Future Science Group (FSG) have announced the publication of a new article in Future Science OA, reporting data demonstrating the possibility of measuring 10 biomarkers relevant to autism spectrum disorder in adult saliva.
With more than 70 biomarkers shown to be of relevance to autism, it is doubtful that a single biomarker will be of use in diagnosis and determination of severity. As such, it is important to develop a clinically relevant and measurable panel of biomarkers. Saliva presents an intriguing opportunity, as it is non-invasive and considered less stressful for patients than collection of urine or blood.
The study, by Helen V Ratajczak (Edmond Enterprises, CT, USA) and Robert B Sothern (University of Minnesota, MN, USA), analysed levels of 10 biomarkers previously noted to be pertinent to autism in saliva from 12 neurotypical, healthy adults. The utilized method was developed with simplicity in mind, with a view towards enabling future testing in autistic adults and, potentially, in children.
“This research is timely, as we desperately need biomarkers of autism spectrum disorder,” commented Francesca Lake, Managing Editor. “The findings, while preliminary, bring us a step closer to our ultimate goal of being effectively able to diagnose and treat autism. We look forward to further studies in more patients, and in those affected by autism.”
“Saliva was chosen because its collection causes the least stress (and the least effect on biomarker concentration),” explained Ratajczak. “Similar results were obtained when 6 men and 6 women read instructions, and an hour later after having instructions given by the principal investigator. Therefore, saliva can be collected by literate individuals without added instruction. In addition, the elapse of an hour between collections did not significantly alter marker concentrations.” The researchers hope to design future studies to further this research, looking to aid diagnosis of autism and determination of severity, and brings us closer to a subject-specific treatment.
Future Science
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Researchers at the University of California, San Diego School of Medicine developed a method to expand the types of chromosomal abnormalities that non-invasive prenatal testing (NIPT) can detect. The study uses a semiconductor sequencing platform to identify small chromosomal deletions or duplications, such as occur in Cri du Chat Syndrome and DiGeorge Syndrome, with a simple blood test from the expectant mother.
Detecting these types of small chromosomal abnormalities with conventional techniques usually requires an invasive procedure to obtain foetal DNA, such as amniocentesis or chorionic villus sampling. These procedures carry a small but concerning risk for miscarriage and infection. Since the recent discovery that foetal DNA can be found in the blood of pregnant women, NIPT has been increasingly used to detect certain chromosomal abnormalities through a maternal blood test. So far, though, NIPT is typically used only to detect abnormalities that result from larger chromosomal abnormalities — too many or too few of a particular chromosome, for example, such as occurs in Down syndrome.
“We have found that NIPT can be extended in a way that allows us to zoom in and examine a small segment of a chromosome,” said Kang Zhang, MD, PhD, professor of ophthalmology and chief of Ophthalmic Genetics at UC San Diego School of Medicine, who led the study with collaborators in China. “And while this study focused on cell-free DNA sequencing in pregnant women, this method could be applied more broadly to other genetic diagnoses, such as analysing circulating tumour DNA for detection of cancer.”
Zhang and his team analysed blood plasma from 1,476 pregnant women with foetal structural abnormalities detected by ultrasound. These women also underwent an invasive diagnostic procedure and conventional foetal DNA analysis. The researchers compared that information to semiconductor sequencing results on circulating foetal DNA obtained from a blood test on the pregnant women at an average gestational age of 24 weeks. The new semiconductor sequencing method detected 69 of 73 (94.5 percent) of abnormalities of a certain size (greater than one million base pairs) detected by the conventional method.
According to the researchers, the cost of NIPT with semiconductor sequencing has the potential to be less expensive than the conventional, invasive prenatal testing method, especially as genetic sequencing technologies continue to decrease in cost.
While promising, there is still need for improvement before this NIPT application can be used clinically. In the study, semiconductor sequencing detected 55 false positives, of which 35 (63.6 percent) were due to maternal, rather than foetal, chromosomal abnormalities. That means the new method will require a validation test to screen out maternal abnormalities.
NIPT with semiconductor sequencing also needs to be tested at early time points in the pregnancy — at 12 to 16 weeks — and the researchers hope to further improve the technique to be able to detect even smaller genetic abnormalities.
The problem is that the more variations they are able to detect, the more they are likely to pick up chromosomal deletions or duplications of unknown clinical significance or with mild clinical consequences. Many of the abnormalities detected could be normal inherited variations.
UC San Diego Health
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University of Utah chemists devised a new way to detect chemical damage to DNA that sometimes leads to genetic mutations responsible for many diseases, including various cancers and neurological disorders.
“We are one step closer to understanding the underlying chemistry that leads to genetic diseases,” says Cynthia Burrows, distinguished professor and chair of chemistry at the university. “We have a way of marking and copying DNA damage sites so that we can preserve the information of where and what the damage was.”
Jan Riedl, a University of Utah postdoctoral fellow and the study’s first author, says 99 percent of DNA lesions – damage to the chemical bases known as A, C, G and T that help form the DNA double helix – are repaired naturally. The rest can lead to genetic mutations, which are errors in the sequence of bases and can cause disease. The new method can “identify and detect the position of lesions that lead to diseases,” he says.
Burrows says: “We are trying to look for the chemical changes in the base that can lead the cell to make a mistake, a mutation. One of the powerful things about our method is we can read more than a single damaged site [and up to dozens] on the same strand of DNA.”
The chemists say their new method will let researchers study chemical details of DNA lesions or damage. Such lesions, if not repaired naturally, accumulate over time and can lead to mutations responsible for many age-related diseases, including colon, breast, liver, lung and melanoma skin cancers; clogged arteries; and neurological ailments such as Huntington’s disease and Lou Gehrig’s disease.
“A method capable of identifying the chemical identity and location in which lesions appear is crucial for determining the molecular etiology [cause] of these diseases,” Burrows and colleague write in their study.
The new method for finding DNA lesions combines other, existing techniques.
First, the researchers find the damage and cut it out of the DNA the same way a cell does naturally, using what is called “base excision repair,” the discovery of which won a Nobel Prize in Chemistry this year for Tomas Lindahl, a scientist in England.
Second, an “unnatural base pair” is inserted at the snipped-out DNA damage site to label it. Instead of natural base pairs C-G and A-T, the Utah chemists used a so-called third or unnatural base pair invented by chemists at the Scripps Research Institute in California. Burrows says her study demonstrates the first practical use of that invention.
Third, the DNA with the damage site labelled by an unnatural third base pair is then amplified or copied millions of times using a well-known existing method called PCR, or polymerase chain reaction. Burrows says the new study’s key innovation was to use base excision repair to snip out the damage and then to insert the unnatural base pair at the damage site, making it possible to make millions of copies of the DNA – a process that normally would be prevented by the damage.
Fourth, another chemical label, named 18-crown-6 ether, is affixed to the unnatural base pair on all the DNA strands, which are then read or sequenced using a kind of nanopore sequencing developed a few years ago by Burrows and Utah chemist Henry White. Such sequencing involves determining the order and location of bases on a DNA strand – including damage sites labell ed by unnatural bases – by passing the strand through a molecule-size pore or nanopore.
People are born with their genome or genetic blueprint of 3 billion base pairs, “and then stuff happens,” Burrows says. “There’s damage from oxidative stress due to inflammation and infection, too much metabolism, or environmental chemicals.”
The new method seeks “molecular details that define how our genome responds to what we eat and the air we breathe, and ends up being healthy or not,” she says.
University of Utah
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There’s a typical ‘career’ for some allergic people, and it starts very early on the skin: babies develop atopic dermatitis, food allergies may follow, then comes asthma and later on hay fever. A group of scientists led by Ingo Marenholz and Young-Ae Lee at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), working with colleagues from several institutions, has now identified seven genetic risk loci for this course of disease. Two of these loci were previously unknown and mainly influence the connection between atopic dermatitis and asthma. According to the study, the regions that determine the risk for atopic dermatitis are mainly those that also determine the risk for the further development of the typical allergic career. This course of disease is also called the ‘atopic march.’ The scientists analysed data from nearly 20,000 people.
For their meta-analysis, the researchers concentrated on cases where atopic dermatitis preceded asthma. They included 12 studies with 2,428 patients and 17,034 healthy people. All of these studies were genome-wide association studies (GWAS) based on millions of genetic variants called Single Nucleotide Polymorphisms (SNPs).
It is the first GWAS for the atopic march and showed for the first time that there are specific genetic loci influencing the march’s unfortunate course. ‘Seen from a physician’s perspective, the prominent role of atopic dermatitis genes for later-onset of asthma is very interesting,“ says Young-Ae Lee.
Max Delbrück Center for Molecular Medicine
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Combining the investigative tools of genetics, transcriptomics, epigenetics and metabolomics, a Duke Medicine research team has identified a new molecular pathway involved in heart attacks and death from heart disease.
The researchers found that stress on a component of cells called the endoplasmic reticulum (ER) is associated with risk of future heart events, and it can be detected in bits of molecular detritus circulating in the blood.
“ER stress has long been linked to Type 1 diabetes and Parkinson’s disease, among others, but this is the first indication that it is also playing a role in common heart attacks and death from heart disease,” said senior author Svati H. Shah, M.D., associate professor of medicine and faculty at the Molecular Physiology Institute at Duke. “It’s also exciting that we are able to measure this ER stress in a small drop of blood, providing a potential way to intercede and lower the risk of a major cardiovascular event.”
Even after mapping the human genome and finding genetic traits associated with cardiovascular disease, the mechanisms underlying the inherited susceptibility to this disease have not been fully understood. Shah said the Duke team’s research approach — using a variety of analytical methods measuring over a million data points in 3,700 patients — enabled them to fill in some of the missing steps leading to cardiovascular disease, which is often inherited.
“With genetics, everyone is lumped together if they share a trait,” Shah said. “But everyone knows if you have two people with the same trait, but one is overweight, smokes and has a bad lifestyle, that person has a different pathway that led to heart disease than someone who is normal weight, doesn’t smoke, eats right and exercises.”
The Duke team focused on the intermediates between the genes and the disease pathway. This involved metabolomics — an analysis of the metabolites, or trace chemicals, left behind as the by-products from cellular processes.
Among a group of 3,700 patients referred for cardiac catheterization in the CATHGEN study, Shah and colleagues performed a genome-wide analysis of specific metabolite levels that had previously been identified as predictors of cardiovascular disease.
In their earlier work, the researchers had flagged these metabolites as markers for cardiovascular disease, but had not known how they were generated or what the underlying biological pathways were. The current study resolved that question, finding that these genes were directly linked to ER stress, which occurs when the endoplasmic reticulum organelle becomes overworked in its job managing excess and damaged cellular proteins.
Shah and colleagues then took an epigenetics and transcriptomics approach to determine what the differences were between patients with high or low levels of metabolites. Once again, the ER stress pathway came up as a key component.
“Using this multi-platform ‘omics’ approach, we identified these novel genetic variants associated with metabolite levels and with cardiovascular disease itself,” Shah said. “We don’t believe that the metabolites themselves are causing heart attacks — they might just be by-products of a dysregulated process that people are genetically susceptible to — but that’s something we need to study further.”
