Showing papers by "Kumamoto University published in 2010"

Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus

Abstract: Concept of Diabetes Mellitus: Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long‐term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder.

alpha-Catenin as a tension transducer that induces adherens junction development.

Abstract: α-Catenin can respond to myosinII-mediated forces in cell–cell junctions through a force-dependent interaction with vinculin that regulates adherens junction development.

Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1.

Abstract: Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca(2+) concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.

Epithelial–mesenchymal transition in cancer development and its clinical significance

Abstract: The epithelial-mesenchymal transition (EMT) plays a critical role in embryonic development. EMT is also involved in cancer progression and metastasis and it is probable that a common molecular mechanism is shared by these processes. Cancer cells undergoing EMT can acquire invasive properties and enter the surrounding stroma, resulting in the creation of a favorable microenvironment for cancer progression and metastasis. Furthermore, the acquisition of EMT features has been associated with chemoresistance which could give rise to recurrence and metastasis after standard chemotherapeutic treatment. Thus, EMT could be closely involved in carcinogenesis, invasion, metastasis, recurrence, and chemoresistance. Research into EMT and its role in cancer pathogenesis has progressed rapidly and it is now hypothesized that novel concepts such as cancer stem cells and microRNA could be involved in EMT. However, the involvement of EMT varies greatly among cancer types, and much remains to be learned. In this review, we present recent findings regarding the involvement of EMT in cancer progression and metastasis and provide a perspective from clinical and translational viewpoints.

Noncontact Tactile Display Based on Radiation Pressure of Airborne Ultrasound

Abstract: This paper describes a tactile display which provides unrestricted tactile feedback in air without any mechanical contact. It controls ultrasound and produces a stress field in a 3D space. The principle is based on a nonlinear phenomenon of ultrasound: Acoustic radiation pressure. The fabricated prototype consists of 324 airborne ultrasound transducers, and the phase and intensity of each transducer are controlled individually to generate a focal point. The DC output force at the focal point is 16 mN and the diameter of the focal point is 20 mm. The prototype produces vibrations up to 1 kHz. An interaction system including the prototype is also introduced, which enables users to see and touch virtual objects.

Preparation of p-type CaFe2O4 photocathodes for producing hydrogen from water.

Abstract: An (hk0)-oriented p-type CaFe2O4 (Eg: 1.9 eV) photocathode was prepared, and hydrogen and oxygen gases were produced from a photocell short-circuited by connecting the CaFe2O4 and n-type TiO2 electrodes under illumination without applying an external voltage. The open-circuited voltage was 0.97 V and the short-circuit current was about 200 μA/cm2, and the amount of evaluated hydrogen and oxygen gases after 2 days of reaction were about 70 and 4 μmol, respectively.

Predicting remaining useful life of rotating machinery based artificial neural network

Abstract: Accurate remaining useful life (RUL) prediction of machines is important for condition based maintenance (CBM) to improve the reliability and cost of maintenance. This paper proposes artificial neural network (ANN) as a method to improve accurate RUL prediction of bearing failure. For this purpose, ANN model uses time and fitted measurements Weibull hazard rates of root mean square (RMS) and kurtosis from its present and previous points as input. Meanwhile, the normalized life percentage is selected as output. By doing that, the noise of a degradation signal from a target bearing can be minimized and the accuracy of prognosis system can be improved. The ANN RUL prediction uses FeedForward Neural Network (FFNN) with Levenberg Marquardt of training algorithm. The results from the proposed method shows that better performance is achieved in order to predict bearing failure.

Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma

Abstract: Many studies have shown that tumor-associated macrophages (TAMs) contribute to tumor development and poor prognosis in various cancers. In this study, we investigated the macrophage populations and phenotypes, and their correlation to angiogenesis, immunosuppression, and clinical prognosis in intrahepatic cholangiocarcinoma (ICC). CD68 (+) and CD163 (+) macrophage infiltration was analyzed in paraffin-embedded tissue samples from 39 patients. CD163 is used as a marker of M2 macrophages. Neovascularization and infiltration of forkhead box P3 (FOXP3) (+) regulatory T cells were also evaluated. The number of CD68 (+) and CD163 (+) macrophages was positively correlated with the numbers of vessels and regulatory T cells. The number of CD163 (+) cells was more closely associated with them. Intrahepatic cholangiocarcinoma (ICC) patients with high counts of CD163 (+) macrophages showed poor disease-free survival (P = 0.0426). The macrophage density was not correlated with overall survival. In an in vitro study using ICC cell lines (HuCCT1, RBE, and MEC) and human macrophages, tumor cell supernatant (TCS) from cell lines induced an activation of signal transducers and activators of transcription-3 (Stat3) and macrophage polarization toward the M2 phenotype. Tumor cell supernatant (TCS) from HuCCT1 most strongly induced Stat3 activation and production of cytokines and other bioactive molecules such as interleukin (IL)-10, vascular endothelial growth factor (VEGF)-A, transforming growth factor (TGF)-beta, and matrix metalloproteinase (MMP)-2. Down-regulation of Stat3 by siRNA significantly suppressed the production of IL-10 and VEGF-A. These results provide suggestive evidence that TAMs contribute to cancer progression via Stat3 activation, and CD163 is useful for evaluating M2 TAMs and predicting the clinical prognosis of ICC patients.

Simple Photoreduction of Graphene Oxide Nanosheet under Mild Conditions

Abstract: Graphene oxide (GO) nanosheets were reduced by UV irradiation in H2 or N2 under mild conditions (at room temperature) without a photocatalyst. Photoreduction proceeded even in an aqueous suspension of nanosheets. The GO nanosheets reduced by this method were analyzed by X-ray photoelectron spectroscopy and Raman spectroscopy. It was found that epoxy groups attached to the interiors of aromatic domains of the GO nanosheet were destroyed during UV irradiation to form relatively large sp2 islands resulting in a high conductivity. I−V curves were measured by conductive atomic force microscopy (AFM; perpendicular to a single nanosheet) and a two-electrode system (parallel to the nanosheet). They revealed that photoreduced GO nanosheets have high conductivities, whereas nonreduced GO nanosheets are nearly insulating. Ag+ adsorbed on GO nanosheets promoted the photoreduction. This photoreduction method was very useful for photopatterning a conducting section of micrometer size on insulating GO. The developed pho...

MicroRNA expression profiling of exfoliated colonocytes isolated from feces for colorectal cancer screening

Abstract: To reduce the colorectal cancer (CRC) mortality rate, we have reported several CRC screening methods using colonocytes isolated from feces. Expression analysis of oncogenic microRNA (miRNA) in peripheral blood was recently reported for CRC detection. In the present study, we conducted miRNA expression analysis of exfoliated colonocytes isolated from feces for CRC screening. Two hundred six CRC patients and 134 healthy volunteers were enrolled in the study. miRNA expression of the miR-17-92 cluster, miR-21, and miR-135 in colonocytes isolated from feces as well as frozen tissues was analyzed by quantitative real-time PCR. The expression of the miR-17-92 cluster, miR-21, and miR-135 was significantly higher in CRC tissues compared with normal tissues. The exfoliated colonocytes of 197 CRC patients and 119 healthy volunteers were analyzed because of the presence of sufficient miRNA concentration. miR-21 expression did not differ significantly between CRC patients and healthy volunteers (P = 0.6). The expression of miR-17-92 cluster and miR-135 was significantly higher in CRC patients than in healthy volunteers (P < 0.0001). The overall sensitivity and specificity by using miRNA expression was 74.1% (146/197; 95% confidence interval, 67.4-80.1) and 79.0% (94/119; 95% confidence interval, 70.6-85.9), respectively. Sensitivity was dependent only on tumor location (P = 0.0001). miRNA was relatively well conserved in exfoliated colonocytes from feces both of CRC patients and healthy volunteers. miRNA expression analysis of the isolated colonocytes may be a useful method for CRC screening. Furthermore, oncogenic miRNA highly expressed in CRC should be investigated for CRC screening tests in the future.

IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation

Abstract: Macrophage colony-stimulating factor (M-CSF) regulates the production, survival and function of macrophages through Fms, the receptor tyrosine kinase. Recently, interleukin-34 (IL-34), which shares no sequence homology with M-CSF, was identified as an alternative Fms ligand. Here, we provide the first evidence that these ligands indeed resemble but are not necessarily identical in biological activity and signal activation. In culture systems tested, IL-34 and M-CSF showed an equivalent ability to support cell growth or survival. However, they were different in the ability to induce the production of chemokines such as MCP-1 and eotaxin-2 in primary macrophages, the morphological change in TF-1-fms cells and the migration of J774A.1 cells. Importantly, IL-34 induced a stronger but transient tyrosine phosphorylation of Fms and downstream molecules, and rapidly downregulated Fms. Even in the comparison of active domains, these ligands showed no sequence homology including the position of cysteines. Interestingly, an anti-Fms monoclonal antibody (Mab) blocked both IL-34-Fms and M-CSF-Fms binding, but another MAb blocked only M-CSF-Fms binding. These results suggested that IL-34 and M-CSF differed in their structure and Fms domains that they bound, which caused different bioactivities and signal activation kinetics/strength. Our findings indicate that macrophage phenotype and function are differentially regulated even at the level of the single receptor, Fms.

Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study)

Abstract: Summary Background Fluorouracil and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are widely used as first-line or second-line chemotherapy for metastatic colorectal cancer. However, infusional fluorouracil-based regimens, requiring continuous infusion and implantation of an intravenous port system, are inconvenient. We therefore planned an open-label randomised controlled trial to verify the non-inferiority of irinotecan plus oral S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; IRIS) to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer. Methods Between Jan 30, 2006, and Jan 29, 2008, 426 patients with metastatic colorectal cancer needing second-line chemotherapy from 40 institutions in Japan were randomly assigned by a computer-based minimisation method to receive either FOLFIRI (n=213) or IRIS (n=213). In the FOLFIRI group, patients received folinic acid (200 mg/m 2 ) and irinotecan (150 mg/m 2 ) and then a bolus injection of fluorouracil (400 mg/m 2 ) on day 1 and a continuous infusion of fluorouracil (2400 mg/m 2 ) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m 2 ) on days 1 and 15 and S-1 (40–60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was progression-free survival, with a non-inferiority margin of 1·333. Statistical analysis was on the basis of initially randomised participants. This study is registered with ClinicalTrials.gov, number NCT00284258. Findings All randomised patients were included in the primary analysis. After a median follow-up of 12·9 months (IQR 11·5–18·2), median progression-free survival was 5·1 months in the FOLFIRI group and 5·8 months in the IRIS group (hazard ratio 1·077, 95% CI 0·879–1·319, non-inferiority test p=0·039). The most common grade three or four adverse drug reactions were neutropenia (110 [52·1%] of 211 patients in the FOLFIRI group and 76 [36·2%] of 210 patients in the IRIS group; p=0·0012), leucopenia (33 [15·6%] in the FOLFIRI group and 38 [18·1%] in the IRIS group; p=0·5178), and diarrhoea (ten [4·7%] in the FOLFIRI group and 43 [20·5%] in the IRIS group; p Interpretation Progression-free survival with IRIS is not inferior to that with FOLFIRI in patients receiving second-line chemotherapy for metastatic colorectal cancer. Treatment with IRIS could be an additional therapeutic option for second-line chemotherapy in metastatic colorectal cancer. Funding Taiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.

Solution of the Structure of the TNF-TNFR2 Complex

Abstract: Tumor necrosis factor (TNF) is an inflammatory cytokine that has important roles in various immune responses, which are mediated through its two receptors, TNF receptor 1 (TNFR1) and TNFR2. Antibody-based therapy against TNF is used clinically to treat several chronic autoimmune diseases; however, such treatment sometimes results in serious side effects, which are thought to be caused by the blocking of signals from both TNFRs. Therefore, knowledge of the structural basis for the recognition of TNF by each receptor would be invaluable in designing TNFR-selective drugs. Here, we solved the 3.0 angstrom resolution structure of the TNF-TNFR2 complex, which provided insight into the molecular recognition of TNF by TNFR2. Comparison to the known TNFR1 structure highlighted several differences between the ligand-binding interfaces of the two receptors. Additionally, we also demonstrated that TNF-TNFR2 formed aggregates on the surface of cells, which may be required for signal initiation. These results may contribute to the design of therapeutics for autoimmune diseases.

