially lethal DNA lesions are repaired efficiently by two major DSB repair pathways : homologous recombination and non-homologous end joining ( NHEJ ) . We investigated NHEJ in Arabidopsis thaliana and tobacco ( Nicotiana tabacum ) by introducing DNA double-strand breaks through inducible expression of I-SceI , followed by amplification of individual repair junction sequences by single-molecule PCR . Using this process over 300 NHEJ repair junctions were analysed in each species . In contrast to previously published variation in DSB repair between Arabidopsis and tobacco , the two species displayed similar DSB repair profiles in our experiments . The majority of repair events resulted in no loss of sequence and small ( 1-20 bp ) deletions occurred at a minority ( 25-45% ) of repair junctions . Approximately of the observed repair events contained larger deletions ( >20 bp ) and a similar percentage contained insertions . Strikingly , insertion events in tobacco were associated with large genomic deletions at the site of the DSB that resulted in increased micro-homology at the sequence junctions suggesting the involvement of a non-classical NHEJ repair pathway . The generation of DSBs through inducible expression of I-SceI , in combination with single molecule PCR , provides an effective and efficient method for analysis of individual repair junctions and will prove a useful tool in the analysis of NHEJ .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22389691"}
{"sentence": "Dimethyl sulfoxide ( DMSO ) , a well-known differentiation inducer in several myeloid cells , also induces a reversible G(1) arrest in many cell lines . We recently showed that DMSO induces a G(1) phase arrest in Chinese hamster ovary ( CHO ) cells , by restoring contact inhibition and preventing high density-dependent apoptosis . CHO cells are frequently used in cell biology and mutagenesis studies due to their good growth capacity and ease of manipulation but are very difficult to synchronize by serum starvation since they detach from monolayers when they reach confluence . In this study we investigated the possibility of using DMSO to reversibly synchronize CHO cells in the G(1) phase of the cell cycle and analysed whether toxic effects follow the arrest using growth curve , sister chromatid exchange and micronuclei assays . We carried out a kinetic analysis of the arrest by DMSO and re-entry into the cell cycle after drug release by cytofluorimetric analysis of DNA content and bromodeoxyuridine incorporation . We show that CHO cells are efficiently and reversibly arrested in G(1) by DMSO in concentrations ranging between 1 and 2% . In our experiments , >90% of cells grown for 96 h in presence of the drug were arrested in G(1) and synchronously re-entered S phase approximately 8-12 h after release . Furthermore , expression levels of p27 were down-regulated during G(1) progression and cyclin D3 and E expression patterns were similar to those observed after serum starvation . No detectable cytotoxicity or genetic damage were induced in G(1) released cells as revealed by the tests employed . Our results show that DMSO is a very powerful inducer of G(1) synchronization in CHO cells without detectable cytotoxic or genetic effects in cell populations released from G(1) arrest . DMSO synchronization represents a model system in which to analyse protein activities regulating G(1) progression and investigate the response of G(1) cells to mutagen treatments .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 1, 0], "id": "12202630"}
{"sentence": "INTRODUCTION The insulin-like growth factor I receptor ( IGF-IR ) pathway plays a major role in cancer growth , tumor cell survival and resistance to therapy . BACKGROUND Preclinical evidence that targeting the IGF-IR is effective in cancer treatment has been accumulating for almost 2 decades . Early clinical trials revealed an acceptable safety profile together with pharmacodynamic evidence that the receptor can be targeted successfully . It is premature to draw conclusions regarding the therapeutic potential of this class of compounds but well-documented single-agent activity was noted during phase I evaluations , and recent evidence from a phase-II study suggests that co-administration of an anti-IGF-1R antibody with chemotherapy for non-small-cell lung cancer ( NSCLC ) improves objective response rate and progression-free survival . VIEWPOINTS These early results are a strong indication for continued research on the targeting of IGF-R , particularly in the treatment of NSCLC . CONCLUSIONS Today , IGF-1R targeting appears a promising approach , more than two dozen compounds have been developed and clinical trials are underway .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20965410"}
{"sentence": "The epidemiologic association between asbestos exposure and human malignant mesothelioma is well established . However , the molecular mechanisms linking asbestos exposure of humans and the subsequent mesothelioma formation is not well understood . The most frequent genetic changes found so far in human malignant mesothelioma ( HMM ) are deletions and point mutations in the tumor suppressor genes p16INK4a and NF2 . Whereas homozygous deletions appear to be the predominant mechanism leading to p16/CDKN2A inactivation , inactivating point mutations coupled with allelic loss mainly occur at the NF2 locus . In the present study , asbestos-treated human mesothelial cells ( HMC ) , SV40-transformed human mesothelial cells ( MeT-5A ) and a human mesothelioma cell line ( COLO ) were investigated for genetic changes of cell cycle genes ( cyclin D1 , p16INK4a , RB1 , CDK2 ) using multicolor fluorescence in situ hybridization ( mFISH ) in interphase cells . The results show that cyclin D1 is unaffected in all investigated cells . The p16INK4a gene locus was shown to be mutated in COLO cells but not in HMC . After labeling of CDK2 and RB1 , hemizygous loss of one allele of each gene was observed in asbestos-treated HMC whereas gene amplification of these genes was detectable in MeT-5A and COLO cells . Our data indicate that disarrangement of the RB1 dependent pathway seems to be involved in mesothelioma formation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12643444"}
{"sentence": "BACKGROUND : Previously , we have observed that highly unsaturated dietary ( n-3 ) fatty acids inhibit cell proliferation in conjunction with stimulation of insulin-like growth factor-binding protein ( IGFBP)-6 secretion in Caco-2 cells , a human colon carcinoma cell line . METHODS : To test the converse hypothesis that inhibition of endogenous IGFBP-6 secretion stimulates Caco-2 cell proliferation , cells were transfected with the antisense IGFBP-6 expression construct or pcDNA3 vector only , and single colonies resistant to G418 sulfate were isolated . RESULTS : Our initial studies indicated that three antisense clones grew faster and produced less IGFBP-6 than two pcDNA3 clones , so antisense IGFBP-6 #5 and pcDNA3 #8 were selected for further detailed analysis . Both the control and antisense clones grew in serum-free medium reaching a plateau density at day eight . However , the antisense clone grew at a rate faster than that of the control and reached a final density that was 31 +/- 3% higher than the control . Northern blot , ligand blot and immunoblot analyses revealed that accumulation of IGFBP-6 mRNA and concentrations of IGFBP-6 peptide produced by the antisense clone were decreased by 80-90% compared to the control . The doubling times of the antisense and control clones were 21.9 +/- 0.4 and 24.8 +/- 0.3 h ( P < 0.05 ) , respectively . Exogenous IGF-I and IGF-II ( 0.2-200 nmol/L ) stimulated proliferation of both the control and antisense clones in a dose-dependent manner , but the relative potency and efficacy of IGF-II was higher in the antisense clone compared to the control . These results indicate that suppression of IGFBP-6 secretion correlates with an increase in the basal rate of Caco-2 cell growth . CONCLUSIONS : Our findings are consistent with the hypothesis that IGFBP-6 inhibits cell growth by binding to endogenously produced IGF-II , thereby preventing IGF-II from interacting with the IGF-I receptor to stimulate cellular proliferation by an autocrine mechanism .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12084030"}
