KI News

People who take proton pump inhibitors for stomach acid reflux run a greater risk of chronic kidney disease than those who take H2-receptor antagonists for the same complaint, a new study published in Gastroenterology reports. Proton pump inhibitors (PPIs) are amongst the most widely sold drugs in the world, including Sweden. Last year, almost ten per cent of the Swedish population took them to alleviate heartburn or prevent stomach ulcers. The first drug, Omeprazol, was launched at the end of the 1980s under the name Losec, but today there are numerous similar products on the market. These drugs spare many people the necessity of having to undergo ulcer surgery and as they are also very effective against heartburn they are extremely popular. Earlier research suggested that PPI’s may be associated with an increased risk of kidney disease. For this present study, researchers at Karolinska Institutet compared the risk of kidney damage on taking PPIs with the somewhat less potent H2-receptor antagonists. The observation study was conducted on some 100,000 long-term users of PPIs from Stockholm and just under 10,000 equally long-term users of H2-receptor antagonists. They found that PPI users had a 26 per cent higher risk of developing chronic kidney disease compared to those who used H2-receptor antagonists and that there was also a correlation between PPI and acute kidney disease. The risk of kidney damage also increased with higher dose taken. The team stresses that the study only indicates a correlation and does not imply causation. However, since millions of people take these drugs every day, a relatively rare adverse reaction can affect a large number of people. “Doctors need to weigh up the pros and cons much more when prescribing PPIs, and revise periodically the need to continue or not with the treatment” says lead author Juan Jesus Carrero, docent at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics. “Many people take PPIs for years and without a clear indication. These drugs should not be taken if they’re not needed, the dose should be cut to the minimum necessary. The possibility to use a H2-receptor antagonist instead should be also contemplated. There might also be reason for patients on long-term PPI medication to take annual kidney function tests. We hope that our results will make the public and the prescribing doctors more aware of the risks of this adverse reaction.” The study was carried out in collaboration with Stockholm County Council, Leiden University (Netherlands) and Johns Hopkins University (USA), and financed by grants from several bodies, including the Swedish Heart and Lung Foundation. None of the researchers have reported any commercial interest in the study. Publication Association Between Proton Pump Inhibitor Use and Risk o Progression of Chronic Kidney Disease. Derk C.F. Klatte, Alessandro Gasparini, Hong Xu, Pietro de Deco, Marco Trevisan, Anna L.V. Johansson, Björn Wettermark, Johan Ärnlöv, Cynthia J. Janmaat, Bengt Lindholm, Friedo W. Dekker, Josef Coresh, Morgan E. Grams, Juan J. Carrero. Gastroenterology, online 2 August 2017, DOI: http://dx.doi.org/10.1053/j.gastro.2017.05.046.

A new study published in the journal Nature Neuroscience, looking at some 6,000 families, demonstrates that mutations that occur after fertilisation play an important role in autism.  Over the last decade, mutations in more than 60 different genes have been linked to autism spectrum disorders (ASD). Some of these are spontaneous, non-inherited mutations and are present in only a few of our cells. Such mutations can occur in a sperm or egg, or in some of the embryo’s cells after fertilisation. These mutations are called postzygotic mutations, PZMs, or somatic mutations. The later the PZMs occur during embryonal development, the fewer the cells that will carry them, making it more difficult to detect them. If the mutation occurs in a very small percentage of the cells, there is a risk it will be missed during regular gene mapping, so-called exome sequencing. To detect PZMs, researchers in the new study used data that had previously been collected from 5,947 families who had a child with autism spectrum disorder. They then re-sequenced parts of the DNA from these children using three independent sequencing techniques in parallel. This mapping revealed that 7.5% of the children had autism spectrum disorder that was related to PZMs. Of these, 83% had not been detected at the original analysis of their genome. Some PZMs affect genes that are known to be linked with autism or other neuropsychiatric disorders, while others affect genes that are known to be active in brain development but have not previously been linked with ASD. By comparing sequencing data, which is primarily on DNA from blood, with data from the public brain banks, which shows when in development (from fetus to adult) these genes are expressed, the researchers also discovered the time point in development when the mutations occurred, and in which areas of the brain they occurred. These analyses showed that PZMs in individuals with ASD occur disproportionately often in the amygdala. “This was exciting for us because the amygdala has been proposed as a region of the brain that is important in autism. The study contributes by further supporting the hypothesis that complex disturbances in the brain, such as epilepsy, intellectual disorders, schizophrenia and brain malformations, can originate from non-inherited mutations that occur at a certain point in prenatal development”, says Christina Hultman, Professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and responsible for Swedish data on autism. Publication Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Elaine T Lim et al, Nature Neuroscience, online 17 July 2017, doi: 10.1038/nn.4598