Duke Medicine
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An inherited disease of myelin marked by slow, progressive neurological impairment is caused by mutations of a gene that controls lipid metabolism, a finding that may shed insight into mechanisms to control the course of multiple sclerosis (MS), a Yale team has found.
Mutations in a single gene, called FAM126A, causes a panoply of pathologies, such as developmental delay, intellectual disability, peripheral neuropathy, and muscle wasting, in addition to congenital cataracts. Until now the precise function of the gene was unknown.
The labs of Yale cell biologists Pietro De Camilli and Karin Reinisch found that the protein encoded by the gene, called hyccin, helps produce a lipid crucial to formation of the myelin sheaths that surround and protect the axons of neurons throughout the nervous system.
Their labs, working with other groups in the United States, Italy, and Germany, analysed cells from patients suffering from the disease known as Hypomyelination and Congenital Cataract and found that FAM126A mutations results in the destabilization of an enzyme complex crucial to production of myelin.
In MS, the course of the disease is critically dependent upon the reformation of myelin sheaths after immune system attacks then destroys them, eventually leading to the death of the neurons. The researchers hypothesize that the lipid that hyccin helps generate may play a key role in creation of myelin sheaths in normal development as well as in recovering MS patients.
Yale University
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Researchers have found that a genetic variant is linked with an increased risk of fatty liver disease in obese youth; however, children with the variant tend to have lower total and LDL cholesterol levels.
As indicated by the condition’s name, fat accumulates in the liver cells of patients with fatty liver disease. The variant analysed in this study lies within the gene that codes for the transmembrane 6 superfamily member 2 (TM6SF2) protein, which helps regulate the liver’s metabolism of fat.
The findings may help investigators develop new ways to prevent or treat liver damage in patients with fatty liver disease and to ameliorate heart problems in obese children and adolescents. ‘The effect of the studied TM6SF2 gene variant on human metabolism is quite fascinating as it predisposes obese kids to accumulate hepatic fat, but at the same time it seems to protect them from cardiovascular complications,’ said Dr. Nicola Santoro, senior author of the Hepatology study. ‘I think the future of this protein might be in the prevention and therapy of cardiovascular diseases.’
EurekAlert
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An improved gene therapy treatment can cure mice with cystic fibrosis (CF). Cell cultures from CF patients, too, respond well to the treatment. Those are the encouraging results of a study presented by the KU Leuven Laboratory for Molecular Virology and Gene Therapy.
Cystic fibrosis or mucoviscidosis is a genetic disorder that makes the mucus in the body thick and sticky, which in turn causes clogging in, for instance, the airways and the gastrointestinal tract. The symptoms can be treated, but there is no cure for the disorder.
Cystic fibrosis is caused by mutations in the CFTR gene. This gene contains the production code for a protein that functions as a channel through which chloride ions and water flow out of cells. In the cells of CF patients, these chloride channels are dysfunctional or even absent, so that thick mucus starts building up.
“A few years ago, a new drug was launched that can repair dysfunctional chloride channels”, Professor Zeger Debyser explains. “Unfortunately, this medicine only works in a minority of CF patients. As for the impact of gene therapy, previous studies suggested that the treatment is safe, but largely ineffective for cystic fibrosis patients. However, as gene therapy has recently proven successful for disorders such as haemophilia and congenital blindness, we wanted to re-examine its potential for cystic fibrosis”.
That is why lead authors Dragana Vidović and Marianne Carlon examined an improved gene therapy treatment based on inserting the genetic material for chloride channels – coded by the CFTR gene – into the genome of a recombinant AAV viral vector, which is derived from the relatively innocent AAV virus. The researchers then used this vector to ‘smuggle’ a healthy copy of the CFTR gene into the affected cells.
Both in mice with cystic fibrosis and in gut cell cultures from CF patients, this approach yielded positive results. “We administered the rAAV to the mice via their airways. Most of the CF mice recovered. In the patient-derived cell cultures, chloride and fluid transport were restored”.
There is still a long way to go before gene therapy can be used to treat cystic fibrosis patients, Debyser clarifies: “We must not give CF patients false hope. Developing a treatment based on gene therapy will take years of work. For one thing, our study did not involve actual human beings, only mice and patient-derived cell cultures. Furthermore, we still have to examine how long the therapy works. Repeated doses might be necessary. But gene therapy clearly is a promising candidate for further research towards a cure for cystic fibrosis”.
KU Leuven
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When it comes to needles and drawing blood, most patients agree that bigger is not better. But in the first study of its kind, Rice University bioengineers have found results from a single drop of blood are highly variable, and as many as six to nine drops must be combined to achieve consistent results.
The study examines the variation between blood drops drawn from a single finger-prick. The results suggest that health care professionals must take care to avoid skewed results as they design new protocols and technologies that rely on finger-prick blood.
“We began looking at this after we got some surprising results from our controls in an earlier study,” said lead investigator Rebecca Richards-Kortum, Rice’s Malcolm Gillis University Professor and director of Rice 360°: Institute for Global Health Technologies. “Students in my lab are developing novel, low-cost platforms for anaemia, platelet and white blood cell testing in low-resource settings, and one of my students, Meaghan Bond, noticed there was wide variation in some of the benchmark tests that she was performing on hospital-grade blood analysers.”
The benchmark controls are used to gauge the accuracy of test results from the new technology under study, so the variation among the control data was a sign that something was amiss. What wasn’t immediately clear was whether the readings resulted from a problem with the current experiments or actual variations in the amount of haemoglobin, platelets and white blood cells (WBC) in the different drops of blood.
