tbuckley/cabot-search huggingface dataset:
The RNA-binding protein SRSF3 has an essential role in megakaryocyte maturation and platelet production
Authors: Shen Y. Heazlewood, Tanveer Ahmad, Monika Mohenska, Belinda B. Guo, Pradnya Gangatirkar, Emma C. Josefsson, Sarah L. Ellis, Madara Ratnadiwakara, Huimin Cao, Benjamin Cao, Chad K. Heazlewood, Brenda Williams, Madeline Fulton, Jacinta F. White, Mirana Ramialison, Susan K. Nilsson, Minna-Liisa Änkö
Journal: Blood (2021)

RNA processing is increasingly recognized as a critical control point in the regulation of different hematopoietic lineages including megakaryocytes responsible for the production of platelets. Platelets are anucleate cytoplasts that contain a rich repertoire of RNAs encoding proteins with essential platelet functions derived from the parent megakaryocyte. It is largely unknown how RNA binding proteins contribute to the development and functions of megakaryocytes and platelets. We show that serine-arginine-rich splicing factor 3 (SRSF3) is essential for megakaryocyte maturation and generation of functional platelets. Megakaryocyte-specific deletion of Srsf3 in mice led to macrothrombocytopenia characterized by megakaryocyte maturation arrest, dramatically reduced platelet counts, and abnormally large functionally compromised platelets. SRSF3 deficient megakaryocytes failed to reprogram their transcriptome during maturation and to load platelets with RNAs required for normal platelet function. SRSF3 depletion led to nuclear accumulation of megakaryocyte mRNAs, demonstrating that SRSF3 deploys similar RNA regulatory mechanisms in megakaryocytes as in other cell types. Our study further suggests that SRSF3 plays a role in sorting cytoplasmic megakaryocyte RNAs into platelets and demonstrates how SRSF3-mediated RNA processing forms a central part of megakaryocyte gene regulation. Understanding SRSF3 functions in megakaryocytes and platelets provides key insights into normal thrombopoiesis and platelet pathologies as SRSF3 RNA targets in megakaryocytes are associated with platelet diseases.
Abstract 12355: An Engineered High-Affinity ACE2 Peptide Therapeutically Alleviates Lung Vascular Endothelial Injury and Mortality Induced by Distinct SARS-CoV-2 Variants
Authors: Lianghui Zhang, Anthony F Gugliuzza1, Erik Procko, Jalees Rehman, Asrar B Malik
Journal: Circulation (2021)

Introduction: Vaccine hesitancy and the continuous emergence of SARS-CoV-2 variants of concern that partially escape vaccine-induced immune responses highlight the urgent need for the development of effective therapeutics for COVID-19 patients. Hypothesis: The Engineered high-affinity ACE2 peptide has a therapeutic effect for SARS-CoV-2 and its variant-induced acute lung vascular injury. Methods: K18-hACE2 transgenic mice were inoculated with SARS-CoV-2 WA-1/2020 or P.1 variant of concerns to induce acute lung injury. The sACE2 2 .v2.4-IgG1 was injected once a day for consecutively 7 days starting from 12 hours at 10 mg/kg/day or 24 hours at 15 mg/kg/day post-SARS-CoV-2 inoculation. Results: We demonstrated that the higher binding affinity of sACE2 2 .v2.4-IgG1 to S proteins of the original SARS-CoV-2 WA-1/2020 isolate and the B.1.1.7 (Alpha, UK isolate), B.1.351 (Beta, South Africa isolate), P.1 (Gamma, Brazil isolate), and B.1.617.2 (Delta, India isolate) SARS-CoV-2 variants of concern compared to wild-type soluble ACE2. Using humanized K18-hACE2 mice, we found that both SARS-CoV-2 isolate WA-1/2020 and the P.1 variant of concern induced severe acute lung endothelial injury, which resulted in the severe transvascular leak, lung edema, and death. The P.1 variant induced severe lung vascular leak and death at an earlier time point at Day 5 compared to WA-1 at Day 7, consistent with increased viral entry and replication. Treatment with sACE2 2 .v2.4-IgG1 decoy peptide could be initiated as late as 24h after inoculation with a lethal dose of the SARS-CoV-2 WA-1/2020 isolate and profoundly reduces lung vascular injury and mortality. For the P.1 variant of concern, ACE2 2 .v2.4-IgG1 decoy peptide markedly improved survival and reduced lung vascular injury if administered early at 12 hours post-inoculation. Conclusion: sACE2 2 .v2.4-IgG1 has an exceptional therapeutic efficacy to SARS-CoV-2 WA-1/2020 and variant P.1 -induced acute lung vascular injury.
Abstract 144: Importance of Release Velocity for Improved Hemodynamic Power at Varying Chest Compression Depths
Authors: Joshua W Lampe, Tai Yin, George Bratinov, Josiah Garcia, Theodore Weiland, Christopher L Kaufman, Lance B Becker
Journal: Circulation (2013)

Introduction: During cardiac arrest, chest compression (CC) release velocity or waveform has been suggested to be important for coronary perfusion and returning blood flow to the heart. A detailed ...
IMMU-22. THE IMPACT OF MICROGLIA MODULATION ON GBM PROGRESSION IN SYNGENEIC MOUSE MODELS
Authors: Marie-Françoise Ritz, Tala Shekarian, Tomás A Martins, Philip Schmassmann, Gregor Hutter
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The tumor immune microenvironment (TME) of Glioblastoma consists of almost myeloid-derived macrophages and microglia called TAMs. We have shown that the disruption of CD47-Sirpα-axis induces an antitumor activity of TAMs against GBM in immune-deficient mice, through increases of phagocytosis of tumor cells by TAMs. We have aimed to study the role of microglia and its activation/depletion on GBM progression, in the syngeneic GBM model in immune-competent mice. We have studied the interplay of innate and adaptive immune response after activation and depletion of microglia and the effect on tumor progression and outcome of the mice. MATERIAL AND METHODS We used different colonies of genetically modified immunocompetent mouse strains to genetically activate/deplete microglia in the tumor context. We generated Sall1 CreERT2/fl mice and Cre-negative littermates. The application of Tamoxifen in this constellation leads to the excision of the transcription factor Sall1 and subsequent enhanced microglia activity. Conversely, we generated Sall1 CreERT2 x Csf1r fl/fl animals and the respective heterozygous and Cre-negative littermates in which Tamoxifen treatment leads to inactivation of microglia through the deletion of Csf1r. Glioblastoma tumors were induced by intracerebral injection of GL261, CT2A, or retrovirus-induced PDGF-Akt in pups and Tamoxifen treatment was started once the tumors were detected. RESULTS We observed a survival advantage in tumor-bearing mice after activation of microglia in Sall1 CreERT/fl animals compared to Cre-negative littermates. Genetic depletion of microglia in this model resulted in a shorter lifespan in microglia-depleted animals compared to Cre-negative littermates. Furthermore, the iTME in these tumors is subjected to scRNAseq analysis to identify mechanistic insights. CONCLUSION Microglia are important players in tumor development and progression of glioblastoma in mouse models. These cells may be targeted in future immunotherapeutic approaches for patients.
Entecavir Prevents HBV Reactivation During Direct Acting Antivirals for HCV/HBV Dual Infection: A Randomized Trial
Authors: Pin-Nan Cheng, Chun-Jen Liu, Chi-Yi Chen, Kuo-Chih Tseng, Ching-Chu Lo, Cheng-Yuan Peng, Chih-Lin Lin, Hung-Chih Chiu, Yen-Cheng Chiu, Pei-Jer Chen
Journal: Clinical Gastroenterology and Hepatology (2021)
AD-linked R47H-<i>TREM2</i>mutation induces disease-enhancing microglial states via AKT hyperactivation
Authors: Faten A. Sayed, Lay Kodama, Li Fan, Gillian K. Carling, Joe C. Udeochu, David Le, Qingyun Li, Lu Zhou, Man Ying Wong, Rose Horowitz, Pearly Ye, Hansruedi Mathys, Minghui Wang, Xiang Niu, Linas Mazutis, Xueqiao Jiang, Xueting Wang, Fuying Gao, Matthew Brendel, Maria Telpoukhovskaia, Tara E. Tracy, Georgia Frost, Yungui Zhou, Yaqiao Li, Yue Qiu, Zuolin Cheng, Guoqiang Yu, John Hardy, Giovanni Coppola, Fei Wang, Michael A. DeTure, Bin Zhang, Lei Xie, John Q. Trajnowski, Virginia M. Y. Lee, Shiaoching Gong, Subhash C. Sinha, Dennis W. Dickson, Wenjie Luo, Li Gan
Journal: Science Translational Medicine (2021)

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD.
Abstract 9173: Perioperative Change in Left Ventricular Systolic Function Predicts Long-Term Mortality After CABG
Authors: Michael Downey, Matthew Hooks, Amy Gravely, Niyada Naksuk, Melissa Buelt-Gebhardt, Selma Carlson, Venkatakrishna N Tholakanahalli, Selcuk Adabag
Journal: Circulation (2021)

Introduction: Nearly 1/3 rd of patients undergoing CABG have concurrent left ventricular systolic dysfunction (LVEF&lt;50%). But the perioperative changes in LVEF is not well understood in these patients. Hypothesis: We hypothesized that patients with preoperative LV systolic dysfunction would have an improvement in LVEF post-CABG. Methods: We studied 549 patients with LVEF&lt;50% who underwent CABG as part of the Surgical Treatment for Ischemic Heart Failure (STICH) trial and had pre- and post-operative (at 4 months) LVEF assessment using the same cardiac imaging modality. All imaging tests were interpreted at a core lab. Patients were classified into 3 groups according to change in LVEF: improved (&gt;5% increase), unchanged, and worsened (&gt;5% decrease). Results: Of the 549 patients (mean age 61.4±9.6 years, 13% women), 240 (43.7%) had improved LVEF (from 25.9±8.6% to 39.5±10.5%; p&lt;0.001), 220 (40.1%) had unchanged, and 89 (16.2%) had worsened LVEF (from 34.4±7.8% to 23.6±7.8%; p&lt;0.001) following surgery (Figure). On multivariate logistic regression, improvement in LVEF was inversely associated with baseline LVEF (OR 0.74, p&lt;0.0001) and prior myocardial infarction (OR 0.56, p=0.028), but had a positive association with age (OR 1.10, p=0.045) and concurrent surgical ventricle restoration (OR 1.93, p=0.0004). Most notably, a &gt;5% decrease in LVEF post-CABG was associated with higher long-term mortality (log-rank p=0.019). Conclusions: Almost 50% of patients with LV systolic dysfunction had a significant improvement in LVEF after CABG. However, 16% of patients, who had worsened LVEF perioperatively had a higher long-term mortality risk and may benefit from further investigation.
Abstract 11232: Role of Line-1 Retrotransposition in Atherosclerosis
Authors: Andres Pulgarin, Rolando A Cuevas, Cynthia St Hilaire, Dennis Bruemmer, Imad Al Ghouleh
Journal: Circulation (2021)

Introduction: LINE-1 (L1) retrotransposons are a class of transposable elements comprising ~21% of the human genome. L1-retrostransposed elements move within the genome, where they profoundly alter gene function. Somatic L1 insertions, or retrotranspositions (RTNs), were implicated in multiple diseases including cancer. However, this literature has been mainly confined to epithelial tissue, and the role of L1 in cardiovascular diseases is unknown. Specifically, whether L1 presence and activity in vascular cells has a functional role in atherosclerosis, a disease characterized by extensive vascular remodeling, inflammation and plaque formation, remains unexplored. Hypothesis: L1 expression and RTN in vascular endothelial cells (ECs) leads to endothelial activation in atherosclerosis. Methods: L1 mRNA expression was analyzed by qRT-PCR in postmortem coronary artery specimens from patients with atherosclerosis and non-diseased controls. Immunofluorescence (IF) in coronary tissue was performed for ORF1p, a L1 encoded polypeptide required for active RTN. In vitro, qRT-PCR was used to assess L1 expression in primary human aortic ECs (HAEC) treated with proatherogenic inflammatory stimuli TNFα, IL6, oxidized LDL (oxLDL) and IL1β. Active RTN was assessed by FACS and IF in a purpose-built human umbilical vein EC line (CRL2922) L1 RTN detection system. Results: L1 mRNA was increased in atherosclerotic human coronary arteries and positively correlated with age and histologically-assessed disease severity. ORF1p expression increased in EC of atherosclerotic plaques indicative of increased L1 activity. L1 expression and retrotransposition was induced in ECs in vitro by TNFα, IL-6 and oxLDL. Finally, de novo L1 insertion alone resulted in upregulation of genes involved in EC activation and atherosclerosis (ICAM1, MCP-1, IL6, NOR), and this effect was further enhanced by co-treatment with TNFα, IL-6 and oxLDL. Conclusions: Our results identify a disease-related increase in L1 in the vascular endothelium under atherosclerotic conditions that contributes to EC activation. These data support a permissive environment during atherosclerosis for L1 activity and unveil a previously unrecognized role for L1 in this disease’s pathophysiology.
Addition of Nonauthor Collaborator Names of the COMEBAC Study
Journal: JAMA (2021)

The Writing Committee for the COMEBAC Study Group; Luc Morin, MD, MSc; Laurent Savale, MD, PhD; Tài Pham, MD, PhD; Romain Colle, MD, PhD; Samy Figueiredo, MD, PhD; Anatole Harrois, MD, PhD; Matthieu Gasnier, MD; Anne-Lise Lecoq, MD, PhD; Olivier Meyrignac, MD, PhD; Nicolas Noel, MD, PhD; Elodie Baudry, MD; Marie-France Bellin, MD; Antoine Beurnier, MD; Walid Choucha, MD; Emmanuelle Corruble, MD, PhD; Laurent Dortet, PharmD, PhD; Isabelle Hardy-Leger, MA; François Radiguer, MA; Sabine Sportouch, MA; Christiane Verny, MD; Benjamin Wyplosz, MD, PhD; Mohamad Zaidan, MD, PhD; Laurent Becquemont, MD, PhD; David Montani, MD, PhD; Xavier Monnet, MD, PhD
Abstract 12350: Modulation of Fibrosis Arrhythmogenicity Improves the Accuracy of Patient-Specific Computational Modeling in Persistent Atrial Fibrillation
Authors: Fima Macheret, Savannah F Bifulco, Griffin D Scott, Kirsten T Kwan, Nazem W Akoum, Patrick M Boyle
Journal: Circulation (2021)

Introduction: Computational models incorporating left atrial (LA) anatomy and fibrosis from MRI can identify post-ablation recurrence mechanisms in persistent atrial fibrillation (PsAF) patients. However, model accuracy is limited since fibrosis arrhythmogenicity (FA) is simulated identically across all models. Hypothesis: In each model, there exists an optimal FA level such that pre- and post-ablation simulation behaviors match the corresponding patient’s clinical outcome. Methods: 50 LA models were constructed from pre- and ≥90 days post-ablation late gadolinium enhanced MRI in 25 PsAF patients. Virtual pacing was used to probe for arrhythmia inducibility due to AF-like reentrant drivers (RD; i.e., rotors) or atrial flutter (AFL)-like macro-reentry (MR). FA variability was modeled in all patients by altering conduction velocity (CV) ±10% vs baseline (71.5cm/s). No recurrence (NR) was defined as ≥2 years arrhythmia-free. Pre-ablation, accuracy was assessed by confirming ≥1 RD was inducible; post-ablation models for patients with AF, AFL, or NR were screened for RD, MR, or non-inducibility, respectively. Results: At baseline FA, 26/50 (52%) models had simulations matching clinical outcome. When simulations with modulated FA were added, 36/50 (72%) models had simulations matching clinical outcome (Fig A; two-sample proportion t-test, p=0.034). FA modulation improved accuracy in three scenarios: eliminating non-inducible pre-ablation models; unmasking RD inducibility in post-ablation models for patients with AF recurrence; and abolishing inducibility in post-ablation models for NR patients (activation maps shown in Figs B-D, respectively). Conclusion: Modulation of FA in computational models of PsAF improved correlation between simulation behavior and clinical outcomes. This suggests that if FA can be quantified pre-ablation (e.g., via biomarker assay), it could create a new paradigm for model personalization with improved accuracy.
Social determinants of diabetes, hypertension, stroke, and coronary heart disease in Black Caribbean and Black African women aged 40 years or older in south London: findings from 70 582 primary care records from 2000–18
Authors: Mariam Molokhia, Sarah Yousif, Stevo Durbaba, Mark Ashworth, Seeromanie Harding
Journal: The Lancet (2021)
First-Line Immune Checkpoint Inhibitor-Based Sequential Therapies for Advanced Hepatocellular Carcinoma: Rationale for Future Trials
Authors: Giuseppe Cabibbo, Maria Reig, Ciro Celsa, Ferran Torres, Salvatore Battaglia, Marco Enea, Giacomo Emanuele Maria Rizzo, Salvatore Petta, Vincenza Calvaruso, Vito Di Marco, Antonio Craxì, Amit G. Singal, Jordi Bruix, Calogero Cammà
Journal: Liver Cancer (2021)

Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies.A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences.ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases.Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC.
What Can We Learn from COVID-19 Drug Development and Access for Non-Pandemic Diseases? A Chinese Perspective
Authors: Hui Zhang, Zhiping Guo, Lijun Shen, Yongguang Yang, Zhenxiang Zhang, Yuming Wang
Journal: The American Journal of Bioethics (2021)

This article refers to:Helpful Lessons and Cautionary Tales: How Should COVID-19 Drug Development and Access Inform Approaches to Non-Pandemic Diseases?
Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing’s Syndrome
Authors: Lynnette K Nieman
Journal: Endocrine Reviews (2021)

Abstract Endogenous Cushing’s syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are often delayed. Thus, there are many opportunities for basic and clinical research leading to better tests, faster diagnosis, and optimized medical treatments. This review focuses on CS caused by excessive adrenocorticotropin (ACTH) production. It describes current concepts of the regulation of ACTH synthesis and secretion by normal corticotropes and mechanisms by which dysregulation occurs in corticotrope (termed “Cushing’s disease”) and noncorticotrope (so-called ectopic) ACTH-producing tumors. ACTH causes adrenal gland synthesis and pulsatile release of cortisol; the excess ACTH in these forms of CS leads to the hypercortisolism of endogenous CS. Again, the differences between healthy individuals and those with CS are highlighted. The clinical presentations and their use in the interpretation of CS screening tests are described. The tests used for screening and differential diagnosis of CS are presented, along with their relationship to cortisol dynamics, pathophysiology, and negative glucocorticoid feedback regulation in the two forms of ACTH-dependent CS. Finally, several gaps in current understanding are highlighted in the hope of stimulating additional research into this challenging disorder.