An international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH) has identified mutations in a gene that can reduce the risk of developing type 2 diabetes, even in people who have risk factors such as obesity and old age. The results focus the search for developing novel therapeutic strategies for type 2 diabetes; if a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease.
The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the new study, researchers describe the genetic analysis of 150,000 patients showing that rare mutations in a gene called SLC30A8 reduce risk of type 2 diabetes by 65 percent. The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility around the globe. The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes. However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk — and how large an effect could be expected.
‘This work underscores that human genetics is not just a tool for understanding biology: it can also powerfully inform drug discovery by addressing one of the most challenging and important questions — knowing which targets to go after,’ said co-senior author David Altshuler, deputy director and chief academic officer at the Broad Institute and a Harvard Medical School professor at Massachusetts General Hospital.
The use of human genetics to identify protective mutations holds great potential. Mutations in a gene called CCR5 were found to protect against infection with HIV, the virus that causes AIDS; drugs have been developed that block the CCR5 protein. A similar protective association for heart disease set off a race to discover new cholesterol-lowering drugs when mutations in the gene PCSK9 were found to lower cholesterol levels and heart disease risk. The new type 2 diabetes study suggests that CCR5 and PCSK9 are likely just the beginning but that it will take large numbers of samples and careful sleuthing to find additional genes with similar protective properties.
The study grew out of a research partnership that started in 2009 involving the Broad Institute, Massachusetts General Hospital, Pfizer Inc., and Lund University Diabetes Centre in Sweden, which set out to find mutations that reduce a person’s risk of type 2 diabetes. The research team selected people with severe risk factors for diabetes, such as advanced age and obesity, who never developed the disease and in fact had normal blood sugar levels. They focused on a set of genes previously identified as playing a role in type 2 diabetes and used next-generation sequencing to search for rare mutations.
The team identified a genetic mutation that appeared to abolish function of the SLC30A8 gene and that was enriched in non-diabetic individuals studied in Sweden and Finland. The protection was surprising, because studies in mice had suggested that mutations in SLC30A8 might have the opposite effect — increasing rather than decreasing risk of type 2 diabetes. However, because this particular genetic variation was exceedingly rare outside of Finland, it proved difficult to obtain additional evidence to corroborate the initial discovery by the Broad/MGH/Pfizer Inc./Lund team.
Then, in 2012, these unpublished results were shared with deCODE genetics, who uncovered a second mutation in an Icelandic population that also appeared to abolish function of the gene SLC30A8. That mutation independently reduced risk for type 2 diabetes and also lowered blood sugar in non-diabetics without any evident negative consequences.
‘This discovery underscores what can be accomplished when human genetics experts on both sides of the Atlantic come together to apply their craft to founder populations, enabling us to find rare mutations with large effects on disease risk,’ said Kari Stefannson, CEO of deCODE genetics.
Finally, the team set out to ask if the effects of SLC30A8 protective mutations were limited to the two mutations found in populations in Finland and Iceland. As part of the NIH-funded T2D-GENES Project, chaired by Mike Boehnke at the University of Michigan, the Broad Institute had performed sequencing of 13,000 samples drawn from multiple ethnicities. The T2D-GENES Project joined the collaboration, found ten more mutations in the same gene, and again saw a protective effect. Combining all the results confirmed that inheriting one copy of a defective version of SLC30A8 led to a 65 percent reduction in risk of diabetes.
‘Through this partnership, we have been able to identify genetic mutations related to loss of gene function, which are protective against type 2 diabetes,’ said Tim Rolph, Vice President and Chief Scientific Officer of Cardiovascular, Metabolic & Endocrine Disease Research at Pfizer Inc. ‘Such genetic associations provide important new insights into the pathogenesis of diabetes, potentially leading to the discovery of drug targets, which may result in a novel medicine.’
Broad Institute
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:14Study pinpoints protective mutations for type 2 diabetes
In most cases of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, a toxin released by cells that normally nurture neurons in the brain and spinal cord can trigger loss of the nerve cells affected in the disease, Columbia researchers report.
The toxin is produced by star-shaped cells called astrocytes and kills nearby motor neurons. In ALS, the death of motor neurons causes a loss of control over muscles required for movement, breathing, and swallowing. Paralysis and death usually occur within 3 years of the appearance of first symptoms.
The report follows the researchers’ previous study, which found similar results in mice with a rare, genetic form of the disease, as well as in a separate study from another group that used astrocytes derived from patient neural progenitor cells. The current study shows that the toxins are also present in astrocytes taken directly from ALS patients.
‘I think this is probably the best evidence we can get that what we see in mouse models of the disease is also happening in human patients,’ said the study’s senior author, Serge Przedborski, MD, PhD, the Page and William Black Professor of Neurology (in Pathology and Cell Biology), Vice Chair for Research in the department of Neurology, and co-director of Columbia’s Motor Neuron Center.
The findings also are significant because they apply to the most common form of ALS, which affects about 90 percent of patients. Scientists do not know why ALS develops in these patients; the other 10 percent of patients carry one of 27 genes known to cause the disease.
‘Now that we know that the toxin is common to most patients, it gives us an impetus to track down this factor and learn how it kills the motor neurons,’ Dr. Przedborski said. ‘Its identification has the potential to reveal new ways to slow down or stop the destruction of the motor neurons.’
In the study, Dr. Przedborski and study co-authors Diane Re, PhD, and Virginia Le Verche, PhD, associate research scientists, removed astrocytes from the brain and spinal cords of six ALS patients shortly after death and placed the cells in petri dishes next to healthy motor neurons. Because motor neurons cannot be removed from human subjects, they had been generated from human embryonic stem cells in the Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, also at CUMC.
Within two weeks, many of the motor neurons had shrunk and their cell membranes had disintegrated; about half of the motor neurons in the dish had died. Astrocytes removed from people who died from causes other than ALS had no effect on the motor neurons. Nor did other types of cells taken from ALS patients.
The researchers confirmed that the cause of the motor neurons’ death was a toxin released into the environment by immersing healthy motor neurons in the astrocytes’ culture media. The presence of the media, even without astrocytes, killed the motor neurons.
The researchers have not yet identified the toxin released by the astrocytes. But they did discover the nature of the neuronal death process triggered by the toxin. The toxin triggers a biochemical cascade in the motor neurons that essentially causes them to undergo a controlled cellular explosion.
Drs. Przedborski, Re, and Le Verche found that they could prevent astrocyte-triggered motor neuron death by inhibiting one of the key components of this molecular cascade.
These findings may lead to a way to prevent motor neuron death in patients and potentially prolong life. But the therapeutic potential of such inhibition is far from clear. ‘For example, we don’t know if this would leave patients with living but dysfunctional neurons,’ Dr. Przedborski said. The researchers are now testing the idea of inhibition in animal models of ALS.
The development of new therapies for ALS has been disappointing, with more than 30 clinical trials ending with no new treatments since the 1995 FDA approval of riluzole.
The lack of progress may be partly because animal models used to study ALS do not completely recreate the human disease. The new all-human cell model of ALS created for the current study may improve scientists’ ability to identify useful drug targets, particularly for the most common form of the disease.
‘Although there are many neuro-degenerative disorders, only for a handful do we have access to a simplified model that is relevant to the disease and can therefore potentially be used for high-throughput drug screening. So this model is quite special,’ Dr. Przedborski said. ‘Here we have a spontaneous disease phenotype triggered by the relevant tissue that causes human illness. That’s one important thing. The other important thing is that this model is derived entirely from human elements. This is probably the closest, most natural model of human ALS that we can get in a dish.’
Columbia University Medical Center
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:14Toxin from brain cells triggers neuron loss in human ALS model
Neuroblastoma is one of the most common and lethal types of childhood cancers. A researcher at the University of Texas Health Science Center at San Antonio unveils the important role of microRNAs in regulating neuroblastoma development, pointing to new therapeutic possibilities.
Neuroblastomas, which account for 15 percent of childhood cancer deaths, happen when some cells do not differentiate and grow as they should. A promising type of therapy called differentiation therapy targets these malignant cells so that they can resume the process of differentiating into mature cells.
Unlike conventional chemotherapies, this new approach to cancer therapy has fewer toxic side effects, and gives hope for a cancer treatment that is gentler on young bodies. But so far only a few differentiation agents have been successfully used to treat neuroblastoma, and more than half of the young patients treated with such agents still see their cancer return.
To find new treatments, researchers needed improved laboratory screening techniques, and now one has been developed by Liqin Du, Ph.D., an assistant professor in the Department of Cellular and Structural Biology, and her team at the Greehey Children’s Cancer Research Institute at the UT Health Science Center.
MicroRNAs are small RNA molecules involved in gene expression, and play an important role in cell development. This screening approach revealed several microRNA molecules that induce the process of cell differentiation, and those are key to developing new drugs.
‘Development of new agents for treating neuroblastoma has been greatly hampered by the lack of efficient high-throughput screening approaches,’ Dr. Du said. ‘In our study, we applied a novel high-content screening approach that we recently developed to investigate the role of microRNAs in neuroblastoma differentiation.
‘We identified a set of novel microRNAs that are potent inducers of neuroblastoma cell differentiation and found that mimics (synthetic fragments of nucleic acid used to raise microRNA levels in cells) of some of the identified microRNAs are much more potent in inducing neuroblastoma cell differentiation than the current differentiation treatments.
‘These mimics are promising new drugs for neuroblastoma differentiation therapy,’ Dr. Du said. ‘We look forward to investigating this further in the future.’
UT Health Science Center San Antonio
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:14Improved lab screening technique opens door for new pediatric neuroblastoma therapies
Before doctors like Matthias Kretzler can begin using the results of molecular research to treat patients, they need science to find an effective way to match genes with the specific cells involved in disease. As Kretzler explains, finding that link would eventually let physicians create far more effective diagnostic tools and treatments.
‘Among many uses, it would allow us to develop cell-type targeted therapies,’ said Kretzler, a University of Michigan professor of internal medicine and computational medicine and bioinformatics. He recently collaborated with Princeton University professor Olga Troyanskaya on a way to match genes to cells. ‘If you identify a [disease] that is in the liver or in the kidney, you could target those areas and not affect other parts of the body,’ he said.
Although scientists have decoded the human genome — the list of all the genes in human cells — they still have great difficulty determining the specific genes that are activated to make a kidney cell as opposed to a liver or heart cell.
In theory, an easy way to link genes to cells would be to isolate a cell and test it. However, solid human tissue is so closely packed that even the finest surgical techniques cannot separate types of cells efficiently enough for analysis. A kidney biopsy, for example, produces a mix of several different types of cells that Kretzler dismisses as ‘kidney soup.’
Princeton University and University of Michigan researchers have developed a system that allows computers to ‘virtually dissect’ a kidney in a way that surgery cannot. The machine uses data from an array of gene-activity measurements in patients’ kidney biopsies to mathematically separate cells and identify genes that are turned on in a specific cell type. The researchers identified 136 genes involved in the creation of a critical kidney cell called a podocyte, tiny cells that serve as filters in the kidneys and are frequently involved in kidney disease.
‘We call it in-silico nano-dissection,’ said Troyanskaya, a professor of computer science and the Lewis-Sigler Institute for Integrative Genomics. Using a large database of such gene-activity measurements to track genetic lineage allows scientists to refine their analysis through thousands of measurements, something that would be impossible with individual cell cultures, she said.
The method has proven far faster and significantly more effective than current techniques. Researchers from Kretzler’s lab at Michigan and Troyanskaya’s at Princeton reported that they had identified 136 genes involved in the creation of a critical kidney cell called a podocyte. In decades of research, only 46 had been previously identified.
‘The potential for this is huge,’ said Behzad Najafian, a University of Washington assistant professor of pathology who specializes in renal pathology. ‘I believe this novel technique, which is a significant improvement in cell lineage-specific gene-expression analysis, will not only help us understand the pathophysiology of kidney diseases better through biopsy studies, but also provides a strong tool for discovery or validation of cell-specific urine or plasma biomarkers.’
Princeton University
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:13Tracking genes on the path to genetic treatment
A team of researchers from UCLA’s Henry Samueli School of Engineering and Applied Science has developed a Google Glass application and a server platform that allow users of the wearable, glasses-like computer to perform instant, wireless diagnostic testing for a variety of diseases and health conditions.
With the new UCLA technology, Google Glass wearers can use the device’s hands-free camera to capture pictures of rapid diagnostic tests (RTDs), small strips on which blood or fluid samples are placed and which change colour to indicate the presence of HIV, malaria, prostate cancer or other conditions. Without relying on any additional devices, users can upload these images to a UCLA-designed server platform and receive accurate analyses — far more detailed than with the human eye — in as little as eight seconds.
The new technology could enhance the tracking of dangerous diseases and improve public health monitoring and rapid responses in disaster-relief areas or quarantine zones where conventional medical tools are not available or feasible, the researchers said.
‘This breakthrough technology takes advantage of gains in both immunochromatographic rapid diagnostic tests and wearable computers,’ said principal investigator Aydogan Ozcan, the Chancellor’s Professor of Electrical Engineering and Bioengineering at UCLA and associate director of UCLA’s California NanoSystems Institute. ‘This smart app allows for real-time tracking of health conditions and could be quite valuable in epidemiology, mobile health and telemedicine.’
In addition to designing the custom RDT–reader app for Google Glass, Ozcan’s team implemented server processes for fast and high-throughput evaluation of test results coming from multiple devices simultaneously. Finally, the researchers developed a web portal where users can view test results, maps charting the geographical spread of various diseases and conditions, and the cumulative data from all the tests they have submitted over time.
To submit images for test results, Google Glass users only need to take photos of RTD strips or other commonly available in-home tests, then upload the images wirelessly through the device to the UCLA-designed web portal. The technology permits quantified reading of the results to a few-parts-per-billion level of sensitivity — far greater than that of the naked eye — thus eliminating the potential for human error in interpreting results, which is a particular concern if the user is a health care worker who routinely deals with many different types of tests.
To gauge the accuracy and efficiency of the technology, the UCLA team used an in-home HIV test designed by OraSure Technologies and a prostate-specific antigen test made by JAJ International. The researchers took images of tests under normal, indoor, fluorescent-lit room conditions. They submitted more than 400 images of the two tests, and the RDT reader and server platform were able to read the images 99.6 percent of the time. In every case in which the technology successfully read the images, it returned accurate and quantified test results, according to the team.
The researchers also tested more than 300 blurry images or images of the testing device taken under various natural-usage scenarios and achieved a read rate of 96.6 percent.
The UCLA Henry Samueli School of Engineering and Applied Science
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:13Google Glass app for instant medical diagnostic test results
Significance: Understanding more about how the different types of cells in breast tissue develop improves our knowledge of breast cancer. TAZ represents a potential new target for drug therapies to treat aggressive types of breast cancer.
Background: In cancer, normal cells can become unpredictable or aggressive and thus difficult to treat with anti-cancer drugs. This is especially true in breast cancer. By identifying the genes responsible for this change in cells from breast tissue, researchers hope to identify a way to stop or reverse it.
In breast tissue, there are two main types of cells: luminal cells and basal cells. Normally luminal cells are ‘programmed’ by a particular class of proteins (transcription factors), which prevent them from becoming basal cells, and vice-versa.
Previous work led by Charlotte Kuperwasser, principal investigator, determined that some common forms of breast cancer originate from luminal cells while some rarer forms of breast cancer originate from basal cells.
Findings: The research team identified a gene, TAZ, which controls whether breast cells behave more like basal cells or more like luminal cells, information that might be important in understanding and potentially treating certain difficult-to-treat forms of breast cancer. TAZ helps to regulate how different genes operate in different cell types.
How the Study Was Conducted: The research team identified TAZ by testing the function of more than 1,000 genes to determine which were involved in ‘reprogramming’ luminal and basal cells, therefore reversing lineage commitment.
To further identify the role of TAZ, the research team studied breast tissue at different stages of development using two groups of mice: a control group with the TAZ gene and an experimental group of knock-out mice with the TAZ gene deleted. (Cells in breast tissue are renewed/developed during puberty, pregnancy, and nursing.)
The team also looked at the levels of the TAZ gene in tumours from women with either luminal or basal tumours.
Results: The research team found that the experimental group had an imbalance of cell populations in breast tissue: too many luminal and too few basal. The control group had a normal ratio of luminal to basal cells. In breast tissue from women with cancer, they found high levels of TAZ in basal but not luminal tumours.
Discussion: First author Adam Skibinski, M.D./Ph.D. student at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University:
‘We’ve known for a long time that breast cells can lose their normal identity when they become cancerous, but we are now realising that normal cells can change their characteristics as well in response to transcription factors like TAZ. This might be a factor in the development of breast cancer.’
Tufts University
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:13Study identifies gene important to breast development and breast cancer
Biomarkers for bone formation and resorption predict outcomes for men with castration-resistant prostate cancer, a team of researchers from UC Davis and their collaborators have found. Their study also found that the markers identified a small group of patients who responded to the investigational drug atrasentan. The markers’ predictive ability could help clinicians match treatments with individual patients, track their effectiveness and affect clinical trial design.
Castration-resistant prostate cancer does not respond to hormone treatments and often metastasises to bone. This led researchers to wonder if increased bone turnover markers might predict the course of the disease.
‘We found that patients with high levels of these markers in the blood had a much shorter lifespan compared to patients with low levels,’ said lead author Primo Lara, associate director for translational research at the UC Davis Comprehensive Cancer Center. ‘By measuring bone turnover in prostate cancer patients, we can determine how well they do.’
Healthy bone maintains a balance between formation and resorption, generating new bone while recycling old. Prostate cancer throws off this balance. Researchers hoped this mechanism would help them track the cancer. To investigate this potential link, the team tested blood serum in 778 patients for both resorption (N-telopeptide, pyridinoline) and formation markers (C-terminal collagen propeptide, bone alkaline phosphatase) and found elevated levels of each of the markers predicted poor prognosis.
Perhaps most interesting, elevated marker levels also predicted whether patients would respond to a specific drug. About 6 percent of patients with the highest marker levels responded to atrasentan, and investigational drug abandoned because it failed in clinical trials. Lara and colleagues believe this may be related to study design.
‘Atrasentan kept coming up short in randomised trials because the drug only works for a small group,’ Lara said. ‘Because certain drugs only succeed in a fraction of patients, drug makers need to factor in these bone metabolism markers in their trial design. They need to target the patients most likely to benefit.’
In addition to determining which patients might respond best to a specific treatment, these markers could be used to track their response during treatment. Marker status could also stratify patients equally within different study arms. Balancing these studies could potentially make them more accurate and identify the niche value of drugs like atrasentan whose effectiveness is not evident in large populations.
‘I think the days of doing empirical studies on all comers should end,’ Lara said. ‘You need to have an appropriate database of patients and perform a rigorous analysis to find the subset who will benefit from an investigational drug.’
UC Davis Comprehensive Cancer Center
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:13Bone turnover markers predict prostate cancer outcomes
Changes to two previously unstudied genes are the centrepiece of a new theory regarding the cause and development of endometriosis, a chronic and painful disease affecting 1 in 10 women.
The discovery by Northwestern Medicine scientists suggests epigenetic modification, a process that enhances or disrupts how DNA is read, is an integral component of the disease and its progression. Matthew Dyson, PhD, research assistant professor of Obstetrics and Gynecology-Reproductive Biology Research and Serdar Bulun, MD, chair of Obstetrics and Gynecology also identified a novel role for a family of key gene regulators in the uterus.
‘Until now, the scientific community was looking for a genetic mutation to explain endometriosis,’ said Dr. Bulun, a member of the Center for Genetic Medicine and the Robert H. Lurie Comprehensive Cancer Center. ‘This is the first conclusive demonstration that the disease develops as a result of alterations in the epigenetic landscape and not from classical genetic mutations.’
Women develop endometriosis when cells from the lining of the uterus, usually shed during menstruation, grow in other areas of the body. The persistent survival of these cells results in chronic pelvic pain and infertility. Although the cause of the disease has remained unknown on a cellular level, there have been several different models established to explain its development.
Endometriosis only occurs in menstruating primates, suggesting that the unique evolution behind uterine development and menstruation are linked to the disease. Scientists consider retrograde menstruation – cells moving up the fallopian tubes and into the pelvis – as one probable cause.
