Stress distribution of the patellofemoral joint in the anatomic V-shape and curved dome-shape femoral component: a comparison of resurfaced and unresurfaced patellae.

PURPOSE: Whether to resurface the patella in knee replacement remains a controversial issue. The geometrical design of the trochlear groove in the femoral component could play an important role in determining the stress distribution on the patellofemoral joint, but this has not been sufficiently reported on. This study attempted to determine the effect of implant design on contact mechanics by means of a finite element method. METHODS: Two designs, an anatomical V-shape design (VSD) and a dome-shape design (DSD), for the anterior trochlear surface in a contemporary femoral component were chosen for examining the contact characteristics. The use and absence of patella resurfacing was simulated. The stress and strain distribution on the patellar bone and the polyethylene component were calculated for comparison. RESULTS: Without patellar resurfacing, the maximal compressive strain in the patellar bone in the VSD model was about 20 % lower than the DSD model. On the other hand, with resurfacing, the maximal strain for the VSD model was 13.3 % greater than for DSD. Uneven stress distribution at the bone-implant interface was also noted for the two designs. CONCLUSION: The femoral component with a V-shape trochlear groove reduced the compressive strain on the unresurfaced patella. If resurfacing the patella, the femoral component with a curved domed-shape design might reduce the strain in the remaining patellar bone. Uneven stress could occur at the bone-implant interface, so design modifications for improving fixation strength and medialization of the patellar button would be helpful in reducing the risk of peg fracture or loosening. LEVEL OF EVIDENCE: III.

Matrix metalloproteinase-11 as a marker of metastasis and predictor of poor survival in urothelial carcinomas.

BACKGROUND AND OBJECTIVES: Urothelial carcinomas (UC) of urinary bladder (UB) and upper urinary tract (UT) are heterogeneous diseases with high morbidity and mortality. We looked for genes with metalloendopeptidase activity in a published UBUC transcriptomic database (GSE31684):MMP-11 was the most significant, showing stepwise up-regulation. We analyzed MMP-11 expression and association with clinicopathologic factors and survival in our well-characterized cohort of UCs. METHODS: We determined MMP-11 expression in 295 UBUCs and 340 UTUCs with immunohistochemistry, evaluated by H-score. In a retrospective study, MMP-11 expression was correlated with clinicopathologic features and with disease-specific survival (DSS) and metastasis-free survival (MeFS). The statistical significance was evaluated with univariate and multivariate analyses. RESULTS: High MMP-11 expression was significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular and perineural invasion, and frequent mitoses. In multivariate Cox regression analyses, which adjusted for standard clinicopathologic characteristics, MMP-11 expression was independently associated with cancer-specific mortality (hazard ratio [HR] in UTUC:3.027, P = 0.005; in UBUC: 2.631, P = 0.010) and with metastasis development (HR in UTUC:2.261, P = 0.018; in UBUC:1.801, P = 0.026). CONCLUSIONS: MMP-11 overexpression is associated with aggressive tumor phenotype and unfavorable clinical outcome in UTUC and UBUC, suggesting it may serve as a novel prognostic and therapeutic target. J. Surg. Oncol. 2016;113:700-707. © 2016 Wiley Periodicals, Inc.

Patellofemoral kinematics during deep knee flexion after total knee replacement: a computational simulation.

PURPOSE: Actions requiring deep knee flexion, such as kneeling and squatting, are challenging to perform after total knee replacement (TKR), though many manufactures emphasize that their knee prostheses could safely achieve high flexion. Little is known about the patellofemoral kinematics during deep flexion. This study aimed to track the movement of the patella during kneeling and squatting through dynamic computational simulation. METHODS: A validated knee model was used to analyse the patellar kinematics after TKR, including shifting, tilting and rotation. The data were captured from full extension to 135° of knee flexion. For kneeling, an anterior force of 500 N was applied perpendicularly on the tibial tubercle as the knee flexed from 90° to 135°. For squatting, a ground reaction force was applied through the tibia from full extension to 135° of flexion. RESULTS: This study found that patellar shifting and rotation in kneeling were similar to those while squatting. However, during kneeling, the patella had a greater medial tilt and showed signs of abrupt patellar tilt owning to an external force being concentrated on the tibial tubercle. CONCLUSIONS: In terms of squatting and kneeling movements, the latter is a more strenuous action for the patellofemoral joint after TKR due to the high forces acting on the tibial tubercle. It is suggested that overweight patients or those requiring high flexion should try to avoid kneeling to reduce the risk of the polyethylene wear. Further modification of trochlear geometry may be required to accommodate abrupt changes in patellar tilting. LEVEL OF EVIDENCE: II.

Prognostic significance of cyclin D1 polymorphisms on prostate-specific antigen recurrence after radical prostatectomy.

BACKGROUND: Cyclin D1 (CCND1) is an important cell-cycle regulator involved in carcinogenesis and progression of prostate cancer. We tested whether genetic variations within the CCND1 gene are related to clinical outcomes in prostate cancer patients receiving radical prostatectomy. METHODS: A total of 320 clinical localized prostate cancer patients who underwent radical prostatectomy in Taiwan were prospectively follow-up in this study. A total of 5 tagged single-nucleotide polymorphisms that captured the genetic variability across the CCND1 gene were genotyped, and the prognostic significance on prostate-specific antigen (PSA) recurrence was assessed using the Kaplan-Meier analysis and Cox regression model. RESULTS: We found a polymorphism, rs9344, and 2 haplotypes, GAGG and CTGG, consisting of rs667515, rs2450254, rs9344, and rs678653, were associated with PSA recurrence (P ≤ 0.033). After adjusting for other clinicopathologic predictors, including age, PSA levels, pathologic stage, Gleason score, and surgical margin, rs9344 and the haplotype CTGG remained significant (P ≤ 0.044). The model based on clinical variables plus CCND1 rs9344 or haplotype showed improvement over the model without genetic information, as indicated by ≥ 7.2 % net reclassification improvement (P ≤ 0.040), integrated discrimination index (P ≤ 0.041), and likelihood ratio test (P ≤ 0.028). CONCLUSION: Our data suggest that the CCND1 rs9344 and a specific haplotype CTGG may be prognostic factors for PSA recurrence after radical prostatectomy.

Laparoendoscopic single-site retroperitoneoscopic adrenalectomy versus conventional retroperitoneoscopic adrenalectomy: initial experience by the same laparoscopic surgeon.

PURPOSE: The purpose of this study was to demonstrate our initial experience with and the feasibility of laparoendoscopic single-site retroperitoneoscopic adrenalectomy (LESS-RA). PATIENTS AND METHODS: 54 patients undergoing conventional retroperitoneoscopic adrenalectomy were compared with 27 patients undergoing LESS-RA. The adrenal tumors were considered to be benign preoperatively and <6 cm. Age, sex, laterality, body mass index, surgical indications, time to resuming oral intake, tumor size, operation time, estimated blood loss, intravenous or intramuscular analgesics (pethidine) and postoperative hospital stay were compared between the two groups. Analysis of covariance was applied to analyze postoperative hospital stay and time to resuming oral intake. RESULTS: The length of postoperative hospital stay was significantly higher in the conventional retroperitoneoscopic adrenalectomy group in the adjusted and unadjusted model. The time to resuming oral intake was significant shorter in the LESS-RA group, but was not significant after adjusting opioid analgesics dosage. No conversions to an open or conventional retroperitoneoscopic approach were necessary. There were neither complications nor blood transfusions in both groups. CONCLUSIONS: LESS-RA for benign adrenal tumors is a feasible surgical procedure when tumors are <6 cm. Further clinical research is warranted to define the role of LESS in adrenal surgery and to prove its efficacy over conventional laparoscopic surgery.

Sexual dysfunction in women with ketamine cystitis: a case-control study.

