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Research on resilience and vulnerability can offer very valuable information for optimizing design and assessment of interventions and policies aimed at fostering adolescent health. This paper used the adversity level associated with family functioning and the positive adaptation level, as measured by means of a global health score, to distinguish four groups within a representative sample of Spanish adolescents aged 13–16 years: maladaptive, resilient, competent and vulnerable. The aforementioned groups were compared in a number of demographic, school context, peer context, lifestyles, psychological and socioeconomic variables, which can facilitate or inhibit positive adaptation in each context. In addition, the degree to which each factor tended to associate with resilience and vulnerability was examined. The majority of the factors operated by increasing the likelihood of good adaptation in resilient adolescents and diminishing it in vulnerable ones. Overall, more similarities than differences were found in the factors contributing to explaining resilience or vulnerability. However, results also revealed some differential aspects: psychological variables showed a larger explicative capacity in vulnerable adolescents, whereas factors related to school and peer contexts, especially the second, showed a stronger association with resilience. In addition, perceived family wealth, satisfaction with friendships and breakfast frequency only made a significant contribution to the explanation of resilience. The current study provides a highly useful characterization of resilience and vulnerability phenomena in adolescence. [This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission.]

Entre los objetivos de la Fundacion Respira se encuentra aumentar el conocimiento de las enfermedades respiratorias entre la ciudadania. En este contexto se enmarcan los llamados Anos SEPAR (Sociedad Espanola de Neumologia y Cirugia Toracica). Bajo esta denominacion se agrupan un conjunto de actividades que giran en torno a una enfermedad o una problematica que representa un grave problema de salud para la comunidad, y que repercute tanto en la poblacion como en los profesionales y la administracion sanitaria. Esta iniciativa ha facilitado que SEPAR y la Fundacion Respira no solo incrementen su impacto social, sino que ademas den cumplimiento a uno de sus principales objetivos como sociedad y fundacion cientificas: prevenir la morbimortalidad de las enfermedades respiratorias a traves del incremento de la sensibilizacion e informacion de la poblacion general espanola. Las principales guias sobre el abordaje diagnostico y manejo terapeutico de la enfermedad pulmonar obstructiva cronica (EPOC), entre las que destaca nuestra guia GesEPOC, la Guia Espanola de la EPOC, definen la EPOC como una enfermedad «esencialmente caracterizada por una limitacion cronica al flujo aereo poco reversible y asociada principalmente al humo de tabaco»1,2. Existen evidencias clinicas, morfologicas y epidemiologicas incontestables que relacionan el papel etiologico del tabaquismo en la EPOC. Actualmente, la EPOC constituye un problema de salud publica de alta magnitud debido al alto impacto en la morbimortalidad de los sujetos que la padecen: los estudios epidemiologicos ponen de manifiesto unas perspectivas de crecimiento de la prevalencia para los proximos anos a nivel mundial3. En Espana, se sabe que aproximadamente 18.000 personas mueren al ano por esta enfermedad, que tambien origina un elevado coste social y sanitario3,4. Por otra parte, el estudio «EPI-SCAN»5 estima que, actualmente, entre los 21,4 millones de espanoles con una edad entre 40 y 80 anos, hay 2.185.764 que presentan EPOC (10,2%). Por sexos, las cifras corresponden a 1.571.868 varones y 628.102 mujeres. En este mismo estudio se estima que el 73% de la poblacion aun no esta diagnosticada, es decir, aproximadamente 1.600.000 sujetos

This research is part of the 2006 edition of the Health Behavior in School-aged Children (HBSC) study. The data presented were composed of a sample of 15942 Spanish adolescents ranging from 13 to 18 years of age. The instruments used included a variety of questions related to substance consumption among adolescents, their bio-psycho-social adjustment and developmental contexts, all of which are part of the HBSC study instrument bank. Through classification analysis, as well as significance and effect size tests, we obtained relevant information about the current epidemiology of substance consumption among Spanish adolescents. These results are representative of the Spanish adolescent population which allows the typical risk profile attributed to young people to be clarified. A gradual adjustment can be seen in terms of substance consumption levels in youth and that same level in their friends. Likewise, the analysis of the developmental context (family, friends and school) provides important information when it comes to preventing substance consumption, thus showing the advantages that coherence and connection have between the different environments where youth live, grow up and develop.

In laboratory studies, acquired resistance to long-term antihormonal therapy in breast cancer evolves through two phases over 5 y. Phase I develops within 1 y, and tumor growth occurs with either 17β-estradiol (E 2 ) or tamoxifen. Phase II resistance develops after 5 y of therapy, and tamoxifen still stimulates growth; however, E 2 paradoxically induces apoptosis. This finding is the basis for the clinical use of estrogen to treat advanced antihormone-resistant breast cancer. We interrogated E 2 -induced apoptosis by analysis of gene expression across time (2–96 h) in MCF-7 cell variants that were estrogen-dependent (WS8) or resistant to estrogen deprivation and refractory (2A) or sensitive (5C) to E 2 -induced apoptosis. We developed a method termed differential area under the curve analysis that identified genes uniquely regulated by E 2 in 5C cells compared with both WS8 and 2A cells and hence, were associated with E 2 -induced apoptosis. Estrogen signaling, endoplasmic reticulum stress (ERS), and inflammatory response genes were overrepresented among the 5C-specific genes. The identified ERS genes indicated that E 2 inhibited protein folding, translation, and fatty acid synthesis. Meanwhile, the ERS-associated apoptotic genes Bcl-2 interacting mediator of cell death (BIM; BCL2L11) and caspase-4 (CASP4), among others, were induced. Evaluation of a caspase peptide inhibitor panel showed that the CASP4 inhibitor z-LEVD-fmk was the most active at blocking E 2 -induced apoptosis. Furthermore, z-LEVD-fmk completely prevented poly (ADP-ribose) polymerase (PARP) cleavage, E 2 -inhibited growth, and apoptotic morphology. The up-regulated proinflammatory genes included IL, IFN, and arachidonic acid-related genes. Functional testing showed that arachidonic acid and E 2 interacted to superadditively induce apoptosis. Therefore, these data indicate that E 2 induced apoptosis through ERS and inflammatory responses in advanced antihormone-resistant breast cancer.

Leptin is an adipocyte-derived hormone which stimulates β-oxidation in peripheral tissues and prevents steatosis. Because leptin production naturally increases during adult life, we have hypothesized that leptin receptors might undergo a physiological and gradual desensitization during ageing. Therefore we have characterized in three- five- and ten-month old mice i) the weight of different white adipose pads, heart and liver, ii) lipid content in these tissues/organs, and iii) responsiveness to acute leptin, measured in terms of phosphorylation of signal transducer and activator of transcription 3 (STAT3) and protein kinase B (Akt). In this study we have detected that leptin-mediated STAT3 phosphorylation appears to be preserved in cardiac tissue even in 10-month old animals but not in adipose tissue and liver of five- and ten-month old mice, respectively. Nevertheless, leptin increased pAkt content in the liver of these mice. In a parallel study we have analyzed the functionality of leptin signalling pathways in 10-month old obese mice and we have observed that the STAT3 pathway appears to be only operative in the heart whereas the Akt pathway remains functional both in heart and liver. Nevertheless, hepatic lipids increased almost 300% compared to age-matched lean controls. Our data demonstrate that during adult life there is a lost of leptin receptor functionality which is tissue-dependent and mainly affects the STAT3 pathway. Otherwise we demonstrate that the antisteatotic effect of leptin is independent of the Akt signalling pathway.

Resumen La obesidad, bien conocida como factor de riesgo cardiovascular, puede asimismo comportar una importante afectacion respiratoria. Las alteraciones respiratorias relacionadas con la obesidad abarcan desde la simple alteracion de la funcion ventilatoria, sin consecuencias sobre el intercambio gaseoso, hasta la situacion mas grave, la insuficiencia respiratoria hipercapnica caracteristica del sindrome de obesidad hipoventilacion. Mas recientemente se ha senalado la presencia de un incremento de prevalencia de asma de probable etiologia multifactorial pero en el que puede desempenar un papel importante la inflamacion. La hipoventilacion en el sujeto obeso es el resultado de complejas interacciones que implican a las alteraciones de la mecanica ventilatoria y a anomalias del control ventilatorio. Otras dos entidades (enfermedad pulmonar obstructiva cronica y sindrome de apnea hipopnea del sueno [SAHS]), frecuentemente presentes en los pacientes obesos, pueden potenciarla o agravarla. La prevalencia de hipoventilacion en el obeso se encuentra subestimada y es frecuente que el diagnostico solo se establezca con motivo de una exacerbacion o cuando el paciente es estudiado por sospecha de SAHS. El manejo ventilatorio de estos pacientes, mediante CPAP o ventilacion no invasiva (VNI) dependera de la situacion clinica subyacente y de la presencia o no de otra comorbilidad. Tanto la VNI como la CPAP han mostrado su eficacia no solo en el control de las alteraciones gasometricas, sino tambien en la mejora de la calidad de vida y en la supervivencia de los pacientes.

We hypothesized that Leishmania kDNA may be present in urine of patients with cutaneous leishmaniasis (CL). Urine samples and standard diagnostic specimens were collected from patients with skin lesions. kDNA polymerase chain reaction (PCR) was performed on samples from patients and 10 healthy volunteers from non-endemic areas. Eighty-six of 108 patients were diagnosed with CL and 18 (21%) had detectable Leishmania Viannia kDNA in the urine. Sensitivity and specificity were 20.9% (95% confidence interval [CI] 12.3-29.5%) and 100%. Six of 8 patients with mucocutaneous involvement had detectable kDNA in urine versus 12 of 78 patients with isolated cutaneous disease (P < 0.001). L. (V.) braziliensis (N = 3), L. (V.) guyanensis (N = 6), and L. (V.) peruviana (N = 3) were identified from urine. No healthy volunteer or patient with an alternate diagnosis had detectable kDNA in urine. Sensitivity of urine PCR is sub-optimal for diagnosis. On the basis of these preliminary data in a small number of patients, detectable kDNA in urine may identify less localized forms of infection and inform treatment decisions.

Este articulo tiene el objetivo de tratar en profundidad uno de los modelos mas revolucionarios e influyentes para la comprension de las variables y procesos que explican la salud humana. A partir de una nueva vision en el analisis de las consecuencias del holocausto nazi, un medico-sociologo -Aaron Antonovsky-, consiguio influir en la medicina y la ciencia del comportamiento, facilitando las claves para el optimo desarrollo de la salud publica actual. A pesar de que esta teoria empezo a forjarse en los anos 70 del siglo XX, su desarrollo real y su expansion estan sucediendo en los ultimos anos. De hecho, en Espana existe muy poca literatura con base cientifica que analice con detalle las claves teoricas del modelo. Este trabajo trata de cubrir esa carencia y, para ello, y en primer lugar, expone como surgio el constructo salutogenesis, el contexto sociocultural que lo impulso, asi como la importancia que adquiere en la salud publica actual. Con este objetivo, en estas paginas se analizan las bases teoricas del modelo salutogenico, con especial enfasis en sus antecedentes y precursores, asi como en sus inicios, desarrollo y expansion actual.

Cross-national analyses explore the consistency of the relationship between negative school experiences and involvement in bullying across 40 European and North American countries, using the 2006 (40 countries n = 197,502) and 2002 (12 countries, n = 57,007) WHO-HBSC surveys. Measures include two Cumulative Negative School Perception (CNSP) scales, one based on 6 mandatory items (2006) and another including an additional 11 items (2002). Outcome measures included bullying perpetration, victimization and involvement as both bully and victim. Logistic regression analyses suggested that children with only 2-3 negative school perceptions, experience twice the relative odds of being involved in bullying as compared with children with no negative school perceptions. Odds Ratios (p < 0.001) increase in a graded fashion according to the CNSP, from about 2.2 to over 8.0. Similar consistent effects are found across gender and almost all countries. Further research should focus on the mechanisms and social context of these relationships.

Background: Basal-like breast (BLB) cancer accounts for ∼15% of all breast cancers diagnosed. Patients with BLB cancer are typically younger, present with higher tumor grade and despite recent advances in therapy, still have a poor outcome. BLB cancers are the most proliferative breast tumor sub-type, are commonly triple-negative (ER-, PgR-, HER2/neu-), and often harbor mutations in TP53 and BRCA1. The biological drivers of disease progression in this tumor subtype remains poorly understood. Recently, VAV3, a guanine nucleotide exchange factor and a member of the of the Rho/Rac/Cdc42 GTPase superfamily, has been reported as overexpressed and oncogenic in ER+ breast cancer cells. Our preliminary studies using publicly available microarray data indicates a consistent lack of VAV3 in BLB cancer, particularly those patients with shorter survival time following chemotherapy. We therefore hypothesize that VAV3 is a novel biomarker of BLB cancer and potential predictor of chemosensitivity in this subtype. Materials and Methods: Gene expression microarray technology, qRTPCR and western blotting was used to investigate relative expression of VAV3 in a panel of breast cancer cell lines and tumors. Array Comparative Genomic Hybridization and Fluorescence in Situ Hybridization were used to evaluate VAV3 gene copy number. BLB cancer cell lines stably overexpressing VAV3 were developed to evaluate the role of VAV3 in sensitivity to chemotherapy. Results: Unsupervised hierarchical clustering revealed low VAV3 expression in BLB tumors compared to all other intrinsic subtypes. Consistently lower VAV3 mRNA and protein expression were observed in BLB cancer cell lines compared to luminal epithelial cell lines, consistent with our in silico observations. We confirmed that low VAV3 expression in the BLB cancer cell lines is not due to gene copy number loss. Ectopic expression of VAV3 in MDA-MB-231 BLB cancer cells significantly enhanced their sensitivity to cisplatin. Discussion: A consistent lack of VAV3 gene expression is evident in BLB tumors, however the mechanism underlying this loss is yet to be elucidated. Our findings support a hypothesis that low VAV3 expression is a potential diagnostic biomarker of BLB cancer, and that VAV3 expression may be a predictor of response to chemotherapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-23.

