Human sperm may hold the potential to serve as biomarkers of the future health of newborn infants, according to a new study by a Wayne State University School of Medicine research team. The study, “Sperm RNA elements as markers of health,” from the lab of Stephen Krawetz, Ph.D., the Charlotte B. Failing Professor of Fetal Therapy and Diagnosis in the WSU Department of Obstetrics and Gynecology and Center for Molecular Medicine and Genetics, indicates that RNA found in male sperm not only shows promise as a determinant in successful live birth, it may also tell us more about the health of a child as it matures. “We explored the opportunity of using sperm RNA elements as a predictor of human health, with applications at the fertility clinic that would go hand-in-hand with the new neonatal intensive care unit genome sequencing to better health outcomes,” said Dr. Krawetz, associate director of the C.S. Mott Center for Human Growth and Development. “This leaves the intriguing possibility that, while sperm RNAs delivered to the egg inform the success of live birth, they may also open a pathway to understanding the birth and potential health of each child. At fertilization, sperm delivers a structurally distinct genome, along with a complement of ribonucleic acids, or RNAs, and proteins to the immature egg cell. To test the hypothesis, sperm RNA elements corresponding to specific genes were characterized as a function of disease association. Dr. Krawetz’s team surveyed a total of 278,605 sperm RNA elements called short exon-sized sequences, or SREs, associated with diseases. This functional association of SREs may indicate a future phenotype, providing improved understanding of the father’s contribution to the life course of the child as well as the current state of paternal health. In the future, if those SREs that are mutated or modified can be identified, researchers and physicians may be able to not only forecast disease or conditions, but develop ways to prevent them. Wayne State University www.med.wayne.edu/news/2017/12/01/sperm-rna-may-serve-as-biomarkers-of-future-health-wsu-researchers-find/
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 09:32:182021-01-08 11:09:00Sperm RNA may serve as biomarkers of future health
The facts about prostate cancer can be confusing. It’s the third most common cancer type among Americans –161,000 men will be diagnosed this year, the National Cancer Institute estimates. Yet according to the NCI, 98.6% will be alive in 5 years. While it’s often not lethal, prostate cancer still kills lots of men –21,000 this year–because it’s so common. Many of its victims have metastatic disease at the time of diagnosis–their cancer has already spread. Can we catch potentially lethal cancers earlier to save some of these men? This week, a team at Cold Spring Harbor Laboratory (CSHL) published encouraging results of a pilot study testing a new way of pinpointing the minority who have aggressive disease at the time of diagnosis–a fact that usually determines whether they will have surgery or not. Current procedure calls for a predictive diagnostic biopsy, in which a needle is inserted into the organ at various locations, sometimes guided by MRI and ultrasound. The new method, which is proposed as a way of augmenting pre-surgical biopsy results, not replacing them, uses advanced genomic tools to analyse what doctors call “biopsy cores.” In standard diagnostic biopsies, pathologists examine the tissue collected in these cores, usually a dozen, and assign an overall grade called a Gleason score, based on changes in glandular architecture. A score of 6 or lower is usually interpreted to mean a cancer is slow-growing or “indolent.” Yet some men with borderline Gleason scores undergo surgery and are found to have aggressive cancers. Other times, men with high Gleason scores are found to have indolent cancers upon surgery. The newly tested method, devised by CSHL Professor Michael Wigler and Associate Professor Alexander Krasnitz, draws the raw material for further analysis from the standard pre-surgical biopsy. The team sequences the genomes of several hundred single cells sampled from each patient’s diagnostic biopsy cores. They search for certain patterns—for the presence of DNA disturbances called copy-number variations (CNVs). Using computational methods to compare CNV patterns, the team looks for cells whose CNV profiles harbour the same irregularities. This is a sign of clonality. Cancerous tumours are composed of clonal cells—genetically aberrant cells that derive from a single wayward ancestor. The CSHL method assigns a number to each set of biopsy cores, based on how many of the cores contain clonal cells, how many clonal cells each contains, and how far such cells have dispersed within the prostate. In tests on 8 patients based on collaborations with NYU and Cornell University medical centres, the CSHL testing method yielded assessments of tumours that more closely matched the verdict of post-surgical pathological analysis (which reveal actual pathology) than the corresponding pre-surgical predictive biopsies, according to first author Joan Alexander, M.D. “This is important because treatment decisions in such cases depend on the pre-surgical biopsy, not the surgical specimen,” Krasnitz comments. “We think single-cell analysis could potentially augment traditional biopsy-core histopathology, significantly improving risk assessment and informing treatment decisions, especially in borderline cases.” Cold Spring Harbor Laboratory www.cshl.edu/new-method-determine-surgery-prostate-tumors-pose-lethal-threat/
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 09:32:182021-01-08 11:08:59Method to determine before surgery which prostate tumours pose a lethal threat
People who inherit genetic changes which alter the function of their immune system are at increased risk of developing Hodgkin lymphoma, a major new study reports. Scientists at The Institute of Cancer Research, London, identified six new genetic changes that increase the risk of developing Hodgkin lymphoma – one of the most common cancers in young adults. Many of the DNA changes seemed to affect the function of the immune system, and three had previously been associated with autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or lupus. The researchers stressed that the link did not mean people with autoimmune diseases are at increased risk of lymphoma, but did offer important genetic clues for understanding both lymphoma and autoimmune diseases better. One of the genetic changes discovered increases the risk of Hodgkin lymphoma by more than a third and others by at least 15% each – information that could point to new targeted drugs for the disease. Research at the ICR is underpinned by generous contributions from our supporters. Find out more about how you can contribute to our mission to make the discoveries to defeat cancer. Scientists at the ICR analysed genetic data from 5,314 cases of Hodgkin lymphoma and 16,749 controls, from four different European studies. The study is the largest of its kind for Hodgkin lymphoma. For most people, Hodgkin lymphoma can be successfully treated with first-line therapies – but there is a need for new treatments for those for whom first line treatment has failed. The researchers identified six new single-letter changes in DNA that were linked to the development of Hodgkin lymphoma – and five of these affect the way a type of white blood cell, called B cells, develop. Hodgkin lymphoma is a cancer of the B cells – which are responsible for producing antibodies as a critical