tbuckley/cabot-search huggingface dataset:
Undifferentiated Sarcomas in Children Harbor Clinically Relevant Oncogenic Fusions and Gene Copy-Number Alterations: A Report from the Children's Oncology Group
Authors: Theodore W. Laetsch, Angshumoy Roy, Lin Xu, Jennifer O. Black, Cheryl M. Coffin, Yueh-Yun Chi, Jing Tian, Sheri L. Spunt, Douglas S. Hawkins, Julia A. Bridge, D. Williams Parsons, Stephen X. Skapek
Journal: Clinical Cancer Research (2018)

Purpose: A comprehensive analysis of the genomics of undifferentiated sarcomas (UDS) is lacking. We analyzed copy-number alterations and fusion status in patients with UDS prospectively treated on Children's Oncology Group protocol ARST0332.Experimental Design: Copy-number alterations were assessed by OncoScan FFPE Express on 32 UDS. Whole-exome and transcriptome libraries from eight tumors with sufficient archived material were sequenced on HiSeq (2 × 100 bp). Targeted RNA-sequencing using Archer chemistry was performed on two additional cases.Results: Five-year overall survival for patients with UDS was 83% (95% CI, 69%-97%) with risk-adapted therapy (surgery, chemotherapy, and radiotherapy). Both focal and arm-level copy-number alterations were common including gain of 1q (8/32, 25%) and loss of 1p (7/32, 22%), both of which occurred more often in clinically defined high-risk tumors. Tumors with both loss of 1p and gain of 1q carried an especially poor prognosis with a 5-year event-free survival of 20%. GISTIC analysis identified recurrent amplification of FGF1 on 5q31.3 (q = 0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q = 0.07). Known oncogenic fusions were identified in eight of 10 cases analyzed by next-generation sequencing.Conclusions: Pediatric UDS generally has a good outcome with risk-adapted therapy. A high-risk subset of patients whose tumors have copy-number loss of 1p and gain of 1q was identified with only 20% survival. Oncogenic fusions are common in UDS, and next-generation sequencing should be considered for children with UDS to refine the diagnosis and identify potentially targetable drivers. Clin Cancer Res; 24(16); 3888-97. ©2018 AACR.
Abstract 17765: A Meta-analysis of Outcomes at Two and Five Years After the Conclusion of Randomised Controlled Trials of Statin Therapy
Authors: Jordan Fulcher, Rachel O'Connell, Val Gebski, Anthony Keech
Journal: Circulation (2015)

Introduction: We examined the long term outcomes for patients in randomised statin trials to investigate if benefits are maintained from on-trial statin therapy Methods: Using published time to event outcome data for statin and control arm participants with long term observational follow-up, we performed inverse variance meta-analyses of derived hazard ratios at trial end, two years post trial and five years post trial for mortality outcomes, major coronary events and incident cancer. Results: Long term follow-up data was available for patients for various endpoints from eight statin vs control trials (Table 1). Where reported, similar proportions of patients from each trial arm used statin therapy after trial end. Combined results showed significant reductions in the risk of all-cause mortality, cardiovascular mortality coronary mortality and major coronary events for patients in the statin arm at trial end. For three trials, benefits of prior statin therapy on total mortality five years post trial appeared greater than at study close whereas they remained similar or slightly smaller among the other four trials. In combination the majority of the accrued trial benefits appeared preserved at two years post trial and five years post trial, with the magnitude of risk reduction being only slightly smaller over this time. No effect was observed on the risk of cancer at any timepoint (Table 2). Conclusions: Participants allocated statin therapy in randomised trials maintained cardiovascular and mortality benefits for at least five years after trial end.
TCTAP A-152 Clinical Outcomes of Contemporary Drug-eluting Stents in Patients With and Without Diabetes Mellitus : Multi-Group Propensity-Score Analysis Using Data from Stent-Specific, Multi-Center, Prospective Registries
Authors: Osung Kwon, Jung-Bok Lee, Sun Hack Lee, Sangwoo Park, Tae-Oh Kim, Yong-Hoon Yoon, Sang Yong Om, Minsoo Kim, Hanbit Park, Sang-Cheol Cho, Ungjeong Do, Jung Ae Hong, Kyusup Lee, Chulhyun Lee, Do-Yoon Kang, Pil Hyung Lee, Jung-Min Ahn, Soo-Jin Kang, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Duk-Woo Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2018)
Differential but Complementary HIF1α and HIF2α Transcriptional Regulation
Authors: Nicholas L. Downes, Nihay Laham-Karam, Minna U. Kaikkonen, Seppo Ylä-Herttuala
Journal: Molecular Therapy (2018)

