Combined DNA Methylation and Gastric Microbiome Marker Predicts Helicobacter pylori-Negative Gastric Cancer.

Background/Aims: While DNA methylation and gastric microbiome are each associated with gastric cancer (GC), their combined role in predicting GC remains unclear. This study investigated the potential of a combined DNA methylation and gastric microbiome signature to predict Helicobacter pylori-negative GC. Methods: In this case-control study, we conducted quantitative methylation-specific polymerase chain reaction to measure the methylation levels of DKK3, SFRP1, EMX1, NKX6-1, MIR124-3, and TWIST1 in the gastric mucosa from 75 H. pylori-negative patients, including chronic gastritis (CG), intestinal metaplasia (IM), and GC. A combined analysis of DNA methylation and gastric microbiome, using 16S rRNA gene sequencing, was performed in 30 of 75 patients. Results: The methylation levels of DKK3, SFRP1, EMX1, MIR124-3, and TWIST1 were significantly higher in patients with GC than in controls (all q<0.05). MIR124-3 and TWIST1 methylation levels were higher in patients with IM than those with CG and also in those with GC than in those with IM (all q<0.05). A higher methylation level of TWIST1 was an independent predictor for H. pylori-negative GC after adjusting for age, sex, and atrophy (odds ratio [OR], 15.15; 95% confidence interval [CI], 1.58 to 145.46; p=0.018). The combination of TWIST1 methylation and GC microbiome index (a microbiome marker) was significantly associated with H. pylori-negative GC after adjusting for age, sex, and atrophy (OR, 50.00; 95% CI, 1.69 to 1,476; p=0.024). Conclusions: The combination of TWIST1 methylation and GC microbiome index may offer potential as a biomarker for predicting H. pylori-negative GC.

Human papillomavirus Detection Rates in Bowen's Disease: Correlation with Pelvic and Digital Region Involvement and Specific p53 Immunostaining Patterns.

BACKGROUND: The relationship between human papillomavirus (HPV) and Bowen's disease (BD) is not fully understood. OBJECTIVES: To investigate the differences in HPV detection rates in BD samples across various body regions and analyze the expression patterns of p53, p16, and Ki-67 in relation to HPV presence. METHODS: Tissue samples from patients diagnosed with BD, confirmed through histopathology, were retrospectively collected. Next-generation sequencing was used for HPV DNA detection. Immunohistochemistry (IHC) for p16, p53, and Ki-67 was performed. RESULTS: Out of 109 patients with BD, 21 (19.3%) were HPV-positive. All identified types were α-HPVs, with HPV-16 being the most common. The HPV detection rate was significantly higher in the pelvic (69.2%, P<0.001) and digital (50.0%, P=0.022) areas compared to those in the other regions. HPV presence was significantly correlated with p53 negativity (P=0.002), the p53 "non-overexpression" IHC pattern (P<0.001), and p53-p16 immunostain pattern discordance (P<0.001). Conversely, there was no notable association between HPV presence and p16 positivity, the p16 IHC pattern, or Ki-67 expression. CONCLUSIONS: Our findings suggest the oncogenic role of sexually transmitted and genito-digitally transmitted α-HPVs in pathogenesis of BD in the pelvic and digital regions.

Identification of novel Carnobacterium maltaromaticum strains in bone marrow samples of patients with acute myeloid leukemia using a metagenomic binning approach.

The aim of this study aimed to examine the existence of a bacterial metagenome in the bone marrow of patients with acute myeloid leukemia (AML). We re-examined whole-genome sequencing data from the bone marrow samples of seven patients with AML, four of whom were remitted after treatment, for metagenomic analysis. After the removal of human reads, unmapped reads were used to profile the species-level composition. We used the metagenomic binning approach to confirm whether the identified taxon was a complete genome of known or novel strains. We observed a unique and novel microbial signature in which Carnobacterium maltaromaticum was the most abundant species in five patients with AML or remission. The complete genome of C. maltaromaticum "BMAML_KR01," which was observed in all samples, was 100% complete with 8.5% contamination and closely clustered with C. maltaromaticum strains DSM20730 and SF668 based on single nucleotide polymorphism variations. We identified five unique proteins that could contribute to cancer progression and 104 virulent factor proteins in the BMAML_KR01 genome. To our knowledge, this is the first report of a new strain of C. maltaromaticum in patients with AML. The presence of C. maltaromaticum and its new strain in patients indicates an urgent need to validate the existence of this bacterium and evaluate its pathophysiological role.

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.

