Scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health are the first to report immune signatures differentiating two subgroups of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): “classical” and “atypical.” This complex, debilitating disease is characterized by symptoms ranging from extreme fatigue after exertion to difficulty concentrating, headaches, and muscle pain. Typically, symptoms of ME/CFS begin suddenly following a flu-like infection, but a subset of cases classified by the investigators as “atypical” follows a different disease course, either from triggers preceding symptoms by months or years, or accompanied by the later development of additional serious illnesses. To uncover evidence of these disease types, first author Mady Hornig, MD, director of translational research at CII and associate professor of Epidemiology at Mailman, and colleagues used immunoassays to measure levels of 51 immune biomarkers in cerebrospinal fluid samples taken from 32 cases of classical and 27 cases of atypical ME/CFS. All study participants were diagnosed using the same standard criteria, but atypical cases either had prior histories of viral encephalitis, illness after foreign travel or blood transfusion, or later developed a concurrent malady—seizure disorders, multiple sclerosis-like demyelinating disorders, Gulf War Illness, or a range of cancers—at rates much higher than seen in the general population. Their analysis revealed lower levels of immune molecules in individuals with atypical ME/CFS than those with a classical presentation and course of illness, including dramatically lower levels of interleukin 7 (IL7), a protein linked to viral infections, and interleukin 17A (IL 17A) and chemokine (C-X-C motif) ligand 9 (CXCL9), inflammatory molecules implicated in a variety of neurological disorders. “We now have biological evidence that the triggers for ME/CFS may involve distinct pathways to disease, or, in some cases, predispose individuals to the later development of serious comorbidities,” says Hornig. “Importantly, our results suggest that these early biomarker profiles may be detectable soon after diagnosis of ME/CFS, laying a foundation for better understanding of and treatments for this complex and poorly understood illness.” “Early identification of patients who meet the usual clinical criteria when first diagnosed but then go on to develop atypical features would help clinicians like myself identify and treat these complex cases and even prevent fatal outcomes,” says co-author Daniel L. Peterson, MD, principal clinician at Sierra Internal Medicine in Incline Village, NV. The new study builds on earlier research by Hornig and collaborators that found robust evidence of distinct stages in ME/CFS. A pair of 2015 publications based on analyses of blood and cerebrospinal fluid showed differences in the immune signatures of ME/CFS patients who had the disease for three years or less as compared with those who had been ill for more than three years. The researchers reported that patients were flush with cytokines and chemokines until around the three-year mark—suggesting an over-activated immune response in that phase of the illness; thereafter the immune system showed evidence of “exhaustion,” and levels of immune molecules dropped. In the new study, both subsets of ME/CFS patients showed signs of an unbalanced or dysregulated immune system within the central nervous system, with immune markers different than those seen in healthy individuals. However, the dampened immune profiles previously observed after the three-year mark were only observed in individuals with the classical form of the disease, not in those with atypical ME/CFS. Among subjects in the atypical group, levels of cytokines and chemokines were more likely to remain steady or increase. According to Hornig, instead of the immune exhaustion seen in later phases of classical ME/CFS, atypical patients may be experiencing a “smouldering inflammatory process” in which the immune system is still working to recover, although she acknowledges that much work remains to be done to confirm this hypothesis. Alternatively, these findings could suggest a pathway to disease in atypical individuals that involves biomarkers not captured in the 51-molecule assay, potentially even involving non-immune-related processes. Atypical individuals may also have genetic susceptibilities that lead their immune systems to respond differently than in classical cases.
Columbia University Mailman School of Public Health] www.mailman.columbia.edu/public-health-now/news/scientists-discover-biological-evidence-atypical-chronic-fatigue-syndrome
A new laboratory technique developed by researchers at Baylor College of Medicine and other institutions can rapidly test the effectiveness of treatments for life-threatening breast cancer metastases in bone. “For a number of breast cancer patients, the problem is metastasis – the dissemination of breast tumour cells to other organs – after the primary tumour has been eliminated,” said corresponding author Dr. Xiang Zhang, associate professor of molecular and cellular biology and the Lester and Sue Smith Breast Center at Baylor. “Metastases, however, tend to respond differently than the primary tumour to the treatment in part due to residing in a different organ with a different microenvironment.” Until now, there has not been an effective experimental platform to study metastatic tumours in their new microenvironment. “We have created an experimental system in which we can mimic the interactions between cancer cells and bone cells, as bone is the place where breast cancer, and many other cancers too, disseminates most frequently,” said Zhang, who also is a McNair Scholar at Baylor. “We have developed a system that allows us to test many different drug responses simultaneously to discover the therapy that can selectively act on metastatic cancer cells and minimize the effect on the bone.” To mimic the interactions between metastatic breast cancer cells and bone cells in a living system in the lab, Zhang and his colleagues developed a bone metastasis model, called bone-in culture array, by fragmenting mouse bones that already contain breast cancer cells. The scientists determined that the bone-in culture maintains the micro-environmental characteristics of bone metastasis in living animal models, and the cancer cells maintain the gene expression profile, the growth pattern and their response to therapies. Using the bone-in model, the researchers determined that the drug danusertib preferentially inhibits bone metastasis. They also found that other drugs stimulate the growth of slow-growing cancer cells in the bone. In addition to determining the effect of drugs in the growth of metastasis in bone, the bone-in culture can be used to investigate mechanisms involved in bone colonization by cancer cells. Implications for cancer treatment “We think that this new system has the potential to be applied not only to breast cancer but to other cancers that also metastasize to the bone,” Zhang said. “This technique can be scaled up to larger sample sizes, which would help accelerate the process of discovering metastatic cancer treatments. We have already found a few interesting drugs. We will keep looking for more and focus on those that are most promising.”
