tbuckley/cabot-search huggingface dataset:
Vaccines for immunoprevention of cancer
Authors: Tomohiro Enokida, Alvaro Moreira, Nina Bhardwaj
Journal: Journal of Clinical Investigation (2021)

The immunoprevention of cancer and cancer recurrence is an important area of concern for the scientific community and society as a whole. Researchers have been working for decades to develop vaccines with the potential to alleviate these health care and economic burdens. So far, vaccines have made more progress in preventing cancer than in eliminating already established cancer. In particular, vaccines targeting oncogenic viruses, such as the human papillomavirus and the hepatitis B virus, are exceptional examples of successful prevention of virus-associated cancers, such as cervical cancer and hepatocellular carcinoma. Cancer-preventive vaccines targeting nonviral antigens, such as tumor-associated antigens and neoantigens, are also being extensively tested. Here, we review the currently approved preventive cancer vaccines; discuss the challenges in this field by covering ongoing preclinical and clinical human trials in various cancers; and address various issues related to maximizing cancer vaccine benefit.
CONTEMPORARY SEX DIFFERENCES IN SHORT- AND LONG-TERM MORTALITY AMONG PATIENTS WITH ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Ziwei Xi, Hong Qiu, Tingting Guo, Yong Wang, Jianan Li, Yang Li, Kefei Dou, Weixian Yang, Shubin Qiao, Bo Xu, YueJin Yang, Runlin Gao
Journal: Journal of the American College of Cardiology (2021)
Comparative immune profiling of acute respiratory distress syndrome patients with or without SARS-CoV-2 infection
Authors: Mikael Roussel, Juliette Ferrant, Florian Reizine, Simon Le Gallou, Joelle Dulong, Sarah Carl, Matheiu Lesouhaitier, Murielle Gregoire, Nadège Bescher, Clotilde Verdy, Maelle Latour, Isabelle Bézier, Marie Cornic, Angélique Vinit, Céline Monvoisin, Birgit Sawitzki, Simon Leonard, Stéphane Paul, Jean Feuillard, Robin Jeannet, Thomas Daix, Vijay K. Tiwari, Jean Marc Tadié, Michel Cogné, Karin Tarte
Journal: Cell Reports Medicine (2021)

Acute respiratory distress syndrome (ARDS) is the main complication of coronavirus disease 2019 (COVID-19), requiring admission to the intensive care unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS differs from other causes of ARDS remains unknown. To address this question, here, we build 3 cohorts of patients categorized in COVID-19-ARDS+, COVID-19+ARDS+, and COVID-19+ARDS-, and compare, by high-dimensional mass cytometry, their immune landscape. A cell signature associating S100A9/calprotectin-producing CD169+ monocytes, plasmablasts, and Th1 cells is found in COVID-19+ARDS+, unlike COVID-19-ARDS+ patients. Moreover, this signature is essentially shared with COVID-19+ARDS- patients, suggesting that severe COVID-19 patients, whether or not they experience ARDS, display similar immune profiles. We show an increase in CD14+HLA-DRlow and CD14lowCD16+ monocytes correlating to the occurrence of adverse events during the ICU stay. We demonstrate that COVID-19-associated ARDS displays a specific immune profile and may benefit from personalized therapy in addition to standard ARDS management.
Sustained Effect of a Brief Video in Reducing Public Stigma Toward Individuals With Psychosis: A Randomized Controlled Trial of Young Adults
Authors: Doron Amsalem, John C. Markowitz, Samantha E. Jankowski, Lawrence H. Yang, Linda Valeri, Sarah A. Lieff, Yuval Neria, Lisa B. Dixon
Journal: American Journal of Psychiatry (2021)