OBJECTIVE: • To conduct a case-control study evaluating clinical symptom severity and sexual dysfunction in women with ketamine cystitis (KC). PATIENTS AND METHODS: • In total, 29 patients with KC and 27 controls completed the symptoms survey. • Participants completed a visual pelvic pain analogue scale, an O'Leary-Sant Interstitial Cystitis Symptom Index and Problem Index questionnaire, a Female Sexual Function Index, and a short form of the Chinese Health Questionnaire-12. RESULTS: • Both the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index scores were significantly higher in patients with KC compared to controls (P < 0.001). • The prevalence of sexual dysfunction was high in patients with KC. • There was a difference in total adjusted Female Sexual Function Index scores between the patients with KC and controls: mean (sd) total Female Sexual Function Index score 17.65 (6.15) for KC cases vs 25.87 (4.16) for controls (P < 0.001). • Except for the sexual desire domain of female sexual dysfunction, patients with KC scored lower on all domains compared to controls. • There was no significant difference between patients with KC and controls with respect to mental health as evaluated by the Chinese Health Questionnaire-12. CONCLUSIONS: • Sexual dysfunction and KC symptoms severely impacted on quality of life. • Mental health had no significant difference between patients with KC and controls.

Protein kinase C inhibitor prevents renal apoptotic and fibrotic changes in response to partial ureteric obstruction.

UNLABELLED: What's known on the subject? and What does the study add? Protein kinase C inhibitor (PKCI) can decrease glomerular and tubular cell apoptosis and mitosis and attenuate collagen accumulation and fibronectin expression in a PUUO rat model. Although the role of PKC has been well studied in diabetic nephropathy, there is no report on its role in obstructive nephropathy. This investigation evaluated the processes that were associated with the activation of PKCα and PKCß pathways and showed that PKCI played an important role in the protection of renal function during ureteric obstruction. OBJECTIVES: • To investigate the expression of the protein kinase C (PKC) pathway after partial unilateral ureteric obstruction (PUUO). • To evaluate the therapeutic potential of a PKC inhibitor (PKCI) in obstructive nephropathy. MATERIALS AND METHODS: • Thirty-six rats were divided into three groups. One sham-operated group served as the control. The other two groups received PUUO surgery, after which one group received no treatment and the other group was treated with PKCI, chelerythrine. • The severity of hydronephrosis and renal morphology were assessed: tubular and glomerularcell apoptosis, mitosis and interstitial fibrosis were examined using immunohistochemistry. • Western immunoblots were performed to determine fibronectin, transforming growth factor-ß (TGF-ß), and PKC isoform levels. RESULTS: • Two weeks after PUUO surgery, hydronephrosis progressively developed. Tubular-interstitial fibrosis, collagen deposition and fibronectin expression were increased. • PUUO also activated the expression of PKCα and PKCß and the translocation of PKCs from cell cytosol to cell membranes. • Treatment with PKCI significantly decreased PKCα and PKCß expression and translocation in the renal cortex. • Treatment with PKCI also reduced the severity of hydronephrosis, decreased both glomerular and tubular cell apoptosis and mitosis, and attenuated the collagen and fibronectin accumulation in renal interstitium. CONCLUSIONS: • Renal tubular apoptosis and interstitial fibrosis after obstructive nephropathy are associated with PKCα and PKCß activation. • The PKCI, chelerythrine, is capable of decreasing PKC expression and translocation in the renal cortex, suggesting that this inhibitor may have therapeutic potential in the protection of renal function in the first few weeks after PUUO surgery.

Green tea catechins decrease oxidative stress in surgical menopause-induced overactive bladder in a rat model.

