tbuckley/cabot-search huggingface dataset:
Endogenous Tumor Suppressor microRNA-193b: Therapeutic and Prognostic Value in Acute Myeloid Leukemia
Authors: Raj Bhayadia, Kathrin Krowiorz, Nadine Haetscher, Razan Jammal, Stephan Emmrich, Askar Obulkasim, Jan Fiedler, Adrian Schwarzer, Arefeh Rouhi, Michael Heuser, Susanne Wingert, Sabrina Bothur, Konstanze Döhner, Tobias Mätzig, Michelle Ng, Dirk Reinhardt, Hartmut Döhner, C. Michel Zwaan, Marry van den Heuvel Eibrink, Dirk Heckl, Maarten Fornerod, Thomas Thum, R. Keith Humphries, Michael A. Rieger, Florian Kuchenbauer, Jan-Henning Klusmann
Journal: Journal of Clinical Oncology (2018)

Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo. Results miR-193b exerted important, endogenous, tumor-suppressive functions on the hematopoietic system. miR-193b-3p was downregulated in several cytogenetically defined subgroups of pediatric and adult AML, and low expression served as an independent indicator for poor prognosis in pediatric AML (risk ratio ± standard error, −0.56 ± 0.23; P = .016). miR-193b-3p expression improved the prognostic value of the European LeukemiaNet risk-group stratification or a 17-gene leukemic stemness score. In knockout mice, loss of miR-193b cooperated with Hoxa9/Meis1 during leukemogenesis, whereas restoring miR-193b expression impaired leukemic engraftment. Similarly, expression of miR-193b in AML blasts from patients diminished leukemic growth in vitro and in mouse xenografts. Mechanistically, miR-193b induced apoptosis and a G1/S-phase block in various human AML subgroups by targeting multiple factors of the KIT-RAS-RAF-MEK-ERK (MAPK) signaling cascade and the downstream cell cycle regulator CCND1. Conclusion The tumor-suppressive function is independent of patient age or genetics; therefore, restoring miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms.
Antisocial Personality as a Neurodevelopmental Disorder
Authors: Adrian Raine
Journal: Annual Review of Clinical Psychology (2018)

Although antisocial personality disorder (APD) is one of the most researched personality disorders, it is still surprisingly resistant to treatment. This lack of clinical progress may be partly due to the failure to view APD as a neurodevelopmental disorder and to consider early interventions. After first defining what constitutes a neurodevelopmental disorder, this review evaluates the extent to which APD meets neurodevelopmental criteria, covering structural and functional brain imaging, neurocognition, genetics and epigenetics, neurochemistry, and early health risk factors. Prevention and intervention strategies for APD are then outlined, focusing on addressing early biological and health systems, followed by forensic and clinical implications. It is argued both that APD meets criteria for consideration as a neurodevelopmental disorder and that consideration should be given both to the possibility that early onset conduct disorder is neurodevelopmental in nature, and also to the inclusion of psychopathy as a specifier in future Diagnostic and Statistical Manual revisions of APD.
Fructose metabolism and metabolic disease
Authors: Sarah A. Hannou, Danielle E. Haslam, Nicola M. McKeown, Mark A. Herman
Journal: Journal of Clinical Investigation (2018)

Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease.
Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update
Authors: Gregory P. Kalemkerian, Navneet Narula, Erin B. Kennedy, William A. Biermann, Jessica Donington, Natasha B. Leighl, Madelyn Lew, James Pantelas, Suresh S. Ramalingam, Martin Reck, Anjali Saqi, Michael Simoff, Navneet Singh, Baskaran Sundaram
Journal: Journal of Clinical Oncology (2018)

