Identification of a Functional Variant in the <i>MICA</i> Promoter Which Regulates <i>MICA</i> Expression and Increases HCV-Related Hepatocellular Carcinoma Risk

Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. We previously identified the association of SNP rs2596542 in the 5' flanking region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region and found that a SNP rs2596538 located at 2.8 kb upstream of the MICA gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele was found to exhibit higher transcriptional activity than that containing the A allele. Moreover, SNP rs2596538 showed stronger association with HCV-induced HCC (P = 1.82×10−5 and OR = 1.34) than the previously identified SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with the expression of MICA and the risk for HCV-induced HCC.</p

Clinical Usefulness of the VS Classification System Using Magnifying Endoscopy with Blue Laser Imaging for Early Gastric Cancer

Background. Blue laser imaging (BLI) enables the acquisition of more information from tumors’ surfaces compared with white light imaging. Few reports confirm the validity of magnifying endoscopy (ME) with BLI (ME-BLI) for early gastric cancer (EGC). We aimed to assess the detailed endoscopic findings from EGCs using ME-BLI. Methods. We enrolled 386 consecutive patients with 417 EGCs that were diagnosed using ME-BLI and resected by endoscopic submucosal dissection. Using the VS classification system, three highly experienced endoscopists (HEEs) and three less experienced endoscopists (LEEs) evaluated the demarcation line (DL), microsurface pattern (MSP), and microvascular pattern (MVP) within the endoscopic images of EGCs obtained using ME-BLI, assigning high-confidence (HC) or low-confidence (LC) levels. We investigated the clinicopathological features associated with each confidence level. Results. The HEEs’ evaluations determined the presence of DL in 99%, irregular MSP in 96%, and irregular MVP in 96%, and the LEEs’ evaluations determined the presence of DL in 98%, irregular MSP in 95%, and irregular MVP in 95% of the EGCs. When DL was present, HC levels in the Helicobacter pylori- (H. pylori-) eradicated group and noneradicated group were evident in 65% and 89%, a difference that was significant (p<0.001). Conclusions. In the diagnosis of EGC with ME-BLI, the VS classification system with ME-NBI can be applied, but identifying the DL after H. pylori was difficult

Guanine- 5-carboxylcytosine base pairs mimic mismatches during DNA replication

The genetic information encoded in genomes must be faithfully replicated and transmitted to daughter cells. The recent discovery of consecutive DNA conversions by TET family proteins of 5-methylcytosine into 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine (5caC) suggests these modified cytosines act as DNA lesions, which could threaten genome integrity. Here, we have shown that although 5caC pairs with guanine during DNA replication in vitro, G·5caC pairs stimulated DNA polymerase exonuclease activity and were recognized by the mismatch repair (MMR) proteins. Knockdown of thymine DNA glycosylase increased 5caC in genome, affected cell proliferation via MMR, indicating MMR is a novel reader for 5caC. These results suggest the epigenetic modification products of 5caC behave as DNA lesions

A Genome-Wide Association Study of Nephrolithiasis in the Japanese Population Identifies Novel Susceptible Loci at 5q35.3, 7p14.3, and 13q14.1

Nephrolithiasis is a common nephrologic disorder with complex etiology. To identify the genetic factor(s) for nephrolithiasis, we conducted a three-stage genome-wide association study (GWAS) using a total of 5,892 nephrolithiasis cases and 17,809 controls of Japanese origin. Here we found three novel loci for nephrolithiasis: RGS14-SLC34A1-PFN3-F12 on 5q35.3 (rs11746443; P = 8.51×10−12, odds ratio (OR) = 1.19), INMT-FAM188B-AQP1 on 7p14.3 (rs1000597; P = 2.16×10−14, OR = 1.22), and DGKH on 13q14.1 (rs4142110; P = 4.62×10−9, OR = 1.14). Subsequent analyses in 21,842 Japanese subjects revealed the association of SNP rs11746443 with the reduction of estimated glomerular filtration rate (eGFR) (P = 6.54×10−8), suggesting a crucial role for this variation in renal function. Our findings elucidated the significance of genetic variations for the pathogenesis of nephrolithiasis

Metachronous multiple esophageal squamous cell carcinomas and Lugol-voiding lesions after endoscopic mucosal resection

Background and study aims: Endoscopic mucosal resection (EMR) has been applied to the treatment of superficial esophageal squamous cell carcinoma (SCC). The incidence and characteristics of metachronous multiple esophageal SCCs and Lugol-voiding lesions (LVLs) were investigated in a retrospective study in patients who had undergone EMR for superficial esophageal SCC. Patients and methods: 96 patients with esophageal SCC who had been treated by EMIR were followed up by endoscopy for 12 months or longer. Clinicopathologic parameters such as tumor size and location and presence of LVLs were examined. Results: 10 patients (10%) had synchronous multiple SCCs, and 12 (13%) developed metachronous multiple SCCs. The mean annual incidence of newly diagnosed tumor was 4.4%. The incidence of a speckled pattern of LVLs was 20/74 (27%) in patients with solitary SCC, 5/10 (50%) in synchronous multiple SCC, and 10/12 (83%) in metachronous multiple SCC. The incidence of the presence of speckled pattern of LVLs was significantly higher in patients with multiple SCCs than in those with solitary SCC (68% vs. 27%, P = 0.0004). Conclusions: Patients who have undergone EMR for esophageal SCC, especially those with metachronous multiple LVLs in the background mucosa, should undergo follow-up with close endoscopic observation using Lugol staining

Cerebral Microbleeds Are Associated with Worse Cognitive Function in the Nondemented Elderly with Small Vessel Disease

Background: Cerebral small vessel disease (SVD) is a leading cause of cognitive decline in the elderly. Cerebral microbleeds (CMBs) have emerged as an important manifestation of cerebral SVD, in addition to lacunar infarcts and white matter lesions (WMLs). We investigated whether the presence and location of CMBs in elderly subjects were associated with cognitive function, independent of lacunar infarcts and WMLs. Methods: One hundred and forty-eight nondemented elderly with SVD, defined as the presence of lacunar infarcts and/or WMLs on magnetic resonance imaging (MRI), were studied. Executive function and global cognition were assessed by the Frontal Assessment Battery (FAB) and Mini-Mental State Examination (MMSE), respectively. The differences in the scores for the FAB and MMSE between CMB-positive and CMB-negative subjects were calculated after adjusting for possible confounders. Results: The mean age of the subjects was 72.4 w 8.6 years. CMBs were detected in 48 subjects (32%), with a mean number of CMBs per subject of 1.6 (range 0-31). Among CMB-positive subjects, 42 (87.5%) had CMBs in deep or infratentorial regions with or without lobar CMBs, and 6 (12.5%) had CMBs in strictly lobar regions. The presence of CMBs was significantly associated with FAB and MMSE scores after adjustment for age, years of education, brain volume and the presence of lacunar infarcts (for the FAB) or severe WMLs (for the MMSE). The presence of CMBs in the basal ganglia, in the thalamus or in the lobar regions was associated with FAB scores, while that in the lobar regions was associated with MMSE scores. However, there was no association between CMBs in the infratentorial regions and cognitive parameters. Conclusions: In nondemented elderly with SVD on MRI, the presence of CMBs was independently associated with worse executive and global cognitive functions. CMBs seemed to reflect hypertensive microangiopathy in this population, and CMBs in specific areas may play an important role in cognitive function. i 2014 S. Karger AG, Base