Objective: Public stigma is a barrier to care and increases the duration of untreated psychosis among individuals with first-episode psychosis. The authors recently demonstrated the efficacy of a 90-second social contact–based video intervention in reducing such stigma. That proof-of-concept study was the first to employ so brief an antistigma intervention in a sample of young adults. The authors now present a randomized controlled replication study with baseline, postintervention, and 30-day follow-up assessments. The authors aimed to replicate their previous findings and to show a persisting benefit for the video intervention. Methods: Using a crowdsourcing platform (Amazon Mechanical Turk), the authors recruited and assigned 1,055 participants ages 18–30 years to a brief video-based intervention, to a written vignette intervention containing the same material, or to a nonintervention control condition. In the 90-second video, a 22-year-old African American woman with schizophrenia humanized the illness through her emotional description of living a meaningful and productive life. Results: A three-by-three group-by-time multivariate analysis of variance showed a significant group-by-time interaction for the total scores of all five stigma-related domains: social distance, stereotyping, separateness, social restriction, and perceived recovery. Post hoc pairwise tests showed greater reductions in the video group compared with the vignette and control groups at the postintervention and 30-day follow-up assessments, while the vignette group differed from the control group at the postintervention assessment but not at the 30-day assessment. Conclusions: This randomized controlled study replicated and strengthened the authors' earlier findings, further showing month-long sustained stigma reduction in the social contact–based video intervention arm. A 90-second video sufficed to humanize schizophrenia and reduce stigma. Further research should examine longer-term sustainability, assess changes in behavior, and determine optimal effective video length.
Periosteal Tissue Engineering: Current Developments and Perspectives
Authors: Yiting Lou, Huiming Wang, Guanchen Ye, Yongzheng Li, Chao Liu, Mengfei Yu, Binbin Ying
Journal: Advanced Healthcare Materials (2021)

Abstract Periosteum, a highly vascularized bilayer connective tissue membrane plays an indispensable role in the repair and regeneration of bone defects. It is involved in blood supply and delivery of progenitor cells and bioactive molecules in the defect area. However, sources of natural periosteum are limited, therefore, there is a need to develop tissue‐engineered periosteum (TEP) mimicking the composition, structure, and function of natural periosteum. This review explores TEP construction strategies from the following perspectives: i) different materials for constructing TEP scaffolds; ii) mechanical properties and surface topography in TEP; iii) cell‐based strategies for TEP construction; and iv) TEP combined with growth factors. In addition, current challenges and future perspectives for development of TEP are discussed.
INITIAL, MAXIMUM, AND DELTA TROPONIN AND MORTALITY IN COVID-19
Authors: Ronaldo Go, Brent Klinkhammer, Steven Hollenberg, David Landers, Zoltan Turi, Taya Glotzer, Sameer Jamal, Lucy Safi, Noha Gayed, Matthew Fata, Neel Shah, Roshan Shah, Spencer Haber, Thomas Jaten, Jana Tancredi, Elli Gourna-Paleoudis, Themba Nyirenda, Michael Marafelias, Joseph Parrillo
Journal: Journal of the American College of Cardiology (2021)
Abstract 16947: Mitochondrial Calcium Uniporter Channel Blockade Ameliorates Sepsis Induced Cardiomyopathy
Authors: Akshay Kumar, Edmund Carvalho, Santhanam Shanmughapriya, Madesh Muniswamy
Journal: Circulation (2018)

