Genomic makeup of colorectal cancers predicts immune system ability to fight tumours
Colorectal cancers heavily bedecked with tumour-related proteins called neoantigens are likely to be permeated with disease-fighting white blood cells, researchers at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard report in a new study. Because such an influx of white blood cells often signifies an immune system attack on cancer, the discovery will sharpen research into therapies that make tumours more vulnerable to such an attack.
The discovery was made by combining several data sets from patients in two large health-tracking studies, the Nurses’ Health Study and the Health Professionals Follow-up Study. Researchers first performed whole-exome sequencing on colorectal tumour samples from 619. This information was merged with data from tests of the immune system’s response to the tumours and with patient clinical data, including length of survival.
“We were looking for genetic features that predict how extensively a tumour is infiltrated by lymphocytes [certain white blood cells] and which types of lymphocytes are present,” said study co-lead author, Marios Giannakis, MD, PhD, medical oncologist and clinical investigator at the Dana-Farber Gastrointestinal Cancer Treatment Center, and researcher at the Broad Institute of MIT and Harvard. “We found that tumours with a high ‘neoantigen load’ – which carry large quantities of neoantigens – tended to be infiltrated by a large number of lymphocytes, including memory T cells, which provide protection against previously encountered infections and diseases. Patients whose tumours had high numbers of neoantigens also survived longer than those with lower neoantigen loads.”
Neoantigens are deviant forms of protein antigens, which are found on normal cells. Genetic mutations often cause cancer cells to produce abnormal proteins, some of which get lifted to the cell surface, where they serve as a red flag to the immune system that something is amiss with the cell.
“There can be hundreds or thousands of neoantigens on tumour cells,” Giannakis explained. “Only a few of these may actually provoke T cells to infiltrate a tumour. But the more neoantigens on display, the greater the chance that some of them will spark an immune system response.”
Therapies known as immune checkpoint inhibitors work by removing some of the barriers to an immune system attack on cancer. Although these agents have produced astonishing results in some cases, they’re generally effective only in patients whose immune system has already launched an immune response to cancer. By showing that tumours with high antigen loads are apt to be laced with T cells – and therefore to have provoked an immune response – the study may help investigators identify which patients are most likely to benefit in new clinical trials of immune checkpoint inhibitors.
The study’s genomic analysis of colorectal tumour samples also found several often-mutated genes that had not previously been strongly associated with the disease, including BCL9L, RBM10, CTCF, and KLF5. The discovery of their prevalence in colorectal cancer suggests that they may be valuable targets for new therapies.
Dana-Farber Cancer Institute
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Led by researchers at the University of Pittsburgh School of Medicine, an international panel of pathologists and clinicians has reclassified a type of thyroid cancer to reflect that it is non-invasive and has a low risk of recurrence. The name change is expected to reduce the psychological and medical consequences of a cancer diagnosis, potentially affecting thousands of people worldwide.
The incidence of thyroid cancer has been rising partly due to early detection of tumours that are indolent or non-progressing, despite the presence of certain cellular abnormalities that are traditionally considered cancerous, explained senior investigator Yuri Nikiforov, M.D., Ph.D., professor of pathology and director of Pitt’s Division of Molecular and Genomic Pathology.
“This phenomenon is known as over-diagnosis,” Dr. Nikiforov said. “To my knowledge, this is the first time in the modern era a type of cancer is being reclassified as a non-cancer. I hope that it will set an example for other expert groups to address nomenclature of various cancer types that have indolent behaviour to prevent inappropriate and costly treatment.”
University of Pittsburgh School of Medicine
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Imagine attempting to bake a cake—except you have to go to different stores for flour and milk, drive across town to get eggs and call a friend to borrow a cake pan.
This is the kind of disjointed scenario many scientists face when they attempt to gather data scattered across small databases and hard-to-search PDF files.
“It’s not that the data doesn’t exist,” said Andrew Su, associate professor at The Scripps Research Institute (TSRI). “The data just isn’t stored in a way that scientists can easily access.”
“Open data is vital for progress and research,” added TSRI Assistant Professor of Molecular and Experimental Medicine Ben Good. “We need to break down those barriers.”
To solve this problem, Su, Good and their colleagues at TSRI have integrated biomedical data into Wikidata, a public, editable database where researchers can easily link genes, proteins and more.
Technological breakthroughs in the last 10 years have led to rapid increases in the volume and rate of biomedical research, which in turn has led to a rapid growth in biomedical knowledge. However, this knowledge is currently fragmented across countless resources—from online databases to supplementary data files to individual facts in individual papers.
“As a research community, we spend a lot of time searching for good resources and trying to link them together,” said TSRI Research Associate Tim Putman, who was first author of one of the studies. “It’s cringeworthy.”
Even when databases are open to the public, current knowledge isn’t always organized in a uniform way, Putman explained.
Rather than leave each research group to tackle data integration individually, Wikidata offers a new model for organizing all this information. Built on the same principles as Wikipedia, Wikidata enables anyone to add new information to an open community database.
While other Wikidata editors have added information on millions of items as diverse as works of art to U.S. cities, the TSRI team has focused on adding information on biomedical concepts.
TSRI Research Associate Sebastian Burgstaller-Muehlbacher, first author on one study, added data on all human and mouse genes, all human diseases and all drugs approved by the U.S. Food and Drug Administration.
Putman then extended Wikidata with a focus on microbial genomes. With all this information collected in one system, researchers can more easily spot connections between diseases, pathogens and biological processes. As an example, Putman used the model to show that other microorganisms in the body can influence chlamydia infections.
As a proof of concept, Putman led the development of a genome browser based on Wikidata. Rather than having to develop one browser for every sequenced genome, this genome browser allows users to browse any genome that has been loaded into Wikidata.
“You can zoom in on a gene, click on it and the sequence will pop up,” said Good. The genome browser will then link back to the original Wikidata entry.
In the end, the researchers plan to have a comprehensive, uniform database that is easy to search and open to anyone who wants to add data and link related concepts.
“We think this data should all be open,” said Su. “This just makes intuitive sense.”
The Scripps Research Institute
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Researchers at the Perelman School of Medicine at the University of Pennsylvania and other institutions have uncovered a site of genetic variation that identified which patients with Parkinson’s disease are more likely to have tremors versus difficulty with balance and walking. The Penn team also found that patients with this genetic variation had a slower rate of Parkinson’s disease progression, and lower amounts of alpha-synuclein in the brain. Alpha-synuclein is a protein that experts know plays a role in the development of Parkinson’s disease.
