Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

KI News

Updated: 46 min 56 sec ago

KI starts collaborative efforts with other higher education institutions

Mon, 12/03/2018 - 09:42
Karolinska Institutet has recently started a number of Vinnova-financed joint projects with other Swedish higher education institutions, to improve the capacity to collaborate. According to Pro-Vice-Chancellor Karin Dahlman-Wright, collaboration is not an end in itself, but rather a means to strengthen the quality and relevance of research and education. “By working interdisciplinary, we are able to adopt new and exciting approaches,” she says. The Swedish Government has long signalled its expectation on higher education institutions to disseminate and share their knowledge. Karin Dahlman-Wright believes that, as an internationally renowned medical university that accounts for a large proportion of Swedish academic medical research, KI should set a leading example when it comes to implementing research results and knowledge. Even though collaboration with the healthcare and private sectors already forms a natural part of KI’s activities, the way in which such collaboration contributes to societal impact is not always clearly visible. Karin Dahlman-Wright believes that KI must be better at drawing inspiration from those around us. “To this end, it is our ambition for KI to be an active partner in KLOSSnet – a national network consisting of 35 Swedish higher education institutions formed last year with the goal to provide opportunities to share experiences and ideas in a relatively informal manner.” In order to further encourage and improve collaboration, the innovation agency Vinnova last year invited Sweden’s higher education institutes to apply for joint project funding in a programme totalling SEK 100 million. “As a result of this initiative, KI is now a partner in five projects that are being coordinated at KI under an umbrella project known as SKISS which aims to strengthen KI’s strategic collaborative capacity. Our hope is that these projects will in various ways demonstrate the possibilities offered by collaboration,” explains Kerstin Lundin, the project leader of SKISS. According to Karin Dahlman-Wright, Sweden’s higher education institutions need to join forces to ensure that collaboration with society is seen as a natural part of research and education. “Joint investment by Vinnova and the participating universities offers us the opportunity to develop and disseminate existing working methods and test new ones,” she says. SKISS and its five sub-projects have a three-year timeline, although the work will continue long after 2020. One of the projects aims to facilitate exchange of personnel between KI and external organisations with which we collaborate. Karin Dahlman-Wright also hopes that the projects will lead to KI developing more strategic partnerships. “The more external partners we collaborate with, the greater the benefits of our research to society. KI already collaborates with a great many different organisations, but we must begin to work more strategically with respect to with whom we work with,” she says, and continues: “Our industry collaborations provide a means towards further exploiting our research results, while at the same time gaining access to unique expertise, methodologies and technologies.”  On the question of why collaboration is a more pressing question today than previously, Kerstin Lundin replies that this is because society at large is changing so rapidly. “If universities are going to keep up, we must be better at interacting with one another and spreading our knowledge in many different ways and through a variety of forums. In this way, we will be able to strengthen our research and education now and in the future.” Text: Sara Schedin

250,000 developmental cells sequenced

Thu, 08/03/2018 - 15:59
Researchers from the global Human Cell Atlas Consortium report that they have sequenced a quarter of a million separate cells that are of importance for early development of organs such as the liver, skin and kidneys. Sten Linnarsson at Karolinska Institutet is participating in the project. Using powerful single-cell genome analysis tools, researchers from Human Developmental Cell Atlas (HDCA), one part of the ambitious Human Cell Atlas (HCA) project, have collected genomic data from over 250,000 cells from a range of donated developing human tissues. The HDCA programme will create genomic reference maps of all the cells that are important for human development, aiming to revolutionise our understanding of health and disease, from miscarriages and developmental disorders, through to cancer and ageing. The Swedish part of the project is focusing on the development of the brain, lung and heart, and on first trimester development. Researchers from Karolinska Institutet, Stockholm University, KTH Royal Institute of Technology and Science for Life Laboratory are collaborating to discover how these organs develop in order to understand normal human development and shed light on developmental disorders. Affect large numbers of children Professor Sten Linnarsson at the Department of Medical Biochemistry and Biophysics is one of the researchers behind the development of the techniques which enable the project. “About a third of neurological disorders are developmental in origin, including autism, schizophrenia and intellectual disability,” says Professor Linnarsson. “Developmental heart disorders are the most common complications in newborns, and incomplete lung development is the most common cause of death in extremely premature babies. Learning about how these organs develop will help us make progress on disorders that severely affect large numbers of babies and children.” This news article is based on a press release from Wellcome Sanger Institute.

Fluoroquinolones linked to increased risk of aortic disease

Thu, 08/03/2018 - 09:46
New research from a Swedish and Danish team of researchers led from Karolinska Institutet lend additional support to a link between treatment with fluoroquinolone antibiotics and an increased risk of acute aortic disease. The study is published in the esteemed journal The BMJ. Fluoroquinolone antibiotics are used globally to treat a variety of infections. Recent observational studies have raised concerns that they may be associated with a more than twofold increase in the risk of acute and life-threatening aortic disease (aortic aneurysm or dissection). However, due to limitations in study design, it has not been possible to draw firm conclusions. To assess whether there actually is a link, researchers from Karolinska Institutet and Lund University in Sweden and Statens Serum Institut in Denmark analysed data from Swedish national health registers. The researchers were then able to compare the risk of aortic aneurysm or dissection among more than 360,000 treatment episodes of fluoroquinolones with the risk among the same number of treatment episodes of amoxicillin, another type of antibiotic. 66 per cent increased risk The results show a 66 per cent increase in the risk of aortic aneurysm or dissection in patients treated with fluoroquinolone antibiotics. This corresponded to an absolute difference of 82 cases per 1 million treatment courses with fluoroquinolone antibiotics. “Our results confirm the findings in the previous studies but suggest that the increased risk is not as pronounced as indicated by those studies”, says Björn Pasternak, associate professor at Karolinska Institutet’s Department of Medicine, Solna, who led the study. Like the previous ones, the current study is an observational study that is unable to prove a causal relationship. However, according to Björn Pasternak, because of its size and methodological design, it provides the most reliable results so far. “Although the absolute risk increase was relatively small, the study’s findings should be interpreted in the context of the widespread use of fluoroquinolones. Our overall objective is to help inform clinical practice through high-quality evidence”. Induce the activity of certain enzymes The researchers also highlight a possible mechanism that might explain the association. “One of the factors involved in the development of aortic disease is increased activity in tissue-degrading enzymes known as matrix metalloproteinases. We know that fluoroquinolones induce the activity of these enzymes, which is also thought to underlie the more well-known adverse effect of tendon pain and rupture”, says Björn Pasternak. There was no specific funding for this study, but the researchers received support from the Strategic Research Area in Epidemiology at Karolinska Institutet, Swedish Government ALF project funding and the Lundbeck Foundation during the conduct of the study. Publication ”Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study” Björn Pasternak, Malin Inghammar, Henrik Svanström The BMJ, online 8 March 2018, doi: 10.1136/bmj.k678

New study shows how multimorbidity restricts life in the elderly

Wed, 07/03/2018 - 08:00
Multiple neuropsychiatric diseases are major predisposing factors for functional decline in older people and may play a greater role in this age-related phenomenon than cardiovascular diseases, according to a new study by researchers at Karolinska Institutet published in PLOS Medicine. A progressive decline in physical function, commonly referred to as functional decline, is a strong health determinant in older people. The accumulation of chronic diseases, multimorbidity, plays a major role in functional decline and has a negative impact on quality of life. Cardiovascular and neuropsychiatric diseases are common in older people and tend to cluster in the same individuals. Understanding the associations between cardiovascular and neuropsychiatric multimorbidity and functional decline may assist in managing the health and care of people with multimorbidity. In a new study, researchers at Karolinska Institutet aimed to find out how the increasing number and the combination of cardiovascular and neuropsychiatric diseases are associated with two important measures of physical function in older people: walking speed and activities of daily living (ADL). Using data from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K), they examined how these functions were affected in 2,385 older people with and without cardiovascular disease (such as ischemic heart disease, heart failure, and atrial fibrillation) and neuropsychiatric disease (such as mood disorders, dementia, and stroke). Neuropsychiatric diseases may play a greater role During the 9-year follow-up, individuals with multiple cardiovascular and neuropsychiatric diseases had the steepest declines in walking speed and ADL independence. The researchers observed significant declines over time for both walking speed and ADL in older people with one or more neuropsychiatric diseases, but only for walking speed in those with cardiovascular multimorbidity. “Our findings suggest that the presence of multiple neuropsychiatric diseases may play a greater role in functional decline in older people than multiple cardiovascular diseases. Both patients and physicians should be aware that neuropsychiatric diseases are major predisposing factors for functional decline”, says Davide Vetrano, PhD student at Karolinska Institutet’s Department of Neurobiology, Care Sciences and Society. The study was supported by the funders of the Swedish National study on Aging and Care, SNAC: the Ministry of Health and Social Affairs, Sweden, the participating County Councils and Municipalities, and the Swedish Research Council. Specific grants were received from the Swedish Research Council for Medicine and the Swedish Research Council for Health, Working life and Welfare, Catholic University of Rome, Lindhés Advokatbyrå AB, Stiftelsen för Gamla Tjänarinnor, and Stonhes Stiftelse. Publication ”Trajectories of functional decline in older adults with neuropsychiatric and cardiovascular multimorbidity: A Swedish cohort study” Davide L. Vetrano, Debora Rizzuto, Amaia Calderón-Larrañaga, Graziano Onder, Anna-Karin Welmer, Roberto Bernabei, Alessandra Marengoni, Laura Fratiglioni PLOS Medicine, online 6 March 2018, doi: 10.1371/journal.pmed.1002503

The body’s “glucostat” identified

Tue, 06/03/2018 - 18:00
It is the pancreatic islets that have the overall responsibility for maintaining normal blood glucose levels in our bodies, according to a new study by researchers at Karolinska Institutet in Sweden and the University of Miami Miller School of Medicine, USA. The findings, published in the scientific journal Cell Metabolism, have important implications for certain diabetes treatments. Blood glucose levels are tightly regulated in the living organism. Levels that are too low (hypoglycemia) or too high (hyperglycemia) are severe threats to our health, the latter resulting in diabetes. Target glycemic levels vary between different animal species, meaning that a normal blood glucose concentration in mice can, for example, be considered diabetic to humans. Exactly how the glucose homeostasis is controlled is unknown, but it has been shown to involve several different organs such as the liver, the hypothalamus in the brain and the hormone-releasing part of the pancreas called the pancreatic islets or islets of Langerhans. However, the interaction between these organs is complex, and each one of them has its own glucose set point. “We wanted to test whether there is a leading organ or mechanism that maintains normal blood glucose levels within the characteristic narrow range in different animal species,” says first author Rayner Rodriguez-Diaz, researcher at the University of Miami Miller School of Medicine, USA, and Karolinska Institutet, Sweden. “Our hypothesis was that the glycemic set point results from the pancreatic islets working as an organ, where the hormonal output is governed by features and mechanisms intrinsic to the islet tissue.” The glucostat in our bodies To test this hypothesis, the researchers transplanted pancreatic islets from different species, including humans, into diabetic and non-diabetic mice. They then measured blood glucose levels and glucose tolerance in the recipient mice. “We found that the engrafted islets transferred the glycemic levels of the donor species. This indicates that the pancreatic islets have the overall responsibility for maintaining normal blood glucose levels, making them the ‘glucostat’ in our bodies,” says principal investigator Per-Olof Berggren, Professor at the Rolf Luft Research Centre for Diabetes and Endocrinology at Karolinska Institutet’s Department of Molecular Medicine and Surgery. An interesting finding was that, in humans in contrast to rodents, the cells releasing the hormone glucagon in the pancreatic islets are of crucial importance for the regulation of insulin-producing cells, and thus the regulation of blood glucose levels. Implications for regenerative approaches “This means that it is imperative to use human pancreatic islets when investigating how this complex microorgan regulates glucose homeostasis under normal conditions, and why this is not functioning in diabetes,” says Alejandro Caicedo, researcher at the University of Miami Miller School of Medicine. “Our findings have implications for transplantation and regenerative approaches to the treatment of diabetes, because restoring normal blood glucose levels may require more than replacing only the insulin-producing cells.” According to the researchers, in order to cure diabetes with the help of stem cell technology in the future, it will be necessary to obtain all the cells found in the pancreatic islets and then create artificial islets for transplantation. “Furthermore, therapeutic strategies using glucagon receptor antagonists as hypoglycemic agents need to be reassessed, as they directly affect the pancreatic islets’ ability to function as glucostats,” says Professor Berggren. The research was funded by the Diabetes Research Institute Foundation (DRIF), National Institutes of Health (NIH), American Diabetes Association, the Swedish Diabetes Association, the Swedish Research Council, Novo Nordisk Foundation, the Family Erling-Perssons Foundation, the Strategic Research Program in Diabetes at Karolinska Institutet, the European Research Council, the Knut and Alice Wallenberg Foundation, Skandia Insurance Company, Diabetes and Wellness Foundation, the Berth von Kantzow Foundation, and the Stichting af Jochnick Foundation. Publication ”Paracrine interactions within the pancreatic islet determine the glycemic set point” Rayner Rodriguez-Diaz, R. Damaris Molano, Jonathan R. Weitz, Midhat H. Abdulreda, Dora M. Berman, Barbara Leibiger, Ingo B. Leibiger, Norma S. Kenyon, Camillo Ricordi, Antonello Pileggi, Alejandro Caicedo, Per-Olof Berggren Cell Metabolism, online 6 March 2018, doi:10.1016/j.cmet.2018.01.015

She wants to take science out of the laboratories

Mon, 05/03/2018 - 10:32
A few questions to Lilian Kisiswa, senior postdoc at the Department of Cell and Molecular Biology at Karolinska Institutet and organiser-in-chief of Hjärnfestivalen – Brain Awareness Week – in Stockholm, 10 – 17 March. Tell us about Hjärnfestivalen – what exciting things will be happening? “Hjärnfestivalen 2018 is a seven-day festival that will offer the general public opportunities to learn about current brain research, ask brain researchers, patients and experts questions, and even try their hand at being brain researchers. Hjärnfestivalen is free and open to visitors of all ages and will consist of exhibitions, interactive activities, short presentations, panel discussions and workshops.” The festival is organised by the Vetenskap i Samhället (Science in Society) association. Can you tell us something about the association and why you are involved? “Vetenskap i Samhället, ViS, is a non-profit organisation that is made up of researchers, mainly from Karolinska Institutet. The aim is to give the general public opportunities to interact with researchers and disseminate knowledge about science, through organising activities such as  Hjärnfestivalen. We want to take science out of the laboratories and reach a wider audience. I have always been interested in outreach and I have been engaged in various public activities outside Sweden for many years, for example the Smarter UK Group, the Cardiff Brain Awareness Committee, and the Cardiff Neuroscience Café.” This is the second time you’re organising Hjärnfestivalen in Stockholm. Last time, in 2016, it was in September. Now it’s been moved to the middle of March. Why? “Hjärnfestivalen has always been part of the international DANA Brain Awareness Week, BAW, which is a global campaign that aims to increase public awareness of the progress and benefits of brain research. BAW is always held the second week in March but last time we had to hold the festival in Stockholm at a later date for various reasons. We’re particularly happy that we managed to match the date of BAW this time.” Is there anything in particular that you yourself are looking forward to in connection with the festival? “Oh, it’s hard to choose! I think we have an excellent programme and I’m looking forward to all the sessions. But if I have to choose, I’m looking forward to the Brain Fair. It’s incredibly beautiful to see the close interaction between the researchers and the audience.” Some of the KI researchers at Hjärnfestivalen All lectures will be held in Swedish. Nitya Jayaram-Lindström Effekten av beroende på samhället, Kulturhuset 10 March. Sven Bremberg Depression bland unga, Kulturhuset 10 March. Charlotte Skoglund Hjärnutveckling: ADHD and NPF, Tekniska Museet 11 March. Torbjörn Vestberg Hjärnboll – vad gör Rinaldo, Messi och Zlatan till världsstjärnor? ABF-huset 12 March. Robin Fondberg Varför gillar vi vissa smaker och inte andra? – Vetenskapen av smak Restaurangakademien 12 Mars Alva Appelgren Återkoppling och viljan att utvecklas, Stockholms stadsbibliotek 13 March. Carl Johan Sundberg Hjärnan och träning, ABF-huset 14 March. Armita Golkar Det syns inte – musical and panel discussion, Maximteatern 17 March. More details in the KI calendar

Promising therapeutic approach for spinal cord injuries

Thu, 01/03/2018 - 18:00
The healing ability of the central nervous system is very limited and injuries to the brain or spinal cord often result in permanent functional deficits. Researchers at Karolinska Institutet report in the scientific journal Cell that they have found an important mechanism that explains why this happens. Using this new knowledge, they were able to improve functional recovery following spinal cord injury in mice. In many organs, damaged tissue can be repaired by generating new cells of the type that were lost. However, after an injury to the central nervous system, a special type of scar tissue is formed which inhibits this regeneration. Injuries to the brain and spinal cord therefore often lead to permanent loss of functional ability. It was recognised more than a century ago that nerve fibres of the central nervous system fail to grow through the scar tissue that forms at a lesion. However, this scar tissue is a complex mesh of different cell types and molecules, and it has been unclear exactly how the scar tissue blocks nerve fibre regrowth. By studying mice with spinal cord injuries, researchers at Karolinska Institutet have now identified an important mechanism behind this inhibition of nerve fibre regeneration. “Our findings give an important explanation as to why functional recovery is so limited following injury to the central nervous system,” says Christian Göritz, Associate Professor at the Department of Cell and Molecular Biology and Lau fellow at Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet. Identified an important cell type The researchers found that the explanation lies in a small population of cells lining blood vessels that gives rise to a large part of the scar tissue. Inhibiting scar formation by these blood vessel-associated cells allowed some nerve fibres to grow through the injury and reconnect with other nerve cells. This resulted in improved functional recovery following spinal cord injury in mice. “Further studies are now needed to explore whether this knowledge can be used to promote recovery following injury to the central nervous system in humans,” says Christian Göritz. The research was supported by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, the National Genomics Infrastructure, Uppsala Multidisciplinary Center for Advanced Computational Science, the Portuguese government Foundation for Science and Technology, the Hållsten Research Foundation, the European Union's Seventh Framework Programme, the Swedish Research Council, the Swedish Brain Foundation, Ming Wai Lau Centre for Reparative Medicine, the Swedish Cancer Foundation, JPND DACAPO-AD, Wings for Life Foundation, the Tobias Foundation, the Swedish Foundation for Strategic Research, and Torsten Söderberg Foundation. Publication ”Reducing pericyte-derived scarring promotes recovery after spinal cord injury” David Oliveira Dias, Hoseok Kim, Daniel Holl, Beata Werne Solnestam, Joakim Lundeberg, Marie Carlén, Christian Göritz, Jonas Frisén Cell, online 1 March 2018, doi: 10.1016/j.cell.2018.02.004

Lithium treatment for bipolar disorder linked to lowest risk of rehospitalisation

Wed, 28/02/2018 - 17:00
Individuals with bipolar disorder have the lowest risk of rehospitalisation if treated with lithium, according to a study from Karolinska Institutet in Sweden published in JAMA Psychiatry. Long-acting injections of antipsychotics were also effective, reducing the risk of rehospitalisation by 30 per cent compared with their oral counterparts. Bipolar disorder is characterised by alternating periods of depression and elevated mood (mania), and is usually treated either with mood stabilising or antipsychotic drugs. Lithium is considered to be the most effective mood stabiliser, but only a few studies have been conducted comparing the long-term effects of different drugs in bipolar disorder. In order to determine which treatment is most effective, researchers at Karolinska Institutet compared the risk of re-admission to hospital in more than 18,000 patients in Finland who had previously been hospitalised for bipolar disorder. Each patient was used as their own control and compared during periods with and without treatment. Should remain first-line treatment  During an average follow-up time of more than seven years, lithium treatment was associated with the lowest risk of rehospitalisation in mental or physical disease, with a risk reduction of about 30 per cent compared with no treatment at all. Long-acting injections of antipsychotic drugs were also effective. The risk of re-admission was around 30 per cent lower if patients were treated with long-acting injections compared to their receiving the same antipsychotic medication but orally. The most commonly prescribed antipsychotic drug for bipolar disorder, quetiapine (Seroquel), which is given in tablet form, reduced the risk by only 7 per cent. “The prescription of lithium has decreased steadily in recent years, but our results show that lithium should remain the first line of treatment for patients with bipolar disorder. Long-acting injections might offer a safe, effective option for patients for whom lithium is not suitable”, says Jari Tiihonen, specialist doctor and professor at Karolinska Institutet’s Department of Clinical Neuroscience. The research was funded by the Finnish Ministry of Social Affairs and Health. No company has financed this particular study, but several of the authors are associated with and have previously received funding/fees from pharmaceutical companies in different contexts. Two of the authors are employed by the contract research organisation EPID Research. The scientific article provides more detailed information about potential conflicts of interest. Publication ”Real-World Effectiveness of Pharmacologic Treatments for the Prevention of Rehospitalization in a Finnish Nationwide Cohort of Patients With Bipolar Disorder” Markku Lähteenvuo, Antti Tanskanen, Heidi Taipale, Fabian Hoti, Pia Vattulainen, Eduard Vieta, Jari Tiihonen JAMA Psychiatry, online 28 February 2018

