tbuckley/cabot-search huggingface dataset:
Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study
Authors: Alessandro M. Vannucchi, Benedetta Sordi, Alessandro Morettini, Carlo Nozzoli, Loredana Poggesi, Filippo Pieralli, Alessandro Bartoloni, Alessandro Atanasio, Filippo Miselli, Chiara Paoli, Giuseppe G. Loscocco, Andrea Fanelli, Ombretta Para, Andrea Berni, Irene Tassinari, Lorenzo Zammarchi, Laura Maggi, Alessio Mazzoni, Valentina Scotti, Giorgia Falchetti, Danilo Malandrino, Fabio Luise, Giovanni Millotti, Sara Bencini, Manuela Capone, Marie Pierre Piccinni, Francesco Annunziato, Paola Guglielmelli, Francesco Mannelli, Giacomo Coltro, Duccio Fantoni, Miriam Borella, Enrica Ravenda, Benedetta Peruzzi, Roberto Caporale, Lorenzo Cosmi, Francesco Liotta, Letizia Lombardelli, Federica Logiodice, Anna Vanni, Lorenzo Salvati, Chiara Lazzeri, Manuela Bonizzoli, Adriano Peris, Giovanni Cianchi, Alberto Bosi, Michela Pucatti, Paolo Fontanari, Silvia Benemei, Marco Matucci Cerinic, Lucia Turco
Journal: Leukemia (2020)

Abstract Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71–93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 &lt; 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and thrombocytopenia. Improvement of inflammatory cytokine profile and activated lymphocyte subsets was observed at day 14. In this prospective cohort of aged and high-risk comorbidity patients with severe COVID-19, compassionate-use ruxolitinib was safe and was associated with improvement of pulmonary function and discharge home in 85.3%. Controlled clinical trials are necessary to establish efficacy of ruxolitinib in COVID-19.
M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer
Authors: Michal Hensler, Lenka Kasikova, Karel Fiser, Jana Rakova, Petr Skapa, Jan Laco, Tereza Lanickova, Ladislav Pecen, Iva Truxova, Sarka Vosahlikova, Irena Moserova, Ivan Praznovec, Vit Drochytek, Martina Rehackova, Tomas Brtnicky, Lukas Rob, Vladimir Benes, Jelena Pistolic, Ludek Sojka, Ales Ryska, Catherine Sautes-Fridman, Wolf Herve Fridman, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases. Methods RNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8 + T cells, CD20 + B cells, DC-LAMP + (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46 + (natural killer) cells and CD68 + CD163 + M2-like tumor-associated macrophages (TAMs), abundance of PD-1 + (programmed cell death 1), LAG-3 + (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples. Results 1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome. Conclusions Immunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.
Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial
Authors: Peter J Goadsby, David W Dodick, Jessica Ailani, Joel M Trugman, Michelle Finnegan, Kaifeng Lu, Armin Szegedi
Journal: The Lancet Neurology (2020)
Plasmablastic Morphology—An Independent Prognostic Factor With Clinical and Laboratory Correlates: Eastern Cooperative Oncology Group (ECOG) Myeloma Trial E9486 Report by the ECOG Myeloma Laboratory Group
Authors: Philip R. Greipp, Traci Leong, John M. Bennett, Jean P. Gaillard, Bernard Klein, James A. Stewart, Martin M. Oken, Neil E. Kay, Brian Van Ness, Robert A. Kyle
Journal: Blood (1998)
Addressing Influenza Vaccination Disparities During the COVID-19 Pandemic
Authors: Lisa A. Grohskopf, Leandris C. Liburd, Robert R. Redfield
Journal: JAMA (2020)

