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1.  Lysyl oxidase secreted by tumour endothelial cells promotes angiogenesis and metastasis 
British Journal of Cancer  2013;109(8):2237-2247.
Molecules that are highly expressed in tumour endothelial cells (TECs) may be candidates for specifically targeting TECs. Using DNA microarray analysis, we found that the lysyl oxidase (LOX) gene was upregulated in TECs compared with its expression in normal endothelial cells (NECs). LOX is an enzyme that enhances invasion and metastasis of tumour cells. However, there are no reports on the function of LOX in isolated TECs.
TECs and NECs were isolated to investigate LOX function in TECs. LOX inhibition of in vivo tumour growth was also assessed using β-aminopropionitrile (BAPN).
LOX expression was higher in TECs than in NECs. LOX knockdown inhibited cell migration and tube formation by TECs, which was associated with decreased phosphorylation of focal adhesion kinase (Tyr 397). Immunostaining showed high LOX expression in human tumour vessels in vivo. Tumour angiogenesis and micrometastasis were inhibited by BAPN in an in vivo tumour model.
LOX may be a TEC marker and a possible therapeutic target for novel antiangiogenic therapy.
PMCID: PMC3798951  PMID: 24045659
lysyl oxidase; tumour endothelial cells; tumour angiogenesis
2.  Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma 
British Journal of Cancer  2013;109(8):2072-2078.
We previously reported that expressions of the pro-angiogenic cytokines angiopoietin-2 (Ang-2), follistatin, granulocyte colony-stimulating factor, hepatocyte growth factor, leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor were associated with the response to sorafenib in patients with advanced hepatocellular carcinoma (HCC). The aim of the present study is to examine the same relationship in a larger cohort.
In the current retrospective cohort study, we measured serum levels of the eightcytokines in 120 consecutive HCC patients who were treated with sorafenib. We evaluated the effects of increased expression of serum cytokines on progression-free survival (PFS) and overall survival (OS).
Elevated expression of Ang-2 correlated both with significantly shorter PFS (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.21–2.81), and OS (HR, 1.95; 95% CI, 1.21–3.17). Patients with more than three cytokines expressed above the median similarly had significantly shorter PFS (HR, 1.98; 95% CI, 1.30–3.06) and OS (HR, 1.94; 95% CI, 1.19–3.22). Differences in OS were evident in cases with the evidence of macroscopic vascular invasion or extrahepatic metastasis.
High expression of Ang-2 or more than cytokines in serum is associated with poor PFS and OS in HCC patients treated with sorafenib.
PMCID: PMC3798958  PMID: 24045661
angiogenesis; angiopoietin-2; cytokine; hepatocellular carcinoma; sorafenib
3.  Effect of hepatic arterial infusion chemotherapy of 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma in the Nationwide Survey of Primary Liver Cancer in Japan 
British Journal of Cancer  2013;109(7):1904-1907.
The efficacy of hepatic arterial infusion chemotherapy for the treatment of advanced hepatocellular carcinoma (HCC) remains unclear.
The outcome of 476 patients with HCC who underwent hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin (HAIC) were compared with 1466 patients who did not receive active therapy.
A survival benefit of the therapy after adjusting for known risk factors was observed (hazard ratio, 0.48; 95% CI, 0.41–0.56; P<0.0001). In propensity score-matched analysis (n=682), median survival time was longer for patients who underwent chemotherapy (14.0 months) than for patients who did not receive active treatment (5.2 months, P<0.0001).
For advanced HCC, HAIC is considered to be an effective treatment.
PMCID: PMC3790188  PMID: 24008659
chemotherapy; 5-fluorouracil; cisplatin; liver neoplasm; hepatocellular carcinoma; propensity score
4.  Protumoral roles of melanoma inhibitory activity 2 in oral squamous cell carcinoma 
British Journal of Cancer  2013;108(7):1460-1469.
The role of melanoma inhibitory activity 2 (MIA2) was examined in human oral squamous cell carcinoma (OSCC).
