tbuckley/cabot-search huggingface dataset:
Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders
Authors: Julie C. Ullman, Kevin T. Mellem, Yannan Xi, Vyas Ramanan, Hanne Merritt, Rebeca Choy, Tarunmeet Gujral, Lyndsay E.A. Young, Kerrigan Blake, Samnang Tep, Julian R. Homburger, Adam O’Regan, Sandya Ganesh, Perryn Wong, Terrence F. Satterfield, Baiwei Lin, Eva Situ, Cecile Yu, Bryan Espanol, Richa Sarwaikar, Nathan Fastman, Christos Tzitzilonis, Patrick Lee, Daniel Reiton, Vivian Morton, Pam Santiago, Walter Won, Hannah Powers, Beryl B. Cummings, Maarten Hoek, Robert R. Graham, Sanjay J. Chandriani, Russell Bainer, Anna A. DePaoli-Roach, Peter J. Roach, Thomas D. Hurley, Ramon C. Sun, Matthew S. Gentry, Christopher Sinz, Ryan A. Dick, Sarah B. Noonberg, David T. Beattie, David J. Morgans Jr., Eric M. Green
Journal: Science Translational Medicine (2024)

Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.
Azithromycin during Routine Well-Infant Visits to Prevent Death
Authors: Ali Sié, Mamadou Ouattara, Mamadou Bountogo, Valentin Boudo, Thierry Ouedraogo, Guillaume Compaoré, Clarisse Dah, Cheik Bagagnan, Elodie Lebas, Huiyu Hu, Jessica Rice, Travis C Porco, Benjamin F Arnold, Thomas M Lietman, Catherine E Oldenburg
Journal: New England Journal of Medicine (2024)

BackgroundMass distribution of azithromycin to children 1 to 59 months of age has been shown to reduce childhood all-cause mortality in some sub-Saharan African regions, with the largest reduction seen among infants younger than 12 months of age. Whether the administration of azithromycin at routine health care visits for infants would be effective in preventing death is unclear.MethodsWe conducted a randomized, placebo-controlled trial of a single dose of azithromycin (20 mg per kilogram of body weight) as compared with placebo, administered during infancy (5 to 12 weeks of age). The primary end point was death before 6 months of age. Infants were recruited at routine vaccination or other well-child visits in clinics and through community outreach in three regions of Burkina Faso. Vital status was assessed at 6 months of age.Download a PDF of the Research Summary.ResultsOf the 32,877 infants enrolled from September 2019 through October 2022, a total of 16,416 infants were randomly assigned to azithromycin and 16,461 to placebo. Eighty-two infants in the azithromycin group and 75 infants in the placebo group died before 6 months of age (hazard ratio, 1.09; 95% confidence interval [CI], 0.80 to 1.49; P=0.58); the absolute difference in mortality was 0.04 percentage points (95% CI, −0.10 to 0.21). There was no evidence of an effect of azithromycin on mortality in any of the prespecified subgroups, including subgroups defined according to age, sex, and baseline weight, and no evidence of a difference between the two trial groups in the incidence of adverse events.ConclusionsIn this trial conducted in Burkina Faso, we found that administration of azithromycin to infants through the existing health care system did not prevent death. (Funded by the Bill and Melinda Gates Foundation; CHAT ClinicalTrials.gov number, NCT03676764.) Quick Take Azithromycin during Well-Infant Visits to Prevent Death 2m 2s
Long-Term Outcomes of Resynchronization–Defibrillation for Heart Failure
Authors: John L Sapp, Soori Sivakumaran, Calum J Redpath, Habib Khan, Ratika Parkash, Derek V Exner, Jeff S Healey, Bernard Thibault, Laurence D Sterns, Nhat Hung N Lam, Jaimie Manlucu, Ahmed Mokhtar, Glen Sumner, Stuart McKinlay, Shane Kimber, Blandine Mondesert, Mario Talajic, Jean Rouleau, C Elizabeth McCarron, George Wells, Anthony S L Tang
Journal: New England Journal of Medicine (2024)

