tbuckley/cabot-search huggingface dataset:
Abstract 70: PARP1 as a potential therapeutic target in Merkel cell carcinoma
Authors: Renata Ferrarotto, Shirley Su, Lixia Diao, A Karina Eterovic, Victor Prieto, William Morrison, Jing Wang, Bonnie Glisson, Merrill Kies, Diana Bell
Journal: Clinical Cancer Research (2017)

Abstract Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin tumor. Patients with incurable disease are treated with the same chemotherapy agents utilized in small-cell lung cancer (SCLC) achieving similar responses. Overexpression of PARP1 is common in SCLC and promising antitumor activity of PARP inhibitors is being demonstrated in early clinical trials. Furthermore, PARP inhibitors are active in a subset of tumors harboring mutations in DNA-damage repair (DDR) genes and benefit correlates to response to platinum. Based on its similarities with SCLC, its association with DNA damage by UV light, and its sensitivity to platin, our study explores PARP1 as a therapeutic target in MCC. Methods: We evaluated the prevalence of PARP1 expression by immunohistochemistry in 19 MCC. Polyoma virus (MCPyV) status was evaluated by staining with anti-MCPyV antibody in the tissue specimens. Exome-sequencing of 263 genes was performed in 14 patients' samples using next-generation sequencing. Only mutations predicted to impair protein function in 17 genes related to DDR or mismatch repair were included in our analysis. Fisher's exact test was used for statistical significance. Results: The majority of MCC express PARP1 (84%), suggesting underlying defects in DNA damage repair. Approximately half of the tumors (47%) were associated with MCPyV. There was no statistical correlation between PARP1 expression and MCPyV status or primary site of disease. Mutations in genes predicted to impair DDR was identified in 9 samples (64%), occurred exclusively in head and neck primaries, and correlated with mutations in TP53 or RB1 (P=0.03). Mutations in ARID1A predictive to be loss-of-function and potentially confer sensitivity to PARP inhibitors were found in 36% of the patients, exclusively in MCPyV negative samples (P=0.003). Mutations in TP53 and/or RB1 were more frequent in MCPyV negative tumors (P=0.03). Conclusions: In spite of the small sample size, the high prevalence of PARP1 expression in MCC samples, similarly to SCLC, suggests that patients with MCC might also benefit from PARP1 inhibitors. Furthermore, the frequent mutations in genes involved in DNA-damage repair and ARID1A, particularly in the MCPyV negative cases, merits further characterization. Taken together, we believe clinical trials with PARP inhibitors in MCC patients should be considered. Citation Format: Renata Ferrarotto, Shirley Su, Lixia Diao, A Karina Eterovic, Victor Prieto, William Morrison, Jing Wang, Bonnie Glisson, Merrill Kies, Diana Bell. PARP1 as a potential therapeutic target in Merkel cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 70.
TTI-621 (SIRPαFc), an Immune Checkpoint Inhibitor Blocking the CD47 “Do Not Eat” Signal, Induces Objective Responses in Patients with Advanced, Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Stephen M Ansell, Ian W. Flinn, Michael B. Maris, Owen A. O'Connor, Alexander Lesokhin, Anjali S. Advani, Mark D. Minden, Mary Beth M. Percival, Lisa Ds Johnson, Tina Catalano, Meghan Irwin, Penka S. Petrova, Robert A. Uger, Eric L Sievers, Robert W. Chen
Journal: Blood (2017)
Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies
Authors: Anita Sveen, Jarle Bruun, Peter W. Eide, Ina A. Eilertsen, Lorena Ramirez, Astrid Murumägi, Mariliina Arjama, Stine A. Danielsen, Kushtrim Kryeziu, Elena Elez, Josep Tabernero, Justin Guinney, Hector G. Palmer, Arild Nesbakken, Olli Kallioniemi, Rodrigo Dienstmann, Ragnhild A. Lothe
Journal: Clinical Cancer Research (2017)

