tbuckley/cabot-search huggingface dataset:
Abstract 464: Improvement in Return of Spontaneous Circulation With a Cardiac Arrest Video Review and Team-Focused Mechanical CPR Program
Authors: Daniel M Rolston, Timmy Li, Casey Owens, Ghania Haddad, Timothy J Palmieri, Veronika Blinder, Jennifer L Wolff, Michael Cassara, Qiuping Zhou, Lance B Becker
Journal: Circulation (2019)

Introduction: Survival from cardiac arrest remains suboptimal. Pre-hospital studies demonstrate monitoring cardiopulmonary resuscitation (CPR) quality and utilizing team-focused resuscitation improve outcomes in cardiac arrest. Video review provides Emergency Departments (EDs) with the ability to monitor CPR quality and provide feedback to individuals and teams. We evaluated for improvement in the proportion of patients achieving return of spontaneous circulation (ROSC), survival-to-admission and discharge, pre and post-initiation of a cardiac arrest video review and team-focused mechanical CPR program. Methods: In 2018, our ED began a video review program of cardiac arrests, consisting of biweekly meetings with a multidisciplinary team; and mechanical CPR with the LUCAS ® 3. A revised team-focused approach to resuscitation was created using swim-lane diagrams and a priority payoff matrix. In-situ simulation was used to disseminate this new approach. Using data from 2017 as the pre-intervention group for comparison, we assessed for differences in outcomes after implementation of our intervention using χ 2 tests and multivariable logistic regression. Results: A total of 242 patients were analyzed; 106 (43.8%) pre-intervention and 136 (56.2%) post-intervention. Both groups were similar (Table). The proportion achieving ROSC increased from 26.5% to 41.6% post-intervention (p=0.019). There were non-significant increases in survival-to-admission (26.4% vs. 35.3%; p = 0.140) and survival-to-discharge (5.6% vs. 10.3%; p = 0.194) after our intervention. Controlling for age, sex, initial rhythm, witnessed arrest, and bystander CPR, the odds of ROSC were higher post-intervention (OR: 2.52; 95% CI: 1.08, 5.90). Conclusions: Implementation of a video review and team-focused mechanical CPR program increased ROSC in our ED. Our intervention may also improve survival-to-admission and discharge, but this study was underpowered to detect these differences.
Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer
Authors: Eiko Hayase, Robert R. Jenq
Journal: Genome Medicine (2021)

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune inhibitory pathways. Administration of ICIs augments T cell-mediated immune responses against tumor, resulting in improved overall survival in cancer patients. It has emerged that the intestinal microbiome can modulate responses to ICIs via the host immune system and that the use of antibiotics can lead to reduced efficacy of ICIs. Recently, reports that fecal microbiota transplantation can lead to ICI therapy responses in patients previously refractory to therapy suggest that targeting the microbiome may be a viable strategy to reprogram the tumor microenvironment and augment ICI therapy. Intestinal microbial metabolites may also be linked to response rates to ICIs. In addition to response rates, certain toxicities that can arise during ICI therapy have also been found to be associated with the intestinal microbiome, including in particular colitis. A key mechanistic question is how certain microbes can enhance anti-tumor responses or, alternatively, predispose to ICI-associated colitis. Evidence has emerged that the intestinal microbiome can modulate outcomes to ICI therapies via two major mechanisms, including those that are antigen-specific and those that are antigen-independent. Antigen-specific mechanisms occur when epitopes are shared between microbial and tumor antigens that could enhance, or, alternatively, reduce anti-tumor immune responses via cross-reactive adaptive immune cells. Antigen-independent mechanisms include modulation of responses to ICIs by engaging innate and/or adaptive immune cells. To establish microbiome-based biomarkers of outcomes and specifically modulate the intestinal microbiome to enhance efficacy of ICIs in cancer immunotherapy, further prospective interventional studies will be required.
Abstract 403: Critical Role for Dipeptidyl Peptidase-4 Activity in the Pathogenesis of Experimental Autoimmune Myocarditis
Authors: Yasuhiro Maejima, Yusuke Ito, Natsuko Tamura, Mitsuaki Isobe
Journal: Circulation Research (2016)

Autoimmune myocarditis is the most common cause of heart failure among young adults and is a major precursor of dilated cardiomyopathy. We have shown that dipeptidyl peptidase-4 (DPP-4) plays a detrimental role in the pathogenesis of experimental autoimmune myocarditis (EAM) in mice. To elucidate how DPP-4 induces cardiac dysfunction in the EAM heart, mouse EAM models were given normal diet (CONT-group, N = 6), or a diet mixed with linagliptin, a potent DPP-4 inhibitor (83 mg/kg chow corresponding to around 3 mg/kg oral dosing) (LINA-group, N = 6). After 21-day of EAM induction, left ventricular ejection fraction was significantly higher in LINA-group than in CONT-group (72.6 ± 6.6%* vs. 60.1 ± 9.2%, * P &lt; 0.05). Immunostaining demonstrated that the number of RORγt-positive Th17 cells, a subset of T-lymphocytes expressing high level of enzymatically active DPP-4, infiltrated to the EAM hearts was significantly smaller in LINA-group than in CONT-group (46.9 ± 2.4 RFU* vs. 116.8 ± 8.6 RFU, * P &lt; 0.05). Consistently, the activity of DPP-4 in the EAM hearts was significantly lower in LINA-group than in CONT-group. Mass spectrometry analysis using lysates from the EAM hearts co-immunoprecipitated with Flag-DPP-4 recombinant protein demonstrated that DPP-4 interacts with cathepsin-G (CTSG), a plasma membrane-bound serine protease, in the EAM hearts. Co-immunoprecipitation assay verified the physical interaction between CTSG and DPP-4. The CTSG activity in the EAM hearts was markedly elevated, and treatment with linagliptin effectively suppressed the CTSG activity in the EAM hearts. We also found that DPP-4 significantly suppressed the activity of α1-antichymotrypsin, a protease which can catalyzes CTSG and is activated in response to EAM. Finally, we demonstrated that the level of angiotensin II, a major product catalyzed by CTSG, in the EAM hearts was significantly decreased in LINA-group than in CONT-group. Thus, these results suggest that DPP-4 expressing on the surface of Th17 cells physically interacts with CTSG, thereby enhancing CTSG activity by suppressing α1-antichymotrypsin, which, in turn, promoting the accumulation of angiotensin II, in the EAM hearts. In conclusion, DPP-4 derived from Th17 cells aggravates cardiac dysfunction during EAM.
Covid-19: Pfizer vaccine could provide lasting immunity, small study suggests
Authors: Elisabeth Mahase
Journal: BMJ (2021)

New research looking at the Pfizer BioNTech covid-19 vaccine has provided early indication that it’s likely to produce strong and lasting immunity, although the findings are based on a small number of people.1

Researchers from Washington University School of Medicine in the US looked at the antigen-specific B cell responses in peripheral blood (for 41 people) and draining lymph nodes (for 14 people) who received two doses of Pfizer vaccine.

The study, published in Nature , found that nearly four months after the first dose, people who received the Pfizer vaccine still had germinal centres in their lymph nodes producing plasma and memory B cells directed against the SARS-CoV-2 virus.

Lead author Ali Ellebedy, who is associate …
Heterofunctional Particles as Single Cell Sensors to Capture Secreted Immunoglobulins and Isolate Antigen‐Specific Antibody Secreting Cells
Authors: Katily Ramirez, Shuya Kyu, Doan Nguyen, So‐Yun Han, Ye Lim Lee, John Bradley, Troy Randall, Ignacio Sanz, Frances Eun‐Hyung Lee, Todd Sulchek
Journal: Advanced Healthcare Materials (2021)

