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Since tumors in different human organs may have different tumor microenvironments, we evaluate time-course changes in all tumor locations after pembrolizumab treatment in urothelial carcinoma (UC) to examine the differences in efficacy of pembrolizumab per organ. Further, we uncover the usefulness of inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), CRP, and kinetics of these markers to predict pembrolizumab success and relation to overall survival (OS) in UC.A total of 115 cancerous lesions from 44 UC patients were measurable based on RECIST 1.1 criteria. The serum CRP and NLR levels were measured at baseline prior to pembrolizumab treatment and at least every 3 weeks just prior to pembrolizumab administration.Site-specific success (ie, patients with CR/PR/SD by RESIST 1.1) rates for pembrolizumab treatments were as follows: primary tumors: 67%, lymph node: 70%, lung: 44%, liver: 40%, and peritoneal metastasis: 56%. Focusing on the major metastasis sites, lymph nodes and lungs, we examined the relationships between NLR, CRP, or that kinetics and pembrolizumab success. In lymph nodes, both early NLR kinetics (P = .005) and CRP kinetics (P = .035) was a predictor for pembrolizumab success. On the other hand, none of 4 was not in lung metastases. Regarding to the mortality, the multivariate analysis revealed that early NLR kinetics was a prognostic biomarker for OS among the 4, independent of performance status and liver metastasis.We revealed that site-specific pembrolizumab success in UC. Early NLR kinetics was a predictor for lymph node pembrolizumab success and OS in our cohorts.

In this study, a corrosion-stable silica membrane was developed to be used in H2 purification during the hydrogen iodide decomposition (2HI → H2 + I2), which is a new application of the silica membranes. From a practical perspective, the membrane separation length was enlarged up to 400 mm and one end of the membrane tubes was closed to avoid any thermal variation along the membrane length and sealing issues. The silica membranes consisted of a three-layer structure comprising a porous α-Al2O3 ceramic support, an intermediate layer, and a top silica layer. The intermediate layer was composed of γ-Al2O3 or silica, and the top silica layer that is H2 selective was prepared via counter-diffusion chemical vapor deposition of a hexyltrimethoxysilane. To the best of our knowledge, this is the first report of 400-mm-long closed-end silica membranes supported on Si-formed α-Al2O3 tubes produced via chemical vapor deposition method. A 400-mm-long closed-end membrane using a Si-formed α-Al2O3 tube exhibited a higher H2/SF6 selectivity of 1240 but lower H2 permeance of 1.4 × 10−7 mol Pa−1 m−2 s−1 with compared with the membrane using a γ-Al2O3-formed α-Al2O3 tube (907 and 5.6 × 10−7 mol Pa−1 m−2 s−1, respectively). The membrane using the Si-formed α-Al2O3 tube was more stable in corrosive HI gas than a membrane with a γ-Al2O3-formed α-Al2O3 tube after 300 h of stability tests. In conclusion, the developed silica membranes using the Si-formed α-Al2O3 tubes seem suitable for membrane reactors that produce H2 on large scale using HI decomposition in the thermochemical iodine–sulfur process.

The thermochemical water-splitting iodine–sulfur process facilitates hydrogen production. This study proposes a new loop operation by subdividing the process configuration into four sections before transferring the continuous operation. The loop operation should define the section affecting the fluctuations to easily stabilize the system. The proposed loop operation was validated by analyzing the material and heat balances using a process simulator. The calculated results showed that the material balances of the respective loop sections were closed without component discharge to outside sections. The loop operation would transfer to the continuous operation by connecting all sections. Considering the switching of operation modes, the material and heat balance showed no or little difference, indicating that two operation modes can only be changed by switching the pipelines. Thus, the loop sections can be operated individually to stabilize the IS process system, and the loop operation can be transferred smoothly to the continuous operation.

In the activation of cell-mediated adaptive immune responses that play major roles in the elimination of virus-infected or tumor cells, it is important that dendritic cells present antigen peptides on major histocompatibility complex (MHC) class I molecules and activate pathogen-specific cytotoxic T lymphocytes (CTL). As exogenous peptide antigens are generally presented on MHC class II but not class I, the development of a method for exogenous antigen delivery that facilitates MHC class I presentation is necessary for a potentially effective vaccine that is expected to provoke cell-mediated adaptive immune responses. Here, we developed extracellular vesicles that incorporate antigenic proteins by utilizing endosomal sorting complexes required for transport (ESCRT)-mediated vesicle formation pathway. Furthermore, we proved that these vesicles could deliver their contents to the cytoplasm of dendritic cells and activate antigen-specific CTLs. These technologies could be applied to the development of novel CTL-inducing peptide vaccines.

To differentiate between infectious and non-infectious diseases occurring in immunocompromised patients without acquired immunodeficiency syndrome (AIDS) using high-resolution computed tomography (HRCT).HRCT images of 555 patients with chest complications were reviewed retrospectively. Infectious diseases (n=341) included bacterial pneumonia (n=123), fungal infection (n=80), septic emboli (n=11), tuberculosis (n=15), pneumocystis pneumonia (n=101), and cytomegalovirus pneumonia (n=11), while non-infectious diseases (n=214) included drug toxicity (n=84), infiltration of underlying diseases (n=83), idiopathic pneumonia syndrome (n=34), diffuse alveolar haemorrhage (n=8), and pulmonary oedema (n=5). Lung parenchymal abnormalities were compared between the two groups using the χThe χ2 test results showed significant differences in many HRCT findings between the two groups. Multiple logistic regression analysis results indicated the presence of nodules with a halo and the absence of interlobular septal (ILS) thickening were the significant indicators that could differentiate infectious from non-infectious diseases. ILS thickening was generally less frequent among most infectious diseases and more frequent among most non-infectious diseases, with a good odds ratio (7.887, p0.001). The sensitivity and accuracy for infectious diseases in the absence of ILS thickening were better (70% and 73%, respectively) than those of nodules with a halo (19% and 48%, respectively), while the specificity in the nodules with a halo was better (93%) than that of ILS thickening (78%).The presence of nodules with a halo or the absence of ILS thickening tends to suggest infectious disease. Specifically, ILS thickening seems to be a more reliable indicator.