Effective vascular regeneration could provide therapeutic benefit for multiple pathologies, especially in chronic peripheral artery disease (PAD) and myocardial ischemia. The hypoxia inducible factors (HIFs) mediate the cellular transcriptional response to hypoxia and regulate multiple processes that are required for angiogenesis to ultimately restore perfusion and oxygen supply. In endothelial cells, both HIF1α and HIF2α are known to contribute to this role; however, the extent and individual roles of each of these HIFα remain unclear. To characterize the individual roles of HIFα, we sequenced the transcriptional outputs of stabilized forms of HIF1α and HIF2α, where they regulated 701 and 1,454 genes, respectively. HIF1α transcription primarily regulated metabolic reprogramming, whereas HIF2α exerted a larger role in regulating angiogenic extracellular signaling, guidance cues, and extracellular matrix remodeling factors. Furthermore, HIF2α almost exclusively regulated a large and diverse subset of transcription factors and coregulators that contribute to its diverse roles in hypoxia. Further understanding of how HIFs regulate cellular processes in hypoxia and angiogenesis could offer new avenues to modulate physiological angiogenesis to enhance revascularisation in ischemic conditions and other pathologies. Effective vascular regeneration could provide therapeutic benefit for multiple pathologies, especially in chronic peripheral artery disease (PAD) and myocardial ischemia. The hypoxia inducible factors (HIFs) mediate the cellular transcriptional response to hypoxia and regulate multiple processes that are required for angiogenesis to ultimately restore perfusion and oxygen supply. In endothelial cells, both HIF1α and HIF2α are known to contribute to this role; however, the extent and individual roles of each of these HIFα remain unclear. To characterize the individual roles of HIFα, we sequenced the transcriptional outputs of stabilized forms of HIF1α and HIF2α, where they regulated 701 and 1,454 genes, respectively. HIF1α transcription primarily regulated metabolic reprogramming, whereas HIF2α exerted a larger role in regulating angiogenic extracellular signaling, guidance cues, and extracellular matrix remodeling factors. Furthermore, HIF2α almost exclusively regulated a large and diverse subset of transcription factors and coregulators that contribute to its diverse roles in hypoxia. Further understanding of how HIFs regulate cellular processes in hypoxia and angiogenesis could offer new avenues to modulate physiological angiogenesis to enhance revascularisation in ischemic conditions and other pathologies.
Impact of direct acting antiviral treatment in hospital admission rates in patients with cirrhosis and hepatitis C virus infection
Authors: Á.H. Romero, L.C. del Campo, E.G. Domínguez, M.B. Valbuena, M.L.M. Alonso, R.M. Gómez, G.C. Tortajada, I.F. Vázquez
Journal: Journal of Hepatology (2018)
Sleep disturbance in psoriasis: a case-controlled study
Authors: P. Jensen, C. Zachariae, L. Skov, R. Zachariae
Journal: British Journal of Dermatology (2018)

