Targeting androgen receptor and trail: a novel treatment paradigm for breast cancer / 中国药理学与毒理学杂志

OBJECTIVE TNF- related apoptosis- inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors. However, most breast cancer cells are resistant to TRAIL- induced apoptosis. Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance. METHODS To identify modulators of TRAIL-induced apoptosis, we carried out a genome wide siRNA screen. To validate the screening result, we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model. Finally, we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy. RESULTS We unexpectedly identified androgen receptor (AR) to be responsible for TRAIL resistance. While AR is classically viewed as the key factor in prostate cancer progression, we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple- negative breast cancers (TNBC) that are highly aggressive with poor prognosis. Importantly, breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance. AR overexpression in MDA- MB- 231 and MDA- MB- 436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis. AR overexpression also induced TRAIL resistance in breast tumors in vivo. Further, we observed an upregulation of the TRAIL receptor, death receptor 5 (DR5) in breast cancer cells, following the removal or inhibition of AR by its antagonists Casodex and MDV3100. Treatment with AR antagonists also enhanced TRAIL- induced breast cancer cell apoptosis. CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis, in part, by suppressing DR5 expression, and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.

Neurotransmitter systems in mouse airways / 中国药理学与毒理学杂志

OBJECTIVE The objective of this study was to characterize the neurotransmitter systems that cause constriction of murine airways. METHODS Murine precision cut lung slices (PCLS) and trachea were prepared, placed into perfusion chambers equipped with platinum electrodes and stimulated transmurally (1.0 ms, 50 V, 0.1- 30 Hz). To measure PCLS constriction, changes in airway luminal area in response to electric field stimulation (EFS) were captured as video images quantified using Image J software. For trachea, changes in isometric tension were recorded using Grass force transducers. Frequency response curves were generated in the absence and the presence of the inhibitors magnesium, atropine and capsaicin and responses analyzed and compared using a student' s t- test (P<0.05). RESULTS EFS caused airway constriction in a frequency-dependent manner that was best fit by a biphasic curve. Neuron-specific stimulation was verified by Mg2+ blockade. Maximum airway constriction to 30 Hz EFS in PCLS was (51.8±3.0)% while tracheal constriction averaged (551±80)mg. Interestingly, in PCLS the muscarinic receptor antagonist atropine (10 μmol · L- 1) blocked (99.5 ± 7.2)% of EFS induced constriction at 1 Hz, but only blocked (23.3±3.8)% of EFS induced constriction at 30 Hz and eliminated the first phase but not the second phase of the biphasic EFS response. Treatment with capsaicin to deplete sensory neurotransmitters significantly increased EFS constriction supporting the presence of sensory neurotransmitter systems in airways. CONCLUSION These data are consistent with parasympathetic constriction of airways by acetylcholine at lower EFS frequencies while higher frequencies release sensory dilator neurotransmitters. These data provide evidence for multiple nerve types innervating airways which may provide novel targets for treatment of lung disease.

Post community hospital discharge rehabilitation attendance: Self-perceived barriers and participation over time

<p><b>INTRODUCTION</b>This study aimed to examine the attendance rates of post-discharge supervised rehabilitation as recommended by the multidisciplinary team at discharge among subacutely disabled adults and the barriers preventing adherence.</p><p><b>MATERIALS AND METHODS</b>Patients were from a community hospital, aged 40 years or older. They had been assessed by a multidisciplinary team to benefit from rehabilitation after discharge, were mentally competent and communicative. We used a sequential qualitative-quantitative mixed methods study design. In the initial qualitative phase, we studied the patient-perceived barriers to adherence to rehabilitation using semi-structured interviews. Emerging themes were then analysed and used to develop a questionnaire to measure the extent of these barriers. In the subsequent quantitative phase, the questionnaire was used with telephone follow-up at 3, 6, 9 and 12 months after discharge.</p><p><b>RESULTS</b>Qualitative phase interviews (n = 41) revealed specific perceived financial, social, physical and health barriers. At the start of the quantitative phase (n = 70), 87.1% of the patients viewed rehabilitation as beneficial, but overall longitudinal attendance rate fell from 100% as inpatient to 20.3% at 3 months, 9.8% at 6 months, 6.3% at 9 months and 4.3% at 12 months. The prevalence of physical and social barriers were high initially but decreased with time. In contrast, the prevalence of financial and perceptual barriers increased with time.</p><p><b>CONCLUSION</b>Attendance of post-hospitalisation rehabilitation in Singapore is low. Self-perceived barriers to post-discharge rehabilitation attendance were functional, social, financial and perceptual, and their prevalence varied with time.</p>

Prevalence of the metabolic syndrome in patients presenting to the University Hospital of the West Indies: a need to adopt proactive screening and specific management policy / Prevalencia del síndrome metabólico en pacientes que acuden al Hospital Universitario de West Indies: necesidad de adoptar un tamizaje proactivo y políticas de tratamiento específico