Introduccion El objetivo de este estudio ha sido analizar la prevalencia, las actitudes y las caracteristicas del tabaquismo en la poblacion de pacientes sometidos a oxigenoterapia cronica domiciliaria (OCD) en la Comunidad de Madrid. Pacientes y metodos De un total de 11.174 sujetos que cumplian los criterios de inclusion, se obtuvo una muestra representativa de 845 sujetos. De ellos 461 (54,6%) eran hombres. La edad media fue de 78,25 anos [IC95%:77,55�78,95; Dt=10,36]. Se realizo un estudio descriptivo transversal basado en cuestionarios y acompanado de cooximetria. Resultados 48 sujetos (5,7%; IC95%: 4,3�7,5%) eran fumadores y 438 (51,8%; IC95%: 48,5�55,2%) exfumadores. La tasa de fumadores activos fue mas alta en el grupo de sujetos con 60 o menos anos (?2; p

BACKGROUND: Primary care is the ideal setting for early identification of patients with non-alcoholic fatty liver disease (NAFLD). NAFLD is a potentially progressive disease that may lead to cirrhosis and liver cancer but is frequently underrecognized because subjects at risk are often not evaluated. Controlled attenuation parameter (CAP) is a reliable method for non-invasive quantification of liver fat. It has the advantage of simultaneous measurement of liver stiffness (LS), an estimate of liver fibrosis. There is no information on CAP in subjects with risk factors from primary care. AIM: To investigate the prevalence of hepatic steatosis, as estimated by CAP, in subjects from the community with metabolic risk factors and correlate findings with clinical and biochemical characteristics and LS. PATIENTS AND METHODS: Population-based study of 215 subjects with metabolic risk factors without known liver disease identified randomly from a primary care center. A control group of 80 subjects matched by age and sex without metabolic risk factors was also studied. CAP and LS were assessed using Fibroscan. RESULTS: Subjects with risk factors had CAP values higher than those of control group (268±64 vs 243±49dB/m,p 280dB/m) in subjects with risk factors was 43%. In multivariate analysis, fatty liver index (FLI) and HOMA were independent predictive factors of severe steatosis. There was a direct correlation between CAP and FLI values (r = 0.52,p

In the last few years, considerable interest has been aroused in the treatment of chronic obstructive pulmonary disease (COPD) and the dearth of therapeutic options has been replaced by a far more proactive treatment approach, reflected in the development of the various guidelines and recommendations of the scientific societies. There are three main steps in the treatment of COPD: prevention of the disease, treatment of its symptoms, progression and complications, and recovery of physical function through respiratory rehabilitation. Considerable advances have been produced in these three dimensions, but limitations have been detected, indicating areas for improvement. The most effective means to prevent the disease is smoking cessation. While there are moderately effective drugs to help individuals quit, no drugs are available to prevent relapses. Moreover, due to health policies, most patients with COPD do not receive drug treatment for smoking. The treatment of COPD and its complications is based on the use of bronchodilators, which improve symptoms and quality of life and, to a greater or lesser extent, prevent exacerbations. However, treatment aimed at the underlying pathogenic causes of the disease, which should be antiinflammatory treatment, remains an unresolved issue due to the discouraging results obtained with inhaled corticosteroids, which should always be used in combination with a bronchodilator. The development of new antiinflammatory agents, such as roflumilast, could improve the management of patients with the most severe disease and repeated exacerbations. Lastly, although respiratory rehabilitation is highly effective in helping patients recover their ability to exercise, few patients have access to this option. As with the treatment of smoking, there is a need to implement respiratory rehabilitation through simple and effective programs and with the support of the health administration.

BACKGROUND Traditional detection of Leishmania from ulcers involves collection of invasive specimens that cause discomfort, require technical expertise, and carry risks of invasive procedures. We compared traditional diagnostic methods with a molecular noninvasive filter paper-based method for the diagnosis of cutaneous leishmaniasis. METHODS Consecutive patients presenting to the Leishmania Clinic at Hospital Nacional Cayetano Heredia were enrolled. Polymerase chain reaction (PCR) was performed on lesion scrapings, aspirates, and filter paper impressions. The reference standard was any 2 of 5 tests positive: smear, aspirate culture, invasive-specimen PCR (scrapings and aspirates), filter paper PCR, and leishmanin skin test. Outcome measures were sensitivity and specificity. Leishmania speciation was performed by PCR-restriction fragment length polymorphism (RFLP) of positive specimens. RESULTS Forty-five patients with 66 lesions were enrolled. Of 52 lesions diagnosed as cutaneous leishmaniasis, 50 were positive by PCR of invasive specimens versus 48 by PCR of filter papers (P=.930). Sensitivity and specificity of PCR on invasively obtained specimens were 94.2% (95% confidence interval [CI], 87.9%-100%) and 92.9% (95% CI, 79.4%-100%). Sensitivity and specificity of filter paper PCR were 92.3% (95% CI, 85.1%-99.5%) and 100%. Culture, smear, and leishmanin skin test all had inferior sensitivities, compared with PCR of invasive or noninvasive specimens (P

Aims: To describe the prevalence of recent use of alcohol, medication, and illegal drugs among patients who attended emergency departments (EDs) as a result of suffering an injury due to any external mechanism and to identify factors associated with alcohol and drug use. Methods: A cross-sectional study was conducted in eight university hospitals in Spain. Participants were adult patients admitted to a trauma ED. Oral fluid was used to test for psychoactive substances analyzed by gas chromatography-mass spectrometry. Socio-demographic data and information on circumstances of the injury were collected through interviews. Results: The analysis included 1579 patients admitted to the EDs (56.4% men). Among Young people (= 40 years, 7.4% of men and 1.6% of women were positive for any illegal substance, and 16.3% and 11.0% respectively for alcohol. Prevalence of substance detected varied across mechanism of injury, gender and age group. Night-time injury was associated with substance use. Conclusions: A high proportion of injured patients who were treated in an EDs tested positive for psychoactive drugs. Routine testing at trauma departments would maximize the identification of patients who may benefit from referral to specialized addiction treatment centers, or brief interventions. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Objective Our previous study indicated that partially hydrogenated fat (PHF) diets, rich in trans -isomers, alter plasma lipids and increase the lipogenesis rate on adipose tissue in rats at a young age. In the present study we investigated the effects of dietary PHF on the expression of genes associated with glucose and lipid metabolism in rat adipose tissue. Methods Female Wistar rats were fed normolipidic diets containing PHF (rich in trans -fatty acids and poor in polyunsaturated fatty acids [PUFAs]), soy oil (rich in ω-6 PUFAs), and fish oil (rich in ω-3 PUFAs) during gestation and lactation; young male pups were fed the same diets from weaning until 120 d of life. The mRNA expression of peroxisome proliferator-activated receptor-γ, tumor necrosis factor-α, resistin, adiponectin, and leptin were analyzed in retroperitoneal adipose tissue (RET) using real time polymerase chain reaction. Results The PHF group showed the highest triacylglycerol, glucose, and insulin levels and the lowest plasma adiponectin level. The RET of PHF incorporated trans -fatty acids, whereas fish oil and soy oil groups had increased ω-3 and ω-6 PUFAs, respectively. In the RET the PHF group had the highest resistin and tumor necrosis factor-α levels and the lowest adiponectin and peroxisome proliferator-activated receptor-γ gene expressions, whereas the fish oil group had the highest peroxisome proliferator-activated receptor-γ and the lowest leptin gene expression. Conclusion Prolonged intake of PHF has a negative effect on the expression of genes in RET when compared with diets with ω-6 and ω-3 PUFAs. These changes may be an effect of the smaller proportions of PUFAs in this fat, instead of being only caused by trans -fatty acids.

