Groningen Research Institute for Asthma and COPD

Annual Report 2016

UMCG

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Content

Mission statement ................................................................................................................. 3

Introduction ........................................................................................................................... 4

Perspectives .......................................................................................................................... 8

The year 2016 in review .......................................................................................................10

Highlights ..........................................................................................................................10

Prizes/Awards ...................................................................................................................11

Visitors ..............................................................................................................................11

Special Topics ......................................................................................................................13

Special topic 1 ..................................................................................................................13

Special topic 2 ..................................................................................................................15

Special topic 3 ..................................................................................................................17

Special topic 4 ..................................................................................................................18

Special topic 5 ..................................................................................................................19

Special topic 6 ..................................................................................................................20

Special topic 7 ..................................................................................................................25

Departments .........................................................................................................................28

Members 2016 .....................................................................................................................30

International collaboration 2016 ............................................................................................32

GRIAC Seminar program 2016 .............................................................................................36

GRIAC research meetings 2016 ...........................................................................................38

GRIAC Brainstorm sessions 2016 ........................................................................................41

Research projects 2016 ........................................................................................................42

Publications 2016 .................................................................................................................50

Dissertations .....................................................................................................................50

Publications SCI journals ..................................................................................................51

Publications in Dutch ........................................................................................................68

Contributions to other research institutes ..........................................................................69

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Mission statement

The mission of GRIAC is the multidisciplinary translational study of obstructive airway and pulmonary diseases and healthy ageing

Program leaders:

Prof. dr. Reinoud Gosens and Prof. dr. Gerard H.Koppelman Visiting address: University Medical Center Groningen Hanzeplein 1 NL-9713 GZ Groningen Website: www.griac.nl

Secretariat: Ms. Georgette Hoogendijk Dept. Pediatric Pulmonology and Pediatric Allergology Beatrix Children’s Hospital University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 1036 Fax: 31-50-361 1704 Email: g.h.koppelman@umcg.nl and r.gosens@rug.nl

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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. The main theme of GRIAC is unravelling the underlying mechanisms of the development, progression and remission of airway obstruction, allergy and airway hyperresponsiveness, their mutual interactions, and their relevance to treatment. These phenomena are important risk factors for the development of asthma and COPD and crucial characteristics in their clinical pictures. 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). 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 Genetics, Pharmaceutical Technology and Biopharmacy, and the Groningen Transplantation Center. Furthermore, collaboration exists with the Department of Analytical Biochemistry (University Center for Pharmacy).

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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. GRIAC operates within the University Medical Center Groningen (UMCG) and its overarching research theme “Healthy Ageing”, and partially within the Groningen Research Institute of Pharmacy (GRIP), with a focus on Molecular Life and Health. Research within GRIAC focuses on the main challenges of obstructive airway and pulmonary disease, as well as pulmonary fibrosis: • Identifying risk factors for the development, progression and remission of disease • Identifying disease-related genes, gene pathways, gene functionality and gene regulation and their relation to specific phenotypes of obstructive airways disease and pulmonary fibrosis • Unravelling the pathophysiology of allergen-, environmental- and smoke- induced disease, in humans, animal models, and in vitro cell systems • Unravelling the effects of disease-related inflammation on lung function, hyperresponsive- ness and remodeling of large and small airways • Defining new targets for personalized (drug and device) intervention and evaluation of intervention strategies, which includes the development of novel approaches in preventive medicine • Development of noninvasive or less invasive tools to assess severity of disease and effects (and side effects) of treatment. Scope of research These challenges are investigated particularly in asthma and COPD, resulting in integrated subprograms on: 1. Epidemiology and genomics 2. Molecular Medicine: Pathophysiology and pathogenesis of chronic lung disease and drug target identification. 3. Clinical Medicine: Assessment, modulation of and intervention in disease severity, progression and remission Epidemiology and genomics The longstanding expertise in identifying risk factors and the availability of large, prospective, long-term follow up of patient-based and population-based cohorts (such as LifeLines) and the collaboration with the Department of Genetics enables extensive sub-programs, including exposomics, (epi)genome-wide association, genome-wide interactions and transcriptome sequencing studies. This has resulted in identification of numerous novel genetic loci related to asthma and COPD onset and progression. Proteomic and lipidomic research has led to identification of disease susceptibility and progression markers. GRIAC has a longstanding collaboration with the proteomics facility, and recently incorporated its first member from the European Research Institute on the Biology of Ageing (ERIBA), strengthening its focus on bioinformatic analyses of integrated genomic datasets. Molecular medicine GRIAC is actively engaged in studies linking clinical outcomes to pathophysiology, also on a molecular basis. Often based on outcomes from and also involving 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. In vivo and in vitro silencing and overexpression of genes are now established techniques that are operational at the UMCG and GRIP, including the development of knock out and transgenic mouse models, and the

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use of RNA interference and pharmacological modulation of cells and tissue slices. Fundamental to this line of research is the exploration of intracellular and intercellular pathways and interactions relevant for tissue repair, disease development, progression and remission, as well as for the exploration of novel drug targets. Clinical medicine Patient-centered research is at the heart of GRIAC. Our translational research approach includes large-scale clinical management in primary care, clinical and intervention studies in allergy, food allergy, asthma and COPD. Because it is moving towards precision medicine (predictive, preventative, personalized, and participatory) in obstructive and pulmonary disease, GRIAC is in an excellent position to incorporate genomic markers in intervention studies. GRIAC is actively engaged in the development of clinical questionnaires for disease diagnosis and monitoring of disease control. Pulmonary rehabilitation and novel, personalized bronchoscopic intervention techniques are evaluated for the treatment of COPD. 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 members of the Board of directors, scientific staff and post-docs 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. 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

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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.

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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. Within each sub-program, specific research goals are complemented with an overarching emphasis on healthy ageing, (personalized) drug development, societal impact and the relevance of infrastructure. As listed below, this GRIAC approach has resulted in important achievements in past years and in new targets to work on for the future. The strategic sub-programs • Epidemiology and genomics: Study approaches integrating epidemiological and genomic techniques are customary at GRIAC. Epidemiological studies encompassing endogenous, environmental and lifestyle risk factors, in general and patient-based population and from the prenatal phase to mature age. Genomic studies are performed at the level of genetics, 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), and these are integrated with proteomic approaches. • Molecular Medicine: The focus here is on role of allergens, smoking and other lifestyle factors in pathophysiology and pathogenesis of environment-induced diseases including asthma, COPD, and pulmonary fibrosis. In vivo studies in humans and animal models (including transgenerational models) using mice and unrestrained guinea pigs are used to identify disease mechanisms and drug targets. 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, adhesion and interactions with other cell types and with their environment, including the extracellular matrix. Signaling pathways and the function of susceptibility genes that were identified in the epidemiology and genomics subprogram are studied in cells and tissue explants (e.g. lymphocyte subsets, epithelial cells, fibroblasts, intact airway and smooth muscle preparations). Interactions between different cell types are studied by using cells obtained from sputum induction and nasal brushings as well as airway wall and lung tissue obtained by bronchoscopy, surgical biopsy or surgical resection. • Clinical Medicine: Assessment, modulation and intervention in disease severity, progression and remission: Disease outcome assessment is being studied with techniques such as exhaled breath analyses, nasal epithelial gene expression, and small airway dysfunction. 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. Output, visibility and (external) funding Productivity of GRIAC is at present overall very good and recently, GRIAC was assessed by the Standard Evaluation Protocol (SEP, see ‘special topics’ for more details). 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

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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, COPD, and pulmonary fibrosis 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.

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The year 2016 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 2016.

Highlights In relation to the thesis defences of Dr. R. Hoffmann and Dr. D. van Hemelen minisymposia were organized. Speakers at these symposia were national and international leading researchers. On September 23, 2016 the Children's Allergy & Asthma Center in the UMCG was officially opened with a symposium. See ‘special topics’ for more details. Prof. Dr. G.H. Koppelman received a Lung Foundation Netherlands consortium grant together with researchers from the Academic Medical Center Amsterdam and the Erasmus Medical Center Rotterdam. See ‘special topics’ for a short description of the project. W. van Geffen, MD, received an European Respiratory Society Short-Term Fellowship to acquire new insights into pulmonary physiology at the Royal Brompton Hospital in London. Dr. A. Faiz received a 2-year junior investigator grant from the Lung Foundation Netherlands for his research proposal entitled: Understanding the genetic and epigenetic drivers of cigarette smoke susceptibility in COPD. See ‘special topics’ for a short description of the project. Prof. Dr. P.J. Wijkstra had his inaugural lecture entitled ‘Chronische beademing: een adembenemende ontwikkeling’ (English: “Chronic Ventilation: a breathtaking development”) on December 13th. Three GRIAC researchers retired in 2016: Prof. D.S. Postma (April 1), Prof. A.E. Dubois (April 15), and Prof. H. Meurs (December 9). To celebrate this, retirement symposia were organized. Speakers at these symposia were national and international leading researchers. See ‘special topics’ for more details. Prof. Dr. H.M. Boezen was awarded as Fellow of the European Respiratory Society. Prof. Dr. M. Schmidt was awarded as Fellow of the British Pharmacological Society. Prof. Dr. D.S. Postma obtained the COPD10 UK award for scientific contribution to the field. On March 24, Prof. Dr. I.H. Heijink hosted a visit by donors of the Lung Foundation Netherlands to the EXPIRE lab. The feedback was very positive. Prof. Dr. B.N Melgert obtained a fellowship for the innovation of teaching from the University of Groningen. Dr. J.F.M. van Boven will be representing GRIAC in the junior board of the “Dutch FDA” (College ter beoordeling van geneesmiddelen).

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Prof. Dr. I.H. Heijink organized the NRS-symposium ‘Lung Repair and Regeneration’ on November 11 in Amsterdam in collaboration with Dr. R.J. Rottier from Erasmus MC, Rotterdam. Approximately 70 participants attended the meeting.

Prizes/Awards Dr. M. de Vries won an international trainee scholarship from the American Thoracic Society. D. van der Plaat, MSc, won an abstract scholarship from the American Thoracic Society. A.I.R. Spanjer, MSc, won the Translational Research Prize from the Federation of European Pharmacological Societies (EPHAR) and the European Association for Clinical Pharmacology and Therapeutics (EACPT). M. Ketelaar won a travel grant for best oral abstract at the International Severe Asthma Forum 2016 (ISAF). W. van Geffen, MD, won the Young Researcher Grant from the European Respiratory Society. Dr. L.E.M. Kistemaker won the best young investigator abstract award of assembly 5 (Inflammatory Airways Diseases and Clinical Allergy) of the European Respiratory Society. Dr. M. Duiverman won the best abstract award in noninvasive ventilatory support of the European Respiratory Society. M. Ketelaar received a Talent Grant from the Ubbo Emmius-Junior Scientific Masterclass (UEF-JSM Talent Grant, University of Groningen). Dr. L.E.M. Kistemaker won the Netherlands Respiratory Society Swieringa Thesis Award. Prof. Dr. H.M. Boezen was awarded as Fellow of the European Respiratory Society. Prof. Dr. M. Schmidt was awarded as Fellow of the British Pharmacological Society. Prof. Dr. D.S. Postma obtained the COPD10 UK award for scientific contribution to the field.

Visitors Prof. Dr. I. Adcock, Imperial College London, UK. February 29, 2016. Dr. R.C.J. Langen, Maastricht University, Maastricht. February 29, 2016. Prof. Dr. E.C. de Jong, Academic Medical Center, Amsterdam. February 29, 2016. Prof. Dr. L. Koenderman, University Medical Center Utrecht, Utrecht. February 29, 2016. Prof. Dr. C. Taube, Leiden University Medical Center, Leiden. March 23, 2016. Prof. Dr. R. Penn, Thomas Jefferson University, Philadelphia, USA. March 31 & Dec 9, 2016. Prof. Dr. S.T. Holgate, Southamptom General Hospital, UK. April 1, 2016. Prof. Dr. S.T. Weiss, Harvard Medical School, Boston, USA. April 1, 2016.

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Prof. Dr. P.J. Sterk, Academic Medical Center, Amsterdam. April 1, 2016. Prof. Dr. E. Bleecker, Wake Forest University, Winston-Salem, USA. April 1, 2016. Dr. H. de Groot, Reinier de Graaf Hospital, Delft. April 15, 2016. Dr. Y. Meijer, University Medical Center Utrecht, April 15, 2016. Prof. Dr. M. Peters-Golden, University of Michigan, USA. April 28, 2016. Dr. K. Affleck, GlaxoSmithKline, UK. July 7-8, 2016. Dr. A. Yeo, GlaxoSmithKline, UK. July 7-8, 2016. Dr. J. Betts, GlaxoSmithKline, UK. July 7-8, 2016. Dr. Prakash, Mayo Clinic, Rochester, USA. December 1, 2016. Dr. S. Kelada, University of North Carolina, USA. November 14-15, 2016. Prof. Dr. K. Racké, University of Bonn, Germany. December 9, 2016. Prof. Dr. A.J. Halayko, University of Manitoba, Canada. December 9, 2016. Prof. Dr. A. Stewart, University of Melbourne, Australia. December 9, 2016. Prof. Dr. J. Hourihane, University College Cork, Ireland. December 12, 2016

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Special Topics

Special topic 1

Retirement of Professors Postma, Dubois and Meurs from GRIAC in 2016

2016 marked a great change within GRIAC with three renowned GRIAC investigators retiring

from their scientific positions, and new young GRIAC investigators joining the board. To

celebrate the scientific careers of these investigators, retirement symposia were organized,

which featured many local, national and international speakers.

On April 1st, Prof. Dr. Dirkje Postma retired at the UMCG. It is nearly impossible to sum up

everything that Dirkje did for respiratory research, health care and education in Groningen,

the Netherlands and internationally. Dirkje is one of the founding chairs of the Groningen

Research Institute for Asthma and COPD (GRIAC). She managed to bring together a large

number of respiratory researchers from different disciplines, with focus on clinical, basic

and/or translational science and across all research areas of asthma and COPD.

Dirkje put asthma genetics on the

map with her landmark paper in the

New England Journal of Medicine in

1995. A group of researchers, led by

Dirkje, described the linkage between

bronchial hyperresponsiveness and

genetic markers on chromosome

5q31-q33. Dirkje has contributed over

800 scientific papers to date, is/was a

mentor of more than 85 PhD students

and many more fellows, post-docs

and PIs. She had a leading role in the

foundation of the Netherlands Respiratory Society (NRS) and the national programme of lung

research. She was a valued physician by her patients and a valued educator by all her

trainees. In all respects and by objective standards, Dirkje is the most successful respiratory

researcher in the Netherlands to date (quote Peter Sterk).

At the symposium several scientists that played key roles in her scientific career, took the

stage to (often from a historical perspective) review the field to which they, mostly in

collaboration with Dirkje and others, contributed. They provided personal perspectives on

both science as well as working with Dirkje. Many, many beautiful moments were described.