component of the immune system. The study also picked out clear differences in genetic risk between two different subtypes of Hodgkin Lymphoma – nodular sclerosis Hodgkin Lymphoma (NSHL) and mixed cellularity Hodgkin Lymphoma (MCHL). For example, a single-letter change located in DNA near the gene LPP increased the risk of NSHL by 37%, but had little effect on the risk of developing MCHL. Professor Richard Houlston, Professor of Molecular and Population Genetics at the ICR, said: “Hodgkin lymphoma is a cancer of immune cells called B cells, and our study links the risk of the disease to changes in the genes that control how B cells develop. Interestingly, we found that some of the genetic changes we have linked to Hodgkin lymphoma have previously been associated with the risk of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. “It doesn’t mean that if you develop an autoimmune disease you are at increased risk of lymphoma, but it does offer fascinating genetic clues to these diseases. The new information could point towards new ways of diagnosing, treating, or even helping to prevent Hodgkin lymphoma.” Institute of Cancer Research www.icr.ac.uk/news-archive/genetic-link-found-between-the-immune-system-and-lymphoma
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 09:32:182021-01-08 11:08:59Genetic link found between the immune system and lymphoma
Australian researchers have developed a new risk scoring system for children with leukaemia based on missing DNA fragments or ‘microdeletions’. The risk score will allow doctors to better predict the chance of relapse of a subgroup of kids currently hidden in a lower risk group. The international study, led by Australian researchers at Children’s Cancer Institute, discovered that searching for specific gene microdeletions found only in leukaemia, when combined with two other test results, provides doctors with a more accurate way to categorise patient risk than the current approach. The study tested 475 patients from 6 different children’s hospitals in Australia and New Zealand enrolled on a clinical trial sponsored by ANZCHOG, the Australian and New Zealand Children’s Haematology and Oncology Group. The patients were all children with non-high-risk B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), a subtype of acute lymphoblastic leukaemia (ALL), the most common childhood cancer with survival rates typically near 90%. Most children with ALL have B-cell precursor acute lymphoblastic leukaemia. Study leader, Associate Professor Rosemary Sutton, said the most intensive treatment for BCP-ALL patients was usually given to the 11% or so of children in the high-risk category to limit side effects for kids who don’t need it. “Children in the standard and medium risk category in the study were given less intensive treatment than high-risk patients. But about one in six of them relapsed. Obviously, some children needed more intensive treatment than previously thought – but which ones?” she said. Prof Sutton said she and her collaborators developed a new kind of risk score which builds on a bone marrow test, the minimal residual disease or MRD test developed at Children’s Cancer Institute, which gives doctors early warning that treatment may not be working. The MRD test is so sensitive it can detect just one cancer cell in a million bone marrow cells surviving cancer treatment. The test was a huge boon for some children with leukaemia on this same trial, since it alerted doctors that they had a very high risk of relapsing. Consequently, they were treated very intensively with chemotherapy and bone marrow transplants, and the survival rate of this subgroup doubled. But MRD alone is not enough. “For the standard to medium risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk”, said Prof Sutton. “So, we supplemented MRD results with two other pieces of patient information, the presence or absence of specific gene microdeletions and a score called the NCI (National Cancer Institute) risk, based on age and white blood cell count. “We tested for microdeletions in 9 genes involved in leukaemia and found that two of the genes, IKZF1 (called ‘Ikaros’) and P2RY8-CRLF2, were important predictors of relapse,” she said. These measures were combined to calculate a risk score for each patient of ‘0’ (no risk factors), to ‘2+’ (several). The study found that children with a ‘2+’ score were most likely to relapse or die within 7 years after treatment started, while those with a ‘0’ score least likely. The same microdeletions were found to be important for predicting relapse in a cohort of Dutch children with leukaemia and the new scoring system was validated by researchers in The Netherlands. If the new risk score system is adopted in future, doctors could give children with a ‘2+’ risk more intensive treatment with the aim of improving their survival. Dr Toby Trahair, paper co-author and oncologist at Kids’ Cancer Centre at Sydney Children’s Hospital, Randwick said the scoring system could make a big difference to the success of childhood leukaemia treatment. Children’s Cancer Institute ccia.org.au/missing-dna-fragments-hold-clue-predicting-childhood-leukaemia-relapse/
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 09:32:182021-01-08 11:08:59Missing DNA fragments hold clue to predicting childhood leukaemia relapse
Researchers at Rice University and the University of Texas MD Anderson Cancer Center have refined and, for the first time, run in vivo tests of a method that may allow nanotube-based probes to locate specific tumours in the body. Their ability to pinpoint tumours with sub-millimetre accuracy could eventually improve early detection and treatment of ovarian cancer. The non-invasive technique relies on single-walled carbon nanotubes that can be optically triggered to emit shortwave infrared light. For this study, the researchers used the technique to pinpoint small concentrations of nanotubes inside rodents. The lab of co-author Dr. Robert Bast Jr., an expert in ovarian cancer and vice president for translational research at MD Anderson, inserted gel-bound carbon nanotubes into the ovaries of rodents to mimic the accumulations that are expected for nanotubes linked to special antibodies that recognize tumour cells. The rodents were then scanned with the Rice lab’s custom-built optical device to detect the faint emission signatures of as little as 100 picograms of nanotubes. The device irradiated the rodents with intense red light from an array of light-emitting diodes and read fluorescent signals with a specialized sensitive detector. Because different types of tissue absorb emissions from the nanotubes differently, the scanner took readings from many locations to triangulate the tumour’s exact location, as confirmed by later MRI scans. Weisman said it should be possible to noninvasively find small ovarian tumours within rodents used for medical research by linking nanotubes to antibody biomarkers and administering the biomarkers intravenously. The biomarkers would accumulate at the tumour site. He said more refined versions of the optical scanner may then be able to locate a tumour within seconds, and further advances may extend the method’s application to human cancer detection. The new results suggested that antibody-nanotube probes could potentially detect tumours with as few as 100 ovarian cancer cells, which could make it a valuable tool for early detection. Rice University news.rice.edu/2017/11/30/researchers-advance-technique-to-detect-ovarian-cancer-2/
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 09:32:182021-01-08 11:08:59Researchers advance technique to detect ovarian cancer