Purpose In response to advances in the field, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) recently updated their recommendations for molecular testing for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The molecular testing guideline was reviewed for developmental rigor by methodologists. Then an ASCO Expert Panel reviewed the content and the recommendations. Results The ASCO Expert Panel determined that the recommendations from the CAP/IASLC/AMP molecular testing guideline are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the guideline with minor modifications. Recommendations This update clarifies that any sample with adequate cellularity and preservation may be tested and that analytical methods must be able to detect mutation in a sample with as little as 20% cancer cells. It strongly recommends against evaluating epidermal growth factor receptor (EGFR) expression by immunohistochemistry for selection of patients for EGFR-targeted therapy. New for 2018 are recommendations for stand-alone ROS1 testing with additional confirmation testing in all patients with advanced lung adenocarcinoma, and RET, ERBB2 (HER2), KRAS, and MET testing as part of larger panels. ASCO also recommends stand-alone BRAF testing in patients with advanced lung adenocarcinoma. Recommendations are also provided for testing methods for lung cancers that have a nonadenocarcinoma non-small-cell component, for patients with targetable mutations who have relapsed on targeted therapy, and for testing the presence of circulating cell-free DNA. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .
Successful closure of esophagomediastinal fistula with endoclips and an endoloop after endoscopic submucosal dissection
Authors: Chao-jun Zhu, Xiao-bei Luo, Eliza Fong, Zhen Wang, Yang Bai, Ze-long Han, Side Liu
Journal: Endoscopy (2018)

Perforation, bleeding, mediastinal emphysema, and postoperative stricture are the most common complications associated with esophageal endoscopic submucosal dissection (ESD) [1]. However, though rare, esophagobronchial fistula or esophagomediastinal fistula can also develop after ESD. Conventional treatments of esophageal fistula include surgery, esophageal covered stent implantation, and other endoscopic methods involving the use of endoclips or fibrin glue [2] [3] [4] [5].
Phase 1b/3 study of avelumab-based combination regimens in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL).
Authors: Robert W. Chen, Stephen Maxted Ansell, Pier Luigi Zinzani, Jeffrey L. Vacirca, Armando Lopez-Guillermo, Martin Hutchings, Wojciech Jurczak, Georg Hess, Steven Le Gouill, Fritz Offner, Armando Santoro, Gilles A. Salles, Daria Stypinski, Douglas Laird, Dmitri Pavlov, Giovanna Andreola, Kolette D. Fly, Adrian Woolfson, Graham P Collins
Journal: Journal of Clinical Oncology (2017)

TPS7575 Background: Approximately 50% of patients (pts) with advanced DLBCL are refractory to or relapse following first line R-CHOP therapy. Pts with R/R DLBCL have limited treatment options and a poor prognosis. This study assesses immunotherapy-based regimens containing avelumab (a fully human IgG1 anti–PD-L1 antibody) in combination with utomilumab (a novel 4-1BB agonist), azacitidine, rituximab, and/or conventional chemotherapy (CT; bendamustine) in pts with R/R DLBCL. Methods: JAVELIN DLBCL (NCT02951156) is a global, multicenter, randomized, open-label, 2-component(phase 1b followed by phase 3) study of avelumab-based combination regimens in R/R DLBCL. In phase 1b, up to 84 pts will be randomized 1:1:1 to receive avelumab/rituximab/utomilumab, or avelumab/azacitidine/utomilumab, or avelumab/rituximab/bendamustine. The primary phase 1b objectives are preliminary assessments of dose-limiting toxicities (n = 6 per arm) and efficacy (objective response [OR]; n = 28 per arm). One regimen from phase 1b will be selected for phase 3 evaluation in 220 additional pts randomized 1:1 to the chosen regimen or investigator’s choice CT (rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin). The primary phase 3 objective is to demonstrate progression-free survival (PFS) superiority of the avelumab-based regimen over CT. Overall survival is a key secondary endpoint. Eligible pts have completed up to 4 lines of prior rituximab/multiagent CT, and/or have failed autologous stem cell transplantation (ASCT), or are not eligible for intensive CT or ASCT. Other eligibility criteria include ECOG PS ≤1 and no prior therapy with a checkpoint inhibitor. Treatment with avelumab, utomilumab, and azacitidine will be continued until the pt no longer receives clinical benefit; rituximab and bendamustine are limited to 8 and 6 cycles, respectively. OR and PFS will be assessed per Lugano disease classification criteria. Other secondary efficacy endpoints include disease control, duration of response, time to response, and minimal residual disease burden. Safety, PK, immunogenicity, pt-reported outcomes, and biomarkers will also be evaluated. Clinical trial information: NCT02951156.
Computational Analysis of Genomic Abnormalities from a Phase 3 Trial of Rigosertib in Higher-Risk MDS: Simulation of a Predictive Signature for Clinical Response
Authors: Guillermo Garcia-Manero, Michael E. Petrone, Steven M. Fruchtman, Bernard Brownstein, Hannes Loferer, Nozar Azarnia, Shireen Vali, Neeraj Kumar Singh, Shahabuddin Usmani, Himanshu Grover, Taher Abbasi, Lewis R. Silverman
Journal: Blood (2016)
Abstract 16882: Prescribed Flow in 3D Printed Models for Determination of Coronary Ischemia: A Comparison to a Computational Fluid Dynamic-based Assessment
Authors: Kranthi K Kolli, Guanglei Xiong, Seongmin Ha, Hilary Soohoo, James K Min
Journal: Circulation (2016)

Introduction: Advances in coronary computed tomography angiography (CCTA) imaging and 3D printing have enabled fabrication of physical models of coronary arterial geometry. Computational fluid dyna...
Sirolimus Is Effective in Refractory Immune Thrombocytopenia: Results of an Open-Label Prospective Multicenter Trial in China
Authors: Lei Gao, Hongju Yan, Sanbin Wang, Fang Liu, Jishi Wang, Xiaobing Huang, Tonghua Yang, Yanqi Zhang, Shifeng Lou, Huimin Li, Cheng Zhang, Yao Liu, Kong Peiyan, Hong Liu, Li Gao, Xiangui Peng, Yi Su, Yinghao Lu, Feng Li, Defu Zeng, Xi Zhang
Journal: Blood (2017)
Src inhibitors potentiate UCN-01-induced apoptosis in human multiple myeloma cells through mechanisms involving disruption of the MEK1/2/ERK1/2 pathway and anti-angiogenesis in vitro and in vivo
Authors: Yun Dai, Rena Shah, Shuang Chen, Xin-Yan Pei, Paul Dent, Steven Grant
Journal: Cancer Research (2008)

1476   We previously reported that MEK1/2 inhibitors and agents targeting Ras (e.g., farnesyltransferase inhibitors or HMG-CoA reductase inhibitors) blocked UCN-01-mediated ERK1/2 activation in human multiple myeloma (MM) cells, resulting in synergistic lethality (Dai et al. Blood 100:3333, 2002; Pei et al. Clin Cancer Res 11:4589, 2005; Dai et al. Blood 109:4415, 2007). Because Src is involved in Ras/Raf/MEK/ERK activation, the possibility arose that targeting Src might analogously potentiate the anti-MM activity of Chk1 inhibitors. The goal of this study was to determine whether dual Src/Abl inhibitors, including BMS354825 (dasatinib) or SKI-606, interact with UCN-01, and to elucidate the underlying mechanisms. Co-exposure of human MM cells (e.g., U266, RPMI8226, MM.1S, or, MM.1R) to minimally toxic concentrations of UCN-01 (e.g., 100-150 nM) and either BMS354825 (e.g., 500-800 nM) or SKI-606 (e.g., 1-2 uM) dramatically induced apoptosis. Co-administration of either BMS354825 or SKI-606 largely diminished ERK1/2 phosphorylation/activation in MM cells exposed to UCN-01, accompanied by enhanced Thr4/Tyr15 dephosphorylation/activation of cdc2 and DNA damage (reflected by increased gammaH2A.X expression). Ectopic expression of kinase inactive (K297R) or dominant-negative (K296R/Y528F) mutant Src prevented ERK1/2 activation by UCN-01 and significantly sensitized U266 cells to this agent. Moreover, U266 ectopically expressing either active mutant Ras (Q61L) or constitutively active MEK1 displayed significant resistance to combined treatment with SKI-606 and UCN-01, suggesting that Src inhibitors act upstream of Ras/Raf/MEK to potentiate UCN-01 lethality. Conversely, stable expression of dominant-negative mutant Ras (S17N) markedly sensitized MM cells to this combination regimen. Lastly, co-administration of BMS354825 (50mg/kg) and UCN-01 (0.5mg/kg) resulted in a significant reduction in tumor size in athymic nude mice inoculated with MM.1S cells, compared to the effects of these agents administered individually. This was associated with a striking induction of apoptosis (manifested by TUNEL staining) in tumor tissues obtained from mice that had received combined treatment. Moreover, the drug combination resulted in a dramatic inhibition of angiogenesis (reflected by reduced numbers of microvascular vessels exhibiting expression of the murine endothelial marker CD31). Together, these findings indicate that Src inhibitors act through a Ras/Raf/MEK-dependent mechanism to prevent ERK1/2 activation in UCN-01-treated MM cells, resulting in the synergistic induction of cell death in vitro and in vivo. They also suggest that the in vivo activity of a regimen combining BMS354825 and UCN-01 may involve anti-angiogenic effects.
Baseline ultrasound examination as possible predictor of relapse in patients affected by juvenile idiopathic arthritis (JIA)
Authors: Orazio De Lucia, Viviana Ravagnani, Francesca Pregnolato, Arvena Hila, Irene Pontikaki, Maurizio Gattinara, Micol Romano, Valeria Gerloni, Sara Pieropan, Antonella Murgo, Maurizio Rossini, Rolando Cimaz, Pier Luigi Meroni
Journal: Annals of the Rheumatic Diseases (2018)

Objectives To define the correlation between joint ultrasonography and clinical examination in patients with juvenile idiopathic arthritis (JIA) and to assess whether synovitis detected by ultrasonography in clinically inactive patients predicts arthritis flares. Methods 88 consecutive patients with JIA—46 (52%) with persistent oligoarthritis, 15 (17%) with extended oligoarthritis, 15 (17%) with rheumatoid factor-negative polyarthritis and 12 (14%) with other forms of JIA, all clinically inactive for a minimum of 3 months—underwent ultrasound (US) assessment of 44 joints. Joints were scanned at study entry for synovial hyperplasia, joint effusion and power Doppler (PD) signal. Patients were followed clinically for 4 years. Results US was abnormal in 20/88 (22.7%) patients and in 38/3872 (0.98%) joints. Extended oligoarthritis and rheumatoid factor-negative polyarthritis were more frequent in US-positive than in US-negative patients (35.0% vs 11.8% and 30.0% vs 13.2%, respectively; P=0.005). During 4 years of follow-up, 41/88 (46.6%) patients displayed a flare; 26/68 (38.2%) were US-negative and 15/20 (75%) were US-positive at baseline. Abnormality on US examination, after correction for therapy modification, significantly increased the risk of flare (OR=3.8, 95% CI 1.2 to 11.5). The combination of grey scale and PD abnormalities displayed a much higher predictive value of relapse (65%, 13/20) than grey scale alone (33%, 6/18). Conclusions US abnormalities are a strong predictor of relapse at individual patient level. Irrespective of treatment, the risk of flare in US-positive versus US-negative patients was almost four times higher. In case of US abnormalities, patients should be carefully followed regardless of both the International League of Associations for Rheumatology and Wallace categories.
Farm Exposure Influences Skin Microbiota In Infancy
Authors: Cheryl A. Steiman, Douglas Fadrosh, Michael D. Evans, Rose F. Vrtis, Brent Olson, Kathrine L. Barnes, Christine M. Seroogy, Casper G. Bendixsen, Susan V. Lynch, James E. Gern
Journal: Journal of Allergy and Clinical Immunology (2018)
Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation
Authors: Leandro Z. Agudelo, Duarte M.S. Ferreira, Igor Cervenka, Galyna Bryzgalova, Shamim Dadvar, Paulo R. Jannig, Amanda T. Pettersson-Klein, Tadepally Lakshmikanth, Elahu G. Sustarsic, Margareta Porsmyr-Palmertz, Jorge C. Correia, Manizheh Izadi, Vicente Martínez-Redondo, Per M. Ueland, Øivind Midttun, Zachary Gerhart-Hines, Petter Brodin, Teresa Pereira, Per-Olof Berggren, Jorge L. Ruas
Journal: Cell Metabolism (2018)
Multiplex PCR for detection of plasmid-mediated colistin resistance determinants, mcr-1, mcr-2, mcr-3, mcr-4 and mcr-5 for surveillance purposes
Authors: Ana Rita Rebelo, Valeria Bortolaia, Jette S Kjeldgaard, Susanne K Pedersen, Pimlapas Leekitcharoenphon, Inge M Hansen, Beatriz Guerra, Burkhard Malorny, Maria Borowiak, Jens Andre Hammerl, Antonio Battisti, Alessia Franco, Patricia Alba, Agnes Perrin-Guyomard, Sophie A Granier, Cristina De Frutos Escobar, Surbhi Malhotra-Kumar, Laura Villa, Alessandra Carattoli, Rene S Hendriksen
Journal: Eurosurveillance (2018)

