A pan-cancer analysis unveiling the function of NR4A family genes in tumor immune microenvironment, prognosis, and drug response.

BACKGROUND: NR4A family genes play crucial roles in cancers. However, the role of NR4A family genes in cancers remains paradoxical as they promote or suppress tumorigenesis. OBJECTIVE: We aimed to conduct comprehensive analyses of the association between the expression of NR4A family genes and tumor microenvironment (TME) based on bioinformatics methods. METHODS: We collected RNA-seq data from 33 cancer types and 20 normal tissue sites from the TCGA and GTEx databases. Expression patterns of NR4A family genes and their associations with DNA methylation, miRNA, overall survival, drug responses, and tumor microenvironment were investigated. RESULTS: Significant downregulation of all NR4A family genes was observed in 15 cancer types. DNA promoter methylation and expression of NR4A family genes were negatively correlated in five cancers. The expression of 10 miRNAs targeting NR4A family genes was negatively correlated with the expression of NR4A family genes. High expression of all NR4A family genes was associated with poor prognosis in stomach adenocarcinoma and increased expressions of NR4A2 and NR4A3 were associated with poor prognosis in adrenocortical carcinoma. In addition, we found an elevated expression of NR4A2, which enhances the response to various chemotherapeutic drugs, whereas NR4A3 decreases drug sensitivity. Interestingly, in breast cancer, NR4A3 was significantly associated with C2 (IFN-γ dominant), C3 (inflammatory), and C6 (TGF-ß dominant) immune subtypes and infiltrated immune cell types, implying both oncogenic and tumor-suppressive functions of NR4A3 in breast cancer. CONCLUSION: The NR4A family genes have the potential to serve as a diagnostic, prognostic, and immunological marker of human cancers.

Factors associated with the timely diagnosis of malaria and the utilization of types of healthcare facilities: a retrospective study in the Republic of Korea.

BACKGROUND: This study aimed to analyze trends in the timely diagnosis of malaria cases over the past 10 years in relation to the utilization of different types of healthcare facilities. METHODS: The study included 3,697 confirmed and suspected cases of malaria reported between January 1, 2013, and December 31, 2022, in the national integrative disease and healthcare management system. Some cases lacking a case report or with information missing from the case report were excluded from the analysis. A generalized linear model with a Poisson distribution was constructed to estimate risk ratios and 95% confidence intervals adjusted for other variables, such as distance. RESULTS: When cases involving diagnosis >5 days after symptom onset in confirmed patients (5DD) were examined according to the type of healthcare facility, the risk ratio of 5DD cases was found to be higher for tertiary hospitals than for public health facilities. Specifically, the risk ratio was higher when the diagnosis was established at a tertiary hospital, even after a participant had visited primary or secondary hospitals. In an analysis adjusted for the distance to each participant's healthcare facility, the results did not differ substantially from the results of the crude analysis. CONCLUSION: It is imperative to improve the diagnostic capabilities of public facilities and raise awareness of malaria at primary healthcare facilities for effective prevention and control.

Current Status of Human Papillomavirus-Targeted Therapies Development in Head and Neck Cancer.

PURPOSE: While the incidence of smoking-related head and neck squamous cell carcinoma (HNSCC) has been declining, that of human papillomavirus (HPV)-mediated HNSCC has rapidly increased in the past decades worldwide. Despite rapid advances in therapeutics for solid tumors with novel immunotherapy and targeted therapeutic agents, no breakthroughs have yet been made in the treatment of advanced HPV+ HNSCCs. This review aims to summarize the concepts and designs, early trial results, and future directions of various HPV-targeted experimental therapeutics for HPV+ HNSCC. MATERIALS AND METHODS: Guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, a systemic literature search of PubMed was conducted for HPV-targeted therapeutics using the following search terms: HPV, head and neck squamous cell carcinoma, and therapy. For clinical trial data, publications, major oncology conference abstracts, and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov) information were reviewed. This review focused on the ones that are in the clinical stage and currently in active ongoing evaluation. The therapeutics not actively evaluated in HNSCC, in the preclinical stage, or terminated for further development were excluded. RESULTS: Diverse approaches are being actively explored to target HPV+ HNSCC, including therapeutic vaccines of various modalities, HPV-specific immune cell-activating agents, and adaptive cellular therapeutics. All these novel agents use immune-based mechanisms and target constitutively expressed oncogenic HPV E6 and/or E7 viral proteins. Most therapeutics demonstrated excellent safety but single-agent activities are only modest. Many are being tested in combination with immune checkpoint inhibitors. CONCLUSION: Our review summarized various novel HPV-targeted therapeutics that are in the clinical phase for HPV+ HNSCC. Early-phase trial data suggest the feasibility and promising efficacy. Further strategies, including selecting the optimal combination and understanding and overcoming resistant mechanisms, are warranted for successful development.

