tbuckley/cabot-search huggingface dataset:
Pilocytic astrocytoma demethylation and transcriptional landscapes link bZIP transcription factors to immune response
Authors: Christian F Aichmüller, Murat Iskar, David T W Jones, Andrey Korshunov, Bernhard Radlwimmer, Marcel Kool, Aurelie Ernst, Stefan M Pfister, Peter Lichter, Marc Zapatka
Journal: Neuro-Oncology (2020)

Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. While genome and transcriptome landscapes are well studied, data of the complete methylome, tumor cell composition, and immune infiltration are scarce.We generated whole genome bisulfite sequence (WGBS) data of 9 PAs and 16 control samples and integrated available 154 PA and 57 control methylation array data. RNA sequence data of 49 PAs and 11 control samples as well as gene expression arrays of 248 PAs and 28 controls were used to assess transcriptional activity.DNA-methylation patterns of partially methylated domains suggested high stability of the methylomes during tumorigenesis. Comparing tumor and control tissues of infra- and supratentorial location using methylation arrays revealed a site specific pattern. Analysis of WGBS data revealed 9381 significantly differentially methylated regions (DMRs) in PA versus control tissue. Enhancers and transcription factor (TF) motifs of five distinct TF families were found to be enriched in DMRs. Methylation together with gene expression data-based in silico tissue deconvolution analysis indicated a striking variation in the immune cell infiltration in PA. A TF network analysis showed a regulatory relation between basic leucine zipper (bZIP) transcription factors and genes involved in immune-related processes.We provide evidence for a link of focal methylation differences and differential gene expression to immune infiltration.
Screening and assessment tools for gaming disorder: A comprehensive systematic review
Authors: Daniel L. King, Samuel R. Chamberlain, Natacha Carragher, Joel Billieux, Dan Stein, Kai Mueller, Marc N. Potenza, Hans Juergen Rumpf, John Saunders, Vladan Starcevic, Zsolt Demetrovics, Matthias Brand, Hae Kook Lee, Marcantonio Spada, Katajun Lindenberg, Anise M.S. Wu, Tagrid Lemenager, Ståle Pallesen, Sophia Achab, Mike Kyrios, Susumu Higuchi, Naomi A. Fineberg, Paul H. Delfabbro
Journal: Clinical Psychology Review (2020)

The inclusion of gaming disorder (GD) as an official diagnosis in the ICD-11 was a significant milestone for the field. However, the optimal measurement approaches for GD are currently unclear. This comprehensive systematic review aimed to identify and evaluate all available English-language GD tools and their corresponding evidence. A search of PsychINFO, PsychArticles, ScienceDirect, Scopus, Web of Science, and Google Scholar identified 32 tools employed in 320 studies (N = 462,249 participants). The evaluation framework examined tools in relation to: (1) conceptual and practical considerations; (2) alignment with DSM-5 and ICD-11 criteria; (3) type and quantity of studies and samples; and (4) psychometric properties. The evaluation showed that GD instrumentation has proliferated, with 2.5 tools, on average, published annually since 2013. Coverage of DSM-5 and ICD-11 criteria was inconsistent, especially for the criterion of continued use despite harm. Tools converge on the importance of screening for impaired control over gaming and functional impairment. Overall, no single tool was found to be clearly superior, but the AICA-Sgaming, GAS-7, IGDT-10, IGDS9-SF, and Lemmens IGD-9 scales had greater evidential support for their psychometric properties. The GD field would benefit from a standard international tool to identify gaming-related harms across the spectrum of maladaptive gaming behaviors.
Tumor microenvironment-activated self-recognizing nanodrug through directly tailored assembly of small-molecules for targeted synergistic chemotherapy
Authors: Yang Li, Jinyan Lin, Zhixiong Cai, Peiyuan Wang, Qiang Luo, Cuiping Yao, Yun Zhang, Zhenqing Hou, Jingfeng Liu, Xiaolong Liu
Journal: Journal of Controlled Release (2020)
Response to: ‘Effectiveness and safety of ruxolitinib for the treatment of refractory systemic idiopathic juvenile arthritis like associated with interstitial lung disease: case report’ by Bader-Meunier <i>et al</i>
Authors: Vivian E Saper, Guangbo Chen, Purvesh Khatri, Elizabeth D Mellins
Journal: Annals of the Rheumatic Diseases (2020)

MAS definitions were per Ravelli et al. 11 †Before lung disease: up to 6 months before diagnosis of lung disease, because true onset of lung disease is not known.‡At or during lung disease: from 6 months before diagnosis of lung disease and thereafter.§n=46 patients with sJIA, parenchymal lung disease and exposure to IL-1/IL-6 inhibition.IL, interleukin; MAS, macrophage activation syndrome; sJIA, systemic juvenile idiopathic arthritis.
Hepatitis D virus: is it all in the family?
Authors: Anders Boyd, Gilles Wandeler
Journal: Gut (2020)

Hepatitis delta virus (HDV) infection is the most severe form of chronic viral hepatitis: HDV-infected individuals are more likely to die from advanced liver disease compared with hepatitis B virus (HBV)-infected without HDV and their risk of developing hepatocellular carcinoma is up to nine times higher.1 HDV is a defective virus, using the HBV surface antigen to enter hepatocytes. Pegylated interferon-alfa is currently the only recommended therapy for HDV infection, although treatment success remains unacceptably low. The recent development of novel treatments, including the entry inhibitor bulevirtide, may improve treatment outcomes. Thus, understanding the epidemiology of HDV is crucial for planning and implementing efficient testing and management strategies.

According to a recent meta-analysis, HDV infection, as determined by the presence of anti-HDV antibodies, affects 7% of HBV-infected persons in sub-Saharan Africa (SSA), with a pooled prevalence reaching 26% of general hepatitis B surface antigen (HBsAg)-positive individuals in Central Africa.2 Therefore, in specific regions, chronic HDV infection may well be an important barrier to the WHO’s HBV elimination objectives, including the significant reduction of HBV-related mortality.3 However, our knowledge of the epidemiological determinants of HDV infection has remained insufficient, especially in high endemic regions of SSA. The study by Besombes et al 4 published in Gut is a welcome addition to the …
Nanobody-based CD38-specific heavy chain antibodies induce killing of multiple myeloma and other hematological malignancies
Authors: Levin Schriewer, Kerstin Schütze, Katharina Petry, Julia Hambach, William Fumey, Julia Koenigsdorf, Natalie Baum, Stephan Menzel, Björn Rissiek, Kristoffer Riecken, Boris Fehse, Jana Larissa Röckendorf, Joanna Schmid, Birte Albrecht, Hans Pinnschmidt, Francis Ayuk, Nicolaus Kröger, Mascha Binder, Gunter Schuch, Timon Hansen, Friedrich Haag, Gerhard Adam, Friedrich Koch-Nolte, Peter Bannas
Journal: Theranostics (2020)

Rationale: CD38 is a target for the therapy of multiple myeloma (MM) with monoclonal antibodies such as daratumumab and isatuximab.Since MM patients exhibit a high rate of relapse, the development of new biologics targeting alternative CD38 epitopes is desirable.The discovery of single-domain antibodies (nanobodies) has opened the way for a new generation of antitumor therapeutics.We report the generation of nanobody-based humanized IgG1 heavy chain antibodies (hcAbs) with a high specificity and affinity that recognize three different and non-overlapping epitopes of CD38 and compare their cytotoxicity against CD38-expressing hematological cancer cells in vitro, ex vivo and in vivo.Methods: We generated three humanized hcAbs (WF211-hcAb, MU1067-hcAb, JK36-hcAb) that recognize three different non-overlapping epitopes (E1, E2, E3) of CD38 by fusion of llama-derived nanobodies to the hinge-and Fc-domains of human IgG1.WF211-hcAb shares the binding epitope E1 with daratumumab.We compared the capacity of these CD38-specific hcAbs and daratumumab to induce CDC and ADCC in CD38-expressing tumor cell lines in vitro and in patient MM cells ex vivo as well as effects on xenograft tumor growth and survival in vivo.Results: CD38-specific heavy chain antibodies (WF211-hcAb, MU1067-hcAb, JK36-hcAb) potently induced antibody-dependent cellular cytotoxicity (ADCC) in CD38-expressing tumor cell lines and in primary patient MM cells, but only little if any complement-dependent cytotoxicity (CDC).In vivo, CD38-specific heavy chain antibodies significantly reduced the growth of systemic lymphomas and prolonged survival of tumor bearing SCID mice.Conclusions: CD38-specific nanobody-based humanized IgG1 heavy chain antibodies mediate cytotoxicity against CD38-expressing hematological cancer cells in vitro, ex vivo and in vivo.These promising results of our study indicate that CD38-specific hcAbs warrant further clinical development as therapeutics for multiple myeloma and other hematological malignancies.
Psychological features and somatosensory characteristics of patellofemoral pain (PhD Academy Award)
Authors: Liam Maclachlan
Journal: British Journal of Sports Medicine (2020)