Richards-Kortum and Bond designed a simple protocol to test whether there was actual variation, and if so, how much. They drew six successive 20-microliter droplets of blood from 11 donors. As an additional test to determine whether minimum droplet size might also affect the results, they drew 10 successive 10-microliter droplets from seven additional donors.
All droplets were drawn from the same finger-prick, and the researchers followed best practices in obtaining the droplets; the first drop was wiped away to remove contamination from disinfectants, and the finger was not squeezed or “milked,” which can lead to inaccurate results. For experimental controls, they use venipuncture, the standard of care in most hospitals, to draw tubes of blood from an arm vein.
Each 20-microliter droplet was analysed with a hospital-grade blood analyser for haemoglobin concentration, total WBC count, platelet count and three-part WBC differential, a test that measures the ratio of different types of white blood cells, including lymphocytes and granulocytes. Each 10-microliter droplet was tested for haemoglobin concentration with a popular point-of-care blood analyser used in many clinics and blood centres.
“A growing number of clinically important tests are performed using finger-prick blood, and this is especially true in low-resource settings,” Bond said. “It is important to understand how variations in finger-prick blood collection protocols can affect point-of-care test accuracy as well as how results might vary between different kinds of point-of-care tests that use finger-prick blood from the same patient.”
Bond and Richards-Kortum found that haemoglobin content, platelet count and WBC count each varied significantly from drop to drop.
“Some of the differences were surprising,” Bond said. “For example, in some donors, the haemoglobin concentration changed by more than two grams per deciliter in the span of two successive drops of blood.”
Bond and Richards-Kortum found that averaging the results of the droplet tests could produce results that were on par with venous blood tests, but tests on six to nine drops blood were needed to achieve consistent results.
“Finger-prick blood tests can be accurate and they are an important tool for health care providers, particularly in point-of-care and low-resource settings,” Bond said. “Our results show that people need to take care to administer finger-prick tests in a way that produces accurate results because accuracy in these tests is increasingly important for diagnosing conditions like anaemia, infections and sickle-cell anemia, malaria, HIV and other diseases.”
Rice University
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A simple, ultrasensitive microRNA sensor developed by researchers from the School of Science at Indiana University-Purdue University Indianapolis, the IU School of Medicine and the IU Melvin and Bren Simon Cancer Center holds promise for the design of new diagnostic strategies and, potentially, for the prognosis and treatment of pancreatic and other cancers.
In a study the IUPUI researchers describe their design of the novel, low-cost, nanotechnology-enabled reusable sensor. They also report on the promising results of tests of the sensor’s ability to identify pancreatic cancer or indicate the existence of a benign condition by quantifying changes in levels of microRNA signatures linked to pancreatic cancer.
‘We used the fundamental concepts of nanotechnology to design the sensor to detect and quantify biomolecules at very low concentrations,’ said Rajesh Sardar, Ph.D., who developed the sensor. ‘We have designed an ultrasensitive technique so that we can see minute changes in microRNA concentrations in a patient’s blood and confirm the presence of pancreatic cancer.’ Sardar is an assistant professor of chemistry and chemical biology in the School of Science at IUPUI and leads an interdisciplinary research program focusing on the intersection of analytical chemistry and the nanoscience of metallic nanoparticles.
‘If we can establish that there is cancer in the pancreas because the sensor detects high levels of microRNA-10b or one of the other microRNAs associated with that specific cancer, we may be able to treat it sooner,’ said Murray Korc, M.D., the Myles Brand Professor of Cancer Research at the IU School of Medicine and a researcher at the IU Simon Cancer Center. Korc worked with Sardar to improve the sensor’s capabilities and led the testing of the sensor and its clinical uses as well as advancing the understanding of pancreatic cancer biology.
‘That’s especially significant for pancreatic cancer, because for many patients it is symptom-free for years or even a decade or more, by which time it has spread to other organs, when surgical removal is no longer possible and therapeutic options are limited,’ said Korc. ‘For example, diagnosis of pancreatic cancer at an early stage of the disease followed by surgical removal is associated with a 40 percent five-year survival. Diagnosis of metastatic pancreatic cancer, by contrast, is associated with life expectancy that is often only a year or less.
‘The beauty of the sensor designed by Dr. Sardar is its ability to accurately detect mild increases in microRNA levels, which could allow for early cancer diagnosis,’ Korc added.
Over the past decade, studies have shown that microRNAs play important roles in cancer and other diseases, such as diabetes and cardiovascular disorders. The new IUPUI nanotechnology-based sensor can detect changes in any of these microRNAs.
The sensor is a small glass chip that contains triangular-shaped gold nanoparticles called ‘nanoprisms.’ After dipping it in a sample of blood or another body fluid, the scientist measures the change in the nanoprism’s optical property to determine the levels of specific microRNAs.
‘Using gold nanoprisms may sound expensive, but it isn’t because these particles are so very tiny,’ Sardar said. “It’s a rather cheap technique because it uses nanotechnology and needs very little gold. $250 worth of gold makes 4,000 sensors. Four thousand sensors allow you to do at least 4,000 tests. The low cost makes this technique ideal for use anywhere, including in low-resource environments in this country and around the world.’
IUSM
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Steps forward in the hunt for easily measurable biomarkers of autism
, /in E-News /by 3wmediaFuture Science Group (FSG) have announced the publication of a new article in Future Science OA, reporting data demonstrating the possibility of measuring 10 biomarkers relevant to autism spectrum disorder in adult saliva.
With more than 70 biomarkers shown to be of relevance to autism, it is doubtful that a single biomarker will be of use in diagnosis and determination of severity. As such, it is important to develop a clinically relevant and measurable panel of biomarkers. Saliva presents an intriguing opportunity, as it is non-invasive and considered less stressful for patients than collection of urine or blood.
The study, by Helen V Ratajczak (Edmond Enterprises, CT, USA) and Robert B Sothern (University of Minnesota, MN, USA), analysed levels of 10 biomarkers previously noted to be pertinent to autism in saliva from 12 neurotypical, healthy adults. The utilized method was developed with simplicity in mind, with a view towards enabling future testing in autistic adults and, potentially, in children.
“This research is timely, as we desperately need biomarkers of autism spectrum disorder,” commented Francesca Lake, Managing Editor. “The findings, while preliminary, bring us a step closer to our ultimate goal of being effectively able to diagnose and treat autism. We look forward to further studies in more patients, and in those affected by autism.”
“Saliva was chosen because its collection causes the least stress (and the least effect on biomarker concentration),” explained Ratajczak. “Similar results were obtained when 6 men and 6 women read instructions, and an hour later after having instructions given by the principal investigator. Therefore, saliva can be collected by literate individuals without added instruction. In addition, the elapse of an hour between collections did not significantly alter marker concentrations.” The researchers hope to design future studies to further this research, looking to aid diagnosis of autism and determination of severity, and brings us closer to a subject-specific treatment. Future Science
New technique could expand number of diseases detected by non=invasive prenatal testing
, /in E-News /by 3wmediaResearchers at the University of California, San Diego School of Medicine developed a method to expand the types of chromosomal abnormalities that non-invasive prenatal testing (NIPT) can detect. The study uses a semiconductor sequencing platform to identify small chromosomal deletions or duplications, such as occur in Cri du Chat Syndrome and DiGeorge Syndrome, with a simple blood test from the expectant mother.
Detecting these types of small chromosomal abnormalities with conventional techniques usually requires an invasive procedure to obtain foetal DNA, such as amniocentesis or chorionic villus sampling. These procedures carry a small but concerning risk for miscarriage and infection. Since the recent discovery that foetal DNA can be found in the blood of pregnant women, NIPT has been increasingly used to detect certain chromosomal abnormalities through a maternal blood test. So far, though, NIPT is typically used only to detect abnormalities that result from larger chromosomal abnormalities — too many or too few of a particular chromosome, for example, such as occurs in Down syndrome.
“We have found that NIPT can be extended in a way that allows us to zoom in and examine a small segment of a chromosome,” said Kang Zhang, MD, PhD, professor of ophthalmology and chief of Ophthalmic Genetics at UC San Diego School of Medicine, who led the study with collaborators in China. “And while this study focused on cell-free DNA sequencing in pregnant women, this method could be applied more broadly to other genetic diagnoses, such as analysing circulating tumour DNA for detection of cancer.”
Zhang and his team analysed blood plasma from 1,476 pregnant women with foetal structural abnormalities detected by ultrasound. These women also underwent an invasive diagnostic procedure and conventional foetal DNA analysis. The researchers compared that information to semiconductor sequencing results on circulating foetal DNA obtained from a blood test on the pregnant women at an average gestational age of 24 weeks. The new semiconductor sequencing method detected 69 of 73 (94.5 percent) of abnormalities of a certain size (greater than one million base pairs) detected by the conventional method.
According to the researchers, the cost of NIPT with semiconductor sequencing has the potential to be less expensive than the conventional, invasive prenatal testing method, especially as genetic sequencing technologies continue to decrease in cost.
While promising, there is still need for improvement before this NIPT application can be used clinically. In the study, semiconductor sequencing detected 55 false positives, of which 35 (63.6 percent) were due to maternal, rather than foetal, chromosomal abnormalities. That means the new method will require a validation test to screen out maternal abnormalities.
NIPT with semiconductor sequencing also needs to be tested at early time points in the pregnancy — at 12 to 16 weeks — and the researchers hope to further improve the technique to be able to detect even smaller genetic abnormalities.
The problem is that the more variations they are able to detect, the more they are likely to pick up chromosomal deletions or duplications of unknown clinical significance or with mild clinical consequences. Many of the abnormalities detected could be normal inherited variations. UC San Diego Health
New way to find DNA damage
, /in E-News /by 3wmediaUniversity of Utah chemists devised a new way to detect chemical damage to DNA that sometimes leads to genetic mutations responsible for many diseases, including various cancers and neurological disorders.
“We are one step closer to understanding the underlying chemistry that leads to genetic diseases,” says Cynthia Burrows, distinguished professor and chair of chemistry at the university. “We have a way of marking and copying DNA damage sites so that we can preserve the information of where and what the damage was.”
Jan Riedl, a University of Utah postdoctoral fellow and the study’s first author, says 99 percent of DNA lesions – damage to the chemical bases known as A, C, G and T that help form the DNA double helix – are repaired naturally. The rest can lead to genetic mutations, which are errors in the sequence of bases and can cause disease. The new method can “identify and detect the position of lesions that lead to diseases,” he says.
Burrows says: “We are trying to look for the chemical changes in the base that can lead the cell to make a mistake, a mutation. One of the powerful things about our method is we can read more than a single damaged site [and up to dozens] on the same strand of DNA.”
The chemists say their new method will let researchers study chemical details of DNA lesions or damage. Such lesions, if not repaired naturally, accumulate over time and can lead to mutations responsible for many age-related diseases, including colon, breast, liver, lung and melanoma skin cancers; clogged arteries; and neurological ailments such as Huntington’s disease and Lou Gehrig’s disease.
“A method capable of identifying the chemical identity and location in which lesions appear is crucial for determining the molecular etiology [cause] of these diseases,” Burrows and colleague write in their study.
The new method for finding DNA lesions combines other, existing techniques.
First, the researchers find the damage and cut it out of the DNA the same way a cell does naturally, using what is called “base excision repair,” the discovery of which won a Nobel Prize in Chemistry this year for Tomas Lindahl, a scientist in England.
Second, an “unnatural base pair” is inserted at the snipped-out DNA damage site to label it. Instead of natural base pairs C-G and A-T, the Utah chemists used a so-called third or unnatural base pair invented by chemists at the Scripps Research Institute in California. Burrows says her study demonstrates the first practical use of that invention.
Third, the DNA with the damage site labelled by an unnatural third base pair is then amplified or copied millions of times using a well-known existing method called PCR, or polymerase chain reaction. Burrows says the new study’s key innovation was to use base excision repair to snip out the damage and then to insert the unnatural base pair at the damage site, making it possible to make millions of copies of the DNA – a process that normally would be prevented by the damage.
Fourth, another chemical label, named 18-crown-6 ether, is affixed to the unnatural base pair on all the DNA strands, which are then read or sequenced using a kind of nanopore sequencing developed a few years ago by Burrows and Utah chemist Henry White. Such sequencing involves determining the order and location of bases on a DNA strand – including damage sites labell ed by unnatural bases – by passing the strand through a molecule-size pore or nanopore.
People are born with their genome or genetic blueprint of 3 billion base pairs, “and then stuff happens,” Burrows says. “There’s damage from oxidative stress due to inflammation and infection, too much metabolism, or environmental chemicals.”
The new method seeks “molecular details that define how our genome responds to what we eat and the air we breathe, and ends up being healthy or not,” she says. University of Utah
Neurodermatitis genes influence other allergies
, /in E-News /by 3wmediaThere’s a typical ‘career’ for some allergic people, and it starts very early on the skin: babies develop atopic dermatitis, food allergies may follow, then comes asthma and later on hay fever. A group of scientists led by Ingo Marenholz and Young-Ae Lee at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), working with colleagues from several institutions, has now identified seven genetic risk loci for this course of disease. Two of these loci were previously unknown and mainly influence the connection between atopic dermatitis and asthma. According to the study, the regions that determine the risk for atopic dermatitis are mainly those that also determine the risk for the further development of the typical allergic career. This course of disease is also called the ‘atopic march.’ The scientists analysed data from nearly 20,000 people.
For their meta-analysis, the researchers concentrated on cases where atopic dermatitis preceded asthma. They included 12 studies with 2,428 patients and 17,034 healthy people. All of these studies were genome-wide association studies (GWAS) based on millions of genetic variants called Single Nucleotide Polymorphisms (SNPs).
It is the first GWAS for the atopic march and showed for the first time that there are specific genetic loci influencing the march’s unfortunate course. ‘Seen from a physician’s perspective, the prominent role of atopic dermatitis genes for later-onset of asthma is very interesting,“ says Young-Ae Lee. Max Delbrück Center for Molecular Medicine
Cellular stress process identified in cardiovascular disease
, /in E-News /by 3wmediaCombining the investigative tools of genetics, transcriptomics, epigenetics and metabolomics, a Duke Medicine research team has identified a new molecular pathway involved in heart attacks and death from heart disease.
The researchers found that stress on a component of cells called the endoplasmic reticulum (ER) is associated with risk of future heart events, and it can be detected in bits of molecular detritus circulating in the blood.
“ER stress has long been linked to Type 1 diabetes and Parkinson’s disease, among others, but this is the first indication that it is also playing a role in common heart attacks and death from heart disease,” said senior author Svati H. Shah, M.D., associate professor of medicine and faculty at the Molecular Physiology Institute at Duke. “It’s also exciting that we are able to measure this ER stress in a small drop of blood, providing a potential way to intercede and lower the risk of a major cardiovascular event.”
Even after mapping the human genome and finding genetic traits associated with cardiovascular disease, the mechanisms underlying the inherited susceptibility to this disease have not been fully understood. Shah said the Duke team’s research approach — using a variety of analytical methods measuring over a million data points in 3,700 patients — enabled them to fill in some of the missing steps leading to cardiovascular disease, which is often inherited.
“With genetics, everyone is lumped together if they share a trait,” Shah said. “But everyone knows if you have two people with the same trait, but one is overweight, smokes and has a bad lifestyle, that person has a different pathway that led to heart disease than someone who is normal weight, doesn’t smoke, eats right and exercises.”
The Duke team focused on the intermediates between the genes and the disease pathway. This involved metabolomics — an analysis of the metabolites, or trace chemicals, left behind as the by-products from cellular processes.
Among a group of 3,700 patients referred for cardiac catheterization in the CATHGEN study, Shah and colleagues performed a genome-wide analysis of specific metabolite levels that had previously been identified as predictors of cardiovascular disease.
In their earlier work, the researchers had flagged these metabolites as markers for cardiovascular disease, but had not known how they were generated or what the underlying biological pathways were. The current study resolved that question, finding that these genes were directly linked to ER stress, which occurs when the endoplasmic reticulum organelle becomes overworked in its job managing excess and damaged cellular proteins.
Shah and colleagues then took an epigenetics and transcriptomics approach to determine what the differences were between patients with high or low levels of metabolites. Once again, the ER stress pathway came up as a key component.
“Using this multi-platform ‘omics’ approach, we identified these novel genetic variants associated with metabolite levels and with cardiovascular disease itself,” Shah said. “We don’t believe that the metabolites themselves are causing heart attacks — they might just be by-products of a dysregulated process that people are genetically susceptible to — but that’s something we need to study further.” Duke Medicine
Research in the news: How a mutated gene wreaks havoc on white matter
, /in E-News /by 3wmediaAn inherited disease of myelin marked by slow, progressive neurological impairment is caused by mutations of a gene that controls lipid metabolism, a finding that may shed insight into mechanisms to control the course of multiple sclerosis (MS), a Yale team has found.
Mutations in a single gene, called FAM126A, causes a panoply of pathologies, such as developmental delay, intellectual disability, peripheral neuropathy, and muscle wasting, in addition to congenital cataracts. Until now the precise function of the gene was unknown.
The labs of Yale cell biologists Pietro De Camilli and Karin Reinisch found that the protein encoded by the gene, called hyccin, helps produce a lipid crucial to formation of the myelin sheaths that surround and protect the axons of neurons throughout the nervous system.
Their labs, working with other groups in the United States, Italy, and Germany, analysed cells from patients suffering from the disease known as Hypomyelination and Congenital Cataract and found that FAM126A mutations results in the destabilization of an enzyme complex crucial to production of myelin.
In MS, the course of the disease is critically dependent upon the reformation of myelin sheaths after immune system attacks then destroys them, eventually leading to the death of the neurons. The researchers hypothesize that the lipid that hyccin helps generate may play a key role in creation of myelin sheaths in normal development as well as in recovering MS patients. Yale University
Gene variant may increase risk of liver disease in obese youth
, /in E-News /by 3wmediaResearchers have found that a genetic variant is linked with an increased risk of fatty liver disease in obese youth; however, children with the variant tend to have lower total and LDL cholesterol levels.
As indicated by the condition’s name, fat accumulates in the liver cells of patients with fatty liver disease. The variant analysed in this study lies within the gene that codes for the transmembrane 6 superfamily member 2 (TM6SF2) protein, which helps regulate the liver’s metabolism of fat.
The findings may help investigators develop new ways to prevent or treat liver damage in patients with fatty liver disease and to ameliorate heart problems in obese children and adolescents. ‘The effect of the studied TM6SF2 gene variant on human metabolism is quite fascinating as it predisposes obese kids to accumulate hepatic fat, but at the same time it seems to protect them from cardiovascular complications,’ said Dr. Nicola Santoro, senior author of the Hepatology study. ‘I think the future of this protein might be in the prevention and therapy of cardiovascular diseases.’ EurekAlert
Gene therapy: a promising candidate for cystic fibrosis treatment
, /in E-News /by 3wmediaAn improved gene therapy treatment can cure mice with cystic fibrosis (CF). Cell cultures from CF patients, too, respond well to the treatment. Those are the encouraging results of a study presented by the KU Leuven Laboratory for Molecular Virology and Gene Therapy.
Cystic fibrosis or mucoviscidosis is a genetic disorder that makes the mucus in the body thick and sticky, which in turn causes clogging in, for instance, the airways and the gastrointestinal tract. The symptoms can be treated, but there is no cure for the disorder.
Cystic fibrosis is caused by mutations in the CFTR gene. This gene contains the production code for a protein that functions as a channel through which chloride ions and water flow out of cells. In the cells of CF patients, these chloride channels are dysfunctional or even absent, so that thick mucus starts building up.
“A few years ago, a new drug was launched that can repair dysfunctional chloride channels”, Professor Zeger Debyser explains. “Unfortunately, this medicine only works in a minority of CF patients. As for the impact of gene therapy, previous studies suggested that the treatment is safe, but largely ineffective for cystic fibrosis patients. However, as gene therapy has recently proven successful for disorders such as haemophilia and congenital blindness, we wanted to re-examine its potential for cystic fibrosis”.
That is why lead authors Dragana Vidović and Marianne Carlon examined an improved gene therapy treatment based on inserting the genetic material for chloride channels – coded by the CFTR gene – into the genome of a recombinant AAV viral vector, which is derived from the relatively innocent AAV virus. The researchers then used this vector to ‘smuggle’ a healthy copy of the CFTR gene into the affected cells.
Both in mice with cystic fibrosis and in gut cell cultures from CF patients, this approach yielded positive results. “We administered the rAAV to the mice via their airways. Most of the CF mice recovered. In the patient-derived cell cultures, chloride and fluid transport were restored”.
There is still a long way to go before gene therapy can be used to treat cystic fibrosis patients, Debyser clarifies: “We must not give CF patients false hope. Developing a treatment based on gene therapy will take years of work. For one thing, our study did not involve actual human beings, only mice and patient-derived cell cultures. Furthermore, we still have to examine how long the therapy works. Repeated doses might be necessary. But gene therapy clearly is a promising candidate for further research towards a cure for cystic fibrosis”. KU Leuven
Blood test results vary from drop to drop in finger prick tests
, /in E-News /by 3wmediaWhen it comes to needles and drawing blood, most patients agree that bigger is not better. But in the first study of its kind, Rice University bioengineers have found results from a single drop of blood are highly variable, and as many as six to nine drops must be combined to achieve consistent results.
The study examines the variation between blood drops drawn from a single finger-prick. The results suggest that health care professionals must take care to avoid skewed results as they design new protocols and technologies that rely on finger-prick blood.
“We began looking at this after we got some surprising results from our controls in an earlier study,” said lead investigator Rebecca Richards-Kortum, Rice’s Malcolm Gillis University Professor and director of Rice 360°: Institute for Global Health Technologies. “Students in my lab are developing novel, low-cost platforms for anaemia, platelet and white blood cell testing in low-resource settings, and one of my students, Meaghan Bond, noticed there was wide variation in some of the benchmark tests that she was performing on hospital-grade blood analysers.”
