bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4473: SRRM4 drives treatment-induced neuroendocrine transdifferentiation of prostate adenocarcinoma under androgen receptor pathway inhibition
Authors: Li Yinan 
Published: July 2017

Abstract
Treatment-induced neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of castration-resistant prostate cancer that typically does not respond to AR pathway inhibition (ARPI) and its diagnosis is increasing. To understand its development, we analyzed transcriptomes of prostate tumors to identify t-NEPC-specific RNA splicing. Interestingly, more than 66% of the splice events are predicted to be regulated by the RNA splicing factor, Serine/Arginine Repetitive Matrix 4 (SRRM4). We confirmed in vitro and in vivo that one SRRM4 target gene is the RE1-Silencer Factor (REST), a master regulator of neurogenesis. SRRM4 strongly stimulates adenocarcinoma cells to express t-NEPC biomarkers and this is exacerbated by ARPI. ARPI combined with gain of SRRM4 results in adenocarcinoma cells to assume multicellular spheroid morphology and establishes progressive NEPC xenografts. These SRRM4 actions are further enhanced by loss-of-function of TP53. We conclude that SRRM4 drives t-NEPC progression. This knowledge may guide the development of novel therapeutics aimed at t-NEPC.
Citation Format: Yinan Li. SRRM4 drives treatment-induced neuroendocrine transdifferentiation of prostate adenocarcinoma under androgen receptor pathway inhibition [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 4473. doi:10.1158/1538-7445.AM2017-4473
Abstract 4480: SerRS is a key inhibitor of VEGFA through both transcriptional and translational controls
Authors: Liu Ze , Shi Yi , Zhang Qian , Yang Xianglei 
Published: July 2017

Abstract
Vascular endothelial growth factor A (VEGFA) is the most important mediator of angiogenesis and a major target for cancer therapy. Recent studies from our lab revealed that seryl-tRNA synthetase (SerRS), by counteracting transcription factor c-Myc in the nucleus, is the crucial transcriptional repressor of VEGFA and a potent inhibitor of angiogenesis (1,2). Here we report that SerRS controls the expression of VEGFA not only in the nucleus but also in the cytoplasm through mediating its translational readthrough. Translational read-through of the VEGFA mRNA generates a novel isoform called VEGF-Ax that, compared with the non-readthrough isoform VEGF165, has a 22-amino acid C-terminal extension and much weakened angiogenic activity (3,4). Interestingly, serine was identified as the amino acid inserted in the place of the UGA stop codon during the read-through (3). In unpublished work, wWe findound that SerRS can bind to the 3’UTR region of the VEGFA mRNA. The binding anchors SerRS to charge serine onto tRNASec (the tRNA for the 21st amino acid selenocysteine that decodes the UGA stop codon), while preventing the charged serine from being modified into selenocysteine. SerRS binding also blocks the release factors (eRFs) from terminating translation at the stop codon. Therefore, SerRS is the key mediator of the translational readthrough that generates VEGF-Ax. Collectively, we have established that a member of the aminoacyl-tRNA synthetase family plays a critical role in regulating VEGF and angiogenesis through both transcriptional and translational controls.
References
1. Xu X, Shi Y, Zhang HM, Swindell EC, Marshall AG, Guo M, Kishi S, Yang XL*. Unique domain appended to vertebrate tRNA synthetase is essential for vascular development. Nat Commun. 2012 Feb 21;3:681.
2. Shi Y, Xu X, Zhang Q, Fu G, Mo Z, Wang GS, Kishi S, Yang XL*. tRNA synthetase counteracts c-Myc to develop functional vasculature. Elife. 2014 Jun 17;3:e02349.
3. Eswarappa SM, Potdar AA, Koch WJ, Fan Y, Vasu K, Lindner D, Willard B, Graham LM, DiCorleto PE, Fox PL. Programmed translational readthrough generates antiangiogenic VEGF-Ax. Cell. 2014 Jun 19;157(7):1605-18.
4. Xin H, Zhong C, Nudleman E, Ferrara N. Evidence for Pro-angiogenic Functions of VEGF-Ax. Cell. 2016 Sep 22;167(1):275-284.
Citation Format: Ze Liu, Yi Shi, Qian Zhang, Xianglei Yang. SerRS is a key inhibitor of VEGFA through both transcriptional and translational controls [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 4480. doi:10.1158/1538-7445.AM2017-4480
Abstract 4488: Tumor suppressor phosphatase PHLPP1 regulates transcription factor activity and gene expression in inflammation
Authors: Katsenelson Ksenya Cohen , Stender Joshua D. , Glass Christopher K. , Newton Alexandra C. 
Published: July 2017

Abstract
Epigenetic mechanisms play a key role in cancer and are a major contributor in driving the aberrantly high levels of oncogenic receptor tyrosine kinases (RTK) in cancer. Understanding mechanisms leading to altered transcription of oncogenes and tumor suppressors has the potential to provide new therapeutic targets. Here we show that the PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a tumor suppressor that directly dephosphorylates and inactivates Akt, has an additional function of regulating approximately 10% of the transcriptome. Specifically, we used non-biased high-throughput RNA-sequencing and chromatin immunoprecipitation-sequencing techniques to analyze genome-wide mRNA levels and acetylation patterns of genes in cells from wild-type and PHLPP1 knockout mice. De novo motif analysis of the promoter for the genes regulated by PHLPP1 identified enrichment in the recognition motifs for a number of transcription factors, including ones involved in inflammatory signaling. Biochemical analysis revealed that PHLPP1 regulates the phosphorylation and activation of these transcription factors, such that loss of PHLPP1 leads to enhanced inflammatory signaling. Our data support a model in which PHLPP1 dephosphorylates specific transcription factors to act as the brakes to inflammatory signaling, a hallmark of cancer.
Citation Format: Ksenya Cohen Katsenelson, Joshua D. Stender, Christopher K. Glass, Alexandra C. Newton. Tumor suppressor phosphatase PHLPP1 regulates transcription factor activity and gene expression in inflammation [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 4488. doi:10.1158/1538-7445.AM2017-4488
Abstract 4491: Modulation of p63 expression by phosphorylation of RBM38 at S195 via miR-203
Authors: ZHANG YANHONG , YAN WENSHENG , ZHANG JIN , CHEN XINBIN 
Published: July 2017

Abstract
p63, a p53 family protein, acts as a sequence-specific DNA-binding transcriptional factor to regulate the expression of target genes involving in various cellular processes, including growth suppression and epithelial development. RBM38, a RNA-binding protein, is a target of p53 family and is known to interact with its target mRNAs and regulate their expression via mRNA stability. Previously, we found that RBM38 negatively regulates p63 mRNA stability through binding to the AU/U-rich element in 3′ untranslated region (3′-UTR). We also found that phosphorylation of RBM38 at Ser195 alters the conformation and function of RBM38 protein. However, it is unclear whether phosphorylation of RBM38 or miR-203 alters the ability of RBM38 to regulate p63 expression. In this study, we found that in both MCF7 and HaCaT cells, wild-type RBM38 and S195A mutant, but not phosphor-mimic S195D mutant, inhibit p63 mRNA stability, suggesting that Ser195 phosphorylation abrogates the ability of RBM38 to repress the expression of p63. Importantly, we found that phosphorylation of RBM38 disrupts the binding of RBM38 to the U-rich element in p63 3′-UTR. Additionally, we found that miR-203 inhibitor increases, whereas miR203 mimic decreases p63 expression through binding to p63 3′-UTR, consistent with a previous report. Interestingly, we found that the ability of RBM38 to repress p63 expression is disrupted by miR-203 inhibitor but enhanced by miR-203 mimic. Furthermore, we found that wild-type RBM38 protein, but not phosphor-mimic S195D mutant, physically interacts with Ago2, indicating that RBM38 may inhibit p63 mRNA stability by modulating Ago2-miR-203 complex to bind to the U-rich element in p63 3′-UTR. Together, we uncovered a novel mechanism by which RBM38 modulates p63 expression via miR-203.
Note: This abstract was not presented at the meeting.
Citation Format: YANHONG ZHANG, WENSHENG YAN, JIN ZHANG, XINBIN CHEN. Modulation of p63 expression by phosphorylation of RBM38 at S195 via miR-203 [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 4491. doi:10.1158/1538-7445.AM2017-4491
Abstract 451: Germ free mice accelerate cachexia-associated cancer
Authors: Neves Rodrigo Xavier das , Roy Soumen , Dzutsev Amiran , Huang April , Smith Loretta , Difilippantonio Simone , Misty Hawes , Seelaender Marília , Trinchieri Giorgio 
Published: July 2017