Baylor College www.bcm.edu/news/cancer-breast/new-breast-cancer-metastasis-technique
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Research led by scientists at the University of Birmingham has revealed a new cause of high blood pressure which could lead to major changes in managing the disease. High blood pressure, also known as hypertension, often goes unnoticed but if left untreated can increase the risk of heart attack and stroke. Studies estimate that one in four adults suffer from hypertension, but most patients have no identifiable cause for the condition. However, it is known that in up to 10 per cent of hypertensive patients the overproduction of the adrenal hormone aldosterone – a condition known as primary aldosteronism or Conn syndrome – is the cause of disease. Now the University of Birmingham-led study has, for the first time, made the important discovery that a large number of patients with Conn syndrome do not only overproduce aldosterone but also the stress hormone cortisol. Professor Wiebke Arlt, Director of the Institute of Metabolism and Systems Research (IMSR) at the University of Birmingham, said: “Our findings show that the adrenal glands of many patients with Conn syndrome also produce too much cortisol, which finally explains puzzling results of previous studies in Conn patients. “These previous studies had found increased rates of type 2 diabetes, osteoporosis and depression in Conn patients – problems typically caused by overproduction of cortisol, also termed Cushing syndrome, and not by too much aldosterone.” The authors of the University of Birmingham-led study, conducted in collaboration with a group of scientists from Germany, decided to name this new cause of hypertension – the combined overproduction of aldosterone and cortisol – as Connshing syndrome. At present, many Conn syndrome patients are treated with drugs that are directed against the adverse effects of aldosterone. However, this leaves the cortisol excess untreated. Second author of the study, published in JCI Insight, Dr Katharina Lang – an academic clinical lecturer at IMSR – said: “These findings are very likely to change clinical practice. “Patients will now need to undergo more detailed assessment to clarify whether they suffer from Conn or Connshing syndrome.
University of Birmingham www.birmingham.ac.uk/news/latest/2017/04/connshing-syndrome.aspx
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DGIST research team led by Professor CheolGi Kim has developed a biosensor platform which has 20 times faster detection capability than the existing biosensors using magnetic patterns resembling a spider web. The sensing capability of a biosensor is determined by the resolution of the sensor and the movement and reaction rate of molecules. Many research groups in Korea and other countries have been improving the resolution through the development of nanomaterials but there has been a limitation to improve the sensors’ sensitivity due to the low diffusion transport of biomolecules toward the sensing region. Professor Kim and his research team used a magnetic field in order to overcome the drawback that the movement of biomolecules such as proteins and DNA is slow when the transport only depends on diffusion. The biomolecules labelled with superparamagnetic particles and the use of an external magnetic field enabled the movement of the biomolecules to be easily controlled and detected with an ultra-sensitive magnetic sensor. The research team developed a new biosensor platform using a spider web-shaped micro-magnetic pattern. It improved the sensing ability of the biosensor as it increased the ability to collect low-density biomolecules by attracting biomolecules labelled with the superparamagnetic particles to the sensing area. The first author Byeonghwa Lim at DGIST’s Ph.D program of Emerging Materials Science elaborated on the biosensor platform, "We placed a spider web-shaped micro-magnetic pattern which was designed to move the superparamagnetic particles toward the center of the biosensor and a high sensitivity biosensor on the platform. When a rotating magnetic field is applied to a spider web-shaped magnetic pattern, it can attract biomolecules labelled with superparamagnetic particles faster to the sensor. The speed of the movement is very fast and it can detect the subject 20 times faster than the diffusion method." The research team also succeeded in monitoring the biomolecules conjugated to the superparamagnetic particles at a distance from the sensing area by utilizing the biosensor platform. In addition, the team has identified that the superparamagnetic particles not only play the role of biomolecular cargo for transportation, but also act as labels for the sensor to indicate the location of biomolecules. Professor Kim stated "The existing biosensors require long time to detect low density biomolecules and result in poor sensing efficiency as they only depend on diffusion. The magnetic field based biosensor platform improves the collection capability of biomolecules and increases the speed and sensitivity of the biomolecules movement. Therefore, we are planning to use this platform for early diagnosis as well as recurrence diagnosis of diseases such as cancer. "
Recent advances in large-scale clinical DNA sequencing have led to genetic diagnoses for many rare disease patients, but the diagnosis rate based on these approaches is still far from perfect. On average, clinicians are unable to provide a genetic diagnosis for over half of patients in the clinic. The lack of a clear genetic diagnosis can lead to profound uncertainty about patients’ long-term prognoses, treatment options, and family planning decisions. In a new Science Translational Medicine study, a team led by researchers from the Broad Institute of MIT and Harvard and the National Institute of Neurological Disorders and Stroke adds RNA sequencing to the diagnostic toolkit to identify disease-causing mutations buried inside the genome. The researchers sequenced the RNA from muscle samples of 50 patients with undiagnosed genetic muscle disorders — who had undergone extensive genetic testing — and, in conjunction with DNA sequence information and a reference database, successfully located pathogenic mutations that had previously gone undetected in one-third of the patients. The study firmly positions RNA sequencing as a tool that adds additional power to the existing set of technologies deployed to solve genetic disease mysteries. “For some patients, we know that there is variation in the human genome, with an effect on the transcript, that we just haven’t been capturing with our traditional genetic sequencing methods,” says senior author Daniel MacArthur, co-director of the Medical and Population Genetics Program at the Broad Institute and group leader at Massachusetts General Hospital. “With RNA sequencing, we were able to take a set of patients who had gone through diagnostic odysseys — often lasting many years, where many methods had been used to try to detect the cause of their disease without success — and find the biological answers that previous technologies had missed.” Having a molecular diagnosis in-hand is a medical milestone for some patients and their families, and opens the door to potential therapies while offering some peace of mind. “For example, one patient’s family had opted to delay having other children until they knew the genetic basis of her condition,” MacArthur adds. “Our clinical collaborators were able to report that they had found the genetic cause, and now the parents have the option of prenatal testing for that mutation.” The study demonstrates that RNA sequencing, or RNA-seq, applied to relevant tissue samples and coupled with genetic analysis, can detect pathogenic mutations hidden in the noncoding sections of a gene, highlight relevant mutations missed in the noise of whole-genome analysis, and rule out other genetic variants suspected to cause disease. Previously, the technology was rarely applied in a clinical setting, and then only for single patients when specific mutations were already suspected — but the research team saw the potential for RNA-seq to augment other clinical tools earlier in diagnostics.
