tbuckley/cabot-search huggingface dataset:
CLN7 gene therapy: hope for an ultra-rare condition
Authors: Jon J. Brudvig, Jill M. Weimer
Journal: Journal of Clinical Investigation (2022)

CLN7 Batten disease, also known as variant late infantile neuronal ceroid lipofuscinosis type 7 (vLINCL7), is an ultra-rare form of Batten disease that presents early in life with severe neurological symptoms, including visual deficits, motor problems, and frequent seizures. There is high unmet need for disease-modifying therapies, as no existing treatment can halt progression or prevent premature death. In this issue of the JCI, Chen et al. present an AAV gene therapy for CLN7 that shows marked benefit in a mouse model of CLN7 Batten disease, paving the way for a phase I trial. The candidate gene therapy shows benefit for histopathology, behavioral abnormalities, and survival in mice and offers an acceptable safety profile in both mice and rats. Questions remain regarding dose, scaling, and timing of administration for patients, but this work is a substantial step forward for a very challenging disease.
108MO Safety and efficacy outcomes with durvalumab after sequential chemoradiotherapy (sCRT) in stage III, unresectable NSCLC (PACIFIC-6)
Authors: M.C. Garassino, J. Mazieres, M. Reck, C. Chouaid, H. Bischoff, N. Reinmuth, L. Cove-Smith, T. Mansy, D. Cortinovis, M.R. Migliorino, A. Delmonte, J. Garcia Sánchez, L.E. Chara Velarde, R. Bernabe, L. Paz-Ares, I. Diaz Perez, N. Trunova, K. Foroutanpour, C. Faivre-Finn
Journal: Annals of Oncology (2022)
Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial
Authors: Shehu U Abdullahi, Binta W Jibir, Halima Bello-Manga, Safiya Gambo, Hauwa Inuwa, Aliyu G Tijjani, Nura Idris, Aisha Galadanci, Mustapha S Hikima, Najibah Galadanci, Awwal Borodo, Abdulkadir M Tabari, Lawal Haliru, Aisha Suleiman, Jamila Ibrahim, Brittany C Greene, Djamila L Ghafuri, Mark Rodeghier, James C Slaughter, Fenella J Kirkham, Kathleen Neville, Adetola Kassim, Edwin Trevathan, Lori C Jordan, Muktar H Aliyu, Michael R DeBaun
Journal: The Lancet Haematology (2021)
Abstract P115: Association Of Circulating And Fecal Butyrate And Other Short Chain Fatty Acids With Blood Pressure And Hypertension: Results From The SPIRIT Trial
Authors: Curtis Tilves, Hsin-Chieh Yeh, Nisa Maruthur, Stephen Juraschek, Edgar R Miller, Karen White, Lawrence J Appel, Noel T Mueller
Journal: Circulation (2022)

Background: Short chain fatty acids (SCFAs) are the microbially-derived end products of dietary fiber fermentation. The SCFA butyrate is a signaling molecule shown to influence blood pressure (BP) in mouse models. The association of butyrate and other SCFAs on BP in humans is unclear, due in part to predominantly cross-sectional analyses and to differences in which biospecimens (blood vs. fecal) SCFAs were measured. Longitudinal studies including both circulating and fecal SCFAs are lacking. Objective: Investigate the cross-sectional and longitudinal associations of fecal and serum SCFAs with hypertension and changes in BP. Methods: We leveraged existing data from the SPIRIT trial, which randomized 121 adult cancer survivors with overweight/obesity to a behavioral weight loss intervention, metformin, or self-directed weight loss. Of participants with serum and fecal SCFAs measured at baseline (N=111), a subset also had serum (N=93) and fecal (N=89) SCFA measurements 12 months later. We used Poisson regression with robust error variance to estimate associations of serum or fecal SCFAs with hypertension at baseline (adjusting for age, sex, BMI, and fiber intake). In longitudinal analyses, we assessed the percent change in serum or fecal SCFAs from baseline with corresponding 12-month changes in BP (covariates listed in Table ). Results: Participants were aged 60.2±8.9 years, 78.4% female, and 46.9% identified as White. Higher baseline fecal butyrate was inversely associated with prevalent hypertension (standardized PR [95%CI]: 0.71 [0.54, 0.92]). In longitudinal analyses ( Table ), a 10% increase in fecal butyrate from baseline levels was significantly and inversely associated with systolic BP, and a 10% increase in serum butyrate was significantly and inversely associated with systolic and diastolic BPs. Associations of butyrate with BP were not modified by sex or race. Conclusion: Increased serum or fecal butyrate is associated with lowered BP. Butyrate may be a target for SCFA-centered BP-lowering interventions.
Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial
Authors: Ole Fröbert, Matthias Götberg, David Erlinge, Zubair Akhtar, Evald H. Christiansen, Chandini R. MacIntyre, Keith G. Oldroyd, Zuzana Motovska, Andrejs Erglis, Rasmus Moer, Ota Hlinomaz, Lars Jakobsen, Thomas Engstrøm, Lisette O. Jensen, Christian O. Fallesen, Svend E Jensen, Oskar Angerås, Fredrik Calais, Amra Kåregren, Jörg Lauermann, Arash Mokhtari, Johan Nilsson, Jonas Persson, Per Stalby, Abu K.M.M. Islam, Afzalur Rahman, Fazila Malik, Sohel Choudhury, Timothy Collier, Stuart J. Pocock, John Pernow
Journal: Circulation (2021)

Observational and small, randomized studies suggest that influenza vaccine may reduce future cardiovascular events in patients with cardiovascular disease.We conducted an investigator-initiated, randomized, double-blind trial to compare inactivated influenza vaccine with saline placebo administered shortly after myocardial infarction (MI; 99.7% of patients) or high-risk stable coronary heart disease (0.3%). The primary end point was the composite of all-cause death, MI, or stent thrombosis at 12 months. A hierarchical testing strategy was used for the key secondary end points: all-cause death, cardiovascular death, MI, and stent thrombosis.Because of the COVID-19 pandemic, the data safety and monitoring board recommended to halt the trial before attaining the prespecified sample size. Between October 1, 2016, and March 1, 2020, 2571 participants were randomized at 30 centers across 8 countries. Participants assigned to influenza vaccine totaled 1290 and individuals assigned to placebo equaled 1281; of these, 2532 received the study treatment (1272 influenza vaccine and 1260 placebo) and were included in the modified intention to treat analysis. Over the 12-month follow-up, the primary outcome occurred in 67 participants (5.3%) assigned influenza vaccine and 91 participants (7.2%) assigned placebo (hazard ratio, 0.72 [95% CI, 0.52-0.99]; P=0.040). Rates of all-cause death were 2.9% and 4.9% (hazard ratio, 0.59 [95% CI, 0.39-0.89]; P=0.010), rates of cardiovascular death were 2.7% and 4.5%, (hazard ratio, 0.59 [95% CI, 0.39-0.90]; P=0.014), and rates of MI were 2.0% and 2.4% (hazard ratio, 0.86 [95% CI, 0.50-1.46]; P=0.57) in the influenza vaccine and placebo groups, respectively.Influenza vaccination early after an MI or in high-risk coronary heart disease resulted in a lower risk of a composite of all-cause death, MI, or stent thrombosis, and a lower risk of all-cause death and cardiovascular death, as well, at 12 months compared with placebo. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02831608.
Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report
Authors: Patrick J. Leavey, Nadia N. Laack, Mark D. Krailo, Allen Buxton, R. Lor Randall, Steven G. DuBois, Damon R. Reed, Holcombe E. Grier, Douglas S. Hawkins, Bruce Pawel, Helen Nadel, Richard B. Womer, G. Douglas Letson, Mark Bernstein, Kenneth Brown, Alexis Maciej, Paul Chuba, Atif A. Ahmed, Daniel J. Indelicato, Dian Wang, Neyssa Marina, Richard Gorlick, Katherine A. Janeway, Leo Mascarenhas
Journal: Journal of Clinical Oncology (2021)

The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma.
Abstract P125: Change In Low-density Lipoprotein Cholesterol And Risk Of Subsequent Cardiovascular Events Among Patients With Myocardial Infarction
Authors: Sheila M Manemann, Sarah Cohen, Stephanie R Reading, Sina Noshad, Naimisha Movva, Susan Weston, Jill Killian, Alanna Chamberlain
Journal: Circulation (2022)

