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HoC_dynamic_1_shot_test

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HoC_dynamic_1_shot0

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cellular senescence is considered as a tumor suppressive mechanism . Recent evidence indicates however that senescent cells secrete various growth factors and cytokines , some of which may paradoxically promote cancer progression . This phenomenon termed senescence-associated secretory phenotype ( SASP ) must be inhibited in order for anti-proliferative agents to be effective . The present study was designed to determine whether the β-catenin destruction complex ( BCDC ) , known to integrate the action of various growth factors and cytokines , would represent a suitable target to inhibit the activity of SASP components . For this , we carried out experiments to determine the effect of drug-induced senescence on secretion of SASP , β-catenin transactivation , and the relationship between these processes . Moreover , genetic and pharmacological approaches were used to define the implication of BCDC in mediating the effects of SASP components on cell migration and resistance to drugs . The findings indicate that drug-induced senescence was associated with expression of various Wnt ligands in addition to previously known SASP components . Beta catenin transactivation and expression of genes implicated in epithelial-mesenchymal transition ( EMT ) also increased in response to drug-induced SASP . These effects were prevented by Pyrvinium , a recently described activator of BCDC . Pyrvinium also suppressed the effects of SASP on cell migration and resistance to doxorubicin . Together , these findings provide insights on the potential role of BCDC in mediating the effects of drug-induced SASP on cancer cell invasion and resistance to therapy , and suggest that targeting this pathway may represent an effective approach to enhance the activity of current and prospective anti-cancer therapeutics . OUTPUT: enabling replicative immortality;activating invasion and metastasis INPUT: PURPOSE We recently reported that overexpression of epidermal growth factor receptor ( EGFR ) positively correlated with radioresistance of murine carcinomas . Because cyclin D1 is a downstream sensor of EGFR activation , the present study investigated whether a relationship exists between the extent of cyclin D1 expression and in vivo radiocurability of murine tumors . We further investigated the influence of radiation on cyclin D1 expression and the expression of p27 , an inhibitor of the cyclin D1 downstream pathway , as well as the relationship of these molecular determinants to cell proliferation and induced apoptosis in tumors exposed to radiation . METHODS AND MATERIALS Cyclin D1 expression was assayed in nine carcinomas syngeneic to C3Hf/Kam mice using Western blot analysis . These tumors greatly differed in their radioresponse as assessed by TCD(50) . The expression of cyclin D1 and p27 proteins was determined by Western blotting . Cell proliferative activity in tumors was determined by proliferating cell nuclear antigen ( PCNA ) immunochemistry . The effect of irradiation on the expression of cyclin D1 or p27 proteins and on PCNA positivity was determined in the radiosensitive OCa-I and in the radioresistant SCC-VII tumors . RESULTS Cyclin D1 expression varied among tumors by 40-fold , and its magnitude positively correlated with poorer tumor radioresponse ( higher TCD(50) values ) . The level of cyclin D1 expression paralleled that of EGFR . A 15-Gy dose reduced constitutive expression of cyclin D1 in the radiosensitive OCa-I tumors , but had no influence on expression of cyclin D1 in the radioresistant SCC-VII tumors . In contrast , 15 Gy increased the expression of p27 in radiosensitive tumors and reduced it in radioresistant tumors . Radiation induced no significant apoptosis or change in the percentage of PCNA-positive ( proliferating ) cells in SCC-VII tumors with high cyclin D1 levels , but it induced significant apoptosis and a decrease in the percentage of proliferating cells in OCa-I tumors with low cyclin D1 expression . CONCLUSION Our findings show a positive correlation between cyclin D1 expression and tumor radioresistance . The expression of cyclin D1 and p27 was modified by radiation and was associated with cellular response to radiation , but this depended on the pretreatment level of cyclin D1 expression . These findings may have important clinical implications : The pretreatment assessment of cyclin D1 expression could serve as a useful predictor of radiotherapy outcome and assist in selecting an effective treatment modality . OUTPUT:

sustaining proliferative signaling;evading growth suppressors;resisting cell death

HoC_dynamic_1_shot1

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: "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 ." OUTPUT: activating invasion and metastasis INPUT: "We have used a combination of vitamin A ( all-trans-retinyl palmitate ) , 5-fluorouracil ( 5-FU ) and radiation to treat human head and neck squamous cell carcinoma ( HNSCC ) . This chemoradiotherapy is called "" FAR therapy. "" In this study we examined the effects of all-trans-retinoic acid ( ATRA ) , the active metabolite of vitamin A , and ATRA plus 5-FU on two HNSCC cell lines ( YCU-N861 and YCU-H891 ) to gain insight into the molecular mechanisms of FAR therapy . ATRA at 1 mM ( the order of concentration found in HNSCC tumors treated with FAR therapy ) inhibited cell proliferation and caused G1 cell cycle arrest in both cell lines . This was associated with a decrease in cyclin D1 , an increase in p27(Kip1) and a reduction in the hyperphosphorylated form of retinoblastoma protein ( pRB ) . With YCU-N861 cells , ATRA also caused a decrease in Bcl-2 and Bcl-X(L) and an increase in Bax . Both ATRA and 5-FU activated c-Jun N-terminal kinase ( JNK ) 1 and the combination of both agents resulted in additive or synergistic activation of JNK1 , and also enhanced the induction of apoptosis . The YCU-H891 cells , in which the epidermal growth factor receptor ( EGFR)-signal transducer and activator of transcription 3 ( Stat3 ) pathway is constitutively activated , were more resistant to treatments with ATRA , 5-FU and the combination of both agents than YCU-N861 cells . A dominant negative Stat3 construct strongly enhanced the cellular sensitivity of this cell line to 5-FU but not to ATRA . In addition there is evidence that activation of Stat3 is associated with cellular resistance to radiation in HNSCC . Therefore , the addition to FAR therapy of agents that inhibit activation of the Stat3 pathway may enhance the clinical response of patients with HNSCC to FAR therapy ." OUTPUT:

sustaining proliferative signaling;evading growth suppressors;resisting cell death

HoC_dynamic_1_shot2

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 &lt ; 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 . OUTPUT: sustaining proliferative signaling INPUT: BACKGROUND Insulin-like growth factor I ( IGF-I ) stimulates cell proliferation and inhibits apoptosis in the lung and other tissues by interacting with the IGF-I receptor . The major binding protein for IGF-I , insulin-like growth factor-binding protein 3 ( IGFBP-3 ) , modulates the effects of IGF-I but also inhibits cell growth and induces apoptosis independent of IGF-I and its receptor . In a prospective study of men in Shanghai , China , we examined the association between serum levels of IGF-I and IGFBP-3 and the subsequent risk of lung cancer . METHODS From 1986 to 1989 , serum was collected from 18,244 men aged 45-64 years living in Shanghai without a history of cancer . We analyzed IGF-I and IGFBP-3 levels in serum from 230 case patients who developed incident lung cancer during follow-up and from 740 control subjects . RESULTS Among 230 case patients and 659 matched control subjects , increased IGF-I levels were not associated with increased risk of lung cancer . However , for subjects in the highest quartile relative to the lowest quartile of IGFBP-3 , the odds ratio ( OR ) for lung cancer , adjusted for smoking and IGF-I , was 0.50 ( 95% confidence interval [ CI ] = 0.25 to 1.02 ) . When the analysis was restricted to ever smokers ( 184 case patients and 344 matched control subjects ) , the OR for lung cancer in men in the highest quartile of IGFBP-3 relative to those in the lowest quartile , adjusted for smoking and IGF-I , was 0.41 ( 95% CI = 0.18 to 0.92 ) . CONCLUSIONS In this prospective study of Chinese men , higher serum levels of IGF-I did not increase the risk of lung cancer . However , subjects with higher serum levels of IGFBP-3 were at reduced risk of lung cancer . This finding is consistent with experimental data that indicate that IGFBP-3 can inhibit cellular proliferation and induce apoptosis independent of IGF-I and the IGF-I receptor . OUTPUT:

sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot3

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Often the use of cytotoxic drugs in cancer therapy results in stable disease rather than regression of the tumor , and this is typically seen as a failure of treatment . We now show that DNA damage is able to induce senescence in tumor cells expressing wild-type p53 . We also show that cytotoxics are capable of inducing senescence in tumor tissue in vivo . Our results suggest that p53 and p21 play a central role in the onset of senescence , whereas p16(INK4a) function may be involved in maintaining senescence . Thus , like apoptosis , senescence appears to be a p53-induced cellular response to DNA damage and an important factor in determining treatment outcome . OUTPUT: enabling replicative immortality;genomic instability and mutation;resisting cell death INPUT: p53 and INK4a/ARF mutations promote tumorigenesis and drug resistance , in part , by disabling apoptosis . We show that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16(INK4a) . Hence , tumors with p53 or INK4a/ARF mutations-but not those lacking ARF alone-respond poorly to cyclophosphamide therapy in vivo . Moreover , tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53 , p16(INK4a) , and senescence markers , and typically acquire p53 or INK4a mutations upon progression to a terminal stage . Finally , mice bearing tumors capable of drug-induced senescence have a much better prognosis following chemotherapy than those harboring tumors with senescence defects . Therefore , cellular senescence contributes to treatment outcome in vivo . OUTPUT:

enabling replicative immortality;genomic instability and mutation;resisting cell death

HoC_dynamic_1_shot4

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Transforming growth factor beta ( TGF-β ) signaling has been implicated in driving tumor progression and metastasis by inducing stem cell-like features in some human cancer cell lines . In this study , we have utilized a novel murine cell line NMuMG-ST , which acquired cancer stem cell ( CSC ) phenotypes during spontaneous transformation of the untransformed murine mammary cell line NMuMG , to investigate the role of autocrine TGF-β signaling in regulating their survival , metastatic ability , and the maintenance of cancer stem cell characteristics . We have retrovirally transduced a dominant-negative TGF-β type II receptor ( DNRII ) into the NMuMG-ST cell to abrogate autocrine TGF-β signaling . The expression of DNRII reduced TGF-β sensitivity of the NMuMG-ST cells in various cell-based assays . The blockade of autocrine TGF-β signaling reduced the ability of the cell to grow anchorage-independently and to resist serum deprivation-induced apoptosis . These phenotypes were associated with reduced levels of active and phosphorylated AKT and ERK , and Gli1 expression suggesting that these pathways contribute to the growth and survival of this model system . More interestingly , the abrogation of autocrine TGF-β signaling also led to the attenuation of several features associated with mammary stem cells including epithelial-mesenchymal transition , mammosphere formation , and expression of stem cell markers . When xenografted in athymic nude mice , the DNRII cells were also found to undergo apoptosis and induced significantly lower lung metastasis burden than the control cells even though they formed similar size of xenograft tumors . Thus , our results indicate that autocrine TGF-β signaling is involved in the maintenance and survival of stem-like cell population resulting in the enhanced metastatic ability of the murine breast cancer cells . OUTPUT: resisting cell death;activating invasion and metastasis INPUT: Insulin-like growth factor I ( IGF-I ) and IGF-II stimulate cancer cell proliferation via interaction with the type I IGF receptor ( IGF-IR ) . We put forward the hypothesis that IGF-IR mediates cancer cell growth by regulating amino acid transport , both when sufficient nutrients are present and when key nutrients such as glutamine are in limited supply . We examined the effects of alphaIR3 , the monoclonal antibody recognizing IGF-IR , on cell growth and amino acid transport across the cell membrane in a human neuroblastoma cell line , SK-N-SH . In the presence of alphaIR3 ( 2 micro/ml ) , cell proliferation was significantly attenuated in both control ( 2 mM glutamine ) and glutamine-deprived ( 0 mM glutamine ) groups . Glutamine deprivation resulted in significantly increased glutamate ( system X(AG)(-) ) , MeAIB ( system A ) , and leucine ( system L ) transport , which was blocked by alphaIR3 . Glutamine ( system ASC ) and MeAIB transport was significantly decreased by alphaIR3 in the control group . Addition of alphaIR3 significantly decreased DNA and protein biosynthesis in both groups . Glutamine deprivation increased the IGF-IR protein on the cell surface . Our results suggest that activation of IGF-IR promotes neuroblastoma cell proliferation by regulating trans-membrane amino acid transport . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot5

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: evading growth suppressors;sustaining proliferative signaling INPUT: In vitro model systems for studying uterine leiomyomas are limited in that human-derived leiomyoma cells grow poorly in culture compared with normal myometrial cells and begin to senesce early , at approximately passage 10 in our studies . To our knowledge , a good in vitro human-derived cell culturing system for leiomyomas does not exist . In an attempt to fill this void , we have immortalized a uterine leiomyoma cell line by inducing telomerase activity , which allows cells to bypass their normal programmed senescence . Telomerase activity was induced by infecting the target ( uterine leiomyoma and normal myometrial ) cells with a retroviral vector containing hTERT , the gene for the catalytic subunit of telomerase . Subsequent analysis by RT-PCR and the telomeric repeat amplification protocol assay confirmed expression of the inserted gene and induction of telomerase activity in leiomyoma and myometrial cells . Analysis of cells for estrogen receptor-alpha and progesterone receptor proteins by Western blotting showed no change in expression of these proteins between the immortalized and parental leiomyoma and myometrial cells . Both immortalized and parental myometrial and leiomyoma cells expressed the smooth muscle-specific cytoskeletal protein alpha-actin and were negative for mutant p53 protein as evidenced by immunocytochemical staining . The immortalized leiomyoma and myometrial cells showed no anchorage-independent growth , with the exception of a small subpopulation of immortalized leiomyoma cells at a higher passage that did form two to three small colonies ( per 50,000 cells ) in soft agar . None of the immortalized cells were tumorigenic in nude mice . In conclusion , our data show the successful insertion of the hTERT gene into leiomyoma and myometrial cells and the immortalization of these cell lines without phenotypic alteration from the parental cell types ( up to 200 population doublings ) . These cells should help to advance research in understanding the molecular pathways involved in the conversion of a normal myometrial cell to a leiomyoma cell and the mechanisms responsible for the growth of uterine leiomyomas . Answers to these questions will undoubtedly lead to the development of more effective treatment and intervention regimens for clinical cases of uterine leiomyoma . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot6

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: "BACKGROUND The epidermal growth factor receptor ( EGFR ) is a validated therapeutic target in non-small cell lung cancer ( NSCLC ) . However , current single agent receptor targeting does not achieve a maximal therapeutic effect , and some mutations confer resistance to current available agents . In the current study we have examined , in different NSCLC cell lines , the combined effect of RNA interference targeting the EGFR mRNA , and inactivation of EGFR signaling using different receptor tyrosine kinase inhibitors ( TKIs ) or a monoclonal antibody cetuximab . METHODS NSCLC cells ( cell lines HCC827 , H292 , H358 , H1650 , and H1975 ) were transfected with EGFR siRNA and/or treated with the TKIs gefitinib , erlotinib , and afatinib , and/or with the monoclonal antibody cetuximab . The reduction of EGFR mRNA expression was measured by real-time quantitative RT-PCR . The down-regulation of EGFR protein expression was measured by western blot , and the proliferation , viability , caspase3/7 activity , and apoptotic morphology were monitored by spectrophotometry , fluorimetry , and fluorescence microscopy . The combined effect of EGFR siRNA and different drugs was evaluated using a combination index . RESULTS EGFR-specific siRNA strongly inhibited EGFR protein expression almost equally in all cell lines and inhibited cell growth and induced cell apoptosis in all NSCLC cell lines studied , albeit with a different magnitude . The effects on growth obtained with siRNA was strikingly different from the effects obtained with TKIs . The effects of siRNA probably correlate with the overall oncogenic significance of the receptor , which is only partly inhibited by the TKIs . The cells which showed weak response to TKIs , such as the H1975 cell line containing the T790M resistance mutation , were found to be responsive to siRNA knockdown of EGFR , as were cell lines with downstream TKI resistance mutations . The cell line HCC827 , harboring an exon 19 deletion mutation , was more than 10-fold more sensitive to TKI proliferation inhibition and apoptosis induction than any of the other cell lines . Cetuximab alone had no relevant in vitro activity at concentrations obtainable in the clinic . The addition of EGFR siRNA to either TKIs or cetuximab additively enhanced growth inhibition and induction of apoptosis in all five cell lines , independent of the EGFR mutation status ( wild-type or sensitizing mutation or resistant mutation ) . The strongest biological effect was observed when afatinib was combined with an EGFR-specific siRNA . CONCLUSIONS EGFR knockdown by siRNA further decreases the cell growth of lung cancer cells that are treated with TKIs or cetuximab alone , confirming that single agent drug targeting does not achieve a maximal biological effect . The siRNA inhibits EGFR oncogenic activity that bypasses downstream "" resistance "" mutations such as KRAS and PTEN . The combined treatment of siRNA and EGFR inhibitory agents is additive . The combination of a potent , irreversible kinase inhibitor such as afatinib , with EGFR-specific siRNAs should be further investigated as a new strategy in the treatment of lung cancer and other EGFR dependent cancers , including those with downstream resistance mutations ." OUTPUT: resisting cell death;sustaining proliferative signaling;genomic instability and mutation INPUT: BACKGROUND Modulation of the expression of retinoic acid receptors ( RAR ) alpha and gamma in adult rat prostate by testosterone ( T ) suggests that RAR signaling events might mediate some of the androgen effects on prostate cells . METHOD In this study , we examined the interactions between T and retinoic acid ( RA ) in cell growth of human prostate carcinoma cells , LNCaP , and their relationship with the expression of RAR and epidermal growth factor receptor ( EGF-R ) . RESULTS Both T and RA , when administered alone , stimulated 3H-thymidine incorporation in LNCaP cells in a dose-dependent manner ; the effect of each agent was reciprocally attenuated by the other agent . Testosterone treatment of LNCaP cells also resulted in dose dependent , biphasic increases in RAR alpha and gamma mRNAs ; increases paralleled that of 3H-thymidine incorporation and were attenuated by the presence of 100 nM RA . These results suggest a link between RAR signaling and the effect of T on LNCaP cell growth . Gel electrophoretic mobility shift assays revealed the presence of putative androgen responsive element ( ARE ) in the promoter region of RAR alpha gene , suggesting that a direct AR-DNA interaction might mediate the effects of T on RAR alpha gene . Furthermore , treatment of LNCaP cells with 20 nM T resulted in an increase in EGF-R . In contrast , EGF-R was suppressed by 100 nM RA that also suppressed the effect of T. CONCLUSIONS Current results demonstrate interactions between T and RA in the expression of RARs and cell growth in LNCaP cells . The presence of putative ARE in the promoter of the RAR alpha gene suggests that AR-DNA interaction might mediate the effects of T on RAR alpha gene . The opposite effects of T and RA on the expression of RAR and EGF-R suggest that signal events of these receptors might be involved in the interaction between T and RA in the control of LNCaP cell growth . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot7

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: While human embryonic stem cells ( hESCs ) and human embryonal carcinoma cells ( hECCs ) have been studied extensively at the levels of the genome , transcriptome , proteome and epigenome our knowledge of their corresponding metabolomes is limited . Here , we present the metabolic signatures of hESCs and hESCs obtained by untargeted gas chromatography coupled to mass spectrometry ( GC-MS ) . Whilst some metabolites are common to both cell types , representing the self-renewal and house-keeping signatures , others were either higher ( e.g. , octadecenoic acid , glycerol-3-phosphate , 4-hydroxyproline ) or lower ( e.g. , glutamic acid , mannitol , malic acid , GABA ) in hESCs ( H9 ) compared to hECCs ( NTERA2 ) , these represent cell type specific signatures . Further , our combined results of GC-MS and microarray based gene expression profiling of undifferentiated and OCT4-depleted hESCs are consistent with the Warburg effect which is increased glycolysis in embryonic cells and tumor cells in the presence of O(2) while oxidative phosphorylation ( OXPHOS ) is impaired or even shut down . RNAi-based OCT4 knock down mediated differentiation resulted in the activation of the poised OXPHOS machinery by expressing missing key proteins such as NDUFC1 , UQCRB and COX , increase in TCA cycle activity and decreased lactate metabolism . These results shed light on the metabolite layer of pluripotent stem cells and could potentially establish novel metabolic markers of self renewal and pluripotency . OUTPUT: cellular energetics INPUT: The metabolic detoxification capacity may critically regulate the susceptibility of human tissues to cancer development . We used standardized and quantitative , reverse transcription-polymerase chain reaction ( StaRT-PCR ) and microarray chip techniques to analyze transcript levels of multiple detoxification enzymes in cultured normal human oral keratinocytes ( NOK ) and the Siman virus 40 T antigen-immortalized oral keratinocyte line SVpgC2a , viewing the latter as a model of a benign tumor state . With good agreement between the 2 methodologies , NOK and SVpgC2a were found to express transcripts for cytochrome P450 enzymes ( CYPs ) , factors related to CYP induction and enzymes involved in conjugation reactions or detoxification of reactive oxygen . The cell types expressed similar levels of CYP 2B6/7 , CYP 2E1 , P450 oxidoreductase , the aryl hydrocarbon receptor nuclear translocator , sulfotransferase 1A1 , sulfotransferase 1A3 , epoxide hydrolase , glutathione S-transferase M3 , glutathione S-transferase pi and catalase , superoxide dismutase 1 , glutathione peroxidase 1 and glutathione peroxidase 3 . In contrast , SVpgC2a exhibited comparatively higher levels of CYP1A1 , 1B1 , aryl hydrocarbon receptor , glutathione S-transferase M1 , 2 , 4 , 5 , glutathione S-transferase theta 1 and superoxide dismutase 2 and comparatively lower levels of UDP glycosyltransferase 2 and microsomal glutathione S-transferase 1 . Some transcripts , e.g. , CYP 2A6/7 , were not detected by either standard , non quantitative RT-PCR or the above methods , whereas others were barely quantifiable by StaRT-PCR , i.e. , were present at 1-10 molecules/10(6) molecules of actin . Overall , the expression analysis demonstrated presence of mRNA for multiple enzymes involved in foreign compound metabolism and detoxification pathways , including several enzymes not previously reported for oral epithelium . Generally , the comparison of NOK from 2 individuals indicated relatively similar transcript levels of these enzymes . In contrast , differences between NOK and SVpgC2a , e.g. , for CYP1B1 , may reflect alteration caused by immortalization and aid identification of early stage tumor markers in oral epithelium . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot8

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cell division and apoptosis are two crucial components of tumor biology and the importance of increased cell proliferation and reduced cell death have made them valid therapeutic targets . The plant kingdom is a relatively underexploited cache of novel drugs , and crude extracts of plants are known for their synergistic activity . The present study assessed the anti-proliferative activity of the medicinal plant Centrosema pubescens Benth . Centrosema pubescens dichloromethane extract ( CPDE ) inhibited the proliferation of HL-60 ( promyelocytic acute leukaemia ) cells with an IC₅₀ value of 5 μg/ml . Further studies also showed that CPDE induces growth arrest at the G1 phase and specifically down-regulates the expressions of cyclin E and CDK2 and up-regulates p27(CKI) levels . These events apparently lead to the induction of apoptosis , which was demonstrated qualitatively by a DNA fragmentation assay and propidium iodide staining . Quantitative assessment of the effective arrest of the cell cycle and of apoptosis was confirmed by flow cytometry . CPDE exhibited negligible cytotoxicity even at the highest dose tested ( 100 μg/ml ) in both normal peripheral blood mononuclear cells and in an in vitro model ( HL-60 ) . Our results strongly suggest that CPDE arrests the cell cycle at the G1 phase and triggers apoptosis by caspase activation . OUTPUT: evading growth suppressors;resisting cell death INPUT: We investigated the direct effects of LH-releasing hormone ( LH-RH ) antagonist , Cetrorelix , on the growth of HTOA human epithelial ovarian cancer cell line . RT-PCR revealed the expression of mRNA for LH-RH and its receptor in HTOA cells . Cetrorelix , at concentrations between 10(-9) and 10(-5) M , exerted a dose-dependent antiproliferative action on HTOA cells , as measured by 5-bromo-2'-deoxyuridine incorporation into DNA . Flow cytometric analysis indicated that Cetrorelix , at 10(-5) M , arrested cell cycle in HTOA cells , at G1 phase , after 24 h of treatment . Western blot analysis of cell cycle-regulatory proteins demonstrated that treatment with Cetrorelix ( 10(-5) M ) for 24 h did not change the steady-state levels of cyclin D1 , cyclin E , and cyclin-dependent kinase ( Cdk)4 but decreased the levels of cyclin A and Cdk2 . The protein levels of p21 ( a Cdk inhibitor ) and p53 ( a suppressor of tumor cell growth and a positive regulator for p21 expression ) were increased by Cetrorelix , but the levels of p27 ( a Cdk inhibitor ) did not change significantly . Flow cytometric analysis and terminal deoxynucleotidyltransferase-mediated deoxyuridine 5-triphosphate nick end labeling staining demonstrated that Cetrorelix ( 10(-5) M ) induced apoptosis in HTOA cells . In conclusion , Cetrorelix directly inhibits the proliferation of human epithelial ovarian cancer cells through mechanisms mediated by LH-RH receptor and involving multiple events in cell cycle progression , including G1 phase cell cycle arrest coupled with down-regulation of cyclin A-Cdk2 complex levels , presumably attributable to an up-regulation of p53 and p21 protein levels and apoptosis . OUTPUT:

sustaining proliferative signaling;evading growth suppressors;resisting cell death

HoC_dynamic_1_shot9

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: INTRODUCTION A subpopulation of cancer cells , tumor-initiating cells , is believed to be the driving force behind tumorigenesis and resistance to radiation and chemotherapy . The persistence of tumor-initiating cells may depend on altered regulation of DNA damage and checkpoint proteins , as well as a reduced propensity to undergo apoptosis or senescence . METHODS To test this hypothesis , we isolated CD24-/low/CD44+ tumor-initiating cells ( as mammospheres ) from MCF-7 breast cancer cells grown in adherent monolayer culture , and carried out a comprehensive comparison of cell death and DNA damage response pathways prior to and after exposure to ionizing radiation in mammospheres and monolayer MCF-7 cells . Single and double-strand break repair was measured by single-cell gel electrophoresis . The latter was also examined by phosphorylation of histone H2AX and formation of 53BP1 and Rad51 foci . Apoptosis was quantified by flow-cytometric analysis of annexin V-binding and senescence was analyzed on the basis of cellular beta-galactosidase activity . We employed the telomeric repeat amplification protocol to quantify telomerase activity . Expression of key DNA repair and cell cycle regulatory proteins was detected and quantified by western blot analysis . RESULTS Our data demonstrate that in comparison to the bulk population of MCF-7 cells ( predominantly CD24+/CD44+ ) , the MCF-7 mammosphere cells benefit from a multifaceted approach to cellular protection relative to that seen in monolayer cells , including a reduced level of reactive oxygen species , a more active DNA single-strand break repair ( SSBR ) pathway , possibly due to a higher level of expression of the key SSBR protein , human AP endonuclease 1 ( Ape1 ) , and a significantly reduced propensity to undergo senescence as a result of increased telomerase activity and a low level of p21 protein expression . No significant difference was seen in the rates of double-strand break repair ( DSBR ) between the two cell types , but DSBR in mammospheres appears to by-pass the need for H2AX phosphorylation . CONCLUSIONS Enhanced survival of MCF-7 tumor-initiating cells in response to ionizing radiation is primarily dependent on an inherent down-regulation of the senescence pathway . Since MCF-7 cells are representative of cancer cells that do not readily undergo apoptosis , consideration of senescence pathways may play a role in targeting stem cells from such tumors . OUTPUT: enabling replicative immortality;evading growth suppressors;genomic instability and mutation;resisting cell death INPUT: Id proteins are negative regulators of basic helix-loop-helix transcription factors , which are critical for expression of genes associated with cellular differentiation . Previous studies have shown that overexpression of Id-1 delays cellular senescence in several cell types , including fibroblasts , mammary epithelial cells , and keratinocytes . Although previous studies have demonstrated the expression of Id-1 in endothelium , the regulation of Id-1 has not been studied in these cells . In this report , a retroviral vector was used to overexpress Id-1 in human endothelial cells . Sustained expression of Id-1 resulted in a 2- to 3-fold increase in the total number of population doublings ( replicative capacity ) of the cells compared with vector-treated controls , which correlated with low levels of p16 , p21 , and p27 expression . The cells , however , were not immortalized and did eventually undergo senescence despite elevated Id-1 levels . Senescence was characterized by a dramatic increase in p16 , but not p21 and p27 . Under these experimental conditions , telomerase activity was not detected and the telomeres became progressively shorter with time . These results demonstrate the importance of Id-1 in endothelial cell proliferation and indicate that Id-1 represses p16 expression , resulting in delayed senescence . These findings may have implications in the development of endothelial cell-derived tumors . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot10

