KI News

Researchers at Karolinska Institutet have found a new way of preventing resistance to cytostatics used in the treatment of cancers such as medulloblastoma, the most common form of malignant brain tumour in children. The promising results of this experimental study are based on a combination of the drug temozolomid and other extant drugs that inhibit an enzyme instrumental in DNA repair in cancer cells. The study, which is published in the journal Nature Communications, was conducted on human tumour cells and on mice, and offers hope of a much improved therapy for a severe form of cancer. This says the research team is particularly valuable for children, whose brains are still developing and who thus run the highest risk of injury from the radiotherapy often used against malignant brain tumours. “Now that we’ve tested already available drugs, the published results enable us to move on to clinical trials relatively quickly, which is very good news indeed,” says Dr Malin Wickström, one of the researchers behind the study. The treatment of cancer often involves different forms of cytostatic drugs as well as surgery and radiotherapy. However, tumour cells develop strategies for resisting these drugs, most commonly to produce more of a particular protein or enzyme able to repair the DNA damage caused by the chemotherapy.  In the present experimental study, the researchers have sought means of inhibiting the DNA-repair enzyme MGMT (O6-methylguanine-DNA-methyltransferase), which plays a key part in cytostatic resistance. One finding was that a cell signal pathway called Wingless and its central signal molecule, beta-catenin, can regulate the production of MGMT in the tumour cell. Common form of paediatric brain tumour Blocking Wingless/beta-catenin also inhibits the MGMT enzyme, which in turn prevents cytostatic resistance. This was particularly the case for temozolomid, which is often used to treat medulloblastoma, the most common form of paediatric brain tumour. “By combining temozolomid with Wingless inhibitors, we’ve been able to cancel out the resistance developed by the tumour, rendering it susceptible to the tumour-killing effect of temozolomid,” says principal investigator and docent, Dr John Inge Johnsen. “We hope that the results will give rise to a new drug combination therapy and improve prospects for a very vulnerable patient group.” Dr Wickström and Dr Johnsen work at the paediatric oncology unit of the Department of Women’s and Children’s Health at Karolinska Institutet. The study was done in cooperation with Dr. Ninib Baryawno at Harvard University in the US, and financed with grants from the Swedish Childhood Cancer Foundation, the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Märta and Gunnar V. Philipson Foundation, the Mary Béve Foundation for Childhood Cancer Research, the Dämman Foundation and the Erna and Olav Aakre Foundation for Cancer Research. Further information on childhood medulloblastoma Publication Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance Malin Wickström, Cecilia Dyberg, Jelena Milosevic, Christer Einvik, Raul Calero, Baldur Sveinbjörnsson, Emma Sandén, Anna Darabi, Peter Siesjö, Marcel Kool, Per Kogner, Ninib Baryawno, John Inge Johnsen Nature Communications, online 25 November 2015, doi:10.1038/ncomms9904

A population of ‘stop cells’ in the brainstem is essential for the ability of mice to stop their locomotion, according to a new study by scientists at Karolinska Institutet. In an article published in the journal Cell, they report a brainstem pathway specifically dedicated to enforce locomotor arrest: its selective activation stops locomotion, while its silencing favors it. The study thus identifies a novel descending modality essential for gating the episodic nature of locomotor behavior. Locomotion is an essential motor behaviour needed for survival in both humans and animals. It has an episodic nature: we move when we want or need and, equally well, we can terminate ongoing movements. This episodic control has generally been attributed to descending excitatory signals in the brainstem that contact and activate neuronal circuits in the spinal cord. But is the stop of locomotion only due to a lack of activating signals from the brainstem or is there a dedicated stop signal? In the present study, the researchers Julien Bouvier and Vittorio Caggiano together with Professor Ole Kiehn and colleagues studied how the complex brainstem neuronal circuits control locomotion in mice. They used advanced methods, including optogenetics, which makes it possible to selectively activate specific groups of neurons with light, as well as genetic silencing to selectively block neuronal activity. Somewhat unexpectedly, they found a population of excitatory neurons that turned out to be essential for the ability of mice to stop. When those ‘stop cells’ are activated, mice immediately halt their locomotion. Conversely, when those neurons are silenced, mice had difficulties when trying to stop walking. The clock in the network “We found that the ‘stop cells’ depress the neuronal networks involved in generating the locomotor rhythm, the clock in the network, and not the motor neurons that directly contract muscles”, says Ole Kiehn, who leads the laboratory behind the study at Karolinska Institutet’s Department of Neuroscience. “In this way activity in the ‘stop cells’ allows the animal to make a gracious stop without losing its muscle tone, just as we experience ourselves when we voluntarily stop for example in front of an obstacle.” Although the study addresses the normal brain function the findings may provide insights to how locomotion is affected in the diseased brain. “For example, in Parkinson’s disease, a pronounced motor symptom is a gait disturbance with freezing of the gait”, says Ole Kiehn. “it is possible that the `stop cells´ have an abnormally increased activity in Parkinson’s disease, contributing to the gait disturbances.” The study was financed with grants from the Swedish Brain Foundation, the Söderberg Foundations, the Swedish Research Council, the European Research Council, an EMBO fellowship, and by the NIH. View our press release about this study More about Ole Kiehn's research Publication Descending command neurons in the brainstem that halt locomotion Julien Bouvier*, Vittorio Caggiano*, Roberto Leiras, Vanessa Caldeira, Carmelo Bellardita, Kira Balueva, Andrea Fuchs, and Ole Kiehn Cell, online 19 November 2015, DOI: http://dx.doi.org/10.1016/j.cell.2015.10.074