Background: Among patients who experience a myocardial infarction (MI), elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for experiencing a subsequent cardiovascular (CV) event; however, real-world evidence is lacking in regard to how changes in LDL-C levels after a MI hospitalization are related to subsequent CV events. Methods: Adults with a hospitalized MI and an available baseline LDL-C (closest LDL-C within 2 years prior to hospital discharge) between 2012 and 2018 within a 27-county region across MN and WI were included for study. For each LDL-C measurement during follow-up (starting with the first LDL-C &gt;30 days after baseline and ≤1-year post-discharge), percent change from baseline LDL-C was calculated. Patients were followed for subsequent CV events (composite endpoint 1: MI, ischemic stroke [IS], coronary artery bypass grafting [CABG], percutaneous coronary intervention [PCI]; composite endpoint 2: MI, IS, CABG, PCI, CV death). Cox models were used to evaluate the association between time-dependent LDL-C percent change and CV events, stratified by baseline LDL-C (&lt;70, 70-99, ≥100 mg/dL). Results: Among 3,034 MI patients identified, 740 (24%), 940 (31%) and 1354 (45%) had a baseline LDL-C &lt;70, 70-99 and ≥100 mg/dL, respectively. After a mean follow-up of 3.4 years, 471 and 667 patients experienced the composite endpoint 1 and 2, respectively. After covariate adjustment, a trend towards a lower risk of CV events with decreasing LDL-C from baseline, compared to those with no change or an increase in LDL-C, was observed among those with a LDL-C &lt;70 and &gt; 100 mg/dl but not in those with a LDL-C 70-99 mg/dL (Table). Conclusions: In a population-based cohort of MI patients, there is evidence that patients with a decrease in LDL-C after MI may have a reduced risk of subsequent CV events. These results underscore the importance of lowering LDL-C after a MI and may help to identify subgroups at highest risk for additional CV events and those who may benefit from targeted LDL-C treatment recommendations.
Report of the First International Symposium on NUT Carcinoma
Authors: Christopher A. French, Michael L. Cheng, Glenn J. Hanna, Steven G. DuBois, Nicole G. Chau, Christine L. Hann, Simone Storck, Ravi Salgia, Matteo Trucco, Jennifer Tseng, Anastasios Stathis, Richard Piekarz, Ulrich M. Lauer, Christophe Massard, Kelly Bennett, Shodeinde Coker, Ulrike Tontsch-Grunt, Martin L. Sos, Sida Liao, Catherine J. Wu, Kornelia Polyak, Sarina A. Piha-Paul, Geoffrey I. Shapiro
Journal: Clinical Cancer Research (2022)

Abstract NUT carcinoma is a rare, aggressive cancer defined by rearrangements of the NUTM1 gene. No routinely effective treatments of NUT carcinoma exist, despite harboring a targetable oncoprotein, most commonly BRD4-NUT. The vast majority of cases are fatal. Poor awareness of the disease is a major obstacle to progress in the treatment of NUT carcinoma. While the incidence likely exceeds that of Ewing sarcoma, and BRD4-NUT heralded the bromodomain and extra-terminal domain (BET) inhibitor class of selective epigenetic modulators, NUT carcinoma is incorrectly perceived as “impossibly rare,” and therefore receives comparatively little private or governmental funding or prioritization by pharma. To raise awareness, propagate scientific knowledge, and initiate a consensus on standard and targeted treatment of NUT carcinoma, we held the First International Symposium on NUT Carcinoma on March 3, 2021. This virtual event had more than eighty attendees from the Americas, Europe, Asia, and Australia. Patients with NUT carcinoma and family members were represented and shared perspectives. Broadly, the four areas discussed by experts in the field included (1) the biology of NUT carcinoma; (2) standard approaches to the treatment of NUT carcinoma; (3) results of clinical trials using BET inhibitors; and (4) future directions, including novel BET bromodomain inhibitors, combinatorial approaches, and immunotherapy. It was concluded that standard chemotherapeutic approaches and first-generation BET bromodomain inhibitors, the latter complicated by a narrow therapeutic window, are only modestly effective in a minority of cases. Nonetheless, emerging second-generation targeted inhibitors, novel rational synergistic combinations, and the incorporation of immuno-oncology approaches hold promise to improve the prognosis of this disease.
17P Safety and tolerability of sintilimab (sint) combination therapy in patients with advanced or recurrent non-small cell lung cancer (NSCLC): Pooled safety analysis of ORIENT 11 and ORIENT 12 studies
Authors: G. Gao, Y. Zhao, J. Zhou, B. Li, J. Li, F. Min, Q. Zhu, H. Li, C. Zhou, L. Zhang
Journal: Annals of Oncology (2022)
141O Durvalumab (D) ± tremelimumab (T) + platinum-etoposide (EP) in 1L extensive-stage (ES) SCLC: Characteristics of long-term survivors in the CASPIAN study
Authors: N. Reinmuth, J.W. Goldman, M.C. Garassino, Y. Chen, K. Hotta, A. Poltoratskiy, D. Trukhin, M.J. Hochmair, J.H. Ji, M. Özgüroğlu, G. Statsenko, O. Voitko, N.V. Conev, I. Bondarenko, H. Mann, M. Xie, Y. Shrestha, P. Chugh, T. Dalvi, L. Paz-Ares
Journal: Annals of Oncology (2022)
Annals Graphic Medicine - Dr. Mom: Which Hospital Snack Are You?
Authors: Grace E. Farris
Journal: Annals of Internal Medicine (2022)

