A team of researchers from UCLA and Harvard University have demonstrated a technique that, by measuring the physical properties of individual cells in body fluids, can diagnose cancer with a high degree of accuracy.
The technique, which uses a deformability cytometer to analyse individual cells, could reduce the need for more cumbersome diagnostic procedures and the associated costs, while improving accuracy over current methods. The initial clinical study analysed pleural fluid samples from more than 100 patients.
Pleural fluid, a natural lubricant of the lungs as they expand and contract during breathing, is normally present in spaces surrounding the lungs. Medical conditions such as pneumonia, congestive heart failure and cancer can cause an abnormally large buildup of the fluid, which is called a pleural effusion.
When cytopathologists screen for cancer in pleural effusions, they perform a visual analysis of prepared cells extracted from the fluid. Preparing cells for this analysis can involve complicated and time-consuming dyeing or molecular labelling, and the tests often do not definitively determine the presence of tumour cells. As a result, additional costly tests often are required.
The method in the UCLA–Harvard study, developed previously by the UCLA researchers, requires little sample preparation, relying instead on the imaging of cells as they flow through in microscale fluid conduits.
Imagine squeezing two balloons, one filled with water and one filled with honey. The balloons would feel different and would deform differently in your grip. The researchers used this principle on the cellular level by using a fluid grip to ‘squeeze’ individual cells that are 10,000 times smaller than balloons—a technique called ‘deformability cytometry.’ The amount of a cell’s compression can provide insights about the cell’s makeup or structure, such as the elasticity of its membrane or the resistance to flow of the DNA or proteins inside it. Cancer cells have a different architecture and are softer than healthy cells and, as a result, ‘deform’ differently.
Using deformability cytometry, researchers can analyse more than 1,000 cells per second as they are suspended in a flowing fluid, providing significantly more detail on the variations within each patient’s sample than could be detected using previous physical analysis techniques.
The researchers also noted that the more detailed information they obtained improved the sensitivity of the test: Some patient samples that were not identified as cancerous via traditional methods were found to be so through deformability cytometry. These results were verified six months later.
‘Building off of these results, we are starting studies with many more patients to determine if this could be a cost-effective diagnostic tool and provide even more detailed information about cancer origin,’ said Dino Di Carlo, associate professor of bioengineering at the UCLA Henry Samueli School of Engineering and Applied Science and a co-principal investigator on the research. ‘It could help to reduce laboratory workload and accelerate diagnosis, as well as offer doctors a new way to improve clinical decision-making.’
University of California – Los Angeles
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By linking antibodies to certain diseases, researchers at UC Santa Barbara have found a way to uncover and confirm environmental triggers
By cross referencing the amino acid sequence of peptides strongly associated with illnesses with a library of known peptides, researchers may be able to map antigens with identical sequences to their environment, thus uncovering and confirming environmental triggers for diseases such as Type-1 diabetes, schizophrenia, and autism.
You may be sensitive to gluten, but you’re not sure. Perhaps you can’t put your finger on a recurring malaise, and your doctor is at a loss to figure it out. A diagnostic method recently developed by UC Santa Barbara professor Patrick Daugherty can reveal — on a molecular level — the factors behind conditions thought to have environmental triggers. By decoding an individual’s immune system, this elegant and accurate method can demystify, diagnose and provide further insight into conditions like celiac disease, multiple sclerosis, pre-eclampsia and schizophrenia.
‘We have two goals,’ said Daugherty, a researcher with the Department of Chemical Engineering at UCSB and the campus’s Center for BioEngineering. ‘We want to identify diagnostic tests for diseases where there are no blood diagnostics … and we want to figure out what might have given rise to these diseases.’
The process works by mining an individual’s immunological memory — a veritable catalogue of the pathogens and antigens encountered by his or her immune system.
‘Every time you encounter a pathogen, you mount an immune response,’ said Daugherty. The response comes in the form of antibodies that are specific to the antigens — molecular, microbial, chemical — your body is resisting, and the formation of ‘memory cells’ that are activated by subsequent encounters with the antigen. Responses can vary, from minor reactions — a cough, or a sneeze — to serious autoimmune diseases in which the body turns against its own tissues and its immune system responds by destroying them, such as in the case of Type 1 diabetes and celiac disease.
‘The trick is to determine which antibodies are linked to specific diseases,’ said Daugherty. Celiac disease sufferers, for example, will have certain antibodies in their blood that bind to specific peptides — short chains of amino acids — present in wheat, barley and rye. These peptides are the gluten that is the root of allergies and sensitivities in some people. Like a lock and key, these antibodies — the locks — bind only to certain sequences of amino acids that comprise the peptides — the keys.
‘People with celiac disease have two particular antibody types in their blood, which have proved to be enormously useful for diagnosis,’ said Daugherty.
However, sheer variety and number of antibodies present in a person’s blood at any given time has been a challenge for researchers trying to link specific illnesses with specific antibody molecules. One antigen can stimulate the production of many antibodies in response. What’s more, each individual’s antibodies to even the same antigen differ slightly in their form. The idea of using molecular separation to find the disease antibodies has been around for over 20 years, said Daugherty, but no one had figured quite how to sift through the vast amount of molecules.
To sort through perhaps tens of thousands of antibody molecules present in a person’s blood, the research team — including John T. Ballew from UCSB’s Biomolecular Science and Engineering graduate program, now a postdoctoral associate with the Koch Institute for Integrative Cancer Research at MIT — mixed a sample of a subject’s blood, which contains the antibody molecules, with a vast number of different peptides (about 10 billion).
‘All the keys associate with their preferred lock,’ said Daugherty. ‘The peptides that can bind to an antibody, do so.’ The researchers then pull out the disease-bound pairs, in a process that progressively decreases the number of antibodies-peptide pairs that are most unique to a particular disease. Repeated with subsequent patients who may have the same symptoms, phenotypes or genetic dispositions, continues to whittle down the size of the peptide pool. Further in vitro evolution of the best draft peptides can identify the particular sequence of amino acid keys that fit into the antibody locks. This sequence can be used to confirm the antibodies in question as the biomarkers specifically associated with the disease.
