A team led by scientists at The Scripps Research Institute (TSRI) and Johns Hopkins University School of Medicine has uncovered a big clue to how bacteria may promote some colon cancers.
The study used novel metabolomic technologies to reveal molecular evidence suggesting a vicious circle in which cancerous changes in colon cells promote the growth of bacterial conglomerations called biofilms, and biofilms in turn promote cancer development.
On the whole, the findings suggest that removing bacterial biofilms could be a key strategy for preventing and treating colon cancers, which currently kill about 50,000 Americans per year. The study also revealed an apparent metabolic marker of biofilm-associated colon cancers.
The research, which used sophisticated “metabolomics” techniques, was a collaboration between groups led by Gary Siuzdak, professor of chemistry, molecular and computational biology and senior director of the Scripps Center for Metabolomics at TSRI, Cynthia L. Sears, professor of medicine, oncology and molecular microbiology and immunology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health, and David Edler, associate professor at the Karolinska Institute.
A previous study led by Sears and colleagues provided evidence that the tissue in and around cancers of the ascending colon, on the right side of the abdomen, almost always harbours bacterial conglomerations called biofilms.
“In the current study, we wanted to understand more about what was happening,” said Caroline H. Johnson, member of the Scripps Center for Metabolomics and co-first author of the new report with Christine M. Dejea of Johns Hopkins. “In particular, we wanted to determine if there was a metabolic link between the biofilm and colon cancer.”
Metabolites are small molecules in blood and tissues that are products of the myriad metabolic processes in cells. More than 10,000 distinct metabolites normally can be found in humans.
The team began the search with an “unbiased screen,” a wide-net technique—using advanced liquid chromatography and mass spectrometry and their XCMS metabolomic cloud-based platform—that registered the levels of thousands of metabolites in a set of colon tissue samples from patients at Johns Hopkins and at the Karolinska Institute in Sweden.
The data showed that polyamines were important in general and one metabolite—N1, N12-diacetylspermine—was particularly prominent, on average about nine times more abundant in cancerous tissue, compared to nearby non-cancerous tissue.
In further tests, the team found that even among cancerous samples, the same metabolite was four times more abundant in the presence of biofilms. In other words, the cancerous cells and the biofilms both seemed to be contributing to its overproduction.
With a sophisticated technique called “nanostructure imaging mass spectrometry” (NIMS), the team was able to map the precise locations of N1, N12-diacetylspermine in tissue samples, confirming its higher levels in both tumours and biofilms.
The researchers also carried out a technique called “global isotope metabolomics,” using an isotope of N1, N12-diacetylspermine to trace its metabolic fate in cells in an unbiased manner, finding that it appears to be a metabolic end-product.
That colon tumours would produce abnormally high amounts of N1, N12-diacetylspermine is not surprising. The molecule belongs to a family of metabolites called polyamines, which are known to have roles in driving cell growth and which are commonly up-regulated in cancers as well as in healthy fast-growing tissues. N1, N12-diacetylspermine itself has been observed at higher levels in colon cancer and is considered a potential biomarker for early cancer diagnosis.
But why would bacterial biofilms also be linked to higher levels of N1, N12-diacetylspermine? It turns out that bacteria, too, use polyamines to drive their own cells’ proliferation and to build biofilms. Polyamines are such ancient, ubiquitous molecules that bacteria apparently can even use those produced by their animal hosts.
Thus, biofilms may promote cancer in the colon by inducing chronic inflammation and associated cell proliferation. That increased cell proliferation would be accompanied by a rise in the production of polyamines. Resident bacteria, in turn, could use this abundance of polyamines to make more biofilms—completing the vicious circle. Along the way, levels of the by-product N1, N12-diacetylspermine would be driven higher and higher.
The Scripps Research Institute
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Diagnosing a heart attack can require multiple tests using expensive equipment. But not everyone has access to such techniques, especially in remote or low-income areas. Now scientists have developed a simple, thermometer-like device that could help doctors diagnose heart attacks with minimal materials and cost.
Sangmin Jeon and colleagues note that one way to tell whether someone has had a heart attack involves measuring the level of a protein called troponin in the person’s blood. The protein’s concentration rises when blood is cut off from the heart, and the muscle is damaged. Today, detecting troponin requires bulky, expensive instruments and is often not practical for point-of-care use or in low-income areas. Yet three-quarters of the deaths related to cardiovascular disease occur in low- and middle-income countries. Early diagnosis could help curb these numbers, so Jeon’s team set out to make a sensitive, more accessible test.
Inspired by the simplicity of alcohol and mercury thermometers, the researchers created a similarly straightforward way to detect troponin. It involves a few easy steps, a glass vial, specialized nanoparticles, a drop of ink and a skinny tube. When human serum with troponin — even at a minute concentration — is mixed with the nanoparticles and put in the vial, the ink climbs up a protruding tube and can be read with the naked eye, just like a thermometer.
American Chemical Society
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The over-active immune cells responsible for asthma depend on the gene BCL11B to develop into mature cells, according to a study. The identification of this gene’s role could help in the search for asthma therapies.
Innate lymphoid cell 2 (ILC2), one of a recently discovered class of innate immune cells, is responsible for regenerating respiratory tissues following influenza virus infection. However, an excess of active ILC2 cells can cause lung inflammation, leading to asthma. Researchers hope that targeting BCL11B will enable them to regulate the creation of ILC2s.
‘Before now, asthma treatment has focussed on treating symptoms,’ says Professor Gordon Dougan, a senior author and group leader at the Wellcome Trust Sanger Institute. ‘Now that we have joined the dots between the development of ILC2 cells and the expression of BCL11B, we can begin looking for drug targets that will tackle asthma’s root cause.’
In previous research, it has been found that deleting both copies of the Bcl11b gene in a mouse embryo will cause the animal to die at birth. To observe the reason for this, researchers treated normal mice with Tamoxifen to disable the Bcl11b gene. Three weeks after treatment, these mice were found to have just 6 per cent of the normal number of ILC2 cells because no new ILC2 cells were developed from the progenitor cells in the blood. The treated mice became extremely vulnerable to influenza infection.
