Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and IMAGe association.

We describe a case of acquired monosomy 7 myelodysplastic syndrome (MDS) in a boy with congenital adrenocortical insufficiency, genital anomalies, growth delay, skin hyperpigmentation, and chronic lung disease. Some of his clinical manifestations were suggestive of dyskeratosis congenita (DC), while other features resembled IMAGe association. DC has been linked to mutations in telomere maintenance genes. The genetic basis of IMAGe association is unknown, although mice harboring a mutation in a telomere maintenance gene, Tpp1, have adrenal hypoplasia congenita. We considered the possibility that this patient has a defect in telomere function resulting in features of both DC and IMAGe association.

Pilocytic astrocytoma in a child with Noonan syndrome.

Noonan syndrome (NS; MIM 163950) is an autosomal dominant dysmorphic syndrome characterized by distinct facial features, cardiac anomalies, short stature, and motor delay. Activating mutations in PTPN11, encoding the protein tyrosine phosphatase SHP2, are associated with about 50% of cases. Mutations in other genes in the RAS/mitogen-activated protein kinase signaling pathway are responsible for many of the remainder of cases. While mutations in this pathway are found in a variety of malignancies, including solid tumors, there are few reports of solid tumors in individuals with NS. We report here a patient with PTPN11 mutation-associated NS and a pilocytic astrocytoma.

Complex network theory for the identification and assessment of candidate protein targets.

In this work we use complex network theory to provide a statistical model of the connectivity patterns of human proteins and their interaction partners. Our intention is to identify important proteins that may be predisposed to be potential candidates as drug targets for therapeutic interventions. Target proteins usually have more interaction partners than non-target proteins, but there are no hard-and-fast rules for defining the actual number of interactions. We devise a statistical measure for identifying hub proteins, we score our target proteins with gene ontology annotations. The important druggable protein targets are likely to have similar biological functions that can be assessed for their potential therapeutic value. Our system provides a statistical analysis of the local and distant neighborhood protein interactions of the potential targets using complex network measures. This approach builds a more accurate model of drug-to-target activity and therefore the likely impact on treating diseases. We integrate high quality protein interaction data from the HINT database and disease associated proteins from the DrugTarget database. Other sources include biological knowledge from Gene Ontology and drug information from DrugBank. The problem is a very challenging one since the data is highly imbalanced between target proteins and the more numerous nontargets. We use undersampling on the training data and build Random Forest classifier models which are used to identify previously unclassified target proteins. We validate and corroborate these findings from the available literature.

The antioxidant conundrum in cancer.

The health-related effects of interactions between reactive oxygen species (ROS) and dietary antioxidants and the consequences of dietary antioxidant supplementation on human health are by no means clear. Although ROS, normal byproducts of aerobic metabolism, are essential for various defense mechanisms in most cells, they can also cause oxidative damage to DNA, proteins, and lipids, resulting in enhanced disease risk. Dietary antioxidants (e.g., vitamin E, vitamin C, beta-carotene, and selenium), as well as endogenous antioxidant mechanisms, can help maintain an appropriate balance between the desirable and undesirable cellular effects of ROS. However, any health-related effects of interactions between dietary antioxidants and ROS likely depend on the health status of an individual and may also be influenced by genetic susceptibilities. Clinical studies of antioxidant supplementation and changes in either oxidative status, disease risk, or disease outcome have been carried out in healthy individuals, populations at risk for certain diseases, and patients undergoing disease therapy. The use of antioxidants during cancer therapy is currently a topic of heated debate because of an overall lack of clear research findings. Some data suggest antioxidants can ameliorate toxic side effects of therapy without affecting treatment efficacy, whereas other data suggest antioxidants interfere with radiotherapy or chemotherapy. Overall, examination of the evidence related to potential interactions between ROS and dietary antioxidants and effects on human health indicates that consuming dietary antioxidant supplements has pros and cons for any population and raises numerous questions, issues, and challenges that make this topic a fertile field for future research. Overall, current knowledge makes it premature to generalize and make specific recommendations about antioxidant usage for those at high risk for cancer or undergoing treatment.

An evidence-based approach to cancer prevention clinical trials.

