Reflections on the responsible conduct of cancer research

Most cancer researchers regularly practice the responsible conduct of research (RCR) without consciously considering it. As professional scientists, we simply do what we are trained to do. However, as we train a new generation of cancer researchers in our laboratories, we must be vigilant against undue complacency. In an age when misconduct in research is receiving more media attention than ever before, we should periodically take a moment of pause and reflect upon the meaning and practice of responsibly conducting research. Rather than meeting minimum standards in a compliance-driven manner, we should practice forethought and periodically consider how we can improve. We, as leaders in cancer research, must then push our peers to do the same. By embedding RCR into the culture of cancer research through a multilayer approach, including regular assessment at the levels of individual research groups, departmentally, and institutionally, we will become a model discipline in the responsible conduct of research

Prevention and Management of Bone Metastases in Lung Cancer: A Review

Abstract:Approximately 30 to 40% of patients with advanced lung cancer will develop bone metastases in the course of their disease, resulting in a significant negative impact on both morbidity and survival. Skeletal complications of bone metastases include pain, pathologic fractures, spinal cord compression, and hypercalcemia. Total medical care costs are greater among patients with bone metastases who develop skeletal complications. A randomized phase III trial of the third generation bisphosphonate zoledronic acid has shown clinical benefit in the management of a subgroup of patients with bone metastases from lung cancer. Zoledronic acid treatment was associated with a reduction in both the risk of, and time to, a skeletal-related event. One of the markers of bone resorption, N-telopeptide, is both prognositic for development of skeletal-related events and predictive for benefit from zoledronic acid. In preclinical models, bisphosphonates have also demonstrated antitumor activity and are therefore currently being evaluated in adjuvant trials. Inhibition of the receptor activator of nuclear factor kappa B ligand-RANK pathway can reduce osteoclast-mediated bone resorption, and trials comparing receptor activator of nuclear factor kappa B ligand inhibitors with bisphosphonates are ongoing, including patients with lung cancer. In this article, we review the management of bone metastases and hypercalcemia as well as potential future directions for bone directed therapies in patients with lung cancer

First principles predictions of thermophysical properties of refrigerant mixtures

We present pair potentials for fluorinated methanes and their dimers with CO2 based on ab initio potential energy surfaces. These potentials reproduce the experimental second virial coefficients of the pure fluorinated methanes and their mixtures with CO2 without adjustment. Ab initio calculations on trimers are used to model the effects of nonadditive dispersion and induction. Simulations using these potentials reproduce the experimental phase-coexistence properties of CH3F within 10% over a wide range of temperatures. The phase coexistence curve of the mixture of CH2F2 and CO2 is reproduced with an error in the mole fractions of both phases of less than 0.1. The potentials described here are based entirely on ab initio calculations, with no empirical fits to improve the agreement with experiment

Chemical immobilization of adult female Weddell seals with tiletamine and zolazepam: effects of age, condition and stage of lactation

BACKGROUND: Chemical immobilization of Weddell seals (Leptonychotes weddellii) has previously been, for the most part, problematic and this has been mainly attributed to the type of immobilizing agent used. In addition to individual sensitivity, physiological status may play an important role. We investigated the use of the intravenous administration of a 1:1 mixture of tiletamine and zolazepam (Telazol(®)) to immobilize adult females at different points during a physiologically demanding 5–6 week lactation period. We also compared performance between IV and IM injection of the same mixture. RESULTS: The tiletamine:zolazepam mixture administered intravenously was an effective method for immobilization with no fatalities or pronounced apnoeas in 106 procedures; however, there was a 25 % (one animal in four) mortality rate with intramuscular administration. Induction time was slightly longer for females at the end of lactation (54.9 ± 2.3 seconds) than at post-parturition (48.2 ± 2.9 seconds). In addition, the number of previous captures had a positive effect on induction time. There was no evidence for effects due to age, condition (total body lipid), stage of lactation or number of captures on recovery time. CONCLUSION: We suggest that intravenous administration of tiletamine and zolazepam is an effective and safe immobilizing agent for female Weddell seals. Although individual traits could not explain variation in recovery time, we suggest careful monitoring of recovery times during longitudinal studies (> 2 captures). We show that physiological pressures do not substantially affect response to chemical immobilization with this mixture; however, consideration must be taken for differences that may exist for immobilization of adult males and juveniles. Nevertheless, we recommend a mass-specific dose of 0.50 – 0.65 mg/kg for future procedures with adult female Weddell seals and a starting dose of 0.50 mg/kg for other age classes and other phocid seals

A broad introduction to the design and construction of biosafety laboratories in low-resource settings : enhancement of CBRN capacities of South East Asia in addressing CBRN risk mitigation concerning CBRN first response, biosafety and biosecurity, awareness raising and legal framework

