tbuckley/cabot-search huggingface dataset:
Fatty acids and evolving roles of their proteins in neurological, cardiovascular disorders and cancers
Authors: Rahul Mallick, Sanjay Basak, Asim K. Duttaroy
Journal: Progress in Lipid Research (2021)

The dysregulation of fat metabolism is involved in various disorders, including neurodegenerative, cardiovascular, and cancers. The uptake of long-chain fatty acids (LCFAs) with 14 or more carbons plays a pivotal role in cellular metabolic homeostasis. Therefore, the uptake and metabolism of LCFAs must constantly be in tune with the cellular, metabolic, and structural requirements of cells. Many metabolic diseases are thought to be driven by the abnormal flow of fatty acids either from the dietary origin and/or released from adipose stores. Cellular uptake and intracellular trafficking of fatty acids are facilitated ubiquitously with unique combinations of fatty acid transport proteins and cytoplasmic fatty acid-binding proteins in every tissue. Extensive data are emerging on the defective transporters and metabolism of LCFAs and their clinical implications. Uptake and metabolism of LCFAs are crucial for the brain's functional development and cardiovascular health and maintenance. In addition, data suggest fatty acid metabolic transporter can normalize activated inflammatory response by reprogramming lipid metabolism in cancers. Here we review the current understanding of how LCFAs and their proteins contribute to the pathophysiology of three crucial diseases and the mechanisms involved in the processes.
Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort
Authors: Matteo Bianchi, Sergey V. Kozyrev, Antonella Notarnicola, Lina Hultin Rosenberg, Åsa Karlsson, Pascal Pucholt, Simon Rothwell, Andrei Alexsson, Johanna K. Sandling, Helena Andersson, Robert G. Cooper, Leonid Padyukov, Anna Tjärnlund, Maryam Dastmalchi, Jennifer R. S. Meadows, Louise Pyndt Diederichsen, Øyvind Molberg, Hector Chinoy, Janine A. Lamb, Lars Rönnblom, Kerstin Lindblad‐Toh, Ingrid E. Lundberg
Journal: Arthritis & Rheumatology (2021)

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case-control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant- and gene-level enrichment analyses, was implemented to explore genotype-phenotype relations.Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle-specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
Platelet Phagocytosis via P‐selectin Glycoprotein Ligand 1 and Accumulation of Microparticles in Systemic Sclerosis
Authors: Angelo A. Manfredi, Giuseppe A. Ramirez, Cosmo Godino, Annalisa Capobianco, Antonella Monno, Stefano Franchini, Enrico Tombetti, Sara Corradetti, Jörg H. W. Distler, Marco E. Bianchi, Patrizia Rovere‐Querini, Norma Maugeri
Journal: Arthritis & Rheumatology (2021)

