tbuckley/cabot-search huggingface dataset:
DDRE-32. SETD2 HISTONE METHYLTRANSFERASE MUTATION STATUS PREDICTS TREATMENT RESPONSE IN GLIOBLASTOMA: STRATEGIES TO OVERCOME CHEMORESISTANCE
Authors: Michael Goldstein, Nishanth Gabriel, Matthew Inkman, Jin Zhang, Sonika Dahiya
Journal: Neuro-Oncology (2021)

Abstract A major challenge in GBM treatment is tumor resistance to radiation and chemotherapy. A hallmark of GBM is the frequent mutation of epigenetic modifiers resulting in alteration of epigenetic signaling pathways. However, the effect of epigenetic signaling on chemotherapy response in GBM remains unknown. SETD2 is a histone methyl transferase that facilitates H3K36 tri-methylation. Here, we unveil the role of SETD2 mutations that frequently occur in GBM in tumor resistance to temozolomide chemotherapy. Targeted sequencing of the SETD2 gene in GBM tumor samples revealed that SETD2 mutations are associated with reduced overall survival in patients with methylated MGMT (methyl-guanine methyl transferase) promotor who received temozolomide. Consequently, we demonstrate that loss of SETD2 results in reduced H3K36me3 levels and a profound temozolomide resistance in GBM cells. MGMT-deficient tumors can acquire chemoresistance due to disrupted mismatch repair (MMR), a DNA repair pathway that converts primary temozolomide-induced DNA lesions into toxic DNA double-strand breaks. Strikingly, we found that SETD2 loss abrogates the expression of the MMR factor MSH6 indicating that chemoresistance in SETD2-deficient cells us due to disrupted MMR. Mechanistically, we show that SETD2 regulates MMR by promoting transcription of the MSH6 gene in GBM. Epigenetic modifiers have specific antagonists capable of reversing chromatin alterations induced by these modifiers. This provides a unique opportunity to restore chemotherapy response in SETD2-mutant GBM by targeting the antagonists of SETD2. We demonstrate that combined targeting of H3K36me3-specific histone de-methylases KDM4A and NO66 restores H3K36me3 levels along with MSH6 expression and sensitivity to temozolomide in SETD2-deficient GBM cells. Thus, our findings establish SETD2 mutation as a novel molecular marker predictive of chemotherapy response in GBM and provide a framework for a novel approach to overcome chemotherapy resistance in this malignant brain tumor by targeting an epigenetic pathway.
Abstract 6945: A Pacemaker Red Herring and a Hypertrophic Cardiomyopathy Copycat
Authors: Inbar Raber, Nicholas Palmeri, Usman A Tahir, Peter Zimetbaum
Journal: Circulation (2021)

A 53-year old man with a history of hypertension, atrial flutter, and complete heart block with a dual chamber pacemaker presented to the hospital due to concern for pacemaker malfunction. Remote pacemaker monitoring found over-sensing events. He works in an automobile repair shop and his family history is notable for a son with Wolf Parkinson White syndrome treated with ablation. On presentation to the emergency department, he had normal vital signs and no lab abnormalities. His electrocardiogram showed sequential atrioventricular pacing at 60 beats per minute. He underwent an echocardiogram which showed a newly reduced left ventricular ejection fraction of 40-45% with global left ventricular hypokinesis, and left ventricular hypertrophy. The patient’s over-sensing events were initially concerning for pacemaker malfunction, particularly because he is known to be pacemaker-dependent. The differential diagnosis for the over-sensing events included battery depletion, insulation failure, insufficient programmed sensitivity value, and electromagnetic interference. An electrogram of one of the over-sensing events revealed simultaneous over-sensing of the both the atrial and right ventricular leads and otherwise stable lead parameters, which was consistent with electromagnetic interreference during arc-welding. The differential diagnosis for the left ventricular hypertrophy included sarcomeric hypertrophic cardiomyopathy, left ventricular hypertrophy secondary to hypertension, and hypertrophic cardiomyopathy phenocopies including Danon disease, Fabry Disease, Pompe disease, and PRKAG2 syndrome. Due to his family history of pre-excitation, genetic testing was conducted and demonstrated a pathogenic variant in the PRKAG2 gene. Shared decision-making with the patient informed his choice to upgrade his pacemaker to an implantable cardioverter defibrillator for primary cardiovascular prevention. The diagnosis of PRKAG2 syndrome served as the catalyst for his family members to undergo genetic testing. This case highlights the need for a high index of suspicion for hypertrophic cardiomyopathy phenocopies when pre-excitation and ventricular hypertrophy collocate to the same patient or family.
Single Nucleotide Polymorphisms of Cytokine Genes in Warm Autoimmune Hemolytic Anemias: Relationship with Clinical and Hematological Parameters
Authors: Anna Zaninoni, Bruno Fattizzo, Juri Alessandro Giannotta, Elisa Fermo, Nicola Cecchi, Paola Bianchi, Wilma Barcellini
Journal: Blood (2021)
A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts
Authors: Andreas Mackensen, Linda Hanssens, Matthias Stelljes, Wolfgang A Bethge, Tobias Feuchtinger, Annette Künkele, Michael Aigner, Alisa Yakushina, Sandra Karitzky, Silke Holtkamp, Mario Assenmacher, Marion Jurk, Georg Rauser, Dina Schneider, Claudia Rossig
Journal: Blood (2021)
Abstract 10332: Biventricular Function and Shock Severity Predicts Mortality in Cardiac Intensive Care Unit Patients
Authors: Barry Burstein, Sean Van Diepen, Brandon Wiley, Nandan S Anavekar, Jacob C Jentzer
Journal: Circulation (2021)

Introduction: Ventricular dysfunction contributes to shock in cardiac intensive care unit (CICU) patients. We aimed to describe the associations between ventricular dysfunction with in-hospital mortality across the spectrum of shock severity. Hypothesis: Patients with biventricular dysfunction (BVD) have higher mortality at each Society for Cardiovascular Angiography and Intervention (SCAI) shock stage. Methods: We identified CICU patients from 2007 to 2015 with available echocardiography data within 1 day of admission. Left ventricular systolic dysfunction (LVSD) was defined as left ventricular ejection fraction &lt;40% and right ventricular systolic dysfunction (RVSD) as moderate or greater systolic dysfunction by semi-quantitative assessment; BVD included the presence of both LVSD and RVSD. Predictors of in-hospital mortality were determined after adjustment using multivariable logistic regression. Results: We included 3,158 patients with a mean age of 68.2±14.6 years; 51.8% had acute coronary syndromes. LVSD was present in 22.3%, RVSD in 11.8%, and 16.4% had BVD. Hospital mortality increased with SCAI shock stage and was incrementally higher in patients with LVSD, RVSD and BVD across SCAI shock stages (Figure); patients with BVD had higher mortality in each SCAI shock stage. After adjustment, there was no difference in in-hospital mortality for patients with LVSD or RVSD versus those without ventricular dysfunction (p &gt;0.05), but BVD was independently associated with higher in-hospital mortality (adjusted HR 1.815, 95% CI 1.237-2.663, p = 0.0023). Adding ventricular dysfunction to SCAI shock stage increased discrimination for hospital mortality (AUC 0.784 vs. 0.766, p &lt;0.001). Conclusions: Among patients admitted to the CICU, BVD was independently associated with higher hospital mortality after adjustment for shock severity. Echocardiographic assessment may augment clinical risk stratification using the SCAI shock classification.
Abstract 10777: Circulating and Adipose Tissue Levels of CD147 Are Linked to Vascular Dysfunction in Obese Diabetic Adults
Authors: Mohamed M Ali, Chandra Hassan, MArio MAsrur, Francesco M Bianco, Abeer M Mahmoud
Journal: Circulation (2021)

Background: Extracellular matrix metalloproteinase inducer (EMMPRIN; CD147) is a transmembrane glycoprotein that stimulates the production of matrix metalloproteinases (MMPs). These MMPs mediate vascular remodeling and are considered biomarkers for cardiovascular risk. The activity of CD147 depends mainly on its glycosylation, which varies significantly among different conditions. However, it is unclear if CD147 glycosylation or its role in MMP upregulation is influenced by the diabetic milieu characterized by high glucose levels and abundant glycation end products (AGEs). In this study, we sought to investigate the differential expression and glycosylation levels of CD147 in obese, diabetic (OB-T2D) individuals compared to non-OB controls. Methods: Blood and adipose tissue (AT) samples were obtained from OB-T2D individuals and controls (n=40, each). DEXA scanning was used for body composition analyses. Flow-induced dilation (FID) was assessed in vivo in the brachial artery and ex vivo in AT-isolated arterioles. Other cardiometabolic risk factors related to glucose and lipid metabolism and systemic inflammation were measured. Results: Circulating CD147 was considerably greater in OB individuals, mirroring the glycosylated CD147 and the N-acetylglucosaminyltransferase, MGAT5 protein levels in the AT. Within the OB-T2D group, AT and circulating CD147 correlated with higher body mass index, total and visceral fat percentage, fasting plasma glucose and insulin, insulin resistance measurement (HOMA-IR), glycosylated hemoglobin, systolic BP, and plasma levels of MMP2/9, AGEs (Carboxymethyl lysine and methyl-glyoxal-lysine dimer), C-reactive protein, interleukin 6, and tumor necrosis factor-alpha. AT-arteriolar FID was significantly lower in the OB-T2D individuals across all pressure gradients, while carotid pulse wave velocity (PWV) was higher, indicating arterial stiffness. CD147 correlated negatively with brachial artery and AT-arteriolar FID and flow-induced nitric oxide production and positively with PWV. Conclusion: Our findings imply that vascular dysfunction in OB-T2D patients is linked to higher levels of CD147 and its glycosylated fraction, which in turn is associated with other cardiometabolic risk factors.
BIOM-41. LIVE-CELL IMAGING SHOWS UNEVEN SEGREGATION OF EXTRACHROMOSOMAL DNA ELEMENTS AND TRANSCRIPTIONALLY ACTIVE EXTRACHROMOSOMAL DNA CLUSTERS IN CANCER
Authors: Eunhee Yi, Amit Gujar, Molly Guthrie, Hoon Kim, Dacheng Zhao, Kevin Johnson, Samirkumar Amin, Sunit Das, Nathaniel Jillette, patricia Clow, Albert Cheng, Roel Verhaak
Journal: Neuro-Oncology (2021)

Abstract Oncogenic extrachromosomal DNA elements (ecDNAs) promote intratumoral heterogeneity, creating a barrier for successful cancer treatments. The underlying mechanisms are poorly understood and studies are hampered in part by a lack of adequate tools enabling studies of ecDNA behavior. Here, we show that single-cell ecDNA copy numbers greatly vary between tumor cells, both in vitro and in patient glioblastoma specimens, suggesting uneven ecDNA segregation during mitosis. We established a CRISPR-based approach which leverages unique ecDNA breakpoint sequences to tag ecDNA with fluorescent markers in living cells. Applying this method during mitosis revealed disjointed ecDNA inheritance patterns, providing an explanation for rapid ecDNA accumulation in cancer. Post-mitosis, ecDNAs tended to cluster and clustered ecDNAs colocalized with RNA polymerase II, promoting transcription of cargo oncogenes. Our observations provide direct evidence for uneven segregation of ecDNA and sheds new light on mechanisms through which ecDNAs contribute to oncogenesis.
Abstract 11467: Biomimetic Microrna-Laden Small Extracellular Vesicle-Derived Vehicles Increase Pro-Reparative Phenotype in Cardiac Endothelial Cells
Authors: Sruti Bheri, Brandon P Kassouf, Michael E Davis
Journal: Circulation (2021)

