bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2174: A high-throughput, high-content assay for the discovery of new inhibitors of DNA double-strand break repair
Authors: Surovtseva Yulia , Jairam Vikram , Sundaram Ranjini , Bindra Ranjit , Herzon Seth 
Published: July 2016

Abstract
DNA repair pathways are being intensively investigated as targets for chemotherapeutic interventions. Despite the immense interest in this area, few whole-cell screens for the discovery of DNA repair inhibitors have been described. We have developed an automated, whole-cell, high-throughput assay for the unbiased discovery of inhibitors of the non-homologous end joining (NHEJ) and homologous recombination HR) repair pathways, the two primary pathways that ameliorate DNA double-strand breaks. Our assay enables indirect measurement of DNA repair activity by monitoring the kinetics of γH2AX and 53BP1 foci resolution after treatment with ionizing radiation (IR) and candidate DNA damage response (DDR) inhibitor. We also have developed a unique platform of secondary assays to rank-order the potency of lead compounds and gain insights into their mechanism of action. In addition to hit validation and rigorous exclusion of false-positive hits, our follow-up platform includes orthogonal assays for measuring mutagenic NHEJ and HR repair activity, as well as high-throughput assays for quantitative analysis of cell viability and cell cycle. Notably, both our primary and secondary assays are fully-automated and may be applied to screen large libraries of compounds.
We validated our high-throughput assay using known DDR and DNA damage checkpoint inhibitors, and applied this screen toward the evaluation of 2,366 structurally-diverse small molecules with known bioactivity. Vorinostat and quercetin, compounds known to possess DDR inhibitory activity, were identified in the screen, supporting the sensitivity of our approach. Notably, the screen also lead to the identification of cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, as potent inhibitors of DNA double-strand break repair. Many studies have noted the anticancer properties of the cardiac glycosides, but the basis of this activity has remained a “black box”. Our data suggest an explanation for this long-standing unsolved problem, and argue that this activity should be taken into consideration when evaluating other clinical applications of these agents. Because these compounds are already approved for use in humans, we believe they are excellent candidates for repurposing as chemo and radiosensitizers.
Citation Format: Yulia Surovtseva, Vikram Jairam, Ranjini Sundaram, Ranjit Bindra, Seth Herzon. A high-throughput, high-content assay for the discovery of new inhibitors of DNA double-strand break repair. [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 2174.
Abstract 2227: Positive correlation between the gamma-H2AX and PD-L1 expressions in lung squamous cell carcinoma
Authors: Osoegawa Atsushi , Hashimoto Takafumi , Takumi Yohei , Abe Miyuki , Hiraishi Hitomi , Suehiro Shuji , Miyawaki Michiyo , Sugio Kenji 
Published: July 2016

Abstract
Lung cancer is a leading cause of cancer death worldwide. Recently, molecular targeting therapy has been developed and it has shown promising results against advanced lung cancer. Among them, lung squamous cell carcinoma has fewer treatment options because it is not driven by oncogenic mutations, but by alterations in tumor suppressor genes and subsequent chromosomal instability. Programmed death-ligand 1 (PD-L1) is one of the immune checkpoint molecules that is expressed on the surface of tumor cells, where it inhibits activities of cytotoxic T cells. Recent studies revealed that the PD-1/PD-L1 blockade could improve the overall survival in lung squamous cell carcinoma, potentially because it carries high mutation burdens and neoantigens which could be targeted by cytotoxic T cells. We hypothesized that DNA damage could accumulate in tumors with high mutation burdens, thereby inducing the PD-L1 expression on tumor cells, sensitizing them to anti-PD-1 therapy. An immunohistochemical analysis of 41 consecutive lung squamous cell carcinoma cases, which received surgery at our institution between April 2013 and March 2014, revealed that a high PD-L1 expression was observed in 15 patients (37%) that was associated related with a poor recurrence-free survival (p = 0.028). The PD-L1 expression level was also positively associated with the γH2AX expression (a direct marker for DNA damage) (p = 0.02). The γH2AX expression in tumor cell nuclei was confirmed by immunofluorescent staining. It forms foci in tumor cell nuclei, indicating the incidence of DNA double strand breaks. Our findings demonstrate for the first time that the nuclear γH2AX expression in lung squamous cell carcinoma is positively associated with the PD-L1 expression. Further studies are warranted to investigate whether γH2AX could be a biomarker for PD-1 targeting therapy and whether combination therapy with PD-1 targeting therapy and a DNA-damaging agent has synergistic effects.
Citation Format: Atsushi Osoegawa, Takafumi Hashimoto, Yohei Takumi, Miyuki Abe, Hitomi Hiraishi, Shuji Suehiro, Michiyo Miyawaki, Kenji Sugio. Positive correlation between the gamma-H2AX and PD-L1 expressions in lung squamous cell 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 2227.
Abstract 2270: A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast cancer
Authors: Buckley Niamh E. , Haddock Paula , De Matos Simoes Ricardo , Parkes Eileen , Irwin Gareth , Emmert-Streib Frank , McQuaid Stephen , Kennedy Richard D. , Mullan Paul B. 
Published: July 2016

Abstract
Triple negative (TNBCs) and the closely related Basal-like (BLBCs) breast cancers are a loosely defined collection of cancers with poor clinical outcomes. Both show strong similarities with BRCA1-mutant breast cancers and BRCA1 dysfunction, or ‘BRCAness’, is observed in a large proportion of sporadic BLBCs. BRCA1 expression and function has been shown in vitro to modulate responses to radiation and chemotherapy. Exploitation of this knowledge in the treatment of BRCA1-mutant patients has had varying degrees of success. This reflects the significant problem of accurately detecting those patients with BRCA1 dysfunction. Moreover, not all BRCA1 mutations/loss of function result in the same histology/pathology or indeed have similar effects in modulating therapeutic responses. Given the poor clinical outcomes and lack of targeted therapy for these subtypes, a better understanding of the biology underlying these diseases is required in order to develop novel therapeutic strategies.
We have discovered a consistent NFκB hyperactivity associated with BRCA1 dysfunction as a consequence of increased Reactive Oxygen Species (ROS). This biology is found in a subset of BRCA1-mutant and triple negative breast cancer cases and confers good outcome. The increased NFκB signalling results in an anti-tumour microenvironment which may allow CD8+ cytotoxic T cells to suppress tumour progression. However, tumours lacking this NFκB-driven biology have a more tumour-promoting environment and so are associated with poorer prognosis. Tumour-derived gene expression data and cell line models imply that these tumours may benefit from alternative treatment strategies such as reprogramming the microenvironment and targeting the IGF and AR signalling pathways.
Citation Format: Niamh E. Buckley, Paula Haddock, Ricardo De Matos Simoes, Eileen Parkes, Gareth Irwin, Frank Emmert-Streib, Stephen McQuaid, Richard D. Kennedy, Paul B. Mullan. A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast 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 2270.
Abstract 2275: Intestine-specific homeobox (ISX) upregulates E2F1 expression and related oncogenic activities in HCC
Authors: Wang Shen-Nien , Wang Li-Ting , Hsu Shih-Hsien 
Published: July 2016