Neuroblastoma is a cancer in children that originates in the sympathetic nervous system and has a high mortality. Current treatment includes chemotherapy and radiotherapy with their potentially severe side effects; there is therefore an urgent need for a new improved drug.  One potential treatment strategy is to use a drug to target deviant molecular signalling caused by changes in genes. The Wingless (Wnt) signalling pathway is important in the development of nerve cells. One current study has shown that approximately one in four neuroblastoma patients have at least one gene change in the part of the Wnt signalling pathway that is important for cell maturation and migration, the so-called Rho/Rac signalling pathway. “Our results indicate that the signalling molecule Rho and the enzyme Rho kinase, ROCK, have been activated in neuroblastoma patients. High expression of the ROCK enzyme has been shown to be linked to poorer survival of the patients”, comments Cecilia Dyberg, researcher at the Department of Women's and Children's Health, Karolinska Institutet and first author of the study which will be published in the journal PNAS. In studies on cells in vitro and in mice, the researchers observed that when they inhibited ROCK, the tumour cells differentiated, i.e. they matured to less harmful cells, and the tumours stopped growing. The researchers also saw that inhibiting the ROCK enzyme caused the MYCN oncogene, which is linked to the incidence of neuroblastoma, to be degraded to a greater extent and disappear. In some parts of the world, the drug used to target ROCK is used clinically to treat diseases other than cancer, and researchers believe that similar drugs targeting Rho/Rac signalling can be a new promising treatment for neuroblastoma. This research has been financed by grants from the Swedish Childhood Cancer Foundation, the Swedish Research Council, Swedish Cancer Society, the Swedish Foundation for Strategic Research, Märta and Gunnar V. Philipson’s Foundation, Mary Béve’s Foundation for Childhood Cancer Research, Eva and Oscars Ahrén’s Foundation, Magnus Bergvall’s Foundation, Anna-Brita and Bo Castegren’s Memorial Foundation and the Cancer Research Funds of Radiumhemmet. Publications Rho-associated kinase is a therapeutic target in neuroblastoma Cecilia Dyberg, Susanne Fransson, Teodora Andonova, Baldur Sveinbjörnsson, Jessika Lännerholm-Palm, Thale K. Olsen, David Forsberg, Eric Herlenius, Tommy Martinsson, Bertha Brodin, Per Kogner, John Inge Johnsen and Malin Wickström. PNAS, Proceedings of the National Academy of Sciences, online 24 July 2017, doi: 10.1073/pnas.1706011114

A genetic predisposition to higher blood calcium levels was associated with an increased risk of coronary artery disease and heart attack, according to a study published by JAMA. Calcium has a vital role in many biological processes in the body such as blood clotting. It is unclear whether lifelong elevated serum calcium may be causally associated with coronary artery disease (CAD) risk. Susanna C. Larsson, PhD, of the Karolinska Institutet, Stockholm, and colleagues conducted a method of analysis using genetic information known as mendelian randomization to examine the association of serum calcium with CAD and myocardial infarction (MI; heart attack). Mendelian randomization is the use of genetic variants that have a specific influence on possible risk factors to assess associations with explicit outcomes. The analysis included 184,305 individuals (60,801 CAD cases [approximately 70 percent with MI] and 123,504 noncases) and six genetic variants related to serum calcium levels. The researchers found that a genetic predisposition to higher serum calcium levels was associated with an increased risk of CAD and heart attack. “Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown,” the authors write. Publication Association of Genetic Variants Related to Serum Calcium Levels with Coronary Artery Disease and Miocardial Infarction Susanna C. Larsson, Stephen Burgess, Karl Michaëlsson JAMA, 25 juli 2017, 2017;318(4):371-380, doi:10.1001/jama.2017.8981

Subsequent to a diagnosis of dementia, the patient’s contact with the dental care services diminishes and oral health is impaired. This has been revealed by a major register-based study from Karolinska Institutet published in the scientific journal Alzheimer’s & Dementia. Researchers at Karolinska Institutet, using register data, have examined utilisation of dental health services and oral health among a large number of individuals before and after a dementia diagnosis. Information on diagnoses and cognitive function has been compiled for around 58,000 persons registered in the Swedish Dementia Registry, SveDem, from 2007 to 2015. Information relating to dental health was obtained from Tandhälsoregistret (dental health registry). “We observed that the number of visits to dentists saw a dramatic decrease after a dementia diagnosis and that the reduction in utilisation of dental health services was more predominant with patients who experienced a more rapid degeneration in cognitive function,” explains Maria Eriksdotter, Professor of Geriatrics at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet. A low MMSE score (Mini-Mental State Examination) – a method used to indicate cognitive impairment – represented a risk factor in terms of losing teeth. Poor oral health, tooth decay and loosening of teeth may cause pain, reduced quality of life and difficulties eating, resulting in poor nutrition. “It may be the case that patients forget to visit the dentist or put other types of health care first, as dental care is separate from other medical services. We require better organisation to detect these patients and ensure that they attend their dental health check-ups,” says Gunilla Sandborgh Englund, Professor at the Department of Dental Medicine, Karolinska Institutet. The research has been financed by Alzheimerfonden (the Swedish Alzheimer foundation), Stockholm County Council (the SOF project), the Swedish Research Council and the Swedish Association of Local Authorities and Regions. Publication Dental care utilization in patients with different types of dementia. A longitudinal nationwide study of 58037 individuals, Seyed-Mohammad Fereshtehnejad, Sara Garcia-Ptacek, Dorota Religa, Jacob Holmer, Kåre Buhlin, Maria Eriksdotter, Gunilla Sandborgh-Englund, Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, online 8 July 2017, doi: 10.1016/j.jalz.2017.05.004

