tbuckley/cabot-search huggingface dataset:
Angiotensin II receptor 1 controls profibrotic Wnt/β-catenin signalling in experimental autoimmune myocarditis
Authors: Marcin Czepiel, Dario Diviani, Agnieszka Jaźwa-Kusior, Karolina Tkacz, Filip Rolski, Ryszard T Smolenski, Maciej Siedlar, Urs Eriksson, Gabriela Kania, Przemysław Błyszczuk
Journal: Cardiovascular Research (2021)

Abstract Aims Angiotensin (Ang) II signalling has been suggested to promote cardiac fibrosis in inflammatory heart diseases; however, the underlying mechanisms remain obscure. Using Agtr1a-/- mice with genetic deletion of angiotensin receptor type 1 (ATR1) and the experimental autoimmune myocarditis (EAM) model, we aimed to elucidate the role of Ang II-ATR1 pathway in development of heart-specific autoimmunity and post-inflammatory fibrosis. Methods and results EAM was induced in wild-type (WT) and Agtr1a-/- mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund’s adjuvant. Agtr1a-/- mice developed myocarditis to a similar extent as WT controls at day 21 but showed reduced fibrosis and better systolic function at day 40. Crisscross bone marrow chimaera experiments proved that ATR1 signalling in the bone marrow compartment was critical for cardiac fibrosis. Heart infiltrating, bone-marrow-derived cells produced Ang II, but lack of ATR1 in these cells reduced transforming growth factor beta (TGF-β)-mediated fibrotic responses. At the molecular level, Agtr1a-/- heart-inflammatory cells showed impaired TGF-β-mediated phosphorylation of Smad2 and TAK1. In WT cells, TGF-β induced formation of RhoA-GTP and RhoA-A-kinase anchoring protein-Lbc (AKAP-Lbc) complex. In Agtr1a-/- cells, stabilization of RhoA-GTP and interaction of RhoA with AKAP-Lbc were largely impaired. Furthermore, in contrast to WT cells, Agtr1a-/- cells stimulated with TGF-β failed to activate canonical Wnt pathway indicated by suppressed activity of glycogen synthase kinase-3 (GSK-3)β and nuclear β-catenin translocation and showed reduced expression of Wnts. In line with these in vitro findings, β-catenin was detected in inflammatory regions of hearts of WT, but not Agtr1a-/- mice and expression of canonical Wnt1 and Wnt10b were lower in Agtr1a-/- hearts. Conclusion Ang II-ATR1 signalling is critical for development of post-inflammatory fibrotic remodelling and dilated cardiomyopathy. Our data underpin the importance of Ang II-ATR1 in effective TGF-β downstream signalling response including activation of profibrotic Wnt/β-catenin pathway.
Abstract 15343: Fizz1 Acts as an Endogenous Antagonist of Bone Marrow-Derived Cardiac Protective Adiponectin in a Myocardial Infarction Mouse Model
Authors: Yong Sook Kim, Dong Im Cho, Youngkeun Ahn
Journal: Circulation (2018)

Introduction: Fizz1 (found in inflammatory zone 1 or resistin like α) is known to be upregulated in anti-inflammatory macrophages and to modulate lipid profile in atherosclerosis. Hypothesis: The r...
Outcome of Double-Blind Placebo-Controlled Food Challenges in Shrimp-Sensitized Participants
Authors: Shirly Jiang, Divya Kumar, Shu Cao, Jessica Fitzpatrick, Andrew Long, Margaret Woch, Jenny Johansson, Kari Nadeau, Sharon Chinthrajah, Sayantani Sindher
Journal: Journal of Allergy and Clinical Immunology (2021)
Healthy lifestyle, endoscopic screening, and colorectal cancer incidence and mortality in the United States: A nationwide cohort study
Authors: Kai Wang, Wenjie Ma, Kana Wu, Shuji Ogino, Andrew T. Chan, Edward L. Giovannucci, Mingyang Song
Journal: PLoS Medicine (2021)

Background Healthy lifestyle and screening represent 2 major approaches to colorectal cancer (CRC) prevention. It remains unknown whether the CRC-preventive benefit of healthy lifestyle differs by endoscopic screening status, and how the combination of healthy lifestyle with endoscopic screening can improve CRC prevention. Methods and findings We assessed lifestyle and endoscopic screening biennially among 75,873 women (Nurses’ Health Study, 1988 to 2014) and 42,875 men (Health Professionals Follow-up Study, 1988 to 2014). We defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption, and diet. We calculated hazard ratios (HRs) and population-attributable risks (PARs) for CRC incidence and mortality in relation to healthy lifestyle score according to endoscopic screening. Participants’ mean age (standard deviation) at baseline was 54 (8) years. During a median of 26 years (2,827,088 person-years) follow-up, we documented 2,836 incident CRC cases and 1,013 CRC deaths. We found a similar association between healthy lifestyle score and lower CRC incidence among individuals with and without endoscopic screening, with the multivariable HR per one-unit increment of 0.85 (95% CI, 0.80 to 0.90) and 0.85 (95% CI, 0.81 to 0.88), respectively (P-interaction = 0.99). The fraction of CRC cases that might be prevented (PAR) by endoscopic screening alone was 32% (95% CI, 31% to 33%) and increased to 61% (95% CI, 42% to 75%) when combined with healthy lifestyle (score = 5). The corresponding PAR (95% CI) increased from 15% (13% to 16%) to 51% (17% to 74%) for proximal colon cancer and from 47% (45% to 50%) to 75% (61% to 84%) for distal CRC. Results were similar for CRC mortality. A limitation of our study is that our study participants are all health professionals and predominantly whites, which may not be representative of the general population. Conclusions Our study suggests that healthy lifestyle is associated with lower CRC incidence and mortality independent of endoscopic screening. An integration of healthy lifestyle with endoscopic screening may substantially enhance prevention for CRC, particularly for proximal colon cancer, compared to endoscopic screening alone.
Information and Communication Theoretical Understanding and Treatment of Spinal Cord Injuries: State-of-The-Art and Research Challenges
Authors: Ozgur B. Akan, Hamideh Ramezani, Meltem Civas, Oktay Cetinkaya, Bilgesu A. Bilgin, Naveed A. Abbasi
Journal: IEEE Reviews in Biomedical Engineering (2021)

Among the various key networks in the human body, the nervous system occupies central importance. The debilitating effects of spinal cord injuries (SCI) impact a significant number of people throughout the world, and to date, there is no satisfactory method to treat them. In this paper, we review the major treatment techniques for SCI that include promising solutions based on information and communication technology (ICT) and identify the key characteristics of such systems. We then introduce two novel ICT-based treatment approaches for SCI. The first proposal is based on neural interface systems (NIS) with enhanced feedback, where the external machines are interfaced with the brain and the spinal cord such that the brain signals are directly routed to the limbs for movement. The second proposal relates to the design of self-organizing artificial neurons (ANs) that can be used to replace the injured or dead biological neurons. Apart from SCI treatment, the proposed methods may also be utilized as enabling technologies for neural interface applications by acting as bio-cyber interfaces between the nervous system and machines. Furthermore, under the framework of Internet of Bio-Nano Things (IoBNT), experience gained from SCI treatment techniques can be transferred to nano communication research.
The need for a prediction model assessment framework – Authors' reply
Authors: Mohammad S Jalali, Catherine DiGennaro, Devi Sridhar
Journal: The Lancet Global Health (2021)

We appreciate the feedback provided by Islam and Khosravi on our assessment.1 We agree that journals play an important role in prioritising transparency and reproducibility in publication decisions. Transparency guidelines have been developed. More than 1100 journal publishers have adopted the Transparency and Openness Promotion guidelines,2 including several journals that published models evaluated in our analysis. Despite these important initiatives and ongoing improvements, journals' peer review processes do not fully assess and control for model transparency.
Cytokines of Ejaculate from Men with Chronic Prostatitis/chronic Pelvic Pain Syndromes Treated by Extracorporeal Shockwave Therapy
Authors: I. Gorpynchenko, K. Nurimanov, T. Poroshina, V. Savchenko, G. Drannik, Lawrence Dubuske
Journal: Journal of Allergy and Clinical Immunology (2021)
A Chimeric GM-CSF/IL18 Receptor to Sustain CAR T-cell Function
Authors: Shannon Lange, Laurens G.L. Sand, Matthew Bell, Sagar L. Patil, Deanna Langfitt, Stephen Gottschalk
Journal: Cancer Discovery (2021)

