The novel prognostic marker SPOCK2 regulates tumour progression in melanoma.

Secreted protein acidic and cysteine rich/osteonectin, cwcv and kazal-like domain proteoglycan 2 (SPOCK2) is a protein that regulates cell differentiation and growth. Recent studies have reported that SPOCK2 plays important roles in the progression of various human cancers; however, the role of SPOCK2 in melanoma remains unknown. Therefore, this study investigated the roles of SPOCK2 and the related mechanisms in melanoma progression. To evaluate the clinical significance of SPOCK2 expression in patients with melanoma, we analysed the association between SPOCK2 expression and its prognostic value for patients with melanoma using systematic multiomic analysis. Subsequently, to investigate the roles of Spock2 in melanoma progression in vitro and in vivo, we knocked down Spock2 in the B16F10 melanoma cell line. High SPOCK2 levels were positively associated with good prognosis and long survival rate of patients with melanoma. Spock2 knockdown promoted melanoma cell proliferation by inducing the cell cycle and inhibiting apoptosis. Moreover, Spock2 downregulation significantly increased cell migration and invasion by upregulating MMP2 and MT1-MMP. The increased cell proliferation and migration were inhibited by MAPK inhibitor, and ERK phosphorylation was considerably enhanced in Spock2 knockdown cells. Therefore, Spock2 could function as a tumour suppressor gene to regulate melanoma progression by regulating the MAPK/ERK signalling pathway. Additionally, Spock2 knockdown cell injection induced considerable tumour growth and lung metastasis in C57BL6 mice compared to that in the control group. Our findings suggest that SPOCK2 plays crucial roles in malignant progression of melanoma and functions as a novel therapeutic target of melanoma.

PM2.5 Induces Pyroptosis via Activation of the ROS/NF-κB Signaling Pathway in Bronchial Epithelial Cells.

Background and Objectives: Fine particulate matter, PM2.5, is becoming a major threat to human health, particularly in terms of respiratory diseases. Pyroptosis is a recently discovered and distinct form of cell death, characterized by pore formation in the cell membrane and secretions of proinflammatory cytokines. There has been little research on the effect of PM2.5 on pyroptosis, especially in airway epithelium. We investigated whether PM2.5-related oxidative stress induces pyroptosis in bronchial epithelial cells and defined the underlying mechanisms. Materials and Methods: After exposure of a BEAS-2B cell line to PM2.5 concentration of 20 µg/mL, reactive oxygen species (ROS) levels, parameters related to pyroptosis, and NF-κB signaling were measured by Western blotting, immunofluorescence, and ELISA (Enzyme-linked immunosorbent assay). Results: PM2.5 induced pyroptotic cell death, accompanied by LDH (Lactate dehydrogenase) release and increased uptake of propidium iodide in a dose-dependent manner. PM2.5 activated the NLRP3-casp1-gasdermin D pathway, with resulting secretions of the proinflammatory cytokines IL-1ß and IL-18. The pyroptosis activated by PM2.5 was alleviated significantly by NLRP3 inhibitor. In PM2.5-exposed BEAS-2B cells, levels of intracellular ROS and NF-κB p65 increased. ROS scavenger inhibited the expression of the NLRP3 inflammasome, and the NF-κB inhibitor attenuated pyroptotic cell death triggered by PM2.5 exposure, indicating that the ROS/NF-κB pathway is involved in PM2.5-induced pyroptosis. Conclusions: These findings show that PM2.5 exposure can cause cell injury by NLRP3-inflammasome-mediated pyroptosis by upregulating the ROS/NF-κB pathway in airway epithelium.

Long-Term Health Effects of Work Trajectories Among Middle-Aged and Older Adults: The Mediating Role of Work, Material, and Social Environments.

