Δ40p53α suppresses tumor cell proliferation and induces cellular senescence in hepatocellular carcinoma cells.

Splice variants of certain genes impact on genetic biodiversity in mammals. The tumor suppressor TP53 gene (encoding p53) plays an important role in the regulation of tumorigenesis in hepatocellular carcinoma (HCC). Δ40p53α is a naturally occurring p53 isoform that lacks the N-terminal transactivation domain, yet little is known about the role of Δ40p53α in the development of HCC. Here, we first report on the role of Δ40p53α in HCC cell lines. In the TP53+/Δ40 cell clones, clonogenic activity and cell survival dramatically decreased, whereas the percentage of senescence-associated ß-galactosidase (SA-ß-gal)-positive cells and p21 (also known as WAF1, CIP1 and CDKN1A) expression significantly increased. These observations were clearly attenuated in the TP53+/Δ40 cell clones after Δ40p53α knockdown. In addition, exogenous Δ40p53 expression significantly suppressed cell growth in HCC cells with wild-type TP53, and in those that were mutant or null for TP53 Notably, Δ40p53α-induced tumor suppressor activity was markedly attenuated in cells expressing the hot-spot mutant Δ40p53α-R175H, which lacks the transcription factor activity of p53. Moreover, Δ40p53α expression was associated with increased full-length p53 protein expression. These findings enhance the understanding of the molecular pathogenesis of HCC and show that Δ40p53α acts as an important tumor suppressor in HCC cells.

Balloon enteroscopy-assisted radial incision and cutting method for refractory hepaticojejunostomy anastomotic strictures.

BACKGROUND: Balloon enteroscopy-assisted balloon dilation and temporary biliary stent placement are effective for hepaticojejunostomy anastomotic strictures (HJAS), but the re-stenosis rates are relatively high. We examined the feasibility and efficacy of a novel treatment technique for refractory HJAS, called balloon enteroscopy-assisted radial incision and cutting (BE-RIC). METHODS: Between January 2016 and June 2018, 11 patients with refractory HJAS that recurred after balloon dilation and/or stent placement, underwent BE-RIC. We evaluated the technical success, clinical success, adverse events, and re-stenosis rates associated with BE-RIC. RESULTS: The technical success rate of BE-RIC was 91 % (10/11). Clinical success was achieved in all patients who underwent technically successful procedures. The procedure-related adverse event rate was 9 % (1/11). No re-stenosis was observed during the follow-up period; 9 patients were followed up for more than 6 months, and of these, 5, 4, and 2 patients were followed up for more than 12, 18, and 24 months, respectively, without re-stenosis. CONCLUSIONS: BE-RIC for refractory HJAS showed favorable results. BE-RIC might be a useful option for treating refractory HJAS.

Combined side-by-side and stent-in-stent method for triple metal stenting in patients with malignant hilar biliary obstruction.

BACKGROUND AND AIM: Endoscopic placement of three branched self-expandable metallic stents (SEMS) for high-grade malignant hilar biliary obstruction (MHBO) is technically challenging. We examined the feasibility and efficacy of a novel stenting method combining side-by-side and stent-in-stent (SBSIS) placement for MHBO. METHODS: Between January 2015 and December 2018, 27 consecutive patients with high-grade MHBO underwent SBSIS placement. We evaluated the technical success, functional success, recurrent biliary obstruction (RBO), adverse events other than RBO, and reintervention success rates associated with SBSIS placement. RESULTS: Technical success rate was 85% (23/27). Insertion of the third SEMS failed in four patients, and median diameter of the common bile duct (CBD) was significantly smaller in patients in whom technical failure occurred (5 mm vs 8 mm; P = 0.004). Functional success was achieved in all patients in whom the procedure was a technical success. Rate of adverse events other than RBO was 15% (4/27). RBO rate was 43% (10/23), and median time to RBO was 157 days. Success rate of endoscopic reintervention for RBO was 89% (8/9). CONCLUSION: SBSIS placement showed favorable results and is a promising option in patients with high-grade MHBO requiring triple metal stenting. However, it might be preferable to avoid SBSIS in patients with a narrow CBD. Clinical Trial Registry: UMIN000035721.

Assessing the diagnostic yield of controllable biopsy-forceps for biliary strictures.

OBJECTIVE: Biliary forceps biopsies are essential for differentially diagnosing biliary strictures and evaluating the preoperative superficial intraductal spread of bile duct cancers; however, these biopsies are technically demanding and time consuming. Using controllable biopsy-forceps (C-BF), which enable the tip's angle to be adjusted by up to 90°, may facilitate the procedure and improve the diagnostic yield for biliary biopsies. This study aimed to examine the efficacy of C-BF associated with the diagnosis of biliary strictures. MATERIALS AND METHOD: Between 2009 and 2015, 110 patients with biliary strictures underwent biliary biopsies using C-BF. We retrospectively evaluated the diagnostic yield of C-BF for biliary strictures and determined the success rate associated with obtaining adequate samples during mapping biopsies to evaluate the superficial intraductal tumor spread. RESULTS: The technical success rate for biliary biopsies using C-BF was 99% (109/110). The sensitivity, specificity and accuracy of the diagnoses of biliary strictures were 60% (46/77), 100% (33/33) and 72% (79/110), respectively. Regarding the mapping biopsy procedures, adequate samples were successfully obtained from 96% (22/23), 92% (11/12), 80% (12/15), 75% (9/12) and 31% (5/16) of the intrapancreatic common bile ducts, upper common bile ducts, confluences of the hepatic ducts, right intrahepatic bile ducts and left intrahepatic bile ducts, respectively. CONCLUSIONS: C-BF may facilitate biliary cannulation and mapping biopsies of the common bile duct and the right intrahepatic bile duct. However, given that the diagnostic sensitivity was 60%, further modifications are expected and necessary to maximize the utility of the controllable mechanism.

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels and liver fibrosis: A meta-analysis.

BACKGROUND AND AIM: A reliable, non-invasive biomarker for diagnosis of liver fibrosis in chronic liver disease patients is needed. The aim of this study was to assess by meta-analysis the efficacy of measuring serum levels of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP), a novel and promising biomarker, for staging liver fibrosis and predicting the development of hepatocellular carcinoma and overall survival. METHODS: We performed a meta-analysis using online journal database searches. We identified 39 studies, 21 of which met the criteria for meta-analysis. Sensitivity and specificity of WFA+ -M2BP for assessing liver fibrosis staging in chronic liver diseases with broad etiologies were determined. Hazard ratios with 95% confidence intervals were also used for predicting hepatocellular carcinoma development and overall survival. RESULTS: With WFA+ -M2BP, the sensitivity and specificity for predicting significant fibrosis (≥ F2), advanced fibrosis (≥ F3), and liver cirrhosis (= F4) were 0.690 and 0.778, 0.764 and 0.758, and 0.818 and 0.839, respectively. Sensitivity and specificity for diagnosing liver fibrosis in patients with hepatitis C virus were mostly higher than those in overall patients. However, sensitivity and specificity for diagnosing liver fibrosis in patients with hepatitis B virus were lower than those in overall patients. Overall, hazard ratios for development of hepatocellular carcinoma and overall survival were 5.946 and 1.068, respectively. CONCLUSIONS: These results suggest that serum WFA+ -M2BP is a reliable predictor for liver fibrosis staging and a good substitute for liver biopsy. It is also useful for predicting both hepatocellular carcinoma development and overall survival.

Simultaneous Versus Sequential Side-by-Side Bilateral Metal Stent Placement for Malignant Hilar Biliary Obstructions.

BACKGROUND: Endoscopic bilateral self-expandable metallic stent (SEMS) placement for malignant hilar biliary obstructions (MHBOs) is technically demanding, and a second SEMS insertion is particularly challenging. A simultaneous side-by-side (SBS) placement technique using a thinner delivery system may mitigate these issues. AIMS: We aimed to examine the feasibility and efficacy of simultaneous SBS SEMS placement for treating MHBOs using a novel SEMS that has a 5.7-Fr ultra-thin delivery system. METHODS: Thirty-four patients with MHBOs underwent SBS SEMS placement between 2010 and 2016. We divided the patient cohort into those who underwent sequential (conventional) SBS placement between 2010 and 2014 (sequential group) and those who underwent simultaneous SBS placement between 2015 and 2016 (simultaneous group), and compared the groups with respect to the clinical outcomes. RESULTS: The technical success rates were 71% (12/17) and 100% (17/17) in the sequential and simultaneous groups, respectively, a difference that was significant (P = .045). The median procedure time was significantly shorter in the simultaneous group (22 min) than in the sequential group (52 min) (P = .017). There were no significant group differences in the time to recurrent biliary obstruction (sequential group: 113 days; simultaneous group: 140 days) or other adverse event rates (sequential group: 12%; simultaneous group: 12%). CONCLUSIONS: Simultaneous SBS placement using the novel 5.7-Fr SEMS delivery system may be more straightforward and have a higher success rate compared to that with sequential SBS placement. This new method may be useful for bilateral stenting to treat MHBOs.

Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects.

BACKGROUND: Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects. METHODS: Our case-control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk. RESULTS: Overall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk. CONCLUSIONS: Our data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk.

Endoscopic ultrasound-guided cystogastrostomy for successful drainage of pancreatic pseudocyst: a pediatric case report.

A 15-year-old boy was admitted to our hospital with a recent increase in the size of a preexisting pancreatic pseudocyst. At 11 years of age, he was diagnosed with acute lymphoid leukemia (ALL) and received chemotherapy with L-asparaginase (L-Asp); he developed the pancreatic pseudocyst following L-Asp-induced acute pancreatitis. The pancreatic pseudocyst had increased to 120mm in diameter. He developed epigastralgia and portal hypertension. Endoscopic ultrasound (EUS)-guided cystogastrostomy with the placement of a 7-cm 7-Fr plastic stent and a 5-Fr NB pigtail catheter led to the near-complete resolution of the pseudocyst. There were no signs of recurrence within the first year after intervention. EUS-guided drainage, increasingly used for pseudocysts, should be considered as an effective treatment approach for pediatric pancreatic pseudocysts.

Diagnostic accuracy of real-time tissue elastography for the staging of liver fibrosis: a meta-analysis.

OBJECTIVE: To evaluate the overall accuracy of real-time tissue elastography (RTE) for the staging of liver fibrosis. METHODS: We systematically reviewed 15 studies (1,626 subjects) in which sensitivity and specificity of RTE for liver fibrosis are available. For each cut-off stage of fibrosis, i.e., F ≥ 1, F ≥ 2, F ≥ 3, and F ≥ 4, summary sensitivity and specificity were estimated using a bivariate random-effects model. Publication bias was assessed using funnel plots and Egger's test. RESULTS: Summary sensitivity and specificity were 0.79 and 0.76 for F ≥ 2, 0.82 and 0.81 for F ≥ 3, and 0.74 and 0.84 for F ≥ 4, respectively. Meta-regressions revealed scoring methods of RTE and liver diseases in the samples might not influence sensitivity and specificity of RTE. However, the estimated accuracy of RTE might be overestimated due to publication bias (p = 0.004 for F ≥ 2, p < 0.001 for F ≥ 3, and p = 0.002 for F ≥ 4). CONCLUSIONS: RTE is not highly accurate for any cut-off stage of fibrosis. Compared with findings of meta-analyses on Transient Elastography and Acoustic Radiation Force Impulse imaging, the overall accuracy of RTE seems to be nearly identical for the evaluation of significant liver fibrosis, but less accurate for the evaluation of cirrhosis. KEY POINTS: • Non-invasive methods for evaluating liver fibrosis are necessary to replace liver biopsy. • ARFI is as accurate as TE for evaluating liver fibrosis. • RTE may be as accurate as TE and ARFI for fibrosis. • RTE may be less accurate than TE and ARFI for cirrhosis. • The estimated accuracy of RTE may be overestimated by publication bias.

Case of cholangiocellular carcinoma in a patient with glycogen storage disease type Ia.

Glycogen storage disease (GSD) type Ia is caused by a deficiency in glucose-6-phosphatase. Long-term complications, including renal disease, gout, osteoporosis and pulmonary hypertension, develop in patients with GSD type Ia. In the second or third decade, 22-75% of GSD type Ia patients develop hepatocellular adenoma (HCA). In some of these patients, the HCA evolves into hepatocellular carcinoma. However, little is known about GSD type Ia patients with HCA who develop cholangiocellular carcinoma (CCC). Here, we report for the first time, a patient with GSD type Ia with HCA, in whom intrahepatic CCC was developed.

Association between variations in the fat mass and obesity-associated gene and pancreatic cancer risk: a case-control study in Japan.

BACKGROUND: It is clear that genetic variations in the fat mass and obesity-associated (FTO) gene affect body mass index and the risk of obesity. Given the mounting evidence showing a positive association between obesity and pancreatic cancer, this study aimed to investigate the relation between variants in the FTO gene, obesity and pancreatic cancer risk. METHODS: We conducted a hospital-based case-control study in Japan to investigate whether genetic variations in the FTO gene were associated with pancreatic cancer risk. We genotyped rs9939609 in the FTO gene of 360 cases and 400 control subjects. An unconditional logistic model was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between rs9939609 and pancreatic cancer risk. RESULTS: The minor allele frequency of rs9939609 was 0.18 among control subjects. BMI was not associated with pancreatic cancer risk. Compared with individuals with the common homozygous TT genotype, those with the heterozygous TA genotype and the minor homozygous AA genotype had a 48% (OR=1.48; 95%CI: 1.07-2.04), and 66% increased risk (OR=1.66; 95%CI: 0.70-3.90), respectively, of pancreatic cancer after adjustment for sex, age, body mass index, cigarette smoking and history of diabetes. The per-allele OR was 1.41 (95%CI: 1.07-1.85). There were no significant interactions between TA/AA genotypes and body mass index. CONCLUSIONS: Our findings indicate that rs9939609 in the FTO gene is associated with pancreatic cancer risk in Japanese subjects, possibly through a mechanism that is independent of obesity. Further investigation and replication of our results is required in other independent samples.

[Hepatocarcinogenesis in NASH].

With the increase of lifestyle-related diseases, metabolic syndrome has clearly increased in recent years. Fatty liver, which is the manifestation of metabolic syndrome in the liver, has received little attention because it is not the actual cause of death. However, with the developing increase of metabolic syndrome, non-alcoholic fatty liver disease(NAFLD), especially nonalcoholic steatohepatits(NASH), has increased, and has received much attention. In chronic liver disease, liver cirrhosis develops, finally leading to liver failure. The most serious chronic liver disease is progression to liver cancer. Once hepatic fibrosis develops, the hepatic carcinogenic rate has been increased. Hepatic carcinogenic rate has been reported to reach 8%per year in hepatitis type C-related liver cirrhosis. Although little has been reported about NASH-related liver cancer, NASH-related hepatic carcinogenic rate reached to about 2. 6%per year. In this review, we will describe the epidemiology, gender differences, risk factors and pathogenesis of NASH-related liver cancer.

An overview of genetic polymorphisms and pancreatic cancer risk in molecular epidemiologic studies.

BACKGROUND: Although pancreatic cancer has been extensively studied, few risk factors have been identified, and no validated biomarkers or screening tools exist for early detection in asymptomatic individuals. We present a broad overview of molecular epidemiologic studies that have addressed the relationship between pancreatic cancer risk and genetic polymorphisms in several candidate genes and suggest avenues for future research. METHODS: A comprehensive literature search was performed using the PubMed database. RESULTS: Overall, individual polymorphisms did not seem to confer great susceptibility to pancreatic cancer; however, interactions of polymorphisms in carcinogen-metabolizing genes, DNA repair genes, and folate-metabolizing genes with smoking, diet, and obesity were shown in some studies. The major problem with these studies is that, due to small sample sizes, they lack sufficient statistical power to explore gene-gene or gene-environment interactions. Another important challenge is that the measurement of environmental influence needs to be improved to better define gene-environment interaction. It is noteworthy that 2 recent genome-wide association studies of pancreatic cancer have reported that variants in ABO blood type and in 3 other chromosomal regions are associated with risk for this cancer, thus providing new insight into pancreatic cancer etiology. CONCLUSIONS: As is the case in other complex diseases, common, low-risk variants in different genes may act collectively to confer susceptibility to pancreatic cancer in individuals with repeated environmental exposures, such as smoking and red meat intake. Clarification of gene-gene and gene-environmental interaction is therefore indispensable for future studies. To address these issues, a rigorously designed molecular epidemiologic study with a large sample is desirable.

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10-8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

Inflammatory cytokines modulate chemokine production patterns of HepG2 cells toward initially inclined direction.