Clinicians have long noted that the presence of tremors, rather than balance and walking problems, as the initial or dominant symptom of Parkinson’s may suggest slower progression of the disease. The Penn-led study is one of the first to link this difference to a specific genetic variation. Tremor-dominant patients are also less likely to develop dementia, although this symptom was not assessed in the study.
“We have never understood the reason why some people present with more tremor vs. walking/balance difficulties in Parkinson’s disease,” said the study’s lead author, Christine A. Cooper, MD, a fellow in movement disorders at Penn Medicine. “This finding gives us information, for the first time, that has implications for diagnosis, prognosis, treatment, and prevention efforts.”
In the study, the investigators ranked 251 Parkinson’s disease patients at the University of Pennsylvania Health System on tremor and balance/walking scores. They then looked at the patients’ genotypes to see if there were correlations between ten genetic variations previously associated with Parkinson’s disease and the primary symptoms that the patients displayed.
The researchers found that 39 of the 251 patients who had a genetic variation known as the GG genotype at the rs356182 SNP 3’ to the SNCA gene were more likely to have: 1) tremors rather than walking/balance problems; 2) slower physical progression of the disease; and 3) lower levels of alpha-synuclein in the brain. Patients were followed up to seven years in some cases. The investigators carried out the same type of analysis with an additional group of 559 patients at three other clinical sites in the United States and found similar results for the association between the genotype and the type of PD symptoms.
“This is how we can start thinking about precision medicine in action,” said the study’s senior author, Alice S. Chen-Plotkin, MD, an assistant professor of neurology at Penn. “We found that a relatively common genetic variation can both serve as a biomarker for and influence the disease course of Parkinson’s patients. This opens up the possibility of achieving a hallmark of precision medicine: targeted therapies for different ‘versions’ of what was once thought to be a single disease.”
University of Pennsylvania Health System
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A quick, reliable and cost-effective mobility assessment tool may help to identify elderly patients at risk for adverse post-surgery outcomes, according to Wake Forest Baptist Medical Center researchers.
In their study of 197 men and woman over age 69 who underwent elective, non-cardiac, inpatient surgery at Wake Forest Baptist over a 20-month period, the researchers found that the participants’ preoperative scores on the Mobility Assessment Tool: Short Form (MAT-sf) were predictive of early postoperative complications, longer hospital stays and discharges to nursing homes.
“Preoperative assessment of patient characteristics that may lead to adverse postoperative outcomes is important to patients, their families and their surgeons, especially with older adults, in whom complications are more likely,” said Leanne Groban, M.D., professor of anaesthesiology at Wake Forest Baptist and lead author of the study.
“Mobility is a powerful indicator of overall health in the elderly, and our results indicate that self-reported mobility, as measured by the MAT-sf, can complement existing assessment tools in determining which patients are at risk of adverse postoperative outcomes.”
The MAT-sf features animated video clips of 10 common physical activities, each followed by questions about the participant’s ability to perform the particular task. In addition to the MAT-sf, participants in the study also underwent four other commonly employed preoperative risk assessments. After controlling for factors such as the participants’ age, sex and body mass index and their scores on the other tests, the researchers found that low (poor) scores on the MAT-sf were associated with short-term complications, later time to discharge and increased nursing home placement to a greater degree than any of the other indicators.
“The traditional risk assessments may be too comprehensive, too focused on single organ systems or too impractical to be effective in this setting,” Groban said.
The next steps, she said, are to validate these findings in a larger, multi-centre study and to test whether preoperative strength and balance training might limit undesirable postoperative outcomes in older adults with mobility limitations.
“Studies such as this will help determine future clinical pathways aimed at reducing adverse outcomes while improving patients’ functionality and speeding their return to independence,” Groban said.
Wake Forest University
www.wakehealth.edu/News-Releases/2016/Mobility_Assessment_Tool_May_Help_Predict_Early_Postoperative_Outcomes_for_Older_Adults.htm
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Researchers at the University at Buffalo Research Institute on Addictions have discovered how a gene in the brain’s dopamine system can play an important role in prolonging lifespan: it must be coupled with a healthy environment that includes exercise.
The study was led by Panayotis (Peter) K. Thanos, senior research scientist at RIA.
Thanos and his team studied the genes in dopamine to assess their impact on lifespan and behaviour in mice. Dopamine is a neurotransmitter that helps control the brain’s reward and pleasure centres and helps regulate physical mobility and emotional response.
The researchers found that the dopamine D2 receptor gene (D2R) significantly influences lifespan, body weight and locomotor activity, but only when combined with an enriched environment that included social interaction, sensory and cognitive stimulation and, most critically, exercise.
“The incorporation of exercise is an important component of an enriched environment and its benefits have been shown to be a powerful mediator of brain function and behaviour,” Thanos says.
The mice in the enriched environment lived anywhere from 16 to 22 percent longer than those in a deprived environment, depending on the level of D2R expression.
“These results provide the first evidence of D2R gene-environment interaction playing an important role in longevity and aging,” Thanos says. “The dichotomy over genes versus environment has provided a rigorous and long debate in deciphering individual differences in longevity. In truth, there exists a complex interaction between the two which contribute to the differences.”
Research exploring this genetic-environmental interaction should lead to a better understanding and prediction of the potential benefits of specific environments, such as those including exercise, on longevity and health during aging.
University at Buffalo Research Institute on Addictions
www.buffalo.edu/ria/news_events/latest_news.host.html/content/shared/university/news/news-center-releases/2016/04/056.detail.html
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Researchers at UMass Medical School have identified a new molecular pathway critical for maintaining the smooth muscle tone that allows the passage of materials through the digestive system. This finding, based on studying calcium ion-controlled pathways in mice, may lead to new treatments for a host of digestive disorders ranging from common gastroesophageal reflux disease (GERD), to swallowing disorders, incontinence and pancreatitis.
“We are excited about the potential to target identified genes to treat disorders such as reflux and incontinence,” said Ronghua ZhuGe, PhD, associate professor of microbiology and physiological systems and a senior author of the study. “Knowing how these muscles stay contracted for such long periods of time will allow us to develop potential new treatments for these diseases. The next step is to see whether this molecular mechanism in mice also operates in humans.”
The human body, and those of other mammals, contains a number of ring-shaped structures made of smooth muscle encircling openings in hollow organs such as the intestines and bladder called sphincters. Smooth muscle is involuntarily controlled, unlike the muscles we use to walk, for example, so that we don’t need to consciously move digested food from stomach to small intestine. Dysfunction in the sphincters, either structurally or functionally, can have severe consequences leading to diseases that impair the ability of the muscle to contract or relax. This can lead to achalasia, which makes it difficult to swallow; gastroesophageal reflux disease (GERD), which allows stomach acid to enter the oesophagus or incontinence of the bowels.
“A healthy sphincter opens transiently but remains closed most of the time, maintaining a basal tone. This basal tone requires constant generation of force produced by the contraction of smooth muscle cells that make up the sphincters,” said Dr. ZhuGe. “However, the genetics governing how the sphincter smooth muscle stays contracted for such long periods of time remains unknown.”
Smooth muscle operates by generating force as the muscle motor protein myosin and actin filaments move past each other. This happens after a molecule called the myosin regulatory light chain (MLC) is turned on through a common molecular transformation called phosphorylation. How much phosphorylation takes place is controlled by the relative amounts of two enzymes; calcium dependent MLC kinase (MLCK), which promotes phosphorylation, and calcium independent MLC phosphatase (MLCP), which reverses phosphorylation. Through this process, contraction and relaxation of the muscle is achieved.
To understand the molecular mechanism responsible for the involuntary and continuous contraction of the sphincter muscle, Dr. ZhuGe and colleagues examined the internal anal sphincter that controls bowel continence in mice. They showed that genetic deletion of the MLCP enzyme in the smooth muscle had no effect on the basal tone of the mouse sphincter, but deletion of MLCK essentially abolishes the basal tone and mice become incontinent as a result.
“Although previous biochemical studies suggested that lower MLCP activity may be related to the basal tone of this sphincter, our genetic study indicates this doesn’t seem to be the case. It turns out MLCK is essential for the tone formation,” said ZhuGe. “This prompted us to look for specific calcium signals that regulate MLCK.”
Co-author Lawrence Lifshitz, PhD, associate professor of molecular medicine, said, “Calcium signalling is our favourite subject. We originally hypothesized that localized releases of calcium inside the cell, near target ion channels, might do the trick, as we knew that such releases can regulate the contraction of smooth muscle in blood vessels and airways.”
But experiments showed that these local calcium releases have no direct role in muscle tone. Instead, three types of ion channels act in concert to generate a rise in cytosolic calcium which eventually results in MLCK activation and muscle tone.
To test this hypothesis, ZhuGe’s group teamed up with Minsheng Zhu, PhD, at Nanjing University in China, to generate a line of mice in which one of these channels could be turned off in smooth muscle only. “These mice were a powerful tool for establishing our hypothesis,” said ZhuGe. “They helped us identify the Tmem16a (also called Ano1) gene as a critical component for basal tone formation and fecal continence. When we were able to turn off the TMEM16A channels in these mice, they lost the majority of the basal tone and became incontinent. ”
UMass Medical School
www.umassmed.edu/news/news-archives/2016/04/umms-scientists-identify-genes-that-control-smooth-muscle-contraction-in-digestive-system/
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Myopia, also known as short-sightedness or near-sightedness, is the most common disorder affecting the eyesight and it is on the increase. The causes are both genetic and environmental. The Consortium for Refractive Error and Myopia (CREAM) has now made important progress towards understanding the mechanisms behind the development of the condition. This international group of researchers includes scientists involved in the Gutenberg Health Study of the University Medical Center of Johannes Gutenberg University Mainz (JGU). The team has uncovered nine new genetic risk factors which work together with education-related behaviour as the most important environmental factor causing myopia to generate the disorder. The results of the study ‘Genome-wide joint meta-analyses of genetic main effects and interaction with education level identify additional loci for refractive error: The CREAM Consortium’ have recently been published in the scientific journal Nature Communications.
There has been a massive rise in the prevalence of short-sightedness across the globe in recent decades and this upwards trend is continuing. It is known from previous studies of twins and families that the risk of acquiring short-sightedness is determined to a large extent by heredity. However, the myopia-causing genes that had been previously identified do not alone sufficiently explain the extent to which the condition is inherited. In addition to the genetic causes of myopia there are also environmental factors, the most significant of which are education-related behaviour patterns. “We know from the Gutenberg Health Study conducted at Mainz that the number of years of education increases the risk of developing myopia,’ said Professor Norbert Pfeiffer, Director of the Department of Ophthalmology at the Mainz University Medical Center.
With the aim of identifying genetic mutations relating to myopia and acquiring better insight into the development of the condition, the international research group CREAM carried out a meta-analysis of data collected from around the world. The data compiled for this analysis originated from more than 50,000 participants who were analysed in 34 studies. The second largest group of participants was formed by the more than 4,500 subjects of the Gutenberg Health Study of the Mainz University Medical Center. ‘In the field of genetic research, international cooperation is of particular importance. This is also borne out by this study, to which we were able to make a valuable contribution in the form of data from our Gutenberg Health Study,’ continued Professor Norbert Pfeiffer. ‘And in view of the fact that a survey undertaken by the European Eye Epidemiology Consortium with the help of the Gutenberg Health Study shows that about one third of the adult population of Europe is short-sighted, it is essential that we learn more about its causes in order to come up with possible approaches for future treatments.’
Aware that environmental effects and hereditary factors reinforce one another in the development of myopia, the scientists devised a novel research concept for their investigations. They used a statistical analysis technique that takes into account both the effects of the environmental and hereditary factors and does so in equal measure and simultaneously. Their efforts were crowned with success as they were able to classify nine previously unknown genetic risk factors.
Risk-associated gene involved in the development of short-sightedness
These newly discovered genetic variants are associated with proteins which perform important functions when it comes to the transmission of signals in the eye. One of these genes is of particular interest because it plays a major role in the transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the eye. Previous studies have shown that there is greater activation of the gene in question in eyes that are myopic. The results of current research substantiate this conclusion. The CREAM researchers interpret this as evidence that this newly discovered risk-related gene is actually involved in the development of short-sightedness. This represents significant initial headway towards understanding how genetic causes interact with the level of education as an environmental factor to produce the heterogeneity of myopia. Further research will be needed to clarify the details of how the mechanisms actually work and interact with one another.