The purpose of this qualitative study is to investigate young people's perceptions, in Barcelona, Spain, about the evolution, magnitude, causes and determinants of traffic crashes, to describe their opinions on road safety regulations, and to explore their suggestions and proposals. Interviews were conducted with 43 key informants and 12 focus groups involving 98 participants. Discussion guides were designed to get insight on perceptions of relevance and trends in road traffic injuries, determinants of these, regulations and enforcement, as well as to gather their own ideas for reducing traffic injuries. Young people are aware that traffic injuries are a relevant and increasingly serious problem. The main determinants identified are: driving under the influence of drugs and alcohol, fatigue, night driving, unsafe infrastructures, age of drivers and lack of public transport alternatives. Young people admit that fines, speed cameras and alcohol breath testing reduce risky driving. They prefer community work to fines. They have a poor image of public administrations in charge of prevention of traffic injuries. They demand information on traffic regulations and politicians' decisions, and a considerable increase in weekend and night time public transport. Effectiveness of interventions to reduce traffic injuries can be improved by taking the recipients' perceptions into account.

Insulin resistance is a hallmark of late pregnancy both in human and rat. Adipose tissue is one of the tissues that most actively contributes to this reduced insulin sensitivity. The aim of the present study was to characterize the molecular mechanisms of insulin resistance in adipose tissue at late pregnancy. To this end, we analyzed the insulin signaling cascade in lumbar adipose tissue of nonpregnant and pregnant (d 20) rats both under basal and insulin-stimulated conditions. We found that the levels of relevant signaling proteins, such as insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3-kinase, 3-phosphoinositide-dependent kinase-1, ERK1/2, and phosphatase and tensin homolog (PTEN) did not change at late pregnancy. However, insulin-stimulated tyrosine phosphorylation of both IR and IRS-1 were significantly decreased, coincident with decreased IRS-1/p85 association and impaired phosphorylation of AKR mouse thymoma viral protooncogene (Akt) and ERK1/2. This impaired activation of IRS-1 occurred together with an increase of IRS-1 phosphorylation at serine 307 and a decrease in adiponectin levels. To corroborate the role of IRS-1 in adipose tissue insulin resistance during pregnancy, we treated pregnant rats with the antidiabetic drug englitazone. Englitazone improved glucose tolerance, and this pharmacological reversal of insulin resistance was paralleled by an increase of adiponectin levels in adipose tissue as well as by a reduction of IRS-1 serine phosphorylation. Furthermore, the impaired insulin-stimulated tyrosine phosphorylation of IRS-1 in adipose tissue of pregnant animals could be restored ex vivo by treating isolated adipocytes with adiponectin. Together, our findings support a role for adiponectin and serine phosphorylation of IRS-1 in the modulation of insulin resistance in adipose tissue at late pregnancy.

Our aim in performing this study was to analyze in vivo the cell death mechanism induced by toxic doses of digitalis compounds on guinea-pig cardiomyocytes. We analyzed three study groups of five male guinea pigs each. Guinea pigs were intoxicated under anesthesia with ouabain or digoxin (at a 50-60% lethal dose); the control group did not receive digitalis. A 5-hours period elapsed before guinea pig hearts were extracted to obtain left ventricle tissue. We carried out isolation of mitochondria and cytosol, cytochrome c and caspase-3 and -9 determination, and electrophoretic analysis of nuclear DNA. TdT-mediated DUTP-X nick end labeling (TUNEL) reaction was performed in histologic preparations to identify in situ apoptotic cell death. Ultrastructural analysis was performed by electron microscopy. Electrophoretic analysis of DNA showed degradation into fragments of 200-400 base pairs in digitalis-treated groups. TUNEL reaction demonstrated the following: in the control group

La enfermedad pulmonar obstructiva cronica (EPOC) se caracteriza por la presencia de obstruccion poco reversible al flujo aereo, que aparece como consecuencia de una reaccion inflamatoria anomala ante la exposicion a agentes nocivos, habitualmente el humo de tabaco. No es sorprendente que su tratamiento farmacologico, por tanto, se base en el empleo de farmacos broncodilatadores y antiinflamatorios, es decir, corticoides inhalados. Dentro de los farmacos broncodilatadores, los agonistas β 2 actuan a traves de la relajacion de la fibra muscular lisa, pero tambien se ha descrito un mecanismo antiinflamatorio adicional. Aunque su utilizacion no impida la progresion de la enfermedad, si determina una mejoria en las pruebas de funcion pulmonar, asi como una disminucion de los sintomas. Estos resultados son mas patentes con el uso de los agonistas ?2 de accion prolongada, que tambien se asocian a una reduccion de las exacerbaciones y a un incremento de la tolerancia al ejercicio, de manera que, a fecha de hoy, los adrenergicos β 2 de accion corta se recomiendan en pacientes con enfermedad leve, poco sintomaticos, mientras que en los que requieren tratamiento de forma regular es aconsejable el uso de adrenergicos β 2 de accion prolongada. En cuanto a los corticoides inhalados, su mayor eficacia se observa en pacientes con enfermedad grave, en quienes consiguen mejorar la calidad de vida y reducir el numero de exacerbaciones; por lo tanto, estan recomendados en este grupo de pacientes. Por otra parte, cada vez se dispone de mayor evidencia de que los corticoides inhalados pueden asociarse a una reduccion de la mortalidad, lo que podria llevar a cambiar las recomendaciones actuales.

Background: The MPOWER strategy encourages suitable monitoring of the tobacco epidemic among health professionals in all countries. Objective: To analyse the prevalence of and attitudes towards tobacco use among Spanish health professionals. Methods: A study was conducted based on an online survey. The study population consisted of health professionals (primary care physicians, specialist physicians and nurses). The questionnaire used included questions about tobacco consumption, knowledge of and attitudes towards smoking. The sample size was calculated according to a database with 9,500 e-mail addresses and listings of health centres and hospitals all over Spain. Statistical analysis was done using the SPSS software programme. Results: The study group comprised a total of 612 health professionals: 322 were women (52.6%), 196 were nurses and 416 were physicians. 11.7% of health professionals were smokers (9.6% regular smokers and 2.1% occasional smokers) and 41.3% were ex-smokers. Within the group of daily smokers, differences were observed between the nurses and the physicians: 11.2 versus 8.9% (p = 0.009). Smoking was recognized as a chronic disorder by 58.2% of health professionals, and 54.6% knew that the most effective intervention to help quit is a combination of psychological and pharmacological treatment. 56% of health professionals always asked their patients about their tobacco consumption. Conclusions: 11.7% of Spanish health professionals are smokers. We found that they have low knowledge about strategies to quit smoking and that there is a low level of therapeutic intervention on smokers.

El Estado colombiano definió los sistemas de gestión de calidad y control interno como herramientas de gestión de obligatoria implementación bajo los referentes de la Norma Técnica de Calidad en la Gestión Pública y el Modelo Estándar de Control Interno. Posteriormente, en pro del mejoramiento continuo de la administración pública y de la mejora de la gestión, se especificaron lineamientos adicionales asociados a las políticas de desarrollo administrativo, los cuales generaron en las entidades públicas la incorporación de requerimientos que impactan estos sistemas produciendo desgastes administrativos, fallas en el control de los procesos, desinformación y sobrecostos, entre otros. Este proyecto de investigación buscó crear una propuesta metodológica que permita a los entes gubernamentales nacionales incorporar algunos conceptos como políticas, requerimientos, temas o componentes (entre otros significados) a sus modelos de gestión de calidad y normas de control interno realizados previamente y basados en esos modelos. Por lo anterior, analizada la Teoría de Creación del Conocimiento Organizacional de Nonaka y Kakeuchi, frente a los sistemas de gestión de calidad y control interno aplicables a las entidades del Estado colombiano del ámbito nacional, se identificó un vínculo que reconoce la existencia de condiciones que facilitan el flujo del conocimiento a través de la socialización entre individuos y organizaciones, toda vez que se establecen lineamientos que propician, regulan, justifican y promueven la generación de nuevos conceptos, para incorporarlos a la gestión institucional. Definida la propuesta, se realizó un ejercicio de validación en la ANLA para incorporar el objeto de conocimiento “participación ciudadana y control social” a sus sistemas y se estableció que la articulación de las fases de creación del conocimiento organizacional con los sistemas de gestión, facilita la incorporación de nuevos objetos de conocimiento garantizando la integridad de los sistemas ya implementados. Colombian Government established the quality management and internal control as mandatory tools of management, according to Quality Technical Standards NTCGP:1000 and the Standard Model of Internal Control, incorporated by government in decrees 4485 of 2009 and 1599 of 2005 respectively. Moreover, looking for the continuous improvement of public administration and the capability to enhance its arrangement, Colombian government has defined another kind of policies and organizational methodologies mainly related to the administrative development, which has induced to national government entities to incorporate the requirements that affect among others implemented quality systems, involving administrative wastage, out of control over processes, not enough information and overcosts. Current research project tries to create a methodological purpose that let national government entities, incorporate some concepts as policies, requirements, topics or components (among other meanings) to its models of quality management and internal control standards accomplished previously and based on those models are a complement that must be adopted. Therefore and once analized the Theory of Organizational Knowledge Creation raised by Nonaka and Takeuchi in their book “The Knowledge Creating Company”, the quality management systems and internal control standards applied to national government entities, there is an identified linkage that recognizes that some conditions help to the knowledge flow, between people, groups and organizations, due that policies bring on, adjust, control and promote the new concepts generation, getting its incorporation to institutional management. Once the methodological purpose is defined, there was a validation test in National Authority of Environmental Licenses Agency, in order to incorporate the knowledge object named “Citizen participation and social control” to the implemented systems, that let establish and link up the creation phases of organizational knowledge to the quality management systems and internal control, so incorporate new knowledge objects assure wholeness to implemented systems in an easier way.

Many nanoparticles (NPs) have toxic effects on multiple cell lines. This toxicity is assumed to be related to their accumulation within cells. However, the process of internalization of NPs has not yet been fully characterized. In this study, the cellular uptake, accumulation, and localization of titanium dioxide nanoparticles (TiO2 NPs) in rat (C6) and human (U373) glial cells were analyzed using time-lapse microscopy (TLM) and transmission electron microscopy (TEM). Cytochalasin D (Cyt-D) was used to evaluate whether the internalization process depends of actin reorganization. To determine whether the NP uptake is mediated by phagocytosis or macropinocytosis, nitroblue tetrazolium (NBT) reduction was measured and the 5-(N-ethyl-N-isopropyl)-amiloride was used. Expression of proteins involved with endocytosis and exocytosis such as caveolin-1 (Cav-1) and cysteine string proteins (CSPs) was also determined using flow cytometry. TiO2 NPs were taken up by both cell types, were bound to cellular membranes and were internalized at very short times after exposure (C6, 30 min; U373, 2h). During the uptake process, the formation of pseudopodia and intracellular vesicles was observed, indicating that this process was mediated by endocytosis. No specific localization of TiO2 NPs into particular organelles was found: in contrast, they were primarily localized into large vesicles in the cytoplasm. Internalization of TiO2 NPs was strongly inhibited by Cyt-D in both cells and by amiloride in U373 cells; besides, the observed endocytosis was not associated with NBT reduction in either cell type, indicating that macropinocytosis is the main process of internalization in U373 cells. In addition, increases in the expression of Cav-1 protein and CSPs were observed. In conclusion, glial cells are able to internalize TiO2 NPs by a constitutive endocytic mechanism which may be associated with their strong cytotoxic effect in these cells; therefore, TiO2 NPs internalization and their accumulation in brain cells could be dangerous to human health.

To evaluate the process and the results of the pilot phase of the Parenting skills development programme for families (PSP), an evidence-based strategy to promote positive parenting skills in socio-educational and community settings.Before-after quasi-experimental design without a control group for the evaluation of the pilot phase of the PSD carried out in Barcelona (Spain) between October 2011 and June 2013. Eleven groups were established with the participation of 128 parents and 28 professionals. The intervention consisted of 10 or 11 sessions. Information was collected through questionnaires for parents and in-depth individual or group interviews for professionals. Parenting skills were identified through a questionnaire with six dimensions. The situation before the intervention (T0) and immediately after (T1) was compared.In T1 the number of participants decreased to 83 (retention=64.8%). Participants showed a high level of satisfaction with different dimensions of the program. On a maximum score of 10, the satisfaction of professionals was 8.7. Several key aspects and areas for improvement were identified for the future of the intervention. The quantitative analysis revealed improvements in all parenting skills dimensions and these improvements were consistent with the results of the qualitative analysis.The results of the pilot phase of this program suggest that a universal intervention on parenting skills can improve wellbeing among parents.