An impressive 380 people visited the symposium, from all across the country, and abroad.

The celebration of her work was reinforced by several prizes and recognitions during the

ceremony:

Dirkje received the Thomassen à Thuessinkpenning for her exceptional contributions

to the University Medical Center Groningen.

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Dirkje was declared NVALT (Dutch Society for Physicians for lung diseases and

tuberculosis) honorary member.

The establishment of a “Dirkje Postma Talent award” by the Longfonds. A 200.000 €

award will be awarded to a young researcher.

On April 15th, 2016 Prof. Dr. Ewoud Dubois, internist-allergologist at the University Medical

Center Groningen, said farewell to the Beatrix Children's Hospital. To thank his great

commitment to pediatric allergology, a symposium was organised to honor his farewell,

entitled “the identity of pediatric allergy”. The speakers of this symposium addressed the

developments in allergy research in recent years. In addition, attention was paid to the many

studies and PhD students that Prof. Dubois has supervised. We also looked forward to the

promising future of the pediatric allergology in Groningen. With many interested parties, and

even a special contribution of young patients and a musical contribution, it certainly was a

special day. Prof Dubois has been very important in the past 25 years for the pediatric

allergology within the University Medical Center Groningen and will be succeeded by Dr.

Aline Sprikkelman. He will still be involved in various scientific studies in the coming years.

In honor of the retirement of Prof. Dr. Herman Meurs, a farewell symposium was organized

on December 9th, 2016 to celebrate the scientific achievements Herman has made during

his career. The symposium featured many close scientific collaborators of Herman, who

made it all the way from overseas to join Herman on this wonderful day: Prof. Alastair

Stewart (Melbourne, Australia) with whom Herman did his sabbatical, Profs. Raymond Penn

(Jefferson University) and Andrew Halayko (University of Manitoba), and Prof. Harm

Maarsingh (Palm Beach Atlantic University), former PhD student of Herman.

Herman contributed several key findings to the scientific literature and was best known for

his work on the mechanisms of airway hyperresponsiveness. Key findings include the role of

muscarinic receptors and their cross-talk with beta receptors, and the role of nitric oxide

metabolism and the enzyme arginase. The scientific lectures presented at the symposium

were centered around these scientific themes, and were followed by an inspiring tour though

Herman's life as scientist and mentor, presented by Herman himself.

On behalf of all members of GRIAC, we thank everyone for making these events enjoyable

and memorable. Most importantly, we thank Professors Postma, Dubois and Meurs for all

their valuable contributions they have made to GRIAC over the past years.

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Special topic 2

Excellent assessment of the research program of GRIAC: Opportunities ahead

Gerard Koppelman and Reinoud Gosens

The Standard Evaluation Protocol of GRIAC 2009-2015

In 2015, the research institutes of the University Medical Center Groningen and the

University of Groningen were assessed using the Standard Evaluation Protocol 2015 – 2021,

(https://www.knaw.nl/nl/actueel/publicaties/standard-evaluation-protocol-2015-2021) which is

the protocol for Research Assessments in the Netherlands. In 2016, after a round of rebuttal,

the final report was published. The three main topics for this research assessment were

research quality, societal relevance and viability, and this was scored at 1 (World leading/

excellent); 2 (very good); 3 (good); and 4 (unsatisfactory).

What were the conclusions of the review committee?

Research quality: Score : 1 out of 4

GRIAC is a large, mature, research group. The research undertaken by GRIAC is of very

high quality and internationally competitive (potentially in the top 3% of respiratory research

worldwide). The reasons for this include: the focus on expression of asthma and COPD in

the natural setting across the life course, the establishment of disease cohorts, the

infrastructure for deep phenotyping, the strong translational activities, cross fertilization of

specialties within GRIAC, high performing and effective pathology laboratory, strong

collaboration and networking and investments in disease stratification. GRIAC has a rich and

diverse publication output of top quality. A proportion of the publications needs to be in

specialized more practical journals that do not attract the greatest impact but yet are crucial

for promulgating translational research. It is important to note that GRIAC is ranked 3rd out of

300 research centers in Europe for in the field of airways diseases and number one in the

Netherlands (source Expertscape). A strong input by patients into discussing research

priorities and individual projects has been achieved by incorporating a Patients’ Forum into

GRIAC.

Relevance to society; Score: 1 out of 4

GRIAC is a real beacon of success for its outreach activities. Indeed, this is among the most

remarkable distinguishing features of this research grouping. The effectiveness of their ability

to move research into practical settings becomes very clear when looking at indices of

activity such as: leadership in professional societies, advisory boards, roles in local/national

government; active promulgation of their research to healthcare professionals, patients and

the public at large; production of educational materials; strong interaction with companies,

patent applications and setting up of a spin-off company. In all areas the team shows an

impressive creativity and enthusiasm for developing policy and practice.

Viability: Score: 2 out of 4

The performance of the group on all indicators bodes well for its continued success and

viability and there can be no doubt that their current activity will continue to produce high

quality results. With a change in leadership there is an opportunity to create a visionary plan

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for its future development to take full advantage of the technology revolution and the

population and patient disease cohorts. The SWOT analysis gives some insight into issues

that will need to be addressed in a forward looking strategy. First of all, the task of the new

and ambitious leaders following in the footsteps of the retiring, a world class and charismatic

leader, in April 2016 will be a challenge. Other challenges are: acquiring national and EU

funding to enable multidisciplinary research (e.g. in consortia); pushing the bar higher in

securing more grants to enable talented individuals to become leaders in their own right;

framing some challenges in lung disease such as stratifying airways disease along causal

pathways and develop therapeutics accordingly with GRIP; applying novel technology

platforms such as imaging, biosensors, biomarker exploration; using multi-omics approaches

in addition to genomics (systems approaches); developing relationships with the diagnostic

devices and imaging industries e.g. to explore remote monitoring the exposome to explore

gene/environmental interactions; considering interfacing with other disease areas, where

appropriate (e.g. COPD/lung cancer and asthma/other allergic diseases).

GRIACs response: Opportunities ahead

GRIAC has welcomed the assessment of the committee. In board meetings, the GRIAC

retreat as well as in a brainstorm session with principal and young investigators, we have

discussed our challenges ahead based on this assessment.

We found strong support of our multidisciplinary, translational approach. We acknowledge

that a proportion of the publications are necessarily in specialized, more practical journals

that do not have the highest impact but are still crucial for disseminating translational

research. We aim to continue our method of collaboration within GRIAC, which is aimed at

stimulation multidisciplinary research.

Regarding our outreach activities, we would like to thank the patients from our patient

advisory board for their advices and notice that GRIAC sets an example for patient

participation in research. For the next years, we intend to generate a possibility for patients

and the general public to communicate with researchers at GRIAC, by supporting and

generating interactive webpages at the GRIAC website. In addition, we advise the possibility

of webpages within the individual research institute’s domains containing general information

for the public in lay Dutch.

We acknowledge that we can take our integrative genomic approach in translational science

to a next level. This would require the establishment of GRIAC core facilities in new

technology application and bioinformatics. The integration of GRIP within GRIAC allows for

opportunities to direct our integrative genomics approach towards identification of drug

targets and subsequent drug discovery. This topic was clearly prioritized by GRIAC

members, and future investments in GRIAC translational multi-omics would include

equipment (robotics for sample preparation of patient samples for genomics analysis,

including epigenomics and single cell sequencing), IT-infrastructure and continuous

bioinformatics staff support. We will also build on our world-leading position in implementing

lung devices in COPD. Furthermore, to enhance our viability we strongly support new

young scientists in obtaining personal grants (i.e. 3 grants in 2015) and started a postdoc

mentoring system to help talented researchers become leaders in their fields.

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Special topic 3

Patient participation to improve quality of research and health care within GRIAC

Machteld Hylkema

GRIAC highly values the contribution from patients to improve clinical study design and

research grant proposals and help in choosing priority areas. Since a few years now, GRIAC

has a board of 10-12 patients with asthma and COPD that meets 4 times per year. They

review studies at an early stage of project development, through to hearing final reports of

completed studies. The patients’ input helps with ensuring the research is relevant and the

outcomes are clearly communicated to the end users. Last year, the following project

updates and proposals were presented and discussed (table 1). Besides that, patients and

researchers were trained in two separate meetings by dr. Truus Teunissen from the Lung

Foundation Netherlands, on what criteria are being used by the Lung Foundation

Netherlands for evaluation of patient participation in project proposals.

Table 1. Project reports and proposals in 2015/2016

Project report Researcher

A pro-inflammatory role for the Frizzled-8 receptor in chronic bronchitis.

Anita Spanjer, Molecular Pharmacology

A new proteogenomic approach to identify unique patient-specific protein variants and causal pathways important in development of COPD.

Corry-Anke Brandsma, Pathology

Oxidative stress inhibits lung regeneration: mechanisms and new oppurtunities for therapy

Reinoud Gosens, Molecular Pharmacology

The sweet taste of tolerance: a new vaccin against allergens for sustained suppression of allergic asthma.

Martijn Nawijn, Medical Biology

The use of ICS/laba during complaints in mild asthma.

Jan Willem Kocks, General Practice

To stop unnecessary use of inhalation corticosteroids in COPD.

Jan Willem Kocks, General Practice

Epigenetic reprogramming of basal-like lung stem cells to treat chronic mucus hypersecretion.

Machteld Hylkema, Pathology

Nasal high-flow therapy for the treatment of COPD exacerbations.

Marieke Duiverman, Pulmonary Diseases and Home Mechanical Ventilation

The Puffin study for individual advise for children with asthma.

Gerard Koppelman, Pediatric Pulmonology and Pediatric Allergology

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Special topic 4

The lung eQTL database and consortium: origin

and history.

Wim Timens

It started all in 2007; Peter Paré and Yohan Bossé in

interaction with Merck / Rosetta Inpharmatics

developed an initiative for extensive GWAS and RNA-

expression analysis of archival lung tissue that was

extensively clinically characterized and annotated. In

this early development phase I (WT) spent some time

as visiting scientist in the iCapture Institute in

Vancouver and this way was enabled to be involved in this initiative. This led to a research

proposal to Merck Inc. in which the three academic participants (University of British

Columbia, Laval University and UMCG) provided lung tissue with all extensive characteristics

of about 1200 patients and MSD/ Rosetta performed all GWAS analysis and RNA expression

analysis as well as all subsequent bio-informatics. This combined analysis led to a unique

dataset including eQTL (expression quantitative trait loci): “genomic loci that contribute to

variation in expression levels of mRNAs” . All raw data were made available to the

participants. At the start the PI’s in this project were: Peter Paré (UBC), Yohan Bossé

(Laval), and Wim Timens (UMCG) in collaboration with Gregory Opiteck, Jonathan Derry,

David Nickle, and Christine Suver (Merck/Rosetta). Soon after the start Don Sin (UBC),

Michel Laviolette (Laval) and Dirkje Postma (UMCG) joined as PI’s. After the formal project

was finished, the collaboration continued as the “Lung eQTL consortium” with David Nickle

and Ke Hao as Merck collaborators. After retirement of Michel Laviolette and Dirkje Postma,

Philippe Joubert and Maarten van den Berge took their places.

The Lung eQTL database has proven an enormous asset for further research in the three

University environments but also in numerous collaborations. These have led to date to more

than 40 high level publications, up to 20 in progress and many more to be expected to rise

from this initiative.

Key publication:

Hao K, Bossé Y, Nickle DC, Paré PD, Postma DS, Laviolette M, Sandford A, Hackett TL,

Daley D, Hogg JC, Elliott WM, Couture C, Lamontagne M, Brandsma CA, Berge M van den,

Koppelman G, Reicin AS, Nicholson DW, Malkov V, Derry JM, Suver C, Tsou JA, Kulkarni A,

Zhang C, Vessey R, Opiteck GJ, Curtis SP, Timens W*, Sin DD*. Lung eQTLs to help reveal

the molecular underpinnings of asthma. PLoS Genet. 2012;8(11):e1003029.

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Special topic 5

Opening of Pediatric Allergy & Asthma Center in the UMCG

Aline Sprikkelman

The number of children with one or more allergic diseases continues to increase*. To

generate the best, highly specialized care for these children, the UMCG has opened the

Pediatric Allergy & Asthma Center. In the center, doctors, nurses and researchers from

different departments will work together in the diagnosis and treatment of children with

(suspected) allergic diseases and asthma. The center is part of the Beatrix Children's

Hospital of the University Medical Center Groningen and was officially opened with a

symposium on September 23rd, 2016.

The Pediatric Allergy & Asthma Center offers expertise in the field of diagnosis and treatment

of allergic diseases of the respiratory tract, the skin and the gastrointestinal tract as well as

food or drug allergy or allergy to insect venom. The focus is on complex care for children who

have severe several allergies at once, or children who develop a severe allergic reaction to

drugs used for the treatment of cancer or arthritis. Such an allergic reaction can be

expressed by a reaction of the skin, eyes or respiratory tract, but also by the cardiovascular

tract or gastrointestinal tract.

Where, for example hay fever will trigger irritated eyes and problems with the upper

respiratory tract, a food or insect venom allergy can give a very serious and life-threatening

reaction, such as anaphylactic shock. In such a shock, the airways can swell dangerously,

blood pressure can drop severely and organ failure may occur. In that case, direct

administration of adrenaline is important to stop the reaction. Without treatment, a severe

allergic reaction be fatal. But there are also less severe acute reactions. An allergic reaction

to a cancer treatment, for which no alternative is available, can be life-threatening as well.

Care for these complex patients will be designed in close cooperation and coordination with

the health care providers and hospitals in the region. In addition to patient care the center

offers tailored education and research activities. The center brings together nurses, doctors

and researchers from different departments, such as (pediatric) allergy, (pediatric)

pulmonology, dermatology and ENT specialists.

* It is expected that 50% of people in the European Union has an allergic condition in 2025. Of these, some 100

million people have allergic rhinitis, 70 million people have asthma, and 17 million people have a food allergy. Of

these, 3.5 million children will suffer from food allergy.

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Special topic 6

Genetics underlying COPD in never-smokers

Diana van der plaat, Kim de Jong, Judith Vonk, Dirkje Postma, Marike Boezen

Departments of Epidemiology and Pulmonology

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the

world and is characterized by impaired pulmonary function and progressive airway

obstruction.1,2 There are multiple risk factors for developing COPD (Figure 1), among others,

exposure to cigarette smoke (passive or in utero), occupational exposure to dusts and

chemicals (such as vapors, gases, dusts, fumes (VGDF), and pesticides); indoor and outdoor

air pollution; chronic asthma or bronchitis; history of lower respiratory-tract infections and/or

pulmonary tuberculosis; poor nutrition and poor socioeconomic status.(1-3) Cigarette smoke

exposure is considered the most important risk factor and about 13% of the smokers develop

COPD.(4,5) On the other hand, there is a considerable proportion of COPD patients (25-

45%) that do not have smoking as underlying cause of their disease.14 In developing

countries this proportion is higher compared to developed countries, but even in the

Netherlands approximately 16% of the COPD patients are never-smokers.(6)

Figure 1: Risk factors for COPD (Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD): Global Strategy for the Diagnosis, Management, and Prevention of COPD(7))

COPD is usually the result of an interplay between poor lung development and lung growth,

(long-term) exposure to noxious particles or gases and, (epi-) genetic susceptibility.(8) The

diagnosis of COPD is largely based on the presence of airway obstruction, which is

commonly diagnosed based on the spirometry measurements of forced expiratory volume in

one second (FEV1) and its ratio to forced vital capacity (FEV1/FVC).4 Unfortunately, relatively

little is known about underlying mechanisms of COPD in never-smokers, since usually this

group is excluded from analysis or there is no special focus on this group.(9) Common

21

genetic variants underlying lung function (FEV1, FVC and FEV1/FVC) or COPD have been

identified by several genome-wide association (GWA) studies.(10-14) Among others, the

Nicotinic Cholinergic Receptor (CHRNA3/5), Family With Sequence Similarity 13 (FAM13A)

and hedgehog-interacting protein (HHIP) were reported. However, these studies were

performed in only ever-smokers or population based studies including both ever- and never-

smokers.

We have performed several GWA studies in specifically never-smokers using data from three

Dutch population based cohort studies, i.e. the LifeLines study (n=5,070), the Vlagtwedde-

Vlaardingen study (n=432) and the Rotterdam study (n=1,126). We assessed the association

between single nucleotide polymorphisms (SNPs) and lung function (FEV1, FEV1/FVC and

FEF25-75) or airway obstruction. The information from these studies may ultimately contribute

to the understanding of cellular and molecular pathways involved in lung function impairment

and the development of COPD.

First, we were able to replicated associations between FEV1/FVC and two SNPs annotated

to the well-known COPD genes HHIP and FAM13A in never-smokers.(15) The two SNPs

were also associated with gene expression levels of HHIP and FAM13A in lung tissue. In

addition, the genetic risk score analysis showed that the combined effect estimate for the two

independent SNPs accounted for a 2.4% lower FEV1/FVC level, a credible clinically relevant

effect (Figure 2).

Figure 2. Genetic risk score (GRS) analysis of the risk alleles in FAM13A and HHIP on FEV1/FVC level in the identification cohort. Genetic risk scores where created by adding up the number of alleles (risk alleles) for both HHIP and FAM13A SNPs associated with a lower FEV1/FVC level. A value of 0 means no risk alleles for both SNPs, and a value of 4 means a subjects is carrying all four risk alleles of both SNPs. The mean FEV1/FVC levels and 95% CI are given for each GRS based on a median age and a mean height.

Of interest, a substantial proportion of our study population, i.e. 6%, was carrying all four risk

alleles. HHIP is known to play an important role in fetal lung branching development and

silencing of HHIP was shown to lead to differential expression of about 300 genes enriched

for cell growth, lung extracellular matrix and genes associated with COPD.(16). FAM13A

may play a role in emphysema development and loss of FAM13A resulted in increased cell

proliferation and activation of b-catenin signaling.(17) We concluded that the genes HHIP

and FAM13A confer a risk for airway obstruction in general that is not driven exclusively by

22

cigarette smoking. Moreover, these two genes might have an impact on the prevalence of

COPD worldwide, especially in countries were COPD due to smoking is less prevalent.

Next, we performed a GWA study on small airways obstruction using the spirometric

measurement of forced expiratory flow at 25%-75% of forced vital capacity (FEF25–75).(18)

The risk allele of the same SNP annotated to HHIP was genome-wide associated with a 98

mL/s lower FEF25-75 level. In the sensitivity analysis excluding subjects with predominantly

large airways obstruction, a SNP annotated to Mitochondrial Trans-2-Enoyl-CoA Reductase

(MECR) was genome-wide significant, and in addition associated with gene expression

levels of MECR and Erythrocyte Membrane Protein Band 4.1 (EPB41). MECR is involved in

mitochondrial fatty acid synthesis and over-expression of MECR increases Peroxisome

proliferator-activated receptor alpha (PPARα) activity, which might play a role in emphysema

progression.(19,20) This study therefore provided novel insights into the role of the well-

known COPD gene HHIP in both the small and large airways and showed supportive

evidence for the role of the novel gene MECR in specifically small airways obstruction.

The last GWA study was on airway obstruction, which can be defined as either

FEV1/FVC<70% or FEV1/FVC<lower limit of normal (LLN).[submitted] There is a

considerable controversy about which definition should be used in research and clinical

practice, since both may lead to misclassifications.(21-24) Only few genetic regions were

overlapping between previous GWA studies, due to the usage of different airway obstruction

definitions and populations. We therefore aimed to assess the genetic overlap between the

two definitions of airway obstruction in the same never-smoking individuals of our Lifelines

cohort. We expected a reasonable overlap in associated SNPs between the two definitions,

since based on either definition 96% of the never-smokers were classified into the same

group (either having or not having obstruction). Surprisingly, only 4% of the SNPs were

overlapping between the two definitions at p<10-4 and 26% at p<0.05 (Figure 3).

Figure 3. Venn diagrams showing the overlap between the two definitions of airway obstruction for the number of subjects classified as having airway obstruction and the number of identified SNPs with p<10-4.

This implies that the definition of airway obstruction and the strategy (discovery-replication

design) have a substantial influence on the GWAS results, and thus on which variants are

23

selected for replication. Finally, our results also suggest that genes FABP7 and NFYC(-AS1)

could play a role in the pathogenesis of airway obstruction in never-smokers.

In conclusion, we identified several SNPs associated with lung function or airway obstruction

in specifically never-smokers. The genes HHIP, FAM13A, FABP7 and NFYC are

susceptibility genes for the development of airway obstruction and showed to have an effect

regardless of exposure to cigarette smoking. HHIP is involved in the development of both

small and large airways and our data suggests that MECR plays a role in specifically small

airways obstruction. In addition, the definition of airway obstruction had a substantial

influence on which genes were associated with airway obstruction and therefore it is

important for future studies to use the same definition or to focus more on specific COPD

subtypes.

References

(1) Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. The Lancet 2009;374(9691):733-743.

(2) Zeng G, Sun B, Zhong N. Non-smoking-related chronic obstructive pulmonary disease: a neglected entity? Respirology 2012 Aug;17(6):908-912.

(3) Viegi G, Pistelli F, Sherrill DL, Maio S, Baldacci S, Carrozzi L. Definition, epidemiology and natural history of COPD. Eur Respir J 2007 Nov;30(5):993-1013.

(4) Fletcher C, Peto R, Tinker C, Speizer FE. The Natural History of Chronic Bronchitis and Emphysema. Postgrad Med J 1977 06;53(620):351-351.

(5) Rennard SI, Vestbo J. COPD: the dangerous underestimate of 15%. Lancet 2006 Apr 15;367(9518):1216-1219.

(6) Terzikhan N, Verhamme KM, Hofman A, Stricker BH, Brusselle GG, Lahousse L. Prevalence and incidence of COPD in smokers and non-smokers: the Rotterdam Study. Eur J Epidemiol 2016 Aug;31(8):785-792.

(7) Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD 2017. 2017.

(8) Postma DS, Kerkhof M, Boezen HM, Koppelman GH. Asthma and chronic obstructive pulmonary disease: common genes, common environments? Am J Respir Crit Care Med 2011 Jun 15;183(12):1588-1594.

(9) Sexton P, Black P, Wu L, Sommerville F, Hamed M, Milne D, et al. Chronic obstructive pulmonary disease in non-smokers: a case-comparison study. COPD 2014 Feb;11(1):2-9.

(10) Wilk JB, Shrine NR, Loehr LR, Zhao JH, Manichaikul A, Lopez LM, et al. Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. Am J Respir Crit Care Med 2012 Oct 1;186(7):622-632.

(11) Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet 2010 Jan;42(1):45-52.

(12) Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, et al. Genome-wide association study identifies five loci associated with lung function. Nat Genet 2010 Jan;42(1):36-44.

(13) Soler Artigas M, Loth DW, Wain LV, Gharib SA, Obeidat M, Tang W, et al. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat Genet 2011 Sep 25;43(11):1082-1090.

(14) Wain LV, Shrine N, Miller S, Jackson VE, Ntalla I, Artigas MS, et al. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir Med 2015 Oct;3(10):769-781.

(15) van der Plaat DA, de Jong K, Lahousse L, Faiz A, Vonk JM, van Diemen CC, et al. Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A. J Allergy Clin Immunol 2017 Feb;139(2):533-540.

(16) Zhou X, Baron RM, Hardin M, Cho MH, Zielinski J, Hawrylkiewicz I, et al. Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP. Hum Mol Genet 2012 Mar 15;21(6):1325-1335.

24

(17) Jiang Z, Lao T, Qiu W, Polverino F, Gupta K, Guo F, et al. A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of beta-catenin. Am J Respir Crit Care Med 2016 Feb 10.

(18) van der Plaat DA, de Jong K, Lahousse L, Faiz A, Vonk JM, van Diemen CC, et al. The Well-Known Gene HHIP and Novel Gene MECR Are Implicated in Small Airway Obstruction. Am J Respir Crit Care Med 2016 Nov 15;194(10):1299-1302.

(19) Parl A, Mitchell SL, Clay HB, Reiss S, Li Z, Murdock DG. The mitochondrial fatty acid synthesis (mtFASII) pathway is capable of mediating nuclear-mitochondrial cross talk through the PPAR system of transcriptional activation. Biochem Biophys Res Commun 2013 Nov 15;441(2):418-424.

(20) Lee JH, Hanaoka M, Kitaguchi Y, Kraskauskas D, Shapiro L, Voelkel NF, et al. Imbalance of apoptosis and cell proliferation contributes to the development and persistence of emphysema. Lung 2012 Feb;190(1):69-82.

(21) Mohamed Hoesein FAA, Zanen P, Lammers JJ. Lower limit of normal or FEV1/FVC <0.70 in diagnosing COPD: An evidence-based review. Respir Med 2011 6;105(6):907-915.

(22) Medbo A, Melbye H. Lung function testing in the elderly--can we still use FEV1/FVC<70% as a criterion of COPD? Respir Med 2007 Jun;101(6):1097-1105.

(23) Hardie JA, Buist AS, Vollmer WM, Ellingsen I, Bakke PS, Morkve O. Risk of over-diagnosis of COPD in asymptomatic elderly never-smokers. Eur Respir J 2002 Nov;20(5):1117-1122.

(24) Roberts SD, Farber MO, Knox KS, Phillips GS, Bhatt NY, Mastronarde JG, et al. FEV1/FVC ratio of 70% misclassifies patients with obstruction at the extremes of age. Chest 2006 Jul;130(1):200-206.

25

Special topic 7

Granted projects in 2016

De-implementation of unnecessary Inhaled Corticosteroids use in COPD - Dr. Jan

Willem Kocks (UMCG), Dr. Job van Boven (UMCG), Dr. Tjard Schermer (Radboud MC)

Granted by Citrien Fund, sponsored by ZonMW via the ‘Nederlandse Federatie van

Universitair Medische Centra’ (NFU).

Both asthma and COPD are prevalent chronic obstructive lung diseases that cause, among

other things: cough and shortness of breath. Inhaled Corticosteroids (ICS) are indicated for

the treatment of asthma but only to a limited extent in the treatment of COPD. Only for those

COPD patients that experience 2 or more exacerbations per year or are treated in hospital

for at least 1 exacerbation and for those COPD patients that also suffer from asthma is a

treatment with ICS indicated.

Even though limited indication for ICS in COPD has been incorporated in Dutch treatment

recommendations for general practitioners for several years, no reduction in ICS

prescriptions in patient groups that are not indicated for use has been seen.

In addition to increasing health care costs the use of ICS is also associated with side-effects.

Both local (e.g. oral thrush, hoarseness and dysphonia) and systemic (e.g. increases the

chance of pneumonia, cataract and osteoporosis). Stressing the need to restrict the use to

only the indicated patients.

This study’s primary aim is reducing ICS prescriptions by educating both GP’s and

pharmacists on the optimal use of ICS in COPD. GP and pharmacists regularly organize

pharmacotherapy meetings during which new developments are discussed

(FarmacoTherapeutisch Overleg, FTO). The project will use these meetings to present the

newest developments in the field of ICS use in COPD patients. At the end of the meeting the

GP’s receive an A4 paper sheet with decision tree for the correct indication per individual

patient. Patients are selected from pharmacy dispensing records and patients that received

oral storoid courses are excluded.

GP’s are requested to study the list and proceed with discontinuation in those patients that

qualify. Additionally, education is given via publications in the professional and public media.

The study is considered successful if 10% of this group has stopped using ICS 12 months

after the intervention.

This study’s features several secondary aims, among which:

Identifying barriers and facilitators in the process of starting and stopping with ICS. Both

from the perspective of the professional as well as from the perspective of the patient.

This is achieved via focus groups.

Assess medical costs before and after the intervention.

Assess exacerbation rates before and after the intervention.

26

Understanding the genetic and epigenetic drivers of cigarette smoke susceptibility in

COPD - Dr. Alen Faiz (UMCG)

Granted by Lung Foundation Netherlands, junior investigator grant

Chronic obstructive pulmonary disease (COPD) is a highly prevalent and debilitating

respiratory disease, characterized by chronic inflammation leading to accelerated lung

function decline. The major risk factor for COPD is inhalation of noxious particles and gases,

particularly cigarette smoking in the developed world. Despite this fact, only a subset of 20-

30% of smokers are susceptible and will ultimately develop COPD. This suggests that

genetic factors also play an important role in the development of this disease. Interestingly,

specifically in COPD, the inflammation associated with smoke exposure remains even after

subjects have quit smoking. It is currently postulated that this may be caused by persistent

epigenetic changes, e.g. DNA-methylation. I hypothesise that smoking susceptibility is

determined by genetic variations affecting gene-expression in bronchial epithelium, the first

line of defence against the inhaled toxins. Furthermore, I put forward that prolonged smoking

in combination with genetic variations in susceptible individuals leads to DNA-methylation

that persists after smoking cessation, leading to persistent inflammation.

I will assess the influence of genetic polymorphisms on the transcriptional response of the

bronchial epithelium to smoke exposure. To this end, smoking-induced expression

Quantitative Trait Loci (eQTLs) will be investigated in a unique cohort of subjects with and

without COPD before and after smoking. Furthermore, I will investigate whether changes in

DNA-methylation after smoking cessation are different in patients with COPD compared to

asymptomatic smokers. Finally, I will validate these newly identified genetic variants and

DNA-methylation sites in-vitro using cutting edge genome editing technology (CRISPR–

Cas9). This study will allow early identification of susceptible subjects and provide new and

important insights into the persistent epigenetic changes caused by smoking with the

ultimate aim to provide new treatment targets for early intervention.

