Strategies for the development of tdm for targeted anticancer agents

Most of the novel targeted anticancer agents share classical characteristics that define drugs as candidates for blood concentration monitoring: long-term therapy; high interindividual but restricted intraindividual variability; significant drug-drug and drug- food interactions; correlations between concentration and efficacy/ toxicity with rather narrow therapeutic index; reversibility of effects; and absence of early markers of response. Surprisingly though, therapeutic concentration monitoring has received little attention for these drugs despite reiterated suggestions from clinical pharmacologists. Several issues explain the lack of clinical research and development in this field: global tradition of empiricism regarding treatment monitoring, lack of formal conceptual framework, ethical difficulties in the elaboration of controlled clinical trials, disregard from both drug manufacturers and public funders, limited encouragement from regulatory authorities, and practical hurdles making dosage adjustment based on concentration monitoring a difficult task for prescribers. However, new technologies are soon to help us overcome these obstacles, with the advent of miniaturized measurement devices able to quantify circulating drug concentrations at the point-of-care, to evaluate their plausibility given actual dosage and sampling time, to determine their appropriateness with reference to therapeutic targets, and to advise on suitable dosage adjustment. Such evolutions could bring conceptual changes into the clinical development of drugs such as anticancer agents, while increasing the therapeutic impact of population PK-PD studies and systematic reviews. Research efforts in that direction from the clinical pharmacology community will be essential for patients to receive the greatest benefits and the least harm from new anticancer treatments. The example of imatinib, the first commercialized tyrosine kinase inhibitor, will be outlined to illustrate a potential research agenda for the rational development of therapeutic concentration monitoring.

Reconciling global mammal prioritization schemes into a strategy.

The huge conservation interest that mammals attract and the large datasets that have been collected on them have propelled a diversity of global mammal prioritization schemes, but no comprehensive global mammal conservation strategy. We highlight some of the potential discrepancies between the schemes presented in this theme issue, including: conservation of species or areas, reactive and proactive conservation approaches, conservation knowledge and action, levels of aggregation of indicators of trend and scale issues. We propose that recently collected global mammal data and many of the mammal prioritization schemes now available could be incorporated into a comprehensive global strategy for the conservation of mammals. The task of developing such a strategy should be coordinated by a super-partes, authoritative institution (e.g. the International Union for Conservation of Nature, IUCN). The strategy would facilitate funding agencies, conservation organizations and national institutions to rapidly identify a number of short-term and long-term global conservation priorities, and act complementarily to achieve them.

Thyroid cancer mortality and incidence: a global overview.

In most areas of the world, thyroid cancer incidence has been appreciably increasing over the last few decades, whereas mortality has steadily declined. We updated global trends in thyroid cancer mortality and incidence using official mortality data from the World Health Organization (1970-2012) and incidence data from the Cancer Incidence in Five Continents (1960-2007). Male mortality declined in all the major countries considered, with annual percent changes around -2/-3% over the last decades. Only in the United States mortality declined up to the mid 1980s and increased thereafter. Similarly, in women mortality declined in most countries considered, with APCs around -2/-5% over the last decades, with the exception of the UK, the United States and Australia, where mortality has been declining up to the late 1980s/late 1990s to level off (or increase) thereafter. In 2008-2012, most countries had mortality rates (age-standardized, world population) between 0.20 and 0.40/100,000 men and 0.20 and 0.60/100,000 women, the highest rates being in Latvia, Hungary, the Republic of Moldova and Israel (over 0.40/100,000) for men and in Ecuador, Colombia and Israel (over 0.60/100,000) for women. In most countries, a steady increase in the incidence of thyroid cancer (mainly papillary carcinomas) was observed in both sexes. The declines in thyroid cancer mortality reflect both variations in risk factor exposure and changes in the diagnosis and treatment of the disease, while the increases in the incidence are likely due to the increase in the detection of this neoplasm over the last few decades.

Differential effects of glutamate transporter inhibitors on the global electrophysiological response of astrocytes to neuronal stimulation

Astrocytes are responsible for regulating extracellular levels of glutamate and potassium during neuronal activity. Glutamate clearance is handled by glutamate transporter subtypes glutamate transporter 1 and glutamate-aspartate transporter in astrocytes. DL-threo-beta-benzyloxyaspartate (TBOA) and dihydrokainate (DHK) are extensively used as inhibitors of glial glutamate transport activity. Using whole-cell recordings, we characterized the effects of both transporter inhibitors on afferent-evoked astrocyte currents in acute cortical slices of 3-week-old rats. When neuronal afferents were stimulated, passive astrocytes responded by a rapid inward current followed by a persistent tail current. The first current corresponded to a glutamate transporter current. This current was inhibited by both inhibitors and by tetrodotoxin. The tail current is an inward potassium current as it was blocked by barium. Besides inhibiting transporter currents, TBOA strongly enhanced the tail current. This effect was barium-sensitive and might be due to a rise in extracellular potassium level and increased glial potassium uptake. Unlike TBOA, DHK did not enhance the tail current but rather inhibited it. This result suggests that, in addition to inhibiting glutamate transport, DHK prevents astrocyte potassium uptake, possibly by blockade of inward-rectifier channels. This study revealed that, in brain slices, glutamate transporter inhibitors exert complex effects that cannot be attributed solely to glutamate transport inhibition.

