tbuckley/cabot-search huggingface dataset:
Abstract 13433: Enhancing Autophagic Flux Maintains Mitochondrial Homeostasis in Cardiac Ischemia/Reperfusion Injury
Authors: Lihao He, Jing Yang, Yuxin Chu, Jin He, Yutao Hua, Yunxi Chen, Scott W Ballinger, Martin E Young, Sumanth Prabhu, Min Xie
Journal: Circulation (2021)

Introduction and Hypothesis: Histone deacetylase (HDAC) inhibition enhances cardiomyocyte autophagic activity, mitochondria biogenesis, and blunts ischemia/reperfusion (I/R) injury when given at the time of reperfusion. Similarly, augmentation of autophagic flux using a specific autophagy-inducing peptide, Tat-Beclin (TB), is cardioprotective by reducing infarct ~50% and improved systolic function. TB increases autophagic flux and reduced reactive oxygen species (ROS) in the infarct border zone, which is abolished in ATG7 KO mice. We will test whether TB cleans damaged mitochondria and induces mitochondrial biogenesis during cardiac I/R injury. Methods: 8-12-week-old, wild-type, C57BL6 mice were randomized into two groups: TB and Tat-Scrambled (TS) control peptide. Each group was subjected to I/R surgery (45min ischemia, 24h reperfusion). Mitochondrial abundance, quality, and dynamics were assayed. In addition, cultured adult mouse ventricular myocytes (AMVMs) from conditional cardiomyocyte ATG7 knockout (ATG7 KO) and control mice, and neonatal rat ventricular myocytes (NRVMs) treated with ATG7 and control siRNA were used to evaluate the role of autophagy. Results: TB increased mitochondria DNA (mtDNA) content in the border zone significantly. In NRVMs subjected to I/R, TB reduced cell death by ~40%, decreased ROS, and increased mtDNA content significantly by ~50%. TB also increased the intact mtDNA significantly. Moreover, TB promoted the expression of PGC1α (a major driver of mitochondrial biogenesis) both in the infarct border zone and NRVMs subjected to I/R by ~40%, and increased levels of mitochondrial dynamics gene transcripts Drp1, Fis1, and MFN1 / 2. Conversely, ATG7 knockdown in NRVMs and cardiomyocyte-specific ATG7 KO in myocardium abolished the beneficial effects of TB on mtDNA content. To test the changes in the myocardium are cardiomyocyte-specific, we verified the effects of TB and the loss of ATG7 in isolated AMVMs. Conclusions: Autophagic flux is an essential process to mitigate myocardial reperfusion injury acting, at least in part, by inducing PGC1α-mediated mitochondrial biogenesis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce I/R injury in myocardial infarction.
STEM-07. PRC2 MAINTAINS A CANCER STEM CELL PHENOTYPE IN GLIOBLASTOMA MULTIFORME VIA CHROMATIN MODIFICATION OF H3K27me3
Authors: Jack Korleski, Sweta Shudir, Christopher Caputo, Bachchu Lal, Yuan Rui, Jordan Green, Hernando Lopez-Bertoni, John Laterra
Journal: Neuro-Oncology (2021)

Abstract Multi-potent stem-like cells (i.e. cancer stem cells, CSCs) are critical determinants of tumor propagation, therapeutic resistance, and recurrence in glioblastoma (GBM). Modifications in chromatin architecture play a fundamental role in the tumor cell phenotype of GBM. The polycomb repressor complex 2 (PRC2) is a key histone modifier that supports multi-potency and oncogenesis via H3K27 trimethylation (H3K27me3). Understanding how these epigenetic modifications cooperatively drive cancer cell stemness should unveil new targets for therapeutic development in GBM. Using a combination of next-generation sequencing, bioinformatics, and molecular approaches we identified EZH2, the catalytic domain of the PRC2 complex, as a critical mediator of reprograming events in GBM cells. We found that EZH2 is highly induced in response to transgenic Oct4/Sox2 with global increases in H3K27me3. Pharmacological inhibition of EZH2 diminishes self-renewal capacity of GBM neurospheres concurrent with a reduction in gene expression levels of markers and drivers of stemness. Furthermore, we identified and validated a set of 6 putative tumor suppressor genes repressed by Oct4 and Sox2 in a PRC2-dependent manner. We identified miR-217 as an EZH2 regulator in GBM cells and miR-217 reconstitution using advanced nanoparticle formulations re-activates the PRC2-repressed tumor suppressors, inhibited tumor growth and enhanced the effects of ionizing radiation in an orthotopic model of GBM. Taken together, these data show that PRC2-mediated chromatin changes in H3K27me3 help regulate the stem-cell phenotype induced by Oct4 and Sox2 in GBM cells and predict that targeting EZH2 could have therapeutic benefit in GBM.
Abstract 11614: Investigating Outcomes in Patients with Pulmonary Hypertension Diagnosed with Covid-19 in a Tertiary Pulmonary Hypertension Referral Center
Authors: Jennifer DeSalvo, Veronica Franco, Raymond L Benza, Curt Daniels, Debra Kittel, Amy Alexander, Elie Homsy, Lauren Lastinger, Saurabh Rajpal
Journal: Circulation (2021)

Introduction: Preexisting endothelial dysfunction and effects of selective pulmonary vasodilator therapy are postulated to prevent vascular remodeling and decrease morbidity and mortality in pulmonary arterial hypertension (PAH) patients with COVID-19. However, research on outcomes in PAH patients with COVID-19 is limited. We studied morbidity and mortality from COVID-19 in a tertiary PAH referral center. Methods: Of 596 clinic patients on at least one PAH specific medication, 27 patients were diagnosed with COVID-19 between March 2020 and January 2021. Retrospectively evaluated outcomes included mortality, hospitalization, intensive care unit admission (ICU), mechanical ventilation (MV), extracorporeal membrane oxygenation (ECMO), lung transplant, and hospital readmission within 30 days. Results: Of 27 PAH patients with COVID-19 (mean age=60 years; 74% female; 96% non-Hispanic; 74% White), 15 (56%) were hospitalized, 7 (26%) died, and 1 (4%) underwent ECMO followed by lung transplant. Hospitalized patients, compared to non-hospitalized patients, had higher mean age (64 vs 56 years), number of patients on IV prostacyclin (20% vs 0%), mean REVEAL 2.0 score (8.4 vs 6.5), and moderate-severe RV dysfunction (6, 40% vs 3, 25%). There was no difference in NYHA FC and mean pulmonary arterial pressure (45 mm Hg vs 43.7 mm Hg) between hospitalized and non-hospitalized patients. Complications during hospitalization included worsened hypoxemia (13, 87%), cardiac ischemia (4, 15%), new or worsening arrhythmias (3, 11%), and acute kidney injury (AKI) (6, 22%). Four patients (27%) required ICU admission and MV. Of these, 2 (50%) had new or worsening arrhythmias and all 4 (100%) had AKI. Of 15 patients hospitalized, 5 (19%) were readmitted to the hospital within 30 days. The 7 patients who died during hospitalization, compared to 8 who survived, had increased rates of ICU admission and MV (43% vs 12.5%) and higher REVEAL 2.0 scores (10.1 vs 6.9). Conclusion: COVID-19 in hospitalized PAH patients was associated with high rates of multi-organ complications, mortality, ICU admission, and hospital re-admission. Advanced age, IV prostacyclin therapy, higher REVEAL score, moderate to severe RV dysfunction, and AKI were associated with adverse outcomes.
Abstract 11086: MG53 Suppresses NfκB Activation to Mitigate Age-Related Heart Failure
Authors: xiaoliang wang, XIUCHUN LI, Hannah Ong, Tao Tan, Ki Ho H Park, Zehua Bian, Xunchang Zou, Erin Haggard, Paul M Janssen, Robert E Merritt, Timothy M Pawlik, Bryan Whitson, Nahush Mokadam, Lei Cao, Hua Zhu, Jianjie Ma, Chuanxi Cai
Journal: Circulation (2021)