‘ These innate immune cells are essential in the fight against infection but having too many can cause serious problems ‘
Scientists also observed mice with just one copy of the Bcl11b gene, rather than the normal two copies. They were surprised to find that reducing Bcl11b expression led to significantly higher numbers of mature ILC2 cells than were found in normal, wild-type, mice. This indicates that the activity of the gene may supress the production of mature cells as well as helping early cells to develop.
‘These innate immune cells are essential in the fight against infection but having too many can cause serious problems,’ says Dr Pentao Liu, a corresponding author from the Sanger Institute. ‘BCL11B has to be there to help ILC2 progenitor cells to reach maturity but it must also be active to suppress the over-creation of mature cells. Our focus must now be on finding a way to manipulate gene expression to boost or reduce cell populations as required.’
Sanger Institute
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Researchers discovered a new mechanism of how fluorescent proteins can change colour. It enables the microscopic visualization of individual cells in their three-dimensional environment in living organisms.
Researchers at ETH Zurich’s Department of Biosystems Science and Engineering in Basel have developed a new microscopy technique that enables for the first time to selectively visualize individual cells within the complex, three-dimensional tissue of a living organism. The researchers have thus succeeded in capturing spectacular microscopic images, such as in the nervous system of a zebrafish larva, a preferred model organism for research. Motor neurons in the spinal cord can be seen in the researchers’ images; at the same time, a single neuron with all its extensions is highlighted in another colour.
An observation by William Dempsey, post-doc in the group of ETH professor Periklis Pantazis, led to the new application. He worked with a special class of fluorescent proteins that change colour when irradiated with laser light of a specific wavelength. One such ‘chameleon protein’ is called Dendra 2, which normally emits green light when illuminated with blue light. The emission of Dendra 2 is however shifted into the red when it is irradiated by intensive violet or ultraviolet (UV) laser light.
Dempsey and Pantazis specifically discovered that when Dendra 2 is irradiated by both a blue and a red laser at the same time, the protein’s colour can also change to red. For this dual-colour illumination low intensity laser light is sufficient. In contrast to high intensity violet or UV irradiation it does not damage living cells.
ETH professor Pantazis and his colleagues then had an idea of how this finding could be deployed in light microscopy. Fluorescent proteins can be used to make whole cells, precise cell structures or single molecules visible. For the first time, the ETH researcher’s discovery permits a single cell or group of molecules located within a desirable part of a living organism to be highlighted with one colour, while all the other cells or molecules remain visible with another colour.
The research group showed that when used individually, two different laser beams cannot change a chameleon protein’s colour. But when the two beams are combined and directed in a way that they meet at a certain point on the object, then the proteins in focus change colour. In contrast, the proteins that are not activated at the same time by the two lasers retain their original colour.
The researchers have developed a simple and inexpensive colour filter, which can be used with the conventional confocal laser microscopes that are found in many biomedical research institutes. When mounted between the laser source and object, the filter divides the laser light into separate blue and red beams that are directed on to a small focal point on the object.
In the case of the zebrafish larva, which is transparent and therefore well suited for microscopy, the ETH researchers used Dendra 2 to colour neurons. They then focused the combined laser beam’s focal point on the cell body of a single neuron in a live, anesthetized zebrafish. The local Dendra 2 molecules became red, spread throughout the entire cell and dyed the cell extensions. All other cells, even in the immediate vicinity of the targeted cell, remained green.
The ability to make individual neurons visible could be of great importance, for example, in the precise mapping of the brain, according to Pantazis. Since the method is suitable for individual cell targeting in living organisms, it could also be used to examine dynamic processes; for example, what happens to individual cells or a group of molecules when researchers treat an organism with active pharmaceutical ingredients. Embryo development could also be examined in more detail. “Our method allows for a three-dimensional analysis in an elegant manner,” explains Pantazis. “This is a very nice example of how you can take a result from basic research and use it to provide a solution for a technically challenging issue.” Pantazis hopes the technique will be used more broadly in biomedical research in the future and is in talks with microscope manufacturers to implement this technology.
wavelength of light.
ETH Zurich
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New research into the causes of the excessive inflammation that drives multiple sclerosis has identified a faulty “brake” within immune cells, a brake that should be controlling the inflammation. This points to a potential target for developing new therapies to treat multiple sclerosis and could have important implications for other autoimmune diseases, such as the colon disease colitis and the chronic skin condition atopic dermatitis.
Further, the work has produced new research models of multiple sclerosis symptoms such as movement disorders and balance control problems that have, until now, resisted efforts to mimic them effectively in the lab. These models represent important new tools in the efforts to better understand – and eventually cure – MS and other autoimmune conditions.
The researchers determined that a mutation in the gene Nlrp12 was causing immune cells known as T cells to go haywire. Normally, the researchers determined, the protein the gene produces acts as a brake within T cells to control the inflammatory response. But a mutation in that gene disrupts the natural process and provokes severe inflammation – with effects the researchers found most intriguing.
To the researchers’ surprise, the resulting inflammation did not produce the paralysis often associated with multiple sclerosis. It did, however, produce other MS symptoms — such as movement disorders and problems with balance control – which scientists have struggled to replicate in experimental lab settings.
“It’s important to note that MS is a spectrum disorder – some patients present with paralyzing conditions and some patients don’t,” said researcher John Lukens, PhD, of the University of Virginia School of Medicine Department of Neuroscience and its Center for Brain Immunology and Glia. “Not everybody’s symptoms are the same, so this might give us a glimpse into the etiology or pathogenesis of that family of MS.”
By blocking the inflammatory response, doctors may one day be able to control the symptoms it causes, both in MS and in other diseases driven by hyperinflammation.
University of Virginia
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The gene and hormone soup that enables women to breastfeed their newborns also can be a recipe for breast cancer, particularly when the first pregnancy is after age 30.
Researchers have now found that the gene DNMT1 is essential to maintaining breast, or mammary, stem cells, that enable normal rapid growth of the breasts during pregnancy, as well as the cancer stem cells that may enable breast cancer. They’ve learned that the DNMT1 gene also is highly expressed in the most common types of breast cancer.
Conversely, ISL1 gene, a tumour suppressor and natural control mechanism for stem cells, is nearly silent in the breasts during pregnancy as well as cancer, said Dr. Muthusamy Thangaraju, biochemist at the Medical College of Georgia at Georgia Regents University.
“DNMT1 directly regulates ISL1,” Thangaraju said. “If the DNMT1 expression is high, this ISL1 gene is low.” They first made the connection when they knocked out DNMT1 in a mouse and noted the increase in ISL1. Then they got busy looking at what happened in human breast cancer cells.
They found ISL1 is silent in most human breast cancers and that restoring higher levels to the human breast cancer cells dramatically reduces the stem cell populations and the resulting cell growth and spread that are hallmarks of cancer.
When they eliminated the DNMT1 gene in a breast-cancer mouse model, “The breast won’t develop as well,” Thangaraju said, but neither would about 80 percent of breast tumours. The deletion even impacted super-aggressive, triple-negative breast cancer.
The findings point toward new therapeutic targets for breast cancer and potentially using blood levels of ISL1 as a way to diagnose early breast cancer, the researchers report. In fact, they’ve found that the anti-seizure medication valproic acid, already used in combination with chemotherapy to treat breast cancer, appears to increase ISL1 expression, which may help explain why the drug works for these patients, he said. The scientists are screening other small molecules that might work as well or better.
Georgia Regents University and Health System
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UCLA researchers have discovered that for women with a relatively common inherited genetic mutation, known as the KRAS-variant, an abrupt lowering of oestrogen in the body may increase the risk for breast cancer and impact the biology of their breast cancer. Scientists also found that women with the KRAS-variant are more likely to develop a second primary breast cancer, independent of a first breast cancer.
The two-year study, led by Dr. Joanne Weidhaas, a professor of radiation oncology at the UCLA Jonsson Comprehensive Cancer Center and director of translational research at the David Geffen School of Medicine, analysed data from more than 1,700 women with breast cancer who submitted DNA samples to be tested for the inherited KRAS-variant. The study also included a group of women with the KRAS-variant who were cancer-free, as well as biological models to scientifically confirm the clinical findings.
Weidhaas’ team found that acute oestrogen withdrawal, as experienced after removal of the ovaries or when hormone replacement therapy was discontinued, and/or a low oestrogen state were associated with breast cancer in women with the KRAS-variant. Acute oestrogen withdrawal also triggered breast cancer formation in KRAS-variant biological models used in the study. In addition, up to 45 percent of breast cancer patients with the KRAS-variant eventually developed a second independent breast cancer — representing a 12-fold greater risk than women with breast cancer who did not have the KRAS-variant.
“Although we had evidence that the KRAS-variant was a stronger predictor of cancer risk for women than men, we did not previously have a scientific explanation for this observation,” Weidhaas said. “This study’s findings, showing that oestrogen withdrawal can influence cancer risk for women with the KRAS-variant, begins to provide some answers.”
The findings are contrary to some past research suggesting that women on combination hormone replacement therapy are more likely to develop breast cancer, but the study is in agreement with follow-up studies which found that oestrogen alone might actually protect women from breast cancer.
“The KRAS-variant may be a genetic difference that could actually help identify women who could benefit from continuing oestrogen, or at a minimum, at least tapering it appropriately,” Weidhaas said. “We hope that there are real opportunities to personalize risk-reducing strategies for these women, through further defining the most protective oestrogen management approaches, as well as by understanding the impact of different treatment alternatives at the time of a woman’s first breast cancer diagnosis.”
University of California – Los Angeles
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Normal skin contains an unexpectedly high number of cancer-associated mutations, according to a study. The findings illuminate the first steps cells take towards becoming a cancer and demonstrate the value of analysing normal tissue to learn more about the origins of the disease.
The study revealed that each cell in normal facial skin carries many thousands of mutations, mainly caused by exposure to sunlight. Around 25 per cent of skin cells in samples from people without cancer were found to carry at least one cancer-associated mutation.
Ultra-deep genetic sequencing was performed on 234 biopsies taken from four patients revealing 3,760 mutations, with more than 100 cancer-associated mutations per square centimetre of skin. Cells with these mutations formed clusters of cells, known as clones, that had grown to be around twice the size of normal clones, but none of them had become cancerous.
‘With this technology, we can now peer into the first steps a cell takes to become cancerous,’ explains Dr Peter Campbell, a corresponding author from the Wellcome Trust Sanger Institute. ‘These first cancer-associated mutations give cells a boost compared to their normal neighbours. They have a burst of growth that increases the pool of cells waiting for the next mutation to push them even further.
‘We can even see some cells in normal skin that have taken two or three such steps towards cancer. How many of these steps are needed to become fully cancerous? Maybe five, maybe 10, we don’t know yet.’
The mutations observed showed the patterns associated with the most common and treatable form of skin cancer linked to sun exposure, known as cutaneous squamous cell carcinoma, rather than melanoma, a rarer and sometimes fatal form of skin cancer.
‘The burden of mutations observed is high but almost certainly none of these clones would have developed into skin cancer,’ explains Dr Iñigo Martincorena, first author from the Sanger Institute. ‘Because skin cancers are so common in the population, it makes sense that individuals would carry a large number of mutations. What we are seeing here are the hidden depths of the iceberg, not just the relatively small number that break through the surface waters to become cancer.’
Skin samples used in this study were taken from four people aged between 55 and 73 who were undergoing routine surgery to remove excess eyelid skin that was obscuring vision. The mutations had accumulated over each individual’s lifetime as the eyelids were exposed to sunshine. The researchers estimate that each sun-exposed skin cell accumulated on average a new mutation in its genome for nearly every day of life.
‘These kinds of mutations accumulate over time – whenever our skin is exposed to sunlight, we are at risk of adding to them,’ explains Dr Phil Jones, a corresponding author from the Sanger Institute and the MRC Cancer Unit at the University of Cambridge. ‘Throughout our lives we need to protect our skin by using sun-block lotions, staying away from midday sun and covering exposed skin wherever possible. These precautions are important at any stage of life but particularly in children, who are busy growing new skin, and older people, who have already built up an array of mutations.’