MIA2 role was examined by immunohistochemistry of human OSCCs and knockdown studies using human 3 OSCC cell lines with MIA2 expression.
MIA2 expression was observed in 62 (66.7%) of 93 OSCCs and was associated with tumour expansion and nodal metastasis. Melanoma inhibitory activity 2 expression was inversely correlated with intratumoral infiltration of lymphocytes. Invasion and anti-apoptotic survival were reduced by MIA2 knockdown in HSC3 cells. MOLT-3 lymphocytes infiltrating the HSC3 cell layer was enhanced by MIA2 knockdown or MIA2 depletion with the antibody. In HSC3 cells, MIA2 knockdown decreased the expressions of vascular endothelial growth factor (VEGF), VEGF-C, and VEGF-D. The downregulation of VEGF-C and -D was caused by inhibition of p38 and extracellular signal-regulated kinase (ERK)1/2, respectively. Melanoma inhibitory activity 2 was co-precipitated with integrin α4 andα5 in HSC3 cells. Integrin α4 knockdown decreased p38 phosphorylation and increased apoptosis, whereas integrin α5 knockdown decreased c-Jun N-terminal kinase (JNK) phosphorylation and apoptosis. Inhibition of JNK decreased apoptosis in the HSC3 cells.
These findings suggest that the roles of MIA2 might be based on the variety of the integrins and the subtypes of mitogen-activated protein kinase.
PMCID: PMC3629429  PMID: 23511560
apoptosis; VEGF; integrin; MAPK
5.  Neonatal Fc receptor for IgG (FcRn) expressed in the gastric epithelium regulates bacterial infection in mice 
Mucosal immunology  2011;5(1):87-98.
Neonatal Fc receptors for immunoglobulin (Ig)G (FcRn) assume a central role in regulating host IgG levels and IgG transport across polarized epithelial barriers. We have attempted to elucidate the contribution of FcRn in controlling Helicobacter infection in the stomach. C57BL/6J wild-type or FcRn−/− mice were infected with Helicobacter heilmannii, and gastric lesions, bacterial load and the levels of antigen-specific IgG in serum and gastric juice were analyzed. The elevated levels of anti-H. heimannii IgG in gastric juice were observed exclusively in wild-type mice but not in FcRn−/− mice. In contrast, an increase in lymphoid follicles and bacterial loads along with deeper gastric epithelium invasion were noted in FcRn−/− mice. C57BL/6J wild-type or FcRn−/− mice were also infected with Helicobacter pylori SS1, and the results of the bacterial load in stomachs of these mice and the anti-H. pylori IgG levels in serum and gastric juice were similar to those from H. heilmannii infection. Our data suggest that FcRn can be functionally expressed in the stomach, which is involved in transcytosis of IgG, and prevent colonization by H. heilmannii and the associated pathological consequences of infection.
PMCID: PMC3964614  PMID: 22089027
6.  Downregulation of miR-126 induces angiogenesis and lymphangiogenesis by activation of VEGF-A in oral cancer 
British Journal of Cancer  2012;107(4):700-706.
MicroRNA (miRNA)-126 (miR-126) is an endothelial-specific miRNA located within intron 7 of epidermal growth factor-like domain 7 (EGFL7). However, the role of miR-126 in cancer is controversial.
We examined the function of miR-126 in oral squamous cell carcinoma (OSCC) cells. Furthermore, a series of 118 cases with OSCC were evaluated for the expression levels of miR-126.
MicroRNA-126 (miR-126) was associated with cell growth and regulation of vascular endothelial growth factor-A activity, and demethylation treatment increased expression levels of miR-126 and EGFL7 in OSCC cells. A significant association was found between miR-126 expression and tumour progression, nodal metastasis, vessel density, or poor prognosis in OSCC cases. In the multivariate analysis, decreased miR-126 expression was strongly correlated with disease-free survival.
The present results suggest that miR-126 might be a useful diagnostic and therapeutic target in OSCC.
