tbuckley/cabot-search huggingface dataset:
Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus <i>via</i> interferon-λ <i>in vitro</i> and in mice
Authors: Lucie Sauerhering, Alexandra Kupke, Lars Meier, Erik Dietzel, Judith Hoppe, Achim D. Gruber, Stefan Gattenloehner, Biruta Witte, Ludger Fink, Nina Hofmann, Tobias Zimmermann, Alexander Goesmann, Andrea Nist, Thorsten Stiewe, Stephan Becker, Susanne Herold, Christin Peteranderl
Journal: European Respiratory Journal (2020)

While severe coronavirus infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use. We elucidated the molecular mechanisms by which the cyclophilin inhibitors cyclosporin A (CsA) and alisporivir (ALV) restrict MERS-CoV to validate their suitability as readily available therapy in MERS-CoV infection. Calu-3 cells and primary human alveolar epithelial cells (hAECs) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including calcineurin, nuclear factor of activated T-cells (NFATs) or mitogen-activated protein kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by quantitative real-time PCR and 50% tissue culture infective dose. Data were validated in a murine MERS-CoV infection model. Both CsA and ALV reduced MERS-CoV titres and viral RNA replication in Calu-3 cells and hAECs, improving epithelial integrity. While neither calcineurin nor NFAT inhibition reduced MERS-CoV propagation, blockade of c-Jun N-terminal kinase diminished infectious viral particle release but not RNA accumulation. Importantly, CsA induced interferon regulatory factor 1 (IRF1), a pronounced type III interferon (IFNλ) response and expression of antiviral genes. Downregulation of IRF1 or IFNλ increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo , correlating with elevated lung IFNλ levels and improved outcome. We provide evidence that cyclophilin inhibitors efficiently decrease MERS-CoV replication in vitro and in vivo via upregulation of inflammatory antiviral cell responses, in particular IFNλ. CsA might therefore represent a promising candidate for treating MERS-CoV infection.
Health Care Utilization of Homeless Minors With Diabetes in New York State From 2009 to 2014
Authors: Rie Sakai-Bizmark, Laurie A. Mena, Dennys Estevez, Eliza J. Webber, Emily H. Marr, Lauren E.M. Bedel, Jennifer K. Yee
Journal: Diabetes Care (2020)

OBJECTIVE This study aims to describe differences in health care utilization between homeless and nonhomeless minors with diabetes. RESEARCH DESIGN AND METHODS Data from the Healthcare Cost and Utilization Project’s Statewide Inpatient Database from New York for years 2009–2014 were examined to identify pediatric patients &amp;lt;18 years old with diabetes. Outcomes of interest included hospitalization rate, in-hospital mortality, admission through the emergency department (ED), diabetic ketoacidosis (DKA), hospitalization cost, and length of stay (LOS). Other variables of interest included age-group, race/ethnicity, insurance type, and year. Multivariate logistic regression models were used for in-hospital mortality, admission through ED, and DKA. Log-transformed linear regression models were used for hospitalization cost, and negative binomial regression models were used for LOS. RESULTS A total of 643 homeless and 10,559 nonhomeless patients were identified. The hospitalization rate was higher among homeless minors, with 3.64 per 1,000 homeless population compared with 0.38 per 1,000 in the nonhomeless population. A statistically significant higher readmission rate was detected among homeless minors (20.4% among homeless and 14.1% among nonhomeless, P &amp;lt; 0.01). Lower rates of DKA (odds ratio 0.75, P = 0.02), lower hospitalization costs (means ratio 0.88, P &amp;lt; 0.01), and longer LOS (incidence rate ratio 1.20, P &amp;lt; 0.01) were detected among homeless minors compared with nonhomeless minors. CONCLUSIONS This study found that among minors with diabetes, those who are homeless experience a higher hospitalization rate than the nonhomeless. Housing instability, among other environmental factors, may be targeted for intervention to improve health outcomes.
Urine biopsy technologies: Cancer and beyond
Authors: Chun Kwan Chen, Junchen Liao, Man Sze Li, Bee Luan Khoo
Journal: Theranostics (2020)

