Association analysis of the DISC1 gene with schizophrenia in the Japanese population and DISC1 immunoreactivity in the postmortem brain

The Disrupted-in-Schizophrenia 1 (DISC1) gene plays a role in the regulation of neural development. Previous evidence from genetic association and biological studies implicates the DISC1 gene as having a role in the pathophysiology of schizophrenia. In the present study, we explored the association between DISC1 missense mutation rs821616 (Ser704Cys) single nucleotide polymorphism (SNP) and four other SNPs (rs1772702, rs1754603, rs821621, rs821624) in the related haplotype block and schizophrenia in the Japanese population. We could not find a significant association of selected SNPs with schizophrenia after correction for multiple testing. We performed a meta-analysis of the Ser704Cys variant in schizophrenia using data from the present study and five previous Japanese population studies, and found no association with schizophrenia. We also examined DISC1 immunoreactivity in postmortem prefrontal cortex specimens of schizophrenia patients compared to control samples. The immunoreactivity revealed a significant decrease of DISC1 protein expression in the schizophrenia samples after ruling out potential confounding factors. However, the Ser704Cys variant did not show effects on DISC1 immunoreactivity. These results provide evidence that this functional genetic variation of DISC1 do not underlie the pathophysiology of schizophrenia in the Japanese population.     

Association study of BDNF with completed suicide in the Japanese population

We explored the association between the brain-derived neurotrophic factor gene with suicide using 307 Japanese completed suicides, 380 healthy controls, and data from previously published samples. The meta-analyses of the valine with methionine in codon 66 (Val66Met) single nucleotide polymorphism (SNP) showed that the Met-allele tended to be associated with attempted suicide in Asian populations, but not with the completed suicide.     

Japanese version of The Cancer Genome Atlas,JCGA, established using fresh frozen tumors obtained from 5143 cancer patients

This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single‐center study called “High‐tech Omics‐based Patient Evaluation” or “Project HOPE” conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole‐exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed “Shizuoka Multi‐omics Analysis Protocol” developed in‐house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non–cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.     

Clinicopathological studies of minimal thyroid and oridinary thyroid cancers

Clinicopathological studies were carried out on 27 patients with minimal thyroid cancer and 56 with ordinary thyroid cancer at Kanazawa University, from April, 1979 to December, 1982. There was a significant difference in the rate of preoperative diagnosis between the minimal and the ordinary cancer groups. Subtotal thyroidectomy with modified neck dissection was usually performed in both groups. The histological types in minimal cancer group included 16 papillary carcinomas, 7 nonencapsulated sclerosing carcinomas, one follicular carcinoma, one anaplastic carcinoma with squamous cell metaplasia and two multiple mixed carcinomas. There was no significant difference in the rates of intrathyroidal and lymph node metastases between the two groups. While the metastatic lesions of sclerosing carcinoma were localized to the central cervical lymph nodes, the ordinary cancer in general and the papillary variant of minimal cancer metastasized not only to the central cervical lymph nodes but also to the ipsilateral and even to the contralateral jugular lymph nodes.     

Altered Expression of Hepatic CYP1A Enzymes in Rat Hepatocarcinogenesis

Hyperplastic nodules of the liver were induced by treating male F344 rats with a combination of diethylnitrosamine and partial hepatectomy. The livers were examined for the expression of cytochrome P450 (CYP) enzymes, mainly CYP1A1 and CYP1A2; the amount and activity of the enzymes in the nricrosomes were assessed by enzymatic and immunological methods. Levels of CYP1A mRNAs were assayed by Northern blotting. In the liver bearing hyperplastic nodules, the total amount of microsomal CYP enzymes decreased to about 50% of the control. The microsomal activities for the CYP1A2-mediated activation of carcinogenic heterocyclic amines decreased to about 20% of the corresponding controls, in association with decreases in the levels of mRNA and protein of CYP1A2. Furthermore, the inducibility of CYP1A2 by CYP1A inducers such as 3-methoxy-4-aminoazobenzene and 3-methylcholanthrene was also decreased at the mRNA, protein and activity levels. On the other hand, CYP1A1 enzyme, which was undetectable in control rat liver, appeared in the liver bearing hyperplastic nodules, but its inducibility by a CYP1A inducer decreased slightly. The present findings indicated that individual CYP1A enzymes are differently regulated, and the expression of CYP1A2 is reduced preferentially in the liver bearing hyperplastic nodules.     

Decreased Levels of 2-Amino-3-methylimidazo[4,5-f]quinoline-DNA Adducts in Rats Treated with β-Carotene, α-Tocopherol and Freeze-dried Aloe

To assess mechanisms of chemoprevention of hepatocarcinogenesis by trans -β-carotene (β-C), DL-α-tocopherol (α-T), and freeze-dried whole leaves of Kidachi aloe (Aloe), formation of 2-amino-3-methylimidazo[4,5- f ]quinoline (IQ)-DNA adducts was measured by ³²P-post-labeling analysis, and CYP1A1 and CYP1A2 protein levels were analyzed by ELISA. Group 1 rats were fed diet containing 0.02%β-C, 1.5%α-T or 30% Aloe over an 8-day period, while group 2 was given basal diet alone. On day 7, all animals were subjected to two-thirds partial hepatectomy (PH). Twelve hours after PH, they received a single dose of the carcinogenic food pyrolysate IQ (100 mg/kg) intragastrically, to initiate hepatocarcinogenesis. Rats were killed 6, 12, 24 and 48 h after IQ administration. The levels of adducts, expressed as relative adduct labeling values in rats treated with β-C, α-T and Aloe, were decreased as compared with the control group at hour 24 (36 h after PH), with a significant difference in the case of the β-C group (46.4% of the control value). Similarly, all showed a tendency for decrease at hour 48. Furthermore, the levels of CYP1A2, known to be responsible for activation of IQ, showed a significant reduction at hour 24. It is concluded that β-C, and possibly also α-T and Aloe, have the potential to reduce IQ-DNA adduct formation, presumably as a result of decreased formation of active metabolites. The results may explain, at least in part, the previously observed inhibitory effects of these compounds on induction of preneoplastic hepatocellular lesions.     

Effect of gonadotropin-releasing hormone antagonist on ovarian and uterine weights in immature female rats

The immature rat uterotrophic assay has been proposed as a screening test method for detecting estrogenic and antiestrogenic chemicals. Although the immature rat uterotrophic assay is advantageous because the test animals are not traumatized by the ovariectomizing process, the effect of endogenous estrogen on ovarian and uterine weight in the immature animals that are used in immature rat uterotrophic assay has not received much attention. In this study, 19-day-old rats were treated with antide, a gonadotropin-releasing hormone antagonist, antide, to block gonadal production of endogenous estrogen. Uterine and ovarian weights of the antide-treated animals were markedly lower than those of control animals. This finding suggests that endogenous gonadal estrogen may already be acting on the uterus and ovaries in immature rats. Blocking endogenous estrogen with a gonadotropin-releasing hormone antagonist may enhance the sensitivity of the immature rat uterotrophic assay; however, the possibility that this protocol may interfere with the ability of the immature rat uterotrophic assay to detect centrally-mediated effects can not be discounted.