tbuckley/cabot-search huggingface dataset:
Abstract 12316: Carnitine O-octanoyltransferase Inhibition Attenuates Human Aortic Valve Interstitial Cell Calcification by Correcting Energetic Mitochondrial State
Authors: Takehito Okui, Masaya Iwashita, Maximillian A Rogers, Shiori Kuraoka, Arda Halu, Yoshikazu Sawada, Masanori Aikawa, Sasha A Singh, Elena Aikawa
Journal: Circulation (2021)

Background: Cardiovascular calcification is a critical pathology associated with increased cardiovascular risk, but there are no FDA-approved anti-calcification therapies. Through an unbiased screening approach, we previously identified carnitine O-octanoyltransferase (CROT) as a novel contributing factor to vascular calcification, but whether it can inhibit calcification in cardiac valves remains unknown. Here we investigated CROT-associated mechanisms of calcification in human valvular interstitial cells (VICs). Methods and Results: Human VICs were isolated from aortic valve leaflets of patients undergoing valve replacement surgeries at Brigham and Women’s Hospital, and cultured in osteogenic medium (OM) to induce calcification. OM increased CROT mRNA expression (1.83±0.41 fold-change; p&lt;0.05). Tissue-nonspecific alkaline phosphatase activity, a key regulator of calcification, was also increased by OM (8.80±3.81 fold-change; p&lt;0.001) and reduced by CROT siRNA treatment (0.48±0.19 fold-change; p&lt;0.01). CROT siRNA decreased calcium deposition (Alizarin red staining; &gt;99.9%; p&lt;0.001). We previously showed that mitochondria dysfunction contributes to vascular calcification. We therefore, assessed mitochondrial function in VICs by measuring oxygen consumption rate and extracellular acidification rate. Basal and maximal respiration, spare respiratory capacity and ATP production increased in VICs after OM stimulation (1.73±0.48, p&lt;0.01; 1.75±0.34, p&lt;0.01; 2.11±0.63, p&lt;0.05; 1.75±0.38, p&lt;0.05; respectively), indicating mitochondrial dysfunction. These parameters were corrected to normal state followed by CROT siRNA treatment. The combined data of oxygen consumption and extracellular acidification rates indicated that osteogenic condition induced mitochondria energetic state that was corrected to quiescent state by CROT siRNA treatment. Conclusions: CROT promotes calcification of human aortic VICs. CROT inhibition attenuates the calcification of VICs via correcting mitochondrial dysfunction induced by osteogenic environment. CROT inhibition is an attractive approach as a therapy for aortic valve calcification, a major unmet medical need.
CTIM-23. EVIDENCE OF T CELL ACTIVATION AND INTRATUMORAL NIVOLUMAB-PRESENCE IN GLIOBLASTOMA PATIENTS TREATED WITH NIVOLUMAB AND BEVACIZUMAB
Authors: Signe Skadborg, Simone Maarup, Arianna Draghi, Annie Borch, Inge Marie Svane, Benedikte Hasselbalch, Hans Poulsen, Ulrik Lassen, Sine Hadrup
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is an aggressive brain tumor with a dismal prognosis. Salvage neurosurgical resection is performed if possible and GBM patients are hereafter treated with Stupp’s regime as standard treatment in the primary setting. However, after relapse, treatment in the recurrent setting shows very limited effect. We are monitoring the immune system of patients participating in a phase II clinical trial, where patients with recurrent GBM receive Nivolumab and Bevacizumab, treatments blocking PD1 and VEGF, respectively. The clinical trial consists of two arms. Arm A includes patients where surgical removal of the tumor is possible, and arm B includes patients who are only able to receive medical treatment. Arm A has received Nivolumab 7 days prior to surgery. Single cells suspension was produced from the resected tumors and blood samples was collected from patients through the course of treatment, wherefrom PBMCs (peripheral blood mononuclear cells) were purified. All samples were immunophenotyped using multi-color flow cytometry, to identify and follow the distribution of various immune cell types, and determine their expression of activating and inhibitory molecules over the course of treatment, in the periphery and in the tumor. An activated subset of T cells was characterized by CD103 (tissue residence), CD39 (antigen exposure) and CD69 (cytotoxicity). Such T cell populations were significantly enriched in the tumor. Importantly, we could demonstrate the presence of Nivolumab in the tumor, using an anti-IgG4 antibody to detect Nivolumab binding to T cells. We observed IgG4 positive T cell in the tumor digest, suggesting T cells binding Nivolumab are present in the tumor. Additional data analysis will be performed prior to the conference. With this we hope to gain further knowledge of the immune system’s role in tumor clearance in the brain and the impact of immunotherapy hereupon.
IRDye 800CW 2-deoxyglucose: A near infrared metabolic optical imaging agent
Authors: Joy Kovar, William Volcheck, Mike Olive, Melanie Simpson
Journal: Cancer Research (2007)

5527  Cancer cells are often characterized by a high metabolic rate exemplified in dramatically elevated glucose uptake. This biological activity has been exploited for noninvasive imaging by positron emission tomography using glucose analogues such as 35F-2-deoxy-D-glucose to generate a tumor-localized signal. In this work, our goal was to adapt a similar methodology for optical imaging of tumors in mice. We selected a fluorochrome with maximal excitation and emission wavelengths in the near infrared (NIR) spectral range (700-900 nm), where low absorption coefficients of tissues allow greater optical sensitivity, deeper tissue penetration, and low autofluorescence. The NIR fluorochrome, IRDye 800CW (excitation/emission of 778 nm/794 nm), was covalently coupled to 2-deoxyglucose (2DG). The resultant conjugate was evaluated first for specificity and sensitivity in vitro. Specificity of the agent was assessed using an In-Cell Western assay, in which concentration dependence of label uptake was established by fluorescence changes in a high throughput microplate format. Uptake of the labeled agent was specifically blocked in a dose dependent manner by addition of unlabeled 2-deoxyglucose. Subsequent in vivo studies were conducted to optimize dosing, clearance, and the optimal time post-injection for signal capture in nude mice. A research prototype imager, optimized to detect IRDye 800CW signal, was used to characterize the IRDye 800CW-2DG optical agent in subcutaneous tumors derived from either an epithelial carcinoma (A431 cells), colorectal carcinoma (SW620 cells), or prostate carcinomas (PC3M-LN4 and 22Rv1). In all cases, the tumors were clearly imaged with good signal to noise characteristics. This pilot demonstration suggests IRDye 800CW-2DG will be an excellent general optical imaging tool for studying tumor biology in mice.
Abstract 10656: Patient-Level Phenotype Network Identifies a Unique Subgroup Defined by Mild Pulmonary Hypertension and Clinical Resilience
Authors: Ruisheng Wang, Bradley Maron
Journal: Circulation (2021)

Background: Mild pulmonary hypertension (PH) is associated with increased mortality; however, the determinants of resilience in this population are not known. Most risk models overlook relationships between variables. We hypothesized that a patient-patient network will identify novel parameters that inform survival in mild PH. Methods: We analyzed clinical and outcome data (N=87 variables) retrospectively for patients with mean pulmonary artery pressure 19-24 mmHg in the Veterans Affairs Clinical Assessment, Reporting, and Tracking database. A patient-patient network was assembled using Pearson correlation coefficients (|r|&gt;0.5) using patients’ clinical variables. NetworkX was used to identify distinct network modules, and a feature selection method ranked variable importance for patient module assignment. Results: The cohort (N=4,551; 96.6% male, 68 [63-74] yr) included patients with a history of heart failure (43%) and hypertension (88%). The patient-patient network had 43,509 edges and N=20 modules (Figure, A), which were associated with a variable clinical profile. At a median follow-up of 1181 [565-1944] d, the all-cause mortality rate range was: 15.9% (M1) - 37.9% (M14). Compared to M2-20, mortality was significantly lower for M1 (P&lt;0.0001) (Figure, B). The most important variable driving patient assignment to M1 was pulmonary artery compliance (6.0 [4.7-7.1] mL/mmHg; cohort-normalized value=2.7). Conclusions: The mild PH patient-patient network identified numerous subphenotypes that are associated with variable clinical and outcome profiles. Using this unbiased approach, pulmonary artery compliance was associated unexpectedly with resilience.
Abstract 13944: Young, Non-Hispanic Black Males and Females Exhibit Divergent Peripheral and Cerebral Vascular Reactivity
Authors: Zachary T Martin, John D Akins, Jordan C Patik, Bryon M Curtis, Jeremiah C Campbell, Guillermo Olvera, Robert Brothers
Journal: Circulation (2021)