Objective— Perivascular adipose tissue of normotensive rats releases a transferable factor that induces relaxation by opening voltage-dependent K + (K v ) channels. The relevance of these observations to hypertension is unknown. Methods and Results— We characterized mesenteric perivascular adipose tissue from 3-month-old Wistar Kyoto rats (WKY) and aged-matched spontaneously hypertensive rats (SHR). Mesenteric bed (MB) weight and MB total lipid content were lower in SHR than in WKY. Freshly isolated MB adipocytes were smaller in SHR. Plasma triglycerides, glycerol, nonesterified free-fatty acids, and cholesterol were also lower in SHR. Plasma and mesenteric leptin were correlated with the quantity of mesenteric fat. To study vascular function, the MB was cannulated and perfused at a constant 2 mL/min flow. The K v channel blocker 4-aminopyridine (4-AP; 2 mmol/L) increased perfusion pressure less in SHR MB than WKY and was directly correlated with the mesenteric fat amount. In isolated mesenteric artery rings, 4-AP (2 mmol/L) induced a contractile effect that was attenuated in SHR compared with WKY. The anticontractile effects of perivascular fat were reduced in SHR mesenteric artery rings compared with WKY. Conclusions— Differences in visceral perivascular adipose tissue mass and function may contribute to the increased vascular resistance observed in SHR.

Cholecystokinin (CCK) is a postprandial hormone that elicits a satiating effect and regulates feeding behaviour. CCK has been shown to enhance the effect of leptin in several experimental paradigms. The goal of this work was to characterize the effect of endogenous CCK on plasma leptin content by using CCK receptor antagonists. Therefore, we administered SR-27897, a selective CCK1 receptor antagonist, and L-365260, a selective CCK2 receptor antagonist, to fed and food-deprived rats and determined plasma leptin concentration by enzyme immunoassay. Plasma insulin and glucose concentration as well as food intake were also determined. Under our conditions, SR-27897 increased plasma concentration of leptin both in fed and food-deprived rats. It also increased food intake as well as plasma concentration of insulin in fed animals. L-365260 increased plasma leptin concentration only in fed rats. In animals receiving exogenous leptin, CCK-8 increased the ratio between the concentration of leptin in cerebrospinal fluid and plasma. These results show that CCK receptor antagonists increases plasma concentration of leptin and suggest that endogenous CCK may facilitate the uptake of plasma leptin to the cerebrospinal fluid.

The most common cause of infant mortality is diarrhea; the most common cause of bacterial diarrhea is Campylobacter jejuni, which is also the primary cause of motor neuron paralysis. The first step in campylobacter pathogenesis is adherence to intestinal mucosa. We found that such binding was inhibited in vitro by human milk and, with high avidity, by alpha1,2-fucosylated carbohydrate moieties containing the H(O) blood group epitope (Fuc alpha 1,2Gal beta 1,4GlcNAc em leader ). In studies on the mechanism of adherence, campylobacter, which normally does not bind to Chinese hamster ovary cells, bound avidly when the cells were transfected with a human alpha1,2-fucosyltransferase gene that caused overexpression of H-2 antigen; binding was specifically inhibited by H-2 ligands (lectins Ulex europaeus and Lotus tetragonolobus and H-2 monoclonal antibody), H-2 mimetics, and human milk oligosaccharides. Human milk oligosaccharides inhibited campylobacter colonization of mice in vivo and human intestinal mucosa ex vivo. Campylobacter colonization of nursing mouse pups was inhibited if their dams had been transfected with a human alpha1,2-fucosyltransferase gene that caused expression of H(O) antigen in milk. We conclude that campylobacter binding to intestinal H-2 antigen is essential for infection. Milk fucosyloligosaccharides and specific fucosyl alpha1,2-linked molecules inhibit this binding and may represent a novel class of antimicrobial agents.

Subunits of the SWI/SNF chromatin-remodeling complex are tumor suppressors that are inactivated in ~20% of all cancers, yet few targeted treatments have shown selective activity in SWI/SNF-mutant cancers. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by SWI/SNF dysregulation. Given that two-year survival following standard high-dose chemotherapy and radiation in SCCOHT is less than 35%, a great need exists for effective targeted therapies to improve outcomes for these women. We previously demonstrated that SCCOHT tumors are driven by inactivating mutations in SMARCA4, one of two mutually exclusive SWI/SNF ATPases. In addition, we have shown that SCCOHT lacks expression of the alternative SWI/SNF ATPase, SMARCA2. We have now found through integrated genomic and functional analyses in SCCOHT tumors and cell lines that SMARCA4 loss correlates with increased expression of receptor tyrosine kinases (RTKs) including the platelet derived growth factor receptors (PDGFRs). Through integration of high-throughput RNA interference and drug screens in SCCOHT cells we have identified sensitivity to RTK knockdown and RTK inhibitors including the FDA-approved oncology drug, ponatinib. These data corroborate prior studies showing RTK dependence in rhabdoid tumors, rare cancers that are also driven by mutations in the SWI/SNF complex. Of the known ponatinib targets, PDGFR-alpha and FGFR1 were highly expressed in SCCOHT tumors, as confirmed in RNA-Seq data (four tumors) and a SCCOHT tissue microarray (TMA; ten tumors). Furthermore, PDGFR-alpha and -beta phosphorylation and downstream signaling are inhibited by ponatinib in SCCOHT cells, suggesting that these tumors are sensitive to ponatinib due to dependence on signaling through these RTKs. Finally, given ponatinib’s potency in vitro and the proposed mechanism of action, we tested this agent in xenograft models of SCCOHT. In addition to confirming efficacy in a SCCOHT cell line xenograft model, superior efficacy was demonstrated in two patient-derived xenograft (PDX) models of SCCOHT with ponatinib. Thus, ponatinib effectively targets SWI/SNF-mutant SCCOHT tumors through inhibition of PDGFR signaling and may have clinical utility for the treatment of these cancers. Citation Format: Jessica Diane Lang, William Hendricks, Pilar Ramos, Holly Yin, Chris Sereduk, Jeffrey Kiefer, Yemin Wang, Anthony N. Karnezis, Bernard Weissman, David Huntsman, Jeffrey Trent. Targeting the platelet derived growth factor receptor (PDGFR) with the receptor tyrosine kinase inhibitor ponatinib in small cell carcinoma of the ovary, hypercalcemic type [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1238. doi:10.1158/1538-7445.AM2017-1238

