tbuckley/cabot-search huggingface dataset:
Abstract 11068: Smad3-Deficiency in Murine Smooth Muscle Cells Causes Global Defects in Expression of Focal Adhesion Components, but Drives Subset-Specific Compensatory Mechanisms Promoting Matrix Degradation and Oxidative Stress
Authors: Emily E Bramel, Tyler J Creamer, Muzna Saqib, Wendy A Camejo Nunez, Loyal A Goff, Elena Gallo MacFarlane
Journal: Circulation (2021)

The pathogenesis of aortic aneurysms caused by mutations that impair TGF-β/Smad signaling without completely ablating it remains unclear. To investigate TGF-β’s role independently of its developmental functions, we used mouse models to inactivate Smad3 specifically in smooth muscle cells (SMCs) at 6 weeks of age, when postnatal matrix deposition is largely completed. This intervention was sufficient to induce dilation in the aortic root, but not the ascending aorta. To identify factors underlying this regional vulnerability, we analyzed aortas from control and Smad3-deficient mice by single-cell transcriptomics 10 weeks and 18 weeks after deletion, when dilation is undetectable and moderate, respectively. Three major SMC clusters were identified regardless of genotype or time-point. In situ hybridization showed that the aortic root and proximal ascending aorta were enriched in SMCs expressing cluster-defining transcripts for Cluster 3 and 2, while distal ascending and aortic arch were for Cluster 1. At the early time-point, all SMC clusters showed defective expression of genes coding for components ( Fblim1 , Svil , Tes and Tln1 ) and regulators ( Abra and Rock1) of focal adhesions in response to Smad3 inactivation. These defects associated with Cluster 3-specific upregulation of positive effectors of the TGF-β pathway, such as Tgfb2, and down-regulation of negative regulators of Angiotensin II signaling, such as Rgs2 and Rgs4 . At the later time point, whereas Smad3-deficient SMCs in Cluster 3 retained a similar profile, those in Cluster 2 showed transcriptional alterations consistent with increased TGF-β/Smad2 activation, accompanied by upregulation of Neat1 , a lnc-RNA critical for SMC phenotypic switching. These included potentially adaptive changes, such as upregulation of genes coding for collagen and its processing enzymes ( Col1a2 , Col3a1, Lox and Loxl1), and maladaptive ones such as upregulation of proteases ( Fap and Mmp9) , and upregulation of enzymes promoting oxidative stress ( Nox4 ). These data suggest that Smad3-deficiency causes defective expression of focal adhesion machinery in SMCs, initiating secondary subset-specific compensatory mechanisms driving localized pathogenic increases in proteolysis and oxidative stress.
EPCO-12. STING IS SILENCED IN GBM BY PROMOTER METHYLATION THAT IS ESTABLISHED BY TISSUE OF ORIGIN
Authors: Justin Low, Vidyalakshmi Chandramohan, Michelle Bowie, Michael Brown, Matthew Waitkus, Aaron Briley, Kevin Stevenson, Rebecca Fuller, Zachary Reitman, Andrea Muscat, Seethalakshmi hariharan, Janell Hostettler, Nicholas Wong, Matthias Gromeier, David M Ashley
Journal: Neuro-Oncology (2021)

Abstract STING (Stimulator of interferon genes) is an initiator of endogenous antitumor immunity. Loss of STING expression has been observed in various cancer types. Here we describe a mechanism of STING suppression that is common to brain tumors, occurring through regional promoter hypermethylation (RPH) near its transcriptional start site. The RPH-mediated suppression of STING expression is selective to normal brain and neuroectoderm-derived tumors, but not present in most other tumor types and cells in the brain tumor microenvironment. A pan-cancer comparison revealed that STING RPH levels in tumors correlate with the respective tissue of origin, including tumors metastasizing to the brain. We demonstrate that STING RPH suppression in glioma cells may be reversed by treatment with decitabine, a DNA methyltransferase inhibitor that is used in the treatment of hematologic malignancies. Collectively, our results suggest that the epigenetic silencing of STING occurs early in brain development and may provide an immunosuppressive context for the genesis of brain tumors. Furthermore, our findings that STING suppression in brain tumor cells can be reversed by epigenetic modulation have significant therapeutic implications for the treatment of glioblastoma and potentially other STING-silenced, immunologically-cold cancers.
Abstract 13881: Nogo-B Receptor is Essential for Preserving Histone Acetylation-Mediated CCM1/2 Expression in Endothelial Cells and Preventing Cerebrovascular Hemorrhage
Authors: Zhi Fang, wenquan hu, Xiaoran Sun, Xiang Wang, Ji Ma, Thomas Palaia, Louis Ragolia, Qing R Miao
Journal: Circulation (2021)

Cerebral cavernous malformations (CCMs) are enlarged leaking vascular lesions in the brain caused by loss-of-function mutations in CCM1/2/3 genes or loss of expression. Although we previously showed that Nogo-B receptor (NgBR) knockout in endothelial cells (ECs) results in CCMs-like cerebrovascular lesions in the mouse embryo, the molecular mechanism by which NgBR regulates CCM1/2 expression has not been elucidated. Here, we show that temporal genetic depletion of NgBR in ECs at both the postnatal and adult stages results in CCM1/2 expression deficiency and consequently CCMs-like lesions such as enlarged vessels, blood-brain barrier (BBB) hyperpermeability, and cerebral hemorrhage. These cerebrovascular defects in the brain of NgBR endothelial-specific knockout (ecKO) mice can be rescued by adeno-associated virus (AAV)-mediated overexpression of CCM1 and CCM2 genes. To reveal the molecular mechanism, we used RNA-seq analysis to examine changes in the transcriptome. Surprisingly, we found that acetyltransferase HBO1 was downregulated in NgBR deficient ECs. The mechanistic study elucidated that NgBR is required for maintaining the expression of CCM1/2 in ECs via HBO1-mediated histone acetylation. ChIP-qPCR data further demonstrated that loss of NgBR impairs the binding of both the HBO1 and acetylated H4K5/K12 at the promoter of CCM1 and CCM2 genes. Similarly, AAV-mediated overexpression of HBO1 restores the acetylation of H4K5/K12 and rescues the CCMs-like cerebrovascular defects in the brain of NgBR ecKO mice. Our findings on epigenetic regulation of CCM1 and CCM2 provide a perspective that NgBR and HBO1-mediated histone H4 acetylation may be targeted for preventing the onset of CCMs-like cerebrovascular disease.
Abstract 11180: Contemporary Evidence on Risk Stratification of Anticoagulated Non-Valvular Atrial Fibrillation Patients Grouped by Cha <sub>2</sub> D <sub>2</sub> -vasc Score Levels
Authors: Gregory Y Lip, Richard Murphy, Farhad Sahiar, Amol Dhamane, Mauricio Ferri, Patrick Hlavacek, Madison Preib, Allison Keshishian, Cristina Russ, Lisa Rosenblatt, Steve Deitelzweig
Journal: Circulation (2021)

Introduction: The CHA 2 DS 2 -VASc score is an established tool to determine the risk of stroke among atrial fibrillation (AF) patients. The goal of this retrospective claims analysis is to evaluate the incidence of stroke/systemic embolism (SE) and major bleeding (MB) events among patients with non-valvular AF (NVAF) who initiated an oral anticoagulant (OAC; apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin) relative to their CHA 2 DS 2 -VASc score. Methods: Adult NVAF patients who initiated OACs were identified from 01JAN2013-31MAR2019 using data from five insurance claims databases. Patients were required to have 12 months continuous enrollment prior to index (OAC claim date) and were followed to the earliest of OAC discontinuation, death, disenrollment, or study end. Results were stratified by CHA 2 DS 2 -VASc score on index: low (0 for males and 1 for females), moderate (1 for males and 2 for females), high risk 1 (2-3 for males and 3 for females) and high risk 2 (≥4 for males and females). The incidence rate and cumulative incidence were reported for stroke/SE and MB, defined by hospitalization with a primary diagnosis of the respective outcomes. Results: A total of 1,141,097 NVAF patients were identified including 29,298 low risk, 95,584 moderate risk, 327,766 high risk 1 and 688,449 high risk 2 patients. The median follow-up time for all patients was 160 days. The incidence of stroke/SE and MB was 1.3 and 4.1 per 100 person years, respectively. Cumulative incidence for stoke/SE and MB increased across risk groups (Figure). Significant differences were seen for both stroke/SE and MB, when comparing the high risk 1 or high risk 2 group to the low-risk reference group. Conclusions: Assessing stroke/SE and MB events by CHA 2 DS 2 -VASc risk category demonstrates the differences in the rate of events according to the risk groups and provides insight for anticoagulated NVAF patients with clinical risk factors.
