tbuckley/cabot-search huggingface dataset:
Severe GI Toxicities Remain a Significant Source of Clinical Meaningful Morbidity Especially in Older Patients Receiving Autologous Transplant for Lymphoma
Authors: Geoffrey Shouse, Annabel Kate Frank, Sanjay K. Aggarwal, Edward Kavalerchik, John K Frazer, Paul Finnegan, Bita Fakhri
Journal: Blood (2021)
Abstract 12010: High Risk Population Of Screen Detected Atrial Fibrillation
Authors: Yoshiki Nagata, Nicole Lowres, Takashi Yamagami, Hongbing Wang, Don Nutbeam, Ben B Freedman
Journal: Circulation (2019)

Introduction: Asymptomatic atrial fibrillation (AF) contribute to a substantial proportion of strokes. Detecting asymptomatic AF would provide an opportunity to prevent ischemic stroke by instituti...
Reply to Drs. Liao and Peng
Authors: Woo Hyun Paik, Sang Hyub Lee
Journal: Endoscopy (2021)

See also: Anchoring of fully covered self-expandable metal stents: selected patients or all?Endoscopy 2021; 53(12): 1290-1290DOI: 10.1055/a-1616-0618
Abstract 12053: Age is a Predictor of Right Atrial Drivers in Human Persistent Atrial Fibrillation
Authors: Benjamin Buck, Aleksei Mikhailov, Ning LI, Anuradha Kalyanasundaram, Brian Hansen, Stanislav Zakharkin, John Hummel, Vadim V Fedorov
Journal: Circulation (2021)

Introduction: Persistent atrial fibrillation (perAF) may be maintained by localized extra-pulmonary vein (PV) drivers. Most clinical studies have focused on left atrial (LA) sources ablation, but right atrial (RA) arrhythmogenic substrate, due to certain comorbidities, may also maintain perAF. Hypothesis: Patient (Pt)-specific characteristics and comorbidities may predict occurrence of RA AF drivers. Methods: Consecutive Pts (n=105) underwent driver ablation in addition to PV isolation for perAF after panoramic multi-electrode mapping (MEM) at a single medical center. Logistic regression (LR) models were used to characterize the relationship between Pt characteristics and presence of AF drivers in each atrium. LR was used to predict 12-month AF-free survival. Results: Pts were 63.1±9.9 years old, 24.8% female, 21.9% in HF, 76.2% had HTN, 24.8% had DM, 22.9% had CAD and 59.0% had OSA. MEM identified a mean of 1.6±1.2 LA drivers and 1.4±1.2 RA drivers per Pt. Forty two Pts had drivers in both LA and RA, 19 in RA only, and 26 in LA only. Older age was a predictor of RA drivers presence (p=0.06), factors that predicted presence of LA drivers were female gender (p=0.19), HTN (p=0.03), and comorbidity score (p = 0.07). CHADS 2 -VASc score and LVEF predicted both LA and RA drivers. Following ablation, 75% of the Pts sustained sinus rhythm after 6 months, 70% after 12 months and 72% after 18 months. AF recurrence within 12 months of ablation was associated with DM (p=0.03), BMI (p=0.03) and RV systolic pressure (p=0.07). Presence of RA drivers was not associated with the 12 and 18-months freedom from AF. Conclusions: In this cohort of perAF patients, older age and higher CHADS 2 -VASc score predicted RA driver occurrence. These preliminary findings suggest that patient-specific clinical characteristics may uniquely impact LA vs RA myocardium by promoting development of chamber-specific arrhythmogenic structural and functional substrates of AF drivers.
A unique circulating miRNA profile highlights thrombo-inflammation in Behçet’s syndrome
Authors: Giacomo Emmi, Giacomo Bagni, Elena Lastraioli, Francesca Di Patti, Alessandra Bettiol, Claudia Fiorillo, Matteo Becatti, Elena Silvestri, Maria Letizia Urban, Lorenzo Emmi, Domenico Prisco, Annarosa Arcangeli
Journal: Annals of the Rheumatic Diseases (2021)

