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金沢大学先進予防医学研究センター / 金沢大学医薬保健研究域医学系, Hepatic arterial infusion chemotherapy (HAIC) has been employed as an alternative therapy to sorafenib for the patients with advanced hepatocellular carcinoma (HCC). In this study, we performed a comparative analysis of various immune cell responses including tumor-associated antigen (TAA)-specific T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in advanced HCC patients treated with HAIC. Thirty-six HCC patients were examined in the study. Interferon gamma enzyme-linked immunospot assays were performed to examine the frequency of TAA-specific T cells. The frequencies of Tregs and MDSCs were examined by multicolor fluorescence-activated cell sorting analysis. The treatment with HAIC using interferon (IFN)/5-fluorouracil (FU) or IFN/FU + cisplatin modulated the frequencies of various immune cells. In 22.2 % of patients, the frequency of TAA-specific T cells increased after HAIC. Although the frequency of Tregs decreased after HAIC, it was not associated with the prognosis of patients. An analysis of prognostic factors for overall survival identified diameter of the tumor (

Although sorafenib is a standard drug for advanced hepatocellular carcinoma (HCC), little is known about a patient's clinical course after treatment. We investigated the effect of post-progression survival (PPS) and progression-free survival (PFS) on overall survival (OS) in patients whose advanced HCC was treated by sorafenib.We searched in the PubMed database for reports with survival data of patients with HCC treated with sorafenib monotherapy, and selected reports with 20 or more patients each that provided data for both OS and PFS or time to progression (TTP). Median PPS (mPPS) was defined as the period obtained by subtracting median PFS or TTP (mPFS/TTP) from median OS (mOS). We identified 56 reports with 5803 patients. We investigated the correlation of mOS and either mPPS or mPFS/TTP using weighted linear regression.Median PPS correlated with mOS (r = 0.834) very strongly, whereas mPFS/TTP did not correlate with mOS as highly as PPS did (r = 0.546). When we stratified survival data by Child-Pugh classification, a significantly greater average percentage of mPPS to mOS was seen in Child-Pugh class A (54.4 ± 17.6%) than in Child-Pugh class B (32.0 ± 11.6%) (P = 0.015).PPS highly correlated with OS, and its importance should be more emphasized for advanced HCC patients treated after sorafenib therapy, whereas we need to take more care in interpreting the results of PFS to evaluate treatment efficacy in clinical trials of advanced HCC.

We propose a prepayment model of mortgage based on a structural approach in order to analyze prepayment risk of mortgage-backed securities (MBS). We introduce a continuous process named prepayment cost process. Specifically, each mortgager's prepayment time is defined by the first time when her or his prepayment cost process falls below zero, but prepayment cost processes are supposed to be unobservable in the market. We also introduce a risk unique to each loan pool of mortgages, called a loan pool risk (LPR), and we regard LPR as a systematic risk other than interest rate. Using the model, we discuss the conditional distribution of prepayment times and a risk-neutral valuation of pass-through MBS. It is shown that each mortgager's conditional non-prepayment probability and the posterior distribution of LPR play quite important roles in our study.

This study investigated the characteristics of shallow groundwater quality under agricultural areas dominated by rice paddy fields, vegetable fields, and a residential zone on an alluvial basin by examining spatial distributions of Cl\u., Na\u+, NO\u-\d3, and SO²\d4\u- concentrations. Seasonal changes in spatial distribution of ion concentrations during one cultivation period and the causes of the changes were discussed. Changes in spatial distribution of Cl. and Na+ concentrations of the groundwater were mainly affected by seasonal changes in precipitation concentrations. NO\u-\d3 concentration was strongly influenced by fertilization of vegetable fields and a following heavy rainfall. Elevated NO\u-\d3 concentration was less likely to occur under paddy fields than under vegetable fields. It was suggested that paddy fields might mitigate NO\u-\d3 contamination of shallow groundwater possibly because of denitrification in paddy soil in an anaerobic state during ponding. As for SO²\d4\u-, it was acknowledged that there could be a specific point source near a particular observation well.

