-
Hiromi Hikita,
Kenichiro Enooku, Yumiko Satoh,
Haruhiko Yoshida,
Hayato Nakagawa,
Ryota Masuzaki,
Ryosuke Tateishi,
Yoko Soroida,
Mamiko Sato,
Atsushi Suzuki,
Hiroaki Gotoh,
Tomomi Iwai,
Hiromitsu Yokota,
Kazuhiko Koike,
Yutaka Yatomi,
Hitoshi Ikeda
[show abstract]
[hide abstract]
ABSTRACT: AIM: Although perihepatic lymph node enlargement (PLNE) is reportedly associated with the negative outcome of interferon therapy for chronic hepatitis C, there were limitations in that the results were obtained in patients with various genotypes, viral loads and treatment regimens. We aimed to precisely clarify the significance of PLNE in interferon therapy for chronic hepatitis C. METHODS: Between December 2004 and June 2005, 112 patients with hepatitis C virus (HCV) genotype 1 and HCV RNA of more than 100 KIU/mL were enrolled, who underwent pegylated interferon-α plus ribavirin therapy thereafter. PLNE was defined as a perihepatic lymph node of more than 1 cm in the longest axis by ultrasonography. RESULTS: The sustained virological response (SVR) rate was lower in patients with PLNE (4/22, 18.2%) than in those without (37/90, 41.1%; P = 0.045) and viral load decline was smaller in patients with PLNE than in those without (P = 0.028). The proportion of PLNE positive patients was the smallest in the SVR group (P = 0.033) among the patient groups divided by the treatment outcome. PLNE was retained as a negative predictor for SVR by multivariate logistic regression analysis (P = 0.012). Furthermore, PLNE was not significantly associated with the mutations at HCV core protein and at interferon sensitivity-determining region, or interleukin-28B polymorphism in 45 patients with HCV genotype 1, enrolled between December 2011 and March 2012. CONCLUSION: PLNE is a negative predictor for SVR in patients with HCV genotype 1 and HCV RNA of more than 100 KIU/mL treated with pegylated interferon-α plus ribavirin, independent of other known predictors for SVR.
Hepatology Research 01/2013; · 2.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Quantitative analysis of the leukemia fusion gene by real-time PCR is a sensitive method to monitor minimal residual disease; the data obtained are very useful to evaluate the disease stage and prognosis, contributing to the clinical practice of hematology. However, there is no standard laboratory procedure for leukemia genetic testing. Therefore, this genetic testing has some problems related to precision management. To minimize analytical error factors, normalization by an internal control gene is necessary. Additionally, it is important to choose a gene suitable for leukemia gene expression analysis because the expression of an internal standard gene changes due to various factors. In this study, we examined analytical error factors (RNA extraction efficiency, reverse transcription reaction efficiency) and evaluated an internal control gene. As a result, in RNA extraction, the extraction efficiency of the acid-guanidium-phenol-chloroform (AGPC) method was high compared to the silica method. The reverse transcription reaction efficiency was significantly different with each reaction reagent. Furthermore, since three kinds of gene (18s rRNA, GUS, beta-actin) had few differences between samples, they were considered to be suitable as internal standards.
Rinsho byori. The Japanese journal of clinical pathology 08/2012; 60(8):740-7.
-
Yoko Soroida,
Ryunosuke Ohkawa,
Hayato Nakagawa, Yumiko Satoh,
Haruhiko Yoshida,
Hiroto Kinoshita,
Ryosuke Tateishi,
Ryota Masuzaki,
Kenichiro Enooku,
Shuichiro Shiina,
Takahisa Sato,
Shuntaro Obi,
Tadashi Hoshino,
Ritsuko Nagatomo,
Shigeo Okubo,
Hiromitsu Yokota,
Kazuhiko Koike,
Yutaka Yatomi,
Hitoshi Ikeda
[show abstract]
[hide abstract]
ABSTRACT: Mitochondrial isoenzyme of creatine kinase (MtCK) is reportedly highly expressed in hepatocellular carcinoma (HCC). Clinical relevance of serum MtCK activity in patients with HCC was assessed using a novel immuno-inhibition method.
Among patients with cirrhosis caused by hepatitis B or C virus, 147 patients with HCC (12 with the first occurrence and 135 with recurrence) and 92 patients without HCC were enrolled.
Serum MtCK activity was higher in cirrhotic patients with HCC than in those without HCC or healthy subjects. Elevated serum MtCK activity in HCC patients decreased after radiofrequency ablation. In case of prediction of HCC, MtCK had a sensitivity of 62.6% and a specificity of 70.7% at a cut-off point of 8.0 U/L, with an area under the receiver operating curve of 0.722 vs. 0.713 for alpha-fetoprotein (AFP) and 0.764 for des-gamma-carboxy prothrombin (DCP). Among the HCC patients, serum MtCK activity was elevated in 52.9% individuals with serum AFP level < 20 ng/ml and 63.2% individuals with serum DCP level < 40 mAu/ml. Even in patients with a single HCC ≤ 2 cm, the sensitivity of serum MtCK activity for the prediction of HCC was 64.4%, which was comparable to the overall sensitivity. This increased activity was due to an increase in ubiquitous MtCK, not sarcomeric MtCK, and the enhanced mRNA expression of ubiquitous MtCK was observed in cell lines originating from HCCs in contrast to healthy liver tissues.
Serum MtCK activity merits consideration as a novel marker for HCC to be further tested as for its diagnostic and prognostic power.
Journal of Hepatology 04/2012; 57(2):330-6. · 9.26 Impact Factor
-
Yuko Kageyama,
Hitoshi Ikeda,
Naoko Watanabe,
Masakazu Nagamine,
Yoshika Kusumoto,
Mitsuru Yashiro, Yumiko Satoh,
Tatsuo Shimosawa,
Koji Shinozaki,
Tomoaki Tomiya, [......],
Takako Nishikawa,
Natsuko Ohtomo,
Yasushi Tanoue,
Hiromitsu Yokota,
Takatoshi Koyama,
Kazuhiro Ishimaru,
Yasuo Okamoto,
Yoh Takuwa,
Kazuhiko Koike,
Yutaka Yatomi
[show abstract]
[hide abstract]
ABSTRACT: Sinusoidal vasoconstriction, in which hepatic stellate cells operate as contractile machinery, has been suggested to play a pivotal role in the pathophysiology of portal hypertension. We investigated whether sphingosine 1-phosphate (S1P) stimulates contractility of those cells and enhances portal vein pressure in isolated perfused rat livers with Rho activation by way of S1P receptor 2 (S1P(2) ). Rho and its effector, Rho kinase, reportedly contribute to the pathophysiology of portal hypertension. Thus, a potential effect of S1P(2) antagonism on portal hypertension was examined. Intravenous infusion of the S1P(2) antagonist, JTE-013, at 1 mg/kg body weight reduced portal vein pressure by 24% without affecting mean arterial pressure in cirrhotic rats induced by bile duct ligation at 4 weeks after the operation, whereas the same amount of S1P(2) antagonist did not alter portal vein pressure and mean arterial pressure in control sham-operated rats. Rho kinase activity in the livers was enhanced in bile duct-ligated rats compared to sham-operated rats, and this enhanced Rho kinase activity in bile duct-ligated livers was reduced after infusion of the S1P(2) antagonist. S1P(2) messenger RNA (mRNA) expression, but not S1P(1) or S1P(3) , was increased in bile duct-ligated livers of rats and mice and also in culture-activated rat hepatic stellate cells. S1P(2) expression, determined in S1P 2LacZ/+ mice, was highly increased in hepatic stellate cells of bile duct-ligated livers. Furthermore, the increase of Rho kinase activity in bile duct-ligated livers was observed as early as 7 days after the operation in wildtype mice, but was less in S1P 2-/- mice. Conclusion: S1P may play an important role in the pathophysiology of portal hypertension with Rho kinase activation by way of S1P(2) . The S1P(2) antagonist merits consideration as a novel therapeutic agent for portal hypertension. (HEPATOLOGY 2012).
Hepatology 04/2012; 56(4):1427-38. · 11.66 Impact Factor
-
Yumiko Satoh,
Kazuhiko Mori,
Kentaro Kitano,
Joji Kitayama,
Hiromitsu Yokota,
Hiroki Sasaki,
Hiroshi Uozaki,
Masashi Fukayama,
Yasuhiro Seto,
Hirokazu Nagawa,
Yutaka Yatomi,
Daiya Takai
[show abstract]
[hide abstract]
ABSTRACT: Prediction of peritoneal recurrence in gastric cancer patients is important for application of adjuvant chemotherapy. After surgery, occasional patients have peritoneal recurrence despite negative cytology of the peritoneal washings. Thus, molecular detection of a subliminal number of cancer cells in peritoneal washings may overcome the sensitivity limitation of conventional cytology. In this study, expressions of five specific marker genes, namely, TFF1, TFF2, CK20, FABP1 and MUC2, were evaluated for their usefulness as markers of micro-dissemination. It was found that reverse transcriptase-polymerase chain reaction for these five genes yielded results highly specific for the depth of invasion and disease stage. Furthermore, the expression of CK20, FABP1 and MUC2 was a reliable prognostic indicator of peritoneal metastasis. Our results suggest that evaluation of the expression of CK20, FABP1 and MUC2 in peritoneal washings is a useful tool for identifying patients at high risk of peritoneal recurrence who may need adjuvant chemotherapy.
Japanese Journal of Clinical Oncology 12/2011; 42(2):148-52. · 1.78 Impact Factor
-
Naoko Watanabe,
Hitoshi Ikeda,
Yukio Kume, Yumiko Satoh,
Makoto Kaneko,
Daiya Takai,
Kazuaki Tejima,
Masakazu Nagamine,
Hirosato Mashima,
Tomoaki Tomiya,
Eisei Noiri,
Masao Omata,
Masanori Matsumoto,
Yoshihiro Fujimura,
Yutaka Yatomi
[show abstract]
[hide abstract]
ABSTRACT: Although hepatic stellate cells, endothelial cells, glomerular podocytes and plateles were reported to be a source of ADAMTS13, it is not clarified which source is involved in the regulation of plasma ADAMTS13 activity. It was demonstrated previously that selective hepatic stellate cell damage in rats caused decreased plasma ADAMTS13 activity. To further elucidate the potential contribution of hepatic stellate cells to the regulation of plasma ADAMTS13 activity, this study examined plasma ADAMTS13 activity when hepatic stellate cells proliferate during the process of liver fibrosis by employing rat models of liver fibrosis due to cholestasis, bile duct ligation, and steatohepatitis, a choline-deficient L-amino acid-defined-diet. ADAMTS13 expression was increased with co-localisation with smooth muscle alpha-actin, a marker of hepatic stellate cells, in bile duct-ligated livers up to four weeks, in which a close correlation between ADAMTS13 and smooth muscle alpha-actin mRNA expressions was determined. Plasma ADAMTS13 activity, measured by a sandwich ELISA involving a specific substrate to ADAMTS13, was increased in bile duct-ligated rats with a significant correlation with ADAMTS13 mRNA expression levels in the liver. Furthermore, ADAMTS13 mRNA expression was increased with enhanced mRNA expression in smooth muscle alpha-actin in the livers of rats fed a choline-deficient L-amino acid-defined-diet for 16 weeks, in which increased plasma ADAMTS13 activity was determined. Thus, increased plasma ADAMTS13 activity in cholestasis and steatohepatitis in rats may be due, at least in part, to enhanced ADAMTS13 production in the liver, suggesting a significant role of hepatic stellate cells in the regulation of plasma ADAMTS13 activity.
Thrombosis and Haemostasis 09/2009; 102(2):389-96. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Sphingosine 1-phosphate (Sph-1-P) regulates vascular homeostasis through its receptors like S1P1 and S1P2. While S1P1 works to protect vasculature, S1P2 works antagonistically against it. Therefore, the balance of S1P1 and S1P2 determines the regulation of vascular permeability. In diabetic nephropathy, one of the typical pathological changes is endothelial injury possibly as a result of changes in vascular permeability. Therefore, we hypothesized that the balance of S1P1 and S1P2 expression becomes inappropriate in glomeruli of diabetic nephropathy. To verify the hypothesis, five SD rats with diabetes induced by streptozotocin injection and six control rats injected with only the vehicle were analyzed one year after injection. The glomeruli of the diabetic rats exhibited endothelial injuries. The analysis by real-time PCR revealed that the ratio of S1P2/S1P1 mRNA in the renal cortex of the diabetic rats was significantly higher than that in the non-diabetic control group. Immunohistochemistry revealed that S1P1 was expressed by endothelial and mesangial cells, while S1P2 was mainly expressed by mesangial cells in glomeruli. Furthermore, the ratio of the staining intensity of S1P2 to that of S1P1 in the glomeruli was significantly higher in the diabetic rats. The number of cells expressing PDGF-B, which enhances S1P2 expression, was also higher in the glomeruli of the diabetic rats than in the controls. In conclusion, Sph-1-P signals are preferentially transmitted through S1P2, rather than S1P1, in the glomeruli of rats with diabetic nephropathy. Such unbalanced delivery of the Sph-1-P signals might be involved in the pathogenesis of endothelial injuries.
Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 04/2009; 62(1):53-60. · 1.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Sphingolipids, including ceramide (Cer), sphingosine (Sph), and sphingosine 1-phosphate (Sph-1-P) have recently emerged as signal-transducing molecules. Functionally, a distinguishing characteristic of these lipids is their apparent participation in pro- or anti-proliferative cell regulation pathways. In this study, we examined the involvement of sphingolipids in the fate of FRTL-5 thyroid follicular cells. We first examined the effects of sphingolipids on FRTL-5 cell viability. Sph and Cer induced apoptosis, as revealed by fluorescence microscopy of TUNEL-positive fragmented nuclei and 180-300 bp DNA fragmentation on agarose gel electrophoresis while Sph-1-P was confirmed to prevent FRTL-5 cell apoptosis induced by deprivation of serum and TSH, possibly via cell surface receptors. We then analysed the metabolism of radiolabelled Sph and C(6)-Cer (a synthetic cell-permeable Cer) in FRTL-5 cells by thin layer chromatography, followed by autoradiography. Sph was mainly metabolized to Cer, and then to sphingomyelin, while Sph conversion into Sph-1-P was hardly detected. These changes were not affected by stimulation of the cells with TSH. Our results indicate the involvement of sphingolipid mediators in the fate of FRTL-5 thyroid cells.
Journal of biochemistry 11/2008; 145(1):31-6. · 1.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The metabolism of and sensitivity to drugs differ from individual to individual, and one base polymorphism of drug-metabolizing enzymes is known to play an important role in this difference between individuals. The genotyping of drug-metabolizing enzymes prior to drug administration would help to predict individual reactivity to drugs and possible adverse reactions that may occur, which is essential to realize tailor-made therapy for individual patients. In July 2005, the Pharmacogenomics Working Group, composed of members of the Clinical Genomic Medicine Unit, Pharmaceutical Department, Medical Informatics Department, Clinical Laboratory, Gastroenterology, Cardiovascular Medicine, and Department of Neurology, was established in our university hospital in an attempt to introduce such pharmacogenomic testing. The project was approved by the Institutional Research Ethics Committee of the Faculty of Medicine, the University of Tokyo, and, in August 2006, testing for CYP2C19*2 and CYP2C19*3, enzymes involved in the metabolism of proton pump inhibitors, was started. Furthermore, in August 2007, testing for CYP2C9*3, the enzyme involved in the metabolism of Warfarin, and vitamin K epoxidereductase1 (VKORC1) 6484 C>T was started. In the CYP2C19 genotyping, the high incidence of poor metabolizers has been demonstrated; it was speculated that the test could confirm the adverse effects of the drug, i.e., after administration of the drug to patients. Moreover, testing for CYP2C9*3 and VKORC1 6484 C>T was shown to be useful for the safe administration of warfarin. The pharmacogenomic testing system was successfully established in our university hospital, and the Pharmacogenomics Working Group is still active, playing an important role in this project.
Rinsho byori. The Japanese journal of clinical pathology 09/2008; 56(9):772-80.
-
[show abstract]
[hide abstract]
ABSTRACT: The pathogenic chromosome translocations present in various hematological malignancies result in the formation of fusion genes, which are detected by a reverse transcription-polymerase chain reaction (RT PCR) method. Furthermore, with this method, it is possible to detect minimal residual disease (MRD) sensitively, which is difficult with morphological testing. It has been established that the detection of MRD is important for diagnosis, evaluation of prognosis, and monitoring of leukemia. In particular, quantitative analysis of MRD load transition during the initial phase of treatment is of high prognostic value. At present, however, there is no standard laboratory procedure for leukemia genetic testing. Here, the problems related to external precision management are discussed.
Rinsho byori. The Japanese journal of clinical pathology 06/2008; 56(5):395-401.
-
[show abstract]
[hide abstract]
ABSTRACT: Lysophosphatidic acid (LPA) promotes survival, growth, differentiation, and motility in a variety of cell types, and has been reported to act as a cell survival and growth factor in B lymphocytes. Autotaxin (ATX), through its lysophospholipase D activity, generates LPA from lysophosphatidylcholine (LPC). In this study, we investigated the effects of LPA and also the expression of ATX and LPA receptor, in the human pre-B-cell line Nalm-6. It was found that LPA protects Nalm-6 cells against both spontaneous and staurosporine-induced apoptosis. Furthermore, ATX expression on the cell surface and ATX activity in the cell lysate were detected. No accumulation of LPA in the culture medium was, however, detected when the Nalm-6 cells were cultured with LPC. The pre-B cells were found to express the mRNA transcript for lipid phosphate phosphatase-1 and LPA degradation was inhibited in the presence of the phosphatase inhibitor vanadate, it was surmised that LPA production in the culture medium may have been masked by LPA degradation by this ecto-phosphatase. Abundant expression of LPA receptors, especially, LPA(4), was detected by a real-time polymerase chain reaction technique. Our results suggest an important and autocrine role of LPA in the survival of this well-established model cell line, although the direct involvement of ATX in the production of LPA in these cells was not confirmed.
European Journal Of Haematology 07/2007; 78(6):510-7. · 2.61 Impact Factor
-
Yuki Suzaki,
Masanori Yoshizumi,
Yukio Yamashita,
Shinji Abe,
Koichiro Tsuchiya, Yumiko Satoh,
Yasuhiro Kuroda,
Kazuya Horike,
Masashi Kano,
Yoshio Fukata,
Takashi Kitaichi,
Takaki Hori,
Yutaka Masuda,
Tetsuya Kitagawa,
Kazuo Minakuchi,
Toshiaki Tamaki
[show abstract]
[hide abstract]
ABSTRACT: We previously found that human chymase cleaves big endothelins at the Tyr31-Gly32 bond and produces 31-amino-acid endothelins, endothelins(1-31). Endothelin-1(1-31) has been isolated from a number of human organs, including the heart and lungs. As endothelin-1 has been shown to play a significant role in the paracrine regulation of cardiovascular functions in humans, it is possible that endothelin-1(1-31) may also exhibit biological activity on human tissues. We previously reported that synthetic endothelin-1(1-31) exhibits a number of physiological actions on cultured cells in vitro. In the present study, we investigated the plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy subjects and compared them with those in patients with cardiovascular diseases. Endothelin-1(1-31) and endothelin-1 in human plasma was measured using a sandwich-enzyme-immunoassay system, which was recently described for measurement of endothelin-1(1-31). The plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy volunteers were 19.24 +/- 5.70 and 15.54 +/- 4.45 pg/ml (n = 5), respectively. We also measured plasma concentrations of endothelin-1(1-31) and endothelin-1 before and after surgery in patients with abdominal aortic aneurysms. Before surgery, plasma concentrations of endothelin-1(1-31) and endothelin-1 in these patients were higher than those in healthy individuals. After surgery, both endothelin-1(1-31) and endothelin-1 in plasma decreased to levels similar to those of healthy subjects. This suggests that endothelin-1(1-31) may have similar physiological significance to endothelin-1 in patients with atherosclerosis.
Journal of Cardiovascular Pharmacology 02/2003; 41 Suppl 1:S83-7. · 2.29 Impact Factor
-
Yuki Suzaki,
Masanori Yoshizumi,
Yukio Yamashita,
Shinji Abe,
Koichiro Tsuchiya, Yumiko Satoh,
Yasuhiro Kuroda,
Kazuya Horike,
Masashi Kano,
Yoshio Fukata,
Takashi Kitaichi,
Takaki Hori,
Yutaka Masuda,
Tetsuya Kitagawa,
Kazuo Minakuchi,
Toshiaki Tamaki
[show abstract]
[hide abstract]
ABSTRACT: We previously found that human chymase cleaves big endothelins at the Tyr31‐Gly32 bond and produces 31‐amino‐acid endothelins, endothelins(1–31). Endothelin‐1(1–31) has been isolated from a number of human organs, including the heart and lungs. As endothelin‐1 has been shown to play a significant role in the paracrine regulation of cardiovascular functions in humans, it is possible that endothelin‐1(1–31) may also exhibit biological activity on human tissues. We previously reported that synthetic endothelin‐1(1–31) exhibits a number of physiological actions on cultured cells in vitro. In the present study, we investigated the plasma concentrations of endothelin‐1(1–31) and endothelin‐1 in healthy subjects and compared them with those in patients with cardiovascular diseases. Endothelin‐1(1–31) and endothelin‐1 in human plasma was measured using a sandwich‐enzymeimmunoassay system, which was recently described for measurement of endothelin‐1(1–31). The plasma concentrations of endothelin‐ 1(1–31) and endothelin‐1 in healthy volunteers were 19.24 ± 5.70 and 15.54 ± 4.45 pg/ml (n = 5), respectively. We also measured plasma concentrations of endothelin‐1(1–31) and endothelin‐1 before and after surgery in patients with abdominal aortic aneurysms. Before surgery, plasma concentrations of endothelin‐1(1–31) and endothelin‐1 in these patients were higher than those in healthy individuals. After surgery, both endothelin‐ 1(1–31) and endothelin‐1 in plasma decreased to levels similar to those of healthy subjects. This suggests that endothelin‐1(1–31) may have similar physiological significance to endothelin‐1 in patients with atherosclerosis.
Journal of Cardiovascular Pharmacology 12/2002; 41:S83–S87. · 2.29 Impact Factor
