Proscillaridin A effects on histone acetylation and C-MYC degradation in acute lymphoblastic leukemia

La leucémie lymphoblastique aiguë (LLA) représente environ 25% des cancers pédiatriques diagnostiqués chaque année. Dans 80 % des cas, une rémission complète est observée. Cependant, les patients résistants aux traitements ainsi que les patients en rechute présentent un mauvais pronostique. Les altérations épigénétiques sont des facteurs essentiels dans le développement et la progression de la maladie, ainsi qu’à la résistance aux traitements. Lors d’un criblage de médicaments approuvés par la FDA, nous avons découvert des molécules ayant des caractéristiques anticancéreux et épigénétiques. Pour évaluer l’activité de ces molécules, nous avons procédé à un criblage secondaire sur plusieurs lignées cellulaires leucémiques. Nous avons découvert qu’une de ces molécules, un glucoside cardiotonique appelé la proscillaridine A, avait une activité anticancéreuse spécifique pour des cellules leucémiques. Nous faisons donc l’hypothèse que la proscillaridine A pourrait avoir des effets épigénétiques et anticancéreux dans des modèles précliniques de LLA. Pour tester cette hypothèse, nous avons traité deux lignées cellulaires de LLA Nalm-6 (LLA pre-B) et Molt-4 (T-LLA) in vitro pendant 2 à 96 heures à des doses pertinentes sur le plan clinique. Nous avons alors pu observer une inhibition de croissance qui était dépendante de la dose administrée dans les deux lignées cellulaires, avec des valeurs de 50% d’inhibition de croissance (CI50) de 3.0 nM pour les Nalm-6 et de et 2.3 nM pour les Molt-4. De plus, nos études sur le cycle cellulaire par BrdU démontrent un arrêt en phase G2/M. Nous avons également détecté par immunobuvardage de type western des baisses significatives de l’acétylation de résidus de l’histone 3. Les niveaux d’expression des enzymes responsables de cette acétylation, les histones acétyltransférases CBP, P300 et TIP60 ainsi que de l’oncogène C-MYC étaient également diminuées. Par des analyses de séquençage de l’ARN, nous avons observé une augmentation de l’expression des gènes impliquées dans les processus d’apoptose et de différentiation cellulaire, ainsi qu’une diminution des gènes impliqués dans la prolifération cellulaire comme en particulier les gènes cibles de C-MYC. Ces résultats prometteurs suggèrent le potentiel prometteur de la proscillaridine A comme nouvelle thérapie pour les patients atteints de LLA.

ENVIRONMENTAL INFLUENCES AND EPIGENETIC MECHANISMS IN RISK FOR DEPRESSION

Thesis (Ph.D, Psychology) -- Queen's University, 2016-10-04 17:37:07.888

Manifestações orais associadas ao consumo da droga de abuso MDMA

O uso para fins ou meios festivos de lazer da droga ilícita MDMA, também chamado de Ecstasy ou Moly, tem vindo a aumentar drasticamente em Portugal e no Mundo. Esta situação desafia os profissionais de saúde para vários parâmetros na saúde oral e geral. O objetivo desta dissertação visa avaliar e descrever as lesões e patologias na cavidade oral que estão relacionadas com o consumo da substância ilícita MDMA. As consequências para a cavidade oral podem ser a xerostomia, o bruxismo, as cáries rampantes, a doença periodontal, o desgaste e a erosão dentária, e as lesões dos tecidos moles. Os indivíduos consumidores podem apresentar carências nutricionais e um estímulo aumentado à dor. A gestão do prognóstico e o tratamento realizado aos consumidores de MDMA, pois afeta vários órgãos e sistemas no corpo humano, requer uma abordagem multidisciplinar que inclui educação, prevenção e tratamento integrados. Esta revisão bibliográfica teve com base artigos publicados em revistas científicos e monografias disponíveis em vários motores de busca. As palavras-chave usadas foram: “ecstasy”, “MDMA”, “oral manifestations”, “oral health”, “substance abuse”, ”overdose treatment”, “xerostomia” e “methamenfetamine” e a sua conjugação. As situações orais, perante as mais prevalentes comorbidades patogénicas relacionadas com o MDMA e outras dependências ilícitas, necessitam de mais atenção e reforço em relação à prática clínica e aos serviços de saúde. Uma das dificuldades para o tratamento correto destes indivíduos é a falta de informação sobre o assunto referente à prática na clínica dentária. A omissão sobre o consumo por parte do paciente bem como de uma recaída no uso, apresentam dúvidas sobre o fator em causa ou até mesmo no diagnóstico. São, muitas vezes, os Médicos Dentistas os primeiros a terem a oportunidade de diagnosticar o aparecimento de possíveis alterações surgidas em virtude do consumo de MDMA.