It is unclear why activated platelets and platelet-derived microparticles (MPs) accumulate in the blood of patients with systemic sclerosis (SSc). This study was undertaken to investigate whether defective phagocytosis might contribute to MP accumulation in the blood of patients with SSc.Blood samples were obtained from a total of 81 subjects, including 25 patients with SSc and 26 patients with stable coronary artery disease (CAD). Thirty sex- and age-matched healthy volunteers served as controls. Studies were also conducted in NSG mice, in which the tail vein of the mice was injected with MPs, and samples of the lung parenchyma were obtained for analysis of the pulmonary microvasculature. Tissue samples from human subjects and from mice were assessed by flow cytometry and immunochemical analyses for determination of platelet-neutrophil interactions, phagocytosis, levels and distribution of P-selectin, P-selectin glycoprotein ligand 1 (PSGL-1), and HMGB1 on platelets and MPs, and concentration of byproducts of neutrophil extracellular trap (NET) generation/catabolism.Activated P-selectin+ platelets and platelet-derived HMGB1+ MPs accumulated in the blood of SSc patients but not in the blood of healthy controls. Patients with CAD, a vasculopathy independent of systemic inflammation, had fewer P-selectin+ platelets and a negligible number of MPs. The expression of the receptor for P-selectin, PSGL-1, in neutrophils from SSc patients was significantly decreased, raising the possibility that phagocytes in SSc do not recognize activated platelets, leading to a failure of phagocytosis and continued neutrophil release of MPs. As evidence of this process, activated platelets were not detected in the neutrophils from SSc patients, whereas they were consistently present in the neutrophils from patients with CAD. HMGB1+ MPs elicited generation of NETs, which were only detected in the plasma of SSc patients. In mice, P-selectin-PSGL-1 interaction resulted in platelet phagocytosis in vitro and influenced the ability of MPs to elicit NETs, endothelial activation, and migration of leukocytes through the pulmonary microvasculature.The clearance of activated platelets via PSGL-1 limits the undesirable effects of MP-elicited neutrophil activation. This balance is disrupted in patients with SSc. Its reconstitution might curb vascular inflammation and prevent fibrosis.
P-45 An open-label, phase 2 study of patritumab deruxtecan in patients with previously treated advanced/metastatic colorectal cancer
Authors: K. Raghav, T. Yoshino, H. Taniguchi, S. Tejpar, A. Vogel, Z. Wainberg, K. Yamaguchi, M. Fakih, K. Pedersen, K. Bando, H. Kawakami, J. Beck, M. Kanai, Y. Liu, S. Mekan, G. Pudussery, Y. Qiu, S. Kopetz
Journal: Annals of Oncology (2021)
Global genome analysis reveals a vast and dynamic anellovirus landscape within the human virome
Authors: Cesar A. Arze, Simeon Springer, Gytis Dudas, Sneha Patel, Agamoni Bhattacharyya, Harish Swaminathan, Carlo Brugnara, Simon Delagrave, Tuyen Ong, Avak Kahvejian, Yann Echelard, Erica G. Weinstein, Roger J. Hajjar, Kristian G. Andersen, Nathan L. Yozwiak
Journal: Cell Host & Microbe (2021)

Anelloviruses are a ubiquitous component of healthy human viromes and remain highly prevalent after being acquired early in life. The full extent of "anellome" diversity and its evolutionary dynamics remain unexplored. We employed in-depth sequencing of blood-transfusion donor(s)-recipient pairs coupled with public genomic resources for a large-scale assembly of anellovirus genomes and used the data to characterize global and personal anellovirus diversity through time. The breadth of the anellome is much greater than previously appreciated, and individuals harbor unique anellomes and transmit lineages that can persist for several months within a diverse milieu of endemic host lineages. Anellovirus sequence diversity is shaped by extensive recombination at all levels of divergence, hindering traditional phylogenetic analyses. Our findings illuminate the transmission dynamics and vast diversity of anelloviruses and set the foundation for future studies to characterize their biology.
The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity
Authors: Yisheng He, Jiang Ma, Xiaoyu Fan, Liang Ding, Xinxin Ding, Qing-Yu Zhang, Ge Lin
Journal: Acta Pharmaceutica Sinica B (2021)

Pyrrolizidine alkaloids (PAs) are the most common phytotoxins with documented human hepatotoxicity. PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts, thereby causing cytotoxicity. This study investigated the role of the gut-liver axis in PA intoxication and the underlying mechanisms. We exposed mice to retrorsine (RTS), a representative PA, and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier function. Using mice with tissue-selective ablation of P450 activity, we found that hepatic P450s, but not intestinal P450s, were essential for PA bioactivation. Besides, in RTS-exposed, bile duct-cannulated rats, we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert enterotoxicity. The impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium (DSS)-induced chronic colitis. DSS treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione, thereby suppressing the PA detoxification pathway. Compared to RTS-exposed normal mice, the colitic mice displayed more severe RTS-induced hepatic vasculature damage, fibrosis, and steatosis. Overall, our findings provide the first mode-of-action evidence of PA-induced enterotoxicity and highlight the importance of gut barrier function in PA-induced liver injury.
Salivary Gland Hypofunction and/or Xerostomia Induced by Nonsurgical Cancer Therapies: ISOO/MASCC/ASCO Guideline
Authors: Valeria Mercadante, Siri Beier Jensen, Derek K. Smith, Kari Bohlke, Jessica Bauman, Michael T. Brennan, Robert P. Coppes, Niels Jessen, Narinder K. Malhotra, Barbara Murphy, David I. Rosenthal, Arjan Vissink, Jonn Wu, Deborah P. Saunders, Douglas E. Peterson
Journal: Journal of Clinical Oncology (2021)

