A new device for studying tumour cells can trap 10,000 individual cells in a single chip.
The technique, developed at the University of Michigan, could one day help screen potential cancer treatments based on an individual patient’s tumour and help researchers better understand so-called cancer stem cells. It also sheds light on a controversy: are large cells or small cells more likely to be cancer stem cells?
Cancer cells are not all the same, and one theory holds that no more than 5 percent of the cells in a tumour are cancer stem cells. These few may be the only cells capable of causing a relapse or metastasis.
‘Most normal cells will die if they are not anchored to something, but cancer stem cells can survive. They can become circulating tumour cells and come to another area of the body,’ said Euisik Yoon, professor of electrical engineering and computer science, and biomedical engineering.
The team led by Yoon designed and made a device that takes advantage of this ability in hopes of understanding cancer stem cells better: how to identify them, what causes them to grow or die, and how to target them with cancer treatments. Their chip contains up to 12,800 wells for catching individual cancer cells. The team tested the chip with breast cancer cells, donated by researchers in the U-M Comprehensive Cancer Center.
They mixed the cells into a solution and ran the liquid through tiny channels in a plastic chip. Each channel was lined with chambers for trapping single cells.
The chambers have small openings to a parallel channel, which creates a draft that draws cells in — sort of like the drain in a sink. Once a cell is trapped, it blocks that opening and stops the draft. This ensures that, most of the time, only one cell is pulled into each chamber.
The walls of the chamber are coated so that the cell can’t latch on. As a result, normal cells that can’t cause metastases die over the course of a few days, leaving behind just the cancer stem cells. These cells reproduce in their chambers, forming tiny floating colonies, or tumorspheres.
While the ability to isolate 10,000 individual cells is impressive, it wouldn’t be useful if the team had to manually record every one, as required by most devices that capture cancer cells. The key is their computer algorithm, capable of combing through the microscope images and assessing the size and number of cells in each well. The algorithm’s particular talent is identifying cells no matter whether they show up dimly or brightly in the microscope image.
‘Our method is special because we really want to enable the study of many cells at once,’ said Yu-Heng Cheng, a doctoral student in electrical engineering and computer science. ‘Cancer cells have many different appearances, and our algorithm recognizes them.’
University of Michigan
www.mcancer.org/news/archive/cancer-stem-cells-new-method-analyzes-10000-cells-once
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While searching for a non-invasive way to detect prostate cancer cells circulating in blood, Duke Cancer Institute researchers have identified some blood markers associated with tumour resistance to two common hormone therapies.
In a study, the Duke-led team reported that they isolated multiple key gene alterations in the circulating prostate tumour cells of patients who had developed resistance to abiraterone or enzalutamide.
Enzalutamide is a drug that blocks the male androgen receptor, and abiraterone is a drug that lowers testosterone levels. Both drugs are approved to treat hormone-resistant prostate cancer, but the tumours typically develop resistance within a few years.
The study, focusing on a small number of patients and using sophisticated blood analysis technology, demonstrated that circulating tumour cells detected in blood have the potential to reveal important genetic information that could guide treatments selection in the future, and suggest targets for new therapies.
“We have developed a method that allows us to examine the whole genome of rare circulating cancer cells in the blood, which is unique in each patient, and which can change over time during treatment,” said senior author Andrew Armstrong, M.D., a medical oncologist and co-director of Genitourinary Clinical-Translational Research at the Duke Cancer Institute (DCI).
“Among the genomic changes in the patients’ individual cancers, we were able to find key similarities between the cancer cells of men who have hormone-resistant prostate cancer,” Armstrong said. “Our goal is to develop a ‘liquid biopsy’ that would be non-invasive, yet provide information that could guide clinical decisions.”
Armstrong and colleagues from the DCI and the Duke Molecular Physiology Institute used a process called array-based comparative genomic hybridization to analyse the genome of the circulating tumour cells of 16 men with advanced, treatment-resistant prostate cancer. The technique enabled them to determine which genes had extra copies and which regions were deleted.
Focusing both on genes that have previously been implicated in tumour progression, plus other genes important to cancer biology, the researchers found changes in multiple genetic pathways that appear to be in common among the men’s circulating tumour cells.
“Our research provides evidence supporting the ability to measure gains and losses of large scale sections of the circulating tumour cells genome in men with prostate cancer,” said co-author Simon Gregory, Ph.D., director of the Section of Genomics and Epigenetics in the Duke Molecular Physiology Institute. “We are now evaluating this method combined with higher resolution DNA mutational studies and measurements of RNA splice variants in CTCs to determine their clinical relevance to patients and treatment resistance.”
Should these common alterations be similarly identified in larger studies, they could be used as biomarkers as part of a blood-based liquid biopsy to help determine what treatments would be most effective. The findings could also point to new targets for drug development.
One such large prospective clinical validation study is underway now at the Duke Cancer Institute, which is examining how the mutations develop in the context of enzalutamide or abiraterone therapy, and how the mutations relate to other key genetic events.
Duke University
corporate.dukehealth.org/news-listing/duke-team-identifies-blood-biomarkers-drug-resistant-cancer-tumor-cells?h=nl
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Scientists from the Welcome Trust Sanger Institute and their collaborators have discovered 17 rare human genetic variations associated with risk factors for diseases such as heart disease and diabetes.
The research shows how large-scale genomic datasets can be used to help identify potential novel biological targets for studying cardiovascular and other diseases.
Genetics have been implicated in cardiovascular and blood diseases for some time, however as these are complex diseases, it is extremely difficult to find specific genetic causes. In this study, scientists studied the genomes of almost 36,000 healthy people with European ancestry, looking for rare genetic links to 20 known risk factors for disease, such as raised levels of cholesterol or haemoglobin in the blood.
Two previous large-scale projects provided the whole genome sequences needed: the UK10K project – a study of the genetic code of 10,000 people that aims to better understand links between rare genetic variations and disease; and the 1000 genome project. From this data, the scientists created a resource called a dense imputation panel, which is freely accessible to the scientific community. The panel holds so much detail that it can fill in the gaps or ‘impute’ data missing from lower resolution genetic studies.
The level of detail the imputation panel provides enabled the scientists to look at specific disease risk factors, and find 17 new genetic variants. Of these, 16 would have been extremely difficult to find without the imputation panel data.
