tbuckley/cabot-search huggingface dataset:
Bladder cancer global unbiased chromatin landscape characterization by DHS-seq to identify novel features unique for each stage of progression.
Authors: Lyuba Varticovski, Sohyoung Kim, Michael Nickerson, Lars Grontved, Qizong Lao, Bethtrice Thompson, Dan Theodorescu, Gordon Hager
Journal: Journal of Clinical Oncology (2014)

e15500 Background: Metastatic bladder cancer carries poor prognosis and, in spite of extensive sequencing efforts, only few known driving mutations have been identified for this tumor type. However, mutations or deletions of chromatin modifying enzymes may be responsible for altered gene expression involving an estimate of >2,300 coding sequences in high-grade bladder cancer. Thus, chromatin organization may play an important role in bladder cancer initiation and progression. Methods: In vivo passaging of human poorly tumorigenic cell line (T24), selection of tumorigenic (T24T) and subsequently metastatic lines to the lung (FLT) or liver (SLT) provide a valuable model for analysis of mechanisms associated with tumor progression. Using these cells, we obtained whole exome sequencing, microarray and DNase I hypersensitivity combined with deep sequencing (DHS-seq). Bioinformatics of DHS-seq was performed using algorithms developed at LRBGE and compared with changes in mRNA expression using Ingenuity Pathways (IPA). Results: Mutations in several genes, including p53, RAS, TERT, and chromatin remodeler UTX (KDM6A), were detected in all cell lines. But only few additional mutations were associated with progression to metastatic phenotypes, including mutations in DNMT1. In spite of paucity of driver mutations, changes in gene expression marked progression from poorly tumorigenic T24 to tumorigenic but weakly metastatic cells T24T, with the highest score seen in genes involved in Cell-to-Cell interaction, decrease in genes involved in cell adhesion and changes in genes associated with EMT. Gene expression profile for most genes correlated with changes in DHS-seq. However, DHS analysis identified many additional novel changes, some located in upstream and downstream enhancer regions and some were unique for each stage of tumor progression. Conclusions: Our analysis of bladder cancer progression shows feasibility of establishing clinically relevant signature based on global unbiased chromatin landscape analysis. Combination of exome sequencing, microarray and DHS analysis offers valuable new information on bladder cancer biology and tumor progression.
Abstract 1288: Targeting the Hippo pathway in NF-2 deficient papillary kidney cancers
Authors: Carole Sourbier, Penny Liao, Christopher J. Ricketts, Darmood Wei, Youfeng Yang, Sarah M. Baranes, Toshiki Kijima, Louis S. Krane, Myriem Boufraqech, Lernik Ohanjanian, Ben Gibbs, Ming-Hui Wei, Len Neckers, Cathy D. Vocke, W. Marston Linehan.
Journal: Cancer Research (2016)