Abstract
Intestine-specific homeobox (ISX), a newly identified proto-oncogene, is known to regulate cell proliferation and drive hepatocellular carcinoma (HCC) formation; however, the underlying mechanisms linking gene expression and tumor formation remain obscure. In this study, we showed that ISX transcriptionally activates E2F1 expression and related oncogenic activity by directly binding to its promoter region. Mechanistically, forced ISX expression upregulated the expression and nucleus translocation of the E2F1-DP1 complex phosphorylated by the cyclin D1-CDKs complex, which promoted oncogenic activities of ISX-E2F1 axis in hepatoma cells. In addition, co-expression of both ISX and E2F1 significantly promoted cell proliferation and anti-apoptotic signals instead of apoptosis and autophagy induced by the tumor suppressors p53 and RB1. In contrast, short hairpin RNA-mediated attenuation of ISX and E2F1, respectively, in hepatoma cells decreased cell proliferation and malignant transformation in vitro and in vivo. The mRNA expression was compared in 238 paired specimens of HCC and adjacent normal tissues, and E2F1, as an expression of ISX, pathologically exhibited a tumor-specific expression pattern and was highly correlated with ISX expression, patient survival time, progression stage, and poor prognosis. Taken together, our results highlight that E2F1 is an important downstream gene of ISX in hepatoma progression.
Citation Format: Shen-Nien Wang, Li-Ting Wang, Shih-Hsien Hsu. Intestine-specific homeobox (ISX) upregulates E2F1 expression and related oncogenic activities in HCC. [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 2275.
Abstract 229: A metabolic switch controls cell fate decision-making in intestinal differentiation downstream of the tumor suppressor adenomatous polyposis coli (apc)
Authors: Sandoval Imelda T. , Delacruz Richard Glenn C. , Miller Braden N. , Satterfield Christeena , Olson Kristophor , Hill Shauna , Van Remmen Holly , Rutter Jared , Jones David A. 
Published: July 2016

Abstract
Mutation in the tumor suppressor Adenomatous Polyposis Coli (APC) is the primary initiating mutation in a majority of colon tumors. Recent studies have shown that APC positively correlates with Mitochondrial Pyruvate Carrier 1 (MPC1), a crucial player in pyruvate metabolism and has been reported to repress the Warburg effect and growth in colon cancer cells. Utilizing the zebrafish to examine the relationship between apc and mpc1, we found that mpc1 expression is reduced in embryos harboring a genetic mutation (apcmcr) or diminished expression (apc mo) of apc. Antisense morpholino knockdown of mpc1 in wild type embryos (mpc1 mo) resulted in an array of developmental defects that recapitulated phenotypes of impaired apc function including failed intestinal differentiation. This was accompanied by mitochondrial dysfunction in mpc1 mo as evidenced by a decrease in metabolic respiration and triglyceride levels. We also observed altered mitochondrial function and dysregulation of enzymes involved in pyruvate metabolism in apcmcr and apc mo. Moreover, hMPC1 RNA rescued intestinal differentiation in both zebrafish models of apc deficiency. Meta-analyses using TCGA human tumor samples corroborated our findings in the zebrafish. Our data demonstrate a novel role for apc in pyruvate metabolism through regulation of mpc1 that drives normal intestinal differentiation and support the broader idea that metabolic changes can dictate cell fate programs.
Citation Format: Imelda T. Sandoval, Richard Glenn C. Delacruz, Braden N. Miller, Christeena Satterfield, Kristophor Olson, Shauna Hill, Holly Van Remmen, Jared Rutter, David A. Jones. A metabolic switch controls cell fate decision-making in intestinal differentiation downstream of the tumor suppressor adenomatous polyposis coli (apc). [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 229.
Abstract 2326: LTX-315, an oncolytic peptide, increases anticancer immunity mediated by CTLA4 blockade in an interleukin-2 receptor beta-chain-dependent manner
Authors: Yamazaki Takahiro , Vetizou Marie , Flores Camila , Marabelle Aurelien , Sveinbjørnsson Baldur , Rekdal Øystein , Kroemer Guido , Zitvogel Laurence 
Published: July 2016

Abstract
Intratumoral immunotherapies aim at reducing local immunosuppression as well as reinstating and enhancing systemic anticancer T cell functions without inducing side effects. LTX-315 is a first-in-class oncolytic peptide -based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumour microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid derived-suppressor cells and by increasing the frequency of polyfunctional TH1/TC1 cells with a concomitant raise in their expression of CTLA4 and a drop in PD-1 expression. Logically, in tumours that were resistant to intratumoural or systemic CTLA4 blockade, subsequent local inoculation of LTX-315 cured the animals or caused tumour regressions with abscopal effects(meaning that even malignant lesions that were established in the opposite flank and were not treated by LTX-315 responded to the therapy). This synergistic interaction between CTLA4 blockade and LTX-315 was reduced upon blockade of the β-chain of the interleukin-2 receptor (CD122) which is required for signalling in response to IL-2 and IL-15. This preclinical study provides a strong rationale for administering the oncolytic peptide LTX-315 to patients who are receiving treatment with the CTLA4 blocking antibody ipilimumab.
Citation Format: Takahiro Yamazaki, Marie Vetizou, Camila Flores, Aurelien Marabelle, Baldur Sveinbjørnsson, Øystein Rekdal, Guido Kroemer, Laurence Zitvogel. LTX-315, an oncolytic peptide, increases anticancer immunity mediated by CTLA4 blockade in an interleukin-2 receptor beta-chain-dependent manner. [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 2326.
Abstract 233: Identification of cancer vulnerabilities to metabolic perturbation using genome wide CRISPR screens
Authors: Chandrashekhar Megha , Arreger Michael , Seetharaman Ashwin , Hart Traver , Moffat Jason 
Published: July 2016

Abstract
The CRISPR-Cas9 system provides an effective way to introduce targeted loss-of-function mutations in mammalian cells. The advance that the CRISPR-Cas9 technology brings to human genetics sets the stage for identifying cellular fitness genes that operate either globally (core fitness genes) or specifically within a particular genetic background or environmental context (context-specific fitness genes). In tumors, this is the foundation for the concept of synthetic lethality as genes required in tumor cells but not in adjacent normal tissues should make ideal therapeutic targets with high effectiveness and minimal side effects. Towards this goal, we have developed a second-generation CRISPR gRNA library of 176,500 guides targeting 17,661 human protein-coding genes. We used the library to screen five human cell lines, representing a cross-section of wild type and cancer tissues, to identify genes whose knockouts induce significant fitness defects. Our screens accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and identify novel context-specific vulnerabilities. Interestingly, we identified a specific dependency on mitochondrial activity and we validated this using various complex I inhibitors. This strongly supports the idea that oxidative phosphorylation (OXPHOS) dependency - a clear exception to the Warburg effect - is a targetable weakness of some tumors. In order to further understand this metabolic vulnerability, we performed a synthetic lethal screen to identify sensitizers of OXPHOS inhibition. Our screen revealed that inhibition of mitochondrial OXPHOS sensitizes the cells to loss of other metabolic pathways such as glycolysis, pentose phosphate pathway and lipid biosynthesis. Furthermore, loss of the cytosolic aspartate aminotransferase GOT1 was found to be synthetic lethal with perturbation of OXPHOS. This is consistent with the essential role of the electron transport chain in cell proliferation, which is to enable aspartate synthesis. Additionally, we also find novel genes, whose loss of function might alleviate the affect of OXPHOS perturbation. Our findings demonstrate that CRISPR-Cas9 screens enable a high-resolution view of the genetic vulnerabilities of a cell that may represent therapeutic opportunities in cancer. Further, synthetic lethal chemical-genetic screens can reveal novel functional drug combinations, which will enhance the efficacy of targeted therapies.
Citation Format: Megha Chandrashekhar, Michael Arreger, Ashwin Seetharaman, Traver Hart, Jason Moffat. Identification of cancer vulnerabilities to metabolic perturbation using genome wide CRISPR screens. [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 233.
Abstract 2338: CD39+ Treg cooperate with a CD73-expressing Th1/Th17 subset for Adenosine-mediated immunosuppression in human breast tumors
Authors: Gourdin Nicolas , Rodriguez Céline , Vigano Selena , Durand Isabelle , Faget Julien , Jandus Camilla , Blay Jean Yves , Romero Pedro , Menetrier-Caux Christine , Caux Christophe 
Published: July 2016

