The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis.

Osteoarthritis-the most common form of age-related degenerative whole-joint disease1-is primarily characterized by cartilage destruction, as well as by synovial inflammation, osteophyte formation and subchondral bone remodelling2,3. However, the molecular mechanisms that underlie the pathogenesis of osteoarthritis are largely unknown. Although osteoarthritis is currently considered to be associated with metabolic disorders, direct evidence for this is lacking, and the role of cholesterol metabolism in the pathogenesis of osteoarthritis has not been fully investigated4-6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes7,8. Here we show that the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. Osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1) and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, retinoic acid-related orphan receptor alpha (RORα) was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. These results indicate that osteoarthritis is a disease associated with metabolic disorders and suggest that targeting the CH25H-CYP7B1-RORα axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.

The Cereblon-AMPK (AMP-Activated Protein Kinase) Axis in Chondrocytes Regulates the Pathogenesis of Osteoarthritis.

OBJECTIVE: AMP-activated protein kinase (AMPK) dysregulation is implicated in osteoarthritis (OA), but the mechanisms underlying this dysregulation remain unclear. We investigated the role of cereblon, a substrate-recognition protein within the E3-ligase ubiquitin complex, in AMPK dysregulation and OA pathogenesis. METHODS: Cereblon expression was examined in human (n=5) and mouse (n=10) OA cartilage. The role of cereblon was investigated through its adenoviral overexpression (n=10) or knockout (KO, n=15) in destabilization of the medial meniscus (DMM)-operated mice. The therapeutic potentials of the chemical cereblon degrader, TD-165, and the AMPK activator, metformin, were assessed through intra-articular (IA) injection to mice (n=15). RESULTS: Immunostaining revealed that cereblon is upregulated in human and mouse OA cartilage. In DMM model mice, cartilage destruction was exacerbated by overexpression of cereblon in mouse joint tissues (OARSI grade; 1.11 [95% CI: 0.50 to 2.75]), but inhibited in global (-2.50 [95% CI: -3.00 to -1.17]) and chondrocyte-specific (-2.17 [95% CI: -3.14 to -1.06]) cereblon KO mice. The inhibitory effects were more pronounced in mice fed a high-fat diet compared to a regular diet. The degradation of cereblon through IA injection of TD-165 inhibited OA cartilage destruction (-2.47 [95% CI: -3.22 to -1.56]). Mechanistically, cereblon exerts its catabolic effects by negatively modulating AMPK activity within chondrocytes. Consistently, activation of AMPK by IA injection of metformin inhibited posttraumatic OA cartilage destruction (-1.20 ([95% CI: -1.89 to -0.45]). CONCLUSIONS: The cereblon-AMPK axis acts as a catabolic regulator of OA pathogenesis and seems to be a promising therapeutic target in animal models of OA.

Does it matter who harmed whom? A cross-cultural study of moral judgments about harm by and to insiders and outsiders.

This cross-cultural study compared judgments of moral wrongness for physical and emotional harm with varying combinations of in-group vs. out-group agents and victims across six countries: the United States of America (N = 937), the United Kingdom (N = 995), Romania (N = 782), Brazil (N = 856), South Korea (N = 1776), and China (N = 1008). Consistent with our hypothesis we found evidence of an insider agent effect, where moral violations committed by outsider agents are generally considered more morally wrong than the same violations done by insider agents. We also found support for an insider victim effect where moral violations that were committed against an insider victim generally were seen as more morally wrong than when the same violations were committed against an outsider, and this effect held across all countries. These findings provide evidence that the insider versus outsider status of agents and victims does affect moral judgments. However, the interactions of these identities with collectivism, psychological closeness, and type of harm (emotional or physical) are more complex than what is suggested by previous literature. Supplementary information: The online version contains supplementary material available at 10.1007/s12144-023-04986-3.

