tbuckley/cabot-search huggingface dataset:
Abstract 11802: Evaluation of Family Risk of Rheumatic Heart Disease With Systematic Echocardiographic Screening: Data From the Provar+ Study
Authors: Juliane Franco, Bruno R Nascimento, Kaciane Oliveira, Marcia Barbosa, Nayana F Arantes, Andrea Z Beaton, Luana A Mello, Maria Cecília L Nascif, Guilherme C Oliveira, Breno C Camargos Mucelli Spolaor, Carolina F Campos, Victor R Silva, Marcelo Augusto A Nogueira, Antonio L Ribeiro, Craig A Sable, Maria P Nunes
Journal: Circulation (2021)

Introduction: Rheumatic Heart Disease (RHD) is determined by a complex interaction between socioeconomic environment and host susceptibility. Relatives of patients with advanced RHD share both, and may be at high-risk. We aimed to use echocardiographic (echo) family screening to evaluate the risk of RHD among 1 st degree relatives of patients with advanced RHD. Methods: From Feb 2020 - Jun 2021 patients with advanced RHD were consecutively enrolled in the University Hospital’s outpatient clinics. Consented 1 st degree relatives were invited for echo screening (2012 World Heart Federation Criteria) utilizing handheld devices (GE VSCAN) by non-physicians, with telemedicine interpretation by 2 experts. Matched controls (spouses, neighbors) living in the same household were also enrolled in a 1:5 fashion. A confirmatory full echo (GE Vivid IQ) was scheduled if abnormalities were observed, and all positive RHD cases were referred for follow-up. Results: In 16 months, 202 relatives and 42 controls of 117 patients were screened, including 114 children, 68 siblings and 20 parents. Mean age was 41±18 years, 62% were women and 214 (88%) lived with the index case for &gt;10 years. At total 51 (21%) individuals had hypertension, 17 (7%) diabetes, 5 reported a previous stroke and only 5 (all relatives) had personal history of RHD. Among index cases, 73% reported current or past prescription of Penicillin. Echo findings suggestive of RHD were observed in 0 controls and 14 (7%) relatives (p=0.08), being 11 with mitral valve (MV) disease and 3 with mixed (mitral and aortic valve (AV)) disease. Eleven patients had mild/moderate MV regurgitation, 4 with associated MV stenosis and abnormal morphology. Two patients had mild AV regurgitation and abnormal AV morphology, associated with mild AV and MV stenosis, and 1 patient had bioprostheses in the MV and AV. One case of mild left ventricular dysfunction was observed, and 1 patient had indication of commissurotomy for MV stenosis at the time of diagnosis. Conclusions: First-degree relatives of individuals with clinical RHD are at greater risk of having RHD and family screening should be considered. Genotyping studies are warranted to better understand individual and family susceptibility to RHD, in addition to socioeconomic conditions.