The spread of short-sightedness is a worldwide phenomenon. Particularly in South East Asia the incidence of myopia in school children has increased notably over the last decades. This is likely due to an improvement in educational attainment. People who read a great deal also perform a lot of close-up work, usually in poor levels of daylight. The eye adjusts to these visual habits and the eyeball becomes more elongated than normal as a result. But if it becomes too elongated, the cornea and lens focus the image just in front of the retina instead of on it so that distant objects appear blurry. The individual in question is then short-sighted.
Johannes Gutenberg University Mainz www.uni-mainz.de/presse/20232_ENG_HTML.php
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Abbott demonstrated a prototype of the company’s next-generation molecular diagnostics platform at a recent scientific event hosted for its customers from across the globe. At the event, molecular laboratory directors and researchers had hands-on interaction with the prototype and were able to provide additional feedback on the system prior to further stages of development.
Abbott’s new system is currently being designed from the ground up based on extensive input from laboratory customers. For example, health systems around the world are often challenged with higher testing volumes with staffing and budget constraints, including in the molecular laboratories.
“Our molecular lab customers tell us they are facing pressures to do more with less,” said John Carrino, divisional vice president, research and development, Molecular Diagnostics, Abbott. “Abbott’s next-generation molecular system is being designed to have a faster turnaround time, greater flexibility to run any test at any time, an ability to run higher volumes and automation to increase lab efficiency – all without compromising the testing performance and quality for which our organization is highly regarded.”
Additionally, customer insights suggest a need for a broad testing menu in the molecular lab. Abbott currently offers one of the broadest molecular testing menus for infectious diseases such as HIV, hepatitis and tuberculosis, as well as sexually transmitted infections such as human papillomavirus (HPV), chlamydia and gonorrhea, among others tests.
“Abbott’s molecular diagnostics can provide the information needed to help guide some of life’s most important health decisions,” said Andrea Wainer, president, Molecular Diagnostics, Abbott. “Our accurate, reliable and quality tests could allow clinicians to make more informed treatment decisions to help improve patient care.” In addition to the new molecular system, Abbott will be launching next-generation systems in blood screening, immunoassay, clinical chemistry, hematology and point of care testing in the near future. All of the systems will be built on the same software and hardware platforms to enable more automation and to simplify the user experience for Abbott’s customers.
Shimadzu has released the first Application Handbook “Clinical”. It contains most advanced technologies and solutions such as chromatography, mass spectrometry, spectroscopy and life sciences instruments. With nearly 140 pages, the Application Handbook “Clinical” covers 47 real life applications related to hot subjects such as Vitamin D, steroids, immunosuppressants, catecholamines and amino acids analysis. The book is free of charge and can be downloaded (17 MB) at www.shimadzu. eu/clinical.
In clinical applications, analytical instruments unfold a multitude of benefits. They support the quality of human life. The concentration of medications in Therapeutic Drug Monitoring (TDM) is assured, even though this may change according to age and health conditions and is dependent on gender, genetic constitution or interferences with other drugs. They help to save lives, particularly when it comes to time-critical situations, e.g. through acute intoxication, medical or drug abuse. They analyse over- and undersupply of vitamins, minerals and trace elements. They are applied in genomics, proteomics and metabolomics and also uncover fraud in sports, particularly in animal or human doping. At the same time, analytical systems support health protection of animals and humans, even in the long-term. Clinical applications benefit from Shimadzu’s complete portfolio covering chromatography and mass spectrometry (GC, GC-MS, GC-MS/MS, HPLC, UHPLC, LC-MS, LC-MS/MS); spectroscopy (UVVis, FTIR, AAS, EDX, ICP-OES); life sciences (MALDI-(TOF)-MS); microchip- electrophoresis; biopharmaceutical (aggregate sizer); observation of medical microbubbles in targeted drug delivery using the HPV-X2 ultra high-speed camera.
Shimadzu breaks new grounds by rethinking the use of mature technologies to develop new unique systems such as the iMScope TRIO. It combines an optical microscope with a mass spectrometer for insights on the molecular level.
For next-generation brain science, Shimadzu provides LABNIRS, an imaging technology for visualization of brain functions by functional near-infrared spectroscopy (fNIRS).
Some analytical technologies used in the clinical world
Chromatographic separation in gas phase for analysis of volatile and semi volatile components is in use in the clinical field since many years. Gas chromatography is a key technique for quantitative analysis of alcohol in blood.
HPLC and UHPLC systems are able to quantitatively analyse substances in blood, serum, plasma and urine containing multiple compounds by separating and detecting target substances. Shimadzu offers a wide variety of application- specific systems such as automated sample pretreatment systems for amino acid analysis or on-line sample trapping for quantification of drugs or metabolites.
Gas chromatography-mass spectrometry (GC-MS) is a hyphenated technique combining the separating power of GC with the detection power of MS to identify different substances within a sample. Mass spectrometry is a wide-ranging analytical technique which involves the production, subsequent separation and identification of charged species according to their mass to charge (m/z) ratio. It is well known for analysis of drug abuse.
Liquid chromatography-mass spectrometry (LC-MS) is an analytical chemistry technique that combines the physical separation capabilities of LC with the mass analysis capabilities of MS, bringing together very high sensitivity and high selectivity. Its application is oriented towards the separation, general detection and potential identification of compounds of particular masses in the presence of other chemicals (e.g. complex mixtures like blood, serum, plasma or urine). Its use is spreading in the clinical field (research and routine) as a replacement of immunoassays thanks to the capability of multiplexing analysis and reduced risk of cross-reaction in immuno-assays.
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Genomic makeup of colorectal cancers predicts immune system ability to fight tumours
, /in E-News /by 3wmediaGenomic makeup of colorectal cancers predicts immune system ability to fight tumours
Colorectal cancers heavily bedecked with tumour-related proteins called neoantigens are likely to be permeated with disease-fighting white blood cells, researchers at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard report in a new study. Because such an influx of white blood cells often signifies an immune system attack on cancer, the discovery will sharpen research into therapies that make tumours more vulnerable to such an attack.
