tbuckley/cabot-search huggingface dataset:
Abstract 12033: Heart Rate and Estimated Glomerular Filtration Rate Decline in Kidney Transplant Recipients
Authors: Ekamol Tantisattamo, Pornthira Mutirangura, Natchaya Polpichai, Sakditad Saowapa, Natsuki Eguchi
Journal: Circulation (2021)

Introduction: Heart rate (HR) is one of the biomarkers reflecting sympathetic nervous system. It has been showed to be associated with decline in kidney function in general population. We aim to examine association between HR and change in estimated glomerular filtration rate (eGFR) in kidney transplant recipients (KTR). Hypothesis: We hypothesize that the higher HR is associated with more rapid decline in eGFR in KTR. Methods: A single center retrospective cohort study was conducted to examine association between mean HR among 4 office visits at 12-, 24-, 36-, and 48-weeks post-transplant and rate of eGFR change between 12- and 48-weeks post-transplantation by using multiple linear regression. In addition, association of the mean HR with rapid eGFR change defined as eGFR decline beyond a median eGFR change between 12- and 48-weeks post-transplantation of the unadjusted study population was tested by using multiple logistic regression. Results: Of all 105 KTR, mean age±SD was 54.33±11.60 years old and 61% was female. Median HR was 76/minute (IQR 69.5, 82.75). Mean eGFR were 57.23±1.74 and 60.58±1.89 ml/min/1.73 m 2 at 12 and 48 weeks, respectively with an increase in mean eGFR of -3.35±1.43 ml/min/1.73 m 2 (p 0.0211). Median rate of eGFR change was 4.31 ml/min/1.73 m 2 /year (IQR -5.75, 15.39). Every 1 beat/minute increase in HR was associated with a decline in eGFR of 0.3 ml/min/1.73 m 2 /year (β -0.297, p 0.093, 95%CI -0.644936, 0.0507214) and 1.01 time higher the odds of rapid change in eGFR (OR 1.007, p 0.662, 95%CI 0.9726614, 1.044582). After adjusted for age, gender, type of transplant, and induction immunosuppression, increase in 1 beat/minutes of HR was significantly associated with 0.39 ml/min/1.73 m 2 /year decline in eGFR (β -0.385, p 0.036, 95%CI -0.7456678, -0.0254736). Conclusions: Increased HR is associated with more rapid decline in eGFR in KTRs. Further studies are required elucidate underlying mechanisms by taken into account of immunological and non-immunological factors.
Abstract 13245: Cardiovascular Risk Burden in Relation to Dementia and Brain Structural Imaging Markers: A Study From UK Biobank
Authors: Yaying Cao, Chengwu Feng, Jing Chen, Wei Gan, Yuan Ma, Yonghua Hu, Klodian Dhana, Jie Shen, yan zheng, Changzheng Yuan, Geng Zong
Journal: Circulation (2021)

Introduction: Cardiovascular risk burden is associated with higher all-cause dementia risk. However, the roles of cardiovascular disease (CVD) and genetic background, and the associations of cardiovascular risk burden with dementia subtypes and brain structure, need to be examined. Hypothesis: We hypothesized that the Framingham General Cardiovascular Risk Score (FGCRS) would be associated with all-cause and subtypes of dementia and brain structure. Methods: We conducted a prospective study among 354,654 participants free of CVD and dementia at baseline (2006-2010, mean age 56.4 years) within UK Biobank. CVD risk burden was evaluated by baseline FGCRS. Dementia case was identified from hospital inpatient records and death register data. Brain MRI volume markers were available for 15,104 participants since 2014. Logistic and linear regression models were used for dementia risk and brain volumes, respectively. Results: During a median 12.0 years of follow-up, 3,996 all-cause dementia cases were identified. Higher FGCRS was associated with an increased all-cause dementia risk after adjusting for demographic, major lifestyle, clinical factors, and polygenic risk score (PRS) of Alzheimer’s disease (AD). Comparing the high vs. low tertile of FGCRS, the odds ratios (ORs) and 95% CIs were 1.26 (1.12, 1.42) for all-cause dementia, 1.67 (1.33, 2.09) for AD, and 1.53 (1.08, 2.17) for vascular dementia (all P trend &lt; 0.05). Incident stroke and coronary heart disease accounted for 13% (95% CI: 9%, 19%) of the association of FGCRS with all-cause dementia. Interaction was not detected for FGCRS and PRS on risk of all-cause or any subtype of dementia (all P for interaction &gt; 0.05). We observed an 83% (95% CI: 47%, 128%) higher all-cause dementia risk comparing the high-high vs. low-low for FGCRS-PRS category. For standardized brain volumes, higher FGCRS was associated with greater log-transformed white matter hyperintensities, smaller cortical volume, and smaller grey matter volume. Conclusions: Cardiovascular risk burden was associated with higher dementia risk and neurodegeneration-related brain volume markers. The association of cardiovascular risk burden with all-cause dementia was partly explained by CVD onset and independent of dementia genetic risk.
Unconvincing Evidence of SARS-CoV-2–Associated Myositis in Autopsied Muscles
Authors: Marinos C. Dalakas
Journal: JAMA Neurology (2021)