Managing Social-Business Tensions: A Review and Research Agenda for Social Enterprise

In a world filled with poverty, environmental degradation, and moral injustice, social enterprises offer a ray of hope. These organizations seek to achieve social missions through business ventures. Yet social missions and business ventures are associated with divergent goals, values, norms, and identities. Attending to them simultaneously creates tensions, competing demands, and ethical dilemmas. Effectively understanding social enterprises therefore depends on insight into the nature and management of these tensions. While existing research recognizes tensions between social missions and business ventures, we lack any systematic analysis. Our paper addresses this issue. We first categorize the types of tensions that arise between social missions and business ventures, emphasizing their prevalence and variety. We then explore how four different organizational theories offer insight into these tensions, and we develop an agenda for future research. We end by arguing that a focus on social-business tensions not only expands insight into social enterprises, but also provides an opportunity for research on social enterprises to inform traditional organizational theories. Taken together, our analysis of tensions in social enterprises integrates and seeks to energize research on this expanding phenomenon.

Assessment of speed of human locomotion using a differential satellite global positioning system.

PURPOSE: The objective was to explore whether a satellite-based navigation system, global positioning system used in differential mode (DGPS), could accurately assess the speed of running in humans. METHODS: A subject was equipped with a portable GPS receptor coupled to a receiver for differential corrections, while running outdoors on a straight asphalt road at 27 different speeds. Actual speed (reference method) was assessed by chronometry. RESULTS: The accuracy of speed prediction had a standard deviation (SD) of 0.08 km x h(-1) for walking, 0.11 km x h(-1) for running, yielding a coefficient of variation (SD/mean) of 1.38% and 0.82%, respectively. There was a highly significant linear relationship between actual and DGPS speed assessment (r2 = 0.999) with little bias in the prediction equation, because the slope of the regression line was close to unity (0.997). CONCLUSION: the DGPS technique appears to be a valid and inconspicuous tool for "on line" monitoring of the speed of displacement of individuals located on any field on earth, for prolonged periods of time and unlimited distance, but only in specific environmental conditions ("open sky"). Furthermore, the accuracy of speed assessment using the differential GPS mode was improved by a factor of 10 as compared to non-differential GPS.

Early attentional processes distinguish selective from global motor inhibitory control : An electrical neuroimaging study

The rapid stopping of specific parts of movements is frequently required in daily life. Yet, whether selective inhibitory control of movements is mediated by a specific neural pathway or by the combination between a global stopping of all ongoing motor activity followed by the re-initiation of task-relevant movements remains unclear. To address this question, we applied time-wise statistical analyses of the topography, global field power and electrical sources of the event-related potentials to the global vs selective inhibition stimuli presented during a Go/NoGo task. Participants (n = 18) had to respond as fast as possible with their two hands to Go stimuli and to withhold the response from the two hands (global inhibition condition, GNG) or from only one hand (selective inhibition condition, SNG) when specific NoGo stimuli were presented. Behaviorally, we replicated previous evidence for slower response times in the SNG than in the Go condition. Electrophysiologically, there were two distinct phases of event-related potentials modulations between the GNG and the SNG conditions. At 110âeuro"150 ms post-stimulus onset, there was a difference in the strength of the electric field without concomitant topographic modulation, indicating the differential engagement of statistically indistinguishable configurations of neural generators for selective and global inhibitory control. At 150âeuro"200 ms, there was topographic modulation, indicating the engagement of distinct brain networks. Source estimations localized these effects within bilateral temporo-parieto-occipital and within parieto-central networks, respectively. Our results suggest that while both types of motor inhibitory control depend on global stopping mechanisms, selective and global inhibition still differ quantitatively at early attention-related processing phases.

Forecasting the effects of global warming on biodiversity

The demand for accurate forecasting of the effects of global warming on biodiversity is growing, but current methods for forecasting have limitations. in this article, we compare and discuss the different uses of four forecasting methods: (1) models that consider species individually, (2) niche-theory models that group species by habitat (more specifically, by environmental conditions under which a species can persist or does persist), (3) general circulation models and coupled ocean-atmosphere-biosphere models, and (4) specics-area curve models that consider all species or large aggregates of species. After outlining the different uses and limitations of these methods, we make eight primary suggestions for improving forecasts. We find that greater use of the fossil record and of modern genetic studies would improve forecasting methods. We note a Quaternary conundrum: While current empirical and theoretical ecological results suggest that many species could be at risk from global warming, during the recent ice ages surprisingly few species became extinct. The potential resolution of this conundrum gives insights into the requirements for more accurate and reliable forecasting. Our eight suggestions also point to constructive synergies in the solution to the different problems.