Broad Institute of MIT and Harvard www.broadinstitute.org/news/rna-sequencing-applied-tool-solve-patients%E2%80%99-diagnostic-mysteries
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A gene involved in brain development that can lead to severe disability and infant death has been identified by scientists. Mutations in the gene cause profound developmental problems and seizures in young children, researchers have found. Scientists and doctors worked with children with a range of severe problems, including seizures and abnormal brain scans, and discovered that the infants all had mutations in a gene known as PLAA. The researchers have named the condition PLAA-associated neurodevelopment disorder, or PLAAND. By making a mouse with the same mutation as found in patients, the team – led by the University of Edinburgh – showed how this gene had to function properly for the healthy brain to develop. PLAA is essential for signalling cells to clear build-up of damaged proteins, which is crucial for brain cell function, the researchers say. Cells in children with PLAAND have lost this ability and damaged proteins build up, causing severe problems in brain development and at synapses – parts of brain cells that communicate with other cells. Insights learned from the study may enable scientists to uncover new drugs to treat this rare disease. They could also shed light on conditions such as Alzheimer’s disease, in which there is also an issue with damaged protein build up. Pinpointing mutations in this gene that lead to such severe outcomes in the affected children is an important advance. Children affected with PLAAND die before the age of six and most heart-breaking for their families is that they fail to meet any developmental milestones. There is no treatment currently available. In identifying this gene and the processes it controls, we have made significant steps in understanding its role in healthy brain development, which will help us target drug studies in future.
University of Edinburgh www.ed.ac.uk/news/2017/fatal-childhood-disorder-gene
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Randox is a global leader in healthcare diagnostics, with more than 370 million people across 145 countries receiving a medical diagnosis from one of our products each day. For more than 30 years Randox has been shaping the future of clinical diagnostics with our pioneering high quality, cost effective laboratory solutions. Join us at stand #13 on Monday 12th June, 11 am, for an exclusive brunch, where we will be launching 6 exciting new products into the European market.
In addition to this launch, we will be hosting LIVE demonstrations of these products, featuring; Acusera 24.7 the most powerful QC data management software, the RX altona semi-automated & Modena fully automated clinical chemistry analysers and our Evidence Evolution & Evidence MultiSTAT. There will also be talks on our new HDL3-C Reagent and its use in more extensive lipid profiling.
These will take place Monday to Wednesday at the following times: 11:00-11:20 12:20-12:40 12:45-13:05 13:10-13:30 15:10-15:30 Don’t miss your opportunity to find out more about these laboratory innovations for yourself. Education Randox will also be hosting two ISWs at the Euromedlab conference. These are being held on Tuesday 13th and Wednesday 14th June. The details for these educational events are; EduW16 – Meeting ISO 15189 requirements for Uncertainty of Measurement
·When: Tuesday 13th June 2017
·Time: 15:45-16:45
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·Speaker: Margaret Fick
·Chair: Prof. MM. Corsi Romanelli MD PHD
Book your place now – https://measurement-uncertainty-eduw-16.eventbrite.co.uk
EduW31 – A rapid multi-analyte biochip array for early stroke diagnosis
·When: Wednesday 14th June 2017
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·Speakers: Jim Curry and Dr. Konstantinos Makris
·Chair: Prof. MM. Corsi Romanelli MD PHD
Book your place now – https://www.eventbrite.co.uk/e/eduw-31-a-rapid-multi-analyte-biochip-array-for-early-stroke-diagnosis-tickets-33215586714
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This article presents data from a multicenter evaluation of the VERIS HCV assay that runs on the DxN VERIS Molecular Diagnostics System.* The study by Braun et al. was published online at the Journal of Clinical Microbiology in February 2017, and is to be published in print in the journal’s April issue. Data includes an assessment of system performance related to precision, analytical sensitivity, analytical measurement range and clinical specificity. The study featured a large number of tests performed by ten (10) participating evaluation sites based in the United Kingdom, Germany, Italy, Spain and France.
Study results demonstrated overall precision with a standard deviation (SD) of 0.22 log IU/mL or lower for each level tested. This was despite the challenges involved with the evaluation of a high number of sites. The analytical sensitivity observed among the sites was between 6.2 and 9.0 IU/mL. A broad linear range and detection of all HCV genotypes were also demonstrated.
The data is robust owing to the large numbers of tests performed. The analytical results demonstrate that the VERIS HCV assay meets the recommendations of current clinical guidelines for patient management in terms of performance and precision. The consistency of the VERIS HCV assay’s analytical performance is, in part, ascribed to the fully automated capabilities of the DxN VERIS System.
To review the full abstract please visit http://jcm.asm.org/content/early/2017/01/27/JCM.02163-16.abstract.
