Chronic morphine treatment attenuates cell growth of human BT474 breast cancer cells by rearrangement of the ErbB signalling network.

There is increasing evidence that opioid analgesics may interfere with tumour growth. It is currently thought that these effects are mediated by transactivation of receptor tyrosine kinase (RTK)-controlled ERK1/2 and Akt signalling. The growth of many breast cancer cells is dependent on hyperactive ErbB receptor networks and one of the most successful approaches in antineoplastic therapy during the last decade was the development of ErbB-targeted therapies. However, the response rates of single therapies are often poor and resistance mechanisms evolve rapidly. To date there is no information about the ability of opioid analgesics to interfere with the growth of ErbB-driven cancers. Here we demonstrate that ErbB2 overexpressing BT474 human breast cancer cells carry fully functional endogenous µ-opioid receptors. Most interestingly, the acute opioid effects on basal and Heregulin-stimulated ERK1/2 and Akt phosphorylation changed considerably during chronic Morphine treatment. Investigation of the underlying mechanism by the use of protein kinase inhibitors and co-immunoprecipitation studies revealed that chronic Morphine treatment results in rearrangement of the ErbB signalling network leading to dissociation of ERK1/2 from Akt signalling and a switch from ErbB1/ErbB3 to ErbB1/ErbB2-dependent cell growth. In chronically Morphine-treated cells Heregulin-stimulated ERK1/2 signalling is redirected via a newly established PI3K- and metalloproteinase-dependent feedback loop. Together, these alterations result in apoptosis of BT474 cells. A similar switch in Heregulin-stimulated ERK1/2 signalling from an ErbB2-independent to an ErbB2-, PI3K- and metalloproteinase-dependent mechanism was also observed in κ-opioid receptor expressing SKBR3 human mammary adenocarcinoma cells. The present data demonstrate that the ErbB receptor network of human breast cancer cells represents a target for chronic Morphine treatment. Rearrangement of ErbB signalling by chronic Morphine may provide a promising strategy to enhance the sensitivity of breast cancer cells to ErbB-directed therapies and to prevent the development of escape mechanisms

The Holy Grail: A road map for unlocking the climate record stored within Mars' polar layered deposits

In its polar layered deposits (PLD), Mars possesses a record of its recent climate, analogous to terrestrial ice sheets containing climate records on Earth. Each PLD is greater than 2 ​km thick and contains thousands of layers, each containing information on the climatic and atmospheric state during its deposition, creating a climate archive. With detailed measurements of layer composition, it may be possible to extract age, accumulation rates, atmospheric conditions, and surface activity at the time of deposition, among other important parameters; gaining the information would allow us to “read” the climate record. Because Mars has fewer complicating factors than Earth (e.g. oceans, biology, and human-modified climate), the planet offers a unique opportunity to study the history of a terrestrial planet’s climate, which in turn can teach us about our own planet and the thousands of terrestrial exoplanets waiting to be discovered. During a two-part workshop, the Keck Institute for Space Studies (KISS) hosted 38 Mars scientists and engineers who focused on determining the measurements needed to extract the climate record contained in the PLD. The group converged on four fundamental questions that must be answered with the goal of interpreting the climate record and finding its history based on the climate drivers. The group then proposed numerous measurements in order to answer these questions and detailed a sequence of missions and architecture to complete the measurements. In all, several missions are required, including an orbiter that can characterize the present climate and volatile reservoirs; a static reconnaissance lander capable of characterizing near surface atmospheric processes, annual accumulation, surface properties, and layer formation mechanism in the upper 50 ​cm of the PLD; a network of SmallSat landers focused on meteorology for ground truth of the low-altitude orbiter data; and finally, a second landed platform to access ~500 ​m of layers to measure layer variability through time. This mission architecture, with two landers, would meet the science goals and is designed to save costs compared to a single very capable landed mission. The rationale for this plan is presented below. In this paper we discuss numerous aspects, including our motivation, background of polar science, the climate science that drives polar layer formation, modeling of the atmosphere and climate to create hypotheses for what the layers mean, and terrestrial analogs to climatological studies. Finally, we present a list of measurements and missions required to answer the four major questions and read the climate record. 1. What are present and past fluxes of volatiles, dust, and other materials into and out of the polar regions? 2. How do orbital forcing and exchange with other reservoirs affect those fluxes? 3. What chemical and physical processes form and modify layers? 4. What is the timespan, completeness, and temporal resolution of the climate history recorded in the PLD

Concentration-Dependent Effects of a Dietary Ketone Ester on Components of Energy Balance in Mice

