tbuckley/cabot-search huggingface dataset:
Cartilage Oligomeric Matrix Protein promotes epithelial-mesenchymal transition by interacting with Transgelin in Colorectal Cancer
Authors: Weilong Zhong, Huiqin Hou, Tianyu Liu, Shuai Su, Xiaonan Xi, Yusheng Liao, Runxiang Xie, Ge Jin, Xiang Liu, Lanping Zhu, Hongxia Zhang, Xueli Song, Cheng Yang, Tao Sun, Hailong Cao, Bangmao Wang
Journal: Theranostics (2020)

Background and Purpose: The role of the cartilage oligomeric matrix protein (COMP) in epithelial-mesenchymal transition (EMT) in tumor progression has been studied, but its exact regulatory mechanism remains unknown. Methods: The interaction between COMP and the actin-binding protein transgelin (TAGLN) was identified by interaction protein prediction and co-immunoprecipitation and verified through the stochastic optical reconstruction microscopy (STORM) and duolink experiments. Western blot and immunofluorescence analyses were conducted to detect the changes in EMT-related markers after COMP overexpression and knockdown. Molecular docking and Biacore of the interaction interface of COMP/TAGLN revealed that Chrysin directly targeted COMP. The promotion of COMP and the Chrysin inhibition of EMT were detected through the cell migration, invasion, apoptosis, and xenotransplantation of nude mice. Results: COMP interacts with TAGLN in EMT in colorectal cancer to regulate cytoskeletal remodeling and promote malignant progression. COMP is highly expressed in highly malignant colorectal cancer and positively correlated with TAGLN expression. COMP knockdown can inhibit colorectal cancer metastasis and invasion, whereas COMP overexpression promotes EMT in colorectal cancer. Through virtual screening of the protein interaction interface, Chrysin, a flavonoid compound extracted from Oroxylum indicum, was found to have the highest docking score to the COMP/TAGLN complex. Chrysin inhibited COMP, thereby preventing EMT and the malignant progression of colorectal cancer. Conclusions: This study illustrated the role of COMP in EMT and suggested that COMP/TAGLN may be a potential tumor therapeutic target. Chrysin exhibits obvious antitumor effects. This work provides a preliminary antitumor therapy to target COMP or its interaction protein to inhibit EMT.
Comparative effectiveness of first-line tumour necrosis factor inhibitor versus non-tumour necrosis factor inhibitor biologics and targeted synthetic agents in patients with rheumatoid arthritis: results from a large US registry study
Authors: Dimitrios A Pappas, Gregory St John, Carol J Etzel, Stefano Fiore, Taylor Blachley, Toshio Kimura, Rajeshwari Punekar, Kelechi Emeanuru, Jeannie Choi, Susan Boklage, Joel M Kremer
Journal: Annals of the Rheumatic Diseases (2020)

This study evaluated the comparative effectiveness of a tumour necrosis factor inhibitor (TNFi) versus a non-TNFi (biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs)) as the first-line treatment following conventional synthetic DMARDs, as well as potential modifiers of response, observed in US clinical practice.Data were from a large US healthcare registry (Consortium of Rheumatology Researchers of North America Rheumatoid Arthritis Registry). The analysis included patients (aged ≥18 years) with a documented diagnosis of rheumatoid arthritis (RA), a valid baseline Clinical Disease Activity Index (CDAI) score of >2.8 and no prior bDMARD or tsDMARD use. Outcomes were captured at 1-year postinitiation of a TNFi (adalimumab, etanercept, certolizumab pegol, golimumab or infliximab) or a non-TNFi (abatacept, tocilizumab, rituximab, anakinra or tofacitinib) and included CDAI, 28-Joint Modified Disease Activity Score, patient-reported outcomes (including the Health Assessment Questionnaire Disability Index, EuroQol-5 Dimension score, sleep, anxiety, morning stiffness and fatigue) and rates of anaemia. Groups were propensity score-matched at baseline to account for potential confounding.There were no statistically significant differences observed between the TNFi and non-TNFi treatment groups for outcomes assessed, except the incidence rate ratio for anaemia, which slightly favoured the TNFi group (19.04 per 100 person-years) versus the non-TNFi group (24.01 per 100 person-years, p=0.03). No potential effect modifiers were found to be statistically significant.The findings of no significant differences in outcomes between first-line TNF versus first-line non-TNF groups support RA guidelines, which recommend individualised care based on clinical judgement and consideration of patient preferences.
Serosurveillance and the COVID-19 Epidemic in the US
Authors: Tyler S. Brown, Rochelle P. Walensky
Journal: JAMA (2020)

Fiona P. Havers, MD, MHS; Carrie Reed, PhD; Travis Lim, DrPH; Joel M. Montgomery, PhD; John D. Klena, PhD; Aron J. Hall, DVM; Alicia M. Fry, MD; Deborah L. Cannon, BS; Cheng-Feng Chiang, PhD; Aridth Gibbons, BS; Inna Krapiunaya, MS; Maria Morales-Betoulle, PhD; Katherine Roguski, MPH; Mohammad Ata Ur Rasheed, PhD; Brandi Freeman, PhD; Sandra Lester, PhD; Lisa Mills, PhD; Darin S. Carroll, PhD; S. Michele Owen, PhD; Jeffrey A. Johnson, PhD; Vera Semenova, PhD; Carina Blackmore, DVM; Debra Blog, MD; Shua J. Chai, MD; Angela Dunn, MD; Julie Hand, MSPH; Seema Jain, MD; Scott Lindquist, MD; Ruth Lynfield, MD; Scott Pritchard, MPH; Theresa Sokol, MPH; Lynn Sosa, MD; George Turabelidze, MD; Sharon M. Watkins, PhD; John Wiesman, DrPH; Randall W. Williams, MD; Stephanie Yendell, DVM; Jarad Schiffer, MS; Natalie J. Thornburg, PhD
Loss of SPEG Inhibitory Phosphorylation of Ryanodine Receptor Type-2 Promotes Atrial Fibrillation
Authors: Hannah M. Campbell, Ann P. Quick, Issam Abu-Taha, David Y. Chiang, Carlos F. Kramm, Tarah A. Word, Sören Brandenburg, Mohit Hulsurkar, Katherina M. Alsina, Hui-Bin Liu, Brian Martin, Dennis Uhlenkamp, Oliver M. Moore, Satadru K. Lahiri, Eleonora Corradini, Markus Kamler, Albert J.R. Heck, Stephan E. Lehnart, Dobromir Dobrev, Xander H.T. Wehrens
Journal: Circulation (2020)

Enhanced diastolic calcium (Ca2+) release through ryanodine receptor type-2 (RyR2) has been implicated in atrial fibrillation (AF) promotion. Diastolic sarcoplasmic reticulum Ca2+ leak is caused by increased RyR2 phosphorylation by PKA (protein kinase A) or CaMKII (Ca2+/calmodulin-dependent kinase-II) phosphorylation, or less dephosphorylation by protein phosphatases. However, considerable controversy remains regarding the molecular mechanisms underlying altered RyR2 function in AF. We thus aimed to determine the role of SPEG (striated muscle preferentially expressed protein kinase), a novel regulator of RyR2 phosphorylation, in AF pathogenesis.Western blotting was performed with right atrial biopsies from patients with paroxysmal AF. SPEG atrial knockout mice were generated using adeno-associated virus 9. In mice, AF inducibility was determined using intracardiac programmed electric stimulation, and diastolic Ca2+ leak in atrial cardiomyocytes was assessed using confocal Ca2+ imaging. Phosphoproteomics studies and Western blotting were used to measure RyR2 phosphorylation. To test the effects of RyR2-S2367 phosphorylation, knockin mice with an inactivated S2367 phosphorylation site (S2367A) and a constitutively activated S2367 residue (S2367D) were generated by using CRISPR-Cas9.Western blotting revealed decreased SPEG protein levels in atrial biopsies from patients with paroxysmal AF in comparison with patients in sinus rhythm. SPEG atrial-specific knockout mice exhibited increased susceptibility to pacing-induced AF by programmed electric stimulation and enhanced Ca2+ spark frequency in atrial cardiomyocytes with Ca2+ imaging, establishing a causal role for decreased SPEG in AF pathogenesis. Phosphoproteomics in hearts from SPEG cardiomyocyte knockout mice identified RyR2-S2367 as a novel kinase substrate of SPEG. Western blotting demonstrated that RyR2-S2367 phosphorylation was also decreased in patients with paroxysmal AF. RyR2-S2367A mice exhibited an increased susceptibility to pacing-induced AF, and aberrant atrial sarcoplasmic reticulum Ca2+ leak, as well. In contrast, RyR2-S2367D mice were resistant to pacing-induced AF.Unlike other kinases (PKA, CaMKII) that increase RyR2 activity, SPEG phosphorylation reduces RyR2-mediated sarcoplasmic reticulum Ca2+ release. Reduced SPEG levels and RyR2-S2367 phosphorylation typified patients with paroxysmal AF. Studies in S2367 knockin mouse models showed a causal relationship between reduced S2367 phosphorylation and AF susceptibility. Thus, modulating SPEG activity and phosphorylation levels of the novel S2367 site on RyR2 may represent a novel target for AF treatment.
Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity
Authors: Longze Sha, Ting Chen, Yu Deng, Tingfu Du, Kaili Ma, Wanwan Zhu, Yan Shen, Qi Xu
Journal: Theranostics (2020)

Rationale: Dysfunction or reduced levels of EAAT2 have been documented in epilepsy. We previously demonstrated the antiepileptic effects of Hsp90 inhibitor 17AAG in temporal lobe epilepsy by preventing EAAT2 degradation. Because of the potential toxicities of 17AAG, this study aimed to identify an alternative Hsp90 inhibitor with better performance on Hsp90 inhibition, improved blood-brain barrier penetration and minimal toxicity. Methods: We used cell-based screening and animal models of epilepsy, including mouse models of epilepsy and Alzheimer's disease, and a cynomolgus monkey model of epilepsy, to evaluate the antiepileptic effects of new Hsp90 inhibitors. Results: In both primary cultured astrocytes and normal mice, HSP990 enhanced EAAT2 levels at a lower dose than other Hsp90 inhibitors. In epileptic mice, administration of 0.1 mg/kg HSP990 led to upregulation of EAAT2 and inhibition of spontaneous seizures. Additionally, HSP990 inhibited seizures and improved cognitive functions in the APPswe/PS1dE9 transgenic model of Alzheimer's disease. In a cynomolgus monkey model of temporal lobe epilepsy, oral administration of low-dose HSP990 completely suppressed epileptiform discharges for up to 12 months, with no sign of hepatic and renal toxicity. Conclusions: These results support further preclinical studies of HSP990 treatment for temporal lobe epilepsy.
Meningococcal disease surveillance in the Asia–Pacific region (2020): The global meningococcal initiative
Authors: Aye Mya Min Aye, Xilian Bai, Ray Borrow, Sotharith Bory, Josefina Carlos, Dominique A. Caugant, Chien-Shun Chiou, Vo Thi Trang Dai, Ener Cagri Dinleyici, Prakash Ghimire, Setyo Handryastuti, Jung Yeon Heo, Amy Jennison, Hajime Kamiya, Loong Tonnii Sia, Jay Lucidarme, Helen Marshall, Nina Dwi Putri, Senjuti Saha, Zhujun Shao, James Heng Chiak Sim, Vinny Smith, Muhamed-Kheir Taha, Phan Van Thanh, Usa Thisyakorn, Kinley Tshering, Julio Vázquez, Balaji Veeraraghavan, Saber Yezli, Bingqing Zhu
Journal: Journal of Infection (2020)

