Role of SYT11 in human pan-cancer using comprehensive approaches.

BACKGROUND: Synaptotagmin 11 (SYT11) plays a pivotal role in neuronal vesicular trafficking and exocytosis. However, no independent prognostic studies have focused on various cancers. In this study, we aimed to summarize the clinical significance and molecular landscape of SYT11 in various tumor types. METHODS: Using several available public databases, we investigated abnormal SYT11 expression in different tumor types and its potential clinical association with prognosis, methylation profiling, immune infiltration, gene enrichment analysis, and protein-protein interaction analysis, and identified common pathways. RESULTS: TCGA and Genotype-Tissue Expression (GTEx) showed that SYT11 was widely expressed across tumor and corresponding normal tissues. Survival analysis showed that SYT11 expression correlated with the prognosis of seven cancer types. Additionally, SYT11 mRNA expression was not affected by promoter methylation, but regulated by certain miRNAs and associated with cancer patient prognosis. In vitro experiments further verified a negative correlation between the expression of SYT11 and miR-19a-3p in human colorectal, lung, and renal cancer cell lines. Moreover, aberrant SYT11 expression was significantly associated with immune infiltration. Pathway enrichment analysis revealed that the biological and molecular processes of SYT11 were related to clathrin-mediated endocytosis, Rho GTPase signaling, and cell motility-related functions. CONCLUSIONS: Our results provide a clear understanding of the role of SYT11 in various cancer types and suggest that SYT11 may be of prognostic and clinical significance.

Elevated level of PLRG1 is critical for the proliferation and maintenance of genome stability of tumor cells.

Pleiotropic regulator 1 (PLRG1), a highly conserved element in the spliceosome, can form a NineTeen Complex (NTC) with Prp19, SPF27, and CDC5L. This complex plays crucial roles in both pre-mRNA splicing and DNA repair processes. Here, we provide evidence that PLRG1 has a multifaceted impact on cancer cell proliferation. Comparing its expression levels in cancer and normal cells, we observed that PLRG1 was upregulated in various tumor tissues and cell lines. Knockdown of PLRG1 resulted in tumor-specific cell death. Depletion of PLRG1 had notable effects, including mitotic arrest, microtubule instability, endoplasmic reticulum (ER) stress, and accumulation of autophagy, ultimately culminating in apoptosis. Our results also demonstrated that PLRG1 downregulation contributed to DNA damage in cancer cells, which we confirmed through experimental validation as DNA repair impairment. Interestingly, when PLRG1 was decreased in normal cells, it induced G1 arrest as a self-protective mechanism, distinguishing it from effects observed in cancer cells. These results highlight multifaceted impacts of PLRG1 in cancer and underscore its potential as a novel anti-cancer strategy by selectively targeting cancer cells. [BMB Reports 2023; 56(11): 612-617].

Prevalence, Trend, and Risk Factors for Early Chronic Obstructive Pulmonary Disease: An Analysis of the Nationwide Population-Based Survey from 2010 to 2019 in South Korea.

This study aimed to evaluate the prevalence, trends, and risk factors of early chronic obstructive pulmonary disease (COPD) by using a nationally representative sample. The datasets of the Korea National Health and Nutrition Examination Survey 2010-2019 were used, where 80,860 individuals were identified; of these, 9,045 participants aged 40-49 years who underwent spirometry with no missing data were analyzed. Early COPD was defined as forced expiratory volume in 1 s /forced vital capacity ratio < the lower limit of normal (2.5th percentile) in individuals aged <50 years without a history of asthma, inhaler therapy, or persistent respiratory symptoms. The prevalence and trend of early COPD were estimated according to features such as smoking status and pack-years. Joinpoint regression analysis was used to analyze the significant annual change in the trend according to sex, smoking status, and pack-years. A complex sample multivariable-adjusted regression model was used to identify factors affecting early COPD. The estimated population size during 2010-2019 was 82,326,178. Early COPD was present in 4.5% of patients (6.5% of men and 2.3% of women). It was present in 7.7% of current smokers, followed by former and never smokers. Among smokers with ≥ 10 pack-years, early COPD was present in 8.2%, whereas it was present in 2.6% of smokers with < 10 pack-years. Joinpoint regression analyses found a recent decrease in the trend of prevalence in males who were former and current smokers. The multivariable-adjusted logistic regression model showed that being male, lower educational level, smoking status, and pack-years were factors that affected the presence of early COPD. Continued surveillance of this pre-disease condition is required, and further research are warrant.

