Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice

MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4(+) T, CD8(+) T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFNγ, na?ve Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFNγ and decreased numbers of not only NK cells but also CD4(+) T and CD8(+) T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells.     

Identification of vitronectin as a novel serum marker for early breast cancer detection using a new proteomic approach

Purpose

Breast cancer is the most frequent malignancy in women. However, no useful serum markers with high sensitivity and specificity for the detection of early breast cancer have been identified. The search for biological markers of early breast cancer is of continual interest in experimental and clinical breast cancer research. We recently described a simple and highly reproducible three-step proteome analysis for identifying potential disease-marker candidates among the low-abundance serum proteins.

Methods

Serum samples from breast ductal carcinoma in situ (DCIS) patients and normal controls were subjected to a three-step serum proteome analysis. The steps were the following: first, immunodepletion of most abundant proteins; second, fractionation using reverse-phase high-performance liquid chromatography; and third, separation using two-dimensional electrophoresis (2-DE). Differences revealed by protein staining were further confirmed by Western blotting, immunohistochemical staining, and enzyme-linked immunosorbent assays (ELISA).

Results

Twenty-two upregulated and 26 downregulated spots were detected on the 2-DE gels, and a total of 33 proteins were identified by liquid chromatography and tandem mass spectrometry. Western blotting confirmed that the level of vitronectin was significantly increased in DCIS patients compared with that of normal controls. Immunohistochemical staining of vitronectin in breast cancer tissue revealed high expression in small vessel walls surrounding cancer cells and the extracellular matrix of stroma. Moreover, vitronectin serum concentrations, as measured by ELISA, were significantly increased in patients with DCIS or more advanced breast cancer compared with those of normal controls.

Conclusions

Vitronectin could serve as a promising serum marker for the detection of primary breast cancer.     

Randomized controlled trial of single‐agent glimepiride and pioglitazone in Japanese patients with type 2 diabetes: A comparative study

Aims/Introduction: To compare first‐line, single‐agent glimepiride and pioglitazone in Japanese patients with type 2 diabetes uncontrolled by diet and exercise with respect to glycemic control, safety and metabolic changes. Materials and Methods: Patients with previously untreated type 2 diabetes were enrolled in a multicenter, randomized, non‐blind, parallel‐group trial of glimepiride (0.5–6 mg/day) or pioglitazone (15–45 mg/day) for 6 months. Results: A total of 191 patients aged 30–75 years were randomized. Similar percentages of patients attained the primary end‐point, with glycated hemoglobin < 6.9% at month 6 with glimepiride and pioglitazone, respectively (61.2 vs 56.8%, P = 0.64). At month 6, the following significant (P < 0.05) intragroup changes in mean plasma lipid concentrations were noted as compared with baseline: total cholesterol decreased from 203.5 to 195.5 mg/dL and low‐density lipoprotein (LDL)‐cholesterol decreased from 124.5 to 116.3 mg/dL in the glimepiride group, whereas high‐density lipoprotein (HDL)‐cholesterol increased from 51.6 to 56.0 mg/dL and triglycerides decreased from 167.6 to 143.6 mg/dL in the pioglitazone group. The only symptomatic adverse events were mild‐to‐moderate in four patients receiving pioglitazone, and constipation in one patient receiving glimepiride. Similar numbers of patients experienced asymptomatic hypoglycemia (<60 mg/dL) in the glimepiride and pioglitazone groups (n = 7 and 5, respectively). Conclusions: There was no statistically significant difference between glimepiride and pioglitazone with respect to glycemic control, and both agents were well tolerated. Glimepiride significantly lowered total cholesterol and LDL‐cholesterol, whereas pioglitazone increased HDL‐cholesterol. This trial was registered with University Hospital Medical Information Network (UMIN), Japan, UMIN000004582. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00115.x, 2011)     

Rosette-forming glioneuronal tumor of the fourth ventricle with bilateral olivary degeneration

Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle has been recognized as a new type of glioneuronal tumor. RGNTs are typically located in the infratentorial midline with involvement of the fourth ventricle. They occasionally involve the aqueduct and/or vermis. RGNTs of unusual anatomical sites or those with unusual findings have been reported. The present case reports describe RGNT of the fourth ventricle with bilateral olivary degeneration. It is important to accumulate imaging findings and biological behaviors of RGNTs given the limited number of cases.     

Targeting fibroblast growth factor receptor 3 enhances radiosensitivity in human squamous cancer cells

Conventional therapies including radiation therapy cannot cure squamous cell carcinoma (SCC), and new treatments are clearly required. Our recent studies have shown that SCC cell lines exhibiting radioresistance show significant upregulation of the fibroblast growth factor receptor 3 (FGFR3) gene. We hypothesized that inhibiting FGFR3 would suppress tumor cell radioresistance and provide a new treatment approach for human SCCs. In the present study, we found that RNA interference-mediated FGFR3 depletion in HSC-2 cells, a radioresistant cell line, induced radiosensitivity and inhibited tumor growth. Use of an FGFR3 inhibitor (PD173074) obtained similar results with suppression of the autophosphorylation extracellular signal-regulated kinase pathway in HSC-2 cells and lung cancer cell lines. Moreover, the antitumor growth effect of the combination of PD173074 and radiation in vivo was also greater than that with either drug alone or radiation alone. Our results provided novel information on which to base further mechanistic study of radiosensitization by inhibiting FGFR3 in human SCC cells and for developing strategies to improve outcomes with concurrent radiotherapy.     

Risk-stratified survival rates and predictors of biochemical recurrence after radical prostatectomy in a Nara,Japan, cohort study

Background  

The aim of this study was to evaluate the oncological outcomes in patients who underwent radical prostatectomy in various risk groups.