tbuckley/cabot-search huggingface dataset:
Alternative Splicing Mediated by RNA-Binding Protein RBM24 Facilitates Cardiac Myofibrillogenesis in a Differentiation Stage-Specific Manner
Authors: Serena Huei-An Lu, Kang-Zheng Lee, Paul Wei-Che Hsu, Liang-Yu Su, Yu-Chen Yeh, Chien-Yuan Pan, Su-Yi Tsai
Journal: Circulation Research (2021)

Background: Mutations in genes encoding sarcomeric proteins lead to failures in sarcomere assembly, the building blocks of contracting muscles, resulting in cardiomyopathies that are a leading cause of morbidity and mortality worldwide. Splicing variants of sarcomeric proteins are crucial at different stages of myofibrillogenesis, accounting for sarcomeric structural integrity. RBM24 (RNA-binding motif protein 24) is known as a tissue-specific splicing regulator that plays an essential role in cardiogenesis. However, it had been unclear if the developmental stage-specific alternative splicing facilitated by RBM24 contributes to sarcomere assembly and cardiogenesis. Our aim is to study the molecular mechanism by which RBM24 regulates cardiogenesis and sarcomere assembly in a temporal-dependent manner. Methods: We ablated RBM24 from human embryonic stem cells (hESCs) using CRISPR/Cas9 techniques. Results: Although RBM24 −/− hESCs still differentiated into sarcomere-hosting cardiomyocytes, they exhibited disrupted sarcomeric structures with punctate Z-lines due to impaired myosin replacement during early myofibrillogenesis. Transcriptomics revealed &gt;4000 genes regulated by RBM24 . Among them, core myofibrillogenesis proteins (eg, ACTN2 [α-actinin 2], TTN [titin], and MYH10 [non-muscle myosin IIB]) were misspliced. Consequently, MYH6 (muscle myosin II) cannot replace nonmuscle myosin MYH10, leading to myofibrillogenesis arrest at the early premyofibril stage and causing disrupted sarcomeres. Intriguingly, we found that the ABD (actin-binding domain; encoded by exon 6) of the Z-line anchor protein ACTN2 is predominantly excluded from early cardiac differentiation, whereas it is consistently included in human adult heart. CRISPR/Cas9-mediated deletion of exon 6 from ACTN2 in hESCs, as well as forced expression of full-length ACTN2 in RBM24 −/− hESCs, further corroborated that inclusion of exon 6 is critical for sarcomere assembly. Overall, we have demonstrated that RBM24-facilitated inclusion of exon 6 in ACTN2 at distinct stages of cardiac differentiation is evolutionarily conserved and crucial to sarcomere assembly and integrity. Conclusions: RBM24 acts as a master regulator to modulate the temporal dynamics of core myofibrillogenesis genes and thereby orchestrates sarcomere organization.
Abstract 9138: Thioredoxin-Interacting Protein is a Regulator of Redox Homeostasis in Diabetic Cardiomyopathy
Authors: Jun Yoshioka
Journal: Circulation (2021)

Introduction: Although the precise pathogenesis of diabetic cardiac damage remains unclear, potential mechanisms include increased oxidative stress. Thioredoxin-interacting protein (Txnip) is a binding partner and an endogenous inhibitor of antioxidative thioredoxin. Txnip is a highly glucose-responsive gene that mediates cellular damage. Hypothesis: This study was designed to provide direct in vivo evidence that the specific molecular interaction between Txnip and thioredoxin controls redox balance in the diabetic heart. Methods and Results: High glucose increased Txnip expression, leading to decreased thioredoxin activities and oxidative stress in mouse embryonic fibroblasts. The Txnip-thioredoxin complex was observed in cells overexpressing wild-type Txnip but not in cells overexpressing Txnip Cys247-to-Ser mutant (C247S), showing that Txnip C247 is an essential cysteine for this interaction. Then, the role of the Txnip-thioredoxin interaction was evaluated in the diabetic heart, using our newly-developed cardiomyocyte-specific Txnip C247S “knock-in” mutant mice. Injections of streptozotocin in these animals induced type 1 diabetes. Prolonged hyperglycemia upregulated myocardial expression of Txnip both in Txnip C247S mutant mice and their littermate wild-type controls. Interestingly, loss of Txnip’s inhibition of thioredoxin in Txnip C247S mutant hearts increased reduced/oxidized glutathione (GSH/GSSG) ratio and decreased TUNEL-positive cardiomyocytes, indicative of less oxidative stress and apoptosis within the diabetic myocardium in Txnip C247S mutant animals. Echocardiographic assessments did not detect any functional differences in left ventricular (LV) parameters between genotypes both at baseline and under diabetic conditions. However, hemodynamic analyses with beta-adrenergic stimulation revealed a masked functional phenotype that Txnip C247S diabetic hearts had a higher LV contractile reserve than wild-type diabetic hearts. Conclusions: These data demonstrate that hyperglycemia-induced Txnip is responsible for cardiomyocyte damage in the diabetic heart through the direct inhibition of thioredoxin and increased oxidative stress.
춘계학술대회 : 포스터발표 ; 자가면역성 간질환의 임상상
Authors: 김영남, 박철희, 정낙소, 권오상, 김선숙, 권소영, 최덕주, 김주현
Journal: Clinical and Molecular Hepatology (2005)

배경/목적: 최근 자가면역성 간질환의 진단이 점차로 늘어나고 있는 추세로 원인 미상의 만성 간질환에서 중요한 원인이 되고 있다. 자가면역성 간질환(Autoimmune liver disease)에는 자가면역성 간염(Autoimmune hepatitis, AIH), 자가 면역성 담관염(Autoimmune cholangitis, AIC), 원발성 담즙성 간경변증(Primary biliary cirrhosis, PBC), 원발성 경화성 담관염(Primary s
Abstract P371: Fusion Of C-type Natriuretic Peptide With Elastin-like Polypeptide For Enhanced Pharmacological Activity
Authors: James D Jowett, Susan Arnold, Bret Umsted, Dave Sendecki, Dave Dickerhoff, John Lee
Journal: Circulation Research (2021)

C-type natriuretic peptide (CNP) is a pluripotent molecule produced by the endothelium and myocardium with therapeutic potential in pulmonary hypertension, myocardial infarction, and heart failure. However, the native peptide’s short elimination half-life of under 3 minutes limits its use clinically. To improve the pharmacokinetic profile of CNP we recombinantly expressed the CNP peptide as a fusion with an elastin-like polypeptide (ELP). ELPs are biopolymers that undergo reversible temperature-dependent phase separation and form a subcutaneous depot upon injection. CNP-ELP fusion proteins were expressed in E. coli , purified, and showed in vitro potency 2-4 fold less than native CNP. When administered subcutaneously in mice CNP-ELP showed a significantly enhanced PK profile due to the slow release of the fusion into the circulation with detectable fusion protein 24 hours after a single injection. In addition, the CNP-ELP increased growth velocity in mice significantly greater than that of native peptide indicating an in vivo activation of the CNP receptor, NPR-B. These findings represent a new method of administering a long acting CNP peptide for treatment of different cardiovascular diseases.
Transcriptomic Signitures of Azacitidine (AZA) and Decitabine (DAC) Resistance in MDS and CMML
Authors: Faezeh Darbaniyan, Caleb Class, Guillermo Montalban-Bravo, Rashmi Kanagal-Shamanna, Marcos Estecio, Yue Lu, Kelly A. Soltysiak, Kelly S. Chien, Hui Yang, Koji Sasaki, Irene Ganan-Gomez, Simona Colla, Kim-Anh Do, Guillermo Garcia-Manero, Yue Wei
Journal: Blood (2021)
Abstract 10488: Overexpression of MFN2 Alleviates Sorafenib-Induced Cardiomyocyte Necroptosis via the MAM-CaMKIIδ Pathway in vitro and in vivo
Authors: Ziping Song, haixu song, Dan Liu, Xiaoxiang Tian, Chenghui Yan, Han Yaling
Journal: Circulation (2021)

