Predictive capability of material screening by fast neutron activation analysis using laser-driven neutron sources.

Bright, short-pulsed neutron beams from laser-driven neutron sources (LANSs) provide a new perspective on material screening via fast neutron activation analysis (FNAA). FNAA is a nondestructive technique for determining material elemental composition based on nuclear excitation by fast neutron bombardment and subsequent spectral analysis of prompt γ-rays emitted by the active nuclei. Our recent experiments and simulations have shown that activation analysis can be used in practice with modest neutron fluences on the order of 105 n/cm2, which is available with current laser technology. In addition, time-resolved γ-ray measurements combined with picosecond neutron probes from LANSs are effective in mitigating the issue of spectral interference between elements, enabling highly accurate screening of complex samples containing many elements. This paper describes the predictive capability of LANS-based activation analysis based on experimental demonstrations and spectral calculations with Monte Carlo simulations.

Graft-infiltrating host dendritic cells play a key role in organ transplant rejection.

Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection.

Positive association between serum thymic stromal lymphopoietin and anti-citrullinated peptide antibodies in patients with rheumatoid arthritis.

Thymic stromal lymphopoietin (TSLP) has been suggested recently to play an important role in the pathophysiology of rheumatoid arthritis (RA). However, there is little information on serum TSLP concentrations in RA and its clinical significance. The present study investigated whether serum TSLP concentrations were affected in patients with RA. Using an enzyme-linked immunosorbent assay (ELISA), we measured TSLP concentrations in the serum obtained from 100 patients with RA, 60 patients with osteoarthritis (OA) and 34 healthy volunteers. We also investigated the correlation between serum TSLP concentrations and clinical parameters of disease activity in RA [disease activity score using 28 joint counts (DAS28)-C-reactive protein (CRP), DAS28-erythrocyte sedimentation rate (ESR), Clinical Disease Activity Index (CDAI]), patient's/-physician's Visual Analogue Scale (VAS), swollen joints count, tender joints count, CRP, ESR and matrix metalloproteinase-3 (MMP-3) concentrations]. In addition, we investigated the correlation between serum TSLP concentrations and anti-citrullinated peptide antibody (ACPA) and serum tumour necrosis factor (TNF)-α. Serum TSLP levels in patients with RA were significantly higher than those in patients with OA and in healthy volunteers. Interestingly, serum TSLP concentrations were correlated significantly with ACPA titres, but not with other clinical parameters. There was a significant increase in serum TSLP concentrations in patients with RA, which was correlated positively with serum ACPA titres. These findings suggest that in patients with RA, TSLP may play a role in ACPA production by B cells.

The circadian clock functions as a potent regulator of allergic reaction.

Symptoms and laboratory parameters of allergic diseases exhibit prominent ~24-h variations. For instance, in most allergic rhinitis patients, symptoms worsen overnight or early in the morning. Accordingly, there are benefits to nighttime dosing of anti-allergy medications in such patients. Although the circadian pathophysiology of allergic diseases is well documented, the biological basis of this phenomenon remains poorly understood. Recent studies have begun to reveal that the internal timekeeping system termed the circadian clock plays a key role in temporal regulation of allergic reaction, and may therefore underlie the circadian pathophysiology of allergic diseases. Here, we review new knowledge that highlights the emerging role of the circadian clock as a potent regulator of allergic reactions. Given the strong influence of circadian rhythms on allergic diseases, we believe that research on how the time of day impacts allergic reaction which we may call 'chronoallergology' will provide new insight into previously unknown aspects of the biology of allergies. Such knowledge should facilitate novel strategies for prevention and treatment of these diseases.

Allergen-specific basophil reactivity exhibits daily variations in seasonal allergic rhinitis.

It remains poorly understood how symptoms in allergic rhinitis are most severe during overnight or early in the morning. The circadian clock consisting of a network of several 'clock genes' including Clock drives daily rhythms in physiology. This study showed that allergen-induced surface CD203c expression on basophils in seasonal allergic rhinitis caused by Japanese cedar pollen exhibited a time-of-day-dependent variation associated with temporal variations in canonical circadian clock gene expression. We also found that bone-marrow-derived basophils (BM basophils) generated from wild-type mice exhibited a time-of-day-dependent variation in IgE-mediated IL-4 and histamine production, which was not observed in BM basophils generated from Clock-mutated mice. Therefore, allergen-specific basophil reactivity shows daily variations depending on the circadian clock activity in basophils, which could partly explain temporal symptomatic variations in allergic rhinitis. Additionally, circadian variations in CD203c expression should be considered for interpretation of this biomarker in clinical research.