The thermochemical water-splitting iodine–sulfur (IS) process requires corrosion-resistant materials owing to usage of corrosive fluids, such as a mixture of HI–I2–H2O. Fluoropolymers, such as PTFE and PFA, are adaptable as lining materials for protecting plant components. However, there has been a concern: PTFE and PFA have the ability to permeate various permeants. From the viewpoint of corrosion of the base material, the permeation characteristics of HI and I2 should be evaluated to improve the integrity of the IS process. In this study, permeation tests on PTFE and PFA membranes were performed to measure the permeated fluxes of HI and I2, and the effects of the operating conditions on them were investigated. The introduction of a permeability parameter could be successful for normalizing the permeated fluxes for a specific membrane thickness and a vapor pressure. Then, the empirical formula of the permeability was given as an Arrhenius-type equation to use as a plant design. Finally, based on the results, the proper conditions for design of a lining material for the inhibition of HI and I2 permeation are summarized.

An electrochemical membrane Bunsen reaction using a cation exchange membrane (CEM) is a key to achieving iodine-sulfur (IS) thermochemical water splitting for the mass-production of hydrogen. In this study, we prepared a radiation-grafted CEM with a high ion exchange capacity (IEC) and a highly-porous Au-electroplated anode, and then used them for the membrane Bunsen reaction to reduce cell overvoltage. The high ionic content of our CEM led to low resistivity for proton transport, while the high porosity of the electrode led to a large effective surface area for anodic SO2 oxidation. The cell overvoltage for the membrane Bunsen reaction was significantly reduced to 0.21 V at 200 mA/cm2, one-third of that achieved using a commercial CEM and non-porous anode. From the analysis of the current-voltage characteristics, the grafted CEM was demonstrated to play a dominant role in the overvoltage reduction compared to the porous Au anode.

Background Both pre-supplementary motor area (pre-SMA) and SMA-proper (SMA) must play important roles in visuomotor sequence learning. However, functional differences between the pre-SMA and SMA have not been well studied in humans. Objective To elucidate the functional differences between the pre-SMA and SMA in sequence learning in humans. Methods To induce LTP/LTD, we administered quadripulse transcranial magnetic stimulation (QPS) with an inter-stimulus interval of 5 or 50 ms (QPS-5/50) over the pre-SMA or SMA in healthy volunteers. The sham stimulation was also done as a control. We studied the effects of LTP/LTD in the pre-SMA/SMA on a new sequence learning and the performance of well-learned sequence by using sequence learning task called the “2 × 10 task”. Effects on the simple choice reaction time task were also studied for comparison. Results QPS-5 over the pre-SMA increased the error rate without any changes in movement speed. When administered over the SMA, QPS-5 decreased, and QPS-50 increased the rate of reaction time reduction across trials without changes in the error rate. QPS over neither the pre-SMA nor SMA affected the performances of a well-learned sequence or a simple choice reaction time task. Conclusions Our findings that QPS over the pre-SMA correlated with sequence learning performance and that over the SMA with execution speed are consistent with the previous results in animals and humans. Our results lend further support to the utility of QPS for modulating motor learning in humans.

Reduced cortical plasticity has been previously reported in older adult as compared with young adults. However, the effects of dopamine on this plasticity reduction remain unknown. Here, we assessed the effects of high-dose (200 mg) and medium-dose (100 mg) L-3,4-dihydroxyphenylalanine (L-DOPA) intake on the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS) in older adults (aged ∼65 years). The subjects were 32 (200 mg) and 20 (100 mg) healthy older adult volunteers. This study was designed as a double-blind, crossover and placebo-controlled trial on one dose of L-dopa. Two hours after taking L-DOPA or placebo-drug, QPS was applied over the motor cortex. Motor evoked potentials were recorded to evaluate the motor cortical excitability changes. We found that both doses of L-DOPA enhanced LTP after QPS in older adults as one group. We classified subjects into QPS responders and QPS nonresponders. Both L-DOPA doses produced significant LTP enhancement in QPS nonresponders, whereas either of doses did not produce significant LTP enhancement in QPS responders. Collectively, our findings suggest that the neural plasticity reductions observed in older adults could be partly improved by dopamine.

Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.

In this study, the catalytic decomposition of hydrogen iodide was theoretically and experimentally investigated in a silica-based ceramic membrane reactor to assess the reactor's suitability for thermochemical hydrogen production. The silica membranes were fabricated by depositing a thin silica layer onto the surface of porous alumina ceramic support tubes via counter-diffusion chemical vapor deposition of hexyltrimethoxysilane. The performance of the silica-based ceramic membrane reactor was evaluated by exploring important operating parameters such as the flow rates of the hydrogen iodide feed and the nitrogen sweep gas. The influence of the flow rates on the hydrogen iodide decomposition conversion was investigated in the lower range of the investigated feed flow rates and in the higher range of the sweep-gas flow rates. The experimental data agreed with the simulation results reasonably well, and both highlighted the possibility of achieving a conversion greater than 0.70 at decomposition temperature of 400 °C. Therefore, the developed silica-based ceramic membrane reactor could enhance the total thermal efficiency of the thermochemical process.

