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Background: Epstein–Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5–16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea. Methods: A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV–ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed. Results: A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan–Meier survival curve. However, this effect was evident only in males. Conclusions: EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females. [ABSTRACT FROM AUTHOR]

Nanoencapsulation of living cells within artificial shells is a powerful approach for augmenting the inherent capacity of cells and enabling the acquisition of extrinsic functions. However, the current state of the field requires the development of nanoshells that can dynamically sense and adapt to environmental changes by undergoing transformations in form and composition. This paper reports the compositional transformation of an enzyme‐embedded nanoshell of Fe3+‐trimesic acid complex to an iron phosphate shell in phosphate‐containing media. The cytocompatible transformation allows the nanoshells to release functional molecules without loss of activities and biorecognition, while preserving the initial shell properties, such as cytoprotection. Demonstrations include the lysis and killing of Escherichia coli by lysozyme, and the secretion of interleukin‐2 by Jurkat T cells in response to paracrine stimulation by antibodies. This work on micrometric Transformers will benefit the creation of cell‐in‐shell nanobiohybrids that can interact with their surroundings in active and adaptive ways. [ABSTRACT FROM AUTHOR]

We aimed to investigate whether mitochondrial dysfunction in extracellular cerebrospinal fluid (CSF), which is associated with autophagy and mitophagy, might be involved in neurological outcomes in adult patients with hemorrhagic moyamoya disease (MMD) whose pathogenesis related to poor outcomes is not well-known. CSF samples were collected from 43 adult MMD patients and analyzed according to outcomes at 3 months. Fluorescence-activated cell sorter analysis (FACS) and the JC-1 red/green ratio were used to assess mitochondrial cells and intact mitochondrial membrane potential (MMP). We performed quantitative real-time polymerase chain reaction and Western blotting analyses of autophagy and mitophagy-related markers, including HIF1α, ATG5, pBECN1, BECN1, BAX, BNIP3L, DAPK1, and PINK1. Finally, FACS analysis with specific fluorescence-conjugated antibodies was performed to evaluate the potential cellular origin of CSF mitochondrial cells. Twenty-seven females (62.8%) with a mean age of 47.4 ± 9.7 years were included in the study. Among 43 patients with hemorrhagic MMD, 23 (53.5%) had poor outcomes. The difference in MMP was evident between the two groups (2.4 ± 0.2 in patients with poor outcome vs. 3.5 ± 0.4 in patients with good outcome; p = 0.02). A significantly higher expression (2–ΔCt) of HIF1α, ATG5, DAPK1 followed by BAX and BNIP3L mRNA and protein was also observed in poor-outcome patients compared to those with good outcomes. Higher percentage of vWF-positive mitochondria, suggesting endothelial cell origins, was observed in patients with good outcome compared with those with poor outcome (25.0 ± 1.4% in patients with good outcome vs. 17.5 ± 1.5% in those with poor outcome; p < 0.01). We observed the association between increased mitochondrial dysfunction concomitant with autophagy and mitophagy in CSF cells and neurological outcomes in adult patients with hemorrhagic MMD. Further prospective multicenter studies are needed to determine whether it has a diagnostic value for risk prediction. [ABSTRACT FROM AUTHOR]

3Comparisons of gastric cancer-specific survival depending on Helicobacter pylori eradication. The benefits of gastric cancer-specific survival were observed in the successfully eradicated group before (a) and after (b) propensity score matching compared to non-eradicated group, with statistical significance (P < 0.001). Correction: Effect of Helicobacter pylori eradication after subtotal gastrectomy on the survival rate of patients with gastric cancer: follow-up for up to 15 years. [Extracted from the article]

Background: The incidence and mortality rates of colorectal cancer (CRC) has been reported to be strongly associated to sex/gender difference. CRC shows sexual dimorphism, and sex hormones have been shown to affect the tumor immune microenvironment. This study aimed to investigate location-dependent sex differences in tumorigenic molecular characteristics in patients with colorectal tumors, including adenoma and CRC. Methods: A total of 231 participants, including 138 patients with CRC, 55 patients with colorectal adenoma, and 38 healthy controls, were recruited between 2015 and 2021 at Seoul National University Bundang Hospital. All patients underwent colonoscopy and acquired tumor lesion samples were further analyzed for programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) expression, deficient mismatch repair (dMMR), and microsatellite instability (MSI) status. This study was registered with ClinicalTrial.gov, number NCT05638542. Results: The average of combined positive score (CPS) was higher in serrated lesions and polyps (lesions/polyps) compared to conventional adenomas (5.73 and 1.41, respectively, P < 0.001). No significant correlation was found between sex and PD-L1 expression within the groups, regardless of histopathological diagnosis. In multivariate analysis where each sex was further stratified by tumor location due to their interaction in CRC, PD-L1 expression was inversely correlated with males having proximal CRC with a CPS cutoff of 1 (Odds ratio (OR) 0.28, P = 0.034). Females with proximal CRC showed a significant association with dMMR/MSI-high (OR 14.93, P = 0.032) and high EGFR expression (OR 4.17, P = 0.017). Conclusion: Sex and tumor location influenced molecular features such as PD-L1, MMR/MSI status and EGFR expression in CRC, suggesting a possible underlying mechanism of sex-specific colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: Single-cell RNA sequencing (scRNA-seq) enables the systemic assessment of intratumoral heterogeneity within tumor cell populations and in diverse stromal cells of the tumor microenvironment. Gain of treatment resistance during tumor progression or drug treatment are important subjects of tumor-centric scRNA-seq analyses, which are hampered by scarce tumor cell portions. To guarantee the inclusion of tumor cells in the data analysis, we developed a prescreening strategy for lung adenocarcinoma.Methods: We obtained candidate genes that were differentially expressed between normal and tumor cells, excluding stromal cells, from the scRNA-seq data. Tumor cell-specific expression of the candidate genes was assessed via real-time reverse transcription-polymerase chain reaction (RT-PCR) using lung cancer cell lines, normal vs. lung cancer tissues, and lymph node biopsy samples with or without metastasis.Results: We found that CEA cell adhesion molecule 5 (CEACAM5) and high mobility group box 3 (HMGB3) were reliable markers for RT-PCR-based prescreening of tumor cells in lung adenocarcinoma.Conclusions: The prescreening strategy using CEACAM5 and HMGB3 expression facilitates tumor-centric scRNA-seq analyses of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

The human ventromedial prefrontal cortex (vmPFC) has been traditionally associated with decision-making under risk. Neuroimaging studies of such decision-making processes have largely focused on patients with vmPFC lesions or pathological gambling behavior, leading to a relative paucity of work focusing on the structural variability of the vmPFC in healthy individuals. To address this, we developed a decision-making task that allowed healthy players to choose to participate in either low stakes or high-stakes gambling on a trial-by-trial basis, and computed a metric that indexes the propensity for engaging in gambles with greater potential payoffs. We leveraged voxel-based morphometric analyses to examine the association between prefrontal gray matter volume and individual differences in the propensity for seeking high-risk/high-reward situations. Our analyses showed that vmPFC gray matter volume was inversely correlated with an increased tendency for engaging in high-stakes gambling. These results converge with findings from functional neuroimaging and brain lesion studies of vmPFC, and further extend them to show that normative variability in brain structure could also underpin risk-taking behavior. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in children; survivors experience long-term cognitive and motor deficits. To date, studies predicting outcome following pediatric TBI have primarily focused on acute behavioral responses and proxy measures of injury severity; unsurprisingly, these measures explain very little of the variance following heterogenous injury. In adults, certain acute imaging biomarkers help predict cognitive and motor recovery following moderate to severe TBI. This multi-center, retrospective study, characterizes the day-of-injury computed tomographic (CT) reports of pediatric, adolescent, and young adult patients (2 months to 21 years old) who received inpatient rehabilitation services for TBI (n = 247). The study also determines the prognostic utility of CT findings for cognitive and motor outcomes assessed by the Pediatric Functional Independence Measure, converted to age-appropriate developmental functional quotient (DFQ), at discharge from rehabilitation. Subdural hematomas (66%), contusions (63%), and subarachnoid hemorrhages (59%) were the most common lesions; the majority of subjects had less severe Rotterdam CT scores (88%, ≤ 3). After controlling for age, gender, mechanism of injury, length of acute hospital stay, and admission DFQ in multivariate regression analyses, the highest Rotterdam score (β = -25.2, p < 0.01) and complete cisternal effacement (β = -19.4, p < 0.05) were associated with lower motor DFQ, and intraventricular hemorrhage was associated with lower motor (β = -3.7, p < 0.05) and cognitive DFQ (β = -4.9, p < 0.05). These results suggest that direct detection of intracranial injury provides valuable information to aid in prediction of recovery after pediatric TBI, and needs to be accounted for in future studies of prognosis and intervention. [ABSTRACT FROM AUTHOR]