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Scientists at the Francis Crick Institute and UCL have found that unstable chromosomes within lung tumours increase the risk of cancer returning after surgery, and have used this new knowledge to determine the risk of relapse up to a year before the cancer returns. These are the first findings from the Cancer Research UK-funded TRACERx lung cancer study. TRACERx is the first study to look at the evolution of cancer in real time and immense detail. Researchers followed patients all the way from diagnosis through to either disease relapse or cure after surgery, tracking and analysing how their cancer developed. Professor Charles Swanton, the study’s lead researcher based at the Crick, said: "The TRACERx study is Cancer Research UK’s single biggest investment in lung cancer, and for the first time we’ve revealed new insights into how tumours evolve and evade treatment, a leading cause of cancer death. "We believe that this invaluable data generated during TRACERx will be seized upon by research teams across the world, helping us to answer more questions about lung cancer biology. We’ve only scraped the surface in terms of what is possible by looking at tumour evolution in such detail." In one study scientists analysed tumours from 100 non-small cell lung cancer (NSCLC) patients. They found that unstable chromosomes are the driving force behind genetic diversity within tumours. They also showed that patients with a high proportion of unstable chromosomes in their tumour were more than four times more likely to have their cancer return, or die from their disease, within two years. This is because genetically diverse tumours are more likely to evolve, spread and become drug resistant, making a patient’s cancer much harder to treat. Dr Mariam Jamal-Hanjani, lead author based at the UCL Cancer Institute, said: "Determining the relationship between diversity within tumours and patient survival is one of the primary goals of TRACERx, so to find evidence for this so early on in the study is really encouraging. "We’ve also identified what causes lung cancer to advance, providing us with insight into the biological processes that shape the evolution of the disease." Armed with this discovery, researchers conducted a second study, published today in Nature, to investigate whether this genetic diversity could be tracked clinically. Using blood samples from 96 of the 100 patients, they demonstrated that the patchwork of genetic faults present in non-small cell lung cancer, could be monitored using bits of DNA in the blood that have broken off from a tumour (circulating tumour DNA). They then analysed blood taken from 24 patients after surgery for NSCLC, and accurately identified more than 90 per cent of those destined to relapse – up to a year before clinical imaging could confirm the disease’s return. This finding opens up numerous opportunities for new drug trials in lung cancer to try to prevent relapse. Monitoring benefit from chemotherapy after surgery is not currently possible as there are often no clinical signs of disease. With this in mind, the team also compared circulating tumour DNA levels immediately before and after chemotherapy was given to patients following surgery. When levels of tumour DNA in the blood were not reduced following chemotherapy, the disease returned, suggesting that at least part of the tumour had become resistant to treatment. The results provide a new means to monitor treatment after surgery, and point to an avenue for new treatments to target parts of the tumour that are resistant to existing approaches.
Francis Crick Institute www.crick.ac.uk/news/science-news/2017/04/26/tracking-unstable-chromosomes-helps-predict-lung-cancers-return/
A gene previously identified as critical for tumour growth in many human cancers also maintains intestinal stem cells and encourages the growth of cells that support them, according to results of a study led by Johns Hopkins researchers. The finding adds to evidence for the intimate link between stem cells and cancer, and advances prospects for regenerative medicine and cancer treatments. Study leader Linda M. S. Resar, M.D., professor of medicine, oncology and pathology at the Institute for Cellular Engineering at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center, has been studying genes in the high-mobility group (HMG) family for over two decades. Several years ago, while creating a genetically engineered mouse that expresses high levels of the mouse HMGA1 gene to investigate its role in leukaemia, Resar and her colleagues made the chance finding that the intestines of these animals were much larger and heavier than those of “wild-type” animals (or control mice that were not genetically modified). The mouse intestines were also riddled with polyps, abnormal growths projecting from the intestinal lining that can be precursors of cancer. In fact, polyps in humans frequently progress to colon cancer, which is why they are removed during screening colonoscopies in people over 50 and others at risk for colon cancer. To better understand how HMGA1 affected the rodents’ intestines, Resar and Lingling Xian, M.D., Ph.D., research associate at the Johns Hopkins University School of Medicine, and their colleagues examined the transgenic animals’ intestinal cells to determine which ones were expressing this gene. Several different experiments localized the active gene and its protein to stem cells buried within the crypts, or deep grooves in the intestinal lining. After isolating these stem cells from both transgenic and wild-type mice, the researchers found that those carrying the HMGA1 transgene multiplied far more rapidly, forming identical daughter cells in a process called self-renewal, which is a defining property of all stem cells. These transgenic stem cells also readily created intestinal tissues called “organoids” in laboratory dishes. These organoids had more stem cells than those isolated from wild-type mice. Further investigation, says Resar, showed that these unusual properties arise from the ability of HMGA1 to turn on several genes involved in the Wnt pathway, a network of proteins necessary for embryonic development and stem cell activity. Stem cells do not function in isolation, explains Resar. They need a “niche” to survive and maintain an undifferentiated state. From the French word nicher, which means to build a nest, a niche is a nest-like compartment comprised of cells that secrete growth factors and other proteins that help stem cells survive. The niche also prevents stem cells from morphing into mature intestinal cells until new intestinal cells are needed. Intestinal stem cells are particularly important because a new intestinal lining is generated about every 4-5 days. Looking further into the intestinal crypts of both the transgenic and wild-type mice, the research team made what they consider a surprising finding: Not only was HMGA1 causing the stem cells themselves to self-renew or proliferate more rapidly in the transgenic animals, but it was also increasing the number of Paneth cells, a type of niche cell known to support intestinal stem cells. Additional experiments showed that the protein produced by HMGA1 activates another gene called Sox9, which is directly responsible for turning stem cells into Paneth cells. “We suspected that HMGA1 might generate new stem cells, but we were extremely surprised that it also helps support these cells by building a niche,” Resar says. “We believe that our experiments provide the first example of a factor that both expands the intestinal stem cell compartment and builds a niche.” Many genes that are involved in the growth and development of embryos or adult stem cells also play roles in cancer, Resar adds. After scanning the Cancer Genome Atlas, a database of genes expressed in human cancers, the research team discovered that the activity of both HMGA1 and SOX9 genes are tightly correlated in normal colon tissue, and both genes become highly overexpressed in colon cancer. “This tells us that the pathway turned on by HMGA1 in normal intestinal stem cells becomes disrupted and hyperactive in colon cancer,” Resar says.
John Hopkins Hospital www.hopkinsmedicine.org/news/media/releases/single_gene_encourages_growth_of_intestinal_stem_cells_supporting_niche_cellsand_cancer_
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Scientists discover biological evidence of “atypical” Chronic Fatigue Syndrome
, /in E-News /by 3wmediaScientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health are the first to report immune signatures differentiating two subgroups of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): “classical” and “atypical.” This complex, debilitating disease is characterized by symptoms ranging from extreme fatigue after exertion to difficulty concentrating, headaches, and muscle pain.
Typically, symptoms of ME/CFS begin suddenly following a flu-like infection, but a subset of cases classified by the investigators as “atypical” follows a different disease course, either from triggers preceding symptoms by months or years, or accompanied by the later development of additional serious illnesses.
