Researchers have developed a more precise way of diagnosing suicide risk, by developing blood tests that work in everybody, as well as more personalized blood tests for different subtypes of suicidality that they have newly identified, and for different psychiatric high-risk groups. The research team, led by scientists at Indiana University School of Medicine, also showed how two apps, one based on a suicide risk checklist and the other on a scale for measuring feelings of anxiety and depression, work along with the blood tests to enhance the precision of tests and to suggest lifestyle, psychotherapeutic and other interventions. Lastly, they identified a series of medications and natural substances that could be developed for preventing suicide. "Our work provides a basis for precision medicine and scientific wellness preventive approaches," said Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience at IU School of Medicine and attending psychiatrist and research and development investigator at the Richard L. Roudebush Veterans Affairs Medical Center. The research builds on earlier studies from the Niculescu group. "Suicide strikes people in all walks of life. We believe such tragedies can be averted. This landmark larger study breaks new ground, as well as reproduces in larger numbers of individuals some of our earlier findings,” said Dr. Niculescu. There were multiple steps to the research, starting with serial blood tests taken from 66 people who had been diagnosed with psychiatric disorders, followed over time, and who had at least one instance in which they reported a significant change in their level of suicidal thinking from one testing visit to the next. The candidate gene expression biomarkers that best tracked suicidality in each individual and across individuals were then prioritized using the Niculescu group’s Convergent Functional Genomics approach, based on all the prior evidence in the field. Next, working with the Marion County (Indianapolis, Ind.) Coroner’s Office, the researchers tested the validity of the biomarkers using blood samples drawn from 45 people who had committed suicide. The biomarkers were then tested in another larger, completely independent group of individuals to determine how well they could predict which of them would report intense suicidal thoughts or would be hospitalized for suicide attempts. The biomarkers identified by the research are RNA molecules whose levels in the blood changed in concert with changes in the levels of suicidal thoughts experienced by the patients. Among the findings reported in the current paper were:
An algorithm that combines biomarkers with the apps that was 90 percent accurate in predicting high levels of suicidal thinking and 77 percent accurate in predicting future suicide-related hospitalizations in everybody, irrespective of gender and diagnosis.
A refined set of biomarkers that apply universally in predicting risk of suicide among both male and female patients with a variety of psychiatric illnesses, including new biomarkers never before linked to suicidal thoughts and behavior.
Four new subtypes of suicidality were identified (depressed, anxious, combined, and non-affective/psychotic), with different biomarkers being more effective in each subtype.
Biomarkers that were associated with specific diagnoses and genders, such as one, known as LHFP, that appears to be a very strong predictor for depressed men.
Two of the biomarkers, APOE and IL6, have broad evidence for involvement in suicidality and potential clinical utility as targets for drug therapies, as well as suggest a neurodegenerative and inflammatory component to the predisposition to suicide. APOE is responsible for proteins involved with managing cholesterol and fats, and some forms of the gene have been strongly implicated as risks for Alzheimer’s disease. IL6 expresses proteins involved in the body’s inflammation response.
Indiana University School of Medicine news.medicine.iu.edu/releases/2017/08/precision-medicine-opens-door-scientific-wellness-preventive-approaches-suicide.shtml
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Researchers at UC San Diego Moores Cancer Center, with colleagues from Memorial Sloan Kettering Cancer Center and Fox Chase Cancer Center, have determined that a specific region of the small bowel, called the duodenal-jejunal flexure or DJF, shows a high frequency of gastrointestinal stromal tumours (GISTs) with mutations of the NF1 gene. The small bowel, where approximately 30 percent of all GISTs occur, is divided into three anatomically, histologically and functionally distinct segments: the duodenum, jejunum and ileum. Most small bowel GISTs are associated with KIT mutations. However, a subset of GISTs have mutations in other genes, such as NF1. “Where the duodenum transitions into the jejunum, we are finding an over-representation of NF1-mutated GIST,” said Jason Sicklick, MD, surgical oncologist at Moores Cancer Center. NF1 can be mutated both somatically (within tumour DNA) or in the germline (part of the hereditary condition called Neurofibromatosis type 1 [NF-1]). Patients with NF-1 are 34 times more likely to develop GIST than unaffected individuals. “Genomic testing for some of these patients revealed occult germline NF1 mutations with no other obvious clinical symptoms of NF-1,” said Sicklick. “Anyone with a GIST should undergo tumour genetic testing. Currently only 8 to 15 percent of patients get tested. For those patients with NF1 mutations, there are implications for family members of patients who test positive for hereditary NF-1, as they also may be at increased risk of developing cancers, including GIST.” According to the National Institutes of Health, NF-1 is a condition characterized by changes in skin colouring and the growth of tumours along nerves in the skin, brain and other parts of the body, such as the GI tract. The signs and symptoms of this condition vary widely among affected persons. NF-1 occurs in one in 3,000 to 4,000 individuals worldwide. GIST represents the most common type of sarcoma in the GI tract, with an annual incidence of 6.8 cases per million people in the United States. These tumours start in special cells in the wall of the GI tract, called the interstitial cells of Cajal (ICCs). ICCs are sometimes dubbed the “pacemakers” of the GI tract because they signal the muscles in the digestive system to contract through peristalsis, moving food and liquid through the system. Sicklick and colleagues at Moores Cancer Center are searching for a personalized approach to GIST tumours that become progressively resistant to treatment. Ultimately, more than 95 percent of patients with drug-resistant GIST succumb to their cancer, highlighting the necessity for alternative therapeutic targets. “Patients with GIST should have their tumours profiled with next-generation sequencing panels,” said first author Adam Burgoyne, MD, PhD, medical oncologist at Moores Cancer Center. “We are uncovering a subset of patients, including patients with mutations of KIT, who have downstream mutations that may render them insensitive to conventional targeted therapy.” Sicklick added: “This insight helps physicians to know which drugs will or won’t work in order to properly treat these deadly tumors. Of critical importance in NF1 mutant GIST, standard-of-care drug regimens aren’t effective.” Sicklick’s recent GIST research has also identified new gene fusions and mutations associated with subsets of GIST patients. He and his team also provided the first evidence that the Hedgehog signalling pathway is central to the formation of GIST, which are frequently driven by the KIT oncogene.
Moores Cancer Center health.ucsd.edu/news/releases/Pages/2017-08-18-GIST-tumors-linked-NF1-mutations-genetic-testing-needed.aspx
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For nearly 20 years, Tatyana Golovkina, PhD, a microbiologist, geneticist and immunologist at the University of Chicago, has been working on a particularly thorny problem: Why are some people and animals able to fend off persistent viral infections while others can’t? Mice from a strain called I/LnJ are especially good at this. They can control infection with retroviruses from very different families by producing specific antibodies that coat viruses and render them innocuous. Golovkina, a Professor of Microbiology, was interested in what makes these mice special, so she began searching for the genes responsible for their remarkable immune response. In a new study she and her colleagues identify this gene. They also began to uncover more clues how it might work to control anti-virus immune responses. Using a process called positional cloning, in which researchers progressively narrow down the location of a gene on the chromosome, they pinpointed it within the major histocompatibility complex (MHC) locus. The MHC locus is a well-known region of the genome involved with the immune system so it makes sense that the gene was located there, but this was a disconcerting discovery. “It was a bummer at first because there are tons of genes within the MHC locus all controlling immune response, not only against viruses, but also many other microbial pathogens and non-microbial disorders,” she said. “Most of the time when people map a gene to the MHC they give up and stop there, with an assumption that the gene encodes for one of the two major MHC molecules, MHC class I or and MHC class II.” But with the help of a biochemist, Lisa Denzin from Rutgers University, and a computational biologist, Aly Khan from the Toyota Technological Institute at Chicago, Golovkina and her team identified a gene called H2-Ob that enables this resistance. Together with another gene called H2-Oa, it makes a molecule called H2-O in mice and HLA-DO in humans. H2-O has been known for years as a negative regulator of the MHC class II immune response, meaning that it shuts down the immune response. Most researchers thought it was there to prevent autoimmune responses, which attack the body’s own tissues. But in this case, none of the I/LnJ mice showed signs of autoimmunity, so H2-O must have another purpose. Golovkina and her team discovered another interesting thing when they crossed I/LnJ mice that were resistant to infections with ones that were more susceptible. The resultant F1 mice were susceptible to infection. This indicated that the I/LnJ H2-Ob gene was recessive; both parents had to have a copy of the mutated gene to pass it on their offspring, and the product of the gene should be a non-functional protein. “That was really surprising,” Golovkina said. “Almost all pathogen-resistant mechanisms discovered so far are dominant, meaning that something needs to be gained to resist.” The immune system response to a virus in susceptible mice lasts three to four weeks, then the H2-O molecule tells it to stop. But the I/LnJ mice, which respond vigorously to infections, have a mutation on H2-Ob that makes it inactive. So, after they launch an immune response, it never shuts off. This keeps persistent retroviruses in check. Golovkina hypothesizes that while letting the immune response keep running may keep chronic infections in check, such as retroviruses or hepatitis B and C, other pathogens like tuberculosis can take advantage of a persistent immune response because they can get access to certain cells when they’re coated with antibodies (and I/LnJ mice happen to be susceptible to TB and produced anti-TB antibodies). At some point during the evolution of these genes, it was more advantageous to be able to switch off the immune response to some infections (such as intracellular bacterial pathogens), but it came at the cost of not being able to fight other long-term infections. Now that her team has identified the gene underlying anti-retrovirus and potentially anti-hepatitis B and C responses, Golovkina says that further research should be done to create genetic therapies to manipulate the function of this gene, or develop molecules that could interfere with the function of H2-O to allow the virus-specific response in chronically infected people.
University of Chicago Medicine sciencelife.uchospitals.edu/2017/08/15/scientists-identify-gene-that-controls-immune-response-to-chronic-viral-infections/
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Every cell in the body, whether skin or muscle or brain, starts out as a generic cell that acquires its unique characteristics after undergoing a process of specialization. Nowhere is this process more dramatic than it is in red blood cells. In order to make as much room as possible for the oxygen-carrying protein haemoglobin, pretty much everything else inside these precursor red blood cells–nucleus, mitochondria, ribosomes and more–gets purged. Jam-packing red blood cells with haemoglobin is essential. Doing so ensures that all the body’s tissues and organs are well nourished with oxygen to carry on their normal functions. But how does this cell remodelling take place to begin with? For more than 20 years, Daniel Finley, professor of cell biology at Harvard Medical School, has been on a quest to unravel the process behind this profound cellular transformation. Now, thanks to advances in technology and a fortuitous meeting with researchers in a lab at Boston Children’s Hospital, Finley and his collaborators have identified the mechanism behind red blood cell specialization and revealed that it is controlled by an enzyme he first studied in 1995. During cell specialization, unwanted parts of a generic, immature cell are removed by the proteasome, protein-gobbling strings of molecules, or the cells’ "trash compactors," says study first author Anthony Tuan Nguyen, an HMS MD-PhD student. The researchers set out to find the mechanism that controls which parts get destroyed and which parts are spared before the precursor red blood cell becomes a full-fledged one. Finley had a hunch that the process was controlled by an enzyme called UBE2O, which he and colleagues identified in the 1990s. The enzyme marks cell parts for destruction by tagging them with a small protein called ubiquitin. This tagging allows the proteasome to recognize cells destined for destruction. The vast machinery, known as the ubiquitin-proteasome system (UPS), is switched on constantly throughout the body to remove unnecessary proteins and keep cells free of clutter. Previously, UPS had not been linked to the specialization of red blood cells. However, in his early research on UBE2O, Finley had noticed large amounts of the enzyme present in immature red blood cells. That was a powerful clue. The combination of UBE2O’s pronounced presence and its known function as cellular debris-remover made it a promising candidate for the role of a key regulator of cell specialization. Yet, back when he first came to this realization, Finley had neither the technology nor the funding to analyse red blood cell development at the necessary molecular detail. "It was the fish that got away," he said. Twenty years later, the pieces Finley needed to reopen his abandoned investigation fell into place when he met Mark Fleming, HMS professor of pathology at Boston Children’s Hospital. While studying blood cells, Fleming had identified a mutant mouse that lacked the UBE2O enzyme. Knowing that Finley was interested in the enzyme and its possible role in cell specialization, Fleming contacted him. The researchers observed that mice without the enzyme were anaemic, a marker of red blood cell deficiency. The observation supported the notion that UBE2O may play a role in red blood cell development. Using a series of tests that relied on large-scale protein analyses not available in earlier decades, the researchers confirmed the enzyme’s role. Their results revealed that immature red blood cells lacking UBE2O retained hundreds of proteins and failed to become specialized. The researchers also demonstrated that when isolated from immature red blood cells and tested in other cell types, UBE2O still marked the right proteins for destruction, suggesting that the enzyme is the primary regulator of red blood cell specialization. The researchers have yet to determine whether the mechanism they found in red blood cells controls specialization of other cells as well. Finley says it probably does. "I think our work calls attention to the complicated processes behind the development of specialized cells, which is seen throughout nature," Finley said. Because the enzyme plays an important role in the development of red blood cells, the researchers say they hope their work could lead to therapies for certain blood disorders and blood cancers. The present study revealed that, in mice, UBE2O deficiency powerfully suppressed the symptoms of a blood disorder known as beta thalassemia. This aspect of the research is particularly tantalizing to Nguyen, who has a gene mutation linked to the condition.