A fresh study from Karolinska Institutet can quell any fears there might be of an increased risk of fetal and neonatal mortality for mothers who have been inoculated with the Pandemrix vaccine for H1N1-influensa while pregnant. The results are published in British Medical Journal (BMJ). A large portion of the Swedish population had themselves vaccinated against the new H1N1-influensan (also known as swine flu) in connection with the 2009-2010 outbreak. Since then, there has been much debate surrounding the Pandemrix vaccine, especially after research had shown that it increases the risk of narcolepsy in children and adolescents and young adults. Dr Jonas F. Ludvigsson, paediatrician and professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet, therefore decided with his colleagues to examine if the vaccination of pregnant women could affect fetuses and newborn babies.  A study published in 2013 in the European Journal of Epidemiology gave reassurances on the supposed increased risk of low birth-weight, stunted growth or premature birth; these results have now been complemented by this present study in BMJ showing that vaccination with Pandemrix during pregnancy has no effect on the risk of fetal/neonatal mortality either. No higher risk The researchers analysed a total of 275,500 pregnancies, 41,183 of which had been exposed to Pandemrix. During the follow-up period, there were 1,172 stillbirths, 380 neonatal deaths (0-6 days after birth) and 706 infant deaths (7 days up to 4.6 years). This, say the team, means that there is no higher risk of foetal/infant death for women vaccinated while pregnant. This same result was found on comparing fetuses exposed to the vaccine with their unvaccinated siblings. The study was financed with grants from the Swedish Research Council and the Swedish Research Council for Health, Working Life and Welfare (FORTE). Jonas Ludvigsson is also a paediatrician at Örebro University Hospital. Publication Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design Jonas F. Ludvigsson, Peter Ström, Cecilia Lundholm, Sven Cnattingius, Anders Ekbom, Åke Örtqvist, Nils Feltelius, Fredrik Granath, Olof Stephansson BMJ,  online 16 November 2015, doi: http://dx.doi.org/10.1136/bmj.h5585

Patients who undergo surgery for oesophageal cancer early in the week – on a Monday or Tuesday – have a higher chance of long-term survival than those who have surgery at the end of the working week. This is according to a new study from Karolinska Institutet published in the scientific journal Annals of Surgery. “The mechanism behind our results is still unknown,” says Jesper Lagergren, consultant and professor of surgery at Karolinska Institutet and King's College London. “But it’s possible that surgical precision to some extent declines towards the end of the week, due perhaps to the accumulated burden on the surgeon and his or her team.” Oesophageal cancer surgery is time-consuming and exacting (taking on average six and a half hours), and it is a recognised fact that the experience of the surgeon has a substantial impact on the patient’s chance of survival. In the present study, the researchers examined a total of 1,748 patients operated on for oesophageal cancer in Sweden between 1987 and 2010, and found that five-year mortality was 13 per cent higher for patients who had undergone surgery on a Wednesday to a Friday than for those who had been operated on during a Monday or Tuesday; this after controlling for age, other diseases, stage and type of tumour (histology), pre-treatment with cytostatics and radiotherapy, and the surgeon’s experience of oesophageal cancer surgery. Strongest for early-stage tumours The link between weekday of surgery and survival was strongest for early-stage tumours (0-I), moderate for medium-stage tumours (II) and non-existent for advanced-stage tumours (III-IV). The lack of effect for advanced tumours can be due to the generally low likelihood of being cured; the chances of surviving up to five years after the operation are about 10 per cent. With early-stage tumours, it is more the surgery that determines the outcome. “More studies are needed to confirm these results, before anyone goes and issues clinical recommendations,” says Professor Lagergren. “But if these results end up being corroborated by future research, oesophageal cancer surgery should be planned to take place primarily at the beginning of the week.” The research was financed by the Swedish Research Council and the Swedish Cancer Society. Jesper Lagergren is affiliated to Karolinska Institutet's Department of Molecular Medicine and Surgery.  More on Jesper Lagergren's research Our press release about this study Publication Weekday of esophageal cancer surgery and its relation to prognosis Jesper Lagergren, Fredrik Mattsson & Pernilla Lagergren Annals of Surgery, online 10 November 2015, doi: 10.1097/SLA.0000000000001324

Karolinska Institutet’s 154 new doctors officially received their degrees on 13 November at the 2015 conferment ceremony in Stockholm City Hall. Tribute was also paid to the year’s jubilee doctors, who received PhDs at KI 50 years ago.    More photos from the evening can be found on Instagram.  

A high body mass index (BMI) is linked to longer survival terms for several chronic serious diseases. A large European epidemiological study now shows that the protective effect does not apply to all patients with a high BMI. The findings, which are published in the Journal of the American Society of Nephrology, indicate that chronic inflammation plays an important part in this so-called obesity paradox. Obesity increases the risk of numerous diseases and has well-documented adverse effects on health. So it might seem paradoxical for it also to be linked to longer survival terms for the same chronic diseases for which it is a risk factor. This ‘obesity paradox’ has been observed for several chronic diseases, such as serious kidney disease, coronary artery disease, heart failure, stroke, rheumatoid arthritis, type 2 diabetes, cancer and dementia. A common denominator of all these chronic diseases is that persistent low-grade inflammation is a common feature. Researchers have now examined for the first time if inflammation influences the documented link between high BMI and survival in patients with a severe kidney disease requiring haemodialysis. Their epidemiological study included about 6,000 such patients, half of whom showed signs of low-grade chronic inflammation. “We found that high BMI had a protective action, by which I mean that it was linked to longer survival rates for the dialysis patients with chronic inflammation,” says the study’s lead author Peter Stenvinkel, MD, PhD, Professor at the Department of Clinical Science, Intervention and Technology at Karolinska Institutet. “On the other hand, we observed no such protective effect of high BMI in dialysis patients who were inflammation free. This correlation remains even after controlling for a large number of other factors that can influence survival rates for this patient group.” Reflect stored nutrient reserves There are several reasons for why a high BMI protects patients with chronic inflammation. According to the team behind the study, a high BMI can reflect stored nutrient reserves in the form of body fat and muscle mass and a good appetite, which are particularly important for people with severe kidney disease. Differences in the ability to repair damaged tissue with stem cells can also have some part to play in the observed association. Earlier studies have shown that the formation of new stem cells is boosted by fat mass but inhibited by inflammation. Since BMI (kg/m2) is determined by both muscle and fat mass, this commonly used metric is a relatively poor measure of body composition. The study does therefore not say whether the protection for inflamed dialysis patients is provided by the higher amount of fat or muscle, or both. “The study shows that overweight dialysis patients showing signs of chronic inflammation should not be recommended to lose weight,” says Professor Stenvinkel. “It is however, important to address the causes of the inflammation. It is up to future studies to show if a high BMI also protects other patient groups with chronic inflammation, such as those with heart failure, stroke, dementia, chronic pulmonary disease, rheumatism and cancer.” The study was conducted by a European epidemiological workgroup (ARO) financed by the pharmaceutical company Amgen. Peter Stenvinkel is also a senior physician at the Division of Nephrology of Karolinska University Hospital in Stockholm, Sweden. Publication The Paradoxical Association Between Body Mass Index and Mortality in Hemodialysis patients is Modified by Inflammation Peter Stenvinkel, Iain A. Gillespie, Jamie Tunks, Janet Addison, Florian Kronenberg, Tilman B. Drueke, Daniele Marcelli, Guntram Schernthaner, Kai-Uwe Eckardt, Jürgen Floege, Marc Froissart, Stefan D Anker on behalf the ARO Steering Committee (collaborators) J Am Soc Nephrol, online 13 November 2015

Karolinska Institutet is the coordinator of a collaborative project between Swedish and Vietnamese universities that was launched in November at ceremonies in Ho Chi Minh City and Hanoi attended by KI representatives. The Training and Research Academic Collaboration (TRAC) – Sweden-Vietnam was launched at two ceremonies in Vietnam on 10 and 11-12 November. Mattias Larsson, a researcher from the Department of Public Health Science, and Linus Olson a researcher from the Department of Women’s and Children’s Health, who will be coordinating the project from their base in Vietnam, were present at the ceremonies, along with Professor Carl Johan Sundberg, representing the Karolinska Institutet management. This is the first time that five Swedish universities have established a common infrastructure for research and education with partners in another country. The Swedish participants are KI, Uppsala, Göteborg, Linköping and Umeå universities, which will be teaming up with Hanoi Medical University, the University of Medicine and Pharmacy HCMC and the Research Institute for Child Health at the National Hospital of Paediatrics in Hanoi. The aim of the collaboration is to develop an academic centre for education and research in the interests of global health.  “We hope to be able to develop more joint education programmes at first, second and third-cycle level with both Swedish and Asian students, and encourage more student exchanges,” says project coordinator Dr Larsson. The Swedish universities have been engaged in a variety of collaborations with Vietnamese institutions over the years, and TRAC builds upon the contacts that have been created in the country. Besides education, the collaboration can help KI researchers tackle health problems that are important for a large portion of the global population. Ninety-four million people live in Vietnam, which means large patient groups. “Researchers can quickly gain experience of diseases that are common in Vietnam and that are currently rare, but on the increase, in Sweden,” says Dr Larsson. “One example is the rise in antibiotic resistance, which is a very real problem in hospitals. If we can help reduce the spread of infection in low and middle-income countries, we have the potential not only to save many lives but also to prevent their spread to Europe and Sweden.” TRAC has received a three-year grant of five million kronor from the Swedish Foundation for International Cooperation in Research and Higher Education (STINT); the participating universities are to make an equivalent contribution in the form of working hours. Text: Karin Söderlund Leifler

A mechanical valve prosthesis has a better survival record than a biological valve prosthesis, according to a large registry study from Karolinska Institutet. The finding, which is published in the European Heart Journal, can be highly significant, since the use of biological valve prostheses has increased in all age groups in recent years. Which type of prosthetic valve is better for relatively young patients undergoing heart surgery for an aortic valve replacement: mechanical or biological? This has been the subject of quite intense discussion amongst doctors and researchers in recent years. In this latest registry study, the researchers examined over 4,500 Swedish patients in the 50 to 69 age-group who had had an aortic valve replacement. “We show that patients who had received a mechanical prosthesis had better survival rates than those who had received a biological prosthesis,” says Ulrik Sartipy, associate professor at the Department of Molecular Medicine and Surgery at Karolinska Institutet, and cardiac surgeon at Karolinska University Hospital’s Department of Cardiothoracic Surgery. “Our results are important since the trend in Sweden and abroad in recent years has been towards a greater use of biological valve prostheses in relatively young patients, which has no backing in clinical therapy guidelines.” Apart from long-term survival, the group also examined other consequences of the heart valve operations and found that the risk of stroke was similar for both kinds of prosthesis. Patients who had received a biological prosthesis were more likely to need to re-operate the aortic valve, but they also had a lower risk of serious bleeding, a finding that confirms previous studies. Aortic valve replacement surgery  Roughly 280,000 people around the world undergo aortic valve replacement surgery every year. Mechanical prostheses are more durable but the patients need to take blood thinning drugs for the rest of their lives. Biological valve prostheses are normally made from cow or pig tissue. “Biological valve prostheses have been used more and more in young patients in recent years, partly because these patients don’t have to take blood thinners,” says Natalie Glaser, doctoral student at the Karolinska Institutet’s Department of Molecular Medicine and Surgery, and physician at Karolinska University Hospital’s Department of Cardiothoracic Surgery. “Our research shows that mechanical valve prostheses should be the preferred option for young patients.” The study was financed with grants from the Swedish Society of Medicine, Karolinska Institutet’s Foundations and Funds and the Mats Kleberg Foundation, and with a donation from Fredrik Lundberg. View our press release about this study Publication Aortic valve replacement with mechanical vs. biological prostheses in patients aged 50–69 years Natalie Glaser, Veronica Jackson, Martin J. Holzmann, Anders Franco-Cereceda, and Ulrik Sartipy European Heart Journal, online 12 November 2015

A registry study conducted at Karolinska Institutet and published in The British Journal of Psychiatry shows that the risk of premature death is about 2.5 times higher for people with autism spectrum disorder than for the rest of the population. Autism spectrum disorder (ASD) comprises neurodevelopmental conditions that affect social interaction and communication, as well as behavioural flexibility. Researchers at Karolinska Institutet have now been able to demonstrate that the risk of premature death for the first group applies to both women and men, many different causes of death, and individuals with and without concomitant intellectual disability. “We can now see that the ASD group has a higher mortality risk in almost all cause-of-death categories, which means that knowledge of autism is essential for all medical specialties,” says Professor Sven Bölte, head of the Centre of Neurodevelopmental Disorders at Karolinska Institutet (KIND). The first series of analyses in the study concerned overall mortality, regardless of cause of death. During the follow-up period, 2.6 per cent of the ASD group had died, compared to almost 1 per cent of the controls. “We see an association between ASD and an increased risk of premature death,” says Tatja Hirvikoski, researcher at Karolinska Institutet and head of research and development for the Stockholm County Council’s Habilitation Services. “A particularly at-risk group is women with ASD and intellectual disability.” The group of people with ASD but no intellectual disability, however, had a higher risk of death from one specific cause: suicide. “There’s a very clear connection between ASD without intellectual disability and a raised suicide risk,” says Dr Hirvikoski. “Clinical guidelines for suicidal patients must be followed when dealing with people with ASD.” Data for the participants with ASD was extracted from the Swedish patient registry, while that for the control group came from the population registry; both sets were then linked to the causes of death registry. The study included over 27,000 individuals with ASD, of whom 6,400 also had an intellectual disability, and some 2.5 million individuals from the general population. The individuals in the comparison group were matched to those in the ASD group as regards county of residence, sex and age. This large registry study – the largest of its kind – was a joint project between three departments at Karolinska Institutet: The Department of Clinical Neuroscience, the Department of Women’s and Children’s Health and the Department of Medical Epidemiology and Biostatistics.  Publication Premature mortality in autism spectrum disorder Tatja Hirvikoski, Ellenor Mittendorfer-Rutz, Marcus Boman, Henrik Larsson, Paul Lichtenstein and Sven Bölte The British Journal of Psychiatry, online 5 November 2015, http://dx.doi.org/10.1192/bjp.bp.114.160192  

A study from Karolinska Institutet shows that a new test for prostate cancer is better at detecting aggressive cancer than PSA. The new test, which has undergone trial in 58,818 men, discovers aggressive cancer earlier and reduces the number of false positive tests and unnecessary biopsies. The results are published in the scientific journal The Lancet Oncology.  Prostate cancer is the second most common cancer among men worldwide, with over 1.2 million diagnosed in 2012. In number of men diagnosed with prostate cancer increases and within 20 years over 2 million men are estimated to be diagnosed yearly. Currently, PSA is used to diagnose prostate cancer, but the procedure has long been controversial. “PSA can’t distinguish between aggressive and benign cancer,” says principal investigator Henrik Grönberg, MD, PhD, Professor of Cancer Epidemiology at Karolinska Institutet. “Today, men who don’t have cancer or who have a form of cancer that doesn’t need treating must go through an unnecessary, painful and sometimes dangerous course of treatment. On top of this, PSA misses many aggressive cancers. We therefore decided to develop a more precise test that could potentially replace PSA.” The new so-called STHLM3 test is a blood test that analyzes a combination of six protein markers, over 200 genetic markers and clinical data (age, family history and previous prostate biopsies). The test has been developed by researchers at Karolinska Institutet in collaboration with Thermo Fisher Scientific, which provided the protein and genetic marker assays used in the clinical study. Reduced the number of biopsies The study, which is presented in The Lancet Oncology, included 58,818 men from Stockholm aged 50 to 69 and was conducted between 2012 and 2014. The STHLM3 test and PSA were performed on all participants and then compared. The results show that the STHLM3 test reduced the number of biopsies by 30 percent without compromising patient safety. In addition, the STHLM3 test found aggressive cancers in men with low PSA values (1-3 ng/ml) – cancers that are currently going undetected. “This is indeed promising results. If we can introduce a more accurate way of testing for prostate cancer, we’ll spare patients unnecessary suffering and save resources for society”, says Professor Grönberg. “The STHLM3 tests will be available in Sweden in March 2016 and we will now start validating it in other countries and ethnic groups”. The study was financed by the Stockholm County Council. Professor Grönberg is a researcher at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet. View our press release about this study More about the STHLM3 project Publication Prostate cancer screening in men 50-69 years (STHLM3): a prospective population-based diagnostic study Henrik Grönberg, Jan Adolfsson, Markus Aly, Tobias Nordström, Peter Wiklund, Yvonne Brandberg, James Thompson, Fredrik Wiklund, Johan Lindberg, Mark Clements, Lars Egevad, Martin Eklund The Lancet Oncology, online November 9, 2015, http://dx.doi.org/10.1016/S1470-2045(15)00361-7