UNLABELLED: What's known on the subject? and What does the study add? Ovary hormone deficiency and the age-related changes in post-menopausal women are subjected to a number of urological dysfunctions, including overactive bladder syndrome. Green tea is a popular healthy drink worldwide and its extract catechin has strong anti-inflammatory and antioxidant properties. EGCG, the major type of catechin, is an antioxidant polyphenol flavonoid isolated from green tea. EGCG supplement could prevent ovariectomy-induced bladder dysfunction in a dose-related manner through its anti-oxidant, anti-fibrosis and anti-apoptosis effects. OBJECTIVE: To evaluate whether green tea extract, epigallocatechin gallate (EGCG), could prevent ovariectomy-induced overactive bladder (OAB) and to investigate its antioxidant, anti-apoptotic and anti-fibrosis effects. MATERIALS AND METHODS: In all, 48 female Sprague-Dawley rats were divided into four groups. After bilateral ovariectomy, the first group served as the ovariectomy control, the second group received EGCG 1 µM/kg daily i.p. injection after ovariectomy surgery, and the third group received EGCG 10 µM/kg daily i.p. injection. The fourth group was taken as the sham without ovariectomy surgery. The rats were killed after 6 months after ovariectomy surgery. Cystometrograms were performed for the measure of bladder overactivity. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) assay was used to evaluate apoptotic cells. Western immunoblots were performed to determine the expressions of inflammatory markers, apoptosis-associated proteins and oxidative stress markers. RESULTS: Long-term ovariectomy significantly increased non-voiding contractions and decreased bladder compliance. Treatment with EGCG significantly increased bladder compliance and diminished non-voiding contractions. Ovariectomy significantly increased apoptotic cells and enhanced interstitial fibrosis in bladders. The expression of caspase-3 significantly increased, while that of Bcl-2 notably decreased after ovariectomy. Inflammatory and fibrosis markers, TGF-ß, fibronectin and type I collagen expressions were significantly increased after 6 months of ovariectomy surgery. Treatment with EGCG significantly decreased TGF-ß and type I collagen expressions. Oxidative stress markers, nitrotyrosine and protein carbonylation levels were significantly increased in the ovariectomy group. EGCG could attenuate this oxidative damage in dose-dependent fashion. CONCLUSIONS: Ovariectomy increased oxidative damage, enhanced voiding frequency and decreased bladder compliance. EGCG could restore ovariectomy-induced bladder dysfunction in a dose-dependent fashion through antioxidant, anti-fibrosis and anti-apoptosis effects.

The impact of androgen receptor CAG repeat polymorphism on andropausal symptoms in different serum testosterone levels.

INTRODUCTION: In addition to a depletion of androgen, attenuated action of androgen receptor (AR) might also contribute to andropausal symptoms. AIM: To evaluate the interaction of AR cytosine adenine guanine (CAG) repeat polymorphism and serum testosterone levels and their effect on andropausal symptoms in aging Taiwanese men. METHODS: From August 2007 to April 2008, a free health screening for men older than 40 years was conducted by a medical center in Kaohsiung City, Taiwan. All participants received physical examination, answered questionnaires to collect their demographic information and medical histories, completed the Androgen Deficiency in the Aging Male (ADAM) questionnaire, and provided 20-cm(3) whole blood samples for biochemical and genetic evaluation. MAIN OUTCOME MEASURES: The ADAM questionnaire was used to evaluate andropausal symptoms. Serum albumin, total testosterone (TT), and sex hormone-binding globulin levels were measured. Free testosterone level was calculated. AR gene CAG repeat polymorphism was determined by direct sequencing. RESULTS: Seven hundred two men with the mean age of 57.2 ± 6.5 years were included. There was no significant association between TT levels and the distribution of AR CAG repeat polymorphism. When TT levels were above 340 ng/dL, subjects with AR CAG repeat lengths ~25 showed significantly higher risk of developing andropausal symptoms, as compared with those with AR CAG repeat lengths ~22 (P = 0.006), but this was not observed when TT levels were 340 ng/dL or below. Age and number of comorbidities were also independent risk factors for andropausal symptoms. CONCLUSION: In subjects with normal TT concentration, those with longer AR CAG repeat lengths have a higher risk of developing andropausal symptoms. Age and number of comorbidities can also influence the appearance of andropausal symptoms. In clinical practice, a multifactorial approach to evaluate andropausal symptoms and the interactions between those risk factors is suggested.

The association of eNOS G894T polymorphism with metabolic syndrome and erectile dysfunction.