BackgroundThe Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) showed a greater benefit with respect to mortality at 5 years among patients who received cardiac-resynchronization therapy (CRT) than among those who received implantable cardioverter–defibrillators (ICDs). However, the effect of CRT on long-term survival is not known.MethodsWe randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more (or a paced QRS duration of 200 msec or more) to receive either an ICD alone or a CRT defibrillator (CRT-D). We assessed long-term outcomes among patients at the eight highest-enrolling participating sites. The primary outcome was death from any cause; the secondary outcome was a composite of death from any cause, heart transplantation, or implantation of a ventricular assist device.Download a PDF of the Research Summary.ResultsThe trial enrolled 1798 patients, of whom 1050 were included in the long-term survival trial; the median duration of follow-up for the 1050 patients was 7.7 years (interquartile range, 3.9 to 12.8), and the median duration of follow-up for those who survived was 13.9 years (interquartile range, 12.8 to 15.7). Death occurred in 405 of 530 patients (76.4%) assigned to the ICD group and in 370 of 520 patients (71.2%) assigned to the CRT-D group. The time until death appeared to be longer for those assigned to receive a CRT-D than for those assigned to receive an ICD (acceleration factor, 0.80; 95% confidence interval, 0.69 to 0.92; P=0.002). A secondary-outcome event occurred in 412 patients (77.7%) in the ICD group and in 392 (75.4%) in the CRT-D group.ConclusionsAmong patients with a reduced ejection fraction, a widened QRS complex, and NYHA class II or III heart failure, the survival benefit associated with receipt of a CRT-D as compared with ICD appeared to be sustained during a median of nearly 14 years of follow-up. (RAFT ClinicalTrials.gov number, NCT00251251.) Quick Take Resynchronization–Defibrillation for Heart Failure 2m 16s
Seeking More Time with Synchrony
Authors: Lynne Warner Stevenson, Jay A. Montgomery
Journal: New England Journal of Medicine (2024)

Clinical outcomes for patients who have heart failure with reduced ejection fraction continue to improve with the selection of effective therapies and their increasing duration of use. Randomized, controlled trials usually measure the efficacy of a therapy for a limited time, after which its longer-term efficacy is blurred by the crossover of patients to the active treatment after the trial has been completed. If a therapy is tested in patients who have advanced heart failure, its benefits may soon be obvious during the trial. However, earlier initiation of therapy, before symptoms of heart failure have become severe, may have a . . .
Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19
Authors: Bin Cao, Yeming Wang, Hongzhou Lu, Chaolin Huang, Yumei Yang, Lianhan Shang, Zhu Chen, Rongmeng Jiang, Yihe Liu, Ling Lin, Ping Peng, Fuxiang Wang, Fengyun Gong, Honglin Hu, Cong Cheng, Xiangyang Yao, Xianwei Ye, Hourong Zhou, Yinzhong Shen, Chenfan Liu, Chunying Wang, Zhennan Yi, Bijie Hu, Jiuyang Xu, Xiaoying Gu, Jingshan Shen, Yechun Xu, Leike Zhang, Jia Fan, Renhong Tang, Chen Wang
Journal: New England Journal of Medicine (2024)

BackgroundSimnotrelvir is an oral 3-chymotrypsin–like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial.MethodsIn this phase 2–3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19–related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed.ResultsA total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, −35.8 hours [95% CI, −60.1 to −12.4]; P=0.006 by Peto–Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], −1.51±0.14 log10 copies per milliliter; 95% CI, −1.79 to −1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate.ConclusionsEarly administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.)
JAK Inhibition in STAT1 Gain-of-Function–Mediated Treatment-Resistant Autoimmune Hepatitis
Authors: Nedim Hadžić, Maesha Deheragoda, Austen Worth, Sanjay Bansal, Marianne Samyn, Maaike Kusters
Journal: New England Journal of Medicine (2024)

Autoimmune hepatitis has a complex pathogenesis. Treatment-resistant cases may benefit from genetic analysis and more targeted immune treatments.
Efficacy and safety of an early oral switch in low-risk Staphylococcus aureus bloodstream infection (SABATO): an international, open-label, parallel-group, randomised, controlled, non-inferiority trial
Authors: Achim J Kaasch, Luis Eduardo López-Cortés, Jesús Rodríguez-Baño, José Miguel Cisneros, M Dolores Navarro, Gerd Fätkenheuer, Norma Jung, Siegbert Rieg, Raphaël Lepeule, Laetitia Coutte, Louis Bernard, Adrien Lemaignen, Katrin Kösters, Colin R MacKenzie, Alex Soriano, Stefan Hagel, Bruno Fantin, Matthieu Lafaurie, Jean-Philippe Talarmin, Aurélien Dinh, Thomas Guimard, David Boutoille, Tobias Welte, Stefan Reuter, Jan Kluytmans, Maria Luisa Martin, Emmanuel Forestier, Hartmut Stocker, Virginie Vitrat, Pierre Tattevin, Anna Rommerskirchen, Marion Noret, Anne Adams, Winfried V Kern, Martin Hellmich, Harald Seifert, Adoración Valiente, Marina de Cueto, Ángel Rodríguez, José Molina, Julia Fischer, Gregor Paul, Sébastien Gallien, Vincent Fihman, Marion Lacasse, Francois Coustillères, Christian Becker, André Fuchs, Laura Morata, Sebastian Weis, Diane Ponscarme, Lydie Khatchatourian, Elisabeth Rouveix, Dominique Merrien, Raphaël Lecomte, Jacobien Veenemans, Helem H. Vilchez, Johanna Kessel, Marc J.M. Bonten, Jan Rupp, Laurent Hocqueloux, Frederic Lucht, Jean-Paul Stahl, Anne Vlek, Reinhild Prinz-Langenohl, Violaine Tolsma
Journal: The Lancet Infectious Diseases (2024)
Oral bacteria accelerate pancreatic cancer development in mice
Authors: Elias Saba, Maria Farhat, Alaa Daoud, Arin Khashan, Esther Forkush, Noam Hallel Menahem, Hasnaa Makkawi, Karthikeyan Pandi, Sarah Angabo, Hiromichi Kawasaki, Inbar Plaschkes, Oren Parnas, Gideon Zamir, Karine Atlan, Michael Elkin, Lior Katz, Gabriel Nussbaum
Journal: Gut (2024)

Objective Epidemiological studies highlight an association between pancreatic ductal adenocarcinoma (PDAC) and oral carriage of the anaerobic bacterium Porphyromonas gingivalis , a species highly linked to periodontal disease. We analysed the potential for P. gingivalis to promote pancreatic cancer development in an animal model and probed underlying mechanisms. Design We tracked P. gingivalis bacterial translocation from the oral cavity to the pancreas following administration to mice. To dissect the role of P. gingivalis in PDAC development, we administered bacteria to a genetically engineered mouse PDAC model consisting of inducible acinar cell expression of mutant Kras ( Kras + /LSL-G12D; Ptf1a-CreER, iKC mice). These mice were used to study the cooperative effects of Kras mutation and P. gingivalis on the progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. The direct effects of P. gingivalis on acinar cells and PDAC cell lines were studied in vitro. Results P. gingivalis migrated from the oral cavity to the pancreas in mice and can be detected in human PanIN lesions. Repetitive P. gingivalis administration to wild-type mice induced pancreatic acinar-to-ductal metaplasia (ADM), and altered the composition of the intrapancreatic microbiome. In iKC mice, P. gingivalis accelerated PanIN to PDAC progression. In vitro, P. gingivalis infection induced acinar cell ADM markers SOX9 and CK19, and intracellular bacteria protected PDAC cells from reactive oxygen species-mediated cell death resulting from nutrient stress. Conclusion Taken together, our findings demonstrate a causal role for P. gingivalis in pancreatic cancer development in mice.
Can rheumatologists unequivocally diagnose axial spondyloarthritis in patients with chronic back pain of less than 2 years duration? Primary outcome of the 2-year SPondyloArthritis Caught Early (SPACE) cohort
Authors: Mary Lucy Marques, Sofia Ramiro, Miranda van Lunteren, Rosalinde Anne Stal, Robert BM Landewé, Marleen van de Sande, Karen Minde Fagerli, Inger Jorid Berg, Maikel van Oosterhout, Sofia Exarchou, Roberta Ramonda, Désirée van der Heijde, Floris A van Gaalen
Journal: Annals of the Rheumatic Diseases (2024)

To investigate the prevalence of axial spondyloarthritis (axSpA) in patients with chronic back pain (CBP) of less than 2 years (2y) duration referred to the rheumatologist, the development of diagnosis over time, and patient characteristics of those developing
Depression, anxiety and stress among female student-athletes: a systematic review and meta-analysis
Authors: Ling Beisecker, Patrick Harrison, Marzia Josephson, J D DeFreese
Journal: British Journal of Sports Medicine (2024)

Objective To identify, quantify and analyse determinants of depression, anxiety and stress symptoms among female student-athletes. Design Systematic review and meta-analysis. Data sources Five online databases (PubMed, CINAHL, PsychInfo, SportDiscus and Web of Science) searched from inception through 14 September 2023. Hand-searches and contacting authors for eligible studies. Eligibility criteria for selecting studies Articles were included if they were published in English, included female student-athletes competing at National Collegiate Athletic Association institutions, and measured symptom-level depression, anxiety and/or stress. Results and summary We screened 2415 articles; 52 studies (N=13 849) were included in the systematic review with 13 studies qualifying for meta-analysis. Seventeen determinants were identified including injury (eg, concussions), health (eg, sleep hygiene) and social factors (eg, social support). As data specific to female student-athletes was delineated from studies that included other populations, we observed 16 studies (30.7%) reported that identifying as female was a meaningful determinant of depression, anxiety and stress in athletes. Results of the meta-analysis ( k =13, N=5004) suggested a small but significant association ( r =0.15, 95% CI 0.05 to 0.24, p=0.004) between other determinants and depression, anxiety, and stress among female student-athletes. Conclusion Coaches, trainers and clinicians are key contributors in supporting female student-athlete mental health, with responsibilities for integrating mental skill training, sleep hygiene education and regular assessments. Comprehensive mental health and tailored education programmes considering determinants such as injury, health and social factors specific to female student-athletes are needed to enhance mental health equity in sport. PROSPERO registration number CRD42022362163.
Corticosteroid-resistant immune-related adverse events: a systematic review
Authors: Eveline Daetwyler, Till Wallrabenstein, David König, Laura C Cappelli, Jarushka Naidoo, Alfred Zippelius, Heinz Läubli
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient’s immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend—as first line treatment—(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.
Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4<sup>+</sup>naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma
Authors: Magdalena Kovacsovics-Bankowski, Johanna M Sweere, Connor P Healy, Natalia Sigal, Li-Chun Cheng, William D Chronister, Shane A Evans, John Marsiglio, Berit Gibson, Umang Swami, Alyssa Erickson-Wayman, Jordan P McPherson, Yoko S Derose, Annaleah Larson Eliason, Carlos O Medina, Ramji Srinivasan, Matthew H Spitzer, Ngan Nguyen, John Hyngstrom, Siwen Hu-Lieskovan
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Immune-related adverse events (irAEs) are major barriers of clinical management and further development of immune checkpoint inhibitors (ICIs) for cancer therapy. Therefore, biomarkers associated with the onset of severe irAEs are needed. In this study, we aimed to identify immune features detectable in peripheral blood and associated with the development of severe irAEs that required clinical intervention. Methods We used a 43-marker mass cytometry panel to characterize peripheral blood mononuclear cells from 28 unique patients with melanoma across 29 lines of ICI therapy before treatment (baseline), before the onset of irAEs (pre-irAE) and at the peak of irAEs (irAE-max). In the 29 lines of ICI therapy, 18 resulted in severe irAEs and 11 did not. Results Unsupervised and gated population analysis showed that patients with severe irAEs had a higher frequency of CD4 + naïve T cells and lower frequency of CD16 + natural killer (NK) cells at all time points. Gated population analysis additionally showed that patients with severe irAEs had fewer T cell immunoreceptor with Ig and ITIM domain (TIGIT + ) regulatory T cells at baseline and more activated CD38 + CD4 + central memory T cells (TCM) and CD39 + and Human Leukocyte Antigen-DR Isotype (HLA-DR) + CD8 + TCM at peak of irAEs. The differentiating immune features at baseline were predominantly seen in patients with gastrointestinal and cutaneous irAEs and type 1 diabetes. Higher frequencies of CD4 + naïve T cells and lower frequencies of CD16 + NK cells were also associated with clinical benefit to ICI therapy. Conclusions This study demonstrates that high-dimensional immune profiling can reveal novel blood-based immune signatures associated with risk and mechanism of severe irAEs. Development of severe irAEs in melanoma could be the result of reduced immune inhibitory capacity pre-ICI treatment, resulting in more activated TCM cells after treatment.