‘The diagnostic performance of the reagents generated with this approach is excellent,’ said Daugherty. ‘We can discover biomarkers with as little as a drop of blood, and the peptides discovered can be adapted into preferred low cost testing platforms widely used in clinical practice.’
The amino acid sequence of the evolved peptides, when cross-referenced with a database of known proteins, can identify the antigens (that contain the same peptide sequence). This, in turn, can then yield clues into what factors in the patient’s environment may have contributed to the disease. The process may be used to gain insight on diseases that are thought to have environmental triggers, including Type-1 diabetes, autism, schizophrenia/bipolar disorder, Crohn’s disease, Parkinson’s disease, and perhaps even Alzheimers disease. In cases, such as Graves’ disease, where an antibody is identified as the cause (as opposed to simply an indicator) knowing the antibody’s structure can lead to more effective therapies.
‘If you can get rid of the antibody, you can treat the disease,’ said Daugherty. ‘By finding these keys, you can block the antibody.’
University of California – Santa Barbara
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In light of new research, Dr André Lacroix suggests genetic screening to find ‘silent carriers’.
Genetic research suggests to Dr. André Lacroix, professor at the University of Montreal, that clinicians’ understanding and treatment of a form of Cushing’s syndrome affecting both adrenal glands will be fundamentally changed, and that moreover, it might be appropriate to begin screening for the genetic mutations that cause this form of the disease. ‘Screening family members of bilateral adrenal Cushing’s syndrome patients with genetic mutations may identify affected silent carriers,’ Lacroix said ‘The development of drugs that interrupt the defective genetic chemical link that causes the syndrome could, if confirmed to be effective in people, provide individualised specific therapies for hypercortisolism, eliminate the current practice of removing both adrenal glands, and possibly prevent disease progression in genetically affected family members.’ Adrenal glands sit above the kidneys are mainly responsible for releasing cortisol, a stress hormone. Hypercortiolism means a high level of the adrenal hormone cortisol, which causes many symptoms including weight gain, high blood pressure, diabetes, osteoporosis, concentration deficit and increased cardiovascular deaths.
Cushing’s syndrome can be caused by corticosteroid use (such as for asthma or arthritis), a tumour on the adrenal glands, or a pituitary gland that releases too much ACTH. The pituitary gland sits under the brain and releases various hormones that regulate our bodies’ mechanisms.
Jérôme Bertherat is a researcher at Cochin Hospital in Paris. In the study he showed that 55% of Cushing’s Syndrome patients with bilaterally very enlarged adrenal glands have mutations in a gene that predisposes to the development of adrenal tumours. This means that bilateral adrenal Cushing’s is much more hereditary than previously thought. The new knowledge will also enable clinicians to undertake genetic screening. Hervé Lefebvre is a researcher at the University Hospital in Rouen, France. His research shows that the adrenal glands from the same type of patients with two large adrenal glands can produce ACTH, which is normally produced by the pituitary gland. Hormone receptors are the chemical link that cause a cell to behave differently when a hormone is present. Several misplaced hormone receptors cause the ACTH to be produced in the enlarged benign adrenal tissue. Knowing this means that researchers might be able to develop drugs that interrupt the receptors for these hormones and possibly even prevent the benign tissue from developing in the first place.
Université de Montréal.
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Hugo Technology, the medical technology repair and service specialist, has been appointed to support BioFire’s FilmArray System – a multi-purpose device which identifies numerous respiratory viruses and bacteria, eg: adenovirus, influenza and bordetella pertussis– a bacterium that is a cause of whooping cough. Hugo has an ongoing contract with BioFire based in Salt Lake City, Utah, which is known for developing, manufacturing and selling the fastest, highest-quality machines in the world for DNA analysis. Hugo will take responsibility for repairing and maintaining the equipment which will be sent to its new £700,000 (€815,000) Bromsgrove facility. This facility was designed specifically to match the needs of Hugo’s growing client base of leading original equipment manufacturers (OEMs). Biomedical service engineers for Hugo Technology have spent two weeks in Salt Lake City being trained on the Film Array System which integrates sample preparation, amplification, detection and analysis into one process to detect emerging infectious diseases in just one hour. The user-friendly FilmArray System is used in hospital-based, clinical laboratories across the USA and Europe. Hugo employs more than 50 people across the UK servicing medical devices and equipment for OEMs both at home and across Europe. Accredited to ISO 13485 medical device quality management standard and ISO 9001:2008, Hugo’s facility and field engineer teams provide support to some of the world’s largest OEMs including: Philips, Nipro, Moog, Nutricia, Therapy Equipment, Cosmed, Nikkiso, Care Innovations-GE and Teleflex.
www.FilmArray.com
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Women who are members of families with BRCA2 mutations but who test negative for the family-specific BRCA2 mutations are still at greater risk for developing breast cancer compared with women in the general population.
Women with certain mutations in their BRCA1 or BRCA2 genes are at increased risk for breast cancer. However, if a woman who comes from a BRCA family tests negative for her family-specific BRCA mutation, her risk for breast cancer is considered to be the same as someone in the general population, according to the National Cancer Institute. This study, however, suggests that it may not always be true.
‘We found that women who test negative for family-specific BRCA2 mutations have more than four times the risk for developing breast cancer than the general population,’ said Gareth R. Evans, M.B.B.S., M.D., M.R.C.P., F.R.C.P., honorary professor of medical genetics and cancer epidemiology at the Manchester Academic Health Science Center at the University of Manchester in the United Kingdom. ‘We also found that any increased risk for breast cancer is largely limited to BRCA2 families with strong family history and other genetic factors.
