bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4437: Small non-coding RNA profiling from prostate cancer plasma by deep sequencing
Authors: Liu Xianghua , Hunter Andrew , Zhang Qing , He Quanyuan , Benton Annemarie , Ortiz Gerri , Pannu Vaishali , Xiao Nick , Miglarese Mark , Spetzler David 
Published: July 2017

Abstract
Background: Prostate cancer (PCa) is the most common non-skin cancer among American men. MicroRNAs (miRNAs) are critical post-transcriptional regulators and involved in prostate cancer tumorigenesis. The aim of this study is to identify a PCa-specific expression profile of miRNAs from plasma to guide prostate cancer diagnosis and therapeutic treatment.
Methods: Plasma was collected from 5 PCa patients and 5 normal men. Circulating RNA was extracted from 1) 200ul plasma or 2) the pellets of anti-Ago2 immunoprecipitations from 500ul plasma using the miRNeasy Serum/Plasma kit (Qiagen), with addition of glycogen as a carrier. Small RNA libraries were constructed using the NEBNext Multiplex Small RNA Prep Set for Illumina® (New England. BioLabs). The cDNA library fragments were purified by Blue Pippin (Sage Science) for extraction of 140-160 bp size fraction containing small RNA inserts. Equimolar amounts of cDNA library samples were pooled and were sequenced in a single flowcell on an Illumina HiSeq2500 with 50 cycle kit and rapid run model.
Bioinformatics analysis: Adaptor was firstly removed from the raw reads, and the sequences were mapped to several small RNA databases by using bowtie1 with 1 mismatch. The multiple aligned reads were weighted to the mapped small RNAs based on their unique mapped reads counts. We then calculated the RPM (reads per million) as indicator of the expression levels of the small RNA. To get confident analysis results, we discarded the small RNAs whose averages of the raw reads counts in cancer and normal groups are smaller than 25 and only focus on the mature microRNAs. The moderate t-test is applied to find the differently expressed (DE) microRNAs between normal and cancer group.
Results: Two major small RNA classes identified from total plasma are miRNA (47.7%) and yRNA (35.0%). The percentage of miRNA increased to 85.3% by Ago2-IP method. The compositions of categories of small RNAs in cancer and normal samples are similar. We identified 28 and 22 differential miRNAs (&gt;2 fold change between cancer and normal group) by total plasma and Ago-2 IP methods respectively.
Conclusions: We discovered a unique expression profile of miRNA detectable in the plasma from prostate cancer patients. Extracted RNA from the pellets of anti-Ago2 immunoprecipitations can enhance the detection of miRNA. Expand study to confirm these findings are needed.
Citation Format: Xianghua Liu, Andrew Hunter, Qing Zhang, Quanyuan He, Annemarie Benton, Gerri Ortiz, Vaishali Pannu, Nick Xiao, Mark Miglarese, David Spetzler. Small non-coding RNA profiling from prostate cancer plasma by deep sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4437. doi:10.1158/1538-7445.AM2017-4437
Abstract 444: Monocarboxylate transporter 1 inhibition with AZD3965 increases cancer cell dependence on bioenergetic metabolism predicating combination therapy with mitochondrial inhibitors
Authors: Beloueche-Babari Mounia , Galobart Teresa Casals , Wantuch Slawomir , Smith Paul D. , Leach Martin O. 
Published: July 2017