The discovery was made by combining several data sets from patients in two large health-tracking studies, the Nurses’ Health Study and the Health Professionals Follow-up Study. Researchers first performed whole-exome sequencing on colorectal tumour samples from 619. This information was merged with data from tests of the immune system’s response to the tumours and with patient clinical data, including length of survival.
“We were looking for genetic features that predict how extensively a tumour is infiltrated by lymphocytes [certain white blood cells] and which types of lymphocytes are present,” said study co-lead author, Marios Giannakis, MD, PhD, medical oncologist and clinical investigator at the Dana-Farber Gastrointestinal Cancer Treatment Center, and researcher at the Broad Institute of MIT and Harvard. “We found that tumours with a high ‘neoantigen load’ – which carry large quantities of neoantigens – tended to be infiltrated by a large number of lymphocytes, including memory T cells, which provide protection against previously encountered infections and diseases. Patients whose tumours had high numbers of neoantigens also survived longer than those with lower neoantigen loads.”
Neoantigens are deviant forms of protein antigens, which are found on normal cells. Genetic mutations often cause cancer cells to produce abnormal proteins, some of which get lifted to the cell surface, where they serve as a red flag to the immune system that something is amiss with the cell.
“There can be hundreds or thousands of neoantigens on tumour cells,” Giannakis explained. “Only a few of these may actually provoke T cells to infiltrate a tumour. But the more neoantigens on display, the greater the chance that some of them will spark an immune system response.”
Therapies known as immune checkpoint inhibitors work by removing some of the barriers to an immune system attack on cancer. Although these agents have produced astonishing results in some cases, they’re generally effective only in patients whose immune system has already launched an immune response to cancer. By showing that tumours with high antigen loads are apt to be laced with T cells – and therefore to have provoked an immune response – the study may help investigators identify which patients are most likely to benefit in new clinical trials of immune checkpoint inhibitors.
The study’s genomic analysis of colorectal tumour samples also found several often-mutated genes that had not previously been strongly associated with the disease, including BCL9L, RBM10, CTCF, and KLF5. The discovery of their prevalence in colorectal cancer suggests that they may be valuable targets for new therapies. Dana-Farber Cancer Institute
Panel reclassifies thyroid tumour to curb over-diagnosis of cancer
, /in E-News /by 3wmediaLed by researchers at the University of Pittsburgh School of Medicine, an international panel of pathologists and clinicians has reclassified a type of thyroid cancer to reflect that it is non-invasive and has a low risk of recurrence. The name change is expected to reduce the psychological and medical consequences of a cancer diagnosis, potentially affecting thousands of people worldwide.
The incidence of thyroid cancer has been rising partly due to early detection of tumours that are indolent or non-progressing, despite the presence of certain cellular abnormalities that are traditionally considered cancerous, explained senior investigator Yuri Nikiforov, M.D., Ph.D., professor of pathology and director of Pitt’s Division of Molecular and Genomic Pathology.
“This phenomenon is known as over-diagnosis,” Dr. Nikiforov said. “To my knowledge, this is the first time in the modern era a type of cancer is being reclassified as a non-cancer. I hope that it will set an example for other expert groups to address nomenclature of various cancer types that have indolent behaviour to prevent inappropriate and costly treatment.” University of Pittsburgh School of Medicine
Researcher help build a biomedical knowledgebase
, /in E-News /by 3wmediaImagine attempting to bake a cake—except you have to go to different stores for flour and milk, drive across town to get eggs and call a friend to borrow a cake pan.
This is the kind of disjointed scenario many scientists face when they attempt to gather data scattered across small databases and hard-to-search PDF files.
“It’s not that the data doesn’t exist,” said Andrew Su, associate professor at The Scripps Research Institute (TSRI). “The data just isn’t stored in a way that scientists can easily access.”
“Open data is vital for progress and research,” added TSRI Assistant Professor of Molecular and Experimental Medicine Ben Good. “We need to break down those barriers.”
To solve this problem, Su, Good and their colleagues at TSRI have integrated biomedical data into Wikidata, a public, editable database where researchers can easily link genes, proteins and more.
Technological breakthroughs in the last 10 years have led to rapid increases in the volume and rate of biomedical research, which in turn has led to a rapid growth in biomedical knowledge. However, this knowledge is currently fragmented across countless resources—from online databases to supplementary data files to individual facts in individual papers.
“As a research community, we spend a lot of time searching for good resources and trying to link them together,” said TSRI Research Associate Tim Putman, who was first author of one of the studies. “It’s cringeworthy.”
Even when databases are open to the public, current knowledge isn’t always organized in a uniform way, Putman explained.
Rather than leave each research group to tackle data integration individually, Wikidata offers a new model for organizing all this information. Built on the same principles as Wikipedia, Wikidata enables anyone to add new information to an open community database.
While other Wikidata editors have added information on millions of items as diverse as works of art to U.S. cities, the TSRI team has focused on adding information on biomedical concepts.
TSRI Research Associate Sebastian Burgstaller-Muehlbacher, first author on one study, added data on all human and mouse genes, all human diseases and all drugs approved by the U.S. Food and Drug Administration.
Putman then extended Wikidata with a focus on microbial genomes. With all this information collected in one system, researchers can more easily spot connections between diseases, pathogens and biological processes. As an example, Putman used the model to show that other microorganisms in the body can influence chlamydia infections.
As a proof of concept, Putman led the development of a genome browser based on Wikidata. Rather than having to develop one browser for every sequenced genome, this genome browser allows users to browse any genome that has been loaded into Wikidata.
“You can zoom in on a gene, click on it and the sequence will pop up,” said Good. The genome browser will then link back to the original Wikidata entry.
In the end, the researchers plan to have a comprehensive, uniform database that is easy to search and open to anyone who wants to add data and link related concepts.
“We think this data should all be open,” said Su. “This just makes intuitive sense.” The Scripps Research Institute
Genetic variation that predicted type and rate of physical decline in patients with Parkinson’s Disease
, /in E-News /by 3wmediaResearchers at the Perelman School of Medicine at the University of Pennsylvania and other institutions have uncovered a site of genetic variation that identified which patients with Parkinson’s disease are more likely to have tremors versus difficulty with balance and walking. The Penn team also found that patients with this genetic variation had a slower rate of Parkinson’s disease progression, and lower amounts of alpha-synuclein in the brain. Alpha-synuclein is a protein that experts know plays a role in the development of Parkinson’s disease.