The potential of the silica membrane reactors for use in the decomposition of hydrogen iodide (HI) was investigated by simulation with the aim of producing CO2-free hydrogen via the thermochemical water-splitting iodine-sulfur process. Simulation model validation was done using the data derived from an experimental membrane reactor. The simulated results showed good agreement with the experimental findings. The important process parameters determining the performance of the membrane reactor used for HI decomposition, namely, reaction temperature, total pressures on both the feed side and the permeate side, and HI feed flow rate were investigated theoritically by means of a simulation. It was found that the conversion of HI decomposition can be improved by up to four times (80%) or greater than the equilibrium conversion (20%) at 400 °C by employing a membrane reactor equipped with a tubular silica membrane. The features to design the membrane reactor module for HI decomposition of the thermochemical iodine-sulfur process were discussed under a wide range of operation conditions by evaluating the relationship between HI conversion and number of membrane tubes.

It is essential to understand the combined effects of elevated CO2 and temperature on phytoplankton-zooplankton link when attempting to predict climate change responses of freshwater ecosystems. Phytoplankton species differ in stoichiometric and fatty acids composition, and this may result in phytoplankton-mediated effect on zooplankton at elevated CO2 and temperature. Beyond the isolated analysis of CO2 or temperature effect, few studies have assessed zooplankton growth under the phytoplankton-mediated effects of elevated CO2 and temperature. In this study, three algal species (green alga, diatom, cyanobacteria) were fed on zooplankton Daphnia magna, under the conditions of CO2 concentrations of ambient (390 ppm) and elevated (1000 ppm) levels and temperatures at 20, 25 and 30 °C. Elevated CO2 increased the algal biomass, while it reduced the phosphorus (P) and ω3 polyunsaturated fatty acids (ω3 PUFAs) to carbon (C) ratios. Elevated temperature decreased the P/C ratios in all algal cultures and ω3 PUFAs/C ratios in the diatom and the cyanobacteria cultures. Phytoplankton-mediated effect of elevated CO2 reduced the growth of zooplankton fed on the green and the mixed three algae culture. The stimulation of zooplankton fed on the diatom and the cyanobacteria by elevated temperature can be offset by decreasing food P and ω3 PUFAs contents. The combined effects of elevated CO2 and temperature on the growth of daphnids were mainly mediated by ω3 PUFAs/C ratios in the phytoplankton. Rising temperature as a combined direct and indirectly phytoplankton-mediated effect on zooplankton may be able to ameliorate the negative effects of elevated CO2. The results indicated that the combined effects of increased CO2 and temperature increased the fatty acid content of the green alga but not the other algae. This study highlighted that climate change with simultaneously increasing temperature and CO2 may entangle the carbon transfer in freshwater planktonic communities.

Objective The indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (RNU) or upfront RNU followed by adjuvant chemotherapy (AC). Materials and methods Among 966 UTUC patients, we identified 89 with clinical nodal involvement who received either NAC before RNU nor AC after upfront RNU. Cox proportional hazard models were employed to evaluate the impact of chemotherapy modality on the oncological outcomes. Results Of the patient cohort, 36 (40.4%) received NAC followed by RNU, whereas 53 (59.6%) underwent RNU followed by AC. Multivariate analysis revealed that tumor size ≥3 cm, clinical T4, and gemcitabine and cisplatin regimen were independent risk factors for disease recurrence, whereas NAC followed by RNU was an independent factor for favorable RFS. Furthermore, regarding cancer-specific survival (CSS), NAC followed by RNU remained an independent factor for favorable CSS. According to Kaplan-Meier analysis, the 1-year and 2-year RFS were 67.9% and 47.0%, respectively, in the NAC+RNU group, which were significantly higher than those in the RNU+AC group (43.9% and 24.6%, respectively, P = 0.006). Moreover, the 1-year and 2-year CSS were 80.5% and 64.2%, respectively, in the NAC+RNU group, which were higher than those in the RNU+AC group (68.6% and 48.2%, respectively, P = 0.016). Conclusion For node-positive UTUC patients, NAC followed by RNU was more clinically beneficial than RNU followed by AC.

Purpose To investigate whether a history of non–muscle-invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. Patients and Methods A total of 282 patients who were diagnosed with cT2-T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n = 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n = 51). Results The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P = .004). Five-year recurrence-free survival and cancer-specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P = .039) and 76.1% versus 61.6% (P = .005), respectively. Progressive MIBC (hazard ratio, 2.170; P = .008) was independently associated with cancer death. In the primary MIBC group, the 5-year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P = .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. Conclusion MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy.

Light-sheet microscopy offers new possibilities to efficiently visualize large tissue samples in three dimensions. Volumetric 3D imaging can uncover detailed information about the inner landscape of tumors, which can improve cancer diagnosis and therapy. This Forum article highlights the advantages of using light-sheet microscopy for pathological examinations of intact tumor specimens.

Highly unsaturated fatty acids such as 20:5n3 (EPA) are both hormone precursors and cell membrane components, making them important nutrients for aquatic animals. Many animals must obtain EPA from their diets because they cannot synthesize enough EPA to meet their requirements, and algae are the main source of EPA in aquatic ecosystems. In a previous study, we detected EPA in the faeces of Danio rerio, a freshwater fish, even though the fish consumed a green algae diet that did not contain EPA. The objective of this study was to determine why EPA was detected in fish faeces. A significant positive relationship was detected between the number of heterotrophic protozoa and the concentration of EPA in the faeces, which suggests that this EPA was of protozoan origin. In addition, another experiment showed that protozoa adhered to faeces far more than the green algal diet remnants, which indicates that protozoa preferred to swarm on faeces. Furthermore, we cultured protozoa in an EPA-free medium and fed them a bacterial diet also lacking EPA, and found that Cyclidium sp. synthesized EPA de novo. The results demonstrate that protozoa produce essential fatty acids and enhance the nutritional quality of animal faeces in detritus-based food webs in freshwater ecosystems.

Hydrogen production from nuclear energy has attracted considerable interest as a clean energy solution to address the challenges of climate change and environmental sustainability. With respect to the large-scale and economical production of hydrogen using nuclear energy, the thermochemical water-splitting iodine-sulfur (IS) process is a promising method. The IS process uses sulfur and iodine compounds to decompose water into its elemental constituents, hydrogen and oxygen, by using three coupled chemical reactions: the Bunsen reaction; sulfuric acid decomposition; and hydrogen iodide (HI) decomposition. The decomposition of HI is the efficiency-determining step of the process. In this work, a membrane reactor with a silica membrane closed on one end was designed, and its potential for hydrogen production from HI decomposition was explored. In the reactor-module design, only one end of the membrane tube was fixed, while the closed-end of the tube was freely suspended to avoid thermal expansion effects. The closed-end silica membranes were prepared for the first time by a counter-diffusion chemical vapor deposition of hexyltrimethoxysilane. In application, HI conversion of greater than 0.60 was achieved at a decomposition temperature of 400 °C, which is three times greater than the equilibrium conversion (0.20). Thus, the membrane reactor with closed-end silica membrane was shown to produce a successful equilibrium shift in the production of hydrogen via HI decomposition in the thermochemical IS process.

An anaerobic membrane bioreactor was configured for methanogenic degradation of cellulose-containing sewage. The degradation performance and microbial changes were evaluated under five hydraulic retention times (HRTs). The results indicated the methane production was largely enhanced with 92.6% efficiency of chemical oxygen demand (COD) converting to methane and 80% proportion of methane in produced biogas, meanwhile the biomass yield presented the fewest at the shortest HRT 8 h. Enhanced methane production with decreased biomass yield was attributed to an association between fungi and methanogens. Microbial analysis showed fungi Basidiomycota and methanogen Methanoregula apparently established the association, especially Basidiomycota reaching 93% relative abundance at HRT 8 h. Specific methanogenic activity (SMA) and biochemical methane potential (BMP) tests suggested the association was derived from H 2 production by fungi and H 2 consumption by methanogens, during the process of cellulose degradation. The methanogenic degradation of cellulose-containing sewage was markedly promoted via the fungi-methanogens syntrophic association.

The IS process is the most deeply investigated thermochemical water-splitting hydrogen production cycle. It is in a process engineering stage in JAEA to use industrial materials for components. Important engineering tasks are verification of integrity of the total process and stability of hydrogen production in harsh environment. A test facility using corrosion-resistant materials was constructed. The hydrogen production ability was 100 L/h. Operation tests of each section were conducted to confirm basic functions of reactors and separators, etc. Then, a trial operation for integration of the sections was successfully conducted to produce hydrogen of about 10 L/h for 8 hours.

The decomposition of hydrogen iodide in the thermochemical water splitting iodine–sulfur process at an intermediate temperature (400 °C) using a catalytic membrane reactor was reported here, for the first time. The performance of a catalytic membrane reactor based on a hexyltrimethoxysilane-derived silica membranes (H2 permeance of 9.4 × 10−7 mol Pa−1 m−2 s−1 and H2/N2 selectivity of over 80.0.) was evaluated at 400 °C by varying the HI flow rates of 2.6, 4.7, 6.9, 8.4, and 9.7 mL min−1. The silica membranes were prepared by counter-diffusion chemical vapor deposition method on γ-alumina-coated α-alumina tubes. Hydrogen was successfully extracted from the membrane reactor using the silica membrane at 400 °C. A significant increase in HI conversion was achieved. The conversion achieved at an HI flow rate of 2.6 mL min−1 was approximately 0.60, which was greater than the equilibrium conversion in HI decomposition (0.22).

A scaffold-hopping strategy towards a new pyrazolo[1,5- a ]pyridine based core using molecular hybridization of two structurally distinct EP 1 antagonists, followed by structure-activity relationship-guided optimization, resulted in the identification of potent EP 1 antagonists exemplified by 4c , 4f , and 4j , which were shown to reduce pathological intravesical pressure in rats when administered at 1 mg/kg iv.

Current R&D on the thermochemical water splitting iodine-sulfur (IS) process in Japan Atomic Energy Agency (JAEA) is summarized. Reactors were fabricated with industrial materials and verified by test operations: a Bunsen reactor, a H2SO4 decomposer, and a HI decomposer. Component materials of the reactors were stable in the operation environment. Small amount of H2SO4 in the anolyte solution in an electro-electrodialysis (EED) cell had no negative impact on cell performance parameters. Relationship between cell solution composition and temperature and cell parameters was formulated by experimental data. Demonstration of the test facility with process design of 100 L/h hydrogen production is performed to verify integrity of process components and stability of hydrogen production. Tests of sections were first conducted individually to show material processing rates were controllable. Based on the result, an 8-h continuous operation of the total IS process was performed in February 2016 with H2 production rate of 10 L/h. Demonstrations are planned for longer operation period and higher H2 production rate after improvement of components to prevent troubles.

