Particulate matter-induced gene expression patterns in human-derived cells based on 11 public gene expression datasets.

BACKGROUND: Exposure to particulate matter (PM) and house dust mite (HDM) can change the expression patterns of inflammation-, oxidative stress-, and cell death-related genes. We investigated the changes in gene expression patterns owing to PM exposure. OBJECTIVE: This study examined the changes in gene expression patterns following PM exposure. METHODS: We searched for differentially expressed genes (DEGs) following PM exposure using five cell line-based RNA-seq or microarray datasets and six human-derived datasets. The enrichment terms of the DEGs were assessed. RESULTS: DEG analysis yielded two gene sets. Thus, enrichment analysis was performed for each gene set, and the enrichment terms related to respiratory diseases were presented. The intersection of six human-derived datasets and two gene sets was obtained, and the expression patterns following PM exposure were observed. CONCLUSIONS: Two gene sets were obtained for cells treated with PM and their expression patterns were presented following verification in human-derived cells. Our findings suggest that exposure to PM2.5 and HDM may reveal changes in genes that are associated with diseases, such as allergies, highlighting the importance of mitigating PM2.5 and HDM exposure for disease prevention.

Epigenome-wide Association Study for Tic Disorders in Children: A Preliminary Study in Korean Population.

Objective: : Tic disorders can affect the quality of life in both childhood and adolescence. Many factors are involved in the etiology of tic disorders, and the genetic and epigenetic factors of tic disorders are considered complex and heterogeneous. Methods: : In this study, the differentially methylated regions (DMRs) between normal controls (n = 24; aged 6-15; 7 females) and patients with tic disorders (n = 16; aged 6-15; 5 females) were analyzed. We performed an epigenome-wide association study of tic disorders in Korean children. The tics were assessed using Yale Global Tic Severity Scale. The DNA methylation data consisted of 726,945 cytosine phosphate guanine (CpG) sites, assessed using the Illumina Infinium MethylationEPIC (850k) BeadChip. The DNA methylation data of the 40 participants were retrieved, and DMRs between the four groups based on sex and tic disorder were identified. From 28 male and 16 female samples, 37 and 38 DMRs were identified, respectively. We analyzed the enriched terms and visualized the network, heatmap, and upset plot. Results: : In male, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed hypomethylated patterns in the ligand, receptor, and second signal transductors of the PI3K-Akt and MAPK signaling pathway (most cells were indicated as green color), and in female, the opposite patterns were revealed (most cells were indicated as red color). Five mental disorder-related enriched terms were identified in the network analysis. Conclusion: : Here, we provide insights into the epigenetic mechanisms of tic disorders. Abnormal DNA methylation patterns are associated with mental disorder-related symptoms.

Four modeling approaches to study restrictions on everyday life and social activities due to chronic diseases with consequences of suicidal behavior.

The purpose of this study was to discover the association between disability in everyday life and social activities due to chronic diseases and suicidal ideation (SI), suicidal plan (SP), and suicidal attempt (SA) from the Korea National Health and Nutrition Examination Survey (KNHANES), considering the cross-sectional design of this study, 2016-2018 dataset. Variables for finding the associated factors of SI, SP, and SA were confirmed through random forest (RF), decision tree, generalized linear model (GLM), and support vector machine (SVM), and the performance of each model is listed. A total of 17,323 (males: 7,530, females: 9793) responders from the KNHANES from 2016 to 2018 were employed for the study. The relationship between restrictions on daily life, social activities, and three stages of suicidal behaviors due to diseases were analyzed using the R function (R version 4.2.0), randomForest, ctree, glm, and ksvm. The F1-score is a measure used to evaluate the accuracy of the performance of a model, in the binary classification. The score of 1 indicates good performance, whereas a score of 0 signifies poor performance. Due to chronic diseases, disability in everyday life and social activities lead to suicide behaviors. In our study, we examined the impact of limitations in daily living and social activities on suicidal behaviors among participants. Our findings revealed that for those experiencing such limitations, the odds ratios (ORs) for SIs were 6.10 (95% CI: 3.99-9.34) for males and 2.61 (1.79-3.81) for females. SPs were 3.69 (2.36-5.78) for males and 3.94 (2.70-5.75) for females. Similarly, the odds ratios for SAs were 5.04 (2.51-10.13) for males and 2.71 (1.48-4.98) for females, indicating a significant association between these limitations and increased suicidal behaviors, with variances observed between genders. These results underscore the necessity of addressing daily living and social activity restrictions when considering mental health interventions and suicide prevention strategies. In RF, GLM, and SVM, F1-score were 0.8192, 0.6887, and 0.9687 in SA, respectively. Among the patients with chronic disease, those with sequelae, low incomes, and low levels of education had limitations in daily activities and social activities, which increased the likelihood of suicidal thoughts, planning, and attempts.

