tbuckley/cabot-search huggingface dataset:
Attenuation of Rheumatoid Arthritis Through the Inhibition of Tumor Necrosis Factor–Induced Caspase 3/Gasdermin E–Mediated Pyroptosis
Authors: Zeqing Zhai, Fangyuan Yang, Wenchao Xu, Jiaochan Han, Guihu Luo, Yehao Li, Jian Zhuang, Hongyu Jie, Xing Li, Xingliang Shi, Xinai Han, Xiaoqing Luo, Rui Song, Yonghong Chen, Jianheng Liang, Shufan Wu, Yi He, Erwei Sun
Journal: Arthritis & Rheumatology (2021)

Objective To determine the role of gasdermin E (GSDME)–mediated pyroptosis in the pathogenesis and progression of rheumatoid arthritis (RA), and to explore the potential of GSDME as a therapeutic target in RA. Methods The expression and activation of caspase 3 and GSDME in the synovium, macrophages, and monocytes of RA patients were determined by immunohistochemistry, immunofluorescence, and Western blot analysis. The correlation of activated GSDME with RA disease activity was evaluated. The pyroptotic ability of monocytes from RA patients was tested, and the effect of tumor necrosis factor (TNF) on caspase 3/GSDME‐mediated pyroptosis of monocytes and macrophages was investigated. In addition, collagen‐induced arthritis (CIA) was induced in mice lacking Gsdme , and the incidence and severity of arthritis were assessed. Results Compared to cells from healthy controls, monocytes and synovial macrophages from RA patients showed increased expression of activated caspase 3, GSDME, and the N‐terminal fragment of GSDME (GSDME‐N). The expression of GSDME‐N in monocytes from RA patients correlated positively with disease activity. Monocytes from RA patients with higher GSDME levels were more susceptible to pyroptosis. Furthermore, TNF induced pyroptosis in monocytes and macrophages by activating the caspase 3/GSDME pathway. The use of a caspase 3 inhibitor and silencing of GSDME significantly blocked TNF‐induced pyroptosis. Gsdme deficiency effectively alleviated arthritis in a mouse model of CIA. Conclusion These results support the notion of a pathogenic role of GSDME in RA and provide an alternative mechanism for RA pathogenesis involving TNF, which activates GSDME‐mediated pyroptosis of monocytes and macrophages in RA. In addition, targeting GSDME might be a potential therapeutic approach for RA.
Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial
Authors: Clara K Chow, Emily R Atkins, Graham S Hillis, Mark R Nelson, Christopher M Reid, Markus P Schlaich, Peter Hay, Kris Rogers, Laurent Billot, Michael Burke, John Chalmers, Bruce Neal, Anushka Patel, Tim Usherwood, Ruth Webster, Anthony Rodgers, Andrew Hung, Armand Edison, Angalie E Abraham, Daniel Xu, Mark T Bloch, Gemma Figtree, Janis M Nolde, Andrew Black, Shirley Jansen, Sinjini Biswas, Andrew E Ajani, Revathy Carnagarin, Dylan Wynne, Mikhail Altman, Jay Thakkar, Aravinda Thiagalingam, Harry Klimis
Journal: The Lancet (2021)
Effect of Online 1-Day Cognitive Behavioral Therapy–Based Workshops Plus Usual Care vs Usual Care Alone for Postpartum Depression
Authors: Ryan J. Van Lieshout, Haley Layton, Calan D. Savoy, June S. L. Brown, Mark A. Ferro, David L. Streiner, Peter J. Bieling, Andrea Feller, Steven Hanna
Journal: JAMA Psychiatry (2021)