Recent studies analysing blood samples from people who do not have cancer had revealed a lower burden of mutations, with only a small percentage of individuals carrying a cancer-causing mutation in their blood cells. Owing to sun exposure, skin is much more heavily mutated, with thousands of cancer-associated mutations expected in any adult’s skin.
The results demonstrate the potential of using normal tissue to better understand the origins of cancer. The Cancer Genomics group at the Sanger Institute will continue this work with larger sample numbers and a broader range of tissues to understand how healthy cells transition into cancerous cells.
Sanger Institute
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Ovarian cancer is notoriously difficult to diagnose and treat, making it an especially fatal disease. Researchers at University of California, San Diego School of Medicine and Moores Cancer Center have now identified six mRNA isoforms (bits of genetic material) produced by ovarian cancer cells but not normal cells, opening up the possibility that they could be used to diagnose early-stage ovarian cancer. What’s more, several of the mRNA isoforms code for unique proteins that could be targeted with new therapeutics.
“We were inspired by many studies aimed at using DNA to detect cancer,” said first author Christian Barrett, PhD, bioinformatics expert and project scientist in the UC San Diego School of Medicine Institute for Genomic Medicine. “But we wondered if we could instead develop an ovarian cancer detection test based on tumour-specific mRNA that has disseminated from cancer cells to the cervix and can be collected during a routine Pap test.”
While DNA carries all the instructions necessary for life, its actual sequence contains much more than just the genes that code for proteins. In contrast, mRNAs are complementary copies of just the genes. They carry the recipe for every protein that the cell will produce from the nucleus to the cytoplasm, where cellular machinery can read the recipe and build the corresponding proteins. According to the authors of this study, the advantage of using cancer mRNA for diagnosis rather than DNA is sheer number — a cancer cell might harbour just one or a few copies of a DNA mutation, but mRNA variants can occur in hundreds to thousands of copies per cell.
To determine if mRNAs can be used to distinguish ovarian cancer cells from normal cells, the team developed a custom bioinformatics algorithm and used it to mine two large public databases of genetic information — The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) program, both sponsored by the National Institutes of Health. TCGA is a catalog of RNA and DNA from 500 tumors covering many cancer types, while GTEx is a database of RNA and DNA from normal tissue samples. From these, the researchers were able to analyze mRNA sequence data from 296 ovarian cancers and 1,839 normal tissue samples.
Using this bioinformatics approach, the researchers identified six mRNA isoform molecules that have the tumour specificity required for an early detection diagnostic of ovarian cancer. They also validated their digital results in the real world using RT-quantitative PCR, a gene amplifying technique, to detect the same ovarian cancer-specific mRNA molecules in lab-grown cells.
Beyond their diagnostic potential, some of the mRNA isoforms identified in this study could also act as new therapeutic targets. These mRNA isoforms are predicted to encode proteins with unique amino acid sequences, which might allow them to be specifically targeted with certain therapeutics, such as monoclonal antibodies or T-cell-based vaccines. What’s more, the ovarian cancer-specific mRNA isoforms themselves could also be targeted with new therapeutic drugs.
“Our experimental findings were made in a laboratory and were performed on ovarian cancer cells from cell lines,” said study co-author Cheryl Saenz, MD, a clinical professor of reproductive medicine who specializes in treating gynaecologic cancers. “Clinical trials will need to be conducted on women to confirm the presence of these markers in women that we know have cancer, as well as to document the absence of the markers in women that do not have ovarian cancer.”
University of California – San Diego Health System
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A gene essential to the production of pain-sensing neurons in humans has been identified by an international team of researchers co-led by the University of Cambridge. The discovery could have implications for the development of new methods of pain relief.
The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception.
Pain perception is an evolutionarily-conserved warning mechanism that alerts us to dangers in the environment and to potential tissue damage. However, rare individuals – around one in a million people in the UK – are born unable to feel pain. These people accumulate numerous self-inflicted injuries, often leading to reduced lifespan.
Using detailed genome mapping, two teams of researchers collaborated to analyse the genetic make-up of 11 families across Europe and Asia affected by an inherited condition known as congenital insensitivity to pain (CIP). This enabled them to pinpoint the cause of the condition to variants of the gene PRDM12. Family members affected by CIP carried two copies of the variant; however, if they had only inherited one copy from their parents, they were unaffected.
The team looked at nerve biopsies taken from the patients to see what had gone wrong and found that particular pain-sensing neurons were absent. From these clinical features of the disease, the team predicted that there would be a block to the production of pain-sensing neurons during the development of the embryo – they confirmed this using a combination of studies in mouse and frog models, and in human induced pluripotent stem cells (skin cells that had been reset to their ‘master state’, which enables them to develop into almost any type of cell in the body).
PRDM12 had previously been implicated in the modification of chromatin, a small molecule that attaches to our DNA and acts like a switch to turn genes on and off (an effect known as epigenetics). The researchers showed that all the genetic variants of PRDM12 in the CIP patients blocked the gene’s function. As chromatin is particularly important during formation of particular specialised cell types such as neurons, this provides a possible explanation for why pain-sensing neurons do not form properly in the CIP patients.
‘The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception,’ says Professor Geoff Woods from the Cambridge Institute for Medical Research at the University of Cambridge, who co-led the study. ‘Both are equally important to the development of new pain treatments – if we know the mechanisms that underlie pain sensation, we can then potentially control and reduce unnecessary pain.’
PRDM12 is only the fifth gene related to lack of pain perception to have been identified to date. However, two of the previously-discovered genes have already led to the development of new pain killers that are currently been tested in clinical trials.
University of Cambridge
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Study finds metabolic link between bacterial ‘biofilms’ and colon cancer
, /in E-News /by 3wmediaA team led by scientists at The Scripps Research Institute (TSRI) and Johns Hopkins University School of Medicine has uncovered a big clue to how bacteria may promote some colon cancers.
The study used novel metabolomic technologies to reveal molecular evidence suggesting a vicious circle in which cancerous changes in colon cells promote the growth of bacterial conglomerations called biofilms, and biofilms in turn promote cancer development.
On the whole, the findings suggest that removing bacterial biofilms could be a key strategy for preventing and treating colon cancers, which currently kill about 50,000 Americans per year. The study also revealed an apparent metabolic marker of biofilm-associated colon cancers.
The research, which used sophisticated “metabolomics” techniques, was a collaboration between groups led by Gary Siuzdak, professor of chemistry, molecular and computational biology and senior director of the Scripps Center for Metabolomics at TSRI, Cynthia L. Sears, professor of medicine, oncology and molecular microbiology and immunology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health, and David Edler, associate professor at the Karolinska Institute.
A previous study led by Sears and colleagues provided evidence that the tissue in and around cancers of the ascending colon, on the right side of the abdomen, almost always harbours bacterial conglomerations called biofilms.
“In the current study, we wanted to understand more about what was happening,” said Caroline H. Johnson, member of the Scripps Center for Metabolomics and co-first author of the new report with Christine M. Dejea of Johns Hopkins. “In particular, we wanted to determine if there was a metabolic link between the biofilm and colon cancer.”
Metabolites are small molecules in blood and tissues that are products of the myriad metabolic processes in cells. More than 10,000 distinct metabolites normally can be found in humans.
The team began the search with an “unbiased screen,” a wide-net technique—using advanced liquid chromatography and mass spectrometry and their XCMS metabolomic cloud-based platform—that registered the levels of thousands of metabolites in a set of colon tissue samples from patients at Johns Hopkins and at the Karolinska Institute in Sweden.
The data showed that polyamines were important in general and one metabolite—N1, N12-diacetylspermine—was particularly prominent, on average about nine times more abundant in cancerous tissue, compared to nearby non-cancerous tissue.
In further tests, the team found that even among cancerous samples, the same metabolite was four times more abundant in the presence of biofilms. In other words, the cancerous cells and the biofilms both seemed to be contributing to its overproduction.
With a sophisticated technique called “nanostructure imaging mass spectrometry” (NIMS), the team was able to map the precise locations of N1, N12-diacetylspermine in tissue samples, confirming its higher levels in both tumours and biofilms.
The researchers also carried out a technique called “global isotope metabolomics,” using an isotope of N1, N12-diacetylspermine to trace its metabolic fate in cells in an unbiased manner, finding that it appears to be a metabolic end-product.
That colon tumours would produce abnormally high amounts of N1, N12-diacetylspermine is not surprising. The molecule belongs to a family of metabolites called polyamines, which are known to have roles in driving cell growth and which are commonly up-regulated in cancers as well as in healthy fast-growing tissues. N1, N12-diacetylspermine itself has been observed at higher levels in colon cancer and is considered a potential biomarker for early cancer diagnosis.
But why would bacterial biofilms also be linked to higher levels of N1, N12-diacetylspermine? It turns out that bacteria, too, use polyamines to drive their own cells’ proliferation and to build biofilms. Polyamines are such ancient, ubiquitous molecules that bacteria apparently can even use those produced by their animal hosts.
Thus, biofilms may promote cancer in the colon by inducing chronic inflammation and associated cell proliferation. That increased cell proliferation would be accompanied by a rise in the production of polyamines. Resident bacteria, in turn, could use this abundance of polyamines to make more biofilms—completing the vicious circle. Along the way, levels of the by-product N1, N12-diacetylspermine would be driven higher and higher. The Scripps Research Institute
Thermometer-like device could help diagnose heart attacks
, /in E-News /by 3wmediaDiagnosing a heart attack can require multiple tests using expensive equipment. But not everyone has access to such techniques, especially in remote or low-income areas. Now scientists have developed a simple, thermometer-like device that could help doctors diagnose heart attacks with minimal materials and cost.
Sangmin Jeon and colleagues note that one way to tell whether someone has had a heart attack involves measuring the level of a protein called troponin in the person’s blood. The protein’s concentration rises when blood is cut off from the heart, and the muscle is damaged. Today, detecting troponin requires bulky, expensive instruments and is often not practical for point-of-care use or in low-income areas. Yet three-quarters of the deaths related to cardiovascular disease occur in low- and middle-income countries. Early diagnosis could help curb these numbers, so Jeon’s team set out to make a sensitive, more accessible test.
Inspired by the simplicity of alcohol and mercury thermometers, the researchers created a similarly straightforward way to detect troponin. It involves a few easy steps, a glass vial, specialized nanoparticles, a drop of ink and a skinny tube. When human serum with troponin — even at a minute concentration — is mixed with the nanoparticles and put in the vial, the ink climbs up a protruding tube and can be read with the naked eye, just like a thermometer. American Chemical Society
Identification of gene’s role in asthma could lead to therapy
, /in E-News /by 3wmediaThe over-active immune cells responsible for asthma depend on the gene BCL11B to develop into mature cells, according to a study. The identification of this gene’s role could help in the search for asthma therapies.
Innate lymphoid cell 2 (ILC2), one of a recently discovered class of innate immune cells, is responsible for regenerating respiratory tissues following influenza virus infection. However, an excess of active ILC2 cells can cause lung inflammation, leading to asthma. Researchers hope that targeting BCL11B will enable them to regulate the creation of ILC2s.
‘Before now, asthma treatment has focussed on treating symptoms,’ says Professor Gordon Dougan, a senior author and group leader at the Wellcome Trust Sanger Institute. ‘Now that we have joined the dots between the development of ILC2 cells and the expression of BCL11B, we can begin looking for drug targets that will tackle asthma’s root cause.’
In previous research, it has been found that deleting both copies of the Bcl11b gene in a mouse embryo will cause the animal to die at birth. To observe the reason for this, researchers treated normal mice with Tamoxifen to disable the Bcl11b gene. Three weeks after treatment, these mice were found to have just 6 per cent of the normal number of ILC2 cells because no new ILC2 cells were developed from the progenitor cells in the blood. The treated mice became extremely vulnerable to influenza infection.
