A whole new level of control of cancer gene activity within tumors, has been described by researchers as ‘dark matter’.
It was recently discovered and published in two major studies at the same time in Nature that cancers can evolve to become more aggressive without relying on DNA mutations.
Testing cancers for just the DNA mutations can skip this level of control and therefore fail to predict how cancers may behave and respond to treatment, the researchers say.
Both studies revealed how a level of gene control called ‘epigenetics’ pays a central role in the progression and development of bowel cancer.
The research was led by scientists at The Institute of Cancer Research, London, Human Technopole in Milan and Queen Mary University of London. It was funded by Wellcome, the Medical Research Council (MRC) and Cancer Research UK.
Dark matter could accurately predict cancer’s behavior
The researchers say their findings could change the way cancer is thought about and the way it is treated – and lead to new forms of tests that predict cancer’s behavior more accurately.
The chemical changes that occur to the three-dimensional structure of DNA through epigenetics, do not change the DNA code but it can control access to genes. The researchers said it has increasingly been recognized as playing a major role in the development of cancer.
The influence of epigenetic control on how bowel cancers grow and develop over time was tracked for the first time thanks to the scientists’ work. They managed to track this separately from the influence of mutations to the DNA code, which were mapped at the same time.
For every cancer they examined, the researchers noted important epigenetic changes that they noted were involved in the disease’s ability to evolve and become more aggressive.
‘Something we liken to cancer’s dark matter’
Professor Trevor Graham, director of the center for evolution and cancer at the Institute of Cancer Research, said: “We’ve unveiled an extra level of control for how cancers behave – something we liken to cancer’s ‘dark matter’. For years our understanding of cancer has focused on genetic mutations which permanently change the DNA code. But our research has shown that the way the DNA folds up can change which genes are read without altering the DNA code and this can be very important in determining how cancers behave.
“I hope our work will change the way we think about cancer and its treatment – and should ultimately affect the way patients are treated. Genetic testing for cancer mutations only gives us part of the picture about a person’s cancer – and is blind to ‘epigenetic’ changes to how genes are read. By testing for both genetic and epigenetic changes, we could, potentially, much more accurately predict which treatments will work best for a particular person’s cancer.”
The researchers collected 1,373 samples from 30 bowel cancers and looked at the epigenetic changes as the cancers evolved which was recorded in the first paper.
They noted that epigenetic changes are highly common in cells which have become cancerous and occur around genes already known to drive cancer.
They found they are heritable, meaning they can be inherited by cells with each cell division, and that they contribute to cancer evolution and they influence how cancer cells accumulate DNA mutations.
The changes were also present in cancer cells that had survival advantages which helped them to grown more than other cells.
In the second paper, the researchers were trying to understand why cancer cells within the same tumor can be so different to one another, a characteristic the researchers said, helps some cells develop survival advantages becoming resistant to cancer treatments.
The researchers, wanted to understand whether the diversity of cell types within a tumor was governed by variation in the DNA code or something else. DNA sequences in diverse samples
The researchers wanted to understand whether the diversity of cell types within a tumor is governed by variation in the DNA code, or something else. They looked at the DNA sequence in diverse samples taken from different parts of the same tumor.
They found that less than 2% of changes in the DNA code in independent areas of a tumor were associated with changes in gene activity and that variation in cancer cell characteristics throughout tumors is often governed by factors other than DNA mutations.
The researchers point out that more work needs to be done to determine cause and effect between specific epigenetic changes and modifications to cancer behavior and their findings are observational in nature.
Together, the researchers say that the papers represent a fundamental advance in understanding cancer. They stress DNA mutations are essential for ‘setting the scene’ for a cancer’s development and the way it evolves but importantly note that much of the subsequent behavior of cancer cells is determined by other factors such as epigenetics.
The researchers believe this could help explain why DNA tests don’t always predict how cancers are going to respond to treatment in order to help doctors tailor treatments for patients more effectively. They say it could also give reason as to why some environmental exposures can cause cancer without leading to mutations in the DNA code.