INTRODUCTION: Accumulated evidences have outlined the potential relation between insulin resistance and endothelial dysfunction. The impaired ability of endothelium to synthesize or release nitric oxide may provide a common pathophysiological mechanism in the development of metabolic syndrome (MtS) and erectile dysfunction (ED). AIM: The aim of this article was to investigate the genetic susceptibility of endothelial nitric oxide synthase (eNOS) G894T polymorphism underlying the development of both disorders. METHODS: A total of 590 subjects with a mean (standard deviation) age of 55.3 years (4.1) were enrolled during a free health screening. Complete clinical data and questionnaires were taken for all subjects. Multivariate logistic regression analysis was used to determine the independent predictors of MtS and ED. The eNOS G894T polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism method. MAIN OUTCOME MEASURES: The definition of MtS was according to the modified criteria developed by the Bureau of Health Promotion in Taiwan. Patients with ED were defined as those having a five-item International Index of Erectile Function (IIEF-5) <21. RESULTS: Our results showed that the eNOS 894T allele carriers had significantly higher prevalence of MtS and ED (odds ratio [OR]=1.64, 95% confidence interval [CI]=1.05∼2.56, P=0.02 and OR=1.76, 95% CI=1.11∼2.80, P=0.01, respectively) after adjustment for each other and age. Also the T allele carriers had significantly lower IIEF-5 score and more MtS components than G allele carriers (P<0.01 and P<0.01, respectively), which were significantly associated with an increment of the T allele number (P<0.05). CONCLUSIONS: The eNOS 894T allele carriers are at greater risk for both MtS and ED, suggesting that eNOS G894T gene polymorphism might play an implication as a common genetic susceptibility factor to develop both disorders.

Significant associations of prostate-specific antigen nadir and time to prostate-specific antigen nadir with survival in prostate cancer patients treated with androgen-deprivation therapy.

OBJECTIVE: The influence of prostate-specific antigen (PSA) kinetics on the outcome of metastatic prostate cancer (PCa) after androgen-deprivation therapy (ADT) remains poorly characterised. We evaluated the prognostic significance of PSA nadir and time to PSA nadir as well as their interactive effect on prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT. METHODS: A total of 650 men with advanced or metastatic PCa treated with ADT were studied. The prognostic significance of PSA nadir and time to PSA nadir on PCSM and ACM were analysed using Kaplan-Meier analysis and the Cox regression model. RESULTS: On multivariate analysis, clinical M1 stage, Gleason Score 8-10, PSA nadir ≥ 0.2 ng/ml and time to PSA nadir < 10 months were independent predictors of PCSM and ACM. The combined analysis showed that patient with higher PSA nadir and shorter time to PSA nadir had significantly higher risk of PCSM and ACM compared to those with lower PSA nadir and longer time to PSA nadir (hazard ratios = 6.30 and 4.79, respectively, all P < 0.001). CONCLUSIONS: Our results suggest that higher PSA nadir level and faster time to reach PSA nadir after ADT were associated with shorter survival for PCa.

Endothelin-1 stimulates suppressor of cytokine signaling-3 gene expression in adipocytes.

Endothelin (ET)-1 and suppressor of cytokine signaling (SOCS)-3 were respectively found to regulate energy metabolism and hormone signaling in fat cells. Although ET-1 can also regulate the expression of SOCS-3-stimulating hormones, it is still unknown whether ET-1 regulates SOCS-3 gene expression. This study investigated the pathways involved in ET-1's modulation of SOCS-3 gene expression in 3T3-L1 adipocytes. ET-1 upregulated SOCS-3 mRNA and protein expression in dose- and time-dependent manners. The concentration of ET-1 that increased SOCS-3 mRNA levels by 250-400% was ∼100nM with 2-4h of treatment. Treatment with actinomycin D prevented ET-1-stimulated SOCS-3 mRNA expression, suggesting that the effect of ET-1 requires new mRNA synthesis. Pretreatment with the ET type A receptor (ET(A)R) antagonist, BQ-610, but not the ET type B receptor (ET(B)R) antagonist, BQ-788, prevented the stimulatory effect of ET-1 on SOCS-3 gene expression. The specific inhibitors of either MEK1 (U-0126 and PD-98059), JAK (AG-490), JNK (SP-600125), or PI3K (LY-294002 and wortmannin) reduced ET-1-increased levels of SOCS-3 mRNA and respectively inhibited ET-1-stimulated activities of MEK1, JAK, JNK, and PI3K. These results imply that the ET(A)R, ERK, JAK, JNK, and PI3K are functionally necessary for ET-1's stimulation of SOCS-3 gene expression. Moreover, ET-1 was observed to upregulate expressions of SOCS-1, -2, -3, -4, -5, and -6 mRNAs, but not SOCS-7 or cytokine-inducible SH2-containing protein-1 mRNAs. This suggests that ET-1 selectively affects particular types of SOCS family members. Changes in SOCS gene expressions induced by ET-1 may help explain the mechanism by which ET-1 modulates hormone signaling of adipocytes.