Photophysical, amplified spontaneous emission and charge transport properties of oligofluorene derivatives in thin films.

We investigate the photophysical and amplified spontaneous emission properties of a series of monodisperse solution-processable oligofluorenes functionalized with hexyl chains at the C9 position of each fluorene unit. Thin films of these oligofluorenes are then used in organic field-effect transistors and their charge transport properties are examined. We have particularly focused our attention on the influence of oligofluorene length on the absorption and steady-state fluorescence spectra, on the HOMO/LUMO energy levels, on the photoluminescence lifetime and quantum yield as well as on the amplified spontaneous emission properties and the charge carrier mobilities. Differential scanning calorimetry and X-ray diffraction measurements demonstrate that, among all oligofluorene derivatives used in this study, only the structure and morphology of the pentafluorene film is significantly modified by a thermal treatment above the glass transition temperature, resulting in a 9 nm blue-shift of the fluorescence spectrum without significant changes in the photoluminescence quantum yield and in the amplified spontaneous emission threshold. In parallel, hole field-effect mobility is significantly increased from 8.6 × 10(-7) to 3.8 × 10(-5) cm(2) V(-1) s(-1) upon thermal treatment, due to an increase of crystallinity. This study provides useful insights into the morphological control of oligofluorene thin films and how it affects their photophysical and charge transport properties. Moreover, we provide evidence that, because of the low threshold, the tunability of the amplified spontaneous emission and the photostability of the films, these oligofluorenes are promising candidates for organic solid-state laser applications.

Value of peritoneal cytology in potentially resectable pancreatic cancer.

BACKGROUND: Peritoneal lavage cytology (CY) is used in the diagnosis and staging of various cancers. The clinical significance of positive cytology results in patients with pancreatic cancer is yet to be determined. METHODS: Peritoneal washing samples were collected from consecutive patients with pancreatic cancer between July 1991 and December 2012. The correlations between cytology results, clinicopathological parameters and recurrence patterns were evaluated. The prognostic impact of CY status, regarding resectability and the effectiveness of adjuvant chemotherapy, were analysed. RESULTS: Of 523 included patients, 390 underwent resection. Patients with tumours at least 2 cm in diameter were more likely to have CY+ status than patients with tumours smaller than 2 cm (48 of 312 versus 3 of 78 respectively; P = 0·005) and there was a significant correlation between CY+ status and tumour invasion of the anterior pancreatic capsule (43 of 276 versus 8 of 113 with no invasion of the capsule; P = 0·030). Although the overall survival of patients with resected CY+ tumours was worse than that of patients with resected CY- tumours, it was significantly better than the survival of unresected patients regardless of CY status. Multivariable analysis of all patients who had pancreatectomy did not identify CY+ as an independent prognostic factor. Patients with CY+ tumours tended to develop peritoneal metastasis more often than those with CY- tumours, although not significantly so. The median survival time of 34 patients with resected CY+ tumours who received adjuvant chemotherapy was better than that of 17 patients who had surgery alone, although this was not statistically significant (15·3 versus 10·0 months; P = 0·057). CONCLUSION: CY+ status is not clinically equivalent to gross peritoneal metastasis in patients with pancreatic cancer. Curative resection is still recommended regardless of CY status.

Biological clock dysfunction exacerbates contact hypersensitivity in mice.

BACKGROUND: Immediate-type skin allergic reactions, such as passive cutaneous anaphylactic reaction, are associated with circadian rhythm, but the role of circadian mechanisms on delayed-type skin allergic reactions, such as contact hypersensitivity (CHS), remains uncertain. In mice, CHS, a T-cell-mediated immune response, is a classic model of human allergic contact dermatitis. OBJECTIVES: We investigated whether biological clock dysfunction affects CHS pathogenesis in CLOCK mutant mice compared with wild-type (WT) mice. METHODS: Mice were treated with 2,4,6-trinitro-1-chlorobenzene (TNCB) on the abdominal skin on day 0 (sensitization) and then treated with TNCB on the ears on day 5 (challenge). RESULTS: We found that biological clock dysfunction resulted in severe inflammation. Ear swelling, serum immunoglobulin E level and mast cell number were significantly increased in CLOCK mutant mice compared with WT mice. These results provide evidence that CLOCK mutation promotes the T-helper type 2 immune response and exacerbates CHS. Corticosterone has a protective effect on CHS. The serum corticosterone level lost rhythmicity and showed a decreased daily level in CLOCK mutant mice compared with WT mice, supporting the exacerbating effect of CLOCK mutation on CHS. Adrenalectomy markedly worsened TNCB-induced CHS in WT mice but not in CLOCK mutant mice. In addition, dramatic dexamethasone-induced protection of CHS was observed in CLOCK mutant mice compared with WT mice. CONCLUSIONS: The present results suggest that circadian rhythm might be an important factor in the regulation of CHS via corticosterone rhythmicity and/or level.

Nitrite reduces acute lung injury and improves survival in a rat lung transplantation model.

Ischemia/reperfusion injury (IRI) is the most common cause of early mortality following lung transplantation (LTx). We hypothesized that nitrite, an endogenous source of nitric oxide (NO), may protect lung grafts from IRI. Rat lung grafts were stored in preservation solution at 4°C for 6 hours. Both grafts and recipients were treated with nitrite. Nitrite treatment was associated with significantly higher levels of tissue oxygenation, lower levels of cytokines and neutrophil/macrophage infiltration, lower myeloperoxidase activity, reduced oxidative injury and increased cGMP levels in grafts than in the controls. Treatment with either a nitric oxide scavenger or a soluble guanylyl cyclase (sGC) inhibitor diminished the beneficial effects of nitrite and decreased cGMP concentrations. These results suggest that nitric oxide, generated from nitrite, is the molecule responsible for the effects of nitrite via the nitric oxide/sGC/cGMP pathway. Allopurinol, a xanthine oxidoreductase (XOR) inhibitor, abrogated the protective effects of nitrite, suggesting that XOR is a key enzyme in the conversion of nitrite to nitric oxide. In vitro experiments demonstrated that nitrite prevented apoptosis in pulmonary endothelial cells. Nitrite also exhibits longer survival rate in recipients than control. In conclusion, nitrite inhibits lung IRI following cold preservation and had higher survival rate in LTx model.

Antitumor efficacy of oncolytic herpes simplex virus adsorbed onto antigen-specific lymphocytes.

Although several studies have reported that locally administering oncolytic viruses effectively targets malignancies, the efficacy of systemically administered oncolytic viruses is restricted. Recently, however, it was reported that systemic administration of oncolytic vesicular stomatitis virus adsorbed onto antigen-specific lymphocytes was effective against malignancies. We hypothesized that intravenously administering such virus might have significant potential in treatment of the malignant tumors. We adsorbed oncolytic herpes simplex virus-1 mutant R3616 onto lymphocytes harvested from mice with acquired antitumor immunity. We administered adsorbed R3616 to peritoneally disseminated tumors and analyzed the efficacy of this treatment. Mice administered adsorbed R3616 survived significantly longer than mice administered R3616 adsorbed onto non-specific lymphocytes, or mice administered either virus or tumor antigen-specific lymphocytes alone. In this context, herpes oncolytic virus is a promising treatment not only for primary lesions, but also for multiple metastasizing lesions. This treatment strategy may become one of the most effective methods for systemic virus delivery.

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer.

Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P=0.016). Angiogenesis was significantly higher in treatment group (P=0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P=0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

Glycated albumin but not HbA1c reflects glycaemic control in patients with neonatal diabetes mellitus.

AIMS/HYPOTHESIS: It is difficult to use HbA(1c) as an indicator of glycaemic control in patients with neonatal diabetes mellitus (NDM) because of high levels of fetal haemoglobin (HbF) remaining in the blood. In this study, glycated albumin (GA), which is not affected by HbF, and HbA(1c) were compared to evaluate whether they reflect glycaemic control in patients with NDM. METHODS: This study included five patients with NDM. Age at diagnosis was 38 ± 20 days. Insulin therapy was started in all patients, and levels of GA, HbA(1c) and HbF were measured monthly for 6 months. One-month average preprandial plasma glucose (aPPG) was calculated using self-monitoring of blood glucose. RESULTS: Plasma glucose and GA were elevated (29.7 ± 13.1 mmol/l [n = 5] and 33.3 ± 6.9% [n = 3], respectively) but HbA(1c) was within normal limits (5.4 ± 2.6% [35.5 ± 4.9 mmol/mol]; n = 4) at diagnosis. With diabetes treatment, aPPG (r = -0.565, p = 0.002), GA (r = -0.552, p = 0.003) and HbF (r = -0.855, p < 0.0001) decreased with age, whereas HbA(1c) increased (r = 0.449, p = 0.004). GA was strongly positively correlated with aPPG (r = 0.784, p < 0.0001), while HbA(1c) showed no correlation with aPPG (r = 0.221, p = 0.257) and was significantly inversely correlated with HbF (r = -0.539, p = 0.004). CONCLUSIONS/INTERPRETATION: GA is a useful indicator of glycaemic control in patients with NDM, whereas HbA(1c) is influenced by age-related changes in HbF and does not accurately reflect glycaemic control.

Nutritional predictors of postoperative outcome in pancreatic cancer.

BACKGROUND: Nutritional status plays an important role in the incidence of postoperative complications and the prognosis of various tumours. The prognostic value of preoperative nutritional factors in patients with pancreatic cancer is not known. METHODS: This retrospective study included 268 patients who underwent resection for adenocarcinoma of the pancreas. The predictive value of preoperative nutritional status for postoperative outcome (survival, complications) was assessed. Nutritional factors included the three constitutional indices, serum albumin and Onodera's prognostic nutrition index (PNI), calculated as 10 × serum albumin (g/dl) + 0·005× total lymphocyte count (per mm(3)). RESULTS: In multivariable analysis preoperative low PNI (but not low albumin) was an independent prognostic factor for poor survival: hazard ratio (HR) 1·73 (95 per cent confidence interval (c.i.) 1·21 to 2·47). The accuracy of a PNI value of less than 45 as cut-off for clinically significant preoperative malnutrition in predicting 1- or 2-year survival after surgery was, however, limited (66·4 and 56·3 per cent respectively). Low preoperative albumin concentration and PNI were significantly associated with postoperative complications: odds ratio 1·98 (95 per cent c.i. 1·18 to 3·32) and 2·14 (1·23 to 3·73) respectively. Low PNI and low body mass index were independently associated with pancreatic fistula: HR 2·52 (1·37 to 4·63) and 0·40 (0·17 to 0·93) respectively. CONCLUSION: The PNI is associated with overall survival and postoperative complications, in particular pancreatic fistula, in patients with pancreatic cancer. The moderate accuracy of PNI as a predictor of survival limits its clinical use.

A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer.

In 2005, we initiated a clinical trial that examined the efficacy of the oncolytic virus HF10 to treat pancreatic cancer. Pancreatic cancer continues to have a high mortality rate, despite multimodal treatments for patients, and new therapeutic methods are greatly needed. The current mainstream methods for cancer treatment include biological therapeutics such as trastuzumab (Herceptin) for breast cancer or erlotinib (Tarceva) for non-small cell lung cancer. Oncolytic virus therapy is a new and promising treatment strategy for cancer. Oncolytic viruses are novel biological therapeutics for advanced cancer that appear to have a wide spectrum of anticancer activity with minimal human toxicity. To examine the efficacy of oncolytic virus therapy for pancreatic cancer, we initiated pilot studies by injecting six patients with non-resectable pancreatic cancer with three doses of HF10. All patients were monitored for 30 days for local and systemic adverse effects and were not administered any other therapeutics during this period. There were no adverse side-effects, and we observed some therapeutic potential based on tumor marker levels, survival, pathological findings and diagnostic radiography. The tumors were classified as stable disease in three patients, partial response in one patient and progressive disease in two patients.

Peierls mechanism of the metal-insulator transition in ferromagnetic hollandite K2Cr8O16.

Synchrotron x-ray diffraction experiment shows that the metal-insulator transition occurring in a ferromagnetic state of a hollandite K(2)Cr(8)O(16) is accompanied by a structural distortion from the tetragonal I4/m to monoclinic P112(1)/a phase with a √2×√2×1 supercell. Detailed electronic structure calculations demonstrate that the metal-insulator transition is caused by a Peierls instability in the quasi-one-dimensional column structure made of four coupled Cr-O chains running in the c direction, leading to the formation of tetramers of Cr ions below the transition temperature. This provides a rare example of the Peierls transition of fully spin-polarized electron systems.

Ex vivo application of carbon monoxide in UW solution prevents transplant-induced renal ischemia/reperfusion injury in pigs.

I/R injury is a major deleterious factor of successful kidney transplantation (KTx). Carbon monoxide (CO) is an endogenous gaseous regulatory molecule, and exogenously delivered CO in low concentrations provides potent cytoprotection. This study evaluated efficacies of CO exposure to excised kidney grafts to inhibit I/R injury in the pig KTx model. Porcine kidneys were stored for 48 h in control UW or UW supplemented with CO (CO-UW) and autotransplanted in a 14-day follow-up study. In the control UW group, animal survival was 80% (4/5) with peak serum creatinine levels of 12.0 +/- 5.1 mg/dL. CO-UW showed potent protection, and peak creatinine levels were reduced to 6.9 +/- 1.4 mg/dL with 100% (5/5) survival without any noticeable adverse event or abnormal COHb value. Control grafts at 14 days showed significant tubular damages, focal fibrotic changes and numerous infiltrates. The CO-UW group showed significantly less severe histopathological changes with less TGF-beta and p-Smad3 expression. Grafts in CO-UW also showed significantly lower early mRNA levels for proinflammatory cytokines and less lipid peroxidation. CO in UW provides significant protection against renal I/R injury in the porcine KTx model. Ex vivo exposure of kidney grafts to CO during cold storage may therefore be a safe strategy to reduce I/R injury.

The role and potential use of oral transforming growth factor-beta in the prevention of infant allergy.

The increasing prevalence of allergic diseases in infants and children as well as adults has become an important issue in public health in industrial countries. However, few preventive measures are available to reduce the risk of allergic diseases in infants; e.g. the avoidance of smoking and alcohol consumption during pregnancy and lactation. Therefore, there is an enthusiasm to identify certain factors in foods, nutrients, and environment responsible for the primary prevention of allergic diseases during infancy. In the last decade, TGF-beta in maternal milk has been implicated in the prevention of allergic diseases in infants and young children. This review summarizes the relevant epidemiological reports and highlights the recent animal studies to support the preventive role of orally administered TGF-beta, such as TGF-beta in human milk, in the development of allergic diseases in infants. We also provide suggestions for the potential use of dietary (oral) TGF-beta for the primary prevention of allergic diseases. Further studies to address the scientific validity and mechanistic insight to this Mother Nature-inspired concept are clearly required and will be important to develop new approaches to prevent allergic diseases.

A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer.

BACKGROUND: This multicentre randomised phase III trial was designed to determine whether adjuvant chemotherapy with gemcitabine improves the outcomes of patients with resected pancreatic cancer. METHODS: Eligibility criteria included macroscopically curative resection of invasive ductal carcinoma of the pancreas and no earlier radiation or chemotherapy. Patients were randomly assigned at a 1 : 1 ratio to either the gemcitabine group or the surgery-only group. Patients assigned to the gemcitabine group received gemcitabine at a dose of 1000 mg m(-2) over 30 min on days 1, 8 and 15, every 4 weeks for 3 cycles. RESULTS: Between April 2002 and March 2005, 119 patients were enrolled in this study. Among them, 118 were eligible and analysable (58 in the gemcitabine group and 60 in the surgery-only group). Both groups were well balanced in terms of baseline characteristics. Although heamatological toxicity was frequently observed in the gemcitabine group, most toxicities were transient, and grade 3 or 4 non-heamatological toxicity was rare. Patients in the gemcitabine group showed significantly longer disease-free survival (DFS) than those in the surgery-only group (median DFS, 11.4 versus 5.0 months; hazard ratio=0.60 (95% confidence interval (CI): 0.40-0.89); P=0.01), although overall survival did not differ significantly between the gemcitabine and surgery-only groups (median overall survival, 22.3 versus 18.4 months; hazard ratio=0.77 (95% CI: 0.51-1.14); P=0.19). CONCLUSION: The current results suggest that adjuvant gemcitabine contributes to prolonged DFS in patients undergoing macroscopically curative resection of pancreatic cancer.

PTHrP induces Notch signaling in periodontal ligament cells.

Periodontal ligament (PDL) cells are known to play important roles in tooth eruption and alveolar bone metabolism. We previously reported that PTHrP increases RANKL expression in human PDL cells, suggesting that it promotes odontoclastic root resorption during tooth eruption. While it is known that Notch-related genes play a key role during bone development, the role of the Notch signaling pathway in PDL cells during tooth and bone resorption is less clear. We hypothesized that PTHrP induces a Notch ligand in PDL cells and thereby regulates osteo- and odontoclastogenesis. We found that PTHrP increased Notch1 ligand Jagged1 expression in human PDL cells in a dose- and time-dependent manner. PTHrP-induced Jagged1 up-regulation was mediated by PKA activation, but not by PKC. Jagged1 also promoted RANKL-induced osteoclastogenesis. These results demonstrate that PTHrP induces Jagged1 expression in PDL cells, leading to osteo- and odontoclastogenesis, and thus likely promoting tooth and alveolar bone resorption.