PURPOSE To provide evidence-based recommendations for prevention and management of salivary gland hypofunction and xerostomia induced by nonsurgical cancer therapies. METHODS Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials published between January 2009 and June 2020. The guideline also incorporated two previous systematic reviews conducted by MASCC/ISOO, which included studies published from 1990 through 2008. RESULTS A total of 58 publications were identified: 46 addressed preventive interventions and 12 addressed therapeutic interventions. A majority of the evidence focused on the setting of radiation therapy for head and neck cancer. For the prevention of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer, there is high-quality evidence for tissue-sparing radiation modalities. Evidence is weaker or insufficient for other interventions. For the management of salivary gland hypofunction and/or xerostomia, intermediate-quality evidence supports the use of topical mucosal lubricants, saliva substitutes, and agents that stimulate the salivary reflex. RECOMMENDATIONS For patients who receive radiation therapy for head and neck cancer, tissue-sparing radiation modalities should be used when possible to reduce the risk of salivary gland hypofunction and xerostomia. Other risk-reducing interventions that may be offered during radiation therapy for head and neck cancer include bethanechol and acupuncture. For patients who develop salivary gland hypofunction and/or xerostomia, interventions include topical mucosal lubricants, saliva substitutes, and sugar-free lozenges or chewing gum. For patients with head and neck cancer, oral pilocarpine and oral cevimeline, acupuncture, or transcutaneous electrostimulation may be offered after radiation therapy. Additional information can be found at www.asco.org/supportive-care-guidelines .
Analysis of Physician Use of Social Media
Authors: Irbaz Hameed, Christian T. Oakley, Adham Ahmed, Nyla Naeem, N. Bryce Robinson, N.U. Farrukh Hameed, Mario Gaudino
Journal: JAMA Network Open (2021)

This cross-sectional study assesses social media presence, activity, followers, and research activity among physicians from different surgical and medical specialties at top-rated US hospitals.
The COVID-19 response in the United Arab Emirates: challenges and opportunities
Authors: Ahmed R. Alsuwaidi, Farida I. Al Hosani, Gehad ElGhazali, Basel K. al-Ramadi
Journal: Nature Immunology (2021)

Like other countries in the region, the United Arab Emirates (UAE) was deeply affected by the pandemic. However, its foresight and proactive policies helped to create opportunities out of the challenges and spurred the development of trilateral collaborations involving government, academia and industry.
Association of a High-Efficiency Particulate Air Filter COVID-19 Testing Booth With Testing Capacity, Cost Per Test Acquired, and Use of Personal Protective Equipment
Authors: Kristian R. Olson, Sandra J. Butler, Bonnie B. Blanchfield, Jean M. Bernhardt, Frank Santo, Nour Al-Sultan, Paul F. Currier
Journal: JAMA Network Open (2021)

