Publisher Health

It’s a decade since a police helicopter crashed through the roof of the Clutha Bar in Glasgow.Among those there that Friday night was Michael Byrne. He helped pull survivors from the rubble at the city centre bar, where 10 people lost their lives.Although Michael managed to escape without injury, the emotional impact the tragedy had on him was long-lasting. Video by Morgan SpenceThe BBC Action Line has details of organisations that can offer help and advice if you’ve been affected by issues raised in this video.

Published7 days agoShareclose panelShare pageCopy linkAbout sharingBy Nikki FoxBBC East health correspondentThe sister of a man who died waiting more than eight hours for an ambulance is calling on the government to “take note and take action”.Christopher Hart, 50, was found lifeless in his home in Woodbridge, Suffolk, by his mother, in October 2022.His emergency call, made at 01:00 BST, was graded Category 2, meaning an average wait time of 40 minutes.The Department of Health said ambulance response times had since improved.Mr Hart’s sister, Sheena Clements, told the BBC: “Losing a family member for anyone is hard, it’s emotional, especially if you know things could have been different. “The cardiologist said if he’d had the medical attention, he would have had a chance of surviving of between 93% and 97%. “He had a heart condition and needed a stent.”She added: “All we want is for the government to take notice and do something about it”.Image source, BBC A Prevention of Future Deaths report (PFDR), by the Suffolk coroner, Nigel Parsley, concluded that “due to high service demand, and ambulances waiting to off-load their patients at the local hospitals, no ambulance was immediately available.”It added: “The delay in an ambulance attending meant that potentially life saving treatment could not be given, so that delay directly contributed to Christopher’s death.”Mr Hart called an ambulance at 01:00 on 25 October 2022 after becoming unwell. It was graded as Category 2 and should have meant an average wait time of 40 minutes – and a target wait time of 18 minutes.The ambulance did not arrive until after Mr Hart’s mother discovered her son’s lifeless body at 09:25. He was pronounced dead at 09:35.The coroner added that “had an ambulance for Christopher arrived within the target time, the drugs he could have been given by ambulance personnel, and his early transport to hospital, would, on a balance of probabilities, have saved his life.”Image source, Sarah JonesMrs Clements described her brother as “a kind man, who was well-read and loved his movies and music.”She said their father had passed away 26 years earlier from a heart condition – but her brother’s condition was undiagnosed.The Department of Health (DHSC) said that “no one should have to wait longer than necessary for urgent and emergency care”, adding that responses to Category 2 incidents were almost 20 minutes faster compared to last year. According to NHS England statistics, ambulance response times in the East of England have improved by 30 minutes.However, on 9 November, coroner Mr Parsley said he heard evidence from a patient safety officer at the East of England Ambulance Service Trust (EEAST) that “despite previous measures put in place, there are continuing and regular instances of non-availability of ambulances occurring in Suffolk and the wider East of England region”.A spokesperson for the EEAST said: “Our response times have improved due to work to increase the number of frontline staff and available ambulances, but we recognise there is a lot more work needed by us and our partners to improve our response to patients.”Coroners’ concernsAnalysis by the BBC has found coroners have raised concerns regarding delays to East of England ambulances – or patients dying after waiting in the back of ambulances outside hospitals – on seven separate occasions since January 2023.Anyone written to by a coroner is supposed to reply within 56 days to say what action they will take to prevent further deaths.It is part of the legal process and helps promote change – but that process isn’t always followed by the government.On four occasions where coroners in Norfolk wrote to the Secretary of State regarding ambulance delays, a reply was not received. In the worst breach, the Department of Health failed to meet the deadline by 269 days. The Norfolk coroner’s office confirmed an extension had not been applied for in any of the cases. The Department of Health did not comment on this point.”People die every day but if simple measures can save someone’s life then we should be doing that,” Mrs Clements said.”Bereavement’s hard, but if you know something simple could be done to save your loved one’s life then it makes that bereavement process so much worse.”She said she did not blame the ambulance service for her brother’s death.Unison branch chairman for the EEAST, Glenn Carrington, said the solution was about making sure people could be cared for in the community so that hospitals could free up beds and ambulances would not be left waiting to offload patients.”Winter pressures are kicking in and we need to make sure response times don’t deteriorate,” he said.”When the time starts elapsing because you can’t get to someone, we know their outcomes will be worse – and that really gets to us.”The DHSC added: “We are providing an additional £800m for this winter to support the NHS. “We are also working to get 800 new ambulances on the road and create 5,000 permanent staffed hospital beds to further reduce waiting times.”Follow East of England news on Facebook, Instagram and X. Got a story? Email eastofenglandnews@bbc.co.uk or WhatsApp 0800 169 1830More on this storyMan found dead eight hours after ambulance callPublished24 NovemberMan, 82, faces 16-hour ambulance wait after fallPublished23 AugustWarning ambulance transfer delays risk future deathsPublished30 JanuaryPatient forced to wait in ambulance for 12 hoursPublished4 January’If we are queuing, we can’t get to patients’Published21 November 2022Related Internet LinksNHS ambulance performance dataCoroners prevention of future death reportsThe BBC is not responsible for the content of external sites.