Background & Aims Levels of α-fetoprotein (AFP) are measured for surveillance and diagnosis of hepatocellular carcinoma (HCC). We performed a phase 1 trial to evaluate the safety and efficacy of AFP-derived peptides as an anti-tumor vaccine for patients with advanced HCC, and characterized induction of AFP-specific T-cell receptors (TCRs). Methods We performed a prospective study of 15 patients with HCC seen at Kanazawa University Hospital in Japan from March 2010 through March 2012. Each patient was given a subcutaneous injection of 3 mg AFP-derived peptides (AFP 357 and AFP 403 ) in an emulsion with incomplete Freund's adjuvant every other week for at least 6 weeks. Patients were evaluated every 8 weeks by radiologic imaging; adverse events and toxicities were categorized and graded using the common terminology criteria for adverse events. Criteria for discontinuation included unacceptable toxicities and disease progression defined as progressive disease using the Response Evaluation Criteria In Solid Tumors criteria. Patients' immune responses were monitored using an interferon-gamma enzyme-linked immunospot assay. Peptide-specific TCRs were assessed using a rapid TCR cloning and evaluation system. The observation period was 730 days. A complete response was defined as the disappearance of all tumors; stable disease was defined as tumors whose total diameter remained between >70% and Results We did not observe any serious adverse reactions to the peptides, which were well tolerated. Of the 15 patients who received at least 3 injections, 5 (33%) had an immune response to the peptides. One of the 15 patients had a complete response and disease stabilized in 8 patients. In 4 of the 15 patients, we detected AFP 357 -specific CD8 T cells; we cloned 14 different TCRs with different avidities for the peptide. A TCR with the highest avidity was observed in the patient who achieved a complete response for more than 2 years. Conclusions In a phase 1 trial, administration of AFP-derived peptides to 15 patients with HCC did not cause adverse events and produced T cells with receptors that reacted to the peptides; 1 patient had a complete response and tumor growth slowed in 8 patients. T cells from the patient with a complete response expressed a highly functional TCR induced by the peptide vaccines. UMIN-CTR no: UMIN000003514.

Background & aims Squamous cell carcinoma antigen recognized by T cells 3 (SART3), a tumor-associated antigen expressed in many cancers, functions in tumor rejection. In this study, we investigated its usefulness as an immunotherapeutic target in hepatocellular carcinoma (HCC). Methods The expression of SART3 in hepatoma cell lines and HCC tissues was investigated by immunofluorescence and immunohistochemical analyses. Two peptides derived from SART3 (SART3109 and SART3315) were used for immunological analysis. T-cell responses were investigated by interferon-gamma (IFN-γ) enzyme-linked immunospot and cytotoxic T lymphocyte (CTL) assays using peripheral blood mononuclear cells (PBMCs) in 47 patients, and tumor-infiltrating lymphocytes in 8 of 47 patients with HCC. The safety of immunotherapy using a SART3-derived peptide was investigated by vaccinations of SART3109 in 12 patients with HCC (trial registration: UMIN000005677). Results The immunofluorescence and immunohistochemical analyses showed that SART3 was expressed in six HCC cell lines, and in HCC tissues including of alpha-fetoprotein-negative individuals. SART3-specific CTLs were generated by stimulating PBMCs with the peptides, and they showed cytotoxicity against HCC cells expressing the protein. Of the 47 HCC patients, 25.5% and 10.6% showed significant responses to SART3109 and SART3315, respectively. The infiltration of SART3109-specific IFN-γ-producing CTLs into the tumor site was confirmed. In the vaccination study, no severe adverse events were observed, and the peptide-specific CTLs were newly induced in four of five patients tested. Conclusions SART3 is an immunotherapeutic candidate, and peptides from this antigen may be applied in HCC immunotherapy. Trial registration UMIN000005677.

Inflammation plays a critical role in cancer. The aim of the present study was to investigate the impact of neutrophil to lymphocyte ratio (NLR) on patients with advanced hepatocellular carcinoma (HCC) treated with hepatic arterial infusion chemotherapy (HAIC).We retrospectively evaluated 266 patients with advanced HCC treated with HAIC between March 2003 and December 2012. NLR was calculated from the differential leukocyte count by dividing the absolute neutrophil count by the absolute lymphocyte count.The cut-off level of NLR was set as the median value of 2.87 among all patients in this study. The objective response rate in the patients with low NLR was 37.6%, which was significantly better than that of the patients with high NLR (21.1%; P 0.01). Multivariate analysis revealed that low NLR remained associated with the response to HAIC (P = 0.024). Median progression-free survival and median overall survival in patients with high NLR were 3.2 and 8.0 months, respectively, which were significantly shorter than that of the patients with low NLR (5.6 and 20.7 months; P 0.01 and P 0.01, respectively). High NLR was an independent unfavorable prognostic factor in multivariate analysis. The patient outcome was stratified more clearly by NLR calculated after HAIC added to calculations before HAIC. Serum platelet-derived growth factor-BB level was positively correlated with NLR.Results suggest that NLR is a useful predictor in patients with advanced HCC treated with HAIC. These findings may be useful in determining treatment strategies or in designing clinical chemotherapy trials in future.

