Variations in a gene with multiple functions in neurons are present in approximately 3 percent of all cases of ALS in North American and European populations, both sporadic and familial, making it one of the most common genetic causes of the disease, according to a paper. Led by John Landers, PhD, professor of neurology at UMass Medical School and Jan Veldink, PhD, at University Medical Center Utrecht in the Netherlands, the research was supported by The ALS Association through Project MinE, an international collaboration for gene discovery in ALS, and funded through ALS Ice Bucket donations.
ALS (amyotrophic lateral sclerosis) is a progressive neurodegenerative disease that affects neurons in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. While 10 percent of ALS is familial, meaning it’s genetic, the other 90 percent of ALS cases are considered sporadic, or without a family history. However, it’s very likely that genetics contribute, directly or indirectly, to a much larger percentage of ALS cases.
“The discovery of NEK1 highlights the value of big data in ALS research,” said Lucie Bruijn, PhD, MBA, of The ALS Association. “The sophisticated gene analysis that led to this finding was only possible because of the large number of ALS samples available. The ALS Ice Bucket Challenge enabled The ALS Association to invest in Project MinE’s work to create large biorepositories of ALS biosamples that are designed to allow exactly this kind of research and to produce exactly this kind of result.”
The new gene, called NEK1, was discovered through a genome-wide search for ALS risk genes in more than 1,000 ALS families, and was independently found through different means in an isolated population in the Netherlands. Further analysis in more than 13,000 sporadic ALS individuals compared to controls again revealed the overrepresentation of variants in the same gene. The variations discovered in the gene sequence are predicted to lead to a loss of function of the gene. NEK1 is known to have multiple roles in neurons, including maintenance of the cytoskeleton that gives the neuron its shape and promotes transport within the neuron. In addition, NEK1 has roles in regulating the membrane of the mitochondrion, which supplies energy to neurons, and in repairing DNA. Disruption of each of these functions through other means has been linked to increased risk of ALS.
Understanding the role of NEK1 in disease will provide an important new target for therapy development. The ALS Association is currently funding Landers and Catherine Lutz, PhD, senior research scientist at the Jackson Laboratories in Bar Harbour, Maine, to develop novel mouse models to better understand the consequences of the loss of the protein’s function for the ALS disease process. They will provide rapid access to these models for the broader ALS research community as soon as they are generated. These tools are important for ALS drug development.
UMass Medical School
www.umassmed.edu/news/news-archives/2016/07/new-gene-variants-present-in-3-percent-of-all-als-patients/
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A study by researchers at Children’s Hospital Los Angeles (CHLA), Brigham and Women’s Hospital and the California Department of Public Health suggests that all babies with a known mutation for cystic fibrosis (CF) and second mutation called the 5T allele should receive additional screening in order to better predict the risk of developing CF later in life.
The results indicate that adding specific DNA sequencing to current newborn screenings would allow for early diagnosis in ethnically diverse populations and may increase the number of CF diagnoses in the U.S. over time. Such diagnoses could result in earlier treatment of CF, which could ultimately improve the outcome and prolong the life of a child with the disease.
Newborn screening programs, using a simple blood test taken within 24 to 48 hours of a child’s birth, allow for early detection and treatment of often devastating disorders. In the U.S., millions of newborns are screened each year, and early testing for CF – a progressive, genetic disease that causes persistent lung infections – has been implemented in all 50 states since 2010. CF is an autosomal recessive disorder, meaning that the child must inherit two copies of an abnormal gene in order for the disease to develop.
Each state uses a different screening algorithm to detect newborns with CF. California has implemented a unique algorithm which incorporates full sequencing of the gene responsible for CF, called the CF Transmembrane Conductance Regulator or CFTR. Most other states perform a two-tier screen on the blood that first measures the concentration of the pancreatic enzyme that is elevated in CF. In babies with the highest levels of this enzyme, called immunoreactive trypsinogen (IRT), a secondary screen looks at a selected list of 23 to 140 CFTR mutations known to cause the disease.
According to lead investigator Danieli Salinas, MD, Division of Pediatric Pulmonology at CHLA, these CFTR mutation panels were built based on the most prevalent mutations among severely affected individuals, most of whom were Caucasians.
“If only a commercial panel is applied, a large number of diagnoses are missed among African Americans and Hispanics,” Salinas said. “Missing these causal mutations during newborn screening has the devastating consequence of not detecting CF in these individuals until later in life, when lung damage is already irreversible.”
In California, after detection of one CFTR mutation, the blood sample is sent for CFTR-DNA sequencing to rule out presence of a second pathogenic mutation. California has screened over 4 million newborns for CF since 2007, discovering that – in babies with two mutations – only about one third had classic CF symptoms. Two-thirds of the babies with sequence variants were not found to have CF as indicated by an abnormal chloride sweat test, considered to be the gold standard of CF diagnosis.
“The question became whether the babies in the second group (labeled CFTR-related metabolic syndrome or CRMS) really went on to develop CF, or if benign variants in CFTR were being detected that might never cause a clinical problem,” said senior author Richard B. Parad, MD, MPH.
The researchers evaluated the effect of a specific, common mild CFTR gene variant that is carried by nearly one of 10 people, the 5T allele. They followed the cohort of babies detected through CF newborn screening with a variant detected in both of their CFTR gene copies: one severe CF-causing mutation and one 5T allele. This cohort was followed over eight years to describe clinical outcomes. The researchers were able to generate risk predictions based on the “TG repeat” – a DNA repeating pattern of varying length found directly adjacent to 5T alleles.
Newborns with the 11 TG, a measurement of the length of the repeat, showed no signs of CF during eight years of follow-up. However, 6 percent of babies with the 12 TG developed the disease and nearly 40 percent of children with the 13 TG were considered to have CF within eight years of birth.
“The study’s conclusions show that, depending on the 5T-TG repeat length information, the risk of presenting a natural history consistent with CF can be anticipated,” said Parad. “Right now, these babies are not detected by CF newborn screening in states other than California. Instead of being detected in an asymptomatic state and followed closely, these babies later present with CF symptoms and may have missed an important opportunity to initiate early appropriate therapies during a window of protection that might improve their long term outcome.”
“Having CFTR-DNA sequencing as part of a newborn screening model can unveil the full spectrum of this disorder, through early detection of mild to severe cases in an ethnically diverse population,” added Salinas, who is also an assistant professor of Pediatrics and preventive medicine at the Keck School of Medicine at the University of Southern California. “Studies like this are important to better guide providers and families, by determining which individuals with which mutation combinations should be clinically monitored.”
Children’s Hospital Los Angeles
www.chla.org/press-release/dna-sequencing-uncovers-latent-risk-developing-cystic-fibrosis
Three manuscripts published recently explored the versatility of liquid biopsies by identifying EGFR mutations using circulatingu tumour DNA (ctDNA) in urine and plasma and examining circulating tumour cells (CTCs) in plasma to predict the risk of lung cancer recurrence after surgical resection. Collectively, these findings illustrate the potential and reach of liquid biopsies in both identifying patients suitable for targeted treatment as well as predicting cancer recurrence.
Lung cancer is the most common type of cancer with the highest cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for roughly 85% of lung cancer and most patients present with advanced disease at diagnosis. Surgical resection is the preferred treatment option for patients with medically operable tumours. However, disease recurrence occurs in approximately 50% of cases. Patients with advanced disease are often not candidates for surgical resection and commonly harbour driver mutations that can be targeted by drugs. A major challenge for assessing driver mutations, such as epidermal growth factor receptor (EGFR) mutations, in advanced disease is the scarcity of suitable biopsy tissue for molecular testing. A minimally invasive alternative to invasive tissue biopsy is the use of liquid biopsy, which analyses ctDNA or CTCs in a liquid biological sample (i.e. urine, blood, or serum).