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: The role of T cells in eradicating leukemic cells has been well demonstrated for chronic myeloid leukemia ( CML ) . Type 1 ( T1 ) T-cell cytokines play a major role in this antileukemic immune effect . Studies in cancer patients have demonstrated a decreased T1 cytokine production , measured by enzyme-linked immunosorbent assay ( ELISA ) , in cultures of peripheral blood mononuclear cells . This observation of malignancy-related suppressed T1 cytokines also occurs in untreated chronic-phase ( CP ) CML , raising the question of the influence of different CML treatment regimens on this immunosuppression . Intracellular flow cytometry ( ICF ) has facilitated the evaluation of cytokines on a single-cell level . This study analyzed T1 ( interferon-gamma ) cytokine production in purified peripheral blood T cells by ICF , comparing different therapy approaches for CML . Twenty-one newly diagnosed CP CML patients were compared with 24 patients treated with interferon-alpha ( IFN-alpha ) and to 30 allogeneic bone marrow transplant ( BMT ) recipients ( BCR-ABL negative by reverse-transcriptase polymerase chain reaction , and free of , or having only limited graft-versus-host disease at the time of study ) . Thirty-seven healthy controls were included . Our results showed a significantly decreased T-cell IFN-gamma synthesis in CP CML patients in relation to healthy controls ( P = 0.0007 ) . Treatment with IFN-alpha resulted in a shift from immunosuppression--documented for the group of untreated patients--to immunopotentiation , with an increase of T-cell IFN-gamma production ( P = 0.0266 ) . Notably , BMT enhanced IFN-gamma production of T cells to a level not only exceeding untreated patients ( P &lt ; 0.0001 ) but also healthy volunteers ( P &lt ; 0.0001 ) . The observation of T1 cytokine up-regulation with IFN-alpha therapy indicates that enhanced T-cell function may be achievable in patients with CML , even in the absence of an allo-response . OUTPUT: avoiding immune destruction INPUT: When cells were incubated in the presence of both interferon-gamma ( IFN-gamma ) and all-trans retinoic acid ( ATRA ) , the concentration of IFN-gamma required to induce apoptosis of B-cell lymphoma cells was much lower than that required for myeloid or erythroid cell lines . The concentration of IFN-gamma that effectively inhibited the proliferation of BALM-3 cells was 1/40 of that required for BALM-1 cells . STAT-1 phosphorylation , IRF-1 mRNA and protein expression and RAR-beta expression were enhanced to a greater degree in BALM-3 cells treated with IFN-gamma and ATRA than in BALM-1 cells treated with IFN-gamma and ATRA , suggesting that these IFN-gamma related genes were involved in the induction of apoptosis of BALM-3 cells . OUTPUT:

resisting cell death

HoC_dynamic_1_shot11

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cell invasion is required for neoplastic metastasis . Matrix metalloproteinase-9 ( MMP-9 ) , which degrades the extracellular matrix , is a major component in the process of cancer cell invasion . Sulfuretin is one of the major flavonoids isolated from Rhus verniciflua . Sulfuretin has been used to reduce oxidative stress , platelet aggregation , the inflammatory response and mutagenesis . However , the effect of sulfuretin on breast cancer metastasis is unknown . In this study , we investigated the inhibitory effect of sulfuretin on 12-O-tetradecanoylphorbol-13-acetate ( TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells . Sulfuretin inhibited TPA-induced transcriptional activation of nuclear factor-κB ( NF-κB ) . We demonstrated that sulfuretin mediated the inhibition of TPA-induced MMP-9 expression and that cell invasion in MCF-7 cells involved suppression of the NF-κB pathway . Therefore , inhibiting MMP-9 expression by sulfuretin may have therapeutic potential for controlling breast cancer invasiveness . OUTPUT: activating invasion and metastasis INPUT: BACKGROUND Thrombospondin-1 ( TSP-1 ) promotes breast cancer cell invasion of collagen by upregulating matrix metalloproteinase-9 ( MMP-9 ) production . Stromal TSP-1 may play a role in regulating tumor cell invasion . We hypothesize that fibroblasts promote breast cancer cell invasion by upregulating the production of MMP-9 through TSP-1 . METHODS MDA-MB-231 human breast carcinoma cells were grown alone or in coculture with human fibroblasts . Gelatin zymography and Western immunoblot analysis for MMP-9 were performed on the coculture cell media and the single cell media . Inhibition of fibroblast-mediated breast tumor cell invasion by an anti-TSP-1 or an anti-MMP-9 antibody was evaluated using a modified Boyden chamber . RESULTS Coculture experiments showed an increased production of MMP-9 when compared with breast cancer single cell culture or fibroblast single cell culture experiments as demonstrated by zymography and Western immunoblot analysis . Fibroblast-stimulated MMP-9 production was comparable with TSP-1-stimulated MMP-9 production . Anti-TSP-1 antibody and anti-MMP-9 antibody inhibited fibroblast-stimulated tumor cell invasion to 30% and 26% of controls , respectively ( P <.05 ) . CONCLUSIONS Fibroblasts may regulate breast cancer cell invasion by promoting tumor MMP-9 production through TSP-1 . Inhibition of stromal TSP-1 stimulation of MMP-9 synthesis may prevent matrix degradation necessary for tumor invasion and metastasis . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot12

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: A new cell line of human ovarian clear cell adenocarcinoma ( CCC ) , TU-OC-1 , was established and characterized . The cells showed a polygonal-shaped morphology and grew in monolayers without contact inhibition and were arranged like a jigsaw puzzle . The chromosome numbers ranged from 64 to 90 . A low rate of proliferation was observed , similar to other CCC cell lines tested ( OVTOKO , RMG-I , and OVAS ) , and the doubling time was 38.4h . The respective IC50 values of cisplatin and paclitaxel were 12.2μM and 58.3nM . Mutational analysis revealed that TU-OC-1 cells harbored a PIK3CA mutation at codon 542 ( E542K ) in exon 9 , which is a mutation hot spot on this gene . We observed that phosphorylated Akt protein was overexpressed in TU-OC-1 cells by western blot analysis . Heterotransplantation to nude mice produced tumors that reflected the original . This cell line may be useful to study the chemoresistant mechanisms of CCC and contribute to novel treatment strategies . OUTPUT: genomic instability and mutation INPUT: A cell line designated HUUCLEC was established from a human uterine cervical lymphoepithelial carcinoma obtained from a 61-year-old Japanese woman . The cell line has grown slowly without interruption and serial passages were successively carried out 60 times within 3 years . The cultured cells were spindle or round in shape , showing anaplastic and pleomorphic features , a pavement cell arrangement and multilayering without contact inhibition . The population doubling time of the HUUCLEC line was 72 hours while the chromosomal number varied widely and showed aneuploidy . The modal chromosomal number was stable at the triploid range and marker chromosomes were present ; the Ebstein-Barr virus was absent in the cultured cells . OUTPUT:

evading growth suppressors;genomic instability and mutation

HoC_dynamic_1_shot13

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Onconase ( Onc ) is an amphibian ribonuclease of the pancreatic RNase family that is cytostatic and cytotoxic to several tumor lines . It also shows anti-tumor activity in mouse tumor models and is currently in phase III clinical trials . In animal tests and clinical trials Onc shows lesser toxicity and fewer side effects compared to most chemotherapeutic drugs . Intriguingly , repeated infusions of this protein do not cause apparent immunological reactions in patients . The aim of the present study was to investigate sensitivity to Onc of human lymphocytes during their mitogenic stimulation in response to the polyvalent mitogen phytohemagglutinin ( PHA ) , and in mixed allogeneic lymphocyte cultures . Unexpectedly , we observed that frequency of cells undergoing activation-induced apoptosis was markedly increased in all cultures containing Onc . Apoptosis was measured by flow cytometry using markers that detect activation of caspases , the in situ presence of DNA strand breaks , and loss of fragmented DNA ( 'sub-G1 ' cell subpopulation ) . The enhancement of frequency of activation-induced apoptosis ( up to 244% ) was observed at 4.2-83 nM Onc concentration , which is at least an order magnitude lower than its minimal concentration reported to affect proliferation or induce apoptosis of leukemic and solid tumor cell lines . The cell cycle progression of lymphocytes that responded to PHA mitogenically was not affected at 8.3 or 83 nM Onc concentration . Because activation-induced apoptosis is the key mechanism regulating several in vivo immunological functions including induction of tolerance , the observed effects of Onc may explain the apparent lack of immune reactions to this protein in treated patients . The propensity of Onc to potentiate the activation-induced apoptosis suggests that this drug may have clinical utility as immunomodulating agent , e.g. , to suppress transplant rejection or treat autoimmune diseases . OUTPUT: resisting cell death;avoiding immune destruction INPUT: The ultraviolet radiation present in sunlight is immune suppressive . Recently we showed that solar-simulated ultraviolet radiation ( ultraviolet A + B ; 295-400 nm ) , applied after immunization , suppressed immunologic memory and the elicitation of delayed-type hypersensitivity to the common opportunistic pathogen , Candida albicans . Further , we found that wavelengths in the ultraviolet A region of the solar spectrum ( 320-400 nm ) , devoid of ultraviolet B , were equally effective in activating immune suppression as ultraviolet A + B radiation . Here we report on the mechanisms involved . Maximal immune suppression was found when mice were exposed to solar-simulated ultraviolet radiation 7-9 d post immunization . No immune suppression was found in ultraviolet-irradiated mice injected with monoclonal anti-interleukin-10 antibody , or mice exposed to solar-simulated ultraviolet radiation and injected with recombinant interleukin-12 . Suppressor lymphocytes were found in the spleens of mice exposed to ultraviolet A + B radiation . In addition , antigen-specific suppressor T cells ( CD3+ , CD4+ , DX5+ ) were found in the spleens of mice exposed to ultraviolet A radiation . Applying liposomes containing bacteriophage T4N5 to the skin of mice exposed to solar-simulated ultraviolet A + B radiation , or mice exposed to ultraviolet A radiation , blocked immune suppression , demonstrating an essential role for ultraviolet-induced DNA damage in the suppression of established immune reactions . These findings indicate that overlapping immune suppressive mechanisms are activated by ultraviolet A and ultraviolet A + B radiation . Moreover , our findings demonstrate that ultraviolet radiation activates similar immunologic pathways to suppress the induction of , or the elicitation of , the immune response . OUTPUT:

avoiding immune destruction;genomic instability and mutation

HoC_dynamic_1_shot14

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Alterations of the epidermal growth factor receptor ( EGFR ) gene are common in some forms of cancer and the most frequent is a deletion of exons 2-7 . We have previously shown that this mutant receptor , called DeltaEGFR , confers enhanced tumorigenicity to glioblastoma cells through elevated proliferation and reduced apoptotic rates of the tumor cells in vivo . To understand the molecular mechanisms that underlie DeltaEGFR-enhanced proliferation , we examined the gene products that control cell cycle progression . We found that levels of the cyclin-dependent kinase ( CDK ) inhibitor , p27 , were lower in U87MG.DeltaEGFR tumors than in parental U87MG or control U87MG.DK tumors . Consequently , CDK2-cyclin A activity was also elevated , concomitant with the RB protein hyperphosphorylation . In addition , activated phosphatidylinositol 3-kinase ( PI3-K ) and phosphorylated Akt levels were also elevated in the U87MG.DeltaEGFR tumors . U87MG.DeltaEGFR cells failed to arrest in G(1) in response to serum starvation in vitro and while maintaining high levels of PI3-K activity and hyperphosphorylated RB . Treatment of U87MG.DeltaEGFR cells with LY294002 , a PI3-K inhibitor , caused reduced levels of phosphorylated Akt and concomitantly up-regulated levels of p27 . Expression of a kinase dead dominant-negative Akt mutant in the U87MG.DeltaEGFR cells similarly resulted in up-regulation of p27 and down-regulation of tumorigenicity in vivo . These results suggest that the constitutively active DeltaEGFR can enhance cell proliferation in part by down-regulation of p27 through activation of the PI3-K/Akt pathway . This pathway may represent another therapeutic target for treatment of those aggressive glioblastomas expressing DeltaEGFR . OUTPUT: evading growth suppressors;sustaining proliferative signaling INPUT: OBJECT The intracellular events transducing mitogenic signals from platelet-derived growth factor-beta ( PDGFbeta ) receptor tyrosine kinases are not precisely known . In this study the authors evaluated whether the phosphatidylinositol 3-kinase ( PI3-K)-Akt-p70S6K pathway is expressed in meningiomas , regulates their growth , and transduces mitogenic signals of PDGF-BB . METHODS Nine meningioma tumors obtained in humans were evaluated using Western blot analysis for phosphorylated ( activated ) Akt and phosphorylated p70S6K . Cells cultured from seven of these meningiomas were also screened using Western blot analysis for Akt and for phosphorylated Akt and p70S6K . The authors also evaluated whether PDGF-BB stimulation of meningioma cells was associated with the phosphorylation of Akt and p70S6K known to activate these kinases . In addition , the effects of wortmannin , an inhibitor of P13-K , on proliferation and activation of Akt and p70S6K in meningioma cells stimulated with PDGF-BB were evaluated . Western blots of lysates from meningiomas demonstrated phosphorylated Akt and p70S6K . Treatment with PDGF-BB stimulated phosphorylation of Akt and p70S6K in each meningioma cell culture . Wortmannin ( 500 and 1000 nM ) significantly decreased PDGF-BB stimulation of meningioma cells ( p &lt ; 0.001 ) while it reduced Akt and p70S6K phosphorylation but not mitogen-activated protein kinase/extracellular signal-regulated kinase ( MAPK/ERK ) phosphorylation . CONCLUSIONS These findings indicate that Akt and p70S6K are constitutively expressed and activated in meningioma cells and that the PI3-K-Akt-p70S6K pathway may participate in transduction of mitogenic signals in meningiomas independent of the Raf-1-MEK-1-MAPK/ERK cascade . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot15

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND/AIMS The use of chemotherapy in hepatocellular carcinoma is still controversial . The aim of this study was to investigate whether the combined use of epirubicin and progesterone has a synergistic effect on cell proliferation and apoptosis in HepG2 cells . METHODOLOGY Different concentrations of epirubicin ( 0.1 microg/ml , 0.25 microg/ml and 0.5microg/ml ) or progesterone ( 12.5 microM , 25 microM and 50 microM ) were added to HepG2 cells either alone or in combinations consisting of different concentrations of the two . Their effects on HepG2 cells were studied by ( 1 ) XTT assay for analysis of cell proliferation , ( 2 ) 3H-Thymidine incorporation for DNA synthesis , ( 3 ) annexin V-FITC/ propidium iodide ( PI ) flowcytometery for cell apoptosis , ( 4 ) flowcytometry for cell cycle distributions , and ( 5 ) reverse transcription-polymerase chain reaction for expression of cell cycle modulator , cyclin D1 . RESULTS 50 microM progesterone increased both the cytotoxic and apoptotic effects of 0.1 microg/ml epirubicin on HepG2 cells at 48 hr culture due to 50 microM progesterone accumulated cells in S phase of the cell cycle and subsequently reduced cyclin D1 expression . These effects on HepG2 cells induced by this combination were comparable to those induced by 0.5 microg/ml epirubicin alone . CONCLUSIONS In vitro , progesterone can increase the cytotoxicity and apoptosis induced by epirubicin on HepG2 cells . OUTPUT: resisting cell death;sustaining proliferative signaling INPUT: In human colorectal adenomas or polyps , cyclooxygenase-2 is expressed predominantly by stromal ( or interstitial ) macrophages . Therefore , we tested the hypothesis that macrophage cyclooxygenase-2 has paracrine pro-tumorigenic activity using in vitro models of macrophage-epithelial cell interactions . We report that macrophages can promote tumorigenic progression of intestinal epithelial cells ( evidenced by decreased cell-cell contact inhibition , increased proliferation and apoptosis , gain of anchorage-independent growth capability , decreased membranous E-cadherin expression , up-regulation of cyclooxygenase-2 expression , down-regulation of transforming growth factor-beta type II receptor expression and resistance to the anti-proliferative activity of transforming growth factor-beta(1) ) in a paracrine , cyclooxygenase-2-dependent manner . Pharmacologically relevant concentrations ( 1-2 microM ) of a selective cyclooxygenase-2 inhibitor had no detectable , direct effect on intestinal epithelial cells but inhibited the macrophage-epithelial cell signal mediating tumorigenic progression . Cyclooxygenase-2-mediated stromal-epithelial cell signalling during the early stages of intestinal tumorigenesis provides a novel target for chemoprevention of colorectal cancer ( and other gastro-intestinal epithelial malignancies , which arise on a background of chronic inflammation , such as gastric cancer ) and may explain the discrepancy between the concentrations of cyclooxygenase inhibitors required to produce anti-neoplastic effects in vitro and in vivo . OUTPUT:

evading growth suppressors;resisting cell death;sustaining proliferative signaling;tumor promoting inflammation

HoC_dynamic_1_shot16

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Telomerase is a ribonucleoprotein consisting of a catalytic subunit , the telomerase reverse transcriptase , TERT , and an integrally associated RNA , TR , which contains a template for the synthesis of short repetitive G-rich DNA sequences at the ends of telomeres . Telomerase can repetitively reverse transcribe its short RNA template , acting processively to add multiple telomeric repeats onto the same DNA substrate . The contribution of enzyme processivity to telomere length regulation in human cells is not well characterized . In cancer cells , under homeostatic telomere length-maintenance conditions , telomerase acts processively , while under nonequilibrium conditions , telomerase acts distributively on the shortest telomeres . To investigate the role of increased telomerase processivity on telomere length regulation in human cells with limited lifespan that are dependent on human TERT ( hTERT ) for lifespan extension and immortalization , we mutated the leucine at position 866 in the reverse transcriptase C motif of hTERT to a tyrosine ( L866Y ) , which is the amino acid found at a similar position in HIV-1 reverse transcriptase . We report that , similar to the previously reported ' gain of function ' Tetrahymena telomerase mutant ( L813Y ) , the human telomerase variant displays increased processivity. hTERT-L866Y , like wild-type hTERT can immortalize and extend the lifespan of limited lifespan cells . Moreover , hTERT-L866Y expressing cells display heterogenous telomere lengths , telomere elongation , multiple telomeric signals indicative of fragile sites and replicative stress , and an increase in short telomeres , which is accompanied by telomere trimming events . Our results suggest that telomere length and homeostasis in human cells may be regulated by telomerase enzyme processivity . OUTPUT: enabling replicative immortality INPUT: A hallmark of cancer cells is the ability to proliferate indefinitely . This acquisition of an immortal lifespan usually requires the activation of telomerase , the enzyme that elongates telomeres . Human telomerase is minimally composed of the reverse transcriptase subunit hTERT , and the RNA subunit hTR . While hTR is ubiquitously expressed in human cells , the hTERT subunit is generally transcriptionally repressed in most normal somatic cells , but is illegitimately activated to restore telomerase activity in cancer cells . Indeed , in the thousands of different human tumours assayed , 85% were scored positive for telomerase activity . However , the levels of telomerase activity detected in tumour samples can vary substantially and even some normal somatic cells have been found to have low levels of enzyme activity . As the functional significance of low levels of telomerase activity is unclear , we investigated whether there is a minimum level of telomerase activity required for tumourigenesis . Using mutants of hTERT that induce varying levels of telomerase activity , we show that there does indeed exist a threshold of activity required for the processes of immortalization , transformation and tumourigenesis . Thus , low levels of activity detected in certain somatic cells would not be expected to contribute to tumourigenesis , nor does the mere detection of telomerase in cancer cells necessarily signify an immortal lifespan . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot17

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Engineered zinc-finger nucleases ( ZFN ) represented an innovative method for the genome manipulation in vertebrates . ZFN introduced targeted DNA double strand breaks ( DSB ) and initiated non-homologous end joining ( NHEJ ) after pronuclear or cytoplasmatic microinjection into zygotes . Resulting frame shift mutations led to functional gene ablations in zebra fish , mice , pigs and also in laboratory rats . Therefore , we targeted the rat Rag1 gene essential for the V(D)J recombination within the immunoglobulin production process and for the differentiation of mature B and T lymphocytes to generate an immunodeficient rat model in the LEW/Ztm strain . RESULTS After microinjection of Rag1 specific ZFN mRNAs in 623 zygotes of inbred LEW/Ztm rats 59 offspring were born from which one carried a 4 bp deletion . This frame shift mutation led to a premature stop codon and a subsequently truncated Rag1 protein confirmed by the loss of the full-length protein in Western Blot analysis . Truncation of the Rag1 protein was characterized by the complete depletion of mature B cells . The remaining T cell population contained mature CD4+/CD3+/TCRαβ+ as well as CD8+/CD3+/TCRαβ+ positive lymphocytes accompanied by a compensatory increase of natural killer cells in the peripheral blood . Reduction of T cell development in Rag1 mutant rats was associated with a hypoplastic thymus that lacked follicular structures . Histological evaluation also revealed the near-complete absence of lymphocytes in spleen and lymph nodes in the immunodeficient Rag1 mutant rat . CONCLUSION The Rag1 mutant rat will serve as an important model for transplantation studies . Furthermore , it may be used as a model for reconstitution experiments related to the immune system , particularly with respect to different populations of human lymphocytes , natural killer cells and autoimmune phenomena . OUTPUT: genomic instability and mutation;avoiding immune destruction INPUT: Environmental carcinogen exposure may play an important role in the incidence of cancer in children . In addition to environmental pollutants , maternal smoking during pregnancy may be a contributing factor . Major carcinogenic components of cigarette smoke and other combustion by-products in the environment include polycyclic aromatic hydrocarbons ( PAH ) . Mouse offspring exposed during midpregnancy to the PAH , benzo[a]pyrene ( B[a]P ) , show significant deficiencies in their immune functions , observed in late gestation which persist for at least 18 months . Tumor incidences in these progeny are 8 to 10-fold higher than in controls . We have demonstrated a significant reduction in thymocytes ( CD4+ CD8+ , CD4+ CD8+ Vbeta8+ , CD4+ CD8+ Vgamma2+ ) from newborn and splenocytes ( CD4+ CD8+ ) from 1-week-old mouse progeny exposed to B[a]P in utero . To investigate possible causes of the observed T cell reduction , we analyzed the thymocytes and splenocytes from progeny and maternal tissues for the presence of B[a]P-DNA adducts . Adducts were detected in maternal , placental and offspring lymphoid tissues at day 19 of gestation , at birth and 1-wk after birth . The presence of B[a]P-DNA adducts in immature T cells may , in part , explain the previously observed T cell immunosuppression and tumor susceptibility in mice exposed to B[a]P in utero . The effects of DNA lesions on progeny T cells may include interference with normal T-cell development . These results provide a possible explanation for the relationship between maternal smoking during pregnancy and childhood carcinogenesis . OUTPUT:

avoiding immune destruction;genomic instability and mutation

HoC_dynamic_1_shot18

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: activating invasion and metastasis;inducing angiogenesis;sustaining proliferative signaling INPUT: 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 . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot19

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: tumor promoting inflammation INPUT: beta-Defensins are small antimicrobial peptides of the innate immune system produced in response to microbial infection of mucosal tissue and skin . We demonstrate that murine beta-defensin 2 ( mDF2beta ) acts directly on immature dendritic cells as an endogenous ligand for Toll-like receptor 4 ( TLR-4 ) , inducing up-regulation of costimulatory molecules and dendritic cell maturation . These events , in turn , trigger robust , type 1 polarized adaptive immune responses in vivo , suggesting that mDF2beta may play an important role in immunosurveillance against pathogens and , possibly , self antigens or tumor antigens . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot20

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: activating invasion and metastasis INPUT: 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 . OUTPUT:

sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot21

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: UVB from solar radiation is both an initiating and promoting agent for skin cancer . We have found that primary human keratinocytes undergo an apoptotic response to UVB . To determine whether these responses are altered during the course of immortalization , we examined markers of apoptosis in primary human foreskin keratinocytes ( HFK ) transduced with either a retroviral vector expressing the E6 and E7 genes of HPV-16 or with empty vector alone ( LXSN-HFK ) . Whereas LXSN-HFK as well as early passage keratinocytes expressing HPV-16 E6 and E7 ( p7 E6/7-HFK ) were both moderately responsive to UVB irradiation , late passage-immortalized keratinocytes ( p27 E6/7-HFK ) were exquisitely sensitive to UVB-induced apoptosis . After exposure to UVB , enhanced annexin V-positivity and internucleosomal DNA fragmentation were observed in p27 E6/7-HFK compared with either LXSN- or p7 E6/7-HFK . Caspase-3 fluorometric activity assays as well as immunoblot analysis with antibodies to caspase-3 and poly(ADP-ribose) polymerase revealed elevated caspase-3 activity and processing at lower UVB doses in p27 E6/7-HFK compared with LXSN- or p7 E6/7-HFK . In addition , the caspase inhibitor DEVD-CHO reduced the apoptotic response and increased survival of all three HFK types . Immunoblot analysis revealed that caspase-8 was activated in all three cell types , but caspase-9 was only activated in p27 E6/7-HFK . Cell cycle analysis further showed that only p27 E6/7-HFK exhibit G(2)/M accumulation that is enhanced by UVB treatment . This accumulation was associated with a rapid down-regulation of Bcl-2 in these cells . The immortalization process subsequent to the expression of HPV E6 and E7 may therefore determine UVB sensitivity by switching the mode of apoptosis from a caspase-8 to a Bcl-2-caspase-9-mediated pathway of apoptosis . OUTPUT: resisting cell death;enabling replicative immortality INPUT: The ultraviolet ( UV ) radiation present in sunlight is immune-suppressive . Recently we showed that solar-simulated UV radiation ( UVA + UVB ; 295-400 nm ) , applied after immunization , suppressed immunological memory and the elicitation of delayed-type hypersensitivity to the common opportunistic pathogen , Candida albicans . Further , we found that wavelengths in the UVA region of the solar spectrum ( 320-400 nm ) , devoid of UVB , were equally effective in activating immune suppression as UVA + UVB radiation . Here we report on the mechanisms involved . No immune suppression was found in UV-irradiated mice injected with monoclonal anti-interleukin ( IL)-10 antibody , or mice exposed to solar-simulated UV radiation and injected with recombinant IL-12 . Antigen-specific suppressor T cells were found in the spleens of mice exposed to UVA + UVB radiation . Applying liposomes containing bacteriophage T4N5 to the skin of mice exposed to solar-simulated UVA + UVB radiation or mice exposed to UVA radiation blocked immune suppression , demonstrating an essential role for UV-induced DNA damage in the suppression of established immune reactions . These findings indicate that UV radiation activates similar immunological pathways to suppress the induction , or the elicitation , of the immune response . OUTPUT:

avoiding immune destruction;genomic instability and mutation

HoC_dynamic_1_shot22

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Androgens and the androgen receptor ( AR ) play important roles in the development of male urogenital organs . We previously found that mice with total AR knockout ( ARKO ) and epithelial ARKO failed to develop normal prostate with loss of differentiation . We have recently knocked out AR gene in smooth muscle cells and found the reduced luminal infolding and IGF-1 production in the mouse prostate . However , AR roles of stromal fibroblasts in prostate development remain unclear . METHODS To further probe the stromal fibroblast AR roles in prostate development , we generated tissue-selective knockout mice with the AR gene deleted in stromal fibroblasts ( FSP-ARKO ) . We also used primary culture stromal cells to confirm the in vivo data and investigate mechanisms related to prostate development . RESULTS The results showed cellular alterations in the FSP-ARKO mouse prostate with decreased epithelial proliferation , increased apoptosis , and decreased collagen composition . Further mechanistic studies demonstrated that FSP-ARKO mice have defects in the expression of prostate stromal growth factors . To further confirm these in vivo findings , we prepared primary cultured mouse prostate stromal cells and found knocking down the stromal AR could result in growth retardation of prostate stromal cells and co-cultured prostate epithelial cells , as well as decrease of some stromal growth factors . CONCLUSIONS Our FSP-ARKO mice not only provide the first in vivo evidence in Cre-loxP knockout system for the requirement of stromal fibroblast AR to maintain the normal development of the prostate , but may also suggest the selective knockdown of stromal AR might become a potential therapeutic approach to battle prostate hyperplasia and cancer . OUTPUT: resisting cell death;sustaining proliferative signaling INPUT: Peptide growth factors have been implicated in progression of prostate cancer ( PCa ) to the androgen-independent state ; however , much of the evidence linking diffusible mitogens and survival factors to this process remains circumstantial . Heparin-binding epidermal growth factor-like growth factor ( HB-EGF ) , a prostate stroma-derived factor , promotes survival , proliferation , and neuroendocrine differentiation of androgen-dependent LNCaP PCa cells in vitro . To test whether sustained exposure to HB-EGF can confer an androgen-independent phenotype , we generated stable populations of LNCaP cells that express constitutively a secreted form of HB-EGF ( LNCaP/sHB ) . LNCaP/sHB cells proliferated more rapidly under androgen-depleted conditions in vitro and formed larger tumors with higher frequency in intact and castrated severe combined immunodeficient mice , in comparison to control cells . LNCaP/sHB tumors also expressed higher levels of the neuroendocrine marker , neuron-specific enolase , compared with control tumors . In castrates , increased neuron-specific enolase expression in LNCaP/sHB tumors was associated with reduced androgen receptor ( AR ) levels . In vitro , AR protein levels were reduced in LNCaP/sHB cells , and in transient transfection assays using an androgen-responsive promoter ( mouse mammary tumor virus-long terminal repeat ) , LNCaP/sHB cells showed reduced sensitivity to dihydrotestosterone compared with controls . This is the first demonstration that continuous exposure of AR-positive PCa cells to a single growth factor can promote an androgen-independent phenotype in vivo . These findings also emphasize the potential role of pathways other than the AR axis in acquisition of androgen independence . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot23