Abstract About 10% of papillary renal cell carcinomas (PRCC) bear mutations in NF2 or SAV1, two members of the Hippo pathway, which controls cell growth by regulating the transcriptional activity of YES1-Associated Protein YAP1. NF2 or SAV1 mutations lead to aberrant YAP1 activation resulting in cell proliferation and anti-apoptotic signals. The src family kinase YES1 is a known regulator of YAP1 transcriptional activity in the context of β-catenin-dependent tumors. Dasatinib and saracatinib are 2 src inhibitors that have shown to also have potent inhibitory effects on YES1. We hypothesized that inhibition of the Hippo pathway might provide a valuable therapeutic approach for patients with PRCC tumors bearing NF2 mutation, and that inhibiting YES1 might inhibit YAP1 in PRCC. Our data demonstrate that inhibition of the Hippo pathway is lethal to NF2-deficient PRCC cell lines, and that inhibiting YES1 with dasatinib or saracatinib effectively inhibits YAP1 and its downstream targets BIRC5 (survivin), CCND1 (cyclin D1) and CTGF (CTGF). Further, dasatinib proves to have an anti-tumor effect in vivo and was cytotoxic in vivo and in vitro, causing G0-G1 cell cycle arrest in NF2-deficient PRCC cell lines. Thus, inhibiting YES1 and the subsequent transcriptional activity of YAP1 with dasatinib or saracatinib might be a viable therapeutic approach for NF2-deficient PRCC tumors. Citation Format: Carole Sourbier, Penny Liao, Christopher J. Ricketts, Darmood Wei, Youfeng Yang, Sarah M. Baranes, Toshiki Kijima, Louis S. Krane, Myriem Boufraqech, Lernik Ohanjanian, Ben Gibbs, Ming-Hui Wei, Len Neckers, Cathy D. Vocke, W. Marston Linehan. Targeting the Hippo pathway in NF-2 deficient papillary kidney cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1288.
Lentiviral Hematopoietic Stem Cell Gene Therapy for Older Patients with X-Linked Severe Combined Immunodeficiency
Authors: Suk See De Ravin, Xiaolin Wu, Narda Theobald, Janet S Lee, John Gray, Imelda Celine Hanson, Luigi Notarangelo, Brian P. Sorrentino, Harry L. Malech
Journal: Blood (2015)
Abstract 4362: T cell repertoire diversification is associated with immune related toxicities following immune checkpoint inhibition in metastatic cancer patients
Authors: David Y. Oh, Jason Cham, Li Zhang, Grant Fong, Mark Klinger, Malek Faham, Lawrence Fong
Journal: Cancer Research (2016)

Abstract Immune checkpoint inhibitors can induce clinical responses to a broad range of tumor types by presumably enhancing T cell responses against the tumor. These treatments are also associated with certain side effects that are also thought to be immune mediated (termed immune-related adverse events, or IRAEs). The mechanism by which IRAEs occur, and biomarkers that may predict IRAE development, are unknown. In prior work (Cha et al. Sci Transl Med 2014), we demonstrated that treating metastatic cancer patients with checkpoint inhibitors blocking CTLA-4 can lead to T cell repertoire diversification. However, we found that prolonged survival was not associated with the induction of high frequency clonotypes, but rather the maintenance of a pre-existing T cell response. Here, we examined whether treatment-induced TCR diversification is related to another clinical outcome: the development of IRAEs. We find that IRAEs are specifically associated with a more diverse T cell repertoire and with an increase in the number of T cell clonotypes, including the generation of de novo clones. This broadening of the circulating T cell repertoire occurred early with treatment, preceding the development of IRAEs. While IRAE patients demonstrate markedly greater diversity in their CD4+ T cells, they demonstrate a greater degree of change in clonal frequencies in their CD8+ T cells after ipilimumab, which may have key implications in the pathogenic mechanism of IRAE development. Finally, clinical response to checkpoint blockade is also associated with increased diversity. These results indicate that immune repertoire diversity following immune checkpoint inhibition can be both detrimental and beneficial to patients with metastatic cancer. Citation Format: David Y. Oh, Jason Cham, Li Zhang, Grant Fong, Mark Klinger, Malek Faham, Lawrence Fong. T cell repertoire diversification is associated with immune related toxicities following immune checkpoint inhibition in metastatic 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 4362.
Abstract 1979: Comprehensive analysis of the dynamics of aberrant WNT signaling on global gene expression and higher order nuclear structure in human cells
Authors: Markus Brown, Darawalee Wangsa, Yue Hu, Thomas Ried
Journal: Cancer Research (2016)

