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Various tubular diseases in patients with multiple myeloma (MM) are caused by monoclonal immunoglobulin light chains (LCs). However, the physicochemical characteristics of the disease-causing LCs contributing to the onset of MM-associated tubular diseases remain unclear. We herein report a rare case of MM-associated combined tubulopathies: non-crystalline light chain proximal tubulopathy (LCPT) and crystalline light chain cast nephropathy (LCCN). The patient's urinary κ-LC (Bence-Jones proteins, BJP-κ PT-CN) was detected through immunofixation. Renal biopsy revealed cytoplasmic vacuoles in swollen proximal tubular cells and distal tubular casts. Immunohistochemistry showed proximal tubular reabsorption granules and distal tubular casts positively stained with an anti-κ-LC antibody. Electron microscopy identified vacuolation and an increased number of lysosomes in proximal tubular epithelial cells without crystalline structures. Distal tubular casts comprised numerous crystals with both rod-shaped and needle-like configurations and tube-shaped materials. To elucidate the molecular mechanisms underlying tubular toxicity, we performed the following physicochemical analyses of BJP-κ PT-CN: N-terminal amino acid sequencing, cDNA cloning, size-exclusion chromatography, thermal shift assays, and X-ray crystallography. The variable segment of BJP-κ PT-CN was derived from the IGKV1-39 gene. The characteristic features of BJP-κ PT-CN were a positively charged surface patch, concentration-dependent monomer-dimer equilibrium, and the R61G mutation. This is the first biochemical and structural characterization of disease-causing BJPs in MM-associated LCPT and crystalline LCCN. The results obtained suggest that these characteristic features enhance protein binding to negatively charged sites on brush-border membranes in proximal tubules and promote the formation of organized casts in distal tubular lumens., (© 2025 Federation of American Societies for Experimental Biology.)

As the demand for polycarbonate (PC) plastic increases over the years, the development of a chemical recycling system to produce virgin-like-quality monomers is indispensable not only to attain completely sustainable cycles but also to contribute to the decrease in global plastic pollution. Herein, potassium carbonate (K 2 CO 3 ) was used as a low-cost, readily available, and highly active solid base catalyst for low-temperature PC methanolysis in the presence of THF as a solvent, producing highly pure and crystalline bisphenol A (BPA) and with a catalytic performance higher than group IIA metal oxides (MgO, CaO, and SrO) and some group IA metal carbonates (NaHCO 3 , KHCO 3 , and Na 2 CO 3 ). THF was the best solvent in aiding the reaction owing to it having a similar polar parameter (δ p ) to that of PC according to Hansen solubility parameters. By the reaction over the catalyst, 100% PC conversion, 97% BPA yield, and 86% dimethyl carbonate yield were achieved within just 20 min at 60 °C. The catalyst possessed an apparent activation energy (E a ) of 52.3 kJ mol -1 , which is the lowest value so far for heterogeneous catalysts, while the mechanistic study revealed that the reaction proceeded via the methoxide pathway. The reusability test demonstrated that the catalyst was reusable at least four times. Furthermore, this catalytic system was successfully applied to actual post-consumer PC wastes and polyesters, including polyethylene terephthalate (PET) and polylactic acid (PLA)., (© 2024 Wiley-VCH GmbH.)

Background: Pancreatic cancer is often diagnosed at advanced stages, and early-stage diagnosis of pancreatic cancer is difficult because of nonspecific symptoms and lack of available biomarkers., Methods: We performed comprehensive serum miRNA sequencing of 212 pancreatic cancer patient samples from 14 hospitals and 213 non-cancerous healthy control samples. We randomly classified the pancreatic cancer and control samples into two cohorts: a training cohort (N = 185) and a validation cohort (N = 240). We created ensemble models that combined automated machine learning with 100 highly expressed miRNAs and their combination with CA19-9 and validated the performance of the models in the independent validation cohort., Results: The diagnostic model with the combination of the 100 highly expressed miRNAs and CA19-9 could discriminate pancreatic cancer from non-cancer healthy control with high accuracy (area under the curve (AUC), 0.99; sensitivity, 90%; specificity, 98%). We validated high diagnostic accuracy in an independent asymptomatic early-stage (stage 0-I) pancreatic cancer cohort (AUC:0.97; sensitivity, 67%; specificity, 98%)., Conclusions: We demonstrate that the 100 highly expressed miRNAs and their combination with CA19-9 could be biomarkers for the specific and early detection of pancreatic cancer., (© 2024. The Author(s).)

Kumada cross-coupling reaction is useful for producing biphenyls, where nickel and copper have been widely investigated as catalysts but mainly homogeneous ones. In this study, we investigated ultrasound-assisted-Kumada cross-coupling reaction over the heterogeneous catalysts in which Ni 2+ , Cu 2+ , or both was immobilized on aminopropylsilane-functionalized-SiO 2 -TiO 2 prepared in the presence of cetyltrimethylammonium bromide (CTAB). The presence of CTAB effectively prevented the particle growth and therefore SiO 2 -TiO 2 fine particles with high surface area (502 m 2  g -1 ) were formed. The Ni 2+ -immobilized catalyst showed high catalytic activity for the ultrasound-assisted-Kumada cross-coupling reaction of a wide variety of substrates and was reusable three times. Performing the reaction under ultrasound irradiation was very effective in significantly accelerating the reaction rate compared with the conventional mechanical method. In contrast to Ni 2+ , Cu 2+ was deposited on the support as crystalline Cu(OH) 2 and the resulting catalysts with Cu 2+ and Ni 2+ -Cu 2+ were less active and less stable under the reaction conditions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

