Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss

Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma

NDE Applications of Radio Wave Emission from Stress and Fracture

It is well-known [1], [2] that when materials are fractured, substantial local electric fields are generated. These fields are capable of accelerating charged particles from the nascent interfaces, giving rise to a class of phenomena known as “exo-emission” or “fracto-emission”. The released “exo-particles”, consisting of electrons, ions, and charged clusters or fragments, can be collected and analyzed directly. Usually, such experiments are performed under conditions of high or ultra-high vacuum. This type of particle emission has been extensively studied previously, most notably by Dickinson and his co-workers [2] — [7]. Except for previous studies of fracturing rock, performed in connection with early-warning detection of earthquakes [8], [9], and the work of Dickinson, little has been done to characterize the radio wave emission that attends material fractures. Furthermore, no previous studies of radio wave emission from the elastically or plastically strained materials have been reported. Early qualitative studies of the visible light and radio wave emission from delaminating layers of adhesively bonded polymers and metals were reported by Derjagun and his co-workers. Emission during deformation suggests itself as a possible method for diagnosing the state of dynamic material strain in situations where contact methods are not feasible or are undesirable. Examples of such potential applications are too numerous to delineate here; they include the detection of high speed particle impacts on spacecraft structures, dynamic test of radioactive, extremely hot or cold structures, and others. We also note that for the elucidation of the detailed mechanism of fracture, radio-wave emission may have advantages over other methods since, unlike acoustic or ultrasonic methods, the speed of propagation of the detected signal is much greater than the speed of the propagating crack-front in the material, so little or no deconvolution is required.</p

The Resident Assessment Instrument-Minimum Data Set 2.0 quality indicators: a systematic review

BackgroundThe Resident Assessment Instrument-Minimum Data Set (RAI-MDS) 2.0 is designed to collect the minimum amount of data to guide care planning and monitoring for residents in long-term care settings. These data have been used to compute indicators of care quality. Use of the quality indicators to inform quality improvement initiatives is contingent upon the validity and reliability of the indicators. The purpose of this review was to systematically examine published and grey research reports in order to assess the state of the science regarding the validity and reliability of the RAI-MDS 2.0 Quality Indicators (QIs).MethodsWe systematically reviewed the evidence for the validity and reliability of the RAI-MDS 2.0 QIs. A comprehensive literature search identified relevant original research published, in English, prior to December 2008. Fourteen articles and one report examining the validity and/or reliability of the RAI-MDS 2.0 QIs were included.ResultsThe studies fell into two broad categories, those that examined individual quality indicators and those that examined multiple indicators. All studies were conducted in the United States and included from one to a total of 209 facilities. The number of residents included in the studies ranged from 109 to 5758. One study conducted under research conditions examined 38 chronic care QIs, of which strong evidence for the validity of 12 of the QIs was found. In response to these findings, the 12 QIs were recommended for public reporting purposes. However, a number of observational studies (n=13), conducted in &quot;real world&quot; conditions, have tested the validity and/or reliability of individual QIs, with mixed results. Ten QIs have been studied in this manner, including falls, depression, depression without treatment, urinary incontinence, urinary tract infections, weight loss, bedfast, restraint, pressure ulcer, and pain. These studies have revealed the potential for systematic bias in reporting, with under-reporting of some indicators and over-reporting of others.ConclusionEvidence for the reliability and validity of the RAI-MDS QIs remains inconclusive. The QIs provide a useful tool for quality monitoring and to inform quality improvement programs and initiatives. However, caution should be exercised when interpreting the QI results and other sources of evidence of the quality of care processes should be considered in conjunction with QI results.<br /