Novel pyrazolo[1,5- a ]pyridine derivatives were designed, synthesized and evaluated as orally active EP 1 antagonists for the treatment of overactive bladder. Matched molecular pair analysis (MMPA) allowed the design of a new series of pyrazolo[1,5- a ]pyridine derivatives 4 – 6 . Structure-activity relationships (SAR) studies of 4 – 6 were performed, leading to identification of the nanomolar-level EP 1 antagonist 4c , which exhibited good pharmacological effect through intraduodenal (id) administration in a 17-phenyltrinor prostaglandin E2-induced bladder contraction model in rats.

A high-performance, H2-permselective silica membrane derived from hexyltrimethoxysilane (HTMOS) was developed for application in the thermochemical water-splitting iodine–sulfur process. Silica membranes, referred to here as HTMOS membranes, were prepared via counter-diffusion chemical vapor deposition on γ-alumina-coated α-alumina support tubes with outer diameters of 10 mm. Special attention was devoted to obtain high H2/HI selectivity, high H2 permeance, and good stability in the presence of corrosive HI gas. The effects of the deposition conditions, temperature, and period were investigated. The HTMOS membrane prepared at 450 °C for 5 min exhibited high H2/HI selectivity (>175) with H2 permeance on the order of 10−7 mol Pa−1 m−2 s−1. On the basis of stability experiments, it was found that the HTMOS membrane was stable upon HI exposure at a temperature of 400 °C for 11 h.

Autophagy is a dynamic recycling system using lysosomal proteolysis that produces new proteins and energy for cellular renovation and homeostasis. Although macroautophagy is known to serve as a survival pathway in many cancer cells, the role of chaperone-mediated autophagy (CMA), a selective protein degradation system, in cancer is not fully understood. Here, we demonstrated that lysosomal proteolysis, but not macroautophagy, attenuated apoptosis induced by the tyrosine kinase inhibitor, crizotinib, in the non-small-cell lung cancer (NSCLC) cell line, EBC1. In EBC1 cells, crizotinib induced BIM-dependent apoptosis, which was enhanced by inhibition of lysosomal proteolysis. Moreover, degradation of the pro-survival protein, MCL1, by the ubiquitin-proteasome system was induced by inhibition of lysosomal proteolysis, and by inhibition of the expression of the CMA mediators, HSC70 (heat shock cognate protein 70 kDa) and LAMP2A (lysosome membrane protein type 2A), suggesting the existence of a CMA-mediated MCL1 stabilization system in cancer cells. Indeed, the same MCL1 stabilization system was also observed in several NSCLC cell lines; in these cells, their specific molecular-targeted drug or ABT-263 (Navitoclax), the specific inhibitor of BCL-2 and BCL-XL, but not of MCL1, effectively induced apoptosis in combination with CMA inhibition. Therefore, our results indicate a novel mechanism of MCL1 stabilization in lung cancers by CMA, and a candidate efficient combination chemotherapy method against lung cancers.

Cation-exchange membranes (CEMs) were developed using a radiation-grafted polymerization method to improve HI-mediated electro-electrodialysis (EED) in thermochemical water-splitting iodine-sulfur processes. The performance of the HI-mediated reaction was improved using the developed CEMs by introducing divinylbenzene (DVB) as the crosslinker. The effects of the crosslinked CEMs on performance indices such as proton conductivity, transport number, and water permeation factor were investigated. Introducing the crosslinks improved the selectivity of H+ and water transport. The permeation mechanism of the proposed EED model was investigated to determine the role of the crosslinkers in this operation. The results indicated that even though the crosslinkers had little effect on the absorption of the HIx solution and the H+ diffusion coefficient, a notable decrease was observed in the I− diffusion coefficient. The crosslinkers inhibited swelling caused by the absorption of the HIx solution that led to volume changes known to suppress H2O permeation.

Relative dose intensity (RDI) is a simple index for evaluation of the amount of drug administered per unit time. We retrospectively investigated the prognostic impact of RDI for patients with metastatic renal cell carcinoma (mRCC) treated with second-line targeted therapy.We enrolled 168 patients with mRCC. We assessed RDI at 4 weeks after second-line targeted therapy induction.The median follow-up after second-line targeted therapy was 18.1 months. The median time-to-treatment-failure (TTF) and overall survival (OS) were 4.9 and 25.4 months, respectively. In the Kaplan-Meier analysis, the median OS of patients with second-line RDI 0.7 was significantly shorter than those with RDI ≥ 0.7 (12.1 vs. 31.3 months; P = .030). In the subgroup analysis, second-line RDI was definitely prognostic in the poor-risk group of the International Metastatic Renal Cell Carcinoma Database Consortium criteria, showing second-line RDI was an independent predictor for both TTF (hazard ratio [HR], 3.6; 95% confidence interval [CI], 1.6-8.0; P = .002) and OS (HR, 3.1; 95% CI, 1.1-8.4; P = .026). Also, assessing the type of second-line regimen, the multivariate analysis showed that second-line RDI was an independent prognostic indicator of TTF (HR, 1.7; 95% CI, 1.0-2.9; P = .040) and OS (HR, 2.7; 95% CI, 1.3-5.7; P = .009) in patients treated with everolimus. In this group, the median TTF and OS of patients with RDI 0.7 were 2.4 and 11.1 months, and those with RDI ≥ 0.7 were 5.3 and 25.9 months, respectively.The results suggest that second-line RDI may be a prognostic predictor for patients with mRCC treated with second-line targeted therapy, particularly in both the International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and everolimus-treated group.