From genetic profile to precision medicine in children with persistent asthma.

The PUFFIN trial (Pharmacogenetics Use For Further treatment Improvement in

childreN). - Prof. dr. A.H. Maitland- van der Zee (AMC), PI, Prof dr GH Koppelman (UMCG),

co-PI, , Dr M. W. Pijnenburg (Erasmus MC), co-PI.

Granted by Lung Foundation Netherlands, consortium grant

Approximately 25% of all children with asthma suffer from uncontrolled asthma despite

maintenance treatment with inhaled corticosteroids (ICS). After optimising adherence to

treatment and inhaler technique, these children are in need of step-up treatment with double

dosage of ICS or addition of a long acting beta-2-agonist (LABA). Both strategies are equally

effective, however response to this step-up treatment varies considerably between individual

children.

Particularly in children, variation in the ADRB2 gene (coding for the beta(2)-adrenergic

receptor B2AR) is associated with these differences in the therapeutic effect of LABA.

Children homozygous for the Arg16 variant (16% of children) receiving a LABA may

experience an increased number of asthma exacerbations and school absenteeism due to

27

increased down regulation of the B2AR. Therefore, in these children LABA should be

avoided and alternative step up treatment should be considered.

In this nationwide, multi-centre Randomized Clinical Trial (RCT) we aim to assess the value

of a precision medicine (PM) approach: genotype-guided treatment in children with

uncontrolled asthma despite ICS compared to non-genotype guided treatment. Participants

will be randomized to ‘the control arm’ (n=150) or ‘precision medicine-guided treatment’

(n=150). In the precision medicine arm, children homozygous (estimated n=24) or

heterozygous for the variant ADRB2 (estimated n= 75) will be treated with a double dose

ICS, while children homozygous for the wild types will be treated with LABA. Children will be

followed for 6 months. In the control arm, children will be randomized to LABA or double

dosage of ICS. Primary outcome will be longitudinal changes in asthma control (Asthma

Control Test scores) in the first three months of the trial. Cost-utility of the intervention

(euro/QALY) will be assessed. (figure)

We hypothesize that genotype-guided treatment leads to better and faster symptom control

in children with uncontrolled asthma despite ICS use, and decreases asthma related costs.

Full information on background, rationale and description of the trial was recently published

in Vijverberg et al, The need for precision medicine clinical trials in childhood asthma:

rationale and design of the PUFFIN trial.Pharmacogenomics. 2017 Mar;18(4):393-401. doi:

10.2217/pgs-2016-0174. Epub 2017 Feb 22.

Children in the study will be randomized to precision medicine-guided treatment based on

ADRB2 genotyping or usual care (control arm). In the control arm children will be randomized

to add on treatment with a long-acting beta2-agonist (LABA) or doubling of the dosage of

inhaled corticosteroids (ICS), the two most common add options in the Netherlands.

28

Departments Dept. Epidemiology University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone 31-50-361 0739 Fax 31-50-361 4493 Principal Investigators: Prof. Dr. H.M. Boezen, 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 Investigators: Prof. Dr. T. van der Molen, Dr. B.M.J. Flokstra – de Blok Associate Principal Investigator: Dr. J.W.H. Kocks Dept. Internal Medicine, div. Allergology University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 2976 Fax: 31-50-3121576 Principal Investigators: Dr. J.N.G. Oude Elberink Dept. Pathology and Medical Biology, div. Medical Biology University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 8043 Fax: 31-50-361 9911 Principal Investigators: Prof. Dr. H.I. Heijink, Dr. M.C. Nawijn, Dr. J.K. Burgess 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, Prof. Dr. R. Gosens, Prof. Dr. B.N. Melgert Dept. Pathology and Medical Biology University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 4684 Fax: 31-50-363 2510 Principal Investigators: Prof. Dr. W. Timens, Dr. M.N. Hylkema, Dr. C.A. Brandsma

29

Dept. Pediatric Pulmonology and Pediatric Allergy Beatrix Children’s Hospital, University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 1107 Fax: 31-50-361 1704 Principal Investigators: Prof. Dr. G.H. Koppelman, Prof. Dr. A.E.J. Dubois, Dr. B.L. Rottier, Dr. A. Sprikkelman Dept. Pulmonary Diseases and Tuberculosis University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 3532 Fax: 31-50-361 9320 Principal Investigators: Prof. Dr. D.S. Postma, Prof. Dr. H.A.M. Kerstjens, Dr. M. van den Berge, Dr. N.H.T. ten Hacken, Dr. D.J. Slebos Working group on Respiratory Insufficiency University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 3235 Fax: 31-50-361 9320 Principal Investigator: Dr. P.J. Wijkstra

30

Members 2016

Other scientific staff

Brandsma C.A., PhD Burgess J.K., PhD Diamant Z., PhD, Prof. Dolga A.M., PhD Duiverman M.L., PhD Flokstra-de Blok B.M.J., PhD Guryev V., PhD Hacken ten N.H.T., MD, PhD Horvatovich P., PhD Klooster K., PhD

Kocks J.W.H., MD, PhD Melgert B.N, PhD, Prof. Nawijn M.C., PhD Rottier B.L., MD, PhD Slebos D.J., MD, PhD Touw D.J., PharmD, PhD, Prof. (associate member) Vrijlandt E.J.L.E., MD, PhD Wempe J.B, MD, PhD Willemse B.W., MD, PhD

Post-docs

Baarsma H.A., PhD Ng-Blichfeldt J-P, PhD Boven van J.F.M., PharmD, PhD Prabhala P., PhD Faiz A. PhD Riemersma R.A., MD, PhD Faria Coimbra Lichtenfels de A.J., PhD Schokker S., PhD Hartman J.E., PhD Tsiligianni I., MD, PhD Han B., PhD Velde van der J.L., MD, PhD Jong de C., PhD Vermeulen C.J., PhD Jong de K., PhD de Vries M., PhD Kersten E.T., MD, PhD Xu C., PhD Kistemaker L.E.M., PhD PhD students

Alma H.J., MSc, MD/PhD student Klijnsma M., MD Baretta H.J., MSc Klooster H. Berg van den M.P.M., MSc Koopmans T., MSc Blokland K.E.C., MSc Kuchibhotla V., MSc Boorsma C.E., PhD Lkhagvadorj L., MD Boudewijn I., MD Metting E.I., MSc Cao J.J., PhD Meyer, K. Msc. Carpaij O., MD Nieuwenhuis M.A.E., MSc Cox C., MSc Ong J., MSc Dierick, B.J.H., MSc Osei E., MSc van Dijk E., MSc Pettersson M.E., MD/PhD student Dijk F.N., MD van der Plaat D.A., MSc Draijer C., MSc Poppinga W., MSc Fattahi F., MSc Pouwels S.D., MSc Faura Tellez G., MSc Román-Rodríguez M., MSc

Scientific Board

Berge van den M., MD, PhD Boezen H.M., PhD, Prof Dubois A.E.J., MD, PhD, Prof Gosens, R., PhD, Prof Heijink H.I., PhD, Prof 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 Oude Elberink J.N.G., MD, PhD Postma D.S., MD, PhD, Prof Schmidt M., PhD, Prof Sprikkelman A.B., MD, PhD Timens W., MD, PhD, Prof Vonk J.M., PhD Wijkstra P.J., MD, PhD, Prof

31

Florez-Sampedro L., MSc Saleh-Langenberg J., MD/PhD student Geffen van W., MD Spanjer A.I.R., MSc Gemert van F.A., MD Song, J., MSc Ginkel van C.D., MD/PhD student Tania N., MSc Han X., MSc Tasena H., MSc Hazenberg A. Veen van der T.A., MSc Hesse L., MSc Vos B.J.P.R., MD/PhD student Honrath B., MSc de Vries G.E., MSc Imkamp K., MD Woldhuis R., MSc Jansen S.R., MSc Wu X., MSc Jong de T., MSc Zeng X., MSc Kennedy Feitosa E., MSc Zeng Z., MSc Ketelaar M., MD/PhD student Zijlstra J., MD Kirenga B.J., MD Zuo H., MSc Kruk D.M.L.W., MSc Zwitserloot A.M. MD

Other research staff Augustijn S. Koops H. Beusekamp B. Laan van der-Boers A. Beverdam H.R. Leever M. Bladder G. Lodewijk M. Boef den, L. Menzen M. Bos I. S.T Niemeijer A., MSc Bouwman J. Nijboer-Brinksma S. Brouwer S. Noordhoek J. Brouwer U. Oomkes-Pilon A.M. Bruin de H.G. Oosterom H. Bruins Slot F.J. Reinders-Luinge M. Dijkstra A.H. Sijgers D. Elzinga C.R.S. Smaalen van M. Goslinga D. Smidt-Huizinga H.D.M. Heijst van E.C.M. Stalman W Horst E.W. Star-Kroesen M. Jonge de O.R.M. Swierenga M. Jonker M.R. Wedzinga A. Kooistra W. Zuidhof A.B Klok P. Zwart G.

32

International collaboration 2016 (As far as related to joint projects and publications in 2016)

Prof. I. Adcock Imperial College London London, UK

Dr. A. Agrawal CSIR Institute of Genomics and

Integrative Biology,

New Delhi, India

Prof. G. Andersson Karolinska Institute Stockholm, Sweden

Prof. S. Andreas Georg-August University Göttingen, Germany

Prof. J. Antó IMIM, CREAL Barcelona, Spain

Prof. E.D. 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

Dr. B. Bohle Medical University of Vienna Vienna, Austria

Dr. J. Bourke Monash University Melbourne, Australia

Dr. Y. Bossé Université de Laval Quebec, Canada

Prof. J. Bousquet INSERM Villejuif, France

Dr. K. Bracke University Hospital of Ghent Ghent, Belgium

Dr. B.S. Brook University of Nottingham Nottingham, UK

Prof. G. Brusselle University Hospital of Ghent Ghent, Belgium

Prof. A. Bush Imperial College London, UK

Prof. C. Carlsten University of British Columbia Vancouver, Canada

Prof. A. Casini Cardiff University Cardiff, UK

Prof J. Chakaya Kenya Medical Research Institute Nairobi, Kenya

Dr. M. Cho Harvard Medical School Boston, USA

Dr W. Chrzanowski University of Sydney Sydney, Australia

Prof. C. Culmsee University of Marburg Marburg, Germany

Prof. R. Dahl Aarhus University Hospital Aarhus, Denmark

Prof. D. Davies University of Southampton Southampton, UK

Dr. N. Doti Institute of Biostructures and

Bioimaging-CNR

Naples, Italy

Dr. A. DunnGalvin Cork University Cork, Ireland

Dr. C. Ehrhardt Trinity College Dublin Dublin, Ireland

Dr. G. Fejer University of Plymouth Plymouth, UK

Prof. J. Fonseca University of Porto Porto, Portugal

Prof. M. Gjomarkaj University of Palermo Palermo, Italy

33

Prof. Dr. C.M. Greene Royal College of Surgeons in Ireland Dublin, Ireland

Dr. S. Guerra University of Arizona Tucson, USA

Dr. T.L. Hackett University of British Columbia Vancouver, Canada

Prof. A.J. Halayko University of Manitoba

Winnipeg, Canada

Prof. L. Han Academy of Military Medical Sciences Beijing, China

Prof P.M. Hansbro

University of Newcastle

Newcastle, Australia

Prof. A.J. Henderson

University of Bristol Bristol, UK

Prof. D. Henshall Royal College of Surgeons in Ireland Dublin, Ireland

Prof. F. Herth University of Heidelberg Heidelberg, Germany

Prof. J.C. Hogg University of British Columbia Vancouver, Canada

Dr. J.W. Holloway University of Southampton Southampton, UK

Prof. J.O. Hourihane Cork University Cork, Ireland

Dr. J.Jaffar The Alfred Hospital Melbourne, Australia

Prof. C. Janson Uppsala University Uppsala, Sweden

Prof. D. Jarvis Imperial College London London, UK

Prof. R.C.M. Jones Plymouth University Plymouth, UK

Prof. G. Joos University Hospital of Ghent Ghent, Belgium

Prof. M. Kamya Makerere University Kampala, Uganda

Prof D. Knight University of Newcastle Newcastle, Australia

Prof. L. Kobzik Harvard School of Public Health Boston, USA

Prof. M. Königshoff University of Colorado Denver, USA

Prof. S. Krauss-

Etschmann

Research Center Borstel Borstel, Germany

Dr. R Krishnan Beth Israel Deaconess Medical Center Boston, USA

Prof. B.N. Lambrecht University Hospital of Ghent Ghent, Belgium

Dr. M. Lenburg Boston University School of Medicine Boston, USA

Prof. C. Lionis University of Heraklion Heraklion, Greece

Dr. S. London National Institute of Environmental

Health Sciences (NIEHS)

North Carolina, USA

Prof. H. Maarsingh Palm Beach Atlantic University West Palm Beach, USA

Dr. K. Malakauskas Lithuanian University of Health

Sciences

Kaunas, Luthuania

Dr. F.O. Martinez Surrey University Guilford, UK

Dr. T. Mauad Sao Paolo University Sao Paolo, Brasil

Dr. E. Melén Karolinska Institute Stockholm, Sweden

Prof. A. Methner Johannes Gutenberg-Universität Mainz Mainz, Germany

34

Dr. S. Meiners Helmholtz Center Munich Munich, Germany

Dr. M. Miravitlles Hospital Universitari Vall d’Hebron Barcelona, Spain

Prof. L.C. de Moraes

Sobrino Porto

State University of Rio de Janeiro Rio de Janeiro, Brazil

Prof. B. Oliver Woolcock Institute Sydney, Australia

Prof. P. Paggiaro University of Pisa Pisa, Italy

Prof. P.D. Paré University of British Columbia Vancouver, Canada

Prof. M. Peters-Golden University of Michigan Medical School Michigan, USA

Dr. A. Le Pham University of Medicine & Pharmacy Ho Chi Minh City,

Vietnam

Dr. H. Pinnock University of Edinburgh Edinburgh, UK

Dr. Y.S. Prakash Mayo Clinic Rochester, USA

Prof. D. Price University of Aberdeen Aberdeen, UK

Prof. N. Probst-Hensch Swiss Tropical and Public Health

Institute

Basel, Switzerland

Dr. B.A. Raby Harvard Medical School Boston, USA

Dr. H.K. Reddel Woolcock Institute of Medical

Research

Sydney, Australia

Dr. M. Rojas University of Pittsburgh Pittsburgh, USA

Prof M. Roth University Hospital Basel, Switzerland

Prof. F. van Roy Flemish Institute of Biotechnology Ghent, Belgium

Prof. L. Rumora University of Zagreb Zagreb, Kroatia

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. M. Schuler University of Wuerzburg Wuerzburg, Germany

Dr. K. Schultz Klinik Bad Reichenhall Bad Reichenhall,

Germany

Dr. J. Schwarze University of Edinburgh Edinburgh, UK

Prof. T. Sigsgaard Aarhus University Aarhus, Denmark

Prof. E. Silverman Harvard Medical School Boston, USA

Prof. D.D. Sin University of British Columbia Vancouver, Canada

Prof. T Sooronbaev Ministry of Health Kyrgyz Republic

Dr. J.B. Soriano University of Madrid Madrid, Spain

Dr. A. Spira Boston University School of Medicine Boston, USA

Prof. B. Ställberg Uppsala University Uppsala, Sweden

35

Dr. K. Steiling Boston University School of Medicine Boston, USA

Dr. G Tjin University of Sydney Sydney, Australia

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. N. Viacheslaev University of Göttingen Göttingen, Germany

Prof. J.P.T. Ward Kings College London London, UK

Prof. M. Weatherall University of Otago Wellington, New Zealand

Dr M. Weckmann University of Luebeck Luebeck, Germany

Prof. S.T. Weiss Harvard Medical School Boston, USA

Prof G. Westergren-

Thorsson

Lund University Lund, Sweden

Prof E.S. White University of Michigan Ann Arbor, USA

Prof. T. Wieland University of Heidelberg Heidelberg, Germany

Prof W. Windisch Lungenklinik Merheim, Kliniken der

Stadt Köln, Universität

Witten/Herdecke

Köln, Germany

Prof. G. Yimer Addis Ababa University Addis Ababa, Ethiopia

36

GRIAC Seminar program 2016

Date Speaker Title 05-01-2016 L. Hesse

Pathology & Medical Biology, UMCG

Successful immunotherapy in a mouse model of allergic asthma

19-01-2016 Prof. M. Idzko

University of Freiburg Germany

Purinergic signalling: from bench to bed side and back again

02-02-2016 Dr. F. Greven

GGD Groningen Air pollution during New Year’s fireworks and daily mortality in the Netherlands

16-02-2016 Dr. J. van Boven, E.I.

Metting, M. Román Rodríguez General Practice UMCG & Primary care research center, Palma de Mallorca

Inhaler technique, the past, the present and the future

01-03-2016 A. Spanjer

Molecular Pharmacology UMCG

The role of WNT receptor Frizzled-8 in inflammation and remodeling in airway disease

15-03-2016 Dr. C. Xu

Pulmonology & Genetics UMCG

DNA methylation changes in childhood - relevance for asthma

05-04-2016 Dr. C.A. Brandsma

Pathology UMCG

Genetic regulation of gene expression changes in COPD

10-05-2016 Prof. Dr. D. Ebo

University of Antwerpen Belgium

Meer weten over allergiediagnostiek? Cannabis: een potent allergeen!

21-06-2016 B. Han

Molecular Pharmacology UMCG

Novel strategies in the treatment of COPD: from oxidative stress to cyclic nucleotide compartments

20-09-2016 H. Tasena

Pathology & Medical Biology, UMCG

MicroRNA signature of Chronic Mucus Hypersecretion in COPD

04-10-2016 Dr. I. Sayers

University of Nottingham UK

Translating lung function genome-wide association studies: New insights for lung biology and treatment opportunities

37

Date Speaker Title 18-10-2016 Dr. A. Faiz

Pulmonology, Pathology & Medical Biology UMCG

Functional validation of findings in GWAS studies

01-11-2016 E.I. Metting

General Practice UMCG

Social implications of asthma and COPD

15-11-2016 Dr. S.N.P. Kelada

University of North Carolina USA

Utilizing mouse genetic diversity to identify novel pathways in allergic airway disease

06-12-2016 Dr. H. Baarsma

Molecular Pharmacology UMCG

Non-canonical WNT-5A repairs endogenous lung repair in COPD

20-12-2016 J. Ong

Pathology & Medical Biology UMCG

Identification of transforming growth factor-beta regulated microRNAs and the microRNA-targetome in primary lung fibroblasts

38

GRIAC research meetings 2016

Date Speaker Title 05-01-2016 Maartje Nieuwenhuis

Pulmonology Genetics of the severity of bronchial hyperreponsiveness in asthma

12-01-2016 Tristan de Jong

ERIBA Transcriptome changes in model organisms

19-01-2016 Navessa Padma Tania

Molecular Pharmacology

Endothelial Follistatin-like 1 regulates postnatal development of the pulmonary vasculature by modulating BMP/Smad signaling

02-02-2016 Wilma Biek-vd Velde

Pulmonology The UMCG research toolbox and research register

09-02-2016 Frank Klont

Analytical Biochemistry Towards validation of promising protein COPD biomarker candidates

16-02-2016 All Discussion motivation letters ATS trainee scholarships 23-02-2016 Hataitip Tasena

Pathology and Medical Biology

Identification of microRNAs that potentially regulate chronic mucus hypersecretion in COPD

08-03-2016 Diana van der Plaat

Epidemiology Role of the gene HHIP in the large and small airways

15-03-2016 Kai Imkamp

Pulmonology Being SMART in COPD lung attacks and more

22-03-2016 Eline van Dijk

Molecular Pharmacology

Ex vivo elastase treatment disrupts parenchymal structure and enhances airway narrowing in precision cut lung slices

29-03-2016 Marlies Ketelaar

Pediatric Pulmonology The role of IL-33/IL1RL1 pathway in human asthma: a possible link between bench and bed?

05-04-2016 Jennie Ong

Pathology and Medical Biology

The effect of TGF-β on the miRNA profile and targetome in primary lung fibroblasts

12-04-2016 Esther Metting

General Practice Observational study of the effect of ICS LABA combination in patients with steroid naïve asthma (GINA II)

29-04-2016 Laura Florez

Sampredo Pharmacokinetics, Toxicology and Targeting

Elucidating the role of MIF in pulmonary fibrosis

03-05-2016 All ATS posters

39

Date Speaker Title 10-05-2016 All ATS oral presentations 24-05-2016 Corneel Vermeulen

Pulmonology DNA methylation profiles of bronchial biopsies in asthma remission

31-05-2016 Dennis Kruk

Pathology and Medical Biology

Mesenchymal stem cells in emphysema, finding the right niche for alveolar repair

07-06-2016 Laura Hesse

Pathology and Medical Biology Maaike de Vries Epidemiology

Successful immunotherapy in a mouse model of allergic asthma Practice session on Veni interviewing

14-06-2016 Alen Faiz

Pathology and Medical Biology, Pulmonology

Genetics and epigenetics of corticosteroids

21-06-2016

All Evaluation and brainstorm of GRIAC research meetings

28-06-2016 Ana Julia de Faria

Coimbra Lichtenfels Epidemiology

Air pollution and DNA methylation: association with lung function and COPD

30-08-2016 All ERS posters and oral presentations 13-09-2016 Reinoud

Gosens/Gerard Koppelman Molecular Pharmacology/ Pediatric Pulmonology GRIAC-chairs

Introduction to GRIAC

20-09-2016 Jennie Ong

Pathology and Medical Biology

Identification of TGF-β-regulated miRNAs and the miRNA-targetome in primary lung fibroblasts

27-09-2016 Claire Cox

Pulmonology Extra fine particle ICS compared to standard-sized particle ICS in smokers and ex-smokers with asthma

04-10-2016 Frank Klont

Analytical Biochemistry Who do we want/need an LC-MS assay for sRAGE?

11-10-2016 Hans Burgerhof

Epidemiology Value of the p-value

40

Date Speaker Title 18-10-2016 Eline van Dijk

Molecular Pharmacology

Parenchymal disruption by ex vivo elastase treatment enhances airway narrowing in mice precision cut lung slices

25-10-2016 All ATS abstracts 01-11-2016 Vera Otermann/Hester

Hoving General Practice

Improving inhaler technique in asthma and COPD patients by combining the knowledge and experience of patients, scientists and health care professionals

15-11-2016 Navessa Padma Tania

Molecular Pharmacology

Developmental and pathological roles of Follistatin-like 1 in the lung

22-11-2016 Hans Burgerhof

Epidemiology Lab statistics

29-11-2016 Victor Guryev

ERIBA Identification of smoke resistance markers in humans through RNA-sequencing data in various old world monkeys

05-12-2016 Nicole Dijk

Pediatric Pulmonology (Pharmaco)genetic effects of IL1RL1 SNPs in ICS users

13-12-2016 Hataitip Tasena

Pathology and Medical Biology

MicroRNAs: Regulators of chronic mucus hypersecretion in COPD?

20-12-2016 Laura Florez-

Sampredo Pharmacokinetics, Toxicology and Targeting

Elucidating the role of the macrophage migration inhibitory factor in PF and COPD

41

GRIAC Brainstorm sessions 2016

Date Initiator Subject

26-01-2016 Prof. D.S. Postma & Prof. H. Meurs, Pulmonology & Molecular Pharmacology UMCG/RUG

How to achieve that GRIAC members receive more awards and prizes

23-02-2016 Dr. J.K. Burgess

Pathology & Medical Biology, UMCG

Regeneration of lung extracellular matrix microenvironment: a novel way forward for lung diseases?

26-04-2016 Dr. A.J.P. van den

Brekel, Central Medical Library, UMCG

How to use PURE to register your scientific output

28-06-2016 Dr. M. van den Berge

Pulmonology UMCG

Measurement of particles in exhaled air, a new small airways measurement. How can we use it for our research?

27-09-2016 I.M. Broeders

Medical sciences RUG/UMCG

Access to LifeLines data. How can we use it for our research?

25-10-2016 Dr. D.O. Warmerdam

Aging Biology UMCG

The Crispr Cas 9 technique. What is it and how can we use it for our research?

21-11-2016 Prof. G.H. Koppelman & Prof. R. Gosens, Pediatric Pulmonology & Molecular Pharmacology UMCG

GRIAC vision 2017 and beyond

42

Research projects 2016 Aimmune Therapeutics Inc., USA. The Palisade Study: Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization in Children and Adults. 2015–2016. Prof.dr.A.E.J.Dubois, Dr. J.N.G. Oude Elberink. MD/PhD-student: M.E. Pettersson AstraZeneca; CARAT; identifying cutoff values. 2014-2017. Prof.dr. T. van der Molen, Dr. BMJ Flokstra – de Blok, Dr. C. de Jong. AstraZeneca: risk to develop pneumonia in COPD: Comparing the effects of fluticasone propionate and budesonide on epithelial defense. 2015-2016. Prof. dr. I. Heijink, Prof. D.S. Postma, Dr. M. van den Berge. Technician: M.R. Jonker. AstraZeneca/Mundipharma/Boehringer Ingelheim: Inhaler Research Workgroup (IRW) study. 2016-2019. Prof. dr. T. van der Molen, Dr. J.W.H. Kocks, E.I. Metting, Dr. S. Schokker, Dr. I Tsiligianni, PhD student: M. Román-Rodríguez Bayer (Grants4Targets): Identification of EPAC1 Pharmacological Inhibitors for the treatment of chronic disorders. 2016. Prof. dr. M. Schmidt, Prof. dr. F. Lezloualch. Boehringer Ingelheim International GmbH: Evaluation of the anti-inflammatory and anti-

remodeling effects of the novel ultralong-acting 2-agonist olodaterol, alone and in concerted action with tiotropium, in an animal model of COPD. 2015-2016. Prof.dr. H. Meurs, Prof.dr. R. Gosens, Dr. H .Maarsingh. Boehringer Ingelheim International GmbH: The protective effects of tiotropium: role of the muscarinic M3 receptor. 2013-2016. Prof.dr. R. Gosens. Research Fellow: Dr. L.E.M. Kistemaker Boehringer Ingelheim International GmbH: The role of TRPA1 in neurogenic inflammation and airway hyperreactivity in asthma. 2016-2017. Dr. L.E.M. Kistemaker, Prof. dr. R. Gosens, Dr. M. van den Berge. Technician: S. Nijboer-Brinksma. Boehringer Ingelheim. Reasons and ExpLanations for ICS initiation in COPD: the RELIC study. 2016-2017. Prof.dr. T. van der Molen, Dr. J.W.H. Kocks, Dr. C. de Jong. Brazil Science Without Borders: Targeting the histone acetyltransferases and histondeacetylase balance in the inflammatory lung diseases asthma and COPD. 2014-2016. Prof.dr. M. Schmidt. Sandwich PhD student: E. Kennedy Feitosa, post-doc: A. Paulino do Nascimento Brazil Science Without Borders: Genes and environments underlying COPD: genetic susceptibiity to air pollution. 2015-2016. Prof.dr. H.M. Boezen, Prof.dr. T. Mauad (Sao Paolo, Brasil). Postdoc: Dr. A.J. de Faria Coimbra Lichtenfels. Brazil - Research Support Foundation of the State of Sao Paolo (FAPESP): Research Fellowship Abroad / Continuous Funding Stream (FAPESP Process number 2016/13384-0): Air pollution and COPD: mediation by epigenetics in the LifeLines cohort study. 2016-2017. Prof.dr. H.M. Boezen, Dr. J.M. Vonk, Dr. A.J. de Faria Coimbra Lichtenfels.

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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: The role of small airways in asthma. Development of the SADT questionnaire. 2011-2016. Prof.dr. T. van der Molen, Prof.dr. D.S. Postma, Dr. M. van den Berge. Chiesi: Focus on clinical use of spirometry in primary care (FOCUS). 2016-2018. Prof.dr. T. van der Molen, Dr. J.W.H. Kocks, Dr. B.M.J. Flokstra – de Blok. PhD student: H.J. Baretta. CSA-Medical USA “RejuvenAir trial": “A Prospective Study of RejuvenAir™ System Radial Spray Cryotherapy to Determine Safety and Histological Effect in the Lung. 2015-2108. Dr. D.J. Slebos, Dr. J.E. Hartman, K. Klooster. 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, Prof.dr. R. Gosens, Prof.dr. D.S. Postma European Union (Horizon 2020): FRESH AIR: prevalence and burden of COPD in Uganda, Kyrgyz Republic, Vietnam and Greece. 2015-2018. Prof.dr. T. van der Molen, prof.dr. N.H. Chavannes, dr. J.F.M. van Boven, PhD student: F. van Gemert. European Union (Horizon 2020): Personalised Connected Care for Complex Chronic Patients (CONNECARE). 2016-2019. Prof.dr. T. van der Molen, Dr. J.W.H. Kocks, E.I. Metting, Dr. M.M.H. Lahr. European Union (Horizon 2020): Advancing Care Coordination and TeleHealth Deployment (ACT@Scale II). 2016-2018. Prof.dr. T. van der Molen, Dr. J.W.H. Kocks, E.I. Metting, Dr. M.M.H. Lahr. Faculty of Mathematics and Natural Sciences. Macrophages in the pathogenesis of pulmonary lung fibrosis and their potential as drug targets. 2011-2016. Prof.dr. B.N. Melgert, Prof.dr. W. Timens, Prof.dr. K. Poelstra. PhD student: C.E. Boorsma. Genentech: Molecular Phenotying of COPD Patients by Inhaled Corticosteroids (ICS) Response. 2015-2017. Dr. C.A. Brandsma, Prof.dr. W.Timens, Prof.dr. D.S. Postma, Dr. M. van den Berge. GlaxoSmithKline: A better understanding of asthma remission: An integrative genomic approach for biomarker development. 2014-2017. Dr. M. van den Berge, Dr. N.H.T. ten Hacken, Prof.dr. W. Timens, Prof.dr. I.H. Heijink, Dr. C. Xu, Prof.dr. G.H. Koppelman, Dr. J.M. Vonk, Prof.dr. D.S. Postma. Post-doc: Dr. C. Vermeulen. GlaxoSmithKline: Single cell sequencing of CD4+ lymphocytes to better understand the molecular mechanisms leading to asthma and its remission. 2015-2017. Dr. M.C. Nawijn, Prof.dr. D.S. Postma, Prof.dr. G.H. Koppelman, Dr. J.M. Vonk, Prof.dr. W. Timens, Prof.dr. I.H. Heijink, Dr. M. van den Berge. GlaxoSmithKline: Real life effects on patient reported outcomes of asthma and COPD patients in Real Life primary care settings (PROSPECT). 2015-2017. Dr. J.W.H. Kocks, Dr. T. Schermer, E.I. Metting.