Iomab with Adoptive Cellular Therapy (Iomab-ACT): A Pilot Study of 131-I Apamistamab Followed By CD19-Targeted CAR T-Cell Therapy for Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma
Authors: Mark B. Geyer, Briana Cadzin, Elizabeth Halton, Peter Kane, Brigitte Senechal, Eileen M. Geoghegan, Vijay Reddy, Mark S. Berger, Dale Ludwig, Neeta Pandit-Taskar, Craig S. Sauter
Journal: Blood (2021)
Abstract 14423: A Retrospective Analysis of a Single-Center Experience With the Tempo Temporary Pacing Lead in Management of Bradyarrhythmia and Other Cardiac Electrophysiology Procedures
Authors: Mitchell Stelzer, Eugene Fu, James Kleman, Nagesh Chopra, Sandosh Padmanabhan, Gregory A Kidwell, anish amin
Journal: Circulation (2021)

Introduction: Acute temporary pacing lead dislodgment may result in cardiac perforation, loss of pacing capture and proarrhythmia by means of under-sensing or mechanical stimulation. We report the results of a single-center retrospective study of the safety and efficacy of the Tempo® Temporary Pacing Lead (BioTrace Medical, Menlo Park, CA), which has a novel active fixation mechanism designed to enhance pacing stability and a soft tip to mitigate perforation. Methods: Twelve consecutive patients (83% male, mean age 71.3 ± 10.1 years) who underwent Tempo Lead placement for temporary pacing (75% symptomatic bradyarrhythmia, 25% other indication) were retrospectively reviewed. Safety (including perforation, new pericardial effusion, and sustained device-related arrhythmias) and efficacy (clinically acceptable pacing thresholds with stable pace capture over the temporary implant duration) data were assessed. The study also evaluated post-procedural practices such as ambulation. Results: The Tempo Lead was successfully positioned and fixed in the right ventricle in all 12 cases with no perforations, pericardial effusions, or device-related arrhythmias. Access was femoral in 8 patients (67%) and jugular in 3 patients (25%), with one access point not indicated. Procedural mean pace capture threshold (PCT) was 0.96 ± 0.74 mA (n=10). Mean lead indwelling duration was 53.5 hours with a range of 20.9 hours to 5.9 days (n= 11). Three patients were ambulatory (at least bed-to-chair) with the Tempo Lead in place without complications and with maintenance of thresholds &lt;1mA. Conclusions: This single-center retrospective analysis demonstrates that the Tempo Lead is safe and effective for temporary pacing and early ambulation in cardiac electrophysiology procedures.