Introduction: Mitochondria serve as critical Ca 2+ sinks, regulating the duration and magnitude of c Ca2+ transients and c Ca2+ entry into the mitochondrion. Mitochondrial calcium uniporter (MCU) channel is activated in conditions of inflammation and oxidative stress.MCU and its activity are potential therapeutic targets for cardiac hypertrophy and heart failure. Hypothesis: Blunting of mCa2+ uptake can contribute to increased cCa2+ transients associated with excitation-contraction coupling and offer cardio protection following sepsis induced stress. Methods: MCU C96A KI generated using CRISPR-Cas9 d10 nickase mRNA co-injected with gRNA into wild-type(C57BL6) zygotes and then implanted into pseudo-pregnant female mice.To elucidate mechanistic role of mCa2+ in modulating cardiac contractility and myocardial bioenergetics, adult cardiomyocytes were isolated from mouse model and subjected to hypoxia/re-oxygenation injury.Polymicrobial Sepsis in 6-week-old C57BL/6J mice were created using Cecal ligation and puncture (CLP) and MCU oxidation at 1, 6, 12 and 24 hours post injury was compared with Sham and control mice (n=15). MCU protein quantification was done with western blot, functional assessment of Reactive oxygen species (ROS) by confocal laser microscopy, echocardiography with Vevo2100 imaging system. Mice were pretreated with MCU blocking agent Ru360 1 hr prior to CLP and compared with the control group at 6 hours. Results: Cardiomyocytes exposed to hypoxia/re-oxygenation(h/R ) stress exhibited increased MitoSOX red fluorescence.MCU oxidation was ubiquitously induced in all tissues post CLP surgery and was most significant at 6 hrs (Fig 1a). Oxidation of MCU was marked by increase in ROS in tissue sections of small Intestine of CLP versus the Sham group(p&lt;0.001). (Fig 1 b &amp;c). Pretreatment with Ru360 ameliorated MCU oxidation at 6 hours post CLP injury. MCUC96AKI had significantly decreased ejection fraction and fractional shortening compared to the wild type mice. Further the survival in MCU C96A KI was significantly better than the WT or MCU KO mice ( p&lt;0.05). Conclusions: Inhibition of mitochondrial calcium uniporter is a potential therapeutic target and protects from sepsis induced cardiomyopathy by mitigating mitophagy.
Glucagon‐like peptide‐1 receptor agonist inhibits aeroallergen‐induced activation of ILC2 and neutrophilic airway inflammation in obese mice
Authors: Shinji Toki, Dawn C. Newcomb, Richard L. Printz, Katherine N. Cahill, Kelli L. Boyd, Kevin D. Niswender, R. Stokes Peebles
Journal: Allergy (2021)

Obesity is a risk factor for the development of asthma. However, pharmacologic therapeutic strategies that specifically target obese asthmatics have not been identified. We hypothesize that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment inhibits aeroallergen-induced early innate airway inflammation in a mouse model of asthma in the setting of obesity.SWR (lean) and TALLYHO (obese) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or PBS for 4 consecutive days concurrent with GLP-1RA or vehicle treatment.TALLYHO mice had greater Alt-Ext-induced airway neutrophilia and lung protein expression of IL-5, IL-13, CCL11, CXCL1, and CXCL5, in addition to ICAM-1 expression on lung epithelial cells compared with SWR mice, and all endpoints were reduced by GLP-1RA treatment. Alt-Ext significantly increased BALF IL-33 in both TALLYHO and SWR mice compared to PBS challenge, but there was no difference in the BALF IL-33 levels between these two strains. However, TALLYHO, but not SWR, mice had significantly higher airway TSLP in BALF following Alt-Ext challenge compared to PBS, and BALF TSLP was significantly greater in TALLYHO mice compared to SWR mice following airway Alt-Ext challenge. GLP-1RA treatment significantly decreased the Alt-Ext-induced TSLP and IL-33 release in TALLYHO mice. While TSLP or ST2 inhibition with a neutralizing antibody decreased airway eosinophils, they did not reduce airway neutrophils in TALLYHO mice.These results suggest that GLP-1RA treatment may be a novel pharmacologic therapeutic strategy for obese persons with asthma by inhibiting aeroallergen-induced neutrophilia, a feature not seen with either TSLP or ST2 inhibition.
A RETROSPECTIVE ANALYSIS OF ATRIAL FIBRILLATION PATIENTS AGED 80 YEARS AND OLDER PRESCRIBED WARFARIN OR A LOW-DOSE DIRECT ORAL ACTING ANTICOAGULANT
Authors: Usman Chaudhry, Usman Chaudhry, Michael Ezekowitz, Edward Gracely, Winson T. George, Catrina Wolfe, Grace Harper, Glenn Harper
Journal: Journal of the American College of Cardiology (2021)
At the heart of microbial conversations: endocannabinoids and the microbiome in cardiometabolic risk
Authors: Ramsha Nabihah Khan, Kristal Maner-Smith, Joshua A. Owens, Maria Estefania Barbian, Rheinallt M. Jones, Crystal R. Naudin
Journal: Gut Microbes (2021)