Abstract The inability of chimeric antigen receptor (CAR) T cells to sustain their effector function after repeated exposure to tumor cells is a major obstacle to their success in patients with solid tumors. To overcome this limitation, we designed a novel chimeric cytokine receptor to create an autocrine loop that links activation-dependent GM-CSF production by CAR T cells to IL18 receptor signaling (GM18). Expression of GM18 in CAR T cells enhanced their effector function in an antigen- and activation-dependent manner. In repeat stimulation assays, which mimic chronic antigen exposure, CAR.GM18 T cells had a significantly greater ability to expand and produce cytokines in comparison with their unmodified counterparts targeting EPHA2 or HER2. In vivo, CAR.GM18 T cells induced tumor regression at cell doses at which standard CAR T cells were ineffective in two solid tumor xenograft models. Thus, our study highlights the potential of hijacking cytokines that are physiologically secreted by T cells to bolster their antitumor activity. Significance: We designed a chimeric cytokine receptor (GM18) that links CAR T-cell activation to MYD88 signaling. GM18 endows CAR T cells with sustained effector function in the setting of chronic antigen exposure, resulting in potent antitumor activity in preclinical solid tumor models. This article is highlighted in the In This Issue feature, p. 1601
Saving Lives: Recognizing and Intervening with Youth at Risk for Suicide
Authors: Alejandra Arango, Polly Y. Gipson, Jennifer G. Votta, Cheryl A. King
Journal: Annual Review of Clinical Psychology (2021)

Suicide is the second leading cause of death for youth in the United States. Fortunately, substantial advances have been achieved in identifying and intervening with youth at risk. In this review, we first focus on advances in proactive suicide risk screening and psychoeducation aimed at improving the recognition of suicide risk. These strategies have the potential to improve our ability to recognize and triage youth at risk who may otherwise be missed. We then review recent research on interventions for youth at risk. We consider a broad range of psychotherapeutic interventions, including crisis interventions in emergency care settings. Though empirical support remains limited for interventions targeting suicide risk in youth, effective and promising approaches continue to be identified. We highlight evidence-based screening and intervention approaches as well as challenges in these areas and recommendations for further investigation.
A Responder Analysis To Demonstrate Dupilumab Treatment Effect Across Objective and Patient-Reported Subjective Endpoints For Patients with Severe Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)
Authors: Claus Bachert, Anju Peters, Enrico Heffler, Joseph Han, Heidi Olze, Oliver Pfaar, Chien-Chia Chuang, Raj Rout, Richa Attre, Ledia Goga, Juby Jacob-Nara, Paul Rowe, Yamo Deniz, Zhen Chen, Siddhesh Kamat, Shahid Siddiqui
Journal: Journal of Allergy and Clinical Immunology (2021)
An effective approach for recombinant production of select SARS-CoV-2 proteins in Escherichia coli
Authors: Sayeh Agah, Catherine Thorpe, Martin Chapman, Sabina Wuenschmann
Journal: Journal of Allergy and Clinical Immunology (2021)

