bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2821: Dual-label microdosing approach to identify chemoresistance to carboplatin and gemcitabine combination chemotherapy
Authors: Zimmermann Maike , Scharadin Tiffany M. , Zhang Hongyong , Lin Tzu-yin , White Ralph W. deVere , Pan Chong-xian , Henderson Paul T. 
Published: May 2015

Abstract
Gemcitabine is commonly given in combination with cisplatin or carboplatin (GC therapy) as the first-line chemotherapy regimen for several malignancies, including bladder cancer. Unfortunately, less than half of patients respond to the therapy, generating a critical need for a test that predicts tumor response to GC therapy. The goal of this project is to measure drug-DNA adducts after administration of a single non-toxic microdose of gemcitabine in combination with carboplatin and correlating the degree of modification to chemotherapy sensitivity.
We have previously shown that resistance to carboplatin may be identified by using a [14C]carboplatin microdose (1% of therapeutic dose), and subsequent measurement of the [14C]-DNA adducts via accelerator mass spectrometry (AMS), an ultrasensitive method used for detecting rare isotopes. We postulate that adduct levels induced in tumors by GC microdoses are proportional to those formed during full dose chemotherapy. Furthermore, we hypothesize that there exists a threshold level of adducts above which tumors respond to GC therapy.
We used bladder cancer cell lines and the nod scid gamma severe combined immunodeficient (NSG) mice containing patient-derived tumor xenografts (PDX) from bladder cancer patients to determine GC-DNA adduct levels using AMS. The NSG mouse is uniquely capable of accepting and propagating tumor tissue engrafted directly from patient biopsy samples. The resulting groups of mice each have identical tumors, but can be treated in a variety of ways with replicate experiments; characteristics that are impossible to achieve in normal clinical studies. We will report progress on developing protocols and preliminary GC microdosing data using the NSG-PDX mouse model of human bladder cancer.
Citation Format: Maike Zimmermann, Tiffany M. Scharadin, Hongyong Zhang, Tzu-yin Lin, Ralph W. deVere White, Chong-xian Pan, Paul T. Henderson. Dual-label microdosing approach to identify chemoresistance to carboplatin and gemcitabine combination chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2821. doi:10.1158/1538-7445.AM2014-2821
Abstract 2823: Low merlin level as a biomarker for sensitivity of ovarian cancer cell lines to FAK inhibition
Authors: Shah Nina R. , Tancioni Isabelle , Ward Kristy K. , Lawson Christine , Chen Xiao Lei , Miller Nichol L.G. , Sulzmaier Florian J. , Uryu Sean , Schlaepfer David D. 
Published: May 2015

Abstract
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that undergoes gene amplification in &gt;20% of serous ovarian cancers. In addition to increased tumor growth and spread, ovarian cancer patients with FAK amplification have a poorer prognosis with decreased overall survival. Merlin, a product of the NF2 tumor suppressor gene, is being evaluated as a biomarker for sensitivity to FAK inhibition in human clinical trials for malignant mesothelioma. As it remains undetermined whether linkages exist between merlin and FAK in other tumor types, we evaluated nine human and two murine ovarian cancer cell lines with sub-micromolar levels of FAK inhibitor (PF-271) for effects on anchorage-independent cell growth. Cells were identified as sensitive (OVCAR3, OVCAR8, HEY, ID8-IP), intermediate (A2780, IGROV1), or resistant (OVCAR10, IGROV1-IP, SKOV3, SKOV3-IP, 5009) to FAK inhibition. Notably, merlin protein levels were high in all resistant cell lines, moderate in intermediate cell lines, and low or undetectable in sensitive cell lines. Oral FAK inhibitor administration reduced orthotopic tumor growth of sensitive (ID8-IP, low merlin) but not resistant (5009, high merlin) murine ovarian carcinoma cells. However, stable knockdown of merlin expression in resistant SKOV3-IP and OVCAR10 human ovarian carcinoma cells did not induce sensitivity to FAK inhibition in vitro. These results support the notion that high merlin expression is correlated with a FAK-inhibitor resistant phenotype, likely through an indirect mechanistic linkage. Nevertheless, merlin protein levels may serve as a biomarker to predict ovarian cancer sensitivity or resistance to FAK inhibitor treatment.
Supported by NIH CA102310
Citation Format: Nina R. Shah, Isabelle Tancioni, Kristy K. Ward, Christine Lawson, Xiao Lei Chen, Nichol L.G. Miller, Florian J. Sulzmaier, Sean Uryu, David D. Schlaepfer. Low merlin level as a biomarker for sensitivity of ovarian cancer cell lines to FAK inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2823. doi:10.1158/1538-7445.AM2014-2823
Abstract 2830: Predictive biomarker identification for response to vantictumab (OMP-18R5; anti-Frizzled) by mining gene expression data of human breast cancer xenografts
Authors: Zhang Chun , Yeung Pete , Beviglia Lucia , Cancilla Belinda , Tang Tracy , Yen Wan-Ching , Gurney Austin , Lewicki John , Hoey Timothy , Kapoun Ann M. 
Published: May 2015

Abstract
The Wnt/β-catenin signaling pathway has been shown to play key roles in both normal development and tumorigenesis (Polakis, 2007; MacDonald et al., 2009).
We have developed a monoclonal antibody, vantictumab, that blocks canonical WNT/β-catenin signaling through binding of five Fzd receptors (1, 2, 5, 7, 8) at a conserved epitope within the extracellular domain. This antibody inhibits the growth of several tumor types, including breast, pancreas, colon and lung. Furthermore, studies also showed that vantictumab reduces tumor-initiating cell frequency and exhibits synergistic activity with standard-of-care chemotherapeutic agents (Gurney et al., 2012).
Predictive biomarkers are central to maximizing clinical benefit by targeting breast cancer patients most likely to respond to vantictumab. We analyzed microarray gene expression data from 8 minimally passaged breast cancer xenograft models (mostly triple-negative) with established in vivo responses to vantictumab combined with paclitaxel (4 responders, 4 non-responders). We utilized support vector machine—recursive feature elimination (SVM-RFE, Guyon et al., 2002) to identify genes that can distinguish between responder and non-responders and SVM for classification. Leave-one-out cross-validation was used to measure positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity of the models. The selected 6-gene signature achieved the best performance with PPV=NPV=sensitivity=specificity=100% in the 8 breast cancer models. In addition, we observed a strong correlation between the gene signature biomarker and the ratio of tumor volume (RTV) observed in the breast xenograft experiments.
The identified 6-gene biomarker was used to predict the response to vantictumab in combination with paclitaxel in 6 additional, HER2-negative breast cancer xenograft models. The efficacy in all 6 models was predicted successfully by the biomarker. Prevalence data for the biomarker will be presented for both HER2-negative and triple-negative breast cancers. The 6-gene biomarker is currently being evaluated in a Phase 1b study of vantictumab in combination with paclitaxel in patients with locally recurrent or metastatic HER2-negative breast cancer.
Citation Format: Chun Zhang, Pete Yeung, Lucia Beviglia, Belinda Cancilla, Tracy Tang, Wan-Ching Yen, Austin Gurney, John Lewicki, Timothy Hoey, Ann M. Kapoun. Predictive biomarker identification for response to vantictumab (OMP-18R5; anti-Frizzled) by mining gene expression data of human breast cancer xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2830. doi:10.1158/1538-7445.AM2014-2830
Abstract 2832: Single nucleotide polymorphisms of DPYD and MTHFR predict adverse events associated with 5-fluorouracil in patients with gastrointestinal cancer
Authors: Toshima Masahide , Ohnuma Shinobu , Tanaka Michiiro , Miura Koh , Fujibuchi Wataru , Kajiwara Taiki , Komura Toshihiro , Musha Hiroaki , Haneda Sho , Kudoh Katsuyoshi , Kohyama Atsushi , Naitoh Takeshi , Unno Michiaki 
Published: May 2015