A new study from Karolinska Institutet shows that the ‘grammar’ of the human genetic code is more complex than that of even the most intricately constructed spoken languages in the world. The findings, published in the journal Nature, explain why the human genome is so difficult to decipher – and contribute to the further understanding of how genetic differences affect the risk of developing diseases on an individual level. “The genome contains all the information needed to build and maintain an organism, but it also holds the details of an individual’s risk of developing common diseases such as diabetes, heart disease and cancer”, says study lead-author Arttu Jolma, doctoral student at the Department of Biosciences and Nutrition. “If we can improve our ability to read and understand the human genome, we will also be able to make better use of the rapidly accumulating genomic information on a large number of diseases for medical benefits.” The sequencing of the human genome in the year 2000 revealed how the 3 billion letters of A, C, G and T, that the human genome consists of, are ordered. However, knowing just the order of the letters is not sufficient for translating the genomic discoveries into medical benefits; one also needs to understand what the sequences of letters mean. In other words, it is necessary to identify the ‘words’ and the ‘grammar’ of the language of the genome. The cells in our body have almost identical genomes, but differ from each other because different genes are active (expressed) in different types of cells. Each gene has a regulatory region that contains the instructions controlling when and where the gene is expressed. This gene regulatory code is read by proteins called transcription factors that bind to specific ‘DNA words’ and either increase or decrease the expression of the associated gene.   Compound words Under the supervision of Professor Jussi Taipale, researchers at Karolinska Institutet have previously identified most of the DNA words recognised by individual transcription factors. However, much like in a natural human language, the DNA words can be joined to form compound words that are read by multiple transcription factors. However, the mechanism by which such compound words are read has not previously been examined. Therefore, in their recent study in Nature, the Taipale team examines the binding preferences of pairs of transcription factors, and systematically maps the compound DNA words they bind to. Their analysis reveals that the grammar of the genetic code is much more complex than that of even the most complex human languages. Instead of simply joining two words together by deleting a space, the individual words that are joined together in compound DNA words are altered, leading to a large number of completely new words. “Our study identified many such words, increasing the understanding of how genes are regulated both in normal development and cancer”, says Arttu Jolma. “The results pave the way for cracking the genetic code that controls the expression of genes.“ This project was supported by the Finnish Academy CoE in Cancer Genetics, Center for Innovative Medicine, Knut and Alice Wallenberg Foundation, Göran Gustafsson Foundations, and the Swedish Research Council. Professor Taipale is also affiliated to the University of Helsinki, Finland. View our press release about this study Publication DNA-dependent formation of transcription factor pairs alters their binding specificity  Jolma A, Yin Y, Nitta KR, Dave K, Popov A, Taipale M, Enge M, Kivioja T, Morgunova E and Taipale J.  Nature, online 9 November 2015, doi: 10.1038/nature15518

A new study from Sweden’s Karolinska Institutet shows that new heart muscle cells in mice are mainly formed directly after birth. After the neonatal period the number of heart muscle cells does not change, and heart growth occurs only by cell size increase, similar to the human heart. The results are presented in the journal Cell. Cardiovascular disease is one of the main causes of the death in the developed world. During a heart attack many heart muscle cells die and the heart loses its ability to work efficiently. The key to restore the lost heart function after injuries is to gain a better understanding of the physiological renewal of muscle cells, but due to technical challenges this has been difficult. In a study published earlier this year in Cell, headed by Dr Olaf Bergmann and Professor Jonas Frisén at Karolinska Institutet’s Department of Cell and Molecular Biology, it was shown that the human heart generates most heart muscle cells during early childhood, and that their number is already defined in the perinatal period. However, it has been disputed whether these findings also apply to the mouse heart, which is an important model for studying heart disease. In this new study, researchers showed that the mouse heart generates a substantial number of muscle cells early in life, as does the human heart. The generation of new heart muscle cells is limited to the neonatal period, and is followed by two waves of DNA synthesis that does not lead to cell division during the second and third postnatal week. “In other words, after the neonatal period most muscle cells lose their ability to divide but not to synthesize DNA. This makes the cells end up with different amounts of genetic material”, says Olaf Bergmann, who headed the recent study. “After the third postnatal week DNA synthesis is barely detectable, and the mouse heart growth mainly by size increase of muscle cells.” Detect division of cells To examine the generation of heart muscle cells, the research team used a combination of methods. One of such was an advanced technique to detect division of cells using the non-radioactive, non-toxic stable isotope nitrogen-15 that was given to the animals and remains in the cell’s DNA of newly-generated cells. This was combined with a technique to estimate the total number of cells so that the growth potential could be studied. In that way this study found that the generation of heart muscle cells is restricted to the neonatal period and does not continue in the juvenile animal. “The next step is to understand why most heart muscle cells stop dividing so early in life”, says Olaf Bergmann. “Our aim is to help the adult heart to generate new muscle cells to replace lost heart tissue after injuries”. The first author of this publication is  Kanar Alkass, postdoctoral researcher at Karolinska Institutet’s Department of Cell and Molecular Biology. The study was financed with grants from Karolinska Institutet, and the Swedish Research Council. Our press release about this study Publication No Evidence for Cardiomyocyte Number Expansion in Preadolescent Mice Kanar Alkass, Joni Panula, Mattias Westman, Ting-Di Wu, Jean-Luc Guerquin-Kern, Olaf Bergmann Cell, November 05, 2015 issue, DOI: http://dx.doi.org/10.1016/j.cell.2015.10.035

In order to improve intensive care in Tanzania, doctoral student Tim Baker from Karolinska Institutet has introduced new procedures for identifying and treating patients with failing vital functions. Dr. Baker and his colleagues have developed a protocol called Vital Signs Directed Therapy (VSDT), which improves intensive care and reduces the mortality rate for some patients. VSDT is a treatment protocol for seriously ill patients that focuses on vital signs: level of consciousness, respiratory rate, oxygenation saturation, heart rate and blood pressure. VSDT is based on the routines that have long been established in intensive care units and operating rooms in Sweden. “We’ve seen that when the protocol is used, treatments have improved and mortality rates for some patients have fallen,” says Dr. Baker, specialist in anaesthesia and intensive care. “The intervention itself is simple and cheap, which means that it is feasible to implement in hospitals in Tanzania and other low-income countries. Our vision is that no patients will die of avoidable causes such as undiagnosed and untreated shock.” Tanzania is a low-income country with 15 anaesthetists for 47 million inhabitants. There are fewer doctors in the entire country than there are at Karolinska University Hospital in Stockholm. Tanzania’s largest hospital, Muhimbili National Hospital in Dar es Salaam, has only four anaesthetists, for the 1,500 inpatients and 16 operating rooms. The condition of critically ill patients continually changes and their treatment needs to be modified at the same pace. In Sweden, nurses at the patients’ bedside adjust their treatments around the clock with the help of goal-directed therapy protocols. When VSDT is used, nurses can treat the critically ill by following the protocol. “Now nurses can carry out tasks that were once the traditional preserve of the doctors,” says Dr. Baker. “The concept of task-shifting has worked well in this research project. The doctors don’t have time to see all deteriorating patients, and now the nurses themselves can adjust their treatment.” Doctoral thesis Critical care in low resource settings Tim Baker, Karolinska Institutet 2015, ISBN: 978-91-7676-049-9.   

Researchers at Karolinska Institutet, SciLifeLab and Centre for Clinical Research, Västerås have been able to explain why a combination of castration therapy and radiation therapy increases survival rates for patients with prostate cancer, compared to if they only receive radiation therapy. The findings, which are presented in the journal Science Translational Medicine, show that castration therapy impairs the DNA-repair machinery of the cancer cells, making them more sensitive to radiation. It is well known that a combination of hormonal castration therapy and radiation therapy significantly increases survival rates for patients with prostate cancer compared to radiation therapy alone. The reasons have however been unknown up until now. The new study led by Thomas Helleday at Karolinska Institutet/SciLifeLab, reveals that castration therapy decreases the amounts of proteins essential for DNA-repair in cancer cells. This impairs the cell’s DNA-repair machinery, making them more sensitive to radiation therapy. More than 250 000 deaths each year Prostate cancer is the second most frequently diagnosed cancer and accounts for 15 percent of all cancers in men world-wide. It is the sixth leading cause of cancer death in males worldwide and causes more than 250 000 deaths every year. The understanding of the mechanisms behind increased survival for prostate cancer-patients that receives combined therapies will hopefully lead to better and more optimized treatments. The current study study is also a part of an upcoming doctoral thesis, which will be defended by Dr Firas L. Tarish at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet on 13 November 2015. The research was financed with grants from the Centre for Clinical Research, a collaboration of Västmanland County Council and Uppsala University, Västmanlands cancerfond, AstraZeneca, Svenska Smärtafonden, Percy Falks stiftelse, and Henning &h Ida Perssons forskningsstiftelse. Publication Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair Firas L. Tarish, Niklas Schultz, Anna Tanoglidi, Hans Hamberg, Henry Letocha, Katalin Karaszi, Freddie C. Hamdy, Torvald Granfors, Thomas Helleday Science Translational Medicine, online 04 Nov 2015, DOI: 10.1126/scitranslmed.aac5671m Vol. 7, Issue 312, pp. 312re11

Four per cent of women between the ages of 15 and 49 in western Uganda live with urinary and/or faecal incontinence caused by genital fistulas. In a new doctoral thesis, Justus Barageine identifies the risk factors in this setting as caesarean section performed by unskilled medical officers, short stature, large babies and prolonged labour.  Two to three million women around the world live with urinary or faecal incontinence caused by genital fistulas. Justus Barageine conducted four sub studies for his thesis. The first is a case-control study, in which short stature, large baby, prolonged labour and surprisingly caesarean section turn out to be risk factors. Secondly, a randomised study concludes that shorter postoperative care involving early discharge with catheter 3-5 days after fistula surgery did not alter the outcomes of treatment or increase the risk of complication when compared with routine late discharge (after two weeks). The other two studies are qualitative and concern the perceived changes in life quality that living with urinary incontinence entails for the women and their husbands. While the women discussed their lives in focus groups, their husbands talked about their own experiences in personal, in-depth interviews. The alarming result is that the women suffer not only social stigmatisation but also depression and serious sexual problems. The interviewed men, who had all remained married, suffered not only from the sexual and financial problems but also felt small, having lost their “hegemonic masculinity”. Justus Barageine is a gynaecologist and studied for his PhD as part of a long-term, Sida-funded research collaboration between Karolinska Institutet and Uganda’s Makerere University. Three of the four studies have already been published, while the fourth is under review by Lancet Global Health. Thesis Genital Fistula Among Ugandan Women: Risk Factors, Treatment Outcomes, and Experiences of Patients & Spouses The public defence was held on 30 October 2015. 

Last Wednesday, 28 October, Karolinska Institutet held its “Global Masters Scholarship Ceremony” in honour of the non-European Master’s students who receive a scholarship on the basis of academic merit every year to cover the cost of their tuition fees at KI. The scholarship was first awarded three years ago, when Sweden introduced tuition fees for students from countries outside the EU. Every year since then, between five and ten scholarships been awarded to students selected from a highly competitive starting field of over 300 each time. Attending the ceremony were Vice-Chancellor Anders Hamsten, Pro-Dean of Higher Education Gunnar Nilsson and representatives of the global Master’s programmes, along with the students themselves and their guests.  In the photo, left to right: Pro-Dean of Higher Education Gunnar Nilsson, Fariha Binte Hossain, Guan Yi Lee, Vice-Chancellor Anders Hamsten. Middle row: Jennifer Wilson, Xenia Mihai. Top row: Ismael Gonzales Flores, Srinivas Bobba, Christopher Brown.

A new study from Karolinska Institutet shows that amyloid-β-peptides, which are thought to be toxic and a suspected cause of Alzheimer’s disease, actually have a biological function. The discovery, which is published in the journal Brain, can help to explain why the so-called cholinergic signal systems are the first to be damaged on the onset of the disease. Research on amyloid-β-peptides in Alzheimer’s disease has mainly been based on their presumed toxicity and causal role in the development of the disease. At the early stages of development, Alzheimer’s disease particularly affects cholinergic signalling via the neurotransmitter acetylcholine, but why this is the case is still unknown. The present study indicates that amyloid-β has a physiological function and influences the balance of acetylcholine in the brain. What the researchers have discovered is that amyloid-β forms particular complexes that they call BAβAC (BChE/AChE/Aβ/ApoE complex). The complexes contain two different enzymes that break down acetylcholine at the synapses between nerve cells or between nerve cells and glial cells. “When amyloid-β binds to them, the enzymes become hyperactive, and the neurotransmitter acetylcholine breaks down more rapidly,” says principal investigator, Dr Taher Darreh-Shori at Karolinska Institutet's Department of Neurobiology, Care Sciences and Society. “This could, in turn, change the functional status of the brain’s neuroglial cells, such as astrocytes and oligodendrocytes.” Surprised the team Another find, which surprised the team, concerns apolipoprotein-e4 (ApoE4), which is the best confirmed genetic risk factor for Alzheimer’s. It is not known how ApoE increases the risk of disease, but previous research has linked ApoE to the accumulation of amyloid-β plaque in the brains of Alzheimer’s patients. “Our results show that ApoE keeps amyloid-β soluble in the form of amyloid-ApoE complexes, which leads to the accumulation of reactive BAβA complexes,” says Dr Darreh-Shori. “High levels of ApoE seem to have a pathological effect on this mechanism, which could cause the cholinergic nerve pathways characteristic of Alzheimer’s to degrade.” He and his co-researchers will now study whether the BAβA complexes differ between the brains of Alzheimer’s patients and healthy people, and if it is possible to cancel their effect. The study was financed by grants from several bodies, including the Åhlén Foundation, the Dementia Foundation of the Swedish Dementia Association, the Olle Engkvist Foundation and the Åke Wiberg Foundation. Publication Amyloid-β peptides act as allosteric modulator of cholinergic signaling through formation of soluble BaβACs Rajnish Kumar; Agneta Nordberg, Taher Darreh-Shori BRAIN, first published online 2 November 2015, DOI: http://dx.doi.org/10.1093/brain/awv318 awv318 

Women with polycystic ovary syndrome (PCOS) have high levels of androgens in their blood, which has been assumed able to affect fetal development during pregnancy. An international team of researchers led from Karolinska Institutet in Sweden has now identified a hormonal mechanism that might explain why women with PCOS run a higher risk of developing symptoms of mental ill-health, such as anxiety and depression, in adulthood. The results, which are based on animal studies, are presented in the journal PNAS.  PCOS affects more than one in ten women of fertile age, and is characterised by small follicles inn one or both ovaries, high levels of testosterone in the blood and irregular periods. Women with PCOS also have problems with obesity and insulin resistance, which puts them at greater risk of developing type 2 Diabetes. They are also more likely to have mental health issues. “Over 60 per cent of these women are diagnosed with at least one psychiatric symptom, such as anxiety, depression or an eating disorder, and suicide is much more common amongst women with PCOS than amongst healthy controls,” says principal investigator Elisabet Stener-Victorin, researcher at the Department of Physiology and Pharmacology at Karolinska Institutet. It is also known that daughters of women with PCOS are more likely to develop the condition, while the sons tend to have problems with obesity and insulin resistance. One of the causes has been assumed to be due to the greater in-utero exposure to male hormones (androgens) via the mother’s blood, but the biological mechanism is unclear. Excessive doses of testosterone In the present PNAS study, the researchers have examined what happens when pregnant rats and their fetuses are exposed to excessive doses of testosterone to mimic the conditions of pregnant women with PCOS. They studied the impact on the placenta and on fetal growth and monitored the offspring – of both sexes – to adulthood, when their behaviour was then tested. Their results show that both male and female offspring exposed to testosterone in a late fetal stage display a higher degree of anxiety-like behaviour as adults than individuals born under normal circumstances. Further experiments allowed the researchers to establish that the testosterone exerts the greatest effect on the amygdala, a region of the brain that plays a part in emotional regulation and behaviour linked to both positive and negative emotions. The group found evidence of disturbances in the activity of the gene regulating the androgen receptor in the amygdale of offspring, and noted changes in the receptors for a type of oestrogen and in the genes that regulate serotonin and GABA, signal substances in the brain known for their involvement in the regulation of anxious behaviour.  Receptors were blocked “But when the androgenic and oestrogenic receptors were blocked by two different drugs, the animals were protected against the development of the anxiety-like behaviour in adulthood,” says Dr Stener-Victorin. “Our results indicate a hitherto unknown biological mechanism that can help us understand why the daughters and sons of women with PCOS develop anxiety as adults.” The study also involved researchers from the Gothenburg University’s Sahlgren Academy, Heilongjiang University of Chinese Medicine (China), the University of Colorado (USA) and the University of Chile. It was funded by grants from the Swedish Research Council, the Novo Nordisk Foundation, the Jane and Dan Ohlsson Foundation, the Wilhelm and Martina Lundgren Research Foundation, the Hjalmar Svensson Research Foundation, the Adlerbert Research Foundation, the Ragnar Söderberg Research Foundation and the Innovative Team of Science and Technology of Heilongjiang Province Universities. View our press release about this study Publication Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring Min Hu, Jennifer E Richard, Manuel Maliqueo, Milana Kokosar, Romina Fornes, Anna Benrick, Thomas Jansson, Claes Ohlsson, Xiaoke Wu, Karolina P Skibicka, Elisabet Stener-Victorin PNAS, online Early Edition the week of November 2, 2015