The benchmark controls are used to gauge the accuracy of test results from the new technology under study, so the variation among the control data was a sign that something was amiss. What wasn’t immediately clear was whether the readings resulted from a problem with the current experiments or actual variations in the amount of haemoglobin, platelets and white blood cells (WBC) in the different drops of blood.
Richards-Kortum and Bond designed a simple protocol to test whether there was actual variation, and if so, how much. They drew six successive 20-microliter droplets of blood from 11 donors. As an additional test to determine whether minimum droplet size might also affect the results, they drew 10 successive 10-microliter droplets from seven additional donors.
All droplets were drawn from the same finger-prick, and the researchers followed best practices in obtaining the droplets; the first drop was wiped away to remove contamination from disinfectants, and the finger was not squeezed or “milked,” which can lead to inaccurate results. For experimental controls, they use venipuncture, the standard of care in most hospitals, to draw tubes of blood from an arm vein.
Each 20-microliter droplet was analysed with a hospital-grade blood analyser for haemoglobin concentration, total WBC count, platelet count and three-part WBC differential, a test that measures the ratio of different types of white blood cells, including lymphocytes and granulocytes. Each 10-microliter droplet was tested for haemoglobin concentration with a popular point-of-care blood analyser used in many clinics and blood centres.
“A growing number of clinically important tests are performed using finger-prick blood, and this is especially true in low-resource settings,” Bond said. “It is important to understand how variations in finger-prick blood collection protocols can affect point-of-care test accuracy as well as how results might vary between different kinds of point-of-care tests that use finger-prick blood from the same patient.”
Bond and Richards-Kortum found that haemoglobin content, platelet count and WBC count each varied significantly from drop to drop.
“Some of the differences were surprising,” Bond said. “For example, in some donors, the haemoglobin concentration changed by more than two grams per deciliter in the span of two successive drops of blood.”
Bond and Richards-Kortum found that averaging the results of the droplet tests could produce results that were on par with venous blood tests, but tests on six to nine drops blood were needed to achieve consistent results.
“Finger-prick blood tests can be accurate and they are an important tool for health care providers, particularly in point-of-care and low-resource settings,” Bond said. “Our results show that people need to take care to administer finger-prick tests in a way that produces accurate results because accuracy in these tests is increasingly important for diagnosing conditions like anaemia, infections and sickle-cell anemia, malaria, HIV and other diseases.” Rice University
Nanotechnology-based sensor developed to measure microRNAs in blood, speed cancer detection
, /in E-News /by 3wmediaA simple, ultrasensitive microRNA sensor developed by researchers from the School of Science at Indiana University-Purdue University Indianapolis, the IU School of Medicine and the IU Melvin and Bren Simon Cancer Center holds promise for the design of new diagnostic strategies and, potentially, for the prognosis and treatment of pancreatic and other cancers.
In a study the IUPUI researchers describe their design of the novel, low-cost, nanotechnology-enabled reusable sensor. They also report on the promising results of tests of the sensor’s ability to identify pancreatic cancer or indicate the existence of a benign condition by quantifying changes in levels of microRNA signatures linked to pancreatic cancer.
‘We used the fundamental concepts of nanotechnology to design the sensor to detect and quantify biomolecules at very low concentrations,’ said Rajesh Sardar, Ph.D., who developed the sensor. ‘We have designed an ultrasensitive technique so that we can see minute changes in microRNA concentrations in a patient’s blood and confirm the presence of pancreatic cancer.’ Sardar is an assistant professor of chemistry and chemical biology in the School of Science at IUPUI and leads an interdisciplinary research program focusing on the intersection of analytical chemistry and the nanoscience of metallic nanoparticles.
‘If we can establish that there is cancer in the pancreas because the sensor detects high levels of microRNA-10b or one of the other microRNAs associated with that specific cancer, we may be able to treat it sooner,’ said Murray Korc, M.D., the Myles Brand Professor of Cancer Research at the IU School of Medicine and a researcher at the IU Simon Cancer Center. Korc worked with Sardar to improve the sensor’s capabilities and led the testing of the sensor and its clinical uses as well as advancing the understanding of pancreatic cancer biology.
‘That’s especially significant for pancreatic cancer, because for many patients it is symptom-free for years or even a decade or more, by which time it has spread to other organs, when surgical removal is no longer possible and therapeutic options are limited,’ said Korc. ‘For example, diagnosis of pancreatic cancer at an early stage of the disease followed by surgical removal is associated with a 40 percent five-year survival. Diagnosis of metastatic pancreatic cancer, by contrast, is associated with life expectancy that is often only a year or less.
‘The beauty of the sensor designed by Dr. Sardar is its ability to accurately detect mild increases in microRNA levels, which could allow for early cancer diagnosis,’ Korc added.
Over the past decade, studies have shown that microRNAs play important roles in cancer and other diseases, such as diabetes and cardiovascular disorders. The new IUPUI nanotechnology-based sensor can detect changes in any of these microRNAs.
The sensor is a small glass chip that contains triangular-shaped gold nanoparticles called ‘nanoprisms.’ After dipping it in a sample of blood or another body fluid, the scientist measures the change in the nanoprism’s optical property to determine the levels of specific microRNAs.
‘Using gold nanoprisms may sound expensive, but it isn’t because these particles are so very tiny,’ Sardar said. “It’s a rather cheap technique because it uses nanotechnology and needs very little gold. $250 worth of gold makes 4,000 sensors. Four thousand sensors allow you to do at least 4,000 tests. The low cost makes this technique ideal for use anywhere, including in low-resource environments in this country and around the world.’ IUSM