tbuckley/cabot-search huggingface dataset:
EPCO-29. GENOMIC PROFILING OF SPORADIC MULTIPLE MENINGIOMAS
Authors: Zeynep Erson-Omay, Tanyeri Barak, Shaurey Vetsa, Arushii Nadar, Danielle Miyagishima, Kanat Yalcin, Stephanie Aguilera, Ketu Mishra-Gorur, Declan McGuone, Robert Fulbright, Murat Gunel, Jennifer Moliterno-Gunel
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION In rare cases, sporadic meningiomas can occur as multiple tumors in the same patient without a known germline mutation. While the underlying mechanism that leads to the formation of these multiple lesions has been hypothesized to be monoclonal or independent, the genomic profiles to support these theories remain understudied. METHODS Patients with an absence of family history of meningioma and prior radiation history with multiple metachronous meningiomas were included. All tissue underwent whole exome sequencing and analysis of somatic single nucleotide variations (SNV), small insertion/deletion (INDEL) events together with copy number variations (CNV) was performed. The genomic findings were correlated with clinical data. RESULTS A cohort of 13 meningiomas and one dural specimen, from five individuals was studied. The majority (9/13 tumors) of tumors had NF2 mutation/Chr22 loss. Four out of 5 cases had a monoclonal origination, whereas one case displayed an independent clonal formation. The somatic profile of dura was unrevealing. In contrast to the current understanding, we found monoclonal formation of multiple meningiomas is not exclusive to NF2 driven cases, as non-NF2 mutated meningiomas can too display a monoclonal etiology. Moreover, multiple monoclonal-originating lesions did not always display a homogenous profile, but rather exhibited heterogeneity through branching evolution, where some lesions acquired genomic alterations associated with aggressive behavior. The histological characterization of multiple meningioma cases does not necessarily overlap with the genomic clustering. CONCLUSION To our knowledge, this is the first study to use unbiased comprehensive genomic methods to reveal the heterogeneity of multiple meningioma genomic profiles. Our extensive genomic characterization of this cohort revealed that monoclonal formation can be observed both in NF2 and non-NF2 mutant meningiomas and can introduce heterogeneity. Therefore, in order to understand the full scope of each individual’s disease, detailed genomic profiling of all lesions, when possible, should be performed.
Abstract 77: CPC 1-2 and Modified Rankin <3 Scoring at Discharge Underestimates the Prevalence and Severity of Cognitive Deficits Seen in Cardiac Arrest Survivors at 3 Months
Authors: Laura K Artman, Mary Ann Peberdy, Joseph P Ornato, Michelle R Gossip, Kathryn P Wilder Schaaf, Jeffrey S Kreutzer
Journal: Circulation (2013)

Background: Cerebral performance category (CPC) and Modified Rankin (MRS) scoring are used commonly to document neurocognitive (NC) function after cardiac arrest (CA) with CPC1-2 or MRS <3 represen...
