tbuckley/cabot-search huggingface dataset:
Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial
Authors: Robert J. Kreitman, Claire Dearden, Pier Luigi Zinzani, Julio Delgado, Tadeusz Robak, Philipp D. le Coutre, Bjørn T. Gjertsen, Xavier Troussard, Gail J. Roboz, Lionel Karlin, Douglas E. Gladstone, Nataliya Kuptsova-Clarkson, Shiyao Liu, Priti Patel, Federico Rotolo, Emmanuel Mitry, Ira Pastan, Francis Giles
Journal: Journal of Hematology & Oncology (2021)

Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL).Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days.Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26-48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3-4 events; these events were generally reversible. No treatment-related deaths were reported.Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy.ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711.
Covid-19: All adults on learning disability register should be prioritised for vaccination, says advisory committee
Authors: Elisabeth Mahase
Journal: BMJ (2021)

The UK government’s vaccine advisory committee has said that all people on the GP Learning Disability Register should now be invited for a covid-19 vaccine as part of priority group 6.

The Joint Committee on Vaccination and Immunisation (JCVI) said that adults with other related conditions such as cerebral palsy should also be invited and that local authorities should help to identify adults with learning disabilities in residential and nursing care, as well as those who require assisted living support and those in shared accommodation with multiple occupancy.

This will mean that at least 150 000 more people …
Is Quality of Life (QOL) Predictive for Clinical Response in Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Patients Treated with Dasatinib?
Authors: Tatiana Ionova, Natalia Bulieva, Anatoly Golenkov, Taras Gritsenko, Lilia Kozlova, Galina Kuchma, Elza Lomaia, Elena Machulaytene, Tatiana Nikitina, Natalia Novitskaya, Elena Usacheva, Tatiana Shneider, Elena Trifonova, Olga Vinogradova, Anna Zinkovskaya
Journal: Blood (2017)
SOURCE: Prediction Models for Overall Survival in Patients With Metastatic and Potentially Curable Esophageal and Gastric Cancer
Authors: Héctor G. van den Boorn, Ameen Abu-Hanna, Nadia Haj Mohammad, Maarten C.C.M. Hulshof, Suzanne S. Gisbertz, Bastiaan R. Klarenbeek, Marije Slingerland, Laurens V. Beerepoot, Tom Rozema, Mirjam A.G. Sprangers, Rob H.A. Verhoeven, Martijn G.H. van Oijen, Koos H. Zwinderman, Hanneke W.M. van Laarhoven
Journal: Journal of the National Comprehensive Cancer Network (2021)

Personalized prediction of treatment outcomes can aid patients with cancer when deciding on treatment options. Existing prediction models for esophageal and gastric cancer, however, have mostly been developed for survival prediction after surgery (ie, when treatment has already been completed). Furthermore, prediction models for patients with metastatic cancer are scarce. The aim of this study was to develop prediction models of overall survival at diagnosis for patients with potentially curable and metastatic esophageal and gastric cancer (the SOURCE study).Data from 13,080 patients with esophageal or gastric cancer diagnosed in 2015 through 2018 were retrieved from the prospective Netherlands Cancer Registry. Four Cox proportional hazards regression models were created for patients with potentially curable and metastatic esophageal or gastric cancer. Predictors, including treatment type, were selected using the Akaike information criterion. The models were validated with temporal cross-validation on their C-index and calibration.The validated model's C-index was 0.78 for potentially curable gastric cancer and 0.80 for potentially curable esophageal cancer. For the metastatic models, the c-indices were 0.72 and 0.73 for esophageal and gastric cancer, respectively. The 95% confidence interval of the calibration intercepts and slopes contain the values 0 and 1, respectively.The SOURCE prediction models show fair to good c-indices and an overall good calibration. The models are the first in esophageal and gastric cancer to predict survival at diagnosis for a variety of treatments. Future research is needed to demonstrate their value for shared decision-making in clinical practice.
Evidence for Modulation of Substance Use Disorders by the Gut Microbiome: Hidden in Plain Sight
Authors: Mariana Angoa-Pérez, Donald M. Kuhn
Journal: Pharmacological Reviews (2021)

The gut microbiome modulates neurochemical function and behavior and has been implicated in numerous central nervous system (CNS) diseases, including developmental, neurodegenerative, and psychiatric disorders. Substance use disorders (SUDs) remain a serious threat to the public well-being, yet gut microbiome involvement in drug abuse has received very little attention. Studies of the mechanisms underlying SUDs have naturally focused on CNS reward circuits. However, a significant body of research has accumulated over the past decade that has unwittingly provided strong support for gut microbiome participation in drug reward. <i>β</i>-Lactam antibiotics have been employed to increase glutamate transporter expression to reverse relapse-induced release of glutamate. Sodium butyrate has been used as a histone deacetylase inhibitor to prevent drug-induced epigenetic alterations. High-fat diets have been used to alter drug reward because of the extensive overlap of the circuitry mediating them. This review article casts these approaches in a different light and makes a compelling case for gut microbiome modulation of SUDs. Few factors alter the structure and composition of the gut microbiome more than antibiotics and a high-fat diet, and butyrate is an endogenous product of bacterial fermentation. Drugs such as cocaine, alcohol, opiates, and psychostimulants also modify the gut microbiome. Therefore, their effects must be viewed on a complex background of cotreatment-induced dysbiosis. Consideration of the gut microbiome in SUDs should have the beneficial effects of expanding the understanding of SUDs and aiding in the design of new therapies based on opposing the effects of abused drugs on the host's commensal bacterial community. <h3>Significance Statement</h3> Proposed mechanisms underlying substance use disorders fail to acknowledge the impact of drugs of abuse on the gut microbiome. <i>β</i>-Lactam antibiotics, sodium butyrate, and high-fat diets are used to modify drug seeking and reward, overlooking the notable capacity of these treatments to alter the gut microbiome. This review aims to stimulate research on substance abuse–gut microbiome interactions by illustrating how drugs of abuse share with antibiotics, sodium butyrate, and fat-laden diets the ability to modify the host microbial community.
Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis
Authors: Canan Kasikara, Maaike Schilperoort, Brennan Gerlach, Chenyi Xue, Xiaobo Wang, Ze Zheng, George Kuriakose, Bernhard Dorweiler, Hanrui Zhang, Gabrielle Fredman, Danish Saleheen, Muredach P. Reilly, Ira Tabas
Journal: Journal of Clinical Investigation (2021)

Efferocytosis, the process through which apoptotic cells (ACs) are cleared through actin-mediated engulfment by macrophages, prevents secondary necrosis, suppresses inflammation, and promotes resolution. Impaired efferocytosis drives the formation of clinically dangerous necrotic atherosclerotic plaques, the underlying etiology of coronary artery disease (CAD). An intron of the gene encoding PHACTR1 contains rs9349379 (A>G), a common variant associated with CAD. As PHACTR1 is an actin-binding protein, we reasoned that if the rs9349379 risk allele G causes lower PHACTR1 expression in macrophages, it might link the risk allele to CAD via impaired efferocytosis. We show here that rs9349379-G/G was associated with lower levels of PHACTR1 and impaired efferocytosis in human monocyte–derived macrophages and human atherosclerotic lesional macrophages compared with rs9349379-A/A. Silencing PHACTR1 in human and mouse macrophages compromised AC engulfment, and Western diet–fed Ldlr–/– mice in which hematopoietic Phactr1 was genetically targeted showed impaired lesional efferocytosis, increased plaque necrosis, and thinner fibrous caps — all signs of vulnerable plaques in humans. Mechanistically, PHACTR1 prevented dephosphorylation of myosin light chain (MLC), which was necessary for AC engulfment. In summary, rs9349379-G lowered PHACTR1, which, by lowering phospho-MLC, compromised efferocytosis. Thus, rs9349379-G may contribute to CAD risk, at least in part, by impairing atherosclerotic lesional macrophage efferocytosis.
Residency Match in the Virtual World
Authors: Charles C. Flippen
Journal: JAMA Neurology (2021)