Researchers at Karolinska Institutet have discovered a cellular mechanism behind the surprising benefits of short, high-intensity interval exercise. Their findings, which are published in the scientific journal PNAS, also provide clues to why antioxidants undermine the effect of endurance training. A few minuets of high-intensity interval exercise is enough to produce an effect at least equivalent to that achieved with traditional much more time-consuming endurance training. High-intensity exercise has become popular with sportspeople and recreational joggers alike, as well as with patients with impaired muscle function. However, one question has so far remained unanswered: how can a few minutes’ high-intensity exercise be so effective? To investigate what happens in muscle cells during high-intensity exercise, the researchers asked male recreational exercisers to do 30 seconds of maximum exertion cycling followed by four minutes of rest, and to repeat the procedure six times. They then took muscle tissue samples from their thighs. “Our study shows that three minutes of high-intensity exercise breaks down calcium channels in the muscle cells,” says principal investigator Håkan Westerblad, professor at Karolinska Institutet’s Department of Physiology and Pharmacology. “This causes a lasting change in how the cells handle calcium, and is an excellent signal for adaptation, such as the formation of new mitochondria.” Mitochondria are like the cell’s power plants, and changes that stimulate the formation of new mitochondria increase muscle endurance. What the researchers found was that the breakdown of calcium channels that was triggered by the high-intensity exercise was caused by an increase in free radicals, which are very reactive and oxidise cellular proteins. Neutralising the radicals The cells therefore have antioxidative systems for trapping and neutralising the radicals. Antioxidants, like vitamins E and C, are also present in food and are common ingredients in dietary supplements. In the present study, the researchers examined what happens when isolated mouse muscles are treated with an antioxidant before and after simulated high-intensity interval exercise. “Our study shows that antioxidants remove the effect on the calcium channels, which might explain why they can weaken muscular response to endurance training,” says Professor Westerblad. “Our results also show that the calcium channels aren’t affected by the three minutes of high-intensity interval exercise in elite endurance athletes, who have built up more effective antioxidative systems.” The study was financed with grants from several bodies, including the Swedish Research Council and the National Centre for Sports Research, and conducted with the participation of research institutions in Switzerland and Lithuania. View a press release about this study Publication Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca2+ leak after one session of high-intensity interval exercise Nicolas Placea, Niklas Ivarsson Tomas Venckunas, Daria Neyroud, Marius Brazaitis, Arthur J. Cheng, Julien Ochala, Sigitas Kamandulis, Sebastien Girard, Gintautas Volungevičius, Henrikas Paužas, Abdelhafid Mekideche, Bengt Kayser, Vicente Martinez-Redondo, Jorge L. Ruas, Joseph D. Bruton, Andre Truffert, Johanna T. Lanner, Albertas Skurvydas, and Håkan Westerblad PNAS, online Early Edition the week of November 2, 2015

New research from Karolinska Institutet shows that hypersexual disorder – known popularly as sex addiction – can be linked to hyperactive stress systems. In a stress regulation test using the cortisone drug dexamethasone, men with hypersexual disorder showed higher levels of stress hormones than controls, a finding that the researchers hope will contribute to improved therapy for this patient group. The results are published in the journal Psychoneuroendocrinology. Hypersexual disorder, or an overactive sex drive, normally entails obsessive thoughts of sex, a compulsion to perform sexual acts, a loss of control, or sexual habits that carry potential problems or risks. The diagnosis is not uncontroversial, however, since there is often co-morbidity with another kind of mental health issue. Psychiatrist and researcher Jussi Jokinen has spent many years trying to find the neurobiological causes of mental illness. In the present study, he and his group at Karolinska Institutet’s Department of Clinical Neuroscience have used what is known as a dexamethasone test to measure the patients’ stress systems. Dexamethasone is a cortisone drug used for depressing the immune system, such as during an anaphylactic shock or an organ transplant; it also serves, however, as a kind of chemical stress test. The study involved 67 men with hypersexual disorder and 39 healthy matched controls. The participants were carefully diagnosed for hypersexual disorder and any co-morbidity with depression or childhood trauma. The researchers gave them a low dose of dexamethasone on the evening before the test to inhibit their physiological stress response, and then in the morning measured their levels of stress hormones cortisol and ACTH. They found that patients with hypersexual disorder had higher levels of such hormones than the healthy controls, a difference that remained even after controlling for co-morbid depression and childhood trauma. Childhood trauma “Aberrant stress regulation has previously been observed in depressed and suicidal patients as well as in substance abusers,” says Professor Jokinen. “In recent years, the focus has been on whether childhood trauma can lead to a dysregulation of the body’s stress systems via so-called epigenetic mechanisms, in other words how their psychosocial environments can influence the genes that control these systems.”  According to the researchers, the results suggest that the same neurobiological system involved in another type of abuse can apply to people with hypersexual disorder. The next step is to see if the psychotherapy given the patients has helped to normalise their physiological stress response. They also plan to perform epigenetic analyses. “This is the first study of neurobiological disorders in this particular patient group,” says Professor Jokinen. “It’s important to study stress systems in patients with different psychiatric diagnoses in order to understand if these biological changes are diagnosis-specific or related to different behaviours, and to take into account the impact that childhood trauma has on later mental health.” The study’s first author was Andreas Chatzittofis, psychiatrist and doctoral student at Karolinska Institutet’s Department of Clinical Neuroscience. The patients were recruited from the Centre for Andrology and Sexual Medicine at Karolinska University Hospital, Huddinge, through the cooperation of consultant and Associate Professor Dr Stefan Arver and psychologist Katarina Görts Öberg,PhD. Jussi Jokinen is also Professor of psychiatry at the Department of Clinical Science at Umeå University. The study was financed with a grant from the Swedish Research Council and through the ALF grant agreement between Stockholm County Council and Karolinska Institutet. Publication HPA axis dysregulation in men with hypersexual disorder. Chatzittofis A, Arver S, Öberg K, Hallberg J, Nordström P, Jokinen J Psychoneuroendocrinology 2015 Oct;63():247-253