The relationship between endogenous creatinine clearance (eCrCl) and renal function values obtained using mathematical formulas has not yet been fully elucidated, especially in patients with upper tract urothelial carcinoma that are treated with radical nephroureterectomy followed by cisplatin-based chemotherapy.Sixty patients who received cisplatin-based chemotherapy for locally advanced or metastatic upper tract urothelial carcinoma after radical nephroureterectomy between 2000 and 2012 were retrospectively identified. eCrCl was measured based on 24-hour urine specimens obtained immediately prior to each cycle of chemotherapy. Renal function was estimated with 4 different formulas: the Cockcroft-Gault, Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Wright formulas. We evaluated the relationship between eCrCl and the renal function values obtained with each formula using the Pearson correlation coefficient and κ statistics.The median eCrCl was 53.9 mL/min. The Pearson correlation coefficients and κ statistics for the relationships between eCrCl and the renal function values obtained with each of the mathematical formulas ranged from 0.600 to 0.763 and from 0.29 to 0.67, respectively. Among the patients with eCrCl of ≥ 60 mL/min, 70%, 60%, 50%, and 20% were estimated to have the renal function values of 60 mL/min by the Cockcroft-Gault, Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Wright formulas, respectively.All 4 of the tested formulas underestimated eCrCl. The values obtained with the Wright formula were most closely associated with eCrCl.

Idiopathic pneumonia syndrome (IPS) is an acute lung dysfunction of non-infectious aetiology and a severe complication following haematopoietic stem cell transplantation (HSCT). Recently, the American Thoracic Society (ATS) updated the concept of IPS and extended the concept to a wider range; it defined IPS as "an idiopathic syndrome of pneumopathy after HSCT, with evidence of widespread alveolar injury and in which infectious aetiologies and cardiac dysfunction, acute renal failure, or iatrogenic fluid overload have been excluded." The ATS also categorised the presumed site of primary tissue injury into three patterns (pulmonary parenchyma, vascular endothelium, and airway epithelium), each of which has several entities. Since the therapeutic strategies for IPS are clearly different from those of infectious diseases, and therapeutic delay causes a poor prognosis, radiologists should be aware of some characteristic HRCT findings of IPS, which includes a wide spectrum of entities. In this article, the characteristic HRCT findings of these entities, including acute interstitial pneumonia/acute respiratory distress syndrome, eosinophilic pneumonia, non-cardiogenic capillary leak syndrome, diffuse alveolar haemorrhage, transfusion-related acute lung injury, organising pneumonia, and bronchiolitis obliterans syndrome, are shown.

Forest disturbance (or land-cover change) and climatic variability are commonly recognised as two major drivers interactively influencing hydrology in forested watersheds. Future climate changes and corresponding changes in forest type and distribution are expected to generate changes in rainfall runoff that pose a threat to river catchments. It is therefore important to understand how future climate changes will effect average rainfall distribution and temperature and what effect this will have upon forest types across Japan. Recent deforestation of the present-day coniferous forest and expected increases in evergreen forest are shown to influence runoff processes and, therefore, to influence future runoff conditions. We strongly recommend that variations in forest type be considered in future plans to ameliorate projected climate changes. This will help to improve water retention and storage capacities, enhance the flood protection function of forests, and improve human health. We qualitatively assessed future changes in runoff including the effects of variation in forest type across Japan. Four general circulation models (GCMs) were selected from the Coupled Model Intercomparison Project Phase 5 (CMIP5) ensemble to provide the driving fields: the Model for Interdisciplinary Research on Climate (MIROC), the Meteorological Research Institute Atmospheric General Circulation Model (MRI-GCM), the Hadley Centre Global Environment Model (HadGEM), and the Geophysical Fluid Dynamics Laboratory (GFDL) climate model. The simulations consisted of an ensemble including multiple physics configurations and different reference concentration pathways (RCP2.6, 4.5, and 8.5), the results of which have produced monthly data sets for the whole of Japan. The impacts of future climate changes on forest type in Japan are based on the balance amongst changes in rainfall distribution, temperature and hydrological factors. Methods for assessing the impact of such changes include the Catchment Simulator modelling frameworks based on the Minimal Advanced Treatments of Surface Interaction and Runoff (MATSIRO) model, which was expanded to estimate discharge by incorporating the effects of forest-type transition across the whole of Japan. The results indicated that, by the 2090s, annual runoff will increase above present-day values. Increases in annual variation in runoff by the 2090s was predicted to be around 14.1% when using the MRI-GCM data and 44.4% when using the HadGEM data. Analysis by long-term projection showed the largest increases in runoff in the 2090s were related to the type of forest, such as evergreen. Increased runoff can have negative effects on both society and the environment, including increased flooding events, worsened water quality, habitat destruction and changes to the forest moisture-retaining function. Prediction of the impacts of future climate change on water generation is crucial for effective environmental planning and management.

Two risk models, the Memorial Sloan Kettering Cancer Center (MSKCC) model and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, have been studied in metastatic renal cell carcinoma (mRCC) treated with targeted therapy.To validate externally the predictive accuracies of the MSKCC and IMDC models for prognosis in mRCC patients treated with first-line and subsequent second-line targeted therapy.A total of 311 patients were assessed retrospectively.All patients underwent targeted therapy.Survival outcomes were assessed using Kaplan-Meier analysis. The predictive ability was evaluated using the c-index.Regarding to the first-line targeted therapy, the 3-yr overall survival (OS) rates of the MSKCC (p0.001) and IMDC models (p0.001) were 76.2% and 77.3%, respectively, in the favorable-risk group; 46.7% and 47.9%, respectively, in the intermediate-risk group; and 13.4% and 15.6%, respectively, in the poor-risk group. The c-indexes were 0.68 for the MSKCC model and 0.69 for the IMDC model in a first-line setting. Regarding the second-line targeted therapy, the 1-yr OS rates of the MSKCC (p0.001) and IMDC models (p0.001) were 80.9% and 90.5%, respectively, in the favorable-risk group; 71.4% and 70.6%, respectively, in the intermediate-risk group; and 31.7% and 24.6%, respectively, in the poor-risk group. The c-indexes were 0.66 for the MSKCC model and 0.65 for the IMDC model in the second-line setting. The study is limited by its retrospective nature.The results may assist physicians in providing more appropriate patient counseling and imply the need for a future prognostic tool in mRCC treated with targeted therapy.Both risk models were useful for the risk stratification in metastatic renal cell carcinoma (mRCC) patients treated with first-line and second-line targeted therapy; however, it might be necessary to further update or optimize the models for our Japanese cohort of mRCC patients.

Three anthocyanins, four flavonols, three aromatic acids and five gallotannins were isolated from Sapria himalayana f. albovinosa in Myanmar. They were identified as cyanidin 3-O-glucoside (1), cyanidin 3-O-xyloside (2) and peonidin 3-O-glucoside (3) (anthocyanins), quercetin 3-O-glucoside (4), quercetin 7-O-glucoside (5), quercetin 3-O-glucuronide (6) and isorhamnetin 3-O-glucoside (7) (flavonols), ellagic acid (8), gallic acid (9) and ethyl gallate (10) (aromatic acids), and 1,2,4,6-tetragalloylglucose (11), 1,4,6-trigalloylglucose (12), 1,2,6-trigalloylglucose (13), 1,2,4-trigalloylglucose (14) and 1,6-digalloylglucose (15) (gallotannins) by UV, LC-MS, acid hydrolysis, NMR and/or HPLC comparisons with authentic samples. The chemical composition of S. myanmarensis was qualitatively the same with that of S. himalayana f. albovinosa. Phenolic compounds of the Rafflesiaceae species including Sapria, Rafflesia and Rhizanthes were isolated and identified in this survey for the first time.

Japan Atomic Energy Agency (JAEA) has been conducting RD one of the important materials is the glass-lined steel for corrosion resistant components such as vessels, pipes and protective sheaths of sensors. This report will present technical matters to improve reliability of the glass-lined protective sheaths of thermocouple. In addition, results of quality confirmation will be presented, which are stress analyses for the glass layer by FEM, tests for heat cycle, bending load and corrosion.

Japan Atomic Energy Agency (JAEA) has been conducting R&D on the thermochemical iodine–sulfur (IS) process for nuclear-powered hydrogen production. The IS process is one of the promising candidates of heat application of the high-temperature gas-cooled reactors. JAEA achieved continuous hydrogen production for one week with a hydrogen production rate of approximately 20 NL/h by using a test apparatus made of glass and fluororesin material. Subsequently, as a next step, JAEA fabricated main chemical reactors made of industrial structural materials and confirmed their integrity in practical corrosive environments in the IS process. Based on the results of these confirmation tests, JAEA has constructed a 100 NL/h-H2-scale test facility made of industrial structural materials. This paper presents an outline and results of hydrogen production tests by using the test facility and reliability improvements by developing a strength estimation method for heat-resistant and corrosion-resistant ceramics components made of silicon carbide.

Background Previous studies showed the prognostic impact of preoperative levels of neutrophil-to-lymphocyte ratio (NLR), plasma fibrinogen, and serum C-reactive protein (CRP) in surgically treated upper tract urothelial carcinoma; however, few papers have discussed the proper use of these indices. Objective To investigate whether combinations of these three markers, as a cumulative marker score (CMS), improve the accuracy of prognostic models following radical nephroureterectomy (RNU). Design, setting, and participants A total of 394 patients from multiple institutions were included. Median follow-up was 30 mo. Intervention All patients underwent RNU without neoadjuvant chemotherapy. Outcome measurements and statistical analysis Associated outcomes were assessed using multivariate analysis. The CMS was defined as the number of elevated levels of preoperative NLR, plasma fibrinogen, and serum CRP. Results and limitations Multivariate analyses revealed that an increasing CMS was independently associated with high rates of disease recurrence, cancer-specific mortality, and all-cause mortality following RNU. Addition of the CMS to a model that included standard clinicopathologic predictors significantly improved predictive accuracy by 2.7% for disease recurrence, 3.9% for cancer-specific mortality, and 4.0% for all-cause mortality, which were the highest among other prognostic models using each marker alone or combinations of two. The study is limited by its retrospective nature. Conclusions Although the use of each inflammatory marker alone may be as predictive as clinicopathologic indices for prognosis, combinations like CMS can provide more accurate prognostic models following RNU. Patient summary Elevation of blood-based inflammatory markers may be useful for predicting prognosis because of their low cost and accessibility. Among blood-based indices, we examined the efficacy of preoperative neutrophil-to-lymphocyte ratio, plasma fibrinogen, and serum C-reactive protein levels. Although use of each marker alone provides additional prognostic information, the combination of all three markers would be more predictive than any single marker or combinations of two.