Individuals with asthma may be at higher risk of becoming severely ill from COVID-19 which targets the respiratory tract and may cause asthma exacerbations. Serological testing can be useful to assess the true spread of COVID-19 and help protect vulnerable individuals. The SARS-CoV-2 spike and nucleocapsid proteins are the primary viral antigens against which antibodies are raised. We developed an efficient method for production of select SARS-CoV-2 proteins in E. coli to facilitate the development of diagnostics, research, and drug discovery. SARS-CoV-2 Spike-RBD, full-length Nucleocapsid, and Nucleocapsid RNA binding domain (BD), were expressed in E. coli under IPTG induction. The proteins were purified using multi-step chromatography techniques. The purity of the SARS-CoV-2 proteins was assessed by LC-MS/MS, and their IgG reactivity tested using COVID-19 positive patients' sera by ELISA. The Spike-RBD and Nucleocapsid proteins were expressed with high yields. The purified proteins had a relative abundance of >95% as assessed by LC-MS/MS with only trace contamination of host cell proteins. All three proteins showed high IgG reactivity (titers >1/10,000) against COVID-19 sera (n=50), with Spike-RBD and Nucleocapsid RNA-BD exhibiting the highest sensitivity. Production of high quality SARS-CoV-2 proteins is feasible in E.coli and the purified proteins will provide useful tools to study the immune responses involved in COVID-19 including antibody and T cell responses, epitope mapping, diagnostics and drug discovery.
The gut microbiome modulates the protective association between a Mediterranean diet and cardiometabolic disease risk
Authors: Dong D. Wang, Long H. Nguyen, Yanping Li, Yan Yan, Wenjie Ma, Ehud Rinott, Kerry L. Ivey, Iris Shai, Walter C. Willett, Frank B. Hu, Eric B. Rimm, Meir J. Stampfer, Andrew T. Chan, Curtis Huttenhower
Journal: Nature Medicine (2021)
Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study
Authors: M. Tempero, D.-Y. Oh, J. Tabernero, M. Reni, E. Van Cutsem, A. Hendifar, D.-T. Waldschmidt, N. Starling, J.-B. Bachet, H.-M. Chang, J. Maurel, R. Garcia-Carbonero, S. Lonardi, L.M. Coussens, L. Fong, L.C. Tsao, G. Cole, D. James, T. Macarulla
Journal: Annals of Oncology (2021)

First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated.RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed.In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events.Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.
Abstract IA015: Molecular stratification: Beyond TCGA
Authors: David Church
Journal: Clinical Cancer Research (2021)

Abstract The molecular endometrial cancer (EC) classification defined by TCGA has improved both understanding of disease biology and clinical risk stratification. In my talk, I will review data for other biomarkers with proven or potential utility to further refine risk stratification in EC. I will also present results of analysis of whole genome sequence data from the large cohort of ECs recruited to the Genomics England 100,000 Genomes Project, and highlight the promise of this initiative to define new tumour subsets and therapeutic targets. Citation Format: David Church. Molecular stratification: Beyond TCGA [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA015.
Abstract PO047: AVB-500, a receptor tyrosine kinase AXL inhibitor, improves response to olaparib in uterine serous cancer
Authors: Michael D. Toboni, Mary Mullen, Jo'an Tankou, Hollie Noia, Alyssa Oplt, Daniel Wilke, Dineo Khabele, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh
Journal: Clinical Cancer Research (2021)

Abstract Objectives: We determined whether inhibition of GAS6/AXL with AVB-500 in combination with olaparib could improve response in HR-proficient (HRP) uterine serous cancer (USC). Methods: Two USC cell lines (ARK1 &amp; ARK4) were radiated with 10Gy, and RAD51 foci were identified by immunofluorescence (IF). These were treated with AVB-500 (Aravive Biologics, Houston, TX) in combination with the poly ADP ribose polymerase (PARP) inhibitor, olaparib. Colony forming assays were assessed after 4 days of treatment with either AVB-500 alone, olaparib alone or combination treatment (olaparib + AVB-500). Colonies were stained and absorbance was obtained to calculate relative cell survival using Graph Pad Prism. In vivo studies were performed using NOD-SCID mice injected with 1 × 107 ARK1 cells intraperitoneally followed by treatment q3 days for 14-day treatment period. Treatment groups were vehicle control, AVB-500 alone, olaparib alone and olaparib with AVB-500. Results: ARK1 and ARK4 cells were found to have an increase in gamma-H2AX and RAD51 foci after radiation that was consistent with HRP. In clonogenic assays, colonies were stained and absorbance was obtained for each experimental arm. Olaparib + AVB-500 had significantly less absorbance than the olaparib only group for ARK1s (0.417nm vs 0.756nm, p=0.001) as well as in ARK4s (0.186nm vs 0.641nm, p=0.003). In an intraperitoneal model with ARK1 tumors, the olaparib + AVB-500 treated group had less tumor weight than those treated with olaparib alone (0.008g vs 0.138g, p=0.002) and AVB-500 alone (0.008g vs 0.145g, p=0.0006) after a 14-day treatment period. Conclusions: AVB-500 in combination with olaparib demonstrates an improved response than olaparib alone with a greater decrease in tumor burden. This was demonstrated in two HRP cell lines. Additional therapeutic and mechanistic experiments are ongoing. Citation Format: Michael D. Toboni, Mary Mullen, Jo'an Tankou, Hollie Noia, Alyssa Oplt, Daniel Wilke, Dineo Khabele, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh. AVB-500, a receptor tyrosine kinase AXL inhibitor, improves response to olaparib in uterine serous cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO047.
Status of the Clinician Investigator in America: An Essential Healthcare Provider Driving Advances in Cancer Care
Authors: Randall F. Holcombe, Claire F. Verschraegen, Andrew E. Chapman, David Gaffney, Richard M. Goldberg, Ruben A. Mesa, Mohammed Milhem, Martha Mims, Edith P. Mitchell, Dan Mulkerin, Srinivasan Vijayakumar
Journal: Journal of the National Comprehensive Cancer Network (2021)