Abstract Isolating cells based on their secreted proteins remain a challenge. The authors demonstrate a capacity for high throughput single‐cell protein secretion analysis and isolation based on heterofunctional particles combined with fluorescence activated cell sorting (FACS). The workflow shows that antibody secreting cells (ASCs) specific for the H1 protein from influenza virus can be isolated from B cells. The workflow consists of incubating anti‐CD27 particles with the ASCs, capturing locally secreted immunoglobulins with Protein G on the particles, and identifying immunoglobulins specific to H1 via fluorescent labeled antigens followed by FACS to enrich antigen‐specific ASCs. Two particles designs, Janus and mixed, are tested with hybridoma cells. Mixed particles are found to improve antibody collection, while Janus particles are found to bind target cells more effectively. Targeted hybridoma cells in coculture with non‐specific hybridoma cells are identified with a sensitivity of 96% and specificity of 98%. Heterofunctional particles are used to capture ASCs that secrete antibodies specific for influenza virus from B cells from healthy adults isolated from blood after vaccination. Positive H1‐tetramer sorted ASCs are validated using single ASC cultures and identify 23/56 cells specific for H1 demonstrating 164‐fold enrichment from total B cells and 14.6‐fold enrichment from total ASCs.
Mutations in DNMT3A, U2AF1, and EZH2 Identify Intermediate-Risk Acute Myeloid Leukemia Patients with Poor Outcome after CR1
Authors: Caner Saygin, Cassandra M. Hirsch, Bartlomiej Przychodzen, Mikkael A. Sekeres, Betty K. Hamilton, Matt Kalaycio, Hetty E. Carraway, Aaron T. Gerds, Sudipto Mukherjee, Aziz Nazha, Ronald Sobecks, Christopher Goebel, Donna M. Abounader, Jaroslaw P. Maciejewski, Anjali S. Advani
Journal: Blood (2017)
MAP3K7-IKK Inflammatory Signaling Modulates AR Protein Degradation and Prostate Cancer Progression
Authors: Zhenlin Huang, Bo Tang, Yinhui Yang, Zhaogang Yang, Lei Shi, Yang Bai, Binyuan Yan, R. Jeffrey Karnes, Jun Zhang, Rafael Jimenez, Liguo Wang, Qiang Wei, Jinjian Yang, Wanhai Xu, Zhankui Jia, Haojie Huang
Journal: Cancer Research (2021)

Androgen receptor (AR) is a major survival factor for prostate cancer. Inflammation is implicated in many cancer types, including prostate cancer. Activation of MAP3K7 (also termed TAK1) and downstream IκB kinase β (IKKβ) by proinflammatory cytokines such as TNFα stimulates NF-κB survival pathways. Paradoxically, MAP3K7 is often deleted in human prostate cancer. Here, we demonstrate that AR protein expression is lower in inflammatory tumor areas compared with non-inflammatory tissues in patients with prostate cancer. Map3k7 knockout increased AR protein levels and activity in the mouse prostate, and MAP3K7 and AR protein levels were inversely correlated in prostate cancer patient specimens. TNFα treatment increased AR protein ubiquitination and proteasomal degradation. Mechanistically, activation of IKKβ by TNFα induced phosphorylation and TRCP1/2 E3 ligase-mediated polyubiquitination and degradation of AR protein. TNFα suppressed prostate cancer proliferation, which could be rescued by blockade of AR degradation. These findings reveal a previously unrecognized tumor suppressive function of the inflammation-activated MAP3K7-IKKβ axis in degrading AR protein. Moreover, they suggest that aberrant elevation of AR protein could be a prognostic biomarker and therapeutic target for MAP3K7-deficient prostate cancer. SIGNIFICANCE: This study identifies that MAP3K7-IKKβ signaling plays a tumor-suppressive role in prostate cancer by degrading AR, revealing potential prognostic and therapeutic strategies for MAP3K7-deficient tumors.
Abstract 461: Evaluation of the Impact of Additional Structured Cardiac Arrest Training on Internal Medicine Residents in a Community Hospital
Authors: Abdullah Zoheb Azhar, Monil Majmundar, Shmuel Golfeyz, Tikal Kansara, Jonna Mercado, Savi Mushiyev
Journal: Circulation (2019)