AIM: Human hepatocytes are known to express an array of inflammatory cytokines and chemokines. In this study, we examined the potential roles of hepatocytes in regulating immune responses in the liver, by assessing the induction of Th1- or Th2-specific chemokines in HepG2 cells after various inflammatory stimulations. METHODS: HepG2 cells were stimulated with IL-1alpha, IFN-gamma, IL-4, IL-10, and/or CCL2, harvested at several time points, and served for the analyses of cytokine/chemokine mRNA expressions by semi-quantitative RT-PCR. RESULTS: (i) IL-1alpha up-regulated mRNA levels of CXCL8, CXCL10, and CCL2. IFN-gamma increased those of CXCL9, CXCL10, and CCL5, while IL-4 or IL-10 had no effect. (ii) Addition of IL-4 to the culture of IFN-gamma-stimulated cells, down-regulated CXCL9 and CXCL10 mRNA levels. (iii) Addition of IFN-gamma to the culture of IL-1alpha-stimulated cells, further up-regulated CXCL9 and CXCL10 mRNA levels. Addition of IL-4 decreased CXCL8 and CXCL10 levels, and increased CCL2 level in IL-1alpha-stimulated cells. (iv) CCL2 induced IL-4 mRNA expression. CONCLUSIONS: IFN-gamma augmented mRNA expression of Th1-specific chemokines (CXCL9 and CXCL10) in HepG2 cells. IL-4 had no effect on those of Th2-spesific chemokines (CCL17 and CCL22); however, it was supposed to augment Th2 response indirectly through the induction of CCL2 under the inflammatory condition. The findings suggest that hepatocytes have ability to promote immune responses in the liver toward the direction, initially determined by the cytokine balances in the local inflammatory region.

Effect of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis C virus infection.

AIM: Many reports have revealed ursodeoxycholic acid (UDCA) to be effective against chronic hepatitis C virus (HCV). However, some cases resist this therapy and the mechanism of action remains unclear. In this study, UDCA was administered to patients with chronic HCV and the correlation between the bile acids of the biliary bile and serum and the drug efficacy was investigated. METHODS: Fifteen patients were given 600 mg/day of UDCA for more than 24 weeks. The serum bile acid concentrations and biliary and serum bile acid were collected before and after 24 weeks of UDCA treatment, and composition determined by high-performance liquid chromatography. RESULTS: The treatment was effective in nine cases (ALT decreased to less than twice the normal values 80 IU/L) and ineffective in six cases. There was no significant difference in the serum bile acid concentrations before and after UDCA treatment between the values of both cases. After UDCA treatment, the serum percentage of UDCA (effective, 62.5 +/- 2.0; ineffective, 53.5 +/- 2.5, (P = 0.02)) and the percentage of chenodeoxycholic acid (CDCA) showed no remarkable changes. In the biliary bile the percentage of CDCA (effective, 30.9 +/- 2.0; ineffective, 20.0 +/- 3.0, (P = 0.007)) and the percentage of UDCA showed no remarkable changes. CONCLUSION: In the effective cases, the percentage of UDCA in the serum and the percentage of CDCA in biliary bile were significantly higher than in the ineffective cases. This indicates that, when effective, CDCA decreases in hepatocytes and this reduction contributes to hepatoprotection.

Cathepsin S, a new serum biomarker of sarcoidosis discovered by transcriptome analysis of alveolar macrophages.

BACKGROUND: Development of reliable new biomarkers remains crucial to improve diagnosis and assessing disease activity in sarcoidosis. The objective of this study was to seek such markers from the gene expression signature of alveolar macrophages by transcriptome analysis. METHODS: Pooled RNA extracted from alveolar macrophages from patients with active sarcoidosis and control patients was subjected to transcriptome analysis using microarrays. Expressed gene intensity in sarcoidosis relative to that in control was calculated. We measured serum cathepsin S (CTSS) concentrations in 89 healthy volunteers, 107 patients with sarcoidosis, 26 with interstitial pneumonia, 150 with pneumoconiosis, and 76 with pulmonary mycobacteriosis by the enzyme-linked immunosorbent assay. RESULTS: Among 12 genes with ratios higher than that of a housekeeping gene, we selected CTSS for scrutinizing protein expression in serum because of the feasibility of the protein assay. CTSS concentrations were significantly increased in sarcoidosis compared with not only controls but also all the other lung diseases. Receiver operating characteristics curve for sarcoidosis and parenchymal lung diseases revealed an area under the curve of 0.800 (95% confidence interval, 0.751-0.850; p=1.4 x 10-18) with 70% sensitivity and 78% specificity at a CTSS concentration of 15.5 ng/ml. A significant trend was identified between CTSS concentrations and the number of affected organs. Serum CTSS concentrations varied in parallel with clinical courses both spontaneously and in response to corticosteroid therapy. Epithelioid cells in granulomas were positive for immunohistochemical staining with CTSS. CONCLUSIONS: CTSS has the potential to be a useful biomarker in sarcoidosis.

Severe Biliary Stricture Dilation Using the Soehendra Stent Retriever with a Short-Type Balloon Enteroscope in Patients with Surgically Altered Anatomies.