The degree of surveillance data and control strategies for invasive meningococcal disease (IMD) varies across the Asia-Pacific region. IMD cases are often reported throughout the region, but the disease is not notifiable in some countries, including Myanmar, Bangladesh and Malaysia. Although there remains a paucity of data from many countries, specific nations have introduced additional surveillance measures. The incidence of IMD is low and similar across the represented countries (<0.2 cases per 100,000 persons per year), with the predominant serogroups of Neisseria meningitidis being B, W and Y, although serogroups A and X are present in some areas. Resistance to ciprofloxacin is also of concern, with the close monitoring of antibiotic-resistant clonal complexes (e.g., cc4821) being a priority. Meningococcal vaccination is only included in a few National Immunization Programs, but is recommended for high-risk groups, including travellers (such as pilgrims) and people with complement deficiencies or human immunodeficiency virus (HIV). Both polysaccharide and conjugate vaccines form part of recommendations. However, cost and misconceptions remain limiting factors in vaccine uptake, despite conjugate vaccines preventing the acquisition of carriage.
Autoantibodies targeting TRIM72 compromise membrane repair and contribute to inflammatory myopathy
Authors: Kevin E. McElhanon, Nicholas Young, Jeffrey Hampton, Brian J. Paleo, Thomas A. Kwiatkowski, Eric X Beck, Ana Capati, Kyle Jablonski, Travis Gurney, Miguel A. Lopez Perez, Rohit Aggarwal, Chester V. Oddis, Wael N. Jarjour, Noah Weisleder
Journal: Journal of Clinical Investigation (2020)

Idiopathic inflammatory myopathies (IIM) involve chronic inflammation of skeletal muscle and subsequent muscle degeneration due to an uncontrolled autoimmune response; however, the mechanisms leading to pathogenesis are not well understood. A compromised sarcolemmal repair process could promote an aberrant exposure of intramuscular antigens with the subsequent initiation of an inflammatory response that contributes to IIM. Using an adoptive transfer mouse model of IIM, we show that sarcolemmal repair is significantly compromised in distal skeletal muscle in the absence of inflammation. We identified autoantibodies against TRIM72 (also known as MG53), a muscle-enriched membrane repair protein, in IIM patient sera and in our mouse model of IIM by ELISA. We found that patient sera with elevated levels of TRIM72 autoantibodies suppress sarcolemmal resealing in healthy skeletal muscle, and depletion of TRIM72 antibodies from these same serum samples rescues sarcolemmal repair capacity. Autoantibodies targeting TRIM72 lead to skeletal muscle fibers with compromised membrane barrier function, providing a continuous source of autoantigens to promote autoimmunity and further amplifying humoral responses. These findings reveal a potential pathogenic mechanism that acts as a feedback loop contributing to the progression of IIM.
Restorative functions of Autologous Stem Leydig Cell transplantation in a Testosterone-deficient non-human primate model
Authors: Kai Xia, Hong Chen, Jiancheng Wang, Xin Feng, Yong Gao, Yi Wang, Rongda Deng, Chunxing Wu, Peng Luo, Min Zhang, Chao Wang, Yong Zhang, Yadong Zhang, Guihua Liu, Xiang'an Tu, Xiangzhou Sun, Weiqiang Li, Qiong Ke, Chunhua Deng, Andy Peng Xiang
Journal: Theranostics (2020)

Rationale: Stem Leydig cells (SLCs) transplantation can restore testosterone production in rodent models and is thus a potential solution for treating testosterone deficiency (TD). However, it remains unknown whether these favorable effects will be reproduced in more clinically relevant large-animal models. Therefore, we assessed the feasibility, safety and efficacy of autologous SLCs transplantation in a testosterone-deficient non-human primate (NHP) model. Methods: Cynomolgus monkey SLCs (CM-SLCs) were isolated from testis biopsies of elderly (> 19 years) cynomolgus monkeys by flow cytometry. Autologous CM-SLCs were injected into the testicular interstitium of 7 monkeys. Another 4 monkeys were injected the same way with cynomolgus monkey dermal fibroblasts (CM-DFs) as controls. The animals were then examined for sex hormones, semen, body composition, grip strength, and exercise activity. Results: We first isolated CD271+ CM-SLCs which were confirmed to expand continuously and show potential to differentiate into testosterone-producing Leydig cells (LCs) in vitro. Compared with CM-DFs transplantation, engraftment of autologous CM-SLCs into elderly monkeys could significantly increase the serum testosterone level in a physiological pattern for 8 weeks, without any need for immunosuppression. Importantly, CM-SLCs transplantation recovered spermatogenesis and ameliorated TD-related symptoms, such as those related to body fat mass, lean mass, bone mineral density, strength and exercise capacity. Conclusion: For the first time, our short-term observations demonstrated that autologous SLCs can increase testosterone levels and ameliorate relevant TD symptoms in primate models. A larger cohort with long-term follow-up will be required to assess the translational potential of autologous SLCs for TD therapy.
High rifampicin-resistant TB cure rates and prevention of severe ototoxicity after replacing the injectable by linezolid in early stage of hearing loss
Authors: Mahamadou Bassirou Souleymane, Alberto Piubello, Ibrahim Mamane Lawan, Souleymane Hassane-Harouna, Mourtala Mohamed Assao-Neino, Alphazazi Soumana, Zelika Hamidou-Harouna, Assiatou Gagara-Issoufou, Nimer Ortuño-Gutiérrez, Alberto Roggi, Valerie Schwoebel, Saïdou Mamadou, Lutgarde Lynen, Bouke De Jong, Armand Van Deun, Tom Decroo
Journal: European Respiratory Journal (2020)

The short treatment regimen (STR) achieves a &gt;80% cure in rifampicin-resistant tuberculosis (RR-TB) patients. However, ototoxicity induced by the injectable is a concern. This is the first study to evaluate the replacement of injectables by linezolid in patients with audiometry abnormalities at baseline or during the treatment. We conducted a retrospective cohort study of all RR-TB patients started on the STR between 2016 and June, 2019, in Niger. Patients underwent audiometry every 2 months in 2016 and every month since 2017. Of 195 patients, 16.9% (33 out of 195) received linezolid from the start (n=17), or switched from injectables to linezolid during treatment (n=16), based on audiometry abnormalities. In 2016, two patients developed severe ototoxicity despite switching to linezolid. Since 2017, no patient developed severe hearing loss or complete deafness. Severe haematological toxicity was observed in 18.1% (six out of 33) of patients on linezolid, none of which was life threatening. The use of linezolid was associated with severe but manageable adverse events (hazard ratio 8.9, 95% CI 2.5–31.5; p=0.001). A total of 90.9% (30 out of 33) of patients on a linezolid-containing STR were cured, and none experienced treatment failure. Three died, but not due to adverse events. Baseline and monthly audiometry monitoring and using linezolid after detection of hearing abnormalities appears effective to prevent severe ototoxicity, while keeping high treatment success and manageable adverse events.
The quality and satisfaction of romantic relationships in transgender people: A systematic review of the literature
Authors: Ellen Marshall, Cris Glazebrook, Sally Robbins-Cherry, Serge Nicholson, Nat Thorne, Jon Arcelus
Journal: International Journal of Transgender Health (2020)