Association of Physical Activity With Risk of Liver Fibrosis, Sarcopenia, and Cardiovascular Disease in Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: International guidelines recommend physical activity for subjects with nonalcoholic fatty liver disease (NAFLD). This study investigated the association of physical activity with risk of liver fibrosis, sarcopenia, and cardiovascular disease (CVD) in NAFLD. METHODS: In this multicenter, retrospective study, 11,690 NAFLD subjects who underwent a health screening program and were assessed for physical activity (metabolic equivalent task [MET]-min/week) between 2014 and 2020 were recruited. Liver fibrosis was assessed by using the fibrosis-4 index, NAFLD fibrosis score, and FibroScan-AST score, sarcopenia by using multi-frequency bioelectric impedance analysis, and CVD risk by using atherosclerotic CVD (ASCVD) risk score, and coronary artery calcium (CAC) score were calculated. RESULTS: The prevalence of fibrosis, sarcopenia, high probability of ASCVD, and high CAC score significantly decreased with increasing quartiles of physical activity (all P for trend <.001). In a fully adjusted model, physical activity above 600 MET-min/week (≥third quartile) was independently associated with a reduced risk of fibrosis (adjusted odds ratio [aOR] = 0.59; 95% confidence interval [CI], 0.40-0.86), sarcopenia (aOR = 0.72; 95% CI, 0.58-0.88), high probability of ASCVD (aOR = 0.58; 95% CI, 0.46-0.73), and high CAC score (aOR = 0.32; 95% CI, 0.13-0.83; all P <.05). In addition, increasing amounts of physical activity were significantly associated with risk reduction between fibrosis, sarcopenia, and high probability of ASCVD (all P for trend <.001). In subjects with sarcopenic obesity or lean NAFLD, physical activity was also independently associated with reduced risk of fibrosis and high probability of ASCVD (all P <.05). CONCLUSIONS: Physical activity showed a protective effect against fibrosis, sarcopenia, and CVD in NAFLD.

Risk Stratification for Sarcopenic Obesity in Subjects With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The impact of the severity of sarcopenic obesity (SO) in nonalcoholic fatty liver disease (NAFLD) on the risk of significant liver fibrosis or cardiovascular disease (CVD) remains unclear. We aimed to identify high-risk subjects with SO for significant liver fibrosis or CVD among subjects with SO and NAFLD. METHODS: This multicenter, retrospective study involved 23,889 subjects with NAFLD who underwent a health screening program (2014-2020). Sarcopenia was defined based on gender-specific sarcopenia index cutoff using multi-frequency bioelectric impedance analysis. High-risk subjects with SO were defined as those with significant liver fibrosis by fibrosis-4 index >2.67 or atherosclerotic CVD risk score >20%. Multivariable logistic regression analysis for identifying high-risk subjects with SO was performed in a cross-sectional cohort with SO, and further validation was performed in a longitudinal cohort. RESULTS: SO prevalence was 5.4% (n = 1297 of 23,889). Older age (unstandardized beta [ß] = 3.23; P < .001), male (ß = 1.66; P = .027), sarcopenia index (ß = -6.25; P = .019), and metabolic syndrome (ß = 1.75; P < .001) were significant risk factors for high-risk SO. Based on a high-risk SO screening model, high-risk subjects with SO had significantly higher odds of significant liver fibrosis (training: adjusted odds ratio [aOR], 3.72; validation: aOR, 2.38) or CVD (training: aOR, 5.20; validation: aOR, 3.71) than subjects without SO (all P < .001). In subgroup analyses, the cumulative incidence of significant liver fibrosis or CVD development was significantly higher in high-risk subjects with SO than in low-risk subjects with SO in a longitudinal cohort considering all-cause mortality and liver transplantation as competing risks (sub-distribution hazard ratio, 5.37; P < .001). CONCLUSION: The high-risk screening model may enable the identification of high-risk subjects with SO with NAFLD.

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.

MAFLD Predicts the Risk of Cardiovascular Disease Better than NAFLD in Asymptomatic Subjects with Health Check-Ups.

BACKGROUND AND AIM: Metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to compensate for the conventional concept of nonalcoholic fatty liver disease (NAFLD). We investigated the superiority of MAFLD versus NAFLD in predicting the risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: A total of 2,144 subjects without a history of ASCVD, who underwent a comprehensive medical health check-up, were selected for the study. The associations between fatty liver status and coronary risk surrogates, such as coronary artery calcium score (CACS), coronary artery disease, quantitative stenosis grade, and 10-year ASCVD risk, were analyzed. RESULTS: MAFLD and NAFLD were identified in 995 (46.4%) and 891 (41.6%) subjects, respectively. Subjects with MAFLD or NAFLD were more likely to be male and had a significantly higher prevalence of central obesity, obesity, hypertension, diabetes, and dyslipidemia (all, p < 0.05) than their counterparts. In terms of coronary risk surrogates, the MAFLD or NAFLD population had a significantly higher proportion of subjects with CACS > 100, coronary artery disease, higher grade of coronary artery stenosis, and higher 10-year ASCVD risk (all, p < 0.05) than their counterparts. Multivariable logistic regression models showed an independent association between MAFLD/NAFLD and coronary risk surrogates (all, p < 0.05). However, NAFLD only, defined as 'NAFLD, but not MAFLD,' was not associated with an increased coronary risk, compared to MAFLD. CONCLUSIONS: Although both MAFLD and NAFLD discriminated different ASCVD risks, MAFLD predicted the risk of ASCVD better than NAFLD in asymptomatic subjects who underwent medical health check-ups.

High-Grade Endometrioid Stromal Sarcoma of the Ovary: Malignant Transformation of Ovarian Mature Cystic Teratoma.

We report an extremely rare case of ovarian high-grade endometrioid stromal sarcoma arising from a mature cystic teratoma with clinicopathologic features, and then we briefly review the pertinent literature. A 62-year-old nulliparous woman presented with lower abdominal pain that had begun 6 months earlier. Magnetic resonance imaging showed two adnexal masses with fat components, which suggested that they were mature cystic teratomas. The eccentric thick rim of the left mass showed irregular invasion of the uterus, which was suggestive of malignancy. Positron emission tomography/computed tomography demonstrated high fluorodeoxyglucose uptake in the corresponding area. The patient underwent debulking cytoreductive surgery. The diagnosis was of an International Federation of Obstetrics and Gynecology stage IIIC high-grade endometrioid stromal sarcoma arising from a mature cystic teratoma. After surgery, the patient received adjuvant chemotherapy with three courses of doxorubicin regimen. The cancer recurred 3 months after surgery, and the patient died of progressive disease. It might be helpful for clinicians to be aware of this rare disease and the poor prognosis when it is at an advanced stage.

Influence of preprocedural glycemic control on clinical outcomes of endovascular therapy in diabetic patients with lower extremity artery disease: an analysis from a Korean multicenter retrospective registry cohort.

BACKGROUND: The influence of intensive glucose control in diabetic patients on the macrovascular outcomes is controversial. Thus, this study aimed to elucidate the effect of preprocedural hemoglobin A1c (HbA1c) on clinical outcomes after endovascular therapy for lower extremity artery disease (LEAD) in diabetic patients. METHODS: Diabetic patients were enrolled from the retrospective cohorts of a Korean multicenter endovascular therapy registry and were divided according to the HbA1c level during index admission into the optimal (< 7.0%) or suboptimal (≥ 7.0%) glycemic control groups. The primary endpoints were major adverse limb events (MALE, a composite of major amputation, minor amputation, and reintervention). RESULTS: Of the 1103 patients enrolled (897 men, mean age 68.2 ± 8.9 years), 432 (39.2%) were classified into the optimal glycemic control group and 671 (60.8%) into the suboptimal glycemic control group. In-hospital events and immediate procedural complications were not different between the two groups. The suboptimal group showed a trend towards a higher incidence of MALE than the optimal group (log-rank p = 0.072). Although no significant differences were found between the two groups in terms of overall survival or amputation, the risk of reintervention was significantly higher in the suboptimal group (log-rank p = 0.048). In the multivariate Cox regression model, suboptimal glycemic control was one of the independent predictors for reintervention. When our data were analyzed according to the initial presentation, suboptimal preprocedural HbA1c significantly increased the incidence of MALE compared with optimal preprocedural HbA1c only in patients with intermittent claudication. CONCLUSION: In diabetic patients undergoing endovascular therapy for LEAD, suboptimal preprocedural HbA1c is associated with an increased risk of adverse limb events, especially in patients with intermittent claudication. Further prospective research will be required to validate the role of more intensive glycemic control on the reduction of adverse limb events in diabetic patients undergoing endovascular therapy for LEAD.

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.

Outcomes and Associated Factors of Discrepant Coronary and Carotid Atherosclerosis.

