Programs for Biomedical Research

Science, Japan

Programs for Biomedical Research

Science, Japan

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Katamura Y.,Programs for Biomedical Research | Aikata H.,Programs for Biomedical Research | Hashimoto Y.,Programs for Biomedical Research | Kimura Y.,Programs for Biomedical Research | And 8 more authors.
Hepatology Research | Year: 2010

We conducted a retrospective cohort study to investigate the efficacy of combination therapy with radiotherapy (RT) and zoledronic acid for bone metastases from hepatocellular carcinoma (HCC). Additionally, we investigated the efficacy of zoledronic acid for non-irradiated bone metastases.Methods: This study consisted of 31 patients who had received RT for bone metastases. Twelve of these patients with 23 sites of bone metastases were also treated with zoledronic acid (Z group). In the Z group, 14 sites received RT and nine sites did not. Nineteen patients with 38 sites of bone metastases were not treated with zoledronic acid (non-Z group). In the non-Z group, 22 sites received RT and 16 did not. We compared survival, pain response, time to pain progression, radiographic response, time to radiographic progression, and safety between groups.Results: While pain response rates were similar between the two groups, time to pain progression rates of irradiated and non-irradiated bone metastases was significantly lower in the Z (0% and 20% at 6 months, respectively) than in the non-Z group (34% and 66% at 6 months, respectively) (P = 0.045 and P = 0.005). Further, while radiographic response rates were similar between the two groups, time to radiographic progression rate of non-irradiated bone metastases was significantly lower in the Z (29% at 3 months) than in the non-Z group (91% at 3 months) (P = 0.009). No significant side-effects were documented.Conclusion: Zoledronic acid delayed the pain progression of both irradiated and non-irradiated bone metastases and the radiographic progression of non-irradiated bone metastases from HCC. © 2010 The Japan Society of Hepatology.


Zhang Y.,Programs for Biomedical Research | Zhang Y.,Hiroshima University | Takahashi S.,Programs for Biomedical Research | Takahashi S.,Hiroshima University | And 9 more authors.
Journal of Gastroenterology and Hepatology (Australia) | Year: 2013

Background and Aim: Changes in microRNA (miRNA) expression have been detected in a broad range of biological processes including cancer. Here we determined the role of miRNA dysregulation in hepatocellular carcinoma (HCC). Methods: We investigated the expression of nine cancer-related miRNAs in HCC. Among these, miR-224 was the most significantly uprgulated in HCC tissues (n=18), compared with normal (n=9) and HCC adjacent non-tumorous liver tissues (n=18). After leading-in currently reported gene targets from Sanger miRBase, we characterized the expression profiles of target genes of miR-224 using cDNA microarray. The altered expression was subsequently validated by real-time polymerase chain reaction and Western blot. The phenotypic changes by miR-224 expression were identified by cell viability, apoptosis, and in vitro scratch assays. Results: The microarray analysis and miRNA target prediction analysis allowed the identification of significant changes in 68 putative gene targets after overexpression of miR-224. The high-ranking genes CDC42, CDH1, PAK2, BCL-2, and MAPK1 were confirmed as important targets of miR-224 and involvement in hepatocarcinogenesis. Overexpression of miR-224 significantly in Hek293 and Huh7 cells altered the expression levels of CDC42, CDH1, PAK2, and BCL-2 at both mRNA and protein levels. Similar changes in the expression of the same genes were also observed in HCC tissues. Via functional analyses, cell proliferation, migration and anti-apoptosis were proved to be affected by miR-224 expression. Conclusion: The results suggest that miR-224 plays a role in cell proliferation, migration, invasion, and anti-apoptosis in HCC by directly binding to its gene targets, implicating this RNA in HCC development and progression. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.


Chayama K.,Programs for Biomedical Research | Chayama K.,Hiroshima University | Chayama K.,RIKEN | Hayes C.N.,Programs for Biomedical Research | And 5 more authors.
Hepatology Research | Year: 2012

Identification of the relationship between the interleukin (IL)-28B genotype and the effect of peginterferon plus ribavirin treatment has had a great impact on the study of antiviral therapy for patients with chronic hepatitis C virus (HCV) infection. Differential expression levels of interferon-stimulated genes (ISG) in the liver and white blood cells based on the IL-28B genotype, which may in turn lead to differences in outcome of therapy, indicate that previous studies should be re-evaluated taking the effect of the IL-28B single nucleotide polymorphism (SNP) into consideration, although the exact mechanism of how variation in IL-28B SNPs affect HCV eradication remains unknown. These results suggest that the genotypes of multiple cell types, including liver and immune cells, contribute to the efficacy of therapy. Studies using human hepatocyte chimeric mice, in which effector cells of the human adaptive immune response are absent, showed that viral load, ISG expression levels and reduction of HCV RNA by interferon are affected by the IL-28B genotype. Genetic differences among hepatocytes may, therefore, contribute to differences in baseline viral loads and response to interferon therapy. Further studies should be done to clarify the mechanism of action of IL-28B SNP on viral load and effect of interferon treatment. Advances in cell culture systems and human hepatocyte chimeric mice, as well as upcoming in vitro and in vivo experimental systems, provide an effective platform to examine the effects of host and viral genetic variation on infection and response to interferon. © 2012 The Japan Society of Hepatology.


Higashiyama M.,Programs for Biomedical Research | Oka S.,Hiroshima University | Tanaka S.,Hiroshima University | Sanomura Y.,Programs for Biomedical Research | And 4 more authors.
Digestive Endoscopy | Year: 2011

Background: Although endoscopic submucosal dissection (ESD) is standard therapy in Japan for gastric epithelial neoplasm, the complication rate is unsatisfactory, with postoperative bleeding as the major complication. The aim of the present study was to determine risk factors for post-ESD bleeding in patients with gastric epithelial neoplasm. Patients and Methods: The study included 764 patients in whom 924 gastric epithelial neoplasms were resected endoscopically between June 2005 and December 2009: the period during which preventative coagulation for all exposed vessels on the artificial ulcer with hemostatic forceps upon completion of ESD was performed routinely. We analyzed the risk factors for bleeding after ESD in relation to the various clinical factors. Results: The post-ESD bleeding rate was 3.0%. Dialysis (vs no dialysis, P = 0.034), operation time >75 min (vs <75 min, P = 0.012) and poor control of bleeding during ESD (vs good control, P = 0.014) were significantly related to post-ESD bleeding. Poor control of bleeding during ESD (vs good control; P = 0.04) and operation time >75 min (vs <75 min; P = 0.012) were significantly related to bleeding after second-look endoscopy. Conclusions: Patients at high risk for post-ESD bleeding in gastric epithelial neoplasm were those undergoing dialysis, those in whom operation time was >75 min, and those in whom bleeding during ESD was poorly controlled. The latter two are risk factors for bleeding even after second-look endoscopy. © 2011 Japan Gastroenterological Endoscopy Society.


Miyake Y.,Programs for Biomedical Research | Okamoto Y.,Programs for Biomedical Research | Onoda K.,Programs for Biomedical Research | Kurosaki M.,Hiroshima University | And 3 more authors.
Psychiatry Research - Neuroimaging | Year: 2010

Eating disorder (ED) patients have severe disturbances in the perception of body shape and weight. The authors investigated brain activation patterns during the perception of distorted body images in various subtypes of ED. Participants comprised 33 patients with EDs (11 with restricting-type anorexia nervosa (AN-R), 11 with binging-purging type anorexia nervosa (AN-BP), 11 with bulimia nervosa (BN)) and 11 healthy women. Functional magnetic resonance imaging was used to examine cerebral response to morphed images of subjects' own bodies, as well as that of another woman. The amygdala was significantly activated in AN-R patients, AN-BP patients, and healthy women in response to their own fat-image, but this did not occur in BN patients. The prefrontal cortex (PFC) was significantly activated in AN-BP patients and healthy women, but not in AN-R and BN patients. Our results showed that the various EDs are different with respect to significant activation of the amygdala and PFC during the processing of participants' own fat-image. Brain activation pattern differences between the various EDs may underlie cognitive differences with respect to distorted body image, and therefore might reflect a general failure to represent and evaluate one's own body in a realistic fashion. © 2009 Elsevier Ireland Ltd. All rights reserved.


Mbarek H.,Tokyo Medical University | Ochi H.,RIKEN | Ochi H.,Programs for Biomedical Research | Urabe Y.,Tokyo Medical University | And 15 more authors.
Human Molecular Genetics | Year: 2011

Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10 -5. We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10 -28 and 3.99 × 10 -37). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10 -21-2.38 × 10 -30). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection. © The Author 2011. Published by Oxford University Press. All rights reserved.


Yoshimura S.,Programs for Biomedical Research | Okamoto Y.,Programs for Biomedical Research | Onoda K.,Programs for Biomedical Research | Matsunaga M.,Programs for Biomedical Research | And 3 more authors.
Journal of Affective Disorders | Year: 2010

Background: Depression is characterized by enhanced self-referential processing of negative emotional stimuli. Imaging studies have suggested that activation of both the medial prefrontal (MPFC) and anterior cingulate cortices (ACC) is associated with self-referential processing. However, whether this pattern of activation occurs in depressed individuals during the self-referential processing of the emotional stimuli had not been investigated to date. Methods: Participants were 13 patients with major depressive disorder and 13 normal controls. We used block-designed functional magnetic resonance imaging (fMRI) to investigate neural activity during the self-referential judgments of positive and negative valenced personality trait words. Results: Compared with the normal controls, the depressed patients showed hyperactivity in the MPFC and the rostral ACC during the self-referential processing of negative words. In addition, the activity of these regions during self-referential processing of the negative stimuli was correlated with the depressive symptom severity. The rostral ACC activity mediated the correlation between the MPFC activity and the depressive symptoms. Functional connectivity analysis revealed positive connectivities between the MPFC, the rostral ACC, and the amygdala. Limitation: Small N and antidepressant effect on imaging data limit the stability of reported findings. Conclusions: The relationships between the MPFC, the rostral ACC, and the amygdala appear to reflect an interaction between the self-referential processing and the negative emotional information processing, and we propose that the strong connection between the MPFC and the rostral ACC is associated with depressive symptoms. © 2009 Elsevier B.V. All rights reserved.


Yanase Y.,Programs for Biomedical Research | Araki A.,Toyo Advanced Technologies Co. | Suzuki H.,Programs for Biomedical Research | Tsutsui T.,Programs for Biomedical Research | And 5 more authors.
Biosensors and Bioelectronics | Year: 2010

Surface plasmon resonance (SPR) sensors provide a useful means to study the interactions of biological molecules and the reaction of living cells on a sensor chip. However, conventional SPR sensors are bulky, expensive and complicated to use as common diagnostic equipment. In this study, we developed a relatively small and simple SPR system, using optical fibers of 250 μm diameter to detect the activation of living cells attached to the fiber tip. For this system, the core of 200 μm diameter with 1 cm length of an optical fiber was coated by gold film with 50 nm thickness to cause plasmon resonance. The light provided by a white LED and attenuated due to a SPR phenomenon in the sensor part was detected and analyzed using a spectrum detector. The difference in solvents with various refractive indexes and protein-bindings to the sensor tip was detected with sufficient sensitivity. Moreover, it detected a sustained increase of AR in a real-time manner, when RBL-2H3 mast cells were fixed onto the fiber tip and stimulated by an antigen. This small fiber SPR system might serve as a useful tool for various clinical examinations either within or outside the body. © 2009 Elsevier B.V. All rights reserved.


Kobayashi T.,Programs for Biomedical Research | Itamoto T.,Programs for Biomedical Research | Tashiro H.,Programs for Biomedical Research | Amano H.,Programs for Biomedical Research | And 5 more authors.
Journal of Hepato-Biliary-Pancreatic Sciences | Year: 2011

Background/purpose Although many factors related to the tumor or the hepatic functional reserve may affect the outcome of partial hepatectomy for hepatocellular carcinoma (HCC), these factors have not yet been intensively investigated in patients with solitary HCC. The purpose of this study is to determine the clinicopathological factors influencing the long-term outcomes of partial hepatectomy for solitary HCC. Methods Data on 266 consecutive patients with a solitary HCC who underwent curative hepatectomy between 1997 and 2006 were analyzed with regard to prognosis. Results Overall survival rates at 3, 5, and 10 years were 89.5, 79.6, and 56.1%, respectively. The significant independent predictors for overall survival included hepatitis C virus infection, liver cirrhosis, and prolonged prothrombin activity. Disease-free survival rates at 3, 5, and 10 years were 51.7, 41.1, and 20.4%, respectively. The significant independent predictors for disease-free survival included elevated levels of aspartate amino transferase, decreased platelet counts, presence of liver cirrhosis, and prolonged prothrombin activity. Tumor-related factors such as tumor size and microscopic vascular invasion were not significant predictors of overall or disease-free survival. Conclusions The long-term outcomes of patients with a solitary HCC who underwent partial hepatectomy mainly depended on the background liver status but not on tumorrelated factors; this suggests that partial hepatectomy is a remarkably effective antitumor therapy. If the hepatic functional reserve is within the permissible range, partial hepatectomy should be considered as the treatment of choice for patients with a solitary HCC. © Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2011.


PubMed | Programs for Biomedical Research
Type: Journal Article | Journal: Journal of gastroenterology and hepatology | Year: 2013

Changes in microRNA (miRNA) expression have been detected in a broad range of biological processes including cancer. Here we determined the role of miRNA dysregulation in hepatocellular carcinoma (HCC).We investigated the expression of nine cancer-related miRNAs in HCC. Among these, miR-224 was the most significantly uprgulated in HCC tissues (n=18), compared with normal (n=9) and HCC adjacent non-tumorous liver tissues (n=18). After leading-in currently reported gene targets from Sanger miRBase, we characterized the expression profiles of target genes of miR-224 using cDNA microarray. The altered expression was subsequently validated by real-time polymerase chain reaction and Western blot. The phenotypic changes by miR-224 expression were identified by cell viability, apoptosis, and in vitro scratch assays.The microarray analysis and miRNA target prediction analysis allowed the identification of significant changes in 68 putative gene targets after overexpression of miR-224. The high-ranking genes CDC42, CDH1, PAK2, BCL-2, and MAPK1 were confirmed as important targets of miR-224 and involvement in hepatocarcinogenesis. Overexpression of miR-224 significantly in Hek293 and Huh7 cells altered the expression levels of CDC42, CDH1, PAK2, and BCL-2 at both mRNA and protein levels. Similar changes in the expression of the same genes were also observed in HCC tissues. Via functional analyses, cell proliferation, migration and anti-apoptosis were proved to be affected by miR-224 expression.The results suggest that miR-224 plays a role in cell proliferation, migration, invasion, and anti-apoptosis in HCC by directly binding to its gene targets, implicating this RNA in HCC development and progression.

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