tbuckley/cabot-search huggingface dataset:
Abstract 1446: Super-enhancer identification via Bru/BrUV-Seq and H3K27Ac ChIP-Seq
Authors: Chunlao Tang, Vipin Yadav, Hui-Rong Qian, Jason B. Cunningham, Hong Gao, Yushi Liu, Jason C. Ting, Steven M. Bray, Philip J. Ebert, Yuhao Lin, Amit Aggarwal, John N. Calley, Bharvin K. Patel
Journal: Cancer Research (2017)

Abstract Transcriptional super-enhancers (SEs) are large clusters of active enhancers that drive expression of genes critical to cell identity and function. In cancer and other human diseases, SEs can be acquired through somatic aberrations. Importantly, SEs and their target genes are particularly sensitive to perturbation, making this mechanism a promising target for both diagnosis and therapy. Histone modification H3K27Ac is a good single predicative marker of active enhancers, though additional marks would help. Accordingly, a common approach to SE identification is using H3K27Ac ChIP-Seq. The non-TSS (transcription start site) histone binding sites (e.g., principally excluding TSS±2.5kb regions) are mapped to genome and then subject to near-neighbor stitching (e.g., within 12.5kb). From the resulted relatively broad regions, SEs are identified by exceptional binding enrichment. Another potentially powerful approach is to use Bru/BrUV-Seq in combination. By directional sequencing of bromouridine(Bru)-labeled nascent RNAs, Bru-Seq has been developed to study nascent transcription. In the derivative BrUV-Seq, UV irradiation is additionally conducted to stabilize transcripts prior to labeling, thereby allowing more sensitive detection of TSSs and unstable transcripts, including enhancer RNAs (eRNAs). It has been shown that eRNAs indicate enhancer activity better than H3K27Ac binding. In this study, both approaches were used to identify SEs for three colon cancer cell lines, HCT-116, SW48, and SW620. We have demonstrated that Bru/BrUV-Seq has advantages in differentiating between mRNAs and eRNAs, and between overlapping transcripts; the reduced complexity helps prevent false identifications, which inflated our results obtained from ChIP-Seq. Citation Format: Chunlao Tang, Vipin Yadav, Hui-Rong Qian, Jason B. Cunningham, Hong Gao, Yushi Liu, Jason C. Ting, Steven M. Bray, Philip J. Ebert, Yuhao Lin, Amit Aggarwal, John N. Calley, Bharvin K. Patel. Super-enhancer identification via Bru/BrUV-Seq and H3K27Ac ChIP-Seq [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 1446. doi:10.1158/1538-7445.AM2017-1446
Abstract 2952: The novel cathepsin L/K inhibitors KGP94 and KGP207 prevent M0 to M2 macrophage differentiation and macrophage-mediated pro-tumor functions
Authors: Samantha S. Dykes, Dietmar W. Siemann
Journal: Cancer Research (2017)

Abstract Tumor-associated macrophages play many important roles in tumor progression, including facilitating tumor cell invasion and angiogenesis. Due to their numerous pro-tumor functions, tumor-associated macrophages represent an important cell population in the design of targeted anti-cancer therapies. Interleukin-4-mediated activation of macrophages resulted in an M2-like, or pro-tumor macrophage phenotype, often associated with increased expression of proteases including the lysosomal cathepsin L. Cathepsin L is important in both macrophage and tumor cell invasion, whereby secreted cathepsin L degrades the extracellular matrix, allowing for cell infiltration. The present study examined the role of cathepsin L in M0 to M2 differentiation and macrophage-mediated tumor cell invasion using the novel cathepsin L/K inhibitors KGP94 and KGP207 [Dr. Kevin Pinney, Baylor University]. KGP94 and KGP207 prevented M2 macrophage motility and invasion in in vitro migration and invasion assays. Moreover, KGP94 and KGP207 reduced macrophage-stimulated invasion of 4T1 murine breast cancer cells. Together, these data suggested that cathepsin L was necessary for macrophage invasion and motility and for macrophage-mediated invasion of breast cancer cells. KGP94 and KGP207 treatment partially prevented IL-4-stimulated M0 to M2 differentiation of macrophages as determined by a decrease in the IL-4-induced expression of the M2 marker Arginase-1 upon drug treatment. Additionally, exogenous recombinant cathepsin L