The isolation and identification of apolipoprotein C-I in hormone-refractory prostate cancer using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry

Androgens play a central role in prostate cancer pathogenesis, and hence most of the patients respond to androgen deprivation therapies. However, patients tend to relapse with aggressive prostate cancer, which has been termed as hormone refractory. To identify the proteins that mediate progression to the hormone-refractory state, we used protein-chip technology for mass profiling of patients＇ sera. This study included 16 patients with metastatic hormone-refractory prostate cancer who were initially treated with androgen deprivation therapy. Serum samples were collected from each patient at five time points： point A, pre-treatment; point B, at the nadir of the prostate- specific antigen （PSA） level; point C, PSA failure; point D, the early hormone-refractory phase; and point E, the late hormone-refractory phase. Using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, we performed protein mass profiling of the patients＇ sera and identified a 6 640-Da peak that increased with disease progression. Target proteins were partially purified, and by amino acid sequencing the peak was identified as a fragment of apolipoprotein C-I （ApoC-I）. Serum ApoC-I protein levels increased with disease progression. On immunohistochemical analysis, the ApoC-i protein was found localized to the cytoplasm of the hormone-refractory cancer cells. In this study, we showed an increase in serum ApoC-I protein levels in prostate cancer patients during their progression to the hormone-refractory state, which suggests that ApoC-I protein is related to progression of prostate cancer. However, as the exact role of ApoC-I in prostate cancer pathogenesis is unclear, further research is required.

Associations of homologous RNA-binding motif gene on the X chromosome(RBMX)and its like sequence on chromosome 9(RBMXL9)with non-obstructive azoospermia

Aim： To investigate the associations of autosomal and X-chromosome homologs of the RNA-binding-motif （RNAbinding-motif on the Y chromosome, RBMY） gene with non-obstructive azoospermia （NOA）, as genetic factors for NOA may map to chromosomes other than the Y chromosome. Methods： Genomic DNA was extracted using a salting-out procedure after treatment of peripheral blood leukocytes with proteinase K from Japanese patients with NOA （n = 67） and normal fertile volunteers （n = 105）. The DNA were analyzed for RBMX by expressed sequence tag （EST） deletion and for the like sequence on chromosome 9 （RBMXL9） by microsatellite polymorphism. Results： We examined six ESTs in and around RBMX and found a deletion of SHGC31764 in one patient with NOA and a deletion of DXS7491 in one other patient with NOA. No deletions were detected in control subjects. The association study with nine microsatellite markers near RBMXL9 revealed that D9S319 was less prevalent in patients than in control subjects, whereas D9S1853 was detected more frequently in patients than that in control subjects. Conclusion： We provide evidence that deletions in or around RBMX may be involved in NOA. In addition, analyses of markers in the vicinity of RBMXL9 on chromosome 9 suggest the possibility that variants of this gene may be associated with NOA. Although further studies are necessary, this is the first report of the association between RBMX and RBMXL9 with NOA. （Asian J Andro12006 Mar; 8： 213-218）

Outcomes of patients older than 75 years with non-metastatic prostate cancer

Objective:Prostate cancer in elderly patients was formerly treated with androgen deprivation therapy.Since the latter of the 1990s new technologies were introduced into treatments,then strategies have varied.We aimed to observe the outcomes of elderly patients treated during transition period and compare each stage with others.Methods:During 2008 and 2010,255 patients with prostate cancer older than 75 years were sequentially treated.With exception of patients with bone and/or visceral metastasis,outcomes of 199 patients with localized and locally advanced stages were examined.Complete records were obtained by the end of 2015.Results:In total,122(61%),28(14%),37(19%)and 12(6%)of patients were in stages T1c-T2a,T2b-c,T3 and T4,respectively.Patients generally presented with abnormal screening or lower urinary tract symptom.Seventy-one percent of patients received androgen deprivation therapy as monotherapy and 22% of the radiation-treated patients added androgen deprivation therapy.Patients in stage T1c-T2a and T2b-c showed a favorable prognosis.Some cancer death appeared in patients with T3 and T4 during observation periods.Twenty-seven percent of patients died from prostate cancer-independent complications:pneumonia,heart disease,and brain vascular disease.Tendency is similar to that of Japanese elderly male population.No remarkable side effects from androgen deprivation therapy were noticed.

Efficacy and Safety of Axitinib as First-Line Therapy in Japanese Patients with Metastatic Renal Cell Carcinoma

Previous study reported that patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib for metastatic renal cell carcinoma (mRCC). In this study, we reviewed our experience of axitinib as a first-line therapy for mRCC in Japanese patients, focusing on its efficacy and safety. We retrospectively assessed 26 patients treated with axitinib as a first-line therapy for mRCC from July 2010 to July 2014 at Chiba Cancer Center and Kinki University Hospital. Observation period was 24.6 ± 18.3 months. The objective response rate was 50.0%, and the median progression-free survival was 27.5 months. Overall survival was not estimable. Common grade 3 adverse events were hypertension in 19 patients and proteinuria in 5 patients. Axitinib demonstrated significant efficacy as a first-line therapy in Japanese patients with mRCC. Careful monitoring and management of the adverse effects may help to control its toxicities.