Studies have shown that the metabolic syndrome (MetS), a major risk factor for the development of Type 2 diabetes mellitus and cardiovascular disease, is higher among psychiatric patients on antipsychotic medications than the general population. While studies on the prevalence of MetS in the Jamaican adult population have been undertaken, no such study has been done on the corresponding psychiatric population. The purpose of this study was to determine the prevalence of MetS in a Jamaican adult psychiatric inpatient population. The study group comprised thirty-eight patients with a primary DSM-IV-TR Axis 1 diagnosis. Criteria for the diagnosis of MetS were the presence of any three or more of five factors as defined by using the International Diabetes Federation (IDF) and American Heart Association/National Heart Lung and Blood Institute (AHA/NHLBI) consensus agreement. The prevalence of MetS in this cohort was 28.9% and was associated with significantly higher abdominal obesity (p = 0.010), elevated blood pressure (p = 0.000), elevated triglycerides (p = 0.019) and low high density lipoprotein-cholesterol (p = 0.016) when compared with patients not diagnosed with MetS. Metabolic syndrome was common in this group of psychiatric patients and likely represents a pathway to the future development of Type 2 diabetes mellitus and cardiovascular disease. Screening and continuous monitoring will allow for early intervention and possibly prevention of increased morbidity and mortality in this vulnerable population.

Los estudios han mostrado que el síndrome metabólico (SMet) - un factor de riesgo mayor para el desarrollo de la diabetes mellitus tipo 2 y la enfermedad cardiovascular - es más alto entre los pacientes psiquiátricos bajo medicamentos antipsicóticos que entre la población general. Si bien se han llevado a cabo estudios sobre la prevalencia del SMet en la población adulta jamaicana, no se han realizado estudios de esta clase en la población psiquiátrica correspondiente. El propósito de este estudio fue determinar la prevalencia del SMet en una población jamaicana adulta de pacientes hospitalizados. El grupo de estudio comprendió treinta y ocho pacientes con diagnóstico primario DSM-IV-TR de eje I. Los criterios para el diagnóstico de SMet se basaron en la presencia de tres o más de cinco factores, los cuales fueron definidos usando el acuerdo por consenso de la Federación Internacional de la Diabetes (FID) y la Asociación Nacional de Cardiología/Instituto Nacional del Corazón, el Pulmón y la Sangre (AHA/NHLBI). La prevalencia de SMet en esta cohorte fue 28.9%, y se hallaba asociada con obesidad abdominal significativamente más alta (p = 0.010), presión sanguínea elevada (p = 0.000), triglicéridos elevados (p = 0.019), y bajos niveles de colesterol-lipoproteína de alta densidad (p = 0.016), al compararse con pacientes no diagnosticados con SMet. El síndrome metabólico fue común en este grupo de pacientes psiquiátricos y probablemente representa una vía al desarrollo futuro de la diabetes mellitus tipo 2 y la enfermedad cardiovascular. El tamizaje así como el monitoreo continuos permitirán la intervención temprana y la posible prevención del aumento de la morbosidad y la mortalidad en esta población vulnerable.

Changing the research culture at the section of psychiatry, the University of the West Indies, Mona / Cambiando la cultura de la investigación en el Departamento de Psiquiatría de la Universidad de West Indies, Mona

OBJECTIVE: To compare the medical research output of the Section of Psychiatry, The University of the West Indies (UWI), Mona, before and after the implementation of strategies aimed at stimulating research. METHOD: Specific strategies such as weekly research and journal club meetings, with an emphasis on team activities and the establishment of bi-annual targets for submission of research papers were instituted in 2000. All research outputs from the Section of Psychiatry over the period 1995 to 2005 were identified from the Departmental Reports of the University of the West Indies and the published abstracts of the UWI Faculty of Medical Sciences and the Caribbean Health Research Council annual research conferences. A number of variables were extracted from each paper and comparisons made between the five-year period before and the five-year period after the implementation of the research enhancing strategies. Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS; version 11.5) and included chi-squared and Mann Whitney U tests. RESULTS: One-hundred and sixty-two items of research output were identified for the entire period under study. In the period after the implementation of the research enhancing strategies, there were significant increases in the total research output (p = 0.008) and refereed publications (p = 0.016). CONCLUSIONS: There were considerable increases in the overall research output of the department as well as in many sub-categories of output. These strategies are presented as a model to other departments seeking to augment their output of research.

