代谢酶基因多态性与前列腺癌易感性的关系

目的 :探讨CYP1A1、NAT2基因多态性与前列腺癌易感性的关系。　方法 :应用PCR RFLP、ASA和自动实时荧光定量分析技术 ,分析 5 8例前列腺癌病人和 112例健康对照者CYP1A1和NAT2基因 4个位点的多态性 ,比较前列腺癌病人与对照组间频率差异。　结果 :前列腺癌组Ile Val多态位点各等位基因和基因型频率与对照组比较差异有显著性 (P <0 .0 5 ) ,其中等位基因G和GG基因型使患前列腺癌的危险度分别提高了 1.5 9倍 (P <0 .0 5 )和 3.0 6倍 (P <0 .0 5 ) ;前列腺癌组MspI多态位点各等位基因和基因型频率与对照组比较差异无显著性 (P>0 .0 5 )。前列腺癌组NAT2慢乙酰化基因型频率与对照组比较差异无显著性 (P >0 .0 5 )。　结论 :CYP1A1Ile Val基因多态与前列腺癌的发生可能有关 ,MspI基因多态和NAT2慢乙酰化基因型与前列腺癌的发生可能无关     

Prostate size influences the outcome after presenting with acute urinary retention

OBJECTIVE: To evaluate the long-term outcome in an open follow-up of a cohort of patients who had had a successful trial without catheter (TWOC) after an episode of acute urinary retention (AUR), as it is now widely accepted that giving an alpha-blocker, e.g. alfuzosin, increases the success rate of TWOC. PATIENTS AND METHODS: In this prospective trial, 81 patients with a first episode of AUR related to benign prostatic obstruction received either sustained-release alfuzosin (40) 5 mg twice daily or placebo (41) for 48 h. The catheter was removed after 24 h of treatment and the patient's ability to void assessed. Those who voided successfully entered an open follow-up, the defined endpoints of which were the date of recurrent AUR, date of bladder outlet surgery, date of last follow-up or death, and factors that influenced the long-term outcome after a successful TWOC were examined. RESULTS: Of the 34 patients who had a successful TWOC (22 on alfuzosin, 12 placebo, P= 0.03), 21 continued on an alpha-blocker at the discretion of their urologist. In all, 26 had a further episode of AUR or surgery during the 6-year follow-up. The mean (median, range) time to the second episode of AUR in the 20 (59%) patients affected was 1.4 (0.6, 0-5.95) years. Nineteen (56%) men had bladder outlet surgery, 13 after a second episode of AUR. The mean time to operation after the first AUR was 1.85 (1.1, 0.04-5.4) years. The remaining eight (24%) patients remained free of further AUR and surgery. The size of the prostate assessed on a digital rectal examination by the admitting urologist was the only factor with a significant effect on the long-term outcome. A postvoid residual of > 50 mL was associated with a greater likelihood of recurrent AUR or surgery, but this was not statistically significant. CONCLUSIONS: This study provides further evidence of the importance of prostate size as a prognostic factor in determining the outcome in patients with prostatic obstruction. Whilst most men presenting with AUR will eventually have prostatic surgery, a significant minority will not. An assessment of risk factors such as prostate size may identify those who require urgent intervention after a successful TWOC. The role of continued medical therapy with alpha-blockers and/or 5alpha-reductase inhibitors after a successful TWOC merits further investigation.     

Breast tumors induced by N‐methyl‐N‐nitrosourea are damaging to bone strength,structure, and mineralization in the absence of metastasis in rats

Current theory on the influence of breast cancer on bone describes metastasis of tumor cells to bone tissue, followed by induction of osteoclasts and bone degradation. Tumor influences on bone health in pre‐ or nonmetastatic models are unknown. Female rats (n = 48, 52 days old) were injected with N‐methyl‐N‐nitrosourea (MNU) to induce breast cancer. Animals were euthanized 10 weeks later, and tumors were weighed and classified histologically. Right femurs were extracted for testing of bone mineral density (BMD) by dual X‐ray absorptiometry (DXA), bone mechanical strength by three‐point bending and femoral neck bending tests, and structure by micro–computed tomography (µCT). Of 48 rats, 22 developed one or more tumors in response to MNU injection by 10 weeks. Presence of any tumor predicted significantly poorer bone health in 17 of 28 measures. In tumored versus nontumored animals, BMD was adversely affected by 3%, force at failure of the femoral midshaft by 4%, force at failure of the femoral neck by 12%, and various trabecular structural parameters by 6% to 27% (all p < .05). Similarly, greater tumor burden, represented by total tumor weight, adversely correlated with bone outcomes: r = ?0.51 for BMD, ?0.42 and ?0.35 for femur midshaft force and work at failure, and between 0.36 and 0.59 (absolute values) for trabecular architecture (all p < .05). Presence of MNU‐induced tumors and total tumor burden showed a negative association with bone health of the femur in rats in the absence of metastasis. Further study is required to elucidate mechanisms for this association. © 2011 American Society for Bone and Mineral Research.     

Bladder outlet obstruction accelerates bladder carcinogenesis

OBJECTIVE

To examine the correlation between partial bladder outlet obstruction (PBOO) and bladder carcinogenesis.

MATERIALS AND METHODS

Female Wistar rats (6 weeks old) were divided into three groups of 10 each: group 1 was exposed to n‐butyl‐n‐butanol nitrosamine (BBN, a carcinogen) in drinking water for 8 weeks; group 2 had PBOO induced surgically after exposure to BBN for 8 weeks; group 3 had a sham operation and the rats drank normal water (control group). After 20 weeks, all of the rats were killed humanely and their bladders analysed.

RESULTS

There were no significant differences in body weight among the groups. The bladder weight of group 2 was significantly greater than either group 1 or group 3. Histopathologically, bladder smooth muscle hypertrophy was the major cause of the increased bladder weight for group 2. In group 2 there were increases in bladder wall thickness and many nipple‐shaped urothelial tumours. Basic fibroblast growth factor and hypoxia‐inducible factor‐1α expression were significantly greater in group 2 than in groups 1 and 3.

CONCLUSIONS

Exposure of the bladder to carcinogens during bladder hyperplasia and hypertrophy induced by PBOO results in a greater incidence of superficial bladder carcinoma.     

Prostate carcinoma cells that have resided in bone have an upregulated IGF-I axis

BACKGROUND: Prostate cancer (PC) has a propensity to metastasize to the skeleton, inducing an osteoblastic response in the host. Recent epidemiological studies have suggested that circulating IGF-I may be important for both the pathogenesis and dissemination of PC. We have postulated that tumor secreted IGF-I in conjunction with endogenous IGF-I contributes to the osteoblastic phenotype characteristic of metastatic PC. METHODS: To test this thesis we studied the established LNCaP PC progression model consisting of three genetically related human PC cell lines. RESULTS: Using RIA, we found serum-free conditioned media (CM) of LNCaP and C4-2 had no measurable IGF-I, whereas IGF-I was easily detected in CM from C4-2B cells at 24 hr (i.e., 1.8 +/- 0.53 ng/mg cell protein). Real-time PCR of IGF-I mRNA showed that C4-2B expressed 100-fold more IGF-I mRNA than LNCaP cells. In addition, C4-2B expression of IGF-I mRNA was substantially increased in the presence of exogenous IGF-I to nearly twofold. While IGFBP-3 and IGFBP-1 were not detectable in the CM of any PC line, all cells secreted IGFBP-2. C4-2B cells produced 40% more IGFBP-2 than LNCaP or C4-2 cells (C4-2B at 167 +/- 43 ng/mg cell protein). RANKL, a product of bone stromal cells, was also differentially expressed: LNCaP had threefold higher RANKL mRNA compared to C4-2 and C4-2B and at least equivalent protein expression. CONCLUSIONS: Our results suggest that PC cells that have metastasized to bone have an upregulated IGF-I regulatory system. This suggests an activated IGF-I axis contributes to the host-PC interaction in promoting osteoblastic metastases.     

New Variants in the Enpp1 and Ptpn6 Genes Cause Low BMD,Crystal‐Related Arthropathy,and Vascular Calcification

A large genome‐wide, recessive, N‐ethyl‐N‐nitrosourea (ENU)‐induced mutagenesis screen was performed on a mixed C57BL/6J and C3H.SW‐H2/SnJ mouse background to identify genes regulating bone mass. Approximately 6500 male and female G₃ hybrid mice were phenotyped at 8 and 10 wk of age by DXA analysis for evidence of changes in unadjusted or body weight–adjusted BMD or BMC. Phenodeviant lines were identified based on statistical criteria that included a false discovery rate (FDR) <20% and Z‐score >2.8. Genome‐wide mapping scans were initiated on 22 lines, with evidence of high or low BMD or BMC that deviated by approximately ?30% to +50% from the means. Several lines were discontinued as showing lack of heritability, but two heritable lines were identified with narrow chromosomal regions that allowed sequencing of potential mutant candidate genes. Novel mutations were identified in the Enpp1 (C397S) gene on chromosome 10 (line 4482) and the Ptpn6 (I482F) gene on chromosome 6 (line 4489) that were both associated with low bone mass. In addition, the phenotype of the Enpp1 mice showed a striking joint disease and calcification of blood vessels including the aorta, myocardium, and renal arteries and capillaries. These results support a role for the Enpp1 gene in the pathogenesis associated with mineralization of articular cartilage and vascular calcification. This work confirms the utility of the chemical mutagenesis approach for identification of potential disease genes and confirms the role of Enpp1 and Ptpn6 in regulating mineralization and skeletal bone mass.     

Cost-effectiveness of Prostate Health Index for prostate cancer detection

Study Type – Diagnostic (cost effectiveness) Level of Evidence 2b What's known on the subject? and What does the study add? The Beckman Coulter prostate health index (phi) was developed as a combination of serum prostate specific antigen (PSA), free PSA and a PSA precursor form [?2]proPSA to calculate the probability of prostate cancer and was used as an aid in distinguishing prostate cancer from benign prostatic conditions for men with PSA test 2–10 ng/mL and non‐suspicious digital rectal examination. Phi has been shown to improve diagnostic accuracy in prostate cancer detection compared with total and free PSA. An earlier 1‐year budget impact analysis revealed it to be a complementary approach to current prostate cancer screening strategies. The current study evaluated the cost‐effectiveness of early prostate cancer detection with phi in combination with a PSA test compared with a PSA test alone from the US societal perspective. The model with over 25 annual screening cycles for men aged 50–75 years indicated that PSA plus phi dominated the PSA test alone in prostate cancer detection and consequent treatment. PSA plus phi may be an important strategy for prostate cancer detection.

OBJECTIVE

• ? To evaluate the cost‐effectiveness of early prostate cancer detection with the Beckman Coulter Prostate Health Index (phi) (not currently available in the USA) adding to the serum prostate‐specific antigen (PSA) test compared with the PSA test alone from the US societal perspective.

PATIENTS AND METHODS

• ? Phi was developed as a combination of PSA, free PSA, and a PSA precursor form [?2]proPSA to calculate the probability of prostate cancer and was used as an aid in distinguishing prostate cancer from benign prostatic conditions for men with a borderline PSA test (e.g. PSA 2–10 ng/mL or 4–10 ng/mL) and non‐suspicious digital rectal examination.
• ? We constructed a Markov model with probabilistic sensitivity analysis to estimate expected costs and utilities of prostate cancer detection and consequent treatment for the annual prostate cancer screening in the male population aged 50–75 years old.
• ? The transition probabilities, health state utilities and prostate cancer treatment costs were derived from the published literature. The diagnostic performance of phi was obtained from a multi‐centre study. Diagnostic related costs were obtained from the 2009 Medicare Fee Schedule.
• ? Cost‐effectiveness was compared between the strategies of PSA test alone and PSA plus phi under two PSA thresholds (≥2 ng/mL and ≥4 ng/mL) to recommend a prostate biopsy.

RESULTS

• ? Over 25 annual screening cycles, the strategy of PSA plus phi dominated the PSA‐only strategy using both thresholds of PSA ≥2 ng/mL and PSA ≥4 ng/mL, and was estimated to save $1199 or $443, with an expected gain of 0.08 or 0.03 quality adjusted life years, respectively.
• ? The probabilities of PSA plus phi being cost effective were approximately 77–70% or 78–71% at a range of $0–$200 000 willingness to pay using PSA thresholds ≥2 ng/mL and ≥4 ng/mL, respectively.

CONCLUSION

• ? The strategy PSA plus phi may be an important strategy for prostate cancer detection at both thresholds of PSA ≥2 ng/mL and PSA ≥4 ng/mL to recommend a prostate biopsy compared with using PSA alone.

     

Prostate stem cells and benign prostatic hyperplasia

Pharmacological approaches are available to medically-managed patients with symptomatic BPH before surgical intervention is required. These include daily treatment with alpha-blockers and 5-alpha-reductase inhibitors alone or in combination. These medical approaches have two major problems. First, treatments are chronic and must be taken daily. Second, there are significant financial costs and quality of life issues for such chronic treatments. Is it possible to develop effective acute therapy for symptomatic BPH without the long-term androgen deprivation-induced side effects? Two seminal but rarely cited studies of Walsh [Peters, Walsh: N Engl J Med 317:599-604, 1987] and Coffey et al. [Sufrin et al.: Invest Urol 13:418-423, 1976], combined with the growing understanding of the stem cell organization of the prostate stromal (S) and epithelial (E) compartments and their reciprocal paracrine and autocrine interactions provides the rationale for an acute approach.The Walsh study documents that: (1) androgen deprivation disrupts the reciprocal interaction between the prostate S and E thereby decreasing the weight of both compartments and (2) once BPH develops, androgen deprivation does not decrease the number of stem cell units in either the S or E compartments since subsequent androgen restoration fully restores the enlarged gland. The Coffey study documents that acute androgen deprivation sensitizes S-E interactions to radiation induced disruptions so that following radiation, androgen restoration does not induce full gland regrowth. Therefore, effective therapy for symptomatic BPH should be achievable by acute treatment with reversible androgen deprivation for a limited period followed by a single dose of conformal external beam radiation before allowing the man to recovery his normal serum testosterone.     

Prostate cancer: a serious disease suitable for prevention

Prostate cancer is among the most common causes of death from cancer in men, and accounts for 10% of all new male cancers worldwide. The diagnosis and treatment of prostate cancer place a substantial physical and emotional burden on patients and their families, and have considerable financial implications for healthcare providers and society. Given that the risk of prostate cancer continues to increase with age, the burden of the disease is likely to increase in line with population life‐expectancy. Reducing the risk of prostate cancer has gained increasing coverage in recent years, with proof of principle shown in the Prostate Cancer Prevention Trial with the type 2 5α‐reductase (5AR) inhibitor, finasteride. The long latency period, high disease prevalence, and significant associated morbidity and mortality make prostate cancer a suitable target for a risk‐reduction approach. Several agents are under investigation for reducing the risk of prostate cancer, including selenium/vitamin E and selective oestrogen receptors modulators (e.g. toremifene). In addition, the Reduction by Dutasteride of Prostate Cancer Events trial, involving >8000 men, is evaluating the effect of the dual 5AR inhibitor, dutasteride, on the risk of developing prostate cancer. A successful risk‐reduction strategy might decrease the incidence of the disease, as well as the anxiety, cost and morbidity associated with its diagnosis and treatment.     

A mouse model for spondyloepiphyseal dysplasia congenita with secondary osteoarthritis due to a Col2a1 mutation

Progeny of mice treated with the mutagen N-ethyl-N-nitrosourea (ENU) revealed a mouse, designated Longpockets (Lpk), with short humeri, abnormal vertebrae, and disorganized growth plates, features consistent with spondyloepiphyseal dysplasia congenita (SEDC). The Lpk phenotype was inherited as an autosomal dominant trait. Lpk/+ mice were viable and fertile and Lpk/Lpk mice died perinatally. Lpk was mapped to chromosome 15 and mutational analysis of likely candidates from the interval revealed a Col2a1 missense Ser1386Pro mutation. Transient transfection of wild-type and Ser1386Pro mutant Col2a1 c-Myc constructs in COS-7 cells and CH8 chondrocytes demonstrated abnormal processing and endoplasmic reticulum retention of the mutant protein. Histology revealed growth plate disorganization in 14-day-old Lpk/+ mice and embryonic cartilage from Lpk/+ and Lpk/Lpk mice had reduced safranin-O and type-II collagen staining in the extracellular matrix. The wild-type and Lpk/+ embryos had vertical columns of proliferating chondrocytes, whereas those in Lpk/Lpk mice were perpendicular to the direction of bone growth. Electron microscopy of cartilage from 18.5 dpc wild-type, Lpk/+, and Lpk/Lpk embryos revealed fewer and less elaborate collagen fibrils in the mutants, with enlarged vacuoles in the endoplasmic reticulum that contained amorphous inclusions. Micro-computed tomography (CT) scans of 12-week-old Lpk/+ mice revealed them to have decreased bone mineral density, and total bone volume, with erosions and osteophytes at the joints. Thus, an ENU mouse model with a Ser1386Pro mutation of the Col2a1 C-propeptide domain that results in abnormal collagen processing and phenotypic features consistent with SEDC and secondary osteoarthritis has been established.     

Prostate cell lines secrete IL-8 in response to Mycoplasma hominis through Toll-like receptor 2-mediated mechanism

BACKGROUND: The roles of Toll-like receptor 2 (TLR2) and Mycoplasma in prostate inflammation remain unclear. We investigated whether Mycoplasma induced inflammatory cytokine secretion through TLR2-mediated mechanism in prostate cancer cell line. METHODS: Cell surface expression of TLR2 on PC-3 cells were examined by flowcytometry. PC-3 cells were stimulated with Mycoplasma hominis (M. hominis), and IL-8 secretion and NF-kappaB activation were examined. RESULTS: PC-3 cells expressed TLR2 mRNA and cell surface TLR2 protein. The membrane fraction of M. hominis induced IL-8 secretion from PC-3 cells and NF-kappaB activation in a concentration-dependent manner. Transient transfection of the dominant negative mutant TLR2(P681H) into PC-3 cells attenuated M. hominis-induced IL-8 secretion and NF-kappaB activation. Antibody against the extracellular TLR2 domain significantly suppressed M. homnis-induced IL-8 secretion from the prostate cell lines including PC-3, PrEC, and transformed myofibroblasts. CONCLUSIONS: These results clearly demonstrate that the prostate cell line can secrete inflammatory cytokine in response to M. hominis through a TLR2-mediated mechanism.     

The 17th Annual Prostate Cancer Foundation scientific retreat: meeting report

Annually the Prostate Cancer Foundation (PCF) organizes a scientific retreat to assemble the premier prostate cancer researchers from around the world to share and review the latest progress made in the field and to evaluate future directions. This report highlights some of the most significant advances made in prostate cancer research in 2010 that were presented at the 17th Annual PCF Scientific Retreat.