Cardiometabolic syndrome encompasses intertwined risk factors such as hypertension, dyslipidemia, elevated triglycerides, abdominal obesity, and other maladaptive metabolic and inflammatory aberrations. As the molecular mechanisms linking cardiovascular disease and metabolic disorders are investigated, endocannabinoids have emerged as molecules of interest. The endocannabinoid system (ECS) of biologically active lipids has been implicated in several conditions, including chronic liver disease, osteoporosis, and more recently in cardiovascular diseases. The gut microbiome is a major regulator of inflammatory and metabolic signaling in the host, and if disrupted, has the potential to drive metabolic and cardiovascular diseases. Extensive studies have unraveled the impact of the gut microbiome on host physiology, with recent reports showing that gut microbes exquisitely control the ECS, with significant influences on host metabolic and cardiac health. In this review, we outline how modulation of the gut microbiome affects host metabolism and cardiovascular health via the ECS, and how these findings could be exploited as novel therapeutic targets for various metabolic and cardiac diseases.
Development and Validation of a Simplified Score to Predict Early Relapse in Newly Diagnosed Multiple Myeloma in a Pooled Dataset of 2,190 Patients
Authors: Gian Maria Zaccaria, Luca Bertamini, Maria Teresa Petrucci, Massimo Offidani, Paolo Corradini, Andrea Capra, Alessandra Romano, Anna Marina Liberati, Donato Mannina, Paolo de Fabritiis, Nicola Cascavilla, Marina Ruggeri, Roberto Mina, Francesca Patriarca, Giulia Benevolo, Angelo Belotti, Gianluca Gaidano, Arnon Nagler, Roman Hájek, Andrew Spencer, Pieter Sonneveld, Pellegrino Musto, Mario Boccadoro, Francesca Gay
Journal: Clinical Cancer Research (2021)

Despite the improvement of therapeutic regimens, several patients with multiple myeloma (MM) still experience early relapse (ER). This subset of patients currently represents an unmet medical need.We pooled data from seven European multicenter phase II/III clinical trials enrolling 2,190 patients with newly diagnosed MM from 2003 to 2017. Baseline patient evaluation included 14 clinically relevant features. Patients with complete data (n = 1,218) were split into training (n = 844) and validation sets (n = 374). In the training set, a univariate analysis and a multivariate logistic regression model on ER within 18 months (ER18) were made. The most accurate model was selected on the validation set. We also developed a dynamic version of the score by including response to treatment.The Simplified Early Relapse in Multiple Myeloma (S-ERMM) score was modeled on six features weighted by a score: 5 points for high lactate dehydrogenase or t(4;14); 3 for del17p, abnormal albumin, or bone marrow plasma cells >60%; and 2 for λ free light chain. The S-ERMM identified three patient groups with different risks of ER18: Intermediate (Int) versus Low (OR = 2.39, P < 0.001) and High versus Low (OR = 5.59, P < 0.001). S-ERMM High/Int patients had significantly shorter overall survival (High vs. Low: HR = 3.24, P < 0.001; Int vs. Low: HR = 1.86, P < 0.001) and progression-free survival-2 (High vs. Low: HR = 2.89, P < 0.001; Int vs. Low: HR = 1.76, P < 0.001) than S-ERMM Low. The Dynamic S-ERMM (DS-ERMM) modulated the prognostic power of the S-ERMM.On the basis of simple, widely available baseline features, the S-ERMM and DS-ERMM properly identified patients with different risks of ER and survival outcomes.
AN ASSESSMENT OF CLINICAL CHARACTERISTICS OF ASCVD PATIENTS WITH HYPERCHOLESTEROLEMIA AND PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA: A REAL-WORLD DATABASE ANALYSIS IN THE US
Authors: Divyagiri Seshagiri, Raquel Lahoz, Assya Achouba, Batul Electriwala, Yingjie Ding, Ji Haeng Heo, Rachel Studer
Journal: Journal of the American College of Cardiology (2021)
The role of autophagy in cardiovascular pathology
Authors: Damián Gatica, Mario Chiong, Sergio Lavandero, Daniel J Klionsky
Journal: Cardiovascular Research (2021)