Recidiva do tratamento ortodôntico por respiração bucal

A respiração bucal é altamente comprometedora no que respeita correto crescimento e desenvolvimento das estruturas craniofaciais, podendo provocar uma série de desvios e alterações, nomeadamente alterações dentofaciais de carácter ortodôntico. O presente trabalho visa a elaboração de uma revisão bibliográfica sobre a recidiva ortodôntica em sujeitos com respiração bucal, dando especial atenção às características clínicas que permitem a identificação do respirador oral, por forma a contribuir para um diagnóstico mais atempado e, consequentemente, para uma maior eficácia do tratamento. Com base numa pesquisa efetuada em 5 bases de dados e com a utilização das palavras chave, foi feito um levantamento bibliográfico da literatura considerada relevante para a temática em estudo e uma seleção da mesma, de acordo com o seu nível de evidência cientifica. A respiração bucal é um dos múltiplos fatores etiológicos de instabilidade dentária que está na origem da recidiva ortodôntica, pelo que é necessária uma intervenção adequada e eficaz com o intuito de minimizar as consequências decorrentes da respiração bucal, antes de qualquer procedimento ortodôntico. O tratamento deve ser multidisciplinar, com associação de várias áreas, entre elas a Ortodontia, a terapia miofuncional, a otorrinolaringologia, e a ortopedia funcional dos maxilares e o diagnóstico precoce é de relevada importância para o sucesso do mesmo.

Evaluation of tumor recurrences after radical prostatectomy using 18F-Choline PET/CT and 3T multiparametric MRI without endorectal coil: a single center experience

The aim os this study is to evaluate and compare the utility of 18F-fluorocholine (18F-CH) PET/CT versus 3-Tesla multiparametric MRI (mpMRI) without endorectal coil to detect tumor recurrences in patients with biochemical relapse following radical prostatectomy (RP). Secondarily, to identify possible prognostic variables associated with mpMRI and 18F-CH PET/CT findings. Retrospective study of 38 patients who developed biochemical recurrence after RP between the years 2011 and 2015 at our institution. PET/CT and mpMRI were both performed within 30 days of each other in all patients. The PET/CT was reviewed by a nuclear medicine specialist while the mpMRI was assessed by a radiologist, both of whom were blinded to outcomes. The median prostate-specific antigen (PSA) value pre-MRI/PET-CT was 0.9 ng/mL (interquartile range 0.4–2.2 ng/mL). There were no differences in the detection rate between 18F-CH PET/CT and mpMRI for local recurrence (LR), lymph node recurrence (LNR) and bone metastases (BM). Separately, mpMRI and 18F-CH PET/CT were positive for recurrence in 55.2% and 52.6% of cases, respectively, and in 65.7% of cases when findings from both modalities were considered together. The detection of LR was better with combined mpMRI and choline PET/CT versus choline PET/CT alone (34.2% vs 18.4%, p = 0.04). Salvage treatment was modified in 22 patients (57.8%) based on the imaging findings. PSA values on the day of biochemical failure were significantly associated with mpMRI positivity (adjusted odds ratio (OR): 30.9; 95% confidence interval (CI): 1.5–635.8). Gleason score > 7 was significantly associated with PET/CT positivity (OR: 13.9; 95% CI: 1.5–125.6). A significant association was found between PSA doubling time (PSADT) (OR: 1.3; 95% CI: 1.0–1.7), T stage (OR: 21.1; 95% CI: 1.6–272.1), and LR. Multiparametric MRI and 18F-CH PET/CT yield similar detection rates for LR, LNR and pelvic BM. The combination of both imaging techniques provides a better LR detection versus choline PET/CT alone. The initially planned salvage treatment was modified in 57.8% of patients due to imaging findings. In addition to PSA values, Gleason score, T stage, and PSADT may provide valuable data to identify those patients that are most likely to benefit from undergoing both imaging procedures.

'Just to get it off my chest': Patients' views on psychotherapy in inflammatory bowel disease

Objective: This study aimed to explore patients' experiences and views on psychotherapy in relation to inflammatory bowel disease (IBD), and Crohn's disease (CD) in particular. Method: This descriptive survey study used semi-structured in-depth interviews with open-ended questions and a qualitative content analysis to summarise responses of 12 CD patients with mental health problems undergoing treatment with antidepressants. Results: Of 12 interviewed CD sufferers, only four received any form of psychotherapy. Two psychotherapy users considered it useful and beneficial. Patients who used psychotherapy with good results reported it improved their disease course, most likely due to improving patients' skills in reducing stress and thus, delaying relapse of the disease. Conclusion: Psychotherapy seems to be under used in IBD patients with mental health problems. Psychotherapy may act as a preventer of disease relapse in some patients and this observation needs to be tested with further quantitative studies. Online therapies may be the answer to limited psychotherapeutic resources in gastroenterology clinics.

Family and carer smoking control programmes for reducing children's exposure to environmental tobacco smoke

BackgroundChildren's exposure to other people's cigarette smoke (environmental tobacco smoke, or ETS) is associated with a range of adverse health outcomes for children. Parental smoking is a common source of children's exposure to ETS. Older children are also at risk of exposure to ETS in child care or educational settings. Preventing exposure to cigarette smoke in infancy and childhood has significant potential to improve children's health worldwide.ObjectivesTo determine the effectiveness of interventions aiming to reduce exposure of children to ETS.Search methodsWe searched the Cochrane Tobacco Addiction Group Specialized Register and conducted additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, EMBASE, CINAHL, ERIC, and The Social Science Citation Index & Science Citation Index (Web of Knowledge). Date of the most recent search: September 2013.Selection criteriaControlled trials with or without random allocation. Interventions must have addressed participants (parents and other family members, child care workers and teachers) involved with the care and education of infants and young children (aged 0 to 12 years). All mechanisms for reduction of children's ETS exposure, and smoking prevention, cessation, and control programmes were included. These include health promotion, social-behavioural therapies, technology, education, and clinical interventions.Data collection and analysisTwo authors independently assessed studies and extracted data. Due to heterogeneity of methodologies and outcome measures, no summary measures were possible and results were synthesised narratively.Main resultsFifty-seven studies met the inclusion criteria. Seven studies were judged to be at low risk of bias, 27 studies were judged to have unclear overall risk of bias and 23 studies were judged to have high risk of bias. Seven interventions were targeted at populations or community settings, 23 studies were conducted in the 'well child' healthcare setting and 24 in the 'ill child' healthcare setting. Two further studies conducted in paediatric clinics did not make clear whether the visits were to well or ill children, and another included both well and ill child visits. Thirty-six studies were from North America, 14 were in other high income countries and seven studies were from low- or middle-income countries. In only 14 of the 57 studies was there a statistically significant intervention effect for child ETS exposure reduction. Of these 14 studies, six used objective measures of children's ETS exposure. Eight of the studies had a high risk of bias, four had unclear risk of bias and two had a low risk of bias. The studies showing a significant effect used a range of interventions: seven used intensive counselling or motivational interviewing; a further study used telephone counselling; one used a school-based strategy; one used picture books; two used educational home visits; one used brief intervention and one study did not describe the intervention. Of the 42 studies that did not show a significant reduction in child ETS exposure, 14 used more intensive counselling or motivational interviewing, nine used brief advice or counselling, six used feedback of a biological measure of children's ETS exposure, one used feedback of maternal cotinine, two used telephone smoking cessation advice or support, eight used educational home visits, one used group sessions, one used an information kit and letter, one used a booklet and no smoking sign, and one used a school-based policy and health promotion. In 32 of the 57 studies, there was reduction of ETS exposure for children in the study irrespective of assignment to intervention and comparison groups. One study did not aim to reduce children's tobacco smoke exposure, but rather aimed to reduce symptoms of asthma, and found a significant reduction in symptoms in the group exposed to motivational interviewing. We found little evidence of difference in effectiveness of interventions between the well infant, child respiratory illness, and other child illness settings as contexts for parental smoking cessation interventions.Authors' conclusionsWhile brief counselling interventions have been identified as successful for adults when delivered by physicians, this cannot be extrapolated to adults as parents in child health settings. Although several interventions, including parental education and counselling programmes, have been used to try to reduce children's tobacco smoke exposure, their effectiveness has not been clearly demonstrated. The review was unable to determine if any one intervention reduced parental smoking and child exposure more effectively than others, although seven studies were identified that reported motivational interviewing or intensive counselling provided in clinical settings was effective.

Descripción de resultados de la reconstrucción de placa plantar en inestabilidad de la segunda articulación metatarsofalángica

Objetivo: Describir los desenlaces funcionales, complicaciones postoperatorias, dolor y satisfacción de un grupo de pacientes con diagnóstico de inestabilidad de segunda articulación metatarsofalángica y lesión de la placa plantar, que fueron intervenidos quirúrgicamente para su reconstrucción en el Hospital Universitario de cuarto nivel Fundación Santa Fé de Bogotá, en el periodo comprendido entre Enero de 2010 hasta Diciembre de 2015. Métodos: Estudio descriptivo de corte transversal que evalúa desenlaces funcionales, dolor y satisfacción para un grupo consecutivo de pacientes con diagnóstico de inestabilidad de la segunda articulación metatarsofalángica que fueron intervenidos quirúrgicamente mediante reconstrucción de la placa plantar entre Enero de 2010 a Diciembre de 2015 en el Hospital Universitario Fundación Santa fe de Bogotá. Resultados: El procedimiento se realizó a 39 pacientes (40 MTF), encontrando mejoría en dolor, función y satisfacción. El dolor postoperatorio paso de severo a leve en el 80% de los pacientes, 67.5% de los pacientes presentaron prueba de aprehensión positiva, 85% alineamiento adecuado, el reporte de escala de AOFAS postoperatoria fue de 87, y los resultados fueron satisfactorios en un 94.5%. La principal complicación con la cirugía fue la extensión residual del dedo operado (22.5%). Conclusiones: La reconstrucción de la placa plantar en casos de inestabilidad metatarsofalángica ha demostrado tener resultados satisfactorios, en el presente estudio encontramos mejoría respecto a dolor, función y satisfacción posterior a la realización del procedimiento. Sin embargo puede presentar complicaciones como extensión residual del dedo o elevación, rigidez y recidiva.