Introduction: In the U.S., cardiovascular and cerebrovascular diseases (CVD) remain more prominent in non-Hispanic black individuals than in other populations. Across most racial/ethnic groups, total CVD prevalence is ~10% lower in females; however, total CVD prevalence in black females (BF) is similar to that of black males (BM). Conversely, BM have ~23% higher age-adjusted stroke mortality compared to BF, a pattern not seen in other groups. While the mechanisms behind these race-by-sex differences are multifactorial, vascular dysfunction likely contributes. Our group and others have demonstrated reduced brachial artery and cerebrovascular vasodilation in black versus white individuals, though much of this work did not specifically address sex differences. To this end, we have recently investigated and reported divergent mechanisms of reduced cutaneous microvascular function in BM and BF; however, more work is needed to better understand whether such findings extend to other vascular regions. Hypothesis: We tested the hypothesis that BF and BM would have divergent degrees of reduced peripheral and cerebral vasodilator responsiveness. Methods: Eleven BF and 15 BM (22 ± 4 vs. 23 ± 3 yrs) underwent testing for brachial artery flow-mediated dilation (FMD; conduit artery function) and post-occlusive reactive hyperemia (PORH; microvascular function), along with cerebrovascular reactivity (CVR) to rebreathing-induced hypercapnia. Results: FMD was greater in BF versus BM (9.10 ± 3.49 vs. 5.84 ± 2.78%; P = 0.02), even when normalized to baseline diameter or shear rate ( P &lt; 0.05 for both). BF had similar PORH when assessed as peak blood velocity (77.1 ± 19.9 vs. 79.4 ± 19.6 cm • s -1 ; P &gt; 0.05) but lower peak blood flow (343.6 ± 169.8 vs. 495.4 ± 196.9 mL/min; P &lt; 0.05) and blood flow AUC (133.6 ± 61.1 vs. 220.3 ± 130.7 mL; P = 0.04) relative to BM. CVR was greater in BF versus BM (0.024 ± 0.010 vs. 0.012 ± 0.006 cm • s -1 • mmHg -1 • mmHg -1 ; P &lt; 0.01). Conclusion: These data suggest that young, BM have lower vascular reactivity than BF during some, but not all, tests of vascular function. More work in this area is needed to better understand the potential biological and social mechanisms influencing sex differences in vascular function and CVD risk in black individuals.
Primary care networks: Where are we? Where is the evidence base? What might the future bring?
Authors: Simon Hodes, Lana Kovacevic
Journal: BMJ (2021)

Since July 2019, practices across England have been encouraged to form Primary Care Networks (PCNs),1 which have become the focus for primary care investment.2 Advantages of PCNs, realised through economies of scale,3 include development of cost effective, community level services; sharing of best practice and IT systems; and improved quality of care.4 The main advantage for PCNs is funding for extra staff through the additional roles reimbursement scheme.5 However, recognised inflexibilities in the scheme mean restrictions on types of staff …
Abstract P312: The Essential Role Of Prak In Preserving Cardiac Function And Insulin Resistance In High Fat Diet-induced Diabetes
Authors: Yu T Zhao, Jianfeng Du, Thomas J Zhao, Hao Wang, Marshall Kadin, Ting C Zhao
Journal: Circulation Research (2021)