Academic Performance and Behavioral Patterns

Identifying the factors that influence academic performance is an essential part of educational research. Previous studies have documented the importance of personality traits, class attendance, and social network structure. Because most of these analyses were based on a single behavioral aspect and/or small sample sizes, there is currently no quantification of the interplay of these factors. Here, we study the academic performance among a cohort of 538 undergraduate students forming a single, densely connected social network. Our work is based on data collected using smartphones, which the students used as their primary phones for two years. The availability of multi-channel data from a single population allows us to directly compare the explanatory power of individual and social characteristics. We find that the most informative indicators of performance are based on social ties and that network indicators result in better model performance than individual characteristics (including both personality and class attendance). We confirm earlier findings that class attendance is the most important predictor among individual characteristics. Finally, our results suggest the presence of strong homophily and/or peer effects among university students

Underweight is independently associated with mortality in post-operative and non-operative patients admitted to the intensive care unit: a retrospective study

BACKGROUND: Low and high body mass index (BMI) have been recently shown to be associated with increased and decreased mortality after ICU admission, respectively. The objective of this study was to determine the impact of BMI on mortality and length of stay in patients admitted to the intensive care unit (ICU). METHODS: In this retrospective cohort study, the Acute Physiology and Chronic Health Evaluation (APACHE) III database of patients admitted to the ICUs of a tertiary academic medical center, from January 1997 to September 2002, was crossed with a Hospital Rule-based Systems database to obtain the height and weight of the patients on admission to the ICU. The cohort was divided in post-operative and non-operative groups. We created the following five subgroups based on the BMI: <18.5, 18.5 to 24.9, 25 to 29.9, 30.0 to 39.9, ≥ 40.0 Kg/m(2). A multiple logistic regression analysis was used to determine the independent impact of BMI on hospital mortality. The ICU length of stay ratio was defined as the ratio of the observed to the predicted LOS. P-value < 0.05 was considered significant. The 95% confidence interval (CI) was calculated for the odds ratio (OR). RESULTS: BMI was available in 19,669 of the 21,790 patients in the APACHE III database; 11,215 (57%) of the patients were admitted post-operatively. BMI < 18.5 was associated with increased mortality in both post-operative (OR = 2.14, 95% CI, 1.39 to 3.28) and non-operative (OR = 1.51, 95% CI, 1.13 to 2.01) patients. Post-operative patients with a BMI between 30.0 to 39.9 had a lower mortality rate (OR = 0.68, 95% CI, 0.49 to 0.94). Post-operative patients with BMI <18.5 or BMI ≥ 40 had an ICU length of stay ratio significantly higher than patients with BMI between 18.5 to 24.9. The addition of BMI < 18.5 did not improve significantly the accuracy of our prognostic model in predicting hospital mortality. CONCLUSIONS: Low BMI is associated with higher mortality in both post- and non-operative patients admitted to the ICU. LOS is increased in post-operative patients with low and high BMIs

Forest-Stream Linkages: Effects of Terrestrial Invertebrate Input and Light on Diet and Growth of Brown Trout (Salmo trutta) in a Boreal Forest Stream

Subsidies of energy and material from the riparian zone have large impacts on recipient stream habitats. Human-induced changes, such as deforestation, may profoundly affect these pathways. However, the strength of individual factors on stream ecosystems is poorly understood since the factors involved often interact in complex ways. We isolated two of these factors, manipulating the flux of terrestrial input and the intensity of light in a 2×2 factorial design, where we followed the growth and diet of two size-classes of brown trout (Salmo trutta) and the development of periphyton, grazer macroinvertebrates, terrestrial invertebrate inputs, and drift in twelve 20 m long enclosed stream reaches in a five-month-long experiment in a boreal coniferous forest stream. We found that light intensity, which was artificially increased 2.5 times above ambient levels, had an effect on grazer density, but no detectable effect on chlorophyll a biomass. We also found a seasonal effect on the amount of drift and that the reduction of terrestrial prey input, accomplished by covering enclosures with transparent plastic, had a negative impact on the amount of terrestrial invertebrates in the drift. Further, trout growth was strongly seasonal and followed the same pattern as drift biomass, and the reduction of terrestrial prey input had a negative effect on trout growth. Diet analysis was consistent with growth differences, showing that trout in open enclosures consumed relatively more terrestrial prey in summer than trout living in covered enclosures. We also predicted ontogenetic differences in the diet and growth of old and young trout, where we expected old fish to be more affected by the terrestrial prey reduction, but we found little evidence of ontogenetic differences. Overall, our results showed that reduced terrestrial prey inputs, as would be expected from forest harvesting, shaped differences in the growth and diet of the top predator, brown trout

Does rearing laying hens in aviaries adversely affect long-term welfare following transfer to furnished cages?