Since the discovery of circulating tumor cells in 1869, technological advances in the study of biomarkers from liquid biopsy have made it possible to diagnose disease in a less invasive way.Although blood-based liquid biopsy has been used extensively for the detection of solid tumors and immune diseases, the potential of urine-based liquid biopsy has not been fully explored.Advancements in technologies for the harvesting and analysis of biomarkers are providing new opportunities for the characterization of other disease types.Liquid biopsy markers such as exfoliated bladder cancer cells, cell-free DNA (cfDNA), and exosomes have the potential to change the nature of disease management and care, as they allow a cost-effective and convenient mode of patient monitoring throughout treatment.In this review, we addressed the advancement of research in the field of disease detection for the key liquid biopsy markers such as cancer cells, cfDNA, and exosomes, with an emphasis on urine-based liquid biopsy.First, we highlighted key technologies that were widely available and used extensively for clinical urine sample analysis.Next, we presented recent technological developments in cell and genetic research, with implications for the detection of other types of diseases, besides cancer.We then concluded with some discussions on these areas, emphasizing the role of microfluidics and artificial intelligence in advancing point-of-care applications.We believe that the benefits of urine biopsy provide diagnostic development potential, which will pave opportunities for new ways to guide treatment selections and facilitate precision disease therapies.
Neural activities classification of left and right finger gestures during motor execution and motor imagery
Authors: Chao Chen, Peiji Chen, Abdelkader Nasreddine Belkacem, Lin Lu, Rui Xu, Wenjun Tan, Penghai Li, Qiang Gao, Duk Shin, Changming Wang, Dong Ming
Journal: Brain-Computer Interfaces (2020)

In this study, a new paradigm containing motor observation, motor execution, and motor imagery was designed to investigate whether motor imagery (MI) and motor execution (ME) of finger gestures can be used to extend commands of practical mBCIs. The subjects were instructed to perform or imagine 30 left and right finger gestures. Hierarchical support vector machine (hSVM) method was applied to classify four tasks (i.e., ME and MI tasks between left and right gestures). The average classification accuracies of motor imagery and execution tasks using fivefold cross-validation were 90.89 ± 9.87% and 74.08 ± 13.42% in first layer and second layer, respectively. The average accuracy of classification of four classes is 83.06 ± 7.29% overall. These results show that performing or imaging finger movements have the potential to extend the commands of the existing BCI, especially for healthy elderly living.
LncRNA CSMD1-1 promotes the progression of Hepatocellular Carcinoma by activating MYC signaling
Authors: Ji Liu, Rui Xu, Shi-Juan Mai, Yu-Shui Ma, Mei-Yin Zhang, Ping-Sheng Cao, Nuo-Qing Weng, Rui-Qi Wang, Di Cao, Wei Wei, Rong-Ping Guo, Yao-Jun Zhang, Li Xu, Min-Shan Chen, Hui-Zhong Zhang, Long Huang, Da Fu, Hui-Yun Wang
Journal: Theranostics (2020)

Emerging evidence suggests that long non-coding RNAs (lncRNA) play critical roles in the development and progression of diverse cancers including hepatocellular carcinoma (HCC), but the underlying molecular mechanisms of lncRNAs that are involved in hepatocarcinogenesis have not been fully explored. Methods: In this study, we profiled lncRNA expression in 127 pairs of HCC and nontumor liver tissues (a Discovery Cohort) using a custom microarray. The expression and clinical significance of lncCSMD1-1 were then validated with qRT-PCR and COX regression analysis in a Validation Cohort (n=260) and two External Validation Cohorts (n=92 and n=124, respectively). In vitro and in vivo assays were performed to explore the biological effects of lncCSMD1-1 on HCC cells. The interaction of lncCSMD1-1 with MYC was identified by RNA pull-down and RNA immunoprecipitation. The role of LncCSMD1-1 in the degradation of MYC protein was also investigated. Results: With microarray, we identified a highly upregulated lncRNA, lncCSMD1-1, which was associated with tumor progression and poor prognosis in the Discovery Cohort, and validated in another 3 HCC cohorts. Consistently, ectopic expression of lncCSMD1-1 notably promotes cell proliferation, migration, invasion, tumor growth and metastasis of HCC cells in in vitro and in vivo experiments. Gene expression profiling on HCC cells and gene sets enrichment analysis indicated that the MYC target gene set was significantly enriched in HCC cells overexpressing lncCSMD1-1, and lncCSMD1-1 was found to directly bind to MYC protein in the nucleus of HCC cells, which resulted in the elevation of MYC protein. Mechanistically, lncCSMD1-1 interacted with MYC protein to block its ubiquitin-proteasome degradation pathway, leading to activation of its downstream target genes. Conclusion: lncCSMD1-1 is upregulated in HCC and promotes progression of HCC by activating the MYC signaling pathway. These results provide the evidence that lncCSMD1-1 may serve as a novel prognostic marker and potential therapeutic target for HCC.
Localized immunoglobulin light chain amyloidosis: Novel insights including prognostic factors for local progression
Authors: Marco Basset, Kamal Hummedah, Christoph Kimmich, Kaya Veelken, Tobias Dittrich, Simone Brandelik, Michael Kreuter, Jessica Hassel, Nikolaus Bosch, Christiane Stuhlmann‐Laeisz, Norbert Blank, Carsten Müller‐Tidow, Christoph Röcken, Ute Hegenbart, Stefan Schönland
Journal: American Journal of Hematology (2020)

In localized light chain amyloidosis (locAL), amyloidogenic light chains (aLC) are produced and deposited locally by a B-cell clone. We present 293 patients with immunohistochemically confirmed locAL. Lung (nodular pulmonary) with 63 patients was the most involved organ. The aLC was λ in 217 cases (κ:λ ratio 1:3). A local B-cell clone was identified in 30% of cases. Sixty-one (21%) had a concomitant autoimmune disorder (cAD). A monoclonal component (MC) were present in 101 (34%) patients and were more frequent in subjects with cAD (51% vs 34%; P = .03). Cigarette smoking was more prevalent in lung locAL (54% vs 37%; P = .018). After a median follow-up of 44 months, 16 patients died and 5- and 10-years locAL progression-free survival (PFS) were 62% and 44%. Interestingly, locAL-PFS was shorter among patients with an identified clonal infiltrate at amyloid deposition site (40 vs 109 months; P = .02) and multinuclear giant cells and/or an inflammatory infiltrate resulted in longer locAL-PFS in lung involvement (65 vs 42 months; P = .01). However, no differences in locAL PFS were observed in patients with cAD, a MC and involved organ site. Treatment was administered in 163 (54%) patients and was surgical in 135 (46%). Median locAL-PFS after first treatment was 56 months. Responders had longer locAL-PFS (78 vs 17 months; P < .001). Three patients with lung locAL and a MC were diagnosed as systemic AL amyloidosis at follow-up. In summary, locAL pathogenesis seems to be heterogeneous and the clonal infiltrate leads local progression.
Population characteristics as important contextual factors in rheumatological trials: an exploratory meta-epidemiological study from an OMERACT Working Group
Authors: Sabrina Mai Nielsen, Helene Storgaard, Torkell Ellingsen, Beverley J Shea, George A Wells, Vivian Andrea Welch, Daniel E Furst, Maarten de Wit, Marieke Voshaar, Carsten Bogh Juhl, Maarten Boers, Reuben Escorpizo, Thasia G Woodworth, Annelies Boonen, Henning Bliddal, Lyn M March, Peter Tugwell, Robin Christensen
Journal: Annals of the Rheumatic Diseases (2020)