Objectives Behçet’s syndrome (BS) is a rare systemic vasculitis often complicated by thrombotic events. Given the lack of validated biomarkers, BS diagnosis relies on clinical criteria. In search of novel biomarkers for BS diagnosis, we determined the profile of plasmatic circulating microRNAs (ci-miRNAs) in patients with BS compared with healthy controls (HCs). Methods ci-miRNA profile was evaluated by microarray in a screening cohort (16 patients with BS and 18 HCs) and then validated by poly(T) adaptor PCR (PTA-PCR) in a validation cohort (30 patients with BS and 30 HCs). Two disease control groups (30 patients with systemic lupus erythematosus (SLE) and 30 patients with giant cell arteritis (GCA) were also analysed. Results From the microarray screening, 29 deregulated (differentially expressed (DE)) human ci-miRNAs emerged. A hierarchical cluster analysis indicated that DE ci-miRNAs clearly segregated patients from controls, independently of clinical features. PTA-PCR analysis on the validation cohort confirmed the deregulation of miR-224-5p, miR-206 and miR-653-5p. The combined receiver operating characteristic (ROC) curve analyses showed that such ci-miRNAs discriminate BS from HCs (and BS with active vs inactive disease), as well as BS from patients with SLE and GCA. The functional annotation analyses (FAAs) showed that the most enriched pathways affected by DE ci-miRNAs (ie, cell–matrix interaction, oxidative stress and blood coagulation) are related to thrombo-inflammatory mechanisms. Accordingly, the expression of the three ci-miRNAs from the validation cohort significantly correlated with leucocyte reactive oxygen species production and plasma lipid peroxidation. Conclusions The ci-miRNA profile identified in this study may represent a novel, poorly invasive BS biomarker, while suggesting an epigenetic control of BS-related thrombo-inflammation.
EXTH-69. FUNCTIONAL GENOMICS UNCOVER GENETIC DEPENDENCIES IN ATRTS
Authors: Daniel Merk, Sophie Hirsch, Foteini Tsiami, Bianca Walter, Lara Haeusser, Sepideh Babaei, Jakob Admard, Nicolas Casadei, Cristiana Roggia, Michael Spohn, Jens Schittenhelm, Stephan Singer, Ulrich Schüller, Federica Piccioni, Nicole Persky, David Root, Manfred Claassen, Marcos Tatagiba, Ghazaleh Tabatabai
Journal: Neuro-Oncology (2021)

Abstract Brain tumors are the leading cause of cancer-related deaths in children. Embryonal brain tumors including medulloblastoma and atypical teratoid rhabdoid tumors (ATRTs) account for 15% of all primary brain and CNS tumors under the age of 14 years, with ATRTs being most prevalent in infants. Despite intensive research efforts, survival estimates for ATRT patients stay relatively low as compared to other tumor entities with a median survival of around 17 months. We here describe genome-wide CRISPR/Cas9 knockout screens in combination with small-molecule drug assays to identify targetable vulnerabilities in ATRTs. Based on functional genomic screening revealing ATRT context-specific genetic vulnerabilities (n = 671 genes), we successfully generated a small-molecule library that shows preferential activity in ATRT cells as compared to a broad selection of other human cancer cell lines. Of note, none of these drugs differentially affect ATRT cells from distinct molecular subgroups, suggesting that top candidate inhibitors might serve as pan-ATRT therapeutic avenues. CDK4/6 inhibitors, among the most potent drugs in our library, are capable of inhibiting tumor growth due to mutual exclusive dependency of ATRTs on either CDK4 or CDK6. Our approach might serve as a blueprint for fostering the identification of functionally-instructed therapeutic strategies in other incurable diseases beyond ATRT, whose genomic profiles also lack actionable alterations so far.
treekoR: identifying cellular-to-phenotype associations by elucidating hierarchical relationships in high-dimensional cytometry data
Authors: Adam Chan, Wei Jiang, Emily Blyth, Jean Yang, Ellis Patrick
Journal: Genome biology (2021)

