Cancer Genes Hypermethylated in Human Embryonic Stem Cells

Developmental genes are silenced in embryonic stem cells by a bivalent histone-based chromatin mark. It has been proposed that this mark also confers a predisposition to aberrant DNA promoter hypermethylation of tumor suppressor genes (TSGs) in cancer. We report here that silencing of a significant proportion of these TSGs in human embryonic and adult stem cells is associated with promoter DNA hypermethylation. Our results indicate a role for DNA methylation in the control of gene expression in human stem cells and suggest that, for genes repressed by promoter hypermethylation in stem cells in vivo, the aberrant process in cancer could be understood as a defect in establishing an unmethylated promoter during differentiation, rather than as an anomalous process of de novo hypermethylation

Effects of phone versus mail survey methods on the measurement of health-related quality of life and emotional and behavioural problems in adolescents

<p>Abstract</p> <p>Background</p> <p>Telephone interviews have become established as an alternative to traditional mail surveys for collecting epidemiological data in public health research. However, the use of telephone and mail surveys raises the question of to what extent the results of different data collection methods deviate from one another. We therefore set out to study possible differences in using telephone and mail survey methods to measure health-related quality of life and emotional and behavioural problems in children and adolescents.</p> <p>Methods</p> <p>A total of 1700 German children aged 8-18 years and their parents were interviewed randomly either by telephone or by mail. Health-related Quality of Life (HRQoL) and mental health problems (MHP) were assessed using the KINDL-R Quality of Life instrument and the Strengths and Difficulties Questionnaire (SDQ) children's self-report and parent proxy report versions. Mean Differences ("d" effect size) and differences in Cronbach alpha were examined across modes of administration. Pearson correlation between children's and parents' scores was calculated within a multi-trait-multi-method (MTMM) analysis and compared across survey modes using Fisher-Z transformation.</p> <p>Results</p> <p>Telephone and mail survey methods resulted in similar completion rates and similar socio-demographic and socio-economic makeups of the samples. Telephone methods resulted in more positive self- and parent proxy reports of children's HRQoL (SMD ≤ 0.27) and MHP (SMD ≤ 0.32) on many scales. For the phone administered KINDL, lower Cronbach alpha values (self/proxy Total: 0.79/0.84) were observed (mail survey self/proxy Total: 0.84/0.87). KINDL MTMM results were weaker for the phone surveys: mono-trait-multi-method mean r = 0.31 (mail: r = 0.45); multi-trait-mono-method mean (self/parents) r = 0.29/0.36 (mail: r = 0.34/0.40); multi-trait-multi-method mean r = 0.14 (mail: r = 0.21). Weaker MTMM results were also observed for the phone administered SDQ: mono-trait-multi-method mean r = 0.32 (mail: r = 0.40); multi-trait-mono-method mean (self/parents) r = 0.24/0.30 (mail: r = 0.20/0.32); multi-trait-multi-method mean r = 0.14 (mail = 0.14). The SDQ classification into borderline and abnormal for some scales was affected by the method (OR = 0.36-1.55).</p> <p>Conclusions</p> <p>The observed differences between phone and mail surveys are small but should be regarded as relevant in certain settings. Therefore, while both methods are valid, some changes are necessary. The weaker reliability and MTMM validity associated with phone methods necessitates improved phone adaptations of paper and pencil questionnaires. The effects of phone versus mail survey modes are partly different across constructs/measures.</p

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

Colorectal carcinomas (CRCs) with high microsatellite instability (MSI-H) share clinicopathological features distinctly different from their microsatellite stable (MSS) counterparts. Unlike MSS cancers, MSI-H CRCs occur predominantly in the right-sided colon and are often characterised by a strong lymphocyte infiltration. A poor differentiation pattern is found in most MSI-H CRCs, even though patients with MSI-H carcinomas seem to have a significantly longer survival after surgical resection. To clarify which factors contribute to the obvious paradoxon of a more favourable prognosis of MSI tumours, several clinical and histopathological features as well as the microsatellite status were evaluated in 120 colorectal cancer cases fulfilling clinical criteria (Bethesda) indicative for familial colorectal cancer. Microsatellite instablity status and lymphocyte infiltration were related to tumour stage and patients' follow-up. Statistical analysis confirmed well-known relations, such as enhanced lymphocyte infiltration accompanied by Crohn's like reaction (CLR) in MSI-H cancers (CLR+ in 27 out of 47 MSI-H vs 14 out of 71 MSS CRCs, P<0.001). However, after stratification for depth of local invasion and penetration of the primary tumour, T3 tumours displaying MSI had a significantly lower rate of distant metastases (M1 in four out of 35 MSI-H vs 20 out of 41 MSS CRCs, P<0.001). A similar tendency was observed for CLR-positive CRCs (M1 in six out of 29 CLR+ vs 17 out of 45 CLR− CRCs, P=0.13). In a logistic regression model, the MSI-H phenotype and the presence of CLR were independent predictors of a low UICC stage (P=0.006 and 0.04, respectively). These data, together with the recent definition of highly immunogenic neo-antigens expressed in MSI-H tumour cells, suggest that MSI-H CRCs elicit a protective host response that may prevent metastasis formation

Is using the strengths and difficulties questionnaire in a community sample the optimal way to assess mental health functioning?

An important characteristic of a screening tool is its discriminant ability or the measure’s accuracy to distinguish between those with and without mental health problems. The current study examined the inter-rater agreement and screening concordance of the parent and teacher versions of SDQ at scale, subscale and item-levels, with the view of identifying the items that have the most informant discrepancies; and determining whether the concordance between parent and teacher reports on some items has the potential to influence decision making. Cross-sectional data from parent and teacher reports of the mental health functioning of a community sample of 299 students with and without disabilities from 75 different primary schools in Perth, Western Australia were analysed. The study found that: a) Intraclass correlations between parent and teacher ratings of children’s mental health using the SDQ at person level was fair on individual child level; b) The SDQ only demonstrated clinical utility when there was agreement between teacher and parent reports using the possible or 90% dichotomisation system; and c) Three individual items had positive likelihood ratio scores indicating clinical utility. Of note was the finding that the negative likelihood ratio or likelihood of disregarding the absence of a condition when both parents and teachers rate the item as absent was not significant. Taken together, these findings suggest that the SDQ is not optimised for use in community samples and that further psychometric evaluation of the SDQ in this context is clearly warranted

Molecular marks for epigenetic identification of developmental and cancer stem cells

Epigenetic regulations of genes by reversible methylation of DNA (at the carbon-5 of cytosine) and numerous reversible modifications of histones play important roles in normal physiology and development, and epigenetic deregulations are associated with developmental disorders and various disease states, including cancer. Stem cells have the capacity to self-renew indefinitely. Similar to stem cells, some malignant cells have the capacity to divide indefinitely and are referred to as cancer stem cells. In recent times, direct correlation between epigenetic modifications and reprogramming of stem cell and cancer stem cell is emerging. Major discoveries were made with investigations on reprogramming gene products, also known as master regulators of totipotency and inducer of pluoripotency, namely, OCT4, NANOG, cMYC, SOX2, Klf4, and LIN28. The challenge to induce pluripotency is the insertion of four reprogramming genes (Oct4, Sox2, Klf4, and c-Myc) into the genome. There are always risks of silencing of these genes by epigenetic modifications in the host cells, particularly, when introduced through retroviral techniques. In this contribution, we will discuss some of the major discoveries on epigenetic modifications within the chromatin of various genes associated with cancer progression and cancer stem cells in comparison to normal development of stem cell. These modifications may be considered as molecular signatures for predicting disorders of development and for identifying disease states

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

A new era for understanding amyloid structures and disease

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention

Sustained long-term improvement with clozapine in schizophrenia Clozapina na esquizofrenia grave: melhora duradoura e sustentada

The present paper reports the long-term use of clozapine in a prospective sample of 46 chronic schizophrenics. In six months, 21 subjects had been excluded for a number of reasons. In four of them the reasons for exclusion were related to lack of response or adverse effects. The median daily clozapine dose was 400 mg in the remaining 25 patients. As a whole, there were remarkable improvements in core dimensions of psychopathology, global cognitive status, and level of functioning. We confirmed that clozapine is effective in a subgroup of schizophrenics with the severest forms of the disease. If tolerated after the first few months it leads to progressive gains in several domains of behavior. Clozapine should be tried in every patient with schizophrenia in whom positive symptoms, disorganization, or bizarre behavior are a matter of incapacitation despite efforts to keep them under control with other drugs.<br>O presente estudo, prospectivo, relata o uso de longo-prazo da clozapina em 46 esquizofrênicos graves, com mais de cinco anos de doença. Com seis meses de uso da droga, 21 indivíduos haviam sido excluídos por diversas razões. Em quatro, a exclusão se deveu a efeitos adversos ou ausência de resposta. A dose mediana de clozapina foi de 400 mg nos demais 25 pacientes. No todo, observamos melhora em dimensões de psicopatologia, estado cognitivo global, e nível funcional. Concluímos que a clozapina é eficaz em um subgrupo de esquizofrênicos com formas graves da doença. Se tolerada depois dos primeiros meses, produz benefícios progressivos em diversos domínios do comportamento. Clozapina deve ser tentada em todo paciente com esquizofrenia incapacitado por sintomas positivos, desorganização, e/ou comportamentos bizarros, que persistem a despeito de esforços para mantê-los sob controle com outras drogas