tbuckley/cabot-search huggingface dataset:
Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation
Authors: Stephan R. Künzel, Maximilian Hoffmann, Silvio Weber, Karolina Künzel, Susanne Kämmerer, Mario Günscht, Erik Klapproth, Johanna S.E. Rausch, Mirna S. Sadek, Tomasz Kolanowski, Stefanie Meyer-Roxlau, Christopher Piorkowski, Sems M. Tugtekin, Stefan Rose-John, Xiaoke Yin, Manuel Mayr, Jan Dominik Kuhlmann, Pauline Wimberger, Konrad Grützmann, Natalie Herzog, Jan-Heiner Küpper, Molly O’Reilly, S. Nashitha Kabir, Laura C. Sommerfeld, Kaomei Guan, Ben Wielockx, Larissa Fabritz, Stanley Nattel, Ursula Ravens, Dobromir Dobrev, Michael Wagner, Ali El-Armouche
Journal: Circulation Research (2021)

Rationale: Fibrosis promotes the maintenance of atrial fibrillation (AF), making it resistant to therapy. Improved understanding of the molecular mechanisms leading to atrial fibrosis will open new pathways toward effective antifibrotic therapies. Objective: This study aims to decipher the mechanistic interplay between PLK2 (polo-like kinase 2) and the profibrotic cytokine OPN (osteopontin) in the pathogenesis of atrial fibrosis and AF. Methods and Results: Atrial PLK2 mRNA expression was 10-fold higher in human fibroblasts than in cardiomyocytes. Compared with sinus rhythm, right atrial appendages and isolated right atrial fibroblasts from patients with AF showed downregulation of PLK2 mRNA and protein, along with increased PLK2 promotor methylation. Genetic deletion as well as pharmacological inhibition of PLK2 induced profibrotic phenotype conversion in cardiac fibroblasts and led to a striking de novo secretion of OPN. Accordingly, PLK2-deficient (PLK2 knockout) mice showed cardiac fibrosis and were prone to experimentally induced AF. In line with these findings, OPN plasma levels were significantly higher only in patients with AF with atrial low-voltage zones (surrogates of fibrosis) compared with sinus rhythm controls. Mechanistically, we identified ERK1/2 as the relevant downstream mediator of PLK2 leading to increased OPN expression. Finally, oral treatment with the clinically available drug mesalazine, known to inhibit ERK1/2, prevented cardiac OPN overexpression and reversed the pathological PLK2 knockout phenotype in PLK2 knockout mice. Conclusions: Abnormal PLK2/ERK1/2/OPN axis function critically contributes to AF-related atrial fibrosis, suggesting reinforcing PLK2 activity and/or OPN inhibition as innovative targets to prevent fibrosis progression in AF. Mesalazine derivatives may be used as lead compounds for the development of novel anti-AF agents targeting fibrosis.
New insights on ocular surface disease in patients with atopic dermatitis treated with dupilumab
Authors: P. Bortoluzzi, S. Ferrucci, D. Galimberti, F. Garavelli, F. Pozzo Giuffrida, A. Pizzati, A.V. Marzano, C. Mapelli
Journal: British Journal of Dermatology (2021)

Our study sought to describe ocular surface alterations at baseline and after 4 months of dupilumab treatment in patients with severe AD. Our findings highlight that all 25 patients showed ocular surface alterations prior to dupilumab treatment. Dupilumab may cause the worsening of clinical or subclinical pre-existing ocular alterations belonging to the spectrum of AKC.
Sentinel Lymph Node Biopsy in Cutaneous Melanoma—Where Do We Stand?
Authors: Michael A. Marchetti, Edmund K. Bartlett
Journal: JAMA Dermatology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Pretomanid for tuberculosis: a systematic review
Authors: Tinne Gils, Lutgarde Lynen, Bouke C. de Jong, Armand Van Deun, Tom Decroo
Journal: Clinical Microbiology and Infection (2021)

BackgroundOutcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed.ObjectivesTo appraise existing evidence on efficacy and safety of pretomanid in tuberculosis.Data SourcesPubmed, clinicaltrials.gov. and Cochrane library.Study eligibility criteriaQuantitative studies presenting original data on clinical efficacy or safety of pretomanid.ParticipantsPatients with tuberculosis.InterventionsTreatment with pretomanid or pretomanid-containing regimens in minimum one study group.MethodsTwo authors independently extracted data and assessed risk of bias. Data on efficacy (early bactericidal activity, bactericidal activity, end-of-treatment outcomes and acquired resistance) and safety were summarized in tables. Mean differences in efficacy outcomes between regimens across studies were calculated.ResultsEight studies were included; four randomized controlled trials on 2-week early bactericidal activity in rifampicin-susceptible tuberculosis, three trials with randomized rifampicin-susceptible tuberculosis arms and a single rifampicin-resistant tuberculosis arm (two on 8-week bactericidal activity, one on end-of-treatment outcomes), one single-arm trial with end-of-treatment outcomes in highly resistant tuberculosis. Activity of pretomanid–moxifloxacin–pyrazinamide was superior to standard treatment on daily change in colony-forming units at days 0–2, 0–56 and 7–56 and time to culture conversion in rifampicin-susceptible tuberculosis (hazard ratio: 1.7; 95% CI 1.1–2.7), but not at end of treatment in one study. This study was stopped due to serious hepatotoxic adverse events, including three deaths, in 4% (95% CI 2–8) patients on pretomanid–moxifloxacin–pyrazinamide and none in controls. In patients with uncomplicated rifampicin-resistant tuberculosis on pretomanid-moxifloxacin-pyrazinamide treatment, 91% (95% CI 59–100) had favourable end-of-treatment outcomes. In patients with highly resistant tuberculosis, 90% (95% CI 83–95) on pretomanid–bedaquiline–linezolid had favourable outcomes six months after treatment, but linezolid-related toxicity was frequent. No acquired resistance to pretomanid was reported.ConclusionsEvidence suggests an important role for pretomanid in rifampicin-resistant and highly resistant tuberculosis. Trials comparing pretomanid to existing core and companion drugs are needed to further define that role.
Navigating the Benefits and Pitfalls of Online Psychiatric Data Collection
Authors: Brittany Quagan, Scott W. Woods, Albert R. Powers
Journal: JAMA Psychiatry (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Activation of Hypothalamic <scp>AMP‐Activated</scp> Protein Kinase Ameliorates Metabolic Complications of Experimental Arthritis
Authors: Patricia Seoane‐Collazo, Eva Rial‐Pensado, Ánxela Estévez‐Salguero, Edward Milbank, Lucía García‐Caballero, Marcos Ríos, Laura Liñares‐Pose, Morena Scotece, Rosalía Gallego, José Manuel Fernández‐Real, Rubén Nogueiras, Carlos Diéguez, Oreste Gualillo, Miguel López
Journal: Arthritis & Rheumatology (2021)

Objective To investigate whether thermogenesis and the hypothalamus may be involved in the physiopathology of experimental arthritis (EA). Methods EA was induced in male Lewis rats by intradermal injection of Freund's complete adjuvant (CFA). Food intake, body weight, plasma cytokines, thermographic analysis, gene and protein expression of thermogenic markers in brown adipose tissue (BAT) and white adipose tissue (WAT), and hypothalamic AMP‐activated protein kinase (AMPK) were analyzed. Virogenetic activation of hypothalamic AMPK was performed. Results We first demonstrated that EA was associated with increased BAT thermogenesis and browning of subcutaneous WAT leading to elevated energy expenditure. Moreover, rats experiencing EA showed inhibition of hypothalamic AMPK, a canonical energy sensor modulating energy homeostasis at the central level. Notably, specific genetic activation of AMPK in the ventromedial nucleus of the hypothalamus (a key site modulating energy metabolism) reversed the effect of EA on energy balance, brown fat, and browning, as well as promoting amelioration of synovial inflammation in experimental arthritis. Conclusion Overall, these data indicate that EA promotes a central catabolic state that can be targeted and reversed by the activation of hypothalamic AMPK. This might provide new therapeutic alternatives to treat rheumatoid arthritis (RA)–associated metabolic comorbidities, improving the overall prognosis in patients with RA.
Incidence and mortality rates of intracranial hemorrhage in hemophilia: a systematic review and meta-analysis
Authors: Anne-Fleur Zwagemaker, Samantha C. Gouw, Julie S. Jansen, Caroline Vuong, Michiel Coppens, Qun Hu, Xiaoqin Feng, Soon K. Kim, Johanna G. Van der Bom, Karin Fijnvandraat
Journal: Blood (2021)
The global burden of fractures
Authors: Jane A Cauley
Journal: The Lancet Healthy Longevity (2021)

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is a systematic scientific effort to quantify the comparative magnitude of health loss due to disease, injury, and risk factors by age, sex, and geographical region.1 In The Lancet Healthy Longevity, the GBD Collaborator Network describes for the first time the absolute number of new and prevalent fractures, the incidence and prevalence rate of fractures, and the number of years lived with disability (YLDs) after fractures from 1990 to 2019.
Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial
Authors: Jorge Cortes, Jane Apperley, Elza Lomaia, Beatriz Moiraghi, Maria Undurraga Sutton, Carolina Pavlovsky, Charles Chuah, Tomasz Sacha, Jeffrey H. Lipton, Charles A. Schiffer, James McCloskey, Andreas Hochhaus, Philippe Rousselot, Gianantonio Rosti, Hugues de Lavallade, Anna Turkina, Christine Rojas, Christopher Kevin Arthur, Lori Maness, Moshe Talpaz, Michael Mauro, Tracey Hall, Vickie Lu, Shouryadeep Srivastava, Michael Deininger
Journal: Blood (2021)
27523 Integrated safety analysis of abrocitinib for the treatment of moderate-to-severe atopic dermatitis (AD) from the phase 2 and phase 3 clinical trial program
Authors: Eric L. Simpson, Jonathan I. Silverberg, Audrey Nosbaum, Kevin Winthrop, Emma Guttman-Yassky, Karin M. Hoffmeister, Min Zhang, Saleem A. Farooqui, Susan Johnson, Andrew Thorpe, Ricardo Rojo
Journal: Journal of the American Academy of Dermatology (2021)
Assessing Clinical Readiness
Authors: Eric A. Elster, Mark W. Bowyer, M. Margaret Knudson
Journal: JAMA Surgery (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Inhibiting Fatty Acid Synthase with Omeprazole to Improve Efficacy of Neoadjuvant Chemotherapy in Patients with Operable TNBC
Authors: Sagar D. Sardesai, Alexandra Thomas, Christopher Gallagher, Filipa Lynce, Yvonne Lynn Ottaviano, Tarah Jean Ballinger, Bryan P. Schneider, Anna Maria Storniolo, Amber Bauchle, Sandra K. Althouse, Susan M. Perkins, Andrea R. Masters, Robert E. Stratford, Zizheng Dong, Jing-Yuan Liu, Jian-Ting Zhang, Kathy D. Miller
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Fatty acid synthase (FASN) is overexpressed in 70% of operable triple-negative breast cancer (TNBC) and is associated with poor prognosis. Proton pump inhibitors selectively inhibit FASN activity and induce apoptosis in TNBC cell lines. Patients and Methods: Patients with operable TNBC were enrolled in this single-arm phase II study. Patients began omeprazole 80 mg orally twice daily for 4–7 days prior to neoadjuvant anthracycline–taxane-based chemotherapy (AC-T) and continued until surgery. The primary endpoint was pathologic complete response (pCR) in patients with baseline FASN overexpression (FASN+). Secondary endpoints included pCR in all surgery patients, change in FASN expression, enzyme activity, and downstream protein expression after omeprazole monotherapy, safety, and limited omeprazole pharmacokinetics. Results: Forty-two patients were recruited with a median age of 51 years (28–72). Most patients had ≥cT2 (33, 79%) and ≥N1 (22, 52%) disease. FASN overexpression prior to AC-T was identified in 29 of 34 (85%) evaluable samples. The pCR rate was 72.4% [95% confidence interval (CI), 52.8–87.3] in FASN+ patients and 74.4% (95% CI, 57.9–87.0) in all surgery patients. Peak omeprazole concentration was significantly higher than the IC50 for FASN inhibition observed in preclinical testing; FASN expression significantly decreased with omeprazole monotherapy [mean change 0.12 (SD, 0.25); P = 0.02]. Omeprazole was well tolerated with no grade ≥ 3 toxicities. Conclusions: FASN is commonly expressed in early TNBC. Omeprazole can be safely administered in doses that inhibit FASN. The addition of omeprazole to neoadjuvant AC-T yields a promising pCR rate that needs further confirmation in randomized studies.
Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival
Authors: Mario Mandalá, James Larkin, Paolo A Ascierto, Michele Del Vecchio, Helen Gogas, C Lance Cowey, Ana Arance, Stéphane Dalle, Michael Schenker, Jean-Jacques Grob, Vanna Chiarion-Sileni, Ivan Marquez-Rodas, Marcus O Butler, Anna Maria Di Giacomo, Jose Lutzky, Luis De La Cruz-Merino, Victoria Atkinson, Petr Arenberger, Andrew Hill, Leslie Fecher, Michael Millward, Nikhil I Khushalani, Veerle de Pril, Maurice Lobo, Jeffrey Weber
Journal: Journal for ImmunoTherapy of Cancer (2021)

Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial.Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups.From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm.Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident.NCT02388906.
Re: Rachel M. Glicksman, Ur Metser, Douglass Vines, et al. Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis. Eur Urol 2021;80:374–82
Authors: Wei Liu, Katherine Zukotynski, Glenn Bauman
Journal: European Urology (2021)
Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer
Authors: Elahe A. Mostaghel, Brett T. Marck, Orpheus Kolokythas, Felix Chew, Evan Y. Yu, Michael T. Schweizer, Heather H. Cheng, Phillip W. Kantoff, Steven P. Balk, Mary-Ellen Taplin, Nima Sharifi, Alvin M. Matsumoto, Peter S. Nelson, R. Bruce Montgomery
Journal: Clinical Cancer Research (2021)

In metastatic castration-resistant prostate cancer (mCRPC) low serum androgens prior to starting abiraterone acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in castration-resistant prostate cancer (CRPC) metastases and associations of intratumoral androgens with response.
DURATION OF DISEASE CONTROL (DDC) OR TIME TO FAILURE OF STRATEGY (TFS) TO EVALUATE A CHEMOTHERAPY STRATEGY IN ADVANCED COLORECTAL CANCER (ACC)
Authors: Chibaudel B, Tournigand C, Perez-Staub N, Bourges O, Maindrault-Goebel F, Andre T, Lledo G, Louvet C, Bonnetain F, De Gramont A
Journal: Annals of Oncology (2009)
The Interleukin‐1 Receptor–Associated Kinase 4 Inhibitor PF‐06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial
Authors: Aaron Winkler, Weiyong Sun, Saurav De, Aiping Jiao, M. Nusrat Sharif, Peter T. Symanowicz, Shruti Athale, Julia H. Shin, Ju Wang, Bruce A. Jacobson, Simeon J. Ramsey, Ken Dower, Tatyana Andreyeva, Heng Liu, Martin Hegen, Bruce L. Homer, Joanne Brodfuehrer, Mera Tilley, Steven A. Gilbert, Spencer I. Danto, Jean J. Beebe, Betsy J. Barnes, Virginia Pascual, Lih‐Ling Lin, Iain Kilty, Margaret Fleming, Vikram R. Rao
Journal: Arthritis & Rheumatology (2021)

To investigate the role of PF-06650833, a highly potent and selective small-molecule inhibitor of interleukin-1-associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting.Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti-citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast-like synoviocyte (FLS) cultures stimulated with Toll-like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs. PF-06650833 was evaluated in vivo in the rat collagen-induced arthritis (CIA) model and the mouse pristane-induced and MRL/lpr models of lupus. Finally, RNA sequencing data generated with whole blood samples from a phase I multiple-ascending-dose clinical trial of PF-06650833 were used to test in vivo human pharmacology.In vitro, PF-06650833 inhibited human primary cell inflammatory responses to physiologically relevant stimuli generated with RA and SLE patient plasma. In vivo, PF-06650833 reduced circulating autoantibody levels in the pristane-induced and MRL/lpr murine models of lupus and protected against CIA in rats. In a phase I clinical trial (NCT02485769), PF-06650833 demonstrated in vivo pharmacologic action pertinent to SLE by reducing whole blood interferon gene signature expression in healthy volunteers.These data demonstrate that inhibition of IRAK4 kinase activity can reduce levels of inflammation markers in humans and provide confidence in the rationale for clinical development of IRAK4 inhibitors for rheumatologic indications.
Persistent SARS-CoV-2 infection: the urgent need for access to treatment and trials
Authors: Ed Moran, Tim Cook, Anna L Goodman, Ravindra K Gupta, Stephen Jolles, David K Menon, David J Roberts, Sinisa Savic, Manu Shankar-Hari, Michael Brown, David M Lowe
Journal: The Lancet Infectious Diseases (2021)
25094 Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study
Authors: Hidemi Nakagawa, Osamu Nemoto, Atsuyuki Igarashi, Hidehisa Saeki, Kenji Kabashima, Manabu Oda, Takeshi Nagata
Journal: Journal of the American Academy of Dermatology (2021)