tbuckley/cabot-search huggingface dataset:
Long-term cardiometabolic disease risk in women with PCOS: a systematic review and meta-analysis
Authors: V Wekker, L van Dammen, A Koning, K Y Heida, R C Painter, J Limpens, J S E Laven, J E Roeters van Lennep, T J Roseboom, A Hoek
Journal: Human Reproduction Update (2020)

Abstract BACKGROUND Polycystic ovary syndrome (PCOS) is associated with cardiometabolic disease, but recent systematic reviews and meta-analyses of longitudinal studies that quantify these associations are lacking. OBJECTIVE AND RATIONALE Is PCOS a risk factor for cardiometabolic disease? SEARCH METHODS We searched from inception to September 2019 in MEDLINE and EMBASE using controlled terms (e.g. MESH) and text words for PCOS and cardiometabolic outcomes, including cardiovascular disease (CVD), stroke, myocardial infarction, hypertension (HT), type 2 diabetes (T2D), metabolic syndrome and dyslipidaemia. Cohort studies and case–control studies comparing the prevalence of T2D, HT, fatal or non-fatal CVD and/or lipid concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) between women with and without PCOS of ≥18 years of age were eligible for this systematic review and meta-analysis. Studies were eligible regardless of the degree to which they adjusted for confounders including obesity. Articles had to be written in English, German or Dutch. Intervention studies, animal studies, conference abstracts, studies with a follow-up duration less than 3 years and studies with less than 10 PCOS cases were excluded. Study selection, quality assessment (Newcastle–Ottawa Scale) and data extraction were performed by two independent researchers. OUTCOMES Of the 5971 identified records, 23 cohort studies were included in the current systematic review. Women with PCOS had increased risks of HT (risk ratio (RR): 1.75, 95% CI 1.42 to 2.15), T2D (RR: 3.00, 95% CI 2.56 to 3.51), a higher serum concentration of TC (mean difference (MD): 7.14 95% CI 1.58 to 12.70 mg/dl), a lower serum concentration of HDL-C (MD: −2.45 95% CI −4.51 to −0.38 mg/dl) and increased risks of non-fatal cerebrovascular disease events (RR: 1.41, 95% CI 1.02 to 1.94) compared to women without PCOS. No differences were found for LDL-C (MD: 3.32 95% CI −4.11 to 10.75 mg/dl), TG (MD 18.53 95% CI −0.58 to 37.64 mg/dl) or coronary disease events (RR: 1.78, 95% CI 0.99 to 3.23). No meta-analyses could be performed for fatal CVD events due to the paucity of mortality data. WIDER IMPLICATIONS Women with PCOS are at increased risk of cardiometabolic disease. This review quantifies this risk, which is important for clinicians to inform patients and to take into account in the cardiovascular risk assessment of women with PCOS. Future clinical trials are needed to assess the ability of cardiometabolic screening and management in women with PCOS to reduce future CVD morbidity.
A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II
Authors: Torayuki Okuyama, Yoshikatsu Eto, Norio Sakai, Kimitoshi Nakamura, Tatsuyoshi Yamamoto, Mariko Yamaoka, Toshiaki Ikeda, Sairei So, Kazunori Tanizawa, Hiroyuki Sonoda, Yuji Sato
Journal: Molecular Therapy (2020)