Whose Data, Whose Risk? Omics Privacy Concerns Should be Defined by Individuals, not Researchers
Authors: Sabrina F. Derrington, Matthew A. Deardorff, Alexander R. Judkins, Xiaowu Gai
Journal: The American Journal of Bioethics (2021)

This article refers to:Toward a Framework for Assessing Privacy Risks in Multi-Omic Research and Databases
Previous tuberculosis disease as a risk factor for chronic obstructive pulmonary disease: a cross-sectional analysis of multicountry, population-based studies
Authors: Katarina Kamenar, Shakir Hossen, Akshay N Gupte, Trishul Siddharthan, Suzanne Pollard, Muhammad Chowdhury, Adolfo L Rubinstein, Vilma E Irazola, Laura Gutierrez, J Jaime Miranda, Antonio Bernabe-Ortiz, Dewan Alam, Bruce Kirenga, Rupert C Jones, Frederik van Gemert, Robert A Wise, William Checkley
Journal: Thorax (2021)

Background Risk factors for COPD in high-income settings are well understood; however, less attention has been paid to contributors of COPD in low-income and middle-income countries (LMICs) such as pulmonary tuberculosis. We sought to study the association between previous tuberculosis disease and COPD by using pooled population-based cross-sectional data in 13 geographically diverse, low-resource settings. Methods We pooled six cohorts in 13 different LMIC settings, 6 countries and 3 continents to study the relationship between self-reported previous tuberculosis disease and lung function outcomes including COPD (defined as a postbronchodilator forced expiratory volume in one second (FEV 1 )/forced vital capacity (FVC) below the lower limit of normal). Multivariable regressions with random effects were used to examine the association between previous tuberculosis disease and lung function outcomes. Results We analysed data for 12 396 participants (median age 54.0 years, 51.5% male); 332 (2.7%) of the participants had previous tuberculosis disease. Overall prevalence of COPD was 8.8% (range 1.7%–15.5% across sites). COPD was four times more common among those with previous tuberculosis disease (25.7% vs 8.3% without previous tuberculosis disease, p&lt;0.001). The adjusted odds of having COPD was 3.78 times higher (95% CI 2.87 to 4.98) for participants with previous tuberculosis disease than those without a history of tuberculosis disease. The attributable fraction of COPD due to previous tuberculosis disease in the study sample was 6.9% (95% CI 4.8% to 9.6%). Participants with previous tuberculosis disease also had lower prebronchodilator Z-scores for FEV 1 (−0.70, 95% CI −0.84 to −0.55), FVC (−0.44, 95% CI −0.59 to −0.29) and the FEV 1 :FVC ratio (−0.63, 95% CI −0.76 to −0.51) when compared with those without previous tuberculosis disease. Conclusions Previous tuberculosis disease is a significant and under-recognised risk factor for COPD and poor lung function in LMICs. Better tuberculosis control will also likely reduce the global burden of COPD.
Abstract 12188: Meta-Analysis Evaluating the Role of Statin in Primary Prevention of Chemotherapy-Induced Cardiotoxicity
Authors: Yutthapong Temtanakitpaisan, Wasawat Vutthikraivit
Journal: Circulation (2021)

Introduction: Chemotherapy-induced cardiotoxicity is a well-known consequence after cancer treatment. There were attempts to identify the role of statin for primary prevention of cardiotoxicity. Due to limitations in previous studies (e.g., small sample size and short follow-up period), conclusions cannot be made. We aimed to assess the role of statin in primary prevention of chemotherapy-induced cardiotoxicity by meta-analysis. Methods: We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2021. Included studies were published cohort (prospective or retrospective) studies and randomized controlled trials (RCTs) that reported the mean change in left ventricular ejection fraction (LVEF) in breast cancer patients who received anthracycline-based or trastuzumab therapy with or without statin. Patients who received statin were considered as statin group while patients who did not receive statin were considered as control group. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate mean difference (MD) and 95% confidence intervals. Results: Three studies from 2011 to 2019 were included in this meta-analysis involving 220 women with breast cancer who undergoing anthracycline-based or trastuzumab therapy (73 in the statin group and 147 in the control group). Mean reduction in LVEF were significantly lower in the statin group as compared with the control group (pooled MD = 6.43%, 95 % confidence interval: 3.61-9.26%, p&lt;0.001, I 2 =88.2%). Conclusions: Our study suggested that stain use in breast cancer patients could prevent a decline in LVEF following anthracycline-based or trastuzumab therapy. Further clinical studies are required to ensure our findings.
