Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

Background: A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. <p/>Methods: Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). <p/>Results: 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m2. MTD was 10 mg/m2; DLTs at 12 (2/4 patients) and 10 mg/m2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1--10 mg/m2. Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. <p/>Conclusions: TP300 had predictable hematologic toxicity, and diarrhea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage

Twitter mood predicts the stock market

Behavioral economics tells us that emotions can profoundly affect individual behavior and decision-making. Does this also apply to societies at large, i.e., can societies experience mood states that affect their collective decision making? By extension is the public mood correlated or even predictive of economic indicators? Here we investigate whether measurements of collective mood states derived from large-scale Twitter feeds are correlated to the value of the Dow Jones Industrial Average (DJIA) over time. We analyze the text content of daily Twitter feeds by two mood tracking tools, namely OpinionFinder that measures positive vs. negative mood and Google-Profile of Mood States (GPOMS) that measures mood in terms of 6 dimensions (Calm, Alert, Sure, Vital, Kind, and Happy). We cross-validate the resulting mood time series by comparing their ability to detect the public's response to the presidential election and Thanksgiving day in 2008. A Granger causality analysis and a Self-Organizing Fuzzy Neural Network are then used to investigate the hypothesis that public mood states, as measured by the OpinionFinder and GPOMS mood time series, are predictive of changes in DJIA closing values. Our results indicate that the accuracy of DJIA predictions can be significantly improved by the inclusion of specific public mood dimensions but not others. We find an accuracy of 87.6% in predicting the daily up and down changes in the closing values of the DJIA and a reduction of the Mean Average Percentage Error by more than 6%

On misunderstanding Heraclitus: The justice of organisation structure

Writers on organisational change often refer to the cosmology of Heraclitus in their work. Some use these references to support arguments for the constancy and universality of organisational change and the consignment to history of organisational continuity and stability. These writers misunderstand the scope of what Heraclitus said. Other writers focus exclusively on the idea that originated with Heraclitus that the universe is composed of processes and not of things. This idea, which has been particularly associated with Heraclitus’s thought from the time of Plato, does indeed provide a rich source of insights into organisational analysis, not least the current trends towards giving proper attention to processual studies of organisational change. Yet there is some uncertainty as to whether Heraclitus actually said that the universe was composed exclusively of processes rather than things, and even if that was what he thought, he intended his ideas on flux to be understood not in isolation but in the context of other aspects of his cosmology. Writers on organisational change seldom make reference to this wider context. Heraclitus was a rational but also a religious thinker. A central element in his thought was the notion of divine Justice, which to a Greek of his era meant the order of the universe. Remote as his Olympian theology may seem today, it sets a crucial and entirely rational context for understanding his ideas about flux. It means that ideas about continuity and stability were quite as important in Heraclitus’s cosmology as his more commonly quoted ideas about change. This paper sets out an overview of Heraclitus’s philosophy, insofar as it appears to have potential relevance to organisational analysis, and discusses how far it supports or contradicts the ideas that organisational change scholars have drawn from it

An Induced Hypersensitive-Like Response Limits Expression of Foreign Peptides via a Recombinant TMV-Based Vector in a Susceptible Tobacco

BACKGROUND: By using tobacco mosaic virus (TMV)-based vectors, foreign epitopes of the VP1 protein from food-and-month disease virus (FMDV) could be fused near to the C-terminus of the TMV coat protein (CP) and expressed at high levels in susceptible tobacco plants. Previously, we have shown that the recombinant TMV vaccines displaying FMDV VP1 epitopes could generate protection in guinea pigs and swine against the FMDV challenge. Recently, some recombinant TMV, such as TMVFN20 that contains an epitope FN20 from the FMDV VP1, were found to induce local necrotic lesions (LNL) on the inoculated leaves of a susceptible tobacco, Nicotiana tabacum Samsun nn. This hypersensitive-like response (HLR) blocked amplification of recombinant TMVFN20 in tobacco and limited the utility of recombinant TMV vaccines against FMDV. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigate the molecular mechanism of the HLR in the susceptible Samsun nn. Histochemical staining analyses show that these LNL are similar to those induced in a resistant tobacco Samsun NN inoculated with wild type (wt) TMV. The recombinant CP subunits are specifically related to the HLR. Interestingly, this HLR in Samsun nn (lacking the N/N'-gene) was able to be induced by the recombinant TMV at both 25°C and 33°C, whereas the hypersensitive response (HR) in the resistant tobacco plants induced by wt TMV through the N/N'-gene pathways only at a permissive temperature (below 30°C). Furthermore, we reported for the first time that some of defense response (DR)-related genes in tobacco were transcriptionally upregulated during HLR. CONCLUSIONS: Unlike HR, HLR is induced in the susceptible tobacco through N/N'-gene independent pathways. Induction of the HLR is associated with the expression of the recombinant CP subunits and upregulation of the DR-related genes

Tactile thermal oral stimulation increases the cortical representation of swallowing

<p>Abstract</p> <p>Background</p> <p>Dysphagia is a leading complication in stroke patients causing aspiration pneumonia, malnutrition and increased mortality. Current strategies of swallowing therapy involve on the one hand modification of eating behaviour or swallowing technique and on the other hand facilitation of swallowing with the use of pharyngeal sensory stimulation. Thermal tactile oral stimulation (TTOS) is an established method to treat patients with neurogenic dysphagia especially if caused by sensory deficits. Little is known about the possible mechanisms by which this interventional therapy may work. We employed whole-head MEG to study changes in cortical activation during self-paced volitional swallowing in fifteen healthy subjects with and without TTOS. Data were analyzed by means of synthetic aperture magnetometry (SAM) and the group analysis of individual SAM data was performed using a permutation test.</p> <p>Results</p> <p>Compared to the normal swallowing task a significantly increased bilateral cortical activation was seen after oropharyngeal stimulation. Analysis of the chronological changes during swallowing suggests facilitation of both the oral and the pharyngeal phase of deglutition.</p> <p>Conclusion</p> <p>In the present study functional cortical changes elicited by oral sensory stimulation could be demonstrated. We suggest that these results reflect short-term cortical plasticity of sensory swallowing areas. These findings facilitate our understanding of the role of cortical reorganization in dysphagia treatment and recovery.</p

Carnivore Translocations and Conservation: Insights from Population Models and Field Data for Fishers (Martes pennanti)

Translocations are frequently used to restore extirpated carnivore populations. Understanding the factors that influence translocation success is important because carnivore translocations can be time consuming, expensive, and controversial. Using population viability software, we modeled reintroductions of the fisher, a candidate for endangered or threatened status in the Pacific states of the US. Our model predicts that the most important factor influencing successful re-establishment of a fisher population is the number of adult females reintroduced (provided some males are also released). Data from 38 translocations of fishers in North America, including 30 reintroductions, 5 augmentations and 3 introductions, show that the number of females released was, indeed, a good predictor of success but that the number of males released, geographic region and proximity of the source population to the release site were also important predictors. The contradiction between model and data regarding males may relate to the assumption in the model that all males are equally good breeders. We hypothesize that many males may need to be released to insure a sufficient number of good breeders are included, probably large males. Seventy-seven percent of reintroductions with known outcomes (success or failure) succeeded; all 5 augmentations succeeded; but none of the 3 introductions succeeded. Reintroductions were instrumental in reestablishing fisher populations within their historical range and expanding the range from its most-contracted state (43% of the historical range) to its current state (68% of the historical range). To increase the likelihood of translocation success, we recommend that managers: 1) release as many fishers as possible, 2) release more females than males (55–60% females) when possible, 3) release as many adults as possible, especially large males, 4) release fishers from a nearby source population, 5) conduct a formal feasibility assessment, and 6) develop a comprehensive implementation plan that includes an active monitoring program

An international review of tobacco smoking in the medical profession: 1974–2004

Background\ud Tobacco smoking by physicians represents a contentious issue in public health, and regardless of what country it originates from, the need for accurate, historical data is paramount. As such, this article provides an international comparison of all modern literature describing the tobacco smoking habits of contemporary physicians.\ud \ud Methods\ud A keyword search of appropriate MeSH terms was initially undertaken to identify relevant material, after which the reference lists of manuscripts were also examined to locate further publications.\ud \ud Results\ud A total of 81 English-language studies published in the past 30 years met the inclusion criteria. Two distinct trends were evident. Firstly, most developed countries have shown a steady decline in physicians' smoking rates during recent years. On the other hand, physicians in some developed countries and newly-developing regions still appear to be smoking at high rates. The lowest smoking prevalence rates were consistently documented in the United States, Australia and the United Kingdom. Comparison with other health professionals suggests that fewer physicians smoke when compared to nurses, and sometimes less often than dentists.\ud \ud Conclusion\ud Overall, this review suggests that while physicians' smoking habits appear to vary from region to region, they are not uniformly low when viewed from an international perspective. It is important that smoking in the medical profession declines in future years, so that physicians can remain at the forefront of anti-smoking programs and lead the way as public health exemplars in the 21st century

Climate-Induced Changes in Spring Snowmelt Impact Ecosystem Metabolism and Carbon Fluxes in an Alpine Stream Network

Although stream ecosystems are recognized as an important component of the global carbon cycle, the impacts of climate-induced hydrological extremes on carbon fluxes in stream networks remain unclear. Using continuous measurements of ecosystem metabolism, we report on the effects of changes in snowmelt hydrology during the anomalously warm winter 2013/2014 on gross primary production (GPP), ecosystem respiration (ER), and net ecosystem production (NEP) in an Alpine stream network. We estimated ecosystem metabolism across 12 study reaches of the 254 km2 subalpine Ybbs River Network (YRN), Austria, for 18 months. During spring snowmelt, GPP peaked in 10 of our 12 study reaches, which appeared to be driven by PAR and catchment area. In contrast, the winter precipitation shift from snow to rain following the low-snow winter in 2013/2014 increased spring ER in upper elevation catchments, causing spring NEP to shift from autotrophy to heterotrophy. Our findings suggest that the YRN transitioned from a transient sink to a source of carbon dioxide (CO2) in spring as snowmelt hydrology differed following the high-snow versus low-snow winter. This shift toward increased heterotrophy during spring snowmelt following a warm winter has potential consequences for annual ecosystem metabolism, as spring GPP contributed on average 33% to annual GPP fluxes compared to spring ER, which averaged 21% of annual ER fluxes. We propose that Alpine headwaters will emit more within-stream respiratory CO2 to the atmosphere while providing less autochthonous organic energy to downstream ecosystems as the climate gets warmer