This quality improvement study compares COVID-19 testing throughput, personal protective equipment use, and cost per test before vs after the introduction of high-efficiency particulate air–filtered, positive-pressure Hexapod personal protection booths at a hospital in Boston, Massachusetts.
O-3 Characterization of KRAS mutation variants and prevalence of KRAS-G12C in gastrointestinal malignancies
Authors: M. Salem, S. El-Refai, W. Sha, A. Grothey, A. Puccini, T. George, J. Hwang, K. Kadakia, L. Musselwhite, E. Van Cutsem, J. Tabernero, J. Tie
Journal: Annals of Oncology (2021)
Safety and immunogenicity of Coronavirus disease 2019 vaccination in patients with chronic liver disease: a multicenter study
Authors: J. T. Wang, Z. Y. Hou, J. X. Liu, Y. Gu, Y. H. Wu, Z. H. Chen, J. S. Ji, S. Q. Diao, Y. W. Qiu, S. Q. Zhou, A. G. Zhang, N. N. Zhang, F. X. Wang, X. Li, Y. Wang, X. Liu, C. Lv, S. B. Chen, D. X. Liu, X. L. Ji, C. Liu, T. Ren, J. W. Sun, Z. W. Zhao, F. Z. Wu, F. X. Li, R. X. Wang, Y. Yan, S. L. Zhang, G. H. Ge, J. B. Shao, S. Y. Yang, Y. F. Huang, D. Xu, X. G. Li, J. W. Ai, M. H. Zheng, L. T. Zhang, Q. Xie, D. Rockey, J. Fallowfield, W. H. Zhang, X. L. Qi
Journal: Journal of Hepatology (2021)
Emerging role of circulating tumor cells in immunotherapy
Authors: Alexey Rzhevskiy, Alina Kapitannikova, Polina Malinina, Arthur Volovetsky, Hamidreza Aboulkheyr Es, Arutha Kulasinghe, Jean Paul Thiery, Anna Maslennikova, Andrei V. Zvyagin, Majid Ebrahimi Warkiani
Journal: Theranostics (2021)

Over the last few years, immunotherapy, in particular, immune checkpoint inhibitor therapy, has revolutionized the treatment of several types of cancer.At the same time, the uptake in clinical oncology has been slow owing to the high cost of treatment, associated toxicity profiles and variability of the response to treatment between patients.In response, personalized approaches based on predictive biomarkers have emerged as new tools for patient stratification to achieve effective immunotherapy.Recently, the enumeration and molecular analysis of circulating tumor cells (CTCs) have been highlighted as prognostic biomarkers for the management of cancer patients during chemotherapy and for targeted therapy in a personalized manner.The expression of immune checkpoints on CTCs has been reported in a number of solid tumor types and has provided new insight into cancer immunotherapy management.In this review, we discuss recent advances in the identification of immune checkpoints using CTCs and shed light on the potential applications of CTCs towards the identification of predictive biomarkers for immunotherapy.
Immune Thrombocytopenic Purpura after vaccination with COVID-19 Vaccine (ChAdOx1 nCov-19)
Authors: Finn-Ole Paulsen, Christoph Schaefers, Florian Langer, Christian Frenzel, Ulrich Wenzel, Felicitas E. Hengel, Carsten Bokemeyer, Christoph Seidel
Journal: Blood (2021)
A Problematic Biomarker Trial Design
Authors: Boris Freidlin, Edward L Korn
Journal: JNCI Journal of the National Cancer Institute (2021)

Efficient biomarker-driven randomized clinical trials are a key tool for implementing precision oncology. A commonly used biomarker phase III design is focused on testing the treatment effect in biomarker-positive and overall study populations. This approach may result in recommending new treatments to biomarker-negative patients when these treatments have no benefit for these patients.
CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study
Authors: Rachel E Sanborn, Omid Hamid, Elisabeth GE de Vries, Patrick A Ott, Javier Garcia-Corbacho, Valentina Boni, Johanna Bendell, Karen A Autio, Daniel C Cho, Ruth Plummer, Mark Stroh, Lawrence Lu, Fiona Thistlethwaite
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Probody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab. Methods Adults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study ( NCT03013491 ). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1). Results Twenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3–4 adverse events (AEs) and grade 3–4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for &gt;12 months in four patients. Conclusions The MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.
Liver-Resident Memory CD8+ T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection
Authors: Daniel Fernandez-Ruiz, Wei Yi Ng, Lauren E. Holz, Joel Z. Ma, Ali Zaid, Yik Chun Wong, Lei Shong Lau, Vanessa Mollard, Anton Cozijnsen, Nicholas Collins, Jessica Li, Gayle M. Davey, Yu Kato, Sapna Devi, Roghieh Skandari, Michael Pauley, Jonathan H. Manton, Dale I. Godfrey, Asolina Braun, Szun Szun Tay, Peck Szee Tan, David G. Bowen, Friedrich Koch-Nolte, Björn Rissiek, Francis R. Carbone, Brendan S. Crabb, Mireille Lahoud, Ian A. Cockburn, Scott N. Mueller, Patrick Bertolino, Geoffrey I. McFadden, Irina Caminschi, William R. Heath
Journal: Immunity (2019)
Association Between Gender-Affirming Hair Removal and Mental Health Outcomes
Authors: Michelle S. Lee, Anthony N. Almazan, Vinod E. Nambudiri, Alex S. Keuroghlian
Journal: JAMA Dermatology (2021)

Gender-affirming medical care is essential for addressing the mental health burdens of transgender and gender-diverse (TGD) populations. 1 Gender-affirming hair removal (GAHR) procedures, including electrolysis and laser hair removal, are desired by nearly 90% of TGD people. 2 However, such services are covered by only 4.6% of insurance plans, 3,4 possibly owing in part to limited evidence of their menatal health benefits.In this study, we investigated the association between GAHR and mental health outcomes.
Ethnic differences in SARS-CoV-2 vaccine hesitancy in United Kingdom healthcare workers: Results from the UK-REACH prospective nationwide cohort study
Authors: Katherine Woolf, I Chris McManus, Christopher A Martin, Laura B Nellums, Anna L Guyatt, Carl Melbourne, Luke Bryant, Mayuri Gogoi, Fatimah Wobi, Amani Al-Oraibi, Osama Hassan, Amit Gupta, Catherine John, Martin D Tobin, Sue Carr, Sandra Simpson, Bindu Gregary, Avinash Aujayeb, Stephen Zingwe, Rubina Reza, Laura J Gray, Kamlesh Khunti, Manish Pareek
Journal: The Lancet Regional Health - Europe (2021)
Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: Ophthalmic findingsSST report no. 13
Authors: Neil M Bressler, Susan B Bressler, Ashley L Childs, Julia A Haller, Barbara S Hawkins, Hilel Lewis, Mathew W MacCumber, Marta J Marsh, Maryann Redford, Paul Sternberg, Matthew A Thomas, George A Williams
Journal: Ophthalmology (2004)
Interactive Web-Based Annotation of Plant MicroRNAs with iwa-miRNA
Authors: Ting Zhang, Jingjing Zhai, Xiaorong Zhang, Lei Ling, Menghan Li, Shang Xie, Minggui Song, Chuang Ma
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract MicroRNAs (miRNAs) are important regulators of gene expression. The large-scale detection and profiling of miRNAs have been accelerated with the development of high-throughput small RNA sequencing (sRNA-Seq) techniques and bioinformatics tools. However, generating high-quality comprehensive miRNA annotations remains challenging due to the intrinsic complexity of sRNA-Seq data and inherent limitations of existing miRNA prediction tools. Here, we present iwa-miRNA, a Galaxy-based framework that can facilitate miRNA annotation in plant species by combining computational analysis and manual curation. iwa-miRNA is specifically designed to generate a comprehensive list of miRNA candidates, bridging the gap between already annotated miRNAs provided by public miRNA databases and new predictions from sRNA-Seq datasets. It can also assist users in selecting promising miRNA candidates in an interactive mode, contributing to the accessibility and reproducibility of genome-wide miRNA annotation. iwa-miRNA is user-friendly and can be easily deployed as a web application for researchers without programming experience. With flexible, interactive, and easy-to-use features, iwa-miRNA is a valuable tool for the annotation of miRNAs in plant species with reference genomes. We also illustrate the application of iwa-miRNA for miRNA annotation using data from plant species with varying genomic complexity. The source codes and web server of iwa-miRNA are freely accessible at http://iwa-miRNA.omicstudio.cloud/.