Sleep is essential for daytime functioning and health. Given the physical symptoms of psoriasis, a higher prevalence of sleep disorders can be expected. So far, the studies examining sleep disturbance in psoriasis have been of less-than-optimal methodological quality and with mixed results.To examine the prevalence of sleep disturbance in patients with plaque psoriasis compared with a control group, to evaluate associations with health-related quality of life (HRQoL) and examine possible disease-related predictors of disturbed sleep.We used a cross-sectional, case-controlled design. Participants included 179 consecutively recruited patients with plaque psoriasis and 105 controls. Measures included psoriasis severity (Psoriasis Area and Severity Index); HRQoL (Dermatology Life Quality Index); insomnia severity [Insomnia Severity Index (ISI)]; sleep quality [Pittsburgh Sleep Quality Index (PSQI)]; stress (Perceived Stress Scale); itch (Itch Severity Scale); and depressive symptoms (Beck Depression Inventory). Analyses included group comparisons and regression analyses to identify predictors of sleep disturbance.A total of 25% of patients with psoriasis reported clinical insomnia (ISI > 15), compared with 10·5% of controls. In all, 53·6% of patients with psoriasis were poor sleepers (PSQI > 5), compared with 21·9% of controls. Itch was statistically significantly associated with all sleep-related outcomes.A higher proportion of patients with psoriasis experience poor sleep than controls from the general population. Itch was the main predictor of impaired sleep. Improved control of psoriasis with decreased itch may improve sleep disturbance in psoriasis.
Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit <sup>+</sup> Cardiac Stem Cells As Regenerative Therapy for Heart Failure)
Authors: Roberto Bolli, Joshua M. Hare, Keith L. March, Carl J. Pepine, James T. Willerson, Emerson C. Perin, Phillip C. Yang, Timothy D. Henry, Jay H. Traverse, Raul D. Mitrani, Aisha Khan, Ivonne Hernandez-Schulman, Doris A. Taylor, Darcy L. DiFede, João A.C. Lima, Atul Chugh, John Loughran, Rachel W. Vojvodic, Shelly L. Sayre, Judy Bettencourt, Michelle Cohen, Lem Moyé, Ray F. Ebert, Robert D. Simari
Journal: Circulation Research (2018)

Rationale: Autologous bone marrow mesenchymal stem cells (MSCs) and c-kit + cardiac progenitor cells (CPCs) are 2 promising cell types being evaluated for patients with heart failure (HF) secondary to ischemic cardiomyopathy. No information is available in humans about the relative efficacy of MSCs and CPCs and whether their combination is more efficacious than either cell type alone. Objective: CONCERT-HF (Combination of Mesenchymal and c-kit + Cardiac Stem Cells As Regenerative Therapy for Heart Failure) is a phase II trial aimed at elucidating these issues by assessing the feasibility, safety, and efficacy of transendocardial administration of autologous MSCs and CPCs, alone and in combination, in patients with HF caused by chronic ischemic cardiomyopathy (coronary artery disease and old myocardial infarction). Methods and Results: Using a randomized, double-blinded, placebo-controlled, multicenter, multitreatment, and adaptive design, CONCERT-HF examines whether administration of MSCs alone, CPCs alone, or MSCs+CPCs in this population alleviates left ventricular remodeling and dysfunction, reduces scar size, improves quality of life, or augments functional capacity. The 4-arm design enables comparisons of MSCs alone with CPCs alone and with their combination. CONCERT-HF consists of 162 patients, 18 in a safety lead-in phase (stage 1) and 144 in the main trial (stage 2). Stage 1 is complete, and stage 2 is currently randomizing patients from 7 centers across the United States. Conclusions: CONCERT-HF will provide important insights into the potential therapeutic utility of MSCs and CPCs, given alone and in combination, for patients with HF secondary to ischemic cardiomyopathy. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02501811.
Pediatric Hypertrophy Cardiomyopathy—Another Case Where Children Are Not Small Adults
Authors: Elizabeth M. McNally
Journal: JAMA Cardiology (2018)