Resumen: Las ciencias de la vida cubren una amplia gama de actividades relacionadas con los organismos vivos. Muchas de estas actividades se llevan a cabo en laboratorios de diagnóstico o investigación u otras instalaciones especializadas, como instalaciones de alojamiento de animales, unidades de cuarentena, invernaderos o instalaciones de producción biológica. Y muchas de estas actividades implican el uso de organismos y otros materiales biológicos que pueden presentar un peligro para las personas que los manipulan, pero también para la comunidad exterior o el medio ambiente, es decir, principalmente animales o plantas, en caso de escape y diseminación. La bioseguridad, y más ampliamente la gestión del riesgo biológico, tiene como objetivo prevenir, limitar o, en términos más generales, controlar estos riesgos. El enfoque de gestión del riesgo biológico se basa en una serie de medidas que involucran prácticas laborales, protección personal, infraestructura de contención y prácticas de gestión. Los propósitos de este primer capítulo son explicar las principales nociones y principios que los arquitectos e ingenieros que puedan trabajar en este campo en particular deben conocer y comprender, y presentar las principales referencias y puntos de vista adoptados en este folleto

Single molecule binding of a ligand to a G-protein-coupled receptor in real time using fluorescence correlation spectroscopy, rendered possible by nano-encapsulation in styrene maleic acid lipid particles

The fundamental importance of membrane proteins in cellular processes has driven a marked increase in the use of membrane mimetic approaches for studying and exploiting these proteins. Nano-encapsulation strategies which preserve the native lipid bilayer environment are particularly attractive. Consequently, the use of poly(styrene co-maleic acid) (SMA) has been widely adopted to solubilise proteins directly from cell membranes by spontaneously forming "SMA Lipid Particles" (SMALPs). G-protein-coupled receptors (GPCRs) are ubiquitous "chemical switches", are central to cell signalling throughout the evolutionary tree, form the largest family of membrane proteins in humans and are a major drug discovery target. GPCR-SMALPs that retain binding capability would be a versatile platform for a wide range of down-stream applications. Here, using the adenosine A2A receptor (A2AR) as an archetypical GPCR, we show for the first time the utility of fluorescence correlation spectroscopy (FCS) to characterise the binding capability of GPCRs following nano-encapsulation. Unbound fluorescent ligand CA200645 exhibited a monophasic autocorrelation curve (dwell time, τD = 68 ± 2 μs; diffusion coefficient, D = 287 ± 15 μm2 s-1). In the presence of A2AR-SMALP, bound ligand was also evident (τD = 625 ± 23 μs; D = 30 ± 4 μm2 s-1). Using a non-receptor control (ZipA-SMALP) plus competition binding confirmed that this slower component represented binding to the encapsulated A2AR. Consequently, the combination of GPCR-SMALP and FCS is an effective platform for the quantitative real-time characterisation of nano-encapsulated receptors, with single molecule sensitivity, that will have widespread utility for future exploitation of GPCR-SMALPs in general

Interactions between RAMP2 and CRF receptors: The effect of receptor subtypes, splice variants and cell context.

Corticotrophin releasing factor (CRF) acts via two family B G-protein-coupled receptors, CRFR1 and CRFR2. Additional subtypes exist due to alternative splicing. CRFR1α is the most widely expressed subtype and lacks a 29-residue insert in the first intracellular loop that is present in CRFR1β. It has been shown previously that co-expression of CRFR1β with receptor activity modifying protein 2 (RAMP2) in HEK 293S cells increased the cell-surface expression of both proteins suggesting a physical interaction as seen with RAMPs and calcitonin receptor-like receptor (CLR). This study investigated the ability of CRFR1α, CRFR1β and CRFR2β to promote cell-surface expression of FLAG-tagged RAMP2. Four different cell-lines were utilised to investigate the effect of varying cellular context; COS-7, HEK 293T, HEK 293S and [ΔCTR]HEK 293 (which lacks endogenous calcitonin receptor). In all cell-lines, CRFR1α and CRFR1β enhanced RAMP2 cell-surface expression. The magnitude of the effect on RAMP2 was dependent on the cell-line ([ΔCTR]HEK 293 > COS-7 > HEK 293T > HEK 293S). RT-PCR indicated this variation may relate to differences in endogenous RAMP expression between cell types. Furthermore, pre-treatment with CRF resulted in a loss of cell-surface FLAG-RAMP2 when it was co-expressed with CRFR1 subtypes. CRFR2β co-expression had no effect on RAMP2 in any cell-line. Molecular modelling suggests that the potential contact interface between the extracellular domains of RAMP2 and CRF receptor subtypes is smaller than that of RAMP2 and CRL, the canonical receptor:RAMP pairing, assuming a physical interaction. Furthermore, a specific residue difference between CRFR1 subtypes (glutamate) and CRFR2β (histidine) in this interface region may impair CRFR2β:RAMP2 interaction by electrostatic repulsion