Epilepsy is a brain disorder which afflicts more than 50 million people worldwide. Many epilepsy patients can control their symptoms through medication, but about 30% suffer from intractable epilepsy and are unable to manage the disease with drugs. Intractable epilepsy causes multiple seizures, permanent mental, physical, and developmental disabilities, and even death. Therefore, surgical removal of the affected area from the brain has been practiced as a treatment for patients with medically refractory seizures, but this too fails to provide a complete solution because only 60% of the patients who undergo surgery are rendered free of seizures.
A Korean research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering at the Korea Advanced Institute of Science and Technology (KAIST) and Professor Dong-Seok Kim of Epilepsy Research Center at Yonsei University College of Medicine has recently identified brain somatic mutations in the gene of mechanistic target of rapamycin (MTOR) as the cause of focal cortical dysplasia type II (FCDII), one of the most important and common inducers to intractable epilepsy, particularly in children. They propose a targeted therapy to lessen epileptic seizures by suppressing the activation of mTOR kinase, a signalling protein in the brain.
FCDII contributes to the abnormal developments of the cerebral cortex, ranging from cortical disruption to severe forms of cortical dyslamination, balloon cells, and dysplastic neurons. The research team studied 77 FCDII patients with intractable epilepsy who had received a surgery to remove the affected regions from the brain. The researchers used various deep sequencing technologies to conduct comparative DNA analysis of the samples obtained from the patients’ brain and blood, or saliva. They reported that about 16% of the studied patients had somatic mutations in their brain. Such mutations, however, did not take place in their blood or saliva DNA.
Professor Jeong Ho Lee of KAIST said, “This is an important finding. Unlike our previous belief that genetic mutations causing intractable epilepsy exist anywhere in the human body including blood, specific gene mutations incurred only in the brain can lead to intractable epilepsy. From our animal models, we could see how a small fraction of mutations carrying neurons in the brain could affect its entire function.”
KAIST
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A new test from Washington University’s Genomic Pathology Services will help physicians quickly zero in on genetic mutations that may be contributing to kidney disease.
Many kidney disorders are difficult to diagnose. To address this problem, scientists and clinicians have developed a diagnostic test that identifies genetic changes linked to inherited kidney disorders. This testing is now available nationwide through Genomic Pathology Services (GPS) at Washington University School of Medicine in St. Louis.
“For many kidney diseases, diagnosis can be an odyssey in which you sequence one gene after another over a long period of time to learn what’s going wrong and what the best options are for treatment,” said GPS chief medical officer and Washington University pathologist Jonathan Heusel, MD, PhD. “It makes more sense to screen all the possible contributing genes at once with a single test and consider options for treatment.”
To make this possible, the GPS team developed the test with kidney disease specialists, including Joseph Gaut, MD, PhD, a renal pathologist.
The test employs next-generation sequencing technology to decode genes associated with kidney disease. Using software developed at the university, clinical genomics specialists analyse and interpret the observed genetic alterations to identify disease-related genetic changes, or variants. They then must determine whether a given variant poses clinical risks based on available medical knowledge.
“The variants have to be evaluated on a case-by-case basis, which can be time-consuming and labour-intensive,” Heusel said.
GPS continues to update the kidney test as new links between kidney problems and DNA are identified.
“We stay abreast of the literature, and as new genes become clinically meaningful, we will incorporate those into the test,” said Catherine Cottrell, PhD, medical director for GPS.
The kidney test will check for:
• Alport syndrome, which is characterized by progressive loss of kidney function, hearing loss and eye abnormalities;
• Nephrotic syndrome, which includes symptoms such as protein in the urine, low blood-protein levels, high levels of cholesterol and triglycerides, and swelling;
• Metabolic disorders associated with renal disease and including other systemic abnormalities such as diabetes, amyloidosis and others;
• Complement (immune system) defects related to kidney disease, including atypical hemolytic uremic syndrome.
Washington University
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Australian researchers have found that so-called ‘triple-negative breast cancers’ are two distinct diseases that likely originate from different cell types. This helps explain why survival prospects for women with the diagnosis tend to be either very good or very bad.
The Sydney-based research team has found a gene that drives the aggressive disease, and hopes to find a way to ‘switch it off’. The aggressive form of triple-negative breast cancer appears to arise from stem cells, while the more benign form appears to arise from specialised cells.
Stem cells have many of the same features as cancers. They are plastic and flexible, and have the ability to proliferate and spread into other tissues – deadly traits in cancers.
Previous studies have shown that breast stem cells are needed for breast growth and development during puberty and pregnancy, although how they evolve from stem cells into specialist cells has been unclear.
The new study has shown that a gene known as ‘inhibitor of differentiation’ (ID4) determines whether a stem cell remains a stem cell, or whether it differentiates into a specialist cell.
Notably, when the high levels of ID4 in a stem cell are ‘switched off’, other genes that drive cell specialisation are ‘switched on’.
Drs Alex Swarbrick and Simon Junankar from Sydney’s Garvan Institute of Medical Research spearheaded this large interdisciplinary study, which links the development of the mammary gland in mice with human breast cancer. Its main finding, that ID4 not only ‘marks’, but appears to control, the highly aggressive form of triple negative breast cancer.
“We found that ID4 is produced at high levels in roughly half of all triple negative breast cancers, and that these cancers have a particularly poor prognosis,” said project leader Dr Alex Swarbrick.
“We also showed that if you block the ID4 gene in experimental models of triple negative breast cancer, the tumour cells stop dividing.”
Garvan Institute of Medical Research
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Researchers sequenced the genomes of members of 13 families severely affected by autism and compared the sequences to those of healthy controls.
They identified genetic variants that had never before been linked to autism.
One affected gene, CTNND2, plays a critical role in brain development and regulates how many other genes function.
Using a novel approach that homes in on rare families severely affected by autism, a Johns Hopkins-led team of researchers has identified a new genetic cause of the disease. The rare genetic variant offers important insights into the root causes of autism, the researchers say. And, they suggest, their unconventional method can be used to identify other genetic causes of autism and other complex genetic conditions.
In recent years, falling costs for genetic testing, together with powerful new means of storing and analysing massive amounts of data, have ushered in the era of the genomewide association and sequencing studies. These studies typically compare genetic sequencing data from thousands of people with and without a given disease to map the locations of genetic variants that contribute to the disease. While genome-wide association studies have linked many genes to particular diseases, their results have so far failed to lead to predictive genetic tests for common conditions, such as Alzheimer’s, autism or schizophrenia.
“In genetics, we all believe that you have to sequence endlessly before you can find anything,” says Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. “I think whom you sequence is as important — if not more so — than how many people are sequenced.”
With that idea, Chakravarti and his collaborators identified families in which more than one female has autism spectrum disorder, a condition first described at Johns Hopkins in 1943. For reasons that are not understood, girls are far less likely than boys to have autism, but when girls do have the condition, their symptoms tend to be severe. Chakravarti reasoned that females with autism, particularly those with a close female relative who is also affected, must carry very potent genetic variants for the disease, and he wanted to find out what those were.
The research team compared the gene sequences of autistic members of 13 such families to the gene sequences of people from a public database. They found four potential culprit genes and focused on one, CTNND2, because it fell in a region of the genome known to be associated with another intellectual disability. When they studied the gene’s effects in zebrafish, mice and cadaveric human brains, the research group found that the protein it makes affects how many other genes are regulated. The CTNND2 protein was found at far higher levels in foetal brains than in adult brains or other tissues, Chakravarti says, so it likely plays a key role in brain development.
While autism-causing variants in CTNND2 are very rare, Chakravarti says, the finding provides a window into the general biology of autism. “To devise new therapies, we need to have a good understanding of how the disease comes about in the first place,” he says. “Genetics is a crucial way of doing that.”