Abstract
Purpose
The aim of this study was to investigate the association between 5-fluorouracil (5-FU)-related adverse events (AEs) in Japanese patients with gastrointestinal cancer treated with 5-FU and the patient genotypes DPYD, MTHFR, OPRT, and TYMS.
Methods
Sequence analyses of 33 gene polymorphisms in four genes were performed using genomic DNA extracted from peripheral blood mononuclear cells of 103 patients with gastric (n = 34) or colorectal (n = 69) cancer. The 5-FU-related AEs of 157 regimens in these 103 patients were evaluated based on the medical records of patients in each of three groups: the intravenous administration group (i.v. group, n = 51), oral administration group (p.o. group, n = 106), and all-regimens group (both i.v. and p.o. group, n = 157). The associations between the incidence of AEs and each genotype were statistically analyzed.
Results
Six single-nucleotide polymorphisms (SNPs) were identified (three SNPs in DPYD: c.496A&gt;G, c.1905+1G&gt;A, and c.2303C&gt;A; two SNPs in MTHFR: c.677C&gt;T and c.1298A&gt;C; and one SNP in OPRT: c.638G&gt;C). Among them, the patients in the all-regimens group carrying any one of three DPYD SNPs showed statistically significant associations with the incidence of AEs of any type and fatigue. Furthermore, the MTHFR SNP c.1298A&gt;C was significantly associated with the incidence of neutropenia. A similar trend was observed in the p.o. group, but not in the i.v. group.
Conclusion
These findings suggest that the DPYD SNPs c.496A&gt;G, c.1905+1G&gt;A, and c.2303C&gt;A and the MTHFR SNP c.1298A&gt;C may be predictive factors for the occurrence of severe 5-FU-related AEs.
Citation Format: Masahide Toshima, Shinobu Ohnuma, Michiiro Tanaka, Koh Miura, Wataru Fujibuchi, Taiki Kajiwara, Toshihiro Komura, Hiroaki Musha, Sho Haneda, Katsuyoshi Kudoh, Atsushi Kohyama, Takeshi Naitoh, Michiaki Unno. Single nucleotide polymorphisms of DPYD and MTHFR predict adverse events associated with 5-fluorouracil in patients with gastrointestinal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2832. doi:10.1158/1538-7445.AM2014-2832
Abstract 2833: Mutation analysis of cancer drivers and DNA repair genes in chemosensitive versus resistant ovarian cancers
Authors: Birkeland Einar , Blaalid Rakel , Bjørnslett Merete , Dørum Anne , Lønning Per Eystein , Knappskog Stian 
Published: May 2015

Abstract
Background: The mechanisms underlying resistance to chemotherapy in ovarian cancer are incompletely understood. Identifying genetic alterations associated with treatment response is decisive in the determination of which patients may benefit from adjuvant chemotherapy.
Methods: Biopsies were collected from twenty patients diagnosed with ovarian cancer who were subjected to post-operative taxane- and platinum-containing chemotherapy. Patients were selected for genetic analyses based on response to chemotherapy, determined as time to relapse (10 sensitive and 10 resistant patients). A panel of 620 genes, including known cancer driver genes, as well as genes involved in DNA repair were analysed by massively parallel sequencing. Alignment and mutation calling was performed using MiSeq Reporter, with further manual filtering of variants to exclude common SNPs. Validation of low quality mutation calls was done by Sanger sequencing.
Results: A median of 6 genes (range: 3 - 45) per patient was found to harbour non-synonymous mutations. Among previously identified driver genes in ovarian cancer, we found mutations in TP53, BRCA1, CDK12, NF1 and CSMD3. These mutations were more common among patients with more advanced disease and higher grade. For example, TP53 mutations were found in 10 out of 12 patients with high grade, stage 3c or 4 disease, and in 2 out of 5 with lower stage and/or grade. One patient was found to have a tumor potentially of a hyper-mutator phenotype with 49 mutations in 45 genes identified within our gene panel. With respect to treatment efficacy, 73 and 40 genes were found to be mutated exclusively in patients with a good and poor response to treatment, respectively.
Conclusion: We describe the profile of mutations in cancer driver genes and DNA repair genes among patients suffering from ovarian cancer according to treatment response.
Citation Format: Einar Birkeland, Rakel Blaalid, Merete Bjørnslett, Anne Dørum, Per Eystein Lønning, Stian Knappskog. Mutation analysis of cancer drivers and DNA repair genes in chemosensitive versus resistant ovarian cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2833. doi:10.1158/1538-7445.AM2014-2833
Abstract 284: Epigenome-wide study of sister study samples replicates and extends cpg sites associated with cigarette smoking
Authors: Harlid Sara Sophia , Xu Zongli , Panduri Vijayalakshmi , Sandler Dale P. , Taylor Jack A. 
Published: May 2015

Abstract
Smoking increases the risk of many diseases -including cancer, and is also linked to blood DNA methylation changes that may be important in disease etiology. The objective of the current study was to identify and confirm potentially novel CpG sites associated with cigarette smoking. To do this we used two epigenome-wide datasets from the Sister Study. One included 908 women with methylation measurements at 27,578 CpG sites using the Illumina HumanMethylation27 BeadChip; the other included 200 women with methylation measurements for 473,844 CpG sites using the Illumina HumanMethylation450 BeadChip. Significant CpGs from the second dataset that were not included in the 27k assay were validated by pyrosequencing in a subset of 476 samples from the first dataset. We were able to successfully confirm smoking associations for nine previously established CpGs and identify two potentially novel CpGs: cg26764244 in GNG12 (p= 9.0×10-10) and cg22335340 in PTPN6 (p=2.9×10-05).In addition to this we provide the first independent confirmation of the association between smoking status and cg02657160 in CPOX (p=7.28x10-7). All 12 CpGs were under-methylated in current smokers and showed increasing percent methylation in former and never smokers. The CPOX CpG proved to be of particular interest as the corresponding enzyme is involved in heme biosynthesis and smoking is known to increase heme production. Our study extends the evidence base for smoking-related changes in DNA methylation.
Citation Format: Sara Sophia Harlid, Zongli Xu, Vijayalakshmi Panduri, Dale P. Sandler, Jack A. Taylor. Epigenome-wide study of sister study samples replicates and extends cpg sites associated with cigarette smoking. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 284. doi:10.1158/1538-7445.AM2014-284
Abstract 2862: Overexpression of nuclear karyopherin alpha2 correlates with poor prognosis in patients with colorectal cancer
Authors: Baek Moo Jun , Jeong Dongjun , Kim Tae Hyun , Kim Chang-Jin , Lee Sang Han , Kim Han J. , Bae Sang Byeong , Ahn Tae Sung 
Published: May 2015

Abstract
Objectives: Karyopherin alpha 2 (KPNA2) is a member of the karyopherin family that moves protein molecules into the nucleus by binding to a specific recognition sequence. It has recently been reported to play an important role in carcinogenesis and cancer progression. The aim of the present study was to elucidate the clinicopathological significance of overexpression of nuclear KPNA2 expression in colorectal cancers.
Methods: KPNA2 expression was investigated by immunohistochemistry on tissue microarrays of 363 cases of colorectal cancer and the association of KPNA2 expression was examined with clinicopathologic features.
Results: Thirty percent (30%) of colorectal cancers demonstrated overexpression of KPNA2. The overexpression of KPNA2 was significantly associated with high pN stages (p=0.005), vascular invasions (p&lt;0.001) and lymphatic invasions (p&lt;0.001). Multivariate Cox regression analysis showed that the overexpression of PKNA2 in pN stage 1, 2 was an independent prognostic factor of decreased survival [HR=2.13 (95% CI: 1.32-3.45, p=0.002)]. The overall survival was significantly decreased in patients of KPNA2 high expression [HR=2.70 (95% CI: 1.74-4.20, p&lt;0.001)]. The cumulative survival was significantly decreased in patients of KPNA2 high expression compared to those of KPNA2 low expression by Kaplan-Meier analysis (log rank test, p&lt;0.001).
Conclusion: The overexpression of KPNA2 can be a valuable poor prognostic marker of colorectal cancer and the KPNA2 can be used in therapeutic strategies.
Citation Format: Moo Jun Baek, Dongjun Jeong, Tae Hyun Kim, Chang-Jin Kim, Sang Han Lee, Han Jo Kim, Sang Byeong Bae, Tae Sung Ahn. Overexpression of nuclear karyopherin alpha2 correlates with poor prognosis in patients with colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2862. doi:10.1158/1538-7445.AM2014-2862
Abstract 2873: A molecular signature predictive of indolent prostate cancer
Authors: Irshad Shazia , Bansal Mukesh , Magnen Clementine L. , Dillon Risham , Castillo-Martin Mireia , Zheng Tian , Aytes Alvaro , Wenske Sven , Guarnieri Paolo , Sumazin Pavel , Benson Mitchell , Shen Michael M. , Califano Andrea , Abate-Shen Cory 
Published: May 2015

Abstract
With more than 230,000 estimated new cases in 2013, prostate cancer represents the most commonly diagnosed cancer in American men. While a subgroup of patients will develop an aggressive and lethal prostate cancer, most present with a low-risk form of the disease that requires little or no treatment. It is therefore crucial to distinguish patients whose tumors are likely to progress to aggressive disease from those whose tumors will remain indolent and for whom treatment may be more detrimental than beneficial.
In our recent study, we hypothesized that low Gleason score prostate tumors can be distinguished as indolent and aggressive based on expression of genes associated with aging and senescence (1). Using gene set enrichment analyses and a decision tree learning model, we identified a 3-gene panel_FGFR1, PMP22, and CDKN1A_that is enriched in indolent prostate cancers and accurately predicts outcome of low Gleason score tumors at both the RNA and protein levels. In particular, protein expression of this 3-gene panel in biopsy samples correctly distinguished Gleason 6 patients who failed active surveillance over a 10-year period.
Following from our initial study, our current efforts are focused on exploiting this 3-gene panel to develop a robust clinical assay for distinguishing indolent and aggressive tumors. We are currently using qRT-PCR, immunofluorescence, and immunohistochemistry assays to assess the most effective way to quantify the simultaneous expression of the 3-gene panel in low Gleason score tumor biopsies/tissues. This quantitative assay will ultimately be applied to a large cohort study assessing the predictive power of the 3-gene signature in patients under active surveillance. We envision that such a prognostic test will significantly improve our ability to predict the outcome of patients with low Gleason score tumors and facilitate appropriate decisions of treatment for men under active surveillance.
1. Irshad S, et al. (2013) A molecular signature predictive of indolent prostate cancer. Science translational medicine 5(202):202ra122.
Citation Format: Shazia Irshad, Mukesh Bansal, Clementine Le Magnen, Risham Dillon, Mireia Castillo-Martin, Tian Zheng, Alvaro Aytes, Sven Wenske, Paolo Guarnieri, Pavel Sumazin, Mitchell Benson, Michael M. Shen, Andrea Califano, Cory Abate-Shen. A molecular signature predictive of indolent prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2873. doi:10.1158/1538-7445.AM2014-2873
Abstract 2876: Genetic polymorphism in the mir-196a as a prognostic biomarker for early breast cancer
Authors: Lee Soo Jung , Chae Yee Soo , Kang Byung Woog , Kim Jong Gwang , Park Ji-Young , Jung Jin Hyang , Park Ho Yong 
Published: May 2015

Abstract
Background: MicroRNAs (miRNA) may play important roles in tumorigenesis by regulating the expressions of proto-oncogenes or tumor suppressor genes. Single nucleotide polymorphisms (SNP) in miRNA-coding genes and miRNA binding site genes might affect miRNA-mediated gene regulation, thereby contributing to the susceptibility or prognosis of cancer. Accordingly, the present study analyzed SNPs located in miRNA and miRNA-binding sites of various genes and their impact on the prognosis for patients with early breast cancer (EBC) by altering miRNA binding efficiency. Methods: Four hundred and fifty-two consecutive patients with curative resection were enrolled in the present study. Three SNPs (rs11614913, rs3746444 and rs1044129 of miR-196a, miR-499a and miR-367, respectively) were selected in Silico analysis for the current study based on several miRNA database and HapMap database. The SNP genotyping was performed using the Sequenom MassARRAY. Results: The median age of all patients was 48 years, and 298 (66.7%) had ER/PR-positive EBC, 64 (14.3%) had HER2-overexpressed EBC, and 79 (17.7%) had triple-negative EBC. The pathologic stages after the surgical resection were as follows: stage I (n=174, 38.5%), stage IIA (n=168, 37.2%), stage IIB (n=54, 11.9%), and stage IIIA (n=56, 12.4%). During the median follow-up of 6.9 (range 0.37 -19.93) years, 67 (14.8%) relapses and 47 (10.4%) deaths occurred. Among the 3 polymorphisms miR-196a rs11614913T&gt;C was significantly associated with disease-free survival (DFS) and distant DFS (DDFS) when adjusted for age, histologic grade, receptor status, and pathologic stage. In particular, the prognostic impact of rs11614913 was limited to the HR- expressed subtype, where the patients bearing the CC genotype showed worse survival in terms of DFS and DDFS compared with those with the TT or TC genotype as a recessive model (HR= 2.571 and P-value=0.031, HR= 4.263 and P-value=0.001, respectively). Meanwhile, there were no statistical differences in patient and tumor characteristics among each genotype of rs11614913. Conclusions: The current study provides evidence that the miR-196a rs11614913T&gt;C polymorphism is a possible prognostic biomarker for patients with HR-expressed early breast cancer.
Citation Format: Soo Jung Lee, Yee Soo Chae, Byung Woog Kang, Jong Gwang Kim, Ji-Young Park, Jin Hyang Jung, Ho Yong Park. Genetic polymorphism in the mir-196a as a prognostic biomarker for early breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2876. doi:10.1158/1538-7445.AM2014-2876