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Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 × Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 x Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant disorder characterized by hair hypopigmentation, abnormal iris pigmentation, and congenital hearing loss. WS1 is caused by mutations in paired box gene 3 ( PAX3 ). We identified a novel PAX3 mutation (c.1107 C>G, p.Ser369Arg) in a Japanese WS1 patient showing abnormal right iris pigmentation, right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism.

ObjectivesTo develop a simple screening scale to predict depression after discharge in patients with acute coronary syndrome after percutaneous coronary intervention (ACS-PCI) and to verify its reliability, validity and cutoff value.DesignProspective longitudinal study was conducted 1 week and 3 months after discharge.SettingTwo hospitals where PCI is performed in Japan.ParticipantsA total of 183 patients were potential candidates for the survey, of whom 42 provided valid responses (response rate: 23.0%).ResultsThe number of items was reduced from 14 to 12 with item-total correlations and principal component analysis. Cronbach’s alpha coefficient was 0.832 and the intraclass correlation coefficient (1, 2) was 0.811 (95% CI 0.650 to 0.898). Significant correlations were observed for concurrent validity (r=0.699, p<0.01) and predictive validity (ρ=0.538, p<0.01). The area under the receiver operating characteristic curve was 0.799 (CI 0.629 to 0.970). A cut-off value of 28 points was obtained from the Youden index and demonstrated a sensitivity of 1.000, specificity of 0.553, positive predictive value (PPV) of 0.190 and negative predictive value of 0.000.ConclusionsThis study developed a simple screening scale for predicting postdischarge depression in patients with ACS-PCI (SDACS-12) and demonstrated its reliability, validity and predictive ability with 12 items. Nevertheless, its results should be interpreted cautiously given the moderate variance explained by PCA and the low specificity and PPV.

The influence of sugar consumption on the risk of colorectal cancer (CRC) remains controversial. Prospective cohort studies focusing on total and specific types of sugar intake among the Asian population who have different patterns of sugar intake sources than American and European populations are scarce. We intended to examine the association of sugar intake with CRC risk among middle‐aged adults in a Japanese large‐scale population‐based cohort study. The participants (42,405 men and 48,600 women) who were 45–74 years old and answered the questionnaire in 1995–1999 in the Japan Public Health Center‐based Prospective Study were followed up until December 2013. Total sugars, total fructose, and specific types of sugar intake were estimated using a validated 147‐item food frequency questionnaire and divided into quintiles (Q1–Q5). We used Cox proportional hazard regression models adjusted for potential confounders to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During the follow‐up, 2118 CRC cases (1226 men and 892 women) were identified. We did not observe any clear association between all types of sugar intake and an increased risk of CRC. Analyses by tumor sites yielded a positive association of total sugar consumption with rectal cancer in women (1.75 [1.07–2.87] for Q1 vs. Q5; p linear trend = 0.03), but no statistically significant trend was detected among men. Sugar intake was not associated with CRC risk in middle‐aged Japanese adults. However, for rectal cancer, the probability of an increased risk among women with a higher total sugar intake cannot be excluded.

The molecular mechanisms underlying the development of pancreatic neuroendocrine tumors (PanNETs) have not been well defined. We report here that the genomic region of the PHLDA3 gene undergoes loss of heterozygosity (LOH) at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis. We also show that the PHLDA3 locus undergoes methylation in addition to LOH, suggesting that a two-hit inactivation of the PHLDA3 gene is required for PanNET development. We demonstrate that PHLDA3 represses Akt activity and Akt-regulated biological processes in pancreatic endocrine tissues, and that PHLDA3 -deficient mice develop islet hyperplasia. In addition, we show that the tumor-suppressing pathway mediated by MEN1, a well-known tumor suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Collectively, these results indicate the existence of a novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs.

