A new blood test promises to predict which people will have severe allergic reactions to foods according to a new study led by Mount Sinai researchers.
To detect food allergies, physicians typically use skin prick tests or blood tests that measure levels of allergen-specific IgE (sIgE), a protein made by the immune system. However, these tests cannot predict the severity of allergic reactions.
Oral food challenges, in which specific allergens are given to patients to ingest under physician supervision to test for signs or symptoms of an allergic reaction, remain the gold standard for diagnosing food allergy even though the tests themselves can trigger severe reactions.
In the newly published study, Mount Sinai researchers from The Mindich Child Health and Development Institute and the Jaffe Food Allergy Institute report that by counting the numbers of one type of immune cell activated by exposure to a food, a simple, safe blood test can accurately predict the severity of each person’s allergic reaction to it. The immune cell measured is the basophil, and the blood test, the basophil activation test or BAT, requires only a small blood sample and provides quick results.
“While providing crucial information about their potential for a severe allergic reaction to a food, having blood drawn for BAT testing is a much more comfortable procedure than food challenges.” says first author Ying Song, MD. “Although food challenges are widely practiced, they carry the risk of severe allergic reactions, and we believe BAT testing will provide accurate information in a safer manner,” says Dr. Song, also a researcher in the Jaffe Food Allergy Institute at The Mount Sinai Hospital.
“Although the blood basophil activation test has been shown to be an important addition to the tools available for discriminating between allergic and non-allergic individuals and predicting the severity of food allergy reactions, at this time it is only approved for research purposes,” says senior author Xiu-Min Li, MD, Professor of Pediatrics at the Icahn School of Medicine.
Mount Sinai Hospital
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Separating circulating cancer cells from blood cells for diagnostic, prognostic and treatment purposes may become much easier using an acoustic separation method and an inexpensive, disposable chip, according to a team of engineers.
‘Looking for circulating tumour cells in a blood sample is like looking for a needle in a haystack,’ said Tony Jun Huang, professor of engineering science and mechanics. ‘Typically, the CTCs are about one in every one billion blood cells in the sample.’
Existing methods of separation use tumour-specific antibodies to bind with the cancer cells and isolate them, but require that the appropriate antibodies be known in advance. Other methods rely on size, deformability or electrical properties. Unlike conventional separation methods that centrifuge for 10 minutes at 3000 revolutions per minute, surface acoustic waves can separate cells in a much gentler way with a simple, low-cost device.
Acoustic-based separations are potentially important because they are non-invasive and do not alter or damage cells. However, in order to be effective for clinical use, they also need to be rapidly and easily applicable.
‘In order to significantly increase the throughput for capturing those rare CTCs, device design has to be optimized for much higher flow rates and longer acoustic working length,’ said Ming Dao, principal research scientist, materials science and engineering, Massachusetts Institute of Technology. ‘With an integrated experimental/modelling approach, the new generation of the device has improved cell sorting throughput more than 20 times higher than previously achieved and made it possible for us to work with patient samples.’
The researchers worked both experimentally and with models to optimize the separation of CTCs from blood. They used an acoustic-based microfluidic device so that the stream of blood could continuously pass through the device for separation. Using the differential size and weight of the different cells they chose appropriate acoustic pressures that would push the CTCs out of the fluid stream and into a separate channel for collection.
Tilted-angle standing surface acoustic waves can separate cells using very small amounts of energy. The power intensity and frequency used in this study are similar to those used in ultrasonic imaging, which has proven to be extremely safe, even for fetuses. Also, each cell experiences the acoustic wave for only a fraction of a second. In addition, cells do not require labelling or surface modification. All these features make the acoustic separation method, termed acoustic tweezers, extremely biocompatible and maximize the potential of CTCs to maintain their functions and native states.
If two sound sources are placed opposite each other and each emits the same wavelength of sound, there will be a location where the opposing sounds cancel each other. Because sound waves have pressure, they can push very small objects, so a cell or nanoparticle will move with the sound wave until it reaches the location where there is no longer lateral movement, in this case, into the fluid stream that moves the separated cells along.
The researchers used two types of human cancer cells to optimize the acoustic separation — HELA cells and MCF7 cells. These cells are similar in size. They then ran an experiment separating these cells and had a separation rate of more than 83 percent. They then did the separation on other cancer cells, ones for which the device had not been optimized, and again had a separation rate of more than 83 percent.
‘Because these devices are intended for use with human blood, they need to be disposable,’ said Huang. ‘We are currently figuring out manufacturing and mass production possibilities.’
Physicians could use the devices to monitor how patients reacted to chemotherapy, for initial diagnosis and for determining treatment and prognosis.
Penn State University
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Scientists at the Translational Genomics Research Institute (TGen), using state-of-the-art genetic technology, have discovered the likely cause of a child’s rare type of severe muscle weakness.
The child was one of six cases in which TGen sequenced – or decoded – the genes of patients with Neuromuscular Disease (NMD) and was then able to identify the genetic source, or likely genetic source, of each child’s symptoms.
‘In all six cases of myopathy, or muscle weakness, these children had undergone extensive, expensive and invasive testing – often over many years – without a successful diagnosis, until they enrolled in our study,’ said Dr. Lisa Baumbach-Reardon, an Associate Professor of TGen’s Integrated Cancer Genomics Division and the study’s senior author.
This is a prime example of the type of ‘personalized medicine’ TGen uses to zero in on diagnoses for patients, and to help their physicians find the best possible treatments.
‘Our results demonstrate the diagnostic value of a comprehensive approach to genetic sequencing,’ said Dr. Baumbach-Reardon. ‘This type of next-generation sequencing can greatly improve the ability to identify pathogenic, or disease-causing, genetic variants with a single, timely, affordable test.’
In one of the six cases, TGen researchers found a unique disease-causing variant, or mutation, in the CACNA1S gene for a child with severe muscle weakness in addition to ophthalmoplegia, or the inability to move his eyes. Properly functioning CACNA1S is essential for muscle movement. More specifically, CACNA1S senses electrical signals from the brain and enables muscles to contract.
‘To our knowledge, this is the first reported case of severe congenital myopathy with ophthalmoplegia resulting from pathogenic variants in CACNA1S,’ said Dr. Jesse Hunter, a TGen Senior Post-Doctoral Fellow, and the study’s lead author.
Learning the specific genetic cause of symptoms is a key step in finding new therapeutic drugs that could treat the patient’s disease.
Translational Genomics Research Institute (TGen)
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Massachusetts General Hospital (MGH) investigators have identified an inflammatory molecule that appears to play an essential role in the autoimmune disorder systemic lupus erythematosus, commonly known as lupus. In their report, the researchers describe finding that a protein that regulates certain cells in the innate immune system – the body’s first line of defence against infection – activates a molecular pathway known to be associated with lupus and that the protein’s activity is required for the development of lupus symptoms in a mouse model of the disease.
“This study is the first demonstration that the receptor TREML4 amplifies the cellular responses transmitted through the TLR7 receptor and that a lack of such amplification prevents the inflammatory overactivation underlying lupus,” says Terry Means, PhD, of the Center for Immunology and Inflammatory Diseases in the MGH Division of Rheumatology, Allergy, and Immunology. “Our preliminary results suggest that TREML4-regulated signalling through TLR7 may be a potential drug target to limit inflammation and the development of autoimmunity.”
Lupus is an autoimmune disorder characterized by periodic inflammation of joints, connective tissues and organs including heart, lungs, kidneys and brain. TLR7 is one of a family of receptors present on innate immune cells like macrophages that have been linked to chronic inflammation and autoimmunity. Animal studies have suggested that overactivation of TLR7 plays a role in lupus, and a gene variant that increases expression of the receptor has been associated with increased lupus risk in human patients. The current study was designed to identify genes for other molecules required for TLR7-mediated immune cell activation.
The MGH-based team conducted an RNA-interference-based genome-scale screen of mouse macrophages, selectively knocking down the expression of around 8,000 genes, and found that TREML4 – one of a family of receptors found on granulocytes and monocytes – amplifies the response of innate immune cells to activation via TLR7. Immune cells from mice lacking TREML4 showed a weakened response to TLR7 activation. When a strain of mice genetically destined to develop a form of TLR7-dependent lupus was crossbred with a strain in which TREML4 expression was suppressed, offspring lacking TREML4 were protected from the development of lupus-associated kidney failure and had significantly lower blood levels of inflammatory factors and autoantibodies than did mice expressing TREML4.
Means notes that identifying the potential role of TREML4 in human lupus may lead to the development of drugs that could prevent or reduce the development or progression of lupus and another autoimmune disorder called Sjögren’s syndrome, which also appears to involve TLR7 overactivation. Future studies are needed to better define the molecular mechanism behind TREML4-induced amplification of TLR7 signaling and to clarify beneficial reactions controlled by TREML4 – for example, the immune response to influenza virus, which the current study found was inhibited by TREML4 deficiency.
Massachusetts General Hospital
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The link between taking aspirin, non-steroidal anti-inflammatory drugs, or NSAIDS, and colorectal cancer prevention is well established, but the mechanisms behind the protective effect have not been understood. A new study, co-led by investigators at Fred Hutchinson Cancer Research Center suggests this protection differs according to variations in DNA.
“We’ve known for a very long time that aspirin, ibuprofen and other NSAIDs are protective for colorectal cancer, but they can’t be used as a preventive agent because of the uncertainty of the risk-benefit ratio – longtime use can lead to gastrointestinal bleeding and other side effects,” said Ulrike “Riki” Peters, Ph.D., M.P.H., co-senior author of the paper and a cancer prevention researcher in the Public Health Sciences Division at Fred Hutchinson Cancer Research Center. “We wanted to investigate if genetic variation determined who is responding particularly well with aspirin – for whom aspirin and NSAID use has particular benefit and for whom it doesn’t.”
For the study, Peters and colleagues – including co-corresponding author and lead biostatistician Li Hsu, Ph.D., also of Fred Hutch, analyzed data from 10 large population-based studies in North America, Australia and Germany. They compared genetic and lifestyle data from 8,624 people who developed colorectal cancer with that of 8,553 people who did not (both groups were matched by age and gender).
While regular use of aspirin and NSAIDS was associated with an overall reduced risk of colorectal cancer, the researchers found no such protective effect among about 9 percent of the study participants who had genetic variations on chromosome 15. What’s more, about 4 percent of the participants who carried two even rarer genotypes on chromosome 12 had an increased risk of colorectal cancer.
Understanding the interplay between such genetic variations and the use of aspirin and NSAIDs, also known as “gene-by-environment interactions,” eventually may help identify those who could benefit most from these medications for cancer prevention as well as those who should steer clear of them.
“Our hope is that we can find a subgroup of the population where the benefits so outweigh the risks that it makes sense to take aspirin or NSAIDs,” Peters said. “But we’re not there yet.”
Fred Hutchinson Cancer Research Center
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A genetic analysis led by UT Southwestern Medical Center researchers suggests that most pancreatic cancers harbour genetic alterations that could be targeted by existing drugs, using their genetic features as a roadmap for treatment. The findings support a precision approach to treating pancreatic cancer, the fourth most deadly cancer for both men and women.