Using data from 14 waves (2003-2016) of the Korean Labor and Income Panel Study (KLIPS) (N = 1,627 individuals aged 45-64; 22778 observations), in this study, we conducted sequence analysis and a multi-categorical variable mediation analysis (1) to examine to what extent long-term work histories exhibit varying degrees of de-standardization and precariousness using sequence analysis (2) to explore the potential mediating effects of work, material, and social environments in the association between multiple work sequences and self-rated health. We found the coexistence of a relatively stable long-term employment pattern and a high prevalence of precariousness. The health and economic risks of precarious work fall disproportionately on older workers. Future researchers should continue to analyze whether the COVID-19 pandemic will lead to long-term changes in the workforce to improve our understanding of and response to working in later life and its health effects.

Diabetes severity is strongly associated with the risk of active tuberculosis in people with type 2 diabetes: a nationwide cohort study with a 6-year follow-up.

BACKGROUND: Many have the rising coincidence of diabetes mellitus (DM) and endemic tuberculosis (TB). We evaluated whether the severity of diabetes is associated with an increased risk of active TB infection. METHODS:  Using a nationally representative database from the Korean National Health Insurance System, 2, 489, 718 people with type 2 DM who underwent a regular health checkup during 2009-2012 were followed up until the end of 2018. The diabetes severity score parameters included the number of oral hypoglycemic agents (≥ 3), insulin use, diabetes duration (≥ 5 years), and the presence of chronic kidney disease (CKD) or cardiovascular disease. Each of these characteristics was scored as one point, and their sum (0-5) was used as the diabetes severity score. RESULTS: We identified 21, 231 cases of active TB during a median follow-up of 6.8 years. Each parameter of the diabetes severity score was associated with an increased risk of active TB (all P < 0.001). Insulin use was the most significant factor related to the risk of TB, followed by CKD. The risk of TB increased progressively with increasing diabetes severity score. After adjusting for possible confounding factors, the hazard ratio (95% confidence interval) for TB were 1.23 (1.19-1.27) in participants with one parameter, 1.39 (1.33-1.44) in those with two parameters, 1.65 (1.56-1.73) in those with three parameters, 2.05 (1.88-2.23) in those with four parameters, and 2.62 (2.10-3.27) in those with five parameters compared with participants with no parameters. CONCLUSION: Diabetes severity was strongly associated in a dose-dependent manner with the occurrence of active TB. People with a higher diabetes severity score may be a targeted group for active TB screening.

Systematic Multiomic Analysis of PKHD1L1 Gene Expression and Its Role as a Predicting Biomarker for Immune Cell Infiltration in Skin Cutaneous Melanoma and Lung Adenocarcinoma.

The identification of genetic factors that regulate the cancer immune microenvironment is important for understanding the mechanism of tumor progression and establishing an effective treatment strategy. Polycystic kidney and hepatic disease 1-like protein 1 (PKHD1L1) is a large transmembrane protein that is highly expressed in immune cells; however, its association with tumor progression remains unclear. Here, we systematically analyzed the clinical relevance of PKHD1L1 in the tumor microenvironment in multiple cancer types using various bioinformatic tools. We found that the PKHD1L1 mRNA expression levels were significantly lower in skin cutaneous melanoma (SKCM) and lung adenocarcinoma (LUAD) than in normal tissues. The decreased expression of PKHD1L1 was significantly associated with unfavorable overall survival (OS) in SKCM and LUAD. Additionally, PKHD1L1 expression was positively correlated with the levels of infiltrating B cells, cluster of differentiation (CD)-8+ T cells, and natural killer (NK) cells, suggesting that the infiltration of immune cells could be associated with a good prognosis due to increased PKHD1L1 expression. Gene ontology (GO) analysis also revealed the relationship between PKHD1L1-co-altered genes and the activation of lymphocytes, including B and T cells. Collectively, this study shows that PKHD1L1 expression is positively correlated with a good prognosis via the induction of immune infiltration, suggesting that PKHD1L1 has potential prognostic value in SKCM and LUAD.

Early Bactericidal Activity of Delpazolid (LCB01-0371) in Patients with Pulmonary Tuberculosis.