The objective of this study was to assess prospectively the diagnostic accuracy of computer-assisted computed tomographic colonography (CTC) in the detection of polypoid (pedunculated or sessile) and nonpolypoid neoplasms and compare the accuracy between gastroenterologists and radiologists. This nationwide multicenter prospective controlled trial recruited 1,257 participants with average or high risk of colorectal cancer at 14 Japanese institutions. Participants had CTC and colonoscopy on the same day. CTC images were interpreted independently by trained gastroenterologists and radiologists. The main outcome was the accuracy of CTC in the detection of neoplasms ≥6 mm in diameter, with colonoscopy results as the reference standard. Detection sensitivities of polypoid vs. nonpolypoid lesions were also evaluated. Of the 1,257 participants, 1,177 were included in the final analysis: 42 (3.6%) were at average risk of colorectal cancer, 456 (38.7%) were at elevated risk, and 679 (57.7%) had recent positive immunochemical fecal occult blood tests. The overall per-participant sensitivity, specificity, and positive and negative predictive values for neoplasms ≥6 mm in diameter were 0.90, 0.93, 0.83, and 0.96, respectively, among gastroenterologists and 0.86, 0.90, 0.76, and 0.95 among radiologists (P<0.05 for gastroenterologists vs. radiologists). The sensitivity and specificity for neoplasms ≥10 mm in diameter were 0.93 and 0.99 among gastroenterologists and 0.91 and 0.98 among radiologists (not significant for gastroenterologists vs. radiologists). The CTC interpretation time by radiologists was shorter than that by gastroenterologists (9.97 vs. 15.8 min, P<0.05). Sensitivities for pedunculated and sessile lesions exceeded those for flat elevated lesions ≥10 mm in diameter in both groups (gastroenterologists 0.95, 0.92, and 0.68; radiologists: 0.94, 0.87, and 0.61; P<0.05 for polypoid vs. nonpolypoid), although not significant (P>0.05) for gastroenterologists vs. radiologists. CTC interpretation by gastroenterologists and radiologists was accurate for detection of polypoid neoplasms, but less so for nonpolypoid neoplasms. Gastroenterologists had a higher accuracy in the detection of neoplasms ≥6 mm than did radiologists, although their interpretation time was longer than that of radiologists.

Background/objectiveAlthough benefits of fish consumption for health are well known, a significant percentage of individuals dislike eating fish. Fish consumption may be influenced by genetic factors in addition to environmental factors. We conducted a genome-wide association study (GWAS) to find genetic variations that affect fish consumption in a Japanese population.MethodsWe performed a two-stage GWAS on fish consumption using 13,739 discovery samples from the Japan Multi-Institutional Collaborative Cohort study, and 2845 replication samples from the other population. We used a semi-quantitative food frequency questionnaire to estimate food intake. Association of the imputed variants with fish consumption was analyzed by separate linear regression models per variant, with adjustments for age, sex, energy intake, principal component analysis components 1–10, and alcohol intake (g/day). We also performed conditional analysis.ResultsWe found 27 single nucleotide polymorphisms (SNPs) located in 12q24 and 14q32.12 that were associated with fish consumption. The 19 SNPs were located at 11 genes including six lead SNPs at the BRAP, ACAD10, ALDH2, NAA25, and HECTD4 regions on 12q24.12-13, and CCDC197 region on 14q32.12. In replication samples, all five SNPs located on chromosome 12 were replicated successfully, but the one on chromosome 14 was not. Conditional analyses revealed that the five lead variants in chromosome 12 were in fact the same signal.ConclusionWe found that new SNPs in the 12q24 locus were related to fish intake in two Japanese populations. The associations between SNPs on chromosome 12 and fish intake were strongly confounded by drinking status.

IntroductionWe examined the correlation between blood levels of dihomo-gamma-linolenic acid (DGLA), which belongs to the n-6 polyunsaturated fatty acids (PUFAs), and obesity in type 2 diabetic patients.Subjects and MethodsThe subjects were 62 type 2 diabetic patients (age 63.3 ± 9.3 years; 35 males and 27 females) who were not taking eicosapentaenoic acid (EPA) agents and were divided into two groups, i.e., an obese group (n = 29) with BMIs >25 kg/m2 and non-obese group (n = 33) with BMIs <25 kg/m2. For the blood PUFA, we measured DGLA, arachidonic acid (AA), EPA and docosahexaenoic acid (DHA) and compared them between the two groups.ResultsThe blood DGLA level was found to be significantly (p < 0.01) higher in the obese group (39.2 ± 12.0 μg/ml) than in the non-obese group (32.1 ± 9.5 μg/ml). The DGLA/AA ratio was also significantly (p < 0.01) higher in the obese group (0.24 ± 0.09) than in the non-obese group (0.19 ± 0.06). However, no significant differences were found in the blood levels of the AA, EPA, DHA or EPA/AA ratios between the two groups. The blood DGLA level showed a significant, positive correlation with BMI (r = 0.367, p < 0.01), waist circumference (r = 0.336, p < 0.01), AST (r = 0.262, p < 0.05), ALT (r = 0.291, p < 0.05), blood triglyceride (r = 0.439, p < 0.0001) and leptin level (r = 0.464, p < 0.001), respectively.ConclusionThese results suggest that high levels of blood DGLA in type 2 diabetic patients with obesity may be attributable to an excessive intake of n-6-PUFA and the decrease in desaturase activity converting DGLA to AA.