Professor Andrea Sottoriva, head of the computational biology research centre at human technopole in Milan, who co-led the research, said: “When we study how cancers evolve over time, we tend to look at DNA mutations, but it’s clear that epigenetic changes also enable cancer to adapt and develop a survival advantage over other cells.
“We have for the first time been able to map epigenetic changes alongside the accumulation of DNA mutations as a colorectal tumor evolves. This provides exciting opportunities to create new treatments for cancer that don’t target the effects of DNA mutations, but instead the epigenetic changes which determine how genes are read.”
‘Open’s up exciting future opportunities’
Professor Kristian Helin, chief executive of the Institute of Cancer Research, and a world leader in the study of epigenetics, said: “This (dark matter) discovery represents an exciting advance in our understanding of cancer biology. Cancer’s ability to rapidly change and evolve is a key reason why it is so hard to treat. Exactly how cancer cells do this, and the factors that control how it can adapt to evade treatment, is not well understood.
“This important work demonstrates the potential role of epigenetic regulation in the development of cancer and the complexity of its behavior. It opens exciting future opportunities to assess cancer using both genetic and epigenetic tests, and eventually to treat cancer with epigenetic-directed drugs.”
The Institution of Cancer Research is is one of the world’s most influential cancer research institutes and can now add ‘dark matter’ to its list of research achievements while it continues researching how to treat the differences between cancers.
Flu shots are now free for everyone in Quebec due to overwhelmed hospital ERs
While the campaign for flu shots has already been underway in Quebec for several weeks, the provincial government announced on Friday that immunization will now be free of charge for any Quebecer over the age of six months.
Previously, only people who met certain criteria (babies, seniors, the chronically ill, etc) were able to get the influenza immunization free of charge, and the vaccination sites set up for COVID-19 were only handling free flu shots. Meanwhile, the general population in Quebec was previously only able to get vaccinated at pharmacies, for a fee.
The decision was made due to the critical state of hospital ERs in the province, particularly at children’s hospitals in Montreal, where kids are being brought in by parents in larger numbers than usual due to rising rates of flu, COVID-19 and RSV infections.
“With the trio of viruses currently circulating, the influenza vaccine is now available free of charge to all Quebecers who wish to take advantage of it. It’s one more tool to limit the pressure on our network.”
—Quebec Health Minister Christian Dubé
To schedule an appointment for a flu shot and/or a COVID-19 shot, please visit the Clic Santé website.
Deadly Bird Flu Outbreak Is The Worst In U.S. History
An ongoing outbreak of a deadly strain of bird flu has now killed more birds than any past flare-up in U.S. history.
The virus, known as highly pathogenic avian influenza, has led to the deaths of 50.54 million domestic birds in the country this year, according to Agriculture Department data reported by Reuters on Thursday. That figure represents birds like chickens, ducks and turkeys from commercial poultry farms, backyard flocks and facilities such as petting zoos.
The count surpasses the previous record of 50.5 million dead birds from a 2015 outbreak, according to Reuters.
Turkeys in a barn on a poultry farm.
On farms, some birds die from the flu directly, while in other cases, farmers kill their entire flocks to prevent the virus from spreading after one bird tests positive. Such farmers have occasionally drawn condemnation from animal welfare advocates for using a culling method known as “ventilation shutdown plus,” which involves sealing off the airways to a barn and pumping in heat to kill the animals.
The virus has raged through Europe and North America since 2021. A variety of wild birds have been affected worldwide, including bald eagles, vultures and seabirds. This month, Peru reported its first apparent outbreak of highly pathogenic avian influenza after 200 dead pelicans were found on a beach.
Pelicans suspected to have died from highly pathogenic avian influenza are seen on a beach in Lima, Peru, on Nov. 24.
The migration of infected wild birds has been a major cause of the spread. Health and wildlife officials urge anyone who keeps domestic birds to prevent contact with their wild counterparts.