PMCID: PMC3419968  PMID: 22836510
miR-126; oral squamous cell carcinoma; angiogenesis; lymphangiogenesis; VEGF-A
7.  Biglycan is a specific marker and an autocrine angiogenic factor of tumour endothelial cells 
British Journal of Cancer  2012;106(6):1214-1223.
We isolated tumour endothelial cells (TECs), demonstrated their abnormalities, compared gene expression profiles of TECs and normal endothelial cells (NECs) by microarray analysis and identified several genes upregulated in TECs. We focused on the gene encoding biglycan, a small leucine-rich repeat proteoglycan. No report is available on biglycan expression or function in TECs.
The NEC and TEC were isolated. We investigated the biglycan expression and function in TECs. Western blotting analysis of biglycan was performed on sera from cancer patients.
Biglycan expression levels were higher in TECs than in NECs. Biglycan knockdown inhibited cell migration and caused morphological changes in TECs. Furthermore, immunostaining revealed strong biglycan expression in vivo in human tumour vessels, as in mouse TECs. Biglycan was detected in the sera of cancer patients but was hardly detected in those of healthy volunteers.
These findings suggested that biglycan is a novel TEC marker and a target for anti-angiogenic therapy.
PMCID: PMC3304426  PMID: 22374465
biglycan; tumour endothelial cells; tumour angiogenesis
8.  Sagittal focusing of synchrotron radiation X-rays using a winged crystal 
Journal of Synchrotron Radiation  2013;20(Pt 2):219-225.
A Si(111) winged crystal has been designed for sagittal focusing of synchrotron radiation X-rays. The results of performance tests at beamlines are reported.
A Si(111) winged crystal has been designed to minimize anticlastic bending and improve sagittal focusing efficiency. The crystal was thin with wide stiffening wings. The length-to-width ratio of the crystal was optimized by finite element analysis, and the optimal value was larger than the ‘golden value’. The analysis showed that the slope error owing to anticlastic bending is less than the Darwin width. The X-rays were focused two-dimensionally using the crystal and a tangentially bent mirror. The observed profiles of the focal spot agreed well with the results of a ray-tracing calculation in the energy range from 8 to 17.5 keV. X-ray diffraction measurements with a high signal-to-noise ratio using this focusing system were demonstrated for a small protein crystal.
PMCID: PMC3573870  PMID: 23412477
sagittal focusing; double-crystal monochromator; winged crystal; two-dimensional focusing; crystal bender; SPring-8
9.  Altered prefrontal lobe oxygenation in bipolar disorder: a study by near-infrared spectroscopy 
Psychological medicine  2008;39(8):1265-1275.
Previous studies have reported prefrontal cortex (PFC) pathophysiology in bipolar disorder.
We examined the hemodynamics of the PFC during resting and cognitive tasks in 29 patients with bipolar disorder and 27 healthy controls, matched for age, verbal abilities and education. The cognitive test battery consisted of letter and category fluency (LF and CF), Sets A and B of the Raven’s Colored Progressive Matrices (RCPM-A and RCPM-B) and the letter cancellation test (LCT). The tissue oxygenation index (TOI), the ratio of oxygenated hemoglobin (HbO2) concentration to total hemoglobin concentration, was measured in the bilateral PFC by spatially resolved near-infrared spectroscopy. Changes in HbO2 concentration were also measured.
The bipolar group showed slight but significant impairment in performance for the non-verbal tasks (RCPM-A, RCPM-B and LCT), with no significant between-group differences for the two verbal tasks (LF and CF). A group × task × hemisphere analysis of variance (ANOVA) on the TOI revealed an abnormal pattern of prefrontal oxygenation across different types of cognitive processing in the bipolar group. Post hoc analyses following a group × task × hemisphere ANOVA on HbO2 concentration revealed that the bipolar group showed a greater increase in HbO2 concentration in the LCT and in RCPM-B, relative to controls.