Background and aimPlasmid-mediated colistin resistance mechanisms have been identified worldwide in the past years. A multiplex polymerase chain reaction (PCR) protocol for detection of all currently known transferable colistin resistance genes (mcr-1 to mcr-5, and variants) in Enterobacteriaceae was developed for surveillance or research purposes. Methods: We designed four new primer pairs to amplify mcr-1, mcr-2, mcr-3 and mcr-4 gene products and used the originally described primers for mcr-5 to obtain a stepwise separation of ca 200 bp between amplicons. The primer pairs and amplification conditions allow for single or multiple detection of all currently described mcr genes and their variants present in Enterobacteriaceae. The protocol was validated testing 49 European Escherichia coli and Salmonella isolates of animal origin. Results: Multiplex PCR results in bovine and porcine isolates from Spain, Germany, France and Italy showed full concordance with whole genome sequence data. The method was able to detect mcr-1, mcr-3 and mcr-4 as singletons or in different combinations as they were present in the test isolates. One new mcr-4 variant, mcr-4.3, was also identified. Conclusions: This method allows rapid identification of mcr-positive bacteria and overcomes the challenges of phenotypic detection of colistin resistance. The multiplex PCR should be particularly interesting in settings or laboratories with limited resources for performing genetic analysis as it provides information on the mechanism of colistin resistance without requiring genome sequencing.
Highly Multiplexed Imaging Mass Cytometry Allows Visualization of Tumor and Immune Cell Interactions of the Tumor Microenvironment in FFPE Tissue Sections
Authors: Mohan Singh, Parvesh Chaudhry, Erik Gerdtsson, Asaf Maoz, Wendy Cozen, James Hicks, Peter Kuhn, Stephen Gruber, Imran Siddiqi, Akil Merchant
Journal: Blood (2017)
Developing a core outcome set for fistulising perianal Crohn’s disease
Authors: Kapil Sahnan, Phil J Tozer, Samuel O Adegbola, Matthew J Lee, Nick Heywood, Angus G K McNair, Daniel Hind, Nuha Yassin, Alan J Lobo, Steven R Brown, Shaji Sebastian, Robin K S Phillips, Phillip F C Lung, Omar D Faiz, Kay Crook, Sue Blackwell, Azmina Verjee, Ailsa L Hart, Nicola S Fearnhead
Journal: Gut (2018)

Objective Lack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn’s disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD. Design Candidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback from their panel (in the second round) and all participants (in the third round) to allow refinement of their scores. Results A total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study. The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician-reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion). Conclusion A fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care.
Abstract 16117: Critical Role of ADAMTS-4 in the Development of Sporadic Thoracic and Abdominal Aortic Aneurysm and Dissection
Authors: Pingping Ren, Michael Hughes, Swapna Krishnamoorthy, Sili Zou, Yanqiu Zheng, John A. Curci, Joseph S. Coselli, Scott A. LeMaire, Hu Ying Shen
Journal: Circulation (2016)

Introduction: ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) levels are increased in human descending thoracic aortic aneurysm and dissection (dTAAD) samples. Hypothesi...
DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk
Authors: Wenbing Xie, Ioannis Kagiampakis, Lixia Pan, Yang W. Zhang, Lauren Murphy, Yong Tao, Xiangqian Kong, Byunghak Kang, Limin Xia, Filipe L.F. Carvalho, Subhojit Sen, Ray-Whay Chiu Yen, Cynthia A. Zahnow, Nita Ahuja, Stephen B. Baylin, Hariharan Easwaran
Journal: Cancer Cell (2018)