Abstract
Monocarboxylate transporters (MCTs) are key mediators of lactate transport that have emerged as promising targets for anti-cancer therapy. The MCT1 inhibitor AZD3965 (AstraZeneca) has shown promising activity in various pre-clinical models and is currently in phase I/II clinical testing. Understanding the impact of this drug on tumour cell metabolism may unravel dependencies that could be exploited for combination therapy. Here we investigate changes in glucose metabolism induced by AZD3965 treatment using 13C NMR isotopomer analysis, and examine their significance for cell survival using mitochondrial metabolism inhibitors.
Exposure of Raji human lymphoma cells to AZD3965 in media supplemented with [1-13C]glucose led to a marked reduction in glucose uptake and lactate production in the cellular growth media alongside a build-up in intracellular [3- 13C]lactate and [1-13C]glucose levels, indicative of blockade of lactate excretion and inhibition of overall glycolytic activity. These effects were concomitant with increased [4-13C]glutamate levels, consistent with re-routing of pyruvate towards mitochondrial metabolism and enhanced flux through oxidative pyruvate dehydrogenase.
Further, AZD3965 treatment was paralleled with a significant increase in levels of steady state Krebs cycle-related metabolites (including succinate, fumarate, acetate and NAD+/NADH) and cellular ATP, as revealed by bioluminescent and 1H NMR analyses, indicating improved mitochondrial metabolism and cellular re-energization.
Co-administration of the mitochondrial complex I inhibitor metformin or the mitochondrial pyruvate carrier inhibitor UK5099 markedly potentiated the anti-proliferative effects of AZD3965 and led to significantly increased cell death, indicating that the observed upregulation in mitochondrial metabolism was necessary to maintain cell survival under MCT1 inhibitor-induced metabolic stress. Similar effects were observed with a second human lymphoma cell line, Hut78.
Our findings show that MCT1 inhibition leads to a shift in cellular metabolism towards mitochondrial bioenergetic metabolism, creating a metabolic vulnerability that could be exploited for combinatorial therapy to increase the efficacy of AZD3965.
Citation Format: Mounia Beloueche-Babari, Teresa Casals Galobart, Slawomir Wantuch, Paul D. Smith, Martin O. Leach. Monocarboxylate transporter 1 inhibition with AZD3965 increases cancer cell dependence on bioenergetic metabolism predicating combination therapy with mitochondrial inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 444. doi:10.1158/1538-7445.AM2017-444
Abstract 4441: Unveil the role of cell-free circulating microRNA in lung cancer
Authors: Bianchi Fabrizio , Melocchi Valentina , Colangelo Tommaso , Cuttano Roberto , Muscarella Lucia Anna , Dama Elisa 
Published: July 2017

Abstract
We previously reported the identification of a signature composed by 34 serum circulating cell-free microRNAs (cf-miRNA) diagnostic for lung cancer. Using this signature, we developed a blood test (miR-test) which was capable of detecting asymptomatic lung cancer in a large cohort (N&gt;1000) of high-risk individuals (&gt;50years and smokers). Interestingly, we now found that a fraction (~30%) of these cf-miRNAs were preferentially expressed in cells of epithelial origin, while another ~30% were more expressed in hematopoietic cells. We reasoned that this cf-miRNA signature could result from the extracellular release of miRNAs from cancer epithelial cells as well as from immune/stromal cells composing the tumor microenvironment. We developed an integrated strategy for the identification of the origin of cf-miRNAs through combined analysis of published circulating and intracellular miRNAs expression datasets (microarray and qRT-PCR based) and of NGS analysis of cf-miRNAs in lung tumors. Our approach will contribute elucidating the biological role of cf-miRNAs in lung cancer and explore eventual therapeutic implications.
Citation Format: Fabrizio Bianchi, Valentina Melocchi, Tommaso Colangelo, Roberto Cuttano, Lucia Anna Muscarella, Elisa Dama. Unveil the role of cell-free circulating microRNA in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4441. doi:10.1158/1538-7445.AM2017-4441
Abstract 4442: micoRNA in FA defective tumor
Authors: Tang Shirley , Gao Li , Kathleen Kathleen , Fink Andrew , Kalvala Arjun , Aguila Brittany , Otterson Gregory , Villalona-Calero Miguel , Duan Wenrui 
Published: July 2017