Research on carcinogenesis and its inhibition has made significant progress in the last 30 years, providing an impressive body of evidence that supports various strategies for cancer prevention. Innovative studies have helped to identify potential causes of cancer, including environmental factors such as diet, and provided valuable information about their mechanisms of action. Hundreds of epidemiologic and experimental studies have focused on possible associations between dietary factors and different types of cancer. During the same period, potential inhibitors of cancer that appeared able to prevent, arrest or reverse cancer development by interfering with one or more steps in the process of carcinogenesis were identified, and the term 'chemoprevention' was coined for this pharmacological approach to cancer prevention. Promising compounds were systematically evaluated for their potential as chemopreventive agents. Numerous agents were determined to be safe and effective in preclinical trials, including naturally occurring vitamins, minerals and phytochemicals as well as synthetic compounds. Based on preclinical results, selected agents have been and are now being evaluated in phase I, II and III clinical interventions for various cancers. Development of valid surrogate end point biomarkers for clinical disease that can be modulated by interventions is essential to accelerate progress in cancer prevention clinical trials.

Efficacy and safety of 6-thioguanine in the management of inflammatory bowel disease.

OBJECTIVE: 6-Thioguanine has been used as an alternative immunomodulator in the treatment of inflammatory bowel disease but data on its efficacy and safety are limited. The aim of this study was to analyse our experience of the efficacy and safety of 6-thioguanine in inflammatory bowel disease. MATERIAL AND METHODS: Patients attending the inflammatory bowel disease clinic who were started on 6-thioguanine therapy were included in this prospective observational study. Indications for initiating 6-thioguanine therapy and other related clinical, pharmacological and laboratory parameters prior to and during therapy were recorded to determine the efficacy and safety of 6-thioguanine. RESULTS: A total of 40 patients were treated with 6-thioguanine, 28 with Crohn's disease, 10 with ulcerative colitis and 2 with indeterminate colitis, at a fixed daily dose of 40 mg and continued for a median duration of 34 weeks (range 2-90 weeks). The indications for 6-thioguanine therapy included previous clinical resistance to thiopurine analogues (n=21), intolerance to thiopurine analogues (n=8) and de novo 6-thioguanine use in steroid refractory disease (n=11). Disease remission was reached in 44%, 73% and 89% of these patient groups at 3, 6 and 12 months, respectively. Inflammatory markers and steroid use were significantly lower during 6-thioguanine therapy compared with in the period before therapy. Therapy was discontinued in 13 patients (33%), mainly because of thrombocytopenia and associated hepatotoxicity. CONCLUSIONS: 6-Thioguanine is a useful addition to treatment in inflammatory bowel disease but the frequent occurrence of hepatotoxicity limits its routine use.

Performance and reporting of clinical breast examination: a review of the literature.

Clinical breast examination (CBE) seeks to detect breast abnormalities or evaluate patient reports of symptoms to find palpable breast cancers at an earlier stage of progression, when treatment is more effective and treatment options are greater than for later stage disease. Evidence suggests that, for some women, CBE can be an important complement to mammography in the earlier detection of breast cancer; CBE identifies some cancers missed by mammography and provides an important screening tool among women for whom mammography is not recommended or women who do not receive high-quality screening mammography according to recommended guidelines. But CBE performance and reporting approaches are inconsistent. Health care providers indicate that they are not confident in their CBE skills and would welcome training. Studies demonstrate that training can enhance CBE performance, measured in terms of execution of CBE components and accuracy. This literature review provides evidence to the extent that it is available, to support the specific recommendations of Saslow, et al. for optimizing CBE performance and reporting and to guide further research on CBE performance characteristics, reporting systems, barriers to high-quality CBE performance, and training.

Micronutrients in cancer chemoprevention.

The selection of micronutrients, defined as essential and nonessential dietary components consumed in minute quantities, for testing in clinical chemoprevention trials is based on the totality of evidence arising from epidemiologic, in vitro, animal, and clinical studies. Those micronutrients that surface with chemopreventive potential, in terms of high efficacy and low toxicity, in early-phase clinical studies are then candidates for large-scale, randomized clinical chemoprevention trials with cancer endpoints. Micronutrients currently being examined in National Cancer Institute (NCI)-sponsored phase I, II, or III chemoprevention trials for prostate, breast, and colon cancers include isoflavones, lycopene, selenized yeast, selenomethionine, selenium, vitamin E, perillyl alcohol, folic acid, vitamin D, calcium, and curcumin. The response to micronutrients may vary not only in magnitude but also in direction. This variation and response likely depend on individual genetic polymorphisms and/or interactions among dietary components that influence absorption, metabolism, or site of action. Research priorities include investigation of possible molecular targets for micronutrients and whether genetic and epigenetic events dictate direction and magnitude of the response.