In this paper, we present a filtering model on a default risk related to mathematical finance. We regard as the time when a default occurs the first hitting time at zero of a one dimensional process which starts at some positive number and is not directly observed. We discuss the conditional law of the hitting time under imperfect information. We use the reference measure change technique and a new formula on a kind of conditional expectation to obtain a so-called hazard rate process. It is also discussed what the relation between the hazard rate process and the conditional law of the hitting time is like.

Phencyclone reacted with S-allyl S-methyl dithiocarbonate derived from the [3,3]-sigmatropic rearrangement of O-allyl S-methyl dithiocarbonate to give an 1:1 mixture of endo and exo [4+2]π cycloadducts. The single crystal X-ray analysis of the exo [4+2]π cycloadduct was performed. The molecules are linked together with the intermolecular edge-to-face interaction between the phenyl hydrogen atom and the phenanthrene ring. The PM3 calculation reproduced the structural feature of the molecular packing.

The cycloaddition of 2,5-bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone with S-allyl S-methyl dithiocarbonate gave the endo cycloadduct whereas phencyclone gave a mixture of the endo and exo cycloadducts. The X-ray analysis of the cycloadduct of phencyclone and S-allyl S-methyl dithiocarbonate indicated the presence of a short contact of Ar–H···OC

The solid beta-cyclodextrin (beta-CyD) complex of O-cinnamyl S-methyl dithiocarbonates (xanthate, 1a), upon heating at 45 degrees C, underwent asymmetric [3,31-sigmatropic rearrangement to give the optically S-(1-phenylallyl) S-methyl dithiocarbonate (2a) with 60% ee. Heating the beta-CyD complex of 2a at 120 degrees C caused extrusion of COS to give cinnamyl methyl sulfide (3a) in high yield. The reaction behavior and role of beta-CyD are discussed based on molecular orbital calculation data.

The pyridine N -oxide-catalyzed thione-to-thiol rearrangement of O , S -dialkyl xanthates was analyzed by semiempirical and ab initio molecular orbital methods. The transition-structure analyses indicate that the attack of pyridine N -oxide toward xanthates proceeds through an S N 2 mechanism to give the dithiolcarbonate anion (RSCOS − ) which acts as actual catalyst.

The purpose of this study was to investigate electrochemical properties of human dentin by measuring the membrane potential. The membrane potential was measured in healthy human dentin, human dentin that had been surface-treated, and various other types of dentin, and the transport numbers were obtained.The conclusions were as follows:1. The transport numbers obtained by measuring the membrane potential of ion-exchange membranes in potassium chloride and sodium chloride solutions indicated that the experimental apparatus used in these experiments produces accurate data for -1.0-0.48 logarithm of ratio of concentration.2. The transport numbers obtained by measuring the membrane potential of healthy human dentin in potassium chloride and sodium chloride solutions indicated that healthy human dentin is negatively charged and that human dentin has ion-selective properties.3. The transport numbers obtained by measuring the membrane potential in human dentin with surface treatment and in various other types of dentin showed that there was no great difference in ion-selectivity. However, a significant difference in ion-selectivity was seen between human dentin treated with tanninfluoride and healthy human dentin.