Breast cancer’s spread routes mapped

Tue, 27/02/2018 - 08:00
Breast cancer spreads to other organs in the body according to certain specific patterns. This has been shown by a team of researchers from Karolinska Institutet and KTH in Sweden and the University of Helsinki in Finland who have mapped breast cancer’s spread routes in patients by studying the cancer cells’ DNA. The study is published in The Journal of Clinical Investigation. Breast cancer is the most common form of cancer in women. In Sweden, almost two thousand patients die of the disease every year. The fatalities are almost exclusively a consequence of tumours in the breast spreading to other organs, such as the skeleton, the brain and the liver. Metastases in the axillary lymph nodes in the armpits are an important risk factor for breast cancer to spread to other organs. What was not known before is if these metastases are responsible for spreading cancer further to other organs or what routes the cancer cells take. Cancer tissue from 20 patients In the new study, the researchers have looked at the DNA in cancer tissue from 20 patients with breast tumours and metastases in both their axillary lymph nodes and other organs. By means of a technique called next-generation sequencing they were able to map the relationship between the cancer cells in the breast and those in metastases in other organs. This enabled them to show the cancer’s spread routes. The study showed that tumour cells are spread from the breast tumour to the axillary lymph nodes and to other organs such as the skeleton and the brain. Metastases then often spread from the first organ to other organs in the next stage. “Our most important finding, however, was that the metastases in the axillary lymph nodes do not seem to spread further to other organs, so even if these metastases can show how aggressive the cancer is, it is not they that cause the spread,” says Johan Hartman, Associate Professor at Karolinska Institutet’s Department of Oncology-Pathology who led the study together with Professor Jonas Bergh at the same department. Early explosion of cancer cells They also found that in certain cases it is a matter of an early explosion of cancer cells from the breast tumour that simultaneously gives rise to metastases in several different organs. The researchers were also able to show that different regions of the breast tumours caused metastases in specific organs in the body. Together the team’s findings can help doctors make clinical decisions on when, where and how many tissue samples should be taken to understand how serious the disease is and adapt the treatment in the best possible way. “The findings also confirm earlier research that shows cancer treatments needs to be adapted to the individual. We hope this will lead to better treatment of metastatic cancer in the future,” Johan Hartman says. The study was led by researchers at Karolinska Institutet in collaboration with researchers from KTH/SciLifeLab and the University of Helsinki. The research was funded through grants from, among others, the Märit and Hans Rausing Fund, the Swedish Cancer Society, and the Cancer Research Funds of Radiumhemmet. Publication “Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes” Ullah I, Karthik GM, Alkodsi A, Kjällquist U, Stålhammar G, Lövrot J, Martinez NF, Lagergren J, Hautaniemi S, Hartman J, Bergh J The Journal of Clinical Investigation, online 26 February 2018, doi:10.1172/JCI96149

Asthmatics show DNA changes in immune cells

Fri, 23/02/2018 - 13:05
Children with asthma have epigenetic DNA changes in certain cells of their immune system, a major international study involving researchers at Karolinska Institutet shows. The finding, which is presented in The Lancet Respiratory Medicine, can one day lead to improved diagnostics and treatment. Asthma is a respiratory disease caused by a chronic inflammation of the airways. An estimated 800,000 people have asthma in Sweden, about 50,000 of whom suffer so seriously that their everyday functioning is impaired. It is thought that asthma is caused by a combination of hereditary and environmental factors, but there are still many knowledge gaps to be filled. Collaborating with Groningen University in the Netherlands amongst other institutes, researchers at Karolinska Institutet have conducted an extensive study of the epigenetic changes that can be related to asthma. Epigenetics governs where and when different genes are active and DNA methylation is one of its most common regulatory mechanisms. The present study shows that asthmatics have a lower degree of DNA methylation in certain immune cells than healthy controls, particularly in what are known as eosinophils, which play a critical part in the asthmatic inflammation. The researchers identified DNA changes in 14 gene regions linked to children’s asthma, but these changes were not present at birth. Key to understanding disease mechanisms “We believe that our findings are key to understanding the disease mechanisms, even if we’ve not yet been able to show that the epigenetic changes actually cause asthma,” says Erik Melén, docent at the Institute of Environmental Medicine, Karolinska Institutet. “Our results suggest that the lower DNA methylation in asthmatics increases activation of the immune cells, which play a central part in the development of asthma.” The study included over 5,000 children from 10 European cohorts, including the Swedish birth cohort BAMSE, which is led by Erik Melén. The research is the result of a longer-standing collaboration with European researchers in the EU MeDALL (Mechanisms of the Development of Allergy) programme. “This is the largest epigenetic asthma study to date and we hope that our discoveries will give rise to better diagnostics and treatment possibilities,” says Dr Melén. “Influencing epigenetic regulation could be a new and interesting therapeutic strategy.” The study was financed by the EU (MeDALL), Formas (the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning), the Swedish Heart-Lung Foundation (the Prince Daniel Grant for Promising Young Researchers), the Swedish Foundation for Strategic Research, Stockholm County Council (ALF funding), the Strategic Research Area in Epidemiology at Karolinska Institutet and the Swedish Research Council. Publication “DNA methylation in childhood asthma: an epigenome-wide meta-analysis” Cheng-Jian Xu, Cilla Söderhäll, Mariona Bustamante, Nour Baïz, Olena Gruzieva, Ulrike Gehring, Dan Mason, Leda Chatzi, Mikel Basterrechea, Sabrina Llop, Maties Torrent, Francesco Forastiere, Maria Pia Fantini, Karin C. Lødrup Carlsen, Tari Haahtela, Andréanne Morin, Marjan Kerkhof, Simon Kebede Merid, Bianca van Rijkom, Soesma A Jankipersadsing, Marc Jan Bonder, Stephane Ballereau, Cornelis J Vermeulen, Raul Aguirre-Gamboa, Prof Johan C de Jongste, Henriette A Smit, Ashish Kumar, Göran Pershagen, Stefano Guerra, Judith Garcia-Aymerich, Dario Greco, Lovisa Reinius, Rosemary RC McEachan, Raf Azad, Vegard Hovland, Petter Mowinckel, Harri Alenius, Nanna Fyhrquist, Nathanaël Lemonnier, Johann Pellet, Charles Auffray, Pieter van der Vlies, Cleo C van Diemen, Yang Li, Cisca Wijmenga, Mihai G. Netea, Miriam F. Moffatt, William O.C.M Cookson, Josep M. Anto, Jean Bousquet, Tiina Laatikainen, Catherine Laprise, Kai-Håkon Carlsen, Davide Gori, Daniela Porta, Carmen Iñiguez, Jose Ramon Bilbao, Manolis Kogevinas, John Wright, Bert Brunekreef, Juha Kere, Martijn C Nawijn, Isabella Annesi-Maesano, Jordi Sunyer, Erik Melén, Gerard H Koppelman The Lancet Respiratory Medicine, online 23 February 2018

Stem cell study may result in stronger muscles in old age

Fri, 23/02/2018 - 11:00
As we grow older, our muscular function declines. A new study by researchers at Karolinska Institutet in Sweden shows how an unexpectedly high number of mutations in the stem cells of muscles impair cell regeneration. This discovery may result in new medication to build stronger muscles even when in old age. The study is published in Nature Communications. It has already been established that natural ageing impairs the function of our skeletal muscles. We also know that the number and the activity of the muscles’ stem cells decline with age. However, the reasons for this has not been fully understood. In a new study, researchers at Karolinska Institutet have investigated the number of mutations that accumulate in the muscle's stem cells (satellite cells). “What is most surprising is the high number of mutations. We have seen how a healthy 70-year-old has accumulated more than 1,000 mutations in each stem cell in the muscle, and that these mutations are not random but there are certain regions that are better protected,” explains Maria Eriksson, Professor at the Department of Biosciences and Nutrition at Karolinska Institutet. The protection declines with age The mutations occur during natural cell division, and the regions that are protected are those that are important for the function or survival of the cells. Nonetheless, the researchers were able to identify that this protection declines with age. “We can demonstrate that this protection diminishes the older you become, indicating an impairment in the cell's capacity to repair their DNA. And this is something we should be able to influence with new drugs,” explains Maria Eriksson. The researchers have benefited from new methods to complete the study. The study was performed using single stem cells cultivated to provide sufficient DNA for whole genome sequencing. Complex mutational burden “We achieved this in the skeletal muscle tissue, which is absolutely unique. We have also found that there is very little overlap of mutations, despite the cells being located close to each other, representing an extremely complex mutational burden,” explains the study's first author, Irene Franco, Postdoc in Maria Eriksson’s research group. The researchers will now continue their work to investigate whether physical exercise can affect the number of accumulated mutations. Is it true that physical exercise from a young age clears out cells with many mutations, or does it result in the generation of a higher number of such cells? Can result in new exercise programmes “We aim to discover whether it is possible to individually influence the burden of mutations. Our results may be beneficial for the development of exercise programmes, particularly those designed for an ageing population,” explains Maria Eriksson. The researchers gained access to the muscle tissue used in the study via a close collaboration with clinical researchers, including Helene Fischer at the Unit for Clinical Physiology at Karolinska University Hospital. The study has been a cooperative project between researchers at Karolinska Institutet, Science for Life Laboratory (SciLifeLab), Uppsala University, Linköping University and Stockholm University, in addition to several affiliated institutes in Italy. The research is financed by the Swedish Research Council, CIMED (Centre for Innovative Medicine), the David and Astrid Hagelén Foundation, the Swedish Society of Medicine, the Gun and Bertil Stohnes Foundation, the Osterman Foundation, the Marianne and Marcus Wallenberg Foundation, Wallenberg Advanced Bioinformatics Infrastructure and the EU Commission funding programme, Marie Skłodowska-Curie. Publication ”Somatic mutagenesis in satellite cells associates with human skeletal muscle aging” Irene Franco, Anna Johansson, Karl Olsson, Peter Vrtačnik, Pär Lundin, Hafdis T. Helgadottir, Malin Larsson, Gwladys Revêchon,Carla Bosia, Andrea Pagnani, Paolo Provero, Thomas Gustafsson, Helene Fischer, Maria Eriksson Nature Communications, online 23 February 2018, doi: 10.1038/s41467-018-03244-6

Suzanne Axell, Yvonne Enman and Ingrid le Roux appointed honorary doctors at Karolinska Institutet

Thu, 22/02/2018 - 09:45
The Board of Research at Karolinska Institutet has awarded honorary doctorates to Suzanne Axell, Yvonne Enman and Ingrid le Roux. They will have their doctorates formally conferred at the university’s traditional ceremony at Stockholm City Hall on 4 May 2018. Each of the new honorary doctors in medicine have received the award for their major contributions within Karolinska Institutet’s sphere of interest. Journalist Suzanne Axell has presented the programme Fråga Doktorn (Ask the Doctor) on Sveriges Television for the past 15 years. The programme, which attracts around one million viewers each week, disseminates medical knowledge and information regarding the latest research through viewer questions, reportage and interviews – often with invited experts from Karolinska Institutet. The work of Suzanne Axell places the patient’s perspective at the heart of the programme. Her positive and welcoming attitude invites viewers to ask their medical questions, something that also provides valuable feedback to researchers and doctors regarding how successful they have been in communicating information to patients. “I am incredibly honoured and delighted to be awarded an honorary doctorate. We have always worked to ensure that Fråga Doktorn remains a programme that anyone can watch and understand. In the programme, my responsibility is to the viewer. I dare to ask the straightforward questions that many people sit and wonder over, and it is especially gratifying to see this acknowledged,” says Suzanne Axell. Yvonne Enman is awarded an honorary doctorate in medicine. She has worked for many years to promote cooperation and communication between researchers and patients. Yvonne’s efforts as a scientific writer have contributed to the strong support enjoyed by research from patients and the public at large, including the field of rheumatic disorders. “Research offers hope to those of us who live with chronic disorders. By telling people about the research being carried out and the progress being made, I can offer them hope. The fact that Karolinska Institutet has seen fit to confer an honorary doctorate on me shows the importance of creating links between research and sufferers. This is important, and a pleasing acknowledgement for me personally. I am delighted and overwhelmed,” says Yvonne Enman. Herself a sufferer from the rheumatic disorder SLE, Yvonne Enman has among other things produced special research supplements for the Swedish Rheumatism Association’s magazine. Through a combination of scientific insight and empathy for the day-to-day problems of patients, her articles have contributed to both a public understanding of research and an understanding among researchers regarding the needs of patients. Through her participation in teaching at Karolinska Institutet, Yvonne Enman has also provided undergraduates and doctoral students with an insight into living with rheumatic illness. Ingrid le Roux, Karolinska Institutet educated physician and resident of South Africa since the 1970s, is awarded an honorary doctorate in medicine. In 1979, she launched an organisation to provide healthcare to vulnerable women and children in a township outside Cape Town. Since then, the organisation – the Philani Maternal, Child Health and Nutrition Trust – has grown to encompass a number of clinics offering maternity and child welfare services in the townships around Cape Town. The organisation’s Mentor Mother Programme recruits local women who have successfully raised children despite the difficult conditions in the townships. They are trained to spread their knowledge and experience to other women through home visits. Today, these Mentor Mothers work in many parts of South Africa as well as in Swaziland and Ethiopia. Through her work, Ingrid le Roux has helped hundreds of thousands of African women to use their own knowledge and energy to improve their own and their children’s health, and to create a more secure life. Philani’s methods have also been evaluated in collaboration with reputable universities. “Becoming an honorary doctor at Karolinska Institutet is fantastic. I can barely think of a greater honour than to receive the acknowledgement of such an internationally recognised university. This highlights work with women and children that has always been at the bottom of the list of priorities for healthcare in many vulnerable areas,” says Ingrid le Roux.   Becoming an honorary doctor at Karolinska Institutet Honorary doctors are individuals on whom a faculty has conferred the honour and dignity of the title Doctor – that is, the right to use this title without meeting the usual formal requirements of the university’s study programmes and other regulations. Karolinska Institutet appointed its first honorary doctors in medicine in 1910 and in odontology in 1949. Since then, approximately 300 honorary doctorates have been conferred. Since 1999, the Board of Research has appointed honorary doctors in its capacity as one of KI’s faculty boards.

Female sex not a protective factor against heart disease in type 1 diabetes

Tue, 20/02/2018 - 16:00
Constrictions of the coronary blood vessels is a possible consequence of type 1 diabetes, and one that can eventually lead to myocardial infarction or heart failure. Generally speaking, women are afflicted by coronary artery disease later than men, but if a woman has type 2 diabetes, the advantage is negated. A new report by researchers from Karolinska Institutet, Gothenburg University and Uppsala University in Sweden published in the journal Diabetes Care now shows that this also sometimes applies to type 1 diabetes. There are few studies analysing the extent of coronary artery disease with coronary angiography in people with type 1 diabetes, most of which were conducted in the 1970s, 80s and 90s on seriously ill patients, revealing extensive constrictions of the coronary artery. Last year, researchers at Karolinska Institutet, Gothenburg University and Uppsala University conducted a large-scale study including all patients in Sweden – just short of 2,800 in number – with type 1 diabetes who had undergone coronary angiography between 2001 and 2013. The patients, 42 per cent of whom were woman, had had diabetes for an average of 35 years and had a mean age of 58. One fifth of the patients had normal coronary arteries, one fifth had one constricted artery, and about half had more than one. “Our results were partly a pleasant surprise,” says Viveca Ritsinger, specialist in internal medicine and researcher at the Department of Medicine at Karolinska Institutet in Solna. “We’d thought that more of the patients would have had extensive coronary artery disease after such a long time with diabetes, but one reason is the for many years ongoing careful  diabetes care we have in Sweden, whereby we’re better able to maintain normal sugar levels soon after disease onset and closely monitor other risk factors for cardiovascular disease.” Identified sex differences In a follow-up study on the same patient group, the researchers have now identified for the first time sex differences in extent of coronary artery disease in type 1 diabetes. They found that the women had slightly less extensive coronary artery disease, but there was no difference in mortality compared to the men over a seven-year follow-up time. They did find, however, that the women had a higher risk of death than women without type 1 diabetes, and that this risk was slightly above the corresponding risk in men. “We know that generally speaking women develop coronary artery disease later and less extensively than men,” says Dr Ritsinger. “Women with type 2 diabetes can, however, become afflicted earlier than women without diabetes. Our finds suggest that this also applies to women with type 1 diabetes.” The fatality rate was in direct proportion to the number of arteries affected for both sexes. Preventive treatments should be considered “So it’s important that we need to keep a close watch on the risk factors for coronary artery disease in people with type 1 diabetes,” explains Dr Ritsinger. “Preventive treatments for coronary artery disease, such as drugs that reduce blood lipids and blood pressure, should be considered at an early stage after onset.” “You have to keep in mind that the patients in our study were diagnosed a long time ago and that the results are not representative for those who are diagnosed today”, says Anna Norhammar, specialist in internal medicine, cardiology and clinical physiology and researcher at the Department of Medicine at Karolinska Institutet in Solna. “However, it is of value to know that there might be an increased risk for coronary artery disease also for women with type 1 diabetes, so that patients can be offered preventive therapies.” The study was funded by the Swedish Heart and Lung Foundation, the Swedish Diabetes Foundation and the Kamprad Family Foundation. Viveca Ritsinger has received consultancy fees from pharmaceutical companies AstraZeneca, Novo Nordisk and Boehringer Ingelheim. Katarina Eeg-Olofsson has received lecture fees from Novo Nordisk, Sanofi and Abbott. Anna Norhammar has received consultancy fees from AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Eli Lilly and Company and Boehringer Ingelheim. No other potential conflict of interest has been reported. Text: Inna Sevelius Publications “Characteristics and prognosis in women and men with type 1 diabetes undergoing coronary angiography - a nationwide registry report” Viveca Ritsinger, Christel Hero, Ann-Marie Svensson, Nawzad Saleh, Bo Lagerqvist, Katarina Eeg-Olofsson, Anna Norhammar Diabetes Care, online 20 February 2018 “Mortality and extent of coronary artery disease in 2776 patients with type 1 diabetes undergoing coronary angiography: A nationwide study” Ritsinger V, Hero C, Svensson AM, Saleh N, Lagerqvist B, Eeg-Olofsson K, Norhammar A European Journal of Preventive Cardiology, online 13 January 2017

Significantly increased suicide risk among unaccompanied refugee minors

Mon, 19/02/2018 - 12:53
In a report written on behalf of the Swedish National Board of Health and Welfare, researchers at Karolinska Institutet have concluded that the risk of suicide among unaccompanied refugee minors and young adults in 2017 was nine times higher than the equivalent figure for the same age group in the Swedish population. Compiling the report presented methodological problems as child refugees do not have Swedish personal identity numbers. Sampling the group has also proven difficult, with unaccompanied refugee minors both arriving during the period in question, but also leaving the country due to rejected asylum applications. For the purpose of the report, researchers have assessed a population of 23,425 unaccompanied asylum-seeking minors and young adults (10-21 years of age) during 2017 and have included only suicides confirmed by the National Board of Forensic Medicine in Sweden. Researchers found 12 confirmed suicides in the group during 2017, equivalent to 51.2 suicides per 100,000 individuals or nine times that for the same age group in the Swedish population. As each completed suicide is indicative of mental ill-health in a far greater proportion of individuals, the researchers recommend the implementation of acute suicide preventive measures aimed at unaccompanied refugee minors and young adults. Mapping of self-harming, attempted suicide, suicide and other mortality among unaccompanied child and adolescent refugees, Department of Clinical Neuroscience, Division of Insurance Medicine, Karolinska Institutet, 2018. Authors: Ana Hagström, Anna-Clara Hollander, Ellenor Mittendorfer-Rutz.

New cell model could lead to treatments for neurological diseases

Fri, 16/02/2018 - 09:02
Researchers from Karolinska Institutet and KTH Royal Institute of Technology have developed a new cell model for human brain helper cells known as astrocytes. The model could potentially be used in large-scale drug screening in the search for treatments for neurological diseases such as Alzheimer’s. The research is published in the scientific journal Stem Cell Reports. Astrocytes are star shaped cells that are found in the brain and spine and were long thought to be the “glue” that binds nerve cells. However, recent advances show that they are in fact responsible for complex regulation of a variety of critical brain functions. They have also proven to be central to neurological diseases such as Alzheimer’s. But for research, these cells prove problematic. “Human astrocytes are significantly more complex than those found in mice, for example, mice do not develop the same brain diseases as humans. We therefore need better ways to study this cell type”, says Anna Falk, associate professor at Karolinska Institutet’s Department of Neuroscience. Nobel Prize-winning technology Together with Anna Herland at KTH and researchers at AstraZeneca, Anna Falk developed a new cell model for human astrocytes. Drawing on Nobel Prize-winning technology, the researchers reprogrammed human skin cells to create induced pluripotent stem cells, or iPS cells, which were then guided with growth factors to become astrocytes. Beginning with stem cells, researchers can produce an infinite number of astrocytes, which is important for the large-scale use within the pharmaceutical industry. “The historically high statistics of clinical failures in developing drugs against neurological diseases have now made drug companies increasingly interested in improved cell models in which human cells are used,” says Anna Herland, assistant senior lecturer at the Department of Micro and Nanosystems at KTH. “Our work has been focused on development of a cell model that follows human embryonic development of astrocytes.” Shows wider functionality Compared with cell models used in the pharmaceutical industry today, Falk and Herland’s model shows wider functionality. A pilot drug screening with a few substances showed that the model has the potential to identify new candidates which can go into drug development for neurological diseases. "Our model of human astrocytes is an important step forward in order to understand and attack human neurological diseases where astrocytes have an important role,” says Anna Herland. “With this model, we can begin to study how astrocytes develop and receive their functional diversity during embryonic development”. The research was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, Vinnova, the European Commission, the Wallenberg Foundations, and the Swedish Knowledge Foundation. This news article is based on a press release from KTH. Publication ”Human iPS-derived astroglia from a stable neural precursor state show improved functionality compared to conventional astrocytic models” Lundin Anders, Delsing Louise, Clausen Maryam, Ricchiuto Piero, Sanchez José, Sabirsh Alan, Mei Ding, Synnergren Jane, Zetterberg Henrik, Brolén Gabriella, Hicks Ryan, Herland Anna, Falk Anna Stem Cell Reports, online 15 February 2018, doi: 10.1016/j.stemcr.2018.01.021