Purpose: Response to standard oncologic treatment is limited in colorectal cancer. The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing; however, drug discovery is currently limited by the lack of translation of CMS to preclinical models.Experimental Design: We analyzed CMS in primary colorectal cancers, cell lines, and patient-derived xenografts (PDX). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n = 459 drugs) to analyze subtype-specific drug sensitivities.Results: The distinct molecular and clinicopathologic characteristics of each CMS group were validated in a single-hospital series of 409 primary colorectal cancers. The new, cancer cell-adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model.Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group. Clin Cancer Res; 24(4); 794-806. ©2017 AACR.
Abstract 15643: Differential Role of Endothelial vs. VSMC STIM1 in Angiogenesis and Arteriogenesis
Authors: Maha Ali, Vishal Mali, Samuel Haddox, Mohamed Trebak, Souad Belmadani, Khalid Matrougui
Journal: Circulation (2016)

Introduction:  We previously reported that stromal-interacting molecule 1 (STIM1) plays opposing roles in vascular smooth muscle vs. endothelial cells in the regulation of vascular reactivity. In the present study, we determined the in vivo role of endothelial vs. VSMC STIM1 on angiogenesis and arteriogenesis in response to chronic ischemia.   Hypothesis:  The specific deletion of STIM1 in endothelial cell blunts angiogenesis and arteriogenesis through the induction of the endoplasmic reticulum stress and oxidative stress. Whereas, the deletion of STIM1 specifically in SMC accelerates the angiogenesis and arteriogenesis in response to chronic ischemia via the reduction in oxidative stress and ER stress.   Methods:  We specifically deleted STIM1 in endothelial cells (Stim1 EC-/-  mice) and in SMC (Stim1 SMC-/-  mice). The ischemic hind limb is the most representative model of peripheral artery disease and ischemic lower extremities that occur in diabetic patients. Stim1 EC-/- , Stim1 SMC-/- , and the wild type mice (WT: C57/Bl6) were submitted to chronic femoral artery ligation and then blood flow recovery was assessed once a week.   Results:  The blood flow recovery, which reflects angiogenesis and arteriogenesis, in Stim1E C-/-  was significantly blunted compared to Stim1 SMC-/-  and WT. Moreover, blood flow recovery in Stim1 SMC-/-  was earlier (2.5 weeks) than in WT (3 weeks). Western blot analysis in the ischemic hind limb muscle revealed the induction of the ER stress-CHOP and BIP, the increase in oxidative stress related to the augmented in the NADPH oxidase activity-Nox1-dependent, and the reduction in VEGFR2 and eNOS phosphorylation in Stim1E C-/-  compared to Stim1 SMC-/-  and WT mice.   Conclusions:  Our data demonstrated that specific deletion of STIM1 in endothelial cell impairs the basic mechanism of angiogenesis and arteriogenesis, while the specific deletion of STIM1 in VSMC accelerates angiogenesis and arteriogenesis, which will benefit type 2 diabetic patients with peripheral artery diseases and chronic ischemia in the lower extremities.
Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B
Authors: Harry L.A. Janssen, Maurizia R. Brunetto, Yoon Jun Kim, Carlo Ferrari, Benedetta Massetto, Anh-Hoa Nguyen, Adarsh Joshi, Jacky Woo, Audrey H. Lau, Anuj Gaggar, G. Mani Subramanian, Eric M. Yoshida, Sang Hoon Ahn, Naoky C.S. Tsai, Scott Fung, Edward J. Gane
Journal: Journal of Hepatology (2017)
Patient Age–Associated Mortality Risk Is Differentiated by <i>BRAF</i> V600E Status in Papillary Thyroid Cancer
Authors: Xiaopei Shen, Guangwu Zhu, Rengyun Liu, David Viola, Rossella Elisei, Efisio Puxeddu, Laura Fugazzola, Carla Colombo, Barbara Jarzab, Agnieszka Czarniecka, Alfred K. Lam, Caterina Mian, Federica Vianello, Linwah Yip, Garcilaso Riesco-Eizaguirre, Pilar Santisteban, Christine J. O’Neill, Mark S. Sywak, Roderick Clifton-Bligh, Bela Bendlova, Vlasta Sýkorová, Mingzhao Xing
Journal: Journal of Clinical Oncology (2017)

Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.
Abstract 12521: Intracellular Fatty Acid Balance Regulated by Elovl6 Plays a Notable Phenotypic Response of Vascular Smooth Muscle Cells via AMPK-KLF4-Dependent Signaling
Authors: Hiroki Matsui, Hiroaki Sunaga, Tasuya Iso, Norimichi Koitabashi, Takashi Matsuzaka, Hitoshi Shimano, Tomoyuki Yokoyama, Masahiko Kurabayashi
Journal: Circulation (2016)

Introduction: Krüppel-like factor 4 (KLF4) is a transcription factor controlling differentiation and proliferation of vascular smooth muscle cells (VSMC). We recently showed that disruption of elongation of long chain fatty acids 6 (Elovl6), rate-limiting enzyme catalyzing the elongation of saturated and monounsaturated, suppressed VSMC proliferation and differentiation via AMP-activated protein kinase (AMPK) activation. However, little is known about the role of KLF4 in passing metabolic stress on to the regulating VSMC proliferation and differentiation. Hypothesis: We examine whether KLF4 is involved in the suppression of Elovl6-disrupted VSMC proliferation. Methods and Results: Immunohistochemical staining of aorta revealed that KLF4 expression was markedly increased in Elovl6-null (Elovl6 -/- ) mice compared with wild-type mice. Western blot analysis also showed that the KLF4 expression was markedly induced in human aortic smooth muscle cell (HASMC) with siRNA-mediated Elovl6 depletion and in Elovl6 -/- mouse aorta. Previous study demonstrated that Elovl6 depletion in VSMC altered long chain fatty acid (LCFA) composition in which palmitate was increased and oleate was decreased. Accordingly, palmitate increased and oleate decreased KLF4 expression. To clarify the effects of KLF4 on cell-cycle regulatory gene expressions and cell proliferation, we examined a siRNA-mediated knockdown of KLF4 in HASMC. The expression of SMα-actin and SM22α genes were decreased in siKLF4-introduced HASMC, and siElovl6-triggered inhibition of cell proliferation was partially recovered by concomitant treatment of siKLF4. Elovl6 depletion in HASMC markedly induced p53 phosphorylation and p21 expression, whereas depletion of KLF4 abrogated the induction of these proteins. We further identified the treatment with AMPK activator (AICAR) significantly induced KLF4 expression, whereas AMPK inhibitor (compound C) markedly inhibited the AICAR-induced or Elovl6-knockdown-induced KLF4 expression. Conclusions: Overall, our results indicate that KLF4 is activated by metabolic stress triggered by perturbed intracellular LCFA composition and AMPK-KLF4 axis plays an indispensable role in controlling VSMC proliferation and differentiation
Abstract 15871: Right Atrial Function Predicts Clinical Failure in Patients With Pulmonary Arterial Hypertension
Authors: Sophia Anastasia Mouratoglou, George Giannakoulas, Vasileios Kamperidis, Vasileios Grosomanidis, Stavros Hadjimiltiades, Haralambos Karvounis
Journal: Circulation (2016)

Introduction: Right ventricular dysfunction is a well recognized determinant of survival in patients with pulmonary arterial hypertension (PAH). However, there is limited data on the role of right ...
Abstract A02: Comparative analysis of breast density among Black, White, and Hispanic women presenting for screening mammography
Authors: Bridget A. Oppong, Chiranjeev Dash, Suzanne Oneill, Kepher Makambi, Tesha Coleman, Lucile L. Adams-Campbell
Journal: Cancer Research (2017)

Abstract Background: Data on ethnic variations in breast density are limited and often not inclusive of underrepresented minorities, including Black and Hispanic women. As breast density is associated with elevated breast cancer risk, investigating racial and ethnic difference may elucidate the observed differences in breast cancer risk among different populations. Methods: We reviewed breast density recorded at the initial mammographic screening study in women presenting to the Capital Breast Care Center (CBCC) and Georgetown University Hospital (GUH) from 2010 to 2014. Patient demographics including race, age at screening, education and menopausal status were abstracted in addition to body mass index (BMI). From imaging reports, we recorded the BI-RADS density categories: 1-fatty, 2-scattered fibroglandular densities, 3-heterogeneously dense and 4-extremely dense. Multivariable unconditional logistic regression was used to identify predictors of breast density. Results: Density categorization was recorded for 2,146 women over the five-year period, with 940 (43.8%) Black, 893 (41.6%), Hispanic and 314 (14.6%) White. Analysis of subject characteristics by low density (categories 1 and 2) and high density (categories 3 and 4) show that high category is observed in younger, Hispanic, nulliparous, premenopausal and non-obese women (P-values &amp;lt;.0001). Obese women are 70% less likely to have high breast density compared to non-obese women. Being Hispanic, premenopausal, and non-obese were predictive of high mammographic density on logistic regression. Conclusion: In this analysis of density distribution in a diverse sample of women presenting for mammography, Hispanic women have the highest breast density, followed by Black women with Whites having the lowest. Unique in our findings is women who identify as Hispanic having the highest breast density and lower rates of obesity. Further investigation of the impact of obesity on breast density in minority women, especially in the understudied Hispanic group is needed. Citation Format: Bridget A. Oppong, Chiranjeev Dash, Suzanne Oneill, Kepher Makambi, Tesha Coleman, Lucile L. Adams-Campbell. Comparative analysis of breast density among Black, White, and Hispanic women presenting for screening mammography [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A02.
Trends in Antiplatelet Therapy Pre and Post Carotid Endarterectomy – A Sticking Point in Current Practice?
Authors: A. Stimpson, None N.Tanner, S. Stevens, J. Ma, B. Tinsley, C. Brown, L. Hpkins, D. Loughran, S. Tate, K. Boyce, R. Harries, D. Bosanquet
Journal: International Journal of Surgery (2017)
Transcriptional regulation in human bladder cancer cells by RalA and RalB via both independent and overlapping pathways
Authors: Gary Oxford, Steven C. Smith, Tonia L. Foreman, Charles R. Owens, Garret M. Hampton, Dan Theodorescu
Journal: Cancer Research (2006)

4276  The monomeric GTPases RalA and RalB have been shown to contribute to human tumorigenesis and cancer progression in a number of ways. In some cases, RalA and RalB appear to have overlapping roles, but for at least two phenotypes, colony formation in soft agar and motility, they have been shown to act antagonistically. RalA and RalB have been shown to regulate a small set of transcription factors - NF-kappaB, the forkhead protein FoxO4, ZONAB - although in some cases, the specificity of transcriptional regulation of RalA vs. RalB remains unclear. What also remains unclear is the relevance of transcriptional regulation mediated by RalA and/or RalB to their roles in human cancer. Here, we studied the importance of RalA and/or RalB to trancriptional regulation in the human bladder cancer cell line, UMUC-3, by combining siRNA depletion Ral with gene expression analysis via microarray. RalA knockdown resulted in significant up-regulation of 95 genes (> 2 fold) and down-regulation of 156 genes (
Abstract 14003: Prognosis Value of Aortic Valve Calcium Scoring After Transcatheter Aortic Valve Implantation performed With New Generation Prosthesis
Authors: Florence Leclercq, Myriam Akodad, Audrey Agullo, Jean Christophe Macia, Gregory Marin, Benoit Lattuca, Thomas Gandet, Laurent Schmutz, Bernard Albat, Guillaume Cayla
Journal: Circulation (2016)

Introduction: The degree of aortic valve calcification has been shown to be associated with paravalvular aortic regurgitation (AR) and mortality after transcatheter aortic valve implantation (TAVI). Hypothesis: Calcium scoring of the aortic valve might no longer be a prognosis factor of adverse events after implantation of new devices designed to reduce paravalvular leaks. Methods: In a prospective monocentric study, Agatson calcium score (CS) was evaluated on multislice computed tomography (MSCT) before TAVI in consecutive patients who had TAVI with balloon expandable SAPIEN XT (n=61) or self expandable CoreValve (n=57) (group 1, n=118), and in patients who received the new generation balloon expandable SAPIEN 3 valve (n=142). Major adverse clinical events were evaluated at 1-month follow-up (VARC-2 criteria) Results: Main clinical characteristics did not significantly differ between the 2 groups excepted concerning logistic Euroscore (20.1% in group 1 vs 15.1% in group 2; p=0.001). Pre procedural CS value was 4092+/- 2176 in group 1 vs 4209+/- 2204 in group 2 (p=0.9). At follow-up incidence of more-than-mild AR was significantly higher in group 1 vs group 2 (n=27; 22.9% and n=10; 7.1 % respectively, p &lt;0.01). CS was associated with occurrence of AR in group 1 (3429 +/- 1505 without AR vs 6234 +/- 2711 with AR; p&lt;0.001), but not in group 2 (4663+/- 3057 vs 4176+/- 2149 respectively; p=0.9). Similarly, CS was associated with adverse clinical events only in group 1 (table 1). A CS value &gt; 6000 was a major predictor of adverse events in group 1 (OR: 106; IC 95: 15.5-727.6; p&lt;0.0001) but not in group 2 (p=0.4). Conclusions: Severe calcifications of the aortic valve evaluated on MSCT appear to be an major prognostic parameter after TAVI performed with the second generation prosthesis but not with the new designed SAPIEN 3 valves. Impact of CS on patient selection before TAVI need probably to be reconsidered with the new generation devices .
Identification and characterization of a novel activating mutation of the FLT3 tyrosine kinase in AML
Authors: J. Jiang, J. G. Paez, J. Lee, R. Bo, R. Stone, D. Deangelo, I. Galinski, E. Fox, E. Weisberg, J. D. Griffin, D. G. Gilliland, M. Meyerson, W. R. Sellers
Journal: Cancer Research (2004)

3941  Hypomethylation of centromeric and pericentromeric repetitive DNA sequences is a widespread feature of many cancers including Wilms tumour, a childhood tumour of the kidney. Hypomethylation in these regions is thought to cause genomic instability which can give rise to subsequent chromosomal rearrangements. We have previously shown that approximately 60% of relapsing Wilms tumours have gain of chromosome 1q. This is a result of various mechanisms including an unbalanced t(1;16)(q12;q11-21) translocation, isochromosome 1q as well as duplication of the q arm. We hypothesized that relapsing tumours may demonstrate more hypomethylation in these regions than non relapsing tumours. We investigated the relationship between relapsing Wilms tumours and satellite DNA hypomethylation using DNA probes from the pericentromeric regions of chromosomes 1 and 16 and the centromeric region of chromosome 1. A total of 85 samples from 76 patients were analysed. 48 samples were from patients who relapsed. 32 were taken at the time of diagnosis and 16 taken at the time of relapse, including 8 matched pairs (i.e samples taken at the time of diagnosis and subsequent relapse from the same patient). 31 samples were taken from patients who did not relapse (follow up >2 years). We found that hypomethylation at all three loci examined was a common feature of Wilms tumour. However, there were no significant differences in the proportion demonstrating satellite hypomethylation between tumours that relapsed versus those that did not. D1Z1 chromosome 1 pericentromeric locus: 66.6% (32/48) hypomethylation in relapsing tumours versus 70.9% (22/31) in non relapsing tumours; D1Z5 chromosome 1 centromeric locus: 77.7% (21/27) relapsing versus 80.9% (17/21) non relapsing tumours; D16Z3 chromosome 16 pericentromeric locus: 22/41 (53.6%) relapsing versus 13/21 (61.9%) non relapsing tumours.In the 8 matched pairs analysed at both diagnosis and relapse, there was no evidence for increasing hypomethylation with clonal evolution, though numbers analysed were small. Paradoxically tumours with gain of chromosome 1q showed a trend towards less hypomethylation (10/16, 62%) than those without 1q gain (13/14, 92.8%) (p=0.086) . This suggests that the observed gain of genomic material on 1q is not solely the result of karyotypic instability induced through hypomethylation and that other mechanisms must be contributing.
Photodynamic and photothermal tumor therapy using phase-change material nanoparticles containing chlorin e6 and nanodiamonds
Authors: Tae-Kyung Ryu, Seung-Woon Baek, Rae-Hyung Kang, Ki-Young Jeong, Dae-Ryong Jun, Sung-Wook Choi
Journal: Journal of Controlled Release (2017)