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Imaging mass spectrometry (IMS) is increasingly used for drug discovery and development to understand target enagement, tissue distribution, drug toxicity, and disease mechanisms, etc. However, this is still a relatively new technique that requires further development validation before it will be an acceptable technique to support regulated development of new drugs. Thus, best practices will need to be established to build more confidence and gain wider acceptance by the scientific community, pharmaceutical industry, and regulatory authorities. The Imaging Mass Spectrometry Society (IMSS) and the Japan Association for Imaging Mass Spectrometry (JAIMS) have conducted a thorough survey to gather information on the current state of IMS and to identify key issues. The survey was sent to researchers or managers in the position who are currently using IMS techniques in support of their drug discovery and development efforts and/or who plan to use such tools as best practices are established. The survey probes questions related to details regarding technical aspects of IMS, which includes data acquisition, data analysis and quantitation, data integrity, reporting, applications, and regulatory concerns. This international survey was conducted online through the Survey Monkey (https://www.surveymonkey.com) in both English and Japanese from September 14 through September 30, 2020.

Daiokanzoto (DKT) and lubiprostone (LPS) are drugs used for constipation, but few studies have compared them. This study examined the effectiveness, adverse events, and medical economic efficiency of DKT and LPS for constipation. Patients who received DKT (DKT group) and those who received LPS (LPS group) during admission to Ogaki Municipal Hospital between November 2012 and May 2016 were enrolled. Drug efficacy was evaluated based on the median value of bowel movement frequency over 1 week before and after drug administration, and their safety was evaluated by the presence or absence of diarrhea, abdominal pain, nausea, and vomiting. To assess medical economic efficiency, drug costs for constipation per week were calculated. The median values (quartile ranges) of bowel movement frequency at 1 week after drug administration were 8.5 (6.0-12.0) in the DKT group and 5 (3.0-7.0) in the LPS group, which was significantly different (p < 0.01). Diarrhea occurred significantly less often in the DKT group (4 cases) than in the LPS group (17 cases) (p < 0.01). The median cost of drugs administered for constipation for 1 week was significantly lower in the DKT group (631 [quartile range, 513-653] yen) than in the LPS group (1431 [1135-2344] yen) (p < 0.01). DKT had a higher immediate effect on constipation and was associated with more frequent bowel movement and fewer adverse events of diarrhea than LPS, suggesting that it may be effective and safe for treating constipation, and DKT is inexpensive.

Sphingolipids constitute a class of bio‐reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non–small‐cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR‐101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1‐positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.

To evaluate the usefulness of imaging mass spectrometry (IMS) technology for assessing drug toxicity, we analyzed animal tissues in an amiodarone (AMD)-induced phospholipidosis model by IMS and confirmed the relationship between the distribution of AMD, its metabolites, and representative phospholipids (phosphatidylcholine, PC) and histological changes. AMD was administered to rats for 7 days at 150 mg/kg/day. The lung, spleen, and mesenteric lymph node were histologically examined and analyzed using IMS. The detection intensities of AMD, its metabolites, and typical PCs were higher in regions infiltrated by foamy macrophages compared with normal areas. This tendency was common in all three organs analyzed in this study. For the spleen, signals for AMD, its metabolites, and typical PCs were significantly more intense in the marginal zone, where foamy macrophages and vacuolated lymphocytes are abundant, than in the other areas. These results indicate that AMD, its metabolites, and PCs accumulate together in foamy or vacuolated cells, which is consistent with the mechanism of AMD-induced phospholipidosis. They also indicate that IMS is a useful technique for evaluating the distribution of drugs and biological components in the elucidation of toxicity mechanisms.

The designed liquid immiscibility of Cu-Ni-Fe-Mo-Si alloy led to separation of the spherical second liquid in the Cu-rich liquid, which solidified into coarse hard grains packed with Laves phase. The coarseness of hard grains was controlled not only by the repulsive interactions in Cu–Fe and Cu–Mo system, but also the refining effect of Ni and Si. CALPHAD analysis of the multicomponent system confirmed the correlation of the calculated fraction of the separated liquid with the observed grain dimensions. It also provided a powerful prediction of the precipitates constituting the hard grains. Almost all of the alloying effects on the observed microstructures were successfully interpreted based on equilibrium immiscibility calculations, although a reason for the refining of spheres with increasing Si remains unclear.

Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC.

The concentration and distribution of a drug or its metabolites in tissues are key factors for understanding drug efficacy or toxicity. Conventional pharmacokinetic studies show that the plasma concentration of a drug is often unrelated to the intra-tissue concentration. Moreover, it is difficult to predict the distribution of a drug in tissues, particularly those with complex structures, even though the overall tissue concentration is measured by using homogenizing procedures. Mass spectrometry imaging (MSI) enables visualization of the spatial distribution and quantities of drugs in tissue sections without labeling, which can significantly impact on the development of new drugs and translational research. Recent advances in instrument technology and the knowledge accumulated to date could further improve the sensitivity, spatial resolution, and reproducibility of MSI. Here we present current applications of matrix-assisted laser desorption/ionization (MALDI)-MSI in pharmacokinetic imaging (PK-imaging) studies, give an overview of MALDI-MSI procedures, highlight the importance of internal standards, and give details of quantitative approaches. We also point out the need for standardizing MALDI-MSI techniques. PK-imaging using standardized MALDI-MSI methods, independent of instrument or technician expertise, is expected to contribute to acquiring reliable data in drug development and translational research in the future.

BACKGROUND Circulating microRNAs (miRNAs) are attracting major interest as potential non-invasive biomarkers for colorectal cancer (CRC). This study aimed to identify a novel serum miRNA biomarker for the early detection and/or evaluating prognosis of CRC patients. PATIENTS AND METHODS Comprehensive miRNA array analysis was carried out using serum samples from patients with colorectal neoplasia and healthy controls. Next, to verify whether the candidate miRNA possessed a secretory potential, we screened miRNA expression levels in culture medium from 2 CRC cell lines, followed by serum analysis from 12 stage IV CRC, 12 adenoma, and 12 control subjects. Thereafter, we validated expression of candidate miRNAs in 179 primary CRC tissues, as well as serum samples from an independent cohort of 211 CRCs, 56 adenomas, and 57 control subjects. RESULTS Through microarray analysis, we identified significantly higher levels of miRNA-1290 (miR-1290) in serum from patients with colorectal adenomas and cancers. We verified miR-1290 overexpression in serum of CRC patients in a training cohort. In the validation cohort, serum miR-1290 levels were significantly up-regulated in patients with colorectal adenomas (P < 0.0001) and cancers (P < 0.0001). Serum miR-1290 levels could robustly distinguish adenoma [area under the curve (AUC) = 0.718] and CRC patients (AUC = 0.830) from normal subjects. High miR-1290 expression in serum and tissue was significantly associated with tumor aggressiveness and poor prognosis. Moreover, serum miR-1290 levels were an independent prognostic factor [hazard ratio (HR) = 4.51; 95% confidence interval (CI) = 1.23-23.69; P = 0.0096] and an independent predictor for tumor recurrence (hazard ratio = 3.92; 95% confidence interval = 1.11-25.14; P = 0.032) in CRC. CONCLUSIONS Serum miR-1290 is a novel biomarker for early detection, recurrence, and prognosis in CRC.

There are only a few treatment options for constipation and limited evidence of suitable treatments. Daiokanzoto (DKT) is a Kampo medicine often used clincally to treat constipation. DKT is a laxative used predominantly in Japan; however, clinical data on its efficacy and safety is lacking. Patients who used DKT, but were intolerant to either magnesium oxide (MgO; MgO group; n=16) or senna extract (Senna group; n=26) were included in the present study. The frequencies of their bowel movements were compared during the 1 week prior to and following DKT administration. Within 24 hours after DKT administration, 93.8% of the patients in the MgO group evacuated their bowels. The median bowel movement frequency 1 week prior to DKT administration was 2.5 and 1 week after DKT administration was significantly increased to 7.5. In the Senna group, within 24 h of DKT administration, 80.8% of the patients evacuated their bowels. The median bowel movement frequency 1 week prior to the DKT treatment was 2.0, which significantly increased to 8.5 1 week after the administration of DKT. The adverse events from DKT treatment were mild and controllable.

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.