MGMT Methylation Is Associated with Human Papillomavirus Infection in Cervical Dysplasia: A Longitudinal Study.

Cervical premalignancy/malignancy, as detected by cervical cytology or biopsy, can develop as a result of human papillomavirus (HPV) infection. Meanwhile, DNA methylation is known to be associated with carcinogenesis. In this study, we thus attempted to identify the association between MGMT methylation and persistent HPV infection using an Epi-TOP MPP assay. Integrative analysis of DNA methylation was carried out here using longitudinal cervical cytology samples of seven patients with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (ASC-US/LSIL). Then, a gene expression analysis using the longitudinal cervical cytology samples and a public database (The Cancer Genome Atlas (TCGA)) was performed. Upon comparing the ASC-US or LSIL samples at the 1st collection and the paired samples at the 2nd collection more than 6 months later, we found that they became hypermethylated over time. Then, using the longitudinal data, we found that the MGMT methylation was associated with HPV infection. Moreover, TCGA dataset revealed an association between downregulated MGMT mRNA expression and poor overall survival. This decreased MGMT mRNA expression was observed to have an inverse relationship with MGMT methylation levels. In this study, we found that the MGMT methylation level could potentially serve as a valuable prognostic indicator for the transition from ASC-US/LSIL to cervical cancer.

Shallow Whole-Genome Sequencing of Cell-Free DNA (cfDNA) Detects Epithelial Ovarian Cancer and Predicts Patient Prognosis.

Despite the progress in diagnostics and therapeutics, epithelial ovarian cancer (EOC) remains a fatal disease. Using shallow whole-genome sequencing of plasma cell-free DNA (cfDNA), we investigated biomarkers that could detect EOC and predict survival. Plasma cfDNA from 40 EOC patients and 20 healthy subjects were analyzed by shallow whole-genome sequencing (WGS) to identify copy number variations (CNVs) and determine the Z-scores of genes. In addition, we also calculated the genome-wide scores (Gi scores) to quantify chromosomal instability. We found that the Gi scores could distinguish EOC patients from healthy subjects and identify various EOC histological subtypes (e.g., high-grade serous carcinoma). In addition, we characterized EOC CNVs and demonstrated a relationship between RAB25 amplification (alone or with CA125), and disease-free survival and overall survival. This study identified RAB25 amplification as a predictor of EOC patient survival. Moreover, we showed that Gi scores could detect EOC. These data demonstrated that cfDNA, detected by shallow WGS, represented a potential tool for diagnosing EOC and predicting its prognosis.

A Study of the Plan and Performance Evaluation Method of an 8-m3 Chamber Using Ventilation Experiments and Numerical Analyses.

With increases in the time spent on indoor activities, the interests and technological demands regarding indoor air quality (IAQ) have also increased. Indoor air pollution is often caused by furniture or construction materials and chemical substances, such as volatile organic compounds (VOCs). As a way to remove such pollutants, efforts have been made to promote the management of indoor air quality through emission experiments. To conduct an experiment, such as the pollutant emission experiment involving substances harmful to the human body, a chamber to control various factors should be developed. By using such chambers, experimental variables can be minimized, quantitative analyses may be conducted, and the basic theory may be discussed. When the chamber is installed, it is not easy to change the existing installed conditions. Therefore, it is necessary to review feasibility with an accurate design. However, there is limited research on both how to quantitatively design the chamber and evaluate it. Therefore, this study investigates suitable chamber design methods and performance through ventilation performance evaluation to discuss potential development methods. In the chamber design step, a computational fluid dynamics (CFD) analysis was performed to estimate the ventilation efficiency according to the inlet and outlet positions to develop an 8-m3 chamber. Next, a ventilation experiment was performed using the tracer gas method for the performance evaluation, while the chamber interior airflow was simulated based on the CFD analysis. In a ventilation experiment using a tracer gas, the variation in gas density leads to concentration imbalance; as a result of concentration imbalance at each point, errors may occur in ventilation efficiency depending on the measurement point, causing the accuracy of the performance evaluation to fall. An attempt was made to resolve this problem by performing the ventilation experiment with a ceiling fan. The result indicated that the performance evaluation could be conducted without altering ventilation efficiency, coinciding with the CFD analysis result. Furthermore, when the concentration field was examined according to time in the CFD analysis, uniform concentration of chamber interior air allowed the ventilation efficiency to be calculated irrespective of the measurement point. Based on the findings, this study suggests a quantitative method of performance evaluation with an experiment in an 8-m3 chamber and a concurrent CFD analysis.