Both indices of cortical activation (TOI and HbO2 concentration) indicated a discrepancy in the PFC function between verbal versus non-verbal processing, indicating task-specific abnormalities in the hemodynamic control of the PFC in bipolar disorder.
PMCID: PMC3480202  PMID: 18812007
Bipolar disorder; near-infrared spectroscopy; prefrontal cortex; tissue hemoglobin saturation
10.  Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians 
Diabetologia  2011;55(4):981-995.
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
11.  Inhibition of renin–angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine 
British Journal of Cancer  2010;103(11):1644-1648.
The renin–angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth.
We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs).
Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis.
The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis.
PMCID: PMC2994224  PMID: 20978506
angiotensin I-converting enzyme inhibitors; angiotensin II type-1 receptor blockers; chemotherapy; gemcitabine; pancreatic cancer; renin–angiotensin system
12.  Serum adiponectin level is not only decreased in metabolic syndrome but also in borderline metabolic abnormalities 
Nutrition & Diabetes  2011;1(10):e18-.
Along with the increasing prevalence of obesity and related diseases, particularly atherosclerotic diseases, metabolic syndrome (MetS) is now a common and major public health issue in many countries around the world. Adiponectin, a protein secreted by the adipose tissue, has become recognized as a key player in the development of MetS. These days, not only MetS but also borderline metabolic/physiological abnormalities, such as impaired fasting glucose, high normal blood pressure and high normal plasma cholesterol, have been reported to be risk factors for atherosclerotic disease. Therefore, we undertook this study to determine the relationship between adiponectin and borderline metabolic/physiological abnormalities, as well as MetS.
A cross-sectional study performed from April 2007 to November 2009.
In 16 892 Japanese adults (10 008 men and 6884 women), we examined the relationship between the serum adiponectin concentration and borderline metabolic/physiological abnormalities or MetS by a questionnaire survey about medical treatment, body size measurement and measurement of laboratory parameters including the serum adiponectin concentration.
Adiponectin showed a significant negative correlation with the number of MetS components. In subjects without overt diabetes mellitus, hypertension or dyslipidemia, the adiponectin concentration also showed a significant negative correlation with the number of borderline metabolic abnormalities.
The decrease of circulating adiponectin may start before the development of diabetes mellitus, hypertension, dyslipidemia or MetS. Adiponectin is an important biomarker for reflecting the adverse influence of visceral fat in persons with MetS, and also in these subclinical states.
PMCID: PMC3302140  PMID: 23455020
adiponectin; visceral fat; metabolic syndrome; borderline metabolic abnormalities; arteriosclerosis
13.  Non-thermal hot electrons ultrafastly generating hot optical phonons in graphite 
Scientific Reports  2011;1:64.
Investigation of the non-equilibrium dynamics after an impulsive impact provides insights into couplings among various excitations. A two-temperature model (TTM) is often a starting point to understand the coupled dynamics of electrons and lattice vibrations: the optical pulse primarily raises the electronic temperature Tel while leaving the lattice temperature Tl low; subsequently the hot electrons heat up the lattice until Tel = Tl is reached. This temporal hierarchy owes to the assumption that the electron-electron scattering rate is much larger than the electron-phonon scattering rate. We report herein that the TTM scheme is seriously invalidated in semimetal graphite. Time-resolved photoemission spectroscopy (TrPES) of graphite reveals that fingerprints of coupled optical phonons (COPs) occur from the initial moments where Tel is still not definable. Our study shows that ultrafast-and-efficient phonon generations occur beyond the TTM scheme, presumably associated to the long duration of the non-thermal electrons in graphite.
PMCID: PMC3216551  PMID: 22355583
14.  In vivo IL‐10 gene delivery attenuates bleomycin induced pulmonary fibrosis by inhibiting the production and activation of TGF‐β in the lung 
Thorax  2006;61(10):886-894.
Idiopathic pulmonary fibrosis is a devastating disorder for which there is no effective treatment. Transforming growth factor (TGF)‐β plays a critical role in provoking fibrosis. Interleukin (IL)‐10 is a potent immunosuppressive cytokine but its effect on the fibrosing process is unclear. A study was undertaken to examine whether IL‐10 affects the production and activation of TGF‐β and thus can attenuate the fibrosis.
Mice were given an intratracheal injection of bleomycin. On day 1 or 14, IL‐10 gene was delivered by rapid intravenous injection of Ringer's solution containing plasmid. Two weeks after the plasmid injection the mice were examined for fibrosis. The effect of IL‐10 on TGF‐β production by alveolar macrophages was assessed.
Even when delivered during the fibrosing phase, IL‐10 gene significantly suppressed the pathological findings, hydroxyproline content, and production of both active and total forms of TGF‐β1 in the lung. Immunohistochemical analyses showed that alveolar macrophages were one of the major sources of TGF‐β1 and IL‐10 diminished the intensity of the staining. IL‐10 also suppressed the expression of αVβ6 integrin, a molecule that plays an important role in TGF‐β activation, on lung epithelial cells. Alveolar macrophages from bleomycin injected mice produced TGF‐β1 spontaneously ex vivo, which was significantly suppressed by treatment of the mice in vivo or by treatment of the explanted macrophages ex vivo with IL‐10.
IL‐10 suppresses the production and activation of TGF‐β in the lung and thus attenuates pulmonary fibrosis, even when delivered in the chronic phase.
PMCID: PMC2104751  PMID: 16809410
interleukin 10; gene therapy; transforming growth factor β; idiopathic pulmonary fibrosis
16.  Citrullinated fibrinogen detected as a soluble citrullinated autoantigen in rheumatoid arthritis synovial fluids 
Annals of the Rheumatic Diseases  2006;65(8):1013-1020.
Anti‐citrullinated protein antibodies (ACPA) are specifically and frequently detected in sera of patients with rheumatoid arthritis (RA). Citrullinated fibrin or fibrinogen is a candidate autoantigen of such antibodies.
To investigate the presence of citrullinated fibrinogen (cFBG) in the plasma or synovial fluid of patients with RA and control patients, and to determine cFBG levels and their relationship with serum markers for RA if it is present.
A sandwich enzyme linked immunosorbent assay (ELISA) to measure cFBG was established using monoclonal antibodies cF16.1 and cF252.1, generated by immunising mice with R16Cit and R252Cit, the fibrinogen Aα chain derived sequences with citrulline at position 16 and 252, respectively, and the presence of cFBG was further investigated with immunoprecipitation‐western blotting.
Positive signals were detected in 11/15 RA synovial fluids (RASFs), but not in osteoarthritis synovial fluids or RA plasma with sandwich ELISA for cFBG using cF16.1 and an anti‐modified citrulline (AMC) antibody. The presence of cFBG in RASFs was confirmed by immunoprecipitation‐western blotting. Furthermore, most RA sera strongly reacted against R16Cit. No relationship was seen between RASF cFBG levels and C reactive protein or anti‐cyclic citrullinated peptide antibody levels of the paired sera.
cFBG is detected as a soluble citrullinated autoantigen in RASFs and may therefore be a genuine candidate antigen for ACPA in patients with RA.
PMCID: PMC1798256  PMID: 16449316
anti‐citrulline‐containing peptide antibody; rheumatoid arthritis; synovial fluid
17.  Frequent immune response to a melanocyte specific protein KU‐MEL‐1 in patients with Vogt‐Koyanagi‐Harada disease 
To isolate autoantigens possibly involved in the pathogenesis of Vogt‐Koyanagi‐Harada (VKH) disease.
Autoantigens recognised by immunoglobulin G antibodies (IgG Ab) in sera from VKH patients were isolated by screening the lambda phage cDNA libraries made from melanocytes and a highly pigmented melanoma cell line with the patients' sera. Presence of IgG specific for the autoantigens in sera from patients with various panuveitis and healthy individuals was evaluated. Relation between the specific IgG and various clinicopathological features was examined.