The Endoplasmic Reticulum Stress-C/EBP Homologous Protein Pathway-Mediated Apoptosis in Macrophages Contributes to the Instability of Atherosclerotic Plaques

Abstract: Objective— To elucidate whether and how the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway in macrophages is involved in the rupture of atherosclerotic plaques. Methods and Results— Increases in macrophage-derived foam cell death in coronary atherosclerotic plaques cause the plaque to become vulnerable, thus resulting in acute coronary syndrome. The ER stress–CHOP/growth arrest and DNA damage-inducible gene-153 (GADD153) pathway is induced in the macrophage-derived cells in atherosclerotic lesions and is involved in plaque formation. However, the role of CHOP in the final stage of atherosclerosis has not been fully elucidated. Many CHOP-expressing macrophages showed apoptosis in advanced ruptured atherosclerotic lesions in wild-type mice, whereas few apoptotic cells were observed in Chop −/− mice. The rupture of atherosclerotic plaques was significantly reduced in high cholesterol–fed Chop −/− / Apoe −/− mice compared with Chop +/+ / Apoe −/− mice. Furthermore, using mice that underwent bone marrow transplantation, we showed that expression of CHOP in macrophages significantly contributes to the formation of ruptures. By using primary cultured macrophages, we further showed that unesterified free cholesterol derived from incorporated denatured low-density lipoprotein was accumulated in the ER and induced ER stress-mediated apoptosis in a CHOP-Bcl2-associated X protein (Bax) pathway-dependent manner. Conclusion— The ER stress-CHOP-Bax–mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques.

Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis

Abstract: Recent accumulating evidence indicates a crucial involvement of macrophage lineage in the pathogenesis of systemic sclerosis (SSc). To analyze the assembly of the monocyte/macrophage population, we evaluated the expression of CD163 and CD204 and various activated macrophage markers, in the inflammatory cells of the skin and in the peripheral blood mononuclear cells (PBMCs) derived from patients with SSc. Skin biopsy specimens from 6 healthy controls and 10 SSc patients (7 limited cutaneous SSc and 3 diffuse cutaneous SSc) were analyzed by immunohistochemistry using monoclonal antibody against CD68 (pan-macrophage marker), CD163 and CD204. Surface and/or intracellular protein expression of CD14 (marker for monocyte lineage), CD163 and CD204 was analysed by flow cytometry in PBMCs from 16 healthy controls and 41 SSc patients (26 limited cutaneous SSc and 15 diffuse cutaneous SSc). Statistical analysis was carried out using Mann-Whitney U test for comparison of means. In the skin from SSc patients, the number of CD163+ cells or CD204+ cells between the collagen fibers was significantly larger than that in healthy controls. Flow cytometry showed that the population of CD14+ cells was significantly greater in PBMCs from SSc patients than that in healthy controls. Further analysis of CD14+ cells in SSc patients revealed higher expression of CD163 and the presence of two unique peaks in the CD204 histogram. Additionally, we found that the CD163+ cells belong to CD14brightCD204+ population. This is the first report indicating CD163+ or CD204+ activated macrophages may be one of the potential fibrogenic regulators in the SSc skin. Furthermore, this study suggests a portion of PBMCs in SSc patients abnormally differentiates into CD14brightCD163+CD204+ subset. The subset specific to SSc may play an important role in the pathogenesis of this disease, as the source of CD163+ or CD204+ macrophages in the skin.

Metallic Pd Nanoparticles Formed by Pd−O−Ce Interaction: A Reason for Sintering-Induced Activation for CO Oxidation

Abstract: Ambient-temperature CO oxidation activity of Pd/CeO2 was found to increase by more than 20 times after thermal aging at 900 °C in air. Although the aging resulted in a significant sintering accompanied by a 92% loss of surface area from 92 to 7 m2·g−1, Pd metal dispersion was preserved at a high value (0.57). The analysis using transmission electron microscopy (TEM), high-angle annular dark-field (HAADF)-scanning transmission electron microscopy (STEM), extended X-ray absorption fine structure (EXAFS), and X-ray photoelectron spectroscopy (XPS) demonstrated that the activation is driven by metal−support interactions followed by phase transformation. Owing to the formation of Pd−O−Ce bonding at the PdO/CeO2 interface, Pd oxide species are highly dispersed into the surface structure of CeO2. The Pd oxide becomes unstable when the temperature reaches ≥800 °C, where thermodynamic PdO/Pd phase equilibrium is reached. Finally, the Pd−O−Ce surface moiety is fragmented into metallic Pd particles with a size of 1 ...

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial

Abstract: Summary Background Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy. Methods The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11·25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. Findings 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by −5·1% (SD 21·0) in the leuprorelin group and by 0·2% (18·2) in the placebo group (difference between groups −5·3%; 95% CI −10·8 to 0·3; p=0·063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was −3·2% (−6·4 to 0·0; p=0·049), but there was no significant difference between the groups after covariate adjustment for the baseline data (−4·1 to 1·6; p=0·392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups −9·8, −17·1 to −2·5; p=0·009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0·727). Interpretation 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. Funding Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.

Cortisol is involved in temperature-dependent sex determination in the Japanese flounder.

Abstract: In vertebrates, sex is normally determined by genotype. However, in poikilothermal vertebrates, including reptiles, amphibians, and fishes, sex determination is greatly influenced by environmental factors, such as temperature. Little is known about the molecular mechanisms underlying environmental sex determination in these species. The Japanese flounder (Paralichthys olivaceus) is a teleost fish with an XX/XY sex determination system. However, XX flounder can be induced to develop into predominantly either phenotypic females or males, by rearing at 18 or 27 C, respectively, during the sex differentiation period. Therefore, the flounder provides an excellent model to study the molecular mechanisms underlying temperature-dependent sex determination. We previously showed that an aromatase inhibitor, an antiestrogen, and 27 C treatments cause masculinization of XX flounder, as well as suppression of mRNA expression of ovary-type aromatase (cyp19a1), a steroidogenic enzyme responsible for the conversion of androgens to estrogens in the gonads. Furthermore, estrogen administration completely inhibits masculinization by these treatments, suggesting suppression of cyp19a1 mRNA expression, and the resultant estrogen biosynthesis may trigger masculinization of the XX flounder induced by high water temperature. Here, we demonstrated that cortisol causes female-to-male sex reversal by directly suppressing cyp19a1 mRNA expression via interference with cAMP-mediated activation and that metyrapone (an inhibitor of cortisol synthesis) inhibits 27 C-induced masculinization of XX flounder. Moreover, cortisol concentrations in 27 C-reared juveniles were significantly higher than in 18 C-reared fishes during sexual differentiation. These results strongly suggest that masculinization by high water temperature is ascribable to elevation of cortisol concentration during gonadal sex differentiation in the flounder.

Recommended nomenclature for five mammalian carboxylesterase gene families: Human, mouse, and rat genes and proteins

Abstract: Mammalian carboxylesterase (CES or Ces) genes encode enzymes that participate in xenobiotic, drug, and lipid metabolism in the body and are members of at least five gene families. Tandem duplications have added more genes for some families, particularly for mouse and rat genomes, which has caused confusion in naming rodent Ces genes. This article describes a new nomenclature system for human, mouse, and rat carboxylesterase genes that identifies homolog gene families and allocates a unique name for each gene. The guidelines of human, mouse, and rat gene nomenclature committees were followed and “CES” (human) and “Ces” (mouse and rat) root symbols were used followed by the family number (e.g., human CES1). Where multiple genes were identified for a family or where a clash occurred with an existing gene name, a letter was added (e.g., human CES4A; mouse and rat Ces1a) that reflected gene relatedness among rodent species (e.g., mouse and rat Ces1a). Pseudogenes were named by adding “P” and a number to the human gene name (e.g., human CES1P1) or by using a new letter followed by ps for mouse and rat Ces pseudogenes (e.g., Ces2d-ps). Gene transcript isoforms were named by adding the GenBank accession ID to the gene symbol (e.g., human CES1_AB119995 or mouse Ces1e_BC019208). This nomenclature improves our understanding of human, mouse, and rat CES/Ces gene families and facilitates research into the structure, function, and evolution of these gene families. It also serves as a model for naming CES genes from other mammalian species.

High temperature causes masculinization of genetically female medaka by elevation of cortisol

Abstract: In poikilothermic vertebrates, sex determination is sometimes influenced by environmental factors such as temperature. However, little is known about the molecular mechanisms underlying environmental sex determination. The medaka (Oryzias latipes) is a teleost fish with an XX/XY sex determination system. Recently, it was reported that XX medaka can be sex-reversed into phenotypic males by high water temperature (HT; 32-34 degrees C) treatment during the sex differentiation period. Here we report that cortisol caused female-to-male sex reversal and that metyrapone (an inhibitor of cortisol synthesis) inhibited HT-induced masculinization of XX medaka. HT treatment caused elevation of whole-body levels of cortisol, while metyrapone suppressed the elevation by HT treatment during sexual differentiation. Moreover, cortisol and 33 degrees C treatments inhibited female-type proliferation of germ cells as well as expression of follicle-stimulating hormone receptor (fshr) mRNA in XX medaka during sexual differentiation. These results strongly suggest that HT induces masculinization of XX medaka by elevation of cortisol level, which, in turn, causes suppression of germ cell proliferation and of fshr mRNA expression.