Inhibiting peripheral and central MAO-B ameliorates joint inflammation and cognitive impairment in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation and the destruction of joints and systemic organs. RA is commonly accompanied by neuropsychiatric complications, such as cognitive impairment and depression. However, the role of monoamine oxidase (MAO) and its inhibitors in controlling neurotransmitters associated with these complications in RA have not been clearly identified. Here, we report that peripheral and central MAO-B are highly associated with joint inflammation and cognitive impairment in RA, respectively. Ribonucleic acid (RNA) sequencing and protein expression quantification were used to show that MAO-B and related molecules, such as gamma aminobutyric acid (GABA), were elevated in the inflamed synovium of RA patients. In primary cultured fibroblast-like synoviocytes in the RA synovium, MAO-B expression was significantly increased by tumor necrosis factor (TNF)-α-induced autophagy, which produces putrescine, the polyamine substrate for GABA synthesis. We also observed that MAO-B-mediated aberrant astrocytic production of GABA was augmented by interleukin (IL)-1ß and inhibited CA1-hippocampal pyramidal neurons, which are responsible for memory storage, in an animal model of RA. Moreover, a newly developed reversible inhibitor of MAO-B ameliorated joint inflammation by inhibiting cyclooxygenase (Cox)-2. Therefore, MAO-B can be an effective therapeutic target for joint inflammation and cognitive impairment in patients with RA.

Obstructive Sleep Apnea and Nonalcoholic Fatty Liver Disease in the General Population: A Cross-Sectional Study Using Nationally Representative Data.

(1) Background: To evaluate the association between obstructive sleep apnea (OSA) and nonalcoholic fatty liver disease (NAFLD) in the general population using a nationally representative sample from South Korea; (2) Methods: This study included 4275 adults aged ≥40 years who completed the snoring, tiredness, observed apnea, high blood pressure, body mass index (BMI), age, neck circumference, and gender (STOP-Bang) questionnaire. The risk of OSA was stratified into low, intermediate, and high grades according to the STOP-Bang score. The prevalence of NAFLD according to the STOP-Bang score was calculated, and the increasing trend was measured. A complex sample multivariable regression analysis with adjustments for possible confounding variables was used to calculate the odds ratio of NAFLD and advanced fibrosis. Subgroup analysis was conducted with stratification based on sex and obesity status; (3) Results: We identified 1021 adults with NAFLD and 3254 adults without NAFLD. The prevalence of NAFLD increased significantly with higher STOP-Bang scores in both men and women. Participants of both sexes with high STOP-Bang scores were more likely to have NAFLD. Compared to non-obese individuals, the risk of NAFLD according to the STOP-Bang score was more intense in obese individuals. With respect to hepatic steatosis, there was no significant association between advanced fibrosis and STOP-Bang score; (4) Conclusions: OSA, the risk of which was measured using the STOP-Bang model, was closely associated with NAFLD in both Korean men and women. Clinicians should consider screening for NAFLD in individuals with a high STOP-Bang score.

TNF-α Induces Mitophagy in Rheumatoid Arthritis Synovial Fibroblasts, and Mitophagy Inhibition Alleviates Synovitis in Collagen Antibody-Induced Arthritis.

Mitophagy is a selective form of autophagy that removes damaged mitochondria. Increasing evidence indicates that dysregulated mitophagy is implicated in numerous autoimmune diseases, but the role of mitophagy in rheumatoid arthritis (RA) has not yet been reported. The aim of the present study was to determine the roles of mitophagy in patient-derived RA synovial fibroblasts (RASFs) and in the collagen antibody-induced arthritis mouse model. We measured the mitophagy marker PTEN-induced putative kinase 1 (PINK1) in RASFs treated with tumor necrosis factor-α (TNF-α) using Western blotting and immunofluorescence. Arthritis was induced in PINK1-/- mice by intraperitoneal injection of an anti-type II collagen antibody cocktail and lipopolysaccharide. RA severity was assessed by histopathology. PINK1 expression and damaged mitochondria increased in TNF-α treated RASFs via increased intracellular levels of reactive oxygen species. PINK1 knockdown RASFs decreased cellular migration and invasion functions. In addition, PINK1-/- mice with arthritis exhibited markedly reduced swelling and inflammation relative to wild-type mice with arthritis. Taken together, these findings suggest that regulation of PINK1 expression in RA could represent a potential therapeutic and diagnostic target for RA.