Some patients exhibit discrepancies in carotid and coronary artery atherosclerosis. This study aimed to define the characteristics and prognosis of these discrepant patients and determine the best strategy to detect pan-vascular atherosclerosis. A database of 5,022 consecutively registered patients who underwent both coronary angiography and carotid ultrasonography, along with clinical and blood laboratory tests, echocardiography, and pulse wave velocity (PWV), was analyzed. The development of cerebro-cardiovascular (CV) events during the follow-up period was also evaluated. A significant proportion of patients (n = 1,741, 35%) presented with a discrepancy between carotid artery plaque and coronary artery disease (CAD). In patients without carotid plaque, male sex (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.20-2.41; P = 0.003), older age (OR, 1.03; 95% CI, 1.01-1.04; P = 0.002), smoking history (OR, 1.58; 95% CI, 1.13-2.20; P = 0.008), lower high-density lipoprotein (HDL) -cholesterol level (OR, 0.97; 95% CI, 0.96-0.98; P < 0.001), and lower common carotid artery end-diastolic velocity (CCA-EDV) (OR, 0.97; 95% CI, 0.95-0.99; P = 0.005) were independently related to the presence of CAD. In patients without CAD, increased PWV was independently related to the presence of carotid plaque. In survival analysis, patients with isolated CAD had a higher probability of composite CV events; those with isolated carotid plaque had a higher probability of heart failure (HF) and mortality than their counterpart groups (P < 0.05). Even in patients without carotid artery plaque, careful coronary evaluation is needed in older or male patients with smoking history, lower HDL-cholesterol level, or lower CCA-EDV. Carotid plaque may be a potential risk factor for HF.

Changes in Bond Strength and Topography for Y-TZP Etched with Hydrofluoric Acid Depending on Concentration and Temperature Conditions.

Background and objectives: This study aimed to investigate the change in bond strength between resin cement and tetragonal zirconia polycrystalline stabilized with 3 to 8 mol% yttrium oxide (Y-TZP) and observe the topographical change of the Y-TZP surface when etched with hydrofluoric acid (HF) solution under different concentration and temperature conditions. Materials and Methods: Non-etched sintered Y-TZP specimens under two different temperature conditions (room temperature and 70-80 °C, respectively), were used as a control, while experimental groups were etched with 5%, 10%, 20%, and 40% HF solutions for 10 min. After zirconia primer and MDP-containing resin cement were applied to the Y-TZP surface, the shear bond strength (SBS) of each experimental group was measured. Results: Under room temperature conditions, the highest SBS value was measured in the 40% HF etching group, representing a significant deviation from the other groups (p < 0.05). In the 70-80 °C tests, the 40% HF etching group also had the highest SBS value, but there was no significant difference when compared to the 20% HF etching group (p > 0.05). From SEM and AFM observations, the HF solution increasingly dissolved the Y-TZP surface grain structure as the concentration and application temperature rose, resulting in high surface roughness and irregularities. Conclusions: Pretreating with either 20% HF solution at 70-80 °C or 40% HF solution at room temperature and 70-80 °C effectively acid etched the Y-TZP surface, resulting in more surface roughness and irregularities. Accounting for the concentration and temperature conditions of the HF solution, using 40% HF solution at room temperature will result in improvements in adhesion between resin cement and Y-TZP.

Critical role for arginase II in osteoarthritis pathogenesis.

OBJECTIVE: Osteoarthritis (OA) appears to be associated with various metabolic disorders, but the potential contribution of amino acid metabolism to OA pathogenesis has not been clearly elucidated. Here, we explored whether alterations in the amino acid metabolism of chondrocytes could regulate OA pathogenesis. METHODS: Expression profiles of amino acid metabolism-regulating genes in primary-culture passage 0 mouse chondrocytes were examined by microarray analysis, and selected genes were further characterised in mouse OA chondrocytes and OA cartilage of human and mouse models. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) or intra-articular (IA) injection of adenoviruses expressing catabolic regulators. The functional consequences of arginase II (Arg-II) were examined in Arg2-/- mice and those subjected to IA injection of an adenovirus encoding Arg-II (Ad-Arg-II). RESULTS: The gene encoding Arg-II, an arginine-metabolising enzyme, was specifically upregulated in chondrocytes under various pathological conditions and in OA cartilage from human patients with OA and various mouse models. Adenovirus-mediated overexpression of Arg-II in mouse joint tissues caused OA pathogenesis, whereas genetic ablation of Arg2 in mice (Arg2-/-) abolished all manifestations of DMM-induced OA. Mechanistically, Arg-II appears to cause OA cartilage destruction at least partly by upregulating the expression of matrix-degrading enzymes (matrix metalloproteinase 3 [MMP3] and MMP13) in chondrocytes via the nuclear factor (NF)-κB pathway. CONCLUSIONS: Our results indicate that Arg-II is a crucial regulator of OA pathogenesis in mice. Although chondrocytes of human and mouse do not identically, but similarly, respond to Arg-II, our results suggest that Arg-II could be a therapeutic target of OA pathogenesis.

