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Abstract Background Advancements in the diagnosis, treatment, and surveillance of castration-resistant prostate cancer (CRPC) have progressed considerably, but a new biomarker that combines existing clinical and pathological data could be useful for a more precise diagnosis and prognosis. Some investigations have found that extracellular vesicle (EV)-derived miRNAs play crucial roles in various types of malignant tumors. The objective of this study was to explore EV miRNA and identify its biologic function as a biomarker for the diagnosis and prognosis of CRPC. Methods Plasma samples were collected from five healthy donors (Control, CT) and 17 CRPC patients, categorizing into two groups based on their endocrine treatment response: partial response (PR; n = 10) and progressive disease (PD; n = 7). Candidate extracellular vesicle (EV) miRNAs were identified using miRNA microarray and RT-qPCR. The biological functions of the selected miRNAs were evaluated using the MTT assay, wound healing assay, trans-well assay, and RNA sequencing in CRPC cells after transient miRNA expression. Results Microarray analysis revealed a significant downregulation of EV-miR-6880-5p in the PD samples compared to both CT and PR samples (p

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.

Abstract 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.

Abstract 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-1β and TNF-α, among others, but the identification of key cytokines are still necessary.

Abstract 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.

Insights from public DNA methylation data derived from cancer or normal tissues from cancer patients or healthy people can be obtained by machine learning. The goal is to determine methylation patterns that could be useful for predicting the prognosis for cancer patients and correcting lifestyles for healthy people. DNA methylation data were obtained from the DNA of 446 healthy participants from the Korean Genome Epidemiology Study (KoGES) and from the DNA of normal tissues or from cancer tissues of 11 types of carcinomas from The Cancer Genome Atlas (TCGA) database. To correct for the batch effect, R’s ComBat function was used. Using the K-mean clustering (k = 3), the survival rates of the cancer patients and the incidence of chronic diseases were compared between the three clusters for TCGA and KoGES, respectively. Based on the public DNA methylation and clinical data of healthy participants and cancer patients, I present an analysis pipeline that integrates and clusters the methylation data from the two groups. As a result of clustering, CpG sites from gene or genomic regions, such as AFAP1, NINJ2, and HOOK2 genes, that correlated with survival rate and chronic disease are presented.

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. 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.

Abstract 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.

The role of differentially methylated regions (DMRs) in nonalcoholic fatty liver disease (NAFLD) is unclear. This study aimed to identify the role of DMR in NAFLD development and progression using the Korean Genome and Epidemiology Study (KoGES) cohort. We used laboratory evaluations and Illumina Methylation 450 k DNA methylation microarray data from KoGES. The correlation between fatty liver index (FLI) and genomic CpG sites was analyzed in 322 subjects. Longitudinal changes over 8 years were confirmed in 33 subjects. To identify CpG sites and genes related to FLI, we obtained enrichment terms for 6765 genes. DMRs were identified for both high (n = 128) and low (n = 194) groups on the basis of FLI 30 in 142 men and 180 women. To confirm longitudinal changes in 33 subjects, the ratio of follow-up and baseline investigation values was obtained. Correlations and group comparisons were performed for the 8 year change values. PITPNM3, RXFP3, and THRB were hypermethylated in the increased FLI groups, whereas SLC9A2 and FOXI3 were hypermethylated in the decreased FLI groups. DMRs describing NAFLD were determined, and functions related to inflammation were identified. Factors related to longitudinal changes are suggested, and blood circulation-related functions appear to be important in the management of NAFLD.

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.

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 TCRβ 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 TCRβ 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.

Abstract Nonalcoholic steatohepatitis (NASH) is considered as a progressive form of nonalcoholic fatty liver disease (NAFLD). To distinguish NASH from nonalcoholic fatty liver (NAFL), we evaluated the diagnostic value of circulating miRNAs. Small RNA sequencing was performed on 12 NAFL patients and 12 NASH patients, and the miRNA expression was compared. After selecting miRNAs for the diagnosis of NASH, we analyzed the diagnostic accuracy of each miRNA and the combination of miRNAs. External validation was performed using quantitative reverse transcription PCR. Among the 2,588 miRNAs, 26 miRNAs significantly increased in the NASH group than in the NAFL group. Among the 26 elevated miRNAs in the NASH group, 8 miRNAs were selected, and in silico analysis was performed. Only four miRNAs (miR-21-5p, miR-151a-3p, miR-192-5p, and miR-4449) showed significant area under the receiver operating characteristic curve (AUC) values for NASH diagnosis. The combination of the four miRNAs showed satisfactory diagnostic accuracy for NASH (AUC 0.875; 95% CI 0.676–0.973). External validation revealed similar diagnostic accuracy for NASH (AUC 0.874; 95% CI 0.724–0.960). NASH represents significantly distinct miRNA expression profile compared with NAFL. The combination of serum circulating miRNAs can be used as a novel biomarker for the NASH diagnosis in NAFLD.

The incidence of nontuberculous Mycobacterium (NTM) lung disease is rapidly increasing; however, its diagnosis and prognosis remain unclear while selecting patients who will respond to appropriate treatment. Differences in DNA methylation patterns between NTM patients with good or poor prognosis could provide important therapeutic targets. We used the Illumina MethylationEPIC (850k) DNA methylation microarray to determine the pattern between differentially methylated regions (DMRs) in NTM patients with good or poor prognosis (n = 4/group). Moreover, we merged and compared 20 healthy controls from previous Illumina Methylation450k DNA methylation microarray data. We selected and visualized the DMRs in the form of heatmaps, and enriched terms associated with these DMRs were identified by functional annotation with the “pathfinder” package. In total, 461 and 293 DMRs (|Log2 fold change| > 0.1 and P < 0.03) were more methylated in patients with four poor and four good prognoses, respectively. Furthermore, 337 and 771 DMRs (|Log2 fold change| > 0.08 and P < 0.001) were more methylated in eight NTM patients and 20 healthy controls, respectively. TGFBr1 was significantly less methylated, whereas HLA-DR1 and HLA-DR5 were more methylated in patients with poor prognosis (compared to those with good prognosis). LRP5, E2F1, and ADCY3 were the top three less-methylated genes in NTM patients (compared with the controls). The mTOR and Wnt signaling pathway-related genes were less methylated in patients with NTM. Collectively, genes related to Th1- cell differentiation, such as TGFBr1 and HLA-DR, may be used as biomarkers for predicting the treatment response in patients with NTM lung disease.

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 TGFβ/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.

Abstracts PURPOSE Machine learning (ML) refers to newly developed computer algorithms that are improved through iterative experiences. ML applications are expected to assist humans in analyzing large amounts of data. This review has outlined the application of ML in analyzing variable vital data such as walking steps, exercise intensity, heart rate, sleeping hours, sleep quality, resting heart rate, blood pressure, and calorie consumption in a day. Vital data consist of different variables that are closely related to genomic or exercise data. The prediction of healthy traits from a vital dataset has become a necessity in personalized medicine. METHODS Considerations and repeated tasks in supervised, semi-supervised, and unsupervised ML methods are presented. ML methods such as artificial neural networks, Bayesian networks, support vector machines, and decision trees have been widely used in biomedical studies to develop predictive models. Through vital data, these models can help in effective and accurate decision-making for a healthier life. PURPOSE Models based on genomic, exercise, and vital datasets provide a healthy lifestyle through regular exercise. We have provided guidelines to help in the selection of these ML methods and their practical application for variable vital data analysis. CONCLUSIONS Our guidelines could serve as a foundation for implementing both participatory medicine and data-driven exercise science.