‘ These innate immune cells are essential in the fight against infection but having too many can cause serious problems ‘
Scientists also observed mice with just one copy of the Bcl11b gene, rather than the normal two copies. They were surprised to find that reducing Bcl11b expression led to significantly higher numbers of mature ILC2 cells than were found in normal, wild-type, mice. This indicates that the activity of the gene may supress the production of mature cells as well as helping early cells to develop.
‘These innate immune cells are essential in the fight against infection but having too many can cause serious problems,’ says Dr Pentao Liu, a corresponding author from the Sanger Institute. ‘BCL11B has to be there to help ILC2 progenitor cells to reach maturity but it must also be active to suppress the over-creation of mature cells. Our focus must now be on finding a way to manipulate gene expression to boost or reduce cell populations as required.’ Sanger Institute
Chameleon proteins make individual cells visible
, /in E-News /by 3wmediaResearchers discovered a new mechanism of how fluorescent proteins can change colour. It enables the microscopic visualization of individual cells in their three-dimensional environment in living organisms.
Researchers at ETH Zurich’s Department of Biosystems Science and Engineering in Basel have developed a new microscopy technique that enables for the first time to selectively visualize individual cells within the complex, three-dimensional tissue of a living organism. The researchers have thus succeeded in capturing spectacular microscopic images, such as in the nervous system of a zebrafish larva, a preferred model organism for research. Motor neurons in the spinal cord can be seen in the researchers’ images; at the same time, a single neuron with all its extensions is highlighted in another colour.
An observation by William Dempsey, post-doc in the group of ETH professor Periklis Pantazis, led to the new application. He worked with a special class of fluorescent proteins that change colour when irradiated with laser light of a specific wavelength. One such ‘chameleon protein’ is called Dendra 2, which normally emits green light when illuminated with blue light. The emission of Dendra 2 is however shifted into the red when it is irradiated by intensive violet or ultraviolet (UV) laser light.
Dempsey and Pantazis specifically discovered that when Dendra 2 is irradiated by both a blue and a red laser at the same time, the protein’s colour can also change to red. For this dual-colour illumination low intensity laser light is sufficient. In contrast to high intensity violet or UV irradiation it does not damage living cells.
ETH professor Pantazis and his colleagues then had an idea of how this finding could be deployed in light microscopy. Fluorescent proteins can be used to make whole cells, precise cell structures or single molecules visible. For the first time, the ETH researcher’s discovery permits a single cell or group of molecules located within a desirable part of a living organism to be highlighted with one colour, while all the other cells or molecules remain visible with another colour.
The research group showed that when used individually, two different laser beams cannot change a chameleon protein’s colour. But when the two beams are combined and directed in a way that they meet at a certain point on the object, then the proteins in focus change colour. In contrast, the proteins that are not activated at the same time by the two lasers retain their original colour.
The researchers have developed a simple and inexpensive colour filter, which can be used with the conventional confocal laser microscopes that are found in many biomedical research institutes. When mounted between the laser source and object, the filter divides the laser light into separate blue and red beams that are directed on to a small focal point on the object.
In the case of the zebrafish larva, which is transparent and therefore well suited for microscopy, the ETH researchers used Dendra 2 to colour neurons. They then focused the combined laser beam’s focal point on the cell body of a single neuron in a live, anesthetized zebrafish. The local Dendra 2 molecules became red, spread throughout the entire cell and dyed the cell extensions. All other cells, even in the immediate vicinity of the targeted cell, remained green.
The ability to make individual neurons visible could be of great importance, for example, in the precise mapping of the brain, according to Pantazis. Since the method is suitable for individual cell targeting in living organisms, it could also be used to examine dynamic processes; for example, what happens to individual cells or a group of molecules when researchers treat an organism with active pharmaceutical ingredients. Embryo development could also be examined in more detail. “Our method allows for a three-dimensional analysis in an elegant manner,” explains Pantazis. “This is a very nice example of how you can take a result from basic research and use it to provide a solution for a technically challenging issue.” Pantazis hopes the technique will be used more broadly in biomedical research in the future and is in talks with microscope manufacturers to implement this technology.
wavelength of light. ETH Zurich
Multiple sclerosis: cause of movement, balance problems
, /in E-News /by 3wmediaNew research into the causes of the excessive inflammation that drives multiple sclerosis has identified a faulty “brake” within immune cells, a brake that should be controlling the inflammation. This points to a potential target for developing new therapies to treat multiple sclerosis and could have important implications for other autoimmune diseases, such as the colon disease colitis and the chronic skin condition atopic dermatitis.
Further, the work has produced new research models of multiple sclerosis symptoms such as movement disorders and balance control problems that have, until now, resisted efforts to mimic them effectively in the lab. These models represent important new tools in the efforts to better understand – and eventually cure – MS and other autoimmune conditions.
The researchers determined that a mutation in the gene Nlrp12 was causing immune cells known as T cells to go haywire. Normally, the researchers determined, the protein the gene produces acts as a brake within T cells to control the inflammatory response. But a mutation in that gene disrupts the natural process and provokes severe inflammation – with effects the researchers found most intriguing.
To the researchers’ surprise, the resulting inflammation did not produce the paralysis often associated with multiple sclerosis. It did, however, produce other MS symptoms — such as movement disorders and problems with balance control – which scientists have struggled to replicate in experimental lab settings.
“It’s important to note that MS is a spectrum disorder – some patients present with paralyzing conditions and some patients don’t,” said researcher John Lukens, PhD, of the University of Virginia School of Medicine Department of Neuroscience and its Center for Brain Immunology and Glia. “Not everybody’s symptoms are the same, so this might give us a glimpse into the etiology or pathogenesis of that family of MS.”
By blocking the inflammatory response, doctors may one day be able to control the symptoms it causes, both in MS and in other diseases driven by hyperinflammation. University of Virginia
Gene found that is essential to maintaining breast and cancer cells
, /in E-News /by 3wmediaThe gene and hormone soup that enables women to breastfeed their newborns also can be a recipe for breast cancer, particularly when the first pregnancy is after age 30.
Researchers have now found that the gene DNMT1 is essential to maintaining breast, or mammary, stem cells, that enable normal rapid growth of the breasts during pregnancy, as well as the cancer stem cells that may enable breast cancer. They’ve learned that the DNMT1 gene also is highly expressed in the most common types of breast cancer.
Conversely, ISL1 gene, a tumour suppressor and natural control mechanism for stem cells, is nearly silent in the breasts during pregnancy as well as cancer, said Dr. Muthusamy Thangaraju, biochemist at the Medical College of Georgia at Georgia Regents University.
“DNMT1 directly regulates ISL1,” Thangaraju said. “If the DNMT1 expression is high, this ISL1 gene is low.” They first made the connection when they knocked out DNMT1 in a mouse and noted the increase in ISL1. Then they got busy looking at what happened in human breast cancer cells.
They found ISL1 is silent in most human breast cancers and that restoring higher levels to the human breast cancer cells dramatically reduces the stem cell populations and the resulting cell growth and spread that are hallmarks of cancer.
When they eliminated the DNMT1 gene in a breast-cancer mouse model, “The breast won’t develop as well,” Thangaraju said, but neither would about 80 percent of breast tumours. The deletion even impacted super-aggressive, triple-negative breast cancer.
The findings point toward new therapeutic targets for breast cancer and potentially using blood levels of ISL1 as a way to diagnose early breast cancer, the researchers report. In fact, they’ve found that the anti-seizure medication valproic acid, already used in combination with chemotherapy to treat breast cancer, appears to increase ISL1 expression, which may help explain why the drug works for these patients, he said. The scientists are screening other small molecules that might work as well or better. Georgia Regents University and Health System
Specific genetic mutation may increase risk for breast cancer after acute oestrogen withdrawal
, /in E-News /by 3wmediaUCLA researchers have discovered that for women with a relatively common inherited genetic mutation, known as the KRAS-variant, an abrupt lowering of oestrogen in the body may increase the risk for breast cancer and impact the biology of their breast cancer. Scientists also found that women with the KRAS-variant are more likely to develop a second primary breast cancer, independent of a first breast cancer.
The two-year study, led by Dr. Joanne Weidhaas, a professor of radiation oncology at the UCLA Jonsson Comprehensive Cancer Center and director of translational research at the David Geffen School of Medicine, analysed data from more than 1,700 women with breast cancer who submitted DNA samples to be tested for the inherited KRAS-variant. The study also included a group of women with the KRAS-variant who were cancer-free, as well as biological models to scientifically confirm the clinical findings.
Weidhaas’ team found that acute oestrogen withdrawal, as experienced after removal of the ovaries or when hormone replacement therapy was discontinued, and/or a low oestrogen state were associated with breast cancer in women with the KRAS-variant. Acute oestrogen withdrawal also triggered breast cancer formation in KRAS-variant biological models used in the study. In addition, up to 45 percent of breast cancer patients with the KRAS-variant eventually developed a second independent breast cancer — representing a 12-fold greater risk than women with breast cancer who did not have the KRAS-variant.
“Although we had evidence that the KRAS-variant was a stronger predictor of cancer risk for women than men, we did not previously have a scientific explanation for this observation,” Weidhaas said. “This study’s findings, showing that oestrogen withdrawal can influence cancer risk for women with the KRAS-variant, begins to provide some answers.”
The findings are contrary to some past research suggesting that women on combination hormone replacement therapy are more likely to develop breast cancer, but the study is in agreement with follow-up studies which found that oestrogen alone might actually protect women from breast cancer.
“The KRAS-variant may be a genetic difference that could actually help identify women who could benefit from continuing oestrogen, or at a minimum, at least tapering it appropriately,” Weidhaas said. “We hope that there are real opportunities to personalize risk-reducing strategies for these women, through further defining the most protective oestrogen management approaches, as well as by understanding the impact of different treatment alternatives at the time of a woman’s first breast cancer diagnosis.” University of California – Los Angeles
Using healthy skin to identify cancer’s origins
, /in E-News /by 3wmediaNormal skin contains an unexpectedly high number of cancer-associated mutations, according to a study. The findings illuminate the first steps cells take towards becoming a cancer and demonstrate the value of analysing normal tissue to learn more about the origins of the disease.
The study revealed that each cell in normal facial skin carries many thousands of mutations, mainly caused by exposure to sunlight. Around 25 per cent of skin cells in samples from people without cancer were found to carry at least one cancer-associated mutation.
Ultra-deep genetic sequencing was performed on 234 biopsies taken from four patients revealing 3,760 mutations, with more than 100 cancer-associated mutations per square centimetre of skin. Cells with these mutations formed clusters of cells, known as clones, that had grown to be around twice the size of normal clones, but none of them had become cancerous.
‘With this technology, we can now peer into the first steps a cell takes to become cancerous,’ explains Dr Peter Campbell, a corresponding author from the Wellcome Trust Sanger Institute. ‘These first cancer-associated mutations give cells a boost compared to their normal neighbours. They have a burst of growth that increases the pool of cells waiting for the next mutation to push them even further.
‘We can even see some cells in normal skin that have taken two or three such steps towards cancer. How many of these steps are needed to become fully cancerous? Maybe five, maybe 10, we don’t know yet.’
The mutations observed showed the patterns associated with the most common and treatable form of skin cancer linked to sun exposure, known as cutaneous squamous cell carcinoma, rather than melanoma, a rarer and sometimes fatal form of skin cancer.
‘The burden of mutations observed is high but almost certainly none of these clones would have developed into skin cancer,’ explains Dr Iñigo Martincorena, first author from the Sanger Institute. ‘Because skin cancers are so common in the population, it makes sense that individuals would carry a large number of mutations. What we are seeing here are the hidden depths of the iceberg, not just the relatively small number that break through the surface waters to become cancer.’
Skin samples used in this study were taken from four people aged between 55 and 73 who were undergoing routine surgery to remove excess eyelid skin that was obscuring vision. The mutations had accumulated over each individual’s lifetime as the eyelids were exposed to sunshine. The researchers estimate that each sun-exposed skin cell accumulated on average a new mutation in its genome for nearly every day of life.
‘These kinds of mutations accumulate over time – whenever our skin is exposed to sunlight, we are at risk of adding to them,’ explains Dr Phil Jones, a corresponding author from the Sanger Institute and the MRC Cancer Unit at the University of Cambridge. ‘Throughout our lives we need to protect our skin by using sun-block lotions, staying away from midday sun and covering exposed skin wherever possible. These precautions are important at any stage of life but particularly in children, who are busy growing new skin, and older people, who have already built up an array of mutations.’
Recent studies analysing blood samples from people who do not have cancer had revealed a lower burden of mutations, with only a small percentage of individuals carrying a cancer-causing mutation in their blood cells. Owing to sun exposure, skin is much more heavily mutated, with thousands of cancer-associated mutations expected in any adult’s skin.
The results demonstrate the potential of using normal tissue to better understand the origins of cancer. The Cancer Genomics group at the Sanger Institute will continue this work with larger sample numbers and a broader range of tissues to understand how healthy cells transition into cancerous cells. Sanger Institute
Ovarian cancer-specific markers set the stage for early diagnosis, personalized treatments
, /in E-News /by 3wmediaOvarian cancer is notoriously difficult to diagnose and treat, making it an especially fatal disease. Researchers at University of California, San Diego School of Medicine and Moores Cancer Center have now identified six mRNA isoforms (bits of genetic material) produced by ovarian cancer cells but not normal cells, opening up the possibility that they could be used to diagnose early-stage ovarian cancer. What’s more, several of the mRNA isoforms code for unique proteins that could be targeted with new therapeutics.
“We were inspired by many studies aimed at using DNA to detect cancer,” said first author Christian Barrett, PhD, bioinformatics expert and project scientist in the UC San Diego School of Medicine Institute for Genomic Medicine. “But we wondered if we could instead develop an ovarian cancer detection test based on tumour-specific mRNA that has disseminated from cancer cells to the cervix and can be collected during a routine Pap test.”
While DNA carries all the instructions necessary for life, its actual sequence contains much more than just the genes that code for proteins. In contrast, mRNAs are complementary copies of just the genes. They carry the recipe for every protein that the cell will produce from the nucleus to the cytoplasm, where cellular machinery can read the recipe and build the corresponding proteins. According to the authors of this study, the advantage of using cancer mRNA for diagnosis rather than DNA is sheer number — a cancer cell might harbour just one or a few copies of a DNA mutation, but mRNA variants can occur in hundreds to thousands of copies per cell.
To determine if mRNAs can be used to distinguish ovarian cancer cells from normal cells, the team developed a custom bioinformatics algorithm and used it to mine two large public databases of genetic information — The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) program, both sponsored by the National Institutes of Health. TCGA is a catalog of RNA and DNA from 500 tumors covering many cancer types, while GTEx is a database of RNA and DNA from normal tissue samples. From these, the researchers were able to analyze mRNA sequence data from 296 ovarian cancers and 1,839 normal tissue samples.
Using this bioinformatics approach, the researchers identified six mRNA isoform molecules that have the tumour specificity required for an early detection diagnostic of ovarian cancer. They also validated their digital results in the real world using RT-quantitative PCR, a gene amplifying technique, to detect the same ovarian cancer-specific mRNA molecules in lab-grown cells.
Beyond their diagnostic potential, some of the mRNA isoforms identified in this study could also act as new therapeutic targets. These mRNA isoforms are predicted to encode proteins with unique amino acid sequences, which might allow them to be specifically targeted with certain therapeutics, such as monoclonal antibodies or T-cell-based vaccines. What’s more, the ovarian cancer-specific mRNA isoforms themselves could also be targeted with new therapeutic drugs.
“Our experimental findings were made in a laboratory and were performed on ovarian cancer cells from cell lines,” said study co-author Cheryl Saenz, MD, a clinical professor of reproductive medicine who specializes in treating gynaecologic cancers. “Clinical trials will need to be conducted on women to confirm the presence of these markers in women that we know have cancer, as well as to document the absence of the markers in women that do not have ovarian cancer.” University of California – San Diego Health System
‘Pain sensing’ gene discovery could help in development of new methods of pain relief
, /in E-News /by 3wmediaA gene essential to the production of pain-sensing neurons in humans has been identified by an international team of researchers co-led by the University of Cambridge. The discovery could have implications for the development of new methods of pain relief.
The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception.
Pain perception is an evolutionarily-conserved warning mechanism that alerts us to dangers in the environment and to potential tissue damage. However, rare individuals – around one in a million people in the UK – are born unable to feel pain. These people accumulate numerous self-inflicted injuries, often leading to reduced lifespan.
Using detailed genome mapping, two teams of researchers collaborated to analyse the genetic make-up of 11 families across Europe and Asia affected by an inherited condition known as congenital insensitivity to pain (CIP). This enabled them to pinpoint the cause of the condition to variants of the gene PRDM12. Family members affected by CIP carried two copies of the variant; however, if they had only inherited one copy from their parents, they were unaffected.
The team looked at nerve biopsies taken from the patients to see what had gone wrong and found that particular pain-sensing neurons were absent. From these clinical features of the disease, the team predicted that there would be a block to the production of pain-sensing neurons during the development of the embryo – they confirmed this using a combination of studies in mouse and frog models, and in human induced pluripotent stem cells (skin cells that had been reset to their ‘master state’, which enables them to develop into almost any type of cell in the body).
PRDM12 had previously been implicated in the modification of chromatin, a small molecule that attaches to our DNA and acts like a switch to turn genes on and off (an effect known as epigenetics). The researchers showed that all the genetic variants of PRDM12 in the CIP patients blocked the gene’s function. As chromatin is particularly important during formation of particular specialised cell types such as neurons, this provides a possible explanation for why pain-sensing neurons do not form properly in the CIP patients.
‘The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception,’ says Professor Geoff Woods from the Cambridge Institute for Medical Research at the University of Cambridge, who co-led the study. ‘Both are equally important to the development of new pain treatments – if we know the mechanisms that underlie pain sensation, we can then potentially control and reduce unnecessary pain.’
PRDM12 is only the fifth gene related to lack of pain perception to have been identified to date. However, two of the previously-discovered genes have already led to the development of new pain killers that are currently been tested in clinical trials. University of Cambridge