Clinicians have long noted that the presence of tremors, rather than balance and walking problems, as the initial or dominant symptom of Parkinson’s may suggest slower progression of the disease. The Penn-led study is one of the first to link this difference to a specific genetic variation. Tremor-dominant patients are also less likely to develop dementia, although this symptom was not assessed in the study.
“We have never understood the reason why some people present with more tremor vs. walking/balance difficulties in Parkinson’s disease,” said the study’s lead author, Christine A. Cooper, MD, a fellow in movement disorders at Penn Medicine. “This finding gives us information, for the first time, that has implications for diagnosis, prognosis, treatment, and prevention efforts.”
In the study, the investigators ranked 251 Parkinson’s disease patients at the University of Pennsylvania Health System on tremor and balance/walking scores. They then looked at the patients’ genotypes to see if there were correlations between ten genetic variations previously associated with Parkinson’s disease and the primary symptoms that the patients displayed.
The researchers found that 39 of the 251 patients who had a genetic variation known as the GG genotype at the rs356182 SNP 3’ to the SNCA gene were more likely to have: 1) tremors rather than walking/balance problems; 2) slower physical progression of the disease; and 3) lower levels of alpha-synuclein in the brain. Patients were followed up to seven years in some cases. The investigators carried out the same type of analysis with an additional group of 559 patients at three other clinical sites in the United States and found similar results for the association between the genotype and the type of PD symptoms.
“This is how we can start thinking about precision medicine in action,” said the study’s senior author, Alice S. Chen-Plotkin, MD, an assistant professor of neurology at Penn. “We found that a relatively common genetic variation can both serve as a biomarker for and influence the disease course of Parkinson’s patients. This opens up the possibility of achieving a hallmark of precision medicine: targeted therapies for different ‘versions’ of what was once thought to be a single disease.” University of Pennsylvania Health System
Mobility assessment tool may help predict early postoperative outcomes for older adults
, /in E-News /by 3wmediaA quick, reliable and cost-effective mobility assessment tool may help to identify elderly patients at risk for adverse post-surgery outcomes, according to Wake Forest Baptist Medical Center researchers.
In their study of 197 men and woman over age 69 who underwent elective, non-cardiac, inpatient surgery at Wake Forest Baptist over a 20-month period, the researchers found that the participants’ preoperative scores on the Mobility Assessment Tool: Short Form (MAT-sf) were predictive of early postoperative complications, longer hospital stays and discharges to nursing homes.
“Preoperative assessment of patient characteristics that may lead to adverse postoperative outcomes is important to patients, their families and their surgeons, especially with older adults, in whom complications are more likely,” said Leanne Groban, M.D., professor of anaesthesiology at Wake Forest Baptist and lead author of the study.
“Mobility is a powerful indicator of overall health in the elderly, and our results indicate that self-reported mobility, as measured by the MAT-sf, can complement existing assessment tools in determining which patients are at risk of adverse postoperative outcomes.”
The MAT-sf features animated video clips of 10 common physical activities, each followed by questions about the participant’s ability to perform the particular task. In addition to the MAT-sf, participants in the study also underwent four other commonly employed preoperative risk assessments. After controlling for factors such as the participants’ age, sex and body mass index and their scores on the other tests, the researchers found that low (poor) scores on the MAT-sf were associated with short-term complications, later time to discharge and increased nursing home placement to a greater degree than any of the other indicators.
“The traditional risk assessments may be too comprehensive, too focused on single organ systems or too impractical to be effective in this setting,” Groban said.
The next steps, she said, are to validate these findings in a larger, multi-centre study and to test whether preoperative strength and balance training might limit undesirable postoperative outcomes in older adults with mobility limitations.
“Studies such as this will help determine future clinical pathways aimed at reducing adverse outcomes while improving patients’ functionality and speeding their return to independence,” Groban said.
Wake Forest University www.wakehealth.edu/News-Releases/2016/Mobility_Assessment_Tool_May_Help_Predict_Early_Postoperative_Outcomes_for_Older_Adults.htm
Certain genes, in healthy environments, can lengthen lifespan
, /in E-News /by 3wmediaResearchers at the University at Buffalo Research Institute on Addictions have discovered how a gene in the brain’s dopamine system can play an important role in prolonging lifespan: it must be coupled with a healthy environment that includes exercise.
The study was led by Panayotis (Peter) K. Thanos, senior research scientist at RIA.
Thanos and his team studied the genes in dopamine to assess their impact on lifespan and behaviour in mice. Dopamine is a neurotransmitter that helps control the brain’s reward and pleasure centres and helps regulate physical mobility and emotional response.
The researchers found that the dopamine D2 receptor gene (D2R) significantly influences lifespan, body weight and locomotor activity, but only when combined with an enriched environment that included social interaction, sensory and cognitive stimulation and, most critically, exercise.
“The incorporation of exercise is an important component of an enriched environment and its benefits have been shown to be a powerful mediator of brain function and behaviour,” Thanos says.
The mice in the enriched environment lived anywhere from 16 to 22 percent longer than those in a deprived environment, depending on the level of D2R expression.
“These results provide the first evidence of D2R gene-environment interaction playing an important role in longevity and aging,” Thanos says. “The dichotomy over genes versus environment has provided a rigorous and long debate in deciphering individual differences in longevity. In truth, there exists a complex interaction between the two which contribute to the differences.”
Research exploring this genetic-environmental interaction should lead to a better understanding and prediction of the potential benefits of specific environments, such as those including exercise, on longevity and health during aging.
University at Buffalo Research Institute on Addictions www.buffalo.edu/ria/news_events/latest_news.host.html/content/shared/university/news/news-center-releases/2016/04/056.detail.html
Genes that control smooth muscle contraction in digestive system identified
, /in E-News /by 3wmediaResearchers at UMass Medical School have identified a new molecular pathway critical for maintaining the smooth muscle tone that allows the passage of materials through the digestive system. This finding, based on studying calcium ion-controlled pathways in mice, may lead to new treatments for a host of digestive disorders ranging from common gastroesophageal reflux disease (GERD), to swallowing disorders, incontinence and pancreatitis.
