The biochemistry and regulation of S100A10: a multifunctional plasminogen receptor involved in oncogenesis

The plasminogen receptors mediate the production and localization to the cell surface of the broad spectrum proteinase, plasmin. S100A10 is a key regulator of cellular plasmin production and may account for as much as 50% of cellular plasmin generation. In parallel to plasminogen, the plasminogen-binding site on S100A10 is highly conserved from mammals to fish. S100A10 is constitutively expressed in many cells and is also induced by many diverse factors and physiological stimuli including dexamethasone, epidermal growth factor, transforming growth factor-alpha, interferon-gamma, nerve growth factor, keratinocyte growth factor, retinoic acid, and thrombin. Therefore, S100A10 is utilized by cells to regulate plasmin proteolytic activity in response to a wide diversity of physiological stimuli. The expression of the oncogenes, PML-RAR alpha and KRas, also stimulates the levels of S100A10, suggesting a role for S100A10 in pathophysiological processes such as in the oncogenic-mediated increases in plasmin production. The S100A10-null mouse model system has established the critical role that S100A10 plays as a regulator of fibrinolysis and oncogenesis. S100A10 plays two major roles in oncogenesis, first as a regulator of cancer cell invasion and metastasis and secondly as a regulator of the recruitment of tumor-associated cells, such as macrophages, to the tumor site.Canadian Cancer Society Research Institute; Canadian Institutes of Health Research; Foundation for Science and Technology of Portuga

Women's experiences of interventions for fear of childbirth in the perinatal period: A meta-synthesis of qualitative research evidence

Issue Fear of childbirth (FOC) can be debilitating, impacting women's lives in pregnancy, the puerperium and beyond. Research investigated various interventions for FOC in the perinatal period, but there been no synthesis of the experiences of women who engaged with these interventions, which would inform clinical practice guidance and the development of future interventions. Aim To conduct a review and synthesis of qualitative studies of interventions for fear of childbirth in the perinatal period and women's experiences of them. Methods A meta-synthesis was performed to examine all relevant qualitative studies describing women's experiences of interventions for FOC, in all languages. A comprehensive search of relevant databases from 1978 to 2019 was conducted. In total, following appraisal, seven qualitative studies were eligible for inclusion. The findings were integrated using thematic synthesis for the final stages in the thematic analysis. Findings One overarching theme “Ownership of Childbirth” and three analytical themes “Facing the fear”, “Feeling empowered”, “Managing the fear with a sense of security” were generated through the synthesis. There were no studies outside of Scandinavia located. Discussion This meta-synthesis provides a new way to describe the process of moving from fear to “Ownership of childbirth”. The first step in the process appears to be acknowledging and identifying the individual's fears. Women can be empowered to self-manage FOC but may be influenced by external factors such as the support of partners and staff. Conclusion These findings provide evidence to inform the development of future interventions for FOC and highlight the need for further qualitative research globally

Pregnancy outcomes in women with severe fear of childbirth

Objective: To compare pregnancy outcomes for women with and without severe fear of childbirth (FOC) reported in the second trimester of pregnancy. Methods: In a prospective cohort study, 389 singleton pregnancies were followed up using medical records of participants in a study investigating FOC in Cork, Republic of Ireland. FOC was measured using the Wijma Delivery Experience Questionnaire Part A (W-DEQ A). Severe FOC was defined as W-DEQ A ≥ 85, moderate FOC, W-DEQ-A 66-84 and low FOC, W-DEQ A 0-65. Outcome measures were birthweight, birthweight centile, gestational age, and Apgar scores at 1 min and Apgar at 5 min. Linear regression was used to assess the association between FOC and each outcome measure with adjustment for maternal age, smoking, parity and marital status. Results: There was no statistically significant difference in mean birthweight (mean difference = −0.03; [95% CI: -444.69, 315.82]), mean birthweight centile (mean difference = 0.03; [95%CI: -15.97, 23.53]), or mean gestational age (mean difference = −0.06; [95%CI: -11.69, 4.82]) in women with severe FOC (n = 18) compared with women with low FOC (n = 371). In the adjusted models, there was only a slight correlation between severe FOC and Apgar scores at 1 min (mean difference = −0.09 [95%CI: -1.28, 0.32]) and Apgar scores at 5 min (mean difference = −0.18 [95%CI: -1.16, 1.08]). Conclusion: While a slight association was noted between severe FOC and Apgar scores, overall findings are reassuring and could inform educational interventions which may alleviate FOC. Awareness of FOC for health care professionals is vital to consider women's mental well-being

European youth care sites serve different populations of adolescents with cannabis use disorder. Baseline and referral data from the INCANT trial