Purpose: Monoacylglycerol O-acyltransferase 1 (MGAT1) is reported to play a key role in the development of diet-induced nonalcoholic fatty liver disease (NAFLD). Thus, this study investigated the effect of exercise on suppression of the MGAT1 pathway in NAFLD tissue of high-fat diet (HFD)-induced obese rats. Methods: Male Sprague-Dawley rats were fed an HFD containing 45% fat for 6 weeks. Upon confirmation that NAFLD had been induced in the obese animals, they were divided into HFD-fed groups provided with exercise (HFD + EXE) or without exercise (HFD) and a group given dietary adjustment (DA) only, for a further 6 weeks of intervention treatment. The 6-week regular moderate aerobic exercise consisted of an accommodation phase with increasing exercise. Lipid accumulation in the liver tissue was determined by Oil Red O staining. The MGAT1 and liver lipogenic gene mRNA levels were measured by qPCR, and their protein levels by western blot assay. Results: Oil Red O staining showed that NAFLD was successfully induced by HFD-fed. The gene expression of MGAT1 was significantly lower in HFD + EXE than HFD. However, there was no significant difference between HFD + EXE and DA. The protein expression of MGAT1 was significantly lower in HFD + EXE than both HFD and DA. Messenger RNA and protein expression of other lipogenic genes were not different among groups. These data indicate that exercise suppresses MGAT1 pathway regardless of HFD feeding; in part, this effect could be greater than DA. Conclusion: Our data suggest that exercise can improve NAFLD, which is probably due to suppression of MGAT1 pathway.

Background Radiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospective studies show that a blockade of PI3Kδ and/or γ, which are abundant in leukocytes, exhibits antitumor immune response by attenuating activity of immune suppressive cells, however, the single blockade of PI3Kδ or γ is not sufficient to completely eliminate solid tumor.Methods We used BR101801, PI3Kδ/γ inhibitor in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was administered daily, and the target tumor site was locally irradiated. We monitored the tumor growth regularly and evaluated the immunological changes using flow cytometry, ELISpot, and transcriptional analysis.Results This study showed that BR101801 combined with irradiation promotes systemic antitumor immunity and abscopal response by attenuating the activity of immune suppressive cells in the CT-26 tumor model. BR101801 combined with irradiation systemically reduced the proliferation of regulatory T cells (Tregs) and enhanced the number of tumor-specific CD8α+ T cells in the tumor microenvironment, thereby leading to tumor regression. Furthermore, the high ratio of CD8α+ T cells to Tregs was maintained for 14 days after irradiation, resulting in remote tumor regression in metastatic lesions, the so-called abscopal effect. Moreover, our transcriptomic analysis showed that BR101801 combined with irradiation promoted the immune-stimulatory tumor microenvironment, suggesting that the combined therapy converts immunologically cold tumors into hot one.Conclusions Our data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.

Abstract Purpose The linkage between the genetic and phenotypic heterogeneity of the tumor has not been thoroughly evaluated. Herein, we investigated how the genetic and metabolic heterogeneity features of the tumor are associated with each other in head and neck squamous cell carcinoma (HNSC). We further assessed the prognostic significance of those features. Methods The mutant-allele tumor heterogeneity (MATH) score (n = 508), a genetic heterogeneity feature, and tumor glycolysis feature (GlycoS) (n = 503) were obtained from the HNSC dataset in the cancer genome atlas (TCGA). We identified matching patients (n = 33) who underwent 18F-fluorodeoxyglucose positron emission tomography (FDG PET) from the cancer imaging archive (TCIA) and obtained the following information from the primary tumor: metabolic, metabolic-volumetric, and metabolic heterogeneity features. The association between the genetic and metabolic features and their prognostic values were assessed. Results Tumor metabolic heterogeneity and metabolic-volumetric features showed a mild degree of association with MATH (n = 25, ρ = 0.4~0.5, P