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: INTRODUCTION A subpopulation of cancer cells , tumor-initiating cells , is believed to be the driving force behind tumorigenesis and resistance to radiation and chemotherapy . The persistence of tumor-initiating cells may depend on altered regulation of DNA damage and checkpoint proteins , as well as a reduced propensity to undergo apoptosis or senescence . METHODS To test this hypothesis , we isolated CD24-/low/CD44+ tumor-initiating cells ( as mammospheres ) from MCF-7 breast cancer cells grown in adherent monolayer culture , and carried out a comprehensive comparison of cell death and DNA damage response pathways prior to and after exposure to ionizing radiation in mammospheres and monolayer MCF-7 cells . Single and double-strand break repair was measured by single-cell gel electrophoresis . The latter was also examined by phosphorylation of histone H2AX and formation of 53BP1 and Rad51 foci . Apoptosis was quantified by flow-cytometric analysis of annexin V-binding and senescence was analyzed on the basis of cellular beta-galactosidase activity . We employed the telomeric repeat amplification protocol to quantify telomerase activity . Expression of key DNA repair and cell cycle regulatory proteins was detected and quantified by western blot analysis . RESULTS Our data demonstrate that in comparison to the bulk population of MCF-7 cells ( predominantly CD24+/CD44+ ) , the MCF-7 mammosphere cells benefit from a multifaceted approach to cellular protection relative to that seen in monolayer cells , including a reduced level of reactive oxygen species , a more active DNA single-strand break repair ( SSBR ) pathway , possibly due to a higher level of expression of the key SSBR protein , human AP endonuclease 1 ( Ape1 ) , and a significantly reduced propensity to undergo senescence as a result of increased telomerase activity and a low level of p21 protein expression . No significant difference was seen in the rates of double-strand break repair ( DSBR ) between the two cell types , but DSBR in mammospheres appears to by-pass the need for H2AX phosphorylation . CONCLUSIONS Enhanced survival of MCF-7 tumor-initiating cells in response to ionizing radiation is primarily dependent on an inherent down-regulation of the senescence pathway . Since MCF-7 cells are representative of cancer cells that do not readily undergo apoptosis , consideration of senescence pathways may play a role in targeting stem cells from such tumors . OUTPUT: enabling replicative immortality;evading growth suppressors;genomic instability and mutation;resisting cell death INPUT: The influence of radiation-induced apoptosis on radiosensitivity was studied in a set of closely related human lymphoblastoid cell lines differing in TP53 status . The clonogenic survival of irradiated TK6 cells ( expressing wild-type TP53 ) , WTK1 cells ( overexpressing mutant TP53 ) , and TK6E6 cells ( negative for TP53 owing to transfection with HPV16 E6 ) was assessed in relation to the induction of apoptosis and its suppression by caspase inhibition or treatment with PMA as well as after treatment with caffeine . Measurements using the alkaline comet assay and pulsed-field electrophoresis of the induction and repair of DNA strand breaks showed similar kinetics of the processing of early DNA damage in these cell lines . The cytochalasin B micronucleus assay revealed identical levels of residual damage in the first postirradiation mitosis of these cells . Abrogation of TP53-dependent apoptosis in TK6E6 cells resulted in a distinct increase in radioresistance . Further suppression of apoptosis as observed in WTK1 cells overexpressing mutant TP53 apparently was not responsible for the high radioresistance of WTK1 cells , since other means of highly efficient suppression of apoptosis ( caspase inhibition or PMA treatment ) increased the clonogenic survival of irradiated TK6 cells only to levels similar to those of TK6E6 cells with abrogated TP53-dependent apoptosis . Considering the similar levels of residual chromosomal damage in TK6E6 cells and WTK1 cells , a hitherto unknown mechanism of tolerance needs to be inferred for these TP53 mutant cells . This residual damage tolerance , however , appears to require an intact G2/M-phase checkpoint function since the relative radioresistance of the WTK1 cells was completely lost upon caffeine treatment , which also resulted in a failure of the TK6 and TK6E6 cells to execute apoptosis . In this situation , the cellular response seems to be dominated entirely by TP53-independent mitotic failure . OUTPUT:

genomic instability and mutation;resisting cell death

HoC_dynamic_1_shot24

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: INTRODUCTION A subpopulation of cancer cells , tumor-initiating cells , is believed to be the driving force behind tumorigenesis and resistance to radiation and chemotherapy . The persistence of tumor-initiating cells may depend on altered regulation of DNA damage and checkpoint proteins , as well as a reduced propensity to undergo apoptosis or senescence . METHODS To test this hypothesis , we isolated CD24-/low/CD44+ tumor-initiating cells ( as mammospheres ) from MCF-7 breast cancer cells grown in adherent monolayer culture , and carried out a comprehensive comparison of cell death and DNA damage response pathways prior to and after exposure to ionizing radiation in mammospheres and monolayer MCF-7 cells . Single and double-strand break repair was measured by single-cell gel electrophoresis . The latter was also examined by phosphorylation of histone H2AX and formation of 53BP1 and Rad51 foci . Apoptosis was quantified by flow-cytometric analysis of annexin V-binding and senescence was analyzed on the basis of cellular beta-galactosidase activity . We employed the telomeric repeat amplification protocol to quantify telomerase activity . Expression of key DNA repair and cell cycle regulatory proteins was detected and quantified by western blot analysis . RESULTS Our data demonstrate that in comparison to the bulk population of MCF-7 cells ( predominantly CD24+/CD44+ ) , the MCF-7 mammosphere cells benefit from a multifaceted approach to cellular protection relative to that seen in monolayer cells , including a reduced level of reactive oxygen species , a more active DNA single-strand break repair ( SSBR ) pathway , possibly due to a higher level of expression of the key SSBR protein , human AP endonuclease 1 ( Ape1 ) , and a significantly reduced propensity to undergo senescence as a result of increased telomerase activity and a low level of p21 protein expression . No significant difference was seen in the rates of double-strand break repair ( DSBR ) between the two cell types , but DSBR in mammospheres appears to by-pass the need for H2AX phosphorylation . CONCLUSIONS Enhanced survival of MCF-7 tumor-initiating cells in response to ionizing radiation is primarily dependent on an inherent down-regulation of the senescence pathway . Since MCF-7 cells are representative of cancer cells that do not readily undergo apoptosis , consideration of senescence pathways may play a role in targeting stem cells from such tumors . OUTPUT: enabling replicative immortality;evading growth suppressors;genomic instability and mutation;resisting cell death INPUT: PURPOSE The roles of terminal sialyl and fucosyl residues in cell surface glycans in the metastatic potential of H7721 cells , a human hepatocarcinoma cell line , were studied . METHODS Neuraminidase and alpha-L-fucosidase were used to remove the sialyl and fucosyl residues , respectively . Cell adhesion to fibronectin ( Fn ) , laminin ( Ln ) , and human umbilical vein epithelial cell ( HUVEC ) , as well as chemotactic cell migration and invasion , were selected as the parameters of metastatic potential ex vivo . RESULTS Sialyl residue is not essential for cell adhesion to Fn , but is important in cell adhesion to Ln and invasion , and is crucial in cell adhesion to HUVEC and migration . In contrast , fucosyl residue contributes more than sialyl residue to cell adhesion to Fn and Ln , but less to adhesion to HUVEC , and is not essential in chemotactic cell migration and invasion . Cell adhesion to HUVEC , migration , and invasion were inhibited by the monoclonal antibody of sialyl Lewis X , but not by the antibody of non-sialyl Lewis X. CONCLUSION Terminal sialyl residues on cell surface glycans are more important than fucosyl residues in mediating cell adhesion to HUVEC and cell migration/invasion , but the reverse is true in cell adhesion to Fn and Ln . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot25

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Genomic instability has long been recognized as the main feature of neoplasia and a factor modulating individual cancer susceptibility . There are attempts to find effective assays of both individual DNA repair capacity and genetic instability , and their relation to the cancer risk . Genetic predisposition plays an important role in the etiology and development of head and neck squamous cell carcinoma ( HNSCC ) . The aim of our study was to search for a correlation between chromosomal instability and DNA repair capacity in HNSCC patients and healthy controls . The chromosomal instability was measured by the number of bleomycin ( BLM)-induced chromosomal aberrations and diepoxybutane ( DEB)-induced sister chromatid exchanges . The DNA repair capacity was assessed using the DEB-induced adaptive response ( AR ) . The HNSCC patients in our study showed a significant increase in chromosomal instability after a preterminal exposure of their lymphocytes to either BLM for the last 5 h or DEB for the last 24 h of incubation . However , the AR was higher in HNSCC patients than in the control group , suggesting an increase in the DNA repair capacity in the cancer patients as compared to the control . There is no correlation between the DNA repair capacity estimated on the basis of preterminal exposures to BLM and DEB and the DNA repair capacity estimated on the basis of the adaptive response to DEB . The preterminal exposure and the adaptive response test may activate different DNA repair mechanisms . OUTPUT: genomic instability and mutation INPUT: The capacity to repair DNA damage is an important factor that affects the therapeutic outcome in cancer treatment . To clarify the cellular repair response , we investigated the kinetics of DNA excision repair initiated by 1,3-bis(2-chloroethyl)-1-nitrosourea ( BCNU ) in human leukemia CCRF-CEM cells at an exponential growth phase in vitro . Using the alkaline single-cell gel electrophoresis ( comet ) assay , we quantitated the repair kinetics as the amount of DNA single-strand breaks that were generated from the incision and were diminished by the rejoining in the repair process . CEM cells could initiate DNA excision repair in response to BCNU by starting an incision reaction . However , the incision capacity came to a plateau at a concentration of 80 to 100 microM or after an incubation time of 90 to 120 minutes . When the cells were pulsed with 40 microM BCNU , the maximal incision occurred at the end of the incubation period , and the repair process was completed within 4 hours When cells were treated with 100 microM BCNU , the incised DNA was not rejoined at 4 hours , suggesting that the repair was not completed . Higher concentrations might surpass the cellular capacity for repair and would be associated with increased cell death . Evaluation of the repair process may provide a clue for therapeutic strategies to improve clinical efficacy if accelerated DNA repair is responsible for the drug resistance . OUTPUT:

genomic instability and mutation;resisting cell death

HoC_dynamic_1_shot26

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Chromosomal DNA must be in single-strand form for important transactions such as replication , transcription , and recombination to occur . The single-strand DNA ( ssDNA ) is more prone to damage than double-strand DNA ( dsDNA ) , due to greater exposure of chemically reactive moieties in the nitrogenous bases . Thus , there can be agents that damage regions of ssDNA in vivo while being inert toward dsDNA . To assess the potential hazard posed by such agents , we devised an ssDNA-specific mutagenesis reporter system in budding yeast . The reporter strains bear the cdc13-1 temperature-sensitive mutation , such that shifting to 37°C results in telomere uncapping and ensuing 5 ' to 3 ' enzymatic resection . This exposes the reporter region , containing three closely-spaced reporter genes , as a long 3 ' ssDNA overhang . We validated the ability of the system to detect mutagenic damage within ssDNA by expressing a modified human single-strand specific cytosine deaminase , APOBEC3G . APOBEC3G induced a high density of substitutions at cytosines in the ssDNA overhang strand , resulting in frequent , simultaneous inactivation of two reporter genes . We then examined the mutagenicity of sulfites , a class of reactive sulfur oxides to which humans are exposed frequently via respiration and food intake . Sulfites , at a concentration similar to that found in some foods , induced a high density of mutations , almost always as substitutions at cytosines in the ssDNA overhang strand , resulting in simultaneous inactivation of at least two reporter genes . Furthermore , sulfites formed a long-lived adducted 2'-deoxyuracil intermediate in DNA that was resistant to excision by uracil-DNA N-glycosylase . This intermediate was bypassed by error-prone translesion DNA synthesis , frequently involving Pol ζ , during repair synthesis . Our results suggest that sulfite-induced lesions in DNA can be particularly deleterious , since cells might not possess the means to repair or bypass such lesions accurately . OUTPUT: genomic instability and mutation INPUT: 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 . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot27

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Blockage of the metastasis process remains a significant clinical challenge , requiring innovative therapeutic approaches . For this purpose , molecules that inhibit matrix metalloproteinases activity or induce the expression of their natural inhibitor , the tissue inhibitor of metalloproteinases ( TIMPs ) , are potentially interesting . In a previous study , we have shown that synthetic ligands binding to cell surface nucleolin/nucleophosmin and known as HB 19 for the lead compound and NucAnt 6L ( N6L ) for the most potent analog , inhibit both tumor growth and angiogenesis . Furthermore , they prevent metastasis in a RET transgenic mice model which develops melanoma . Here , we investigated the effect of N6L on the invasion capacity of MDA-MB-435 melanoma cells . Our results show that the multivalent pseudopeptide N6L inhibited Matrigel invasion of MDA-MB-435 cells in a modified Boyden chamber model . This was associated with an increase in TIMP-3 in the cell culture medium without a change in TIMP-3 mRNA expression suggesting its release from cell surface and/or extracellular matrix . This may be explained by our demonstrated N6L interaction with sulfated glycosaminoglycans and consequently the controlled bioavailability of glycosaminoglycan-bound TIMP-3 . The implication of TIMP-3 in N6L-induced inhibition of cell invasion was evidenced by siRNA silencing experiments showing that the loss of TIMP-3 expression abrogated the effect of N6L . The inhibition of tumor cell invasion by N6L demonstrated in this study , in addition to its previously established inhibitory effect on tumor growth and angiogenesis , suggests that N6L represents a promising anticancer drug candidate warranting further investigation . OUTPUT: activating invasion and metastasis;inducing angiogenesis INPUT: Tumor metastasis represents a complex multistep process that requires migration , invasion , and angiogenesis . In this study , we examined the impact of molecular blockade of the epidermal growth factor receptor on the invasive and metastatic capacity of human squamous cell carcinoma ( SCC ) of the head and neck using in vitro and in vivo model systems . Treatment with the anti-epidermal growth factor receptor antibody C225 attenuated the migration of SCC-1 tumor cells through a chemotaxis chamber in a dose-dependent manner . Incubation of SCC cells with 10-100 nM C225 for 4 h resulted in 40-60% inhibition of cell migration . Furthermore , in the presence of C225 , the capacity of SCC-1 to invade across a layer of extracellular matrix ( Matrigel ) was significantly inhibited . Using an in vivo orthotopic floor-of-mouth xenograft model , locoregional tumor invasion of SCC-1 into muscle , vessel , bone , and perineural tissues was inhibited in C225-treated mice . This inhibition was additionally characterized by down-regulation in the expression of matrix metalloproteinase-9 . These data suggest that inhibition of metastatic potential by C225 may be mediated via decreased migration and invasion of SCC cells . Regarding angiogenesis in vitro , we first studied human umbilical vascular endothelial cells , which established a capillary-like network structure ( tube formation ) in the presence of reconstituted Matrigel . Treatment with C225 reduced cell-to-cell interaction of human umbilical vascular endothelial cells , resulting in disruption of tube formation . The effect of C225 was additionally examined using an in vivo tumor xenograft neovascularization model of angiogenesis . Systemic treatment with C225 not only reduced tumor growth and the number of blood capillaries but also hindered the growth of established vessels toward the tumor . Taken together , these results provide evidence that C225 can suppress tumor-induced neovascularization and metastasis in SCC of the head and neck . OUTPUT:

activating invasion and metastasis;inducing angiogenesis

HoC_dynamic_1_shot28

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Chromosomal DNA must be in single-strand form for important transactions such as replication , transcription , and recombination to occur . The single-strand DNA ( ssDNA ) is more prone to damage than double-strand DNA ( dsDNA ) , due to greater exposure of chemically reactive moieties in the nitrogenous bases . Thus , there can be agents that damage regions of ssDNA in vivo while being inert toward dsDNA . To assess the potential hazard posed by such agents , we devised an ssDNA-specific mutagenesis reporter system in budding yeast . The reporter strains bear the cdc13-1 temperature-sensitive mutation , such that shifting to 37°C results in telomere uncapping and ensuing 5 ' to 3 ' enzymatic resection . This exposes the reporter region , containing three closely-spaced reporter genes , as a long 3 ' ssDNA overhang . We validated the ability of the system to detect mutagenic damage within ssDNA by expressing a modified human single-strand specific cytosine deaminase , APOBEC3G . APOBEC3G induced a high density of substitutions at cytosines in the ssDNA overhang strand , resulting in frequent , simultaneous inactivation of two reporter genes . We then examined the mutagenicity of sulfites , a class of reactive sulfur oxides to which humans are exposed frequently via respiration and food intake . Sulfites , at a concentration similar to that found in some foods , induced a high density of mutations , almost always as substitutions at cytosines in the ssDNA overhang strand , resulting in simultaneous inactivation of at least two reporter genes . Furthermore , sulfites formed a long-lived adducted 2'-deoxyuracil intermediate in DNA that was resistant to excision by uracil-DNA N-glycosylase . This intermediate was bypassed by error-prone translesion DNA synthesis , frequently involving Pol ζ , during repair synthesis . Our results suggest that sulfite-induced lesions in DNA can be particularly deleterious , since cells might not possess the means to repair or bypass such lesions accurately . OUTPUT: genomic instability and mutation INPUT: Although there have been numerous studies of site-specific mutagenesis by dGuo adducts of benzo[a]pyrene diol epoxides ( B[a]P DEs ) , the present study represents the first example of site-specific mutagenesis by dGuo adducts of the highly carcinogenic benzo[c]phenanthrene 3,4-diol 1,2-epoxides ( B[c]Ph DEs ) . The eight adducts that would result from cis- and trans-opening at C-1 of four optically active isomers of B[c]Ph DEs by the N(2)-amino group of dGuo were incorporated into 5'-TTCGAATCCTTCCCCC ( context III ) and 5'-GGGGTTCCCGAGCGGC ( context IV ) at the underlined site . These modified oligonucleotides along with unmodified controls were ligated into single-stranded M13mp7L2 , which were then used to transfect SOS-induced Escherichia coli . Upon replication of the lesions in each of the two sequence contexts , mutational analysis of the progeny was performed by differential hybridization . For the 16 adducts , the mutation frequencies varied over 2 orders of magnitude with a reasonably even distribution ( 0.4-1% for three adducts , 1-2% for six adducts , 3-7.4% for five adducts , and one adduct each at 11 and 39% ) . For all but this last adduct , the mutation frequency for a given B[c]Ph DE adduct was less than for its B[a]P analogue with the same stereochemistry in the same sequence . For the vectors containing adducts with S configuration at the site of attachment of the hydrocarbon to the dGuo base , the main base substitution was G --&gt ; T followed by G --&gt ; A. In contrast , for the vectors containing adducts with R configuration , the main base substitution was G --&gt ; A. The most notable observation in the present study is the low frequency of mutations induced by the B[c]Ph DE-dGuo adducts relative to their B[a]P counterparts . A possible structural basis for this difference is proposed . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot29

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Acrolein ( Acr ) is a ubiquitous environmental pollutant found in cigarette smoke and automobile exhaust . It can also be produced endogenously by oxidation of polyunsaturated fatty acids . The Acr-derived 1,N(2)-propanodeoxyguanosine ( Acr-dG ) adducts in DNA are mutagenic lesions that are potentially involved in human cancers . In this study , monoclonal antibodies were raised against Acr-dG adducts and characterized using ELISA . They showed strong reactivity and specificity toward Acr-dG , weaker reactivity toward crotonaldehyde- and trans-4-hydroxy-2-nonenal-derived 1,N(2)-propanodeoxyguanosines , and weak or no reactivity toward 1,N(6)-ethenodeoxyadenosine and 8-oxo-deoxyguanosine . Using these antibodies , we developed assays to detect Acr-dG in vivo : first , a simple and quick FACS-based assay for detecting these adducts directly in cells ; second , a highly sensitive direct ELISA assay for measuring Acr-dG in cells and tissues using only 1 μg of DNA without DNA digestion and sample enrichment ; and third , a competitive ELISA for better quantitative measurement of Acr-dG levels in DNA samples . The assays were validated using Acr-treated HT29 cell DNA samples or calf thymus DNA , and the results were confirmed by LC-MS/MS-MRM . An immunohistochemical assay was also developed to detect and visualize Acr-dG in HT29 cells as well as in human oral cells . These antibody-based methods provide useful tools for the studies of Acr-dG as a cancer biomarker and of the molecular mechanisms by which cells respond to Acr-dG as a ubiquitous DNA lesion . OUTPUT: genomic instability and mutation INPUT: The Escherichia coli AlkB protein protects against the cytotoxicity of methylating agents by repair of the DNA lesions 1-methyladenine and 3-methylcytosine , which are generated in single-stranded stretches of DNA . AlkB is an alpha-ketoglutarate- and Fe(II)-dependent dioxygenase that oxidizes the relevant methyl groups and releases them as formaldehyde . Here , we identify two human AlkB homologs , ABH2 and ABH3 , by sequence and fold similarity , functional assays , and complementation of the E. coli alkB mutant phenotype . The levels of their mRNAs do not appear to correlate with cell proliferation but tissue distributions are different . Both enzymes remove 1-methyladenine and 3-methylcytosine from methylated polynucleotides in an alpha-ketoglutarate-dependent reaction , and act by direct damage reversal with the regeneration of the unsubstituted bases . AlkB , ABH2 , and ABH3 can also repair 1-ethyladenine residues in DNA with the release of acetaldehyde . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot30

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 μM 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 μM 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 μM . 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 . OUTPUT: tumor promoting inflammation INPUT: The Msh2 DNA mismatch repair gene is one of five genes implicated in the pathogenesis of hereditary nonpolyposis colorectal cancer ( HNPCC ) . To address the possible mechanisms of the site-specific occurrence of HNPCC , the effect of Msh2 deficiency on mutations in different parts of the colon was investigated using the BC-1(lacI)/Msh2 double transgenic mouse . Compared to the Msh2(+/+) mice , Msh2(-/-) mice had an 8-9-fold increase of mutation frequency ( MF ) in the lacI gene from the cecum and the proximal and distal colon . The mutational spectra were also significantly different between Msh2(+/+) and Msh2(-/-) mice , with a significant increase in the frequency of -1 frameshifts and G:C-->A:T base substitutions in the repair-deficient mice . However , in spite of the site-specific predisposition of HNPCC in humans , we found no significant difference in the MF or mutation spectrum between the three parts of the colon in Msh2(+/+) , Msh2(+/-) , or Msh2(-/-) mice . In addition , 11 independent mutants harboring complex mutations within the lacI gene were recovered in the Msh2(-/-) mice . Interestingly , while the Msh2(+/-) mice displayed an overall MF similar to that observed in the wild-type mice , sequencing revealed a significantly different mutational spectrum between Msh2(+/+) and Msh2(+/-) mice , mainly characterized by an increase in -1 frameshifts . Due to the prevalence of frameshift mutations in HNPCC patients , this haploinsufficiency effect of the Msh2 gene in safeguarding genomic integrity may have important implications for human carrier status . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot31

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: A prominent feature of inflammatory diseases is endothelial dysfunction . Factors associated with endothelial dysfunction include proinflammatory cytokines , adhesion molecules , and matrix degrading enzymes . At the transcriptional level , they are regulated by the histone deacetylase sirtuin ( SIRT ) 1 via its actions on the proinflammatory transcription factor nuclear factor-κB ( NF-κB ) . The role of SIRT6 , also a histone deacetylase , in regulating inflammation in endothelial cells is not known . The aim of this study was to determine the effect of SIRT6 knockdown on inflammatory markers in human umbilical vein endothelial cells ( HUVECs ) in the presence of lipopolysaccharide ( LPS ) . LPS decreased expression of SIRT6 in HUVECs . Knockdown of SIRT6 increased the expression of proinflammatory cytokines ( IL-1β , IL-6 , IL-8 ) , COX-prostaglandin system , ECM remodelling enzymes ( MMP-2 , MMP-9 and PAI-1 ) , the adhesion molecule ICAM-1 , and proangiogenic growth factors VEGF and FGF-2 ; cell migration ; cell adhesion to leukocytes . Loss of SIRT6 increased the expression of NF-κB , whereas overexpression of SIRT6 was associated with decreased NF-κB transcriptional activity . Taken together , these results demonstrate that the loss of SIRT6 in endothelial cells is associated with upregulation of genes involved in inflammation , vascular remodelling , and angiogenesis . SIRT6 may be a potential pharmacological target for inflammatory vascular diseases . OUTPUT: activating invasion and metastasis;inducing angiogenesis;tumor promoting inflammation INPUT: A6 is an eight amino acid peptide derived from the non-receptor binding region of urokinase plasminogen activator ( uPA ) , which interferes with the uPA/uPA receptor system . A6 has been synthesized as a potential anti-angiogenic , anti-cancer agent . The current study has investigated the potential therapeutic activity of A6 in the Lewis lung carcinoma ( 3LL ) model of pulmonary metastasis . A6 was found to have direct anti-tumor activity against established 3LL pulmonary metastases at a low tumor burden ( 10-20 colonies per lung ) and was therapeutic in combination with cyclophosphamide at high tumor burdens ( &gt ; 100 colonies per lung ) . Mechanistic studies have revealed that A6 directly inhibits the invasion of 3LL cells through a Matrigel model basement membrane by 40-45% . Moreover , treatment with either A6 or doxorubicin resulted in thicker tubes in endothelial tube formation studies . Our results suggest that A6 , by virtue of its anti-invasive and anti-angiogenic properties , might work additively or synergistically with chemotherapeutic agents and thereby contribute to enhanced therapy of established 3LL cancer metastases . OUTPUT:

activating invasion and metastasis;inducing angiogenesis

HoC_dynamic_1_shot32

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Angiogenic factors produced by monocytes-macrophages are involved in the pathogenesis of chronic inflammatory disorders characterized by persistent angiogenesis . The possibility was tested that interleukin-8 ( IL-8 ) , which is a cytokine that is chemotactic for lymphocytes and neutrophils , is also angiogenic . Human recombinant IL-8 was potently angiogenic when implanted in the rat cornea and induced proliferation and chemotaxis of human umbilical vein endothelial cells . Angiogenic activity present in the conditioned media of inflamed human rheumatoid synovial tissue macrophages or lipopolysaccharide-stimulated blood monocytes was equally blocked by antibodies to either IL-8 or tumor necrosis factor-alpha . An IL-8 antisense oligonucleotide specifically blocked the production of monocyte-induced angiogenic activity . These data suggest a function for macrophage-derived IL-8 in angiogenesis-dependent disorders such as rheumatoid arthritis , tumor growth , and wound repair . OUTPUT: inducing angiogenesis INPUT: Tumor-associated macrophages ( TAM ) have been shown to play an important role in tumor angiogenesis . The purpose of this study was to determine whether monocyte recruitment , activation and differentiation mediated by monocyte chemotactic protein-1 ( MCP-1 ) and macrophage colony stimulating factor ( M-CSF ) modulate the expression of the angiogenic factor , Interleukin ( IL)-8 . Isolated human peripheral blood monocytes secreted low basal levels of IL-8 . Incubation of monocytes with M-CSF or MCP-1 resulted in an up-regulation of IL-8 mRNA and protein expression . The differential expression of IL-8 by monocytes following MCP-1 and M-CSF treatments involved activation of the NFkB transcription factor . Further activation with lipopolysaccharide ( LPS ) caused an increase in IL-8 secretion in monocytes but not in monocyte-derived macrophages ( MDM ) . MDM-conditioned media significantly up-regulated IL-8 expression in human malignant melanoma cells in vitro . In summary , we demonstrated that MCP-1 and M-CSF , critical for monocyte recruitment , activation and differentiation , differentially regulate IL-8 expression and may play an important role in monocyte/macrophage-mediated tumor angiogenesis . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot33

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 ERα-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 ERα 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 . ERα down-regulation was not linked to deregulated expression of transcription factors which drive ERα 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 . OUTPUT: sustaining proliferative signaling INPUT: Recent studies have shown that the antiestrogen tamoxifen ( TAM ) can be used in the treatment of malignant neoplasms other than breast cancer . In the present study , we investigated the expression of estrogen receptor ( ER ) in six malignant rhabdoid tumor ( MRT ) cell lines . Alterations in MRT cell growth in response to estrogen or antiestrogens ( 4-hydroxytamoxifen ( 4-OHT ) , TAM , and ICI 182 780 ) were also investigated . RT-PCR and western blotting showed that ER-alpha was expressed in three of the six MRT cell lines . While 17-beta-estradiol ( E2 ) did not significantly alter MRT cell line proliferation , the hydroxylated tamoxifen metabolite 4-OHT significantly inhibited the growth of all 6 MRT cell lines . However , the steroidal antiestrogen ICI 182 780 did not alter the proliferation of any of the MRT cell lines. 4-OHT induced apoptosis in both ER-alpha-negative and ER-alpha-positive MRT cell lines , as assessed by nuclear morphology and DNA fragmentation . Neither growth inhibition nor induction of apoptosis due to 4-OHT was blocked by the addition of excess E2 . Our data suggested that 4-OHT induced cytotoxic effects against MRT cells , and that these effects were independent of ER expression . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot34

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Context:The ubiquitin-proteasome system and macroautophagy are two major pathways for intracellular protein degradation . Emerging lines of evidence have shown that blockade of ubiquitin-proteasome system by proteasome inhibitors activates macroautophagy.Objective:The purpose of this study was to determine the involvement of autophagy essential gene Beclin 1 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibitors.Design:Autophagy was measured by acidic-trophic dye staining and EGF-LC3 distribution using fluorescence microscopy , as well as LC3-II transition using Western blot . To ascertain the effect of Beclin 1 , cells were transfected with Beclin 1 plasmid or shRNA against Beclin 1 . Cell viability and apoptotic cells were measured using MTT assay and flow cytometry , respectively.Results:Proteasome inhibitors decreased Beclin 1 expression . In addition , treatment with PI3K inhibitors 3-MA or wortmannin , as well as knockdown of Beclin 1 expression , was unable to affect autophagic responses mediated by proteasome inhibitors . Overexpression of Beclin 1 enhanced proteasome inhibitor-mediated cytotoxicity of thyroid cancer cells via suppression of survivin.Conclusions:Proteasome inhibitors cause Beclin 1-independent macroautophagic responses of thyroid cancer cells in a Beclin 1-independent manner . Beclin 1 possesses autophagy-independent antitumoral effects upon exposure of thyroid cancer cells to proteasome inhibitors . OUTPUT: resisting cell death INPUT: The thyroid hormone ( T3 ) blocks proliferation and induces differentiation of neuroblastoma N2a-beta cells that overexpress the beta 1 isoform of the T3 receptor . An element in the region responsible for premature termination of transcription mediates a rapid repression of c-myc gene expression by T3 . The hormone also causes a decrease of cyclin D1 gene transcription , and is able to antagonize the activation of the cyclin D1 promoter by Ras . In addition , a strong and sustained increase of the levels of the cyclin kinase inhibitor ( CKI ) p27(Kip1) are found in T3-treated cells . The increased levels of p27(Kip1) lead to a marked inhibition of the kinase activity of the cyclin-CDK2 complexes . As a consequence of these changes , retinoblastoma proteins are hypophosphorylated in T3-treated N2a-beta cells , and progression through the restriction point in the cell cycle is blocked . OUTPUT:

sustaining proliferative signaling;evading growth suppressors

HoC_dynamic_1_shot35

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cytokines are known to play an important role in host defense by regulating the function , growth , and differentiation of the cells of the immune system . We hypothesize that , in the tumor microenvironment , tumor cells and resident tissue cells ( e.g. , fibroblasts ) also produce cytokines that may regulate the local immune response to tumors . Initially , homogenates of eight head and neck squamous cell carcinomas ( HNSCC ) were assayed for the presence of interleukin-1 ( IL-1 ) , interleukin-4 ( IL-4 ) , interleukin-6 ( IL-6 ) , and granulocyte-macrophage colony-stimulating factor ( GM-CSF ) to establish the presence of these cytokines in the tumors in vivo . We detected IL-1 in all tumor homogenates and IL-4 , IL-6 , and GM-CSF in some homogenates . To assess the ability of HNSCC to produce these cytokines , supernatants of short-term primary cultures of HNSCC were assayed for the same cytokines . No IL-1 was detected , although baseline levels of IL-4 , IL-6 , and GM-CSF were present . However , the stimulation of primary tumor cultures with exogenous IL-1 induced or significantly enhanced production of IL-4 ( p &lt ; 0.01 ) , IL-6 ( p &lt ; 0.001 ) , and GM-CSF ( p &lt ; 0.02 ) . These results support our hypothesis that HNSCC secrete cytokines that may influence the response of local immune cells . Our data also suggest that IL-1 may have a central role in regulating the local immune response through the enhancement or induction of cytokine production by tumor and/or resident tissue cells . OUTPUT: avoiding immune destruction;tumor promoting inflammation INPUT: 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 . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot36