Web ExclusivesFebruary 2022Annals Graphic Medicine - Dr. Mom: Which Hospital Snack Are You?FREEGrace E. Farris, MDGrace E. Farris, MDUniversity of Texas, Austin, Texas (G.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G22-0003 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Kristin KeskeySt Joes Mercy Oakland24 January 2022 Juice Forgot juice. The one in a plastic container with a peel back lid. Born out of desperation! Tara BylsmaBoston Hospital25 January 2022 level up 1 chocolate pudding cup + 2 single serve peanut butter packets + 1 packet of gram cracker crumbles = night float nirvana Author, Article, and Disclosure InformationAffiliations: University of Texas, Austin, Texas (G.E.F.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G21-0024.Author/Illustrator Information: Grace E. Farris, MD, is an assistant professor of medicine at Dell Medical School at the University of Texas in Austin, Texas. You can view her work at her website: www.farrisgrace.com.About Dr. Mom: In Dr. Mom, physician and cartoonist Grace Farris examines work–life balance while mothering and doctoring. Dr. Mom appears monthly in Annals Graphic Medicine at Annals.org.This article was published at Annals.org on 25 January 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics February 2022Volume 175, Issue 2Page: W17-W18 ePublished: 25 January 2022 Issue Published: February 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Bioprinting: A Strategy to Build Informative Models of Exposure and Disease
Authors: Jose Caceres-Alban, Midori Sanchez, Fanny L. Casado
Journal: IEEE Reviews in Biomedical Engineering (2022)

Novel additive manufacturing techniques are revolutionizing fields of industry providing more dimensions to control and the versatility of fabricating multi-material products. Medical applications hold great promise to manufacture constructs of mixed biologically compatible materials together with functional cells and tissues. We reviewed technologies and promising developments nurturing innovation of physiologically relevant models to study safety of chemicals that are hard to reproduce in current models, or diseases for which there are no models available. Extrusion-, inkjet- and laser-assisted bioprinting are the most used techniques. Hydrogels as constituents of bioinks and biomaterial inks are the most versatile materials to recreate physiological and pathophysiological microenvironments. The highlighted bioprinted models were chosen because they guarantee post-printing cellular viability while maintaining desirable mechanical properties of their constitutive bioinks or biomaterial inks to ensure their printability. Bioprinting is being readily adopted to overcome ethical concerns of in vivo models and improve the automation, reproducibility, geometry stability of traditional in vitro models. The challenges for advancing the technological level readiness of bioprinting require overcoming heterogeneity, microstructural complexity, dynamism and integration with other models, to generate multi-organ platforms that can inform about biological responses to chemical exposure, disease development and efficacy of novel therapies.
A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma
Authors: Michael J. Wagner, Yuzheng Zhang, Lee D. Cranmer, Elizabeth T. Loggers, Graeme Black, Sabrina McDonnell, Shannon Maxwell, Rylee Johnson, Roxanne Moore, Pedro Hermida de Viveiros, Lauri Aicher, Kimberly S. Smythe, Qianchuan He, Robin L. Jones, Seth M. Pollack
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Leiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA approved for leiomyosarcoma and liposarcoma. This study aimed to evaluate the safety and efficacy of trabectedin with anti–PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma. Patients and Methods: A single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced leiomyosarcoma and liposarcoma. The phase I portion evaluated safety and feasibility of trabectedin (1, 1.2, and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was objective response rate (ORR) by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression. Results: 33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In Phase 1, dose-limiting toxicities (DLT) were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended Phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800-mg avelumab. Of 23 patients evaluable at RP2D, 3 (13%) had partial response (PR) and 10 (43%) had stable disease (SD) as best response. Six-month PFS was 52%; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells versus those with SD (0.182 vs. 0.067, P = 0.02) or progressive disease (0.182 vs. 0.064, P = 0.01). Conclusions: Although the trial did not meet the primary objective response rate endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.
Abstract P120: Latent Group Trajectory Methods To Study Type 2 Diabetes Epidemiology: A Review Of The Literature
Authors: Sarah OConnor, Miceline Mésidor, Denis Talbot, Paul Poirier, Claudia Blais, Jacinthe Leclerc
Journal: Circulation (2022)