A comprehensive DNA sequencing of pancreatic cancer cases revealed not only a plethora of damaged genes, but potential diagnostic biomarkers that could help identify those with longer or shorter survival, and provide opportunity for new therapeutic interventions.
“We identified a wealth of genetic diversity, including multiple mutated genes that were previously unknown to pancreatic cancer − an important step in gaining a better understanding of this difficult and particularly deadly disease,” said lead author Dr. Agnieszka Witkiewicz, Associate Professor of Pathology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “Importantly, the team was able to identify several genes that may be able to help us to predict outcomes in certain circumstances or serve as good candidates for therapeutic efforts.”
Researchers have long hoped that genetic analysis would provide insight into the biology of pancreatic cancer and define new targets for more effective treatment. Achieving this goal has been hampered by the technical difficulty of isolating pure cancer cells out of the tumour tissue that contains both tumour cells as well as normal cells. The new study overcame this limitation by selectively dissecting cancer cells from pieces of tumour tissue. This method was applied to specifically determine the genetic features of 109 different tumours.
The data showed that the genetic architecture of pancreatic cancer is complex, and each patient’s tumour was found to be unique. The genetic features illuminated ways in which the disease arises, defined events associated with survival, and yielded potential targets for therapeutic intervention.
“While we suspect that genetics can be used as the basis of targeted treatments, this point will only be proven through extensive research and clinical studies, hopefully leading to improved outcomes for patients,” said senior author Dr. Erik Knudsen, Professor of Pathology, and member of the Simmons Cancer Center who holds the Dr. Charles T. Ashworth Professorship in Pathology. “I am considerably more optimistic of the utility of a genetically targeted therapy for pancreatic cancer today than when we began this work.”
Pancreatic cancer is particularly difficult to treat, and is often diagnosed at a late stage when it is no longer amenable to surgical removal. Chemotherapy has a modest effect, and unfortunately the disease progresses in the vast majority of cases. Therefore, new therapeutic regimens are urgently needed.
UT Southwestern Medical Center
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Building on their discovery of a gene linked to eating disorders in humans, a team of researchers at the University of Iowa has now shown that loss of the gene in mice leads to several behavioural abnormalities that resemble behaviours seen in people with anorexia nervosa.
The team, led by Michael Lutter, MD, PhD, assistant professor of psychiatry in the UI Carver College of Medicine, found that mice that lack the oestrogen-related receptor alpha (ESRRA) gene are less motivated to seek out high-fat food when they are hungry and have abnormal social interactions. The effect was stronger in female mice, which also showed increased obsessive-compulsive-like behaviours.
The study also shows that ESRRA levels are controlled by energy status in the mice. Restricting calorie intake to 60 percent of normal over several days significantly increased levels of ESRRA in the brains of normal mice.
“Decreased calorie intake usually motivates animals, including humans, to seek out high-calorie food. These findings suggest that loss of ESRRA activity may disrupt that response,” Lutter says.
Anorexia nervosa and bulimia nervosa are common and severe mental illnesses. Lutter notes that although 50 to 70 percent of the risk of getting an eating disorder is inherited, identifying the genes that mediate this risk has proven difficult. Learn more about the treatment of eating disorders at UI Hospitals and Clinics.
ESRRA is a transcription factor—a gene that turns on other genes. Lutter and his colleagues previously found that a mutation that reduces ESRRA activity is associated with an increased risk for eating disorders in human patients. Although ESRRA is expressed in many brain regions that are disrupted in anorexia, almost nothing was known about its function in the brain. In the new study Lutter’s team manipulated ESRRA in mice to investigate the gene’s role in behaviour.
University of Iowa Hospitals and Clinics
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Innovative gastric cancer-detection technology can be used for the early detection of stomach cancer and for identifying persons at risk for developing the disease. The new detection method, based on breath analysis, has significant advantages over the existing detection technology.
Gastric cancer is one of the most lethal forms of cancer and in most cases, its diagnosis involves an endoscopy (the insertion of a tube into the oesophagus, requiring that the patient fast and receive an intravenous sedative). Treatment is aggressive chemotherapy, radiation and the full or partial removal of the stomach. The disease develops in a series of well-defined steps, but there’s currently no effective, reliable, and non-invasive screening test for picking up these changes early on. Thus, many people succumb to stomach cancer only because it was not diagnosed in time.
The new technology, developed by Prof. Hossam Haick of the Technion Faculty of Chemical Engineering, can be used to detect premalignant lesions at the earliest stage, when healthy cells start becoming cancerous.
The research, published as part of the doctoral thesis of Mr. Haitham Amal, was conducted in conjunction with a Latvian research group headed by Prof. Marcis Leja, based on the largest population sample ever in a trial of this type. 484 people participated in the trial, 99 of whom had already been diagnosed with stomach cancer. All the participants were tested for Helicobacter pylori, a bacterium known to increase the risk for stomach cancer, and two breath samples were taken from each person.
The first sample from each participant was analysed using the GCMS technique, which measures volatile organic substances in exhaled breath. The researchers noted that GCMS technology cannot be used to detect stomach cancer because the testing is very expensive and requires lengthy processing times and considerable expertise to operate the equipment.
The second breath sample was tested using nanoarray analysis, the unique technology developed by Prof. Haick, combined with a pattern recognition algorithm.
The findings:
Based on the concentrations of 8 specific substances (out of 130) in the oral cavity, the new technology can distinguish between three groups: gastric cancer patients, persons who have precancerous stomach lesions, and healthy individuals.
The new technology accurately distinguishes between the various pre-malignant stages.
The new technology can be used to identify persons at risk for developing gastric cancer.
The diagnosis is accurate, regardless of other factors such as age, sex, smoking habits, alcohol consumption and the use of anti-oxidant drugs.
In short, the nano-array analysis method developed by Prof. Haick is accurate, sensitive technology that provides a simple and inexpensive alternative to existing tests (such as GCMS). This new technology offers early, effective detection of persons at risk for developing stomach cancer, without unnecessary invasive tests (endoscopy). In order to assess the accuracy and effectiveness of the new, a wide-scale clinical trial is currently under way in Europe, with thousands of participants who have cancerous or pre-cancerous tumours.
Technion
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A new method for measuring genetic variability within a tumour might one day help doctors identify patients with aggressive cancers that are more likely to resist therapy, according to a study led by researchers now at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
Researchers used a new scoring method they developed called MATH (mutant-allele tumour heterogeneity) to measure the genetic variability among cancer cells within tumours from 305 patients with head and neck cancer. High MATH scores corresponded to tumours with many differences among the gene mutations present in different cancer cells.
Cancers that showed high genetic variability – called ‘intra-tumour heterogeneity’ – correlated with lower patient survival. If prospective studies verify the findings, MATH scores could help identify the most effective treatment for patients and predict a patient’s prognosis.
Researchers have long hypothesized that multiple sub-populations of mutated cells within a single cancer lead to worse clinical outcomes; however, oncologists do not use tumour heterogeneity to guide clinical care decisions or assess disease prognosis because there is no single, easy-to-implement method of doing so in clinical practice.
To address this need, James Rocco, MD, PhD, and his colleagues developed MATH to make it easier for doctors to measure genetic variability in patients’ tumours and to help guide treatment decisions.
The new findings confirm that high genetic variability with a patient’s tumour is related to increased mortality in head and neck squamous cell carcinoma.
‘Genetic variability within tumours is likely why people fail treatment,’ says Rocco, Professor and John and Mary Alford Chair of Head and Neck Surgery and Director of the OSUCCC – James Division of Head and Neck Oncologic Surgery. ‘In patients who have high heterogeneity tumours it is likely that there are several clusters of underlying mutations – in the same tumour – driving the cancer. So their tumours are likely to have some cells that are already resistant to any particular therapy.’
For the current study, Rocco and his team used the MATH tool to analyse retrospective data from 305 head and neck squamous cell carcinoma patients from The Cancer Genome Atlas (TCGA). This National Institutes of Health repository of publicly available data was launched in 2006 as a pilot project and now includes samples from more than 11,000 patients across 33 tumour types. The MATH score was calculated from data obtained by TCGA with a genome sequencing technique called whole-exome sequencing.
Researchers confirmed that high intra-tumour heterogeneity was related to increased mortality in this sub segment of patients. Each 10 percent increase in MATH score corresponded to an 8.8 percent increased likelihood of death.
The relationship between MATH score and mortality was not dependent on HPV (human papilloma virus) status or other molecular characteristics of the tumour.
‘Our retrospective analysis showed that patients with high heterogeneity tumours were more than twice as likely to die compared to patients with low heterogeneity tumors,’ says Rocco. ‘This type of information could refine the dialogue about how we tackle cancer by helping us predict a patient’s treatment success and justify clinical decisions based on the unique makeup of a patient’s tumor.’
EurekAlert
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In a recent study, Virginia Commonwealth University School of Medicine researchers predicted which cirrhosis patients would suffer inflammations and require hospitalization by analysing their saliva, revealing a new target for research into a disease that accounts for more than 30,000 deaths in the United States each year.
The findings could trigger a change in the way researchers study chronic liver disease and associated microbiota, the network of tiny organisms in the human body such as bacteria and fungi that can either bolster an immune system or weaken it.
The breakdown of defences in the mucosa of the gut has long been a signal of inflammation in those with cirrhosis, which sees healthy liver tissue replaced by scar tissue.
The recent findings suggest that another part of the body also can produce warning signs.
“It has been believed that most of the pathogenesis of cirrhosis starts in the gut, which is what makes this discovery so fascinating,” said Jasmohan S. Bajaj, M.D., associate professor of hepatology in the VCU School of Medicine and Hunter Holmes McGuire Veterans Affairs Medical Center.“The fact that saliva, along with fluid in the gut, can be an indicator of inflammation tells us that we need to further explore the oral cavity and its connections to liver disease.”
The paper describes a study of more than 100 cirrhosis patients from VCU and VA Medical Center, 38 of which had to be hospitalized within 90 days because of flare-ups. Researchers found that the ratio of good-to-bad microbes was similar in the saliva as in the stool of these patients who required hospitalization.
Another part of the same study looked at an additional group of more than 80 people with and without cirrhosis. Those with cirrhosis had impaired salivary defenses, mirroring the immune deficiencies that take place in the gut.
“The data suggest that there may be a change in the overall mucosal-immune interface in cirrhosis patients, allowing a more toxic microbiota to emerge in both the gut and oral cavity,” said Phillip B. Hylemon, Ph.D., professor of microbiology and immunology in the VCU School of Medicine and co-author of the paper.
In addition to using oral microbiota to predict the disease status of cirrhosis patients, Hylemon said the new evidence could provide a useful tool for testing treatment protocols for patients with cirrhosis or other diseases driven by inflammation.
Virginia Commonwealth University Scool of Medicine
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Blood test predicts severity of peanut and seafood allergies
, /in E-News /by 3wmediaA new blood test promises to predict which people will have severe allergic reactions to foods according to a new study led by Mount Sinai researchers.
To detect food allergies, physicians typically use skin prick tests or blood tests that measure levels of allergen-specific IgE (sIgE), a protein made by the immune system. However, these tests cannot predict the severity of allergic reactions.
Oral food challenges, in which specific allergens are given to patients to ingest under physician supervision to test for signs or symptoms of an allergic reaction, remain the gold standard for diagnosing food allergy even though the tests themselves can trigger severe reactions.
In the newly published study, Mount Sinai researchers from The Mindich Child Health and Development Institute and the Jaffe Food Allergy Institute report that by counting the numbers of one type of immune cell activated by exposure to a food, a simple, safe blood test can accurately predict the severity of each person’s allergic reaction to it. The immune cell measured is the basophil, and the blood test, the basophil activation test or BAT, requires only a small blood sample and provides quick results.
“While providing crucial information about their potential for a severe allergic reaction to a food, having blood drawn for BAT testing is a much more comfortable procedure than food challenges.” says first author Ying Song, MD. “Although food challenges are widely practiced, they carry the risk of severe allergic reactions, and we believe BAT testing will provide accurate information in a safer manner,” says Dr. Song, also a researcher in the Jaffe Food Allergy Institute at The Mount Sinai Hospital.
“Although the blood basophil activation test has been shown to be an important addition to the tools available for discriminating between allergic and non-allergic individuals and predicting the severity of food allergy reactions, at this time it is only approved for research purposes,” says senior author Xiu-Min Li, MD, Professor of Pediatrics at the Icahn School of Medicine. Mount Sinai Hospital
Sound separates cancer cells from blood samples
, /in E-News /by 3wmediaSeparating circulating cancer cells from blood cells for diagnostic, prognostic and treatment purposes may become much easier using an acoustic separation method and an inexpensive, disposable chip, according to a team of engineers.
‘Looking for circulating tumour cells in a blood sample is like looking for a needle in a haystack,’ said Tony Jun Huang, professor of engineering science and mechanics. ‘Typically, the CTCs are about one in every one billion blood cells in the sample.’
Existing methods of separation use tumour-specific antibodies to bind with the cancer cells and isolate them, but require that the appropriate antibodies be known in advance. Other methods rely on size, deformability or electrical properties. Unlike conventional separation methods that centrifuge for 10 minutes at 3000 revolutions per minute, surface acoustic waves can separate cells in a much gentler way with a simple, low-cost device.
Acoustic-based separations are potentially important because they are non-invasive and do not alter or damage cells. However, in order to be effective for clinical use, they also need to be rapidly and easily applicable.
‘In order to significantly increase the throughput for capturing those rare CTCs, device design has to be optimized for much higher flow rates and longer acoustic working length,’ said Ming Dao, principal research scientist, materials science and engineering, Massachusetts Institute of Technology. ‘With an integrated experimental/modelling approach, the new generation of the device has improved cell sorting throughput more than 20 times higher than previously achieved and made it possible for us to work with patient samples.’
The researchers worked both experimentally and with models to optimize the separation of CTCs from blood. They used an acoustic-based microfluidic device so that the stream of blood could continuously pass through the device for separation. Using the differential size and weight of the different cells they chose appropriate acoustic pressures that would push the CTCs out of the fluid stream and into a separate channel for collection.
Tilted-angle standing surface acoustic waves can separate cells using very small amounts of energy. The power intensity and frequency used in this study are similar to those used in ultrasonic imaging, which has proven to be extremely safe, even for fetuses. Also, each cell experiences the acoustic wave for only a fraction of a second. In addition, cells do not require labelling or surface modification. All these features make the acoustic separation method, termed acoustic tweezers, extremely biocompatible and maximize the potential of CTCs to maintain their functions and native states.
If two sound sources are placed opposite each other and each emits the same wavelength of sound, there will be a location where the opposing sounds cancel each other. Because sound waves have pressure, they can push very small objects, so a cell or nanoparticle will move with the sound wave until it reaches the location where there is no longer lateral movement, in this case, into the fluid stream that moves the separated cells along.
The researchers used two types of human cancer cells to optimize the acoustic separation — HELA cells and MCF7 cells. These cells are similar in size. They then ran an experiment separating these cells and had a separation rate of more than 83 percent. They then did the separation on other cancer cells, ones for which the device had not been optimized, and again had a separation rate of more than 83 percent.
‘Because these devices are intended for use with human blood, they need to be disposable,’ said Huang. ‘We are currently figuring out manufacturing and mass production possibilities.’
Physicians could use the devices to monitor how patients reacted to chemotherapy, for initial diagnosis and for determining treatment and prognosis. Penn State University
Scientists find likely genetic source of muscle weakness
, /in E-News /by 3wmediaScientists at the Translational Genomics Research Institute (TGen), using state-of-the-art genetic technology, have discovered the likely cause of a child’s rare type of severe muscle weakness.
The child was one of six cases in which TGen sequenced – or decoded – the genes of patients with Neuromuscular Disease (NMD) and was then able to identify the genetic source, or likely genetic source, of each child’s symptoms.
‘In all six cases of myopathy, or muscle weakness, these children had undergone extensive, expensive and invasive testing – often over many years – without a successful diagnosis, until they enrolled in our study,’ said Dr. Lisa Baumbach-Reardon, an Associate Professor of TGen’s Integrated Cancer Genomics Division and the study’s senior author.
This is a prime example of the type of ‘personalized medicine’ TGen uses to zero in on diagnoses for patients, and to help their physicians find the best possible treatments.
‘Our results demonstrate the diagnostic value of a comprehensive approach to genetic sequencing,’ said Dr. Baumbach-Reardon. ‘This type of next-generation sequencing can greatly improve the ability to identify pathogenic, or disease-causing, genetic variants with a single, timely, affordable test.’
In one of the six cases, TGen researchers found a unique disease-causing variant, or mutation, in the CACNA1S gene for a child with severe muscle weakness in addition to ophthalmoplegia, or the inability to move his eyes. Properly functioning CACNA1S is essential for muscle movement. More specifically, CACNA1S senses electrical signals from the brain and enables muscles to contract.
‘To our knowledge, this is the first reported case of severe congenital myopathy with ophthalmoplegia resulting from pathogenic variants in CACNA1S,’ said Dr. Jesse Hunter, a TGen Senior Post-Doctoral Fellow, and the study’s lead author.
Learning the specific genetic cause of symptoms is a key step in finding new therapeutic drugs that could treat the patient’s disease. Translational Genomics Research Institute (TGen)
Investigators have found a potential new treatment target lupus
, /in E-News /by 3wmediaMassachusetts General Hospital (MGH) investigators have identified an inflammatory molecule that appears to play an essential role in the autoimmune disorder systemic lupus erythematosus, commonly known as lupus. In their report, the researchers describe finding that a protein that regulates certain cells in the innate immune system – the body’s first line of defence against infection – activates a molecular pathway known to be associated with lupus and that the protein’s activity is required for the development of lupus symptoms in a mouse model of the disease.
“This study is the first demonstration that the receptor TREML4 amplifies the cellular responses transmitted through the TLR7 receptor and that a lack of such amplification prevents the inflammatory overactivation underlying lupus,” says Terry Means, PhD, of the Center for Immunology and Inflammatory Diseases in the MGH Division of Rheumatology, Allergy, and Immunology. “Our preliminary results suggest that TREML4-regulated signalling through TLR7 may be a potential drug target to limit inflammation and the development of autoimmunity.”
Lupus is an autoimmune disorder characterized by periodic inflammation of joints, connective tissues and organs including heart, lungs, kidneys and brain. TLR7 is one of a family of receptors present on innate immune cells like macrophages that have been linked to chronic inflammation and autoimmunity. Animal studies have suggested that overactivation of TLR7 plays a role in lupus, and a gene variant that increases expression of the receptor has been associated with increased lupus risk in human patients. The current study was designed to identify genes for other molecules required for TLR7-mediated immune cell activation.
The MGH-based team conducted an RNA-interference-based genome-scale screen of mouse macrophages, selectively knocking down the expression of around 8,000 genes, and found that TREML4 – one of a family of receptors found on granulocytes and monocytes – amplifies the response of innate immune cells to activation via TLR7. Immune cells from mice lacking TREML4 showed a weakened response to TLR7 activation. When a strain of mice genetically destined to develop a form of TLR7-dependent lupus was crossbred with a strain in which TREML4 expression was suppressed, offspring lacking TREML4 were protected from the development of lupus-associated kidney failure and had significantly lower blood levels of inflammatory factors and autoantibodies than did mice expressing TREML4.
Means notes that identifying the potential role of TREML4 in human lupus may lead to the development of drugs that could prevent or reduce the development or progression of lupus and another autoimmune disorder called Sjögren’s syndrome, which also appears to involve TLR7 overactivation. Future studies are needed to better define the molecular mechanism behind TREML4-induced amplification of TLR7 signaling and to clarify beneficial reactions controlled by TREML4 – for example, the immune response to influenza virus, which the current study found was inhibited by TREML4 deficiency. Massachusetts General Hospital
The link between aspirin, NSAIDs and colon cancer prevention may hinge on genetic variations
, /in E-News /by 3wmediaThe link between taking aspirin, non-steroidal anti-inflammatory drugs, or NSAIDS, and colorectal cancer prevention is well established, but the mechanisms behind the protective effect have not been understood. A new study, co-led by investigators at Fred Hutchinson Cancer Research Center suggests this protection differs according to variations in DNA.
“We’ve known for a very long time that aspirin, ibuprofen and other NSAIDs are protective for colorectal cancer, but they can’t be used as a preventive agent because of the uncertainty of the risk-benefit ratio – longtime use can lead to gastrointestinal bleeding and other side effects,” said Ulrike “Riki” Peters, Ph.D., M.P.H., co-senior author of the paper and a cancer prevention researcher in the Public Health Sciences Division at Fred Hutchinson Cancer Research Center. “We wanted to investigate if genetic variation determined who is responding particularly well with aspirin – for whom aspirin and NSAID use has particular benefit and for whom it doesn’t.”
For the study, Peters and colleagues – including co-corresponding author and lead biostatistician Li Hsu, Ph.D., also of Fred Hutch, analyzed data from 10 large population-based studies in North America, Australia and Germany. They compared genetic and lifestyle data from 8,624 people who developed colorectal cancer with that of 8,553 people who did not (both groups were matched by age and gender).
While regular use of aspirin and NSAIDS was associated with an overall reduced risk of colorectal cancer, the researchers found no such protective effect among about 9 percent of the study participants who had genetic variations on chromosome 15. What’s more, about 4 percent of the participants who carried two even rarer genotypes on chromosome 12 had an increased risk of colorectal cancer.
Understanding the interplay between such genetic variations and the use of aspirin and NSAIDs, also known as “gene-by-environment interactions,” eventually may help identify those who could benefit most from these medications for cancer prevention as well as those who should steer clear of them.
“Our hope is that we can find a subgroup of the population where the benefits so outweigh the risks that it makes sense to take aspirin or NSAIDs,” Peters said. “But we’re not there yet.” Fred Hutchinson Cancer Research Center
Researchers lead collaborative charge to uncover genetic diversity of pancreatic cancer
, /in E-News /by 3wmediaA genetic analysis led by UT Southwestern Medical Center researchers suggests that most pancreatic cancers harbour genetic alterations that could be targeted by existing drugs, using their genetic features as a roadmap for treatment. The findings support a precision approach to treating pancreatic cancer, the fourth most deadly cancer for both men and women.
A comprehensive DNA sequencing of pancreatic cancer cases revealed not only a plethora of damaged genes, but potential diagnostic biomarkers that could help identify those with longer or shorter survival, and provide opportunity for new therapeutic interventions.
“We identified a wealth of genetic diversity, including multiple mutated genes that were previously unknown to pancreatic cancer − an important step in gaining a better understanding of this difficult and particularly deadly disease,” said lead author Dr. Agnieszka Witkiewicz, Associate Professor of Pathology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “Importantly, the team was able to identify several genes that may be able to help us to predict outcomes in certain circumstances or serve as good candidates for therapeutic efforts.”
Researchers have long hoped that genetic analysis would provide insight into the biology of pancreatic cancer and define new targets for more effective treatment. Achieving this goal has been hampered by the technical difficulty of isolating pure cancer cells out of the tumour tissue that contains both tumour cells as well as normal cells. The new study overcame this limitation by selectively dissecting cancer cells from pieces of tumour tissue. This method was applied to specifically determine the genetic features of 109 different tumours.
The data showed that the genetic architecture of pancreatic cancer is complex, and each patient’s tumour was found to be unique. The genetic features illuminated ways in which the disease arises, defined events associated with survival, and yielded potential targets for therapeutic intervention.
“While we suspect that genetics can be used as the basis of targeted treatments, this point will only be proven through extensive research and clinical studies, hopefully leading to improved outcomes for patients,” said senior author Dr. Erik Knudsen, Professor of Pathology, and member of the Simmons Cancer Center who holds the Dr. Charles T. Ashworth Professorship in Pathology. “I am considerably more optimistic of the utility of a genetically targeted therapy for pancreatic cancer today than when we began this work.”
Pancreatic cancer is particularly difficult to treat, and is often diagnosed at a late stage when it is no longer amenable to surgical removal. Chemotherapy has a modest effect, and unfortunately the disease progresses in the vast majority of cases. Therefore, new therapeutic regimens are urgently needed. UT Southwestern Medical Center
Advances in understanding of eating disorders
, /in E-News /by 3wmediaBuilding on their discovery of a gene linked to eating disorders in humans, a team of researchers at the University of Iowa has now shown that loss of the gene in mice leads to several behavioural abnormalities that resemble behaviours seen in people with anorexia nervosa.
The team, led by Michael Lutter, MD, PhD, assistant professor of psychiatry in the UI Carver College of Medicine, found that mice that lack the oestrogen-related receptor alpha (ESRRA) gene are less motivated to seek out high-fat food when they are hungry and have abnormal social interactions. The effect was stronger in female mice, which also showed increased obsessive-compulsive-like behaviours.
The study also shows that ESRRA levels are controlled by energy status in the mice. Restricting calorie intake to 60 percent of normal over several days significantly increased levels of ESRRA in the brains of normal mice.
“Decreased calorie intake usually motivates animals, including humans, to seek out high-calorie food. These findings suggest that loss of ESRRA activity may disrupt that response,” Lutter says.
Anorexia nervosa and bulimia nervosa are common and severe mental illnesses. Lutter notes that although 50 to 70 percent of the risk of getting an eating disorder is inherited, identifying the genes that mediate this risk has proven difficult. Learn more about the treatment of eating disorders at UI Hospitals and Clinics.
ESRRA is a transcription factor—a gene that turns on other genes. Lutter and his colleagues previously found that a mutation that reduces ESRRA activity is associated with an increased risk for eating disorders in human patients. Although ESRRA is expressed in many brain regions that are disrupted in anorexia, almost nothing was known about its function in the brain. In the new study Lutter’s team manipulated ESRRA in mice to investigate the gene’s role in behaviour. University of Iowa Hospitals and Clinics
New technology for early detection of stomach cancer
, /in E-News /by 3wmediaInnovative gastric cancer-detection technology can be used for the early detection of stomach cancer and for identifying persons at risk for developing the disease. The new detection method, based on breath analysis, has significant advantages over the existing detection technology.
Gastric cancer is one of the most lethal forms of cancer and in most cases, its diagnosis involves an endoscopy (the insertion of a tube into the oesophagus, requiring that the patient fast and receive an intravenous sedative). Treatment is aggressive chemotherapy, radiation and the full or partial removal of the stomach. The disease develops in a series of well-defined steps, but there’s currently no effective, reliable, and non-invasive screening test for picking up these changes early on. Thus, many people succumb to stomach cancer only because it was not diagnosed in time.
The new technology, developed by Prof. Hossam Haick of the Technion Faculty of Chemical Engineering, can be used to detect premalignant lesions at the earliest stage, when healthy cells start becoming cancerous.
The research, published as part of the doctoral thesis of Mr. Haitham Amal, was conducted in conjunction with a Latvian research group headed by Prof. Marcis Leja, based on the largest population sample ever in a trial of this type. 484 people participated in the trial, 99 of whom had already been diagnosed with stomach cancer. All the participants were tested for Helicobacter pylori, a bacterium known to increase the risk for stomach cancer, and two breath samples were taken from each person.
The first sample from each participant was analysed using the GCMS technique, which measures volatile organic substances in exhaled breath. The researchers noted that GCMS technology cannot be used to detect stomach cancer because the testing is very expensive and requires lengthy processing times and considerable expertise to operate the equipment.
The second breath sample was tested using nanoarray analysis, the unique technology developed by Prof. Haick, combined with a pattern recognition algorithm.
The findings:
Based on the concentrations of 8 specific substances (out of 130) in the oral cavity, the new technology can distinguish between three groups: gastric cancer patients, persons who have precancerous stomach lesions, and healthy individuals.