Residency Match in the Virtual WorldThe year 2020 has and will continue to be historical because of the economic and social upheaval in our country as a result of the coronavirus disease 2019 (COVID-19) pandemic.Once the pandemic was declared in March 2020, the regulatory bodies for undergraduate and graduate medical education implemented COVID-19 policies for the protection of learners and modification of processes to minimize the effect of the pandemic circumstances on the progress of students and trainees.On May 11, 2020, the Coalition for Physician Accountability's Work Group on Medical Students in the Class of 2021, Moving Across Institutions for Post Graduate Training, and a body of medical training stakeholders from the American Association of Colleges of Osteopathic Medicine, American Association of Medical Colleges, Accreditation Council for Graduate Medical Education, Assembly of Osteopathic Graduate Medical Educators, American Medical Association, Council of Medical Specialty Societies, Educational Commission for Foreign Medical Graduates, and the National Residency Match Program published recommendations to ensure an equitable residency selection process for medical students. 1The recommendations endorsed by the coalition members included (1) discouraging travel rotations except in instances where the students have a specialty interest where a clinical experience is not available in their school's system or an away rotation was needed to meet institution graduation requirements; (2) all residency programs commit to virtual interview processes; and (3) the Electronic Residency Application Service opening and release of Medical Student Performance Evaluations be delayed and done on the same day. 1 These recommendations along with local institutional travel and visitor prohibitions quickly transformed the residency recruitment landscape to a virtual world that presents challenges to programs and student applicants.Students are faced with making specialty choices based only on their third-year medical school clerkship experience and for students pursuing neurology, possibly deciding without a clinical experience if they attend schools without required neurology clinical experiences.The absence of visiting electives along with virtual interviewing significantlyaffectsstudentdecision-makingregardingthe ranking of programs for the Match.These in-person experiences allow students to observe interactions between residents and faculty, along with getting a feel for the culture of a program.Assessing these relationships is a challenge in the virtual space.The benefits of the virtual interview for students include the ability to apply to more programs without regard to travel costs or time.This so-called unlimited opportunity may be double edged as there is likely an opportunity cost with limited interview time and the challenge of ranking a large number of programs.
Repeatability and sensitivity to change of non-invasive end points in PAH: the RESPIRE study
Authors: Andrew J Swift, Frederick Wilson, Marcella Cogliano, Lindsay Kendall, Faisal Alandejani, Samer Alabed, Paul Hughes, Yousef Shahin, Laura Saunders, Charlotte Oram, David Capener, Alex Rothman, Pankaj Garg, Christopher Johns, Matthew Austin, Alistair Macdonald, Jo Pickworth, Peter Hickey, Robin Condliffe, Anthony Cahn, Allan Lawrie, Jim M Wild, David G Kiely
Journal: Thorax (2021)

Abstract End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test–retest repeatability was assessed using the intraclass correlation coefficient and treatment effect size using Cohen’s d statistic. Intraclass correlation coefficients demonstrated excellent repeatability for MRI, 6 min walk test and log to base 10 N-terminal pro-brain natriuretic peptide (log 10 NT-proBNP). The treatment effect size for MRI-derived right ventricular ejection fraction was large (Cohen’s d 0.81), whereas the effect size for the 6 min walk test (Cohen’s d 0.22) and log 10 NT-proBNP (Cohen’s d 0.20) were fair. This study supports further evaluation of MRI as a non-invasive end point for clinical assessment and PAH therapy trials. Trial registration number NCT03841344 .
Excessive <i>O</i> -GlcNAcylation Causes Heart Failure and Sudden Death
Authors: Priya Umapathi, Olurotimi O. Mesubi, Partha S. Banerjee, Neha Abrol, Qinchuan Wang, Elizabeth D. Luczak, Yuejin Wu, Jonathan M. Granger, An-Chi Wei, Oscar E. Reyes Gaido, Liliana Florea, C. Conover Talbot, Gerald W. Hart, Natasha E. Zachara, Mark E. Anderson
Journal: Circulation (2021)

Background: Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O -GlcNAcylation (the attachment of O -linked β-N-acetylglucosamine [ O -GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O -GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA). Failing myocardium is marked by increased O -GlcNAcylation, but whether excessive O -GlcNAcylation contributes to cardiomyopathy and heart failure is unknown. Methods: We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O -GlcNAcylation independent of pathologic stress. Results: We found that OGT transgenic hearts showed increased O -GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O -GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O -GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O -GlcNAc–mediated cardiac pathology. Conclusions: Our data provide evidence that excessive O -GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O -GlcNAcylation is beneficial against pressure overload–induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O -GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.
Abstract 12305: Exercise Capacity and Chronotropic Incompetence in Patients After Mitral Valve Surgery
Authors: Masanori Kanazawa, Maiko Toyoda, Takahiro Seki, Atsuhiro Iguchi, Seisho Takahashi, Yuta Kagaya, Hiroki Saito, Kenjiro Sato, Koki Ito, Masanobu Miura, Masateru Kondo, Satoshi Kawatsu, Hideaki Endo, Katsuhiko Oda, Akihiro Nakamura
Journal: Circulation (2019)

Introduction: Chronotropic incompetence (CI) is sometimes observed during exercise in patients who underwent cardiac surgery, however, little is known concerning the differences between patients wi...
Multifunctional Surfaces for Improving Soft Tissue Integration
Authors: Adriana Vilaça, Rui M. A. Domingues, Hanna Tiainen, Bárbara B. Mendes, Alejandro Barrantes, Rui L. Reis, Manuela E. Gomes, Manuel Gomez‐Florit
Journal: Advanced Healthcare Materials (2021)

