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Background: Alcohol use disorder (AUD) is a worldwide problem. The AUD can take the form of hazardous drinking, binge drinking, or alcohol dependence. The effects of alcohol on cognition can be diverse and complex. Objective: Our study aimed to assess AUD as a risk factor for cognitive impairment. Methods: A literature search was conducted using major electronic databases of PubMed, EMBASE, and Web of Science. Abstracts were screened independently to include data from original research reports. The following keywords were used: alcohol abuse, cognitive impairment, Alzheimer's disease, and dementia. In total, 767 abstracts were retrieved. After removing the duplicates, 76 articles met the criteria for full-text review, of which 41 were included in this report. Results: People with AUD are seen from different geographical areas and cultures. AUD is associated with an increased risk of cognitive impairments, Alzheimer's disease, and dementia, especially vascular dementia. In addition, AUD interacts with comorbidities increasing the risk of cognitive impairment. Conclusion: AUD is associated with an increased risk of cognitive impairments, which may have more than one underlying mechanism. [ABSTRACT FROM AUTHOR]

Abstract Aortic aneurysms represent a major public health burden, and currently have no medical treatment options. The pathophysiology behind these aneurysms is complex and variable, depending on location and underlying cause, and generally involves progressive dysfunction of all elements of the aortic wall. Changes in smooth muscle behavior, endothelial signaling, extracellular matrix remodeling, and to a variable extent inflammatory signaling and cells, all contribute to the dilation of the aorta, ultimately resulting in high mortality and morbidity events including dissection and rupture. A large number of researchers have identified non-coding RNAs as crucial regulators of aortic aneurysm development, both in humans and in animal models. While most work to-date has focused on microRNAs, intriguing information has also begun to emerge regarding the role of long-non-coding RNAs. This review summarizes the currently available data regarding the involvement of non-coding RNAs in aneurysmal aortopathies. Going forward, these represent key potential therapeutic targets that might be leveraged in the future to slow or prevent aortic aneurysm formation, progression and rupture. [ABSTRACT FROM AUTHOR]

Abstract Long intergenic noncoding RNAs (lincRNAs) are increasingly recognized as important mediators of many biological processes relevant to human pathophysiologies, including cardiovascular diseases. In vitro studies have provided important knowledge of cellular functions and mechanisms for an increasing number of lincRNAs. Dysregulated lncRNAs have been associated with cell fate programming and development, vascular diseases, atherosclerosis, dyslipidemia and metabolic syndrome, and cardiac pathological hypertrophy. However, functional interrogation of individual lincRNAs in physiological and disease states is largely limited. The complex nature of lincRNA actions and poor species conservation of human lincRNAs pose substantial challenges to physiological studies in animal model systems and in clinical translation. This review summarizes recent findings of specific lincRNA physiological studies, including MALAT1, MeXis, Lnc-DC and others, in the context of cardiovascular diseases, examines complex mechanisms of lincRNA actions, reviews in vivo research strategies to delineate lincRNA functions and highlights challenges and approaches for physiological studies of primate-specific lincRNAs. Highlights • Long intergenic noncoding RNAs (lincRNA) play regulatory roles in cardiovascular health. • Physiological interrogation of lincRNAs is challenging. • Complementary approaches are often needed in the examination of lincRNA functions in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development.Methods: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient ( ApoE-/-) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization.Results: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1α as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1α and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1α via recruiting the transcription factor specificity protein 1 to the promoter region.Conclusions: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease. [ABSTRACT FROM AUTHOR]

We report a case of pure white cell aplasia (PWCA) postthymoma resection in a 74-year-old male presenting with a 2-week history of fevers, night sweats, and severe febrile neutropenia. His pure white cell aplasia was treated with intravenous immunoglobulin (IVIg), granulocyte colony-stimulating factor (G-CSF), prednisone, and cyclosporine with a mixed response. He also developed immune thrombocytopenia, which responded well to a short course of eltrombopag. With continued cyclosporine treatment, his platelet counts were stable after stopping eltrombopag. The patient's cyclosporine treatment was complicated by renal failure, resulting in cessation of cyclosporine. His PWCA and immune thrombocytopenia significantly worsened after stopping cyclosporine, and unfortunately, he died from multiorgan failure and sepsis. [ABSTRACT FROM AUTHOR]