Concurrent sorption of antimony and lead by iron phosphate and its possible application for multi-oxyanion contaminated soil.

Concurrent stabilization of oxyanions such as antimony (Sb), arsenic (As), and heavy metals including lead (Pb) and manganese (Mn) in contaminated soils is difficult because of their diverse chemical properties. Antimony and As are stabilized by sorption with iron oxides while heavy metals are stabilized by phosphate. Hence, iron phosphate can be used to simultaneously stabilize Sb and Pb. Therefore, this study aimed to evaluate the possibility of simultaneous stabilization of Sb and Pb using iron phosphate. A single and a mixed solution of Sb and Pb were reacted with synthesized iron phosphate. Contaminated soil by Sb, As, Mo, Cr, and Mn was treated with iron phosphate, and bioavailable metal concentrations were evaluated by extracting the soil with 0.05 M ammonium sulfate. In a single solution, Sb(III) and Sb(V) sorption rate ranged up to 97% and 65%, respectively. In a mixed metal solution, Sb sorption increased compared to the single solution and Pb removal reached more than 95% in all cases. The sorption of Sb increased as the pH decreased, but the Sb(III) sorption was less affected by the pH than Sb(V). In various pH ranges, Sb(III) and Sb(V) sorption rates increased by 26 ~ 32% and 38 ~ 68%, respectively, compared to the single solution. Especially, Sb(V) sorption significantly increased in the presence of Pb at lower pH because of the lower solubility of iron phosphate. In soil, iron phosphate slightly decreased bioavailable As, Cr, Mo, Sb, and Mn concentrations. Therefore, metalloids and metals can be simultaneously stabilized by iron phosphate both in solution and soil.

Altered Gastric Microbiota and Inflammatory Cytokine Responses in Patients with Helicobacter pylori-Negative Gastric Cancer.

The role of the gastric mucosal microbiome in Helicobacter pylori-negative gastric cancer (GC) remains unclear. Therefore, we aimed to characterize the microbial alterations and host inflammatory cytokine responses in H. pylori-negative GC. Gastric mucosal samples were obtained from 137 H. pylori-negative patients with GC (n = 45) and controls (chronic gastritis or intestinal metaplasia, n = 92). We performed 16S rRNA gene sequencing (n = 67), a quantitative reverse transcription-polymerase chain reaction to determine the relative mRNA expression levels of TNF (tumor necrosis factor), IL1B (interleukin 1 beta), IL6 (interleukin 6), CXCL8 (C-X-C motif chemokine ligand 8), IL10 (interleukin 10), IL17A (interleukin 17A), TGFB1 (transforming growth factor beta 1) (n = 113), and the correlation analysis between sequencing and expression data (n = 47). Gastric mucosal microbiota in patients with GC showed reduced diversity and a significantly different composition compared to that of the controls. Lacticaseibacillus was significantly enriched, while Haemophilus and Campylobacter were depleted in the cancer group compared to the control group. These taxa could distinguish the two groups in a random forest algorithm. Moreover, the combined relative abundance of these taxa, a GC microbiome index, significantly correlated with gastric mucosal IL1B expression, which was elevated in the cancer group. Overall, altered gastric mucosal microbiota was found to be associated with increased mucosal IL1B expression in H. pylori-negative GC.

Sex-specific associations between gut microbiota and skeletal muscle mass in a population-based study.

BACKGROUND: A gut-muscle axis through which the microbiome influences skeletal muscle has been hypothesized. However, sex-specific association between the characteristics of gut microbiota and skeletal muscle mass has not yet been reported. Herein, we performed sex-specific analyses of faecal microbiota composition for the skeletal muscle mass in a population-based cohort. METHODS: We collected faecal samples of 1052 middle-aged participants (621 men and 431 women) who attended health screenings, and we analysed the intestinal microbiota using 16S rRNA gene sequencing. Relative muscle mass was calculated using a bioelectrical impedance analysis and presented as the skeletal muscle mass index [SMI (%) = total appendicular muscle mass (kg)/weight (kg) × 100]. We categorized the subjects into four groups by the quartile of the SMI. Association tests between gut microbiota and SMI were conducted according to the microbial diversity, taxonomic profiling and functional inference in a sex-stratified manner. RESULTS: The mean age and SMI of the total participants were 44.8 years (standard deviation [SD], 8.2) and 41.4% (SD, 3.9), respectively. After adjustments for possible covariates such as age, body mass index and regular physical activity, the highest quartile (Q4) group of SMI had higher alpha diversity than the lowest quartile (Q1) group in male participants (coefficient = 10.79, P < 0.05, linear regression model), whereas there was no difference in diversity among SMI groups in females. At the species level, Haemophilus parainfluenzae (coefficient = 1.910) and Roseburia faecis (coefficient = 1.536) were more abundant in the highest SMI (Q4) group than in the lowest SMI (Q1) group in males. However, no significant taxon was observed along the SMI groups in females. The gut microbiota of the lowest SMI group (Q1) was enriched with genes involved in biosynthesis of amino acids and energy generation compared with that of the highest SMI group (Q4) in both sexes, although the significance of the inferred pathways was weak (P < 0.05 but the false discovery rate q > 0.05). CONCLUSIONS: In this large sample of middle-aged individuals, this study highlights fundamental sex-specific differences in the microbial diversity, composition and metabolic pathways inferred from gut microbiota according to SMI. The gut microbiota may provide novel insights into the potential mechanisms underlying the sex dependence of skeletal muscle mass.