While health experts do not generally consider highly pathogenic avian influenza to be a major risk to mammals, a black bear cub in Alaska was euthanized earlier this month after contracting the virus. Wildlife veterinarian Dr. Kimberlee Beckmen told the Juneau Empire newspaper that the young cub had a weak immune system.
Over the summer, avian flu also spread among seals in Maine, which the National Oceanic and Atmospheric Administration believed contributed to an unusually high number of seal deaths.
The Centers for Disease Control and Prevention states that the risk “to the general public” from the bird flu outbreak is low. However, the agency recommends precautions like wearing personal protective equipment and thoroughly washing hands for people who have prolonged contact with birds that may be infected.
In April, a Colorado prisoner working at a commercial farm became the first person in the U.S. to test positive for the new strain, though he was largely asymptomatic.
Successful tests in animal models pave way for strategy for universal flu vaccine
An experimental mRNA-based vaccine against all 20 known subtypes of influenza virus provided broad protection from otherwise lethal flu strains in initial tests, according to a study.
This could serve one day as a general preventative measure against future flu pandemics, the researchers from University of Pennsylvania, US, said.
According to the study, tests in animal models showed that the vaccine dramatically reduced signs of illness and protected from death, even when the animals were exposed to flu strains different from those used in making the vaccine.
The “multivalent” vaccine, which the researchers described in a paper published in the journal Science, used the same messenger ribonucleic acid (mRNA) technology employed in the Pfizer and Moderna SARS-CoV-2 vaccines, the study said.
This mRNA technology that enabled those Covid-19 vaccines was pioneered at Penn, the study said.
“The idea here is to have a vaccine that will give people a baseline level of immune memory to diverse flu strains, so that there will be far less disease and death when the next flu pandemic occurs,” said study senior author Scott Hensley.
Influenza viruses periodically cause pandemics with enormous death tolls. The best known of these was the 1918-19 “Spanish flu” pandemic, which killed at least tens of millions of people worldwide.
Flu viruses can circulate in birds, pigs, and other animals, and pandemics can start when one of these strains jumps to humans and acquires mutations that adapt it better for spreading among humans.
Current flu vaccines are merely “seasonal” vaccines that protect against recently circulating strains, but would not be expected to protect against new, pandemic strains. The strategy employed by the Penn researchers is to vaccinate using immunogens – a type of antigen that stimulates immune responses – from all known influenza subtypes in order to elicit broad protection, the study said.
The vaccine is not expected to provide “sterilizing” immunity that completely prevents viral infections. Instead, the new study showed that the vaccine elicited a memory immune response that can be quickly recalled and adapted to new pandemic viral strains, significantly reducing severe illness and death from infections.
“It would be comparable to first-generation SARS-CoV-2 mRNA vaccines, which were targeted to the original Wuhan strain of the coronavirus.
“Against later variants such as Omicron, these original vaccines did not fully block viral infections, but they continue to provide durable protection against severe disease and death,” said Hensley.
The experimental vaccine, when injected and taken up by the cells of recipients, started producing copies of a key flu virus protein, the hemagglutinin protein, for all twenty influenza hemagglutinin subtypes—H1 through H18 for influenza A viruses, and two more for influenza B viruses.
“For a conventional vaccine, immunizing against all these subtypes would be a major challenge, but with mRNA technology it’s relatively easy,” Hensley said.
In mice, the mRNA vaccine elicited high levels of antibodies, which stayed elevated for at least four months, and reacted strongly to all 20 flu subtypes. Moreover, the vaccine seemed relatively unaffected by prior influenza virus exposures, which can skew immune responses to conventional influenza vaccines.
The researchers observed that the antibody response in the mice was strong and broad, whether or not the animals had been exposed to flu virus before.
Hensley and his colleagues currently are designing human clinical trials, he said. The researchers envision that, if those trials are successful, the vaccine may be useful for eliciting long-term immune memory against all influenza subtypes in people of all age groups, including young children.
“We think this vaccine could significantly reduce the chances of ever getting a severe flu infection,” Hensley said.
In principle, he added, the same multivalent mRNA strategy can be used for other viruses with pandemic potential, including coronaviruses.
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