Pim1 kinase: a double-edged sword:The divergent roles of a survival kinase in environment-airway epithelium interaction

Environmental triggers like cigarette smoke, respiratory viruses and house dust mite play an important role in the inception and exacerbation of asthma. In this thesis, we investigated the effects of these environmental triggers on airway epithelial cells. A special role in these studies was reserved for Pim1 kinase, a protein highly expressed in airway epithelial cells and involved in the survival of these cells. We demonstrated with in vivo and in vitro studies that Pim1 kinase plays a protective role in the airway epithelial cells exposed to cigarette smoke and house dust mite. With the studies on the human respiratory virus Rhinovirus, we showed that Pim1 kinase is involved in the replication of human rhinovirus in the airway epithelial cells. Interestingly, we observed that viral replication was significantly reduced by pharmacological inhibition of Pim1 kinase activity. These observations offer a new therapeutic approach against viral infections, which might be highly beneficial for asthma patients who frequently suffer from virally induced asthma exacerbations. Future research should reveal this potential of Pim1 kinase inhibitors as novel therapeutic targets and assess if the beneficial effects of reducing viral replication in airway epithelial cells will transcend the protective role of Pim1 kinase as observed in the studies with cigarette smoke and house dust mite

Kritische vrienden onder de loep

Vanuit de visie dat (a) mogelijkheden voor een vraagstuk samen onderzocht moeten worden en dat (b) verkennen gepaard gaat met ondernemend gedrag, verwondering en verrassing, is deze uitgave geschreven. Deze verhaalt over één initiatief in het bijzonder: de labs Ontdekkingsstraten. Deze hebben plaatsgevonden in Assen en Hardenberg met ondernemers, overheden en studenten van de Hanzehogeschool Groningen en het Alfa-college Hardenberg. De labs Ontdekkingsstraten willen de retail in de binnenstad van Assen en Hardenberg versterken. De labs zijn gerelateerd aan het landelijke project Future-Proof Retail, een initiatief van 23 samenwerkende organisaties met steun van Stichting Detailhandelsfonds. Bij de labs wordt de methode kritischevriend gebruikt; deze is ontwikkeld door middel van design-based onderzoek door het lectoraat Ondernemen in Verandering van de Hanzehogeschool Groningen en het Alfa-college. De kritischevriendmethode bestaat uit een drietal fasen die samen met de proloog de structuur van deze uitgave vormen

Distinctive Responses in an In Vitro Human Dendritic Cell-Based System upon Stimulation with Different Influenza Vaccine Formulations

Vaccine development relies on testing vaccine candidates in animal models. However, results from animals cannot always be translated to humans. Alternative ways to screen vaccine candidates before clinical trials are therefore desirable. Dendritic cells (DCs) are the main orchestrators of the immune system and the link between innate and adaptive responses. Their activation by vaccines is an essential step in vaccine-induced immune responses. We have systematically evaluated the suitability of two different human DC-based systems, namely the DC-cell line MUTZ-3 and primary monocyte-derived DCs (Mo-DCs) to screen immunopotentiating properties of vaccine candidates. Two different influenza vaccine formulations, whole inactivated virus (WIV) and subunit (SU), were used as model antigens as they represent a high immunogenic and low immunogenic vaccine, respectively. MUTZ-3 cells were restricted in their ability to respond to different stimuli. In contrast, Mo-DCs readily responded to WIV and SU in a vaccine-specific way. WIV stimulation elicited a more vigorous induction of activation markers, immune response-related genes and secretion of cytokines involved in antiviral responses than the SU vaccine. Furthermore, Mo-DCs differentiated from freshly isolated and freeze/thawed peripheral blood mononuclear cells (PBMCs) showed a similar capacity to respond to different vaccines. Taken together, we identified human PBMC-derived Mo-DCs as a suitable platform to evaluate vaccine-induced immune responses. Importantly, we show that fresh and frozen PBMCs can be used indistinctly, which strongly facilitates the routine use of this system. In vitro vaccine pre-screening using human Mo-DCs is thus a promising approach for evaluating the immunopotentiating capacities of new vaccine formulations that have not yet been tested in humans

Physical activity in relation to motor performance, exercise capacity, sports participation, parental perceptions, and overprotection in school aged children with a critical congenital heart defect

OBJECTIVE: To depict objectively measured moderate-to-vigorous physical activity (MVPA), motor performance (MP), cardiorespiratory fitness (CRF), organized sports participation, parental perceptions of vulnerability and parenting style in children with a Critical Congenital Heart Disease (CCHD), and to explore whether these factors are associated with MVPA. STUDY DESIGN: A prospective observational cohort study in 62 7-10 years old children with a CCHD. RESULTS: On average, children with CCHD spent 64 min on MVPA per day (accelerometry), 61 % met the international WHO physical activity guideline. Only 12 % had >60 min of MVPA daily. Eighteen percent had a motor delay (movement-assessment-battery-for children-II) and 38 % showed a below average CRF (cardiopulmonary exercise test using the Godfrey ramp protocol). Seventy-seven percent participated in organized sports activities at least once a week. Twenty-one percent of the parents are classified as overprotective (parent protection scale) and 7.3 % consider their child as being vulnerable (child vulnerability scale). A significant positive association was found between MVPA and MP (rs = 0.359), CRF(V̇O 2peak/ml/kg: rs = 0.472 and W peak/kg: rs = 0.396) and sports participation (rs = 0.286). Children who were perceived as vulnerable by their parents showed a significantly lower MVPA (rs = -0.302). No significant associations were found between mean MVPA and parental overprotection. CONCLUSION: Even though the majority of school aged children with a CCHD is sufficiently active, counseling parents regarding the importance of sufficient MVPA and sports participation, especially in parents who consider their child being vulnerable, could be useful. Since motor delays can be detected at an early age, motor development could be an important target to improve exercise capacity and sports participation to prevent inactivity in children with a CCHD

Steenmeel in droge bossen

Op grote schaal treedt op de hogere zandgronden verminderde vitaliteit van bomen en zelfs sterfte van eiken op. Dit komt vooral door droogte en verzuring. Het gebruik van steenmeel in droge bossen zou een oplossing kunnen zijn voor de nadelige effecten van verzuring. In een driejarig OBN-onderzoek is een literatuurstudie gedaan en zijn experimenten uitgevoerd in Het Nationale Park De Hoge Veluwe en in het Mastbos (Breda). In deze veldwerkplaats zijn de resultaten gepresenteerd van dit onderzoek naar het effect van steenmeel op de vitaliteit, groei en vegetatie van eiken, op de bodem- en de bladchemie en op het bodemleven in eikenbossen. Het toepassen van steenmeel lijkt veelbelovend na drie jaar experimenteren, maar meer onderzoek is gewenst. Aan een Plan van Aanpak voor de toediening van steenmeel in de praktijk wordt gewerkt. In het Nationale Park De Hoge Veluwe zijn de experimenten en andere eikenpercelen in de praktijk bekeken en bediscussieerd

A Protective Role of FAM13A in Human Airway Epithelial Cells Upon Exposure to Cigarette Smoke Extract

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease characterized by chronic inflammation upon inhalation of noxious particles, e.g., cigarette smoke. FAM13A is one of the genes often found to be associated with COPD, however its function in the pathophysiology of COPD is incompletely understood. We studied its role in airway epithelial barrier integrity and cigarette smoke-induced epithelial responses. MATERIALS AND METHODS: Protein level and localization of FAM13A was assessed with immunohistochemistry in lung tissue from COPD patients and non-COPD controls. In vitro, FAM13A expression was determined in the absence or presence of cigarette smoke extract (CSE) in primary airway epithelial cells (AECs) from COPD patients and controls by western blotting. FAM13A was overexpressed in cell line 16HBE14o- and its effect on barrier function was monitored real-time by electrical resistance. Expression of junctional protein E-cadherin and β-catenin was assessed by western blotting. The secretion of neutrophil attractant CXCL8 upon CSE exposure was measured by ELISA. RESULTS: FAM13A was strongly expressed in airway epithelium, but significantly weaker in airways of COPD patients compared to non-COPD controls. In COPD-derived AECs, but not those of controls, FAM13A was significantly downregulated by CSE. 16HBE14o- cells overexpressing FAM13A built up epithelial resistance significantly more rapidly, which was accompanied by higher E-cadherin expression and reduced CSE-induced CXCL8 levels. CONCLUSION: Our data indicate that the expression of FAM13A is lower in airway epithelium of COPD patients compared to non-COPD controls. In addition, cigarette smoking selectively downregulates airway epithelial expression of FAM13A in COPD patients. This may have important consequences for the pathophysiology of COPD, as the more rapid build-up of epithelial resistance upon FAM13A overexpression suggests improved (re)constitution of barrier function. The reduced epithelial secretion of CXCL8 upon CSE-induced damage suggests that lower FAM13A expression upon cigarette smoking may facilitate epithelial-driven neutrophilia

Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study

Triple-negative breast cancer is associated with early recurrence and low survival rates. Several trials investigate the safety of a more conservative approach of axillary treatment in clinically T1-2N0 breast cancer. Triple-negative breast cancer comprises only 15 % of newly diagnosed breast cancers, which might result in insufficient power for representative results for this subgroup. We aimed to provide a nationwide overview on the occurrence of (regional) recurrences in triple-negative breast cancer patients with a clinically T1-2N0 status. For this cohort study, 2548 women diagnosed between 2005 and 2008 with clinically T1-2N0 triple-negative breast cancer were selected from the Netherlands Cancer Registry. Follow-up data until 2014 were analyzed using Kaplan–Meier. Sentinel lymph node biopsy was performed in 2486 patients, and (completion) axillary lymph node dissection in 562 patients. Final pathologic nodal status was pN0 in 78.5 %, pN1mi in 4.5 %, pN1 in 12.3 %, pN2–3 in 3.6 %, and pNx in 1.1 %. During a follow-up of 5 years, regional recurrence occurred in 2.9 %, local recurrence in 4.2 % and distant recurrence in 12.2 %. Five-year disease-free survival was 78.7 %, distant disease-free survival 80.5 %, and 5-year overall survival 82.3 %. Triple-negative clinically T1-2N0 breast cancer patients rarely develop a regional recurrence. Their disease-free survival is more threatened by distant recurrence, affecting their overall survival. Consequently, it seems justified to include triple-negative breast cancer patients in randomized controlled trials investigating the safety of minimizing axillary staging and treatment