Gemcitabine is a deoxycytidine analogue that has a broad spectrum of antitumour activity in many solid tumours including pancreatic cancer. We have recently carried out a pharmacogenomic study in ...cancer patients treated with gemcitabine, and found that one genetic polymorphism of an enzyme involved in gemcitabine metabolism can cause interindividual variations in the pharmacokinetics and toxicity of this agent. In this paper, we review recent genetic studies of gemcitabine, and discuss the possibility of individualised cancer chemotherapy based on a pharmacogenomic approach.
Autoimmune pancreatitis is characterised by raised serum levels of IgG4 and IgG4-bearing plasma cells in the inflammatory tissue. 1 Similar pathology can also occur in the larger bile ducts, ...resembling sclerosing cholangitis. 2 We report a patient with hepatitis and chronic cholecystitis, raised IgG4 level, and IgG4-bearing plasma cells in the liver and gall bladder wall, but no evident pancreatic disease. Raised serum IgG4 concentration and IgG4-bearing plasma cell infiltrates have a high sensitivity and specificity for the diagnosis of autoimmune pancreatitis 1 and associated diseases, including sclerosing cholangitis. 2 In the present case, the clinical and histological criteria for definite autoimmune hepatitis were met and, additionally, both biopsies showed hepatitis with abundant IgG4-bearing plasma cells in the liver and gallbladder.
Transgenic mice expressing HCV core protein develop hepatic steatosis and hepatocellular carcinoma (HCC), but the mechanism underlying this process remains unclear. Because PPARα is a central ...regulator of triglyceride homeostasis and mediates hepatocarcinogenesis in rodents, we determined whether PPARα contributes to HCV core protein--induced diseases. We generated PPARα-homozygous, -heterozygous, and -null mice with liver-specific transgenic expression of the core protein gene (Ppara+/+:HCVcpTg, Ppara+/-:HCVcpTg, and Ppara-/-:HCVcpTg mice. Severe steatosis was unexpectedly observed only in Ppara+/+:HCVcpTg mice, which resulted from enhanced fatty acid uptake and decreased mitochondrial β-oxidation due to breakdown of mitochondrial outer membranes. Interestingly, HCC developed in approximately 35% of 24-month-old Ppara+/+: HCVcpTg mice, but tumors were not observed in the other genotypes. These phenomena were found to be closely associated with sustained PPARα activation. In Ppara+/-:HCVcpTg mice, PPARα activation and the related changes did not occur despite the presence of a functional Ppara allele. However, long-term treatment of these mice with clofibrate, a PPARα activator, induced HCC with mitochondrial abnormalities and hepatic steatosis. Thus, our results indicate that persistent activation of PPARα is essential for the pathogenesis of hepatic steatosis and HCC induced by HCV infection.
Sclerosing pancreatitis is a unique form of pancreatitis that is characterized by irregular narrowing of the main pancreatic duct, lymphoplasmacytic inflammation of the pancreas, and ...hypergammaglobulinemia and that responds to glucocorticoid treatment. Preliminary studies suggested that serum IgG4 concentrations are elevated in this disease but not in other diseases of the pancreas or biliary tract.
We measured serum IgG4 concentrations using single radial immunodiffusion and an enzyme-linked immunosorbent assay in 20 patients with sclerosing pancreatitis, 20 age- and sex-matched normal subjects, and 154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjögren's syndrome. Serum concentrations of immune complexes and the IgG4 subclass of immune complexes were determined by means of an enzyme-linked immunosorbent assay with monoclonal rheumatoid factor.
The median serum IgG4 concentration in the patients with sclerosing pancreatitis was 663 mg per deciliter (5th and 95th percentiles, 136 and 1150), as compared with 51 mg per deciliter (5th and 95th percentiles, 15 and 128) in normal subjects (P<0.001). The serum IgG4 concentrations in the other groups of patients were similar to those in the normal subjects. In patients with sclerosing pancreatitis, serum concentrations of immune complexes and the IgG4 subclass of immune complexes were significantly higher before glucocorticoid therapy than after four weeks of such therapy. Glucocorticoid therapy induced clinical remissions and significantly decreased serum concentrations of IgG4, immune complexes, and the IgG4 subclass of immune complexes.
Patients with sclerosing pancreatitis have high serum IgG4 concentrations, providing a useful means of distinguishing this disorder from other diseases of the pancreas or biliary tract.
Autoimmune pancreatitis is characterised by irregular narrowing of the main pancreatic duct, swelling of the pancreas, histological evidence of lymphoplasmacytic inflammation, and high serum ...immunoglobulin G4 (IgG4) concentration. 1- 4 Although the human leucocyte antigen DRB1*0405-DQB1*0401 haplotype has been associated with autoimmune pancreatitis, 5 the role of genetic factors has not yet been fully defined. A new family of genes called Fc receptor-like genes (FCRLs), which have high structural homology with classical FcGAMMA receptor genes, has recently been identified. 6, 7 FCRL3 polymorphisms have been shown to be associated with various autoimmune diseases, such as rheumatoid arthritis, autoimmune thyroid disease, and systemic lupus erythematosus, in Japanese populations. 8, 9 These polymorphisms alter the binding affinity of nuclear factor κB and regulate FCRL3 expression.
Pancreatic adenocarcinoma is an aggressive human malignancy and is characterized by resistance to apoptosis. Recently, NADPH oxidase (Nox) 4-mediated generation of intracellular reactive oxygen ...species (ROS) was proposed to confer antiapoptotic activity and thus a growth advantage to pancreatic cancer cells. The signaling mechanism by which Nox4 transmits cell survival signals remains unclear. Here, we show that both a flavoprotein inhibitor, diphenylene iodonium (DPI), and small interfering RNAs designed to target Nox4 mRNA (siNox4RNAs) inhibited superoxide production in PANC-1 pancreatic cancer cells, and depletion of ROS by DPI or siNox4RNAs induced apoptosis. Parallely, DPI treatment and siNox4RNA transfection blocked activation of the cell survival kinase AKT by attenuating phosphorylation of AKT. Furthermore, AKT phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) on Ser-83 was reduced by DPI and siNox4RNAs. When ASK1Ser83Ala (an AKT phosphorylation-defective ASK1 mutant) was introduced into PANC-1 cells, this mutant alone induced apoptosis. But, addition of DPI or co-transfection of siNox4RNA had no additive effect, indicating that the mutant can substitute for these reagents in apoptosis induction. Taken together, these findings suggest that ROS generated by Nox4, at least in part, transmit cell survival signals through the AKT-ASK1 pathway in pancreatic cancer cells and their depletion leads to apoptosis.
We investigated the effects of heat-killed
MCC1848 on daily mood states in healthy young adults. Participants (n=58) were randomised to receive heat-killed
MCC1848 powder or placebo powder for 4 ...weeks. During the study period, adverse events were recorded in the participant diary. Mood states were assessed before and 2 and 4 weeks after initiation of the intervention. The primary outcomes were the shortened version of the Profile of Mood States 2 (POMS 2) scores. Secondary outcomes included other mood state (State-Trait Anxiety Inventory (STAI); visual analogue scale (VAS)), quality of life (acute form of the SF-36v2), sleep (Athens Insomnia Scale (AIS)) and fatigue (Chalder Fatigue Scale (CFS)) scores. Four weeks of heat-killed
MCC1848 intake, compared to placebo, significantly improved the shortened version of the POMS 2 'friendliness' and the VAS 'relaxed' scores, which are two indicators of positive mood states. On the other hand, heat-killed
MCC1848 intake had no significant effects on negative mood state items (e.g. anger, nervousness, confusion) assessed by the shortened version of the POMS 2, STAI and VAS. AIS and CFS scores also showed no significant differences. No adverse effects were observed with 4 weeks of heat-killed
MCC1848 intake. These results suggest that daily consumption of heat-killed
MCC1848 is safe and has the potential to improve positive mood states.
: UMIN000043697.
Sclerosing pancreatitis is associated with raised concentrations of lgG4. We treated 22 patients with sclerosing pancreatitis, and identified and followed-up three with concomitant hydronephrosis ...caused by ureteral mass, later diagnosed as retroperitoneal fibrosis. We histologically examined the ureteral and pancreatic lesions of these patients and noted abundant infiltration of lgG4-bearing plasma cells in both tissues. Treatment with corticosteroids lowered serum concentrations of lgG4. lgG4 might also have a pathological role in a systemic fibrosing process that includes pancreatic and retroperitoneal lesions.
Autoimmune pancreatitis (AIP) is characterized by high serum IgG4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Although the HLA ...DRB1*0405-DQB1*0401 haplotype and Fc receptor-like 3 polymorphisms have been associated with AIP, the role of other genetic factors is largely unknown. As cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with several autoimmune diseases, we sought to determine if CTLA4 polymorphisms and serum sCTLA4 levels were associated with AIP as well.
Five CTLA4 polymorphisms, located at -1722, -658, and -318 in the promoter, +49 in exon 1, and +6230 in the 3' untranslated region, were genotyped in 59 patients with AIP and 102 healthy subjects. Serum sCTLA4 levels were also determined in cohorts of 52 patients and 32 controls.
Compared with healthy subjects, we found a significant increase in the +6230 G/G genotype (64%vs 42%, odds ratio OR 2.48, P= 0.011) in AIP patients. Haplotype 2, which had the +6230A, was associated with AIP resistance (OR 0.49, P= 0.011). The +49A/A and +6230A/A genotypes were associated with an enhanced risk of relapse (OR 5.45, P= 0.038 and OR 12.66, P= 0.022). Additionally, median serum sCTLA4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL, P < 0.001). The +6230 G/A polymorphism did not influence sCTLA4 levels in AIP patients.
Our findings suggest that AIP is associated with a genetic polymorphism in CTLA4 and is positively correlated with serum sCTLA4 levels.
Background/Aims Alcoholic liver disease (ALD) is one of the leading causes of cirrhosis and yet efficient therapeutic strategies are lacking. Polyenephosphatidylcholine (PPC), a major component of ...essential phospholipids, prevented alcoholic liver fibrosis in baboons, but its precise mechanism remains uncertain. We aimed to explore the effects of PPC on ALD using ethanol-fed peroxisome proliferator-activated receptor α ( Ppara )-null mice, showing several similarities to human ALD. Methods Male wild-type and Ppara -null mice were pair-fed a Lieber-DeCarli control or 4% ethanol-containing diet with or without PPC (30 mg/kg/day) for 6 months. Results PPC significantly ameliorated ethanol-induced hepatocyte damage and hepatitis in Ppara -null mice. These effects were likely a consequence of decreased oxidative stress through down-regulation of reactive oxygen species (ROS)-generating enzymes, including cytochrome P450 2E1, acyl-CoA oxidase, and NADPH oxidases, in addition to restoration of increases in Toll-like receptor 4 and CD14. PPC also decreased Bax and truncated Bid, thus inhibiting apoptosis. Furthermore, PPC suppressed increases in transforming growth factor-β1 expression and hepatic stellate cell activation, which retarded hepatic fibrogenesis. Conclusions PPC exhibited anti-inflammatory, anti-apoptotic, and anti-fibrotic effects on ALD as a result of inhibition of the overexpression of ROS-generating enzymes. Our results demonstrate detailed molecular mechanisms of the anti-oxidant action of PPC.
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