Delpazolid, an oxazolidinone, has been studied in non-clinical studies of efficacy and toxicity and Phase 1 clinical studies. Delpazolid has in vitro activity against Gram-positive bacteria, including Mycobacterium tuberculosis. This study evaluated the bactericidal activity, safety, and pharmacokinetics of delpazolid in patients with pulmonary tuberculosis (TB). Seventy-nine subjects, aged 19 to 75 years with newly diagnosed smear-positive TB with no prior treatment for the current episode and no confirmed resistance to rifampin or isoniazid, were randomized to receive delpazolid 800 mg once a day (QD), 400 mg twice a day (BID), 800 mg BID or 1,200 mg QD or an active control of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) or linezolid 600 mg BID. The primary endpoint was the average daily reduction in log transformed bacterial load, assessed on 7H11 solid-media culture, from days 0 to 14. The average daily decline in log-CFU was 0.044 ± 0.016, 0.053 ± 0.017, 0.043 ± 0.016, and 0.019 ± 0.017, for the delpazolid 800 mg QD, 400 mg BID, 800 mg BID, and the 1,200 mg QD groups, respectively. The average daily decline in log-CFU was 0.192 ± 0.028 for the HRZE group and 0.154 ± 0.023 for the linezolid 600 mg BID group. Three serious adverse events (SAE) were reported, one each in the delpazolid 400 mg BID group (death due to worsening of TB at day 2), the HRZE group (hospitalization due to pleural effusion) and the linezolid group (hyperkalemia); none of the SAEs were assessed as related to study drugs. This study has been registered at ClinicalTrials.gov with registration number NCT02836483.

Small extracellular vesicles derived from patients with persistent atrial fibrillation exacerbate arrhythmogenesis via miR-30a-5p.

Small extracellular vesicles (sEVs) are nanometer-sized membranous vesicles that contribute to the pathogenesis of atrial fibrillation (AF). Here, we investigated the role of sEVs derived from patients with persistent AF in the pathophysiology of AF. First, we evaluated the pathological effects of sEVs derived from the peripheral blood of patients with persistent AF (AF-sEVs). AF-sEVs treatment reduced cell viability, caused abnormal Ca2+ handling, induced reactive oxygen species (ROS) production and led to increased CaMKII activation of non-paced and paced atrial cardiomyocytes. Next, we analyzed the miRNA profile of AF-sEVs to investigate which components of AF-sEVs promote arrhythmias, and we selected six miRNAs that correlated with CaMKII activation. qRT-PCR experiment identified that miR-30a-5p was significantly down-regulated in AF-sEVs, paced cardiomyocytes, and atrial tissues of patients with persistent AF. CaMKII was predicted by bioinformatics analysis as a miR-30a-5p target gene and validated by a dual luciferase reporter; hence, we evaluated the effects of miR-30a-5p on paced cardiomyocytes and validated miR-30a-5p as a pro-arrhythmic signature of AF-sEVs. Consequently, AF-sEVs-loaded with miR-30a-5p attenuated pacing-induced Ca2+-handling abnormalities, whereas AF-sEVs-loaded with anti-miR-30a-5p reversed the change in paced cardiomyocytes. Taken together, the regulation of CaMKII by miR-30a-5p revealed that miR-30a-5p is a major mediator for AF-sEVs-mediated AF pathogenesis. Accordingly, these findings suggest that sEVs derived from patients with persistent AF exacerbate arrhythmogenesis via miR-30a-5p.

Platycodin D attenuates airway inflammation via suppression Th2 transcription factor in a murine model of acute asthma.

