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1.  Emergent photovoltage on SmB6 surface upon bulk-gap evolution revealed by pump-and-probe photoemission spectroscopy 
Scientific Reports  2015;5:8160.
Recent studies suggest that an exemplary Kondo insulator SmB6 belongs to a new class of topological insulators (TIs), in which non-trivial spin-polarized metallic states emerge on surface upon the formation of Kondo hybridization gap in the bulk. Remarkably, the bulk resistivity reaches more than 20 Ω cm at 4 K, making SmB6 a candidate for a so-called bulk-insulating TI. We here investigate optical-pulse responses of SmB6 by pump-and-probe photoemission spectroscopy. Surface photovoltage effect is observed below ~90 K. This indicates that an optically-active band bending region develops beneath the novel metallic surface upon the bulk-gap evolution. The photovoltaic effect persists for >200 µs, which is long enough to be detected by electronics devices, and could be utilized for optical gating of the novel metallic surface.
doi:10.1038/srep08160
PMCID: PMC4313084  PMID: 25640966
2.  Development of pro-apoptotic peptides as potential therapy for peritoneal endometriosis 
Nature communications  2014;5:4478.
Endometriosis is a common gynecological disease associated with pelvic pain and infertility. Current treatments include oral contraceptives combined with non-steroidal anti-inflammatory drugs or surgery to remove lesions, all of which provide a temporary but not complete cure. Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage-display. As most endometriosis occurs on organ surfaces facing the peritoneum, we subtracted a phage display library with female mouse peritoneum tissue and selected phage clones by binding to human endometrial epithelial cells. Proteomics analysis revealed the z13 receptor as the cyclic nucleotide gated channel β3, a sorting pathway protein. We then linked z13 with an apoptosis-inducing peptide and with an endosome-escaping peptide. When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighboring organs. Thus, this study presents a strategy that could be useful to treat peritoneal endometriosis in humans.
doi:10.1038/ncomms5478
PMCID: PMC4109024  PMID: 25047118
3.  Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma 
British Journal of Cancer  2013;109(8):2072-2078.
Background:
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.
Methods:
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).
Results:
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.
Conclusion:
High expression of Ang-2 or more than cytokines in serum is associated with poor PFS and OS in HCC patients treated with sorafenib.
doi:10.1038/bjc.2013.554
PMCID: PMC3798958  PMID: 24045661
angiogenesis; angiopoietin-2; cytokine; hepatocellular carcinoma; sorafenib
4.  Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group 
Blood Cancer Journal  2014;4(10):e252-.
The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR–ABL-negative ALL. Patients aged 15–24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58–75%) and 73% (95% CI 64–80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR–ABL-negative ALL.
doi:10.1038/bcj.2014.72
PMCID: PMC4220650  PMID: 25325302
5.  Radiation-quality-dependent bystander effects induced by the microbeams with different radiation sources 
Journal of Radiation Research  2014;55(Suppl 1):i54.
A central paradigm in radiation biology has been that only cells ‘hit’ by a track of radiation would be affected to induce radiobiological consequences, and cells ‘not hit’ should not be. This is the basis of the current system for risk estimation of radiobiological effects. However, it has recently been challenged by so-called non-targeted effects, such as bystander effect, and such radiation-induced cellular responses may have important implications for risk evaluation of low-dose-rate radiations as well as in tumor radiotherapy. Our group has been studying radiation-quality bystander cellular effects using the microbeams with different radiation sources.
It is essentially important for evaluating risk such a low-dose-rate exposure as the accident of Fukushima Daiichi Nuclear Power Plants to examine bystander effects induced by low-LET electromagnetic radiations, such as X or gamma rays. We have been studying the cellular responses in normal human fibroblasts by targeted cell nucleus irradiations with monochromatic X-ray microbeams (5.35 keV) produced by Photon Factory in High Energy Accelerator Research Organization. The results indicated that the bystander effect in cell- killing effect was observed in the targeted cell nucleus irradiation, not in the random irradiation containing both cell nucleus and cytoplasm by Poisson distribution. The results suggest that energy deposition in cytoplasm is an important role of inducing bystander effects in case of low-LET radiations.
We have also been investigating high-LET-radiation induced bystander effects using the heavy-ion microbeams at Takasaki Ion Accelerators for Advanced Radiation Application in Japan Atomic Energy Agency. Only 0.04% of the total numbers of normal human fibroblasts were irradiated with C-ion (220 MeV), Ne-ion (260 MeV) and Ar-ion (460 MeV) microbeams collimated at 20 μm in diameter. Cell-killing effect and gene mutation at HPRT locus in the cells irradiated with C ions were higher beyond our expectations and returned the estimated values that only 0.04% of the total cells were irradiated when using the specific inhibitor of gap junctions. On the other hand, no induced biological effects were observed in Ne and Ar ions whether the inhibitor was applied or not. The result suggested that the C-ion microbeam was capable of inducing bystander cellular effects via gap junction-mediated cell-cell communication. There is clear evidence that bystander cellular effects are dependent on radiation quality.
It is also important for highly developed heavy-ion radiotherapy to identify bystander effects induced by spatially low-fluence irradiations with heavy-ion beams. We have been investigating the biological effects using human tumor cell lines. The results clearly showed that bystander effects were observed in the carbon-ion irradiation but not in other ions as well as the effects in normal fibroblasts. Furthermore, the bystander cell-killing effect in tumor cell lines was strongly induced in the cells harboring wild-type P53 not in mutated-type P53 cells. The results provide the important implication for a tailor-made therapy using carbon ions.
doi:10.1093/jrr/rrt219
PMCID: PMC3941530
Bystander effect; Microbeam; Gap junction, P53, HPRT
7.  Estrogen oversees the maintenance of the female genetic program in terminally differentiated gonochorists 
Scientific Reports  2013;3:2862.
The sexual plasticity of the gonads is not retained after the completion of sex differentiation in vertebrates, except in some hermaphroditic species. Here, we report that the depletion of estradiol-17β (E2) by aromatase inhibitors (AI) for up to six months resulted in a functional female-to-male sex reversal in sexually-mature adults of two gonochoristic fish species, Nile tilapia and medaka. The sex-reversed fish showed a typical male pattern of E2 and androgen levels, secondary sexual characteristics, and male-like sex behavior, producing fertile sperm. Conversely, co-treatment of E2 inhibited AI-induced sex reversal. In situ hybridization of medaka gonads during AI-induced sex reversal indicated that cysts on the dorsal side of the adult ovaries are the origin of germ cells and Sertoli cells in the newly formed testicular tissue. Gonochoristic fish maintain their sexual plasticity until adulthood and E2 plays a critical role in maintaining the female phenotype.
doi:10.1038/srep02862
PMCID: PMC3791451  PMID: 24096556
8.  Even-skipped homeobox 1 is frequently hypermethylated in prostate cancer and predicts PSA recurrence 
British Journal of Cancer  2012;107(1):100-107.
Background:
DNA methylation is an important epigenetic mechanism in prostate cancer (PCa) progression. Given the role of even-skipped homeobox 1 (EVX1) in the regulation of multiple genes during embryogenesis, we postulated that EVX1 methylation is altered in PCa progression.
Methods:
Bisulphite sequencing and quantitative MethyLight were used to assess methylation in human prostate epithelial cells, four PCa cell lines, liver, lung, spleen, kidney, 35 paired tumour and tumour-associated benign tissues, and 11 normal prostate tissues. Prostate cancer cell lines were treated with 5-azacytidine (AzaC) or trichostatin A (TSA), and expression of EVX1 transcript and variants was assessed by qPCR. Hypermethylation was compared with clinicopathological features in a validation set of 58 patients using microarray.
Results:
Even-skipped homeobox 1 hypermethylation was observed in all four PCa cell lines and 57% of tumours. High-grade tumours exhibited increased methylation compared with intermediate-grade tumours. Even-skipped homeobox 1 expression was induced in PCa cell lines after treatment with AzaC or TSA. In the validation set, 83% of tumours were hypermethylated and hypermethylation was associated with worse recurrence-free survival.
Conclusion:
In this first evaluation of EVX1 methylation in human cancer, EVX1 is one of the most commonly hypermethylated genes observed in PCa and predicted treatment failure in moderate risk patients.
doi:10.1038/bjc.2012.216
PMCID: PMC3389415  PMID: 22596233
EVX1; methylation; prostate cancer; PSA; prognosis
9.  Long-Term Survival after Adrenalectomy for Asynchronous Metastasis of Bladder Cancer to the Bilateral Adrenal Glands 
Case Reports in Urology  2012;2012:425230.
Isolated adrenal metastasis of bladder cancer, particularly the bilateral, is quite rare. Systemic chemotherapy is the treatment of choice for metastatic urothelial carcinoma. However, despite initially promising response rates of approximately 45%–71%, most tumors eventually show progression, and the median survival time following chemotherapy regimen is approximately 14-15 months. Recently, favorable results of surgery for metastatic urothelial carcinoma have been reported. Here, we report a rare case of asynchronous metastasis of bladder cancer to the bilateral adrenal glands with long-term survival after bilateral adrenalectomy. A 69-year-old man underwent radical cystoprostatectomy and ileal conduit urinary diversion for invasive bladder cancer. Ten months later, left adrenalectomy was performed for a left adrenal tumor, revealing metastatic urothelial carcinoma. After adjuvant chemotherapy, a tumor in the right adrenal gland was detected. Right adrenalectomy was done, and the tumor was also found to be metastatic urothelial carcinoma. The patient had an uneventful recovery after starting steroid replacement therapy. Three years later, he was doing well and had no evidence of recurrence. Adrenalectomy for isolated adrenal metastasis of urothelial carcinoma may be a reasonable option, even if such metastases are bilateral.
doi:10.1155/2012/425230
PMCID: PMC3508529  PMID: 23213615
10.  Roles of HAUSP-mediated p53 regulation in central nervous system development 
Cell Death and Differentiation  2011;18(8):1366-1375.
The deubiquitinase HAUSP (herpesvirus-associated ubiquitin-specific protease; also called USP7) has a critical role in regulating the p53-Mdm2 (murine double minute 2) pathway. By using the conventional knockout approach, we previously showed that hausp inactivation leads to early embryonic lethality. To fully understand the physiological functions of hausp, we have generated mice lacking hausp specifically in the brain and examined the impacts of this manipulation on brain development. We found that deletion of hausp in neural cells resulted in neonatal lethality. The brains from these mice displayed hypoplasia and deficiencies in development, which were mainly caused by p53-mediated apoptosis. Detailed analysis also showed an increase of both p53 levels and p53-dependent transcriptional activation in hausp knockout brains. Notably, neural cell survival and brain development of hausp-mutant mice can largely be restored in the p53-null background. Nevertheless, in contrast to the case of mdm2- and mdm4 (murine double minute 4)-mutant mice, inactivation of p53 failed to completely rescue the neonatal lethality of these hausp-mutant mice. These results indicate that HAUSP-mediated p53 regulation is crucial for brain development, and also suggest that both the p53-dependent and the p53-independent functions of HAUSP contribute to the neonatal lethality of hausp-mutant mice.
doi:10.1038/cdd.2011.12
PMCID: PMC3134159  PMID: 21350561
HAUSP; p53; Mdm2; deubiquitination; gene conditional knockout; mouse
11.  Skin advanced glycation end-product accumulation is negatively associated with calcaneal osteo-sono assessment index among non-diabetic adult Japanese men 
Osteoporosis International  2011;23(6):1673-1681.
Summary
This study aims to determine the relationship between advanced glycation end-product (AGE) accumulation in skin tissue and bone strength, assessed by quantitative ultrasound, among healthy adult Japanese men. The results of the study suggest that men with higher AGE accumulation in skin tissue have a lower osteo-sono assessment index.
Introduction
AGE accumulate in bone collagen with age and diabetes and decrease the mechanical properties of bone. Although increased AGE levels are associated with fractures among diabetic patients and elderly women, it is unclear whether a relationship between increased AGE levels and bone strength is present in apparently healthy adult males. The aim of this study was to determine the relationship between AGE accumulation in tissue and the mechanical properties of bone among adult Japanese men, using quantitative ultrasound as a surrogate measure of the latter.
Methods
Skin autofluorescence (AF), which is a noninvasive method for measuring tissue AGEs, and osteo-sono assessment index (OSI), which is determined by quantitative ultrasound, were measured in 193 adult Japanese men (median age 43 years; interquartile range 37.0–55.0 years).
Results
Adjusted for age, BMI, calcium intake, physical activity, smoking status, and education level, log-transformed skin AF had a negative association with log-transformed OSI (β = −0.218, P < 0.01). Adjusted geometric means (95% CI) for OSI across the tertiles of skin AF were 2.81 (2.75–2.87) for the lowest tertile, 2.81 (2.74–2.87) for the middle tertile, and 2.66 (2.61–2.73) for the highest tertile; thus, OSI for the highest skin AF appeared to be 5.0% lower than that for the lowest and middle skin AF tertiles (P < 0.01).
Conclusion
Among apparently healthy adult Japanese men, those with higher skin AF had a lower OSI, indicating a relationship between AGE accumulation and bone strength. A long-term prospective study is required to clarify the causality.
doi:10.1007/s00198-011-1753-4
PMCID: PMC3353116  PMID: 21901479
Advanced glycation end-products; Bone quality; Bone strength; Carbonyl stress; Oxidative stress; Quantitative ultrasound
12.  Roles of HAUSP-mediated p53 regulation in central nervous system development 
Cell death and differentiation  2011;18(8):1366-1375.
The deubiquitinase HAUSP (herpesvirus-associated ubiquitin-specific protease; also called USP7) has a critical role in regulating the p53-Mdm2 (murine double minute 2) pathway. By using the conventional knockout approach, we previously showed that hausp inactivation leads to early embryonic lethality. To fully understand the physiological functions of hausp, we have generated mice lacking hausp specifically in the brain and examined the impacts of this manipulation on brain development. We found that deletion of hausp in neural cells resulted in neonatal lethality. The brains from these mice displayed hypoplasia and deficiencies in development, which were mainly caused by p53-mediated apoptosis. Detailed analysis also showed an increase of both p53 levels and p53-dependent transcriptional activation in hausp knockout brains. Notably, neural cell survival and brain development of hausp-mutant mice can largely be restored in the p53-null background. Nevertheless, in contrast to the case of mdm2- and mdm4 (murine double minute 4)-mutant mice, inactivation of p53 failed to completely rescue the neonatal lethality of these hausp-mutant mice. These results indicate that HAUSP-mediated p53 regulation is crucial for brain development, and also suggest that both the p53-dependent and the p53-independent functions of HAUSP contribute to the neonatal lethality of hausp-mutant mice.
doi:10.1038/cdd.2011.12
PMCID: PMC3134159  PMID: 21350561
HAUSP; p53; Mdm2; deubiquitination; gene conditional knockout; mouse
15.  Molecular Monitoring and Isolation of Previously Uncultured Bacterial Strains from the Sheep Rumen ▿  
To estimate the contribution of uncultured bacterial groups to fiber degradation, we attempted to retrieve both ecological and functional information on uncultured groups in the rumen. Among previously reported uncultured bacteria, fiber-associated groups U2 and U3, belonging to the low-GC Gram-positive bacterial group, were targeted. PCR primers and fluorescence in situ hybridization (FISH) probe targeting 16S rRNA genes or rRNA were designed and used to monitor the distribution of targets. The population size of group U2 in the rumen was as high as 1.87%, while that of group U3 was only 0.03%. Strong fluorescence signals were observed from group U2 cells attached to plant fibers in the rumen. These findings indicate the ecological significance of group U2 in the rumen. We succeeded in enriching group U2 using rumen-incubated rice straw as the inoculum followed by incubation in an appropriate medium with an agent inhibitory for Gram-negative bacteria. Consequently, we successfully isolated two strains, designated B76 and R-25, belonging to group U2. Both strains were Gram-positive short rods or cocci that were 0.5 to 0.8 μm in size. Strain B76 possessed xylanase and α-l-arabinofuranosidase activity. In particular, the xylanase activity of strain B76 was higher than that of xylanolytic Butyrivibrio fibrisolvens H17c grown on cellobiose. Strain R-25 showed an α-l-arabinofuranosidase activity higher than that of strain B76. These results suggest that strains B76 and R-25 contribute to hemicellulose degradation in the rumen.
doi:10.1128/AEM.02606-09
PMCID: PMC2838016  PMID: 20118379
16.  Inactivation of HAUSP in vivo modulates p53 function 
Oncogene  2009;29(9):1270-1279.