This study tests the hypothesis that hens that are reared in aviaries but produce in furnished cages experience poorer welfare in production than hens reared in caged systems. This hypothesis is based on the suggestion that the spatial restriction associated with the transfer from aviaries to cages results in frustration or stress for the aviary reared birds. To assess the difference in welfare between aviary and cage reared hens in production, non-beak trimmed white leghorn birds from both rearing backgrounds were filmed at a commercial farm that used furnished cage housing. The videos were taken at 19 and 21 weeks of age, following the birds' transition to the production environment at 16 weeks. Videos were analysed in terms of the performance of aversion-related behaviour in undisturbed birds, comfort behaviour in undisturbed birds, and alert behaviour directed to a novel object in the home cage. A decrease in the performance of the former behaviour and increase in the performance of the latter two behaviours indicates improved welfare. The results showed that aviary reared birds performed more alert behaviour near to the object than did cage reared birds at 19 but not at 21 weeks of age (P = 0.03). Blood glucose concentrations did not differ between the treatments (P>0.10). There was a significant difference in mortality between treatments (P = 0.000), with more death in aviary reared birds (5.52%) compared to cage birds (2.48%). The higher mortality of aviary-reared birds indicates a negative effect of aviary rearing on bird welfare, whereas the higher duration of alert behavior suggests a positive effect of aviary rearing

TGA2 signaling in response to reactive electrophile species is not dependent on cysteine modification of TGA2

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Reactive electrophile species (RES), including prostaglandins, phytoprostanes and 12-oxo phytodienoic acid (OPDA), activate detoxification responses in plants and animals. However, the pathways leading to the activation of defense reactions related to abiotic or biotic stress as a function of RES formation, accumulation or treatment are poorly understood in plants. Here, the thiol-modification of proteins, including the RES-activated basic region/leucine zipper transcription factor TGA2, was studied. TGA2 contains a single cysteine residue (Cys186) that was covalently modified by reactive cyclopentenones but not required for induction of detoxification genes in response to OPDA or prostaglandin A1. Activation of the glutathione-S-transferase 6 (GST6) promoter was responsive to cyclopentenones but not to unreactive cyclopentanones, including jasmonic acid suggesting that thiol reactivity of RES is important to activate the TGA2-dependent signaling pathway resulting in GST6 activation We show that RES modify thiols in numerous proteins in vivo, however, thiol reactivity alone appears not to be sufficient for biological activity as demonstrated by the failure of several membrane permeable thiol reactive reagents to activate the GST6 promoter.Peer reviewedFinal Published versio

Real-time observation of multiexcitonic states in ultrafast singlet fission using coherent 2D electronic spectroscopy.

Singlet fission is the spin-allowed conversion of a spin-singlet exciton into a pair of spin-triplet excitons residing on neighbouring molecules. To rationalize this phenomenon, a multiexcitonic spin-zero triplet-pair state has been hypothesized as an intermediate in singlet fission. However, the nature of the intermediate states and the underlying mechanism of ultrafast fission have not been elucidated experimentally. Here, we study a series of pentacene derivatives using ultrafast two-dimensional electronic spectroscopy and unravel the origin of the states involved in fission. Our data reveal the crucial role of vibrational degrees of freedom coupled to electronic excitations that facilitate the mixing of multiexcitonic states with singlet excitons. The resulting manifold of vibronic states drives sub-100 fs fission with unity efficiency. Our results provide a framework for understanding singlet fission and show how the formation of vibronic manifolds with a high density of states facilitates fast and efficient electronic processes in molecular systems.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nchem.237