Introduction: Aging is associated with chronic oxidative stress and inflammation that affect the tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. However, it is not clear how MG53 regulates cardiac inflammation during aging. Hypothesis: We hypothesize that the expression of MG53 is associated with age-related heart failure, and treatment with recombinant human MG53 (rhMG53) protein in aged mice might have beneficial effect on the age-related decline of heart function. Methods: qPCR and Western blots were conducted for targeted genes/proteins in non-failing and failing human left ventricular tissues, and mouse heart tissues. A total of sixty mice (24 months, 30 male and 30 female) were enrolled for treatment with rhMG53 (6 mg/kg, subcutaneous, daily for 6 weeks) or saline as control, and subjected to cardiac functional measurement with echocardiography and pressure-volume loop, and cardiac apoptotic and ROS assays. Blood were collected to quantify the serum levels of biomarkers for liver and cardiovascular injury. Results: We demonstrate that the expression of MG53 is reduced in failing human heart and aging mouse heart, concomitant with elevated NFκB activation. We evaluate the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements reveal beneficial effects of rhMG53 treatment in improving heart function of aging mice. Biochemical and histological studies demonstrate the cardioprotective effects of rhMG53 are linked to suppression of NFκB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administration of rhMG53 in aged mice does not have adverse effects on immune response and major vital organ functions. Conclusions: In this study, we showed decreased expression of MG53 and increased NFκB activation in both failing human hearts and aging mouse hearts. Moreover, longitudinal administration of rhMG53 mitigated the heart dysfunction in the aged mice. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.
Management of Metastatic Castration-Resistant Prostate Cancer
Authors: Sandy Srinivas
Journal: Journal of the National Comprehensive Cancer Network (2021)

Notable developments in the management of metastatic castration-resistant prostate cancer (mCRPC) include newer, more sophisticated imaging methods based on prostate-specific membrane antigen (PSMA) PET and development of radionuclide ligands for use with this modality. In the therapeutic area, PSMA PET–guided therapeutics are under study, and PARP inhibitors are being used to treat patients with gene alterations directly or indirectly involved with the homologous recombination repair pathway. Cabazitaxel has emerged as an effective third-line option for patients treated with prior novel hormonal agents and/or prior docetaxel. As investigators learn more about sequencing therapies for mCRPC, previous exposure is an important consideration for choice of treatment at disease progression.
Sex differences in functional limitations and the role of socioeconomic factors: a multi-cohort analysis
Authors: Mikaela Bloomberg, Aline Dugravot, Benjamin Landré, Annie Britton, Andrew Steptoe, Archana Singh-Manoux, Séverine Sabia
Journal: The Lancet Healthy Longevity (2021)

Women are more likely to have functional limitations than are men, partly because of greater socioeconomic disadvantage. However, how sex differences vary by severity of functional limitations remains unclear. We examined sex differences in functional limitations, with attention to socioeconomic factors and severity of limitations.Longitudinal data on limitations in basic activities of daily living (ADL) and instrumental activities of daily living (IADL) and mobility activities were drawn from 62 375 participants from 14 countries. For ADL, IADL, and mobility, participants were categorised based on number of limited activities (0, 1, 2, or ≥3). Sex differences in limitations in four birth cohorts (1895-1929, 1930-38, 1939-45, and 1946-60) were analysed before and after adjustment for socioeconomic factors (education and labour force status).The prevalence of IADL and ADL limitations was higher in women than in men. After adjustment for socioeconomic factors, this sex difference was attenuated. The sex difference in IADL limitations at age 75 years (in the 1895-1929 cohort) was 3·7% before adjustment for socioeconomic factors (95% CI 2·6-4·7) and 1·7% (1·1-2·2) after adjustment. For ADL, the sex difference in limitations at age 75 years (in the 1895-1929 cohort) was 3·2% (2·3-4·1) before adjustment for socioeconomic factors and 1·4% (0·9-1·8) after adjustment. Sex differences in mobility limitations (16·1%, 95% CI 14·4-17·7) remained after adjustment for socioeconomic factors (14·3%, 12·7-15·9). After age 85 years, women were more likely to have three or more IADL or mobility limitations and men were more likely to have one or two limitations.Socioeconomic factors largely explain sex differences in IADL and ADL limitations but not mobility. Sex differences in mobility limitations in midlife are important targets for future research and interventions.National Institute on Aging, UK National Institute for Health Research, European Commission, and US Social Security Administration.
Abstract 10160: Population Eligible for PCSK9i in Spain: A Real-World Analysis
Authors: Juan Cosin Sales, Eduard Sidelnikov, Santiago Villamayor Galli, Miriam Fernandez Delgado, Elena Torres Romero, Alberto Zamora
Journal: Circulation (2021)