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Siemens Healthineers has entered into a definitive agreement to acquire Epocal Inc., a subsidiary of Alere Inc. Epocal Inc. develops and provides point-of-care blood diagnostic systems for healthcare enterprises, including the epoc Blood Analysis System, a handheld, wireless testing solution. Financial details of the transaction are not being disclosed. The transaction is subject to the completion of Abbott’s acquisition of Alere, as well as antitrust approvals and other customary closing conditions. “We want to help our customers innovate care delivery. As one of the market leaders in blood gas, the acquisition of the epoc product line will enable us to provide the right solution in the right setting, all from one partner,” said Peter Koerte, President, Point of Care Diagnostics, Siemens Healthineers. “The epoc product line will seamlessly integrate with our digital ecosystem offering customers the broadest solution available in the market. The acquisition complements our existing offerings in the point of care diagnostics space, with a view to provide customers globally with a full range of blood gas solutions.” Healthcare systems continue to look for ways to elevate patient experience and satisfaction as well as the quality of care. It is a strategic goal of Siemens Healthineers to support healthcare providers worldwide to meet their challenges and excel in their respective environments. Health networks may have varying testing needs near to their patients at the point of care in physician’s offices, clinics, emergency departments and labs. With a complete offering for blood gas diagnostics from a low-volume, single-use handheld device up to a high-volume, multi-use benchtop solution, Siemens Healthineers can help customers improve their workflows and utilize the correct system for the needs of their particular settings. Arterial blood gases are an important routine investigation to monitor the acid-base balance of patients. They play an important role in the work-up and management of critically ill patients and may help in diagnosing pulmonary and metabolic disorders. They indicate the severity of a condition and help to assess treatment. Blood gas test systems are an important component in critical care settings such as hospitals, clinics, emergency departments and pulmonary laboratories. The epoc Blood Analysis System is a handheld, wireless testing solution that provides blood gas, electrolyte and metabolite results near the patient in approximately 30 seconds after sample introduction. The epoc Blood Analysis System is comprised of the epoc room-temperature stable BGEM test card, epoc reader and epoc host2 mobile computer. Each single-use epoc BGEM test card features smartcard technology with a full menu of tests on one card.
www.siemens.com/healthineers
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EKF Diagnostics, the global in vitro diagnostics company, has published a guide to ‘Diabetes and HbA1c testing’ which can be found at EKF’s new Diabetes Portal (www.ekfdiagnostics.com/diabetes-portal.html). This new educational guide draws on EKF’s expertise in the diagnosis and monitoring of diabetes and associated conditions. It provides an overview of the global diabetes ‘epidemic’, symptoms and complications, through to discussion on methods for diagnosis and monitoring using both glucose and HbA1c testing, with consideration given to factors influencing their measurement. Diabetes is a growing issue, particularly in developing countries, with five million people dying from diabetes related complications in 2015 alone. Although not an ‘epidemic’ in the conventional sense, there are currently 415 million people living with diabetes and this is predicted to grow to 642 million by 2040. Approximately 46% of people living with diabetes are doing so without a full and proper diagnosis with subsequent complications, and associated healthcare costs. There are multiple options for the diagnosis of diabetes, most of which involve measuring the level of glycemic control a person exhibits. In addition to methods such as fasting plasma glucose and two-hour plasma glucose, another option is to use glycated hemoglobin (HbA1c) which reflects average plasma glucose over an 8-12 week period. As well as lab-based testing, WHO has approved HbA1c for diabetes diagnosis with a Point of-Care-Testing (POCT) device, providing the test is undertaken by a trained professional adhering to an appropriate External Quality Assurance scheme and using a methodology traceable to the IFCC reference method. POCT HbA1c testing gives a strong indication of both diabetes and pre-diabetes within a timeframe that enables immediate intervention. Since it is not impacted by the same issues as blood glucose monitoring, HbA1c testing is fast becoming the preferred technique for diabetes and pre-diabetes diagnosis and monitoring. There are situations where use of HbA1c is not appropriate though. EKF’s new Guide includes discussion on both glucose and HbA1c testing and where factors may influence measurement of both diagnostic markers. “The often ‘low to no’ maintenance approach to disease management of diabetes is not only dangerous but can also significantly contribute to ongoing healthcare costs. At present, approximately 12% of global health expenditure is spent on diabetes, and without significant changes to the way patients and health systems monitor glycemic control this will surely rise,” said Gavin Jones, Global Product Manager for Diabetes Care at EKF Diagnostics. “To enhance patient outcomes and reduce the cost for long-term healthcare of the diabetic and pre-diabetic population, we aim to improve patient access to diabetes care techniques, whatever their location. This can be achieved by providing affordable, easy-to-use POCT analysers and chemistry assays for both diabetes diagnosis and monitoring.” EKF’s expertise and product range cover all aspects of diabetes care, from research and hospital laboratories to diabetes clinics, emergency rooms and GP surgeries. Products include the Biosen C-Line glucose analyser, which uses chip sensor technology to provide low cost, fast and lab accurate glucose results. Quo-Test and Quo-Lab point-of-care HbA1c analysers that deliver results meeting NGSP and IFCC POC requirements in four minutes. And lastly, to aid the diagnosis and monitoring of diabetes related conditions such as ketoacidosis, EKF offers Beta-Hydroxybutyrate LiquiColor Reagent and the handheld STAT-Site M β-HB strip-based analyser.
www.ekfdiagnostics.com
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An extensive exercise to map genetic variation in Sweden has found 33 million genetic variants, 10 million of which were previously unknown. Large-scale DNA sequencing methods were used to analyse the whole genome of 1,000 individuals from different parts of the country. The study was led by researchers at Uppsala University. “This resource will benefit many national research projects investigating the association between genetic variants and diseases,” says Professor Ulf Gyllensten, Uppsala University and SciLifeLab, who has led the project. The data will also be of immediate use in clinical diagnostics to determine whether a genetic variation in a patient is a cause of disease, or if it is also present among healthy individuals in the population. “Our study shows the presence of millions of previously unidentified genetic variants in Sweden, the majority of which occur at low frequency in the population. It is crucial to identify these low frequency variants to facilitate the diagnosis of genetic diseases,” says Adam Ameur, bioinformatician at Uppsala University and SciLifeLab, who has been responsible for the data analyses. Several groups at SciLifeLab have been involved in the sequencing of the 1,000 DNA samples and in the development of data analysis methods. Very large amounts of data have been generated, over 100 terabytes for the entire project. Integrity and data security have been a high priority since the DNA sequences contain sensitive and personal information about the individuals. “The resource is freely available, which enables researchers to quickly investigate genetic variant frequencies among the 1,000 Swedish individuals. However, a special request must be approved for access to data on individuals, and all processing must be performed within a custom-built computer system with extra high security,” says Gyllensten. This work is part of SciLifeLab’s national project initiative in genomics, which has been made possible by grants from the Knut and Alice Wallenberg Foundation. The variant frequency data is available from swefreq.nbis.se.