Abstract High-throughput single-cell technologies hold the promise of discovering novel cellular relationships with disease. However, analytical workflows constructed for these technologies to associate cell proportions with disease often employ unsupervised clustering techniques that overlook the valuable hierarchical structures that have been used to define cell types. We present treekoR, a framework that empirically recapitulates these structures, facilitating multiple quantifications and comparisons of cell type proportions. Our results from twelve case studies reinforce the importance of quantifying proportions relative to parent populations in the analyses of cytometry data — as failing to do so can lead to missing important biological insights.
CSIG-27. PROTEOMIC ANALYSIS OF GENETICALLY STRATIFIED MENINGIOMA
Authors: Yeasmin Akther, Jemma Dunn, Claire Adams, Vikram Sharma, Matthew Banton, Clemens Hanemann
Journal: Neuro-Oncology (2021)

Abstract WHO grade II and III as well as some WHO grade I meningioma are clinically aggressive. Approximately 60% sporadic meningiomas harbour mutations in the NF2 gene, others in genes including TRAF7, KLF4, AKT1, SMO and PIK3CA . However, the molecular mechanisms behind meningioma tumourigenesis are still unclear. We aim to identify novel biomarkers and therapeutic targets of meningioma by characterising the proteomic landscape. We performed (phosho)proteomic profiling of grade I, II and III meningiomas and three different mutational groups: AKT1 E17K /TRAF7, KLF4 K409Q /TRAF7 and NF2 -/-. We validated differential expression of proteins and phosphoproteins by Western blot on a meningioma validation set and by immunohistochemistry. Looking at all grades bioinformatics analysis revealed commonly upregulated proteins and phosphoproteins to be enriched in Gene Ontology terms associated with RNA metabolism. Validation studies confirmed significant overexpression of proteins such as EGFR and CKAP4 and upregulation and activation of the NIMA-related kinase, NEK9, involved in mitotic progression. Novel proteins described included the nuclear proto-oncogene SET, the splicing factor SF2/ASF and the higher-grade specific protein, Hexokinase 2. For the mutation subtypes we have quantified 4162 proteins across all mutational meningioma subgroups with proteomic profiles of mutational subgroups. Comparative analysis showed 10 proteins were commonly significantly upregulated among all mutational subtypes vs. normal meninges, indicating proteomic landscapes of mutational subtypes to be highly variable. 257 proteins were commonly significantly downregulated and enriched with molecular functions including aldehyde dehydrogenase and oxido-reductase. Mutational subtype-specific analysis identified 162 proteins significantly upregulated in AKT1 E17K /TRAF7 vs. remaining sample groups to be enriched in the oxidative phosphorylation pathway. Less proteins were commonly significantly upregulated in KLF4 K409Q /TRAF7 and NF2 -/- mutant meningioma subtypes respectively. Several of these up-regulated proteins including ANNEXIN-3, CRABP2, CLIC3 were verified. Analyses of 6600 phospho-sites predicted regulatory kinases. Further validation and functional verification of potential candidates is ongoing.
Abstract 11052: The Association Between Left Ventricular Mass and Coronary Artery Calcium Score in Retired National Football League Players
Authors: Genevieve E Smith, Camilo Fernandez, Gregory W Stewart
Journal: Circulation (2021)