The first manuscript entitled, Circulating Free Tumor-derived DNA (ctDNA) Determination of EGFR Mutation Status in Real-World European and Japanese Patients with Advanced NSCLC: the ASSESS Study, used samples from the large ASSESS study to evaluate EGFR mutation status by analysing ctDNA from blood plasma. The results of the study demonstrated that analysing ctDNA from plasma is feasible for the identification of EGFR mutations with mutation status concordance in 1,162 matched samples of 89% (sensitivity 46%; specificity 97%; positive predictive value [PPV] 78%; negative PV 90%). The authors comment that, “Accurate and accessible ctDNA mutation testing to address the unmet need in patients without an available/evaluable tumour sample will be important to enable more patients to receive therapies personalized to the mutation status of their tumor.”
The second manuscript entitled, A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma, analysed samples from patients enrolled in TIGER-X, a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC, to interrogate EGFR activating mutations and the T790M resistance mutation by analysing ctDNA from urine or blood plasma. The results from the study show that ctDNA derived from NSCLC tumours can be detected with high sensitivity in urine and plasma, sensitivity 93% for T790M, 80% L858R, and 83% exon 19 deletions and sensitivity 93% for T790M, 100% L858R, and 87% exon 19 deletions, respectively. The authors comment that, “In conclusion, our data demonstrates that urine testing using mutation enrichment NGS method successfully identifies EGFR mutations in patients with metastatic NSCLC and has a high concordance with tumour and plasma, suggesting that EGFR mutation detection from urine or plasma should be considered as a viable approach for assessing EGFR mutation status.”
Finally, a third manuscript on liquid biopsies entitled, Circulating tumour cells detected in the tumour-draining pulmonary vein are associated with disease recurrence after surgical resection of non-small cell lung cancer, used blood and tumour-draining pulmonary vein samples from patients pre-surgical resection and intra-operatively to analyse CTCs and circulating tumour microemboli (CTM, clusters). The investigators reported that combining CTC/CTM enumeration in tumour-draining pulmonary veins and peripheral blood at the time of curative-intent surgical resection of NSCLC better identifies those patients at higher risk of lung cancer recurrence than peripheral CTC/CTM numbers alone. “In addition to the potential role of CTCs as a prognostic/predictive biomarker, isolation and genetic analysis of individual CTCs from liquid biopsies may shed light on tumour biology and the metastatic process,” said Phil AJ Crosbie, MD, PhD, first author of the article.
The International Association for the Study of Lung Cancer
www.iaslc.org/news/liquid-biopsies-identification-egfr-mutations-and-prediction-lung-cancer-recurrence
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Scientists at The University of Nottingham have demonstrated for the first time that it is possible to selectively sequence fragments of DNA in real time, greatly reducing the time needed to analyse biological samples.
A paper describes a novel technique for highly selective DNA sequencing, called ‘Read Until’. The method, used with real-time nanopore sequencing, enables the user to analyse only DNA strands that contain pre-determined signatures of interest.
Dr Matt Loose, of the Cell and Developmental Biology Research Group in the University’s School of Life Sciences, has been working with the MinION, a new portable DNA sequencing technology produced by biotech company Oxford Nanopore Technologies. All sequencing was carried out at The University of Nottingham Next Generation Sequencing Facility, DeepSeq.
“This is the first time that direct selection of specific DNA molecules has been shown on any device,” said Dr Loose. “We hope that it will enable many future novel applications, especially for portable sequencing. This makes sequencing as efficient as possible and will provide a viable, informatics based alternative to traditional wet lab enrichment techniques. The application of this approach to a wide number of problems from pathogen detection to sequencing targeted regions of the human genome is now within reach.”
The pocket-sized MinION device – the same technology which NASA recently sent to the International Space Station in an effort to investigate whether DNA sequencing is possible in microgravity – employs tiny molecular pores in a membrane that ‘sense’ the sequence of DNA fragments passing through these nanopores, producing minute fluctuations in a current trace. These current traces, termed ‘squiggles’ then need to be converted to DNA bases using base caller software, often located in the cloud. The University of Nottingham team used signal processing techniques to map these squiggles to reference sequences, by passing this step.
In the paper, the Nottingham team go further, showing that this squiggle matching technique can be performed at a rate that enables decisions to be made about the fragment of DNA that is being sequenced before it has completely passed through the nanopore. Depending on the sequence, individual nanopores within the MinION can then be instructed to continue sequencing or to eject the current DNA fragment and start sequencing another. The Nottingham team show that this ‘real-time selective sequencing’, or as some have called it ‘DNA tasting’, can reduce the time needed to sequence key DNA fragments or enable the analysis of pathogen samples where there is host and other DNA present in the sample.
The Read Until method/technique was developed by applying dynamic time warping to match short query current traces to references, demonstrating selection of specific regions of small genomes, individual amplicons from a group of targets, or normalisation of amplicons in a set.
Nottingham University
www.nottingham.ac.uk/news/pressreleases/2016/july/nottingham-researchers-show-novel-technique-that-can-‘taste’-dna.aspx
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Scientists at the Stowers Institute for Medical Research have reported a detailed description of how function-impairing mutations in polr1c and polr1d genes cause Treacher Collins syndrome (TCS), a rare congenital craniofacial development disorder that affects an estimated 1 in 50,000 live births.
Collectively the results of the study reveal that a unifying cellular and biochemical mechanism underlies the etiology and pathogenesis of TCS and its possible prevention, irrespective of the causative gene mutation.
Loss-of-function mutations in three human genes, TCOF1, POLR1C and POLR1D, have been implicated in TCS and are thought to be responsible for about 90 percent of the diagnoses of this congenital craniofacial condition.
The clinical manifestations of TCS include facial anomalies such as small jaws and cleft palate, hearing loss, and respiratory problems. Patients with TCS typically undergo multiple surgeries, but rarely are they fully corrective. By uncovering a mechanism of action common to all three genes, Stowers scientists have advanced scientific understanding of TCS etiology and pathogenesis and identified possible new avenues for preventing or treating the birth defect. This latest study from the laboratory of Stowers Investigator Paul Trainor, Ph.D., focused on Polr1c and Polr1d, whose roles as a genetic cause of TCS were revealed in a 2011 study of a small group of patients who had been diagnosed with TCS but who did not have the TCOF1 mutation. Unlike POLR1C and POLR1D, TCOF1 has been long recognized as a causative gene in TCS and as a result has been more extensively investigated.
“Before we began the study, nothing was known about the role of Polr1c and Polr1d in craniofacial development,” said Kristin Watt, Ph.D., lead author of the PLoS Genetics paper and postdoctoral scientist in the Trainor Lab. “Using zebrafish as our animal model, we set out to explore the functional roles of polr1c and polr1d during embryogenesis and more specifically in craniofacial development.”
Trainor, Watt and their collaborators compared the results of their findings on polr1c and polr1d with their and other labs’ previous research results on Tcof1. In all three loss-of-function models, the researchers found that the chain of cellular events that led to the TCS phenotype of abnormal craniofacial development originated in ribosomes, the cellular components that translate messenger RNA into proteins. Like the Tcof1 gene, polr1c and polr1d mutations were found to perturb ribosome biogenesis, or production of ribosomes, which affects the generation and survival of progenitor neural crest cells, the precursors of craniofacial bone, cartilage and connective tissue.
In animal models of all three causative genes, the scientists determined that deficient ribosome biogenesis triggered a p53-dependent cell death mechanism in progenitor neural crest cells. As a result of the activation of the p53 gene, developing embryos no longer made the quantity of neural crest cells needed to properly form the craniofacial skeleton.
However, in the polr1c and polr1d models as in the Tcof1 models, Stowers scientists found that by experimentally blocking p53 activation, they could restore the neural crest cell population and thereby rescue the animal models’ cranioskeletal cartilage.
Despite the rescue effect, Trainor said that he does not view the “guardian of the genome,” as the p53 gene is often called due to its ability to suppress cancer, as the basis of a potential therapy to prevent or reduce TCS during embryonic development. The p53 gene’s association with cancer makes inhibiting its function too risky, he said.
A less risky and perhaps more effective target for the prevention or treatment of TCS could be enhancing ribosomes, Trainor said, because the loss-of-function mutations in all three causative genes involve ribosome RNA (rRNA) transcription. Polr1c and Polr1d, for example, are subunits of RNA polymerases I and III that are essential for ribosome biogenesis.
“Rather than blocking p53, a better approach may be to try to prevent TCS by treating the problem in ribosome biogenesis that triggers the activation of p53 and the loss of neural crest cells,” said Trainor.
In their research with zebrafish embryos, Trainor and collaborators also determined that polr1c and polr1d are spatiotemporally and dynamically expressed, particularly during craniofacial development. Furthermore, zebrafish embryos with the polr1c and polr1d loss-of-function mutations develop abnormalities in craniofacial cartilage development that mimic the clinical manifestations of TCS in patients. Trainor said that he and his fellow researchers were surprised that mutations in polr1c and polr1d as well as Tcof1 specifically affected craniofacial development, because ribosome biogenesis occurs in every cell of the body. The mutation of a gene that is part of the ribosome complex would be expected to be detrimental to each of these cells, he said. However, in the zebrafish models, the mutation appears to primarily affect progenitor neural crest cells. Trainor said that he and his team theorize that progenitor neural crest cells may be particularly sensitive to deficiencies in ribosome biogenesis during embryogenesis.
Thus, the study revealed new animal models for TCS: zebrafish with polr1c and polr1d loss-of-function mutations. Moreover, the existence of a common mechanism of action may simplify the research, particularly the search for a therapy to prevent or treat TCS. Because of the similarities among the three causative genes, “we may be able to develop creative ways of preventing TCS that will prove effective in at-risk individuals who have one of the gene mutations,” said Trainor, who has investigated the molecular origins and development of TCS and related craniofacial developmental disorders for 10 years.
Stowers Institute for Medical Research
www.stowers.org/media/news/jul-22-2016
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Researchers at the University of Rochester Medical Center recently discovered a genetic link between Long QT Syndrome (LQTS), a rare cardiac rhythm disease, and an increased risk for seizures. The study also found that people with LQTS who experience seizures are at greater risk of sudden cardiac death.
According to research, there is a clear association between the heart and the brain of LQTS patients. Patients carrying LQTS genetic mutations were three times more likely to have experienced seizures in their past, compared to their family members who did not carry those mutations. Interestingly, LQTS patients who had a history of seizures also tended to have worse cardiac symptoms.
David Auerbach, Ph.D., senior instructor of Medicine in the Aab Cardiovascular Research Institute of the University of Rochester Medical Center, and lead author of the study found seizure status to be the strongest predictor of cardiac arrhythmias – the abnormal heart rhythms characteristic of LQTS. In fact, about 20% of the LQTS patients in the study who had a history of seizures had survived at least one lethal cardiac arrhythmia.
You could begin applying these findings to patients today by telling physicians treating LQTS patients to look outside the heart.
Auerbach’s study set a new clinical precedence for the link between seizures and LQTS and provides a case for doctors to pay more attention to what is happening in LQTS patients’ brains or, more broadly, to “look outside the classic organ of interest” in any disease.
As a postdoctoral fellow, Auerbach studied the heart-brain connection in a severe genetic form of epilepsy, and found that cardiac arrhythmias were one cause of sudden unexplained death in people with epilepsy. Now, he investigates the converse – whether a genetic heart disorder is also associated with issues in the brain.
Auerbach tapped into the Rochester-based LQTS Patient Registry to answer this question. This unique resource was developed 40 years ago by the senior author of the study, Arthur Moss, M.D., the Bradford C. Berk, MD, PhD, Distinguished Professor of Medicine at URMC. The registry contains information about more than 18,000 people including LQTS patients and their affected and unaffected family members, who provide a nearly ideal group of controls. “In essence, they have the same genetic makeup, except theoretically, the LQTS-causing mutation,” says Auerbach.
To ensure that the seizures reported in the registry were not merely misdiagnosed cardiac arrhythmias, Auerbach investigated the effect of beta blockers, drugs often prescribed to LQTS patients to prevent cardiac arrhythmias. While the drugs effectively reduced patients’ arrhythmias, they had no effect on seizures, minimizing the chance that the seizures were simply misdiagnosed cardiac side effects.
Looking at the patients’ genetic information, Auerbach and his colleagues found that patients with the three different types of LQTS (LQTS1-3) showed similar heart rhythm symptoms, but vastly different prevalence of seizures. LQTS1 and LQTS2 patients had much higher prevalence of seizures than LQTS3 or no mutation – with LQTS2 at the greatest risk.
Further investigation of the LQTS-causing mutation showed that the specific location of the mutation greatly affected the risk of cardiac arrhythmias and seizures. In one location on the gene, the mutation protected against these symptoms, but in another location on the same gene, the mutation increased the risk of those symptoms. Understanding what each of these mutations does may shed new light on a basic mechanism of seizures and may provide viable therapeutic targets to treat LQTS.
The University of Rochester Medical Center
www.urmc.rochester.edu/news/story/4612/the-heart-brain-connection-the-link-between-lqts-and-seizures.aspx
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Researchers led by the University of Dundee’s Professor Dario Alessi have developed a new method of measuring the activity of disease-causing mutations in the LRRK2 gene, a major cause of inherited Parkinson’s disease.
The team believes this research could help pave the way for future development of a clinical test that could facilitate evaluation of drugs to target this form of the condition.
Mutations in the LRRK2 gene are the most common cause of genetic Parkinson’s disease. The most common disease-causing mutation in this gene increases the activity of the LRRK2 protein three-fold, implying this may contribute towards the symptoms of the disease in patients. It also suggests that drugs that reduce the activity of the protein (LRRK2 inhibitors) may help treat patients with this form of inherited Parkinson’s disease.
“It is important to better understand how disruption in LRRK2 biology causes Parkinson’s disease and whether a drug that targeted the LRRK2 enzyme would offer therapeutic benefit,” said Professor Alessi, lead author on the study.
“Current drug treatments only deal with symptoms of the condition, such as tremors, but do not affect the progression of Parkinson’s disease. An important question is whether an LRRK2 therapy might have potential to slow progression of the condition, which no other current therapy is able to do.”
When the LRRK2 protein is active it stops another cellular protein called Rab10 from fulfilling its function in the body. There are many proteins in the Rab family, and a number of them have been shown to be low in number or deactivated in different forms of Parkinson’s disease.
The new method of measuring these was developed by a collaboration of researchers from Dundee, The Michael J. Fox Foundation for Parkinson’s Research, GSK and the University of Hong Kong. It analyses how much of the Rab10 protein has been deactivated – a process where phosphate groups are added to the Rab10 molecules by the LRRK2 protein – as a measure of heightened LRRK2 protein activity.