“The dense imputation panel used in this study allowed us to search for genetic variations that are much less frequent than ever before, but that individually explain a greater genetic risk. As efforts continue to characterise the genetic underpinnings of complex diseases, the methods we have developed in this study are expected to enable the next wave of discoveries of what causes these diseases, and how we might develop new treatments.”
The researchers then applied an analytical technique called fine-mapping to study hundreds of regions of the human genome that contain genetic risk factors for cardiometabolic disease. For 59 regions, they were able to narrow down the most likely genetic causes to small sets of genetic variants. Combining this fine mapping technique with biological data drilled it down even further and provided additional functional insight into the underlying biology.
Arriving at Duke six years ago at the age of three, the youngster had mild developmental delays and physical characteristics that included a large body and large head circumference. A genetic analysis showed mutation of a specific gene, known as ASXL2, which had never been singled out as causing disease.
The youngster’s doctor, Vandana Shashi, a professor of paediatrics for the Division of Medical Genetics at Duke University School of Medicine, told his parents their son likely had a rare and yet-unidentified disease. And she promised to remain vigilant if any other cases popped up in the medical literature that might provide additional clues.
After none turned up, Shashi set out to see if the mystery case might be solved, instead, using the tools of the Undiagnosed Diseases Network (UDN) at the National Institutes of Health, which links Duke and six other medical teaching sites around the country. The participating centres pool information and innovations about diseases that are so rare they often stump the broader medical community.
Within just six weeks — connected to other UDN research labs and an international database of genes and disease characteristics called GeneMatcher — Shashi had a remarkable trove: Five additional children, all with the same physical features and the ASXL2 gene mutation.
“We can now definitively say this is a newly identified disease,” Shashi said. “With just one case, we could not say the gene mutation was the underlying cause. But with six cases, all with the same ASXL2 mutation, it is definitive.”
The new disease, which still has no name, does have similarities to two other rare genetic disorders arising from related genes. A condition called Bohring-Opitz syndrome is the result of a mutation of the ASXL1 gene, while Bainbridge-Ropers syndrome is caused by a flaw in the ASXL3 gene. Both conditions are also rare, and result in similar, but more severe impairments.
It’s unknown how the ASXL2 genetic mutation arises, but Shashi said identifying the root cause of the children’s condition is a first step, and could help drive new therapies and treatment approaches.
The immediate benefit is to the families of the children, who now have an answer to their most basic question.
“It has been wonderful to be connected to other families who share this genetic condition,” said Teresa Locklear, whose son, Issac, was the first patient to present with the mutation at Duke. “When we started, we hoped we would find other families with children who were older than Isaac, to provide a sort of roadmap for what to expect. But it turns out, Isaac is the oldest and we are the ones sharing our experiences with parents of younger children, and that’s been so rewarding.”
Study co-author Loren del Mar Peña, assistant professor in the Department of Pediatrics at Duke, said reducing isolation for families with a rare disease has tremendous impact.
“These families feel truly alone when their child clearly has a disorder, and yet there is no name for it, and no community of people they can relate to with shared experiences,” Peña said. “This will help them be able to connect with others and compare notes. That’s a huge deal – to know you aren’t the only one and there a five other children out there.”
Duke University
corporate.dukehealth.org/news-listing/network-and-gene-tools-help-quickly-identify-new-rare-genetic-disease
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The 2016 Biotexcel conference ‘Circulating Biomarkers’ will take place at the University of Abertay, Dundee, UK, on 12–13 October, 2016. This is the third such annual meeting and they have fast become one of the highlights of the year for workers in this field. Circulating biomarkers, such as the various forms of circulating DNA, RNA, tumour cells and exosomes, have proved useful for diagnostics and the monitoring of treatment. Previous meetings have seen presentations about the discovery of circulating biomarkers as well as subsequent validation and blood-biopsy test development. This year, the focus is expanding to include other kinds of least-invasive and non-invasive biomarkers. With its unique format, delegates include participants from science, industry, medicine and engineering and dedicated networking sessions allow broad collaborations between the different disciplines to facilitate the development of new diagnostics. The meeting includes presentations from leaders of their fields from the UK, Germany and the USA, including Prof. David Cameron, Edinburgh, UK Prof. Markus Metzler, Germany Prof. Craig Beam, USA, and others) Prof Sue Burchill, Leeds, UK Prof Colin Palmer, Ninewells Hospital, Dundee, UK Prof Angie Cox, Sheffield, UK Dr Clare Vesely, UCL Cancer Institute, London, UK
The topics to be covered are:
Circulating free tumour DNA
Circulating micro RNA
Circulating Tumour Cells
Fluid & Blood Biopsy Biomarkers & Examples of Translation into the Clinic
Case Study: “Biomarker to Diagnostic” Pathway
Non-invasive/Least-invasive biomarkers in Ascites, Hair, Saliva, Urine, CSF, Faeces etc
PDX – Patient Derived Xenograft models for Biomarkers.
The meeting will also have presentations on the latest technology developments from Analytik Jena, Covaris and Angle Plc. In addition to presentations, the meeting will also host a panel debate on “How do we break the translational bottle-neck and move circulating biomarkers into the Clinic?”, a poster session and award as well as a complimentary drinks reception hosted by the Lord Provost at City Chambers for all delegates and a 3-course networking dinner at Malmaison. This meeting is intended to be suitable for researchers and group heads working with circulating biomarkers, researchers working on translational medicine as well as those in the NHS, private labs, pharmaceutical and biotech companies, and service providers.
Please see the Biotexcel webstite (https://biotexcel.com/event/circulating-biomarkers-2016/) for further details of the meeting as well as the speakers and agenda. Registration can be done through the Biotexcel website or the button on the CLi website www.cli-online.com.
Penn State biomaterials scientists have developed a new, inexpensive method for detecting salt concentrations in sweat or other bodily fluids. The fluorescent sensor, derived from citric acid molecules, is highly sensitive and highly selective for chloride, the key diagnostic marker in cystic fibrosis.
‘Salt concentrations can be important for many health-related conditions,’ said Jian Yang, professor of biomedical engineering. ‘Our method uses fluorescent molecules based on citrate, a natural molecule that is essential for bone health.’
