tbuckley/cabot-search huggingface dataset:
Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders
Authors: Bret L. Bostwick, Scott McLean, Jennifer E. Posey, Haley E. Streff, Karen W. Gripp, Alyssa Blesson, Nina Powell-Hamilton, Jessica Tusi, David A. Stevenson, Ellyn Farrelly, Louanne Hudgins, Yaping Yang, Fan Xia, Xia Wang, Pengfei Liu, Magdalena Walkiewicz, Marianne McGuire, Dorothy K. Grange, Marisa V. Andrews, Marybeth Hummel, Suneeta Madan-Khetarpal, Elena Infante, Zeynep Coban-Akdemir, Karol Miszalski-Jamka, John L. Jefferies, Jill A. Rosenfeld, Lisa Emrick, Kimberly M. Nugent, James R. Lupski, John W. Belmont, Brendan Lee, Seema R. Lalani
Journal: Genome Medicine (2017)

De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review. We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites. Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.
Biofabrication: ‘Printability' of Candidate Biomaterials for Extrusion Based 3D Printing: State‐of‐the‐Art (Adv. Healthcare Mater. 16/2017)
Authors: Stuart Kyle, Zita M. Jessop, Ayesha Al‐Sabah, Iain S. Whitaker
Journal: Advanced Healthcare Materials (2017)

3D bioprinting has the potential to replicate complex tissue architecture and biomanufacture physiologically relevant multicellular constructs on demand. In article number 1700264, Stuart Kyle, Iain S. Whitaker, and co-workers review a new generation of bioinks with suitable biocompatibility and high shape/print fidelity, that have the potential to match or exceed the physical, chemical and biological properties of human tissue, when combined with the appropriate cell source. Image of 3D Bioprinter kindly provided by Aether.
Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study
Authors: David Jones, Pol F Boudes, Mark G Swain, Christopher L Bowlus, Michael R Galambos, Bruce R Bacon, Yvonne Doerffel, Norman Gitlin, Stuart C Gordon, Joseph A Odin, David Sheridan, Markus-Alexander Wörns, Virginia Clark, Linsey Corless, Heinz Hartmann, Mark E Jonas, Andreas E Kremer, George F Mells, Peter Buggisch, Bradley L Freilich, Cynthia Levy, John M Vierling, David E Bernstein, Marek Hartleb, Ewa Janczewska, Fedja Rochling, Hemant Shah, Mitchell L Shiffman, John H Smith, Yun-Jung Choi, Alexandra Steinberg, Monika Varga, Harinder Chera, Robert Martin, Charles A McWherter, Gideon M Hirschfield
Journal: The Lancet. Gastroenterology & hepatology (2017)
Abstract 200: Cardiomyocyte-specific Deletion Of Rhoa Accelerates Heart Failure But Prevents Cardiac Fibrosis In Response To Pressure-overload
Authors: Jessica Lauriol, Kimberly Keith, Sanjeewa A Goonasekera, Qingen Ke, Peter Kang, Jeffery D Molkentin, Maria I Kontaridis
Journal: Circulation Research (2013)

Heart failure is a progressive disease characterized by loss of cardiac contractility, interstitial fibrosis, and chamber remodeling. Though several signaling pathways have been identified, the precise mechanisms involved in regulating pathological cardiac responses remain unclear. The Ras-related small G protein RhoA is an identified mediator of in vivo pathological hypertrophy. However, it also promotes cell survival and is cardioprotective after ischemia/repurfusion injury. Therefore, to determine the molecular mechanisms that underlie these opposing roles for RhoA in the myocardium, we generated mice with cardiomyocyte-specific deletion of RhoA (RhoAfl/fl-αMHC-Cre). As compared to wildtype mice, hearts from RhoAfl/fl-αMHC-Cre mice showed similar functional, structural, and growth parameters, both at baseline and in response to acute transverse aortic constriction (TAC) (2wks), suggesting RhoA plays no major role in either homeostatic or acute stress-induced cardiac conditions. However, after exposure to chronic TAC for 8wks, hearts from RhoAfl/fl-αMHC-Cre mice developed an accelerated dilation, with significant loss of contractile function. Mechanistically, cardiomyocyte-specific loss of RhoA reduced ERK1/2 activation and perturbed agonist-evoked calcium cycling, through aberrant IP3 and DAG signaling, indicating that RhoA mediates its cardioprotective effects through regulation of these pathways. Despite this, and surprisingly, hearts from RhoAfl/fl-αMHC mice also showed significantly decreased TAC-induced cardiac fibrosis, with a demonstrated decrease in transcriptional activation of genes involved in the fibrotic response, including the serum response factor (SRF), as well as the secreted factor BMP7. Taken together, our data reveal an interesting, yet highly complex signaling and regulatory mechanism for RhoA, whereby RhoA signaling is both cardioprotective against development of heart failure in response to chronic stress, but also cardio-deleterious through its capacity to activate pro-fibrotic genes.
Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07)
Authors: Dagmar Beier, Martin Proescholdt, Christiane Reinert, Torsten Pietsch, David T W Jones, Stefan M Pfister, Elke Hattingen, Clemens Seidel, Linda Dirven, Ralf Luerding, Jaap Reijneveld, Monika Warmuth-Metz, Matteo Bonsanto, Michael Bremer, Stephanie E Combs, Stefan Rieken, Ulrich Herrlinger, Holger Kuntze, Regine Mayer-Steinacker, Dag Moskopp, Thomas Schneider, Andreas Beringer, Uwe Schlegel, Walter Stummer, Helmut Welker, Astrid Weyerbrock, Frank Paulsen, Stefan Rutkowski, Michael Weller, Wolfgang Wick, Rolf-Dieter Kortmann, Ulrich Bogdahn, Peter Hau
Journal: Neuro-Oncology (2017)

Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy.The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy.Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock.Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.
Examining Bias in Studies of Statin Treatment and Survival in Patients With Cancer
Authors: Louise Emilsson, Xabier García-Albéniz, Roger W. Logan, Ellen C. Caniglia, Mette Kalager, Miguel A. Hernán
Journal: JAMA Oncology (2017)

Patients with cancer who use statins appear to have a substantially better survival than nonusers in observational studies. However, this inverse association between statin use and mortality may be due to selection bias and immortal-time bias.To emulate a randomized trial of statin therapy initiation that is free of selection bias and immortal-time bias.We used observational data on 17 372 patients with cancer from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2007-2009) with complete follow-up until 2011. The SEER-Medicare database links 17 US cancer registries and claims files from Medicare and Medicaid in 12 US states. We included individuals with a new diagnosis of colorectal, breast, prostate, or bladder cancer who had not been prescribed statins for at least 6 months before the cancer diagnosis. Individuals were duplicated, and each replicate was assigned to either the strategy "statin therapy initiation within 6 months after diagnosis" or "no statin therapy initiation." Replicates were censored when they stopped following their assigned strategy, and the potential selection bias was adjusted for via inverse-probability weighting. Hazard ratios (HRs), cumulative incidences, and risk differences were calculated for all-cause mortality and cancer-specific mortality. We then compared our estimates with those obtained using the same analytic approaches used in previous observational studies.Statin therapy initiation within 6 months after cancer diagnosis.Cancer-specific and all-cause mortality using SEER-Medicare data and data from previous studies.Of the 17 372 patients whose data were analyzed, 8440 (49%) were men, and 8932 (51%) were women (mean [SD] age, 76.4 [7.4] years; range, 66-115 years). The adjusted HR (95% CI) comparing statin therapy initiation vs no initiation was 1.00 (0.88-1.15) for cancer-specific mortality and 1.07 (0.93-1.21) for overall mortality. Cumulative incidence curves for both groups were almost overlapping (the risk difference never exceeded 0.8%). In contrast, the methods used by prior studies resulted in an inverse association between statin use and mortality (pooled hazard ratio 0.69).After using methods that are not susceptible to selection bias from prevalent users and to immortal time bias, we found that initiation of therapy with statins within 6 months after cancer diagnosis did not appear to improve 3-year cancer-specific or overall survival.
Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy
Authors: Yan Kong, Xinan Sheng, Xiaowen Wu, Junya Yan, Meng Ma, Jiayi Yu, Lu Si, Zhihong Chi, Chuanliang Cui, Jie Dai, Yiqian Li, Huan Yu, Tianxiao Xu, Huan Tang, Bixia Tang, Lili Mao, Bin Lian, Xuan Wang, Xieqiao Yan, Siming Li, Jun Guo
Journal: Clinical Cancer Research (2017)

