Preanalytical stability of molecular forms of prostate-specific antigen in serum samples (PSA, free PSA, [-2]proPSA) and their impact on fPSA/tPSA ratio and PHI.

BACKGROUND: Prostate cancer is a common cancer in men. Detection methods include the measurement of biomarkers: prostate-specific antigen (PSA), free PSA, [-2]proPSA, and the calculated indices: fPSA/tPSA ratio and Prostate Health Index (PHI). Proper preanalytical conditions are crucial for precise measurement and failure to adhere to protocols or regulations can influence the diagnostic algorithm. We assessed the stability of the above-mentioned biomarkers, fPSA/tPSA ratio and PHI, under various pre-analytical conditions. METHODS: Serum samples from 45 males were collected and stored under specific conditions before tPSA, fPSA, and [-2]proPSA were measured. Subsequently, the fPSA/tPSA and PHI were calculated. RESULTS: tPSA, fPSA, and [-2]proPSA remained stable during the two freeze-thaw cycles. Storage at 4°C and 22°C resulted in stable tPSA concentrations. However, fPSA levels decreased and [-2]proPSA levels increased over time. The fPSA/tPSA ratio remained stable for 72 h, at which point a decrease was observed in the samples kept at 4°C and 22°C. A gradual increase in PHI was observed in the samples kept at 4°C and 22°C. CONCLUSIONS: All biomarkers remained stable during two freeze-thaw cycles. tPSA was the most stable analyte when stored at 4°C, as well as at RT. A gradual increase of [-2]proPSA and a slight decrease in fPSA were observed during the storage test. This led to a decrease in the fPSA/tPSA ratio and an elevation in the PHI. We therefore recommend measuring prostate biomarkers promptly following blood collection. IMPACT: Understanding the pre-analytical stability of prostate biomarkers helps prevent false positive results and improve the accuracy of diagnostics for prostate cancer.

Factors associated with concomitant prostate cancer in benign prostatic hyperplasia patients aged 60 years and above.

OBJECTIVE: Prostate hyperplasia and cancer are more prevalent in middle-aged and elderly men. Previous studies have linked both disorders to androgen receptors. Herein, efforts were made to identify factors associated with prostate cancer in patients ≥60 years, aiming to enhance their health management. METHODS: An analytical framework was established utilizing the "Prostate Cancer Early Warning Dataset" from the National Clinical Medical Science Data Center. Variables selection was conducted through LASSO regression, followed by multifactorial logistic stepwise regression to construct a predictive model. RESULTS: A total of 1,502 patients with BPH and 294 with combined PCa were hereby included. Multivariate regression delineated several independent predictors of PCa coexistence, including age (OR [95% CI]: 1.06 [1.04-1.09], p < 0.001), fPSA/tPSA ratio (OR [95% CI]: 0.01 [0.002-0.05], p < 0.001), serum inorganic phosphorus (OR [95% CI]: 5.85 [2.61-13.15], p < 0.001), globulin levels (OR [95% CI]: 1.06 [1.02-1.11], p = 0.005), serum potassium (OR [95% CI]: 0.58 [0.40-0.86], p = 0.006), low-density lipoprotein (LDL) cholesterol (OR [95% CI]: 1.28 [1.06-1.54], p = 0.009), among others. CONCLUSION: The analysis revealed connections between PCa occurrence in men aged over 60 and BPH, along with specific serum biomarkers such as inorganic phosphorus, globulin, LDL cholesterol, lower fPSA/tPSA ratios and serum potassium.

[Clinical significance of prostatic exosomal protein and PSA in detecting prostate cancer with the PSA gray zone and PI-RADS-3 lesions].

OBJECTIVE: To explore the clinical value of prostatic exosomal protein (PSEP) and PSA in the diagnosis of PCa with PSA in the gray zone (4－10 µg/L) and Prostate Imaging Reporting and Data System category 3 (PI-RADS-3) lesions. METHODS: From 2019 to 2022, 211 patients with the PSA gray zone and PI-RADS-3 lesions underwent prostate multi-parameter MRI, prostate needle biopsy or transurethral resection/enucleation of the prostate. We collected the baseline urine samples from the patients, examined the content of PSEP in the urine by ELISA and evaluated the performance of PSEP and PSA in the diagnosis of PCa. RESULTS: Among the total number of patients, 57 were confirmed with PCa (the positive group) and the other 154 with benign prostate conditions (the negative group) by biopsy pathology. The free PSA level (fPSA), free to total PSA ratio (f/tPSA) and PSEP content were dramatically lower in the positive than in the negative group (all P< 0.01). Uni- and multivariate analyses showed f/tPSA and PSEP to be independent factors for predicting PCa with the PSA gray zone and PI-RADS-3 lesions, with the AUC values of 0.70 and 0.78, best cutoff values of 0.18 and 1.45 µg/L, sensitivity of 84.21% and 70.18%, and specificity of 58.44% and 77.27%, respectively (P< 0.01). The multivariate model with combined use of f/tPSA and PSEP (AUC: 0.82, best cutoff value: 0.31, sensitivity: 82.46%, specificity: 75.32%) outperformed either f/tPSA or PSEP alone in the diagnosis of PCa with the PSA gray zone and PI-RADS-3 lesions (P< 0.01, P = 0.04). CONCLUSION: For patients with the PSA gray zone and PI-RADS-3 lesions, f/tPSA and PSEP are significant predictors of PCa. The multivariate model of PSEP combined with f/tPSA can replace f/tPSA in the detection of PCa to improve diagnostic performance and avoid unnecessary prostate biopsy.

The Two TpsB-Like Proteins in Anabaena sp. Strain PCC 7120 Are Involved in Secretion of Selected Substrates.

The outer membrane of Gram-negative bacteria acts as an initial diffusion barrier that shields the cell from the environment. It contains many membrane-embedded proteins required for functionality of this system. These proteins serve as solute and lipid transporters or as machines for membrane insertion or secretion of proteins. The genome of Anabaena sp. strain PCC 7120 codes for two outer membrane transporters termed TpsB1 and TpsB2. They belong to the family of the two-partner secretion system proteins which are characteristic of pathogenic bacteria. Because pathogenicity of Anabaena sp. strain PCC 7120 has not been reported, the function of these two cyanobacterial TpsB proteins was analyzed. TpsB1 is encoded by alr1659, while TpsB2 is encoded by all5116 The latter is part of a genomic region containing 11 genes encoding TpsA-like proteins. However, tpsB2 is transcribed independently of a tpsA gene cluster. Bioinformatics analysis revealed the presence of at least 22 genes in Anabaena sp. strain PCC 7120 putatively coding for substrates of the TpsB system, suggesting a rather global function of the two TpsB proteins. Insertion of a plasmid into each of the two genes resulted in altered outer membrane integrity and antibiotic resistance. In addition, the expression of genes coding for the Clp and Deg proteases is dysregulated in these mutants. Moreover, for two of the putative substrates, a dependence of the secretion on functional TpsB proteins could be confirmed. We confirm the existence of a two-partner secretion system in Anabaena sp. strain PCC 7120 and predict a large pool of putative substrates.IMPORTANCE Cyanobacteria are important organisms for the ecosystem, considering their contribution to carbon fixation and oxygen production, while at the same time some species produce compounds that are toxic to their environment. As a consequence, cyanobacterial overpopulation might negatively impact the diversity of natural communities. Thus, a detailed understanding of cyanobacterial interaction with the environment, including other organisms, is required to define their impact on ecosystems. While two-partner secretion systems in pathogenic bacteria are well known, we provide a first description of the cyanobacterial two-partner secretion system.

Effect of prostate volume on f/tPSA value: A cross-sectional study.

Previous studies have suggested that there is a positive correlation between prostate-specific antigen (PSA) levels and prostate volume (PV). A better understanding of the possible influence of PV on a ratio of free to total PSA (f/tPSA) may improve the diagnostic value of the prostate disease. The study group consisted of 342 men with lower urinary tract symptoms (LUTS). All patients underwent urinary tract ultrasonography and had tests carried out on PSA, serum glucose, total cholesterol, triglyceride, HDL, LDL and blood pressure. Univariate and multivariate analyses were used to assess the associations between prostate volume and f/tPSA value. We found no obvious relationship between prostate volume and f/tPSA value when PSA >10 ng/ml but did observe a positive correlation when 4 ng/ml < PSA ï¼œ 10 ng/ml (hazard ratio [HR]: 0.0012; 95% confidence interval [CI]: 0.0009-0.0248). With increasing prostate volume, multivariate analysis showed an obvious increase in f/tPSA value (HR: 0.0011; 95% CI: 0.0007-0.0015) (p ≤ .0001). We confirmed that prostate volume could affect the f/tPSA levels in serum. There was an obvious positive correlation between prostate volume and f/tPSA level when PSA levels were between 4 and 10ng/dl. There was no significant correlation between prostate volume and f/tPSA value when PSA >10 ng/ml.