Background: Inactivation of TP53, a tumor suppressor gene, is associated with the development of several malignancies, including gastric cancer (GC). The present study aimed to evaluate the correlation between the overexpression of p53 and survival in different Lauren-type GCs. Methods: From May 2003 to December 2019, 3608 GC patients treated endoscopically or surgically at the Seoul National University Bundang Hospital were enrolled for the study. Immunohistochemical staining for p53 was performed on all endoscopic and surgical gastric specimens. Clinicopathologic characteristics with Lauren classification, survival rate, and cancer recurrence were analyzed according to p53 overexpression. Results: Among 3608 GC patients, p53 overexpression was seen in 1334 patients (37%). p53 overexpression was associated with lower depth of invasion (P = 0.026) and Early gastric cancer (P = 0.044) in intestinal-type GC, and with advanced TNM stage (P < 0.001) and Advanced gastric cancer (P < 0.001) in diffuse-type GC. The overall survival (OS) and GC-specific survival (GCSS) were significantly lower in p53 overexpression positive patients. This significance was more pronounced and enhanced in the diffuse-type GC and was absent in the intestinal-type GC. In multivariate analyses, p53 overexpression was associated with poor OS in both subtypes of GC and cancer recurrence in diffuse-type GC. (OS in intestinal-type: adjusted hazard ratio [aHR] = 1.423, P = 0.022; OS in diffuse-type: aHR = 1.401 P = 0.035; cancer recurrence in diffuse-type: aHR = 1.502, P = 0.039). Conclusion: p53 overexpression was associated with poor prognosis in GC, especially in diffuse-type. In addition, p53 overexpression was associated with early stage disease in intestinal-type GC and with advanced stage disease in diffuse-type GC. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors unleash inhibitory signals on T cells conferred by tumors and surrounding stromal cells. Despite the clinical efficacy of checkpoint inhibitors, the lack of target expression and persistence of immunosuppressive cells limit the pervasive effectiveness of the therapy. These limitations may be overcome by alternative approaches that co-stimulate T cells and the immune microenvironment. Methods: We analyzed single-cell RNA sequencing data from multiple human cancers and a mouse tumor transplant model to discover the pleiotropic expression of the Interleukin 7 (IL-7) receptor on T cells, macrophages, and dendritic cells. Results: Our experiment on the mouse model demonstrated that recombinant IL-7 therapy induces tumor regression, expansion of effector CD8 T cells, and pro-inflammatory activation of macrophages. Moreover, spatial transcriptomic data support immunostimulatory interactions between macrophages and T cells. Conclusion: These results indicate that IL-7 therapy induces anti-tumor immunity by activating T cells and pro-inflammatory myeloid cells, which may have diverse therapeutic applicability. [ABSTRACT FROM AUTHOR]

Objective: It remains unknown whether individuals with a family history (FH) of gastric cancer (GC) are associated with aberrant DNA methylation. The aim of this study was to investigate the association between aberrant DNA methylation and FH of GC. Design: Using quantitative MethyLight assay, MOS, miR124a-3, NKX6-1, EMX1, CDH1, and TWIST1 methylation levels in the noncancerous gastric mucosa was compared between subjects with and without FH based on GC and Helicobacter pylori (Hp) infection. Changes in the methylation levels were evaluated over time after Hp eradication. Results: In Hp-positive GC patients, MOS (P < 0.001), CDH1 (P < 0.001), and TWIST1 (P = 0.004) methylation were decreased in subjects with FH (n = 64) than in those without FH (n = 58). In Hp-positive controls, MOS methylation was lower in subjects with FH (n = 73) than in those without FH (n = 50) (P = 0.042), while miR124a-3 (P = 0.006), NKX6-1 (P < 0.001), and CDH1 (P < 0.001) methylation were higher in subjects with FH. CDH1 methylation constantly decreased from 2 years in GC patients and 3–4 years in controls after Hp eradication (all P < 0.001). A persistent decrease in methylation over time was not observed in other genes after eradication. Conclusion: The methylation of MOS and CDH1 provided an association between aberrant DNA methylation and gastric carcinogenesis in FH of GC, a useful marker for GC risk in individuals with FH. Furthermore, CDH1 methylation decreased after Hp eradication. [ABSTRACT FROM AUTHOR]

Background/Aims: Favorable outcomes of potassium-competitive acid blocker (PCAB)-containing eradication therapy have been reported. In fact, tegoprazan, a recently developed PCAB, was presumed to show good eradication efficacy even for resistant Helicobacter pylori. We aimed to investigate the anti-H. pylori efficacy of tegoprazan compared with that of vonoprazan. Methods: A total of 220 resistant clinical H. pylori isolates were utilized. The anti-H. pylori efficacy of PCABs was determined by evaluating the minimum inhibitory concentrations (MICs) of clarithromycin, fluoroquinolone, metronidazole, and amoxicillin in combination with vonoprazan or tegoprazan by the agar dilution method. The impact of the mutations responsible for resistance development, such as 23S rRNA, gyrA, rdxA, frxA, and pbp1 mutations, was also analyzed. Results: H. pylori growth was significantly inhibited in a medium containing 1 μg/mL clarithromycin with tegoprazan (128 μg/mL). The MICs of clarithromycin (46.3%), fluoroquinolone (46.7%), metronidazole (55.6%), and amoxicillin (34.5%) against resistant H. pylori isolates improved after tegoprazan administration. Tegoprazan demonstrated more frequent susceptibility acquisition with metronidazole than with vonoprazan (20.6% vs 4.7%, p=0.014). However, there were no significant differences depending on the mutational status of each antimicrobial agent. Conclusions: Tegoprazan administration may improve the susceptibility of antimicrobial-resistant H. pylori, independent of acid suppression. [ABSTRACT FROM AUTHOR]

Objective: Helicobacter pylori (HP) is known to play an important role in the development of gastric cancer (GC). The aim of this study was to analyze the effect of HP eradication on the survival rate and cancer recurrence in patients who underwent subtotal gastrectomy for GC. Design: Totally 1,031 patients diagnosed with gastric adenocarcinoma who received surgical treatment at the Seoul National University Bundang Hospital from 2003 to 2017 and positive for HP infection were analyzed. The overall and GC-related survival according to HP eradication were compared; risk factors for GC-specific death and cancer recurrence were analyzed, and propensity score matching (PSM) was performed. Results: Statistically significant benefits of overall and GC-specific survival were observed in the eradicated group compared to the non-eradicated group (P < 0.001), and these benefits were maintained after PSM (P < 0.001) in both of early and advance stage. In Cox proportional hazards multivariate analyses, cancer stage (stage II, adjusted hazard ratio [aHR] = 9.33, P < 0.001; stage III or IV, aHR = 26.17, P < 0.001), and HP positivity (aHR = 3.41, P = 0.001) were independent risk factors for GC-specific death; cancer stage (cancer stage II, aHR = 7.08, P < 0.001; cancer stage III or IV, aHR = 19.64, P < 0.001) and HP positivity (aHR = 2.70; P = 0.005) were independent risk factors for cancer recurrence. Conclusion: Our results suggest that HP needed to be conducted more intensively in patients who are surgically treated for GC, regardless of cancer stage. [ABSTRACT FROM AUTHOR]

The composition of the gut microbiota is influenced by sex hormones and colorectal cancer (CRC). Previously, we reported that 17β-estradiol (E2) inhibits azoxymethane/dextran sulfate sodium (AOM/DSS)-induced tumorigenesis in male mice. Here, we investigated whether the composition of the gut microbiota is different between male and female, and is regulated by estrogen as a secondary outcome of previous studies. We established four groups of mice based on the sex and estrogen status [ovariectomized (OVX) female and E2-treated male]. Additionally, three groups of males were established by treating them with AOM/DSS, and E2, after subjecting them to AOM/DSS treatment. The mice were sacrificed at 21 weeks old. The composition of the gut microbiota was analyzed using 16S rRNA metagenomics sequencing. We observed a significant increase in the microbial diversity (Chao1 index) in females, males supplemented with E2, and males treated with AOM/DSS/E2 compared with normal males. In normal physiological condition, sex difference and E2 treatment did not affect the ratio of Firmicutes/Bacteroidetes (F/B). However, in AOM/DSS-treated male mice, E2 supplementation showed significantly lower level of the F/B ratio. The ratio of commensal bacteria to opportunistic pathogens was higher in females and E2-treated males compared to normal males and females subjected to OVX. Unexpectedly, this ratio was higher in the AOM/DSS group than that determined in other males and the AOM/DSS/E2 group. Our findings suggest that estrogen alters the gut microbiota in ICR (CrljOri:CD1) mice, particularly AOM/DSS-treated males, by decreasing the F/B ratio and changing Shannon and Simpson index by supply of estrogen. This highlights another possibility that estrogen could cause changes in the gut microbiota, thereby reducing the risk of developing CRC. [ABSTRACT FROM AUTHOR]

Advances in genomic technologies and the development of targeted therapeutics are making the use of precision medicine increasingly possible. In this study, we explored whether precision medicine can be applied for the management of refractory/relapsed pediatric solid tumors by discovering actionable alterations using targeted panel sequencing. Samples of refractory/relapsed pediatric solid tumors were tested using a targeted sequencing panel covering the exonic DNA sequences of 381 cancer genes and introns across 22 genes to detect clinically significant genomic aberrations in tumors. The molecular targets were tiered from 1 to 5 based on the presence of actionable genetic alterations, strength of supporting evidence, and drug availability in the Republic of Korea. From January 2016 to October 2018, 55 patients were enrolled. The median time from tissue acquisition to drug selection was 29 d (range 14–39), and tumor profiling was successful in 53 (96.4%) patients. A total of 27 actionable alterations in tiers 1–4 were detected in 20 patients (36.4%), and the majority of actionable alterations were copy number variations. The tiers of molecular alterations were tier 1 (clinical evidence) in 4 variants, tier 2 (preclinical evidence) in 8 variants, tier 3 (consensus opinion) in 2 variants, and tier 4 (actionable variants with a drug that is available in other countries but not in the Republic of Korea) in 9 variants. In one patient with relapsed neuroblastoma with ALK F1174L mutation and ALK amplification, lorlatinib was used in a compassionate use program, and it showed some efficacy. In conclusion, using a targeted sequencing panel to discover actionable alterations in relapsed/refractory pediatric solid tumors was practical and feasible. [ABSTRACT FROM AUTHOR]

Several reports indicate crosstalk between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and estrogen, which has a protective effect in colorectal cancer (CRC). The aim of this study was to investigate the role of Nrf2 signaling in the anti-inflammatory effect of estrogen using Nrf2 knockout (Nrf2 KO) mouse embryonic fibroblasts (MEFs), a powerful system to test the function of target genes due to their easy accessibility, and rapid growth rates. After inducing inflammation by tumor necrosis factor alpha (TNF-α), the effects of 17β-estradiol (E2) on the expression of proinflammatory mediators [i.e., NF-κB and inducible nitric oxide synthase (iNOS)] and estrogen receptors were evaluated by Western blot. In wild type (WT) MEFs, E2 treatment ameliorated TNF-α-induced nuclear translocation of NF-κB and expression of its target protein iNOS. Estrogen receptor beta (ERβ) expression was decreased by TNF-α-induced inflammation and restored by E2 treatment. When treated to WT MEFs, E2 induced nuclear translocation of Nrf2. The inhibitory effect of E2 on TNF-α-induced enhancement of iNOS was markedly dampened in Nrf2 KO MEFs. Notably, ERβ expression was significantly diminished in Nrf2 KO MEFs compared to that in WT cells. Promoter Database (EPD) revealed two putative anti-oxidant response elements (AREs) within the mouse ERβ promoter. Furthermore, in WT MEFs, E2 treatment repressed TNF-α-induced expression of iNOS protein and recovered by 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), a selective ERβ antagonist, treatment, but not in Nrf2 KO MEFs. In conclusion, Nrf2 plays a pivotal role in the anti-inflammatory of estrogen by direct regulating the expression of ERβ. [ABSTRACT FROM AUTHOR]

Alternative polyadenylation (APA) in 3’ untranslated regions (3’ UTR) plays an important role in regulating transcript abundance, localization, and interaction with microRNAs. Length-variation of 3’UTRs by APA contributes to efficient proliferation of cancer cells. In this study, we investigated APA in single cancer cells and tumor microenvironment cells to understand the physiological implication of APA in different cell types. We analyzed APA patterns and the expression level of genes from the 515 single-cell RNA sequencing (scRNA-seq) dataset from 11 breast cancer patients. Although the overall 3’UTR length of individual genes was distributed equally in tumor and non-tumor cells, we found a differential pattern of polyadenylation in gene sets between tumor and non-tumor cells. In addition, we found a differential pattern of APA across tumor types using scRNA-seq data from 3 glioblastoma patients and 1 renal cell carcinoma patients. In detail, 1,176 gene sets and 53 genes showed the distinct pattern of 3’UTR shortening and over-expression as signatures for five cell types including B lymphocytes, T lymphocytes, myeloid cells, stromal cells, and breast cancer cells. Functional categories of gene sets for cellular proliferation demonstrated concordant regulation of APA and gene expression specific to cell types. The expression of APA genes in breast cancer was significantly correlated with the clinical outcome of earlier stage breast cancer patients. We identified cell type-specific APA in single cells, which allows the identification of cell types based on 3’UTR length variation in combination with gene expression. Specifically, an immune-specific APA signature in breast cancer could be utilized as a prognostic marker of early stage breast cancer. [ABSTRACT FROM AUTHOR]

The role of macrophage migration inhibitory factor (MIF) and autophagy in gastric cancer is not clear. We determined H. pylori infection status of the subjects and investigated the expression of MIF and autophagy markers (Atg5, LC3A and LC3B) in human gastric tissue at baseline. Then H. pylori eradication was done for H. pylori positive patients and MIF and Atg5 levels were investigated on each follow-up for both H. pylori-eradicated and H. pylori negative patients. Baseline tissue mRNA expression of MIF, Atg5, LC3A and LC3B was measured by real-time PCR in 453 patients (control 165, gastric dysplasia 82, and gastric cancer 206). Three hundred three patients (66.9%) had H. pylori infection at the time of enrollment. Only within H. pylori-positive group, MIF level was significantly elevated in patients with cancer than in control or dysplasia groups (P<0.05). LC3A and LC3B levels also showed significant differences within H. pylori-positive subgroups. H. pylori-positive dysplasia subgroup showed significantly lower (LC3A) (P<0.05) and higher (LC3B) mRNA levels (P<0.05) than in other subgroups. On follow-up, within H. pylori-eradicated group, Atg5 expression increased sequentially from control to dysplasia and cancer subgroups. Multiple linear regression showed autophagy markers (LC3A, LC3B, and Atg5) directly predicted MIF level (adjusted R2 = 0.492, P<0.001). Serial follow-up showed longitudinal increase in Atg5 level in general, with constantly higher levels in H. pylori-eradicated group than in -negative group. Intestinal metaplasia (IM) group initially showed higher Atg5 expression than the IM-negative group. However, it was reversed between the groups eventually because of the lower rate of increase in IM group. These results suggest a role of MIF and autophagy markers and their interaction in H. pylori-associated gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

