tbuckley/cabot-search huggingface dataset:
Endothelial Responses in Sepsis
Authors: Jérémie Joffre, Judith Hellman, Can Ince, Hafid Ait-Oufella
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Endothelial cells (ECs) are vascular, nonconventional immune cells that play a major role in the systemic response after bacterial infection to limit its dissemination. Triggered by exposure to pathogens, microbial toxins, or endogenous danger signals, EC responses are polymorphous, heterogeneous, and multifaceted. During sepsis, ECs shift toward a proapoptotic, proinflammatory, proadhesive, and procoagulant phenotype. In addition, glycocalyx damage and vascular tone dysfunction impair microcirculatory blood flow, leading to organ injury and, potentially, life-threatening organ failure. This review aims to cover the current understanding of the EC adaptive or maladaptive response to acute inflammation or bacterial infection based on compelling recent basic research and therapeutic clinical trials targeting microvascular and endothelial alterations during septic shock.
NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS
Authors: Cynthia Louis, Fernando Souza-Fonseca-Guimaraes, Yuyan Yang, Damian D’Silva, Tobias Kratina, Laura Dagley, Soroor Hediyeh-Zadeh, Jai Rautela, Seth Lucian Masters, Melissa J. Davis, Jeffrey J. Babon, Bogoljub Ciric, Eric Vivier, Warren S. Alexander, Nicholas D. Huntington, Ian P. Wicks
Journal: The Journal of Experimental Medicine (2020)

Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production, as deletion of NK cells, or specific ablation of GM-CSF production in NK cells, abrogated disease. Synovial NK cell production of GM-CSF is IL-18–dependent. Furthermore, we show that cytokine-inducible SH2-containing protein (CIS) is crucial in limiting GM-CSF signaling not only during inflammatory arthritis but also in experimental allergic encephalomyelitis (EAE), a murine model of multiple sclerosis. Thus, a cellular cascade of synovial macrophages, NK cells, and neutrophils mediates persistent joint inflammation via production of IL-18 and GM-CSF. Endogenous CIS provides a key brake on signaling through the GM-CSF receptor. These findings shed new light on GM-CSF biology in sterile tissue inflammation and identify several potential therapeutic targets.
Approach to Transitioning Food-Allergic Patients to Daily Ingestion of Real Food Equivalents after Clinical Trial Participation
Authors: Jake Kattan, Mary Grace Baker, Amanda Cox, Marion Groetch, Allison Schaible, Roxanne Oriel, Angela Tsuang, Anna Nowak-Wegrzyn, Julie Wang, Scott Sicherer
Journal: Journal of Allergy and Clinical Immunology (2020)

Clinical trials for food allergy (FA) often end with participants not able to ingest the targeted food(s) ad lib. We describe an approach to transition food-allergic post-study participants from study doses to daily ingestion of real food equivalents. Post-study participants were offered transition to real food equivalents, if possible. Starting dose was determined based on the study dose/eliciting dose during exit OFC and confirmed by observed feeding. The daily amounts could be as low as a teaspoon fraction of undiluted food. Patients were also offered supervised interval dose-escalations. Patients evaluated from January 2016-May 2019 were identified, and charts were reviewed. Families without recent follow-up were contacted by telephone. This study was IRB approved. Thirty-seven patients (65% male; median age 8.8 years, range 4-24 years) from 8 studies (epicutaneous milk and peanut; egg, wheat, and peanut oral immunotherapy (OIT); multi-food OIT+omalizumab) underwent transition to real food equivalents for milk, baked/lightly-cooked egg, wheat, peanut, tree nuts, sesame, and/or shrimp. Eighteen patients dose-escalated over a median 1-year period for milk, wheat, peanut, almond, and shrimp; nineteen attended just one dosing visit. Four patients achieved doses at/near meal-sized servings of milk, wheat, or baked egg; the others consumed low-dose quantities. Thirty-seven post-study participants transitioned to daily ingestion of real food equivalents for a variety of foods, with half continuing low-dose and others dose-escalating to as much as meal-sized amounts. Transitioning to real food equivalents after FA therapeutic clinical trial may be a desirable option for patients/families and can be customized to individual goals.
Prospective Analysis of Individual Aeroallergen and Food Sensitization Patterns in the First Three Years of Life in Patients with Atopic Dermatitis: Preliminary Observations from the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) Cohort.
Authors: Steven Proper, John Kroner, Hua He, Lisa Martin, Asel Baatyrbek Kyzy, Jocelyn Biagini Myers, Gurjit Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2020)
Seasonal efficacy of mepolizumab in patients with severe eosinophilic asthma – meta-analysis from two phase 3 trials
Authors: Camille Taillé, Elliot Israel, Jason Lee, Alina Gruber, Steven Smith, Stephen Mallett, Steven Yancey, Eric Bradford, Frank Albers, Mark Liu
Journal: Journal of Allergy and Clinical Immunology (2020)
A randomized phase II study of apalutamide (APA), androgen deprivation therapy (ADT), or APA + ADT in patients (pts) with biochemically relapsed (BCR) prostate cancer (PC).
Authors: Rahul Raj Aggarwal, Joshi J. Alumkal, Russell Zelig Szmulewitz, Celestia S. Higano, Alan Haruo Bryce, Angela Lopez-Gitlitz, Sharon Anne McCarthy, Branko Miladinovic, Kelly McQuarrie, Shibu Thomas, Eric Jay Small
Journal: Journal of Clinical Oncology (2020)

320 Background: While there is no standard therapy for BCR PC following local therapy, intermittent ADT is widely used. We evaluated utility of APA alone, ADT (luteinizing hormone–releasing hormone agonist [LHRHa]) alone, or APA + LHRHa in ADT-naïve BCR PC pts. Methods: Pts with BCR PC after primary definitive local therapy and prostate-specific antigen (PSA) doubling time (PSADT) ≤ 12 mo were randomized 1:1:1 to open-label 240 mg APA daily, LHRHa alone, or APA + LHRHa for 12 mo, followed by a 12-mo observation period off therapy. Pts were stratified by PSADT (&lt; 6 vs 6-12 mo) and age (≤ 70 vs &gt; 70 y). Primary end point: mean change from baseline (BL) in health-related quality of life (HRQoL) per Functional Assessment of Cancer Therapy-Prostate total score at 12 mo. Secondary end points included PSA nadir &lt; 0.2 ng/mL by 7 mo, time to PSA progression (TTPpsa), and time to testosterone (T) recovery. Results: 90 pts (APA, n = 29; LHRHa, n = 30; APA + LHRHa, n = 31) were treated for median of 12 mo with similar distribution of BL characteristics across groups: 67% age ≤ 70 y; 67% PSADT &lt; 6 mo. There was no significant difference in HRQoL in APA vs LHRHa at 12 mo, or between LHRHa vs APA + LHRHa groups. At median follow-up of 30-33 mo, TTPpsa in APA, LHRHa, and APA + LHRHa groups was 26 mo, 31 mo, and 36 mo, respectively. Compared to LHRHa alone, APA + LHRHa resulted in a trend toward improved TTPpsa (HR [95% CI] 0.56 [0.23-1.36], p = 0.196), and APA alone resulted in a trend for shorter TTPpsa (HR 1.09 [0.49-2.43], p = 0.824). PSA nadir &lt; 0.2 ng/mL was reached in 89%, 89%, and 97% in APA, LHRHa, and APA + LHRHa pts. Median time to T recovery was similar in LHRHa and APA + LHRHa groups (23 mo vs 24 mo). Grade 3-4 adverse events (AEs) occurred in 17% of APA, 14% of LHRHa, and 29% of APA + LHRHa pts. The only grade 3-4 AE reported in &gt; 1 pt per group was hypertension (APA, 3%; LHRHa, 0; APA + LHRHa, 13%). Conclusions: Addition of APA to LHRHa resulted in a trend for longer TTPpsa and a higher proportion of pts achieving optimal PSA nadir without significant difference in HRQoL or time to T recovery. Observed AEs were consistent with known safety profiles. Results support further evaluation of APA + LHRHa for a specified duration in BCR PC. Clinical trial information: NCT01790126.
CAMSAP2-mediated noncentrosomal microtubule acetylation drives hepatocellular carcinoma metastasis
Authors: Dongxiao Li, Xiangming Ding, Meng Xie, Zheng Huang, Ping Han, Dean Tian, Limin Xia
Journal: Theranostics (2020)

Rationale: Emerging evidence suggests that noncentrosomal microtubules play an essential role in intracellular transport, cell polarity and cell motility. Whether these noncentrosomal microtubules exist or function in cancer cells remains unclear. Methods: The expression and prognostic values of CAMSAP2 and its functional targets were analyzed by immunohistochemistry in two independent HCC cohorts. Immunofluorescence and co-immunoprecipitation were used for detection of CAMSAP2-decorated noncentrosomal microtubule. Chromatin immunoprecipitation and luciferase report assays were used to determine the c-Jun binding sites in HDAC6 promoter region. In vitro migration and invasion assays and in vivo orthotopic metastatic models were utilized to investigate invasion and metastasis. Results: We reported a microtubule minus‑end‑targeting protein, CAMSAP2, is significantly upregulated in hepatocellular carcinoma (HCC) and correlated with poor prognosis. CAMSAP2 was specifically deposited on microtubule minus ends to serve as a "seed" for noncentrosomal microtubule outgrowth in HCC cells. Upon depletion of CAMSAP2, the noncentrosomal microtubule array was transformed into a completely radial centrosomal pattern, thereby impairing HCC cell migration and invasion. We further demonstrated that CAMSAP2 cooperates with EB1 to regulate microtubule dynamics and invasive cell migration via Trio/Rac1 signaling. Strikingly, both immunofluorescence staining and western blotting showed that CAMSAP2 depletion strongly reduced the abundance of acetylated microtubules in HCC cells. Our results revealed that HDAC6, a promising target for cancer therapy, was inversely downregulated in HCC and uniquely endowed with tumor-suppressive activity by regulation CAMSAP2-mediated microtubule acetylation. Mechanistically, CAMSAP2 activates c-Jun to induce transrepression of HDAC6 through Trio-dependent Rac1/JNK pathway. Furthermore, NSC23766, a Rac1-specific inhibitor significantly inhibited CAMSAP2-mediated HCC invasion and metastasis. Conclusions: CAMSAP2 is functionally, mechanistically, and clinically oncogenic in HCC. Targeting CAMSAP2-mediated noncentrosomal microtubule acetylation may provide new therapeutic strategies for HCC metastasis.
Evaluating the tolerability of a simultaneous focal boost to the gross tumor in prostate SABR: A toxicity and quality-of-life comparison of two prospective trials.
Authors: Yasir Alayed, Melanie Davidson, William Chu, Stanley K. Liu, Chia-Lin Tseng, Patrick Cheung, Danny Vesprini, Hans T. Chung, Gerard Morton, Hima Bindu Musunuru, Ananth Ravi, Renee Korol, Andrea Deabreu, Kristina Commisso, Zeeba Bhounr, Laura D'alimonte, Nicole Mittmann, Alice Dragomir, Liying Zhang, Andrew Loblaw
Journal: Journal of Clinical Oncology (2020)

319 Background: Dose-escalated SABR to the whole prostate may be associated with better outcomes, but at a risk of increased toxicity. An alternative approach is to focally boost the dominant intraprostatic lesion (DIL) seen on MRI. We report the toxicity and quality of life (QOL) outcomes of two phase II trials of prostate and pelvic SABR, with or without a simultaneous DIL boost. Methods: The first trial treated patients with high-risk prostate cancer (PCa) to a dose of 40 Gy to the prostate and 25 Gy to the pelvis in 5 fractions. The second trial treated patients with intermediate-risk and high-risk PCa to a dose of 35 Gy to the prostate, 25 Gy to the pelvis, and a DIL boost up to 50 Gy in 5 fractions. Acute toxicities, late toxicities and QOL were assessed. Results: 30 patients were enrolled in each trial. In the focal boost cohort, the median DIL D90% was 48.3 Gy. There was no significant difference in acute grade ≥2 GI or GU toxicity between the two trials, or cumulative worst late GI or GU toxicity up to 24 months. There was no significant difference in QOL domain scores or minimally clinical important change between the two trials. Conclusions: Prostate and pelvic SABR with a simultaneous DIL boost was feasible and did not lead to a significant change in toxicity or QOL when compared to a cohort that did not receive a focal boost. Further follow-up will be required to assess long-term outcomes. Clinical trial information: NCT02911636.
PIVOTALboost Trial contouring RTQA.
Authors: Isabel Syndikus, Alison Tree, John Staffurth, Helen Mayles, Olivia Frances Naismith, Amir Montazeri, Emma Hall
Journal: Journal of Clinical Oncology (2020)