IntroductionRomantic relationships are often a significant area of individuals' lives and can have a positive impact on wellbeing. There is often a belief within society of romantic relationships ending upon the start of gender affirming transition, however this is often not reflected within clinical work or research studies. Despite this, currently not enough is known about romantic relationships for transgender individuals and their partners, and the impact gender affirming transition can have on the quality and satisfaction of these relationships.AimTo critically and systematically review the available literature examining quality and satisfaction of romantic relationships for transgender individuals and their partners.MethodsUsing PRISMA guidelines, major databases (Pubmed, PsycINFO and Web of Science) and relevant reference lists were searched for suitable articles up to January 2020. Each included article was assessed for methodological quality and the demographic data, methods and findings linked to relationship quality and satisfaction was extracted for analysis.ResultsFrom 151 potentially relevant articles, 14 studies (six quantitative, eight qualitative) were included within the review. Most studies displayed moderate risk of bias due to cross-sectional designs and lack of reflexivity. Findings from quantitative studies suggest a bi-directional relationship between transition, relationship quality and satisfaction and wellbeing. Qualitative studies suggest transition can cause personal challenges for both transgender individuals and partners. Maintenance activities help buffer the impact of these challenges on relationship satisfaction and ensure positives are possible from relationships.DiscussionGender affirming transition can impact on the quality and satisfaction of romantic relationships. Due to additional challenges transgender individuals and their partners may face, adequate support is required at personal, community and clinical level. There is a paucity of research in this area and current studies lack methodological rigor. Future research is essential to gain a further understanding of transgender relationships and the support required.
Khoe-San Genomes Reveal Unique Variation and Confirm the Deepest Population Divergence in Homo sapiens
Authors: Carina M Schlebusch, Per Sjödin, Gwenna Breton, Torsten Günther, Thijessen Naidoo, Nina Hollfelder, Agnes E Sjöstrand, Jingzi Xu, Lucie M Gattepaille, Mário Vicente, Douglas G Scofield, Helena Malmström, Michael de Jongh, Marlize Lombard, Himla Soodyall, Mattias Jakobsson
Journal: Molecular Biology and Evolution (2020)

The southern African indigenous Khoe-San populations harbor the most divergent lineages of all living peoples. Exploring their genomes is key to understanding deep human history. We sequenced 25 full genomes from five Khoe-San populations, revealing many novel variants, that 25% of variants are unique to the Khoe-San, and that the Khoe-San group harbors the greatest level of diversity across the globe. In line with previous studies, we found several gene regions with extreme values in genome-wide scans for selection, potentially caused by natural selection in the lineage leading to Homo sapiens and more recent in time. These gene regions included immunity-, sperm-, brain-, diet-, and muscle-related genes. When accounting for recent admixture, all Khoe-San groups display genetic diversity approaching the levels in other African groups and a reduction in effective population size starting around 100,000 years ago. Hence, all human groups show a reduction in effective population size commencing around the time of the Out-of-Africa migrations, which coincides with changes in the paleoclimate records, changes that potentially impacted all humans at the time.
<i>Notes from the Field:</i> Characteristics of Tetrahydrocannabinol–Containing E-cigarette, or Vaping, Products Used by Adults — Illinois, September–October 2019
Authors: Livia Navon, Isaac Ghinai, Jennifer Layden
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

This report describes an online survey conducted by the Illinois Department of Public Health to increase the amount of data available regarding the prevalence of tetrahydrocannabinol-containing e-cigarette, or vaping, product use.
Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance)
Authors: Raphael Bueno, William G. Richards, David H. Harpole, Karla V. Ballman, Ming-Sound Tsao, Zhengming Chen, Xiaofei Wang, Guoan Chen, Lucian R. Chirieac, M. Herman Chui, Wilbur A. Franklin, Thomas J. Giordano, Ramaswamy Govindan, Mary-Beth Joshi, Daniel T. Merrick, Christopher J. Rivard, Thomas Sporn, Adrie van Bokhoven, Hui Yu, Frances A. Shepherd, Mark A. Watson, David G. Beer, Fred R. Hirsch
Journal: Journal of Thoracic Oncology (2020)