New tests to detect early Lyme disease – which is increasing beyond the summer months –could replace existing tests that often do not clearly identify the infection before health problems occur. In an analysis, scientists from Rutgers University, Harvard University, Yale University, National Institute of Allergy and Infectious Diseases of the NIH and other academic centres, industry and public health agencies say new diagnostic methods offer a better chance for more accurate detection of the infection from the Lyme bacteria. “New tests are at hand that offer more accurate, less ambiguous test results that can yield actionable results in a timely fashion,” said Steven Schutzer, a physician-scientist at Rutgers New Jersey Medical School and senior author. “Improved tests will allow for earlier diagnosis which should improve patient outcomes.” Lyme disease is the most common tick-borne infection in North America and Europe. There are currently over 300,000 cases of Lyme disease annually in the United States alone and the disease is increasing and spreading into new regions. Lyme disease frequently, but not always, presents with a bull’s-eye rash. When the rash is absent, a laboratory test is needed. The only FDA-approved Lyme disease tests, based on technology developed more than two decades ago, rely on detecting antibodies that the body’s immune system makes in response to the disease. These antibody-based tests are the most commonly used tests for Lyme disease and are the current standard. One problem, however, is that many people produce similar – called “cross-reactive” – antibodies in response to other bacteria not associated with Lyme disease, which causes confusing results and makes test accuracy more difficult. “New tests are more exact and are not as susceptible to the same false-positive or false-negative results associated with current tests,” said Schutzer. Schutzer and his colleagues say more accurate testing would help doctors decide when to prescribe the antibiotics used to clear the infection and help avoid severe long-term health problems. Antibody tests can take three weeks or more for the antibody levels to reach a point where the tests can pick up a positive result. Those involved in the paper joined forces after meeting at Cold Spring Harbor Laboratory’s Banbury Center, a non-profit research institution in New York. The meeting organized and chaired by Schutzer and John A. Branda, assistant professor of pathology at Harvard Medical School, focused on current Lyme disease tests and new scientific advances made in increasing the accuracy of the diagnosis.
Rutgers Universityhttps://tinyurl.com/ya2mpslr
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 09:32:182021-01-08 11:08:58New Lyme disease tests could offer quicker, more accurate detection
A large-scale international study led by the University of Exeter Medical School has discovered new genes linked to parents’ lifespan – which could one day be targeted to help prolong human life. How long we live is determined by a range of factors including our lifestyle and how well we treat factors including blood pressure and cholesterol from midlife. However, genetics, and how long our parental relatives lived, also plays a role. Now, the number of genes we know influence lifespan has expanded, potentially paving the way to new therapeutic targets to prolong life. The study, funded by the Medical Research Council and conducted in collaboration with a number of US universities, undertook a genome-wide search for variants influencing how long participants’ parents lived. The team studied 389,166 volunteers who took part in the UK Biobank, with confirmation in the US Health and Retirement Study and the Wisconsin Longitudinal Study. The DNA samples from the volunteers carry the genetics of their biological parents, so provide a practical way of studying exceptionally long lifespans. Eight genetic variants had already been linked for lifespan, mainly involved in heart disease and dementia. The latest study has expanded this to 25 genes in all, with some specific to mothers’ or fathers’ lifespan separately. Dr Luke Pilling, who undertook most of analyses said: “We have identified new pathways that contribute to survival, as well as confirming others. These targets, including inflammatory and cardiovascular pathways, offer potentially modifiable targets to reduce risk of an earlier death and improve health.” Genes involved in senescence, the ‘frozen’ state that cells enter into after being damaged, played an important role in longevity. Drugs targeting senescence have already been shown to extend life in laboratory animals. Genes related to inflammation and auto-immunity-related genes were also prominent, opening up the possibility that precision anti-inflammatory treatments may one day be helpful in extending life. The results confirm that many genetic variants combine to influence human lifespan: no single gene variant was found to be responsible. The study found evidence to suggest that the genetic variants for average lifespan also influence exceptionally long life expectancy. A genetic risk score combining the top ten variants was statistically associated with parents being centenarians.
Exeter Universityhttps://tinyurl.com/yakjsfoj
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 09:32:182021-01-08 11:08:56Parental lifespan genes could hold clue to longer life
There are nine genes that make you gain more weight if you already have a high body mass index, McMaster University researchers have found. “It’s similar to a tiny snow ball at a top of a hill that becomes bigger and bigger when rolling down the hill,” said senior author David Meyre, an associate professor of health research methods, evidence and impact at McMaster University. He also holds the Canada Research Chair in Genetics of Obesity. “The effect of these genes may be amplified by four times, if we compare the 10% of the population at the low end of the body mass index, compared to the 10% at the high end,” he added. The study’s co-first authors are postdoctoral fellow Arkan Abadi and PhD student Akram Alyass, who both work in the Meyre laboratory. Although the increasing average body mass index of the population of several high-income countries has recently plateaued, the researchers note in the study, the cases of extreme forms of obesity are still growing. People who are morbidly obese are at risk of health complications such as diabetes, cardiovascular disease, hypertension and cancers and early death. On top of lifestyle factors such as unhealthy diet and physical inactivity, genetic factors are also known to play an important role, with 50 to 80 per cent of body mass index related to genetics. The researchers looked at 37 genes that are well established as modulating the body mass in 75,230 adults with European ancestry and found the nine with the snowball effect. “These genes may, in part, explain why some individuals experience uncontrolled and constant weight gain across their life, despite the availability of different therapeutic approaches,” said Meyre. “The plausible explanation is that there are interactions between the snowball obesity genes and risk environmental factors.” He added that the idea of preventing obesity in the first place is a good strategy for people with a high genetic risk for obesity. “We have an important message of hope that the carriers of these genes, if they stay in the low end of body mass index through appropriate lifestyle, may minimize the effect of the snowball obesity genes.”
McMaster Universityhttps://tinyurl.com/ya247466
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 09:32:182021-01-08 11:08:56Researchers find genes may ‘snowball’ obesity
When researchers at the University of São Paulo (USP) in Brazil treated human melanoma cell lines with a synthetic compound similar to curcumin, one of the pigments that give turmeric (Curcuma longa) its orange colour, they identified genes with altered expression in potentially invasive tumours and malignant cells resistant to chemotherapy. According to the scientists, if further studies confirm the importance of these genes to disease progression and increasing chemoresistance, it will be possible to explore their future use as biomarkers to assist diagnosis and even as therapeutic targets. “Previous research by collaborators had already shown that DM-1, a compound analogous to curcumin, has anti-tumour activity at low doses. We set out to understand which genes this substance modulates and why it is toxic to melanoma but not to normal cells,” said Érica Aparecida de Oliveira, a postdoctoral scholar at USP’s School of Pharmaceutical Sciences (FCF). As Oliveira explained, there are hundreds of papers attesting to the anti-oxidant, anti-tumoural, anti-microbial and anti-inflammatory properties of curcumin in the scientific literature. However, the therapeutic usefulness of this compound in its natural form is limited owing to poor absorption, rapid metabolization, and water insolubility. To solve this problem, scientists have developed synthetic analogues with minor structural modifications to make the molecule more stable in the organism. DM-1 (sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) was synthesized some years ago by José Agustín Pablo Quincoces Suárez, a professor at Bandeirantes University (UNIBAN). “Experiments with animals conducted by collaborators showed that treatment with DM-1 can promote a reduction in tumour volume. DM-1 has also proved toxic to chemoresistant melanoma cells,” Oliveira said. To unpack DM-1’s mechanism of action, Oliveira resorted to a toxicogenomics platform developed by the research group of FCF-USP professor Gisele Monteiro, a fellow researcher at the investigation. Such platform is comprised of a collection of 6,000 frozen yeast strains, all mutants of the species Saccharomyces cerevisiae, widely used as baker’s and brewer’s yeast. “This yeast’s genome has 6,000 genes, and a different gene has been knocked out in each of these mutants, so we were able to study the effects of the compound in a highly specific manner, gene by gene,” Oliveira said. The 6,000 mutant yeast strains were thawed, spread on plates with 96 small wells, and treated with DM-1. The strains that did not grow in the presence of the curcumin analogue were discarded, leaving an initial group of 211 genes that were affected by the treatment. The next step was to filter the genes in order to identify those with homologues in the human genome since some might be associated with functions specific to yeast. The researchers came up with a second list containing 79 candidate genes, thanks to the aid from bioinformatics tools and from the expertise of Helder Nakaya , another fellow researcher and also a professor at FCF-USP. “We then began to look at public repositories of genomic data from cancer patients, such as The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), to understand how these genes talked to each other,” Oliveira said. The analysis showed most to be associated with cell signalling pathways that favoured tumour progression when active. Examples included the pathways mediated by mitogen-activated protein (MAP) kinase and epidermal growth factor receptor (EGFR). The next step was to investigate which genes were important to the progression of melanoma specifically. This entailed using bioinformatics to focus on the analysis of genomic sequences from melanoma patients. “We performed a data mining exercise to find genes with altered expression during melanoma progression,” Oliveira said. “We identified seven genes that appeared to be important, and when we looked at the public databases, we could see that the expression of these genes was indeed altered in many patients.” In vitro tests with non-chemoresistant parent melanoma cells showed that treatment with DM-1 induced cell death, mainly because it increased expression of a gene known as TOP-1. When this gene is active, it leads to DNA transcription errors and hence causes genomic instability in cells. In chemoresistant melanoma cells, cytotoxicity was caused mainly by increased expression of the gene ADK, which is involved in energy production for cells. “Like curcumin, which can interact with multiple cellular targets and modulate multiple signaling pathways, DM-1 also acts in different ways to promote toxicity in both parent and drug-resistant melanoma cells,” Oliveira said.
EurekAlerthttps://tinyurl.com/ya7hhwwk
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 09:32:182021-01-08 11:08:56Genes associated with progression of melanoma are identified
Researchers from Case Western Reserve University School of Medicine have discovered how unusually long pieces of RNA work in skin cells. The RNA pieces, called “long non-coding RNAs” or “lncRNAs,” help skin cells modulate connective tissue proteins, like collagen, and could represent novel therapeutic targets to promote skin repair. In a recent study, researchers identified specific lncRNAs that control genes and behaviour of mouse skin cells. The team found 111 lncRNAs that work with a highly conserved protein network called the Wnt/β-catenin pathway. The Wnt/β-catenin pathway serves as a signalling hub that helps cells across species adjust gene expression in response to their environment. The new study connects this important pathway to a new form of genetic control—lncRNAs. “LncRNAs are a newly discovered class of genes, and we’ve been working to elucidate their functions and mechanisms as they appear to be critical for human health,” said Ahmad Khalil, PhD, assistant professor of genetics and genome sciences and member of the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine. “Our findings show that the Wnt/β-catenin pathway activates certain lncRNAs to directly control gene expression in skin fibroblast cells.” The team studied skin cells, called dermal fibroblasts, that help hair follicles develop, wounds heal, and generally maintain the structural integrity of skin. Fibroblasts orchestrate these important functions with the help of the Wnt/β-catenin pathway, among others. Sustained activation of the Wnt/β-catenin pathway can cause fibroblasts to overproduce connective tissue proteins, like collagen, causing harmful skin fibrosis. According to the new study, lncRNAs serve as an intermediary between Wnt/β-catenin and fibroblast genes. The researchers showed fibroblasts genetically modified to overproduce β-catenin had 8-14 times higher levels of two specific lncRNAs when compared to control fibroblasts. The researchers named the lncRNAs Wincr1 and Wincr2—Wnt signalling induced non-coding RNA.” The lncRNA levels correlated with significantly higher levels of proteins that help fibroblasts move and contract. The findings suggest disrupting lncRNA levels could change how fibroblasts function in skin. The study adds to a growing body of evidence that lncRNAs could represent a new arena for drug developers. LncRNAs are intriguing therapeutic targets—recent studies by Khalil and others have implicated lncRNAs defects in all kinds of diseases, including infertility and cancer. Said Atit, “Specific lncRNAs that operate downstream of the Wnt/β-catenin pathway could serve as drug targets for chronic and acute skin fibrosis conditions.” The researchers are now working to understand how lncRNAs work in various animal models, and how their dysfunction may promote disease.
Case Western Reserve University School of Medicinehttps://tinyurl.com/yan5xss9
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 09:32:182021-01-08 11:08:55Finding long strands of RNA in skin development and disease
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.
Sperm RNA may serve as biomarkers of future health
, /in E-News /by 3wmediaHuman sperm may hold the potential to serve as biomarkers of the future health of newborn infants, according to a new study by a Wayne State University School of Medicine research team.
The study, “Sperm RNA elements as markers of health,” from the lab of Stephen Krawetz, Ph.D., the Charlotte B. Failing Professor of Fetal Therapy and Diagnosis in the WSU Department of Obstetrics and Gynecology and Center for Molecular Medicine and Genetics, indicates that RNA found in male sperm not only shows promise as a determinant in successful live birth, it may also tell us more about the health of a child as it matures.
“We explored the opportunity of using sperm RNA elements as a predictor of human health, with applications at the fertility clinic that would go hand-in-hand with the new neonatal intensive care unit genome sequencing to better health outcomes,” said Dr. Krawetz, associate director of the C.S. Mott Center for Human Growth and Development. “This leaves the intriguing possibility that, while sperm RNAs delivered to the egg inform the success of live birth, they may also open a pathway to understanding the birth and potential health of each child.
At fertilization, sperm delivers a structurally distinct genome, along with a complement of ribonucleic acids, or RNAs, and proteins to the immature egg cell. To test the hypothesis, sperm RNA elements corresponding to specific genes were characterized as a function of disease association. Dr. Krawetz’s team surveyed a total of 278,605 sperm RNA elements called short exon-sized sequences, or SREs, associated with diseases. This functional association of SREs may indicate a future phenotype, providing improved understanding of the father’s contribution to the life course of the child as well as the current state of paternal health.
In the future, if those SREs that are mutated or modified can be identified, researchers and physicians may be able to not only forecast disease or conditions, but develop ways to prevent them.
Wayne State University
www.med.wayne.edu/news/2017/12/01/sperm-rna-may-serve-as-biomarkers-of-future-health-wsu-researchers-find/
Method to determine before surgery which prostate tumours pose a lethal threat
, /in E-News /by 3wmediaThe facts about prostate cancer can be confusing. It’s the third most common cancer type among Americans –161,000 men will be diagnosed this year, the National Cancer Institute estimates. Yet according to the NCI, 98.6% will be alive in 5 years.
While it’s often not lethal, prostate cancer still kills lots of men –21,000 this year–because it’s so common. Many of its victims have metastatic disease at the time of diagnosis–their cancer has already spread. Can we catch potentially lethal cancers earlier to save some of these men?
This week, a team at Cold Spring Harbor Laboratory (CSHL) published encouraging results of a pilot study testing a new way of pinpointing the minority who have aggressive disease at the time of diagnosis–a fact that usually determines whether they will have surgery or not. Current procedure calls for a predictive diagnostic biopsy, in which a needle is inserted into the organ at various locations, sometimes guided by MRI and ultrasound.
The new method, which is proposed as a way of augmenting pre-surgical biopsy results, not replacing them, uses advanced genomic tools to analyse what doctors call “biopsy cores.” In standard diagnostic biopsies, pathologists examine the tissue collected in these cores, usually a dozen, and assign an overall grade called a Gleason score, based on changes in glandular architecture. A score of 6 or lower is usually interpreted to mean a cancer is slow-growing or “indolent.” Yet some men with borderline Gleason scores undergo surgery and are found to have aggressive cancers. Other times, men with high Gleason scores are found to have indolent cancers upon surgery.
The newly tested method, devised by CSHL Professor Michael Wigler and Associate Professor Alexander Krasnitz, draws the raw material for further analysis from the standard pre-surgical biopsy. The team sequences the genomes of several hundred single cells sampled from each patient’s diagnostic biopsy cores. They search for certain patterns—for the presence of DNA disturbances called copy-number variations (CNVs). Using computational methods to compare CNV patterns, the team looks for cells whose CNV profiles harbour the same irregularities. This is a sign of clonality. Cancerous tumours are composed of clonal cells—genetically aberrant cells that derive from a single wayward ancestor.
The CSHL method assigns a number to each set of biopsy cores, based on how many of the cores contain clonal cells, how many clonal cells each contains, and how far such cells have dispersed within the prostate. In tests on 8 patients based on collaborations with NYU and Cornell University medical centres, the CSHL testing method yielded assessments of tumours that more closely matched the verdict of post-surgical pathological analysis (which reveal actual pathology) than the corresponding pre-surgical predictive biopsies, according to first author Joan Alexander, M.D.
“This is important because treatment decisions in such cases depend on the pre-surgical biopsy, not the surgical specimen,” Krasnitz comments. “We think single-cell analysis could potentially augment traditional biopsy-core histopathology, significantly improving risk assessment and informing treatment decisions, especially in borderline cases.”
Cold Spring Harbor Laboratory
www.cshl.edu/new-method-determine-surgery-prostate-tumors-pose-lethal-threat/
Genetic link found between the immune system and lymphoma
, /in E-News /by 3wmediaPeople who inherit genetic changes which alter the function of their immune system are at increased risk of developing Hodgkin lymphoma, a major new study reports.
Scientists at The Institute of Cancer Research, London, identified six new genetic changes that increase the risk of developing Hodgkin lymphoma – one of the most common cancers in young adults.
Many of the DNA changes seemed to affect the function of the immune system, and three had previously been associated with autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or lupus.
The researchers stressed that the link did not mean people with autoimmune diseases are at increased risk of lymphoma, but did offer important genetic clues for understanding both lymphoma and autoimmune diseases better.
One of the genetic changes discovered increases the risk of Hodgkin lymphoma by more than a third and others by at least 15% each – information that could point to new targeted drugs for the disease.
Research at the ICR is underpinned by generous contributions from our supporters. Find out more about how you can contribute to our mission to make the discoveries to defeat cancer.
Scientists at the ICR analysed genetic data from 5,314 cases of Hodgkin lymphoma and 16,749 controls, from four different European studies.
The study is the largest of its kind for Hodgkin lymphoma.
For most people, Hodgkin lymphoma can be successfully treated with first-line therapies – but there is a need for new treatments for those for whom first line treatment has failed.
The researchers identified six new single-letter changes in DNA that were linked to the development of Hodgkin lymphoma – and five of these affect the way a type of white blood cell, called B cells, develop.
Hodgkin lymphoma is a cancer of the B cells – which are responsible for producing antibodies as a critical component of the immune system.
