Researchers from the RIKEN Center for Integrative Medical Sciences in Japan have identified the first gene to be associated with adolescent idiopathic scoliosis (also called AIS) across Asian and Caucasian populations. The gene is involved in the growth and development of the spine during childhood.
AIS is the most common pediatric skeletal disease, affecting approximately 2% of school-age children. The causes of scoliosis remain largely unknown and brace treatment and surgery are the only treatment options. However, many clinical and genetic studies suggest a contribution of genetic factors.
To understand the causes and development of scoliosis, Dr Ikuyo Kou, Dr Shiro Ikegawa and their team have tried to identify genes that are associated with a susceptibility to develop the condition.
By studying the genome of 1,819 Japanese individuals suffering from scoliosis and comparing it to 25,939 Japanese individuals, the team identified a gene associated with a susceptibility to develop scoliosis on chromosome 6. The association was replicated in Han Chinese and Caucasian populations.
The researchers show that the susceptibility gene, GPR126, is highly expressed in cartilage and that suppression of this gene leads to delayed growth and bone tissue formation in the developing spine. GPR126 is also known to play a role in human height and trunk length.
‘Our finding suggest the interesting possibility that GPR126 may affect both AIS susceptibility and height through abnormal spinal development and growth,’ explain the authors.
‘Further functional studies are necessary to elucidate how alterations in GPR126 increase the risk of AIS in humans,’ they conclude.
Medical News Today
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Researchers from the Masonic Cancer Center, University of Minnesota, and the University’s Brain Tumor Program, have developed a new mouse model of malignant peripheral nerve sheath tumours (MPNST) that allow them to discover new genes and gene pathways driving this type of cancer.
Utilising the Sleeping Beauty transposon method, researchers in the lab of David Largaespada, Ph.D., professor in the Medical School and College of Biological Sciences, were able to use an unbiased approach to generate mouse models of MPNST development that lead to the identification of genes related to this tumour’s development.
MPNST is a genetically diverse, aggressive form of sarcoma impacting connective tissue surrounding nerves that occurs sporadically or in association with Neurofibromatosis Type 1 (NF1) syndrome. The exact cause of MPNST is not known, but symptoms include swelling in the arms and legs, soreness and stiffness at the site of the tumour. MPNSTs are the most common malignancy in adults with NF1 syndrome and leading cause of NF1-related mortality.
Due to the invasive nature and high incidence of metastasis of MPNSTs, surgical resection, radiotherapy and chemotherapeutic treatments have proven to be ineffective for long-term treatment, resulting in 5-year survival rates of less than 25 percent with metastatic disease.
One of the most surprising findings in this research showed the gene FOXR2 is intrinsically linked to the growth of MPNSTs. This gene has not been heavily studied as researchers had not identified a clear function of this gene.
‘By using an unbiased approach, it helped us identify FOXR2 as an important gene in MPNST development and develop experiments to pinpoint the role FOXR2 plays in maintaining the aggressive nature of these tumours,’ said Eric Rahrmann, Ph.D., the paper’s lead author and a postdoctoral fellow in the Largaespada lab. ‘When we turn off FOXR2, the growth ability of these MPNSTs drastically decreases.’
Other findings showed interesting evidence of pathways that could be viable targets for therapeutics. The activation of the Wnt signalling pathway was shown to drive MPNSTs. This pathway has been highly implicated in colon cancer but not previously linked to MPNSTs.
Researchers also found many of the MPNSTs have dual loss of the genes called NF1 and PTEN. This pairing of lost genes causes MPNST formation. Both of these genes have previously been shown as pathways related to MPNSTs but it wasn’t clear the extent to which they work together.
Now, researchers are applying these findings to the testing of therapeutics currently on the market for other drugs. This research is continuing both in the mouse model and within primary tumour settings of human cell lines.
‘We want to know if these drugs, which are not currently directed at MPNSTs, could be repurposed to provide alternate therapies for patients,’ said Largaespada.
Researchers are also looking into more direct ways to target tumours through the Wnt pathway and paired NF1 and PTEN pathways, utilising mouse models and human cell lines in the lab setting.
University of Minnesota
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Researchers at the UCL Institute of Neurology together with international collaborators have identified a new gene, BICD2, which causes both dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraparesis. The team was led by Professor Mary Reilly.
Dominant Congenital Spinal Muscular Atrophy is a disorder of developing anterior horn cells and is characterised by lower limb predominance whereas Hereditary Spastic Paraparesis develops in childhood or adult life and is also a lower limb predominant disorder but of the corticospinal motor neurons.
The importance of this gene for motor nerves is underlined by the simultaneous publication of the same gene causing dominant Congenital Spinal Muscular Atrophy by two other groups.
The identification of the gene by exome sequencing and the subsequent functional work to study the pathogenesis of the disorder formed a major part of the PhD of Dr. Alex Rossor, a PhD student in the MRC Centre for Neuromuscular Diseases in the Institute of Neurology.
UCL Institute of Neurology
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Using the Department of Defense Serum Repository (DoDSR), University of Cincinnati researchers have identified a number of biomarkers for inflammatory bowel disease (IBD), which could help with earlier diagnosis and intervention in those who have not yet shown symptoms.
The DoDSR is a biological repository operated by the U.S. Department of Defense and contains over 50 million human serum specimens, collected primarily from applicants to and members of the U.S. uniformed services.
‘With collaborators from Walter Reed, we were able to identify all of the active duty service men and women who developed IBD and then used the repository to go back and look at various biomarkers to see what each person had in common,’ says Yacyshyn, a professor of medicine at the UC College of Medicine and UC Health gastroenterologist.
