tbuckley/cabot-search huggingface dataset:
Abstract 16827: miR-34a Expression in Cardiac Neonatal Mesenchymal Stem Cells is Essential for Heart Regeneration
Authors: Rachana Mishra, Muthukumar Gunasekaran, Progyaparamita Saha, Xuebin Fu, Yasir M Arfat, Mohamed Abdullah, Lauren Davidson, Aakash Shah, Sudhish Sharma, Sunjay Kaushal
Journal: Circulation (2020)

Advancing chronological age negatively impacts the functional activity of stem cell-based therapies. Despite the early promise stem cell mediated differentiation into selected cellular lineages when injected in the chosen organ, stem cell’s functional unit is the secretome that is directly modulated by chronological aging. However, the precise mechanism driving the secretome potency is unknown. Here we show a single miRNA, influenced by aging, drives the potency of the stem cell secretome at multiple cellular levels by increasing exosome production and directly increasing the levels of independent stem cell paracrine factors. We show differential miRNA microarray analysis of cardiac neonatal mesenchymal stem cells (nMSCs) and adult MSCs (aMSCs) identified miR34a among the top ten differentially expressed miRNAs present in aMSCs but not nMSCs. We demonstrated that miR34a singly inhibits the aMSC’s regenerative abilities in the acute myocardial infarct model by decreasing the secretome potency when compared to nMSCs in knockdown studies of miR-34a. Moreover, overexpression of miR-34a in nMSCs reversed the strong regenerative properties of nMSCs by decreasing their secretome potency. Mechanistically, miR-34a regulates the secretome potency firstly by decreasing Heat Shock Factor 1 (HSF1) levels that directly decreases exosome production and alters the exosome cargo to a less-regenerative phenotype, and secondly by directly inhibiting transcriptional levels of critical stem cell paracrine factors. These results implicate the miR34a-HIF1 pathway as a critical pathway controlling the secretome of MSCs impacted by advancing chronological age. Our findings further advance miRNA-based therapeutic approaches to cardiac repair and heart regeneration by indicating how to improve the quality of secretome of transplanted stem cells.
The complex picture of self-harm during the COVID-19 pandemic
Authors: Ruoling Chen
Journal: The Lancet Regional Health - Europe (2021)

© 2021 The Author. Published by Elsevier. This is an open access article available under a Creative Commons licence. 
The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1016/j.lanepe.2021.100123
Abstract 16623: Interim Acute and 30-day Results of the Flash Registry
Authors: Catalin Toma
Journal: Circulation (2020)

Introduction: FLASH, a prospective multi-center all-comers registry, is designed to evaluate real-world outcomes in pulmonary embolism (PE) patients treated with the FlowTriever System (Inari Medical, Irvine, CA). The FlowTriever System is designed to extract large PE thrombus without a need for thrombolytic drugs. Methods: FLASH will enroll up to 500 patients who will be evaluated through 6 months. The primary endpoint is a major adverse events composite of device-related death and major bleeding at 48 hours, and periprocedural device or procedure-related AEs. Secondary endpoints include changes in acute hemodynamics, utility measures, and longer-term clinical outcomes. Acute data in 203 patients and 30-day data in 170 patients has been analyzed. Results and Conclusion: This analyzed cohort included 10% high-risk and 90% intermediate-risk PE patients. The mean RV/LV ratio was 1.54±0.47, sPESI was 1.54±1.06, concomitant DVT was present in 72% and elevated biomarkers in 97% of patients. The primary endpoint occurred in 2 patients (1%) both were major bleeds (non-ICH). There were no periprocedural device related injuries or clinical deteriorations. No deaths (0% mortality) were reported at 48 hours. Significant on-table improvement in hemodynamics were seen, including an average reduction in mean PA pressure of 20% (6.1 mmHg, p&lt;0.0001) and a reduction in heart rate from a pre-procedure high of 111.9±16.9 bpm to 90.5±16.6 bpm (p&lt;0.0001). Patients with low cardiac index (&lt;2l/min/m 2 ) experienced an 18% on table improvement (0.3 l/min/m 2 , p&lt;0.0001). At 30-day follow-up, one patient had died, unrelated to the procedure (0.6% mortality) and 10 patients were readmitted (1 related, 9 unrelated to the procedure). Dyspnea significantly improved from a pre-procedure Modified Medical Research Council Dyspnea Scale average grade of 2.6±1.4 to 0.76±1.1 at 30 days, and 0.54±1 at 6 months (p&lt;0.0001). In conclusion, early results demonstrate excellent safety with immediate improvements in hemodynamics and low 30-day mortality. Data analysis is ongoing and additional results will be presented at the conference.
Abstract 16176: Newly Identified MiR-6770-3p Dramatically Induces Angiogenesis in Human Endothelial Cells While Uncommonly Decreasing Cell Proliferation
Authors: Marie Besnier, Owen Tang, Elijah Genetzakis, Meghan Finemore, Belinda Di Bartolo, Gemma A Figtree
Journal: Circulation (2020)

