Development of a Si/CdTe semiconductor Compton telescope

We are developing a Compton telescope based on high resolution Si and CdTe imaging devices in order to obtain a high sensitivity astrophysical observation in sub-MeV gamma-ray region. In this paper, recent results from the prototype Si/CdTe semiconductor Compton telescope are reported. The Compton telescope consists of a double-sided Si strip detector (DSSD) and CdTe pixel detectors, combined with low noise analog LSI, VA32TA. With this detector, we obtained Compton reconstructed images and spectra from line gamma-rays ranging from 81 keV up to 356 keV. The energy resolution is 3.8 keV and 7.9 keV at 122 keV and 356 keV, respectively, and the angular resolution is 9.9 degrees and 5.7 degrees at 122 keV and 356 keV, respectively.Comment: 12 pages, 14 figures, submitted to SPIE conference proceedings vol. 5501, "High-Energy Detectors in Astronomy", Glasgow UK, 6/21-6/24 200

Evaluation of transporter-mediated hepatobiliary transport of newly developed ¹⁸F-labeled pitavastatin derivative, PTV-F1, in rats by PET imaging

Quantitative evaluations of the functions of uptake and efflux transporters directly in vivo is desired to understand an efficient hepatobiliary transport of substrate drugs. Pitavastatin is a substrate of organic anion transporting polypeptides (OATPs) and canalicular efflux transporters; thus, it can be a suitable probe for positron-emission tomography (PET) imaging of hepatic transporter functions. To characterize the performance of [¹⁸F]PTV-F1, an analogue of pitavastatin, we investigated the impact of rifampicin (a typical OATP inhibitor) coadministration or Bcrp (breast cancer resistance protein) knockout on [¹⁸F]PTV-F1 hepatic uptake and efflux in rats by PET imaging. After intravenous administration, [¹⁸F]PTV-F1 selectively accumulated in the liver, and the radioactivity detected in plasma, liver, and bile mainly derived from the parent PTV-F1 during the PET study (∼40 min). Coadministration of rifampicin largely decreased the hepatic uptake of [¹⁸F]PTV-F1 by 73%. Because of its lower clearance in rats, [¹⁸F]PTV-F1 is more sensitive for monitoring changes in hepatic OATP1B function that other previously reported OATP1B PET probes. Rifampicin coadministration also significantly decreased the biliary excretion of radioactivity by 65%. Bcrp knockout did not show a significant impact on its biliary excretion.[¹⁸F]PTV-F1 enables quantitative analysis of the hepatobiliary transport system for organic anions

Oncostatin M renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-fluorouracil by inducing hepatocytic differentiation

金沢大学附属病院消化器内科Recent evidence suggests that a certain type of hepatocellular carcinoma (HCC) is hierarchically organized by a subset of cells with stem cell features (cancer stem cells; CSC). Although normal stem cells and CSCs are considered to share similar self-renewal programs, it remains unclear whether differentiation programs are also maintained in CSCs and effectively used for tumor eradication. In this study, we investigated the effect of oncostatin M (OSM), an interleukin 6-related cytokine known to induce the differentiation of hepatoblasts into hepatocytes, on liver CSCs. OSM receptor expression was detected in the majority of epithelial cell adhesion molecule-positive (EpCAM+) HCC with stem/progenitor cell features. OSM treatment resulted in the induction of hepatocytic differentiation of EpCAM+ HCC cells by inducing signal transducer and activator of transcription 3 activation, as determined by a decrease in stemness-related gene expression, a decrease in EpCAM, α-fetoprotein and cytokeratin 19 protein expressions, and an increase in albumin protein expression. OSM-treated EpCAM+ HCC cells showed enhanced cell proliferation with expansion of the EpCAM-negative non-CSC population. Noticeably, combination of OSM treatment with the chemotherapeutic agent 5-fluorouracil (5-FU), which eradicates EpCAM-negative non-CSCs, dramatically increased the number of apoptotic cells in vitro and suppressed tumor growth in vivo compared with either saline control, OSM, or 5-FU treatment alone. Taken together, our data suggest that OSM could be effectively used for the differentiation and active cell division of dormant EpCAM+ liver CSCs, and the combination of OSM and conventional chemotherapy with 5-FU efficiently eliminates HCC by targeting both CSCs and non-CSCs. ©2010 AACR

Randomized, Phase II Study Comparing Interferon Combined with Hepatic Arterial Infusion of Fluorouracil plus Cisplatin and Fluorouracil Alone in Patients with Advanced Hepatocellular Carcinoma