IBD is a group of inflammatory conditions of the colon and small intestine. The main types of IBD are Crohn’s disease and ulcerative colitis; inflammatory bowel diseases are considered autoimmune diseases in which the body’s own immune system attacks elements of the digestive system.
In this study, researchers used the repository to identify 50 cases of Crohn’s disease and 50 cases of ulcerative colitis. They analysed proteins from three samples per case—two taken before and one after diagnosis—using a statistical analysis format.
Certain proteins were found in elevated levels in samples from patients who developed IBD.
‘The selection of proteins we chose to analyse was based on a prior study conducted at UC,’ Yacyshyn says. ‘Although the presence of proteins in those who develop Crohn’s disease varies from those present in ulcerative colitis patients, we were able to show that there were elevated levels of certain proteins in patients who developed IBD.’
‘Future large validation studies are needed to confirm the presence of biomarkers to guide in diagnosis, prevention and management of these patients,’ he adds.
UC Academic Health News
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In a new study, researchers reveal how a key player in cell growth, immunity and the inflammatory response can be transformed into a primary contributor to tumour growth.
Scientists call this Jekyll-and-Hyde molecule NF-kappa B. In healthy cells, it is a powerful ‘first responder,’ a vital part of the body’s immune and inflammatory responses. It spends most of its life in the cell’s cytoplasm, quietly awaiting orders. But when extracellular signals – of a viral or bacterial invasion, for example – set off chemical alarms, the cell unchains this warhorse, allowing it to go into the nucleus where it spurs a flurry of defensive activity, including the transcription of genes that trigger inflammation, promote cell proliferation and undermine cell death.
Researchers have known for years that a hyperactive form of NF-kappa B that gets into the nucleus and stays there is associated with various cancers. But they didn’t know what was keeping it active in the nucleus.
‘Normally in the cell NF-kappa B is in the cytosol, it’s not in the nucleus, and it’s not activated,’ said University of Illinois medical biochemistry professor Lin-Feng Chen, who led the new study. ‘You have to stimulate normal cells to see NF-kappa B in the nucleus. But in cancer cells without any stimulation you can see this nuclear form of NF-kappa B. The cell just won’t die because of this. That is why NF-kappa B is so important in cancer.’
In the new study, Chen’s group found that another molecule known to help regulate gene expression, called BRD4, recognises a specific amino acid on a subunit of the NF-kappa B protein complex after the amino acid has been marked with a specific tag, called an acetyl group. This ‘acetylation’ allows the BRD4 to bind to NF-kappa B, activating it and preventing its degradation in cancer cells.
Previous studies had shown that BRD4’s recognition of the acetylated subunit increased NF-kappa B activation, but this recognition had not been linked to cancer.
BRD4 belongs to a class of molecules that can recognise chemical markers on other proteins and interact with them to spur the marked proteins to perform new tasks. Chemical ‘readers’ such as BRD4 are important players in the field of epigenetics, which focuses on how specific genes are regulated.
‘In epigenetics, there are writers, there are readers and there are erasers,’ Chen said. The writers make modifications to proteins after they are formed, without changing the underlying sequence of the gene that codes for them. These modifications (such as acetylation) signal other molecules (the readers) to engage with the marked proteins in various ways, allowing the proteins to fulfill new roles in the life of the cell. Epigenetic erasers remove the marks when they are no longer of use.
Such protein modifications ‘have been shown to be critically involved in transcription regulation and cancer development,’ the researchers report.
To test whether BRD4 was contributing to the sustained presence of NF-kappa B in the nucleus of cancer cells, Chen and his colleagues exposed lung cancer cells in cell culture and in immune-deficient mice to JQ1, a drug that interferes with BRD4 activity. Exposure to JQ1 blocked the interaction of BRD4 and NF-kappa B, blocked the expression of genes regulated by NF-kappa B, reduced proliferation of lung cancer cells and suppressed the ability of lung cancer cells to induce tumors in immune-deficient mice, the researchers found.
The researchers also discovered that depletion of BRD4 or the treatment of cells with JQ1 induced the degradation of the NF-kappa B subunit recognized by BRD4.
Chen said that BRD4 likely prevents other molecules from recognising the hyperactive NF-kappa B in the nucleus and marking it for degradation.
‘This is an example of how epigenetic regulators and NF-kappa B may one day be targeted for the treatment of cancer,’ he said.
University of Illinois at Urbana Champaign
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A new diagnostic test for a worm infection that can lead to severe enlargement and deformities of the legs and genitals is far more sensitive than the currently used test, according to results of a field study in Liberia, in West Africa, where the infection is endemic.
The new test found evidence of the infection – lymphatic filariasis – in many more people that the standard test had missed.
The study, the first to independently evaluate the new test, was led by researchers at Washington University School of Medicine in St. Louis and funded by the Bill & Melinda Gates Foundation.
The infection affects 120 million people living in 73 countries, leaving some 40 million profoundly disfigured and incapacitated. Both tests detect the presence of worms that cause lymphatic filariasis, a devastating mosquito-borne illness also known as elephantiasis.
But the new test has significant advantages over the test that has been used for more than a decade not only to diagnose the disease, but to map, monitor and evaluate the success of a massive global public health program aimed at completely eliminating the disease by 2020.
‘The older test has had a major impact, but the new one is even better,’ says lead author Gary J. Weil, MD, an infectious diseases specialist at Washington University School of Medine. ‘Annually, medication to treat and prevent the infection is distributed to more than 500 million people worldwide. The improved sensitivity of the new test will help determine whether the mass treatment program has been effective and also identify regions that need additional attention.’
An accompanying editorial by Maria Rebollo, MD, and Moses Bockarie, PhD, at the Centre for Neglected Tropical Diseases in the United Kingdom says the new diagnostic test ‘represents a major breakthrough for rapid diagnosis of lymphatic filariasis in the blood.’
