Groningen Research Institute for Asthma and COPD

Transcription

Groningen Research Institute for Asthma and COPD
Annual Report 2014
UMCG
Content
Mission statement................................................................................................................................... 3
Introduction............................................................................................................................................. 4
Research area .......................................................................................................................................... 7
Perspectives ............................................................................................................................................ 8
The year 2014 in review ........................................................................................................................ 11
Highlights ........................................................................................................................................... 11
Prizes/Awards .................................................................................................................................... 12
Visitors ............................................................................................................................................... 12
Special Topics ........................................................................................................................................ 13
Special Topic 1 ................................................................................................................................... 13
Special Topic 2 ................................................................................................................................... 16
Special Topic 3 ................................................................................................................................... 21
Special Topic 4 ................................................................................................................................... 25
Special Topic 5 ................................................................................................................................... 29
Departments.......................................................................................................................................... 33
Members 2014 ...................................................................................................................................... 35
International collaboration 2014 .......................................................................................................... 37
Seminar program 2014 .......................................................................................................................... 40
Research meetings 2014 - presentations .............................................................................................. 42
Genome-wide nasal gene expression in COPD ..................................................................................... 44
Brainstorm sessions 2014...................................................................................................................... 45
Research projects in 2014 ..................................................................................................................... 46
Publications 2014 .................................................................................................................................. 54
Dissertations ...................................................................................................................................... 54
Publications SCI journals .................................................................................................................. 55
Publications in Dutch ......................................................................................................................... 70
Books / Book chapters....................................................................................................................... 70
Contributions to other research institutes........................................................................................ 70
2
Mission statement
The mission of GRIAC is the multidisciplinary translational study of obstructive airway
and pulmonary diseases and healthy ageing
Program leaders:
Prof.dr. H.M. Boezen
Prof. dr. G.H.Koppelman
Visiting address:
University Medical Center Groningen
Hanzeplein 1
NL-9713 GZ Groningen
Secretariat:
Ms. J. Blokzijl, Dept. Pediatric Pulmonology
and Pediatric Allergy
Beatrix Children’s Hospital
Hanzeplein 1
P.O. Box 30.001
NL-9700 RB Groningen
Phone: 31-50-361 1107
Fax:
31-50-361 1704
Email: [email protected]
and [email protected]
Website: www.griac.nl
Webmaster: Prof.dr. W. Timens
3
Introduction
The Groningen Research Institute for Asthma and COPD (GRIAC) is dedicated to research
on obstructive and pulmonary diseases on the edge of clinical and fundamental research,
arising from a clinical-scientific background. GRIAC operates within the research framework
of the University Medical Center Groningen, which has a central focus on healthy ageing and
the Faculty of Science of the University of Groningen, which has a focus on molecular life
and health. GRIAC is part of the governmentally accredited organization GUIDE (Groningen
University Institute for Drug Exploration) which is embedded in the Groningen School of
Medical Sciences (GSMS). Most research is funded by external support as given by NWO,
Dutch Lung Foundation, the European Community and industry. The research conducted in
Groningen results from internal discussions within the scientific forum of researchers on
asthma and COPD in Groningen and from consortia with researchers from collaborating
institutes inside the Netherlands and abroad.
Participating departments
The multidisciplinary and translational research of GRIAC is the result of an intensive
collaboration between the researchers of GRIAC, consisting of our members from different
disciplines. The disciplines involved are allergology, experimental pulmonology and
inflammation research, epidemiology, general practice, molecular pharmacology, pathology,
paediatric pulmonology and paediatric allergology, pulmonology and respiratory insufficiency.
GRIAC recently added new members from the department of Clinical Pharmacy and from
ERIBA, the European Research Institute for the Biology of Aging. Collaboration is based on
freedom, equivalence and consensus. Extensive collaboration exists with Departments of
Dermatology, Gastroenterology, Genetics, Haematology, Medical oncology and
Transplantation. Furthermore, collaboration exists with the Department of Analytical
Biochemistry (University Center for Pharmacy).
4
How we collaborate
Every two weeks GRIAC organises research meetings for the whole institute in which both
internal and external speakers are invited to venture new ideas and to challenge the
audience. This constitutes also the forum in which different types of research are being
presented to all members of GRIAC. Members of GRIAC participate in very different aspects
of asthma and COPD research, ranging from epidemiology, clinical allergology, pulmonology,
pharmacology, and general practice to basic research in genetics, proteomics, tissue studies,
cell cultures and animal models. Lively discussions always take place. To enhance
collaboration and stimulate new areas of research, GRIAC organises twice yearly a research
retreat and monthly “brainstorm sessions” on a specific topic. These brainstorm sessions are
used to stimulate novel ideas for multidisciplinary research, and to discuss publication ideas
for high impact journals.
During the GRIAC retreat the members of the Board of directors, scientific staff and postdocs of GRIAC discuss future perspectives and new developments in research and explore
potential new collaborations within their research, based on international developments in the
field. During and after the research meeting investigators can discuss their grant proposals
with the staff members, who are expert in a particular field.
Every five years GRIAC organises an internationally well-received symposium aimed at
understanding the differences and similarities between asthma and COPD. In 2014
“Bronchitis IX” has been organized from 23-25th of June in Groningen with again an excellent
international faculty. The theme of Bronchitis IX was “Lungs, on the edge of health and
ageing” (www.bronchitis9.nl).
At every occasion of the defence of a PhD thesis care is taken to also invite a top-researcher
of a particular research field. He or she is asked to judge the thesis and participate in the
PhD defence on site, and, in addition, to give a presentation. When these external visitors
are present, workshops for exchange of ideas are organised for both senior and junior
researchers.
Finally, there are weekly meetings for junior researchers and staff members. At these
meetings there is ample time for discussion on choosing the appropriate study design, the
set-up of research protocols, analyses and interpretation of results of research, and for
preparation and improvements in concepts of abstracts, and oral and poster presentations at
international meetings. Introductory lectures are provided in lung function measurements,
laboratory techniques, genetic research and so on. We aim to make our PhD students
familiar with these research techniques. These weekly GRIAC meetings aim to teach the
understanding of different aspects of the approach towards research on asthma and COPD
in the various disciplines involved in GRIAC in order to improve the level of interdisciplinary
research. PhD courses in epidemiology, statistics and genetic data analyses are being
organised for members of GRIAC and others interested as well.
Organisation
Two program leaders lead the Institute. They have the following tasks:
 Representatives in GSMS and GUIDE
 Contacts with the UMCG
 Contacts with the University of Groningen
 Policy preparation for KNAW, FMW, UMCG and University of Groningen
 Preparing propositions for research development
The coordinators are advised extensively by the Board of GRIAC, consisting of senior
members of the participating departments, who all have their own specific expertise. This
board advises in all aspects of research. The board meets once monthly to exchange ideas
and prepare policies.
5
Research program
GRIAC defines ‘obstructive airway and pulmonary disease’ in relation to healthy ageing, as
its main topic, which is reflected in our mission statement. Research projects have to fit
within this research topic, describing the projects in their mutual cohesion. The tuning of
projects and development into a program is the responsibility of the program leaders of
GRIAC, in exchange with the Scientific Board of the Institute.
Program description
Our research is aimed to stretch from bench to bedside and back with feedback loops.
Central to the research is the goal to translate fundamental findings into the clinical situation
and vice versa, i.e. translational medicine (see figure below).
Clinical research is conducted in
different
patient
groups
in
comparison with normal control
volunteers in order to unravel
underlying mechanisms of the
diseases
(genetics,
aetiology,
pathogenesis, pathophysiology).
Furthermore
responses
to
intervention (mediated by either
medical
therapy,
behavioural
counselling, rehabilitation or other
treatment modalities) as well as
parameters of progression of
disease are being assessed in
relation
to
the
underlying
mechanisms of the disease.
Questions that are generated, but unanswered by clinical research, are approached using in
vitro cellular systems and in vivo animal models. The other way around, hypotheses
generated from in vitro or in vivo research are translated to the general and clinical human
situation.
To this aim GRIAC focuses on the following main topics related to obstructive airway and
pulmonary disease:
 Identification of risk factors for development, progression and remission of disease
 Identification of disease related genes and their functionality
 Unravelling the pathophysiology of allergen-, environment- and smoke- induced
disease, in both humans and animal models
 Unravelling the effects of disease related inflammation on lung function,
hyperresponsiveness and remodelling of large and small airways
 Defining new targets for intervention and evaluation of intervention strategies
 Development of non- or minor invasive tools to assess severity of disease and (side)
effects of treatment.
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Research area
The focus of research is on asthma and COPD, which involves the sub-programs:
1.
2.
3.
4.
Epidemiology: Epidemiological studies on endogenous, environmental and lifestyle
risk factors, both in general and patient-based populations, from prenatal onwards to
old age.
Genomics: Studies on genes, epigenetics, gene expression and function, molecular
mechanisms and gene-gene and gene-environment interactions in disease
development, progression, remission, and severity, as well as disease intervention
(pharmacogenomics).
Pathophysiology and pathogenesis of allergen, smoking and other lifestyle factors,
and
environment-induced diseases: In vivo studies in humans and animal models
using mice and unrestrained guinea pigs. Investigations include lung function
techniques and studies of blood, tissues and/or cells derived from airways or lungs.
Furthermore, in vitro studies assess cellular activation and interaction as well as
signaling pathways in cells and tissue explants (e.g. lymphocyte subsets, epithelial
cells, fibroblasts, intact airway, and smooth muscle preparations). Interactions of
different cell types are studied in cells obtained by sputum induction as well as airway
and lung tissue obtained by bronchoscopy, by surgical biopsy or autopsy. The
Placebo controlled food provocation database provides an excellent method to
investigate the allergic response to foods.
Assessment, modulation and intervention in disease severity, progression and
remission: Disease outcome assessment is being studied with techniques such as
exhaled breath analyses and small airway function. In addition, validated
questionnaires on Quality of Life, drug side effects, hyperresponsiveness and
symptoms are developed for diagnostic purposes as well as outcome assessment.
Interventions can be at the level of cell cultures, animal models and clinical studies
with targeted therapy.
The main strategies to reach our goals are discussed below:
Omics
Genomics/transcriptomics/exposomics
The availability of genetic techniques and the collaboration with the Department of Genetics
(Head: Prof. C. Wijmenga) have greatly extended the genetic sub-programs, allowing
genome-wide association and methylation studies, high throughput genetic SNP detection,
fine-mapping in relevant chromosomal regions and candidate gene studies. Deep
sequencing techniques and analysis strategies are currently being developed.
Since gene-environment interactions are important for understanding complex diseases like
asthma and COPD, these have been explored in several sub-programs, in collaboration with
multiple groups in the Netherlands and abroad. This has resulted in gene-environment
interaction studies on atopy and asthma, and on COPD onset and progression. The GRIAC
group collaborates internationally and takes the lead in some EC-funded FP7 projects
(allergy and asthma: MeDALL; COPD: COPACETIC) on genetics and epigenetics of asthma
and COPD, and in exploration of specific gene-environment interactions in these projects.
The exposome concept refers to the totality of environmental exposures from conception
onwards, and is a novel approach to studying the role of the environment in the development
of lung disease in the Lifelines cohort. Furthermore, GRIAC is leading studies on gene
expression profiling (transcriptomics) and collaborates internationally (University of British
Columbia, Laval University) on studies linking gene expression to (epi)genetic variants
(eQTL analysis).
7
Proteomics/lipidomics
Proteomic and lipidomic research has added important possibilities to develop disease
susceptibility markers and disease progression and intervention tools. To enable clinical
studies that require greater power, continuing and promoting collaboration with general
hospitals in the region has expanded the recruitment population. To enhance the quality of
the collaboration, local physicians in these hospitals are more involved in the research group
and also propose their own studies for discussion in research meetings.
Molecular Medicine
GRIAC is actively engaged in studies linking clinical outcomes to (molecular)
pathophysiology. Often inspired by outcomes from omics studies, the functionality of genes
and proteins in disease is studied using molecular approaches in cells and tissues from
patients, in cell lines and in animal models. Molecular techniques are being used more
effectively and widely, and are being introduced when not present (either in our own labs or
as part of local facilities; for example, the recently developed custom micro-array
development and accompanying data-mining). In vivo and in vitro silencing of genes are now
established techniques that are operational at the University Medical Center and Pharmacy,
including the development of knock out and transgenic mouse models.This has enabled the
use of RNAi and pharmacological modulation of membrane and nuclear receptors and
signaling proteins in cells and tissue slices. Fundamental to this line of research is the
exploration of intracellular pathways relevant for disease development.
Clinical Medicine
Patient centered research is at the heart of GRIAC. Our translational research approach
included clinical and intervention studies in asthma and COPD. Moreover, several cohort
studies, both regional as well as national, are lead by GRIAC investigators. The LifeLines
cohort study is a unique asset for large scale epidemiological research into healthy ageing.
Healthy ageing
“Healthy Aging” has been adopted as the main theme for research and clinical profile of the
UMCG. An important long term project within this theme is “LifeLines” a planned 30-year
survey on risk factors (obtained by questionnaire, objective physiological data and biological
and genomic markers) for disease development, COPD being one of the leading themes.
This fits very well with the research agenda of GRIAC, including co-morbidity and systemic
manifestations of COPD. We are actively participating in the development and sustainment
of this program within the UMCG.
Perspectives
Asthma and COPD research takes place in a lively and rapidly changing field. New
developments will encompass the functional genomics (including exposomics, lipidomics and
proteomics) of asthma and COPD. We envisage that integration of the – omics techniques
will provide novel insight into the disease networks that lead to these obstructive airway
diseases.
The population for genetic analyses in asthma and COPD has been greatly expanded, and
will be expanded even further, allowing replication and association studies. A number of
international genome-wide association studies on asthma and COPD, including analysis on
gene-environment interactions are ongoing, as well as gene methylation studies. This will
lead to identification of novel genes and environmental factors playing a role in disease onset
and progression. We will incorporate integrative genomic approaches in follow up studies.
8
Functional studies on gene variations in asthmatic and healthy individuals are ongoing, both
in cells and in animal studies. Integration of longitudinal epidemiological data with genetics
will provide insight into genetic variants as risk factors for the development, progression or
remission of asthma and COPD. Finally, the integration of newly discovered genes with the
results of gene expression in relevant tissues that are available and/or cell cultures allows
further research into functional relevance and this can be integrated into systems medicine.
Increasingly so, epigenetics (e.g. gene-by-environment interactions and differential (genome
wide) methylation) is focus of our research. Within GRIAC, we translate the findings from
these genomic approaches back to models of disease, such as animal models or cellular
experiments.
The molecular basis of pathophysiology including airway (hyper)responsiveness,
inflammation and remodeling in asthma and COPD is increasingly on the forefront of GRIAC
research. For both asthma and COPD, we will gain better insight into the intricate interplay
between tissue resident celss (epithelial cells, fibroblasts, smooth muscle cells) on one hand
and their interaction with the extracellular matrix and different inflammatory cell types in the
lung on the other. With the recognition that most tissue resident cells are highly plastic
governed by complex interactions between multiple receptor systems and environmental
changes, research will remain focused on unraveling the interactive mechanisms that
determine inflammation and remodeling in chronic airways disease. Newly discovered genes
will be incorporated into our studies on in vitro modification of epithelial, smooth muscle and
fibroblast cell cultures. . In addition, a new area of interest in this research line is tissue repair
in COPD and the role of resident cells (including progenitor cells and structural cells of the
alveoli) in this response.
A focus on the background question of why not all smokers develop COPD will remain a
priority, in association with the consequences of smoking cessation and intervention in the
progression of inflammation and remodeling. This knowledge is enhanced by studies
regarding the effect of smoking (also during pregnancy) on allergy development, asthma
progression and susceptibility to develop COPD as well as the effects on treatment
response. The former topics will be investigated in animal models and in humans.
Exacerbations are sometimes life-threatening occurrences in patients with asthma and
COPD, which may affect activities of daily living, increase symptoms, reduce quality of life,
and affect disease outcome. Research will focus on practical and minimal interventions to
prevent these exacerbations, including research on the underlying mechanisms and the
associated increase in symptoms. Finally, side effects of drugs will be assessed by
questionnaires, which will help to further understand the optimal approach to asthma and
COPD management. Novel techniques like bronchoscopic lung volume reduction in severe
COPD patients are explored and evaluated in relation to their effects on e.g. daily physical
activity.
Physical inactivity, obesity, and a low grade systemic inflammation are increasingly
recognized as important risk factors for the induction and clinical expression of asthma and
COPD. The determinants and consequences of physical inactivity in COPD are
systematically investigated in relation with co-morbid disorders. A physical activity
enhancement strategy has been developed in collaboration with the faculty of human
movement sciences, which may be used in the primary, secondary and tertiary echelons of
our health care system.
Research in the rehabilitation program has been recently reinforced with respect to asthma
and COPD, and is expected to increase the input to and output of the GRIAC program. This
has been expanded by novel invasive techniques such as applying stents in airway walls and
chronic ventilatory support in COPD. As both improve exercise capacity in emphysema this
might lead to a more effective rehabilitation.
9
Notwithstanding the fact that understanding of a disease is of prime importance, the
management of the disease as it exists in current patients is of importance. Thus, it is of
great interest that transmural management of asthma and COPD is becoming more mature.
Collaborative efforts of lung function departments, general practitioners and pulmonologists
in addition to nurse practitioners help to provide better health care for individuals with
respiratory symptoms that affect their daily life. This ultimately may improve the quality of life
of individuals with asthma and COPD.
Output, visibility and (external) funding
Productivity of GRIAC is at present overall very good and the whole GRIAC institute was
graded “excellent”in its most recent Mid Term Review. Results in internal medicine and basic
science have been published in top peer reviewed journals and patents have also been filed.
GRIAC members have been urged to focus on publication strategy and brainstorm sessions
have been organized to even further improve the impact of scientific output. Asthma and
COPD are highly prevalent in the general population, and thus focussing on these two
syndromes is appropriate and has a high societal relevance. At current the priority of the
institute is ranging from cellular models to the underlying disease models to the clinic
(translational research) with transdisciplinarity as a major feature.
The national and international academic reputation of the senior GRIAC members can be
weighted at its merits judging the invitations to address international congresses and their
prominent roles in various national and international research and professional societies and
working groups in addition to their role in EU collaborations. In 2014, the Expertscape
Website graded GRIAC amongst the top institutes in Europe in relation to asthma and
COPD. Moreover, since several of these GRIAC members are relatively young and proven to
develop their high potential in their specific research field (e.g. epidemiology, pediatric and
adult pulmonology, and molecular pharmacology), GRIAC can face its future with confidence.
We will continue to invest in the training of young scientists in the field of obstructive airways
and pulmonary disease, with a focus on multidisciplinary translational research. Given the
true interdisciplinary nature of the institute, we feel confident that ongoing close collaboration
of GRIAC members who share their in-depth knowledge of specific research fields in asthma
and COPD will keep the institute at the internationally acknowledged level of excellence in
the future, and that they will be able to generate sufficient resources to finance this research.
We have shifted our focus from smaller (University Medical Centers) towards larger
(inter)national and interdisciplinary research grants (Lung foundation consortium grants,
NWO TOP grants, European funding) as well as personal grants (VENI, VIDI, VICI and ERC
grants). Within the U4 collaboration of the Universities of Groningen, Ghent, Göttingen and
Uppsala, international collaborations are ongoing for PhD students to stay at 2 or 3 of these
universities for an international PhD project.
10
The year 2014 in review
All contributions to the scientific work in GRIAC are important and highly appreciated. It
cannot be stressed enough that all the scientific output and results obtained are only possible
due to the contribution of every single person who works within our research institute.
Nevertheless, without disrespect to the work of members who are not specifically mentioned,
we like to highlight some topics that drew particular attention in 2014.
Highlights
The Bronchitis IX symposium entitled: Lungs: on the edge of health and aging, organized by
GRIAC, was held from June 23–25 in the UMCG in Groningen. There was an outstanding
program with leading researchers in the field of obstructive pulmonary diseases. The
presentations were highly interesting and followed by lively discussions. The organizing
committee consisted of Dr. M. van de Berge, Prof. G.H. Koppelman, Dr. J.N.G. Oude
Elberink, Prof. W. Timens and C. Verver.
Following the Bronchitis symposium, the COST congress entitled ‘Early origins of chronic
lung disease: a Birds eye view on the ageing lung’ was organized on June 26 and 27, by Dr.
R. Gosens and Dr. M.N. Hylkema. 102 registrants from 19 countries presented their work in
scientific lectures or the poster session. The COST conference was preceded by the 2nd
COST training school on “Molecular Mechanisms of Ageing”, also organized by Dr. R.
Gosens and Dr. M.N. Hylkema. Thirteen participants originating from 6 countries registered
for the summer school that consisted of workshops and scientific sessions. For some of the
scientific sessions, participants benefited from the parallel Bronchitis conference. This not
only ensured high quality speakers from all around the world, but also enabled close
interaction with these researchers during breaks and at the poster session.
In honor of the retirements of Prof. E.J. Duiverman and Prof. J.G.R. de Monchy farewell
symposia were organized and in relation to the thesis defences of Dr. O.E.M. Savenije, Dr.
D. Ierodiakonou, Dr. A. Oldenburger, and Dr. N.J. Goossens minisymposia were organized.
Speakers at these symposia were all national and international leading researchers.
Prof. H.M. Boezen organized, in collaboration with Dr. V. Schlünssen from the Aarhus
University in Denmark, a hot topic symposium at the annual ERS-conference in Munich
entitled: Determine personalized exposure and gene-environment interactions underlying
chronic airway disease; the exposome and the epigenome.
In March and April two information evenings for the general public entitled: the hereditary
causes of asthma and COPD, were organized by Prof. D.S. Postma and Prof. G.H.
Koppelman. These evenings were very well attended.
In March, Dr. H. Oude Elberink organized a patient information day for patients with
Mastocytosis.
Prof. H.M. Boezen was elected chair of the ERS working group 6.4 of the ERS Epidemiology
assembly ‘genes and environment’.
Prof. H. Meurs and Prof. D.S. Postma were awarded as ERS honorary fellow (FERS).
Prof. M. Schmidt was appointed as Teaching Director of the Groningen Research Institute of
Pharmacy.
11
Prizes/Awards
C.E. Boorsma, MSc won the NRS Chiesi Young Investigators award
Dr. O.E.M. Savenije won the NRS Young Investigator SAB award for her thesis
J. Saleh-Langenberg, MSc won an abstract award at the Food Allergy and Anaphylaxis
meeting in Dublin
L. Hesse, MSc won an award for the best poster presentation at the EAACI summer school
E. van Dijk, MSc won the NRS Young Investigators Presentation award
A.I.R. Spanjer, MSc obtained the Presentation Award of the Pharmacy Day, GRIP, 2014.
Visitors
Dr. C. Grainge, University of Southampton, Southampton, UK. January 9, 2014.
Prof. Dr. M. Kabesch, University Hospital Regensburg, Regensburg, Germany. January 14,
2014.
Prof. Dr. A. Bush, Imperial College, London, UK. January 14, 2014.
Dr. S. Krauss-Etschmann, Helmholtz Center, Munich, Germany. February 4, 2014.
Prof. Dr. S.T. Weiss, Channing lab, Harvard University, Boston, USA. March 3, 2014.
Prof. Dr. J. Vestbo, University of Manchester, Manchester, UK. June 17, 2014.
Prof. Dr. I. Sabroe, University of Sheffield, Sheffield, UK. September 2, 2014.
Prof. Dr. T. Sigsgaard, Aarhus University, Denmark. September 23, 2014.
Dr. G.A. Lockett, University of Southampton, Southampton, UK. October 7, 2014.
Prof. Dr. M.C. Michel, University of Mainz, Germany. October 24, 2014.
Prof. Dr. E. Klussmann, Max Delbrück Centrum für Molekulare Medizin (MDC), Berlin,
Germany. October 24, 2014.
Prof. Dr. W. Windisch, University of Witten/Herdecke, Köln, Germany, October 24, 2014.
Prof. Dr. H. Maarsingh, Palm Beach Atlantic University, USA. October 30, 2014.
Prof. Dr. L.C. Porto, Rio de Janeiro State University, Brazil. October 30, 2014.
Prof. Dr. M. Peters-Golden, University of Michigan, Michigan, USA. October 30, 2014.
Dr. A. Kruis, Leiden University Medical Center, Leiden, NL. November 18, 2014.
Prof. Dr. D. Heederick, University of Utrecht, Utrecht, NL. December 16, 2014.
Dr. J. Burgess, University of Sydney, Sydney, Australia. December 19, 2014.
12
Special Topics
Special Topic 1
First results of the GENEVA study: Research on the genetics of food allergy in
children
C. Dorien van Ginkel, Gerard H. Koppelman, Ewoud A. Dubois.
Departments of pediatric pulmonology and pediatric allergy.
Food allergy is a potentially lethal disease and its prevalence is increasing in the Western
world1. Furthermore, food allergy reduces quality of life in patients to a greater extent than
diabetes2 and is strongly heritable3. One study reported a 5-fold increase for the risk of
peanut allergy for a child with a peanut allergic sibling or parents4. Remarkably, only 1 in 2
children suspected to be food allergic and sensitised to food has a positive outcome of a
double blind placebo-controlled food challenge (DBPCFC) and is thereby diagnosed as
clinically reactive5.
We hypothesize that the genetic makeup of a child influences the difference between
sensitisation with and without clinical reactivity to food. Specifically, we hypothesize that
genes that contribute to skin epithelial integrity are associated with clinical food allergy.
To study this hypothesis we use the database of the Food Challenge Unit of the Beatrix
Children’s Hospital of the UMCG which contains phenotypic information on food allergy as
well as other atopic morbidities on over one thousand children who have been diagnosed by
the gold standard test, the Double-Blind Placebo Controlled Food Challenge. This will be
coupled to a DNA collection which will be expanded to include samples from 800 children
and their parents. This will be achieved by collecting DNA from blood- and saliva samples.
We will focus on candidate genes involved in epithelial integrity, and are aiming to perform a
genome-wide association study in the future.
The first results of the GENEVA study examined the association between food allergy and
the filaggrin gene (FLG). The FLG gene is located on chromosome 1q21 and is part of the
epidermal differentiation complex. These genes play an important role in skin barrier function
since the filaggrin protein helps aggregate the epidermal cytoskeleton to form a protein-lipid
barrier6. An impaired barrier function may permit intact proteins to pass the barrier and to
elicit an immune response. Loss of function (LOF) variants of the FLG gene result in a
defective form of the filaggrin protein and have a prevalence of about 10% in Western
populations7. FLG LOF variants are associated with ichtyosis vulgaris, characterized by
palmar hyperlinearity, keratosis pilaris and a fine white scale on the extremities. Ichtyosis
vulgaris is strongly associated with atopy8. Furthermore, the FLG LOF variants are strong
risk factors for atopic dermatitis9 and are associated with allergic rhinitis and sensitization10.
In children with atopic dermatitis, these variants are also associated with asthma11. Other
studies suggest a role of FLG in sensitization to foods and clinical food allergy12.
We showed that in high risk children suspected of being food allergic, those carrying one or
more loss of function variants of the FLG gene are 1.5 times more likely to be clinically
allergic as diagnosed by the DBPCFC than children carrying wild type alleles. This strong
association is replicated using a family based design, confirming the robustness of this
observation13. We furthermore showed that genetic markers may be useful as an addition to
clinical assessment in the diagnosis of food allergy13.
13
Figure 1. Prevalence of food allergy in subjects with and without FLG risk alleles.
The genetic findings of FLG being an important gene for food allergy have led to the dualallergen exposure hypothesis for the pathogenesis of food allergy. This proposes that lowdose cutaneous exposure to food allergens triggers Th2 responses and IgE production by B
cells while early oral exposure induces tolerance by stimulating regulatory T cells and Th1
cells14. This hypothesis is supported by a study showing that epicutaneous exposure to
peanut protein causes Th2-type immunity with high levels of peanut specific IgE and
prevents the development of oral tolerance to peanut15. A recent study showed that early life
environmental exposure to peanuts, as measured by peanut in household dust, is indeed
associated with peanut sensitization and allergy as confirmed by open food challenges, but
only in children carrying FLG mutations16. This percutaneous priming is also proposed for the
role of FLG in asthma and rhinitis10.
In conclusion, we recently showed that in high risk children, loss of function variants of the
filaggrin gene are associated with clinical food allergy, as diagnosed by the double blind
placebo-controlled food challenges. The FLG gene is therefore likely to be important in the
mechanism driving the difference between asymptomatic sensitisation and food allergy, most
likely through an impaired skin barrier. Since children carrying one or more loss of function
variants of the FLG gene are 1.5 times more likely to be food allergic, such genetic markers
may be useful as an addition to clinical assessment in the diagnosis of food allergy.
After completing the DNA collection, we hope to replicate the results of the filaggrin gene in a
larger study population and study the effect and diagnostic role of the other candidate genes.
Furthermore we will use the genome wide data of the LifeLines cohort in the search for new
genetic variants associated with food allergy.
The GENEVA study is supported by grants of the Nutricia Research Foundation and the JK
de Cock stichting.
References
1.
Branum, A. M. & Lukacs, S. L. Food allergy among children in the United States. Pediatrics 124, 1549–55
(2009).
2.
Flokstra-de Blok, B. M. J. et al. Health-related quality of life of food allergic patients: comparison with the
general population and other diseases. Allergy 65, 238–44 (2010).
3.
Tsai, H.-J. et al. Familial aggregation of food allergy and sensitization to food allergens: a family-based
study. Clin. Exp. Allergy 39, 101–9 (2009).
14
4.
Hourihane, J. O., Dean, T. P. & Warner, J. O. Peanut allergy in relation to heredity, maternal diet, and
other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. BMJ 313,
518–21 (1996).
5.
Van den Berg, M. E. et al. Parental eczema increases the risk of double-blind, placebo-controlled
reactions to milk but not to egg, peanut or hazelnut. Int. Arch. Allergy Immunol. 158, 77–83 (2012).
6.
Sandilands, A., Sutherland, C., Irvine, A. D. & McLean, W. H. I. Filaggrin in the frontline: role in skin
barrier function and disease. J. Cell Sci. 122, 1285–94 (2009).
7.
Van den Oord, R. a H. M. & Sheikh, a. Filaggrin gene defects and risk of developing allergic sensitisation
and allergic disorders: systematic review and meta-analysis. Bmj 339, b2433–b2433 (2009).
8.
Smith, F. J. D. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.
Nat. Genet. 38, 337–42 (2006).
9.
Sandilands, A. et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare
mutations in ichthyosis vulgaris and atopic eczema. Nat. Genet. 39, 650–4 (2007).
10.
Weidinger, S. et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J. Allergy Clin.
Immunol. 121, 1203–1209.e1 (2008).
11.
Rodríguez, E. et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in
atopic disease. J. Allergy Clin. Immunol. 123, 1361–70.e7 (2009).
12.
Brown, S. J. et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut
allergy. J. Allergy Clin. Immunol. 127, 661–7 (2011).
13.
Van Ginkel, C. D. et al. Loss-of-function variants of the filaggrin gene are associated with clinical reactivity
to foods. Allergy (2015).
14.
Lack, G. Update on risk factors for food allergy. J. Allergy Clin. Immunol. 129, 1187–97 (2012).
15.
Strid, J., Hourihane, J., Kimber, I., Callard, R. & Strobel, S. Epicutaneous exposure to peanut protein
prevents oral tolerance and enhances allergic sensitization. Clin. Exp. Allergy 35, 757–66 (2005).
16.
Brough, H. a et al. Peanut allergy: Effect of environmental peanut exposure in children with filaggrin lossof-function mutations. J. Allergy Clin. Immunol. 134, 867–875.e1 (2014).
15
Special Topic 2
New avenues for Epac in inflammation and tissue remodeling in COPD
Anouk Oldenburger, Wim Timens, Herman Meurs, Harm Maarsingh, Martina Schmidt
Departments of molecular pharmacology and pathology.
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the
airways and the lung parenchyma, further characterized by airway obstruction and
remodeling (1). Symptoms are treated with glucocorticosteroids, anticholinergics, β2-agonists
or phosphodiesterase (PDE)-4 inhibitors (2,3). Both β2-agonists and PDE4 inhibitors elevate
the second messenger cyclic AMP (cAMP), although by distinct mechanisms (4,5). The two
main effectors of cAMP are protein kinase A (PKA) and the exchange protein directly
activated by cAMP (Epac), which consists of the two isoforms Epac1 and Epac2.
Epac1 and Epac2: Inflammation
An important cytokine that is increased in COPD is interleukin-8 (IL-8). Our data indicate that
Epac and PKA decrease cigarette smoke extract (CSE)-induced IL-8 release by airway
smooth muscle (ASM) cells, via inhibition of NF-κB and ERK signalling, respectively.
Importantly, we also observed reduced Epac1 expression in lung tissue from COPD patients
(6,7).
To investigate the potential cause for the downregulation of Epac1, we studied microRNAs
(miRNAs). MiRNAs are epigenetic regulators involved in fine-tuning of cellular activities by
posttranscriptional repression of mRNA. In COPD patients, miRNA-7 is increased in serum
(8). We investigated the potential interaction of Epac1 and miRNA-7. CSE induced miRNA-7
specifically in human ASM cells. In line, miRNA-7 was increased in bronchial smooth muscle
of COPD stage II patients isolated by laser dissection. Importantly, Epac1 expression is
reduced in miRNA-7 overexpressing human ASM cells (Figure 1). Our data implicate that
upregulation of miRNA-7 by cigarette smoke correlates with the downregulation of Epac1 in
COPD (8).
Both Epac1 and Epac2 seem to be implicated in the reduction of CSE-induced IL-8 release
from human ASM cells. However, phospholipase Cε (PLCε), a direct effector of Epac, acts
pro-inflammatory. To translate our findings on inflammation in vitro to the in vivo situation,
Epac1-/-, Epac2-/- and PLCε-/- mice were exposed to cigarette smoke for 5 days. We
demonstrated that compared to wild-type (WT) mice exposed to cigarette smoke, the number
of total inflammatory cells, macrophages, and neutrophils as well as IL-6 release were lower
in Epac2-/- mice, which was also the case for neutrophils and IL-6 in PLCε-/- mice (Figure 2,
ref 9). Compared to WT mice exposed to cigarette smoke, the number of macrophages was
reduced in Epac1-/- mice. Whereas, the numbers of lymphocytes, only present in low
numbers in BALF of air-exposed WT mice, were increased in Epac1-/- mice. Together our
data indicated that particularly Epac2 acts pro-inflammatory in vivo (9).
Aberrant epithelial repair is also regarded as a pathophysiological feature of COPD. It is of
interest that the A-kinase anchoring protein (AKAP) family member AKAP9 enhanced the
endothelial barrier function in concert with Epac1. AKAPs compartmentalize cellular cAMP
upon generation of multiprotein complexes. We found that CSE reduced the barrier function
in human bronchial epithelial cells, a process accompanied by a reduced membrane
expression of E-cadherin and AKAP9 (Figure 1). Silencing of AKAP9 reduced the functional
epithelial barrier and prevented the ability of st-Ht31, an inhibitor of AKAP-PKA interactions,
to restore membrane localization of E-cadherin. Our data indicate that AKAP9 maintains the
bronchial epithelial barrier function and may be important in the pathophysiology of COPD
(10).
16
Altogether, Epac1 and Epac2 seem to be involved in cigarette smoke induced inflammation,
although with a clear distinction regarding their relative contribution. Compartmentalization of
cAMP driven by AKAP family members, may be responsible for the distinct biological effects
of cAMP.
Figure 1: (A) In human bronchial epithelial cells, cigarette smoke extract reduces the barrier function (resistance)which is
prevented by St-Ht31,
a inhibitory
peptide of AKAP-PKA interactions. In addition, the expression of both AKAP9 and ERemodeling:
Epac1
and Epac2
cadherin is reduced by cigarette smoke extract (further details see ref 9). (B) In airway smooth muscle cells, cigarette
smoke extract enhances miRNA-7 levels. Overexpression of miRNA-7 inhibits the protein expression of Epac1. In
bronchial smooth muscle of COPD patients a upregulation of miRNA-7 is observed. (C) Epac: implications for structural
lung cell functioning(further details see ref 6).
17
Tissue remodeling is another feature of COPD and covers different characteristics of the
disease such as mucus hypersecretion, airway fibrosis and emphysema. The majority of
extracellular matrix (ECM) proteins, including collagens and fibronectin, are produced by
fibroblasts. Alterations in the tightly controlled balance of production and degradation of ECM
proteins causes structural changes in the lung such as emphysema, characterized by
excessive degradation of parenchymal ECM , and (small) airway fibrosis characterized by
excessive deposition of ECM proteins (1). Although a role for cAMP in the regulation of
remodeling has been shown (4,5), the exact role of the cAMP effectors Epac and PKA on the
different aspects of remodeling is not completely known.
Interestingly, it has been reported that cAMP-elevating drugs reduce collagen I synthesis in
human lung fibroblasts. A PDE inhibitor and a cAMP analog have been shown to reduce
MMP9 and TIMP1 gene expression and activity in different cell types. CSE exposure of the
human bronchial epithelial cell line 16HBE14o- leads to increase of MMP9 mRNA and
thereby of the MMP9/TIMP1 ratio. Induction of MMP9 mRNA was reduced by specific PKA
activation. Pro-MMP9 levels induced by CSE were reduced by the fenoterol, an effect
specifically mimicked by pharmacological activation of PKA. PKA inhibition may enhance the
MMP9/TIMP1 ratio and thereby reduce emphysema. In contrast, activation of PKA may
reduce emphysema by a decrease of the MMP9/TIMP1 ratio (further details see ref 6).
In addition, we tried to identify the role of Epac1 and Epac2 in remodeling processes in the
lung by exposure of Epac1-/- and Epac2-/- mice to cigarette smoke. We demonstrated that
Epac1-/- mice expressed higher levels of TGF-β1, collagen I and fibronectin. We propose
that Epac1, but not Epac2, acts anti-fibrotic. Concerning mucus hypersecretion, Epac1-/- and
Epac2-/- were characterized by a constitutively higher expression of MUC5AC mRNA at
basal level (Figure 2). We observed that goblet cells tended to be increased in Epac2-/- and
PLCε-/- mice, whereas primarily Epac1-/- mice tended to stain positive for the inducer of
goblet cell differentiation SPDEF (9).
Overall, we identified distinct roles of Epac1 and Epac2 in remodeling processes. This
suggest that Epac1 alone controls remodeling. In contrast, both Epac1 and Epac2 seem to
control MUC5AC (9). Similar as for inflammation, compartmentalization of Epac by AKAPs
will most likely define a potential role of AKAP-dependent compartmentalization of cAMP in
remodeling processes.
18
Figure 2: (A) In an acute mouse model of cigarette smoke exposure, Epac2, possibly via PLCε, enhances neutrophils (left
panel). Epac1 bears the capacity to reduce the deposition of collagen I in lung tissue (right panel) . (B) Both Epac1 and Epac2
regulate mucus hypersecretion in mice. (C) Epac1 and Epac2: implications in inflammation and remodelling in vivo. Epac2
contributes to cigarette smoke induced-increase in macrophages and IL-1β release. Possibly via PLCε, Epac2 also enhances
neutrophils and IL-6 release. Epac1 inhibits collagen I and fibronectin deposition. Both Epac1 and Epac2 play an inhibitory role
in mucus hypersecretion. For further details see refs 6, 9.
19
Conclusions
These studies implicate an important role for cAMP in COPD. We defined distinct roles of
Epac1 and Epac2 in inflammation and remodeling. In an acute model of cigarette smoke
exposure in mice, we unraveled pro-inflammatory actions of Epac2. We showed that Epac1
alone is able to reduce remodeling, whereas for the reduction of MUC5AC a concerted
action with Epac2 seemed to be required. Based on our findings, the development of
selective Epac1 and Epac2 activators and/or inhibitors could be of additive value to alleviate
symptoms of COPD. Targeting of these selective Epac activators or inhibitors to specific
areas in the lung represents a future goal. Research into compartmentalization of cAMP by
AKAPs should be another subject of future research.
Acknowledgement
This work was supported by a Long Fonds (grant 3.2.09.34) and a Rosalind Franklin
Fellowship from the University of Groningen to Martina Schmidt. Harm Maarsingh was
supported by the Schering-Plough Research Institute (Oss, The Netherlands).
References
1.
Hogg JC, Timens W: The pathology of chronic obstructive pulmonary disease. Annual Rev Pathol 2009, 4,
435-459
2.
Hoonhorst SJ, Ten Hacken NH, Vonk JM, Timens W, Hiemstra PS, Lapperre TS, Sterk PJ, Postma DS:
Steroid resistance in COPD? overlap and differential anti-inflammatory effects in smokers and ex-smokers.
PloS One 2014, 9, e87443
3.
Meurs H, Oenema TA, Kistemaker LE, Gosens R: A new perspective on muscarinic receptor antagonism in
obstructive airways diseases. Curr Opin Pharmacol 2013, 13, 316-323
4.
Oldenburger A., Maarsingh H, Schmidt M: Multiple facets of cAMP signalling and physiological impact:
CAMP compartmentalization in the lung. Pharmaceuticals 2012, 5, 1291-1331
5.
Dekkers BG, Racke K, Schmidt M: Distinct PKA and epac compartmentalization in airway function and
plasticity. Pharmacol Therap 2013, 137, 248-265
6.
Oldenburger A: New avenues for Epac in inflammation and tissue remodelling in COPD. Thesis 2014,
University Groningen.
7.
Oldenburger A, Roscioni SS, Jansen E, Menzen MH, Halayko AJ, Timens W, Meurs H, Maarsingh H,
Schmidt M: Potential anti-inflammatory role of the cAMP effectors Epac and PKA: implications in chronic
obstructive pulmonary disease. PLoS ONE 2012, 7, e31574
8.
Oldenburger A, van Basten B, Kooistra W, Meurs H, Maarsingh H, Krenning G, Timens W, Schmidt M:
Interaction between Epac1 and miRNA-7 in airway smooth muscle cells. Naunyn Schmiedebergs Arch
Pharmacol 2014, 387, 795-7
9.
Oldenburger A, Timens W, Bos S, Smit M, Smrcka AV, Laurent A, Cao J, Hylkema M, Meurs H, Maarsingh
H, Lezoualc'h F, Schmidt M: Epac1 and Epac2 are differentially involved in inflammatory and remodeling
processes induced by cigarette smoke. FASEB J 2014, 28, 4617-28
10. Oldenburger A, Poppinga WJ, Kos F, de Bruin HG, Rijks WJ, Heijink IH, Timens W, Meurs H, Maarsingh H,
Schmidt M: A-kinase anchoring proteins contribute to the loss of E-cadherin and bronchial epithelial barrier
by cigarette smoke. Am J Physiol 2014, 15, 306, C585-97
20
Special Topic 3
Occupational pesticide exposure increases risk for COPD
Kim de Jong, Judith M. Vonk, Dirkje S. Postma, H. Marike Boezen
Departments of epidemiology and pulmonology
Chronic obstructive pulmonary disease (COPD) is characterized by persistent and often
progressive airflow obstruction caused by and abnormal inflammatory response to noxious
particles and gases. Tobacco smoking is considered to be the main risk factor for COPD, yet
a substantial proportion of 15–20% of all cases has been attributed to occupational
exposures (1), with proportions up to 30% in never smokers (2). Because occupational
exposures are common, yet also potentially modifiable contributors to the global burden of
COPD, it is important to determine which occupational factors drive the development of this
disease.
Within two Dutch general populations based cohorts, i.e. the LifeLines cohort study and the
Vlagtwedde-Vlaardingen study, we estimated occupational exposure to amongst others
pesticides using a job exposure matrix (JEM). The JEM classified subjects based on ISCO88 job codes into no, low and high exposure categories (0/1/2).
First, we showed cross-sectional associations between pesticide exposure and lower levels
of FEV1 and FEV1/FVC in 11,851 individuals from the LifeLines cohort study and 2,364
subjects included in the last survey (1989/1990) of the Vlagtwedde-Vlaardingen cohort (see
figure 1 for associations in LifeLines). Subjects with high levels of exposure to pesticides had
also an increased risk for COPD gold stage 2 and higher (OR = 1.95 (0.92 – 4.13) in
LifeLines and OR = 1.78 (1.14 – 2.79) in Vlagtwedde-Vlaardingen) (3). There were no
consistent associations between exposure to pesticides and the FEF25-75%, a marker of small
airways obstruction (4).
Figure 1. Cross-sectional associations between occupational pesticide exposure and the level of FEV1 (A) and FEV1/FVC (B),
for he whole group and stratified according to smoking status (never/ever smoker) in the LifeLines cohort study. Associations
with FEV1 were significantly stronger (p<0.05) for ever compared to never smokers.
Additionally within 12,772 observations from 2,527 subjects assessed between 1965 and
1990 in the Vlagtwedde-Vlaardingen cohort we found that subjects with high pesticide
exposure had an accelerated decline in FEV1 and FEV1%IVC (figure 2) (5). Especially within
smokers these implied substantial losses of lung function, for example smokers with high
21
exposure to pesticides had 7 ml/year larger decline in FEV1 compared to smokers without
pesticide exposure.
Interestingly, in both the cross-sectional (FEV1) and longitudinal study (FEV1 and FEV1%IVC)
we found significantly stronger associations in ever compared to never smokers, suggesting
synergistic effects of tobacco smoke and pesticide exposure. For example for a pesticide like
Paraquat the primary mechanism for toxicity is related to its cyclic redox reactions and
consequently free radical generation resulting in oxidative damage of the lung tissue. It is
very well likely that the effect of exposure to such a pesticide is more pronounced when antioxidant systems are already depleted by cigarette smoking and the lung is already damage
by free radicals from tobacco smoke.
Fig 2. Estimated course of FEV1 (A) and FEV1%IVC (B) for subjects with high exposure to VGDF only (VGDF + : Pesticides -)
and subjects with joint high exposure to VGDF and pesticides (VGDF + : Pesticides +) compared to unexposed subjects,
modeled for time (years) since first survey after the age of 30 years in the Vlagtwedde-Vlaardingen cohort (1965-1990).
Finally common genetic variation may affect individual susceptibility to exposures such as
pesticides. We therefore assessed interactions between single nucleotide polymorphisms
and pesticide exposure on the level of FEV1 in a genome-wide manner. We identified one
common genetic variant (prevalence minor allele ~25%) in NOS1 that increased
susceptibility to high levels of pesticide exposure in both the LifeLines cohort study (12,400
subjects) and the Vlagtwedde-Vlaardingen study (1,436 subjects) (figure 3) (6).
The NOS1 gene encodes for neuronal nitric oxide synthase that synthesizes endogenous
nitric oxide (NO) from arginine. In the human lung, NOS1 was found in submucosal nerves
and endothelial cells (7). Interestingly this gene has been implicated in pesticide toxicity as
well as in COPD pathogenesis. This suggests that excess release of NO may underlie
pesticide toxicity in the lungs and subsequently lead to an impaired lung function, a hallmark
of COPD.
22
Figure 3. Associations of no, low and high occupational exposure to pesticides and the level of FEV 1 (ml) in the LifeLines cohort
(A) and Vlagtwedde-Vlaardingen cohort (B) stratified for NOS1 rs482555 genotype.
Apart from a few small scale cross-sectional studies that found associations between specific
types of pesticides and lower levels of FEV1 and FVC in occupationally exposed farmers
from Sri-Lanka (8), South Korea (9) and Costa Rica (10), relatively few studies have focused
on the effects of pesticide exposure on lung function (11). To our knowledge no studies thus
far have shown associations between pesticide exposure and the longitudinal decline of lung
function.
Globally, the agricultural sector employs more than 1.1 billion workers worldwide (about 34%
of the global working force) (12) potentially putting a large amount of workers at risk for
pesticide exposure. Additionally, people living in agriculture-intensive regions may be at risk
for exposure due to pesticide drift (13). This may be especially relevant in a densely
populated country as the Netherlands where large numbers of people live near greenhouses
and pesticide-treated farmland. Little is known about the risks of people living in the vicinity of
these pesticide-treated areas in the Netherlands, and such risks were not taken into account
during the approval process for pesticides’ entry on the Dutch market. Growing concerns
about these risks have led to a first advisory report of a Committee of the Health Council of
the Netherlands, and consequently the initiation of an exposure study among people living in
the vicinity of greenhouses and pesticide-treated farmland that will be carried out in 2015 and
2016.
Publication of the above mentioned studies led to a reaction from the Dutch parliament, but
the approval process for pesticides’ entry of the Dutch marked will not be reconsidered
based on these findings (14) (Rijksoverheid).
References
1. Balmes J, Becklake M, Blanc P, Henneberger P, Kreiss K, Mapp C, et al. American thoracic society statement:
Occupational contribution to the burden of airway disease. American journal of respiratory and critical care
medicine. 2003;167(5):787-97.
2. Hnizdo E, Sullivan PA, Bang KM, Wagner G. Association between chronic obstructive pulmonary disease and
employment by industry and occupation in the US population: A study of data from the third national health and
nutrition examination survey. American Journal of Epidemiology. 2002 October 15;156(8):738-46.
23
3. de Jong K, Boezen HM, Kromhout H, Vermeulen R, Postma DS, Vonk JM, et al. Pesticides and other
occupational exposures are associated with airway obstruction: The LifeLines cohort study. Occup Environ Med.
2014 Feb;71(2):88-96.
4. de Jong K, Boezen HM, Kromhout H, Vermeulen R, Vonk JM, Postma DS, et al. Occupational exposure to
vapors, gases, dusts, and fumes is associated with small airways obstruction. Am J Respir Crit Care Med. 2014
Feb 15;189(4):487-90.
5. de Jong K, Boezen HM, Kromhout H, Vermeulen R, Postma DS, Vonk JM. Association of occupational
pesticide exposure with accelerated longitudinal decline in lung function. Am J Epidemiol. 2014 Jun
1;179(11):1323-30.
6. de Jong K, Vonk JM, Kromhout H, Vermeulen R, Postma DS, Boezen HM, et al. NOS1: A susceptibility gene
for reduced level of FEV1 in the setting of pesticide exposure. Am J Respir Crit Care Med. 2014 Nov
15;190(10):1188-90.
7. Kobzik L, Bredt DS, Lowenstein CJ, Drazen J, Gaston B, Sugarbaker D, et al. Nitric oxide synthase in human
and rat lung: Immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol. 1993 Oct;9(4):371-7.
8. Peiris-John RJ, Ruberu DK, Wickremasinghe AR, van-der-Hoek W. Low-level exposure to organophosphate
pesticides leads to restrictive lung dysfunction. Respir Med. 2005 10;99(10):1319-24.
9. Cha ES, Lee YK, Moon EK, Kim YB, Lee Y, Jeong WC, et al. Paraquat application and respiratory health
effects among south korean farmers. Occupational and Environmental Medicine. 2012 June 01;69(6):398-403.
10. Schenker M, Stoecklin M, Lee K, Lupercio R, Zeballos RJ, Enright P, et al. Pulmonary function and exerciseassociated changes with chronic low-level paraquat exposure. American journal of respiratory and critical care
medicine. 2004;170(7):773-9.
11. Hoppin JA. Pesticides and respiratory health: Where do we go from here? Occup Environ Med. 2014
Feb;71(2):80,2013-101876. Epub 2013 Nov 12.
12. International Labour Office. Global employment trends 2012. Geneva: International Labour Organization;
2012. Report No.: ISBN 978-92-2-124924-5 (print).
13. Lee SJ, Mehler L, Beckman J, Diebolt-Brown B, Prado J, Lackovic M, et al. Acute pesticide illnesses
associated with off-target pesticide drift from agricultural applications: 11 states, 1998-2006. Environ Health
Perspect. 2011 Aug;119(8):1162-9.
14. Ministerie van Economische Zaken. Reactie op artikel werkgerelateerde longziekte COPD bij boeren en
kwekers als gevolg van het gebruik van pesticiden. 3 December 2014.
24
Special Topic 4
Targeted lung denervation for chronic obstructive pulmonary disease
Dirk-Jan Slebos
Department of pulmonology
We recently performed the first-in-human study investigating bronchoscopic radio-frequent
ablation of the parasympathetic pulmonary nerves in patients. This new bronchoscopic
minor-invasive therapy called “targeted lung denervation” (TLD) is a potential future
treatment option for patients with advanced COPD. The first results show that TLD in
patients with COPD is feasible, safe and has clinical benefit which appears both durable and
dose dependent [ref 1].
Targeted lung denervation (TLD) is a novel bronchoscopic therapy that ablates the
parasympathetic innervation of the lungs and has a similar proposed mechanism of action to
anticholinergic drugs. TLD therapy is delivered via a dual-cooled radiofrequency (RF)
catheter (Holaira, Inc., Minneapolis, MN, USA) (figure 1) designed to target tissue heating at
depth thereby producing a narrow band of ablation around the main bronchi while minimizing
effects to the inner surface of the airway.
Figure 1 - dual-cooled
radiofrequency catheter
As RF current passes from the electrode through the airway and surrounding tissues, these
tissues are heated. Coolant continuously circulated through the electrode and balloon
removes heat from the surface of the airway wall. The net effect is targeted tissue ablation at
depth with minimal heating and damage of the inner surface of the airway.
This targeted tissue ablation is intended to disrupt motor axons within bronchial nerve
branches running along the outside of the main bronchi, thereby blocking parasympathetic
signaling to the lungs and decreasing neuronal release of acetylcholine. This decrease in
acetylcholine reduces airway obstruction in the whole lung by decreasing smooth muscle
tone and mucous production (figure 2).
25
Figure 2- Targeted Lung Denervation is intended to block parasympathetic signaling and reduce acetylcholine release from the
nerve endings.
In a first-in-human study we investigated the safety and feasibility of TLD therapy using two
energy doses (20 and 15 watts) in patients with moderate to severe COPD. In a nonrandomized, prospective study COPD patients were included with a post-bronchodilator
FEV1 of 30-60% of predicted normal values and with a 15% or greater relative increase in
FEV1 following inhalation of 80μg ipratropium bromide.
TLD-Treatment procedure
Figure 3 – TLD Procedureroom
Due to the construction of this first generation device,
procedures were performed via rigid bronchoscopy
under
general
anesthesia
in
2
sequential
bronchoscopies (figure 3). The dual-cooled catheter
was placed through the rigid bronchoscope and a
flexible bronchoscope placed beside it for visualization.
The electrode was placed and activated in up to 8
rotational positions per bronchus to achieve complete
circumferential treatment. Total balloon inflation times
were approximately 3 minutes per activation.
Bronchoscopic and fluoroscopic visualization was used
to guide in electrode positioning throughout treatment
(figure 3).
Figure 4: Fluoroscopic view (A) and
Bronchoscopic view (B) of the
electrode during the procedure. The
electrode is indicated by the arrow.
Results
Twelve patients were included in the 20watt cohort and an additional 10 patients were
included as part of the 15watt cohort. Baseline characteristics were similar between the two
cohorts. The primary safety endpoint was achieved in 100% (11/11) in the 20watt cohort and
26
90% (9/10) in the 15watt cohort. The one subject that failed to meet the endpoint had a
sustained decline in lung function over time.
The RF energy applied to the airway wall resulted in local asymptomatic airway blanching,
which resolved at the 3 month follow-up bronchoscopy in all 10 of the 15watt patients, and in
8 of the 11- 20watt patients with long-term follow up (figure 5).
Figure 5 - Bronchoscopic confirmation of airway healing after TLD: (A) Left main bronchus pre-treatment (B) During treatment
(C) Immediately post-Treatment (D) 3 month follow-up.
In the 20watt group, one patient had a superficial tissue defect at the first treatment site seen
at 30 days, a second patient had a small 1.5 mm perforation through the thin tissue of the
main carina also discovered at 30 days, and the third patient had a superficial tissue defect
at the initial treatment site just distal to the main carina, as well as a 4 mm granuloma at the
second treatment site.
Figure 6: Secondary efficacy endpoints. Data represented as mean. Error bars represent standard error of the mean. *p<0.05
compared to baseline. FEV1: Forced Expiratory Volume in 1 second. FVC: Forced Vital Capacity. Cycle Erg. Endurance: Cycle
Ergometry Endurance. SGRQ: St. George’s Respiratory Questionnaire
27
The procedure was feasible in all cases and technical success was 98%, with 326 of 332
expected treatment sites able to be treated. No device related adverse events occurred
during the procedure. The results of FEV1 (% relative change), FVC, cycle ergometry
endurance and SGRQ at each time point assessed are shown in figure 6.
Discussion
This first-in-human clinical trial evaluated the novel “targeted lung denervation” (TLD)
therapy, designed to ablate the parasympathetic pulmonary nerves surrounding the main
bronchi thereby decreasing bronchomotor tone in patients with COPD.
This study
demonstrated TLD to be feasible, safe, and potentially beneficial. The primary endpoint was
met in 95% of patients and technical success was 98%. Tendency toward improvements in
lung function, exercise capacity, and HRQL were observed in the 20watt cohort. These
improvements tended to be larger than those seen in the 15watt cohort.
TLD has the potential to overcome many of the limitations of inhaled drugs for the treatment
of COPD. First, TLD may eliminate inhaler compliance issues for the 63% of new tiotropium
users who discontinue treatment after 1 year. Second, TLD would not be subject to the peak
and trough variations seen with drugs. Third, TLD may eliminate variable regional drug
delivery and deposition in patients with obstructive lung disease by ablating the nerves that
travel throughout the bronchial tree independent of regional airflow obstruction. Fourth, by
interfering with parasympathetic nerve derived acetylcholine by two different mechanisms,
the combination of TLD + inhaled anticholinergic drugs, as suggested by figure 7, may have
a synergistic effect that results in a reduction in airway obstruction and mucus production, as
well as inhibition of local airway inflammation induced by non-neural muscarinic action.
In this paper we introduced TLD, a novel bronchoscopic treatment concept for symptomatic
patients suffering from COPD. Based on the concept of ablating parasympathetic pulmonary
nerves, TLD was shown to be feasible, safe, and potentially clinically effective. The
beneficial effects appear durable, dose dependent and potentially additive to inhaled
anticholinergics.
Further investigation and progressive product
development is currently underway. A new catheter
and RF system have been developped, allowing a
single outpatient 45 mins procedure (figure 7). This
system will be tested and used in the “AIRFLOW-1
trial” (NCT02058459): A Sequential 2-Phase
Multicenter, Randomized Study to Optimize Dose
Selection and Evaluate Safety After Treatment with
the Holaira™ Lung Denervation System in Patients
with Moderate to Severe COPD.
Figure 7. The new generation TLD system
Reference:
Slebos DJ, Klooster K, Koegelenberg CF, Theron J, Styen D, Valipour A, Mayse M, Bolliger CT. Targeted lung
denervation for moderate to severe COPD: a pilot study. Thorax. 2015 Mar 4. [Epub ahead of print]
28
Special Topic 5
Granted projects in 2014
In 2014 GRIAC researchers were very succesfull in obtaining grants. The summaries of the
most prestigious granted proposals are outlined below.
Initiation of HOme MEchanical ventilation at home in a selective group of patients with
chronic hypercapnic Respiratory failUre in the Netherlands (HOMERUN)
Dr. P.J. Wijkstra (UMCG), Prof. H.A.M. Kerstjens (UMCG), A. Hazenberg (UMCG) Dr. M.
Gaytant ( UMCU), A.Otte ( MUMC), R. van den Biggelaar ( ErasmusMC)
Granted by ZonmW
Home mechanical ventilation (HMV) in the Netherlands routinely starts in a clinical setting
supervised by one of the 4 HMV centers. Depending on the local organization this can be
done on different wards. The proposed intervention to be studied is initiation of HMV at home
as compared to in hospital initiation in different settings. Our hypothesis is that initiation of
chronic ventilatory support at home is not inferior to a hospital-based initiation.
Patients with chronic respiratory insufficiency due to a neuromuscular disease (NMD) or
thoracic cage problem who are referred for chronic ventilator support and > 18 years of age
can be included.
The primary outcome parameter is the arterial carbon dioxide (PaCO2). Secondary
parameters are health related quality of life questionnaires, lung function and costs.
Tissue repair in COPD: WNT you get it right?
Dr. R. Gosens (UMCG), Dr. J. Stolk (LUMC), Prof. M. Königshof (Helmholtz Zentrum
München).
Granted by Netherlands Lung Foundation
COPD is a chronic lung disease caused primarily by smoking. COPD patients suffer from
airflow limitation caused by airway inflammation and remodelling and tissue destruction in the
lung parenchyma. The damaged lung cannot be repaired with current medical technology.
Halting tissue destruction or reversing the existing damage are therefore important
challenges for pulmonary research.
It is now feasible to promote tissue repair using novel stem cell therapy and pharmacological
approaches that specifically target the WNT pathway. The WNT pathway, which regulates
lung development in utero and is required for tissue homeostasis and repair, is inadequately
activated in COPD.
In this project, pulmonologists, pharmacologists and (stem) cell biologists will form a
consortium to for the first time target the WNT pathway to promote tissue repair in COPD
using pharmacological and cell therapy approaches. We postulate that in COPD, WNT
signalling that drives tissue repair is out of balance due to interference by inflammation,
inappropriate TGF-β activation and ER stress. This redirects WNT signalling to other
transcriptional programs, thereby preventing repair, and promoting remodelling instead.
Restoring this balance will boost repair of the damaged lung.
We will use functional studies and gene expression profiling in vulnerable cell populations
including alveolar epithelial cells, parenchymal fibroblasts and microvascular pulmonary
29
endothelial cells from COPD patients and controls. This way, we aim to understand the
mechanisms that distort adequate WNT signalling in COPD. Furthermore, we will evaluate
cell therapy and novel drugs that restore WNT mediated repair. We will focus on bone
marrow-derived mesenchymal stromal cells (BM-MSCs) as a known source and target of
WNT ligands. We are currently investigating MSCs for their therapeutic potential in COPD
patients.
Collectively, we will establish key mechanisms fundamental to inadequate repair in COPD
and identify novel therapeutic targets to reactivate repair in COPD.
Design, synthesis and validation of potent and isozyme selective arginase inhibitors
for therapeutic use in asthma
Prof. A.S.S. Dömling (Drug Design, RUG), Prof. H. Meurs (Molecular Pharmacology, RUG),
Prof. P.H. Elsinga (Nuclear Medicine and Molecular Imaging, RUG)
Granted by Grant Technology Foundation STW
Allergic asthma is a chronic inflammatory obstructive airway disease, characterized by
attacks of breathlessness due to periods of intermittent airflow obstruction. The prevalence
and morbidity of this disease have steadily risen worldwide during the last few decades.
Many patients with asthma are poorly controlled by current drug treatment with ß 2-agonists
and corticosteroids, in particular patients with severe asthma characterized by chronic
symptoms, severe exacerbations, progressive loss of lung function and frequent
hospitalization. Therefore, new therapeutic options are highly warranted. Recent studies in
animal models and in asthma patients have revealed that the arginine metabolizing enzyme
arginase has a key role in allergic airway inflammation, obstruction, hyperresponsiveness
and remodeling, and therefore represents an attractive and entirely novel target for the
treatment of this disease. Two isoenzymes (types 1 and 2) have been identified, which are
differentially expressed in the body and may regulate different biological functions. Enhanced
expression of particularly arginase 1 appears to be involved asthma, although the exact role
of both subtypes remains to be established. Thus far, no arginase inhibitors are available for
therapeutic treatment. Aim of the present project is to develop novel potent isozyme-selective
arginase inhibitors by structure-based drug design, using unique advanced chemical
technology. Potential application of these inhibitors for the treatment of asthma will be
investigated by state-of-the art pharmacological and Positron Emission Tomography imaging
methods, using animal models of acute and chronic asthma as well as human lung tissue. It
is envisaged that these inhibitors will give more insight in the pathophysiology of the disease
and provide novel effective treatment options.
Identifying causal mechanisms of the inception of asthma through a novel
experimental model for the interaction on the PCDH1 gene and environment
Dr. M. Nawijn (UMCG), Prof. G.H. Koppelman (UMCG), Prof. L. Bont (UMCU), Prof. B.
Lambrecht (University of Ghent)
Granted by Netherlands Lung Foundation
Asthma starts in early childhood. The inception of asthma occurs in a susceptible child upon
exposure to environmental triggers, typically respiratory viral infections and sensitization to
aero-allergens. Current treatment suppresses airway inflammation but does not cure asthma.
To progress towards curative treatment, we need to understand the inception of asthma
rather than the chronic inflammation characterizing established asthma. Since opportunities
30
to perform such studies in young children are limited, there is an urgent need for
experimental models to understand the inception of asthma. We propose to base such
models on relevant asthma susceptibility genes.
This study integrates major recent discoveries by the consortium. We identified
Protocadherin-1 (PCDH1) as a novel asthma and bronchial hyperresponsiveness (BHR)
gene, and show its interaction with SMAD3, another asthma gene, in airway epithelium.
Based on these human data we generated PCDH1 knockout mice that display spontaneous
BHR as well as exaggerated house-dust mite induced BHR. In addition, we identified
respiratory syncytial virus infection as an important cause of recurrent wheezing in the first
three years of life.
We aim to dissect the PCDH1/SMAD3 pathway during the inception of asthma by exposing
PCDH1 deficient mice and controls to aeroallergens and respiratory syncytial virus-infection.
We will test the critical role of the airway epithelium for asthma inception in vivo. We will
translate these findings to the human disease using primary bronchial epithelial cells
obtained from asthmatic children, adult asthma patients and controls. Moreover, we will
evaluate human lung epithelial organoids, a novel 3D culture system, as an individualized
screening platform for testing novel interventions. We have brought together a
multidisciplinary consortium of excellent clinicians and scientists with an outstanding track
record for productive collaboration in translational asthma research.
This consortium will reveal key mechanisms in the inception of asthma, resulting in novel
treatment targets.
A window of opportunity: Prevention of epigenetic programming of asthma
Prof. G.H. Koppelman (UMCG), Dr. U. Gerhring (UU) , Dr. A. Wijga (RIVM), Prof. H.A. Smit
(UMCU) on behalf of the PIAMA consortium
Granted by the Netherlands Lung Foundation
Children with asthma are at increased risk of developing a lung function deficit in adulthood.
Importantly, the risk factors related to asthma and lung function impairment operate already
in utero and infancy, critical periods of lung development. There is ample evidence that
environmental exposures during different stages of childhood affect the risk of asthma and
lung function impairment later in life. The impact of these environmental exposures may
critically depend on timing.
It is becoming increasingly clear that environmental exposures, e.g. air pollution and
(passive) smoking, and indoor exposures like endotoxin may cause epigenetic modifications
of our DNA. This impacts especially the respiratory epithelium, the cell layer that is the first
line of defence against inhaled environmental stimuli. Important asthma genes are expressed
in the epithelium, yet it is unknown how epigenetic programming regulates airway epithelial
gene expression and if this affects asthma and lung function development.
This project will investigate if environmental exposures during different stages of childhood
(in utero / infancy, preschool, school and early adolescence) affect asthma risk and lung
function impairment. We will do so by analyzing data from the PIAMA birth cohort followed up
to age 16. We will determine if environmental factors result in changes in DNA methylation of
airway epithelial cells at age 16 and subsequently link DNA methylation to DNA
polymorphisms and gene expression in these nasal epithelial cells.
This opens a new perspective on asthma prevention, in particular since each stage of
childhood has its specific setting for prevention. Our multidisciplinary approach will integrate
the environment, DNA polymorphisms, DNA methylation in respiratory epithelium, and their
31
effects on gene transcription in the same children. We ultimately will determine causal
networks that are active in the airway epithelium leading to asthma and the associated lung
function deficit in adulthood.
32
Departments
Dept. Epidemiology
Hanzeplein 1
P.O. Box 30.001
Phone 31-50-361 0739
Fax
31-50-361 4493
Principal Investigators: Prof. Dr. H.M. Boezen, Dr. M. Kerkhof, Dr. J.M. Vonk
Dept. General Practice
University of Groningen, Faculty of Medical Sciences
A. Deusinglaan 1
NL-9713 AV Groningen
Phone 31-50-363 2963
Fax
31-50-363 2964
Principal Investigator: Prof. Dr. T. van der Molen
Dept. Internal Medicine, div. Allergology
Hanzeplein 1
P.O. Box 30.001
Phone: 31-50-361 2976
Fax: 31-50-3121576
Principal Investigators: Prof. Dr. J.G.R. de Monchy, Dr. J.N.G. Oude Elberink
Dept. Pathology and Medical Biology, Div. Medical Biology, Experimental
Pulmonology and Inflammation Research
Hanzeplein 1
P.O. Box 30.001
Phone: 31-50-361 8043
Fax: 31-50-361 9911
Principal Investigators: Dr. H.I. Heijink
University Centre for Pharmacy
University of Groningen
A. Deusinglaan 1
NL-9713 AV Groningen
Phone 31-50-363 3197
Fax: 31-50-363 6908
Principal Investigators: Prof. Dr. M.A. Schmidt, Prof. Dr. H. Meurs, Dr. R. Gosens, Dr. B.N.
Melgert
Dept. Pathology and Medical Biology
Hanzeplein 1
P.O. Box 30.001
Phone: 31-50-361 4684
Fax: 31-50-363 2510
Principal Investigators: Prof. Dr. W. Timens, Dr. M.N. Hylkema
33
Dept. Pediatric Pulmonology and Pediatric Allergy
Beatrix Children’s Hospital, University Medical Center Groningen
Hanzeplein 1
P.O. Box 30.001
Phone: 31-50-361 1107
Fax: 31-50-361 1704
Principal Investigators: Prof. Dr. G.H. Koppelman, Prof. Dr. E.J. Duiverman, Prof. Dr. A.E.J.
Dubois
Dept. Pulmonary Diseases and Tuberculosis
Hanzeplein 1
P.O. Box 30.001
Phone: 31-50-361 3532
Fax: 31-50-361 9320
Principal Investigators: Prof. Dr. D.S. Postma, Prof. Dr. H.A.M. Kerstjens, Dr. N.H.T. ten
Hacken, Dr. M. van den Berge
Working group on Respiratory Insufficiency
Hanzeplein 1
P.O. Box 30.001
Phone: 31-50-361 3235
Fax: 31-50-361 9320
Principal Investigator: Dr. P.J. Wijkstra
34
Members 2014
Scientific Board
Boezen H.M., PhD, Prof
Dubois A.E.J., MD, PhD, Prof
Duiverman E.J., MD, PhD, Prof
Gosens, R., PhD
Heijink H.I., PhD
Hylkema M.N., PhD
Kerstjens H.A.M., MD, PhD, Prof
Koppelman G.H., MD, PhD, Prof
Meurs H., PhD, Prof
Molen van der T., MD, PhD, Prof
Monchy de J.G.R., MD, PhD, Prof
Oude Elberink J.N.G., MD, PhD
Postma D.S., MD, PhD, Prof
Schmidt M.A., PhD, Prof
Timens W., MD, PhD, Prof
Vonk J.M., PhD
Wijkstra P.J., MD, PhD
Other scientific staff
Berge van den M., MD, PhD
Brand P.L.P., MD, PhD, Prof. (associate
member)
Brandsma C.A., PhD
Diamant Z., PhD, Prof.
Flokstra-de Blok B.M.J., PhD
Guryev V., PhD
Hacken ten N.H.T., MD, PhD
Heide van der S., PhD
Kerkhof M., MD, PhD
Post-docs
Bidan, C. PhD
Faiz, A. PhD
Hartman J.E., PhD
Jong de C., PhD
Jong de K., PhD
Maarsingh E.J., PhD
Riemersma R.A., MD, PhD
PhD students
Alma H.J., MD/PhD student
Altenburg W.A., MSc
Berkhof, F., MSc
Boorsma C.E., MSc
Boudewijn I, MD
Cao, J.J. MSc,
van Dijk E., MSc
Dijk F.N., MD
Dijkstra A.E., MSc
Draijer C., MSc
Fattahi F., MSc
Faura Tellez G., MSc
Figarska S.M., MSc
Franciosi L., MSc
Gemert van F.A., MD
Ginkel van C.D., MD/PhD student
Goossens N.J., MD/PhD student
Grotenboer N.S., MSc
Han B., MSc
Kocks J.W.H., MD, PhD
Melgert B.N, PhD
Nawijn M.C., PhD
Rottier B.L., MD, PhD
Slebos D.J., MD, PhD
Touw D.J., PhD, Prof. (associate member)
Vrijlandt E.J.L.E., MD, PhD
Wempe J.B, MD, PhD
Willemse B.W., MD, PhD
Schokker S., PhD
Sopi R., PhD
Tsiligianni I., MD, PhD
Velde van der J.L., MD, PhD
Wright D.B., PhD
Xu C., PhD
Klijnsma M., MSc
Klooster K.
Koopmans T., MSc
Kumawat K., MSc
Metting E.I., MSc
Meyer, K. Msc.
Nieuwenhuis M.A.E., MSc
Oenema T.A., PhD
Oldenburger A., MSc
Osei E., MSc
Poppinga W., MSc
Pouwels S.D., MSc
Rajendran V., MSc
Robbe P., MSc
Rozeveld D., MSc
Saleh-Langenberg J., MD/PhD student
Sattarzadeh A., MSc
Savenije O.E.M., MD
Spanjer A.I.R., MSc
35
Hazenberg A.
Hesse L., MSc
Hoffmann R.F., MSc
Hoonhorst S.J.M., MSc
Ierodiakonou D., MD
Jong de L., MSc
Kennedy Feitosa E., MSc
Ketelaar M., MD/PhD student
Kirenga B.J., MSc
Kistemaker L.E.M., MSc
Struik F.M., MSc
Song, J., MSc
Tania N., MSc
Vos B.J.P.R., MD/PhD student
de Vries G.E., MSc
de Vries M., MSc
Vroegop J.S., MD
van der Wiel E., MD
Zeng X., MSc
Zijlstra J., MD
Other research staff
Augustijn S.
Beusekamp B.
Beverdam H.R.
Bladder G.
Bos I. S.T
Bouwman J.
Brouwer S.
Brouwer U.
Bruin de H.G.
Bruins Slot F.J.
Eems van der M.R.
Elzinga C.R.S.
Gras R.
Heijst van E.C.M.
Heuving M.E.
Homan A.A.J.
Jankipersadsing S.A.
Jonge de O.R.M.
Jonker M.R.
Kooistra W.
Klok P.
Koops H.
Kukler J.
Laan van der-Boers A.
Leever M.
Leij van der J., PhD
Lodewijk M.
Medema S.
Menzen M.
Noordhoek J.
Oeseburg D.S.
Oomkes-Pilon A.M.
Oosterom H.
Platteel M.
Rakers J.A.
Reinders-Luinge M.
Rijkom van B.
Smaalen van M.
Smidt-Huizinga H.D.M.
Smit M.
Staal R.
Star-Kroesen M.
Swierenga M.
Wedzinga A.
Zuidhof A.B
Zwart G.
36
International collaboration 2014
(As far as related to joint projects and publications in 2014)
Prof. S. Andreas
Georg-August University
Göttingen, Germany
Prof. J. Antó
IMIM, CREAL
Barcelona, Spain
Prof. E. Bateman
University of Cape Town
Cape Town, South Africa
Prof. R. Beasley
Medical Research institute of New
Zealand
Wellington, New Zealand
Dr. C. Bidan
University of Grenoble
Grenoble, France
Prof. E.R. Bleecker
Wake Forest School of Medicine
Winston Salem, USA
Dr. B. Bohle
Medical University of Vienna
Vienna, Austria
Dr. Y. Bossé
Université de Laval
Quebec, Canada
Prof. J. Bousquet
INSERM
Villejuif, France
Prof. G. Brusselle
University Hospital of Ghent
Ghent, Belgium
Dr. J.K. Burgess
Woolcock Institute
Sydney, Australia
Prof. A. Bush
Imperial College
London, UK
Prof. R.H. Casaburi
Harbor-UCLA medical center
Torrance, USA
Dr. M. Cho
Harvard Medical School
Boston, USA
Prof. R. Dahl
Odense University Hospital
Odense, Denmark
Prof. D. Davies
University of Southampton
Southampton, UK
The EAACI Food Allergy and Anaphylaxis Guidelines Group
Dr. G. Fejer
University of Plymouth
Plymouth, UK
Prof. J. Fonseca
University of Porto
Porto, Portugal
Prof. M. Gjomarkaj
University of Palermo
Palermo, Italy
Prof. R.S. Goldstein
University of Toronto
Toronto, Canada
Prof. Dr. C.M. Greene
Royal College of Surgeons in Ireland
Dublin, Ireland
Dr. T.L. Hackett
University of British Columbia
Vancouver, Canada
Prof. A.J. Halayko
University of Manitoba
Winnipeg, Canada
Prof. A.J. Henderson
University of Bristol
Bristol, UK
Prof. F. Herth
University of Heidelberg
Heidelberg, Germany
Prof. J.C. Hogg
Vancouver, Canada
Dr. J.W. Holloway
University of Southampton
Southampton, UK
37
Prof. C. Janson
Uppsala University
Uppsala, Sweden
Prof. D. Jarvis
Imperial College London
London, UK
Prof. G. Joos
Ghent, Belgium
Prof. M. Kamya
Makerere University
Kampala, Uganda
Prof. L. Kobzik
Harvard School of Public Health
Boston, USA
Prof. M. Königshoff
Helmholtz Center Munich
München, Germany
Dr. R. Korstanje
The Jackson Laboratory
Bar Harbor, USA
Dr. S. KraussEtschmann
Helmholtz Center Munich
Munich, Germany
Dr. R. Krishnan
Boston, USA
Prof. H. Kubo
Tohoku University
Sendai, Japan
Prof. B.N. Lambrecht
Ghent, Belgium
Dr. M. Lenburg
Boston University School of Medicine
Boston, USA
Dr. S. London
National Institute of Environmental
Health Sciences (NIEHS)
North Carolina, USA
Dr. H. Maarsingh
Palm Beach Atlantic University
West Palm Beach, USA
Dr. K. Malakauskas
Lithuanian University of Health
Sciences
Kaunas, Luthuania
Dr. F.O. Martinez
Oxford University
Oxford, UK
Dr. E. Melén
Karolinska Institute
Stockholm, Sweden
Prof. D.A. Meyers
Wake Forest School of Medicine
Winston Salem, USA
Dr. M. Miravitlles
Hospital Universitari Vall d’Hebron
Barcelona, Spain
Prof. T. Miyazawa
St. Marianna University school of
Medicine
State University of Rio de Janeiro
Kawasaki, Japan
Woolcock Institute
Sydney, Australia
Dr. E. Pace
University of Palermo
Palermo, Italy
Prof. P.D. Pare
Vancouver, Canada
Prof. M. Peters-Golden
University of Michigan Medical School
Michigan, USA
Prof. E. Pizzichini
Universidade Federal de Santa
Catarina
Florianópolis, Brasil
Dr. J. Porsasz
Harbor-UCLA medical center
Torrance, USA
Prof. D. Price
University of Aberdeen
Aberdeen, UK
Prof. N. Probst-Hensch
Swiss Tropical and Public Health
Institute
Basel, Switzerland
Prof. L.C. de Moraes
Sobrino Porto
Dr. B. Oliver
Rio de Janeiro, Brazil
38
Dr. B.A. Raby
Boston, USA
Dr. H.K. Reddel
University of Sydney
Sydney, Australia
Prof. F. van Roy
Flemish Institute of Biotechnology
Ghent, Belgium
Prof. I. Sabroe
University of Sheffield
Sheffield, UK
Prof. S. dos Santos
Valenca
Federal University of Rio de Janeiro
Rio de Janeiro, Brazil
Dr. I. Sayers
University of Nottingham
Nottingham, UK
Dr. K. Schulz
Klinik Bad Reichenhall
Dr. J. Schwarze
University of Edinburgh
Bad Reichenhall,
Germany
Edinburgh, UK
Prof. F. Sciurba
UPMC
Pittsburgh, PA, USA
Prof. T. Sigsgaard
Aarhus University
Aarhus, Denmark
Dr. P. Shah
Royal Brompton Hospital
London, UK
Prof. E. Silverman
Boston, USA
Prof. D.D. Sin
Vancouver, Canada
Prof. L. Sorokin
University of Münster
Münster, Germany
Dr. A. Spira
Boston, USA
Dr. K. Steiling
Boston, USA
Dr. K. Tantisira
Boston, USA
Prof. M. Tobin
University of Leicester
Leicester, UK
Prof. T. Troosters
University of Leuven
Leuven, Belgium
Prof. N. Tzanakis
University of Crete
Heraklion, Greece
Prof. M. Weatherall
University of Otago
Wellington, New Zealand
Prof. S.T. Weiss
Boston, USA
Prof. J. Wess
National Institute of Health
Bethesda, USA
39
Seminar program 2014
Date
Speaker
Title
09-01-2014
Dr. C. Grainge
University of
Southampton, UK
Effect of bronchoconstriction on airway remodelling in
asthma
21-01-2014
S. Hoonhorst
Pulmonology
UMCG
Results of TI Pharma 1-108
04-02-2014
Dr. S. KraussEtschmann
Helmholtz Center
Munich, Germany
Prenatal smoke exposure and postnatal phenotype
18-02-2014
B. van Anrooij
Allergology
UMCG
Markers for anaphylaxia
03-03-2014
Prof. S. Weiss
Channing Lab,
Harvard University
Boston, USA
Does childhood asthma develop into COPD?: results
from the CAMP study
01-04-2014
Prof. H. Meurs
Molecular
Pharmacology,
University Centre for
Pharmacy, Groningen
‘Arthritic’ airway: a novel mechanism of airway
hyperresponsiveness? A sabbatical report
15-04-2014
E. van der Wiel
Pulmonology
UMCG
Small airway dysfunction in asthma; new tools and
clinical features
06-05-2014
Dr. J.W.H. Kocks
General Practice
UMCG
From cluster analysis in obstructive lung disease to GP
research networks: experiences from New Zealand
03-06-2014
C. Draijer
Pharmacokinetics,
Toxicology and
Targeting
RUG
The influence of sex hormones in the development of
asthma
17-06-2014
Prof. J. Vestbo
University of
Manchester
UK
Biomarkers in COPD – ECLIPSE and epidemiology
40
Date
Speaker
02-09-2014
Prof. I. Sabroe
University of Sheffield
UK
Title
Mechanisms of airway inflammation
23-09-2014
Prof. T. Sigsgaard
Institute of
Environmental and
Occupational Medicine
Aarhus University,
Denmark
Health, exposure and genetics in young Danish
farmers: 15 years of follow up on asthma and allergy
07-10-2014
Dr. G.A. Lockett
University of
Southampton
UK
Genetics and epigenetics of allergy
04-11-2014
M. Nieuwenhuis
Pulmonology
UMCG
Genetics of asthma and its phenotypes:
hyperresponsiveness, severity and remission
18-11-2014
A. Kruis
Public Health and
Primary Care
LUMC
The effectiveness of integrated disease management
in COPD patients
02-12-2014
Dr. P. Wijkstra & Prof.
