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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