Depending on the patients’ genotype, the same drug may have different efficacies or side effects. With the cost of genomic analysis decreasing and reliability of analysis methods improving, vast amount of genomic information has been made available. Several studies in pharmacology have been based on genomic information to select the optimal drug, determine the dose, predict efficacy, and prevent side effects. This paper reviews the tissue specificity and genomic information of cancer. If the tissue specificity of cancer is low, cancer is induced in various organs based on a single gene mutation. Basket trials can be performed for carcinomas with low tissue specificity, confirming the efficacy of one drug for a single gene mutation in various carcinomas. Conversely, if the tissue specificity of cancer is high, cancer is induced in only one organ based on a single gene mutation. An umbrella trial can be performed for carcinomas with a high tissue specificity. Some drugs are effective for patients with a specific genotype. A companion diagnostic strategy that prescribes a specific drug for patients selected with a specific genotype is also reviewed. Genomic information is used in pharmacometrics to identify the relationship among pharmacokinetics, pharmacodynamics, and biomarkers of disease treatment effects. Utilizing genomic information, sophisticated clinical trials can be designed that will be better suited to the patients of specific genotypes. Genomic information also provides prospects for innovative drug development. Through proper genomic information management, factors relating to drug response and effects can be determined by selecting the appropriate data for analysis and by understanding the structure of the data. Selecting pre-processing and appropriate machine-learning libraries for use as machine-learning input features is also necessary. Professional curation of the output result is also required. Personalized medicine can be realized using a genome-based customized clinical trial design.

Noninvasive techniques for evaluating the severity of nonalcoholic fatty liver disease (NAFLD) have shown limited diagnostic performance. MicroRNAs (miRNAs) are useful biomarkers for diagnosing and monitoring the progression and treatment response to several diseases. Here, we evaluated whether serum exosomal miRNAs could be used for the diagnosis and prognosis of NAFLD severity. Exosomal miRNAs were isolated from the sera of 41 patients with NAFLD (diagnosed using liver biopsy) for microarray profiling. The degree of NAFLD severity was determined using inflammation, steatosis, and ballooning scores and the NAFLD activity score (NAS). Correlations between miRNA expression, clinical and biochemical parameters, and mRNA expression were analyzed. Overall, 25, 11, 13, and 14 miRNAs correlated with the inflammation score, steatosis score, ballooning score, and NAS, respectively, with 33 significant correlations observed between 27 miRNAs and six clinical variables. Eight miRNAs (let-7b-5p, miR-378h, -1184, -3613-3p, -877-5p, -602, -133b, and 509-3p) showed anticorrelated patterns with the corresponding mRNA expression. In fibrosis, 52 and 30 interactions corresponding to high miRNA-low mRNA and low miRNA-high mRNA expression, respectively, were observed. The present results therefore suggest that serum exosomal miRNAs can be used to evaluate NAFLD severity and identify potential targets for NAFLD treatment.

Coxsackievirus B3 (CVB3), a member of Picornaviridae family, is an important human pathogen that causes a wide range of diseases, including myocarditis, pancreatitis, and meningitis. Although CVB3 has been well demonstrated to target murine neural progenitor cells (NPCs), gene expression profiles of CVB3-infected human NPCs (hNPCs) has not been fully explored. To characterize the molecular signatures and complexity of CVB3-mediated host cellular responses in hNPCs, we performed QuantSeq 3′ mRNA sequencing. Increased expression levels of viral RNA sensors (RIG-I, MDA5) and interferon-stimulated genes, such as IFN-β, IP-10, ISG15, OAS1, OAS2, Mx2, were detected in response to CVB3 infection, while IFN-γ expression level was significantly downregulated in hNPCs. Consistent with the gene expression profile, CVB3 infection led to enhanced secretion of inflammatory cytokines and chemokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). Furthermore, we show that type I interferon (IFN) treatment in hNPCs leads to significant attenuation of CVB3 RNA copy numbers, whereas, type II IFN (IFN-γ) treatment enhances CVB3 replication and upregulates suppressor of cytokine signaling 1/3 (SOCS) expression levels. Taken together, our results demonstrate the distinct molecular patterns of cellular responses to CVB3 infection in hNPCs and the pro-viral function of IFN-γ via the modulation of SOCS expression.

MicroRNAs (miRNAs) are known for their role in mRNA silencing via interference pathways. Repetitive elements (REs) share several characteristics with endogenous precursor miRNAs. In this study, 406 previously identified and 1,494 novel RE-derived miRNAs were sorted from the GENCODE v.19 database using the RepeatMasker program. They were divided into six major types, based on their genomic structure. More novel RE-derived miRNAs were confirmed than identified as RE-derived miRNAs. In conclusion, many miRNAs have not yet been identified, most of which are derived from REs.

The complete mitochondrial genome of the freshwater bryozoan Pectinatella magnifica was sequenced. The circular mitochondrial genome is 17,539 bp and consists of 13 protein-coding, two ribosomal RNA, and 22 transfer RNA genes (GenBank accession no. MG546680). The Bayesian comparative analysis of molecular evolution rates revealed no acceleration of the mitochondrial DNA (mtDNA) evolution of P. magnifica. Results of maximum likelihood analysis showed that this species clustered with other species of the phylum Bryozoa.

SINE-VNTR-Alu (SVA) elements are present in hominoid primates and are divided into 6 subfamilies (SVA-A to SVA-F) and active in the human population. Using a bioinformatic tool, 22 SVA element-associated genes are identified in the human genome. In an analysis of genomic structure, SVA elements are detected in the 5' untranslated region (UTR) of HGSNAT (SVA-B), MRGPRX3 (SVA-D), HYAL1 (SVA-F), TCHH (SVA-F), and ATXN2L (SVA-F) genes, while some elements are observed in the 3'UTR of SPICE1 (SVA-B), TDRKH (SVA-C), GOSR1 (SVA-D), BBS5 (SVA-D), NEK5 (SVA-D), ABHD2 (SVA-F), C1QTNF7 (SVA-F), ORC6L (SVA-F), TMEM69 (SVA-F), and CCDC137 (SVA-F) genes. They could contribute to exon extension or supplying poly A signals. LEPR (SVA-C), ALOX5 (SVA-D), PDS5B (SVA-D), and ABCA10 (SVA-F) genes also showed alternative transcripts by SVA exonization events. Dominant expression of HYAL1_SVA appeared in lung tissues, while HYAL1_noSVA showed ubiquitous expression in various human tissues. Expression of both transcripts (TDRKH_SVA and TDRKH_noSVA) of the TDRKH gene appeared to be ubiquitous. Taken together, these data suggest that SVA elements cause transcript isoforms that contribute to modulation of gene regulation in various human tissues.

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. [ABSTRACT FROM AUTHOR]

Estuary reopening is a means of restoring estuarine habitats, which has recently been implemented in a few developed countries. The regeneration of a brackish zone in the Nakdong River Estuary (NRE), South Korea, were tested through a series of barrage reopening. During the same period, we conducted extensive fish surveys in the upper part of the NRE barrage on a monthly basis from 2017 to 2021, and subsequently determined whether fish populations and communities were affected by the reopening. The results showed that the reopening of the NRE hardly affected the fish community structure, as non-native species such as Erythroculter erythropterus and Lepomis macrochirus maintained their dominance. Still, we discovered that certain euryhaline species are positively affected by estuary reopening, as total 46 Japanese eels (Anguilla japonica) were captured after the reopening, which had not been detected before the reopening. By comparing the size structure of various fish species, we discovered that size distribution of native and migratory species presented more positively skewed pattern after the reopening, while size structure in non-native species remained relatively unchanged normally distributed pattern. Piecewise structural equation modelling revealed that the NRE had become more complex ecosystem, as migratory fish species abundance and biomass started to show a positive correlation with hydraulic factors such as discharge and negative correlation with seasonality after the reopening. We concluded that estuary reopening created some changes in migratory and native freshwater species but such changes were not notably detected in non-native species. Therefore, appropriate sluice operation methodologies, such as considering the migration seasons of migratory species, should be developed. Additionally, human-involved management policies are required to regulate non-native species populations. [ABSTRACT FROM AUTHOR]