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: OBJECTIVES Lymph node metastasis is among the most important prognostic factors for patients with esophageal squamous cell carcinoma after curative esophagectomy ; however , the extent of lymphadenectomy is still controversial . The objective of the present study was to determine the frequency of lymphatic metastases and to study the pattern of lymph node metastasis in a large study population . METHODS The data from 1361 patients with thoracic esophageal squamous cell carcinoma who underwent curative R0 esophagectomy were retrospectively examined . Logistic regression analysis was used to identify the factors associated with lymph node metastasis . RESULTS Of the 1361 patients , 714 ( 52.5% ) were found to have lymph node metastasis . The frequency of lymph node metastasis increased as the tumor invasion increased . Paratracheal nodes were the most frequent metastasis nodes ( 15.9% ) . The frequency of lymph node metastasis was 9.8% in the neck , 18.0% in the upper mediastinum , 18.9% in the middle mediastinum , 11.8% in the lower mediastinum , and 28.4% in the abdomen . Of these 714 patients , 424 ( 31.2% ) presented with 1 field involvement , 255 ( 18.7% ) with 2 fields , and 35 ( 2.6% ) with 3 fields involvement . Logistic regression analysis revealed tumor length ( P<.001 ) , tumor invasion ( P<.001 ) , tumor differentiation ( P=.003 ) , and lymphovascular invasion ( P<.001 ) were risk factors for lymph node metastasis . Tumor location ( P<.001 ) , tumor invasion ( P=.003 ) , lymphovascular invasion ( P=.004 ) , and paratracheal lymph node involvement ( P=.002 ) were identified as risk factors for cervical lymph node metastasis . CONCLUSIONS Metastases were more frequent in the abdomen than in the neck . Total mediastinal and upper abdominal lymphadenectomy should be carefully conducted . Certain factors , such as tumor location , depth of tumor invasion , lymphovascular invasion , and paratracheal lymph node involvement , might be helpful in determining the need to perform cervical lymphadenectomy in individual patients . OUTPUT: activating invasion and metastasis INPUT: BACKGROUND &amp ; OBJECTIVE There is little ideal predictor available on evaluating the lymph node metastatic potential of breast carcinoma . This study was designed to determine the expression of gene products of E-cadherin ( epithelial ) , N-cadherin ( nerve ) , and matrix metalloproteinase-9 ( MMP-9 ) in breast carcinoma tissue and investigate their association with the invasion and metastasis of breast carcinoma . METHODS The authors examined the expressions of E-cadherin , N-cadherin , and MMP-9 in 72 cases of breast carcinoma(39 cases with lymph node metastasis and 33 cases without lymph node metastasis ) by immunohistochemistry . Multivariable Cox proportional hazards model was used to analyze the patients ' prognosis . RESULTS The average ranks of E-cadherin in lymph node metastasis group and no lymph node metastasis group were 29.19 and 45.14 , respectively , with significant difference ( P &lt ; 0.001 ) . The expression of E-cadherin was correlated inversely with the metastasis of breast carcinoma . The average ranks of N-cadherin and MMP-9 were 40.04 and 42.97 in lymph node metastasis group , and 32.32 and 28.85 in no lymph node metastasis group , both with significant difference ( P &lt ; 0.05 ) , and these expressions were positively correlated with the lymph node metastasis of breast carcinoma . The patients who had high expression of E-cadherin had a longer survival time . CONCLUSION Expression of E-cadherin , N-cadherin , and MMP-9 are associated strongly with lymph node metastasis of breast carcinoma . These proteins are indicators of metastasis potential and prognosis of breast carcinoma . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot37

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Metastasis is a major cause of death of patients with malignant tumors . Matrix metalloproteinases ( MMPs ) are important for the migration and invasion of various types of cancer cell . Propofol is a known anesthetic agent , widely used for short-term anesthesia and for longer-term sedation . Propofol inhibits the proliferation of a variety of tumor cells , but there is no available information regarding propofol-inhibited migration and invasion of tumor cells in vitro . In this study , we investigated the effects of propofol on the migration and invasion of human lung carcinoma A549 cells . Wound healing assay and Boyden chamber assays indicated that propofol inhibited the migration and invasion of A549 cells in vitro . Gelatin zymographic analysis showed the inhibitory effect of propofol on the activation of expression MMP-2 . Western blot analysis also indicated that propofol suppressed the protein expiration of growth factor receptor-bound protein 2 ( GRB2 ) , Jun N-terminal kinases 1/2 ( p-JNK1/2 ) , p-p38 , MMP-2 and MMP-9 in A549 cells . Results from real-time PCR assay also showed that propofol inhibited the mRNA gene expression of MMP-2 , -7 and -9 , and enhanced that of tissue inhibitor of metalloproteinase 1 ( TIMP1 ) and TIMP2 in A549 cells . Taken together , these data show that propofol inhibits MMP-2 and -9 mRNA and protein expressions , resulting in suppression of lung cancer cell invasion and migration in vitro . OUTPUT: activating invasion and metastasis INPUT: BACKGROUND &amp ; OBJECTIVE Usually pituitary adenomas are histological benign and grow slowly , but a proportion of them will become locally aggressive , and develop into invasive pituitary adenomas . The reasons for these differences in tumor behavior are poorly understood . Pituitary adenomas are abounding blood vessels . Angiogenesis and tumor invasion both require degradation of the extracellular matrix components to allow cell migration . The matrix metalloproteinases ( MMPs ) and their nature inhibitors-the tissue inhibitors of metalloproteinases ( TIMPs ) may play a central role in these processes . The aggressive mechanism of pituitary adenomas was studied through investigating the expression of MMP-9 , MMP-2 , TIMP-1 , and TIMP-2 in both invasive and non-invasive adenomas . METHODS Sixty-one surgical removed pituitary adenomas ( forty-nine cases invasive and twelve non-invasive adenomas ) were investigated . Immunohistochemistry staining ( SP method ) was used to detect the expression of MMP-9 , MMP-2 , TIMP-1 , and TIMP-2 in two groups . The results were treated with semi-quantitative method and analyzed by using non-parameter rank sum test . RESULTS Immunohistochemical staining of tumor cells for MMP-9 , TIMP-1 , MMP-2 , and TIMP-2 were noted 95.9% ( 47/49 ) , 57.1% ( 28/49 ) , 75.5% ( 37/49 ) and 89.8% ( 44/49 ) in invasive adenomas , and 100% ( 12/12 ) , 91.7% ( 11/12 ) , 66.7% ( 8/12 ) , and 91.7% ( 11/12 ) in non-invasive adenomas , respectively . Invasive tumors were significantly less expressing TIMP-1 and TIMP-2 ( P &lt ; 0.05 ) . There was no significant difference for MMP-9 or MMP-2 between invasive and non-invasive groups ( P &gt ; 0.05 ) . CONCLUSIONS TIMP-1 and TIMP-2 may play a key role in invasive pituitary adenomas to biological behavior . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot38

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND : CD81 is a transmembrane protein that serves as a putative receptor for hepatitis C virus . In addition , CD81 has been suggested to be involved in a broad range of other cellular functions . Its putative implication in tumorigenesis has so far , however , remained largely unexplored . To assess the candidacy of CD81 as a tumor suppressor in gastric cancer development , we investigated its expression and function in a series of primary gastric tumors and gastric tumor-derived cell lines . METHODS : The expression and concomitant methylation status of the CD81 gene and its effect on tumor development and cellular signaling were evaluated . RESULTS : CD81 mRNA levels were found to be low in 16 of 40 ( 40% ) primary tumors and 9 of 14 ( 64.2% ) cell lines , and these low expression levels were found to correlate with the stage and grade of the tumors . Genomic alterations of CD81 were not encountered , whereas its expression could be re-activated in low expressing cells upon 5-aza-dC treatment . Bisulfite DNA sequencing analysis of 10 CpG sites within the 5 ' proximal region of the CD81 gene promoter revealed that the observed transcriptional silencing was tightly associated with aberrant hypermethylation . Subsequent restoration of CD81 expression induced a G(1) cell cycle arrest and apoptosis , whereas siRNA-mediated CD81 down-regulation promoted cell proliferation and attenuated cellular responses to various apoptotic stress stimuli . Also the colony-forming ability of the tumor cells could be inhibited and enhanced through CD81 up- and down-regulation , respectively . CD81 was found to inhibit p38 ( but not ERK , JNK and AKT ) phosphorylation and its growth suppressive effect could be abolished through p38 up- and down-regulation . CONCLUSION : From our data we conclude that epigenetic inactivation of CD81 is a common feature of gastric tumors and that this inactivation may render growth and survival advantages to the tumor cells , at least partially through p38 signaling . OUTPUT: evading growth suppressors;resisting cell death;sustaining proliferative signaling INPUT: This study was set up to investigate the relationships between the formation and removal of DNA damage in form of 8-oxodeoxyguanosine ( 8-oxodG ) in neonatal ( day 16 of gestation ) as compared to adult rats . The hypothesis addressed was whether the rapidly dividing foetal tissue has an enhanced requirement of DNA repair providing protection against potentially mutagenic DNA damages such as 8-oxodG . The activity of the primary 8-oxodG-repair protein OGG1 was measured by a DNA incision assay and the expression of OGG1 mRNA was measured by Real-Time PCR normalised to 18S rRNA . The tissue level of 8-oxodG was measured by HPLC-ECD . We found a 2-3-fold increased incision activity in the foetal control tissue , together with a 3-15-fold increase in mRNA of OGG1 as compared to liver tissue from adult rats . The levels of 8-oxodG in the foetal tissue were unaltered as compared to the adult groups . To increase the levels of 8-oxodG , the rats received an injection ( i.p. ) of the hepatotoxin 2-nitropropane . The compound induced significant levels of 8-oxodG in male rat livers 5h after the injection and in the foetuses 24h after the injection , while the female rats showed no increase in 8-oxodG . The incision activity was slightly depressed in both male and female liver tissue and in the foetal tissue 5h after the injection , but significantly increased from 5 to 24h after the injection . However , it did not reach levels significantly above the control levels . In conclusion , this study confirms that foetal tissue has increased levels of OGG1 mRNA and correspondingly an enhanced incision activity on an 8-oxodG substrate in a crude tissue extract . OUTPUT:

genomic instability and mutation;tumor promoting inflammation

HoC_dynamic_1_shot39

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cell division and apoptosis are two crucial components of tumor biology and the importance of increased cell proliferation and reduced cell death have made them valid therapeutic targets . The plant kingdom is a relatively underexploited cache of novel drugs , and crude extracts of plants are known for their synergistic activity . The present study assessed the anti-proliferative activity of the medicinal plant Centrosema pubescens Benth . Centrosema pubescens dichloromethane extract ( CPDE ) inhibited the proliferation of HL-60 ( promyelocytic acute leukaemia ) cells with an IC₅₀ value of 5 μg/ml . Further studies also showed that CPDE induces growth arrest at the G1 phase and specifically down-regulates the expressions of cyclin E and CDK2 and up-regulates p27(CKI) levels . These events apparently lead to the induction of apoptosis , which was demonstrated qualitatively by a DNA fragmentation assay and propidium iodide staining . Quantitative assessment of the effective arrest of the cell cycle and of apoptosis was confirmed by flow cytometry . CPDE exhibited negligible cytotoxicity even at the highest dose tested ( 100 μg/ml ) in both normal peripheral blood mononuclear cells and in an in vitro model ( HL-60 ) . Our results strongly suggest that CPDE arrests the cell cycle at the G1 phase and triggers apoptosis by caspase activation . OUTPUT: evading growth suppressors;resisting cell death INPUT: Photodynamic therapy ( PDT ) may trigger apoptosis or necrosis in cancer cells . Several steps in the induction and execution of apoptosis require high amounts of adenosine-5'-triphosphate ( ATP ) . Because the mitochondrial membrane potential ( delta psi ) decreases early in apoptosis , we raised the question about the mechanisms of maintaining a sufficiently high ATP level . We therefore monitored delta psi and the intracellular ATP level of apoptotic human epidermoid carcinoma cells ( A431 ) after photodynamic treatment with aluminum ( III ) phthalocyanine tetrasulfonate . A maximum of caspase-3-like activity and nuclear fragmentation was found at fluences of about 4 J cm(-2) . Under these conditions apoptotic cells reduced delta psi rapidly , while the ATP level remained high for 4-6 h after treatment for cells supplied with glucose . To analyze the contribution of glycolysis to the energy supply during apoptosis , experiments were carried out with cells deprived of glucose . These cells showed a rapid drop of ATP content and neither caspase activation nor nuclear fragmentation could be detected . We conclude that the use of glucose as a source of ATP is obligatory for the execution of PDT-induced apoptosis . OUTPUT:

resisting cell death;cellular energetics

HoC_dynamic_1_shot40

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: evading growth suppressors INPUT: Recent studies have shown that the transcription factor , nuclear factor kappaB ( NF-kappaB ) , regulates critical survival pathways in a variety of different cell types , including human pancreatic cancer cells . The activation of NF-kappaB is controlled by proteasome-mediated degradation of its endogenous polypeptide inhibitor , inhibitor of nuclear factor kappaBalpha . We investigated the effects of PS-341 , a peptide boronate inhibitor of the proteasome in human pancreatic cancer cells in vitro and in vivo . Comparison of PS-341's effects on the growth of eight different human pancreatic cancer cell lines revealed marked heterogeneity in drug responsiveness , ranging from highly resistant ( IC50 &gt ; 10 microM ; Panc-48 , HS766T , and Mia-PaCa-2 ) to extremely sensitive ( IC50 &lt ; 40 nM ; L3.6pl , Hpaf2 , and BxPC3 ) . However , these effects did not correlate with differential inhibition of NF-kappaB activation . Direct quantification of apoptosis revealed that PS-341's effects on cell growth largely correlated with sensitivity to programmed cell death . Evaluation of PS-341's effects on established orthotopic tumor xenografts demonstrated that biweekly intravenous administration of the maximum-tolerated dose of the drug ( 1 mg/kg ) led to significant reductions in the volumes of L3.6pl tumors but not Mia-PaCa-2 tumors . Laser scanning cytometer-mediated quantification of drug-induced apoptosis in the xenografts confirmed that PS-341 induced DNA fragmentation and activation of caspase-3 in L3.6pl tumors but not in Mia-PaCa-2 tumors . However , histological examination of drug-treated tumors revealed extensive central necrosis and reductions in microvessel density and VEGF expression in both tumor types . Taken together , our results demonstrate that PS-341 inhibits the growth of human pancreatic tumors via direct effects on tumor cells and indirect effects on the tumor vasculature . OUTPUT:

resisting cell death;inducing angiogenesis

HoC_dynamic_1_shot41

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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-α ) , 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-1α and NF-κB transcription factors are important players for the establishment of a pro-inflammatory and potentially oncogenic environment . HIF-1α 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-1α 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-1α 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 . OUTPUT: activating invasion and metastasis INPUT: 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 . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot42

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: CONTEXT Papillary thyroid carcinoma ( PTC ) is the most frequent thyroid tumor and is responsible for the overall increase in thyroid cancer incidence . S100A11 ( calgizzarin ) , a member of the S100 Ca(2+)-binding protein family , is involved in several different biological processes . S100A11 has been found up-regulated in PTC , both at the mRNA and protein levels . OBJECTIVE Through a combination of expression analysis and functional in vitro and in vivo studies , we have attempted to gain insight into the relevance of S100A11 overexpression in PTC biology . DESIGN The expression of the S100A11 gene in PTC was investigated in several gene expression data sets . The effect of S100A11 silencing on the hallmarks of the malignant phenotype of several PTC-derived cell lines was investigated . In NIH3T3 cells , the cooperation of S100A11 with the different PTC-specific oncogenes was assessed . RESULTS We found that the S100A11 gene expression is frequently up-regulated in PTC , anaplastic thyroid carcinoma , but not in follicular thyroid carcinoma . S100A11 overexpression was also detected in PTC-derived cell lines , which were then used for functional studies . S100A11 silencing in PTC-derived cell lines did not affect cell proliferation , whereas it reduced the loss of contact inhibition , anchorage-independent growth , and resistance to anoikis . Cotransfection experiments in NIH3T3 cells showed that overexpression of the S100A11 gene was able to enhance the transforming capabilities of the different PTC-associated oncogenes by affecting the loss of contact inhibition , anchorage-independent growth , and in vivo tumor formation . CONCLUSION Our data indicate that S100A11 overexpression exerts a protumoral functional role in PTC pathogenesis . OUTPUT: evading growth suppressors INPUT: We have recently identified ICBP90 as being a protein able to bind in vitro a CCAAT box of the topoisomerase II alpha gene promoter . The aim of the present work was to check whether ICBP90 is able to regulate in vivo topoisomerase II alpha expression in human lung fibroblasts under various proliferating conditions . Transient transfection experiments performed on moderately growing human lung fibroblasts ( 50% of confluence ) showed that overexpression of ICBP90 is associated with an elevation of topoisomerase II alpha expression and an increase of the cell proliferation rate . In highly proliferating human lung fibroblasts ( 20% confluence ) overexpression of ICBP90 had no effect . In contrast , in non-proliferating fibroblasts ( 100% confluence ) overexpression of ICBP90 allowed recovery of topoisomerase II alpha expression levels with a concomitant overgrowth of confluent cell cultures . Our results show that ICBP90 regulates topoisomerase II alpha expression and is able to overcome cell contact inhibition signaling , suggesting that increased ICBP90 expression may be involved in carcinogenesis . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot43

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Mice defective in the mismatch repair ( MMR ) gene Msh2 manifest an enhanced predisposition to skin cancer associated with exposure to UVB radiation . This predisposition is further heightened if the mice are additionally defective for the nucleotide excision repair gene Xpc . To test the hypothesis that the predisposition of Msh2 mutant mice to skin cancer reflects a mutator phenotype associated with increased proliferation of skin cells following exposure to UV radiation , Msh2 mutant mice were exposed to the tumor promoter TPA . Such mice showed a robust proliferative response in the skin , but did not manifest evidence of dysplasia or neoplasia . We conclude that the predisposition of Msh2 mice to UVB radiation-induced skin cancer reflects an interaction between the processes of mismatch repair and some other excision repair mode , the exact nature of which remains to be established . OUTPUT: genomic instability and mutation INPUT: 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 . OUTPUT:

genomic instability and mutation;evading growth suppressors

HoC_dynamic_1_shot44

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: CDKN1C/P57 is a cyclin-dependent kinase inhibitor implicated in different human cancers , including hepatocellular carcinoma ( HCC ) ; however , little is known regarding the role of CDKN1C/P57 and its regulation in HCC . In this study , we show that the down-regulation of Notch1 and Notch3 in two HCC cell lines resulted in Hes1 down-regulation , CDKN1C/P57 up-regulation , and reduced cell growth . In line with these data , we report that CDKN1C/P57 is a target of transcriptional repression by the Notch effector , Hes1 . We found that the up-regulation of CDKN1C/P57 by cDNA transfection decreased tumor growth , as determined by growth curve , flow cytometry analysis , and cyclin D1 down-regulation , without affecting the apoptosis machinery . Indeed , the expression of Bax , Noxa , PUMA , BNIP(3) , and cleaved caspase-3 was not affected by CDKN1C/P57 induction . Morphologically CDKN1C/p57-induced HCC cells became flat and lengthened in shape , accumulated the senescence-associated β-galactosidase marker , and increased P16 protein expression . Evaluation of senescence in cells depleted both for Hes1 and CDKN1C/P57 revealed that the senescent state really depends on the accumulation of CDKN1C/p57 . Finally , we validated our in vitro results in primary HCCs , showing that Hes1 protein expression inversely correlates with CDKN1C/P57 mRNA levels . In addition , reduced Hes1 protein expression is accompanied by a shorter time to recurrence after curative resection , suggesting that Hes1 may represent a biomarker for prediction of patients with poor prognosis . OUTPUT: resisting cell death;enabling replicative immortality INPUT: Natural killer ( NK ) and CD56(+) T cells are thought to play a central role in antitumour immunity . Their cytolytic activities are controlled by a variety of receptors including CD94 and killer immunoglobulin-like receptors ( KIR ) , which bind to major histocompatibility complex ( MHC ) class I molecules on target cells and mediate cell activation or inhibition . We have examined the numbers , phenotypes and antitumour cytotoxic functions of hepatic NK and CD56(+) T cells isolated from 22 patients with hepatic malignancy and 19 healthy donors . Flow cytometry revealed that NK cell numbers were increased among hepatic mononuclear cells in malignancy compared to histologically normal livers ( mean : 38% vs 27% ; P=0.03 ) , but CD56(+) T cell numbers were not ( 28% vs 27% ) . NK cells and CD56(+) T cells from tumour-bearing livers exhibited lymphokine-activated killing of K562 targets and T cell receptor-mediated lysis of P815 cells . The expression of CD94 and the KIR isotypes CD158a , CD158b and KIR3DL1 by CD56(+) T cells and NK cells was significantly and consistently reduced in tumour-bearing livers compared to healthy livers ( P<0.05 in all cases ) . Simultaneous ligation of CD158a , CD158b and KIR3DL1 caused an overall partial inhibition of CD56(+) T cell cytotoxic activity , suggesting that the observed reductions in KIR(+) cell numbers in malignancy are likely to lead to enhanced cytotoxicity . Our results suggest that , while hepatic CD56(+) T cells are not expanded in malignancy , downregulation of KIR and CD94 expression may be a mechanism by which the hepatic immune system can be activated to facilitate tumour rejection . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot45

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: When the prostate cancer cells become unresponsive to androgen therapy , resistance to chemotherapy becomes imminent , resulting in high mortality . To combat this situation , lycopodine , a pharmacologically important bioactive component derived from Lycopodium clavatum spores , was tested against hormone sensitive ( LnCaP ) and refractory ( PC3 ) prostate cancer cells in vitro . This study aims to check if lycopodine has demonstrable anti-cancer effects and if it has , to find out the possible mechanism of its action . The MTT assay was performed to evaluate the cytotoxic effect . Depolarization of mitochondrial membrane potential , cell cycle , EGF receptor activity and apoptosis were recorded by FACS ; profiles of different anti- and pro-apoptotic genes and their products were studied by semi-quantitative RT-PCR , indirect-ELISA , western blotting . Drug-DNA interaction was determined by CD spectroscopy . Administration of lycopodine down-regulated the expression of 5-lipoxygenase and the 5-oxo-ETE receptor ( OXE receptor1 ) and EGF receptor , and caused up-regulation of cytochrome c with depolarization of mitochondrial inner membrane potential , without palpable change in p53 activity , resulting in apoptosis , cell arrest at G0/G1 stage and ultimately reduced proliferation of cancer cells ; concomitantly , there was externalization of phosphotidyl serine residues . CD spectroscopic analysis revealed intercalating property of lycopodine with DNA molecule , implicating its ability to block cellular DNA synthesis . The overall results suggest that lycopodine is a promising candidate suitable for therapeutic use as an anti-cancer drug . OUTPUT: resisting cell death;sustaining proliferative signaling INPUT: 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 . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot46

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Prohibiting angiogenesis is an important therapeutic approach for fighting cancer and other angiogenic related diseases . Research focused on proteins that regulate abnormal angiogenesis has attracted intense interest in both academia and industry . Such proteins are able to target several angiogenic factors concurrently , thereby increasing the possibility of therapeutic success . Aquaporin-1 ( AQP1 ) is a water channel membrane protein that promotes tumour angiogenesis by allowing faster endothelial cell migration . In this study we test the hypothesis that AQP1 inhibition impairs tumour growth in a mouse model of melanoma . After validating the inhibitor efficacy of two different AQP1 specific siRNAs in cell cultures , RNA interference experiments were performed by intratumoural injections of AQP1 siRNAs in mice . After 6 days of treatment , AQP1 siRNA treated tumours showed a 75 % reduction in volume when compared to controls . AQP1 protein level , in AQP1 knockdown tumours , was around 75 % that of the controls and was associated with a significant 40 % reduced expression of the endothelial marker , Factor VIII . Immunofluorescence analysis of AQP1 siRNA treated tumours showed a significantly lower microvessel density . Time course experiments demonstrated that repeated injections of AQP1 siRNA over time are effective in sustaining the inhibition of tumour growth . Finally , we have confirmed the role of AQP1 in sustaining an active endothelium during angiogenesis and we have shown that AQP1 reduction causes an increase in VEGF levels . In conclusion , this study validates AQP1 as a pro-angiogenic protein , relevant for the therapy of cancer and other angiogenic-related diseases such as psoriasis , endometriosis , arthritis and atherosclerosis . OUTPUT: inducing angiogenesis INPUT: Recent reports provide evidence that some growth factors behave as inhibitors of the apoptosis of the endothelial cells , bringing forward the concept of vascular survival as a post-angiogenesis process . At least two different vasculature development processes occur within a tumor : the angiogenic ( formation of new vessels ) and the vascular survival pathway , which is devoted to the preservation of the newly-formed vessels in layers that lose contact with the adjacent normal tissue . We developed a method to assess these processes in tissue samples . We noted that differences among tumors may exist not only in the tumor angiogenic activity ( TAA ) but also in the vascular survival ability ( VSA ) . One third of the highly angiogenic breast cancer cases examined had a poor ability to maintain high vessel density in inner tumor areas . Both parameters are independently related to prognosis , while VSA was directly related to tumor dimensions and node involvement . Patients with high TAA and VSA had a particularly poor prognosis . It is suggested that although cancer angiogenic activity is important for the local invasion and dissemination into vessels and lymphatics , the VSA may be important for the effective formation of viable tumor foci in lymph nodes or distant organs . Recognition and quantification of the vascular survival ability in human tumors may significantly improve the prognostic value of the assessment of tumor vasculature , and may help to stratify patients for clinical trials with novel anti-angiogenic or angiotoxic drugs . Elucidation of the pathways may provide additional targets for antiangiogenic therapy . OUTPUT:

inducing angiogenesis;activating invasion and metastasis

HoC_dynamic_1_shot47

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Onconase ( Onc ) is an amphibian ribonuclease of the pancreatic RNase family that is cytostatic and cytotoxic to several tumor lines . It also shows anti-tumor activity in mouse tumor models and is currently in phase III clinical trials . In animal tests and clinical trials Onc shows lesser toxicity and fewer side effects compared to most chemotherapeutic drugs . Intriguingly , repeated infusions of this protein do not cause apparent immunological reactions in patients . The aim of the present study was to investigate sensitivity to Onc of human lymphocytes during their mitogenic stimulation in response to the polyvalent mitogen phytohemagglutinin ( PHA ) , and in mixed allogeneic lymphocyte cultures . Unexpectedly , we observed that frequency of cells undergoing activation-induced apoptosis was markedly increased in all cultures containing Onc . Apoptosis was measured by flow cytometry using markers that detect activation of caspases , the in situ presence of DNA strand breaks , and loss of fragmented DNA ( 'sub-G1 ' cell subpopulation ) . The enhancement of frequency of activation-induced apoptosis ( up to 244% ) was observed at 4.2-83 nM Onc concentration , which is at least an order magnitude lower than its minimal concentration reported to affect proliferation or induce apoptosis of leukemic and solid tumor cell lines . The cell cycle progression of lymphocytes that responded to PHA mitogenically was not affected at 8.3 or 83 nM Onc concentration . Because activation-induced apoptosis is the key mechanism regulating several in vivo immunological functions including induction of tolerance , the observed effects of Onc may explain the apparent lack of immune reactions to this protein in treated patients . The propensity of Onc to potentiate the activation-induced apoptosis suggests that this drug may have clinical utility as immunomodulating agent , e.g. , to suppress transplant rejection or treat autoimmune diseases . OUTPUT: resisting cell death;avoiding immune destruction INPUT: The effects of dose per fraction on the ability of amifostine exposure to elevate angiostatin levels in the serum of mice and to inhibit spontaneous metastases formation using the well-characterized murine Sa-NH sarcoma were investigated . Amifostine was administered intraperitoneally at doses of 50 , 100 , or 200 mg/kg every other day for 6 days to C3Hf/Kam mice until tumors reached an average size of 8 mm in diameter . Amifostine was again administered immediately following surgical removal of the tumor-bearing limbs by amputation , and then once more 2 days later . Nontumor-bearing control animals were treated using the same dosing and surgery schedules . The average number of pulmonary metastases per animal was determined for each experimental group . A significant reduction ( P <.05 ) in the average number of pulmonary metastases was observed only in the group of animals exposed to a dose per fraction of 50 mg/kg . A dose of 100 mg/kg was less effective while 200 mg/kg had no effect on metastases formation in this study . The effects of amifostine exposure on serum levels of the angiogenesis inhibitor angiostatin were also determined using Western analysis . Correlating with the antimetastatic effect measured , exposure of animals to 50 mg/kg of amifostine resulted in a four-fold enhanced serum level of angiostatin above control levels . This phenomenon occurred in both tumor-bearing as well as nontumor-bearing animals . In contrast , a dose of 200-mg/kg amifostine administered intraperitoneally under these conditions had no measurable effect on angiostatin serum levels in this animal system . The enhanced ability of relatively low doses of amifostine to inhibit spontaneous metastases formation suggests that effective antimetastatic therapies with amifostine can be designed with minimal toxic side effects . While the dose responses for angiostatin production and metastases inhibition by amifostine are well correlated , the precise mechanism of action underlying these phenomena is unclear but is suggestive of a redox driven process(es) . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot48

