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The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7, 672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67–2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25–1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23–1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84–4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63–0.67)]. Conclusions: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients., 非アルコール性脂肪性肝疾患（NAFLD）関連疾患の疾患感受性遺伝子を用いたリスク予測 --全ゲノム関連解析によって4つの疾患感受性遺伝子を同定--. 京都大学プレスリリース. 2018-02-15.

Aim: We aimed to identify the candidates for antiviral therapy, among patients who are hepatitis C virus (HCV) carriers with normal serum aminotransferase (ALT), focused on the inhibition of hepatocellular carcinoma (HCC). Methods: Four hundred and sixty-four HCV carriers with normal serum ALT and 129 HCV carriers with persistently normal ALT (PNALT) and platelet (PLT) counts ≥150 000/μL who received liver biopsies were enrolled. HCV carriers with normal serum ALT were divided into four groups according to their ALT levels (≤30 U/L or 31–40 U/L) and PLT counts (≥150 000/μL or

Comparative genomic hybridization (CGH) using 40 cell lines derived from malignant melanomas (MMs) revealed frequent amplification at 7q33-q34 containing BRAF gene, which often is mutated in MM. We found this gene to be amplified to a remarkable degree in the MM cell lines that exhibited high-level gains at 7q33-q34 in CGH. Among 40 cell lines, the eight lines that revealed neither BRAF nor NRAS mutations showed even higher levels of BRAF mRNA expression than the 32 mutated lines, although DNA amplification at 7q33-q34 was not detected in every lines overexpressing BRAF. MM cells that carried wild-type BRAF and NRAS showed constitutive overexpression of B-Raf protein and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), even after serum starvation. Not only downregulation of the endogenously overexpressed wild-type B-Raf by antisense oligonucleotide but also a treatment with an inhibitor of mitogen-activated protein kinase kinase (MAPKK, MEK) reduced phosphorylated ERK1/2 and cell growth, whereas the exogenously expressed wild-type B-Raf promoted cell growth in MM cells. Our results provide the evidence that overexpression of wild-type B-Raf, in part but not always as a result of gene amplification, is one of the mechanisms underlying constitutive activation of the MAPK pathway that stimulates growth of MM cells.

Background/Aim: Hepatocellular carcinoma frequently develops during the advanced stages of chronic hepatitis C. We examined whether interferon prevents the development of hepatocellular carcinoma in chronic hepatitis C patients. Methods: Japanese patients with chronic hepatitis C ( n =1.148; 117 with portal fibrous expansion (F1), 636 with bridging fibrosis (F2), 355 with bridging fibrosis and architectural distortion (F3)) and 40 cirrhotic (F4) patients were treated with interferon. These patients were followed from 1 to 7 years after interferon therapy. Blood tests and image analysis were serially performed to assess response to interferon and to detect hepatocellular carcinoma. Fifty-five cirrhotic type C patients (control F4) not receiving interferon were enrolled in this study. Results: Sustained (SR: 27.5%) and transient (TR: 23.0%) responders totaled 50.5%, while 49.5% did not respond to interferon. SR showed an improvement in disease stage reflected by increased platelet counts. Fifty-two patients (9 F2, 36 F3, and 7 F4) developed hepatocellular carcinoma in the follow-up period; 3 SR, 8 TR, and 41 non-responders (NR). The cumulative incidence of hepatocellular carcinoma in F2 was significantly lower ( p =0.019) in SR compared with NR, but not in SR in F3 and F4 patients. However, the cumulative incidence of hepatocellular carcinoma was significantly decreased in all SR ( p =0.0001) and TR ( p =0.0397) compared with all NR. Conclusion: These results indicate that interferon therapy in chronic hepatitis C patients lowered the rate of progression of hepatocellular carcinoma in sensitive cases but not in patients in an advanced stage.

A 65-year-old man who presented with adrenal insufficiency was admitted on Feburuary 9, 1988. CT scan showed bilateral swelling of adrenals; open biopsy of the tumor revealed non-Hodgkin's lymphoma. The serum level of catecholamines and calcitonin was elevated. A combination chemotherapy was started. After 3 courses of the treatment remission was achieved, following recovery from adrenal insufficiency. In November, 1988, he had pulmonary infiltration and high fever, resolved by the administration of antibiotics and antifungal drugs. On January 27, 1989, he underwent emergency operation because of perforation of gastric ulcer. In Feburuary, tumor increased in size, and the disease became progressive. On April 2, 1989, he died of respiratory failure. Autopsy revealed a definite diagnosis of malignant lymphoma, diffuse large cell type. Immunohistological studies revealed B cell origin of the cells based on positive LCA and pan B markers.