Effects of Different Centrifugation Protocols on the Detection of EGFR Mutations in Plasma Cell-Free DNA.

OBJECTIVES: Various preanalytical factors, including the collection tube, storage conditions, and centrifugation, affect the detection results of plasma cell-free DNA (cfDNA). We compared the effect of different centrifugation protocols on the detection of EGFR mutations in cfDNA. METHODS: We analyzed 117 plasma specimens from 110 patients with non-small cell lung cancer using the cobas EGFR Mutation Test v2 (Roche Diagnostics). We compared the identified EGFR mutations and semiquantitative index values from the 1- and 2-step centrifugation groups and confirmed the clinical impact of differences in the results after further high-speed centrifugation. RESULTS: We detected EGFR mutations in 44 (37.6%) and 47 (40.2%) samples that were centrifuged once and twice, respectively; the 2 groups showed an 89.7% (105/117) concordance and a strong correlation in their semiquantitative index values (r = 0.929). Among the 12 inconsistent result pairs, 9 samples of 2-step centrifugation (75%) were consistent with the results of a recent tissue biopsy. CONCLUSIONS: Additional high-speed centrifugation has been shown to increase the sensitivity of EGFR mutation detection in a commercial in vitro diagnostic real-time polymerase chain reaction device and is an optimal preanalytical factor for detecting low-allele frequency gene mutations using low concentrations of cfDNA.

Enpp2 Expression by Dendritic Cells Is a Key Regulator in Migration.

Enpp2 is an enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which exhibits a wide variety of biological functions. Here, we examined the biological effects of Enpp2 on dendritic cells (DCs), which are specialized antigen-presenting cells (APCs) characterized by their ability to migrate into secondary lymphoid organs and activate naïve T-cells. DCs were generated from bone marrow progenitors obtained from C57BL/6 mice. Enpp2 levels in DCs were regulated using small interfering (si)RNA or recombinant Enpp2. Expression of Enpp2 in LPS-stimulated mature (m)DCs was high, however, knocking down Enpp2 inhibited mDC function. In addition, the migratory capacity of mDCs increased after treatment with rmEnpp2; this phenomenon was mediated via the RhoA-mediated signaling pathway. Enpp2-treated mDCs showed a markedly increased capacity to migrate to lymph nodes in vivo. These findings strongly suggest that Enpp2 is necessary for mDC migration capacity, thereby increasing our understanding of DC biology. We postulate that regulating Enpp2 improves DC migration to lymph nodes, thus improving the effectiveness of cancer vaccines based on DC.

Pancreatic cancer induces muscle wasting by promoting the release of pancreatic adenocarcinoma upregulated factor.

Cancer cachexia is a highly debilitating condition characterized by weight loss and muscle wasting that contributes significantly to the morbidity and mortality of pancreatic cancer. The factors that induce cachexia in pancreatic cancer are largely unknown. We previously showed that pancreatic adenocarcinoma upregulated factor (PAUF) secreted by pancreatic cancer cells is responsible for tumor growth and metastasis. Here, we analyzed the relation between pancreatic cancer-derived PAUF and cancer cachexia in mice and its clinical significance. Body weight loss and muscle weight loss were significantly higher in mice with Panc-1/PAUF tumors than in those with Panc-1/Mock tumors. Direct administration of rPAUF to muscle recapitulated tumor-induced atrophy, and a PAUF-neutralizing antibody abrogated tumor-induced muscle wasting in Panc-1/PAUF tumor-bearing mice. C2C12 myotubes treated with rPAUF exhibited rapid inactivation of Akt-Foxo3a signaling, resulting in Atrogin1/MAFbx upregulation, myosin heavy chain loss, and muscle atrophy. The neutrophil-to-lymphocyte ratio and body weight loss were significantly higher in pancreatic cancer patients with high PAUF expression than in those with low PAUF expression. Analysis of different pancreatic cancer datasets showed that PAUF expression was significantly higher in the pancreatic cancer group than in the nontumor group. Analysis of The Cancer Genome Atlas data found associations between high PAUF expression or a high DNA copy number and poor overall survival. Our data identified tumor-secreted circulating PAUF as a key factor of cachexia, causing muscle wasting in mice. Neutralizing PAUF may be a useful therapeutic strategy for the treatment of pancreatic cancer-induced cachexia.

RNA demethylation by FTO stabilizes the FOXJ1 mRNA for proper motile ciliogenesis.

Adenosine N6-methylation (m6A) is one of the most pervasive mRNA modifications, and yet the physiological significance of m6A removal (demethylation) remains elusive. Here, we report that the m6A demethylase FTO functions as a conserved regulator of motile ciliogenesis. Mechanistically, FTO demethylates and thereby stabilizes the mRNA that encodes the master ciliary transcription factor FOXJ1. Depletion of Fto in Xenopus laevis embryos caused widespread motile cilia defects, and Foxj1 was identified as one of the major phenocritical targets. In primary human airway epithelium, FTO depletion also led to FOXJ1 mRNA destabilization and a severe loss of ciliated cells with an increase of neighboring goblet cells. Consistently, Fto knockout mice showed strong asthma-like phenotypes upon allergen challenge, a result owing to defective ciliated cells in the airway epithelium. Altogether, our study reveals a conserved role of the FTO-FOXJ1 axis in embryonic and homeostatic motile ciliogenesis.

Association between electronic cigarette use and metabolic syndrome in the Korean general population: A nationwide population-based study.

OBJECTIVES: Although smoking is known to have a negative impact in patients with metabolic syndrome (MetS), only a few studies have examined the association between electronic cigarette (e-cig) use and MetS. METHODS: Among 22,948 participants in the 6th Korea National Health and Nutrition Examination Survey, 14,738 (13,459 [91.3%] never, 954 [6.5%] ever, and 325 [2.2%] current e-cig users) were selected. The relationship between e-cig exposure and MetS (based on the National Cholesterol Education Program Adult Treatment Panel [NCEP-ATP] III criteria) was evaluated using a multivariable logistic regression analysis. An unweighted analysis was performed to evaluate this association without a sampling weight. A subgroup analysis was performed among active smokers to compare dual users with never e-cig users. RESULTS: Among current e-cig users, 85.0% were dual users, 12.7% were former cigarette users, and 2.2% were only e-cig users. After adjustment for covariates, abdominal obesity and hypertriglyceridemia were significantly associated with current e-cig exposure (odds ratio [OR]: 1.88, 95% confidence interval [CI]: 1.41-2.50 and OR: 1.32, 95% CI: 1.00-1.74 respectively [compared with the never e-cig users group]). Compared with never e-cig users, current e-cig users showed an OR of 1.27 (95% CI: 0.96-1.70, Ptrend = 0.01) for MetS. In the unweighted analysis, the OR for MetS in current e-cig users was 1.40 (95% CI: 1.08-1.81, Ptrend <0.01). Compared with never e-cig users, dual users showed a higher OR for abdominal obesity (OR: 1.71, 95% CI: 1.25-2.34, Ptrend <0.001). CONCLUSIONS: Current e-cig exposure was associated with an increased risk of MetS. Dual use of e-cigs and cigarettes was associated with abdominal obesity. Further longitudinal studies and better assessment of e-cig use and type are needed to clarify this relationship.

Association of serum ferritin and lung function in tobacco-naïve postmenopausal women: Analysis of population-based nationally representative data.

INTRODUCTION: Ferritin regulates iron homeostasis, and is involved in the inflammation in the lung, especially in smokers; however, its associations on pulmonary function in nonsmokers remain unclear. OBJECTIVES: The present study aimed to evaluate the association between serum ferritin and lung function in a tobacco-naïve postmenopausal women. METHODS: In this study, 25 534 individuals were enrolled, among who 5338 tobacco-naïve individuals were identified; of those, 342 men and 2879 women (742 pre- and 2137 postmenopausal) with data of serum ferritin, lung function and covariates were included. To evaluate the association of ferritin and lung function, multivariable-adjusted linear regression analyses was used including the factors of predicted value of forced expiratory volume in 1 second (FEV1 %) and forced vital capacity (FVC%). Logistic regression analyses were used to measure the relationship between ferritin and restrictive and obstructive lung disease. RESULTS: In premenopausal women, FEV1 %/FVC was weakly but positively associated with serum ferritin, and after adjusting for covariates, the association was without statistical significance. No significant association between ferritin and obstructive lung disease was observed. In postmenopausal women, predicted FVC% was negatively associated with serum ferritin, and ferritin was dose-dependently related with risk for restrictive lung disease. The odds ratio for restrictive lung disease in postmenopausal women was 2.285 at T3 and 1.560 at T2 relative to that at T1. CONCLUSIONS: High serum ferritin level was significantly associated with lower FVC% and increased risk of restrictive lung disease in tobacco-naïve postmenopausal women. Further study is needed to determine the mechanism underlying the current findings.

