bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 82: Genomic profiling of PDX models across 14 tumor types reveals novel targeted therapeutic opportunities
Authors: Dong Hua , Zhang Zhixiang , Zhang Baoyuan , Tang Xuzhen , Qiang Xiangnan , Qin Yuxin , Yang Shuqun , Yan Yunbiao , Zhang Norman , Gu Qingyang , Ji Qunsheng 
Published: July 2016

Abstract
Introduction: Large efforts have been made to detect somatic alterations and corresponding transcriptome changes in cancer patients, which are expected to bring about significant improvements in precision cancer medicine. Here we report a comprehensive list of driver genes and new targets identified in a large pan-cancer cohort of 550 Patient Derived Xenograft (PDX) models across 14 tumor types.
Material and methods: For each PDX model with passages 2-4, we performed comprehensive genomic analyses, including whole exome sequencing (WES), SNP6.0 array, and RNASeq (or microarray). The genomic data were used for extrapolating genomic SNV, CNV, mRNA expression levels, and for identifying gene fusions. Genomic profiling data were generated in internal and analyzed by in-house validated pipelines.
Results: 220 PDXs were identified to have actionable driver gene mutations /and/or amplifications among 550 models. We identified novel genomic alterations in a number of the PDX models. Significant portion of the models were validated with targeted therapeutic agents (TKI, Abs etc.) and certain cytotoxic agents. All processed data could be accessed via OncoWuXi database: http://onco.wuxiapptec.com and corresponding OncoWuXi APP (App store or onco.wuxiapptec.com/oncowuxi.apk
Conclusions:
We have established a large panel of PDX models with comprehensive genomic annotation and identified novel targets, with open access database and App. These models could serve as a platform for Mouse Clinical Trial and for pre-clinical development of next generation targeted therapeutic drugs.
Citation Format: Hua Dong, Zhixiang Zhang, Baoyuan Zhang, Xuzhen Tang, Xiangnan Qiang, Yuxin Qin, Shuqun Yang, Yunbiao Yan, Norman Zhang, Qingyang Gu, Qunsheng Ji. Genomic profiling of PDX models across 14 tumor types reveals novel targeted therapeutic opportunities. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 82.
Abstract 820: Molecular epidemiological studies of germinal center-associated nuclear protein (ganp) in the development of human sporadic breast cancers
Authors: Kuwahara Kazuhiko , Ito Hidemi , Kuzushima Kiyotaka , Iwata Hiroji , Tanaka Hideo , Matsuo Keitaro 
Published: July 2016

Abstract
[Introduction]
The altered expression of germinal center-associated nuclear protein (GANP), a member of mammalian TREX2 complex, has been observed in various tumors. Previously, we demonstrated that deficiency of GANP developed mammary gland tumors resembling human breast cancers in two mouse models. In addition, we showed that decreased expression of GANP was an independent prognostic factor of human breast cancer in a retrospective cohort study. These results suggested that GANP might be associated with breast cancer development. Although a little is know about functional significance of ganp polymorphisms, we explored possible association.
[Methods]
We conducted a case-control study to examine association between ganp polymorphisms and risk of breast cancer among Japanese population within the framework of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). Cases are 694 incident cases who had been diagnosed as breast cancer at Aichi Cancer Center Hospital (ACCH) during 2001-2005. A total of 1,376 non-cancer controls were patients who visited ACCH at same period as cases and were confirmed to have no evidence of cancer. Controls were individually matched for age and menopausal status with cases. ganp polymorphisms were assessed by iCOGS chip (Reference: Michailidou K et al. Nat. Genet. 2013;45:353-361). Multivariable conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each locus.
[Results]
Ten out of 13 polymorphisms, in high linkage disequilibrium, showed statistically significant associations with breast cancer risk. For instance, in rs2839186, the OR for those with AA alleles compared with those with GG alleles is 0.41 (95% CI, 0.23-0.72, p = 0.002) in genotype model. As compared with those with G allele, the OR for those without was 0.40 (95% CI, 0.23-0.71, p = 0.002) in recessive model. On the other hand, in dominant model, the OR for those with A allele was 0.95 (95% CI, 0.78-1.16, p = 0.635) in comparison to those without that.
[Conclusion]
In this study, we clearly show that mutant SNPs in rs2839186 decrease breast cancer risk. We are currently analyzing if the ganp SNPs affect the prognosis of breast cancer patients.
Citation Format: Kazuhiko Kuwahara, Hidemi Ito, Kiyotaka Kuzushima, Hiroji Iwata, Hideo Tanaka, Keitaro Matsuo. Molecular epidemiological studies of germinal center-associated nuclear protein (ganp) in the development of human sporadic breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 820.
Abstract 825: Myc-nick promotes efferocytosis through M2 macrophage polarization
Authors: Zhong Xiancai , Lee Ha-Na , Surh Young-Joon 
Published: July 2016

Abstract
Resolution of inflammation is an active process which is important for maintaining or restoring homeostasis in response to inflammatory insult. Failure in resolution results in persistent and chronic inflammation which increases the risk of cancer development. Efferocytosis, an essential part of resolution of inflammation, is defined as phagocytic removal of apoptotic cells, especially neutrophils, at the inflamed site, thereby preventing exposure of tissue to toxic intracellular components. It is carried out by a distinct group of phagocytes including anti-inflammatory macrophages (M2 type). Therefore, M2 macrophages represent a key component of the cellular proresolving mechanism and a potential factor for prevention of inflammation-associated cancer. Dysregulation, often overexpression, of c-Myc drives dedifferentiation of cancer cells to acquire capacity for self-renewal and metastasis, which accounts for poor prognosis in cancer patients. A cytoplasmic N-terminal part of full length c-Myc, termed Myc-nick, has been reported to promote differentiation of myoblasts. In the present study, we investigated whether Myc-nick is involved in M2 macrophage polarization and promotion of efferocytosis. We found that ectopic expression of Myc-nick in mouse bone marrow derived macrophages (BMDM) promoted the M2 macrophage polarization through upregulation of interleukin 10 (IL-10) and peroxisome proliferator activated receptor gamma (PPARγ). Furthermore, overexpression of exogenous Myc-nick in BMDM increased capture of apoptotic cells by BMDM through upregulation of a class of phosphatidyl serine (PS) receptors including T-cell immunoglobulin and mucin domain containing 4 (Timd4). PS constitutes one of ‘eat-me’ signals carried by apoptotic cells. PS receptors present on the surface of macrophages are important to recognize, engulf and finally clear apoptotic cells via phagocytosis. In addition, Myc-nick-induced efferocytosis was found to be tightly associated with K (lysine) acetyltransferase 2A (Kat2a/Gcn5). This may lead to the acetylation of transcription factors that regulate expression of PS receptor proteins. In conclusion, activation of M2 macrophages by Myc-nick facilitates efferocytosis and hence resolution of inflammation, and this may suppress inflammation-associated cancer progression.
Citation Format: Xiancai Zhong, Ha-Na Lee, Young-Joon Surh. Myc-nick promotes efferocytosis through M2 macrophage polarization. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 825.
Abstract 83: MicroRNAs associated with the p53 tumor suppressor signaling network are differentially expressed in triple negative breast cancer cell lines
Authors: Moses Malcolm M. , Godfrey Sherette S. , Lusk Niageria Q. , Rorie Checo J. 
Published: July 2016

Abstract
“Triple-negative” breast cancer (TNBC) is an aggressive subtype of breast cancer that appears prevalently in African American women below the age of 35, and has no known biomarker that can be targeted for drug therapy. This aggressive breast cancer phenotype is due to its high mitotic index and high metastatic potential, and may be due to the fact that up to 80% of TNBC has a mutation in the p53 tumor suppressor gene. The p53 tumor suppressor gene signaling pathway can be mediated by microRNAs (miRNAs) which are short sequences of RNA (∼22nt) that target protein coding mRNA and mark them for degradation. Characterization of the miRNA profiles in TNBC cells compared to normal breast cell lines may provide potential targets in treating TNBC. In this study, microarray analysis was performed on TNBC cell lines HCC1806, HCC70, and MB157 and the normal breast cells AG11132. The expression levels of miRNAs found to play a role in the p53 tumor suppressor gene signaling pathway were compared between the normal and TNBC cell lines. The miRNAs let-7b, let-7a, miR-29a, miR-100, let-7f, miR-34a, miR-15b, miR-21, miR-16, and miR-22 displayed the greatest differences in expression levels between the normal and TNBC cell lines, thereby implicating them as potential biomarkers for TNBC and potential drug treatment targets. These miRNAs can be studied further to determine their role in mediating the p53 tumor suppressor gene signaling pathway in these cells for their potential use in the diagnosis and treatment of TNBC.
Citation Format: Malcolm M. Moses, Sherette S. Godfrey, Niageria Q. Lusk, Checo J. Rorie. MicroRNAs associated with the p53 tumor suppressor signaling network are differentially expressed in triple negative breast cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 83.
Abstract 830: Pin1 is a novel target of withaferin A, a mammary cancer chemopreventative steroidal lactone from Withania somnifera
Authors: Samanta Suman K. , Singh Shivendra V. 
Published: July 2016

Abstract
We have shown previously that naturally occurring steroidal lactone withaferin A (WA) inhibits breast cancer development in a transgenic mouse model. Mammary cancer chemoprevention by WA in vivo was associated with suppression of peptidyl-prolyl isomerase Pin1 protein. Pin1 is known to regulate diverse cellular processes including cell proliferation, cell cycle progression, apoptosis, and migration. Moreover, Pin1 is overexpressed in breast tumor and its expression is positively correlated with tumor grade. Thus, we studied functional significance of Pin1 downregulation by WA. Consistent with in vivo observations, Pin1 protein and mRNA expression was decreased upon WA treatment in human breast cancer cells irrespective of ER, HER-2 or p53 status. Overexpression of Pin1 partly reversed the growth inhibitory effect of WA in both MCF-7 (wild-type p53) and SUM159 (mutant p53) cells. However, WA-induced mitotic arrest and apoptosis were partly abrogated only in MCF-7 cells upon ectopic expression of Pin1 perhaps due to p53 stabilization. Molecular docking suggested covalent binding of WA with Cys113 of Pin1, which was confirmed by mass spectrometry. Overexpression of mutant (C113A) Pin1 augmented WA-mediated inhibition of cell survival as well as mitotic arrest and apoptosis in MCF-7 cells indicating that decreased catalytic activity of Pin1 is essential for growth inhibition by WA in breast cancer cells. Taken together, the present study suggests a critical role for Pin1 in WA-mediated growth inhibition of breast cancer. This study was supported by the grant CA142604 awarded by the National Cancer Institute.
Citation Format: Suman K. Samanta, Shivendra V. Singh. Pin1 is a novel target of withaferin A, a mammary cancer chemopreventative steroidal lactone from Withania somnifera. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 830.
Abstract 837: Reproducibility of efficacy results for chemopreventive agents in the methylnitrosourea-induced rat mammary cancer model
Authors: Steele Vernon E. , Lubet Ronald A. , Grubbs Clinton J. 
Published: July 2016

Abstract
Perhaps the greatest question in biological science is: Can results be reproduced? This problem is of particular concern for a group whose primary mission is to screen for potentially effective agents and rank results by activity. The reproducibility of testing specific agents for chemopreventive activity, testing the same agent in various protocols, and testing multiple agents of a given mechanistic class in the MNU-induced model of ER+ breast cancer in Sprague-Dawley rats is presented. The model employs female virgin Sprague-Dawley rats on a standard 4% Teklad diet which develop ER+ mammary cancers (adenocarcinomas) following MNU injection at 50 days of age (DOA). Preventive agents were given by gavage or diet starting at 55 DOA, and animals monitored for tumor development until approximately 170 DOA. Seven agents which we had previously studied and which were strongly positive [tamoxifen, vorozole (an aromatase inhibitor), Targretin, gefitinib] or strongly negative (naproxen, Lipitor, metformin) were examined in the assays presented. These study results confirmed our previous data. We next tested these same agents in animals given a Western diet (high fat, low calcium) and again obtained the same results. We had thought that the altered physiology and potentially altered pharmacokinetics of rats on a Western diet might alter the observed chemopreventive efficacy. These studies show that the direct repetition of clearly positive and negative agents can be achieved and, in fact, repeated with a significant variation in diet. Importantly, in terms of reproducibility, we find that multiple agents of the same mechanistic class give similar results. Thus, various SERMs (tamoxifen, toremifene, Arzoxifene), RXR agonists (targretin, UAB-30, 4Me-UAB-30), EGFR inhibitors (gefitinib, Erlotinib, lapatinib) are all highly positive (70-95% reduction of cancer multiplicity). In contrast, the negative classes COX inhibitors (naproxen, sulindac, aspirin) or statins (atorvastatin or simvastatin) have been consistently negative (&lt;20% reduction). Therefore, reproducibility of efficacy results appears to be quite solid in our chemoprevention agent development program for rat mammary cancer testing, and we can, with significant certainty, trust our results.
Citation Format: Vernon E. Steele, Ronald A. Lubet, Clinton J. Grubbs. Reproducibility of efficacy results for chemopreventive agents in the methylnitrosourea-induced rat mammary cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 837.
Abstract 844: High-resolution microbiome profiling and meta-analysis yields insight into microbial consortia associated with colorectal cancer
Authors: White James R. , Drewes Julia , Sears Cynthia L. 
Published: July 2016

Abstract
Colorectal cancer (CRC) continues to be the second leading cause of cancer-related deaths globally. While multiple environmental factors are associated with incidence of CRC, multiple studies have reported that CRC is frequently linked with an altered colonic microbiota both in terms of taxonomic composition as well as structural organization. However, differences in study design and analysis methodologies among CRC microbiome profiling studies have generated inconsistent findings. To identify bacterial taxa consistently associated with CRC, we applied a uniform microbiome analysis methodology to sequence datasets followed by meta-analysis.
Raw 16S rRNA amplicon sequence datasets from 12 studies including two new Malaysian cohorts were collected and analyzed using the Resphera Insight high-resolution taxonomic assignment protocol. Taxonomic abundances within each dataset were then assessed for significant enrichment or depletion in colorectal carcinoma samples versus controls. Alpha diversity and differences in predicted functional capacity were assessed utilizing QIIME and PICRUSt, respectively.
Several bacterial species were consistently enriched in colorectal carcinoma samples relative to healthy controls including Fusobacterium nucleatum, Fusobacterium necrophorum, Leptotrichia trevisanii, Bacteroides fragilis, Parvimonas micra, Peptostreptococcus stomatis, and Gemella morbillorum. In contrast to other studies that have generally described Fusobacteria as enriched in CRC relative to controls, we identified multiple fusobacterial members that were often not strongly linked with CRC including Fusobacterium varium and Cetobacterium somerae. Evaluating functional predictions inferred from taxonomic composition, we observed consistent enrichment of specific KEGG categories in CRC including glycosyltransferases and carbohydrate digestion and absorption.
Applying a uniform high-resolution analysis protocol for microbiome profiling enabled detection of specific species that were strongly associated with CRC across multiple studies. These findings demonstrate that higher level analyses (e.g. those at the genus or family level) may be insufficient for detection of indicator taxa in some populations.
Citation Format: James R. White, Julia Drewes, Cynthia L. Sears. High-resolution microbiome profiling and meta-analysis yields insight into microbial consortia associated with colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 844.
Abstract 85: Macrophage inflammatory protein-1β and interleukin 15 modulate gene expression patterns associated with prostate cancer progression
Authors: Rohena-Rivera Krizia , Aponte-Colón Diana A. , Sánchez-Vázquez María M. , Cadilla Carmen L. , Martínez-Ferrer Magaly 
Published: July 2016