OBJETIVO: Comparar la producción médico-investigativa del Departamento de Psiquiatría de la Universidad de West Indies (UWI), Mona, antes y después de la implementación de las estrategias encaminadas a estimular la investigación. MÉTODO: En el año 200, se instituyeron estrategias específicas, tales como reuniones semanales del club de investigación y publicaciones, con énfasis en las actividades en equipo y el establecimiento de objetivos semestrales para la presentación de trabajos de investigación. Todas las producciones investigativas del Departamento de Psiquiatría durante el periodo de 1995 al 2005, fueron identificadas a partir de los informes Departamentales de la Universidad de West Indies y los resúmenes publicados por las conferencias anuales de la Facultad de Ciencias Médicas de UWI y el Consejo Caribeño de Investigaciones de la Salud. Se extrajeron un número de variables de cada trabajo y se hicieron comparaciones entre el quinquenio anterior y el posterior a la implementación de las estrategias del perfeccionamiento de las investigaciones. Se realizaron análisis estadísticos con el Paquete Estadístico para las Ciencias Sociales (SPSS; versión 11.5) y se incluyeron pruebas U de Mann-Whitney y Chi-cuadrado. RESULTADOS: Se identificaron ciento sesenta y dos ítems de output investigativo para todo el periodo en estudio. En el periodo posterior a la implementación de las estrategias de perfeccionamiento de las investigaciones, hubo aumentos significativos en la producción investigativa total (p = 0.008) y en las publicaciones referenciadas (p = 0.016). CONCLUSIONES: Hubo aumentos considerables en la producción investigativa general del departamento, así como en muchas subcategorías de producción. Estas estrategias se presentan como un modelo para otros departamentos que buscan aumentar su producción investigativa.

A comparison of the objective structured clinical examination results across campuses of the University of the West Indies (2001 and 2002) / Una Comparación del Examen Clínico Objetivo Estructurado Resultados en los Campus de la Universidad de West Indies (2001 y 2002)

OBJECTIVE: To compare the performance of medical students in the Objective Structured Clinical Examination (OSCE) of thefinal MBBS Examination across the four campuses of The University of the West Indies, over a two-year period DESIGN AND METHODS: All final examination results of the Medicine and Therapeutics OSCE were collectedfrom the Faculty of Medical Science at the four campuses of The University of the West Indies and analyzed using both parametric (t-tests and ANOVAs) and non-parametric tests (chi-squared tests). RESULTS: Results indicated that students achieved significantly higher mean scores in the 2002 examination than in 2001 (t = 3.85, df = 415, p = 0.000). There were no significant differences between campuses with regards to the mean corrected score in 2001. Also in 2001, in adult stations, all campuses achieved significantly higher scores than Jamaica. However, in Jamaica, mean child health station scores were significantly higher than all other campuses and, the mean score in Trinidad and Tobago was higher than the Bahamas and Barbados. In 2002, all other campuses achieved significantly higher scores than Trinidad and Tobago and females performed significantly better than males with regards to overall mean scores (t = 2.814, df = 189, p = 0.005). Also in 2002, Barbados achieved significantly higher mean corrected scores than Trinidad and Tobago (F = 4.649, df = 3191; p = 0.004) and Barbados and Trinidad and Tobago both obtained significantly higher mean child health station scores than Jamaica. CONCLUSIONS: The important conclusion from this study is that the OSCE scores in Medicine and Therapeutics are generally uniform across the four campuses of the University, thereby confirming the consistency of the approach to teaching and helping to validate the efficacy and veracity of the medical graduate being produced by The University of the West Indies

Objetivo: Comparar el rendimiento académico de los estudiantes de medicina en el examen clínico objetivo estructurado del examen final de MBBS, en los cuatro campus de La Universidad de West Indies, en un período de dos años. Diseño y métodos: Se recopilaron todos los resultados del examen final de ECOE de Medicina y Terapéutica de la Facultad de Ciencias Médicas, en los cuatro campus de la Universidad de West Indies. Los datos fueron analizados usando tanto tests paramétricos (tests t y ANOVAs) como tests no paramétricos (tests de chi-quadrado). Resultados: Los resultados indicaron que los estudiantes alcanzaron puntuaciones significativamente más altas en el examen del 2001 que en el del 2002 (t = 3.85, df = 415, p = .000). No hubo diferencias significativas entre los distintos campus con respecto a los resultados corregidos promedios 2001. También en 2001, en las unidades asistenciales de adultos, todos los campus lograron resultados significativamente más altos que Jamaica. Sin embargo, en Jamaica, los resultados promedios de las unidades pediátricas fueron significativamente más altos que en todos los otros campus, y el resultado promedio en Trinidad y Tobago fue más alto que en Bahamas y Barbados. En 2002, todos los otros campus lograron resultados significativamente más altos que Trinidad y Tobago, y las mujeres obtuvieron rendimientos significativamente mejores que los de los hombres, con respecto a los resultados promedios generales (t = 2.814, df = 189, p = .005). También en 2002, Barbados alcanzó resultados corregidos promedios significativamente más altos que Trinidad y Tobago (F = 4.649, df = 3,191; p = .004), mientras que Barbados así como Trinidad y Tobago, obtuvieron resultados significativamente más altos en la unidades pediátricas, en comparación con Jamaica. Conclusiones: La conclusión principal de este estudio es que los resultados del OSCE en Medicina y Terapéutica son generalmente uniformes en los cuatro campus de la Universidad, confirmando de ese modo la solidez del enfoque de la enseñanza, y contribuyendo a validar la eficacia y calidad del graduado de medicina egresado de la Universidad de West Indies.