Introduction: There are approximately 200,000 cases of in-hospital cardiac arrest (IHCA) annually in the United States. Of these cases, only 40-50% achieve return of spontaneous circulation (ROSC) and only 20-30% are discharged. Though most hospital staff are trained in cardiac arrest resuscitation, a significant disparity in resuscitation has been noted between different hospital settings. We thus instituted additional structured cardiac arrest training in an Internal Medicine residency program, to supplement the biennial advanced cardiac life support (ACLS) training. Hypothesis: We hypothesized that institution of a dedicated structured cardiac arrest team (code team) in addition to monthly training for those on the team, would improve the confidence, skills, and leadership level, of residents at managing an IHCA situation. Methods: A structured code team with specific roles for each resident was instituted in a New York City-based community hospital. Training was guided by audio-visual lectures and then reinforced by performing mock cardiac arrest drills. Resident assessments were done pre and post-training through an anonymous standardized questionnaire. Summative measures of mean confidence, mean ACLS skills, and leadership were evaluated. Uni and bivariate analysis, and T-tests for statistical significance were performed using STATA 15 software. Results: Our sample of 32 residents showed an increase in mean learning scores across all the three domains. Confidence scores increased from 7.23 to 8.44, ACLS skills increased from 7.40 to 8.57 and leadership scores increased from 6.56 to 7.88. Paired T-tests demonstrated high significance (P&lt;0.000). Conclusion: This study demonstrates the effectiveness of additional structured cardiac arrest training on confidence, skills, and leadership of resident physicians in an Internal Medicine program. The next phase of this study will be to re-evaluate knowledge and confidence at 3 and 6 months after training.
Abstract 397: Regional Differences in Periaortic Adipose Tissue
Authors: Khanh-Van Tran, Timothy Fitzgibbons, Silvia Corvera
Journal: Circulation Research (2016)

Introduction: To combat obesity and associated comorbidities, it is vital to have an in-depth understanding of the adipose tissue. The presence of brown adipose tissue is associated with decrease risk of T2DM while the opposite is true for the presence of visceral white adipose tissue. In this study, we examined the adipocyte populations surrounding the thoracic and abdominal aorta of C57Bl/6J mice. Methods: We utilized the aortic ring assay to examine the adipocytes arising from the thoracic and abdominal regions of the aorta. We previously found that adipocyte progenitors proliferate when tissue is embedded in Matrigel. C57Bl/6J mice were sacrificed, thoracic and abdominal aorta fragments were removed, embedded in Matrigel matrix and allowed to proliferate in the absence or in the presence of Rosiglitazone, a PPARγ agonist. Explants were then fixed in formaldehyde for immunofluorescence analysis or used for RNA extraction and subsequently real-time PCR. Results: Classically, cells that arise from the aorta fragments are spindle-like and express several endothelial cell markers, such as CD31, CD34 and vWF. We found that in the presence of rosiglitazone, cells arising from the aorta accumulate lipid droplets to take on an adipocyte phenotype. In the presence of rosiglitazone, the expression of CD31 and CD34 are decreased and expressions of adiponectin and perilipin are increased. The perilipin staining patterns in these cells are consistent with that of adipocytes, i.e. surrounding a lipid droplet. Adipocytes around the abdominal aorta have higher mRNA levels of Hoxc9, a homeobox gene expressed higher in white adipocytes than brown adipocytes. Conversely, adipocytes arising from the thoracic aorta have higher expression of UCP-1 and cidea, markers of brown adipocytes. Conclusion: Results show that adipocytes from thoracic and abdominal regions of the aorta have different genotypes and phenotypes. Cells surrounding the thoracic aorta may have more of a “beige,” in between white and brown phenotype, as opposed to a classic white adipocyte phenotype seen in fat cells surrounding the abdominal aorta. Our e x vivo aortic ring model is a tool that can provide valuable insight into the role that adipocytes play in different regions of the aorta.
Cascade of care during the first 36 months of the treatment as prevention for hepatitis C (TraP HepC) programme in Iceland: a population-based study
Authors: Sigurdur Olafsson, Ragnheidur H Fridriksdottir, Thorvardur J Love, Thorarinn Tyrfingsson, Valgerdur Runarsdottir, Ingunn Hansdottir, Ottar M Bergmann, Einar S Björnsson, Birgir Johannsson, Bryndis Sigurdardottir, Arthur Löve, Gudrun E Baldvinsdottir, Ubaldo Benitez Hernandez, Thorolfur Gudnason, Maria Heimisdottir, Margaret Hellard, Magnus Gottfredsson
Journal: The Lancet. Gastroenterology & hepatology (2021)
Abstract 33: Unlocking Reprogramming Capability: Silencing Antiplasticity Gene p63 Enhances the Reprogramming of Fibroblasts into Induced Cardiomyocytes
Authors: Vivekkumar Patel, Austin Cooney, Elsa Flores, Vivek Singh, Megumi Mathison, Deepthi Sanagasetti, Lisa Mullany, Jianchang Yang, Todd Rosengart
Journal: Circulation Research (2016)

