<div><h4>Exosomes From IgE-Stimulated Mast Cells Aggravate Asthma-Mediated Atherosclerosis Through circRNA CDR1as-Mediated Endothelial Cell Dysfunction in Mice.</h4><i>Yang H, Chen J, Liu S, Xue Y, ... Wang J, Zhao H</i><br /><b>Background</b><br />IgE has been known for mediating endothelial cell dysfunction and mast cell (MC) activation to fuel asthma-aggravated high-fat diet-induced atherosclerosis. However, it remains unclear for the mechanism of asthma-mediated atherosclerosis, especially the potential involvement of IgE in the exacerbation of asthma-mediated atherosclerosis with a standard laboratory diet, and the cross talk between endothelial cells and MCs.<br /><b>Methods</b><br />Asthma-mediated atherosclerosis mice models under a standard laboratory diet and FcεR1 knock-out mice were used to determine the role of IgE-FcεR1 signaling in asthma-mediated atherosclerosis, which was assessed by Oil Red O staining and immunohistochemistry. Various in vitro assays including nanoparticle tracking analysis and transmission electron microscopy were used to evaluate exosome characteristics. Immunofluorescence and fluorescent in situ hybridization approaches were used to evaluate the effect and mechanism of MC-secreted exosomes encapsulated circular RNA CDR1as (cerebellar degeneration-related 1 antisense) on endothelial cells in vivo and in vitro. Finally, cohort studies examined the plasma CDR1as levels in patients with atherosclerosis with or without allergies.<br /><b>Results</b><br />Asthma mice with a standard laboratory diet showed increased atherosclerotic lesions and inflammatory infiltration depending on IgE-FcεR1 signal. FcεR1 knockout mice and blockage of IgE-FcεR1 signaling with IgE monoclonal antibody, omalizumab, all significantly alleviated asthma-mediated atherosclerosis and vascular inflammatory remodeling. Anti-inflammation with dexamethasone and stabilization of MC with cromolyn partially alleviated atherosclerotic lesions and mitigated the inflammatory infiltration in arteries. Mechanistically, IgE stimulation upregulates MC CDR1as expression in exosomes and upregulates the endothelial cell adhesive factors VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) via the CDR1as-FUS (fused in sarcoma)-phos-p65 axis. Knockdown of CDR1as in vivo significantly decreased the endothelial adhesion function and mitigated asthma-mediated atherosclerosis. Furthermore, a cohort study indicated higher plasma CDR1as levels in patients with atherosclerosis with allergies than in patients with atherosclerosis and healthy controls.<br /><b>Conclusions</b><br />Exosomes from IgE-stimulated MCs aggravated atherosclerosis through circular RNA CDR1as-mediated endothelial dysfunction, providing a novel insight into asthma-mediated atherosclerosis and potential diagnostic and therapeutic targets.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 01 Mar 2024; 44:e99-e115</small></div>

<div><h4>Altered whole blood thrombin generation and hyperresponsive platelets in patients with pancreatic cancer.</h4><i>Willems RAL, Konings J, Huskens D, Middelveld H, ... de Laat B, Roest M</i><br /><b>Background</b><br />Thromboembolic disease is a major complication in patients with pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC often have altered blood cell counts, which are associated with venous thromboembolism (VTE) development. The high thrombotic risk in patients with PDAC may be partially caused by procoagulant blood cells.<br /><b>Objectives</b><br />The aim of this study was to compare blood cell-dependent coagulation between patients with PDAC (n = 18) and healthy controls matched for age and sex (n = 18).<br /><b>Methods</b><br />Thrombin generation (TG) was measured in whole blood (WB) and plasma. The capacity of platelets to release granules (PGRCs) was measured in WB. We explored the occurrence of thromboembolic events in patients with PDAC during a 6-month follow-up.<br /><b>Results</b><br />Patients showed an increased endogenous thrombin potential in WB compared with controls. This difference was not observed in plasma, indicating a procoagulant effect of blood cells. Both in WB and plasma, the lag time was prolonged in patients compared with controls. Patients had hyperresponsive platelets, with a shorter time to peak granule release. Of the 18 patients with PDAC, 4 developed a venous thromboembolism (22%) and 1 developed an arterial thrombosis (6%). A shorter lag time in WB, but not in plasma, and an increased PGRC were associated with thromboembolic events.<br /><b>Conclusion</b><br />Patients with PDAC have an increased and delayed WB TG coagulation profile compared with controls. A shorter lag time in WB TG and increased PGRC are associated with the incidence of thromboembolic events. Platelets appear to be key players in thrombosis development. Measuring hemostasis in WB could improve thrombosis risk estimation in patients with PDAC.<br /><br />Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 Apr 2024; 22:1132-1144</small></div>