The work that will be presented strongly suggests the identification of a unique vulnerability of Small Cell Carcinoma of the Ovary-Hypercalcemic Type (SCCOHT) to PDGFR inhibition. SCCOHT is an aggressive subtype of ovarian cancer afflicting young women and children with fewer than 35% of patients surviving two years after diagnosis. Currently, these patients must endure high dose chemotherapy because no effective targeted therapies have been identified. We previously demonstrated that these tumors are driven by inactivating mutations in SMARCA4, one of two ATPases in the SWI/SNF chromatin-remodeling complex. In addition, we have also shown that SCCOHT lacks expression of the alternative SWI/SNF ATPase, SMARCA2. SWI/SNF is a key tumor suppressor complex in diverse cancers and its members are mutationally inactivated in up to 50% of other ovarian cancer subtypes. However, no therapeutic approaches selective for SWI/SNF-dysregulation in cancers are routinely used. We have now found through multiomic (DNA/RNA), pathway analysis, immunohistochemistry and functional studies in SCCOHT tumors and cell lines that SMARCA4 loss correlates with increased expression of receptor tyrosine kinases (RTKs) including the platelet derived growth factor receptors (PDGRs). Through integration of high-throughput RNA interference and drug screens in SCCOHT cell lines we have also identified sensitivity to RTK knockdown and inhibitors such as ponatinib. These data corroborate prior studies showing RTK dependence in rhabdoid tumors, rare cancers that are also driven by mutations in the SWI/SNF complex. As ponatinib is approved for cancer treatment and showed great potency, we tested this agent in two patient-derived xenograft (PDX) models of SCCOHT. Ponatinib significantly reduced tumor growth in both models. Of the known ponatinib targets, PDGFR and FGFR1 were highly expressed in SCCOHT tumors, suggesting that SCCOHTs are sensitive to ponatinib through the expression of these RTKs. Further, PDGFR-alpha phosphorylation and downstream signaling are strongly inhibited by ponatinib in SCCOHT. In summary we believe this finding may allow a way to be exploited therapeutically through the FDA-approved inhibitor ponatinib. Citation Format: Jessica D. Lang, William Hendricks, Pilar Ramos, Holly Yin, Chris Sereduk, Jeffrey Kiefer, Yemin Wang, Anthony N. Karnezis, Bernard Weissman, David Huntsman, Jeffrey Trent. TARGETING AND EFFICACY OF THE RECEPTOR TYROSINE KINASE INHIBITOR PONATINIB IN SMALL CELL CARCINOMA OF THE OVARY, HYPERCALCEMIC TYPE, WORKS THROUGH INHIBITION OF PLATELET DERIVED GROWTH FACTOR RECEPTOR (PDGFR) [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-090.

PURPOSE: Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a rare ovarian cancer that predominantly affects young women with a median age of 24 years. Although half of the tumors are diagnosed at an early stage, the prognosis is dismal due to lack of effective treatment options. In response to drastic increase of protein translation and cellular stress during malignant transformation, cancer cells have evolved to highly depend on protein surveillance pathways to correct or degrade unfolded and misfolded proteins to ensure protein homeostasis. Inhibition of these protein surveillance pathways has been proven to selectively target cancer cells. Particularly, inhibition of proteasome, which degrades more than 80% of cellular proteins, by selective inhibitors leads to accumulation of its substrates and consequently results in activation of apoptotic pathways in highly proliferative cancer cells. However, resistance occurs frequently. As a result several combinational treatments have been investigated in clinical trials with various drugs, such as HDAC6 inhibitor, which shuts down the aggresome-mediated proteolysis. Therefore, we aimed to determine the promise of inhibiting both protein degradation pathways as a novel therapeutic strategy for SCCOHT. EXPERIMENTAL PROCEDURE: Concentration-effect relationships were determined for both proteasome and HDAC6 inhibitors, alone or in combination, in SCCOHT cell lines and other ovarian carcinoma cell lines using a 3-day cell viability assay measured by crystal violet staining. Cell apoptosis was measured by live cell imaging with activated caspase-3/7. Drug action mechanism was interrogated by Western blotting. RESULT: SCCOHT cells are hypersensitive to both proteasome inhibitor (Bortezomib) and HDAC6 inhibitor (ACY-1215) with IC50 around low nM and μM, respectively. In addition, both Bortezomib and ACY-1215 inhibited cell proliferation and induced apoptosis in SCCOHT cells. Treatment with ACY-1215 led to inhibition of the aggresome as evidenced by an increased level of acetyl-tubulin, accumulation of polyubiquitinated proteins and upregulation of the unfolded protein response. Combination of Bortezomib and ACY-1215 led to an increased level of poly-ubiquitinated proteins, stronger suppression of cell proliferation and more apoptosis compared to either drug alone in SCCOHT cells, with some dosing having synergistic effect. CONCLUSION: Our data suggest that ACY-1215 or Bortezomib alone significantly suppressed the growth and induced apoptosis of SCCOHT cells. Combination of ACY-1215 and Bortezomib synergistically increased growth suppression and cell apoptosis and thereby may be a potential rational therapeutic strategy for SCCOHT. Citation Format: Yuting Shary Chen, Yemin Wang, Anthony Karnezis, Pilar Ramos, Holly Yine, Bernard Weissman, Jeffrey Trent, David Huntsman. THE PROMISE OF COMBINATIONAL TREATMENT OF HISTONE DEACETYLASE 6 INHIBITOR ACY-1215 AND PROTEASOME INHIBITOR BORTEZOMIB IN SCCOHT [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-084.

PURPOSE: SCCOHT is a rare, poorly differentiated and very deadly ovarian tumor that mainly affects young women with the median age in twenties. Recently, we and others have discovered that the genome of SCCOHT was minimally disturbed compared to common malignancies with the inactivation mutations of SMARCA4 being the only recurrent genetic alternation in SCCOHT genome. SMARCA4 is the ATPase of the SWI/SNF chromatin-remodeling complex, which is the master regulator of gene transcription through controlling the accessibility of chromatin and therefore plays critical roles in many biological processes such as cell cycle control, apoptosis, and differentiation. Recently, a genetic antagonism has been observed between some SWI/SNF complex components and the histone methyltransferase EZH2 of the polycomb repressive complex 2 (PRC2), suggesting that EZH2 may be a vulnerable target in certain SWI/SNF-deficient tumor. Therefore, we aimed to determine the promise of defeating SCCOHT through targeting EZH2 in the present study. METHODS: The EZH2 protein expression was determined by immunohistochemistry on the SCCOHT tissue microarray. Cell viability, cell cycle and apoptosis were measured by crystal violet staining, FACS analysis and live cell imaging with activated caspase-3/7 staining, respectively. The proteomic profiles of SCCOHT cells were determined by Mass Spectrometry using the TMT-labeled peptide fractions. Two SCCOHT xenograft mouse models were established from BIN67 and SCCOHT1 cells, respectively, in immune-deficient mice were used for the evaluation of EPZ-6438 efficacy in vivo. RESULT: All (24/24) SCCOHT expressed abundant EZH2 protein. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to two EZH2 inhibitors (GSK126 and EPZ-6438) and EZH2 shRNA. Furthermore, EPZ-6438 induced cell cycle arrest, apoptosis and cell differentiation in SCCOHT cells, accompanying by the induction of genes involved in cell proliferation, apoptosis and differentiation. Treatment of EPZ-6438 in SCCOHT xenograft-bearing mice delayed tumor progression, improved the survival of mice. Further, re-expression of SMARCA4 suppressed the expression of EZH2 and the global level of histone H3K27 trimethylation, induced the expression of PRC2 targets that are induced by EZH2 inhibitors and triggered differentiation of SCCOHT cells. In addition, we also discovered that SCCOHT cells are hypersensitive to multiple inhibitors of histone deacetylase (HDAC), which is known to cooperate with EZH2 to silence certain target genes. Combined treatment of EPZ-6438 and Quisinostat (an HDAC inhibitor) synergistically suppressed the proliferation of SCCOHT cells. CONCLUSION: Our data suggest that EZH2 is a promising therapeutic target for fighting SCCOHT. Combined pharmacological targeting of both EZH2 and HDAC may provide a novel treatment option for SCCOHT patients. Citation Format: Yemin Wang, Shary Chen, Anthony Karnezis, Nancy Dos Santos, Pilar Ramos, Sarah Maines-Bandiera, Christine Chow, Bernard Weissman, Jeffrey Trent, David Huntsman. THE METHYLTRANSFERASE EZH2 IS A VULNERABLE TARGET IN SMALL CELL CARCINOMA OF THE OVARY, HYPERCALCEMIC TYPE (SCCOHT) [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP32.

