A University of Queensland researcher has found molecular doorways that could be used to help deliver drugs into the brain to treat neurological disorders.
Dr Rosemary Cater from UQ’s Institute for Molecular Bioscience led a team which discovered that an essential nutrient called choline is transported into the brain by a protein called FLVCR2.
“Choline is a vitamin-like nutrient that is essential for many important functions in the body, particularly for brain development,” Dr Cater said.
“We need to consume 400-500 mg of choline per day to support cell regeneration, gene expression regulation, and for sending signals between neurons.”
Dr Cater said that until now, little was known about how dietary choline travels past the layer of specialised cells that separates the blood from the brain.
“This blood-brain barrier prevents molecules in the blood that are toxic to the brain from entering,” she said.
“The brain still needs to absorb nutrients from the blood, so the barrier contains specialised cellular machines — called transporters — that allow specific nutrients such as glucose, omega-3 fatty acids and choline to enter.

“While this barrier is an important line of defence, it presents a challenge for designing drugs to treat neurological disorders.”
Dr Cater was able to show that choline sits in a cavity of FLVCR2 as it travels across the blood-brain barrier and is kept in place by a cage of protein residues.
“We used high-powered cryo-electron microscopes to see exactly how choline binds to FLVCR2,” she said.
“This is critical information for understanding how to design drugs that mimic choline so that they can be transported by FLVCR2 to reach their site of action within the brain.
“These findings will inform the future design of drugs for diseases such as Alzheimer’s and stroke.”
The research also highlights the importance of eating choline-rich foods — such as eggs, vegetables, meat, nuts and beans.
The research is published in Nature and funded by the National Institutes of Health.

Several lawmakers questioned whether the company had become so large — with tentacles in every aspect of the nation’s medical care — that the effects of the hack were outsize.In a tense Senate hearing on Wednesday, lawmakers sharply criticized UnitedHealth Group’s handling of the cyberattack that paralyzed the U.S. health care system, citing the failure of its security systems and the potential disclosure of sensitive medical information of millions of Americans.Democratic and Republican senators questioned whether the cyberattack of Change Healthcare, which manages a third of all U.S. patient records and some 15 billion transactions a year, was so vast because UnitedHealth is too deeply embedded in nearly every aspect of the nation’s medical care. UnitedHealth Group is not only the parent of Change but also the parent of the country’s largest health insurer and a big pharmacy benefit manager (Optum). United also oversees nearly one in 10 doctors in the country.“The Change hack is a dire warning about the consequences of ‘too big to fail’ mega-corporations gobbling up larger and larger shares of the health care system,” said Senator Ron Wyden, the Oregon Democrat who is the chairman of the Finance Committee.The U.S. health system was thrust into chaos after the Feb. 21 attack on Change, which serves as a digital highway between health insurers and hospitals and doctors. Patients could not fill prescriptions, and hospitals and doctors faced a severe cash crunch because they could not be paid for their care.UnitedHealth’s chief executive, Andrew Witty, was summoned to testify before both the Senate Finance Committee and the House Energy and Commerce Committee.On Wednesday morning, he defended the company’s efforts to restore services and apologized.“As a result of this malicious cyberattack, patients and providers have experienced disruptions and people are worried about their private health data. To all those impacted, let me be very clear: I am deeply, deeply sorry,” he said.But Mr. Witty acknowledged the lax digital security that enabled hackers to enter Change’s network and conceded that United fumbled initial efforts to help cover payments for providers.Just last week, United began to reveal that hackers did get access to some patient data, although Mr. Witty told the senators it would be quite a while before the company would have a solid grasp on how extensive that breach of patient information was.Mr. Witty said that UnitedHealth was working with regulators to determine when and how to begin communicating with people who were affected.“We want to try and avoid piecemeal communication,” he said.United was forced to shut Change’s systems down completely for several weeks, prompting tense exchanges between senators and Mr. Witty over the pace of reimbursements to hospitals and other providers.Mr. Witty told senators that “claims flow across the entire country is essentially back to normal.” Mr. Wyden said that he had heard from providers who filed claims in February that it would take until at least June to be reimbursed.“We can move absolutely faster than that,” Mr. Witty said, asking to be put in touch with any organization that had complained to Mr. Wyden.“Practically every provider I bump into is waiting to be paid,” Mr. Wyden shot back.Minutes later, Senator Marsha Blackburn, Republican of Tennessee, echoed Mr. Wyden, accusing Mr. Witty of presenting a “rosy” portrayal of the reimbursement process and saying that her office had been bombarded by calls from health providers waiting to be paid.Senator Marsha Blackburn, Republican of Tennessee, accused Mr. Witty of presenting a “rosy” portrayal of the reimbursement process.Ting Shen for The New York TimesOne hospital in the state had a backlog of Medicare claims equivalent to a month of revenue, Ms. Blackburn noted.“Every day they call to get an update. Every single day they’re calling. And they get the runaround every single day, repeatedly,” she said. “It’s like you all can’t figure this out.”Mr. Witty also acknowledged that the company paid a $22 million ransom to the attackers, saying “the decision to pay a ransom was mine. This was one of the hardest decisions I’ve ever hard to make.”The F.B.I. and other authorities are investigating the hack.UnitedHealth has been criticized for being circumspect about the details of the attack.“You’ve been all over the map in terms of personal accountability,” Mr. Wyden told Mr. Witty. “You have consistently downplayed your role in this.”Mr. Wyden said that UnitedHealth had failed to enforce the most basic kind of cybersecurity measure — so-called multifactor authentication.Mr. Witty said that as of Wednesday, all of UnitedHealth’s “external-facing systems” were deploying that form of authentication. The company had also brought in outside groups to do additional scanning of the company’s technology, he added, and had hired Mandiant, a cybersecurity firm, as an adviser.“This is some basic stuff that was missed,” Senator Thom Tillis, Republican of North Carolina, said, holding up a copy of the book “Hacking for Dummies.”The hearing gave Mr. Witty the chance to offer a more detailed timeline of the hack and the response to it.The cybercriminals gained access to Change’s systems on Feb. 12, nine days before UnitedHealth realized it needed to shut them down. Mr. Witty emphasized that the company quickly prevented the attack from spreading beyond Change to the parent company or any of its other units, like Optum or the health insurer. “We contained the blast range just to Change,” he said.Mr. Witty also argued the vulnerability of the health care system to hacks goes way beyond United, which he said repeals an attempted intrusion every 70 seconds alone. He said that because United only acquired the Change system 18 months ago, it had been unable to fully revamp Change’s “legacy technologies” that made it vulnerable to the hack.Mr. Witty said at a different point in the hearing that he was sympathetic to providers who were reluctant to use Change again.“The reason why it’s taken longer than you might expect to recover is we’ve literally built this platform back from scratch, so that we can reassure people that there are not elements of the old attacked environment within the new technology,” he said.United’s acquisition of the Change network in 2022 was held up by some senators as an example of mass consolidation in the health care industry. The Justice Department, which oversees health insurers, tried to block United’s purchase of Change, but failed to persuade a federal judge that the deal was anticompetitive.Senator Elizabeth Warren, Democrat of Massachusetts, labeled UnitedHealth “a monopoly on steroids,” noting more than once that it was the 11th largest company in the world.She accused United of taking advantage of the chaos created by the hack to acquire even more doctors’ practices, saying it now oversaw one in 10 of the nation’s doctors.Mr. Witty disputed her claims, pointing to sectors where United did not do business. “Despite our size, we own no hospitals in America and no drug manufacturers,” he said.

The LatestBaby aspirin is routinely prescribed to people who survive heart attacks. But there’s another vulnerable group who benefit from daily low-dose aspirin: pregnant women at risk of developing pre-eclampsia, life-threatening high blood pressure.It’s a factor in up to one in 20 pregnancies in the United States, and one of the leading causes of maternal mortality nationwide. Pre-eclampsia is the top cause of maternal death among Black women, who die of pregnancy-related complications at rates almost triple those of white women.But not enough pregnant women are getting the word that low-dose aspirin can help. Now leading experts are hoping to change that.Gary Cameron/ReutersBack Story: Aspirin reduces the odds of certain complications.The U.S. Preventive Services Task Force, an influential panel of experts that issues national guidance, has for 10 years been recommending that women who are at risk for pre-eclampsia start taking baby aspirin when they are 12 weeks pregnant.Both the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support the recommendation, saying low-dose aspirin is safe and not likely to cause complications. The optimal time to start is before 16 weeks of pregnancy, though it can be initiated later, the groups advise.Those at risk for developing pre-eclampsia include anyone who had pre-eclampsia during a previous pregnancy, as well as those carrying twins, triplets or other multiples; those who have kidney disease, autoimmune disease, Type 1 or Type 2 diabetes; and those with chronic hypertension.A pregnant woman may also be at risk if she is pregnant for the first time, is 35 or older, has a body mass index greater than 30, or has a family history of pre-eclampsia.Taking aspirin reduces the risk of pre-eclampsia by 15 percent, while reducing the risk of premature birth by 20 percent and reducing the risk of another complication, intrauterine growth restriction, by 18 percent, studies have found.The Problem: Women and their doctors haven’t gotten the news.Despite all the data, too few pregnant women at risk are taking baby aspirin, and too few doctors recommend it. A 2022 study found that Black women are less likely to be told to take baby aspirin, even when they meet the criteria.Pre-eclampsia itself is far from a household term: One in five families, and one in four Black families, has never heard of it, according to a new survey conducted by the Harris Poll for the March of Dimes.In addition, only about one in five families surveyed said they were familiar with interventions like baby aspirin.“Baby aspirin has been out there for a while, but a lot of patients don’t know about it and a lot of providers aren’t screening patients appropriately,” said Dr. Elizabeth Cherot, president and chief executive of the March of Dimes.“It’s low-dose aspirin,” she added. “It’s over-the-counter, it’s available, it’s accessible. But there seem to be barriers preventing high-risk patients from taking it as a preventive measure.”The Fix: A national campaign to raise awareness.The March of Dimes, which fights for the health of mothers and babies, on Wednesday announced it was starting a campaign called “Low Dose, Big Benefits,” to raise awareness among health providers and pregnant women regarding the benefits of low-dose aspirin.The campaign features the U.S. Olympian Allyson Felix, who developed pre-eclampsia during her first pregnancy and had to have an emergency cesarean section at 32 weeks.Having had the condition once, Ms. Felix knew she might develop it again during her second pregnancy, so she decided to take baby aspirin. She had a normal full-term pregnancy with her second child, who was born on April 10.“This project is about getting the message out there for families and pregnant people as well as health care personnel,” Dr. Cherot said. “Patients should be asking their providers about low-dose aspirin.”

