Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer

ObjectivesIn patients with a rising prostate-specific antigen (PSA) level during treatment with androgen deprivation therapy, identification of men who progress to bone metastasis and death remains problematic. Accurate risk stratification models are needed to better predict risk for bone metastasis and death among patients with castration-resistant prostate cancer (CRPC). This study evaluates whether alkaline phosphatase (AP) kinetics predicts bone metastasis and death in patients with CRPC.Methods and materialsA retrospective cohort study of 9,547 patients who underwent treatment for prostate cancer was conducted using the Center for Prostate Disease Research Multi-center National Database. From the entire cohort, 347 were found to have CRPC and, of those, 165 had 2 or more AP measurements during follow-up. To determine the AP velocity (APV), the slope of the linear regression line of all AP values was plotted over time. Rapid APV was defined as the uppermost quartile of APV values, which was found to be ≥6.3 IU/l/y. CRPC was defined as 2 consecutive rising PSA values after achieving a PSA nadir<4 ng/ml and documented testosterone values less than 50 ng/dl. The primary study outcomes included bone metastasis–free survival (BMFS) and overall survival (OS).ResultsRapid APV and PSA doubling time (PSADT) less than 10 months were strong predictors of both BMFS and OS in a multivariable analysis. Faster PSADT was a stronger predictor for BMFS (odds ratio [OR] = 12.1, P<0.0001 vs. OR = 2.7, P = 0.011), whereas rapid APV was a stronger predictor of poorer OS (OR = 5.11, P = 0.0001 vs. OR = 3.98, P = 0.0034). In those with both a rapid APV and a faster PSADT, the odds of developing bone metastasis and death exceeded 50%.ConclusionAPV is an independent predictor of OS and BMFS in patients with CRPC. APV, in conjunction with PSA-based clinical parameters, may be used to better identify patients with CRPC who are at the highest risk of metastasis and death. These findings need validation in prospective studies.     

Isolation,synthesis and characterization of ω-TRTX-Cc1a,a novel tarantula venom peptide that selectively targets L-type CaV channels

Spider venoms are replete with peptidic ion channel modulators, often with novel subtype selectivity, making them a rich source of pharmacological tools and drug leads. In a search for subtype-selective blockers of voltage-gated calcium (Ca_V) channels, we isolated and characterized a novel 39-residue peptide, ω-TRTX-Cc1a (Cc1a), from the venom of the tarantula Citharischius crawshayi (now Pelinobius muticus). Cc1a is 67% identical to the spider toxin ω-TRTX-Hg1a, an inhibitor of Ca_V2.3 channels. We assembled Cc1a using a combination of Boc solid-phase peptide synthesis and native chemical ligation. Oxidative folding yielded two stable, slowly interconverting isomers. Cc1a preferentially inhibited Ba²⁺ currents (I_Ba) mediated by L-type (Ca_V1.2 and Ca_V1.3) Ca_V channels heterologously expressed in Xenopus oocytes, with half-maximal inhibitory concentration (IC₅₀) values of 825 nM and 2.24 μM, respectively. In rat dorsal root ganglion neurons, Cc1a inhibited I_Ba mediated by high voltage-activated Ca_V channels but did not affect low voltage-activated T-type Ca_V channels. Cc1a exhibited weak activity at Na_V1.5 and Na_V1.7 voltage-gated sodium (Na_V) channels stably expressed in mammalian HEK or CHO cells, respectively. Experiments with modified Cc1a peptides, truncated at the N-terminus (ΔG1–E5) or C-terminus (ΔW35–V39), demonstrated that the N- and C-termini are important for voltage-gated ion channel modulation. We conclude that Cc1a represents a novel pharmacological tool for probing the structure and function of L-type Ca_V channels.     

Respiratory effects of buprenorphine/naloxone alone and in combination with diazepam in naive and tolerant rats

Respiratory depression has been attributed to buprenorphine (BUP) misuse or combination with benzodiazepines. BUP/naloxone (NLX) has been marketed as maintenance treatment, aiming at preventing opiate addicts from self-injecting crushed pills. However, to date, BUP/NLX benefits in comparison to BUP alone remain debated. We investigated the plethysmography effects of BUP/NLX in comparison to BUP/solvent administered by intravenous route in naive and BUP-tolerant Sprague-Dawley rats, and in combination with diazepam (DZP) or its solvent. In naive rats, BUP/NLX in comparison to BUP significantly increased respiratory frequency (f, P < 0.05) without altering minute volume (V_E). In combination to DZP, BUP/NLX significantly increased expiratory time (P < 0.01) and decreased f (P < 0.01), tidal volume (V_T, P < 0.001), and V_E (P < 0.001) while BUP only decreased V_T (P < 0.5). In BUP-tolerant rats, no significant differences in respiratory effects were observed between BUP/NLX and BUP. In contrast, in combination to DZP, BUP/NLX did not significantly alter the plethysmography parameters, while BUP increased inspiratory time (P < 0.001) and decreased f (P < 0.01) and V_E (P < 0.001). In conclusion, differences in respiratory effects between BUP/NLX and BUP are only significant in combination with DZP, with increased depression in naive rats but reduced depression in BUP-tolerant rats. However, BUP/NLX benefits in humans remain to be determined.     