Background. Daikenchuto (DKT) is a Kampo medicine used for the treatment of constipation. In this study, we evaluated the effectiveness of DKT against constipation. Patients and Methods. Thirty-three patients administered DKT for constipation were selected and divided into low-dose (7.5 g DKT; n=22) and high-dose (15 g DKT; n=11) groups. We retrospectively evaluated weekly defaecation frequency, side effects, and clinical laboratory data. Results. Median defaecation frequencies after DKT administration (5, 5.5, 5, and 8 for the first, second, third, and fourth weeks, resp.) were significantly higher than that before DKT administration (2) in all 33 cases (P<0.01). One case (3%) of watery stool, one case of loose stools (3%), and no cases of abdominal pain (0%) were observed. Median defaecation frequencies in the high-dose group (7 and 9) were significantly higher than those in the low-dose group (4 and 3) in the first (P=0.0133) and second (P=0.0101) weeks, respectively. There was no significant change in clinical laboratory values. Conclusion. We suggest that DKT increases defaecation frequency and is safe for treating constipation.

Slug and Vimentin genes play a critical role in regulating epithelial-mesenchymal transition (EMT) via downregulation of epithelial markers and upregulation of mesenchymal markers. The present study evaluated the clinical significance of Slug and Vimentin expression as potential disease biomarkers in colorectal cancer (CRC). At first, the biological role of Slug in CRC was assessed by RNA interference in CRC cell lines to assess tumor progression, invasion and migration. Next, we analyzed Slug and Vimentin expression in surgical tissue specimens from 181 CRC patients (Cohort 1) by quantitative real-time reverse transcription-PCR and 208 patients (Cohort 2) by immunohistochemistry. Knockdown of Slug using small interfering RNA in CRC cell lines resulted in inhibition of EMT, reduced cell proliferation, invasion and migration in CRC cells. Interestingly, Slug and Vimentin expression in cancer tissues was significantly higher in patients with higher T stage, lymph node involvement, liver metastasis and advanced tumor node metastasis stages. A significant correlation was observed between Slug and Vimentin expression in CRC (messenger RNA: ρ = 0.546, protein: ρ = 0.405), and increased expression of Slug and Vimentin was significantly associated with poor prognosis. Furthermore, increased expression of Slug emerged as an independent prognostic factor and a predictive marker of lymph node metastasis in CRC patients. Our data provide novel evidence for the biological and clinical significance of Slug and Vimentin expression as potential predictive biomarkers for identifying patients with lymph node metastasis or poor prognosis in CRC.

Sphingosine kinase 1 (SPHK1) overexpression in malignant cells has been reported. Mouse Friend cells showed higher SPHK1 but not SPHK2 expression compared with other mouse cell lines. A Sphk1 promoter analysis demonstrated the region between − 53 bp and the first exon as the minimal promoter. Further promoter truncation revealed the importance of a MYB-binding site. EMSA using this region as the probe demonstrated one band containing c-MYB protein, and its intensity decreased during erythroid differentiation with hexamethylane bisacetamide (HMBA), a potent inducer of erythroid differentiation of Friend cells. ChIP assay also revealed in vivo binding of c-MYB. c-MYB overexpression and siRNA for c-Myb affected SPHK1 expression, confirming the important regulatory role of c-MYB in SPHK1 expression. HMBA reduced c-MYB expression rapidly. Induced differentiation by HMBA caused a marked and rapid reduction of SPHK1 mRNA, protein and enzyme activity leading to the rapid decrease of cellular sphingosine 1-phosphate level. Moreover, terminally differentiated cells did not resume SPHK1 expression. Compared with original Friend cells, stable overexpression of wild-type SPHK1 showed higher cell proliferation, resistance to cell death by serum depletion. Interestingly, HMBA-induced differentiation of these cells was delayed but not completely suppressed. In contrast, SPHK inhibitor and its siRNA inhibited cell growth and enhanced HMBA-induced differentiation significantly, suggesting that SPHK1 delayed HMBA-induced differentiation by its cell proliferation-promoting activity. Effects of pertussis toxin, a G-protein-coupled receptor inhibitor, and S1P receptor antagonist on Friend cell growth and differentiation were negligible, suggesting the importance of the intracellular SPHK1/S1P signaling in Friend cells.