Micro-RNAs (miRs) are small non-coding RNAs that alter the expression of multiple mRNA targets. Although they participate in physiological processes, dysregulation of their expression is implicated in various diseases. We investigated whether miRs could be involved in the regulation of FXYD1 expression, a sub-unit of the Na+/K+-ATPase pump, that we previously described as both cardio- and vasculoprotective, under oxidative stress conditions. Using in silico analysis, we identified 3 potential miRs that could target FXYD1 mRNA: miR-3178, miR-3960 and miR-6770-3p. Using a FXYD1-3’UTR-luciferase reporter assay, we found that the overexpression of miR-6770-3p in HEK293T cells resulted in the largest reduction in luciferase activity, showing a strong targeting of FXYD1 mRNA. A mutation of the binding site in the 3’UTR of FXYD1 restored luciferase activity, confirming the binding site of miR-6770-3p. Mir-6770-3p is a novel miR that currently has no known function. MiR-6770-3p is the minor strand of its 5p/3p miR duplex in both the human endothelial cell (EC) line, EA.hy.926, and human dermal microvascular (HMVECs). Its overexpression dramatically increased endothelial tube formation in a Matrigel angiogenesis assay (&gt;4 fold change vs. control transfection, p&lt;0.05) and was also associated with a 2-3-fold increase of VEGFR2 and Endoglin mRNA levels, respectively, in both cell types. Conversely, it was also uncommonly associated with a decrease in cell proliferation, suggesting that the pro-angiogenic effect of miR-6770-3p was not due to increased proliferation. Interestingly and contrary to our previous findings, miR-6770-3p was the major strand in Human Umbilical Vein ECs (HUVECs). In this cell type, overexpression of the 3p strand in fact decreased tube formation, while retaining its negative effect on proliferation. The difference in miR major and minor strand may partly explain the differences in functional behaviours in HUVECs, as compared to HMVECs. In conclusion, we have identified a novel miR which has the potential to modulate vessel formation in vitro, and induce critical regulators of angiogenesis; however, further work is required to better understand how this miR performs these functions.
Abstract 13163: Clinical Impact of Contralateral Carotid Occlusion During Carotid Intervention in Contemporary Practice: An Analysis of the National Cardiovascular Data Registry Peripheral Vascular Intervention Registry
Authors: Anna K Krawisz, Kenneth Rosenfield, Christopher J White, Michael R Jaff, Joseph Campbell, kevin kennedy, Thomas T Tsai, Beau M Hawkins, William S Jones, Eric A Secemsky
Journal: Circulation (2020)

Introduction: Contralateral carotid occlusion (CCO) is an established high-risk feature for carotid endarterectomy (CEA) and is a reason to recommend carotid artery stenting (CAS). Recent observational data have called into question whether CCO remains a high-risk feature for CEA. We investigated the clinical impact of CCO among patients undergoing CEA and CAS in a contemporary nationwide registry. Hypothesis: CCO confers an elevated risk of in-hospital adverse events among patients undergoing CEA, but not CAS. Methods: All patients undergoing CEA or CAS from 2005-2019 in the NCDR CARE and PVI registries were included. The primary exposure was the presence of a CCO. The outcome was a composite of in-hospital death, stroke, and myocardial infarction. Analyses were stratified by treatment with CEA or CAS. Multivariable logistic regression models were used to identify factors associated with adverse outcomes. Results: Among 58,423 patients, 4,624 (7.9%) patients had a CCO. Of those, 68.9% (N=3,185) underwent CAS and 31.1% (N=1,439) underwent CEA. The average age of patients with CCO was 69.5±9.7, 32.6% were female, 92.8% were Caucasian, 51.7% had a prior TIA or stroke, and 45.4% had symptomatic disease. Over the study period, there was a 4.3% decline in procedures performed on patients with CCO (p &lt;0.001), but CAS remained the primary revascularization strategy (7.8% CAS vs 3.5% CEA in 2019Q2). Unadjusted rates of the composite outcome were lower after CAS (3.2%) than after CEA (3.9%). Following adjustment, CCO was associated with a 60% increase in odds of an adverse outcome after CEA (95%CI 1.2-2.12, p=0.0013) (Figure). There was no increase in risk for patients treated with CAS (adjusted OR 0.99, 95%CI 0.79-1.22, p=0.89). Conclusions: In this contemporary nationwide registry analysis, CCO remains an important predictor of increased risk in patients undergoing CEA, but not CAS. These data support the continued use of CCO to guide carotid revascularization strategy.
Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence
Authors: Zhong Wu, Jin Zhou, Xiaoyang Zhang, Zhouwei Zhang, Yingtian Xie, Jie bin Liu, Zandra V. Ho, Arpit Panda, Xintao Qiu, Paloma Cejas, Israel Cañadas, Fahire Goknur Akarca, James M. McFarland, Ankur K. Nagaraja, Louisa B. Goss, Nikolas Kesten, Longlong Si, Klothilda Lim, Yanli Liu, Yanxi Zhang, Ji Yeon Baek, Yang Liu, Deepa T. Patil, Jonathan P. Katz, Josephine Hai, Chunyang Bao, Matthew Stachler, Jun Qi, Jeffrey J. Ishizuka, Hiroshi Nakagawa, Anil K. Rustgi, Kwok-Kin Wong, Matthew Meyerson, David A. Barbie, Myles Brown, Henry Long, Adam J. Bass
Journal: Nature Genetics (2021)
Abstract 14407: The Longer-term Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia
Authors: Frederick J Raal, Robert S Rosenson, Laurens F Reeskamp, G. Kees Hovingh, John J Kastelein, Paolo Rubba, Shazia Ali, Poulabi Banerjee, Kuo-Chen Chan, Nagwa Khilla, Robert Pordy, Yi Zhang, Daniel Gaudet
Journal: Circulation (2020)

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic lipid disorder characterized by markedly elevated LDL-C and premature ASCVD. For HoFH patients (pts) with complete loss of low-density lipoprotein receptor (LDLR) function in both copies of the LDLR gene (null mutations) and some other HoFH pts, statins and PCSK9 inhibitors have limited to no efficacy, presenting a great unmet medical need. The efficacy and safety of evinacumab (EVIN; an angiopoietin-like protein 3 inhibitor) in HoFH pts was assessed during the double-blind treatment period (DBTP) of a phase 3 trial (NCT03399786). Objective: To examine longer-term efficacy and safety of EVIN in pts with HoFH who participated in the subsequent open-label treatment period (OLTP) of this phase 3 study. Methods: Patients with HoFH on stable lipid-lowering therapies (± lipoprotein apheresis) and screening LDL-C ≥70 mg/dL who completed the 24-week DBTP entered the 24-week OLTP and received IV EVIN 15 mg/kg every 4 weeks. Results: In total, 64 pts completed the DBTP and received open-label EVIN. Mean (standard deviation [SD]) baseline LDL-C at DBTP entry was 250.5 (162.3) mg/dL. From baseline to Week 48, EVIN reduced mean LDL-C by 46.3% (mean [SD] reduction of 134.3 [117.3] mg/dL). At Week 48, mean LDL-C reductions with open-label EVIN were 42.7% and 55.8% for pts who received EVIN (n=44) vs placebo (n=20) during the DBTP, respectively ( Figure ). LDL-C reduction observed at Week 48 was similar for pts with null/null mutations (n=19; 47.2%) versus non-null/null mutations (n=39; 45.9%). Adverse events (AEs) occurred in 47 pts (73.4%) during the OLTP; the most common were nasopharyngitis (9.4%) and headache (9.4%). During the OLTP, serious AEs occurred in 7 pts (10.9%; all pts received EVIN during the DBTP); none were considered related to study treatment. Conclusions: In pts with HoFH, EVIN showed substantial and sustained LDL-C reduction regardless of LDLR function and was generally well tolerated.
Therapeutic Modulation of RNA Splicing in Malignant and Non-Malignant Disease
Authors: Ettaib El Marabti, Omar Abdel-Wahab
Journal: Trends in Molecular Medicine (2021)