Gastric cancer with Epstein-Barr virus heterogeneity: Evaluation of the frequency, clinicopathologic features, and genomic profiles.

Epstein-Barr virus (EBV)-associated gastric carcinoma accounts for approximately 10% of gastric carcinomas worldwide and is characterized by distinct clinicopathological features. Recently, the use of EBV as a reliable biomarker for immunotherapy of gastric cancer has been gaining focus. We aimed to investigate the frequency and clinicopathological characteristics of gastric cancer with EBV heterogeneity. EBV status was evaluated using EBV-encoded RNA in situ hybridization in 3499 consecutive surgical cases of gastric cancer. We selected heterogeneous EBV cases and evaluated their clinicopathological features. CD8, programmed death-ligand 1 status, and genomic profiles were separately evaluated in each EBV-positive and EBV-negative area of heterogeneous cases. EBV positivity was identified in 214 (6.1 %) cases, of which four (1.9 %) were found to be EBV heterogeneous. Of the four heterogeneous EBV cases, three were composed of two histologically distinct patterns that correlated with EBV status. The EBV-positive area consisted of poorly differentiated adenocarcinomas with increased lymphocytic infiltration. Notably, the fraction of EBV-positive cells was more infiltrative, and metastatic tumors in the lymph nodes were all EBV-positive. The average number of CD8-positive cells was higher in EBV-positive areas than in EBV-negative areas (P = 0.030). Each EBV-positive and EBV-negative area revealed some different genomic alterations, including FGFR2 amplification. In conclusion, we have reported four cases of gastric cancer with heterogeneous EBV status, which accounted for 1.9% of EBV-positive gastric cancers. Each EBV-positive and-negative area revealed a distinct histological pattern, immune microenvironment, and some different genomic profiles.

Changes in salivary matrix metalloproteinase-3, -8, and -9 concentrations after 6 weeks of non-surgical periodontal therapy.

BACKGROUND: Studies using salivary inflammatory biomarkers for diagnosing and monitoring the progression of periodontal disease have garnered increased attention in recent years. The present study aimed to identify changes in clinical parameters and concentrations of salivary matrix metalloproteinases (MMPs) following 6 weeks of non-surgical periodontal therapy (NSPT). METHODS: A 6-week NSPT program was applied to 51 adults aged ≥ 20 years. The program involved scaling, root planing, and professional toothbrushing for healthy participants and those with periodontal disease. Patients with periodontal disease underwent professional toothbrushing during all three visits. Periodontal pocket depth (PD) and gingival bleeding were assessed at week 0, week 3, and week 6, and saliva samples were collected to measure the concentrations of MMP-3, -8, and -9. RESULTS: All clinical parameters were improved in the periodontal disease groups following the NSPT course. Compared with healthy participants, the patients with periodontal disease showed increased concentrations of salivary MMP-3, -8, and -9. During the 6-week program, patients with periodontal disease also showed significant reductions in PD and gingival bleeding during the third week; no significant reduction was found during the sixth week. Significant reductions in the concentrations of salivary MMP-3, -8, and -9 were also noted in the periodontal disease group at week 3. The sensitivity and specificity of MMP-3 for predicting periodontitis were 81.8% and 55.5%, respectively. CONCLUSION: The present study found that NSPT resulted in reductions of salivary MMP-3, -8, and -9, and identified the potential of MMP-3 as a biomarker in the diagnosis of periodontal disease. These findings may serve as foundational data for future studies into the development of diagnostic kits for periodontal disease.