检测血流加速时间在妊娠期高血压中的应用

目的通过分析子宫动脉、脐动脉、胎儿大脑中动脉的血流加速时间,结合围产儿预后,探讨加速时间在妊娠期高血压疾病中的应用价值。方法应用彩色多普勒超声技术,对90例妊娠期高血压疾病孕妇和90例同孕周无年龄差别的正常孕妇对照研究,妊娠期高血压疾病孕妇分为妊娠期高血压组、轻度子痫前期组和重度子痫前期组。依次测定子宫动脉、脐动脉、胎儿大脑中动脉的加速时间（acceleration time,AT）,妊娠期高血压疾病患者围产儿分为预后不良组和预后良好组,采用方差分析或t检验比较加速时间在各组中的变化。结果正常妊娠子宫动脉、脐动脉和大脑中动脉AT值均随孕周的增加而延长;子宫动脉AT值、脐动脉AT值在轻度子痫前期组和重度子痫前期组均缩短（P〈0．01）,而大脑中动脉AT值延长（P〈0．01）;预后不良组与预后良好组比较子宫动脉、脐动脉AT值缩短,大脑中动脉AT值延长,各组间比较差异均有统计学意义。结论妊娠期高血压疾病患者血流加速时间发生明显变化,这种变化与妊高征胎儿的预后密切相关。     

Area under the concentration–time curve to minimum inhibitory concentration ratio as a predictor of vancomycin treatment outcome in methicillin-resistant Staphylococcus aureus bacteraemia

There have been few clinical studies on the association between the 24-h area under the concentration–time curve (AUC₂₄) to minimum inhibitory concentration (MIC) ratio and vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus (MRSA) infections. Patients with MRSA bacteraemia between July 2009 and January 2012 were analysed retrospectively. All adult patients treated with vancomycin for ≥72 h without dialysis were included. The MIC was determined by Etest and broth microdilution (BMD). Initial steady-state AUC₂₄ was estimated using a Bayesian model, and the AUC₂₄/MIC cut-off value for differentiating treatment success and failure was calculated by classification and regression tree (CART) analysis. In total, 76 patients were enrolled; vancomycin treatment failure occurred in 20 patients (26.3%). Catheter-related infection was the most frequent (35.5%), followed by surgical site infection (26.3%), whilst 25 (32.9%) had complicated infections. In univariate analysis, decreased MRSA vancomycin susceptibility (MIC ≥ 1.5 mg/L) and vancomycin trough levels (15–20 mg/L) were not associated with treatment outcomes. In the CART analysis, low initial vancomycin AUC₂₄/MIC (<430 by Etest; <398.5 by BMD) was associated with a higher treatment failure rate (50.0% vs. 25.0%, P = 0.039 by Etest; 45.0% vs. 23.2%; P = 0.065 by BMD). In multivariate analysis, low initial vancomycin AUC₂₄/MIC was a significant risk factor for treatment failure [adjusted odds ratio (aOR) = 4.39, 95% confidence interval (CI), 1.26–15.35 by Etest; aOR = 3.73, 95% CI 1.10–12.61 by BMD]. In MRSA bacteraemia, a low initial vancomycin AUC₂₄/MIC is an independent risk factor for vancomycin treatment failure.     

Residence time modeling of hot melt extrusion processes

The hot melt extrusion process is a widespread technique to mix viscous melts. The residence time of material in the process frequently determines the product properties. An experimental setup and a corresponding mathematical model were developed to evaluate residence time and residence time distribution in twin screw extrusion processes.The extrusion process was modeled as the convolution of a mass transport process described by a Gaussian probability function, and a mixing process represented by an exponential function. The residence time of the extrusion process was determined by introducing a tracer at the extruder inlet and measuring the tracer concentration at the die. These concentrations were fitted to the residence time model, and an adequate correlation was found. Different parameters were derived to characterize the extrusion process including the dead time, the apparent mixing volume, and a transport related axial mixing. A 2³ design of experiments was performed to evaluate the effect of powder feed rate, screw speed, and melt viscosity of the material on the residence time. All three parameters affect the residence time of material in the extruder.In conclusion, a residence time model was developed to interpret experimental data and to get insights into the hot melt extrusion process.