Factors related to tumor response rate from TCGA three omics data-variants, expression, methylation.

The Cancer Genome Atlas (TCGA) and its patient-derived multi-omics datasets have been the backbone of cancer research, and with novel approaches, it continues to shed new insight into the disease. In this study, we delved into a method of multi-omics integration of patient datasets and the association of biological pathways related to the disease. First, across thirty-three types of cancer present in TCGA, we merged genomic mutations and drug response datasets and filtered for the viable variant-drug response combinations available in TCGA, containing more than three samples for each drug response label with RNA sequencing (RNA-seq) and genomic methylation data available for each patient. We identified two distinct combinations in TCGA, one being pancreatic adenocarcinoma patients with/without rs121913529 variant in KRAS gene treated with gemcitabine, and the other low-grade glioma with/without rs121913500 variant in IDH1 gene administered with temozolomide. In these two groups, different patterns of gene expression were observed in the pathways often associated with cancer progression, such as mTOR and PDGF between the patients with complete response and progressive disease. Our result will provide yet another example of the relevance of these biological pathways in cancer drug response and a way for multi-omics integration in cancer datasets.

Comparing variants related to chronic diseases from genome-wide association study (GWAS) and the cancer genome atlas (TCGA).

BACKGROUND: Several genome-wide association studies (GWAS) have been performed to identify variants related to chronic diseases. Somatic variants in cancer tissues are associated with cancer development and prognosis. Expression quantitative trait loci (eQTL) and methylation QTL (mQTL) analyses were performed on chronic disease-related variants in TCGA dataset. METHODS: MuTect2 calling variants for 33 cancers from TCGA and 296 GWAS variants provided by LocusZoom were used. At least one mutation was found in TCGA 22 cancers and LocusZoom 23 studies. Differentially expressed genes (DEGs) and differentially methylated regions (DMRs) from the three cancers (TCGA-COAD, TCGA-STAD, and TCGA-UCEC). Variants were mapped to the world map using population locations of the 1000 Genomes Project (1GP) populations. Decision tree analysis was performed on the discovered features and survival analysis was performed according to the cluster. RESULTS: Based on the DEGs and DMRs with clinical data, the decision tree model classified seven and three nodes in TCGA-COAD and TCGA-STAD, respectively. A total of 11 variants were commonly detected from TCGA and LocusZoom, and eight variants were selected from the 1GP variants, and the distribution patterns were visualized on the world map. CONCLUSIONS: Variants related to tumors and chronic diseases were selected, and their geological regional 1GP-based proportions are presented. The variant distribution patterns could provide clues for regional clinical trial designs and personalized medicine.

Cytokine levels reflect tic symptoms more prominently during mild phases.