<div><h4>High-Serum Brain-Derived Neurotrophic Factor Levels Are Associated With Decreased Risk of Poststroke Cognitive Impairment.</h4><i>Chang X, You J, Yang P, He Y, ... Zhang Y, Zhu Z</i><br /><b>Background</b><br />BDNF (brain-derived neurotrophic factor) is widely implicated in the pathophysiological process of stroke, but the effect of BDNF on poststroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between baseline serum BDNF and the risk of PSCI at 3 months in a multicenter study based on a preplanned ancillary study of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke).<br /><b>Methods</b><br />We examined serum BDNF levels at baseline and used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke. PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. Logistic regression analyses were performed to evaluate the association between serum BDNF and the risk of 3-month PSCI.<br /><b>Results</b><br />In this ancillary study, a total of 660 patients with ischemic stroke with hypertension were included, and 593 patients (mean age, 59.90±10.44 years; 410 males and 183 females) were finally included in this analysis. According to mini-mental state examination score, after adjustment for age, sex, education, baseline National Institutes of Health Stroke Scale score, <i>APOE ɛ4</i> carriers, and other potential confounders, the odds ratio of PSCI for the highest tertile of BDNF was 0.60 ([95% CI, 0.39-0.94]; <i>P</i>=0.024) compared with the lowest tertile. Multiple-adjusted spline regression model showed a linear association of serum BDNF levels with PSCI at 3 months (<i>P</i> value for linearity=0.010). Adding serum BDNF to conventional prognostic factors slightly improved the risk reclassification of PSCI (net reclassification improvement: 27.46%, <i>P</i>=0.001; integrated discrimination index: 1.02%, <i>P</i>=0.015). Similar significant findings were observed when PSCI was defined by the Montreal Cognitive Assessment score.<br /><b>Conclusions</b><br />Elevated serum BDNF levels were associated with a decreased risk of PSCI at 3 months, suggesting that serum BDNF might be a potential predictive biomarker for PSCI among patients with ischemic stroke with hypertension.<br /><br /><br /><br /><small>Stroke: 01 Mar 2024; 55:643-650</small></div>

<div><h4>Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19 B cell tumors: a phase 1/2 trial.</h4><i>Marin D, Li Y, Basar R, Rafei H, ... Shpall EJ, Rezvani K</i><br /><AbstractText>There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19<sup>+</sup> B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 10<sup>7</sup> and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nat Med: 01 Mar 2024; 30:772-784</small></div>

<div><h4>Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum.</h4><i>Mätlik K, Baffuto M, Kus L, Deshmukh AL, ... Pearson CE, Heintz N</i><br /><AbstractText>Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington\'s disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nat Genet: 01 Mar 2024; 56:383-394</small></div>