Addressing hERG activity while maintaining favorable potency, selectivity and pharmacokinetic properties of PPARδ modulators.

One of the most commonly used strategies to reduce hERG (human ether-a-go-go) activity in the drug candidates is introduction of a carboxylic acid group. During the optimization of PPARδ modulators, some of the compounds containing a carboxylic acid were found to inhibit the hERG channel in a patch clamp assay. By modifying the basicity of the imidazole core, potent and selective PPARδ modulators that do not inhibit hERG channel were identified. Some of the modulators have excellent pharmacokinetic profiles in mice.

Optimization of the efflux ratio and permeability of covalent irreversible BTK inhibitors.

Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule 9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule 1.

Discovery of a potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor (TP0438836) for the treatment of type 2 diabetes.

The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To achieve low absorption in the new series, we performed an optimization study based on a strategy to increase TPSA. Fortunately, the optimization of an aglycon moiety and a side chain of the distal aglycon moiety led to the identification of compound 30b as a potent and low-absorbable SGLT1 inhibitor. Compound 30b showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose-lowering effect in diabetic rats.

Elevated prostate specific antigen and reduced 10-year survival among a cohort of Danish men consecutively referred from primary care to an urological department during 2005-2006.

It remains unclear whether total prostate specific antigen (tPSA) or complex PSA (cPSA) has the best diagnostic performance. Additionally, the utility of percentage free PSA (%fPSA) is still debated. Our objectives were to compare the diagnostic performances of tPSA, cPSA, and %fPSA among patients referred from GP to an Urological Specialist and to investigate prognostic factors and survival in the cohort. A total of 1261 consecutive male patients without previously known prostate cancer (PCa) were referred to the same Department of Urology during June 2005 to August 2006. Some 299 patients were diagnosed with PCa and 962 patients were found without PCa. Among the PCa patients, the median age, tPSA, cPSA, and %fPSA levels were 70.8 years, 13.4 µg/L, 10.8 µg/L, and 12.6%. For patients without PCa the results were 67.5 years, 2.5 µg/L, 1.9 µg/L, and 24.9%. The sensitivity, specificity, PVpos, PVneg, and efficiency of tPSA and cPSA were overlapping (p > .05). In the tPSA interval >4 µg/L - ≤20 µg/L, %fPSA excluded PCa with a PVneg of 72.4%; 38.5% of PCa patients had a tPSA concentration >20 µg/L at the time of referral and these patients had a reduced 10-year survival as compared to patients with tPSA concentrations ≤20 µg/L. In conclusion, tPSA and cPSA showed similar diagnostic performances. %fPSA provided additional diagnostic information at tPSA concentrations >4 µg - ≤20 µg/L. The high percentage of patients with tPSA concentrations >20 µg/L indicate delayed use of tPSA resulting in advanced disease at presentation and reduced patient survival.

The age-specific reference intervals for tPSA, fPSA, and %fPSA in healthy Han ethnic male.

INTRODUCTION: Prostate cancer (PC) is one of the most common malignancies in male, and has become the fastest growing malignancy in recent years. Prostate specific antigen (PSA) is widely used as a tumor marker to screen for PC. Many studies have been performed to define the reference intervals (RIs) for total circulating PSA (tPSA). The results were different among different nations and races, even in the same race. Few researches have been performed on the RIs of free PSA (fPSA) and the ratio of free to total PSA (%fPSA). In this study, we aimed to simultaneously determine the age-specific RIs for tPSA, fPSA, and %fPSA in the healthy Han ethnic male. METHODS: A total of 1862 apparently healthy male aged from 21 to 94 years were included in our study. Nonparametric 95th percentile intervals were used to define the RIs. RESULTS: The reference limits in different age groups (21-50, 51-60, 61-70, 71-80, and ≥81 years) were 2.07, 3.59, 4.93, 6.83, and 7.73 ng/mL for tPSA, and 0.60, 0.76, 0.83, 1.30, and 2.41 ng/mL for fPSA. The RIs of %fPSA were ≥0.16 for 21-50 years and ≥0.13 for male over 50 years old. CONCLUSIONS: We established age-specific RIs for tPSA, fPSA and %fPSA. The newly established RIs should be more suitable for Chinese Han ethnic male. It will be valuable for physicians to make exact medical decision and appropriate medical intervention.

