Suzuki-Miyaura Cross-Coupling Reaction Using Palladium Catalysts Supported on Phosphine Periodic Mesoporous Organosilica.

Phosphine periodic mesoporous organosilicas (R-P-PMO-TMS: R=Ph, tBu), which possess electron-donating alkyl substituents on the phosphorus atom, were synthesized using bifunctional compounds with alkoxysilyl- and phosphino groups, bis[3-(triethoxysilyl)propyl]phenylphosphine borane (1 a) and bis[3-(triethoxysilyl)propyl]-tert-butylphosphine borane (1 b). Immobilization of Pd(0) species was performed to give R-P-Pd-PMO-TMS: R=Ph (2 a), tBu (3 a), respectively. The Pd(0) immobilized 2 a and 3 a were applicable as catalysts for Suzuki-Miyaura cross-coupling reactions of aryl chlorides with phenylboronic acid. It was revealed that 3 a bearing more electron-donating tBu groups exhibited higher catalytic activity. Various functional groups including both electron withdrawing and donating substituents were compatible in the system. The recyclability of 3 a was examined to support its moderate utility for the recycle use.

Synthesis of Multiblock Copolymer Composed of Biodegradable Poly(butylene succinate) and Poly(2-pyrrolidone): Impact of Each Block Length on the Mechanical Properties.

A series of multiblock copolymers comprising a systematic combination of biomass-originated and biodegradable poly(butylene succinate) (PBS) and poly(2-pyrrolidone) (PA4) units is synthesized with various mean degrees of polymerization (mDP) of each unit. Despite the inherent immiscibility of PBS and PA4, multiblock structure allows to mix the two components in the solution-cast films from solution. The mechanical properties of the cast films are highly dependent on the mDP of each unit, as demonstrated by tensile tests. The film of the copolymer with the lowest mDP of each unit (PBS: 17, PA4: 10) is transparent and exhibits extremely high elongation at break (> 400%) and high tensile stress (39.5 MPa) with strain hardening. The films with 50% or higher crystallinity are brittle and opaque, while a decrease in crystallinity can result in higher elongation, as revealed by wide-angle X-ray diffraction measurements.

Effects of Helicobacter pylori on the glutathione-related pathway in gastric epithelial cells.

Virulence factors of Helicobacter pylori (H. pylori) are diverse, so various biological responses happen in a host infected with H. pylori. The aim of this study is to conduct the metabolomics-based evaluation on H. pylori infection. AGS human gastric carcinoma cells were infected with H. pylori strain 26695, and then the altered metabolite pathways in the infected AGS cells were analyzed by metabolomics. Metabolites related to the glutathione (GSH) cycle were downregulated by H. pylori infection. Next, we evaluated the effects of H. pylori on the GSH-related pathway in AGS cells infected with H. pylori isolated from patients with atrophic gastritis (AG), duodenal ulcer (DU) and gastric cancer (GC). We found that the declined degree of GSH levels and oxidative stress were greater in AGS cells infected with GC strains than DU and AG-derived strains. There were no significant differences in almost mRNA expressions of GSH-related factors among different clinical strains, but the protein expression of glutathione synthetase was lower in AGS cells infected with GC-derived strains than DU and AG-derived strains. Our data demonstrates that GC-derived H. pylori-induced oxidative stress in a host is stronger and GC-derived strains may have suppressive influences on the host's GSH-related defense systems.

Adrenic acid induces oxidative stress in hepatocytes.

Adrenic acid (ADA), which is an endogenously synthesized polyunsaturated free fatty acid, was significantly increased in nonalcoholic fatty liver disease (NAFLD) patients and NAFLD-model mice compared with the corresponding controls in our previous study. To elucidate the involvement of ADA in NAFLD and nonalcoholic steatohepatitis (NASH), we examined ADA-induced lipotoxicity in human hepatocarcinoma HepG2 cells. The ROS production in HepG2 cells was increased by exposure to ADA. It was also shown that the treatment with ADA decreased cell viability in a dose-dependent manner. The N-Acetyl-L-Cysteine pretreatment counteracted this ADA-induced ROS production and cell death. Furthermore, ADA modulated the expressions of SOD2, HO-1 and Gpx1 as antioxidant enzymes. These findings suggest that ADA could induce oxidative stress accompanied by cell death, providing new insights into lipotoxicity that is involved in the pathogenesis of NAFLD and NASH.