Exogenous ketones may provide therapeutic benefit in treatment of obesity. Administration of the ketone ester (KE) R,S-1,3-butanediol acetoacetate diester (BD-AcAc) decreases body weight in mice, but effects on energy balance have not been extensively characterized. The purpose of this investigation was to explore concentration-dependent effects of BD-AcAc on energy intake and expenditure in mice. Forty-two male C57BL/6J mice were randomly assigned to one of seven isocaloric diets ( = 6 per group): (1) Control (CON, 0% KE by kcals); (2) KE5 (5% KE); (3) KE10 (10% KE); (4) KE15 (15% KE); (5) KE20 (20% KE); (6) KE25 (25% KE); and (7) KE30 (30% KE) for 3 weeks. Energy intake and body weight were measured daily. Fat mass (FM), lean body mass (LBM), and energy expenditure (EE) were measured at completion of the study. Differences among groups were compared to CON using ANOVA and ANCOVA. Mean energy intake was similar between CON and each concentration of KE, except KE30 which was 12% lower than CON ( \u3c 0.01). KE25 and KE30 had lower body weight and FM compared to CON, while only KE30 had lower LBM ( \u3c 0.03). Adjusted resting and total EE were lower in KE30 compared to CON ( \u3c 0.03), but similar for all other groups. A diet comprised of 30% energy from BD-AcAc results in lower energy intake, coincident with lower body weight and whole animal adiposity; while KE20 and KE25 have significantly lower body weight and adiposity effects independent of changes in energy intake or expenditure

Concentration-Dependent Effects of a Dietary Ketone Ester on Components of Energy Balance in Mice

Objectives: Exogenous ketones may provide therapeutic benefit in treatment of obesity. Administration of the ketone ester (KE) R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) decreases body weight in mice, but effects on energy balance have not been extensively characterized. The purpose of this investigation was to explore concentration-dependent effects of BD-AcAc2 on energy intake and expenditure in mice.Methods: Forty-two male C57BL/6J mice were randomly assigned to one of seven isocaloric diets (n = 6 per group): (1) Control (CON, 0% KE by kcals); (2) KE5 (5% KE); (3) KE10 (10% KE); (4) KE15 (15% KE); (5) KE20 (20% KE); (6) KE25 (25% KE); and (7) KE30 (30% KE) for 3 weeks. Energy intake and body weight were measured daily. Fat mass (FM), lean body mass (LBM), and energy expenditure (EE) were measured at completion of the study. Differences among groups were compared to CON using ANOVA and ANCOVA.Results: Mean energy intake was similar between CON and each concentration of KE, except KE30 which was 12% lower than CON (P < 0.01). KE25 and KE30 had lower body weight and FM compared to CON, while only KE30 had lower LBM (P < 0.03). Adjusted resting and total EE were lower in KE30 compared to CON (P < 0.03), but similar for all other groups.Conclusions: A diet comprised of 30% energy from BD-AcAc2 results in lower energy intake, coincident with lower body weight and whole animal adiposity; while KE20 and KE25 have significantly lower body weight and adiposity effects independent of changes in energy intake or expenditure

The Holy Grail: A road map for unlocking the climate record stored within Mars' polar layered deposits

In its polar layered deposits (PLD), Mars possesses a record of its recent climate, analogous to terrestrial ice sheets containing climate records on Earth. Each PLD is greater than 2 ​km thick and contains thousands of layers, each containing information on the climatic and atmospheric state during its deposition, creating a climate archive. With detailed measurements of layer composition, it may be possible to extract age, accumulation rates, atmospheric conditions, and surface activity at the time of deposition, among other important parameters; gaining the information would allow us to “read” the climate record. Because Mars has fewer complicating factors than Earth (e.g. oceans, biology, and human-modified climate), the planet offers a unique opportunity to study the history of a terrestrial planet’s climate, which in turn can teach us about our own planet and the thousands of terrestrial exoplanets waiting to be discovered. During a two-part workshop, the Keck Institute for Space Studies (KISS) hosted 38 Mars scientists and engineers who focused on determining the measurements needed to extract the climate record contained in the PLD. The group converged on four fundamental questions that must be answered with the goal of interpreting the climate record and finding its history based on the climate drivers. The group then proposed numerous measurements in order to answer these questions and detailed a sequence of missions and architecture to complete the measurements. In all, several missions are required, including an orbiter that can characterize the present climate and volatile reservoirs; a static reconnaissance lander capable of characterizing near surface atmospheric processes, annual accumulation, surface properties, and layer formation mechanism in the upper 50 ​cm of the PLD; a network of SmallSat landers focused on meteorology for ground truth of the low-altitude orbiter data; and finally, a second landed platform to access ~500 ​m of layers to measure layer variability through time. This mission architecture, with two landers, would meet the science goals and is designed to save costs compared to a single very capable landed mission. The rationale for this plan is presented below. In this paper we discuss numerous aspects, including our motivation, background of polar science, the climate science that drives polar layer formation, modeling of the atmosphere and climate to create hypotheses for what the layers mean, and terrestrial analogs to climatological studies. Finally, we present a list of measurements and missions required to answer the four major questions and read the climate record. 1. What are present and past fluxes of volatiles, dust, and other materials into and out of the polar regions? 2. How do orbital forcing and exchange with other reservoirs affect those fluxes? 3. What chemical and physical processes form and modify layers? 4. What is the timespan, completeness, and temporal resolution of the climate history recorded in the PLD

Unlocking the Climate Record Stored within Mars’ Polar Layered Deposits

In the icy beds of its polar layered deposits (PLD), Mars likely possesses a record of its recent climate history, analogous to terrestrial ice sheets that contain records of Earth's past climate. Both northern and southern PLDs store information on the climatic and atmospheric state during the deposition of each layer (WPs: Becerra et al.; Smith et al). Reading the climate record stored in these layers requires detailed measurements of layer composition, thickness, isotope variability, and near-surface atmospheric measurements. We identify four fundamental questions that must be answered in order to interpret this climate record and decipher the recent climatic history of Mars: 1. Fluxes: What are the present and past fluxes of volatiles, dust, and other materials into and out of the polar regions? 2. Forcings: How do orbital/axial forcing and exchange with other reservoirs affect those fluxes? 3. Layer Processes: What chemical and physical processes form and modify layers? 4. Record: What is the timespan, completeness, and temporal resolution of the climate history recorded in the PLD? In a peer reviewed report (1), we detailed a sequence of missions, instruments, and architecture needed to answer these questions. Here, we present the science drivers and a mission concept for a polar lander that would enable a future reading of the past few million years of the Martian climate record. The mission addresses as-yet-unachieved science goals of the current Decadal Survey and of MEPAG for obtaining a record of Mars climate and has parallel goals to the NEXSAG and ICE-SAG reports

The quality of life and well-being of employees of an educational institution for children with conduct disorders

This Diploma Thesis is dealing with the quality of life and the overall well-being of people working with youth with problematic behaviour. Historical and theoretical background of the life quality and well-being concepts is summarised in the theoretical part. Scientific knowledge gained in this area up to now is presented to the readers, including the impact of demographic characteristics (age, sex, nationality), state of health and social relations on the well-being of individuals, methods the quality of life can be measured and the possibilities of its enhancement. The theoretical part is followed by a less extensive chapter concentrating on the profession of expert pedagogical staff, teachers and social workers in educational institutions where the youth with problematic behaviour is concentrated. Specifics of the work with such clients are outlined there, focusing on those making this work hard mainly as regards the psychological resistance of the expert pedagogical staff. The empirical part is based on data gained from research questionnaire analysis. The institution in which the research was conducted is briefly introduced together with the research methods used. The results initially expected by he author and the reasons for her expectations are presented and afterwards confronted with the actual..

Model of chronic Morphine-induced changes in ErbB signalling.

<p>The scheme depicts the differences in Heregulin-stimulated ErbB signalling in control and chronically Morphine-treated BT474 cells. In control cells, stimulation with Heregulin leads to activation of ERK1/2 and Akt signalling via ErbB1/ErbB3 heterodimers. While AG1478 blocks both Heregulin-stimulated ERK1/2 and Akt signalling, inhibition of PI3K by Wortmannin specifically prevents Akt signalling. Because ErbB3 phosphorylation and PI3K activation is dependent on the presence of a dimerized ErbB member with catalytic activity, these results indicate that Heregulin-stimulated ERK1/2 signalling is predominantly mediated through ErbB1. The failure of Wortmannin to affect ERK1/2 activation in control cells further implicates that Heregulin stimulates Akt signalling via ErbB3. Chronic Morphine treatment alters mitogenic signalling by rearrangement of ErbB heterodimers. Whereas Heregulin still stimulates Akt signalling via ErbB1/ErbB3, ERK1/2 signalling is now accomplished by ErbB1/2 heterodimers. These are activated indirectly by an EGF-like ligand liberated from Heregulin in a PI3K (Wortmannin)- and metalloproteinase (EGCG)-dependent manner.</p