“We are excited about the potential to target identified genes to treat disorders such as reflux and incontinence,” said Ronghua ZhuGe, PhD, associate professor of microbiology and physiological systems and a senior author of the study. “Knowing how these muscles stay contracted for such long periods of time will allow us to develop potential new treatments for these diseases. The next step is to see whether this molecular mechanism in mice also operates in humans.”
The human body, and those of other mammals, contains a number of ring-shaped structures made of smooth muscle encircling openings in hollow organs such as the intestines and bladder called sphincters. Smooth muscle is involuntarily controlled, unlike the muscles we use to walk, for example, so that we don’t need to consciously move digested food from stomach to small intestine. Dysfunction in the sphincters, either structurally or functionally, can have severe consequences leading to diseases that impair the ability of the muscle to contract or relax. This can lead to achalasia, which makes it difficult to swallow; gastroesophageal reflux disease (GERD), which allows stomach acid to enter the oesophagus or incontinence of the bowels.
“A healthy sphincter opens transiently but remains closed most of the time, maintaining a basal tone. This basal tone requires constant generation of force produced by the contraction of smooth muscle cells that make up the sphincters,” said Dr. ZhuGe. “However, the genetics governing how the sphincter smooth muscle stays contracted for such long periods of time remains unknown.”
Smooth muscle operates by generating force as the muscle motor protein myosin and actin filaments move past each other. This happens after a molecule called the myosin regulatory light chain (MLC) is turned on through a common molecular transformation called phosphorylation. How much phosphorylation takes place is controlled by the relative amounts of two enzymes; calcium dependent MLC kinase (MLCK), which promotes phosphorylation, and calcium independent MLC phosphatase (MLCP), which reverses phosphorylation. Through this process, contraction and relaxation of the muscle is achieved.
To understand the molecular mechanism responsible for the involuntary and continuous contraction of the sphincter muscle, Dr. ZhuGe and colleagues examined the internal anal sphincter that controls bowel continence in mice. They showed that genetic deletion of the MLCP enzyme in the smooth muscle had no effect on the basal tone of the mouse sphincter, but deletion of MLCK essentially abolishes the basal tone and mice become incontinent as a result.
“Although previous biochemical studies suggested that lower MLCP activity may be related to the basal tone of this sphincter, our genetic study indicates this doesn’t seem to be the case. It turns out MLCK is essential for the tone formation,” said ZhuGe. “This prompted us to look for specific calcium signals that regulate MLCK.”
Co-author Lawrence Lifshitz, PhD, associate professor of molecular medicine, said, “Calcium signalling is our favourite subject. We originally hypothesized that localized releases of calcium inside the cell, near target ion channels, might do the trick, as we knew that such releases can regulate the contraction of smooth muscle in blood vessels and airways.”
But experiments showed that these local calcium releases have no direct role in muscle tone. Instead, three types of ion channels act in concert to generate a rise in cytosolic calcium which eventually results in MLCK activation and muscle tone.
To test this hypothesis, ZhuGe’s group teamed up with Minsheng Zhu, PhD, at Nanjing University in China, to generate a line of mice in which one of these channels could be turned off in smooth muscle only. “These mice were a powerful tool for establishing our hypothesis,” said ZhuGe. “They helped us identify the Tmem16a (also called Ano1) gene as a critical component for basal tone formation and fecal continence. When we were able to turn off the TMEM16A channels in these mice, they lost the majority of the basal tone and became incontinent. ”
UMass Medical School www.umassmed.edu/news/news-archives/2016/04/umms-scientists-identify-genes-that-control-smooth-muscle-contraction-in-digestive-system/
New genetic risk factors for myopia discovered
, /in E-News /by 3wmediaMyopia, also known as short-sightedness or near-sightedness, is the most common disorder affecting the eyesight and it is on the increase. The causes are both genetic and environmental. The Consortium for Refractive Error and Myopia (CREAM) has now made important progress towards understanding the mechanisms behind the development of the condition. This international group of researchers includes scientists involved in the Gutenberg Health Study of the University Medical Center of Johannes Gutenberg University Mainz (JGU). The team has uncovered nine new genetic risk factors which work together with education-related behaviour as the most important environmental factor causing myopia to generate the disorder. The results of the study ‘Genome-wide joint meta-analyses of genetic main effects and interaction with education level identify additional loci for refractive error: The CREAM Consortium’ have recently been published in the scientific journal Nature Communications.
There has been a massive rise in the prevalence of short-sightedness across the globe in recent decades and this upwards trend is continuing. It is known from previous studies of twins and families that the risk of acquiring short-sightedness is determined to a large extent by heredity. However, the myopia-causing genes that had been previously identified do not alone sufficiently explain the extent to which the condition is inherited. In addition to the genetic causes of myopia there are also environmental factors, the most significant of which are education-related behaviour patterns. “We know from the Gutenberg Health Study conducted at Mainz that the number of years of education increases the risk of developing myopia,’ said Professor Norbert Pfeiffer, Director of the Department of Ophthalmology at the Mainz University Medical Center.
With the aim of identifying genetic mutations relating to myopia and acquiring better insight into the development of the condition, the international research group CREAM carried out a meta-analysis of data collected from around the world. The data compiled for this analysis originated from more than 50,000 participants who were analysed in 34 studies. The second largest group of participants was formed by the more than 4,500 subjects of the Gutenberg Health Study of the Mainz University Medical Center. ‘In the field of genetic research, international cooperation is of particular importance. This is also borne out by this study, to which we were able to make a valuable contribution in the form of data from our Gutenberg Health Study,’ continued Professor Norbert Pfeiffer. ‘And in view of the fact that a survey undertaken by the European Eye Epidemiology Consortium with the help of the Gutenberg Health Study shows that about one third of the adult population of Europe is short-sighted, it is essential that we learn more about its causes in order to come up with possible approaches for future treatments.’
Aware that environmental effects and hereditary factors reinforce one another in the development of myopia, the scientists devised a novel research concept for their investigations. They used a statistical analysis technique that takes into account both the effects of the environmental and hereditary factors and does so in equal measure and simultaneously. Their efforts were crowned with success as they were able to classify nine previously unknown genetic risk factors.