Abstract The organization of the genome in the nucleus is complex and dynamic. Features of the nuclear architecture, including the spatial arrangement of genomic sequences, the structure of chromatin, and the accessibility of regulatory DNA elements modulate nuclear processes such as gene transcription DNA replication, DNA repair, RNA processing, and mRNA transport. However, the interplay between nuclear architecture and gene expression is poorly understood. We propose to elucidate the impact of silencing the prominent transcription factor, TCF7L2, the major effector of the WNT signaling pathway, on the transcriptional equilibrium and nuclear architecture of the nucleus in human colorectal cancer cells. Our multidisciplinary approach combines targeted silencing of TCF7L2, 3D-FISH, RNA-seq, and Hi-C chromosome conformation capture, in parallel with mathematical modeling to delineate structure/function relationships in the interphase nucleus. This approach will elucidate the intricacies of a dynamic cellular signaling pathway in three-dimensional space. Citation Format: Markus Brown, Darawalee Wangsa, Yue Hu, Thomas Ried. Comprehensive analysis of the dynamics of aberrant WNT signaling on global gene expression and higher order nuclear structure in human 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 1979.
Abstract 2708: Development of an individualized 3D transport model of topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma
Authors: Abbas Shirinifard, Suresh Thiagarajan, Yogesh T. Patel, Abigail D. Davis, Megan O. Jacus, Stacy L. Throm, Jessica Roberts, Vinay Daryani, Clinton F. Stewart, András Sablauer.
Journal: Cancer Research (2016)

Abstract Resistance to chemotherapeutics and targeted therapies in pediatric solid tumors including neuroblastoma is a common cause of poor clinical outcome. These failures in part stem from shortcomings in understanding inter- and intra-tumor heterogeneities of drug penetration due to heterogeneities in blood perfusion. Herein we propose to develop an individualized 3D transport model of topotecan (TPT) for a patient-derived orthotopic xenograft model of pediatric NB5 neuroblastoma to account for inter- and intra-tumor heterogeneities in blood perfusion. The transport model uses a 3D reaction-diffusion equation to simulate diffusion of TPT from blood vessels into the tumor tissue and its flux in and out of intracellular space. Our transport model takes three types of inputs to predict TPT exposure maps defined over the volume of an individual tumor: a) plasma concentration-time profiles from an individualized physiologically-based pharmacokinetic (PBPK) model of TPT (separate cohort), b) 3D blood perfusion map of the individual tumor from contrast enhanced ultrasound (CEUS) using VisualSonics VEVO 2100 imaging system, and c) in vitro TPT cellular uptake and efflux kinetics from two-photon imaging. We use in vitro pharmacodynamics (PD) experiments with NB5 cells exposed to TPT to derive probabilistic PD-rules for drug effects (e.g., γ-H2AX response). Based on these rules and the exposure maps, we then compute probabilities of effects for the entire tumor volume. We will validate the predicted drug effect maps by comparing them to the observed effects measured by immunohistochemistry marker for γ-H2AX from the same tumor (location matched) using spatial correlation techniques. Citation Format: Abbas Shirinifard, Suresh Thiagarajan, Yogesh T. Patel, Abigail D. Davis, Megan O. Jacus, Stacy L. Throm, Jessica Roberts, Vinay Daryani, Clinton F. Stewart, András Sablauer. Development of an individualized 3D transport model of topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma. [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 2708.
Abstract 4315: Effects of increased dietary fat consumption on prostate cancer progression in genetically engineered mice
Authors: Marco A. De Velasco, Yurie Kura, Yuji Hatanaka, Takashi Oki, Yutaka Yamamoto, Koichi Sugimoto, Yasunori Mori, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2016)

