tbuckley/cabot-search huggingface dataset:
Ruxolinitib As Salvage Therapy for Chronic Graft-Versus-Host Disease
Authors: Badri Modi, Michael Hernandez-Henderson, Erin Kopp, Dongyun Yang, Karen Huelsman, Pietro Sollena, Jasmine M. Zain, Haris Ali, Monzr M. Al Malki, Ricardo Spielberger, Sanjeet Dadwal, Amandeep Salhotra, Stephen J. Forman, Pablo Parker, Ryotaro Nakamura
Journal: Blood (2017)
Local delivery of the anti-tumorigenic interleukin-4 (IL-4) cytokine to tumors using an oncolytic adenovirus
Authors: Dawn E. Post, Misako Hwang, Erwin G. Van Meir
Journal: Cancer Research (2005)

1359  Hypoxia is a distinctive attribute of solid tumors that is linked with therapeutic resistance and reduced patient survival in many human cancers. One approach to develop therapeutic strategies targeting hypoxic tumor utilizes the hypoxia-inducible factor (HIF), a transcription factor that is activated in response to hypoxia and tumor-specific genetic alterations. Genes that are transcriptionally activated by HIF encode proteins involved in tumor cell survival and growth. To exploit HIF activation in tumors for therapeutic purposes, we generated novel bi-directional hypoxia/HIF-responsive promoters (Gene Therapy 2001). One of these promoters was then incorporated in an adenovirus genome to regulate the expression of the E1A replication gene, thus producing a hypoxia/HIF-dependent replicative adenovirus (HYPR-Ad#1) with a cytolytic life cycle. In preclinical studies, HYPR-Ad#1 conditionally replicates under hypoxia, kills hypoxic cells, and displays antitumor activity including the prevention of tumor formation and growth inhibition of established tumors. In addition, combining the oncolytic power of HYPR-Ad#1 with BCNU, a chemotherapy that is effective against normoxic cells, led to further tumor growth reduction compared to the monotherapies (Oncogene 2003, Clin Can Res 2004). As a means to enhance the antitumor abilities of HYPR-Ad#1, we have generated a novel second generation virus in which the Ad E1A and interleukin-4 (IL-4) genes are co-regulated by the bidirectional hypoxia/HIF-responsive promoter present within the virus (HYPR-IL4-Ad). IL-4 is a cytokine that exhibits multimodal antitumor activity including the induction of a host immune response against the tumor and inhibition of tumor angiogenesis. The local delivery of IL-4 is important as its systemic expression has serious toxic side effects and this protein has a short half-life. Our preliminary studies in culture demonstrate that HYPR-IL4-Ad expresses IL-4, replicates, and kills tumor cells in a hypoxia/HIF-dependent fashion. We are currently evaluating the antitumor potential of this virus using both human tumor cell lines xenografted in nude mice and immunocompetent rodent tumor models. For the latter, we have characterized two rat glioma cell lines (9L and RG2) and found that they are efficiently infected by wild-type human Ads and undergo cytolysis. These tumor models are valuable tools that will allow us to further study the modulation of the host immune response by this virus. The use of an oncolytic Ad that locally delivers IL-4 to the tumor microenvironment is novel and should exhibit enhanced anti-tumor capabilities compared to the parental HYPR-Ad virus. Most importantly, HYPR-IL4-Ad can be used as a therapy for all solid tumors that develop hypoxia or activated HIF regardless of tissue type or genetic composition.
Epicardial Adipose Tissue Volume As a Marker of Subclinical Coronary Atherosclerosis in Rheumatoid Arthritis
Authors: George A. Karpouzas, Panteha Rezaeian, Sarah R. Ormseth, Ivana Hollan, Matthew J. Budoff
Journal: Arthritis & Rheumatology (2021)

Objective To assess epicardial adipose tissue volume (EATV) and its link to coronary atherosclerosis and plaque morphology in patients with rheumatoid arthritis (RA) and in age‐ and sex‐matched controls. Methods Computed tomography angiography was used to evaluate EATV and coronary plaque in 139 RA patients and 139 non‐RA controls. All models assessing the effect of EATV on plaque were adjusted for age, sex, hypertension, diabetes, dyslipidemia, smoking status, family history of coronary artery disease, and obesity (body mass index of ≥30 kg/m 2 ). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results Mean ± SD log‐transformed EATV was similar in patients with RA (4.69 ± 0.36) and controls (4.70 ± 0.42). EATV was higher in RA patients with atherosclerosis compared to those without atherosclerosis ( P = 0.046). In stratified analyses, EATV was associated with the number of segments with plaque in RA patients (rate ratio 1.20 [95% CI 1.01–1.41] per 1‐SD increment of log‐unit increase in EATV) but not in controls ( P for interaction = 0.089). Likewise, EATV (per 1‐SD log‐unit increase) was related to the presence of multivessel or obstructive disease (OR 1.63 [95% CI 1.04–2.61]), noncalcified plaque (OR 1.78 [95% CI 1.17–2.70]), and vulnerable plaque (OR 1.77 [95% CI 1.03–3.04]) in RA patients but not in controls ( P for interaction ≤ 0.048 for each). Among RA patients, EATV was associated with the number of segments with plaque in those with RA for &lt;10 years who did not develop any cardiovascular risk factors and who were not obese ( P for interaction ≤ 0.017). Conclusion Despite similar EATVs in RA patients and controls, EATVs were associated with greater plaque burden and presence of plaques with a noncalcified component and vulnerability features only in RA patients. EAT may be more pathogenic in RA and play a role in early‐stage atherosclerosis. Its value as a biomarker of subclinical atherosclerosis and cardiovascular risk in RA warrants further studies.
Patient-Reported Outcomes Bridge an Important Gap in Identifying Risk for Early Endocrine Therapy Discontinuation
Authors: Lynne I Wagner
Journal: JNCI Journal of the National Cancer Institute (2021)

I have had the following experience dozens of times while seeing patients alongside a mentor and colleague, who is a highly admired and well-seasoned oncologist.We enter the exam room and my colleague asks, "Mrs Smith, how are you?"The patient smiles and politely responds, "I'm fine."My colleague begins his examination by reviewing her symptom ratings on the questionnaire she completed prior to our entering the room."Your pain is a 4, fatigue an 8, and anxiety a 6!" After completing this clinical encounter, my colleague exits the room, and his puzzled expression clearly conveys his frustration.He wonders aloud, "Why do patients say they're fine?Why don't they really tell me how they're doing?I've been treating Mrs Smith for 10 years.She can tell me anything."This scenario is all too common, as evidenced by accumulating research documenting the lack of concordance between clinicianand patient-rated symptoms and quality of life (1-3).This discrepancy reflects the complexity of patient-provider communication, particularly in the context of cancer treatment.Patients face inherent disincentives to reporting symptoms and toxicities.Patients do not want to distract their oncology team from treating their cancer, and many understand that reports of treatment-related symptoms may result in dose reductions, delays, or discontinuation.Patients are understandably reluctant to spontaneously report symptoms, and providers assume patients will initiate these conversations.Fortunately, patient-reported outcomes (PROs) measures, the gold standard for quantifying symptoms from the patient's perspective (4,5), provide an opportunity to bridge this communication gap and, in doing so, measurably improve care.In a randomized controlled trial, routine PRO assessment resulted in a survival advantage over usual care among patients receiving treatment for advanced cancer (6).Given increased availability of oral therapies, which are often taken on a long-term basis, extending this research to patients with elevated risk for elective discontinuation would generate opportunities to intervene to promote adherence.Patients receiving therapies assumed to be well tolerated may not be routinely assessed for side effects, thus they may be uniquely at risk for nonadherence and not receiving maximum benefit of treatment.
Identification of SARS-CoV-2–specific immune alterations in acutely ill patients
Authors: Rose-Marie Rébillard, Marc Charabati, Camille Grasmuck, Abdelali Filali-Mouhim, Olivier Tastet, Nathalie Brassard, Audrey Daigneault, Lyne Bourbonnière, Sai Priya Anand, Renaud Balthazard, Guillaume Beaudoin-Bussières, Romain Gasser, Mehdi Benlarbi, Ana Carmena Moratalla, Yves Carpentier Solorio, Marianne Boutin, Negar Farzam-kia, Jade Descôteaux-Dinelle, Antoine Philippe Fournier, Elizabeth Gowing, Annemarie Laumaea, Hélène Jamann, Boaz Lahav, Guillaume Goyette, Florent Lemaître, Victoria Hannah Mamane, Jérémie Prévost, Jonathan Richard, Karine Thai, Jean-François Cailhier, Nicolas Chomont, Andrés Finzi, Michaël Chassé, Madeleine Durand, Nathalie Arbour, Daniel E. Kaufmann, Alexandre Prat, Catherine Larochelle
Journal: Journal of Clinical Investigation (2021)