Compared to other methods used for chloride detection, Yang’s citrate-based fluorescent material is much more sensitive to chloride and is able to detect it over a far wider range of concentrations. Yang’s material is also sensitive to bromide, another salt that can interfere with the results of traditional clinical laboratory tests. Even trace amounts of bromide can throw off test results. With the citrate-based sensor, Yang’s group can distinguish the difference between chloride and bromide. The group is also working to establish a possible new standard for bromide detection in diagnosis of the disease.
Yang is collaborating with Penn State electrical engineer professor Zhiwen Liu to build a handheld device that can measure salt concentrations in sweat using his citrate-based molecules and a cell phone. This could be especially useful in developing countries where people have limited access to expensive analytical equipment.
‘We are developing a platform material for sensing that is low cost, can be automated, requires no titration by trained staff or expensive instrumentation as in hospitals, and provides fast, almost instantaneous, results,’ said Liu.
‘Beyond cystic fibrosis, our platform can also be used for many other diseases, such as metabolic alkalosis, Addison’s disease, and amyotrophic lateral sclerosis. All of those diseases display abnormal concentrations of chloride in the urine, serum or cerebral spinal fluid,’ Yang said.
According to the U.S. National Library of Medicine, cystic fibrosis is a common genetic disease within the white population in the United States. The disease occurs in 1 in 2,500 to 3,500 white newborns. Cystic fibrosis is less common in other ethnic groups, affecting about 1 in 17,000 African Americans and 1 in 31,000 Asian Americans.’
Penn State
news.psu.edu/story/426864/2016/09/20/research/low-cost-sensor-cystic-fibrosis-diagnosis-based-citrate
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Researchers have discovered that a protein found naturally in cells that provides some protection from viruses is responsible for creating mutations that drive resistance to tamoxifen treatment in breast cancer. Because the protein, known as APOBEC3B, is found in elevated quantities in other kinds of cancer cells, the finding explains differential responses to treatment and opens the door to boosting the effectiveness of tamoxifen and related breast cancer therapies that inhibit the ability of oestrogen to stimulate tumour growth.
As they report, University of Minnesota Professor and Howard Hughes Medical Institute Investigator Reuben Harris, Ph.D., Professor of Medicine and Masonic Cancer Center Director Douglas Yee, M.D., and colleagues analysed primary breast cancers from human patients along with studies of human breast cancer cell lines growing in mice to elucidate the relationship between presence of APOBEC3B and development of tamoxifen resistance. They found that 1) the more APOBEC3B a breast cancer contained, the less benefit patients received from tamoxifen for treatment of their recurrent disease; 2) depletion of APOBEC3B in a cancer cell line results in delayed development of tamoxifen resistance; and 3) increased production of active APOBEC3B by a cancer cell line accelerates development of resistance.
Previous studies had linked higher concentrations of the protein APOBEC3B with increased levels of mutation and poorer outcomes for patients with breast cancer, but a causal connection had not been established between this enzyme and the development of therapy resistance. By using both clinical data and mouse models, Harris, Yee and colleagues were able to show that APOBEC3B is responsible for the reduced response to tamoxifen therapy in breast cancer.
The findings open a new door for improving the effectiveness of tamoxifen in treating breast cancer by discovering ways to prevent APOBEC3B from mutating the cancer cell’s DNA. Because APOBEC3B has been implicated as a major cause of mutations in bladder, lung and other cancer types, the results could potentially be applied to boosting the success of therapies against other tumours as well.
“It’s not just breast cancer,” Yee said. “In treatment of all metastatic cancer, patients will eventually develop resistance and progress. What are the mechanisms of resistance? [APOBEC3B] is proving to be a major driver of resistance and something we’re continuing to actively investigate.”
The big challenge now is to try to identify exactly how APOBEC3B alters a cell’s DNA to induce tamoxifen resistance. “We know how it mutates DNA, but we don’t know exactly which genes are mutated to confer tamoxifen resistance,” Harris said. “If it turns out APOBEC3B mutates a known pathway, such a result may point to additional therapies.”
University of Minnesota
twin-cities.umn.edu/news-events/culprit-found-breast-cancer-resistance-tamoxifen
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Researchers from ERIBA, Radboud UMC, XJTU, Saarland University, CWI and UMC Utrecht have made a big step towards a better understanding of the human genome. By identifying large DNA variants in 250 Dutch families, the researchers have clarified part of the ‘dark matter’, the great unknown, of the human genome. These new data enable researchers from all over the world to study the DNA variants and use the results to better understand genetic diseases.
Although our knowledge of the human DNA is extensive, it is nowhere near complete. For instance, our knowledge of exactly which changes in our DNA are responsible for a certain disease is often insufficient. This is related to the fact that no two people have exactly the same DNA. Even the DNA molecules of identical twins have differences, which occur during their development and ageing. Some differences ensure that not everybody looks exactly alike, while others determine our susceptibility to particular diseases. Knowledge about the DNA variants can therefore tell us a lot about potential health risks and is a first step towards personalized medicine. Many small variants in the human genome – the whole of genetic information in the cell – have already been documented. Although it is known that larger structural variants play an important role in many hereditary diseases, these variants are also more difficult to detect and are, therefore, much less investigated.
By comparing the DNA of 250 healthy Dutch families with the reference DNA database the researchers were able to identify 1.9 million variants affecting multiple DNA ‘letters’. These variants include large sections of DNA that have disappeared, moved or even appear out of nowhere. When this happens in the middle of a gene that encodes a certain protein, it is likely that the functionality of the gene, and thus the production of the protein, is compromised. However, large structural variants often occur just before or after the coding part of a gene. The effect of this type of variation is hard to predict.
In the paper two occasions are described in which an extra piece of DNA was found just outside the coding region of a gene. In these occasions the variants had a demonstrable effect on the gene regulation. This proves that even structural variants that occur outside the coding regions need to be monitored closely in future DNA screenings. The catalogue of variants provided by this research enables other scientists to predict the occurrence of large structural variants from the known profile of the smaller ones. This technique opens new possibilities for studying the effects of large structural changes in our genomes.
Additionally, the research resulted in the discovery of large parts of DNA that were not included in the genome reference. This ‘extra’ DNA does contain parts that could be involved in the production of proteins. One of the extra pieces of DNA that was described in the paper is a new ‘ZNF’ gene that has previously never been found in humans. Nevertheless it appears to be present in roughly half of the Dutch population. This particular gene is a member of the ZNF gene family that was known from the reference genomes of several species of apes. The new variant will now be added to the human reference database. Authors subsequently showed that this gene is also present in genomes of several other human populations, however its function remains unknown. The fact that these and other pieces of ‘dark matter’ now have been placed on the genetic map enables scientists worldwide to study them and use the results to better understand human genetic diseases.