The new test also has a longer shelf life, estimated at two years without refrigeration, compared with three months for the older version, and is expected to cost less.
Weil’s research team worked with colleagues at the Liberian Institute for Medical Research to conduct a side-by-side comparison of the new test strip and the currently used test. They evaluated the tests in 503 people ranging in age from 6 to 89.
Both versions of the test are manufactured by Alere Scarborough Inc. of Maine and detect the presence in the blood of a protein produced by the worm parasite Wuchereria bancrofti that causes lymphatic filariasis. The new test is performed by pricking the finger and placing a person’s blood onto the test strip, which looks similar to an over-the-counter pregnancy test. Like many pregnancy tests, the lymphatic filariasis test is positive if two lines appear in the test window and negative if only one line shows.
The study’s results show that the new test is highly sensitive, detecting nearly 26 percent more infections of lymphatic filariasis than the standard test (124/503 infections vs. 98/503 infections). The new test also was easier to perform and results were easier to read.
‘This gives us some indication of the numbers of infections we were missing with the older test,’ Weil says. ‘On a global scale, it’s a huge number of cases. We need to have an accurate test to be sure we are reaching all the people who have the disease or are at risk of developing it.’
Worldwide, some 1.4 billion people are at risk of lymphatic filariasis, which is endemic in many countries in Africa, Southeast Asia and other tropical regions. Worm larvae deposited by the bite of an infected mosquito enter the body and migrate to the lymphatic system, where they mature into adult worms.
The thread-like parasitic worms can live and reproduce in the body for years. Ultimately, this damages the lymphatic vessels that drain fluid from the tissues and causes the enormous swelling and disabling deformity of the legs and in males, the scrotum.
Weil has been active for years in efforts to eliminate lymphatic filariasis via mass drug administration, an approach that involves giving antifilarial drugs to everyone in areas with high infection rates. Organizers of the Global Programme to Eliminate Lymphatic Filariasis, launched in 2000, co-ordinate periodic, repeated mass drug administration of antifilarial medications to more than 500 million people annually, making it the world’s largest public health intervention program based on mass drug administration.
Washington University School of Medicine
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The World Health Organisation (WHO) has urged countries with possible cases of novel coronavirus to share information. The move comes after Saudi Arabia said the development of diagnostic tests had been delayed by patent rights on the NCoV virus by commercial laboratories.
Twenty-two deaths and 44 cases have been reported worldwide since 2012, the WHO says. NCoV is from the same family of viruses as the one that caused Severe Acute Respiratory Syndrome (Sars). An outbreak of Sars in 2003 killed about 770 people. However, NCoV and Sars are distinct from each other, the WHO says.
The virus first emerged in Saudi Arabia, which is where most cases have since arisen. Saudi Deputy Health Minister Ziad Memish raised his concerns at the World Health Assembly in Geneva.
‘We are still struggling with diagnostics and the reason is that the virus was patented by scientists and is not allowed to be used for investigations by other scientists,’ he said. ‘I think strongly that the delay in the development of … diagnostic procedures is related to the patenting of the virus.’
WHO chief Margaret Chan expressed dismay at the information.
‘Why would your scientists send specimens out to other laboratories on [sic] a bilateral manner and allow other people to take intellectual property rights on a new disease?’ she asked.
‘Any new disease is full of uncertainty.’
She is urging the WHO’s 194 member states to only share ‘viruses and specimens with WHO collaborating centres… not in a bilateral manner.’
She added: ‘I will follow it up. I will look at the legal implications together with the Kingdom of Saudi Arabia. No IP (intellectual property) should stand in the way of you, the countries of the world, to protect your people.’
BBC
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Johns Hopkins researchers say they have discovered specific chemical alterations in two genes that, when present during pregnancy, reliably predict whether a woman will develop postpartum depression.
The epigenetic modifications, which alter the way genes function without changing the underlying DNA sequence, can apparently be detected in the blood of pregnant women during any trimester, potentially providing a simple way to foretell depression in the weeks after giving birth, and an opportunity to intervene before symptoms become debilitating.
The findings are of the small study involving 52 pregnant women.
‘Postpartum depression can be harmful to both mother and child,’ says study leader Zachary Kaminsky, Ph.D., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. ‘But we don’t have a reliable way to screen for the condition before it causes harm, and a test like this could be that way.’
It is not clear what causes postpartum depression, a condition marked by persistent feelings of sadness, hopelessness, exhaustion and anxiety that begins within four weeks of childbirth and can last weeks, several months or up to a year. An estimated 10 to 18 percent of all new mothers develop the condition, and the rate rises to 30 to 35 percent among women with previously diagnosed mood disorders. Scientists long believed the symptoms were related to the large drop-off in the mother’s oestrogen levels following childbirth, but studies have shown that both depressed and non-depressed women have similar oestrogen levels.
By studying mice, the Johns Hopkins researchers suspected that oestrogen induced epigenetic changes in cells in the hippocampus, a part of the brain that governs mood. Kaminsky and his team then created a complicated statistical model to find the candidate genes most likely undergoing those epigenetic changes, which could be potential predictors for postpartum depression. That process resulted in the identification of two genes, known as TTC9B and HP1BP3, about which little is known save for their involvement in hippocampal activity.
Kaminsky says the genes in question may have something to do with the creation of new cells in the hippocampus and the ability of the brain to reorganise and adapt in the face of new environments — two elements important in mood. In some ways, he says, oestrogen can behave like an antidepressant, so that when inhibited, it adversely affects mood.
The researchers later confirmed their findings in humans by looking for epigenetic changes to thousands of genes in blood samples from 52 pregnant women with mood disorders. Jennifer L. Payne, M.D., director of the Johns Hopkins Women’s Mood Disorders Center, collected the blood samples. The women were followed both during and after pregnancy to see who developed postpartum depression.
The researchers noticed that women who developed postpartum depression exhibited stronger epigenetic changes in those genes that are most responsive to oestrogen, suggesting that these women are more sensitive to the hormone’s effects. Specifically, two genes were most highly correlated with the development of postpartum depression. TTC9B and HP1BP3 predicted with 85 percent certainty which women became ill.
John Hopkins Medicine
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Using a novel method of analysing genetic variations in families, researchers at Johns Hopkins have found that individually harmless genetic variations affecting related biochemical processes may team up to increase the risk of schizophrenia. They say their findings bring some clarity to the murky relationship between genetics and schizophrenia, and may lead to a genetic test that can predict which medications will be effective for individual patients.
‘It’s long been clear that schizophrenia runs in families, but schizophrenia as a simple inherited disease didn’t make sense from an evolutionary point of view because people with the disease tend to have fewer children and the disease-causing genetic variants shouldn’t survive,’ says Dimitri Avramopoulos, M.D., Ph.D., an associate professor of psychiatry in the McKusick-Nathans Institute of Genetic Medicine. Moreover, he says, studies searching for schizophrenia-linked gene variants have found only weak connections to a few genes — nothing that would explain the persistent prevalence of the disease, which affects about 1 percent of the population.
Most geneticists believe that the culprit in so-called complex genetic diseases such as schizophrenia is not just one genetic variant, but more than one acting in concert. It’s also likely that individual cases of the disease are caused by different combinations of variants, Avramopoulos says. He and fellow researchers took this hypothesis a step further, theorising that while our bodies can usually compensate for one faulty gene that affects a particular system, more than one hit to the same system is likely to tip people toward disease.
The research team devised a technique for analysing gene-sequencing data that explores whether variants cluster in a subset of cases in a non-random way. After finding support for their hypothesis in previously obtained data on 123 families with at least two schizophrenia-affected members, they decided to sequence genes connected through a biochemical chain reaction that has been linked to the disease in 48 inpatients. Known as the neuregulin signalling pathway, that chain reaction relays signals within the nervous system.
As they had predicted, the researchers found that some of the families had multiple neuregulin signalling-related variants while others had none, a distribution that was highly unlikely to result from chance. Moreover, the schizophrenia patients with neuregulin signalling variants experienced more hallucinations but less impairment than the other schizophrenia patients in the study.
‘These results support the idea that there’s no single genetic recipe for schizophrenia, but that a build-up of mutations in a pathway related to the disease — like neuregulin signalling — can be the culprit,’ Avramopoulos says. ‘The results are also evidence for the current theory that schizophrenia isn’t a single disease at all, but a suite of related disorders.’ Those patients in the study who did not have neuregulin signalling-related variants likely carried variants in a different pathway instead, he notes.
While the results of the study were surprisingly clear-cut given the small number of families in the study, Avramopoulos cautions that larger studies are needed to confirm the results before drawing any firm conclusions. He also plans to study the exact roles of the schizophrenia-linked variants the team identified. Finally, the encouraging results mean it would be worthwhile to apply the new analytic method to other common diseases, such as diabetes and heart disease, which also appear to have complex genetic roots.
John Hopkins University School of Medicine
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Our ability to analyse the genetic make-up of the human body has rapidly improved over the last few decades. The genetic basis of different diseases is gradually being deciphered through scientific research and more and more people are having genetic tests to diagnose or predict illness within the health care system.
Genetic tests developed over the past thirty years have focussed on identifying the cause for a range of different conditions. Targeted genetic testing looking at particular genes within the genetic code has thus been widely used. Techniques have now moved on so much, that it is often easier and cheaper to examine the entire genetic code, rather than home in on particular genes suggested by symptoms or a family history.
Genetic tests to date have therefore largely been done to answer particular questions; ‘Have I got a high chance of breast cancer?’ or ‘Have I inherited the condition in my family?’ Modern day genetic testing can also answer questions we haven’t posed, and which might reveal entirely unexpected risk of disease.
But what do our genes really say about us? And what if a genetic test showed something that wasn’t expected that could affect you in later life? And what is the effect on the individual’s family?
The University of Southampton is currently conducting a study, funded by Cancer Research UK and National Institute for Health Research, which is exploring the ethical issues in discovering unexpected genetic test results otherwise known as incidental findings (IFs). Through interviews with patients and health professionals the study is outlining how future clinical practice may have to change to incorporate the possibility discovering such incidental findings.
Professor Anneke Lucassen, a clinical geneticist at the University of Southampton and consultant in clinical genetics at Southampton General Hospital, comments: ‘Moving from targeted to broad genetic testing is resulting in a growing ethical and moral debate about how such tests should be used. There are questions we need to be thinking about as new technologies enter mainstream use.
‘Unlike an X-ray where you might unexpectedly find a tumour that needs management now, with genetic testing you might predict something that could happen in 10 or 20 years’ time. If you predict a genetic disease with any certainty, you are also potentially predicting something about their relatives who have not asked for the test. Should their relatives be told that they might also be at risk?
‘Medical technology is advancing at a rapid rate and could help a lot of people and their families, but the clinical guidelines and the advice for health professionals about communication and decision making needs to catch up.’
Anyone wanting to take part in the study should email cels@soton.ac.uk
University of Southampton
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Identification of gene associated with adolescent idiopathic scoliosis
, /in E-News /by 3wmediaResearchers from the RIKEN Center for Integrative Medical Sciences in Japan have identified the first gene to be associated with adolescent idiopathic scoliosis (also called AIS) across Asian and Caucasian populations. The gene is involved in the growth and development of the spine during childhood.
AIS is the most common pediatric skeletal disease, affecting approximately 2% of school-age children. The causes of scoliosis remain largely unknown and brace treatment and surgery are the only treatment options. However, many clinical and genetic studies suggest a contribution of genetic factors.
To understand the causes and development of scoliosis, Dr Ikuyo Kou, Dr Shiro Ikegawa and their team have tried to identify genes that are associated with a susceptibility to develop the condition.
By studying the genome of 1,819 Japanese individuals suffering from scoliosis and comparing it to 25,939 Japanese individuals, the team identified a gene associated with a susceptibility to develop scoliosis on chromosome 6. The association was replicated in Han Chinese and Caucasian populations.
The researchers show that the susceptibility gene, GPR126, is highly expressed in cartilage and that suppression of this gene leads to delayed growth and bone tissue formation in the developing spine. GPR126 is also known to play a role in human height and trunk length.
‘Our finding suggest the interesting possibility that GPR126 may affect both AIS susceptibility and height through abnormal spinal development and growth,’ explain the authors.
‘Further functional studies are necessary to elucidate how alterations in GPR126 increase the risk of AIS in humans,’ they conclude. Medical News Today
Researchers develop model for better testing, targeting of MPNST
, /in E-News /by 3wmediaResearchers from the Masonic Cancer Center, University of Minnesota, and the University’s Brain Tumor Program, have developed a new mouse model of malignant peripheral nerve sheath tumours (MPNST) that allow them to discover new genes and gene pathways driving this type of cancer.
Utilising the Sleeping Beauty transposon method, researchers in the lab of David Largaespada, Ph.D., professor in the Medical School and College of Biological Sciences, were able to use an unbiased approach to generate mouse models of MPNST development that lead to the identification of genes related to this tumour’s development.
MPNST is a genetically diverse, aggressive form of sarcoma impacting connective tissue surrounding nerves that occurs sporadically or in association with Neurofibromatosis Type 1 (NF1) syndrome. The exact cause of MPNST is not known, but symptoms include swelling in the arms and legs, soreness and stiffness at the site of the tumour. MPNSTs are the most common malignancy in adults with NF1 syndrome and leading cause of NF1-related mortality.
Due to the invasive nature and high incidence of metastasis of MPNSTs, surgical resection, radiotherapy and chemotherapeutic treatments have proven to be ineffective for long-term treatment, resulting in 5-year survival rates of less than 25 percent with metastatic disease.
One of the most surprising findings in this research showed the gene FOXR2 is intrinsically linked to the growth of MPNSTs. This gene has not been heavily studied as researchers had not identified a clear function of this gene.
‘By using an unbiased approach, it helped us identify FOXR2 as an important gene in MPNST development and develop experiments to pinpoint the role FOXR2 plays in maintaining the aggressive nature of these tumours,’ said Eric Rahrmann, Ph.D., the paper’s lead author and a postdoctoral fellow in the Largaespada lab. ‘When we turn off FOXR2, the growth ability of these MPNSTs drastically decreases.’
Other findings showed interesting evidence of pathways that could be viable targets for therapeutics. The activation of the Wnt signalling pathway was shown to drive MPNSTs. This pathway has been highly implicated in colon cancer but not previously linked to MPNSTs.
Researchers also found many of the MPNSTs have dual loss of the genes called NF1 and PTEN. This pairing of lost genes causes MPNST formation. Both of these genes have previously been shown as pathways related to MPNSTs but it wasn’t clear the extent to which they work together.
Now, researchers are applying these findings to the testing of therapeutics currently on the market for other drugs. This research is continuing both in the mouse model and within primary tumour settings of human cell lines.
‘We want to know if these drugs, which are not currently directed at MPNSTs, could be repurposed to provide alternate therapies for patients,’ said Largaespada.
Researchers are also looking into more direct ways to target tumours through the Wnt pathway and paired NF1 and PTEN pathways, utilising mouse models and human cell lines in the lab setting. University of Minnesota
New gene identified for Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraparesis
, /in E-News /by 3wmediaResearchers at the UCL Institute of Neurology together with international collaborators have identified a new gene, BICD2, which causes both dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraparesis. The team was led by Professor Mary Reilly.
Dominant Congenital Spinal Muscular Atrophy is a disorder of developing anterior horn cells and is characterised by lower limb predominance whereas Hereditary Spastic Paraparesis develops in childhood or adult life and is also a lower limb predominant disorder but of the corticospinal motor neurons.
The importance of this gene for motor nerves is underlined by the simultaneous publication of the same gene causing dominant Congenital Spinal Muscular Atrophy by two other groups.
The identification of the gene by exome sequencing and the subsequent functional work to study the pathogenesis of the disorder formed a major part of the PhD of Dr. Alex Rossor, a PhD student in the MRC Centre for Neuromuscular Diseases in the Institute of Neurology. UCL Institute of Neurology
Biomarkers discovered for inflammatory bowel disease
, /in E-News /by 3wmediaUsing the Department of Defense Serum Repository (DoDSR), University of Cincinnati researchers have identified a number of biomarkers for inflammatory bowel disease (IBD), which could help with earlier diagnosis and intervention in those who have not yet shown symptoms.
The DoDSR is a biological repository operated by the U.S. Department of Defense and contains over 50 million human serum specimens, collected primarily from applicants to and members of the U.S. uniformed services.
‘With collaborators from Walter Reed, we were able to identify all of the active duty service men and women who developed IBD and then used the repository to go back and look at various biomarkers to see what each person had in common,’ says Yacyshyn, a professor of medicine at the UC College of Medicine and UC Health gastroenterologist.
IBD is a group of inflammatory conditions of the colon and small intestine. The main types of IBD are Crohn’s disease and ulcerative colitis; inflammatory bowel diseases are considered autoimmune diseases in which the body’s own immune system attacks elements of the digestive system.
In this study, researchers used the repository to identify 50 cases of Crohn’s disease and 50 cases of ulcerative colitis. They analysed proteins from three samples per case—two taken before and one after diagnosis—using a statistical analysis format.
Certain proteins were found in elevated levels in samples from patients who developed IBD.
‘The selection of proteins we chose to analyse was based on a prior study conducted at UC,’ Yacyshyn says. ‘Although the presence of proteins in those who develop Crohn’s disease varies from those present in ulcerative colitis patients, we were able to show that there were elevated levels of certain proteins in patients who developed IBD.’
‘Future large validation studies are needed to confirm the presence of biomarkers to guide in diagnosis, prevention and management of these patients,’ he adds. UC Academic Health News
Team finds mechanism linking key inflammatory marker to cancer
, /in E-News /by 3wmediaIn a new study, researchers reveal how a key player in cell growth, immunity and the inflammatory response can be transformed into a primary contributor to tumour growth.
Scientists call this Jekyll-and-Hyde molecule NF-kappa B. In healthy cells, it is a powerful ‘first responder,’ a vital part of the body’s immune and inflammatory responses. It spends most of its life in the cell’s cytoplasm, quietly awaiting orders. But when extracellular signals – of a viral or bacterial invasion, for example – set off chemical alarms, the cell unchains this warhorse, allowing it to go into the nucleus where it spurs a flurry of defensive activity, including the transcription of genes that trigger inflammation, promote cell proliferation and undermine cell death.
Researchers have known for years that a hyperactive form of NF-kappa B that gets into the nucleus and stays there is associated with various cancers. But they didn’t know what was keeping it active in the nucleus.
‘Normally in the cell NF-kappa B is in the cytosol, it’s not in the nucleus, and it’s not activated,’ said University of Illinois medical biochemistry professor Lin-Feng Chen, who led the new study. ‘You have to stimulate normal cells to see NF-kappa B in the nucleus. But in cancer cells without any stimulation you can see this nuclear form of NF-kappa B. The cell just won’t die because of this. That is why NF-kappa B is so important in cancer.’
In the new study, Chen’s group found that another molecule known to help regulate gene expression, called BRD4, recognises a specific amino acid on a subunit of the NF-kappa B protein complex after the amino acid has been marked with a specific tag, called an acetyl group. This ‘acetylation’ allows the BRD4 to bind to NF-kappa B, activating it and preventing its degradation in cancer cells.
Previous studies had shown that BRD4’s recognition of the acetylated subunit increased NF-kappa B activation, but this recognition had not been linked to cancer.
BRD4 belongs to a class of molecules that can recognise chemical markers on other proteins and interact with them to spur the marked proteins to perform new tasks. Chemical ‘readers’ such as BRD4 are important players in the field of epigenetics, which focuses on how specific genes are regulated.
‘In epigenetics, there are writers, there are readers and there are erasers,’ Chen said. The writers make modifications to proteins after they are formed, without changing the underlying sequence of the gene that codes for them. These modifications (such as acetylation) signal other molecules (the readers) to engage with the marked proteins in various ways, allowing the proteins to fulfill new roles in the life of the cell. Epigenetic erasers remove the marks when they are no longer of use.
Such protein modifications ‘have been shown to be critically involved in transcription regulation and cancer development,’ the researchers report.
To test whether BRD4 was contributing to the sustained presence of NF-kappa B in the nucleus of cancer cells, Chen and his colleagues exposed lung cancer cells in cell culture and in immune-deficient mice to JQ1, a drug that interferes with BRD4 activity. Exposure to JQ1 blocked the interaction of BRD4 and NF-kappa B, blocked the expression of genes regulated by NF-kappa B, reduced proliferation of lung cancer cells and suppressed the ability of lung cancer cells to induce tumors in immune-deficient mice, the researchers found.
The researchers also discovered that depletion of BRD4 or the treatment of cells with JQ1 induced the degradation of the NF-kappa B subunit recognized by BRD4.
Chen said that BRD4 likely prevents other molecules from recognising the hyperactive NF-kappa B in the nucleus and marking it for degradation.
‘This is an example of how epigenetic regulators and NF-kappa B may one day be targeted for the treatment of cancer,’ he said. University of Illinois at Urbana Champaign
New test better detects elephantiasis worm infection
, /in E-News /by 3wmediaA new diagnostic test for a worm infection that can lead to severe enlargement and deformities of the legs and genitals is far more sensitive than the currently used test, according to results of a field study in Liberia, in West Africa, where the infection is endemic.
The new test found evidence of the infection – lymphatic filariasis – in many more people that the standard test had missed.
The study, the first to independently evaluate the new test, was led by researchers at Washington University School of Medicine in St. Louis and funded by the Bill & Melinda Gates Foundation.
The infection affects 120 million people living in 73 countries, leaving some 40 million profoundly disfigured and incapacitated. Both tests detect the presence of worms that cause lymphatic filariasis, a devastating mosquito-borne illness also known as elephantiasis.
But the new test has significant advantages over the test that has been used for more than a decade not only to diagnose the disease, but to map, monitor and evaluate the success of a massive global public health program aimed at completely eliminating the disease by 2020.
‘The older test has had a major impact, but the new one is even better,’ says lead author Gary J. Weil, MD, an infectious diseases specialist at Washington University School of Medine. ‘Annually, medication to treat and prevent the infection is distributed to more than 500 million people worldwide. The improved sensitivity of the new test will help determine whether the mass treatment program has been effective and also identify regions that need additional attention.’
An accompanying editorial by Maria Rebollo, MD, and Moses Bockarie, PhD, at the Centre for Neglected Tropical Diseases in the United Kingdom says the new diagnostic test ‘represents a major breakthrough for rapid diagnosis of lymphatic filariasis in the blood.’
The new test also has a longer shelf life, estimated at two years without refrigeration, compared with three months for the older version, and is expected to cost less.
Weil’s research team worked with colleagues at the Liberian Institute for Medical Research to conduct a side-by-side comparison of the new test strip and the currently used test. They evaluated the tests in 503 people ranging in age from 6 to 89.
Both versions of the test are manufactured by Alere Scarborough Inc. of Maine and detect the presence in the blood of a protein produced by the worm parasite Wuchereria bancrofti that causes lymphatic filariasis. The new test is performed by pricking the finger and placing a person’s blood onto the test strip, which looks similar to an over-the-counter pregnancy test. Like many pregnancy tests, the lymphatic filariasis test is positive if two lines appear in the test window and negative if only one line shows.
The study’s results show that the new test is highly sensitive, detecting nearly 26 percent more infections of lymphatic filariasis than the standard test (124/503 infections vs. 98/503 infections). The new test also was easier to perform and results were easier to read.
‘This gives us some indication of the numbers of infections we were missing with the older test,’ Weil says. ‘On a global scale, it’s a huge number of cases. We need to have an accurate test to be sure we are reaching all the people who have the disease or are at risk of developing it.’
Worldwide, some 1.4 billion people are at risk of lymphatic filariasis, which is endemic in many countries in Africa, Southeast Asia and other tropical regions. Worm larvae deposited by the bite of an infected mosquito enter the body and migrate to the lymphatic system, where they mature into adult worms.
The thread-like parasitic worms can live and reproduce in the body for years. Ultimately, this damages the lymphatic vessels that drain fluid from the tissues and causes the enormous swelling and disabling deformity of the legs and in males, the scrotum.
Weil has been active for years in efforts to eliminate lymphatic filariasis via mass drug administration, an approach that involves giving antifilarial drugs to everyone in areas with high infection rates. Organizers of the Global Programme to Eliminate Lymphatic Filariasis, launched in 2000, co-ordinate periodic, repeated mass drug administration of antifilarial medications to more than 500 million people annually, making it the world’s largest public health intervention program based on mass drug administration. Washington University School of Medicine
WHO urges information sharing over novel coronavirus
, /in E-News /by 3wmediaThe World Health Organisation (WHO) has urged countries with possible cases of novel coronavirus to share information. The move comes after Saudi Arabia said the development of diagnostic tests had been delayed by patent rights on the NCoV virus by commercial laboratories.
Twenty-two deaths and 44 cases have been reported worldwide since 2012, the WHO says. NCoV is from the same family of viruses as the one that caused Severe Acute Respiratory Syndrome (Sars). An outbreak of Sars in 2003 killed about 770 people. However, NCoV and Sars are distinct from each other, the WHO says.
The virus first emerged in Saudi Arabia, which is where most cases have since arisen. Saudi Deputy Health Minister Ziad Memish raised his concerns at the World Health Assembly in Geneva.
‘We are still struggling with diagnostics and the reason is that the virus was patented by scientists and is not allowed to be used for investigations by other scientists,’ he said. ‘I think strongly that the delay in the development of … diagnostic procedures is related to the patenting of the virus.’
WHO chief Margaret Chan expressed dismay at the information.
‘Why would your scientists send specimens out to other laboratories on [sic] a bilateral manner and allow other people to take intellectual property rights on a new disease?’ she asked.
‘Any new disease is full of uncertainty.’
She is urging the WHO’s 194 member states to only share ‘viruses and specimens with WHO collaborating centres… not in a bilateral manner.’
She added: ‘I will follow it up. I will look at the legal implications together with the Kingdom of Saudi Arabia. No IP (intellectual property) should stand in the way of you, the countries of the world, to protect your people.’ BBC
Genetic predictors of postpartum depression
, /in E-News /by 3wmediaJohns Hopkins researchers say they have discovered specific chemical alterations in two genes that, when present during pregnancy, reliably predict whether a woman will develop postpartum depression.
The epigenetic modifications, which alter the way genes function without changing the underlying DNA sequence, can apparently be detected in the blood of pregnant women during any trimester, potentially providing a simple way to foretell depression in the weeks after giving birth, and an opportunity to intervene before symptoms become debilitating.
The findings are of the small study involving 52 pregnant women.
‘Postpartum depression can be harmful to both mother and child,’ says study leader Zachary Kaminsky, Ph.D., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. ‘But we don’t have a reliable way to screen for the condition before it causes harm, and a test like this could be that way.’
It is not clear what causes postpartum depression, a condition marked by persistent feelings of sadness, hopelessness, exhaustion and anxiety that begins within four weeks of childbirth and can last weeks, several months or up to a year. An estimated 10 to 18 percent of all new mothers develop the condition, and the rate rises to 30 to 35 percent among women with previously diagnosed mood disorders. Scientists long believed the symptoms were related to the large drop-off in the mother’s oestrogen levels following childbirth, but studies have shown that both depressed and non-depressed women have similar oestrogen levels.
By studying mice, the Johns Hopkins researchers suspected that oestrogen induced epigenetic changes in cells in the hippocampus, a part of the brain that governs mood. Kaminsky and his team then created a complicated statistical model to find the candidate genes most likely undergoing those epigenetic changes, which could be potential predictors for postpartum depression. That process resulted in the identification of two genes, known as TTC9B and HP1BP3, about which little is known save for their involvement in hippocampal activity.
Kaminsky says the genes in question may have something to do with the creation of new cells in the hippocampus and the ability of the brain to reorganise and adapt in the face of new environments — two elements important in mood. In some ways, he says, oestrogen can behave like an antidepressant, so that when inhibited, it adversely affects mood.
The researchers later confirmed their findings in humans by looking for epigenetic changes to thousands of genes in blood samples from 52 pregnant women with mood disorders. Jennifer L. Payne, M.D., director of the Johns Hopkins Women’s Mood Disorders Center, collected the blood samples. The women were followed both during and after pregnancy to see who developed postpartum depression.
The researchers noticed that women who developed postpartum depression exhibited stronger epigenetic changes in those genes that are most responsive to oestrogen, suggesting that these women are more sensitive to the hormone’s effects. Specifically, two genes were most highly correlated with the development of postpartum depression. TTC9B and HP1BP3 predicted with 85 percent certainty which women became ill. John Hopkins Medicine
Family studies suggest rare genetic mutations team up to cause schizophrenia
, /in E-News /by 3wmediaUsing a novel method of analysing genetic variations in families, researchers at Johns Hopkins have found that individually harmless genetic variations affecting related biochemical processes may team up to increase the risk of schizophrenia. They say their findings bring some clarity to the murky relationship between genetics and schizophrenia, and may lead to a genetic test that can predict which medications will be effective for individual patients.
‘It’s long been clear that schizophrenia runs in families, but schizophrenia as a simple inherited disease didn’t make sense from an evolutionary point of view because people with the disease tend to have fewer children and the disease-causing genetic variants shouldn’t survive,’ says Dimitri Avramopoulos, M.D., Ph.D., an associate professor of psychiatry in the McKusick-Nathans Institute of Genetic Medicine. Moreover, he says, studies searching for schizophrenia-linked gene variants have found only weak connections to a few genes — nothing that would explain the persistent prevalence of the disease, which affects about 1 percent of the population.
Most geneticists believe that the culprit in so-called complex genetic diseases such as schizophrenia is not just one genetic variant, but more than one acting in concert. It’s also likely that individual cases of the disease are caused by different combinations of variants, Avramopoulos says. He and fellow researchers took this hypothesis a step further, theorising that while our bodies can usually compensate for one faulty gene that affects a particular system, more than one hit to the same system is likely to tip people toward disease.
The research team devised a technique for analysing gene-sequencing data that explores whether variants cluster in a subset of cases in a non-random way. After finding support for their hypothesis in previously obtained data on 123 families with at least two schizophrenia-affected members, they decided to sequence genes connected through a biochemical chain reaction that has been linked to the disease in 48 inpatients. Known as the neuregulin signalling pathway, that chain reaction relays signals within the nervous system.
As they had predicted, the researchers found that some of the families had multiple neuregulin signalling-related variants while others had none, a distribution that was highly unlikely to result from chance. Moreover, the schizophrenia patients with neuregulin signalling variants experienced more hallucinations but less impairment than the other schizophrenia patients in the study.
‘These results support the idea that there’s no single genetic recipe for schizophrenia, but that a build-up of mutations in a pathway related to the disease — like neuregulin signalling — can be the culprit,’ Avramopoulos says. ‘The results are also evidence for the current theory that schizophrenia isn’t a single disease at all, but a suite of related disorders.’ Those patients in the study who did not have neuregulin signalling-related variants likely carried variants in a different pathway instead, he notes.
While the results of the study were surprisingly clear-cut given the small number of families in the study, Avramopoulos cautions that larger studies are needed to confirm the results before drawing any firm conclusions. He also plans to study the exact roles of the schizophrenia-linked variants the team identified. Finally, the encouraging results mean it would be worthwhile to apply the new analytic method to other common diseases, such as diabetes and heart disease, which also appear to have complex genetic roots. John Hopkins University School of Medicine
New genetic tests, more information
, /in E-News /by 3wmediaOur ability to analyse the genetic make-up of the human body has rapidly improved over the last few decades. The genetic basis of different diseases is gradually being deciphered through scientific research and more and more people are having genetic tests to diagnose or predict illness within the health care system.
Genetic tests developed over the past thirty years have focussed on identifying the cause for a range of different conditions. Targeted genetic testing looking at particular genes within the genetic code has thus been widely used. Techniques have now moved on so much, that it is often easier and cheaper to examine the entire genetic code, rather than home in on particular genes suggested by symptoms or a family history.
Genetic tests to date have therefore largely been done to answer particular questions; ‘Have I got a high chance of breast cancer?’ or ‘Have I inherited the condition in my family?’ Modern day genetic testing can also answer questions we haven’t posed, and which might reveal entirely unexpected risk of disease.
But what do our genes really say about us? And what if a genetic test showed something that wasn’t expected that could affect you in later life? And what is the effect on the individual’s family?
The University of Southampton is currently conducting a study, funded by Cancer Research UK and National Institute for Health Research, which is exploring the ethical issues in discovering unexpected genetic test results otherwise known as incidental findings (IFs). Through interviews with patients and health professionals the study is outlining how future clinical practice may have to change to incorporate the possibility discovering such incidental findings.
Professor Anneke Lucassen, a clinical geneticist at the University of Southampton and consultant in clinical genetics at Southampton General Hospital, comments: ‘Moving from targeted to broad genetic testing is resulting in a growing ethical and moral debate about how such tests should be used. There are questions we need to be thinking about as new technologies enter mainstream use.
‘Unlike an X-ray where you might unexpectedly find a tumour that needs management now, with genetic testing you might predict something that could happen in 10 or 20 years’ time. If you predict a genetic disease with any certainty, you are also potentially predicting something about their relatives who have not asked for the test. Should their relatives be told that they might also be at risk?
‘Medical technology is advancing at a rapid rate and could help a lot of people and their families, but the clinical guidelines and the advice for health professionals about communication and decision making needs to catch up.’
Anyone wanting to take part in the study should email cels@soton.ac.uk University of Southampton