Comparative proteomics of Helicobacter pylori strains reveals geographical features rather than genomic variations.

Helicobacter pylori, a pathogen of various gastric diseases, has many genome sequence variants. Thus, the pathogenesis and infection mechanisms of the H. pylori-driven gastric diseases have not been elucidated. Here, we carried out a large-scale proteome analysis to profile the heterogeneity of the proteome expression of 7 H. pylori strains by using an LC/MS/MS-based proteomics approach combined with a customized database consisting of nonredundant tryptic peptide sequences derived from full genome sequences of 52 H. pylori strains. The nonredundant peptide database enabled us to identify more peptides in the database search of MS/MS data compared with a simply merged protein database. Using this approach, we carried out proteome analysis of genome-unknown strains of H. pylori at as large a scale as genome-known ones. Clustering of the H. pylori strains using proteome profiling slightly differed from the genome profiling and more clearly divided the strains into two groups based on the isolated area. Furthermore, we identified phosphorylated proteins and sites of the H. pylori strains and obtained the phosphorylation motifs located in the N-terminus that are commonly observed in bacteria.

Novel Autoantibody Signatures in Sera of Patients with Pancreatic Cancer, Chronic Pancreatitis and Autoimmune Pancreatitis: A Protein Microarray Profiling Approach.

Identification of disease-associated autoantibodies is of high importance. Their assessment could complement current diagnostic modalities and assist the clinical management of patients. We aimed at developing and validating high-throughput protein microarrays able to screen patients' sera to determine disease-specific autoantibody-signatures for pancreatic cancer (PDAC), chronic pancreatitis (CP), autoimmune pancreatitis and their subtypes (AIP-1 and AIP-2). In-house manufactured microarrays were used for autoantibody-profiling of IgG-enriched preoperative sera from PDAC-, CP-, AIP-1-, AIP-2-, other gastrointestinal disease (GID) patients and healthy controls. As a top-down strategy, three different fluorescence detection-based protein-microarrays were used: large with 6400, intermediate with 345, and small with 36 full-length human recombinant proteins. Large-scale analysis revealed 89 PDAC, 98 CP and 104 AIP immunogenic antigens. Narrowing the selection to 29 autoantigens using pooled sera first and individual sera afterwards allowed a discrimination of CP and AIP from PDAC. For validation, predictive models based on the identified antigens were generated which enabled discrimination between PDAC and AIP-1 or AIP-2 yielded high AUC values of 0.940 and 0.925, respectively. A new repertoire of autoantigens was identified and their assembly as a multiplex test will provide a fast and cost-effective tool for differential diagnosis of pancreatic diseases with high clinical relevance.

T-cell trafficking plays an essential role in tumor immunity.

Distinct populations of effector memory T cells use different homing receptors to traffic to the skin and gut. Whether tissue-selective T cells are needed for early rejection of a neoplasm growing in these tissues remains an open question. We chose to study an allogeneic tumor model because growth of such a fully mismatched tumor would signify a profound immune deficit. We implanted allogeneic tumor cells in the skin or gut of mice deficient in either α(1,3) fucosyltransferases IV and VII, enzymes critical for generating E-selectin ligands on skin-homing T cells, or ß7 integrin, a component of the α4ß7 integrin ligand for the mucosal adressin MAdCAM. During the first 9 days after tumor implantation, FucTVII-/- mice showed a profoundly impaired capacity to reject tumors growing in the skin, but readily rejected tumors implanted in the gut. Rejection of tumors in the skin was even more impaired in mice deficient in both FucTIV and FucTVII. This impairment was corrected by infusion of T cells from normal mice. By contrast, ß7 integrin-/- mice showed profoundly impaired rejection of tumors in the gut, but no defect in the skin tumor rejection. These differences were unrelated to antigen recognition or effector function of T cells, since all strains of mice were capable of generating tumor-specific CTLs in vitro against the tumor cell line used in vivo. These results demonstrate that T-cell homing defects in vivo impair immune surveillance of peripheral epithelial tissues in a specific and selective fashion.

Increased Levels of Branched-Chain Amino Acid Associated With Increased Risk of Pancreatic Cancer in a Prospective Case-Control Study of a Large Cohort.

BACKGROUND & AIMS: A marker is needed to identify individuals at risk for pancreatic cancer. Increases in branched-chain amino acids (BCAAs) have been associated with pancreatic cancer. We performed a prospective case-control study to study the association between plasma BCAA levels and risk of pancreatic cancer in a large cohort. METHODS: We conducted a nested case-control study selected from 30,239 eligible participants 40-69 years old within the Japan Public Health Center-based prospective study. Over 16.4 years, 170 newly diagnosed pancreatic cancer cases were identified. Each case was matched to 2 controls by age, gender, geographic area, and fasting time at blood collection. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer were calculated using conditional logistic regression models with adjustment for potential confounding factors. RESULTS: Increased plasma BCAA levels at baseline were associated with an increased risk of pancreatic cancer. Compared with the lowest quartile of BCAA levels, the OR in the highest quartile was 2.43 (95% CI 1.21-4.90), and the OR per 1 SD increase in BCAA levels was 1.32 (95% CI 1.05-1.67). The association was especially strong for cases with blood samples collected at least 10 years before cancer diagnosis (OR per SD 1.60, 95% CI 1.10-2.32) compared with those detected less than 10 years before diagnosis (OR per SD 1.16, 95% CI 0.86-1.57). CONCLUSIONS: In an analysis of data from the Japan Public Health Center-based prospective study, we found an association between increased plasma BCAA level and increased risk of pancreatic cancer-particularly when the increase in BCAAs was observed at least 10 years before diagnosis. These findings add to the growing body of evidence for the association between BCAA levels and pancreatic cancer risk.

Enantioselective Friedel-Crafts Alkylation Reaction of Heteroarenes with N-Unprotected Trifluoromethyl Ketimines by Means of Chiral Phosphoric Acid.

An enantioselective Friedel-Crafts alkylation reaction of pyrroles and indoles with N-unprotected trifluoromethyl ketimines by use of chiral phosphoric acid provided α-trifluoromethylated primary amines bearing chiral tetrasubstituted carbon centers in high yields and with high to excellent enantioselectivities. The present reaction is unique to N-unprotected trifluoromethyl ketimines. No reaction took place with N-p-methoxyphenyl (PMP)-substituted ketimine. Corresponding α-trifluoromethylated amines were transformed without loss of enantioselectivity.

ß-hydroxybutyrate protects hepatocytes against endoplasmic reticulum stress in a sirtuin 1-independent manner.

ß-hydroxybutyrate (BHB), a major ketone body in mammals, is produced from fatty acids through mitochondrial fatty acid oxidation in hepatocytes. To elucidate the role of BHB in the hepatic endoplasmic reticulum (ER), we examined the effects of BHB on hepatic ER stress induced by tunicamycin. In mouse hepatoma Hepa1c1c7 cells, BHB treatment suppressed the protein expression of ER stress responsive genes and increased cell viability, while reducing the protein expression of apoptosis inducible genes, without causing any alterations in the protein expression of sirtuin 1 (SIRT1) or the phosphorylation of AMP-activated protein kinase. The intraperitoneal administration of BHB also reduced the protein expression of ER stress responsive genes in mouse livers. In human hepatoma HepG2 cells, the protein expression levels of ER stress responsive genes were increased by the partial inhibition of BHB production with siRNA targeting endogenous 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lyase, whereas they were decreased by promoting BHB production with fenofibrate. These findings revealed that BHB helps to suppress hepatic ER stress via a SIRT1-independent pathway, and it might be possible to manipulate ER stress by regulating BHB production genetically or pharmacologically.

Photocurable Urushiol Analogues Bearing Methacryloxy-Containing Side chains.

Photocurable urushiol analogues were synthesized using eugenol (an ingredient of clove oil) as the starting material. Photo-induced radical polymerization with 2,2-dimethoxy-2-phenylacetophenone as a photo-initiator took place in the film prepared from the urushiol analogue-bearing methacryloxy groups at the ends of their side chains. Successful polymerization was confirmed by infrared spectroscopy measurements of the film before and after photo-irradiation. Strain-induced elastic buckling instability for mechanical measurement tests revealed that the Young's moduli of the photo-irradiated samples were 4-5 times higher than the films without photo-irradiation. This was attributed to the formation of a highly cross-linked structure through polymerization of the methacrylic moieties and oxidative polymerization of the catechol moieties. Photo-induced surface texturing was also performed for the films prepared on a substrate using a photomask. Negative-tone patterns were successfully obtained after development by soaking in cyclohexanone over several minutes. The preparation of such patterned surfaces was of particular relevance as the obtained surface can serve as a scaffold for cell adhesion, protein immobilization, and the immobilization of other chemicals with spatial disposition.