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P499The role of fibroblast-myocyte electrotonic coupling in the formation of unidirectional blocks
Authors: L Gomez-Cid, A S De La Nava, V Casasnovas-Orus, D Sanz-Gutierrez, A Liberos, I Hernandez-Romero, M Guillem, F Atienza, A M Climent, F Fernandez-Aviles
Journal: Cardiovascular Research (2018)
The impact of pulmonary arterial hypertension therapy in patients with portopulmonary hypertension: a single tertiary center cohort analysis
Authors: F. Nevens, H. Peeters, W. Laleman, C. Verslype, S. van der Merwe, D. Monbaliu, J. Pirenne, M. Delcroix
Journal: Journal of Hepatology (2018)
Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target
Authors: Dabin Liu, Chi Chun Wong, Li Fu, Huarong Chen, Liuyang Zhao, Chuangen Li, Yunfei Zhou, Yanquan Zhang, Weiqi Xu, Yidong Yang, Bin Wu, Gong Cheng, Paul Bo-San Lai, Nathalie Wong, Joseph J. Y. Sung, Jun Yu
Journal: Science Translational Medicine (2018)

Nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed world; however, mechanisms that contribute to its formation are largely unknown, and targeted therapy is currently not available. Our RNA sequencing analysis of NAFLD-HCC samples revealed squalene epoxidase (SQLE) as the top outlier metabolic gene overexpressed in NAFLD-HCC patients. Hepatocyte-specific Sqle transgenic expression in mice accelerated the development of high-fat, high-cholesterol diet-induced HCC. SQLE exerts its oncogenic effect via its metabolites, cholesteryl ester and nicotinamide adenine dinucleotide phosphate (NADP+). Increased SQLE expression promotes the biosynthesis of cholesteryl ester, which induces NAFLD-HCC cell growth. SQLE increased the NADP+/NADPH (reduced form of NADP+) ratio, which triggered a cascade of events involving oxidative stress-induced DNA methyltransferase 3A (DNMT3A) expression, DNMT3A-mediated epigenetic silencing of PTEN, and activation of AKT-mTOR (mammalian target of rapamycin). In human NAFLD-HCC and HCC, SQLE is overexpressed and its expression is associated with poor patient outcomes. Terbinafine, a U.S. Food and Drug Administration-approved antifungal drug targeting SQLE, markedly inhibited SQLE-induced NAFLD-HCC cell growth in NAFLD-HCC and HCC cells and attenuated tumor development in xenograft models and in Sqle transgenic mice. Suppression of tumor growth by terbinafine is associated with decreased cholesteryl ester concentrations, restoration of PTEN expression, and inhibition of AKT-mTOR, consistent with blockade of SQLE function. Collectively, we established SQLE as an oncogene in NAFLD-HCC and propose that repurposing SQLE inhibitors may be a promising approach for the prevention and treatment of NAFLD-HCC.
Molecular and histological characterization of the pathological events in a model of cirrhosis and hepatocarcinoma
Authors: M.P. Castro-Gil, J.E. Torres-Mena, C.D. López, S. Muñoz-Montero, R.M. Salgado-Curiel, E. Krötzsch, J.I. Pérez-Carreón
Journal: Journal of Hepatology (2018)
Primary spontaneous bacterial peritonitis prophylaxis is associated with greater ICU admission and 30-day mortality compared to secondary spontaneous bacterial peritonitis prophylaxis
Authors: J.S. Bajaj, P. Tandon, J. O’leary, F. Wong, S. Biggins, G. Garcia-Tsao, P. Kamath, B. Maliakkal, M. Fallon, P.J. Thuluvath, J. Lai, R. Subramanian, H.E. Vargas, L. Thacker, R. Reddy
Journal: Journal of Hepatology (2018)
P165The dihydropyridine calcium antagonist nicardipine reduces aortic smooth muscle cell viability, proliferation and migration
Authors: R Stamatiou, I Aidonidis, C Malavaki, E Paraskeva, A Hatziefthimiou
Journal: Cardiovascular Research (2018)

Several physiologic substances were identified to potentiate platelet activation induced by primary agonists.Thrombopoietin (TPO) is not only a growth and development factor for the platelet precursor cell, but also can potentiate platelet response to ADP, collagen, thrombin, epinephrine, serotonin, and vasopressin.Nowadays an increasing number of patients may be chronically treated with aspirin alone or in combination with P2Y12 receptor inhibitors prior to acute coronary syndrome manifestation.Surprisingly, several studies identified aspirin pretreatment as an independent risk factor for adverse thrombotic events.Purpose: of the study was to evaluate the impact of antiplatelet pretreatment on platelet priming in patients with ST segment elevation myocardial infarction (STEMI).Materials and methods.We enrolled 40 male patients admitted to ICU due to STEMI.Levels of TPO, stromal cell derived factor 1 (SCD1) and myeloproliferative leukemia virus oncogene (MPL) were measured in plasma samples obtained at admission, on the 2nd and the 7th days since STEMI manifestation with commercially available ELISA kits.Platelet functional testing was performed at admission and on the 7th day by impedance and lumiaggregometry.Results: 33.3% of patients received antiplatelet therapy (23.3% aspirin only) before STEMI manifestation.Those patients with aspirin pretreatment were older (p ¼ 0.049), more likely to be hypertensive.There was no difference in platelet count, PCT or MPV in pretreated and non-pretreated groups.ADP induced platelet aggregation at admission was significantly suppressed by prior aspirin treatment: 0.0 (0.0 ;4.0) vs 2.0 (1.0; 7.0) Ohm, p ¼ 0.031.All patients revealed moderately to significantly elevated TPO levels at admission with no differences in those with and without pretreatment: 264.82 (153.32;337.64) vs 256.49(161.17;299.41) pg/mL, p ¼ 0.869.In aspirin naı ¨ve patients TPO dynamics was of U-shape with significant reduction on the 2nd day, compared to aspirin pretreated patients (p ¼ 0.047)."Monotonous" profiles of TPO were associated with significantly higher levels of secreted ATP in ADP stimulated platelets: 0.42 (0.2; 0.8) vs 0.16 (0.0; 0.33) nmole, p ¼ 0.03.Moderate to strong negative correlations between TPO, SCD1, MPL and collagen, but not ADP induced platelet aggregation and secretion were detected.Conclusion.Aspirin pretreatment significantly modifies thrombopoietin profiles in STEMI patients.Platelet functional heterogeneity in patients with STEMI is deepened through unequal exposure to platelet primers.
Assessment of portal hypertension evolution in hepatitis C virus cirrhosis patients with baseline large oesophageal varices after sustained virological response
Authors: M. Abadia, M. Montes, D. Ponce, Rubén Fernandez, J. Poza, E. Marín, M. Romero, T. Hernández, C. Froilán, A. García-Sánchez, J. Novo, P. Castillo, F.J. Garcia-Samaniego Rey, A.O. Martin
Journal: Journal of Hepatology (2018)
Liver stiffness measurement predicts short-term liver related-morbidity of allogeneic hematopoietic stem cell transplantation
Authors: T. Karlas, W. Tina, B. Sebastian, D. Christine, L. Franziska, D. Niederwieser, B. Gerhard, J. Mössner, J. Wiegand, V. Keim, G.-N. Franke
Journal: Journal of Hepatology (2018)
P313Substrate for arrhythmias in acute atrial dilatation
Authors: S Cannazzaro, M Scardigli, R Coppini, L M Loew, C Tesi, E Cerbai, F S Pavone, C Poggesi, L Sacconi, C Ferrantini
Journal: Cardiovascular Research (2018)