To uncover evidence of these disease types, first author Mady Hornig, MD, director of translational research at CII and associate professor of Epidemiology at Mailman, and colleagues used immunoassays to measure levels of 51 immune biomarkers in cerebrospinal fluid samples taken from 32 cases of classical and 27 cases of atypical ME/CFS. All study participants were diagnosed using the same standard criteria, but atypical cases either had prior histories of viral encephalitis, illness after foreign travel or blood transfusion, or later developed a concurrent malady—seizure disorders, multiple sclerosis-like demyelinating disorders, Gulf War Illness, or a range of cancers—at rates much higher than seen in the general population.
Their analysis revealed lower levels of immune molecules in individuals with atypical ME/CFS than those with a classical presentation and course of illness, including dramatically lower levels of interleukin 7 (IL7), a protein linked to viral infections, and interleukin 17A (IL 17A) and chemokine (C-X-C motif) ligand 9 (CXCL9), inflammatory molecules implicated in a variety of neurological disorders.
“We now have biological evidence that the triggers for ME/CFS may involve distinct pathways to disease, or, in some cases, predispose individuals to the later development of serious comorbidities,” says Hornig. “Importantly, our results suggest that these early biomarker profiles may be detectable soon after diagnosis of ME/CFS, laying a foundation for better understanding of and treatments for this complex and poorly understood illness.”
“Early identification of patients who meet the usual clinical criteria when first diagnosed but then go on to develop atypical features would help clinicians like myself identify and treat these complex cases and even prevent fatal outcomes,” says co-author Daniel L. Peterson, MD, principal clinician at Sierra Internal Medicine in Incline Village, NV.
The new study builds on earlier research by Hornig and collaborators that found robust evidence of distinct stages in ME/CFS. A pair of 2015 publications based on analyses of blood and cerebrospinal fluid showed differences in the immune signatures of ME/CFS patients who had the disease for three years or less as compared with those who had been ill for more than three years. The researchers reported that patients were flush with cytokines and chemokines until around the three-year mark—suggesting an over-activated immune response in that phase of the illness; thereafter the immune system showed evidence of “exhaustion,” and levels of immune molecules dropped.
In the new study, both subsets of ME/CFS patients showed signs of an unbalanced or dysregulated immune system within the central nervous system, with immune markers different than those seen in healthy individuals. However, the dampened immune profiles previously observed after the three-year mark were only observed in individuals with the classical form of the disease, not in those with atypical ME/CFS. Among subjects in the atypical group, levels of cytokines and chemokines were more likely to remain steady or increase.
According to Hornig, instead of the immune exhaustion seen in later phases of classical ME/CFS, atypical patients may be experiencing a “smouldering inflammatory process” in which the immune system is still working to recover, although she acknowledges that much work remains to be done to confirm this hypothesis. Alternatively, these findings could suggest a pathway to disease in atypical individuals that involves biomarkers not captured in the 51-molecule assay, potentially even involving non-immune-related processes. Atypical individuals may also have genetic susceptibilities that lead their immune systems to respond differently than in classical cases.
Columbia University Mailman School of Public Health]
www.mailman.columbia.edu/public-health-now/news/scientists-discover-biological-evidence-atypical-chronic-fatigue-syndrome
New technique tests therapies for breast cancer metastasis
, /in E-News /by 3wmediaA new laboratory technique developed by researchers at Baylor College of Medicine and other institutions can rapidly test the effectiveness of treatments for life-threatening breast cancer metastases in bone.
“For a number of breast cancer patients, the problem is metastasis – the dissemination of breast tumour cells to other organs – after the primary tumour has been eliminated,” said corresponding author Dr. Xiang Zhang, associate professor of molecular and cellular biology and the Lester and Sue Smith Breast Center at Baylor. “Metastases, however, tend to respond differently than the primary tumour to the treatment in part due to residing in a different organ with a different microenvironment.”
Until now, there has not been an effective experimental platform to study metastatic tumours in their new microenvironment.
“We have created an experimental system in which we can mimic the interactions between cancer cells and bone cells, as bone is the place where breast cancer, and many other cancers too, disseminates most frequently,” said Zhang, who also is a McNair Scholar at Baylor. “We have developed a system that allows us to test many different drug responses simultaneously to discover the therapy that can selectively act on metastatic cancer cells and minimize the effect on the bone.”
To mimic the interactions between metastatic breast cancer cells and bone cells in a living system in the lab, Zhang and his colleagues developed a bone metastasis model, called bone-in culture array, by fragmenting mouse bones that already contain breast cancer cells.
The scientists determined that the bone-in culture maintains the micro-environmental characteristics of bone metastasis in living animal models, and the cancer cells maintain the gene expression profile, the growth pattern and their response to therapies.
Using the bone-in model, the researchers determined that the drug danusertib preferentially inhibits bone metastasis. They also found that other drugs stimulate the growth of slow-growing cancer cells in the bone.
In addition to determining the effect of drugs in the growth of metastasis in bone, the bone-in culture can be used to investigate mechanisms involved in bone colonization by cancer cells.
Implications for cancer treatment
“We think that this new system has the potential to be applied not only to breast cancer but to other cancers that also metastasize to the bone,” Zhang said. “This technique can be scaled up to larger sample sizes, which would help accelerate the process of discovering metastatic cancer treatments. We have already found a few interesting drugs. We will keep looking for more and focus on those that are most promising.”
Baylor College
www.bcm.edu/news/cancer-breast/new-breast-cancer-metastasis-technique
Scientists name ‘Connshing syndrome’ as a new cause of high blood pressure
, /in E-News /by 3wmediaResearch led by scientists at the University of Birmingham has revealed a new cause of high blood pressure which could lead to major changes in managing the disease.
High blood pressure, also known as hypertension, often goes unnoticed but if left untreated can increase the risk of heart attack and stroke.
Studies estimate that one in four adults suffer from hypertension, but most patients have no identifiable cause for the condition.
However, it is known that in up to 10 per cent of hypertensive patients the overproduction of the adrenal hormone aldosterone – a condition known as primary aldosteronism or Conn syndrome – is the cause of disease.
Now the University of Birmingham-led study has, for the first time, made the important discovery that a large number of patients with Conn syndrome do not only overproduce aldosterone but also the stress hormone cortisol.
