Clinical and molecular features of patients with IDH1 wild-type primary glioblastoma presenting unexpected short-term survival after gross total resection.

BACKGROUND: This study investigated the factors influencing short-term survivors (STS) after gross total resection (GTR) in patients with IDH1 wild-type primary glioblastoma. METHODS: We analyzed five independent cohorts who underwent GTR, including 83 patients from Kitasato University (K-cohort), and four validation cohorts of 148 patients from co-investigators (V-cohort), 66 patients from the Kansai Molecular Diagnosis Network for the Central Nervous System tumors, 109 patients from the Cancer Genome Atlas, and 40 patients from the Glioma Longitudinal AnalySiS. The study defined STS as those who had an overall survival ≤ 12 months after GTR with subsequent radiation therapy, and concurrent and adjuvant temozolomide (TMZ). RESULTS: The study included 446 patients with glioblastoma. All cohorts experienced unexpected STS after GTR, with a range of 15.0-23.9% of the cases. Molecular profiling revealed no significant difference in major genetic alterations between the STS and non-STS groups, including MGMT, TERT, EGFR, PTEN, and CDKN2A. Clinically, the STS group had a higher incidence of non-local recurrence early in their treatment course, with 60.0% of non-local recurrence in the K-cohort and 43.5% in the V-cohort. CONCLUSIONS: The study revealed that unexpected STS after GTR in patients with glioblastoma is not uncommon and such tumors tend to present early non-local recurrence. Interestingly, we did not find any significant genetic alterations in the STS group, indicating that such major alterations are characteristics of GB rather than being reliable predictors for recurrence patterns or development of unexpected STS.

Effects of oral intake of plasmacytoid dendritic cells-stimulative lactic acid bacterial strain on pathogenesis of influenza-like illness and immunological response to influenza virus.

Lactococcus lactis ssp. lactis JCM5805 has been shown to be a rare lactic acid bacterium that can activate plasmacytoid dendritic cells in both murine and human species. In this study, we carried out a randomised placebo-controlled double-blind experiment to evaluate its effect on the pathogenesis of influenza-like illness during the winter season. A total of 213 volunteers were divided into two groups, which received either yogurt made with L. lactis JCM5805 or a placebo beverage daily for 10 weeks. In the JCM5805 group, the cumulative incidence days of 'cough' and 'feverishness', which are defined as major symptoms of an influenza-like illness, were significantly decreased compared with the placebo group. In addition, peripheral blood mononuclear cells prepared from volunteers were cultured in the presence of inactivated human influenza virus A/H1N1 (A/PR/8/34). IFN-α elicited by A/H1N1 tended to be higher in the JCM5805 group compared with the placebo group, and an IFN-α-inducible antiviral factor, interferon-stimulated gene 15 (ISG15), elicited by A/H1N1 was significantly higher in the JCM5805 group compared with the placebo group after the intake period. These results suggest that intake of JCM5805 is able to prevent the pathogenesis of an influenza-like illness via enhancement of an IFN-α-mediated response to the influenza virus.

Losartan elevates the serum high-molecular weight-adiponectin isoform and concurrently improves insulin sensitivity in patients with impaired glucose metabolism.

Adiponectin is an adipocyte hormone that ameliorates insulin resistance and prevents diabetes. Patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are at a high risk of developing diabetes and cardiovascular diseases. Since treatment with angiotensin II receptor blockers retards the development of diabetes, the effects of losartan on serum adiponectin levels were examined with regard to insulin sensitivity in pre-diabetic patients. Sixty-five patients with IFG/IGT (42 males, 23 females, 63+/-13 years old) were randomized to receive 25-100 mg of losartan (n=33) or a calcium channel blocker (CCB, n=32) for 3 months. Before and after the treatment, changes in blood pressure, insulin sensitivity (HOMA-R) and serum concentrations of high molecular weight (HMW)-adiponectin and free fatty acid (FFA) were assessed. At baseline, the HMW-adiponectin concentration negatively correlated with the patient's body mass index, HOMA-R and triglyceride levels, and positively correlated with high-density lipoprotein (HDL)-cholesterol levels. However, the HMW-adiponectin concentration showed no correlation with blood pressure. HMW-adiponectin concentrations were similar between the losartan group and the CCB group. Both the losartan and CCB treatments similarly and significantly reduced the mean blood pressure (107+/-7 mmHg to 95+/-7 mmHg, p<0.0001, and 104+/-6 mmHg to 93+/-9 mmHg, p<0.0001, respectively). Losartan treatment resulted in a significant increase in HMW-adiponectin concentrations (45.9%) and a significant decrease in HOMA-R (23.9%) and FFA concentrations (26.5%); the percent changes were greater than those induced by CCB treatment (p<0.001, p<0.05 and p<0.01, respectively). We conclude that losartan increases the serum HMW-adiponectin concentration and concurrently improves insulin sensitivity in subjects with IFG/IGT. These results suggest that losartan may prevent diabetes by increasing serum adiponectin levels.

l-Ornithine affects peripheral clock gene expression in mice.