This new experimental assay is straightforward, requires only small amounts of sample material and is suitable for adapting to analyse large samples. This contrast with current mass spectrometry technology that is more complex and cumbersome and requires larger sample sizes.
While acknowledging that more work is needed, the researchers believe this breakthrough could help with future drug developments for patients with this form of Parkinson’s disease.
Professor Alessi continued, “The prediction is that elevation of LRRK2 activity leads to Parkinson’s disease, and this is now testable using our assay. The expectation is that if a sub-group of patients can be identified with elevated LRRK2 activity, these individuals might benefit most from LRRK2 inhibitors.
University of Dundee
www.dundee.ac.uk/news/2016/lab-method-sheds-light-on-how-genetic-mutations-cause-inherited-parkinsons-disease.php
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Researchers at the University of Alabama at Birmingham have found that the amount of proteins excreted in the urine of preterm infants with acute kidney injury, or AKI, is different from that excreted by infants with healthy kidneys.
The study was led by principal investigator David Askenazi, M.D.
“The findings in this study could help physicians better diagnose kidney health in newborns,” said Askenazi, associate professor in the UAB Department of Pediatrics and director of UAB’s Pediatric and Infant Center for Acute Nephrology. “Having better diagnostic tests to diagnose kidney injury will have an important impact on how we care for infants and how we prognosticate outcomes, and will enable us to design studies to prevent and/or mitigate kidney damage in these very vulnerable babies.”
Improving the ability to diagnose AKI, a sudden decline in kidney function, is critical, as approximately 25 percent of preterm infants develop AKI. Compared to those without AKI, preterm infants with this common problem have a lower chance for survival, increased hospital stays and increased hospital expenditures.
Importantly, premature infants are at high risk for chronic kidney disease, and AKI may be an important cause for this.
Investigators took a single drop of urine from 113 preterm infants and measured 14 urine proteins. The concentrations of many of these proteins, including cystatin c, neutrophil gelatinase-associated lipocalin, osteopontin, clusterin and alpha glutathione S-transferase, were higher in preterm infants who later showed abnormal kidney function, compared to their counterparts with normal function.
“Additional studies to determine how AKI contributes to chronic kidney disease in these newborns are underway,” Askenazi said. “Improving our ability to diagnose AKI accurately is critical to improving our understanding of the natural course of disease and developing strategies to improve outcomes.”
University of Alabama at Birmingham
www.uab.edu/news/innovation/item/7485-acute-kidney-injury-identifiable-in-preterm-infants
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Not only is breast cancer more than one disease, but a single breast cancer tumour can vary within itself, a finding that University of Pittsburgh Cancer Institute (UPCI) researchers discovered has the potential to lead to very different patient treatment plans depending on the tumour sample and diagnostic testing used.
The results demonstrate that tumour sampling techniques used with newly developed “personalized medicine” gene expression profile tests may need to be refined to ensure that the most appropriate tumour sections are selected for testing.
“These tests are a good thing—they’ve done an incredible job identifying women with breast cancers that have a low risk of recurrence who don’t need chemotherapy, saving them from the toxicity and discomfort of unnecessary treatment,” said Adrian V. Lee, Ph.D., professor of pharmacology and chemical biology at UPCI, partner with UPMC CancerCenter. “However, as with any new technology, we need to understand how these tests work, and we’re finding that the sampling process, which involves liquefying tumours, loses information that could be important in determining the best treatment plan for patients with more aggressive tumours.”
Gene expression profiling is an increasingly popular type of test that tells doctors what certain genes are doing in a tissue sample, such as causing the cells to actively divide and multiply. Several tests have been developed in recent years to aid oncologists in developing breast cancer treatment plans. They involve taking a small bit of the tumour—or multiple small bits mixed together—and testing it.
The tests can tell oncologists if the cancer has a low, intermediate or high risk of recurring. The level of risk can help doctors and patients decide whether an aggressive treatment plan involving chemotherapy is beneficial or likely to do more harm than good.
Dr. Lee and his team examined 71 cases of a type of breast cancer called “estrogen-receptor-positive” that was caught early and hadn’t yet spread to other parts of the body. In all cases, the tumour had been removed and samples taken for gene expression profiling. A total of 181 samples were taken from various parts of the tumours, and the researchers measured the expression of 141 different genes from five different types of gene expression profile tests commonly used for breast cancer tumours.
For 25 percent of the patients, their tumours received a different risk of recurrence score depending on which sample was processed.
“This indicates that one part of the tumour is more aggressive than another part. If an oncologist were to know this, he or she would likely recommend a treatment plan tailored to destroy the most aggressive section of the tumour,” said Dr. Lee.
Because the patients in this study were all caught early, their risk of recurrence was low to begin with, and there weren’t enough recurrences to make a meaningful determination on whether they would have done better if more samples were tested from their tumours.
“It would be valuable to repeat this study with a much larger group of breast cancer patients and follow them over time so that we could definitively determine if the way sampling is done with these tests is, indeed, resulting in patients getting cancer recurrences that wouldn’t have happened if the sampling process was changed,” said Dr. Lee.
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Prostate cancer patients have been offered hope after scientists at Newcastle University have identified a new group of molecules that could be targeted to slow tumour growth.
Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically.
Experts used an advanced screening technique which found hundreds of genes were affected by the male hormone testosterone. It is believed this could lead to new diagnostic tests and treatments.
Among the 700 genes identified was an important set that add sugar groups – known as glycans – to the surface of prostate cancer cells. This group has never been investigated before.
Treatments targeting glycan sugar groups have been developed for other types of the illness, such as breast cancer. It is hoped these treatments could also be used for prostate cancer.
Results of the research suggest that testosterone changes glycans to make cancer cells more likely to survive, grow and spread to other parts of the body.
Scientists say there is the potential to target these glycans which could stop the growth and spread of tumours and save lives.
Dr Jennifer Munkley, Research Associate at the Institute of Genetic Medicine, Newcastle University, co-led the three-year research project with Professor David Elliott.
She said: “Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically.
“Now we have identified these glycans we will be able to develop strategies to inhibit them and help patients with this condition.
Glycans have the potential to be used as part of a diagnostic test to help doctors decide which prostate cancers need treatment.
One in eight men will be diagnosed with the condition. It is the most common cancer in UK males, and there is a need to identify how the disease progresses and for treatment options to be established.
Researchers at Newcastle University used a technique, called RNA-sequencing, to identify the new set of genes that are important.
The genes identified may provide novel ways the disease can be monitored in patients to predict the most aggressive prostate cancers that need to be treated.
Simon Grieveson, Head of Research Funding at Prostate Cancer UK, said: “There’s a desperate need for more treatments for men with advanced prostate cancer, who currently have too few options available to them.
“However, in order to develop new, effective treatments, we need to understand more about the genetic makeup of aggressive prostate cancers and identify what makes them tick.
“This promising research has unearthed a new group of genes which could play a part in cancer cell survival and development, and could pave the way for new treatments in the future.
Newcastle University
www.ncl.ac.uk/press/news/2016/07/prostatecancerstudy/
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 09:33:212021-01-08 11:10:02Prostate cancer study may lead to new diagnostic tests and treatments
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New gene variants present in 3 percent of all ALS patients
, /in E-News /by 3wmediaVariations in a gene with multiple functions in neurons are present in approximately 3 percent of all cases of ALS in North American and European populations, both sporadic and familial, making it one of the most common genetic causes of the disease, according to a paper. Led by John Landers, PhD, professor of neurology at UMass Medical School and Jan Veldink, PhD, at University Medical Center Utrecht in the Netherlands, the research was supported by The ALS Association through Project MinE, an international collaboration for gene discovery in ALS, and funded through ALS Ice Bucket donations.