Uppsala University www.uu.se/en/media/news/article/?id=9160&area=2,4,10,16,24&typ=artikel&lang=en
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Yale experts and their partners in a national research consortium have identified several genes and gene clusters associated with the immune response to influenza (“flu”) vaccination. The findings point to the prospect of using genetic profiles to predict individual responses to the flu vaccine. The global impact of influenza is substantial, with seasonal epidemics estimated to result in 3-5 million cases of severe illness, and 250,000 to 500,000 deaths annually worldwide. Vaccination is the best way to protect against flu infection, but the composition of the seasonal vaccine changes from year to year. Moreover, effectiveness of the vaccine varies widely among individuals. Previous studies, including a study done at Yale, have sought to identify changes in gene expression associated with successful flu vaccination but focused on relatively small numbers of participants. The new study included six different cohorts receiving the flu vaccine from across the country; research centres included Yale, the Baylor Research Institute, Emory University, the Mayo Clinic, and the National Institutes of Health. The size of the cohort — more than 500 individuals — allowed researchers to not only identify genes and gene clusters associated with vaccine response, but also confirm these findings in an independent cohort of participants. Analysing the data, the research team identified several gene “signatures,” or groups of genes, that were associated with a stronger response to the flu vaccine. The response was determined by increases in antibodies that protect against infection. We “were able to identify genes at baseline, before vaccination, that would predict how individuals would respond to the vaccine,” said Ruth Montgomery, associate professor of medicine at Yale School of Medicine and a co-author. The researchers also found that the while the genes were predictive of a robust vaccine response in adults younger than age 35, those same genes did not improve responses in adults over age 60. “Another finding is that genes that contribute to good immune response are different in young and older people,” Montgomery noted. “Surprisingly, we found that baseline differences, both at the gene and module level, were inversely correlated between young and older participants,” added Steven Kleinstein, associate professor of pathology at Yale School of Medicine and a corresponding author on the study. The reasons for these age differences warrant further study, said the researchers. The findings offer new insights into the biology of vaccine response. They may also help investigators predict responses in individuals and develop strategies to improve vaccines, or treatments to boost the immune system’s response to vaccination, the researchers noted.
Yale University news.yale.edu/2017/08/25/study-identifies-genes-linked-better-immune-response-flu-vaccine
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In a study of nearly 9,000 people treated for solid tumour cancers, researchers found that radiation treatment and tobacco use were linked to higher rates of blood-based DNA mutations that could lead to higher risk for blood cancers like leukaemia. The study revealed new risk factors for “clonal haematopoiesis,” a medical phenomenon in which genetic mutations are found in the blood cells of patients who do not have an existing blood cancer. Twenty-five percent of the patients in the study had clonal haematopoiesis. Of the subset of patients they actively followed, those with clonal haematopoiesis had a small – 1 percent – but increased, estimated incidence of developing blood cancer later on. “The presence of clonal haematopoiesis can lead to an increased risk for subsequent blood cancers,” said UNC Lineberger’s Catherine Coombs, MD. “We wouldn’t recommend forgoing treatment that is medically indicated because the risk of a secondary cancer is relatively low, but it is important to closely watch those patients who are high-risk.” The study analysed genetic changes from 8,810 MSK cancer patients. The researchers found clonal haematopoiesis in 25 percent of patients, with the highest incidence in patients with thyroid cancer, and the lowest in patients with germ cell tumours. Mutations were more common in older people, with the odds of clonal haematopoiesis increasing 6 percent for each decade above age 30. Clonal haematopoiesis was also strongly associated with current or former tobacco use. “A major risk factor for developing clonal haematopoiesis that can be modified or changed is tobacco use," Coombs said. They also found a higher frequency of patients with clonal haematopoiesis who had received radiation therapy. Forty-one percent of patients with clonal haematopoiesis received radiation, compared to 35 percent of patients who did not have clonal haematopoiesis, and had received radiation. Risk for developing a secondary blood cancer was very small in the patient population overall. Only 19 out of the 5,394 patients the researchers actively followed developed a new blood cancer within 18 months. However, for patients who did get a blood cancer, the risk was higher for patients who had clonal haematopoiesis. One percent of patients with clonal haematopoiesis were estimated to develop a secondary cancer, which was three times higher than the estimated 0.3 percent for patients who developed blood cancer and did not have clonal haematopoiesis. “This has been borne out by other groups: if you have these clonal haematopoiesis mutations, you have a greater risk for developing hematologic cancer than do patients who don’t have them,” she said.
UNC School of Medicine news.unchealthcare.org/news/2017/august/researchers-find-genetic-precursors-of-leukemia-in-patients-treated-for-non-blood-cancers
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Parkinson’s disease is an insidious disease: by the time it manifests as the typical motor dysfunctions such as tremors or muscle rigidity, portions of the brain have already been irreversibly destroyed. By this stage, the disease will have often begun already decades earlier. In search of an early portent of the disease, researchers led by Prof. Paul Wilmes, head of the Eco-Systems Biology Group at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg, may now have found one in the gut: they have shown that the bacterial community in the gut of Parkinson’s patients differs from that of healthy people even at a very early stage of the disease. Experts have long been discussing the notion that Parkinson’s disease originates far outside the brain. According to the "dual hit" hypothesis, a hitherto unknown pathogen intrudes into the body through two ports of entry: the nose or the gastrointestinal tract. Once there, it sets a pathological process in motion, above all the misfolding of the protein alpha-synuclein. This is a protein whose exact function remains unknown. Among other things, it is presumed to be involved in the excretion of messengers such as dopamine. The misfolding of this protein could propagate through the nerve pathways, where – decades later – it produces the typical clumping in the dopaminergic cells, known as Lewy bodies, that are characteristic of Parkinson’s. Ultimately, nerve cells start to die off and the typical symptoms of Parkinson’s disease appear. The researchers led by Wilmes, together with physicians Prof. Brit Mollenhauer and Prof. Wolfgang Oertel and their teams in Göttingen, Kassel and Marburg, explored the question of whether the early events in the course of the disease also change the bacterial community, the microbiome, at the two possible ports of entry. They took samples from the nose and gut of 76 Parkinson’s patients and 78 healthy control people who are taking part in a long-term study. They also examined the microbiome of 21 subjects diagnosed with iRBD, Idiopathic Rapid-Eye-Movement Sleep Behaviour Disorder. People with this sleep disorder have a greatly elevated risk of developing Parkinson’s disease later in life. It turned out that the bacterial community of the gut differed considerably between all three groups. "Parkinson’s patients could be differentiated from healthy controls by their respective gut bacteria," explains the first author Dr. Anna Heintz-Buschart from the Eco-Systems Biology Group. And the majority of the differential bacteria showed similar trends in the iRBD group. For example, certain germs were more prevalent in one group while the count was lower in others. In the samples from the subjects’ nasal cavities, however, the researchers found no such differences. The study also revealed that certain gut microbes are associated with non-motor Parkinson’s symptoms, for example depression. "We hope that, by comparing the groups, we will learn to better understand the role of the microbiome in the process of the disease and to find out what changes occur and when," Paul Wilmes explains. "This might deliver new starting points for early treatment of the disease. It would also be essential knowledge for one day being able to use the absence or presence of certain bacteria as a biomarker for early detection of the disease."
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Precision medicine opens the door to scientific wellness preventive approaches to suicide
, /in E-News /by 3wmediaResearchers have developed a more precise way of diagnosing suicide risk, by developing blood tests that work in everybody, as well as more personalized blood tests for different subtypes of suicidality that they have newly identified, and for different psychiatric high-risk groups.
The research team, led by scientists at Indiana University School of Medicine, also showed how two apps, one based on a suicide risk checklist and the other on a scale for measuring feelings of anxiety and depression, work along with the blood tests to enhance the precision of tests and to suggest lifestyle, psychotherapeutic and other interventions. Lastly, they identified a series of medications and natural substances that could be developed for preventing suicide.
"Our work provides a basis for precision medicine and scientific wellness preventive approaches," said Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience at IU School of Medicine and attending psychiatrist and research and development investigator at the Richard L. Roudebush Veterans Affairs Medical Center.
The research builds on earlier studies from the Niculescu group.
"Suicide strikes people in all walks of life. We believe such tragedies can be averted. This landmark larger study breaks new ground, as well as reproduces in larger numbers of individuals some of our earlier findings,” said Dr. Niculescu.
There were multiple steps to the research, starting with serial blood tests taken from 66 people who had been diagnosed with psychiatric disorders, followed over time, and who had at least one instance in which they reported a significant change in their level of suicidal thinking from one testing visit to the next. The candidate gene expression biomarkers that best tracked suicidality in each individual and across individuals were then prioritized using the Niculescu group’s Convergent Functional Genomics approach, based on all the prior evidence in the field.
Next, working with the Marion County (Indianapolis, Ind.) Coroner’s Office, the researchers tested the validity of the biomarkers using blood samples drawn from 45 people who had committed suicide.
The biomarkers were then tested in another larger, completely independent group of individuals to determine how well they could predict which of them would report intense suicidal thoughts or would be hospitalized for suicide attempts.
The biomarkers identified by the research are RNA molecules whose levels in the blood changed in concert with changes in the levels of suicidal thoughts experienced by the patients. Among the findings reported in the current paper were:
Indiana University School of Medicine
news.medicine.iu.edu/releases/2017/08/precision-medicine-opens-door-scientific-wellness-preventive-approaches-suicide.shtml
GIST tumours linked to NF1 mutations
, /in E-News /by 3wmediaResearchers at UC San Diego Moores Cancer Center, with colleagues from Memorial Sloan Kettering Cancer Center and Fox Chase Cancer Center, have determined that a specific region of the small bowel, called the duodenal-jejunal flexure or DJF, shows a high frequency of gastrointestinal stromal tumours (GISTs) with mutations of the NF1 gene.
The small bowel, where approximately 30 percent of all GISTs occur, is divided into three anatomically, histologically and functionally distinct segments: the duodenum, jejunum and ileum. Most small bowel GISTs are associated with KIT mutations. However, a subset of GISTs have mutations in other genes, such as NF1.
“Where the duodenum transitions into the jejunum, we are finding an over-representation of NF1-mutated GIST,” said Jason Sicklick, MD, surgical oncologist at Moores Cancer Center.
NF1 can be mutated both somatically (within tumour DNA) or in the germline (part of the hereditary condition called Neurofibromatosis type 1 [NF-1]). Patients with NF-1 are 34 times more likely to develop GIST than unaffected individuals.
“Genomic testing for some of these patients revealed occult germline NF1 mutations with no other obvious clinical symptoms of NF-1,” said Sicklick. “Anyone with a GIST should undergo tumour genetic testing. Currently only 8 to 15 percent of patients get tested. For those patients with NF1 mutations, there are implications for family members of patients who test positive for hereditary NF-1, as they also may be at increased risk of developing cancers, including GIST.”
According to the National Institutes of Health, NF-1 is a condition characterized by changes in skin colouring and the growth of tumours along nerves in the skin, brain and other parts of the body, such as the GI tract. The signs and symptoms of this condition vary widely among affected persons. NF-1 occurs in one in 3,000 to 4,000 individuals worldwide.
GIST represents the most common type of sarcoma in the GI tract, with an annual incidence of 6.8 cases per million people in the United States. These tumours start in special cells in the wall of the GI tract, called the interstitial cells of Cajal (ICCs). ICCs are sometimes dubbed the “pacemakers” of the GI tract because they signal the muscles in the digestive system to contract through peristalsis, moving food and liquid through the system.
Sicklick and colleagues at Moores Cancer Center are searching for a personalized approach to GIST tumours that become progressively resistant to treatment. Ultimately, more than 95 percent of patients with drug-resistant GIST succumb to their cancer, highlighting the necessity for alternative therapeutic targets.
“Patients with GIST should have their tumours profiled with next-generation sequencing panels,” said first author Adam Burgoyne, MD, PhD, medical oncologist at Moores Cancer Center. “We are uncovering a subset of patients, including patients with mutations of KIT, who have downstream mutations that may render them insensitive to conventional targeted therapy.”
Sicklick added: “This insight helps physicians to know which drugs will or won’t work in order to properly treat these deadly tumors. Of critical importance in NF1 mutant GIST, standard-of-care drug regimens aren’t effective.”
Sicklick’s recent GIST research has also identified new gene fusions and mutations associated with subsets of GIST patients. He and his team also provided the first evidence that the Hedgehog signalling pathway is central to the formation of GIST, which are frequently driven by the KIT oncogene.
Moores Cancer Center
health.ucsd.edu/news/releases/Pages/2017-08-18-GIST-tumors-linked-NF1-mutations-genetic-testing-needed.aspx
Scientists identify gene that controls immune response to chronic viral infections
, /in E-News /by 3wmediaFor nearly 20 years, Tatyana Golovkina, PhD, a microbiologist, geneticist and immunologist at the University of Chicago, has been working on a particularly thorny problem: Why are some people and animals able to fend off persistent viral infections while others can’t?
Mice from a strain called I/LnJ are especially good at this. They can control infection with retroviruses from very different families by producing specific antibodies that coat viruses and render them innocuous.
Golovkina, a Professor of Microbiology, was interested in what makes these mice special, so she began searching for the genes responsible for their remarkable immune response. In a new study she and her colleagues identify this gene. They also began to uncover more clues how it might work to control anti-virus immune responses.
Using a process called positional cloning, in which researchers progressively narrow down the location of a gene on the chromosome, they pinpointed it within the major histocompatibility complex (MHC) locus. The MHC locus is a well-known region of the genome involved with the immune system so it makes sense that the gene was located there, but this was a disconcerting discovery.
“It was a bummer at first because there are tons of genes within the MHC locus all controlling immune response, not only against viruses, but also many other microbial pathogens and non-microbial disorders,” she said. “Most of the time when people map a gene to the MHC they give up and stop there, with an assumption that the gene encodes for one of the two major MHC molecules, MHC class I or and MHC class II.”
But with the help of a biochemist, Lisa Denzin from Rutgers University, and a computational biologist, Aly Khan from the Toyota Technological Institute at Chicago, Golovkina and her team identified a gene called H2-Ob that enables this resistance. Together with another gene called H2-Oa, it makes a molecule called H2-O in mice and HLA-DO in humans.