Effects of 0.6 mg/kg Intravenous Alteplase on Vascular and Clinical Outcomes in Middle Cerebral Artery Occlusion Japan Alteplase Clinical Trial II (J-ACT II)

Abstract: Background and Purpose— The purpose of this study was to evaluate further the efficacy of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in patients with middle cerebral artery occlusion in a postmarketing Phase IV trial of prospective cohort study design. Methods— Alteplase was given intravenously at 0.6 mg/kg to patients with ischemic stroke within 3 hours of onset with MR angiography-documented middle cerebral artery occlusion. Vascular outcome was evaluated by MR angiography at 6 and 24 hours after symptom onset based on the modified Mori grade. The primary end points also included a favorable outcome (modified Rankin Scale 0 to 1 at 3 months after onset) and incidence of symptomatic intracranial hemorrhage within 36 hours after treatment. The impact of recanalization on clinical outcome was assessed by stepwise logistic regression analysis. Results— Fifty-eight patients were enrolled. Recanalization was noted in 51.7% on 6-hour MR angiography and 69.0% on 24-hour MR angiography. A ...

Mechanisms of skin fibrosis in systemic sclerosis

Abstract: Systemic sclerosis (SSc) or scleroderma is an acquired disorder which typically results in fibrosis of the skin and internal organs. Skin fibrosis, the hallmark of this disease, is defined as excess deposition and accumulation of extracellular matrix, mainly type I collagen, in the dermis. Dermal fibroblasts isolated from lesional skin of SSc patients and cultured in vitro exhibit increased synthesis of collagen and decreased collagenase activity, consistent with the disease phenotype. This review focuses on the recent progress in the research for molecular mechanisms of skin fibrosis in SSc. The upregulated collagen production at transcriptional level in SSc fibroblasts involves various regulators including cytokines or transcription factors. Among them, transforming growth factor (TGF)-beta/Smad signaling is likely to play a key role in the pathogenesis of SSc, and the autocrine TGF-beta signaling hypothesis can explain intrinsic activation of collagen promoter in SSc fibroblasts. Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases might also contribute to the excess accumulation of collagen in the dermis.

Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease

Abstract: Aims Two multicentre, randomized, double-blind, placebo-controlled Phase II studies assessed the safety and efficacy of the oral protease-activated receptor 1 (PAR-1) antagonist E5555 in addition to standard therapy in Japanese patients with acute coronary syndrome (ACS) or high-risk coronary artery disease (CAD). Methods and results Patients with ACS ( n = 241) or high-risk CAD ( n = 263) received E5555 (50, 100, or 200 mg) or placebo once daily for 12 (ACS patients) or 24 weeks (CAD patients). The incidence of TIMI major, minor, and minimal bleeds requiring medical attention was similar in the placebo and combined E5555 (atopaxar) groups (ACS: 6.6% placebo vs. 5.0% E5555; CAD: 1.5% placebo vs. 1.5% E5555). There were no TIMI major bleeds and three CURE major bleeds (two with placebo; one with 100 mg E5555). There was a numerical increase in ‘any’ TIMI bleeding with the E5555 200 mg dose (ACS: 16.4% placebo vs. 23.0% E5555, P = 0.398; CAD: 4.5% placebo vs. 13.2% E5555, P = 0.081). The rate of major cardiovascular adverse events in the combined E5555 group was not different from placebo (ACS: 6.6% placebo vs. 5.0% E5555, P = 0.73; CAD: 4.5% placebo vs. 1.0% E5555, P = 0.066). There was a statistically significant dose-dependent increase in liver function abnormalities and QTcF with E5555. At trough dosing levels in both populations, mean inhibition of platelet aggregation was >90% with 100 and 200 mg E5555, and 20–60% with 50 mg E5555. Conclusion E5555 (50, 100, and 200 mg) did not increase clinically significant bleeding, although there was a higher rate of any TIMI bleeding with the highest two doses. All doses tested achieved a significant level of platelet inhibition. There was a significant dose-dependent increase in liver function abnormalities and QTcF. Although further study is needed, PAR-1 antagonism may have the potential to be a novel pathway for platelet inhibition to add on to the current standard of care therapy.