Transcriptional Silencing of the Wnt-Antagonist DKK1 by Promoter Methylation Is Associated with Enhanced Wnt Signaling in Advanced Multiple Myeloma

The Wnt/β-catenin pathway plays a crucial role in the pathogenesis of various human cancers. In multiple myeloma (MM), aberrant auto-and/or paracrine activation of canonical Wnt signaling promotes proliferation and dissemination, while overexpression of the Wnt inhibitor Dickkopf1 (DKK1) by MM cells contributes to osteolytic bone disease by inhibiting osteoblast differentiation. Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these findings suggest that DKK1 is part of a negative feedback loop in MM and may act as a tumor suppressor. In line with this hypothesis, we show here that DKK1 expression is low or undetectable in a subset of patients with advanced MM as well as in MM cell lines. This absence of DKK1 is correlated with enhanced Wnt pathway activation, evidenced by nuclear accumulation of β-catenin, which in turn can be antagonized by restoring DKK1 expression. Analysis of the DKK1 promoter revealed CpG island methylation in several MM cell lines as well as in MM cells from patients with advanced MM. Moreover, demethylation of the DKK1 promoter restores DKK1 expression, which results in inhibition of β-catenin/TCF-mediated gene transcription in MM lines. Taken together, our data identify aberrant methylation of the DKK1 promoter as a cause of DKK1 silencing in advanced stage MM, which may play an important role in the progression of MM by unleashing Wnt signaling

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survival and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM – a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 (IL-6) expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26

Which factors explain variation in intention to disclose a diagnosis of dementia? A theory-based survey of mental health professionals

Background: For people with dementia, patient-centred care should involve timely explanation of the diagnosis and its implications. However, this is not routine. Theoretical models of behaviour change offer a generalisable framework for understanding professional practice and identifying modifiable factors to target with an intervention. Theoretical models and empirical work indicate that behavioural intention represents a modifiable predictor of actual professional behaviour. We identified factors that predict the intentions of members of older people's mental health teams (MHTs) to perform key behaviours involved in the disclosure of dementia. Design: Postal questionnaire survey. Participants: Professionals from MHTs in the English National Health Service. Methods: We selected three behaviours: Determining what patients already know or suspect about their diagnosis; using explicit terminology when talking to patients; and exploring what the diagnosis means to patients. The questionnaire was based upon the Theory of Planned Behaviour (TPB), Social Cognitive Theory (SCT), and exploratory team variables. Main outcomes: Behavioural intentions. Results: Out of 1,269 professionals working in 85 MHTs, 399 (31.4%) returned completed questionnaires. Overall, the TPB best explained behavioural intention. For determining what patients already know, the TPB variables of subjective norm, perceived behavioural control and attitude explained 29.4% of the variance in intention. For the use of explicit terminology, the same variables explained 53.7% of intention. For exploring what the diagnosis means to patients, subjective norm and perceived behavioural control explained 48.6% of intention. Conclusion: These psychological models can explain up to half of the variation in intention to perform key disclosure behaviours. This provides an empirically- supported, theoretical basis for the design of interventions to improve disclosure practice by targeting relevant predictive factors. Trial Registration: ISRCTN15871014

Regression with Empirical Variable Selection: Description of a New Method and Application to Ecological Datasets

Despite recent papers on problems associated with full-model and stepwise regression, their use is still common throughout ecological and environmental disciplines. Alternative approaches, including generating multiple models and comparing them post-hoc using techniques such as Akaike's Information Criterion (AIC), are becoming more popular. However, these are problematic when there are numerous independent variables and interpretation is often difficult when competing models contain many different variables and combinations of variables. Here, we detail a new approach, REVS (Regression with Empirical Variable Selection), which uses all-subsets regression to quantify empirical support for every independent variable. A series of models is created; the first containing the variable with most empirical support, the second containing the first variable and the next most-supported, and so on. The comparatively small number of resultant models (n = the number of predictor variables) means that post-hoc comparison is comparatively quick and easy. When tested on a real dataset – habitat and offspring quality in the great tit (Parus major) – the optimal REVS model explained more variance (higher R2), was more parsimonious (lower AIC), and had greater significance (lower P values), than full, stepwise or all-subsets models; it also had higher predictive accuracy based on split-sample validation. Testing REVS on ten further datasets suggested that this is typical, with R2 values being higher than full or stepwise models (mean improvement = 31% and 7%, respectively). Results are ecologically intuitive as even when there are several competing models, they share a set of “core” variables and differ only in presence/absence of one or two additional variables. We conclude that REVS is useful for analysing complex datasets, including those in ecology and environmental disciplines

The Effect of Interpersonal Psychotherapy and other Psychodynamic Therapies versus ‘Treatment as Usual’ in Patients with Major Depressive Disorder

Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Interpersonal psychotherapy and other psychodynamic therapies may be effective interventions for major depressive disorder, but the effects have only had limited assessment in systematic reviews.Cochrane systematic review methodology with meta-analysis and trial sequential analysis of randomized trials comparing the effect of psychodynamic therapies versus ‘treatment as usual’ for major depressive disorder. To be included the participants had to be older than 17 years with a primary diagnosis of major depressive disorder. Altogether, we included six trials randomizing a total of 648 participants. Five trials assessed ‘interpersonal psychotherapy’ and only one trial assessed ‘psychodynamic psychotherapy’. All six trials had high risk of bias. Meta-analysis on all six trials showed that the psychodynamic interventions significantly reduced depressive symptoms on the 17-item Hamilton Rating Scale for Depression (mean difference −3.12 (95% confidence interval −4.39 to −1.86;P<0.00001), no heterogeneity) compared with ‘treatment as usual’. Trial sequential analysis confirmed this result.We did not find convincing evidence supporting or refuting the effect of interpersonal psychotherapy or psychodynamic therapy compared with ‘treatment as usual’ for patients with major depressive disorder. The potential beneficial effect seems small and effects on major outcomes are unknown. Randomized trials with low risk of systematic errors and low risk of random errors are needed

Highly symmetric POVMs and their informational power

We discuss the dependence of the Shannon entropy of normalized finite rank-1 POVMs on the choice of the input state, looking for the states that minimize this quantity. To distinguish the class of measurements where the problem can be solved analytically, we introduce the notion of highly symmetric POVMs and classify them in dimension two (for qubits). In this case we prove that the entropy is minimal, and hence the relative entropy (informational power) is maximal, if and only if the input state is orthogonal to one of the states constituting a POVM. The method used in the proof, employing the Michel theory of critical points for group action, the Hermite interpolation and the structure of invariant polynomials for unitary-antiunitary groups, can also be applied in higher dimensions and for other entropy-like functions. The links between entropy minimization and entropic uncertainty relations, the Wehrl entropy and the quantum dynamical entropy are described.Comment: 40 pages, 3 figure

Key signaling nodes in mammary gland development and cancer: β-catenin

β-Catenin plays important roles in mammary development and tumorigenesis through its functions in cell adhesion, signal transduction and regulation of cell-context-specific gene expression. Studies in mice have highlighted the critical role of β-catenin signaling for stem cell biology at multiple stages of mammary development. Deregulated β-catenin signaling disturbs stem and progenitor cell dynamics and induces mammary tumors in mice. Recent data showing deregulated β-catenin signaling in metaplastic and basal-type tumors suggest a similar link to reactivated developmental pathways and human breast cancer. The present review will discuss β-catenin as a central transducer of numerous signaling pathways and its role in mammary development and breast cancer

Characterization of a Gene Family Encoding SEA (Sea-urchin Sperm Protein, Enterokinase and Agrin)-Domain Proteins with Lectin-Like and Heme-Binding Properties from Schistosoma japonicum

BackgroundWe previously identified a novel gene family dispersed in the genome of Schistosoma japonicum by retrotransposon-mediated gene duplication mechanism. Although many transcripts were identified, no homolog was readily identifiable from sequence information.Methodology/Principal FindingsHere, we utilized structural homology modeling and biochemical methods to identify remote homologs, and characterized the gene products as SEA (sea-urchin sperm protein, enterokinase and agrin)-domain containing proteins. A common extracellular domain in this family was structurally similar to SEA-domain. SEA-domain is primarily a structural domain, known to assist or regulate binding to glycans. Recombinant proteins from three members of this gene family specifically interacted with glycosaminoglycans with high affinity, with potential implication in ligand acquisition and immune evasion. Similar approach was used to identify a heme-binding site on the SEA-domain. The heme-binding mode showed heme molecule inserted into a hydrophobic pocket, with heme iron putatively coordinated to two histidine axial ligands. Heme-binding properties were confirmed using biochemical assays and UV-visible absorption spectroscopy, which showed high affinity heme-binding (KD = 1.605×10?6 M) and cognate spectroscopic attributes of hexa-coordinated heme iron. The native proteins were oligomers, antigenic, and are localized on adult worm teguments and gastrodermis; major host-parasite interfaces and site for heme detoxification and acquisition.ConclusionsThe results suggest potential role, at least in the nucleation step of heme crystallization (hemozoin formation), and as receptors for heme uptake. Survival strategies exploited by parasites, including heme homeostasis mechanism in hemoparasites, are paramount for successful parasitism. Thus, assessing prospects for application in disease intervention is warranted