Introduction: Ckit+ progenitor cells (CPCs) release small extracellular vesicles (sEVs) which are vital for CPC-based recovery after myocardial infarction (MI). sEVs transport RNA cargo within a complex lipid/protein bilayer required for sEV trafficking and endocytosis. However, being cell-derived, sEV yield, cargo content and concentration are often variable. Synthetic sEV-mimics allow for cargo control, but their basic phospholipid membrane often results in rapid clearance. Here, we use thin film hydration (TFH) and electroporation to develop sEV-like vesicles (ELVs) with an sEV membrane and mimic-like cargo control. We hypothesize that (1) ELVs with cardioprotective microRNA (miR) cargo will improve functional outcomes from cardiac endothelial cells (CECs) compared to sEVs alone and (2) electroporated ELVs will functionally outperform TFH ELVs. Methods: sEVs were isolated from CPC conditioned media with ultracentrifugation. ELVs were synthesized from sEVs by removing inherent miR cargo and then loading endothelial specific miR126 through TFH or electroporation. For TFH, sEVs were dissolved in an organic solvent to form a lipid bilayer and then loaded with miR126 to initiate ELV self-assembly. For electroporation, miR126 was added to sEVs by varying voltage pulses. ELVs were characterized for size and concentration. Both cargo clearance and miR126 loading were quantified with a Quant-iT miR kit. Functionality of both ELV designs was assessed by delivering miR126+ ELVs to CECs for angiogenesis and proliferation. Results: ELVs on a similar scale to sEVs were successfully formed using both methods, despite variability in concentration. ELV miR126 loading capacity after cargo removal was higher and tunable with electroporation compared to TFH. Electroporation also preserved more membrane proteins than TFH. When delivered to CECs, electroporated miR126+ ELVs increased angiogenesis and proliferation compared to sEVs over 24 hours, in a dose-dependent manner. Conclusion: Using an sEV-like membrane with customizable miR cargo allows for improved functional outcomes from cardiac cells, with electroporated samples having more cargo tunability. Beyond miR126, this work highlights a delivery vehicle for combination miR therapy after MI.
Comparison of routinely collected data with clinical trial adjudicated direct follow-up: post-hoc analyses of serious cardiovascular events from the United Kingdom-based ASCEND randomized trial
Authors: C Harper, M Mafham, W Herrington, N Staplin, W Stevens, K Wallendszus, R Haynes, M Landray, S Parish, L Bowman, J Armitage
Journal: JAMA Network Open (2021)
Abstract 10795: <i>Adam10</i> Gene Deficiency Impairs Kidney Function via Suppressing Klotho Shedding
Authors: Bo Zhang, Shirley Wang, Kai Chen, Zhongjie Sun
Journal: Circulation (2021)

A Disintegrin and Metalloproteinase 10 (ADAM10) is a member of the ADAM family of cell membrane-anchored proteins which processes and influences the functions of its substrates by in-/activating them or by liberating biologically active fragments. ADAM10 is primarily expressed in kidney epithelial cells. Thus, the objective of this study is to investigate whether ADAM10 is involved in the regulation and maintenance of normal kidney function. Tamoxifen-inducible kidney-specific cre (Ksp) and ADAM170-floxed mice were cross-bred for generating Ksp/ADAM10-floxed mice. Injection of tamoxifen initiated deletion of the ADAM10 gene and led to a significant reduction in ADAM10 protein expression in renal distal and proximal tubule cells. Notably, knockout of the ADAM10 gene largely decreased soluble Klotho levels in urine, indicating that ADAM10 is a critical enzyme in shedding Klotho. We found that renal sodium excretion was decreased in kidney-specific ADAM1 0 knockout mice (ADAM10 -/-), suggesting that ADMA10 deficiency results in an increase in Na reabsorption or Na retention. Urinary potassium output tended to increase in ADAM10 -/- mice although it did not reach a significant level. It is interesting that ADAM10 gene deficiency compromises renal tubular function leading to Na retention. Glomerular filtration rate (GFR) was dramatically decreased in ADAM10 -/- mice, indicating that ADAM10 deficiency impairs glomerular function. Interestingly, treatment with recombinant Klotho improved renal glomerular function. Therefore, ADAM10 gene knockout impairs kidney function likely via suppressing Klotho shedding.
Prevention of SARS-CoV-2 transmission during a large, live, indoor gathering (SPRING): a non-inferiority, randomised, controlled trial
Authors: Constance Delaugerre, Frantz Foissac, Hendy Abdoul, Guillaume Masson, Laure Choupeaux, Eric Dufour, Nabil Gastli, Severine Mercier Delarue, Marie Laure Néré, Marine Minier, Audrey Gabassi, Maud Salmona, Malika Seguineau, Sarah Schmitt, Sébastien Tonglet, Alexis Olivier, Claire Poyart, Jerôme Le Goff, Xavier Lescure, Solen Kernéis, Jean-Marc Tréluyer
Journal: The Lancet Infectious Diseases (2021)

Mass indoor gatherings were banned in early 2020 to prevent the spread of SARS-CoV-2. We aimed to assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation.
Abstract 11220: Cardiac Bridging Integrator 1 Gene Therapy Rescues Diabetic Cardiomyopathy in Mice
Authors: Jing Li, Bradley Richmond, Maureen Walsh, Ryan Bia, Kikuyo Shaw, J David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M Shaw, Tingting Hong
Journal: Circulation (2021)

Introduction: Diabetes is a major cause of heart failure with preserved ejection fraction (HFpEF), which has limited diagnostic tools and therapeutic options. Abnormal remodeling in the t-tubule calcium handling cardiac bridging integrator 1 (cBIN1)-microdomains has emerged as key to the pathophysiology of failing cardiomyocytes, which can be targeted for cardiac functional improvement. It remains unclear whether cBIN1 replacement therapy is effective in restoring cardiac function in diabetic HFpEF. Hypothesis: We hypothesized that cBIN1 gene therapy rescues diastolic failure in mice with diabetic cardiomyopathy. Methods: 9-wks old male and female db/db mice that received retro-orbital injection of 1x10 11 vg of AAV9 transducing GFP or cBIN1 were compared to non-diabetic control db/m littermates injected with AAV9-GFP (N = 16 mice per group). Mice were terminated 8-wks later for tissue acquisition, imaging, as well as biochemical analysis. Echocardiography, exercise tolerance, and plasma cBIN1 score (CS, an inverse index of plasma cBIN1 concentration) were obtained before and after gene therapy. Results: db/db mice developed diastolic failure with reduced E/A, increased E/e’, exercise intolerance, and cardiac hypertrophy with reduced tissue cBIN1 levels and corresponding elevations in plasma CS. Supporting our hypothesis, AAV9-cBIN1 normalized E/A and E/e’ and improved exercise tolerance in db/db mice, which can be distinguished by plasma CS as an inverse marker of cBIN1-microfolds and cardiomyocyte remodeling (Figure 1). Preservation of cBIN1-microdomains in db/db cardiomyocytes reorganized functional SERCA2a and rescued mitochondrial respiration with diminished oxidative stress. Conclusions: Exogenous cBIN1 normalizes lusitropic function of diabetic hearts through microdomain-organized effective calcium handling and mitochondrial respiration. cBIN1 gene therapy is a new and effective method for guided treatment of diabetic HFpEF.
Changes in the Microrna Expression Profile in Patients Undergoing Autologous Steam Cell Transplantation
Authors: Damian Mikulski, Izabela Dróżdż, Ewelina Perdas, Konrad Stawiski, Mateusz Nowicki, Małgorzata Misiewicz, Piotr Strzałka, Agnieszka Wierzbowska, Wojciech Fendler
Journal: Blood (2021)
Abstract 11316: Analytical Validation for an Integrated Risk Tool for Cardiovascular Disease Combining Conventional Risk Factors and Polygenic Risk Inferred from Snp Array and Low-Pass Whole Genome Sequencing
Authors: Carla Giner Delgado, Eva Gradovich, R. Michael Sivley, Karola Rehnstrom, Andreas Heger, William Tarran, Alexander Lachapelle, Peter Donnelly, Michael E Weale, Gilean McVean, Priyanka Seth, Vincent Plagnol
Journal: Circulation (2021)

Genetic risk factors contribute to cardiovascular disease (CVD) risk and are imperfectly captured by family history. The development of integrated risk tools (IRT) that integrate polygenic risk scores (PRS) with conventional risk factors enables improved risk assessment. However, IRTs rely on accurate estimation of the genetic component across millions of genetic variants, either typed or imputed. To support two real-world implementations of CVD IRTs, we present analytical validation data for three biosample types (whole blood, saliva and buccal swab samples) and two genetic assay technologies (a custom-designed genotyping array (845,608 markers) and low pass whole genome sequencing (lpWGS) with 1.8x average read depth, both combined with computational imputation) across 48 ethnically-diverse donors. IRT measurements (range 4%-23%) were performed on the 10-year CVD risk percentage scale, assuming a non-genetic (pooled cohort equations) risk component of 10%. We find measurement errors are below 1% across the three biosample types, so that an IRT of 4% will at most be measured as 3% or 5%. Array and lpWGS showed different bias-variance trade offs. The array technology was more reproducible, with a standard deviation on the percentage scale of 0.09 (0.072-0.129 95% CI) for blood samples compared with 0.30 (0.201-0.617 95% CI) for lpWGS. In contrast, the array technology showed somewhat larger bias when compared with high depth sequencing data (mean absolute error on the percentage scale of 0.49 (0.217-0.755 95% CI) for blood samples against 0.30 (0.008-0.597 95% CI) for lpWGS, partially reflecting the sequencing basis of the reference data. Pass rate was high for both technologies and all three biosample types. In conclusion, both genotyping array and lpWGS approaches were appropriate and performed well for the purpose of assessing the genetic component of integrated cardiovascular disease risk using either blood, saliva or buccal samples.