tbuckley/cabot-search huggingface dataset:
Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period
Authors: Francis Berenbaum, Francisco J Blanco, Ali Guermazi, Kenji Miki, Takaharu Yamabe, Lars Viktrup, Rod Junor, William Carey, Mark T Brown, Christine R West, Kenneth M Verburg
Journal: Annals of the Rheumatic Diseases (2020)

Objective Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up. Methods This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient’s Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study. Results From March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE –0.62±0.18, p=0.0006), WOMAC Physical Function (–0.71±0.17, p&lt;0.0001) and PGA-OA (–0.19±0.07, p=0.0051). For tanezumab 2.5 mg, there was a statistically significant improvement in WOMAC Pain and Physical Function, but not PGA-OA. Rapidly progressive osteoarthritis (RPOA) was observed in 1.4% (4/283) and 2.8% (8/284) of patients in the tanezumab 2.5 mg and tanezumab 5 mg groups, respectively and none receiving placebo. Total joint replacements (TJRs) were similarly distributed across all three treatment groups (6.7%–7.8%). Tanezumab-treated patients experienced more paraesthesia (5 mg) and hypoaesthesia (both doses) than placebo. Conclusion Tanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups. Trial registration number NCT02709486 .
Endocrine and metabolic link to coronavirus infection
Authors: Stefan R. Bornstein, Rinkoo Dalan, David Hopkins, Geltrude Mingrone, Bernhard O. Boehm
Journal: Nature Reviews Endocrinology (2020)

Type 2 diabetes mellitus and hypertension are the most common comorbidities in patients with coronavirus infections. Emerging evidence demonstrates an important direct metabolic and endocrine mechanistic link to the viral disease process. Clinicians need to ensure early and thorough metabolic control for all patients affected by COVID-19.
BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax
Authors: Victor S. Lin, Thomas E. Lew, Sasanka M. Handunnetti, Piers Blombery, Tamia Nguyen, David A. Westerman, Bryone J. Kuss, Constantine S. Tam, Andrew W. Roberts, John F. Seymour, Mary Ann Anderson
Journal: Blood (2020)
Comparison of therapy‐related and de novo core binding factor acute myeloid leukemia: A bone marrow pathology group study
Authors: Heesun J. Rogers, Xiaoqiong Wang, Yan Xie, Adam R. Davis, Beenu Thakral, Sa A. Wang, Gautam Borthakur, Miguel D. Cantu, Elizabeth M. Margolskee, John K. S. Philip, Madina Sukhanova, Adam Bagg, Carlos E. Bueso‐Ramos, Attilio Orazi, Daniel A. Arber, Eric D. Hsi, Robert P. Hasserjian
Journal: American Journal of Hematology (2020)

This multi-institutional study retrospectively evaluated clinicopathologic and genetic characteristics in 351 patients with core-binding-factor acute myeloid leukemia (CBF-AML), comprising 69 therapy-related (t-CBF-AML) and 282 de novo cases. The T-CBF-AML patients were older, had lower WBC counts, and slightly higher hemoglobin than patients with de novo disease. Secondary cytogenetic abnormalities were more frequent in patients with de novo disease than t-CBF-AML (57.1% vs 41.1%, P = .026). Patients with secondary cytogenetic abnormalities had longer overall survival (OS) than those without abnormalities (median 190 vs 87 months, P = .021); trisomy 8, trisomy 22, and loss of the X or Y chromosome were associated with longer OS. In the 165 cases performed of targeted gene sequencing, pathogenic mutations were detected in 75.7% of cases, and were more frequent in de novo than in therapy-related disease (P = .013). Mutations were found in N/KRAS (37.0%), FLT3 (27.8%), KIT (17.2%), TET2 (4.9%), and ASXL1 (3.9%). The TET2 mutations were associated with shorter OS (P = .012) while N/KRAS mutation was associated with longer OS in t(8;21) AML patients (P = .001). The KIT mutation did not show prognostic significance in this cohort. Although they received similar therapy, t-CBF-AML patients had shorter OS than de novo patients (median 69 vs 190 months, P = .038). In multivariate analysis of all patients, older age and absence of any secondary cytogenetic abnormalities were significant predictors of shorter OS. Among the t-CBF-AML subset, age and hemoglobin were significant on multivariate analysis. This study demonstrated that although de novo and t-CBF-AML patients share many features, t-CBF-AML patients have worse clinical outcome than de novo patients.
Infantile Diarrhoea and Vomiting
Authors: M. B. Alexander
Journal: BMJ (1948)