Abstract
Our group and others have previously reported that Treg infiltrating (Ti-Treg) breast tumors have a negative impact on patients’ outcome. We further reported their selective recruitment in the tumor environment through CCL22 secretion and expansion upon ICOS engagement by plasmacytoïd dendritic cells.
Here, we investigated the mechanism of Ti-Treg mediated suppression and observed that Ti-Treg express high CD39 levels. CD39 is an ectonucleotidase that cooperates with CD73 to degrade the danger signal ATP into immunosuppressive Adenosine (Ado). The potency of Ado mediated suppression is illustrated in Adenosine-Deaminase (ADA)-deficient patients unable to degrade Ado and developing severe immunodeficiency.
We further show that, in contrast to murine Treg, human CD39+Treg do not express CD73 enabling them only to degrade ATP into AMP. Within T cells, CD73 expression was mainly associated with naïve CD8+ T cells and a subset of memory conventional CD4+ T cells (Tconv) that exhibit Th1/Th17 characteristics (CXCR3+CCR6+CCR4negIFNγhighIL17+). CD39+ Treg isolated from healthy donor blood, in presence of exogenous ATP, potently inhibit purified CD73+ but not CD73neg Tconv, proliferation and cytokine production (IFNγ, TNFα). By using enzymatic inhibitors, we demonstrated the involvement of CD39 and CD73 through Treg/Tconv cooperation for Ado mediated immunosuppression. Of importance, when integrated in [Treg-CD4+CD73+] high density coculture, CD4+CD73neg T cells expressing similar levels of Ado receptors (A2A, A2B) are also inhibited.
In conclusion, our findings support the existence of an Ado mediated immunosuppression loop in the tumor through cooperation between CD39highTreg and CD73-expressing Th1/Th17 subsets in the breast tumor environment.
The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement n°602200.
Citation Format: Nicolas Gourdin, Céline Rodriguez, Selena Vigano, Isabelle Durand, Julien Faget, Camilla Jandus, Jean Yves Blay, Pedro Romero, Christine Menetrier-Caux, Christophe Caux. CD39+ Treg cooperate with a CD73-expressing Th1/Th17 subset for Adenosine-mediated immunosuppression in human breast tumors. [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 2338.
Abstract 234: Mitochondrial morphology as a biomarker of cancer phenotype and drug response
Authors: Giedt Randy J. , Fumene Fergulio Paolo , Pathania Divya , Yang Katherine S. , Kilcoyne Aoife , Vinegoni Claudio , Mitchison Tim J. , Weissleder Ralph 
Published: July 2016

Abstract
Mitochondria, critical organelles in quiescent and dividing cells, have been shown to vary in number, mass, and shape. While previous work has focused on understanding molecular mechanisms underlying changes in normal and immortalized cells, less is known about longer-term mitochondrial behavior such as morphological patterns in individual cells and overall populations, the heterogeneity and functional consequences of these patterns, and ultimately how potential mitochondrial heterogeneity can be exploited in the clinic. Indeed, while previous studies have been conducted illustrating mitochondrial dysfunction and morphological alterations in certain tumor types, more comprehensive analyses across tumor and cell types, as well as from cells derived from individual patients, have yet to be conducted. A primary impediment to this work is the technical challenge of consistently assaying mitochondrial morphology in diverse cell types where fixation procedures, collection techniques, and differing optical qualities between samples make potential analyses a challenging application.
We have developed an image based analytical technique to phenotype mitochondrial morphology in different cancers, including in vitro cancer cell lines and patient derived cancer cells. Our methodology is based on a combination of novel, clinically relevant collection and fixation techniques, and advanced image processing and computer learning analysis methodologies. Our results demonstrate that i) cancer cells of different origins, including patient-derived xenografts, express highly diverse mitochondrial phenotypes; ii) a given phenotype is characteristic of a cell population and fairly constant over time; iii) mitochondrial patterns correlate with cell metabolomics measurements and iv) therapeutic interventions can alter mitochondrial phenotypes in drug-sensitive cancers as measured in pre- versus post-treatment fine needle aspirates in mice. These observations shed light on the role of mitochondrial dynamics in the biology and drug response of cancer cells.
Citation Format: Randy J. Giedt, Paolo Fumene Fergulio, Divya Pathania, Katherine S. Yang, Aoife Kilcoyne, Claudio Vinegoni, Tim J. Mitchison, Ralph Weissleder. Mitochondrial morphology as a biomarker of cancer phenotype and drug response. [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 234.