<div><h4>The role of N-terminal phosphorylation of DGK-θ.</h4><i>Barbernitz MX, Devine LR, Cole RN, Raben DM</i><br /><AbstractText>Diacylglycerol kinases (DGKs) are lipid kinases that mediate the phosphorylation of diacylglycerol (DAG) leading to the production of phosphatidic acid (PtdOH). To examine the role of phosphorylation on DGK-θ, we first identified the phosphorylated sites on endogenous DGK-θ from mouse brain and found four sites: S15, S17, which we refer to phosphomotif-1 sites, and S22 and S26 which we refer to as phosphomotif-2 sites. This study focused on the role of these phosphorylated sites on enzyme activity, membrane binding, thermal stability, and cellular half-life of DGK-θ. After generating a construct devoid of all non-catalytic phosphorylation sites (4A), we also generated other constructs to mimic phosphorylation of these residues by mutating them to glutamate (E). Our data demonstrate that an increase in membrane affinity requires the phosphorylation of all four endogenous sites as the phosphomimetic 4E but not other phosphomimietics. Furthermore, 4E also shows an increase in basal activity as well as an increase in the Syt1-induced activity compared to 4A. It is noteworthy that these phosphorylations had no effect on the thermal stability or cellular half-life of this enzyme. Interestingly, when only one phosphorylation domain (phosphomotif-1 or phosphomotif-2) contained phosphomimetics (S15E/S17E or S22E/S26E), the basal activity was also increased but membrane binding affinity was not increased. Furthermore, when only one residue in each domain mimicked an endogenous phosphorylated serine (S15E/S22E or S17E/S26E), the Syt1-induced activity as well as membrane binding affinity decreased relative to 4A. These results indicate that these endogenous phosphorylation sites contribute differentially to membrane binding and enzymatic activity.</AbstractText><br /><br />Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Lipid Res: 01 Mar 2024; 65:100506</small></div>

<div><h4>Finasteride delays atherosclerosis progression in mice and is associated with a reduction in plasma cholesterol in men.</h4><i>McQueen P, Molina D, Pinos I, Krug S, ... Kane MA, Amengual J</i><br /><AbstractText>Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect of finasteride on cardiovascular disease remains elusive. We evaluated the role of finasteride on atherosclerosis using low-density lipoprotein (LDL) receptor-deficient (Ldlr<sup>-/-</sup>) mice. Next, we examined the relevance to humans by analyzing the data deposited between 2009 and 2016 in the National Health and Nutrition Examination Survey. We show that finasteride reduces total plasma cholesterol and delays the development of atherosclerosis in Ldlr<sup>-/-</sup> mice. Finasteride reduced monocytosis, monocyte recruitment to the lesion, macrophage lesion content, and necrotic core area, the latter of which is an indicator of plaque vulnerability in humans. RNA sequencing analysis revealed a downregulation of inflammatory pathways and an upregulation of bile acid metabolism, oxidative phosphorylation, and cholesterol pathways in the liver of mice taking finasteride. Men reporting the use of finasteride showed lower plasma levels of cholesterol and LDL-cholesterol than those not taking the drug. Our data unveil finasteride as a potential treatment to delay cardiovascular disease in people by improving the plasma lipid profile.</AbstractText><br /><br />Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Lipid Res: 01 Mar 2024; 65:100507</small></div>

<div><h4>PI(4,5)P binding sites in the Ebola virus matrix protein VP40 modulate assembly and budding.</h4><i>Johnson KA, Budicini MR, Bhattarai N, Sharma T, ... Li S, Stahelin RV</i><br /><AbstractText>Ebola virus (EBOV) causes severe hemorrhagic fever in humans and is lethal in a large percentage of those infected. The EBOV matrix protein viral protein 40 kDa (VP40) is a peripheral binding protein that forms a shell beneath the lipid bilayer in virions and virus-like particles (VLPs). VP40 is required for virus assembly and budding from the host cell plasma membrane. VP40 is a dimer that can rearrange into oligomers at the plasma membrane interface, but it is unclear how these structures form and how they are stabilized. We therefore investigated the ability of VP40 to form stable oligomers using in vitro and cellular assays. We characterized two lysine-rich regions in the VP40 C-terminal domain (CTD) that bind phosphatidylinositol-4,5-bisphosphate (PI(4,5)P<sub>2</sub>) and play distinct roles in lipid binding and the assembly of the EBOV matrix layer. The extensive analysis of VP40 with and without lipids by hydrogen deuterium exchange mass spectrometry revealed that VP40 oligomers become extremely stable when VP40 binds PI(4,5)P<sub>2</sub>. The PI(4,5)P<sub>2</sub>-induced stability of VP40 dimers and oligomers is a critical factor in VP40 oligomerization and release of VLPs from the plasma membrane. The two lysine-rich regions of the VP40 CTD have different roles with respect to interactions with plasma membrane phosphatidylserine (PS) and PI(4,5)P<sub>2</sub>. CTD region 1 (Lys221, Lys224, and Lys225) interacts with PI(4,5)P<sub>2</sub> more favorably than PS and is important for VP40 extent of oligomerization. In contrast, region 2 (Lys270, Lys274, Lys275, and Lys279) mediates VP40 oligomer stability via lipid interactions and has a more prominent role in release of VLPs.</AbstractText><br /><br />Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Lipid Res: 01 Mar 2024; 65:100512</small></div>

<div><h4>Changes in soluble LDL receptor and lipoprotein fractions in response to diet in the DIETFITS weight loss study.</h4><i>Krauss RM, Fisher LM, King SM, Gardner CD</i><br /><AbstractText>Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology. Changes in sLDLR were significantly positively associated with changes in plasma cholesterol, triglycerides, apoB, large-sized and medium-sized VLDL, and small and very small LDL, and inversely with changes in large LDL and HDL. The lipoprotein subfraction associations with sLDLR were independent of age, sex, diet, and BMI, but all except for large LDL were reduced to insignificance when adjusted for triglyceride change. Principal component analysis identified three independent clusters of changes in lipoprotein subfractions that accounted for 78% of their total variance. Change in sLDLR was most strongly correlated with change in the principal component that was loaded positively with large VLDL and small and very small LDL and negatively with large LDL and HDL. In conclusion, sLDLR is a component of a cluster of lipids and lipoproteins that are characteristic of atherogenic dyslipidemia.</AbstractText><br /><br />Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Lipid Res: 01 Mar 2024; 65:100503</small></div>

<div><h4>Disordered gut microbiota and alterations in the serum metabolome are associated with venous thromboembolism.</h4><i>Fan Z, Xu S, Deng Y, Wei L, Yang J, Xing X</i><br /><b>Introduction</b><br />The gut microbiome plays a crucial role in various diseases, and its regulation is a potential treatment option for these conditions. However, the relationship between the gut microbiome and venous thromboembolism (VTE) remains poorly explored.<br /><b>Methods</b><br />In this study, we collected feces and serum samples from 8 VTE patients and 7 healthy controls. The gut microbiota and serum metabolites were analyzed using 16S rRNA gene sequencing and liquid chromatography-mass spectrometry, respectively. Additionally, a combined analysis of microbiota and metabolome was performed.<br /><b>Results</b><br />The alpha and beta diversity between the VTE and control groups were significantly different. Patients with VTE exhibited an overgrowth of Blautia, Roseburia, Coprococcus, and Ruminococcus. Moreover, serum metabolomics analysis revealed altered levels of choline and lithocholic acid. Pathway enrichment analysis indicated a significant upregulation of bile secretion pathways. In addition, a positive correlation was observed between the levels of serum choline and lithocholic acid and the abundance of gut flora enriched in the VTE group.<br /><b>Conclusion</b><br />This study provided novel insights into the disordered gut microbiota and serum metabolome associated with VTE, suggesting potential common pathological mechanisms between VTE and arterial thrombosis. Targeted modulation of the gut microbiome may hold promise as a preventive and therapeutic approach for VTE.<br /><br />Copyright © 2024. Published by Elsevier Ltd.<br /><br /><small>Thromb Res: 01 Mar 2024; 235:68-74</small></div>