Peripheral T cell lymphoma of the nasopharynx with expansion of EBV-positive B cells masquerading as an extranodal NK/T cell lymphoma, nasal type.

Epstein-Barr virus-infected B cells are found at high frequency in peripheral T cell lymphoma. Herein, we report a case involving excessive EBV-positive B cells accompanying peripheral T cell lymphoma, not otherwise specified in the nasopharynx masquerading as nasopharyngeal extranodal NK/T cell lymphoma. A large number of Epstein-Barr virus-infected B cells infiltrate in between CD3-positive cytotoxic tumor T cells, as if EBV was infecting tumor T cells. After chemotherapy, the T cell lymphoma population decreased, but the B cell population expanded to form EBV-positive diffuse large B cell lymphoma in the tonsils and nasopharynx. At the follow-up, bone marrow biopsy exhibited infiltration of composite peripheral T cell lymphoma, not otherwise specified, and EBV-positive diffuse large B cell lymphoma. Although this condition is rare, the cell lineage of EBV-infected cells must be confirmed when diagnosing extranodal NK/T cell lymphoma to exclude the possibility of misdiagnosis by Epstein-Barr virus-infected B cells.

Corticosteroid-induced drug reaction with eosinophilia and systematic symptoms successfully treated with a tumor necrosis factor alpha inhibitor.

BACKGROUND: Despite recent advances in the treatment of drug reaction with eosinophilia and systemic symptoms (DRESS), the mainstay of treatment involves discontinuing the culprit drugs and administering topical or systemic corticosteroid. OBJECTIVE: The clinical use of a tumor necrosis factor (TNF)-alpha inhibitor was rarely explored in treatment of DRESS. METHODS: We present a case of corticosteroid-induced DRESS that was successfully treated with a TNF-alpha inhibitor without sequalae. RESULTS: This is the first case report that showed the clinical use of a TNF alpha inhibitor in treating corticosteroids- induced DRESS and immediate hypersensitivity reactions. The HLA-B*5801 was identified as a possible genetic factor associated with a corticosteroid-induced DRESS. CONCLUSIONS: A TNF-alpha inhibitor could be a primary option in treating DRESS, especially in patients with hypersensitivity reaction to corticosteroids.

Composite follicular lymphoma and classic Hodgkin lymphoma.

Composite lymphoma is very rare and a combination of Hodgkin lymphoma and non-Hodgkin lymphoma and even histiocytic tumors can occur. Because of the unfamiliarity, not only can this cause diagnostic problems, but can also affect treatment plan. We report a case of composite lymphoma in a 40-year-old male. Initial biopsy showed a composite lymphoma of follicular lymphoma grade 1 and classic Hodgkin lymphoma. After chemotherapy, another lymph node was taken because of disease progression, which revealed follicular lymphoma, grade 3a without Hodgkin lymphoma component.

Gut Microbiota Composition across Normal Range Prostate-Specific Antigen Levels.

Animal studies have shown the interaction between androgens and the gut microbiome directly and indirectly; however, limited evidence from human studies is available. To evaluate the association between prostate-specific antigen (PSA) levels within the normal range, reflective of androgen receptor activity, and the gut microbiota composition, a cross-sectional analysis was performed in 759 Korean men aged between 25 and 78 years with normal PSA levels of ≤4.0 ng/mL. We evaluated the biodiversity of gut microbiota as well as the taxonomic and functional signatures associated with PSA levels using 16S rRNA gene sequencing data. PSA levels within the normal range were categorized into three groups: lowest quartile (G1), interquartile range (G2, reference), and highest quartile (G3). The G3 group had higher microbial richness than the G2 group, although it was dominated by a few bacteria. An increase in Escherichia/Shigella abundance and a reduction in Megamonas abundance in the G3 group were also detected. A U-shaped relationship was observed between the three groups across most analyses, including biodiversity, taxonomic composition, and inferred pathways in the gut microbiota. This study showed different microbiota patterns across PSA levels within the normal range. Further studies are required to elucidate the role of microbiota in regulating PSA levels.

Low-level alcohol consumption and cancer mortality.

The effect of light-to-moderate alcohol consumption on cancer risk remains controversial. We examined the association between low-level alcohol consumption and cancer mortality. A cohort study included 331,984 Korean adults free of cancer at baseline who underwent a comprehensive health checkup examination. Participants were categorized into never drinkers, former drinkers, and current drinkers who were further divided into light, moderate, heavy, and very heavy drinkers. Vital status and cancer-related deaths were ascertained through links to national death records. During 1,633,906 person-years of follow-up (median 5.3 years interquartile range 3.8-6.2), 374 cancer-related deaths were identified (cancer-cause mortality rate of 23 per 105 person-years). When former and never drinkers were classified as non-drinkers, the light drinkers had a lowest risk of cancer mortality compared with non-drinkers and other current drinkers (J-shaped); however, with consideration of lifetime abstinence history, current drinking was positively associated with cancer mortality in a dose-dependent manner. When changes in alcohol drinking status and confounders during follow-up were updated as time-varying covariates and never drinkers were used as the reference, the multivariable-adjusted hazard ratios (HRs) (95% confidence intervals, CIs) for cancer mortality among current light, moderate, heavy, and very heavy drinkers were 1.58 (1.03-2.43), 2.28 (1.41-3.70), 2.34 (1.42-3.85), and 2.97 (1.80-4.90), respectively, and the highest risk of cancer mortality was observed in former drinkers, who had an HR (95% CI) of 3.86 (2.38-6.28). Alcohol consumption was significantly and positively associated with an increased risk of cancer mortality in a dose-dependent manner, beginning with light drinkers.

Prognostic value of tumor budding in gallbladder cancer: application of the International Tumor Budding Consensus Conference scoring system.

Tumor budding (TB), a histopathological manifestation of epithelial-mesenchymal transition, is an important step in cancer invasion and metastasis development. TB has been considered a strong prognostic indicator in colorectal cancer. The International Tumor Budding Consensus Conference (ITBCC) scoring system is the standardized method used for patient outcome prediction in several human tumors. We investigated the clinicopathological implications and applicability of TB measured using the ITBCC scoring system in gallbladder cancer (GBC). The TB grades assigned to the 78 GBC patients were as follows: Bd1 (low TB), 41 (52.6%) patients; Bd2 (intermediate TB), 22 (28.2%) patients; and Bd3 (high TB), 15 (19.2%) patients. A higher TB grade correlated with a poorer histological differentiation (P < 0.000), higher pT category (P < 0.000), the involvement of surgical resection margin (P = 0.005), presence of nodal metastasis (P < 0.000), lymphatic and venous invasion (P < 0.000), and perineural invasion (P = 0.004). Univariate Cox regression analysis revealed that a poor histological grade, high pT category, lymphatic invasion, perineural invasion, and intermediate to high TB grades were associated with worse 5-year overall survival and disease-free survival. TB was not significantly associated with death or recurrence risk in multivariate Cox analysis. The interobserver agreement of TB grading was substantial. This study is the first to apply the ITBCC scoring system and suggest the prognostic value of TB in GBC.

Gene expression in the striatum of cynomolgus monkeys after chronic administration of cocaine and heroin.

Cocaine and heroin cause impairment of neural plasticity in the brain including striatum. This study aimed to identify genes differentially expressed in the striatum of cynomolgus monkeys in response to cocaine and heroin. After chronic administration of cocaine and heroin in the monkeys, we performed large-scale transcriptome profiling in the striatum using RNA-Seq technology and analysed functional annotation. We found that 547 and 1238 transcripts were more than 1.5-fold up- or down-regulated in cocaine- and heroin-treated groups, respectively, compared to the control group, and 3432 transcripts exhibited differential expression between cocaine- and heroin-treated groups. Functional annotation analysis indicated that genes associated with nervous system development (NAGLU, MOBP and TTL7) and stress granule disassembly (KIF5B and KLC1) were differentially expressed in the cocaine-treated group compared to the control group, whereas gene associated with neuron apoptotic process (ERBB3) was differentially expressed in the heroin-treated group. In addition, IPA network analysis indicated that genes (TRAF6 and TRAF3IP2) associated with inflammation were increased by the chronic administration of cocaine and heroin. These results provide insight into the correlated molecular mechanisms as well as the upregulation and down-regulation of genes in the striatum after chronic exposure to cocaine and heroin.

Establishment and Characterization of Immortalized Miniature Pig Pancreatic Cell Lines Expressing Oncogenic K-RasG12D.