H2-O has been known for years as a negative regulator of the MHC class II immune response, meaning that it shuts down the immune response. Most researchers thought it was there to prevent autoimmune responses, which attack the body’s own tissues. But in this case, none of the I/LnJ mice showed signs of autoimmunity, so H2-O must have another purpose.
Golovkina and her team discovered another interesting thing when they crossed I/LnJ mice that were resistant to infections with ones that were more susceptible. The resultant F1 mice were susceptible to infection. This indicated that the I/LnJ H2-Ob gene was recessive; both parents had to have a copy of the mutated gene to pass it on their offspring, and the product of the gene should be a non-functional protein.
“That was really surprising,” Golovkina said. “Almost all pathogen-resistant mechanisms discovered so far are dominant, meaning that something needs to be gained to resist.”
The immune system response to a virus in susceptible mice lasts three to four weeks, then the H2-O molecule tells it to stop. But the I/LnJ mice, which respond vigorously to infections, have a mutation on H2-Ob that makes it inactive. So, after they launch an immune response, it never shuts off. This keeps persistent retroviruses in check.
Golovkina hypothesizes that while letting the immune response keep running may keep chronic infections in check, such as retroviruses or hepatitis B and C, other pathogens like tuberculosis can take advantage of a persistent immune response because they can get access to certain cells when they’re coated with antibodies (and I/LnJ mice happen to be susceptible to TB and produced anti-TB antibodies).
At some point during the evolution of these genes, it was more advantageous to be able to switch off the immune response to some infections (such as intracellular bacterial pathogens), but it came at the cost of not being able to fight other long-term infections.
Now that her team has identified the gene underlying anti-retrovirus and potentially anti-hepatitis B and C responses, Golovkina says that further research should be done to create genetic therapies to manipulate the function of this gene, or develop molecules that could interfere with the function of H2-O to allow the virus-specific response in chronically infected people.
University of Chicago Medicine
sciencelife.uchospitals.edu/2017/08/15/scientists-identify-gene-that-controls-immune-response-to-chronic-viral-infections/
Make way for haemoglobin
, /in E-News /by 3wmediaEvery cell in the body, whether skin or muscle or brain, starts out as a generic cell that acquires its unique characteristics after undergoing a process of specialization. Nowhere is this process more dramatic than it is in red blood cells.
In order to make as much room as possible for the oxygen-carrying protein haemoglobin, pretty much everything else inside these precursor red blood cells–nucleus, mitochondria, ribosomes and more–gets purged. Jam-packing red blood cells with haemoglobin is essential. Doing so ensures that all the body’s tissues and organs are well nourished with oxygen to carry on their normal functions.
But how does this cell remodelling take place to begin with?
For more than 20 years, Daniel Finley, professor of cell biology at Harvard Medical School, has been on a quest to unravel the process behind this profound cellular transformation.
Now, thanks to advances in technology and a fortuitous meeting with researchers in a lab at Boston Children’s Hospital, Finley and his collaborators have identified the mechanism behind red blood cell specialization and revealed that it is controlled by an enzyme he first studied in 1995.
During cell specialization, unwanted parts of a generic, immature cell are removed by the proteasome, protein-gobbling strings of molecules, or the cells’ "trash compactors," says study first author Anthony Tuan Nguyen, an HMS MD-PhD student.
The researchers set out to find the mechanism that controls which parts get destroyed and which parts are spared before the precursor red blood cell becomes a full-fledged one.
Finley had a hunch that the process was controlled by an enzyme called UBE2O, which he and colleagues identified in the 1990s. The enzyme marks cell parts for destruction by tagging them with a small protein called ubiquitin. This tagging allows the proteasome to recognize cells destined for destruction. The vast machinery, known as the ubiquitin-proteasome system (UPS), is switched on constantly throughout the body to remove unnecessary proteins and keep cells free of clutter.
Previously, UPS had not been linked to the specialization of red blood cells. However, in his early research on UBE2O, Finley had noticed large amounts of the enzyme present in immature red blood cells. That was a powerful clue. The combination of UBE2O’s pronounced presence and its known function as cellular debris-remover made it a promising candidate for the role of a key regulator of cell specialization. Yet, back when he first came to this realization, Finley had neither the technology nor the funding to analyse red blood cell development at the necessary molecular detail.
"It was the fish that got away," he said.
Twenty years later, the pieces Finley needed to reopen his abandoned investigation fell into place when he met Mark Fleming, HMS professor of pathology at Boston Children’s Hospital. While studying blood cells, Fleming had identified a mutant mouse that lacked the UBE2O enzyme. Knowing that Finley was interested in the enzyme and its possible role in cell specialization, Fleming contacted him.
The researchers observed that mice without the enzyme were anaemic, a marker of red blood cell deficiency. The observation supported the notion that UBE2O may play a role in red blood cell development.
Using a series of tests that relied on large-scale protein analyses not available in earlier decades, the researchers confirmed the enzyme’s role. Their results revealed that immature red blood cells lacking UBE2O retained hundreds of proteins and failed to become specialized.
The researchers also demonstrated that when isolated from immature red blood cells and tested in other cell types, UBE2O still marked the right proteins for destruction, suggesting that the enzyme is the primary regulator of red blood cell specialization.
The researchers have yet to determine whether the mechanism they found in red blood cells controls specialization of other cells as well. Finley says it probably does.
"I think our work calls attention to the complicated processes behind the development of specialized cells, which is seen throughout nature," Finley said.
Because the enzyme plays an important role in the development of red blood cells, the researchers say they hope their work could lead to therapies for certain blood disorders and blood cancers. The present study revealed that, in mice, UBE2O deficiency powerfully suppressed the symptoms of a blood disorder known as beta thalassemia. This aspect of the research is particularly tantalizing to Nguyen, who has a gene mutation linked to the condition.
EurekAlert
www.eurekalert.org/pub_releases/2017-08/hms-mwf081817.php
Siemens Healthineers to acquire Epocal from Alere to complete its blood gas portfolio
, /in E-News /by 3wmediaSiemens Healthineers has entered into a definitive agreement to acquire Epocal Inc., a subsidiary of Alere Inc. Epocal Inc. develops and provides point-of-care blood diagnostic systems for healthcare enterprises, including the epoc Blood Analysis System, a handheld, wireless testing solution. Financial details of the transaction are not being disclosed. The transaction is subject to the completion of Abbott’s acquisition of Alere, as well as antitrust approvals and other customary closing conditions.
“We want to help our customers innovate care delivery. As one of the market leaders in blood gas, the acquisition of the epoc product line will enable us to provide the right solution in the right setting, all from one partner,” said Peter Koerte, President, Point of Care Diagnostics, Siemens Healthineers. “The epoc product line will seamlessly integrate with our digital ecosystem offering customers the broadest solution available in the market. The acquisition complements our existing offerings in the point of care diagnostics space, with a view to provide customers globally with a full range of blood gas solutions.”