Successful NK cell-based immunotherapy for leukaemia

Thu, 15/02/2018 - 11:48
Researchers at Karolinska Institutet have explored NK cell-based immunotherapy on patients with treatment-resistant leukaemia. The study, which is published in the scientific journal Clinical Cancer Research, shows that the new therapy is effective against several types of leukaemia. NK (natural killer) cells are a special type of white blood cell discovered at Karolinska Institutet in the 1970s that can recognise and kill cancer cells. In recent years, much knowledge has been generated on the biology of the cells and their ability to recognise tumour cells. Research into immunotherapy, in which the immune system is stimulated to attack cancer cells, has also made great strides forward. The potential of NK cells as a form of immunotherapy has not, however, been fully explored. Researchers at Karolinska Institutet have now tested an NK cell-based immunotherapy on 16 patients with treatment-resistant leukaemia of the types myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) or transitional MDS/AML phases. The patients were treated with activated NK cells from related donors. Some patients became symptom-free Six of the patients displayed objective responses to the treatment, some even attaining complete remission and thus becoming symptom-free. Five of these six patients became healthy enough to undergo curative stem cell transplantation, an intervention that was not possible before the NK cell treatment. Three of them have now survived for over three years, one for over five. The infusion of NK cells produced no serious adverse effects. “Our study shows that patients with MDS, AML and MDS/AML can be treated with NK cell-based immunotherapy and that the therapy can be highly efficacious,” says Professor Hans-Gustaf Ljunggren at Karolinska Institutet’s Department of Medicine in Huddinge, who initiated and led the study with departmental colleague Professor Karl-Johan Malmberg. Open the way for new clinical studies “The results open the way for new clinical studies, where there is potential for further improvements to study design that includes producing the next generation of NK cell-based immunotherapy,” says Andreas Björklund, specialist doctor at Karolinska University Hospital, who had clinical responsibility for the patients treated using the new therapy. The study was financed by several bodies, including the Tobias Foundation, the Swedish Cancer Society, the Swedish Research Council and Stockholm County Council. Jeffrey S. Miller and Karl-Johan Malmberg serves on the Scientific Advisory Board of Fate Therapeutics. Hans-Gustaf Ljunggren serves on the Scientific Advisory Board of CellProtect Nordic Pharmaceuticals and HOPE Bio-Sciences; on the Board of Directors of Vycellix; and is a collaborator with Fate Therapeutics. Publication “Complete Remission with Reduction of High-risk Clones following Haploidentical NK Cell Therapy against MDS and AML” Andreas T. Björklund, Mattias Carlsten, Ebba Sohlberg, Lisa L. Liu, Trevor Clancy, Mohsen Karimi, Sarah Cooley, Jeffrey S. Miller, Monika Klimkowska, Marie Schaffer, Emma Watz, Kristina Wikström, Pontus Blomberg, Björn Engelbrekt Wahlin, Marzia Palma, Lotta Hansson, Per Ljungman, Eva Hellström-Lindberg, Hans-Gustaf Ljunggren, Karl-Johan Malmberg Clinical Cancer Research, online 14 February 2018, doi: 10.1158/1078-0432.CCR-17-3196

Possible new principle for cancer therapy

Thu, 15/02/2018 - 09:09
A study published in Science Translational Medicine shows that small molecules that specifically inhibit an important selenium-containing enzyme may be useful in combating cancer. When researchers at Karolinska Institutet treated cancer in mice using these molecules, they observed rapid tumoricidal effects. Researchers now hope that this new principle for cancer treatment will eventually be developed for use in humans. Humans need the chemical element selenium for good health. The selenium-containing enzyme thioredoxin reductase 1 (TrxR1) can be used to support the growth of various cells and to protect them from harmful forms of oxygen radicals, known as oxidative stress. Selenium intake has long been a topic of discussion in connection with cancer, although results have proved inconclusive and the correlation between selenium intake and cancer growth is extremely complex. Raised levels of TrxR1 can be seen in several forms of cancer and are linked to worse prognoses in head and neck, lung and breast cancers. Researchers therefore analysed almost 400,000 different molecules in the search for new and more specific TrxR1 inhibitors than those previously available. They discovered three different molecules that met their search criteria. Sure enough, when tested, these same molecules also proved to be active as cancer medicines. It proved possible to effectively treat over 60 different types of cancer cell under laboratory conditions. Normal cells were however much less sensitive to these molecules. Sensitive to oxidative stress “This effectiveness against cancer may be a result of cancer cells’ seemingly greater sensitivity to oxidative stress when compared to normal cells, which in turn can be utilised in cancer therapy,” says Professor Elias Arnér, Department of Medical Biochemistry and Biophysics at Karolinska Institutet, who led the study. Researchers also found rapid tumoricidal effects when treating head and neck or breast cancers in mice, without obvious side-effects. The new molecules have yet to be tested on humans, but it is already known that several different cancer medicines currently in use, including cisplatin and melfalan, inhibit TrxR1. Thus far, whether or not this inhibition of the enzyme is important to the effectiveness of these medicines has remained unknown, but this study suggests that this might well be the case. Researchers now intend to further develop the new TrxR1 inhibitors to offer a new form of cancer therapy. Effective against multiple forms of cancer “My hope is that we will be able to develop new treatments, effective against multiple forms of cancer but with few side-effects. This seems to work in mouse models and we are therefore hopeful that this principle for treatment can be developed for humans, even if this will require many years of further research,” says Elias Arnér. The study has been carried out in collaboration with researchers at the National Institutes of Health (NIH) in the United States. This research was funded by Karolinska Institutet, the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, NIH, National Center for Advancing Translational Sciences, the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and Oblique Therapeutics AB. Elias Arnér and NIH are listed as applicants for three patents based on the discoveries made in this study, with several co-authors named as co-inventors. Owe Orwar and William C Stafford are employees and shareholders in a company that develops TrxR1 inhibitors for clinical use. Publication ”Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy” William C Stafford, Xiaoxiao Peng, Maria Hägg Olofsson, Xiaonan Zhang, Diane K Luci, Li Lu, Qing Cheng, Lionel Trésaugues, Thomas S Dexheimer, Nathan P Coussens, Martin Augsten, Hanna-Stina Martinsson Ahlzén, Owe Orwar, Arne Östman, Sharon Stone-Elander, David J Maloney, Ajit Jadhav, Anton Simeonov, Stig Linder och Elias S.J. Arnér Science Translational Medicine, online 14 February 2018, doi: 10.1126/scitranslmed.aaf7444

Atlas of brain blood vessels provides fresh clues to brain diseases

Wed, 14/02/2018 - 19:00
Even though diseases of the brain vasculature are some of the most common causes of death in the West, knowledge of these blood vessels is limited. Now researchers from Uppsala University and Karolinska Institutet present in the journal Nature a detailed molecular atlas of the cells that form the brain’s blood vessels and the life-essential blood-brain barrier. The atlas provides new knowledge regarding the functions of the cells and the barrier, and clues to which cell types are involved in different diseases. The vasculature of the brain is, like elsewhere on the body, made up of arteries, veins and thin, intervening vessels called capillaries through which the main exchange of oxygen, nutrients and waste products takes place. However, the vessels of the brain differ from others in one important respect – the so-called blood-brain barrier, which acts as a filter that blocks certain substances from passing through the vessel walls, thus protecting the brain from potentially toxic products while letting through whatever it needs for its structure and function. “It is becoming increasingly clear that a fully functional blood-brain barrier is essential to brain health and that a dysfunctional barrier is a factor of many brain diseases,” says study leader Christer Betsholtz, professor at Uppsala University and Karolinska Institutet's Department of Medicine, Huddinge. “The structure of the blood-brain barrier hasn’t been fully known, and so a detailed atlas of the brain’s vasculature and its barrier functionality is needed.” Cellular and molecular atlas Using a relatively new technique called single cell RNA sequencing, the researchers have produced a cellular and molecular atlas of the mouse brain vasculature. The blood vessels were broken apart in individual cells, which were then, one by one, mapped in accordance with their gene expression patterns and compared. The basic cell type and any gradual specialisations could then be ascertained for each cell. Finally, the molecular map was matched with the corresponding anatomy in tissue analyses using specific markers. “For the first time we’ve been able to show in detail how the blood-brain barrier differs among the various types of brain blood vessels,” says lead author Michael Vanlandewijck, assistant professor at Uppsala University and Karolinska Institutet and director of the Single Cell Analysis Unit at Karolinska Institutet’s and AstraZeneca’s Integrated Cardio Metabolic Centre (ICMC). It was long thought that the blood-brain barrier was made up of specialised endothelial cells in the blood vessels; the new study shows, however, that there are probably many other types of cells involved in the maintenance of the blood-brain barrier as well, including cells called pericytes in the capillary walls. The researchers were also able to establish the molecular identity of another cell type in the vascular wall, a kind of connective tissue cell located in a narrow space just outside the brain’s blood vessels. “This space has been posited to act as the brain’s lymph system, so it’ll now be incredibly interesting to study these cells further using the markers we’ve found,” says Dr Vanlandewijck. Links disease-causing genes to specific cell types The atlas means that a number of genes with known or presumed function in different brain diseases can now be associated with specific cell types in the brain’s vasculature. “We already have results indicating that many more cell types than previously thought are involved in neurovascular diseases such as Alzheimer’s and brain tumours,” says Professor Betsholtz. “We’re now able to study this systematically in different diseases with the same type of analyses as we’ve used here.” The study was conducted by researchers at Uppsala University and Karolinska Institutet and colleagues in France, Finland, Switzerland, Japan and China. It was financed by AstraZeneca, the Swedish Research Council, the European Research Council (ERC), the Leducq Foundation, the Swedish Cancer Society, the Knut and Alice Wallenberg Foundation, the Swedish Brain Fund, the Swiss National Science Foundation and the Synapsis Foundation. Publication A molecular atlas of cell types and zonation in the brain vasculature Michael Vanlandewijck, Liqun He, Maarja Andaloussi Mäe, Johanna Andrae, Koji Ando, Francesca Del Gaudio, Khayrun Nahar, Thibaud Lebouvier, Bàrbara Laviña, Leonor Gouveia, Ying Sun, Elisabeth Raschperger, Markus Räsänen, Yvette Zarb, Naoki Mochizuki, Annika Keller, Urban Lendahl, Christer Betsholtz Nature, online 14 February 2018. DOI: 10.1038/nature25739

Ewa Ehrenborg new Vice-Dean

Wed, 14/02/2018 - 16:36
Professor Ewa Ehrenborg has been appointed the new vice-dean for collaboration with Stockholm County Council (SLL), with a particular focus on education at Karolinska University Hospital. Radical changes are taking place in the healthcare field in Stockholm, changes that impact on KI. Karolinska University Hospital is being reorganised under a new business model and a large volume of outpatient care is being moved out. In order to make sure that high quality education can still be obtained at the hospital, KI created the office of vice-dean for collaboration with SLL, with a focus on education, in 2017. This year, this role has been assigned to Ewa Ehrenborg, professor of molecular cardiovascular medicine at the Department of Medicine, Solna. “The appointment is a very important one, especially in light of the consequence analysis of Karolinska University Hospital’s new business model that was done during my predecessor Carl-Fredrik Wahlgren’s time,” she says. The consequence analysis showed that action needs to be taken to ensure that students, especially medical students, can attain certain intended learning outcomes and degree objectives. There is now an agreement with concrete solutions on how to achieve this. Professor Ehrenborg will be putting her energies into monitoring progress. “A great deal of healthcare is moving out and the students need to be at local hospitals, academic specialist centres and so on, so that they can deal with patients with common and acute conditions and learn to independently diagnose and treat them.” Part of Professor Ehrenborg’s role is to make sure that education at KI maintains a high level of quality. To this end she will be working closely with, amongst other bodies, the various clinics and units at Karolinska University Hospital. “The hospital’s new business concept also creates new opportunities for learning that we want our students to enjoy.” Professor Ehrenborg was awarded KI’s Pedagogical Prize in 2017 for having developed interprofessional learning and student-activating teaching that integrate closely with the latest research. The office of vice-dean also includes ensuring the availability of teaching environments where students from different professions can learn from each other and together, as well as clinical training environments. The office of vice-dean is a temporary half-time position during 2018 and reports to the dean of education, Annika Östman Wernerson. “Ewa Ehrenborg is a doctor and a researcher with a wide contact network in education,” says Professor Östman Wernerson. “For many years, she’s been the director and coordinator of the Centre for Clinical Education, where she has worked hard to raised the quality of Work-Integrated Learning on our programmes. She’s therefore highly suited to the important office of vice-dean for collaboration.” Text: Ann Patmalnieks 

Professor Janne Lehtiö new Scientific Director of SciLifeLab

Wed, 14/02/2018 - 10:36
Karolinska Institutet has chosen a new Scientific Director for SciLifeLab, Sweden’s largest life science research centre. Professor Janne Lehtiö will act as a catalyst for collaboration between KI and SciLifeLab. Janne Lehtiö, professor in clinical proteomics at KI:s Department of Oncology-Pathology, has been appointed Scientific Director of SciLifeLab. The centre for molecular biosciences, a collaboration between host universities Karolinska Institutet (KI), KTH Royal Institute of Technology, Stockholm University and Uppsala University, develops advanced technologies for dissemination to researchers across the country.  The assignment includes acting as the representative for and coordinator of KI’s participation in the centre, as well as supporting management on issues related to SciLifeLab. Janne Lehtiö will be taking up the post with immediate effect. “It is exciting and important work. I hope that I can be a catalyst for collaboration between the various researchers. Hopefully, I will be able to contribute to two-way communication and mutual understanding. Researchers at KI must be made aware of how they can utilise the facilities. SciLifeLab is an important hub for technology-driven research, that can interact with basic and clinical research.” believes Janne Lehtiö. “It is extremely interesting to see this type of technology used in point-of-care clinical studies. In future, this may lead to improved individualised care for cancer patients. The post of Scientific Director is equivalent to 20% of a full-time position. Janne Lehtiö will continue to perform his ordinary duties in parallel with the new position. Since 2008, he has been the leader of a research group studying cancer and proteomics. “My own research deals with developing new methods for proteomics and applying these to individual cancer treatments. The primary focus is on lung and breast cancer and leukaemia, both in children and adults.” He is also director of Karolinska University Hospital’s clinical proteomics facility and is involved in the Swedish national infrastructure for biological mass spectrometry (BioMS), where Stockholm hosts the National Node for Proteogenomics and Chemical Proteomics.  Janne Lehtiö obtained an MSc in biochemistry at Helsinki University and a PhD in bioengineering at KTH. After defending his thesis, Janne worked in industry in the field of biomarker research. He also has experience of close collaboration with Karolinska University Hospital. Professor Karin Dahlman-Wright, KI’s pro-vice-chancellor, thinks along the same lines as Janne Lehtiö. “We must ensure that all KI researchers have sufficient knowledge of the technologies available at SciLifeLab. It is also important that  there are good lines of communication between KI’s management, SciLifeLab and the KI researchers working there,” she says. Karin Dahlman-Wright herself held the position of Scientific Director at SciLifeLab between 2013 and 2015. The position then remained unfilled, whereupon Professor Lars Engstrand took on the task during a transitional period.  “Lars Engstrand did an excellent job but it is now time for KI to seek a more long-term solution,” says Karin Dahlman Wright. “Janne Lehtiö’s broad technological and methodological expertise, combined with his long experience of managing infrastructure at local, regional and national level, makes him ideally suited to the task,” continues Karin Dahlman-Wright. “His close collaboration with clinical operations as director of the clinical proteomics core facility is an additional advantage.” She is now looking forward to Janne Lehtiö taking responsibility for increasing knowledge about the research carried out at SciLifeLab and how it can be applied to the healthcare sector. She emphasises the importance of SciLifeLab’s operations even outside of KI. “The government is investing heavily in SciLifeLab and it is vital that we make a broad impact across Sweden.” Text: Ann Patmalnieks

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