ALS (amyotrophic lateral sclerosis) is a progressive neurodegenerative disease that affects neurons in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. While 10 percent of ALS is familial, meaning it’s genetic, the other 90 percent of ALS cases are considered sporadic, or without a family history. However, it’s very likely that genetics contribute, directly or indirectly, to a much larger percentage of ALS cases.
“The discovery of NEK1 highlights the value of big data in ALS research,” said Lucie Bruijn, PhD, MBA, of The ALS Association. “The sophisticated gene analysis that led to this finding was only possible because of the large number of ALS samples available. The ALS Ice Bucket Challenge enabled The ALS Association to invest in Project MinE’s work to create large biorepositories of ALS biosamples that are designed to allow exactly this kind of research and to produce exactly this kind of result.”
The new gene, called NEK1, was discovered through a genome-wide search for ALS risk genes in more than 1,000 ALS families, and was independently found through different means in an isolated population in the Netherlands. Further analysis in more than 13,000 sporadic ALS individuals compared to controls again revealed the overrepresentation of variants in the same gene. The variations discovered in the gene sequence are predicted to lead to a loss of function of the gene. NEK1 is known to have multiple roles in neurons, including maintenance of the cytoskeleton that gives the neuron its shape and promotes transport within the neuron. In addition, NEK1 has roles in regulating the membrane of the mitochondrion, which supplies energy to neurons, and in repairing DNA. Disruption of each of these functions through other means has been linked to increased risk of ALS.
Understanding the role of NEK1 in disease will provide an important new target for therapy development. The ALS Association is currently funding Landers and Catherine Lutz, PhD, senior research scientist at the Jackson Laboratories in Bar Harbour, Maine, to develop novel mouse models to better understand the consequences of the loss of the protein’s function for the ALS disease process. They will provide rapid access to these models for the broader ALS research community as soon as they are generated. These tools are important for ALS drug development.
UMass Medical School www.umassmed.edu/news/news-archives/2016/07/new-gene-variants-present-in-3-percent-of-all-als-patients/
DNA sequencing uncovers latent risk for developing cystic fibrosis
, /in E-News /by 3wmediaA study by researchers at Children’s Hospital Los Angeles (CHLA), Brigham and Women’s Hospital and the California Department of Public Health suggests that all babies with a known mutation for cystic fibrosis (CF) and second mutation called the 5T allele should receive additional screening in order to better predict the risk of developing CF later in life.
The results indicate that adding specific DNA sequencing to current newborn screenings would allow for early diagnosis in ethnically diverse populations and may increase the number of CF diagnoses in the U.S. over time. Such diagnoses could result in earlier treatment of CF, which could ultimately improve the outcome and prolong the life of a child with the disease.
Newborn screening programs, using a simple blood test taken within 24 to 48 hours of a child’s birth, allow for early detection and treatment of often devastating disorders. In the U.S., millions of newborns are screened each year, and early testing for CF – a progressive, genetic disease that causes persistent lung infections – has been implemented in all 50 states since 2010. CF is an autosomal recessive disorder, meaning that the child must inherit two copies of an abnormal gene in order for the disease to develop.
Each state uses a different screening algorithm to detect newborns with CF. California has implemented a unique algorithm which incorporates full sequencing of the gene responsible for CF, called the CF Transmembrane Conductance Regulator or CFTR. Most other states perform a two-tier screen on the blood that first measures the concentration of the pancreatic enzyme that is elevated in CF. In babies with the highest levels of this enzyme, called immunoreactive trypsinogen (IRT), a secondary screen looks at a selected list of 23 to 140 CFTR mutations known to cause the disease.
According to lead investigator Danieli Salinas, MD, Division of Pediatric Pulmonology at CHLA, these CFTR mutation panels were built based on the most prevalent mutations among severely affected individuals, most of whom were Caucasians.
“If only a commercial panel is applied, a large number of diagnoses are missed among African Americans and Hispanics,” Salinas said. “Missing these causal mutations during newborn screening has the devastating consequence of not detecting CF in these individuals until later in life, when lung damage is already irreversible.”
In California, after detection of one CFTR mutation, the blood sample is sent for CFTR-DNA sequencing to rule out presence of a second pathogenic mutation. California has screened over 4 million newborns for CF since 2007, discovering that – in babies with two mutations – only about one third had classic CF symptoms. Two-thirds of the babies with sequence variants were not found to have CF as indicated by an abnormal chloride sweat test, considered to be the gold standard of CF diagnosis.
“The question became whether the babies in the second group (labeled CFTR-related metabolic syndrome or CRMS) really went on to develop CF, or if benign variants in CFTR were being detected that might never cause a clinical problem,” said senior author Richard B. Parad, MD, MPH.
The researchers evaluated the effect of a specific, common mild CFTR gene variant that is carried by nearly one of 10 people, the 5T allele. They followed the cohort of babies detected through CF newborn screening with a variant detected in both of their CFTR gene copies: one severe CF-causing mutation and one 5T allele. This cohort was followed over eight years to describe clinical outcomes. The researchers were able to generate risk predictions based on the “TG repeat” – a DNA repeating pattern of varying length found directly adjacent to 5T alleles.
Newborns with the 11 TG, a measurement of the length of the repeat, showed no signs of CF during eight years of follow-up. However, 6 percent of babies with the 12 TG developed the disease and nearly 40 percent of children with the 13 TG were considered to have CF within eight years of birth.
“The study’s conclusions show that, depending on the 5T-TG repeat length information, the risk of presenting a natural history consistent with CF can be anticipated,” said Parad. “Right now, these babies are not detected by CF newborn screening in states other than California. Instead of being detected in an asymptomatic state and followed closely, these babies later present with CF symptoms and may have missed an important opportunity to initiate early appropriate therapies during a window of protection that might improve their long term outcome.”
“Having CFTR-DNA sequencing as part of a newborn screening model can unveil the full spectrum of this disorder, through early detection of mild to severe cases in an ethnically diverse population,” added Salinas, who is also an assistant professor of Pediatrics and preventive medicine at the Keck School of Medicine at the University of Southern California. “Studies like this are important to better guide providers and families, by determining which individuals with which mutation combinations should be clinically monitored.”
Children’s Hospital Los Angeles www.chla.org/press-release/dna-sequencing-uncovers-latent-risk-developing-cystic-fibrosis
Identification of EGFR mutations and prediction of lung cancer recurrence
, /in E-News /by 3wmediaThree manuscripts published recently explored the versatility of liquid biopsies by identifying EGFR mutations using circulatingu tumour DNA (ctDNA) in urine and plasma and examining circulating tumour cells (CTCs) in plasma to predict the risk of lung cancer recurrence after surgical resection. Collectively, these findings illustrate the potential and reach of liquid biopsies in both identifying patients suitable for targeted treatment as well as predicting cancer recurrence.
Lung cancer is the most common type of cancer with the highest cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for roughly 85% of lung cancer and most patients present with advanced disease at diagnosis. Surgical resection is the preferred treatment option for patients with medically operable tumours. However, disease recurrence occurs in approximately 50% of cases. Patients with advanced disease are often not candidates for surgical resection and commonly harbour driver mutations that can be targeted by drugs. A major challenge for assessing driver mutations, such as epidermal growth factor receptor (EGFR) mutations, in advanced disease is the scarcity of suitable biopsy tissue for molecular testing. A minimally invasive alternative to invasive tissue biopsy is the use of liquid biopsy, which analyses ctDNA or CTCs in a liquid biological sample (i.e. urine, blood, or serum).