Macroautophagy/autophagy is a conserved catabolic recycling pathway in which cytoplasmic components are sequestered, degraded, and recycled to survive various stress conditions. Autophagy dysregulation has been observed and linked with the development and progression of several pathologies, including cardiovascular diseases, the leading cause of death in the developed world. In this review, we aim to provide a broad understanding of the different molecular factors that govern autophagy regulation and how these mechanisms are involved in the development of specific cardiovascular pathologies, including ischemic and reperfusion injury, myocardial infarction, cardiac hypertrophy, cardiac remodelling, and heart failure.
USE OF EXTRACORPOREAL CARDIOPULMONARY RESUSCITATION IN A CASE OF CARDIAC ARREST DUE TO ETHYLENE GLYCOL POISONING
Authors: Margot Yopes, Heidi Lumish, Elizabeth Wang, Johanna Ben-Ami, Alison Thompson, Raphael Rosen, Kevin Clerkin, Matthew Finn, Yuji Kaku, Amirali Masoumi, Subhani Chandra, Daniel O'Connor, Koji Takeda, Daniel Brodie, Gabriel Sayer, Nir Uriel, Justin Fried
Journal: Journal of the American College of Cardiology (2021)
Kidney function and obstructive lung disease: a bidirectional Mendelian randomisation study
Authors: Sehoon Park, Soojin Lee, Yaerim Kim, Semin Cho, Kwangsoo Kim, Yong Chul Kim, Seung Seok Han, Hajeong Lee, Jung Pyo Lee, Kwon Wook Joo, Chun Soo Lim, Yon Su Kim, Dong Ki Kim
Journal: European Respiratory Journal (2021)

Background Additional study is warranted to investigate the causal effects between kidney function and obstructive lung disease. Methods This study was a bidirectional two-sample Mendelian randomisation (MR) analysis. The Chronic Kidney Disease Genetics (CKDGen) genome-wide association study (GWAS) meta-analysis for estimated glomerular filtration rate (eGFR) including individuals of European ancestry (n=567 460) provided the genetic instrument for kidney function and outcome summary statistics. A GWAS for forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) including individuals of European ancestry from the UK Biobank (n=321 047) provided the genetic instrument for FEV 1 /FVC and outcome data. A polygenic score (PGS) analysis was performed to test the causal estimates from kidney function to binary obstructive lung disease outcomes, including COPD, asthma and FEV 1 /FVC &lt;70%, and to perform nonlinear MR with individual-level UK Biobank data. Results The causal estimates by summary-level MR indicated that genetically predicted increased kidney function was significantly associated with increased FEV 1 /FVC z-scores (10% increase in eGFR; β=0.055, 95% CI 0.024–0.086). The PGS for increased eGFR showed a significant association with a reduced risk of FEV 1 /FVC &lt;70% (OR 0.93, 95% CI 0.87–0.99), COPD (OR 0.93, 95% CI 0.87–0.99) and late-onset (age ≥50 years) asthma (OR 0.93, 95% CI 0.88–0.99). The nonlinear MR demonstrated that the causal effect from eGFR to FEV 1 /FVC was apparent in eGFR ranges &lt;60 mL·min −1 ·1.73 m −2 . Conversely, genetically predicted FEV 1 /FVC showed nonsignificant causal estimates of eGFR change (β=0.568%, 95% CI −0.458–1.605%). Conclusion This study supports kidney function impairment as a causative factor for obstructive lung disease.
Limited haplotype diversity underlies polygenic trait architecture across 70 years of wheat breeding
Authors: Michael F. Scott, Nick Fradgley, Alison R. Bentley, Thomas Brabbs, Fiona Corke, Keith A. Gardner, Richard Horsnell, Phil Howell, Olufunmilayo Ladejobi, Ian J. Mackay, Richard Mott, James Cockram
Journal: Genome biology (2021)