‘It is likely that these women inherit genetic factors other than BRCA-related genes that increase their breast cancer risk,’ he explained. ‘About 77 single nucleotide polymorphisms [SNPs—genetic variations that can help track the inheritance of disease genes within families] are linked to breast cancer risk. Identification of additional SNPs is necessary to understand why some of the BRCA-negative women from BRCA families are at higher risk.’
The authors note that specialists should use caution when stating that a woman’s breast cancer risk is the same as that of the general population following a negative test, because it may not be true for some women who come from BRCA2 families with a strong family history.
Evans and colleagues used data from the M6-Inherited Cancer in England study, which has screened families of individuals with breast and/or ovarian cancer for mutations in BRCA1 and 2 since 1996. Details on affected individuals, and all tested and untested relatives, were entered into a Filemaker Pro-7 database. From 807 BRCA families, the researchers identified 49 women who tested negative for the family-specific BRCA mutation, but subsequently developed breast cancer. The researchers called these women ‘phenocopies.’
Of the 49 phenocopies identified, 22 were among 279 women who tested negative from BRCA1 families, and 27 were among 251 women who tested negative from BRCA2 families. When the researchers stratified the phenocopies based on their age (30-39, 40-49, 50-59, and 69-80), they found that in each age range there were about twice as many cases of breast cancer as would have been expected from the general population.
Next, to conduct risk analyses, Evans and colleagues calculated the ‘observed versus expected ratio’ (O/E), a ratio of observed risk for breast cancer in BRCA-negative women from BRCA families, versus the risk expected for any woman in the general population.
They found the O/E for phenocopies from BRCA1 families was not substantially higher than that of the general population; however, the O/E for phenocopies from BRCA2 families was 4.57, leading them to conclude that the more than fourfold increased risk for breast cancer among BRCA-negative women is largely limited to BRCA-negative women from BRCA2 families.
When the researchers considered the date of predictive testing (the date on which BRCA testing was done for an individual) instead of the date of family ascertainment (the date the first family member of the individual was referred to genetic service), O/E dropped from 4.57 to 2.01, ‘because there is less follow-up in the predictive test group from time of testing and we may be unaware of breast cancers that have occurred in the near past,’ explained Evans.
American Association for Cancer Research
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A team of researchers has brought new clarity to the picture of how gene-environmental interactions can kill nerve cells that make dopamine. Dopamine is the neurotransmitter that sends messages to the part of the brain that controls movement and co-ordination. Their discoveries include identification of a molecule that protects neurons from pesticide damage.
‘For the first time, we have used human stem cells derived from Parkinson’s disease patients to show that a genetic mutation combined with exposure to pesticides creates a ‘double hit’ scenario, producing free radicals in neurons that disable specific molecular pathways that cause nerve-cell death,’ says Stuart Lipton, M.D., Ph.D., professor and director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and senior author of the study.
Until now, the link between pesticides and Parkinson’s disease was based mainly on animal studies and epidemiological research that demonstrated an increased risk of disease among farmers, rural populations, and others exposed to agricultural chemicals.
In the new study, Lipton, along with Rajesh Ambasudhan, Ph.D., research assistant professor in the Del E. Webb Center, and Rudolf Jaenisch, M.D., founding member of Whitehead Institute for Biomedical Research and professor of biology at the Massachusetts Institute of Technology (MIT), used skin cells from Parkinson’s patients that had a mutation in the gene encoding a protein called alpha-synuclein. Alpha-synuclein is the primary protein found in Lewy bodies—protein clumps that are the pathological hallmark of Parkinson’s disease.
Using patient skin cells, the researchers created human induced pluripotent stem cells (hiPSCs) containing the mutation, and then ‘corrected’ the alpha-synuclein mutation in other cells. Next, they reprogrammed all of these cells to become the specific type of nerve cell that is damaged in Parkinson’s disease, called A9 dopamine-containing neurons—thus creating two sets of neurons—identical in every respect except for the alpha-synuclein mutation.
‘Exposing both normal and mutant neurons to pesticides—including paraquat, maneb, or rotenone—created excessive free radicals in cells with the mutation, causing damage to dopamine-containing neurons that led to cell death,’ said Frank Soldner, M.D., research scientist in Jaenisch’s lab and co-author of the study.
‘In fact, we observed the detrimental effects of these pesticides with short exposures to doses well below EPA-accepted levels,’ said Scott Ryan, Ph.D., researcher in the Del E. Webb Center and lead author of the paper.
Having access to genetically matched neurons with the exception of a single mutation simplified the interpretation of the genetic contribution to pesticide-induced neuronal death. In this case, the researchers were able to pinpoint how cells with the mutation, when exposed to pesticides, disrupt a key mitochondrial pathway—called MEF2C-PGC1alpha—that normally protects neurons that contain dopamine. The free radicals attacked the MEF2C protein, leading to the loss of function of this pathway that would otherwise have protected the nerve cells from the pesticides.
‘Once we understood the pathway and the molecules that were altered by the pesticides, we used high-throughput screening to identify molecules that could inhibit the effect of free radicals on the pathway,’ said Ambasudhan. ‘One molecule we identified was isoxazole, which protected mutant neurons from cell death induced by the tested pesticides. Since several FDA-approved drugs contain derivatives of isoxazole, our findings may have potential clinical implications for repurposing these drugs to treat Parkinson’s.’
Sanford-Burnham Medical Research Institution
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Scientists are a step closer to understanding how some of the brain’s 100 billion nerve cells co-ordinate their communication.
The University of Bristol research team investigated some of the chemical processes that underpin how brain cells co-ordinate their communication. Defects in this communication are associated with disorders such as epilepsy, autism and schizophrenia, and therefore these findings could lead to the development of novel neurological therapies.
Neurons in the brain communicate with each other using chemicals called neurotransmitters. This release of neurotransmitter from neurons is tightly controlled by many different proteins inside the neuron. These proteins interact with each other to ensure that neurotransmitter is only released when necessary. Although the mechanisms that control this release have been extensively studied, the processes that co-ordinate how and when the component proteins interact is not fully understood.
The School of Biochemistry researchers have now discovered that one of these proteins called ‘RIM1α’ is modified by a small protein named ‘SUMO’ which attaches to a specific region in RIM1α. This process acts as a ‘molecular switch’ which is required for normal neurotransmitter release.
Jeremy Henley, Professor of Molecular Neuroscience in the University’s Faculty of Medical and Veterinary Sciences and the study’s lead author, said: ‘These findings are important as they show that SUMO modification plays a vital and previously unsuspected role in normal brain function.’
Bristol University
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Dr. Hanna Mikkola and researchers at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have identified a specific type of cell and a related cell communication pathway that are key to the successful growth of a healthy placenta. The findings could greatly bolster our knowledge about the potential causes of complications during pregnancy.
Specifically, the findings could help scientists clarify the particular order in which progenitor cells grow in the placenta, which would allow researchers to track foetal development and identify complications. Progenitor cells are cells that develop into other cells and that initiate growth of the placenta.
The placenta is the organ that forms inside the uterus during pregnancy and enables oxygen and nutrients to reach the foetus, but little is understood about the biological mechanisms and cellular processes responsible for this interface. Studying mouse models, Mikkola and her colleagues tracked individual cells in the placenta to determine which cells and which cell communication routes, or signalling pathways, were responsible for the healthy development of the placenta.
The UCLA team was the first to identify the cells that form the placenta: Epcamhi labyrinth trophoblast progenitors, or LaTP cells, can become the various cells necessary to form a specific tissue, in this case the placenta.
Mikkola and her colleagues also found a signalling pathway that consists of hepatocyte growth factor and its receptor, c-Met. The researchers found that this signalling pathway was required for the placenta to keep making LaTP cells. Production of LaTP cells, in turn, continues the production of the different cells needed to maintain the growth and health of the placenta while the foetus is growing. Placental health enables healthy transmission of oxygen and nutrients through the exchange of blood between the foetus and the mother. In the mice, when c-Met signalling stopped, foetal growth slowed, the liver did not develop fully and it produced fewer blood cells, and the foetus died.
‘Identifying this novel c-Met–dependent multipotent labyrinth trophoblast progenitor is a landmark that may help us understand pregnancy complications that are caused by defective placental exchange, such as foetal growth restriction,’ Mikkola said.
University of California – Los Angeles
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It has been estimated that 3 to 4 million people are infected with hepatitis C virus (HCV) each year with the risk of developing liver cirrhosis and/or liver cancer. More than 350,000 people die each year from HCV-related conditions. With earlier detection and diagnosis, patients have a hope of receiving timely treatment and care for improved management of the condition. MP Biomedicals recently obtained the CE Marking for its patented multiparameter HCV test, the Multisure HCV antibody test. This test is intended for the detection and differentiation of Hepatitis C antibodies that may be present in patients with acute or chronic HCV infection. This innovative test is based on the patented reverse-flow technology, giving greater sensitivity and stronger visual signals. Multisure HCV uses human whole blood, plasma or serum. The test is fast and can help differentiate HCV antibodies against both structural and non-structural proteins across six genotypes.
www.mpbio.com
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People from around the country and the world turn to Johan Van Hove, MD, PhD, for advice on a rare metabolic disease known as NKH, which can disrupt the body in devastating and even deadly ways. Now, Van Hove, a University of Colorado medical school professor, has identified a new disease related to NKH, a finding that resolves previously baffling cases including the death of a Colorado girl.
‘This opens the door,’ Van Hove said. ‘I am hopeful that it will eventually lead to major advances in dealing with these diseases.’ The research team led by Van Hove, including scientists from the United States and five other countries, calls the new disease variant NKH.
The discovery is part of the new wave of personalised medicine being pioneered at CU and other institutions, in which researchers and doctors delve into the human genome to determine what is causing disease and use the information to try to fix the problem.
Van Hove has been on the trail of NKH for 22 years. Much of the funding for his research comes from families and others who have encountered the disease.
NKH, short for non-ketotic hyperglycinaemia, occurs in about one in 60,000 births. It involves the amino acid glycine, a building block for many functions including movement and brain activity. When a genetic mutation prevents the body from breaking down excess glycine, it can cause brain problems including severe epilepsy and impaired intellectual development.
Scientists know the symptoms of NKH and also the genes that, when they malfunction, cause it. But a few patients worldwide had symptoms or glycine test results that were similar but did not quite match up.
One of those patients was a Colorado girl. She seemed fine until she was six months old. Then she began to lose muscle tone. She lost some control of her head movements. Seizures came next, along with a range of muscle twitches. By eight she lost her ability to walk. At the end, she spent most of her time curled in the foetal position.
Several years ago, at age 11, she died.
Researchers kept her genetic material, as they did with other patients who seemed to fall outside the NKH symptoms or who had molecular test results that were outside of the NKH pattern. The patients, some of whom are living, were scattered around the globe, in Australia, Lebanon, Canada and other countries as well as in the United States.
By looking into the genomes of this group of 11, Van Hove and his colleagues found that eight shared a genetic glitch different than the ones associated with NKH.
In other words, ‘this is a new disease,’ said Van Hove, who practices at Children’s Hospital Colorado.
More testing is likely to reveal more such patients and, he said, may allow development of a new drug to make life better for patients with variant NKH.
EurekAlert
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Researchers’ new technique improves accuracy, ease of cancer diagnosis
, /in E-News /by 3wmediaA team of researchers from UCLA and Harvard University have demonstrated a technique that, by measuring the physical properties of individual cells in body fluids, can diagnose cancer with a high degree of accuracy.
The technique, which uses a deformability cytometer to analyse individual cells, could reduce the need for more cumbersome diagnostic procedures and the associated costs, while improving accuracy over current methods. The initial clinical study analysed pleural fluid samples from more than 100 patients.
Pleural fluid, a natural lubricant of the lungs as they expand and contract during breathing, is normally present in spaces surrounding the lungs. Medical conditions such as pneumonia, congestive heart failure and cancer can cause an abnormally large buildup of the fluid, which is called a pleural effusion.
When cytopathologists screen for cancer in pleural effusions, they perform a visual analysis of prepared cells extracted from the fluid. Preparing cells for this analysis can involve complicated and time-consuming dyeing or molecular labelling, and the tests often do not definitively determine the presence of tumour cells. As a result, additional costly tests often are required.
The method in the UCLA–Harvard study, developed previously by the UCLA researchers, requires little sample preparation, relying instead on the imaging of cells as they flow through in microscale fluid conduits.
Imagine squeezing two balloons, one filled with water and one filled with honey. The balloons would feel different and would deform differently in your grip. The researchers used this principle on the cellular level by using a fluid grip to ‘squeeze’ individual cells that are 10,000 times smaller than balloons—a technique called ‘deformability cytometry.’ The amount of a cell’s compression can provide insights about the cell’s makeup or structure, such as the elasticity of its membrane or the resistance to flow of the DNA or proteins inside it. Cancer cells have a different architecture and are softer than healthy cells and, as a result, ‘deform’ differently.
Using deformability cytometry, researchers can analyse more than 1,000 cells per second as they are suspended in a flowing fluid, providing significantly more detail on the variations within each patient’s sample than could be detected using previous physical analysis techniques.
The researchers also noted that the more detailed information they obtained improved the sensitivity of the test: Some patient samples that were not identified as cancerous via traditional methods were found to be so through deformability cytometry. These results were verified six months later.
‘Building off of these results, we are starting studies with many more patients to determine if this could be a cost-effective diagnostic tool and provide even more detailed information about cancer origin,’ said Dino Di Carlo, associate professor of bioengineering at the UCLA Henry Samueli School of Engineering and Applied Science and a co-principal investigator on the research. ‘It could help to reduce laboratory workload and accelerate diagnosis, as well as offer doctors a new way to improve clinical decision-making.’ University of California – Los Angeles
Breaking the Code
, /in E-News /by 3wmediaBy linking antibodies to certain diseases, researchers at UC Santa Barbara have found a way to uncover and confirm environmental triggers
By cross referencing the amino acid sequence of peptides strongly associated with illnesses with a library of known peptides, researchers may be able to map antigens with identical sequences to their environment, thus uncovering and confirming environmental triggers for diseases such as Type-1 diabetes, schizophrenia, and autism.
You may be sensitive to gluten, but you’re not sure. Perhaps you can’t put your finger on a recurring malaise, and your doctor is at a loss to figure it out. A diagnostic method recently developed by UC Santa Barbara professor Patrick Daugherty can reveal — on a molecular level — the factors behind conditions thought to have environmental triggers. By decoding an individual’s immune system, this elegant and accurate method can demystify, diagnose and provide further insight into conditions like celiac disease, multiple sclerosis, pre-eclampsia and schizophrenia.
‘We have two goals,’ said Daugherty, a researcher with the Department of Chemical Engineering at UCSB and the campus’s Center for BioEngineering. ‘We want to identify diagnostic tests for diseases where there are no blood diagnostics … and we want to figure out what might have given rise to these diseases.’
The process works by mining an individual’s immunological memory — a veritable catalogue of the pathogens and antigens encountered by his or her immune system.
‘Every time you encounter a pathogen, you mount an immune response,’ said Daugherty. The response comes in the form of antibodies that are specific to the antigens — molecular, microbial, chemical — your body is resisting, and the formation of ‘memory cells’ that are activated by subsequent encounters with the antigen. Responses can vary, from minor reactions — a cough, or a sneeze — to serious autoimmune diseases in which the body turns against its own tissues and its immune system responds by destroying them, such as in the case of Type 1 diabetes and celiac disease.
‘The trick is to determine which antibodies are linked to specific diseases,’ said Daugherty. Celiac disease sufferers, for example, will have certain antibodies in their blood that bind to specific peptides — short chains of amino acids — present in wheat, barley and rye. These peptides are the gluten that is the root of allergies and sensitivities in some people. Like a lock and key, these antibodies — the locks — bind only to certain sequences of amino acids that comprise the peptides — the keys.
‘People with celiac disease have two particular antibody types in their blood, which have proved to be enormously useful for diagnosis,’ said Daugherty.
However, sheer variety and number of antibodies present in a person’s blood at any given time has been a challenge for researchers trying to link specific illnesses with specific antibody molecules. One antigen can stimulate the production of many antibodies in response. What’s more, each individual’s antibodies to even the same antigen differ slightly in their form. The idea of using molecular separation to find the disease antibodies has been around for over 20 years, said Daugherty, but no one had figured quite how to sift through the vast amount of molecules.
To sort through perhaps tens of thousands of antibody molecules present in a person’s blood, the research team — including John T. Ballew from UCSB’s Biomolecular Science and Engineering graduate program, now a postdoctoral associate with the Koch Institute for Integrative Cancer Research at MIT — mixed a sample of a subject’s blood, which contains the antibody molecules, with a vast number of different peptides (about 10 billion).
‘All the keys associate with their preferred lock,’ said Daugherty. ‘The peptides that can bind to an antibody, do so.’ The researchers then pull out the disease-bound pairs, in a process that progressively decreases the number of antibodies-peptide pairs that are most unique to a particular disease. Repeated with subsequent patients who may have the same symptoms, phenotypes or genetic dispositions, continues to whittle down the size of the peptide pool. Further in vitro evolution of the best draft peptides can identify the particular sequence of amino acid keys that fit into the antibody locks. This sequence can be used to confirm the antibodies in question as the biomarkers specifically associated with the disease.
‘The diagnostic performance of the reagents generated with this approach is excellent,’ said Daugherty. ‘We can discover biomarkers with as little as a drop of blood, and the peptides discovered can be adapted into preferred low cost testing platforms widely used in clinical practice.’
The amino acid sequence of the evolved peptides, when cross-referenced with a database of known proteins, can identify the antigens (that contain the same peptide sequence). This, in turn, can then yield clues into what factors in the patient’s environment may have contributed to the disease. The process may be used to gain insight on diseases that are thought to have environmental triggers, including Type-1 diabetes, autism, schizophrenia/bipolar disorder, Crohn’s disease, Parkinson’s disease, and perhaps even Alzheimers disease. In cases, such as Graves’ disease, where an antibody is identified as the cause (as opposed to simply an indicator) knowing the antibody’s structure can lead to more effective therapies.
‘If you can get rid of the antibody, you can treat the disease,’ said Daugherty. ‘By finding these keys, you can block the antibody.’ University of California – Santa Barbara
Are you carrying adrenal Cushing’s syndrome without knowing it?
, /in E-News /by 3wmediaIn light of new research, Dr André Lacroix suggests genetic screening to find ‘silent carriers’.
Genetic research suggests to Dr. André Lacroix, professor at the University of Montreal, that clinicians’ understanding and treatment of a form of Cushing’s syndrome affecting both adrenal glands will be fundamentally changed, and that moreover, it might be appropriate to begin screening for the genetic mutations that cause this form of the disease. ‘Screening family members of bilateral adrenal Cushing’s syndrome patients with genetic mutations may identify affected silent carriers,’ Lacroix said ‘The development of drugs that interrupt the defective genetic chemical link that causes the syndrome could, if confirmed to be effective in people, provide individualised specific therapies for hypercortisolism, eliminate the current practice of removing both adrenal glands, and possibly prevent disease progression in genetically affected family members.’ Adrenal glands sit above the kidneys are mainly responsible for releasing cortisol, a stress hormone. Hypercortiolism means a high level of the adrenal hormone cortisol, which causes many symptoms including weight gain, high blood pressure, diabetes, osteoporosis, concentration deficit and increased cardiovascular deaths.
Cushing’s syndrome can be caused by corticosteroid use (such as for asthma or arthritis), a tumour on the adrenal glands, or a pituitary gland that releases too much ACTH. The pituitary gland sits under the brain and releases various hormones that regulate our bodies’ mechanisms.
Jérôme Bertherat is a researcher at Cochin Hospital in Paris. In the study he showed that 55% of Cushing’s Syndrome patients with bilaterally very enlarged adrenal glands have mutations in a gene that predisposes to the development of adrenal tumours. This means that bilateral adrenal Cushing’s is much more hereditary than previously thought. The new knowledge will also enable clinicians to undertake genetic screening. Hervé Lefebvre is a researcher at the University Hospital in Rouen, France. His research shows that the adrenal glands from the same type of patients with two large adrenal glands can produce ACTH, which is normally produced by the pituitary gland. Hormone receptors are the chemical link that cause a cell to behave differently when a hormone is present. Several misplaced hormone receptors cause the ACTH to be produced in the enlarged benign adrenal tissue. Knowing this means that researchers might be able to develop drugs that interrupt the receptors for these hormones and possibly even prevent the benign tissue from developing in the first place. Université de Montréal.
BioFire Diagnostics outsources maintenance to UK firm
, /in E-News /by 3wmediaHugo Technology, the medical technology repair and service specialist, has been appointed to support BioFire’s FilmArray System – a multi-purpose device which identifies numerous respiratory viruses and bacteria, eg: adenovirus, influenza and bordetella pertussis– a bacterium that is a cause of whooping cough. Hugo has an ongoing contract with BioFire based in Salt Lake City, Utah, which is known for developing, manufacturing and selling the fastest, highest-quality machines in the world for DNA analysis.
www.FilmArray.comHugo will take responsibility for repairing and maintaining the equipment which will be sent to its new £700,000 (€815,000) Bromsgrove facility. This facility was designed specifically to match the needs of Hugo’s growing client base of leading original equipment manufacturers (OEMs). Biomedical service engineers for Hugo Technology have spent two weeks in Salt Lake City being trained on the Film Array System which integrates sample preparation, amplification, detection and analysis into one process to detect emerging infectious diseases in just one hour. The user-friendly FilmArray System is used in hospital-based, clinical laboratories across the USA and Europe.
Hugo employs more than 50 people across the UK servicing medical devices and equipment for OEMs both at home and across Europe. Accredited to ISO 13485 medical device quality management standard and ISO 9001:2008, Hugo’s facility and field engineer teams provide support to some of the world’s largest OEMs including: Philips, Nipro, Moog, Nutricia, Therapy Equipment, Cosmed, Nikkiso, Care Innovations-GE and Teleflex.
Negative BRCA testing may not always imply lowered breast cancer risk
, /in E-News /by 3wmediaWomen who are members of families with BRCA2 mutations but who test negative for the family-specific BRCA2 mutations are still at greater risk for developing breast cancer compared with women in the general population.
Women with certain mutations in their BRCA1 or BRCA2 genes are at increased risk for breast cancer. However, if a woman who comes from a BRCA family tests negative for her family-specific BRCA mutation, her risk for breast cancer is considered to be the same as someone in the general population, according to the National Cancer Institute. This study, however, suggests that it may not always be true.
‘We found that women who test negative for family-specific BRCA2 mutations have more than four times the risk for developing breast cancer than the general population,’ said Gareth R. Evans, M.B.B.S., M.D., M.R.C.P., F.R.C.P., honorary professor of medical genetics and cancer epidemiology at the Manchester Academic Health Science Center at the University of Manchester in the United Kingdom. ‘We also found that any increased risk for breast cancer is largely limited to BRCA2 families with strong family history and other genetic factors.