Introduction: Bronchial asthma is a common chronic inflammatory condition of the airway tissue. Platycodin D (PLD) has antiinflammatory effects in a mouse model of allergic asthma. In this work, the anti-asthma potential of PLD was studied by investigation of its effect to suppress airway inflammation and mucin production, a murine model of asthma and the possible mechanisms.Methods: Mice were randomly assigned to five experimental groups: control, ovalbumin (OVA), OVA+ICS (intranasal fluticasone), OVA+PLD and OVA+PLD/ICS. Airway histological studies were evaluated by the H&E staining; IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid were evaluated by ELISA; GATA3 and IRF4 mRNA of airway were measured by RT-PCR and their protein level were measured by Western blotting.Results: Our study showed that PLD suppressed eosinophilic inflammation and mucin production in bronchial mucosa. Moreover, PLD inhibited production of Th2 cytokines such as IL-4, IL-5, and IL-13. Protein production of GATA3 and IRF4, were also decreased in PLD treated OVA asthma model. Taken together, our results provided evidence that PLD inhibits the airway inflammation via suppression of Th2 transcription factor production.Conclusion: These findings suggest that PLD may effectively ameliorate the progression of asthma. These results suggest that PLD could be used as a therapy for allergic asthma.

Association of Underlying Comorbidities and Sites of tuberculosis: an analysis using surveillance data.

BACKGROUND: Tuberculosis (TB) is a highly heterogeneous disease that can affect any organ. Extrapulmonary TB (EPTB) is more difficult to diagnose due to various clinical presentations. Depending on the characteristics of the patient, the involved site of TB may vary. However, data on clinical characteristics of EPTB are inconsistent and insufficient. This study aimed to identify the characteristics of patients with pulmonary TB (PTB) and EPTB and describe characteristic differences for each involved site. METHODS: We systemically collected data of TB patients included in the national surveillance system in South Korea from July 2018 to June 2019 and compared the characteristics of patients with EPTB with that of PTB. RESULTS: A total of 7674 patients with a mean age of 60.9 years were included. Among them, 6038 (78.7%) patients were diagnosed with PTB and 1636 (21.3%) with EPTB. In PTB group, the mean age (61.7 ± 18.7 vs. 57.8 ± 19.9) and proportion of male sex (63.3% vs. 50.1%) were higher, but the body mass index was lower (21.2 ± 3.4 vs. 22.7 ± 3.5) than that of the EPTB group. Prevalence of diabetes (20.5% vs. 16.9%) and chronic lung disease (5.1% vs. 2.9%) were higher in PTB group, meanwhile, those of chronic kidney disease (CKD) (2.7% vs. 5.4%) and long-term steroid use (0.4% vs. 1.0%) were higher in EPTB group. Abdominal TB was more prevalent in patients with chronic liver disease (odds ratio [OR]: 2.69, 95% CI: 1.52-4.74), and urogenital TB was more prevalent in patients with CKD (OR: 2.75, 95% CI: 1.08-6.99). CONCLUSIONS: We found that underlying comorbidities were closely associated with the location of TB development, and therefore, the possibility of EPTB should be carefully evaluated while monitoring for underlying disease in TB-endemic areas.

Increased Healthcare Delays in Tuberculosis Patients During the First Wave of COVID-19 Pandemic in Korea: A Nationwide Cross-Sectional Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused disruptions to healthcare systems, consequently endangering tuberculosis (TB) control. We investigated delays in TB treatment among notified patients during the first wave of the COVID-19 pandemic in Korea. METHODS: We systemically collected and analyzed data from the Korea TB cohort database from January to May 2020. Groups were categorized as 'before-pandemic' and 'during-pandemic' based on TB notification period. Presentation delay was defined as the period between initial onset of symptoms and the first hospital visit, and healthcare delay as the period between the first hospital visit and anti-TB treatment initiation. A multivariate logistic regression analysis was performed to evaluate factors associated with delays in TB treatment. RESULTS: Proportion of presentation delay > 14 days was not significantly different between two groups (48.3% vs. 43.7%, P = 0.067); however, proportion of healthcare delay > 5 days was significantly higher in the during-pandemic group (48.6% vs. 42.3%, P = 0.012). In multivariate analysis, the during-pandemic group was significantly associated with healthcare delay > 5 days (adjusted odds ratio = 0.884, 95% confidence interval = 0.715-1.094). CONCLUSION: The COVID-19 pandemic was associated with healthcare delay of > 5 days in Korea. Public health interventions are necessary to minimize the pandemic's impact on the national TB control project.

Latent Tuberculosis Cascade of Care Among Healthcare Workers: A Nationwide Cohort Analysis in Korea Between 2017 and 2018.

BACKGROUND: In 2017, Korea implemented nationwide latent tuberculosis infection (LTBI) project targeting healthcare workers (HCWs). We aimed to assess its performance using the cascade of care model. METHODS: We included 45,503 employees of medical institutions with positive interferon-gamma release assay result who participated between March 2017 and December 2018. We described percentages of LTBI participants completing each step in the cascade of care. Poisson regression model was conducted to assess individual characteristics and factors associated with not-visiting clinics for further care, not-initiating LTBI treatment, and not-completing treatment. RESULTS: Proportions of visiting clinics and initiating and completing treatment in HCWs were 54.9%, 38.5%, and 32.0%, respectively. Despite of less likelihood of visiting clinics and initiating LTBI treatment, older age ≥ 65 years were more likely to complete treatment (adjusted relative risk [aRR], 0.80; 95% confidence interval [CI], 0.64-0.99), compared to young age < 35 years. Compared to nurses, doctors were less likely to visit clinic; however, were more likely to initiate treatment (aRR, 0.88; 95% CI, 0.81-0.96). Those who visited public health centers were associated with not-initiating treatment (aRR, 1.34; 95% CI, 1.29-1.40). When treated at private hospitals, 9-month isoniazid monotherapy was less likely to complete treatment, compared to 3-month isoniazid and rifampicin combination therapy (aRR, 1.33; 95% CI, 1.16-1.53). CONCLUSION: Among employees of medical institutions with LTBI, only one third completed treatment. Age, occupation, treatment center, and initial regimen were significantly related to LTBI treatment performance indicators. Rifampicin-based short treatment regimens were effective under standard of care.

Marivivens aquimaris sp. nov., isolated from seawater.

A Gram-stain-negative, strictly aerobic, non-flagellated, rod-shaped bacterium, designated GSB7T, was isolated from seawater collected at the Yellow Sea coast of South Korea. Catalase and oxidase activities were positive. Growth occurred at pH 6.0-9.0 (optimum pH 7.0), 10-40 °C (optimum 30 °C) and with 0-8% NaCl (optimum 1-2%). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain GSB7T belonged to the genus Marivivens, showing the sequence similarities of 96.3, 96.1, and 96.0% with Marivivens niveibacter HSLHS2T, Limimaricola hongkongensis DSM17492T, and Marivivens donghaensis AM-4T, respectively. The respiratory quinone was ubiquinone-10 and the major fatty acids were summed feature 8 (C18:1 ω7c and/or C18:1 ω6c), C18:1 ω7c 11-methyl, C16:0 and C10:0 3-OH. The polar lipids comprised phosphatidylglycerol, diphosphatidylglycerol, one unidentified aminolipid, and five unidentified lipids. The DNA G + C content calculated from the whole-genome sequence was 60.6 mol%. On the basis of phenotypic, chemotaxonomic and genotypic characteristics presented in this study, strain GSB7T is suggested to represent a novel species of the genus Marivivens, for which the name Marivivens aquimaris sp. nov. is proposed. The type strain is GSB7T (= KCTC 82026T = JCM 34042T).

Glucagon-like peptide 1 receptor (GLP-1R) agonist relieved asthmatic airway inflammation via suppression of NLRP3 inflammasome activation in obese asthma mice model.

