Increases in norepinephrine release and ovarian cyst formation during ageing in the rat

<p>Abstract</p> <p>Background</p> <p>Depletion of ovarian follicles is associated with the end of reproductive function in ageing females. Recently, it has been described that this process parallels increases in the concentration of norepinephrine (NE) in the rat ovary. In sexually mature rats, experimentally-induced increases in the sympathetic tone of the ovary is causally related to ovarian cyst formation and deranged follicular development. Thus, there is a possibility that increased ovarian NE concentrations represent changes in the activity of sympathetic nerves, which consequently participate in the process of ovarian cyst formation observed during ageing in the human and experimental animal models.</p> <p>Methods</p> <p>Sprague-Dawley rats between 6 and 14 months old were used to analyse the capacity of the ovary to release ³H-NE recently incorporated under transmural depolarisation in relation to changes in the ovarian follicular population. Morphometric analysis of ovarian follicles and real time PCR for Bcl2 and Bax mRNA were used to assess follicular atresia.</p> <p>Results</p> <p>From 8 months old, the induced release of recently incorporated ³H-norepinephrine (³H-NE) from the ovary and ovarian NE concentrations increased, reaching their peak values at 12 months old and remained elevated up to 14 months old. Increases in sympathetic nerve activity paralleled changes in the follicular population, as well as disappearance of the corpus luteum. In contrast, luteinised follicles, precystic follicles, and cystic follicles increased. During this period, the relationship between Bax and Bcl2 mRNAs (the proapoptotic/antiapoptotic signals) increased, suggesting atresia as the principal mechanism contributing to the decreased follicular population. When NE tone was increased, the mRNA ratio favoured Bcl2 to Bax and antiapoptotic signals dominated this period of development. Thus, these changing ratios could be responsible for the increase in luteinised follicles, as well as precystic and cystic follicles.</p> <p>Conclusion</p> <p>These data suggest that the ageing process in the ovary of the Sprague-Dawley rat is accompanied by an increased sympathetic tone of the ovary. Consequently, this sympathetic change could be related to a neuroendocrine-driven formation of a polycystic condition similar to that observed in the sympathetic-activated adult ovary.</p

Influence of environment on the corrosion of glass–metal connections

'Glass sensors' of the eighteenth century Backer glass and the sixteenth century enamel from Limoges have been chosen for a series of experiments. Combinations of these materials with different base materials such as copper and bronze has been investigated. To create surface changes on the 'glass sensor', a corrosion process was induced in a controlled environment. A variety of corrosive agents such as hydrochloric acid, sulfuric acid, water and formaldehyde were used. The sample immersed in the corrosive solution was exposed alternately to light and high temperature for a total of 38 weeks. During this period, macroscopic and microscopic observations were made and series of tests such as SEM/EDS and Raman spectroscopy were performed on the surface of the samples. ICP-MS methods were used to determine the change in the chemical composition of the solutions where the samples had corroded. The primary aim of this study was to identify the impact of a number of external corrosive variables such as temperature, humidity and local environment to identify the most damaging environments for glass–metal objects. The obtained results showed the chemical and physical phenomena acting on the surface of the glass, metal or in the place of their joints. Information obtained on this study was used to explain the influence of the environment on the surface of glass–metal materials. Results can be used in the design of conservation work as well as for sustainable conservation

Influence of a high fat diet during adolescence on the reinforcing effects of cocaine and alcohol

RESUMEN La adolescencia es un período de especial vulnerabilidad en el desarrollo del ser humano, en el que se dan grandes cambios a nivel estructural y funcional (Spear, 2000; Chambers et al., 2003). En esta etapa de gran vulnerabilidad, los jóvenes muestran trastornos de la alimentación, consumo de sustancias, búsqueda de sensaciones y conductas de riesgo (Bava and Tapert, 2010). Actualmente, el consumo excesivo de comida especialmente rica en azúcares y grasas, se ha convertido en un serio problema para nuestra sociedad, habiéndose producido un incremento en las tasas de obesidad a nivel mundial que afecta particularmente a la población adolescente. La alimentación está regulada tanto por mecanismos homeostáticos como hedónicos. Un malfuncionamiento de cualquiera de estos sistemas puede provocar una alteración en la alimentación y producir obesidad (Kenny et al., 2011). El sistema de refuerzo, constituido esencialmente por el sistema dopaminérgico mesocorticolímbico, regula la motivación para buscar o consumir estímulos reforzantes como las drogas o la comida altamente palatable. Por lo tanto, el consumo de drogas o la alimentación por razones hedónicas activan las mismas vías del refuerzo. Inicialmente nuestro organismo se desarrolló en un contexto caracterizado por la escasez nutricional y conseguir alimentos era el principal objetivo a alcanzar en el día a día. Ya que nuestro cuerpo procesa los alimentos de forma rápida, mostramos una preferencia innata por las comidas con alto contenido calórico y energético. Este tipo de alimentos, al igual que la cocaína o el alcohol, producen liberación de dopamina en el sistema de recompensa cerebral. Hoy en día, en la sociedad de la abundancia y la variedad de alimentos, comemos no sólo por hambre, sino también por placer (Gold, 2011). Por lo tanto, comer por placer afecta a los mecanismos neurales relacionados con el refuerzo y promueve el mantenimiento de esta conducta (ver revisión Avena et al., 2008; Volkow et al., 2013). En resumen, tanto los reforzadores naturales como las drogas estimulan el circuito cerebral de recompensa, produciendo placer y euforia. El estado nutricional es un importante factor modulador en el desarrollo de la adicción, y algunos estudios han mostrado similitudes psicológicas y biológicas entre la ingesta de comida rápida y la adicción a las drogas, (Garber and Lustig, 2011; Avena et al., 2012). Por ejemplo, tanto la adicción a las drogas como la obesidad pueden ser definidas como trastornos en los que el valor de determinado refuerzo (droga o comida) está anormalmente incrementado en relación y a expensas de otros refuerzos. La adicción a drogas y los atracones de comida se caracterizan por una pérdida de control sobre la conducta consumatoria, la escalada, la dependencia y el ansia por consumir (craving), mostrando ambos trastornos una elevada comorbilidad (Swanson et al., 2011). Numerosos estudios han puesto de manifiesto que el consumo de drogas durante la adolescencia incrementa la probabilidad de desarrollar dependencia y problemas relacionados con estas sustancias en la edad adulta (Arteaga et al., 2010; Merline et al., 2004). Se ha propuesto igualmente una teoría de puerta de entrada también para la comida y el abuso de sustancias (Degenhardt y cols., 2008). Esta teoría postula que la ingesta compulsiva de comida puede facilitar el desarrollo de otros comportamientos desadaptativos, como es el consumo de drogas. Por el momento, los estudios preclínicos indican que el atracón de comida rica en azúcar provoca a una sensibilización conductual a la anfetamina (Avena y Hoebel, 2003) y aumenta la autoadministración de alcohol (Avena y cols., 2004). Se han realizado estudios utilizando comida rica en azúcar, sin embargo, los estudios con comida rica en grasa son escasos. Hasta la fecha todavía no se han evaluado las consecuencias de realizar atracones de grasa durante la adolescencia sobre el consumo de drogas como la cocaína y el alcohol. Tampoco conocemos los efectos de suspender el consumo de una dieta alta en grasas, sobre los efectos gratificantes de la cocaína o el alcohol. Así pues, el objetivo de la presente tesis doctoral ha sido evaluar cómo una dieta alta en grasa consumida durante la adolescencia, puede modificar los efectos reforzantes de la cocaína y el alcohol. Estudiamos dos tipos diferentes de consumo de la dieta alta en grasa, el acceso continuado a la dieta rica en grasa (los animales consumen la dieta durante todo el periodo de tiempo correspondiente, sin limitar su acceso) y el atracón, que es un acceso limitado e intermitente. Este último patrón se ha demostrado que induce un consumo de grasa en forma de atracones (Puhl y cols., 2011; Bocarsly y cols., 2011). En el protocolo de administración intermitente los ratones tienen acceso a la dieta rica en grasa solo durante 2 horas los lunes, miércoles y viernes con un acceso ilimitado a la dieta estándar. Como metodología principal para evaluar la respuesta a la cocaína y el alcohol utilizamos los paradigmas de Condicionamiento de la Preferencia de Lugar y el procedimiento de Autoadministración operante. El Condicionamiento de la Preferencia de lugar es el paradigma más utilizado para medir el efecto de las claves ambientadas asociadas con los efectos reforzantes de las drogas (Aguilar et al., 2013). Por otro lado, el modelo de autoadministración operante evalúa directamente la motivación del animal por conseguir la sustancia. Ambos modelos proporcionan una evaluación completa de los efectos reforzantes de las drogas, ya que nos permiten medir tanto las claves individuales como las externas. También hemos estudiado los efectos metabólicos que estos tipos de dieta grasa producían en los niveles plasmáticos de leptina, grelina y corticosterona. Igualmente, hemos estudiado mediante la reacción en cadena de la polimerasa (PCR) en tiempo real, la expresión de genes pertenecientes a los sistemas dopaminérgico, cannabinoide y opioide, debido a su implicación tanto en el refuerzo inducido por las drogas como por la comida. En cuanto a los resultados obtenidos, en el primer estudio hemos observado que, aunque no hay cambios en ninguna de las conductas estudiadas mientras se mantiene el consumo de grasa, el cese de esta dieta produce un incremento en el nivel de ansiedad, aumenta la respuesta aguda a la cocaína y produce condicionamiento de la preferencia de lugar con dosis subumbrales de cocaína. Todo esto se acompaña por cambios a nivel de expresión del gen para el receptor opioide mu, el cannabinoide CB1 y GHSR. Por otro lado, observamos el poder de la dieta rica en grasa como refuerzo alternativo, ya que cuando la administramos tras condicionar a los animales con una dosis efectiva, éstos tardan menos en extinguir la preferencia y no presentan reinstauración con dosis con las que el grupo control sí reinstaura la preferencia de lugar. En el segundo estudio hemos evaluado el efecto de realizar atracones de una dieta rica en grasa y hemos observado que provocan un aumento en la sensibilidad a dosis subumbrales de cocaína en el condicionamiento de la preferencia de lugar y se autoadministran más cocaína que el grupo con dieta estándar. Por otro lado, observamos también cambios en la expresión de los genes responsables de los receptores opioide mu, cannabinoide CB1 y de la grelina GHSR. En el tercer estudio realizamos el mismo procedimiento que en el estudio anterior, pero con el fin de evaluar si este tipo de administración de dieta rica en grasa también incrementaba la sensibilidad al alcohol. De nuevo encontramos que los animales que realizan atracones son más sensibles a dosis subumbrales de alcohol y se autoadministran más que el grupo con dieta estándar. Además, presentan cambios a nivel de expresión de genes tras la autoadministración, diferentes a los obtenidos con la simple administración de la grasa en estudios anteriores. En el cuarto estudio evaluamos si estos efectos sobre la ingesta de alcohol tenían un efecto a largo plazo, incluso habiendo cesado el consumo de grasa. Observamos cómo los animales que realizaron atracones durante la adolescencia y llevaban 15 días sin acceso a la grasa seguían presentando un incremento en la autoadministración de alcohol, pero ya no eran más sensibles a los efectos reforzantes de una dosis subumbral de alcohol en el condicionamiento de la preferencia de lugar. En el quinto estudio evaluamos el papel que tiene un estrés crónico, como es el aislamiento, en la modulación que produce la dieta rica en grasa en atracón sobre los efectos reforzantes de la cocaína. Observamos resultados opuestos a los obtenidos con animales agrupados, ya que los animales aislados con una dieta estándar fueron más sensibles a dosis subumbrales de cocaína que los que realizaron atracones de dieta rica en grasa. Además, los grupos que desarrollaron la preferencia (aislados dieta estándar y agrupados dieta atracón grasa) también presentaron niveles incrementados de leptina. En el sexto y último estudio trazamos un perfil conductual con todos los grupos que hemos utilizado en la presente tesis doctoral, observando que los animales que realizan atracones de grasa presentan pocas alteraciones conductuales. Únicamente exhiben un incremento en la actividad locomotora y conductas agresivas en la interacción social con un oponente. Sí que observamos déficits a nivel de aprendizaje espacial con los animales que comen comida rica en grasa de forma continuada y además de un comportamiento agresivo. En ambos tipos de dieta, el cese del consumo produce un incremento en el nivel de ansiedad. Los resultados obtenidos nos indican el consumo de una dieta alta en grasa de forma continuada produce efectos muy diferentes a los producidos por el consumo intermitente en atracón. Mientras que el consumo en forma de atracón no produce grandes efectos metabólicos, incrementa la sensibilidad a los efectos reforzantes del alcohol y la cocaína. Sin embargo, el consumo de grasa de forma continuada produce grandes cambios metabólicos, como hiperleptinemia y aumento de peso, pero no afecta la respuesta a la cocaína. Sin embargo, tras el cese en el consumo continuado de una dieta alta en grasa, aparece un incremento en la respuesta a los efectos condicionados reforzantes de la cocaína, confirmando así que el sistema de refuerzo ha quedado sensibilizado tras el consumo de grasa. Ambos tipos de dieta alta en grasa produce cambios en la expresión génica de los receptores opioide mu, cannabinoide CB1 y del receptor de grelina GHSR, indicando que ambos patrones de consumo de grasa modifican de forma diferente la función del sistema de refuerzo cerebral, produciendo consecuencias a largo plazo, incluso cuando la comida rica en grasa ya no está disponible. Nuestro trabajo demuestra que los hábitos nutricionales no solo producen alteraciones metabólicas en nuestro organismo o modifican nuestro peso corporal. También modifican nuestro SNC y alteran la forma en que respondemos a las drogas de abuso. Una de las principales aportaciones de este trabajo es la demostración de que la dieta grasa consumida de forma continuada, que induce grandes cambios metabólicos y obesidad, así como alteraciones conductuales, no parece modular la respuesta a las drogas hasta que esta deja de consumirse, momento en el que observamos una respuesta incrementada. Sin embargo, los atracones de grasa, que no alteran metabólicamente al sujeto, ni modifican su peso corporal o su conducta, sí que incrementan la respuesta a drogas como la cocaína o el etanol, incluso cuando ya ha dejado de consumirse. Por lo tanto, esperamos que los artículos que componen la presente Tesis Doctoral ayuden a incrementar el conocimiento y la conciencia sobre la importancia de los hábitos nutricionales en el abordaje de un problema multifactorial como es la adicción a las drogas.  ABSTRACT Adolescence is a highly vulnerable developmental period in which numerous structural and functional maturational changes occur (Spear, 2000; Chambers et al., 2003). In this early stage of vulnerability, adolescents exhibit eating disorders, substance abuse, novelty-seeking and risk-taking behaviors (Bava and Tapert, 2010). Regarding these environmental hazards, the rise in obesity rates worldwide has encouraged extensive research to improve understanding of this problem, in which the excessive intake of food, especially sugar-rich and high-fat food has become a serious problem for society. As we know, addiction is a chronic and multifactorial relapsing disorder resulting from an interaction of biological and environmental aspects, characterized by a loss of control in the use of the substance and relapse (Koob and Volkow, 2010). Developmental factors are important components of vulnerability, with strong evidence supporting that exposure to drugs of abuse during adolescence leads to a significantly higher likelihood of drug dependence and drug-related problems in adulthood. Feeding is regulated by homeostatic and hedonic mechanisms. Abnormalities in these functions can cause several feeding alterations and produce obesity (Kenny et al., 2011). The reward system, which is essentially constituted by the dopamine mesocorticolimbic system, regulates motivation to seek and take rewarding stimuli, such as drugs or highly palatable food. Therefore, drug abuse or hedonic eating activate the same reward pathways. Our body was initially developed in a context characterized by nutritional deficiencies and getting food was the daily main objective to achieve. It processes foods quickly and we have innate preference for high energy meals, especially those high in fat and sugar, because in a situation of scarcity those would be the energy stores that would help us to survive. This type of food, like drugs of abuse, produces a dopamine release in the brain reward system, which explains its pleasurable effects. Nowadays, there is such abundance and variety of food, that this survival-oriented evolutionary adaptation has lost its sense, since we eat not only for hunger, but also for pleasure (Gold, 2011). Thus, hedonic eating affects neural mechanisms connected with reward and maintains this behavior (For reviews: Avena et al., 2008; Volkow et al., 2013). In summary, both natural reinforcers and drugs stimulate the brain reward circuit, producing pleasure and euphoria. The nutritional status is an important factor in the development of addiction, since some studies indicate psychological and biological similarities between fast food intake and addiction to drugs, sharing common reward mechanisms (Garber and Lustig, 2011; Avena et al., 2012). For example, both drug addiction and obesity can be defined as disorders in which the value of the type of reinforcement (drug or food, respectively) is abnormally increased in relationship to other reinforcements (Avena et al., 2012; Volkow et al., 2013). Drug addiction and binge eating are characterized by a loss of control over consummatory behaviors, exhibiting escalation, dependence and craving when the reward is not available, and both present a high comorbidity (Swanson et al., 2011). Several studies report that drug use during adolescence often predicts an increased likelihood of continued use into adulthood (Arteaga et al., 2010; Merline et al., 2004). Based on these relationships, a Theory of Gateway has also been proposed for eating disorders and substance abuse (Degenhardt et al., 2008), in which it is postulated that eating disorders, such as binge eating, can lead to the development of another desadaptive behavior, such as drug abuse. At the moment, preclinical studies indicate, for example, that intake of certain types of sugar leads to a sensitization to amphetamine (Avena and Hoebel, 2003) and to an increase in alcohol self-administration (Avena et al., 2004). Studies with sugar are abundant, unlike studies with high-fat food and drug vulnerability. For example, there are no studies reporting the effects of bingeing on fat during adolescence and vulnerability to drug abuse, like cocaine or alcohol, nor are there studies examining the effects of interrupting fat consumption on the subsequent vulnerability to drugs like cocaine or alcohol. Thus, the objective of the present work was to evaluate how a high-fat diet exposure during adolescence modulates the reinforcing effects of cocaine and alcohol. We studied two different types of fat diet consumption: continuous access (animals have ad libitum access to high-fat food without a limit) and the intermittent and limited access. The latter has been shown to induce a binge eating pattern (Puhl and cols., 2011; Bocarsly et al., 2011), and our protocol is based on that used by Corwin et al. (1998). Here, mice had access to the high-fat diet only for 2 hours every Monday, Wednesday and Friday, with ad libitum access to the standard diet. The main methodology employed to assess the vulnerability to cocaine and alcohol rewarding effects was the Conditioned Place Preference paradigm and the operant Self-Administration procedure. The conditioned place preference is the most commonly used test to evaluate the environmental cues conditioned to the rewarding effects of the drug (Aguilar et al., 2013), while the self-administration procedure evaluates directly the animals’ motivation to obtain the substance of abuse. Both models provide a complete scenario to evaluate vulnerability to drug abuse, since they allow us to measure both the external and the individual cues. We have also studied some metabolic effects on circulating leptin, ghrelin and corticosterone levels and examined changes in gene expression with real time polymerase chain reaction (rt-PCR) related to dopaminergic, opioid and endocannabinoid systems, because of their involvement in the rewarding properties of drugs and food. Regarding our results, in the first study we observed no effects on the behavioral response to drugs while fat is available. However, following fat discontinuation, mice exhibited increased anxiety, augmented locomotor response to cocaine, and developed preference for subthreshold doses of cocaine. In addition, there were changes in MOr, CB1 and GHSR gene expression. On the other hand, we observed how high-fat diets act as an alternative reinforcer, as its administration after conditioned place preference reduces the number of sessions required to extinguish the preference and decreased sensitivity to drug priming-induced reinstatement. In the second study, we observed that animals that binged on fat were more sensitive to the reinforcing effects of a subthreshold dose of cocaine in the conditioned place preference and enhanced self-administration. We also observed changes in MOr, CB1 and GHSR gene expression. In the third study, we employed the same procedure as in the former study, but with the aim of evaluating if the increased sensitivity also arises with alcohol. Animals in the high-fat binge group presented more sensitivity to the rewarding effects of subthreshold doses of ethanol and greater ethanol consumption with a higher motivation to obtain the drug. In addition, they presented changes in gene expression after the self-administration procedure which are different from those found with the fat administration alone. In the fourth study, we evaluated if these effects of bingeing on fat and alcohol intake would have a long term consequences, even when fat consumption is interrupted. Our results showed how after 15 days from the last binge session, animals still presented a greater ethanol consumption, but they were not sensitive to subthreshold doses in the conditioned place preference anymore. The fifth study aimed to evaluate the role of chronic stress, such as isolation, on the modulatory effects of fat on the rewarding properties of cocaine. We observed opposite effects as those found in grouped animals, as isolated mice with a standard diet access were more sensitive to subthreshold doses of cocaine than those fed with a fat binge eating pattern. In addition, the groups that developed preference (isolated with standard diet and grouped with high-fat binge) were those who presented increased circulating leptin levels. In the sixth and last study, we drew a behavioral profile with the groups used in the present doctoral thesis, and found a few alterations in animals that binge on fat, such as hyperlocomotion and aggressive behaviors. On the other hand, we observed marked spatial learning deficits in animals eating fat continuously as well as increased attack behaviors with conspecifics. In both diet patterns, discontinuation of fat led to an increase in anxiety levels. Our results show that bingeing on fat is quite different from eating fat continuously. While the former does not produce great metabolic effects, it produces significant changes in the sensitivity to drugs such as alcohol and cocaine. On the other hand, continuously eating fat produces big metabolic changes like hyperleptinemia and increased bodyweight and but has no effect regarding vulnerability to drug use. However, when access to fat is interrupted (withdrawal period), the increased response to the rewarding effects of drugs arises, confirming that the reward system has become sensitized. Both fat consumption patterns produce several changes in gene expression of mu opioid receptor, of cannabinoid receptor CB1 and of ghrelin receptor GHSR, indicating that both patterns of fat consumption changed the reward system function in different manners, having long-lasting effects, even when fat is no longer available. Our work shows that the nutritional habits not only produce metabolic alterations in our organism or modify our body weight, they also modify our CNS and change the way w