Postpartum depression (PPD) affects as many as 20% of mothers, yet just 1 in 10 of these women receives evidence-based treatment. The COVID-19 pandemic has increased PPD risk, reduced treatment access, and shifted preferences toward virtual care.To determine whether an online 1-day cognitive behavioral therapy (CBT)-based workshop added to treatment as usual improves PPD, anxiety, social support, mother-infant relationship quality, and infant temperament more than treatment as usual alone.This randomized clinical trial included 403 women with PPD who were recruited across Ontario, Canada, during the COVID-19 pandemic (April 20 to October 4, 2020). Women with Edinburgh Postnatal Depression Scale (EPDS) scores of at least 10 who were 18 years or older and had an infant younger than 12 months were eligible.Women were randomly assigned to receive a live, interactive online 1-day CBT-based workshop delivered by a registered psychotherapist, psychiatrist, or clinical psychology graduate student in addition to treatment as usual (n = 202) or to receive treatment as usual and wait-listed to receive the workshop 12 weeks later (n = 201).The primary outcome was change in PPD (EPDS scores) in experimental and wait list control groups 12 weeks after baseline. Secondary outcomes included maternal anxiety (7-item Generalized Anxiety Disorder Questionnaire [GAD-7]), social support (Social Provisions Scale), quality of the mother-infant relationship (Postpartum Bonding Questionnaire), and infant temperament (Infant Behavior Questionnaire-Revised Very Short Form).Participants all identified as women with a mean (SD) age of 31.8 (4.4) years. The workshop led to significant mean (SD) reductions in EPDS scores (from 16.47 [4.41] to 11.65 [4.83]; B = -4.82; P < .001) and was associated with a higher odds of exhibiting a clinically significant decrease in EPDS scores (odds ratio, 4.15; 95% CI, 2.66-6.46). The mean (SD) GAD-7 scores decreased from 12.41 (5.12) to 7.97 (5.54) after the workshop (B = -4.44; 95% CI, -5.47 to -3.38; P < .001) and participants were more likely to experience a clinically significant change (odds ratio, 3.09; 95% CI, 1.99-4.81). Mothers also reported improvements in bonding (B = -3.22; 95% CI, -4.72 to -1.71; P < .001), infant-focused anxiety (B = -1.64; 95% CI, -2.25 to 1.00; P < .001), social support (B = 3.31; 95% CI, 1.04 to 5.57; P < .001), and positive affectivity/surgency in infants (B = 0.31; 95% CI, 0.05 to 0.56; P < .001).In this randomized clinical trial, an online 1-day CBT-based workshop for PPD provides an effective, brief option for mothers, reducing PPD and anxiety as well as improving social support, the mother-infant relationship, and positive affectivity/surgency in offspring.ClinicalTrials.gov Identifier: NCT04485000.
Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy
Authors: Elyse O. Kharbanda, Jacob Haapala, Malini DeSilva, Gabriela Vazquez-Benitez, Kimberly K. Vesco, Allison L. Naleway, Heather S. Lipkind
Journal: JAMA (2021)

Ai-ris Y. Collier, MD; Katherine McMahan, MS; Jingyou Yu, PhD; Lisa H. Tostanoski, PhD; Ricardo Aguayo, BS; Jessica Ansel, NP; Abishek Chandrashekar, MS; Shivani Patel, BA; Esther Apraku Bondzie, BA; Daniel Sellers, BS; Julia Barrett, BS; Owen Sanborn, BS; Huahua Wan, MS; Aiquan Chang, BA; Tochi Anioke, BS; Joseph Nkolola, PhD; Connor Bradshaw, BS; Catherine Jacob-Dolan, BS; Jared Feldman, BS; Makda Gebre, MSc; Erica N. Borducchi, PhD; Jinyan Liu, PhD; Aaron G. Schmidt, PhD; Todd Suscovich, PhD; Caitlyn Linde, PhD; Galit Alter, PhD; Michele R. Hacker, ScD; Dan H. Barouch, MD, PhD
Fibroblast growth factors: the keepers of endothelial normalcy
Authors: Michael Simons
Journal: Journal of Clinical Investigation (2021)

Endothelial cells (ECs) under physiologic and pathologic conditions are capable of substantial plasticity that includes the endothelial-mesenchymal transition (EndMT). Notably, in the hypoxic pulmonary circulation EndMT likely drives increases in the pulmonary arterial blood pressure, leading to pulmonary arterial hypertension (PAH). However, it is unclear whether suppressing EndMT can prevent PAH development or mitigate established disease. In this issue of the JCI, Woo et al. generated mice with EC-specific deletion of FGFR1 and -2 and mice with EC-specific expression of a constitutively active FGFR1 to determine the role of FGF signaling in PAH. Mice with FGFR1/2 deletion in ECs that were exposed to hypoxic conditions developed extensive EndMT and more severe PAH than control mice. Animals with the constitutively active endothelial FGFR were protected from hypoxia-induced EndMT and PAH development. These findings suggest that FGF signaling may promote vascular resilience and prevent hypoxia-induced development of EndMT and PAH.
Abstract #3321: Eugenol and isoeugenol as antiproliferative agents in skin cancer cells
Authors: Jenny Hennen, Michaela Kalmes, Brunhilde Blömeke
Journal: Cancer Research (2009)

Chemotherapeutic approaches using non-toxic plant derived substances may be one of the strategies to defeat skin cancer. Phenolic derivatives like eugenol (4-allyl-2-methoxyphenol) and its isoform isoeugenol (2-methoxy-4-propenylphenol) are present in a variety of plants such as Syzgium aromaticum (clove), Pimenta racemosa (bay leaves), and Cinnamomum verum (cinnamon leaf). Although eugenol and isoeugenol are naturally occurring and toxicologically harmless, several physiological activities of them have been described pointing to a cytoprotective role for both substances. The fact that eugenol was recently found to cause melanoma growth suppression both in vivo and in vitro (Ghosh et al., 2005) prompted us to investigate whether both substances exhibit antiproliferative properties in a non-melanoma skin cancer cell line. In the present study, we therefore studied the in vitro effects of eugenol and isoeugenol on cell cycle progression of human epidermoid carcinoma A431 cells and could show that both substances arrested the cancer cells in the G0/G1 phase of the cell cycle in a dose dependent manner. The mechanisms by which eugenol and isoeugenol exhibit this cell cycle arrest in A431 cells still remains unclear and definitely needs further investigation. However, in our previous studies on the molecular mechanisms of action of eugenol and isoeugenol in keratinocytes we found that the antiproliferative properties of both substances are mediated through the arylhydrocarbon receptor (AhR). Both, eugenol and isoeugenol provoked translocation of the AhR into the nucleus, AhR target gene expression and AhR dependent modulation of cell cycle regulatory proteins involved in the transition from the G0/G1 phase of the cell cycle to the S phase. Based on these results we hypothesize that the antiproliferative effects of eugenol and isoeugenol in A431 cells are also mediated through the AhR. Taken together, these results give strong reason to assume that the AhR might be a good target for the development of chemotherapeutic substances and furthermore, both eugenol and isoeugenol might act as such chemotherapeutic agents against skin cancer.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3321.
ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention
Authors: Sidney C. Smith, Ted E. Feldman, John W. Hirshfeld, Alice K. Jacobs, Morton J. Kern, Spencer B. King, Douglass A. Morrison, William W. O’Neill, Hartzell V. Schaff, Patrick L. Whitlow, David O. Williams, Elliott M. Antman, Sidney C. Smith, Cynthia D. Adams, Jeffrey L. Anderson, David P. Faxon, Valentin Fuster, Jonathan L. Halperin, Loren F. Hiratzka, Sharon Ann Hunt, Alice K. Jacobs, Rick Nishimura, Joseph P. Ornato, Richard L. Page, Barbara Riegel
Journal: Journal of the American College of Cardiology (2005)
<i>Drosophila</i> Evolution over Space and Time (DEST): A New Population Genomics Resource
Authors: Martin Kapun, Joaquin C B Nunez, María Bogaerts-Márquez, Jesús Murga-Moreno, Margot Paris, Joseph Outten, Marta Coronado-Zamora, Courtney Tern, Omar Rota-Stabelli, Maria P García Guerreiro, Sònia Casillas, Dorcas J Orengo, Eva Puerma, Maaria Kankare, Lino Ometto, Volker Loeschcke, Banu S Onder, Jessica K Abbott, Stephen W Schaeffer, Subhash Rajpurohit, Emily L Behrman, Mads F Schou, Thomas J S Merritt, Brian P Lazzaro, Amanda Glaser-Schmitt, Eliza Argyridou, Fabian Staubach, Yun Wang, Eran Tauber, Svitlana V Serga, Daniel K Fabian, Kelly A Dyer, Christopher W Wheat, John Parsch, Sonja Grath, Marija Savic Veselinovic, Marina Stamenkovic-Radak, Mihailo Jelic, Antonio J Buendía-Ruíz, Maria Josefa Gómez-Julián, Maria Luisa Espinosa-Jimenez, Francisco D Gallardo-Jiménez, Aleksandra Patenkovic, Katarina Eric, Marija Tanaskovic, Anna Ullastres, Lain Guio, Miriam Merenciano, Sara Guirao-Rico, Vivien Horváth, Darren J Obbard, Elena Pasyukova, Vladimir E Alatortsev, Cristina P Vieira, Jorge Vieira, Jorge Roberto Torres, Iryna Kozeretska, Oleksandr M Maistrenko, Catherine Montchamp-Moreau, Dmitry V Mukha, Heather E Machado, Keric Lamb, Tânia Paulo, Leeban Yusuf, Antonio Barbadilla, Dmitri Petrov, Paul Schmidt, Josefa Gonzalez, Thomas Flatt, Alan O Bergland
Journal: Molecular Biology and Evolution (2021)

Abstract Drosophila melanogaster is a leading model in population genetics and genomics, and a growing number of whole-genome data sets from natural populations of this species have been published over the last years. A major challenge is the integration of disparate data sets, often generated using different sequencing technologies and bioinformatic pipelines, which hampers our ability to address questions about the evolution of this species. Here we address these issues by developing a bioinformatics pipeline that maps pooled sequencing (Pool-Seq) reads from D. melanogaster to a hologenome consisting of fly and symbiont genomes and estimates allele frequencies using either a heuristic (PoolSNP) or a probabilistic variant caller (SNAPE-pooled). We use this pipeline to generate the largest data repository of genomic data available for D. melanogaster to date, encompassing 271 previously published and unpublished population samples from over 100 locations in &amp;gt;20 countries on four continents. Several of these locations have been sampled at different seasons across multiple years. This data set, which we call Drosophila Evolution over Space and Time (DEST), is coupled with sampling and environmental metadata. A web-based genome browser and web portal provide easy access to the SNP data set. We further provide guidelines on how to use Pool-Seq data for model-based demographic inference. Our aim is to provide this scalable platform as a community resource which can be easily extended via future efforts for an even more extensive cosmopolitan data set. Our resource will enable population geneticists to analyze spatiotemporal genetic patterns and evolutionary dynamics of D. melanogaster populations in unprecedented detail.
Computer-aided X-ray screening for tuberculosis and HIV testing among adults with cough in Malawi (the PROSPECT study): A randomised trial and cost-effectiveness analysis
Authors: Peter MacPherson, Emily L. Webb, Wala Kamchedzera, Elizabeth Joekes, Gugu Mjoli, David G. Lalloo, Titus H. Divala, Augustine T. Choko, Rachael M. Burke, Hendramoorthy Maheswaran, Madhukar Pai, S. Bertel Squire, Marriott Nliwasa, Elizabeth L. Corbett
Journal: PLoS Medicine (2021)

Suboptimal tuberculosis (TB) diagnostics and HIV contribute to the high global burden of TB. We investigated costs and yield from systematic HIV-TB screening, including computer-aided digital chest X-ray (DCXR-CAD).In this open, three-arm randomised trial, adults (≥18 years) with cough attending acute primary services in Malawi were randomised (1:1:1) to standard of care (SOC); oral HIV testing (HIV screening) and linkage to care; or HIV testing and linkage to care plus DCXR-CAD with sputum Xpert for high CAD4TBv5 scores (HIV-TB screening). Participants and study staff were not blinded to intervention allocation, but investigator blinding was maintained until final analysis. The primary outcome was time to TB treatment. Secondary outcomes included proportion with same-day TB treatment; prevalence of undiagnosed/untreated bacteriologically confirmed TB on day 56; and undiagnosed/untreated HIV. Analysis was done on an intention-to-treat basis. Cost-effectiveness analysis used a health-provider perspective. Between 15 November 2018 and 27 November 2019, 8,236 were screened for eligibility, with 473, 492, and 497 randomly allocated to SOC, HIV, and HIV-TB screening arms; 53 (11%), 52 (9%), and 47 (9%) were lost to follow-up, respectively. At 56 days, TB treatment had been started in 5 (1.1%) SOC, 8 (1.6%) HIV screening, and 15 (3.0%) HIV-TB screening participants. Median (IQR) time to TB treatment was 11 (6.5 to 38), 6 (1 to 22), and 1 (0 to 3) days (hazard ratio for HIV-TB versus SOC: 2.86, 1.04 to 7.87), with same-day treatment of 0/5 (0%) SOC, 1/8 (12.5%) HIV, and 6/15 (40.0%) HIV-TB screening arm TB patients (p = 0.03). At day 56, 2 SOC (0.5%), 4 HIV (1.0%), and 2 HIV-TB (0.5%) participants had undiagnosed microbiologically confirmed TB. HIV screening reduced the proportion with undiagnosed or untreated HIV from 10 (2.7%) in the SOC arm to 2 (0.5%) in the HIV screening arm (risk ratio [RR]: 0.18, 0.04 to 0.83), and 1 (0.2%) in the HIV-TB screening arm (RR: 0.09, 0.01 to 0.71). Incremental costs were US$3.58 and US$19.92 per participant screened for HIV and HIV-TB; the probability of cost-effectiveness at a US$1,200/quality-adjusted life year (QALY) threshold was 83.9% and 0%. Main limitations were the lower than anticipated prevalence of TB and short participant follow-up period; cost and quality of life benefits of this screening approach may accrue over a longer time horizon.DCXR-CAD with universal HIV screening significantly increased the timeliness and completeness of HIV and TB diagnosis. If implemented at scale, this has potential to rapidly and efficiently improve TB and HIV diagnosis and treatment.clinicaltrials.gov NCT03519425.
Effect of Salt Substitution on Cardiovascular Events and Death
Authors: Bruce Neal, Yangfeng Wu, Xiangxian Feng, Ruijuan Zhang, Yuhong Zhang, Jingpu Shi, Jianxin Zhang, Maoyi Tian, Liping Huang, Zhifang Li, Yan Yu, Yi Zhao, Bo Zhou, Jixin Sun, Yishu Liu, Xuejun Yin, Zhixin Hao, Jie Yu, Ka-Chun Li, Xinyi Zhang, Peifen Duan, Faxuan Wang, Bing Ma, Weiwei Shi, Gian Luca Di Tanna, Sandrine Stepien, Sana Shan, Sallie-Anne Pearson, Nicole Li, Lijing L. Yan, Darwin Labarthe, Paul Elliott
Journal: New England Journal of Medicine (2021)

Salt substitutes with reduced sodium levels and increased potassium levels have been shown to lower blood pressure, but their effects on cardiovascular and safety outcomes are uncertain.
Amoxicillin Rash in Infectious Mononucleosis
Authors: Anaas Moncef Mergoum
Journal: New England Journal of Medicine (2021)

A 7-year-old girl presented with an itchy rash after 1 week of treatment with amoxicillin for pharyngitis. She had erythematous papules and macules on her face, trunk, arms, and legs. The result of a mononuclear spot test was positive, and a diagnosis of amoxicillin rash in infectious mononucleosis was made.
Endoscopic full-thickness resection of T1 colorectal cancers: a retrospective analysis from a multicenter Dutch eFTR registry
Authors: Liselotte W. Zwager, Barbara A. J. Bastiaansen, Bas W. van der Spek, Dimitri N. Heine, Ramon M. Schreuder, Lars E. Perk, Bas L. A. M. Weusten, Jurjen J. Boonstra, Hedwig van der Sluis, Hugo J. Wolters, Frank C. Bekkering, Svend T. Rietdijk, Matthijs P. Schwartz, Wouter B. Nagengast, W. Rogier ten Hove, Jochim S. Terhaar sive Droste, Francisco J. Rando Munoz, Marije S. Vlug, Hanneke Beaumont, Martin H. M. G. Houben, Tom C. J. Seerden, Thomas R. de Wijkerslooth, Eric A. R. Gielisse, Yark Hazewinkel, Rogier de Ridder, Jan-Willem A. Straathof, Manon van der Vlugt, Lianne Koens, Paul Fockens, Evelien Dekker
Journal: Endoscopy (2021)

Complete endoscopic resection and accurate histological evaluation for T1 colorectal cancer (CRC) are critical in determining subsequent treatment. Endoscopic full-thickness resection (eFTR) is a new treatment option for T1 CRC < 2 cm. We aimed to report clinical outcomes and short-term results.Consecutive eFTR procedures for T1 CRC, prospectively recorded in our national registry between November 2015 and April 2020, were retrospectively analyzed. Primary outcomes were technical success and R0 resection. Secondary outcomes were histological risk assessment, curative resection, adverse events, and short-term outcomes.We included 330 procedures: 132 primary resections and 198 secondary scar resections after incomplete T1 CRC resection. Overall technical success, R0 resection, and curative resection rates were 87.0 % (95 % confidence interval [CI] 82.7 %-90.3 %), 85.6 % (95 %CI 81.2 %-89.2 %), and 60.3 % (95 %CI 54.7 %-65.7 %). Curative resection rate was 23.7 % (95 %CI 15.9 %-33.6 %) for primary resection of T1 CRC and 60.8 % (95 %CI 50.4 %-70.4 %) after excluding deep submucosal invasion as a risk factor. Risk stratification was possible in 99.3 %. The severe adverse event rate was 2.2 %. Additional oncological surgery was performed in 49/320 (15.3 %), with residual cancer in 11/49 (22.4 %). Endoscopic follow-up was available in 200/242 (82.6 %), with a median of 4 months and residual cancer in 1 (0.5 %) following an incomplete resection.eFTR is relatively safe and effective for resection of small T1 CRC, both as primary and secondary treatment. eFTR can expand endoscopic treatment options for T1 CRC and could help to reduce surgical overtreatment. Future studies should focus on long-term outcomes.
A novel inhibitor of N6-methyladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities
Authors: Guoyou Xie, Xu-Nian Wu, Yuyi Ling, Yalan Rui, Deyan Wu, Jiawang Zhou, Jiexin Li, Shuibin Lin, Qin Peng, Zigang Li, Hongsheng Wang, Hai-Bin Luo
Journal: Acta Pharmaceutica Sinica B (2021)

N6-methyladenosine (m6A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m6A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m6A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPβ. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.