Baseline Glomerular Filtration Rate and Cisplatin- Induced Renal Toxicity in Urothelial Cancer Patients.

BACKGROUND: Cisplatin eligibility for clinical trials has been defined as glomerular filtration rate (GFR) ≥ 60 mL/min due to the risk of nephrotoxicity in patients with renal impairment. For urothelial cancer, substitution of carboplatin instead of cisplatin compromises outcomes. We evaluated change in GFR in patients treated with cisplatin despite baseline GFR < 60 mL/min to determine risk of nephrotoxicity. PATIENTS AND METHODS: Patients treated between 2009 and 2014 at our institution were identified by the institutional review board-approved cystectomy database. GFR percentage change was compared by age (< 75 vs. ≥ 75 years), pretreatment GFR (< 60 vs. ≥ 60 mL/min), therapy setting (neoadjuvant, adjuvant, or metastatic), primary disease site, and comorbidities (diabetes, hypertension, and hyperlipidemia). The associations between overall survival and age or GFR were also assessed. RESULTS: There were 81 patients who received cisplatin-based therapy and whose pre- and posttreatment GFR were available. Median GFR change was -1.6% for patients with pretreatment GFR < 60 mL/min compared to -10.9% for patients with pretreatment GFR ≥ 60 mL/min (P = .17). Therapy setting was the only factor in our study to be significantly associated with GFR change (P = .027). No association was found between overall survival and pre- or posttreatment GFR, GFR percentage change, or age. CONCLUSION: Our data support the hypothesis that urothelial cancer patients with GFR < 60 mL/min do not experience a greater decline in renal function after cisplatin compared to patients with GFR ≥ 60 mL/min. If validated, this may extend the option of cisplatin-based therapy to previously ineligible patients.

Phosphorylation of Complexin by PKA Regulates Activity-Dependent Spontaneous Neurotransmitter Release and Structural Synaptic Plasticity.

Synaptic plasticity is a fundamental feature of the nervous system that allows adaptation to changing behavioral environments. Most studies of synaptic plasticity have examined the regulated trafficking of postsynaptic glutamate receptors that generates alterations in synaptic transmission. Whether and how changes in the presynaptic release machinery contribute to neuronal plasticity is less clear. The SNARE complex mediates neurotransmitter release in response to presynaptic Ca(2+) entry. Here we show that the SNARE fusion clamp Complexin undergoes activity-dependent phosphorylation that alters the basic properties of neurotransmission in Drosophila. Retrograde signaling following stimulation activates PKA-dependent phosphorylation of the Complexin C terminus that selectively and transiently enhances spontaneous release. Enhanced spontaneous release is required for activity-dependent synaptic growth. These data indicate that SNARE-dependent fusion mechanisms can be regulated in an activity-dependent manner and highlight the key role of spontaneous neurotransmitter release as a mediator of functional and structural plasticity.

Estimation of the inter- and intrasubject variability of the diurnal serum cortisol rhythm in healthy male subjects to evaluate the biomarker potential for drug target engagement.

OBJECTIVE: Changes in the cortisol diurnal rhythm have been found in neuropsychiatric diseases, including anxiety and depression. The aim of this study was to investigate the reliability and reproducibility of cortisol diurnal rhythm in healthy males, through determination of the inter- and intrasubject variability, to facilitate evaluation of this biomarker for drug target engagement. MATERIALS AND METHODS: This open-label, 2-period study design evaluated serum cortisol release over a 24-hour period in 18 healthy males. A cosinor model was used to model the cortisol diurnal rhythm, and the inter- and intrasubject coefficients of variation (CVs) were calculated across the 2 periods. RESULTS: Three significant cortisol concentration peaks were observed at ~7 AM, 1 PM, and 7 PM. The intersubject CVs (%) for the amplitude, acrophase, and midline estimating statistic of rhythm (MESOR) were 18.2, 19.3, and 16.8, respectively. The intrasubject CVs (%) were 11.2, 7.6, and 6.9, respectively. The inter- and intrasubject CVs (%) for the lunch-induced 1 PM peak and the >dinner-induced 7 PM peak were 22.1, 17.3, 44.7, and 22.1 respectively. CONCLUSIONS: Assessment of serum cortisol diurnal rhythm suggests that the amplitude, acrophase, and MESOR, but not the meal-induced peaks, have the potential to be a reliable biomarker in drug development targeting the hypothalamic-pituitary-adrenocortical (HPA) axis.