Abstract
The Fanconi Anemia (FA) pathway is essential for human cells to maintain integrity following DNA damage. This pathway is involved in the endogenous repair of double stranded DNA breaks and homologous recombination as well as repair of DNA cross-linking caused by exogenous agents. Cancers with defective FA pathway are expected to be more sensitive to cross-link based therapy, or to treatments in which additional repair mechanisms are targeted. We have recently reported the detection of up to 20% of NSCLC to be FA functionally inactive (lack of FANCD2 foci formation in the nucleus of proliferating cells by triple stain immunofluorescence, FATSI negative). MicroRNAs (miRs, miRNA) are small, 19-25 nucleotide, single stranded, non-coding RNA molecules that have regulatory roles in humans by targeting mRNAs via cleaved or translational repression which can affect the output of protein coding genes and cause various changes in developmental and physiological processes including cancer. It has been published that some miRNAs are tumor suppressors, and others are oncogenes. However, microRNAs and the FA pathway in relationship to lung cancer progression remain unknown. In order to elucidate the role of FA related miRs in human lung cancer development or treatment, we analyzed miR expression in lung cancer cells and patient lung tumors. Several cell lines were generated using RNAi technology with FANCD2 deficiency and confirmed via reduction in FANCD2 protein expression. Using Nanostring counter technology, microRNA array analysis was performed on FANCD2 foci positive and foci negative tumors as well as matching normal lung tissues. A cluster of microRNAs (mir-431, 377, 376c, 200c, 26a, 135a, and let-7e) were found to be up-regulated, and miR-494,205, 630, 145,671 were found to be down-regulated in the foci negative tumors samples compared to matching non-tumor lung tissue. The same group of miRs were upregulated and its corresponding group were down-regulated in the foci negative tumors as compared to foci positive tumors. These findings indicate that the FA pathway may regulate downstream genes through regulation of microRNAs in lung cancer. In order to validate this hypothesis, specific miRs were be analyzed with Real-Time Quantitative PCR via foci positive and foci negative samples (cell and patient tissue) in hopes of finding significant and consistent regulation. This study contributes to further understanding in miRNA and cancer pathology that may be applicable to futuristic lung cancer treatment.
Citation Format: Shirley Tang, Li Gao, Kathleen Kathleen, Andrew Fink, Arjun Kalvala, Brittany Aguila, Gregory Otterson, Miguel Villalona-Calero, Wenrui Duan. micoRNA in FA defective tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4442. doi:10.1158/1538-7445.AM2017-4442
Abstract 4454: MED12 is recurrently mutated in Middle Eastern colorectal cancer
Authors: Siraj Abdul K. , Masoodi Tariq , Bu Rong , Al-Dayel Fouad , Al-Kuraya Khawla S. 
Published: July 2017

Abstract
Colorectal cancer (CRC) is a common cancer and a leading cause of cancer deaths. Previous studies have identified a number of key steps in the evolution of CRC but our knowledge of driver mutations in CRC remains incomplete. Recognizing the potential of studying different human populations to reveal novel insights in disease pathogenesis, we conducted genomic analysis of CRC in Saudi patients. In the discovery phase of the study, we conducted whole-genome sequencing of tumor and corresponding germline DNA in 27 CRC patients. In addition to known driver mutations, we identified three MED12 somatic mutations. In the replication phase, we employed a next-generation sequencing approach to capture and sequence MED12 and other candidate genes in a larger sample of 400 CRC patients and confirmed the enrichment for recurrent MED12 mutations. In order to gain insight into a plausible biological mechanism for the potential role of MED12 mutations in CRC, we studied CRC cell lines that differ substantially in the expression level of MED12, and found the latter to be correlated inversely with TGF-beta signaling and directly with apoptosis in response to chemotherapeutic agents. Importantly, these correlations were replicated when MED12 expression was experimentally manipulated. Our data expand the recently described role of MED12 as a tumor suppressor in other cancers to include CRC, and suggest TGF-beta signaling as a potential mediator of this effect.
Citation Format: Abdul K. Siraj, Tariq Masoodi, Rong Bu, Fouad Al-Dayel, Khawla S. Al-Kuraya. MED12 is recurrently mutated in Middle Eastern colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4454. doi:10.1158/1538-7445.AM2017-4454
Abstract 4457: Inverse relationship between exon 8 single nucleotide polymorphism (c.1293 C&gt;T) of gigaxonin and human tumor cell growth
Authors: Srivatsan Eri S. , Hwang Kimberly J. , Ko Albert , Chatoff Jenna R. , Basak Saroj K. , Venkatesan Natarajan , Palma-Diaz Fernando , Lewis Michael S. , Bomont Pascale , Wang Marilene B. 
Published: July 2017