Background/Introduction: Pathophysiological processes as cardiac overload or dyssynchronic contraction produces mechanical stretch that is an arrhythmogenic factor.Stretch can induce an increase in Naþ influx into myocytes related to an activation of the Naþ/Hþ and reverse mode of the Naþ/Ca2þ exchangers, increasing intracellular Ca2þ and giving rise to detrimental electrophysiological changes.Eleclazine, a selective inhibitor of INaL, could prevent these effects taking in account that this current is associated to the intracellular Ca2þ increase due to stretch.Purpose: The aim of this study was to investigate, by the ventricular fibrillation (VF) spectral analysis, whether eleclazine prevents some arrhythmogenic electrophysiological effects due to acute ventricular local stretch.Methods: In twelve Langendorff-perfused rabbit hearts VF recordings were obtained using epicardial multiple electrodes on the left ventricle free wall under control conditions and during perfusion of different concentrations of eleclazine (0.35, 0.7 and 1.4 mM).VF was induced by pacing at increasing frequencies, without interrupting coronary perfusion.After the induction of VF, stretch was produced by an "ad hoc" device introduced to the left ventricle and maintained for three minutes.Dominant frequency (DF) of VF and spectral concentration (SpC) were determined using spectral techniques.A two-factor ANOVA test was used and significance was reached when p<0.05.Results: Myocardial stretch significantly increased DF with respect to pre-stretch values in control conditions (12.9 6 3.4 vs. 16.7 6 4.6 Hz) and also during the eleclazine perfusion at the concentrations 0.35 lM (12.6 6 3.7 vs. 15.0 6 3.6 Hz) and 0.7 lM (11.9 6 2.1 vs. 14.0 6 2.6 Hz), but not at 1.4 lM (11.8 6 4.8 vs. 12.16 3.0 Hz, ns).The magnitude of the stretch-induced increment in DF under 1.4 lM eleclazine was significantly lower than in control conditions (control: 32.3 %, 1.4 lM: 10.5 %).The significant stretch-induced decrease in SpC in control conditions (31.2 6 10.8 vs. 22.4 6 4.7 %) was also observed under 0.35 lM eleclazine effects (30.1 6 8.8 vs. 23.2 6 6.0 %), whereas the highest concentrations of drug prevented this reduction (0.7 lM: 28.1 6 6.9 vs. 24.6 6 5.2 %, ns; 1.4 lM: 33.5 6 10.9 vs. 40.1 6 16.2 %, ns).Moreover, during stretch, arrhythmia regularity and organization, evaluated by SpC, was greater under 1.4 lM eleclazine than in control conditions (control: 22.4 6 4.7 %; 1.4 lM: 40.1 6 16.2 %). Conclusion:The accelerating and disorganizing effects on ventricular activation during the arrhythmia, promoted by acute myocardial stretch, are reduced by the selective late sodium current inhibitor eleclazine.
Magnetically driven drug delivery systems improving targeted immunotherapy for colon-rectal cancer
Authors: Renata Grifantini, Monia Taranta, Lisa Gherardini, Ilaria Naldi, Matteo Parri, Alberto Grandi, Ambra Giannetti, Sara Tombelli, Gioia Lucarini, Leonardo Ricotti, Susanna Campagnoli, Elisa De Camilli, Gualtiero Pelosi, Francesco Baldini, Arianna Menciassi, Giuseppe Viale, Piero Pileri, Caterina Cinti
Journal: Journal of Controlled Release (2018)
Response to H. Nabi et al.
Authors: Ting-Yuan David Cheng, Amy K Darke, Mary W Redman, Karen Kelly, Regina M Santella, Kathy S Albain, Christine B Ambrosone
Journal: JNCI Journal of the National Cancer Institute (2018)

Author(s): Cheng, Ting-Yuan David; Darke, Amy K; Redman, Mary W; Kelly, Karen; Santella, Regina M; Albain, Kathy S; Ambrosone, Christine B
Projected Cancer Incidence Rates and Burden of Incident Cancer Cases in HIV-Infected Adults in the United States Through 2030
Authors: Meredith S. Shiels, Jessica Y. Islam, Philip S. Rosenberg, H. Irene Hall, Evin Jacobson, Eric A. Engels
Journal: Annals of Internal Medicine (2018)

Persons living with HIV (PLWH) have an elevated risk for certain types of cancer. With modern antiretroviral therapy, PLWH are aging and cancer rates are changing.