Even among patients considered to be functionally eligible for major lung resection, some experience postoperative dyspnea. Based on our previous study with quantitative computed tomography (CT), we hypothesized that postoperative dyspnea is associated with the collapse of the remaining lung, and thus, prediction of the postoperative lung volume may contribute to risk assessment for postoperative dyspnea.We measured the emphysematous lung volume and functional lung volume (FLV) separately on whole lung CT using an image analysis software in 290 patients undergoing major lung resection for cancer between January 2006 and December 2012. The postoperative FLV was predicted by a stepwise multiple regression analysis.Fourteen patients complained of postoperative dyspnea (complicated group), five of them presented with chronic respiratory failure. The postoperatively measured FLV was significantly lower in the complicated group than in the control group (P 0.01). The postoperative FLV could be calculated using preoperative variables, including the forced vital capacity, number of resected segments, FLV, and emphysematous lung volume. The predicted postoperative FLV was significantly lower in the complicated group than in the control group (P 0.01, area under the curve = 0.78; sensitivity 86%; specificity 73%). The predicted postoperative FLV was also useful in distinguishing complicated patients from matched-control patients who had similar preoperative pulmonary function (P = 0.02).Postoperative dyspnea is likely accompanied by a collapse of the remaining lung. Quantitative assessment of the lung morphology on preoperative CT is useful to screen for patients at risk of postoperative dyspnea.

EGFR is an important therapeutic target for non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, are effective in cases with EGFR-activating mutations. However, most such cases become resistant through a secondary EGFR mutation, T790M. While the second-generation TKI afatinib has a higher affinity for double-mutant EGFRs, better efficacy is needed. Combining afatinib with the anti-EGFR monoclonal antibody cetuximab improves clinical outcomes, but the mechanism is unclear. Here we examined this effect using erythroleukemic K562 cells. The activating EGFR mutation L858R is sensitive to first-generation TKIs, and adding T790M confers resistance to these drugs. This double-mutant EGFR was moderately sensitive to afatinib, but responded weakly to cetuximab. Combined afatinib and cetuximab synergistically increased their cytotoxicity for K562 cells expressing the double-mutant EGFR. Apoptosis in these cells followed induction of the pro-apoptotic protein BIM. Unexpectedly, afatinib caused redistribution of EGFR to the cell surface through Rab11a-dependent recycling. Cetuximab reduced cell-surface EGFR, and total EGFR decreased synergistically when cetuximab was combined with afatinib. Our results suggest that the synergistic effect exerted by afatinib and cetuximab on NSCLCs is associated with BIM induction and alterations in EGFR status.

To investigate whether a footbath inhibits spasticity in the hemiplegic lower limbs of post-stroke patients.Randomized, controlled study.Rehabilitation education and research hospital.Twenty-two post-stroke patients were randomly allocated to control or experimental groups. After relaxing in a supine posture for 30min, the experimental group subject's legs were immersed in 41°C water below the knee joint for 15min, while the control group remained in a resting posture.Modified Ashworth Scale (MAS) scores of the affected triceps surae muscle and F-wave parameters (i.e., F-wave amplitude, F/M ratio, and F-wave persistence) were recorded before, immediately after, and 30min after each intervention. Physiological parameters were simultaneously monitored to determine the thermo-therapeutic mechanisms and side effects of footbath usage.At the time immediately after the intervention, F-wave amplitudes decreased significantly in the experimental group, compared to the control group (p0.01, difference: -106.8; 95% CI; -181.58 to -32.09). F-wave amplitudes decreased significantly after 30-min intervention in the experimental group, with a total reduction of 161.2μV being recorded compared to 8.8μV increase in the control group (p0.01, difference: -170.0; 95% CI; -252.73 to -87.33). There were also significant differences between the experimental and control group for both F/M ratio and F-wave persistence, immediately after and 30min after the intervention. Further, there were significant differences between the experimental and control group for the MAS scores immediately after the intervention (p0.05, difference: -0.72; 95% CI; -1.262 to -0.193), and 30min after the intervention (p0.05, difference: -0.73; 95% CI; -1.162 to -0.293).These findings demonstrate that the use of footbaths is an effective non-pharmacological anti-spastic treatment for use in stroke rehabilitation.

The ESCRT-0 complex, consisting of the hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and the signal-transducing adaptor molecule (STAM) proteins, recognizes ubiquitylated cargo during the initial step of endosomal sorting. The endosomal accumulation of overexpressed Hrs has been reported previously to be associated with endosome enlargement. In this study, we have found that co-expressing exogenous STAM1 in Hrs-overexpressing cells leads to a diffuse localization for a large part of the Hrs accumulated on endosomes and a recovery of the impaired cargo protein degradation process, thus suggesting that exogenous STAM abrogates the abnormalities of the Hrs-positive endosomes. A fluorescently labeled Hrs, introduced into the cells by membrane permeabilization, exhibited endosomal localization in the absence of STAM1 and gradually dissociated from the endosomes upon the sequential addition of recombinant STAM1. Furthermore, when microinjected into cells, the fluorescently labeled Hrs also showed endosomal accumulation; however, ESCRT-0 complexes formed prior to the microinjection did not. Analysis of the state of the complex in HeLa cells using blue-native PAGE revealed that the membrane-associated Hrs exists partly as a monomer and not only in the STAM1-bound form. Thus, our data suggest that the membrane binding and dissociation cycle of the ESCRT-0 proteins on the endosomal membrane is a critical step during the cargo sorting process.