The brain researcher and neurophysiologist Professor Allen Counter has passe away after a time of illness. Counter was a professor at Harvard University and foreign adjunct professor at Karolinska Institutet, KI. He had strong ties to Sweden, and in 2004 he was appointed General Council of Sweden to Boston and New England. “Allen was a true friend of KI and Sweden, and through his extensive international network or in research, health care, politics, industry and the arts, he contributed in a unique way to strengthen KI in the international arena. Allen will be deeply missed”, says Jan Hillert, Head of the Department of Clinical Neuroscience, where Counter was a foreign adjunct professor. ´ Counter was a clinical professor of neurology at Harvard University and worked as a neurophysiologist at the Massachusetts General Hospital in Boston, USA. He also played d a key role as the Head of the Harvard Foundation for Intercultural and Race Relations. Counter was very successful in attracting research funding from the private sector. Counter had longstanding and strong ties to KI and Sweden. He joined KI as a visiting researcher in 1978 and remained connected to KI until his death. He earned his Ph D at KI’s Department of Physiology in 1992, and was appointed visiting professor in 2009. In 2015 he was appointed foreign adjunct professor. Counter collaborated with many scientists at KI, especially Professor Erik Borg, Professor Tom Brismar, Professor Lou Brundin and Professor Tomas Olsson. "Allen remained extremely loyal to KI and he was equally as loyal as a colleague and friend", says Professor Tomas Olsson. Counter also collaborated with researchers at other universities in Sweden, especially Professor Göran Laurell at the Department of Surgical Sciences at Uppsala University. Counter’s research evolved around the inner ear and brain development. Allen Counter was 73 years old.

KI’s research is at the leading edge of impact according to the Swedish Research Council’s (SRC) Research Barometer for 2017 with the highest proportion of highly cited publications compared to other universities and colleges in Sweden. The SRC’s Research Barometer provides an overview of the state of Swedish research through some thirty indicators including financial resources, research staff and results generated by way of research publications and citation impact. This year’s barometer shows KI to have had the highest citation impact for scientific articles published during the period of 2013-2015 with the number of highly cited publications rising from 12 percent in 2008-2010 to 14 percent in 2013-2015.

Infections in surgically implanted heart valves are more common in patients who have been given a biological prosthetic valve than in those with a mechanical one, a study from Karolinska Institutet published today in the journal Circulation shows. Some 1,500 people undergo aortic valve replacement every year in Sweden, about 75 per cent of whom receive a biological valve (from a pig or calf), the remainder a mechanical one. A complication that carries a high fatality risk is prosthetic valve endocarditis, which occurs when the new valve is infected by bacteria. Until now, there have been no figures on whether the infection frequency differs between the two valve types. It has also been unknown how common infections in an artificial heart valve are. The present study included over 26,500 patients who received a prosthetic heart valve between 1995 and 2012, 940 of whom developed prosthetic valve endocarditis. The risk of infection in the artificial valve was about 50 per cent higher with a biological prosthesis than with a mechanical. The follow-up time was up to 18 years. “We hadn’t expected this large difference,” says Natalie Glaser, doctoral student at Karolinska Institutet’s Department of Molecular Medicine and Surgery. “Our results are important as they tell us more about complications following the surgical replacement of aortic valves.” The current European cardiology guidelines state that there is no difference in the incidence of infection between the two types of implant. Dr Glaser argues that this could be because former studies were too small to reveal any difference and were done on patients who were operated on decades ago.  The present study has also provided updated figures on the commonality of the complication, which affected a total of around 0.5 per cent of patients per year. It also shows that the fatality rate was as high as 16 per cent within a month of diagnosed infection and 50 per cent within five years. “The choice of valve prosthesis is very much decided by the patient’s age,” says principal investigator Ulrik Sartipy, heart surgeon at Karolinska University Hospital and docent at Karolinska Institutet’s Department of Molecular Medicine and Surgery. “Biological valves are usually used for older patients for medical reasons, partly because such valves do not require life-long treatment with anticoagulants. In our study, those who had received biological valves were on average 13 years older than those who were given mechanical ones, but this we’ve compensated for in our comparison.” The study was financed with grants from several bodies, including the Swedish Heart and Lung Foundation, the Mats Kleberg Foundation and the Magnus Bergvall Foundation. Martin Holzmann has reported that he receives a consultancy fee from Actelion and Pfizer. Publication Prosthetic valve endocarditis after surgical aortic valve replacement Natalie Glaser, Veronica Jackson, Martin Holzmann, Anders Franco-Cereceda and Ulrik Sartipy Circulation, online 17 July 2017, doi.org/10.1161/CIRCULATIONAHA.117.028783

