Methylation of TET2, CBL and CEBPA in Ph-negative myeloproliferative neoplasms

A loss-of-function mutation of TET2, CBL and CEBPA has been implicated in the pathogenesis or leukaemic transformation of myeloproliferative neoplasm. As tumour suppressor genes may potentially be inactivated by promoter hypermethylation, the authors studied the methylation status of these genes in three cell lines and diagnostic marrow samples from 45 patients with myeloproliferative neoplasm (MPN) (essential thrombocythaemia, N=34; polycythaemia vera, N=7 and primary myelofibrosis, N=4) by methylation-specific PCR. TET2 was heterozygously methylated in MEG-01 and K562 but completely unmethylated in HEL. On the other hand, both CBL and CEBPA were completely unmethylated in all three cell lines. In the primary marrow samples, methylation of TET2 occurred in two (5.9%) patients with essential thrombocythaemia (4.4% of all patients), both without JAK2 V617 mutation, but not in polycythaemia vera or primary myelofibrosis. There was no association between TET2 methylation with the type of MPN (p=0.713). Hypermethylation of CBL or CEBPA was not detected in any patients. In summary, methylation of TET2, CBL and CEBPA is infrequent in MPN at diagnosis. The role of methylation of these genes at the time of leukaemic transformation warrants further study.published_or_final_versio

Confounding, homogeneity and collapsibility for causal effects in epidemiologic studies

Detection of confounding and confounders is important for observational studies, and especially so for epidemiologic studies. Miettinen and Cook (1981) derived two criteria for detecting confounders. Using a model, Wickramaratne and Holford (1987) proved that the two criteria are necessary but not sufficient conditions for confounders. We take uniform nonconfounding to mean there is no confounding at a coarse-subpopulation-level obtained by pooling any number of subpopulations. We discuss the necessity and sufficiency of the two criteria for uniform nonconfounding. The concepts of homogeneity and collapsibility for causal effects are also defined, and the relation among confounding, homogeneity and collapsibility is discussed. We show that the common causal effect over all fine subpopulations is just the causal effect of the whole population.published_or_final_versio

Confounding, homogeneity and collapsibility for causal effects in epidemiologic studies

Detection of confounding and confounders is important for observational studies, and especially so for epidemiologic studies. Miettinen and Cook (1981) derived two criteria for detecting confounders. Using a model, Wickramaratne and Holford (1987) proved that the two criteria are necessary but not sufficient conditions for confounders. We take uniform nonconfounding to mean there is no confounding at a coarse-subpopulation-level obtained by pooling any number of subpopulations. We discuss the necessity and sufficiency of the two criteria for uniform nonconfounding. The concepts of homogeneity and collapsibility for causal effects are also defined, and the relation among confounding, homogeneity and collapsibility is discussed. We show that the common causal effect over all fine subpopulations is just the causal effect of the whole population.published_or_final_versio

Methylation of miR-34a, miR-34b/c, miR-124-1 and miR-203 in Ph-negative myeloproliferative neoplasms

BACKGROUND: MicroRNA (miR) miR-34a, -34b/c, -124-1 and -203 are tumor suppressor miRs implicated in carcinogenesis. METHODS: We studied DNA methylation of these miRs in Philadelphia-negative (Ph-ve) myeloproliferative neoplasms (MPNs). Methylation-specific PCR (MSP), verified by direct sequencing of the methylated MSP products, was performed in cell lines, normal controls and diagnostic marrow samples of patients with MPNs. RESULTS: Methylation of these miRs was absent in the normal controls. miR-34b/c were homozygously methylated in HEL cells but heterozygously in MEG-01. In HEL cells, homozygous miR-34b/c methylation was associated with miR silencing, and 5-aza-2'-deoxycytidine treatment led to re-expression of both miR-34b and miR-34c, consistent with that both miRs are under the regulation of the same promoter CpG island. miR-34a was heterozygously methylated in MEG-01 and K-562. miR-203 was completely unmethylated in K-562 and SET-2 but no MSP amplification was found in both HEL and MEG-01, suggestive of miR deletion. In primary samples, four each had miR-34b/c and -203 methylation, in which two had concomitant methylation of miR-34b/c and -203. miR-34a was methylated in one patient and none had methylation of miR-124-1. Seven patients (15.6%) had methylation of at least one of the four miRs. miR methylation did not correlate with clinical parameters, disease complications or JAK2 V617F mutation. CONCLUSION: This is the first report of miR hypermethylation in MPNs. miR-203 hypermethylation is not specific to Ph+ve leukemias but also present in Ph-ve MPNs. miR-34b/c methylation was associated with reversible miR silencing. There was no correlation of miR methylation with clinical demographic data or outcome.published_or_final_versio

Aberrant p15 gene promoter methylation in therapy-related myelodysplastic syndrome and acute myeloid leukaemia: Clinicopathological and karyotypic associations

Seventeen patients with therapy-related myelodysplastic syndrome/acute myeloid leukaemia (t-MDS/AML) were examined for aberrant p15 gene methylation by methylation-specific polymerase chain reaction. Ten patients (58%) showed p15 methylation, which was significantly related to monosomy/deletion of chromosome 7q, but not to antecedent chemotherapy, blast count, leukaemic evolution or survival. In three of six patients with marrow samples obtained prior to the diagnosis of t-MDS/AML, p15 methylation predated disease development by up to 2 years. Bone marrow transplantation led to the disappearance of p15 methylation in one patient. These results showed that p15 methylation was an early event in the evolution of some t-MDS/AML patients.link_to_OA_fulltex

Rare coding SNP in DZIP1 gene associated with late-onset sporadic Parkinson's disease

We present the first application of the hypothesis-rich mathematical theory to genome-wide association data. The Hamza et al. late-onset sporadic Parkinson's disease genome-wide association study dataset was analyzed. We found a rare, coding, non-synonymous SNP variant in the gene DZIP1 that confers increased susceptibility to Parkinson's disease. The association of DZIP1 with Parkinson's disease is consistent with a Parkinson's disease stem-cell ageing theory.Comment: 14 page

A prospective cohort study to investigate parental stress and child health in low-income Chinese families: protocol paper

Introduction Chronic stress has adverse effects on health. Adults and children from low-income families are subject to multiple sources of stress. Existing literature about economic hardship mostly focuses on either adults or children but not both. Moreover, there is limited knowledge on the relationship between parental generalised stress and child health problems. This study aims to explore the bidirectional relationship between parental stress and child health in Chinese low-income families and to identify other modifiable factors influencing this relationship. Methods and analysis This prospective cohort study will sample 254 low-income parent–child pairs and follow them up for 24 months with assessments at three time points (baseline, 12 and 24 months) on parental stress, health-related quality of life (HRQOL) and child health and behaviour using both subjective measures and objective physiological parameters. This study will collect data using standardised measures on HRQOL and behaviours of children as well as on HRQOL, mental health and stress levels of parents along with physiological tests of allostatic load and telomere length. The mediating or moderating effect of family harmony, parenting style and neighbourhood conditions will also be assessed. Data will be analysed using latent growth modelling and cross-lagged path analysis modelling to examine the bidirectional effect of parental stress and child health over time. Mediation and moderation analysis will also be conducted to examine the mechanism by which the variables relate. Ethics and dissemination This study was approved by the institutional review board of the University of Hong Kong—the Hospital Authority Hong Kong West Cluster, reference no: UW 16-415. The study findings will be disseminated through peer-reviewed publications and international conferences.published_or_final_versio

Particles and fields in fluid turbulence

The understanding of fluid turbulence has considerably progressed in recent years. The application of the methods of statistical mechanics to the description of the motion of fluid particles, i.e. to the Lagrangian dynamics, has led to a new quantitative theory of intermittency in turbulent transport. The first analytical description of anomalous scaling laws in turbulence has been obtained. The underlying physical mechanism reveals the role of statistical integrals of motion in non-equilibrium systems. For turbulent transport, the statistical conservation laws are hidden in the evolution of groups of fluid particles and arise from the competition between the expansion of a group and the change of its geometry. By breaking the scale-invariance symmetry, the statistically conserved quantities lead to the observed anomalous scaling of transported fields. Lagrangian methods also shed new light on some practical issues, such as mixing and turbulent magnetic dynamo.Comment: 165 pages, review article for Rev. Mod. Phy

Designing sequential transcription logic: a simple genetic circuit for conditional memory

The ability to learn and respond to recurrent events depends on the capacity to remember transient biological signals received in the past. Moreover, it may be desirable to remember or ignore these transient signals conditioned upon other signals that are active at specific points in time or in unique environments. Here, we propose a simple genetic circuit in bacteria that is capable of conditionally memorizing a signal in the form of a transcription factor concentration. The circuit behaves similarly to a "data latch" in an electronic circuit, i.e. it reads and stores an input signal only when conditioned to do so by a "read command". Our circuit is of the same size as the well-known genetic toggle switch (an unconditional latch) which consists of two mutually repressing genes, but is complemented with a "regulatory front end" involving protein heterodimerization as a simple way to implement conditional control. Deterministic and stochastic analysis of the circuit dynamics indicate that an experimental implementation is feasible based on well-characterized genes and proteins. It is not known, to which extent molecular networks are able to conditionally store information in natural contexts for bacteria. However, our results suggest that such sequential logic elements may be readily implemented by cells through the combination of existing protein-protein interactions and simple transcriptional regulation.Comment: 20 pages, 5 figures; supplementary material available upon request from the author

Evaluation of alternative respiratory syndromes for specific syndromic surveillance of influenza and respiratory syncytial virus: a time series analysis

<p>Abstract</p> <p>Background</p> <p>Syndromic surveillance is increasingly being evaluated for its potential for early warning of increased disease activity in the population. However, interpretation is hampered by the difficulty of attributing a causative pathogen. We described the temporal relationship between laboratory counts of influenza and respiratory syncytial virus (RSV) detection and alternative groupings of Emergency Department (ED) respiratory diagnoses.</p> <p>Methods</p> <p>ED and laboratory data were obtained for the south-eastern area of Sydney, NSW for the period 1 June 2001 - 1 December 2006. Counts of ED visits and laboratory confirmed positive RSV and influenza cases were aggregated by week. Semi-parametric generalized additive models (GAM) were used to determine the association between the incidence of RSV and influenza and the incidence of respiratory syndrome ED presentations while controlling for temporal confounders.</p> <p>Results</p> <p>For every additional RSV laboratory count, ED diagnoses of bronchiolitis increased by 3.1% (95%CI: 2.7%-3.5%) in the same week. For every additional influenza laboratory count, ED diagnoses of influenza-like illness increased by 4.7% (95%CI: 4.2%-5.2%) one week earlier.</p> <p>Conclusion</p> <p>In this study, large increases in ED diagnoses of bronchiolitis and influenza-like illness were independent and proxy indicators for RSV and influenza activity, respectively.</p