Introduction: Literature suggests that increased left ventricular mass (LVM) is a predictor of coronary heart disease and mortality in the general population, and that increased LVM is associated with higher CAC. However, the association between LVM and subclinical atherosclerosis as indicated by absolute CAC has not been widely explored in retired elite athletes, who may have had or still have increased LVM as a result of exercise adaptation. Thus, we sought to investigate this association in a cohort of retired National Football League (NFL) players. Methods: This cross-sectional study included 632 retired NFL players aged 40 and older (mean age 56.4 ± 9.7 yrs; 51.3% Black) that participated in NFL Player Care Foundation health screenings. Two-dimensional echocardiogram was used to determine LVM according to American Society of Echocardiology guidelines and indexed to height to obtain left ventricular mass index (LVMI, g/m 2.7 ). LVH was considered as LVMI &amp;gt 49.2 g/m 2.7 . Multi-variable logistic regression models were utilized to determine the association of LVM with the highest quintile of CAC (CAC = 264-6239) after adjusting for traditional cardiometabolic risk factors. Results: The mean LVM of study participants was 220.8 ± 56.6 g and the prevalence of LVH 16.9%. LVM was highest in the 2 nd quintile of CAC, with LVM in the highest quintile of CAC significantly lower than that of the first and second quintiles and not significantly different from that of the 3 rd or 4 th quintiles. Multi-variable logistic regression models revealed that increasing LVM was associated with decreased odds for the highest quintile of CAC (odds ratio [OR]: 0.99, 95% confidence interval [CI] 0.99 - 1.00, p = 0.0486), with no such association for LVH (OR: 0.72, 95% CI 0.37-1.41, p = 0.3429). Conclusion: Odds for increased atherosclerotic cardiovascular disease risk, as indicated by the highest quintile of CAC, are decreased by augmented LVM within physiological range in this cohort of retired NFL players, possibly reflective of a potential protective effect of high lifetime exercise dose. These results suggest that there may be lingering or carryover effect of early life cardiovascular fitness, even in middle-aged retired athletes.
NIR Light‐Triggered Quantitative Pulsed Drug Release
Authors: Yang Yang, Kaiqi Long, Yiqun Wang, Lei Li, Jiayue Shi, Jican Liu, Lingxi Kong, Lin Yu, Jiandong Ding, Zhili Huang, Weiping Wang, Changyou Zhan
Journal: Advanced Healthcare Materials (2021)

Quantitative drug release is important for improving therapeutic efficiency and avoiding side effects. While using long-term delivery system for repeated therapies, it is indispensable but challenging to accurately control the drug dosing. Here, a photocleavable prodrug loaded hydrogel is proposed for near infrared (NIR) light-triggered quantitative pulsed drug release. IR783, a commercially available NIR fluorescent dye, is conjugated with methyl honokiol (mHNK) to give a photocleavable IR783-mHNK prodrug. Injectable glycol chitosan (GC) hydrogel is chosen as a reservoir, in which IR783-mHNK can be efficiently loaded via electrostatic and hydrophobic interactions. Upon 680 nm light-emitting diode (LED) light irradiation, IR783-mHNK cleaves and mHNK is released. Notably, it is found that IR783-mHNK presents synchronous photocleavage-fluorescence bleaching phenomenon. The released amount of mHNK is visible by measuring the residual fluorescent intensity of hydrogel. Quantitative drug release is achieved by controlling irradiation duration and the drug release process is visible by fluorescence imaging. The prodrug-loaded hydrogel shows good stability, minimum leakage and efficient light responsibility both in vitro and in vivo. After light triggering, monitorable quantitative mHNK release and on-demand sleep-promotiing effect are verified in mice without toxicities.
Abstract 14310: Anti-GM-CSF Monoclonal Antibody Gimsilumab Improved Ventilator-Free Survival, Decreased Hospitalization Length, and Prevented NT-proBNP Rise in Invasively Ventilated Patients With Hyperinflammatory COVID-19 Pneumonia: A Subgroup Analysis From the Breathe Trial Suggests Neurohormonal Role for GM-CSF Inhibition
Authors: Robert L Gottlieb, Frederick M Lang, Gerard J Criner, Kusum S Mathews, Tisha S Wang, Todd W Rice, Deepu Madduri, Simon Lowry
Journal: Circulation (2021)

