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1.  Synergistic Effect of Geranylgeranyltransferase Inhibitor, GGTI, and Docetaxel on the Growth of Prostate Cancer Cells 
Prostate Cancer  2011;2012:989214.
Most advanced prostate cancers progress to castration resistant prostate cancer (CRPC) after a few years of androgen deprivation therapy and the prognosis of patients with CRPC is poor. Although docetaxel and cabazitaxel can prolong the survival of patients with CRPC, inevitable progression appears following those treatments. It is urgently required to identify better or alternative therapeutic strategies. The purpose of this study was to confirm the anti-cancer activity of zoledronic acid (Zol) and determine whether inhibition of geranylgeranylation in the mevalonate pathway could be a molecular target of prostate cancer treatment. We examined the growth inhibitory effect of Zol in prostate cancer cells (LNCaP, PC3, DU145) and investigated a role of geranylgeranylation in the anticancer activity of Zol. We, then, evaluated the growth inhibitory effect of geranylgeranyltransferase inhibitor (GGTI), and analyzed the synergy of GGTI and docetaxel by combination index and isobolographic analysis. Zol inhibited the growth of all prostate cancer cell lines tested in a dose-dependent manner through inhibition of geranylgeranylation. GGTI also inhibited the prostate cancer cell growth and the growth inhibitory effect was augmented by a combination with docetaxel. Synergism between GGTI and docetaxel was observed across a broad range of concentrations. In conclusion, our results demonstrated that GGTI can inhibit the growth of prostate cancer cells and has synergistic effect with docetaxel, suggesting its potential role in prostate cancer treatment.
PMCID: PMC3195320  PMID: 22111007
2.  Duration of androgen deprivation therapy with maximum androgen blockade for localized prostate cancer 
BMC Urology  2011;11:7.
Primary androgen deprivation therapy (ADT) is a treatment option not only for advanced but also for localized prostate cancer. However, the appropriate duration for primary ADT for localized prostate cancer has not been defined and few studies have addressed this issue. In this study, we aimed to determine the appropriate duration of ADT for localized prostate cancer.
Sixty-eight consecutive patients with localized prostate cancer who underwent a prostatectomy following neoadjuvant ADT were retrospectively reviewed. Factors associated with pT0, which is regarded as serious cancer cell damage or elimination, were investigated.
Of the 68 males, 24 (35.3%) were classified as pT0. The median duration of neoadjuvant ADT in the pT0 and non-pT0 groups was 9 months and 7.5 months, respectively (p = 0.022). The duration of neoadjuvant ADT from when PSA reached < 0.2 ng/ml to surgery was longer in the pT0 group than that in the non-pT0 group (median 5 months against 3 months, p = 0.011). pT0 was achieved in 5 of 6 patients (83.3%) who received ADT for ≥10 months after PSA reached < 0.2 ng/ml. No other clinical characteristics predicted conversion to pT0.
Continuous ADT for ≥10 months after PSA reached < 0.2 ng/ml induced serious prostate cancer cell damage in most patients (> 80%) and may be sufficient to treat localized prostate cancer.
PMCID: PMC3116482  PMID: 21569574
3.  Effect of gatifloxacin against Mycoplasma genitalium-related urethritis: an open clinical trial 
Sexually Transmitted Infections  2011;87(5):389-390.
Mycoplasma genitalium and Chlamydia trachomatis are the primary pathogens detected from non-gonococcal urethritis (NGU). In this study, the efficacy of gatifloxacin was examined against M genitalium-related urethritis.
The study was an open clinical trial evaluating the effectiveness of gatifloxacin with 200 mg doses twice a day for 7 days against male NGU.
Between March and September 2008, 169 male patients were enrolled, and microbiological and clinical cure rates could be evaluated in 86 patients detected with C trachomatis or M genitalium and in 135 with NGU, respectively. Microbiological cure rates of gatifloxacin against C trachomatis and M genitalium were 100% and 83%, respectively, and the total clinical cure rate was 99%.
Analysis of in-vivo and in-vitro data from the literature of fluoroquinolone efficacies against M genitalium suggests that a MIC90 of 0.125 μg/ml or less may be useful for optimal activity against M genitalium infection.
PMCID: PMC3252599  PMID: 21531704
Antibiotics; clinical trials; mycoplasma; NGU
4.  Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study 
Ingestion of cranberry (Vaccinium macrocarpon Ait.) has traditionally been utilized for prevention of urinary tract infections. The proanthocyanidins (PACs) in cranberry, in particular the A-type linkages have been implicated as important inhibitors of primarily P-fimbriated E. coli adhesion to uroepithelial cells. Additional experiments were required to investigate the persistence in urine samples over a broader time period, to determine the most effective dose per day and to determine if the urinary anti-adhesion effect following cranberry is detected within volunteers of different origins.
Two separate bioassays (a mannose-resistant hemagglutination assay and an original new human T24 epithelial cell-line assay) have assessed the ex-vivo urinary bacterial anti-adhesion activity on urines samples collected from 32 volunteers from Japan, Hungary, Spain and France in a randomized, double-blind versus placebo study. An in vivo Caenorhabditis elegans model was used to evaluate the influence of cranberry regimen on the virulence of E. coli strain.
The results indicated a significant bacterial anti-adhesion activity in urine samples collected from volunteers that consumed cranberry powder compared to placebo (p < 0.001). This inhibition was clearly dose-dependent, prolonged (until 24 h with 72 mg of PAC) and increasing with the amount of PAC equivalents consumed in each cranberry powder regimen. An in vivo Caenorhabditis elegans model showed that cranberry acted against bacterial virulence: E. coli strain presented a reduced ability to kill worms after a growth in urines samples of patients who took cranberry capsules. This effect is particularly important with the regimen of 72 mg of PAC.
Administration of PAC-standardized cranberry powder at dosages containing 72 mg of PAC per day may offer some protection against bacterial adhesion and virulence in the urinary tract. This effect may offer a nyctohemeral protection.
PMCID: PMC2873556  PMID: 20398248
5.  Genetic Profiles of Fluoroquinolone-Resistant Escherichia coli Isolates Obtained from Patients with Cystitis: Phylogeny, Virulence Factors, PAIusp Subtypes, and Mutation Patterns▿  
Journal of Clinical Microbiology  2009;47(3):791-795.
The low virulence of quinolone- and fluoroquinolone-resistant Escherichia coli strains is known, although the reasons for this remain unclear. We surveyed the mutation patterns of quinolone resistance determining regions (QRDRs), phylogenetic distribution, prevalence of 18 urovirulence genes, and PAIusp subtypes in 89 fluoroquinolone-resistant E. coli (FQREC) isolates obtained from patients with cystitis and compared them with those of their fluoroquinolone-susceptible counterparts (FQSEC). Phylogenetic group B2 was significantly less prevalent in FQREC than in FQSEC (49% versus 78%; P = 0.0138), but it still dominated, followed by phylogroup D (35%), in FQREC. When the prevalences of virulence factor (VF) genes were compared between FQREC and FQSEC, sfa/foc, cnf1, hly, kpsMT, ompT, ibeA, usp, and iroN showed significantly lower prevalences in FQREC than in FQSEC (1.1% versus 24% [P < 0.0001], 0% versus 29% [P < 0.0001], 7.9% versus 33% [P < 0.0001], 74% versus 90% [P = 0.01], 71% versus 87% [P = 0.017], 5.6% versus 37% [P < 0.0001], 54% versus 82% [P < 0.0001], and 7.9% versus 32% [P = 0.0001], respectively), whereas aer, iha, and ETTT showed significantly higher prevalences in FQREC (85% versus 36% [P < 0.0001], 66% versus 29% [P < 0.0001], and 53% versus 16% [P < 0.0001], respectively). Furthermore, a similar difference in prevalences of uropathogenic VF genes was seen between FQREC and FQSEC in phylogroup B2. This indicated that the low virulence in FQREC was intimately correlated with a lesser distribution of VFs in phylogroup B2, which dominated in FQREC and FQSEC. It was interesting that the mutation pattern of Ser83Leu and Asp87Asn encoded in gyrA and Ser80Ile and Glu84Val encoded in parC was frequently found in FQREC isolates that belonged to phylogroup B2 and that most of these isolates showed PAIusp subtype 2a. PAIusp subtypes 1a, 1b, and 2b, which were frequently seen in FQSEC, were rarely found in FQREC. These results suggested that the acquisition of fluoroquinolone resistance, e.g., mutations in QRDRs, might be a specific event in limited strains, such as those that possess PAIusp subtype 2a in phylogroup B2.
PMCID: PMC2650943  PMID: 19158256
6.  Mechanisms of Resistance to Imipenem and Ampicillin in Enterococcus faecalis 
We found ampicillin- and imipenem-resistant isolates of vanA-possessing Enterococcus faecalis with MICs of 8 to 16 μg/ml and 4 to 32 μg/ml, respectively. There have been few reports about penicillin- and imipenem-resistant E. faecalis. Two mechanisms of beta-lactam resistance in E. faecalis, the production of beta-lactamase and the overproduction of penicillin-binding proteins (PBPs), have been reported. The resistant isolates in the current study did not produce any beta-lactamases and analysis of the PBPs showed no overproduction. However, the affinities of PBP4 for beta-lactams in the resistant strains were lower than those of susceptible strains but the affinities of other PBPs for beta-lactams did not change. Accordingly, whole pbp4 fragments from these resistant isolates were sequenced. Two amino acid substitutions at positions 520 and 605 were observed in the highly resistant strains compared to the susceptible ones, Pro520Ser and Tyr605His, and a single Tyr605His amino acid substitution was found in the low-resistance strains. These two point mutations exist in the region between the active-site-defining motifs SDN and KTG of the penicillin-binding domain, the main target of beta-lactams. A strong correlation was seen between these substitutions and decreasing affinities of PBP4 to beta-lactams. In E. faecalis, resistance due to mutations in PBPs has not been reported, though it has in Enterococcus faecium. Our results suggest that development of high-level resistance to penicillins and imipenem depends on point mutations of PBP4 at positions 520 and 605.
PMCID: PMC1168717  PMID: 15980374
7.  Outbreak of Cefozopran (Penicillin, Oral Cephems, and Aztreonam)-Resistant Neisseria gonorrhoeae in Japan 
Antimicrobial Agents and Chemotherapy  2001;45(12):3603-3606.
We have previously reported that the Neisseria gonorrhoeae isolates from clinical failure cases treated with cefdinir and aztreonam, β-lactams exhibited high MICs. These resistant isolates were clearly separated from the isolates exhibiting a low level of resistance to β-lactams as shown by the MIC distribution of cefozopran. Restriction fragment length polymorphism DNA typing revealed that the outbreak of cefozopran-resistant isolates in Kitakyushu, Japan, occurred as a result of clonal spread.
PMCID: PMC90878  PMID: 11709349
8.  Reduced Clinical Efficacy of Pazufloxacin against Gonorrhea Due to High Prevalence of Quinolone-Resistant Isolates with the GyrA Mutation 
Forty-two men with gonococcal urethritis were treated with an oral dosage of 200 mg of pazufloxacin, a new fluoroquinolone, three times daily for 3 days. Only 28 of the 42 men (66.7%) had negative culture results for Neisseria gonorrhoeae during follow-up. Of the 42 isolates, 41 could be recultured for antibiotic susceptibility testing and DNA sequencing. In 26 of the 41 isolates (63.4%), GyrA mutations with or without ParC mutations were identified. Among the 26 isolates, 23 contained a single GyrA mutation, 1 contained two GyrA mutations, and 2 contained three mutations including double GyrA and single ParC mutations. A single Ser-91-to-Phe mutation, which was detected in 14 of the 26 isolates, was the most common GyrA mutation, followed by an Ala-75 to Ser mutation and an Asp-95 to Asn or Gly mutation in GyrA. All three isolates with two or three mutations contained the Ser-91-to-Phe GyrA mutation. Eleven of the 14 isolates with the single Ser-91-to-Phe mutation within GyrA and all 3 isolates with two or three mutations persisted after pazufloxacin treatment. On the other hand, all 15 wild-type and 9 mutant isolates with a substitution at codon Ala-75 or Asp-95 were eradicated. The mean MIC of pazufloxacin for mutants with the single Ser-91-to-Phe mutation in GyrA was 66-fold higher than that for the wild type. The results obtained in this study suggest that a high prevalence of fluoroquinolone-resistant gonococcal isolates with the Ser-91-to-Phe mutation in GyrA reduced the efficacy of pazufloxacin as treatment for gonococcal urethritis.
PMCID: PMC105501  PMID: 9517935

Results 1-8 (8)