Tic disorder is a neuropsychiatric condition that affects 3% of all children and can have a significant impact on their quality of life. Cytokines, interferons, interleukins, lymphokines, and tumor necrosis factors are involved in the neuroinflammatory circuitry of tic disorders. This study aimed to identify the cytokines involved in the pathogenesis of tic disorders. We enrolled 44 patients with tic disorder and 38 healthy controls. Patients were free of psychotropic medications for at least 3 weeks. Whole blood samples were analyzed using a Luminex® human cytokine multiplex assay kit. Patients were divided into groups with "mild tics" and "above moderate tics" based on Yale Global Tic Severity Scale (YGTSS) scores for comparison. The final analysis included 35 patients (28 male and 7 female) and 31 controls (20 male and 11 female). In the mild tic group, interleukin (IL)-12 p70 negatively correlated with motor tic scores. Granulocyte-macrophage colony-stimulating factor, IL-4, IL-8, and tumor necrosis factor (TNF)-α were positively correlated to phonic tic scores. IL-12 p40 and TNF-α were positively correlated to total tic scores. IL-12 p70 and IL-17a negatively correlated to impairment scores and total YGTSS scores. Tic disorder patients and healthy controls exhibit different cytokine profiles. Only patients with mild symptoms exhibit significant correlations, suggesting that the correlations between cytokine levels and tic symptoms are more relevant during the mild or remission phases. Our results present the importance of IL-1ß and TNF-α, among others, but the identification of key cytokines are still necessary.

Integrative Approaches of DNA Methylation Patterns According to Age, Sex and Longitudinal Changes.

Background: In humans, age-related DNA methylation has been studied in blood, tissues, buccal swabs, and fibroblasts, and changes in DNA methylation patterns according to age and sex have been detected. To date, approximately 137,000 samples have been analyzed from 14,000 studies, and the information has been uploaded to the NCBI GEO database. Methods: A correlation between age and methylation level and longitudinal changes in methylation levels was revealed in both sexes. Here, 20 public datasets derived from whole blood were analyzed using the Illumina BeadChip. Batch effects with respect to the time differences were correlated. The overall change in the pattern was provided as the inverse of the coefficient of variation (COV). Results: Of the 20 datasets, nine were from a longitudinal study. All data had age and sex as common variables. Comprehensive details of age-, sex-, and longitudinal change-based DNA methylation levels in the whole blood sample were elucidated in this study. ELOVL2 and FHL2 showed the maximum correlation between age and DNA methylation. The methylation patterns of genes related to mental health differed according to age. Age-correlated genes have been associated with malformations (anteverted nostril, craniofacial abnormalities, and depressed nasal bridge) and drug addiction (drug habituation and smoking). Conclusion: Based on 20 public DNA methylation datasets, methylation levels according to age and longitudinal changes by sex were identified and visualized using an integrated approach. The results highlight the molecular mechanisms underlying the association of sex and biological age with changes in DNA methylation, and the importance of optimal genomic information management.

The Activation of the LIMK/Cofilin Signaling Pathway via Extracellular Matrix-Integrin Interactions Is Critical for the Generation of Mature and Vascularized Cardiac Organoids.

The generation of mature and vascularized human pluripotent stem cell-derived cardiac organoids (hPSC-COs) is necessary to ensure the validity of drug screening and disease modeling. This study investigates the effects of cellular aggregate (CA) stemness and self-organization on the generation of mature and vascularized hPSC-COs and elucidates the mechanisms underlying cardiac organoid (CO) maturation and vascularization. COs derived from 2-day-old CAs with high stemness (H-COs) and COs derived from 5-day-old CAs with low stemness (L-COs) were generated in a self-organized microenvironment via Wnt signaling induction. This study finds that H-COs exhibit ventricular, structural, metabolic, and functional cardiomyocyte maturation and vessel networks consisting of endothelial cells, smooth muscle cells, pericytes, and basement membranes compared to L-COs. Transcriptional profiling shows the upregulation of genes associated with cardiac maturation and vessel formation in H-COs compared with the genes in L-COs. Through experiments with LIMK inhibitors, the activation of ROCK-LIMK-pCofilin via ECM-integrin interactions leads to cardiomyocyte maturation and vessel formation in H-COs. Furthermore, the LIMK/Cofilin signaling pathway induces TGFß/NODAL and PDGF pathway activation for the maturation and vascularization of H-COs. The study demonstrates for the first time that LIMK/Cofilin axis activation plays an important role in the generation of mature and vascularized COs.