Study by Brigham investigators revealed how genetic changes in certain types of brain cells may contribute to the inflammatory response seen in Alzheimer’s disease
Immune-regulating brain cells known as microglia are known to play a role in the progression of Alzheimer’s disease (AD). A new study by investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, explores how the genetics of microglia contribute to neuroinflammation and, in turn, AD. The team revealed that a reduction of INPP5D, a gene found in microglia, results in neuroinflammation and increases the risk for AD. Their results, which have important implications for the design of microglia-centered therapeutics for Alzheimer’s disease and related disorders, are published in Nature Communications.
“We know that microglia play important roles in the healthy and diseased brain, but, in many cases the molecular mechanisms underlying this relationship are poorly understood,” said corresponding author Tracy Young-Pearse, PhD, from the Department of Neurology at Brigham and Women’s Hospital. “If we’re able to identify and understand the significance of specific genes that play a role in neuroinflammation, we can more readily develop effective, targeted therapeutics.”
Neuroinflammation is important to monitor in people with neurodegenerative diseases, but it can be difficult to detect, especially in the early stages of AD. The earlier neurologists can identify it, the earlier they can treat it. Microglia are clearly involved in the process of neuroinflammation, but there are many unanswered questions regarding the molecular pathways involved.
The team used a variety of experimental approaches to probe the relationship between levels of INPP5D and a specific type of brain inflammation, activation of the inflammasome. As part of their study, the team compared human brain tissue from patients with AD and a control group. They found lower levels of INPP5D in the tissues of patients with AD and when INPP5D was reduced, it activated inflammation. In parallel, they used living human brain cells derived from stem cells to study the intricate molecular interactions within microglia that mediate inflammatory processes with a reduction of INPP5D. These studies identified specific proteins that could be inhibited to block inflammasome activation in microglia.
Although the team’s work represents the most comprehensive analysis of INPP5D in the AD brain, it remains to be determined whether INPP5D should be targeted with therapeutics. The team notes that their findings suggest INPP5D activity in AD brains is complex and future studies are needed to understand if INPP5D can be targeted to prevent cognitive decline in patients with AD.
“Our results highlight an exciting promise for INPP5D, but some questions still remain,” said Young-Pearse. “Future studies examining the interaction between INPP5D activity and inflammasome regulation are essential to improve our understanding of microglia in AD and to help develop a comprehensive toolbox of therapeutics that can be deployed to treat each of the molecular roads that lead to AD.”

