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The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML. Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.

Human dental pulp cells (DPCs), which are known to contain a subset of stem cells capable of reforming a dentin and pulp-like complex upon in vivo transplantation, were isolated from third molars of three healthy donors and differentiated to a matrix mineralisation phenotype using by culture in dexamethasone and l-ascorbic acid. qRT-PCR analysis of insulin-like growth factor ( IGF) axis gene expression indicated that all genes, except insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein-1 ( IGFBP-1), were expressed in DPCs. During differentiation upregulation of insulin-like growth factor binding protein-2 (IGFBP-2) and downregulation of insulin-like growth factor binding protein-3 (IGFBP-3) expression was observed. Changes in IGFBP-2 and IGFBP-3 mRNA expression were confirmed at the protein level by ELISA of DPC conditioned medium functional analysis indicated that IGF1 stimulated the differentiation of DPCs and that the activity of the growth factor was enhanced by pre-complexation with IGFBP-2 but inhibited by pre-complexation with IGFBP-3. Therefore changes in IGFBP-2 and -3 expression during differentiation form part of a co-ordinated functional response to enhance the pro-differentiative action of IGF1 and represent a novel mechanism for the regulation of DPC differentiation., Highlights • IGF axis expression is characterised in human dental pulp cells (DPCs). • Reciprocal changes are identified in expression of IGFBP-2 and -3 during matrix mineralisation of DPCs • This forms part of a functional co-ordinated response during the IGF1 stimulated differentiation of DPCs.

To determine the occurrence of cancer-related fatigue, the methods used to assess it, and the efficacy of the available treatments, we performed literature searches that identified English-language publications on these topics. Twenty-seven studies were identified in which the quantitative estimation of the occurrence of cancer-related fatigue was an end point. Fifty-six were judged to be relevant to the assessment of fatigue, and 10 randomized controlled clinical trials of treatments of cancer-related fatigue were retrieved. The occurrence of cancer-related fatigue was found to range from 4% to 91%, depending on the population studied and the methods of assessment. Few population-based studies and no longitudinal studies of cancer-related fatigue have been performed. The methods of fatigue assessment were highly variable. Exercise programs show promise to prevent or treat fatigue in some subsets of cancer patients, and the use of epoetin alfa for correction of anemia has been shown to ameliorate fatigue. The number of subjects in the treatment trials was small and their methodologic quality was inconsistent.

To assess the effects, associations, mechanisms of action, and safety of B vitamins and, separately, berries and their constituents on age-related neurocognitive disorders-primarily Alzheimer's (AD) and Parkinson's disease (PD).MEDLINE and CAB Abstracts. Additional studies were identified from reference lists and technical experts.Vitamins B1, B2, B6, B12, and folate, and a dozen types of berries and their constituents were evaluated. Human, animal, and in vitro studies were evaluated. Outcomes of interest from human studies were neurocognitive function or diagnosis with AD, cognitive decline, PD, or related conditions. Intervention studies, associations between dietary intake and outcomes, and associations between B vitamin levels and outcomes were evaluated. Specific mechanisms of action were evaluated in animal and in vitro studies. Studies were extracted for study design, demographics, intervention or predictor, and neurocognitive outcomes. Studies were graded for quality and applicability.In animal studies, deficiencies in vitamins B1 or folate generally cause neurological dysfunction; supplementation with B6, B12, or folate may improve neurocognitive function. In animal experiments folate and B12 protect against genetic deficiencies used to model AD; thiamine and folate also affect neurovascular function and health. Human studies were generally of poor quality. Weak evidence suggests possible benefits of B1 supplementation and injected B12 in AD. The effects of B6 and folate are unclear. Overall, dietary intake studies do not support an association between B vitamin intake and AD. Studies evaluating B vitamin status were mostly inadequate due to poor study design. Overall, studies do not support an association between B vitamin status and age-related neurocognitive disorders. Only one study evaluated human berry consumption, finding no association with PD. Animal studies of berries have almost all been conducted by the same research group. Several berry constituents have been shown to affect brain and nerve tissue function. Blueberry and strawberry extract were protective of markers of disease, although effects on neurocognitive tests were less consistent. Berry extracts may protect against the deleterious effects of compounds associated with AD. Reporting of adverse events was uncommon. When reported, actual adverse events from B vitamins were rare and minor.The current research on B vitamins is largely inadequate to confidently assess their mechanisms of action on age-related neurocognitive disorders, their associations with disease, or their effectiveness as supplements. B vitamin supplementation may be of value for neurocognitive function, but the evidence is inconclusive.

Human tissues often support large, complex microbial communities growing as biofilms that can cause a variety of infections. As a result of an increased use of implanted medical devices, the incidence of these biofilm-associated diseases is increasing: the non-shedding surfaces of these devices provide ideal substrata for colonisation by biofilm-forming microbes. The consequences of this mode of growth are far-reaching. As microbes in biofilms exhibit increased tolerance towards antimicrobial agents and decreased susceptibility to host defence systems, biofilm-associated diseases are becoming increasingly difficult to treat. Not surprisingly, therefore, interest in biofilms has increased dramatically. The application of microscopic and molecular techniques has revolutionised our understanding of biofilm structure, composition, organisation, and activities, resulting in important advances in the prevention and treatment of biofilm-related diseases. The purpose of this book, which was first published in 2003, is to bring these advances to the attention of clinicians and medical researchers.

Long-term aim is to determine optimum interventions to reduce dental caries in children in disadvantaged communities and minimise the effects of exclusion from health care systems, of ethnic diversity, and health inequalities.Generation of initial explanatory models, study protocol and development of two standardised measures. First, to investigate how parental attitudes may impact on their children's oral health-related behaviours and second, to assess how dentists' attitudes may impact on the provision of dental care.Core research team, lead methodologists, 44 consortium members from 18 countries. To complete the development of the questionnaire, the initial set of items was administered to parents (n = 23) with children in nursery schools in Dundee, Scotland and sent to the same parents one week later. A standardised measure examining barriers to providing dental care for children aged 3 to 6 years was developed. 20 dentists working in primary dental care in Scotland completed the measure on two different occasions separated by one week.Explanatory models were developed. Family questionnaire: test-retest reliability excellent (r = 0.93 por = 0.001) with very good internal reliability (alpha = 0.89). Dentists questionnaire: excellent test-re-test reliability r = 0.88, (alpha = 0.90).Interaction between consortium members enhanced the validity of the questionnaires and protocols for different cultural locations. There were challenges in developing and delivering this multi-centre study. Experience gained will support the development of substantive trials and longitudinal studies to address the considerable international health disparity of childhood dental caries.