Units for the treatment of enteritis of infants were estab- lished at most of the infectious diseases hospitals adminis- tered by the Loncdon County Council.The unit at the North-Eastern Hospital came under my care in January, 1945.The cases recorded in this paper were admitted during the years 1945 and 1946.Early in 1947 the unit was moved to more suitable accommodation in single-cell wards.The experience of that year is not comparable with that of previous years and has therefore been excluded.The object of this paper is to describe the organization and working of the unit, to discuss the type of case treated, and to analyse the results of treatment.Organization Accommodation and Equipment.-Throughoutthe period 1945-6 the unit was contained in two wards of the composite, or Hiorns, type (Harries and Mitman, 1947).Each ward was designed to provide accommodation for 31 patients, distributed as follows: 5 in single cells, 6 in double cells, and 20 in groups of 4 in the five bays of the
Abstract 15670: MicroRNA Profiling Points to MMP9 as a Critical Contributor to Intense Exercise-Induced Vascular Stiffening
Authors: Cira Rubies, Montserrat Batlle, Nadia Castillo, Guerau Fernandez, Maria Sanz-de la Garza, Marta Sitges, Josep Brugada, Lluís Mont, Eduard Guasch
Journal: Circulation (2017)

Introduction: Moderate exercise reduces the atherosclerosis burden, but recent clinical and experimental data suggest that extreme-trained endurance athletes might be at an increased risk of cardio...
Critical Illness in Patients With COVID-19
Authors: Deborah J. Cook, John C. Marshall, Robert A. Fowler
Journal: JAMA (2020)

Giacomo Grasselli, MD; Alberto Zangrillo, MD; Alberto Zanella, MD; Massimo Antonelli, MD; Luca Cabrini, MD; Antonio Castelli, MD; Danilo Cereda, MD; Antonio Coluccello, MD; Giuseppe Foti, MD; Roberto Fumagalli, MD; Giorgio Iotti, MD; Nicola Latronico, MD; Luca Lorini, MD; Stefano Merler, MS; Giuseppe Natalini, MD; Alessandra Piatti, MD; Marco Vito Ranieri, MD; Anna Mara Scandroglio, MD; Enrico Storti, MD; Maurizio Cecconi, MD; Antonio Pesenti, MD; COVID-19 Lombardy ICU Network; Emiliano Agosteo; Valentina Alaimo; Giovanni Albano; Andrea Albertin; Armando Alborghetti; Giorgio Aldegheri; Benvenuto Antonini; Enrico Barbara; Nicolangela Belgiorno; Mirko Belliato; Annalisa Benini; Enrico Beretta; Leonardo Bianciardi; Stefano Bonazzi; Massimo Borelli; Enrico Boselli; Nicola Bronzini; Carlo Capra; Livio Carnevale; Giampaolo Casella; Gianpaolo Castelli; Emanuele Catena; Sergio Cattaneo; Davide Chiumello; Silvia Cirri; Giuseppe Citerio; Sergio Colombo; Davide Coppini; Alberto Corona; Paolo Cortellazzi; Elena Costantini; Remo Daniel Covello; Gianluca De Filippi; Marco Dei Poli; Federica Della Mura; Giulia Evasi; Raquel Fernandez-Olmos; Andrea Forastieri Molinari; Marco Galletti; Giorgio Gallioli; Marco Gemma; Paolo Gnesin; Lorenzo Grazioli; Stefano Greco; Paolo Gritti; Paolo Grosso; Luca Guatteri; Davide Guzzon; Fabiola Harizay; Roberto Keim; Giovanni Landoni; Thomas Langer; Andrea Lombardo; Annalisa Malara; Elena Malpetti; Francesco Marino; Giovanni Marino; Maurizio Giovanni Mazzoni; Guido Merli; Antonio Micucci; Francesco Mojoli; Stefano Muttini; Adriana Nailescu; Mauro Panigada; Paolo Perazzo; Giovanni Battista Perego; Nicola Petrucci; Angelo Pezzi; Alessandro Protti; Danilo Radrizzani; Maurizio Raimondi; Marco Ranucci; Frank Rasulo; Mario Riccio; Roberto Rona; Claudio Roscitano; Patrizia Ruggeri; Antonello Sala; Giuseppe Sala; Luca Salvi; Pietro Sebastiano; Paolo Severgnini; Ilaria Sforzini; Francesco Donato Sigurtà; Matteo Subert; Paola Tagliabue; Carmine Troiano; Roberto Valsecchi; Uberto Viola; Giovanni Vitale; Massimo Zambon; Elena Zoia
Transition to quantitative faecal immunochemical testing from guaiac faecal occult blood testing in a fully rolled-out population-based national bowel screening programme
Authors: Gavin Clark, Judith A Strachan, Frank A Carey, Thomas Godfrey, Audrey Irvine, Alisson McPherson, Jess Brand, Annie S Anderson, Callum G Fraser, Robert JC Steele
Journal: Gut (2020)

Objective Faecal immunochemical tests (FIT) are replacing guaiac faecal occult blood tests (FOBT) in colorectal cancer (CRC) screening. Data from the first year of FIT screening were compared with those from FOBT screening and assumptions based on a pilot evaluation of FIT. Design Data on uptake, positivity, positive predictive value (PPV) for CRC and higher-risk adenoma from participants in the first year of the FIT-based Scottish Bowel Screening Programme (n=919 665), with a threshold of 80 µg Hb/g faeces, were compared with those from the penultimate year of the FOBT-based programme (n=862 165) and those from the FIT evaluation (n=66 225). Results Overall, uptake of FIT was 63.9% compared with 56.4% for FOBT. Positivity was 3.1% and 2.2% with FIT and FOBT; increases were seen in both sexes, and across age range and deprivation. More CRC and adenomas were detected by FIT, but the PPV for CRC was less (5.2% with FIT and 6.4% with FOBT). However, for higher-risk adenoma, PPV was greater with FIT (24.3% with FIT and 19.3% with FOBT). In the previous FIT evaluation, uptake was 58.5% with FIT compared with 54.0% with FOBT; positivity was 2.5% with FIT and 2.0% with FOBT. Conclusion Transition to FIT from FOBT produced higher uptake and positivity with lower PPV for CRC and higher PPV for adenoma. The FIT pilot evaluation underestimated uptake and positivity. Introducing FIT at the same threshold as the evaluation caused a 67.2% increase in colonoscopy demand instead of a predicted 10%.
Emerging carrier‐free nanosystems based on molecular self‐assembly of pure drugs for cancer therapy
Authors: Xuanbo Zhang, Na Li, Shenwu Zhang, Bingjun Sun, Qin Chen, Zhonggui He, Cong Luo, Jin Sun
Journal: Medicinal Research Reviews (2020)

Abstract The potential toxicity of nanocarrier excipients and complicated preparation technologies have impeded the clinical application of nanomedicine. Recently, pure drug‐assembled nanosystems (PDANS) have been widely investigated, due to the unique self‐assembly characteristics of pure drug molecules. PDANS provides a facile nanoplatform for developing carrier‐free nanomedicine. Herein, the recent trends in PDANS for cancer therapy are outlined. First, the emerging strategies to develop single pure drug‐based nanoassemblies are discussed. Second, co‐assembly of two or more pure drugs for efficient combination therapy is overviewed. Then, the functional self‐assembly of non‐cytotoxic agents in tumor sites is presented. Finally, the rational design and self‐assembly mechanisms of these unique nanoplatforms are highlighted.
Innate and Acquired Resistance to Anti-EGFR Therapy—Letter
Authors: Janardan P. Pandey
Journal: Clinical Cancer Research (2020)

I read with great interest the recent article by Parseghian and colleagues (1), presenting a review of the mechanisms underlying the innate and acquired resistance to anti-EGFR therapy. This "in-depth review" of the resistance mechanisms, however, does not include the possible host antibody responses to the immunogenic epitopes present on the therapeutic anti-EGFR mAbs, such as cetuximab and panitumumab (2). Both cetuximab and panitumumab express GM (γ marker) allotypes that are highly immunogenic in subjects lacking these determinants. For instance, GM 3 allotype is expressed in the CH1 region of cetuximab (3). Subjects lacking GM 3 could have preexisting anti-GM 3 antibodies because of maternal–fetal incompatibility (4). The administered cetuximab and the preexisting anti-GM 3 antibodies would form immune complexes that would be removed from the system by phagocytic cells, leading to de novo resistance to cetuximab therapy. Repeated infusion of cetuximab could also generate anti-GM 3 antibodies, leading to acquired resistance to this immunotherapy.Similar resistance mechanisms could also be envisioned for panitumumab therapy. In summary, effective "personalized immunotherapeutic approaches" must take into account the immunogenicity of GM allotypes expressed on the therapeutic antibodies.No potential conflicts of interest were disclosed.J.P. Pandey's laboratory is currently supported by grants from the NIH and the Cystic Fibrosis Foundation.
The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer
Authors: Xiaying Zheng, Mengge Huang, Lei Xing, Rui Yang, Xiaosong Wang, Rong Jiang, Luyu Zhang, Junxia Chen
Journal: Molecular Cancer (2020)

Abstract Background Increasing studies have shown that circRNA is closely related to the carcinogenesis and development of many cancers. However, biological functions and the underlying molecular mechanism of circRNAs in triple-negative breast cancer (TNBC) remain largely unclear so far. Methods Here, we investigated the expression pattern of circRNAs in four pairs of TNBC tissues and paracancerous normal tissues using RNA-sequencing. The expression and prognostic significance of circSEPT9 were evaluated with qRT-PCR and in situ hybridization in two TNBC cohorts. The survival curves were drawn by the Kaplan-Meier method, and statistical significance was estimated with the log-rank test. A series of in vitro and in vivo functional experiments were executed to investigate the role of circSEPT9 in the carcinogenesis and development of TNBC. Mechanistically, we explored the potential regulatory effects of E2F1 and EIF4A3 on biogenesis of circSEPT9 with chromatin immunoprecipitation (ChIP), luciferase reporter and RNA immunoprecipitation (RIP) assays. Furthermore, fluorescent in situ hybridization (FISH), luciferase reporter and biotin-coupled RNA pull-down assays were implemented to verify the relationship between the circSEPT9 and miR-637 in TNBC. Results Increased expression of circSEPT9 was found in TNBC tissues, which was positively correlated with advanced clinical stage and poor prognosis. Knockdown of circSEPT9 significantly suppressed the proliferation, migration and invasion of TNBC cells, induced apoptosis and autophagy in TNBC cells as well as inhibited tumor growth and metastasis in vivo. Whereas up-regulation of circSEPT9 exerted opposite effects. Further mechanism research demonstrated that circSEPT9 could regulate the expression of Leukemia Inhibitory Factor (LIF) via sponging miR-637 and activate LIF/Stat3 signaling pathway involved in progression of TNBC. More importantly, we discovered that E2F1 and EIF4A3 might promote the biogenesis of circSEPT9. Conclusions Our data reveal that the circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer through circSEPT9/miR-637/LIF axis. Therefore, circSEPT9 could be used as a potential prognostic marker and therapeutical target for TNBC.
Abstract 200: Nanofibrous Microsphere Mediated High Engraftment of hESC Derived Cardiomyocytes Improves Rat Heart Function After Infarction
Authors: Zhong Wang
Journal: Circulation Research (2017)

Cell-based therapy is a promising strategy to regenerate the injured heart after myocardial infarction. However, the current strategies only show modest therapeutic benefits largely due to the low engraftment and poor regeneration of functional cardiac muscle tissue. To address these critical issues in heart regeneration, we applied poly (L-lactic acid) nanofibrous hollow microspheres (NF-HMS) as cell carriers to transplant human embryonic stem cell (hESC) derived cardiomyocytes (CMs) into infarcted rat hearts. Our studies showed that, 28 days after cell transplantation, graft size of the CM+NF-HMS group (1.85 ± 0.72 mm 2 ) was significantly higher than that of the CM only group (0.49 ± 0.34 mm 2 ) (P&lt;0.01), resulting in a 3.78 fold increase of CM engraftment by application of NF-HMS. Consequently, the reduction of infarct size in CM+NF-HMS group was significantly greater than that of the CM only group (42.58% versus 12.07% reduction). Furthermore, the grafted cells could couple with host cells as indicated by connexin 43 connections between grafted and host cells. Functionally, the left ventricular ejection fraction and fractional shortening in CM+NF-HMS group was significantly improved compared with CM only and PBS control groups. The increased engraftment of CMs in CM+NF-HMS group also promoted a higher density of vasculature in the infarction border zone. Thus, the highly engrafted transplantation of CMs using NF-HMS as a cell carrier resulted in significant improvement of CM engraftment, revascularization, and functional performance, providing an exciting strategy for heart regeneration.
Regional coordination and bottom-up response of general practitioners in Belgium and the Netherlands
Authors: Josefien van Olmen, Roy Remmen, Paul Van Royen, Hilde Philips, Veronique Verhoeven, Sibyl Anthierens
Journal: BMJ (2020)

General practitioners are at the core of the healthcare response to the emerging covid-19 epidemic in European health systems. 1 The coordination of primary care differs across countries; we describe the response in Belgium and the Netherlands.
Defining biomarkers to predict symptoms in subjects with and without allergy under natural pollen exposure
Authors: Mehmet Gökkaya, Athanasios Damialis, Thomas Nussbaumer, Isabelle Beck, Nikolaos Bounas-Pyrros, Sebastian Bezold, Marie M. Amisi, Franziska Kolek, Antonia Todorova, Adam Chaker, Lorenz Aglas, Fatima Ferreira, Frank A. Redegeld, Jens O. Brunner, Avidan U. Neumann, Claudia Traidl-Hoffmann, Stefanie Gilles
Journal: Journal of Allergy and Clinical Immunology (2020)
Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial
Authors: Sarah B Goldberg, Kurt A Schalper, Scott N Gettinger, Amit Mahajan, Roy S Herbst, Anne C Chiang, Rogerio Lilenbaum, Frederick H Wilson, Sacit Bulent Omay, James B Yu, Lucia Jilaveanu, Thuy Tran, Kira Pavlik, Elin Rowen, Heather Gerrish, Annette Komlo, Richa Gupta, Hailey Wyatt, Matthew Ribeiro, Yuval Kluger, Geyu Zhou, Wei Wei, Veronica L Chiang, Harriet M Kluger
Journal: The Lancet Oncology (2020)
Continuous Ketamine Infusion for Pain as an Opportunity for Psychotherapy for PTSD: A Case Series of Ketamine-Enhanced Psychotherapy for PTSD and Pain (KEP-P2)
Authors: Benjamin M. Keizer, John D. Roache, John R. Jones, Ryan J. Kalpinski, John H. Porcerelli, John H. Krystal
Journal: Psychotherapy and Psychosomatics (2020)
Impact of left atrial diameter on outcome in patients undergoing edge‐to‐edge mitral valve repair: results from the German <scp>TRAnscatheter</scp> Mitral valve Interventions (<scp>TRAMI</scp>) registry
Authors: Christos Iliadis, Stephan Baldus, Daniel Kalbacher, Peter Boekstegers, Wolfgang Schillinger, Taoufik Ouarrak, Ralf Zahn, Christian Butter, Christine S. Zuern, Ralph Stephan von Bardeleben, Jochen Senges, Raffi Bekeredjian, Holger Eggebrecht, Roman Pfister
Journal: European Journal of Heart Failure (2020)

ABSTRACT Background Left atrial (LA) dimension is a marker of disease severity and outcome in primary and secondary mitral regurgitation. In transcatheter mitral valve repair, LA enlargement might additionally impact on device handling and technical success through an altered anatomy and atrial annular dilatation. Methods and results Data from the multicentre German TRAnscatheter Mitral valve Interventions registry (TRAMI) were used to analyse the association of baseline LA diameter by tertiles with efficacy, safety and long‐term clinical outcome in patients undergoing edge‐to‐edge repair with MitraClip. In 520 of 843 patients prospectively enrolled in TRAMI, baseline LA diameter were reported [median (interquartile range) LA diameter in tertiles: 44 (40–46) mm, 51 (48–53) mm and 60 (55–66) mm]. Larger LA diameters were significantly associated with secondary aetiology of mitral regurgitation, lower ejection fraction, larger left ventricle, male sex and atrial fibrillation (all P &lt; 0.05). Technical success was not different across tertiles (96%, 95.4% and 98.4%, respectively; P = 0.43) as were major in‐hospital cardiovascular and cerebral adverse events (mortality, myocardial infarction or stroke: 1.8%, 1.2% and 4.4%, respectively; P = 0.11 across tertiles). However, 4‐year mortality significantly increased with larger LA diameter (32.9%, 46.4% and 51.7%, respectively; P &lt; 0.01), as did hospitalization in survivors (60%, 67.6% and 78.9%, respectively; P &lt; 0.05). The association between LA diameter and outcome remained significant after multivariable adjustment including baseline left ventricular end‐diastolic diameter. Conclusion Left atrial enlargement is a strong and independent predictor of adverse long‐term outcome after transcatheter mitral valve repair. Further study is warranted to examine whether timely intervention may have the potential to modify outcome.
The Origin of Additive Genetic Variance Driven by Positive Selection
Authors: Li Liu, Yayu Wang, Di Zhang, Zhuoxin Chen, Xiaoshu Chen, Zhijian Su, Xionglei He
Journal: Molecular Biology and Evolution (2020)

Abstract Fisher’s fundamental theorem of natural selection predicts no additive variance of fitness in a natural population. Consistently, studies in a variety of wild populations show virtually no narrow-sense heritability (h2) for traits important to fitness. However, counterexamples are occasionally reported, calling for a deeper understanding on the evolution of additive variance. In this study, we propose adaptive divergence followed by population admixture as a source of the additive genetic variance of evolutionarily important traits. We experimentally tested the hypothesis by examining a panel of ∼1,000 yeast segregants produced by a hybrid of two yeast strains that experienced adaptive divergence. We measured &amp;gt;400 yeast cell morphological traits and found a strong positive correlation between h2 and evolutionary importance. Because adaptive divergence followed by population admixture could happen constantly, particularly in species with wide geographic distribution and strong migratory capacity (e.g., humans), the finding reconciles the observation of abundant additive variances in evolutionarily important traits with Fisher’s fundamental theorem of natural selection. Importantly, the revealed role of positive selection in promoting rather than depleting additive variance suggests a simple explanation for why additive genetic variance can be dominant in a population despite the ubiquitous between-gene epistasis observed in functional assays.