Polyunsaturated fatty acids, lung function, and health-related quality of life in patients with chronic obstructive pulmonary disease.

BACKGROUND: Dietary polyunsaturated fatty acids (PUFA) are thought to modify systemic inflammation. The present study aimed to evaluate the relationship between PUFA intake, lung function, and health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD). METHODS: In this study, we used the dataset of 6th Korea National Health and Nutrition Examination Survey, in which, a total of 22,948 individuals including 573 participants with a high probability of developing COPD were enrolled. Participants with missing data for the investigated variables were excluded. Linear regression analyses were used to evaluate the association between PUFA intake (omega-3 [N3], omega-6 [N6], and total) with lung function, and HRQoL. HRQoL was determined according to the European Quality of Life-5 Dimensions (EQ-5D). Subgroup analysis of older patients was performed. Age, sex, body mass index, smoking, alcohol, education, residence, total calorie intake, and predicted FEV1% were adjusted in all analyses. RESULTS: Although lung function was not associated with PUFA intake, EQ-5D index was remarkably associated with N3, N6, and total PUFA intake in a dose-dependent manner. This association was more pronounced in elderly COPD patients. Mean levels of N3, N6, and total PUFA intake were significantly higher in patients having better HRQoL with respect to mobility, self-care, and usual activities. CONCLUSION: Our results suggest that N3, N6, and total PUFA intake are associated with HRQoL in COPD patients. This association may be attributed to mobility, self-care, and usual activities. Further longitudinal study is required to clarify this relationship.

Endobronchial fungal infection caused by Candida albicans with main bronchus obstruction: a case report.

Endobronchial fungal infection (EBFI) is a rare form of pulmonary fungal infection that especially affects immunocompromised patients. Furthermore, EBFI resulting in obstruction of the main bronchus is extremely rare. With the development of bronchoscopic techniques, rare cases of EBFI have been reported. A 68-year-old female was referred to the Department of Pulmonology for confusion and obtundation. The patient was diagnosed with septic shock due to acute pyelonephritis followed by obstructive EBFI. We performed bronchoscopic biopsy and endobronchial aspiration for culture. Biopsy showed yeast-like fungus and Candida albicans grew in the culture. EBFI has been under-recognized because of difficulties in confirming the diagnosis. Endobronchial ultrasound-guided transbronchial needle aspiration and bronchoscopy are used to improve the diagnosis of thoracic infection, such as tuberculosis. The role of bronchoscopy in the diagnosis of infectious diseases of the trachea or main bronchi is expected to widen in the future.

Subretinal transplantation of human embryonic stem cell-derived retinal pigment epithelium (MA09-hRPE): A safety and tolerability evaluation in minipigs.

This study aimed to determine the safety and tolerability of the subretinal injection of hESC-derived RPE cells at higher doses than the established clinical dose (5 × 104 cells/150 µL) by using minipigs. The hESC-derived RPE cells (60 or 120 × 104 cells/150 µL) were injected in subretinal region, and minipigs were sacrificed at Weeks 4, 8, and 12 post-surgery. Time-course examination was performed by using fundus photography, optical coherence tomography (OCT), histopathology, and fluorescence in situ hybridization (FISH). After surgery, retinal bleb and pigmentation were seen and retinal bleb became smaller gradually. In histopathology, cell clusters consisting of a uniform population of the round to oval cells were seen at the subretinal injection site. In immunohistochemistry, most of the cells were positive for anti-CD3 and CD45 antibodies but negative for anti-human nuclei antibody; transplanted cells were not detectable by DNA probe in FISH assay. Cell clusters were thought to be a host immune response to trauma or transplanted cells. There were no other changes related to subretinal RPE cell injection. These results suggested that subretinal injection of hESC-derived RPE cells (60 and 120 × 104 cells/150 µL) in minipigs is well-tolerated and safe.