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NCOG-17. FACTORS INFLUENCING POOR INDEPENDENCE LEVEL FOLLOWING RESECTION OF THE RIGHT TEMPORO-PARIETAL GLIOBLASTOMAS
Authors: Mitsutoshi Nakada, Riho Nakajima, Hirokazu Okita, Masashi Kinoshita
Journal: Neuro-Oncology (2021)

Abstract In glioma surgeries, cognitive outcomes for the dominant hemisphere have gained much attention compared to the non-dominant hemisphere. For non-dominant hemispheric glioblastomas, we previously observed decreased independence level following glioblastoma resection of the posterior temporal to the parietal lobes. Here, we investigated the reason for the poor Karnofsky Performance Status (KPS) in such glioblastomas. A total of 41 patients with resection of the right cerebral hemispheric primary glioblastoma were enrolled for the study. Several kinds of neuropsychological functions and KPS of the brain regions were evaluated at pre- and postoperative 3 months by performing the Spearman’s correlation analysis and voxel-based lesion symptom mapping (VLSM). Additionally, the correlation between the resected volume of each gyrus or white matter tract and neuropsychological function score was analyzed. KPS at chronic phase (73.6) declined significantly compared with preoperation (81.0, p = 0.020). Functional factors influencing the KPS were general cognitive function, visuospatial cognition, emotion recognition, executive function, and apathy. The VLSM analysis revealed that the resection of the ventral parietal lobe and supramarginal gyrus (VPL-SMG) resulted in significantly poor KPS. Among the functional factors affecting KPS, VPL-SMG resection contributed to significantly lower scores in visuospatial cognition, emotion recognition, and apathy than those without resection (p = 0.0045, 0.047, and 0.0002, respectively). Further, we investigated whether the damage of the VPL-SMG could result in KPS related functional deficit. We found visuospatial cognition related to the posterior occipital lobe, SMG, arcuate fasciculus (AF), and dorsal superior longitudinal fasciculus, emotion recognition to the middle to inferior occipital gyrus and AF, and apathy to the inferior parietal lobe and middle temporal gyrus. We concluded that deficits of visuospatial cognition, emotion recognition, and apathy due to the damage of the cortical and white matter areas, including the VPL-SMG, were responsible for KPS of the non-dominant hemispheric glioblastomas.
Correspondence to proton pump inhibitors and risk of colorectal cancer
Authors: Chen Dong, Yun-Hsun Lee, Tzu-Yang Tan, Chung-Chin Yao, James Cheng-Chung Wei
Journal: Gut (2021)

We have read with interest the paper by Abrahami et al on the risk of colorectal cancer (CRC) with long-term proton pump inhibitor (PPI) usage with a new user and active comparator design (PPI users n=1 293 749 and histamine-2 receptor antagonist (H2RA) users n=292 387, from 1 January 1990 to 30 April 2018 with 1-year follow-up).1 The authors found that overall use of PPI did not increase the risk of CRC (HR 1.02, 95% CI 0.92 to 1.14). However, the HR increased by 2–4 years (HR 1.45, 95% CI 1.28 to 1.60) and more than 4 years (HR 1.60, 95% CI 1.42 to 1.80) with cumulative duration of PPI usage. Similar patterns were …
Abstract P499: Histone H4K20 Trimethylation Is Differentially Regulated In Heart Disease
Authors: Samuel Hickenlooper, Kathryn Davis, Steven Valdez, Ryan Bia, Marta Szulik, Sarah Franklin
Journal: Circulation Research (2021)

It has been well established that many cardiac pathologies result from dynamic changes in gene expression and conversely that modulating key epigenetic factors in murine models is capable of preventing or abrogating ischemic injury and pathological remodeling. One epigenetic mechanism is the post-translational modification of histones, which are reversibly methylated on lysine (K) residues and can accept up to three methyl groups (Me1, Me2 and Me3). In the heart, significant changes in global levels of histone H3K4Me3 and H3K9Me3 have been previously reported to be upregulated and downregulated, respectively, during hypertrophy and failure in mice. However, the majority of post-translational modifications on histones have never been examined to quantify global abundance in the heart during disease. In particular, histone H4K20Me3 is important in heterochromatin formation and gene repression in non-cardiac cells but has never been evaluated in the heart. Therefore, we utilized cardiac tissue from three animal models of cardiac stress and employed western blotting and mass spectrometry to quantify the global abundance of total histone H4 and H4K20 methylation. We specifically evaluated tissue from mice subjected to LAD ligation, transverse aortic banding and isoproterenol infusion (via mini-osmotic pump). In addition, we also utilized primary neonatal cardiomyocytes treated with the hypertrophic agonist phenylephrine to quantify H4K20 methylation. Our data show that global levels of histone H4K20Me3 are differentially regulated in some models of cardiac dysfunction, but not all (i.e. isoproterenol infusion). In addition, we measured the abundance of histone methyltransferases and demethylases (via western blotting and qPCR) which are responsible for adding or removing this methyl mark in mouse cardiac tissue, and compared this to published data from human heart failure patients. These analyses allowed us to identify two enzymes, the methyltransferase Smyd5 and demethylase KDM7B, which are also differentially expressed in cardiac tissue during disease. Together these results are the first analysis of histone H4K20 methylation in the heart and suggest a novel role for this methylation site in the pathophysiology of cardiovascular disease.
Abstract 12998: S-Cysteinylation of Plasma and Serum Albumin is Associated With Risk Factors of Atherosclerotic Cardiovascular Disease
Authors: Zachary Wilson, Abdulbaril Olagunju, Ghazwan Elias, Daniel Krause, Linda Pham, Paul Kang, Joshua Jeffs, Nilojan Jehanathan, Erandi Kapuruge, Chad Borges, Christian S Breburda
Journal: Circulation (2021)

Introduction: Albumin oxidation or S-cysteinylation (S-Cys) of its free cysteine residue has been shown to be a measure of oxidative stress. While it is subject to artificial ex-vivo elevations, freshly processed samples could serve as a theoretical biomarker of any number of inflammatory states. Hypothesis: S-Cys Albumin is associated with atherosclerotic cardiovascular disease (ASCVD) and its risk factors that increase oxidative stress. Methods: We enrolled 137 patients evaluated for chest pain in a single-center cross-sectional study from May 2016 through March 2020. Plasma and serum samples were gathered and immediately processed for analysis of intact albumin by high pressure liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS). Statistical analysis included a spearman’s coefficient, and two-tailed linear regression of the relative fractional abundance (RFA) of S-Cys albumin and clinical variables. Results: S-Cys-albumin levels were significantly decreased in those with a previous history of coronary stenting (Plasma β=-0.032, p=0.005; Serum β=-0.032, p=0.012; n=24) and MDD (Plasma β=-0.016, p=0.132; Serum β=-0.026, p=0.021, n=34). S-Cys-albumin levels were significantly elevated in those with a previous history of peripheral artery disease (Plasma β=0.051, p=0.015; Serum β=0.055, p= 0.016; n=6) and chronic infections (Plasma β=0.023, p=0.033; Serum β=0.021, p =0.069; n=30). CAD by history was not significantly different (Plasma β=0.012, p=0.19; Serum β=0.01, p =0.3; n=57). Spearman’s coefficient demonstrated a positive correlation between age (plasma rho = 0.1877, p = 0.0576; serum rho 0.2641, p = 0.007; n=103), BMI (plasma rho = 0.2089, p = 0.0342; serum rho = 0.1287, p = 0.195; n=103), Framingham risk score (plasma rho = 0.2607, p = 0.0523; serum rho = 0.3595, p = 0.0065; n=56), ASCVD risk score (plasma rho = 0.3526, p = 0.0083; serum rho = 0.472, p = 0.0003; n=55), heart rate (plasma rho = 0.2225, p = 0.0239, serum rho = 0.1678, p = 0.0902; n=103) and NT-pro-BNP (plasma rho = 0.3398, p = 0.0319; serum rho 0.3937, p = 0.012; n=40). Conclusion: S-Cysteinylated Albumin is associated with several measure of ASCVD and its risk factors. It may be a marker of the underlying oxidative stress.
Abstract 12273: Correlation Between Aortic Strain and Native T1 Value in Hypertrophic Cardiomyopathy
Authors: Shoko Hachiya, Hisanori Kosuge, Yasuhiro Fujita, Satoshi Hida, Hirofumi Tomiyama, Taishiro Chikamori
Journal: Circulation (2021)