Dual-labeled chemiluminescence enzyme immunoassay for simultaneous measurement of total prostate specific antigen (TPSA) and free prostate specific antigen (FPSA).

The specificity for early diagnostic of prostate-specific antigen (PSA) is low because the current technology mostly allows the detection of only one biomarker at one time. In this work, a dual-labeled chemiluminescence enzyme immunoassay (CLEIA) for simultaneous measurement of total PSA (TPSA) and free PSA (FPSA) was proposed. Anti-PSA McAb (Mab1) was immobilized on a microplate as the solid phase, horseradish peroxidase (HRP)-labeled anti-TPSA monoclonal antibody (McAb2) and alkaline phosphatase (ALP)-labeled anti-FPSA McAb3 were used as detection antibodies. Two chemiluminescence reactions of HRP with luminol and ALP with 4-methoxy-4-(3-phosphate-phenyl)-spiro-(1,2-dioxetane-3,2'-adamantane) (AMPPD) were used as the signal detecting system. Based on a sandwich model, the amount of FPSA and TPSA could be determined simultaneously. The effects of several physico-chemical parameters were studied and optimized. Cross-reactivities of six common tumor markers in serum were studied. The proposed method presented the sensitivity of 0.03 ng ml-1 and 0.05 ng ml-1 for FPSA and TPSA respectively, with low cross-reactivities. Compared with the results from commercial chemiluminescent kits there was good correlation, indicating that this established method could be used to simultaneously to measure the concentrations of FPSA and TPSA in one serum sample and also could greatly facilitate the early diagnosis for PCa in clinical practice.

Evaluating Quantum Dot Performance in Homogeneous FRET Immunoassays for Prostate Specific Antigen.

The integration of semiconductor quantum dots (QDs) into homogeneous Förster resonance energy transfer (FRET) immunoassay kits for clinical diagnostics can provide significant advantages concerning multiplexing and sensitivity. Here we present a facile and functional QD-antibody conjugation method using three commercially available QDs with different photoluminescence (PL) maxima (605 nm, 655 nm, and 705 nm). The QD-antibody conjugates were successfully applied for FRET immunoassays against prostate specific antigen (PSA) in 50 µL serum samples using Lumi4-Tb (Tb) antibody conjugates as FRET donors and time-gated PL detection on a KRYPTOR clinical plate reader. Förster distance and Tb donor background PL were directly related to the analytical sensitivity for PSA, which resulted in the lowest limits of detection for Tb-QD705 (2 nM), followed by Tb-QD655 (4 nM), and Tb-QD605 (23 nM). Duplexed PSA detection using the Tb-QD655 and Tb-QD705 FRET-pairs demonstrated the multiplexing ability of our immunoassays. Our results show that FRET based on QD acceptors is suitable for multiplexed and sensitive biomarker detection in clinical diagnostics.

Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer.

The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8-12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann-Whitney-Wilcoxon Tests, the relative-median-change of tPSA (-0.1% vs. -86.8%; p = 0.02), fPSA (12.1% vs. -55.3%; p = 0.03) and [-2]proPSA (8.1% vs. -59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. -46.3%; p = 0.06). In Kaplan-Meier analyses, declining fPSA and [-2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6-16.4 vs. 10 months, 95% CI: 3.5-16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [-2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7-34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [-2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.

Chemotypes sensitivity and predictivity of in vivo outcomes for cytotoxic assays in THLE and HepG2 cell lines.

In the present study, we demonstrate the utility of in vitro ATP depletion assays in both THLE and HepG2 cells for predicting the toxicological outcome in Exploratory Toxicology Studies across 446 Pfizer proprietary compounds. Our results suggest a higher likelihood of selecting suitable compounds for in vivo safety studies by using cytotoxicity assays in multiple cell-lines over a single cell line. In addition, we demonstrate that different cell-lines have different sensitivities to compounds depending on their ionization state, that is, acid, base or neutral. HepG2 cells are more sensitive for basic compounds, whereas THLE cells have a relatively higher sensitivity for the acidic and neutral compounds. These in vitro cytotoxicity assays when combined with physicochemical properties (cLogP >3 and topological polar surface area (TPSA) <75Å(2)), are the most effective means to prioritize compounds having a lower probability of causing adverse events in vivo.

A Rational Approach To Antitubercular Drug Design: Molecular Docking, Prediction of ADME Properties and Evaluation of Antitubercular Activity of Novel Isonicotinamide Scaffold.

INTRODUCTION: One of the most devastating and leading diseases is Tuberculosis (TB), caused by Mycobacterium tuberculosis. Even though many synthetic drugs are available in the market, to increase the therapeutic efficacy and reduce toxicity. Isoniazid is the primary drug used in the treatment of tuberculosis. METHODS: The main objective of the study is to perform molecular docking studies and synthesize the derivatives of isonicotinamide along with the anti-tubercular activity. The isonicotinamide derivatives (a-j) are prepared using isoniazid, carbon disulphate, methyl cyanide, and benzaldehyde derivatives and characterized by TLC, IR, 1HNMR, and Mass spectroscopy. The enzyme decaprenylphosphoryl-D-ribose oxidase (DprE1) of M. tuberculosis had good binding capacity with all the ligands revealed in molecular docking studies. In-vitro studies indicated that all the ligands showed anti-tuberculosis with strain M. tuberculosis. RESULTS: The analysis was based on the binding energy and minimum inhibitory concentration (MIC). The highest and lowest binding energy is -4.22 Kcal/mol (f) and -8.45 Kcal/mol (d), and the MIC for compound d was found to be 644.22 nM. Among all the ligands, compound 5d has the most cytotoxic effect and lower IC50 values and better bioavailability. CONCLUSION: This investigation helps in the development of better anti-tubercular therapy.

Phage Display's Prospects for Early Diagnosis of Prostate Cancer.

Prostate cancer (PC) is the second most diagnosed cancer among men. It was observed that early diagnosis of disease is highly beneficial for the survival of cancer patients. Therefore, the extension and increasing quality of life of PC patients can be achieved by broadening the cancer screening programs that are aimed at the identification of cancer manifestation in patients at earlier stages, before they demonstrate well-understood signs of the disease. Therefore, there is an urgent need for standard, sensitive, robust, and commonly available screening and diagnosis tools for the identification of early signs of cancer pathologies. In this respect, the "Holy Grail" of cancer researchers and bioengineers for decades has been molecular sensing probes that would allow for the diagnosis, prognosis, and monitoring of cancer diseases via their interaction with cell-secreted and cell-associated PC biomarkers, e.g., PSA and PSMA, respectively. At present, most PSA tests are performed at centralized laboratories using high-throughput total PSA immune analyzers, which are suitable for dedicated laboratories and are not readily available for broad health screenings. Therefore, the current trend in the detection of PC is the development of portable biosensors for mobile laboratories and individual use. Phage display, since its conception by George Smith in 1985, has emerged as a premier tool in molecular biology with widespread application. This review describes the role of the molecular evolution and phage display paradigm in revolutionizing the methods for the early diagnosis and monitoring of PC.

Head-to-head comparison of prostate health index and urinary PCA3 for predicting cancer at initial or repeat biopsy.

PURPOSE: We performed a head-to-head comparison of the PHI (Prostate Health Index) and PCA3. MATERIALS AND METHODS: We evaluated PHI and PCA3 performance in 211 patients undergoing initial (116) or repeat (95) prostate biopsy. Multivariable logistic regression analysis was done using the AUC to test the accuracy of PHI and PCA3 for predicting prostate cancer in the overall population and in each setting. Decision curve analysis was used to compare the clinical benefit of different models. RESULTS: Overall, the AUC of the PHI (0.70) was significantly higher than the AUC of PCA3 (0.59), total prostate specific antigen (0.56) and free-to-total prostate specific antigen (0.60) (p = 0.043, 0.002 and 0.037, respectively). PHI was more accurate than PCA3 for predicting prostate cancer in the initial setting (AUC 0.69 vs 0.57) and in the repeat setting (AUC 0.72 vs 0.63), although no statistically significant difference was observed. Including PCA3 in the base multivariable model (prostate specific antigen plus free-to-total prostate specific antigen plus prostate volume) did not increase predictive accuracy in either setting (AUC 0.79 vs 0.80 and 0.75 vs 0.76, respectively). Conversely, including PHI in the base multivariable model improved predictive accuracy by 5% (AUC 0.79 to 0.84) and 6% (AUC 0.75 to 0.81) in the initial and repeat prostate biopsy settings, respectively. On decision curve analysis the highest net benefit was observed when PHI was added to the base multivariable model. CONCLUSIONS: PHI and PCA3 provide a significant increase in sensitivity and specificity compared to all other examined markers and they may help guide biopsy decisions. PCA3 does not increase the accuracy of predicting prostate cancer when PHI is assessed.

