bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 87: Clustered somatic mutations are frequent in transcription factor binding motifs in melanoma and other cutaneous malignancies
Authors: Colebatch Andrew J. , di Stefano Leon , Wong Stephen Q. , Papenfuss Anthony T. , McArthur Grant A. 
Published: July 2016

Abstract
We sought to explore the etiology, frequency and clinicopathologic associations of clustered noncoding hotspot mutations in cutaneous malignancies (melanoma, basal cell carcinoma (BCC) and Merkel cell carcinoma (MCC)). We did so by applying a sliding window approach which identified clusters in melanoma whole exome and genome sequencing data. These regions were then evaluated for recurrence in other skin malignancies by using whole exome data from BCC and MCC samples; motifs were extracted using a maximum expectation algorithm. We then sequenced 170 annotated melanoma clinical samples using a targeted amplicon panel which permitted analysis of clinicopathological correlations. Numerous recurrent clustered hotspot mutations were identified in melanoma whole exome and genome data sets in proximal promoters, with some gene-associated clusters present in up to 25% of cases. Mutations were clustered around canonical ETS and SP1 transcription factor binding sites and had a clear UV signature. These promoter mutations correlated with overall mutation load and NF1 mutation status, and showed significant enrichment in specific melanoma subtypes (desmoplastic and lentigo maligna melanoma), sun exposed anatomical locations, male gender, ulceration and increasing age. Identical clusters were identified in BCC and MCC samples, including several previously annotated in melanoma. In conclusion, we identify a novel class of mutation in cutaneous malignancies which rather than being defined by a particular genomic position are related to a position in a transcription factor binding motif. These mutations are also independent of cell of origin. Clinicopathologic correlation and mutation analysis support an etiologic role for chronic UV irradiation.
Citation Format: Andrew J. Colebatch, Leon di Stefano, Stephen Q. Wong, Anthony T. Papenfuss, Grant A. McArthur. Clustered somatic mutations are frequent in transcription factor binding motifs in melanoma and other cutaneous malignancies. [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 87.
Abstract 870: Derivation and characterization of antibodies from immune checkpoint blockade treated cancer patients
Authors: Branum Mark , Smith Laura , Brett Heather , Algate Paul , Greenfield Brad , Brown William , Swiderek Kristine M. 
Published: July 2016

Abstract
The IgG+ memory B cell repertoire of cancer patients demonstrating durable responses to immune checkpoint blockade therapy has been interrogated to identify tumor specific antibodies. Matched serum and PBMC samples have been collected from 10 melanoma patients with durable responses to treatment with ipilimumab. A panel of 7 well characterized melanoma cell lines with a diverse set of oncogenic driver mutations has been employed to assess durable responder patient serum reactivity to cell surface determinants in a live-cell flow cytometry assay. IgG+ memory B cells obtained from several prioritized durable responder melanoma patients have been plated out on 384 well plates at monoclonal density. The memory B cells have been activated in a short term culture system optimized to expand the clonal B cells and induce secretion of IgG. Antibodies secreted from clonally expanded B cells have been screened using live cell high throughput multiplex flow cytometry assays against a panel of melanoma cell lines. A prioritized subset of antibodies, selected on the basis of tumor cell line binding profiles and antibody v-region sequences, has been cloned and expressed as recombinant IgG1. A cell surface target for a prioritized antibody has been identified and the in vitro analysis and characterization of the antibody including functional activity and immunohistochemistry staining on tumor and normal tissues has been carried out in preparation for in vivo testing of efficacy.
Citation Format: Mark Branum, Laura Smith, Heather Brett, Paul Algate, Brad Greenfield, William Brown, Kristine M. Swiderek. Derivation and characterization of antibodies from immune checkpoint blockade treated cancer patients. [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 870.
Abstract 875: Acquisition of chemoresistance in tumor cells requires crosstalk between dying and remnant live tumor cells via HMGB1
Authors: Zhou Junmin , Chen Xianghong , Gilvary Danielle L. , Tejera Melba Marie , Eksioglu Erika A. , Trinh Thu Le , Wei Sheng , Djeu Julie 
Published: July 2016

Abstract
Chemoresistance often develops during drug treatment in cancer patients but its mechanism remains unclear. To understand acquisition of drug resistance, we investigated whether tumor cells dying during drug treatment might signal to neighboring live cells to program themselves for survival in the drug-containing environment. The experimental design was to identify a factor in the supernatants of docetaxel (DTX)-treated human DU145 and PC3 prostate tumor cells that could cause live tumor cells to resist apoptosis and cell death under docetaxel. We discovered that dying cells release HMGB1 which can bind TLR4 or RAGE on live tumor cells causing the induction of cytoplasmic Clusterin (CLU). We demonstrated that CLU is a potent prosurvival protein that can trap Bax from translocating to the mitochondria to cause caspade 3 activation and subsequent apoptosis. Proof of this pathway came from the ability of anti-HMGB1to prevent supernatants from dying cells to induce CLU in newly-plated tumor cells. The receptors for HMGB1 were identified by use of anti-TLR4 and anti-RAGE, which prevented recombinant HMGB1 or dying cell supernatants from inducing CLU in newly-plated tumor cells, causing them to subsequently succumb to DTX toxicity. Moreover, overexpression of anti-sense CLU in tumor cells abrogated their ability to respond to recombinant HMGB1 or dying cell supernatants to induce drug resistance. Most importantly, standard chemotherapeutic agents including gemcitabine, taxol, Ara-C, doxorubicin, cisplatin, etoposide and carboplatin, can cause the release of HMGB1 from dying tumor cells, implicating this crosstalk between dying and live tumor cells as a common pathway towards multi-drug resistance.
Citation Format: Junmin Zhou, Xianghong Chen, Danielle L. Gilvary, Melba Marie Tejera, Erika A. Eksioglu, Thu Le Trinh, Sheng Wei, Julie Djeu. Acquisition of chemoresistance in tumor cells requires crosstalk between dying and remnant live tumor cells via HMGB1. [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 875.
Abstract 893: Diffuse gastric adenocarcinoma often harbors KMT2C mutations resulting in malignant phenotypes and worse overall survival
Authors: Cho Soo-Jeong , Yoon Changhwan , Lee Jun Ho , Chang Kevin K. , Aksoy Bulent A. , Park Do Joong , Yoon Sam S. 
Published: July 2016

Abstract
Purpose: The Lauren diffuse type of gastric adenocarcinoma (DGA) is genomically stable compared to the intestinal type, but the primary driver mutations in DGA are still being defined. Lysine (K) -specific methyltransferase 2C (KMT2C), also known as mixed lineage leukemia 3 (MLL3), is a histone methyltransferase involved in transcriptional coactivation and can be mutated in gastric cancer. The purpose of this study was to determine the frequency of KMT2C mutation in DGA and to elucidate the role of KMT2C in DGA tumorigenesis and progression.
Methods: Whole exome sequencing was performed on matched tumor samples of 27 patients with DGA who underwent potentially curative surgical resection. Immunohistochemistry (IHC) was performed for KMT2C protein expression on these same tumors and on an additional 289 tumors from a separate cohort of patients with DGA. KMT2C overexpression in DGA cell lines (MKN-45 and SNU-668) using lentiviral transduction and KMT2C shRNA knockdown in normal gastric epithelial cells were examined in several in vitro assays.
Results: Thirty-eight percent of the 27 sequenced DGA specimens harbored somatic mutations in KMT2C. The next most frequent mutation, CDH1, which encodes E-cadherin, was found in 28% of specimens. Patients with KMT2C mutation tended to have worse overall survival (OS) compared to patients without the mutation (p = 0.194). Additional tumor tissue for IHC analysis was only available from 11 of 27 patients. Among this group, patients with tumors expressing KMT2C protein had better OS compared to patients whose tumors did not express KMT2C (p = 0.034). In an external validation set of 289 DGA samples, KMT2C expression again correlated with better OS (p = 0.009). In the DGA cell lines, KMT2C overexpression reduced proliferation by 32-39%, soft agar colony formation by 75-77%, spheroid cell formation by 77-78%, cell migration by 52-60%, and cell invasion by 50-74%. KMT2C overexpression also increased resistance to 5-FU and cisplatin chemotherapy. KMT2C shRNA knockdown in gastric epithelial cells increased proliferation, soft agar colony formation, migration, and invasion by 1.7- to 25-fold.
Conclusions: KMT2C is frequently mutated in DGA, and loss of KMT2C protein expression correlates with worse OS. Restoration of KMT2C expression in DGA cell lines reduces cancer stem-like cell and malignant phenotypes. Thus, KMT2C may be a novel therapeutic target for patients with DGA.
Citation Format: Soo-Jeong Cho, Changhwan Yoon, Jun Ho Lee, Kevin K. Chang, Bulent A. Aksoy, Do Joong Park, Sam S. Yoon. Diffuse gastric adenocarcinoma often harbors KMT2C mutations resulting in malignant phenotypes and worse overall survival. [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 893.
Abstract 900: In vivo modeling of NRAS-mutant melanoma reveals differential preventative efficacy amongst SPF30 sunscreens
Authors: Holderbaum Andrea M. , Hennessey Rebecca C. , Gillahan James E. , Bonilla Anamaria , Delaney Conor , Kladney Raleigh D. , Tober Kathleen L. , Oberyszyn Tatiana M. , Burd Christin E. 
Published: July 2016