Background: Cardiovascular (CV) diseases are the leading cause of mortality globally. Reducing low-density lipoprotein cholesterol (LDL-C) is a proven strategy to decrease risk of acute CV events. The study aimed to estimate a PCSK9i-eligible population in Spain. Methods: We conducted a retrospective cohort study based on real-world data from the IQVIA Spanish Electronic Medical Records primary care database. Adult (≥18 y.o.) patients registered in the database between 2014 and 2020, diagnosed with myocardial infarction (MI), unstable angina (UA), ischemic stroke (IS), transient ischemic attack (TIA) or peripheral artery disease (PAD) and with at least 1 measurement of LDL-C or total cholesterol were included in the study and followed up for up to 12 months from the initial diagnosis. Results: The study included 9,516 patients; mean (SD) age was 67.7 (12.5) years, 63.9% were male and mean LDL-C was 117.3 (38.8) mg/dL. In the study population 28.5% of patients suffered an MI as most severe event during the study period, 10.0% had UA, 18.7% were diagnosed with IS, 13.6% with TIA, and 29.3% with PAD. At the time of last available LDL-C assessment (≥3 months after diagnosis), 64.4% of patients were on lipid lowering therapy (LLT). Of those, 45.4% were on high-intensity LLT (high-intensity statins with/without ezetimibe or PCSK9 inhibitors), 46.9% on moderate-intensity statins, and 7.7% on low-Intensity LLT (low-intensity statins, ezetimibe alone or non-statin LLT). Overall, 12.9% of treated patients achieved LDL-C levels &lt;55 mg/dL; this proportion was the highest among those on high-intensity statins and any statin combined with ezetimibe (63.2%), followed by patients on moderate intensity statins (32.6%) and those on low-intensity LLTs (3.1%). A total of 17.1% of patients receiving optimized LLT had an LDL-C&gt;100 mg/dL (LDL-C reimbursement threshold for PCSK9i in Spain). Conclusions: More than 85% of patients at very-high risk of cardiovascular events in our cohort do not achieve LDL-C &lt;55 mg/dL recommended by 2019 ESC/EAS guidelines for management of dyslipidemia. More than 17% of the patients have LDL-C &gt;100 mg/dL despite being treated with maximally tolerated LLT and, therefore, would be eligible for using PCSK9i within Spanish reimbursement criteria.
Abstract 12778: A High Physiological Stress Response is Dependent on Call Type in Firefighters
Authors: Paige J Rynne, Stephanie Donahue, Megan A Carty, Rachel L Dickinson, Meghan Lashley, Emily H Reeve, Julia Gilpin, Carly McMorrow, Andrew A Almeida, Will Sherman, Myra Arsenault, Deborah L Feairheller
Journal: Circulation (2021)