In vacuum carburizing of steels, short-time carburizing is usually followed by a diffusion period to eliminate the filmlike cementite (θGB) grown on the austenite (γ) grain boundary surface. In order to obtain the θGB amount during the process, the conventional model estimates the amount of cementite (θ) with the equilibrium fractions for local C contents within a framework of the finite difference method (FDM), which overestimates the amount of θGB observed after several minutes of carburizing. In our newly developed model, a parabolic law is assumed for the growth of θGB and the rate controlling process is considered to be Si diffusion rejected from θ under the isoactivity condition. In contrast, the rate constant for the dissolution of θGB is considered to be controlled by Cr diffusion of θ. Both rate coefficients (α) were validated using multicomponent diffusion simulation for the moving velocity of the γ/θ interface. A one-dimensional (1-D) FDM program calculates an increment of θGB for all grid points by the updated diffusivities and local equilibrium using coupled CALPHAD software. Predictions of the carbon (C) profile and volume fraction of cementite represent the experimental analysis much better than the existing models, especially for both short-time carburization and the cyclic procedure of carburization and diffusion processes.

Aims To evaluate the relationship between vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) levels in gastric cancer tissue and clinicopathological features and to determine whether these factors were correlated with survival. Materials and methods We analysed tissue samples from 58 patients with gastric cancer and used 24 normal gastric mucosae as controls. Tissue levels of VEGF and HGF were measured in tissue extracts by enzyme-linked immunosorbent assay. Results HGF and VEGF levels were significantly higher in gastric cancer tissue than in matched normal gastric mucosa. VEGF levels were significantly increased in cancer tissue from cases involving lymphatic invasion. HGF levels were significantly increased according to the disease stage. Patients with high levels of VEGF or HGF showed significantly worse survival rates than patients with low levels. Using multivariate analysis, a high level of VEGF or HGF was an independent factor predicting poor survival. Conclusions Intratumoral levels of HGF and VEGF are an important prognostic determinant in gastric cancer. The current findings suggest that high concentrations of HGF and VEGF may induce aggressive tumour growth and metastasis.

Purpose Serum CXCL5 levels in patients with colorectal cancer (CRC) were assessed to evaluate correlation with clinicopathologic features and prognosis. The effects of CXCL5 on CRC cells were also investigated in vitro . Methods Based on cytokine array analysis, CXCL5 was identified as a novel prognostic serum marker. Serum levels of CXCL5 were assessed in 250 CRC patients and 33 normal volunteers by enzyme-linked immunosorbent assay (ELISA), and their relation to clinicopathologic findings and survival investigated. CXCL5 levels in CRC cell lines were also measured by ELISA, and CXCL5 and CXCR2 expression was evaluated by immunohistochemistry. To investigate the biological role of the CXCL5/CXCR2 axis, recombinant human CXCL5 and CXCR2 neutralisation antibodies were used for proliferation, migration and invasion assays. Results Preoperative serum CXCL5 was significantly elevated in patients with CRC compared with healthy volunteers ( p = 0.013). High serum CXCL5 was significantly associated with female sex ( p = 0.0098) and liver metastasis ( p = 0.0040). Univariate analysis correlated elevated CXCL5 with poor overall survival ( p = 0.0002). Multivariate analysis showed that elevated CXCL5 was a significant and independent prognostic factor of survival in all CRC patients ( p = 0.038). CRC cells secreted CXCL5, and administration of recombinant human CXCL5 promoted proliferation, migration and partial invasion. These effects were generally inhibited by CXCR2 neutralisation antibody. Conclusions Preoperative serum CXCL5 could serve as a novel predictive marker for prognosis determination of CRC patients. CXCL5/CXCR2 axis might be associated with colorectal cancer progression.

Background: The aim of the present study was to evaluate the efficacy and safety of double balloon enteroscopy (DBE) in children with inflammatory bowel disease (IBD). Methods: A total of 106 DBE procedures in 67 patients were performed at Mie University Hospital from January 2008 to June 2011. Of these, 17 procedures in 12 children and adolescents with established or suspected Crohn's disease (CD) were included in the present study. The procedure, sedation, efficacy, and safety of DBE were evaluated. Results: Mean patient age was 12.9 years (range, 3–19 years). Patients ≤15 years old had general anesthesia. The procedures included the oral approach (n= 9), the anal approach (n= 4), and the ileostomal approach (n= 4). The mean procedure duration was 60 min. Accurate diagnosis was obtained in 7/8 cases (88%) of suspected CD. Only one case was diagnosed as indeterminate colitis, although the total small and large bowel was examined on DBE and pathology. Procedure tolerance was acceptable and recovery was uneventful in all cases. No serious complications were encountered. Conclusions: With regard to the present limited IBD pediatric case series, DBE is a safe and effective procedure.

Based on the solute drag model, a practical model incorporating the segregation effect is proposed to calculate grain growth rates in carbon steels. The segregation effect is modeled using two factors: the difference in atomic diameter between a solvent and a substitutional element, and the solubility of a substitutional element. By including the segregation energy, the proposed model enables the simulated retardation of grain growth by the addition of microalloying elements. The calculated grain growth rate by the proposed model shows reasonable correspondence between grain growth rates for experimental and calculated results. The temperature dependence of the grain growth rate is also well simulated.

Based on the solute drag model, a practical model incorporating the segregation effect is proposed to calculate grain growth rates in carbon steels. The segregation effect is modelled using two factors: the difference in atomic diameter between a solvent and a substitutional element, and the solubility of a substitutional element. By including the segregation energy, the proposed model enables the simulated retardation of grain growth by the addition of microalloying elements. The calculated grain growth rate by the proposed model shows reasonable correspondence between grain growth rates for experimental and calculated results. The temperature dependence of the grain growth rate is also well simulated.

In order to predict microstructures during vacuum carburizing, the model which simulates not only the carbon(C) diffusion but also growth/dissolution of cementite(θ) is required. For development of a new model we applied vacuum carburizing to low alloy steels and analyzed the distribution of C and θ by GD-OES and image analysis of microstructures. The C in retained austenite(γ) phase after carburizing was also measured by lattice constants obtained from XRD. We also simulated multi-component diffusion with γ matrix and θ layer to analyze a velocity of the moving interface. The new carburizing model was proposed based on the findings, which suggest that C in γ phase at the carburizing surface is supersaturated and corresponds to C concentration for metastable equilibrium condition to graphite. The growth and dissolution of the θ follow a square root of time with the coefficients controlled by diffusion of Si in γ and Cr in θ respectively. The required parameters such as diffusivity coefficients are obtained by the CALPHAD method. The calculated C distributions and volume fractions of θ represent the experimental results.

In vacuum carburizing of steels, a short-time carburizing is usually followed by a diffusion period to eliminate the film-like cementite (θ) grown on austenite (γ) grain boundary surface. Due to a radical reaction with decomposed hydro-carbon gas, the surface C content in γ was found higher than the solubility of θ. It was recognized as the metastable equilibrium of supersaturated γ with graphite until the θ covered all the surfaces. Based on this finding, a calculation model predicting not only C concentration profiles but also quantitatively the grain-boundary θ has been developed in this work.The existing model estimates the amount of θ with the equilibrium fractions for local C contents in a framework of finite difference method (FDM). Even with the equilibrium surface condition of γ plus θ with graphite, it overrates the amount of θ observed after several minutes of carburizing. In the developed model, a parabolic law was assumed for the thickening of θ, and the rate controlling process was considered Si diffusion rejected from θ under the isoactivity condition of γ/θ interface and supersaturated γ. The rate coefficient (αSi) has been validated using multicomponent diffusion simulation for moving velocity of the γ/θ interface. A 1-D FDM program calculates an increment of θ for all gridpoints using the updated diffusivities and local equilibrium by a coupled CALPHAD software. Predictions of carbon profile and volume fraction of cementite represent the experimental analysis much better than the existing models especially for short-time carburizing.

目的:胃癌症例における術前C-reactive protein（CRP）値と予後との関係，および，腫瘍微小環境とCRP値について検討した．方法:胃癌の診断にて胃切除を施行した91例を対象とした．術前CRP値と臨床病理学的因子，予後および，腫瘍内サイトカイン濃度（interleukin-1β，interleukin-6，interleukin-1ra）を測定し，CRP値との関連について検討した．結果:病理組織学的因子とCRP値との間に有意な関連は認めなかった．しかし，CRP高値（CRP≧1.0mg/dl）を示す症例では，有意に予後が不良であった．また，腫瘍組織内IL-1β濃度は，CRP高値例でCRP低値（CRP結論:胃癌術前CRP値は予後に影響を与えており，CRP値上昇は炎症性サイトカインを中心とする腫瘍内微小環境と密接な関係があることが示唆された．