The new technology accurately distinguishes between the various pre-malignant stages.
The new technology can be used to identify persons at risk for developing gastric cancer.
The diagnosis is accurate, regardless of other factors such as age, sex, smoking habits, alcohol consumption and the use of anti-oxidant drugs.
In short, the nano-array analysis method developed by Prof. Haick is accurate, sensitive technology that provides a simple and inexpensive alternative to existing tests (such as GCMS). This new technology offers early, effective detection of persons at risk for developing stomach cancer, without unnecessary invasive tests (endoscopy). In order to assess the accuracy and effectiveness of the new, a wide-scale clinical trial is currently under way in Europe, with thousands of participants who have cancerous or pre-cancerous tumours. Technion
Genomics tool could help predict tumour aggressiveness, treatment outcomes
, /in E-News /by 3wmediaA new method for measuring genetic variability within a tumour might one day help doctors identify patients with aggressive cancers that are more likely to resist therapy, according to a study led by researchers now at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
Researchers used a new scoring method they developed called MATH (mutant-allele tumour heterogeneity) to measure the genetic variability among cancer cells within tumours from 305 patients with head and neck cancer. High MATH scores corresponded to tumours with many differences among the gene mutations present in different cancer cells.
Cancers that showed high genetic variability – called ‘intra-tumour heterogeneity’ – correlated with lower patient survival. If prospective studies verify the findings, MATH scores could help identify the most effective treatment for patients and predict a patient’s prognosis.
Researchers have long hypothesized that multiple sub-populations of mutated cells within a single cancer lead to worse clinical outcomes; however, oncologists do not use tumour heterogeneity to guide clinical care decisions or assess disease prognosis because there is no single, easy-to-implement method of doing so in clinical practice.
To address this need, James Rocco, MD, PhD, and his colleagues developed MATH to make it easier for doctors to measure genetic variability in patients’ tumours and to help guide treatment decisions.
The new findings confirm that high genetic variability with a patient’s tumour is related to increased mortality in head and neck squamous cell carcinoma.
‘Genetic variability within tumours is likely why people fail treatment,’ says Rocco, Professor and John and Mary Alford Chair of Head and Neck Surgery and Director of the OSUCCC – James Division of Head and Neck Oncologic Surgery. ‘In patients who have high heterogeneity tumours it is likely that there are several clusters of underlying mutations – in the same tumour – driving the cancer. So their tumours are likely to have some cells that are already resistant to any particular therapy.’
For the current study, Rocco and his team used the MATH tool to analyse retrospective data from 305 head and neck squamous cell carcinoma patients from The Cancer Genome Atlas (TCGA). This National Institutes of Health repository of publicly available data was launched in 2006 as a pilot project and now includes samples from more than 11,000 patients across 33 tumour types. The MATH score was calculated from data obtained by TCGA with a genome sequencing technique called whole-exome sequencing.
Researchers confirmed that high intra-tumour heterogeneity was related to increased mortality in this sub segment of patients. Each 10 percent increase in MATH score corresponded to an 8.8 percent increased likelihood of death.
The relationship between MATH score and mortality was not dependent on HPV (human papilloma virus) status or other molecular characteristics of the tumour.
‘Our retrospective analysis showed that patients with high heterogeneity tumours were more than twice as likely to die compared to patients with low heterogeneity tumors,’ says Rocco. ‘This type of information could refine the dialogue about how we tackle cancer by helping us predict a patient’s treatment success and justify clinical decisions based on the unique makeup of a patient’s tumor.’ EurekAlert
Mouth, as well as gut, could hold key to liver disease flare-ups
, /in E-News /by 3wmediaIn a recent study, Virginia Commonwealth University School of Medicine researchers predicted which cirrhosis patients would suffer inflammations and require hospitalization by analysing their saliva, revealing a new target for research into a disease that accounts for more than 30,000 deaths in the United States each year.
The findings could trigger a change in the way researchers study chronic liver disease and associated microbiota, the network of tiny organisms in the human body such as bacteria and fungi that can either bolster an immune system or weaken it.
The breakdown of defences in the mucosa of the gut has long been a signal of inflammation in those with cirrhosis, which sees healthy liver tissue replaced by scar tissue.
The recent findings suggest that another part of the body also can produce warning signs.
“It has been believed that most of the pathogenesis of cirrhosis starts in the gut, which is what makes this discovery so fascinating,” said Jasmohan S. Bajaj, M.D., associate professor of hepatology in the VCU School of Medicine and Hunter Holmes McGuire Veterans Affairs Medical Center.“The fact that saliva, along with fluid in the gut, can be an indicator of inflammation tells us that we need to further explore the oral cavity and its connections to liver disease.”
The paper describes a study of more than 100 cirrhosis patients from VCU and VA Medical Center, 38 of which had to be hospitalized within 90 days because of flare-ups. Researchers found that the ratio of good-to-bad microbes was similar in the saliva as in the stool of these patients who required hospitalization.
Another part of the same study looked at an additional group of more than 80 people with and without cirrhosis. Those with cirrhosis had impaired salivary defenses, mirroring the immune deficiencies that take place in the gut.
“The data suggest that there may be a change in the overall mucosal-immune interface in cirrhosis patients, allowing a more toxic microbiota to emerge in both the gut and oral cavity,” said Phillip B. Hylemon, Ph.D., professor of microbiology and immunology in the VCU School of Medicine and co-author of the paper.
In addition to using oral microbiota to predict the disease status of cirrhosis patients, Hylemon said the new evidence could provide a useful tool for testing treatment protocols for patients with cirrhosis or other diseases driven by inflammation. Virginia Commonwealth University Scool of Medicine