‘It is likely that these women inherit genetic factors other than BRCA-related genes that increase their breast cancer risk,’ he explained. ‘About 77 single nucleotide polymorphisms [SNPs—genetic variations that can help track the inheritance of disease genes within families] are linked to breast cancer risk. Identification of additional SNPs is necessary to understand why some of the BRCA-negative women from BRCA families are at higher risk.’
The authors note that specialists should use caution when stating that a woman’s breast cancer risk is the same as that of the general population following a negative test, because it may not be true for some women who come from BRCA2 families with a strong family history.
Evans and colleagues used data from the M6-Inherited Cancer in England study, which has screened families of individuals with breast and/or ovarian cancer for mutations in BRCA1 and 2 since 1996. Details on affected individuals, and all tested and untested relatives, were entered into a Filemaker Pro-7 database. From 807 BRCA families, the researchers identified 49 women who tested negative for the family-specific BRCA mutation, but subsequently developed breast cancer. The researchers called these women ‘phenocopies.’
Of the 49 phenocopies identified, 22 were among 279 women who tested negative from BRCA1 families, and 27 were among 251 women who tested negative from BRCA2 families. When the researchers stratified the phenocopies based on their age (30-39, 40-49, 50-59, and 69-80), they found that in each age range there were about twice as many cases of breast cancer as would have been expected from the general population.
Next, to conduct risk analyses, Evans and colleagues calculated the ‘observed versus expected ratio’ (O/E), a ratio of observed risk for breast cancer in BRCA-negative women from BRCA families, versus the risk expected for any woman in the general population.
They found the O/E for phenocopies from BRCA1 families was not substantially higher than that of the general population; however, the O/E for phenocopies from BRCA2 families was 4.57, leading them to conclude that the more than fourfold increased risk for breast cancer among BRCA-negative women is largely limited to BRCA-negative women from BRCA2 families.
When the researchers considered the date of predictive testing (the date on which BRCA testing was done for an individual) instead of the date of family ascertainment (the date the first family member of the individual was referred to genetic service), O/E dropped from 4.57 to 2.01, ‘because there is less follow-up in the predictive test group from time of testing and we may be unaware of breast cancers that have occurred in the near past,’ explained Evans. American Association for Cancer Research
Genetic mutation increases risk of Parkinson’s disease from pesticides
, /in E-News /by 3wmediaA team of researchers has brought new clarity to the picture of how gene-environmental interactions can kill nerve cells that make dopamine. Dopamine is the neurotransmitter that sends messages to the part of the brain that controls movement and co-ordination. Their discoveries include identification of a molecule that protects neurons from pesticide damage.
‘For the first time, we have used human stem cells derived from Parkinson’s disease patients to show that a genetic mutation combined with exposure to pesticides creates a ‘double hit’ scenario, producing free radicals in neurons that disable specific molecular pathways that cause nerve-cell death,’ says Stuart Lipton, M.D., Ph.D., professor and director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and senior author of the study.
Until now, the link between pesticides and Parkinson’s disease was based mainly on animal studies and epidemiological research that demonstrated an increased risk of disease among farmers, rural populations, and others exposed to agricultural chemicals.
In the new study, Lipton, along with Rajesh Ambasudhan, Ph.D., research assistant professor in the Del E. Webb Center, and Rudolf Jaenisch, M.D., founding member of Whitehead Institute for Biomedical Research and professor of biology at the Massachusetts Institute of Technology (MIT), used skin cells from Parkinson’s patients that had a mutation in the gene encoding a protein called alpha-synuclein. Alpha-synuclein is the primary protein found in Lewy bodies—protein clumps that are the pathological hallmark of Parkinson’s disease.
Using patient skin cells, the researchers created human induced pluripotent stem cells (hiPSCs) containing the mutation, and then ‘corrected’ the alpha-synuclein mutation in other cells. Next, they reprogrammed all of these cells to become the specific type of nerve cell that is damaged in Parkinson’s disease, called A9 dopamine-containing neurons—thus creating two sets of neurons—identical in every respect except for the alpha-synuclein mutation.
‘Exposing both normal and mutant neurons to pesticides—including paraquat, maneb, or rotenone—created excessive free radicals in cells with the mutation, causing damage to dopamine-containing neurons that led to cell death,’ said Frank Soldner, M.D., research scientist in Jaenisch’s lab and co-author of the study.
‘In fact, we observed the detrimental effects of these pesticides with short exposures to doses well below EPA-accepted levels,’ said Scott Ryan, Ph.D., researcher in the Del E. Webb Center and lead author of the paper.
Having access to genetically matched neurons with the exception of a single mutation simplified the interpretation of the genetic contribution to pesticide-induced neuronal death. In this case, the researchers were able to pinpoint how cells with the mutation, when exposed to pesticides, disrupt a key mitochondrial pathway—called MEF2C-PGC1alpha—that normally protects neurons that contain dopamine. The free radicals attacked the MEF2C protein, leading to the loss of function of this pathway that would otherwise have protected the nerve cells from the pesticides.
‘Once we understood the pathway and the molecules that were altered by the pesticides, we used high-throughput screening to identify molecules that could inhibit the effect of free radicals on the pathway,’ said Ambasudhan. ‘One molecule we identified was isoxazole, which protected mutant neurons from cell death induced by the tested pesticides. Since several FDA-approved drugs contain derivatives of isoxazole, our findings may have potential clinical implications for repurposing these drugs to treat Parkinson’s.’ Sanford-Burnham Medical Research Institution
Scientists identify protein responsible for controlling communication between brain cells
, /in E-News /by 3wmediaScientists are a step closer to understanding how some of the brain’s 100 billion nerve cells co-ordinate their communication.
The University of Bristol research team investigated some of the chemical processes that underpin how brain cells co-ordinate their communication. Defects in this communication are associated with disorders such as epilepsy, autism and schizophrenia, and therefore these findings could lead to the development of novel neurological therapies.
Neurons in the brain communicate with each other using chemicals called neurotransmitters. This release of neurotransmitter from neurons is tightly controlled by many different proteins inside the neuron. These proteins interact with each other to ensure that neurotransmitter is only released when necessary. Although the mechanisms that control this release have been extensively studied, the processes that co-ordinate how and when the component proteins interact is not fully understood.
The School of Biochemistry researchers have now discovered that one of these proteins called ‘RIM1α’ is modified by a small protein named ‘SUMO’ which attaches to a specific region in RIM1α. This process acts as a ‘molecular switch’ which is required for normal neurotransmitter release.
Jeremy Henley, Professor of Molecular Neuroscience in the University’s Faculty of Medical and Veterinary Sciences and the study’s lead author, said: ‘These findings are important as they show that SUMO modification plays a vital and previously unsuspected role in normal brain function.’ Bristol University
Research may help scientists understand what causes pregnancy complications
, /in E-News /by 3wmediaDr. Hanna Mikkola and researchers at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have identified a specific type of cell and a related cell communication pathway that are key to the successful growth of a healthy placenta. The findings could greatly bolster our knowledge about the potential causes of complications during pregnancy.
Specifically, the findings could help scientists clarify the particular order in which progenitor cells grow in the placenta, which would allow researchers to track foetal development and identify complications. Progenitor cells are cells that develop into other cells and that initiate growth of the placenta.
The placenta is the organ that forms inside the uterus during pregnancy and enables oxygen and nutrients to reach the foetus, but little is understood about the biological mechanisms and cellular processes responsible for this interface. Studying mouse models, Mikkola and her colleagues tracked individual cells in the placenta to determine which cells and which cell communication routes, or signalling pathways, were responsible for the healthy development of the placenta.
The UCLA team was the first to identify the cells that form the placenta: Epcamhi labyrinth trophoblast progenitors, or LaTP cells, can become the various cells necessary to form a specific tissue, in this case the placenta.
Mikkola and her colleagues also found a signalling pathway that consists of hepatocyte growth factor and its receptor, c-Met. The researchers found that this signalling pathway was required for the placenta to keep making LaTP cells. Production of LaTP cells, in turn, continues the production of the different cells needed to maintain the growth and health of the placenta while the foetus is growing. Placental health enables healthy transmission of oxygen and nutrients through the exchange of blood between the foetus and the mother. In the mice, when c-Met signalling stopped, foetal growth slowed, the liver did not develop fully and it produced fewer blood cells, and the foetus died.
‘Identifying this novel c-Met–dependent multipotent labyrinth trophoblast progenitor is a landmark that may help us understand pregnancy complications that are caused by defective placental exchange, such as foetal growth restriction,’ Mikkola said. University of California – Los Angeles
Hepatitis C antibody test obtains CE mark
, /in E-News /by 3wmediaIt has been estimated that 3 to 4 million people are infected with hepatitis C virus (HCV) each year with the risk of developing liver cirrhosis and/or liver cancer. More than 350,000 people die each year from HCV-related conditions. With earlier detection and diagnosis, patients have a hope of receiving timely treatment and care for improved management of the condition. MP Biomedicals recently obtained the CE Marking for its patented multiparameter HCV test, the Multisure HCV antibody test. This test is intended for the detection and differentiation of Hepatitis C antibodies that may be present in patients with acute or chronic HCV infection. This innovative test is based on the patented reverse-flow technology, giving greater sensitivity and stronger visual signals. Multisure HCV uses human whole blood, plasma or serum. The test is fast and can help differentiate HCV antibodies against both structural and non-structural proteins across six genotypes.
www.mpbio.comMedical mystery solved
, /in E-News /by 3wmediaPeople from around the country and the world turn to Johan Van Hove, MD, PhD, for advice on a rare metabolic disease known as NKH, which can disrupt the body in devastating and even deadly ways. Now, Van Hove, a University of Colorado medical school professor, has identified a new disease related to NKH, a finding that resolves previously baffling cases including the death of a Colorado girl.
‘This opens the door,’ Van Hove said. ‘I am hopeful that it will eventually lead to major advances in dealing with these diseases.’ The research team led by Van Hove, including scientists from the United States and five other countries, calls the new disease variant NKH.
The discovery is part of the new wave of personalised medicine being pioneered at CU and other institutions, in which researchers and doctors delve into the human genome to determine what is causing disease and use the information to try to fix the problem.
Van Hove has been on the trail of NKH for 22 years. Much of the funding for his research comes from families and others who have encountered the disease.
NKH, short for non-ketotic hyperglycinaemia, occurs in about one in 60,000 births. It involves the amino acid glycine, a building block for many functions including movement and brain activity. When a genetic mutation prevents the body from breaking down excess glycine, it can cause brain problems including severe epilepsy and impaired intellectual development.
Scientists know the symptoms of NKH and also the genes that, when they malfunction, cause it. But a few patients worldwide had symptoms or glycine test results that were similar but did not quite match up.
One of those patients was a Colorado girl. She seemed fine until she was six months old. Then she began to lose muscle tone. She lost some control of her head movements. Seizures came next, along with a range of muscle twitches. By eight she lost her ability to walk. At the end, she spent most of her time curled in the foetal position.
Several years ago, at age 11, she died.
Researchers kept her genetic material, as they did with other patients who seemed to fall outside the NKH symptoms or who had molecular test results that were outside of the NKH pattern. The patients, some of whom are living, were scattered around the globe, in Australia, Lebanon, Canada and other countries as well as in the United States.
By looking into the genomes of this group of 11, Van Hove and his colleagues found that eight shared a genetic glitch different than the ones associated with NKH.
In other words, ‘this is a new disease,’ said Van Hove, who practices at Children’s Hospital Colorado.
More testing is likely to reveal more such patients and, he said, may allow development of a new drug to make life better for patients with variant NKH. EurekAlert