BACKGROUND: Balloon enteroscopy (BE) can be used for endoscopic retrograde cholangiography (ERC) to treat biliary strictures in patients with surgically altered anatomies. However, biliary strictures, including bilioenteric anastomotic strictures, are often very severe and dilation catheters cannot pass through them. The Soehendra stent retriever (SSR) is like a screw drill and can be useful for dilating severe strictures, but the utility of SSR during BE-assisted ERC (BE-ERC) is unclear. This study aimed to examine the efficacy and safety of a dilation technique using the SSR during BE-ERC. METHODS: Between 2014 and 2018, 28 patients with surgically altered gastrointestinal anatomies and severe biliary strictures underwent BE-ERC, and the SSR was used for the dilation procedures. We evaluated the technical success, therapeutic success, and adverse event rates associated with SSR dilation. RESULTS: The technical success rate was 93% (26/28). The procedures undertaken on two patients with non-anastomotic strictures failed technically because the SSR was not long enough to reach the strictures. The therapeutic success rate was 96% (25/26) for the patients whose procedures were technically successful. The adverse event rate was 7% (2/28), and the adverse events were mild and improved with conservative management. No bleeding or duct perforations occurred. CONCLUSIONS: Although the indications for using the SSR in patients with non-anastomotic strictures should be considered based on the distance between the tip of the scope and the stricture's location, SSR dilation may be a useful option during BE-ERC if a biliary stricture is very severe.

Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice.

Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Tabernaemontana divaricate, attenuates hepatic fibrosis in mice. We have previously shown that CnP inhibits non-alcoholic steatohepatitis (NASH) using a methionine-choline-deficient (MCD) diet-fed mouse model. However, little is known about the CnP mediated inhibition of hepatic steatosis in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse models. CnP (0.5 and 1 µg/g/body weight) was co-administered along with a high-fat diet to male BALB/c mice. After nine weeks of administering the high-fat diet, hepatic steatosis, triglyceride, and hepatic fat metabolism-related markers were examined. Administration of a high-fat diet for 9 weeks was found to induce hepatic steatosis. CnP dose-dependently attenuated the high-fat diet-induced hepatic steatosis. The diet also attenuated hepatic peroxisome proliferator-activated receptor alpha (PPARA) mRNA levels. PPARA is known to be involved in ß-oxidation. CnP upregulated the mRNA levels of hepatic PPARA and its target genes, such as carnitine palmitoyl transferase 1 (CPT1) and CPT2, in a dose-dependent manner in the liver. Furthermore, levels of hepatic ß-hydroxybutyrate, which is a type of ketone body, were increased by CnP in a dose-dependent manner. Finally, CnP increased the expression of the autophagosomal marker LC3-II and decreased the expression of p62, which are known to be selectively degraded during autophagy. These results indicate that CnP inhibits hepatic steatosis through the stimulation of ß-oxidation and autophagy in the liver. Therefore, CnP might prove to be a suitable therapeutic target for NAFLD.

Prediction model for pancreatic cancer risk in the general Japanese population.

Genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with pancreatic cancer susceptibility. We sought to replicate the associations of 61 GWAS-identified SNPs at 42 loci with pancreatic cancer in Japanese and to develop a risk model for the identification of individuals at high risk for pancreatic cancer development in the general Japanese population. The model was based on data including directly determined or imputed SNP genotypes for 664 pancreatic cancer case and 664 age- and sex-matched control subjects. Stepwise logistic regression uncovered five GWAS-identified SNPs at five loci that also showed significant associations in our case-control cohort. These five SNPs were included in the risk model and also applied to calculation of the polygenic risk score (PRS). The area under the curve determined with the leave-one-out cross-validation method was 0.63 (95% confidence interval, 0.60-0.66) or 0.61 (0.58-0.64) for versions of the model that did or did not include cigarette smoking and family history of pancreatic cancer in addition to the five SNPs, respectively. Individuals in the lowest and highest quintiles for the PRS had odds ratios of 0.62 (0.42-0.91) and 1.98 (1.42-2.76), respectively, for pancreatic cancer development compared with those in the middle quintile. We have thus developed a risk model for pancreatic cancer that showed moderately good discriminatory ability with regard to differentiation of pancreatic cancer patients from control individuals. Our findings suggest the potential utility of a risk model that incorporates replicated GWAS-identified SNPs and established demographic or environmental factors for the identification of individuals at increased risk for pancreatic cancer development.