Abstract
The syndrome of cancer cachexia is currently defined as a state of ill health, malnutrition and physical wasting with marked white adipose tissue (WAT) and skeletal muscle mass wasting, representing the clinical consequence of a chronic and systemic inflammatory response. Over the last decade, WAT has been recognized as an important endocrine organ, and earning a lot of attention during cancer cachexia development. We investigated the role of microbiota along the cachexia associated cancer. We performed experiments with conventional and Germ Free mice (GF) (n=6 in each group) of 8-10 weeks old C57B/6, which were subcutaneously injected with LLC cells [4x106 cells in 0.2 mL; Tumor-bearing, (TB) or PBS control (C)]. We performed Immunohistochemistry, RT- qPCR, and Western Blot. We observed that GF Tumor-bearing mice have increased several symptoms of the cachexia compared to conventional TB mice. The WAT mass was decreased 50% in GF Tumor-bearing mice compared to all groups, which indicates a pathway related to lipolysis, as we found increased level of phosphorylated enzymes in GF Tumor-bearing mice. We also observed that GF Tumor bearing mice decreased skeletal muscle mass and gene expression that are related with atrophy were increased in GF Tumor bearing mice. Our data suggested that homeostasis of microbiota may impair the development of the cachexia syndrome.
Citation Format: Rodrigo Xavier das Neves, Soumen Roy, Amiran Dzutsev, April Huang, Loretta Smith, Simone Difilippantonio, Hawes Misty, Marília Seelaender, Giorgio Trinchieri. Germ free mice accelerate cachexia-associated 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 451. doi:10.1158/1538-7445.AM2017-451
Abstract 4522: Hypoxia-induced alteration of mitochondrial dynamics is linked to chemoresistance in ovarian cancer
Authors: Han Youngjin , Kim Boyun , Song Yong Sang 
Published: July 2017

Abstract
Hypoxia, commonly observed in the tumor microenvironment, has been shown to be related to the cancer hallmarks. Hypoxia generates reactive oxygen species (ROS), inducing changes in mitochondrial function and structure in various diseases. Mitochondria, dynamic intracellular organelles, go through incessant processes of fission and fusion for efficient generation of energy. We investigated alterations in mitochondrial networks under hypoxic conditions (&lt; 1 % O2) and subsequent effects of the mitochondrial alteration on drug response in ovarian cancer cells. Mitochondrial fission was prevalent in cancer cells under hypoxic conditions. Translocation of phospho-Drp1 (Ser616), a biochemically active mitochondrial fission protein, to mitochondria was enhanced under hypoxic conditions. An increase in ROS production was accompanied under hypoxic conditions. ROS scavenging reversed the hypoxia-elicited mitochondrial fission, while exogenous H2O2 treatment promoted mitochondrial fission. These results strongly implicate that ROS are important modulators of mitochondrial dynamics under hypoxia. Interestingly, hypoxia-induced mitochondrial fission altered the response of cancer cells to cisplatin (CDDP). Ovarian cancer cells in hypoxic and normoxic conditions were differentially affected by CDDP when mitochondrial fission was inhibited. Taken together, the alteration of mitochondrial dynamics, a cellular adaptation to hypoxia, is associated with chemoresistance. Mitochondria adapted to the hypoxic tumor microenvironment could be a potential target for anti-cancer therapy.
Citation Format: Youngjin Han, Boyun Kim, Yong Sang Song. Hypoxia-induced alteration of mitochondrial dynamics is linked to chemoresistance in ovarian 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 4522. doi:10.1158/1538-7445.AM2017-4522
Abstract 4526: Attenuation of hypoxia in solid tumor with multifunctional upconversion nanoparticles to enhance photodynamic therapy
Authors: Zhang Yan , Li Jingqiu , Hu Jun , Yang Xiangliang 
Published: July 2017

Abstract
As a non-invasive therapeutic technique, photodynamic therapy (PDT) requires sufficient oxygen in order to generate adequate singlet oxygen upon the excitation of photosensitizer using an appropriate light wavelength. It has limited efficacy in preexisting hypoxia in tumor and PDT-induced hypoxia, owing to the limit oxygen level in the tissue and the consumption of the oxygen during the PDT treatment. Herein, taking advantage of hyperbaric oxygen (HBO), multifunctional upconversion nanovehicle is constructed to overcome the above-mentioned problems. HBO provides timely oxygen supply during the treatment, which greatly enhances the photodynamic effect of the loaded nanoparticles, as demonstrated by the accelerated generation of 1O2 and elevated cytotoxicity. Tumor growth is greatly regressed in the HBO-PDT treated mice. Our finding provides new insights into the modulation of unfavourable tumor microenvironment with the perfect marriage between HBO and NIR-light sensitized upconversion nanoparticles to overcome the current limitation of cancer photodynamic therapies.
Note: This abstract was not presented at the meeting.
Citation Format: Yan Zhang, Jingqiu Li, Jun Hu, Xiangliang Yang. Attenuation of hypoxia in solid tumor with multifunctional upconversion nanoparticles to enhance photodynamic 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 4526. doi:10.1158/1538-7445.AM2017-4526
Abstract 4538: UniConSig: A new algorithm for genome wide quantification of gene functions and disease associations
Authors: Chi Xu , Anurag Meenakshi , Maureen Sartor A. , Wang Xiaosong 
Published: July 2017

Abstract
One of the greatest hurdles for cancer biologists is to identify the cancer-causal genes from thousands of candidate genes suggested by large-scale genomics or deep sequencing studies. In our previous study, we discovered that cancer genes possess a complicated yet distinct “gene concept signature.” Concept Signatures include cancer-related signaling pathways, molecular interactions, transcriptional motifs, protein domains, and gene ontologies. We developed a Concept Signature (or ConSig) analysis that prioritizes the biological importance of candidate genes underlying cancer by computing their strength of association with those cancer-related signature concepts. The ConSig analysis has facilitated the discovery of a recurrent ESR1-CCDC170 gene fusion in more aggressive Luminal B breast cancers (Nat. Commun. 2014) as well as TLK2, MAP3K3, and MYST3 amplifications in aggressive luminal breast cancer (Nat. Commun. 2016, J. Pathol. 2014, Oncogene In press). Nevertheless, current candidate gene prioritization methods, including ConSig, are subject to bias from redundancy in the compiled knowledgebase (also known as gene concept database). This leads to variation of the gene ranking and jeopardizes the reliability of the priority methods. In light of these problems, we developed an innovative, universal algorithm called uniConSig. By penalizing overlapping concepts with a stable parameter, “effective concept number”, we reduced the fluctuation in uniConSig scores, and stabilized the ranking of the genes even with the randomly duplicated gene concept databases. We tested the uniConSig algorithm by identifying known cancer genes based on a cancer gene list, and found that the uniConSig algorithm demonstrated significantly enhanced prioritization of known cancer genes compared to the ConSig algorithm, and the results are stable even in the presence of randomly duplicated gene concept databases. In addition, we used calculations based on the dominant/recessive cancer gene lists, and were able to provide a quantitative measure of the potential dominant/recessive functions of human genes underlying cancer. As an example application of this algorithm, we show that the uniConSig scores can directly reveal the primary oncogene targets from genomic amplicons in breast cancer.To our knowledge, UniConSig is the first tool for genome-wide quantification of gene functions and disease associations. UniConSig has broad applications on gene prioritization for genomic-based studies to discover new disease causal genes or new gene functions.
Citation Format: Xu Chi, Meenakshi Anurag, Sartor A. Maureen, Xiaosong Wang. UniConSig: A new algorithm for genome wide quantification of gene functions and disease associations [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 4538. doi:10.1158/1538-7445.AM2017-4538
Abstract 4547: Structural, thermodynamics and kinetics role of novel hot-spot mutations of BCR-ABL1 in resistance towards "Ibs" inhibitors
Authors: Laurini Erik , Marson Domenico , Boccardo Silvia , Fermeglia Maurizio , Pricl Sabrina 
Published: July 2017

Abstract
The present contribution integrates structural, computational, and molecular biology techniques to understand the eventual role of our newly reported hot-spot mutations of the BCR-ABL1 KD in TKI resistance observed in CML patients (1) using a "two-tier level" investigation: isolated KDs and SH2-liker-SH3-KD BCR-ABL1 constructs.
Specifically, in silico experiments will disclose the effects exerted by the “hot-spot” BCR-ABL1 mutations on the protein structure, thermodynamic stability, and ability to interfere with BCR-ABL1 binding to specific TKIs (e.g., imatinib, dasatinib, and ponatinib).
Structural biology (e.g., SAXS) evidences of wild type and mutant isolated KDs and SH2-linker-SH3-KD (SSK) constructs (per se and in complex with TKIs) will be discussed to support in silico predictions. Direct drug binding thermodynamics and kinetics to both KD and SSK constructs will be measured using isothermal titration calorimetry and surface plasmon resonance.
In vitro kinase assays will monitor the ability of these mutant isoforms to auto-phosphorylate and to phosphorylate a substrate peptide.
(1) Gibbons DL, Pricl S, Posocco P, et al., Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3550-5. doi: 10.1073/pnas.1321173111
Note: This abstract was not presented at the meeting.
Citation Format: Erik Laurini, Domenico Marson, Silvia Boccardo, Maurizio Fermeglia, Sabrina Pricl. Structural, thermodynamics and kinetics role of novel hot-spot mutations of BCR-ABL1 in resistance towards "Ibs" 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 4547. doi:10.1158/1538-7445.AM2017-4547
Abstract 4549: Identification of clinically relevant patterns in complex genomic interactions of glioblastoma multiforme
Authors: Dimitrova Nevenka , Volyanskyy Konstantin , Menkovski Vlado , Cheung Yee Him , Zhong Minghao , Fallon John T. , Vail Eric 
Published: July 2017

Abstract
Background: In clinical practice of complex diseases such as cancer it is a challenging task to correctly identify driving factors and specific interactions between multitudes of genomic and clinical variables. In cancer where patterns are heterogeneous and involve highly complex interactions of biological pathways, this is by far a non-trivial task. Using novel approaches in machine learning, we demonstrate the ability to quantitatively and accurately reveal and describe patterns in genomic and clinical data.
Method: We developed a computational framework based on a number of interacting learners performing extensive pattern search and data characterization. This framework is multilevel and involves steps of relevant data transformations. We formulate and apply contextually relevant criteria to distinguish and rank iteratively obtained findings and identify hidden relations between features and characteristic connections to the clinical outcome.
Summary: We successfully tested our method on the public data of Glioblastoma Multiforme (GBM) from The Cancer Genome Atlas (TCGA). We identify interacting sets of genomic variables to represent clinically relevant subgroups of samples. We observe a dense presence of interacting known cellular processes in GBM such as EGFR, FGFR, ERK, RAS, MAPK, P53, as well as novel such as calcium signaling, kinesin motor and protein kinase pathways, tubulin and microtubule binding, phorbol esters/diacylglycerol binding domain (C1 domain), purine ribonucleoside triphosphate binding, positive regulation of phospholipase activity and others. The top ranking pathways recap the well-known and new biology. In addition, compared to known genes in the literature, we also observe involvement of novel genes in GBM subtype characterization. Finally, we propose two-fold solution: identification of distinctive patterns in the input genomic and output clinical data, and specific format of their interactions.
Citation Format: Nevenka Dimitrova, Konstantin Volyanskyy, Vlado Menkovski, Yee Him Cheung, Minghao Zhong, John T. Fallon, Eric Vail. Identification of clinically relevant patterns in complex genomic interactions of glioblastoma multiforme [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 4549. doi:10.1158/1538-7445.AM2017-4549