A recent phase 3 trial with soluble herpes simplex virus 2 (HSV-2) glycoprotein D (gD2t) in adjuvant failed to show protection against genital herpes. We postulated that live attenuated HSV-2 would provide more HSV antigens for induction of virus-specific antibodies and cellular immunity than would gD2t. We previously reported an HSV-2 mutant, HSV2-gD27, in which the nectin-1 binding domain of gD2 is altered so that the virus is impaired for infecting neural cells, but not epithelial cells, in vitro and is impaired for infecting dorsal root ganglia in mice (K. Wang, J. D. Kappel, C. Canders, W. F. Davila, D. Sayre, M. Chavez, L. Pesnicak, and J. I. Cohen, J Virol 86:12891-12902, 2012, doi:10.1128/JVI.01055-12). Here we report that the mutations in HSV2gD27 were stable when the virus was passaged in cell culture and during acute infection of mice. HSV2-gD27 was attenuated in mice when it was inoculated onto the cornea, intramuscularly (i.m.), intravaginally, and intracranially. Vaccination of mice i.m. with HSV2-gD27 provided better inhibition of challenge virus replication in the vagina than when the virus was used to vaccinate mice intranasally or subcutaneously. Comparison of i.m. vaccinations with HSV2-gD27 versus gD2t in adjuvant showed that HSV2-gD27 induced larger reductions of challenge virus replication in the vagina and reduced latent viral loads in dorsal root ganglia but induced lower serum neutralizing antibody titers than those obtained with gD2t in adjuvant. Taken together, our data indicate that a live attenuated HSV-2 vaccine impaired for infection of neurons provides better protection from vaginal challenge with HSV-2 than that obtained with a subunit vaccine, despite inducing lower titers of HSV-2 neutralizing antibodies in the serum. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The present study assessed the functional contribution of the lncRNA myocardial infarction-associated transcript (MIAT) to atherosclerosis and carotid artery disease. Methods: We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies. The lncRNA MIAT was identified as the most upregulated noncoding RNA transcript in carotid plaques compared with nonatherosclerotic control arteries, which was confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. Results: Experimental knockdown of MIAT , using site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs) but also increased their apoptosis. MIAT mechanistically regulated SMC proliferation through the EGR1 (Early Growth Response 1)-ELK1 (ETS Transcription Factor ELK1)-ERK (Extracellular Signal-Regulated Kinase) pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat -/- and Miat -/- ApoE -/- mice, and Yucatan LDLR -/- mini-pigs, as well, confirmed the regulatory role of this lncRNA in SMC de- and transdifferentiation and advanced atherosclerotic lesion formation. Conclusions: The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs, and the proinflammatory properties of macrophages, as well. What Is New? * The contribution of long noncoding RNAs to the development and progression of vascular disease remains largely unknown. * The long noncoding RNA Myocardial Infarction Associated Transcript (MIAT) had previously been discovered in genome-wide association and transcriptomic profiling studies using diseased cardiovascular specimens and experimental models. * We describe a novel role for MIAT in regulating proliferation and transdifferentiation of arterial smooth muscle cells and inflammatory activity in macrophages, as well, during atherosclerotic plaque development and progression. What Are the Clinical Implications? * Long noncoding RNAs possess key regulatory functions, directly interacting and mediating expression and functionality of proteins, other RNAs, and DNA, as well. * The long noncoding RNA MIAT plays a key role during atherosclerotic plaque development and lesion destabilization. Its expression becomes highly increased in high-risk patients with vulnerable plaques. * Therapeutic targeting of MIAT , using antisense oligonucleotides, offers novel treatment options for patients with advanced atherosclerosis in carotid arteries at risk of stroke. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs), VEGF/VEGF receptor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers including non-small-cell lung cancer (NSCLC). This study aims to evaluate the utility of plasma cell-free DNA (cfDNA) as a prognostic biomarker and efficacy predictor of chemotherapy (CT) with or without these precision therapies in NSCLC patients. Peripheral cfDNA levels in 154 NSCLC patients were quantified before and after the first target cycle of chemotherapy. The correlations of cfDNA with tumor burden, clinical characteristics, progression-free survival (PFS)/disease-free survival (DFS), objective response ratio (ORR), and therapy regimens were analyzed respectively. Baseline cfDNA, but not post-chemotherapeutic cfDNA, positively correlates with tumor burden. Notably, cfDNA kinetics (cfDNA Ratio, the ratio of post-chemotherapeutic cfDNA to baseline cfDNA) well distinguished responsive individuals (CR/PR) from the non-responsive (PD/SD). Additionally, cfDNA Ratio was found negatively correlated with PFS in lung adenocarcinoma (LUAD), but not lung squamous-cell carcinoma (LUSC) which may be due to a limited number of LUSC patients in this cohort. LUAD patients with low cfDNA Ratio have prolonged PFS and improved ORR, compared to those with high cfDNA Ratio. When stratified by therapy regimen, the predictive value of cfDNA Ratio is significant in patients with chemotherapy plus VEGFIs, while more patients need be included to validate the value of cfDNA Ratio in other regimens. Thus, the kinetics of plasma cfDNA during chemotherapy may function as a prognostic biomarker and efficacy predictor for NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis progression is modulated by interactions with the adaptive immune system. Humoral immunity can help protect against atherosclerosis formation; however, the existence, origin, and function of putative atherogenic antibodies are controversial. How such atherosclerosis-promoting antibodies could affect the specific composition and stability of plaques, as well as the vasculature generally, remains unknown.Methods: We addressed the overall contribution of antibodies to atherosclerosis plaque formation, composition, and stability in vivo (1) with mice that displayed a general loss of antibodies, (2) with mice that had selectively ablated germinal center-derived IgG production, or (3) through interruption of T-B-cell interactions and further studied the effects of antibody deficiency on the aorta by transcriptomics.Results: Here, we demonstrate that atherosclerosis-prone mice with attenuated plasma cell function manifest reduced plaque burden, indicating that antibodies promote atherosclerotic lesion size. However, the composition of the plaque was altered in antibody-deficient mice, with an increase in lipid content and decreases in smooth muscle cells and macrophages, resulting in an experimentally validated vulnerable plaque phenotype. Furthermore, IgG antibodies enhanced smooth muscle cell proliferation in vitro in an Fc receptor-dependent manner, and antibody-deficient mice had decreased neointimal hyperplasia formation in vivo. These IgG antibodies were shown to be derived from germinal centers, and mice genetically deficient for germinal center formation had strongly reduced atherosclerosis plaque formation. mRNA sequencing of aortas revealed that antibodies are required for the sufficient expression of multiple signal-induced and growth-promoting transcription factors and that aortas undergo large-scale metabolic reprograming in their absence. Using an elastase model, we demonstrated that absence of IgG results in an increased severity of aneurysm formation.Conclusions: We propose that germinal center-derived IgG antibodies promote the size and stability of atherosclerosis plaques, through promoting arterial smooth muscle cell proliferation and maintaining the molecular identity of the aorta. These results could have implications for therapies that target B cells or B-T-cell interactions because the loss of humoral immunity leads to a smaller but less stable plaque phenotype. [ABSTRACT FROM AUTHOR]