I investigated the psychological factors and somatosensory characteristics in persons who had patellofemoral pain (PFP). I did this by studying how psychological factors and pain profiles: (1) presented in PFP, (2) differed between those with and without the condition, (3) related to pain and disability, (4) differed between subgroups of different PFP severities and (5) changed over time.

Pain is the poorly understood primary symptom of PFP that may have a range of underpinning mechanisms. The presence of patellofemoral joint dysfunction may result in nociception. When prolonged, nociception may catalyse altered inhibitory and sensitising processes1 that create a combined nociceptive/nociplastic profile. In lieu of tissue pathology, PFP may be purely nociplastic and driven by factors beyond the site of pain.2

Psychological factors are known to influence the experience of pain.3 In chronic musculoskeletal pain conditions, psychological factors such as anxiety, …
Biomarkers for Hepatobiliary Cancers
Authors: Jean‐Charles Nault, Augusto Villanueva
Journal: Hepatology (2020)

The clinical management of primary liver cancers such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) has significantly changed in the last 3 years. The introduction of systemic therapies, including immune‐based therapies and biomarker‐driven therapies, has significantly improved survival, particularly in patients at advanced stages of disease. Survival is still poor, and projections from the World Health Organization underscore the need to improve outcomes in these patients. Biomarkers have emerged as powerful tools for the diagnosis, prognosis, and prediction of treatment responses to improve patient stratification and maximize clinical benefits. Recent advances in understanding the molecular alterations of HCC have not yet translated into biomarkers. Some reasons for the lack of progress are the absence of druggable mutations in the majority of liver cancers and the significant heterogeneity of the disease. In contrast, several therapeutic targets have been identified in CCA, and biomarker‐driven therapies are currently under evaluation in phase 2/3 clinical trials. Here, we summarize the status on biomarker development for HCC and CCA.
Resource Utilization for Patients With Distal Radius Fractures in a Pediatric Emergency Department
Authors: Keith J. Orland, Adam Boissonneault, Andrew M. Schwartz, Rahul Goel, Robert W. Bruce, Nicholas D. Fletcher
Journal: JAMA Network Open (2020)

Improvement of clinician understanding of acceptable deformity in pediatric distal radius fractures is needed.To assess how often children younger than 10 years undergo a potentially unnecessary closed reduction using procedural sedation in the emergency department for distal radial metaphyseal fracture and the associated cost implications for these reduction procedures.This retrospective cross-sectional study included 258 consecutive children younger than 10 years who presented to a single, level I, pediatric emergency department and who had a distal radius fracture with or without ulna involvement between January 1, 2016, and December 31, 2017. Reductions were deemed to be potentially unnecessary if the coronal and sagittal plane angulation of the radius bone measured less than 20° and shortening measured less than 1 cm on initial injury radiographs. Use of procedural sedation or transfer status to another facility was noted if present. Statistical analysis was performed from April 2019 to June 2019.Potentially unnecessary reduction was the primary outcome. Radiographic findings were measured to determine reduction necessity. Additional variables measured were age, sex, time in the emergency department, transfer status, required reduction procedure, use of sedation, and cost associated with care.Of the 258 participants studied, 156 (60%) were male, with a mean (SD) age of 6.7 (2.3) years. Among 142 patients (55%) who underwent closed reduction with procedural sedation in the emergency department, 38 (27%) procedures were determined to be potentially unnecessary. Review of Common Procedural Terminology charges revealed an approximately $7000 difference between the stated cost of a reduction procedure in the emergency department vs a cast application in an outpatient orthopedic clinic for distal radial metaphyseal fractures. The mean (SD) maximal angulation in either plane for fractures that underwent appropriate reduction was 30.6° (10.3°) compared with 13.9° (4.5°) for those unnecessarily reduced (P < .001). Patients who were transfers from other facilities were more than twice as likely to undergo a potentially unnecessary reduction (odds ratio, 2.3; 95% CI, 1.1-5.0; P = .03).The findings suggest that improved awareness of these acceptable deformities in young children may be associated with limiting the number of children requiring reduction with sedation, improving emergency department efficiency, and substantially reducing health care costs.
Epigallocatechin-3-gallate inhibits the PDGF-induced VEGF expression in human vascular smooth muscle cells at multiple signaling levels
Authors: Jung S. Park, Boo A. Shin, Ik J. Chung, Kyung K. Kim, Bong W. Ahn, Young Do Jung
Journal: Cancer Research (2006)

1928  Platelet-derived growth factor (PDGF) has been known to induce vascular endothelial growth factor (VEGF) expression in human vascular smooth muscle cells (hVSMCs). Previously, we reported that Erk-1/2 and AP-1 pathways are crucial in the PDGF-induced VEGF expression in hVSMCs (Int. J. Onc. 2005). In this study, we investigated the effect of epigallocatechin-3-gallate (EGCG) on the PDGF-induced VEGF expression in hVSMCs and the underlying molecular mechanisms. EGCG were found to inhibit dose-dependently the VEGF expression and activation of PDGF receptor, Erk-1/2 and AP-1 induced by PDGF. Moreover, cell free studies demonstrated that EGCG could directly inhibit the Erk-1/2 activities and AP-1-DNA binding. Conditioned media from the hVSMCs treated with PDGF could remarkably stimulate the in vitro growth of human umbilical vein endothelial cells (HUVEC) but the media from the EGCG-pretreated hVSMCs lost the stimulatory activity for HUVEC proliferation. These results suggest that EGCG may exert the anti-angiogenic effect by inhibiting the PDGF-induced VEGF expression at multiple signaling levels.
Abstract P3-10-17: CREBBP alterations lead to CDK4/6 inhibitor sensitivity in triple negative breast cancer
Authors: Rachael Natrajan
Journal: Cancer Research (2020)

Abstract Fundamental to the effective clinical use of new therapeutic agents for cancer is the identification of genetic biomarkers of sensitivity as well as the identification of additional patient populations who would benefit from treatment. Here, through an unbiased functional genomics approach in a model of aggressive disease using cancer cell line spheroid cultures, we have uncovered a role for the histone acetyltransferase CREBBP as a tumour suppressor in aggressive hard to treat triple-negative breast cancers (TNBCs). We find that CREBBP protein expression is altered in a substantial proportion of TNBCs, as well as other solid tumours, including lung and lymphoma where CREBBP inactivating mutations are common. We found CREBBP alterations are associated with higher genomic heterogeneity and poorer patient survival in TNBCs and resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with clinical CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in spheroids, cell line xenografts and patient derived models from multiple tumour types with CREBBP alterations. Here we provide the pre-clinical and mechanistic rationale for assessing CREBBP alterations as a biomarker of single-agent CDK4/6 inhibitor response in a new patient population. This represents a novel synthetic lethal approach to targeting triple negative breast cancers with limited therapeutic options. Citation Format: Rachael Natrajan. CREBBP alterations lead to CDK4/6 inhibitor sensitivity in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-17.
Infections as a Risk Factor for and Prognostic Factor After Substance-Induced Psychoses
Authors: Carsten Hjorthøj, Marie Stefanie Kejser Starzer, Michael Eriksen Benros, Merete Nordentoft
Journal: American Journal of Psychiatry (2020)

Objective: Previous studies have suggested that infections increase the risk of schizophrenia. In this study, the authors aimed to investigate 1) whether infections increase the risk of substance-induced psychosis, and 2) whether infections increase the risk of converting from substance-induced psychosis to schizophrenia. Methods: The study data were drawn from the combined nationwide Danish registers and included all people born in Denmark since 1981. The authors used Cox proportional hazards regression with infections as time-varying covariates, estimating hazard ratios and 95% confidence intervals. Infections were operationalized both as any infection and by the site of infection. Results: The study included 2,256,779 individuals, for whom 3,618 cases of incident substance-induced psychosis were recorded. Any infection increased the risk of substance-induced psychosis (hazard ratio=1.30, 95% CI=1.22–1.39). For the first 2 years, the risk was doubled. Hepatitis was the infection most strongly associated with substance-induced psychosis (hazard ratio=3.42, 95% CI=2.47–4.74). Different types of infections were linked with different types of substance-induced psychosis. Most associations remained significant after controlling for potential confounders, such as substance use disorders. Only hepatitis predicted conversion to schizophrenia after substance-induced psychosis (hazard ratio=1.87, 95% CI=1.07– 3.26). Conclusions: The study results support the hypothesis of an immunological component to psychosis.
A T-cell–redirecting bispecific G-protein–coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma
Authors: Kodandaram Pillarisetti, Suzanne Edavettal, Mark Mendonça, Yingzhe Li, Mark Tornetta, Alexander Babich, Nate Majewski, Matt Husovsky, Dara Reeves, Eileen Walsh, Diana Chin, Leopoldo Luistro, Jocelin Joseph, Gerald Chu, Kathryn Packman, Shoba Shetty, Yusri Elsayed, Ricardo Attar, François Gaudet
Journal: Blood (2020)
Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study
Authors: Stijn E Verleden, Naoya Tanabe, John E McDonough, Dragoş M Vasilescu, Feng Xu, Wim A Wuyts, Davide Piloni, Laurens De Sadeleer, Stijn Willems, Cindy Mai, Jeroen Hostens, Joel D Cooper, Erik K Verbeken, Johny Verschakelen, Craig J Galban, Dirk E Van Raemdonck, Thomas V Colby, Marc Decramer, Geert M Verleden, Naftali Kaminski, Tillie-Louise Hackett, Bart M Vanaudenaerde, James C Hogg
Journal: The Lancet Respiratory Medicine (2020)
Antitubercular nanocarrier monotherapy: Study of In Vivo efficacy and pharmacokinetics for rifampicin
Authors: Jiří Trousil, Oto Pavliš, Pavla Kubíčková, Miša Škorič, Věra Marešová, Ewa Pavlova, Kenneth D. Knudsen, You-Shan Dai, Matthew Zimmerman, Véronique Dartois, Jia-You Fang, Martin Hrubý
Journal: Journal of Controlled Release (2020)
No Association Between Vitamin D Supplementation and Risk of Colorectal Adenomas or Serrated Polyps in a Randomized Trial
Authors: Mingyang Song, I-Min Lee, JoAnn E. Manson, Julie E. Buring, Rimma Dushkes, David Gordon, Joseph Walter, Kana Wu, Andrew T. Chan, Shuji Ogino, Charles S. Fuchs, Jeffrey A. Meyerhardt, Edward L. Giovannucci
Journal: Clinical Gastroenterology and Hepatology (2020)
Using dual checkpoint blockade to treat fibrolamellar hepatocellular carcinoma
Authors: Enrico N De Toni, Daniel Roessler
Journal: Gut (2020)

We have read with interest the paper by Gerbes et al ,1 which highlights the current developments in the treatment of hepatocellular carcinoma (HCC). Fibrolamellar HCC (FL-HCC) is, in contrast to HCC,2 an infrequent tumour, most often occurring in adolescents or young adults without underlying liver disease.3 Chemotherapy-based regimens are typically used to treat FL-HCC based on studies in small patients’ cohorts and case series.3 Despite anecdotal reports of response to systemic treatment, the prognosis of advanced FL-HCC is poor.4 

The development of immune checkpoint inhibitors (ICP) is drastically changing the approach to the treatment of HCC. In particular, recent trials showed that immunoncological treatment can be potentiated if ICP are used in combination.5 6 This is exemplified by the use of nivolumab/ipilimumab,7 and by the results of the phase III IMBRAVE 150 trial, which recently marked …