α-Synuclein (α-Syn) is a protein related to synucleinopathies with high expression in the central nervous system and erythrocytes which are a major source of peripheral α-Syn. Recent reports have suggested the presence of α-Syn within extracellular vesicles (EVs) derived from erythrocytes, potentially contributing to the pathogenesis of synucleinopathies. While Lewy bodies, intracellular inclusions containing aggregated α-Syn, are prominently observed within the brain, their occurrence in peripheral neurons implies the dissemination of synucleinopathy pathology throughout the body via the propagation of α-Syn. In this study, we found erythrocytes and circulating EVs obtained from plasma contained α-Syn, which was separated into four major forms using high-resolution clear native-PAGE and isoelectric focusing. Notably, erythrocyte α-Syn was classified into full-length and C-terminal truncated forms, with truncation observed between Y133 and Q134 as determined by LC-MS/MS analysis. Our finding revealed that C-terminally truncated α-Syn, which was previously reported to exist solely within the brain, was also present in erythrocytes and circulating EVs obtained from plasma., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Herein, a low-cost and readily available sodium aluminate (NaAlO 2 ) was used as a solid base catalyst for the depolymerization of polycarbonate (PC) via methanolysis in the presence of tetrahydrofuran (THF) as a solvent. NaAlO 2 was highly active for the reaction, and the performance was comparable to that of soluble strong base SrO and much higher than those of MgO and CaO. By the reaction over the catalyst, a highly pure and crystalline bisphenol A (BPA) was obtained. Among tested organic solvents, THF was the best in aiding PC methanolysis over NaAlO 2 due to the polarity similar to PC according to Hansen solubility parameters (HSPs). At 60 °C, 98.1% PC conversion and 96.8% BPA yield were achieved within just 2 h. NaAlO 2 was reusable without any severe catalyst deactivation in at least four runs. The mechanistic study revealed that the reaction proceeded via the methoxide pathway, with THF aiding the dissolution of PC. The reaction over NaAlO 2 possessed a low apparent activation energy ( E a ) of 75.1 kJ mol -1 , which is the lowest ever reported so far for the reaction over solid catalysts.

Background: The establishment of a formal diagnosis of post-traumatic stress disorder (PTSD) for children and adolescents is the foundation for advancing pertinent clinical research and formulating proper treatment and management. However, a validated diagnostic tool for PTSD in children and adolescents is lacking in Japan. Objective: To examine the cross-cultural validity and reliability of the Japanese Clinician-Administered PTSD Scale for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), child and adolescent version (CAPS-CA-5-J). Method: Overall, 73 children who had experienced potentially traumatic events were recruited from three medical facilities. The linguistically validated CAPS-CA-5-J was conducted by trained psychiatrists and psychologists. Additionally, children and their caretakers completed questionnaires such as the UCLA PTSD reaction index for DSM-5 (PTSD-RI-5), Depression Self-Rating Scale for Children (DSRDC), and Strength and Difficulties Questionnaire (SDQ); 16 participants were randomly selected for the inter-rater reliability assessment. Results: Owing to missing values in the CAPS-CA-5-J and PTSD-RI-5, 68 children were included in the final analysis. Regarding reliability, the CAPS-CA-5-J showed excellent internal consistency (Cronbach's alpha coefficient = 0.90) and interrater agreement (kappa coefficient = 0.88). Convergent validity was supported by a strong correlation between the total severity scale of the CAPS-CA-5-J and the PTSD-RI-5 scores (Pearson's correlation coefficient = 0.82). Divergent validity was indicated by a moderate correlation between the CAPS-CA-5-J and DSRDC, and no correlation was found with the SDQ scores. Conclusions: This study is the first to validate a structured clinical interview for children and adolescents with PTSD in Japan. The psychometric properties of the CAPS-CA-5-J were good enough and comparable to those reported in previous validation studies. Therefore, the CAPS-CA-5-J can be considered reliable and valid for use in Japan.

Purpose:  Less-invasive early diagnosis of lung cancer is essential for improving patient survival rates. The purpose of this study is to demonstrate that serum comprehensive miRNA profile is high sensitive biomarker to early-stage lung cancer in direct comparison to the conventional blood biomarker using next-generation sequencing (NGS) technology combined with automated machine learning (AutoML)., Methods: We first evaluated the reproducibility of our measurement system using Pearson's correlation coefficients between samples derived from a single pooled RNA sample. To generate comprehensive miRNA profile, we performed NGS analysis of miRNAs in 262 serum samples. Among the discovery set (57 patients with lung cancer and 57 healthy controls), 1123 miRNA-based diagnostic models for lung cancer detection were constructed and screened using AutoML technology. The diagnostic faculty of the best performance model was evaluated by inspecting the validation samples (74 patients with lung cancer and 74 healthy controls)., Results: The Pearson's correlation coefficients between samples derived from the pooled RNA sample ≥ 0.98. In the validation analysis, the best model showed a high AUC score (0.98) and a high sensitivity for early stage lung cancer (85.7%, n = 28). Furthermore, in comparison to carcinoembryonic antigen (CEA), a conventional blood biomarker for adenocarcinoma, the miRNA-based model showed higher sensitivity for early-stage lung adenocarcinoma (CEA, 27.8%, n = 18; miRNA-based model, 77.8%, n = 18)., Conclusion: The miRNA-based diagnostic model showed a high sensitivity for lung cancer, including early-stage disease. Our study provides the experimental evidence that serum comprehensive miRNA profile can be a highly sensitive blood biomarker for early-stage lung cancer., (© 2023. The Author(s).)