{"sentence": "Novel photosensitizers Hypocrellin A ( HA ) and Hypocrellin B ( HB ) , lipid soluble perylquinone derivatives of the genus Hypericum have a strong photodynamic effect on tumors and viruses . However , the mechanisms of tumor cell death induced by HA and HB are still unclear . In this study , we attempt to elucidate the photodynamic effects of HA and HB compounds in poorly differentiated ( CNE2 ) and moderately differentiated ( TW0-1 ) human nasopharyngeal carcinoma ( NPC ) cells as well as human mucosal colon ( CCL-220.1 ) and bladder ( SD ) cells . Using these cell lines we investigated few hall marks of apoptotic commitments in a drug and light dose dependent manner . Tumor cells photoactivated with HA and HB showed cell size shrinkage and an increase in the sub-diploid DNA content . A loss of membrane phospholipid asymmetry associated with apoptosis was induced by all tumor cell lines as evidenced by the externalization of phosphatidylserine . Western blot analysis of poly ( ADP-ribose ) polymerase , a caspases substrate , showed the classical cleavage pattern ( 116 to 85kDa ) associated with apoptosis in HA and HB-treated cell lysates . In addition , PARP cleavage was blocked by using tetrapepdide caspases inhibitors such as DEVD or z-VAD . These results demonstrate that tumor cell death induced by HB and HA is mediated by caspase proteases . This study also identifies both colon and bladder cells were more sensitive cell lines than NPC ( CNE2 and TWO-1 ) cell lines .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "17585441"}
{"sentence": "In spite of the fact that they occur at high rates , the clinical responses of BRAF(V600) mutant metastatic melanoma to BRAF inhibitors are usually short-lasting , with most cases progressing within less than 8 mo . Immunomodulatory strategies initiated after progression have recently been reported to be poorly efficient . By characterizing the immunological interactions between T cells and cancer cells in clinical material as well as the influence of the FDA-approved BRAF inhibitor vemurafenib on the immune system , we aimed at unraveling new strategies to expand the efficacy of adoptive T-cell transfer , which represents one of the most promising approaches currently in clinical development for the treatment of metastatic melanoma . Here we show that blocking the BRAF-MAPK pathway in BRAF signaling-addicted melanoma cells significantly increases the ability of T cells contained in clinical grade tumor-infiltrating lymphocytes to recognize autologous BRAF(V600) mutant melanoma cell lines in vitro . Antitumor reactivity was improved regardless of the class of antigen recognized by tumor-specific CD8(+) T cells . Microarray data suggests that improved tumor recognition is associated with modified expression of MHC Class I-associated proteins as well as of heat-shock proteins . In conclusion , our preclinical data suggest that an appropriately timed sequential treatment of BRAF(V600) mutant melanoma with vemurafenib and adoptive T-cell transfer might result in synergistic antineoplastic effects owing to an increased immunogenicity of cancer cells .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23264894"}
{"sentence": "BACKGROUND Glioblastoma is the most common and most aggressive form of malignant glioma and is very difficult to treat . Controlling tumour cell invasion and angiogenesis is essential to improve the prognosis of glioblastoma patients . Since constitutive activation of nuclear factor-\u03baB ( NF-\u03baB ) is necessary for tumour progression , NF-\u03baB may be an important pharmacological target for this disease . Our study aimed to evaluate the antitumour effects of parthenolide , a NF-\u03baB inhibitor , in two human glioblastoma cell lines ( U87MG and U373 ) and in glioblastoma xenografts . Furthermore , we aimed to investigate the molecular mechanisms underlying these effects . METHODS The anti-invasive and anti-angiogenic effects of parthenolide were analysed using in vitro invasion and angiogenesis assays . Parthenolide-induced growth inhibition of glioblastoma cells in vitro was determined using the MTT ( methyl thiazolyl tetrazolium ) assay . In addition , the effect of parthenolide on orthotropic implantation in vivo was evaluated using an intracerebral human glioblastoma xenograft model . RESULTS We found that parthenolide suppresses proliferation , invasion , and tumour- induced angiogenesis of glioblastoma cells . Molecular studies demonstrated that parthenolide suppresses gene and protein expression of angiogenic factors . Furthermore , parthenolide reduced Akt phosphorylation and activated mitochondrial signalling , suggesting that the antitumour function of parthenolide may be mediated not only by the inhibition of NF-\u03baB but also by the inhibition of Akt signalling and the activation of apoptotic proteins . Parthenolide suppressed neovascularity and tumour growth in glioblastoma xenografts . CONCLUSION The present study identified parthenolide as a new therapeutic agent for glioblastomas .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "23039130"}
{"sentence": "HER-2/neu gene expression , DNA ploidy and proliferation index were studied in 250 cases of breast cancer . Expression of HER-2/neu was determined by using an antibody to the HER-2/neu receptor . Ki-67 antibody was used to determine the proliferation index of the breast cancers , and the Feulgen method was used to assess DNA amounts in the tumor cells . Histochemical staining was quantitated by image analysis . Of the cancers studied , 72 were positive for overexpression of HER-2/neu protein ; of these , 62 ( 86% ) possessed near-tetraploid DNA content , and 47 ( 65% ) had more than one G0G1 stem line ( polyploid ) of DNA distribution . Cells from the cases negative for HER/2-neu overexpression contained DNA amounts that ranged from diploid to varying degrees of aneuploid . A significant difference in the amounts of cellular proliferation in HER-2/neu overexpressing cancers was found between those that expressed the HER-2/neu receptor on their membranes and those that exhibited mainly cytoplasmic receptors .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1363346"}
{"sentence": "Testicular Germ Cell Tumors ( TGCT ) and patient-derived cell lines are extremely sensitive to cisplatin and other interstrand cross-link ( ICL ) inducing agents . Nevertheless , a subset of TGCTs are either innately resistant or acquire resistance to cisplatin during treatment . Understanding the mechanisms underlying TGCT sensitivity/resistance to cisplatin as well as the identification of novel strategies to target cisplatin-resistant TGCTs have major clinical implications . Herein , we have examined the proficiency of five embryonal carcinoma ( EC ) cell lines to repair cisplatin-induced ICLs . Using \\u03b3H2AX staining as a marker of double strand break formation , we found that EC cell lines were either incapable of or had a reduced ability to repair ICL-induced damage . The defect correlated with reduced Homologous Recombination ( HR ) repair , as demonstrated by the reduction of RAD51 foci formation and by direct evaluation of HR efficiency using a GFP-reporter substrate . HR-defective tumors cells are known to be sensitive to the treatment with poly(ADP-ribose) polymerase ( PARP ) inhibitor . In line with this observation , we found that EC cell lines were also sensitive to PARP inhibitor monotherapy . The magnitude of sensitivity correlated with HR-repair reduced proficiency and with the expression levels and activity of PARP1 protein . In addition , we found that PARP inhibition strongly enhanced the response of the most resistant EC cells to cisplatin , by reducing their ability to overcome the damage . These results point to a reduced proficiency of HR repair as a source of sensitivity of ECs to ICL-inducing agents and PARP inhibitor monotherapy , and suggest that pharmacological inhibition of PARP can be exploited to target the stem cell component of the TGCTs ( namely ECs ) and to enhance the sensitivity of cisplatin-resistant TGCTs to standard treatments .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23251575"}
{"sentence": "As the result of genetic alterations and tumor hypoxia , many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A ( LDHA ) , which is encoded by a target gene of c-Myc and hypoxia-inducible factor ( HIF-1 ) . Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation , but its role in tumor maintenance and progression has not been established . Furthermore , how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is not well understood . Here , we report that reduction of LDHA by siRNA or its inhibition by a small-molecule inhibitor ( FX11 [ 3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid] ) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine . Furthermore , we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts . When used in combination with the NAD(+) synthesis inhibitor FK866 , FX11 induced lymphoma regression . Hence , inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors . Our studies document a therapeutical approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutical targeting of cancer energy metabolism .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20133848"}
{"sentence": "D-Limonene , a common monoterepene has been shown to have antiproliferative , apoptosis-inducing and chemopreventive effects . In the present study , we have investigated the effects of D-limonene on the growth of 7,12-dimethylbenz[a]anthracene ( DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate ( TPA)-promoted skin tumor development . We found that D-limonene ( 50 and 100 mg/kg body weight ) treatments to the mouse skin significantly reduced the TPA-induced ( a ) edema and hyperplasia ( p < 0.001 ) ; ( b ) expression of cyclooxygenase-2 ; ( c ) ornithine decarboxylase activity ( p < 0.001 ) ; and ( d ) [ (3)H ] thymidine incorporation into DNA ( p < 0.001 ) . In addition , treatment of D-limonene effectively restored the level of reduced glutathione , glutathione peroxidase , glutathione reductase , glutathione S-transferase , catalase and malondialdehyde production in TPA-treated mouse skin . In a two-stage skin tumorigenesis study , D-limonene significantly reduced the tumor burden ( p < 0.005 ) and tumor incidence as compared to DMBA/TPA-treated mice . D-Limonene treatment also extended the latency period of tumor development from 4 to 9 weeks . D-Limonene treatment decreased the expression level of Ras , Raf and phosphorylation of extracellular signal-regulated protein kinase 1/2 in DMBA/TPA-induced tumors . A decrease in the expression of Bcl-2 and an increase in Bax expression were also observed in tumor tissues of mice treated with D-limonene . Taken together , our findings suggest that D-limonene may exert its chemopreventive activity through the inhibition of inflammation , oxidative stress and Ras-signaling as well as the induction of pro-apoptotic state during TPA-mediated promotion of DMBA-induced skin cancer in mouse model .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "22318307"}
{"sentence": "Melanoma cells express and interact with laminins ( LMs ) and other basement membrane components during invasion and metastasis . In the present study we have investigated the production and migration-promoting activity of laminin isoforms in melanoma . Immunohistochemistry of melanoma specimens and immunoprecipitation/western blotting of melanoma cell lines indicated expression of laminin-111/121 , laminin-211 , laminin-411/421 , and laminin-511/521 . Laminin-332 was not detected . In functional assays , laminin-111 , laminin-332 , and laminin-511 , but not laminin-211 and laminin-411 , strongly promoted haptotactic cell migration either constitutively or following stimulation with insulin-like growth factors . Both placenta and recombinant laminin-511 preparations were highly active , and the isolated recombinant IVa domain of LM\u03b15 also promoted cell migration . Function-blocking antibodies in cell migration assays revealed \u03b16\u03b21 integrin as the major receptor for laminin-111 , and both \u03b13\u03b21 and \u03b16\u03b21 integrins for laminin-332 and laminin-511 . In contrast , isolated LM\u03b15 IVa domain-promoted melanoma cell migration was largely mediated via \u03b1V\u03b23 integrin and inhibited by RGD peptides . Given the ubiquitous expression of \u03b15 laminins in melanoma cells and in melanoma-target tissues/anatomical structures , as well as the strong migration-promoting activity of these laminin isoforms , the \u03b15 laminins emerge as putative primary extracellular matrix mediators of melanoma invasion and metastasis via \u03b13\u03b21 and other integrin receptors .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21195710"}
{"sentence": "OBJECTIVE To investigate the relationship between lymphangiogenesis and lymphatic metastasis in cervical squamous carcinoma . METHODS Eighty cases of invasive cervical squamous cancer were selected as objects of our study . Double immunohistochemical staining with antibodies against lymphatic vessel endothelial hyaluronan receptor 1 and Ki-67 was used to label the lymphatic vessels and mark the proliferative lymphatic vessels in cervical squamous cancer . The peritumoral lymphatic vessel density and intratumoral lymphatic vessel density was assessed . The lymphatic vessels proliferation index was evaluated by calculating Ki-67 proliferation index ( PI ) to reflect the lymphangiogenesis of cervical squamous cancer . Then the correlation between lymphangiogenesis and clinicopathologic features of cervical squamous cancer was analyzed . RESULTS The LVD of cervical cancer ( 15.23 \ufffd 3.6 ) was clearly higher than that of the adjacent normal cervical subepithelial tissues ( 9.9 \ufffd 2.5 , P < 0.001 ) . The peritumoral lymphatic vessel density of cervical cancer ( 18.75 \ufffd 4.3 ) was significantly higher than the intratumoral lymphatic vessel density of cervical cancer ( 11.71 \ufffd 4.9 , P < 0.001 ) . Lymphatic PI ( LPI ) of cervical cancer ( 0.258 \ufffd 0.07 ) was higher than that of the adjacent normal cervical subepithelial tissues ( 0.068 \ufffd 0.08 , P < 0.001 ) . The peritumoral lymphatic vessel PI of cervical cancer ( 0.324 \ufffd 0.06 ) was notably higher than the intratumoral lymphatic vessel PI of cervical cancer ( 0.232 \ufffd 0.06 , P < 0.001 ) . Peritumoral lymphatic vessel density and peritumoral lymphatic vessel were clearly associated with the lymph node metastasis ( P = 0.001 and P = 0.002 , respectively ) and lymphovascular space invasion ( P = 0.024 and P = 0.01 , respectively ) . CONCLUSIONS The high density of peritumoral lymphatic vessels is a potential predictor of more aggressive phenotype of cervical squamous cancer .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22968518"}