Endoscopic Hemostasis in Porcine Gastrointestinal Tract Using CO2 Low-Temperature Plasma Jet.

BACKGROUND: Recently, atmospheric low-temperature plasma (LTP) has attracted attention as a novel medical tool that might be useful for achieving hemostasis. However, conventional plasma sources are too big for use with endoscopes, and the efficacy of LTP for achieving hemostasis in cases of gastrointestinal bleeding is difficult to investigate. In this study, to solve the problem, we developed a 3D-printed LTP jet that has a diameter of 2.8 mm and metal body for endoscopic use. The characteristics, hemostasis efficacy, and safety were investigated. MATERIALS AND METHODS: On investigating the basic characteristics of the developed plasma jet, the electron densities, gas temperatures, and reactive species were measured by emission spectroscopy and thermocouple. To evaluate the efficacy of such hemostatic treatment, porcine gastrointestinal bleeding was treated with the device. In addition, to investigate the safety of such treatment, the CO2 LTP-treated tissue was compared with tissue that was treated with clipping-based or argon plasma coagulation-based hemostasis for 5 d, and hematoxylin and eosin staining was used to evaluate tissue damage in the treated regions. RESULTS: The measurement of emission spectroscopy, power, and electron density of various gas plasmas suggested that a high-density (1014 cm-3) LTP of CO2 was generated by the LTP jet, and the gas temperature was 41.5°C at 3 mm from the outlet of the LTP jet. The CO2 LTP achieved hemostasis of oozing blood by 70 ± 20 s. In addition, the CO2 LTP resulted in earlier recovery than clipping-based or argon plasma coagulation-based hemostases, and the treated regions had no damage by the CO2 LTP treatment. CONCLUSIONS: These results indicated that the developed LTP plasma jet has the potential to be used for endoscopic hemostasis.

Metabolome analysis for pancreatic cancer risk in nested case-control study: Japan Public Health Center-based prospective Study.

Discovery of a high-risk group for pancreatic cancer is important for prevention of pancreatic cancer. The present study was conducted as a nested case-control study including 170 pancreatic cancer cases and 340 matched controls of our population-based cohort study involving 30 239 subjects who answered a baseline questionnaire and supplied blood samples. Twelve targeted metabolites were quantitatively analyzed by gas chromatography/tandem mass spectrometry. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were calculated using conditional logistic regression models. Statistically significant P-value was defined as P < .05. Increasing 1,5-anhydro-d-glucitol (1,5-AG) levels were associated with a decreasing trend in pancreatic cancer risk (OR of quartile 4 [Q4], 0.50; 95% CI, 0.27-0.93; P = .02). Increasing methionine levels were also associated with an increasing trend of pancreatic cancer risk (OR of Q4, 1.79; 95% CI, 0.94-3.40: P = .03). Additional adjustment for potential confounders attenuated the observed associations of 1,5-AG and methionine (P for trend = .06 and .07, respectively). Comparing subjects diagnosed in the first 0-6 years, higher levels of 1,5-AG, asparagine, tyrosine and uric acid showed a decreasing trend for pancreatic cancer risk (P for trend = .04, .04, .04 and .02, respectively), even after adjustment for potential confounders. We found that the 12 target metabolites were not associated with pancreatic cancer risk. However, metabolic changes in the subjects diagnosed in the first 0-6 years showed a similar tendency to our previous reports. These results might suggest that these metabolites are useful for early detection but not for prediction of pancreatic cancer.

Serum apolipoprotein A2 isoforms in autoimmune pancreatitis.

Recently, apolipoprotein A2 (apoA2) isoforms have been reported as candidate serum/plasma biomarkers of pancreatic cancer. However, the distribution of apoA2 isoforms in patients with autoimmune pancreatitis (AIP) has not been investigated yet. In this study, we evaluated the distribution of serum apoA2 isoforms; i.e., homodimer apoA2-ATQ/ATQ, heterodimer apoA2-ATQ/AT, and homodimer apoA2-AT/AT, in AIP patients and healthy volunteers (HV) using enzyme-linked immunosorbent assays, and the clinical characteristics and serum levels of each apoA2 isoform in 32 AIP patients and 38 HV were investigated. The calculated apoA2-ATQ/AT levels of the AIP patients were significantly lower than those of the HV, which agreed with results obtained for patients with pancreatic cancer. Interestingly, most of the AIP patients exhibited high levels of apoA2-ATQ along with low levels of apoA2-AT, indicating that the processing of the C-terminal regions of apoA2 dimer was inhibited in the AIP patients. This specific distribution of serum apoA2 isoforms might provide important information about the disease states of AIP patients and aid the differential diagnosis of AIP versus pancreatic cancer.