Jenny Selander, researcher at the Institute of Environmental Medicine (IMM), is to receive SEK 8 million from AFA Försäkring for research on how physical and chemical work environment risks affect the risk of developing cardiac and vascular diseases. Earlier studies indicate that exposure to physical and chemical work environment factors can elevate the risk of cardiac and vascular disease. Few studies, however, have focused on the impact when people are exposed to more than one environmental risk of heart and vascular disease in women in particular, or taken health and socioeconomic status in early life into consideration.  The project “Cardiac diseases in people of working age – a unified approach to determine the significance of the physical and chemical work environment” studies concurrent effects, gender-specific differences in risk and individual risk factors. Examples of the kind of work environment risk focused on include noise, air pollution, vibrations, and physical and strenuous work. The project is expected to contribute to explaining the relationship between physical and chemical work environment factors and the risk of cardiac and vascular disease. It is hoped that it will also lead to possibilities to design better preventive work. AFA Försäkring is making grants totalling SEK 50 million to six new research projects within the framework of an R&D programme focusing on research for a working life without cardiac and vascular diseases.

Universities have an important role to play in combating the increase in mental ill-health among children and adolescents. More resources should be devoted to research in this field. These are the views of many of the participants at the seminar that KI organised in Almedalen. “The incidence of self-reported mental ill-health among boys and girls has doubled over the past 30 years. In addition, the suicide rate is not decreasing among young people as it is in all the other age groups”, said Magnus Jägerskog, Secretary General of Bris, Children’s Rights in Society. He presented a new report on mental ill-health among children, produced in collaboration with Sven Bremberg, researcher at the Department of Public Health, Karolinska Institutet. However, the cause of this increase in mental ill-health among children is unclear, with more research needed in order to find answers. Magnus Jägerskog argued that society has fallen short, and continues to fall short, when it comes to supporting children and adolescents. “According to the UN Convention on the Rights of the Child, which has now also become law, children have a right to have their voices heard in matters which concern them. But when children describe their perceptions of healthcare, we see a number of problems”, he said. He highlighted several proposed measures that he believed would require broad political reforms. Examples included equal care for children throughout the country, investments in jobs for young people and investments in training in child and adolescent psychiatry. Bris also collected a petition containing 10,000 names under the heading of #psykbryt, demanding: Equal care in all county councils. More funding for research into mental ill-health. That every case of child suicide be investigated. What can we do to improve children’s mental health? Danuta Wasserman is a professor in the Department of Public Health, KI, and has extensive experience of working with suicide prevention. She presented a method which her research group had evaluated in partnership with researchers from a range of other European countries. “Our research indicates that by helping people to help themselves, you can reduce the rate of attempted suicide by 50 per cent and the incidence of depression by 30 per cent among young people”, she said.  Pupils are able to take part in interventions such as a supervised role play in which they can explore their feelings and learn coping strategies. She quoted one participant: “This is the first time in my life that my friend has said he has also been suffering from poor mental health and I have now realised that other people can feel as bad as I have”. “This is the first time in my life that my friend has said he has also been suffering from poor mental health. The method is now being introduced in Stockholm County in order to improve mental health and reduce the number of suicides and attempted suicides among school pupils. Danuta Wasserman also took the opportunity to provide some general advice on how to improve your mental health: sleep, exercise, read books and watch films.  “This is really nothing new, this is something even my grandmother knew. But it bears repeating. Schools and society as a whole need to embrace these simple suggestions”, she said. Another KI researcher who is focusing on mental ill-health is Emily Holmes, a professor in the Department of Clinical Neuroscience. She spoke about her research into post-traumatic stress disorder (PTSD), a condition that can emerge following severe traumatic experiences, for example war. People with PTSD often experience intrusive memories, known as flashbacks, in which they involuntarily relive moments from these experiences. “We have found that the computer game Tetris, combined with other behavioural psychology interventions, can reduce the incidence of flashbacks”, she said. A small study has been carried out among young refugees who have recently arrived in Sweden. Emily Holmes presented figures that indicated mental ill-health accounts for more than 15 per cent of the total burden of disease in the West, which is greater than all forms of cancer combined. However, barely two per cent of the research budget is spent on mental ill-health in the EU.  “We need research in order to evaluate the methods we use today, but also to find new treatment methods. Children and adolescents have their whole lives ahead of them; we have the chance to make a difference!  Children and adolescents have their whole lives ahead of them; we have the chance to make a difference!  The subsequent debate also featured Ida Höckerstrand and Sofie Hallberg, the instigators of Ångestpodden [the Anxiety Podcast], Mikael Dahlqvist, Social Democrat politician and member of the Riksdag’s Committee on Health and Welfare, and KI’s Acting Vice-Chancellor Karin Dahlman-Wright. The moderator Carl Johan Sundberg asked: How can we reach out to young people? “We started Ångestpodden because we felt that it was needed. We think that our podcast has become popular because we speak the same language as young people. It is important to talk with young people, rather than about them. We give them a voice”, said Sofie Hallberg. Ångestpodden has over 30,000 listeners each month. “Many of the young people who contact us are suffering, but don’t have anyone to talk to. They don’t know where to turn. That’s not how it should be”, said Ida Höckerstrand. She argued that it would be interesting to see research that investigated the link between mental ill-health and the fact that many young people are currently living a large part of their lives on social media. Who is responsible for the issue of mental ill-health? “The Swedish Government is responsible for ensuring that Sweden complies with the Convention on the Rights of the Child”, said Magnus Jägerskog. Mikael Dahlqvist confirmed that this is an important issue. “This is a serious situation we are faced with. Swedish municipalities and county councils have initiated a number of projects in this area”, he said. Karin Dahlman-Wright, Acting Vice-Chancellor of KI, pointed out that health services have responsibility for providing healthcare, but that universities have a responsibility to disseminate existing knowledge and ensure that society benefits from research.  “We also have to test and evaluate methods – and turn back if need be. Researchers also need to determine what problems need solving. What can be more important than ensuring that our children and adolescents are well”, she said. Text and photo: Cecilia Odlind

