bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4670: Polymorphisms in DNA repair genes, chemotherapy and survival in bladder cancer
Authors: Ricceri Fulvio , Sacerdote Carlotta , Polidoro Silvia , Guarrera Simonetta , Allione Alessandra , Critelli Rossana , Critelli Rossana , Russo Alessia , Gontero Paolo , Destefanis Paolo , Matullo Giuseppe , Vineis Paolo 
Published: June 2012

Abstract
Bladder cancer (BC) survival is highly influenced by environmental and predisposing genetic factors. In the last decades growing evidence of the major role played by DNA repair systems in the survival after a BC has been provided.
The objectives of the study are to assess the relationship between DNA Repair Genes polymorphisms and survival by treatment in bladder cancer patients.
We conducted a hospital-based case-control investigation at S. Giovanni Battista hospital in Turin, where about half of the incident BC in the Turin metropolitan area are treated. Cases are histologically confirmed incident BC patients, male, aged 40 to 75 years and resident in the Turin metropolitan area. Each patient filled in a questionnaire on history of tobacco smoking, occupational history, 24-hours medication use recall and food habits, and provided a blood sample. We followed up BC patients for death and recurrences using municipal registry office, death's certificate, hospital discharge, medical records and pathologists’ reports. In the cohort of BC patients, we genotyped 36 Single Nucleotide Polymorphisms (SNPs) in 10 DNA Repair Genes.
We analyzed survival on BC patients using a Cox proportional-hazards regression model for codominant and per-allele scenario, adjusted for age, stage and grading and stratified by therapy (chemotherapy vs no or other therapies). Chemotherapy group include patients tretated with systemic and local chemotherapy with different therapeutic plans (Carboplatinum doublets, Gencitabin, Epirubicin, etc).
We identified 456 BC patients which were followed-up for mortality (median follow-up 62 months). In multivariate analysis both stage and grade predicted the outcome in a statistically significant way, after adjustment for age. Our preliminary analyses showed that the variant alleles in two SNPs in XRCC1 gene (rs 2854509 and rs 3213255) confer a significant lower risk of death and one SNP in ERCC2 gene (rs 171140) confers a significant higher risk of death compared to the wild type (analyses adjusted by age, stage and grading) only in the group of treated with chemotherapy.
Our findings suggest a link between DNA repair genes variation and survival in BC patients that become evident only in patients treated with chemotherapy. We hypothesize that levels of DNA adducts or other DNA damages inducted by chemotherapy, are partially due to the individual DNA repair activity, resulting in a different response to chemotherapy and, consequentially, in different survival rates.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4670. doi:10.1158/1538-7445.AM2011-4670
Abstract 468: Down-regulation of TNFSF15 (VEGI) in tumor vasculature under inflammatory conditions is a pre-requisite of tumor neovascularization
Authors: Deng Weimin , Lu Yi , Gu Xin , Liang Paulina Huang , Yao Zhi , Li Luyuan 
Published: June 2012

Abstract
Tumor necrosis factor superfamily-15 (TNFSF15; VEGI) is an endogenous inhibitor of neovascularization. TNFSF15 is largely produced by quiescent vascular endothelial cells in an established vasculature but is markedly down-regulated in endothelial cells undergoing proliferation such as those in tumors or at a wound site. Recombinant TNFSF15 is a potent inhibitor of endothelial cell proliferation and tumor growth. We hypothesize that TNFSF15 as a negative regulator of angiogenesis must be down-regulated prior to the initiation of angiogenesis, and that the inflammatory conditions created by cancer cells and infiltrating lymphocytes lead to TNFSF15 down-modulation in the microenvironment, permitting new blood vessel growth. We analyzed normal ovary tissues (n=12) and clinical specimens of ovarian cancer (n=86; including stages I, II, III and IV) for the expression of TNFSF15, the endothelial cell marker PECAM (CD31), and tumor-infiltrating T-cell markers CD4 and CD25. We found that the degree of T-cell infiltration increases markedly while TNFSF15 expression diminishes as the disease progresses. We then determined the influence of human ovarian cancer cell line OVCAR-3 cell conditioned media on cytokine production by human CD4+ T-cells and CD4+CD25+ Treg cells, as well as the influence of the conditioned media of the latter two cells on TNFSF15 expression in human umbilical vein endothelial cells (HUVEC). We found that the conditioned media of Th1 or Treg cells can inhibit HUVEC TNFSF15 expression only after the lymphocytes being treated with OVCAR-3 conditioned media. Interestingly, we further found that mouse ovarian cancer ID8 cells implanted subcutaneously on mice treated with TNFSF15 shRNA at the injection sites exhibit significantly greater tumor growth rates compared with control shRNA treated ones. Our findings indicate that TNFSF15 plays a critical role in the maintenance of vascular stability as its down-modulation is a pre-requisite for the initiation of tumor neovascularization, and that TNFSF15 down-regulation is carried out by tumor-infiltrating T-cells under the influence of the cancer cells in the microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 468. doi:10.1158/1538-7445.AM2011-468
Abstract 4693: High expression levels of NOXA are important for p53-mediated hypersensitivity in testicular germ cell tumor (TGCT) cells
Authors: Gutekunst Matthias , Oren Moshe , Weilbacher Andrea , Dengler Michael A. , Aulitzky Walter E. , van der Kuip Heiko 
Published: June 2012

Abstract
Consistent with the excellent clinical results in testicular germ cell tumors (TGCT), most cell lines derived from this cancer such as NTERA-2D1 show an exquisite sensitivity to Cisplatin. It is well accepted that the high susceptibility of TGCT cells to apoptosis is responsible for this hypersensitive phenotype. However, the role of the p53 pathway remains controversial.
Using RNA interference-mediated gene silencing, we systematically investigated the impact of DNA damage kinases upstream of p53, p53 itself, as well as apoptosis-related p53 targets on this hypersensitivity. Unexpectedly, neither knockdown of ATM, ATR, or DNA-PK alone nor ATM/ATR double knockdown or ATM/ATR/DNA-PK triple knockdown had any significant protective effect on survival of NTERA-2D1 cells upon Cisplatin. However, siRNA-mediated silencing of p53 was sufficient to completely abrogate hypersensitivity demonstrating that in these cells p53 acts preferentially as a pro-apoptotic factor. This is also supported by the finding that NTERA-2D1 cells were not only hypersensitive to Cisplatin but also to non-genotoxic inducers of p53 such as the Mdm2 antagonist Nutlin-3 and the proteasome inhibitor Bortezomib. Screening of different p53 targets revealed that the pro-apoptotic function of p53 was dependent on NOXA, since silencing of this p53 target almost completely mimicked the effect of the p53 knockdown. Importantly, both constitutive and Cisplatin-induced levels of NOXA were significantly reduced in resistant NTERA-2D1 cells obtained by either short-term differentiation or cultivation with increasing Cisplatin concentrations. Furthermore, comparison of a panel of p53 wildtype tumor cell lines revealed exceptionally high NOXA levels in the most sensitive cell line NTERA-2D1.
In conclusion, our data indicate that the hypersensitivity of TGCT cells is a result of their unique sensitivity to pro-apoptotic functions of p53 mediated by exceptionally high levels of NOXA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4693. doi:10.1158/1538-7445.AM2011-4693
Abstract 470: Role of Fli1 in hematopoietic stem cell-derived fibroblast promotion of tumor cell migration and invasion
Authors: McDonald Lindsay T. , Neitzke Daniel J. , Findlay Victoria J. , Turner David P. , Watson Patricia M. , Watson Dennis K. , LaRue Amanda C. 
Published: June 2012

Abstract
Cells and paracrine factors of the tumor microenvironment play a central role in tumor angiogenesis, invasion, migration and proliferation, making the tumor microenvironment an exciting therapeutic target. Among the most prominent cell types in the tumor stroma are fibroblasts, termed carcinoma-associated fibroblasts (CAFs). We have identified a novel population of CAFs and CAF precursors (circulating fibroblast precursors, CFPs) that are of hematopoietic stem cell (HSC) origin. These cells preferentially migrate and differentiate in response to tumor and their inhibition results in decreased tumor size. While these studies have identified a novel HSC-derived CAF population, the mechanisms by which these cells promote tumorigenesis are unknown. Previous studies have indicated a critical role for Fli1, an Ets family transcription factor, in regulation of HSCs and differentiation/maturation of hematopoietic lineages. Additionally, loss of Fli1 has been associated with cancer progression. Based on these findings, we hypothesize that HSC-derived CFPs/CAFs directly affect tumor cell migration and invasion and that loss of Fli1 in CFPs/CAFs enhances these effects. To address this hypothesis, we examined the ability of HSC-derived fibroblast populations to affect tumor cell migration and invasion in vitro. Fibroblasts were established from peripheral blood and bone marrow of normal mice and mutant Fli1 mice expressing a truncated Fli1 protein (Fli1ΔCTA) lacking the carboxy-terminal regulatory (CTA) domain. The effects of conditioned media from these fibroblast populations on tumor cell migration and invasion were examined in chemotactic transwell migration assays and matrigel-based invasion assays, respectively. Data show that conditioned media from all HSC-derived fibroblast populations promoted migration and invasion of tumor cells versus control, and that this effect was significantly enhanced using conditioned media from fibroblasts derived from Fli1ΔCTA/Fli1ΔCTA mice. Ongoing studies are directed at identifying the mechanisms by which Fli1 target genes affect HSC-derived fibroblast modulation of tumor cell migration and invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 470. doi:10.1158/1538-7445.AM2011-470
Abstract 4708: Preclinical development of an anti-miR-21 compound for hepatocellular carcinoma
Authors: Marcusson Eric G. , Balakrishnan Asha , Chang Aaron N. , Bhat Balkrishen , Goga Andrei 
Published: June 2012

Abstract
micro-RNA-21 is frequently over-expressed and has been shown to correlate with poor outcome in multiple cancer types. Its genomic locus is amplified in some cancer types and miR-21 is also transactivated by several known cancer drivers (e.g. STAT3 and Ras). We have used a publically available data set from 86 patients to show that miR-21 is over-expressed in hepatocellular carcinoma (HCC). The treatment options for HCC are limited, thus making it the third leading cause of cancer related deaths worldwide. Additional treatments for HCC are greatly needed.
We investigated the therapeutic potential of inhibiting miR-21 with chemically modified oligonucleotides known as anti-miRs using models of HCC, including a genetically engineered mouse model of HCC driven by an inducible, activated form of Ras. Short term treatment with the anti-miR led to a reduction in tumor formation. Furthermore, inhibition of miR-21 was clearly demonstrated by analysis of genome wide mRNA expression data from treated versus untreated tumors. This data showed that genes containing the mir-21 octamer sequence were the most significantly over-enriched among up-regulated genes compared to all of the other 65,535 possible octamers. We also determined the effect of long-term anti-miR-21 treatment on the survival in this mouse model of HCC. anti-miR-21 treated mice demonstrated a highly significant survival advantage (p&lt;0.0001) over saline and control anti-miR treated mice. Our findings suggest that miR-21 is a promising candidate for the therapeutic intervention of liver cancer and further highlights the potential of anti-miR-mediated inhibition of microRNAs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4708. doi:10.1158/1538-7445.AM2011-4708
Abstract 4731: Population specific microRNA expression and biological implications
Authors: Huang R. Stephanie , Gamazon Eric R. , Ziliak Dana , Zhang Wei , Im Hae Kyung , Wing Claudia , Duan Shiwei , Bleibel Wasim K. , Cox Nancy J. , Dolan M. Eileen 
Published: June 2012

Abstract
Population differences are commonly observed for many complex traits including response to chemotherapy. These differences may be attributed to the combined effect of socioeconomic, environmental, genetic and epigenetic factors. Indeed, genome-wide genetic and gene expression differences have been reported among different ethnic populations. Furthermore, we have previously reported population differences in cellular sensitivity to carboplatin, daunorubicin and ara-C and have established that both genetic variants and gene expression contribute to these observed population differences. Here we set out to evaluate to what extent population differences may be explained by an epigenetic factor, namely microRNA (miRNA) expression. We characterized genome-wide miRNA expression in unrelated 54 CEU (Utah residents with northern and western European ancestry) and 55 YRI (African from Ibadan, Nigeria) HapMap lymphoblastoid cell lines (LCLs) using the Exiqon miRCURYTM LNA arrays and evaluated baseline mRNA expression using Affymetrix GeneChip® Human Exon 1.0 ST array. Forty-one miRNA expression traits were found to differ significantly between these 2 ethnic groups (pBonferroni corrected&lt;0.05). The potential biological function of these observed differentially expressed miRNAs was explored by examining their relationship with mRNA expression and cellular sensitivity to carboplatin, daunorubicin and cytaribin. After multiple testing adjustment (false discovery rate (FDR)&lt;0.1), we identified 25 and 32 of the 41 differentially expressed miRNAs that were significantly correlated with 530 and 729 mRNA expression levels in the CEU and YRI samples, respectively. Among them, six differentially expressed miRNAs showed significant levels of correlation with 6 differentially expressed mRNAs (FDR&lt;0.1). A substantial proportion (63%) of these miRNAs correlated with cellular sensitivity to chemotherapeutic agents (FDR&lt;0.05). Lastly, upon performing a genome-wide association study between SNPs and miRNA expression, we identified a large number of SNPs showing high levels of population differentiation that affected the expression of these differentially expressed miRNAs, suggesting the role of genetic variants in mediating the observed population differences. In conclusion, the differentially expressed miRNAs we catalog in this study may explain observed population differences in mRNA expression and cellular sensitivity to chemotherapeutic drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4731. doi:10.1158/1538-7445.AM2011-4731
Abstract 4734: Modeling acquired resistance to MAPK pathway inhibitors in KRAS mutant tumors
Authors: Liu Bonnie , O'Brien Carol , Song Kyung , Spoerke Jill , Moffat John , Seshagiri Somasekar , Friedman Lori S. , Belvin Marcia , Lackner Mark , Hatzivassiliou Georgia 
Published: June 2012