To explore whether trial population characteristics modify treatment responses across various interventions, comparators and rheumatic conditions.In this meta-epidemiological study, we included trials from systematic reviews available from the Cochrane Musculoskeletal Group published up to 23 April 2019 in Cochrane Library with meta-analyses of five or more randomised controlled trials (RCTs) published from year 2000. From trial reports, we extracted data on 20 population characteristics. For characteristics with sufficient data (ie, available for ≥2/3 of the trials), we performed multilevel meta-epidemiological analyses.We identified 19 eligible systematic reviews contributing 187 RCTs (212 comparisons). Only age and sex were explicitly reported in ≥2/3 of the trials. Using information about the country of the trials led to sufficient data for five further characteristics, that is, 7 out of 20 (35%) protocolised characteristics were analysed. The meta-regressions showed effect modification by economic status, place of residence, and, nearly, from healthcare system (explaining 4.8%, 0.9% and 1.5% of the between-trial variation, respectively). No effect modification was demonstrated from age, sex, patient education/health literacy or predominant religion.This study demonstrates the scarce reporting of most population characteristics, hampering investigation of their impact with meta-research. Our sparse results suggest that place of residence (ie, continent of the trial), economic status (based on World Bank classifications) and healthcare system (based on WHO index for health system performance) may be important in explaining the variation in treatment response across trials. There is an urgent need for consistent reporting of important population characteristics in trials.CRD42019127642.
Early Indolent Course of Crohn’s Disease in Newly Diagnosed Patients Is Not Rare and Possibly Predictable
Authors: Henit Yanai, Idan Goren, Lihi Godny, Nitsan Maharshak, Yulia Ron, Irit Avni Biron, Haim Leibovitzh, Hagar Banai Eran, Maya Aharoni Golan, Keren Rabinowitz, Tomer Ziv Baran, Inbar Lavie, Karin Yadgar, Keren Zonensain, Uri Kopylov, Shomron Ben Horin, Rami Eliakim, Matti Waterman, Yehuda Chowers, Shay Ben-Shachar, Iris Dotan
Journal: Clinical Gastroenterology and Hepatology (2020)
A decade of next‐generation sequencing in genodermatoses: the impact on gene discovery and clinical diagnostics*
Authors: F.P.‐C. Chiu, B.J. Doolan, J.A. McGrath, A. Onoufriadis
Journal: British Journal of Dermatology (2020)

Discovering the genetic basis of inherited skin diseases is fundamental to improving diagnostic accuracy and genetic counselling. In the 1990s and 2000s, genetic linkage and candidate gene approaches led to the molecular characterization of several dozen genodermatoses, but over the past decade the advent of next-generation sequencing (NGS) technologies has accelerated diagnostic discovery and precision.This review examines the application of NGS technologies from 2009 to 2019 that have (i) led to the initial discovery of gene mutations in known or new genodermatoses and (ii) identified involvement of more than one contributing pathogenic gene in individuals with complex Mendelian skin disorder phenotypes.A comprehensive review of the PubMed database and dermatology conference abstracts was undertaken between January 2009 and December 2019. The results were collated and cross-referenced with OMIM.We identified 166 new disease-gene associations in inherited skin diseases discovered by NGS. Of these, 131 were previously recognized, while 35 were brand new disorders. Eighty-five were autosomal dominant (with 43 of 85 mutations occurring de novo), 78 were autosomal recessive and three were X-linked. We also identified 63 cases harbouring multiple pathogenic mutations, either involving two coexisting genodermatoses (n = 13) or an inherited skin disorder in conjunction with other organ system phenotypes (n = 50).NGS technologies have accelerated disease-gene discoveries in dermatology over the last decade. Moreover, the era of NGS has enabled clinicians to split complex Mendelian phenotypes into separate diseases. These genetic data improve diagnostic precision and make feasible accurate prenatal testing and better-targeted translational research.
Studies of nanoparticle delivery with in vitro bio-engineered microtissues
Authors: Mingze Sun, Jinhyung Lee, Yupeng Chen, Kazunori Hoshino
Journal: Bioactive Materials (2020)

A variety of engineered nanoparticles, including lipid nanoparticles, polymer nanoparticles, gold nanoparticles, and biomimetic nanoparticles, have been studied as delivery vehicles for biomedical applications. When assessing the efficacy of a nanoparticle-based delivery system, in vitro testing with a model delivery system is crucial because it allows for real-time, in situ quantitative transport analysis, which is often difficult with in vivo animal models. The advent of tissue engineering has offered methods to create experimental models that can closely mimic the 3D microenvironment in the human body. This review paper overviews the types of nanoparticle vehicles, their application areas, and the design strategies to improve delivery efficiency, followed by the uses of engineered microtissues and methods of analysis. In particular, this review highlights studies on multicellular spheroids and other 3D tissue engineering approaches for cancer drug development. The use of bio-engineered tissues can potentially provide low-cost, high-throughput, and quantitative experimental platforms for the development of nanoparticle-based delivery systems.
Emerging immunotherapies for malignant glioma: from immunogenomics to cell therapy
Authors: Gavin P Dunn, Timothy F Cloughesy, Marcela V Maus, Robert M Prins, David A Reardon, Adam M Sonabend
Journal: Neuro-Oncology (2020)

Abstract As immunotherapy assumes a central role in the management of many cancers, ongoing work is directed at understanding whether immune-based treatments will be successful in patients with glioblastoma (GBM). Despite several large studies conducted in the last several years, there remain no FDA-approved immunotherapies in this patient population. Nevertheless, there are a range of exciting new approaches being applied to GBM, all of which may not only allow us to develop new treatments but also help us understand fundamental features of the immune response in the central nervous system. In this review, we summarize new developments in the application of immune checkpoint blockade, from biomarker-driven patient selection to the timing of treatment. Moreover, we summarize novel work in personalized immune-oncology by reviewing work in cancer immunogenomics–driven neoantigen vaccine studies. Finally, we discuss cell therapy efforts by reviewing the current state of chimeric antigen receptor T-cell therapy.
Cholangiocarcinoma 2020: the next horizon in mechanisms and management
Authors: Jesus M. Banales, Jose J. G. Marin, Angela Lamarca, Pedro M. Rodrigues, Shahid A. Khan, Lewis R. Roberts, Vincenzo Cardinale, Guido Carpino, Jesper B. Andersen, Chiara Braconi, Diego F. Calvisi, Maria J. Perugorria, Luca Fabris, Luke Boulter, Rocio I. R. Macias, Eugenio Gaudio, Domenico Alvaro, Sergio A. Gradilone, Mario Strazzabosco, Marco Marzioni, Cédric Coulouarn, Laura Fouassier, Chiara Raggi, Pietro Invernizzi, Joachim C. Mertens, Anja Moncsek, Sumera I. Ilyas, Julie Heimbach, Bas Groot Koerkamp, Jordi Bruix, Alejandro Forner, John Bridgewater, Juan W. Valle, Gregory J. Gores
Journal: Nature Reviews Gastroenterology & Hepatology (2020)

Abstract Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome–Associated Cardiomyopathy
Authors: Ulrich Hanses, Mandy Kleinsorge, Lennart Roos, Gökhan Yigit, Yun Li, Boris Barbarics, Ibrahim El-Battrawy, Huan Lan, Malte Tiburcy, Robin Hindmarsh, Christof Lenz, Gabriela Salinas, Sebastian Diecke, Christian Müller, Ibrahim Adham, Janine Altmüller, Peter Nürnberg, Thomas Paul, Wolfram-Hubertus Zimmermann, Gerd Hasenfuss, Bernd Wollnik, Lukas Cyganek
Journal: Circulation (2020)

Background: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS–mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. Methods: Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 ( LZTR1 ). We generated induced pluripotent stem cell–derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level. Results: Patients’ induced pluripotent stem cell–derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS–mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype. Conclusions: Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell–derived cardiomyocytes from NS patients carrying biallelic variants in LZTR1 and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.