partially stimulated the expression of Arginase-1 in M0 macrophages. Together, these data suggest that cathepsin L plays a role in macrophage M0 to M2 differentiation. In conclusion, the novel cathepsin L/K inhibitors KGP94 and KGP207 prevented M0 to M2 differentiation, macrophage invasion, and macrophage-stimulated invasion of breast cancer cells. These data highlight the importance of cathepsin L in macrophage functions and suggest that cathepsin L inhibition is a viable approach for the treatment of tumors associated with high macrophage infiltration. Citation Format: Samantha S. Dykes, Dietmar W. Siemann. The novel cathepsin L/K inhibitors KGP94 and KGP207 prevent M0 to M2 macrophage differentiation and macrophage-mediated pro-tumor functions [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 2952. doi:10.1158/1538-7445.AM2017-2952
Evolution of the prevalence of hepatitis C virus infection and hepatitis C virus genotype distribution in human immunodeficiency virus-infected patients in Italy between 1997 and 2015
Authors: B. Rossetti, F. Bai, A. Tavelli, M. Galli, A. Antinori, F. Castelli, G. Pellizzer, A. Cozzi-Lepri, S. Bonora, A.d'Arminio Monforte, M. Puoti, A. De Luca
Journal: Clinical Microbiology and Infection (2017)
Abstract LB-030: Specific missense mutations in <i>TP53</i> elicit contrasting biochemical and biological outcomes affecting prostate cancer progression
Authors: Jennifer J. McCann, Jeffry L. Dean, Renee De Leeuw, Matthew J. Schiewer, Christopher M. McNair, Karen E. Knudsen
Journal: Cancer Research (2017)

Abstract Prostatic adenocarcinoma (PCa) remains the most frequently diagnosed cancer type and the third leading cause of cancer death in men in the United States. While organ-confined disease is manageable, treatment options for disseminated PCa remain limited. First-line therapy for metastatic PCa functions through targeting the androgen receptor (AR) signaling axis, as AR activity is required for tumor maintenance. However, while treatment is initially effective, these tumors invariably recur, displaying reactivation of AR signaling despite continued therapeutic targeting. Moreover, no durable treatment currently exists for this ultimately fatal disease stage, termed castrate-resistant PCa (CRPC). Significantly, recent high profile, genome-wide studies have revealed that missense mutations in the TP53 gene occur in nearly all cancer types, and these mutations frequently occur at specific TP53 “hotspots”. Interestingly, enrichment of certain hotspot p53 mutants specifically occurs in PCa. While the underlying causes of PCa-enriched mutations remain undefined, their presence elicits contrasting, pro-oncogenic biochemical and biological phenotypes. Unpublished data suggests that mutant p53 isoforms act in a mutation-specific fashion to drive PCa progression through alterations in the canonical activity of p53, identified through characterization of their related transcriptomes and cistromes. Biologically, these mutant p53 isoforms also confer differential proliferative and survival phenotypes. Moreover they act in a mutation-dependent fashion in response to castration therapy both in vitro and in vivo. Mechanistically, pro-oncogenic mutant p53 appears to manipulate both conventional and novel pathways leading to PCa progression. These findings both corroborate and expand the recent findings that mutations in p53 drive cancer progression, and further suggest a critical role for p53 mutations as regulators of disease progression in PCa. Citation Format: Jennifer J. McCann, Jeffry L. Dean, Renee De Leeuw, Matthew J. Schiewer, Christopher M. McNair, Karen E. Knudsen. Specific missense mutations in TP53 elicit contrasting biochemical and biological outcomes affecting prostate cancer progression [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 LB-030. doi:10.1158/1538-7445.AM2017-LB-030
Abstract P391: Temporal Trends in Medical Therapies for Hospitalized ST- and Non-ST Elevation Myocardial Infarction: The Atherosclerosis Risk in Communities (ARIC) Study Community Surveillance
Authors: Emily C O'Brien, Chris D Baggett, Alvaro Alonso, Wayne D Rosamond
Journal: Circulation (2012)

