Second messengers in cancer:Cyclic AMP meets β-catenin in tumor progression

During tumor progression, behavioral changes of tumor cells play an important role. This allows tumor cells to constantly adapt to the requirements imposed by the tumor environment. Typical behaviors of tumor cells are the capability to unrestrained cell division, the capability for dissemination, and the ability to control formation of new blood vessels. It is becoming increasingly clear that such changes are not only controlled by the tumor cells itself, but by an interplay between the tumor cells and the tumor microenvironment. Prostaglandin E2 is a key inflammatory mediator in the tumor microenvironment that influences these behaviors. Recent evidence suggests that prostaglandin E2 increases the activation of β-catenin, of which it is known that it plays an important role in tumor progression. The studies presented in this thesis focus on the role of prostaglandin E2 in relation to β-catenin during tumor progression. It is shown that prostaglandin E2 increases activation of β-catenin via the cyclic AMP effectors PKA and Epac. It is demonstrated, in the pediatric tumor neuroblastoma, that this interaction enhances cell division and resistance to cell death. In addition, this interaction activates a cell program that allows epithelial tumor cells to transition into mesenchymal tumor cells with increased motility, an important characteristic underlying metastasis. Further, this thesis describes how Epac influences the balance between β-catenin-dependent gene transcription in normal and low oxygen conditions and how Epac inhibition potentiates the effects of the anticancer agent retinoic acid. Together, these findings suggest that PKA and Epac-dependent β-catenin activation plays a significant role in the effects of prostaglandin E2 on tumor progression. This, together with the recent development of pharmacological Epac inhibitors, makes these findings therapeutically interesting for the treatment of cancer

Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells

Contains fulltext : 88395.pdf (publisher's version ) (Open Access)BACKGROUND: ATP-binding cassette (ABC) transporters protect cells against unrelated (toxic) substances by pumping them across cell membranes. Earlier we showed that many ABC transporters are highly expressed in hematopoietic stem cells (HSCs) compared to more committed progenitor cells. The ABC transporter expression signature may guarantee lifelong protection of HSCs but may also preserve stem cell integrity by extrusion of agents that trigger their differentiation. Here we have studied whether non-hematopoietic stem cells (non-HSCs) exhibit a similar ABC transporter expression signature as HSCs. RESULTS: ABC transporter expression profiles were determined in non-hematopoietic stem cells (non-HSCs) from embryonic, neonatal and adult origin as well as in various mature blood cell types. Over 11,000 individual ABC transporter expression values were generated by Taqman Low Density Arrays (TLDA) to obtain a sensitivity comparable with quantitative real-time polymerase chain reactions. We found that the vast majority of transporters are significantly higher expressed in HSCs compared to non-HSCs. Furthermore, regardless their origin, non-HSCs exhibited strikingly similar ABC transporter expression profiles that were distinct from those in HSCs. Yet, sets of transporters characteristic for different stem cell types could be identified, suggesting restricted functions in stem cell physiology. Remarkably, in HSCs we could not pinpoint any single transporter expressed at an evidently elevated level when compared to all the mature blood cell types studied. CONCLUSIONS: These findings challenge the concept that individual ABC transporters are implicated in maintaining stem cell integrity. Instead, a distinct ABC transporter expression signature may be essential for stem cell function. The high expression of specific transporters in non-HSCs and mature blood cells suggests a specialized, cell type dependent function and warrants further functional experiments to determine their exact roles in cellular (patho)physiology

Impact of colorectal cancer screening on cancer-specific mortality in Europe: A systematic review

Background: Populations differ with respect to their cancer risk and screening preferences, which may influence the performance of colorectal cancer (CRC) screening programs. This review aims to

Implementation of the kidney team at home intervention:Evaluating generalizability, implementation process, and effects

Research has shown that a home-based educational intervention for patients with chronic kidney disease results in better knowledge and communication, and more living donor kidney transplantations (LDKT). Implementation research in the field of renal care is almost nonexistent. The aims of this study were (1) to demonstrate generalizability, (2) evaluate the implementation process, and (3) to assess the relationship of intervention effects on LDKT-activity. Eight hospitals participated in the project. Patients eligible for all kidney replacement therapies (KRT) were invited to participate. Effect outcomes were KRT-knowledge and KRT-communication, and treatment choice. Feasibility, fidelity, and intervention costs were assessed as part of the process evaluation. Three hundred and thirty-two patients completed the intervention. There was a significant increase in KRT-knowledge and KRT-communication among participants. One hundred and twenty-nine out of 332 patients (39%) had LDKT-activity, which was in line with the results of the clinical trials. Protocol adherence, knowledge, and age were correlated with LDKT-activity. This unique implementation study shows that the results in practice are comparable to the previous trials, and show that the intervention can be implemented, while maintaining quality. Results from the project resulted in the uptake of the intervention in standard care. We urge other countries to investigate the uptake of the intervention