Outcome assessment of a complex mental health intervention in the workplace. Results from the MENTUPP pilot study

Objective Multicomponent interventions are recommendable to achieve the greatest mental health benefits, but are difficult to evaluate due to their complexity. Defining long-term outcomes, arising from a Theory of Change (ToC) and testing them in a pilot phase, is a useful approach to plan a comprehensive and meaningful evaluation later on. This article reports on the pilot results of an outcome evaluation of a complex mental health intervention and examines whether appropriate evaluation measures and indicators have been selected ahead of a clustered randomised control trial (cRCT). Methods The MENTUPP pilot is an evidence-based intervention for Small and Medium Enterprises (SMEs) active in three work sectors and nine countries. Based on our ToC, we selected the MENTUPP long-term outcomes, which are reported in this article, are measured with seven validated scales assessing mental wellbeing, burnout, depression, anxiety, stigma towards depression and anxiety, absenteeism and presenteeism. The pilot MENTUPP intervention assessment took place at baseline and at 6 months follow-up. Results In total, 25 SMEs were recruited in the MENTUPP pilot and 346 participants completed the validated scales at baseline and 96 at follow-up. Three long-term outcomes significantly improved at follow-up (p < 0.05): mental wellbeing, symptoms of anxiety, and personal stigmatising attitudes towards depression and anxiety. Conclusions The results of this outcome evaluation suggest that MENTUPP has the potential to strengthen employees’ wellbeing and decrease anxiety symptoms and stigmatising attitudes. Additionally, this study demonstrates the utility of conducting pilot workplace interventions to assess whether appropriate measures and indicators have been selected. Based on the results, the intervention and the evaluation strategy have been optimised.Output Status: Forthcoming/Available Online Additional co-authors: Holland Carolyn; Leduc Caleb; Leduc Mallorie; Ni Dhalaigh Doireann; O’Brien Cliodhna;; Purebl György; Reich Hanna; Ross Victoria; Rugulies Reiner; Sanches Sarita; Thompson Katherine; Van Audenhove Chantal; MENTUPP consortium member

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa

Implementation and evaluation of a multi-level mental health promotion intervention for the workplace (MENTUPP): study protocol for a cluster randomised controlled trial

Background Well-organised and managed workplaces can be a source of wellbeing. The construction, healthcare and information and communication technology sectors are characterised by work-related stressors (e.g. high workloads, tight deadlines) which are associated with poorer mental health and wellbeing. The MENTUPP intervention is a flexibly delivered, multi-level approach to supporting small- and medium-sized enterprises (SMEs) in creating mentally healthy workplaces. The online intervention is tailored to each sector and designed to support employees and leaders dealing with mental health difficulties (e.g. stress), clinical level anxiety and depression, and combatting mental health-related stigma. This paper presents the protocol for the cluster randomised controlled trial (cRCT) of the MENTUPP intervention in eight European countries and Australia. Methods Each intervention country will aim to recruit at least two SMEs in each of the three sectors. The design of the cRCT is based on the experiences of a pilot study and guided by a Theory of Change process that describes how the intervention is assumed to work. SMEs will be randomly assigned to the intervention or control conditions. The aim of the cRCT is to assess whether the MENTUPP intervention is effective in improving mental health and wellbeing (primary outcome) and reducing stigma, depression and suicidal behaviour (secondary outcome) in employees. The study will also involve a process and economic evaluation. Conclusions At present, there is no known multi-level, tailored, flexible and accessible workplace-based intervention for the prevention of non-clinical and clinical symptoms of depression, anxiety and burnout, and the promotion of mental wellbeing. The results of this study will provide a comprehensive overview of the implementation and effectiveness of such an intervention in a variety of contexts, languages and cultures leading to the overall goal of delivering an evidence-based intervention for mental health in the workplace

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

ϒ production in p–Pb collisions at √sNN=8.16 TeV

ϒ production in p–Pb interactions is studied at the centre-of-mass energy per nucleon–nucleon collision √sNN = 8.16 TeV with the ALICE detector at the CERN LHC. The measurement is performed reconstructing bottomonium resonances via their dimuon decay channel, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and −4.46 < ycms < −2.96, down to zero transverse momentum. In this work, results on the ϒ(1S) production cross section as a function of rapidity and transverse momentum are presented. The corresponding nuclear modification factor shows a suppression of the ϒ(1S) yields with respect to pp collisions, both at forward and backward rapidity. This suppression is stronger in the low transverse momentum region and shows no significant dependence on the centrality of the interactions. Furthermore, the ϒ(2S) nuclear modification factor is evaluated, suggesting a suppression similar to that of the ϒ(1S). A first measurement of the ϒ(3S) has also been performed. Finally, results are compared with previous ALICE measurements in p–Pb collisions at √sNN = 5.02 TeV and with theoretical calculations.publishedVersio