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A new non-invasive method of predicting the risk of developing a severe form of liver disease could ensure patients receive early and potentially life-saving medical intervention before irreversible damage is done.
Using information collected in a liver biopsy study, researchers at Cardiff University have developed a method of determining the onset of non-alcoholic steatohepatitis (NASH) through the analysis of lipids, metabolites and clinical markers in blood.
NASH is the most extreme form of non-alcoholic fatty liver disease (NAFLD) – a range of conditions caused by a build-up of fat in the liver. With NASH, inflammation of the liver damages the cells, potentially causing scarring and cirrhosis.
Currently, the diagnosis of NASH can only be done with a liver biopsy – an invasive and costly procedure. The new research could lead to a simple blood test that could catch the onset of NASH before inflammation damages the liver.
Dr You Zhou from Cardiff University’s Systems Immunity Research Institute said: “Many people with non-alcoholic steatohepatitis do not have symptoms and are not aware they are developing a serious liver problem. As such, diagnosis often comes after irreversible damage is done. Our quicker and less invasive method of diagnosis could mean that more people with non-alcoholic fatty liver disease could be easily tested to determine whether they are progressing to non-alcoholic steatohepatitis, the more severe form of the disease.”
A healthy liver should contain little or no fat. It’s estimated that around 20% of people in the UK have early stages of NAFLD where there are small amounts of fat in their liver. NASH is estimated to affect up to 5% of the UK population and is now considered to be one of the main causes of cirrhosis – a condition where irregular bumps replace the smooth liver tissue, making it harder and decreasing the amount of healthy cells to support normal functions. This can lead to complete liver failure.
Common risk factors for both NAFLD and NASH are obesity, lack of physical exercise and insulin resistance. But if detected and managed at an early stage, it’s possible to stop both NAFLD and NASH from getting worse.
The new method of NASH diagnosis will undergo further investigation with a view to developing a simple blood test that can be used by clinicians to provide effective medical care for patients at high risk of the disease.
Cardiff University
www.cardiff.ac.uk/news/view/482735-non-invasive-diagnosis
ETH researchers have discovered a molecule in liver cells that controls the release of fat into the bloodstream. This “lock keeper” is present in large quantities in overweight people and leads indirectly to vascular narrowing.
Anyone attending Munich’s famous Oktoberfest will know it can leave physical traces; fatty foods and plenty of alcohol cause the liver to work overtime. This organ stores a portion of any fat consumed (and also converts alcohol to fat), but releases it again once the revelry is over.
However, should the excesses continue – and if they are not offset by exercise and sport – the person becomes overweight and diabetic, leading to a condition known as fatty liver. If corrective action is taken in time, the liver can usually recover completely from its fatty degeneration. In severe cases the organ becomes inflamed – a condition that is almost impossible to treat.
Fatty liver is also associated with elevated blood fat values. When the liver becomes fatty it seeks relief by releasing fat into the bloodstream, including “good” fat in the form of high density lipoprotein (HDL), but also “bad” fat, such as low density lipoprotein (LDL), and its precursor, very low density lipoprotein (VLDL).
If the concentration of LDL and VLDL in the blood is too high, vascular constriction forms through atherosclerotic plaques. Should a plaque detach itself, there is a real risk of a vascular blockage, which results in a heart attack or stroke.
Markus Stoffel, Professor of Molecular Health Sciences at ETH Zurich, has been working with his team in collaboration with other scientists in Switzerland, Germany and the US to gain a closer understanding of the connection between excess weight, fatty liver and vascular constriction. And this has led to a surprising discovery: the scientists succeeded to identify a protein in liver cells known as vigilin, which acts as a kind of “lock keeper”. It regulates the release of fats, including VLDL, from the liver into the bloodstream.
The researchers found vigilin in large quantities in the liver cells of overweight mice – and humans. “The level of vigilin in the liver cells of people with fatty livers bears a strong correlation with the percentage of fat in the liver,” explains Stoffel. “In other words, the more fat liver cells contain, the higher the quantity of vigilin.”
In a study the ETH professor and his co-workers demonstrate that the primary function of vigilin is to regulate proteins that transport fat out of the liver. However, the molecule does not bind directly to these transport proteins, but rather to certain points of the associated messenger RNA.
The messenger RNA is the transcription of a gene. It represents the construction plan for the associated protein and is transported from the cell nucleus to the ribosomes. These molecular machines use the messenger RNA to build the protein.
The assumption is that vigilin supplies the ribosomes with the messenger RNA to which it is bound. But it is not just a transport vehicle, it also accelerates production of the associated protein.
One of these proteins “promoted” by vigilin is apolipoprotein B (ApoB), which is responsible for exporting triglycerides from the liver. Triglycerides also promote vascular calcification when present in concentrated form in overweight people.
In order to establish the causal relationship between vigilin and vascular calcification, the researchers stemmed formation of this protein in the livers of mice using a new process of RNA interference. As a consequence of this intervention, these animals suffered far less from atherosclerosis than animals who processed vigilin normally. By contrast, increased vigilin formation led to substantial deposits in the vessels.
“Vigilin intervenes at the level of gene regulation, which has barely been investigated to date,” says Stoffel. Our knowledge of how genes are regulated at the level of DNA is improving all the time. And the regulatory processes by which DNA templates are transcribed into messenger RNA are increasingly understood. But regulation of the step from messenger RNA to protein is something we know much less about. This makes the knowledge that vigilin has a regulatory function at this level all the more valuable. And researchers are particularly excited by the fact that vigilin is the first RNA-binding protein found in the context of fatty livers and diabetes.
ETH Zurich
www.ethz.ch/en/news-and-events/eth-news/news/2016/09/vigilin-the-lock-keeper.html
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Cancer stem cells: New method analyses 10,000 cells at once
, /in E-News /by 3wmediaA new device for studying tumour cells can trap 10,000 individual cells in a single chip.
The technique, developed at the University of Michigan, could one day help screen potential cancer treatments based on an individual patient’s tumour and help researchers better understand so-called cancer stem cells. It also sheds light on a controversy: are large cells or small cells more likely to be cancer stem cells?