The soil-borne pathogen Phytophthora capsici causes severe destruction of Capsicum spp. Resistance in Capsicum against P. capsici is controlled by numerous minor quantitative trait loci (QTLs) and a consistent major QTL on chromosome 5. Molecular markers on Capsicum chromosome 5 have been developed to identify the predominant genetic contributor to resistance but have achieved little success. In this study, previously reported molecular markers were used to reanalyze the major QTL region on chromosome 5 (6.2 Mbp to 139.2 Mbp). Candidate resistance gene analogs (RGAs) were identified in the extended major QTL region including 14 nucleotide binding site leucine-rich repeats, 3 receptor-like kinases, and 1 receptor-like protein. Sequence comparison of the candidate RGAs was performed between two Capsicum germplasms that are resistant and susceptible, respectively, to P. capsici. 11 novel RGA-based markers were developed through high-resolution melting analysis which were closely linked to the major QTL for P. capsici resistance. Among the markers, CaNB-5480 showed the highest cosegregation rate at 86.9% and can be applied to genotyping of the germplasms that were not amenable by previous markers. With combination of three markers such as CaNB-5480, CaRP-5130 and CaNB-5330 increased genotyping accuracy for 61 Capsicum accessions. These could be useful to facilitate high-throughput germplasm screening and further characterize resistance genes against P. capsici in pepper. [ABSTRACT FROM AUTHOR]

The soil-borne pathogen Phytophthora capsici causes severe destruction of Capsicum spp. Resistance in Capsicum against P. capsici is controlled by numerous minor quantitative trait loci (QTLs) and a consistent major QTL on chromosome 5. Molecular markers on Capsicum chromosome 5 have been developed to identify the predominant genetic contributor to resistance but have achieved little success. In this study, previously reported molecular markers were used to reanalyze the major QTL region on chromosome 5 (6.2 Mbp to 139.2 Mbp). Candidate resistance gene analogs (RGAs) were identified in the extended major QTL region including 14 nucleotide binding site leucine-rich repeats, 3 receptor-like kinases, and 1 receptor-like protein. Sequence comparison of the candidate RGAs was performed between two Capsicum germplasms that are resistant and susceptible, respectively, to P. capsici. 11 novel RGA-based markers were developed through high-resolution melting analysis which were closely linked to the major QTL for P. capsici resistance. Among the markers, CaNB-5480 showed the highest cosegregation rate at 86.9% and can be applied to genotyping of the germplasms that were not amenable by previous markers. With combination of three markers such as CaNB-5480, CaRP-5130 and CaNB-5330 increased genotyping accuracy for 61 Capsicum accessions. These could be useful to facilitate high-throughput germplasm screening and further characterize resistance genes against P. capsici in pepper. [ABSTRACT FROM AUTHOR]

The aims of this study were to demonstrate the trends in seropositivity and the eradication therapy rate for Helicobacter pylori (H. pylori) over an 18-year period in an asymptomatic Korean population and to explore the factors associated with H. pylori seropositivity and its eradication therapy. In total, 23,770 subjects (aged 17–97 years) from a health examination center participated in this cross-sectional study from January 2016 to June 2017. Questionnaires that included questions about the participants’ H. pylori eradication therapy history were collected, and anti-H. pylori IgG antibodies were measured. Among the eligible subjects, the seroprevalence of H. pylori infection was 41.5%. The H. pylori eradication therapy rate increased continuously from 2005 (13.9%) to 2011 (19.3%) and then increased again until the first half of 2017 (23.5%) (P < 0.001). After exclusion of subjects with a history of gastric surgery, gastric cancer, H. pylori eradication therapy, or gastric symptoms, H. pylori seropositivity was 43.9% in 16,885 subjects, which was significantly lower than the seropositivities in 1998 (66.9%), 2005 (59.6%), and 2011 (54.4%). The risk factors associated with H. pylori seropositivity according to multivariable analysis were male sex (odds ratio (OR) 1.34, 95% confidence interval (CI): 1.23–1.46), medium educational level (OR 1.17, 95% CI: 1.05–1.31), medium household income level (OR 1.10, 95% CI: 1.03–1.19), and age of 60–69 years (OR 8.78, 95% CI: 6.41–11.85). The observed downward trend in H. pylori seroprevalence and increase in H. pylori eradication over the 18-year period will affect upper gastrointestinal disorders in South Korea. [ABSTRACT FROM AUTHOR]

• Are there similarities in executive attention pathophysiology following TBI and in normal age-related decline?. • We derived a biomarker of executive attention pathophysiology that was common to both aging-related and post-TBI-related impairments, and in moderate-severe TBI. • Our findings identify biomarkers to track recovery, impact of interventions and guide development of targeted therapeutics following brain injuries. Executive attention impairments are a persistent and debilitating consequence of traumatic brain injury (TBI). To make headway towards treating and predicting outcomes following heterogeneous TBI, cognitive impairment specific pathophysiology first needs to be characterized. In a prospective observational study, we measured EEG during the attention network test aimed at detecting alerting, orienting, executive attention and processing speed. The sample (N = 110) of subjects aged 18–86 included those with and without traumatic brain injury: n = 27, complicated mild TBI; n = 5, moderate TBI; n = 10, severe TBI; n = 63, non-brain-injured controls. Subjects with TBI had impairments in processing speed and executive attention. Electrophysiological markers of executive attention processing in the midline frontal regions reveal that, as a group, those with TBI and elderly non-brain-injured controls have reduced responses. We also note that those with TBI and elderly controls have responses that are similar for both low and high-demand trials. In subjects with moderate-severe TBI, reductions in frontal cortical activation and performance profiles are both similar to that of controls who are ∼4 to 7 years older. Our specific observations of frontal response reductions in subjects with TBI and in older adults is consistent with the suggested role of the anterior forebrain mesocircuit as underlying cognitive impairments. Our results provide novel correlative data linking specific pathophysiological mechanisms underlying domain-specific cognitive deficits following TBI and with normal aging. Collectively, our findings provide biomarkers that may serve to track therapeutic interventions and guide development of targeted therapeutics following brain injuries. [ABSTRACT FROM AUTHOR]

Most studies of Composite solid electrolytes (CSEs) are composed of a polymer matrix and ceramic fillers. Polymer matrix–based CSEs are prepared by dissolving a polymer and lithium (Li) salt in a toxic organic solvent; then, a ceramic filler is added, and the toxic solvent is evaporated. These electrolytes contain 80%–90% polymer; however, they still have low thermal and electrochemical stability and unsatisfactory suppression of Li dendrite growth compared to inorganic ceramic electrolytes (ICEs). Ceramic matrix–based CSEs have high electrochemical and thermal stability, and good interfacial contact with electrodes. In this study, ceramic matrix–based CSEs were fabricated at a low temperature using a nontoxic solvent via the cold sintering process (CSP). Then, polyvinylidene fluoride (PVDF) and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) were introduced on the LiTa 2 PO 8 (LTPO) particle interface. In addition, the effect of the ratio of LTPO–PVDF and PVDF–LiTFSI at the LTPO particle interface on the microstructure and electrochemical properties of composite pellets was investigated. LTPO–PVDF pellets exhibited a relative density of 82%–86%, and high adhesion between LTPO particles was observed due to the formation of PVDF–LiTFSI amorphous layer on the particle interface. The LTPO–PVDF composite pellets exhibited a high total ionic conductivity of 4.59 × 10−4 S/cm at room temperature (RT), negligible electronic conductivity of 3.89 × 10−8 S/cm, low activation energy of 0.259 eV, and sufficient electrochemical stability. Coin cells with LiMn 0.6 Fe 0.4 PO 4 (LMFP) cathode exhibited a high initial discharge capacity of ∼145 mAh/g and capacity retention of approximately 85% after 50 cycles at RT. These results prove that the CSP is an ideal fabrication method for CSEs than the conventional methods that use toxic solvents and that introducing an amorphous layer at the particle interface in ceramic matrix–based CSEs improves their ionic conductivity. [ABSTRACT FROM AUTHOR]

Most studies of Composite solid electrolytes (CSEs) are composed of a polymer matrix and ceramic fillers. Polymer matrix–based CSEs are prepared by dissolving a polymer and lithium (Li) salt in a toxic organic solvent; then, a ceramic filler is added, and the toxic solvent is evaporated. These electrolytes contain 80%–90% polymer; however, they still have low thermal and electrochemical stability and unsatisfactory suppression of Li dendrite growth compared to inorganic ceramic electrolytes (ICEs). Ceramic matrix–based CSEs have high electrochemical and thermal stability, and good interfacial contact with electrodes. In this study, ceramic matrix–based CSEs were fabricated at a low temperature using a nontoxic solvent via the cold sintering process (CSP). Then, polyvinylidene fluoride (PVDF) and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) were introduced on the LiTa 2 PO 8 (LTPO) particle interface. In addition, the effect of the ratio of LTPO–PVDF and PVDF–LiTFSI at the LTPO particle interface on the microstructure and electrochemical properties of composite pellets was investigated. LTPO–PVDF pellets exhibited a relative density of 82%–86%, and high adhesion between LTPO particles was observed due to the formation of PVDF–LiTFSI amorphous layer on the particle interface. The LTPO–PVDF composite pellets exhibited a high total ionic conductivity of 4.59 × 10−4 S/cm at room temperature (RT), negligible electronic conductivity of 3.89 × 10−8 S/cm, low activation energy of 0.259 eV, and sufficient electrochemical stability. Coin cells with LiMn 0.6 Fe 0.4 PO 4 (LMFP) cathode exhibited a high initial discharge capacity of ∼145 mAh/g and capacity retention of approximately 85% after 50 cycles at RT. These results prove that the CSP is an ideal fabrication method for CSEs than the conventional methods that use toxic solvents and that introducing an amorphous layer at the particle interface in ceramic matrix–based CSEs improves their ionic conductivity. [ABSTRACT FROM AUTHOR]

The colonic response to stress is greater in female rats than in male rats. The aim of this study was to evaluate the effect of probiotics in the repeated water avoidance stress (rWAS)-induced colonic microinflammation model of Wistar rats in a sex-specific manner. The three groups (no-stress, WAS, and WAS with probiotics) were exposed to r-WAS for 1 h daily for 10 days, and Lactobacillus farciminis was administered by oral gavage for 10 days to animals in the probiotics group. The visceromotor response (VMR) to colorectal distension (CRD) was assessed using a barostat and noninvasive manometry before and after WAS exposure. Immunohistochemistry for mast cells and real-time polymerase chain reaction (RT-PCR) for detection of mucosal cytokines were performed using distal colon tissue after the animals were sacrificed. Significant reduction of VMR to CRD (visceral analgesia) was observed at 60 mmHg in the female WAS group (P = 0.045), but not in males. In addition, the female WAS with probiotics group showed a significantly lower colonic mucosal mast cell count in comparison to the female WAS group (P = 0.013), but this phenomenon was not observed in the male group. The colonic mucosal mRNA levels of interferon-γ (IFNR), tumor necrosis factor-α (TNFA), interleukin (IL) 6, and IL17 were higher in the female WAS group than in the male WAS group. The mRNA levels of IFNR, TNFA, and IL6 were significantly decreased in WAS females who received probiotics (all P < 0.050). In conclusion, rWAS is induced in a sex-specific manner. A 10-day-long treatment with L. farciminis is an effective therapy for rWAS-induced colonic microinflammation in female rates, but not in male rats. [ABSTRACT FROM AUTHOR]

The aging-associated cellular and molecular changes in esophagus have not been established, yet. Thus we evaluated histological structure, interstitial cells of Cajal (ICCs), neuronal nitric oxide synthase (nNOS)-positive cells, and contractility in the esophagus of Fischer 344 rat at different ages (6-, 31-, 74-weeks, and 2-years). The lamina propria thickness and endomysial area were calculated. The immunoreactivity of c-Kit, nNOS and protein gene product (PGP) 9.5 was counted after immunohistochemistry. Expression of c-Kit, stem cell factor (SCF), nNOS and PGP 9.5 mRNA was measured by real-time PCR, and expression of c-Kit and nNOS protein was detected by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS) were conducted. The lamina propria thickness increased (6 week vs 2 year, P = 0.005) and the endomysial area of longitudinal muscle decreased with aging (6 week vs 2 year, P<0.001), while endomysial area of circular muscle did not significantly decrease. The proportions of NOS-immunoreactive cells and c-Kit-immunoreactive areas declined with aging (6 week vs 2 year; P<0.001 and P = 0.004, respectively), but there was no significant change of PGP 9.5-immunopositiviy. The expressions of nNOS, c-Kit and SCF mRNA also reduced with aging (6 week vs 2 year; P = 0.006, P = 0.001 and P = 0.006, respectively), while the change of PGP 9.5 mRNA expression was not significant. Western blot showed the significant decreases of nNOS and c-Kit protein expression with aging (6 week vs 2 year; P = 0.008 and P = 0.012, respectively). The EFS-induced esophageal contractions significantly decreased in 2-yr-old rat compared with 6-wk-old rats, however, L-NG-Nitroarginine methylester did not significantly increase the spontaneous and EFS-induced contractions in the 6-wk- and 2-yr-old rat esophagus. In conclusion, an increase of lamina propria thickness, a decrease of endomysial area, c-Kit, SCF and NOS expression with preserved total enteric neurons, and contractility in aged rat esophagus may explain the aging-associated esophageal dysmotility. [ABSTRACT FROM AUTHOR]

The gastric accommodation reflex is an important mechanism in gastric physiology. However, the aging-associated structural and functional changes in gastric relaxation have not yet been established. Thus, we evaluated the molecular changes of interstitial cell of Cajal (ICC) and neuronal nitric oxide synthase (nNOS) and the function changes in the corpus of F344 rats at different ages (6-, 31-, 74-wk and 2-yr). The proportion of the c-Kit-positive area in the submucosal border (SMB) and myenteric plexus (MP) layer was significantly lower in the older rats, as indicated by immunohistochemistry. The density of the nNOS-positive immunoreactive area also decreased with age in the SMB, circular muscle (CM), and MP. Similarly, the percent of nNOS-positive neuronal cells per total neuronal cells and the proportion of nNOS immunoreactive area of MP also decreased in aged rats. In addition, the mRNA and protein expression of c-Kit and nNOS significantly decreased with age. Expression of stem cell factor (SCF) and the pan-neuronal marker PGP 9.5 mRNA was significantly lower in the older rats than in the younger rats. Barostat studies showed no difference depending on age. Instead, the change of volume was significantly decreased by L-NG63-nitroarginine methyl ester in the 2-yr-old rats compared with the 6-wk-old rats (P = 0.003). Taken together, the quantitative and molecular nNOS changes in the stomach might play a role in the decrease of gastric accommodation with age. [ABSTRACT FROM AUTHOR]

Humanized pigs have been developed to reduce the incidence of immune rejection in xenotransplantation, but significant concerns remain, such as transmission of viral zoonosis. Porcine endogenous retroviruses (PERV), which exist in the genome of pigs, are produced as infectious virions from all porcine cells and cause zoonosis. Here, we examined the possibility of zoonosis of hosts under conditions of immune suppression or xenotransplantation of cells producing host-adapted viruses. Upon transplantation of PERV-producing porcine cells into mice, no transmission of PERV was detected, whereas, transmission of PERV from mice transplanted with mouse-adapted PERV-producing cells was detected. In addition, the frequency of PERV transmission was increased in CsA treated mice transplanted with PERV-producing murine cells, compared with PERV-producing porcine cells. Transmission of PERV to host animals did not affect weight but immune responses, in particular, the number of T cells from PERV-transmitted mice, were notably reduced. The observed risk of PERV zoonosis highlights the requirement for thorough evaluation of viral zoonosis under particular host conditions, such as immunosuppressive treatment and transplantation with host-adapted virus-producing cells. [ABSTRACT FROM AUTHOR]

Background: A large-scale study was performed to identify the risk factors for developing synchronous and metachronous colorectal cancer (CRC) in gastric cancer (GC) patients, including microsatellite instability (MSI) and p53 overexpression. Methods: A total of 1041 GC patients who underwent endoscopic resection or surgery and underwent colonoscopy simultaneously or during surveillance for GC were consecutively enrolled. Clinicopathologic characteristics, MSI, and p53 overexpression were compared between the GC patients with and those without synchronous and metachronous CRC. Results: Of the 1041 patients, CRCs were detected in 67 (6.4 %) patients with GC. Forty-six (4.4 %) had synchronous CRC and 21 (2.0 %) had metachronous CRC. Univariate analysis indicated that age ≥63 years ( P < 0.001), male sex ( P = 0.005), and p53 overexpression ( P = 0.040) were significantly associated with a higher incidence of CRC. However, body mass index, smoking, tumor location, tumor multiplicity, tumor histology, TNM stage, and MSI were not significantly associated with the incidence of CRC. Age ≥63 years (OR: 5.881; 95 % CI: 3.083-11.221; P < 0.001) and male sex (OR: 2.933; 95 % CI: 1.307-6.584; P = 0.009) were risk factors for CRC in GC patients according to multivariate analysis. Conclusions: GC patients who are male and/or ≥63 years old are recommended to receive colonoscopy to detect CRC. MSI and p53 overexpression were not useful molecular markers for predicting CRC in GC. [ABSTRACT FROM AUTHOR]