Background: p38 regulated/activated protein kinase (PRAK) plays a crucial role in modulating cell death and survival. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high fat diet (HFD). Methods: Wild type and PRAK -/- mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance test and insulin tolerance test were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Results: HFD induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared to wild type littermates. As compared to wild type, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high fat diet intervention. High fat diet intervention displayed a decline in fractional shortening (FS) and ejection fraction (EF). However, deletion of PRAK exacerbated the decline in EF and FS as compared to wild type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared to wild type controls. Conclusion: Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.
Abstract 10197: Cavin1, a Novel Actor in Drug Induced Long Qt
Authors: Zeina Al Sayed, Celine Pereira, Charlene Jouve, Jean S Hulot
Journal: Circulation (2021)

Introduction: Many drugs have been pulled from the market due to their undesirable effect in prolonging the QT interval by altering cardiac ion currents, notably I Kr generated by hERG. This cardiotoxic impact is however extremely variable between individuals and the mechanisms underlying this variability remain undiscovered. Previously, we identified a higher expression of CAVIN1, an essential protein for caveolae biogenesis, in cardiomyocytes (CM) derived from individuals with high susceptibility to develop sotalol-induced long QT. Hypothesis: CAVIN1 can modulate cardiomyocytes’ response to drugs. Methods: We used induced pluripotent stem cells-derived-CM (iCM) from 3 subjects with the highest sensitivity (HS) to sotalol (ie, those with the highest increase in QTc) and 3 others with the lowest sensitivity to sotalol (LS). Results: cardiac repolarization and I Kr were similar between HS-iCM and LS-iCM at baseline. However, HS-iCM displayed a significantly higher prolongation of the repolarization phase along with a decrease in I Kr in response to sotalol and other drugs targeting hERG (E4031, vandetanib, and clarithromycin). CAVIN1 mRNA and protein levels were increased by 2-fold in the HS-iCM. Overexpressing CAVIN1 in the LS-iCM using adenovirus induced higher sensitivity to sotalol and the other hERG blockers. In contrast, CAVIN1 knockdown using siRNA in the HS-iCM switched their phenotype to a lower sensitivity to hERG blockers. We observed that CAVIN1 overexpression in LS-iCM and HEK cells changed hERG distribution within cells with accumulation at the membrane. We applied Methyl-β-cyclodextrin, a detergent that removes caveolae from membranes, and found that caveolae depletion induced prolonged repolarization associated with a decrease in CAVIN1 and hERG sarcolemmal expression, and their accumulation in the cytoskeleton. In contrast with the LS-iCM, sotalol application in the HS-iCM promoted hERG internalization into the cytoskeleton. Conclusions: We identified CAVIN1 as a novel modulator of cardiac repolarization in response to drug by promoting hERG internalization. This represents a novel mechanism sustaining the inter-individual variability in response to drugs.
Abstract 11228: Social Determinants of Rates of Resuscitation in Out-of-Hospital Sudden Death Victims
Authors: Hannah M Jones, Susan Keen, Jason Zhang, Kaitlin Shartle, Elizabeth Senter, Catherine Sauter, Feng-Chang Lin, Ross J Simpson
Journal: Circulation (2021)