Alterations in metabolic pathways in gastric epithelial cells infected with Helicobacter pylori.

Helicobacter pylori (H. pylori), which is a spiral-shaped Gram-negative microaerobic bacterium, is a causative pathogen. The entry of H. pylori into gastric epithelial cells involves various host signal transduction events, and its virulence factors can also cause a variety of biological responses. In this study, AGS human gastric carcinoma cells were infected with CagA-positive H. pylori strain ATCC43504, and then the metabolites in the AGS cells after the 2-, 6- and 12-h infections were analyzed by GC/MS-based metabolomic analysis. Among 67 metabolites detected, 11 metabolites were significantly altered by the H. pylori infection. The metabolite profiles of H. pylori-infected AGS cells were evaluated on the basis of metabolite pathways, and it was found that glycolysis, tricarboxylic acid (TCA) cycle, and amino acid metabolism displayed characteristic changes in the H. pylori-infected AGS cells. At 2 h post-infection, the levels of many metabolites related to TCA cycle and amino acid metabolism were lower in H. pylori-infected AGS cells than in the corresponding uninfected AGS cells. On the contrary, after 6-h and 12-h infections the levels of most of these metabolites were higher in the H. pylori-infected AGS cells than in the corresponding uninfected AGS cells. In addition, it was shown that the H. pylori infection might regulate the pathways related to isocitrate dehydrogenase and asparagine synthetase. These metabolite alterations in gastric epithelial cells might be involved in H. pylori-induced biological responses; thus, our findings are important for understanding H. pylori-related gastric diseases.

Multifocal cysts and incidence of pancreatic cancer concomitant with intraductal papillary mucinous neoplasm.

OBJECTIVES: The present study was conducted in order to elucidate the relationship between the number of cyst-existing regions and incidence of pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm (IPMN), which currently remains unclear. METHODS: Subjects comprised 141 patients undergoing resection for IPMN (Non-invasive IPMN (IPMN with low-to high-grade dysplasia): N = 94, invasive IPMN: N = 31, and PDAC concomitant with IPMN: N = 16) between November 2000 and February 2017. A logistic regression analysis was performed to assess the relationship between the number of cyst-existing regions (one region/two or more regions) and incidence of PDAC concomitant with IPMN, adjusted by clinical characteristics. Cyst-existing regions were defined by the number of anatomical parts of the pancreas: the head/body/tail of the pancreas. RESULTS: Multiple cyst-existing regions (two or more regions) correlated with the incidence of PDAC concomitant with IPMN (PDAC concomitant with IPMN in one region vs. two or more regions: 3/66 vs. 13/75, multivariable odds ratio [OR] = 4.11, 95% confidence interval [CI] = 1.22 to 18.8, P = 0.02). In contrast, multiple cyst-existing regions did not correlate with the incidence of IPMN (invasive IPMN in one region vs. two or more regions: 13/66 vs. 18/75, OR = 1.19, 95% CI = 0.52 to 2.76, P = 0.67). CONCLUSIONS: Multifocal cysts correlated with the incidence of PDAC concomitant with IPMN, and may be a high-risk factor for PDAC concomitant with IPMN.

Pancreatic inflammation and atrophy are not associated with pancreatic cancer concomitant with intraductal papillary mucinous neoplasm.

BACKGROUND: Inflammation-induced carcinogenesis in pancreatic ductal adenocarcinoma (PDAC) has been reported; however, its involvement in PDAC with intraductal papillary mucinous neoplasm (IPMN) remains unclear. We herein investigated the relationship between pancreatic atrophy and inflammation and the incidence of PDAC concomitant with IPMN. METHODS: This study included 178 consecutive patients who underwent surgical resection for PDAC with IPMN (N = 21) and IPMN (N = 157) between April 2001 and October 2016. A multivariable logistic regression analysis was conducted to assess the relationship between pancreatic inflammation and atrophy and the incidence of PDAC concomitant with IPMN, with adjustments for clinical characteristics and imaging features. Pathological pancreatic inflammation and atrophy were evaluated in resected specimens. RESULTS: High degrees of pancreatic inflammation and atrophy were not associated with the incidence of PDAC with IPMN (multivariable odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.07 to 3.33, P = .52, adjusted by clinical characteristics, OR = 0.9, 95% CI = 0.10 to 5.86, P = .91, adjusted by imaging studies; OR = 0.2, 95% CI = 0.009 to 1.31, P = .10, adjusted by clinical characteristics, OR = 0.2, 95% CI = 0.01 to 1.43, P = .12, adjusted by imaging studies, respectively). CONCLUSIONS: Pancreatic inflammation and atrophy were not associated with pancreatic cancer concomitant with IPMN.