KU‐MEL‐1 was found to be one of the 81 isolated positive clones representing 35 distinct genes, which is a previously isolated melanoma antigen preferentially expressed in melanocytes. The IgG Ab specific for KU‐MEL‐1 was detected in sera from patients with VKH in significantly higher amounts than in sera from patients with Behçet's disease, sarcoidosis, and from healthy individuals. Positive serum KU‐MEL‐1 Ab was significantly associated with HLA‐DRB1*0405 and male VKH patients.
KU‐MEL‐1 was identified as a new autoantigen for VKH. The highly frequent induction of IgG Ab for KU‐MEL‐1 in HLA‐DRB1*0405 positive VKH patients may suggest the possible involvement of KU‐MEL‐1 specific CD4+ T cells in the pathogenesis of VKH, suggesting the possible use in the development of diagnostic and therapeutic treatments for VKH patients.
PMCID: PMC1860214  PMID: 16481377
Vogt‐Koyanagi‐Harada disease; KU‐MEL‐1; DNA cloning; autoimmunity; uveitis
18.  Prognostic factors and treatment effects for hepatocellular carcinoma in Child C cirrhosis 
British Journal of Cancer  2008;98(7):1161-1165.
The aim of this study is to elucidate the prognostic factors and the treatment effect on survival in hepatocellular carcinoma (HCC) patients with Child C cirrhosis. Out of 3330 newly discovered HCC patients, 157 consecutive HCC individuals with Child C cirrhosis were enrolled. The prognostic factors were examined by Cox proportional hazards regression analysis and their survival was compared by propensity score-matched analysis. Multivariate analysis revealed that high serum bilirubin (>3 mg dl−1), the presence of uncontrollable ascites, and a high platelet count (>8 × 104 mm−3), so-called background liver factors, as well as multiple tumours, large tumours (>3 cm), high alpha-fetoprotein (>400 ng ml−1), and the presence of portal vein thrombus, so-called tumour factors, were factors of poor prognosis. While transcatheter arterial chemoembolisation (TACE) was a factor of good prognosis (relative risk=0.50, 95%CI=0.27–0.89, P=0.019), local ablation therapy and transcatheter arterial chemoinfusion (TAI) were not significant prognostic factors. The survival of patients who received TACE was superior to matched patients without active treatment (P=0.009); however, we did not observe survival benefit after local ablation therapy or TAI. These results suggested that tumour factors as well as background liver factors are prognostic factors of HCC even in patients with Child C cirrhosis, and selective use of TACE in these patients provides survival benefit.
PMCID: PMC2359634  PMID: 18349849
decompensated cirrhosis; prognostic factors; hepatocellular carcinoma; therapy
19.  A Conformational Switch in the Ligand Binding Domain Regulates the Dependence of the Glucocorticoid Receptor on Hsp90 
Journal of molecular biology  2007;368(3):729-741.
Steroid hormone receptors (SRs) are transcription factors that act as regulatory switches by altering gene expression in response to ligands. The highly conserved ligand-binding domain (LBD) of SRs is a precise but versatile molecular switch that can adopt distinct conformations. Differential stabilization of these conformations by ligands, DNA response elements and transcriptional coregulators controls the activity of SRs in a gene- and cell-specific manner. In the case of the glucocorticoid receptor (GR), high affinity ligand binding requires the interaction of the LBD with the heat shock protein 90 (Hsp90). Here we show that the dependence of the ligand binding ability of GR on Hsp90 can be modified by the replacement of single amino acids within an allosteric network that connects the buried ligand-binding pocket and a solvent exposed coregulator interaction surface. Each of the identified mutations distinctively altered the equilibrium between alternative GR conformations, indicating that the Hsp90 dependence of SRs may correlate with differences in the conformational dynamics of these receptors. Our results suggest that Hsp90 stabilizes the GR ligand-binding pocket indirectly by utilizing the allosteric network, while allowing the receptor to remain structurally uncommitted. Thus, in addition to ensuring the accessibility of the GR ligand-binding pocket to ligands, Hsp90 seems to enable hormones and coregulators to act as allosteric effectors, which forms the basis for gene- and cell-specific responses of GR to ligands.
PMCID: PMC2596751  PMID: 17367809
Glucocorticoid Receptor; Steroid Hormone Receptors; Hsp90 Dependence; Ligand-Binding Domain Structure; Gene Regulation
20.  Serum asymmetric dimethylarginine as a marker of coronary microcirculation in patients with non-insulin dependent diabetes mellitus: correlation with coronary flow reserve 
Heart  2005;91(12):1607-1608.
PMCID: PMC1769209  PMID: 16287749
coronary disease; diabetes mellitus; microcirculation; nitric oxide synthase
21.  When is Onuf's nucleus involved in multiple system atrophy? A sphincter electromyography study 
Background: External anal sphincter (EAS) electromyography (EMG) abnormalities can distinguish multiple system atrophy (MSA) from Parkinson's disease in the first five years after disease onset. However, the prevalence of the abnormalities in the early stages of MSA is unknown.
Objectives: To present EAS-EMG data in the various stages of MSA.
Methods: 84 patients with "probable" MSA were recruited (42 men, 42 women; mean age 62 years (range 47 to 78); mean disease duration 3.2 years (0.5 to 8.0; <1 year in 25%); 50 cerebellar form (MSA-C), 34 parkinsonian form (MSA-P)). EAS motor unit potential (MUP) analysis and EMG cystometry were carried out in all patients.
Results: The overall prevalence of neurogenic change of the EAS MUP was 62%—52% in the first year after disease onset, increasing to 83% by the fifth year (p<0.05); it also increased with severity of gait disturbance (p<0.05), storage and voiding disorders, and detrusor sphincter dyssynergy (NS). The neurogenic change was not correlated with sex, age, MSA-P/C, postural hypotension, constipation, erectile dysfunction in men, underactive or acontractile detrusor, or detrusor overactivity. In 17 incontinent patients without detrusor overactivity or low compliance, urinary incontinence was more severe in those with neurogenic change than in those without (p<0.05).
Conclusions: Involvement of Onuf's nucleus in MSA is time dependent. Before the fifth year of illness, the prevalence of neurogenic change does not seem to be high, so a negative result cannot exclude the diagnosis of MSA.
PMCID: PMC1739429  PMID: 16291887
22.  Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study 
Annals of the Rheumatic Diseases  2008;68(10):1580-1584.
To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis.
In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues.
143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient’s request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients.
In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.
PMCID: PMC2732899  PMID: 19019888
23.  Course of damage to the hallux over 5 years after forefoot resection arthroplasty in rheumatoid arthritis patients 
International Orthopaedics  2006;31(4):477-481.
A retrospective study of 34 feet from 20 consecutive patients with rheumatoid arthritis was performed to investigate the development of damage to the hallux over 5 years after forefoot resection arthroplasty. Radiographically we analysed changes in two valgus angles and the interphalangeal joint (IP) damage of the hallux. These parameters were measured preoperatively, 12 months postoperatively, and at the latest follow-up. Although the average HVA (between the first metatarsal and the proximal phalanx) significantly decreased from 38.7° preoperatively to 8.66° postoperatively, the angle increased to 23.0° during the first 12 months following surgery. Further deterioration of the angle at the last follow-up was not detected (25.3°; P=0.252). The average IPV (between the proximal phalanx and the distal phalanx) angle significantly increased from 6.65° preoperatively to 12.1° 12 months postoperatively and thereafter slightly increased to 13.3° at the latest follow-up. The average of the Sharp/van der Heijde score of the IP joint significantly increased from 5.71 preoperatively to 8.58 12 months postoperatively and thereafter slightly increased to 9.65 at the latest follow-up. The deterioration and destruction process of the hallux after resection arthroplasty occurred soon after surgery, and the progression of the deformity was temporary.
PMCID: PMC2267628  PMID: 16957889
24.  Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn’s disease 
Gut  2005;54(6):789-796.
Background and aims: A characteristic feature of Crohn’s disease (CD) is mesenteric adipose tissue hypertrophy. Mesenteric adipocytes or specific proteins secreted by them may play a role in the pathogenesis of CD. We recently identified adiponectin as an adipocyte specific protein with anti-inflammatory properties. Here we report on expression of adiponectin in mesenteric adipose tissue of CD patients.
Methods and results: Mesenteric adipose tissue specimens were obtained from patients with CD (n = 22), ulcerative colitis (UC) (n = 8) and, for controls, colon carcinoma patients (n = 28) who underwent intestinal resection. Adiponectin concentrations were determined by enzyme linked immunosorbent assay, and adiponectin mRNA levels were determined by real time quantitative reverse transcription-polymerase chain reaction. Tissue concentrations and release of adiponectin were significantly increased in hypertrophied mesenteric adipose tissue of CD patients compared with normal mesenteric adipose tissue of CD patients (p = 0.002, p = 0.040, respectively), UC patients (p = 0.002, p = 0.003), and controls (p<0.0001, p<0.0001). Adiponectin mRNA levels were significantly higher in hypertrophied mesenteric adipose tissue of CD patients than in paired normal mesenteric adipose tissue from the same subjects (p = 0.024). Adiponectin concentrations in hypertrophied mesenteric adipose tissue of CD patients with an internal fistula were significantly lower than those of CD patients without an internal fistula (p = 0.003).
Conclusions: Our results suggest that adipocytes in hypertrophied mesenteric adipose tissue produce and secrete significant amounts of adiponectin, which could be involved in the regulation of intestinal inflammation associated with CD.
PMCID: PMC1774527  PMID: 15888786
Crohn’s disease; fat wrapping; mesenteric adipocyte; adiponectin
25.  Novel quantitative assessment of myocardial perfusion by harmonic power Doppler imaging during myocardial contrast echocardiography 
Heart  2005;91(2):183-188.
Objective: To test the hypothesis that the power of the received signal of harmonic power Doppler imaging (HPDI) is proportional to the bubble concentration under conditions of constant applied acoustic pressure, and to determine whether a new quantitative method can overcome the acoustic field inhomogeneity during myocardial contrast echocardiography (MCE) and identify perfusion abnormalities caused by myocardial infarction.
Methods: The relation between Levovist concentration and contrast signal intensity (CI) of HPDI was investigated in vitro under conditions of constant acoustic pressure. MCE was performed during continuous infusion of Levovist with intermittent HPDI every sixth cardiac cycle in 11 healthy subjects and 25 patients with previous myocardial infarction. In the apical views myocardial CI (CImyo) was quantified in five myocardial segments. The CI from the left ventricular blood pool adjacent to the segment was also measured in dB and subtracted from the CImyo (relative CI (RelCI)).
Results: CI had a logarithmic correlation and the calculated signal power a strong linear correlation with Levovist concentration in vitro. Thus, a difference in CI of X dB indicates a microbubble concentration ratio of 10X/10. In normal control subjects, CImyo differed between the five segments (p < 0.0001), with a lower CImyo in deeper segments. However, RelCI did not differ significantly between segments (p  =  0.083). RelCI was lower (p < 0.0001) in the 39 infarct segments (mean (SD) −18.6 (2.8) dB) than in the 55 normal segments (mean (SD) −15.1 (1.6) dB). RelCI differed more than CImyo between groups.
Conclusions: The new quantitative method described can overcome the acoustic field inhomogeneity in evaluation of myocardial perfusion during MCE. RelCI represents the ratio of myocardium to blood microbubble concentrations and may correctly reflect myocardial blood volume fraction.
PMCID: PMC1768702  PMID: 15657228
myocardial contrast echocardiography; contrast agent; harmonic power Doppler; ultrasound attenuation; myocardial blood volume

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