Objective: In situ cellular reprogramming of cardiac fibroblasts into (induced) cardiomyocytes (iCMs) represents a promising new potential intervention for the treatment of heart failure. Despite encouraging in vivo data in rodent myocardial infarction models, the relative resistance of human cells to reprogramming may be a significant barrier to the clinical application of this new therapy. We hypothesized that knockdown of the anti-plasticity gene p63 could therefore be used to enhance cellular reprogramming efficiency. Methods: p63 knockout (KO) murine embryonic fibroblasts (MEFs) and MEFs treated with p63 silencing shRNA were assessed for expression of the cardiomyocyte marker Cardiac Troponin T (cTnT) and pro-cardiogenic genes, with or without the treatment with known cardiac transcription factors Hand2 and Myocardin (HM). Results: After 3 wks in culture, expression of the cardiomyocyte marker cTnT (FACS) was significantly greater in p63 KO MEFs than in wild-type (WT) MEFs or WT MEFs treated with transcription factors Hand2 and Myocardin (39% ± 8%, 2.0% ± 1% and 2.7 ± 0.3%, respectively, p &lt; 0.05). Treatment of p63 KO MEFs with Hand2 and Myocardin further increased cTnT expression up to 74% ± 3%. Treatment of WT MEFs with p63 shRNA likewise yielded a 20-fold increase in cTnT expression (qPCR) without HM and a 600-fold increase with HM when compared to non-silencing shRNA treated MEFs. Consistent with these findings, p63 KO or p63 shRNA-treated MEFs demonstrated increased expression (qPCR) of pro-cardiogenic genes Gata4, Mef2c and Tbx5 compared to naïve or non-silencing shRNA treated MEFs. After treatment with p63 shRNA, adult human epidermal cells also demonstrated increased expression of cTnT, myosin heavy chain and pro-cardiogenic genes when analyzed by qPCR. Conclusions: Downregulation of the anti-plasticity gene p63 enhances cellular reprogramming efficiency and iCM generation, as reflected in the increased expression of the cardiomyocyte marker cTnT and pro-cardiogenic genes Gata4, Mef2c and Tbx5. Use of such cellular plasticity enhancing strategies may be a useful strategy to overcome barriers to cellular reprogramming in the clinical arena.
Tumor-Naïve Multimodal Profiling of Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma
Authors: Justin M. Burgener, Jinfeng Zou, Zhen Zhao, Yangqiao Zheng, Shu Yi Shen, Shao Hui Huang, Sareh Keshavarzi, Wei Xu, Fei-Fei Liu, Geoffrey Liu, John N. Waldron, Ilan Weinreb, Anna Spreafico, Lillian L. Siu, John R. de Almeida, David P. Goldstein, Michael M. Hoffman, Daniel D. De Carvalho, Scott V. Bratman
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Circulating tumor DNA (ctDNA) enables personalized treatment strategies in oncology by providing a noninvasive source of clinical biomarkers. In patients with low ctDNA abundance, tumor-naïve methods are needed to facilitate clinical implementation. Here, using locoregionally confined head and neck squamous cell carcinoma (HNSCC) as an example, we demonstrate tumor-naïve detection of ctDNA by simultaneous profiling of mutations and methylation. Experimental Design: We conducted CAncer Personalized Profiling by deep Sequencing (CAPP-seq) and cell-free Methylated DNA ImmunoPrecipitation and high-throughput sequencing (cfMeDIP-seq) for detection of ctDNA-derived somatic mutations and aberrant methylation, respectively. We analyzed 77 plasma samples from 30 patients with stage I–IVA human papillomavirus–negative HNSCC as well as plasma samples from 20 risk-matched healthy controls. In addition, we analyzed leukocytes from patients and controls. Results: CAPP-seq identified mutations in 20 of 30 patients at frequencies similar to that of The Tumor Genome Atlas (TCGA). Differential methylation analysis of cfMeDIP-seq profiles identified 941 ctDNA-derived hypermethylated regions enriched for CpG islands and HNSCC-specific methylation patterns. Both methods demonstrated an association between ctDNA abundance and shorter fragment lengths. In addition, mutation- and methylation-based ctDNA abundance was highly correlated (r &amp;gt; 0.85). Patients with detectable pretreatment ctDNA by both methods demonstrated significantly worse overall survival (HR = 7.5; P = 0.025) independent of clinical stage, with lack of ctDNA clearance post-treatment strongly correlating with recurrence. We further leveraged cfMeDIP-seq profiles to validate a prognostic signature identified from TCGA samples. Conclusions: Tumor-naïve detection of ctDNA by multimodal profiling may facilitate biomarker discovery and clinical use in low ctDNA abundance applications.
Abatacept is second to rituximab at risk of HBsAg reverse seroconversion in patients with rheumatic disease
Authors: Ming-Han Chen, I-Cheng Lee, Ming-Huang Chen, Ming-Chih Hou, Chang-Youh Tsai, Yi-Hsiang Huang
Journal: Annals of the Rheumatic Diseases (2021)

Background Hepatitis B surface antigen (HBsAg) reverse seroconversion (RS) can happen in patients with rheumatoid arthritis (RA) with resolved hepatitis B (RHB) undergoing biological disease-modifying antirheumatic drugs (bDMARDs). But the incidence and risk factors need to be delineated. Methods From 2003 to 2019, 1937 patients with RA with available HBsAg and antibody to hepatitis B virus (HBV) core antigen data were retrospectively reviewed, and 489 patients with RHB undergoing bDMARDs treatment were identified. Factors associated with HBsAg RS were analysed. Results During 67 828 person-months of follow-up, 27 (5.5%) patients developed HBsAg RS after bDMARD treatment. As compared with those without HBsAg RS, patients with HBsAg RS were older, had lower frequency of antibody to HBsAg (anti-HBs), and lower baseline anti-HBs levels. In multivariate analysis, rituximab, abatacept and baseline negative for anti-HBs were the independent risk factors for HBsAg RS (adjusted HR: 87.76, 95% CI: 11.50 to 669.73, p&lt;0.001; adjusted HR: 60.57, 95% CI: 6.99 to 525.15, p&lt;0.001; adjusted HR: 5.15, 95% CI: 2.21 to 12.02, p&lt;0.001, respectively). The risk of HBsAg RS was inversely related to the level of anti-HBs. Both rituximab and abatacept might result in anti-HBs loss, and abatacept had a cumulative incidence of HBsAg RS of 35.4%–62.5% in patients with low titers or negative of anti-HBs. Conclusions Not only rituximab, but also abatacept has a high risk of HBV reactivation in patient with RA with RHB. Anti-HBs positivity cannot confer HBV reactivation-free status if the anti-HBs levels are not high enough for patients with RHB on rituximab and abatacept treatment.