Cardiac-specific delivery by cardiac tissue-targeting peptide-expressing exosomes.

Naturally occurring RNA carriers such as exosomes might be an untapped source of effective delivery vehicles. However, if exosomes are to be exploited for therapeutic applications, they must target specific tissues or cell types to avoid off-target effects. This study evaluated whether genetic modification of exosomes could enhance exosome delivery to heart cells and heart tissue without toxicity. Exosomes expressing cardiac-targeting peptide (CTP)-Lamp2b on the exosomal membrane (CTP-Exo) were generated by introducing vectors encoding CTP-Lamp2b into HEK 293 cells. The expression of CTP-Lamp2b peptide on exosomes was stabilized by attaching glycosylation sequences. Exosomes expressing only Lamp2b on exosomal membranes (CTL-Exo) were generated as a control. The in vitro and in vivo uptake of CTL-Exo and CTP-Exo was evaluated in cell lines and mice. Both exosomes were delivered to HEK 293 and H9C2 cells. The delivery of the exosome was not different between CTP-Exo and CTL-Exo in HEK 293 cells, whereas the delivery of CTP-Exo was 16% greater than that of CTL-Exo in H9C2 cells (P = 0.047). Cell viability was maintained at almost 100% with different dosages of both CTL-Exo and CTP-Exo. Moreover, compared with CTL-Exo, the in vivo delivery of exosomes to the hearts of mice was increased by 15% with CTP-Exo (P = 0.035). The delivery to livers and spleens was not different between the two exosomes. Genetic modification of exosomes by expressing CTP-Lamp2b on the exosomal membrane enhanced exosome delivery to heart cells and the heart tissue. These results suggested that CTP-Exo might be used as a therapeutic tool for heart disease.

Educational inequality in female cancer mortality in Korea.

We evaluated the influence of socioeconomic factors on female cancer mortality using death data from the Cause of Death Statistics and the Korean Population and Housing Census databases collected in 2001, 2006, and 2011. We estimated Relative Index of Inequality (RII) of female cancer mortality using Poisson regression analysis. RII greater than 1 indicates increased mortality risk for women at the lowest educational level compared with women at the highest educational level. The RII for cervical cancer mortality was persistently greater than 1 for the entire study period, with a gradual increase over time. Subgroup analysis stratified by age (25-44 and 45-64 yr) revealed that younger women had increased RIIs of mortality due to cervical cancer and ovarian cancer during the entire study period. Older women had higher RII only for cervical cancer mortality, but the value was much lower than that for younger women. The RII for breast cancer mortality was greater than 1 for younger women since 2006. In conclusion, socioeconomic inequality in female cancer mortality has persisted for the last decade in Korea, which was most evident for cervical cancer, and for younger women.

Factors That Predict Persistent Smoking of Cancer Survivors.

We conducted this cross-sectional study to elucidate factors that predict persistent smoking of the Korean cancer survivors. The subjects were 130 adult (≥19 yr old) cancer survivors who were smokers at the diagnosis of cancer and have participated in the Korean National Health and Nutrition Examination Surveys conducted from 2007 to 2011. We categorized them into the persistent smokers and the quitters, according to change in smoking status between the time of cancer diagnosis and the time of the survey. Factors associated with persistent smoking were evaluated using the multiple logistic regression analysis. During 7.52 yr (standard deviation = 0.34) after the cancer diagnosis, 59.6% of the 130 cancer survivors have continued to smoke. After adjusting for covariates, following factors were independently associated with the risk of persistent smoking: female, low income, high-risk alcohol use, high body mass index (≥ 25 kg/m(2)), presence of household members who smoke, and longer duration of smoking. Alcohol Use Disorders Identification Test showed a positive association with the risk of persistent smoking (P for trend = 0.012). In conclusion, more efforts for smoking cessation should be in place for the cancer survivors with those risk factors associated with the persistent smoking.

Lack of Association between Insufficient Intake of Multiple Vitamins and Frailty in Older Adults Who Consume Sufficient Energy and Protein: A Nationwide Cross-Sectional Study.

Frailty is a complex condition that intensifies with age and is marked by decreased physiological function. We rigorously investigated the effects of lower vitamin intake on frailty using data from 665 adults aged over 65 years who consumed sufficient recommended daily energy and protein intakes from the Korean Nutrition and Health Survey, 2016-2019. The definition of frailty was modified based on Fried et al.'s definition of weight loss, exhaustion, weakness, slowness, and low energy expenditure. Based on daily intake, we analyzed vitamins such as vitamin A, thiamine, riboflavin, niacin, folic acid, and vitamin C. Our results of logistic regression showed that increasing multiple deficiencies in several kinds of vitamins (mild to moderate to severe) is not associated with frailty (odds ratio: 1, 1.24 (0.24-3.10), 0.82 (0.28-2.39), p for trend = 0.626) in older adults who consumed sufficient calories and proteins. A subgroup analysis of age and sex, which may interfere with the relationship between vitamin intake and frailty, showed that vitamin intake was not associated with frailty when sufficient energy and proteins were consumed. Furthermore, there was no difference in the prevalence of frailty between the groups with sufficient and insufficient intakes of individual vitamins.

Small extracellular vesicle-mediated CRISPR-Cas9 RNP delivery for cardiac-specific genome editing.

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Although clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) gene editing holds immense potential for genetic manipulation, its clinical application is hindered by the absence of an efficient heart-targeted drug delivery system. Herein, we developed CRISPR-Cas9 ribonucleoprotein (RNP)-loaded extracellular vesicles (EVs) conjugated with cardiac-targeting peptide (T) for precise cardiac-specific genome editing. RNP complexes containing Cas9 and single guide RNA targeting miR-34a, an MI-associated molecular target, were loaded into EVs (EV@RNP). Gene editing by EV@RNP attenuated hydrogen peroxide-induced apoptosis in cardiomyocytes via miR-34a inhibition, evidenced by increased B-cell lymphoma 2 levels, decreased Bcl-2-associated X protein levels, and the cleavage of caspase-3. Additionally, to improve cardiac targeting in vivo, we used click chemistry to form functional T-EV@RNP by conjugating T peptides to EV@RNP. Consequently, T-EV@RNP-mediated miR-34a genome editing might exert a protective effect against MI, reducing apoptosis, ameliorating MI injury, and facilitating the recovery of cardiac function. In conclusion, the genome editing delivery system established by loading CRISPR/Cas9 RNP with cardiac-targeting EVs is a powerful approach for precise and tissue-specific gene therapy for cardiovascular disease.

Variability in the serial interval of COVID-19 in South Korea: a comprehensive analysis of age and regional influences.

Introduction: Quantifying the transmissibility over time, particularly by region and age, using parameters such as serial interval and time-varying reproduction number, helps in formulating targeted interventions. Moreover, considering the impact of geographical factors on transmission provides valuable insights into the effectiveness of control measures. Methods: Drawing on a comprehensive dataset of COVID-19 cases in South Korea, we analyzed transmission dynamics with a focus on age and regional variations. The dataset, compiled through the efforts of dedicated epidemiologists, includes information on symptom onset dates, enabling detailed investigations. The pandemic was divided into distinct phases, aligning with changes in policies, emergence of variants, and vaccination efforts. We analyzed various interventions such as social distancing, vaccination rates, school closures, and population density. Key parameters like serial interval, heatmaps, and time-varying reproduction numbers were used to quantify age and region-specific transmission trends. Results: Analysis of transmission pairs within age groups highlighted the significant impact of school closure policies on the spread among individuals aged 0-19. This analysis also shed light on transmission dynamics within familial and educational settings. Changes in confirmed cases over time revealed a decrease in spread among individuals aged 65 and older, attributed to higher vaccination rates. Conversely, densely populated metropolitan areas experienced an increase in confirmed cases. Examination of time-varying reproduction numbers by region uncovered heterogeneity in transmission patterns, with regions implementing strict social distancing measures showing both increased confirmed cases and delayed spread, indicating the effectiveness of these policies. Discussion: Our findings underscore the importance of evaluating and tailoring epidemic control policies based on key COVID-19 parameters. The analysis of social distancing measures, school closures, and vaccine impact provides valuable insights into controlling transmission. By quantifying the impact of these interventions on different age groups and regions, we contribute to the ongoing efforts to combat the COVID-19 pandemic effectively.