CBIO-08. ENDOGENOUS DNA DOUBLE STRAND BREAKS ACTIVATE HETEROGENOUS DNA DAMAGE SIGNALING IN IDH1/2 MUTANT GLIOMAS
Authors: Gaspar Kitange, Rachael Vaubel, Jann Sarkaria
Journal: Neuro-Oncology (2021)

Abstract Isocitrate dehydrogenase 1/2 (IDH1/2) mutations are common in astrocytic glioma and are frequently coupled with TP53 and ATRX mutations. Collectively, these alterations cause genomic instability leading to high basal DNA double strand breaks (DSBs). Understanding how IDH/TP53/ATRX mutant cells process endogenous DSBs may help exploit inhibitors of DNA damage response (DDR) for the treatment of patients with IDH mutant gliomas. Through systematic effort to uncover the mechanisms involved in repair of endogenous DSBs in IDH1/2 mutant GBMs, we have discovered that high basal phosphorylated DNA-PK (p-DNA-PK) was characteristic of an IDH1/TP53/ATRX mutant GBM164 patient derived xenograft (PDX) but not in another IDH1 mutant GBM196 PDX. Immunofluorescence (IF) studies in patient specimen from which GBM164 was derived showed that p-DNA-PK co-localized with g-H2AX, 53BP1 or H4K20me2 (but not p-RPA) the known surrogates of DSBs. In contrast, p-DNA-PK was absent in the patient specimen from which GBM196 was derived, which otherwise had equally intense g-H2AX immunostaining colocalized with p-RPA. An independent IF study involving 11 IDH1 wild-type (WT) and 11 IDH1 mutant GBM patient samples, the p-DNA-PK was observed in 3 (27%) of 11 IDH1 mutant samples while IDH1 WT tumors were negative for p-DNA-PK. A telomere specific fluorescence in situ hybridization (Tel-FISH) confirmed elevated alternative lengthening of telomere (ALT) activity in GBM196 (but not in GBM164) indicative of HR proficiency. Consistently, HR related genes, including BRCA1 and MRE11A, were found upregulated in ALT-positive GBM196 as compared to those in GBM164. Interestingly, ALT+ GBM196 cells were highly vulnerable to inhibitors of ATM and ATR pathways. In conclusion, IDH1/TP53/ATRX mutant gliomas can be subdivided into HR-mediated ALT-positive group, which repairs the endogenous DSBs by HR (e.g. GBM196) and an ALT-negative/p-DNA-PK group, which repairs DSBs by c-NHEJ (e.g. GBM164) and this subdivision can be developed as a prescient biomarker of sensitivity to DDR inhibitors.
Abstract 11876: Instantaneous Wave-Free Ratio and Fractional Flow Reserve Are Helpful in the Assessment of Anomalous Aortic Origin of a Coronary Artery
Authors: Tam T Doan, Athar M Qureshi, Srinath Gowda, Shagun Sachdeva, Dana L Reaves-O'Neal, Silvana M Molossi
Journal: Circulation (2021)

Background: Anomalous aortic origin of a coronary artery (AAOCA) is the second most common cause of sudden cardiac death in youth during exertion. An optimal method to risk stratify patients with AAOCA and atypical symptoms is yet to be defined. Hypothesis: Invasive intracoronary hemodynamic flow measurement can be helpful in scenarios when there is conflict between clinical presentation and non-invasive studies. Methods: Case series of patients &lt;21 years old with AAOCA who underwent cardiac catheterization with instantaneous wave-free ratio (iFR)/fractional flow reserve (FFR) measurement at baseline and during adenosine and dobutamine infusion. Baseline iFR &lt; 0.89 and/or FFR &lt;0.8 were considered hemodynamically significant. All patients underwent dobutamine stress cardiac MRI to evaluate for inducible myocardial ischemia during provocative stress. Post-op assessment was described in patients who underwent surgical intervention. Results: A total of 8 patients, including 3 AAOCA of a left (AAOLCA) and 5 AAOCA of a right coronary artery (AAORCA) underwent cardiac catheterization including iFR and FFR measurement [Table]. iFR and FFR were reassuring in 4 patients, and suggestive of significantly impaired coronary flow in 2 AAOLCA and 2 AAORCA. There were no catheterization complications. Shared decision making was discussed, 2 patients with AAOLCA underwent successful surgical repair (patient 4 had normalized iFR/FFR after surgery and patient 8 is awaiting post-op assessment), and 2 are awaiting surgical scheduling. Patients not intervened upon are exercising with no restrictions, except one with concerns for cardiomyopathy. Conclusions: Invasive assessment using iFR/FFR with adenosine and dobutamine is helpful in shared decision making of AAOCA with conflicting noninvasive data and contribute to return to play after surgery. Long-term follow-up is essential to understand the predictive values of iFR/FFR in patients with AAOCA.
Abstract 12878: Left Atrial Labyrinth in Fetal Hypoplastic Left Heart Syndrome is Associated With Worse Prognosis
Authors: Amna Qasim, Tam Doan, Betul YIlmaz Furtun, Shaine A Morris
Journal: Circulation (2021)

Introduction: Hypoplastic left heart syndrome (HLHS) with restrictive atrial septum (RAS) is associated with poor outcomes. A subset of patients with HLHS have cor-triatriatum sinister, which often presents as a complex network of folds within the LA, which we referred to as LA-labyrinth (Figure 1). Hypothesis: We hypothesize that LA labyrinth is associated with worse clinical outcomes among those with a RAS compared to patients without LA-labyrinth. Methods: In a single-center retrospective cohort study, all fetuses with HLHS (2010-2020) were included. Fetuses with inadequate images, no follow-up data, pregnancy termination, or postnatal comfort care were excluded. All fetal echocardiograms were reviewed. RAS was defined as a ratio of forward/reverse pulmonary vein velocity time integral (PV-VTI) &lt; 5. Kaplan-Meier analysis from 20 weeks’ gestation was performed to evaluate freedom from the primary outcome (fetal demise, postnatal death, or transplant) by 1-year postnatal life (72 weeks total). Results: Of 241 fetuses with HLHS, 179 met inclusion criteria. RAS was present in 43 (24%), and LA-labyrinth was seen in 9 (5%), of which 6 also had RAS. Freedom from death/transplant was worse in RAS with LA labyrinth vs. no LA labyrinth and vs. HLHS-unrestrictive atrial septum (Figure 2). Among those with RAS, those with LA labyrinth were more likely to have early atrial septal intervention (4/6 vs 10/34), and to die or need transplant (4/6 vs 12/37, p = 0.022). Conclusions: LA-labyrinth is seen in HLHS with RAS and is associated with worse outcomes than RAS alone. The unique left atrial anatomy may need to be taken into consideration during prenatal counseling and postnatal planning.
MDS and MDS/MPN Genomic Subgroups Demonstrate Differential E <i>x Vivo</i> Drug Sensitivity
Authors: Michael A Spinner, Steven A Schaffert, Henning Stehr, Marianne T Santaguida, Ryosuke Kita, Alexey Aleshin, James L Zehnder, Peter L. Greenberg
Journal: Blood (2021)
Safety and Short-Term Efficacy of Venetoclax Combined with Azacitidine in Acute Myeloid Leukemia: A Single Institution Experience
Authors: Wen-Jing Yu, Jinsong JIA, Jing Wang, Fei-Fei Tang, Lizhong Gong, Xiaohong Liu, Xiaolu Zhu, Xiaosu Zhao, Xiao Jun Huang, Hao Jiang
Journal: Blood (2021)
Abstract 11244: Illness Perception and the Impact of a Definitive Diagnosis on Women with Ischemia Without Obstructive Coronary Artery Disease: A Qualitative Study
Authors: Leslie Tseng, Samit Shah, Leslie Curry, Erica S Spatz
Journal: Circulation (2021)

Introduction: Women are more likely to have ischemia and no obstructive coronary artery disease (INOCA), and the underlying pathologies of this diagnosis (such as microvascular dysfunction and coronary vasospasm) are often not distinguished. Comprehensive invasive physiology testing at the time of invasive coronary angiography (ICA) allows for improved diagnostic accuracy. However, despite increased recognition of INOCA and expanding access to testing, data lacks on the impact of receiving a mechanism-based, definitive diagnosis (DD) on women. Methods: We are conducting in-depth telephone interviews with women with INOCA who recently underwent ICA. Respondents are asked about understanding of diagnosis, healthcare experiences, and health status prior to and following ICA. The interviews are transcribed and analyzed using the constant comparison method. Results: To date, 17 women were interviewed (median age: 55), 14 of whom underwent physiology testing and 13 of whom received a DD. Through iterative coding, four major themes emerged: (1) Illness perception and communication: A DD equipped women with a better understanding of their symptoms and subsequent functional status and provided tools for communication; (2) Psychological toll: A DD relieved frustration with repeated testing, lack of validation, and fear about prognosis; (3) Identity: A DD served as a turning point for reclaiming their personal and professional identity; (4) Lifestyle changes and outlook: A DD brought relief and hope for the future and motivation for a healthier lifestyle. See quotes in Table. Conclusions: Women with INOCA were eager to share experiences (89% participated). Overall, they described the physical, emotional, interpersonal, and financial toll of seeking a diagnosis for their symptoms. Those who received a DD reported better understanding of disease, healthcare experiences, and well-being. Next steps are to continue interviews until thematic saturation is reached.
Abstract P361: Reduced Cardiac Tmem65 In Mouse Hearts Results In Intercalated Disc Defects And Eventual Dilated Cardiomyopathy With Cardiac Fibrosis
Authors: Allen C Teng, Liyang Gu, Michelle Di Paola, Zachary Williams, Aaron Au, Neal Callaghan, Farigol Hakem Zadeh, Yu-Qing Zhao, Meena Fatah, Diptendu Chatterjee, J. J Jourdan, Craig A Simmons, Thomas Kislinger, Christopher Yip, Robert G Gourdie, Robert M Hamilton, Anthony Gramolini
Journal: Circulation Research (2021)

The intercalated disc (ICD) is unique membrane structure that is indispensable to normal heart function. However, its structural organization is not well understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin 43 (Cx43) localization in cultured mouse neonatal cardiomyocytes. Here, we investigated the role of Tmem65 in ICD organization in vivo . A mouse model was established by injecting CD1 mouse pups (3-7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 (or scrambled) shRNA. Quantitative polymerase chain reaction (qPCR) and immunoblots confirmed greater than 85% reduction in Tmem65 expression (7.1±0.7% remained for Tmem65 proteins; 14.4±2.5% remained for Tmem65 transcripts, n =4) in mouse ventricles compared to control hearts. Tmem65 knockdown (KD) mice exhibited heart failure-like symptoms as early as 3 weeks post viral administration. Specifically, Tmem65 KD mice developed eccentric hypertrophic cardiomyopathy in 3 weeks and dilated cardiomyopathy with severe cardiac fibrosis in 7 weeks, as confirmed by H&amp;E and Masson’s Trichrome staining. Echocardiography and electrocardiography, respectively, showed depressed hemodynamics (19.27±1.46ml/min for cardiac output in control hearts vs. 6.63±0.52ml/min for Tmem65 KD hearts, n =6) and impaired conduction, including prolonged PR (22.7±1.85ms in control hearts vs. 28.89±3.85ms in Tmem65 KD hearts, n≥8), QRS intervals (10.47±0.42ms in control hearts vs. 16.35±0.36ms in Tmem65 KD hearts, n≥8), and slowed heart rate (415±10bpm in control hearts vs. 347±16bpm in Tmem65 KD hearts, n≥8) in Tmem65 KD mouse hearts. Immunoprecipitation and super-resolution microscopy confirmed the physical interaction and localization between Tmem65 and voltage-gated sodium channel β subunit (β1) at the ICD and this interaction was evidently required for the establishment of perinexal nanodomains and voltage-gated sodium channel 1.5 (NaV1.5) localization to the ICD. Disrupting Tmem65 function, thus, impaired perinexal structure, reduced conduction velocity, and ultimately resulted in cardiomyopathy in vivo .