Transposable Elements-Derived MicroRNA Expression Patterns in TCGA Dataset for 10 Species.

MicroRNAs (miRNAs) are a class of non-coding RNAs that act as regulators of disease. An evolutionary approach to the disease could reveal factors such as diagnosis, treatment, and prognosis prediction. The expression patterns of transposable element (TEs)-derived miRNAs could help elucidate diseases, and their evolutionary patterns are also valuable. The 34 miRNAs were compared in terms of stage survival and tumor status in 33 carcinomas from TCGA. Expression levels were compared using a t-test and presented as differentially expressed miRNAs (DEMs). For DEMs showing statistically specific expression patterns for 3 conditions (normal and cancer, early and advanced stage, and survival), interactions with related genes in 10 species, including humans, were compared. The enrichment term was discovered for the gene-miRNA interactions. In 18 out of the 33 carcinomas, at least one miRNA was retrieved with P < .05 and |fold change| >.05. A total of 128 DEMs for the 9 miRNAs were identified. Based on the TargetScan database, interactions between miRNAs and genes in 10 species, including humans, were confirmed. The evolutionarily conserved miR-130a was observed in all 10 species, whereas miR-151a was only observed in humans. GO terms of related genes were selected for the miRNAs commonly found in each species. Evolutionary analysis of TE-derived disease-associated miRNAs was performed, and the evolutionarily conserved miR-130a-related carcinomas included renal and thyroid cancers. Human and rhesus monkey-specific miR-625 is associated with various carcinomas.

Relationship between DNA methylation changes and skeletal muscle mass.

BACKGROUND: Sarcopenia is a disease diagnosed in the elderly. In patients with sarcopenia, the muscle mass decreases every year. The occurrence of sarcopenia is greatly affected by extrinsic factors such as eating habits, exercise, and lifestyle. The present study aimed to determine the relationship between muscle mass traits and genes affected by epigenetic factors with three different adjustment methods using Korean Genome and Epidemiology Study (KOGES) data. RESULTS: We conducted a demographic study and DNA methylation profiling by three studies according to the muscle mass index (MMI) adjustment methods: appendicular skeletal muscle mass divided by body weight (MMI1); appendicular skeletal muscle mass divided by square of height (MMI2); appendicular skeletal muscle mass divided by BMI (MMI3). We analyzed differentially methylated regions (DMRs) for each group. We then restricted our subjects to be top 30% (T30) and bottom 30% (B30) based on each MMI adjustment method. Additionally, we performed enrichment analysis using PathfindR to evaluate the relationship between identified DMRs and sarcopenia. A total of 895 subjects were included in the demographic study. The values of BMI, waist, and hip showed a significant difference in all three groups. Among 446 participants, 44 subjects whose DNA methylation profiles were investigated were included for DNA methylation analysis. The results of enrichment analysis showed differences between groups. In the women group through MMI1 method, only the glutamatergic synapse pathway showed a significant result. In the men group through MMI2 method, the adherens junction pathway was the most significant. Women group through MMI2 method showed similar results, having an enriched Rap1 signaling pathway. In men group through MMI3 method, the Fc epsilon RI signaling pathway was the most enriched. Particularly, the notch signaling pathway was significantly enriched in women group through MMI3 method. CONCLUSION: This study presents results about which factor should be concerned first in muscle mass index (MMI) adjustment. The present study suggested that GAB2 and JPH3 in MMI1 method, HLA-DQB1 and TBCD in MMI2 method, GAB2, NDUFB4 and ISPD in MMI3 method are potential genes that can have an impact on muscle mass. It could enable future epigenetic studies of genes based on annotation results. The present study is a nationwide study in Korea with the largest size up to date that compares adjustment indices for MMI in epigenetic research.

The Effect of DNA Methylation in the Development and Progression of Chronic Kidney Disease in the General Population: An Epigenome-Wide Association Study Using the Korean Genome and Epidemiology Study Database.

BACKGROUND: Although knowledge of the genetic factors influencing kidney disease is increasing, epigenetic profiles, which are associated with chronic kidney disease (CKD), have not been fully elucidated. We sought to identify the DNA methylation status of CpG sites associated with reduced kidney function and examine whether the identified CpG sites are associated with CKD development. METHOD: We analyzed DNA methylation patterns of 440 participants in the Korean Genome and Epidemiology Study (KoGES) with estimated glomerular filtration rates (eGFRs) ≥ 60 mL/min/1.73 m2 at baseline. CKD development was defined as a decrease in the eGFR of <60 at any time during an 8-year follow-up period ("CKD prediction" analysis). In addition, among the 440 participants, 49 participants who underwent a second methylation profiling were assessed for an association between a decline in kidney function and changes in the degree of methylation of CpG sites during the 8 years ("kidney function slope" analysis). RESULTS: In the CKD prediction analysis, methylation profiles of a total of 403,129 CpG sites were evaluated at baseline in 440 participants, and increased and decreased methylation of 268 and 189 CpG sites, respectively, were significantly correlated with the development of CKD in multivariable logistic regression. During kidney function slope analysis using follow-up methylation profiles of 49 participants, the percent methylation changes in 913 CpG sites showed a linear relationship with the percent change in eGFR during 8 years. During functional enrichment analyses for significant CpG sites found in the CKD prediction and kidney function slope analyses, we found that those CpG sites represented MAPK, PI3K/Akt, and Rap1 pathways. In addition, three CpG sites from three genes, NPHS2, CHCHD4, and AHR, were found to be significant in the CKD prediction analysis and related to a decline in kidney function. CONCLUSION: It is suggested that DNA methylation on specific genes is associated with the development of CKD and the deterioration of kidney function.

Correlation between Harris hip score and gait analysis through artificial intelligence pose estimation in patients after total hip arthroplasty.

BACKGROUND: Recently, open pose estimation using artificial intelligence (AI) has enabled the analysis of time series of human movements through digital video inputs. Analyzing a person's actual movement as a digitized image would give objectivity in evaluating a person's physical function. In the present study, we investigated the relationship of AI camera-based open pose estimation with Harris Hip Score (HHS) developed for patient-reported outcome (PRO) of hip joint function. METHOD: HHS evaluation and pose estimation using AI camera were performed for a total of 56 patients after total hip arthroplasty in Gyeongsang National University Hospital. Joint angles and gait parameters were analyzed by extracting joint points from time-series data of the patient's movements. A total of 65 parameters were from raw data of the lower extremity. Principal component analysis (PCA) was used to find main parameters. K-means cluster, X-squared test, Random forest, and mean decrease Gini (MDG) graph were also applied. RESULTS: The train model showed 75% prediction accuracy and the test model showed 81.8% reality prediction accuracy in Random forest. "Anklerang_max", "kneeankle_diff", and "anklerang_rl" showed the top 3 Gini importance score in the Mean Decrease Gini (MDG) graph. CONCLUSION: The present study shows that pose estimation data using AI camera is related to HHS by presenting associated gait parameters. In addition, our results suggest that ankle angle associated parameters could be key factors of gait analysis in patients who undergo total hip arthroplasty.

Accelerometer-derived physical activity analysis of elderly osteoarthritis patients.

