mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Clinical trials indicate efficacy of drugs inhibiting the mammalian target of rapamycin (mTOR) in the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NET); however, information on detailed expression and activity patterns of mTOR in these tumours is sparse. We investigated the expression of mTOR and expression as well as phosphorylation of its downstream targets 4EBP1, S6K and eIF4E in a cohort of 99 human GEP-NET by immunohistochemistry. We correlated our findings with clinicopathological variables and patient prognosis. We found that 61, 93, 80, 69, 57 and 79% of GEP-NET were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1), nuclear p-4EBP1, phospho-S6K (p-S6K) and phospho-eIF4E (p-eIF4E) respectively. mTOR expression and activity were higher in foregut than in midgut tumours. In foregut tumours, expression of mTOR was higher when distant metastases were present (P=0.035). Strong mTOR activity was associated with higher proliferative capacity. In patients with stage IV midgut tumours, strong p-S6K expression was associated with poor disease-specific survival (P=0.048). In conclusion, mTOR shows considerable variations in expression and activity patterns in GEP-NET in dependence of tumour location and metastatic status. We hypothesise that these differences in mTOR expression and activity might possibly influence response to mTOR inhibitors.     

A prognostic gene expression index in ovarian cancer—validation across different independent data sets

Ovarian carcinoma has the highest mortality rate among gynaecological malignancies. In this project, we investigated the hypothesis that molecular markers are able to predict outcome of ovarian cancer independently of classical clinical predictors, and that these molecular markers can be validated using independent data sets. We applied a semi‐supervised method for prediction of patient survival. Microarrays from a cohort of 80 ovarian carcinomas (TOC cohort) were used for the development of a predictive model, which was then evaluated in an entirely independent cohort of 118 carcinomas (Duke cohort). A 300‐gene ovarian prognostic index (OPI) was generated and validated in a leave‐one‐out approach in the TOC cohort (Kaplan‐Meier analysis, p = 0.0087). In a second validation step, the prognostic power of the OPI was confirmed in an independent data set (Duke cohort, p = 0.0063). In multivariate analysis, the OPI was independent of the post‐operative residual tumour, the main clinico‐pathological prognostic parameter with an adjusted hazard ratio of 6.4 (TOC cohort, CI 1.8–23.5, p = 0.0049) and 1.9 (Duke cohort, CI 1.2–3.0, p = 0.0068). We constructed a combined score of molecular data (OPI) and clinical parameters (residual tumour), which was able to define patient groups with highly significant differences in survival. The integrated analysis of gene expression data as well as residual tumour can be used for optimized assessment of the prognosis of platinum‐taxol‐treated ovarian cancer. As traditional treatment options are limited, this analysis may be able to optimize clinical management and to identify those patients who would be candidates for new therapeutic strategies. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Sleep disorders in childhood-onset myotonic dystrophy type 1

Slowness, fatigue, and learning difficulties are common in young patients with myotonic dystrophy type 1. These features may indicate poor sleep quality. The aim of this study was to search for sleep disorders in this population. This prospective study used questionnaires, genetic testing, night-time polysomnography and multiple sleep latency tests to evaluate objective daytime sleepiness. Twenty-one patients were included. Mean age was 15.0+/-3.0. Age of onset of myotonic disorders was after birth and before 10 years old. Age of diagnosis was 12.0+/-2.9. Fatigue was reported by 76% of patients, while somnolence was present in 52%. Sleep was disturbed by numerous microarousals (mean 16.6+/-7.3/h of sleep) caused by abnormal respiratory events (6/21 patients) and/or periodic limb movements (8/21 patients). In young patients with DM1, complaints of fatigue and/or somnolence should lead to a polysomnography to look for sleep apnea syndrome and/or periodic limb movement, which were present in two-thirds of our population.     

Team Management of the Female Athlete Triad

The noninflammatory, diffuse syndrome recognized as fibromyalgia primarily affects women between puberty and menopause. Symptoms, in addition to musculoskeletal pain and tender points, can include fatigue, nonrestorative sleep, and depression. A precipitating event such as abrupt cessation of exercise, physical injury, or prior debilitating illness can often be identified. Aerobic exercise is usually protective, but sporadic training patterns or other precipitants can place even well-trained athletes at risk. Patients need to know that they can alter the course of this syndrome. Treatment should include attempts to reverse the precipitating event, plus education, aerobic exercise, correction of any sleep disturbance, analgesia, and physical therapy.     

Analysis of the response of human keratinocytes to Malassezia globosa and restricta strains

Malassezia spp. are saprophyte yeasts involved in skin diseases with different degrees of severity. The aim of our study was to analyze the response of human epidermal keratinocytes to Malassezia globosa and restricta strains evaluating the host defence mechanisms induced by Malassezia spp. colonization. Our results showed a different modulation of the inflammatory and immunomodulatory cytokine pathways obtained with the different strains of Malassezia tested. In addition, this expression is altered by blocking the TLR2 receptor. In comparison with M. furfur, M. globosa and restricta displayed an unexpected and striking cytotoxicity on keratinocytes. The differences observed could be related to the different modalities of interaction between keratinocytes and Malassezia strains, but also to their growth condition. Taken together, these results indicate that M. globosa or M. restricta colonization exert a different control on the cytokine inflammatory response activated in the human keratinocyte in which TLR2 might be involved. M. globosa and M. restricta may play a synergistic role in the exacerbation of skin diseases in which both are found.     

Screening of the topical anti-inflammatory activity of some Central American plants

Hexane, chloroform and methanol extracts of seven herbal drugs used in the folk medicine of Central America against skin disorders (Aristolochia trilobata leaves and bark, Bursera simaruba bark, Hamelia patens leaves, Piper amalago leaves, and Syngonium podophyllum leaves and bark) were evaluated for their topical anti-inflammatory activity against the Croton oil-induced ear oedema in mice. Most of the extracts induced a dose-dependent oedema reduction. The chloroform extract of almost all the drugs exhibited interesting activities with ID(50) values ranging between 108 and 498 micro g/cm(2), comparable to that of indomethacin (93 micro g/cm(2)). Therefore, the tested plants are promising sources of principles with high anti-inflammatory activity.