Characterization of an Acute Myeloid Leukemia Murine Model Driven By MLL/AF9: Effect of Retroviral Insertion Sites and Somatic Mutations on Gene Expression
Authors: Hui Mei Lee, Niloofar Zandvakili, Rhea Desai, Peter J. Browett, Purvi M Kakadia, Stefan K. Bohlander
Journal: Blood (2021)
DCIR and its ligand asialo-biantennary N-glycan regulate DC function and osteoclastogenesis
Authors: Tomonori Kaifu, Rikio Yabe, Takumi Maruhashi, Soo-Hyun Chung, Hiroaki Tateno, Noriyuki Fujikado, Jun Hirabayashi, Yoichiro Iwakura
Journal: The Journal of Experimental Medicine (2021)

Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor with a carbohydrate recognition domain and an immunoreceptor tyrosine-based inhibitory motif. Previously, we showed that Dcir−/− mice spontaneously develop autoimmune enthesitis and sialadenitis, and also develop metabolic bone abnormalities. However, the ligands for DCIR functionality remain to be elucidated. Here we showed that DCIR is expressed on osteoclasts and DCs and binds to an asialo-biantennary N-glycan(s) (NA2) on bone cells and myeloid cells. Osteoclastogenesis was enhanced in Dcir−/− cells, and NA2 inhibited osteoclastogenesis. Neuraminidase treatment, which exposes excess NA2 by removing the terminal sialic acid of N-glycans, suppressed osteoclastogenesis and DC function. Neuraminidase treatment of mice ameliorated collagen-induced arthritis and experimental autoimmune encephalomyelitis in a DCIR-dependent manner, due to suppression of antigen presentation by DCs. These results suggest that DCIR activity is regulated by the modification of the terminal sialylation of biantennary N-glycans, and this interaction is important for the control of both autoimmune and bone metabolic diseases.
Functional enrichment of alternative splicing events with NEASE reveals insights into tissue identity and diseases
Authors: Zakaria Louadi, Maria L. Elkjaer, Melissa Klug, Chit Tong Lio, Amit Fenn, Zsolt Illes, Dario Bongiovanni, Jan Baumbach, Tim Kacprowski, Markus List, Olga Tsoy
Journal: Genome biology (2021)

Alternative splicing (AS) is an important aspect of gene regulation. Nevertheless, its role in molecular processes and pathobiology is far from understood. A roadblock is that tools for the functional analysis of AS-set events are lacking. To mitigate this, we developed NEASE, a tool integrating pathways with structural annotations of protein-protein interactions to functionally characterize AS events. We show in four application cases how NEASE can identify pathways contributing to tissue identity and cell type development, and how it highlights splicing-related biomarkers. With a unique view on AS, NEASE generates unique and meaningful biological insights complementary to classical pathways analysis.
Abstract P469: Scale-up And Characterization Of Therapeutic Mesenchymal Stromal Cell-derived Extracellular Vesicles
Authors: Selen Uman, Jason A Burdick
Journal: Circulation Research (2021)

Introduction: Early studies have shown therapeutic benefits of mesenchymal stromal cells (MSCs) in cardioprotection due to their angiogenic, proliferative, anti-apoptotic and anti-inflammatory properties, which are now attributed to secreted factors such as extracellular vesicles (EVs). While MSC-EVs have shown promise in small animals for cardiovascular therapies, large animal studies are required to evaluate the therapeutic benefit of MSC-EVs for clinical translation. One of the biggest challenges for large animal studies is the need to generate clinically-relevant quality and quantity of EVs without batch-to-batch variations that could compromise efficacy. This study aims to explore three different cell culture methods (traditionally-used tissue culture plates (TCP), 3-D printed bioscaffolds in a perfusion system (P), and microcarriers in dynamic spinner flask conditions (M)) to scale-up the production of MSC-EVs across four different biological donors and rigorously investigate EV yield, size, shape, and content. Methods: MSCs were isolated from the iliac crest of four different Yucatan minipigs using heparinized syringes, and cells were expanded to passage four, at which point they were seeded onto the respective cell culture methods. EVs were collected from conditioned medium (CM) via differential ultracentrifugation. EV size, distribution, yield, and protein concentration were studied using Nanoparticle Tracking Analysis (NTA) and microBCA assays. Results: Both perfusion bioreactor and spinner flask systems enabled sustained maintenance of large numbers of cells. Across biological donors and fabrication methods, modes remained within 50-150 nm and were not statistically different. Microcarrier-based spinner flasks and perfusion bioreactor set-ups both improved EV yield, up to 6 times in efficiency. Ongoing research focuses on examining differences in EV content across biological donors using RNA-sequencing and proteomics.
Abstract 11879: The Genetic Characteristics Based on Next Generation Sequencing in Patients With Hypertrophic Cardiomyopathy
Authors: JIE Wang, Fuyao Yang, Yuchi Han, Yucheng Chen
Journal: Circulation (2021)

Objective: This study aimed to explore the genetic epidemiological characteristics in patients with hypertrophic cardiomyopathy (HCM). Methods: We prospectively enrolled 383 unrelated HCM probands who received genetic testing and 3.0 T cardiac MRI examination, including 118 familial HCM and 265 sporadic HCM. The diagnosis of HCM is based on the diagnostic criteria of the American Heart Association and American College of Cardiology guidelines. Patients with familial HCM underwent targeted next generation sequencing including 117 candidate pathogenic genes associated with cardiomyopathies, while sporadic HCM underwent whole-exome sequencing. The genotypic characteristics were analyzed. Results: Among the 383 unrelated Chinese HCM probands, we reported 56 new pathogenic or likely pathogenic gene site mutations, including 3 new rare non-sarcomeric gene mutations and 53 new sarcomeric gene mutations. According to the analysis of genotypic characteristics, it was found that the frequency of rare genes was 3.4%, and the positive rate of sarcomere protein gene detection was 62.4%. Among them, MYH7 and MYBPC3 are the most common pathogenic genes, accounting for 61.9% of sarcomere protein gene mutations. Additionally, in the included HCM population, there was no significant difference in the positive detection rate of sarcomere protein gene between familial HCM and sporadic HCM (66.1% vs 64%, P = 0.7). The proportion of sporadic HCM carrying polygenic mutations was higher than that of familial HCM (11.2% vs. 1.8%, P = 0.003). Conclusion: We reported 56 new gene mutations, which expanded the gene spectrum of HCM. Additionally, the frequency of rare disease genes in the HCM cohort is 3.4%, and the composition ratio of sarcomere protein gene is similar to that of North American or European HCM populations. However, the gene positive rate of sporadic HCM is similar to that of familial HCM, but the composition ratio of genotypes is different.
Effect of Levofloxacin Prophylaxis on Rates of Febrile Neutropenia in Patients Receiving DA-EPOCH-R Chemotherapy for Aggressive Lymphomas
Authors: Brent Alexander Parker, Mina Dehghani, Selay Lam, Chai Wye Phua, Cheryl Foster, Kang Howson-Jan, Joy Mangel
Journal: Blood (2021)
DDRE-42. TOWARDS PRECISION MEDICINE: AUTOMATED DRUG SCREENING PLATFORM UTILIZING TUMOR-ORGANOIDS TO IDENTIFY PATIENT-SPECIFIC DRUG-RESPONSES IN MENINGIOMA
Authors: Gerhard Jungwirth, Adrian Paul, Cao Junguo, Andreas Unterberg, Amir Abdollahi, Christel Herold-Mende
Journal: Neuro-Oncology (2021)

Abstract Tumor-organoids (TO) are mini-tumors generated from tumor tissue preserving its genotype and phenotype by maintaining the cellular heterogeneity and important components of the tumor microenvironment. We recently developed a protocol to reliably establish TOs from meningioma (MGM) in large quantities. The use of TOs in combination with lab automation holds great promise for drug discovery and screening of comprehensive drug libraries. This might help to tailor patient-specific therapy in the future. The aim of our study was to establish an automated drug screening platform utilizing TOs. For this purpose, we established TOs by controlled reaggregation of freshly prepared single cell suspension of MGM tissue samples in the high-throughput format of 384-well plates. The drug screening was performed fully automated by utilizing the robotic liquid handler Hamilton Microlab STAR and a drug library containing 166 FDA-approved oncology agents. Viability was assessed with CellTiterGlo3D. In total, we performed the drug screening with 166 drugs on TOs from 11 patients suffering from MGM (n=8 WHO°I, n=2 WHO°II, n=1 WHO°III). The top five most effective drugs resulted in a decrease of TO viability ranging from 84.6–63.3%. K-means clustering analysis resulted in groupings of drugs with similar modes of action. One cluster consisted of epigenetic drugs while another cluster consisted of several proteasome inhibitors. However, when looking at a patient-individual level, in 11 patients 44 of 166 drugs, were among the top 10 most effective drugs, providing strong evidence for heterogeneous drug-responses in MGM patients. Taken together, we successfully developed an automated drug screening platform pipeline utilizing TOs from MGM to identify patient-specific drug-responses. The observed intra-individual differences of drug responses mandate for a personalized testing of comprehensive drug libraries in TOs to tailor more effective therapies in MGM patients.