BACKGROUND: Because disability in Osteoarthritis (OA) may change physical activity (PA), which might affect the disease progression, it is important to measure a patient's daily PA to study the relationship between a patient's PA and disease progression. OBJECTIVE: The objective of the present study was to investigate the relationship between PA and patients with OA and people without OA using data from the Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: Demographic study was conducted to obtain data of comorbidities of participants. PA was compared between the group with OA (OA group) and the group without OA (non-OA group). In addition, PAs of OA patients with comorbidities and those without comorbidities were compared. The cut-off of moderate to vigorous physical activity (MVPA) was obtained through a receiver operating characteristic (ROC) curve. RESULTS: In the demographic study, there were significantly more educated participants in the OA group (p < .001). Actigraph data showed a significant decrease in MVPA (p < .001) but a significant increase in light activity (p = .002) in the OA group. In addition, the OA group showed significantly lower light PA but significantly higher MVPA in ≥10 min bout length. OA patients with comorbidities showed higher MVPA than OA patients without comorbidities (p = .044). The cut-off point of MVPA was 7.071 min/day when ROC curve was conducted. CONCLUSIONS: The present study suggests that patients with OA and low activity need a certain level of physical activity and a cut-off point for MVPA is presented which accounts for comorbidities in OA patients.

Cross-reactive humoral immunity of clade 2 Oka and MAV/06 strain-based varicella vaccines against different clades of varicella-zoster virus.

The currently used Japanese Oka and Korean MAV/06-attenuated varicella vaccine strains belong to clade 2 genotype varicella-zoster viruses (VZV). More than seven clades of VZV exist worldwide. In this study, we investigated the cross-reactivity of antibodies induced by clade 2 genotype vaccines against VZV strains belonging to clades 1, 2, 3, and 5 using a fluorescent antibody to membrane antigen (FAMA) test. Among 59 donors, 29 were vaccinated with the MAV/06 strain MG1111 (GC Biopharma, South Korea) and the other 30 were vaccinated with the Oka strain VARIVAX (Merck, USA). The sera were titrated using FAMA tests prepared with six different VZV strains (two vaccine strains, one wild-type clade 2 strain, and one each of clade 1, 3, and 5 strains). The ranges of geometric mean titers (GMTs) of FAMA against six different strains were 158.7-206.5 and 157.6-238.9 in MG1111 and VARIVAX groups, respectively. GMTs of the MG1111 group against all six strains were similar; however, GMTs of the VARIVAX group showed differences of approximately 1.5-fold depending on the strains. Nevertheless, the GMTs of the two vaccinated groups for the same strain were not significantly different. These results suggest that both MG1111 and VARIVAX vaccinations induce cross-reactive humoral immunity against other clades of VZV.

Factors for risk stratification of patients with actinic keratosis using integrated analysis of clinicopathological features and gene expression patterns.

BACKGROUND: Actinic keratosis (AK) is considered as precursor lesion of invasive squamous cell carcinoma. Molecular studies on AK are limited because of too small size of the biopsy specimen to obtain enough DNA or RNA. METHODS: Twenty biopsy cases of AK, followed by second same-sited biopsies, were included. Ten cases were diagnosed with total regression (regression group), while the other 10 were diagnosed with invasive carcinoma (progression group) in the follow-up biopsies. Using digital spatial profiling (DSP) technology, whole-gene expression analysis defined by specific regions of interest was performed for all 20 cases. After the clinicopathological features were assessed, separate and integrated analyses of these features and gene expression patterns were performed using machine-learning technology. All analyses were performed on both lesion keratinocytes (KT) and infiltrated stromal lymphocytes (LC). RESULTS: Among the 18,667 genes assessed, 33 and 72 differentially expressed genes (DEGs) between the regression and progression groups were found in KT and LC respectively. The primary genes distinguishing the two groups were KRT10 for KT and CARD18 for LC. Clinicopathological features were weaker in risk stratification of AK progression than the gene expression patterns. Pathways associated with various cancers were upregulated in the progression group of KT, whereas the nucleotide-binding oligomerization domain (NOD)-like receptor signalling pathway was upregulated in the progression of LC. CONCLUSION: Gene expression patterns were effective for risk stratification of AK progression, and their distinguishing power was higher than that of clinicopathological features.

Small RNA sequencing of small extracellular vesicles secreted by umbilical cord mesenchymal stem cells following replicative senescence.

BACKGROUND: Umbilical cord mesenchymal stem cells (UCMSC) are subsets of multipotent stem cells involved in immune modulation, tissue regeneration, and antimicrobial defense. Cellular senescence is associated with the onset of aging-related diseases and small extracellular vesicles (sEVs) are important mediators of senescence and aging. OBJECTIVE: However, little is known about the role and function of microRNAs (miRNAs) carried by UCMSC-derived sEVs. To analyze the expression profiles of miRNAs secreted by senescent UCMSC, small RNA sequencing of the miRNAs within the sEVs was performed in this study. METHODS: UCMSC cultures underwent serial passaging beyond passage number 20 to achieve replicative senescence, which was confirmed by various methods, including increased senescence-associated ß-gal staining and cytokine secretion levels. sEVs derived from non-senescent and senescent UCMSC were isolated and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblot analysis. RESULTS: Small RNA sequencing of the miRNAs within the sEVs revealed senescence-associated differences in the miRNA composition, as shown by the upregulation of miR-122-5p and miR-146a-5p, and downregulation of miR-125b-5p and miR-29-3p. In addition, total RNA sequencing analysis showed that PENK, ITGA8, and TSIX were upregulated, whereas AKR1B10, UNC13D, and IL21R were downregulated by replicative senescence in UCMSC. In sEVs, upregulated genes were linked to downregulated miRNAs, and vice versa. In the gene-concept network analysis, five gynecologic terms were retrieved. CONCLUSIONS: The study provides an insight into the cellular characteristics of UCMSC following replicative senescence and emphasizes the importance of monitoring passage numbers of UCMSC for further therapeutic use.

Demographic and Genome Wide Association Analyses According to Muscle Mass Using Data of the Korean Genome and Epidemiology Study.

BACKGROUND: Sarcopenia is commonly found in the elderly due to a decline in muscle mass. Many researchers have performed genome-wide association studies (GWAS) to find genetic risk factors of sarcopenia. Although many studies have discovered sarcopenia associated single nucleotide polymorphisms (SNPs), most of them are studies targeting Caucasians. The purpose of this study was to evaluate genetic correlation according to muscle mass in middle aged Koreans using data of the Korean Genome and Epidemiology Study (KOGES), a large population-based genomic cohort study. METHODS: Baseline participants were 10,030 subjects aged 40 to 69 years who were from Ansan or Anseong in Gyeonggi-do, South Korea. Among them, 9,351 subjects with laboratory data available were included in this study. To identify sarcopenia associated variants, those in the top 30% and bottom 30% of muscle mass index (MMI) were compared. A total of 7,452 people with an MMI of 30-70% were excluded. A total of 1,004 people were also excluded due to missing data. Finally, 895 people were selected for this study. The Korea Biobank Array generated 500,568 SNPs for this dataset. RESULTS: When subjects were divided into top 30% and bottom 30% of MMI, the top 30% had 169 men and 308 women and the bottom 30% had 220 men and 198 women. In men, age, body mass index (BMI), waist and hip were significantly (P < 0.005) different between top 30% and bottom 30% MMI groups. In women, age, BMI, waist, hip, and hypertension history were significantly different between the two MMI groups. There were 13 significant SNPs in men and 14 significant SNPs in women. Genes associated with variants in men based on the single-nucleotide polymorphism database (dbSNP) were LRP1B containing rs11679458 and RGS6 containing rs11848300. A gene associated with variants in women was Pi4K2A, which contained rs1189312 as a variant. In addition, rs11189312 was associated with expression quantitative trait loci (eQTL) of ZFYVE27 in skeletal muscles and other SNPs of ZFYVE27 (rs10882883, rs17108378, rs35077384) known to be associated with spastic paraplegia. The eQTL analysis revealed that rs11189312 was a variant associated with SNPs of ZFYVE27. CONCLUSIONS: In the demographic study, significant results were found in BMI, waist, hip, history of hyperlipidemia, and sedentary life status in male group, and significant results were found in BMI, waist, hip, and hypertension history in female group. Variant rs11189312 was found to be a novel variant affecting ZFYVE27 expressed in skeletal muscles, suggesting that rs11189312 might be related to sarcopenia as a novel discovery of this study. Further study is needed to determine the association between sarcopenia and ZFYVE27 known to be associated with spastic paraplegia.

Novel peptide-based vaccine targeting heat shock protein 90 induces effective antitumor immunity in a HER2+ breast cancer murine model.

BACKGROUND: Heat shock protein 90 (HSP90) is a protein chaperone for most of the important signal transduction pathways in human epidermal growth factor receptor 2-positive (HER2+) breast cancer, including human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor and Akt. The aim of our study is to identify peptide-based vaccines and to develop an effective immunotherapeutics for the treatment of HER2+ breast cancer. METHODS: HSP90-derived major histocompatibility complex (MHC) class II epitopes were selected using in silico algorithms and validated by enzyme-linked immunospot (ELISPOT). In vivo antitumor efficacy was evaluated in MMTVneu-transgenic mice. HSP90 peptide-specific systemic T-cell responses were assessed using interferon gamma ELISPOT assay, and immune microenvironment in tumors was evaluated using multiplex immunohistochemistry and TCRß sequencing. RESULTS: First, candidate HSP90-derived MHC class II epitopes with high binding affinities across multiple human HLA class II genotypes were identified using in silico algorithms. Among the top 10 peptides, p485 and p527 were selected as promising Th1 immunity-inducing epitopes with low potential for Th2 immunity induction. The selected MHC class II HSP90 peptides induced strong antigen-specific T cell responses, which was induced by cross-priming of CD8+ T cells in vivo. The HSP90 peptide vaccines were effective in the established tumor model, and their efficacy was further enhanced when combined with stimulator of interferon genes (STING) agonist and/or anticytotoxic T lymphocyte-associated antigen-4 antibody in MMTVneu-transgenic mice. Increased tumor rejection was associated with increased systemic HSP90-specific T-cell responses, increased T-cell recruitment in tumor microenvironment, intermolecular epitope spreading, and increased rearrangement of TCRß by STING agonist. CONCLUSIONS: In conclusion, we have provided the first preclinical evidence of the action mechanism of HSP90 peptide vaccines with a distinct potential for improving breast cancer treatment.

Crosstalk between mucosal microbiota, host gene expression, and sociomedical factors in the progression of colorectal cancer.

Various omics-based biomarkers related to the occurrence, progression, and prognosis of colorectal cancer (CRC) have been identified. In this study, we attempted to identify gut microbiome-based biomarkers and detect their association with host gene expression in the initiation and progression of CRC by integrating analysis of the gut mucosal metagenome, RNA sequencing, and sociomedical factors. We performed metagenome and RNA sequencing on colonic mucosa samples from 13 patients with advanced CRC (ACRC), 10 patients with high-risk adenoma (HRA), and 7 normal control (NC) individuals. All participants completed a questionnaire on sociomedical factors. The interaction and correlation between changes in the microbiome and gene expression were assessed using bioinformatic analysis. When comparing HRA and NC samples, which can be considered to represent the process of tumor initiation, 28 genes and five microbiome species were analyzed with correlation plots. When comparing ACRC and HRA samples, which can be considered to represent the progression of CRC, seven bacterial species and 21 genes were analyzed. When comparing ACRC and NC samples, 16 genes and five bacterial species were analyzed, and four correlation plots were generated. A network visualizing the relationship between bacterial and host gene expression in the initiation and progression of CRC indicated that Clostridium spiroforme and Tyzzerella nexilis were hub bacteria in the development and progression of CRC. Our study revealed the interactions of and correlation between the colonic mucosal microbiome and host gene expression to identify potential roles of the microbiome in the initiation and progression of CRC. Our results provide gut microbiome-based biomarkers that may be potential diagnostic markers and therapeutic targets in patients with CRC.