Healthcare systems continue to look for ways to elevate patient experience and satisfaction as well as the quality of care. It is a strategic goal of Siemens Healthineers to support healthcare providers worldwide to meet their challenges and excel in their respective environments. Health networks may have varying testing needs near to their patients at the point of care in physician’s offices, clinics, emergency departments and labs. With a complete offering for blood gas diagnostics from a low-volume, single-use handheld device up to a high-volume, multi-use benchtop solution, Siemens Healthineers can help customers improve their workflows and utilize the correct system for the needs of their particular settings.
Arterial blood gases are an important routine investigation to monitor the acid-base balance of patients. They play an important role in the work-up and management of critically ill patients and may help in diagnosing pulmonary and metabolic disorders. They indicate the severity of a condition and help to assess treatment. Blood gas test systems are an important component in critical care settings such as hospitals, clinics, emergency departments and pulmonary laboratories.
The epoc Blood Analysis System is a handheld, wireless testing solution that provides blood gas, electrolyte and metabolite results near the patient in approximately 30 seconds after sample introduction. The epoc Blood Analysis System is comprised of the epoc room-temperature stable BGEM test card, epoc reader and epoc host2 mobile computer. Each single-use epoc BGEM test card features smartcard technology with a full menu of tests on one card.
www.siemens.com/healthineers
EKF Diagnostics publishes ‘Diabetes and HbA1c testing’ guide
, /in E-News /by 3wmediaEKF Diagnostics, the global in vitro diagnostics company, has published a guide to ‘Diabetes and HbA1c testing’ which can be found at EKF’s new Diabetes Portal (www.ekfdiagnostics.com/diabetes-portal.html). This new educational guide draws on EKF’s expertise in the diagnosis and monitoring of diabetes and associated conditions. It provides an overview of the global diabetes ‘epidemic’, symptoms and complications, through to discussion on methods for diagnosis and monitoring using both glucose and HbA1c testing, with consideration given to factors influencing their measurement.
Diabetes is a growing issue, particularly in developing countries, with five million people dying from diabetes related complications in 2015 alone. Although not an ‘epidemic’ in the conventional sense, there are currently 415 million people living with diabetes and this is predicted to grow to 642 million by 2040. Approximately 46% of people living with diabetes are doing so without a full and proper diagnosis with subsequent complications, and associated healthcare costs.
There are multiple options for the diagnosis of diabetes, most of which involve measuring the level of glycemic control a person exhibits. In addition to methods such as fasting plasma glucose and two-hour plasma glucose, another option is to use glycated hemoglobin (HbA1c) which reflects average plasma glucose over an 8-12 week period. As well as lab-based testing, WHO has approved HbA1c for diabetes diagnosis with a Point of-Care-Testing (POCT) device, providing the test is undertaken by a trained professional adhering to an appropriate External Quality Assurance scheme and using a methodology traceable to the IFCC reference method. POCT HbA1c testing gives a strong indication of both diabetes and pre-diabetes within a timeframe that enables immediate intervention.
Since it is not impacted by the same issues as blood glucose monitoring, HbA1c testing is fast becoming the preferred technique for diabetes and pre-diabetes diagnosis and monitoring. There are situations where use of HbA1c is not appropriate though. EKF’s new Guide includes discussion on both glucose and HbA1c testing and where factors may influence measurement of both diagnostic markers.
“The often ‘low to no’ maintenance approach to disease management of diabetes is not only dangerous but can also significantly contribute to ongoing healthcare costs. At present, approximately 12% of global health expenditure is spent on diabetes, and without significant changes to the way patients and health systems monitor glycemic control this will surely rise,” said Gavin Jones, Global Product Manager for Diabetes Care at EKF Diagnostics. “To enhance patient outcomes and reduce the cost for long-term healthcare of the diabetic and pre-diabetic population, we aim to improve patient access to diabetes care techniques, whatever their location. This can be achieved by providing affordable, easy-to-use POCT analysers and chemistry assays for both diabetes diagnosis and monitoring.”
EKF’s expertise and product range cover all aspects of diabetes care, from research and hospital laboratories to diabetes clinics, emergency rooms and GP surgeries. Products include the Biosen C-Line glucose analyser, which uses chip sensor technology to provide low cost, fast and lab accurate glucose results. Quo-Test and Quo-Lab point-of-care HbA1c analysers that deliver results meeting NGSP and IFCC POC requirements in four minutes. And lastly, to aid the diagnosis and monitoring of diabetes related conditions such as ketoacidosis, EKF offers Beta-Hydroxybutyrate LiquiColor Reagent and the handheld STAT-Site M β-HB strip-based analyser.
www.ekfdiagnostics.com
Millions of uncommon genetic variants found in Swedish study
, /in E-News /by 3wmediaAn extensive exercise to map genetic variation in Sweden has found 33 million genetic variants, 10 million of which were previously unknown. Large-scale DNA sequencing methods were used to analyse the whole genome of 1,000 individuals from different parts of the country. The study was led by researchers at Uppsala University.
“This resource will benefit many national research projects investigating the association between genetic variants and diseases,” says Professor Ulf Gyllensten, Uppsala University and SciLifeLab, who has led the project.
The data will also be of immediate use in clinical diagnostics to determine whether a genetic variation in a patient is a cause of disease, or if it is also present among healthy individuals in the population.
“Our study shows the presence of millions of previously unidentified genetic variants in Sweden, the majority of which occur at low frequency in the population. It is crucial to identify these low frequency variants to facilitate the diagnosis of genetic diseases,” says Adam Ameur, bioinformatician at Uppsala University and SciLifeLab, who has been responsible for the data analyses.
Several groups at SciLifeLab have been involved in the sequencing of the 1,000 DNA samples and in the development of data analysis methods. Very large amounts of data have been generated, over 100 terabytes for the entire project. Integrity and data security have been a high priority since the DNA sequences contain sensitive and personal information about the individuals.
“The resource is freely available, which enables researchers to quickly investigate genetic variant frequencies among the 1,000 Swedish individuals. However, a special request must be approved for access to data on individuals, and all processing must be performed within a custom-built computer system with extra high security,” says Gyllensten.
This work is part of SciLifeLab’s national project initiative in genomics, which has been made possible by grants from the Knut and Alice Wallenberg Foundation.
The variant frequency data is available from swefreq.nbis.se.
Uppsala University
www.uu.se/en/media/news/article/?id=9160&area=2,4,10,16,24&typ=artikel&lang=en
Study identifies genes linked to better immune response to flu vaccine
, /in E-News /by 3wmediaYale experts and their partners in a national research consortium have identified several genes and gene clusters associated with the immune response to influenza (“flu”) vaccination. The findings point to the prospect of using genetic profiles to predict individual responses to the flu vaccine.
The global impact of influenza is substantial, with seasonal epidemics estimated to result in 3-5 million cases of severe illness, and 250,000 to 500,000 deaths annually worldwide. Vaccination is the best way to protect against flu infection, but the composition of the seasonal vaccine changes from year to year. Moreover, effectiveness of the vaccine varies widely among individuals.