DDRE-25. WSD0628: A BRAIN PENETRABLE ATM INHIBITOR AS A RADIOSENSITIZER FOR THE TREATMENT OF GBM AND METASTATIC CNS TUMOR
Authors: wei zhong, Lily Liu, Claire Sun, Zhihua Mu
Journal: Neuro-Oncology (2021)

Abstract ATM (ataxia telangiectasia mutated) kinase, activated by DNA double-strand breaks, promotes DNA repair as well as activates DNA damage checkpoint and plays a key role for resistance to radiotherapy and chemotherapy. ATM function loss confers hypersensitivity to ionizing radiation evidenced by ataxia-telangiectasia (A-T) cells. Thus, pharmacological inhibition of ATM kinase is expected to suppress DSB DNA repair, block checkpoint controls and enhance the therapeutic effect of radiotherapy and other DNA double-strand breaks-inducing chemotherapy. Herein, we report a discovery of a potent, selective, orally bioavailable, and brain penetrable ATM inhibitor WSD0628, as a radiosensitizer for GBM and metastatic CNS tumors with IC50 against ATM &amp;lt; 1nM with high selectivity ( &amp;gt;400 folds) for ATR and DNA-PK. WSD0628 is highly selective over other kinases. In-vitro MDCKII transfected cells and Caco-2 assays have shown that WSD0628 is highly permeable and not a substrate of P-gp or BCRP, two main efflux transporters expressed on human BBB. Preclinical CNS PK studies in rat and mouse confirmed good brain penetration of WSD0628 with Kp,uu,brain and Kp,uu,csf &amp;gt; 0.3. Significant prolongation of overall survival for mice bearing GBM PDX intracranial model was achieved by treatment with WSD0628 (5mpk, QD) combo with radiation. Moreover, WSD0628 shows low PK variation liability without aldehyde oxidase (AO) metabolism, low hERG liability ( &amp;gt;30 uM), and good safety window based on DRF studies. Taken together, our data provide a good rationale for WSD0628 to be developed toward clinic combo with radiation for the treatment of patients with GBM and cancers with CNS metastasis.
CBIO-01. INHIBITION OF EXTRACELLULAR CARBONIC ANHYDRASES INHIBITS GLIOBLASTOMA CELL INVASION
Authors: Martin Proescholdt, Zhenwei Qiu, Johannes Falter, Anette Lohmeier, Nils-Ole Schmidt
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Malignant gliomas metabolize glucose preferably by glycolysis which is in accordance with the Warburg effect. This induces a high demand of glucose combined with a significant lactic acid load. The hypoxia-inducible carbonic anhydrase (CA) IX has been shown to moderate the extrusion of hydrogen ions into the extracellular space. Since the acidification of the extracellular environment contributes to host tissue invasion due to activation of proteolytic enzymes, we hypothesized that CA IX plays an important role in malignant glioma Recently, specific small molecule inhibitors of this enzyme have been developed and may provide an innovative strategy for anti – invasive treatment. METHODS Two established and 4 primary GBM cell lines (2 with mesenchymal and 2 with proneural transcriptional profile) were exposed to the CAIX inhibitor U104 under normoxic and hypoxic conditions. Cell toxicity was measured by ATP and crystal violet assay. For invasion assessment, a matrigel invasion chamber system with 8 µm pore size polycarbonate filter was used. CAIX expression was analyzed by quantitative RTPCR and Western Blot. RESULTS Hypoxia significantly induced CAIX expression in all cell lines. Invasiveness increased significantly under hypoxic conditions in the mesenchymal cells (p &amp;lt; 0.01). Regardless of oxygenation status, the mesenchymal group displayed significantly higher invasiveness compared to the proneural group (p = 0.006). Looking at all cell lines, invasion is significantly inhibited by U104, both under normoxic and hypoxic conditions (p &amp;lt; 0.01). However, while the mesenchymal group showed the highest susceptibility to CAIX inhibition followed by the proneurally differentiated group, the established cell lines were entirely refractory to CAIX inhibition. CONCLUSION Our data demonstrate that CAIX inhibition can effectively inhibit invasion in malignant glioma cells independent from oxygenation status, however the effects are significantly influenced by cell type specific biological features.
Abstract 14186: A Regional, Multidisciplinary Program to Streamline and Track Care of Aortic Dissection Patients
Authors: beth whippo, Matthew C Chia, jennifer schroeder, Jessica Kolek, Christopher K Mehta, Patricia Vassallo, S. Christopher Malaisrie, Andrew W Hoel
Journal: Circulation (2021)

Introduction: Acute aortic dissection (AAD) represents a medical emergency warranting management by multiple medical and surgical specialties. These specialties contribute unique expertise to the management of both immediate and long-term needs for patients with AAD. We hypothesize that coordinated, multidisciplinary care tracked using an automated dashboard can improve care for patients with AAD. Methods: This was a single-center, retrospective analysis of all AAD from February 2018 through April 2021. Clinicians from cardiology, cardiac and vascular surgery worked with administrative leadership to develop the program to streamline the coordinated care of patients with AAD. Concurrently, a provider-facing dashboard was developed to track volume and program performance using automated data abstraction from the institutional Enterprise Data Warehouse. Data elements included patient demographics, comorbidities, clinical data on dissection treatment and patient outcomes. These elements were compared in a pre-/post- design after the launch of the dashboard (Jan 20) using the Fisher exact test, the Kaplan-Meier method, and the log-rank test. Results: 238 patients were treated for AAD during the study period, with 134 patients prior to the program’s launch and 104 patients after. These included Stanford Type A and B dissections, which were similarly distributed pre-/post- period (p = 0.69). After the launch of the program outcome metrics improved (figure 1). Overall survival was similar at one (88.7% vs 84.8%, p = 0.36) and three months (85.5% vs. 82.3%, p = 0.46) Conclusions: Patients with AAD have complex care needs involving multiple specialties. Despite limited long-term follow up after program implementation, our results demonstrate the feasibility of tracking a comprehensive aortic care program with an automated dashboard. Combining multidisciplinary care with robust analytic support may improve the longitudinal care of these patients.
Abstract 9865: Temporal Dynamics of T Cell Response After Cardiac Injury
Authors: Tabito Kino, Lindsay Kraus, Marcus J Wagner, Sadia Mohsin
Journal: Circulation (2021)

Introduction: Neonatal heart can regenerate after myocardial injury unlike adult heart. Its capacity diminishes and disappears by post neonatal day 7 (P7). Recent studies have shown that immune cells especially T cells plays an important role to regulate inflammation, however, their role in cardiac regeneration/repair after injury is understudied. Therefore, in the present study we will characterize the temporal dynamics of T cells in neonatal and adult heart after injury and will study how temporal regulation is essential to maintain repair processes. Hypothesis: Regulatory T cells plays an important role in mediating reparative processes after ischemic cardiac injury. Methods and Results: Myocardial infarction (MI) was induced in neonatal mice at P2 (n=30) and in 8-week-old (n=10) C57BL/6 mice by ligating the left anterior descending artery (LAD). CD4+, CD8+ and Foxp3+ T cells were sorted by FACS at post MI day 2, 3, 4, 5 and 7 in neonatal mice and post MI day 7 in adult mice and analyzed for the differences in transcriptome by ultra-low input RNA sequencing. Flow cytometry analysis showed CD4+ T cells peaked at post MI day 4 compared to CD8+ T cells that peaked at post MI day 7. FoxP3+ T cells increased at post MI day 2 and diminished by post MI day 7 which coincides with the non-regenerative window of the heart. CD4+ and Foxp3+ T subsets showed increased expression of transcript in anatomical structure morphogenesis and regulation of response to stimulus. Our data showed 11.2%, 12.8% and 13.4% genes in CD4+, CD8+ and Foxp3+ T cells subsets were upregulated in neonatal mice versus adult animals. Enrichment analysis resulted that cellular component morphogenesis and cell development were activated in CD4+ T cells, and cellular component biogenesis and organelle organization were elevated in Foxp3+ T cells in neonatal mice. In addition, chromosome organization and cell cycle were upregulated in CD8+ T cells. Additionally, Foxp3+ T cells showed 198 genes uniquely expressed in neonatal hearts which are involved in cardiomyocytes proliferation and myofibroblasts phenotype transition. Conclusions: CD4+/CD8+/Foxp3+ regulate inflammation and mediate reparative processes in cardiac cells including myocytes and fibroblast after myocardial ischemic injury.
MYD88 L265P Augments Proximal B-Cell Receptor Signaling in Large B-Cell Lymphomas Via an Interaction with DOCK8
Authors: Elisa Mandato, Qingsheng Yan, Jing Ouyang, Julia Paczkowska, Yan Qin, Yansheng Hao, Kamil Bojarczuk, Julia Hansen, Lee N. Lawton, Margaret A. Shipp
Journal: Blood (2021)
Abstract 9950: Right Ventricular Hemodynamic Forces: Linking Pulmonary Insufficiency to Wall Motion in Repaired Tetralogy of Fallot Patients
Authors: Yue-hin Loke, Francesco Capuano, Sarah Kollar, Merih Cibis, Pieter Kitslaar, Elias Balaras, Johan Reiber, Gianni Pedrizzetti, Laura Olivieri
Journal: Circulation (2021)

Introduction: Patients with repaired Tetralogy of Fallot (rTOF) will develop right ventricle (RV) dysfunction from chronic pulmonary insufficiency (PI). Cardiac magnetic resonance (CMR) biomarkers informs timing of pulmonary valve replacement (PVR), but do not clarify the direct impact of PI on myocardial biomechanics. 4D flow studies have shown that RV hemodynamic forces (HDF) are altered in rTOF. In this study, we derived HDF in rTOF, exclusively using RV wall motion from conventional cine. Methods: This was a retrospective study using CMR of rTOF patients who had no PVR at time of imaging. Feature-tracking (QStrain, Medis) was used to capture RV wall motion from cine imaging. A novel diffeomorphic mapping technique was used to calculate 3D RV kinematic models (Figure 1A) and global HDF vector generated throughout the cardiac cycle. The RVOT-to-Diaphragm HDF vector was isolated for analysis. Global longitudinal strain, QRS duration and RV size/function were collected. Repeat analysis was performed on subgroup of rTOF who had subsequent PVR and follow-up CMR. Results: 44 rTOF studies (21±11 years) were included with regurgitant fraction (PR%) 33±15%, RV ejection fraction 50±5%, and RV end-diastolic volume 144±37 mL/m 2 . PR% correlated with RVOT-to-Diaphragm HDF vector in diastole (Figure 1B). Higher diastolic:systolic HDF ratio correlated with lower RV ejection fraction (R = -0.31, p = 0.04), lower global longitudinal strain (R = -0.38, p = 0.009), and longer QRS duration (R = 0.44, p = 0.004). 9 rTOF patients had follow-up CMR after PVR and demonstrated decrease in RVOT-to-Diaphragm HDF (Figure 1C). Conclusions: PI in rTOF patients is correlated to diastolic HDF exerted along the direction of the RVOT. Diastolic HDF correlates with RV dysfunction in rTOF patients, and as a global parameter can be captured by RV wall motion without the need to analyze 4D flow details. HDF is a potential biomarker that may provide early detection of RV dysfunction and inform PVR timing.
DDRE-41. TREATMENT OF REFRACTORY PITUITARY NEOPLASMS WITH TEMOZOLOMIDE IN THREE PATIENTS
Authors: Kelsey Duncan, Baha Arafah, Lisa Rogers
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND There is relatively little information regarding the efficacy of temozolomide (TMZ) for pituitary adenomas; less than 100 cases treated with TMZ are reported, with a variable response rate of 50-75%, depending on response criteria. METHODS Retrospective review of patients with pituitary tumors treated with TMZ at University Hospitals Cleveland Medical Center. RESULTS Three patients were identified. Patient age at the time of TMZ treatment was 20, 51, and 70 years. Two were female, one male. Histology was prolactinoma in two and Cushing’s disease in one. Each patient had undergone multiple surgeries and medical treatments with insufficient response or relapse. Two had received radiosurgery; it was withheld in a 20 year old male due to concerns of optic nerve radiation injury. A 5d q 28d regimen was used in each, beginning at 150mg/M2 daily for initial dose then increased to 200mg/M2 daily. Diplopia and headache improved in one patient, whose serum prolactin significantly declined (222.8 to 81.9 ng/ml). Headache resolved in another patient and prolactin remained stable. In the patient with Cushing’s disease, headaches improved and ACTH remained elevated but stable. The tumor remained stable on MRI in each patient. There were no adverse effects from TMZ used over 5 to 29 months. CONCLUSIONS Our clinical experience adds to the limited published information regarding the effectiveness of TMZ for pituitary adenomas. In our case series, clinical improvement was noted in each of 3 patients with pituitary adenomas that had failed or recurred after other therapies. Serum prolactin significantly declined in one patient. This data suggests a beneficial role for TMZ in treating pituitary adenomas.
Abstract 10487: Right Thoracotomy versus Conventional Median Sternotomy in Redo Cardiac Surgery: A 10-Year Single-Centre Experience
Authors: Clarissa Ng Yin Ling, Jacob Chacko, David Bleetman, Habib Khan, Donald Whitaker, Ranjit Deshpande, Olaf Wendler, Max Baghai
Journal: Circulation (2021)

Introduction: Minimally invasive cardiac surgery (MICS) has been gaining popularity over conventional sternotomy due to reduced invasiveness. However, in redo cardiac surgery when the risks are higher due to adhesions, few studies compare long-term outcomes. Objective: We aim to compare the perioperative and long-term mortality and stroke/TIA rate in patients undergoing median sternotomy and right thoracotomy for redo cardiac surgery. Secondary outcomes were post-operative and total hospital stay, blood products used, return to theatre and new renal replacement therapy (RRT). Methods: We retrospectively analysed a cohort of 127 sternotomy patients and 29 right thoracotomy patients for redo cardiac surgery between 2010-2020. All patients underwent valve repair or replacement. Patients requiring concomitant cardiac procedures were included. Results: In-hospital and long-term follow-up were 100% and 98.1% complete and a maximum of 10.4 years. There were 52 deaths (33.3%) within the follow-up period. Perioperative mortality was 16.5% in sternotomy versus 3.45% in MICS, although this difference was insignificant after adjustment for logistic EuroSCORE (HR 0.38, [0.05-2.79]). In multivariate analysis, long-term mortality was significantly lower in MICS (HR 0.30 [0.10-0.85]). Adjusted Kaplan-Meier curves revealed lower long-term mortality in the MICS group (p&lt;0.0001). Differences in stroke/TIA rates were insignificant (odds ratio 3.23 [0.85-12.8]). There were significantly less RBC (p=0.0001) and total blood products (p=0.0032) used in the MICS group. All 12 patients who returned to theatre for bleeding complications were in the sternotomy group. Although mean post-operative and total hospital stay and new RRT were lower in the MICS group, these differences were insignificant. Conclusion: MICS for redo cardiac surgery is a safe and effective alternative to median sternotomy without compromising both short-term and long-term clinical outcomes.
Abstract P449: Connexin43 As A Therapeutic For Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Jing Zhang, Fabian Zanella, William H Bradford, Kyohei Fujita, Ioannis Karakikes, Robert C Lyon, Valeria Mezzano, Jason D Roberts, Cassiano Carromeu, Yusu Gu, Jody L Martin, Alysson R Muotri, Melvin Scheinman, Kirk L Peterson, Farah Sheikh
Journal: Circulation Research (2021)

Limited efforts have been focused on the interventions which could therapeutically alter arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), a fatal cardiac disease of the desmosomal (mechanical) cell-cell junction. The desmosome is a critical target for intervention as mutations in desmosomal genes underlie 40-50% of ARVD/C populations and its dysregulation is associated with severe cardiac electrical and structural alterations, which facilitate myocardial failure, arrhythmias and premature death in these populations. Cardiomyocyte reduction of the predominant ventricular gap junction protein connexin43 is a molecular alteration that underlies desmosomal deficits and arrhythmias in ARVD/C. However, the role of connexin43 in structural alterations associated with ARVD/C remains unclear. We intervened with connexin43 reduction in human and mouse models of ARVD/C via connexin43 restoration strategies, which revealed beneficial effects in both ARVD/C models. We show ARVD/C human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes that recapitulate desmosomal structural defects and reveal connexin43 diminution alterations that are reflective of disease found in donor ARVD/C hearts. Connexin43 restoration was sufficient to rescue cardiac physiological deficits and increase desmosomal gene expressions in ARVD/C hiPSC derived cardiomyocytes, encompassing structural alterations. In vivo studies exploiting a mouse model of ARVD/C harboring severe desmosomal structural alterations revealed that cardiac connexin43 restoration was sufficient to prolong lifespan and restore cardiac desmosomal proteins. Herein, we provide evidence for non-canonical functions for connexin43, classically associated with electrical function, in the mechanical modulation of junctions. Our findings have broad implications in exploiting connexin43 as a therapeutic in advanced diseases associated with cardiac structural defects.