Polystyrene nanoparticles incorporate into the endoplasmic reticulum and disturb translation during meiotic maturation in mouse oocytes.

Polystyrene (PS) is one of the most common polymers that cause plastic pollution after release into the environment. Although a growing body of evidence has shown the adverse effects of PS on living organisms including humans, their effects on mammalian oocytes have not been extensively studied. In this study, we investigated the effect of exposure to PS-nanoparticle (PS-NPs) on meiotic maturation in mouse oocytes. We found that exogenous PS-NPs internalized into oocytes after penetrating the zona pellucida and accumulated in the cytoplasm of oocytes during meiotic maturation. Exposure to PS-NPs did not affect meiotic resumption but inhibited meiotic maturation by impairing spindle assembly and chromosome alignment. Moreover, exposure to PS-NPs increased oxidative stress and mitochondrial aggregation during meiotic maturation. Notably, internalized PS-NPs localized around the endoplasmic reticulum (ER) and disturbed translation in oocytes. Therefore, it is suggested that PS-NPs impair meiotic maturation not only by increasing oxidative stress and mitochondrial dysfunction, but also by decreasing translation efficiency after incorporating into the ER during meiotic maturation in mouse oocytes.

Evaluating the spatial and temporal patterns of the severe fever thrombocytopenia syndrome in Republic of Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is a new infectious disease with a high mortality rate and increased incidence in Republic of Korea since the first case was reported in 2013. The average mortality rate varies by region and year but remains high in Asia. This study aimed to evaluate the spatial and temporal patterns of SFTS cases reported to the national Disease Control and Prevention Agency (KDCA). We analysed the spatial and temporal distribution of SFTS and observed changes in areas vulnerable to the disease. We analysed data concerning 1086 confirmed SFTS patients from 2013 to 2019 categorized according to the 247 district level administrative units. To better understand the epidemiology of SFTS, we carried out spatiotemporal analyses on a yearly basis and also calculated and mapped spatial clusters of domestic SFTS by global (regional) and local Moran's indices. To observe the annual changes in SFTS incidence rate, scan statistics for each city and district were calculated. The incidence rate showed significant clustering in specific regions, which reoccurred annually in some regions. In Republic of Korea, SFTS clusters have been expanding into the southern regions, with annual clusters concentrated between May and October. This pattern allows prediction of SFTS occurrences through spatiotemporal analysis, which makes it possible to guide measures of disease prevention.

The epidemiological characteristics and spatio-temporal analysis of childhood hand, foot and mouth disease in Korea, 2011-2017.

OBJECTIVES: Hand-foot-mouth disease (HFMD) is a common viral infection in children, with a significant disease burden due to its high contagion rate. This report studied the epidemiological characteristics as well as the chronological and geographical distribution of HFMD in children younger than 6 years of age in Korea. METHODS: This report established a database by integrating population and geographical data from health insurance claims for HFMD between 2011 and 2017, with an age restriction of ≤6 years, and explored the epidemiological characteristics of both HFMD patients and hospitalized cases in Korea. The relative risk ratio and spatio-temporal scan statistics were calculated by administrative district, using SaTScan. RESULTS: Over a 7-year period, 1,879,342 children under the age of 6 were diagnosed with HFMD (8.4 of 100 persons younger than 6 years of age). Seasonal incidence tended to increase from week 17 (May) peak between weeks 29 (July) and 39 (September), and increase rapidly in 1- to 2-year cycles. HFMD primarily occurred in children younger than 4 years of age. Furthermore, the greatest proportion of cases occurred at ages 1 (39.2%) and 2 (25.7%). Overall, 92.6% of all cases occurred before the age of 6. The proportion of cases before the age of 6was slightly higher in males. The timing of HFMD epidemics differed over the years. In 2015, the HFMD cumulative incidence was the lowest (5.5/1,000), and the spatio-temporal cluster (RR 2.32) was predominantly located south-central Korea, covering 65 counties for twenty-two weeks. In 2016, however, its cumulative incidence was high (RR 6.34) over a short period (11 weeks) in specific areas such as Ulsan, Daegu, Busan, and Gyeongnam. Also, the southern parts of Korea were found to have a higher rate of hospitalization. CONCLUSIONS: HFMD in Korea is common in children younger than 6 years of age, and it tends to peak in the summer.