Inhibition of EP2/EP4 prostanoid receptor-mediated signaling suppresses IGF-1-induced proliferation of pancreatic cancer BxPC-3 cells via upregulating γ-glutamyl cyclotransferase expression.

Inhibition of prostaglandin E2 signaling via EP2/EP4 prostanoid receptors suppresses Insulin-like growth factor (IGF)-1-induced proliferation of pancreatic cancer BxPC-3 cells. To better understand the mechanism of EP2/EP4 signaling for controlling cell proliferation, we performed metabolome analyses in BxPC-3 cells treated with IGF-1 alone or IGF-1 plus EP2/EP4 inhibitors. These analyses revealed increased g-aminobutyric acid and 5-oxoproline production following the addition of EP2/EP4 inhibitors to IGF-1-treated cells. The expression of a 5-oxoproline-catalyzing enzyme, γ-glutamylcyclotransferase (GGCT), was also upregulated by IGF-1 treatment and further enhanced by the addition of EP2/EP4 inhibitors. Knockdown of GGCT expression resulted in the loss of suppressive effects of EP2/EP4 inhibitors on IGF-1-induced BxPC-3 cell proliferation, whereas GGCT overexpression repressed the basal proliferation of BxPC-3 cells but did not affect the suppressive effects of EP2/EP4 inhibitors. To summarize, we propose a role for EP2/EP4 signaling in regulating IGF-1-induced cell proliferation, in which EP2/EP4 signaling represses IGF-1-induced GGCT expression, which mediates and whose amount controls a branch of IGF-1 signaling to promote cell proliferation via extracellular signal-regulated kinase phosphorylation.

Polymorphisms in folic acid metabolism genes do not associate with cancer cachexia in Japanese gastrointestinal patients.

We used clinical data from Iga General Hospital to examine the association between polymorphisms in MTR (methionine synthase) A2756G (rs1805087), MTRR (methionine synthase reductase) His595Tyr (rs10380), MTHFR (methylenetetrahydrofolate reductase) C677T (rs1801133), MTHFR A1298C (rs1801131) and SHMT (serine hydroxymethyltransferase) C1420T (rs1979277), which are genes involved in folate metabolism, and the risk of weight loss in patients with gastrointestinal cancers, with the aim of establishing personalized palliative care for each patient based on genetic information. The data from 59 patients (37 males and 22 females) with gastrointestinal cancers who visited the outpatient clinic for cancer chemotherapy and palliative care at Iga General Hospital from December 2011 to August 2015 were analyzed. There was no significant association between the single nucleotide polymorphisms (SNPs) in the folate metabolizing genes examined and weight loss defined as weight loss of more than 5 percent or more than 10 percent during the first 6 months after initiation of chemotherapy. We did not detect any significant association between any of the SNPs examined and overall survival of patients. The present study indicated that these SNPs have relatively limited or no roles in the genesis of cachexia in patients with gastrointestinal cancers; however, further investigations into the roles of these folate metabolizing genes in the context of cancer palliative care, from clinical, biological and epidemiological viewpoints are warranted.

Neutrophils induce smooth muscle hyperplasia via neutrophil elastase-induced FGF-2 in a mouse model of asthma with mixed inflammation.

BACKGROUND: Bronchial asthma is traditionally characterized by chronic allergic inflammation, including eosinophilia and elevated Th2 cytokines. Recently, IL-17-derived neutrophil infiltration was shown to correlate with asthma severity and airway remodelling. OBJECTIVE: To investigate the role of IL-17-derived neutrophils in airway remodelling in chronic bronchial asthma. METHODS: We utilized house dust mite antigen-induced mouse models of asthma. Intranasal sensitization and chronic antigen challenge caused a mixed allergic inflammation that included eosinophils and neutrophils (Mix-in group). We neutralized IL-17 and fibroblast growth factor (FGF-2) and investigated the mechanism of airway remodelling in the Mix-in group. RESULTS: The Mix-in group displayed neutrophilic infiltration and high levels of IL-17 in lung tissue. The Mix-in group also exhibited more bronchial smooth muscle hyperplasia. IL-17 neutralization decreased the magnitude of all of these effects in the Mix-in group. Antibody arrays revealed an increase in FGF-2 in the Mix-in Group relative to the Eo-ip group, and FGF-2 elevation was associated with smooth muscle hypertrophy/hyperplasia. High concentrations of neutrophil elastase enhanced E-cadherin/ß-catenin signalling in bronchial epithelial cells. Neutrophil elastase inhibitor treatment decreased FGF-2 production and E-cadherin/ß-catenin signalling, which inhibited smooth muscle hyperplasia. CONCLUSION: The IL-17/neutrophil axis may play an important role in airway remodelling by contributing to smooth muscle hypertrophy/hyperplasia in mixed allergic inflammation and accordingly represents an attractive therapeutic target for severe asthma.

A case of unresectable combined hepatocellular cholangiocarcinoma showing favorable response to LFP therapy.

A woman in her 50s was admitted to our hospital because of multiple tumors detected in her liver. She was diagnosed with combined hepatocellular cholangiocarcinoma using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and biopsy of the liver tumors. We judged the tumors to be unresectable because they were found in both lobes of the liver, with a tumor thrombus being found in the main left portal vein. The pathological findings showed that the tumors exhibited characteristics of hepatocellular carcinoma. Therefore, sorafenib was administered;however, 6 months later, the disease progressed. Consequently, she received second-line chemotherapy with a one-shot intra-arterial injection of cisplatin, but this too was ineffective, and her general condition worsened. As hence, we changed the regimen to 5-fluorouracil continuous infusion and consecutive low dose cisplatin (LFP) therapy. After one cycle of chemotherapy with LFP, Gd-EOB-DTPA-enhanced MRI showed markedly decreased sizes and numbers of tumors. To date, she has completed six cycles of LFP therapy, and almost all her tumors are no longer visible on MRI. She has recovered to a good state and has achieved long-term survival. Thus, this case indicates that although LFP therapy is generally selected for cases of advanced hepatocellular carcinoma, it also appears to be effective for long-term disease control in cases of hepatocellular cholangiocarcinoma.

Carbon dioxide insufflation is useful for obtaining clear images of the bile duct during peroral cholangioscopy (with video).

BACKGROUND: Peroral cholangioscopy (POCS) is useful for the diagnosis of various bile duct lesions. However, it is often difficult to obtain clear images because of bile or biliary sludge in the bile duct, even after vigorous irrigation of the bile duct with saline solution. Therefore, this study investigated whether inflation with carbon dioxide (CO(2)) yields clearer images of the bile duct than conventional saline solution irrigation during POCS. OBJECTIVE: To evaluate the clinical utility and safety of CO(2) insufflation into the bile duct to obtain clear images in POCS observations by comparing this method with conventional saline solution irrigation. SETTING: A single center. DESIGN: Case-control study. PATIENTS: Nineteen patients with suspected biliary diseases. INTERVENTIONS: CO(2) insufflation into the bile duct during POCS. MAIN OUTCOME MEASUREMENTS: The quality and safety of this method. RESULT: The quality of the images of the bile duct lumen with CO(2) insufflation (10 patients) was significantly superior to those with saline solution irrigation (9 patients) in both clarity (P < .05) and color (P < .05). In particular, extremely clear images could be obtained from the middle part of common bile duct to the right and left hepatic duct. No serious POCS-related complications occurred. There was no significant change in the venous partial pressure of the CO(2) level during the procedure. LIMITATIONS: The number of patients examined was small. CONCLUSIONS: CO(2) insufflation is useful for obtaining clear images of the bile duct during POCS, which makes it possible to determine the qualitative diagnosis and the extent of various bile duct lesions.

Ultrasonically activated shears in gastrectomy for large gastric cancers.

PURPOSE: High-frequency ultrasound energy was introduced in gastrointestinal surgery to improve dissection and coagulation. We assessed the safety and efficacy of ultrasonic dissection compared with standard electrosurgery in gastrectomy for large gastric cancers, which is associated with high morbidity. METHODS: The subjects of this retrospective study were 52 patients who underwent gastrectomy for gastric cancers, > or =7 cm in diameter. Gastrectomy was performed with ultrasonically activated shears (UAS) between January 2005 and June 2006 (UAS group, n = 26) and with standard electrosurgery between July 2003 and December 2004 (control group, n = 26). We compared morbidity, operating time, and intraoperative blood loss between the two groups. RESULTS: The mean operating time and intraoperative blood loss were significantly lower in the UAS group than in the control group. Morbidity in the UAS group was also lower, but the difference was not significant. CONCLUSION: Our findings showed that UAS gastrectomy was safe, with significantly shorter operating times and less intraoperative blood loss than standard electrosurgery.

Stimulation effect of Dnmt3L on the DNA methylation activity of Dnmt3a2.

Quantification of DNA methyltransferases Dnmt3a and Dnmt3a2, and Dnmt3L in isolated male gonocytes in day 16.5 embryos confirmed that not Dnmt3a but Dnmt3a2 and Dnmt3L were the major Dnmt3s. The expression level of Dnmt3L constituted 5- to 10-fold molar excess compared to that of Dnmt3a2. The stimulation property of the DNA methylation activity of Dnmt3a2 with Dnmt3L towards substrate DNA in naked or nucleosomes was similar to that of Dnmt3a. However, the DNA methylation activity of not Dnmt3a but Dnmt3a2 was severely inhibited at the physiological salt concentration. Interestingly, the activity of Dnmt3a2 was significantly detected in the presence of Dnmt3L even at the physiological salt concentration. This indicates that Dnmt3a2 functions only in the presence of Dnmt3L in male gonocytes, and may explain why Dnmt3L is required specifically in mouse gonocytes for DNA methylation.