tbuckley/cabot-search huggingface dataset:
Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease
Authors: Sherif S. Farag, Mohammad Abu Zaid, Jennifer E. Schwartz, Teresa C. Thakrar, Ann J. Blakley, Rafat Abonour, Michael J. Robertson, Hal E. Broxmeyer, Shuhong Zhang
Journal: New England Journal of Medicine (2021)

Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).
Eradication of Chronic HCV Infection: Improvement of Dysbiosis Only in Patients Without Liver Cirrhosis
Authors: Freya Wellhöner, Nico Döscher, Franziska Woelfl, Marius Vital, Iris Plumeier, Silke Kahl, Andrej Potthoff, Michael Peter Manns, Dietmar Helmut Pieper, Markus Cornberg, Heiner Wedemeyer, Benjamin Heidrich
Journal: Hepatology (2021)

Background and Aims It is well accepted that liver diseases and their outcomes are associated with intestinal microbiota, but causality is difficult to establish. The intestinal microbiota are altered in patients with hepatitis C. As chronic HCV infection can now be cured in almost all patients, it is an ideal model to study the influence of liver disease on the microbiota. Approach and Results We aimed to prospectively analyze the changes in the gut microbiome in patients who received direct‐acting antivirals (DAA) and achieved sustained virological response (SVR). Amplicon sequencing of the V1‐V2 region in the 16S ribosomal RNA gene was performed in stool samples of patients with chronic hepatitis C. Patients in the treatment group received DAA (n = 65), whereas in the control group, no DAA were given (n = 33). Only patients achieving SVR were included. The alpha diversity increased numerically but not significantly from baseline to SVR at week 24 or 48 (SVR24/48; 2.784 ± 0.248 vs. 2.846 ± 0.224; P = 0.057). When stratifying for the presence of liver cirrhosis, a significant increase in diversity was only seen in patients without cirrhosis. Differences in the microbial community structure induced by the achievement of SVR were only observed in patients without liver cirrhosis. In patients with liver cirrhosis and in the control group, no significant differences were observed. Conclusions In conclusion, the achievement of SVR24/48 in patients with chronic HCV was associated with changes in the intestinal microbiota. However, these changes were only seen in patients without liver cirrhosis. A major role of liver remodeling on the intestinal microbiota is indicated by the dynamics of the intestinal microbial community structure depending on the stage of fibrosis in patients resolving chronic hepatitis C.
Cachexia and Dietetic Interventions in Patients With Esophagogastric Cancer: A Multicenter Cohort Study
Authors: Willemieke P.M. Dijksterhuis, Anouk E.J. Latenstein, Jessy Joy van Kleef, Rob H.A. Verhoeven, Jeanne H.M. de Vries, Marije Slingerland, Elles Steenhagen, Joos Heisterkamp, Liesbeth M. Timmermans, Marian A.E. de van der Schueren, Martijn G.H. van Oijen, Sandra Beijer, Hanneke W.M. van Laarhoven
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: Cachexia is common in patients with esophagogastric cancer and is associated with increased mortality. Nutritional screening and dietetic interventions can be helpful in preventing evolvement of cachexia. Our aim was to study the real-world prevalence and prognostic value of pretreatment cachexia on overall survival (OS) using patient-reported weight loss, and to explore dietetic interventions in esophagogastric cancer. Materials and Methods: Patients with esophagogastric cancer (2015–2018), regardless of disease stage, who participated in the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP) and completed patient-reported outcome measures were included. Data on weight loss and dietetic interventions were retrieved from questionnaires before start of treatment (baseline) and 3 months thereafter. Additional patient data were obtained from the Netherlands Cancer Registry. Cachexia was defined as self-reported &gt;5% half-year body weight loss at baseline or &gt;2% in patients with a body mass index (BMI) &lt;20 kg/m 2 according to the Fearon criteria. The association between cachexia and OS was analyzed using multivariable Cox proportional hazard analyses adjusted for sex, age, performance status, comorbidities, primary tumor location, disease stage, histology, and treatment strategy. Results: Of 406 included patients, 48% had pretreatment cachexia, of whom 65% were referred for dietetic consultation at baseline. The proportion of patients with cachexia was the highest among those who received palliative chemotherapy (59%) or best supportive care (67%). Cachexia was associated with decreased OS (hazard ratio, 1.52; 95% CI, 1.11–2.09). Median weight loss after 3-month follow-up was lower in patients with cachexia who were referred to a dietician at baseline compared with those who were not (0% vs 2%; P =.047). Conclusions: Nearly half of patients with esophagogastric cancer have pretreatment cachexia. Dietetic consultation at baseline was not reported in more than one-third of the patients with cachexia. Because cachexia was independently associated with decreased survival, improving nutritional screening and referral for dietetic consultation are warranted to prevent further deterioration of malnutrition and mortality.
Judith D Brown
Authors: Janet Rich
Journal: BMJ (2021)