Abstract
Gigaxonin, a product of the Giant Axonal Neuropathy (GAN) gene located on chromosome 16, is involved in intermediate filament processing of neural cells and vimentin fibers in fibroblasts. Previous studies have shown an interaction between p16 and gigaxonin in cisplatin mediated ubiquitination of NFkB. Genomic studies have indicated higher frequency (44.25%) of exon 8 single nucleotide polymorphism (SNP) (c.1293 C&gt;T) of gigaxonin in the individuals of Caucasian population compared to normal population (22%). The polymorphism frequency is much lower in individuals of other ethnicities. To determine the relationship to tumors, we analyzed exon 8 polymorphism in HPV positive and negative cervical and head and tumors. Our studies showed a 47.25% polymorphic frequency in these tumors. There was no relationship between the presence of polypmorphism and HPV status. However, there was an inverse relationship between polymorphism and tumor recurrence. Our studies have further shown higher expression of gigaxonin protein in cancer cell lines containing the polymorphic T allele. Growth assays in vitro and in soft agar have shown a direct relationship between the presence of the T allele and slower cell line growth. Our results therefore indicate that in addition to p16 expression, exon 8 SNP could also serve as a diagnostic marker of chemo sensitivity in human tumors.
Citation Format: Eri S. Srivatsan, Kimberly J. Hwang, Albert Ko, Jenna R. Chatoff, Saroj K. Basak, Natarajan Venkatesan, Fernando Palma-Diaz, Michael S. Lewis, Pascale Bomont, Marilene B. Wang. Inverse relationship between exon 8 single nucleotide polymorphism (c.1293 C&gt;T) of gigaxonin and human tumor cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4457. doi:10.1158/1538-7445.AM2017-4457
Abstract 4458: Regulation of MYC protein stability by mutant KRAS in pancreatic ductal adenocarcinoma
Authors: Vaseva Angelina V. , Blake Devon R. , Azam Salma H. , Gilbert Karim T. , Pecot Chad V. , Pearce Kenneth H. , Herring Laura E. , Graves Lee M. , Houghton Peter J. , Der Channing J. 
Published: July 2017

Abstract
With the nearly 100% mutation frequency of KRAS in pancreatic ductal adenocarcinoma (PDAC), the development of therapeutic strategies to target KRAS is a high priority for the pancreatic cancer field. In the current study, we aimed to identify signaling changes caused by the acute suppression of mutant KRAS in PDAC cell lines. Strikingly, acute suppression of mutant KRAS in PDAC cell lines caused potent and rapid proteasome-dependent degradation of MYC protein. Ablation of MYC also suppressed PDAC growth both in vitro and in vivo, indicating a critical driver role for MYC in KRAS-dependent PDAC maintenance. A mechanism by which RAS effector signaling regulates MYC protein stability has been described, however we determined that this mechanism cannot fully account for how endogenous mutant KRAS stabilizes MYC protein in PDAC cells. We verified a role for the Raf-MEK-ERK but not the PI3K-AKT-GSK3β effector signaling pathway. Unexpectedly, we also excluded a role for MYC protein phosphorylation at MYC residue T58, and determined that ubiquitin ligases other than FBW7 are involved. These findings prompted us to search for additional KRAS-dependent protein kinases that facilitate MYC protein stability. We applied multiple screening strategies. First, we developed a novel fluorescence-based system to monitor real-time MYC protein degradation in PDAC cells and we adapted this system for use in a high-throughput flow-cytometry based assay. Second, we applied a mass spectrometry-based approach to profile the human kinome for KRAS-dependent changes in protein kinases. Finally, we applied gain-of-function (Cancer Toolkit) and loss-of-function (CRISPR/Cas9) genetic screens to identify signaling regulators of MYC protein stability. The results of these screens will be presented.
Citation Format: Angelina V. Vaseva, Devon R. Blake, Salma H. Azam, Karim T. Gilbert, Chad V. Pecot, Kenneth H. Pearce, Laura E. Herring, Lee M. Graves, Peter J. Houghton, Channing J. Der. Regulation of MYC protein stability by mutant KRAS in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4458. doi:10.1158/1538-7445.AM2017-4458
Abstract 4469: Targeting the tri-snRNP complex for triple-negative breast cancer therapy
Authors: Chan Stefanie , Sridhar Praveen , Lock Ying-Jie , Petrocca Fabio 
Published: July 2017