A combination of substances that impacts chemical modifications in the DNA of tumours and triggers the tumours to differentiate into harmless nerve cells could represent a new method of treating aggressive forms of neuroblastoma. The new method has been proposed by researchers at Karolinska Institutet, after studies using mice showed that the combination treatment resulted in a significant suppression in tumour growth. The study, published in PNAS, also questions a hypothesis within the research field that could result in potentially harmful wrong treatment of children with neuroblastoma. Neuroblastoma affects the peripheral nervous system in children and is a tumour disease with different facets. A number of these tumours disappear naturally and others respond well to the treatment available. There are however some types of neuroblastoma that are very aggressive and, in many cases, do not respond to treatment. Mortality among these high-risk patients is high and there is therefore a substantial requirement for new and efficient methods of treatment. Significant suppression in tumour growth During the study, the researchers treated mice with the substance AZA, which blocks and eliminates methyl groups from the DNA of cancer cells, aiming to activate genes that fight the origins of neuroblastoma. AZA was then combined with treatment with retinoic acid (RA), a substance that has the capacity to make certain tumour cells differentiate, mature, into harmless nerve cells. Neither AZA nor RA could individually suppress the growth of high-risk tumours, but the combination treatment resulted in a significant suppression in tumour growth in the mice. The treatment induced expression of a factor called HIF2α, why the researchers also tested a combination with a HIF2α inhibitor. Such inhibitors have been proposed as an alternative treatment for neuroblastoma as the HIF2α protein has previously been described as being coupled to more aggressive forms of neuroblastoma. HIF2α inhibitor are currently being subject to clinical trials for treatment of other tumour diseases. “Interestingly, it emerged that the effect of our combination treatment with AZA and RA was, in fact, counteracted by the HIF2α inhibitor. Moreover, analyses of large volumes of patient data show that HIF2α is not coupled to aggressive types of neuroblastoma, but can be linked to a lower risk and improved survival for patients,” explains Johan Holmberg, researcher at the Ludwig Institute for Cancer Research and the Department of Cell and Molecular Biology at Karolinska Institutet. Potentially harmful wrong treatment with HIF2α The role played by the HIF2α inhibitors requires further study before they can be used to treat neuroblastoma patients,” confirm the researchers. “In addition to demonstrating the effect of a new potential combination treatment, our study questions a hypothesis that may result in potentially harmful wrong treatment of children with neuroblastoma. The study could therefore be of importance for future clinical applications,” says Johan Holmberg. The research has been financed by StratCan, the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Swedish Research Council, the Ludwig Institute for Cancer Research and the Knut and Alice Wallenberg Foundation. Publication: “Combined epigenetic and differentiation based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression”. Isabelle Westerlund, Yao Shi, Konstantinos Toskas, Stuart M Fell, Shuijie Li, Olga Surova, Erik Södersten, Per Kogner, Ulrika Nyman, Susanne Schlisio & Johan Holmberg. Proceedings of the National Academy of Sciences (PNAS), online 10 July 2017. For more information, please contact: Johan Holmberg, researcher The Department of Cell and Molecular Biology, Karolinska Institutet The Ludwig Institute of Cancer Research Tel: +46 (0)72-221 27 02 Email: Johan.Holmberg@ki.se