{"sentence": "Post-translational modification of proteins by ubiquitin ( Ub ) regulates a host of cellular processes , including protein quality control , DNA repair , endocytosis , and cellular signaling . In the ubiquitination cascade , a thioester-linked conjugate between the C-terminus of Ub and the active site cysteine of a ubiquitin-conjugating enzyme ( E2 ) is formed . The E2 conjugate interacts with a ubiquitin ligase ( E3 ) to transfer Ub to a lysine residue on a target protein . The flexibly linked E2 conjugates have been shown to form a range of structures in solution . In addition , select E2 conjugates oligomerize through a noncovalent \" backside \" interaction between Ub and E2 components of different conjugates . Additional studies are needed to bridge the gap between the dynamic monomeric conjugates , E2 oligomers , and the mechanisms of ubiquitination . We present a new 2.35 \u00c5 crystal structure of an oligomeric UbcH5c conjugate . The conjugate forms a staggered linear oligomer that differs substantially from the \" infinite spiral \" helical arrangement of the only previously reported structure of an oligomeric conjugate . Our structure also differs in intraconjugate conformation from other structurally characterized conjugates . Despite these differences , we find that the backside interaction mode is conserved in different conjugate oligomers and is independent of intraconjugate relative E2-Ub orientations . We delineate a common intraconjugate E2-binding surface on Ub . In addition , we demonstrate that an E3 CHIP ( carboxyl terminus of Hsp70 interacting protein ) interacts directly with UbcH5c oligomers , not only with conjugate monomers . These results provide insights into the conformational diversity of E2 conjugates and conjugate oligomers , and into their compatibility and interactions with E3s , which have important consequences for the ubiquitination process .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22551455"}
{"sentence": "Ataxia-telangiectasia mutated ( ATM ) is a high molecular weight protein serine/threonine kinase that plays a central role in the maintenance of genomic integrity by activating cell cycle checkpoints and promoting repair of DNA double-strand breaks . Little is known about the regulatory mechanisms for ATM expression itself . MicroRNAs are naturally existing regulators that modulate gene expression in a sequence-specific manner . Here , we show that a human microRNA , miR-421 , suppresses ATM expression by targeting the 3'-untranslated region ( 3'UTR ) of ATM transcripts . Ectopic expression of miR-421 resulted in S-phase cell cycle checkpoint changes and an increased sensitivity to ionizing radiation , creating a cellular phenotype similar to that of cells derived from ataxia-telangiectasia ( A-T ) patients . Blocking the interaction between miR-421 and ATM 3'UTR with an antisense morpholino oligonucleotide rescued the defective phenotype caused by miR-421 overexpression , indicating that ATM mediates the effect of miR-421 on cell cycle checkpoint and radiosensitivity . Overexpression of the N-Myc transcription factor , an oncogene frequently amplified in neuroblastoma , induced miR-421 expression , which , in turn , down-regulated ATM expression , establishing a linear signaling pathway that may contribute to N-Myc-induced tumorigenesis in neuroblastoma . Taken together , our findings implicate a previously undescribed regulatory mechanism for ATM expression and ATM-dependent DNA damage response and provide several potential targets for treating neuroblastoma and perhaps A-T .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "20080624"}
{"sentence": "Elderly patients with acute myeloid leukemia generally have a poor prognosis and a highly heterogeneous clinical outcome . Prognostic indicators are required for and aid in patient stratification . However , the prognostic value of genetic mutations and immunophenotypic features in elderly normal karyotype acute myeloid leukemia , the largest cytogenetic risk group , remains unclear . We investigated the genetic mutations NPM1 , FLT3-ITD , and FLT3-TKD and expression of the membrane antigens CD7 , CD15 , CD34 , and CD56 in 144 elderly patients with de novo normal karyotype acute myeloid leukemia to retrospectively analyze the prognostic and clinical relevance of these parameters . CD7 , CD15 , CD34 , and CD56 were expressed in 24% , 47% , 52% , and 15% of patients , respectively . NPM1 and FLT3-ITD mutations were detected in 51% and 17% of patients , respectively . Complete remission was obtained in 94 patients ( 65% ) , and the median overall survival was 16.5 months . Univariate analysis detected 5 markers with prognostic relevance : high leukocyte count , FLT3-ITD mutations , NPM1 mutations , CD34 expression , and CD56 expression in acute myeloid leukemia blasts . In multivariate analysis , patients with NPM1 predicted a higher complete remission ( CR ) rate ( P = .016 ) , longer event-free survival ( P = .008 ) , and longer overall survival ( P = .049 ) . FLT3-ITD mutations predicted a shorter event-free survival ( P = .002 ) and shorter overall survival ( P < .001 ) . CD56 remained an independent predictor for lower CR rate ( P = .021 ) and shorter event-free survival ( P = .002 ) . Our data highlight the prognostic importance of both genetic and immunophenotypic characteristics in this population of elderly patients with newly diagnosed normal karyotype acute myeloid leukemia . By combining genetic and immunophenotypic markers , we can divide patients into distinct prognostic groups with important implications for prognostic stratification and risk-adapted therapy .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22939316"}
{"sentence": "OBJECTIVE To explore the efficacy and side effects of icotinib hydrochloride in the treatment of patients with advanced non-small cell lung cancer ( NSCLC ) . METHODS The efficacy and side effects of icotinib hydrochloride in treatment of 59 cases with stage IV NSCIC and followed-up from March 2009 to January 2012 were retrospectively analyzed . RESULTS Twenty seven patients ( 45.8% ) showed partial response ( PR ) , 17 patients ( 28.8% ) achieved SD , and 15 ( 25.4% ) had progressive disease . The objective response rate ( ORR ) was 45.8% ( 27/59 ) , and disease control rate ( DCR ) was 74.6% ( 44/59 ) . Among the 23 patients with EGFR mutation , ORR was 73.9% ( 17/23 ) , and DCR was 95.7% ( 22/23 ) . Thirty six patients ( 61.0% ) achieved remission of symptoms to varying degrees . The main symptoms relieved were cough , asthmatic suffocating , pain and hoarseness . The major adverse events were mild skin rash ( 35.6% ) and diarrhea ( 15.3% ) . Others were dry skin , nausea and stomach problems . The efficacy of icotinib hydrochloride were related to the ECOG performance status , smoking history , EGFR mutation and rash significantly ( P < 0.05 ) . CONCLUSIONS Monotherapy with icotinib hydrochloride is effective and tolerable for patients with advanced NSCLC , especially with EGFR mutation .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23159001"}
{"sentence": "E6-associated protein ( E6-AP ) is a dual function protein . It acts as an E3 ubiquitin-protein ligase enzyme and coactivator of steroid hormone receptors such as estrogen ( ER\u03b1 ) and progesterone ( PR ) receptors . It promotes the degradation of ER\u03b1 and PR through the ubiquitin-proteasome pathway . Furthermore , it has been shown that the levels of E6-AP are inversely associated with that of ER\u03b1 in human breast tumors . But the role of wild-type human E6-AP and its ubiquitin-protein ligase activity in mammary tumorigenesis is still unknown . To investigate this role , the authors utilized transgenic mice lines that specifically overexpress either the wild-type human E6-AP ( E6-AP(WT) ) or the ubiquitin-protein ligase defective E6-AP that contains C833S mutation ( E6-AP(C833S) ) in the mammary gland . To further substantiate the role of E6-AP in the development of breast tumorigenesis , it was also examined the expression of E6-AP in a large cohort of human breast cancer samples . The transgenic mice that overexpress wild-type E6-AP ( E6-AP(WT) ) fail to develop mammary tumors . Unlike the E6-AP(WT) mice , the E6-AP(C833S) mice that overexpress ubiquitin-protein ligase defective E6-AP protein develop mammary hyperplasia with a median latency of 18months . These observations suggest that the inactivation of the ubiquitin-protein ligase function of E6-AP is sufficient to initiate the process of mammary tumor development . Furthermore , the data also suggests that E6-AP exerts its effects on target cells by modulating the protein levels and functions of ER\u03b1 and PR . In addition , it was found in human breast cancer patients that the level of E6-AP is decreased in invasive breast tumors compared to normal breast tissue . Moreover , the authors also show that the survival patterns for E6-AP negative patients were worse compared to E6-AP positive patients . Taken together , these data suggests that E6-AP may act as a tumor suppressor in breast .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21553290"}
{"sentence": "Epidermal growth factor receptor ( EGFR ) gene amplification and overexpression are commonly present in glioblastoma , and confer advantages of growth , invasiveness and radio/chemotherapy-resistance for tumour cells . Here , we assessed the role of EGFR activation for downstream mitogenic signalling in the commonly used glioblastoma cell line U251 . Despite the high expression level , activation of EGFR under standard culture conditions was low . Intact EGFR function was verified by the rapid phosphorylation of EGFR and downstream mitogen-activated protein(MAP) kinase ERK1/2 upon addition of exogenous EGF to serum-starved cells . By contrast , addition of fetal bovine serum ( FBS ) activated downstream ERK1/2 via the MAP kinase kinase without phosphorylating EGFR . A phosphoreceptor tyrosine kinase array showed FBS-induced activation of insulin-like growth factor-1 receptor ( IGF-1R),and the IGF-1R inhibitor AG1024 inhibited FBS-induced phosphorylation of ERK1/2 , implying IGF-1R as the major driver of FBS-associated mitogenic signalling in the absence of exogenous EGF . These findings have important implications for in vitro drug testing in glioblastoma . Moreover , activation of ERK1/2 was also strongly influenced by growth state and cell density of U251 cultures . Re-seeding exponentially growing cultures at high cell density induced p27/CDKN1B expression and suppressed P-ERK1/2 indicating a certain regulation of proliferation by contact inhibition . Strikingly , highly activated ERK1/2 signalling and cell cycle progression occurred when cells were released from plateau phase regardless of high seeding density . This phenomenon might implicate a proliferation response in the early recurrence observed after clinical therapy in glioblastoma patients . However , whether it will recapitulate in vivo remains to be demonstrated .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "24022637"}
{"sentence": "Trinucleotide repeat ( TNR ) expansions and deletions are associated with human neurodegenerative diseases and prostate cancer . Recent studies have pointed to a linkage between oxidative DNA damage , base excision repair ( BER ) and TNR expansion , which is demonstrated by the observation that DNA polymerase \\u03b2 ( pol \\u03b2 ) gap-filling synthesis acts in concert with alternate flap cleavage by flap endonuclease 1 ( FEN1 ) to mediate CAG repeat expansions . In this study , we provide the first evidence that the repair of a DNA base lesion can also contribute to CAG repeat deletions that were initiated by the formation of hairpins on both the template and the damaged strand of a continuous run of ( CAG)(20 ) or ( CAG)(25 ) repeats . Most important , we found that pol \\u03b2 not only bypassed one part of the large template hairpin but also managed to pass through almost the entire length of small hairpin . The unique hairpin bypass of pol \\u03b2 resulted in large and small deletions in coordination with FEN1 alternate flap cleavage . Our results provide new insight into the role of BER in modulating genome stability that is associated with human diseases .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23258707"}
{"sentence": "Lesion-specific enzymes repair different forms of DNA damage , yet all lesions elicit the same checkpoint response . The common intermediate required to mount a checkpoint response is thought to be single-stranded DNA ( ssDNA ) , coated by replication protein A ( RPA ) and containing a primer-template junction . To identify factors important for initiating the checkpoint response , we screened for genes that , when overexpressed , could amplify a checkpoint signal to a weak allele of chk1 in fission yeast . We identified Ast1 , a novel member of the XPG-related family of endo/exonucleases . Ast1 promotes checkpoint activation caused by the absence of the other XPG-related nucleases , Exo1 and Rad2 , the homologue of Fen1 . Each nuclease is recruited to DSBs , and promotes the formation of ssDNA for checkpoint activation and recombinational repair . For Rad2 and Exo1 , this is independent of their S-phase role in Okazaki fragment processing . This XPG-related pathway is distinct from MRN-dependent responses , and each enzyme is critical for damage resistance in MRN mutants . Thus , multiple nucleases collaborate to initiate DNA damage responses , highlighting the importance of these responses to cellular fitness .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23211746"}
{"sentence": "Little is known about the requirements for human T-cell leukemia virus type I ( HTLV-I ) entry , including the identity of the cellular receptor(s) . Recently , we have generated an HTLV-I surface glycoprotein ( SU ) immunoadhesin , HTSU-IgG , which binds specifically to cell-surface protein(s) critical for HTLV-I-mediated entry in cell lines . Here , expression of the HTLV-I SU binding protein on primary cells of the immune system was examined . The immunoadhesin specifically bound to adult T cells , B cells , NK cells , and macrophages . Cell stimulation dramatically increased the amount of binding , with the highest levels of binding on CD4(+) and CD8(+) T cells . Naive ( CD45RA(high) , CD62L(high) ) CD4(+) T cells derived from cord blood cells , in contrast to other primary cells and all cell lines examined , bound no detectable HTLV-I SU . However , following stimulation , the level of HTSU-IgG binding was rapidly induced ( fewer than 6 hours ) , reaching the level of binding seen on adult CD4(+) T cells by 72 hours . In contrast to HTLV-I virions , the soluble HTSU-IgG did not effect T-cell activation or proliferation . When incubated with human peripheral blood mononuclear cells in a mixed leukocyte reaction , HTSU-IgG inhibited proliferation at less than 1 ng/mL . These results indicate that cell-surface expression of the HTLV SU binding protein is up-regulated during in vitro activation and suggest a role for the HTLV-I SU binding proteins in the immunobiology of CD4(+) T cells .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12506039"}
{"sentence": "The soluble hexavalent chromium Cr ( VI ) used in industrial welding is an environmental contaminant widely recognized to act as a carcinogen , mutagen and teratogen towards humans and animals . The carcinogenic potential of metals is a major issue in defining human health risk from exposure . In the present investigation , 93 welders and 60 control subjects with similar mean ages , smoking prevalences and alcohol consumption were enrolled for DNA damage analysis in blood leucocytes by Micronucleus assay ( MN ) and the Comet assay . DNA repair inhibition was also analyzed by assessing XPD gene polymorphism . Welders showed a significant increase in micronucleated cells compared to controls with respect to their smoking habits and alcohol consumption , age and years of exposure ( P<0.05 ) . Results indicated that the welders had a larger mean comet tail length than that of the controls ( P<0.05 ) . The current study suggested that chronic occupational exposure to Cr ( VI ) during welding could lead to increased levels of DNA damage and repair inhibition .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20593913"}
{"sentence": "Previous studies have shown that copy-number variants ( CNVs ) contribute to the risk of complex developmental phenotypes . However , the contribution of global CNV burden to the risk of sporadic congenital heart disease ( CHD ) remains incompletely defined . We generated genome-wide CNV data by using Illumina 660W-Quad SNP arrays in 2,256 individuals with CHD , 283 trio CHD-affected families , and 1,538 controls . We found association of rare genic deletions with CHD risk ( odds ratio [ OR ] = 1.8 , p = 0.0008 ) . Rare deletions in study participants with CHD had higher gene content ( p = 0.001 ) with higher haploinsufficiency scores ( p = 0.03 ) than they did in controls , and they were enriched with Wnt-signaling genes ( p = 1 \u00d7 10(-5) ) . Recurrent 15q11.2 deletions were associated with CHD risk ( OR = 8.2 , p = 0.02 ) . Rare de novo CNVs were observed in of CHD trios ; 10 out of 11 occurred on the paternally transmitted chromosome ( p = 0.01 ) . Some of the rare de novo CNVs spanned genes known to be involved in heart development ( e.g. , HAND2 and GJA5 ) . Rare genic deletions contribute of the population-attributable risk of sporadic CHD . Second to previously described CNVs at 1q21.1 , deletions at 15q11.2 and those implicating Wnt signaling are the most significant contributors to the risk of sporadic CHD . Rare de novo CNVs identified in CHD trios exhibit paternal origin bias .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22939634"}
{"sentence": "Previous epidemiologic observational and experimental studies investigated the potential of antioxidant micronutrients to modulate cancer risk , but these studies produced inconsistent results . In this pilot , randomized , double-blind , placebo-controlled clinical trial ( n = 47 ) , we assessed the effects of an antioxidant micronutrient combination ( 800 mg dl-alpha-tocopherol acetate , 24 mg beta-carotene , 1.0 g vitamin C , 200 microg l-selenomethionine , 7.2 mg riboflavin , 80 mg niacin , 60 mg zinc , 5 mg manganese ) given daily over 4 months on oxidative and inflammatory biomarkers in patients with a history of sporadic colorectal adenoma . Plasma tumor necrosis factor-alpha ( TNF-alpha ) , interleukin-6 , and F2-isoprostane concentrations were measured using ELISAs , and cystine ( CySS ) was measured using high-performance liquid chromatography . Plasma TNF-alpha concentration decreased in the active treatment group by 37% relative to the placebo group ( P = 0.002 ) , and CySS decreased by 19% ( P = 0.03 ) ; however , interleukin-6 and F2-isoprostane concentrations decreased in antioxidant-treated nonsmokers but increased in smokers , although these findings were not statistically significant . The decreases of TNF-alpha and CySS were more pronounced in nonsmokers . These data suggest that ( a ) an antioxidant micronutrient cocktail can modulate biomarkers of oxidative stress and inflammation in humans and ( b ) the effects of antioxidant micronutrient supplementation on biomarkers of inflammation and oxidative stress may differ according to smoking status .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20200432"}
{"sentence": "Evidence suggests that stem-like cells are responsible for initiation , maintenance and recurrence of solid tumors , including Glioblastoma Multiforme ( GBM ) . GBM is an intractable , highly lethal tumor of the central nervous system . Although epidermal growth factor receptor ( EGFR ) is highly expressed in many GBMs , anti-EGFR therapies have been unsuccessful as treatment . Few studies have examined EGFR activation in GBM stem cells ( GSCs ) to determine if patient-specific GSCs are amenable to anti-EGFR therapy pre-clinically . We hypothesized that EGFR activation in GSCs varied between patients and was an important determinant of responsiveness to anti-EGFR therapy . Cell cycle and apoptosis analysis was performed on tumor-spheres by immuncytochemistry in the presence and absence of the AG1478 . Second messenger pathways operative in these processes were elucidated by immunoblotting . EGFR activated AKT and inactivated GSK3beta in EGFR+/PTEN+ GSCs . AG1478 and erlotinib significantly decreased the total number of tumor-spheres that EGFR+/ PTEN+ GSCs generated and the rate of sphere formation . Inhibition of EGFR signaling by AG1478 increased GSC senescence and apoptosis , likely via inhibition of AKT and activation of GSK3beta . Sphere formation by EGFR-/ PTEN- GSCs was independent of EGF stimulation , but dependant on B27 growth supplement . Our data suggest that EGFR+/PTEN+ GSCs are susceptible to anti-EGFR therapy in vitro .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 1, 0], "id": "20734923"}
{"sentence": "The ASPP2 ( also known as 53BP2L ) tumor suppressor is a proapoptotic member of a family of p53 binding proteins that functions in part by enhancing p53-dependent apoptosis via its C-terminal p53-binding domain . Mounting evidence also suggests that ASPP2 harbors important nonapoptotic p53-independent functions . Structural studies identify a small G protein Ras-association domain in the ASPP2 N terminus . Because Ras-induced senescence is a barrier to tumor formation in normal cells , we investigated whether ASPP2 could bind Ras and stimulate the protein kinase Raf/MEK/ERK signaling cascade . We now show that ASPP2 binds to Ras-GTP at the plasma membrane and stimulates Ras-induced signaling and pERK1/2 levels via promoting Ras-GTP loading , B-Raf/C-Raf dimerization , and C-Raf phosphorylation . These functions require the ASPP2 N terminus because BBP ( also known as 53BP2S ) , an alternatively spliced ASPP2 isoform lacking the N terminus , was defective in binding Ras-GTP and stimulating Raf/MEK/ERK signaling . Decreased ASPP2 levels attenuated H-RasV12-induced senescence in normal human fibroblasts and neonatal human epidermal keratinocytes . Together , our results reveal a mechanism for ASPP2 tumor suppressor function via direct interaction with Ras-GTP to stimulate Ras-induced senescence in nontransformed human cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23248303"}
{"sentence": "Rho GTPases are signaling molecules known to control cell motility . Several recent studies have suggested a role for Rho proteins in mediating tumor metastasis independent of their affects on cell proliferation . As Rho proteins require post-translational modification with a geranlygeranyl moiety for full activity , we tested the affect of blocking geranylation on localization , downstream signaling , and stimulation of invasion . Expression of a constitutively active Rho construct in A375 melanoma cells dramatically stimulated invasion through Matrigel membranes ; however , a constitutively active RhoA mutated so that it cannot be geranylated , failed to stimulate invasion . Moreover , expression of epitope or GFP tagged modifications of this nongeranylatable constitutively active Rho demonstrated that geranylation is necessary for correct cellular localization of Rho . Geranylation was also found to be necessary for full downstream activation of serum response factor mediated transcription . Pharmacologic inhibition of Rho geranylation produced similar inhibition of Rho localization , signaling , and invasion . Our results suggest that inhibition of Rho geranylation may be an attractive pharmacologic target for inhibiting melanoma metastasis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12445208"}
