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1.  Inhibition of NEDD8 Conjugation Pathway by Novel Molecules: Potential Approaches to Anticancer Therapy 
Molecular oncology  2012;6(3):10.1016/j.molonc.2012.01.003.
Cancer cells can survive through the upregulation of cell cycle and the escape from apoptosis induced by numerous cellular stresses. In the normal cells, these biological cascades depend on scheduled proteolytic degradation of regulatory proteins via the ubiquitin-proteasome pathway. Therefore, interruption of regulated proteolytic pathways leads to abnormal cell-proliferation. Ubiquitin ligases called SCF complex (consisting of Skp-1, cullin, and F-box protein) or CRL (cullin-RING ubiquitin ligase) are predominant in a family of E3 ubiquitin ligases that control a final step in ubiquitination of diverse substrates. To a great extent, the ubiquitin ligase activity of the SCF complex requires the conjugation of NEDD8 to cullins, i.e. scaffold proteins. This review is anticipated to review the downregulation system of NEDD8 conjugation by several factors including a chemical compound such as MLN4924 and protein molecules (e.g. COP9 signalosome, inactive mutant of Ubc12, and NUB1/NUB1L). Since the downregulation of NEDD8 conjugation affects cell cycle progression by inhibiting the ligase activity of SCF complexes, such knowledge in the NEDD8 conjugation pathway will contribute to the more magnificent therapies that selectively suppress tumorigenesis.
PMCID: PMC3826113  PMID: 22306028
Ubiquitination; SCF complex; NEDD8; MLN4924; Ubc12; NUB1
2.  Chronic kidney disease in patients with ileal conduit urinary diversion 
While renal dysfunction is often observed in patients following urinary diversion due to bladder cancer, there have been few studies on this subject. A cross-sectional study was performed on the renal function of ileal conduit urinary diversion patients and the prevalence and risk factors for chronic kidney disease (CKD) were examined. Patients with ileal conduit urinary diversion (n=102), who were being followed-up as outpatients and who were in stable condition, as well as age- and gender-matched healthy control subjects (n=63) were selected for this study. The prevalence of CKD was compared between the patients and healthy subjects. Next, the clinical factors associated with the presence of CKD were investigated in the patients with ileal conduit diversion using logistic regression analysis. The prevalence of CKD was significantly higher in the patients with ileal conduit diversion compared with the healthy subjects [60 patients (58.8%) vs. 11 healthy subjects (17.5%), P<0.0001]. The mean decrease in the estimated glomerular filtration rate per year of the patients with urinary diversion was 0.95±2.0 ml/min/1.73 m2. Multiple logistic regression analysis revealed that the independent and significant factors associated with the presence of CKD were older age and the presence of hypertension, urolithiasis and a past history of hydronephrosis. In conclusion, an increased prevalence of CKD was revealed in the patients with ileal conduit urinary diversion, suggesting the need for better management of hypertension, urolithiasis and hydronephrosis following surgery.
PMCID: PMC3494134  PMID: 23226756
chronic kidney disease; urinary diversion; ileal conduit; bladder cancer
3.  Urinary levels of Hepatocarcinoma-intestine-pancreas/Pancreatitis-associated protein as a diagnostic biomarker in patients with bladder cancer 
BMC Urology  2012;12:24.
To assess the possibility of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) as a biological marker for detecting Bladder cancer (BCa), we examined the expression of HIP/PAP in both BCa specimens and BCa cell lines and measured HIP/PAP levels in urine from patients with BCa.
HIP/PAP expression in BCa samples was evaluated by western blot analysis, and urinary levels of HIP/PAP in patients with BCa were measured by enzyme-linked immunosorbent assay. Urine samples were collected from 10 healthy volunteers and 109 with benign urological disorders as controls, and from 101 patients who were diagnosed with BCa.
HIP/PAP was highly expressed in BCa samples as compared with control bladder. Urinary HIP/PAP concentrations were significantly higher in BCa patients than in controls (median value; 3.184 pg/mL vs. 55.200 pg/mL, P <0.0001, by Mann–Whitney U test). Urinary HIP/PAP levels in BCa patients correlated positively with pathological T stages and progression-risk groups among non-muscle invasive BCa (P = 0.0008, by Kruskal-Wallis test). Regarding the recurrence-risk classifications of non-muscle invasive BCa, the urinary levels of HIP/PAP were significantly higher in the intermediate than in the low risk group (P = 0.0002, by Mann–Whitney U test). Based on a cut-off of 8.5 pg/mL, the ability of urinary HIP/PAP levels to detect BCa had a sensitivity of 80.2%, specificity of 78.2%, positive predictive value (PPV) of 75.7%, and negative predictive value (NPV) of 82.3%.
HIP/PAP was abundantly expressed in BCa, and the urinary levels of HIP/PAP could be a novel and potent biomarker for detection of BCa, and also for predicting the risks of recurrence- and progression-risk of non-muscle invasive BCa. A large scale study will be needed to establish the usefulness of this biomarker.
PMCID: PMC3487857  PMID: 22943287
Bladder cancer; Urinary marker; HIP/PAP; ELISA; ROC
4.  ABO-incompatible kidney transplantation in elderly patients over 60 years of age 
International Urology and Nephrology  2012;44(5):1563-1570.
Patients aged 60 years and older represent the fastest-growing population with end-stage renal disease worldwide, and the need for a kidney transplant among this population is increasing. Due to the severe shortage of deceased donors in Japan, ABO-incompatible living donor kidney transplantation has been performed since the late 1980s. Excellent long-term outcomes have been achieved, and the rates of graft survival in these patients are currently similar to those in recipients of ABO-compatible grafts. However, the outcomes of ABO-incompatible kidney transplantation in elderly patients over 60 years of age have not been well studied yet.
Patients and methods
We studied 4 elderly kidney transplant patients who received their grafts from ABO-incompatible living donors at our institution between December 2006 and December 2011, focusing on the immunosuppressive protocols, complications and graft survivals. The mean observation period was 21.5 months (range, 8 months to 62 months). Our immunosuppressive protocols were as follows: to remove the anti-A/B antibodies, the patients underwent 4–8 sessions of double-filtration plasmapheresis and/or plasma exchange prior to kidney transplantation until the anti-A/B titers were less than 1:16. For the patients with low anti-A/B titers (<1:512), the immunosuppressive protocol consisted of a single dose of rituximab (150 mg/m2). The patients with high anti-A/B antibody titers (≥1:512) underwent splenectomy and received 2 doses of rituximab. The pretransplant immunosuppressive protocol included B-lymphocyte suppression with 4 weeks of mycophenolate mofetil (0.5 g/day for low-titer protocol and 1 g/day for high-titer protocol).
All 4 patients underwent successful transplantation. At the end of follow-up, their mean serum creatinine was 1.18 mg/dl. No patient experienced antibody-mediated rejection or acute cellular rejection. Late-onset neutropenia occurred in two cases. Two cases experienced cytomegalovirus reactivation by cytomegalovirus antigenemia. In one patient, diffuse hemorrhage required surgical intervention. However, there were no severe complications.
Although a careful evaluation of patients is needed, ABO-incompatible kidney transplantation may become a viable treatment option for elderly patients with end-stage renal disease.
PMCID: PMC3444708  PMID: 22828739
Kidney transplantation; ABO-incompatible; Elderly patients; Desensitization protocol
5.  Albuminuria-reducing effect of angiotensin II receptor blocker plus hydrochlorothiazide combination therapy in renal transplant recipients 
In recent years, the combined use of angiotensin II receptor blockers (ARBs) and low-dose diuretics has become clinically possible. Moreover, the GUARD and J-CORE studies have confirmed that the addition of low-dose diuretics to renin-angiotensin system inhibitors reduces albuminuria. In this study, we investigated the clinical effects of a combination drug containing an ARB and a low-dose diuretic in renal transplant recipients. A total of 13 renal transplant recipients who were receiving the maximum dose of the ARB and presenting with microalbuminuria [urine albumin-creatinine ratio (ACR) of 30–300 mg/g-Cre] were converted to a single pill combination drug containing the same amount of the ARB and 12.5 mg of hydrochlorothiazide (HCTZ) and an intervention study of a crossover trial design was conducted. The clinical parameters were measured at baseline, 3 months after ARB/HCTZ conversion and 3 months after reverting to the ARB and the resulting data were compared. Serum creatinine (S-Cre) and uric acid (UA) levels at 3 months after conversion were significantly higher than those at baseline. The levels of the estimated glomerular filtration rate (eGFR) and ACR at 3 months were significantly lower than those at baseline. S-Cre and UA levels at 3 months after reversion were significantly lower than those at 3 months after conversion. The eGFR and levels of ACR and UA at 3 months after ARB reversion were significantly higher than those at 3 months after conversion. The results of this preliminary study suggest that the combination drug containing an ARB and low-dose diuretic was effective for reducing microalbuminuria in renal transplant recipients. In the future, larger cohort studies are needed to confirm these findings.
PMCID: PMC3460262  PMID: 23060931
renal transplant recipients; angiotensin II receptor blockers; hydrochlorothiazide; combination therapy; microalbuminuria
6.  Hyperbaric oxygen therapy for painful bladder syndrome/interstitial cystitis resistant to conventional treatments: long-term results of a case series in Japan 
BMC Urology  2011;11:11.
There is no confirmed strategy for treating painful bladder syndrome/interstitial cystitis (PBS/IC) with unclear etiology. Therefore, a pilot study was carried out to evaluate the efficacy and safety of hyperbaric oxygen (HBO) therapy in treatment-resistant PBS/IC patients.
HBO treatment (2.0 ATA for 60 minutes/day × 5 days/week for 2 or 4 weeks) was performed on 11 patients with severe symptoms that had not been improved by previous therapy regimens between December 2004 and July 2009.
Seven of the 11 patients demonstrated persistent improvement in symptoms during the 12 months after HBO treatment. These responders demonstrated a decrease in the pelvic pain scale and urgency scale from 7.7 ± 1.0 and, 6.6 ± 0.9 to 3.4 ± 2.5 and 4.3 ± 2.4 after 12 months, respectively (p < 0.05). The total score of the interstitial cystitis symptom index and 24-hour urinary frequency demonstrated a significant sustained decrease from the baseline. Two responders, who received an additional course of HBO 12 and 13 months after initial treatment, respectively, did not suffer impairment for more than two years. There was one case of transient eustachian tube dysfunction and three cases of reversible exudative otitis media as a consequence of HBO treatment.
HBO is a potent treatment for PBS/IC patients resistant to conventional therapy. It was well tolerated and provided maintained amelioration of pain, urgency and urinary frequency for at least 12 months.
PMCID: PMC3116481  PMID: 21609485
7.  Association of Prostate Cancer and Manganese Superoxide Dismutase AA Genotype Influenced by Presence of Occult Cancer in Control Group 
Urology  2008;72(2):238-242.
To investigate whether the inclusion of occult cancer in the control group can influence the association of prostate cancer and the polymorphism of manganese superoxide dismutase (MnSOD).
Prostate specimens and sera were obtained from 194 deceased men who did not have a history of prostate cancer. Eighteen-core biopsy specimens and whole-mount sections were evaluated histologically. The MnSOD genotype of the specimens was determined by polymerase chain reaction restriction fragment length polymorphism analysis.
Tumors were present in 57 of the prostates, and biopsy detected 33 (including 1 false-positive finding). It detected 17 (1 false-positive finding) and missed 14 tumors in the subgroup of 135 specimens with a prostatic-specific antigen <4 ng/mL. The MnSOD AA genotype was associated with prostate cancer found in the step-sectioned specimens vs the control group in whom the absence of occult prostate cancer had been verified. However, no association was found if the control group consisted of subjects with negative biopsy results from the overall group or the subgroup with a prostatic-specific antigen level of <4 ng/mL.
The MnSOD AA genotype was associated with prostate cancer in our study; however, contamination of occult prostate cancer in the control group reduced the power of analysis and might yield seemingly negative results. Epidemiologic studies should strive to include control groups with a verified absence of occult cancer.
PMCID: PMC2561904  PMID: 18571701
8.  MnSOD Genotype and Prostate Cancer Risk as a Function of NAT Genotype and Smoking Status 
In vivo (Athens, Greece)  2009;23(1):7-12.
Cigarette smoke contains carcinogenic aromatic and heterocyclic amines that are metabolized by N-acetyltransferase (NAT). These carcinogens also produce reactive oxygen species that are metabolized by manganese superoxide dismutase (MnSOD). The association between prostate cancer (PCA) and the polymorphism of MnSOD and NAT, and cigarette smoking was investigated.
Materials and Methods
DNA samples from 187 PCA patients and 175 age-matched controls were genotyped for MnSOD, NAT1 and NAT2 by PCR restriction fragment length polymorphism analysis and DNA sequencing.
MnSOD AA genotype, as compared to MnSOD VV and VA, was associated with PCA (odds ratio, 1.65; 95% confidence interval, 1.03–2.66]. There was no association of PCA with NAT or smoking. Results of exploratory analyses of the data suggest that the association of PCA and MnSOD exists only in the subpopulation of rapid NAT1 genotypes and smokers.
The present study demonstrates the association of PCA and MnSOD. Oxidative stress and cigarette smoking may play an important role in the carcinogenesis of the prostate in those who have MnSOD AA and rapid NAT1 genotypes.
PMCID: PMC2670457  PMID: 19368118
Prostate cancer; prostate-specific antigen; manganese superoxide dismutase; N-acetyltransferase; smoking; polymorphism
9.  Occult Prostate Cancer Effects the Results of Case Control Studies Due to Verification Bias 
Anticancer research  2008;28(5B):3007-3010.
Epidemiological studies of prostate cancer (PCA) which are based on case control comparisons may be effected by verification bias. Verification bias exists when the experimental group has verified PCA, while the control group is presumed to be cancer free, but this is not histologically verified. Materials and
Review of the literature and our recent experience with case control studies of PCA in an autopsy model. Results: When autopsied prostates were evaluated for cancer based on prostatic specific antigen <4 ng/ml, negative biopsy or both criteria, the contamination rate was 22%, 15% or 12%, respectively. The effect of contamination by occult PCA alters the odds ratio and p-value of the results.
It is important to recognize that contamination of the control population by occult carcinomas reduces the reliability of the results. Rigorous characterization of the experimental and control groups is needed in order to preserve the integrity of the conclusions.
PMCID: PMC2662609  PMID: 19031947
Prostate cancer; polymorphisms; autopsy; occult cancer; prostate specific antigen

Results 1-9 (9)