Introduction: The progression of type 2 diabetes (T2D) is unique to each patient and can be depicted through individual temporal trajectories. Latent group trajectory methods (latent growth mixture models [LGMM] or latent class growth analysis [LCGA]) can be used to classify similar individual trajectories in a priori non-observed groups (latent groups), sharing common characteristics. Although increasingly used in the field of T2D epidemiology, many questions remain regarding the utilization of these methods. Objective: To review the literature of longitudinal studies using latent group trajectory methods among individuals with T2D. Methods: MEDLINE (Ovid), EMBASE, CINAHL and Web of Science were searched through August 25 th , 2021. Data were collected on the type of method used (LGMM or LGCA), characteristics of studies and quality of reporting using the GRoLTS-Checklist. Results: From the 4,694 citations screened, a total of 38 studies were included. The studies were published between 2010 and 2021. Total follow-ups ranged from 8 weeks to 11 years, with 95% (36 out of 38) studies with a follow-up of 1 year of more. The characteristics of studies are presented in Table 1. Regarding the quality of reporting, trajectory groups were adequately presented, however many studies failed to report important decisions made for the trajectory group identification. Many studies considered trajectory groups as exposures to a subsequent outcome. Yet, issues in relation with selection bias, immortal bias and residual confounding were suspected and poorly addressed. Conclusions: Although LCGA were preferred, the context of utilization, data sources and research questions were diverse and unrelated to the type of method used. We recommend authors to clearly report the decisions made in trajectory groups identification.
Association Between SARS-CoV-2 Viral Load in Wastewater and Reported Cases, Hospitalizations, and Vaccinations in Milan, March 2020 to November 2021
Authors: Giovanni Nattino, Sara Castiglioni, Danilo Cereda, Petra Giulia Della Valle, Laura Pellegrinelli, Guido Bertolini, Elena Pariani
Journal: JAMA (2022)

2][3] This surveillance intends to overcome the limitations of traditional surveillance indicators, 4 such as the number of positive tests, which depends on test availability and indications, or COVID-19-related hospitalizations, which occur weeks after the spread of SARS-CoV-2 and do not include mild or asymptomatic cases.This study evaluated the association between SARS-CoV-2 load in urban wastewater and surveillance indicators of infection prevalence and severity in Milan, Italy.
Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study
Authors: Fanny Chasseloup, Isabelle Bourdeau, Antoine Tabarin, Daniela Regazzo, Charles Dumontet, Nataly Ladurelle, Lucie Tosca, Larbi Amazit, Alexis Proust, Raphael Scharfmann, Tiphaine Mignot, Frédéric Fiore, Stylianos Tsagarakis, Dimitra Vassiliadi, Dominique Maiter, Jacques Young, Anne-Lise Lecoq, Vianney Deméocq, Sylvie Salenave, Hervé Lefebvre, Lucie Cloix, Philippe Emy, Rachel Dessailloud, Delphine Vezzosi, Carla Scaroni, Mattia Barbot, Wouter de Herder, François Pattou, Martine Tétreault, Gilles Corbeil, Margot Dupeux, Benoit Lambert, Gérard Tachdjian, Anne Guiochon-Mantel, Isabelle Beau, Philippe Chanson, Say Viengchareun, André Lacroix, Jérôme Bouligand, Peter Kamenický
Journal: The Lancet Diabetes & Endocrinology (2021)
Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial
Authors: Patrick Y Wen, Alexander Stein, Martin van den Bent, Jacques De Greve, Antje Wick, Filip Y F L de Vos, Nikolas von Bubnoff, Myra E van Linde, Albert Lai, Gerald W Prager, Mario Campone, Angelica Fasolo, Jose A Lopez-Martin, Tae Min Kim, Warren P Mason, Ralf-Dieter Hofheinz, Jean-Yves Blay, Daniel C Cho, Anas Gazzah, Damien Pouessel, Jeffrey Yachnin, Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Vivek Subbiah
Journal: The Lancet Oncology (2021)