The first manuscript entitled, Circulating Free Tumor-derived DNA (ctDNA) Determination of EGFR Mutation Status in Real-World European and Japanese Patients with Advanced NSCLC: the ASSESS Study, used samples from the large ASSESS study to evaluate EGFR mutation status by analysing ctDNA from blood plasma. The results of the study demonstrated that analysing ctDNA from plasma is feasible for the identification of EGFR mutations with mutation status concordance in 1,162 matched samples of 89% (sensitivity 46%; specificity 97%; positive predictive value [PPV] 78%; negative PV 90%). The authors comment that, “Accurate and accessible ctDNA mutation testing to address the unmet need in patients without an available/evaluable tumour sample will be important to enable more patients to receive therapies personalized to the mutation status of their tumor.”
The second manuscript entitled, A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma, analysed samples from patients enrolled in TIGER-X, a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC, to interrogate EGFR activating mutations and the T790M resistance mutation by analysing ctDNA from urine or blood plasma. The results from the study show that ctDNA derived from NSCLC tumours can be detected with high sensitivity in urine and plasma, sensitivity 93% for T790M, 80% L858R, and 83% exon 19 deletions and sensitivity 93% for T790M, 100% L858R, and 87% exon 19 deletions, respectively. The authors comment that, “In conclusion, our data demonstrates that urine testing using mutation enrichment NGS method successfully identifies EGFR mutations in patients with metastatic NSCLC and has a high concordance with tumour and plasma, suggesting that EGFR mutation detection from urine or plasma should be considered as a viable approach for assessing EGFR mutation status.”
Finally, a third manuscript on liquid biopsies entitled, Circulating tumour cells detected in the tumour-draining pulmonary vein are associated with disease recurrence after surgical resection of non-small cell lung cancer, used blood and tumour-draining pulmonary vein samples from patients pre-surgical resection and intra-operatively to analyse CTCs and circulating tumour microemboli (CTM, clusters). The investigators reported that combining CTC/CTM enumeration in tumour-draining pulmonary veins and peripheral blood at the time of curative-intent surgical resection of NSCLC better identifies those patients at higher risk of lung cancer recurrence than peripheral CTC/CTM numbers alone. “In addition to the potential role of CTCs as a prognostic/predictive biomarker, isolation and genetic analysis of individual CTCs from liquid biopsies may shed light on tumour biology and the metastatic process,” said Phil AJ Crosbie, MD, PhD, first author of the article.
The International Association for the Study of Lung Cancer www.iaslc.org/news/liquid-biopsies-identification-egfr-mutations-and-prediction-lung-cancer-recurrence
Novel technique that can ‘taste’ DNA
, /in E-News /by 3wmediaScientists at The University of Nottingham have demonstrated for the first time that it is possible to selectively sequence fragments of DNA in real time, greatly reducing the time needed to analyse biological samples.
A paper describes a novel technique for highly selective DNA sequencing, called ‘Read Until’. The method, used with real-time nanopore sequencing, enables the user to analyse only DNA strands that contain pre-determined signatures of interest.
Dr Matt Loose, of the Cell and Developmental Biology Research Group in the University’s School of Life Sciences, has been working with the MinION, a new portable DNA sequencing technology produced by biotech company Oxford Nanopore Technologies. All sequencing was carried out at The University of Nottingham Next Generation Sequencing Facility, DeepSeq.
“This is the first time that direct selection of specific DNA molecules has been shown on any device,” said Dr Loose. “We hope that it will enable many future novel applications, especially for portable sequencing. This makes sequencing as efficient as possible and will provide a viable, informatics based alternative to traditional wet lab enrichment techniques. The application of this approach to a wide number of problems from pathogen detection to sequencing targeted regions of the human genome is now within reach.”
The pocket-sized MinION device – the same technology which NASA recently sent to the International Space Station in an effort to investigate whether DNA sequencing is possible in microgravity – employs tiny molecular pores in a membrane that ‘sense’ the sequence of DNA fragments passing through these nanopores, producing minute fluctuations in a current trace. These current traces, termed ‘squiggles’ then need to be converted to DNA bases using base caller software, often located in the cloud. The University of Nottingham team used signal processing techniques to map these squiggles to reference sequences, by passing this step.
In the paper, the Nottingham team go further, showing that this squiggle matching technique can be performed at a rate that enables decisions to be made about the fragment of DNA that is being sequenced before it has completely passed through the nanopore. Depending on the sequence, individual nanopores within the MinION can then be instructed to continue sequencing or to eject the current DNA fragment and start sequencing another. The Nottingham team show that this ‘real-time selective sequencing’, or as some have called it ‘DNA tasting’, can reduce the time needed to sequence key DNA fragments or enable the analysis of pathogen samples where there is host and other DNA present in the sample.
The Read Until method/technique was developed by applying dynamic time warping to match short query current traces to references, demonstrating selection of specific regions of small genomes, individual amplicons from a group of targets, or normalisation of amplicons in a set.
Nottingham University www.nottingham.ac.uk/news/pressreleases/2016/july/nottingham-researchers-show-novel-technique-that-can-‘taste’-dna.aspx
Similarities unite three distinct gene mutations of Treacher Collins Syndrome
, /in E-News /by 3wmediaScientists at the Stowers Institute for Medical Research have reported a detailed description of how function-impairing mutations in polr1c and polr1d genes cause Treacher Collins syndrome (TCS), a rare congenital craniofacial development disorder that affects an estimated 1 in 50,000 live births.
Collectively the results of the study reveal that a unifying cellular and biochemical mechanism underlies the etiology and pathogenesis of TCS and its possible prevention, irrespective of the causative gene mutation.
Loss-of-function mutations in three human genes, TCOF1, POLR1C and POLR1D, have been implicated in TCS and are thought to be responsible for about 90 percent of the diagnoses of this congenital craniofacial condition.
The clinical manifestations of TCS include facial anomalies such as small jaws and cleft palate, hearing loss, and respiratory problems. Patients with TCS typically undergo multiple surgeries, but rarely are they fully corrective. By uncovering a mechanism of action common to all three genes, Stowers scientists have advanced scientific understanding of TCS etiology and pathogenesis and identified possible new avenues for preventing or treating the birth defect. This latest study from the laboratory of Stowers Investigator Paul Trainor, Ph.D., focused on Polr1c and Polr1d, whose roles as a genetic cause of TCS were revealed in a 2011 study of a small group of patients who had been diagnosed with TCS but who did not have the TCOF1 mutation. Unlike POLR1C and POLR1D, TCOF1 has been long recognized as a causative gene in TCS and as a result has been more extensively investigated.
“Before we began the study, nothing was known about the role of Polr1c and Polr1d in craniofacial development,” said Kristin Watt, Ph.D., lead author of the PLoS Genetics paper and postdoctoral scientist in the Trainor Lab. “Using zebrafish as our animal model, we set out to explore the functional roles of polr1c and polr1d during embryogenesis and more specifically in craniofacial development.”
Trainor, Watt and their collaborators compared the results of their findings on polr1c and polr1d with their and other labs’ previous research results on Tcof1. In all three loss-of-function models, the researchers found that the chain of cellular events that led to the TCS phenotype of abnormal craniofacial development originated in ribosomes, the cellular components that translate messenger RNA into proteins. Like the Tcof1 gene, polr1c and polr1d mutations were found to perturb ribosome biogenesis, or production of ribosomes, which affects the generation and survival of progenitor neural crest cells, the precursors of craniofacial bone, cartilage and connective tissue.