Background: The continued success of oncological therapeutics is dependent on the mitigation of treatment-related adverse events, particularly cardiovascular toxicities. As such, there is an import...
Helen Salisbury: E-consultations are increasing the GP workload
Authors: Helen Salisbury
Journal: BMJ (2021)

Helen Salisbury: E-consultations are increasing the GP workload Helen Salisbury GP Easy and convenient access to a GP must be a good thing, and that's arguably what the switch to remote consulting has facilitated.With the move to more telephone consultations, people can talk to their GP anywhere without having to make a journey or take time off work.
Development of Novel CAR Therapies for Diffuse Large B-Cell Lymphoma Using Genome-Wide Overexpression Screens
Authors: Mat Legut, Zoran Gajic, Maria Guarino, Eleni Mimitou, Stephanie Hao, Jahan Rahman, Teresa Davoli, Peter Smibert, Catherine S. Diefenbach, Neville Sanjana
Journal: Blood (2021)
The Outcome of Fatherhood in Patients with Philadelphia Negative Myeloproliferative Neoplasms, a Single Institution Experience"
Authors: Elrazi Awadelkarim Ali, Mohammad Abu-Tineh, Yousef Hailan, Qusai Ali Al-maharmeh, Zakaria Omar Maat, Anas M Babiker, Bashir Ali, Abdellatif Salah Ismail, Mohamed A Yassin
Journal: Blood (2021)
Neurosurgery at the crossroads of immunology and nanotechnology. New reality in the COVID-19 pandemic
Authors: Vladimir A. Ljubimov, Arshia Ramesh, Saya Davani, Moise Danielpour, Joshua J. Breunig, Keith L. Black
Journal: Advanced Drug Delivery Reviews (2021)

Neurosurgery as one of the most technologically demanding medical fields rapidly adapts the newest developments from multiple scientific disciplines for treating brain tumors. Despite half a century of clinical trials, survival for brain primary tumors such as glioblastoma (GBM), the most common primary brain cancer, or rare ones including primary central nervous system lymphoma (PCNSL), is dismal. Cancer therapy and research have currently shifted toward targeted approaches, and personalized therapies. The orchestration of novel and effective blood–brain barrier (BBB) drug delivery approaches, targeting of cancer cells and regulating tumor microenvironment including the immune system are the key themes of this review. As the global pandemic due to SARS-CoV-2 virus continues, neurosurgery and neuro-oncology must wrestle with the issues related to treatment-related immune dysfunction. The selection of chemotherapeutic treatments, even rare cases of hypersensitivity reactions (HSRs) that occur among immunocompromised people, and number of vaccinations they have to get are emerging as a new chapter for modern Nano neurosurgery.
Measuring the impact of COVID-19 on sexual and reproductive health in the UK: web-panel surveys with qualitative follow-up
Authors: Nigel Field, Emily Dema, Andrew J Copas, Soazig Clifton, Anne Conolly, Margaret Blake, Julie Riddell, Raquel Boso Perez, Clare Tanton, Malachi Willis, Chris Bonell, Pam Sonnenberg, Catherine H Mercer, Kirstin R Mitchell
Journal: The Lancet (2021)
Abstract 11740: Outcomes of Durable Left Ventricular Assist Device Implantation in Patients With End Stage Renal Diseases- Latest Outcomes From Nationwide Inpatient Sample (2015-2018)
Authors: Krishna Prasad Kurpad, Sumit Sohal, Harsh Mehta, sheetal vasundara mathai, Keith A Hawthorne, Matthew Montgomery, Saurabh Kapoor, Sergio Waxman
Journal: Circulation (2021)

Introduction: Left ventricular assist devices (LVAD) improve survival in patients with advanced heart failure however their use in patients with concomitant end stage renal disease (ESRD) is limited. Previous studies demonstrate higher mortality and morbidity in this subset of patients. Our aim was to assess in-hospital outcomes in patients who undergo LVAD implantation with and without ESRD in a national cohort. Methods: Using Nationwide Inpatient Sample (NIS) for years 2015-2018, all patients who underwent LVAD implantation during the hospitalization were identified. Cohort was divided into two groups, with and without ESRD. Baseline characteristics, comorbidities, in-hospital outcomes were compared between both the groups. Statistical significance was assigned at p&lt;0.05. Analysis was performed using STATA. Results: A total of 7185 patients underwent LVAD implantation between 2015-2018. 150 patients (2.09%) had ESRD at baseline. Despite having similar baseline characteristics and comorbidities in both groups (Table 1), the in-hospital mortality was significantly higher in patients with ESRD (43.33% vs 7.46% p-value: 0.001). Similarly, patients in ESRD group had longer length of stay (92.56 ±11.6 days vs a 33.72±0.73 days, p=0.001) and their cost of stay was also significantly higher ($2,179,827 vs $915,699, p=0.001). After multivariable analysis, ESRD remained an independent predictor of inpatient mortality (OR: 3.68, 95% CI (1.06-12.6), p=0.03). The bleeding, infectious and thromboembolic outcomes (Table 2) were also significantly higher in patients with ESRD undergoing LVAD implantation. Conclusions: Patients who are ESRD and receive LVAD during their admission are at higher risk of mortality, bleeding, infectious and thromboembolic events. More studies are required to improve management strategies and identify specific subgroup of patients who would benefit from LVAD implantation in this subset.
Abstract 16894: Association Between Flow Mediated Vasodilation and Coronary Artery Disease
Authors: Chandana Shekar, Dong Li, Lavanya Cherukuri, Kashif Shaikh, Sajad Hamal, Divya Birudaraju, Shivani Shodhan, Negin Nezarat, Christopher Dailing, Ferdinand Flores, Sion Roy, Matthew Budoff
Journal: Circulation (2018)

Introduction: Flow-mediated vasodilatation rate (FMD) is an ultrasound measurement often used to assess vascular endothelial function. Endothelial dysfunction causes coronary atherosclerosis by decreasing nitric oxide levels, which alters vasodilation and causes destabilization of established plaque. Hence, FMD has been proposed to be a surrogate marker of atherosclerosis severity and predictive of cardiovascular outcomes. Hypothesis: We intend to evaluate the relationship between the severity of Coronary Artery Disease (CAD) and FMD. We hypothesize that patients with lower FMD would have more severe CAD when compared to individuals with higher FMD. Methods: We identified 291 patients (169 [58%] male, mean age 59.6 ± 11.3 years), clinically referred for Coronary Artery Calcium(CAC) Scoring and Coronary Computed Tomography Angiography (CCTA) at our center. After informed consent, we measured brachial artery FMD using ultrasound (UNEXEF, Unex, Japan). CAC was measured using Agatston method. Segment Involvement Score (SIS; the total number of segments with any plaque), Segment Stenosis Score (SSS; the sum of maximal stenosis score per segment), Total Plaque Score (TPS; the sum of all segments plaque burden) were assessed using the 17-segment model with CCTA. We calculated the median FMD. We used multivariate regression analysis to analyze the association between FMD and the markers of CAD (i.e., CAC, TPS, SSS, SIS), after adjusting for confounding variables. Results: Median FMD in the group was 4.1% (25%-75%: 2.2-6.0). After multivariable analysis, individuals with FMD lower than 4.1% were noted to have significantly higher CAC (p=0.024), TPS (0.024), SSS (p=0.015) and SIS (p=0.010). (Table 1) Conclusions: We conclude that impaired FMD rate is an indicator of more severe coronary artery disease. Further studies to evaluate non-invasive ultrasound FMD measurement as a tool for predicting subclinical atherosclerosis and mechanisms are warranted. This could also serve to provide additive information for risk stratification of patients and cardiovascular outcomes.
Abstract 9964: Influence of Worsening Heart Failure During Hospitalization on the Prognosis in Patients with Acute Decompensated Heart Failure
Authors: Erika Yamamoto, Takao Kato, Hidenori Yaku, Takeshi Morimoto, YASUTAKA INUZUKA, Yodo Tamaki, Neiko Ozasa, Yukihito Sato, Koichiro Kuwahara, Takeshi Kimura
Journal: Circulation (2021)