John Hopkins Medicine
Nobody likes getting the flu, but for some people, fluids and rest aren’t enough. A small number of children who catch the influenza virus fall so ill they end up in the hospital — perhaps needing ventilators to breathe — even while their family and friends recover easily. New research by Rockefeller University scientists, helps explain why: a rare genetic mutation.
The researchers scrutinized blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital. Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova discovered that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.
“This is the first example of a common, isolated and life-threatening infection of childhood that is shown to be also a genetic disease,” says Casanova. The good news from these results, however, is that clinicians have a new treatment option for children who mysteriously develop severe cases of the flu. “This finding suggests that one could treat severe flu of childhood with interferon, which is commercially available,” says Casanova, who is professor and head of the St. Giles Laboratory of Human Genetics of Infectious Disease at Rockefeller, as well as a Howard Hughes Medical Institute investigator.
The fact that a child’s genes could affect the severity of her illness wasn’t a surprise to the members of Casanova’s lab, who have been studying this phenomenon for decades. For instance, they have discovered genetic differences that help explain why the herpes simplex virus — which causes innocuous cold sores in most people — can, in rare cases, lead to potentially fatal infections that spread to the brain.
Turning their attention to influenza, Michael J. Ciancanelli, a research associate and senior member of Casanova’s lab, and his colleagues sequenced all genes in the genomes of the young girl who survived her dangerous bout of the flu and her parents, looking for mutations that might explain her vulnerability. Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.
What emerged from their work was the finding that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon, a critical part of the body’s response to viral infections. “No other mutations could have explained her reaction to the influenza virus,” says Ciancanelli. “Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare.”
Indeed, when they infected a sample of her blood cells that normally produce interferon —plasmacytoid dendritic cells — the researchers measured no interferon. In contrast, blood cells from her parents, who each carried only one mutated version of the gene, produced healthy amounts of interferon when exposed to influenza. “That really was definitive proof that a single, non-mutated copy of this gene is enough to allow people to mount a response to the virus,” says Ciancanelli.
Rockefeller Hospital
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Researchers have identified a new host of gene variants that could make people vulnerable to sporadic motor neurone disease.
Until recently, it was thought that genetics made little contribution to the disease – also termed amyotrophic lateral sclerosis (ALS) – and that the environment was mostly to blame.
Motor neurone disease (MND) is a group of diseases in which the nerve cells in the brain and spinal cord controlling the muscles that enable us to move, speak, breathe and swallow to slowly degenerate and die.
Death is caused by respiratory failure, which typically occurs within 2 to 5 years of developing this debilitating condition.
‘This is an advance in knowledge about the role genetics is likely to play in sporadic forms of motor neurone disease,’ says the University of Sydney’s Associate Professor Roger Pamphlett, a co-author of the new study.
‘The findings indicate that the genetic changes underlying many cases of sporadic motor neurone disease could stem from one of two sources,’ Associate Professor Pamphlett says.
‘Sufferers either have a rare combination of genetic changes they inherited from their otherwise normal parents, or they have newly-arising changes in genes that were not present in their parents.’
In an effort to identify genetic variants that may play a role in the disease, the researchers sequenced the protein-coding genes of 44 MND-affected individuals and their parents.
They found that two in five MND-affected individuals had inherited rare, recessive gene variants from their parents, and a quarter had developed novel gene variants that were not present in their parents. The researchers believe these gene variants are ‘promising candidates’ for playing a role in the development of motor neurone disease.
Many of these ‘genetic suspects’ have been identified in other brain-related disease, including Alzheimer’s disease, Parkinson’s disease and autism. Also, many are involved in biological processes or metabolic pathways implicated in the development of motor neurone disease.
While the researchers cannot yet point to a potential therapeutic application of their findings, identifying genetic changes that underlie MND is the first step in finding ways to manipulate these changes using gene therapy.
University of Sydney
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A blood test undertaken between 10 to 14 weeks of pregnancy may be more effective in diagnosing Down syndrome and two other less common chromosomal abnormalities than standard non-invasive screening techniques, according to a multicentre study led by a UC San Francisco researcher.
In the study, which followed pregnancy outcomes in close to 16,000 women, the cell-free DNA blood test resulted in correctly identifying all 38 foetuses with Down syndrome, a condition associated with cognitive impairments and an increased risk of several medical disorders. The diagnosis was confirmed by newborn exam, prenatal or postnatal genetic analysis.
The test focuses on the small percentage of foetal DNA found floating in a pregnant woman’s blood. DNA is amplified by PCR, and sequenced so that comparisons can be made between relative amounts of each chromosome’s DNA. A greater quantity of DNA is indicative of some chromosomal conditions, including Down syndrome, which is characterized by an extra copy of chromosome 21, one of the 23 pairs of chromosomes.
When the same women underwent standard screening, 30 of the 38 foetuses with Down syndrome were flagged, according to the study published on April 1, 2015, in the New England Journal of Medicine. The screening comprises a blood draw in which hormones and proteins associated with chromosomal defects are identified, together with an ultrasound of the nuchal fold fluid in the back of the neck, an excess of which is suggestive of Down syndrome.
The average age of the pregnant women was 30 and approximately one-quarter were over 35 – the age at which women have traditionally been considered high risk and offered prenatal invasive testing with procedures like amniocentesis.
A second compelling advantage of cell-free DNA analysis, reported by the researchers who were led by first author Mary Norton, MD, professor of clinical obstetrics and gynaecology at UCSF, was the relatively low incidence of Down syndrome misdiagnoses. While standard testing is acknowledged to result in a large number of false positives, these were significantly less likely with the cell-free DNA tool. There were nine false positives resulting from this method, vs. 854 with standard screening.
University of Central Florida
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Genetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung’s disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it.
About one in every 5,000 babies is born with Hirschsprung’s disease, which causes bowel obstruction and can be fatal if not treated. The disease arises early in development when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world.
The genetic causes of Hirschsprung’s disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. His research group took on the condition in 1990, and in 2002, it performed the first-ever genomewide association study to identify common variants linked to the disease.
But while Chakravarti’s and other groups have identified several genetic variants associated with Hirschsprung’s, those variants do not explain most cases of the disease. So Chakravarti and colleagues conducted a new genomewide association study of the disease, comparing the genetic markers of more than 650 people with Hirschsprung’s disease, their parents and healthy controls. One of their findings was a variant in a gene called Ret that had not been previously associated with the disease, although other variations in Ret had been fingered as culprits.
The other finding was of a variant near genes for several so-called semaphorins, proteins that guide developing nerve cells as they grow toward their final targets. Through studies in mice and zebrafish, the researchers found that the semaphorins are indeed active in the developing enteric nervous system, and that they interact with Ret in a system of signals called a pathway.
‘It looks like the semaphorin variant doesn’t by itself lead to Hirschsprung’s, but when there’s a variant in Ret too, it causes the pathway to malfunction and can cause disease,’ Chakravarti says. ‘We’ve found a new pathway that guides development of the enteric nervous system, one that nobody suspected had this role.’
Chakravarti notes that the genetic puzzle of Hirschsprung’s is still missing some pieces, and no clinical genetic test yet exists to assess risk for the disease. Most of the genetic variants that have so far been connected to this rare disease are themselves relatively common and are associated with less severe forms of the disease. The hunt continues for rare variants that can explain more severe cases.
EurekAlert
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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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Mutations taking place only in the brain responsible for intractable epilepsy identified
, /in E-News /by 3wmediaEpilepsy is a brain disorder which afflicts more than 50 million people worldwide. Many epilepsy patients can control their symptoms through medication, but about 30% suffer from intractable epilepsy and are unable to manage the disease with drugs. Intractable epilepsy causes multiple seizures, permanent mental, physical, and developmental disabilities, and even death. Therefore, surgical removal of the affected area from the brain has been practiced as a treatment for patients with medically refractory seizures, but this too fails to provide a complete solution because only 60% of the patients who undergo surgery are rendered free of seizures.
A Korean research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering at the Korea Advanced Institute of Science and Technology (KAIST) and Professor Dong-Seok Kim of Epilepsy Research Center at Yonsei University College of Medicine has recently identified brain somatic mutations in the gene of mechanistic target of rapamycin (MTOR) as the cause of focal cortical dysplasia type II (FCDII), one of the most important and common inducers to intractable epilepsy, particularly in children. They propose a targeted therapy to lessen epileptic seizures by suppressing the activation of mTOR kinase, a signalling protein in the brain.
FCDII contributes to the abnormal developments of the cerebral cortex, ranging from cortical disruption to severe forms of cortical dyslamination, balloon cells, and dysplastic neurons. The research team studied 77 FCDII patients with intractable epilepsy who had received a surgery to remove the affected regions from the brain. The researchers used various deep sequencing technologies to conduct comparative DNA analysis of the samples obtained from the patients’ brain and blood, or saliva. They reported that about 16% of the studied patients had somatic mutations in their brain. Such mutations, however, did not take place in their blood or saliva DNA.
Professor Jeong Ho Lee of KAIST said, “This is an important finding. Unlike our previous belief that genetic mutations causing intractable epilepsy exist anywhere in the human body including blood, specific gene mutations incurred only in the brain can lead to intractable epilepsy. From our animal models, we could see how a small fraction of mutations carrying neurons in the brain could affect its entire function.” KAIST
Genetic test for inherited kidney diseases
, /in E-News /by 3wmediaA new test from Washington University’s Genomic Pathology Services will help physicians quickly zero in on genetic mutations that may be contributing to kidney disease.
Many kidney disorders are difficult to diagnose. To address this problem, scientists and clinicians have developed a diagnostic test that identifies genetic changes linked to inherited kidney disorders. This testing is now available nationwide through Genomic Pathology Services (GPS) at Washington University School of Medicine in St. Louis.
“For many kidney diseases, diagnosis can be an odyssey in which you sequence one gene after another over a long period of time to learn what’s going wrong and what the best options are for treatment,” said GPS chief medical officer and Washington University pathologist Jonathan Heusel, MD, PhD. “It makes more sense to screen all the possible contributing genes at once with a single test and consider options for treatment.”
To make this possible, the GPS team developed the test with kidney disease specialists, including Joseph Gaut, MD, PhD, a renal pathologist.
The test employs next-generation sequencing technology to decode genes associated with kidney disease. Using software developed at the university, clinical genomics specialists analyse and interpret the observed genetic alterations to identify disease-related genetic changes, or variants. They then must determine whether a given variant poses clinical risks based on available medical knowledge.
“The variants have to be evaluated on a case-by-case basis, which can be time-consuming and labour-intensive,” Heusel said.
GPS continues to update the kidney test as new links between kidney problems and DNA are identified.
“We stay abreast of the literature, and as new genes become clinically meaningful, we will incorporate those into the test,” said Catherine Cottrell, PhD, medical director for GPS.
The kidney test will check for:
• Alport syndrome, which is characterized by progressive loss of kidney function, hearing loss and eye abnormalities;
• Nephrotic syndrome, which includes symptoms such as protein in the urine, low blood-protein levels, high levels of cholesterol and triglycerides, and swelling;
• Metabolic disorders associated with renal disease and including other systemic abnormalities such as diabetes, amyloidosis and others;
• Complement (immune system) defects related to kidney disease, including atypical hemolytic uremic syndrome. Washington University
Switch that may tame most aggressive breast cancers
, /in E-News /by 3wmediaAustralian researchers have found that so-called ‘triple-negative breast cancers’ are two distinct diseases that likely originate from different cell types. This helps explain why survival prospects for women with the diagnosis tend to be either very good or very bad.
The Sydney-based research team has found a gene that drives the aggressive disease, and hopes to find a way to ‘switch it off’. The aggressive form of triple-negative breast cancer appears to arise from stem cells, while the more benign form appears to arise from specialised cells.
Stem cells have many of the same features as cancers. They are plastic and flexible, and have the ability to proliferate and spread into other tissues – deadly traits in cancers.
Previous studies have shown that breast stem cells are needed for breast growth and development during puberty and pregnancy, although how they evolve from stem cells into specialist cells has been unclear.
The new study has shown that a gene known as ‘inhibitor of differentiation’ (ID4) determines whether a stem cell remains a stem cell, or whether it differentiates into a specialist cell.
Notably, when the high levels of ID4 in a stem cell are ‘switched off’, other genes that drive cell specialisation are ‘switched on’.
Drs Alex Swarbrick and Simon Junankar from Sydney’s Garvan Institute of Medical Research spearheaded this large interdisciplinary study, which links the development of the mammary gland in mice with human breast cancer. Its main finding, that ID4 not only ‘marks’, but appears to control, the highly aggressive form of triple negative breast cancer.
“We found that ID4 is produced at high levels in roughly half of all triple negative breast cancers, and that these cancers have a particularly poor prognosis,” said project leader Dr Alex Swarbrick.
“We also showed that if you block the ID4 gene in experimental models of triple negative breast cancer, the tumour cells stop dividing.” Garvan Institute of Medical Research
New autism-causing genetic variant identified
, /in E-News /by 3wmediaResearchers sequenced the genomes of members of 13 families severely affected by autism and compared the sequences to those of healthy controls.
They identified genetic variants that had never before been linked to autism.
One affected gene, CTNND2, plays a critical role in brain development and regulates how many other genes function.
Using a novel approach that homes in on rare families severely affected by autism, a Johns Hopkins-led team of researchers has identified a new genetic cause of the disease. The rare genetic variant offers important insights into the root causes of autism, the researchers say. And, they suggest, their unconventional method can be used to identify other genetic causes of autism and other complex genetic conditions.
In recent years, falling costs for genetic testing, together with powerful new means of storing and analysing massive amounts of data, have ushered in the era of the genomewide association and sequencing studies. These studies typically compare genetic sequencing data from thousands of people with and without a given disease to map the locations of genetic variants that contribute to the disease. While genome-wide association studies have linked many genes to particular diseases, their results have so far failed to lead to predictive genetic tests for common conditions, such as Alzheimer’s, autism or schizophrenia.
“In genetics, we all believe that you have to sequence endlessly before you can find anything,” says Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. “I think whom you sequence is as important — if not more so — than how many people are sequenced.”
With that idea, Chakravarti and his collaborators identified families in which more than one female has autism spectrum disorder, a condition first described at Johns Hopkins in 1943. For reasons that are not understood, girls are far less likely than boys to have autism, but when girls do have the condition, their symptoms tend to be severe. Chakravarti reasoned that females with autism, particularly those with a close female relative who is also affected, must carry very potent genetic variants for the disease, and he wanted to find out what those were.
The research team compared the gene sequences of autistic members of 13 such families to the gene sequences of people from a public database. They found four potential culprit genes and focused on one, CTNND2, because it fell in a region of the genome known to be associated with another intellectual disability. When they studied the gene’s effects in zebrafish, mice and cadaveric human brains, the research group found that the protein it makes affects how many other genes are regulated. The CTNND2 protein was found at far higher levels in foetal brains than in adult brains or other tissues, Chakravarti says, so it likely plays a key role in brain development.
While autism-causing variants in CTNND2 are very rare, Chakravarti says, the finding provides a window into the general biology of autism. “To devise new therapies, we need to have a good understanding of how the disease comes about in the first place,” he says. “Genetics is a crucial way of doing that.” John Hopkins Medicine
Genetic mutation helps explain why, in rare cases, flu can kill
, /in E-News /by 3wmediaNobody likes getting the flu, but for some people, fluids and rest aren’t enough. A small number of children who catch the influenza virus fall so ill they end up in the hospital — perhaps needing ventilators to breathe — even while their family and friends recover easily. New research by Rockefeller University scientists, helps explain why: a rare genetic mutation.
The researchers scrutinized blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital. Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova discovered that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.
“This is the first example of a common, isolated and life-threatening infection of childhood that is shown to be also a genetic disease,” says Casanova. The good news from these results, however, is that clinicians have a new treatment option for children who mysteriously develop severe cases of the flu. “This finding suggests that one could treat severe flu of childhood with interferon, which is commercially available,” says Casanova, who is professor and head of the St. Giles Laboratory of Human Genetics of Infectious Disease at Rockefeller, as well as a Howard Hughes Medical Institute investigator.
The fact that a child’s genes could affect the severity of her illness wasn’t a surprise to the members of Casanova’s lab, who have been studying this phenomenon for decades. For instance, they have discovered genetic differences that help explain why the herpes simplex virus — which causes innocuous cold sores in most people — can, in rare cases, lead to potentially fatal infections that spread to the brain.
Turning their attention to influenza, Michael J. Ciancanelli, a research associate and senior member of Casanova’s lab, and his colleagues sequenced all genes in the genomes of the young girl who survived her dangerous bout of the flu and her parents, looking for mutations that might explain her vulnerability. Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.
What emerged from their work was the finding that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon, a critical part of the body’s response to viral infections. “No other mutations could have explained her reaction to the influenza virus,” says Ciancanelli. “Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare.”
Indeed, when they infected a sample of her blood cells that normally produce interferon —plasmacytoid dendritic cells — the researchers measured no interferon. In contrast, blood cells from her parents, who each carried only one mutated version of the gene, produced healthy amounts of interferon when exposed to influenza. “That really was definitive proof that a single, non-mutated copy of this gene is enough to allow people to mount a response to the virus,” says Ciancanelli. Rockefeller Hospital
Motor Neurone Disease – researchers identify new group of gene suspects
, /in E-News /by 3wmediaResearchers have identified a new host of gene variants that could make people vulnerable to sporadic motor neurone disease.
Until recently, it was thought that genetics made little contribution to the disease – also termed amyotrophic lateral sclerosis (ALS) – and that the environment was mostly to blame.
Motor neurone disease (MND) is a group of diseases in which the nerve cells in the brain and spinal cord controlling the muscles that enable us to move, speak, breathe and swallow to slowly degenerate and die.
Death is caused by respiratory failure, which typically occurs within 2 to 5 years of developing this debilitating condition.
‘This is an advance in knowledge about the role genetics is likely to play in sporadic forms of motor neurone disease,’ says the University of Sydney’s Associate Professor Roger Pamphlett, a co-author of the new study.
‘The findings indicate that the genetic changes underlying many cases of sporadic motor neurone disease could stem from one of two sources,’ Associate Professor Pamphlett says.
‘Sufferers either have a rare combination of genetic changes they inherited from their otherwise normal parents, or they have newly-arising changes in genes that were not present in their parents.’
In an effort to identify genetic variants that may play a role in the disease, the researchers sequenced the protein-coding genes of 44 MND-affected individuals and their parents.
They found that two in five MND-affected individuals had inherited rare, recessive gene variants from their parents, and a quarter had developed novel gene variants that were not present in their parents. The researchers believe these gene variants are ‘promising candidates’ for playing a role in the development of motor neurone disease.
Many of these ‘genetic suspects’ have been identified in other brain-related disease, including Alzheimer’s disease, Parkinson’s disease and autism. Also, many are involved in biological processes or metabolic pathways implicated in the development of motor neurone disease.
While the researchers cannot yet point to a potential therapeutic application of their findings, identifying genetic changes that underlie MND is the first step in finding ways to manipulate these changes using gene therapy. University of Sydney
Detecting Down Syndrome in early pregnancy
, /in E-News /by 3wmediaA blood test undertaken between 10 to 14 weeks of pregnancy may be more effective in diagnosing Down syndrome and two other less common chromosomal abnormalities than standard non-invasive screening techniques, according to a multicentre study led by a UC San Francisco researcher.
In the study, which followed pregnancy outcomes in close to 16,000 women, the cell-free DNA blood test resulted in correctly identifying all 38 foetuses with Down syndrome, a condition associated with cognitive impairments and an increased risk of several medical disorders. The diagnosis was confirmed by newborn exam, prenatal or postnatal genetic analysis.
The test focuses on the small percentage of foetal DNA found floating in a pregnant woman’s blood. DNA is amplified by PCR, and sequenced so that comparisons can be made between relative amounts of each chromosome’s DNA. A greater quantity of DNA is indicative of some chromosomal conditions, including Down syndrome, which is characterized by an extra copy of chromosome 21, one of the 23 pairs of chromosomes.
When the same women underwent standard screening, 30 of the 38 foetuses with Down syndrome were flagged, according to the study published on April 1, 2015, in the New England Journal of Medicine. The screening comprises a blood draw in which hormones and proteins associated with chromosomal defects are identified, together with an ultrasound of the nuchal fold fluid in the back of the neck, an excess of which is suggestive of Down syndrome.
The average age of the pregnant women was 30 and approximately one-quarter were over 35 – the age at which women have traditionally been considered high risk and offered prenatal invasive testing with procedures like amniocentesis.
A second compelling advantage of cell-free DNA analysis, reported by the researchers who were led by first author Mary Norton, MD, professor of clinical obstetrics and gynaecology at UCSF, was the relatively low incidence of Down syndrome misdiagnoses. While standard testing is acknowledged to result in a large number of false positives, these were significantly less likely with the cell-free DNA tool. There were nine false positives resulting from this method, vs. 854 with standard screening. University of Central Florida
New genetic clues emerge on origin of Hirschsprung’s disease
, /in E-News /by 3wmediaGenetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung’s disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it.
About one in every 5,000 babies is born with Hirschsprung’s disease, which causes bowel obstruction and can be fatal if not treated. The disease arises early in development when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world.
The genetic causes of Hirschsprung’s disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. His research group took on the condition in 1990, and in 2002, it performed the first-ever genomewide association study to identify common variants linked to the disease.
But while Chakravarti’s and other groups have identified several genetic variants associated with Hirschsprung’s, those variants do not explain most cases of the disease. So Chakravarti and colleagues conducted a new genomewide association study of the disease, comparing the genetic markers of more than 650 people with Hirschsprung’s disease, their parents and healthy controls. One of their findings was a variant in a gene called Ret that had not been previously associated with the disease, although other variations in Ret had been fingered as culprits.
The other finding was of a variant near genes for several so-called semaphorins, proteins that guide developing nerve cells as they grow toward their final targets. Through studies in mice and zebrafish, the researchers found that the semaphorins are indeed active in the developing enteric nervous system, and that they interact with Ret in a system of signals called a pathway.
‘It looks like the semaphorin variant doesn’t by itself lead to Hirschsprung’s, but when there’s a variant in Ret too, it causes the pathway to malfunction and can cause disease,’ Chakravarti says. ‘We’ve found a new pathway that guides development of the enteric nervous system, one that nobody suspected had this role.’
Chakravarti notes that the genetic puzzle of Hirschsprung’s is still missing some pieces, and no clinical genetic test yet exists to assess risk for the disease. Most of the genetic variants that have so far been connected to this rare disease are themselves relatively common and are associated with less severe forms of the disease. The hunt continues for rare variants that can explain more severe cases. EurekAlert
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