D.S. Postma
Respiratory insufficiency
& Pulmonology
UMCG
The link between NRS, National roadmap lung
research and GRIAC
16-12-2014
Prof. D. Heederick
IRAS
University of Utrecht
What are health effects from living near livestock
producing industries: a Dutch experience
19-12-2014
Dr. J. Burgess
Woolcock Institute of
Medical Research
Sydney, Australia
Unravelling the contributions of the extracellular matrix
to airway remodelling in asthma
41
Research meetings 2014 - presentations
Date
Speaker
Title
07-01-2014
Laura Hesse
Medical Biology,
Experimental
Pulmonology and
Inflammation Research
Vitamin D as adjuvant in a therapeutic vaccine for
allergic asthma
14-01-2014
Karin Klooster
Pulmonology
Lung volume reduction coil treatment in COPD
patients with homogeneous emphysema reduces
hyperinflation and airway resistance
21-01-2014
Gerard Koppelman
Pediatric Pulmonology
GRIAC-chair
Introduction to GWAS and array analysis
28-01-2014
Jun Jun Cao
Pathology
Effect of maternal smoking during pregnancy on
airway epithelial differentiation in 1-day-old pups
04-02-2014
Loes Kistemaker
Molecular
Pharmacology
A regulatory role for the muscarinic M3 receptor in
airway inflammation and remodelling
18-02-2014
Nicole Dijk
TRPA1 in asthmatic children, a replication study in
PIAMA
25-02-2014
Maartje Nieuwenhuis
Pulmonology
Genetic interaction between ATP2A2 and ORMDL3, a
calcium handling origin of asthma
04-03-2014
Eline van Dijk
Molecular
Pharmacology
WNT-5B: role in inflammation, repair and interaction
with oxidative stress in pulmonary fibroblasts
11-03-2014
Vijay Rajendran
Pathology
Role of microRNAs in regulating the pulmonary
fibroblasts function in COPD
18-03-2014
Corry-Anke Brandsma
Pathology
Introduction to basic laboratory techniques
25-03-2014
Emmanuel Osei
Pathology & Medical
Biology
Crosstalk between epithelium and fibroblasts;
implications for COPD
01-04-2014
Karolin Meijer
Pathology
Prenatal programming by maternal smoking during
pregnancy
08-04-2014
Ilse Boudewijn
Pulmonology
CT-scan identified pulmonary changes with smoking
and aging in healthy smokers and never-smokers
42
Date
Speaker
Title
15-04-2014
Grissel Faura Tellez
& Medical Biology,
Experimental
Pulmonology and
Protocadherin-1: and the challenge of not getting
fooled
22-04-2014
Irene Heijink
Medical Biology,
Experimental
Pulmonology and
&
Reinoud Gosens
Molecular
Pharmacology
Pro-Con discussion: Lung repair in COPD is
feasible/not feasible
27-05-2014
Anita Spanjer
Molecular
Pharmacology
The role of the Frizzled-8 receptor in COPD patients
with chronic mucus hypersecretion
03-06-2014
Jan Willem Kocks
General Practice
How to prepare a GRIAC poster
10-06-2014
Juan Song
Pathology
Epigenetic reprogramming of mucin synthesis in
primary airway epithelial cells
17-06-2014
Tim Koopmans
Molecular
Pharmacology
WNT-5A modulates mitochondrial calcium handling in
airway smooth muscle
16-09-2014
Maaike de Vries
Medical Biology,
Experimental
Pulmonology and
Pim1 kinase, a new therapeutic target in virus-induced
asthma exacerbations
23-09-2014
Néomi Grotenboer
& Medical Biology,
Experimental
Pulmonology and
Role of asthma susceptibility gene IL1RL1 in TLR
signaling
30-09-2014
Christina Draijer
Pharmacokinetics,
Toxicology and
Targeting
Two faces of M2 macrophages in asthma
07-10-2014
Maartje Nieuwenhuis
Pulmonology
GWAS, lung eQTLs and asthma phenotypes
43
Date
Speaker
Title
14-10-2014
Grietje de Vries
Pulmonology
Heart failure and sleep apnea
21-10-2014
David Wright
Molecular
Pharmacology
The role of laminins in modulating ASM phenotype
04-11-2014
Daan Pouwels
Medical Biology,
Experimental
Pulmonology and
Increased serum levels of the RAGE-activating
DAMPs LL37, HMGB1 and S100A9 during
exacerbation in COPD patients
11-11-2014
Laura Hesse
Medical Biology,
Experimental
Pulmonology and
Vitamin D as an adjuvants in a specific immunotherapy
for allergic asthma
18-11-2014
Dirkje Postma
Pulmonology
The Dutch hypothesis
25-11-2014
Wilfred Poppinga
Molecular
Pharmacology
Cyclic AMP compartmentalization in obstructive
pulmonary disease
02-12-2014
Ilse Boudewijn
Pulmonology
Genome-wide nasal gene expression in COPD
44
Brainstorm sessions 2014
Date
Initiator
Subject
28-01-2014
Dr. D. Wright
Molecular
Pharmacology
RUG
Lung Fund project on the regulation of inflammatory
cell recruitment to the lung by extracellular matrix
proteins, such as laminins
11-03-2014
Prof. Dr. D.S. Postma
Pulmonology
UMCG
Bronchial hyperresponsiveness (for an ERC grant
application)
22-04-2014
Dr. B. Melgert
Pharmacokinetics,
Toxicology and
Targeting UMCG
New targets for COPD
23-09-2014
Dr. J.M. Vonk
Epidemiology
UMCG
Comorbidities in COPD
28-10-2014
Dr. I. Heijink & Dr. M.
Nawijn
Medical Biology,
Experimental
Pulmonology and
UMCG
Next generation epithelial cell culture: organoids and
3D cell culture models
45
Research projects in 2014
Aeris Medical, USA. A randomized Controlled Multi-center Trial of the AeriSeal® System in
Patients with Advanced Emphysema: ASPIRE-trial, FDA-IDE RCT, Aeris USA. 2012-2018,
Dr. D.J. Slebos.
Almirall educational grant: Self-reported side effects of inhaled corticosteroids in patients with
COPD, an educational project focusing on feasibility and benefits. 2012-2015. Dr. C. de
Jong, Prof.dr. T. van der Molen.
AstraZeneca: The risk to develop pneumonia in COPD: Comparing the effects of fluticasone
propionate and budesonide on airway epithelial barrier function. 2011-2014. Dr. I.H. Heijink,
Dr. M. van den Berge, Dr. N.H.T. ten Hacken, Prof.dr. W. Timens, Prof.dr. A.J.M. van
Oosterhout, Prof.dr. D.S. Postma
AstraZeneca; Health status guided-COPD care; the MARCH study. 2008-2016. Prof.dr. T.
van der Molen, Prof.dr. H.A.M. Kerstjens. Res. Fellows: Dr. J.W.H. Kocks, Dr. C. de Jong.
AstraZeneca; Evaluation of unexplained exercise induced dyspnea in mild to moderate
COPD. 2008-2014. Prof.dr. T. van der Molen, Prof.dr. H.A.M. Kerstjens, Dr. L.H. Steenhuis.
Res. Fellow: J.S. Vroegop.
AstraZeneca; CARAT; identifying cutoff values. 2014-2016. Prof.dr. T. van der Molen, Dr.
BMJ Flokstra – de Blok, Dr. C. de Jong.
Boehringer Ingelheim International GmbH:, Evaluation of the anti-inflammatory and antiremodeling effects of the novel ultralong-acting 2-agonist olodaterol, alone and in concerted
action with tiotropium, in an animal model of COPD. 2012-2014. Prof.dr. H. Meurs, Dr. R.
Gosens, Dr. H .Maarsingh. Junior Research Fellow: M. Smit.
Boehringer Ingelheim International GmbH: The protective effects of tiotropium: role of the
muscarinic M3 receptor. 2013-2015. Dr. R. Gosens. Research Fellow: L. Kistemaker
Boehringer Ingelheim International GmbH. A phase II/III randomised, double blind, placebocontrolled, parallel group trial to evaluate safety and efficacy of tiotropium inhalation solution
(2.5 mcg and 5 mcg) administered once daily in the afternoon via respimat inhaler for 12
weeks in patients 1 to 5 years old with persistent asthma. 2012-2015. Dr. E.J.L.E. Vrijlandt,
Dr. B.W.M. Willemse, M. van Smaalen
Brazil Science Without Borders: Targeting the histone acetyltransferases and
histondeacetylase balance in the inflammatory lung diseases asthma and COPD. 2012-2015.
Prof.dr. M. Schmidt. Sandwich PhD student: E. Kennedy Feitosa, post-doc: vacancy
CAPES/NUFFIC (Edital 68/2013): Activation of nuclear factor (erythroid=derived 2)-like 2
(Nrf2) & antioxidant response element (ARE) as therapeutic target for tissue repair in chronic
degenerative lung disease. 2013-2017. Prof.dr. S. dos Santos; Prof.dr. L.C. de Moraes
Sobrino Porto; Prof.dr. M. Schmidt
Chiesi: FAIR studie: Role of small particle steroids and LABA in COPD. 2011-2014. Dr. M.
van den Berge, Dr. N.H.T. ten Hacken, Prof.dr. D.S. Postma. PhD student: E van der Wiel
Chiesi: the role of small airways in asthma. Development of the SADT questionnaire. 20112016. Prof.dr. T. van der Molen, Prof.dr. D.S. Postma, Dr. M. van den Berge.
46
Chiesi: CHF-5843, a novel long-acting anticholinergic, alone and in concerted action with
CHF-6001, a PDE inhibitor, in a guinea pig model of COPD. 2013-2014. Dr. R. Gosens,
Prof.dr. H. Meurs, Prof.dr. M. Schmidt. Postdoc: T.A. Oenema.
CSA Medical: Prospective Study of RejuvenAir™ System Radial Spray Cryotherapy to
Determine Safety and Histological Effect in the Lung. 2013-2014. Dr. DJ Slebos, K. Klooster.
European Community (KP7, Innovative Medicines Initiative). PROactive. Physical Activity as
a Crucial Patient Reported Outcome in COPD. 2009-2015. Prof.dr. M. Decramer, Prof.dr. T.
Troosters, Prof.dr. W. MacNee, Prof.dr. C. Roussos, Prof.dr. M Polkey, Dr. P. de Boer,
Prof.dr. T. van der Molen, Dr. S. Schokker, Dr. C. de Jong.
European Community (FP7); European Union MeDALL-mechanisms of the Development of
Allergy. 2010-2015. Prof.dr. D.S. Postma, Prof.dr. G.H. Koppelman, Prof.dr. C. Wijmenga.
Postdocs: Dr. M. Kerkhof, Dr. C. Xu, technician: S.A. Jankipersadsing, B. van Rijkom.
European Community (FP7); European Union MeDALL-mechanisms of the Development of
Allergy. 2010-2015. Dr. M.C. Nawijn, Prof.dr. G.H. Koppelman, Prof.dr. A van Oosterhout.
Technician:U. Brouwer.
Faculty of Mathematics and Natural Sciences. Macrophages in the pathogenesis of
pulmonary lung fibrosis and their potential as drug targets. 2011-2015. Dr. B.N. Melgert,
Prof.dr. K. Poelstra. PhD student: C.E. Boorsma.
European Union/COST action (European Cooperation in the field of Scientific and Technical
Research): Developmental Origins of Chronic Lung Disease. 2012-2016. Dr. M.N. Hylkema,
Dr. R. Gosens, Prof.dr. D.S. Postma
Goedebuure / Air Liquide: Cost-effectiveness of obstRuctivE Sleep apnea Therapy (REST
study): Comparison of MRA therapy versus CPAP therapy in moderate OSAS. 2011-2014.
Dr. P.J. Wijkstra , Prof.dr. H.A.M. Kerstjens. PhD-student: G de Vries
Groningen Graduate School of Science (Ubbo Emmius PhD-position); Key role of A-kinase
anchoring proteins in the pathophysiology of asthma. 2011-2015. Prof.dr. M. Schmidt, Dr. H.
Maarsingh. PhD-student: B. Han.
GSK/IVAX/MSD/NAF (3.4.04.013) Stichting Astma Bestrijding; Predictive factors in children
aged 1- 5 years with recurrent respiratory symptoms for the development of asthma at the
age of 6-10 years. 2005-2014. Prof.dr. E.J. Duiverman, Prof.dr. T. van der Molen. Post-doc:
Dr. S. Schokker.
GSK/Unlock. Health economics of COPD. 2011-2015. Prof.dr. M.J. Postma, Prof.dr. T van
der Molen, Dr. M. Roman (Mallorca). PhD student: J. van Boven
GSMS: An old dilemma: Asthma with irreversible airway obstruction or COPD? 2009-2014.
Dr. N.H.T. ten Hacken, Dr. M.N. Hylkema, Prof.dr. W. Timens and Prof.dr. D.S. Postma. PhD
student: F. Fattahi.
GSMS/Joint project University of Southampton: Unravelling the protective role of Pim kinases
in airways diseases. 2011-2014. Dr. M.C. Nawijn Prof.dr. D.E. Davies. PhD student: M. de
Vries
47
GSMS/Joint project University of Southampton: Functional characterisation of PCDH1, a
novel gene for asthma and bronchial hyperresponsiveness. 2011-2015. Prof.dr. G.H.
Koppelman, Prof.dr. J. Holloway, Dr. M.C. Nawijn, Dr. B.M. Willemse. PhD student: G. Faura
Tellez
GSMS/ Shantou University Medical College, China (Abel Tasman bursaal). Effect of toxic
exposures during pregnancy on fetal immune and lung development. 2012-2016. Dr. M.N.
Hylkema, Prof.dr. X. Huo. PhD student: J.J. Cao
GSMS/Shantou University Medical College. Genes, environment and respiratory health
2011-2015. Prof.dr. H. M. Boezen. PhD Student: X. Zeng
GSMS/TianJin Medical University. Maternal smoking during pregnancy: Aberrant epigenetic
regulation of genes involved in lung development, ageing and repair. 2013-2016. Dr. M.N.
Hylkema, Prof.dr. M. Rots. PhD student: J. Song
GSMS-UBC: Dysfunctional crosstalk between epithelial cells and fibroblasts contributes to
abnormal tissue repair and remodeling processes in COPD. 2013-2017. Dr. C.A. Brandsma,
Dr. I.H. Heijink, Prof.dr. W. Timens, Prof.dr. D.S. Postma, Dr. T.L. Hackett, Dr. S.
Wadsworth. PhD student: E. Osei
Holaira, USA: Evaluation of the Innovative Pulmonary Solutions System for Targeted Lung
Denervation Therapy in patients with moderate to severe COPD, “IPS-1”. 2011-2014. Dr.
D.J. Slebos.
Holaira, USA: A Sequential Two Phase Multicenter, Randomized Study to Optimize Dose
Selection and Evaluate Safety After Treatment with the Holaira™ Lung Denervation System
in Patients with Moderate to Severe COPD, 2014-2018 The AIRFLOW-1 trial. Dr DJ Slebos,
Dr J Hartman, K. Klooster.
International Primary Care Respiratory Group. UNLOCK: Uncovering and Noting Long-term
Outcomes in COPD to enhance Knowledge. 2010-2016. Dr. N. Chavannes, Dr. I. Tsiligianni,
Prof.dr. D. Price, Prof.dr. T. van der Molen.
IPCRG: The I-HARP SERVICE: international, cross-sectional evaluation of inhaler technique
and associated predictors of asthma control in patients receiving fixed dose combination
inhaled corticosteroid / long-acting beta2-agonist therapy in general practice. 2011-2014.
Prof.dr. D. Price, Prof.dr. T. van der Molen, E.C.M. van Heijst.
IPCRG: Fresh Air: prevalence and burden of COPD in a rural area of sub-Saharan Africa.
2010-2016. Prof.dr. T. van der Molen, Dr. N.H. Chavannes, Dr. C. de Jong. PhD student:
F.A. van Gemert
IPCRG: Fresh Air: Biomass fuel induced COPD, prevalence and pathophysiology. 20102016. Prof.dr. T. van der Molen, Dr. C. de Jong. PhD student: BJ. Kirenga
IPCRG: Does the use of inhaled corticosteroids reduce diabetic control in patients with
concomitant COPD and Diabetes: an international primary care cohort study. 2014-2016. Dr.
J.W.H. Kocks, Prof.dr. T van der Molen, Prof.dr. D. Price.
Longfonds/ZonMW/Boston Scientific: Unraveling Targets of Therapy in Bronchial
Thermoplasty
in
Severe
Asthma:
TASMA
Study,
Multicenter
trial
(AMC/London/Heidelberg/UMCG). 2014-2016. UMCG: Dr. D.J. Slebos, Dr. N.H.T. Ten
Hacken
48
MD/PhD: Voedselallergie, een cross-cultureel vergelijk: kwaliteit van leven, socioeconomische impact, kennisniveau van patiënten en huisartsen. 2010 - 2014. Prof.dr. A.E.J.
Dubois, Prof.dr. E.J. Duiverman, Prof.dr. T. van der Molen, Dr. B.M.J. Flokstra-de Blok.
MD/PhD student: N.J. Goossens.
MD/PhD/ALK: Epinephrine auto-injector prescription, compliance and quality of life. 2011 –
2016. Prof.dr. A.E.J. Dubois, Dr. B.M.J. Flokstra-de Blok. MD/PhD student: J. SalehLangenberg
MD/PhD: COPD in primary care and pulmonary rehabilitation: discovering the dynamics of
the Minimal Clinically Important Difference (MCID) 2014-2018. Prof.dr. T van der Molen, Dr.
C. de Jong. PhD student: H.J. Alma
MD/PhD: Insensitivity to glucocorticosteroid treatment in obstructive pulmonary diseases.
2009-2014. Dr. N.H.T. ten Hacken, Prof.dr. A.J.M. van Oosterhout, Dr. I.H. Heijink. MD/PhD
student: J. Zijlstra
MD/PhD: Translating asthma associated genetic variation in IL33 and IL1RL1 into
pathophysiology and clinical expression of asthma. 2013 – 2017. Prof.dr. G.H. Koppelman
and Dr. M.C. Nawijn. MD/PhD student: M. Ketelaar
MD/PhD. Genetics of food allergy. 2013-2018. Prof.dr. A.E.J. Dubois, Prof.dr. G.H.
Koppelman. MD/PhD student: C.D. van Ginkel
MD/PhD: Diagnosis, treatment and risk factors for therapy failure of Hymenoptera venom
allergy. 2012-2016. Prof.dr. A.E.J. Dubois, Dr. J.N.G. Oude Elberink. PhD-student: B.J.P.R
Vos
NAF 08.014: The role of acetylcholine in chronic inflammation and remodelling in asthma and
COPD. 2010-2014. Dr. R. Gosens, Prof.dr. H.A.M. Kerstjens, Prof.dr. P.S. Hiemstra. PhD
student: L.E.M. Kistemaker.
NAF 3.2.10.042. Wnt/Frizzled signalling in small airway remodelling in COPD. 2010-2015.
Dr. R. Gosens, Dr. H.I. Heijink, Dr. W.M. Blankesteijn. PhD student: A.I.R. Spanjer.
NAF 3.4.06.044: The effect of chronic non–invasive ventilation at home after treatment of
acute respiratory failure in hypercapnic COPD patients. 2007-2014. Dr. P.J. Wijkstra,
Prof.dr.H.A.M. Kerstjens. PhD student: F.M. Struik; research nurse: G. Bladder
NAF, special grant for translational research in Pediatric Pulmonology: Asthma phenotypes.
2009-2015. Prof.dr. G.H. Koppelman, Prof.dr. J.C. de Jongste. PhD students: N.S.
Grotenboer, F.N. Dijk
NAF 3.2.09.055: Protocadherin-1 expression in airway epithelium: Investigations into a novel
cause of bronchial hyperresponsiveness and asthma. 2009-2016. Prof.dr. G.H. Koppelman,
Dr. M.C. Nawijn, Prof.dr. D.S. Postma.
NAF 3.2.09.034: The novel cAMP effector Epac: new avenues in the treatment of
inflammation, tissue remodelling and airway narrowing in COPD. 2009-2014. Prof.dr. M.
Schmidt, Prof.dr. W. Timens, Prof.dr. H. Meurs. PhD student: A. Oldenburger.
NAF 3.2.09.036: Th17 responses in asthma: Protection against atopy versus development of
non-allergic asthma. 2010-2014. Dr. M.N.Hylkema, Dr. I. Wouters. PhD student: P. Robbe.
49
NAF 3.2.09.031. The role of alternatively activated macrophages in the pathogenesis of
asthma. 2011-2015. Dr. B.N. Melgert, Dr. M.N. Hylkema, Prof.dr. K. Poelstra. PhD student C.
Draijer.
NAF 3.2.11.015: A-kinase anchoring proteins as novel drug targets in the development and
progression of airway obstruction in COPD. 2011-2015. Prof.dr. M. Schmidt, Dr. H.