INNV-31. NEURO-ONCOLOGY OUTPATIENT SATISFACTION IS MAINTAINED IN THE ERA OF COVID-19 TELEMEDICINE
Authors: Zoey Petitt, James Herndon, Oren Gottfried, Christina Cone, Daniel Landi, Mustafa Khasraw, Henry Friedman, David M Ashley, Annick Desjardins, Katherine Peters, Margaret Johnson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The use of telemedicine increased during the COVID-19 pandemic. However, the impact on patient satisfaction in the Neuro-oncology population is unknown. This quality improvement project compares outpatient satisfaction before and during the COVID-19 pandemic as well as in-person versus telemedicine platforms during the pandemic. METHODS We performed an IRB-exempt retrospective analysis of aggregate de-identified outpatient satisfaction scores among Neuro-oncology patients seen at The Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke University. The Clinician &amp; Group Consumer Assessment of Healthcare Providers and Systems (CG-CAHPS) is a survey developed and distributed by Press Ganey Associates, and is the most widely used outpatient satisfaction survey in the United States. We compared pre-COVID-19 CG-CAHPS scores from patients who received in-person care at the PRBTC between April 2019 and March 2020 to COVID-19 pandemic CG-CAHPS scores (i.e. those who received either telemedicine or in-person care at the PRTBTC) from April 2020 to March 2021. RESULTS Approximately 1448 surveys were completed for both in-person and telemedicine visits. During the pandemic, 48.6% of surveys represented telemedicine, with monthly variations from 84.6% (April 2020) to 21.4% (March 2021). Patient satisfaction scores pre-COVID-19 were similar to those during the pandemic: overall provider rating from 0-10 (9.28 v 9.36), knowledge of medical history (96.9% v 95.4%), listens carefully (96.6% v 96.9%), shows respect (97.2% v 98.1%), and time spent (93.2% v 95.5%). During the COVID-19 pandemic, in-person and telemedicine demonstrate similar levels of satisfaction: overall provider rating from 0-10 (9.29 v 9.48), knowledge of medical history (94.9% v 96.1%), listens carefully (95.4% v 99.0%), shows respect (97.5% v 99.0%), and time spent (94.7% v 96.7%). CONCLUSION Outpatient satisfaction prior to and during the COVID-19 pandemic was similar. Patients reported similar satisfaction between in-person and telemedicine platforms. We support the ongoing use of telemedicine for outpatient Neuro-oncology.