373 Background: The PIVOTALboost trial (ISRCTN80146950) recruits patients with intermediate and high risk, localised prostate cancer; it tests the role of pelvic node radiotherapy and the effectiveness of a focal intra-prostate IMRT boost. Prior to opening to recruitment a contouring QA program was designed aiming to improve consistency in clinical outlining. Methods: Intra-prostatic boosting was a new treatment method for all but 3 trial centers. Guidelines for boost contouring and pelvic node outlining were circulated. Clinicians were sent two different cases with the clinical case description, biopsy details, the diagnostic pre-biopsy multi-parametric MRI (T2W and DWI sequences) and planning CT and MRI scans. They were asked to contour prostate, seminal vesicle (CTVp, CTVpsv), lymph node (CTVn) for 1 case and boost volume (GTVpb) for both cases. The 3 lead trial clinicians contoured the cases independently, agreed on gold standard outlines and criteria for failing the submission. Center’ benchmark case submissions were reviewed and standardized feedback forms returned to each clinician. General issues were addressed during a trial launch workshop. Results: There was good agreement of the contours for CTVp, CTVpsv and CTVn between the 3 lead clinicians for the gold standard; more discussions were required to agree GTVpb. Criteria for re-submission were: contours &gt;6mm beyond or &gt;3mm inside the superior and inferior level, included OARs, excluded SV base or extracapsular extension. In addition, for GTVpb, the wrong segment, extension outside CTVp, outlining abnormalities &lt;5mm in diameter or a volume &gt; or &lt; 50% of the gold standard. 35 center and 54 clinicians submitted outlines: for CTVp/psv 24/54 failed, CTVn 14/54 failed, GTVpb 23/48 failed (6 investigators did not submit a volume). All center passed the re-submission; for the on trial outlining review, 9 centres have not recruited a patient for the on trial review process, 18 passed and 8 failed. Conclusions: Errors and inconsistencies were common in the benchmark outlining exercises for the trial. Individual feedback, guidelines and clinical support has reduced outlining variations without delaying the opening of the trial; it has helped to standardize contouring and engage clinicians in the trial process. Clinical trial information: 80146950.
Cancer stage and quality of life in bladder cancer.
Authors: Hannah McCloskey, Sean McCabe, Kathryn Gessner, Pauline Filippou, Judy Hamad, Allison Mary Deal, Angela Smith, John L. Gore
Journal: Journal of Clinical Oncology (2020)

466 Background: Bladder cancer requires treatment and surveillance which varies in intensity by disease stage. Our objective was to evaluate stage-specific differences in generic and bladder cancer-specific quality of life (QOL) among a large bladder cancer cohort. Methods: We performed a cross-sectional survey of bladder cancer patients using the Bladder Cancer Advocacy Network Patient Survey Network and Inspire platforms to determine generic and bladder cancer-specific QOL using the EORTC QLQ-C30 and Bladder Cancer Index. Patients were also queried regarding demographic, socioeconomic and clinical characteristics. We present descriptive statistics and a multiple linear regression model to identify factors independently associated with QOL domain score. Results: 972 respondents self-identified as patients with bladder cancer. Among respondents, 41% were female and 97% were white. The mean age was 67.6 years (range 29 to 93 years). Patients identified as having non-muscle-invasive bladder cancer (NMIBC, n=578 [63%]), MIBC (n=270, 30%), and metastatic bladder cancer (n=63, 7%). On bivariable analysis ( Table), lower stage was significantly associated with better generic (p&lt;0.01) and bladder-cancer specific QOL (p&lt;0.01). This associated persisted on multivariable analysis adjusted for age, sex, race, years since diagnosis, and comorbidity (p&lt;0.01 for generic, urinary, sexual, and bowel QOL). Conclusions: Disease stage significantly impacts generic and bladder cancer-specific QOL among bladder cancer survivors. Differential impact by stage may be important for the development of tailored interventions to improve QOL for bladder cancer patients. [Table: see text]
Association of De Ritis Ratio and Neutrophil Lymphocyte Ratio with renal functional decline and all-cause mortality in renal cell carcinoma.
Authors: Cathrine Keiner, Margaret Meagher, Dattatraya Patil, Kazutaka Saito, Devin Patel, Fady Ghali, Raksha Dutt, Nathan Miller, Aaron Bradshaw, Fang Wan, Yosuke Yasuda, Yasuhisa Fuji, Viraj A. Master, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2020)

741 Background: We sought to investigate utility of pre-operative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and De Ritis Ratio as predictors of all-cause mortality (ACM) and renal functional decline renal cell carcinoma (RCC). Methods: Multi-institutional retrospective analysis of patients undergoing surgery for RCC. Multivariable analysis (MVA) was conducted to elucidate independent risk factors for ACM, de novo estimated glomerular filtration rate (eGFR)&lt;45 ml/min/1.73m2 and eGFR&lt;30 ml/min/1.73m2. Kaplan-Meier analysis (KMA) was used to investigate ACM, and de novo CKD. Results: 2928 patients were analyzed [1850 Male/1078 Female, median follow up 30.5 months, median tumor size 4.5 cm, 1741 partial nephrectomy (PN)/1187 radical nephrectomy (RN)]. 690 patients had NLR ≥ 3, while 208 patients had NLR ≥ 6; 110 patients had PLR ≥ 3; and 474 patients had De Ritis Ratio ≥ 3. MVA for risk factors associated with worsened ACM showed male sex (OR 1.6, p=0.02), HTN (OR 2.1, p=0.001), increasing tumor size (OR 1.12, p&lt;0.001), clear cell RCC (OR 2.0, p=0.001), RN (OR 1.6, p=0.048), NLR≥ 6 (OR=2.4, p=0.001), Di Ritis Ratio≥3 (OR 2.4, p&lt;0.001), and de novo eGFR&lt;45 (OR=1.6, p=0.015) to be independent risk factors. MVA for factors associated with development of eGFR&lt;45 included increasing age (OR 1.03, p&lt;0.001), male (OR 1.5, p=0.01), HTN (OR 2.3, p&lt;0.001), clear cell RCC (OR 2.2, p&lt;0.001), RN (OR 6.8, p=0.03), NLR≥6 (OR 2.0, p=0.002), and Di Ritis Ratio≥3 (OR 2.3, p&lt;0.001) to be independently associated. Variables associated with development of eGFR&lt;30 included age (OR 1.05, p&lt;0.001), DM (OR=3.01, p&lt;0.001), black race (OR 1.9, p=0.005), Di Ritis Ratio≥3 (OR 2.0, p=0.001), and NLR≥6 (OR 2.1, p=0.002). PLR was not associated with OS, de novo eGFR&lt;45, or de novo eGFR&lt;30. On KMA, NLR≥6 was associated with worse OS (p&lt;0.001). Di Ritis ratio ≥1.5 was associated with worse OS p&lt;0.001 and Di Ritis ratio (≥3) was associated decreased freedom from of de novo eGFR&lt;45 (p=0.026). Conclusions: Elevated NLR and De Ritis Ratio were associated with functional decline and worsened OS, while PLR was not predictive. These markers may be helpful in identifying high-risk patients.
A role for connexin-43 in Duchenne muscular dystrophy cardiomyopathy
Authors: Robin M. Shaw, Jeffrey E. Saffitz
Journal: Journal of Clinical Investigation (2020)

The cardiomyopathy of Duchenne muscular dystrophy (DMD) is an important cause of morbidity and mortality in affected males with this dreaded muscle disease. Previous studies have implicated changes in expression and subcellular localization of connexin-43 (Cx43), the major ventricular gap junction protein, in DMD cardiomyopathy. In this issue of the JCI, Himelman et al. explore how hypophosphorylation of Cx43 at a triplet of serine residues (S325/S328/S330) in the regulatory C-terminus contributes to multiple features of the cardiomyopathy phenotype. Using a mouse model of DMD cardiomyopathy in which phosphomimetic glutamic acids are substituted for serines at these residues in Cx43, Himelman et al. observed reduced gap junction remodeling and lateralization of Cx43 immunosignals, protection against isoproterenol-induced arrhythmias, and improved Ca2+ homeostasis. This study contributes to the understanding of pathologic Cx43 remodeling and encourages further research into developing strategic interventions to mitigate cardiac dysfunction and arrhythmias in DMD patients.
Association of Penicillin Allergy Documentation and Antibiotic Use: A National Inpatient Study
Authors: Kimberly Blumenthal, Xiaoqing Fu, Yuqing Zhang, Kristi Kuper, Lucas Schulz, Tanaya Bhowmick, Michael Postelnick, Francesca Lee, Rochelle Walensky
Journal: Journal of Allergy and Clinical Immunology (2020)
Author Correction: Interaction between the microbiome and TP53 in human lung cancer
Authors: K. Leigh Greathouse, James R. White, Ashely J. Vargas, Valery V. Bliskovsky, Jessica A. Beck, Natalia von Muhlinen, Eric C. Polley, Elise D. Bowman, Mohammed A. Khan, Ana I. Robles, Tomer Cooks, Bríd M. Ryan, Noah Padgett, Amiran H. Dzutsev, Giorgio Trinchieri, Marbin A. Pineda, Sven Bilke, Paul S. Meltzer, Alexis N. Hokenstad, Tricia M. Stickrod, Marina R. Walther-Antonio, Joshua P. Earl, Joshua C. Mell, Jaroslaw E. Krol, Sergey V. Balashov, Archana S. Bhat, Garth D. Ehrlich, Alex Valm, Clayton Deming, Sean Conlan, Julia Oh, Julie A. Segre, Curtis C. Harris
Journal: Genome biology (2020)

Following publication of the original paper [1], the authors submitted a new Additional file 5 to replace the one containing formatting issues. The updated Additional file 5 is published in this correction.
Cardiac screening of athletes: consensus needed for clinicians on indications for follow-up echocardiography testing
Authors: Jessica J Orchard, John W Orchard, Andre La Gerche, Christopher Semsarian
Journal: British Journal of Sports Medicine (2020)

Many sporting teams, leagues and federations now mandate cardiac screening of athletes. The most common screening protocol in Australian sports involves a personal/family history and physical examination, together with a resting 12-lead ECG.1 Some bodies, such as the Union Cycliste Internationale, the England and Wales Cricket Board and the UK Football Association also mandate two-dimensional transthoracic echocardiography as part of the standard screen. While echocardiography is sometimes used as a screening tool, the variable use of this modality in cardiac screening programmes raises the issue of when this test should be used as a diagnostic tool for the follow-up evaluation of other screening abnormalities. There is a need for clear consensus guidance, which should take into account the additional costs, as well as the potential benefits of echocardiography and the potential harms of incidental findings.

We audited the national cardiac screening programme of elite men’s and women’s Australian cricket.2 The protocol consists of history, physical examination and ECG. Overall, 2.0% of ECGs were abnormal or had ≥2 borderline findings according to the international criteria for athlete ECG interpretation,3 although 5.5% of cases had an echocardiogram, which …
IL-1β, IL-6, and IL-8-inducing Potential of Indoor Settled Dust from Homes One and Two-Years Post-Hurricane Maria in San Juan, Puerto Rico
Authors: Hayat Srour, Summer Pellechio, Ruslan Fomenko, Benjamin Bolanos, Filipa Godoy-Vitorino, Juan Maestre, Kerry Kinney, Humberto Cavallin
Journal: Journal of Allergy and Clinical Immunology (2020)