44

GlaxoSmithKline: GOLD D Patients in Primary Care: A Group Whose Clinical Outcomes Can Easily Be Improved. 2015-2018. Prof.dr. T van der Molen, Dr. J.W.H. Kocks, Dr. C. de Jong. Goedebuure / Air Liquide: Cost-effectiveness of obstRuctivE Sleep apnea Therapy (REST study): Comparison of MRA therapy versus CPAP therapy in moderate OSAS. 2011-2017. 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. 2011-2016. Prof.dr. M. Schmidt, Dr. H. Maarsingh. PhD-student: B. Han. Groningen Research Institute for Pharmacy (MPDI fellowship): Role of MIF in pulmonary fibrosis. 2015-2019. Prof.dr. B.N. Melgert, Prof.dr. G.J. Poelarends, PhD student: L. Florez-Sampedro Groningen Research Institute for Pharmacy (Erik Frijlink Patents): Role of MIF in pulmonary fibrosis. 2016-2020. Prof.dr. B.N. Melgert, Prof.dr. G.J. Poelarends, Prof Dr P. Olinga. PhD student: S.S. Song GSMS: An old dilemma: Asthma with irreversible airway obstruction or COPD? 2009-2017. 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/University of Southampton: Functional characterisation of PCDH1, a novel gene for asthma and bronchial hyperresponsiveness. 2011-2017. Prof.dr. G.H. Koppelman, Prof.dr. J. Holloway, Dr. M.C. Nawijn, Dr. B.M. Willemse. PhD student: G. Faura Tellez GSMS/University of Marburg, Germany. The role of mitochondrial SK channels in oxidative stress. 2014-2018. Dr. A.M. Dolga, Prof. dr. C. Culmsee. PhD student: B. Honrath 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 2011-2016. 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 GSMS/University of Newcastle (Australia): Fibroblast Senescence as a driver of pulmonary fibrosis. 2016-2020. Prof.dr J.K. Burgess, Prof.dr. D. Knight. PhD-student: K.E.C. Blokland. GSMS: MicroRNA regulation of chronic mucus hypersecretion in COPD. 2015-2019. Prof.dr. W. Timens, Prof.dr. I.H. Heijink, Dr. C.A. Brandsma. PhD-student: H. Tasena. GSMS/University of Newcastle (Australia): The role of β-catenin in the development of the asthmatic epithelial phenotype. 2016-2020. Prof. dr. I.H. Heijink, Dr. M.C. Nawijn, Prof. dr. D. Knight. PhD-student: V. Kuchibhotla.

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GSMS/University of Sydney: Lung ageing and tissue remodeling in COPD. 2016-2020. Dr. C.A. Brandsma, Prof. dr. W. Timens, Prof. dr. I.H. Heijink, Dr. M. de Vries, Dr. M. van den Berge, Dr. P. Horvatovich, Dr. V. Guryev, Dr. B. Oliver. PhD-student: R. Woldhuis. 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. 2010-2018. 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. 2011-2017. Prof.dr. D. Price, Prof.dr. T. van der Molen, E.C.M. van Heijst. IPCRG: Fresh Air Uganda: prevalence and burden of COPD in a rural area of sub-Saharan Africa. 2010-2017. 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. 2010-2018. Prof.dr. T. van der Molen, Dr. C. de Jong. PhD student: B.J. Kirenga KNMP: Shared decision making inhalers. 2016-2018. Dr. J.W.H. Kocks, E.I. Metting. Lung Alliance Netherlands. National clinical managed care pathway for patients hospitalized for a COPD exacerbation. 2015-2017. Prof.dr. H.A.M. Kerstjens. PhD Student: M. Klijnsma Lung Foundation Netherlands consortium grant 6.1.15.017. Mesenchymal stem cells in emphysema: finding the right niche for alveolar repair. 2015-2019. UMCG: Prof. dr. I.H. Heijink, Dr. N. ten Hacken. PhD-student: D.M.L.W. Kruk. Lung Foundation Netherlands/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 Lung Foundation Netherlands 3.2.10.042. Wnt/Frizzled signalling in small airway remodelling in COPD. 2010-2016. Prof.dr. R. Gosens, Prof.dr. H.I. Heijink, Dr. W.M. Blankesteijn. PhD student: A.I.R. Spanjer. Lung foundation Netherlands, special grant for translational research in Pediatric Pulmonology: Asthma phenotypes. 2009-2017. Prof.dr. G.H. Koppelman, Prof.dr. J.C. de Jongste. PhD students: F.N. Dijk Lung Foundation Netherlands 3.2.09.055: Protocadherin-1 expression in airway epithelium: Investigations into a novel cause of bronchial hyperresponsiveness and asthma. 2009-2017. Prof.dr. G.H. Koppelman, Dr. M.C. Nawijn, Prof.dr. D.S. Postma. Lung Foundation Netherlands 3.2.09.031. The role of alternatively activated macrophages in the pathogenesis of asthma. 2011-2016. Prof.dr. B.N. Melgert, Dr. M.N. Hylkema, Prof.dr. K. Poelstra. PhD student: C. Draijer.

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Lung Foundation Netherlands 3.2.11.015: A-kinase anchoring proteins as novel drug targets in the development and progression of airway obstruction in COPD. 2011-2016. Prof.dr. M. Schmidt, Dr. H. Maarsingh, Prof.dr. H.I. Heijink. PhD-student: W. Poppinga. Lung Foundation Netherlands 3.2.11.025: Epithelial cells alarming the immune system in COPD – at the root of COPD susceptibility? 2011-2016. 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. Lung Foundation Netherlands 3.2.12.044: The functional relevance of microRNAs in COPD; elucidating their role in regulating pulmonary fibroblast function in COPD development. 2012-2017. Dr. C.A. Brandsma, Prof.dr. W. Timens, Prof.dr. DS Postma, Prof.dr. A. van de Berg, Dr. J. Kluiver. PhD-student: J. Ong Lung Foundation Netherlands 3.2.12.083: Follistatin-like 1, a crucial factor in lung development, as a novel regulator in COPD. 2012-2017. Prof. dr. R. Gosens, Prof.dr. M. Schmidt, Prof.dr. H. Maarsingh. PhD student: N.P. Tania Lung Foundation Netherlands 3.2.12.079: Laminin α4 and α5 as regulators of airway inflammation and remodelling in allergic asthma. 2013-2017. Dr. B.G.J. Dekkers, Prof.dr. L.M. Sorokin, Prof.dr. H. Meurs. Post-doc: Dr. P. Prabhala Lung Foundation Netherlands 3.2.11.013: Prenatal programming by maternal smoking during pregnancy: susceptibility for development of COPD. 2012-2017. Dr. M.N. Hylkema, Prof.dr. W. Timens, Prof.dr. L. Kobzik. PhD student: K. Meyer Lung Foundation Netherlands 4.1.13.007. Genes and exposures underlying COPD onset. 2013 – 2016. Consortium grant 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 Lung Foundation Netherlands 1.14.001. Prevention of epigenetic programming of asthma. 2014 – 2018. Consortium grant in collaboration with University of Utrecht and RIVM. Prof. dr. G.H. Koppelman, Dr. U. Gehring, Prof. dr. H. A. Smit, Dr. A. Wijga. Lung Foundation Netherlands 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. Consortium grant 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 Lung Foundation Netherlands 6.1.14.009: Tissue repair in COPD: WNT you get it right? 2014-2018. Prof.dr. R. Gosens, Dr. J. Stolk, Dr. M. Königshoff. Postdoc: Dr. J-P Ng-Blichfeldt, post-doc (LUMC): Dr. P. Khedoe. Lung Foundation Netherlands 4.1.15.002: Does high baseline oxidative stress attenuate macrophage function during exacerbations of COPD and asthma? 2015-2020. Prof.dr. B.N. Melgert, Dr. R. Lutter, Dr. F.O. Martinez, Prof.dr. H.A.M. Kerstjens; 2 PhD vacancies, 2 technician vacancies. Lung Foundation Netherlands junior investigator grant 4.2.15.039JO: Neuronal remodeling: a novel perspective on airway hyperresponsiveness in asthma. 2016-2019. Dr. L.E.M. Kistemaker.

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Lung Foundation Netherlands junior investigator grant 5.2.15.057JO: Treatment of chronic REspiratory failure in COPD patients with Non-invasive ventilation: Starting at home and selecting the Right Patient; the RECONSIDER study. 2016-2020. Dr. M.L.Duiverman 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. Saleh-Langenberg 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. 2009-2016. 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 MD/PhD: Severity of Anaphylaxis. 2015-2017. Prof.dr. A.E.J.Dubois, Prof.dr.G.H.Koppelman. MD/PhD student: M.E. Pettersson. MRC: The roles of Pellino-1 in the control of airway viral infection. 2015-2016. Prof. Dr. Ian Sabroe, Prof. I. H.Heijink. Technician: M.R. Jonker. National Health and Medical Research Council Australia APP1099569. Fibroblast Senescence as a driver of pulmonary fibrosis. 2016-2019. NHMRC research project in collaboration with University of Newcastle Australia. Prof.dr. D. Knight, Prof.dr J.K. Burgess, Prof.dr. G. Westall, Prof.dr. G. Laurent, Prof.dr. S. Mutsaers, Dr. C. Prele. National Health And Medical Research Council Australia (NHMRC): Elucidation of the Aetiology of Airway Remodelling in COPD; 2016-2020. Dr. B. Oliver, Prof. dr. I. Adcock, Dr. C.A. Brandsma. PhD student: R. Woldhuis Novartis: Effects of a combination of the beta-adrenoceptor agonist indacaterol and the muscarinic receptor antagonist glycopyrrolate on intrapulmonary airway constriction. 2015-2017. Prof.dr. M. Schmidt. Post-doc: Dr. B. Han 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) 2009-2017. Prof.dr. A.E.J. Dubois, Prof.dr. T. van der Molen, Dr. B.M.J. Flokstra-de Blok.

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PneumRx/BTG, 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, Dr. J.E. Hartman, Dr. N.H.T. Ten Hacken PneumRx/BTG: Lung Volume Reduction Coil for Treatment in Patients with Emphysema (RENEW-Crossover) Study, 2013-2018. Dr. D.J. Slebos, K. Klooster, Dr. J.E. Hartman, Dr. N.H.T. Ten Hacken PneumRx/BTG:Identifying REsponders and exploring mechanisms of ACTION of the endobronchial coil treatment for emphysema (“REACTION”-TRIAL), UMCG & Royal Brompton. 2014-2017. Dr. D.J. Slebos, Dr. J.E. Hartman, PhD student: W. van Geffen, MD. 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 – 2016. 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”. 2014-2018. Dr D.J. Slebos, Dr J.E. Hartman, K. Klooster. PulmonX Inc. Lung Function Improvement after Bronchoscopic Lung Volume Reduction with Pulmonx Endobronchial Valves used in Treatment of Emphysema: “LIBERATE STUDY”, 2015-2019. Dr. D.J. Slebos, Dr. J.E. Hartman, Dr. N.H.T. Ten Hacken, K. Klooster. Roche (Basel, Switzerland): Pirfenidone in Crohn’s disease and other fibrotic disorders. 2016-2017. Prof.dr. B.N.Melgert, Prof. dr. G. Dijkstra SMF; Remission and progression of asthma: genetic and epigenetic regulation. 2012-2016. Prof.dr. D.S. Postma, Prof.dr. G.H. Koppelman, Dr. J.M. Vonk. PhD student: M.A.E. Nieuwenhuis. 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. MD/PhD-student: C.D. van Ginkel. technician: A. Oomkes-Pilon STW Open Technology Programme: Design, synthesis and validation of potent and isozyme selective arginase inhibitors for therapeutic use in asthma. 2015-2020. Prof. dr. A.S.S. Dömling, Prof. dr. H. Meurs, Prof. dr. P.H. Elsinga. PhD student: M.P.M. van den Berg TEVA the Netherlands: Center for Translational Pediatric Pulmonology. 2016 - 2020 Prof.dr. G.H. Koppelman, Prof.dr.D.S. Postma, Dr. M.N. Nawijn, Dr. B.W.M. Willemse, Dr. E. Kersten. Ubbo Emmius Sandwich Scholarship. Studies on the potential role of Epac between interactions of A. fumigatus and host. 2014-2018. Joint project University of Bejing, China. Prof.dr. M. Schmidt, Prof.dr. L. Han. PhD student: X. Han. Ubbo Emmius Sandwich Scholarship. Airway epithelial-to-mesenchymal transition. Compartmentalized cyclic AMP signaling? 2014-2018. Joint project University of Gottingen, Germany. Prof.dr. M. Schmidt, Prof.dr. N. Viacheslaev. PhD student: H. Zuo. 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

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University Medical Center Groningen: Work absence, productivity loss and indirect costs in patients with asthma, COPD and ACOS. 2016-2017. Dr. J.W.H. Kocks, Dr. B.M.J. Flokstra - de Blok, Dr. J.F.M. van Boven, Prof.dr. T van der Molen, M. Román-Rodríguez, Prof.dr. J.B. Soriano. PhD Student: B.J.H. Dierick University Medical Center Groningen (Doelmatigheidsonderzoek). Improving Quality of Life and reducing length of stay for COPD exacerbations by protocolised care. 2014-2016. Prof.dr. H.A.M. Kerstjens, Dr N.H.T. ten Hacken. PhD Student: M. Klijnsma. Research nurse: A. Niemeijer. University Medical Center Groningen (Doelmatigheidsonderzoek) & Stichting Vrienden van het Beatrixkinderziekenhuis (Grantnumber 671437): GERAS-project NeoLifes (prof dr AF Bos)/Neolifes-lungs. Dr. E.J.L.E. Vrijlandt, W.Stalman, M. van Smaalen ZonMW 016.126.307: On the origins of airway smooth muscle thickening in asthma. Vidi-award. 2012-2017. Prof.dr. R. Gosens. PhD students: T. Koopmans, E. van Dijk. Technician: M. Menzen 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 ZonMW 80-83600-98-42014. Implementatie van therapeutic drug monitoring middels dried blood spots in de dagelijkse praktijk. 2015-2017. Prof. dr. D.J. Touw. PhD student: H. Veenhof ZonMW. Citrienfonds: Doen of laten? Terugdringen van onnodige zorg. Afbouwen onnodig gebruik van inhalatie corticosteroïden bij COPD. 2016-2018. Dr. J.W.H. Kocks, Dr. T Schermer, Dr. C. de Jong, Dr. J. van Boven, Prof.dr. T. van der Molen, Dr. R. Riemersma, E. Brill, Dr. M. van den Berge. Also a substantial contribution for several projects has been obtained from the Stichting Astma Bestrijding (SAB) and the Northern CARA Foundation (NCS). Research projects of the GRIAC spin-off company Aquilo: Aquilo: Evaluation of two novel compounds in a guinea pig model of acute asthma. 2015-2016. Prof.dr. R. Gosens, Dr. L.E.M. Kistemaker. Aquilo: Evaluation of two novel compounds on airway remodeling in guinea pig lung slices. 2015-2016. Prof.dr. R. Gosens, Dr. L.E.M. Kistemaker. Aquilo: Evaluation of two novel compounds in an animal model of chronic asthma. 2015-2016. Prof.dr. R. Gosens, Dr. L.E.M. Kistemaker.