The potential role of herbal extract Wedelolactone for treating particle-induced osteolysis: an in vivo study.

BACKGROUND: Osteolysis is one of the most prevalent clinical complications affecting people who undergo total joint replacement (TJR). Wedelolactone (WDL) is a coumestan compound derived from the Wedelia chinensis plant and has been demonstrated to exhibit anti-inflammatory properties. This study aimed to investigate the oral administration of WDL as a potential treatment for particle-induced osteolysis using a well-established mice calvarial disease model. METHODS: Thirty-two C57BL/6 J mice were randomized into four groups: Sham, vehicle, osteolysis group with oral WDL treatment for 4 weeks (WDL 4w), and osteolysis group treated for 8 weeks (WDL 8w). Micro-CT was used to quantitatively analyze the bone mineral density (BMD), bone volume/tissue volume (BV/TV) and trabecular bone thickness (Tb.Th). Osteoclast numbers were also measured from histological slides by two investigators who were blind to the treatment used. RESULTS: The results from micro-CT observation showed that BMD in the WDL 8w group improved significantly over the vehicle group (p < 0.05), but there was no significant difference between WDL 4w and 8w for BV/TV and Tb.Th. Osteoclast numbers in the WDL 4w group were also lower than the vehicle group (p < 0.05), but the difference between WDL 8w and 4w groups was not significant. CONCLUSIONS: Particle-induced osteolysis is an inevitable long-term complication after TJR. The results of this animal study indicate that an oral administration of WDL can help reduce the severity of osteolysis without adverse effects.

Evaluation of graphene-derived bone scaffold exposure to the calvarial bone_in-vitro and in-vivo studies.

Graphene is a novel material which has recently been gaining great interest in the biomedical fields. Our previous study observed that graphene-derived particles help induce bone formation in a murine calvarial model. Here, we further developed a blended graphene-contained polycaprolactone (PCL/G) filament for application in a 3D-printed bone scaffold. Since implants are expected to be for long-term usage, in vitro cell culture and in vivo scaffold implants were evaluated in a critical-size bone defect calvarial model for over 60 weeks. Graphene greatly improved the mechanical strength by 30.2% compared to pure PCL. The fabricated PCL/G scaffolds also showed fine cell viability. In animal model, an abnormal electroencephalogram power spectrum and early signs of aging, such as hair graying and hair loss, were found in the group with a PCL/G scaffold compared to pure PCL scaffold. Neither of the abnormal symptoms caused death of all animals in both groups. The long-term use of graphene-derived biomaterials for in-vivo implants seems to be safe. But the comprehensive biosafety still needs further evaluation.

Low exposure to melamine increases the risk of urolithiasis in adults.

Melamine, a widely used chemical found in many products in daily use, became a public health concern due to melamine-associated urinary stone formation in children. In adults, it is still unknown whether low-dose melamine exposure may also cause urolithiasis. To address this question, we studied 211 Taiwanese patients diagnosed with calcium urolithiasis and 211 age- and gender-matched controls. All patients completed a detailed questionnaire and provided blood and urine samples for biochemical analysis. Urinary melamine concentrations were measured by triple-quadrupole liquid chromatography tandem mass spectrometry. Compared with those whose urinary melamine levels were below the detection limit of the method, patients with urinary melamine levels of up to 3.11 ng/ml and those with levels of ≥3.12 ng/ml had 3.01- and 7.64-fold increased risk, respectively, of calcium urolithiasis after adjusting for educational level, fluid intake, cigarette smoking, betel quid chewing, alcohol drinking, urinary uric acid, calcium, creatinine, and estimated creatinine clearance rate. The population attributable risk of calcium urolithiasis averaged 50% when melamine was detected in the urine, after considering other covariates. MALDI-TOF mass spectrometry detected melamine in the stones of nine representative patients who had measurable urinary melamine levels. Thus, low-dose melamine exposure can play an important role in calcium urolithiasis in Taiwanese adults.