Penile Epidermoid Cyst Consisted of Multiple Foci: A Case Report

Penile epidermoid cysts are uncommon, and a small number of cases have been reported worldwide. We present the first documented patient with a penile epidermoid cyst which consisted of multiple focuses. A 37-year-old man presented to our department with a chief complaint of an asymptomatic, soft mass in the ventral part of the penis. The mass was nontender, freely movable and measuring 3 cm within the dermis. MRI (magnetic resonance imaging) revealed a high signal intensity on both T1- and T2-weighted images. Excision of the cyst was performed under local anesthesia. Macroscopically, the cut surface of the mass appeared to be full of a cheese-like material and the cyst consisted of multiple focuses. The cyst did not contain skin appendages. The pathological diagnosis was an epidermoid cyst of the penis. No recurrence has been noted in the year since the operation.

A single nucleotide polymorphism in SPA TA17 may be a genetic risk factor for Japanese patients with meiotic arrest

Genetic mechanisms have been implicated as a cause of some cases of male infertility. Recently, 10 novel genes involved in human spermatogenesis were identified by microarray analysis of human testicular tissue. One of these is spermatogenesis-associated 17 （SPATA17）. To investigate whether defects in the SPATA17 gene are associated with azoospermia due to meiotic arrest, a mutational analysis was conducted, in which the SPATA17 coding regions of 18 Japanese patients with this condition were sequenced. A statistical analysis was carried out that included 18 patients with meiotic arrest, 20 patients with Sertoli-cell-only syndrome （SCOS） and 96 healthy control men. No mutations were found in SPA TA17. However, three coding single nucleotide polymorphisms （cSNPs： SNP 1-SNP3） were detected in the patients with meiotic arrest. No significant differences in the genotype or allele frequencies of SNP1 and SNP2 were found between patients with meiotic arrest and the others. However, the frequency of the SNP3 allele was significantly elevated in the meiotic arrest group （P 〈 0.05）. This study suggests that SPATA17 may play a critical role in human spermatogenesis, especially in meiosis.

Zoledronic acid combined with androgendeprivation therapy may prolong time to castration-resistant prostate cancer in hormone-naı¨ve metastatic prostate cancer patients e A propensity scoring approach

Objective:To clarify the oncological benefit of zoledronic acid for hormone-naive metastatic prostate cancer,patient outcome of androgen deprivation therapy with zoledronic acid(ADT+Z)and androgen deprivation therapy alone(ADT)was compared.Methods:Fifty-two patients with pathologically confirmed metastatic prostate cancer were prospectively enrolled and treated with combined androgen blockade(goserelin and bicalutamide)with zoledronic acid(4 mg every 4 weeks for 24 months).A propensity score-match with logistic regression analysis was applied to select 50 pair-matched cohorts(both from ADT+Z and from historical control cohorts who had undergone ADT alone),and patient outcomes were compared.Results:Patients with ADT+Z had significantly longer time to progression(TTP)than those with ADT(median TTP;24.2 vs.14.0 months,p=0.0092),while no significant difference of overall survival between two groups(p=0.1502).Multivariate analysis for biochemical recurrence revealed treatment with ADT was the sole independent prognostic factor(HR:1.724,95%CI:1.06-2.86,p=0.0297).Conclusion:Combination of zoledronic acid with ADT may prolong time to castration resistant prostate cancer.

Cavernous Nerve Graft Reconstruction with a Novel Artificial Conduit during Robot-Assisted Laparoscopic Radical Prostatectomy

The interposition sural nerve graft has been attempted occasionally during radical prostatectomy for the recovery of continence and erectile function;however, nerve autograft may result in adverse events for the patient. Here, we present our initial experiences using NerbridgeTM, a novel conduit for peripheral nerve regeneration, rather than utilizing sural nerve grafting, in robot-assisted laparoscopic radical prostatectomy to overcome autograft problems such as prolongation of operation time and postoperative abnormal sensation. This novel artificial conduit interposition can be technically feasible when combined with robotic surgery, and prospective randomized controlled trials with high patients-numbers and long follow-up periods are warranted.