Cancer cells are not all the same, and one theory holds that no more than 5 percent of the cells in a tumour are cancer stem cells. These few may be the only cells capable of causing a relapse or metastasis.
‘Most normal cells will die if they are not anchored to something, but cancer stem cells can survive. They can become circulating tumour cells and come to another area of the body,’ said Euisik Yoon, professor of electrical engineering and computer science, and biomedical engineering.
The team led by Yoon designed and made a device that takes advantage of this ability in hopes of understanding cancer stem cells better: how to identify them, what causes them to grow or die, and how to target them with cancer treatments. Their chip contains up to 12,800 wells for catching individual cancer cells. The team tested the chip with breast cancer cells, donated by researchers in the U-M Comprehensive Cancer Center.
They mixed the cells into a solution and ran the liquid through tiny channels in a plastic chip. Each channel was lined with chambers for trapping single cells.
The chambers have small openings to a parallel channel, which creates a draft that draws cells in — sort of like the drain in a sink. Once a cell is trapped, it blocks that opening and stops the draft. This ensures that, most of the time, only one cell is pulled into each chamber.
The walls of the chamber are coated so that the cell can’t latch on. As a result, normal cells that can’t cause metastases die over the course of a few days, leaving behind just the cancer stem cells. These cells reproduce in their chambers, forming tiny floating colonies, or tumorspheres.
While the ability to isolate 10,000 individual cells is impressive, it wouldn’t be useful if the team had to manually record every one, as required by most devices that capture cancer cells. The key is their computer algorithm, capable of combing through the microscope images and assessing the size and number of cells in each well. The algorithm’s particular talent is identifying cells no matter whether they show up dimly or brightly in the microscope image.
‘Our method is special because we really want to enable the study of many cells at once,’ said Yu-Heng Cheng, a doctoral student in electrical engineering and computer science. ‘Cancer cells have many different appearances, and our algorithm recognizes them.’
University of Michigan www.mcancer.org/news/archive/cancer-stem-cells-new-method-analyzes-10000-cells-once
Blood biomarkers in drug-resistant cancer tumour cells
, /in E-News /by 3wmediaWhile searching for a non-invasive way to detect prostate cancer cells circulating in blood, Duke Cancer Institute researchers have identified some blood markers associated with tumour resistance to two common hormone therapies.
In a study, the Duke-led team reported that they isolated multiple key gene alterations in the circulating prostate tumour cells of patients who had developed resistance to abiraterone or enzalutamide.
Enzalutamide is a drug that blocks the male androgen receptor, and abiraterone is a drug that lowers testosterone levels. Both drugs are approved to treat hormone-resistant prostate cancer, but the tumours typically develop resistance within a few years.
The study, focusing on a small number of patients and using sophisticated blood analysis technology, demonstrated that circulating tumour cells detected in blood have the potential to reveal important genetic information that could guide treatments selection in the future, and suggest targets for new therapies.
“We have developed a method that allows us to examine the whole genome of rare circulating cancer cells in the blood, which is unique in each patient, and which can change over time during treatment,” said senior author Andrew Armstrong, M.D., a medical oncologist and co-director of Genitourinary Clinical-Translational Research at the Duke Cancer Institute (DCI).
“Among the genomic changes in the patients’ individual cancers, we were able to find key similarities between the cancer cells of men who have hormone-resistant prostate cancer,” Armstrong said. “Our goal is to develop a ‘liquid biopsy’ that would be non-invasive, yet provide information that could guide clinical decisions.”
Armstrong and colleagues from the DCI and the Duke Molecular Physiology Institute used a process called array-based comparative genomic hybridization to analyse the genome of the circulating tumour cells of 16 men with advanced, treatment-resistant prostate cancer. The technique enabled them to determine which genes had extra copies and which regions were deleted.
Focusing both on genes that have previously been implicated in tumour progression, plus other genes important to cancer biology, the researchers found changes in multiple genetic pathways that appear to be in common among the men’s circulating tumour cells.
“Our research provides evidence supporting the ability to measure gains and losses of large scale sections of the circulating tumour cells genome in men with prostate cancer,” said co-author Simon Gregory, Ph.D., director of the Section of Genomics and Epigenetics in the Duke Molecular Physiology Institute. “We are now evaluating this method combined with higher resolution DNA mutational studies and measurements of RNA splice variants in CTCs to determine their clinical relevance to patients and treatment resistance.”
Should these common alterations be similarly identified in larger studies, they could be used as biomarkers as part of a blood-based liquid biopsy to help determine what treatments would be most effective. The findings could also point to new targets for drug development.
One such large prospective clinical validation study is underway now at the Duke Cancer Institute, which is examining how the mutations develop in the context of enzalutamide or abiraterone therapy, and how the mutations relate to other key genetic events.
Duke University corporate.dukehealth.org/news-listing/duke-team-identifies-blood-biomarkers-drug-resistant-cancer-tumor-cells?h=nl
New genetic links for heart disease risk factors identified
, /in E-News /by 3wmediaScientists from the Welcome Trust Sanger Institute and their collaborators have discovered 17 rare human genetic variations associated with risk factors for diseases such as heart disease and diabetes.
The research shows how large-scale genomic datasets can be used to help identify potential novel biological targets for studying cardiovascular and other diseases.
Genetics have been implicated in cardiovascular and blood diseases for some time, however as these are complex diseases, it is extremely difficult to find specific genetic causes. In this study, scientists studied the genomes of almost 36,000 healthy people with European ancestry, looking for rare genetic links to 20 known risk factors for disease, such as raised levels of cholesterol or haemoglobin in the blood.
Two previous large-scale projects provided the whole genome sequences needed: the UK10K project – a study of the genetic code of 10,000 people that aims to better understand links between rare genetic variations and disease; and the 1000 genome project. From this data, the scientists created a resource called a dense imputation panel, which is freely accessible to the scientific community. The panel holds so much detail that it can fill in the gaps or ‘impute’ data missing from lower resolution genetic studies.
The level of detail the imputation panel provides enabled the scientists to look at specific disease risk factors, and find 17 new genetic variants. Of these, 16 would have been extremely difficult to find without the imputation panel data.
“The dense imputation panel used in this study allowed us to search for genetic variations that are much less frequent than ever before, but that individually explain a greater genetic risk. As efforts continue to characterise the genetic underpinnings of complex diseases, the methods we have developed in this study are expected to enable the next wave of discoveries of what causes these diseases, and how we might develop new treatments.”
The researchers then applied an analytical technique called fine-mapping to study hundreds of regions of the human genome that contain genetic risk factors for cardiometabolic disease. For 59 regions, they were able to narrow down the most likely genetic causes to small sets of genetic variants. Combining this fine mapping technique with biological data drilled it down even further and provided additional functional insight into the underlying biology.
Sanger Trust www.sanger.ac.uk/news/view/new-genetic-links-heart-disease-risk-factors-identified
Network and gene tools help quickly identify new, rare genetic disease
, /in E-News /by 3wmediaThe first patient was a mystery.
Arriving at Duke six years ago at the age of three, the youngster had mild developmental delays and physical characteristics that included a large body and large head circumference. A genetic analysis showed mutation of a specific gene, known as ASXL2, which had never been singled out as causing disease.
The youngster’s doctor, Vandana Shashi, a professor of paediatrics for the Division of Medical Genetics at Duke University School of Medicine, told his parents their son likely had a rare and yet-unidentified disease. And she promised to remain vigilant if any other cases popped up in the medical literature that might provide additional clues.
After none turned up, Shashi set out to see if the mystery case might be solved, instead, using the tools of the Undiagnosed Diseases Network (UDN) at the National Institutes of Health, which links Duke and six other medical teaching sites around the country. The participating centres pool information and innovations about diseases that are so rare they often stump the broader medical community.
Within just six weeks — connected to other UDN research labs and an international database of genes and disease characteristics called GeneMatcher — Shashi had a remarkable trove: Five additional children, all with the same physical features and the ASXL2 gene mutation.
“We can now definitively say this is a newly identified disease,” Shashi said. “With just one case, we could not say the gene mutation was the underlying cause. But with six cases, all with the same ASXL2 mutation, it is definitive.”
The new disease, which still has no name, does have similarities to two other rare genetic disorders arising from related genes. A condition called Bohring-Opitz syndrome is the result of a mutation of the ASXL1 gene, while Bainbridge-Ropers syndrome is caused by a flaw in the ASXL3 gene. Both conditions are also rare, and result in similar, but more severe impairments.
It’s unknown how the ASXL2 genetic mutation arises, but Shashi said identifying the root cause of the children’s condition is a first step, and could help drive new therapies and treatment approaches.
The immediate benefit is to the families of the children, who now have an answer to their most basic question.
“It has been wonderful to be connected to other families who share this genetic condition,” said Teresa Locklear, whose son, Issac, was the first patient to present with the mutation at Duke. “When we started, we hoped we would find other families with children who were older than Isaac, to provide a sort of roadmap for what to expect. But it turns out, Isaac is the oldest and we are the ones sharing our experiences with parents of younger children, and that’s been so rewarding.”
Study co-author Loren del Mar Peña, assistant professor in the Department of Pediatrics at Duke, said reducing isolation for families with a rare disease has tremendous impact.
“These families feel truly alone when their child clearly has a disorder, and yet there is no name for it, and no community of people they can relate to with shared experiences,” Peña said. “This will help them be able to connect with others and compare notes. That’s a huge deal – to know you aren’t the only one and there a five other children out there.”
Duke University corporate.dukehealth.org/news-listing/network-and-gene-tools-help-quickly-identify-new-rare-genetic-disease
MEETING PREVIEW: Circulating Biomarkers 2016
, /in E-News /by 3wmediaThe 2016 Biotexcel conference ‘Circulating Biomarkers’ will take place at the University of Abertay, Dundee, UK, on 12–13 October, 2016. This is the third such annual meeting and they have fast become one of the highlights of the year for workers in this field.
Circulating biomarkers, such as the various forms of circulating DNA, RNA, tumour cells and exosomes, have proved useful for diagnostics and the monitoring of treatment. Previous meetings have seen presentations about the discovery of circulating biomarkers as well as subsequent validation and blood-biopsy test development. This year, the focus is expanding to include other kinds of least-invasive and non-invasive biomarkers. With its unique format, delegates include participants from science, industry, medicine and engineering and dedicated networking sessions allow broad collaborations between the different disciplines to facilitate the development of new diagnostics.
The meeting includes presentations from leaders of their fields from the UK, Germany and the USA, including
Prof. David Cameron, Edinburgh, UK
Prof. Markus Metzler, Germany
Prof. Craig Beam, USA, and others)
Prof Sue Burchill, Leeds, UK
Prof Colin Palmer, Ninewells Hospital, Dundee, UK
Prof Angie Cox, Sheffield, UK
Dr Clare Vesely, UCL Cancer Institute, London, UK
The topics to be covered are:
The meeting will also have presentations on the latest technology developments from Analytik Jena, Covaris and Angle Plc.
In addition to presentations, the meeting will also host a panel debate on “How do we break the translational bottle-neck and move circulating biomarkers into the Clinic?”, a poster session and award as well as a complimentary drinks reception hosted by the Lord Provost at City Chambers for all delegates and a 3-course networking dinner at Malmaison.
This meeting is intended to be suitable for researchers and group heads working with circulating biomarkers, researchers working on translational medicine as well as those in the NHS, private labs, pharmaceutical and biotech companies, and service providers.
Please see the Biotexcel webstite (https://biotexcel.com/event/circulating-biomarkers-2016/) for further details of the meeting as well as the speakers and agenda. Registration can be done through the Biotexcel website or the button on the CLi website www.cli-online.com.
Low-cost sensor for cystic fibrosis diagnosis based on citrate
, /in E-News /by 3wmediaPenn State biomaterials scientists have developed a new, inexpensive method for detecting salt concentrations in sweat or other bodily fluids. The fluorescent sensor, derived from citric acid molecules, is highly sensitive and highly selective for chloride, the key diagnostic marker in cystic fibrosis.
‘Salt concentrations can be important for many health-related conditions,’ said Jian Yang, professor of biomedical engineering. ‘Our method uses fluorescent molecules based on citrate, a natural molecule that is essential for bone health.’
Compared to other methods used for chloride detection, Yang’s citrate-based fluorescent material is much more sensitive to chloride and is able to detect it over a far wider range of concentrations. Yang’s material is also sensitive to bromide, another salt that can interfere with the results of traditional clinical laboratory tests. Even trace amounts of bromide can throw off test results. With the citrate-based sensor, Yang’s group can distinguish the difference between chloride and bromide. The group is also working to establish a possible new standard for bromide detection in diagnosis of the disease.
Yang is collaborating with Penn State electrical engineer professor Zhiwen Liu to build a handheld device that can measure salt concentrations in sweat using his citrate-based molecules and a cell phone. This could be especially useful in developing countries where people have limited access to expensive analytical equipment.
‘We are developing a platform material for sensing that is low cost, can be automated, requires no titration by trained staff or expensive instrumentation as in hospitals, and provides fast, almost instantaneous, results,’ said Liu.
‘Beyond cystic fibrosis, our platform can also be used for many other diseases, such as metabolic alkalosis, Addison’s disease, and amyotrophic lateral sclerosis. All of those diseases display abnormal concentrations of chloride in the urine, serum or cerebral spinal fluid,’ Yang said.
According to the U.S. National Library of Medicine, cystic fibrosis is a common genetic disease within the white population in the United States. The disease occurs in 1 in 2,500 to 3,500 white newborns. Cystic fibrosis is less common in other ethnic groups, affecting about 1 in 17,000 African Americans and 1 in 31,000 Asian Americans.’
Penn State news.psu.edu/story/426864/2016/09/20/research/low-cost-sensor-cystic-fibrosis-diagnosis-based-citrate
Culprit found in breast cancer resistance to tamoxifen
, /in E-News /by 3wmediaResearchers have discovered that a protein found naturally in cells that provides some protection from viruses is responsible for creating mutations that drive resistance to tamoxifen treatment in breast cancer. Because the protein, known as APOBEC3B, is found in elevated quantities in other kinds of cancer cells, the finding explains differential responses to treatment and opens the door to boosting the effectiveness of tamoxifen and related breast cancer therapies that inhibit the ability of oestrogen to stimulate tumour growth.
As they report, University of Minnesota Professor and Howard Hughes Medical Institute Investigator Reuben Harris, Ph.D., Professor of Medicine and Masonic Cancer Center Director Douglas Yee, M.D., and colleagues analysed primary breast cancers from human patients along with studies of human breast cancer cell lines growing in mice to elucidate the relationship between presence of APOBEC3B and development of tamoxifen resistance. They found that 1) the more APOBEC3B a breast cancer contained, the less benefit patients received from tamoxifen for treatment of their recurrent disease; 2) depletion of APOBEC3B in a cancer cell line results in delayed development of tamoxifen resistance; and 3) increased production of active APOBEC3B by a cancer cell line accelerates development of resistance.
Previous studies had linked higher concentrations of the protein APOBEC3B with increased levels of mutation and poorer outcomes for patients with breast cancer, but a causal connection had not been established between this enzyme and the development of therapy resistance. By using both clinical data and mouse models, Harris, Yee and colleagues were able to show that APOBEC3B is responsible for the reduced response to tamoxifen therapy in breast cancer.
The findings open a new door for improving the effectiveness of tamoxifen in treating breast cancer by discovering ways to prevent APOBEC3B from mutating the cancer cell’s DNA. Because APOBEC3B has been implicated as a major cause of mutations in bladder, lung and other cancer types, the results could potentially be applied to boosting the success of therapies against other tumours as well.
“It’s not just breast cancer,” Yee said. “In treatment of all metastatic cancer, patients will eventually develop resistance and progress. What are the mechanisms of resistance? [APOBEC3B] is proving to be a major driver of resistance and something we’re continuing to actively investigate.”
The big challenge now is to try to identify exactly how APOBEC3B alters a cell’s DNA to induce tamoxifen resistance. “We know how it mutates DNA, but we don’t know exactly which genes are mutated to confer tamoxifen resistance,” Harris said. “If it turns out APOBEC3B mutates a known pathway, such a result may point to additional therapies.”
University of Minnesota twin-cities.umn.edu/news-events/culprit-found-breast-cancer-resistance-tamoxifen
Mapping the ‘dark matter’ of human DNA
, /in E-News /by 3wmediaResearchers from ERIBA, Radboud UMC, XJTU, Saarland University, CWI and UMC Utrecht have made a big step towards a better understanding of the human genome. By identifying large DNA variants in 250 Dutch families, the researchers have clarified part of the ‘dark matter’, the great unknown, of the human genome. These new data enable researchers from all over the world to study the DNA variants and use the results to better understand genetic diseases.
Although our knowledge of the human DNA is extensive, it is nowhere near complete. For instance, our knowledge of exactly which changes in our DNA are responsible for a certain disease is often insufficient. This is related to the fact that no two people have exactly the same DNA. Even the DNA molecules of identical twins have differences, which occur during their development and ageing. Some differences ensure that not everybody looks exactly alike, while others determine our susceptibility to particular diseases. Knowledge about the DNA variants can therefore tell us a lot about potential health risks and is a first step towards personalized medicine. Many small variants in the human genome – the whole of genetic information in the cell – have already been documented. Although it is known that larger structural variants play an important role in many hereditary diseases, these variants are also more difficult to detect and are, therefore, much less investigated.
By comparing the DNA of 250 healthy Dutch families with the reference DNA database the researchers were able to identify 1.9 million variants affecting multiple DNA ‘letters’. These variants include large sections of DNA that have disappeared, moved or even appear out of nowhere. When this happens in the middle of a gene that encodes a certain protein, it is likely that the functionality of the gene, and thus the production of the protein, is compromised. However, large structural variants often occur just before or after the coding part of a gene. The effect of this type of variation is hard to predict.
In the paper two occasions are described in which an extra piece of DNA was found just outside the coding region of a gene. In these occasions the variants had a demonstrable effect on the gene regulation. This proves that even structural variants that occur outside the coding regions need to be monitored closely in future DNA screenings. The catalogue of variants provided by this research enables other scientists to predict the occurrence of large structural variants from the known profile of the smaller ones. This technique opens new possibilities for studying the effects of large structural changes in our genomes.
Additionally, the research resulted in the discovery of large parts of DNA that were not included in the genome reference. This ‘extra’ DNA does contain parts that could be involved in the production of proteins. One of the extra pieces of DNA that was described in the paper is a new ‘ZNF’ gene that has previously never been found in humans. Nevertheless it appears to be present in roughly half of the Dutch population. This particular gene is a member of the ZNF gene family that was known from the reference genomes of several species of apes. The new variant will now be added to the human reference database. Authors subsequently showed that this gene is also present in genomes of several other human populations, however its function remains unknown. The fact that these and other pieces of ‘dark matter’ now have been placed on the genetic map enables scientists worldwide to study them and use the results to better understand human genetic diseases.
EurekAlert www.eurekalert.org/pub_releases/2016-10/su-mt100716.php
Non-invasive diagnosis
, /in E-News /by 3wmediaA new non-invasive method of predicting the risk of developing a severe form of liver disease could ensure patients receive early and potentially life-saving medical intervention before irreversible damage is done.
Using information collected in a liver biopsy study, researchers at Cardiff University have developed a method of determining the onset of non-alcoholic steatohepatitis (NASH) through the analysis of lipids, metabolites and clinical markers in blood.
NASH is the most extreme form of non-alcoholic fatty liver disease (NAFLD) – a range of conditions caused by a build-up of fat in the liver. With NASH, inflammation of the liver damages the cells, potentially causing scarring and cirrhosis.
Currently, the diagnosis of NASH can only be done with a liver biopsy – an invasive and costly procedure. The new research could lead to a simple blood test that could catch the onset of NASH before inflammation damages the liver.
Dr You Zhou from Cardiff University’s Systems Immunity Research Institute said: “Many people with non-alcoholic steatohepatitis do not have symptoms and are not aware they are developing a serious liver problem. As such, diagnosis often comes after irreversible damage is done. Our quicker and less invasive method of diagnosis could mean that more people with non-alcoholic fatty liver disease could be easily tested to determine whether they are progressing to non-alcoholic steatohepatitis, the more severe form of the disease.”
A healthy liver should contain little or no fat. It’s estimated that around 20% of people in the UK have early stages of NAFLD where there are small amounts of fat in their liver. NASH is estimated to affect up to 5% of the UK population and is now considered to be one of the main causes of cirrhosis – a condition where irregular bumps replace the smooth liver tissue, making it harder and decreasing the amount of healthy cells to support normal functions. This can lead to complete liver failure.
Common risk factors for both NAFLD and NASH are obesity, lack of physical exercise and insulin resistance. But if detected and managed at an early stage, it’s possible to stop both NAFLD and NASH from getting worse.
The new method of NASH diagnosis will undergo further investigation with a view to developing a simple blood test that can be used by clinicians to provide effective medical care for patients at high risk of the disease.
Cardiff University www.cardiff.ac.uk/news/view/482735-non-invasive-diagnosis
Vigilin, the lock keeper
, /in E-News /by 3wmediaETH researchers have discovered a molecule in liver cells that controls the release of fat into the bloodstream. This “lock keeper” is present in large quantities in overweight people and leads indirectly to vascular narrowing.
Anyone attending Munich’s famous Oktoberfest will know it can leave physical traces; fatty foods and plenty of alcohol cause the liver to work overtime. This organ stores a portion of any fat consumed (and also converts alcohol to fat), but releases it again once the revelry is over.
However, should the excesses continue – and if they are not offset by exercise and sport – the person becomes overweight and diabetic, leading to a condition known as fatty liver. If corrective action is taken in time, the liver can usually recover completely from its fatty degeneration. In severe cases the organ becomes inflamed – a condition that is almost impossible to treat.
Fatty liver is also associated with elevated blood fat values. When the liver becomes fatty it seeks relief by releasing fat into the bloodstream, including “good” fat in the form of high density lipoprotein (HDL), but also “bad” fat, such as low density lipoprotein (LDL), and its precursor, very low density lipoprotein (VLDL).
If the concentration of LDL and VLDL in the blood is too high, vascular constriction forms through atherosclerotic plaques. Should a plaque detach itself, there is a real risk of a vascular blockage, which results in a heart attack or stroke.
Markus Stoffel, Professor of Molecular Health Sciences at ETH Zurich, has been working with his team in collaboration with other scientists in Switzerland, Germany and the US to gain a closer understanding of the connection between excess weight, fatty liver and vascular constriction. And this has led to a surprising discovery: the scientists succeeded to identify a protein in liver cells known as vigilin, which acts as a kind of “lock keeper”. It regulates the release of fats, including VLDL, from the liver into the bloodstream.
The researchers found vigilin in large quantities in the liver cells of overweight mice – and humans. “The level of vigilin in the liver cells of people with fatty livers bears a strong correlation with the percentage of fat in the liver,” explains Stoffel. “In other words, the more fat liver cells contain, the higher the quantity of vigilin.”
In a study the ETH professor and his co-workers demonstrate that the primary function of vigilin is to regulate proteins that transport fat out of the liver. However, the molecule does not bind directly to these transport proteins, but rather to certain points of the associated messenger RNA.
The messenger RNA is the transcription of a gene. It represents the construction plan for the associated protein and is transported from the cell nucleus to the ribosomes. These molecular machines use the messenger RNA to build the protein.
The assumption is that vigilin supplies the ribosomes with the messenger RNA to which it is bound. But it is not just a transport vehicle, it also accelerates production of the associated protein.
One of these proteins “promoted” by vigilin is apolipoprotein B (ApoB), which is responsible for exporting triglycerides from the liver. Triglycerides also promote vascular calcification when present in concentrated form in overweight people.
In order to establish the causal relationship between vigilin and vascular calcification, the researchers stemmed formation of this protein in the livers of mice using a new process of RNA interference. As a consequence of this intervention, these animals suffered far less from atherosclerosis than animals who processed vigilin normally. By contrast, increased vigilin formation led to substantial deposits in the vessels.
“Vigilin intervenes at the level of gene regulation, which has barely been investigated to date,” says Stoffel. Our knowledge of how genes are regulated at the level of DNA is improving all the time. And the regulatory processes by which DNA templates are transcribed into messenger RNA are increasingly understood. But regulation of the step from messenger RNA to protein is something we know much less about. This makes the knowledge that vigilin has a regulatory function at this level all the more valuable. And researchers are particularly excited by the fact that vigilin is the first RNA-binding protein found in the context of fatty livers and diabetes.
ETH Zurich www.ethz.ch/en/news-and-events/eth-news/news/2016/09/vigilin-the-lock-keeper.html