Analysis of MicroRNA in Bile Cytologic Samples Is Useful for Detection and Diagnosis of Extrahepatic Cholangiocarcinoma.

OBJECTIVES: This study aimed to develop reliable biomarkers that improve the ability of bile cytology to diagnose cholangiocarcinoma vs benign biliary lesions. METHODS: Many studies indicate that microRNAs (miRNAs) are potential candidates for the early diagnosis of cancer. We analyzed the expression of five tumor-associated miRNAs (miR-31-5p, miR-122-5p, miR-378d, miR-182-5p, and miR-92a-3p) in cytology samples using quantitative reverse transcription polymerase chain reaction. We collected 52 surgically resected tissue samples, 84 cytologic specimens from smears (53 cases of cancer and 31 cases of noncancer), and 40 residual sediments after smearing for routine cytology at Hiroshima University Hospital. RESULTS: The expression of miR-31-5p, miR-378d, and miR-122-5p was significantly higher in cancer tissues than those in normal tissues, while miR-182-5p expression was lower. The expression of miR-31-5p, miR-378d, miR-182-5p, and miR-92a-3p was significantly higher in detached cell samples from smears of cholangiocarcinoma cases than in those from noncancer cases. CONCLUSIONS: These results suggest that the analysis of miRNAs in bile cytologic specimens is a promising auxiliary tool for distinguishing cholangiocarcinoma from benign biliary lesions.

Advanced hepatocellular carcinoma with response to lenvatinib after atezolizumab plus bevacizumab.

RATIONALE: Various treatments are available for treating hepatocellular carcinoma (HCC). The immune checkpoint inhibitor combination of atezolizumab plus bevacizumab was recently approved for the treatment of unresectable HCC, but there are few reports on the failure of the combination treatment. Here, we present a case of unresectable HCC with adrenal metastasis that was eventually operated on after lenvatinib (LEN) treatment that followed failed treatment with atezolizumab plus bevacizumab. PATIENT CONCERNS: A 68-year-old man was diagnosed with non-alcoholic steatohepatitis-based HCC with adrenal metastasis. DIAGNOSIS: Cirrhosis was classified as Child-Pugh score of 5. HCC was diagnosed as Barcelona Clinic Liver Cancer stage C. INTERVENTIONS: We initiated treatment with atezolizumab plus bevacizumab. Liver dysfunction appeared 2 days after the first administration but was improved by intravenous rehydration and did not appear after the second course. The HCC shrank, but the adrenal metastasis grew bigger after the fourth course, so we changed the therapy to LEN. After HCC and adrenal metastasis were necrotic by LEN, conversion surgery was performed. OUTCOMES: After successful conversion therapy, the general condition of the patient was good, and has been carefully followed for 4 months to date without any evidence of further recurrences. LESSONS: This case showed that even if atezolizumab plus bevacizumab is not effective, multidisciplinary treatment such as LEN and conversion surgery is possible. Given the efficacy of LEN after atezolizumab plus bevacizumab, it is important to consider that there is a possibility of cure even when first-line treatment is not effective for a patient with unresectable HCC.

Case report of hepatic pseudocyst: A rare manifestation of liver metastasis from an anal squamous cell carcinoma.

INTRODUCTION: Liver metastasis of an anal squamous cell carcinoma (SCC) with a pseudocyst is uncommon. There are many diseases which form hepatic cystic lesions and sometimes it is difficult to arrive at an accurate diagnosis. PRESENTATION OF CASE: A 69-year-old woman visited our hospital with complaints of bloody stool and difficult defecation. A palpable mass in the anal canal was found on digital examination. The laboratory tests revealed anemia and raised levels of SCC antigen. On endoscopy a type 2 tumor was identified in the anal canal and biopsy revealed SCC. The patient was diagnosed with advanced anal SCC (cT2N1aM0, cStage IIIA) as a result of the examination and underwent chemoradiotherapy (CRT); unfortunately the tumor persisted after CRT. A salvage abdominoperineal resection with D2 and left lateral lymph node dissection was conducted. Histopathologically, the tumor was diagnosed as poorly differentiated SCC. She was readmitted for fever 3 weeks after surgery, and the abdominal CT showed multiple low density areas with enhancement at the edge of the liver, suggesting abscess or metastasis. The metastatic SCC was revealed by cytology of liver drainage and liver biopsy. DISCUSSION: Anal cancers are sometimes encountered however; a pseudo cystic presentation of a liver metastasis is very rare which makes it difficult to distinguish from other diseases. CONCLUSION: We present a case of SCC in the anal canal with liver metastasis presenting as a hepatic pseudocyst.

The prolyl isomerase Pin1 increases ß-cell proliferation and enhances insulin secretion.

The prolyl isomerase Pin1 binds to the phosphorylated Ser/Thr-Pro motif of target proteins and enhances their cis-trans conversion. This report is the first to show that Pin1 expression in pancreatic ß cells is markedly elevated by high-fat diet feeding and in ob/ob mice. To elucidate the role of Pin1 in pancreatic ß cells, we generated ß-cell-specific Pin1 KO (ßPin1 KO) mice. These mutant mice showed exacerbation of glucose intolerance but had normal insulin sensitivity. We identified two independent factors underlying impaired insulin secretion in the ßPin1 KO mice. Pin1 enhanced pancreatic ß-cell proliferation, as indicated by a reduced ß-cell mass in ßPin1 KO mice compared with control mice. Moreover, a diet high in fat and sucrose failed to increase pancreatic ß-cell growth in the ßPin1 KO mice, an observation to which up-regulation of the cell cycle protein cyclin D appeared to contribute. The other role of Pin1 was to activate the insulin-secretory step: Pin1 KO ß cells showed impairments in glucose- and KCl-induced elevation of the intracellular Ca2+ concentration and insulin secretion. We also identified salt-inducible kinase 2 (SIK2) as a Pin1-binding protein that affected the regulation of Ca2+ influx and found Pin1 to enhance SIK2 kinase activity, resulting in a decrease in p35 protein, a negative regulator of Ca2+ influx. Taken together, our observations demonstrate critical roles of Pin1 in pancreatic ß cells and that Pin1 both promotes ß-cell proliferation and activates insulin secretion.

Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations.

Prolyl isomerases are divided into three groups, the FKBP family, Cyclophilin and the Parvulin family (Pin1 and Par14). Among these isomerases, Pin1 is a unique prolyl isomerase binding to the motif including pSer/pThr-Pro that is phosphorylated by kinases. Once bound, Pin1 modulates the enzymatic activity, protein stability or subcellular localization of target proteins by changing the cis- and trans-formations of proline. Several studies have examined the roles of Pin1 in the pathogenesis of cancers and Alzheimer's disease. On the other hand, recent studies have newly demonstrated Pin1 to be involved in regulating glucose and lipid metabolism. Interestingly, while Pin1 expression is markedly increased by high-fat diet feeding, Pin1 KO mice are resistant to diet-induced obesity, non-alcoholic steatohepatitis and diabetic vascular dysfunction. These phenomena result from the binding of Pin1 to several key factors regulating metabolic functions, which include insulin receptor substrate-1, AMPK, Crtc2 and NF-κB p65. In this review, we focus on recent advances in elucidating the physiological roles of Pin1 as well as the pathogenesis of disorders involving this isomerase, from the viewpoint of the relationships between signal transductions and metabolic functions.

Role of Uric Acid Metabolism-Related Inflammation in the Pathogenesis of Metabolic Syndrome Components Such as Atherosclerosis and Nonalcoholic Steatohepatitis.

Uric acid (UA) is the end product of purine metabolism and can reportedly act as an antioxidant. However, recently, numerous clinical and basic research approaches have revealed close associations of hyperuricemia with several disorders, particularly those comprising the metabolic syndrome. In this review, we first outline the two molecular mechanisms underlying inflammation occurrence in relation to UA metabolism; one is inflammasome activation by UA crystallization and the other involves superoxide free radicals generated by xanthine oxidase (XO). Importantly, recent studies have demonstrated the therapeutic or preventive effects of XO inhibitors against atherosclerosis and nonalcoholic steatohepatitis, which were not previously considered to be related, at least not directly, to hyperuricemia. Such beneficial effects of XO inhibitors have been reported for other organs including the kidneys and the heart. Thus, a major portion of this review focuses on the relationships between UA metabolism and the development of atherosclerosis, nonalcoholic steatohepatitis, and related disorders. Although further studies are necessary, XO inhibitors are a potentially novel strategy for reducing the risk of many forms of organ failure characteristic of the metabolic syndrome.

Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus.

BACKGROUND: Insulin resistance with elevated glucose is a risk factor for non-alcoholic steatohepatitis (NASH). We investigated the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor luseogliflozin on NASH development using a rodent model. METHODS: Mice were treated with both nicotinamide and streptozotocin (NA/STZ) to reduce insulin secretory capacity, and then fed a high fat diet containing trans fatty acids (HFDT) for 8 weeks. The NA/STZ HFDT-fed mice were divided into two groups, either treated with luseogliflozin or untreated, during this period. The glucose elevations in the NA/STZ-treated and HFDT-fed mice were significantly improved by luseogliflozin administration. While HFDT feeding induced NASH development as shown by liver weight gain with lipid accumulation and increased serum alanine aminotransferase, these changes were all attenuated in the group treated with luseogliflozin. In addition, fibrotic change and increases in collagen deposition with upregulations of collagen1 and smooth muscle actin and inflammatory cytokine expressions observed in the HFDT-fed mouse livers were also normalized by luseogliflozin administration. CONCLUSIONS: Taken together, these results obtained in mice demonstrate the favorable effects of administering SGLT2 inhibitors, for the treatment of NASH associated with diabetes mellitus. We anticipate that these agents would be applicable to humans.

The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model.

Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnel-positive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia.