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Purpose: Effective enrollment and treatment of patients in cancer clinical trials require definition and coordination of roles and responsibilities among clinic and research personnel., Materials and Methods: We developed a survey that incorporated modified components of the Survey of Physician Attitudes Regarding the Care of Cancer Survivors. Surveys were administered to clinic nursing staff and research personnel at a National Cancer Institute-designated comprehensive cancer center. Results were analyzed using χ 2 -tests, t tests, and analyses of variance., Results: Surveys were completed by 105 staff members (n = 50 research staff, n = 55 clinic staff; 61% response rate). Research staff were more likely to feel that they had the skills to answer questions, convey information, and provide education for patients on trials (all P < .05). Both clinic and research staff reported receipt of communication about responsibilities in fewer than 30% of cases, although research staff reported provision of such information in more than 60% of cases. Among 20 tasks related to care of patients in trials, no single preferred model of responsibility assignment was selected by the majority of clinic staff for nine tasks (45%) or by research staff for three tasks (15%). Uncertainty about which team coordinates care was reported by three times as many clinic staff as research staff ( P = .01). There was also substantial variation in the preferred model for delivery of care to patients in trials ( P < .05)., Conclusion: Knowledge, attitudes, and perception of care and responsibilities for patients on clinical trials differ between and among clinic and research personnel. Additional research about how these findings affect efficiency and quality of care on clinical trials is needed.

This work describes the discovery and characterization of novel 6-(1 H-pyrazolo[4,3- b]pyridin-3-yl)amino-benzo[ d]isothiazole-3-carboxamides as mGlu 4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu 4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC 50 = 50.1 nM, 50.5% GluMax) and selective mGlu 4 PAM with an excellent rat DMPK profile ( in vivo rat CL p = 3.1 mL/min/kg, t 1/2 = 445 min, CYP1A2 IC 50 > 30 μM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.

Three-dimensional vertically aligned nano- and micropillars have emerged as promising tools for a variety of biological applications. Despite their increasing usage, the interaction mechanisms of cells with these rigid structures and their effect on single- and collective-cell behaviors are not well understood for different cell types. In the present study, we examine the response of glioma cells to micropillar arrays using a new microfabricated platform consisting of rigid silicon micropillar arrays of various shapes, sizes, and configurations fabricated on a single platform. We compare collective- and single-cell behaviors at micropillar array interfaces and show that glial cells under identical chemical conditions form distinct arrangements on arrays of different shapes and sizes. Tumor-like aggregation and branching of glial cells only occur on arrays with feature diameters greater than 2 μm, and distinct transitions are observed at interfaces between various arrays on the platform. Additionally, despite the same side-to-side spacing and gaps between micropillars, single glial cells interact with the flat silicon surface in the gap between small pillars but sit on top of larger micropillars. Furthermore, micropillars induced local changes in stress fibers and actin-rich filopodia protrusions as the cells conformed to the shape of spatial cues formed by these micropillars.

This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Opioids have been the mainstay for management of acute postoperative pain for several decades. Extensive use, however, has been associated with multiple side effects. Multimodal approaches that incorporate nonopioid medications and techniques have been observed to achieve optimum pain control whilst decreasing side effects. Such strategies are particularly important to consider for opioid-dependent and tolerant patients with various comorbidities undergoing different types of surgery. This review assesses recent data on nonopioid analgesics for postoperative pain control, highlighting evidence of their safety profiles in contemporary pain management.

Cellular signal transduction occurs in the context of dynamic multiprotein complexes in highly ramified pathways. These complexes in turn interact with the cytoskeleton, protein scaffolds, membranes, lipid rafts, and specific subcellular organelles, contributing to the exquisitely tight regulation of their localization and activity. However, these realities of drug target biology are not addressed by currently available drug discovery platforms. In this article, we describe the use of protein-fragment complementation assays (PCAs) to assess drugs and drug targets in the context of their native environment. The PCA process allows for the detection of protein-protein complexes following the expression of full-length mammalian genes linked in-frame to polypeptide fragments of rationally dissected reporter genes. If cellular activity causes the association of two proteins linked to complementary reporter fragments, the interaction of the proteins of interest enables refolding of the fragments, which can then generate a quantifiable signal. Using a PCA based on a yellow fluorescent protein, we demonstrate that functional (p50/p65) complexes of the heterodimeric nuclear factor-kappaB transcription factor, as well as the transcription factor subunit p65 and its modulator IkappaBalpha, can be visualized and monitored in live cells. We observed similar responses of the PCA assays to the activities of the cognate endogenous proteins, including modulation by known agonists and antagonists. A proof-of-concept high throughput screen was carried out using the p50/p65 cell line, and potent inhibitors of this pathway were identified. These assays record the dynamic activity of signaling pathways in living cells and in real time, and validate the utility of PCA as a novel approach to drug discovery.