Professor Wiebke Arlt, Director of the Institute of Metabolism and Systems Research (IMSR) at the University of Birmingham, said: “Our findings show that the adrenal glands of many patients with Conn syndrome also produce too much cortisol, which finally explains puzzling results of previous studies in Conn patients.
“These previous studies had found increased rates of type 2 diabetes, osteoporosis and depression in Conn patients – problems typically caused by overproduction of cortisol, also termed Cushing syndrome, and not by too much aldosterone.”
The authors of the University of Birmingham-led study, conducted in collaboration with a group of scientists from Germany, decided to name this new cause of hypertension – the combined overproduction of aldosterone and cortisol – as Connshing syndrome.
At present, many Conn syndrome patients are treated with drugs that are directed against the adverse effects of aldosterone. However, this leaves the cortisol excess untreated.
Second author of the study, published in JCI Insight, Dr Katharina Lang – an academic clinical lecturer at IMSR – said: “These findings are very likely to change clinical practice.
“Patients will now need to undergo more detailed assessment to clarify whether they suffer from Conn or Connshing syndrome.
University of Birmingham
www.birmingham.ac.uk/news/latest/2017/04/connshing-syndrome.aspx
20 Times Faster Biosensor
, /in E-News /by 3wmediaDGIST research team led by Professor CheolGi Kim has developed a biosensor platform which has 20 times faster detection capability than the existing biosensors using magnetic patterns resembling a spider web.
The sensing capability of a biosensor is determined by the resolution of the sensor and the movement and reaction rate of molecules. Many research groups in Korea and other countries have been improving the resolution through the development of nanomaterials but there has been a limitation to improve the sensors’ sensitivity due to the low diffusion transport of biomolecules toward the sensing region.
Professor Kim and his research team used a magnetic field in order to overcome the drawback that the movement of biomolecules such as proteins and DNA is slow when the transport only depends on diffusion. The biomolecules labelled with superparamagnetic particles and the use of an external magnetic field enabled the movement of the biomolecules to be easily controlled and detected with an ultra-sensitive magnetic sensor.
The research team developed a new biosensor platform using a spider web-shaped micro-magnetic pattern. It improved the sensing ability of the biosensor as it increased the ability to collect low-density biomolecules by attracting biomolecules labelled with the superparamagnetic particles to the sensing area.
The first author Byeonghwa Lim at DGIST’s Ph.D program of Emerging Materials Science elaborated on the biosensor platform, "We placed a spider web-shaped micro-magnetic pattern which was designed to move the superparamagnetic particles toward the center of the biosensor and a high sensitivity biosensor on the platform. When a rotating magnetic field is applied to a spider web-shaped magnetic pattern, it can attract biomolecules labelled with superparamagnetic particles faster to the sensor. The speed of the movement is very fast and it can detect the subject 20 times faster than the diffusion method."
The research team also succeeded in monitoring the biomolecules conjugated to the superparamagnetic particles at a distance from the sensing area by utilizing the biosensor platform. In addition, the team has identified that the superparamagnetic particles not only play the role of biomolecular cargo for transportation, but also act as labels for the sensor to indicate the location of biomolecules.
Professor Kim stated "The existing biosensors require long time to detect low density biomolecules and result in poor sensing efficiency as they only depend on diffusion. The magnetic field based biosensor platform improves the collection capability of biomolecules and increases the speed and sensitivity of the biomolecules movement. Therefore, we are planning to use this platform for early diagnosis as well as recurrence diagnosis of diseases such as cancer. "
DGIST
en.dgist.ac.kr/site/dgist_eng/menu/508.do?siteId=dgist_eng&snapshotId=3&pageId=429&cmd=read&contentNo=34358
RNA sequencing applied as a tool to solve patients’ diagnostic mysteries
, /in E-News /by 3wmediaRecent advances in large-scale clinical DNA sequencing have led to genetic diagnoses for many rare disease patients, but the diagnosis rate based on these approaches is still far from perfect. On average, clinicians are unable to provide a genetic diagnosis for over half of patients in the clinic. The lack of a clear genetic diagnosis can lead to profound uncertainty about patients’ long-term prognoses, treatment options, and family planning decisions.
In a new Science Translational Medicine study, a team led by researchers from the Broad Institute of MIT and Harvard and the National Institute of Neurological Disorders and Stroke adds RNA sequencing to the diagnostic toolkit to identify disease-causing mutations buried inside the genome.
The researchers sequenced the RNA from muscle samples of 50 patients with undiagnosed genetic muscle disorders — who had undergone extensive genetic testing — and, in conjunction with DNA sequence information and a reference database, successfully located pathogenic mutations that had previously gone undetected in one-third of the patients. The study firmly positions RNA sequencing as a tool that adds additional power to the existing set of technologies deployed to solve genetic disease mysteries.
“For some patients, we know that there is variation in the human genome, with an effect on the transcript, that we just haven’t been capturing with our traditional genetic sequencing methods,” says senior author Daniel MacArthur, co-director of the Medical and Population Genetics Program at the Broad Institute and group leader at Massachusetts General Hospital. “With RNA sequencing, we were able to take a set of patients who had gone through diagnostic odysseys — often lasting many years, where many methods had been used to try to detect the cause of their disease without success — and find the biological answers that previous technologies had missed.”
Having a molecular diagnosis in-hand is a medical milestone for some patients and their families, and opens the door to potential therapies while offering some peace of mind. “For example, one patient’s family had opted to delay having other children until they knew the genetic basis of her condition,” MacArthur adds. “Our clinical collaborators were able to report that they had found the genetic cause, and now the parents have the option of prenatal testing for that mutation.”
The study demonstrates that RNA sequencing, or RNA-seq, applied to relevant tissue samples and coupled with genetic analysis, can detect pathogenic mutations hidden in the noncoding sections of a gene, highlight relevant mutations missed in the noise of whole-genome analysis, and rule out other genetic variants suspected to cause disease. Previously, the technology was rarely applied in a clinical setting, and then only for single patients when specific mutations were already suspected — but the research team saw the potential for RNA-seq to augment other clinical tools earlier in diagnostics.
Broad Institute of MIT and Harvard
www.broadinstitute.org/news/rna-sequencing-applied-tool-solve-patients%E2%80%99-diagnostic-mysteries
Cause of fatal childhood disorder revealed in gene study
, /in E-News /by 3wmediaA gene involved in brain development that can lead to severe disability and infant death has been identified by scientists.
Mutations in the gene cause profound developmental problems and seizures in young children, researchers have found.
Scientists and doctors worked with children with a range of severe problems, including seizures and abnormal brain scans, and discovered that the infants all had mutations in a gene known as PLAA. The researchers have named the condition PLAA-associated neurodevelopment disorder, or PLAAND.
By making a mouse with the same mutation as found in patients, the team – led by the University of Edinburgh – showed how this gene had to function properly for the healthy brain to develop.
PLAA is essential for signalling cells to clear build-up of damaged proteins, which is crucial for brain cell function, the researchers say.
Cells in children with PLAAND have lost this ability and damaged proteins build up, causing severe problems in brain development and at synapses – parts of brain cells that communicate with other cells.
Insights learned from the study may enable scientists to uncover new drugs to treat this rare disease. They could also shed light on conditions such as Alzheimer’s disease, in which there is also an issue with damaged protein build up.
Pinpointing mutations in this gene that lead to such severe outcomes in the affected children is an important advance.
Children affected with PLAAND die before the age of six and most heart-breaking for their families is that they fail to meet any developmental milestones. There is no treatment currently available. In identifying this gene and the processes it controls, we have made significant steps in understanding its role in healthy brain development, which will help us target drug studies in future.
University of Edinburgh
www.ed.ac.uk/news/2017/fatal-childhood-disorder-gene
Find out how Randox are shaping the future of clinical diagnostics at Euromedlab
, /in E-News /by 3wmediaRandox is a global leader in healthcare diagnostics, with more than 370 million people across 145 countries receiving a medical diagnosis from one of our products each day. For more than 30 years Randox has been shaping the future of clinical diagnostics with our pioneering high quality, cost effective laboratory solutions. Join us at stand #13 on Monday 12th June, 11 am, for an exclusive brunch, where we will be launching 6 exciting new products into the European market.
In addition to this launch, we will be hosting LIVE demonstrations of these products, featuring; Acusera 24.7 the most powerful QC data management software, the RX altona semi-automated & Modena fully automated clinical chemistry analysers and our Evidence Evolution & Evidence MultiSTAT. There will also be talks on our new HDL3-C Reagent and its use in more extensive lipid profiling.
These will take place Monday to Wednesday at the following times:
11:00-11:20 12:20-12:40 12:45-13:05 13:10-13:30 15:10-15:30
Don’t miss your opportunity to find out more about these laboratory innovations for yourself.
Education
Randox will also be hosting two ISWs at the Euromedlab conference. These are being held on Tuesday 13th and Wednesday 14th June. The details for these educational events are;
EduW16 – Meeting ISO 15189 requirements for Uncertainty of Measurement
· When: Tuesday 13th June 2017
· Time: 15:45-16:45
· Where: Trianti Hall
· Speaker: Margaret Fick
· Chair: Prof. MM. Corsi Romanelli MD PHD
Book your place now – https://measurement-uncertainty-eduw-16.eventbrite.co.uk
EduW31 – A rapid multi-analyte biochip array for early stroke diagnosis
· When: Wednesday 14th June 2017
· Time: 14:30-15:30
· Where: Hall A
· Speakers: Jim Curry and Dr. Konstantinos Makris
· Chair: Prof. MM. Corsi Romanelli MD PHD
Book your place now – https://www.eventbrite.co.uk/e/eduw-31-a-rapid-multi-analyte-biochip-array-for-early-stroke-diagnosis-tickets-33215586714
Study on the Analytical Performance of the DxN VERIS System HCV Assay
, /in E-News /by 3wmediaThis article presents data from a multicenter evaluation of the VERIS HCV assay that runs on the DxN VERIS Molecular Diagnostics System.* The study by Braun et al. was published online at the Journal of Clinical Microbiology in February 2017, and is to be published in print in the journal’s April issue. Data includes an assessment of system performance related to precision, analytical sensitivity, analytical measurement range and clinical specificity. The study featured a large number of tests performed by ten (10) participating evaluation sites based in the United Kingdom, Germany, Italy, Spain and France.
Study results demonstrated overall precision with a standard deviation (SD) of 0.22 log IU/mL or lower for each level tested. This was despite the challenges involved with the evaluation of a high number of sites. The analytical sensitivity observed among the sites was between 6.2 and 9.0 IU/mL. A broad linear range and detection of all HCV genotypes were also demonstrated.
The data is robust owing to the large numbers of tests performed. The analytical results demonstrate that the VERIS HCV assay meets the recommendations of current clinical guidelines for patient management in terms of performance and precision. The consistency of the VERIS HCV assay’s analytical performance is, in part, ascribed to the fully automated capabilities of the DxN VERIS System.
To review the full abstract please visit http://jcm.asm.org/content/early/2017/01/27/JCM.02163-16.abstract.
Tracking unstable chromosomes helps predict lung cancer’s return
, /in E-News /by 3wmediaScientists at the Francis Crick Institute and UCL have found that unstable chromosomes within lung tumours increase the risk of cancer returning after surgery, and have used this new knowledge to determine the risk of relapse up to a year before the cancer returns. These are the first findings from the Cancer Research UK-funded TRACERx lung cancer study.
TRACERx is the first study to look at the evolution of cancer in real time and immense detail. Researchers followed patients all the way from diagnosis through to either disease relapse or cure after surgery, tracking and analysing how their cancer developed.
Professor Charles Swanton, the study’s lead researcher based at the Crick, said: "The TRACERx study is Cancer Research UK’s single biggest investment in lung cancer, and for the first time we’ve revealed new insights into how tumours evolve and evade treatment, a leading cause of cancer death.
"We believe that this invaluable data generated during TRACERx will be seized upon by research teams across the world, helping us to answer more questions about lung cancer biology. We’ve only scraped the surface in terms of what is possible by looking at tumour evolution in such detail."
In one study scientists analysed tumours from 100 non-small cell lung cancer (NSCLC) patients. They found that unstable chromosomes are the driving force behind genetic diversity within tumours.
They also showed that patients with a high proportion of unstable chromosomes in their tumour were more than four times more likely to have their cancer return, or die from their disease, within two years.
This is because genetically diverse tumours are more likely to evolve, spread and become drug resistant, making a patient’s cancer much harder to treat.
Dr Mariam Jamal-Hanjani, lead author based at the UCL Cancer Institute, said: "Determining the relationship between diversity within tumours and patient survival is one of the primary goals of TRACERx, so to find evidence for this so early on in the study is really encouraging.
"We’ve also identified what causes lung cancer to advance, providing us with insight into the biological processes that shape the evolution of the disease."
Armed with this discovery, researchers conducted a second study, published today in Nature, to investigate whether this genetic diversity could be tracked clinically.
Using blood samples from 96 of the 100 patients, they demonstrated that the patchwork of genetic faults present in non-small cell lung cancer, could be monitored using bits of DNA in the blood that have broken off from a tumour (circulating tumour DNA).
They then analysed blood taken from 24 patients after surgery for NSCLC, and accurately identified more than 90 per cent of those destined to relapse – up to a year before clinical imaging could confirm the disease’s return.
This finding opens up numerous opportunities for new drug trials in lung cancer to try to prevent relapse.
Monitoring benefit from chemotherapy after surgery is not currently possible as there are often no clinical signs of disease.
With this in mind, the team also compared circulating tumour DNA levels immediately before and after chemotherapy was given to patients following surgery. When levels of tumour DNA in the blood were not reduced following chemotherapy, the disease returned, suggesting that at least part of the tumour had become resistant to treatment.
The results provide a new means to monitor treatment after surgery, and point to an avenue for new treatments to target parts of the tumour that are resistant to existing approaches.
Francis Crick Institute
www.crick.ac.uk/news/science-news/2017/04/26/tracking-unstable-chromosomes-helps-predict-lung-cancers-return/
Single gene encourages growth of intestinal stem cells, supporting “Niche” cells-and cancer
, /in E-News /by 3wmediaA gene previously identified as critical for tumour growth in many human cancers also maintains intestinal stem cells and encourages the growth of cells that support them, according to results of a study led by Johns Hopkins researchers. The finding adds to evidence for the intimate link between stem cells and cancer, and advances prospects for regenerative medicine and cancer treatments.
Study leader Linda M. S. Resar, M.D., professor of medicine, oncology and pathology at the Institute for Cellular Engineering at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center, has been studying genes in the high-mobility group (HMG) family for over two decades. Several years ago, while creating a genetically engineered mouse that expresses high levels of the mouse HMGA1 gene to investigate its role in leukaemia, Resar and her colleagues made the chance finding that the intestines of these animals were much larger and heavier than those of “wild-type” animals (or control mice that were not genetically modified). The mouse intestines were also riddled with polyps, abnormal growths projecting from the intestinal lining that can be precursors of cancer. In fact, polyps in humans frequently progress to colon cancer, which is why they are removed during screening colonoscopies in people over 50 and others at risk for colon cancer.
To better understand how HMGA1 affected the rodents’ intestines, Resar and Lingling Xian, M.D., Ph.D., research associate at the Johns Hopkins University School of Medicine, and their colleagues examined the transgenic animals’ intestinal cells to determine which ones were expressing this gene. Several different experiments localized the active gene and its protein to stem cells buried within the crypts, or deep grooves in the intestinal lining.
After isolating these stem cells from both transgenic and wild-type mice, the researchers found that those carrying the HMGA1 transgene multiplied far more rapidly, forming identical daughter cells in a process called self-renewal, which is a defining property of all stem cells. These transgenic stem cells also readily created intestinal tissues called “organoids” in laboratory dishes. These organoids had more stem cells than those isolated from wild-type mice.
Further investigation, says Resar, showed that these unusual properties arise from the ability of HMGA1 to turn on several genes involved in the Wnt pathway, a network of proteins necessary for embryonic development and stem cell activity.
Stem cells do not function in isolation, explains Resar. They need a “niche” to survive and maintain an undifferentiated state. From the French word nicher, which means to build a nest, a niche is a nest-like compartment comprised of cells that secrete growth factors and other proteins that help stem cells survive. The niche also prevents stem cells from morphing into mature intestinal cells until new intestinal cells are needed. Intestinal stem cells are particularly important because a new intestinal lining is generated about every 4-5 days.
Looking further into the intestinal crypts of both the transgenic and wild-type mice, the research team made what they consider a surprising finding: Not only was HMGA1 causing the stem cells themselves to self-renew or proliferate more rapidly in the transgenic animals, but it was also increasing the number of Paneth cells, a type of niche cell known to support intestinal stem cells. Additional experiments showed that the protein produced by HMGA1 activates another gene called Sox9, which is directly responsible for turning stem cells into Paneth cells.
“We suspected that HMGA1 might generate new stem cells, but we were extremely surprised that it also helps support these cells by building a niche,” Resar says. “We believe that our experiments provide the first example of a factor that both expands the intestinal stem cell compartment and builds a niche.”
Many genes that are involved in the growth and development of embryos or adult stem cells also play roles in cancer, Resar adds. After scanning the Cancer Genome Atlas, a database of genes expressed in human cancers, the research team discovered that the activity of both HMGA1 and SOX9 genes are tightly correlated in normal colon tissue, and both genes become highly overexpressed in colon cancer. “This tells us that the pathway turned on by HMGA1 in normal intestinal stem cells becomes disrupted and hyperactive in colon cancer,” Resar says.
John Hopkins Hospital
www.hopkinsmedicine.org/news/media/releases/single_gene_encourages_growth_of_intestinal_stem_cells_supporting_niche_cellsand_cancer_