Whole-exome sequencing (WES) has become a standard method for detecting genetic variants in human diseases. Although the primary use of WES data has been the identification of single nucleotide variations and indels, these data also offer a possibility of detecting copy number variations (CNVs) at high resolution. However, WES data have uneven read coverage along the genome owing to the target capture step, and the development of a robust WES-based CNV tool is challenging. Here, we evaluate six WES somatic CNV detection tools: ADTEx, CONTRA, Control-FREEC, EXCAVATOR, ExomeCNV and Varscan2. Using WES data from 50 kidney chromophobe, 50 bladder urothelial carcinoma, and 50 stomach adenocarcinoma patients from The Cancer Genome Atlas, we compared the CNV calls from the six tools with a reference CNV set that was identified by both single nucleotide polymorphism array 6.0 and whole-genome sequencing data. We found that these algorithms gave highly variable results: visual inspection reveals significant differences between the WES-based segmentation profiles and the reference profile, as well as among the WES-based profiles. Using a 50% overlap criterion, 13-77% of WES CNV calls were covered by CNVs from the reference set, up to 21% of the copy gains were called as losses or vice versa, and dramatic differences in CNV sizes and CNV numbers were observed. Overall, ADTEx and EXCAVATOR had the best performance with relatively high precision and sensitivity. We suggest that the current algorithms for somatic CNV detection from WES data are limited in their performance and that more robust algorithms are needed. [ABSTRACT FROM AUTHOR]

Background: Obesity is known to be associated with an increased risk of gastric cardia cancer but not with noncardia cancer. In terms of gastric dysplasia, few studies have evaluated its relationship with obesity. In addition, no study on the relationship between obesity and the risk of gastric cancer has analyzed the status of Helicobacter pylori infection. Methods: A case-control study was designed to investigate the relationship between obesity and the risk of gastric cancer and dysplasia adjusted for the status of H. pylori infection in Koreans. Nine hundred ninety-eight gastric cancer patients, 313 gastric dysplasia patients, and 1,288 subjects with normal endoscopic findings were included. Results: As gender differences could be the largest confounding factor, the risk of gastric cancer and dysplasia with an increasing body mass index (BMI) was analyzed in men and women, separately, and was adjusted for age, smoking, drinking, family history of gastric cancer, H. pylori infection, atrophic gastritis, intestinal metaplasia, and serum pepsinogen I/pepsinogen II ratio. Obesity (BMI 25 kg/m or greater but less than 30 kg/m) was associated with increased risk of early gastric cancer [adjusted odds ratio (aOR) 1.657; 95 % confidence interval (CI) 1.086-2.528; P = 0.019] and well or moderately differentiated adenocarcinoma (aOR 1.566; 95 % CI 1.011-2.424; P = 0.044) compared with normal BMI status (BMI < 23 kg/m) in men. Obesity was related to gastric dysplasia (aOR 2.086; 95 % CI 1.011-4.302; P = 0.047) in women. Conclusions: The effect of obesity on gastric cancer showed a gender difference. That is, in men it was related to increased risk of early gastric cancer and well or moderately differentiated adenocarcinoma, but it was associated with gastric dysplasia in women regardless of H. pylori infection in Korea. Further research into this difference is necessary. [ABSTRACT FROM AUTHOR]

Mig6 is a feedback inhibitor that directly binds, inhibits and drives internalization of ErbB-family receptors. Mig6 selectively targets activated receptors. Here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src. Crystal structures of human EGFR-Mig6 complexes reveal the structural basis for enhanced phosphorylation of primed Mig6 and show how Mig6 rearranges after phosphorylation by EGFR to effectively irreversibly inhibit the same receptor that catalyzed its phosphorylation. This dual phosphorylation site allows Mig6 to inactivate EGFR in a manner that requires activation of the target receptor and that can be modulated by Src. Loss of Mig6 is a driving event in human cancer; analysis of 1,057 gliomas reveals frequent focal deletions of ERRFI1, the gene that encodes Mig6, in EGFR-amplified glioblastomas. [ABSTRACT FROM AUTHOR]

A bi‐directional deformable block‐based motion‐estimation algorithm to improve the accuracy of a motion prediction in a 360‐degree video, used for motion compensated frame‐rate up conversion (MC‐FRUC) is proposed. The block shapes are adaptively deformed to predict a motion based on the coordinate of the current block, considering the geometric property of the equi‐rectangular projection of 360‐degree videos. Experimental results demonstrate that the proposed technique can significantly improve the visual quality of the videos as compared with the conventional MC‐FRUC. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor-β1 (TGF-β1) has dual roles inhibiting and promoting carcinogenesis. Although many researchers have conducted association studies between TGFB1 C-509T polymorphism and the risk of developing gastric cancer, the results are not uniform. Methods: We genotyped 1028 gastric cancer patients and 958 controls by the polymerase chain reaction-restriction fragment length polymorphism method. Immunohistochemistry was performed to assess the expression of TGF-β1 in the cancer and noncancerous tissues of 120 gastric cancer patients. mRNA expression was also measured in noncancerous gastric mucosa by qRT-PCR in the 282 subjects. Results: The CT genotype in the TGFB1 C-509T polymorphism was associated with an increased risk of gastric cancer development (adjusted OR 1.35, 95 % CI 1.07-1.71, P = 0.013), especially for intestinal-type cancer (adjusted OR 1.43, 95 % CI 1.08-1.90, P = 0.014). More frequent TGF-β1 expression was found in the center of cancer tissue in the TGFB1-509T carrier group than in the others (90.5 % vs. 72.2 %, P = 0.010). T-carriers also presented higher expression level of gastric TGF-β1 mRNA than non T-carriers (median 1.29 vs. 0.80, P = 0.004) when they were infected by H. pylori. Cancer patients showed elevated gastric TGFB1gene expression compared to the control group (median 1.22 vs. 0.89, P = 0.009). Conclusions: The carcinogenic effect of TGF-β1 might be associated with increased gastric TGF-β1 expression in subjects with the T allele of TGFB1-509. [ABSTRACT FROM AUTHOR]

Background: Identification of the causative genes of retinitis pigmentosa (RP) is important for the clinical care of patients with RP. However, a comprehensive genetic study has not been performed in Korean RP patients. Moreover, the genetic heterogeneity found in sensorineural genetic disorders makes identification of pathogenic mutations challenging. Therefore, high throughput genetic testing using massively parallel sequencing is needed. Results: Sixty-two Korean patients with nonsyndromic RP (46 patients from 18 families and 16 simplex cases) who consented to molecular genetic testing were recruited in this study and targeted exome sequencing was applied on 53 RP-related genes. Causal variants were characterised by selecting exonic and splicing variants, selecting variants with low allele frequency (below 1%), and discarding the remaining variants with quality below 20. The variants were additionally confirmed by an inheritance pattern and cosegregation test of the families, and the rest of the variants were prioritised using in-silico prediction tools. Finally, causal variants were detected from 10 of 18 familial cases (55.5%) and 7 of 16 simplex cases (43.7%) in total. Novel variants were detected in 13 of 20 (65%) candidate variants. Compound heterozygous variants were found in four of 7 simplex cases. Conclusion: Panel-based targeted re-sequencing can be used as an effective molecular diagnostic tool for RP. [ABSTRACT FROM AUTHOR]

The immunoglobulin (Ig)-like domain containing receptor 1 (ILDR1) gene encodes angulin-2/ILDR1, a recently discovered tight junction protein, which forms tricellular tight junction (tTJ) structures with tricellulin and lipolysis-stimulated lipoprotein receptor (LSR) at tricellular contacts (TCs) in the inner ear. Previously reported recessive mutations within ILDR1 have been shown to cause severe to profound nonsyndromic sensorineural hearing loss (SNHL), DFNB42. Whole-exome sequencing of a Korean multiplex family segregating partial deafness identified a novel homozygous ILDR1 variant (p.P69H) within the Ig-like domain. To address the pathogenicity of p.P69H, the angulin-2/ILDR1 p.P69H variant protein, along with the previously reported pathogenic ILDR1 mutations, was expressed in angulin-1/LSR knockdown epithelial cells. Interestingly, partial mislocalization of the p.P69H variant protein and tricellulin at TCs was observed, in contrast to a severe mislocalization and complete failure of tricellulin recruitment of the other reported ILDR1 mutations. Additionally, three-dimensional protein modeling revealed that angulin-2/ILDR1 contributed to tTJ by forming a homo-trimer structure through its Ig-like domain, and the p.P69H variant was predicted to disturb homo-trimer formation. In this study, we propose a possible role of angulin-2/ILDR1 in tTJ formation in the inner ear and a wider audiologic phenotypic spectrum of DFNB42 caused by mutations within ILDR1. [ABSTRACT FROM AUTHOR]

Background Severe to profound sensorineural hearing loss (SNHL) requires cochlear implantation (CI) for auditory rehabilitation. Etiologic diagnoses can contribute to candidacy selection and decision-making regarding the timing of successful CI. However, few studies have been performed to address the etiologic spectrum of severe SNHL in the population where there is no consanguineous marriage and the majority of SNHL cases are sporadic in small sized families. The authors sought to comprehensively understand the etiologies of Korean cochlear implantees by incorporating the targeted resequencing of 204 candidate deafness genes (TRS-204) and a phenotype-driven candidate gene approach. Methods Ninety-three that consented to molecular genetic testing and underwent at least one molecular genetic test were included. Patients with a characteristic Phenotypic marker were subject to Sanger sequencing to detect variants in corresponding candidate genes. The rest of patients without any prominent phenotype were tested on GJB2. Next, TRS-204 was applied in GJB2- negative cases without any phenotypic marker. In addition, the sibling recurrence-risk of SNHL among families with non-diagnostic genotypes after TRS-204 was performed to gain insight of etiologies in non-diagnostic cases. Results Overall, we could find causative variants in 51 (54.8%) of the 93 cochlear implantees. Thirty (32.3%) probands could be diagnosed by direct Sanger sequencing of candidate genes selected by their phenotypes. GJB2 sequencing added 10 subjects to the group with a diagnostic genotype. TRS-204 could detect a causative variant from additional 11 cases (11.8%). We could not detect any pathogenic deletion or duplication on 204 target genes. The sibling recurrence-risk of SNHL among 42 genetically undiagnosed families with 0.03 (1/38) was significantly lower than among genetically diagnosed recessive families with 0.19 (7/37). Conclusion Despite that the majority of severe or more degree of SNHL occurs sporadically in Koreans, at least 54.8% of such cases that were willing to join the genetic study in the Korean population are monogenic Mendelian disorders with convincing causative variants. This study also indicates that a substantial portion of unsolved cases after applying our current protocol are predicted to have non-genetic or complex etiology rather than a Mendelian genetic disorder involving new genes beyond the 204 target genes. [ABSTRACT FROM AUTHOR]

To perform their biological functions, individual genes exhibit varying ranges of expression levels. Thus, considering the intrinsic variability of gene expression can improve geneset-based functional analyses which are typically used to interpret transcriptome data. Through the extensive quantitative analysis of the expressional variability of individual genes using large collections of transcriptome and proteome data, we found the existence of the intrinsic variability of gene expression at the transcriptional level. Interestingly, genes under post-translational regulation were not sensitively regulated at the transcriptional level. Because genes have intrinsically different levels of regulation at the transcription and translation stages, the functional geneset-based interpretation of transcriptome data should only include genes that are significantly varied at the transcriptional level. Thus, by removing genes with low transcriptional variation from the DNA microarray data, we showed that geneset enrichment analysis could provide improved resolution in prioritizing target functional pathways in several different experimental datasets. [ABSTRACT FROM AUTHOR]

Abstract: Let be an elliptic curve with j-invariant 0 defined over a number field K. In this paper, we give a simple condition on K which determines whether all cubic twists of have the same root number or not. This is a cubic twist analogue to the work [D-D] of Dokchitser and Dokchitser on quadratic twists of elliptic curves. [Copyright &y& Elsevier]

Background: The relationship between alcohol intake and the risk for gastric cancer is not fully understood. The association between alcohol consumption and the risk for gastric cancer was investigated in the Korean population with the ALDH2 genotype. Methods: From 2003 to 2008, 445 patients with gastric cancer and 370 control subjects ≥ 50 years of age were included in the analysis. Logistic regression models including age, gender, education, smoking and drinking status, Helicobacter pylori infection and ALDH2 genotype were evaluated to estimate the adjusted odds ratios (ORs) for the development of gastric cancer. Results: For all subjects, the risk for gastric cancer was increased in ex-drinkers [OR 1.68, 95% confidence interval (CI) 1.07-2.64], but not in current drinkers. Subjects with inactive ALDH2 *2 allele(s) showed a lower level of alcohol consumption than ALDH2 *1/*1 homozygotes (P < 0.001). Among the ALDH2 *1/*2 carriers (n = 243), current/ex-drinkers had a significantly increased risk for gastric cancer compared with never/rare drinkers (OR 2.80, 95% CI 1.51-5.19). Among heavy drinkers (n = 115), ALDH2 *1/*2 heterozygotes had a 4-fold increased risk for gastric cancer compared with *1/*1 homozygotes (OR 4.26, 95% CI 1.10-16.47); however, no risk increase was seen among never/rare drinkers. Conclusions: A dose-response association between alcohol intake and the risk for gastric cancer was not observed. However, ALDH2 polymorphisms were found to modify the susceptibility to the development of gastric cancer associated with alcohol intake, especially in case of ALDH2 *1/*2 genotype. The findings suggest an alcohol-ALDH2 genotype interaction in gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

We aimed to investigate the incidence of sugammadex-induced anaphylaxis in a large Korean population. We retrospectively investigated the incidence of sugammadex-induced anaphylaxis between 2013 and 2019 from the database of the Korea Institute of Drug Safety-Risk Management-Korea Adverse Event Reporting System (KIDS-KAERS). We estimated the incidence of sugammadex-induced anaphylaxis from the KIDS-KAERS database, assuming that the reporting efficiency was 10%, 50%, and 100%, respectively. We also investigated its annual sales volume in Korea and assumed that the exposure to sugammadex was 95% of the estimated sales volume. During the study period, 1,401,630 sugammadex vials were sold, and 19 cases of sugammadex-induced anaphylaxis were identified in the KIDS-KAERS database. The estimated incidence of sugammadex-induced anaphylaxis was 0.0143%, 0.00279%, and 0.0014%, assuming a reporting efficiency of 10%, 50%, and 100%, respectively. All patients, except for one with a missing record, fully recovered after anaphylaxis. The incidence of sugammadex-induced anaphylaxis identified in the national pharmacovigilance database was lower than previously reported rates in other countries. Therefore, its use in general anesthesia should not be hindered by concerns about the resulting risk of anaphylaxis in Korea. [ABSTRACT FROM AUTHOR]

The ability of single-cell genomics to resolve cellular heterogeneity is highly appreciated in cancer and is being exploited for precision medicine. In the recent decade, we have witnessed the incorporation of cancer genomics into the clinical decision-making process for molecular-targeted therapies. Compared with conventional genomics, which primarily focuses on the specific and sensitive detection of the molecular targets, single-cell genomics addresses intratumoral heterogeneity and the microenvironmental components impacting the treatment response and resistance. As an exploratory tool, single-cell genomics provides an unprecedented opportunity to improve the diagnosis, monitoring, and treatment of cancer. The results obtained upon employing bulk cancer genomics indicate that single-cell genomics is at an early stage with respect to exploration of clinical relevance and requires further innovations to become a widely utilized technology in the clinic. [ABSTRACT FROM AUTHOR]

Presents information on a study which investigated the track-width dependence of metal-particle tape medium noise, using a high-resolution positioning stage to produce narrow-track recordings. Utilization of a porous air-bearing tape system to perform the experiments; Variations in signal power for square wave recording; Observation on the track-width dependence of the head-medium noise.

Simple Summary: Microphthalmia-associated transcription factor (MITF) has been reported to play a role in the progression of melanoma and other cancer types. However, the biological role of MITF in clear cell renal cell carcinoma (ccRCC) is largely unknown. In this study, we elucidate the role of MITF in the progression of ccRCC. MITF- and MITF-mediated signaling pathways were investigated in ccRCC cell through MITF knockdown as well as overexpression of MITF in vitro and in vivo. MITF contributed to cell proliferation, migration, invasion and tumor growth in ccRCC through activation of the RhoA/YAP signaling pathways. This study suggests that MITF has potential as a therapeutic target in ccRCC. Microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor involved in the lineage-specific regulation of melanocytes, osteoclasts and mast cells. MITF is also involved in the progression of melanomas and other carcinomas, including the liver, pancreas and lung. However, the role of MITF in clear cell renal cell carcinoma (ccRCC) is largely unknown. This study investigates the functional role of MITF in cancer and the molecular mechanism underlying disease progression in ccRCC. MITF knockdown inhibited cell proliferation and shifted the cell cycle in ccRCC cells. In addition, MITF knockdown reduced wound healing, cell migration and invasion compared with the controls. Conversely, MITF overexpression in SN12C and SNU482 cells increased cell migration and invasion. Overexpression of MITF activated the RhoA/YAP signaling pathway, which regulates cell proliferation and invasion, and increased YAP signaling promoted cell cycle-related protein expression. Additionally, tumor formation was impaired by MITF knockdown and enhanced by MITF overexpression in vivo. In summary, MITF expression was associated with aggressive tumor behavior, and increased the migratory and invasive capabilities of ccRCC cells. These effects were reversed by MITF suppression. These results suggest that MITF is a potential therapeutic target for the treatment of ccRCC. [ABSTRACT FROM AUTHOR]

Background: Although immunomodulators are widely prescribed in patients with Crohn's disease (CD), it is unclear whether there is a difference in treatment outcomes between thiopurines and methotrexate (MTX). Objective: To compare the risk of clinical failure between thiopurines and MTX in bio-naïve patients with CD. Design: Nationwide, population-based study. Methods: We used claims data from the Korean National Health Insurance Service. After inverse probability of treatment weighting, logistic regression and Cox proportional hazard analyses were used to evaluate the risk of clinical failure in bio-naïve patients with CD treated with thiopurine (thiopurine group) or MTX (MTX group). Results: Overall, 10,296 adult and pediatric patients with CD [9912 (96.3%) and 384 (3.7%) in the thiopurine and MTX groups, respectively] were included. The odds ratios (ORs) of failure to induce remission were significantly higher in the MTX group than in the thiopurine group [adjusted OR (aOR), 1.115; 95% confidence interval (CI), 1.045–1.190; p = 0.001]. However, the opposite result was observed only in patients without concomitant steroid use: the MTX group had a lower risk of induction failure than the thiopurine group (aOR, 0.740; 95% CI, 0.673–0.813; p < 0.001). The risk of overall maintenance failure was higher in the MTX group than in the thiopurine group [adjusted hazard ratio (aHR), 1.117; 95% CI, 1.047–1.191; p = 0.001]. The risk of overall maintenance failure was higher in the standard-dose MTX group than in the low-dose MTX group (aHR, 1.296; 95% CI, 1.134–1.480; p < 0.001). There was no significant difference in the risk of maintenance failure according to the administration route of MTX. Conclusion: Thiopurine is more effective than MTX in inducing and maintaining remission in bio-naïve patients with CD; however, the concomitant use of steroids influences inducing remission. Plain language summary: Differences in treatment efficacy between thiopurine and methotrexate in patients with Crohn's disease who were not treated with biologics Immunomodulators (IMMs) used in the treatment of Crohn's disease (CD) include medications such as thiopurine and methotrexate (MTX). Although IMMs are widely prescribed for patients with CD, it remains unclear whether treatment outcomes differ according to the specific types and dosages of IMMs and administration routes of MTX. In this study, we investigated the risk of treatment failure between thiopurines and MTX in CD patients not undergoing biologic treatment. Patients treated with MTX had a higher risk of maintenance failure than those treated with thiopurines. There was no difference in the risk of treatment failure according to the dosage of thiopurine. However, the risk of maintenance failure was higher in patients receiving standard-dose MTX than in those receiving low-dose MTX. There was no difference in the risk of maintenance failure according to the administration route of MTX. Our study enriches the knowledge regarding the treatment efficacy of thiopurines and MTX for patients with CD and may help clinicians develop appropriate treatment plans. [ABSTRACT FROM AUTHOR]

Simple Summary: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that has gained considerable interest as a therapeutic target for cancer due to its key involvement in growth arrest and apoptosis of tumor cells. Moreover, GSK-3, especially GSK-3β, limits the activation of NK cells, key innate effectors in cancer immunosurveillance, triggered by diverse activating receptors. However, the role of GSK-3 in the regulation of activating ligands on target cells that confer susceptibility to NK cells remains unclear and is the aim of this study. Here, we provide evidence that GSK-3α primarily restrains the expression of ligands for activating receptors such as NKG2D, NKp30 but not DNAM-1, thereby reducing target susceptibility to NK cells. Thus, our results suggest a distinct role of GSK-3 isoforms in target cells vs NK cells for regulating NK cell reactivity and GSK-3α inhibition as a relevant strategy to enhance target susceptibility to NK cells. Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner. [ABSTRACT FROM AUTHOR]

Generalized anxiety disorder (GAD) is marked by uncontrollable, persistent worry and exaggerated response to uncertainty. Here, we review and summarize the findings from the GAD literature that employs functional neuroimaging methods. In particular, the present review focuses on task-based blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. We find that select brain regions often regarded as a part of a corticolimbic circuit (e.g., amygdala, anterior cingulate cortex, prefrontal cortex) are consistently targeted for a priori hypothesis-driven analyses, which, in turn, shows varying degrees of abnormal BOLD responsivity in GAD. Data-driven whole-brain analyses show the insula and the hippocampus, among other regions, to be affected by GAD, depending on the task used in each individual study. Overall, while the heterogeneity of the tasks and sample size limits the generalizability of the findings thus far, some promising convergence can be observed in the form of the altered BOLD responsivity of the corticolimbic circuitry in GAD. [ABSTRACT FROM AUTHOR]

Objective: To identify genetic variations which is associated with gastric cancer (GC) risk according to Helicobacter pylori infection. Methods: This study incorporated 527 GC patients and 441 controls from a cohort at Seoul National University Bundang Hospital. The associations between GC risk and single nucleotide polymorphisms were calculated, stratified by H. pylori status, adjusting for age, sex, and smoking. mRNA expression from non-cancerous gastric mucosae was evaluated using reverse transcription quantitative polymerase chain reaction. Results: In the entire cohort, genome-wide association study showed no significant variants reached the genome-wide significance level. In the H. pylori–positive group, rs2671655 (chr17:47,468,020;hg19, GH17J049387 enhancer region) was identified at a genome-wide significance level, which was more pronounced in diffuse type GC. There was no significant variant in the H. pylori–negative group, indicating the effect modification of rs2671655 by H. pylori. Among the target genes of GH17J049387 enhancer (PHB1, ZNF652 and SPOP), PHB1 mRNA was expressed more in cases than in controls, who were not affected by H. pylori. By contrast, an increase in ZNF652 and SPOP in GC was observed only in the H. pylori–negative group (P < 0.05). Mediation analysis showed that PHB1 (P = 0.0238) and SPOP (P = 0.0328) mediated the effect of rs2671655 on GC risk. The polygenic risk score was associated with the number of rs2671655 risk alleles only in the H. pylori–positive group (P = 0.0112). Conclusion: After H. pylori infection, rs2671655 may increase GC risk, especially in diffuse-type GC, by regulating the expression of several genes that consequently modify susceptibility to GC. [ABSTRACT FROM AUTHOR]