Pabinafusp alfa (JR-141) is a novel enzyme drug that crosses the blood-brain barrier by transcytosis via transferrin receptors. In order to establish its efficacy and safety, a multicenter, single-arm, open-label phase 2/3 clinical trial was conducted in 28 Japanese patients with mucopolysaccharidosis II (MPS-II, Hunter syndrome) by intravenous administrations of 2.0 mg/kg of pabinafusp alfa for 52 weeks. The primary efficacy endpoint was changes in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF). Secondary endpoints included assessments of neurocognitive development for central efficacy, and changes in plasma HS and dermatan sulfate (DS) concentrations for peripheral efficacy. HS concentrations in the CSF significantly decreased from baseline to week 52 (p < 0.001), suggesting continuous inhibition of substrate accumulations in the CNS, i.e., hitherto unaddressed progressive neurodegeneration. Evaluations of neurocognitive developments showed positive changes in 21 of the 28 patients. Serum HS and DS concentrations, liver and spleen volumes, and other assessments suggested the peripheral efficacy of pabinafusp alfa was comparable to that of idursulfase. Drug-related adverse events were mild or moderate in severity, transient, and manageable. The results establish delivery across the BBB of pabinafusp alfa as an effective therapeutic for treating both the CNS and peripheral symptoms of patients with MPS-II.
Intestinal loads of OXA-48-producing Klebsiella pneumoniae in colonized patients determined from surveillance rectal swabs
Authors: Fernando Lázaro-Perona, María Rodríguez-Tejedor, Guillermo Ruiz-Carrascoso, Beatriz Díaz-Pollán, Belén Loeches, Juan Carlos Ramos-Ramos, Jesús Mingorance
Journal: Clinical Microbiology and Infection (2020)
Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer
Authors: Chenghua Liang, Xiangyang Bai, Cuiling Qi, Qingxue Sun, Xiaoyan Han, Tianyun Lan, Haibo Zhang, Xiaoming Zheng, Rongpu Liang, Ju Jiao, Zongheng Zheng, Jiafeng Fang, Purun Lei, Yan Wang, Diana Möckel, Josbert M. Metselaar, Gert Storm, Wim E. Hennink, Fabian Kiessling, Hongbo Wei, Twan Lammers, Yang Shi, Bo Wei
Journal: Biomaterials (2020)
Tralokinumab plus topical corticosteroids for the treatment of moderate‐to‐severe atopic dermatitis: results from the double‐blind, randomized, multicentre, placebo‐controlled phase III ECZTRA 3 trial*
Authors: J.I. Silverberg, D. Toth, T. Bieber, A.F. Alexis, B.E. Elewski, A.E. Pink, D. Hijnen, T.N. Jensen, B. Bang, C.K. Olsen, A. Kurbasic, S. Weidinger
Journal: British Journal of Dermatology (2020)

Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin-13, a key driver of atopic dermatitis (AD).To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate-to-severe AD who were candidates for systemic therapy.This was a double-blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator's Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks.At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9-21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8-30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups.Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate-to-severe AD.
Next-generation Sequencing of Cerebrospinal Fluid: How Can a Liquid be Like a Solid?
Authors: Melina E. Marmarelis, Joshua M. Bauml
Journal: Clinical Cancer Research (2020)

The APOLLO investigators showed that next-generation sequencing of cerebrospinal fluid can reveal molecular alterations-how should this affect our management approach?See related article by Xing et al., p. 6168.
Biological and environmental predictors of heterogeneity in neurocognitive ageing
Authors: Lars Nyberg, Carl-Johan Boraxbekk, Daniel Eriksson Sörman, Patrik Hansson, Agneta Herlitz, Karolina Kauppi, Jessica K. Ljungberg, Hugo Lövheim, Anders Lundquist, Annelie Nordin Adolfsson, Anna Oudin, Sara Pudas, Michael Rönnlund, Mikael Stiernstedt, Anna Sundström, Rolf Adolfsson
Journal: Ageing Research Reviews (2020)