Background: The majority of the human genome comprises noncoding sequences, which are in part transcribed as long noncoding RNAs (lncRNAs). lncRNAs exhibit multiple functions, including the epigenetic control of gene expression. In this study, the effect of the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) on atherosclerosis was examined.Methods: The effect of MALAT1 on atherosclerosis was determined in apolipoprotein E-deficient (Apoe-/-) MALAT1-deficient (Malat1-/-) mice that were fed with a high-fat diet and by studying the regulation of MALAT1 in human plaques.Results: Apoe-/- Malat1-/- mice that were fed a high-fat diet showed increased plaque size and infiltration of inflammatory CD45+ cells compared with Apoe-/- Malat1+/+ control mice. Bone marrow transplantation of Apoe-/- Malat1-/- bone marrow cells in Apoe-/- Malat1+/+ mice enhanced atherosclerotic lesion formation, which suggests that hematopoietic cells mediate the proatherosclerotic phenotype. Indeed, bone marrow cells isolated from Malat1-/- mice showed increased adhesion to endothelial cells and elevated levels of proinflammatory mediators. Moreover, myeloid cells of Malat1-/- mice displayed enhanced adhesion to atherosclerotic arteries in vivo. The anti-inflammatory effects of MALAT1 were attributed in part to reduction of the microRNA miR-503. MALAT1 expression was further significantly decreased in human plaques compared with normal arteries and was lower in symptomatic versus asymptomatic patients. Lower levels of MALAT1 in human plaques were associated with a worse prognosis.Conclusions: Reduced levels of MALAT1 augment atherosclerotic lesion formation in mice and are associated with human atherosclerotic disease. The proatherosclerotic effects observed in Malat1-/- mice were mainly caused by enhanced accumulation of hematopoietic cells. [ABSTRACT FROM AUTHOR]

Background Hypertonic saline (HS) has been used clinically for treatment of cerebral edema for decades. Previously we have demonstrated that HS alleviates cerebral edema via regulating water/ion channel protein and attenuating neuroinflammation. However, whether HS treatment triggers microglia polarization and its regulatory mechanism during this process is unclear. Methods and results The Sprague-Dawley (SD) rats that underwent right-sided middle cerebral artery occlusion (MCAO) were used for assessment of neuroinflammation and microglia functions. Treatment of 10% HS not only significantly reduced infarct size and ipsilateral ischemic hemispheric brain water content (BWC) via attenuating ischemia-induction of TNF-α, IL-1β, microglia M1 markers (iNOS, CD86) and miR-200b, but also increased neurotrophic factors such as IL-10 and IL-4, microglia M2 markers (Arg1, CD206) and Krüppel-like factor 4 (KLF4). Similar changes were confirmed in primary microglial cells subjected to hypoxia with/without HS in vitro . Importantly, overexpression of miR-200b was able to induce microglia M1 polarization via directly targeting KLF4. Restoring KLF4 expression abolished this effect. On the contrary, miR-200b inhibitor or KLF4 overexpression led to microglia M2 polarization. Mechanistically, KLF4 directly binds to promoter region of Agr1, thus inducing its transcription. Similar to treatment of HS, experimental overexpression of KLF4 in vivo exerted significant beneficial effects on ischemia-induced cerebral edema. However, knockdown of KLF4 abrogated the benefits of HS. Conclusions Hypertonic saline regulates microglial M2 polarization via miR-200b/KLF4 during its treatment of cerebral edema. This study may provide new insights of HS-related therapy for cerebral edema. [ABSTRACT FROM AUTHOR]

Introduction: Understanding tissue level transcriptome responses to activation of innate immunity in humans drives novel mechanistic insights and therapeutics. Long intergenic noncoding RNAs (lincRNAs) show tissue-specific expression patterns, supporting their potential roles in regulating localized responses in inflammatory disorders. Hypothesis: Novel human lincRNAs regulate monocyte- and adipose tissue-specific inflammatory responses to lipopolysaccharide (LPS). Methods and Results: We performed an inpatient endotoxin challenge (1 ng/kg LPS) in healthy humans to induce inflammation. We examined the transcriptome change of CD14+ monocytes (n=15) and adipose tissue (n=25) via RNA-seq. Differential expression (DE) analysis showed that among the 261 and 42 DE lincRNAs post-LPS in monocytes and adipose tissue, respectively (fold change ≥ 2, FDR < 0.05), only 9 overlapped, suggesting a divergent tissue-specific transcriptome response to endotoxemia. CTB-41I6.2 , a monocyte-enriched lincRNA not expressed in mouse, is one of the top DE lincRNAs specifically in monocytes but not in adipose tissue. To study the functional impact of CTB-41I6.2 , we used antisense oligonucleotide to knockdown CTB-41I6.2 in THP-1 monocytes and found reduced LPS-induced IL6 expression (Figure), but no effects on other inflammatory genes, including TNF , CCL5 , CXCL9 , and CCR7. Nuclear/cytosolic fractionation supported that CTB-41I6.2 is expressed in both compartments and knockdown did not affect the expression of cis -genes. Knockdown of CTB-41I6.2 also led to reduced CD86 mRNA at baseline without LPS stimulation. As CD86 engagement has been implicated to positively regulate IL-6 production, CTB-41I6.2 may modulate IL6 expression through a CD86-dependent manner. Conclusions: CTB-41I6.2 is a novel monocyte-enriched lincRNA that represents monocyte-specific in vivo response to endotoxemia and acts as a positive regulator of LPS-induced IL6 expression. [ABSTRACT FROM AUTHOR]