Abstract
Background: Acquired resistance to antitumor therapies underlies one of the challenges in effectively treating cancer. Understanding the mechanisms of acquired drug resistance may lead to elucidation of redundant oncogenic pathways and the development of more effective therapies. The RAS/RAF/MEK pathway is active in over 30% of human tumors, often due to mutation in BRAF or RAS family members. Several MEK inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in various stages of clinical development. These inhibitors are allosteric and act by binding to a hydrophobic pocket adjacent to the ATP binding pocket to inhibit MEK kinase activity. Preclinical studies using randomly mutagenized MEK cDNAs have identified mutations in MEK that upon transfection in MEK sensitive lines can render them resistant to MEK inhibitors. The strongest effects were observed with mutations affecting the allosteric binding pocket, thus blocking inhibitor binding. Results: To model acquired resistance to MEK inhibitors 3 independent KRAS mutant tumor cell lines (breast MDA-MB-231, colon HCT116 and LoVo) were grown in the presence of increasing concentrations of the selective MEK inhibitor PD0325901 and pools of MEK resistant cells were characterized versus parental cells. MEK resistant cells were still dependent on the MAPK pathway and sensitive to treatment with inhibitors against the downstream kinase ERK. In all three lines, MEK resistance was associated with acquisition of mutations in the MEK allosteric binding pocket, resulting in lack of signaling inhibition and suggesting that such resistance can arise relatively rapidly and in distinct tumor types. To compare mechanisms of acquired resistance to ERK inhibitors, we also generated HCT116 cells resistant to a selective ERK inhibitor. ERK resistant lines remained sensitive to MEK inhibitors and dependent on the MAPK pathway. Conclusions: Acquired resistance to MEK inhibitors in KRAS mutant cells arises through mutations in MEK that block inhibitor binding so that the inhibitor is no longer effective. In this case, tumors remain dependent on the MAPK pathway and can be targeted by inhibitors that act downstream of mutated target. These studies provide the rationale for future screening of patients with acquired MEK inhibitor resistance for mutations in MEK1 and MEK2. Patients whose resistance is driven through MEK mutations may benefit from treatment with an ERK inhibitor. Combination of MEK and ERK inhibitors may potentially prevent or delay the onset of resistance in MAPK-addicted tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4734. doi:10.1158/1538-7445.AM2011-4734
Abstract 474: Tumor CD57+ immune cell infiltration is a strong independent prognostic factor in stage II-III colorectal cancer
Authors: Boige Valerie , Locher Clara , Svreck Magali , Auperin Anne , Chaput Nathalie 
Published: June 2012

Abstract
Background: CD3+ CD45RO+ tumor infiltrating lymphocytes (TIL) density within colorectal cancer (CRC) has been shown to be a better predictor of outcome than UICC TNM. Conversely, Laghi and coll. showed that CD3+ TIL density was not a prognostic factor in stage III CRC. The aim of our study was to evaluate the prognostic role of immune infiltrating tumor cells in stage II and III CRC patients using a tissue microarray (TMA) analysis.
Methods: A tissu-array was constructed using 202 stage II and III resected CRC (154 CC, 48 rectal cancers) and their matched non tumor tissue (NT). Tumors exhibiting deficient mismatch repair phenotype have been excluded. On the basis of previous data on the prognostic role of immune response in CRC, the following stainings were quantified in tumor (TT) and NT: CD3, CD68, CD57, CD8 and CD4 in order to quantify macrophage, lymphocyte cell infiltration as effectors of IFN-γ production, CXCL9/MIG, PPAR γ, CXCL10/IP-10, INDO, CXCL13/BCA-1. For prognostic analysis, immunohistochemistry (IHC) data was dichotomized at the median value.
Results: All proteins (except CXCL10/IP-10, INDO for which no reliable IHC data could be obtained) were significantly underexpressed in TT as compared to NT (p&lt;0.0001, paired t-test). CD57 expression was significantly correlated with both CD3 and CD8 expression in TT (Spearman rank correlation coefficients equal to 0.41 (p&lt;0.001) and 0.22 (p=0.002) respectively). After the exclusion of patients who received preoperative irradiation for rectal cancer (n=38), and after adjustment for tumor stage, adjuvant chemotherapy and tumor site in Cox models, CD3 and CD57 tumor staining were associated to recurrence-free survival (RFS) (HR=0.48 and 0.33 and p-value=0.02 and 0.003 respectively) whereas none of the NT staining was found to be prognostic. When CD3 and CD57 tumor staining were included together in the Cox model, only CD57 remained significantly associated with RFS (HR=0.37, p=0.015), especially in stage III CRC but without statistically significant interaction between stage and CD57.
Conclusion: Tumor CD57+ immune cell infiltration is associated with prolonged recurrence-free survival in stage II and III colorectal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 474. doi:10.1158/1538-7445.AM2011-474