We study the electronic structure of bulk single crystals and epitaxial films of Fe_{3}O_{4}. Fe 2p core level spectra show clear differences between hard x-ray (HAX) and soft x-ray photoemission ...spectroscopy (PES). The bulk-sensitive spectra exhibit temperature (T) dependence across the Verwey transition, which is missing in the surface-sensitive spectra. By using an extended impurity Anderson full-multiplet model-and in contrast to an earlier peak assignment-we show that the two distinct Fe species (A and B site) and the charge modulation at the B site are responsible for the newly found double peaks in the main peak above T_{V} and its T-dependent evolution. The Fe 2p HAXPES spectra show a clear magnetic circular dichroism (MCD) in the metallic phase of magnetized 100-nm-thick films. The model calculations also reproduce the MCD and identify the contributions from magnetically distinct A and B sites. Valence band HAXPES shows a finite density of states at E_{F} for the polaronic half metal with a remnant order above T_{V} and a clear gap formation below T_{V}. The results indicate that the Verwey transition is driven by changes in the strongly correlated and magnetically active B-site electronic states, consistent with resistivity and optical spectra.
The Markov chain Monte Carlo method is a versatile tool in statistical physics to evaluate multi-dimensional integrals numerically. For the method to work effectively, we must consider the following ...key issues: the choice of ensemble, the selection of candidate states, the optimization of transition kernel, algorithm for choosing a configuration according to the transition probabilities. We show that the unconventional approaches based on the geometric allocation of probabilities or weights can improve the dynamics and scaling of the Monte Carlo simulation in several aspects. Particularly, the approach using the irreversible kernel can reduce or sometimes completely eliminate the rejection of trial move in the Markov chain. We also discuss how the space-time interchange technique together with Walker's method of aliases can reduce the computational time especially for the case where the number of candidates is large, such as models with long-range interactions.
Blockade of the CD40–CD154 costimulatory signal is an attractive strategy for immunosuppression and tolerance induction in organ transplantation. Treatment with anti‐CD154 monoclonal antibodies ...(mAbs) results in potent immunosuppression in nonhuman primates (NHPs). Despite plans for future clinical use, further development of these treatments was halted by complications. As an alternative approach, we have been focusing on the inhibition of the counter receptor, CD40 and have shown that a novel human anti‐CD40 mAb, ASKP1240, markedly prolongs renal allograft survival in NHPs, although allografts eventually underwent chronic allograft nephropathy. On the basis of our previous findings that a CD40–CD154 costimulation blockade induces tolerance to hepatic, but not cardiac, allografts in rodents, we tested here our hypothesis that a blockade of CD40 by ASKP1240 allows acceptance of hepatic allografts in NHPs. A 2‐week ASKP1240 induction treatment prolonged liver allograft survival in NHPs; however, the graft function deteriorated due to chronic rejection. In contrast, a 6‐month ASKP1240 maintenance monotherapy efficiently suppressed both cellular and humoral alloimmune responses and prevented rejection on the hepatic allograft. No serious side effects, including thromboembolic complications, were noted in the ASKP1240‐treated monkeys. We conclude that CD40 blockade by ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.
The authors find that the blockade of CD40 by ASKP1240 ameliorated cellular and humoral alloimmune responses and prevented rejection on hepatic allograft in nonhuman primates, and conclude that ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.
A strategy for inhibiting CD40 has been considered as an alternative approach for immunosuppression because of undesirable effects of anti‐CD154 monoclonal antibodies (mAbs). Previously, we ...demonstrated that ASKP1240, which is a fully human anti‐CD40 mAb, significantly prolonged kidney and liver allograft survival in cynomolgus monkeys without causing thromboembolic complications. Herein, we evaluated the effect of ASKP1240 on pancreatic islet transplantation (PITx) in cynomolgus monkeys. Diabetes was induced by total pancreatectomy, and islet allografts were transplanted into the liver. Following PITx (8201–12 438 IEQ/kg), blood glucose levels normalized promptly in all animals. Control islet allografts were rejected within 9 days (n = 3), whereas ASKP1240 (10 mg/kg) given on postoperative days 0, 4, 7, 11 and 14 (induction treatment, n = 5) significantly prolonged graft survival time (GST) to >15, >23, 210, 250 and >608 days, respectively. When ASKP1240 (5 mg/kg) was administered weekly thereafter up to post‐PITx 6 months (maintenance treatment, n = 4), GST was markedly prolonged to >96, >115, 523 and >607 days. During the ASKP1240 treatment period, both anti‐donor cellular responses and development of anti‐donor antibodies were abolished, and no serious adverse events were noted. ASKP1240 appears to be a promising candidate for immunosuppression in clinical PITx.
The authors find that the blockade of CD40 by ASKP1240 suppresses cellular and humoral alloimmune responses, prolongs pancreatic islet allograft survival in nonhuman primates, and might be a promising approach for immunosuppression in clinical pancreatic islet transplantation.
Mesothelin is expressed in various types of malignant tumour, and we recently reported that expression of mesothelin was related to an unfavourable patient outcome in pancreatic ductal ...adenocarcinoma. In this study, we examined the clinicopathological significance of the mesothelin expression in gastric cancer, especially in terms of its association with the staining pattern.
Tissue specimens from 110 gastric cancer patients were immunohistochemically examined. The staining proportion and intensity of mesothelin expression in tumour cells were analysed, and the localisation of mesothelin was classified into luminal membrane and/or cytoplasmic expression.
Mesothelin was positive in 49 cases, and the incidence of mesothelin expression was correlated with lymph-node metastasis. Furthermore, luminal membrane staining of mesothelin was identified in 16 cases, and the incidence of luminal membrane expression was also correlated with pT factor, pStage, lymphatic permeation, blood vessel permeation, recurrence, and poor patient outcome. Multivariate analysis showed that luminal membrane expression of mesothelin was an independent predictor of overall patient survival.
We described that the luminal membrane expression of mesothelin was a reliable prognostic factor in gastric cancer, suggesting the functional significance of membrane-localised mesothelin in the aggressive behaviour of gastric cancer cells.
The Néel temperature T(N) of quasi-one- and quasi-two-dimensional antiferromagnetic Heisenberg models on a cubic lattice is calculated by Monte Carlo simulations as a function of interchain ...(interlayer) to intrachain (intralayer) coupling J(')/J down to J(')/J approximately = 10(-3). We find that T(N) obeys a modified random-phase approximationlike relation for small J(')/J with an effective universal renormalized coordination number, independent of the size of the spin. Empirical formulas describing T(N) for a wide range of J(') and useful for the analysis of experimental measurements are presented.
Blockade of CD40–CD154 signaling pathway is an attractive strategy to induce potent immunosuppression and tolerance in organ transplantation. Due to its strong immunosuppressive effect shown in ...nonhuman primate experiments, anti‐CD154 monoclonal antibodies (mAbs) have been tried in clinical settings, but it was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule, CD40, has remained an alternative approach. In the previous preliminary study, we have shown that 4D11, a novel fully human anti‐CD40 mAb, has a fairly potent immunosuppressive effect on kidney allograft in nonhuman primates. In this study, we aimed to confirm the efficacy and untoward events of the 2‐week induction and 180‐day maintenance 4D11 treatments. In both, 4D11 significantly suppressed T‐cell‐mediated alloimmune responses and prolonged allograft survival. Addition of weekly 4D11 administration after the induction treatment further enhanced graft survival. Complete inhibition of both donor‐specific Ab and anti‐4D11 Ab productions was obtained only with higher‐dose maintenance therapy. No serious side effect including thromboembolic complications was noted except for a transient reduction of hematocrit in one animal, and decrease of peripheral B‐cell counts in all. These results indicate that the 4D11 appears to be a promising candidate for immunosuppression in clinical organ transplantation.
CD40 costimulatory blockade by 4D11 prolongs renal allograft survival in cynomolgus monkeys. See Editorial by Kirk on page 1701–1720.
Summary
Background
Dehydroxymethylepoxyquinomicin (DHMEQ) is a newly developed compound that inhibits nuclear factor κB activation and is reported to ameliorate animal models of various inflammatory ...diseases without significant adverse effects. Because nuclear factor κB is a transcription factor that plays a critical role in the pathophysiology of asthma, DHMEQ may be of therapeutic benefit in asthma.
Objective
The purpose of this study was to evaluate the effects of DHMEQ on airway inflammation and remodelling in murine models of asthma.
Methods
The BALB/c mice were sensitized and then challenged acutely or chronically with ovalbumin and administered DHMEQ intraperitoneally before each challenge. Inflammation of airways, lung histopathology and airway hyper responsiveness to methacholine challenge were evaluated. In addition, the effect of DHMEQ on production of cytokines and eotaxin‐1 by murine splenocytes, human peripheral blood mononuclear cells and bronchial epithelial cells was investigated.
Results
Airway hyper responsiveness was ameliorated in both acutely and chronically challenged models by treatment with DHMEQ. DHMEQ significantly reduced eosinophilic airway inflammation and levels of Th2 cytokines in bronchoalveolar lavage fluid in the acute model. It also inhibited parameters of airway remodelling including mucus production, peribronchial fibrosis and the expression of α‐smooth muscle actin. Moreover, the production of Th2 cytokines from murine splenocytes and human peripheral blood mononuclear cells and the production of eotaxin‐1 by bronchial epithelial cells were inhibited by DHMEQ.
Conclusions and Clinical Relevance
These results indicate that DHMEQ inhibits allergic airway inflammation and airway remodelling in murine models of asthma. DHMEQ may have therapeutic potential in the treatment of asthma.
Unpreventable allograft rejection is one of the main problems in pancreatic islet transplantation (PIT). Therefore, it is imperative to develop a more effective immunosuppressive strategy. The ...blockade of transcription factors has been a central part of T cell–depleting immunosuppressive therapies, as typified by the use of calcineurin inhibitors. The inhibition of activator protein‐1 (AP‐1) offers a novel strategy for immunosuppression in PIT, although to date, no reports on the effects of AP‐1 inhibition are available. In this study, we investigated the immunosuppressive effects of T‐5224, a c‐Fos/AP‐1‐selective inhibitor, on murine T cells activated by αCD3+αCD28 mAbs. T‐5224 inhibited proliferation, CD25 up‐regulation, and the production of IL‐2 and interferon‐γ. In addition, T‐5224 blocked the nuclear translocation of c‐Fos/AP‐1 in activated murine T cells. In BALB/c (H‐2d)‐to‐C57BL/6J (H‐2b) mouse PIT, the 2‐week administration of T‐5224 prolonged survival of 600 islet allografts in a dose‐dependent manner. When combined with a 2‐week low‐dose tacrolimus, the T‐5224 treatment markedly prolonged allograft survival to over 300 days, while the efficacy was indeterminate when transplanted islet allograft mass was reduced to 300. We conclude that the c‐Fos/AP‐1 inhibition by T‐5224 is a potentially attractive strategy for allogeneic PIT.
The authors provide evidence that the transcription factor activator protein‐1 plays a crucial role during rejection of pancreatic islet allografts in mice, and that the new inhibitor of activator protein‐1, T‐5224, is a potentially attractive candidate for immunosuppressive therapy after pancreatic islet transplantation.
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