Hausp is a deubiquitinase that has been shown to regulate the p53–Mdm2 pathway. Cotransfection of p53 and Hausp stabilizes p53 through the removal of ubiquitin moieties from polyubiquitinated p53. Interestingly, knockout or RNA interference-mediated knockdown of Hausp in human cells also resulted in the stabilization of p53 due to the destabilization of Mdm2, suggesting a dynamic role of Hausp in p53 activation. To understand the physiological functions of Hausp, we generated hausp knockout mice. Hausp knockout mice die during early embryonic development between embryonic days E6.5 and E7.5. The hausp knockout embryos showed p53 activation, but no apparent increase in apoptosis. Embryonic lethality was caused by a dramatic reduction in proliferation and termination in development, in part due to p53 activation and/or abrogation of p53-independent functions. Although deletion of p53 did not completely rescue the embryonic lethality of the hausp knockout, embryonic development was extended in both hausp and p53 double knockout embryos. These data show that Hausp has a critical role in regulating the p53–Mdm2 pathway.
doi:10.1038/onc.2009.427
PMCID: PMC2857765  PMID: 19946331
hausp; p53; mdm2; deubiquitination; gene knockout; mouse
17.  Acidic Mammalian Chitinase Regulates Epithelial Cell via a Chitinolytic-Independent Mechanism 
Acidic mammalian chitinase (AMCase) is produced during and plays an important role in the pathogenesis of Th2-mediated diseases and antiparasite responses. However, the effector responses of AMCase in these settings have not been adequately defined and the relationship(s) between its chitinolytic and other biologic properties have not been investigated. In these studies we demonstrate that AMCase protects airway epithelial cells from Fas ligand (FasL)- and growth factor withdrawal-induced apoptosis. This cytoprotection was associated with Akt phosphorylation and abrogated when the phosphoinositide 3-kinase (PI3K)/Akt pathway was inhibited. Comparable cytoprotection was also seen in experiments comparing wild type AMCase and mutant AMCase that lacked chitinolytic activity. Importantly, the apoptosis-inhibiting effect of enzymatically-active and -inactive AMCase was abrogated by treatment with allosamidin. These studies demonstrate that secreted AMCase feeds back in an autocrine and/or paracrine manner to protect pulmonary epithelial cells from growth factor withdrawal- and FasL-induced apoptosis. They also demonstrate that the cytoprotection is mediated via a PI3K/Akt-dependent and allosamidin-sensitive pathway that is independent of the chitinolytic acvtivity of this chitinase.
doi:10.4049/jimmunol.0803446
PMCID: PMC2666938  PMID: 19342690
asthma; Th2 inflammation; IL-13; chitinase; lung epithelial cells; apoptosis; chemokines
18.  An oncogenic role for the multiple endocrine neoplasia type 1 gene in prostate cancer 
Prostate cancer is the second leading cause of cancer related deaths in US men, largely because of metastasis, which is ultimately fatal. A better understanding of metastasis biology will lead to improved prognostication and therapeutics. We previously reported 11q13.1 gain was independently predictive of recurrence after radical prostatectomy. Multiple endocrine neoplasia I (MEN1) maps to this region of copy number gain in aggressive prostate tumors and was shown to be the only gene at this locus at increased expression in prostate cancer. Here, we demonstrate an oncogenic role for MEN1 in prostate cancer using a variety of independent assays.
doi:10.1038/pcan.2008.45
PMCID: PMC2844124  PMID: 18779856
MEN1; metastasis; oncogene
19.  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.
doi:10.1038/sj.bjc.6604282
PMCID: PMC2359634  PMID: 18349849
decompensated cirrhosis; prognostic factors; hepatocellular carcinoma; therapy
20.  Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C 
British Journal of Cancer  2008;98(3):580-586.