In recent decades, many studies on the treatment and prevention of pancreatic cancer have been conducted. However, pancreatic cancer remains incurable, with a high mortality rate. Although mouse models have been widely used for preclinical pancreatic cancer research, these models have many differences from humans. Therefore, large animals may be more useful for the investigation of pancreatic cancer. Pigs have recently emerged as a new model of pancreatic cancer due to their similarities to humans, but no pig pancreatic cancer cell lines have been established for use in drug screening or analysis of tumor biology. Here, we established and characterized an immortalized miniature pig pancreatic cell line derived from primary pancreatic cells and pancreatic cancer-like cells expressing K-rasG12D regulated by the human PTF1A promoter. Using this immortalized cell line, we analyzed the gene expression and phenotypes associated with cancer cell characteristics. Notably, we found that acinar-to-ductal transition was caused by K-rasG12D in the cell line constructed from acinar cells. This may constitute a good research model for the analysis of acinar-to-ductal metaplasia in human pancreatic cancer.

Health-Risk Behavior-, Mental Health-, and Physical Exercise-Related Risk Factors for Tooth Fractures in Korean Adolescents.

We aimed to determine factors related to tooth fracture experience in Korean adolescents. This study used data from the 14th Korea Youth Risk Behavior Survey in 2018, a cross-sectional web-based survey of health-risk behaviors among a representative sample of Korean middle- and high-school students aged 12-17 years. A total of 60,040 participants were selected using a complex sampling design of the survey from 400 middle schools and 400 high schools. They answered a self-administered questionnaire survey in classrooms. Explanatory variables included those pertaining to health-risk behaviors, mental health, and physical exercise. Complex-sample multivariable logistic regression models were applied to identify factors related to tooth fracture experience in the past 12 months. The overall prevalence of dental fracture experience was 11.4%. Risk factors related to tooth fractures in Korean adolescents were unhealthy behaviors such as alcohol and tobacco consumption; mental health problems including stress, depression, and suicidal ideation; and intensive physical exercise. The major risk factor related to tooth fractures was depression. To prevent tooth fractures among adolescents, schools should strengthen mental health education, encourage mouthguard use during intensive physical exercise, and develop school environments to prevent orofacial injuries. Further studies on various risk factors related to tooth fractures are warranted.

Polygenic analysis of the effect of common and low-frequency genetic variants on serum uric acid levels in Korean individuals.

Increased serum uric acid (SUA) levels cause gout and are associated with multiple diseases, including chronic kidney disease. Previous genome-wide association studies (GWAS) have identified more than 180 loci that contribute to SUA levels. Here, we investigated genetic determinants of SUA level in the Korean population. We conducted a GWAS for SUA in 6,881 Korean individuals, calculated polygenic risk scores (PRSs) for common variants, and validated the association of low-frequency variants and PRS with SUA levels in 3,194 individuals. We identified two low-frequency and six common independent variants associated with SUA. Despite the overall similar effect sizes of variants in Korean and European populations, the proportion of variance for SUA levels explained by the variants was greater in the Korean population. A rare, nonsense variant SLC22A12 p.W258X showed the most significant association with reduced SUA levels, and PRSs of common variants associated with SUA levels were significant in multiple Korean cohorts. Interestingly, an East Asian-specific missense variant (rs671) in ALDH2 displayed a significant association on chromosome 12 with the SUA level. Further genetic epidemiological studies on SUA are needed in ethnically diverse cohorts to investigate rare or low-frequency variants and determine the influence of genetic and environmental factors on SUA.

Hepatic Angiosarcoma: Clinicopathologic Study With an Investigation of ROS1 Gene Rearrangements.

BACKGROUND/AIM: Primary hepatic angiosarcoma (PHA) is a rare disease entity with variable morphologic features. Recent findings regarding ROS1 gene rearrangements in PHA may lead to new targeted therapies. PATIENTS AND METHODS: Thirteen cases (4 resected specimens and 9 biopsy samples) underwent histologic review and morphologic patterns were classified according to a previous study as 1) sinusoidal, 2) peliotic, 3) vasoformative, and 4) solid (epithelioid/spindled). ROS1 immunohistochemistry and investigation of the presence of a ROS1 fusion gene by reverse transcription-polymerase chain reaction were performed in available cases. RESULTS: Eight of 13 cases (62%) showed vasoformative patterns. Three cases (23%) were classified as sinusoidal and two (15%) as solid patterns. Mortality rate was 90% (9/10) except for three patients lost in follow up. Only one patient is still alive and has survived for 8 months with the disease. All cases tested did not have ROS1 expression (0/9) or a ROS1 fusion gene (0/4). CONCLUSION: We report 13 cases of PHA with 90% mortality. Vasoformative PHA is the most common histologic type. New findings on ROS1 fusion gene rearrangements could lead to the development of novel targeted therapeutics for PHA patients with dismal prognosis.