Immune system function varies significantly between individuals, and up to now there has been no effective means of measuring and describing these differences. Now, researchers at Karolinska Institutet have shown that white blood cell composition is unique in individuals, and that the composition of these cells may predict immune system response to various forms of stimulation. The study, which is published in PNAS, paves the way for more individualised treatment of diseases involving the immune system, e.g. autoimmune disorders, allergies and various forms of cancer. The human immune system comprises a complex network of different white blood cells, which coordinate their efforts in order to combat different external and internal threats. This network varies widely between different individuals, but the differences have been difficult to measure and understand. Together with colleagues at the Massachusetts Institute of Technology (MIT) and Stanford University in the USA, researchers at Karolinska Institutet and the Science for Life Laboratory (SciLifeLab) have developed a tool for measuring the unique composition of white blood cells in individuals. Researchers have also found that the test may predict how individuals will respond to a given treatment, e.g. individual response to an influenza vaccine. Measuring the individual’s “immunotypes” “By measuring all populations of white blood cells in the blood at the same time, we can describe the composition of an individual’s immune system and show that this is unique for the individual. We call this measure, the individual’s “immunotype”. We have also found that this immunotype makes the complex immune system more understandable and predictable,” says Petter Brodin, physician and researcher at SciLifeLab and the Department of Medicine, Solna, at Karolinska Institutet. A human immunotype is not constant, but varies over time in response to external factors. In previous studies, Petter Brodin and his research colleagues have shown that in humans individual differences in immune defence can be attributed primarily to the many different environmental factors unique to each individual, e.g. diet, infections, vaccines and microflora. Blood samples from 1,500 individuals In the study in question, the researchers analysed blood samples from approximately 1,500 healthy individuals and tested in vitro how their white blood cells respond to different stimuli. They have also vaccinated individuals against influenza and studied which antibody protection the individuals developed thereafter. It transpired that all different types of stimulation could be predicted based on the individual’s immunotype, which was surprising – according to Petter Brodin. "Our technique can be scaled up, and my hope is that eventually it will be used clinically to predict those individuals who may benefit from a particular immunological treatment or a certain vaccine. The technique may also contribute to more individualised drugs to treat autoimmune disease and allergies, as well as immunotherapy to treat cancer, which can be adapted based on the individual’s immune response,” says Petter Brodin. The study was financed by the National Institute for Health (NIH), the Ragon Institute of MGH, MIT and Harvard, the National Science Foundation, the European Research Council (ERC starting grant), the Swedish Research Council, the Swedish Society for Medical Research, the Swedish Cancer Society and Karolinska Institutet. Publication: "Continuous Immunotypes describe human immune variation and predict various responses".  Kevin J. Kaczorowski, Karthik Shekhar, Dieudonné Nkulikiyimfura, Cornelia L. Dekker, Holden Maecker, Mark M. Davis, Arup K. Chakraborty, Petter Brodin. Proceedings of the National Academy of Sciences (PNAS), online 10 July 2017. For more information, please contact: Petter Brodin, physician, researcher Department of Medicine, Solna, Karolinska Institutet Science for Life Laboratory (SciLifeLab) Phone: +46 (0)8 524 813 96 Email: Petter.Brodin@ki.se

Three researchers from Karolinska Institutet receive a total of SEK 9.5 million in research funding from AFA insurance, for research that will help reduce occupational injuries and long-term sickness absence. Gun Johansson at the Institute of Environmental Medicine receives SEK 2,960,000 to evaluate the effects that organisational and social measures within the workplace in the construction industry have on working conditions, health and occupational injuries. The research project runs until 2019, and the hope is to reduce levels of mental illness in the construction industry, and that the knowledge acquired will lead to fewer occupational injuries. Gunnar Bergström at the Institute of Environmental Medicine receives SEK 4,130,000 to study the link between sickness presenteeism (working while sick) and sickness absence, various types of illnesses, future sickness and decreased productivity. The research project runs until 2019 and is expected to increase knowledge about the relationship between the ability to work/illness, the effects of sickness presenteeism on health and productivity and the positive effects of sickness presenteeism when returning to adapted work after rehabilitation.  Eva Skillgate at the Institute of Environmental Medicine receives SEK 2,500,000 to investigate the significance of work- and lifestyle factors in respect of the risk of neck and back pain resulting in long-term disability, with or without the absence of psychological problems. The research project continues until 2020 and the expectations in terms of the results is that it will be possible to use them for preventive measures against this type of problems.

CIMED, the Center for Innovative Medicine, is changing its focus and have a new board starting from 1 July. In addition to the new board with a greater clinical competence, CIMED is to focus more on supporting clinical research than previously. Research on chronic diseases and diseases with a heavy disease burden will also have a high priority. The CIMED board’s period of office came to an end on 30 June and acting Pro-Vice-Chancellor Anders Ekbom took the formal decision on the changes the day before. The decision was taken in consultation with County Council Director Malin Frenning and the KI- Stockholm County Council (SLL) management team. CIMED, whose objective is to find new treatments for endemic diseases, was inaugurated in 2015 and is funded primarily by SLL, but is a part of KI’s organization. SLL has now reviewed the support it provides to CIMED, which amounts to SEK 81 million annually.  In brief, the decision means that CIMED will have a more distinct focus on supporting clinical research than before. This involves providing support to both clinical research projects that are sought in competition and part-time clinical research positions, and to infrastructure that supports clinical research. The research must also be conducted in the Flemingsberg area. Research on chronic diseases and diseases with a heavy disease burden are to be prioritized. In addition to a new board, CIMED will also have a new head active within clinical research in Flemingsberg. The position will be announced and applied for in open competition.  CIMED’s new board Peter Lönnroth, professor, chair Lars I Eriksson, professor, SLL Anna Martling, professor, SLL Annika Tibell, professor, SLL Karin Dahlman-Wright, professor, KI Ulf Hedin, professor, KI Peter Stenvinkel, professor, KI

Karolinska Institutet and the Karolinska University Hospital will play core roles as Vinnova and the Swedish Research Council (SRC) grant SEK 48 million to the up building of a centre for development of advanced medical products within cell and gene therapies.  The centre, to be known as the Centre for Advanced Medical Products (CAMP), will be led by Pontus Blomberg, acting head of Karolinska Cell Therapy Centre at Karolinska University Hospital and associated professor at the Department of Laboratory Medicine at KI. Matti Sällberg, Professor and head of the Department of Laboratory Medicine, will be a member of the centre’s board. “The investment in CAMP is very gratifying and of great strategic national importance”, says Pontus Blomberg. The areas of cell and gene therapies are gaining ground fast, and products based on cells and genes can already be found as approved drugs. Intensive research is conducted in both Swedish academia and industry to develop the areas further. The grant will support these efforts and the objective is for the centre to be an internationally recognized player in the development of new treatments, and to contribute to national industrial growth within the field. CAMP will have a broad national base with collaborating parties from academia, research institutes, the health and medical care sector, the pharmaceutical industry and bioengineering companies.

Many jobs, medical and otherwise, might one day be performed using artificial intelligence. According to a new study in Acta Orthopaedica by researchers at Karolinska Institutet in collaboration with the Royal Institute of Technology and Danderyd Hospital in Sweden, self-learning programmes can already find fractures with the same accuracy as orthopaedists. Assessing radiographs requires a great deal of expertise and time, with the results very much depending on the doctor. However, artificial intelligence (AI) can simplify and standardise the work considerably, according to Max Gordon, assistant consultant in orthopaedics at Danderyd Hospital and researcher at Karolinska Institutet in Sweden, who has now published a study on how radiographs can be read using computers trained in fracture recognition. “Our study shows that AI networks can make assessments on a par with human specialists, and we hope that we’ll be able to achieve even better results with high-res X-ray images,” says Dr Gordon. Analysis of 256,000 images AI-facilitated image analysis had its major breakthrough in 2012, when the algorithm that astounded the computer world was compared to a human three-times worse at recognising objects in pictures from the internet. In only three years, it was at human level and by 2016 it was twice as good. This made Dr Gordon think about how the technique could be used in the fields of orthopaedics and radiograph analysis. In the present study, the researchers had existing AI image-recognition algorithms go through a total of 256,000 radiographs of hands, wrists and ankles from the Danderyd Hospital archives. The computer was trained how to identify fractures in two thirds of the radiographs under the guidance of the researchers and then was left to independently analyse the remaining images, which were thus completely new to the AI programme. Two consultants simultaneously analysed the same radiographs. The team found that the computer and the doctors made equally accurate analyses given the same image resolution, both finding the presence of a fracture in over 80 per cent of the cases. Many new opportunities The AI programme, which is inspired by the learning processes of the human brain, has the potential to be even better at its job if it has access to greater amounts of data. The researchers have therefore begun a follow-up study based on Danderyd Hospital’s entire orthopaedic archive of over a million high-resolution radiographs. “AI can lead to a more uniform classification and a common standard in radiograph analysis,” says Dr Gordon. “If we can go back to our digital archives, we’ll also be able to do extensive research on survival, the development of disease and work capacity – studies that have been impossible to do owing to the amount of data to process.” Publication “Artificial intelligence for analyzing orthopedic trauma radiographs: Deep learning algorithms - are they on par with humans for diagnosing fractures?” Jakub Olczak, Niklas Fahlberg, Atsuto Maki, Ali Sharif Razavian, Anthony Jilert, André Stark, Olof Sköldenberg, Max Gordon Acta Orthopaedica, 3 July 2017

Óscar Fernandez-Capetillo, professor of cancer therapy at the Department of Medical Biochemistry and Biophysics has been awarded the prize for his pioneering research on how DNA damage can lead to cancer and ageing. Óscar Fernandez-Capetillo researches replicative stress and replicative damage to DNA – in other words, the irregularities that occur when DNA copies itself during cell division. Such damage causes both ageing and cancer. Fernandez-Capetillo’s research interest lies in what causes this replicative stress and how cells discover and repair the resulting damage, a process in which the enzyme ATR kinase plays a key role. He has shown, for instance, that replicative stress accelerates ageing in mammals, and that ATR-blockers are a future cancer drug candidate. His group at Karolinska Institutet is also working on developing a treatment for amyotrophic lateral sclerosis (ALS). Óscar Fernandez-Capetillo was born in 1974. He was made professor of cancer therapy at KI on 1 January 2015. The Erik K Fernström prize The Eric K. Fernström Foundation was established in 1978 and annually awards a Nordic prize and six prizes to young and particularly promising researchers who have made outstanding contributions to medical science. Each medical faculty of the country elects its prize-winner. 