The peripheral circadian clock is entrained by factors in the external environment such as scheduled feeding, exercise, and mental and physical stresses. In addition, recent studies in mice demonstrated that some food components have the potential to control the peripheral circadian clock during scheduled feeding, although information about these components remains limited. l-Ornithine is a type of non-protein amino acid that is present in foods and has been reported to have various physiological functions. In human trials, for example, l-ornithine intake improved a subjective index of sleep quality. Here we demonstrate, using an in vivo monitoring system, that repeated oral administration of l-ornithine at an early inactive period in mice induced a phase advance in the rhythm of PER2 expression. By contrast, l-ornithine administration to mouse embryonic fibroblasts did not affect the expression of PER2, indicating that l-ornithine indirectly alters the phase of PER2. l-Ornithine also increased plasma levels of insulin, glucose and glucagon-like peptide-1 alongside mPer2 expression, suggesting that it exerts its effects probably via insulin secretion. Collectively, these findings demonstrate that l-ornithine affects peripheral clock gene expression and may expand the possibilities of L-ornithine as a health food.

Effects of glucose and plasminogen activator inhibitor-1 on collagen metabolism in the peritoneum.

Nonphysiological solutions containing high glucose levels have been considered an important factor in the etiology of fibrotic changes in long-term continuous ambulatory peritoneal dialysis (CAPD) patients. At the same time, increased Plasminogen Activator Inhibitor (PAI)-1 secretion has been reported to correlate with fibrotic changes. We suspected that the high glucose content of peritoneal dialysis solution may induce peritoneal sclerosis via up-regulation of PAI-1 gene expression. In this study, we evaluated the effects of glucose on PAI-1 activity in peritoneal fibrosis in a rat model of CAPD. The effects of glucose on the expressions of PAI-1 and several other genes correlated with collagen metabolism were also examined in cultured rat peritoneal mesothelial cells and fibroblasts. Sprague-Dawley rats were intraperitoneally injected twice daily for 28 days with phosphate-buffered saline (PBS) (control group), PBS containing 4% glucose (glucose group), or PBS containing 4% glucose plus a PAI-1 inhibitor (PAI-1 inhibitor group). Thickening of the peritoneum with increase the deposition of collagens type I and III in the submesothelial interstitium were observed in the glucose and the PAI-1 inhibitor group, but these were less severe in the PAI-1 inhibitor group. Glucose stimulated expression of the mRNA of PAI-1, collagen type I and III, and tissue inhibitor of metalloproteinase (TIMP)-1 in fibroblasts but not in mesothelial cells. Glucose stimulated matrix metalloproteinase (MMP)-13 mRNA expression in both cell types. The PAI-1 inhibitor suppressed expression of the mRNAs induced by glucose. In conclusion, glucose induces peritoneal fibrosis, including changes in collagen metabolism, by stimulating PAI-1 expression.

Expression of matrix metalloproteinase-9 associated with ets-1 proto-oncogene in rat tubulointerstitial cells.

BACKGROUND: Ets-1 proto-oncogene exhibits multiple activities in the transcriptional regulation of numerous genes including metalloproteinase (MMP)-1, -3 and -9. MMPs play an important role in the remodelling of extracellular matrix in various renal diseases. However, the role of the Ets-1-MMP axis in advanced renal diseases is uncertain. In the present study, we investigated whether Ets-1 is involved in interleukin (IL)-1-mediated expression of MMPs in tubulointerstitial cells. METHODS: Rat renal fibroblasts (NRK-49F) and tubular epithelial cells (NRK-52E) were cultured and allocated to an IL-1beta-treated group (10 ng/ml), a platelet-derived growth factor (PDGF)-BB-treated group (25 ng/ml) and a control group. Protein and mRNA were extracted after 1, 6, 12 and 24 h of treatment. Parallel flasks were treated with 2 muM ets-1 antisense oligodeoxynucleotides (ODNs) before exposure to IL-1beta. The expression of Ets-1 protein was evaluated by western blotting. The activities of MMPs were evaluated by gelatin zymography. The expression of ets-1 and/or MMP-9 mRNA was evaluated semiquantitatively by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In NRK-49F cells, Ets-1 protein increased significantly by 6.8-fold at 6 h, and MMP-9 activity increased significantly by 9.9-fold at 12 h in the IL-1beta-treated group compared with controls. MMP-2 and -3 activities also increased significantly in the IL-1beta-treated group. In NRK-52E cells, Ets-1 protein was 3.1 times higher at 1 h, and the latent form of MMP-9 activity increased 3.4-fold at 6 h in the IL-1beta group compared with controls. However, MMP-2 or MMP-3 activities were not markedly altered by IL-1beta treatment compared with controls. When the cells were treated with ets-1 antisense ODNs before IL-1beta treatment, Ets-1 protein expression decreased at least 50%, and MMP-9 activity was clearly inhibited in both cells. We also confirmed that MMP-9 activity was upregulated on days 21 and 28 in renal cortex of rat crescentic glomerulonephritis. CONCLUSIONS: The Ets-1 transcriptional factor may participate in IL-1beta-mediated MMP-9 expression in tubulointerstitial cells.