Pneumococcal conjugate vaccines for preventing otitis media

BACKGROUND: Acute otitis media (AOM) is a very common early infancy and childhood disease. The marginal benefits of antibiotics on AOM, the increasing problem of bacterial resistance to antibiotics, and the huge estimated direct and indirect annual costs associated with otitis media (OM) have prompted a search for effective vaccines to prevent AOM. OBJECTIVES: To assess the effect of pneumococcal conjugate vaccines (PCVs) in preventing AOM in children up to 12 years of age. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, issue 2), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register; MEDLINE (January 1995 to November 2007); and EMBASE (January 1995 to November 2007). SELECTION CRITERIA: Randomised controlled trials of PCVs to prevent AOM in children aged 12 years or younger, with a follow up of at least six months after vaccination. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial quality and two review authors extracted data. MAIN RESULTS: We included seven trials on 7- to 11-valent PCV (with different carrier proteins). There was large heterogeneity regarding study population, type of conjugate vaccine, and outcome measures between trials, therefore, results were not pooled. The only currently licensed 7-valent PCV Prevenar with CRM197 as carrier protein (CRM197-PCV7) administered during infancy was in two studies associated with a 6% (95% confidence interval (CI) -4% to 16%) and 7% (95% CI 4% to 9%) relative reduction in risk of AOM episodes. Another 7-valent PCV with the outer membrane protein complex of Neisseria meningitidis (N. meningitidis) serogroup B as carrier protein, administered in infancy, did not reduce overall AOM episodes, while an 11-valent PCV with Haemophilus influenzae (H. influenzae) protein D as carrier protein was associated with a relative reduction in risk of AOM episodes of 34% (95% CI 21% to 44%). 9-valent PCV (with CRM197 carrier protein) administered in healthy toddlers was associated with a 17% (95% CI -2% to 33%) relative reduction in risk of OM episodes. CRM197-PCV7 followed by 23-valent pneumococcal polysaccharide vaccination administered after infancy in older children with a history of AOM showed no beneficial effect on further AOM episodes. AUTHORS' CONCLUSIONS: Based on current evidence of the effectiveness of PCVs for the prevention of AOM, the currently licensed 7-valent PCV administered during infancy has marginal beneficial effects. Discrete reductions of 6% to 7% may mean substantial reductions from a public health perspective. Administering PCV7 in older children with a history of AOM appears to have no benefit in preventing further episodes

Validity of the self-administered comorbidity questionnaire in patients with inflammatory bowel disease

Background: The International Consortium for Health Outcomes Measurement has selected the self-administered comorbidity questionnaire (SCQ) to adjust case-mix when comparing outcomes of inflammatory bowel disease (IBD) treatment between healthcare providers. However, the SCQ has not been validated for use in IBD patients. Objectives: We assessed the validity of the SCQ for measuring comorbidities in IBD patients. Design: Cohort study. Methods: We assessed the criterion validity of the SCQ for IBD patients by comparing patient-reported and clinician-reported comorbidities (as noted in the electronic health record) of the 13 diseases of the SCQ using Cohen’s kappa. Construct validity was assessed using the Spearman correlation coefficient between the SCQ and the Charlson Comorbidity Index (CCI), clinician-reported SCQ, quality of life, IBD-related healthcare and productivity costs, prevalence of disability, and IBD disease activity. We assessed responsiveness by correlating changes in the SCQ with changes in healthcare costs, productivity costs, quality of life, and disease activity after 15 months. Results: We included 613 patients. At least fair agreement (κ &gt; 0.20) was found for most comorbidities, but the agreement was slight (κ &lt; 0.20) for stomach disease [κ = 0.19, 95% CI (−0.03; 0.41)], blood disease [κ = 0.02, 95% CI (−0.06; 0.11)], and back pain [κ = 0.18, 95% CI (0.11; 0.25)]. Correlations were found between the SCQ and the clinician-reported SCQ [ρ = 0.60, 95% CI (0.55; 0.66)], CCI [ρ = 0.39, 95% CI (0.31; 0.45)], the prevalence of disability [ρ = 0.23, 95% CI (0.15; 0.32)], and quality of life [ρ = −0.30, 95% CI (−0.37; −0.22)], but not between the SCQ and healthcare or productivity costs or disease activity (|ρ| ⩽ 0.2). A change in the SCQ after 15 months was not correlated with a change in any of the outcomes.Conclusion: The SCQ is a valid tool for measuring comorbidity in IBD patients, but face and content validity should be improved before being used to correct case-mix differences.</p

Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial

Item does not contain fulltextBACKGROUND: Platelet transfusion after acute spontaneous primary intracerebral haemorrhage in people taking antiplatelet therapy might reduce death or dependence by reducing the extent of the haemorrhage. We aimed to investigate whether platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral haemorrhage associated with antiplatelet therapy use. METHODS: We did this multicentre, open-label, masked-endpoint, randomised trial at 60 hospitals in the Netherlands, UK, and France. We enrolled adults within 6 h of supratentorial intracerebral haemorrhage symptom onset if they had used antiplatelet therapy for at least 7 days beforehand and had a Glasgow Coma Scale score of at least 8. With use of a secure web-based system that concealed allocation and used biased coin randomisation, study collaborators randomly assigned participants (1:1; stratified by hospital and type of antiplatelet therapy) to receive either standard care or standard care with platelet transfusion within 90 min of diagnostic brain imaging. Participants and local investigators giving interventions were not masked to treatment allocation, but allocation was concealed from outcome assessors and investigators analysing data. The primary outcome was shift towards death or dependence rated on the modified Rankin Scale (mRS) at 3 months, and analysed by ordinal logistic regression, adjusted for stratification variables and the Intracerebral Haemorrhage Score. The primary analysis was done in the intention-to-treat population and safety analyses were done in the intention-to-treat and as-treated populations. This trial is registered with the Netherlands Trial Register, number NTR1303, and is now closed. FINDINGS: Between Feb 4, 2009, and Oct 8, 2015, 41 sites enrolled 190 participants. 97 participants were randomly assigned to platelet transfusion and 93 to standard care. The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2.05, 95% CI 1.18-3.56; p=0.0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay. INTERPRETATION: Platelet transfusion seems inferior to standard care for people taking antiplatelet therapy before intracerebral haemorrhage. Platelet transfusion cannot be recommended for this indication in clinical practice. FUNDING: The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply, Chest Heart and Stroke Scotland, French Ministry of Health