BACKGROUND: Obesity is a correctable factor for uncontrolled bronchial asthma. However, the effects of glucagon-like peptide-1 receptor (GLP-1R) agonist, a recently approved antiobestic drug, on airway hyperresponsiveness (AHR) and immune responses are not known. METHODS: Mice were fed with high-fat diet (HFD, 60% fat) for 8 weeks to induce obesity. Ovalbumin (OVA) sensitization and challenges were performed for 7 weeks. The mice were injected intraperitoneally with GLP-1R agonist 5 times a week for 4 weeks after OVA sensitization. After AHR measurement, expression of Th2, Th17 cytokines, and interleukin (IL)-33 were measured in BALF and lung tissues. Moreover, IL-1ß and activity level of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) were analyzed to investigate the mechanism of GLP-1R agonist on asthmatic airway inflammation. RESULTS: HFD induced significant weight gain, OVA sensitization and challenge in obese mice made eosinophilic airway inflammation, and increased AHR. Treatment with GLP-1R agonist-induced weight loss suppressed eosinophilic airway inflammation and decreased AHR. Expression of IL-4, 5, and 33 was increased in BALF of obese asthma mice followed by a decrease in response to GLP-1R agonist treatment. Moreover, lung tissue H&E stain revealed that peribronchial inflammation induced by obesity and OVA was effectively suppressed by GLP-1R agonist. Expressions of NLRP3, activated caspase-1, and IL-1ß were increased in lung tissues of obese asthma mice and demonstrated a decrease in response to GLP-1R agonist treatment. CONCLUSIONS: GLP-1R agonist effectively induced weight loss, suppressed eosinophilic bronchial airway inflammation, and AHR in obese asthma mice. These effects were mediated by suppression of NLRP3 inflammasome activity and IL-1ß. GLP-1R agonist is proposed as a novel anti-asthmatic agent targeting the obese asthmatics.

Latent Tuberculosis Infection Screening and Treatment in Congregate Settings (TB FREE COREA): Demographic Profiles of Interferon-Gamma Release Assay Cohort.

In 2017, the Korean government launched an unprecedentedly large-scaled latent tuberculosis infection (LTBI) screening project which covered more than a million individuals in congregate settings. A total of 1,047,689 participants of source population (n = 2,336,157) underwent LTBI testing from 2017 to 2018. The overall LTBI test uptake rate during this project was 44.8%. Workers in daycare centers (83.5%) and kindergartens (78.9%) showed high participation rate. A total of 1,012,206 individuals with valid results of interferon-gamma release assay (IGRA) were selected to constitute the IGRA cohort. Most of the enrolled participants in the IGRA cohort were in their working age. Approximately, three-quarters of total enrolled population were female. Investigating the LTBI prevalence, stages of LTBI care cascade, natural history of LTBI, efficacy of LTBI treatment and cost-effectiveness of LTBI screening are feasible within this IGRA cohort.

Types of multidimensional vulnerability and well-being among the retired in the U.S.

BACKGROUND: An extensive study investigated the risk factors for low well-being in post-retirement. Most previous studies have taken a unidimensional perspective, focusing on single factors such as financial status, physical health, and mental health. OBJECTIVE: Drawing on the vulnerability framework, we first identify and describe the empirical subgroups of vulnerability among retirees in the United States across four major domains of later life: material, physical, social, and mental vulnerability. Then, we investigate the association between vulnerability profiles and well-being. METHOD: The sample included 3,158 retirees aged 65+ who participated in the Health and Retirement Study (HRS). Latent class analysis was utilized to identify the heterogeneous subgroups of vulnerability, and then a series of OLS regression analyses was conducted to examine the relationship between patterns of vulnerability and well-being. RESULTS: Five vulnerability patterns were identified: material vulnerable (12%), health & social vulnerable (14%), material, health & social vulnerable (6%), least vulnerable (34%), and social vulnerable (35%). The health & social vulnerable group had the strongest negative influence on well-being among all subgroups. As the largest subgroup, the social vulnerable group's negative influence on well-being stood out, with a stronger effect than that of material privation experienced by those in the material vulnerable group. CONCLUSION: By empirically identifying subgroups of differential vulnerability patterns among retirees, this study showed that post-retirement vulnerability reflects complex interactions among multiple disadvantages. Findings of this study enhance understanding of the disparities in well-being within the retired population, pointing to the possibility of targeted policy and program development.

Effects of Chronic Low-Dose Internal Radiation on Immune-Stimulatory Responses in Mice.

The Linear-No-Threshold (LNT) model predicts a dose-dependent linear increase in cancer risk. This has been supported by biological and epidemiological studies at high-dose exposures. However, at low-doses (LDR ≤ 0.1 Gy), the effects are more elusive and demonstrate a deviation from linearity. In this study, the effects of LDR on the development and progression of mammary cancer in FVB/N-Tg(MMTVneu)202Mul/J mice were investigated. Animals were chronically exposed to total doses of 10, 100, and 2000 mGy via tritiated drinking water, and were assessed at 3.5, 6, and 8 months of age. Results indicated an increased proportion of NK cells in various organs of LDR exposed mice. LDR significantly influenced NK and T cell function and activation, despite diminishing cell proliferation. Notably, the expression of NKG2D receptor on NK cells was dramatically reduced at 3.5 months but was upregulated at later time-points, while the expression of NKG2D ligand followed the opposite trend, with an increase at 3.5 months and a decrease thereafter. No noticeable impact was observed on mammary cancer development, as measured by tumor load. Our results demonstrated that LDR significantly influenced the proportion, proliferation, activation, and function of immune cells. Importantly, to the best of our knowledge, this is the first report demonstrating that LDR modulates the cross-talk between the NKG2D receptor and its ligands.

Therapeutic potential of miR-21 regulation by human peripheral blood derived-small extracellular vesicles in myocardial infarction.

Small extracellular vesicles (sEVs) as natural membranous vesicles are on the frontiers of nanomedical research, due to their ability to deliver therapeutic molecules such as microRNAs (miRNAs). The miRNA-21 (miR-21) is thought to be involved in the initiation and development of myocardial infarction (MI). Here, we examined whether miR-21 regulation using human peripheral blood-derived sEVs (PB-sEVs) could serve as a potential therapeutic strategy for MI. First, we examined miR-21 levels in hypoxic conditions and validated the ability of PB-sEVs to serve as a potential delivery system for miRNAs. Further, bioinformatics analysis and luciferase assay were performed to identify target genes of miR-21 mechanistically. Among numerous target pathways, we focused on nitrogen metabolism, which remains relatively unexplored compared with other possible miR-21-mediated pathways; hence, we aimed to determine novel target genes of miR-21 related to nitrogen metabolism. In hypoxic conditions, the expression of miR-21 was significantly up-regulated and correlated with nitric oxide synthase 3 (NOS3) levels, which in turn influences cardiac function. The down-regulation of miR-21 expression by PB-sEVs loaded with anti-miR-21 significantly improved survival rates, consistent with the augmentation of cardiac function. However, the up-regulation of miR-21 expression by PB-sEVs loaded with miR-21 reversed these effects. Mechanistically, miR-21 targeted and down-regulated the mRNA and protein expression of striatin (STRN), which could regulate NOS3 expression. In conclusion, we identified a novel therapeutic strategy to improve cardiac function by regulating the expression of miR-21 with PB-sEVs as an miR-21 or anti-miR-21 delivery vehicle and confirmed the miR-21-associated nitrogen metabolic disorders in MI.

Expression of miRNAs in circulating exosomes derived from patients with persistent atrial fibrillation.