Background: MDFT (Multidimensional Family Therapy) is a family based outpatient treatment programme for adolescent problem behaviour. MDFT has been found effective in the USA in adolescent samples differing in severity and treatment delivery settings. On request of five governments (Belgium, France, Germany, the Netherlands, and Switzerland), MDFT has now been tested in the joint INCANT trial (International Cannabis Need of Treatment) for applicability in Western Europe. In each of the five countries, study participants were recruited from the local population of youth seeking or guided to treatment for, among other things, cannabis use disorder. There is little information in the literature if these populations are comparable between sites/countries or not. Therefore, we examined if the study samples enrolled in the five countries differed in baseline characteristics regarding demographics, clinical profile, and treatment delivery setting.Methods: INCANT was a multicentre phase III(b) randomized controlled trial with an open-label, parallel group design. It compared MDFT with treatment as usual (TAU) at and across sites in Berlin, Brussels, Geneva, The Hague and Paris.Participants of INCANT were adolescents of either sex, from 13 through 18 years of age, with a cannabis use disorder (dependence or abuse), and at least one parent willing to take part in the treatment. In total, 450 cases/families were randomized (concealed) into INCANT.Results: We collected data about adolescent and family demographics (age, gender, family composition, school, work, friends, and leisure time). In addition, we gathered data about problem behaviour (substance use, alcohol and cannabis use disorders, delinquency, psychiatric co-morbidity).There were no major differences on any of these measures between the treatment conditions (MDFT and TAU) for any of the sites. However, there were cross-site differences on many variables. Most of these could be explained by variations in treatment culture, as reflected by referral policy, i.e., participants' referral source. We distinguished 'self-determined' referral (common in Brussels and Paris) and referral with some authority-related 'external' coercion (common in Geneva and The Hague). The two referral types were more equally divided in Berlin. Many cross-site baseline differences disappeared when we took referral source into account, but not all.Conclusions: A multisite trial has the advantage of being efficient, but it also carries risks, the most important one being lack of equivalence between local study populations. Our site populations differed in many respects. This is not a problem for analyses and interpretations if the differences somehow can be accounted for. To a major extent, this appeared possible in INCANT. The most important factor underlying the cross-site variations in baseline characteristics was referral source. Correcting for referral source made most differences disappear. Therefore, we will use referral source as a covariate accounting for site differences in future INCANT outcome analyses

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Film remakes, the black sheep of translation

Film remakes have often been neglected by translation studies in favour of other forms of audiovisual translation such as subtitling and dubbing. Yet, as this article will argue, remakes are also a form of cinematic translation. Beginning with a survey of previous, ambivalent approaches to the status of remakes, it proposes that remakes are multimodal, adaptive translations: they translate the many modes of the film being remade and offer a reworking of that source text. The multimodal nature of remakes is explored through a reading of Breathless, Jim McBride's 1983 remake of Jean-Luc Godard's À bout de souffle (1959), which shows how remade films may repeat the narrative of, but differ on multiple levels from, their source films. Due to the collaborative nature of film production, remakes involve multiple agents of translation. As such, remakes offer an expanded understanding of audiovisual translation

Multisite Randomized Trial of a Single-Session Versus Multisession Literacy-Sensitive Self-Care Intervention for Patients With Heart Failure

Self-care training can reduce hospitalization for heart failure (HF), and more intensive intervention may benefit more vulnerable patients, including those with low literacy

Application of Biomarkers in Cancer Risk Management: Evaluation from Stochastic Clonal Evolutionary and Dynamic System Optimization Points of View

Aside from primary prevention, early detection remains the most effective way to decrease mortality associated with the majority of solid cancers. Previous cancer screening models are largely based on classification of at-risk populations into three conceptually defined groups (normal, cancer without symptoms, and cancer with symptoms). Unfortunately, this approach has achieved limited successes in reducing cancer mortality. With advances in molecular biology and genomic technologies, many candidate somatic genetic and epigenetic “biomarkers” have been identified as potential predictors of cancer risk. However, none have yet been validated as robust predictors of progression to cancer or shown to reduce cancer mortality. In this Perspective, we first define the necessary and sufficient conditions for precise prediction of future cancer development and early cancer detection within a simple physical model framework. We then evaluate cancer risk prediction and early detection from a dynamic clonal evolution point of view, examining the implications of dynamic clonal evolution of biomarkers and the application of clonal evolution for cancer risk management in clinical practice. Finally, we propose a framework to guide future collaborative research between mathematical modelers and biomarker researchers to design studies to investigate and model dynamic clonal evolution. This approach will allow optimization of available resources for cancer control and intervention timing based on molecular biomarkers in predicting cancer among various risk subsets that dynamically evolve over time

Genetic Determination and Linkage Mapping of Plasmodium falciparum Malaria Related Traits in Senegal

Plasmodium falciparum malaria episodes may vary considerably in their severity and clinical manifestations. There is good evidence that host genetic factors contribute to this variability. To date, most genetic studies aiming at the identification of these genes have used a case/control study design for severe malaria, exploring specific candidate genes. Here, we performed a family-based genetic study of falciparum malaria related phenotypes in two independent longitudinal survey cohorts, as a first step towards the identification of genes and mechanisms involved in the outcome of infection. We studied two Senegalese villages, Dielmo and Ndiop that differ in ethnicity, malaria transmission and endemicity. We performed genome-scan linkage analysis of several malaria-related phenotypes both during clinical attacks and asymptomatic infection. We show evidence for a strong genetic contribution to both the number of clinical falciparum malaria attacks and the asymptomatic parasite density. The asymptomatic parasite density showed linkage to chromosome 5q31 (LOD = 2.26, empirical p = 0.0014, Dielmo), confirming previous findings in other studies. Suggestive linkage values were also obtained at three additional chromosome regions: the number of clinical malaria attacks on chromosome 5p15 (LOD = 2.57, empirical p = 0.001, Dielmo) and 13q13 (LOD = 2.37, empirical p = 0.0014 Dielmo), and the maximum parasite density during asymptomatic infection on chromosome 12q21 (LOD = 3.1, empirical p<10−4, Ndiop). While regions of linkage show little overlap with genes known to be involved in severe malaria, the four regions appear to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved