No association between a functional polymorphism in the promoter region of the neuropeptide Y gene (−485C > T) and schizophrenia

It has been suggested that hypoactivity of neuropeptide Y (NPY) may be involved in the pathophysiology of schizophrenia. A post-mortem study revealed a decreased level of NPY in the brain of patients with schizophrenia. An increased level of NPY after antipsychotic treatment was also reported in animal brain and cerebrospinal fluid of patients. Previously Itokawa et al. reported a positive association between the functional −485C > T polymorphism in the NPY gene and schizophrenia in a Japanese population. The aim of this study is to replicate their positive findings in an independent Japanese case-control sample. Our sample includes 260 patients with schizophrenia (DSM-IV) and 196 control subjects. No significant differences in distribution of genotype or allele frequencies between patients and controls were observed. Our results suggest that the NPY −485C > T polymorphism may not confer susceptibility to schizophrenia, at least in our sample. Further studies in larger samples are warranted.     

Successful achievement of sustained virological response to triple combination therapy containing simeprevir in two patients with chronic hepatitis C who had failed asunaprevir:Daclatasvir combination therapy

Patients 1 and 2 were treatment‐naive women who had genotype 1b chronic hepatitis C. Both had IL‐28B genotype TT, and amino acid substitutions of core 70 and 91 were both wild type. Search for the presence of resistance‐associated variants (RAV) in non‐structural (NS)3 and NS5A regions confirmed wild‐type D168 and L31, along with Y93H, in both patients. These patients participated in a Japanese phase III clinical study of asunaprevir and daclatasvir at the age of 52 and 67 years, respectively, and were treated with the combination regimen for 24 weeks. However, both experienced post‐treatment relapse, and then treated with triple combination therapy with simeprevir, pegylated interferon (IFN) and ribavirin at the age of 53 and 68 years, respectively, and achieved sustained virological response. A search for RAV prior to simeprevir treatment identified multiple resistance including D168E, Y93H and L31V in both patients. It has been demonstrated that, in many cases, a treatment failure with a combination of asunaprevir and daclatasvir results in acquisition of RAV in NS3 and NS5A regions and that drug‐resistant mutants, particularly those in the NS5A region, survive for a long time. In these cases, direct‐acting antivirals targeted towards the NS5A region may have a limited efficacy. The present case report is based on an idea that a regimen containing IFN with simeprevir could be a therapeutic option particularly for those who are likely to be highly sensitive and tolerable to IFN.     

Breakthrough therapy for peritoneal carcinomatosis of gastric cancer: Intraperitoneal chemotherapy with taxanes

The effect of chemotherapy on peritoneal carcinomatosis (PC) of gastric cancer remains unclear. Recently, the intraperitoneal (IP) administration of taxanes [e.g., paclitaxel (PTX) and docetaxel (DOC)] during the perioperative period has shown promising results. Herein, we summarized the rationale and methodology for using IP chemotherapy with taxanes and reviewed the clinical results. IP administered taxanes remain in the IP space at an extremely high concentration for 48-72 h. The drug directly infiltrates peritoneal metastatic nodules from the surface and then produces antitumor effects, making it ideal for IP chemotherapy. There are two types of perioperative IP chemotherapy with taxanes: neoadjuvant intraperitoneal and systemic chemotherapy and sequential perioperative intraperitoneal chemotherapy (SPIC). In SPIC, patients receive neoadjuvant IP chemotherapy and the same regimen of IP chemotherapy after cytoreductive surgery (CRS) until disease progression. Usually, a taxane dissolved in 500-1000 mL of saline at ordinary temperature is administered through an IP access port on an outpatient basis. According to phase I studies, the recommended doses (RD) are as follows: IP DOC, 45-60 mg/m²; IP PTX [without intravenous (IV) PTX], 80 mg/m²; and IP PTX (with IV PTX), 20 mg/m². Phase II studies have reported a median survival time of 14.4-24.6 mo with a 1-year overall survival of 67%-78%. A phase III study comparing S-1 in combination with IP and IV PTX to S-1 with IV cisplatin started in 2011. The prognosis of patients who underwent CRS was better than that of those who did not; however, this was partly due to selection bias. Although several phase II studies have shown promising results, a randomized controlled study is needed to validate the effectiveness of IP chemotherapy with taxanes for PC of gastric cancer.     

Correlation between serum galectin‐9 levels and liver fibrosis

Background and Aim

Chronic liver diseases progress from chronic inflammation to fibrosis to tumorigenesis. Galectin‐9, a β‐galactoside‐specific animal lectin, is indicated to contribute to all three steps of progression. The aim of this study was to determine which of the three steps was most dominant in elevating the serum galectin‐9 concentration and to test the possibility of galectin‐9 as a serum biomarker.

Methods

Japanese patients with chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), non‐alcoholic fatty liver disease, or alcoholic liver disease who provided informed consent were enrolled in this study. Serum galectin‐9 levels were measured using a sandwich ELISA. Multiple regression analyses were performed using ezr to identify factors that determined serum galectin‐9 concentration.

Results

One hundred one patients with 50 of chronic hepatitis and 51 of liver cirrhosis were enrolled; the cohort included 45 cases of hepatitis C virus infection, 13 cases of hepatitis B virus infection, and 46 cases with HCC‐related complications. The median serum galectin‐9 concentration was 77.54 pg/mL (interquartile range: 18.89–241.9 pg/mL). Multiple linear regression analyses proved Fibrosis‐4 index and aspartate aminotransferase to platelet ratio index, indexes of liver fibrosis, were able to predict the serum galectin‐9 levels with statistical significance. A multiple logistic regression analysis determined 10 pg/mL increase in the serum galectin‐9 concentration presented an odds ratio of 3.90 for liver fibrosis progression.

Conclusions

The serum galectin‐9 concentration represents a potential biomarker of liver fibrosis in patients with chronic liver diseases, regardless of chronic inflammation or the presence of HCC complications. Furthermore, higher serum galectin‐9 levels are a predictor for liver fibrosis progression.     

[11C]Gefitinib ([11C]Iressa): Radiosynthesis, In Vitro Uptake, and In Vivo Imaging of Intact Murine Fibrosarcoma

Objective

Gefitinib (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine, Iressa) is an approved anticancer drug. In this study, we labeled gefitinib with carbon-11 and evaluated [¹¹C]gefitinib to explore its specific binding in intact fibrosarcoma (NFSa)-bearing mice.

Methods

[¹¹C]Gefitinib was synthesized by the reaction of desmethyl precursor (1) with [¹¹C]CH₃I. In vitro uptake of [¹¹C]gefitinib into NFSa, human-A431 epidermoid carcinoma, and Jurkat T cells was determined. Positron emission tomography (PET) imaging using [¹¹C]gefitinib was performed for NFSa-bearing mice.

Results

[¹¹C]Gefitinib accumulated into NFSa cells with 2.1 uptake ratio (UR)/mg protein in cells. Addition of nonradioactive gefitinib decreased uptake in a concentration-dependent manner. [¹¹C]Gefitinib also had high uptake (2.6 UR/mg protein) into epidermal growth factor receptor/tyrosine kinase (EGFR/TK)-rich A431 cells but low uptake (0.2 UR/mg protein) into EGFR/TK-poor Jurkat cells. In vivo distribution study on NFSa-bearing mice by the dissection method revealed that [¹¹C]gefitinib specifically accumulated into the tumor. The ratio of radioactivity in tumors to that in blood and muscle as two comparative regions increased from 0.4 to 6.0 and from 0.6 to 5.0 during this experiment (0–60 min), respectively. PET for NFSa-bearing mice produced a clear tumor image, although high radioactivity was distributed throughout the body. Treatment with nonradioactive gefitinib (100 mg/kg) decreased uptake in the tumor. In vivo metabolite analysis demonstrated that [¹¹C]gefitinib was stable in the tumor, liver, kidney, and blood.

Conclusion

These results demonstrated the promising potential of [¹¹C]gefitinib to serve as a PET ligand for in vivo imaging of NFSa-bearing mice.     

Collagen-Induced Platelet Aggregates,Diabetes, and Aspirin Therapy Predict Clinical Outcomes in Acute Ischemic Stroke

Background: Aggregation of platelets is a trigger for additional development of larger thrombi. This study aimed to identify factors that may affect platelet aggregability and their role in clinical outcomes in acute ischemic stroke. Methods: Consecutive acute ischemic stroke patients (n = 352) who were transferred within 24 hours after its onset were enrolled. Peripheral venous blood was sampled to measure platelet aggregability and other parameters. Results: Mean values of spontaneous small-sized platelet aggregates and collagen- or adenosine diphosphate (ADP)-induced large-sized aggregates were elevated in acute ischemic stroke. In atherothrombotic stroke (n = 178), collagen and ADP-induced large-sized aggregates were positively correlated with HbA1c, respectively. High incidence of the modified Rankin Scales (mRS) 5-6 at discharge was associated with diabetes complication (odds ratio [OR] 8.77, 95% confidence interval [CI] 1.32-57.56). The proportion of patients who were functionally independent (the mRS 0-2) at discharge was lower in the middle tertile of collagen and ADP-induced large-sized aggregates than their low tertile (OR 2.46, 95% CI 1.09-5.58; OR 2.43, 95% CI 1.05-5.59, respectively). Prestroke administration of aspirin recovered the proportion of independence at discharge (OR 0.25, 95% CI 0.06-0.99), and ameliorated incidence of the mRS 5-6. On logistic regression analysis, diabetes, HbA1c, collagen-induced large-sized aggregates, and prestroke administration of aspirin remained independent predictors of clinical outcomes in atherothrombotic stroke. In cardioembolic and lacunar stroke, no relations with clinical outcomes were found. Conclusions: High plasma level of HbA1c is involved in enhanced platelet aggregability in acute atherothrombotic stroke patients, and prestroke administration of aspirin may be beneficial to clinical outcomes.     

Upregulated absorption of dietary palmitic acids with changes in intestinal transporters in non-alcoholic steatohepatitis (NASH)

Background

Palmitic acid is an important risk factor for the pathogenesis of non-alcoholic steatohepatitis (NASH), but changes in palmitic acid intestinal absorption in NASH are unclear. The aim of this study was to clarify changes in palmitic acid intestinal absorption and their association with the pathogenesis of NASH.

Methods

A total of 106 participants were recruited to the study, of whom 33 were control subjects (control group), 32 were patients with NASH Brunt stage 1–2 [early NASH (e-NASH)], and 41 were patients with NASH Brunt stage 3–4 [advanced NASH (a-NASH)]. ¹³C-labeled palmitate was administered directly into the duodenum of all participants by gastrointestinal endoscopy. Breath ¹³CO₂ levels were measured to quantify palmitic acid absorption, and serum Apolipoprotein B-48 (ApoB-48) concentrations were measured after a test meal to quantify absorbed chylomicrons. Expressions of fatty acid (FA) transporters were also examined. The associations of breath ¹³CO₂ levels with hepatic steatosis, fibrosis and insulin resistance was evaluated using laboratory data, elastography results and liver histology findings.

Results

Overall, ¹³CO₂ excretion was significantly higher in e-NASH patients than in the control subjects and a-NASH patients (P < 0.01). e-NASH patients had higher serum ApoB-48 levels, indicating increased palmitic acid transport via chylomicrons in these patients. Jejunal mRNA and protein expressions of microsomal triglyceride transfer protein and cluster of differentiation 36 were also increased in both NASH patient groups. The ¹³CO₂ excretion of e-NASH patients was significantly correlated with the degree of hepatic steatosis, fibrosis and insulin resistance (P = 0.005, P < 0.001, P = 0.019, respectively).

Conclusions

Significantly upregulated palmitic acid absorption by activation of its transporters was evident in patients with NASH, and clinical progression of NASH was related to palmitic acid absorption. These dietary changes are associated with the onset and progression of NASH.