Abstract
Cutaneous melanoma claims the life of one American every hour, and while the etiology of this tumor type is not entirely understood, exposure to ultraviolet (UV) radiation (280-340nm) is a major risk factor. For this reason, the use of UV-blocking sunscreens is strongly advocated; however, few studies have tested the relative efficacy of these agents in preventing melanoma formation in vivo. Here, we employed a new genetically engineered mouse model (TpN61R) to examine the ability of 6 chemically distinct SPF30 sunscreens to prevent melanoma. In this TpN61R model, topical 4-hydroxytamoxifen (4OHT) treatment induces the melanocyte-specific expression of oncogenic NRas as well as inactivation of the p16INK4a tumor suppressor. These genetic lesions co-occur in ∼24% of all human melanomas, making the TpN61R model biologically relevant. Since NRAS mutations are an early and UV-independent event in human melanoma, TpN61R mice were first painted with 4OHT and then exposed to a single dose of 4.5 kJ/m2 UVB light one day later. Exposed skin from TpN61R mice showed transient cyclobutane pyrimidine dimer (CPD) formation, however no evidence of edema or inflammation was observed. Despite these mild effects, UVB exposure reduced the melanoma-free survival of TpN61R mice by 80% and increased tumor incidence rate from 1.2 to 3.4 tumors/mouse. Further experiments using a variety of UVB doses (0.25, 1.0, 2.3 and 9.0 kJ/m2) in the TpN61R model revealed a dose-dependent increase in early melanoma incidence. Together, these data establish the exquisite cooperation of UV light and oncogenic NRas mutations in driving melanoma. Taking advantage of this unique model, we tested the preventative efficacy of SPF30 sunscreens with differing chemical composition. Sunscreens components included UVA (avobenzene), UVB (homosalate, octisalate) and broad spectrum (oxybenzone, octocrylene, zinc oxide) blocking agents. Application of sunscreen prior to UVB exposure decreased DNA damage, delayed melanoma onset and reduced tumor incidence in a sunscreen-dependent manner. Thus, SPF30 sunscreens do not equally prevent UVB-induced, NRAS mutant melanoma. This work establishes the first in vivo system to test sunscreen efficacy in NRAS-driven melanoma and will help direct the development of improved melanoma preventatives.
Citation Format: Andrea M. Holderbaum, Rebecca C. Hennessey, James E. Gillahan, Anamaria Bonilla, Conor Delaney, Raleigh D. Kladney, Kathleen L. Tober, Tatiana M. Oberyszyn, Christin E. Burd. In vivo modeling of NRAS-mutant melanoma reveals differential preventative efficacy amongst SPF30 sunscreens. [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 900.
Abstract 934: Tributyltin-induced dysregulation of inflammatory cytokine levels in human and mouse immune cells
Authors: Lawrence Shanieek , Pellom Samuel T. , Shanker Anil , Whalen Margaret 
Published: July 2016