Bone markers predict survival in castration-resistant prostate cancer patients treated with docetaxel

AIM: To investigate the relationship between clinicopathological features and bone turnover markers in castration-resistant prostate cancer(CRPC) patients treated with docetaxel.METHODS: Thirty-three patients were enrolled in this study. Serum levels of carboxyterminal cross-linked telopeptide of type 1 collagen generated by metalloproteinases(1CTP) and alkaline phosphatase(ALP) were measured at the start of docetaxel chemotherapy. We examined the relationship between clinicopathological features and serum levels of 1CTP and ALP levels in CRPC patients treated with docetaxel.RESULTS: For the total patient group, the mean ± standard deviation(SD) values for docetaxel chemotherapy dose, dose intensity, dosage interval, and num-ber of cycles were 59.3 ± 10.6 mg/m2, 13.9 ± 5.2 mg/m2 per week, 4.7 ± 1.2 wk, and 11.2 ± 7.4, respectively. Fourteen patients died from prostate cancer. Patients were divided into two groups according to mean + SD of serum 1CTP(8.2 ng/m L) and ALP(538.2 IU/L) levels at the start of docetaxel chemotherapy. Patients with lower levels of serum 1CTP and ALP had significantly better survivals than those with higher serum levels(P < 0.05).CONCLUSION: Serum levels of 1CTP and ALP are predictors of survival in patients with CRPC who are treated with docetaxel.

Genetic Variation in the Testis-Specific HASPIN Gene Encoding a Serine/Threonine Protein Kinase in Infertile Japanese Males

HASPIN is a serine/threonine protein kinase predominantly expressed during spermatogenesis and localized in the nucleus. The HASPIN gene is conserved from yeast to mammals and plants. To investigate any possible associations between HASPIN polymorphisms and impaired spermatogenesis in Japanese males, we screened for mutations in the HASPIN coding sequence (CDS) using DNA from 282 sterile male patients and 262 fertile male volunteers. Polymorphisms were found at 10 positions within the HASPIN CDS. Among these 10 polymorphisms, 5 were found only in the infertile group, 3 of which were nonsynonymous. These polymorphisms found only in the infertile patients may be a cause of male infertility and thus valuable candidates for further study of this condition.

System identification and parameter estimation in mathematical medicine： examples demonstrated for prostate cancer

We review our studies on how to identify the most appropriate models of diseases, and how to determine their parameters in a quantitative manner given a short time series of biomarkers, using intermittent androgen deprivation therapy of prostate cancer as an example. Recently, it has become possible to estimate the specific parameters of individual patients within a reasonable time by employing the information concerning other previous patients as a prior. We discuss the importance of using multiple mathematical methods simultaneously to achieve a solid diagnosis and prognosis in the future practice of personalized medicine.

Spermatogonial stem cells： progress and prospects

Twenty years ago, the transplantation of spermatogonial stem cells （SSCs） from a mouse to other recipient mice was shown to be feasible, which clearly demonstrated the functional identity of SSCs. Since then, several important new findings and other technical developments have followed, which included a new hypothesis on their cell kinetics and spermatogonial hierarchy in the testis, a culture method allowing their self-renewal and proliferation, a testis tissue organ culture method, which induced their complete differentiation up to sperm, and the in vitro induction of germ cells from embryonic stem cells and induced pluripotent stem cells. These advancements reinforced or advanced our understanding of this unique cell. Nonetheless, there are many unresolved questions in the study of spermatogonial stem cells and a long road remains until these cells can be used clinically in reproductive medicine.

Physiological Responses to Agonist-Antagonist Superset Resistance Training

Purpose To investigate the physiological responses to low-load,superset resistance training(two exercises for the agonist and antagonist muscles performed without rest between exercises)to failure using elastic bands.Methods Twenty-three athletes were randomized to either a superset group(S,n=12,average age:19.8±1.5 years)or a traditional set group(T,n=11,average age:20.1±1.4 years).Strength,cross-sectional area(CSA)and muscular endurance of the biceps and triceps brachii were assessed before and after 8 weeks.Acute responses(muscle thickness)were measured during one testing session.Results Muscle thickness of the biceps significantly increased in both T group(P<0.05)and S group(P<0.05)after a single bout of Training.The triceps did not show significant increases in either T group(P>0.05)or S group(P>0.05).Blood lactate also increased in both groups after one bout of training(T:from 1.3±0.3 to 5.5±2.4 mmol/L,S:from 1.4±0.5 to 5.1±1.5 mmol/L,P<0.05).After 8-week training,both groups showed significant increases in the biceps(T:13.2%±5.0%;S:12.9%±7.3%,P<0.05)and triceps(T:9.5%±9.3%,S:4.8%±4.1%,P<0.05)without differences between groups.Increases in one repetition maximum for the bench press(7.8%±6.5%,P<0.05)and maximal voluntary contraction for the arm extensors(9.3%±11.6%,P<0.05)were observed for the T group only.Increases in muscular endurance were observed only in the S group for the bench press(26.0%±19.1%,P<0.05)and the barbell curl(17.2%±16.6%,P<0.05).Conclusions Superset training may enhance muscular endurance while attenuating maximal strength gains.There does not appear to be a hypertrophic benefit to performing superset training,but it may provide a time-efficient strategy to achieve adaptations in muscle mass.