Addressing Influenza Vaccination Disparities During the COVID-19 PandemicEach year, influenza poses a substantial burden on communities and health care systems.During the 3 most recent influenza seasons (2016-2017, 2017-2018, and 2018-2019), influenza is estimated to have been associated with 29 million to 45 million illnesses, 14 million to 21 million medical visits, 490 600 to 810 000 hospitalizations, and 34 200 to 61 000 deaths each season in the US. 1 During the fall of 2020, both influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; the virus associated with coronavirus disease 2019 [COVID-19]) are anticipated to circulate.As of August 17, 2020, SARS-CoV-2 has been associated with more than 5.3 million infections and more than 168 000 deaths in the US. 2 Even a moderately severe influenza season in the presence of circulating SARS-CoV-2 would significantly amplify cases of acute respiratory illness, and more intensely stress health care personnel and resources, including hospitals, emergency departments, outpatient departments, and physicians' offices.However, less than half of US adults receive an influenza vaccine each year (Table ). 3 Even after the severe 2017-2018 influenza season, overall vaccine coverage remained at about 45% during the subsequent (2018-2019) season, and long-standing and substantial disparities, particularly by race and ethnicity, persisted
Comment on Löndahl. Number Eight in the Service of Diabetic Foot Ulcer Healing. Diabetes Care 2020;43:515–517
Authors: Robert G. Frykberg
Journal: Diabetes Care (2020)

We appreciate the thoughtful commentary by Londahl (1) on our recent article (2) describing the positive results of our double-blinded, randomized, placebo-controlled trial of the effect of cyclical, pressurized Topical Wound Oxygen (TWO2) therapy for healing chronic diabetic foot ulcers (DFUs). Recognizing that no study can be considered perfect in design, execution, or outcomes, we welcome this opportunity to address the concerns raised by Dr. Londahl pertaining to the aforementioned randomized controlled trial (RCT) (2).

First, we do agree that the results of recent hyperbaric oxygen therapy (HBOT) trials are inconsistent and generally fail to provide robust evidence to support the adjunctive use of HBOT for DFUs (3–5). Much of the failure to provide consistent results is due to study design deficiencies; heterogeneity in study populations, inclusion criteria, and outcome measures (DFU healing vs. amputation); lack of sham controls; and loss of subjects because of adverse events and early terminations (6,7). Furthermore, intention-to-treat (ITT) analyses of all enrolled study populations has not been uniformly reported (3). Another difficulty in this regard …
Accounting for indirect protection in the benefit–risk ratio estimation of rotavirus vaccination in children under the age of 5 years, France, 2018
Authors: Sylvie Escolano, Judith E Mueller, Pascale Tubert-Bitter
Journal: Eurosurveillance (2020)

Background Rotavirus is a major cause of severe gastroenteritis in children worldwide. The disease burden has been substantially reduced in countries where rotavirus vaccines are used. Given the risk of vaccine-induced intussusception, the benefit–risk balance of rotavirus vaccination has been assessed in several countries, however mostly without considering indirect protection effects. Aim We performed a benefit–risk analysis of rotavirus vaccination accounting for indirect protection in France among the 2018 population of children under the age of 5 years. Methods To incorporate indirect protection effects in the benefit formula, we adopted a pseudo-vaccine approach involving mathematical approximation and used a simulation design to provide uncertainty intervals. We derived background incidence distributions from quasi-exhaustive health claim data. We examined different coverage levels and assumptions regarding the waning effects and intussusception case fatality rate. Results With the current vaccination coverage of &lt; 10%, the indirect effectiveness was estimated at 6.4% (+/− 0.4). For each hospitalisation for intussusception, 277.0 (95% uncertainty interval: (165.0–462.1)) hospitalisations for rotavirus gastroenteritis were prevented. Should 90% of infants be vaccinated, indirect effectiveness would reach 57.9% (+/− 3.7) and the benefit–risk ratio would be 192.4 (95% uncertainty interval: 116.4–321.3). At a coverage level of 50%, indirect protection accounted for 27% of the prevented rotavirus gastroenteritis cases. The balance remained in favour of the vaccine even in a scenario with a high assumption for intussusception case fatality. Conclusions These findings contribute to a better assessment of the rotavirus vaccine benefit–risk balance.
Determinants of LV Dilatation in Patients With Hypertrophic Cardiomyopathy and Preserved Systolic Function
Authors: Seth Uretsky, Areeb Bangash, Ethan Rowin, Stephen Horgan, Soichiro Hiramatsu, Glenmore Lasam, Linda D. Gillam, Martin Maron
Journal: JACC. Cardiovascular imaging (2020)
The development of metabolic endotoxemia is dependent on the type of sweetener and the presence of saturated fat in the diet
Authors: Mónica Sánchez-Tapia, Aaron W. Miller, Omar Granados-Portillo, Armando R. Tovar, Nimbe Torres
Journal: Gut Microbes (2020)

Fat and sweeteners contribute to obesity. However, it is unknown whether specific bacteria are selectively modified by different caloric and noncaloric sweeteners with or without a high-fat diet (HFD). Here, we combined extensive host phenotyping and shotgun metagenomics of the gut microbiota to investigate this question. We found that the type of sweetener and its combination with an HFD selectively modified the gut microbiota. Sucralose and steviol glycosides led to the lowest α-diversity of the gut microbiota. Sucralose increased the abundance of B. fragilis in particular, resulting in a decrease in the abundance of occludin and an increase in proinflammatory cytokines, glucose intolerance, fatty acid oxidation and ketone bodies. Sucrose+HFD showed the highest metabolic endotoxemia, weight gain, body fat, total short chain fatty acids (SCFAs), serum TNFα concentration and glucose intolerance. Consumption of sucralose or sucrose resulted in enrichment of the bacterial genes involved in the synthesis of LPS and SCFAs. Notably, brown sugar and honey were associated with the absence of metabolic endotoxemia, increases in bacterial gene diversity and anti-inflammatory markers such as IL-10 and sIgA, the maintenance of glucose tolerance and energy expenditure, similar to the control group, despite the consumption of an HFD. These findings indicate that the type of sweetener and an HFD selectively modify the gut microbiota, bacterial gene enrichment of metabolic pathways involved in LPS and SCFA synthesis, and metabolic endotoxemia associated with different metabolic profiles.
Extracellular Vesicle–Derived miR-124 Resolves Radiation-Induced Brain Injury
Authors: Ron J. Leavitt, Munjal M. Acharya, Janet E. Baulch, Charles L. Limoli
Journal: Cancer Research (2020)

Abstract Radiation-induced cognitive dysfunction (RICD) is a progressive and debilitating health issue facing patients following cranial radiotherapy to control central nervous system cancers. There has been some success treating RICD in rodents using human neural stem cell (hNSC) transplantation, but the procedure is invasive, requires immunosuppression, and could cause other complications such as teratoma formation. Extracellular vesicles (EV) are nanoscale membrane-bound structures that contain biological contents including mRNA, miRNA, proteins, and lipids that can be readily isolated from conditioned culture media. It has been previously shown that hNSC-derived EV resolves RICD following cranial irradiation using an immunocompromised rodent model. Here, we use immunocompetent wild-type mice to show that hNSC-derived EV treatment administered either intravenously via retro-orbital vein injection or via intracranial transplantation can ameliorate cognitive deficits following 9 Gy head-only irradiation. Cognitive function assessed on the novel place recognition, novel object recognition, and temporal order tasks was not only improved at early (5 weeks) but also at delayed (6 months) postirradiation times with just a single EV treatment. Improved behavioral outcomes were also associated with reduced neuroinflammation as measured by a reduction in activated microglia. To identify the mechanism of action, analysis of EV cargo implicated miRNA (miR-124) as a potential candidate in the mitigation of RICD. Furthermore, viral vector–mediated overexpression of miR-124 in the irradiated brain ameliorated RICD and reduced microglial activation. Our findings demonstrate for the first time that systemic administration of hNSC-derived EV abrogates RICD and neuroinflammation in cranially irradiated wild-type rodents through a mechanism involving miR-124. Significance: Radiation-induced neurocognitive decrements in immunocompetent mice can be resolved by systemic delivery of hNSC-derived EVs involving a mechanism dependent on expression of miR-124.
Abstract 6386: Combined PDE4 and VEGFR2 inhibition as a new preclinical rationale in clear cell renal cell carcinoma
Authors: Minghua Cao, Karol Nawalaniec, Yueming Luo, Romana Moench, Li-Li Hsiao, Ana Maria Waaga-Gasser
Journal: Cancer Research (2020)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms have been described. Previous studies have indicated cross-talk between the cAMP pathway and the MAPK pathway, and the elevation of cAMP levels by inhibition of Phosphodiesterase-4 (PDE4) activities can result in growth arrest and/or cell death. In this study we focused on the effects of PDE4 in ccRCC. We first analyzed the expression of PDE4 in human RCC cell lines and found PDE4D to be dominantly expressed. PDE4D CRISPR Knockout (KO) was then performed on Caki-1 RCC cells and normal renal proximal tubular epithelial cells as control. Cell proliferation, cell cycle cAMP, MAPK plus PI3K/AKT signaling pathways were additionally analyzed to define the effects of PDE4D inhibition. PDE4D KO Caki-1 cells showed decreased cell viability and a higher apoptosis rate compared with wild type controls. Increased intracellular cAMP levels in PDE4D KO resulted in downregulated MAPK but not PI3K/AKT signaling in Caki-1 tumor cells. In addition, PDE4D KO Caki-1 cells demonstrated higher sensitivity to VEGFR inhibitors. To conclude, we provide a new preclinical rationale for dual PDE4/VEGFR2 inhibition in patients with ccRCC. While the MAPK signaling pathway is activated in ccRCC, dual inhibitors may improve the anti-tumor effects in a patient subset with evidence of MAPK involvement. Future work involving in vivo models will be useful to better define efficacy of this dual strategy of anti-tumor activity. Citation Format: Minghua Cao, Karol Nawalaniec, Yueming Luo, Romana Moench, Li-Li Hsiao, Ana Maria Waaga-Gasser. Combined PDE4 and VEGFR2 inhibition as a new preclinical rationale in clear cell renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6386.
THU0006 Dqb1 polymorphism in rheumatoid arthritis patients with shared epitope-negative drb1 alleles
Authors: R Zunec, Z Grubic, D Babic-Naglic, N Laktasic-Zerjavic, K Potocki, A Kastelan
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The association of rheumatoid arthritis (RA) with HLA-DRB1 alleles sharing sequences in the third hypervariable region has been reported in several investigations, but genetic analyses suggest the possible involvement of other HLA class II genes in conferring susceptibility. <h3>Objectives</h3> We have investigated the distribution of HLA-DQB1-DRB1 polymorphism in 87 RA patients from southern Croatia and 141 healthy controls. RA patients were predominantly females (83 females vs 5 males). <h3>Methods</h3> All patients and controls were tested for HLA class II alleles (DRB1, DQA1, and DQB1) by PCR-SSP method. <h3>Results</h3> Distribution of predisposing DRB1 alleles according to the shared epitope (SE) model showed that 11 patients were homozygous for the predisposing alleles. Additional 48 patients carried one of the SE predisposing alleles (*0101, *1001, *0401, *0404, *0405, *0408). Distribution of DQB1 alleles among patients with SE-positive DRB1 alleles revealed that all DRB1*0101 and *1001 patients were DQB1*0501 positive. Among twenty patients with SE-positive DRB1*04 alleles, three different DQB1 alleles were observed (DQB1*0301, *0302 and *0201). Remaining 26 patients with SE-negative DRB1 alleles were additionally analysed for the presence of DQB1*0301, *0302 and *0201 alleles. All eight patients with SE negative DRB1*04 alleles (DRB1*0402, *0403, *0407) were DQB1*0302 positive. Among the remaining non DRB1*04 patients, 16 were either DQB1*0301 or *0201 and only two patients did not carry neither DQB1*0301 nor *0201. <h3>Conclusion</h3> These data suggest that in patients with SE negative DRB1 alleles, DQB1*0301, *0302 and *0201 alleles should be considered as a genes contributing to the RA predisposition. DQB1*0301, *0302 and *0201 alleles should be considered as a genes contributing to the RA predisposition.
Abstract 16660: Estradiol-Induced Phosphorylation of Myosin Regulatory Light Chain Leads to Increased Female Cardiomyocyte Contractility
Authors: Georgios Kararigas, Virginie Bito, Karin R Sipido, Vera Regitz-Zagrosek
Journal: Circulation (2011)

Myosin regulatory light chain (Mrlc) controls actin/myosin interactions and modulation of contraction by Mrlc in the heart has been well documented. Notably, mutant mice for Mrlc phosphorylation show defects in cardiac contraction. The sex steroid hormone 17β-estradiol (E2) has been shown to exert several cardioprotective actions. However, little is known about the effects of E2 on the regulation of Mrlc and contractile function. Here, we tested the hypothesis that E2 increases the phosphorylation of Mrlc, which in turn leads to improved cardiomyocyte contractile function. One set of 14-month old female C57BL/6J mice were injected intraperitonealy with 0.2 mg/kg E2 ( n = 8) or vehicle (Ctrl; n = 5). Five hours after injection, cardiomyocytes (CMs) were enzymatically isolated with the Langendorff-perfusion system, which were used for unloaded cell shortening measurements. Another set of female mice with the same age and strain ( n = 6 per group) were treated in exactly the same manner and left ventricles were collected for protein extraction. Western blot analysis revealed that E2-treated CMs had higher levels of phosphorylated Mrlc than Ctrl CMs. Recordings of unloaded cell shortening at 1, 2 and 4 Hz demonstrated that the treatment with E2 improved CM contractile function compared to Ctrl CMs. In particular, at 1 Hz there was a 29.6% increase (adjusted P = 0.005), at 2 Hz a 31.5% increase (adjusted P = 0.009) and at 4 Hz a 29.3% increase (adjusted P = 0.01). For each frequency, 37 E2-treated and 45 Ctrl CMs were measured. Similarly, there was a significant increase in the rate of contraction of E2-treated CMs compared to controls. To our knowledge, our present work is the first to implicate E2 in the modulation of Mrlc phosphorylation leading to improved contractile function.
A Gastric Submucosal Polypoid Lesion With Whitish Protuberance
Authors: Shin Kashima, Mikihiro Fujiya, Takuma Goto
Journal: Clinical Gastroenterology and Hepatology (2020)

A 74-year-old woman had nausea and underwent esophagogastroduodenoscopy. At the greater curvature of the lower body of the stomach, we found a reddened submucosal polypoid lesion (Figure A). At the top of the elevation, a whitish protuberance was detected (Figure B). We initially suspected the whitish protuberance of being a foreign object, such as a fish bone. The surface was shiny and smooth, with vessel-like lines detected inside (Figure C). We therefore suspected as Anisakis. On endoscopic observation, it weaved and migrated deep into submucosa. We then grasped its root using biopsy forceps and completely removed it without tearing off the body (Figure D). After esophagogastroduodenoscopy, she mentioned having eaten raw flatfish the day before. Human anisakiasis is a parasitic disease that develops following the ingestion of raw marine fish containing the third-stage larvae of Anisakis species. The larvae penetrate the gastric or intestinal walls and cause gastrointestinal and/or allergic symptoms. Endoscopic removal of the larvae using biopsy forceps is curative, but once the larvae migrate deep into the gastric submucosa, they must be removed carefully. Because of the global spread of raw seafood consumption, anisakiasis should always be considered as a differential diagnosis in patients with acute abdominal symptoms. This is a case report, and we did not receive any approval from the ethics review board. Written informed consent was obtained from the patient for the publication of this case report and accompanying images.
Prevalence, pathophysiology and management of itch in epidermolysis bullosa*
Authors: M. Papanikolaou, A. Onoufriadis, J.E. Mellerio, L.A. Nattkemper, G. Yosipovitch, M. Steinhoff, J.A. McGrath
Journal: British Journal of Dermatology (2020)

Epidermolysis bullosa (EB) is a highly diverse group of inherited skin disorders, resulting from mutations in genes encoding proteins of the dermoepidermal junction. Itch (pruritus) is one of the most common symptoms across all EB subtypes. It occurs in blistered or wounded sites, or manifests as a generalized phenomenon, thereby affecting both intact skin and healing wounds. The mechanism of pruritus in EB is unclear. It is likely that skin inflammation secondary to barrier disruption, wound healing cascades and dysregulated activation of epidermal sensory nerve endings are all involved in its pathophysiology on the molecular and cellular level. Understanding these mechanisms in depth is crucial in developing optimized treatments for people with EB and improving quality of life. This review summarizes current evidence on the prevalence, mechanisms and management of itch in EB.
Incomplete Response of Gastroesophageal Reflux Symptoms Poorly Predicts Erosive Esophagitis or Barrett’s Esophagus
Authors: Joel H. Rubenstein, Li Jiang, Jacob E. Kurlander, Joan Chen, Valbona Metko, Maryam Khodadost, Kimberly Nofz, Trivellore Raghunathan
Journal: Clinical Gastroenterology and Hepatology (2020)