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a myeloid cell growth factor and pro-inflammatory cytokine, may drive the overactive host immune response in COVID-19. We conducted a clinical trial assessing the anti-GM-CSF monoclonal antibody gimsilumab for hyperinflammatory COVID-19 pneumonia (BREATHE). Here, we report a pre-specified subgroup analysis demonstrating a signal of benefit in patients invasively ventilated at baseline. Methods: BREATHE (NCT04351243) was a double-blind, randomized, placebo-controlled trial at 21 US locations. Patients were randomized 1:1 to receive two doses of IV gimsilumab or placebo one week apart. The study included hospitalized COVID-19 patients with hyperinflammation (CRP ≥50 mg/L or ferritin ≥1,000 ng/mL) and pre-ARDS lung injury or ARDS. The primary endpoint was all-cause mortality at day 43, and key secondary outcomes assessed ventilator use and hospitalization length. Results: 225 patients were randomized and dosed. 41 patients were invasively ventilated at baseline. Steroid use and baseline characteristics were generally balanced across study arms in this subgroup. Ventilated patients treated with gimsilumab demonstrated improvements over placebo on the primary and key secondary endpoints (Table 1). Contrasting the placebo group, gimsilumab-treated patients did not experience a sharp rise in NT-proBNP, a marker of heart failure, through day 43 (Figure 1). Conclusions: GM-CSF inhibition may be therapeutic in ventilated COVID-19 patients through a neurohormonal mechanism. More studies are needed to assess the role of GM-CSF in COVID-19-associated cardiomyopathy, volume status, and ARDS.
Abstract 11114: Cardiovascular Disease Burden is Associated with Worsened Clinical Depression
Authors: Radha Dhingra, Fan He, Laila Al-Shaar, Erika F Saunders, Vernon M Chinchilli, Jeff D Yanosky, Duanping Liao
Journal: Circulation (2021)