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, although there is no proven therapeutic procedure following the termination of sorafenib, hepatic arterial infusion chemotherapy (HAIC) may be a treatment option in advanced HCC. The aim of this study was to evaluate feasibility and efficacy of HAIC for patients with advanced HCC as subsequent therapy.We retrospectively evaluated 27 consecutive patients with advanced HCC who were treated with HAIC following sorafenib between June 2009 and December 2012 at our hospital. Cisplatin (20 mg/m(2) per day) was administered via the hepatic artery for 10 min, prior to the continuous administration of 5-fluorouracil (330 mg/m(2) per day) over 24 h from days 1-5 and 8-12 and the s.c. administration of pegylated interferon α-2b (1 μg/kg) on days 1, 8, 15, and 22. A treatment cycle consisted of 28 days of drug administration followed by 14 days of rest.The toxicity profile showed that hematological toxicities were common, and grade 3/4 neutropenia and thrombocytopenia were observed (51.9% and 48.1%, respectively). Five patients (18.5%) experienced device-related complications. No unexpected adverse reactions and no treatment-related deaths were observed. Partial response was obtained in eight patients (29.6%), and stable disease was noted in nine patients (33.3%). Median progression-free survival and median survival time from initiation of HAIC were 4.0 and 7.6 months, respectively.Because HAIC was well tolerated and exhibited moderate antitumor activity, it is a potentially useful treatment procedure in patients with advanced HCC even after failure of sorafenib.

Antigen-specific T cell therapy, or T cell receptor (TCR) gene therapy, is a promising immunotherapy for infectious diseases and cancers. However, a suitable rapid and direct screening system for antigen-specific TCRs is not available. Here, we report an efficient cloning and functional evaluation system to determine the antigen specificity of TCR cDNAs derived from single antigen-specific human T cells within 10 d. Using this system, we cloned and analyzed 380 Epstein-Barr virus-specific TCRs from ten healthy donors with latent Epstein-Barr virus infection and assessed the activity of cytotoxic T lymphocytes (CTLs) carrying these TCRs against antigenic peptide-bearing target cells. We also used this system to clone tumor antigen-specific TCRs from peptide-vaccinated patients with cancer. We obtained 210 tumor-associated antigen-specific TCRs and demonstrated the cytotoxic activity of CTLs carrying these TCRs against peptide-bearing cells. This system may provide a fast and powerful approach for TCR gene therapy for infectious diseases and cancers.

The slow cycling main ring synchrotron (MR) is located the furthest downstream in the J-PARC accelerator cascade. It became available for user operation in 2009 and provides high-intensity 30 GeV proton beams for various experiments on particle and nuclear physics. The MR has two beam extraction systems: a fast extraction system for beam delivery to the neutrino beam line of the Tokai-to-Kamioka (T2K) experiment and a slow extraction system for beam delivery to the hadron experimental hall. After a nine-month beam shutdown during the recovery from the Great East Japan Earthquake, the J-PARC facility resumed beam operation in December 2011. The MR delivers a 160–200kW beam to the T2K experiment and a 3.5–6kW beam to users in the hadron experimental hall. In this paper, a brief review of the MR and the recent status of beam operation are presented. Near-future plans for a beam intensity upgrade are also discussed.

Pyridine N-oxides bearing electron-donating substituents (III) are efficient catalysts for rearrangement of O-alkyl S-methyl dithiocarbonates (xanthates) (I) to the corresponding S-alkyl S-methyl dithiocarbonates (dithiolcarbonates) (II). Of the catalysts tested, 4-piperidinopyridine N-oxide (IIIh) is the best from the viewpoints of catalytic activity and solubility in I. Heating of I in the presence of catalytic amounts (0.02-0.05 molar eq) of IIIh gave II together with the symmetric S, S-dialkyl and S, S-dimethyl dithiocarbonates in good yields. The catalytic behavior of donor-substituted pyridine N-oxides is discussed on the basis of kinetic and molecular orbital calculation data. The complete calculation of the perturbation equation on the initial stage of the reaction was consistent with the experimentally observed activity of the catalysts.

Pyridine N-oxides bearing electron-donating substituents (III) are efficient catalysts for rearrangement of O-alkyl S-methyl dithiocarbonates (xanthates) (I) to the corresponding S-alkyl S-methyl dithiocarbonates (dithiolcarbonates) (II). Of the catalysts tested, 4-piperidinopyridine N-oxide (IIIh) is the best from the viewpoints of catalytic activity and solubility in I. Heating of I in the presence of catalytic amounts (0.02-0.05 molar eq) of IIIh gave II together with the symmetric S, S-dialkyl and S, S-dimethyl dithiocarbonates in good yields. The catalytic behavior of donor-substituted pyridine N-oxides is discussed on the basis of kinetic and molecular orbital calculation data. The complete calculation of the perturbation equation on the initial stage of the reaction was consistent with the experimentally observed activity of the catalysts.

We propose a prepayment model of mortgage based on a structural approach in order to analyze prepayment risk of mortgage-backed securities (MBS). We introduce a continuous process named prepayment cost process. Specifically, each mortgager’s prepayment time is defined by the first time when her or his prepayment cost process falls below zero, but prepayment cost processes are supposed to be unobservable in the market. We also introduce a risk unique to each loan pool of mortgages, called a loan pool risk (LPR), and we regard LPR as a systematic risk other than interest rate. Using the model, we discuss the conditional distribution of prepayment times and a risk-neutral valuation of pass-through MBS. It is shown that each mortgager’s conditional non-prepayment probability and the posterior distribution of LPR play quite important roles in our study.

Mortgage-backed securities (MBS) have been rapidly increasing in issued total amount recently in Japan.

We propose a new nonlinear filtering model for a better estimation of credit rating transition matrix consistent with the hypothesis that rating transition intensities as well as dynamics of financial asset prices depend on some unobservable macroeconomic factor. We attempt a branching particle filter method to numerically obtain the conditional distribution of the latent factor. For an illustration, we analyze a rating transition history of Japanese enterprises. As a result, we realize that our model can capture some contagion effect of credit events and an interpolative role of financial market information on the rating transition intensities.

The transition structures of the thione-to-thiol rearrangement of O-(2-dimethylaminoethyl and 2-methylthio-) S-methyl xanthates in several solvents were located by semiempirical molecular orbital method (PM3) using the conductor-like screening model (COSMO) approach. Each transition state transforms into the ion-pair intermediate with a three-membered ring structure (aziridinium or thiiranium), indicating that the rearrangement proceeds through an ionic intermediate with the anchimeric assistance of the neighboring group. The intermediary structures in gas phase are also analyzed by ab initio and density functional theory calculations.

The title compound (6) was synthesized by the base-induced condensation of 3-(isocyanotosylmethyl)benzaldehyde as a new bifunctional reactant for the synthesis of [2n]metacyclophanes. The treatments of 6 with silver triflate in several molar ratios in THF at room temperature afforded only 2:1 silver triflate complex on the basis of the 1H NMR and the analytical data.

An attempt has been made to develop an on-line measuring system which allows one to avoid troublesome processes of remeasurement in bubble chamber film analysis by using a conventional digitizer with the aid of an inexpensive minicomputer. The essential feature of the system is an on-line diagnosis of the measuring accuracy by means of a parabolic fitting test of individual tracks on each view and a spatial reconstruction test after the measurement on three views. This enables an operator to make a remeasturement, when necessary, immediately after the diagnosis. The rate of success in track-reconstruction amounts to 99% in the analysis of 597 tracks from two-prong events. The measuring speed has also been improved effectively by more than a factor of two over that of an off-line system owing to the use of an automatic sequence and interlocking of operation.

A 2 year-old-girl admitted to our department with a chief complaint of a mass on the tongue base. Resection of the lesion was carried out under a clinical diagnosis of the benign tumor and followed up for 2 years. Pathological examination of the tissue showed the thyroid tissue which is not malignant. A normal thyroid gland was proved to be present in the neck by the CT scan and thyroid scintigram.Lingual thyroid with cervical thyroid is comparatively rare. Montgomery reported that the lingual thyroid without the cervical thyroid was 65 per cent.We surveyed 172 cases of the lingual thyroid for the last 87 years in Japan. There was the ratio of 1 to 5 between male and female, female predominated. Age was most in teens. Lingual thyroid with absence of the cervical thyroid gland was 58. 1 per cent.Thyroid-function tests and the thyroid scintigram are necessary on the posterior dorsal surface tumor of the tongue before treatment.

In order to observe the fast longitudinal bunch structure at the KEK proton accelerator, a wide band wall current pick-up was installed in the 20 MeV transport line and main synchrotron ring (0.5~12 GeV). The characteristics of the pick-up and some results are described.

Obtaining T cell receptor repertoires specific for cancer antigens in individuals is of great significance in terms of their relationships with the clinical courses and therapeutic application such as adoptive transfer. However, full analyses of T cell receptor (TCR) sequences have been difficult because of the inefficiency of T cell cloning, heterogeneity of T cells or the heterodimeric structures of TCRs. Here, we revealed complete landscapes of cancer antigen-specific TCRs using a novel TCR cloning system; hTEC10 (human TCR efficient cloning within 10 days) [1].