Purpose: Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma.Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1, and P16INK4a , by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated.Results: Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%), and P16INK4a loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in Cdk4, Ccnd1, and P16INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations (P = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss, and Ccnd1 gain plus P16INK4a loss.Conclusions: Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. Clin Cancer Res; 23(22); 6946-57. ©2017 AACR.
Feasibility of bevacizumab combined with gemcitabine in treatment of platinum-resistant epithelial ovarian cancer.
Authors: Ai Kogiku, Shoji Nagao, Kazuhiro Suzuki, Kasumi Yamamoto, Tokihiro Senda, Miho Kitai, Takaya Shiozaki, Kazuko Matsuoka, Tamotsu Sudo, Satoshi Yamaguchi
Journal: Journal of Clinical Oncology (2017)

e17064 Background: We assessed the efficacy and safety of a combination chemotherapy comprising gemcitabine and bevacizumab for the treatment of platinum-resistant recurrent ovarian cancer. Here we report the results of the interim analysis. Methods: Eligible patients showed recurrent, measurable tumors that had progressed within 6 months after the completion of platinum-based chemotherapy. Patients received gemcitabine (1000 mg/m 2 ) on days 1and 8 and bevacizumab (15 mg/kg) on day1 every 3 weeks until disease progression or unacceptable toxicity levels were observed. The primary end point was the proportion of patients who completed three cycles of scheduled chemotherapy. Results: Twelve patients were enrolled in this study and three patients are still undergoing chemotherapy. The proportion of patients who completed three cycles of chemotherapy was 77.8 % (7/9), and response rate was 66.7 % (6/9). Grade ≥ 3 neutropenia, thrombocytopenia, and hypertension were observed in five, one, and one patients, respectively. There was no GI perforation or death in our study. Conclusions: Combination chemotherapy of comprising gemcitabine and bevacizumab was safe and effective in patients with platinum-resistant recurrent ovarian cancer. Therefore, it is important to continue this study. Clinical trial information: 000016619.
Transposable Element Exaptation into Regulatory Regions Is Rare, Influenced by Evolutionary Age, and Subject to Pleiotropic Constraints
Authors: Corinne N. Simonti, Mihaela Pavličev, John A. Capra
Journal: Molecular Biology and Evolution (2017)

Transposable element (TE)-derived sequences make up approximately half of most mammalian genomes, and many TEs have been co-opted into gene regulatory elements. However, we lack a comprehensive tissue- and genome-wide understanding of how and when TEs gain regulatory activity in their hosts. We evaluated the prevalence of TE-derived DNA in enhancers and promoters across hundreds of human and mouse cell lines and primary tissues. Promoters are significantly depleted of TEs in all tissues compared with their overall prevalence in the genome (P < 0.001); enhancers are also depleted of TEs, though not as strongly as promoters. The degree of enhancer depletion also varies across contexts (1.5–3×), with reproductive and immune cells showing the highest levels of TE regulatory activity in humans. Overall, in spite of the regulatory potential of many TE sequences, they are significantly less active in gene regulation than expected from their prevalence. TE age is predictive of the likelihood of enhancer activity; TEs originating before the divergence of amniotes are 9.2 times more likely to have enhancer activity than TEs that integrated in great apes. Context-specific enhancers are more likely to be TE-derived than enhancers active in multiple tissues, and young TEs are more likely to overlap context-specific enhancers than old TEs (86% vs. 47%). Once TEs obtain enhancer activity in the host, they have similar functional dynamics to one another and non-TE-derived enhancers, likely driven by pleiotropic constraints. However, a few TE families, most notably endogenous retroviruses, have greater regulatory potential. Our observations suggest a model of regulatory co-option in which TE-derived sequences are initially repressed, after which a small fraction obtains context-specific enhancer activity, with further gains subject to pleiotropic constraints.
PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells
Authors: Jiangmei Li, Zhen Gao, Dan Zhao, Lunfeng Zhang, Xinhua Qiao, Yingying Zhao, Hong Ding, Panpan Zhang, Junyan Lu, Jia Liu, Hualiang Jiang, Cheng Luo, Chang Chen
Journal: Cancer Research (2017)

Abstract While phosphatidylinositol 4-kinase (PI4KIIα) has been identified as a potential target for antitumor therapy, the clinical applications of PI4KIIα are limited by a lack of specific inhibitors. Here we report the first small-molecule inhibitor (SMI) of human PI4KIIα. Docking-based and ligand-based virtual screening strategies were first employed to identify promising hits, followed by two rounds of kinase activity inhibition validation. 2-(3-(4-Chlorobenzoyl)thioureido)-4-ethyl-5-methylthiophene-3-carboxamide (PI-273) exhibited the greatest inhibitory effect on PI4KIIα kinase activity (IC50 = 0.47 μmol/L) and suppressed cell proliferation. Surface plasmon resonance and thermal shift assays indicated that PI-273 interacted directly with PI4KIIα. Kinetic analysis identified PI-273 as a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI), which contrasted with most other PI kinase inhibitors that bind the ATP binding site. PI-273 reduced PI4P content, cell viability, and AKT signaling in wild-type MCF-7 cells, but not in PI4KIIα knockout MCF-7 cells, indicating that PI-273 is highly selective for PI4KIIα. Mutant analysis revealed a role of palmitoylation insertion in the selectivity of PI-273 for PI4KIIα. In addition, PI-273 treatment retarded cell proliferation by blocking cells in G2–M, inducing cell apoptosis and suppressing colony-forming ability. Importantly, PI-273 significantly inhibited MCF-7 cell-induced breast tumor growth without toxicity. PI-273 is the first substrate-competitive, subtype-specific inhibitor of PI4KIIα, the use of which will facilitate evaluations of PI4KIIα as a cancer therapeutic target. Cancer Res; 77(22); 6253–66. ©2017 AACR.
Application of the Radio-Guided Occult Lesion Localization Technique for Renal Lumpectomy
Authors: Jesus Andres Betancourt Hernández, Cesar Vera Donoso, Manuel Martinez-Sarmiento, Juan Jose Monserrat, Pilar Bello Jarque, Francisco Boronat Tormo
Journal: Clinical Nuclear Medicine (2017)

Incidence of small renal masses is increasing, and preservation of healthy kidney tissue along surgical removal is a challenge, especially if the tumor is small or nonexophytic. To facilitate the location and complete excision of the tumor during surgery, we have implemented the application of the radio-guided occult lesion localization technique from initial idea to clinical application.
ACC/AHA/HRS 2006 Key Data Elements and Definitions for Electrophysiological Studies and Procedures
Authors: Alfred E Buxton, Hugh Calkins, David J Callans, John P DiMarco, John D Fisher, H Leon Greene, David E Haines, David L Hayes, Paul A Heidenreich, John M Miller, Athena Poppas, Eric N Prystowsky, Mark H Schoenfeld, Peter J Zimetbaum, David C Goff, Frederick L Grover, David J Malenka, Eric D Peterson, Martha J Radford, Rita F Redberg
Journal: Circulation (2006)
TCT-652 Incidence, Predictors and Clinical Outcomes of Device Malposition Following Transcatheter Aortic Valve Implantation for Degenerative Bioprosthetic Surgical Valves: Insights from the VIVID Registry
Authors: Ashish Shah, Eric Horlick, Mark Osten, Ran Kornowski, Alec Vahanian, Dominique Himbert, Massimo Napodano, Giuseppe Bruschi, Henrik Nissen, Matheus Simonato dos Santos, Thierry Lefevre, Jose Maria Hernandez, Francesco Maisano, Markus Kasel, Diego Gaia, Rui Campante Teles, Sabine Bleiziffer, Marco Barbanti, Corrado Tamburino, Antonio Colombo, Azeem Latib, Elizabeth Perpetua, Didier Tchetche, Anna Petronio, Enrico Ferrari, Hendrik Treede, Thomas Walther, Josep Rodés-Cabau, Danny Dvir
Journal: Journal of the American College of Cardiology (2016)
A Potential Mechanism of Calcified Nodule Formation in the Common Femoral Artery: A Histopathological Study
Authors: Saita Ten, Fujii Kenichi, Hao Hiroyuki, Shibuya Masahiko, Imanaka Takahiro, Kawai Keiji, Tamaru Hiroto, Sumiyoshi Akinori, Horimatsu Tetsuo, Nishimura Machiko, Masuyama Tohru, Ishihara Masaharu
Journal: Circulation (2016)
Dr. Floyd G. Turner&lt;subtitle&gt;1889–1960&lt;/subtitle&gt;
Authors: Ora Marshino
Journal: JNCI Journal of the National Cancer Institute (1960)

Journal Article Dr. Floyd G. Turner: 1889–1960 Get access Ora Marshino Ora Marshino Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 24, Issue 5, May 1960, Pages 1239–1240, https://doi.org/10.1093/jnci/24.5.1239 Published: 01 May 1960
Heterogeneity in Definitions of Endpoints for Clinical Trials of Ulcerative Colitis: A Systematic Review for Development of a Core Outcome Set
Authors: Christopher Ma, Remo Panaccione, Richard N. Fedorak, Claire E. Parker, Tran M. Nguyen, Reena Khanna, Corey A. Siegel, Laurent Peyrin-Biroulet, Geert D’Haens, William J. Sandborn, Brian G. Feagan, Vipul Jairath
Journal: Clinical Gastroenterology and Hepatology (2017)
Preserving the ‘commons’: addressing the sustainable use of antibiotics through an economic lens
Authors: C.M. Morel, S.E. Edwards, S. Harbarth
Journal: Clinical Microbiology and Infection (2017)

As the growth of antibiotic resistance has resulted in large part from widespread use of antibiotics, every effort must be made to ensure their sustainable use.This narrative review aims to assess the potential contribution of health economic analyses to sustainable use efforts.The work draws on existing literature and experience with health economic tools.The study examines some of the weaknesses in the health, regulatory, and industry arenas that could contribute to inappropriate or suboptimal prescribing of antibiotics and describes how economic analysis could be used to improve current practice by comparing both costs and health outcomes to maximize societal wellbeing over the longer-term. It finds that economic considerations underpinning current antibiotic prescribing strategies are incomplete and short-termist, with the result that they may foster suboptimal use. It also stresses that perverse incentives that drive antibiotic sales and inappropriate prescribing practices must be dis-entangled for sustainable use policies to gain traction. Finally, payment structures can be used to re-align incentives and promote optimal prescribing and sustainable use more generally. In particular, eliminating or altering reimbursement differentials could help steer clinical practice more deliberately towards the minimization of selection pressure and the resulting levels of antibiotic resistance.This work highlights the need for appropriately designed cost-effectiveness analyses, incentives analysis, and novel remuneration systems to underpin sustainable use policies both within and beyond the health sector.