QOLP-20. DIETARY, ACTIVITY, AND QUALITY OF LIFE METRICS IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA IMPLEMENTING A KETOGENIC DIET: RESULTS OF A PHASE 1 CLINICAL TRIAL
Authors: Thomas Nelson, Gillian Gresham, Amelia Welborn, L J Amaral, Brandon Noorvash, Laura Lockshon, Mourad Tighiouart, Sungjin Kim, Alexandra Mack, Jeremy Rudnick, Scott Irwin, Stephen Freedland, Jethro Hu
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Emerging evidence suggests that a ketogenic diet (KD) may limit neoplastic growth, but limited data exist regarding the effect of KD on daily activity, cognition, and health-related quality-of-life (HRQOL) for patients with glioblastoma. METHODS Newly diagnosed GBM patients participating in a single-arm phase 1 trial of a 16-week KD plus standard-of-care measured BID blood glucose and ketone levels (Keto-Mojo), captured continuous activity data (Fitbit), and completed quality-of-life (QLQ30) surveys and Montreal Cognitive Assessments (MoCA) at baseline, Week 8, and study end (up to 16 weeks). NCT03451799. RESULTS All patients (n = 14; 57% female; median age 55 years) maintained blood ketones above 0.3 mM &amp;gt; 50% of study duration (mean per-patient days in ketosis = 87%). Mean glucose (mg/dl) and ketone levels decreased through the study – Weeks 1/2: glucose 94.9 (SD:16.5), ketones 1.44 (SD:5.82); Weeks 3/4: glucose 94.1 (SD:12.9), ketones 1.34 (SD:0.9); Final two weeks: glucose 92.3 (SD:13.3), ketones 1.13 (SD:0.7). On average, patients walked 6,836 steps/day (SD:5,129), spending 14.3 hours sedentary (SD:6.45) and 43.6 minutes (SD:60.4) in high-intensity activity. Sleep duration was 6.8 hours (SD:2.26). Patients (n = 9) with OS &amp;gt; 14.6 mo from diagnosis demonstrated greater minutes of high-intensity activity (58.2 vs 20.7, p = 0.001), downtrending glucose (p = 0.001), and higher ketone levels (1.40 vs 1.11, p = 0.026). Activity data corroborated the tolerability of KD with stable-to-increased activity by study end. MoCA scores were stable from baseline (mean 23.4/30, SD:4.16) to study end (mean 24.8/30, SD:7.12; p = 0.38). When viewed as a composite score, HRQOL was stable-to-improving in 10/14 patients at Week 8 and EOS. CONCLUSION The use of wearable technology and at-home testing allowed for remote monitoring of activity and diet adherence. Good adherence and stable HRQOL and activity levels were observed in this phase 1 trial.
Single-cell characterization of dog allergen–specific T cells reveals TH2 heterogeneity in allergic individuals
Authors: Céline Vandamme, Marja Rytkönen-Nissinen, Tapio Lönnberg, Jukka Randell, Rauno J. Harvima, Tuure Kinnunen, Tuomas Virtanen
Journal: Journal of Allergy and Clinical Immunology (2021)

Allergen-specific type 2 CD4+ TH2 cells are critically involved in the pathogenesis of IgE-mediated allergic diseases. However, the heterogeneity of the TH2 response has only recently been appreciated.We sought to characterize at the single-cell level the ex vivo phenotype, transcriptomic profile, and T-cell receptor (TCR) repertoire of circulating CD4+ T cells specific to the major dog allergens Can f 1, Can f 4, and Can f 5 in subjects with and without dog allergy.Dog allergen-specific memory CD4+ T cells were detected ex vivo by flow cytometry using a CD154-based enrichment assay and single-cell sorted for targeted gene expression analysis and TCR sequencing.Dog allergen-specific T-cell responses in allergic subjects were dominantly of TH2 type. TH2 cells could be phenotypically further divided into 3 subsets, which consisted of TH2-like (CCR6-CXCR3-CRTH2-), TH2 (CCR6-CXCR3-CRTH2+CD161-), and TH2A (CCR6-CXCR3-CRTH2+CD161+CD27-) cells. All these subsets were nonexistent within the allergen-specific T-cell repertoire of healthy subjects. Single-cell transcriptomic profiling confirmed the TH2-biased signature in allergen-specific T cells from allergic subjects and revealed a TH1/TH17 signature in nonallergic subjects. TCR repertoire analyses showed that dog allergen-specific T cells were diverse and allergic subjects demonstrated less clonality compared to nonallergic donors. Finally, TCR and transcriptomic analyses revealed a close relationship between TH2-like, TH2, and TH2A cells, with the last ones representing the most terminally differentiated and highly polarized subtype.Our study demonstrates heterogeneity within allergen-specific TH2 cells at the single-cell level. The results may be utilized for improving immune monitoring after allergen immunotherapy and for designing targeted immunomodulatory approaches.