RNA splicing is the enzymatic process by which non-protein coding sequences are removed from RNA to produce mature protein-coding mRNA. Splicing is thereby a major mediator of proteome diversity as well as a dynamic regulator of gene expression. Genetic alterations disrupting splicing of individual genes or altering the function of splicing factors contribute to a wide range of human genetic diseases as well as cancer. These observations have resulted in the development of therapies based on oligonucleotides that bind to RNA sequences and modulate splicing for therapeutic benefit. In parallel, small molecules that bind to splicing factors to alter their function or modify RNA processing of individual transcripts are being pursued for monogenic disorders as well as for cancer.
Abstract 13398: 4D Flow Cardiac MRI Reveals Subtle Diastolic Dysfunction in Young Adults Born Premature
Authors: Philip A Corrado, Jacob A Macdonald, Christopher J François, Marlowe W Eldridge, Kara Goss, Oliver Wieben
Journal: Circulation (2020)

Introduction: Individuals born premature have smaller ventricular chambers volumes and a reduced cardiac reserve during exercise. Epidemiologic studies demonstrate increased risk of developing heart failure by young adulthood, though whether this is due primarily to systolic or diastolic dysfunction remains unresolved. Hypothesis: We hypothesize that either systolic or diastolic function, quantified as intraventricular kinetic energy (KE) during systolic and diastolic phases, respectively, will be altered in both ventricles of young adults born premature. Methods: A total of 56 young adults participated in this observational cardiac MRI study: 35 subjects born moderately to extremely premature (birth weight &lt;1500 g or gestational age ≤32 weeks), and 21 age-matched term-born subjects. Each subject underwent cardiac MRI, including cine cardiac structure/function assessment and four-dimensional flow-encoded MRI (4D flow MRI). Five 4D flow parameters, normalized by end diastolic volume (EDV) to control for heart size, were extracted from each ventricle’s KE-time curve: average KE/EDV, peak systolic KE/EDV, early diastolic (E-wave) KE/EDV, late diastolic (A-wave) KE/EDV, and the ratio of E-wave KE to A-wave KE. Results: Average KE/EDV and peak systolic KE/EDV were similar between term and preterm subjects. Preterm-born subjects had increased A-wave KE/EDV in the RV and decreased E/A KE ratio in both ventricles (Table 1), indicating subtle diastolic dysfunction. The E/A KE ratio was moderately correlated with stroke volume index in both ventricles (LV: R=0.37, P=0.005; RV: R=0.32, P=0.02). Conclusions: Our results suggest that diastolic dysfunction, along with reduced chamber size, contributes to the reduced stroke volume seen in individuals born premature. In addition, diastolic dysfunction may further limit cardiac functional reserve and increase early heart failure risk in this population.
Skin checks and skin cancer diagnosis in Australian general practice before and during the COVID‐19 pandemic, 2011–2020
Authors: J. Roseleur, D.A. Gonzalez‐Chica, J. Emery, N.P. Stocks
Journal: British Journal of Dermatology (2021)

Reports from several European countries suggest COVID-19 had a profound impact on referral for cancer diagnoses. A Dutch study using their National Cancer Registry reported that skin cancer diagnosis reduced by 60% six weeks after the first confirmed case of COVID-19 was identified in that country, while for other cancer types, this reduction was 26%.1 In the United Kingdom, reductions of 56% for referrals of all skin cancers and 53% in diagnoses for skin cancers were reported2 , with similar results found in one Australian state.3.
City-level vulnerability to temperature-related mortality in the USA and future projections: a geographically clustered meta-regression
Authors: Claire R Lay, Marcus C Sarofim, Alina Vodonos Zilberg, Dave M Mills, Russell W Jones, Joel Schwartz, Patrick L Kinney
Journal: The Lancet Planetary Health (2021)

Extreme heat exposure can lead to premature death. Climate change is expected to increase the frequency, intensity, and duration of extreme heat events, resulting in many additional heat-related deaths globally, as well as changing the nature of extreme cold events. At the same time, vulnerability to extreme heat has decreased over time, probably due to a combination of physiological, behavioural, infrastructural, and technological adaptations. We aimed to account for these changes in vulnerability and avoid overstated projections for temperature-related mortality. We used the historical observed decrease in vulnerability to improve future mortality estimates.We used historical mortality and temperature data from 208 US cities to quantify how observed changes in vulnerability from 1973 to 2013 affected projections of temperature-related mortality under various climate scenarios. We used geographically structured meta-regression to characterise the relationship between temperature and mortality for these urban populations over the specified time period. We then used the fitted relationships to project mortality under future climate conditions.Between Oct 26, 2018, and March 9, 2020, we established that differences in vulnerability to temperature were geographically structured. Vulnerability decreased over time in most areas. US mortalities projected from a 2°C increase in mean temperature decreased by more than 97% when using 2003-13 data compared with 1973-82 data. However, these benefits declined with increasing temperatures, with a 6°C increase showing only an 84% decline in projected mortality based on 2003-13 data.Even after accounting for adaptation, the projected effects of climate change on premature mortality constitute a substantial public health risk. Our work suggests large increases in temperature will require additional mitigation to avoid excess mortality from heat events, even in areas with high air conditioning coverage in place.The US Environmental Protection Agency and Abt Associates.
The genetic mechanism of heterosis utilization in maize improvement
Authors: Yingjie Xiao, Shuqin Jiang, Qian Cheng, Xiaqing Wang, Jun Yan, Ruyang Zhang, Feng Qiao, Chuang Ma, Jingyun Luo, Wenqiang Li, Haijun Liu, Wenyu Yang, Wenhao Song, Yijiang Meng, Marilyn L. Warburton, Jiuran Zhao, Xiangfeng Wang, Jianbing Yan
Journal: Genome biology (2021)

In maize hybrid breeding, complementary pools of parental lines with reshuffled genetic variants are established for superior hybrid performance. To comprehensively decipher the genetics of heterosis, we present a new design of multiple linked F1 populations with 42,840 F1 maize hybrids, generated by crossing a synthetic population of 1428 maternal lines with 30 elite testers from diverse genetic backgrounds and phenotyped for agronomic traits.
Synthetic anti-angiogenic genomic therapeutics for treatment of neovascular age-related macular degeneration
Authors: Jing Wang, Xiang Shi, Qiyu Bo, Hong Wang, Fang Wei, Jun Liu, Hao Wang, Liuwei Zhang, Yan Qi, Zhen Li, Qixian Chen, Xiaodong Sun
Journal: Asian Journal of Pharmaceutical Sciences (2021)

In light of the intriguing potential of anti-angiogenic approach in suppressing choroidal neovascularization, we attempted to elaborate synthetic gene delivery systems encapsulating anti-angiogenic plasmid DNA as alternatives of clinical antibody-based therapeutics. Herein, block copolymer of cyclic Arg-Gly-Asp-poly(ethylene glycol)-poly(lysine-thiol) [RGD-PEG-PLys(thiol)] with multifunctional components was tailored in manufacture of core-shell DNA delivery nanoparticulates. Note that the polycationic PLys segments were electrostatically complexed with anionic plasmid DNA into nanoscaled core, and the tethered biocompatible PEG segments presented as the spatial shell (minimizing non-specific reactions in biological milieu). Furthermore, the aforementioned self-assembly was introduced with redox-responsive disulfide crosslinking due to the thiol coupling. Hence, reversible stabilities, namely stable in extracellular milieu but susceptible to disassemble for liberation of the DNA payloads in intracellular reducing microenvironment, were verified to facilitate transcellular gene transportation. In addition, RGD was installed onto the surface of the proposed self-assemblies with aim of targeted accumulation and internalization into angiogenic endothelial cells given that RGD receptors were specifically overexpressed on their cytomembrane surface. The proposed anti-angiogenic DNA therapeutics were validated to exert efficient expression of anti-angiogenic proteins in endothelial cells and elicit potent inhibition of ocular neovasculature post intravitreous administration. Hence, the present study approved the potential of gene therapy in treatment of choroidal neovascularization. In light of sustainable gene expression properties of DNA therapeutics, our proposed synthetic gene delivery system inspired prosperous potentials in long-term treatment of choroidal neovascularization, which should be emphasized to develop further towards clinical translations.