Introduction: CVD and impaired cardiovascular health is noticeably more prevalent in firefighters (FF) than the general population, with over 50% of line-of-duty deaths being cardiovascular related. Many FF have hypertension but less than 25% have their BP under control. The BP and HR response to different calls and job activity in FF is unknown. Thus, we aimed to evaluate and quantify the physiological stress resulting from different types of calls and job activity (fire, medical, riding apparatus) through ambulatory blood pressure (ABP) monitoring. Hypothesis: We hypothesize that fire calls will result in the largest BP surge in FF compared to other types of calls and work conditions. Methods: FF (n=41; 37M, 4F) wore an ABP monitor for at least 12-hours while working. BP was measured every 30 min during daytime and 60 min during nighttime, if worn overnight. Data was analyzed when &gt; 70% of readings were captured. FF were instructed to force an ABP reading when the pager sounded and whenever they felt they entered a stressful situation. Activity and call type were documented on a log sheet for each measurement. Results: The FF were experienced (16.9 ± 11.9 yrs as FF), overweight (BMI: 30.3 + 4.6 kg/m 2 ), middle aged (41.2 ± 13.1 yrs), and hypertensive with average ABP over the 12 hr shift at 131 ± 13.4 / 79.3 ± 8.8 mmHg and HR 75.7 ± 8.8 bpm. Systolic BP surged 19.2 ± 12.2 with fire calls and 18.7 ± 8.1 mmHg with medical calls. Diastolic BP surged 10.5 ± 9.9 with fire and 16.5 ± 10.5 mmHg with medical calls. There were no differences in BP, HR, or BP surge levels ( P &gt;0.05 for all) between the types of measurements (fire, medical, apparatus, alarms). Compared to average ABP values, the response was higher with fire calls (143.9/85.5 mmHg, 85.5 bpm) than medical calls (139.0/87.0 mmHg, 90.5 bpm). Physiological responses were also high when FF rode apparatus (139.8/83.7 mmHg, 81.9 bpm) and received false alarms (137.6/82.6 mmHg, 83.4 bpm). Conclusion: Fire and medical calls resulted in the greatest CV response. On average, fire calls resulted in a 9% increase in systolic BP and medical calls a 9% increase in diastolic BP and a 16% increase in HR. Further investigation in a larger population is warranted to substantiate these results as well as study other variables that may affect BP and HR responses in FF.
Abstract 10634: Out with the Old: Transvenous Extraction of Leads Older Than 15 Years
Authors: Francis Phan, Saket Sanghai, Uday G Sandhu, Christopher Verdick, Andrew Gray, Angela Krebsbach, Peter Jessel, Charles Henrikson
Journal: Circulation (2021)

Background: Lead dwell time is the single strongest predictor of failure and complications in transvenous lead extraction. Objectives: To report the success rate and complications of transvenous lead extractions with implant dwell time of at least 15 years. Methods: Procedural and patient data were prospectively collected into a database. The excimer laser was the primary method for lead extraction with use of mechanical rotational sheaths and femoral snares at operator discretion. Results: A total of 443 patients between 2011-2020 underwent lead extraction (707 leads) primarily for infection or device failure at our high-volume center. 40 patients with 69 leads &gt;15 years old were included in this cohort (Table 1). Mean patient age was 53.5 +/- 18.5 years, 67.5% were male. Mean lead dwell time was 19.3 +/- 4.2 years. 35 of 40 (87.5%) patients had successful extraction of all leads (62 of 69 leads - 89.9%). The 5 patients without fully successful extractions resulted in 7 abandoned leads or lead fragments (mean lead age 19.6 +/- 2.3 years). 2 of these patients had abandoned leads (3 total) that were clinically significant. One patient experienced right atrial appendage perforation requiring surgical repair and recovered well. One patient experienced new complete heart block requiring 2 minutes of CPR but did well thereafter. There was no procedure-related mortality. Conclusions: Despite challenges posed by older leads, very old leads can be safely and effectively extracted with low complication rates.
Abstract 13986: De Novo Occurrence Of Fragmented QRS Waves In V5 And 6 Leads After Successful Nuss Surgery For Pectus Excavatum Considering QRS Wave Axis And Width And Heart Compression On Computed Tomography
Authors: Nobusada Funabashi, Kohki Nakamura, takehio sasaki, Shigeto Naito, Yoshio Kobayashi
Journal: Circulation (2021)