Objective: To examine the association between prevalent cardiovascular diseases (CVDs) and CVD risk factors and depression symptoms in a US general population sample. Methods: US adults in the 2013-14 and 2015-16 National Health and Nutrition Examination Survey were included. CVDs (coronary heart disease [CHD], congestive heart failure [CHF], stroke) and CVD risk factors: current smoking; hypertension [HTN]; diabetes mellitus [DM]; and dyslipidemia; systolic BP (SBP), HbA1C, fasting plasma glucose (FPG), serum cholesterol (C), triglycerides (TG), HDL-C, and LDL-C were based on patient-report or lab tests, or medication prescriptions. The sum of HTN, DM, dyslipidemia, and current smoking represented a CVD risk score variable (range: 0-4). Depression symptoms were assessed using the 9-item Patient Health Questionnaire (PHQ-9): 0-9 (none-mild); 10-27 (moderate-to-severe). Logistic regression models were used to assess the association between CVDs and moderate-to-severe depression. Results: A total of 12,105 participants (52% females, 64% Caucasians) of mean (SE) age of 46.8 (0.3) years and BMI of 29.2 (0.1) kg/m 2 were included. Moderate-to-severe depression was prevalent among 8.1% of participants. The proportions (%) of CVD risk score categories of 0-4 were: 20.5; 31.4; 32.1; 14.6; 1.5. After adjusting for age, race, sex, BMI, marital and educational status, participants with risk scores of 1; 2; 3; and 4 had 1.3 (95% CI: 0.8-2.1); 2.4 (1.5-3.7); 5.0 (3.2-7.8); and 5.5 (2.9-10.4) times higher odds of having moderate-to-severe depression, compared to those without CVD risk. One percent higher HbA1C and a five mg/dl decrease in HDL-C were associated with 1.1 (95% CI: 1.1-1.2) and 1.0 (95% CI: 1.0-1.1) times higher odds of having moderate-to-severe depression, respectively. Self-reported CHD; stroke; CHF; and any CVD were associated with 3.5 (1.8-6.7); 1.7 (0.7-3.9); 2.1 (1.3-3.4); and 2.1 (1.2-3.6) times higher odds of having moderate-to-severe depression, after additional adjustment for current smoking, LDL-C, SBP, and FPG. Conclusions: Prevalent CVDs and CVD risk factors are significantly associated with depression symptoms in the US general population, underscoring the need to integrate mental and physical healthcare services.
TAMI-72. DIVERSITY OF CELLULAR COMMUNICATION IN GLIOBLASTOMA
Authors: Kevin Joseph, Lea Vollmer, Vidyha Ravi, Jürgen Beck, Ulrich Hofmann, Oliver Schnell, Dieter Henrik Heiland
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Owing to recent advances in understanding of the active functional states exhibited within glioblastoma (GBM), intra-tumoral cellular signaling has moved into focus of neuro-oncology. In this study, we aim to explore the diversity of transcellular signaling and investigate correlations between transcriptional dynamics and functional signaling. METHODS Electrophysiological characterization of GBM was carried out using planar microelectrodes and Ca2+ imaging, in both 2D cell culture as well as in our novel human cortical GBM model. Exposure to physiologically relevant conditions present within the tumor was carried out to identify specific signaling cells of interest and capture the signaling diversity in response to environmental conditions. Transcriptional dynamics and plasticity were examined by means of scRNA-sequencing with CRISPR based perturbation, spatial transcriptomics and deep long-read RNA-sequencing. RESULTS Electrophysiological profiles of multiple primary GBM cell lines revealed characteristics of scale-free networks (R2=0.875), confirmed in both 2D culture as well as a human neocortical GBM model. When GBM was cultured in a “in-vivo” like environment, basal activity was significantly higher (50%, p=0.01). Cellular signaling was directly correlated to changes in the environment, like hypoxia or glutamatergic activation, and total inhibition of electrical signaling required the usage of synaptic inhibitors. Using single-cell RNA sequencing and proteomics, several synaptogenesis related genes were identified to play a crucial role in the lineage states present in GBM. CRISPR based perturbation of these genes resulted in alterations in cellular morphology and decreased cellular connectivity (p&amp;lt; 0.01), with loss of scale free features (R2=0.35), and transcriptomic loss of developmental lineages (FDR&amp;lt; 0.01), leading to significant inhibition of GBM stress response. CONCLUSION Our findings highlight the role of electrical signaling in glioblastoma. Cellular stressors induce intercellular signaling, leading to transcriptional adaptation suggesting that there exists a highly complex and powerful mechanism for dynamic transcriptional state adaptation.
Immunogenicity of the COVID-19 mRNA vaccine in adolescents with juvenile idiopathic arthritis on treatment with TNF inhibitors
Authors: Dimitra Dimopoulou, George Vartzelis, Foteini Dasoula, Maria Tsolia, Despoina Maritsi
Journal: Annals of the Rheumatic Diseases (2021)

<h3>ABSTRACT</h3> DPANN archaea are primarily known based on genomes from metagenomes and single cells. We reconstructed a complete population genome for <i>Candidatus</i> “Forterrea”, a Diapherotrite with a predicted symbiotic lifestyle probably centered around nucleotide metabolism and RuBisCO. Genome-wide analysis of sequence variation provided insights into the processes that shape its population structure in the deep subsurface. The genome contains many transposons, yet reconstruction of a complete genome from a short-read insert dataset was possible because most occurred only in some individuals. Accuracy of the final reconstruction could be verified because the genome displays the pattern of cumulative GC skew known for some archaea but more typically associated with bacteria. Sequence variation is highly localized, and most pronounced around transposons and relatively close to the origin of replication. Patterns of variation are best explained by homologous recombination, a process previously not described for DPANN archaea.
Effect of MAGE-C1 Gene Expression on Prognosis and Effectiveness of Bortezomib-Containing Courses in Multiple Myeloma
Authors: Eleonora Makunina, Larisa Mendeleeva, Vadim L. Surin, Irina V. Galtseva, Julia O. Davidova, Maxim Solovev, Maiia Firsova, Valery G. Savchenko
Journal: Blood (2021)