Comparative effectiveness review: prostate cancer antigen 3 testing for the diagnosis and management of prostate cancer.

PURPOSE: We compared the effectiveness of PCA3 (prostate cancer antigen 3) and select comparators for improving initial or repeat biopsy decision making in men at risk for prostate cancer, or treatment choices in men with prostate cancer. MATERIALS AND METHODS: MEDLINE®, EMBASE®, Cochrane Database and gray literature were searched from January 1990 through May 2012. Included studies were matched, and measured PCA3 and comparator(s) within a cohort. No matched analyses were possible. Differences in independent performance estimates between PCA3 and comparators were computed within studies. Studies were assessed for quality using QUADAS (Quality Assessment of Diagnostic Accuracy Studies) and for strength of evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. RESULTS: Among 1,556 publications identified, 34 observational studies were analyzed (24 addressed diagnostic accuracy and 13 addressed treatment decisions). Most studies were conducted in opportunistic cohorts of men referred for procedures and were not designed to answer key questions. Two study biases (partial verification and sampling) were addressed by analyses, allowing some conclusions to be drawn. PCA3 was more discriminatory than total prostate specific antigen increases (eg at an observed 50% specificity, summary sensitivities were 77% and 57%, respectively). Analyses indicated that this finding holds for initial and repeat biopsies, and that the markers were independent predictors. For all other biopsy decision making comparisons and associated health outcomes, strength of evidence was insufficient. For treatment decision making, strength of evidence was insufficient for all outcomes and comparators. CONCLUSIONS: PCA3 had a higher diagnostic accuracy than total prostate specific antigen increases, but strength of evidence was low (limited confidence in effect estimates). Strength of evidence was insufficient to conclude that PCA3 testing leads to improved health outcomes. For all other outcomes and comparators, strength of evidence was insufficient.

SRD5A1 and SRD5A2 are associated with treatment for benign prostatic hyperplasia with the combination of 5α-reductase inhibitors and α-adrenergic receptor antagonists.

PURPOSE: Common treatments for benign prostatic hyperplasia include 5α-reductase inhibitors and α-adrenergic receptor antagonists. However, these treatments can only partially decrease the risk of benign prostatic hyperplasia progression. SRD5A1 and SRD5A2 are 5α-reductase inhibitor targets. We investigated the association between drug efficacy and single nucleotide polymorphisms in the SRD5A1 and SRD5A2 genes in a Chinese population. MATERIALS AND METHODS: We genotyped 11 tagging single nucleotide polymorphisms in the SRD5A1 and SRD5A2 genes in a total of 426 benign prostatic hyperplasia cases and 1,008 controls from Xinhua Hospital, Shanghai, People's Republic of China. Cases were treated with type II 5α-reductase inhibitors and α-adrenergic receptor antagonists. We tested the association of tagging single nucleotide polymorphisms with benign prostatic hyperplasia risk/progression, clinical characteristics at baseline, including the I-PSS (International Prostate Symptom Score) and total prostate volume, and changes in clinical characteristics after treatment. RESULTS: The 11 tagging single nucleotide polymorphisms were not significantly associated with benign prostatic hyperplasia risk or progression (each p >0.05). In the SRD5A1 gene rs6884552 and rs3797177 were significantly associated with baseline I-PSS (p = 0.04 and 0.003, respectively). In the SRD5A2 gene rs523349 (V89L) and rs9332975 were significantly associated with baseline total prostate volume (p = 0.01 and 0.001, respectively). In SRD5A1 rs166050 was significantly associated with the posttreatment change in total prostate volume (p = 0.04). In SRD5A2 rs523349 and rs612224 were significantly associated with the posttreatment I-PSS change (p = 0.03 and 0.009, respectively). CONCLUSIONS: SRD5A1 and SRD5A2 single nucleotide polymorphisms are significantly associated with the clinical characteristics of benign prostatic hyperplasia and the efficacy of benign prostatic hyperplasia treatment.

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs.

3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4ß2(∗) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4ß2(∗) nAChR. All evaluated compounds are partial agonists or antagonists at α4ß2(∗), with reduced or no effects on α3ß4(∗) with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.