Abstract Prostate cancer is a highly heterogeneous disease and evidence indicates that lifestyle and environmental factors can contribute to cancer-related deaths. Accumulating data also suggests that increased dietary fat consumption may promote and increase the risk of prostate cancer-related morbidity and mortality. However, data between studies is inconsistent and a direct link between increased consumption of dietary fat and the promotion of prostate cancer remains unclear. Here, we present our findings from a preclinical study of increased dietary fat consumption and its effects on prostate tumor growth and progression using genetically engineered mouse models of prostate cancer. We determined the effects of a high fat diet on tumor cell proliferation and apoptosis in vivo using a well-established mouse model of prostate cancer. Twenty-week-old mice, with conditional biallelic deletion of PTEN, harboring castration-naïve or castration-resistant prostate tumors were randomized and assigned to a standard laboratory diet (4% fat) or a high-fat diet (HFD, 13.6% fat) for 8 weeks. In both tumor models, mice fed a HFD had increased expression levels of proteins associated with proliferation and decreased levels of apoptosis markers. To determine the long term effects of a HFD, we used a mouse model of advanced prostate cancer. Mice with concomitant inactivation of PTEN and p53 develop tumors that progress quickly and are characterized with increased metastatic development and decreased survival compared to PTEN knockout mice. PTEN/p53 double knockout mice were randomized and assigned to control or HFD experimental groups after weaning. Our findings revealed that mice fed a HFD resulted in obesity that led to decreased progression-free survival and overall survival rates compared to mice fed a standard diet. Our results provide evidence to support the effects of high dietary fat consumption and increased prostate cancer risk, and provide a platform to investigate chemoprevention strategies. Citation Format: Marco A. De Velasco, Yurie Kura, Yuji Hatanaka, Takashi Oki, Yutaka Yamamoto, Koichi Sugimoto, Yasunori Mori, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Effects of increased dietary fat consumption on prostate cancer progression in genetically engineered mice. [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 4315.
Abstract SY15-01: SWI/SNF (BAF) complex mutations in cancer: Mechanisms and vulnerabilities
Authors: Charles W.M. Roberts.
Journal: Cancer Research (2016)

Abstract Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least nine different SWI/SNF subunits, collectively identified in twenty percent of all cancers. These include recurrent mutations of ARID1A (BAF250a) in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers and neuroblastoma; of the BRG1 (SMARCA4) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when SNF5 (SMARCB1/INI1/BAF47) became the first SWI/SNF subunit linked to tumor suppression over fifteen years ago when it was found to be biallelically inactivated in nearly all cases of a highly aggressive type of pediatric cancer called malignant rhabdoid tumor (MRT). Despite the extremely aggressive and lethal nature of MRT we have shown that these cancers are diploid and have remarkably simple genomes. We now study the complex using mouse models, cell lines and primary human tumor samples. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented including our recent efforts that identify EZH2 and polycomb complexes as potential therapeutic vulnerabilities in these cancers. Citation Format: Charles W.M. Roberts. SWI/SNF (BAF) complex mutations in cancer: Mechanisms and vulnerabilities. [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 SY15-01.
Abstract 2838: The role of cyclin D1-associated kinase activity in the regulation of autophagy and senescence in gastric cancer cells
Authors: Leandro Vargas, Sindy Bravo, Claudio Valenzuela, Nelson E. Brown
Journal: Cancer Research (2016)

Abstract Introduction: Cyclin D1 regulates cell cycle progression through its ability to bind and activate cyclin-dependent kinases 4 and 6 (CDK4/6). Recent work carried out in mammary epithelial cells (MECs) propagated in vitro has revealed that the functional status of cyclin D1 modulates a balance between senescence and autophagy, two processes commonly disrupted in human cancers. Thus, in contrast to the commonly held assumption that autophagy is an effector process of senescence, inhibition of autophagy was accompanied by an induction or exacerbation of senescence in MECs deficient in cyclin D1-associated kinase activity, a reflection of the pro-survival function of autophagy in these cells. Materials and methods: In the present study, we set out to confirm these findings in gastric cancer cell lines (AGS, MKN-45 and KATO III) that may differ in their ability to induce senescence. To this end, we first treated AGS (cyclin D1+; pRB+; p53+) cells with Palbociclib (a specific inhibitor of cyclin D-CDK4/6 complexes), Spautin-1 (a specific inhibitor of autophagy), or a combination of these drugs, and assessed the effect of the treatment on the ability of these cells to proliferate or undergo senescence. Results and discussion: Unlike what was previously reported, our results suggest that autophagy is not required for the implementation of the senescent phenotype in AGS cells treated with Palbociclib. Nonetheless, senescent cells in which autophagy was disrupted were larger and often displayed multiple nuclei, suggesting the existence of different senescence programs depending on autophagy function. Citation Format: Leandro Vargas, Sindy Bravo, Claudio Valenzuela, Nelson E. Brown. The role of cyclin D1-associated kinase activity in the regulation of autophagy and senescence in gastric cancer 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 2838.
Abstract 2450: MYCN and TFAP4 promote neuroblastoma malignancy by cooperating in the regulation a subset of target genes involved in cancer cell growth and metastasis
Authors: Chengyuan Xue, Denise M. Yu, Samuele Gherardi, Jessica Koach, Giorgio Milazzo, Laura Gamble, Bing Liu, Amanda Russell, Tao Liu, Belamy B. Cheung, Glenn M. Marshall, Giovanni Perini, Michelle Haber, Murray D. Norris
Journal: Cancer Research (2016)

Abstract Amplification of the MYCN oncogene, a member of the MYC family of transcriptional regulators, is one of the most powerful prognostic markers identified for poor outcome in neuroblastoma, the most common extracranial solid cancer in childhood. While MYCN has been established as a key driver of malignancy in neuroblastoma, the underlying molecular mechanisms are poorly understood. Transcription factor activating enhancer binding protein-4 (TFAP4), which plays important roles in cancer progression, has been reported to be a direct transcriptional target of MYC. In this study, we have shown that high expression of TFAP4 in primary neuroblastoma patients is associated with poor clinical outcome and furthermore that siRNA-mediated suppression of TFAP4 in MYCN-expressing neuroblastoma cells impaired migration and colony formation, and led to an increased proportion of cells in G1/S phase of the cell cycle. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that TFAP4 expression is positively regulated by MYCN through direct promoter binding. In addition, when MYCN was overexpressed in neuroblastoma cells, TFAP4 was required for the observed increase in cell migration. Microarray analysis identified genes regulated by both MYCN and TFAP4 in neuroblastoma cells, including Phosphoribosyl-pyrophosphate synthetase-2 (PRPS2) and Syndecan-1 (SDC1), which are involved in cancer cell proliferation and metastasis. Overall this study unveils a complex regulatory circuit in which MYCN by elevating TFAP4 expression, cooperates with it to control a specific set of genes involved in tumor progression. These findings highlight the existence of a MYCN-TFAP4 axis in MYCN-driven neuroblastoma as well as identifying relevant therapeutic targets for aggressive forms of this disease. Citation Format: Chengyuan Xue, Denise M. Yu, Samuele Gherardi, Jessica Koach, Giorgio Milazzo, Laura Gamble, Bing Liu, Amanda Russell, Tao Liu, Belamy B. Cheung, Glenn M. Marshall, Giovanni Perini, Michelle Haber, Murray D. Norris. MYCN and TFAP4 promote neuroblastoma malignancy by cooperating in the regulation a subset of target genes involved in cancer cell growth and metastasis. [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 2450.
Flow-mediated arterial dilation is abnormal in congestive heart failure
Authors: D. Hayoz, H. Drexler, T. Münzel, B. Hornig, A. M. Zeiher, H. Just, H. R. Brunner, R. Zelis
Journal: Circulation (1993)

Backround. Abnormalities in endothelium-dependent relaxation to acetylcholine have been reported in congestive heart failure (CHF). The purpose of this study was to determine whether there are abnormalities in flow-mediated large vessel relaxation in patients with chronic CHF. Methods and Results. The dilator response of the radial artery was measured by a new high precision A-mode ultrasound device in response to release of 10 minutes of forearm arterial occlusion (reactive hyperemic blood flow response, (HBF). Radial arterial blood velocity was measured simultaneously, and blood flow was calculated. In nine patients with chronic CHF, there was a small but insignificant reduction of peak RHFB (p=0.09) when compared with nine age-matched control subjects