Alterations in Docosahexaenoic Acid-Related Lipid Cascades in Inflammatory Bowel Disease Model Mice.

BACKGROUND: Inflammatory bowel disease (IBD) is an intestinal disorder, involving chronic and relapsing inflammation of the digestive tract. Dysregulation of the immune system based on genetic, environmental, and other factors seems to be involved in the onset of IBD, but its exact pathogenesis remains unclear. Therefore, radical treatments for ulcerative colitis and Crohn's disease remain to be found, and IBD is considered to be a refractory disease. AIMS: The aim of this study is to obtain novel insights into IBD via metabolite profiling of interleukin (IL)-10 knockout mice (an IBD animal model that exhibits a dysregulated immune system). METHODS: In this study, the metabolites in the large intestine and plasma of IL-10 knockout mice were analyzed. In our analytical system, two kinds of analysis (gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry) were used to detect a broader range of metabolites, including both hydrophilic and hydrophobic metabolites. In addition, an analysis of lipid mediators in the large intestine and ascites of IL-10 knockout mice was carried out. RESULTS: The levels of a variety of metabolites, including lipid mediators, were altered in IL-10 knockout mice. For example, high large intestinal and plasma levels of docosahexaenoic acid (DHA) were observed. In addition, arachidonic acid- and DHA-related lipid cascades were upregulated in the ascites of the IL-10 knockout mice. CONCLUSIONS: Our findings based on metabolite profiles including lipid mediators must contribute to development of researches about IBD.

Proton Pump Inhibitors Increase the Susceptibility of Mice to Oral Infection with Enteropathogenic Bacteria.

BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the most frequently prescribed medications. Side effects including an increased risk of intestinal infections have been reported. It is assumed that PPIs can increase susceptibility to enteropathogens; however, the underlying mechanisms are unknown. Here in this study, we explored whether Lansoprazole (Laz), one of the PPIs, increases the susceptibility to enteropathogens, and further investigated the mechanism of it. METHODS: Mice were administered Laz intraperitoneally once daily and orally infected with Citrobacter rodentium (C. rodentium). The establishment of intestinal infection was assessed by histology and inflammatory cytokine expression levels measured by quantitative PCR. To test whether Laz changes the intestinal environment to influence the susceptibility, intestinal pH, microbiota, metabolites and immune cell distributions were evaluated via pH measurement, 16S rRNA gene sequencing, metabolome, and flow cytometry analyses after Laz administration. RESULTS: Colitis was induced with less C. rodentium in Laz-treated mice as compared with the controls. We found that increased numbers of C. rodentium could reach the cecum following Laz administration. Laz increased pH in the stomach but not in the intestines. It induced dysbiosis and changed the metabolite content of the small intestine. However, these changes did not lead to alterations of immune cell distribution. CONCLUSIONS: Laz raised susceptibility to C. rodentium as increased numbers of the pathogen reach the site of infection. Our results suggest that it was due to increased stomach pH which allowed more peroral enteropathogens to pass the stomach, but not because of changes of intestinal environment.

[Possibility of Metabolite Biomarkers for Early Detection of Cancer].

Recently, the omics analysis, which comprehensively analyzed the biological molecules such as DNA, RNA, protein and low molecular weight metabolites, has been developed. The metabolome analysis that comprehensively analyzes low molecular weight metabolites is one of the most recent omics analysis, and attracts rising attention. Evaluating the metabolite alterations and clarifying the metabolite profiles in the body will lead to understandings of biological information, and the metabolome analysis has the potential of elucidation of novel pathological conditions and discovery of metabolite biomarkers. In this article, we explain the characteristics of the omics analysis. Regarding the metabolome analysis, its detailed explanations are carried out, and we also introduce our metabolite biomarker research about pancreatic cancer using the metabolome analysis.