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: activating invasion and metastasis;resisting cell death;tumor promoting inflammation;sustaining proliferative signaling INPUT: AIM To develop a simple , fast and inexpensive approach as well as an instrument for detection of gene mutation . METHODS Pyrosequencing based on bioluminometry assay was employed to detect gene mutation . Pyrosequencing is a method of sequencing by synthesis step-by-step using four enzymes , DNA-polymerase , ATP sulfurylase , luciferase and apyrase . The signal was produced by detecting pyrophosphate released during a dNTP incorporation . For mutation detection , a DNA fragment was amplified by PCR at first , followed by a single-stranded DNA preparation . In the second step , a short primer was annealed to the position just before the mutation point . Finally , specific dNTPs were added in terms of the template sequence . The mutation species can be readily determined by the sequence . RESULTS A new instrument was developed for gene mutation detection by pyrosequencing . To iteratively inject small amount of each dNTP for the sequencing reaction , capillaries were used to connect dNTP reservoirs and the reaction chamber . Each dNTP was delivered by adding a gas pressure on the top of a corresponding dNTP reservoir , by which 0.2 microL of dNTP can be exactly added each time . It was theoretically proved that undesired liquid seep through the capillary did not affect the sequencing reactions in pyrosequencing . In addition , the three possible variants ( wildtype , mutant and heterozygote ) of a mutant point Cys275Ser in P53 gene exon 8 were determined by pyrosequencing using the instrument . A simple method was also described for rapidly distinguishing the type of a variant . CONCLUSION The developed method is very simple , and the corresponding instrument is inexpensive and easy to operate , which can be used to detect many types of mutation . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot49

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: OBJECTIVE To construct the eukaryotic expression vector for Max interacting protein 1 ( Mxi1 ) . METHODS The full length cDNA of Mxi1 gene obtained from fetal lymphocyte and KG1 cells were inserted into plasmid pDs-red2-N1 respectively to generate pDs-red2-N1/Mri1 ( wild/mutation type ) . Then the recombinant vector was transfected into Cos-7 cells via liposome. 48 hours post transfection , mRNA of Mri1 gene was detected by RT-PCR and Mxi1 protein expression was detected by flow cytometry and fluorescence microscope in the Cos-7 cells . RESULTS The eukaryotic expression vector of Mxi1 was constructed and transfected into eukaryotic cells successfully . The expression of red fluorescence protein in the transfected Cos-7 cells was observed under fluorescence microscope which implied the expression of Mxi1 . The transfect efficiency of both wild and mutation type were in a high level in 3 days after transfected , which lasted to 6 d . RT-PCR amplified the total RNA extracted from the transfected Cos-7 cells could find increased mRNA level of Mxi1 gene . CONCLUSION We successfully constructed the eukaryote expression vector for Mri1 gene ; Cos-7 cells transfected with the vector via liposome could express Mxi1 protein . These could be useful for the further study of the Myc gene modulation . OUTPUT: genomic instability and mutation INPUT: OBJECTIVE To investigate the expression and mutation of MTA1 , nm23H1 and E-cadherin(E-cad) genes in ovarian carcinoma ( OC ) in relation to lymph node ( LN ) metastasis . METHODS A panel of normal ovarian tissues , primary OC specimens and corresponding LNS was examined for mRNA expression and mutation of MTA1 and nm23H1 and protin expression of E-cad genes by using RT-PCR , RT-PCR-SSCP and immunohistochemistry . RESULTS The frequency of MTA1 over expression was 100%(7/7) in primary OC with metastasis but only 38.5%(5/13) in those without metastasis ( P = 0.0103 ) . Overexpression of MTA1 was observed in 87.5%(6/7) of LNS with metastasis but in only 23%(3/13) of LNS without metastasis ( P = 0.0118 ) . In contrast with MTA1 , low expression of nm23H1 mRNA was seen in 7 of 7 OC with metastasis but only in 4 of 13(30%) of those without metastasis ( P = 0.0043 ) . Low nm23H1 expression was also seen in 7 of 7 LNS with metastasis but only in 5 of 13 ( 38.5% ) nonmetastatic LNS ( P = 0.0102 ) . Meantime , no expression of E-cad protein was observed in 7 of 7 OC with metastasis but in 6 of 13(46.2%) of those without metastasis ( P = 0.044 ) . In correlation analysis of the three genes , MTA1 reversely correlated with nm23H1 and E-cad respectively ( r = -0.903 , -0.803 ) , and positive correlation existed between nm23H1 and E-cad ( r = 0.724 ) . No mutation of MTA1 , nm23H1 and was found by SSCP analysis . CONCLUSION The mRNA expression of MTA1 , nm23H1 and E-cad is positively and negatively correlated with LN metastasis . The expression abnormalities but not the mutations of the three genes are frequent events related to LN metastasis of ovarian cancer . OUTPUT:

activating invasion and metastasis;genomic instability and mutation

HoC_dynamic_1_shot50

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND : CD81 is a transmembrane protein that serves as a putative receptor for hepatitis C virus . In addition , CD81 has been suggested to be involved in a broad range of other cellular functions . Its putative implication in tumorigenesis has so far , however , remained largely unexplored . To assess the candidacy of CD81 as a tumor suppressor in gastric cancer development , we investigated its expression and function in a series of primary gastric tumors and gastric tumor-derived cell lines . METHODS : The expression and concomitant methylation status of the CD81 gene and its effect on tumor development and cellular signaling were evaluated . RESULTS : CD81 mRNA levels were found to be low in 16 of 40 ( 40% ) primary tumors and 9 of 14 ( 64.2% ) cell lines , and these low expression levels were found to correlate with the stage and grade of the tumors . Genomic alterations of CD81 were not encountered , whereas its expression could be re-activated in low expressing cells upon 5-aza-dC treatment . Bisulfite DNA sequencing analysis of 10 CpG sites within the 5 ' proximal region of the CD81 gene promoter revealed that the observed transcriptional silencing was tightly associated with aberrant hypermethylation . Subsequent restoration of CD81 expression induced a G(1) cell cycle arrest and apoptosis , whereas siRNA-mediated CD81 down-regulation promoted cell proliferation and attenuated cellular responses to various apoptotic stress stimuli . Also the colony-forming ability of the tumor cells could be inhibited and enhanced through CD81 up- and down-regulation , respectively . CD81 was found to inhibit p38 ( but not ERK , JNK and AKT ) phosphorylation and its growth suppressive effect could be abolished through p38 up- and down-regulation . CONCLUSION : From our data we conclude that epigenetic inactivation of CD81 is a common feature of gastric tumors and that this inactivation may render growth and survival advantages to the tumor cells , at least partially through p38 signaling . OUTPUT: evading growth suppressors;resisting cell death;sustaining proliferative signaling INPUT: ZBP-89 ( ZNF148 ) is a Zinc finger Binding Protein of 89 kDa that binds GC-rich DNA elements . Originally , it was expression cloned using a DNA element mediating EGF regulation of the gastrin promoter . ZBP-89 functions as both a transcriptional activator and repressor . A variety of extracellular regulators including TGFbeta , retinoic acid and butyrate stimulate ZBP-89 gene expression . Butyrate activation of p21WAF1 is potentiated by ZBP-89 through the recruitment of the co-activator p300 , while chronic stimulation by butyrate increases ZBP-89 gene expression correlating with cell differentiation . ZBP-89 stimulates growth arrest and apoptosis through its ability to bind the p21WAF1 promoter or its ability to form protein-protein interactions with p53 . ZBP-89 protein is elevated in a variety of gastrointestinal cancers as well as the pancreas . In particular , ZBP-89 is normally expressed in pancreatic islets and ducts and in about 30% of pancreatic adenocarcinomas . OUTPUT:

evading growth suppressors;resisting cell death

HoC_dynamic_1_shot51

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Colorectal cancer ( CRC ) arises as the consequence of progressive changes from normal epithelial cells through polyp to tumor , and thus is an useful model for studying metabolic shift . In the present study , we studied the metabolomic profiles using high analyte specific gas chromatography/mass spectrometry ( GC/MS ) and liquid chromatography tandem mass spectrometry ( LC/MS/MS ) to attain a systems-level view of the shift in metabolism in cells progressing along the path to CRC . Colonic tissues including tumor , polyps and adjacent matched normal mucosa from 26 patients with sporadic CRC from freshly isolated resections were used for this study . The metabolic profiles were obtained using GC/MS and LC/MS/MS . Our data suggest there was a distinct profile change of a wide range of metabolites from mucosa to tumor tissues . Various amino acids and lipids in the polyps and tumors were elevated , suggesting higher energy needs for increased cellular proliferation . In contrast , significant depletion of glucose and inositol in polyps revealed that glycolysis may be critical in early tumorigenesis . In addition , the accumulation of hypoxanthine and xanthine , and the decrease of uric acid concentration , suggest that the purine biosynthesis pathway could have been substituted by the salvage pathway in CRC . Further , there was a step-wise reduction of deoxycholic acid concentration from mucosa to tumors . It appears that to gain a growth advantage , cancer cells may adopt alternate metabolic pathways in tumorigenesis and this flexibility allows them to adapt and thrive in harsh environment . OUTPUT: cellular energetics INPUT: 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 . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot52

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Signal transducers and activators of transcription 3 ( Stat3 ) is activated by cytokines and growth factors in lung cancers and regulates expression of genes implicated in cell growth , survival , and transformation . Previously , we found that mice with a deletion of the G protein-coupled receptor , family C , group 5 , member a ( Gprc5a ) gene develop lung tumors , indicating that Gprc5a is a tumor suppressor . Herein , we show that epithelial cells from Gprc5a knockout mouse lung ( Gprc5a(-/-) cells ) survive better in vitro in medium deprived of exogenous growth factors and form more colonies in semisolid medium than their counterparts from wild-type mice ( Gprc5a(+/+) cells ) . Stat3 tyrosine 705 phosphorylation and expression of several Stat3-regulated antiapoptotic genes were higher in Gprc5a(-/-) than in Gprc5a(+/+) cells . Both cell types secreted leukemia inhibitory factor ( Lif ) ; however , whereas Stat3 activation was persistent in Gprc5a(-/-) cells , it was transient in Gprc5a(+/+) cells . Lung adenocarcinoma cells isolated from Gprc5a(-/-) mice also exhibited autocrine Lif-mediated Stat3 activation . The level of Socs3 , the endogenous Stat3 inhibitory protein , was higher in Gprc5a(+/+) than in Gprc5a(-/-) cells , and expression of the tumor suppressor stabilized Socs3 . Inhibition of Stat3 signaling in Gprc5a(-/-) normal and cancer cells by the Janus-activated kinase 2 inhibitor AG490 or by a dominant negative Stat3(Y705F) increased starvation-induced apoptosis and inhibited colony formation . These results show that persistent Stat3 activation is important for the survival and transformation of Gprc5a(-/-) lung cells and suggest that the tumor suppressive effects of Gprc5a are mediated , at least in part , by inhibition of Stat3 signaling through Socs3 stabilization . OUTPUT: sustaining proliferative signaling INPUT: To investigate the significance of sialylation and sulfation of lactosylceramide in transformed cells , we established ganglioside GM3- and lactosylsulfatide ( SM3)-reconstituted cells by transfecting cDNAs of GM3 synthase and cerebroside sulfotransferase into the J5 subclone of 3LL Lewis lung carcinoma cells . The J5 clone was selected for the transfection of these genes because it lacks GM3 and SM3 but accumulates lactosylceramide . The anchorage-dependent growth of both GM3- and SM3-reconstituted cells was similar . However , anchorage-independent growth ( as measured by colony-forming ability in soft agar ) of the SM3- reconstituted cells was almost completely lost , which supports our previous observation showing the suppression of tumorigenic potential in vivo and beta1 integrin gene expression induced by the introduction of cerebroside sulfotransferase gene ( Kabayama et al. [ 2001 ] J. Biol . Chem. , 276 , 26777-26783 ) . The GM3-reconstituted cells formed a significantly higher number of colonies in soft agar compared to mock-transfected cells and began to proliferate and become resistant to apoptosis when serum was depleted , indicating that endogenous GM3 is essential for maintaining these fundamental properties of malignant cells . We also found that serum-induced ERK1/2 activation was suppressed in the GM3-reconstituted cells , suggesting that anchorage-independent cell cycle initiation by endogenous GM3 is elicited through pathway(s) independent of ERK1/2 activation . The selective down-regulation of platelet-derived growth factor ( PDGF)-dependent ERK1/2 activation in the GM3-reconstituted cells was due to the substantial decreases of PDGF alpha receptor mRNA and protein , but in the SM3-reconstituted cells PDGF alpha receptor expression was similar to mock cells . Thus , endogenously produced GM3 and SM3 differentially and distinctly regulate tumor-progression ability , that is , GM3 leads the transformed phenotype of J5 cells to promotion and SM3 to abrogation . OUTPUT:

resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot53

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: activating invasion and metastasis;evading growth suppressors;genomic instability and mutation;sustaining proliferative signaling INPUT: The early stages of head and neck cancer are presumed to require a senes of genetic alterations that are not represented by a distinct clinical phenotype . Therefore , genes with altered expression in the preneoplasia may be useful for the early detection of this highly recurrent cancer . In this study , we immortalized normal human oral keratinocytes ( NHOK ) by retroviral-mediated infection of HPV 16 transforming oncogenes , E6 and E7 ( HOK16E6E7 ) . Using the Affymetrix gene chip ( U95Av2 ) , we identified 177 known genes and EST that were overexpressed at least 3-fold or above in the immortalized cells , while 133 were down-regulated compared to NHOK . Northern blot analysis showed elevated levels of p55CDC in the immortalized cells , while NHOK showed high basal expression of small proline rich protein ( SPRR2 ) . The altered expression of these genes maybe associated with cellular proliferation or differentiation and the early stages of oral carcinogenesis . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot54

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: sustaining proliferative signaling INPUT: Recent epidemiological and experimental investigations suggest a close relationship between cyclooxygenase ( COX ) and pathogenesis of colorectal cancer . There are two isoforms , COX-1 and COX-2 , which differ in physiological functions and distribution . This study is to investigate the possible roles of both isoforms in the proliferation of colon carcinoma cells . A human colon carcinoma cell line , COLO 320DM , was transfected with an eukaryotic expression vector ( pEF-BOS ) carrying cDNA of either COX-1 or COX-2 . Both COX-1 and COX-2-expressing cells exhibited a similar enzyme activity , 8-10 nmol/10 min/mg of protein . Growth rates of both COX-expressing cells were increased by about 2 fold as compared with mock-transfected cells . The stimulated growth of the COX-expressing cells was confirmed by the increased DNA synthesis as assessed by [ 3H]thymidine incorporation . Furthermore , expression of epidermal growth factor receptor ( EGFR ) was markedly increased in the COX-expressing cells as examined by reverse transcriptase-polymerase chain reaction ( RT-PCR ) . A COX inhibitor , indomethacin , suppressed the stimulated growth , increased DNA synthesis and induction of epidermal growth factor receptor in the COX-1 and COX-2-transfected cells . These results suggest that not only COX-2 but COX-1 is involved in the proliferation of human colon carcinoma cells through the induction of EGFR . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot55

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: The cellular mechanisms of anti-androgen-induced tumor regression have not been investigated in great detail . We have compared the induction of cell death in the androgen-dependent , non-invasive LNCaP prostate cancer cell line by Casodex and TNF-alpha . Both agents induce a dose and time-dependent decrease in cell viability in vitro . However , Casodex does not induce classical DNA fragmentation to oligonucleosomes typically induced by TNF-alpha , but rather induces cleavage to form intermediate 60 kb DNA fragments . RT-PCR based analysis demonstrates that in LNCaP cells Casodex coordinately alters the expression of steady-state level of mRNAs of several matrix metalloproteases and their cognate inhibitors ( most notably MMP2 and TIMP1 ) . Zymography and reverse zymography confirm that the ratio of metalloprotease(s) to inhibitor(s) is altered in favor of activation of the proteases . In a small percentage of the treated LNCaP cells , the activation of the extracellular matrix ( ECM)-proteases by Casodex also induces an invasive phenotype . The acquisition of an invasive phenotype is not seen when LNCaP cells are treated with TNF-alpha , and is not seen when the LNCaP cells are treated with both compounds simultaneously , suggesting that the phenomenon may be specific to particular classes of compounds . These observations have significant implications in the treatment of prostate cancer , since the appearance of a more aggressive phenotype following treatment is clearly undesirable . OUTPUT: resisting cell death;activating invasion and metastasis INPUT: Neutrophils have become recognised as important contributors to the effectiveness of tumour eradication by photodynamic therapy ( PDT ) . In this study , we have used the mouse SCCVII squamous cell carcinoma model to investigate the activity of neutrophils in tumours treated by PDT . Tumour levels of neutrophilic myeloperoxidase ( MPO ) demonstrated not only a massive and sustained sequestration of these cells in PDT-treated tumours but also revealed their activated state evidenced by the presence of released MPO . Among the adhesion molecules expressed on tumour vascular endothelium , ICAM-1 appears to be of primary importance in the invasion of neutrophils into PDT-treated tumours , because its functional blocking with monoclonal antibodies reduced the tumour cure rate . A marked upregulation of its ligands CD11b/CD18 and CD11c/CD18 found on neutrophils associated with PDT-treated tumours supports this assumption . To evaluate the role of inflammatory cytokines regulating neutrophil activity , neutralising antibodies were given to mice before PDT treatment . The results suggest that IL-1beta activity is critical for the therapeutic outcome , since its neutralisation diminished the cure rates of PDT-treated tumours . No significant effect was observed with anti-IL-6 and anti-TNF-alpha treatment . Further flow cytometry-based examination of neutrophils round in PDT-treated tumours revealed that these cells express MHC class II molecules , which suggests their engagement as antigen-presenting cells and involvement in the development of antitumour immune response . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot56

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Acute leukemia is a disorder of the hematopoietic system characterized by the expansion of a clonal population of cells blocked from differentiating into mature cells . Recent studies have shown that chalcones and their derivatives induce apoptosis in different cell lines . Since new compounds with biological activity are needed , the aim of this study was to evaluate the cytotoxic effect of three synthetic chalcones , derived from 1-naphthaldehyde and 2-naphthaldehyde , on human acute myeloid leukemia K562 cells and on human acute lymphoblastic leukemia Jurkat cells . Based on the results , the most cytotoxic compound ( A1 ) was chosen for further analysis in six human acute leukemia cells and in a human colon adenocarcinoma cell line ( HT-29 ) . Chalcone A1 significantly reduced the cell viability of K562 , Jurkat , Kasumi , U937 , CEM and NB4 cells in a concentration and time-dependent manner when compared with the control group ( IC(50) values between ∼1.5μM and 40μM ) . It was also cytotoxic to HL-29 cells . To further examine its effect on normal cells , peripheral blood lymphocytes collected from healthy volunteers were incubated with the compound . It has also been incubated with human fibroblasts cultured from bone marrow ( JMA ) . Chalcone A1 is non-cytotoxic to PBL cells and to JMA cells . A1 caused significant cell cycle arrest in all phases according to the cell line , and increased the proportion of cells in the sub G0/G1 phase . To evaluate whether this chalcone induced cell death via an apoptotic or necrotic pathway , cell morphology was examined using fluorescence microscopy . Cells treated with A1 at IC(50) demonstrated the morphological characteristic of apoptosis , such as chromatin condensation and formation of apoptotic bodies . Apoptosis was confirmed by externalization of phosphatidylserine , which was detected by the Annexin V-FITC method , and by DNA fragmentation . The results suggest that chalcone A1 has potential as a new lead compound for cancer therapy . OUTPUT: evading growth suppressors;sustaining proliferative signaling;resisting cell death INPUT: Investigation has been conducted to delineate the action of some phenolic compounds of natural origin in four human tumor cell lines : acute myeloblastic leukemia ( HL-60 ) , chronic myelogenic leukemia ( K-562 ) , breast adenocarcinoma ( MCF-7 ) and cervical epithelial carcinoma ( HeLa ) . In cells grown in appropriate media the phenolics curcumin , yakuchinone B , resveratrol and capsaicin exhibited growth inhibition as assessed by trypan blue dye exclusion . It was evident from the results of the MTT reduction assay and [ (3)H]thymidine incorporation into nuclear DNA that the phenolics were cytotoxic and inhibited cell proliferation . Dose response studies indicated curcumin to be most cytotoxic towards HL-60 , K-562 and MCF-7 but did not show much activity in HeLa cells . On the other hand , yakuchinone B , although less active than curcumin , displayed cytotoxicity towards all four cell lines . Resveratrol was cytotoxic only in leukemic cells , while capsaicin was marginally cytotoxic . All these phenolics did not elicit any cytotoxic activity as judged by the above parameters towards lymphocytes purified from normal human blood . When cells treated with phenolics were stained with propidium iodide and examined under a fluorescent microscope , characteristic apoptotic features such as chromatin condensation and nuclear fragmentation were observed . Scoring of cells with apoptotic and non-apoptotic features showed positive correlation of apoptotic index with dose of phenolic , and fragmented DNA extracted free of genomic DNA displayed on gel electrophoresis a typical ladder pattern . These phenolics which have human exposure are known cancer chemopreventive agents and their action as inducers of apoptosis in tumor cells suggest their potential use in a strategy for cancer control . OUTPUT:

resisting cell death

HoC_dynamic_1_shot57

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Dietary antioxidants , such as the carotenoids , may protect DNA from oxidative damage . This has been proposed to explain the epidemiological association between higher consumption of fruits and vegetables , which are rich in antioxidants , and lower incidence of cancer . However , this remains to be demonstrated conclusively . The effects of carotenoid supplementation on 1 ) baseline DNA damage , 2 ) susceptibility of cellular DNA to oxidative attack , and 3 ) DNA repair were measured in the human lymphocyte cell line Molt-17 . Baseline DNA damage , susceptibility to oxidant attack ( 100 mumol/l H2O2 for 5 min at 4 degrees C ) , and disappearance of DNA single-strand breaks ( SSB ) after oxidative challenge were monitored by single-cell gel electrophoresis . DNA repair patch synthesis activity in cell extracts was determined using assays that measure nucleotide incorporation during repair of oxidative lesions in template DNA . Unlike single-cell gel electrophoresis , the parameters measured with these assays are not dependent on strand break religation . There was no evidence that beta-carotene , lutein , or beta-cryptoxanthin supplementation protected cellular DNA from oxidation under basal conditions or after oxidative challenge . However , only carotenoid-supplemented cells exhibited a significant decrease in numbers of SSB over a 2-h period after treatment with H2O2 . Carotenoid supplementation did not provoke any detectable change in repair patch synthesis activity . We conclude that supplementation with carotenoids at 8 mumol/l does not provide significant antioxidant protection for DNA in Molt-17 lymphocytes but may enhance recovery of cells from oxidative challenge , as measured by loss of SSB . We argue that these data are most consistent with carotenoids acting to enhance DNA strand break repair . OUTPUT: genomic instability and mutation;tumor promoting inflammation INPUT: We examined the influence of the level of dietary protein or vitamin E ( VE ) on oxidative damage to DNA , lipids , and protein in the liver after total body irradiation ( TBI ) with X-rays at 1 or 4 Gy . Levels of 8-hydroxydeoxyguanosine , thiobarbituric acid-reactive substances , and protein carbonyls in the liver did not differ among the groups that did not receive TBI . However , oxidative damage to lipids and protein was increased by TBI only in the 1% protein group . DNA damage , lipid peroxidation , or protein oxidation in the liver was increased by TBI in a dose-dependent manner , and the damage was consistently higher in the 1% than in the 20% protein group . In the 1% protein group , a greater decrease in relative spleen weight by TBI was also observed . Concentrations of antioxidants ( vitamins C and E and glutathione ) in the liver were lower and the concentration of nonheme iron in the liver was higher in the 1% than in the 20% protein group . Mice fed a 1% protein diet became susceptible to TBI-induced oxidative damage , and decreases in antioxidant levels and an increase in iron level were involved in the mechanism of this susceptibility . These results suggest that dietary VE and protein can prevent oxidative damage to DNA , lipid , and protein in mice subjected to TBI . Consumption of a VE-free diet significantly increased 8-hydroxydeoxyguanosine levels in DNA from mice fed the 1% protein diet with TBI , but such changes were not detected in DNA from mice fed the 20% protein diet . OUTPUT:

tumor promoting inflammation;genomic instability and mutation

HoC_dynamic_1_shot58

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Hepatocyte growth factor ( HGF ) , a mesenchymal-derived factor which regulates growth , motility , and morphogenesis of epithelial and endothelial cells , functions as a hepatotrophic and renotrophic factor for regeneration of the liver and kidney . We have now obtained evidence that transforming growth factor-beta 1 ( TGF-beta 1 ) and glucocorticoids are negative regulators for HGF gene expression . When TGF-beta 1 or dexamethasone was added to cultures of MRC-5 human embryonic lung fibroblasts and HL-60 human promyelocytic leukemic cells , the amount of HGF secreted into the culture medium was inhibited to 30-40% of that of control cultures by 10 ng/ml TGF-beta 1 and to 40-50% by 10(-6) M dexamethasone . The inhibitory effect of TGF-beta 1 and dexamethasone on HGF synthesis in MRC-5 cells was additive , thereby suggesting that TGF-beta 1 and dexamethasone exert effects through distinct mechanisms . Hydrocortisone also inhibited HGF synthesis with the same potency as dexamethasone ; however , testosterone , estriol , and beta-estradiol had no effect . The rate of HGF synthesis in MRC-5 cells , as measured by pulse labeling with [ 35S]methionine and subsequent immunoprecipitation , was suppressed to 30-40% of the control with 10 ng/ml TGF-beta 1 , and to 30-45% by 10(-6) M dexamethasone . HGF mRNA levels in MRC-5 cells and HL-60 cells were dose-dependently suppressed by TGF-beta 1 and dexamethasone ; 10 ng/ml TGF-beta 1 suppressed HGF mRNA levels to 32% and 35% of control culture , respectively , in MRC-5 cells and HL-60 cells , and 10(-6) M dexamethasone suppressed to 43% and 38% , respectively . Thus , TGF-beta 1 and glucocorticoids seem to inhibit HGF synthesis by suppressing the expression of the HGF gene . We propose that a negative regulation of HGF gene expression by TGF-beta 1 or glucocorticoids may be involved in physiological or pathological processes during tissue regeneration . OUTPUT: sustaining proliferative signaling INPUT: Expression of angiogenic factors is upregulated in hyperplastic mucosa adjacent to colon cancer , and this upregulation is closely associated with cancer growth and metastasis . We investigated the role of histone acetylation in vascular endothelial growth factor ( VEGF ) expression in hyperplastic mucosa adjacent to orthotopic colon cancer in mice . In the hyperplastic mucosa adjacent to KM12SM tumor in the cecum of athymic mice , VEGF upregulation was associated with hypoxia-inducible factor ( HIF)-1alpha induction . The hyperplastic mucosa also showed hypoacetylation of histone H4 and reduction of both p53 and von Hippel-Lindau ( VHL ) proteins . To examine the effects of growth factors and cytokines on histone acetylation and levels of p53 , VHL and HIF-1alpha , the rat intestinal epithelial cell line IEC6 was treated with epidermal growth factor ( EGF ) and interleukin ( IL)-15 for 35 days . Acetylated histone H4 , p53 protein and ubiquitinated protein levels were reduced , whereas HIF-1alpha production was upregulated in EGF- and IL-15-treated IEC6 cells . These findings suggest that EGF- or IL-15-induced histone H4 hypoacetylation is associated with repression of p53 and VHL genes in intestinal epithelial cells . The subsequent suppression of protein ubiquitination leads to upregulation of VEGF production by HIF-1alpha retention . OUTPUT:

inducing angiogenesis;sustaining proliferative signaling

HoC_dynamic_1_shot59

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: γ-Tocotrienol and sesamin are phytochemicals that display potent anticancer activity . Since sesamin inhibits the metabolic degradation of tocotrienols , studies were conducted to determine if combined treatment with sesamin potentiates the antiproliferative effects of γ-tocotrienol on neoplastic mouse ( +SA ) and human ( MCF-7 and MDA-MB-231 ) mammary cancer cells . Results showed that treatment with γ-tocotrienol or sesamin alone induced a significant dose-responsive growth inhibition , whereas combination treatment with these agents synergistically inhibited the growth of +SA , MCF-7 and MDA-MB-231 mammary cancer cells , while similar treatment doses were found to have little or no effect on normal ( mouse CL-S1 and human MCF-10A ) mammary epithelial cell growth or viability . However , sesamin synergistic enhancement of γ-tocotrienol-induced anticancer effects was not found to be mediated from a reduction in γ-tocotrienol metabolism . Rather , combined treatment with subeffective doses of γ-tocotrienol and sesamin was found to induce G1 cell cycle arrest , and a corresponding decrease in cyclin D1 , CDK2 , CDK4 , CDK6 , phospho-Rb , and E2F1 levels , and increase in p27 and p16 levels . Additional studies showed that the antiproliferative effect of combination treatment did not initiate apoptosis or result in a decrease in mammary cancer cell viability . Taken together , these findings indicate that the synergistic antiproliferative action of combined γ-tocotrienol and sesamin treatment in mouse and human mammary cancer cells is cytostatic , not cytotoxic , and results from G1 cell cycle arrest . OUTPUT: evading growth suppressors;sustaining proliferative signaling;resisting cell death INPUT: 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 . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot60

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Identification of the proteins that are associated with estrogen receptor ( ER ) status is a first step towards better understanding of the hormone-dependent nature of breast carcinogenesis . Although a number of gene expression analyses have been conducted , protein complement has not been systematically investigated to date . Because proteins are primary targets of therapeutic drugs , in this study , we have attempted to identify proteomic signatures that demarcate ER-positive and -negative breast cancers . Using highly enriched breast tumor cells , replicate analyses from 3 ERα+ and 3 ERα- human breast tumors resulted in the identification of 2,995 unique proteins with ≥2 peptides . Among these , a number of receptor tyrosine kinases and intracellular kinases that are abundantly expressed in ERα+ and ERα- breast cancer tissues were identified . Further , label-free quantitative proteome analysis revealed that 236 proteins were differentially expressed in ERα+ and ERα- breast tumors . Among these , 141 proteins were selectively up-regulated in ERα+ , and 95 proteins were selectively up-regulated in ERα- breast tumors . Comparison of differentially expressed proteins with a breast cancer database revealed 98 among these have been previously reported to be involved in breast cancer . By Gene Ontology molecular function , dehydrogenase , reductase , cytoskeletal proteins , extracellular matrix , hydrolase , and lyase categories were significantly enriched in ERα+ , whereas selected calcium-binding protein , membrane traffic protein , and cytoskeletal protein were enriched in ERα- breast tumors . Biological process and pathway analysis revealed that up-regulated proteins of ERα+ were overrepresented by proteins involved in amino acid metabolism , proteasome , and fatty acid metabolism , while up-regulated proteins of ERα- were overrepresented by proteins involved in glycolysis pathway . The presence and relative abundance of 4 selected differentially abundant proteins ( liprin-α1 , fascin , DAP5 , and β-arrestin-1 ) were quantified and validated by immunohistochemistry . In conclusion , unlike in vitro cell culture models , the in vivo signaling proteins and pathways that we have identified directly from human breast cancer tissues may serve as relevant therapeutic targets for the pharmacological intervention of breast cancer . OUTPUT: cellular energetics INPUT: 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 . OUTPUT:

sustaining proliferative signaling;activating invasion and metastasis

HoC_dynamic_1_shot61

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Aims : RAS-induced tumorigenesis has been suggested to follow a three-stage model consisting of an initial RAS activation , senescence induction , and evasion of p53-dependent senescence checkpoints . While reactive oxygen species ( ROS ) act as second messengers in RAS-induced senescence , they are also involved in oncogenic transformation by inducing proliferation and promoting mutations . In the current work , we investigated the role of extracellular superoxide dismutase ( SOD3 ) in RAS-induced senescence and immortalization in vitro and in vivo . We used a mouse embryonic fibroblast ( MEF ) primary cell model together with immortalized and transformed human cell lines derived from papillary and anaplastic thyroid cancer . Results : Based on our data , sod3 RNA interference in H-RasV12-transduced cells markedly inhibited cell growth , while sod3 over-expression in MEFs initially caused a proliferative burst followed by the activation of DNA damage checkpoints , induction of p53-p21 signal transduction , and senescence . Subsequently , sod3-transduced MEF cells developed co-operative p21-p16 down-regulation and acquired transformed cell characteristics such as increased telomerase activity , loss of contact inhibition , growth in low-nutrient conditions , and in vivo tumorigenesis . Interestingly , as reported previously with RAS , we showed a dose-dependent response to SOD3 in vitro and in vivo involving transcriptional and non-transcriptional regulatory mechanisms . Innovation : SOD3 may mediate H-RasV12-induced initiation of primary cell immortalization . Conclusions : Our results indicate that SOD3 influences growth signaling in primary and cancer cells downstream of the ras oncogene and could serve as a therapy target at an early tumorigenesis phase . OUTPUT: enabling replicative immortality;evading growth suppressors;genomic instability and mutation;tumor promoting inflammation;sustaining proliferative signaling INPUT: 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 . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot62

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Agricultural products and by products provide the primary materials for a variety of technological applications in diverse industrial sectors . Agro-industrial wastes , such as cotton and curaua fibers , are used to prepare nanofibers for use in thermoplastic films , where they are combined with polymeric matrices , and in biomedical applications such as tissue engineering , amongst other applications . The development of products containing nanofibers offers a promising alternative for the use of agricultural products , adding value to the chains of production . However , the emergence of new nanotechnological products demands that their risks to human health and the environment be evaluated . This has resulted in the creation of the new area of nanotoxicology , which addresses the toxicological aspects of these materials . PURPOSE AND METHODS Contributing to these developments , the present work involved a genotoxicological study of different nanofibers , employing chromosomal aberration and comet assays , as well as cytogenetic and molecular analyses , to obtain preliminary information concerning nanofiber safety . The methodology consisted of exposure of Allium cepa roots , and animal cell cultures ( lymphocytes and fibroblasts ) , to different types of nanofibers . Negative controls , without nanofibers present in the medium , were used for comparison . RESULTS The nanofibers induced different responses according to the cell type used . In plant cells , the most genotoxic nanofibers were those derived from green , white , and brown cotton , and curaua , while genotoxicity in animal cells was observed using nanofibers from brown cotton and curaua . An important finding was that ruby cotton nanofibers did not cause any significant DNA breaks in the cell types employed . CONCLUSION This work demonstrates the feasibility of determining the genotoxic potential of nanofibers derived from plant cellulose to obtain information vital both for the future usage of these materials in agribusiness and for an understanding of their environmental impacts . OUTPUT: genomic instability and mutation INPUT: The mouse polyomavirus encodes a tumor-suppressor gene inactivator in its large T protein and a proto-oncogene activator in its middle T protein . We have used site-directed mutagenesis to selectively inactivate the former function without affecting the latter . Two mutant viruses were constructed to encode altered large T proteins that fail to bind the retinoblastoma tumor-suppressor gene product pRB , along with normal small and middle T proteins . The pRB-binding mutants proved to be defective in immortalization of primary rat embryo fibroblasts by a variety of tests . Yet they proved capable of transforming both primary and established fibroblasts in culture . Most importantly , the inability of these mutants to bind pRB had little effect on their ability to induce tumors in mice . We conclude that induction of multiple tumor types in this system does not depend on large T-pRB interactions but rather on middle T-dependent pathways . In addition , the ability of this virus to immortalize cells in culture is not essential to its ability to induce tumors in the animal . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot63

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Although tumor-associated macrophages ( TAMs ) are involved in tumor growth and metastasis , the mechanisms controlling their pro-tumoral activities remain largely unknown . The transcription factor c-MYC has been recently shown to regulate in vitro human macrophage polarization and be expressed in macrophages infiltrating human tumors . In this study , we exploited the predominant expression of LysM in myeloid cells to generate c-Myc(fl/fl) LysM(cre/+) mice , which lack c-Myc in macrophages , to investigate the role of macrophage c-MYC expression in cancer . Under steady-state conditions , immune system parameters in c-Myc(fl/fl) LysM(cre/+) mice appeared normal , including the abundance of different subsets of bone marrow hematopoietic stem cells , precursors and circulating cells , macrophage density , and immune organ structure . In a model of melanoma , however , TAMs lacking c-Myc displayed a delay in maturation and showed an attenuation of pro-tumoral functions ( e.g. , reduced expression of VEGF , MMP9 , and HIF1α ) that was associated with impaired tissue remodeling and angiogenesis and limited tumor growth in c-Myc(fl/fl) LysM(cre/+) mice . Macrophage c-Myc deletion also diminished fibrosarcoma growth . These data identify c-Myc as a positive regulator of the pro-tumoral program of TAMs and suggest c-Myc inactivation as an attractive target for anti-cancer therapy . OUTPUT: avoiding immune destruction INPUT: Melanocyte stimulating hormone ( alpha-MSH , alpha-melanotropin),Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Ly-Pro-Va l-NH2 , regulates melanogenesis within epidermal melanocytes of many animals . An MSH analogue ( [ Nle4,D-Phe7]alpha-MSH ) that exhibits superpotency and prolonged biological activity has been synthesized , biologically characterized , and is presently in clinical trials to determine its possible clinical use in tanning of the skin . It also has potential for the diagnosis , localization , and chemotherapy of melanoma . The effects of this analogue on the growth , metastatic behavior , and invasive potential of a melanotic variant of Cloudman S-91 murine melanoma are reported here . In an intracutaneous murine model of melanoma cell tumor growth , the analogue did not increase primary tumor growth ( size ) after the period of administration of the peptide hormone analogue and did not affect spontaneous lung metastases . Survival times for the control and melanotropin-treated groups were similar , suggesting that overall tumor burden was not affected by treatment with the hormone analogue . Last , melanoma cell invasion through a human amniotic basement membrane in vitro was not enhanced compared to untreated cells . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot64

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: It is well known that cell-mediated immunity is suppressed in patients with neoplastic diseases . We have reported that soluble receptors for interleukin-2 ( sIL-2R ) and tumor necrosis factor ( sTNF-R1 ) are elevated in the serum of patients with advanced colorectal cancer . The presence of these soluble receptors and immunosuppressive cytokines , including interleukin-10 ( IL-10 ) , might be important in the mechanisms of immunosuppression. cis-Diaminedichloroplatinum ( cisplatin ) has been reported to immunomodulate , especially when used in low dose in combination with 5-Fluorouracil ( 5-FU ) . In this study , cisplatin and UFT , a form of uracil and tegafur which is a prodrug of 5-FU , were administered with immunomodulator Polysaccharide K ( PSK ) to ten patients with colorectal cancer , who showed distant metastasis in the liver or lung , and the serum levels of sIL-2R and sTNF-R1 and the production of gamma-interferon ( gamma-INF ) and interleukin-10 by peripheral blood mononuclear cells were measured . The serum concentrations of sIL-2R and the production of IL-10 were reduced ( p &lt ; 0.05 ) after 2 months of treatment . Thus , this combination appeared to have immunomodulative potential in patients with advanced colorectal cancer . OUTPUT: activating invasion and metastasis;avoiding immune destruction INPUT: Immunosuppression of immunoglobulin synthesis seen in patients with multiple myeloma is in part due to immunosuppressive CD5 positive B cells . In a 13 year longitudinal study of an IgA-deficient blood donor who developed multiple myeloma , the presence of immunosuppressive CD5 positive B cells and T cells preceded the diagnosis of overt multiple myeloma and the appearance of immunosuppressive monocytes . These data argue that certain immune defects may be involved in the development of myeloma and are not simply a consequence of overt malignancy . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot65

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Colorectal cancer ( CRC ) arises as the consequence of progressive changes from normal epithelial cells through polyp to tumor , and thus is an useful model for studying metabolic shift . In the present study , we studied the metabolomic profiles using high analyte specific gas chromatography/mass spectrometry ( GC/MS ) and liquid chromatography tandem mass spectrometry ( LC/MS/MS ) to attain a systems-level view of the shift in metabolism in cells progressing along the path to CRC . Colonic tissues including tumor , polyps and adjacent matched normal mucosa from 26 patients with sporadic CRC from freshly isolated resections were used for this study . The metabolic profiles were obtained using GC/MS and LC/MS/MS . Our data suggest there was a distinct profile change of a wide range of metabolites from mucosa to tumor tissues . Various amino acids and lipids in the polyps and tumors were elevated , suggesting higher energy needs for increased cellular proliferation . In contrast , significant depletion of glucose and inositol in polyps revealed that glycolysis may be critical in early tumorigenesis . In addition , the accumulation of hypoxanthine and xanthine , and the decrease of uric acid concentration , suggest that the purine biosynthesis pathway could have been substituted by the salvage pathway in CRC . Further , there was a step-wise reduction of deoxycholic acid concentration from mucosa to tumors . It appears that to gain a growth advantage , cancer cells may adopt alternate metabolic pathways in tumorigenesis and this flexibility allows them to adapt and thrive in harsh environment . OUTPUT: cellular energetics INPUT: The influence of cell shape on the expression of proto-oncogenes was examined in normal and malignant human cells that varied in their sensitivities to contact-inhibition of proliferation . Cells were constrained into varying degrees of roundness by plating onto culture surfaces coated with different concentrations of poly(2-hydroxyethyl methacrylate ) ( poly[HEMA] ) and assayed for proliferation capacity and levels of c-myc , c-ras , c-fos , and c-fes mRNAs . Proliferation of contact-inhibited normal CUA-1 fibroblasts and the variant HT-IFNr cells was highly coupled to cell shape . As these cells became more rounded , a critical degree of roundness was reached at which proliferation ceased . In contrast , proliferation of non-contact-inhibited malignant HT-1080 cells was independent of cell shape . Northern analysis revealed that expression of c-myc and c-ras was highly sensitive to cell shape in the normal CUA-1 cells but not in the malignant HT-1080 or variant HT-IFNr cells . Levels of c-myc and c-ras mRNAs declined to nearly undetectable levels in CUA-1 cells at degrees of roundness that correlated with loss of proliferative ability . Expression of c-fos and c-fes oncogenes were independent of cell shape in all cells tested . Quantification of transcription rates by the nuclear run-off assay showed that shape modulation of c-myc and c-ras oncogene expression occurred at the transcriptional level . These data suggest that changes in cell shape can modulate expression of certain oncogenes and that these changes correlate with the cell's ability to proliferate . Moreover , inability to regulate c-myc and c-ras oncogene expression is associated with loss of shape-dependent growth controls and contact inhibition but that loss of this regulation alone is not sufficient to release cells from contact-inhibited controls . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot66

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: resisting cell death INPUT: 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 . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot67

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: genomic instability and mutation INPUT: 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 . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot68

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Acute leukemia is a disorder of the hematopoietic system characterized by the expansion of a clonal population of cells blocked from differentiating into mature cells . Recent studies have shown that chalcones and their derivatives induce apoptosis in different cell lines . Since new compounds with biological activity are needed , the aim of this study was to evaluate the cytotoxic effect of three synthetic chalcones , derived from 1-naphthaldehyde and 2-naphthaldehyde , on human acute myeloid leukemia K562 cells and on human acute lymphoblastic leukemia Jurkat cells . Based on the results , the most cytotoxic compound ( A1 ) was chosen for further analysis in six human acute leukemia cells and in a human colon adenocarcinoma cell line ( HT-29 ) . Chalcone A1 significantly reduced the cell viability of K562 , Jurkat , Kasumi , U937 , CEM and NB4 cells in a concentration and time-dependent manner when compared with the control group ( IC(50) values between ∼1.5μM and 40μM ) . It was also cytotoxic to HL-29 cells . To further examine its effect on normal cells , peripheral blood lymphocytes collected from healthy volunteers were incubated with the compound . It has also been incubated with human fibroblasts cultured from bone marrow ( JMA ) . Chalcone A1 is non-cytotoxic to PBL cells and to JMA cells . A1 caused significant cell cycle arrest in all phases according to the cell line , and increased the proportion of cells in the sub G0/G1 phase . To evaluate whether this chalcone induced cell death via an apoptotic or necrotic pathway , cell morphology was examined using fluorescence microscopy . Cells treated with A1 at IC(50) demonstrated the morphological characteristic of apoptosis , such as chromatin condensation and formation of apoptotic bodies . Apoptosis was confirmed by externalization of phosphatidylserine , which was detected by the Annexin V-FITC method , and by DNA fragmentation . The results suggest that chalcone A1 has potential as a new lead compound for cancer therapy . OUTPUT: evading growth suppressors;sustaining proliferative signaling;resisting cell death INPUT: 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 . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot69

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Metastasis is a major cause of death of patients with malignant tumors . Matrix metalloproteinases ( MMPs ) are important for the migration and invasion of various types of cancer cell . Propofol is a known anesthetic agent , widely used for short-term anesthesia and for longer-term sedation . Propofol inhibits the proliferation of a variety of tumor cells , but there is no available information regarding propofol-inhibited migration and invasion of tumor cells in vitro . In this study , we investigated the effects of propofol on the migration and invasion of human lung carcinoma A549 cells . Wound healing assay and Boyden chamber assays indicated that propofol inhibited the migration and invasion of A549 cells in vitro . Gelatin zymographic analysis showed the inhibitory effect of propofol on the activation of expression MMP-2 . Western blot analysis also indicated that propofol suppressed the protein expiration of growth factor receptor-bound protein 2 ( GRB2 ) , Jun N-terminal kinases 1/2 ( p-JNK1/2 ) , p-p38 , MMP-2 and MMP-9 in A549 cells . Results from real-time PCR assay also showed that propofol inhibited the mRNA gene expression of MMP-2 , -7 and -9 , and enhanced that of tissue inhibitor of metalloproteinase 1 ( TIMP1 ) and TIMP2 in A549 cells . Taken together , these data show that propofol inhibits MMP-2 and -9 mRNA and protein expressions , resulting in suppression of lung cancer cell invasion and migration in vitro . OUTPUT: activating invasion and metastasis INPUT: 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 . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot70

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Blockage of the metastasis process remains a significant clinical challenge , requiring innovative therapeutic approaches . For this purpose , molecules that inhibit matrix metalloproteinases activity or induce the expression of their natural inhibitor , the tissue inhibitor of metalloproteinases ( TIMPs ) , are potentially interesting . In a previous study , we have shown that synthetic ligands binding to cell surface nucleolin/nucleophosmin and known as HB 19 for the lead compound and NucAnt 6L ( N6L ) for the most potent analog , inhibit both tumor growth and angiogenesis . Furthermore , they prevent metastasis in a RET transgenic mice model which develops melanoma . Here , we investigated the effect of N6L on the invasion capacity of MDA-MB-435 melanoma cells . Our results show that the multivalent pseudopeptide N6L inhibited Matrigel invasion of MDA-MB-435 cells in a modified Boyden chamber model . This was associated with an increase in TIMP-3 in the cell culture medium without a change in TIMP-3 mRNA expression suggesting its release from cell surface and/or extracellular matrix . This may be explained by our demonstrated N6L interaction with sulfated glycosaminoglycans and consequently the controlled bioavailability of glycosaminoglycan-bound TIMP-3 . The implication of TIMP-3 in N6L-induced inhibition of cell invasion was evidenced by siRNA silencing experiments showing that the loss of TIMP-3 expression abrogated the effect of N6L . The inhibition of tumor cell invasion by N6L demonstrated in this study , in addition to its previously established inhibitory effect on tumor growth and angiogenesis , suggests that N6L represents a promising anticancer drug candidate warranting further investigation . OUTPUT: activating invasion and metastasis;inducing angiogenesis INPUT: Nine primary pulmonary carcinomas , one metastatic carcinoma , and two malignant pleural mesotheliomas have been analysed for the expression at the mRNA level of metalloproteinases ( MPs ) and tissue inhibitors of MPs ( TIMPs ) . In situ hybridisation showed TIMP-1 and TIMP-2 transcripts predominantly over tumour stroma and gelatinases evenly distributed over both stromal and tumour cells . While both TIMP-1 and TIMP-2 were expressed in non-neoplastic lungs ( NNL ) as well as in carcinomas , stromelysin 3 ( ST3 ) , 92 kDa gelatinase and interstitial collagenase were expressed only by carcinomas . Expression of these MPs by carcinomas was independent of histologic type and such tumour features as fibrosis or necrosis . The consistent expression of ST3 by all of the carcinomas examined and absence of its expression in NNL indicates that ST3 production is likely associated with the malignant phenotype . However , since 92 kDa gelatinase and interstitial collagenase transcripts were found in some but not all tumour samples , their expression is not a uniform feature of pulmonary carcinomas . The possible prognostic significance of the expression of the latter two enzymes by carcinomas remains to be established . OUTPUT:

resisting cell death

HoC_dynamic_1_shot71

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: AIM To investigate whether luteolin , a highly prevalent flavonoid , reverses the effects of epithelial-mesenchymal transition ( EMT ) in vitro and in vivo and to determine the mechanisms underlying this reversal . METHODS Murine malignant melanoma B16F10 cells were exposed to 1% O(2) for 24 h . Cellular mobility and adhesion were assessed using Boyden chamber transwell assay and cell adhesion assay , respectively . EMT-related proteins , such as E-cadherin and N-cadherin , were examined using Western blotting . Female C57BL/6 mice ( 6 to 8 weeks old ) were injected with B16F10 cells ( 1�10(6) cells in 0.2 mL per mouse ) via the lateral tail vein . The mice were treated with luteolin ( 10 or 20 mg/kg , ip ) daily for 23 d . On the 23rd day after tumor injection , the mice were sacrificed , and the lungs were collected , and metastatic foci in the lung surfaces were photographed . Tissue sections were analyzed with immunohistochemistry and HE staining . RESULTS Hypoxia changed the morphology of B16F10 cells in vitro from the cobblestone-like to mesenchymal-like strips , which was accompanied by increased cellular adhesion and invasion . Luteolin ( 5-50 μmol/L ) suppressed the hypoxia-induced changes in the cells in a dose-dependent manner . Hypoxia significantly decreased the expression of E-cadherin while increased the expression of N-cadherin in the cells ( indicating the occurrence of EMT-like transformation ) , which was reversed by luteolin ( 5 μmol/L ) . In B16F10 cells , luteolin up-regulated E-cadherin at least partly via inhibiting the β3 integrin/FAK signal pathway . In experimental metastasis model mice , treatment with luteolin ( 10 or 20 mg/kg ) reduced metastatic colonization in the lungs by 50% . Furthermore , the treatment increased the expression of E-cadherin while reduced the expression of vimentin and β3 integrin in the tumor tissues . CONCLUSION Luteolin inhibits the hypoxia-induced EMT in malignant melanoma cells both in vitro and in vivo via the regulation of β3 integrin , suggesting that luteolin may be applied as a potential anticancer chemopreventative and chemotherapeutic agent . OUTPUT: activating invasion and metastasis INPUT: Studies were performed to test the hypothesis that urethane-induced murine lung tumors exhibit xenobiotic resistance and alterations in pulmonary cytochrome P-450 enzymes. 1,1-Dichloroethylene , naphthalene , and paraquat were administered to tumor-bearing and control mice to elicit acute lung cytotoxicity , and responses were evaluated in tumors ( papillary and solid ) , uninvolved surrounding tissue , and untreated control lung. 1,1-Dichloroethylene ( 125 mg/kg , i.p. ) and naphthalene ( 225 mg/kg , i.p. ) caused preferential necrosis of Clara cells in control lungs and uninvolved tissue of tumor-bearing lungs . In contrast , papillary and solid tumors were both resistant to 1,1-dichloroethylene-induced cytotoxicity . Paraquat ( 10 , 20 mg/kg , i.v. ) elicited Clara cell damage in control lungs and uninvolved lung tissue of tumor-bearing mice , with minor disruption of the alveolar epithelium . Neither papillary nor solid tumors sustained any apparent cell damage from paraquat . Immunoblots of P-450 enzymes confirmed constitutive expression of CYP2B1 in control lung and uninvolved lung tissue of tumor-bearing mice , but this P-450 enzyme was not detected in either adenomas or carcinomas . Lung CYP1A1 was inducible by beta-naphthoflavone in non-tumor-bearing mice and uninvolved tissue of tumor-bearing mice ; however , inducibility was decreased in adenomas and abolished in carcinomas . These results demonstrate resistance of lung tumor cells to chemically induced cytotoxicity and diminished expression of cytochrome P-450 enzymes in tumors . OUTPUT:

resisting cell death

HoC_dynamic_1_shot72

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: INTRODUCTION Tamoxifen is the most widely prescribed anti-estrogen treatment for patients with estrogen receptor ( ER)-positive breast cancer . However , there is still a need for biomarkers that reliably predict endocrine sensitivity in breast cancers and these may well be expressed in a dynamic manner . METHODS In this study we assessed gene expression changes at multiple time points ( days 1 , 2 , 4 , 7 , 14 ) after tamoxifen treatment in the ER-positive ZR-75-1 xenograft model that displays significant changes in apoptosis , proliferation and angiogenesis within 2 days of therapy . RESULTS Hierarchical clustering identified six time-related gene expression patterns , which separated into three groups : two with early/transient responses , two with continuous/late responses and two with variable response patterns . The early/transient response represented reductions in many genes that are involved in cell cycle and proliferation ( e.g . BUB1B , CCNA2 , CDKN3 , MKI67 , UBE2C ) , whereas the continuous/late changed genes represented the more classical estrogen response genes ( e.g . TFF1 , TFF3 , IGFBP5 ) . Genes and the proteins they encode were confirmed to have similar temporal patterns of expression in vitro and in vivo and correlated with reduction in tumour volume in primary breast cancer . The profiles of genes that were most differentially expressed on days 2 , 4 and 7 following treatment were able to predict prognosis , whereas those most changed on days 1 and 14 were not , in four tamoxifen treated datasets representing a total of 404 patients . CONCLUSIONS Both early/transient/proliferation response genes and continuous/late/estrogen-response genes are able to predict prognosis of primary breast tumours in a dynamic manner . Temporal expression of therapy-response genes is clearly an important factor in characterising the response to endocrine therapy in breast tumours which has significant implications for the timing of biopsies in neoadjuvant biomarker studies . OUTPUT: evading growth suppressors;sustaining proliferative signaling INPUT: We studied the effects of double-strand breaks on intramolecular extrachromosomal homologous recombination in mammalian cells . Pairs of defective herpes thymidine kinase ( tk ) sequences were introduced into mouse Ltk- cells on a DNA molecule that also contained a neo gene under control of the SV40 early promoter/enhancer . With the majority of the constructs used , gene conversions or double crossovers , but not single crossovers , were recoverable . DNA was linearized with various restriction enzymes prior to transfection . Recombination events producing a functional tk gene were monitored by selecting for tk-positive colonies . For double-strand breaks placed outside of the region of homology , maximal recombination frequencies were measured when a break placed the two tk sequences downstream from the SV40 early promoter/enhancer . We observed no relationship between recombination frequency and either the distance between a break and the tk sequences or the distance between the tk sequences . The quantitative effects of the breaks appeared to depend on the degree of homology between the tk sequences . We also observed that inverted repeats recombined as efficiently as direct repeats . The data indicated that the breaks influenced recombination indirectly , perhaps by affecting the binding of a factor(s) to the SV40 promoter region which in turn stimulated or inhibited recombination of the tk sequences . Taken together , we believe that our results provide strong evidence for the existence of a pathway for extrachromosomal homologous recombination in mammalian cells that is distinct from single-strand annealing . We discuss the possibility that intrachromosomal and extrachromosomal recombination have mechanisms in common . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot73

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Spindle cell oncocytoma ( SCO ) of the pituitary gland is a relatively recently established , very rare subtype of adenohypophysis tumours that was introduced as a distinct clinicopathological entity in the fourth edition of WHO classification of the central nervous system tumours ( 2007 ) . It is non-endocrine neoplasm of the anterior pituitary that occurs in adults and usually follows a benign clinical course , corresponding to WHO grade I. Up to now , pituitary SCO have been reported occasionally and only 14 cases of SCO have been documented in the literature . Because of their rarity , the pathogenesis and natural history of these tumours have not been fully characterized . We report two additional cases of SCO occurring in females aged 63 years ( Case 1 ) and 65 years ( Case 2 ) , who presented with pan-hypopituitarism , headache and visual field defect . In both cases , the magnetic resonance imaging showed solid sellar mass of moderate size with suprasellar extension . The clinical and radiological features suggested non-functioning pituitary macroadenomas without evidence of invasive growth . One patient presented with tumour recurrence 3 years after undergoing the previous surgical removal of tumour , which was initially misdiagnosed as schwannoma . The first tumour was removed by transsphenoidal surgery and the second one by frontal craniotomy . Histologically and immunohistochemically , both tumours displayed the features typical for SCO of the pituitary . They were composed of interwoven fascicles of spindle cells exhibiting abundant eosinophilic cytoplasm of oncocytic or granular appearance . Mitoses were rarely observed and necrosis was absent . In one case , the advanced lymphocytic infliltration was observed within neoplastic tissue . The tumour cells exhibited immunoreactivity for S-100 protein , galectin-3 , vimentin and epithelial membrane antigen but they were negative for GFAP , anterior pituitary neuroendocrine markers ( prolactin , growth hormone , TSH , ACTH , FSH , LH ) , chromogranin , synaptophysin , cytokeratin CK ( AE1/AE3 ) , smooth muscle actin , desmin , CD34 and CD68 . MIB1 labeling index did not exceed 10% . Ultrastructurally , the tumour cells were rich in mitochondria with lamellar cristae . Moreover , in Case 2 some tumour cells showed a number of giant mitochondria with severely destructed internal matrix . Spindle cell oncocytoma of the anterior pituitary is often misdiagnosed entity of uncertain histogenesis . It should be considered in the differential diagnosis of various sellar-region lesions of oncocytic morphology . OUTPUT: resisting cell death INPUT: We analyzed several factors which could influence the immunogenicity of colon tumor cells , using a series of clones derived from a single chemically induced rat adenocarcinoma cell line . These clones display variable tumorigenic potential in syngeneic immunocompetent animals , and it has been established that in this model the tumorigenicity of the cells depends on their ability to escape immune surveillance . The results show an absence of relationship between tumorigenicity and expression of MHC-class-I antigens , cell adhesion to rat fibroblasts or fibroblast extracellular matrix . The secretion of latent and active TGF beta I appeared to be quite variable from one clone to the other , but was unrelated to tumorigenicity . Unexpectedly , some regressive clones produced elevated levels of this cytokine , suggesting that in this model , spontaneous secretion of TGF beta I is not sufficient to impair the immune system of the host . In contrast , the more tumorigenic clones were more resistant than less tumorigenic ones to cytotoxicity mediated by NK or LAK cells . They also showed arrest of cell proliferation after reaching confluence , something not observed in the less tumorigenic clones . Finally , the strongest relationship with tumorigenicity was found for expression of blood-group carbohydrate antigens . Increased expression of blood-group-H antigen and , conversely , decreased expression of beta-galactoside precursors of this antigen correlated with increased tumorigenicity . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot74

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Chromosomal DNA must be in single-strand form for important transactions such as replication , transcription , and recombination to occur . The single-strand DNA ( ssDNA ) is more prone to damage than double-strand DNA ( dsDNA ) , due to greater exposure of chemically reactive moieties in the nitrogenous bases . Thus , there can be agents that damage regions of ssDNA in vivo while being inert toward dsDNA . To assess the potential hazard posed by such agents , we devised an ssDNA-specific mutagenesis reporter system in budding yeast . The reporter strains bear the cdc13-1 temperature-sensitive mutation , such that shifting to 37°C results in telomere uncapping and ensuing 5 ' to 3 ' enzymatic resection . This exposes the reporter region , containing three closely-spaced reporter genes , as a long 3 ' ssDNA overhang . We validated the ability of the system to detect mutagenic damage within ssDNA by expressing a modified human single-strand specific cytosine deaminase , APOBEC3G . APOBEC3G induced a high density of substitutions at cytosines in the ssDNA overhang strand , resulting in frequent , simultaneous inactivation of two reporter genes . We then examined the mutagenicity of sulfites , a class of reactive sulfur oxides to which humans are exposed frequently via respiration and food intake . Sulfites , at a concentration similar to that found in some foods , induced a high density of mutations , almost always as substitutions at cytosines in the ssDNA overhang strand , resulting in simultaneous inactivation of at least two reporter genes . Furthermore , sulfites formed a long-lived adducted 2'-deoxyuracil intermediate in DNA that was resistant to excision by uracil-DNA N-glycosylase . This intermediate was bypassed by error-prone translesion DNA synthesis , frequently involving Pol ζ , during repair synthesis . Our results suggest that sulfite-induced lesions in DNA can be particularly deleterious , since cells might not possess the means to repair or bypass such lesions accurately . OUTPUT: genomic instability and mutation INPUT: OBJECTIVE To explore the adduct characteristics of styrene and DNA . METHODS The adduct reactions between styrene , urinary mandalic acid(MA) , phenylglyoxalic acid(PGA) , mercapturic acid of styrene ( UMA ) and DNA were studied by ultraviolet spectral analysis . The SO-DNA adducts by 32P-post labeled method , the chemical structures of SO-DNA adducts by GC-MS and NMR were also studied . RESULTS SO combined with DNA at O6 , N2 positions of dGMP to form six adducts , but styrene , urinary mandalic acid , phenylglyoxalic acid and mercapturic acid of styrene did not react with DNA to form adduct . CONCLUSIONS Styrene formed adduct with DNA through its active center metabolite--SO after entering the body . SO combined with DNA at O6 , N2 positions of dGMP to form adducts . If these DNA adducts are not repaired or are mis-repaired before cell duplication , the gene mutation and chemical damage would happen . No adduct reactions are seen among other metabolites of styrene . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot75

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Hepatocellular carcinoma ( HCC ) , one of the most frequent and deadliest cancers , has been increasing considerably in the United States . In the absence of a proven effective therapy for HCC , novel chemopreventive strategies are urgently needed to lower the current morbidity and mortality of HCC . Recently , we have reported that resveratrol , a compound present in grapes and red wine , significantly prevents diethylnitrosamine ( DENA)-induced liver tumorigenesis in rats , although the mechanism of action is not completely understood . In the present study , we have examined the underlying mechanisms of resveratrol chemoprevention of hepatocarcinogenesis by investigating the effects of resveratrol on oxidative damage and inflammatory markers during DENA-initiated rat liver carcinogenesis . There was a significant increase in hepatic lipid peroxidation and protein oxidation in carcinogen control animals compared with their normal counterparts at the end of the study ( 20 weeks ) . Elevated expressions of inducible nitric oxide synthase and 3-nitrotyrosine were noticed in the livers of the same animals . Dietary resveratrol ( 50-300 mg/kg ) administered throughout the study reversed all the aforementioned markers in a dose-responsive fashion in rats challenged with DENA . Resveratrol also elevated the protein and mRNA expression of hepatic nuclear factor E2-related factor 2 ( Nrf2 ) . Results of the present investigation provide evidence that attenuation of oxidative stress and suppression of inflammatory response mediated by Nrf2 could be implicated , at least in part , in the chemopreventive effects of this dietary agent against chemically induced hepatic tumorigenesis in rats . The outcome of this study may benefit the development of resveratrol in the prevention and intervention of human HCC . OUTPUT: tumor promoting inflammation INPUT: This is a case report of a 69-year-old woman with sarcomatoid hepatocellular carcinoma ( HCC ) , which was diagnosed clinically as hemangioma . She was first admitted to our university hospital , complaining of general fatigue in December , 1988 , and cholelithiasis and liver cirrhosis with hepatic tumor in Segment 8 were diagnosed . The serum AFP level was within normal range , and the tumor was diagnosed as hemangioma radiologically . She underwent only cholecystectomy and was well without any therapy for the liver tumor up until March in 1991 when she was readmitted to our university hospital due to rapidly progressive liver dysfunction . The size of the liver tumor was unchanged . Despite intensive care , she died of hepatic failure due to cirrhosis in a decompensation state . At autopsy , a well defined yellowish white tumor of 3 cm in maximum diameter was seen in the cirrhotic liver . Although the largest part of the tumor revealed necrosis and hyalinization , a sarcomatoid part composed of spindle-shaped cells was noted in the peripheral portion . In addition , some necrotic ghost cells , probably hepatocellular carcinoma , were also noted . Low molecular cytokeratin , which is always found in HCCs , was seen in spindle-shaped sarcomatoid cells . The liver tumor was diagnosed as sarcomatoid HCC from these pathological findings . We report this histologically unusual HCC with an immunohistochemical study . OUTPUT:

resisting cell death

HoC_dynamic_1_shot76

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Spindle cell oncocytoma ( SCO ) of the pituitary gland is a relatively recently established , very rare subtype of adenohypophysis tumours that was introduced as a distinct clinicopathological entity in the fourth edition of WHO classification of the central nervous system tumours ( 2007 ) . It is non-endocrine neoplasm of the anterior pituitary that occurs in adults and usually follows a benign clinical course , corresponding to WHO grade I. Up to now , pituitary SCO have been reported occasionally and only 14 cases of SCO have been documented in the literature . Because of their rarity , the pathogenesis and natural history of these tumours have not been fully characterized . We report two additional cases of SCO occurring in females aged 63 years ( Case 1 ) and 65 years ( Case 2 ) , who presented with pan-hypopituitarism , headache and visual field defect . In both cases , the magnetic resonance imaging showed solid sellar mass of moderate size with suprasellar extension . The clinical and radiological features suggested non-functioning pituitary macroadenomas without evidence of invasive growth . One patient presented with tumour recurrence 3 years after undergoing the previous surgical removal of tumour , which was initially misdiagnosed as schwannoma . The first tumour was removed by transsphenoidal surgery and the second one by frontal craniotomy . Histologically and immunohistochemically , both tumours displayed the features typical for SCO of the pituitary . They were composed of interwoven fascicles of spindle cells exhibiting abundant eosinophilic cytoplasm of oncocytic or granular appearance . Mitoses were rarely observed and necrosis was absent . In one case , the advanced lymphocytic infliltration was observed within neoplastic tissue . The tumour cells exhibited immunoreactivity for S-100 protein , galectin-3 , vimentin and epithelial membrane antigen but they were negative for GFAP , anterior pituitary neuroendocrine markers ( prolactin , growth hormone , TSH , ACTH , FSH , LH ) , chromogranin , synaptophysin , cytokeratin CK ( AE1/AE3 ) , smooth muscle actin , desmin , CD34 and CD68 . MIB1 labeling index did not exceed 10% . Ultrastructurally , the tumour cells were rich in mitochondria with lamellar cristae . Moreover , in Case 2 some tumour cells showed a number of giant mitochondria with severely destructed internal matrix . Spindle cell oncocytoma of the anterior pituitary is often misdiagnosed entity of uncertain histogenesis . It should be considered in the differential diagnosis of various sellar-region lesions of oncocytic morphology . OUTPUT: resisting cell death INPUT: Cells dissociated from spontaneous and transplanted tumours of C3HJax mammary gland have been cultured on polylysine and gelatin substrates . The isolated cells proliferated to form monolayers with high degree of organoid structure as indicated by formation of alveolar cavities . Differences were observed in the cell attachment , growth pattern , number and size of alveolar cavities , cells which lined the cavity and cell morphology on polylysine and gelatin substrates as compared to conventional cell culture plastic surface . On polylysine more than 90% cells attached rapidly , within 15-45 min after plating , with or without serum and formed confluent monolayers marked by presence of large and small alveolar cavities . Multiple interacting cell types took part in organization of the cavity . Cells lining the cavity constantly proliferated and rearranged to expand it . On gelatin , 60-70% cells attached over a period of 6-24 hr in presence of serum and formed confluent monolayers dominated by small alveolar cavities . Cells forming the cavities were epithelial in nature and cavities once formed did not increase in size . Upon subculture , the cell morphology on these substrates was strikingly different . On polylysine , the predominant cell type had numerous irregular microvilli whereas on gelatin , cells had smoother boundaries with a few stunted cytoplasmic extensions . The cell attachment on conventional surface was low , 40-50% . When seeded at high cell density , formation of alveolar cavities was suppressed and at low cell density , cultures were marked by contact inhibition of cells and failure to attain confluence . These results suggest differential behaviour and interaction of mammary tumour epithelium with the substrates used . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot77

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: In this study , laboratory experiments were carried out in order to come to a better understanding of the fate of polycyclic aromatic hydrocarbons ( PAHs ) in the marine environment and especially on their bioaccumulation , biotransformation and genotoxic effects in fish . Juveniles of turbot ( Scophthalmus maximus ) were exposed to PAHs through different routes via ( 1 ) a mixture of dissolved PAHs , ( 2 ) a PAH-polluted sediment and ( 3 ) an oil fuel elutriate . Fish were exposed 4 days followed by a 6-day depuration period . In each experiment , PAH concentrations in the seawater of the tanks were analysed regularly by gas chromatography coupled with mass spectrometry . Muscle and liver samples were also analysed for parent PAH levels and PAH bioconcentration factors were calculated . Biotransformation was evaluated by measuring the levels of PAH metabolites in fish bile . Genotoxicity was assessed by the alkaline comet assay . Regardless of exposure route , the parent PAH concentrations in the liver and muscle showed a peak level 1 day after the beginning of the exposure , followed by a decrease up to the background level towards the end of the experiment , except for the exposure to dissolved PAHs for which levels were relatively low throughout the study . As a consequence , no bioaccumulation was observed in fish tissues at the end of the experiment . In contrast , regardless of exposure routes , a rapid production of biliary metabolites was observed throughout the whole exposure experiment . This was especially true for 1-hydroxypyrene , the major metabolite of pyrene . After 6 days of recovery in clean water , a significant decrease in the total metabolite concentrations occurred in bile . Fish exposed through either route displayed a significant increase in DNA strand breaks after 4 days of exposure , and significant correlations were observed between the level of biliary PAH metabolites and the level of DNA lesions in fish erythrocytes . Overall results indicate that exposure to either a mixture of dissolved PAHs , a PAH-contaminated sediment or a dispersed oil fuel elutriate leads to biotransformation and increase in DNA damage in fish . The quantification of PAH metabolites in bile and DNA damage in erythrocytes appear to be suitable for environmental monitoring of marine pollution either in the case of accidental oil spills or sediment contamination . OUTPUT: genomic instability and mutation INPUT: Prevention of environmentally related cancer will be enhanced by the availability of sensitive early warning systems and by improvements in quantitative assessment of human risks . Accordingly , we have carried out a series of molecular epidemiologic studies aimed at validating a panel of biologic markers , including carcinogen-DNA and -protein adducts , sister chromatid exchange , micronucleus formation , DNA strand breaks , and DNA repair capacity . Results from three such studies illustrate the usefulness of these biomarkers in elucidating low-dose-response relationships , correlations between biomarkers , and the range of variation in biomarkers between individuals exposed to similar concentrations of carcinogens . Low-level workplace or ambient exposures to styrene , ethylene oxide , and polycyclic aromatic hydrocarbons ( PAH ) were associated with significant increases in both molecular dose of carcinogens ( adducts ) and various markers of preclinical effects . Correlations between biomarkers varied by exposure . For example , in the styrene study , sister chromatid exchange frequency was not correlated with any of the markers , in contrast to the studies of ethylene oxide and PAH . Significant molecular effects were observed not only in occupationally exposed people but also in residents of an area in Poland characterized by high levels of air pollution . For example , the mean PAH-DNA level in exposed residents ( winter sample ) was 30.4 adducts per 10(8) nucleotides . This level was significantly higher than that of adducts seen in summer samples from the same area ( 4.2/10(8) , or in winter samples from residents of a rural area ( 11.01/10(8) . Significant seasonal variation in PAH-DNA adduct formation in this group was consistent with recorded fluctuations in air pollution levels . Striking interindividual variation was observed in all three exposed populations . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot78

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: activating invasion and metastasis;inducing angiogenesis;resisting cell death INPUT: 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 &lt ; 0.05 ) and among differentiation group ( P &lt ; 0.05 ) . MVD showed significant difference between live and death group , early and late stage group , and T1-2 and T3-4 group ( P &lt ; 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 . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot79

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: enabling replicative immortality;genomic instability and mutation INPUT: Cellular senescence is the genetically programmed cessation of cellular proliferation . We have recently mapped a putative senescence gene(s) on the X chromosome of Chinese hamster embryo ( CHE ) cells . In the present study , we have utilized microcell-mediated chromosome transfer ( microcell fusion ) to test whether : ( i ) the human X chromosome exhibits similar genetic potential to induce senescence and ( ii ) the deletion or inactivation of the X-linked senescence gene(s) in CHE cells is associated with nickel-induced immortalization . A normal CHE or human X chromosome was first introduced into mouse-cell hybrids , then transferred by microcell fusion into a nickel-transformed , immortal male CHE cell line ( Ni-2/TGR ) with an X deletion ( Xq1 ) . Microcell fusion of the normal CHE X chromosome into tumorigenic Ni-2/TGR cells yielded senescence of all X recipient clones . The normal human X chromosome induced dominant senescence of tumorigenic Ni-2/TGR cells in only 17% of the resulting microcell hybrids ( 14/81 ) . Karyotypic analyses of 13 non-senescing human X chromosome-derived microcell hybrid clones revealed that none of these clones retained the complete X. A normal CHE X chromosome induced senescence of 75% of hybrids obtained with another immortal and tumorigenic nickel-transformed male CHE cell line ( Ni-6/TGR ) , which exhibited no visible deletion of the X chromosome , while the normal human X chromosome , only induced senescence in 19% of these hybrids . Transfer of the normal CHE or human X chromosome into spontaneously transformed and tumorigenic cell lines , CHO/TGR or V79/TGR , had little or no effect on their growth . These data suggest that both human and CHE cells possess similar X-linked genetic activities that regulate the process of cellular senescence , and that in Chinese hamster cells nickel-induced immortalization but not that of CHO or V79 cells is associated with inactivation of an X-linked senescence gene . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot80

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: sustaining proliferative signaling INPUT: 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 . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot81

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Telomerase is a ribonucleoprotein enzyme that functions to maintain telomeres , the terminal DNA that protects chromosomal integrity , regulating cellular replicative life span . Telomerase is not expressed in most normal human somatic cells but is active in stabilizing telomeres of certain self-renewing cell populations and most malignant cells , making the enzyme an appealing target for anticancer therapy . We describe here a novel cross-species approach to telomerase inhibition . Ectopic expression of the human telomerase catalytic reverse transcriptase component in murine cells inhibited endogenous murine telomerase activity . Using this approach , telomerase inhibition in immortal murine fibroblasts resulted in critical telomere shortening , leading to slowed proliferation , abnormal morphology , altered cell cycle , and telomere dysfunction with cytogenetic instability , followed by apoptotic cell death . Subpopulations of two telomerase-inhibited clones escaped widespread apoptosis , showing proliferative recovery in culture despite persistently inhibited telomerase activity with progressive telomere shortening and dysfunction . This study , by targeting immortal murine cells for telomerase inhibition , demonstrates the importance of telomerase to murine cell immortalization and telomere maintenance . Moreover , the murine model used here should prove useful in further evaluating telomerase inhibition as an anticancer therapy . OUTPUT: enabling replicative immortality;resisting cell death INPUT: Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer . Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination , we have measured telomere length , telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5 . In all mortal populations , telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures . When transformed cells reached crisis , the length of the telomeric TTAGGG repeats was only approximately 1.5 kbp and many dicentric chromosomes were observed . In immortal cells , telomere length and frequency of dicentric chromosomes stabilized after crisis . Telomerase activity was not detectable in control or extended lifespan populations but was present in immortal populations . These results suggest that chromosomes with short ( TTAGGG)n tracts are recombinogenic , critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot82

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Many cancer cells metabolize glucose preferentially via pyruvate to lactate instead to CO(2) and H(2)O ( oxidative phosphorylation ) even in the presence of oxygen ( Warburg effect ) . Dichloroacetate ( DCA ) is a drug which is able to shift pyruvate metabolism from lactate to acetyl-CoA ( tricarboxylic acid cycle ) by indirect activation of pyruvate dehydrogenase ( PDH ) . This can subsequently lead to an increased flow of oxygen in the respiratory chain , associated with enhanced generation of reactive oxygen species ( ROS ) which may cause apoptosis . In order to investigate if DCA may be suitable for neuroblastoma therapy , it was investigated on three human neuroblastoma cell lines whether DCA can reduce lactate production and enhance oxygen consumption . The data show , that DCA ( in the low millimolar range ) is able to reduce lactate production , but there was only a slight shift to increased oxygen consumption and almost no effect on cell vitality , proliferation and apoptosis of the three cell lines investigated . Therefore , DCA at low millimolar concentrations seems to be only of minor efficacy for neuroblastoma treatment . OUTPUT: cellular energetics;resisting cell death INPUT: 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 &gt ; 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 . OUTPUT:

cellular energetics;resisting cell death;activating invasion and metastasis

HoC_dynamic_1_shot83

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Inflammatory response plays an important role not only in the normal physiology but also in the pathology such as cancers . As chronic inflammations are associated with malignancies , it is important to prevent inflammation-mediated neoplastic formation , promotion and/or progression . One possible intervention will be using cancer chemopreventive agents such as curcumin ( CUR ) , a potent anti-inflammatory and anti-oxidative stress compound . Polyunsaturated fatty acids ( PUFA ) such as docosahexaenoic acid ( DHA ) or eicosapentaenoic acid ( EPA ) are potent anti-inflammatory agents by decreasing the production of inflammatory eicosanoids , cytokines , and reactive oxygen species ( ROS ) . The present study aims at examining whether CUR with DHA or EPA would have synergistic anti-inflammatory effects in RAW 264.7 cells . Non-toxic concentrations of single and combination of the compounds were investigated at 6 , 12 and 24h . The nitric oxide ( NO ) suppression effects were most prominent at 24h . All the combinations of CUR and DHA or EPA with lower concentrations of CUR 5 microM and 25 microM of DHA or EPA were found to have synergistic effects in suppressing LPS-stimulated NO and endogenous NO levels . Importantly , very low doses of CUR 2.5 microM and DHA or EPA of 0.78 microM could synergistically suppress the LPS-induced prostaglandin E(2) ( PGE(2) ) . The combinations were also found to suppress iNOS , COX-2 , 5-lipoxygenase ( 5-LOX ) and cPLA(2) but induce HO-1 . Taken together , the present study clearly shows the synergistic anti-inflammatory as well as anti-oxidative stress effects of CUR and PUFA . OUTPUT: tumor promoting inflammation INPUT: 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 . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot84

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cigarette smoke ( CS ) is a rich source of radicals , predisposing the cell to oxidative stress resulting in inflammation . Chronic inflammation is a recognized risk factor for carcinogenesis . Cyclooxygenase-2 ( COX-2 ) is a mediator of inflammatory pathway and may , therefore , contribute to carcinogenesis . There are several reports that suggest the association between CS and COX-2 associated risk to cancer . In the present study , we examined the role of celecoxib ( a selective COX-2 inhibitor ) in modulating the oxidative stress caused by CS inhalation in mice . CS exposure for a period of 10 weeks caused oxidative stress in the pulmonary and hepatic tissues , as evident from the increase in lipid peroxidation levels ( LPO ) and decrease in reduced glutathione ( GSH ) levels . Celecoxib ( 125 mg/kg body weight for 8 weeks ) administration to CS inhaling mice reduced the oxidative stress by decreasing the LPO levels and enhancing the GSH levels in comparison to the CS-exposed group . CS exposure repressed the enzymatic antioxidant defense system , as evident from the decrease in catalase ( CAT ) and superoxide dismutase ( SOD ) activities . Co-adminstration of celecoxib considerably reversed the changes in the enzymatic antioxidant defense system . Histopathological studies of lungs showed that CS exposure induced alveolar wall destruction and air space enlargement . In co-treated group , the alveolar septa were thicker than normal with apparent infiltration of inflammatory cells . In CS-exposed group , hepatic tissue exhibited vacuolization and macrophage infiltration . Co-treatment with celecoxib restored the normal histoarchitechture in hepatic tissues of CS inhaling mice . Thus , the present study demonstrated that celecoxib adminstration reduced the oxidative stress-mediated risk to carcinogenesis , due to its ability to boost the antioxidant defense system . OUTPUT: tumor promoting inflammation INPUT: Chromated copper arsenate , which is used worldwide as a wood preservative , can adversely affect human health . Accumulating evidence suggests that chromium ( Cr ) and arsenic ( As ) can potentially disrupt the redox balance and cause respiratory diseases and cancer in humans . The present study was designed to determine the combined toxic effects of these metals in the lungs and to clarify the specific molecules that are stimulated by combined exposure to both metals . Male C57BL/6J mice were intratracheally instilled with arsenate [ As(V) ] , hexavalent chromium [ Cr(VI) ] , or a combination of both metals . Mice were sacrificed 2 days after treatment to collect bronchoalveolar lavage fluid and lung tissue samples . Inflammation , cytotoxicity , apoptosis , and oxidative stress markers were measured . Our results indicated that administration of Cr(VI) alone or in combination with As(V) induced neutrophil-dominant inflammation as well as phosphorylation of mitogen-activated protein kinases ; effects of treatment with As(V) alone were comparatively less potent . By analyzing the production of interleukin-6 and activity of lactate dehydrogenase and caspase , we confirmed that co-treatment intensified pulmonary injury and that it was accompanied by oxidative stress , as confirmed by marked increases in the production of reactive oxygen species , reduced glutathione content , and thioredoxin reductase ( TRXRD ) activity . Expressed mRNA levels of heme oxygenase-1 , glutamylcysteine ligase , glutathione peroxidase 2 , thioredoxin ( TRX ) 1 , and TRXRD1 were also enhanced by co-treatment , whereas treatment with As(V) alone reduced the mRNA expression level of TRX2 . Our data suggest that co-treatment with As(V) exacerbated Cr(VI)-induced pulmonary injury and that this effect may be exerted through a disruption in the balance among several antioxidant genes . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot85

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: A common metabolic change in cancer is the acquisition of glycolytic phenotypes . Increased expression of glycolytic enzymes is considered as one contributing factor . The role of mitochondrial defects in acquisition of glycolytic phenotypes has been postulated but remains controversial . Here we show that functional defects in mitochondrial respiration could be induced by oncogenic H-Ras(Q61L) transformation , even though the mitochondrial contents or mass was not reduced in the transformed cells . First , mitochondrial respiration , as measured by mitochondrial oxygen consumption , was suppressed in NIH-3T3 cells transformed with H-Ras(Q61L) . Second , oligomycin or rotenone did not reduce the cellular ATP levels in the H-Ras(Q61L) transformed cells , suggesting a diminished role of mitochondrial respiration in the cellular energy metabolism . Third , inhibition of glycolysis with iodoacetic acid reduced ATP levels at a much faster rate in H-Ras(Q61L) transformed cells than in the vector control cells . The reduction of cellular ATP levels was reversed by exogenously added pyruvate in the vector control cells but not in H-Ras(Q61L) transformed cells . Finally when compared to the HRas(Q61L) transformed cells , the vector control cells had increased resistance toward glucose deprivation . The increased resistance was dependent on mitochondrial oxidative phosphorylation since rotenone or oligomycin abolished the increased survival of the vector control cells under glucose deprivation . The results also suggest an inability of the H-Ras(Q61L) transformed cells to reactivate mitochondrial respiration under glucose deprivation . Taken together , the data suggest that mitochondrial respiration can be impaired during transformation of NIH-3T3 cells by oncogeneic H-Ras(Q61L) . OUTPUT: cellular energetics INPUT: UNLABELLED ABC transporters like P-glycoprotein ( P-gp/ABCB1 ) are membrane proteins responsible for the transport of toxic compounds out of non-malignant cells and tumor tissue . AIM To investigate the effect of glycolysis and the tissue redox state on P-gp expression in multicellular tumor spheroids derived from prostate adenocarcinoma cells ( DU-145 ) , glioma cells ( Gli36 ) , and the human cervix carcinoma cell line KB-3-1 transfected with a P-gp-EGFP fusion gene that allows monitoring of P-gp expression in living cells . During cell culture of DU-145 , Gli36 , and KB-3-1 tumor spheroids P-gp expression was observed as well as increased lactate and decreased pyruvate levels and expression of glycolytic enzymes . Inhibition of glycolysis for 24 h by either iodoacetate ( IA ) or 2-deoxy-D-glucose ( 2-DDG ) downregulated P-gp expression which was reversed upon coincubation with the radical scavenger ebselen as shown by semi-quantitative immunohistochemisty in DU-145 and Gli36 tumor spheroids , and by EGFP fluorescence in KB-3-1 tumor spheroids . Consequently endogenous ROS generation in DU-145 tumor spheroids was increased in the presence of either IA or 2-DDG , which was abolished upon coincubation with ebselen . Exogenous addition of pyruvate significantly reduced ROS generation , increased P-gp expression as well as efflux of the P-gp substrate doxorubicin . Doxorubicin transport was significantly blunted by 2-DDG and IA , indicating that inhibition of glycolysis reversed the multidrug resistance phenotype . In summary our data demonstrate that P-gp expression in tumor spheroids is closely related to the glycolytic metabolism of tumor cells and can be downregulated by glycolysis inhibitors via mechanisms that involve changes in the cellular redox state . OUTPUT:

cellular energetics

HoC_dynamic_1_shot86

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Tumor endothelial marker ( TEM ) 5 is an adhesion G-protein-coupled receptor upregulated in endothelial cells during tumor and physiologic angiogenesis . So far , the mechanisms leading to upregulation of TEM5 and its function during angiogenesis have not been identified . Here , we report that TEM5 expression in endothelial cells is induced during capillary-like network formation on Matrigel , during capillary morphogenesis in a three-dimensional collagen I matrix , and upon confluence on a two-dimensional matrix . TEM5 expression was not induced by a variety of soluble angiogenic factors , including VEGF and bFGF , in subconfluent endothelial cells . TEM5 upregulation was blocked by toxin B from Clostridium difficile , an inhibitor of the small GTPases Rho , Rac , and Cdc42 . The Rho inhibitor C3 transferase from Clostridium botulinum did not affect TEM5 expression , whereas the Rac inhibitor NSC23766 suppressed TEM5 upregulation . An excess of the soluble TEM5 extracellular domain or an inhibitory monoclonal TEM5 antibody blocked contact inhibition of endothelial cell proliferation resulting in multilayered islands within the endothelial monolayer and increased vessel density during capillary formation . Based on our results we conclude that TEM5 expression during capillary morphogenesis is induced by the small GTPase Rac and mediates contact inhibition of proliferation in endothelial cells . OUTPUT: inducing angiogenesis;evading growth suppressors INPUT: Odontogenic tumors originate from the remains of migrating enamel epithelium after the completion of normal tooth genesis . These enamel epithelium remnants exhibit the ability to recapitulate the events that occur during tooth formation . Several lines of evidence suggest that aberrance in the signaling pathways similar to the ones that are used during tooth development , including the WNT pathway , might be the cause of odontogenic tumorigenesis and maintenance . In this study we demonstrated that WNT5A expression was intense in both the epithelial component of ameloblastomas , the most common epithelial odontogenic tumor , and in this tumor's likely precursor cell , the enamel epithelium located at the cervical loop of normal developing human tooth buds . Additionally , when WNT5A was overexpressed in enamel epithelium cells ( LS-8 ) , the clones expressing high levels of WNT5A ( S ) exhibited characteristics of tumorigenic cells , including growth factor independence , loss of anchorage dependence , loss of contact inhibition , and tumor formation in immunocompromised mice . Moreover , overexpression of WNT5A drastically increased LS-8 cell migration and actin reorganization when compared with controls . Suppression of endogenous WNT5A in LS-8 cells ( AS ) greatly impaired their migration and AS cells failed to form significant actin reorganization and membrane protrusion was rarely seen . Taken together , our data indicate that WNT5A signaling is important in modulating tumorigenic behaviors of enamel epithelium cells in ameloblastomas . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot87

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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-α ) , 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-1α and NF-κB transcription factors are important players for the establishment of a pro-inflammatory and potentially oncogenic environment . HIF-1α 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-1α 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-1α 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 . OUTPUT: activating invasion and metastasis INPUT: Histone H3 methylation at lysine 4 ( K4 ) is associated with euchromatic regions and is thought to be important for the transcriptional activation of genes during differentiation . In this study , we found that di- and tri-methylation of histone H3 at K4 and acetylation of histones H3 and H4 from the promoter/enhancer to the transcribed region close to the transcription initiation site of the solute carrier family 2 , member 5 ( SLC2A5 ) gene , and its expression , were induced by differentiation of intestine-like Caco-2 cells . These effects were accompanied by contact inhibition of cell growth of these cells . Furthermore , these modifications were induced by co-treatment with a synthetic glucocorticoid hormone dexamethasone and a p44/42 mitogen-activated protein kinase inhibitor PD89059 . Our results suggest that methylation of histone H3 at K4 and acetylation of histones H3 and H4 are involved in SLC2A5 gene induction associated with intestinal differentiation of Caco-2 cells . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot88

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Folate ( vitamin B9 ) is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate ( dTMP ) and s-adenosylmethionine ( AdoMet ) . The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance , but still unclear . We recently demonstrated that sensitivity to low folate availability is affected by the rate of polyamine biosynthesis , which is prominent in prostate cells . We , therefore , hypothesized that prostate cells might be highly susceptible to genetic , epigenetic and phenotypic changes consequent to folate restriction . RESULTS We studied the consequences of long-term , mild folate depletion in a model comprised of three syngenic cell lines derived from the transgenic adenoma of the mouse prostate ( TRAMP ) model , recapitulating different stages of prostate cancer ; benign , transformed and metastatic . High-performance liquid chromatography analysis demonstrated that mild folate depletion ( 100 nM ) sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines . Random oligonucleotide-primed synthesis ( ROPS ) revealed a significant increase in uracil misincorporation and DNA single strand breaks , while spectral karyotype analysis ( SKY ) identified five novel chromosomal rearrangements in cells grown with mild folate depletion . Using global approaches , we identified an increase in CpG island and histone methylation upon folate depletion despite unchanged levels of total 5-methylcytosine , indicating a broad effect of folate depletion on epigenetic regulation . These genomic changes coincided with phenotype changes in the prostate cells including increased anchorage-independent growth and reduced sensitivity to folate depletion . CONCLUSIONS This study demonstrates that prostate cells are highly susceptible to genetic and epigenetic changes consequent to mild folate depletion as compared to cells grown with supraphysiological amounts of folate ( 2 microM ) routinely used in tissue culture . In addition , we elucidate for the first time the contribution of these aspects to consequent phenotype changes in epithelial cells . These results provide a strong rationale for studying the effects of folate manipulation on the prostate in vivo , where cells might be more sensitive to changes in folate status resulting from folate supplementation or antifolate therapeutic approaches . OUTPUT: genomic instability and mutation INPUT: 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 . OUTPUT:

tumor promoting inflammation;inducing angiogenesis

HoC_dynamic_1_shot89

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Liver cancer , predominantly hepatocellular carcinoma ( HCC ) , represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation . Due to dismal prognosis and limited therapeutic intervention , chemoprevention has emerged as a viable approach to reduce the morbidity and mortality of HCC . Pomegranate fruit is a rich source of phytochemicals endowed with potent antioxidant and anti-inflammatory properties . We previously reported that pomegranate phytochemicals inhibit diethylnitrosamine ( DENA)-initiated hepatocarcinogenesis in rats though nuclear factor E2-related factor 2 ( Nrf2)-mediated antioxidant mechanisms . Since Nrf2 also acts as a key mediator of the nuclear factor-kappaB ( NF-κB)-regulated inflammatory pathway , our present study investigated the anti-inflammatory mechanisms of a pomegranate emulsion ( PE ) during DENA-induced rat hepatocarcinogenesis . Rats were administered with PE ( 1 or 10 g/kg ) 4 weeks before and 18 weeks following DENA initiation . There was a significant increase in hepatic expressions of inducible nitric oxide synthase , 3-nitrotyrosine , heat shock protein 70 and 90 , cyclooxygenase-2 and NF-κB in DENA-exposed rat livers . PE dose-dependently suppressed all aforementioned elevated inflammatory markers . A conspicuous finding of this study involves lack of cardiotoxicity of PE as assessed by monitoring cardiac function using noninvasive echocardiography . Our results provide substantial evidence that suppression of the inflammatory cascade through modulation of NF-κB signaling pathway may represent a novel mechanism of liver tumor inhibitory effects of PE against experimental hepatocarcinogenesis . Data presented here coupled with those of our earlier study underline the importance of simultaneously targeting two interconnected molecular circuits , namely , Nrf2-mediated redox signaling and NF-κB-regulated inflammatory pathway , by pomegranate phytoconstituents to achieve chemoprevention of HCC . OUTPUT: tumor promoting inflammation INPUT: 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 . OUTPUT:

tumor promoting inflammation;genomic instability and mutation

HoC_dynamic_1_shot90

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Ataxia-telangiectasia mutated ( ATM ) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity . However , ATM also has been implicated in metabolic regulation , and ATM deficiency is associated with elevated reactive oxygen species ( ROS ) . ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer , underscoring the importance of cellular pathways involved in redox homeostasis . We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS . We show that in response to elevated ROS , ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy . Importantly , elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin , which also rescues lymphomagenesis in Atm-deficient mice . Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy , identifying an integration node for the cellular damage response with key pathways involved in metabolism , protein synthesis , and cell survival . OUTPUT: resisting cell death;tumor promoting inflammation INPUT: 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 . OUTPUT:

evading growth suppressors;genomic instability and mutation

HoC_dynamic_1_shot91

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: ATM(Tel1) and ATR(Rad3) checkpoint kinases phosphorylate the C-terminus of histone H2AX ( H2A in yeasts ) in chromatin flanking DNA damage , establishing a recruitment platform for checkpoint and repair proteins . Phospho-H2A/X ( gammaH2A/X)-binding proteins at double-strand breaks ( DSBs ) have been characterized , but those required for replication stress responses are unknown . Here , we present genetic , biochemical , small angle X-ray scattering ( SAXS ) , and X-ray structural studies of the Schizosaccharomyces pombe Brc1 , a 6-BRCT-domain protein that is structurally related to Saccharomyces cerevisiae Rtt107 and mammalian PTIP . Brc1 binds gammaH2A to form spontaneous and DNA damage-induced nuclear foci . Spontaneous Brc1 foci colocalize with ribosomal DNA repeats , a region prone to fork pausing and genomic instability , whereas DNA damage-induced Brc1 foci colocalize with DSB response factors. gammaH2A binding is critical for Brc1 function . The 1.45 A resolution crystal structure of Brc1-gammaH2A complex shows how variable BRCT insertion loops sculpt tandem-BRCT phosphoprotein-binding pockets to facilitate unique phosphoprotein-interaction specificities , and unveils an acidic DNA-mimicking Brc1 surface . From these results , Brc1 docking to gammaH2A emerges as a critical chromatin-specific response to replication-associated DNA damage . OUTPUT: genomic instability and mutation INPUT: DNA double-strand breaks ( DSBs ) trigger ATM ( ataxia telangiectasia mutated ) signalling and elicit genomic rearrangements and chromosomal fragmentation if misrepaired or unrepaired . Although most DSB repair is ATM-independent , approximately 15% of ionizing radiation ( IR)-induced breaks persist in the absence of ATM-signalling. 53BP1 ( p53-binding protein 1 ) facilitates ATM-dependent DSB repair but is largely dispensable for ATM activation or checkpoint arrest . ATM promotes DSB repair within heterochromatin by phosphorylating KAP-1 ( KRAB-associated protein 1 , also known as TIF1beta , TRIM28 or KRIP-1 ; ref. 2 ) . Here , we show that the ATM signalling mediator proteins MDC1 , RNF8 , RNF168 and 53BP1 are also required for heterochromatic DSB repair . Although KAP-1 phosphorylation is critical for 53BP1-mediated repair , overall phosphorylated KAP-1 ( pKAP-1 ) levels are only modestly affected by 53BP1 loss. pKAP-1 is transiently pan-nuclear but also forms foci overlapping with gammaH2AX in heterochromatin . Cells that do not form 53BP1 foci , including human RIDDLE ( radiosensitivity , immunodeficiency , dysmorphic features and learning difficulties ) syndrome cells , fail to form pKAP-1 foci. 53BP1 amplifies Mre11-NBS1 accumulation at late-repairing DSBs , concentrating active ATM and leading to robust , localized pKAP-1 . We propose that ionizing-radiation induced foci ( IRIF ) spatially concentrate ATM activity to promote localized alterations in regions of chromatin otherwise inhibitory to repair . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot92

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Diphenyl ditelluride ( DPDT ) is a potential prototype for the development of novel biologically active molecules . Thus , it is important to evaluate the toxic effects of this compound . In the present study , we evaluated the cytotoxic , genotoxic and mutagenic properties of DPDT in Chinese hamster fibroblast ( V79 ) cells , in strains of the yeast Saccharomyces cerevisiae both proficient and deficient in several DNA repair pathways and in Salmonella typhimurium . DPDT induced frameshift mutations in both S.typhimurium and a haploid wild-type strain of S.cerevisiae . Mutants of S.cerevisiae defective in base excision repair and recombinational repair were more sensitive to DPDT . The results of a lactate dehydrogenase leakage assay suggest that DPDT is cytotoxic to V79 cells . At cytotoxic concentrations , this compound increased thiobarbituric reactive species levels and decreased the glutathione:GSSH ratio in yeast and V79 cells . DPDT generated single- and double-strand DNA breaks in V79 cells , both with and without metabolic activation , as revealed by alkaline and neutral comet assays . Moreover , an induction of oxidative DNA base damage was indicated by a modified comet assay using formamidopyrimidine DNA glycosylase and endonuclease III . Treatment with DPDT also induced micronucleus formation in V79 cells . Pre-incubation with N-acetylcysteine reduced DPDT's oxidative , genotoxic and mutagenic effects in yeast and V79 cells . Our results suggest that the toxic and mutagenic properties of DPDT may stem from its ability to disturb the redox balance of the cell , which leads to oxidative stress and the induction of DNA damage . OUTPUT: genomic instability and mutation INPUT: Mutations in the gene encoding cytosolic Cu,Zn-superoxide dismutase ( SOD1 ) have been linked to familial amyotrophic lateral sclerosis ( FALS ) . However the molecular mechanisms of motor neuron death are multi-factorial and remain unclear . Here we examined DNA damage , p53 activity and apoptosis in SH-SY5Y human neuroblastoma cells transfected to achieve low-level expression of either wild-type or mutant Gly(93)-->Ala ( G93A ) SOD1 , typical of FALS . DNA damage was investigated by evaluating the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine ( 8-oxodGuo ) and DNA strand breaks . Significantly higher levels of DNA damage , increased p53 activity , and a greater percentage of apoptotic cells were observed in SH-SY5Y cells transfected with G93A SOD1 when compared to cells overexpressing wild-type SOD1 and untransfected cells . Western blot , FACS , and confocal microscopy analysis demonstrated that G93A SOD1 is present in the nucleus in association with DNA . Nuclear G93A SOD1 has identical superoxide dismutase activity but displays increased peroxidase activity when compared to wild-type SOD1 . These results indicate that the G93A mutant SOD1 association with DNA might induce DNA damage and trigger the apoptotic response by activating p53 . This toxic activity of mutant SOD1 in the nucleus may play an important role in the complex mechanisms associated with motor neuron death observed in ALS pathogenesis . OUTPUT:

genomic instability and mutation;resisting cell death

HoC_dynamic_1_shot93

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Genomic instability drives tumorigenesis , but how it is initiated in sporadic neoplasias is unknown . In early preneoplasias , alterations at chromosome fragile sites arise due to DNA replication stress . A frequent , perhaps earliest , genetic alteration in preneoplasias is deletion within the fragile FRA3B/FHIT locus , leading to loss of Fhit protein expression . Because common chromosome fragile sites are exquisitely sensitive to replication stress , it has been proposed that their clonal alterations in cancer cells are due to stress sensitivity rather than to a selective advantage imparted by loss of expression of fragile gene products . Here , we show in normal , transformed , and cancer-derived cell lines that Fhit-depletion causes replication stress-induced DNA double-strand breaks . Using DNA combing , we observed a defect in replication fork progression in Fhit-deficient cells that stemmed primarily from fork stalling and collapse . The likely mechanism for the role of Fhit in replication fork progression is through regulation of Thymidine kinase 1 expression and thymidine triphosphate pool levels ; notably , restoration of nucleotide balance rescued DNA replication defects and suppressed DNA breakage in Fhit-deficient cells . Depletion of Fhit did not activate the DNA damage response nor cause cell cycle arrest , allowing continued cell proliferation and ongoing chromosomal instability . This finding was in accord with in vivo studies , as Fhit knockout mouse tissue showed no evidence of cell cycle arrest or senescence yet exhibited numerous somatic DNA copy number aberrations at replication stress-sensitive loci . Furthermore , cells established from Fhit knockout tissue showed rapid immortalization and selection of DNA deletions and amplifications , including amplification of the Mdm2 gene , suggesting that Fhit loss-induced genome instability facilitates transformation . We propose that loss of Fhit expression in precancerous lesions is the first step in the initiation of genomic instability , linking alterations at common fragile sites to the origin of genome instability . OUTPUT: genomic instability and mutation;sustaining proliferative signaling;enabling replicative immortality INPUT: 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 . OUTPUT:

evading growth suppressors;genomic instability and mutation

HoC_dynamic_1_shot94

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cancer cells constantly adapt to oxidative phosphorylation ( OXPHOS ) suppression resulting from hypoxia or mitochondria defects . Under the OXPHOS suppression , AMP-activated protein kinase ( AMPK ) regulates global metabolism adjustments , but its activation has been found to be transient . Whether cells can maintain cellular ATP homeostasis and survive beyond the transient AMPK activation is not known . Here , we study the bioenergetic adaptation to the OXPHOS inhibitor oligomycin in a group of cancer cells . We found that oligomycin at 100 ng/ml completely inhibits OXPHOS activity in 1 h and induces various levels of glycolysis gains by 6 h , from which we calculate the bioenergetic organizations of cancer cells . In glycolysis-dominant cells , oligomycin does not induce much energy stress as measured by glycolysis acceleration , ATP imbalance , AMPK activation , AMPK substrate acetyl-CoA carboxylase phosphorylation at Ser(79) , and cell growth inhibition . In OXPHOS-dependent LKB1 wild type cells , oligomycin induces 5-8% ATP drops and transient AMPK activation during the initial 1-2 h . After AMPK activation is completed , oligomycin-induced increase of acetyl-CoA carboxylase phosphorylation at Ser(79) is still detected , and cellular ATP is back at preoligomycin treatment levels by sustained elevation of glycolysis . Cell growth , however , is inhibited without an increase in cell death and alteration in cell cycle distribution . In OXPHOS-dependent LKB1-null cells , no AMPK activation by oligomycin is detected , yet cells still show a similar adaptation . We also demonstrate that the adaptation to oligomycin does not invoke activation of hypoxia-induced factor . Our data suggest that cancer cells may grow and survive persistent OXPHOS suppression through an as yet unidentified regulatory mechanism . OUTPUT: cellular energetics INPUT: p32/gC1qR/C1QBP/HABP1 is a mitochondrial/cell surface protein overexpressed in certain cancer cells . Here we show that knocking down p32 expression in human cancer cells strongly shifts their metabolism from oxidative phosphorylation ( OXPHOS ) to glycolysis . The p32 knockdown cells exhibited reduced synthesis of the mitochondrial-DNA-encoded OXPHOS polypeptides and were less tumorigenic in vivo . Expression of exogenous p32 in the knockdown cells restored the wild-type cellular phenotype and tumorigenicity . Increased glucose consumption and lactate production , known as the Warburg effect , are almost universal hallmarks of solid tumors and are thought to favor tumor growth . However , here we show that a protein regularly overexpressed in some cancers is capable of promoting OXPHOS . Our results indicate that high levels of glycolysis , in the absence of adequate OXPHOS , may not be as beneficial for tumor growth as generally thought and suggest that tumor cells use p32 to regulate the balance between OXPHOS and glycolysis . OUTPUT:

cellular energetics

HoC_dynamic_1_shot95

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: activating invasion and metastasis;resisting cell death;tumor promoting inflammation;sustaining proliferative signaling INPUT: The contribution of a type II restriction-modification system ( R-M system ) to genome integrity and cell viability was investigated . We established experimental conditions which enabled the achievement of hemimethylated and unmethylated states for the specific bases of the recognition sequences of the host's DNA . To achieve this , we constructed the MboII R-M system containing only one ( i.e . M2.MboII ) out of two functional MboII methyltransferases found in Moraxella bovis . Using the incomplete R-M system we were able to perturb the balance between methylation and restriction in an inducible manner . We demonstrate that upon the SOS-induced DNA repair in the mitomycin C treated cells , restriction significantly reduces cell viability . Similar results for the well-studied wild type EcoRI R-M system , expressed constitutively in Escherichia coli , were obtained . Our data provide further insights into the benefits and disadvantages of maintaining of a type II R-M system , highlighting its impact on host cell fitness . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot96

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth . We observed promoter methylation and loss of expression in neurofilament heavy polypeptide ( NEFH ) in a significant proportion of primary esophageal squamous cell carcinoma ( ESCC ) samples that were of a high tumor grade and advanced stage . RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo , whereas forced expression of NEFH significantly inhibited cell growth and colony formation . Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase , via activation of the Akt/beta-catenin pathway , resulting in enhanced aerobic glycolysis and mitochondrial dysfunction . The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of beta-catenin expression , and was decreased by the treatment of 2-Deoxyglucose , a glycolytic inhibitor , or API-2 , an Akt inhibitor . Loss of NEFH activates the Akt/beta-catenin pathway and increases glycolysis and mitochondrial dysfunction . Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways . OUTPUT: cellular energetics INPUT: Acidosis commonly observed in solid tumors like pancreatic cancer promotes genetic instability and selection of a more malignant phenotype of cancer cells . Overexpression or activation of integral membrane proteins mediating H+ efflux may contribute to extracellular acidification . Neurotensin ( NT ) induces intracellular alkalinization and stimulates interleukin-8 production in pancreatic cancer cells and , as demonstrated here , the stable NT analog Lys(8)-psi-Lys(9)NT(8-13) enhances the amiloride-sensitive , Na+-dependent transmembrane H+ flux by a factor of 2.05+/-0.28 and 2.69+/-0.07 in BxPC-3 and PANC-1 pancreatic cancer cells , respectively , by phosphorylation of the Na+/H+ exchanger 1 ( NHE1 ) . Human genome-wide gene expression analysis was performed to detect effects of Lys(8)-psi-Lys(9)NT(8-13) on BxPC-3 cells . Results indicated upregulation of genes involved in regulation of NHE1 , hypoxic response and glycolysis in response to Lys(8)-psi-Lys(9)NT(8-13) even under normoxic conditions . Therefore , our findings suggest that growth factors like NT may be implicated in the early progression of pancreatic cancer by localized acidification and induction of an aerobic glycolytic phenotype with higher metastatic potential in small cell aggregates . OUTPUT:

cellular energetics

HoC_dynamic_1_shot97

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Acute leukemia is a disorder of the hematopoietic system characterized by the expansion of a clonal population of cells blocked from differentiating into mature cells . Recent studies have shown that chalcones and their derivatives induce apoptosis in different cell lines . Since new compounds with biological activity are needed , the aim of this study was to evaluate the cytotoxic effect of three synthetic chalcones , derived from 1-naphthaldehyde and 2-naphthaldehyde , on human acute myeloid leukemia K562 cells and on human acute lymphoblastic leukemia Jurkat cells . Based on the results , the most cytotoxic compound ( A1 ) was chosen for further analysis in six human acute leukemia cells and in a human colon adenocarcinoma cell line ( HT-29 ) . Chalcone A1 significantly reduced the cell viability of K562 , Jurkat , Kasumi , U937 , CEM and NB4 cells in a concentration and time-dependent manner when compared with the control group ( IC(50) values between ∼1.5μM and 40μM ) . It was also cytotoxic to HL-29 cells . To further examine its effect on normal cells , peripheral blood lymphocytes collected from healthy volunteers were incubated with the compound . It has also been incubated with human fibroblasts cultured from bone marrow ( JMA ) . Chalcone A1 is non-cytotoxic to PBL cells and to JMA cells . A1 caused significant cell cycle arrest in all phases according to the cell line , and increased the proportion of cells in the sub G0/G1 phase . To evaluate whether this chalcone induced cell death via an apoptotic or necrotic pathway , cell morphology was examined using fluorescence microscopy . Cells treated with A1 at IC(50) demonstrated the morphological characteristic of apoptosis , such as chromatin condensation and formation of apoptotic bodies . Apoptosis was confirmed by externalization of phosphatidylserine , which was detected by the Annexin V-FITC method , and by DNA fragmentation . The results suggest that chalcone A1 has potential as a new lead compound for cancer therapy . OUTPUT: evading growth suppressors;sustaining proliferative signaling;resisting cell death INPUT: It is crucial for organ homeostasis that epithelia have effective mechanisms to restrict motility and cell proliferation in order to maintain tissue architecture . On the other hand , epithelial cells need to rapidly and transiently acquire a more mesenchymal phenotype , with high levels of cell motility and proliferation , in order to repair epithelia upon injury . Cross talk between cell-cell and cell-matrix signaling is crucial for regulating these transitions . The Pak1-betaPIX-GIT complex is an effector complex downstream of the small GTPase Rac1 . We previously showed that translocation of this complex from cell-matrix to cell-cell adhesion sites was required for the establishment of contact inhibition of proliferation . In this study , we provide evidence that this translocation depends on cadherin function . Cadherins do not recruit the complex by direct interaction . Rather , we found that inhibition of the normal function of cadherin or Pak1 leads to defects in focal adhesion turnover and to increased signaling by phosphatidylinositol 3-kinase . We propose that cadherins are involved in regulation of contact inhibition by controlling the function of the Pak1-betaPIX-GIT complex at focal contacts . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot98

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Identification of the proteins that are associated with estrogen receptor ( ER ) status is a first step towards better understanding of the hormone-dependent nature of breast carcinogenesis . Although a number of gene expression analyses have been conducted , protein complement has not been systematically investigated to date . Because proteins are primary targets of therapeutic drugs , in this study , we have attempted to identify proteomic signatures that demarcate ER-positive and -negative breast cancers . Using highly enriched breast tumor cells , replicate analyses from 3 ERα+ and 3 ERα- human breast tumors resulted in the identification of 2,995 unique proteins with ≥2 peptides . Among these , a number of receptor tyrosine kinases and intracellular kinases that are abundantly expressed in ERα+ and ERα- breast cancer tissues were identified . Further , label-free quantitative proteome analysis revealed that 236 proteins were differentially expressed in ERα+ and ERα- breast tumors . Among these , 141 proteins were selectively up-regulated in ERα+ , and 95 proteins were selectively up-regulated in ERα- breast tumors . Comparison of differentially expressed proteins with a breast cancer database revealed 98 among these have been previously reported to be involved in breast cancer . By Gene Ontology molecular function , dehydrogenase , reductase , cytoskeletal proteins , extracellular matrix , hydrolase , and lyase categories were significantly enriched in ERα+ , whereas selected calcium-binding protein , membrane traffic protein , and cytoskeletal protein were enriched in ERα- breast tumors . Biological process and pathway analysis revealed that up-regulated proteins of ERα+ were overrepresented by proteins involved in amino acid metabolism , proteasome , and fatty acid metabolism , while up-regulated proteins of ERα- were overrepresented by proteins involved in glycolysis pathway . The presence and relative abundance of 4 selected differentially abundant proteins ( liprin-α1 , fascin , DAP5 , and β-arrestin-1 ) were quantified and validated by immunohistochemistry . In conclusion , unlike in vitro cell culture models , the in vivo signaling proteins and pathways that we have identified directly from human breast cancer tissues may serve as relevant therapeutic targets for the pharmacological intervention of breast cancer . OUTPUT: cellular energetics INPUT: Previous studies with selenium and/or vitamin E in prostate carcinogenesis animal models have been negative , but these models may not involve oxidative stress mechanisms . In this study , we examined the potential of selenomethionine and alpha-tocopherol to modulate prostate cancer development in the testosterone plus estradiol-treated NBL rat , a model that does involve sex hormone-induced oxidative stress mechanisms and prostatic inflammation . One week following the implantation with hormone-filled Silastic implants , rats were fed diets containing l-selenomethionine ( 1.5 or 3.0 mg/kg ) , DL-alpha-tocopherol acetate ( 2,000 or 4,000 mg/kg ) , or a natural ingredient control diet ( NIH-07 ) . The development of prostate carcinomas was not affected by dietary treatment with either agent . Food intake , body weight , and mortality were also not affected . The high dose of selenomethionine reduced the severity of epithelial dysplasia in the lateral prostate that was not associated with inflammation , and alpha-tocopherol reduced in a dose-related fashion the incidence of marked inflammation and marked epithelial dysplasia in the lateral prostate , regardless of whether these lesions were associated with inflammation. alpha-Tocopherol significantly increased the incidence of adenocarcinomas of the mammary glands at both dietary concentrations . Collectively , our findings suggest that selenomethionine and alpha-tocopherol supplementation does not prevent prostate cancer in rats fed diets with nutritionally adequate levels of selenium and vitamin E. Importantly , the results of the current animal studies and those reported previously were fully predictive of the outcome of the Selenium and Vitamin E Cancer Prevention Trial . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot99

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Death receptors ( DR ) of the TNF family function as anti-tumor immune effector molecules . Tumor cells , however , often exhibit DR-signaling resistance . Previous studies indicate that radiation can modify gene expression within tumor cells and increase tumor cell sensitivity to immune attack . The aim of this study is to investigate the synergistic effect of sub-lethal doses of ionizing radiation in sensitizing colorectal carcinoma cells to death receptor-mediated apoptosis . METHODOLOGY/PRINCIPAL FINDINGS The ability of radiation to modulate the expression of multiple death receptors ( Fas/CD95 , TRAILR1/DR4 , TRAILR2/DR5 , TNF-R1 and LTβR ) was examined in colorectal tumor cells . The functional significance of sub-lethal doses of radiation in enhancing tumor cell susceptibility to DR-induced apoptosis was determined by in vitro functional sensitivity assays . The longevity of these changes and the underlying molecular mechanism of irradiation in sensitizing diverse colorectal carcinoma cells to death receptor-mediated apoptosis were also examined . We found that radiation increased surface expression of Fas , DR4 and DR5 but not LTβR or TNF-R1 in these cells . Increased expression of DRs was observed 2 days post-irradiation and remained elevated 7-days post irradiation . Sub-lethal tumor cell irradiation alone exhibited minimal cell death , but effectively sensitized three of three colorectal carcinoma cells to both TRAIL and Fas-induced apoptosis , but not LTβR-induced death . Furthermore , radiation-enhanced Fas and TRAIL-induced cell death lasted as long as 5-days post-irradiation . Specific analysis of intracellular sensitizers to apoptosis indicated that while radiation did reduce Bcl-X(L) and c-FLIP protein expression , this reduction did not correlate with the radiation-enhanced sensitivity to Fas and/or TRAIL mediated apoptosis among the three cell types . CONCLUSIONS/SIGNIFICANCE Irradiation of tumor cells can overcome Fas and TRAIL resistance that is long lasting . Overall , results of these investigations suggest that non-lethal doses of radiation can be used to make human tumors more amenable to attack by anti-tumor effector molecules and cells . OUTPUT: resisting cell death INPUT: BACKGROUND Non-alcoholic fatty liver disease ( NAFLD ) is associated with obesity , insulin resistance and hepatic steatosis . Non-alcoholic steatohepatitis ( NASH ) is a serious consequence of NAFLD where chronic tissue damage and inflammation result in fibrosis which may progress to cirrhosis . Transforming growth factor beta1 ( TGFbeta1 ) , proinflammatory cytokines and oxidative stress are thought to play crucial roles in the pathogenesis of these conditions . The contributions of individual liver cell types to fibrogenesis remain controversial and the influence of selenium status has not been investigated . METHODS In this study we have used a cell culture model of fat-loading using oleate-treated human hepatoblastoma ( C3A ) cells to investigate how fat-loading and selenium status might influence the production of collagen in response to TGFbeta1 . The secretion of inflammatory cytokines was also investigated , together with the epithelial character of the treated cells . RESULTS We found that in response to treatment with TGFbeta1 , C3A cells produced mRNA encoding the pro-alphaI chain of procollagen I , secreted procollagen I peptide , up-regulated production of the proinflammatory cytokine interleukin-8 ( IL-8 ) and the mesenchymal marker vimentin , and down-regulated albumin production . Most of these responses were considerably enhanced when cells were fat-loaded with oleate and were attenuated by selenium addition at a dose that optimised the expression of thioredoxin reductase and glutathione peroxidase . CONCLUSIONS Our data establish that both fat-loading and suboptimal selenium status enhance collagen and IL-8 production by C3A hepatocytes in response to TGFbeta1 , possibly as part of an epithelial to mesenchymal transition . GENERAL SIGNIFICANCE These findings suggest that the hepatocyte may be an important contributor to the pathogenesis of fibrosis associated with NAFLD . OUTPUT:

tumor promoting inflammation