Although the oxidative stress frequently occurs in patients with chronic hepatitis C, its role in future hepatocellular carcinoma (HCC) development is unknown. Hepatic 8-hydroxydeoxyguanosine (8-OHdG) was quantified using liver biopsy samples from 118 naïve patients who underwent liver biopsy from 1995 to 2001. The predictability of 8-OHdG for future HCC development and its relations to epidemiologic, biochemical and histological baseline characteristics were evaluated. During the follow-up period (mean was 6.7±3.3 years), HCC was identified in 36 patients (30.5%). Univariate analysis revealed that 16 variables, including 8-OHdG counts (65.2±20.2 vs 40.0±23.5 cells per 105 μm2, P<0.0001), were significantly different between patients with and without HCC. Cox proportional hazard analysis showed that the hepatic 8-OHdG (P=0.0058) and fibrosis (P=0.0181) were independent predicting factors of HCC. Remarkably, 8-OHdG levels were positively correlated with body and hepatic iron storage markers (vs ferritin, P<0.0001 vs hepatic iron score, P<0.0001). This study showed that oxidative DNA damage is associated with increased risk for HCC and hepatic 8-OHdG levels are useful as markers to identify the extreme high-risk subgroup. The strong correlation between hepatic DNA damage and iron overload suggests that the iron content may be a strong mediator of oxidative stress and iron reduction may reduce HCC incidence in patients with chronic hepatitis C.
doi:10.1038/sj.bjc.6604204
PMCID: PMC2243145  PMID: 18231107
oxidative stress; free radicals; 8-hydroxydeoxyguanosine; iron; hepatitis C virus; immunohistochemistry
21.  Neutrophilic inflammation in childhood bronchial asthma 
Thorax  2005;60(8):704-705.
doi:10.1136/thx.2005.043075
PMCID: PMC1747494  PMID: 16061715
22.  Echolucent neointimal hyperplasia “dark wall” after sirolimus eluting stent implantation 
Heart  2004;90(10):1143.
doi:10.1136/hrt.2003.011023
PMCID: PMC1768498  PMID: 15367508
Images in cardiology
23.  Percutaneous treatment of giant coronary aneurysm with multiple polytetrafluoroethylene (PTFE) covered stents 
Heart  2004;90(6):637.
doi:10.1136/hrt.2003.023531
PMCID: PMC1768259  PMID: 15145865
Images in cardiology
24.  Implications of plasma concentrations of adiponectin in patients with coronary artery disease 
Heart  2004;90(5):528-533.
Objective: To investigate whether concentrations of plasma adiponectin constitute a significant coronary risk factor, with particular focus on the relation between plasma concentrations of adiponectin and the development of acute coronary syndrome (ACS).
Subjects and methods: Plasma concentrations of adiponectin were measured in 123 patients with coronary artery disease (CAD) and in 17 control participants. Patients were divided into three groups according to condition type: acute myocardial infarction (AMI) group (n  =  59), unstable angina pectoris (UAP) group (n  =  28), and stable angina pectoris (SAP) group (n  =  36).
Results: Plasma concentrations of adiponectin correlated negatively with body mass index (r  =  −0.18, p < 0.05), serum triglyceride (r  =  −0.25, p < 0.01), and fasting glucose concentrations (r  =  −0.21, p < 0.05), but correlated positively with age (r  =  0.26, p < 0.01), high density lipoprotein cholesterol concentrations (r  =  0.35, p < 0.01), and low density lipoprotein particle size (r  =  0.37, p < 0.01). Plasma concentrations of adiponectin in patients with ACS, in both the AMI and UAP groups, were significantly lower than those in patients with SAP and in the control group (ACS, 6.5 (3.0) μg/ml; SAP, 11.3 (5.9) μg/ml; control 12.8 (4.3) μg/ml; p < 0.01). Additionally, plasma concentrations of adiponectin in patients with CAD (7.9 (4.6) μg/ml, p < 0.01) were significantly lower than in the control group. There were, however, no significant differences between patients with SAP and the control group (p  =  0.36). Multiple logistic regression analysis showed that smoking, fasting glucose concentration, and low log adiponectin concentration correlated independently with the development of an ACS.
Conclusions: The findings suggest that measurement of plasma concentrations of adiponectin may be of use for assessing the risk of CAD and may be related to the development of ACS.
doi:10.1136/hrt.2003.011114
PMCID: PMC1768199  PMID: 15084551
adiponectin; LDL particle size; acute coronary syndrome; coronary artery disease; coronary risk factor

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