Previous studies, including a study done at Yale, have sought to identify changes in gene expression associated with successful flu vaccination but focused on relatively small numbers of participants. The new study included six different cohorts receiving the flu vaccine from across the country; research centres included Yale, the Baylor Research Institute, Emory University, the Mayo Clinic, and the National Institutes of Health. The size of the cohort — more than 500 individuals — allowed researchers to not only identify genes and gene clusters associated with vaccine response, but also confirm these findings in an independent cohort of participants.
Analysing the data, the research team identified several gene “signatures,” or groups of genes, that were associated with a stronger response to the flu vaccine. The response was determined by increases in antibodies that protect against infection.
We “were able to identify genes at baseline, before vaccination, that would predict how individuals would respond to the vaccine,” said Ruth Montgomery, associate professor of medicine at Yale School of Medicine and a co-author.
The researchers also found that the while the genes were predictive of a robust vaccine response in adults younger than age 35, those same genes did not improve responses in adults over age 60. “Another finding is that genes that contribute to good immune response are different in young and older people,” Montgomery noted.
“Surprisingly, we found that baseline differences, both at the gene and module level, were inversely correlated between young and older participants,” added Steven Kleinstein, associate professor of pathology at Yale School of Medicine and a corresponding author on the study. The reasons for these age differences warrant further study, said the researchers.
The findings offer new insights into the biology of vaccine response. They may also help investigators predict responses in individuals and develop strategies to improve vaccines, or treatments to boost the immune system’s response to vaccination, the researchers noted.
Yale University
news.yale.edu/2017/08/25/study-identifies-genes-linked-better-immune-response-flu-vaccine
Researchers find genetic precursors of leukaemia in patients treated for non-blood cancers
, /in E-News /by 3wmediaIn a study of nearly 9,000 people treated for solid tumour cancers, researchers found that radiation treatment and tobacco use were linked to higher rates of blood-based DNA mutations that could lead to higher risk for blood cancers like leukaemia.
The study revealed new risk factors for “clonal haematopoiesis,” a medical phenomenon in which genetic mutations are found in the blood cells of patients who do not have an existing blood cancer. Twenty-five percent of the patients in the study had clonal haematopoiesis. Of the subset of patients they actively followed, those with clonal haematopoiesis had a small – 1 percent – but increased, estimated incidence of developing blood cancer later on.
“The presence of clonal haematopoiesis can lead to an increased risk for subsequent blood cancers,” said UNC Lineberger’s Catherine Coombs, MD. “We wouldn’t recommend forgoing treatment that is medically indicated because the risk of a secondary cancer is relatively low, but it is important to closely watch those patients who are high-risk.”
The study analysed genetic changes from 8,810 MSK cancer patients. The researchers found clonal haematopoiesis in 25 percent of patients, with the highest incidence in patients with thyroid cancer, and the lowest in patients with germ cell tumours. Mutations were more common in older people, with the odds of clonal haematopoiesis increasing 6 percent for each decade above age 30. Clonal haematopoiesis was also strongly associated with current or former tobacco use.
“A major risk factor for developing clonal haematopoiesis that can be modified or changed is tobacco use," Coombs said.
They also found a higher frequency of patients with clonal haematopoiesis who had received radiation therapy. Forty-one percent of patients with clonal haematopoiesis received radiation, compared to 35 percent of patients who did not have clonal haematopoiesis, and had received radiation.
Risk for developing a secondary blood cancer was very small in the patient population overall. Only 19 out of the 5,394 patients the researchers actively followed developed a new blood cancer within 18 months. However, for patients who did get a blood cancer, the risk was higher for patients who had clonal haematopoiesis. One percent of patients with clonal haematopoiesis were estimated to develop a secondary cancer, which was three times higher than the estimated 0.3 percent for patients who developed blood cancer and did not have clonal haematopoiesis.
“This has been borne out by other groups: if you have these clonal haematopoiesis mutations, you have a greater risk for developing hematologic cancer than do patients who don’t have them,” she said.
UNC School of Medicine
news.unchealthcare.org/news/2017/august/researchers-find-genetic-precursors-of-leukemia-in-patients-treated-for-non-blood-cancers
Altered bacterial communities in the gut could be an indicator for Parkinson’s disease
, /in E-News /by 3wmediaParkinson’s disease is an insidious disease: by the time it manifests as the typical motor dysfunctions such as tremors or muscle rigidity, portions of the brain have already been irreversibly destroyed. By this stage, the disease will have often begun already decades earlier. In search of an early portent of the disease, researchers led by Prof. Paul Wilmes, head of the Eco-Systems Biology Group at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg, may now have found one in the gut: they have shown that the bacterial community in the gut of Parkinson’s patients differs from that of healthy people even at a very early stage of the disease.
Experts have long been discussing the notion that Parkinson’s disease originates far outside the brain. According to the "dual hit" hypothesis, a hitherto unknown pathogen intrudes into the body through two ports of entry: the nose or the gastrointestinal tract. Once there, it sets a pathological process in motion, above all the misfolding of the protein alpha-synuclein. This is a protein whose exact function remains unknown. Among other things, it is presumed to be involved in the excretion of messengers such as dopamine. The misfolding of this protein could propagate through the nerve pathways, where – decades later – it produces the typical clumping in the dopaminergic cells, known as Lewy bodies, that are characteristic of Parkinson’s. Ultimately, nerve cells start to die off and the typical symptoms of Parkinson’s disease appear.
The researchers led by Wilmes, together with physicians Prof. Brit Mollenhauer and Prof. Wolfgang Oertel and their teams in Göttingen, Kassel and Marburg, explored the question of whether the early events in the course of the disease also change the bacterial community, the microbiome, at the two possible ports of entry. They took samples from the nose and gut of 76 Parkinson’s patients and 78 healthy control people who are taking part in a long-term study. They also examined the microbiome of 21 subjects diagnosed with iRBD, Idiopathic Rapid-Eye-Movement Sleep Behaviour Disorder. People with this sleep disorder have a greatly elevated risk of developing Parkinson’s disease later in life.
It turned out that the bacterial community of the gut differed considerably between all three groups. "Parkinson’s patients could be differentiated from healthy controls by their respective gut bacteria," explains the first author Dr. Anna Heintz-Buschart from the Eco-Systems Biology Group. And the majority of the differential bacteria showed similar trends in the iRBD group. For example, certain germs were more prevalent in one group while the count was lower in others. In the samples from the subjects’ nasal cavities, however, the researchers found no such differences. The study also revealed that certain gut microbes are associated with non-motor Parkinson’s symptoms, for example depression.
"We hope that, by comparing the groups, we will learn to better understand the role of the microbiome in the process of the disease and to find out what changes occur and when," Paul Wilmes explains. "This might deliver new starting points for early treatment of the disease. It would also be essential knowledge for one day being able to use the absence or presence of certain bacteria as a biomarker for early detection of the disease."
EurekAlert
www.eurekalert.org/pub_releases/2017-08/uol-abc082917.php