The NewsA lifesaving cancer treatment may itself cause cancers, the Food and Drug Administration reported on Tuesday.The treatment, called CAR-T, was first approved in November 2017 for life-threatening blood cancers. But, the F.D.A. said, it had received 19 reports of new blood cancers in patients who received the treatment.A composite colored scanning electron micrograph of T cells, blue, and a lymphoma cancer cell, red.Steve Gschmeissner/Science SourceA Number That Sums It Up: Thousands of lives have been saved with CAR-T.CAR-T involves removing a type of white blood cell — T cells — from a patient’s blood, then genetically engineering to make proteins — chimeric antigen receptors (CAR) — which allow the T cells to attach to cancer cells and kill them. The engineered cells are then infused back into the patient’s blood.The F.D.A. has approved six commercial CAR-T products. Cancer specialists said the treatments have saved the lives of thousands of patients with blood cancers. Even if there is a causal link between the treatments and a small risk of a new blood cancer, the regulators said on Tuesday, the benefits of the treatment outweigh the risks. That sentiment was echoed by doctors involved in cancer treatment.While the hypothetical risk was known, “we haven’t observed it” in patients, Dr. Marcela V. Maus, director of cellular immunotherapy at Massachusetts General Hospital, said.Dr. John DiPersio, director of the center for genetic and cellular immunotherapy at Washington University School of Medicine in St. Louis, said his center had treated 500 to 700 patients. And, he said, “I haven’t seen a single one” develop a new T cell cancer.CAR-T therapy has been reserved for patients who would die without it, he added.“They are all going to die and they are all going to die quickly without this treatment. It saves their life,” Dr. DiPersio said. “It works in a substantial portion of patients. The benefit is enormous.”Facts to Keep in Mind: What triggered the F.D.A.’s investigation.The F.D.A. said in its announcement that the reports of additional cancers included serious consequences — hospitalizations and deaths. And, the agency said, it is known that the way CAR-T cells are produced has a risk of causing cancers in recipients.When patients’ T cells are engineered to make proteins that attack cancer cells, a virus helps slip new genes into T cell DNA. That has the potential to disrupt other genes, leading to cancer.But there are other potential explanations. CAR-T therapy is used when patients have already had at least one round of conventional treatments with intense chemotherapy and, often, radiation. Those treatments can themselves elicit new blood cancers. Even without chemotherapy or radiation, Dr. Maus added, patients with blood cell cancers are especially susceptible to developing other blood cell cancers.What Happens Next: The search for a smoking gun.One unanswered question, Dr. Maus and Dr. DiPersio said, is whether the new cancers involved T cells carrying the added CAR proteins. That does not prove the gene insertion caused the cancers. But Dr. DiPersio said, “it is more of a smoking gun.”The F.D.A. did not describe any anticipated outcomes of its investigation but said that it was “evaluating the need for regulatory action.”

Published40 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Lisa McManusBy Hannah RitchieBBC News, SydneyAustralia’s prime minister has given a national apology to survivors of the thalidomide scandal and their families. It comes over 60 years after the morning sickness drug started causing birth defects in babies globally. “This apology takes in one of the darkest chapters in Australia’s medical history,” Anthony Albanese told parliament on Wednesday.It is the first time the government has acknowledged its role in the tragedy. “To the survivors – we apologise for the pain thalidomide has inflicted on each and every one of you each and every day. We are sorry. We are more sorry than we can say,” Mr Albanese said, addressing a crowd of survivors and their families in the chamber. The exact number of people affected in Australia remains unknown, but more than 140 survivors have registered for a financial support programme since 2020.In 2019, a report found that 20% of Australia’s thalidomide cases could have been avoided if leaders had acted sooner. Survivor Trish Jackson, 61, told the BBC she hoped the apology would give “a bit of peace” to families. “[But] it should have been done years ago when parents were still alive, when mothers were still alive. Some survivors have even died and not gotten to hear this.”Developed in Germany in the 1950s, thalidomide was originally used as a sedative or tranquiliser, but soon became widely promoted around the world as a morning sickness drug. As usage increased, so too did reports of birth defects – usually in the form of significantly shortened limbs.It was an Australian report in The Lancet medical journal that first warned the world of thalidomide’s dangers in 1961, and it was taken off the market soon after. By then an estimated 10,000 babies globally had been born with disabilities.For decades, survivors have fought for acknowledgments of wrongdoing and compensation. Canada introduced financial assistance for survivors in 1991, and in 2010 the UK issued a national apology to those affected. But it wasn’t until a landmark Senate inquiry in 2019 that Australia took action to support survivors. Its financial scheme provided a one-off payment of up to A$500,000 ($332,000; £261,000) to survivors, followed by annual payments of between A$5,000 and A$60,000.The programme was later closed to new applicants, but on Wednesday Mr Albanese reopened it “to ensure that anyone who may have missed the previous opportunity to apply does not miss out”. More on this storyHow Australia has ‘lagged’ on thalidomide responsePublished3 April 2019Thalidomide survivor welcomes lifelong help offerPublished29 September 2022

While past research has indicated that moderate alcohol consumption can lower one’s risk of cardiovascular disease (CVD), more recent studiessuggest that moderate levels of drinking may be hazardous to heart health. A new analysis led by Boston University School of Public Health and Friedman School of Nutrition Science and Policy at Tufts University (Friedman School) now sheds new insight on this complex relationship between alcohol consumption and the progression of CVD.
Published in the journal BMC Medicine, the study found that alcohol consumption may have counteractive effects on CVD risk, depending on the biological presence of certain circulating metabolites — molecules that are produced during or after a substance is metabolized and studied as biomarkers of many diseases.
The researchers observed a total of 60 alcohol consumption-related metabolites, identifying seven circulating metabolites that link long-term moderate alcohol consumption with an increased risk of CVD, and three circulating metabolites that link this same drinking pattern with a lower risk of CVD.
The findings provide a better understanding of the molecular pathway of long-term alcohol consumption and highlight the need for and direction of further research on these metabolites to inform targeted prevention and treatment of alcohol-related CVD.
“The study findings demonstrate that alcohol consumption may trigger changes of our metabolomic profiles, potentially yielding both beneficial and harmful outcomes,” says Dr.Chunyu Liu, assistant professor of biostatistics at BUSPH and co-corresponding/co-senior author of the study along with Dr.Jiantao Ma, assistant professor in the Division of Nutrition Epidemiology and Data Science at the Friedman School. “Because the majority of our study participants are moderate alcohol consumers, our findings contribute to the ongoing discussion about the relationship between moderate alcohol drinking and heart health.
“However, rather than definitively settling that debate, this study underscores the intricate effects of alcohol consumption on cardiovascular health and generates a useful hypothesis for future investigations,” Dr. Liu says.
For the study, the researchers examined blood samples to measure the association between the cumulative average consumption of beer, wine, and liquor and 211 metabolites among 2,428Framingham Heart Study Offspring Study participants, who are the children of participants in the long-running Boston University-basedFramingham Heart Study, over 20 years. Among the participants, 636 developed CVD over the study period.

Among the 60 drinking-related metabolites, 13 metabolites had a stronger association with alcohol consumption in women than in men, perhaps due to women’s generally smaller body size and likely higher blood alcohol concentration after consuming the same amount of alcohol as men.
The results also showed that consumption of different types of alcohol was linked to different metabolomic responses, with beer consumption generating a slightly weaker association overall than wine and liquor. In roughly two-thirds of the 60 metabolites, higher plasma levels were detected in participants who consumed greater amounts of alcohol.
Branched-chain amino acids (BCAAs), were among the metabolites that were not associated with alcohol consumption.
The researchers then calculated two alcohol consumption-associated metabolite scores, which had opposite associations with the development of CVD.
“While our study presents intriguing findings, validation through state-of-the-art methods and large and diverse study populations is crucial,” Dr. Ma says. “To enhance reliability, we aim to conduct larger-scale research involving a more diverse racial and ethnic background, as the current study participants are all white. In addition, we will expand our study to integrate with other molecular markers such as genetic information to illustrate the complex relationships between alcohol consumption, metabolite features, and cardiovascular risk.”
The study was funded by the National Institute on Alcohol Abuse and Alcoholism. Data collection in the Framingham Heart Study was supported by the National Heart, Lung, and Blood Institute.

Optimal windows exist for action and perception during the 0.8 seconds of a heartbeat, according to research published November 28 in the open access journal PLOS Biology. The sequence of contraction and relaxation is linked to changes in the motor system and its ability to respond to stimulation, and this could have implications for treatments for depression and stroke that excite nerve cells.
The ways in which we perceive and engage with the world are influenced by internal bodily processes such as heartbeats, respiration and digestion. Cardiac activity can influence auditory and visual perception, and touch and sensory perceptions have been shown to be impaired during the systolic phase of the cardiac cycle when blood vessels are briefly distended.
Esra Al of the Max Planck Institute for Human Cognitive and Brain Sciences, Germany, and colleagues, wanted to understand whether there were changes in cortical and corticospinal excitability — the ability to respond to stimuli — across the cardiac cycle. 37 healthy human volunteers aged between 18 and 40 years received a series of transcranial magnetic stimulation (TMS) pulses — non-invasive short magnetic pulses that stimulate nerve cells — above the right side of the brain.
Motor and cortical responses as well as heartbeats were measured during the pulses and the authors found that higher excitability was recorded during the systolic phase. These simultaneous recordings of brain activity, heart activity, and muscle activity, suggest the timing of heartbeats and their neural processing are linked to changes in the excitability of the motor system.
TMS is used in treatments for depression and recovery after stroke. The research raises questions about whether these could be fine-tuned to improve results, as well as contributing to a greater understanding of brain-body interactions in health and in disease.
The authors add, “Intriguingly, this study uncovers a remarkable connection between the human heart and brain, revealing distinct time windows tailored for action and perception.”

For more than a century, American cities have been sliced and diced by high-traffic roadways. Interstate highways and wide arterials are now a defining feature of most metropolitan areas, their constant flow of cars spewing pollution into nearby neighborhoods.
Researchers have only just begun to understand the health risks posed by all that pollution. Long-term exposure to traffic-related air pollution — a complex mixture of exhaust from tailpipes, brake and tire wear, and road dust — has been linked to increased rates of cardiovascular disease, asthma, lung cancer and death.
New research from the University of Washington suggests those health risks are also seen in people traveling busy roads. A study published Nov. 28 in the Annals of Internal Medicine found that unfiltered air from rush-hour traffic significantly increased passengers’ blood pressure, both while in the car and up to 24 hours later.
“The body has a complex set of systems to try to keep blood pressure to your brain the same all the time. It’s a very complex, tightly regulated system, and it appears that somewhere, in one of those mechanisms, traffic-related air pollution interferes with blood pressure,” said Joel Kaufman, a UW physician and professor of environmental and occupational health sciences who led the study.
An earlier experiment by Kaufman’s lab found that exposure to diesel exhaust fumes increased blood pressure in a controlled environment. The roadway traffic study was designed to test that finding in a real-world setting by isolating the effects of traffic-related air pollution.
Researchers drove healthy participants between the ages of 22 and 45 through rush-hour Seattle traffic while monitoring their blood pressure. On two of the drives, unfiltered road air was allowed to enter the car, mirroring how many of us drive. On the third, the car was equipped with high-quality HEPA filters that blocked out 86% of particulate pollution. Participants did not know whether they were on a clean air drive or a roadway air drive.
Breathing unfiltered air resulted in net blood pressure increases of more than 4.50 mm Hg (millimeters of mercury) when compared to drives with filtered air. The increase occurred rapidly, peaking about an hour into the drive and holding steady for at least 24 hours. Researchers did not test past the 24-hour mark.

The size of the increase is comparable to the effect of a high-sodium diet.
“We know that modest increases in blood pressure like this, on a population level, are associated with a significant increase in cardiovascular disease,” Kaufman said. “There is a growing understanding that air pollution contributes to heart problems. The idea that roadway air pollution at relatively low levels can affect blood pressure this much is an important piece of the puzzle we’re trying to solve.”
The findings also raise questions about ultrafine particles, an unregulated and little-understood pollutant that has become a source of growing concern among public health experts. Ultrafine particles are less than 100 nanometers in diameter, much too small to be seen. Traffic-related air pollution contains high concentrations of ultrafine particles. In the study, unfiltered air contained high levels of ultrafine particles, though the overall level of pollution as measured by fine particle concentration (PM 2.5) was relatively low, equivalent to an AQI of 36.
“Ultrafine particles are the pollutant that were most effectively filtered in our experiment — in other words, where the levels are most dramatically high on the road and low in the filtered environment,” Kaufman said. “So, the hint is that ultrafines may be especially important [for blood pressure]. To actually prove that requires further research, but this study provides a very strong clue as to what’s going on.”
Traffic-related air pollution is the main cause of air quality variation from community to community in most U.S. metropolitan areas.
“This study is exciting because it takes the gold-standard design for laboratory studies and applies it in an on-roadway setting, answering an important question about the health effects of real-world exposures. Studies on this topic often have a challenging time separating the effects of pollution from other roadway exposures like stress and noise, but with our approach the only difference between drive days was air pollution concentration,” said Michael Young, a former UW postdoctoral fellow in the Department of Environmental and Occupational Health Sciences and lead author of the new study. “The findings are valuable because they can reproduce situations that millions of people actually experience every day.”
This research was funded by the U.S. Environmental Protection Agency and the National Institutes of Health.

A government anti-smoking plan also includes costlier cigarettes and a ban on disposable vapes. Smoking is the leading cause of avoidable deaths in France.France will ban smoking on beaches, near public buildings like schools and in public parks and forests next year, the French government said on Tuesday, as it unveiled plans to curb the habit by making it slightly more expensive and far less attractive, especially to younger people.“We have won battles,” Aurélien Rousseau, France’s health minister, said at a news conference in Paris. Noting that the smoking rate for 17-year-olds had already dropped to 16 percent in 2022 — down from 25 percent in 2017 — he added that “tobacco remains a major public health scourge.”The government’s plan is part of an ambitious effort to produce the first “no-tobacco generation” by 2032.While anti-smoking campaigners welcomed some of the measures announced by Mr. Rousseau, they said that lofty objective would be hard to achieve if the government did not act even more forcefully to push up the price of cigarettes.Smoking rates in France have remained roughly unchanged since 2019 after decades of regularly declining, according to French public health authorities.Nearly a quarter of French adults, or about 12 million people, still smoke daily, compared with just 11.5 percent of U.S. adults who smoke regularly, according to the Centers for Disease Control and Prevention. And smoking is still the leading cause of avoidable mortality in France, causing about 75,000 deaths per year.Mr. Rousseau said the government wanted to continue “de-normalizing” smoking in outdoor settings by making smoking-authorized areas the exception, not the rule. (Smoking inside most public establishments like restaurants, cafés and clubs has been strictly forbidden for more than a decade.)Previously, local authorities had already barred people from smoking at more than 7,000 outdoor locations, including at beaches, forests and parks across the country, Mr. Rousseau said, but there was no nationwide ban.Violators of the new ban could be fined, but Mr. Rousseau said the details of any penalties still needed to be worked out.The government also wants to make tobacco increasingly unattractive for young people, mainly by banning disposable, single-use vapes that are heavily marketed toward teenagers, which would fulfill a promise that was first made by Prime Minister Élisabeth Borne in September.Mr. Rousseau said those vapes — nicknamed “puffs” in France — were “each more colorful and attractive than the last” but were “an aberration from the point of view of public health or of their environmental impact.”Aurélien Rousseau, France’s health minister, at The National Assembly in Paris on Tuesday.Ludovic Marin/Agence France-Presse — Getty ImagesThe government also wants to extend the requirement that all tobacco and vaping products have plain packaging, which is already required for cigarette packs.Crucially, Mr. Rousseau said the government was aiming for a minimum price of 13 euros per pack of cigarettes, or about $14, by 2027. A pack currently costs about $12 on average in France.Anti-smoking groups welcomed measures like the bans on outside smoking and on disposable vapes but said the planned price increases would not go far enough to significantly reduce smoking rates.Marion Catellin, the director of the Alliance Against Tobacco, said the government’s target price for 2027 was too low — her organization was hoping for a price of 16 euros per pack — and that the cost of individual packs would likely reach 13 euros anyway through inflation.Ms. Catellin said that if the government did not show “political courage” by raising taxes on cigarettes, it would struggle to reach the goal of a “no-tobacco” generation by 2032.“We are very disappointed,” she said. “This plan represents a policy of small steps in the face of very ambitious objectives.”The government can enact most of the measures announced by Mr. Rousseau by decree and will do so early next year, he said. The ban on disposable vapes will require legislation that is expected to go to Parliament next month. Mr. Rousseau said pharmacists will also be allowed to prescribe nicotine substitution medication to help smokers quit.Countries around the world have taken conflicting public health approaches to smoking.In May, Australia announced sweeping new regulations that aimed to reduce smoking and vaping, while neighboring New Zealand announced last week that it wanted to repeal a law — previously celebrated as a model for other nations — that would have gradually banned all cigarette sales in the country over the course of several decades.

Researchers from WEHI (Melbourne, Australia) have solved a mystery about the most important driver of cancer development — a mutant protein found in half of all cancers — and how it contributes to tumour growth.
The p53 protein is a tumour suppressor that plays a crucial role in preventing the formation of cancerous cells. But when it mutates and becomes defective in cells, the protein can significantly boost a person’s risk of cancer development.
In a first, researchers have revealed what behaviours of the mutated protein are critical for fuelling tumour growth — a discovery that could offer new directions for the development of treatment options.
At a glance Findings show, for the first time, what traits of the mutant p53 protein are critical for driving cancer growth. Mutations of this protein are the biggest driver of cancer development and are found in half of all human cancers around the globe. The discovery will help rethink ways to therapeutically treat cancers with p53 mutations, leading to new and improved cancer treatments in future.

When it works properly, the p53 protein serves as a powerful defence mechanism against cancer development by ensuring that cells with compromised DNA either get repaired or removed from our body.
Mutations to this protein can be triggered by a variety of environmental factors — such as exposure to UV radiation — if the body’s cell division process goes awry, or if they are genetically inherited.
These abnormalities can lead to a dysfunctional protein that has lost the crucial ability to regulate cellular responses that prevent tumour development and growth. This is known as loss-of-function.
Additionally, some researchers believe these mutations can also lead to a supercharged protein that helps cancerous cells survive and proliferate, known as gain-of-function.
In a new study, published in Cancer Discovery, researchers from WEHI and Trento University (Italy) have answered an age-old question by proving which function helps mutant p53 fuel tumour growth.
Associate Professor Gemma Kelly, a co-corresponding author of the paper, said understanding how exactly these mutations contribute to cancer is critical to understanding how to treat patients bearing cancers with the dysfunctional proteins.

“Our study has provided the first evidence to show that it is actually the loss-of-function that impacts cancer growth. We found no evidence of gain-of-function contributing to cancer growth,” Assoc Prof Kelly, a Laboratory Head in WEHI’s Blood Cells and Blood Cancer Division, said.
“This is significant because until now, there was not much evidence available to properly show whether it is the protein’s loss or gain-of-function that spurs cancer growth.
“If you look at all cancers of humanity, about 50% of them have a mutation in p53. Specific cancers like those of the pancreas, lung and breast, commonly have defects in these proteins.
“Our findings have transformed our understanding of these mutations, which help rethink how they can be targeted in the development of new cancer treatments.”
Unprecedented data exploration
The study utilised the powerful gene editing tool CRISPR to remove 12 different, mutated versions of the protein with reported gain-of-function effects. Researchers found there was no change to the behaviour of cancer cells, in growth or response to chemotherapy.
Leveraging a significant collaboration with The University of Trento (Italy), the research team was also able to restore p53’s normal functions that were lost when the protein mutated. They found this reduced cancer growth in pre-clinical models.
First author Dr Zilu Wang used these models and data from the DepMap database in an in-depth way that had never been done before to consolidate the findings.
“Having these tools at my disposal allowed me to assess 157 different p53 mutations,” Dr Wang said.
“The mutations I looked at basically account for at least 90% of human cancers with defects in p53, which will provide crucial insight when informing the development of new anti-cancer strategies.”
Future treatments
Co-corresponding author, Professor Andreas Strasser, said the findings could prevent hundreds of millions of dollars being wasted on developing ineffective drugs.
“There is research underway that is working towards finding the first therapeutics to target gain-of-function traits,” Prof Strasser, Head of WEHI’s Blood Cells and Blood Cancer Division, said.
“Our findings indicate there is no further merit in this therapeutic avenue and the focus needs to shift to restoring the mutant protein’s lost function and normal tumour suppressor ability.”