Abstract
The effects of Tributyltin (TBT), a widespread environmental contaminant, on the induction of in vivo and ex vivo cytokine production and secretion were investigated. Human monocyte-depleted peripheral blood mononuclear cells and different groups of Balb/C mice were stimulated with desired concentrations of TBT (200-2.5 nM for human studies and 200-25 nM for mouse studies). The quantitative determination of IFNγ, TNFα and IL-1β was performed in mouse sera by MagPix analysis and western blot. The levels of these cytokines were measured at different time points: 6, 12, 24 and 48 h after injection. Analysis of IFNγ and TNFα in human cells were conducted by ELISA and western blot. MAPK and NF-κB pathways were inhibited to determine TBT-induced dysregulation of IFNγ and TNFα. Inhibition of the p38 and p44/42 pathways blocked the TBT-induced elevation of IFNγ, while the inhibition of the p38 pathway blocked the TBT-induced elevation of TNFα. Results showed that TBT increased the levels of IFNγ, TNFα and IL-1β in the sera of mice. IFNγ and TNFα secretion from human monocyte-depleted peripheral blood mononuclear cells also increased, showing striking agreement in the response to TBT between the mouse and human systems. These data suggest that TBT exposure can result in an inflammatory environment, which could predispose the host to various immunopathologies.
Grant U54CA163066 from the National Institute of Health
Citation Format: Shanieek Lawrence, Samuel T. Pellom, Anil Shanker, Margaret Whalen. Tributyltin-induced dysregulation of inflammatory cytokine levels in human and mouse immune cells. [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 934.
Abstract 935: Oral cancer cells may hijack stem cell altruism to survive during extreme hypoxia, and exposure to chemotherapeutic drugs
Authors: Bhuyan Rashmi , Li Hong , Gayan Sukanya , Pal Bidisha , Bayat-Mokhtari Reza , Phukan Jyotirmoy , Baishya Debabrata , Sarma Anupam , Talukdar Joyeeta , Alkurdi Manaf Muhammad , Tasabehji Wael , Bhuyan Seema , Gogoi Gayatri , Pulu Ista , Yeger Herman , Das Bikul 
Published: July 2016

Abstract
The mechanism of tumor hypoxia induced reprogramming of cancer cells are not understood well. Hypoxia might activate evolutionary preserved cellular defense mechanism that could contribute to tumor progression and metastasis. We recently described that during hypoxia/oxidative stress, human embryonic stem cells (hES) exhibit an altruistic defense mechanism, where a few cells reprogram to a highly undifferentiated state, and secrete glutathione to protect rest of the community of cells from oxidative stress induced DNA damage (Das B et al, Stem Cells, 2012). The altruistic stem cells phenotype exhibited high HIF-2alpha and low p53 activity. After a few weeks, the reprogrammed cells, although highly fit to survives, underwent spontaneous apoptosis/differentiation by re-activating the p53/MDM2 oscillation. Thus, the reprogrammed cells sacrificed its own fitness to enhance the fitness of the rest of the community, an altruistic behavior (Das B et al. Stem Cells, 2012). Here, we investigated the potential hijacking of the altruistic defense mechanism by oral cancer cells during exposure to hypoxia. We exposed the four oral cancer cell lines SCC-25, SCC-15, SCC-9 and SCC-5 to extreme hypoxia followed by re-oxygenation for 72 hours. We found that while majority of cancer cells underwent apoptosis, a few cancer cell lines survived, exhibited side-population (SP) phenotype, high level of HIF-2alpha, Nanog, Sox-2 and MYC. The SP cells exhibited migratory activity, as well as high tumorigenic and metastatic activity in NOD/SCID mice. ChIP assay indicated that HIF-2alhpa interact with MYC and NOTCH1. The conditioned media of SP cells exhibited high level of glutathione, and ability to protect non-SP cells from cisplatin-induced toxicity. These results indicate that HIF-2alpha and MYC may cooperate to reprogram a few oral cancer cells to altruistic stemness phenotype. The altruistic phenotype that exhibited cytoprotective activity against cisplatin mediated toxicity. Thus, similar to bacteria, where altruistic biofilm exhibit novel drug resistance mechanism, stem cell altruism may serve as a novel drug resistance mechanism in oral cancer.
Citation Format: Rashmi Bhuyan, Hong Li, Sukanya Gayan, Bidisha Pal, Reza Bayat-Mokhtari, Jyotirmoy Phukan, Debabrata Baishya, Anupam Sarma, Joyeeta Talukdar, Manaf Muhammad Alkurdi, Wael Tasabehji, Seema Bhuyan, Gayatri Gogoi, Ista Pulu, Herman Yeger, Bikul Das. Oral cancer cells may hijack stem cell altruism to survive during extreme hypoxia, and exposure to chemotherapeutic drugs. [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 935.
Abstract 949: Epigenetic silencing of microRNA-34a promotes cholangiocarcinoma growth by regulating Notch pathway
Authors: Kwon Hyunjoo , Song Kyoungsub , Han Chang , Zhang Jinqing , Ungerleider Nathan , Yao Lu , Wu Tong 
Published: July 2016

Abstract
Aberrant expression and regulation of microRNAs (miRNAs) have been found in multiple cancers and their dysregulation importantly contribute to the tumorigenic processes. Among these miRNAs, miRNA-34a (miR-34a) functions as a tumor suppressor and its dysregulation has been reported in several cancers. In this study, we investigated epigenetic regulation and biological function of miR-34a in human cholangiocarcinoma cells. Our data indicate that miR-34a expression is epigenetically silenced in human cholangiocarcinoma cells (CCLP1, SG231, Hucct1 and TFK1) compared to the nonmalignant biliary epithelial cells (H69). Treatment of human cholangiocarcinoma cells with the DNA methylation inhibitor, 5’aza-2’deoxycytidine (5-Aza-CdR), or the EZH2 (enhancer of zeste 2 polycomb repressive complex 2) inhibitor, GSK126, enhanced the expression of miR-34a. In parallel, knockdown of EZH2 by shRNA also significantly decreased miR-34a expression in human cholangiocarcinoma cells. We further showed that DNA methylation and EZH2-mediated histone H3 lysine 27 trimethylation (H3K27Me3) repressed miR-34a gene expression, as determined by methylation-specific PCR and chromatin immunoprecipitation. The DNA methylation and EZH2-mediated H3K27Me3 independently repress miR-34a expression in cholangiocarcinoma cells since treatment of 5-Aza-CdR and GSK126 had no effect on H3K27me3 and DNMT1 levels, respectively. Functional analyses revealed that miR-34a mimic decreased cholangiocarcinoma cell proliferation, colony formation and migration, in vitro. Moreover, we identified Notch1, Notch2 and Jagged 1, which are the major receptors and ligands of the Notch pathway, as miR-34a target genes in cholangiocarcinoma cells. Accordingly, forced overexpression of miR-34a significantly decreased the expression of Notch1, Notch2 and Jagged1, as determined by Western blotting and qRT-PCR analyses. Our results provide novel evidence that miR-34a expression is epigenetically silenced by DNA methylation and EZH2 in human cholangiocarcinoma cells. Thus, epigenetic induction of miR-34a or miR-34a replacement therapy may represent a novel therapeutic approach for the treatment of cholangiocarcinoma.
Citation Format: Hyunjoo Kwon, Kyoungsub Song, Chang Han, Jinqing Zhang, Nathan Ungerleider, Lu Yao, Tong Wu. Epigenetic silencing of microRNA-34a promotes cholangiocarcinoma growth by regulating Notch pathway. [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 949.
Abstract 953: miR-31 targets ARID1A to enhance the progression of oral carcinoma
Authors: Lu Wen-Cheng , Lin Shu-Chun , Chang Kuo-Wei 
Published: July 2016

Abstract
miR-31 is an oncogenic microRNA in several malignancies including oral squamous cell carcinoma (OSCC). However, the function of miR-31 in modulating the stem cell properties in OSCC has not yet been explored. AT-rich interacting domain (ARID) containing protein members play pluripotent roles in modulating chromatin accessibility of the transcription machineries for gene expression. ARID1A has been shown suppressive to several malignancies and the driver mutations in ARID1A gene are noted in tumors. In this study, we identified that miR-31 targets ARID1A in OSCC, and a reverse expression between miR-31 and ARID1A was noted in OSCC tumors. Furthermore, the miR-31 induced migration, invasion, CSC cell population and stemness gene expression were rescued by ARID1A expression in OSCC cells. ARID1A suppressed the transcription activity of a panel of stemness markers through its affinity to A-T rich region in the promoters. A reverse correlation between ARID1A and these stem cell markers was also seen in OSCC tumors. miR-31+/ARID1A− OSCC cell subclone exhibited higher potency in sphere formation, as well as tumorigenesis and neck metastasis in nude mice relative to other cell subclones. In addition, tumors carrying high miR-31 expression and low ARID1A expression had the worst survival. In summary, this study provides novel mechanistic clues demonstrating that miR-31 targets ARID1A to enrich the stemness properties for OSCC progression.
Citation Format: Wen-Cheng Lu, Shu-Chun Lin, Kuo-Wei Chang. miR-31 targets ARID1A to enhance the progression of oral carcinoma. [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 953.