Abstract
Prostate Cancer (PCa) is the second-leading cause of cancer-related deaths in the United States. Inflammation is associated with PCa development and progression. Cytokines such as macrophage inflammatory protein-1β (MIP1β or CCL4) and Interleukin 15 (IL-15) are differentially expressed in prostate cancer patients with recurrent disease (MIP1β) or recurrence-free survival (IL-15). However, the specific pathway by which these cytokines affect PCa progression is unknown. We evaluated the changes in gene expression patterns using in vivo models of prostate cancer and microarray analysis. To generate prostate tumors in vivo we used a mouse orthotopic xenograft model. Androgen-receptor-positive (AR+) cells, 22RV1, were orthotopically injected in the anterior prostate lobes. MIP1β and IL-15 were administered bi-weekly with intraperitoneal injections during 4 weeks. Tumor tissue was collected and snap frozen for RNA extraction, and microarray analysis with the Affymetrix Human Gene 2.0 Gene Array. Differences in gene expression were analyzed with Ingenuity Pathway Analysis (IPA) software and confirmation was done via real-time PCR. Microarray analysis showed 179 genes differentially expressed between MIP1β and control. In addition, 952 genes were differentially expressed between IL-15 and control. Ingenuity Pathway Analysis revealed that MIP1β affected networks associated with cell development, proliferation and movement while IL-15 affected networks involved in lymphocyte development and movement, cell death, and the inhibition of cancer cell invasion. Knowledge of the role of MIP1β and IL-15 in the alteration of gene expression patterns is pertinent to elucidate the significance of these cytokines in prostate cancer progression.
Citation Format: Krizia Rohena-Rivera, Diana A. Aponte-Colón, María M. Sánchez-Vázquez, Carmen L. Cadilla, Magaly Martínez-Ferrer. Macrophage inflammatory protein-1β and interleukin 15 modulate gene expression patterns associated with prostate cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 85.
Abstract 857: Diagnostic test system for sensitive, specific and reproducible detection of EML4-ALK RNA fusion transcripts in the blood of patients with NSCLC
Authors: Mellert Hestia , Jackson Leisa , Maar Dianna , Shelton Dawne , Pestano Gary 
Published: July 2016

Abstract
Clinical testing for the detection of RNA fusions in tissue currently include FISH, IHC, PCR and NGS. However, approximately 30% of patients with advanced non-small cell lung cancer (NSCLC) are not candidates for tissue biopsies and in some cases where tissue is obtained, it is not always of sufficient quantity for molecular testing. For these reasons, the detection of nucleic acids in circulation has become increasingly relevant to clinical testing. In this study, we have focused on the development of an EML4-ALK diagnostic test system that includes the prospective collection of whole blood and the reproducible detection of mRNA fusion transcripts by a PCR-based technology. The focus was on the detection of EML4-ALK transcripts from donors with and without previously diagnosed NSCLC. Pre-analytic complexity was reduced by restricting the handling of samples to 72 hours from time of sample receipt to test result. Recovery methods for RNA extraction from donor plasma were then optimized to enrich for RNA recovered from both circulating-free, and RNA within blood vesicles, including platelets and exosomes. A two-step reverse transcription and Droplet Digital™ PCR (RT-ddPCR) method was evaluated in detection testing using a multiplexed EML4-ALK assay that includes variants 1, 2 and 3. Analytic assay specificity and sensitivity was examined for RT-ddPCR efficiency using a cell-line positive for EML4-ALK variant 1 and in vitro RNA designed to mimic variants 1, 2, and 3. Analytic sensitivity was determined to be 0.2% of fusion RNA spiked into a background of normal plasma. Precision studies were conducted with two different amounts of input RNA (high and low), over three consecutive days, three runs in one day and with two operators. The SD of detected fusion transcripts in this study did not exceed 25%. Finally, normal (n = 10) and FISH positive NSCLC donor (n = 9) plasma samples were processed for the recovery of RNA and tested for EML4-ALK fusions. All FISH positive cases were accurately detected by the RT-ddPCR test with EML4-ALK variant copies ranging from 13 to 150 copies. EML4-ALK fusion transcripts were not identified in normal donor plasma. We conclude that the developed test system is highly suited for a 72 hour test to result turnaround, reproducible and sensitive detection of diagnostic fusion RNA variants, including EML4-ALK in blood in the clinical laboratory.
Citation Format: Hestia Mellert, Leisa Jackson, Dianna Maar, Dawne Shelton, Gary Pestano. Diagnostic test system for sensitive, specific and reproducible detection of EML4-ALK RNA fusion transcripts in the blood of patients with NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 857.