In animal models of all three causative genes, the scientists determined that deficient ribosome biogenesis triggered a p53-dependent cell death mechanism in progenitor neural crest cells. As a result of the activation of the p53 gene, developing embryos no longer made the quantity of neural crest cells needed to properly form the craniofacial skeleton.
However, in the polr1c and polr1d models as in the Tcof1 models, Stowers scientists found that by experimentally blocking p53 activation, they could restore the neural crest cell population and thereby rescue the animal models’ cranioskeletal cartilage.
Despite the rescue effect, Trainor said that he does not view the “guardian of the genome,” as the p53 gene is often called due to its ability to suppress cancer, as the basis of a potential therapy to prevent or reduce TCS during embryonic development. The p53 gene’s association with cancer makes inhibiting its function too risky, he said.
A less risky and perhaps more effective target for the prevention or treatment of TCS could be enhancing ribosomes, Trainor said, because the loss-of-function mutations in all three causative genes involve ribosome RNA (rRNA) transcription. Polr1c and Polr1d, for example, are subunits of RNA polymerases I and III that are essential for ribosome biogenesis.
“Rather than blocking p53, a better approach may be to try to prevent TCS by treating the problem in ribosome biogenesis that triggers the activation of p53 and the loss of neural crest cells,” said Trainor.
In their research with zebrafish embryos, Trainor and collaborators also determined that polr1c and polr1d are spatiotemporally and dynamically expressed, particularly during craniofacial development. Furthermore, zebrafish embryos with the polr1c and polr1d loss-of-function mutations develop abnormalities in craniofacial cartilage development that mimic the clinical manifestations of TCS in patients. Trainor said that he and his fellow researchers were surprised that mutations in polr1c and polr1d as well as Tcof1 specifically affected craniofacial development, because ribosome biogenesis occurs in every cell of the body. The mutation of a gene that is part of the ribosome complex would be expected to be detrimental to each of these cells, he said. However, in the zebrafish models, the mutation appears to primarily affect progenitor neural crest cells. Trainor said that he and his team theorize that progenitor neural crest cells may be particularly sensitive to deficiencies in ribosome biogenesis during embryogenesis.
Thus, the study revealed new animal models for TCS: zebrafish with polr1c and polr1d loss-of-function mutations. Moreover, the existence of a common mechanism of action may simplify the research, particularly the search for a therapy to prevent or treat TCS. Because of the similarities among the three causative genes, “we may be able to develop creative ways of preventing TCS that will prove effective in at-risk individuals who have one of the gene mutations,” said Trainor, who has investigated the molecular origins and development of TCS and related craniofacial developmental disorders for 10 years.
Stowers Institute for Medical Research www.stowers.org/media/news/jul-22-2016
The Heart-Brain Connection: The link between LQTS and seizures
, /in E-News /by 3wmediaResearchers at the University of Rochester Medical Center recently discovered a genetic link between Long QT Syndrome (LQTS), a rare cardiac rhythm disease, and an increased risk for seizures. The study also found that people with LQTS who experience seizures are at greater risk of sudden cardiac death.
According to research, there is a clear association between the heart and the brain of LQTS patients. Patients carrying LQTS genetic mutations were three times more likely to have experienced seizures in their past, compared to their family members who did not carry those mutations. Interestingly, LQTS patients who had a history of seizures also tended to have worse cardiac symptoms.
David Auerbach, Ph.D., senior instructor of Medicine in the Aab Cardiovascular Research Institute of the University of Rochester Medical Center, and lead author of the study found seizure status to be the strongest predictor of cardiac arrhythmias – the abnormal heart rhythms characteristic of LQTS. In fact, about 20% of the LQTS patients in the study who had a history of seizures had survived at least one lethal cardiac arrhythmia.
You could begin applying these findings to patients today by telling physicians treating LQTS patients to look outside the heart.
Auerbach’s study set a new clinical precedence for the link between seizures and LQTS and provides a case for doctors to pay more attention to what is happening in LQTS patients’ brains or, more broadly, to “look outside the classic organ of interest” in any disease.
As a postdoctoral fellow, Auerbach studied the heart-brain connection in a severe genetic form of epilepsy, and found that cardiac arrhythmias were one cause of sudden unexplained death in people with epilepsy. Now, he investigates the converse – whether a genetic heart disorder is also associated with issues in the brain.
Auerbach tapped into the Rochester-based LQTS Patient Registry to answer this question. This unique resource was developed 40 years ago by the senior author of the study, Arthur Moss, M.D., the Bradford C. Berk, MD, PhD, Distinguished Professor of Medicine at URMC. The registry contains information about more than 18,000 people including LQTS patients and their affected and unaffected family members, who provide a nearly ideal group of controls. “In essence, they have the same genetic makeup, except theoretically, the LQTS-causing mutation,” says Auerbach.
To ensure that the seizures reported in the registry were not merely misdiagnosed cardiac arrhythmias, Auerbach investigated the effect of beta blockers, drugs often prescribed to LQTS patients to prevent cardiac arrhythmias. While the drugs effectively reduced patients’ arrhythmias, they had no effect on seizures, minimizing the chance that the seizures were simply misdiagnosed cardiac side effects.
Looking at the patients’ genetic information, Auerbach and his colleagues found that patients with the three different types of LQTS (LQTS1-3) showed similar heart rhythm symptoms, but vastly different prevalence of seizures. LQTS1 and LQTS2 patients had much higher prevalence of seizures than LQTS3 or no mutation – with LQTS2 at the greatest risk.
Further investigation of the LQTS-causing mutation showed that the specific location of the mutation greatly affected the risk of cardiac arrhythmias and seizures. In one location on the gene, the mutation protected against these symptoms, but in another location on the same gene, the mutation increased the risk of those symptoms. Understanding what each of these mutations does may shed new light on a basic mechanism of seizures and may provide viable therapeutic targets to treat LQTS.
The University of Rochester Medical Center www.urmc.rochester.edu/news/story/4612/the-heart-brain-connection-the-link-between-lqts-and-seizures.aspx
Method sheds light on how genetic mutations cause inherited Parkinson’s disease
, /in E-News /by 3wmediaResearchers led by the University of Dundee’s Professor Dario Alessi have developed a new method of measuring the activity of disease-causing mutations in the LRRK2 gene, a major cause of inherited Parkinson’s disease.
The team believes this research could help pave the way for future development of a clinical test that could facilitate evaluation of drugs to target this form of the condition.
Mutations in the LRRK2 gene are the most common cause of genetic Parkinson’s disease. The most common disease-causing mutation in this gene increases the activity of the LRRK2 protein three-fold, implying this may contribute towards the symptoms of the disease in patients. It also suggests that drugs that reduce the activity of the protein (LRRK2 inhibitors) may help treat patients with this form of inherited Parkinson’s disease.
“It is important to better understand how disruption in LRRK2 biology causes Parkinson’s disease and whether a drug that targeted the LRRK2 enzyme would offer therapeutic benefit,” said Professor Alessi, lead author on the study.
“Current drug treatments only deal with symptoms of the condition, such as tremors, but do not affect the progression of Parkinson’s disease. An important question is whether an LRRK2 therapy might have potential to slow progression of the condition, which no other current therapy is able to do.”
When the LRRK2 protein is active it stops another cellular protein called Rab10 from fulfilling its function in the body. There are many proteins in the Rab family, and a number of them have been shown to be low in number or deactivated in different forms of Parkinson’s disease.
The new method of measuring these was developed by a collaboration of researchers from Dundee, The Michael J. Fox Foundation for Parkinson’s Research, GSK and the University of Hong Kong. It analyses how much of the Rab10 protein has been deactivated – a process where phosphate groups are added to the Rab10 molecules by the LRRK2 protein – as a measure of heightened LRRK2 protein activity.
This new experimental assay is straightforward, requires only small amounts of sample material and is suitable for adapting to analyse large samples. This contrast with current mass spectrometry technology that is more complex and cumbersome and requires larger sample sizes.
While acknowledging that more work is needed, the researchers believe this breakthrough could help with future drug developments for patients with this form of Parkinson’s disease.
Professor Alessi continued, “The prediction is that elevation of LRRK2 activity leads to Parkinson’s disease, and this is now testable using our assay. The expectation is that if a sub-group of patients can be identified with elevated LRRK2 activity, these individuals might benefit most from LRRK2 inhibitors.
University of Dundee www.dundee.ac.uk/news/2016/lab-method-sheds-light-on-how-genetic-mutations-cause-inherited-parkinsons-disease.php
Acute kidney injury identifiable in preterm infants
, /in E-News /by 3wmediaResearchers at the University of Alabama at Birmingham have found that the amount of proteins excreted in the urine of preterm infants with acute kidney injury, or AKI, is different from that excreted by infants with healthy kidneys.
The study was led by principal investigator David Askenazi, M.D.
“The findings in this study could help physicians better diagnose kidney health in newborns,” said Askenazi, associate professor in the UAB Department of Pediatrics and director of UAB’s Pediatric and Infant Center for Acute Nephrology. “Having better diagnostic tests to diagnose kidney injury will have an important impact on how we care for infants and how we prognosticate outcomes, and will enable us to design studies to prevent and/or mitigate kidney damage in these very vulnerable babies.”
Improving the ability to diagnose AKI, a sudden decline in kidney function, is critical, as approximately 25 percent of preterm infants develop AKI. Compared to those without AKI, preterm infants with this common problem have a lower chance for survival, increased hospital stays and increased hospital expenditures.
Importantly, premature infants are at high risk for chronic kidney disease, and AKI may be an important cause for this.
Investigators took a single drop of urine from 113 preterm infants and measured 14 urine proteins. The concentrations of many of these proteins, including cystatin c, neutrophil gelatinase-associated lipocalin, osteopontin, clusterin and alpha glutathione S-transferase, were higher in preterm infants who later showed abnormal kidney function, compared to their counterparts with normal function.
“Additional studies to determine how AKI contributes to chronic kidney disease in these newborns are underway,” Askenazi said. “Improving our ability to diagnose AKI accurately is critical to improving our understanding of the natural course of disease and developing strategies to improve outcomes.”
University of Alabama at Birmingham www.uab.edu/news/innovation/item/7485-acute-kidney-injury-identifiable-in-preterm-infants
Sampling method used for new breast cancer tests may lead to underestimate of risk
, /in E-News /by 3wmediaNot only is breast cancer more than one disease, but a single breast cancer tumour can vary within itself, a finding that University of Pittsburgh Cancer Institute (UPCI) researchers discovered has the potential to lead to very different patient treatment plans depending on the tumour sample and diagnostic testing used.
The results demonstrate that tumour sampling techniques used with newly developed “personalized medicine” gene expression profile tests may need to be refined to ensure that the most appropriate tumour sections are selected for testing.
“These tests are a good thing—they’ve done an incredible job identifying women with breast cancers that have a low risk of recurrence who don’t need chemotherapy, saving them from the toxicity and discomfort of unnecessary treatment,” said Adrian V. Lee, Ph.D., professor of pharmacology and chemical biology at UPCI, partner with UPMC CancerCenter. “However, as with any new technology, we need to understand how these tests work, and we’re finding that the sampling process, which involves liquefying tumours, loses information that could be important in determining the best treatment plan for patients with more aggressive tumours.”
Gene expression profiling is an increasingly popular type of test that tells doctors what certain genes are doing in a tissue sample, such as causing the cells to actively divide and multiply. Several tests have been developed in recent years to aid oncologists in developing breast cancer treatment plans. They involve taking a small bit of the tumour—or multiple small bits mixed together—and testing it.
The tests can tell oncologists if the cancer has a low, intermediate or high risk of recurring. The level of risk can help doctors and patients decide whether an aggressive treatment plan involving chemotherapy is beneficial or likely to do more harm than good.
Dr. Lee and his team examined 71 cases of a type of breast cancer called “estrogen-receptor-positive” that was caught early and hadn’t yet spread to other parts of the body. In all cases, the tumour had been removed and samples taken for gene expression profiling. A total of 181 samples were taken from various parts of the tumours, and the researchers measured the expression of 141 different genes from five different types of gene expression profile tests commonly used for breast cancer tumours.
For 25 percent of the patients, their tumours received a different risk of recurrence score depending on which sample was processed.
“This indicates that one part of the tumour is more aggressive than another part. If an oncologist were to know this, he or she would likely recommend a treatment plan tailored to destroy the most aggressive section of the tumour,” said Dr. Lee.
Because the patients in this study were all caught early, their risk of recurrence was low to begin with, and there weren’t enough recurrences to make a meaningful determination on whether they would have done better if more samples were tested from their tumours.
“It would be valuable to repeat this study with a much larger group of breast cancer patients and follow them over time so that we could definitively determine if the way sampling is done with these tests is, indeed, resulting in patients getting cancer recurrences that wouldn’t have happened if the sampling process was changed,” said Dr. Lee.
University of Pittsburgh Cancer Institute
www.upmc.com/media/NewsReleases/2016/Pages/lee-tumorhetero-gep-cancerresearch.aspxProstate cancer study may lead to new diagnostic tests and treatments
, /in E-News /by 3wmediaProstate cancer patients have been offered hope after scientists at Newcastle University have identified a new group of molecules that could be targeted to slow tumour growth.
Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically.
Experts used an advanced screening technique which found hundreds of genes were affected by the male hormone testosterone. It is believed this could lead to new diagnostic tests and treatments.
Among the 700 genes identified was an important set that add sugar groups – known as glycans – to the surface of prostate cancer cells. This group has never been investigated before.
Treatments targeting glycan sugar groups have been developed for other types of the illness, such as breast cancer. It is hoped these treatments could also be used for prostate cancer.
Results of the research suggest that testosterone changes glycans to make cancer cells more likely to survive, grow and spread to other parts of the body.
Scientists say there is the potential to target these glycans which could stop the growth and spread of tumours and save lives.
Dr Jennifer Munkley, Research Associate at the Institute of Genetic Medicine, Newcastle University, co-led the three-year research project with Professor David Elliott.
She said: “Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically.
“Now we have identified these glycans we will be able to develop strategies to inhibit them and help patients with this condition.
Glycans have the potential to be used as part of a diagnostic test to help doctors decide which prostate cancers need treatment.
One in eight men will be diagnosed with the condition. It is the most common cancer in UK males, and there is a need to identify how the disease progresses and for treatment options to be established.
Researchers at Newcastle University used a technique, called RNA-sequencing, to identify the new set of genes that are important.
The genes identified may provide novel ways the disease can be monitored in patients to predict the most aggressive prostate cancers that need to be treated.
Simon Grieveson, Head of Research Funding at Prostate Cancer UK, said: “There’s a desperate need for more treatments for men with advanced prostate cancer, who currently have too few options available to them.
“However, in order to develop new, effective treatments, we need to understand more about the genetic makeup of aggressive prostate cancers and identify what makes them tick.
“This promising research has unearthed a new group of genes which could play a part in cancer cell survival and development, and could pave the way for new treatments in the future.
Newcastle University www.ncl.ac.uk/press/news/2016/07/prostatecancerstudy/