Individual differences in cognitive performance increase with advancing age, reflecting marked cognitive changes in some individuals along with little or no change in others. Genetic and lifestyle factors are assumed to influence cognitive performance in ageing by affecting the magnitude and extent of age-related brain changes (i.e., brain maintenance or atrophy), as well as the ability to recruit compensatory processes. The purpose of this review is to present findings from the Betula study and other longitudinal studies, with a focus on clarifying the role of key biological and environmental factors assumed to underlie individual differences in brain and cognitive ageing. We discuss the vital importance of sampling, analytic methods, consideration of non-ignorable dropout, and related issues for valid conclusions on factors that influence healthy neurocognitive ageing.
Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial
Authors: Ina Jochmans, Aukje Brat, Lucy Davies, H Sijbrand Hofker, Fenna E M van de Leemkolk, Henri G D Leuvenink, Simon R Knight, Jacques Pirenne, Rutger J Ploeg, Daniel Abramowicz, Neal Banga, Frederike J Bemelman, Michiel GH Betjes, Richéal Burns, Virginia Chiocchia, Maarten HL Christiaans, Tom Darius, Jeroen de Jonge, Aiko PJ de Vries, Olivier Detry, Luuk B Hilbrands, H Sijbrand Hofker, Arjan WJ Hoksbergen, Volkert AL Huurman, Mirza M Idu, Daniel Jacobs-Tulleneers-Thevissen, Ina Jochmans, Maria Kaisar, Nada Kanaan, Diederik Kimenai, Dirk Kuypers, Alain Le Moine, Carl Marshall, Nicolas Meurisse, Dimitri Mikhalski, Cyril Moers, Diethard Monbaliu, Willemijn N Nijboer, S Azam Nurmohamed, John O'Callaghan, Vassilios Papalois, Lissa Pipeleers, Paul PC Poyck, Isabel Quiroga, Caren Randon, Geert W Schurink, Marc Seelen, Laszlo Szabo, Raechel J Toorop, Marcel CG van de Poll, Michel FP van der Jagt, Steven Van Laecke, Arjan D van Zuilen, Laurent Weekers, Dirk Ysebaert
Journal: The Lancet (2020)
Antibiotics are as good as surgery for appendicitis, study reports
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Antibiotics could be used instead of appendectomy to treat appendicitis in some patients, according to a study that compared the treatments in 1552 patients.1

Researchers carried out a non-blinded, non-inferiority, randomised trial comparing a 10 day course of antibiotics with appendectomy in appendicitis patients across 25 centres in the US. They reported that antibiotics were non-inferior to appendectomy at 30 days, based on a quality of life questionnaire (mean difference, 0.01 points; 95% confidence interval, -0.001 to 0.03).

The researchers said their findings “may be particularly relevant during the covid-19 pandemic, as patients and clinicians weigh the benefits and …
Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Authors: Naoka Tamura, Nadeem Shaikh, Daniel Muliaditan, Tanya N. Soliman, Jennifer R. McGuinness, Eleni Maniati, Daniela Moralli, Mary-Anne Durin, Catherine M. Green, Frances R. Balkwill, Jun Wang, Kit Curtius, Sarah E. McClelland
Journal: Cancer Research (2020)

Abstract Chromosomal instability (CIN) comprises continual gain and loss of chromosomes or parts of chromosomes and occurs in the majority of cancers, often conferring poor prognosis. Because of a scarcity of functional studies and poor understanding of how genetic or gene expression landscapes connect to specific CIN mechanisms, causes of CIN in most cancer types remain unknown. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynecologic malignancy in the Western world, with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosomal aberrations and knowledge of causative mechanisms would represent an important step toward combating this disease. Here we perform the first in-depth functional characterization of mechanisms driving CIN in HGSC in seven cell lines that accurately recapitulate HGSC genetics. Multiple mechanisms coexisted to drive CIN in HGSC, including elevated microtubule dynamics and DNA replication stress that can be partially rescued to reduce CIN by low doses of paclitaxel and nucleoside supplementation, respectively. Distinct CIN mechanisms indicated relationships with HGSC-relevant therapy including PARP inhibition and microtubule-targeting agents. Comprehensive genomic and transcriptomic profiling revealed deregulation of various genes involved in genome stability but were not directly predictive of specific CIN mechanisms, underscoring the importance of functional characterization to identify causes of CIN. Overall, we show that HGSC CIN is complex and suggest that specific CIN mechanisms could be used as functional biomarkers to indicate appropriate therapy. Significance: These findings characterize multiple deregulated mechanisms of genome stability that lead to CIN in ovarian cancer and demonstrate the benefit of integrating analysis of said mechanisms into predictions of therapy response.
Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i
Authors: Reinhard Dummer, Celeste Lebbé, Victoria Atkinson, Mario Mandalà, Paul D. Nathan, Ana Arance, Erika Richtig, Naoya Yamazaki, Caroline Robert, Dirk Schadendorf, Hussein A. Tawbi, Paolo A. Ascierto, Antoni Ribas, Keith T. Flaherty, Neha Pakhle, Catarina D. Campbell, Daniel Gusenleitner, Aisha Masood, Jan C. Brase, Eduard Gasal, Georgina V. Long
Journal: Nature Medicine (2020)
Epigenetic Neuropharmacology: Drugs Affecting the Epigenome in the Brain
Authors: Miklos Toth
Journal: The Annual Review of Pharmacology and Toxicology (2020)

This review explores how different classes of drugs, including those with therapeutic and abuse potential, alter brain functions and behavior via the epigenome. Epigenetics, in its simplest interpretation, is the study of the regulation of a genes' transcriptional potential. The epigenome is established during development but is malleable throughout life by a wide variety of drugs, with both clinical utility and abuse potential. An epigenetic effect can be central to the drug's therapeutic or abuse potential, or it can be independent from the main effect but nevertheless produce beneficial or adverse side effects. Here, I discuss the various epigenetic effects of main pharmacological drug classes, including antidepressants, antiepileptics, and drugs of abuse.
Comparison of clinical outcomes of patients infected with KPC- and NDM-producing Enterobacterales: a retrospective cohort study
Authors: Hyeonji Seo, Hwa Jung Kim, Min Jae Kim, Yong Pil Chong, Sung-Han Kim, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim, Jun Hee Woo, Jiwon Jung
Journal: Clinical Microbiology and Infection (2020)
Evolocumab in Children with Heterozygous Familial Hypercholesterolemia
Authors: Sarah D. de Ferranti
Journal: New England Journal of Medicine (2020)

Heterozygous familial hypercholesterolemia — in contrast to the more rare and more severe homozygous familial hypercholesterolemia — is a common genetic cholesterol disorder affecting approximately 1 in 250 persons and resulting in an increased risk of premature atherosclerotic cardiovascular disease.1 Autopsies and subclinical vascular studies indicate that childhood hypercholesterolemia leads to atherosclerosis. Two randomized, controlled trials have shown that reducing low-density lipoprotein (LDL) cholesterol levels with statins in childhood benefits subclinical vascular measures, delaying or even regressing carotid intima–media thickness,1 and late follow-up of one trial showed fewer events of atherosclerotic cardiovascular disease in treated children than in their affected . . .
Impact of anatomic site on antigen-presenting cells in cancer
Authors: Maria Zagorulya, Ellen Duong, Stefani Spranger
Journal: Journal for ImmunoTherapy of Cancer (2020)

Checkpoint blockade immunotherapy (CBT) can induce long-term clinical benefits in patients with advanced cancer; however, response rates to CBT vary by cancer type. Cancers of the skin, lung, and kidney are largely responsive to CBT, while cancers of the pancreas, ovary, breast, and metastatic lesions to the liver respond poorly. The impact of tissue-resident immune cells on antitumor immunity is an emerging area of investigation. Recent evidence indicates that antitumor immune responses and efficacy of CBT depend on the tissue site of the tumor lesion. As myeloid cells are predominantly tissue-resident and can shape tumor-reactive T cell responses, it is conceivable that tissue-specific differences in their function underlie the tissue-site-dependent variability in CBT responses. Understanding the roles of tissue-specific myeloid cells in antitumor immunity can open new avenues for treatment design. In this review, we discuss the roles of tissue-specific antigen-presenting cells (APCs) in governing antitumor immune responses, with a particular focus on the contributions of tissue-specific dendritic cells. Using the framework of the Cancer-Immunity Cycle, we examine the contributions of tissue-specific APC in CBT-sensitive and CBT-resistant carcinomas, highlight how these cells can be therapeutically modulated, and identify gaps in knowledge that remain to be addressed.
Pharmacologic Approach to Sinoatrial Node Dysfunction
Authors: Pietro Mesirca, Vadim V. Fedorov, Thomas J. Hund, Angelo G. Torrente, Isabelle Bidaud, Peter J. Mohler, Matteo E. Mangoni
Journal: The Annual Review of Pharmacology and Toxicology (2020)

The spontaneous activity of the sinoatrial node initiates the heartbeat. Sino-atrial node dysfunction (SND) and sick sinoatrial (sick sinus) syndrome are caused by the heart's inability to generate a normal sinoatrial node action potential. In clinical practice, SND is generally considered an age-related pathology, secondary to degenerative fibrosis of the heart pacemaker tissue. However, other forms of SND exist, including idiopathic primary SND, which is genetic, and forms that are secondary to cardiovascular or systemic disease. The incidence of SND in the general population is expected to increase over the next half century, boosting the need to implant electronic pacemakers. During the last two decades, our knowledge of sino-atrial node physiology and of the pathophysiological mechanisms underlying SND has advanced considerably. This review summarizes the current knowledge about SND mechanisms and discusses the possibility of introducing new pharmacologic therapies for treating SND.
Abstract B07: Rho-mediated gene transcription promotes BRAFi resistance in de-differentiated melanoma cells
Authors: Sean A. Misek, Kate M. Appleton, Tom S. Dexheimer, Erika M. Lisabeth, Roger S. Lo, Scott D. Larsen, Kathleen A. Gallo, Richard R. Neubig
Journal: Cancer Research (2020)

Abstract The goal of this study is to identify pharmacologically tractable resistance mechanisms, and ultimately to prevent or reverse drug resistance in melanoma. We demonstrate that a subset of BRAFi-resistant melanoma cell lines showed diminished expression of melanocyte differentiation markers (e.g., Sox10). The transcriptional signature of 15% of treatment-naïve TCGA SKCM (skin cutaneous melanoma) tumors is similar to that of de-differentiated BRAFi-resistant cell lines. This transcriptional signature in BRAFi-resistant melanoma cells and human tumors is associated with increased Rho activation and increased expression of a RhoA/C gene signature. Using a machine learning approach, we predict that these tumors have decreased sensitivity to multiple BRAF/MEK inhibitors, consistent with our observations in multiple cell line models. De-differentiated tumors are predicted to have increased sensitivity to multiple ROCK inhibitors, and this prediction was validated in multiple BRAFi-resistant cell line models. Since ROCK is one of the canonical Rho effector proteins, these data suggest that melanoma cells and tumors with low differentiation characteristics activate the Rho pathway and are sensitive to Rho pathway inhibition. As a consequence of the effect of Rho on the actin cytoskeleton, Rho regulates gene transcription through modulating transcriptional co-activators such as MRTFA and YAP1. Both MRTFA and YAP1 are activated in de-differentiated BRAFi-resistant cells and are predicted to be activated in human tumors with a similar transcriptomic profile. Consistent with our predictions, melanoma cells with MRTFA activation are sensitive to an MRTFA pathway inhibitor and those with high YAP1 activity are sensitive to indirect blockade of YAP1 activation. In total, these results demonstrate that over the course of drug resistance a subset of cells and tumors lose melanocyte lineage characteristics and gain Rho activation. In summary, our work has used bioinformatics/ML approaches to identify Rho-mediated gene transcription as an important, targetable mechanism of BRAFi resistance in de-differentiated melanomas. We experimentally demonstrate the efficacy of this approach in multiple BRAFi-resistant models, highlighting the potential of targeting Rho-mediated transcription for treating drug-resistant melanomas. Citation Format: Sean A. Misek, Kate M. Appleton, Tom S. Dexheimer, Erika M. Lisabeth, Roger S. Lo, Scott D. Larsen, Kathleen A. Gallo, Richard R. Neubig. Rho-mediated gene transcription promotes BRAFi resistance in de-differentiated melanoma cells [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B07.
Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu-opioid receptor signalling in humans and mice
Authors: Anne Abot, Eve Wemelle, Claire Laurens, Adrien Paquot, Nicolas Pomie, Deborah Carper, Arnaud Bessac, Xavier Mas Orea, Christophe Fremez, Maxime Fontanie, Alexandre Lucas, Jean Lesage, Amandine Everard, Etienne Meunier, Gilles Dietrich, Giulio G Muccioli, Cedric Moro, Patrice D Cani, Claude Knauf
Journal: Gut (2020)

Objective The enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes. Design We measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human. Results We found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic. Conclusions Using a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.