Objective: This randomized phase II trial compared the response rates to treatment with interferon (IFN) combined with hepatic arterial infusion of fluorouracil (FU) plus cisplatin (CDDP) or FU alone in patients with advanced hepatocellular carcinoma (HCC). Methods: A total of 114 patients with measurable advanced HCC were enrolled and randomized into 2 groups. FU (300 mg/m2, days 1–5, days 8–12) with or without CDDP (20 mg/m2, days 1 and 8) was administered via the hepatic artery. IFNα-2b was administered 3 times per week for 4 weeks. Results: The response rates were 45.6% for the IFN/FU + CDDP group and 24.6% for the IFN/FU group. The response rate was significantly higher in the IFN/FU + CDDP group (p = 0.030). The median overall survival period was 17.6 months in the IFN/FU + CDDP group versus 10.5 months in the IFN/FU group (p = 0.522). The median progression-free survival period was 6.5 months in the IFN/FU + CDDP group versus 3.3 months in the IFN/FU group (p = 0.0048). Hematological toxicity was common, but no toxicity-related deaths were observed. Conclusion: These results show the clinical efficacy of adding CDDP to the hepatic arterial infusion of FU in combined chemotherapy regimens with IFN

Virological effects and safety of combined double filtration plasmapheresis (DFPP) and interferon therapy in patients with chronic hepatitis C: A preliminary study

金沢大学医学部附属病院内科Purpose: In patients with chronic genotype 1b hepatitis C and a high viral load, the viral load was reduced by double filtration plasmapheresis (DFPP), followed by combined interferon and ribavirin therapy. The safety and virological effects of this treatment method were preliminarily investigated. Methods: In nine patients with chronic hepatitis C, DFPP was performed three times on days 1, 2, and 4, and the administration of interferon and ribavirin was initiated immediately after DFPP on day 1. Result: The HCV RNA was undetectable in all patients after the plasma was passed through a plasma fractionator (second filter) in the DFPP circuit. After 2 weeks, the HCV RNA tended to decrease in the DFPP group more than in the control group (-2.45 ± 1.12 versus -1.57 ± 0.95, P = 0.073). However, this decrease was not attributable to a sustained virological response (SVR) (22.2% versus 18.2%, P = 0.822). Most of the adverse events were caused by the interferon and ribavirin combination therapy. Conclusion: DFPP can be safely performed concomitantly with interferon and ribavirin combination therapy in chronic hepatitis C patients. The combination may contribute to an early virological response. The effect of DFPP on the SVR and its significance remain to be clarified. © 2006 Elsevier Ireland Ltd. All rights reserved

Frequency of CD45RO+ subset in CD4+CD25high regulatory T cells associated with progression of hepatocellular carcinoma

金沢大学医薬保健研究域医学系The purpose of this study was to assess the properties of CD4+CD25high/low/negative T cell subsets and analyze their relation with dendritic cells (DCs) in patients with hepatocellular carcinoma (HCC). In HCC patients, the prevalence of CD45RO+ cells in CD4+CD25high T cells was increased and associated with higher frequencies of plasmacytoid DCs. Larger proportions of this T cell subset were detected in the patients with larger tumor burdens. These results suggest that increased frequencies of the CD45RO+ subset in CD4+CD25high Tregs in HCC patients may establish the immunosuppressive environment cooperatively with tolerogenic plasmacytoid DCs to promote disease progression of liver cancer. © 2011

Differential gene expression profiling in blood from patients with digestive system cancers

金沢大学医薬保健研究域医学系To develop a non-invasive and sensitive diagnostic test for cancer using peripheral blood, we evaluated gene expression profiling of blood obtained from patients with cancer of the digestive system and normal subjects. The expression profiles of blood-derived total RNA obtained from 39 cancer patients (11 colon cancer, 14 gastric cancer, and 14 pancreatic cancer) was clearly different from those obtained from 15 normal subjects. By comparing the gene expression profiles of cancer patients and normal subjects, 25 cancer-differentiating genes (p3) were identified and an " expression index" deduced from the expression values of these genes differentiated the validation cohort (11 colon cancer, 8 gastric cancer, 18 pancreatic cancer, and 15 normal subjects) into cancer patients and normal subjects with 100% (37/37) and 87% (13/15) accuracy, respectively. Although, the expression profiles were not clearly different between the cancer patients, some characteristic genes were identified according to the stage and species of the cancer. Interestingly, many immune-related genes such as antigen presenting, cell cycle accelerating, and apoptosis- and stress-inducing genes were up-regulated in cancer patients, reflecting the active turnover of immune regulatory cells in cancer patients. These results showed the potential relevance of peripheral blood gene expression profiling for the development of new diagnostic examination tools for cancer patients. © 2010 Elsevier Inc

Prolonged recurrence-free survival following OK432-stimulated dendritic cell transfer into hepatocellular carcinoma during transarterial embolization

金沢大学医薬保健研究域医学系Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0.1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 106 of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0.046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology