KI News

A study conducted by researchers from the Karolinska Institute shows that patients with an experience of violence have an increased risk to carry out repeated suicide attempts. In a multicenter study conducted at the emergency hospitals in Stockholm, Gothenburg and Umeå, patients who have survived a suicide attempt have been interviewed. The interviews include their experiences of using violence and being exposed to violence. Of the 355 patients included in the study 78 repeated a suicide attempt during the follow-up period of six months. The risk of repeating an attempt proved to be associated with their reported experiences of violence. A specific finding among the women in the study was that exposure to violence as an adult was associated with repeated violent suicide attempts. “Our results support the hypothesis that experiences of violence could be associated with the development of suicidal behavior. Better identification of patients' experiences of violence may enhance suicide risk assessments,” says researcher Axel Haglund at the Karolinska Institute. Publication ”Interpersonal violence and the prediction of short-term risk of repeat suicide attempt” Axel Haglund, Åsa Lindh, Henrik Lysell, Ellinor Salander Renberg, Jussi Jokinen, Margda Waern, Bo Runeson Scientific Reports, published online 14 November 2016. DOI:10.1038/srep36892

Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival, and nonhematologic toxic effects were more frequent in the tailored dose-dense group, according to a study appearing in the November 8 issue of JAMA. Dose-dense therapy, defined as delivery of chemotherapy at shorter intervals without increasing the cumulative dose, has been suggested as a means to improve efficacy of chemotherapy for early breast cancer. Dosing of most chemotherapy agents is calculated based on body surface area, which leads to large interpatient variability in toxic effects and efficacy. Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy. Jonas Bergh, M.D., of the Karolinska Institutet and University Hospital, Stockholm, Sweden, and colleagues randomly assigned 2,017 women who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer to receive tailored dose-dense adjuvant chemotherapy (n = 1,006) or standard chemotherapy (n = 1,011). The study was conducted at 86 sites in Sweden, Germany, and Austria. Among the randomized patients, 2,000 received study treatment (at least 1 cycle of chemotherapy). Median follow-up time was 5.3 years. The researchers found that the groups did not differ in 5-year overall survival (92 percent [tailored dose-dense group] vs 90 percent [control group]) or 5-year distant disease-free survival (89 percent vs 87 percent). The tailored dose-dense group had significantly better event-free survival (EFS) than the control group (5-year EFS, 87 percent vs 82 percent). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (53 percent) in the tailored dose-dense group and 366 (37 percent) in the control group. The authors write that an individual patient data meta-analysis would help to assess whether chemotherapy dose intensification in early breast cancer should be reserved for specific subgroups of patients. Publication ”Tailored, Dense-Dose Chemotherapy for Early Breast Cancer Does Not Result in Significant Improvement in Recurrence-Free Survival.” Theodoros Foukakis, Gunter von Minckwitz, Nils-Olof Bengtsson, Yvonne Brandberg, Birgitta Wallberg, Tommy Fornander, Brigitte Mlineritsch, Sabine Schmatloch, Christian F. Singer, Günther Steger, Daniel Egle, Eva Karlsson, Lena Carlsson, Sibylle Loibl, Michael Untch, Mats Hellström, Hemming Johansson, Harald Anderson, Per Malmström, Michael Gnant, Richard Greil, Volker Möbus, Jonas Bergh. JAMA published online 8 November 2016. doi:10.1001/jama.2016.15865 Press release text by JAMA. Read the full article here.

Previous experiments have raised concerns that general anaesthetics and surgery for infants increases the risk of learning difficulties and sub-standard school performance. New research presented in the international journal JAMA Pediatrics now suggests that these fears are unwarranted. Over the past few decades, a series of experiments in which very young animals were sedated and examined for signs of brain damage or cognitive impairment have fuelled concerns amongst paediatricians and patient organisations around the world that infants subjected to general anaesthetic and surgery early in life are more at risk of underdeveloped neurocognitive faculties, with the impact on their education this implies.  Major study on children and young adults under twenty A major national study, led by Lars I Eriksson and Fredrik Granath at Karolinska Institutet, and supported by the country’s healthcare system and school and conscription data, has been conducted to ascertain whether children who were exposed to general anaesthetics and surgery at an early age run a similar risk. The study was based on epidemiological data and conducted on all children born between 1973 and 1993. “Using a cohort of over two million children, we compared the results of those who had undergone surgery before the age of four with those who had not,” says principal investigator Lars I Eriksson. “We found a marginal difference in school results in year 9 between both groups and similar results when we analysed the results in connection with national service at the age of 18. The differences found were several times smaller than those relating to gender, educational level of parents or month of birth (i.e. age when starting school). In light of the study we conclude that there is no cause for alarm as regards performing necessary surgery on infants." Publication "Association of Anesthesia and Surgery During Childhood With Academic Performance" Pia Glatz, Rolf H Sandin, Nancy L Pedersen, Anna-Karin Bonamy, Lars I Eriksson, Fredrik Granath JAMA Pediatrics, published 7 November 2016. doi: 10.1001./jamapediatrics.2016.3470

Repeated violent crimes in released prisoners can be prevented with effective psychiatric treatment, according to an article published in the international journal JAMA.  In a large registry study published in The Journal of the American Medical Association (JAMA), researchers from Karolinska Institutet and University of Oxford show that rates of violent reoffending in certain groups of released prisoners dropped substantially during periods when they were on psychotropic medications (antipsychotics, stimulants, or medications for addictive disorders). Individuals released from prison have high rates of violent reoffending. While psychiatric and substance use disorders are overrepresented among jail and prison populations, it has remained uncertain whether treatment with psychotropic medications reduces violent recidivism. By studying more than 22,000 released prisoners over an eight-year period (2005-2013), researchers have now been able to examine the associations between major classes of psychotropic medications and violent reoffending. Results demonstrate that rates of violent reoffending decreased The results from the current study demonstrate that rates of violent reoffending decreased by 42% when individuals were receiving antipsychotics after release, by 38% when dispensed psychostimulants, and by 52% when receiving medications for addictive disorders. These were done by comparing individuals to themselves (i.e. during periods with and without medication), as a way to reduce bias from individual difference in selection into treatment. "We have shown that three classes of psychotropic medications (antipsychotics, psychostimulants, and medications used for addictive disorders) may reduce violent reoffending," says Zheng Chang, postdoctoral researcher at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. "However, it is also important to note that many psychotropic medications can have adverse side effects, so our findings should be considered along with other potential benefits and harms associated with these medications, including potential diversion and misuse.” Enhancing medication after prison release needs evaluation For comparison, the researchers secondarily investigated the associations of prison-based psychological treatments with violent reoffending. Results suggested the magnitudes of the reduction associated with psychotropic medications were as strong as and possibly stronger than for widely disseminated psychological programs in prison.  “Enhancing medication after prison release needs evaluation as a possibly cost-effective crime reduction alternative,” says Zheng Chang. “Because of the high prevalence of psychiatric and substance use disorder among prisoners and strong links with premature mortality, effective treatments for them could also have a substantial public health benefit.” The study was based on observational data, so caution is warranted in interpreting these results. Further research is needed to understand the causal nature of this association. The study was financed with grants from the Wellcome Trust, the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, the Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM) framework, the European Union Seventh Framework Programme, and the National Institute of Mental Health. Publication "Association between prescription of major psychotropic medications and violent reoffending after prison release" Zheng Chang, Paul Lichtenstein, Niklas Långström, Henrik Larsson, Seena Fazel JAMA, published 1 November 2016.  doi:10.1001/jama.2016.15380

Three research project led from Karolinska Institute will this year share SEK 41 Million in grants from the Erling-Persson Family Foundation. Researchers at KI are also partners in a project led from the Royal Institute of Technology (KTH), which will now receive a large grant from the foundation. In its support of scientific research the Erling-Persson Family Foundation prioritizes projects with a focus on medicine and healthcare. The Foundation has a preference for research that is close to the patient and application-oriented, as well as built on collaboration across scientific boundaries. Platform for registry-based randomized clinical trials in heart failure Project: A platform for and conduct of the first Registry-Randomized Clinical Trial in heart failure: The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFPEF) Projekt leader: Dr Lars H. Lund, Department of Medicine, Solna, Karolinska Institutet. Partners: The Swedish national heart failure registry, RiksSvik, and Uppsala Clinical Research Center. Funding: SEK 10 Million over a period of three years. To determine whether a medical treatment is effective, it needs to be studied in a randomized clinical trial (RCT).  However, conventional RCTs are becoming increasingly complex and costly. The Registry-based Randomized Clinical Trial (RRCT) is a novel concept pioneered in Sweden that builds a trial platform on an existing health care registry to perform an RCT. Heart failure is common, deadly and associated with poor quality of life. In heart failure, the patient suffers from an impaired ability to pump blood, or impaired ability to fill the heart with blood. Heart failure with impaired pumping is treatable, but heart failure with impaired filling is equally common and serious, and there is no proven therapy.  Spironolactone is an existing inexpensive drug that reduces mortality in heart failure with impaired pumping. It is promising also in impaired filling, but the efficacy of this ‘new use’ of an existing drug needs to be proven in a randomized trial. “However, this this will not be done by the industry, because spironolactone is generic, and industry has no incentive to finance research unless on a patent-protected drug”, says heart specialist and principal investigator Lars H. Lund. “The purpose of our project is therefore to test the in-expensive spironolactone, and at the same time build a platform for similar randomized clinical trials for drugs in the future.“  Improved prostate cancer diagnosis – further development of the Stockholm3 test Project: The Individualized Prostate Cancer Diagnosis Pipeline Projekt leader: Professor Henrik Grönberg, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet Partners: Karolinska University Hospital, Stockholm County Council and Prostate Cancer UK Grant: SEK 28 million distributed over three years. Prostate cancer is the most common form of cancer in Sweden with over 10,000 cases and 2,500 deaths every year. The aim of the project is to reduce the number of deaths from prostate cancer by developing new and safer diagnostic tests that better identify and help treating aggressive prostate cancer and implement these tests in routine clinical care. An important first step has already been taken with the development of Stockholm3 test, a blood-based prostate cancer test that combines genetic and protein markers. The Stockholm3 test was evaluated in 2012-2014 on over 58,000 men in the Stockholm region and the results have been presented in The Lancet Oncology and other medical journals. The studies have demonstrated the benefits of the test, which include a higher detection rate of aggressive prostate cancer and fewer men that need to take an unnecessary prostate biopsy. The support from the Erling-Persson Family Foundation makes it possible to further develop new diagnostic tests for prostate cancer. One example is a combination of the Stockholm3 test and magnetic resonance imaging scans to further improve the identification of aggressive prostate cancer. The researchers will also develop methods for assessing tissue samples using genome sequencing and enabling the treatment of metastatic cancer, i.e. cancer that has spread beyond the prostate. They hope to clinically implement further improvements of the prostate cancer diagnostic pathway within three years. “The Stockholm3 test is already available for men in Sweden via the Karolinska University Hospital Laboratory,” says Henrik Grönberg, consultant and professor of cancer epidemiology, who has also patented the test. “We’re now taking the next step, which means that we’re looking at how we can improve the whole prostate cancer diagnostic pathway. This will include developing and implementing new technology and improved processes, which will allow us to detect aggressive cancer earlier and reduce today’s problem of over-diagnosis.” The elimination of Malaria in Zanzibar – a case study for Africa Project: Is Malaria elimination possible in Zanzibar? A case study for Africa. Projekt leader: Professor Anders Björkman, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. Partner: Zanzibar Malaria Control Program Funding: SEK 3 Million over a three year period. Ever since the 1980s, Professor Anders Björkman and his group have been interested in strategies to decrease mortality and incidence of Malaria including novel methods for diagnosing and treating the disease. The research group has also focused on the evolution of resistance to new antimalarial drugs. In recent years, the research has mainly been conducted on Zanzibar, but also on mainland Tanzania, in Mali and in Guinea Bissau. Zanzibar has been successful in decreasing the incidence of Malaria to a very low level – which is unique in an area with high endemic rates – and the research group is now continuing its work towards a possible total elimination of the disease. To achieve this, new intervention strategies have to be introduced, specifically targeting residual parasite reservoirs and using new surveillance tools and strategies, including new molecular surveillance tools. The aim of the project is to present a possible proof of concept concerning malaria elimination from a highly endemic region or a country. This  would be globally unique. Development of nanotechnology for the ultra-sensitive detection of blood-borne markers in lung and breast cancer Project: Detection and analysis of tumour- and blood-borne markers using new nanotechnology for the early diagnosis and monitoring of cancer Project leader: Professor Jan Linnros, School of Information and Communication Technology, Royal Institute of Technology (KTH). KI researchers: Professor Rolf Lewensohn, and Dr Kristina Viktorsson, Department of Oncology-Pathology, Karolinska Institutet. Other partners: Amelie Eriksson Karlström, professor at the School of Biotechnology, KTH; Afshin Ahmadian, professor at the School of Biotechnology, KTH and SciLifeLab; and Björn Samel, researcher for Acreo Swedish ICT. Grant: SEK 29.8 Million distributed over three years. With solid tumours, tumour markers are important for revealing metastasis and predicting the effect of therapies, such as modern target-seeking therapy. Unfortunately, samples from the tumour are often difficult to take owing to the location of the tumour, and usually only a minimal amount of tumour is extracted that can be used for biomarker analysis. Normally, however, tumours secrete small amounts of tissue fragments (exosomes) into the blood that reflect the tumour’s RNA, microRNA and surface proteins. Freely circulating tumour DNA is also often found in the patients’ blood. Technologies are therefore needed that can identify tumour markers robustly and quantitatively from extremely small amounts of such material. The project group at KTH, Karolinska Institutet and SciLifeLab will be developing silicon chip-based methods using nano-biosensors to isolate exosomes and other material to study their protein, RNA and microRNA expression. The function of the sensors is based on the ability of antibodies and other so-called binders to capture and bind tumour-exosomes, allowing the measurement of the signal pathways – something that, in turn, reflects the properties of the tumour. In this way, the group wants to create methods for early detection and diagnosis of cancer but also to reveal the presence of therapeutic tumour targets such as; mutated cell receptors like EGFR and EML4-Alk important in lung cancer.The researchers’ focus will be on samples from patients with non-small cell lung cancer, the most common form of this disease, and breast cancer. Besides diagnostics blood samples will also be analysed during lung cancer treatment with target-seeking drugs towards mutated growth factor receptors orimmunological signaling pathways. “Thanks to this generous donation from the Erling-Persson Family Foundation, we hope that our partnership with KTH will lead to an analysis platform based on nanochips for biomarker studies of tumour and blood, and thus to a new tool for more effective personalised cancer treatments,” says Professor Lewensohn.

Researchers at Karolinska Institutet have measured the absolute numbers of short, non-coding, RNA sequences in individual embryonic stem cells. The new method could improve the understanding of how our genes are regulated and different cell types develop. When information in our genes is used, for example to build a protein, it is first translated to messenger-RNA which functions as a blueprint for the protein. Our cells also contain non-coding, short, RNA sequences that do not contribute to the formation of proteins and whose functions are partly unknown. The best known of these is micro RNA (miRNAs), which can interact with the messenger RNA, and thereby regulate genes and cell function. Researchers at Karolinska Institutet have now mapped the presence of short RNA-sequences in an individual cell. Previous research on short RNA molecules is based on analysis of many cells simultaneously, making it difficult to study the precise function. “Our knowledge of the function of short RNA molecules is quite general. We have a picture of the general mechanisms, but it is less clear what specific role these molecules play in different types of cells or diseases,” says Rickard Sandberg, professor at the Department of Cell and Molecular Biology, who is also affiliated to the Stockholm center of Ludwig Cancer Research. Two types of embryonic stem cells were analysed with single-cell transcriptomics The analysis was done using single-cell transcriptomics, a technique which makes it possible to measure the absolute numbers of short RNA molecules in a cell. Two types of embryonic stem cells were used, intended to mimic the early embryo, before and after it has attached to the uterine lining. The researchers could detect large numbers of small RNAs in both cell states, including miRNA as well as shorter RNA fragments (tRNA and snoRNA) whose function is largely unknown. The researchers also found that large numbers of miRNAs are expressed differently in the two cell states. “This is basic research and a demonstration that the method works, giving suggestions for further research. To map the levels of short RNA molecules in a cell is a first step in identifying the specific function of these molecules,” says Omid Faridani, one of the lead authors of the study. In the long run, Rickard Sandberg can imagine clinical applications of the method. “We are, for example, interested in the role short RNA molecules play during embryonic development. We hope that, with more knowledge, this method could be used to identify which embryos have the best chance to develop, which would then be used to improve current IVF treatments,” he says. Publication “Single-cell sequencing of the small-RNA transcriptome” Omid R. Faridani, Ilgar Abdullayev, Michael Hagemann-Jensen, John P. Schell, Fredrik Lanner and Rickard Sandberg Nature Biotechnology, online 31 October 2016. DOI: 10.1038/nbt.3701

A previously unknown safety mechanism in our immune system keeps the body free from autoimmune diseases. Researchers from Karolinska Institutet have discovered that a cell in our inherited immune system can prevent our adaptive (learned) immune system from reacting to the body’s native cells, which can otherwise lead to autoimmune diseases such as SLE. The study is published in the academic journal Nature Immunology. Autoimmune diseases and allergies, in which the immune system triggers an immunological reaction in sufferers, are becoming increasingly common. In some cases, such as the rheumatic disease SLE, the immune system reacts to the body’s own cells. One of the most important components of our learned (adaptive) immune system is the white blood cells called B lymphocytes, which are one of the main causal factors of many autoimmune diseases, including SLE, since it is these cells that start to react to the body’s native structures, giving rise to the symptoms. “Our research group has been interested in B lymphocytes and what goes wrong in the regulation of different types of autoimmune disease,” says Professor Mikael Karlsson at the Department of Microbiology, Cell and Tumour Biology. Neutrophils have a crucial function in their interaction with B lymphocytes It has long been known that a certain type of cell in the inherited immune system called a neutrophil plays an important part in wound healing and the early stages of the immune response. Through their studies on laboratory mice, the team from KI has now discovered that neutrophils have another crucial function in their interaction with B lymphocytes. What they found was a safety mechanism that prevents B lymphocytes from reacting to endogenous antigens. “We have discovered a previously unknown mechanism in the immune system that prevents autoimmune disease and that could be lacking, we think, in people with autoimmune diseases such as SLE,” says Professor Karlsson. When an inflammation occurs in the body, the neutrophils cause the B lymphocytes in the spleen to start producing antibodies that retard an infection. At the same time, however, the neutrophils also communicate with a kind of immune cell called an NKT cell, instructing it to regulate the response to prevent over-reaction. It is known that SLE patients do not have as many NKT cells as other people, which could be a contributing factor to the failure of the body to regulate B lymphocytes. “Apart from our discovery being interesting in general terms of how the immune system works, it can also be very important for people with other autoimmune diseases,” says Professor Karlsson. “We think that this mechanism could be used to regulate B lymphocytes in different morbid conditions and that it could be a way forward for stopping SLE.” The study was financed with grants from several bodies, including the Swedish Research Council, the Swedish Rheumatism Association and the Olle Engkvist Byggmästare Foundation. Publication  “Neutrophils license iNKT cells to regulate self-reactive mouse B cell responses” Thomas Hägglöf, Saikiran K. Sedimbi, Jennifer L. Yates, Roham Parsa, Briana Hauff Salas, Robert A. Harris, Elizabeth A. Leadbetter and Mikael C. I. Karlsson Nature Immunology, published online 31 October 2016, doi: 10.1038/ni.3583  

Last Thursday (27 October), the Swedish Research Council announced the grants it will be awarding in the category of medicine and health. The total sum is almost SEK 980 million, of which KI researchers will receive SEK 524,325,017. Of the 1,160 applications submitted, 254 have been approved, 128 of which were from KI. The grant funds will be distributed over the years from 2016 to 2020. The decision covers five categories of grant: project grants (107 at KI), starting grants (16 at KI), project grants for the development of methods for replacement, reduction and refinement of animal experiments (3R) (3 at KI), grants for half-time position in clinical research environment (2 at KI) and a doctoral programme grant in bioinformatics. Read more about the grants awarded in this call for applications on the Swedish Research Council website.

Earlier this autumn, the Karolinska Institutet board (konsistoriet) asked Acting Vice-Chancellor Karin Dahlman-Wright to draft an action plan in response to the recommendations made by Heckscher’s independent inquiry into KI’s handling of the Macchiarini affair. The action plan is based on the Strategy 2018 roadmap and clarifies important areas of improvement for the university. But it also contains measures in direct response to the Heckscher investigation and KI’s internal audit of the Department of Clinical Science, Intervention and Technology (Clintec). On 10 October, the board voted to adopt the intentions of the action plan, and tasked the Vice-Chancellor with their development and implementation. The Vice-Chancellor is to present a timetable based on the plan at the board meeting of 5 December. The action plan is based on three principal areas: internal culture and leadership at KI; quality issues, including compliance; and organisation, including KI’s relationship with Karolinska University Hospital. The plan is to detail the measures to be taken for all the recommendations made by the Heckscher inquiry and the audit report. Much of KI will be engaged in carrying out the proposals set out in the action plan, which involves both immediate and more long-term changes. “We now need to pull together to make sure that KI becomes even better and stronger,” says Karin Dahlman-Wright, acting vice-chancellor at KI. “We want no one ever doubting that KI is a university characterised by high quality and sound ethics.” The measures include: internal training to promote sustainable leadership clear rules for ensuring that any departure from the delegation of authority is properly documented enhanced hiring procedures improved research documentation  

According to earlier recommendations, women ought to avoid endoscopy during pregnancy.  New analyzes by researchers from the Karolinska Institute and Columbia University could question these recommendations. In a collaborative study between the Karolinska Institutet and Columbia University, New York, US, researchers have examined the outcome in more than 3000 pregnancies where the women underwent endoscopy during pregnancy. Leader of these studies has been Professor Jonas F Ludvigsson of Department of Medical Epidemiology and Biostatistics at KI. Until now, endoscopy has been discouraged during pregnancy for few that it may be detrimental to the pregnancy and the fetes. Earlier studies have however been based on less then a few hundred women, often with severe underlying gastrointestinal disease that may have had a larger impact on pregnancy outcome than the endoscopy. Endoscopy is an umbrella term for upper endoscopy (”gastroscopy”), lower endoscopy (colonoscopy) or endoscopic retrograde cholangiopancreatographies. Compared to pregnancies of women with no endoscopy during pregnancy, women with endoscopy were at increased risk of a number of adverse pregnancy outcome. However, through the use of different comparison groups the researchers were able to disentangle the effect of the endoscopy per se, and the underlying disease. When restricting the analysis to women with no severe gastrointestinal disease, the difference in pregnancy outcome between women with and without endoscopy during pregnancy was minimal, and when comparing births within the same mother, for which only 1 birth had been exposed to endoscopy (and the other birth not), the researchers found no association between endoscopy and gestational age or birth weight. Congenital malformation was not linked to endoscopy in any analysis. Publication Outcomes of Pregnancies for Women Undergoing Endoscopy While They Were Pregnant—a Nationwide Cohort Study Jonas F. Ludvigsson, Benjamin Lebwohl, Anders Ekbom, Ravi Kiran, Peter HR. Green, Jonas Höijer, Olof Stephansson NCBI, published online 20 October 2016. doi: 10.1053/j.gastro.2016.10.016

Breast cancer is the most common cancer type in women in Sweden and worldwide. It has long been known that not all breast cancers are similar: Luminal tumours consist mostly of cells that are similar to those found in the inner lining of the breast ducts (luminal mammary gland cells), whereas others can have cells more similar to the outer layer of the breast epithelium (basal cells). It is believed that this diversity originates from mutations in different stem cells or progenitor cells. The identities of these peculiar progenitor cell populations and their tumour forming capabilities are incompletely understood. In a new study, published in Nature Cell Biology, researchers at Karolinska Institutet describe rare populations of basal and luminal progenitor cells that contribute to normal mammary gland development and serve as tumour-initiating cells specifically for luminal breast cancers. The newly discovered progenitor cell populations express Lgr6, a cell surface receptor protein that is commonly associated with stem cells in the hair follicle, skin, lung, and tongue. Marker for mammary gland progenitor cells The research group at the Department of Biosciences and Nutrition at Karolinska Institutet in Huddinge, led by Leander Blaas and Rune Toftgård, teamed up with researchers at the Crick Institute in London to isolate and analyze progenitor cells marked by the receptor Lgr6 during normal mammary gland development and the development of tumours. Using a genetic mouse model, in which these cells can be labelled with a fluorescent protein, the research team could show that Lgr6+ cells expand during puberty and help to build the organ. Once the mammary gland is fully developed, Lgr6+ cells do not seem to play an active role in maintaining the epithelium. During pregnancy, however, they surprisingly become reactivated and help to form the milk-producing structures (alveoli). Although, Lgr6-expressing cells only comprise ~2 – 4 % of all mammary gland epithelial cells, their progeny contribute substantially to the organ’s development and it’s main function, the production of milk. Needed for efficient tumour growth Parallel to their analyses of Lgr6+ cells in normal development, the researchers tested whether mutations in these cells could result in the formation of mammary gland tumours. When they induced two different combinations of mutations in these cells, luminal tumours appeared in both mouse models, suggesting that rare Lgr6+ cells are potent cells of origin for breast cancer. Next, they traced Lgr6-expressing cells in different mouse models of basal and luminal breast cancer. These experiments revealed a specific contribution to development and maintenance of luminal mammary gland tumours. Strikingly, when they depleted Lgr6+ cells in a mouse model of luminal breast cancer, the resulting tumours appeared later, were smaller, and appeared to be less aggressive. “Lgr6+ cells are rather rare and still, they seem to fuel luminal tumour growth and strongly affect the composition of a tumour”, says Leander Blaas, a lead author of the study. “In a next step, we want to perform a detailed, molecular characterization of these cells in normal mammary glands and in tumours. Most progenitor and tumour-initiating cells are isolated using very broad and non-specific markers. Using Lgr6 as a marker, we are able to specifically isolate and characterize such cells and determine their properties.” The Lgr6 receptor is expressed in approximately 50% of human breast cancers and its overexpression may be associated with patient survival. Thus, this work will also benefit research into human breast cancer and therapies targeting tumour-maintaining cells. The work at KI was supported through funding from the Swedish Cancer Society, the Swedish Research Council, the Marie Skłodowska-Curie actions, and the Wenner Gren Foundation. Publication "Lgr6 labels a rare population of mammary gland progenitor cells that are able to originate luminal mammary tumours" Leander Blaas, Fabio Pucci, Hendrik A.Messal, Agneta B. Andersson, E. Josue Ruiz,Marco Gerling, Iyadh Douagi, Bradley Spencer-Dene, AlexandraMusch, RichardMitter, Leena Bhaw, Richard Stone, Dorothee Bornhorst, Abdul K. Sesay, Jos Jonkers, Gordon Stamp, IlariaMalanchi, Rune Toftgård and Axel Behrens. Nature Cell Biology, published online 31 October 2016. DOI:10.1038/ncb3434 

On Thursday 27 October, the House of Ageing Research in Stockholm hosted a theme day to draw attention to research on ageing and related diseases. Queen Silvia was in attendance and held an opening address in Aula Medica on the KI Solna campus. The doors opened early at the House of Ageing Research for the hosts – The Aging Research Center, The Swedish Dementia Centre and The Stockholm Gerontology Research Centre – to receive the visitors, who were able to spend the morning testing their sense of smell, training their memory in the Brain Lab, and asking questions to the house’s experts. In the afternoon, the focus shifted onto presentations on geriatric research in Aula Medica – but not until Queen Silvia had arrived and been welcomed by KI’s acting vice-chancellor Karin Dahlman-Wright.

In two articles published in Cell Stem Cell, scientists from Karolinska Institutet and Lund University present results that warrant a modification of the protocol for making dopamine. The new protocol is now ready for clinical use. One of the challenges facing future medical research is to be able to use cell therapy to treat Parkinson’s disease, the severe symptoms of which are caused by the degeneration of the dopamine-producing cells in the brain. The key to success for future cell therapy is the ability to generate new cells from stem cells, and the aim is to be able to transplant the new dopamine cells to patients with Parkinson’s disease. In the papers now published in Cell Stem Cell, researchers from Karolinska Institutet and Lund University present the results of a collaboration between a group led by Thomas Perlmann (KI/Ludwig Cancer Research) and a group led by Malin Parmar (Lund). Research result is extremely relevant to cell therapy The first paper presents the results of single-cell RNA sequencing, which the researchers conducted to study the early development of dopamine cells in detail. Using pregnant transgenic mice containing a fluorescent marker, they purified and sequenced the most relevant cells from the embryos. This allowed them to reconstruct with extremely high resolution the total gene expression during the development of dopamine cells and closely related cell types. “We found, completely to our surprise, that during their early development, dopamine cells are very closely related to a type of cell that forms close to the area in which dopamine cells are normally formed,” says Professor Perlmann. “The closely related cell type develops into what are called STN cells, which are neurons that use glutamic acid to transmit their signals and that don’t degenerate during Parkinson’s disease. This result is extremely relevant to cell therapy research since all important markers previously used as a guide for making dopamine cells have now proved common to both nerve cell types.” New knowledge modified the protocol for making dopamine cells In the other paper, the authors describe how RNA sequencing was used to analyse global gene expression in over 30 batches of human cells prepared from stem cells, which were then transplanted into a rat model for Parkinson’s disease. Their analysis showed that the markers that are normally used are not at all predictive of good clinical outcomes. However, the results from the first paper showing that the markers are not actually unique to dopamine cells but are also expressed in STN cell explain this lack of predictability. The transplants did indeed often contain many STN cells in addition to the clinically effective dopamine cells. With this knowledge, the protocol for making dopamine cells could then be modified. The new protocol proved superior to the old one and is now ready for clinical use. “Both these papers are excellent examples of how important advances can be achieved when groups engaged in both basal and clinical/translation research collaborate. For Swedish research, productive interaction across university boundaries, which in this case has led to important advances for translational stem cell research, is also highly gratifying,” says Professor Perlmann. Publications Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages Nigel Kee, Nikolaos Volakakis, Agnete Kirkeby, Lina Dahl, Helena Storvall, Sara Nolbrant, Laura Lahti, Åsa K. Björklund, Linda Gillberg, Eliza Joodmardi, Rickard Sandberg, Malin Parmar, Thomas Perlmann5 Cell Stem Cell. Published online 27 october 2016. http://dx.doi.org/10.1016/j.stem.2016.10.003 Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson’s Disease Agnete Kirkeby, Sara Nolbrant, Katarina Tiklova, Andreas Heuer, Nigel Kee, Tiago Cardoso, Daniella Rylander Ottosson, Mariah J. Lelos, Pedro Rifes, Stephen B. Dunnett, Shane Grealish, Thomas Perlmann, Malin Parmar Cell Stem Cell. Published online 27 october 2016.  DOI: http://dx.doi.org/10.1016/j.stem.2016.09.004

A small molecule that can turn short-lived ‘killer T-cells’ into long-lived, renewable cells that can last in the body for a longer period of time, activating when necessary to destroy tumour cells, could help make cell-based immunotherapy a realistic prospect to treat cancer. In an article published in Nature, Professor Randall Johnson from Karolinska Institutet and researchers from University of cambridge have identified a new role for a molecule labeled 2-hydroxyglutarat, or 2-HG, which is known to accelerate the abnormal growth of tumor cells. The research team has shown that a slightly altered version of the molecule also plays a normal but critical role in T-cell function: it can affect the T cells to be in a "memory mode". This is a situation where the cells can renew themselves, survive a long time and reactivate to fight infections or cancer. The complete pressrelease from the University of Cambridge can be found below. Publication S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate Petros A. Tyrakis, Asis Palazon, David Macias, Kian. L. Lee, Anthony. T. Phan, Pedro Veliça, Jia You, Grace S. Chia, Jingwei Sim, Andrew Doedens, Alice Abelanet, Colin E. Evans, John R. Griffiths, Lorenz Poellinger, Ananda. W. Goldrath & Randall S. Johnson Nature, published online 26 October 2016. doi:10.1038/nature20165

On October 24, date of the UN anniversary, students at Karolinska Institutet for the second time around, organized the Global Health Night. With its 1 000 guests and speakers from among others Karolinska Institutet, Sida and WHO, it was an evening that put the spotlight on global health. KI News was there.     Film: Susanna Forsell Read more about Global Health Night 2016

The bellygenes initiative, coordinated by researchers at Karolinska Institutet and the University Medical Centre Groningen, will study the genetic makeup of 800,000 Europeans in relation to irritable bowel syndrome and associated symptoms. Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder, reducing quality of life in 10-15% of people worldwide (women more than men). Although some contributing factors have been identified, IBS pathophysiology remains largely unknown. Human genetic studies are contributing to the development of personalized treatment options, but in IBS these have been few and underpowered to deal with its complex and heterogeneous nature. A large-scale project, the bellygenes initiative, is now aiming to overcome this issues by studying IBS in relation to the genetic makeup of some 800,000 Europeans from well-established cohorts, biobanks and patients' collections. "This represents an unmatched opportunity to tackle IBS genetics for the first time with adequate statistical power" says bellygenes coordinator Mauro D'Amato from the Unit of Clinical Epidemiology, Department of Medicine, Karolinska Institutet. "We hope to reveal pathophysiological pathways that can help explain the etiology of IBS, inform a molecular reclassification of patients, and ultimately provide novel biological targets for increased therapeutic precision". The bellygenes initiative received support from the BioMolecular resources Research Infrastructure - large prospective cohorts, for accessing data from UK Biobank, LifeLines,Estonian Biobank EGCUT and HUNT. Several other population-based and case-control cohorts are studied as part of a large established IBS collaborative network of international scientists and clinicians.  

Labour dystocia, or the failure of the uterus to contract properly during labour, is a serious problem in obstetrics. A new study from Karolinska Institutet demonstrates a simple method that can make it easier for doctors to assess and treat the condition. The study is published in the journal PLOS ONE and was part-financed by the Bill and Melinda Gates Foundation. Labour dystocia  causes the woman to undergo painful but ineffective labour, and while her contractions come regularly there is no dilation of the cervix and the baby does not push through the birth canal. All kinds of muscular fatigue produce lactic acid, and this includes the uterine musculature. The main cause of lactic acid production is anoxia (oxygen starvation), which in labour dystocia can stretch over long periods of time, leading to the accumulation of lactate. In Sweden alone, some 20,000 women are diagnosed every year with labour dystocia, which results in arrested labour. Although the underlying causes are not yet known, the condition is treated with oxytocin, the effects of which, however, vary from one individual to the next. Studies at Karolinska Institutet and Stockholm South General (Söder) Hospital demonstrate a close link between levels of uterine lactate and amniotic fluid lactate (ALF). An analysis of the amniotic fluid that leaks out during labour can give obstetricians valuable information on the current lactic acid level of the uterus. “We’ve developed a clinical application that measures the level of lactate in the amniotic fluid,” says Eva Wiberg Itzel, associate professor at Department of Clinical Research and Education, Karolinska Institutet, South Hospital. “This means that we’re able to deal more effectively with the individual woman’s labour.” The study shows that oxytocin stimulation works well in the event of an arrested labour when the level of AFL is low. In 75 per cent of cases, the baby was spontaneously delivered vaginally, with a C-section frequency of only 9 per cent. In the group with high lactate readings, the rate of spontaneous vaginal delivery was much lower and C-section much higher: 36 per cent and 37 per cent respectively. Arrested labour and high lactate levels were also more likely to lead to complications such as post partum haemorrhage and infections and neonatal anoxia. The results of the study point towards a possible improvement in perinatal care for mother and child in Sweden and elsewhere. “Many women around the world die from complications associated with labour dystocia,” says Dr Wiberg Itzel. “Being able to measure individual differences in lactate production means that we can tailor and individualise the assessments we make ahead of each delivery. Above all, it means that we can use oxytocin where it has the best effect” The study was also financed by grants from the Johan & Jacob Söderberg Foundation and the Olle Engkvist Byggmästare Foundation. Publication “Amniotic fluid lactate (AFL): a new predictor of labor outcome in dystocic deliveries” Eva Wiberg-Itzel, Andrea B Pembe, Hans Järnbert-Pettersson, Margareta Norman, Anna-Carin Wihlbäck, Irene Hoesli, Monya Todesco Bernasconi, Elie Azria, Helena Åkerud and Elisabet Darj. PLOS ONE, published online 26 October, 2016, doi: 10.1371/journal.pone.0161546  

Gabriel Wikström, Swedish Minister for Health Care, Public Health and Sport, visited Karolinska Institutet on Friday 21 October to learn more about Karolinska Institutet and to discuss collaboration with the healthcare sector. During his visit, the minister visited research environments on the Karolinska Institutet Solna campus and listened to lectures by scientists who both conduct research at the university and work in clinics. After the visit Gabriel Wikström said he learned that KI works on the basis of a very close partnership with the healthcare sector, but that this relationship needs to be even stronger. He also wants to see KI contribute to closing the health gap in society, which the Swedish government has pledged to do. “It’s one of the most important questions, and if we’re to achieve this goal we need to learn more about the field,” says Mr Wikström. “We also need to know how to implement methods and projects more effectively than we do today.” Can KI help with this? “I believe so, and by what I’ve seen here today considerable progress has been made in this field, not only regarding medical treatment, but also in terms of preventative work, and that’s what’s needed if we’re going to end health disparities in society,” says Mr Wikström. The first stop during his visit was SciLifeLab (Science for Life Laboratory), a national center for molecular biosciences with focus on health and environmental research.  Here, scientists quickly performing DNA sequencing for numerous purposes, including diagnosing rare congenital diseases, a technique that can mean life or death for patients who need an immediate diagnosis to ensure proper treatment. “I found it fascinating,” says Mr Wikström. “It’s fantastic to see how quickly things are moving, in terms of both new techniques and how they affect work processes, the educational content of courses and the way researchers are able to collaborate with others.” KI’s acting vice-chancellor, Karin Dahlman-Wright, says it’s vital that the Minster for Healthcare and Public Health has a chance to visit the university and find out more about Karolinska Institutet. “In the past few years, there’s been a lot of focus on the groundbreaking research we do here. But we also do a great deal that has a more immediate effect on human health, such as our clinical research, and that’s the side of our work that we’re highlighting during today’s visit,” she says. Text: Selma Wolofsky

Top row, from the left: Karin Dahlman-Wright, Acting Vice-Chancellor, Alejandro Cabello Lopez, Mexico, Public Health, Simeng Yan, China, Public Health, Maria Masucci, Deputy Vice-Chancellor for International Affairs, Sabbir Ahmed, Bangladesh, Toxicology, Gunnar Nilsson, Pro-Dean of Higher Education. Bottom row, from the left: Stephanie Super, Chile, Global Health, Lana Al Soufi, Syria, Global Health, Ka Wai Lee, Hong Kong, Molecular Techniques in Life Science, Shupei Zhang, China, Biomedicine, Isabel Hernandez, Mexico, Bioentreprenurship.   For the fifth consecutive year, the Karolinska Institutet Global Master’s Scholarships have been awarded to students outside of Europe. The Global Master’s programmes offered by Karolinska Institutet received more applications than any other Swedish university for the autumn 2016 semester. The eight master’s students out of the 1,200 who applied each received a scholarship worth from SEK 180,000 to SEK 360,000 at a ceremony on 19 October. The scholarship, which is provided by the Swedish Council for Higher Education, is meant to cover tuition fees. “This is a key part of KI’s strategy and efforts to be a more international university,” says Gunnar Nilsson, Pro-Dean of Higher Education at KI, who also enjoyed meeting the students in person. Awards on grounds of merit The scholarship is awarded solely on grounds of merit, and is based on the students’ grades, work experience and research experience and a letter of justification that they write themselves in their application. One of the scholars is Ka Wai Lee from Hong Kong, who is studying molecular techniques in life science – a master’s programme offered jointly by KI, KTH and Stockholm University. “The reason I chose KI, like many of the others here, was its good reputation and quality,” says Ka Wai Lee. “I also love my courses and the lectures are great. It’s awesome that I can go to different universities and study what they actually specialise in. It’s a combination that really suits me.” Scholar Isabel Hernandez from Mexico is on the master’s programme in bioentrepreneurship: “I really like this programme in entrepreneurship because it enables two different but mutually complementary worlds, research and entrepreneurship, to cooperate, and I think this makes a difference for the patients,” she says. Over 3,000 students applied Ahead of the autumn 2016 semester, over 3,000 students from 128 countries applied to KI’s global master’s programmes, putting KI ahead of any other university in terms of the number of applicants per international master’s programme. Acting vice-chancellor Karin Dahlman-Wright attended the ceremony to hand out the scholarships: “It’s wonderful,” she says. “These are incredibly ambitious students from all over the world.” Text and photo: Susanna Forsell

Three young researchers at Karolinska Institutet have been awarded the Ragnar Söderberg Fellowship in Medicine for 2016, and are each to receive a research grant of SEK 8 million over five years. The three awardees are Magda Bienko, Nicola Crosetto and Simon Elsässer, all also affiliated to at SciLifeLab.  The Ragnar Söderberg Fellowship in Medicine is awarded to promising young researchers at the start of their careers to help them establish innovative research environments and develop as independent scientists. This year, five researchers have been awarded grants, three of whom are group leaders at Karolinska Institutet’s Department of Medical Biochemistry and Biophysics (MBB).  Spatial organisation of the genome in breast cancer Fellow: Magda Bienko, Assistant Professor, MBB Most human cancers contain alterations in the number and structure of chromosomes that are associated with poor prognosis. In breast cancer chromosomal alterations represent a major mutation type that causes deregulated expression of many genes, which in turn can fuel tumor progression. Independently of the type of alteration, chromosomal rearrangements will exert a global effect on the architecture of the genome, which in turn will affect global gene expression profiles. To fully understand the pathologic consequences of chromosomal alterations, a thorough picture of the 3D structure of rearranged cancer genomes is needed. Using state-of-the-art methods of sequencing and microscopy, Magda Bienko studies how structural chromosome changes affect the spatial organisation of the entire genome with the aim of building a catalogue of the different chromosome changes and focusing on local topologies in the most commonly occurring breast cancer genes. Thanks to the laboratory’s unique microscopy tools, she is able to pick out structural details direct in the cells and monitor their activity. The objective of Magda Bienko’s project is to understand the principles for how the genome adapts to the dramatic structural changes that occur in breast cancer. Potentially, she will be able to discover new universal weaknesses in cancer cells that can lead to new treatment strategies. More about Magda Bienko's research Advanced determination of cellular variation in a tumour Follow: Nicola Crosetto, Assistant Professor, MBB For the past few decades, many leading cancer centres around the world have started developing therapy programmes based on the concept of personalised cancer medicine instead of treating all cancers as the same. However, despite huge investments in the field, many such targeted treatments fail, probably because the individual tumour comprises its own highly complex ecosystem consisting of millions of cells with different properties. This variation, referred to as intra-tumour heterogeneity” (ITH), goes a long way to determining how, and even if the tumour will respond to treatment, and if it will generate life-threatening metastases. New, reliable methods need to be developed that can measure and visualise ITH, and then convert the information into something doctors can use. Nicola Crosetto is taking up this challenge by developing advanced techniques and algorithms for measuring different parameters in cancer samples and using them to chart ITH in breast cancer patients treated with neoadjuvant chemotherapy prior to surgery. The project uniquely integrates the state-of-the-art technology being developed at the Science for Life Lab with clinical expertise from Karolinska University Hospital, helping to place Sweden at the cutting edge of personalised cancer therapy. More about Nicola Crosetto's research The relevance of short peptides coded by sORFs Fellow: Simon Elsässer, Assistant Professor, MBB Cells are teeming with short peptides (sPEPs) translated by short open reading frames (sORFs). However, despite their abundance, their function remains a mystery. Recent analyses of the entire genome and mass-spectrometry studies have shown that there are over a thousand different sPEPs in mammalian cells. Studies of a handful of sPEPs reveal that many of them are involved in human biology and relatable to disease. The aim of Simon Elsässer’s project is to systematically identify and name the short peptides coded by sORFs, and determine their place in the cell, their peptide stability and their molecular function. The project is the first of its kind: no previous study has been set up to understand the function of the myriad human sPEPs and to identify potential biomarkers and peptides for drugs to act against. More about Simon Elsässer's research Swedish text (here in translation) and photo: The Ragnar Söderberg Foundation View a film from the Ragnar Söderberg Foundation Ragnar Söderberg Fellow in Medicine 2016 from Ragnar Söderbergs stiftelse on Vimeo.