We investigated the associations between hsMAD2 mRNA expression in tumor cells and sensitivity to paclitaxel or patient prognosis in neuroblastoma. Fifty-one formalin-fixed paraffin-embedded tumor samples were manually microdissected to collect tumor cells, and RNA was purified. Nineteen clinical samples of advanced neuroblastoma showed appropriate quality of the isolated RNA for real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses. The hsMAD2 expression levels were determined by real-time RT-PCR in 4 neuroblastoma cell lines and 19 clinical samples. The sensitivity to paclitaxel was assessed by WST-8 colorimetric assays and flow cytometry. HsMAD2 expression of the clinical samples was investigated for its association with prognosis in advanced neuroblastoma patients. There was a significant positive correlation between hsMAD2 mRNA expression and the sensitivity to paclitaxel in four neuroblastoma cell lines. High hsMAD2 expression may be correlated with paclitaxel-induced apoptosis. Kaplan–Meier survival curves were stratified by hsMAD2 expression using the median value as a cut-off point and analyzed for prognostic significance by the log-rank test (P = 0.0467). Furthermore, multivariate survival analysis revealed that only hsMAD2 expression had a significant impact on the overall survival rate. Our results may warrant clinical application of paclitaxel in neuroblastoma treatment for poor prognosis patients.

Background: Interleukin-6 (IL-6) binds both the membrane and soluble forms of the IL-6 receptor (sIL-6R), which induces a complex with gp130, and proliferation of tumour cells. The aim of this study is to clarify the relationship between tumoral sIL-6R expression and disease progression in colorectal cancer patients. Methods: We measured tissue concentrations of sIL-6R in tumour and normal mucosa from 161 colorectal cancer patients undergoing surgery, and in supernatants from colon cancer cell lines. The expression of IL-6, IL-6R and gp130 was evaluated by immunohistochemical analysis. Results: Loss of tumour expression of sIL-6R as defined by sIL-6R Ca/N ratio

MRIで嚢胞性髄膜腫と診断した犬3例をその画像所見から人医療のナタの分類より、タイプ別に分類し、手術を行った。タイプIIIの症例1、2は造影されている充実性の腫瘍のみ摘出し、タイプIIの症例3は造影されている嚢胞壁と腫瘍の両方を摘出した。その結果、全症例において症状の改善がみられ、症例1は嚢胞の内容液の分泌能が低下し、症例2、3は嚢胞が消滅した。症例3は腫瘍が新たに摘出部位の反対側から発生したが、3年生存している。

下大静脈内腫瘍栓子を合併した腎腫瘍摘出術では，手術操作による腫瘍栓子の遊離や空気塞栓症が生じる可能性がある．このような致死的な合併症を回避するためには，腫瘍栓子の形態を経時的に観察しつつ循環動態の変動に対しても迅速に対応する必要がある．われわれは，経食道心エコー（TEE）だけでなく肺動脈カテーテルを用いたモニタリングを行うとともに，下肢のうっ血予防と手術視野の確保のため，さらに腫瘍塞栓症や空気塞栓症による緊急開心術への移行に備えて部分体外循環を使用することにより，合併症なく麻酔管理を行うことができた3症例を経験したので報告する．

In our previous paper, the eutectic liquid that appears between the cementite (θ) foil and austenite was proposed to be most suitable for rapid transient-liquid-phase (TLP) bonding of steels. A partial substitution with Cr was required for metastable θ to be thermodynamically stable up to the solidus temperature. On the other hand, the liquid region disappeared quickly by C diffusion, leaving severe Cr segregation along the bonded interface. The present study aims to decrease the ratio of Cr substitution in θ so as to eliminate the homogenization step and allow the use of steel parts as-bonded. Compared to θ with a higher Cr substitution, the synthesized θ with 1 mass% Cr (1Cr-θ) showed an enhanced tendency to decompose on cooling from 1373 K. However, the 1Cr-θ foil was confirmed to give the eutectic liquid that dissolved V during TLP bonding of V-microalloyed steels. After holding for 180 s at 1453 K, a gradient ferrite–pearlite microstructure was obtained in the bond without any boundaries or hard layers due to Cr segregation. The bonded steel showed a tensile strength and elongation corresponding to those of the original V-steel.