Membrane emulsification using anodic porous alumina is an effective method for preparing monodisperse droplets with controlled sizes. In this study, membrane emulsification using anodic porous alumina was applied to the preparation of size-controlled particles composed of composite metal oxides. To obtain size-controlled composite metal oxide particles, membrane emulsification was performed using an aqueous solution containing a water-soluble monomer and metal salts as a dispersed phase. After the membrane emulsification, composite metal oxide particles were obtained by solidifying the droplets in a continuous phase and subsequent heat treatment. Here, as a demonstration of this process, the fabrication of size-controlled LiCoPO 4 particles, which are considered high-potential cathode active materials for Li-ion secondary batteries (LIBs), was investigated. The application of the obtained LiCoPO 4 particles as cathode active materials for LIBs was also investigated. The results of this study showed that LiCoPO 4 particles with controlled sizes could be fabricated on the basis of this process and that their cathode properties could be improved by optimizing the heat treatment conditions and particle sizes. According to this process, size-controlled particles composed of various metal oxides can be fabricated by changing the metal salt in the dispersed phase, and the resulting size-controlled particles are expected to be applied not only as cathode active materials for LIBs but also as components of various functional devices., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

α-Synuclein is a protein linked to various synuclein-associated diseases ('synucleinopathies'), including Parkinson's disease, dementia with Lewy Bodies and multiple system atrophy, and is highly expressed in the central nervous system and in erythrocytes. Moreover, α-synuclein-containing erythrocyte-derived extracellular vesicles may be involved in the pathogenesis of synucleinopathies and their progression across the blood-brain barrier. Several post-translational modifications of α-synuclein have been reported in brain inclusions, including S129 phosphorylation, but fewer have been found in erythrocytes. In this study, we analysed the post-translational modifications of erythrocyte α-synuclein using liquid chromatography-mass spectrometry. We found that all lysine residues in the α-synuclein protein could be modified by acetylation, glycation, ubiquitination or SUMOylation but that phosphorylation, nitration and acylation were uncommon minor post-translational modifications in erythrocytes. Since the post-translational modification of lysine residues has been implicated in both membrane association and protein clearance, our findings provide new insight into how synucleinopathies may progress and suggest possible therapeutic strategies designed to target α-synuclein., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Background: Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline., Methods: In this cross-sectional study, we enrolled Japanese non-centenarians (eligible participants aged 20-80 years) from the Tohoku Medical Megabank Community-Based Cohort Study and centenarians and supercentenarians (aged 101-115 years) from the Tokyo Centenarian Study and the Japanese Semi-supercentenarian Study. We assessed participants' whole-blood DNA methylation profiles and then developed sex-specific and non-specific first-generation epigenetic clocks by elastic net regression, calculated individuals' epigenetic ages, and assessed their age acceleration. We also screened for age-related CpG sites in non-centenarians by epigenome-wide linear regression analyses and ANOVA. We subsequently investigated which CpG sites in centenarians and supercentenarians had DNA methylation patterns following the age-related findings obtained from non-centenarians and which did not. We further characterised CpG sites with hypermethylation or hypomethylation in the centenarians and supercentenarians using enrichment and protein-protein interaction network analyses., Findings: We enrolled 421 non-centenarians (231 [55%] women and 190 [45%] men; age range 20-78 years), recruited between May 20, 2013, and March 31, 2016, and 94 centenarians and supercentenarians (66 women [70%] and 28 [30%] men; age range 101-115 years), recruited between Jan 20, 2001, and April 17, 2018. Non-sex-specific epigenetic clock showed the highest accuracy (r=0·96) based on which centenarians and supercentenarians had negative epigenetic age acceleration. Epigenome-wide association analyses further showed that centenarians and supercentenarians had younger-than-expected epigenetic states (DNA methylation profiles similar to those of non-centenarians) for 557 CpG sites enriched in cancer-related and neuropsychiatric-related genes, whereas these individuals had advanced (or older) epigenetic states for 163 CpG sites represented by genes related to TGF-β signalling, which is involved in anti-inflammatory responses and known to contribute to healthy ageing., Interpretation: These results indicate that exceptionally healthy longevity depends not only on maintaining young epigenetic states but also on advanced states of specific epigenetic regions., Funding: The Japan Agency for Medical Research and Development, KDDI Research, and Keio University., Translation: For the Japanese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests SK reports a grant from the Japan Society for the Promotion of Science (JSPS), unrelated to the current work. MN reports salary support from KDDI Corporation, the parent company of KDDI Research. EA reports a grant from JSPS, unrelated to the current work. RO reports a grant from JSPS unrelated to the current work. HOh reports grants from JSPS and the Japan Agency for Medical Research and Development (AMED), unrelated to the current work. SU reports a grant from JSPS, unrelated to the current work. TH reports participation in the board of Genome Analytics Japan, unrelated to of the current work. YS reports a grant from JSPS, unrelated to the current work. YO-Y reports a grant from JSPS, unrelated to the current work. YAr reports grants from JSPS and AMED, unrelated to the current work. AY reports salary support from KDDI. HOk reports involvement as a scientific advisor of SanBio and K Pharma and a grant from AMED, unrelated to of the current work. MS reports grants from JSPS, unrelated to the current work, and from AMED for the current work. YK reports grants from JSPS and AMED, unrelated to the current work, and from Keio University for the current work. AS reports grants from JSPS, AMED, National Cancer Center Japan, IQVIA, and Fujifilm, unrelated to the current work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

We performed numerical experiments to investigate the mixing of stratified suspensions composed of different particle types by gravitational sedimentation. The mixing process is controlled by a dimensionless group Y_{m}∼U_{f}/U_{St1}, where U_{f} is a typical velocity of a macroscopic sedimenting finger and U_{St1} is the Stokes settling velocity of a single spherical particle in the upper suspension. The effects of components of Y_{m}, in particular, terminal velocities of particles, were investigated. For Y_{m}=100, no large difference was observed for the difference of components of Y_{m}, and it was confirmed that the mixing rate is determined by Y_{m}, because macroscopic (vessel-scale) mixing is dominant for large Y_{m}. For Y_{m}=5, macroscopic mixing and microscopic (individual particle-level) mixing due to the particle terminal velocity difference are of the same order, while completely different mixing patterns were observed for positive, zero, and negative terminal velocity differences: macroscopic mixing is promoted by the increase in apparent density due to microscopic mixing, small macroscopic mixing is suppressed by the individual particle settling, and jetting mixing occurs owing to pure liquid layer formation.

Background: Skills Training in Affective and Interpersonal Regulation (STAIR) Narrative Therapy (SNT) has shown efficacy in alleviating symptoms of posttraumatic stress disorder (PTSD) and improving emotion regulation and interpersonal skills among individuals with complex trauma, such as childhood abuse. Although this therapy is expected to be effective for patients with complex PTSD (CPTSD), no study has directly assessed diagnostic and symptom outcomes. Moreover, the potential of therapy to achieve good outcomes in non-Western countries remains unclear., Objective: This pilot study examined the feasibility, safety, and outcomes of SNT for CPTSD among women with a history of childhood abuse in a Japanese clinical setting., Methods: Ten women aged 21-54 years ( M  = 29.1 years) with childhood-abuse-related ICD-11 CPTSD were enrolled in this study. The International Trauma Interview and International Trauma Questionnaire were administered to diagnose CPTSD and assess its severity. Symptoms of dissociation and depression, difficulties in emotion regulation and interpersonal relationships, quality of life, and negative cognitions were assessed pretreatment, midtreatment (after the STAIR phase), and immediately posttreatment (after the Narrative Therapy phase), in addition to 3 months after treatment., Results: Seven of the 10 participants completed the treatment. The therapists' adherence to the therapy protocol was 96.4%, ranging from 93.6% to 100% across therapists. Serious adverse events were not observed. Among the seven completers, six at posttreatment and all at follow-up no longer met CPTSD diagnosis. Exploratory analyses using the linear mixed-effects model showed significant improvements at posttreatment and follow-up for almost all the variables., Conclusions: The results provide preliminary evidence for the feasibility and safety of SNT for CPTSD in a Japanese clinical setting. This study is the first to report the use of SNT for individuals diagnosed with ICD-11 CPTSD using reliable clinician and self-report measures., Highlights: This study examined the feasibility and safety of STAIR Narrative Therapy for women with ICD-11 CPTSD related to childhood abuse in a Japanese clinical setting.High therapy adherence was observed.No serious adverse events occurred., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: The use of heated tobacco products (HTP) has increased exponentially in Japan since 2016; however, their effects on health remain a major concern., Methods: Tsuruoka Metabolome Cohort Study participants ( n = 11,002) were grouped on the basis of their smoking habits as never smokers (NS), past smokers (PS), combustible tobacco smokers (CS), and HTP users for <2 years. Peripheral blood mononuclear cells were collected from 52 participants per group matched to HTP users using propensity scores, and DNA and RNA were purified from the samples. DNA methylation (DNAm) analysis of the 17 smoking-associated DNAm biomarker genes (such as AHRR , F2RL3 , LRRN3 , and GPR15 ), as well as whole transcriptome analysis, was performed., Results: Ten of the 17 genes were significantly hypomethylated in CS and HTP users compared with NS, among which AHRR , F2RL3 , and RARA showed intermediate characteristics between CS and NS; nonetheless, AHRR expression was significantly higher in CS than in the other three groups. Conversely, LRRN3 and GPR15 were more hypomethylated in HTP users than in NS, and GPR15 expression was markedly upregulated in all the groups when compared with that in NS., Conclusions: HTP users (switched from CS <2 years) display abnormal DNAm and transcriptome profiles, albeit to a lesser extent than the CS. However, because the molecular genetic effects of long-term HTP use are still unknown, long-term molecular epidemiologic studies are needed., Impact: This study provides new insights into the molecular genetic effects on DNAm and transcriptome profiles in HTP users who switched from CS., (©2021 The Authors; Published by the American Association for Cancer Research.)

To separate and collect microparticles such as cells, the behavior of particles in fibrous filters was investigated. It is essential to understand, in detail, the motion of particles in microscale flows, because Re is often small, and particles exhibit complex behaviors such as changes in relative position and spreading owing to hydrodynamic interactions. We calculated the motion of microparticles passing through the fibrous bed using the Stokesian dynamics method, in which hydrodynamic interaction is considered, theoretically. The fibrous bed was modeled by particles and five types of structures (a monolayer with fiber volume fractions φ of 3%, 4%, and 5%, and a bilayer with φ = 3%-5% and 5%-3%) were considered. Our numerical results showed that the particles moved in a complicated manner, and spread throughout the fibrous bed. It was found that the behavior of individual microparticles varied depending on the internal structure, although the average permeation velocity was primarily determined by the fiber volume fraction. This great dependence of the behavior of particle assemblage on the internal structure of the fibrous bed was caused by the individual particle motion under the influence of the layers in front of and behind them, owing to the hydrodynamic interaction.

A metal-organic framework (MOF) consisting of Cu-benzenetricarboxylic acid was processed under ultrahigh pressure (5 GPa) and at temperature of up to 500 °C. The products were characterized with TEM, FTIR, and XAFS. The decomposition of the MOF started at 200 °C at 5 GPa. This temperature was much lower than that in the vacuum. Single-nanometer Cu nanoparticles were obtained in carbon matrix, which was significantly smaller than the Cu particles prepared at ambient pressure. The catalytic activity for Huisgen cycloaddition was examined, and the sample processed at 5 GPa showed a much improved performance compared with that of the MOF-derived Cu nanoparticles prepared without high pressure.

The purpose of this study was to investigate the association between xanthine oxidoreductase (XOR) activity and a high risk of cardiovascular disease (CVD) in a general Japanese population. The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a general population-based cohort study in Iwate prefecture. The cardiovascular risk was calculated using the Framingham Risk Score (FRS). A total of 1605 of the 1631 participants (98.4%) had detectable XOR activity. Multiple regression analysis demonstrated that XOR activity was independently associated with body mass index (β = 0.26, p < 0.001), diabetes (β = 0.09, p < 0.001), dyslipidemia (β = 0.08, p = 0.001), and uric acid (β = 0.13, p < 0.001). Multivariate analysis showed that the highest quartile of XOR activity was associated with a high risk for CVD (FRS ≥ 15) after adjustment for baseline characteristics (OR 2.93, 95% CI 1.16-7.40). The area under the receiver operating characteristic curves of the FRS with XOR activity was 0.81 ( p = 0.008). XOR activity is associated with a high risk for CVD, suggesting that high XOR activity may indicate cardiovascular risk in a general Japanese population.

Alongside TiO 2 , Magneli-phase titanium suboxide having the composition of Ti n O 2 n -1 is a kind of attractive functional materials composed of titanium. However, there still remain problems to be overcome in the synthesis of titanium suboxide; the existing synthesis methods require high temperature typically over 1000 °C and/or postsynthesis purification. This study presents a novel approach to synthesis of titanium suboxide nanoparticles through solid-phase reaction of TiO 2 with TiH 2 . Crystal phases of titanium suboxide were easily controlled by changing TiO 2 /TiH 2 molar ratios in a TiO 2 -TiH 2 mixed precursor, and a series of titanium suboxide nanoparticles including Ti 2 O 3 , Ti 3 O 5 , Ti 4 O 7 , and Ti 8 O 15 were successfully obtained. The reaction of TiO 2 with TiH 2 proceeded at a relatively low temperature due to the high reactivity of TiH 2 , giving titanium suboxide nanoparticles without any postsynthesis purification. Ti 2 O 3 nanoparticles and TiO 2 were applied as solid acid catalysts for reaction of furfural with 2-propanol. Ti 2 O 3 showed a high catalytic activity and high selectivity for acetalization of furfural, while TiO 2 showed only poor activity for transfer hydrogenation of furfural. The difference in catalytic properties is discussed in terms of the acid properties of Ti 2 O 3 and TiO 2 .

Nobiletin is a one of the polymethoxyflavones contained in the peel of citrus fruits, such as Citrus depressa. In this study, the effect of nobiletin-induced relaxation on phenylephrine (PE)-induced contraction of endothelium-denuded rat aorta was investigated. Nobiletin inhibited PE- or KCl-induced contractions in a concentration-dependent manner in endothelium-intact and -denuded aortas. However, this relaxation was stronger in PE-induced contractions than in KCl-induced contractions; moreover, the nobiletin-induced relaxation was significantly increased on PE-induced contraction in endothelium-intact aorta. ODQ significantly inhibited the nobiletin-induced relaxation in endothelium-denuded aorta; however, SQ22536 did not affect the relaxation. In addition, IBMX synergistically enhanced the nobiletin-induced relaxation. Nobiletin increased cGMP levels in aorta. Also, IBMX significantly increased cGMP content in aorta, and ODQ significantly reduced cGMP levels. Nobiletin-induced relaxation was significantly inhibited by the Ca 2+ -activated K + (BK) channel inhibitor iberiotoxin (IbTX) and the ATP-sensitive K + (K ATP ) channel inhibitor glybenclamide. Sodium nitroprusside-induced relaxation was suppressed by IbTX, but not by glybenclamide. These results suggest that nobiletin inhibits PE-induced contractions of endothelium-denuded rat aorta by increasing cGMP levels via GC activation. Moreover, the present findings indicate the possibility that nobiletin opened BK channels by a cGMP-related signal, but K ATP channels were opened by a cGMP-nonrelated signal in rat aorta., (Copyright © 2019 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Anaplastic lymphoma kinase (ALK) is an oncogenic receptor tyrosine kinase that is activated by gene amplification and mutation in neuroblastomas. ALK inhibitors can delay the progression of ALK-driven cancers, but are of limited use owing to ALK inhibitor resistance. Here, we show that resistance to ALK inhibitor in ALK-driven neuroblastomas can be attenuated by combination treatment with a p53 activator. Either ALK inhibition or p53 activator treatment induced cell cycle arrest, whereas combination treatment induced apoptosis, and prevented tumour relapse both in vitro and in vivo. This shift toward apoptosis, and away from cell-cycle arrest, in the presence of an ALK inhibitor and a p53 activator, is mediated by inhibition of the ALK-AKT-FOXO3a axis leading to a specific upregulation of SOX4. SOX4 cooperates with p53 to upregulate the pro-apoptotic protein PUMA. These data therefore suggest a novel combination therapy strategy for treating ALK-driven neuroblastomas., Competing Interests: The authors declare that they have no conflict of interest.

We launched an integrative multi-omics database, iMETHYL (http://imethyl.iwate-megabank.org). iMETHYL provides whole-DNA methylation (~24 million autosomal CpG sites), whole-genome (~9 million single-nucleotide variants), and whole-transcriptome (>14 000 genes) data for CD4 + T-lymphocytes, monocytes, and neutrophils collected from approximately 100 subjects. These data were obtained from whole-genome bisulfite sequencing, whole-genome sequencing, and whole-transcriptome sequencing, making iMETHYL a comprehensive database., Competing Interests: The authors declare no conflict of interest.

Ataxia-telangiectasia mutated (ATM) protein is a member of the phosphatidylinositol 3-phosphate kinase (PI3-K)-related protein kinase (PIKK) family and is implicated in the initiation of signaling pathways following DNA double strand breaks (DSBs) elicited by exposure to ionizing irradiation (IR) or radiomimetic compounds. Loss of function of the ATM gene product results in the human genetic disorder ataxia-telangiectasia (A-T) characterized by neurodegeneration, immunodeficiency, genomic instability, and cancer predisposition. In response to DSBs, ATM is activated and phosphorylates Ser/Thr-Gln (S/T-Q) sequences on numerous proteins participating in DNA-damage responses. Among these proteins, phosphorylation of the tumor suppressor p53 at Ser15 is known as a target for ATM, which leads to the dissociation of MDM2, an E3 ubiquitin ligase, from p53 to prevent MDM2-dependent p53 degradation. Ser46 on p53 is phosphorylated in response to DSBs and contributes to the preferential transactivation of pro-apoptotic genes, such as p53AIP1, Noxa, and PUMA, to prevent tumor formation. Our group have shown that not only ATM preferentially phosphorylates S/T-Q sequences, but also Ser46, which is a noncanonical site with an S-P sequence for ATM. Ser46 on p53 is directly phosphorylated by ATM in a p53 conformation-dependent manner using the ATP analogue-accepting ATM mutant (ATM-AS) system. This protocol summarizes an approach to identify direct numerous targets for ATM kinase and is used to elucidate ATM signaling pathways in the DNA damage responses.

Serous adenocarcinoma of the cervix (SACC) is a very rare tumor. Our study aimed to characterize the immune profile and human papillomavirus (HPV) status of SACC, in comparison with other serous adenocarcinomas arising in the female genital tract. The pathological specimens obtained from 81 patients with serous carcinoma of the uterine cervix (n = 12), 29 endometrium, 20 ovary and 20 patients with mucinous carcinoma of the uterine cervix were reviewed. We assessed the expression of WT-1, p53, p16, HER2, CEA, and CA125 by immunohistochemistry and HPV DNA by PCR in 12 SACC samples. Their immune profile was compared with that of uterine papillary serous carcinoma (UPSC), ovarian serous adenocarcinoma (OSA), and mucinous endocervical adenocarcinoma (MEA). WT-1 and HER2 were expressed in very few SACC samples (0 and 0%, respectively), but p16, CA125, CEA and p53 were present in 100, 92, 58 and 50%, respectively. The difference in WT-1 expression between SACC and UPSC, MEA is not significant, but SACC differ significantly from OSA (p < 0.01). HPV DNA (type 16 or 18) was detected in 4 of the 12 SACC. The immunophenotype of SACC was similar to UPSC, whereas the frequency of expression of WT-1 was significantly lower in SACC than OSA. It appeared that p53 expression was associated with worse clinical outcome in patients with SACC, and that HPV infection was related to its occurrence.

Communication between cancer cells and their microenvironment controls cancer progression. Although the tumor suppressor p53 functions in a cell-autonomous manner, it has also recently been shown to function in a non-cell-autonomous fashion. Although functional defects have been reported in p53 in stromal cells surrounding cancer, including mutations in the p53 gene and decreased p53 expression, the role of p53 in stromal cells during cancer progression remains unclear. We herein show that the expression of α-smooth muscle actin (α-SMA), a marker of cancer-associated fibroblasts (CAFs), was increased by the ablation of p53 in lung fibroblasts. CAFs enhanced the invasion and proliferation of lung cancer cells when cocultured with p53-depleted fibroblasts and required contact between cancer and stromal cells. A comprehensive analysis using a DNA chip revealed that tetraspanin 12 (TSPAN12), which belongs to the tetraspanin protein family, was derepressed by p53 knockdown. TSPAN12 knockdown in p53-depleted fibroblasts inhibited cancer cell proliferation and invasion elicited by coculturing with p53-depleted fibroblasts in vitro, and inhibited tumor growth in vivo. It also decreased CXC chemokine ligand 6 (CXCL6) secretion through the β-catenin signaling pathway, suggesting that cancer cell contact with TSPAN12 in fibroblasts transduced β-catenin signaling into fibroblasts, leading to the secretion of CXCL6 to efficiently promote invasion. These results suggest that stroma-derived p53 plays a pivotal role in epithelial cancer progression and that TSPAN12 and CXCL6 are potential targets for lung cancer therapy.

In lung cancer progression, p53 mutations are more often observed in invasive tumors than in noninvasive tumors, suggesting that p53 is involved in tumor invasion and metastasis. To understand the nature of p53 function as a tumor suppressor, it is crucial to elucidate the detailed mechanism of the alteration in epithelial cells that follow oncogenic KRAS activation and p53 inactivation. Here, we report that KRAS activation induces epithelial-mesenchymal transition and that p53 inactivation is required for cell motility and invasiveness. Furthermore, TSPAN2, a transmembrane protein, is responsible for cell motility and invasiveness elicited by p53 inactivation. TSPAN2 is highly expressed in p53-mutated lung cancer cells, and high expression of TSPAN2 is associated with the poor prognosis of lung adenocarinomas. TSPAN2 knockdown suppresses metastasis to the lungs and liver, enabling prolonged survival. TSPAN2 enhances cell motility and invasiveness by assisting CD44 in scavenging intracellular reactive oxygen species., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

The p53 tumor suppressor protein is a transcription factor controlling various outcomes, such as growth arrest and apoptosis, through the regulation of different sets of target genes. The nuclear mitotic apparatus protein (NuMA) plays important roles in spindle pole organization during mitosis and in chromatin regulation in the nucleus during interphase. Although NuMA has been shown to colocalize with several nuclear proteins, including high-mobility-group proteins I and Y and GAS41, the role of NuMA during interphase remains unclear. Here we report that NuMA binds to p53 to modulate p53-mediated transcription. Acute and partial ablation of NuMA attenuates the induction of the proarrested p21 gene following DNA damage, subsequently causing impaired cell cycle arrest. Interestingly, NuMA knockdown had little effect on the induction of the p53-dependent proapoptotic PUMA gene. Furthermore, NuMA is required for the recruitment of cyclin-dependent kinase 8 (Cdk8), a component of the Mediator complex and a promoter of p53-mediated p21 gene function. These data demonstrate that NuMA is critical for the target selectivity of p53-mediated transcription.

Melanization is one of the major immune responses in arthropods. Prophenoloxidases (proPOs) catalyze the oxidation of mono- or o-diphenols, a reaction that is the key initial step of melanin formation. Well-characterized proPOs from crustaceans are synthesized in haemocytes and are released into plasma in response to microbial attack. However, PO activity does exist in the plasma of haemolymph without pathogenic infections. Here, we demonstrate that a novel type of proPO contributes to such PO activity in the plasma fraction of haemolymph of crustaceans. The novel enzyme, which was purified from the plasma of the kuruma prawn (Marsupenaeus japonicus), possessed strong and specific monophenol and o-diphenol oxidation activity compared with that of known haemocyte-type proPO. Amino acid sequence analyses indicated that this enzyme was distinct from the known proPO. The cDNA sequence and deduced amino acid sequence of this enzyme has a putative binuclear copper center, and showed approximately 30% and 20% identity with the primary structures of reported proPO and haemocyanin sequences of the kuruma prawn, respectively. Reverse transcription PCR analysis showed that this enzyme was synthesized in the hepatopancreas rather than in haemocytes. Although the primary structure and enzymatic properties of this novel enzyme suggested that it is a phenoloxidase, its biogenesis, tissue distribution, and oligomeric state resemble those of haemocyanin, which belongs to the same protein family (type III copper protein). This novel proPO enzyme may share a role with the already characterized version, itself a major component of the innate immune system in crustaceans., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The hydrodynamic effect on a thin particle layer, which moves relative to fluid by an external force, is investigated theoretically and numerically. Because of the presence of layer ends, the arrangement of particles in the layer is anisotropic and the drag force acting on them varies according to the position. The resulting relative motion of particles brings about the spreading of the layer. We have studied such a diffusive behavior of particle layers, which have various internal arrangements. We have assumed a non-Brownian system in which the particles move relatively owing to only the variance of hydrodynamic force. The hydrodynamic force on each particle was calculated by Stokesian dynamics approach. The results show that the relative motion of particles is greatly influenced by the internal arrangement of the particle layer. In consequence, the overall diffusive motion of particle layer varies with the arrangement even if the particle concentration is similar. It is in contrast to the gradient diffusion of Brownian particles.

Background: Detrusor instability is one of the most common problems in patients with lower urinary tract obstructive diseases, such as benign prostatic hyperplasia. Adenosine triphosphate (ATP) has been associated as a neuronal component in the detrusor instability., Materials and Methods: Ninety-six female Splague-Dawley rats were studied. Outflow obstructions were created by ligature of the urethra over which a catheter was placed. Changes in the bladder capacity, and an isovolumetric contractile response to pharmacologic antagonists were studied in the obstructed rats for a period of from one day to four weeks., Results: The bladder capacity of rats obstructed for four weeks increased significantly. Maximum bladder contraction pressure with the use of atropine medication was inhibited in 60 percent and, 30 percent of in the control group, respectively. The inhibitory effect of the maximum bladder contraction pressure by the pyridoxalphosphate-6-azophenyl-2', 4'-disulphonate (PPADS) dosage after the atropine dosage was not recognized it in the control group, but the effect was recognized powerfully in the obstructed group., Conclusion: In the obstructed bladder rat, strong rise of the bladder contraction by P2X receptor with a lower urinary obstruction was accepted, and that result reflects positively. Therefore, it was guessed that the result was an end of the compensatory mechanism of unstable bladder.

Background: The detrusor contraction involves an atropine resistant, nonadrenergic noncholinergic (NANC), component. Since adenosine triphosphate (ATP) has been proposed as a NANC transmitter, the role of ATP-receptors in the lower urinary tract was examined., Materials and Methods: The isovolumetric bladder contractions and the urethral pressure were monitored after intra-arterial administration of ATP analogues and other drugs in 52 female SD rats under intraperitoneal urethane anesthesia., Results: alpha beta metATP induced a rapid, phasic increase of the maximal bladder pressure immediately after the drug administration, which was followed by a decrease during the P 2 X-purinoceptor desensitization period, but it did not affect the resting bladder pressure. RB-2 did not affect both the maximal bladder pressure and the resting bladder pressure. As for the urethral functions, alpha beta metATP induced a decrease of the resting urethral pressure during the P 2 X-purinoceptors desensitization period, while RB-2 induced a increase of the resting urethral pressure in contrast. ATP, alpha beta metATP and RB-2 did not changed the maximal urethral relaxation., Conclusion: The results will indicate that ATP produces detrusor contractions through the P 2 X-purinoceptor. Although ATP dose not affect urethral relaxation during voiding phase, it controls the urethral tone during collecting phase by both the excitation of P 2 X-purinoceptor and the inhibition of P 2 Y-purinoceptor.