Maarsingh, Dr. H.I. Heijink. PhD-student: W. Poppinga.
NAF 3.2.10.060: Vitamin D3 as adjuvant in a therapeutic vaccine for allergic asthma. 20112015. Prof.dr. A.J.M. van Oosterhout, Dr. J.H.N. Oude Elberink, Dr. M.C. Nawijn. PhDstudent: L. Hesse.
NAF 3.2.11.025: Epithelial cells alarming the immune system in COPD – at the root of COPD
susceptibility? 2011-2015. Dr. M.C. Nawijn, Dr. N.H.T. ten Hacken, Prof.dr. A.J. van
Oosterhout, Dr. I.H. Heijink. PhD-student: S.D. Pouwels.
NAF 3.2.11.024: Abnormal tissue repair and remodeling in COPD; from genomics to
biological function. 2011-2014. Dr. C.A. Brandsma, Dr. M. van den Berge, Prof.dr. W.
Timens. Post-doc: C.A. Brandsma, technician: S. Brouwer
NAF 3.2.12.044: The functional relevance of microRNAs in COPD; elucidating their role in
regulating pulmonary fibroblast function in COPD development. 2012-2016. Dr. C.A.
Brandsma, Prof.dr. W. Timens, Prof.dr. DS Postma. PhD-student: V. Rajendran, J. Ong
NAF 3.2.12.083: Follistatin-like 1, a crucial factor in lung development, as a novel regulator in
COPD. 2012-2017. Dr. H. Maarsingh, Dr. M. van den Hoff, Prof.dr. M. Schmidt. PhD student:
N.P. Tania
NAF 3.2.12.079: Laminin α4 and α5 as regulators of airway inflammation and remodelling in
allergic asthma. 2013-2016. Dr. B.G.J. Dekkers, Prof.dr. L.M. Sorokin, Prof.dr. H. Meurs.
Post-doc: Dr. D.B. Wright
NAF 3.2.11.013: Prenatal programming by maternal smoking during pregnancy: susceptibility
for development of COPD. 2012-2016. Dr. M.N. Hylkema, Prof.dr. L. Kobzik. PhD student:
K. Meyer
Netherlands Lung Foundation 4.1.13.007. Genes and exposures underlying COPD onset.
2013 – 2016. Nederlands Longfonds consortium project in collaboration with Erasmus
Medical Center. Prof.dr. H.M. Boezen, Prof.dr. C.M. van Duijn, Dr. C.C. van Diemen, Prof.dr.
D.S. Postma. Postdoc: Dr. K. de Jong. PhD students: D. van der Plaat, I. Nedeljković
Netherlands Lung Foundation 1.14.001. Prevention of epigenetic programming of asthma.
2014 – 2018. Nederlands Longfonds consortium project in collaboration with University of
Utrecht and RIVM. Prof. dr. G.H. Koppelman, Dr. U. Gehring, Prof. dr. H. A. Smit, Dr. A.
Wijga.
Netherlands Lung Foundation 5.1.14.020 Identifying causal mechanisms of the inception of
asthma through a novel experimental model for the interaction on the PCDH1 gene and
environment. 2014 – 2017. Nederlands Longfonds consortium project in collaboration with
University of Utrecht and University of Ghent. Dr. M. Nawijn, Prof. dr. G.H. Koppelman, Prof.
dr. L. Bont , Prof. dr. B. Lambrecht
Netherlands Lung Foundation 6.1.14.009: Tissue repair in COPD: WNT you get it right?
2014-2018. Dr. R. Gosens, Dr. J. Stolk, Dr. M. Königshoff. Postdoc: Dr. J-P Ng-Blichfeldt (as
of 01-03-2015); 1 post-doc vacancy.
50
Northern CARA Foundation: Characterization of macrophage subsets in airways of patients
with COPD and their controls. 2014-2015. Dr. B.N. Melgert, C.E. Boorsma
Northern CARA Foundation: Characterization of macrophage subsets in airway biopsies of
healthy controls. 2014-2015. Dr. B.N. Melgert, C. Draijer
Novartis: Effects of (combinations of) beta-adrenoceptor agonists and muscarinic receptor
antagonists on intrapulmonary airway constriction. 2012-2014. Dr. H. Maarsingh, Prof.dr. M.
Schmidt. Post-doc: Dr. R. Sopi
Nycomed; Development of the Clinical Short-form Inhaled Corticosteroid Questionnaire
Scale. 2008-2014. Prof.dr. T. van der Molen, Prof.dr. R. Sanderman, Prof.dr. D.S. Postma.
Post-doc: J.M. Foster.
Pender Foundation for Pulmonary Fibrosis: Exchange of fresh human lung tissue of patients
transplanted for pulmonary fibrosis between RUG/UMCG (Groningen) and Erasmus MC
(Rotterdam). 2014-2018. Dr. B.N. Melgert, Dr. B. van den Blink
Phadia; In vitro Diagnostiek en Eerstelijns Allergie Leidraad (IDEAL) 2009-2016. Prof.dr.
A.E.J. Dubois, Prof.dr. T. van der Molen, Dr. B.M.J. Flokstra-de Blok.
PneumRx, Inc. USA: Lung Volume Reduction Coil for Treatment in Patients with
Emphysema (RENEW) Study, FDA-IDE RCT, PneumRx, Inc. USA. 2012-2018. Dr. D.J.
Slebos, K. Klooster
PneumRx, Icc: The safety and feasibility of re-treating patients with severe emphysema with
the RePneu LVRC system: a pilot study (RECOIL study). 2014-2015. Dr. D.J. Slebos, K.
Klooster.
PulmonX Inc: A Multi-center, Prospective, Randomized, Controlled, one-way Crossover
Investigation of Endobronchial Valve Therapy vs Standard of Care in Homogeneous
Emphysema: IMPACT trial. 2014 – 2015. Dr D.J. Slebos, Dr N.H.T. Ten Hacken, Dr J.E.
Hartman, K. Klooster..
PulmonX Inc: Study of proactive treatment of collateral ventilation in CV-positive emphysema
patients before EBV treatment: “MIND THE GAP”. 2014-2016. Dr D.J. Slebos, Dr J.E.
Hartman, K. Klooster.
RESMED : SERVE-HF; The SERVE-HF trial is investigating the value of adaptive servoventilation (ASV) to improve morbidity and mortality rates in heart failure patients with
predominant central sleep apnoea. 2012-2014. Dr. P.J. Wijkstra , Prof.dr. H.A.M. Kerstjens.
PhD-student: G de Vries.
Rosetta Inpharmatics ; LKR57970: Identification of key mechanistic drivers of lung disease.
2009-2014. Prof.dr. W. Timens, Prof.dr. D.S. Postma. (Lung eQTL Study, together with
University of British Columbia, Vancouver (P. Pare) and Hospital Laval, Quebec (Y. Bosse)).
SBOH: Improving COPD care by optimising inhalation technique in elderly. 2012-2014. Dr.
J.W.H. Kocks, Prof.dr. T. van der Molen. Researcher: M. Dijkstra.
SMF; Remission and progression of asthma: genetic and epigenetic regulation. 2012-2015.
Prof.dr. D.S. Postma, Prof.dr. G.H. Koppelman, Dr. J.M. Vonk. PhD student: M.A.E.
Nieuwenhuis.
51
STW Improvement of Diagnostic mEthods for ALlergy assessment. Cashew allergy in
children as a showcase (IDEAL/ORCA study). 2012-2016. Prof.dr. A.E.J. Dubois, Dr. B.M.J.
Flokstra-de Blok. technician: A. Oomkes-Pilon
STW Open Technology Programme: Design, synthesis and validation of potent and isozyme
selective arginase inhibitors for therapeutic use in asthma. 2014-2020. Prof. dr. A.S.S.
Dömling, Prof. dr. H. Meurs, Prof. dr. P.H. Elsinga, 2 PhD students, 1 postdoc: vacancies
Top Instituut Pharma 1-108; Groningen, Utrecht; Acute and chronic inflammatory responses
induced by smoking in individuals susceptible and non-susceptible for development of
COPD: from complex disease phenotype toward novel tailor-made therapy. 2008-2014.
Prof.dr. D.S. Postma, Prof.dr. L. Koenderman, Prof.dr. J.W.J. Lammers, Dr. N.H.T. ten
Hacken, Dr. P. Zanen, Dr. R. Schweizer, Prof.dr. R.P.H. Bischoff. Technicians; J. van der
Leij, M. Lodewijk, T. Bijma, S. Brouwer. PhD students: S.J.M. Hoonhorst, L. Franciosi.
Research nurse. R.G.A. Hiltermann-Tilanus.
Top Instituut Pharma 1-201; Groningen, Maastricht, Utrecht; Transition of systemic
inflammation into multiorgan pathology. 2008-2014. Prof.dr. A.M.W.J. Schols, Prof.dr. E.F.M.
Wouters, Prof.dr. W. Buurman, Prof.dr. W. Lamers, Dr. E. Blaak, Dr. R. Langen, Dr. H.
Gosker, Prof.dr. L. Koenderman, Prof.dr J.W.J. Lammers, Dr. L. Ulfman, Prof.dr. D.S.
Postma. PhD student: R.F. Hoffmann, Technician: S.M. Brandenburg.
University of Groningen. The role of Wnt signaling in airway smooth muscle remodeling in
asthma. 2010-2014. Dr. R. Gosens. PhD student: K. Kumawat
University of Groningen. Macrophages in the pathogenesis of pulmonary lung fibrosis and
COPD and their potential as drug targets. 2011-2015. Dr. B.N. Melgert. PhD student: C.E.
Boorsma
University of Groningen. Application of eHealth to improve care for asthma and COPD
patients in primary care: from focus groups to data mining. 2012-2016. Prof.dr. T. van der
Molen, Prof.dr. R. Sanderman. PhD student: E.I. Metting
University Medical Center Groningen (Innovative research): “A structured life style
intervention on enhancement of daily physical activity and physical fitness in COPD patients
in the first, second, and third line. 2006-2014. Dr. N.H.T. ten Hacken, Dr. M.H. de Greef, Dr.
J.B. Wempe. PhD-student: W. Altenburg.
University Medical Center Groningen (doelmatigheidsonderzoek): Feasibility of an allergy
service in primary care. 2013-2015. Dr. B.M. Flokstra-de Blok. Prof.dr. A.E.J. Dubois, Prof.dr.
T. van der Molen, Dr. J.N.G. Oude Elberink, Dr. M.L.A. Schuttelaar, Prof.dr. P.J. Coenraads.
University Medical Center Groningen / GSK NL: Phenotyping airways disease by cluster
analysis in primary care. 2013-2014. Dr. J.W.H. Kocks, Prof.dr. T. van der Molen, Prof.dr. R.
Beasley, Prof.dr. M. Weatherall
ZonMW 016.126.307: On the origins of airway smooth muscle thickening in asthma. Vidiaward. 2012-2017. Dr. R. Gosens. PhD students: T. Koopmans, E. van Dijk. Technician: M.
Menzen
ZonMW 80-82305-97-11018. A randomized controlled trial to evaluate the performance of
bronchoscopic lungvolume reduction for patients with severe COPD using the best
responder criteria (STELVIO trial). 2010-2014. Dr. D.J. Slebos. Dr. N.H.T. ten Hacken. PhDstudent: K. Klooster
52
ZonMW 837002501. Initiation of HOme MEchanical ventilation at home in patients with
chronic hypercapnic Respiratory failUre in the Netherlands (HOMERUN). 2014-2018. Dr. P.J.
Wijkstra, Prof.dr. H.A.M. Kerstjens. PhD-student: R. van den Biggelaar
Zorggroep Zwolle: Development of patient satisfaction with care questionnaire and validation
of HowRu & HowRwe questionnaires. 2012-2015. Dr. J.W.H. Kocks, Prof.dr. H.J.G. Bilo, Dr.
M.H. Blanker. Student researcher: J. Rutgers.
Also a substantial contribution for several projects has been obtained from the Stichting
Astma Bestrijding (SAB).
53
Publications 2014
Dissertations
O.E.M. Savenije
Origins of asthma in childhood: an approach by longitudinal wheezing phenotypes
13-01-2014
Promotores: Prof. Dr. D.S. Postma, Prof. Dr. G.H. Koppelman
Copromotor: Dr. M. Kerkhof
D. Ierodiakonou
Genetic and environmental interplay in asthma severity and its underlying airway pathology
03-03-2014
Promotores: Prof. Dr. D.S. Postma, Prof. Dr. H.M. Boezen, Prof. Dr. G.H. Koppelman
Copromotor: Dr. J.M. Vonk
S.M. Figarska
Genetics of healthy aging
26-05-2014
Promotor: Prof. Dr. H.M. Boezen
A.E. Dijkstra
Chronic mucus hypersecretion and airway wall structure: genes and environment
17-06-2014
Promotores: Prof. Dr. D.S. Postma, Prof. Dr. H.J.M. Groen, Prof. Dr. H.M. Boezen
N.J. Goossens
Health-related quality of life in food allergic patients - Beyond Borders.
30-06-2014
Promotores: Prof. Dr. A.E.J. Dubois, Prof. Dr. E.J. Duiverman, Prof. Dr. T. van der Molen
Copromotor: Dr. B.M.J. Flokstra – de Blok
K. de Jong
Genes and environment underlying lung health
22-09-2014
Promotores: Prof. Dr. H.M. Boezen, Prof. Dr. D.S. Postma
A. Oldenburger
New avenues for EPAC in inflammation and tissue remodeling in COPD
31-10-2014
Promotores: Prof. Dr. M. Schmidt, Prof. Dr. W. Timens, Prof. Dr. H. Meurs, Prof. Dr. H.
Maarsingh
S.J.M. Hoonhorst
COPD: Recognizing the susceptible smoker.
10-12-2014
Promotor: Prof. Dr. D.S. Postma
Copromotor: Dr. N.T.H. ten Hacken
54
Publications SCI journals
Akhabir L, Bérubé JC, Bossé Y, Laviolette M, Hao K, Nickle DC, Timens W, Sin DD, Paré
PD, Postma DS, Sandford AJ. Lung expression quantitative trait loci data set identifies
important functional polymorphisms in the asthma-associated IL1RL1 region. J Allergy Clin
Immunol. 2014;34(3):729-731.
Alkhouri H, Poppinga WJ, Tania NP, Ammit A, Schuliga M. Regulation of pulmonary
inflammation by mesenchymal cells. Pulm Pharmacol Ther 2014;29:156-165.
van Anrooij B, Kluin PM, Oude Elberink JN, Kluin-Nelemans JC. CD30 in systemic
mastocytosis. Immunol Allergy Clin North Am. 2014;34(2):341-355.
Baker KE, Bonvini SJ, Donovan C, Foong RE, Han B, Jha A, Shaifta Y, Smit M, Johnson JR,
Moir LM. Novel drug targets for asthma and COPD: lessons learned from in vitro and in vivo
models. Pulm Pharmacol Ther 2014;29:181-198.
Berge van den M, Steiling K, Timens W, Hiemstra PS, Sterk PJ, Heijink IH, Liu G, Alekseyev
YO, Lenburg ME, Spira A, Postma DS. Airway gene expression in COPD is dynamic with
inhaled corticosteroid treatment and reflects biological pathways associated with disease
activity. Thorax. 2014;69(1):14-23.
Berkhof FF, Hesselink AM, Vaessen DL, Uil SM, Kerstjens HA, van den Berg JW. The effect
of an outpatient care on-demand-system on health status and costs in patients with COPD. A
randomized trial. Respir Med 2014;108:1163-1170.
Berkhof FF, Metzemaekers L, Uil SM, Kerstjens HA, van den Berg JW. Health status in
patients with coexistent COPD and heart failure: a validation and comparison between the
Clinical COPD Questionnaire and the Minnesota Living with Heart Failure Questionnaire. Int
J Chron Obstruct Pulmon Dis 2014;9:999-1008.
Bertsias A, Tsiligianni IG, Duijker G, Siafakas N, Lionis C, Cretan CAP Research Group.
Studying the burden of community-acquired pneumonia in adults aged >/=50 years in
primary health care: an observational study in rural Crete, Greece. NPJ Prim Care Respir
Med 2014;24:14017.
Bidad K, Nawijn MC, van Oosterhout AJ, van der Heide S, Elberink JN. Basophil activation
test in the diagnosis and monitoring of mastocytosis patients with wasp venom allergy on
immunotherapy. Cytometry B Clin Cytom. 2014;86(3):183-190.
Biggelaar RJ van den, Kerstjens HA, de Jong WK. Hemoptysis and hydrocephalus. Follow
the lead. Am J Respir Crit Care Med 2014;189:e6.
Bjermer L, Alving K, Diamant Z, Magnussen H, Pavord I, Piacentini G, Price D, Roche N,
Sastre J, Thomas M, Usmani O. Current evidence and future research needs for FeNO
measurement in respiratory diseases. Respir Med 2014;108:830-841.
Boardman C, Chachi L, Gavrila A, Keenan CR, Perry MM, Xia YC, Meurs H, Sharma P.
Mechanisms of glucocorticoid action and insensitivity in airways disease. Pulm Pharmacol
Ther 2014;29:129-143.
55
Boorsma CE, Dekkers BG, van Dijk EM, Kumawat K, Richardson J, Burgess JK, John AE.
Beyond TGFbeta--novel ways to target airway and parenchymal fibrosis. Pulm Pharmacol
Ther 2014;29:166-180.
Bouma W, Klinkenberg TJ, Van De WC, Timens W, Mariani MA. Removal of a giant
intrathoracic cyst from the Anterior mediastinum. J Cardiothorac Surg 2014,9:152.
Boven van JF, Chavannes NH, van der Molen T, Rutten-van Molken MP, Postma MJ, Vegter
S. Clinical and economic impact of non-adherence in COPD: a systematic review. Respir
Med 2014;108:103-113.
Boven van JF, Stuurman-Bieze AG, Hiddink EG, Postma MJ, Vegter S. Medication
monitoring and optimization: a targeted pharmacist program for effective and cost-effective
improvement of chronic therapy adherence. J Manag Care Pharm 2014;20:786-792.
Boven van JF, Tommelein E, Boussery K, Mehuys E, Vegter S, Brusselle GG, Rutten-van
Molken MP, Postma MJ. Optimizing pharmacotherapy in patients with COPD by communitypharmacists: a cost-effectiveness analysis. J Pharm Belg 2014;(3):15-16.
Boven van JF, Tommelein E, Boussery K, Mehuys E, Vegter S, Brusselle GG, Rutten-van
Molken MP, Postma MJ. Improving inhaler adherence in patients with chronic obstructive
pulmonary disease: a cost-effectiveness analysis. Respir Res 2014;15:66.
Boven van JF, van Raaij JJ, van der Galien R, Postma MJ, van der Molen T, Dekhuijzen PN,
Vegter S. Impact of multiple-dose versus single-dose inhaler devices on COPD patients'
persistence with long-acting beta(2)-agonists: a dispensing database analysis. NPJ Prim
Care Respir Med 2014;24:14069.
Brusse-Keizer M, VanderValk P, Hendrix R, Kerstjens H, van der Palen J. Necessity of
amoxicillin clavulanic acid in addition to prednisolone in mild-to-moderate COPD
exacerbations. BMJ Open Respir Res 2014;1:e000052.
Burgess JK, Gosens R. Airway smooth muscle and fibroblast biology still a leading research
focus for young investigators in the field. Pulm Pharmacol Ther 2014;29:91-92.
Chen L, Ge Q, Tjin G, Alkhouri H, Deng L, Brandsma CA, Adcock I, Timens W, Postma D,
Burgess JK, Black JL, Oliver BG. Effects of cigarette smoke extract on human airway smooth
muscle cells in COPD. Eur Respir J. 2014;44(3):634-646.
Dale PR, Cernecka H, Schmidt M, Dowling MR, Charlton SJ, Pieper MP, Michel MC. The
pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor
agonists in the treatment of airway and bladder disease. Curr Opin Pharmacol 2014;16:3142.
Davis KJ, Landis SH, Oh YM, Mannino DM, Han MK, van der Molen T, Aisanov Z, Menezes
AM, Ichinose M, Muellerova H. Continuing to Confront COPD International Physician Survey:
physician knowledge and application of COPD management guidelines in 12 countries. Int J
Chron Obstruct Pulmon Dis 2014;10:39-55.
Deslee G, Klooster K, Hetzel M, Stanzel F, Kessler R, Marquette CH, Witt C, Blaas S,
Gesierich W, Herth FJ, Hetzel J, van Rikxoort EM, Slebos DJ. Lung volume reduction coil
treatment for patients with severe emphysema: a European multicentre trial. Thorax.
2014;69(11):980-986.
56
van Deursen VM, Damman K, van der Meer P, Wijkstra PJ, Luijckx GJ, van Beek A, van
Veldhuisen DJ, Voors AA. Co-morbidities in heart failure. Heart Fail Rev. 2014;19(2):163172.