Atrial fibrillation (AF), the most common type of cardiac arrhythmia, is thought to be regulated by changes in microRNA (miRNA) expression. However, the evidence for this is inconsistent. The high stability and expression of circulating exosomal miRNAs may allow their use as candidate biomarkers. For the discovery phase, exosomes were isolated from the serum of patients with supraventricular tachycardia (SVT) as the controls (n = 5) and with paroxysmal AF (n = 4) and persistent AF (n = 5) for microarray analysis of miRNAs. Forty-five miRNAs were expressed significantly higher (>1.5-fold) in patients with persistent AF, but not in patients with paroxysmal AF, relative to the levels in patients with SVT control. Notably, expression of 5 miRNAs (miRNA-103a, -107, -320d, -486, and let-7b) was elevated by more than 4.5-fold in patients with persistent AF. For the validation phase, miRNAs were analyzed using quantitative RT-PCR analysis in exosomes from the serum of patients with SVT control (n = 20) and patients with persistent AF (n = 40). These miRNAs and their target genes were involved in atrial function and structure, oxidative stress, and fibrosis pathways. These findings suggest that serum exosomal miRNAs might be used as novel biomarkers to reflect the progression of AF.-Mun, D., Kim, H., Kang, J.-Y., Park, H., Park, H., Lee, S.-H., Yun, N., Joung, B. Expression of miRNAs in circulating exosomes derived from patients with persistent atrial fibrillation.

Age-stratified anti-tuberculosis drug resistance profiles in South Korea: a multicenter retrospective study.

BACKGROUND: The emergence of drug-resistant tuberculosis (DR-TB) is a major healthcare concern worldwide. Here, we analyzed age-related trends in DR-TB rates in South Korea. METHODS: Drug susceptibility test results were collected from patients with culture-confirmed TB between 2015 and 2018 from eight university-affiliated hospitals. Patients were divided into three subgroups: younger (15-34 years), middle (35-59 years), and older (≥60 years) to compare drug-resistance patterns. To evaluate trends in age-stratified drug-resistance, chi-square test for linear trends was performed. RESULTS: Among enrolled native patients aged ≥15 years, 4.1% (179/4417), 1.2% (53/4417) and 7.2% (316/4417) were multidrug-resistant TB (MDR-TB), rifampicin-mono-resistant TB (RR-TB), and isoniazid-mono-resistant TB (Hr-TB), respectively. Proportions of Hr-TB cases were 5.4% (40/734), 7.2% (114/1593), and 7.8% (162/2090) in the younger, middle and older age groups, respectively. MDR/RR-TB case rates decreased significantly with age from 8.6% (63/734) in younger age group to 3.3% (68/2090) in older age group. Fluoroquinolone resistance was highest among second-line drugs, and there were no differences in resistance to fluoroquinolones and second-line injectable drugs among the three age groups. CONCLUSIONS: The number of MDR/RR-TB cases was highest in young patients. Effective public health interventions should include increased focus on rifampicin resistance in young patients.

Effect of nintedanib on airway inflammation in a mouse model of acute asthma.

Objective: New treatments are needed for cases of asthma that are refractory to traditional therapies. In this study, we examined the effect of oral nintedanib, an intracellular inhibitor of tyrosine kinases, on airway hyper-responsiveness (AHR) and airway smooth muscle cells, using a mouse model of experimental asthma. Methods: Asthma was experimentally induced in mice via subcutaneous injection of ovalbumin (OVA). A group of saline-injected mice served as a control group. The OVA mice were then divided into four treatment groups according to the dose of nintedanib. AHR was examined via exposure to vaporized methacholine. Airway inflammation was assessed via bronchoalveolar lavage fluid (BALF) cell counts and Th2 cytokine concentrations. Results: Baseline levels of AHR and airway inflammation were higher in OVA mice than in the control group. Treatment with nintedanib lowered AHR, BALF cell counts and BALF cytokine levels in a dose-dependent fashion. The effect of nintedanib was comparable to that of dexamethasone. In particular, treatment with nintedanib lowered the expression of transforming growth factor-ß1 and inhibited the expression and phosphorylation of platelet-derived growth factor receptor-ß, vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, fibroblast growth factor receptor 2 (FGFR2), FGFR3, and extracellular signal-regulated kinase. Conclusions: Nintedanib lowered AHR and the expression of factors associated with airway inflammation and remodeling in a mouse model of experimental asthma. Our results suggest that nintedanib may be useful in the treatment of asthma.