Previous models, however, have been unable to explain why only 10 percent of women develop the disease when most experience retrograde menstruation at some point. Nor do they explain instances of endometriosis that arise independent of menstruation.
Bulun and Dyson propose that an epigenetic switch permits the expression of the transcription factor GATA6 rather than GATA2, resulting in progesterone resistance and disease development.
‘We believe an overwhelming number of these altered cells reach the lining of the abdominal cavity, survive and grow,’ said Dr. Bulun, obstetrician-gynaecologist-in-chief at Northwestern Memorial’s Prentice Women’s Hospital. ‘These findings could someday lead to the first non-invasive test for endometriosis.’
Clinicians could then prevent the disease by placing teenagers predisposed to this epigenetic change on a birth control pill regimen, preventing the possibility of retrograde menstruation in the first place.
Dyson will also look to use the epigenetic fingerprint resulting from the presence of GATA6 rather than GATA2 as a potential diagnostic tool, since these epigenetic differences are readily detectable.
‘These findings have the potential to shift how we view and treat the disease moving forward,’ Dr. Bulun said.
Feinberg School of Medicine
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:13Findings on cause, progression of endometriosis
The genetic disease ARVC leads to sudden cardiac death and is more common than it has been hitherto assumed. This is reported by an international team of researchers headed by Prof Dr Hendrik Milting from the Heart and Diabetes Center NRW. The molecular biologist working at the Ruhr-Universität’s clinic in Bad Oeynhausen revealed that all families who are known to be affected by the disease share the same genetic origin. There must be other families in Europe who also carry the genetic mutation but who are not yet known.
Scientists have thrown light on the genetic mutation that causes a particularly severe genetic disease (ARVC5) on the Canadian island Newfoundland in 2008. At first, they assumed that it was a genetic anomaly limited to this Canadian province. In 2010, Milting’s team – and at the same time a team of researchers from Copenhagen – proved that the ‘Newfoundland mutation’ did also occur in Europe. Today, the scientists know about affected families in Germany, Denmark, the USA and Canada. They all share common ancestors, as was demonstrated through genetic analysis. The scientists studied the environment of the TMEM43 gene in which the ARVC5-specific mutation is located. The genetic sequence in the neighbourhood of TMEM43 is typically highly variable; in all affected families, however, it was identical over long stretches. These findings verify a shared genetic origin.
The affected Danish and German families are not aware of the degree to which they are related; according to calculations, the mutation originated some 1300 to 1500 years ago. Thus, the ARVC5 mutation in the European families is not a novel mutation but an old European heritage. Therefore, there must be other families with that genetic mutation, who constitute the bridge between the patients in Europe and in North America. Two novel families with that mutation have recently been identified in Madrid. ‘In cases of sudden cardiac death in the family, people should sit up and take notice,’ says Prof Milting. ‘The families that are known to us have lost several male family members within a short space of time, even though they were under medical observation. Women frequently suffer from cardiac arrhythmias.’ Suspected cases must be looked into, warns the molecular biologist, because people carrying that mutation will definitely get the disease. Sudden cardiac death may be prevented if a defibrillator is implanted in good time.
Genetic analyses are increasingly gaining in importance in healthcare settings as prevention and diagnostic tools. ‘Nevertheless, healthcare professionals are called upon to exercise great discretion when deciding which analyses must necessarily be conducted for which patients,’ stresses Hendrik Milting. ‘After all, the objective is not to stigmatise the affected families, but to prevent severe heart diseases or even sudden cardiac death.’ A team of molecular biologists, cardiologists and human geneticists is in charge of this task at the Heart and Diabetes Center NRW.
The acronym ARVC stands for arrhythmogenic right ventricular cardiomyopathy. A considerable number of patients, most of them men, suffer sudden cardiac death without having ever shown any signs of a cardiovascular disease. The average life expectancy of men who have the ARVC5 genetic mutation is about 41 years.
Ruhr University Bochum
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:12Preventing sudden cardiac death through genetic diagnostics
Harvard stem cell scientists have identified a mutation in human cases of acute lymphoblastic leukaemia that likely drives relapse. The research could translate into improved patient care strategies for this particular blood cancer, which typically affects children but is more deadly in adults.
In recent years, a trend toward single-cell analysis has shown that individual cells within a tumour are capable of amassing mutations to make them more aggressive and treatment resistant. So while 99% of a tumour may be destroyed by the initial treatment, a particularly aggressive cell can survive and then cause a cancer patient with the ‘all clear’ to relapse six months later.
Harvard Stem Cell Institute Principal Faculty member David Langenau, PhD, and his lab members in the Department of Pathology at Massachusetts General Hospital used zebrafish to search for these rare, relapse-driving leukaemia cells and then designed therapies that could kill these cells.
The researchers found that at least half of relapse-driving leukemic cells had a mutation that activated the Akt pathway, which rendered cells resistant to common chemotherapy and increased growth. From that insight, Langenau’s lab next examined human acute lymphoblastic leukaemia and discovered that inhibition of the Akt pathway restored leukemic cell responses to front-line chemotherapy.
‘The Akt pathway appears to be a major driver of treatment resistance,’ Langenau said. ‘We also show that this same pathway increases overall growth of leukemic cells and increases the fraction of cells capable of driving relapse.’
Jessica Blackburn, PhD, the study’s first author adds, ‘Our work will likely help in identifying patients that are prone to relapse and would benefit from co-treatment with inhibitors of the Akt pathway and typical front-line cancer therapy.’
In addition to determining how best to translate this finding into the clinic, Langenau hopes to identify other mutations that lead to relapse. The work should identify a host of other potential drug targets for patients with aggressive leukaemia.
Harvard Stem Cell Institute
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:12Common mutation is culprit in acute leukaemia relapse
We may ask you to place cookies on your device. We use cookies to let us know when you visit our websites, how you interact with us, to enrich your user experience and to customise your relationship with our website.
Click on the different sections for more information. You can also change some of your preferences. Please note that blocking some types of cookies may affect your experience on our websites and the services we can provide.
Essential Website Cookies
These cookies are strictly necessary to provide you with services available through our website and to use some of its features.
Because these cookies are strictly necessary to provide the website, refusing them will affect the functioning of our site. You can always block or delete cookies by changing your browser settings and block all cookies on this website forcibly. But this will always ask you to accept/refuse cookies when you visit our site again.
We fully respect if you want to refuse cookies, but to avoid asking you each time again to kindly allow us to store a cookie for that purpose. You are always free to unsubscribe or other cookies to get a better experience. If you refuse cookies, we will delete all cookies set in our domain.
We provide you with a list of cookies stored on your computer in our domain, so that you can check what we have stored. For security reasons, we cannot display or modify cookies from other domains. You can check these in your browser's security settings.
.
Google Analytics Cookies
These cookies collect information that is used in aggregate form to help us understand how our website is used or how effective our marketing campaigns are, or to help us customise our website and application for you to improve your experience.
If you do not want us to track your visit to our site, you can disable this in your browser here:
.
Other external services
We also use various external services such as Google Webfonts, Google Maps and external video providers. Since these providers may collect personal data such as your IP address, you can block them here. Please note that this may significantly reduce the functionality and appearance of our site. Changes will only be effective once you reload the page
Google Webfont Settings:
Google Maps Settings:
Google reCaptcha settings:
Vimeo and Youtube videos embedding:
.
Privacy Beleid
U kunt meer lezen over onze cookies en privacy-instellingen op onze Privacybeleid-pagina.
Study pinpoints protective mutations for type 2 diabetes
, /in E-News /by 3wmediaAn international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH) has identified mutations in a gene that can reduce the risk of developing type 2 diabetes, even in people who have risk factors such as obesity and old age. The results focus the search for developing novel therapeutic strategies for type 2 diabetes; if a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease.
The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the new study, researchers describe the genetic analysis of 150,000 patients showing that rare mutations in a gene called SLC30A8 reduce risk of type 2 diabetes by 65 percent. The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility around the globe. The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes. However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk — and how large an effect could be expected.
‘This work underscores that human genetics is not just a tool for understanding biology: it can also powerfully inform drug discovery by addressing one of the most challenging and important questions — knowing which targets to go after,’ said co-senior author David Altshuler, deputy director and chief academic officer at the Broad Institute and a Harvard Medical School professor at Massachusetts General Hospital.
The use of human genetics to identify protective mutations holds great potential. Mutations in a gene called CCR5 were found to protect against infection with HIV, the virus that causes AIDS; drugs have been developed that block the CCR5 protein. A similar protective association for heart disease set off a race to discover new cholesterol-lowering drugs when mutations in the gene PCSK9 were found to lower cholesterol levels and heart disease risk. The new type 2 diabetes study suggests that CCR5 and PCSK9 are likely just the beginning but that it will take large numbers of samples and careful sleuthing to find additional genes with similar protective properties.
The study grew out of a research partnership that started in 2009 involving the Broad Institute, Massachusetts General Hospital, Pfizer Inc., and Lund University Diabetes Centre in Sweden, which set out to find mutations that reduce a person’s risk of type 2 diabetes. The research team selected people with severe risk factors for diabetes, such as advanced age and obesity, who never developed the disease and in fact had normal blood sugar levels. They focused on a set of genes previously identified as playing a role in type 2 diabetes and used next-generation sequencing to search for rare mutations.
The team identified a genetic mutation that appeared to abolish function of the SLC30A8 gene and that was enriched in non-diabetic individuals studied in Sweden and Finland. The protection was surprising, because studies in mice had suggested that mutations in SLC30A8 might have the opposite effect — increasing rather than decreasing risk of type 2 diabetes. However, because this particular genetic variation was exceedingly rare outside of Finland, it proved difficult to obtain additional evidence to corroborate the initial discovery by the Broad/MGH/Pfizer Inc./Lund team.
Then, in 2012, these unpublished results were shared with deCODE genetics, who uncovered a second mutation in an Icelandic population that also appeared to abolish function of the gene SLC30A8. That mutation independently reduced risk for type 2 diabetes and also lowered blood sugar in non-diabetics without any evident negative consequences.
‘This discovery underscores what can be accomplished when human genetics experts on both sides of the Atlantic come together to apply their craft to founder populations, enabling us to find rare mutations with large effects on disease risk,’ said Kari Stefannson, CEO of deCODE genetics.
Finally, the team set out to ask if the effects of SLC30A8 protective mutations were limited to the two mutations found in populations in Finland and Iceland. As part of the NIH-funded T2D-GENES Project, chaired by Mike Boehnke at the University of Michigan, the Broad Institute had performed sequencing of 13,000 samples drawn from multiple ethnicities. The T2D-GENES Project joined the collaboration, found ten more mutations in the same gene, and again saw a protective effect. Combining all the results confirmed that inheriting one copy of a defective version of SLC30A8 led to a 65 percent reduction in risk of diabetes.
‘Through this partnership, we have been able to identify genetic mutations related to loss of gene function, which are protective against type 2 diabetes,’ said Tim Rolph, Vice President and Chief Scientific Officer of Cardiovascular, Metabolic & Endocrine Disease Research at Pfizer Inc. ‘Such genetic associations provide important new insights into the pathogenesis of diabetes, potentially leading to the discovery of drug targets, which may result in a novel medicine.’ Broad Institute
Toxin from brain cells triggers neuron loss in human ALS model
, /in E-News /by 3wmediaIn most cases of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, a toxin released by cells that normally nurture neurons in the brain and spinal cord can trigger loss of the nerve cells affected in the disease, Columbia researchers report.
The toxin is produced by star-shaped cells called astrocytes and kills nearby motor neurons. In ALS, the death of motor neurons causes a loss of control over muscles required for movement, breathing, and swallowing. Paralysis and death usually occur within 3 years of the appearance of first symptoms.
The report follows the researchers’ previous study, which found similar results in mice with a rare, genetic form of the disease, as well as in a separate study from another group that used astrocytes derived from patient neural progenitor cells. The current study shows that the toxins are also present in astrocytes taken directly from ALS patients.
‘I think this is probably the best evidence we can get that what we see in mouse models of the disease is also happening in human patients,’ said the study’s senior author, Serge Przedborski, MD, PhD, the Page and William Black Professor of Neurology (in Pathology and Cell Biology), Vice Chair for Research in the department of Neurology, and co-director of Columbia’s Motor Neuron Center.
The findings also are significant because they apply to the most common form of ALS, which affects about 90 percent of patients. Scientists do not know why ALS develops in these patients; the other 10 percent of patients carry one of 27 genes known to cause the disease.
‘Now that we know that the toxin is common to most patients, it gives us an impetus to track down this factor and learn how it kills the motor neurons,’ Dr. Przedborski said. ‘Its identification has the potential to reveal new ways to slow down or stop the destruction of the motor neurons.’
In the study, Dr. Przedborski and study co-authors Diane Re, PhD, and Virginia Le Verche, PhD, associate research scientists, removed astrocytes from the brain and spinal cords of six ALS patients shortly after death and placed the cells in petri dishes next to healthy motor neurons. Because motor neurons cannot be removed from human subjects, they had been generated from human embryonic stem cells in the Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, also at CUMC.
Within two weeks, many of the motor neurons had shrunk and their cell membranes had disintegrated; about half of the motor neurons in the dish had died. Astrocytes removed from people who died from causes other than ALS had no effect on the motor neurons. Nor did other types of cells taken from ALS patients.
The researchers confirmed that the cause of the motor neurons’ death was a toxin released into the environment by immersing healthy motor neurons in the astrocytes’ culture media. The presence of the media, even without astrocytes, killed the motor neurons.
The researchers have not yet identified the toxin released by the astrocytes. But they did discover the nature of the neuronal death process triggered by the toxin. The toxin triggers a biochemical cascade in the motor neurons that essentially causes them to undergo a controlled cellular explosion.
Drs. Przedborski, Re, and Le Verche found that they could prevent astrocyte-triggered motor neuron death by inhibiting one of the key components of this molecular cascade.
These findings may lead to a way to prevent motor neuron death in patients and potentially prolong life. But the therapeutic potential of such inhibition is far from clear. ‘For example, we don’t know if this would leave patients with living but dysfunctional neurons,’ Dr. Przedborski said. The researchers are now testing the idea of inhibition in animal models of ALS.
The development of new therapies for ALS has been disappointing, with more than 30 clinical trials ending with no new treatments since the 1995 FDA approval of riluzole.
The lack of progress may be partly because animal models used to study ALS do not completely recreate the human disease. The new all-human cell model of ALS created for the current study may improve scientists’ ability to identify useful drug targets, particularly for the most common form of the disease.
‘Although there are many neuro-degenerative disorders, only for a handful do we have access to a simplified model that is relevant to the disease and can therefore potentially be used for high-throughput drug screening. So this model is quite special,’ Dr. Przedborski said. ‘Here we have a spontaneous disease phenotype triggered by the relevant tissue that causes human illness. That’s one important thing. The other important thing is that this model is derived entirely from human elements. This is probably the closest, most natural model of human ALS that we can get in a dish.’ Columbia University Medical Center
Improved lab screening technique opens door for new pediatric neuroblastoma therapies
, /in E-News /by 3wmediaNeuroblastoma is one of the most common and lethal types of childhood cancers. A researcher at the University of Texas Health Science Center at San Antonio unveils the important role of microRNAs in regulating neuroblastoma development, pointing to new therapeutic possibilities.
Neuroblastomas, which account for 15 percent of childhood cancer deaths, happen when some cells do not differentiate and grow as they should. A promising type of therapy called differentiation therapy targets these malignant cells so that they can resume the process of differentiating into mature cells.
Unlike conventional chemotherapies, this new approach to cancer therapy has fewer toxic side effects, and gives hope for a cancer treatment that is gentler on young bodies. But so far only a few differentiation agents have been successfully used to treat neuroblastoma, and more than half of the young patients treated with such agents still see their cancer return.
To find new treatments, researchers needed improved laboratory screening techniques, and now one has been developed by Liqin Du, Ph.D., an assistant professor in the Department of Cellular and Structural Biology, and her team at the Greehey Children’s Cancer Research Institute at the UT Health Science Center.
MicroRNAs are small RNA molecules involved in gene expression, and play an important role in cell development. This screening approach revealed several microRNA molecules that induce the process of cell differentiation, and those are key to developing new drugs.
‘Development of new agents for treating neuroblastoma has been greatly hampered by the lack of efficient high-throughput screening approaches,’ Dr. Du said. ‘In our study, we applied a novel high-content screening approach that we recently developed to investigate the role of microRNAs in neuroblastoma differentiation.
‘We identified a set of novel microRNAs that are potent inducers of neuroblastoma cell differentiation and found that mimics (synthetic fragments of nucleic acid used to raise microRNA levels in cells) of some of the identified microRNAs are much more potent in inducing neuroblastoma cell differentiation than the current differentiation treatments.
‘These mimics are promising new drugs for neuroblastoma differentiation therapy,’ Dr. Du said. ‘We look forward to investigating this further in the future.’ UT Health Science Center San Antonio
Tracking genes on the path to genetic treatment
, /in E-News /by 3wmediaBefore doctors like Matthias Kretzler can begin using the results of molecular research to treat patients, they need science to find an effective way to match genes with the specific cells involved in disease. As Kretzler explains, finding that link would eventually let physicians create far more effective diagnostic tools and treatments.
‘Among many uses, it would allow us to develop cell-type targeted therapies,’ said Kretzler, a University of Michigan professor of internal medicine and computational medicine and bioinformatics. He recently collaborated with Princeton University professor Olga Troyanskaya on a way to match genes to cells. ‘If you identify a [disease] that is in the liver or in the kidney, you could target those areas and not affect other parts of the body,’ he said.
Although scientists have decoded the human genome — the list of all the genes in human cells — they still have great difficulty determining the specific genes that are activated to make a kidney cell as opposed to a liver or heart cell.
In theory, an easy way to link genes to cells would be to isolate a cell and test it. However, solid human tissue is so closely packed that even the finest surgical techniques cannot separate types of cells efficiently enough for analysis. A kidney biopsy, for example, produces a mix of several different types of cells that Kretzler dismisses as ‘kidney soup.’
Princeton University and University of Michigan researchers have developed a system that allows computers to ‘virtually dissect’ a kidney in a way that surgery cannot. The machine uses data from an array of gene-activity measurements in patients’ kidney biopsies to mathematically separate cells and identify genes that are turned on in a specific cell type. The researchers identified 136 genes involved in the creation of a critical kidney cell called a podocyte, tiny cells that serve as filters in the kidneys and are frequently involved in kidney disease.
‘We call it in-silico nano-dissection,’ said Troyanskaya, a professor of computer science and the Lewis-Sigler Institute for Integrative Genomics. Using a large database of such gene-activity measurements to track genetic lineage allows scientists to refine their analysis through thousands of measurements, something that would be impossible with individual cell cultures, she said.
The method has proven far faster and significantly more effective than current techniques. Researchers from Kretzler’s lab at Michigan and Troyanskaya’s at Princeton reported that they had identified 136 genes involved in the creation of a critical kidney cell called a podocyte. In decades of research, only 46 had been previously identified.
‘The potential for this is huge,’ said Behzad Najafian, a University of Washington assistant professor of pathology who specializes in renal pathology. ‘I believe this novel technique, which is a significant improvement in cell lineage-specific gene-expression analysis, will not only help us understand the pathophysiology of kidney diseases better through biopsy studies, but also provides a strong tool for discovery or validation of cell-specific urine or plasma biomarkers.’ Princeton University
Google Glass app for instant medical diagnostic test results
, /in E-News /by 3wmediaA team of researchers from UCLA’s Henry Samueli School of Engineering and Applied Science has developed a Google Glass application and a server platform that allow users of the wearable, glasses-like computer to perform instant, wireless diagnostic testing for a variety of diseases and health conditions.
With the new UCLA technology, Google Glass wearers can use the device’s hands-free camera to capture pictures of rapid diagnostic tests (RTDs), small strips on which blood or fluid samples are placed and which change colour to indicate the presence of HIV, malaria, prostate cancer or other conditions. Without relying on any additional devices, users can upload these images to a UCLA-designed server platform and receive accurate analyses — far more detailed than with the human eye — in as little as eight seconds.
The new technology could enhance the tracking of dangerous diseases and improve public health monitoring and rapid responses in disaster-relief areas or quarantine zones where conventional medical tools are not available or feasible, the researchers said.
‘This breakthrough technology takes advantage of gains in both immunochromatographic rapid diagnostic tests and wearable computers,’ said principal investigator Aydogan Ozcan, the Chancellor’s Professor of Electrical Engineering and Bioengineering at UCLA and associate director of UCLA’s California NanoSystems Institute. ‘This smart app allows for real-time tracking of health conditions and could be quite valuable in epidemiology, mobile health and telemedicine.’
In addition to designing the custom RDT–reader app for Google Glass, Ozcan’s team implemented server processes for fast and high-throughput evaluation of test results coming from multiple devices simultaneously. Finally, the researchers developed a web portal where users can view test results, maps charting the geographical spread of various diseases and conditions, and the cumulative data from all the tests they have submitted over time.
To submit images for test results, Google Glass users only need to take photos of RTD strips or other commonly available in-home tests, then upload the images wirelessly through the device to the UCLA-designed web portal. The technology permits quantified reading of the results to a few-parts-per-billion level of sensitivity — far greater than that of the naked eye — thus eliminating the potential for human error in interpreting results, which is a particular concern if the user is a health care worker who routinely deals with many different types of tests.
To gauge the accuracy and efficiency of the technology, the UCLA team used an in-home HIV test designed by OraSure Technologies and a prostate-specific antigen test made by JAJ International. The researchers took images of tests under normal, indoor, fluorescent-lit room conditions. They submitted more than 400 images of the two tests, and the RDT reader and server platform were able to read the images 99.6 percent of the time. In every case in which the technology successfully read the images, it returned accurate and quantified test results, according to the team.
The researchers also tested more than 300 blurry images or images of the testing device taken under various natural-usage scenarios and achieved a read rate of 96.6 percent. The UCLA Henry Samueli School of Engineering and Applied Science
Study identifies gene important to breast development and breast cancer
, /in E-News /by 3wmediaSignificance: Understanding more about how the different types of cells in breast tissue develop improves our knowledge of breast cancer. TAZ represents a potential new target for drug therapies to treat aggressive types of breast cancer.
Background: In cancer, normal cells can become unpredictable or aggressive and thus difficult to treat with anti-cancer drugs. This is especially true in breast cancer. By identifying the genes responsible for this change in cells from breast tissue, researchers hope to identify a way to stop or reverse it.
In breast tissue, there are two main types of cells: luminal cells and basal cells. Normally luminal cells are ‘programmed’ by a particular class of proteins (transcription factors), which prevent them from becoming basal cells, and vice-versa.
Previous work led by Charlotte Kuperwasser, principal investigator, determined that some common forms of breast cancer originate from luminal cells while some rarer forms of breast cancer originate from basal cells.
Findings: The research team identified a gene, TAZ, which controls whether breast cells behave more like basal cells or more like luminal cells, information that might be important in understanding and potentially treating certain difficult-to-treat forms of breast cancer. TAZ helps to regulate how different genes operate in different cell types.
How the Study Was Conducted: The research team identified TAZ by testing the function of more than 1,000 genes to determine which were involved in ‘reprogramming’ luminal and basal cells, therefore reversing lineage commitment.
To further identify the role of TAZ, the research team studied breast tissue at different stages of development using two groups of mice: a control group with the TAZ gene and an experimental group of knock-out mice with the TAZ gene deleted. (Cells in breast tissue are renewed/developed during puberty, pregnancy, and nursing.)
The team also looked at the levels of the TAZ gene in tumours from women with either luminal or basal tumours.
Results: The research team found that the experimental group had an imbalance of cell populations in breast tissue: too many luminal and too few basal. The control group had a normal ratio of luminal to basal cells. In breast tissue from women with cancer, they found high levels of TAZ in basal but not luminal tumours.
Discussion: First author Adam Skibinski, M.D./Ph.D. student at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University:
‘We’ve known for a long time that breast cells can lose their normal identity when they become cancerous, but we are now realising that normal cells can change their characteristics as well in response to transcription factors like TAZ. This might be a factor in the development of breast cancer.’ Tufts University
Bone turnover markers predict prostate cancer outcomes
, /in E-News /by 3wmediaBiomarkers for bone formation and resorption predict outcomes for men with castration-resistant prostate cancer, a team of researchers from UC Davis and their collaborators have found. Their study also found that the markers identified a small group of patients who responded to the investigational drug atrasentan. The markers’ predictive ability could help clinicians match treatments with individual patients, track their effectiveness and affect clinical trial design.
Castration-resistant prostate cancer does not respond to hormone treatments and often metastasises to bone. This led researchers to wonder if increased bone turnover markers might predict the course of the disease.
‘We found that patients with high levels of these markers in the blood had a much shorter lifespan compared to patients with low levels,’ said lead author Primo Lara, associate director for translational research at the UC Davis Comprehensive Cancer Center. ‘By measuring bone turnover in prostate cancer patients, we can determine how well they do.’
Healthy bone maintains a balance between formation and resorption, generating new bone while recycling old. Prostate cancer throws off this balance. Researchers hoped this mechanism would help them track the cancer. To investigate this potential link, the team tested blood serum in 778 patients for both resorption (N-telopeptide, pyridinoline) and formation markers (C-terminal collagen propeptide, bone alkaline phosphatase) and found elevated levels of each of the markers predicted poor prognosis.
Perhaps most interesting, elevated marker levels also predicted whether patients would respond to a specific drug. About 6 percent of patients with the highest marker levels responded to atrasentan, and investigational drug abandoned because it failed in clinical trials. Lara and colleagues believe this may be related to study design.
‘Atrasentan kept coming up short in randomised trials because the drug only works for a small group,’ Lara said. ‘Because certain drugs only succeed in a fraction of patients, drug makers need to factor in these bone metabolism markers in their trial design. They need to target the patients most likely to benefit.’
In addition to determining which patients might respond best to a specific treatment, these markers could be used to track their response during treatment. Marker status could also stratify patients equally within different study arms. Balancing these studies could potentially make them more accurate and identify the niche value of drugs like atrasentan whose effectiveness is not evident in large populations.
‘I think the days of doing empirical studies on all comers should end,’ Lara said. ‘You need to have an appropriate database of patients and perform a rigorous analysis to find the subset who will benefit from an investigational drug.’ UC Davis Comprehensive Cancer Center
Findings on cause, progression of endometriosis
, /in E-News /by 3wmediaChanges to two previously unstudied genes are the centrepiece of a new theory regarding the cause and development of endometriosis, a chronic and painful disease affecting 1 in 10 women.
The discovery by Northwestern Medicine scientists suggests epigenetic modification, a process that enhances or disrupts how DNA is read, is an integral component of the disease and its progression. Matthew Dyson, PhD, research assistant professor of Obstetrics and Gynecology-Reproductive Biology Research and Serdar Bulun, MD, chair of Obstetrics and Gynecology also identified a novel role for a family of key gene regulators in the uterus.
‘Until now, the scientific community was looking for a genetic mutation to explain endometriosis,’ said Dr. Bulun, a member of the Center for Genetic Medicine and the Robert H. Lurie Comprehensive Cancer Center. ‘This is the first conclusive demonstration that the disease develops as a result of alterations in the epigenetic landscape and not from classical genetic mutations.’
Women develop endometriosis when cells from the lining of the uterus, usually shed during menstruation, grow in other areas of the body. The persistent survival of these cells results in chronic pelvic pain and infertility. Although the cause of the disease has remained unknown on a cellular level, there have been several different models established to explain its development.
Endometriosis only occurs in menstruating primates, suggesting that the unique evolution behind uterine development and menstruation are linked to the disease. Scientists consider retrograde menstruation – cells moving up the fallopian tubes and into the pelvis – as one probable cause.
Previous models, however, have been unable to explain why only 10 percent of women develop the disease when most experience retrograde menstruation at some point. Nor do they explain instances of endometriosis that arise independent of menstruation.
Bulun and Dyson propose that an epigenetic switch permits the expression of the transcription factor GATA6 rather than GATA2, resulting in progesterone resistance and disease development.
‘We believe an overwhelming number of these altered cells reach the lining of the abdominal cavity, survive and grow,’ said Dr. Bulun, obstetrician-gynaecologist-in-chief at Northwestern Memorial’s Prentice Women’s Hospital. ‘These findings could someday lead to the first non-invasive test for endometriosis.’
Clinicians could then prevent the disease by placing teenagers predisposed to this epigenetic change on a birth control pill regimen, preventing the possibility of retrograde menstruation in the first place.
Dyson will also look to use the epigenetic fingerprint resulting from the presence of GATA6 rather than GATA2 as a potential diagnostic tool, since these epigenetic differences are readily detectable.
‘These findings have the potential to shift how we view and treat the disease moving forward,’ Dr. Bulun said. Feinberg School of Medicine
Preventing sudden cardiac death through genetic diagnostics
, /in E-News /by 3wmediaThe genetic disease ARVC leads to sudden cardiac death and is more common than it has been hitherto assumed. This is reported by an international team of researchers headed by Prof Dr Hendrik Milting from the Heart and Diabetes Center NRW. The molecular biologist working at the Ruhr-Universität’s clinic in Bad Oeynhausen revealed that all families who are known to be affected by the disease share the same genetic origin. There must be other families in Europe who also carry the genetic mutation but who are not yet known.
Scientists have thrown light on the genetic mutation that causes a particularly severe genetic disease (ARVC5) on the Canadian island Newfoundland in 2008. At first, they assumed that it was a genetic anomaly limited to this Canadian province. In 2010, Milting’s team – and at the same time a team of researchers from Copenhagen – proved that the ‘Newfoundland mutation’ did also occur in Europe. Today, the scientists know about affected families in Germany, Denmark, the USA and Canada. They all share common ancestors, as was demonstrated through genetic analysis. The scientists studied the environment of the TMEM43 gene in which the ARVC5-specific mutation is located. The genetic sequence in the neighbourhood of TMEM43 is typically highly variable; in all affected families, however, it was identical over long stretches. These findings verify a shared genetic origin.
The affected Danish and German families are not aware of the degree to which they are related; according to calculations, the mutation originated some 1300 to 1500 years ago. Thus, the ARVC5 mutation in the European families is not a novel mutation but an old European heritage. Therefore, there must be other families with that genetic mutation, who constitute the bridge between the patients in Europe and in North America. Two novel families with that mutation have recently been identified in Madrid. ‘In cases of sudden cardiac death in the family, people should sit up and take notice,’ says Prof Milting. ‘The families that are known to us have lost several male family members within a short space of time, even though they were under medical observation. Women frequently suffer from cardiac arrhythmias.’ Suspected cases must be looked into, warns the molecular biologist, because people carrying that mutation will definitely get the disease. Sudden cardiac death may be prevented if a defibrillator is implanted in good time.
Genetic analyses are increasingly gaining in importance in healthcare settings as prevention and diagnostic tools. ‘Nevertheless, healthcare professionals are called upon to exercise great discretion when deciding which analyses must necessarily be conducted for which patients,’ stresses Hendrik Milting. ‘After all, the objective is not to stigmatise the affected families, but to prevent severe heart diseases or even sudden cardiac death.’ A team of molecular biologists, cardiologists and human geneticists is in charge of this task at the Heart and Diabetes Center NRW.
The acronym ARVC stands for arrhythmogenic right ventricular cardiomyopathy. A considerable number of patients, most of them men, suffer sudden cardiac death without having ever shown any signs of a cardiovascular disease. The average life expectancy of men who have the ARVC5 genetic mutation is about 41 years. Ruhr University Bochum
Common mutation is culprit in acute leukaemia relapse
, /in E-News /by 3wmediaHarvard stem cell scientists have identified a mutation in human cases of acute lymphoblastic leukaemia that likely drives relapse. The research could translate into improved patient care strategies for this particular blood cancer, which typically affects children but is more deadly in adults.
In recent years, a trend toward single-cell analysis has shown that individual cells within a tumour are capable of amassing mutations to make them more aggressive and treatment resistant. So while 99% of a tumour may be destroyed by the initial treatment, a particularly aggressive cell can survive and then cause a cancer patient with the ‘all clear’ to relapse six months later.
Harvard Stem Cell Institute Principal Faculty member David Langenau, PhD, and his lab members in the Department of Pathology at Massachusetts General Hospital used zebrafish to search for these rare, relapse-driving leukaemia cells and then designed therapies that could kill these cells.
The researchers found that at least half of relapse-driving leukemic cells had a mutation that activated the Akt pathway, which rendered cells resistant to common chemotherapy and increased growth. From that insight, Langenau’s lab next examined human acute lymphoblastic leukaemia and discovered that inhibition of the Akt pathway restored leukemic cell responses to front-line chemotherapy.
‘The Akt pathway appears to be a major driver of treatment resistance,’ Langenau said. ‘We also show that this same pathway increases overall growth of leukemic cells and increases the fraction of cells capable of driving relapse.’
Jessica Blackburn, PhD, the study’s first author adds, ‘Our work will likely help in identifying patients that are prone to relapse and would benefit from co-treatment with inhibitors of the Akt pathway and typical front-line cancer therapy.’
In addition to determining how best to translate this finding into the clinic, Langenau hopes to identify other mutations that lead to relapse. The work should identify a host of other potential drug targets for patients with aggressive leukaemia. Harvard Stem Cell Institute