A SILAC-Based Screen for Methyl-CpG Binding Proteins Identifies RBP-J as a DNA Methylation and Sequence-Specific Binding Protein

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Targeted hepatitis C antibody testing interventions: a systematic review and meta-analysis

Testing for hepatitis C virus (HCV) infection may reduce the risk of liver-related morbidity, by facilitating earlier access to treatment and care. This review investigated the effectiveness of targeted testing interventions on HCV case detection, treatment uptake, and prevention of liver-related morbidity. A literature search identified studies published up to 2013 that compared a targeted HCV testing intervention (targeting individuals or groups at increased risk of HCV) with no targeted intervention, and results were synthesised using meta-analysis. Exposure to a targeted testing intervention, compared to no targeted intervention, was associated with increased cases detected [number of studies (n) = 14; pooled relative risk (RR) 1.7, 95 % CI 1.3, 2.2] and patients commencing therapy (n = 4; RR 3.3, 95 % CI 1.1, 10.0). Practitioner-based interventions increased test uptake and cases detected (n = 12; RR 3.5, 95 % CI 2.5, 4.8; and n = 10; RR 2.2, 95 % CI 1.4, 3.5, respectively), whereas media/information-based interventions were less effective (n = 4; RR 1.5, 95 % CI 0.7, 3.0; and n = 4; RR 1.3, 95 % CI 1.0, 1.6, respectively). This meta-analysis provides for the first time a quantitative assessment of targeted HCV testing interventions, demonstrating that these strategies were effective in diagnosing cases and increasing treatment uptake. Strategies involving practitioner-based interventions yielded the most favourable outcomes. It is recommended that testing should be targeted at and offered to individuals who are part of a population with high HCV prevalence, or who have a history of HCV risk behaviour

The relationship between perceived service quality and patient willingness to recommend at a national oncology hospital network

<p>Abstract</p> <p>Background</p> <p>"Willingness to recommend" questions are being increasingly used to measure and manage patient loyalty. Yet, there is little data in the literature correlating the "willingness to recommend" question with commonly used perceived service quality items in surveys to identify the key drivers of the optimal patient experience. We therefore evaluated the relationship between perceived service quality and subsequent single top box "willingness to recommend" scores among oncology patients.</p> <p>Methods</p> <p>A total of 2018 returning cancer patients treated at Cancer Treatment Centers of America^®(CTCA) responded to an internally developed service quality questionnaire, which covered the following dimensions: operations and services, treatment and care with a multidisciplinary team and patient endorsements. Items were measured on a 7-point Likert-type scale ranging from "completely dissatisfied" to "completely satisfied." Patient willingness to, "recommend this facility to friends and associates" was measured on an 11-point scale ranging from "not at all likely" to "extremely likely", which was subsequently dichotomized into two categories: top box response (10) versus all others (0-9). The relationship between perceived service quality and "willingness to recommend" was assessed via Kendall's tau b correlation and univariate and multivariate logistic regression.</p> <p>Results</p> <p>Of the 2018 patients, 959 were newly diagnosed while 1059 were previously treated. 902 were males and 1116 females. The mean age was 54.2 years and the most frequent diagnoses were breast (412), lung (294), prostate (260), colorectal (179) and pancreas (169). 1553 patients said they were "extremely likely" to recommend CTCA to friends and associates, resulting in 77% "top box" responses while 465 (23%) responded in all other categories. The key service quality drivers that were statistically significant in the final logistic model were "team helping you understand your medical condition", "staff genuinely caring for you as an individual", "whole person approach to patient care" and "CTCA medical oncologist."</p> <p>Conclusions</p> <p>In this multi-center study, we demonstrate the predictive significance of perceived service quality as it relates to patient willingness to recommend an oncology service provider. This study is unique in reporting on the role of perceived service quality as a predictor of patient willingness to recommend in a large sample of cancer patients.</p

The representation of patient experience and satisfaction in physician rating sites. A criteria-based analysis of English- and German-language sites

<p>Abstract</p> <p>Background</p> <p>Information on patient experience and satisfaction with individual physicians could play an important role for performance measures, improved health care and health literacy. Physician rating sites (PRSs) bear the potential to be a widely available source for this kind of information. However, patient experience and satisfaction are complex constructs operationalized by multiple dimensions. The way in which PRSs allow users to express and rate patient experience and satisfaction could likely influence the image of doctors in society and the self-understanding of both doctors and patients. This study examines the extent to which PRSs currently represent the constructs of patient experience and satisfaction.</p> <p>Methods</p> <p>First, a systematic review of research instruments for measuring patient experience and satisfaction was conducted. The content of these instruments was analyzed qualitatively to create a comprehensive set of dimensions for patient experience and patient satisfaction. Second, PRSs were searched for systematically in English-language and German-language search engines of Google and Yahoo. Finally, we classified every structured question asked by the different PRS using the set of dimensions of patient experience and satisfaction.</p> <p>Results</p> <p>The qualitative content analysis of the measurement instruments produced 13 dimensions of patient experience and satisfaction. We identified a total of 21 PRSs. No PRSs represented all 13 dimensions of patient satisfaction and experience with its structured questions. The 3 most trafficked English-language PRS represent between 5 and 6 dimensions and the 3 most trafficked German language PRSs between 8 and 11 dimensions The dimensions for patient experience and satisfaction most frequently represented in PRSs included diversely operationalized ones such as <it>professional competence </it>and <it>doctor-patient relationship/support</it>. However, other less complex but nevertheless important dimensions such as <it>communication skills </it>and <it>information/advice </it>were rarely represented, especially in English-language PRSs.</p> <p>Conclusions</p> <p>Concerning the potential impact of PRSs on health systems, further research is needed to show which of the current operationalizations of patient experience and satisfaction presented in our study are establishing themselves in PRSs. Independently of this factual development, the question also arises whether and to what extent health policy can and should influence the operationalization of patient experience and satisfaction in PRSs. Here, the challenge would be to produce a set of dimensions capable of consensus from among the wide range of operationalizations found by this study.</p

Determinants of patient satisfaction in ambulatory oncology: a cross sectional study based on the OUT-PATSAT35 questionnaire

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to identify factors associated with satisfaction with care in cancer patients undergoing ambulatory treatment. We investigated associations between patients' baseline clinical and socio-demographic characteristics, as well as self-reported quality of life, and satisfaction with care.</p> <p>Methods</p> <p>Patients undergoing ambulatory chemotherapy or radiotherapy in 2 centres in France were invited, at the beginning of their treatment, to complete the OUT-PATSAT35, a 35 item and 13 scale questionnaire evaluating perception of doctors, nurses and aspects of care organisation. Additionally, for each patient, socio-demographic variables, clinical characteristics and self-reported quality of life using the EORTC QLQ-C30 questionnaire were recorded.</p> <p>Results</p> <p>Among 692 patients included between January 2005 and December 2006, only 6 were non-responders. By multivariate analysis, poor perceived global health strongly predicted dissatisfaction with care (<it>p </it>< 0.0001). Patients treated by radiotherapy (vs patients treated by chemotherapy) reported lower levels of satisfaction with doctors' technical and interpersonal skills, information provided by caregivers, and waiting times. Patients with primary head and neck cancer (vs other localisations), and those living alone were less satisfied with information provided by doctors, and younger patients (< 55 years) were less satisfied with doctors' availability.</p> <p>Conclusions</p> <p>A number of clinical of socio-demographic factors were significantly associated with different scales of the satisfaction questionnaire. However, the main determinant was the patient's global health status, underlining the importance of measuring and adjusting for self-perceived health status when evaluating satisfaction. Further analyses are currently ongoing to determine the responsiveness of the OUT-PATSAT35 questionnaire to changes over time.</p

APC/CCdh1-Mediated Degradation of the F-Box Protein NIPA Is Regulated by Its Association with Skp1

NIPA (Nuclear Interaction Partner of Alk kinase) is an F-box like protein that targets nuclear Cyclin B1 for degradation. Integrity and therefore activity of the SCFNIPA E3 ligase is regulated by cell-cycle-dependent phosphorylation of NIPA, restricting substrate ubiquitination to interphase. Here we show that phosphorylated NIPA is degraded in late mitosis in an APC/CCdh1-dependent manner. Binding of the unphosphorylated form of NIPA to Skp1 interferes with binding to the APC/C-adaptor protein Cdh1 and therefore protects unphosphorylated NIPA from degradation in interphase. Our data thus define a novel mode of regulating APC/C-mediated ubiquitination

Human Vav1 Expression in Hematopoietic and Cancer Cell Lines Is Regulated by c-Myb and by CpG Methylation

Vav1 is a signal transducer protein that functions as a guanine nucleotide exchange factor for the Rho/Rac GTPases in the hematopoietic system where it is exclusively expressed. Recently, Vav1 was shown to be involved in several human malignancies including neuroblastoma, lung cancer, and pancreatic ductal adenocarcinoma (PDA). Although some factors that affect vav1 expression are known, neither the physiological nor pathological regulation of vav1 expression is completely understood. We demonstrate herein that mutations in putative transcription factor binding sites at the vav1 promoter affect its transcription in cells of different histological origin. Among these sites is a consensus site for c-Myb, a hematopoietic-specific transcription factor that is also found in Vav1-expressing lung cancer cell lines. Depletion of c-Myb using siRNA led to a dramatic reduction in vav1 expression in these cells. Consistent with this, co-transfection of c-Myb activated transcription of a vav1 promoter-luciferase reporter gene construct in lung cancer cells devoid of Vav1 expression. Together, these results indicate that c-Myb is involved in vav1 expression in lung cancer cells. We also explored the methylation status of the vav1 promoter. Bisulfite sequencing revealed that the vav1 promoter was completely unmethylated in human lymphocytes, but methylated to various degrees in tissues that do not normally express vav1. The vav1 promoter does not contain CpG islands in proximity to the transcription start site; however, we demonstrated that methylation of a CpG dinucleotide at a consensus Sp1 binding site in the vav1 promoter interferes with protein binding in vitro. Our data identify two regulatory mechanisms for vav1 expression: binding of c-Myb and CpG methylation of 5′ regulatory sequences. Mutation of other putative transcription factor binding sites suggests that additional factors regulate vav1 expression as well

Expression Profiling of FSHD-1 and FSHD-2 Cells during Myogenic Differentiation Evidences Common and Distinctive Gene Dysregulation Patterns

BACKGROUND: Determine global gene dysregulation affecting 4q-linked (FSHD-1) and non 4q-linked (FSHD-2) cells during early stages of myogenic differentiation. This approach has been never applied to FSHD pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: By in vitro differentiation of FSHD-1 and FSHD-2 myoblasts and gene chip analysis we derived that gene expression profile is altered only in FSHD-1 myoblasts and FSHD-2 myotubes. The changes seen in FSHD-1 regarded a general defect in cell cycle progression, probably due to the upregulation of myogenic markers PAX3 and MYOD1, and a deficit of factors (SUV39H1 and HMGB2) involved in D4Z4 chromatin conformation. On the other hand, FSHD-2 mytubes were characterized by a general defect in RNA metabolism, protein synthesis and degradation and, to a lesser extent, in cell cycle. Common dysregulations regarded genes involved in response to oxidative stress and in sterol biosynthetic process. Interestingly, our results also suggest that miRNAs might be implied in both FSHD-1 and FSHD-2 gene dysregulation. Finally, in both cell differentiation systems, we did not observe a gradient of altered gene expression throughout the 4q35 chromosome. CONCLUSIONS/SIGNIFICANCE: FSHD-1 and FSHD-2 cells showed, in different steps of myogenic differentiation, a global deregulation of gene expression rather than an alteration of expression of 4q35 specific genes. In general, FSHD-1 and FSHD-2 global gene deregulation interested common and distinctive biological processes. In this regard, defects of cell cycle progression (FSHD-1 and to a lesser extent FSHD-2), protein synthesis and degradation (FSHD-2), response to oxidative stress (FSHD-1 and FSHD-2), and cholesterol homeostasis (FSHD-1 and FSHD-2) may in general impair a correct myogenesis. Taken together our results recapitulate previously reported defects of FSHD-1, and add new insights into the gene deregulation characterizing both FSHD-1 and FSHD-2, in which miRNAs may play a role

Statistical Inference of In Vivo Properties of Human DNA Methyltransferases from Double-Stranded Methylation Patterns

DNA methyltransferases establish methylation patterns in cells and transmit these patterns over cell generations, thereby influencing each cell's epigenetic states. Three primary DNA methyltransferases have been identified in mammals: DNMT1, DNMT3A and DNMT3B. Extensive in vitro studies have investigated key properties of these enzymes, namely their substrate specificity and processivity. Here we study these properties in vivo, by applying novel statistical analysis methods to double-stranded DNA methylation patterns collected using hairpin-bisulfite PCR. Our analysis fits a novel Hidden Markov Model (HMM) to the observed data, allowing for potential bisulfite conversion errors, and yields statistical estimates of parameters that quantify enzyme processivity and substrate specificity. We apply this model to methylation patterns established in vivo at three loci in humans: two densely methylated inactive X (Xi)-linked loci ( and ), and an autosomal locus (), where methylation densities are tissue-specific but moderate. We find strong evidence for a high level of processivity of DNMT1 at and , with the mean association tract length being a few hundred base pairs. Regardless of tissue types, methylation patterns at are dominated by DNMT1 maintenance events, similar to the two Xi-linked loci, but are insufficiently informative regarding processivity to draw any conclusions about processivity at that locus. At all three loci we find that DNMT1 shows a strong preference for adding methyl groups to hemi-methylated CpG sites over unmethylated sites. The data at all three loci also suggest low (possibly 0) association of the de novo methyltransferases, the DNMT3s, and are consequently uninformative about processivity or preference of these enzymes. We also extend our HMM to reanalyze published data on mouse DNMT1 activities in vitro. The results suggest shorter association tracts (and hence weaker processivity), and much longer non-association tracts than human DNMT1 in vivo