Dhami S, Panesar SS, Roberts G, Muraro A, Worm M, Bilò MB, Cardona V, Dubois AE,
DunnGalvin A, Eigenmann P, Fernandez-Rivas M, Halken S, Lack G, Niggemann B, Rueff F,
Santos AF, Vlieg-Boerstra B, Zolkipli ZQ, Sheikh A; EAACI Food Allergy and Anaphylaxis
Guidelines Group. Management of anaphylaxis: a systematic review. Allergy.
2014;69(2):168-175.
Diamant Z, Clarke GW, Pieterse H, Gispert J. Disease models of chronic inflammatory
airway disease: applications and requirements for clinical trials. Curr Opin Pulm Med
2014;20:37-45.
Diamant Z, Sidharta PN, Singh D, O'Connor BJ, Zuiker R, Leaker BR, Silkey M, Dingemanse
J. Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in
allergic asthmatics. Clin Exp Allergy 2014;44:1044-1052.
Dickhoff C, Hartemink KJ, Slebos DJ, Symersky P, Vonk-Noordegraaf A. Extrathoracic proof
of intrathoracic trouble. Thorax. 2014;69(8):785.
Dijkstra AE, de Jong K, Boezen HM, Kromhout H, Vermeulen R, Groen HJ, Postma DS,
Vonk JM. Risk factors for chronic mucus hypersecretion in individuals with and without
COPD: influence of smoking and job exposure on CMH. Occup Environ Med.
2014;71(5):346-352.
Dijkstra AE, Smolonska J, van den Berge M, Wijmenga C, Zanen P, Luinge MA, Platteel M,
Lammers JW, Dahlback M, Tosh K, Hiemstra PS, Sterk PJ, Spira A, Vestbo J, Nordestgaard
BG, Benn M, Nielsen SF, Dahl M, Verschuren WM, Picavet HS, Smit HA, Owsijewitsch M,
Kauczor HU, de Koning HJ, Nizankowska-Mogilnicka E, Mejza F, Nastalek P, van Diemen
CC, Cho MH, Silverman EK, Crapo JD, Beaty TH, Lomas DA, Bakke P, Gulsvik A, Bossé Y,
Obeidat MA, Loth DW, Lahousse L, Rivadeneira F, Uitterlinden AG, Hofman A, Stricker BH,
Brusselle GG, van Duijn CM, Brouwer U, Koppelman GH, Vonk JM, Nawijn MC, Groen HJ,
Timens W, Boezen HM, Postma DS; LifeLines Cohort study. Susceptibility to chronic mucus
hypersecretion, a genome wide association study. PLoS One. 2014;9(4):e91621.
Dobbels F, de Jong C, Drost E, Elberse J, Feridou C, Jacobs L, Rabinovich R, Frei A, Puhan
MA, de Boer WI, van der Molen T, Williams K, Pinnock H, Troosters T, Karlsson N, Kulich K,
Rudell K, PROactive consortium, PROactive consortium. The PROactive innovative
conceptual framework on physical activity. Eur Respir J 2014;44:1223-1233.
Eeftens M, Hoek G, Gruzieva O, Mölter A, Agius R, Beelen R, Brunekreef B, Custovic A,
Cyrys J, Fuertes E, Heinrich J, Hoffmann B, de Hoogh K, Jedynska A, Keuken M, Klümper
C, Kooter I, Krämer U, Korek M, Koppelman GH, Kuhlbusch TA, Simpson A, Smit HA, Tsai
MY, Wang M, Wolf K, Pershagen G, Gehring U. Elemental composition of particulate matter
and the association with lung function. Epidemiology. 2014;25(5):648-657.
European Innovation Partnership on Active and Healthy Ageing, Action Plan B3,
Mechanisms of the Development of Allergy, WP 10, Global Alliance against Chronic
Respiratory Diseases, Bousquet J, Addis A, Adcock I, Agache I, Agusti A, Alonso A, AnnesiMaesano I, Anto JM, Bachert C, Baena-Cagnani CE, Bai C, Baigenzhin A, Barbara C,
Barnes PJ, Bateman ED, Beck L, Bedbrook A, Bel EH, Benezet O, Bennoor KS, Benson M,
Bernabeu-Wittel M, Bewick M, Bindslev-Jensen C, Blain H, Blasi F, Bonini M, Bonini S,
Boulet LP, Bourdin A, Bourret R, Bousquet PJ, Brightling CE, Briggs A, Brozek J, Buhl R,
Bush A, Caimmi D, Calderon M, Calverley P, Camargos PA, Camuzat T, Canonica GW,
57
Carlsen KH, Casale TB, Cazzola M, Cepeda Sarabia AM, Cesario A, Chen YZ, Chkhartishvili
E, Chavannes NH, Chiron R, Chuchalin A, Chung KF, Cox L, Crooks G, Crooks MG, Cruz
AA, Custovic A, Dahl R, Dahlen SE, De Blay F, Dedeu T, Deleanu D, Demoly P, Devillier P,
Didier A, Dinh-Xuan AT, Djukanovic R, Dokic D, Douagui H, Dubakiene R, Eglin S, Elliot F,
Emuzyte R, Fabbri L, Fink Wagner A, Fletcher M, Fokkens WJ, Fonseca J, Franco A, Frith P,
Furber A, Gaga M, Garces J, Garcia-Aymerich J, Gamkrelidze A, Gonzales-Diaz S, Gouzi F,
Guzman MA, Haahtela T, Harrison D, Hayot M, Heaney LG, Heinrich J, Hellings PW, Hooper
J, Humbert M, Hyland M, Iaccarino G, Jakovenko D, Jardim JR, Jeandel C, Jenkins C,
Johnston SL, Jonquet O, Joos G, Jung KS, Kalayci O, Karunanithi S, Keil T, Khaltaev N,
Kolek V, Kowalski ML, Kull I, Kuna P, Kvedariene V, Le LT, Lodrup Carlsen KC, Louis R,
MacNee W, Mair A, Majer I, Manning P, de Manuel Keenoy E, Masjedi MR, Melen E, MeloGomes E, Menzies-Gow A, Mercier G, Mercier J, Michel JP, Miculinic N, Mihaltan F,
Milenkovic B, Molimard M, Momas I, Montilla-Santana A, Morais-Almeida M, Morgan M,
N'Diaye M, Nafti S, Nekam K, Neou A, Nicod L, O'Hehir R, Ohta K, Paggiaro P, Palkonen S,
Palmer S, Papadopoulos NG, Papi A, Passalacqua G, Pavord I, Pigearias B, Plavec D,
Postma DS, Price D, Rabe KF, Radier Pontal F, Redon J, Rennard S, Roberts J, Robine JM,
Roca J, Roche N, Rodenas F, Roggeri A, Rolland C, Rosado-Pinto J, Ryan D, Samolinski B,
Sanchez-Borges M, Schunemann HJ, Sheikh A, Shields M, Siafakas N, Sibille Y, Similowski
T, Small I, Sola-Morales O, Sooronbaev T, Stelmach R, Sterk PJ, Stiris T, Sud P, Tellier V,
To T, Todo-Bom A, Triggiani M, Valenta R, Valero AL, Valiulis A, Valovirta E, Van Ganse E,
Vandenplas O, Vasankari T, Vestbo J, Vezzani G, Viegi G, Visier L, Vogelmeier C,
Vontetsianos T, Wagstaff R, Wahn U, Wallaert B, Whalley B, Wickman M, Williams DM,
Wilson N, Yawn BP, Yiallouros PK, Yorgancioglu A, Yusuf OM, Zar HJ, Zhong N, Zidarn M,
Zuberbier T. Integrated care pathways for airway diseases (AIRWAYS-ICPs). Eur Respir J
2014;44:304-323.
Faura Tellez G, Nawijn MC, Koppelman GH. Protocadherin-1: epithelial barrier dysfunction in
asthma and eczema. Eur Respir J. 2014;43(3):671-674.
Foster JM, Schokker S, Sanderman R, Postma DS, van der Molen T. Development of a brief
questionnaire (ICQ-S) to monitor inhaled corticosteroid side-effects in clinical practice.
Allergy. 2014;69(3):372-379.
Franciosi L, Postma DS, van den Berge M, Govorukhina N, Horvatovich PL, Fusetti F,
Poolman B, Lodewijk ME, Timens W, Bischoff R, Ten Hacken NH. Susceptibility to COPD:
Differential Proteomic Profiling after Acute Smoking. PLoS One. 2014;9(7):e102037.
Fuertes E, MacIntyre E, Agius R, Beelen R, Brunekreef B, Bucci S, Cesaroni G, Cirach M,
Cyrys J, Forastiere F, Gehring U, Gruzieva O, Hoffmann B, Jedynska A, Keuken M, Klümper
C, Kooter I, Korek M, Krämer U, Mölter A, Nieuwenhuijsen M, Pershagen G, Porta D,
Postma DS, Simpson A, Smit HA, Sugiri D, Sunyer J, Wang M, Heinrich J. Associations
between particulate matter elements and early-life pneumonia in seven birth cohorts: Results
from the ESCAPE and TRANSPHORM projects. Int J Hyg Environ Health. 2014;217(8):819829.
Garde van de MD, Martinez FO, Melgert BN, Hylkema MN, Jonkers RE, Hamann J. Chronic
exposure to glucocorticoids shapes gene expression and modulates innate and adaptive
activation pathways in macrophages with distinct changes in leukocyte attraction. J Immunol
2014;192:1196-1208.
Gimeno-Santos E, Frei A, Steurer-Stey C, de Batlle J, Rabinovich RA, Raste Y, Hopkinson
NS, Polkey MI, van Remoortel H, Troosters T, Kulich K, Karlsson N, Puhan MA, GarciaAymerich J, PROactive consortium. Determinants and outcomes of physical activity in
patients with COPD: a systematic review. Thorax 2014;69:731-739.
58
Gompelmann D, Herth FJ, Slebos DJ, Valipour A, Ernst A, Criner GJ, Eberhardt R.
Pneumothorax following endobronchial valve therapy and its impact on clinical outcomes in
severe emphysema. Respiration 2014;87(6):485-491.
Gompelmann D, Eberhardt R, Slebos DJ, Brown MS, Abtin F, Kim HJ, Holmes-Higgin D,
Radhakrishnan S, Herth FJ, Goldin J. Diagnostic performance comparison of the Chartis
System and high-resolution computerized tomography fissure analysis for planning
endoscopic lung volume reduction. Respirology 2014;19(4):524-530.
Goossens NJ, Flokstra-de Blok BM, van der Meulen GN, Arnlind MH, Asero R, Barreales L,
Burney P, Cerecedo I, Clausen M, Fernandéz-Rivas M, Frewer L, de la Hoz Caballer B,
Jansson SA, Jedrzejczak-Czechowicz M, Knulst AC, Kowalski ML, Papadopoulos NG,
Purohit A, Rokicka E, Starosta P, Vásquez-Cortés S, Duiverman EJ, Dubois AE. Healthrelated quality of life in food-allergic adults from eight European countries. Ann Allergy
Asthma Immunol. 2014;113(1):63-68.
Guan WJ, Zheng XY, Zheng JP, Boudewijn IM, Telenga ED, van der Wiel E, van der Molen
T, Schiphof L, Ten Hacken NH, S Postma D, van den Berge M. Small airway dysfunction in
asymptomatic bronchial hyperresponsiveness and asthma. Allergy 2014;69:1258-1259.
Hartman JE, Boezen HM, Zuidema MJ, de Greef MH, Ten Hacken NH. Physical activity
recommendations in patients with chronic obstructive pulmonary disease. Respiration
2014;88(2):92-100.
Hazenberg A, Kerstjens HA, Prins SC, Vermeulen KM, Wijkstra PJ. Initiation of home
mechanical ventilation at home: a randomised controlled trial of efficacy, feasibility and costs.
Respir Med. 2014;108(9):1387-1395.
Heijink I, van Oosterhout A, Kliphuis N, Jonker M, Hoffmann R, Telenga E, Klooster K,
Slebos DJ, ten Hacken N, Postma D, van den Berge M. Oxidant-induced corticosteroid
unresponsiveness in human bronchial epithelial cells. Thorax 2014;69(1):5-13.
Heijink IH, Noordhoek JA, Timens W, van Oosterhout AJ, Postma DS. Abnormalities in
airway epithelial junction formation in chronic obstructive pulmonary disease. Am J Respir
Crit Care Med. 2014;189(11):1439-1442.
Heijink IH, Nawijn MC, Hackett TL. Airway epithelial barrier function regulates the
pathogenesis of allergic asthma. Clin Exp Allergy 2014;44:620-630.
Holt S, Sheahan D, Helm C, Tofield C, Corin A, Kocks JW. Little agreement in GOLD
category using CAT and mMRC in 450 primary care COPD patients in New Zealand. NPJ
Prim Care Respir Med 2014;24:14025.
Hoonhorst SJ, Ten Hacken NH, Vonk JM, Timens W, Hiemstra PS, Lapperre TS, Sterk PJ,
Postma DS. Steroid Resistance in COPD? Overlap and Differential Anti-Inflammatory Effects
in Smokers and Ex-Smokers. PLoS One. 2014;9(2):e87443.
Hoonhorst SJ, Ten Hacken NH, Lo Tam Loi AT, Koenderman L, Lammers JW, Telenga ED,
Boezen HM, van den Berge M, Postma DS. Lower Corticosteroid Skin Blanching Response
Is Associated with Severe COPD. PLoS One. 2014;9(3):e91788.
Hoonhorst SJ, Lo Tam Loi AT, Hartman JE, Telenga ED, van den Berge M, Koenderman L,
Lammers JW, Marike Boezen H, Postma DS, Ten Hacken NH. Advanced glycation end
products in the skin are enhanced in COPD. Metabolism. 2014;63(9):1149-1156.
59
Hoonhorst S, Timens W, Koenderman L, Lo Tam Loi AT, Lammers JW, Boezen H, van
Oosterhout A, Postma DS, Ten Hacken N. Increased activation of blood neutrophils after
cigarette smoking in young individuals susceptible to COPD. Respir Res. 2014;15(1):121.
Jones RC, Price D, Ryan D, Sims EJ, von Ziegenweidt J, Mascarenhas L, Burden A, Halpin
DM, Winter R, Hill S, Kearney M, Holton K, Moger A, Freeman D, Chisholm A, Bateman ED;
Respiratory Effectiveness Group. Opportunities to diagnose chronic obstructive pulmonary
disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir
Med. 2014;2(4):267-276.
Jong de K, Boezen HM, Kromhout H, Vermeulen R, Vonk JM, Postma DS; LifeLines cohort
study. Occupational exposure to vapors, gases, dusts, and fumes is associated with small
airways obstruction. Am J Respir Crit Care Med. 2014;189(4):487-490.
Jong de K, Boezen HM, Kromhout H, Vermeulen R, Postma DS, Vonk JM; LifeLines Cohort
study. Pesticides and other occupational exposures are associated with airway obstruction:
the LifeLines cohort study. Occup Environ Med. 2014;71(2):88-96.
Jong de K, Boezen HM, Kromhout H, Vermeulen R, Postma DS, Vonk JM. Association of
Occupational Pesticide Exposure With Accelerated Longitudinal Decline in Lung Function.
Am J Epidemiol. 2014;179(11):1323-1330.
Jong de K, Vonk JM, Kromhout H, Vermeulen R, Postma DS, Boezen HM, LifeLines Cohort
Study. NOS1: a susceptibility gene for reduced level of FEV1 in the setting of pesticide
exposure. Am J Respir Crit Care Med 2014;190:1188-1190.
Kerkhof M, Boezen HM, Granell R, Wijga AH, Brunekreef B, Smit HA, de Jongste JC, Thijs
C, Mommers M, Penders J, Henderson J, Koppelman GH, Postma DS. Transient early
wheeze and lung function in early childhood associated with chronic obstructive pulmonary
disease genes. J Allergy Clin Immunol. 2014;133(1):68-76.
Kirenga BJ, Levin J, Ayakaka I, Worodria W, Reilly N, Mumbowa F, Nabanjja H, Nyakoojo G,
Fennelly K, Nakubulwa S, Joloba M, Okwera A, Eisenach KD, McNerney R, Elliott AM,
Mugerwa RD, Smith PG, Ellner JJ, Jones-Lopez EC. Treatment outcomes of new
tuberculosis patients hospitalized in Kampala, Uganda: a prospective cohort study. PLoS
One 2014;9:e90614.
Kistemaker LE, Bos ST, Mudde WM, Hylkema MN, Hiemstra PS, Wess J, Meurs H,
Kerstjens HA, Gosens R. Muscarinic M(3) receptors contribute to allergen-induced airway
remodeling in mice. Am J Respir Cell Mol Biol 2014;50:690-698.
Klaassen EM, van de Kant KD, Jöbsis Q, Penders J, van Schooten FJ, Quaak M, den Hartog
GJ, Koppelman GH, van Schayck CP, van Eys G, Dompeling E. Integrative genomic analysis
identifies a role for intercellular adhesion molecule 1 in childhood asthma. Pediatr Allergy
Immunol. 2014;25(2):166-172.
Klooster K, Ten Hacken NH, Slebos DJ. The lung volume reduction coil for the treatment of
emphysema: a new therapy in development. Expert Rev Med Devices. 2014;11(5):481-489.
Klooster K, Ten Hacken NH, Franz I, Kerstjens HA, van Rikxoort EM, Slebos DJ. Lung
volume reduction coil treatment in chronic obstructive pulmonary disease patients with
homogeneous emphysema: a prospective feasibility trial. Respiration. 2014;88(2):116-125.
60
Kolahian S, Shahbazfa RAA, Tayefi-Nasrabadi H, Keyhanmanesh R, Ansarin K, Ghasemi H
Rashidi AH, Gosens R, Hanifeh M. Tiotropium effects on airway inflammatory events in the
cat as an animal model for acute cigarette smoke-induced lung inflammation. Exp Lung Res
2014;40: 272-287.
Koning H, van Oosterhout AJ, Brouwer U, den Boef LE, Gras R, Reinders-Luinge M,
Brandsma CA, van der Toorn M, Hylkema MN, Willemse BW, Sayers I, Koppelman GH,
Nawijn MC. Mouse protocadherin-1 gene expression is regulated by cigarette smoke
exposure in vivo. PLoS One 2014;9:e98197.
Koopmans T, Anaparti V, Castro-Piedras I, Yarova P, Irechukwu N, Nelson C, Perez-Zoghbi
J, Tan X, Ward JP, Wright DB. Ca2+ handling and sensitivity in airway smooth muscle:
emerging concepts for mechanistic understanding and therapeutic targeting. Pulm
Pharmacol Ther 2014;29:108-120.
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after ventilatory support for acute respiratory failure: a randomised, controlled, parallel-group
study. Thorax 2014;69(9):826-834.
Struik FM, Wijkstra PJ. Response to: Domiciliary long term non-invasive ventilation in COPD:
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randomized controlled trails Thorax 2014;69(12):1143-1144.
Tania NP, Schmidt M, Gosens R. Activin-A: active in inflammation in COPD. Eur Respir J
2014;43:954-955.
Telenga ED, Hoffmann RF, Ruben t'Kindt, Hoonhorst SJ, Willemse BW, van Oosterhout AJ,
Heijink IH, van den Berge M, Jorge L, Sandra P, Postma DS, Sandra K, Ten Hacken NH.
Untargeted lipidomic analysis in chronic obstructive pulmonary disease. Uncovering
sphingolipids. Am J Respir Crit Care Med. 2014;190(2):155-164.
Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K, Niedoszytko
M, Nedoszytko B, Oude Elberink JN, Kristensen T, Butterfield JH, Triggiani M, AlvarezTwose I, Reiter A, Sperr WR, Sotlar K, Yavuz S, Kluin-Nelemans HC, Hermine O, Radia D,
van Doormaal JJ, Gotlib J, Orfao A, Siebenhaar F, Schwartz LB, Castells M, Maurer M,
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suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis.
Allergy. 2014;69(10):1267-1274.
Valipour A, Slebos DJ, de Oliveira HG, Eberhardt R, Freitag L, Criner GJ, Herth FJ. Expert
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2014;87(6):513-521.
Valk van der JP, Dubois AE, Gerth van Wijk R, Wichers HJ, de Jong NW. Systematic review
on cashew nut allergy. Allergy. 2014;69(6):692-698.
Valk van der RJ, Duijts L, Timpson NJ, Salam MT, Standl M, Curtin JA, Genuneit J, Kerhof
M, Kreiner-Møller E, Cáceres A, Gref A, Liang LL, Taal HR, Bouzigon E, Demenais F, Nadif
R, Ober C, Thompson EE, Estrada K, Hofman A, Uitterlinden AG, van Duijn C, Rivadeneira
F, Li X, Eckel SP, Berhane K, Gauderman WJ, Granell R, Evans DM, St Pourcain B, McArdle
W, Kemp JP, Smith GD, Tiesler CM, Flexeder C, Simpson A, Murray CS, Fuchs O, Postma
DS, Bønnelykke K, Torrent M, Andersson M, Sleiman P, Hakonarson H, Cookson WO,
Moffatt MF, Paternoster L, Melén E, Sunyer J, Bisgaard H, Koppelman GH, Ege M, Custovic
A, Heinrich J, Gilliland FD, Henderson AJ, Jaddoe VW, de Jongste JC; for the EArly
Genetics & Lifecourse Epidemiology (EAGLE) Consortium. Fraction of exhaled nitric oxide
values in childhood are associated with 17q11.2-q12 and 17q12-q21 variant. J Allergy Clin
Immunol. 2014;134(1):46-55.
Veer van der E, Arends S, van der Hoek S, Versluijs JB, de Monchy JG, Oude Elberink JN,
van Doormaal JJ. Predictors of new fragility fractures after diagnosis of indolent systemic
mastocytosis. J Allergy Clin Immunol. 2014;134(6):1413-1421.
Vijverberg SJ, Tavendale R, Leusink M, Koenderman L, Raaijmakers JA, Postma DS,
Koppelman GH, Turner SW, Mukhopadhyay S, Palmer CN, Maitland-van der Zee AH.
Pharmacogenetic analysis of GLCCI1 in three north European pediatric asthma populations
with a reported use of inhaled corticosteroids. Pharmacogenomics. 2014;15(6):799-806.
Vries de M, Heijink IH, Gras R, den Boef LE, Reinders-Luinge M, Pouwels SD, Hylkema MN,
van der Toorn M, Brouwer U, van Oosterhout AJ, Nawijn MC. Pim1 kinase protects airway
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epithelial cells from cigarette smoke-induced damage and airway inflammation. Am J Physiol
Lung Cell Mol Physiol 2014;307:L240-251.
Wekesa C, Kirenga BJ, Joloba ML, Bwanga F, Katamba A, Kamya MR. Chest X-ray vs.
Xpert(R) MTB/RIF assay for the diagnosis of sputum smear-negative tuberculosis in Uganda.
Int J Tuberc Lung Dis 2014;18:216-219.
Wiel van der E, Ten Hacken NH, van den Berge M, Timens W, Reddel HK, Postma DS.
Eosinophilic inflammation in subjects with mild-to-moderate asthma with and without obesity:
disparity between sputum and biopsies. Am J Respir Crit Care Med. 2014;189(10):12811284.
Wiel van der E, Postma DS, van der Molen T, Schiphof-Godart L, Ten Hacken NH, van den
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asthma symptoms and bronchial hyperresponsiveness. Allergy. 2014;69(12):1681-1688.
Wijga AH, Kerkhof M, Gehring U, de Jongste JC, Postma DS, Aalberse RC, Wolse AP,
Koppelman GH, van Rossem L, Oldenwening M, Brunekreef B, Smit HA. Cohort profile: The
Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort. Int J Epidemiol
2014;43(2):527-535.
Wijga AH, Zuidgeest MG, Kerkhof M, Koppelman GH, Smit HA, de Jongste JC. Guidelinerecommended use of asthma medication by children is associated with parental information
and knowledge: the PIAMA birth cohort. Pharmacoepidemiol Drug Saf. 2014;23(4):406-410.
Worth A, Hammersley V, Knibb R, Flokstra-de-Blok B, DunnGalvin A, Walker S, Dubois AE,
Sheikh A. Patient-reported outcome measures for asthma: a systematic review. NPJ Prim
Care Respir Med. 2014;24:14020.
Wright DB, Meurs H, Dekkers BGJ. Integrins: therapeutic targets in airway
hyperresponsiveness and remodelling? Trends Pharmacol Sci 2014;35: 567-574.
Xie X, Dijkstra AE, Vonk JM, Oudkerk M, Vliegenthart R, Groen HJ. Chronic respiratory
symptoms associated with airway wall thickening measured by thin-slice low-dose CT. AJR
Am J Roentgenol. 2014;203(4):W383-390.
Zetstra-van der Woude PA, De Walle HE, Hoek A, Bos HJ, Boezen HM, Koppelman GH, de
Jong-van den Berg LT, Scholtens S. Maternal high-dose folic acid during pregnancy and
asthma medication in the offspring. Pharmacoepidemiol Drug Saf. 2014;23(10):1059-1065.
Zijlstra GJ, Fattahi F, Rozeveld D, Jonker MR, Kliphuis NM, van den Berge M, Hylkema MN,
ten Hacken NH, van Oosterhout AJ, Heijink IH. Glucocorticoids induce the production of the
chemoattractant CCL20 in airway epithelium. Eur Respir J 2014;44:361-370.
Zuur-Telgen MC, Brusse-Keizer MG, van der Palen J, VanderValk PD, Kerstjens HA,
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Zwerink M, van der Palen J, Kerstjens HA, van der Valk P, Brusse-Keizer M, Zielhuis G,
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follow-up of the COPE-II study. Respir Med 2014;108:1481-1490.
Zysman M, Patout M, Miravitlles M, van der Molen T, Lokke A, Hausen T, Didier A, Cuvelier
A, Roche N. COPD and perception of the new GOLD document in Europe. Workshop from
the Societe de pneumologie de langue francaise (SPLF). Rev Mal Respir 2014;31:499-510.
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Publications in Dutch
Hesse L, Oude Elberink JNG Nawijn MC Allergeenspecifieke immunotherapie voor
inhalatieallergenen: het belang van het verhogen van de effectiviteit. 2014. Ned Tijdschrift
voor allergie en asthma;1:62-68
Koppelman GH, Scholtens S, Smit N, Stolk RP. De Lifelines cohort studie: Gezond ouder
worden in 3 generaties. Kinderarts en Wetenschap, Juni 2014.
Melgert BN. Farmaceutische immunologie. Medicines, December 2014.
Oude Elberink JNG. Insectenallergie. In: Werkboek Kinderallergologie, 2e druk, pp137-145,
VU University Press, 2014.
Postma DS. COPD ontstaat al voor de geboorte. Topic 2014;10 12-14
Books / Book chapters
Boezen HM, de Jong K, Vonk JM. Genetic factors in asthma and COPD. In: Annesi-Maesano
I, Lundbäck B, Viegi G, editors. ERS Monograph. ERS, 2014:139-151.
DunnGalvin A, Dubois AE, Flokstra-de Blok BM, Hourihane JO. Living with food allergy:
Cause for concern. In: Madsen CB, Crevel RWR, Mills C and Taylor SL, editors. Risk
managment for food allergy, 1st ed: Elsevier Inc.; 2014. p. 3-24.
Tol van DG, de Bree MJ, Dekker H, van der Molen T. Handboek medische professionaliteit. :
Bohn Stafleu van Loghum; 2014.
Wijkstra PJ, Duiverman ML. Ventilatory support during sleep in patients with COPD. In:
Babak Mokhlesi. Sleep medicine clinics Sleep hypoventilation : A state-of-the -Art overview.
September 2014; 381-390
Contributions to other research institutes
Publications SCI journals
Beljaars L, Schippers M, Reker-Smit C, Martinez FO, Helming L, Poelstra K, Melgert BN.
Hepatic Localization of Macrophage Phenotypes during Fibrogenesis and Resolution of
Fibrosis in Mice and Humans. Front Immunol 2014;5:430.
Berentzen NE, Smit HA, Bekkers MB, Brunekreef B, Koppelman GH, De Jongste JC,
Kerkhof M, Van Rossem L, Wijga AH. Time in bed, sleep quality and associations with
cardiometabolic markers in children: the Prevention and Incidence of Asthma and Mite
Allergy birth cohort study. J Sleep Res. 2014;23(1):3-12.
Berentzen NE, Smit HA, van Rossem L, Gehring U, Kerkhof M, Postma DS, Boshuizen HC,
Wijga AH. Screen time, adiposity and cardiometabolic markers: mediation by physical
activity, not snacking, among 11-year-old children. Int J Obes (Lond). 2014;38(10):13171323.
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Boer de YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ,
Beuers U, van Buuren HR, Drenth JP, den Ouden JW, Verdonk RC, Koek GH, Brouwer
JT, Guichelaar MM, Vrolijk JM, Kraal G, Mulder CJ, van Nieuwkerk CM, Fischer J,
Berg T, Stickel F, Sarrazin C, Schramm C, Lohse AW, Weiler-Normann C, Lerch MM,
Nauck M, Völzke H, Homuth G, Bloemena E, Verspaget HW, Kumar V, Zhernakova A,
Wijmenga C, Franke L, Bouma G; Dutch Autoimmune Hepatitis Study Group; LifeLines
Cohort Study; Study of Health in Pomerania. Genome-wide association study
identifies variants associated with autoimmune hepatitis type 1. Gastroenterology.
2014;147(2):443-452.
Cernecka H, Pradidarcheep W, Lamers, WH, Schmidt M, Michel MC. Rat β₃-adrenoceptor
protein expression: antibody validation and distribution in rat gastrointestinal and urogenital
tissues. Naunyn-Schmiedebergs Arch Pharmacol 2014;387:1117-1127.
Cree IA, Deans Z, Ligtenberg MJ, Normanno N, Edsjo A, Rouleau E, Sole F, Thunnissen E,
Timens W, Schuuring E, Dequeker E, Murray S, Dietel M, Groenen P, van Krieken JH.
Guidance for laboratories performing molecular pathology for cancer patients. J Clin Pathol
2014,67:923-931.
Damoiseaux VA, Proost JH, Jiawan VCR, Melgert BN. Sex differences in the
pharmacokinetics of antidepressants: influence of female sex hormones and oral
contraceptives. Clin Pharmacokin 2014;53:509-519.
Eny KM, Lutgers HL, Maynard J, Klein BE, Lee KE, Atzmon G, Monnier VM, van
Vliet-Ostaptchouk JV, Graaff R, van der Harst P, Snieder H, van der Klauw MM,
Sell DR, Hosseini SM, Cleary PA, Braffett BH, Orchard TJ, Lyons TJ, Howard K,
Klein R, Crandall JP, Barzilai N, Milman S, Ben-Avraham D; LifeLines Cohort Study
Group; DCCT/EDIC Research Group, Wolffenbuttel BH, Paterson AD. GWAS identifies
an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus
for skin fluorescence. Diabetologia. 2014;57(8):1623-1634.
Figarska SM, Vonk JM, Boezen HM. NFE2L2 polymorphisms, mortality, and
metabolism in the general population. Physiol Genomics. 2014;46(12):411-417.
Gaspar L, van de Werken M, Johansson AS, Moriggi E, Owe-Larsson B, Kocks JW,
Lundkvist GB, Gordijn MC, Brown SA. Human cellular differences in cAMP--CREB signaling
correlate with light-dependent melatonin suppression and bipolar disorder. Eur J Neurosci
2014;40:2206-2215.
Girvalaki C, Vardavas C, Papandreou C, Christaki G, Vergetaki A, Tsiligianni IG, Hatzis C,
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between 1989 and 2011. Hormones (Athens) 2014;13:259-267.
Gooden MJ, Wiersma VR, Boerma A, Leffers N, Boezen HM, ten Hoor KA, Hollema H,
Walenkamp AM, Daemen T, Nijman HW, Bremer E. Elevated serum CXCL16 is an
independent predictor of poor survival in ovarian cancer and may reflect
pro-metastatic ADAM protease activity. Br J Cancer. 2014;110(6):1535-1544.
Hoggart CJ, Venturini G, Mangino M, Gomez F, Ascari G, Zhao JH, Teumer A,
Winkler TW, Tšernikova N, Luan J, Mihailov E, Ehret GB, Zhang W, Lamparter D,
Esko T, Macé A, Rüeger S, Bochud PY, Barcella M, Dauvilliers Y, Benyamin B, Evans
DM, Hayward C, Lopez MF, Franke L, Russo A, Heid IM, Salvi E, Vendantam S, Arking
DE, Boerwinkle E, Chambers JC, Fiorito G, Grallert H, Guarrera S, Homuth G,
Huffman JE, Porteous D; Generation Scotland Consortium; LifeLines Cohort study;
GIANT Consortium, Moradpour D, Iranzo A, Hebebrand J, Kemp JP, Lammers GJ, Aubert
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V, Heim MH, Martin NG, Montgomery GW, Peraita-Adrados R, Santamaria J, Negro F,
Schmidt CO, Scott RA, Spector TD, Strauch K, Völzke H, Wareham NJ, Yuan W, Bell
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Paccaud F, Vollenweider P, Bergmann S, Beckmann JS, Tafti M, Hastie ND, Cusi D,
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Leffers N, Daemen T, Helfrich W, Boezen HM, Cohlen BJ, Melief CJ, Nijman HW.
Antigen-specific active immunotherapy for ovarian cancer. Cochrane Database Syst
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Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T, He C, Chasman DI, Esko T,
Thorleifsson G, Albrecht E, Ang WQ, Corre T, Cousminer DL, Feenstra B, Franceschini N,
Ganna A, Johnson AD, Kjellqvist S, Lunetta KL, McMahon G, Nolte IM, Paternoster L, Porcu
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Bierut LJ, Byrne EM, Hottenga JJ, Koller DL, Mangino M, Pers TH, Yerges-Armstrong LM,
Hua Zhao J, Andrulis IL, Anton-Culver H, Atsma F, Bandinelli S, Beckmann MW, Benitez J,
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Devilee P, Dieffenbach AK, Dunning AM, Eiriksdottir G, Eriksson JG, Fasching PA, Ferrucci
L, Flesch-Janys D, Flyger H, Foroud T, Franke L, Garcia ME, García-Closas M, Geller F, de
Geus EE, Giles GG, Gudbjartsson DF, Gudnason V, Guénel P, Guo S, Hall P, Hamann U,
Haring R, Hartman CA, Heath AC, Hofman A, Hooning MJ, Hopper JL, Hu FB, Hunter DJ,
Karasik D, Kiel DP, Knight JA, Kosma VM, Kutalik Z, Lai S, Lambrechts D, Lindblom A, Mägi
R, Magnusson PK, Mannermaa A, Martin NG, Masson G, McArdle PF, McArdle WL, Melbye
M, Michailidou K, Mihailov E, Milani L, Milne RL, Nevanlinna H, Neven P, Nohr EA,
Oldehinkel AJ, Oostra BA, Palotie A, Peacock M, Pedersen NL, Peterlongo P, Peto J,
Pharoah PD, Postma DS, Pouta A, Pylkäs K, Radice P, Ring S, Rivadeneira F, Robino A,
Rose LM, Rudolph A, Salomaa V, Sanna S, Schlessinger D, Schmidt MK, Southey MC,
Sovio U, Stampfer MJ, Stöckl D, Storniolo AM, Timpson NJ, Tyrer J, Visser JA, Vollenweider
P, Völzke H, Waeber G, Waldenberger M, Wallaschofski H, Wang Q, Willemsen G, Winqvist
R, Wolffenbuttel BH, Wright MJ; Australian Ovarian Cancer Study; The GENICA Network;
kConFab; The LifeLines Cohort Study; The InterAct Consortium; Early Growth Genetics
(EGG) Consortium, Boomsma DI, Econs MJ, Khaw KT, Loos RJ, McCarthy MI, Montgomery
GW, Rice JP, Streeten EA, Thorsteinsdottir U, van Duijn CM, Alizadeh BZ, Bergmann S,
Boerwinkle E, Boyd HA, Crisponi L, Gasparini P, Gieger C, Harris TB, Ingelsson E, Järvelin
MR, Kraft P, Lawlor D, Metspalu A, Pennell CE, Ridker PM, Snieder H, Sørensen TI, Spector
TD, Strachan DP, Uitterlinden AG, Wareham NJ, Widen E, Zygmunt M, Murray A, Easton
DF, Stefansson K, Murabito JM, Ong KK. Parent-of-origin-specific allelic associations among
106 genomic loci for age at menarche. Nature. 2014;514(7520):92-97.
Romanos J, Rosén A, Kumar V, Trynka G, Franke L, Szperl A, Gutierrez-Achury J,
van Diemen CC, Kanninga R, Jankipersadsing SA, Steck A, Eisenbarth G, van Heel
DA, Cukrowska B, Bruno V, Mazzilli MC, Núñez C, Bilbao JR, Mearin ML, Barisani D,
Rewers M, Norris JM, Ivarsson A, Boezen HM, Liu E, Wijmenga C; PreventCD Group.
Improving coeliac disease risk prediction by testing non-HLA variants additional
to HLA variants. Gut. 2014 Mar;63(3):415-422.
Simino J, Shi G, Bis JC, Chasman DI, Ehret GB, Gu X, Guo X, Hwang SJ,
Sijbrands E, Smith AV, Verwoert GC, Bragg-Gresham JL, Cadby G, Chen P, Cheng CY,
Corre T, de Boer RA, Goel A, Johnson T, Khor CC; LifeLines Cohort Study,
Lluís-Ganella C, Luan J, Lyytikäinen LP, Nolte IM, Sim X, Sõber S, van der Most
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PJ, Verweij N, Zhao JH, Amin N, Boerwinkle E, Bouchard C, Dehghan A, Eiriksdottir
G, Elosua R, Franco OH, Gieger C, Harris TB, Hercberg S, Hofman A, James AL,
Johnson AD, Kähönen M, Khaw KT, Kutalik Z, Larson MG, Launer LJ, Li G, Liu J, Liu
K, Morrison AC, Navis G, Ong RT, Papanicolau GJ, Penninx BW, Psaty BM, Raffel LJ,
Raitakari OT, Rice K, Rivadeneira F, Rose LM, Sanna S, Scott RA, Siscovick DS,
Stolk RP, Uitterlinden AG, Vaidya D, van der Klauw MM, Vasan RS, Vithana EN,
Völker U, Völzke H, Watkins H, Young TL, Aung T, Bochud M, Farrall M, Hartman CA,
Laan M, Lakatta EG, Lehtimäki T, Loos RJ, Lucas G, Meneton P, Palmer LJ, Rettig
R, Snieder H, Tai ES, Teo YY, van der Harst P, Wareham NJ, Wijmenga C, Wong TY,
Fornage M, Gudnason V, Levy D, Palmas W, Ridker PM, Rotter JI, van Duijn CM,
Witteman JC, Chakravarti A, Rao DC. Gene-age interactions in blood pressure
regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP
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Slagter SN, van Vliet-Ostaptchouk JV, Vonk JM, Boezen HM, Dullaart RP, Kobold
AC, Feskens EJ, van Beek AP, van der Klauw MM, Wolffenbuttel BH. Combined effects
of smoking and alcohol on metabolic syndrome: the LifeLines cohort study. PLoS
One. 2014;9(4):e96406.
Spaans F, Melgert BN, Chiang C, Borghuis T, Klok PA, de Vos P, van Goor H, Bakker WW,
Faas MM. Extracellular ATP decreases trophoblast invasion, spiral artery remodeling and
immune cells in the mesometrial triangle in pregnant rats. Placenta 2014;35:587-595.
Spaans F, Melgert BN, Borghuis T, Klok PA, de Vos P, Bakker WW, van Goor H, Faas MM.
Extracellular adenosine triphosphate affects systemic and kidney immune cell populations in
pregnant rats. Am J Reprod Immunol 2014;72:305-316.
Taghizadeh N, Vonk JM, Boezen HM. Serum uric acid levels and cancer mortality
risk among males in a large general population-based cohort study. Cancer Causes
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Tragante V, Barnes MR, Ganesh SK, Lanktree MB, Guo W, Franceschini N, Smith
EN, Johnson T, Holmes MV, Padmanabhan S, Karczewski KJ, Almoguera B, Barnard J,
Baumert J, Chang YP, Elbers CC, Farrall M, Fischer ME, Gaunt TR, Gho JM, Gieger
C, Goel A, Gong Y, Isaacs A, Kleber ME, Mateo Leach I, McDonough CW, Meijs MF,
Melander O, Nelson CP, Nolte IM, Pankratz N, Price TS, Shaffer J, Shah S,
Tomaszewski M, van der Most PJ, Van Iperen EP, Vonk JM, Witkowska K, Wong CO,
Zhang L, Beitelshees AL, Berenson GS, Bhatt DL, Brown M, Burt A, Cooper-DeHoff
RM, Connell JM, Cruickshanks KJ, Curtis SP, Davey-Smith G, Delles C, Gansevoort
RT, Guo X, Haiqing S, Hastie CE, Hofker MH, Hovingh GK, Kim DS, Kirkland SA,
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Rose LM, Sever P, Shimbo D, Steele L, Stolk RP, Thorand B, Trip MD, van Duijn CM,
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Boerwinkle E, Casas JP, Caulfield MJ, Chakravarti A, Chasman DI, Davidson KW,
Doevendans PA, Dominiczak AF, FitzGerald GA, Gums JG, Fornage M, Hakonarson H,
Halder I, Hillege HL, Illig T, Jarvik GP, Johnson JA, Kastelein JJ, Koenig W,
Kumari M, März W, Murray SS, O'Connell JR, Oldehinkel AJ, Pankow JS, Rader DJ,
Redline S, Reilly MP, Schadt EE, Kottke-Marchant K, Snieder H, Snyder M, Stanton
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