Introduction: Cardiac causes contribute to 53% of sudden deaths. Receiving prompt cardiopulmonary resuscitation (CPR) greatly increases survival from out-of-hospital cardiac arrest. However, social factors may contribute to the likelihood of a witnessed arrest and prompt CPR. Our aim was to compare the social demographics of sudden death victims who did receive CPR versus those who did not receive CPR. Methods: Out-of-hospital deaths of adults aged 18-64 in Wake County, NC, from 2013-2015 were adjudicated based on age, cause, and location of death to identify sudden death victims. Sociodemographic background, clinical characteristics, and CPR initiation were gathered from EMS reports, death certificates, and medical records. Descriptive statistics were compared between victims who did versus did not receive CPR. Chi-square (or Fisher’s exact) tests and t-tests were performed to compare categorical and continuous variables, respectively. We used inverse probability weighting for the association between marital status and CPR initiation when CPR initiation status was missing. Results: Of the 399 sudden death victims, CPR was initiated in 131 (32.8%). Compared to those who did not receive CPR, those who did receive CPR were more likely to be Black (42.5% versus 31.0%, p-value 0.035) and live in a high-income census tract (65,539.6 versus 59,951.0, p-value 0.032). Marital status also differed significantly between the groups, with married individuals receiving higher rates of attempted resuscitation than those who were divorced or widowed (p-value 0.012). There was no difference in sex, residence in a rural census tract, history of incarceration, or prevalence of medical comorbidities among those for whom CPR was initiated compared to those for whom CPR was not initiated. Conclusions: Race, marital status, and income level are associated with attempted resuscitation in victims of sudden death. We found conflicting findings on the role race plays in the rate of attempted resuscitation among victims of sudden death. Because our results suggest a varied relationship between social determinants and attempted resuscitation, we propose bystander CPR training across all sociodemographic groups.
Abstract MP258: The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation
Authors: Nicholas Chavkin, Soichi Sano, Kenneth Walsh
Journal: Circulation Research (2021)

Background: A hallmark of heart failure is cardiac fibrosis, which results from the injury-induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early pro-inflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and Results: The role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction (TAC) surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after TAC surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2-KO mice displayed a pro-inflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, TAC surgery led to the death of all mice by day 6 that was associated with myocardial hyper-inflammation and vascular leakage. Conclusions: Together, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.
Abstract 13099: Correlation of Lipoprotein(a) Levels With Coronary Plaque Morphological Features and Vulnerability: An Optical Coherence Tomography Study
Authors: Chu Xiaopeng, JIN Chongying
Journal: Circulation (2021)

Introduction: High lipoprotein(a) level is a potential independent risk factor for coronary artery disease (CAD). However, the relationship between the Lp(a) value and the morphological characteristics of plaque defined by optical coherence tomography (OCT) has not been completely clarified so far. Meanwhile, no evidence has been raised for a clear cut-off value of Lp(a) for preventing the process of CAD. Hypothesis: Based on the biological properties of Lp(a), We assessed the hypothesis that the Lp(a) levels may relate to the vulnerable features of lipid plaque defined by OCT. Methods: 420 CAD patients who had undergone OCT scan to at least 1 main coronary vessel during 2013-2018 were enrolled. Patients were first stratified into 3 levels according to the values of Lp(a) at admission: Lp(a)&lt;30 mg/dl (Group A), 30-60 mg/dl(Group B), and &gt;60 mg/dl(Group C). After enrolled the cases with Lp(a) &gt;60mg/dl, we chose cases of the other 2 groups matching according to traditional risk factors of CAD to our current analysis. OCT pullbacks of the target vessels were collected and analyzed at every 0.4 mm by 2 independent observers blinded to the clinical data and angiographies with QIVUS software. Results: A total of 90 cases were enrolled into the current study, with 30 cases in each group. Lipid plaque in Group B and Group C had a thinner minimum fibrous cap thickness, wider maximum lipid arc, longer lipid length, and greater lipid index than Group A. The Lp(a) levels significantly correlated with lipid length (r=0.283), the maximum arc of lipid(r=0.293), lipid index(r=0.357), and inversely correlated with minimum fibrous cap thickness (r =-0.403). Multivariate analysis demonstrated that the Lp(a) level was independently associated with TCFA (odds ratio 1.035, 95% confidence interval 1.014-1.057). In addition, the ROC curve analysis results (AUC =0.694, p &lt; 0.001) indicated the Lp(a) is a good diagnostic indicator for detecting TCFA, and the optimal cut-off was 33.65 mg/dl. Conclusions: Our current study indicates that CAD patients with higher Lp(a) level(&gt;30 mg/dl) exhibited a higher prevalence of TCFA and had more other typical vulnerable characteristics defined by OCT. New Lp(a) lowering therapy could aim at a level of &lt; 33.65mg/dl for stabilizing coronary plaque.