Autism spectrum disorders (ASD) are an increasingly diagnosed group of neurodevelopmental disorders. Although heritability suggests a strong genetic component, efforts to identify genes involved have had disappointing results, and the difference in disease state between identical (monozygotic) twins points to a potential role for epigenetic factors. Two new studies have found a significant correlation between DNA methylation (DNAm) patterns and ASD traits. Wong et al. performed a genome-wide analysis of DNAm in a sample of 50 monozygotic twin pairs sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype [1]. Numerous differentially methylated regions associated with ASD were identified and significant correlations between DNAm and quantitatively measured autistic trait scores were reported. Ladd-Acosta et al. examined DNAm in post-mortem brain tissue from 19 autism cases and 21 unrelated controls. Over 485 000 CpG loci were measured across a diverse set of functionally relevant genomic regions and four genome-wide significant differentially methylated regions were identified [2].
1. Wong et al. Mol Psychiatry 2013; doi: 10.1038/mp.2013.114 (www.nature.com/mp/journal/vaop/ncurrent/full/mp201341a.html). 2. Ladd-Acosta et al. Mol Psychiatry 2013; doi: 10.1038/mp.2013.114 (www.nature.com/mp/journal/vaop/ncurrent/full/mp2013114a.htm).
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Early diagnosis of dementia is essential for the instigation of the best treatment regime. This is, however, notoriously difficult, as changes begin occurring many years before any symptoms may be apparent. Identification of a specific genetic cause of early onset dementia (EOD) is important but can be difficult because of pleiotropy, locus heterogeneity and accessibility of gene tests. In this study, the authors assessed the use of next-generation sequencing (NGS) technologies as a quick, accurate and cost effective method for determining a genetic diagnosis in EOD. Gene panel-based technologies were developed to assess 16 genes known to contain dementia-causing mutations and were combined with PCR-based assessments of the C9orf72 hexanucleotide repeat expansion and the octapeptide repeat region of PRNP, the prion protein gene. In a blinded study of 95 samples, very high sensitivity and specificity were shown to be achievable using either Ion Torrent or MiSeq sequencing platforms. Modifications to the gene panel permit accurate detection of structural variation in the amyloid precursor protein, APP. In 2/10 samples which had been selected because they possess a variant of uncertain significance the new technology discovered a causal mutation in genes not previously sequenced. A large proportion (23/85) of samples showed genetic variants of uncertain significance in addition to known mutations. Gene panels, such as this one from the Medical Research Council, UK, and similar technologies are likely to transform the diagnosis of early onset dementia diagnosis, significantly impacting the proportion of patients in whom a genetic cause is identified.
Beck J, et al. Neurobiol Aging 2013; PII: S0197-4580(13)00322-9
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BD Diagnostics and the College of American Pathologists (CAP) have announced the launch of a new strategic alliance that will provide solutions to advance laboratory quality for improved patient outcomes in China and India. BD and CAP announced the collaboration during the American Association for Clinical Chemistry (AACC) Annual Meeting in Houston, Texas.
Laboratories play a critical role in the diagnosis and treatment of disease for the more than 2.5 billion people who live in China and India. The BD/CAP Strategic Alliance will improve access to external quality assurance/proficiency testing (PT) that can have a direct and positive impact on laboratory quality, and therefore, patient outcomes. Together BD and CAP will provide education to improve awareness of global practice standards and training that will help laboratories achieve their quality improvement goals. Additionally, BD will manage PT distribution, including sales, shipping, and first-line client service.
“The clinical laboratory and pathology contribute more than 70 percent of the information used to determine diagnoses and drive treatment decisions,” said CAP President Stanley J. Robboy, MD, FCAP. “CAP has all of the tools necessary to help laboratories improve and monitor efforts that drive quality performance. This strategic alliance with BD will increase access to these essential resources, helping laboratories accelerate their quality improvement journey so that they can contribute to better quality care, differentiate themselves and their institutions, and be recognized globally among the best providers of laboratory and pathology services.”
CAP’s Laboratory Accreditation, Surveys, PT programmes, and other quality management resources combined with BD’s in-depth clinical knowledge of preanalytical systems provide a comprehensive, expert-based toolkit to help laboratories in China and India continuously improve the quality of the testing services they provide to patients. Through participation in CAP accreditation, laboratories in China and India can demonstrate their compliance to the most robust and comprehensive clinical laboratory testing standards in the world. Having operated in China since 1994 and in India since 1996 supporting public and private sector partners in enhancing laboratory standards, BD has extensive experience in deploying clinical expertise and educational resources in these regions, as well as a deep understanding of the unique needs of laboratories throughout these countries. Today in China, there are 18 CAP-accredited laboratories and nearly 100 laboratories participating in PT. In India, of the 71 laboratories participating in CAP PT, 42 have achieved CAP accreditation. BD’s access and logistics experience will support CAP PT importation and ensure more timely delivery and quality, reduce participants’ administrative work, and allow billing in local currency. Market launch of this initiative will begin in China and India in August 2013 with PT distribution initiated in January 2014.
www.bd.com www.cap.org
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Beckman Coulter, Inc., and IRIS Diagnostics announce the launch of the Alifax automated Erythrocyte Sedimentation Rate (ESR) analysis system through a distribution agreement with Alifax.
The automated ESR analysis systems are designed to fit all workloads, including small hospitals, large reference laboratories, core laboratories and satellite locations. The automated ESR system delivers increased productivity, efficiencies in laboratory labour utilization and reduced turnaround times (TAT), along with improved patient outcomes and physician satisfaction.
“This patented technology is a breakthrough in turnaround time – generating subsequent results every 35 seconds or less, versus one hour for standard ESR analysis by the reference Westergren method,” said John Blackwood, senior vice president, Product Management, Beckman Coulter Diagnostics. “The small sample volume and STAT capability are expected to reduce ER waiting times and significantly minimize the need for patient specimen redraws.”
Employing patented technology, the Alifax ESR system provides fully automated, hands-off operation in a small footprint and processes the same whole blood tubes from the hematology analyser.
ESR is a common blood test, and is a non-specific measure of inflammation. Standard ESR analysis is a measure of red cells settling over time, typically one hour, and variations occur in the results, depending on the degree of specimen viscosity and presence of inflammatory proteins. Alifax’s technology measures the kinetics of red blood cell aggregation by capillary photometry and reads aggregation over a ten second period.
www.beckmancoulter.comwww.alifax.com
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Diagnostica Stago S.A.S, a privately held company that provides reference tests and instrumentation in hemostasis, announced that the company has entered a joint research agreement with Bristol-Myers Squibb Company (BMY) to develop an assay for measuring the circulating blood concentration of the oral Factor Xa inhibitor ELIQUIS (apixaban). No commercial assay is presently available to specifically measure apixaban plasma concentration. Terms of the agreement were not disclosed.
“Stago is pleased to have the opportunity to develop this test”, said Tristan Herve, Director of Pharmaceutical Development, “These oral Factor Xa inhibitors address an important unmet need for patients requiring anticoagulant therapy”.
Stago has already completed prototype development and will be applying for health authority approvals of the assay worldwide. Diagnostica Stago retains 100 percent global development and commercialization rights for the assay.
www.stago.com
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Researchers at King’s College London and the University of Manchester, funded by Arthritis Research UK, have developed a new method to identify people that are at a very high-risk of developing rheumatoid arthritis, using a simple blood test and information about their smoking habits.
Rheumatoid arthritis is a potentially crippling autoimmune condition that causes pain and inflammation in the joints. It affects around 400,000 people in the UK and is at present incurable. Many factors are known to contribute to an individual’s risk of developing rheumatoid arthritis. These are divided into two categories: inherited genetic factors (46 genetic risk factors have been identified that increase someone’s risk of developing rheumatoid arthritis) and so called ‘environmental’ factors such as smoking.
This new computer-based technique of prediction modelling allows researchers to combine both genetic and environmental risk factors to estimate an individual’s lifetime risk of developing this disease.
According to the study’s lead researcher, Dr Ian Scott, Department of Genetics & Molecular Medicine at King’s College London, this new prediction modelling technique can also identify people of developing rheumatoid arthritis at a younger age.
‘This new computer-based technique of prediction modelling allows us to estimate someone’s risk of developing rheumatoid arthritis over their lifetime using genetic markers from a single blood test and information about their smoking habits’, explained Dr Scott.
‘I hope that, as we understand the risk factors for rheumatoid arthritis better, our prediction modelling method could be used to screen people for this disease before they develop any symptoms. This is an important first step in trying to develop ways to prevent the onset of rheumatoid arthritis.
‘Within the general population, few individuals that have clinically significant increased risks are likely to be identified using this approach. But targeted screening of people already at an increased risk of rheumatoid arthritis, such as relatives of patients, could identify enough high-risk people to allow researchers to look at ways to prevent rheumatoid arthritis from developing.’
Individuals classed as being high risk, using information from the most important gene associated with rheumatoid arthritis (the HLA-DRB1 gene), are more likely to develop rheumatoid arthritis at a younger age. They could be monitored for early signs of the disease. Treating rheumatoid arthritis early, before significant joint damage has occurred, increases the likelihood that the individual will go into remission (no joint pain or swelling) following treatment.
King’s College London
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Australian researchers have demonstrated a strong association between the FTO (fat and obesity) gene and hip fracture in women. While the gene is already well known to affect diabetes and body fat, this is the first study to show that its high-risk variant can increase the risk of hip fracture by as much as 82%.
The study, undertaken by Dr Bich Tran and Professor Tuan Nguyen from Sydney’s Garvan Institute of Medical Research, examined six gene variants (single nucleotide polymorphisms, or SNPs) of the FTO gene, taken from the DNA of 943 women in the Dubbo Osteoporosis Epidemiology Study (DOES). The women were all over 60, and their bone health was followed between 1989 and 2007. During that period, 102 women had hip fractures.
On average, the risk of fracture is about 11%. The study showed that if a woman has a low-risk genotype, or gene variant, the risk of fracture is 10%. If she has a high-risk genotype, it is 16%.
The authors believe that the findings have the potential to improve prediction of hip fracture. Known risk factors, also to be taken into account, include advancing age, falls, history of fracture, low bone mineral density, low body mass index (BMI) and genetic make-up.
‘We found that for a woman of the same age and same clinical risk factors, those with the high-risk genotype have an increased risk of fracture of 82% – a very high effect in genetic terms,’ said Professor Tuan Nguyen.
‘A genome-wide association study published in 2007 suggested that genetic variants in the FTO gene were associated with variation in BMI. This led us to hypothesise that they might also be associated with variation in hip fracture risk.’
‘The present study tested our hypothesis by examining the association between common variants in the FTO gene and hip fracture.’
‘Our results showed a strong association with hip fracture, with some gene variants doubling the risk of fracture. Interestingly, this was independent of both the bone density and BMI of the women we studied.’
‘We also found that the FTO gene expresses in bone cells, and may have something to do with bone turnover, or remodelling, although its exact mechanisms are unclear.’
‘It’s important to emphasise that, while promising, our finding is a first step. It will need to be replicated in other studies, and its mechanisms clearly understood before it is useful in drug development.’
Garvan Institute of Medical Research
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Determining whether a patient’s lung cancer has spread to nearby lymph nodes is critical for identifying the most effective therapy, but it usually requires surgery. A new study suggests, however, that measuring levels of a particular molecule in a sample of tumour tissue might accurately answer the question.
Researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) have discovered that levels of microRNA-31 (miR-31) predict the spread of the most common form of lung cancer to nearby lymph nodes.
They found that high levels of miR-31 in primary tumour cells predicted lymph node metastasis and poor survival in patients with non-small cell lung cancer (NSCLC). Low expression levels were associated with the absence of metastases and excellent survival.
‘Our findings suggest that microRNA expression in the primary lung tumour can estimate whether the tumour has spread to the lymph nodes and can help direct patients to the most appropriate treatment,’ says principal investigator Tim Lautenschlaeger, MD, a researcher in Radiation Oncology and the OSUCCC – James Experimental Therapeutics Program.
‘Many patients undergo radiation therapy for NSCLC, and particularly those with early stage disease do not routinely undergo surgical staging,’ he explains. ‘Staging with positron emission tomography-computed tomography is very useful but not perfect. MiR-31 and other microRNAs can potentially improve our ability to correctly stage these patients.
‘Additionally, if we can better estimate invasiveness of each patient’s tumour, we could individualise treatment to include the invasive microscopic disease while sparing as much normal tissue as possible.’
An estimated 228,190 cases of lung cancer are expected to occur in the United States in 2013, along with 159,500 deaths from the disease. NSCLC accounts for about 80 percent of all lung-cancer patients. Adenocarcinoma is the most common subtype, representing about 40 percent of all lung cancer cases.
The Ohio State University Comprehensive Cancer Center
The human papillomavirus (HPV) may be to blame for the alarming increase of young adults with oropharyngeal cancer, according to researchers from Henry Ford Hospital in Detroit.
The study reveals an overall 60 percent increase from 1973 and 2009 in cancers of the base of tongue, tonsils, soft palate and pharynx in people younger than age 45.
Among Caucasians, there was a 113 percent increase, while among African-Americans the rate of these cancers declined by 52 percent during that period of time.
But compared to Caucasians and other races, the five-year survival rate remains worse for African Americans.
‘The growing incidence in oropharyngeal cancer has been largely attributed to the sexual revolution of the 1960s and 1970s, which led to an increased transmission of high-risk HPV,’ says study lead author Farzan Siddiqui, M.D., Ph.D., director of the Head & Neck Radiation Therapy Program in the Department of Radiation Oncology at Henry Ford Hospital.
‘We were interested in looking at people born during that time period and incidence of oropharyngeal cancer. Not only were we surprised to find a substantial increase in young adults with cancer of the tonsils and base of tongue, but also a wide deviation among Caucasians and African Americans with this cancer.’
The study – which examined the trends in cancers of the base of tongue, tonsils, soft palate and pharynx among people 45 years-old and younger – will be presented Sept. 23 at the 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO) in Atlanta.
The American Cancer Society estimates about 36,000 people in the U.S. will get oral cavity and oropharyngeal cancers in 2013; an estimated 6,850 people will die of these cancers. Oropharyngeal cancers are more than twice as common in men as in women, and about equally common in African Americans and Caucasians.
Recent medical research has shown that HPV exposure and infection increases the risk of oropharyngeal squamous cell cancer independently of tobacco and alcohol use, two other important risk factors for the disease, according to the National Cancer Institute.
The incidence of oropharyngeal cancer has been growing in recent years due to increasing rates of HPV infection. This has been largely attributed to changes in sexual practices. Studies have shown, however, patients with HPV related head and neck cancer do have a better prognosis and survival.
Henry Ford Hospital in Detroit
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Massachusetts General Hospital (MGH) researchers have identified and validated two rare gene mutations that appear to cause the common form of Alzheimer’s disease (AD) that strikes after the age of 60. The two mutations occur in a gene called ADAM10 – coding for an enzyme involved in processing the amyloid precursor protein – which now becomes the second pathologically-confirmed gene for late-onset AD and the fifth AD gene overall.
In their report the investigators from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) describe how the two mutations in ADAM10 increase generation and accumulation of the toxic amyloid beta (A-beta) protein in the brains of a mouse model of AD. The mutations also reduce generation of new neural cells in hippocampus, a part of the brain essential to learning and memory.
‘This is the first report to document, in animal models, new pathogenic gene mutations for AD since the reports of the original four genes in the 1990s,’ says Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at MGH-MIND and senior author of the Neuron paper. ‘What we found regarding the many effects of these two rare mutations in ADAM10 strongly suggests that diminished activity of this enzyme can cause AD, and these findings support ADAM10 as a promising therapeutic target for both treatment and prevention.’
The process leading to the generation of A-beta – which accumulates in characteristic plaques in the brains of AD patients – begins when the amyloid precursor protein (APP) is cut into smaller proteins by enzymes called secretases. A-beta results if APP is first cut into two segments by an enzyme called beta-secretase, and one of those segments is further cut by a gamma-secretase enzyme to release the toxic A-beta fragment. However, processing of APP by an alpha-secretase enzyme – one of which is ADAM10 – cuts right through the A-beta region in APP. So instead of generating the toxic A-beta fragment, cleavage with alpha-secretase produces a protein fragment that has been reported to protect and stimulate the generation of neurons in brain.
An earlier study by Tanzi’s team reported finding that either of two mutations in ADAM10 increased the risk of AD in seven families with the late-onset form of the disease. Since ADAM10 was already known to be important to alpha-secretase processing of APP, along with having a role in early brain development, the researchers set out to investigate how the observed mutations might lead to the pattern of neurodegeneration characteristic of AD.
Experiments using several strains of transgenic mice – including lines that express both one of the ADAM10 mutations and an APP mutation that leads to AD-like pathology – revealed the following:
AD-associated mutations in ADAM10 reduced the release from neurons in the animals’ brains of the beneficial protein produced by alpha-secretase processing of APP,
Reduced ADAM10 activity caused by the mutations increased the generation of A-beta and its accumulation in plaques, along with producing other AD-associated neurodegenerative signs,
Reduced ADAM10 activity also impaired the generation of new neurons in the hippocampus, one of the areas of the brain most vulnerable to neurodegeneration in AD,
The AD-associated mutations produce these effects by impairing the correct folding of ADAM10 and interfering with its normal functions.
Jaehong Suh, PhD, of the MGH-MIND Genetics and Aging Research Unit, lead author of the Neuron article, says, ‘Our current study shows that reducing ADAM10 activity by these AD-associated mutations delivers a ‘one-two punch’ to the brain – one, decreasing neuroprotective alpha-secretase cleavage products and two, increasing neurotoxic A-beta protein accumulation. Thus, we believe that increasing ADAM10 activity might help to alleviate both genetic and environmental AD risk factors that increase the toxic beta-secretase processing of APP. We’re planning to develop optimal ways to increase ADAM10 activity in brain and to further investigate the molecular structure and regulatory mechanism of the ADAM10 enzyme.’ Suh is an instructor in Neurology, and Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School.
Massachusetts General Hospital
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A genetic test for autism spectrum disorders?
, /in E-News /by 3wmediaAutism spectrum disorders (ASD) are an increasingly diagnosed group of neurodevelopmental disorders. Although heritability suggests a strong genetic component, efforts to identify genes involved have had disappointing results, and the difference in disease state between identical (monozygotic) twins points to a potential role for epigenetic factors. Two new studies have found a significant correlation between DNA methylation (DNAm) patterns and ASD traits. Wong et al. performed a genome-wide analysis of DNAm in a sample of 50 monozygotic twin pairs sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype [1]. Numerous differentially methylated regions associated with ASD were identified and significant correlations between DNAm and quantitatively measured autistic trait scores were reported. Ladd-Acosta et al. examined DNAm in post-mortem brain tissue from 19 autism cases and 21 unrelated controls. Over 485 000 CpG loci were measured across a diverse set of functionally relevant genomic regions and four genome-wide significant differentially methylated regions were identified [2].
1. Wong et al. Mol Psychiatry 2013; doi: 10.1038/mp.2013.114 (www.nature.com/mp/journal/vaop/ncurrent/full/mp201341a.html).
2. Ladd-Acosta et al. Mol Psychiatry 2013; doi: 10.1038/mp.2013.114 (www.nature.com/mp/journal/vaop/ncurrent/full/mp2013114a.htm).
Genetic diagnosis of dementia by next-generation sequencing
, /in E-News /by 3wmediaEarly diagnosis of dementia is essential for the instigation of the best treatment regime. This is, however, notoriously difficult, as changes begin occurring many years before any symptoms may be apparent. Identification of a specific genetic cause of early onset dementia (EOD) is important but can be difficult because of pleiotropy, locus heterogeneity and accessibility of gene tests. In this study, the authors assessed the use of next-generation sequencing (NGS) technologies as a quick, accurate and cost effective method for determining a genetic diagnosis in EOD. Gene panel-based technologies were developed to assess 16 genes known to contain dementia-causing mutations and were combined with PCR-based assessments of the C9orf72 hexanucleotide repeat expansion and the octapeptide repeat region of PRNP, the prion protein gene. In a blinded study of 95 samples, very high sensitivity and specificity were shown to be achievable using either Ion Torrent or MiSeq sequencing platforms. Modifications to the gene panel permit accurate detection of structural variation in the amyloid precursor protein, APP. In 2/10 samples which had been selected because they possess a variant of uncertain significance the new technology discovered a causal mutation in genes not previously sequenced. A large proportion (23/85) of samples showed genetic variants of uncertain significance in addition to known mutations. Gene panels, such as this one from the Medical Research Council, UK, and similar technologies are likely to transform the diagnosis of early onset dementia diagnosis, significantly impacting the proportion of patients in whom a genetic cause is identified.
Beck J, et al. Neurobiol Aging 2013; PII: S0197-4580(13)00322-9
BD and the College of American Pathologists announce strategic alliance to support laboratory quality and performance in India and China
, /in E-News /by 3wmediaBD Diagnostics and the College of American Pathologists (CAP) have announced the launch of a new strategic alliance that will provide solutions to advance laboratory quality for improved patient outcomes in China and India. BD and CAP announced the collaboration during the American Association for Clinical Chemistry (AACC) Annual Meeting in Houston, Texas.
Laboratories play a critical role in the diagnosis and treatment of disease for the more than 2.5 billion people who live in China and India. The BD/CAP Strategic Alliance will improve access to external quality assurance/proficiency testing (PT) that can have a direct and positive impact on laboratory quality, and therefore, patient outcomes. Together BD and CAP will provide education to improve awareness of global practice standards and training that will help laboratories achieve their quality improvement goals. Additionally, BD will manage PT distribution, including sales, shipping, and first-line client service.
“The clinical laboratory and pathology contribute more than 70 percent of the information used to determine diagnoses and drive treatment decisions,” said CAP President Stanley J. Robboy, MD, FCAP. “CAP has all of the tools necessary to help laboratories improve and monitor efforts that drive quality performance. This strategic alliance with BD will increase access to these essential resources, helping laboratories accelerate their quality improvement journey so that they can contribute to better quality care, differentiate themselves and their institutions, and be recognized globally among the best providers of laboratory and pathology services.”
CAP’s Laboratory Accreditation, Surveys, PT programmes, and other quality management resources combined with BD’s in-depth clinical knowledge of preanalytical systems provide a comprehensive, expert-based toolkit to help laboratories in China and India continuously improve the quality of the testing services they provide to patients. Through participation in CAP accreditation, laboratories in China and India can demonstrate their compliance to the most robust and comprehensive clinical laboratory testing standards in the world.
www.bd.com www.cap.orgHaving operated in China since 1994 and in India since 1996 supporting public and private sector partners in enhancing laboratory standards, BD has extensive experience in deploying clinical expertise and educational resources in these regions, as well as a deep understanding of the unique needs of laboratories throughout these countries. Today in China, there are 18 CAP-accredited laboratories and nearly 100 laboratories participating in PT. In India, of the 71 laboratories participating in CAP PT, 42 have achieved CAP accreditation. BD’s access and logistics experience will support CAP PT importation and ensure more timely delivery and quality, reduce participants’ administrative work, and allow billing in local currency. Market launch of this initiative will begin in China and India in August 2013 with PT distribution initiated in January 2014.
Beckman Coulter and IRIS Diagnostics offer automated erythrocyte sedimentation rate analysis systems through distribution agreement with Alifax
, /in E-News /by 3wmediaBeckman Coulter, Inc., and IRIS Diagnostics announce the launch of the Alifax automated Erythrocyte Sedimentation Rate (ESR) analysis system through a distribution agreement with Alifax.
The automated ESR analysis systems are designed to fit all workloads, including small hospitals, large reference laboratories, core laboratories and satellite locations. The automated ESR system delivers increased productivity, efficiencies in laboratory labour utilization and reduced turnaround times (TAT), along with improved patient outcomes and physician satisfaction.
“This patented technology is a breakthrough in turnaround time – generating subsequent results every 35 seconds or less, versus one hour for standard ESR analysis by the reference Westergren method,” said John Blackwood, senior vice president, Product Management, Beckman Coulter Diagnostics. “The small sample volume and STAT capability are expected to reduce ER waiting times and significantly minimize the need for patient specimen redraws.”
Employing patented technology, the Alifax ESR system provides fully automated, hands-off operation in a small footprint and processes the same whole blood tubes from the hematology analyser.
ESR is a common blood test, and is a non-specific measure of inflammation. Standard ESR analysis is a measure of red cells settling over time, typically one hour, and variations occur in the results, depending on the degree of specimen viscosity and presence of inflammatory proteins. Alifax’s technology measures the kinetics of red blood cell aggregation by capillary photometry and reads aggregation over a ten second period.
www.beckmancoulter.comwww.alifax.comDiagnostica Stago enters into joint research agreement with Bristol-Myers Squibb
, /in E-News /by 3wmediaDiagnostica Stago S.A.S, a privately held company that provides reference tests and instrumentation in hemostasis, announced that the company has entered a joint research agreement with Bristol-Myers Squibb Company (BMY) to develop an assay for measuring the circulating blood concentration of the oral Factor Xa inhibitor ELIQUIS (apixaban). No commercial assay is presently available to specifically measure apixaban plasma concentration. Terms of the agreement were not disclosed.
“Stago is pleased to have the opportunity to develop this test”, said Tristan Herve, Director of Pharmaceutical Development, “These oral Factor Xa inhibitors address an important unmet need for patients requiring anticoagulant therapy”.
Stago has already completed prototype development and will be applying for health authority approvals of the assay worldwide. Diagnostica Stago retains 100 percent global development and commercialization rights for the assay.
www.stago.comNew method of identifying people at a high risk of developing rheumatoid arthritis
, /in E-News /by 3wmediaResearchers at King’s College London and the University of Manchester, funded by Arthritis Research UK, have developed a new method to identify people that are at a very high-risk of developing rheumatoid arthritis, using a simple blood test and information about their smoking habits.
Rheumatoid arthritis is a potentially crippling autoimmune condition that causes pain and inflammation in the joints. It affects around 400,000 people in the UK and is at present incurable. Many factors are known to contribute to an individual’s risk of developing rheumatoid arthritis. These are divided into two categories: inherited genetic factors (46 genetic risk factors have been identified that increase someone’s risk of developing rheumatoid arthritis) and so called ‘environmental’ factors such as smoking.
This new computer-based technique of prediction modelling allows researchers to combine both genetic and environmental risk factors to estimate an individual’s lifetime risk of developing this disease.
According to the study’s lead researcher, Dr Ian Scott, Department of Genetics & Molecular Medicine at King’s College London, this new prediction modelling technique can also identify people of developing rheumatoid arthritis at a younger age.
‘This new computer-based technique of prediction modelling allows us to estimate someone’s risk of developing rheumatoid arthritis over their lifetime using genetic markers from a single blood test and information about their smoking habits’, explained Dr Scott.
‘I hope that, as we understand the risk factors for rheumatoid arthritis better, our prediction modelling method could be used to screen people for this disease before they develop any symptoms. This is an important first step in trying to develop ways to prevent the onset of rheumatoid arthritis.
‘Within the general population, few individuals that have clinically significant increased risks are likely to be identified using this approach. But targeted screening of people already at an increased risk of rheumatoid arthritis, such as relatives of patients, could identify enough high-risk people to allow researchers to look at ways to prevent rheumatoid arthritis from developing.’
Individuals classed as being high risk, using information from the most important gene associated with rheumatoid arthritis (the HLA-DRB1 gene), are more likely to develop rheumatoid arthritis at a younger age. They could be monitored for early signs of the disease. Treating rheumatoid arthritis early, before significant joint damage has occurred, increases the likelihood that the individual will go into remission (no joint pain or swelling) following treatment. King’s College London
Fat and obesity gene also affects hip fracture
, /in E-News /by 3wmediaAustralian researchers have demonstrated a strong association between the FTO (fat and obesity) gene and hip fracture in women. While the gene is already well known to affect diabetes and body fat, this is the first study to show that its high-risk variant can increase the risk of hip fracture by as much as 82%.
The study, undertaken by Dr Bich Tran and Professor Tuan Nguyen from Sydney’s Garvan Institute of Medical Research, examined six gene variants (single nucleotide polymorphisms, or SNPs) of the FTO gene, taken from the DNA of 943 women in the Dubbo Osteoporosis Epidemiology Study (DOES). The women were all over 60, and their bone health was followed between 1989 and 2007. During that period, 102 women had hip fractures.
On average, the risk of fracture is about 11%. The study showed that if a woman has a low-risk genotype, or gene variant, the risk of fracture is 10%. If she has a high-risk genotype, it is 16%.
The authors believe that the findings have the potential to improve prediction of hip fracture. Known risk factors, also to be taken into account, include advancing age, falls, history of fracture, low bone mineral density, low body mass index (BMI) and genetic make-up.
‘We found that for a woman of the same age and same clinical risk factors, those with the high-risk genotype have an increased risk of fracture of 82% – a very high effect in genetic terms,’ said Professor Tuan Nguyen.
‘A genome-wide association study published in 2007 suggested that genetic variants in the FTO gene were associated with variation in BMI. This led us to hypothesise that they might also be associated with variation in hip fracture risk.’
‘The present study tested our hypothesis by examining the association between common variants in the FTO gene and hip fracture.’
‘Our results showed a strong association with hip fracture, with some gene variants doubling the risk of fracture. Interestingly, this was independent of both the bone density and BMI of the women we studied.’
‘We also found that the FTO gene expresses in bone cells, and may have something to do with bone turnover, or remodelling, although its exact mechanisms are unclear.’
‘It’s important to emphasise that, while promising, our finding is a first step. It will need to be replicated in other studies, and its mechanisms clearly understood before it is useful in drug development.’ Garvan Institute of Medical Research
MicroRNA-31 might predict lung-cancer spread
, /in E-News /by 3wmediaDetermining whether a patient’s lung cancer has spread to nearby lymph nodes is critical for identifying the most effective therapy, but it usually requires surgery. A new study suggests, however, that measuring levels of a particular molecule in a sample of tumour tissue might accurately answer the question.
Researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) have discovered that levels of microRNA-31 (miR-31) predict the spread of the most common form of lung cancer to nearby lymph nodes.
They found that high levels of miR-31 in primary tumour cells predicted lymph node metastasis and poor survival in patients with non-small cell lung cancer (NSCLC). Low expression levels were associated with the absence of metastases and excellent survival.
‘Our findings suggest that microRNA expression in the primary lung tumour can estimate whether the tumour has spread to the lymph nodes and can help direct patients to the most appropriate treatment,’ says principal investigator Tim Lautenschlaeger, MD, a researcher in Radiation Oncology and the OSUCCC – James Experimental Therapeutics Program.
‘Many patients undergo radiation therapy for NSCLC, and particularly those with early stage disease do not routinely undergo surgical staging,’ he explains. ‘Staging with positron emission tomography-computed tomography is very useful but not perfect. MiR-31 and other microRNAs can potentially improve our ability to correctly stage these patients.
‘Additionally, if we can better estimate invasiveness of each patient’s tumour, we could individualise treatment to include the invasive microscopic disease while sparing as much normal tissue as possible.’
An estimated 228,190 cases of lung cancer are expected to occur in the United States in 2013, along with 159,500 deaths from the disease. NSCLC accounts for about 80 percent of all lung-cancer patients. Adenocarcinoma is the most common subtype, representing about 40 percent of all lung cancer cases. The Ohio State University Comprehensive Cancer Center
HPV linked to growing number of young adults with oropharyngeal cancer
, /in E-News /by 3wmediaThe human papillomavirus (HPV) may be to blame for the alarming increase of young adults with oropharyngeal cancer, according to researchers from Henry Ford Hospital in Detroit.
The study reveals an overall 60 percent increase from 1973 and 2009 in cancers of the base of tongue, tonsils, soft palate and pharynx in people younger than age 45.
Among Caucasians, there was a 113 percent increase, while among African-Americans the rate of these cancers declined by 52 percent during that period of time.
But compared to Caucasians and other races, the five-year survival rate remains worse for African Americans.
‘The growing incidence in oropharyngeal cancer has been largely attributed to the sexual revolution of the 1960s and 1970s, which led to an increased transmission of high-risk HPV,’ says study lead author Farzan Siddiqui, M.D., Ph.D., director of the Head & Neck Radiation Therapy Program in the Department of Radiation Oncology at Henry Ford Hospital.
‘We were interested in looking at people born during that time period and incidence of oropharyngeal cancer. Not only were we surprised to find a substantial increase in young adults with cancer of the tonsils and base of tongue, but also a wide deviation among Caucasians and African Americans with this cancer.’
The study – which examined the trends in cancers of the base of tongue, tonsils, soft palate and pharynx among people 45 years-old and younger – will be presented Sept. 23 at the 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO) in Atlanta.
The American Cancer Society estimates about 36,000 people in the U.S. will get oral cavity and oropharyngeal cancers in 2013; an estimated 6,850 people will die of these cancers. Oropharyngeal cancers are more than twice as common in men as in women, and about equally common in African Americans and Caucasians.
Recent medical research has shown that HPV exposure and infection increases the risk of oropharyngeal squamous cell cancer independently of tobacco and alcohol use, two other important risk factors for the disease, according to the National Cancer Institute.
The incidence of oropharyngeal cancer has been growing in recent years due to increasing rates of HPV infection. This has been largely attributed to changes in sexual practices. Studies have shown, however, patients with HPV related head and neck cancer do have a better prognosis and survival. Henry Ford Hospital in Detroit
Study confirms that rare mutations increase risk of late-onset Alzheimer’s disease
, /in E-News /by 3wmediaMassachusetts General Hospital (MGH) researchers have identified and validated two rare gene mutations that appear to cause the common form of Alzheimer’s disease (AD) that strikes after the age of 60. The two mutations occur in a gene called ADAM10 – coding for an enzyme involved in processing the amyloid precursor protein – which now becomes the second pathologically-confirmed gene for late-onset AD and the fifth AD gene overall.
In their report the investigators from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) describe how the two mutations in ADAM10 increase generation and accumulation of the toxic amyloid beta (A-beta) protein in the brains of a mouse model of AD. The mutations also reduce generation of new neural cells in hippocampus, a part of the brain essential to learning and memory.
‘This is the first report to document, in animal models, new pathogenic gene mutations for AD since the reports of the original four genes in the 1990s,’ says Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at MGH-MIND and senior author of the Neuron paper. ‘What we found regarding the many effects of these two rare mutations in ADAM10 strongly suggests that diminished activity of this enzyme can cause AD, and these findings support ADAM10 as a promising therapeutic target for both treatment and prevention.’
The process leading to the generation of A-beta – which accumulates in characteristic plaques in the brains of AD patients – begins when the amyloid precursor protein (APP) is cut into smaller proteins by enzymes called secretases. A-beta results if APP is first cut into two segments by an enzyme called beta-secretase, and one of those segments is further cut by a gamma-secretase enzyme to release the toxic A-beta fragment. However, processing of APP by an alpha-secretase enzyme – one of which is ADAM10 – cuts right through the A-beta region in APP. So instead of generating the toxic A-beta fragment, cleavage with alpha-secretase produces a protein fragment that has been reported to protect and stimulate the generation of neurons in brain.
An earlier study by Tanzi’s team reported finding that either of two mutations in ADAM10 increased the risk of AD in seven families with the late-onset form of the disease. Since ADAM10 was already known to be important to alpha-secretase processing of APP, along with having a role in early brain development, the researchers set out to investigate how the observed mutations might lead to the pattern of neurodegeneration characteristic of AD.
Experiments using several strains of transgenic mice – including lines that express both one of the ADAM10 mutations and an APP mutation that leads to AD-like pathology – revealed the following:
AD-associated mutations in ADAM10 reduced the release from neurons in the animals’ brains of the beneficial protein produced by alpha-secretase processing of APP,
Reduced ADAM10 activity caused by the mutations increased the generation of A-beta and its accumulation in plaques, along with producing other AD-associated neurodegenerative signs,
Reduced ADAM10 activity also impaired the generation of new neurons in the hippocampus, one of the areas of the brain most vulnerable to neurodegeneration in AD,
The AD-associated mutations produce these effects by impairing the correct folding of ADAM10 and interfering with its normal functions.
Jaehong Suh, PhD, of the MGH-MIND Genetics and Aging Research Unit, lead author of the Neuron article, says, ‘Our current study shows that reducing ADAM10 activity by these AD-associated mutations delivers a ‘one-two punch’ to the brain – one, decreasing neuroprotective alpha-secretase cleavage products and two, increasing neurotoxic A-beta protein accumulation. Thus, we believe that increasing ADAM10 activity might help to alleviate both genetic and environmental AD risk factors that increase the toxic beta-secretase processing of APP. We’re planning to develop optimal ways to increase ADAM10 activity in brain and to further investigate the molecular structure and regulatory mechanism of the ADAM10 enzyme.’ Suh is an instructor in Neurology, and Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Massachusetts General Hospital