Introduction: Worsening heart failure (WHF) during hospitalization has been used as the one of endpoint in assessing treatments for acute decompensated heart failure (ADHF). However, there are few data on WHF and long-term prognosis, especially in Japanese population. Hypothesis: WHF during hospitalization can influence the long-term prognosis in patients with ADHF. Methods and Results: The Kyoto Congestive Heart Failure registry is a prospective multicenter cohort study enrolling 4056 consecutive patients hospitalized for ADHF in Japan. WHF was defined as additional intravenous inotropes, diuretics, respiratory management (noninvasive positive pressure ventilation or intubation), or extracorporeal ultrafiltration after 24 hours from admission. Among 4056 patients, 775 (19.4%) patients developed WHF during hospitalization. Inotropes use in emergency room was significantly higher (8.0% vs 2.7%, p&lt;0.001), whereas diuretics use was significantly lower (45.6% vs 51.7%, p=0.002) in patients with WHF than those without WHF. In-hospital mortality was significantly higher in patients with WHF than in those without WHF (16.3% vs 4.0%, p&lt;0.001). A composite of all-cause death and HF hospitalization at 1-year were compared in 3728 patients who were alive at discharge with available data. Patients with WHF (N=644, 18.3%) were younger (79 [70-85] vs 81 [7-85], p&lt;0.001), more likely to be men (61.7 % vs 53.6%, p&lt;0.001), and more likely to have diabetes (44.7% vs 35.2% p&lt;0.001), chronic kidney disease (57.9% vs 41.3%, p&lt;0.001), and ischemic etiology (41.6% vs 30.7%, p&lt;0.001) than those without WHF (N=3084, 87.4%). After adjusting for confounders, the risk for primary outcome of WHF group remained significant (OR: 1.27, 95%CI: 1.02-1.58, p=0.03). Conclusions: The WHF during hospitalization was associated with worse 1-year clinical outcomes as well as in-hospital mortality in patients with ADHF.
Complete Remissions to PD-1 Blockade in Combination with Reduced-Dose ICE Chemotherapy in Two Cases of Relapsed or Refractory Classical Hodgkin Lymphoma with Bulky Lung Involvement after Failed PD-1 Blockade
Authors: Bing Xiu, Bing Li, Xinyu Zhu, Gangfeng Xiao, Xiu Luo, Zhi-Zhang Yang, Aibin Liang
Journal: Blood (2021)
Immunohistochemical Analysis of Inflammasome Signaling Component Expression Among Patients with Low Risk and High Risk Myelodysplastic Syndrome Using Tissue Microarray
Authors: Tony J Kurian, Kathy McGraw, Sanjay Bridgelall, Rohit Sharma, Qianxing Mo, Wenyi Fan, Jeffrey E. Lancet, Rami S. Komrokji, Seongseok Yun, Ling Zhang
Journal: Blood (2021)
Abstract 11702: Sex Differences in Diabetic Cardiomyopathy: Greater Reduction in Myocardial Perfusion Reserve in Women Than Men Driven by Increased Resting Perfusion
Authors: Jian L Yeo, Gaurav S Gulsin, Emer M Brady, Lavanya Athithan, Jayanth R Arnold, Anvesha Singh, Joseph Henson, Emma Redman, Kamlesh Khunti, Thomas Yates, Leong L Ng, Melanie J Davies, Gerry P McCann
Journal: Circulation (2021)

Introduction: Type 2 diabetes (T2D) confers a higher relative risk of heart failure in women than men. Women also have a greater prevalence of heart failure with preserved ejection fraction (HFpEF), linked to microvascular dysfunction. We hypothesize that sex-specific differences are present in the pathophysiological alterations of myocardial structure, function, and perfusion associated with T2D. Methods: Cross-sectional case-control study. Participants underwent comprehensive cardiac phenotyping with echocardiography and cardiac magnetic resonance with adenosine stress/rest perfusion. Global myocardial perfusion was derived as a mean of three short axis slices. Image analysis was performed by two observers blinded to all participant information. Statistical analysis was performed with independent-sample T-tests or Mann-Whitney test. Results: Individuals with T2D (n=287, 41% female) were compared with age-matched controls (n=87, 41% female). Women with T2D were more obese than men (body mass index 35.7±7.2 vs 32.4±5.3 kg/m 2 , p&lt;0.05). Both women and men with T2D had increased left ventricular (LV) concentric remodelling (greater LV mass/volume ratio), impaired diastolic (higher E/e’) and systolic (lower global longitudinal strain) function compared to controls. LV mass index was significantly increased in women only. Comparing T2D and controls, stress perfusion was not significantly different in both sexes whereas resting perfusion was increased in women (1.4±0.6 vs 1.0±0.4 ml/min/g, p&lt;0.05) but not in men. Consequently, women with T2D have a lower myocardial perfusion reserve than men (2.6±0.9 vs 3.1±0.9, p&lt;0.001). Conclusions: In asymptomatic people with T2D, women have increased LV mass index and lower myocardial perfusion reserve than men, driven primarily by increased resting perfusion. These findings support the growing evidence that microvascular dysfunction partly explains the greater risk of HFpEF in women with T2D.
Statin Discontinuation and Cardiovascular Events Among Older People in Denmark
Authors: Wade Thompson, Lucas Morin, Dorte Ejg Jarbøl, Jacob Harbo Andersen, Martin Thomsen Ernst, Jesper Bo Nielsen, Peter Haastrup, Morten Schmidt, Anton Pottegård
Journal: JAMA Network Open (2021)

Statin use is common in older persons. Given uncertainties in ongoing benefit, changes in health status, and shifting goals of care and preferences, statin discontinuation may be considered in some older persons, although there is currently little evidence to guide this decision.
Clinical Profile and Outcome of COVID Positive Hematology Patients during the COVID-19 Pandemic - an Analytical Cross Sectional Study from a Tertiary Care Centre in India
Authors: Faisal Kassim, Chirag Sunil Lalwani, Hamsini Movva, Sani Kodathumuriyil Sunny, Merlin Moni, Remya Sudevan, Renjitha Bhaskaran, Manoj Unni, Dipu Thareparambil Sathyapalan, Ullas Mony, Neeraj Sidharthan
Journal: Blood (2021)
Abstract 11880: Outcomes of Transcatheter Rheumatic Mitral Valve Repair
Authors: Mohammed Elzeneini, HASSAN ASHRAF, Yazan Assaf, Ahmad Mahmoud, Ayman Elbadawi, Islam Y Elgendy, R D Anderson, Hani Jneid
Journal: Circulation (2021)

Introduction: The aim of this analysis was to investigate if mitral transcatheter edge-to-edge repair (TEER) presents a safe and effective option for patients with severe symptomatic rheumatic mitral regurgitation. Hypothesis: Mitral TEER in rheumatic valvular disease (RVD) is challenging due to leaflet thickening and calcification but is performed in select cases. Limited data exists on its outcomes. Methods: We queried the Nationwide Readmissions Database for hospitalizations for mitral TEER in the United States between 2016 and 2018. Propensity score weighted regression analysis was conducted to evaluate the association of RVD with in-hospital outcomes and 90-day readmissions after mitral TEER. Results: A total of 18,240 mitral TEER procedures were included in analysis, including 1,779 (10%) in patients with RVD. Mitral TEER in patients with RVD was associated with no difference in overall in-hospital mortality compared to patients without RVD (odds ratio [OR] 1.47, 95% confidence interval [CI] 0.94-2.30, p 0.089). However, RVD was associated with higher in-hospital acute myocardial infarction (OR 1.65, 95%CI 1.07-2.56), acute kidney injury (OR 1.58, 95%CI 1.30-1.94), ventricular arrhythmia (OR 1.50, 95%CI 1.12-2.01), high-degree heart block (OR 1.67, 95%CI 1.25-2.23) and conversion to open surgical repair or replacement (OR 2.53, 95%CI 1.02-6.30). Mitral TEER in RVD was also associated with higher 90-day all-cause readmission (hazard ratio [HR] 1.19, 95% CI 1.04-1.47, p 0.012), although there was no difference in heart failure readmission or readmission for surgical repair/replacement. Conclusions: Mitral TEER might be a reasonable option for carefully selected patients with RVD at very high surgical risk who also have favorable anatomy.