Dysregulated immune profiles have been described in symptomatic patients infected with SARS-CoV-2. Whether the reported immune alterations are specific to SARS-CoV-2 infection or also triggered by other acute illnesses remains unclear. We performed flow cytometry analysis on fresh peripheral blood from a consecutive cohort of (a) patients hospitalized with acute SARS-CoV-2 infection, (b) patients of comparable age and sex hospitalized for another acute disease (SARS-CoV-2 negative), and (c) healthy controls. Using both data-driven and hypothesis-driven analyses, we found several dysregulations in immune cell subsets (e.g., decreased proportion of T cells) that were similarly associated with acute SARS-CoV-2 infection and non–COVID-19-related acute illnesses. In contrast, we identified specific differences in myeloid and lymphocyte subsets that were associated with SARS-CoV-2 status (e.g., elevated proportion of ICAM-1+ mature/activated neutrophils, ALCAM+ monocytes, and CD38+CD8+ T cells). A subset of SARS-CoV-2–specific immune alterations correlated with disease severity, disease outcome at 30 days, and mortality. Our data provide an understanding of the immune dysregulation specifically associated with SARS-CoV-2 infection among acute care hospitalized patients. Our study lays the foundation for the development of specific biomarkers to stratify SARS-CoV-2–positive patients at risk of unfavorable outcomes and to uncover candidate molecules to investigate from a therapeutic perspective.
SARS-CoV-2 vaccine hesitancy among patients with rheumatic and musculoskeletal diseases: a message for rheumatologists
Authors: Roberta Priori, Greta Pellegrino, Serena Colafrancesco, Cristiano Alessandri, Fulvia Ceccarelli, Manuela Di Franco, Valeria Riccieri, Rossana Scrivo, Antonio Sili Scavalli, Francesca Romana Spinelli, Fabrizio Conti
Journal: Annals of the Rheumatic Diseases (2021)

<h3>Objectives</h3> To assess the effect of a temporary interruption in subcutaneous (SC) abatacept on immunogenicity, safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial. <h3>Methods</h3> Following a 12-week open-label introduction (period I; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg), patients were randomised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks (period II). At the end of period II, patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept (12-week open-label period III). The co-primary end points were ELISA-detected immunogenicity rate and safety at the end of period II. Efficacy was also monitored. <h3>Results</h3> Of 167 patients entering period I, 72% qualified for period II; during periods II and III, three patients discontinued treatment. Mean (SD) disease duration was 6.6 (6.5) years and Disease Activity Score 28 was 4.8 (0.8). The primary end point was met, with a non-significant increase in immunogenicity upon withdrawal (7/73 placebo vs 0/38 abatacept in period II; p=0.119) which was reversed upon reintroduction of SC abatacept (2/73 vs 1/38, end period III). Safety was comparable regardless of withdrawal, with no unexpected events upon reintroduction. Two patients experienced reactions at the SC injection site. On withdrawal, patients experienced slight worsening in efficacy which improved following reintroduction. <h3>Conclusions</h3> Overall immunogenicity to SC abatacept is low, consistent with intravenous abatacept, and is not significantly affected by a 3-month interruption and reintroduction. This stop–start schedule was well tolerated, with little impact on safety and efficacy. These are important considerations for the clinical use of SC abatacept. <h3>ClinicalTrials gov</h3> Identifier NCT00533897
Abstract 9517: Long-term Outcomes of 2nd Generation DES Compared to BMS in Patients With Acute Myocardial Infarction- A Meta-Analysis of Randomized Controlled Trials
Authors: Aaqib H Malik, Syed Zaid, Srikanth Yandrapalli, Wilbert S Aronow, Cenap Undemir, Hasan Ahmad
Journal: Circulation (2019)

Introduction: The evidence for safety and efficacy of bare metal stent (BMS) compared to the 2nd generation drug-eluting stents (DES-2nd) for acute myocardial infarction (AMI) in a long-term follow...
Artificial intelligence and pathology: From principles to practice and future applications in histomorphology and molecular profiling
Authors: Albrecht Stenzinger, Maximilian Alber, Michael Allgäuer, Philipp Jurmeister, Michael Bockmayr, Jan Budczies, Jochen Lennerz, Johannes Eschrich, Daniel Kazdal, Peter Schirmacher, Alex H. Wagner, Frank Tacke, David Capper, Klaus-Robert Müller, Frederick Klauschen
Journal: Seminars in Cancer Biology (2021)
Comparing functional decline and distress from symptoms in people with thoracic life-limiting illnesses: lung cancers and non-malignant end-stage respiratory diseases
Authors: Matilda Barnes-Harris, Samuel Allingham, Deidre Morgan, Diana Ferreira, Miriam J Johnson, Kathy Eagar, David Currow
Journal: Thorax (2021)

Malignant and non-malignant respiratory diseases account for >4.6 million deaths annually worldwide. Despite similar symptom burdens, serious inequities in access to palliative care persists for people with non-malignant respiratory diseases.To compare functional decline and symptom distress in advanced malignant and non-malignant lung diseases using consecutive, routinely collected, point-of-care national data.The Australian national Palliative Care Outcomes Collaboration collects functional status (Australia-modified Karnofsky Performance Status (AKPS)) and symptom distress (patient-reported 0-10 numerical rating scale) in inpatient and community settings. Five years of data used Joinpoint and weighted scatterplot smoothing.In lung cancers (89 904 observations; 18 586 patients) and non-malignant end-stage respiratory diseases (14 827 observations; 4279 patients), age at death was significantly lower in people with lung cancer (73 years; IQR 65-81) than non-malignant end-stage respiratory diseases (81 years; IQR 73-87 years; p<0.001). Four months before death, median AKPS was 40 in lung cancers and 30 in non-malignant end-stage respiratory diseases (p<0.001). Functional decline was similar in the two groups and accelerated in the last month of life. People with non-malignant diseases accessed palliative care later.Pain-related distress was greater with cancer and breathing-related distress with non-malignant disease. Breathing-related distress increased towards death in malignant, but decreased in non-malignant disease. Distress from fatigue and poor sleep were similar for both.In this large dataset unlike previous datasets, the pattern of functional decline was similar as was overall symptom burden. Timely access to palliative care should be based on needs not diagnoses.
Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine
Authors: Kai Wu, Anne P Werner, Matthew Koch, Angela Choi, Elisabeth Narayanan, Guillaume B E Stewart-Jones, Tonya Colpitts, Hamilton Bennett, Seyhan Boyoglu-Barnum, Wei Shi, Juan I Moliva, Nancy J Sullivan, Barney S Graham, Andrea Carfi, Kizzmekia S Corbett, Robert A Seder, Darin K Edwards
Journal: New England Journal of Medicine (2021)

Variant SARS-CoV-2 and the mRNA-1273 Vaccine How well do serum samples from persons vaccinated with the mRNA-1273 vaccine neutralize the P.1 lineage, the B.1.1.7 lineage, the B.1.1.7 lineage plus t...
Nutritional Status at Diagnosis and Pre-transplant Weight Loss Impact Outcomes of Acute Myeloid Leukemia Patients Following Allogeneic Stem Cell Transplantation
Authors: Dominic Brauer, Donata Backhaus, Rosmarie Pointner, Vladan Vucinic, Dietger Niederwieser, Uwe Platzbecker, Sebastian Schwind, Madlen Jentzsch
Journal: HemaSphere (2021)

The nutritional status at diagnosis, as well as weight loss during chemotherapy, are important factors for morbidity and mortality in cancer patients. They might also influence outcomes in patients with acute myeloid leukemia (AML) receiving allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the body mass index (BMI) at diagnosis, prior to HSCT, and the BMI difference (ΔBMI = BMI HSCT –BMI diagnosis ) in 662 AML patients undergoing allogeneic HSCT. Patients being obese at AML diagnosis had significantly higher nonrelapse mortality (NRM) and shorter overall survival (OS) after HSCT, but no distinct cumulative incidence of relapse than nonobese patients. Weight loss during chemotherapy (ΔBMI &gt; –2) was a strong predictor for higher NRM and shorter OS in univariate and multivariate analyses. These results were observed across all European LeukemiaNet (ELN) 2017 risk groups but especially in patients with favorable or intermediate ELN2017 risk and patients transplanted in morphologic complete remission. Only in patients being obese at AML diagnosis, weight loss did not result in adverse outcomes. ΔBMI &gt; –2 represents a strong, independent, and modifiable risk factor for AML patients treated with HSCT. Nutritional monitoring and supplementation during disease course might improve patients’ outcomes.
Diagnosis of GORD: is the ‘grey area’ expanding?
Authors: Frank Zerbib
Journal: Gut (2021)

In most patients presenting without alarm features, gastro-oesophageal reflux disease (GORD) is diagnosed empirically, based on symptoms assessment and response to medical therapy, mainly proton pump inhibitors (PPIs). Despite its low specificity (placebo response) and the risk of PPI overuse, the empiric PPI trial is cost-effective and recommended as a first line strategy when GORD is suspected.1 Additional testing is indicated when empiric treatment fails to provide adequate symptom relief and/or prior antireflux surgery. In 2017, the so-called ‘Lyon consensus’ experts proposed guidelines for GORD diagnosis based on the results of endoscopy and ambulatory pH (impedance) monitoring. Briefly, these experts considered as a conclusive diagnosis of GORD the presence of Los Angeles grade C/D oesophagitis, peptic stricture, long-segment Barrett’s mucosa or acid exposure time (AET) superior to 6% on pH monitoring. An AET below 4% is considered as definitely normal, and consequently, the experts acknowledged the possibility of an inconclusive diagnosis in patients with an AET between 4% and 6%: the ‘grey area’. In this situation, considering additional parameters (baseline impedance, histology, oesophageal motility abnormalities) may help to shrink this area as much as possible.

In Gut , Rusu et al report the results of a study which …
Case 5-2021: A 68-Year-Old Man with Delirium and Renal Insufficiency
Authors: David B. Hellmann, Jo-Anne O. Shepard, Pamela W. Schaefer, Jacob H. Johnson, Rory K. Crotty
Journal: New England Journal of Medicine (2021)

A 68-year-old man with a history of bladder cancer presented with delirium, renal insufficiency, unintentional weight loss, and leukopenia. Examination was notable for a subtle facial droop on the left side, bibasilar crackles in the lungs, and hepatosplenomegaly. A diagnosis was made.
Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies
Authors: Amit Bar-Or, Michael P. Pender, Rajiv Khanna, Lawrence Steinman, Hans-Peter Hartung, Tap Maniar, Ed Croze, Blake T. Aftab, Gavin Giovannoni, Manher A. Joshi
Journal: Trends in Molecular Medicine (2021)

In our above review there is an error at the bottom of Figure 1 on the left: the text insert "Co-stimulatory survival signals (CD28-B7) inhibit T cell apoptosis allowing interaction with antigen-presenting cells (astrocytes/microglia)" should be replaced with "Co-stimulatory survival signals (B7) produced by EBV-infected B cells inhibit T cell apoptosis, allowing survival of autoreactive T cells".
Every UK hospital should have a respiratory support unit, say doctors
Authors: Zosia Kmietowicz
Journal: BMJ (2021)

Every UK hospital should have a respiratory support unit, say doctors Zosia KmietowiczDoctors from the British Thoracic Society are calling for the NHS to officially recognise, roll out, and fund respiratory support units across the UK.Arrangements that resemble respiratory support units have emerged during the covid-19 pandemic to care for patients outside critical care units and are increasingly recognised as a way to deliver enhanced respiratory support to people with severe lung disease.
Controlled Comparison of L-Folinic Acid Versus Folic Acid for the Treatment of Hyperhomocysteinemia in Hemodialysis Patients
Authors: Angelito Yango, Douglas Shemin, Lance Dworkin, Paul F Jacques, Jacob Selhub, Andrew G Bostom
Journal: Circulation (2001)

P85 Background:The hyperhomocysteinemia found in most hemodialysis patients is refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid. We evaluated whether a high dose L-folinic acid based regimen provided improved total homocysteine (tHcy) -lowering efficacy in chronic hemodialysis patients, as suggested by a recent uncontrolled report. Methods and Results: We block randomized 48 chronic, stable hemodialysis patients based on their screening pre-dialysis tHcy levels, sex, and dialysis center, into 2 groups of 24 subjects treated for 12-weeks with oral folic acid (FA) at 15 mg/day, or an equimolar amount (20 mg/day) of oral L-folinic acid(FNA)[L-5-formyltetrahydrofolate]. All 48 subjects also received 50 mg/day of oral vitamin B6, and 1.0 mg/day of oral vitamin B12. The mean percent (%) reductions (with 95% confidence intervals) in pre-dialysis tHcy were not significantly different: FNA= 22.1% (11.8-31.4%) ; FA=20.7% (11.7-30.5%) ; P= 0.950 by paired t-test. Final on-treatment values (mean with 95% confidence interval) were, FNA: 15.9 μmol/L (14.0-18.0); FA: 16.9 μmol/L (14.8-18.8). Moreover, in those subjects with baseline tHcy levels ≥14 μmol/L, neither treatment resulted in normalization of tHcy levels (i.e., final on-treatment values &lt; 12 μmol/L) among a significantly different, or clinically meaningful number of patients: FNA= 2/22 (9.1%); FA= 2/24 (8.3%); Fisher s exact test of between groups difference, P=1.000. Conclusions: Relative to high dose folic acid, high dose oral L-folinic acid -based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (i.e., &gt; 90%) exhibit mild hyperhomocysteinemia refractory to treatment with either regimen.