Miura M.,Akita University
Biological and Pharmaceutical Bulletin | Year: 2015
Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). According to European LeukemiaNet recommendations, the clinical response of CML patients receiving TKI therapy should be evaluated after 3, 6, and 12 months. For patients not achieving a satisfactory response within 3 months, the mean plasma concentration for the three months of TKI administration must be considered. In TKI therapy for CML patients, therapeutic drug monitoring is a new strategy for dosage optimization to obtain a faster and more effective clinical response. The imatinib plasma trough concentration (C0) should be set above 1000 ng/mL to obtain a response and below 3000 ng/mL to avoid serious adverse events such as neutropenia. For patients with a UGT1A1∗6/∗6,∗6/∗28, or∗28/∗28 genotype initially administered 300-400 mg/d, a target nilotinib C0 of 500 ng/mL is recommended to prevent elevation of bilirubin levels, whereas for patients with the UGT1A1∗1 allele initially administered 600 mg/d, a target nilotinib C0 of 800 ng/mL is recommended. For dasatinib, it is recommended that a higher Cmax or C2 (above 50 ng/mL) to obtain a clinical response and a lower C0 (less than 2.5 ng/mL) to avoid pleural effusion be maintained by once daily administration of dasatinib. Although at present clinicians consider the next pharmacotherapy from clinical responses (efficacy/toxicity) obtained by a fixed dosage of TKI, the TKI dosage should be adjusted based on target plasma concentrations to maximize the efficacy and to minimize the incidence of adverse events. © 2015 The Pharmaceutical Society of Japan.
Imai Y.,Akita University
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2015
Influenza A viruses are the causative agents of seasonal and pandemic infections. Influenza strains have recently emerged that show resistance to anti-viral drugs. Moreover, therapies in critically ill patients with severe influenza are limited, with the current anti-viral drugs showing disappointing results even in the absence of obvious viral resistance. Given the high mortality associated with avian H5N1 or H7N9 infections and the risk of pandemic potentials, effective drugs are needed for the treatment of severe influenza. A virus-host interaction is a multidimensional host response, in which not only genes and protein but also metabolites are up- or down-regulated, and cellular pathways and networks implicated in the viral pathogenesis are perturbed. Thus, it seems an attractive strategy to overcome influenza by targeting host metabolites and/or metabolic pathways involved in viral pathogenesis. Using lipidomics and lipid libraries screening, potectin D1 isomer (PDX) derived from the 15-lipoxygenase product 17S-H(p)DHA and/or 17HDHA precursor, has recently been identified, which suppresses influenza virus replication by inhibiting the nuclear export of viral mRNA rather than regulating resolution of inflammation. Contribution of the protectins to control influenza virus replication and their therapeutic potentials are reviewed here. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". © 2015 Elsevier B.V. All rights reserved.
Okuyama E.,Akita University
Precision Engineering | Year: 2010
In the straightness profile measurement of a mechanical workpiece, hardware datums have been the traditional standard. However, error separation techniques of the surface profile from parasitic motions have been developed. These are known as software datums, which separate the surface profile from the parasitic motions using multiple sensors and/or multiple orientations and realize higher accuracy than that of the hardware datum. However, the conventional software datum cannot measure a large-scale workpiece because the large sampling number causes random error amplification. Furthermore, the conventional software datum assumes that sensor's random noise is small enough in comparison with the parasitic motions. But, the accuracy of the hardware datum has become high. Then, the accuracy of the sensor's random noise is not so small, relatively. In this paper, a next-generation software datum, the two-point method based on the least uncertainty propagation, is proposed. The proposed two-point method consists of weighting and inverse filtering, resulting in the least uncertainty of the estimated surface profile by choosing suitable weighting. © 2009 Elsevier Inc. All rights reserved.
Senoo H.,Akita University
Cell biology international | Year: 2010
HSCs (hepatic stellate cells) (also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells or Ito cells) exist in the space between parenchymal cells and liver sinusoidal endothelial cells of the hepatic lobule and store 50-80% of vitamin A in the whole body as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of vitamin A homoeostasis. In pathological conditions, such as hepatic fibrosis or liver cirrhosis, HSCs lose vitamin A and synthesize a large amount of extracellular matrix components including collagen, proteoglycan, glycosaminoglycan and adhesive glycoproteins. Morphology of these cells also changes from the star-shaped SCs (stellate cells) to that of fibroblasts or myofibroblasts. The hepatic SCs are now considered to be targets of therapy of hepatic fibrosis or liver cirrhosis. HSCs are activated by adhering to the parenchymal cells and lose stored vitamin A during hepatic regeneration. Vitamin A-storing cells exist in extrahepatic organs such as the pancreas, lungs, kidneys and intestines. Vitamin A-storing cells in the liver and extrahepatic organs form a cellular system. The research of the vitamin A-storing cells has developed and expanded vigorously. The past, present and future of the research of the vitamin A-storing cells (SCs) will be summarized and discussed in this review.
Kuriyama S.,Akita University
Oncogene | Year: 2015
Lipoma preferred partner (LPP) is a LIM domain protein, which has multiple functions as an actin-binding protein and a transcriptional coactivator, and it has been suggested that LPP has some roles in cell migration or invasion, however, its role in cancer cells remains to be elucidated. Here, we showed that LPP degraded N-cadherin in lung cancer, PC14PE6 cells via regulating the expression of matrix metalloproteinase 15 (MMP-15), and loss-of-LPP increases collective cell migration (CCM) and dissemination consequently. Knockdown of LPP and its functional partner, Etv5, markedly restores the full-length N-cadherin and increases cell–cell adhesion. We investigated the common target of LPP and Etv5, and found that MMP-15 is transcribed as their direct transcriptional target. Furthermore, MMP-15 could directly digest the N-cadherin extracellular domain. LPP knockdown in PC14PE6 cells increases N-cadherin-dependent CCM in the three-dimensional collagen gel invasion assays, and promoted the dissemination of cancer cells when they were orthotopically implanted in nude mice. Immunohistochemistry of lung adenocarcinoma specimens revealed the heterogeneity of LPP intensity and complementary expression of LPP and N-cadherin in the primary tumors. These findings suggest that loss-of-LPP, Etv5 or MMP-15 can be a prognostic marker of increasing malignancy.Oncogene advance online publication, 1 June 2015; doi:10.1038/onc.2015.155. © 2015 Macmillan Publishers Limited