Risk-associated gene involved in the development of short-sightedness
These newly discovered genetic variants are associated with proteins which perform important functions when it comes to the transmission of signals in the eye. One of these genes is of particular interest because it plays a major role in the transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the eye. Previous studies have shown that there is greater activation of the gene in question in eyes that are myopic. The results of current research substantiate this conclusion. The CREAM researchers interpret this as evidence that this newly discovered risk-related gene is actually involved in the development of short-sightedness. This represents significant initial headway towards understanding how genetic causes interact with the level of education as an environmental factor to produce the heterogeneity of myopia. Further research will be needed to clarify the details of how the mechanisms actually work and interact with one another.
The spread of short-sightedness is a worldwide phenomenon. Particularly in South East Asia the incidence of myopia in school children has increased notably over the last decades. This is likely due to an improvement in educational attainment. People who read a great deal also perform a lot of close-up work, usually in poor levels of daylight. The eye adjusts to these visual habits and the eyeball becomes more elongated than normal as a result. But if it becomes too elongated, the cornea and lens focus the image just in front of the retina instead of on it so that distant objects appear blurry. The individual in question is then short-sighted.
Johannes Gutenberg University Mainz
www.uni-mainz.de/presse/20232_ENG_HTML.php
Abbott demonstrates next-generation molecular diagnostics prototype
, /in E-News /by 3wmediaAbbott demonstrated a prototype of the company’s next-generation molecular diagnostics platform at a recent scientific event hosted for its customers from across the globe. At the event, molecular laboratory directors and researchers had hands-on interaction with the prototype and were able to provide additional feedback on the system prior to further stages of development.
Abbott’s new system is currently being designed from the ground up based on extensive input from laboratory customers. For example, health systems around the world are often challenged with higher testing volumes with staffing and budget constraints, including in the molecular laboratories.
“Our molecular lab customers tell us they are facing pressures to do more with less,” said John Carrino, divisional vice president, research and development, Molecular Diagnostics, Abbott. “Abbott’s next-generation molecular system is being designed to have a faster turnaround time, greater flexibility to run any test at any time, an ability to run higher volumes and automation to increase lab efficiency – all without compromising the testing performance and quality for which our organization is highly regarded.”
Additionally, customer insights suggest a need for a broad testing menu in the molecular lab. Abbott currently offers one of the broadest molecular testing menus for infectious diseases such as HIV, hepatitis and tuberculosis, as well as sexually transmitted infections such as human papillomavirus (HPV), chlamydia and gonorrhea, among others tests.
“Abbott’s molecular diagnostics can provide the information needed to help guide some of life’s most important health decisions,” said Andrea Wainer, president, Molecular Diagnostics, Abbott. “Our accurate, reliable and quality tests could allow clinicians to make more informed treatment decisions to help improve patient care.” In addition to the new molecular system, Abbott will be launching next-generation systems in blood screening, immunoassay, clinical chemistry, hematology and point of care testing in the near future. All of the systems will be built on the same software and hardware platforms to enable more automation and to simplify the user experience for Abbott’s customers.
www.abbottmolecular.comClinical application handbook
, /in E-News /by 3wmediaShimadzu has released the first Application Handbook “Clinical”. It contains most advanced technologies and solutions such as chromatography, mass spectrometry, spectroscopy and life sciences instruments. With nearly 140 pages, the Application Handbook “Clinical” covers 47 real life applications related to hot subjects such as Vitamin D, steroids, immunosuppressants, catecholamines and amino acids analysis. The book is free of charge and can be downloaded (17 MB) at www.shimadzu. eu/clinical.
In clinical applications, analytical instruments unfold a multitude of benefits. They support the quality of human life. The concentration of medications in Therapeutic Drug Monitoring (TDM) is assured, even though this may change according to age and health conditions and is dependent on gender, genetic constitution or interferences with other drugs. They help to save lives, particularly when it comes to time-critical situations, e.g. through acute intoxication, medical or drug abuse. They analyse over- and undersupply of vitamins, minerals and trace elements. They are applied in genomics, proteomics and metabolomics and also uncover fraud in sports, particularly in animal or human doping. At the same time, analytical systems support health protection of animals and humans, even in the long-term. Clinical applications benefit from Shimadzu’s complete portfolio covering chromatography and mass spectrometry (GC, GC-MS, GC-MS/MS, HPLC, UHPLC, LC-MS, LC-MS/MS); spectroscopy (UVVis, FTIR, AAS, EDX, ICP-OES); life sciences (MALDI-(TOF)-MS); microchip- electrophoresis; biopharmaceutical (aggregate sizer); observation of medical microbubbles in targeted drug delivery using the HPV-X2 ultra high-speed camera.
Shimadzu breaks new grounds by rethinking the use of mature technologies to develop new unique systems such as the iMScope TRIO. It combines an optical microscope with a mass spectrometer for insights on the molecular level.
For next-generation brain science, Shimadzu provides LABNIRS, an imaging technology for visualization of brain functions by functional near-infrared spectroscopy (fNIRS).
Some analytical technologies used in the clinical world
- Chromatographic separation in gas phase for analysis of volatile and semi volatile components is in use in the clinical field since many years. Gas chromatography is a key technique for quantitative analysis of alcohol in blood.
- HPLC and UHPLC systems are able to quantitatively analyse substances in blood, serum, plasma and urine containing multiple compounds by separating and detecting target substances. Shimadzu offers a wide variety of application- specific systems such as automated sample pretreatment systems for amino acid analysis or on-line sample trapping for quantification of drugs or metabolites.
- Gas chromatography-mass spectrometry (GC-MS) is a hyphenated technique combining the separating power of GC with the detection power of MS to identify different substances within a sample. Mass spectrometry is a wide-ranging analytical technique which involves the production, subsequent separation and identification of charged species according to their mass to charge (m/z) ratio. It is well known for analysis of drug abuse.
- Liquid chromatography-mass spectrometry (LC-MS) is an analytical chemistry technique that combines the physical separation capabilities of LC with the mass analysis capabilities of MS, bringing together very high sensitivity and high selectivity. Its application is oriented towards the separation, general detection and potential identification of compounds of particular masses in the presence of other chemicals (e.g. complex mixtures like blood, serum, plasma or urine). Its use is spreading in the clinical field (research and routine) as a replacement of immunoassays thanks to the capability of multiplexing analysis and reduced risk of cross-reaction in immuno-assays.
www.shimadzu.eu/clinical