Judith D Brown was educated at Wakefield Girls’ High School, where she did well in all subjects but decided to become a doctor. Following in the footsteps of her great uncle, Sir Leonard Parsons, she chose to train at Birmingham University and to become a paediatrician. After positions in Birmingham she moved to London and worked in Hackney, Cuckfield, and Carshalton while she studied further. As a registrar at …
Covid-19: Norway investigates 23 deaths in frail elderly patients after vaccination
Authors: Ingrid Torjesen
Journal: BMJ (2021)

Covid-19: Norway investigates 23 deaths in frail elderly patients after vaccinationIngrid Torjesen Doctors in Norway have been told to conduct more thorough evaluations of very frail elderly patients in line to receive the Pfizer BioNTec vaccine against covid-19, following the deaths of 23 patients shortly after receiving the vaccine."It may be a coincidence, but we aren't sure," Steinar Madsen, medical director of the Norwegian Medicines Agency (NOMA), told The BMJ. "There is no certain connection between these deaths and the vaccine."
Integrating Multidetector Computed Tomography Into Clinical Practice: Computed Tomography Scanning Shows its Metal⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Basil S. Lewis, David A. Halon
Journal: Journal of the American College of Cardiology (2007)
Particle Stiffness and Surface Topography Determine Macrophage‐Mediated Removal of Surface Adsorbed Particles
Authors: Aaron Lee, Dedy Septiadi, Patricia Taladriz‐Blanco, Mauro Almeida, Laetitia Haeni, Miguel Spuch‐Calvar, Wildan Abdussalam, Barbara Rothen‐Rutishauser, Alke Petri‐Fink
Journal: Advanced Healthcare Materials (2021)

Abstract Cellular surface recognition and behavior are driven by a host of physical and chemical features which have been exploited to influence particle–cell interactions. Mechanical and topographical cues define the physical milieu which plays an important role in defining a range of cellular activities such as material recognition, adhesion, and migration through cytoskeletal organization and signaling. In order to elucidate the effect of local mechanical and topographical features generated by the adsorption of particles to an underlying surface on primary human monocyte‐derived macrophages (MDM), a series of poly( N ‐isopropylacrylamide) (pNIPAM) particles with differing rigidity are self‐assembled to form a defined particle‐decorated surface. Assembly of particle‐decorated surfaces is facilitated by modification of the underlying glass to possess a positive charge through functionalization using 3‐aminopropyltriethoxysilane (APTES) or coating with poly(L‐lysine) (PLL). MDMs are noted to preferentially remove particles with higher degrees of crosslinking (stiffer) than those with lower degrees of crosslinking (softer). Alterations to the surface density of particles enabled a greater area of the particle‐decorated surface to be cleared. Uniquely, the impact of particle adsorption is evinced to have a direct impact on topographical recognition of the surface, suggesting a novel approach for controllably affecting cell‐surface recognition and response.
Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease
Authors: Eriene-Heidi Sidhom, Choah Kim, Maria Kost-Alimova, May Theng Ting, Keith Keller, Julian Avila-Pacheco, Andrew J.B. Watts, Katherine A. Vernon, Jamie L. Marshall, Estefanía Reyes-Bricio, Matthew Racette, Nicolas Wieder, Giulio Kleiner, Elizabeth J. Grinkevich, Fei Chen, Astrid Weins, Clary B. Clish, Jillian L. Shaw, Catarina M. Quinzii, Anna Greka
Journal: Journal of Clinical Investigation (2021)

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of Pdss2kd/kd mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in Pdss2kd/kd mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA-mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases.
Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133)
Authors: Stephen V. Liu, Martin Reck, Aaron S. Mansfield, Tony Mok, Arnaud Scherpereel, Niels Reinmuth, Marina Chiara Garassino, Javier De Castro Carpeno, Raffaele Califano, Makoto Nishio, Francisco Orlandi, Jorge Alatorre-Alexander, Ticiana Leal, Ying Cheng, Jong-Seok Lee, Sivuonthanh Lam, Mark McCleland, Yu Deng, See Phan, Leora Horn
Journal: Journal of Clinical Oncology (2021)

IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported.Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m2 IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted.Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive P = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status.Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.
Translation of a Host Blood RNA Signature Distinguishing Bacterial From Viral Infection Into a Platform Suitable for Development as a Point-of-Care Test
Authors: Ivana Pennisi, Jesus Rodriguez-Manzano, Ahmad Moniri, Myrsini Kaforou, Jethro A. Herberg, Michael Levin, Pantelis Georgiou
Journal: JAMA Pediatrics (2021)

offer reasons for concern.
Risk of Substance Use Disorder and Its Associations With Comorbidities and Psychotropic Agents in Patients With Autism
Authors: Jing-Syuan Huang, Fu-Chi Yang, Wu-Chien Chien, Ta-Chuan Yeh, Chi-Hsiang Chung, Chia-Kuang Tsai, Shih-Jen Tsai, Sung-Sen Yang, Nian-Shen Tzeng, Mu-Hong Chen, Chih-Sung Liang
Journal: JAMA Pediatrics (2021)

The risk of substance use disorder (SUD) in patients with autism spectrum disorder (ASD) remains unclear.To investigate the risk of SUD in patients with ASD and its associations with comorbidities, psychotropic agents (PAs), and mortality.This retrospective, population-based, cohort study of 1 936 512 participants used data from the Taiwan National Health Insurance Research Database and was conducted from January 1, 2000, to December 31, 2015. Included participants attended at least 3 outpatient visits within the 1-year study period for symptomatic ASD as determined by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes. Individuals diagnosed with ASD before 2000, those diagnosed with SUD before the first visit for ASD, and those with missing data were excluded from the analysis. Patients with ASD and non-ASD controls were matched 1:4 by age, sex, and index date.Symptomatic ASD evaluated for at least 3 outpatient visits within the 1-year study period.Adjusted hazard ratios (aHRs) with 95% CIs for SUD, including alcohol use disorder (AUD) and drug use disorder (DUD), and the risk of mortality were calculated. Data were analyzed from March 1 to July 13, 2020.A total of 6599 individuals with ASD (mean [SD] age, 11.9 [5.1] years; 5094 boys [77.2%]; mean [SD] follow-up period, 8.1 [8.3] years; median follow-up period, 4.3 [interquartile range [IQR], 2.3-5.3] years) and 26 396 controls (mean [SD] age, 12.1 [5.8] years; 20 376 boys [77.2%]; mean [SD] follow-up period, 8.6 [8.9] years; median follow-up period, 4.4 [IQR, 2.4-5.4] years) were enrolled in the study. According to multivariable-adjusted analysis, the aHRs for SUD (2.33; 95% CI, 1.89-2.87), AUD (2.07; 95% CI, 1.60-2.63), and DUD (3.00; 95% CI, 2.15-4.58) were significantly higher in the ASD group than in the non-ASD controls. The aHRs for SUD in the ASD subgroups with 1 PA (0.60; 95% CI, 0.43-0.66) and with multiple PAs (0.37; 95% CI, 0.28-0.49) were significantly lower than those in the ASD subgroup with no PAs. Comparisons between patients with ASD and non-ASD controls with the same comorbidities showed higher aHRs for SUD among patients with ASD (range, 1.17-2.55); moreover, the ASD subgroup not receiving any PAs had an aHR of 6.39 (95% CI, 5.11-7.87) for SUD when they had comorbid tic disorder and aHRs of 5.48 (95% CI, 5.12-5.70) for AUD and 5.42 (95% CI, 5.12-5.80) for DUD when they had comorbid impulse control disorder. The mortality risk was significantly higher in patients with ASD and concomitant SUD than in non-ASD controls without SUD (aHR, 3.17; 95% CI, 2.69-3.89).These findings suggest that patients with ASD are vulnerable to the development of SUD. Comorbid ASD and SUD were associated with an increase in mortality risk.
MO01.13 Molecular Risk Stratification is Independent of EGFR Mutation Status in Identifying Early Stage Non-Squamous Non-Small Cell Lung Cancer Patients at Risk for Recurrence and Likely to Benefit from Adjuvant Chemotherapy
Authors: G. Woodard, J. Kratz, G. Haro, M. Gubens, C. Blakely, K. Jones, M. Mann, D. Jablons
Journal: Journal of Thoracic Oncology (2021)
Covid-19: UK approves Moderna vaccine to be given as two doses 28 days apart
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Covid-19: UK approves Moderna vaccine to be given as two doses 28 days apart Elisabeth MahaseThe UK has approved the Moderna covid-19 vaccine and ordered an additional 10 million doses-bringing the total up to 17 million doses to be delivered from spring.1
In older patients with AF, low-dose edoxaban reduced stroke or systemic embolism without increasing major bleeding
Authors: Daniel I. Steinberg
Journal: Annals of Internal Medicine (2021)