Selection has dramatically shaped genetic and phenotypic variation in bread wheat. We can assess the genomic basis of historical phenotypic changes, and the potential for future improvement, using experimental populations that attempt to undo selection through the randomizing effects of recombination.We bred the NIAB Diverse MAGIC multi-parent population comprising over 500 recombinant inbred lines, descended from sixteen historical UK bread wheat varieties released between 1935 and 2004. We sequence the founders' genes and promoters by capture, and the MAGIC population by low-coverage whole-genome sequencing. We impute 1.1 M high-quality SNPs that are over 99% concordant with array genotypes. Imputation accuracy only marginally improves when including the founders' genomes as a haplotype reference panel. Despite capturing 73% of global wheat genetic polymorphism, 83% of genes cluster into no more than three haplotypes. We phenotype 47 agronomic traits over 2 years and map 136 genome-wide significant associations, concentrated at 42 genetic loci with large and often pleiotropic effects. Around half of these overlap known quantitative trait loci. Most traits exhibit extensive polygenicity, as revealed by multi-locus shrinkage modelling.Our results are consistent with a gene pool of low haplotypic diversity, containing few novel loci of large effect. Most past, and projected future, phenotypic changes arising from existing variation involve fine-scale shuffling of a few haplotypes to recombine dozens of polygenic alleles of small effect. Moreover, extensive pleiotropy means selection on one trait will have unintended consequences, exemplified by the negative trade-off between yield and protein content, unless selection and recombination can break unfavorable trait-trait associations.
Questioning a South African hypertension threshold of 150 mm Hg – Authors' reply
Authors: Nikkil Sudharsanan, Alpha Oumar Diallo, Mohammed K Ali, Pascal Geldsetzer, Emily W Gower, Trasias Mukama, Ryan G Wagner, Justine Davies, Maarten J Bijlsma
Journal: The Lancet Healthy Longevity (2021)
Pyrin Inflammasome Activation Abrogates Interleukin‐1 Receptor Antagonist, Suggesting a New Mechanism Underlying Familial Mediterranean Fever Pathogenesis
Authors: Sussi B. Mortensen, Ann‐Brit E. Hansen, Trine H. Mogensen, Marianne A. Jakobsen, Hans C. Beck, Eva B. Harvald, Kate L. Lambertsen, Isik S. Johansen, Ditte C. Andersen
Journal: Arthritis & Rheumatology (2021)

Aberrant pyrin inflammasome activity triggers familial Mediterranean fever (FMF) pathogenesis, but the exact mechanism remains elusive and an obstacle to efficient treatment. We undertook this study to identify pyrin inflammasome-specific mechanisms to improve FMF treatment and diagnostics in the future.Pyrin-specific protein secretion was assessed by proteome analysis in U937-derived macrophages, and specific findings were confirmed in pyrin inflammasome-activated monocytes from healthy blood donors and patients with FMF, stratified according to MEFV genotype categories corresponding to a suspected increase in FMF disease severity.Proteome data revealed a differential secretion pattern of interleukin-1 receptor antagonist (IL-1Ra) from pyrin- and NLRP3-activated U937-derived macrophages, which was verified by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Moreover, pyrin activation significantly reduced IL1RN messenger RNA expression (P < 0.001) and IL-1Ra secretion (P < 0.01) in healthy donor and FMF monocytes, respectively. Independent of MEFV genotype, unstimulated FMF monocytes from colchicine-treated patients secreted lower amounts of IL-1Ra compared to healthy donors (P < 0.05) and displayed decreased ratios of IL-1Ra:IL-1β (P < 0.05), suggesting a reduced antiinflammatory capacity.Our data show an inherent lack of IL-1Ra expression specific to pyrin inflammasome activation, suggesting a new mechanism underlying FMF pathogenesis. The reduced IL-1Ra levels in FMF monocytes suggest a diminished antiinflammatory capacity that potentially leaves FMF patients sensitive to proinflammatory stimuli, regardless of receiving colchicine therapy. Thus, considering the potential clinical consequence of reduced monocyte IL-1Ra secretion in FMF patients, we suggest further investigation into IL-1Ra dynamics and its potential implications for FMF treatment in the future.