Impact of prostate-specific antigen (PSA) nadir and time to PSA nadir on disease progression in prostate cancer treated with androgen-deprivation therapy.

BACKGROUND: The influence of PSA kinetics on the outcome of metastatic prostate cancer after androgen deprivation therapy (ADT) is not well understood. We evaluated the prognostic significance of PSA nadir and time to PSA nadir as well as their potential interactive effect on the progression of disease after ADT. METHODS: A total of 650 men with advanced or metastatic prostate cancer treated with ADT were studied. The prognostic significance of PSA nadir and time to PSA nadir on disease progression were analyzed using Kaplan-Meier analysis and the Cox regression model. RESULTS: We found that both PSA nadir and time to PSA nadir were independent and significant predictors of disease progression. Patients with higher PSA nadir (≥0.2 ng/ml) and shorter time to PSA nadir (<10 months) had significant shorter time to disease progression after adjusting for other covariates. The combined analyses showed a potential synergistic effect of these two variables on disease progression. Patient with higher PSA nadir and shorter time to PSA nadir had significantly higher risk for disease progression compared to those with lower PSA nadir and longer time to PSA nadir (Hazard Ratios (HR) = 3.11, P < 0.001). CONCLUSIONS: We concluded that both PSA nadir and time to PSA nadir are significant predictors of disease progression for prostate cancer patients receiving ADT.

Identification of low-abundance proteins via fractionation of the urine proteome with weak anion exchange chromatography.

BACKGROUND: Low-abundance proteins are difficultly observed on the two-dimensional gel electrophoresis (2-DE) maps of urine proteome, because they are usually obscured by high-abundance proteins such as albumin and immunoglobulin. In this study, a novel fractionation method was developed for enriching low-abundance proteins by removing high-abundance proteins and progressive elution with salts of various concentrations. RESULTS: Stepwise weak anion exchange (WAX) chromatography, which applied DEAE-Sephacel resin with non-fixed volume elution, was used to fractionate urine proteome prior to performing 2-DE. Urine proteome was separated into four fractions by progressively eluting the column with 0 M, 50 mM, 100 mM, and 1 M NaCl solutions. Most of the heavy and light immunoglobulin chains appeared in the eluent. After the high-abundance proteins were removed, various low-abundance proteins were enriched and could be easily identified. The potential of this method for obtaining diversified fractionations was demonstrated by eluting the column separately with Na2SO4 and MgCl2 solutions. The 2-DE maps of the fractions eluted with these different salt solutions of identical ionic strength revealed markedly different stain patterns. CONCLUSION: The present study demonstrated that this fractionation method could be applied for purposes of enriching low-abundance proteins and obtaining diversified fractionations of urine, and potentially other proteomes.

The effect of L-arginine on bladder dysfunction following ovariectomy in a rabbit model.

INTRODUCTION AND HYPOTHESIS: The present study was designed to investigate the effect of nitric oxide precursor, L: -arginine, on bladder function following ovariectomy. METHODS: Twenty-eight New Zealand white female rabbits were separated into seven groups. Groups 1 to 6 underwent ovariectomy surgery. Among them, groups 1 and 2 received ovariectomy without treating with L-arginine. Groups 3, 4, 5, and 6 were given high L-arginine diet and were sacrificed 1, 3, 7, and 14 days after ovariectomy, respectively. Group 7 served as the control group. The effects of L: -arginine on the contractility of bladder tissues were determined in response to various stimulations. In addition, L-arginine effects on the expression of Rho kinase (ROK), protein kinase C potentiated inhibitor (CPI-17), caldesmon (CaD), and calponin (CaP) were studied by immunoblotting. RESULTS: Ovariectomy significantly decreases contractile response to all forms of stimulation. Feeding rabbits L: -arginine significantly increases contractile response at 1 day following ovariectomy, but the response decreases to the control level by 14 days. Ovariectomy increases the expressions of both isoforms of CaD, CaP, and CPI-17; L-arginine treatment induces ROK underexpression, while CaP is overexpressed in the early few days of ovariectomy but returns to the control level at 2 weeks after ovariectomy. CONCLUSIONS: Ovariectomy appreciably reduced bladder contractility. Treatment with L-arginine reversed the ovariectomy-induced bladder dysfunction. Decreased bladder contractile response was observed in the early days following ovariectomy.

p53 codon 72 polymorphism was associated with vulnerability, progression, but not prognosis of bladder cancer in a Taiwanese population: an implication of structural equation modeling to manage the risks of bladder cancer.

INTRODUCTION: p53 codon 72 polymorphism has been reported to be associated with bladder cancer incidence, progression and prognosis, but the association is still under debate. A tentative model was constructed to evaluate the association between p53 codon 72 polymorphism and bladder cancer. SUBJECTS AND METHODS: In this study, a total of 554 participants were enrolled. The genotyping was carried out using PCR-RFLP and DNA direct sequencing. RESULTS: The genotype distribution of p53 codon 72 polymorphism was significantly different between bladder cancer patients and controls (p = 0.039). In logistic regression, diagnostic age and genotype Pro/Pro were the risk factors for developing an invasive tumor. A 4.526-fold risk was estimated for the patients with Pro/Pro genotype as opposed to non-Pro/Pro genotype to develop invasive tumors. However, the extent of p53 codon 72 polymorphism did not predict bladder cancer prognosis. CONCLUSIONS: A conceptual mode was constructed; in addition, the moderating and mediating analysis was also carried out in a structural equation model to resolve possible confounding effects. Taken together, p53 codon 72 polymorphism may be associated with bladder cancer incidence and progression, but not prognosis. Further study is needed to evaluate the usefulness of the constructed model in risk assessment.

Enhanced expression of coxsackievirus and adenovirus receptor in lipopolysaccharide-induced inflammatory macrophages is through TRIF-dependent innate immunity pathway.

AIMS: Inflammatory macrophages have been proposed as a therapeutic target for joint disorders caused by inflammation. This study aimed to investigate the expression and regulation of coxsackievirus-adenovirus receptor (CAR) in lipopolysaccharide (LPS)-stimulated inflammatory macrophages whereby to evaluate the feasibility of virus-directed enzyme prodrug therapy (VDEPT). MAIN METHODS: Macrophage cell lines (RAW264.7 and J774A.1) and primary macrophage cells derived from rat spleen were used to evaluate the expression of CAR protein or CAR mRNA. Specific inhibitors for TLR4 pathway were used to investigate the regulation of CAR expression. CAR expression in rat joints was documented by immunohistochemistry. Conditionally replicating adenovirus, CRAd-EGFP(PS1217L) or CRAd-NTR(PS1217H6), and non-replicating adenovirus CTL102 were used to transduce genes for enhanced green fluorescent protein (EGFP) or nitroreductase (NTR), respectively. The expression of EGFP, NTR, and the toxicity induced by CB1954 activation were evaluated. KEY FINDINGS: The in vitro experiments revealed that CAR upregulation was mediated through the TLR4/TRIF/IRF3 pathway in LPS-stimulated inflammatory macrophage RAW264.7 and J774A.1 cells. The inflammatory RAW264.7 cells upregulated CAR expression following LPS stimulation, leading to higher infectability, increased NTR expression, and enhanced sensitization to CB1954. In animal experiments, the induction of CAR expression was observed in the CD68-expressing primary macrophages and in the CD68-expressing macrophages within joints following LPS stimulation. SIGNIFICANCE: In conclusion, we report an enhanced CAR expression in inflammatory macrophages in vitro and in vivo through the immune response elicited by LPS. Thus, the TLR4/TRIF/IRF3 pathway of macrophages, when activated, could facilitate the therapeutic application of adenovirus-mediated VDEPT.