ACP Journal ClubJanuary 2021In older patients with AF, low-dose edoxaban reduced stroke or systemic embolism without increasing major bleedingDaniel I. Steinberg, MDDaniel I. Steinberg, MDIcahn School of Medicine at Mount Sinai, New York, New York, USA (D.I.S.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202101190-005 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationOkumura K, Akao M, Yoshida T, et al. Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med. 2020;383:1735-45. https://pubmed.ncbi.nlm.nih.gov/32865374Clinical Impact RatingsGIM/FP/GP: Cardiology: Geriatrics: References1 Ansell J. Stroke prevention in atrial fibrillation in the very elderly: anticoagulant therapy is no longer a sin. [Editorial]. J Am Heart Assoc. 2017;6:e006864. [PMID: 28736386] Google Scholar2 Patti G, Lucerna M, Pecen L, et al. Thromboembolic risk, bleeding outcomes and effect of different antithrombotic strategies in very elderly patients with atrial fibrillation: a sub-analysis from the PREFER in AF (PREvention oF Thromboembolic Events–European Registry in Atrial Fibrillation). J Am Heart Assoc. 2017;6:e005657. [PMID: 28736385] Google Scholar3 Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-17. [PMID: 21309657] Google Scholar Author, Article, and Disclosure InformationAffiliations: Icahn School of Medicine at Mount Sinai, New York, New York, USA (D.I.S.)Disclosures: The commentator has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-7312.This article was published at Annals.org on 5 January 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics January 2021Volume 174, Issue 1Page: JC5KeywordsAnticoagulantsAtrial fibrillationDrugsElderlyFallsHazard ratioHemorrhageMyocardial infarctionStroke ePublished: 5 January 2021 Issue Published: January 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Public Mobility and Social Media Attention in Response to COVID-19 in Sweden and Denmark
Authors: Le Zhang, Isabell Brikell, Søren Dalsgaard, Zheng Chang
Journal: JAMA Network Open (2021)

This ecological study evaluates the public mobility and social media attention associated with COVID-19 spread and societal interventions from February 15 to June 14, 2020, in Denmark and Sweden.
Targeting Oxidative Phosphorylation to Increase the Efficacy of Radio- and Immune-Combination Therapy
Authors: Daan F. Boreel, Paul N. Span, Sandra Heskamp, Gosse J. Adema, Johan Bussink
Journal: Clinical Cancer Research (2021)

Abstract As tumors grow, they upregulate glycolytic and oxidative metabolism to support their increased and altered energetic demands. These metabolic changes have major effects on the tumor microenvironment. One of the properties leading to this aberrant metabolism is hypoxia, which occurs when tumors outgrow their often-chaotic vasculature. This scarcity of oxygen is known to induce radioresistance but can also have a disrupting effect on the antitumor immune response. Hypoxia inhibits immune effector cell function, while immune cells with a more suppressing phenotype become more active. Therefore, hypoxia strongly affects the efficacy of both radiotherapy and immunotherapy, as well as this therapy combination. Inhibition of oxidative phosphorylation (OXPHOS) is gaining interest for its ability to combat tumor hypoxia, and there are strong indications that this results in a reactivation of the immune response. This strategy decreases oxygen consumption, leading to better oxygenation of hypoxic tumor areas and eventually an increase in immunogenic cell death induced by radio-immunotherapy combinations. Promising preclinical improvements in radio- and immunotherapy efficacy have been observed by the hypoxia-reducing effect of OXPHOS inhibitors and several compounds are currently in clinical trials for their anticancer properties. Here, we will review the pharmacologic attenuation of tumor hypoxia using OXPHOS inhibitors, with emphasis on their impact on the intrinsic antitumor immune response and how this affects the efficacy of (combined) radio- and immunotherapy.
Interaction with biliary and pancreatic fluids drives supersaturation and drug absorption from lipid-based formulations of low (saquinavir) and high (fenofibrate) permeability poorly soluble drugs
Authors: Estelle J.A. Suys, Daniel H.S. Brundel, David K. Chalmers, Colin W. Pouton, Christopher J.H. Porter
Journal: Journal of Controlled Release (2021)