The study also picked out clear differences in genetic risk between two different subtypes of Hodgkin Lymphoma – nodular sclerosis Hodgkin Lymphoma (NSHL) and mixed cellularity Hodgkin Lymphoma (MCHL).
For example, a single-letter change located in DNA near the gene LPP increased the risk of NSHL by 37%, but had little effect on the risk of developing MCHL.
Professor Richard Houlston, Professor of Molecular and Population Genetics at the ICR, said: “Hodgkin lymphoma is a cancer of immune cells called B cells, and our study links the risk of the disease to changes in the genes that control how B cells develop. Interestingly, we found that some of the genetic changes we have linked to Hodgkin lymphoma have previously been associated with the risk of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
“It doesn’t mean that if you develop an autoimmune disease you are at increased risk of lymphoma, but it does offer fascinating genetic clues to these diseases. The new information could point towards new ways of diagnosing, treating, or even helping to prevent Hodgkin lymphoma.”
Institute of Cancer Research
www.icr.ac.uk/news-archive/genetic-link-found-between-the-immune-system-and-lymphoma
Missing DNA fragments hold clue to predicting childhood leukaemia relapse
, /in E-News /by 3wmediaAustralian researchers have developed a new risk scoring system for children with leukaemia based on missing DNA fragments or ‘microdeletions’.
The risk score will allow doctors to better predict the chance of relapse of a subgroup of kids currently hidden in a lower risk group.
The international study, led by Australian researchers at Children’s Cancer Institute, discovered that searching for specific gene microdeletions found only in leukaemia, when combined with two other test results, provides doctors with a more accurate way to categorise patient risk than the current approach.
The study tested 475 patients from 6 different children’s hospitals in Australia and New Zealand enrolled on a clinical trial sponsored by ANZCHOG, the Australian and New Zealand Children’s Haematology and Oncology Group.
The patients were all children with non-high-risk B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), a subtype of acute lymphoblastic leukaemia (ALL), the most common childhood cancer with survival rates typically near 90%. Most children with ALL have B-cell precursor acute lymphoblastic leukaemia.
Study leader, Associate Professor Rosemary Sutton, said the most intensive treatment for BCP-ALL patients was usually given to the 11% or so of children in the high-risk category to limit side effects for kids who don’t need it.
“Children in the standard and medium risk category in the study were given less intensive treatment than high-risk patients. But about one in six of them relapsed. Obviously, some children needed more intensive treatment than previously thought – but which ones?” she said.
Prof Sutton said she and her collaborators developed a new kind of risk score which builds on a bone marrow test, the minimal residual disease or MRD test developed at Children’s Cancer Institute, which gives doctors early warning that treatment may not be working.
The MRD test is so sensitive it can detect just one cancer cell in a million bone marrow cells surviving cancer treatment. The test was a huge boon for some children with leukaemia on this same trial, since it alerted doctors that they had a very high risk of relapsing. Consequently, they were treated very intensively with chemotherapy and bone marrow transplants, and the survival rate of this subgroup doubled. But MRD alone is not enough.
“For the standard to medium risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk”, said Prof Sutton.
“So, we supplemented MRD results with two other pieces of patient information, the presence or absence of specific gene microdeletions and a score called the NCI (National Cancer Institute) risk, based on age and white blood cell count.
“We tested for microdeletions in 9 genes involved in leukaemia and found that two of the genes, IKZF1 (called ‘Ikaros’) and P2RY8-CRLF2, were important predictors of relapse,” she said.
These measures were combined to calculate a risk score for each patient of ‘0’ (no risk factors), to ‘2+’ (several). The study found that children with a ‘2+’ score were most likely to relapse or die within 7 years after treatment started, while those with a ‘0’ score least likely.
The same microdeletions were found to be important for predicting relapse in a cohort of Dutch children with leukaemia and the new scoring system was validated by researchers in The Netherlands.
If the new risk score system is adopted in future, doctors could give children with a ‘2+’ risk more intensive treatment with the aim of improving their survival.
Dr Toby Trahair, paper co-author and oncologist at Kids’ Cancer Centre at Sydney Children’s Hospital, Randwick said the scoring system could make a big difference to the success of childhood leukaemia treatment.
Children’s Cancer Institute
ccia.org.au/missing-dna-fragments-hold-clue-predicting-childhood-leukaemia-relapse/
Researchers advance technique to detect ovarian cancer
, /in E-News /by 3wmediaResearchers at Rice University and the University of Texas MD Anderson Cancer Center have refined and, for the first time, run in vivo tests of a method that may allow nanotube-based probes to locate specific tumours in the body. Their ability to pinpoint tumours with sub-millimetre accuracy could eventually improve early detection and treatment of ovarian cancer.
The non-invasive technique relies on single-walled carbon nanotubes that can be optically triggered to emit shortwave infrared light.
For this study, the researchers used the technique to pinpoint small concentrations of nanotubes inside rodents. The lab of co-author Dr. Robert Bast Jr., an expert in ovarian cancer and vice president for translational research at MD Anderson, inserted gel-bound carbon nanotubes into the ovaries of rodents to mimic the accumulations that are expected for nanotubes linked to special antibodies that recognize tumour cells. The rodents were then scanned with the Rice lab’s custom-built optical device to detect the faint emission signatures of as little as 100 picograms of nanotubes.
The device irradiated the rodents with intense red light from an array of light-emitting diodes and read fluorescent signals with a specialized sensitive detector. Because different types of tissue absorb emissions from the nanotubes differently, the scanner took readings from many locations to triangulate the tumour’s exact location, as confirmed by later MRI scans.
Weisman said it should be possible to noninvasively find small ovarian tumours within rodents used for medical research by linking nanotubes to antibody biomarkers and administering the biomarkers intravenously. The biomarkers would accumulate at the tumour site. He said more refined versions of the optical scanner may then be able to locate a tumour within seconds, and further advances may extend the method’s application to human cancer detection. The new results suggested that antibody-nanotube probes could potentially detect tumours with as few as 100 ovarian cancer cells, which could make it a valuable tool for early detection.
Rice University
news.rice.edu/2017/11/30/researchers-advance-technique-to-detect-ovarian-cancer-2/
New Lyme disease tests could offer quicker, more accurate detection
, /in E-News /by 3wmediaNew tests to detect early Lyme disease – which is increasing beyond the summer months –could replace existing tests that often do not clearly identify the infection before health problems occur.
In an analysis, scientists from Rutgers University, Harvard University, Yale University, National Institute of Allergy and Infectious Diseases of the NIH and other academic centres, industry and public health agencies say new diagnostic methods offer a better chance for more accurate detection of the infection from the Lyme bacteria.
“New tests are at hand that offer more accurate, less ambiguous test results that can yield actionable results in a timely fashion,” said Steven Schutzer, a physician-scientist at Rutgers New Jersey Medical School and senior author. “Improved tests will allow for earlier diagnosis which should improve patient outcomes.”
Lyme disease is the most common tick-borne infection in North America and Europe. There are currently over 300,000 cases of Lyme disease annually in the United States alone and the disease is increasing and spreading into new regions. Lyme disease frequently, but not always, presents with a bull’s-eye rash. When the rash is absent, a laboratory test is needed.
The only FDA-approved Lyme disease tests, based on technology developed more than two decades ago, rely on detecting antibodies that the body’s immune system makes in response to the disease. These antibody-based tests are the most commonly used tests for Lyme disease and are the current standard.
One problem, however, is that many people produce similar – called “cross-reactive” – antibodies in response to other bacteria not associated with Lyme disease, which causes confusing results and makes test accuracy more difficult.
“New tests are more exact and are not as susceptible to the same false-positive or false-negative results associated with current tests,” said Schutzer.
Schutzer and his colleagues say more accurate testing would help doctors decide when to prescribe the antibiotics used to clear the infection and help avoid severe long-term health problems. Antibody tests can take three weeks or more for the antibody levels to reach a point where the tests can pick up a positive result.
Those involved in the paper joined forces after meeting at Cold Spring Harbor Laboratory’s Banbury Center, a non-profit research institution in New York. The meeting organized and chaired by Schutzer and John A. Branda, assistant professor of pathology at Harvard Medical School, focused on current Lyme disease tests and new scientific advances made in increasing the accuracy of the diagnosis.
Rutgers Universityhttps://tinyurl.com/ya2mpslr
Parental lifespan genes could hold clue to longer life
, /in E-News /by 3wmediaA large-scale international study led by the University of Exeter Medical School has discovered new genes linked to parents’ lifespan – which could one day be targeted to help prolong human life.
How long we live is determined by a range of factors including our lifestyle and how well we treat factors including blood pressure and cholesterol from midlife. However, genetics, and how long our parental relatives lived, also plays a role.
Now, the number of genes we know influence lifespan has expanded, potentially paving the way to new therapeutic targets to prolong life.
The study, funded by the Medical Research Council and conducted in collaboration with a number of US universities, undertook a genome-wide search for variants influencing how long participants’ parents lived. The team studied 389,166 volunteers who took part in the UK Biobank, with confirmation in the US Health and Retirement Study and the Wisconsin Longitudinal Study. The DNA samples from the volunteers carry the genetics of their biological parents, so provide a practical way of studying exceptionally long lifespans.
Eight genetic variants had already been linked for lifespan, mainly involved in heart disease and dementia. The latest study has expanded this to 25 genes in all, with some specific to mothers’ or fathers’ lifespan separately.
Dr Luke Pilling, who undertook most of analyses said: “We have identified new pathways that contribute to survival, as well as confirming others. These targets, including inflammatory and cardiovascular pathways, offer potentially modifiable targets to reduce risk of an earlier death and improve health.”
Genes involved in senescence, the ‘frozen’ state that cells enter into after being damaged, played an important role in longevity. Drugs targeting senescence have already been shown to extend life in laboratory animals.
Genes related to inflammation and auto-immunity-related genes were also prominent, opening up the possibility that precision anti-inflammatory treatments may one day be helpful in extending life.
The results confirm that many genetic variants combine to influence human lifespan: no single gene variant was found to be responsible.
The study found evidence to suggest that the genetic variants for average lifespan also influence exceptionally long life expectancy. A genetic risk score combining the top ten variants was statistically associated with parents being centenarians.
Exeter Universityhttps://tinyurl.com/yakjsfoj
Researchers find genes may ‘snowball’ obesity
, /in E-News /by 3wmediaThere are nine genes that make you gain more weight if you already have a high body mass index, McMaster University researchers have found.
“It’s similar to a tiny snow ball at a top of a hill that becomes bigger and bigger when rolling down the hill,” said senior author David Meyre, an associate professor of health research methods, evidence and impact at McMaster University. He also holds the Canada Research Chair in Genetics of Obesity.
“The effect of these genes may be amplified by four times, if we compare the 10% of the population at the low end of the body mass index, compared to the 10% at the high end,” he added.
The study’s co-first authors are postdoctoral fellow Arkan Abadi and PhD student Akram Alyass, who both work in the Meyre laboratory.
Although the increasing average body mass index of the population of several high-income countries has recently plateaued, the researchers note in the study, the cases of extreme forms of obesity are still growing. People who are morbidly obese are at risk of health complications such as diabetes, cardiovascular disease, hypertension and cancers and early death.
On top of lifestyle factors such as unhealthy diet and physical inactivity, genetic factors are also known to play an important role, with 50 to 80 per cent of body mass index related to genetics.
The researchers looked at 37 genes that are well established as modulating the body mass in 75,230 adults with European ancestry and found the nine with the snowball effect.
“These genes may, in part, explain why some individuals experience uncontrolled and constant weight gain across their life, despite the availability of different therapeutic approaches,” said Meyre. “The plausible explanation is that there are interactions between the snowball obesity genes and risk environmental factors.”
He added that the idea of preventing obesity in the first place is a good strategy for people with a high genetic risk for obesity.
“We have an important message of hope that the carriers of these genes, if they stay in the low end of body mass index through appropriate lifestyle, may minimize the effect of the snowball obesity genes.”
McMaster Universityhttps://tinyurl.com/ya247466
Genes associated with progression of melanoma are identified
, /in E-News /by 3wmediaWhen researchers at the University of São Paulo (USP) in Brazil treated human melanoma cell lines with a synthetic compound similar to curcumin, one of the pigments that give turmeric (Curcuma longa) its orange colour, they identified genes with altered expression in potentially invasive tumours and malignant cells resistant to chemotherapy.
According to the scientists, if further studies confirm the importance of these genes to disease progression and increasing chemoresistance, it will be possible to explore their future use as biomarkers to assist diagnosis and even as therapeutic targets.
“Previous research by collaborators had already shown that DM-1, a compound analogous to curcumin, has anti-tumour activity at low doses. We set out to understand which genes this substance modulates and why it is toxic to melanoma but not to normal cells,” said Érica Aparecida de Oliveira, a postdoctoral scholar at USP’s School of Pharmaceutical Sciences (FCF).
As Oliveira explained, there are hundreds of papers attesting to the anti-oxidant, anti-tumoural, anti-microbial and anti-inflammatory properties of curcumin in the scientific literature. However, the therapeutic usefulness of this compound in its natural form is limited owing to poor absorption, rapid metabolization, and water insolubility. To solve this problem, scientists have developed synthetic analogues with minor structural modifications to make the molecule more stable in the organism.
DM-1 (sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) was synthesized some years ago by José Agustín Pablo Quincoces Suárez, a professor at Bandeirantes University (UNIBAN).
“Experiments with animals conducted by collaborators showed that treatment with DM-1 can promote a reduction in tumour volume. DM-1 has also proved toxic to chemoresistant melanoma cells,” Oliveira said.
To unpack DM-1’s mechanism of action, Oliveira resorted to a toxicogenomics platform developed by the research group of FCF-USP professor Gisele Monteiro, a fellow researcher at the investigation. Such platform is comprised of a collection of 6,000 frozen yeast strains, all mutants of the species Saccharomyces cerevisiae, widely used as baker’s and brewer’s yeast.
“This yeast’s genome has 6,000 genes, and a different gene has been knocked out in each of these mutants, so we were able to study the effects of the compound in a highly specific manner, gene by gene,” Oliveira said.
The 6,000 mutant yeast strains were thawed, spread on plates with 96 small wells, and treated with DM-1. The strains that did not grow in the presence of the curcumin analogue were discarded, leaving an initial group of 211 genes that were affected by the treatment.
The next step was to filter the genes in order to identify those with homologues in the human genome since some might be associated with functions specific to yeast. The researchers came up with a second list containing 79 candidate genes, thanks to the aid from bioinformatics tools and from the expertise of Helder Nakaya , another fellow researcher and also a professor at FCF-USP.
“We then began to look at public repositories of genomic data from cancer patients, such as The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), to understand how these genes talked to each other,” Oliveira said.
The analysis showed most to be associated with cell signalling pathways that favoured tumour progression when active. Examples included the pathways mediated by mitogen-activated protein (MAP) kinase and epidermal growth factor receptor (EGFR).
The next step was to investigate which genes were important to the progression of melanoma specifically. This entailed using bioinformatics to focus on the analysis of genomic sequences from melanoma patients.
“We performed a data mining exercise to find genes with altered expression during melanoma progression,” Oliveira said. “We identified seven genes that appeared to be important, and when we looked at the public databases, we could see that the expression of these genes was indeed altered in many patients.”
In vitro tests with non-chemoresistant parent melanoma cells showed that treatment with DM-1 induced cell death, mainly because it increased expression of a gene known as TOP-1. When this gene is active, it leads to DNA transcription errors and hence causes genomic instability in cells.
In chemoresistant melanoma cells, cytotoxicity was caused mainly by increased expression of the gene ADK, which is involved in energy production for cells.
“Like curcumin, which can interact with multiple cellular targets and modulate multiple signaling pathways, DM-1 also acts in different ways to promote toxicity in both parent and drug-resistant melanoma cells,” Oliveira said.
EurekAlerthttps://tinyurl.com/ya7hhwwk
Finding long strands of RNA in skin development and disease
, /in E-News /by 3wmediaResearchers from Case Western Reserve University School of Medicine have discovered how unusually long pieces of RNA work in skin cells. The RNA pieces, called “long non-coding RNAs” or “lncRNAs,” help skin cells modulate connective tissue proteins, like collagen, and could represent novel therapeutic targets to promote skin repair.
In a recent study, researchers identified specific lncRNAs that control genes and behaviour of mouse skin cells. The team found 111 lncRNAs that work with a highly conserved protein network called the Wnt/β-catenin pathway. The Wnt/β-catenin pathway serves as a signalling hub that helps cells across species adjust gene expression in response to their environment. The new study connects this important pathway to a new form of genetic control—lncRNAs.
“LncRNAs are a newly discovered class of genes, and we’ve been working to elucidate their functions and mechanisms as they appear to be critical for human health,” said Ahmad Khalil, PhD, assistant professor of genetics and genome sciences and member of the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine. “Our findings show that the Wnt/β-catenin pathway activates certain lncRNAs to directly control gene expression in skin fibroblast cells.”
The team studied skin cells, called dermal fibroblasts, that help hair follicles develop, wounds heal, and generally maintain the structural integrity of skin. Fibroblasts orchestrate these important functions with the help of the Wnt/β-catenin pathway, among others. Sustained activation of the Wnt/β-catenin pathway can cause fibroblasts to overproduce connective tissue proteins, like collagen, causing harmful skin fibrosis. According to the new study, lncRNAs serve as an intermediary between Wnt/β-catenin and fibroblast genes.
The researchers showed fibroblasts genetically modified to overproduce β-catenin had 8-14 times higher levels of two specific lncRNAs when compared to control fibroblasts. The researchers named the lncRNAs Wincr1 and Wincr2—Wnt signalling induced non-coding RNA.” The lncRNA levels correlated with significantly higher levels of proteins that help fibroblasts move and contract. The findings suggest disrupting lncRNA levels could change how fibroblasts function in skin. The study adds to a growing body of evidence that lncRNAs could represent a new arena for drug developers. LncRNAs are intriguing therapeutic targets—recent studies by Khalil and others have implicated lncRNAs defects in all kinds of diseases, including infertility and cancer.
Said Atit, “Specific lncRNAs that operate downstream of the Wnt/β-catenin pathway could serve as drug targets for chronic and acute skin fibrosis conditions.” The researchers are now working to understand how lncRNAs work in various animal models, and how their dysfunction may promote disease.
Case Western Reserve University School of Medicinehttps://tinyurl.com/yan5xss9