The Expert Group on Scientific Misconduct at the Central Ethical Review Board of the Swedish Research Council has handed in its review to KI on the case of suspected scientific misconduct regarding the scientifc study "Infusion of amniocytes from extraembryonic membranes and similar mesenchymal stem cells in cases of tissue damage, haemorrhage and/or graft-versus-host disease.". The study was referred to the Central Ethical Review Board last spring by acting Vice-Chancellor Karin Dahlman-Wright as she made the decision to initiate an investigationi on the case. Following the review the case will be further processed before reaching its final decision by KI's Vice-Chancellor, probably during ths fall.

A molecular test can identify which patients will have a very low risk of death from breast cancer up to 20 years after diagnosis, according to a new clinical study by researchers at Karolinska Institutet and University of California, San Francisco (UCSF). The results are published in JAMA Oncology. Since the introduction of screening, more breast cancer tumours with indolent, low-risk behaviour are detected. Better tools to identify such tumours are therefore needed to avoid overtreatment. Testing the expression of 70 genes In the new study, researchers sought to determine whether a 70-gene test with an ultralow risk threshold could accurately and reliably identify tumours with indolent behaviour to assess the risk of fatal breast cancer up to 20 years after diagnosis. The study was run in collaboration with the Stockholm breast cancer study group and the Stockholm tamoxifen (STO-3) trial. The new analysis included postmenopausal breast cancer patients enrolled in the STO-3 trial from 1976 until 1990, randomised to receive tamoxifen treatment versus no systemic therapy. “We concluded that the ultralow risk threshold identifies patients at very low long-term risk of dying from breast cancer,” says Senior author Linda Lindström, researcher at the Department of Biosciences and Nutrition at Karolinska Institutet. “Since breast cancer is such a diverse disease, it is important to be able to identify patients at very low long-term risk.” Important step towards personalised care The test classified 15 per cent of the patients as very low risk patients, showing that such tumours are an inherent part of the spectrum of breast cancers. Women with ultralow risk tumours had an excellent prognosis, whether or not they received tamoxifen. “This is an important step forward for personalising care for women with breast cancer,” says Laura Esserman, breast cancer specialist and professor at UCSF. “We can now test small node-negative breast cancers, and if they are in the ultralow risk category, we can tell women that they are highly unlikely to die of their cancers and do not need aggressive treatment.” The study was financed by California Breast Cancer Research Program BCRP, the Swedish Research Council, the Swedish Research Council for Health, Working life and Welfare (FORTE) and the Gösta Milton Donation Fund. Publication “Use of Molecular Tools to Identify Patients With Indolent Breast Cancers With Ultralow Risk Over 2 Decades”. Laura Esserman, Christina Yau, Carlie Thompson, Laura van 't Veer, Alexander Borowsky, Katherine Hoadley, Nicholas Tobin, Bo Nordenskjöld, Tommy Fornander, Olle Stål, Christopher Benz, and Linda S. Lindström JAMA Oncology, online 29 June 2017. doi:10.1001/jamaoncol.2017.1261

Xiaowei Zhuang is the recipient of the 2017 Lennart Nilsson Award for making breakthrough discoveries in the beautiful world of cell biology, literally making the invisible visible, with the STORM technique that was developed in her laboratory. Xiaowei Zhuang is the David B. Arnold Professor of Science at Harvard University and a Howard Hughes Medical Institute Investigator. In 2006, she pioneered a method that would go on to revolutionize the world of fluorescence microscopy. She developed a single-molecule-based super-resolution light microscopy method called “Stochastic Optical Reconstruction Microscopy” or STORM. It overcame the diffraction limit and extended the spatial resolution of light microscopy by an order of magnitude to a few tens of nanometers. The resolution of STORM was further extended by Xiaowei Zhuang's laboratory to a few nanometers, nearly 100 times higher than conventional diffraction-limited light microscopy. Xiaowei Zhuang has since been using STORM to illuminate the beautiful and small world of biology in the most unexpected ways. Motivation Super-resolution light microscopy techniques have revolutionized the life sciences. With the STORM technique that was developed in Dr Xiaowei Zhuang’s laboratory, she has made breakthrough discoveries in the beautiful world of cell biology, literally making the invisible visible. Her images represent a unique combination of technical mastery, frontline science, and visual esthetics, fitting perfectly in the tradition of Lennart Nilsson. About the Lennart Nilsson Award The Lennart Nilsson Award Foundation was established in 1998 in recognition of the world-renowned Swedish photographer Lennart Nilsson and his extraordinary body of work. The main aim is to promote education, training and research within the medical, biological and engineering sciences through the use of images. This is achieved through the Lennart Nilsson Award, an international award bestowed annually upon an individual in recognition of outstanding contributions within the realm of scientific photography.