Translation of basic discoveries to clinical care for patients with cancer is a difficult process greatly enabled by physician-trained researchers. Three categories of physicians, with responsibilities spanning from laboratory and preclinical research to direct patient care, are involved in the translational research continuum: physician-scientist (PS), clinician investigator (CI), and academic clinician (AC).To define how protected time for research efforts is supported, the Association of American Cancer Institutes (AACI) conducted a survey of their member institutions, obtaining 56 responses documenting time spent in research and clinical activities across multiple cancer disciplines, and providing information about funding streams for the different categories of cancer physicians.Responses showed that PSs and ACs are minimally involved in clinical research activities; the driver or clinical research in academic cancer centers is the CI. A significant concern was a lack of stable funding streams for nonbillable clinical research activities, putting the sustainability of the CI in jeopardy. Limited funding was derived from hospital sources, with most support derived from cancer center sources.This study highlights the importance of the CI in translational cancer medicine and represents a call to action for institutions and research funding agencies to develop new programs targeted toward CI support to ensure continued progress against cancer.
Effects of 20,000 EU of Clinical Center Reference Endotoxin (CCRE) versus placebo on systemic and cardiovascular inflammatory responses in mild asthmatics and healthy volunteers
Authors: Stephen Schworer, Alan Hinderliter, Melissa Caughey, Carole Robinette, Kelly Chason, Allison Burbank, Michelle Hernandez
Journal: Journal of Allergy and Clinical Immunology (2021)
αβγδ T cells play a vital role in fetal human skin development and immunity
Authors: René Reitermaier, Thomas Krausgruber, Nikolaus Fortelny, Tanya Ayub, Pablo Augusto Vieyra-Garcia, Philip Kienzl, Peter Wolf, Anke Scharrer, Christian Fiala, Marita Kölz, Manuela Hiess, Martin Vierhapper, Christopher Schuster, Andreas Spittler, Christof Worda, Wolfgang Weninger, Christoph Bock, Wolfgang Eppel, Adelheid Elbe-Bürger
Journal: The Journal of Experimental Medicine (2021)

T cells in human skin play an important role in the immune defense against pathogens and tumors. T cells are present already in fetal skin, where little is known about their cellular phenotype and biological function. Using single-cell analyses, we identified a naive T cell population expressing αβ and γδ T cell receptors (TCRs) that was enriched in fetal skin and intestine but not detected in other fetal organs and peripheral blood. TCR sequencing data revealed that double-positive (DP) αβγδ T cells displayed little overlap of CDR3 sequences with single-positive αβ T cells. Gene signatures, cytokine profiles and in silico receptor–ligand interaction studies indicate their contribution to early skin development. DP αβγδ T cells were phosphoantigen responsive, suggesting their participation in the protection of the fetus against pathogens in intrauterine infections. Together, our analyses unveil a unique cutaneous T cell type within the native skin microenvironment and point to fundamental differences in the immune surveillance between fetal and adult human skin.