A plane-to-plane bonding by the rapid reaction with liquid phase enables a simplified forming of hollow or complex steel parts. The time for disappearance of transient liquid is absolutely short if a high-carbon filler material controls the Fe–C eutectic liquid at bonding interfaces. Taking advantage of multi-component diffusion simulation, this paper aims to investigate how the behavior of eutectic liquid depends on the constituent in ferrous high-carbon (FHC) foil. Due to the rapid diffusion of carbon in austenite, the FHC foils with dispersed cementite or graphite failed to maintain a prescribed C composition and was predicted to yield a liquid only in the midst of foil. The monophase cementite (θ) foil, on the other hand, resulted in a liquid layer thicker than the initial foil thickness, and that ensures a dissolution of alloying elements in liquid from joined steels.It was possible to synthesize the monophase θ filler by substituting a part of Fe with Cr. Using the Cr-substituted θ filler, microstructures have been analyzed in the quenched samples during bonding of 0.21C–0.8Mn–0.25Si–0.22Cr steels at 1453K. Although the lowest temperature at which a liquid phase was observed was far lower than the simulation, Mn and Si dissolved in liquid layer have been confirmed. The liquid completely disappeared within 180 s and however, the segregation of Cr would remain severe.

An in-situ observation method for structures at high temperature is developed. The new observation device can reveal grain boundaries at high temperature and enables dynamic observation of these boundaries. Grain growth while maintaining microstructure at high temperature is observed by the new observation device with only one specimen for the entire observation, and grain sizes are quantified. The quantifying process reveals two advantages particular to the use of the new observation device: (1) the ability to quantify grain sizes of specified sizes and (2) the results of average grain size for many grains have significantly less errors because the initial structure is the same for the entire observation and the quantifying process. The new observation device has the function to deform a specimen while observing structures at high temperature, so that enables it to observe dynamic recrystallization of steel. The possibility to observe recrystallization is also shown.

Various factors regarding the biological state of tumors or the nutritional status of patients have been reported individually to correlate with prognosis. Identification of defined patient groups based on a prognostic score may improve the prediction of survival and individualization of therapy. The aim of the present study was to identify clinically useful parameters obtainable before treatment that could be used for predicting clinical outcomes in patients with gastric cancer. In 357 consecutive patients who had been treated for potentially curable gastric cancer, we retrospectively analyzed the following clinicopathological factors: sex, age, body mass index, body weight changes, hemoglobin, white blood cell count, neutrophil to lymphocyte (N/L) ratio, serum C-reactive protein (CRP), serum albumin, serum cholinesterase, tumor location, tumor size, histology, and clinical tumor node metastasis (TNM) stage. Factors related to prognosis were evaluated by univariate and multivariate analysis. From univariate analysis, significant differences in survival were found for age, hemoglobin, N/L ratio, serum CRP, serum albumin, serum cholinesterase, tumor size, and clinical T and N grouping. N/L ratio, tumor size, and clinical T grouping were identified as independent prognostic indicators in multivariate analysis. A prognostic score was constructed using these variables to estimate the probability of death. The model gave an area under the receiver operating characteristic curve of 0.85 for prediction of death at 5 years. This model based on N/L ratio, tumor size, and clinical T grouping before treatment offers a very informative scoring system for predicting prognosis of gastric cancer.

Plodia interpunctella Hubner (Lepidoptera: Pyralidae) comprises a model insect to analyse the photoperiodic time-measuring system controlling its larval diapause. In the present study, the effective length of light pulse in night interruption experiments is determined at 25 °C. Various lengths of light pulse are tested by inserting them at the midnight of an LD 12 : 12 h photoperiod. When the light pulse is 15 or 30 min, the incidence of diapause is 86%. To inhibit the induction of diapause effectively, a light pulse of 1.75–2 h is needed. The incidence of diapause is 12% under an LD 12 : 5 : 2 : 5 h photoperiod. To determine the precise role of the light pulse, 2-h light pulses placed at the midnight of an LD 12 : 12 h photoperiod are disrupted systematically by darkness. When a 2-h light pulse is disrupted by 15 min of darkness, diapause is generally prevented (< 29%) regardless of the temporal position of darkness. Longer disruption by darkness induces diapause moderately (37–67%). A Bunsow experiment is also conducted at 25 and 20 °C, in which the main photophase of 12 h of light is combined with 24–72-h scotophases scanned by a 2-h light pulse. The photoperiodic cycle length tested, therefore, varies in the range 36–84 h. In each cycle length, the incidence of diapause fluctuates as the light pulse moves toward dawn. However, no regular and circadian changes in the percentage diapause are observed in relation to diapause determination.