Abstract Metallic implants are widely used in diverse clinical applications to aid in recovery from lesions or to replace native hard tissues. However, the lack of integration of metallic surfaces with soft tissue interfaces causes the occurrence of biomaterial‐associated infections, which can trigger a complicated inflammatory response and, ultimately, implant failure. Here, a multifunctional implant surface showing nanoscale anisotropy, based on the controlled deposition of cellulose nanocrystals (CNC), and biological activity derived from platelet lysate (PL) biomolecules sequestered and presented on CNC surface, is proposed. The anisotropic radial nanopatterns are produced on polished titanium surfaces by spin‐coating CNC at high speed. Furthermore, CNC surface chemistry allows to further sequester and form a coating of bioactive molecules derived from PL. The surface anisotropy provided by CNC guides fibroblasts growth and alignment up to 14 days of culture. Moreover, PL‐derived biomolecules polarize macrophages toward the M2‐like anti‐inflammatory phenotype. These results suggest that the developed multifunctional surfaces can promote soft tissue integration to metallic implants and, at the same time, prevent bacterial invasion, tissue inflammation, and failure of biomedical metallic implants.
Astrocytes mediate the effect of oxytocin in the central amygdala on neuronal activity and affective states in rodents
Authors: Jérôme Wahis, Angel Baudon, Ferdinand Althammer, Damien Kerspern, Stéphanie Goyon, Daisuke Hagiwara, Arthur Lefevre, Lara Barteczko, Benjamin Boury-Jamot, Benjamin Bellanger, Marios Abatis, Miriam Da Silva Gouveia, Diego Benusiglio, Marina Eliava, Andrei Rozov, Ivan Weinsanto, Hanna Sophie Knobloch-Bollmann, Matthew K. Kirchner, Ranjan K. Roy, Hong Wang, Marie Pertin, Perrine Inquimbert, Claudia Pitzer, Jan Siemens, Yannick Goumon, Benjamin Boutrel, Christophe Maurice Lamy, Isabelle Decosterd, Jean-Yves Chatton, Nathalie Rouach, W. Scott Young, Javier E. Stern, Pierrick Poisbeau, Ron Stoop, Pascal Darbon, Valery Grinevich, Alexandre Charlet
Journal: Nature Neuroscience (2021)
Antineutrophil cytoplasm antibody positivity, kidney impairment, and cholesterol embolization
Authors: Tariq E. Farrah, Neeraj Dhaun
Journal: Kidney International (2021)

A 63-year-old woman presented with a painful lower leg lesion. Past medical history included hypertension, cerebrovascular disease, and previous cigarette smoking. Examination revealed a large nodular, necrotic ulcer, and livedo reticularis (Supplementary Figures S1 and S2). Initial investigations showed an elevated C-reactive protein level (60 mg/L; normal <5), eosinophilia (1.26 x 109/L; normal range: 0.04–0.4), and acute kidney injury with a serum creatinine level of 146 μmmol/L (normal range: 60–110), compared to 78 μmmol/L 2 months earlier. The urine protein:creatinine ratio was 146 mg/mmol (normal range: 0–30). Antineutrophil cytoplasm antibodies against myeloperoxidase were elevated (10 IU/ml; normal range: 0–5). The patient then developed painful cyanosis of her toes (Figure 1a) and a contrast-enhanced computed tomography scan showed diffuse, noncalcified atheromatous plaque in the thoracic aorta (Supplementary Figure S3, arrows). A renal biopsy showed focal ischemic glomerulosclerosis and mild tubulointerstitial inflammation. Necrotizing lesions, crescents, and arteritis were absent. A skin biopsy showed dermal arteriolar luminal occlusion with cholesterol clefts (Figure 1b, arrows) and associated endothelial-cell swelling with a reactive inflammatory infiltrate but no features of vasculitis or calciphylaxis. The myeloperoxidase antineutrophil cytoplasm antibody titre spontaneously fell to undetectable levels within 3 months of presentation. Despite supportive care, the patient's kidney function deteriorated to require hemodialysis, and she died a year later. Cholesterol embolization follows fracturing of an atherosclerotic plaque and occurs most commonly following an invasive arterial procedure such as coronary angiography. In 1%–2% of patients, often those with severe atherosclerosis, it may be spontaneous. Cholesterol embolization may present with nonspecific features such as fever, weight loss, and elevated inflammatory markers, and so may mimic systemic autoimmune disease. The initial immune response is characterized by neutrophil infiltration of affected arterioles. Degranulation and release of cytoplasmic antigens by these activated neutrophils may generate antineutrophil cytoplasm antibodies. Diagnosis requires demonstration of cholesterol clefts in occluded blood vessels of affected organs. Treatment is mainly supportive. Download .pdf (14.88 MB) Help with pdf files Supplementary File (PDF)