Background: A 64-year-old man presented with asymptomatic macroscopic hematuria during a follow up for a localized renal cell carcinoma (RCC), which was treated by a right radical nephrectomy 6 years earlier., Methods: X-rays and a ureteroscopic examination revealed multiple papillary tumors filling the right ureteral stump. Surgery was performed to excise the ureteral stump and bladder cuff. The tumor was histologically a grade 2-3 transitional cell carcinoma without muscle invasion., Results/conclusions: Only four patients with a ureteral stump carcinoma, including the present case, have been reported after a nephrectomy for RCC. Considering that this patient had a past history of multiple cancers, genetic or environmental factors may have contributed to the etiology of the ureteral stump tumor.

A 60-year-old male with locally invasive bladder carcinoma (pT4 pNo Mo) had a remarkable leukocytosis of 64,900/mm3 in the peripheral blood count without any findings of inflammatory disease. The grade 3 transitional cell carcinoma (TCC) measuring 60 by 58 mm involved the prostate, but radiological examinations including abdominal CT scan and isotopic bone scan failed to prove distant metastasis. Serum calcium level was within normal level. Negative bone marrow finding for leukemia strongly suggested a leukemoid reaction by the bladder carcinoma. Preoperative arterial chemoembolization utilizing mitomycin C microcapsules and cisplatin infused into the tumor feeding arteries provided a normalization of leukocyte count (8,200/mm3) in association with a substantial tumor reduction, and was followed by radical cystoprostatectomy. Although the leukocyte count maintained a normal range for 2 months postoperatively, leukocytosis recurred and rapidly progressed to a leukocyte count of 51,300/mm3. CT scan revealed intrapelvic tumor recurrence, and serum analysis for granulocyte colony stimulating factor (G-CSF) demonstrated an elevated value of 130.9 pg/ml (normal, less than 30 pg/ml). The patient is now on systemic chemotherapy. The laboratory data and the response to the treatments would indicate that the leukocytosis in this patient is a leukemoid reaction due to the bladder carcinoma which may release G-CSF. Ten cases of bladder tumor representing leukemoid reaction have been reported in the literature.

Tsumura Chorei-to or Tsumura Chorei-to-go-shimotsu-to, was administered to 71 female patients with urethral syndrome 2.5 g three times a day for four weeks. Total efficacy rate of Tsumura Chorei-to in 34 cases was 71%. Tsumura Chorei-to was effective against pollakisuria, miction pain or discomfort, sense of residual urine and lower abdominal discomfort. Total efficacy rate of Tsumura Chorei-to-go-shimotsu-to in 37 cases was 57%. Tsumura Chorei-to-go-shimotsu-to was effective against dysuria, sense of residual urine and lower abdominal discomfort. Uutoward effect rates of Tsumura Chorei-to and Tsumura Chorei-to-go-shimotsu-to were 6% and 14%, respectively. Many of the untoward effects of these two drugs were epigastral discomfort. These two drugs are thought to be effective on patients with urethral syndrome.

The current practice of continent urinary diversion still places the patients under the restraint of the stoma and intermittent catheterization. To overcome these problems, we developed a new technique of urinary diversion of which continent is controlled by the anal sphincter. The isolated ileocecal segment is intussuscepted and interposed between the ureters and the rectum. The conjoined ureters are anastomosed to the stump of the ileal limb, and the antimesenteric portion of the cecal limb is joined to the anterior wall of the rectum. The surgical procedure is simpler than that of the continent reservoirs currently employed. The intussuscepted ileocecal segment prevents fecal reflux to the upper urinary tract and may also inhibit carcinogenesis at the uretero-intestinal junction. Additionally, the rectal capacity is augmented by the side to side anastomosis between the cecal limb and the rectum. Our preliminary experience in 10 cases were satisfactory with respect to voiding function, antireflux mechanism of the intussuscepted ileocecal segment and quality of life. The results will justify further trials with this stomaless continent urinary diversion for those in whom the urethra cannot be used.

The effect of terazosin on the lower urinary tract function was studied by combined recording of bladder and urethral pressures and external sphincter electromyogram in 8 male decerebrate dogs. Reflex micturitions were induced by bladder filling before and after terazosin. The statistical analysis was carried out on the urodynamic parameters. During the collecting phase, terazosin at doses of 10, 30 and 100 micrograms/kg produced a significant decrease in maximum urethral pressure in the dose dependent manner. Threshold pressure was significantly shown to decrease at doses of 30 and 100 micrograms/kg. In the urodynamic parameters of the emptying phase there was a significant decrease in maximum contraction pressure at 10 and 30 micrograms/kg, and in voided volume at 100 micrograms/kg. Terazosin seems to facilitate an initiation of the bladder contraction with a decrease in threshold pressure. In concludes that alpha 1 adrenergic activity seems to take an important role for the maintenance of the urethral pressure and to control the initiation of bladder contraction in modulation with threshold pressure.

Since April 1985, 72 patients with bladder cancer have been treated by transurethral microwave coagulation (TUMC). In this procedure, tumors were irradiated with microwave energy of 100 watts for 2-16 minutes. A total of 20 patients were 70 years old or older, including 5 who were more than 80 years old. These 20 patients have been followed for 6 to 32 months with a median follow-up of 14.7 months. After TUMC, tumors completely disappeared endoscopically and histologically in all patients. Four patients had heterotopic recurrences. In all patients, serious complications were not seen during and after TUMC. Our clinical experience revealed that TUMC was the useful therapeutic method for bladder cancer in elderly or poor-risk patients. In this paper, we describe the technique of TUMC and preliminary clinical results.