Introduction: Aortic stiffness is related to impairment of left ventricular (LV) function and LV remodeling. Myocardial ischemia and fibrosis in hypertrophic cardiomyopathy (HCM) cause ventricular arrhythmia and sudden cardiac death. Magnetic resonance imaging (MRI) can evaluate aortic stiffness and LV function noninvasively. Aortic strain shows the possibility for the assessment of the aortic status and T1 mapping allows the assessment of diffuse myocardial fibrosis. Hypothesis: We assessed the hypothesis that aortic strain is correlated with native T1 values in HCM patients. Methods: Thirty-six HCM patients (mean age : 64±2 years) and forty control subjects (mean age : 58±3 years) with no history of coronary artery disease were examined using a 3T MRI. Cross-sectional aortic areas of the descending aorta were measured and aortic strain was calculated as follows: aortic strain (%) = (maximum aorta area - minimum aorta area)/minimum aorta area х 100. Native T1 values were measured as an averaged T1 values in the septum of 3 short-axis slices of base-to-apex left ventricle myocardium. LV ejection fraction (LVEF), left atrium (LA) dimension and E/e’ were measured by echocardiography. Results: LVEF showed no significant differences between HCM patients and control subjects (66.2±1.1% vs. 64.5±1.0%, p=0.2488). LA dimension and E/e’ in HCM patients were significantly higher than control subjects (LA dimension: 38.3±1.1mm vs 34.9±0.85mm, p=0.0155, E/e’: 13.4±0.95 vs 9.2±0.42, p&lt;0.0001). Native T1 values and aortic strain of the descending aorta in HCM patients were significantly lower than those in control subjects (native T1 values: 1254±8ms vs 1208±8ms, p&lt;0.0001, aortic strain: 7.95±0.66% vs 12.92±1.27%, p=0.0012). Multiple linear regression analysis revealed that aortic strain was correlated with age (β=-0.370, p=0.0014) and native T1 values (β=-0.244, p=0.0448). Conclusions: In HCM patients, aortic strain of the descending aorta was significantly decreased compared to control subjects and correlated with native T1 values. Aortic strain may be a promising factor for myocardial fibrosis in HCM patients.
Abstract 15266: Effect of Nicotine Exposure to Induced Pluripotent Stem Cell Derived Endothelial Cell Therapy in a Murine Model of Peripheral Artery Disease
Authors: Alex Ho Pang H Chan, Caroline Hu, Ngan F Huang
Journal: Circulation (2022)

Introduction: Clinical solutions for peripheral artery disease (PAD) remain elusive due to the many challenges of surgical intervention. Stem cell therapy offer a promising option, but barriers exist to their clinical translatability. Among these include lifestyle choices like tobacco use that may influence the efficacy of stem cell therapy. The objective of this study aims to examine the potential effects of nicotine on human induced pluripotent stem cell derived endothelial cells (iPSC-ECs) therapy in the context of PAD. Hypothesis: Chronic nicotine exposure negatively affects the therapeutic potential of implanted iPSC-ECs in a murine model of PAD. Methods: Mice were implanted with an osmotic pump for controlled exposed to nicotine or saline (control) for 28 days. Plasma cotinine was measured to confirm nicotine exposure. After 28 days of nicotine or saline exposure, the mice underwent induction of hindlimb ischemia and before receiving an injection of 10 6 iPSC-ECs. A second dose of cells were injected to the ischemic limb on day 7 post-surgery. All mice were monitored for blood perfusion recovery using laser Doppler spectroscopy imaging. Survival of the transplanted cells in vivo were tracked by bioluminescence imaging. The mice receiving iPSC-ECs were also imaged for cell survival using bioluminescence imaging. At day 14 post-surgery, mice were euthanized, and the gastrocnemius muscle and thigh muscle were harvested for histological analysis. Results: The average cotinine concentration in sera was ~200 ng/mL, which is within physiological range for a tobacco user. Blood perfusion recovery at day 14 showed trends of nicotine treated groups have hindered perfusion recovery, compared to those treated with saline. Importantly, nicotine exposure trended with poorer perfusion recovery after cell therapy. Bioluminescent imaging showed iPSC-ECs persisted in vivo for all groups without significant difference. Conclusions: Nicotine exposure was associated with poorer blood perfusion recovery after iPSC-EC therapy, compared to control saline exposure, suggesting that nicotine may have adverse effects on iPSC-EC therapy for treatment of PAD.
Abstract 10754: Disrupted N-Cadherin Expression Leads to Sarcomeric Disassembly and Cell Cycle Activation in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Soah Lee, Daniel Lee, Julia Ryan, Sharon Paige, Francisco X Galdos, William R Goodyer, Sean M Wu
Journal: Circulation (2021)