Abstract
Triple negative breast cancers (TNBC) account for ~15% of all breast cancers and the majority of breast cancers in women carrying a BRCA1 germline mutation. Due to the inadequacy of existing treatment, here we sought to identify shared genetic dependencies across different TNBC cell lines with the ultimate goal of uncovering novel therapeutic targets. To this end, we performed a targeted siRNA lethality screen across 11 human breast cell lines focusing on 154 genes, which we previously identified as selectively essential to a genetically-defined TNBC progenitor cell line (BPLER) relative to a myoepithelial-like isogenic cell line (HMLER). Thirty genes scored as recurrently and selectively required for survival of progenitor-like (or basal-A) TNBC lines compared to differentiated cell lines. Genes for proteins involved in RNA splicing were prominent shared dependencies among basal-A TNBC cell lines. Of particular note were those associated with the U4/U6.U5 tri-snRNP complex, including PRPF8 and PRPF38A. Transcriptome-wide RNA-seq analysis of the knockdown of either led to widespread intronic retention, expression of immune system genes and aberrant splicing of transcripts involved in protein translation, proteasome function, mitosis and apoptosis, including the TNBC dependency gene MCL1. As the proteasome and mitosis are also established TNBC vulnerabilities, we have identified specific classes of transcripts that are both particularly susceptible to perturbation of tri-snRNP activity and selectively essential for TNBC, making the tri-snRNP complex an attractive target for downstream drug development.
Citation Format: Stefanie Chan, Praveen Sridhar, Ying-Jie Lock, Fabio Petrocca. Targeting the tri-snRNP complex for triple-negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4469. doi:10.1158/1538-7445.AM2017-4469
Abstract 4472: A subunit of splicing factor 3b, SF3B4, functions as driver of liver cancer via aberrant splicing activity on tumor suppressor KLF4
Authors: Shen Qingyu , Eun Jung Woo , Kim Hyung Seok , Yang Hee Doo , Kim Sang Yean , Nam Suk Woo 
Published: July 2017

Abstract
Alternative splicing is one of the crucial mechanism that contribute to proteome diversity and, as reported, up to 90% of genes are alternatively spliced in human. In the last few years, a large number of mRNA isoforms revealed to contribute many cellular development and disease, including cancer. SF3B4 is one of six subunits of the splicing factor 3b (SF3b) complex which is an important protein complex in U2 snRNP super complex. In this study, we show that SF3B4 expression was overexpressed in a large cohort of human hepatocellular carcinoma (HCC) patients. SF3B4 knockdown caused G1/S cell cycle arrest by recovering p27 expression and simultaneously suppressing cyclins, and CDKs in liver cancer cell. Consistently, Spliceostatin A, a SF3b complex inhibitor, also suppressed liver cancer cell growth with similar effect on cell cycle regulation. In addition, sustained suppression of SF3B4 reduced the in vivo tumor growth rate in mouse xenograft models. Furthermore, SF3B4 knockdown repressed in vitro tumor cell motility and invasion of liver cancer cells. Notably, we observed that SF3B4 knockdown increased alternative transcript splicing event of a large number of genes in liver cancer cells. From this, we found that SF3B4 knockdown caused induction of wildtype KLF4 transcript expression, and thereby exerted anti-tumor growth effect on liver cancer cells. Indeed, ectopic expression of KLF4 mimicked SF3B4 knockdown effect on same cells. Our results suggest that aberrant regulation of SF3B4 contribute to malignant transformation and growth of liver cancer cells by repression of tumor suppressor via unmodulated alternative splicing activity during liver tumorigenesis.
Citation Format: Qingyu Shen, Jung Woo Eun, Hyung Seok Kim, Hee Doo Yang, Sang Yean Kim, Suk Woo Nam. A subunit of splicing factor 3b, SF3B4, functions as driver of liver cancer via aberrant splicing activity on tumor suppressor KLF4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4472. doi:10.1158/1538-7445.AM2017-4472