{"sentence": "Mutations in mitochondrial DNA ( mtDNA ) encoded nucleotide 8993 can cause NARP syndrome ( neuropathy , ataxia , and retinitis pigmentosa ) or MILS ( maternally inherited Leigh syndrome ) . The rare T8993C mutation in the MT-ATP6 gene is generally considered to be clinically milder , but there is marked clinical heterogeneity ranging from asymptomatic carriers to fatal infantile Leigh syndrome . Clinical heterogeneity has mostly been attributed to mtDNA heteroplasmy , but environmental , autosomal , tissue-specific factors , nuclear modifier genes , and mtDNA variations may also modulate disease expression . Here , we report the results of whole mitochondrial genome analysis of a family with m.8993T>C mutation in the MT-ATP6 gene and associated with NARP/MILS , and discuss the familial inheritance , effects of variation in combinations and heteroplasmy levels on the clinical findings . The whole mitochondrial genome was sequenced with average depth of coverage per sample with next-generation sequencing technology . Thus , all heteroplasmic ( >%10 ) and homoplasmic variations were determined ( except for 727C insertion ) and classified according to the associations with mitochondrial diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22819295"}
{"sentence": "Effective glucose diet : We report the development and activity of glucose-conjugated LDH-A inhibitors designed for dual targeting of the Warburg effect ( elevated glucose uptake and glycolysis ) in cancer cells . Glycoconjugation could be applied to inhibitors of many enzymes involved in glycolysis or tumor metabolism .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "24174263"}
{"sentence": "MD-Fraction is a highly purified soluble \u03b2-glucan derived from Grifola frondosa ( an oriental edible mushroom ) . Intraperitoneal ( i.p. ) injection of MD-Fraction has been reported to inhibit tumor growth via enhancement of the host immune system . In this study , we demonstrated that oral administration of MD-Fraction as well as i.p. injection significantly inhibited tumor growth in murine tumor models . After oral administration , MD-Fraction was not transferred to the blood in its free form but was captured by antigen-presenting cells such as macrophages and dendritic cells ( DCs ) present in the Peyer's patch . The captured MD-Fraction was then transported to the spleen , thereby inducing the systemic immune response . Our study showed that MD-Fraction directly induced DC maturation via a C-type lectin receptor dectin-1 pathway . The therapeutic response of orally administered MD-Fraction was associated with ( i ) induced systemic tumor-antigen specific T cell response via dectin-1-dependent activation of DCs , ( ii ) increased infiltration of the activated T cells into the tumor , and ( iii ) decreased number of tumor-caused immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells . Our preclinical study suggests that MD-Fraction is a useful oral therapeutic agent in the management of patients with cancer. \ufffd 2012 Wiley Periodicals , Inc .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23280601"}
{"sentence": "Among salivary gland neoplasms are a group of rare tumors that are histologically identical to benign mixed tumors that inexplicably metastasize ; they have been called metastasizing mixed tumor ( MZMT ) of salivary glands . We report the clinicopathologic features and flow cytometric findings for 11 cases of MZMT . At the time of discovery of metastatic disease , the patients , six women and five men , ranged in age from 20 to 83 years . Primary sites of involvement included the parotid gland ( eight cases ) , submandibular gland ( two cases ) , and the nasal septum ( one case ) . With one exception , all the patients had at least a single recurrences of their primary mixed tumor , but two or more recurrences were the norm before development of metastatic foci . The metastases were discovered from six to 52 years following the occurrence of the primary tumor . Metastatic deposits were identified in bone , lung , regional lymph nodes , skin , kidney , retroperitoneum , oral cavity , pharynx , calvarium , and central nervous system . The metastases either occurred simultaneously with an episode of recurrent mixed tumor ( n = 5 ) or from 5 to 29 years after a recurrence ( n = 6 ) . The treatment of the primary , recurrent , and metastatic neoplasms was surgical excision . Follow-up , ranging from 8 months to 16 years following the diagnosis of MZMT , revealed seven patients to be alive without disease ( 64% ) and two dead of causes unrelated to metastatic disease ( 18% ) . Two patients ( 18% ) died as a direct result of metastatic tumor at 3 and 2 years after metastasis of their mixed tumors . Flow cytometric analysis revealed a diploid DNA cell population in the primary and/or metastatic tumors in nine cases . Aneuploid DNA cell content was identified in two of the cases . DNA ploidy levels and cell proliferation rates were compared with those of conventional benign mixed tumors and also with malignant mixed tumors . Retrospective analysis of histologic parameters ( mitotic rate , cellular pleomorphism , infiltrative growth , vascular or lymphatic invasion ) and flow cytometric analysis failed to identify criteria to predict the development of metastasis in these neoplasms .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1384375"}
{"sentence": "Depression is the most common psychiatric syndrome in cancer patients and adversely affects anti-cancer immune system and life quality of patients . Antidepressant desipramine ( DMI ) is clinically prescribed in the auxiliary treatment of cancer patients . Increasing evidences suggest that DMI has a broad spectrum of target-off biological effects , such as anticancer properties . Our previous study revealed that DMI at the clinical relevant concentrations could induce CHOP-dependent apoptotic death in C6 glioma cells . In this study , we further explored the pro-autophagic effect of DMI in C6 glioma cells and its underlying mechanism . Treatment with DMI could induce autophagic cell death characterized by the formation of autophagosome and the elevated level of autophagic protein Beclin-1 and cellular redistribution of marker LC3 . Meanwhile , DMI inhibited the activation of PI3K-AKT-mTOR pathway which is considered as a negative regulator of autophagy . Furthermore , DMI activated PERK-eIF2\u03b1 and ATF6 of endoplasmic reticulum ( ER ) stress pathway , while knockdown of PERK with the PERK-specific short interfering RNA ( siRNA ) could obviously attenuate the autophagy . The results strongly suggested that DMI could induce autophagy through the PERK-ER stress pathway in C6 glioma cells . Our findings provided new insights into another beneficial potential of antidepressant DMI in the adjuvant therapy of cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22934693"}
{"sentence": "BACKGROUND & AIMS Hepatocytes are considered an exception of the paradigmatic inverse correlation between cell proliferation and terminal differentiation . In fact , hepatic vital functions are guaranteed by proliferating parenchymal cells during liver regeneration . However , a fine molecular characterization of the relationship between proliferation and differentiation in hepatocytes has been hampered by the lack of reliable in vivo or in vitro models . METHODS The hepatocyte terminal differentiation program was characterized in the immortalized , untransformed and differentiated hepatocytic cell line MMH , using several techniques . Particularly , two-dimensional difference gel electrophoresis combined to tandem mass spectrometry proteomic approach was used . Cell cycle and cell adhesion properties of MMH have been altered using either myc-overexpression and MEK1/2 inhibition or a constitutive active beta-catenin mutant , respectively . RESULTS The hepatocyte terminal differentiation program is stimulated by the exit from the cell cycle induced by cell-cell contact . Comparative proteomic analysis of proliferating versus quiescent hepatocytes validated the importance of contact inhibition , identifying 68 differently expressed gene products , representing 49 unique proteins . Notably , enzymes involved in important liver functions such as detoxification processes , lipid metabolism , iron and vitamin A storage and secretion , anti-inflammatory response and exocytosis were found significantly up-regulated in quiescent hepatocytes . Finally , we found that : ( i ) cell cycle arrest induced by MEK1/2 inhibition is not sufficient to induce hepatic product expression ; ( ii ) constitutive activation of beta-catenin counteracts the contact inhibition-induced terminal differentiation . CONCLUSION The hepatocyte terminal differentiation program requires a quiescent state maintained by cell-cell contact through the E-cadherin/beta-catenin pathway , rather than the inhibition of proliferation .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20031246"}
{"sentence": "PURPOSE Steroid hormones and growth factors affect lung cancer , and it is possible they act in concert to influence patient outcome . EXPERIMENTAL DESIGN Primary lung tumors and normal lung tissue were analyzed for expression and localization of estrogen receptor \u03b1 and \u03b2-1 ( ER\u03b1 and ER\u03b2 ) , aromatase , progesterone receptor ( PR ) , and epidermal growth factor receptor ( EGFR ) . RESULTS Tumors expressed higher levels of ER\u03b2 compared to matched normal lung , whereas the reverse was true of PR . High cytoplasmic ER\u03b2 expression was identified as an independent negative prognostic predictor of overall survival ( OS ; HR = 1.67 ) , and low total PR was identified as an independent negative predictor of time to progression ( TTP ; HR = 1.59 ) . After adjusting for stage , age , sex , and smoking , combined high cytoplasmic ER\u03b2 and low total PR showed enhanced effects on OS ( HR = 2.64 ) and on TTP ( HR = 6.02 ) . Further effects on OS were observed when EGFR expression was included ( HR = 5.32 ) . Patients with low cytoplasmic ER\u03b2 , low aromatase , low EGFR , and high total PR had shorter OS than patients with the opposite pattern ( HR = 6.60 ) . Contribution of these markers to survival showed no significant sex differences in a multivariable model . ER\u03b1 was elevated in tumors but was not predictive of survival , and appears to represent a variant ER\u03b1 protein that is only recognized by a C-terminal antibody . CONCLUSIONS Hormonal and EGFR pathways together may contribute to lung cancer prognosis . Lung tumors with high ER\u03b2-1/low PR may define patients with aggressive biology . A validation study is necessary to fully assess the predictive value of these markers .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21062926"}
{"sentence": "Glutathione S-transferase ( GST ) class Mu activity was determined in 145 unrelated hospital patients in Berlin by measuring their conjugation activity towards the specific substrate trans-stilbene oxide ( TSO ) with two substrate concentrations ( 50 and 250 microM ) in homogenates prepared from lymphocytes . Eighty individuals ( 55.2% ) had an activity lower than 10 pmol/min/10(6) lymphocytes and were classified as GST class Mu deficient . In 142 of 145 cases , phenotype was confirmed by the results of a genotyping procedure using the polymerase chain reaction technique . Two fragments of 273 and about 650 bp including one and two introns , respectively , could always be amplified from genomic DNA in individuals with high GST class Mu activity and could not be amplified in persons with impaired glutathione-TSO conjugation activity . This indicates that persons with low activity carry a large deletion mutation within the GST class Mu gene . The enzymatically determined antimode between low and high activity determined as 10 pmol/min/1 million lymphocytes in the assay with 50 microM TSO could be clearly confirmed by genotyping .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1540219"}
{"sentence": "To investigate whether the Bcl-2 gene family is involved in modulating mechanism of apoptosis and change of cell cycle protein induced by curcumin in acute myeloid leukemia HL-60 cell line and primary acute myelogenous leukemic cells , the Bcl-2 family member Mcl-1 , Bax and Bak and cell cycle proteins including P27kipl , P21wafl , cyclin D3 and pRbp- were selected and their expression detected by SABC immuno-histochemical stain method . The attitude of sub-G1 peak in DNA histogram was determined by FCM . The TUNEL positive cell percentage was identified by terminal deoxynucleotidyl transferase ( TdT)-mediated Biotin dUNP end labeling technique . It was found that when HL-60 cells were treated with 25 mumol/L curcumin for 24 h , the expression level of Mcl-1 was down-regulated , but that of Bax and Bak up-regulated time-dependently . There was significant difference in the expression level of Mcl-1 , Bax and Bak between the curcumin-treated groups and control group ( P < 0.05-0.01 ) . At the same time , curcumin had no effect on progress of cell cycle in primaty acute myelogenous leukemia at newly diagnosis , but could increase the peak of Sub-G1 ( P < 0.05 ) , and down-regulate the expression of Mcl-1 and up-regulate the expression of Bax and Bak with the difference being statistically significant . The expression of P27kipl , P21wafl and pRbp- were elevated and that of cyclin D3 decreased in the presence of curcumin . These findings suggested that the Bcl-2 gene family indeed participated in the regulatory process of apoptosis induced by curcumin in HL-60 cells and AML cells . Curcumin can induce apoptosis of primary acute myelogenous leukemic cells and disturb cell cycle progression of HL-60 cells . The mechanism appeared to be mediated by perturbing G0/G1 phases checkpoints which associated with up-regulation of P27kipl , P21wafl and pRbp- expression , and down-regulation of cyclin D3 .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "12674762"}
{"sentence": "The colon carcinoma cell line CC531 is metastatic to liver after splenic injection in syngeneic rats . After repeated in vivo passages , a subline was selected that produced liver metastases at a considerably higher rate than the original cell line . These cells were characterized by increased intracellular glutathione , proliferation and ability to restore glutathione after exposure to oxidative stress , thus indicating an elevated resistance to oxidative stress . Furthermore , the increased metastatic ability was also accompanied by increased proliferation rate , adhesion to extracellular matrix proteins and endothelial cells , and secretion of a 60 kD matrix metalloproteinase . When cultured in vitro for a prolonged time ( more than 30 trypsinizations ) , the cells showed a reduced in vivo metastatic ability , reduced secretion of three metalloproteinases including the 60 kD proteinase , and reduced intracellular glutathione . These results indicate that metastatic ability can be influenced through several adaptive mechanisms , and that the cell's ability to resist oxidative stress and maintain intracellular glutathione are of central importance .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "12498392"}