To determine trends in beer, wine, and liquor consumption among Spanish adolescents in 2002, 2006, and 2010, as well as drunkenness trends during the same period.The study sample was composed of 23,169 adolescents aged 15 to 18 years old: 7,103 in 2002, 10,443 in 2006 and 5,623 in 2010. In the three time points of the study, the data were representative of Spanish adolescent students. We used the alcohol consumption questionnaire designed by the international team of the Health Behavior in School-aged Children (HBSC) study. We estimated odds ratios and 95% confidence intervals through logistic regressions.The main results showed a decrease in frequent consumption of wine and liquor from 2002 to 2010. This decrease was maintained after controlling for the variability due to the participants' gender and age. However, an increasing trend was found in drunkenness episodes in the different cohorts of the adolescents under study.The results of this study are of particular importance in the analysis of the effects of the public health policies implemented during this time period. We also found changes in consumption patterns of the various alcoholic drinks, which may constitute key information in the design of new public health policies.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and understudied cancer with a dismal prognosis. SCCOHT's infrequency has hindered empirical study of its biology and clinical management. However, we and others have recently identified inactivating mutations in the SWI/SNF chromatin remodeling gene SMARCA4 with concomitant loss of SMARCA4 protein in the majority of SCCOHT tumors.(1-4) Here we summarize these findings and report SMARCA4 status by targeted sequencing and/or immunohistochemistry (IHC) in an additional 12 SCCOHT tumors, 3 matched germlines, and the cell line SCCOHT-1. We also report the identification of a homozygous inactivating mutation in the gene SMARCB1 in one SCCOHT tumor with wild-type SMARCA4, suggesting that SMARCB1 inactivation may also play a role in the pathogenesis of SCCOHT. To date, SMARCA4 mutations and protein loss have been reported in the majority of 69 SCCOHT cases (including 2 cell lines). These data firmly establish SMARCA4 as a tumor suppressor whose loss promotes the development of SCCOHT, setting the stage for rapid advancement in the biological understanding, diagnosis, and treatment of this rare tumor type.

Purpose A c-Src inhibitor blocks oestrogen (E 2 )-induced stress and converts E 2 responses from inducing apoptosis to growth stimulation in E 2 -deprived breast cancer cells. A reprogrammed cell line, MCF-7:PF, results in a functional oestrogen receptor (ER). We addressed the question of whether the selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E 2 -stimulated growth in MCF-7:PF cells. Methods Expression of mRNA was measured through real-time RT-PCR. Global gene expression profile was analysed through microarray. Transcriptome profiles were screened by RNA-sequencing. Results Unexpectedly, both 4-OHT and E 2 stimulated cell growth in a concentration-dependent manner. Expression profiling showed a remarkable overlap in genes regulated in the same direction by E 2 and 4-OHT. Pathway enrichment analysis of the 280 genes commonly deregulated in MCF-7:PF cells by 4-OHT and E 2 revealed functions mainly related to membrane, cytoplasm and metabolic processes. Further analysis of 98 genes up-regulated by both 4-OHT and E 2 uncovered a significant enrichment in genes associated with membrane remodelling, cytoskeleton reorganisation, cytoplasmic adapter proteins, cytoplasm organelle proteins and related processes. 4-OHT was more potent than E 2 in up-regulating some membrane remodelling molecules, such as EHD2 , FHL2 , HOMER3 and RHOF . In contrast, 4-OHT acted as an antagonist to inhibit expression of the majority of enriched membrane-associated genes in wild-type MCF-7 cells. Conclusions Long-term selection pressure has changed the cell population responses to 4-OHT. Membrane-associated signalling is critical for 4-OHT-stimulated cell growth in MCF-7:PF cells. This study provides a rationale for the further investigation of target therapy for tamoxifen resistant patients.

The etiology of uterine leiomyomatosis is multifactorial and it is unknown if a relation between anti-Müllerian hormone (hormona anti-mülleriana) and uterine leiomyomatosis exists.To determine the differences of hormona anti-mülleriana levels in women with and without uterine leiomyomatosis.60 women were studied (30 with and 30 without uterine leiomyomatosis). The diagnosis was confirmed by histopathology. Both groups were paired by age and in all them serum levels of hormona antimülleriana were measured using ELISA, also estradiol and progesterone serum levels were determined. hormona anti-mülleriana-RII immunohistochemistry was done in healthy myometrium and in leiomyomas.The mean age between the groups didn't show statistical difference (41.8 +/- 5.6 years vs. 41.4 +/- 5.7 years). Also no differences were found in weight, height and body mass index. Serum levels of hormona antimülleriana were lower in those with leiomyomatosis [0.21 (0-10.4) ng/ml vs. 1.83 (0-6.38) ng/ml, p0.005]. No statistical differences were found in estradiol and progesterone serum levels between the groups. The hormona antimülleriana receptor was no expressed neither in the healthy myometrium nor in the leiomyomas.Women with leiomyomatosis had lower hormona antimülleriana levels. More studies are needed to determine if a relation exists between hormona antimülleriana and uterine leiomyomas.

Background: This study evaluates the changes in Spain between 2006 and 2012, of school-based policies encouraging healthy eating and the undertaking of physical activity (PA). Methods: A longitudinal study was undertaken comprising 277 representative schools from all the regions of Spain. The questionnaires were completed by the school management board. An indicator for school policies on PA was constructed (score 0–4) from the following indicators: (i) participation in PA programmes, (ii) existence of written PA guidelines, (iii) training of teachers about PA and (iv) organization of extracurricular PA activities. For nutrition, indicators similar to the first three for PA were evaluated, together with access to healthy foods (score 0–4). In addition to comparing the scores for 2006 and 2012, multivariate linear regression was used to study the association between the characteristics of the schools and the changes in the scores. Results: The indicators for school-based policies on nutrition and PA improved between 2006 and 2012: the average score for PA increased from 1.33 to 1.79 ( P < 0.001) and that for nutrition from 1.28 to 1.92 ( P < 0.001). The greatest changes were seen regarding the written guidelines for action and participation in PA and nutrition programmes as well as the training of teachers about nutrition. The schools with the least number of students had the highest changes in scores for policies on nutrition ( P < 0.05). Conclusions: There has been an increase of school-based policies on PA and nutrition, although there is still room for improvement.