Introduction: Induction of cardiomyocyte proliferation holds great promise for cardiac regenerative therapy. We showed previously that in the presence of Wnt signaling agonist, the removal of cell-cell contact between cardiomyocytes is the key to drive massive expansion of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). However, the molecular mechanism regulating cell contact-mediated suppression of hiPSC-CM proliferation remains unknown. Hypothesis: We hypothesized that N-cadherin, the major adherens junction molecule expressed in cardiomyocytes, mediates contact inhibition of hiPSC-CM proliferation. Methods/Results: By qPCR and Western blotting, we showed comparable transcript and protein expression level of N-cadherin when hiPSC-CMs were cultured either densely (with cell contact) or sparsely (without cell contact), despite the observed N-cadherin localization at intercellular junction in densely cultured cells only. We disrupted N-cadherin expression with transient transfection of siRNA and found that the loss of N-cadherin expression resulted in 1.75-fold increase in Ki67 expression in densely but not sparsely cultured day 30 hiPSC-CM, suggesting that junction-localized N-cadherin may affect hiPSC-CM proliferation. Furthermore, we found that the loss of N-cadherin expression led to wide-spread sarcomeric disassembly. To examine whether sarcomeric disassembly alone is sufficient to stimulate cell cycle activity in densely cultured hiPSC-CMs, we knocked down α-actinin expression which led to sarcomere disruption and an increase in Ki67+ expression by 1.6-fold in day 30 hiPSC-CMs. Conclusions: Taken together, our results suggest that N-cadherin mediates the previously observed cell-cell contact inhibition of hiPSC-CM proliferation and the disruption of N-cadherin expression in densely cultured hiPSC-CMs leads to sarcomeric disassembly and hiPSC-CM proliferation. Furthermore, we showed that sarcomeric disassembly alone stimulates hiPSC-CM proliferation. These findings support the need for inducing cardiomyocyte dedifferentiation to achieve in situ cardiomyocyte proliferation for developing novel regenerative therapy to treat congenital and adult heart diseases in the future.
Abstract 13524: 3-mercaptopyruvate Sulfurtransferase Deficiency Attenuates Branched-Chain Amino Acids Catabolism to Exacerbate Pressure Overload Heart Failure
Authors: Zhen Li, Huijing Xia, Thomas E Sharp, Kyle Lapenna, Kevin Casin, Ken Liu, John W Calvert, Noriyuki Nagahara, Traci T Goodchild, David J Lefer
Journal: Circulation (2021)

Introduction: Hydrogen sulfide (H 2 S) exerts mitochondria-specific actions that include the preservation of mitochondrial respiration, biogenesis, and ATP synthesis, while inhibiting apoptosis. 3-mercaptopyruvate sulfurtransferase (3-MST) is a mitochondrial H 2 S producing enzyme whose functions in cardiovascular physiology and pathology are yet to be fully elucidated. In the present study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload-induced heart failure. Methods: 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction (TAC) to induce pressure-overload HFrEF. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial function and ATP synthesis efficiency were assessed. Additionally, unbiased metabolomic approaches were utilized to identify key pathways altered by 3-MST deficiency. Results: 3-MST KO mice exhibited increased accumulation of branched-chain amino acids (BCAAs) in the myocardium, resulting in reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise intolerance in HFrEF. Promoting BCAAs catabolism through 3,6-dichlorobenzo1[b]thiophene-2-carboxylaic acid (BT2) treatment mitigated the detrimental effects of 3-MST deficiency and ameliorates the severity of HFrEF. Conclusions: Our data demonstrate that deficiency of 3-MST significantly inhibits BCAAs catabolism and impairs mitochondrial respiration and ATP synthesis efficiency, resulting in worsened HFrEF. These data suggest that 3-MST is critical in the protective response to cardiovascular diseases such as heart failure. Future studies are underway to define the mechanism by which 3-MST regulates BCAAs catabolism.
A Phase II Study of Inotuzumab Ozogamicin for the Treatment of Measurable Residual Disease-Positive B-Cell Acute Lymphoblastic Leukemia
Authors: Nicholas J. Short, Hagop Kantarjian, Yesid Alvarado, Jan A. Burger, Nitin Jain, Marina Konopleva, Farhad Ravandi, Courtney D. DiNardo, Lucia Masarova, Koji Sasaki, Philip A. Thompson, Alessandra Ferrajoli, Jovitta Jacob, Anna Milton, Rebecca Garris, Elias J. Jabbour
Journal: Blood (2021)