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Publications 2016

Dissertations

R.F. Hoffmann Cigarette smoke-induced oxidative stress in COPD. Effects on mitochondrial function, the lipidome and glucocorticoid responsiveness in airway epithelium 29-02-2016 Promotores: Prof. Dr. H.I. Heijink, Prof. Dr. A.J.M. van Oosterhout Co-promotor: Dr. N.H.T. ten Hacken D. van Hemelen Characterization of allergen-specific T cell subsets in allergy 29-02-2016 Promotor: Prof. Dr. A.J.M. van Oosterhout Co-promotores: Dr. M.C. Nawijn, Dr. J.N.G. Oude Elberink H. Klooster Bronchoscopic lung volume reduction. A new treatment modality for patients with severe emphysema 25-04-2016 Promotor: Prof. Dr. H.A.M. Kerstjens Co-promotores: Dr. D.J. Slebos, Dr. N.H.T. ten Hacken, Dr. J.E. Hartman C. Draijer Macrophages in asthma. 3 different types, 2 bad choices, 1 solution 29-04-2016 Promotores: Prof. Dr. B.N. Melgert, Prof. Dr. K. Poelstra Co-promotor: Dr. M.N. Hylkema J. Song Lung epithelial cell differentiation in human and mouse: environment, epigenetics and epigenetic editing 30-05-2016 Promotor: Prof. Dr. M.G. Rots Co-promotor: Dr. M.N. Hylkema J. Cao Early life exposure to toxic environments: effects on lung and immune cell development in mice and men 30-05-2016 Promotor: Prof. Dr. W. Timens Co-promotor: Dr. M.N. Hylkema X. Zeng Genetic and environmental determinants of respiratory health 12-10-2016 Promotor: Prof. Dr. H.M. Boezen Co-promotor: Dr. J.M. Vonk S.R. Jansen Second messengers in cancer. Cyclic AMP meets beta-catenin in tumor progression 24-10-2016 Promotores: Prof. Dr. M. Schmidt, Prof. Dr. R. Gosens

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R. van Altena Multi-drug resistant tuberculosis in the Netherlands. Personalized treatment and outcome 15-11-2016 Promotores: Prof. Dr. T.S. van der Werf, Prof. Dr. H.A.M. Kerstjens Co-promotor: Dr. J.W.C. Alffenaar A.I.R. Spanjer The WNT receptor Frizzled-8 in pulmonary remodelling and inflammation 25-11-2016 Promotores: Prof. Dr. R. Gosens, Prof. Dr. H.I. Heijink, Prof. Dr. H. Meurs, Prof. Dr. D.S. Postma C.E. Boorsma Macrophages: the overlooked target for pulmonary fibrosis and COPD 02-12-2016 Promotores: Prof. Dr. B.N. Melgert, Prof. Dr. W. Timens, Prof. Dr. K. Poelstra W.J. Poppinga Compartmentalized signaling in the lung: A-kinase anchoring proteins as novel drug targets for chronic obstructive pulmonary disease 02-12-2016 Promotores:Prof. Dr. M. Schmidt, Prof. Dr. H. Meurs, Prof. Dr. H. Maarsingh, Prof. Dr. H.I. Heijink J. Saleh-Langenberg Epinephrine auto-injector for anaphylaxis in food allergic patients 12-12-2016 Promotor: Prof. Dr. A.E.J. Dubois Co-promotor: Dr. B.M.J. Flokstra-de Blok B. Han Novel strategies in the treatment of COPD: Focus on oxidative stress and A-kinase anchoring proteins 12-12-2016 Promotores: Prof. Dr. M. Schmidt, Prof. Dr. H. Meurs, Prof. Dr. H. Maarsingh

Publications SCI journals

Aalderen van WM, Grigg J, Guilbert TW, Roche N, Colice G, Postma DS, Hillyer EV, Price DB. Reply. J Allergy Clin Immunol Pract. 2016;4(2):372-3. doi: 10.1016/j.jaip.2015.12.006. Alma H, de Jong C, Jelusic D, Wittmann M, Schuler M, Flokstra-de Blok B, Kocks J, Schultz K, van der Molen T. Health status instruments for patients with COPD in pulmonary rehabilitation: defining a minimal clinically important difference. NPJ Prim Care Respir Med. 2016;26:16041. DOI: 10.1038/npjpcrm.2016.41 Altena van R, Akkerman OW, Alffenaar JC, Kerstjens HA, Magis-Escurra C, Boeree MJ, van Soolingen D, de Lange WC, Bolhuis MS, Hoefsloot W, de Vries G, van der Werf TS. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J. 2016 Dec;48(6):1800-1802. doi:10.1183/13993003.01208-2016.

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Pfaar O, Nell MJ, Boot JD, Versteeg SA, van Ree R, Roger A, Riechelmann H, Sperl A, Oude Elberink JN, Diamant Z, Bachert C. A randomized, 5-arm dose finding study with a mite allergoid SCIT in allergic rhinoconjunctivitis patients. Allergy. 2016 Jul;71(7):967-76. doi: 10.1111/all.12860. Plaat van der DA, de Jong K, Lahousse L, Faiz A, Vonk JM, van Diemen CC, Nedeljkovic I, Amin N, Obeidat M, van Duijn CM, Boezen HM, Postma DS. The Well-Known Gene HHIP and Novel Gene MECR Are Implicated in Small Airway Obstruction. Am J Respir Crit Care Med. 2016;194(10):1299-1302. Postma DS, Wijkstra PJ, Hiemstra PS, Melgert BN, Braunstahl GJ, Hylkema MN, Sterk PJ. The Dutch National Program for Respiratory Research. Lancet Respir Med.2016;4(5):356-357. doi: 10.1016/S2213-2600(16)30035-2. Pouwels SD, Hesse L, Faiz A, Lubbers J, Bodha PK, Ten Hacken NH, van Oosterhout AJ, Nawijn MC, Heijink IH. Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD. Am J Physiol Lung Cell Mol Physiol. 2016;311(5):L881-L892. doi: 10.1152/ajplung.00135.2016. Pouwels SD, Zijlstra GJ, van der Toorn M, Hesse L, Gras R, Ten Hacken NH, Krysko DV, Vandenabeele P, de Vries M, van Oosterhout AJ, Heijink IH, Nawijn MC. Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice. Am J Physiol Lung Cell Mol Physiol. 2016;310(4):L377-86. doi: 10.1152/ajplung.00174.2015. Prayle AP, Jain K, Touw DJ, Koch BC, Knox AJ, Watson A, Smyth AR. The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison. J Cyst Fibros. 2016 Jul;15(4):510-7. doi: 10.1016/j.jcf.2015.07.012. Price DB, Russell R, Mares R, Burden A, Skinner D, Mikkelsen H, Ding C, Brice R, Chavannes NH, Kocks JW, Stephens JW, Haughney J. Metabolic Effects Associated with ICS in Patients with COPD and Comorbid Type 2 Diabetes: A Historical Matched Cohort Study. PLoS One. 2016;11(9):e0162903. doi:10.1371/journal.pone.0162903. Price DB, Colice G, Israel E, Roche N, Postma DS, Guilbert TW, van Aalderen WM, Grigg J, Hillyer EV, Thomas V, Martin RJ. Add-on LABA in a separate inhaler as asthma step-up therapy versus increased dose of ICS or ICS/LABA combination inhaler. ERJ Open Res. 2016;2(2). pii: 00106-2015. Roerdink EM, Flokstra-de Blok BM, Blok JL, Schuttelaar ML, Niggemann B, Werfel T, Van der Heide S, Kukler J, Kollen BJ, Dubois AE. Association of food allergy and atopic dermatitis exacerbations. Ann Allergy Asthma Immunol. 2016;116(4):334-8. doi: 10.1016/j.anai.2016.01.022. Saber A, van der Wekken AJ, Kerner GS, van den Berge M, Timens W, Schuuring E, ter Elst A, van den Berg A, Hiltermann TJ, Groen HJ. Chronic Obstructive Pulmonary Disease Is Not Associated with KRAS Mutations in Non-Small Cell Lung Cancer. PLoS One. 2016;11(3):e0152317. doi: 10.1371/journal.pone.0152317. Saber A, van der Wekken AJ, Kok K, Terpstra MM, Bosman LJ, Mastik MF, Timens W, Schuuring E, Hiltermann TJ, Groen HJ, van den Berg A. Genomic Aberrations in Crizotinib Resistant Lung Adenocarcinoma Samples Identified by Transcriptome Sequencing. PLoS One. 2016;11(4):e0153065. doi:10.1371/journal.pone.0153065.

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Saleh-Langenberg J, Bootsma GM, van Ginkel CD, Kollen BJ, Flokstra-de Blok BM, Dubois AE. The prevalence of food allergy and epinephrine auto-injectors in Dutch food-allergic adolescents. Pediatr Allergy Immunol. 2016;27(7):755-759. doi: 10.1111/pai.12611. Saleh-Langenberg J, Flokstra-de Blok BM, AlAgla N, Kollen BJ, Dubois AE. Late reactions in food-allergic children and adolescents after double-blind, placebo-controlled food challenges. Allergy. 2016;71(7):1069-73. doi:10.1111/all.12923. Saleh-Langenberg J, Flokstra-de Blok BM, Goossens NJ, Kemna JC, van der Velde JL, Dubois AE. The compliance and burden of treatment with the epinephrine auto-injector in food-allergic adolescents. Pediatr Allergy Immunol. 2016;27(1):28-34. doi: 10.1111/pai.12458. Schieck M, Schouten JP, Michel S, Suttner K, Toncheva AA, Gaertner VD, Illig T, Lipinski S, Franke A, Klintschar M, Kalayci O, Sahiner UM, Birben E, Melén E, Pershagen G, Freidin MB, Ogorodova LM, Granell R, Henderson J, Brunekreef B, Smit HA, Vogelberg C, von Berg A, Bufe A, Heinzmann A, Laub O, Rietschel E, Simma B, Genuneit J, Jonigk D, Postma DS, Koppelman GH, Vonk JM, Timens W, Boezen HM, Kabesch M. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages. J Allergy Clin Immunol. 2016;138(2):421-31. doi:10.1016/j.jaci.2015.12.1305. Schwarze J, Fitch PM, Heimweg J, Errington C, Matsuda R, de Bruin HG, van den Berge M, van Oosterhout AJ, Heijink IH. Viral mimic poly-(I:C) attenuates airway epithelial T-cell suppressive capacity: implications for asthma. Eur Respir J. 2016;48(6):1785-1788. doi: 10.1183/13993003.00841-2016. Sciurba FC, Criner GJ, Strange C, Shah PL, Michaud G, Connolly TA, Deslée G, Tillis WP, Delage A, Marquette CH, Krishna G, Kalhan R, Ferguson JS, Jantz M, Maldonado F, McKenna R, Majid A, Rai N, Gay S, Dransfield MT, Angel L, Maxfield R, Herth FJ, Wahidi MM, Mehta A, Slebos DJ; RENEW Study Research Group.. Effect of Endobronchial Coils vs Usual Care on Exercise Tolerance in Patients With Severe Emphysema: The RENEW Randomized Clinical Trial. JAMA. 2016;315(20):2178-89. doi: 10.1001/jama.2016.6261. Singh S, Bodas M, Bhatraju NK, Pattnaik B, Gheware A, Parameswaran PK, Thompson M, Freeman M, Mabalirajan U, Gosens R, Ghosh B, Pabelick C, Linneberg A, Prakash YS, Agrawal A. Hyperinsulinemia adversely affects lung structure and function. Am J Physiol Lung Cell Mol Physiol. 2016;310(9):L837-845. doi:10.1152/ajplung.00091.2015. Singh S, Bodas M, Bhatraju NK, Pattnaik B, Gheware A, Parameswaran PK, Thompson M, Freeman M, Mabalirajan U, Gosens R, Ghosh B, Pabelick C, Linneberg A, Prakash YS, Agrawal A. Author response to letter to editor: Hyperinsulinemia adversely affects lung structure and function. Am J Physiol Lung Cell Mol Physiol. 2016;311(1):L183-184. doi: 10.1152/ajplung.00227.2016. Slebos DJ, Klooster K. Another STEP forward in emphysema treatment. Lancet Respir Med. 2016;4(3):166-7. doi: 10.1016/S2213-2600(16)00062-X. Slebos DJ, Shah PL. Go with the Flow: The Importance of the Assessment of Collateral Ventilation in Endobronchial Valve Treatment. Respiration. 2016;91(4):269-270. doi: 10.1159/000444330.

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Slok AH, Kotz D, van Breukelen G, Chavannes NH, Rutten-van Mölken MP, Kerstjens HA, van der Molen T, Asijee GM, Dekhuijzen PN, Holverda S, Salomé PL, Goossens LM, Twellaar M, In 't Veen JC, van Schayck OC. Effectiveness of the Assessment of Burden of COPD (ABC) tool on health-related quality of life in patients with COPD: a cluster randomised controlled trial in primary and hospital care. BMJ Open. 2016;6(7):e011519. doi: 10.1136/bmjopen-2016-011519. Slok AH, Bemelmans TC, Kotz D, van der Molen T, Kerstjens HA, In 't Veen JC, Chavannes NH, Asijee GM, Rutten-van Mölken MP, van Schayck OC. The Assessment of Burden of COPD (ABC) Scale: A Reliable and Valid Questionnaire. COPD. 2016;13(4):431-8. doi: 10.3109/15412555.2015.1118025. Spanjer AI, Baarsma HA, Oostenbrink LM, Jansen SR, Kuipers CC, Lindner M, Postma DS, Meurs H, Heijink IH, Gosens R, Königshoff M. TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8. FASEB J. 2016;30(5):1823-1835. doi: 10.1096/fj.201500129. Spanjer AI, Menzen MH, Dijkstra AE, van den Berge M, Boezen HM, Nickle DC, Sin DD, Bossé Y, Brandsma CA, Timens W, Postma DS, Meurs H, Heijink IH, Gosens R. A pro-inflammatory role for the Frizzled-8 receptor in chronic bronchitis. Thorax. 2016;71(4):312-322. doi: 10.1136/thoraxjnl-2015-206958. Ställberg B, Teixeira P, Blom C, Lisspers K, Tsiligianni I, Jordan R, Román M, Kleefstra N, Korzh O, Price D, Chavannes N.The prevalence of comorbidities in COPD patients, and their impact on health status and COPD symptoms in primary care patients: a protocol for an UNLOCK study from the IPCRG.NPJ Prim Care Respir Med. 2016 Nov 17;26:16069. doi: 10.1038/npjpcrm.2016.69. Szulcek R, Happé CM, Rol N, Fontijn RD, Dickhoff C, Hartemink KJ, Grünberg K, Tu L, Timens W, Nossent GD, Paul MA, Leyen TA, Horrevoets AJ, de Man FS, Guignabert C, Yu PB, Vonk-Noordegraaf A, van Nieuw Amerongen GP, Bogaard HJ. Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage. Am J Respir Crit Care Med. 2016;193(12):1410-20. doi: 10.1164/rccm.201506-1231OC. Taghizadeh N, Vonk JM, Boezen HM. Lifetime Smoking History and Cause-Specific Mortality in a Cohort Study with 43 Years of Follow-Up. PLoS One. 2016;11(4):e0153310. doi: 10.1371/journal.pone.0153310. Tang FS, Hansbro PM, Burgess JK, Ammit AJ, Baines KJ, Oliver BG. A novel immunomodulatory function of neutrophils on rhinovirus-activated monocytes in vitro. Thorax. 2016;71(11):1039-1049. doi: 10.1136/thoraxjnl-2015-207781. Tang FS, Van Ly D, Spann K, Reading PC, Burgess JK, Hartl D, Baines KJ, Oliver BG. Differential neutrophil activation in viral infections: Enhanced TLR-7/8-mediated CXCL8 release in asthma. Respirology. 2016;21(1):172-9. doi:10.1111/resp.12657. Timmerman JG, Heederik D, Spee T, van Rooy FG, Krop EJ, Koppelman GH, Rustemeyer T, Smit LA. Contact dermatitis in the construction industry: the role of filaggrin loss-of-function mutations. Br J Dermatol. 2016;174(2):348-55. doi: 10.1111/bjd.14215.

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Tkacova R, Dai DL, Vonk JM, Leung JM, Hiemstra PS, van den Berge M, Kunz L, Hollander Z, Tashkin D, Wise R, Connett J, Ng R, McManus B, Paul Man SF, Postma DS, Sin DD. Airway hyperresponsiveness in chronic obstructive pulmonary disease: A marker of asthma-chronic obstructive pulmonary disease overlap syndrome? J Allergy Clin Immunol. 2016;138(6):1571-1579.e10. doi:10.1016/j.jaci.2016.04.022. Tsiligianni I, Metting E, van der Molen T, Chavannes N, Kocks J. Morning and night symptoms in primary care COPD patients: a cross-sectional and longitudinal study. An UNLOCK study from the IPCRG. NPJ Prim Care Respir Med. 2016;26:16040. doi: 10.1038/npjpcrm.2016.40. Tsiligianni IG, Alma HJ, de Jong C, Jelusic D, Wittmann M, Schuler M, Schultz K, Kollen BJ, van der Molen T, Kocks JW. Investigating sensitivity, specificity, and area under the curve of the Clinical COPD Questionnaire, COPD Assessment Test, and Modified Medical Research Council scale according to GOLD using St George's Respiratory Questionnaire cutoff 25 (and 20) as reference. Int J Chron Obstruct Pulmon Dis. 2016;11:1045-1052. doi: 10.2147/COPD.S99793. Valipour A, Slebos DJ, Herth F, Darwiche K, Wagner M, Ficker JH, Petermann C, Hubner RH, Stanzel F, Eberhardt R; IMPACT Study Team.. Endobronchial Valve Therapy in Patients with Homogeneous Emphysema. Results from the IMPACT Study. Am J Respir Crit Care Med. 2016;194(9):1073-1082. PubMed PMID: 27580428. Valk van der JP, Gerth van Wijk R, Flokstra-de Blok BM, van der Velde JL, de Groot H, Wichers HJ, Dubois AE, de Jong NW. No difference in health-related quality of life, after a food challenge with cashew nut in children participating in a clinical trial. Pediatr Allergy Immunol. 2016;27(8):812-817. doi:10.1111/pai.12621. Valk van der JP, Gerth van Wijk R, Dubois AE, de Groot H, de Jong NW. Failure of introduction of cashew nut after a negative oral food challenge test in children. Pediatr Allergy Immunol. 2016;27(6):654-8. doi: 10.1111/pai.12591. Valk van der JP, Gerth van Wijk R, Dubois AE, de Groot H, Reitsma M, Vlieg-Boerstra B, Savelkoul HF, Wichers HJ, de Jong NW. Multicentre Double-Blind Placebo-Controlled Food Challenge Study in Children Sensitised to Cashew Nut. PLoS One. 2016;11(3):e0151055. doi: 10.1371/journal.pone.0151055. Valk van der JP, Gerth van Wijk R, Baumert JL, Nordlee JA, Vlieg-Boerstra BJ, de Groot H, Dubois AE, de Jong NW. Threshold dose distribution and eliciting dose of cashew nut allergy. Ann Allergy Asthma Immunol. 2016;117(6):712-714. doi:10.1016/j.anai.2016.09.007. Van der Velden J, Harkness LM, Barker DM, Barcham GJ, Ugalde CL, Koumoundouros E, Bao H, Organ LA, Tokanovic A, Burgess JK, Snibson KJ. The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma. Sci Rep. 2016;6:26309. doi:10.1038/srep26309. Vries de GE, van der Wal HH, Wijkstra P, van der Meer P. Response: A Portable Device as Sleep-Screening Tool in the Identification of Obstructive Sleep Apnea in Chronic Heart Failure: Which Value Should We Consider as Cutoff? J Card Fail. 2016;22(2):168. doi: 10.1016/j.cardfail.2015.12.003. Vries de M, Bedke N, Smithers NP, Loxham M, Howarth PH, Nawijn MC, Davies DE. Inhibition of Pim1 kinase, new therapeutic approach in virus-induced asthma exacerbations. Eur Respir J. 2016;47(3):783-91. doi:10.1183/13993003.00171-2015.

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Westerik JA, Carter V, Chrystyn H, Burden A, Thompson SL, Ryan D, Gruffydd-Jones K, Haughney J, Roche N, Lavorini F, Papi A, Infantino A, Roman-Rodriguez M, Bosnic-Anticevich S, Lisspers K, Ställberg B, Henrichsen SH, van der Molen T, Hutton C, Price DB. Characteristics of patients making serious inhaler errors with a dry powder inhaler and association with asthma-related events in a primary care setting. J Asthma. 016;53(3):321-329. doi:10.3109/02770903.2015.1099160. Wijkstra PJ, Hazenberg A, van der Aa H. Diaphragm pacing in patients with amyotrophic lateral sclerosis. Lancet Neurol. 2016;15(6):542-543. doi:10.1016/S1474-4422(16)30011-4. Wildenbeest JG, van der Schee MP, Hashimoto S, Benschop KS, Minnaar RP, Sprikkelman AB, Haarman EG, van Aalderen WM, Sterk PJ, Pajkrt D, Wolthers KC. Prevalence of rhinoviruses in young children of an unselected birth cohort from the Netherlands. Clin Microbiol Infect. 2016 Aug;22(8):736.e9-736.e15. Xepapadaki P, Fiocchi A, Grabenhenrich L, Roberts G, Grimshaw KE, Fiandor A, Larco JI, Sigurdardottir S, Clausen M, Papadopoulos NG, Dahdah L, Mackie A, Sprikkelman AB, Schoemaker AA, Dubakiene R, Butiene I, Kowalski ML, Zeman K, Gavrili S, Keil T, Beyer K. Incidence and natural history of hen's egg allergy in the first 2 years of life-the EuroPrevall birth cohort study. Allergy. 2016 Mar;71(3):350-7. Zafari Z, Sin DD, Postma DS, Löfdahl CG, Vonk J, Bryan S, Lam S, Tammemagi CM, Khakban R, Man SF, Tashkin D, Wise RA, Connett JE, McManus B, Ng R, Hollander Z, Sadatsafavi M. Individualized prediction of lung-function decline in chronic obstructive pulmonary disease. CMAJ. 2016;188(14):1004-1011. Zeng X, Xu X, Boezen HM, Huo X. Children with health impairments by heavy metals in an e-waste recycling area. Chemosphere. 2016;148:408-415. doi:10.1016/j.chemosphere.2015.10.078. Zuiker RG, Tribouley C, Diamant Z, Boot JD, Cohen AF, Van Dyck K, De Lepeleire I, Rivas VM, Malkov VA, Burggraaf J, Ruddy MK. Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test. Eur Clin Respir J. 2016 Jul 13;3:31324. doi: 10.3402/ecrj.v3.31324. Zuur MA, Akkerman OW, Touw DJ, van der Werf TS, Cobelens F, Burger DM, Grobusch MP, Alffenaar JW. Dried blood spots can help decrease the burden on patients dually infected with multidrug-resistant tuberculosis and HIV. Eur Respir J. 2016;48(3):932-4. doi: 10.1183/13993003.00599-2016. Zwerink M, Kerstjens HA, van der Palen J, van der Valk P, Brusse-Keizer M, Zielhuis G, Effing T. (Cost-)effectiveness of self-treatment of exacerbations in patients with COPD: 2 years follow-up of a RCT. Respirology. 2016;21(3):497-503. doi: 10.1111/resp.12697. Zwerink M, Effing T, Kerstjens HA, van der Valk P, Brusse-Keizer M, Zielhuis G, van der Palen J. Cost-Effectiveness of a Community-Based Exercise Programme in COPD Self-Management. COPD. 2016;13(2):214-23. doi:10.3109/15412555.2015.1074171.

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Publications in Dutch Metting EI, Riemersma RA, Kocks JW, Piersma-Wichers MG, Sanderman R, van der Molen T. [Asthma/COPD service in general practice. Study into feasibility and effectiveness]. Ned Tijdschr Geneeskd. 2016;160(0):D281. Dutch. PubMed PMID:27378264. van Schayck OC, Slok AH, Kotz D, van Breukelen G, Chavannes NH, Rutten-van Mölken MP, Kerstjens HA, van der Molen T, Asijee GM, Dekhuijzen PN, Holverda S, Salomé PL, Goossens LM, Twellaar M, In 't Veen JC. [Effectiveness of the Assessment of Burden of COPD tool: a cluster-randomised controlled trial]. Ned Tijdschr Geneeskd. 2016;160(0):D955. Dutch.

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Contributions to other research institutes

Dissertations N.C. Petrus Studies on cow’s milk allergy 18-03-2016 University of Amsterdam Promotor: Prof. Dr. W.M.C. van Aalderen Co-promotor: Dr. A.B. Sprikkelman L.I.Z. Kunz Effects of Inhaled corticosteroids on Clinical and Pathological Outcomes in COPD. Insight from the GLUCOLD study 30-11-2016 University of Leiden Promotores: Prof. Dr. P. Hiemstra, Prof. Dr. P. Sterk, Prof. Dr. D.S. Postma

Publications SCI journals Berentzen NE, van Rossem L, Gehring U, Koppelman GH, Postma DS, de Jongste JC, Smit HA, Wijga AH. Overweight patterns throughout childhood and cardiometabolic markers in early adolescence. Int J Obes. 2016;40(1):58-64. DOI: 10.1038/ijo.2015.196 Berentzen NE, Wijga AH, van Rossem L, Koppelman GH, van Nieuwenhuizen B, Gehring U, Spijkerman AM, Smit HA. Family history of myocardial infarction, stroke and diabetes and cardiometabolic markers in children. Diabetologia. 2016;59(8):1666-74. doi: 10.1007/s00125-016-3988-2. PubMed PMID: 27239670. Berg van den SW, Wijga AH, van Rossem L, Gehring U, Koppelman GH, Smit HA, Boer JM. Maternal fish consumption during pregnancy and BMI in children from birth up to age 14 years: the PIAMA cohort study. Eur J Nutr. 2016;55(2):799-808. doi: 10.1007/s00394-015-0901-6. Berm EJ, Odigie B, Bijlsma MJ, Wilffert B, Touw DJ, Maring JG. A clinical validation study for application of DBS in therapeutic drug monitoring of antidepressants. Bioanalysis. 2016;8(5):413-24. doi: 10.4155/bio.15.255. Boer H, Westerink ND, Altena R, Nuver J, Dijck-Brouwer DA, van Faassen M, Klont F, Kema IP, Lefrandt JD, Zwart N, Boezen HM, Smit AJ, Meijer C, Gietema JA. Single-nucleotide polymorphism in the 5-α-reductase gene (SRD5A2) is associated with increased prevalence of metabolic syndrome in chemotherapy-treated testicular cancer survivors. Eur J Cancer. 2016;54:104-111. doi:10.1016/j.ejca.2015.11.009. PubMed PMID: 26751392. Dalmeijer GW, Wijga AH, Gehring U, Renders CM, Koppelman GH, Smit HA, van Rossem L. Fatty acid composition in breastfeeding and school performance in children aged 12 years. Eur J Nutr. 2016;55(7):2199-2207. doi:10.1007/s00394-015-1030-y.

Dijkstra JA, Voerman AJ, Greijdanus B, Touw DJ, Alffenaar JW. Immunoassay Analysis of

Kanamycin in Serum Using the Tobramycin Kit. Antimicrob Agents Chemother.

2016:22;60(8):4646-51. doi: 10.1128/AAC.03025-15.

Fehringer G, Kraft P, Pharoah PD, Eeles RA, Chatterjee N, Schumacher FR, Schildkraut JM, Lindström S, Brennan P, Bickeböller H, Houlston RS, Landi MT, Caporaso N, Risch A, Amin Al Olama A, Berndt SI, Giovannucci EL, Grönberg H, Kote-Jarai Z, Ma J, Muir K, Stampfer MJ, Stevens VL, Wiklund F, Willett WC, Goode EL, Permuth JB, Risch HA, Reid BM,

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