Introduction: On ECG, fragmented QRS waves (fQRS), otherwise known as a notch in the QRS complex, may indicate conduction abnormalities. Pectus excavatum (PEX) physically depresses the heart (mainly the right and left aria (RA, LA)). The Nuss operation is a minimal invasive technique for PEX repair. Hypothesis: We hypothesize that fQRS may occur in PEX even in patients without right bundle branch block (RBBB), and that the Nuss operation would reduce these, depending on the Haller index (HI) of anatomical severity as calculated from CT imaging (CLINICS 2007; 62:599). Methods: 17 patients (14 male, 12±6 years) underwent the Nuss operation for PEX, all of which were successful. HI was significantly improved from 5.62±2.29 to 3.29±0.65 (P=0.0002). Before the Nuss operation, 6 patients had incomplete RBBB; of the 11 without RBBB, 6 (55%) had fQRS waves. We evaluated the degree of RA and LA compression in these PEX patients by CT. Results: We compared 6 patients with fQRS waves but no RBBB before surgery with 5 patients without fQRS waves but no RBBB before surgery, and only LA diameter on CT before surgery was significantly greater in the former than the latter (P=0.004) (Table). Of 6 patients with fQRS waves but no RBBB before surgery, 3 patients (50%) had de novo fQRS waves in V5 and 6 after surgery. There were no significant differences of QRS axis and width before and after surgery in these3 patients who had de novo fQRS waves in V5 and 6 after surgery. Of 5 patients without any fQRS waves but no RBBB before surgery, 4 patients (80%) had de novo fQRS waves in V5 and 6 after surgery. There were no significant differences of QRS axis and width before and after surgery in these 4 patients who had de novo fQRS waves in V5 and 6 after surgery. Conclusions: In patients with PEX, de novo fQRS waves can occur after a successful Nuss operation, especially in the V5 and V6 leads, even in patients without RBBB and without changes of QRS axis and width. This may be caused by heart rotation or some effects of the Nuss procedure.
The postnatal window is critical for the development of sex-specific metabolic and gut microbiota outcomes in offspring
Authors: Laurence Daoust, Béatrice S.-Y. Choi, Sébastien Lacroix, Vanessa Rodrigues Vilela, Thibault Vincent Varin, Stéphanie Dudonné, Geneviève Pilon, Denis Roy, Emile Levy, Yves Desjardins, Benoit Chassaing, André Marette
Journal: Gut Microbes (2021)

The Developmental Origins of Health and Disease (DOHaD) concept has been proposed to explain the influence of environmental conditions during critical developmental stages on the risk of diseases in adulthood. The aim of this study was to compare the impact of the prenatal vs. postnatal environment on the gut microbiota in dams during the preconception, gestation and lactation periods and their consequences on metabolic outcomes in offspring. Here we used the cross-fostering technique, e.g. the exchange of pups following birth to a foster dam, to decipher the metabolic effects of the intrauterine versus postnatal environmental exposures to a polyphenol-rich cranberry extract (CE). CE administration to high-fat high-sucrose (HFHS)-fed dams improved glucose homeostasis and reduced liver steatosis in association with a shift in the maternal gut microbiota composition. Unexpectedly, we observed that the postnatal environment contributed to metabolic outcomes in female offspring, as revealed by adverse effects on adiposity and glucose metabolism, while no effect was observed in male offspring. In addition to the strong sexual dimorphism, we found a significant influence of the nursing mother on the community structure of the gut microbiota based on α-diversity and β-diversity indices in offspring. Gut microbiota transplantation (GMT) experiments partly reproduced the observed phenotype in female offspring. Our data support the concept that the postnatal environment represents a critical window to influence future sex-dependent metabolic outcomes in offspring that are causally but partly linked with gut microbiome alterations.