Background: Reports from large studies using administrative datasets and event registries have characterized recent temporal trends and treatment patterns for AMI. However, few are population based and fewer have examined differences in patterns of treatment for patients presenting with ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI). We examined 21-year trends in the use of 10 medical therapies and procedures by STEMI and NSTEMI classification in the ARIC Community Surveillance Study. Methods: We analyzed data from an estimated 30,986 definite or probable MIs between 1987 and 2008 among residents 35-74 years of age in the four geographically defined US communities of the ARIC Study. Data on medical therapies was obtained through detailed abstraction of the medical records. Classification of STEMI and NSTEMI was based on independent Minnesota coding of electrocardiograms. We used weighted Poisson regression to estimate annual proportions of patients receiving each medication or procedure and age-standardized these estimates to the 2000 U.S. Census population. We then used weighted multivariable Poisson regression controlling for sex, race/center classification, age, and PREDICT mortality risk score to estimate average annual percent changes in medical therapy use over the study period. Results: From 1987 – 2008, 6106 (19.7%) hospitalized events were classified as STEMI, and 20302 (65.5%) were classified as NSTEMI. Among STEMI patients, increases (%; 95% CI) were noted in the use of ACE inhibitors (6.4; 5.7, 7.2), non-aspirin anti-platelets (5.0; 4.0, 6.0), lipid-lowering medications (4.5; 3.1, 5.8), beta blockers (2.7; 2.4, 3.0), aspirin (1.2; 1.0, 1.3), and heparin (0.8; 0.4, 1.3). Among NSTEMI patients, the use of ACE inhibitors (5.5; 5.0, 6.1), non-aspirin anti-platelets (3.7; 2.7, 4.7), lipid-lowering medications (3.0; 1.9, 4.1), beta blockers (4.2; 3.9, 4.4), aspirin (1.9, 1.6; 2.1), and heparin (1.7; 1.3, 2.1) increased. Calcium channel blocker use decreased for both STEMI (−8.8%;−9.6,−8.0) and NSTEMI (−5.6; −6.1,−5.1) patients over the study period. Among STEMI patients, we observed decreases in the use of thrombolytics (−7.2; −7.9, −6.6) and CABG (−2.4%; −3.6, −1.2). We noted similar decreases in the use of thrombolytics (−9.8; −10.7, −8.8) and CABG (−2.5; −3.3, −1.6) among NSTEMI patients. PCI use increased for both STEMI (6.4; 5.8, 7.0) and NSTEMI (5.1; 4.5, 5.7) patients. Increases in the use of stents were documented for both STEMI (4.5; 2.7, 6.2) and NSTEMI patients (1.3; −0.5, 3.2). Conclusion: We found trends of increasing use of evidence-based medicine for both STEMI and NSTEMI patients over the past 21 years. Future research should examine the broader public health impact of increasing adherence to clinical therapy guidelines.
Abstract 5093: In vitro, in vivo and molecular effects of stromal selective targeting by uPAR retargeted oncoytic measles virus on breast cancer progression
Authors: Yuqi Jing, Valery Chavez, Nicolas Acquavella, Doraya El-Ashry, Yuguang Ban, Xi Chen, Jaime Merchan
Journal: Cancer Research (2017)

Abstract The tumor microenvironment is a relevant target for novel biological therapies. While it has been demonstrated that tumor-stromal cell interactions are important in the sensitivity of the cancer cells to oncolytic virues, few studies have investigated the direct effects of an oncolytic virus on the stroma, and its implications on the virus antitumor efficacy. MV-m-uPA and MV-h-uPA are fully retargeted, species specific, oncolytic measles viruses directed against murine or human urokinase receptor (uPAR). The effects of stromal selective targeting by uPAR retargeted MVs were investigated. In vitro infection, gene expression and cytotoxicity by MV-h-uPA and MV-m-uPA were demonstrated in human and murine cancer cells and cancer associated fibroblasts in a species specific manner. In murine fibroblast (3T3)/human breast cancer (T47D) 3-D co-cultures, selective fibroblast targeting by MV-m-uPA inhibited breast cancer cell growth. These effects were validated in vivo, in a human breast cancer xenograft (MDA-MB-231), where intravenous administration of the murine specific MV-m-uPA led to significant tumor growth delay and improved survival compared to controls. Experiments comparing the effects of tumor (MV-h-uPA) vs. stromal (MV-m-uPA) vs. combined treatment showed that tumor and stromal targeting was associated with improved tumor control. Correlative studies demonstrated in vivo tumor targeting, increased apoptosis, and MV-m-uPA induced differential regulation of both stromal (murine) genes and cancer (human) genes associated with inflammation, angiogenesis and survival, among others, indicating viral induced modulation of tumor-stromal interactions. Our results demonstrate for the first time the feasibility of stromal selective targeting by an oncolytic MV, viral induced modulation of the tumor microenvironment, and subsequent tumor growth delay. These findings further validate the critical role of stromal uPAR in cancer progression and the potential of oncolytic viruses as anti-stromal agents. Citation Format: Yuqi Jing, Valery Chavez, Nicolas Acquavella, Doraya El-Ashry, Yuguang Ban, Xi Chen, Jaime Merchan. In vitro, in vivo and molecular effects of stromal selective targeting by uPAR retargeted oncoytic measles virus on breast cancer progression [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 5093. doi:10.1158/1538-7445.AM2017-5093
Abstract 2076: Targeting the FGFR pathway in androgen receptor negative castration resistant prostate cancer
Authors: Colm Morrissey, Eva Corey, Lisha Brown, Ilsa Coleman, Holly Nguyen, Michael Schweizer, Peter Nelson
Journal: Cancer Research (2017)

Abstract Metastatic castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. The continued importance of androgen receptor (AR) signaling as a growth and survival pathway in most advanced prostate cancer (PC) has prompted the development of therapeutics directed toward further suppressing AR ligands or the AR itself. However, total androgen blockade can give rise to AR-negative PC and currently there are no effective therapies for AR-negative PC. We have developed two novel patient-derived xenograft (PDX) models from a liver metastasis and a rib metastasis of a patient with CRPC: LuCaP 173.1 (Neuroendocrine; NE) and LuCaP 173.2 (Double negative: DN (AR-negative and NE-negative)). Using RNA-Seq we observed that both of these lines express high levels of fibroblast growth factors (FGF’s) and downstream effectors. We hypothesized that FGF signaling promotes survival and proliferation of NEPC and DNPC. To determine if blocking the FGFR survival pathway can attenuate the growth of NEPC/DNPC tumors, to characterize the molecular response and resistance to FGF signaling inhibition, and to support further evaluation in the clinic, we treated both PDX models with the FGFR inhibitor CH5183284. CH5183284 significantly reduced LuCaP 173.2 tumor volume (TV) (p&amp;lt;0.0001). The reduction in TV in CH5183284-treated animals bearing LuCaP 173.1 tumors was not as significant. To address this difference, we analyzed FGFR1 expression at the transcript and protein levels. Analysis of the FGFRs in the LuCaP 173.1 PDX model revealed a loss of FGFR1 expression. FGFR2 and FGFR3 transcripts were expressed at similar levels in both PDXs. The loss of FGFR1 expression may explain the low efficacy of CH5183284 in the LuCaP 173.1 PDX model. We are currently assessing the molecular pathways impacted by FGFR inhibition and mechanisms of resistance to treatment in these studies. We have demonstrated that FGFR inhibition attenuated tumor growth in FGFhigh AR-negative PC. We intend to target the FGFR survival pathway in additional NE and DNPC PDX models to investigate tumor heterogeneity in response to therapy and identify mechanisms of resistance. These studies will provide translational evidence that FGFR inhibitors could represent a new therapy for CRPC patients with AR-negative PC. Citation Format: Colm Morrissey, Eva Corey, Lisha Brown, Ilsa Coleman, Holly Nguyen, Michael Schweizer, Peter Nelson. Targeting the FGFR pathway in androgen receptor negative castration resistant prostate 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 2076. doi:10.1158/1538-7445.AM2017-2076
Abstract 4110: Combinatory approaches targeting EGFR, HER2 and c-MET in recurrent SCCHN
Authors: Dongsheng Wang, Kelly R. Magliocca, Sreenivas Nannapaneni, Coner Steuer, Mihir R. Patel, Mark W. El-Deiry, Xu Wang, Zhengjia Chen, Dong M. Shin, Nabil F. Saba, Zhuo G. Chen
Journal: Cancer Research (2017)

Abstract Squamous cell carcinoma of the head and neck (SCCHN) cells that escape cetuximab inhibition exhibit HER2, HER3, and/or c-Met activation. Simultaneous inhibition of EGFR, HER2, HER3 and c-Met presents an attractive clinical strategy for treating SCCHN that has progresses despite EGFR-targeted therapy. In an effort to develop new combination drug therapy options for recurrent SCCHN, we evaluated three different c-Met inhibitors in combination with a pan-HER inhibitor (afatinib/crizotinib, afatinib/tivantinib, afatinib/cabozantinib) and investigated their anti-tumoral effects. SCCHN cell lines (JHU022 highly expresses c-Met, and SCC1-C is cetuximab resistant) as well as patient derived xenograft (PDX) animal models from patients with recurrent SCCHN were investigated. In our cell line study, western-blot assay indicated that activation of EGFR, HER2, and c-Met was blocked in all three combinations. In addition the downstream PI3K/AKT and ERK signaling pathways were inhibited. Sulforhodamin B colorimetric assay (SRB) revealed SCCHN cell growth was more effectively inhibited by the combinations compared to any of the single inhibitors in vitro. Furthermore, the combination was more potent in inducing apoptosis when compared to each of the single treatments. Finally in the PDX study, all treatment groups had significantly greater efficacy compared to the non-treated control group (p&amp;lt;0.005) and all combination treatments exhibited better efficacy in tumor growth inhibition than their respective single inhibitors (p&amp;lt;0.0l). In conclusion, our study demonstrates that targeting EGFR, HER2, and c-Met with combination of their inhibitors is more effective than each of the single inhibitors alone both in vitro and in SCCHN PDX models. This study paves the way for further clinical investigation of this combination in patients with SCCHN who have progressed after cetuximab-based therapy. (This study is supported by NIH/NCI R21 CA182662-01A1 to NFS and ZGC) Citation Format: Dongsheng Wang, Kelly R. Magliocca, Sreenivas Nannapaneni, Coner Steuer, Mihir R. Patel, Mark W. El-Deiry, Xu Wang, Zhengjia Chen, Dong M. Shin, Nabil F. Saba, Zhuo G. Chen. Combinatory approaches targeting EGFR, HER2 and c-MET in recurrent SCCHN [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 4110. doi:10.1158/1538-7445.AM2017-4110
Abstract 4799: Fibroblast growth factor receptor (FGFR) promotes progression of cutaneous squamous cell carcinoma
Authors: Alok R. Khandelwal, Xiaohua Rong, Tara Moore-Medlin, Xiaohua Ma, Amelia Warner, John DiGiovanni, Cherie-Ann O. Nathan
Journal: Cancer Research (2017)

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer (16%) striking 200,000 Americans annually. Increased understanding of the mechanisms involved in pathogeneses of cSCC could identify means to prevent, inhibit and reverse this process. In our previous studies, inhibition of Fibroblast growth factor receptor (FGFR) significantly decreased Ultraviolet B-induced (UVB) epidermal hyperplasia and hyperproliferation in SKH-1 mice suggesting an important role of FGFR signaling in skin cancer prevention. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR2 in cSCC cells and normal epidermal keratinocytes revealed overexpression and increased FGFR2 activity in cSCC cells. Tumor cell-specific overexpression of FGFR2 was detected in human cSCCs and in UVB-induced mouse cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Further, treatment with a selective FGFR inhibitor; AZD4547 significantly decreased proliferation, migration, and invasion of cSCC cells in culture. The decrease in FGFR activation was associated with an inhibition of mTORC1 and mTORC2 signaling markers. Our studies provide mechanistic evidence for the role of FGFR2 in early progression of cSCC and identify FGFR as a putative therapeutic target in the treatment of skin cancer. Citation Format: Alok R. Khandelwal, Xiaohua Rong, Tara Moore-Medlin, Xiaohua Ma, Amelia Warner, John DiGiovanni, Cherie-Ann O. Nathan. Fibroblast growth factor receptor (FGFR) promotes progression of cutaneous squamous cell carcinoma [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 4799. doi:10.1158/1538-7445.AM2017-4799