Abstract 12144: Prognostic Value of Preoperative Cardiac Troponin I and T in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Grafting: A Current Report of the North-Rhine-Westphalia Surgical Myocardial Infarction Registry
Authors: Matthias Thielmann, Lucas Priebe, Daniel WENDT, Sharaf-Eldin Shehada, Anja K Osswald, Alina Zubarevich, Bastian Schmack, Alexander Weymann, Thorsten Wahlers, Yeong Hoon Choi, Arjang Ruhparwar, Oliver J Liakopoulos
Journal: Circulation (2021)

Introduction: The extent of myocardial injury is a major determinant of morbidity and mortality in patients undergoing coronary artery bypass grafting (CABG) with acute coronary syndromes (ACS). More recently, cardiac biomarkers such as troponin I and T have been suggested as predictors for unfavorable outcome. We aimed to evaluate the predictive value of cardiac troponin (I and T) on a multicentric basis. Methods: We obtained multicentric data from a national surgical myocardial infarction registry with 2432 patients undergoing CABG with ACS between 01/2010 and 12/2018. Primary study endpoint was all-cause, in-hospital mortality (IHM) and postoperative major adverse cardiac and cerebrovascular events (MACCE). Multivariable logistic regression models and receiver-operating curve (ROC) analyses were applied to assess predictive value of preoperative cTnI and T for IHM and MACCE following CABG. Results: Patients were 68±11years of age, 78% male, 24.5% had unstable angina (UAP), 50.0% NSTEMI, and 25.4% STEMI, presenting a logEuroSCORE-I of 15.1±15.1% in UAP, 20.3±20.1% in NSTEMI and 23.5±20.0% in STEMI. Preoperative cTnI or T was obtained on admission and preoperatively with 5.4±19.5 and 3.6±10.0ng/mL for cTnI and 0.93±1.7 and 0.90±1.8ng/mL for cTnT. Preoperative cTnI and T was significantly increased between survivors and non-survivors (cTnI:4.2±11.9 vs. 22.4±59.5ng/mL, P &lt;0.05 and cTnT:0.9±1.7 vs. 1.3±1.9ng/mL; P &lt;0.05). STEMI patients demonstrated higher cardiac biomarker levels and worse IHM (12.6%) compared to NSTEMI (7.3%; P &lt;0.01) and UAP patients (4.2%; P &lt;0.01). Multivariable logistic regression analysis revealed cTnI but not cTnT to be a strong and independent predictor for IHM and MACCE ( P &lt;0.001). Preoperative cTnI and T &gt;2xURL showed a significant predictive value for IHM ( P &lt;0.003) and MACCE ( P &lt;0.001). In a ROC analysis, a cTnI value of 10.1ng/mL with an area under curve (AUC) of 0.65 ( P&lt; 0.01) was identified as an optimal cut-off value for IHM and 6.8ng/mL with an AUC of 0.65 ( P &lt;0.001) for MACCE. Conclusions: In this large-scaled national registry, we can confirm that preoperative cardiac troponin I but not T indicates important prognostic information of in-hospital mortality and MACCE rate in ACS patients undergoing CABG surgery.