-Columbia University researchers have found cells inside clogged arteries share similarities with cancer and aggravate atherosclerosis, raising the possibility that anticancer drugs could be used to treat atherosclerosis and prevent heart attacks.
Their study found that smooth muscle cells that normally line the inside of our arteries migrate into atherosclerotic plaques, change their cell identity, activate cancer genes, and proliferate inside the plaques.
“Our study shows that these transformed muscle cells are driving atherosclerosis, opening the door to new ways to treat the disease, potentially with existing cancer drugs,” says Muredach Reilly, MD, the Florence and Herbert Irving Endowed Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons and director of Columbia’s Irving Institute for Clinical and Translational Research.
The study, published April 30 in Circulation, was led by Reilly and Huize Pan, now an assistant professor of medicine at Vanderbilt University Medical Center, who conducted the research when he was an associate research scientist at Columbia.
DNA damage, hyperproliferation
Atherosclerosis is the major cause of heart attacks and stroke around the world and occurs when fat deposits build up inside the arteries. Atherosclerosis can be reduced with a healthy diet or drugs called statins that slow or reverse the buildup of deposits.
Previous studies had found that smooth muscle cells metamorphose into different types of cells inside these atherosclerotic plaques and multiply to make up most cells within the plaques.

Yet until now, few studies had examined the cancer-like properties of the cells and if these changes contributed to atherosclerosis. To learn more, Reilly and Pan closely tracked the development of transformed smooth muscle cells in mice with atherosclerosis and sampled plaques of people with atherosclerosis.
They found striking parallels between changes in the smooth muscle cells and tumor cells, including hyperproliferation, resistance to cell death, and invasiveness.
DNA damage, another hallmark of cancer, accumulated in the mouse and human smooth muscle cells and appears to accelerate atherosclerosis, the researchers found. The researchers could further accelerate atherosclerosis in mice by introducing a genetic mutation that increased DNA damage within the smooth muscle cells. Vascular tissue from healthy mice and people had no signs of smooth muscle cells with the DNA damage found in atherosclerotic plaques.
Reilly adds that they found no evidence of metastasis. “The cells stay inside existing plaques, which makes us think that they behave mostly like benign tumor cells, but more work needs to be done in humans and animal models to address this hypothesis,” he says.
Treating atherosclerosis like cancer
If atherosclerosis is driven by cancer-like cells, anticancer therapies may be a potential new way to treat or prevent the disease.

The researchers explored that idea by treating atherosclerotic mice with a common cancer drug, niraparib, that targets cells with DNA damage. The drug significantly decreased the size of the atherosclerotic plaques and improved plaque stability (stable plaques reduce the odds of having a heart attack).
“This suggests that cancer drugs like niraparib could both prevent the buildup of plaques and treat atherosclerosis once its established,” Reilly says. “But it’s important to note that the experiment with niraparib was proof of a principle and does not directly translate to clinical use.”
Other cancer drugs may also have benefits. “We need more work to select the best targets, safest targeted therapies, and vascular delivery strategies,” Reilly says. “And we need to determine if different people have different types of DNA damage and mutations that drive the disease, and, if so, we can use that information to develop personalized therapies to treat atherosclerosis,” Reilly says.
“Statins are very effective in many people at reducing atherosclerosis and preventing hearts attacks, but some people still have substantial cardiovascular risk. We think more research into the cancer-like properties of atherosclerosis will lead to new treatment options for these patients.”

Better than expected life expectancy in two disadvantaged areas in England is probably due to population change according to local residents and professionals.
In the UK, people from the most disadvantaged areas can expect to die nine years earlier compared with people from the least disadvantaged areas while people in the north of England have lower life expectancy, higher infant mortality and worse health and wellbeing compared with national averages.
The study, funded by the NIHR School for Public Health Research, was a collaboration between Lancaster University, the London School of Hygiene and Tropical Medicine, the University of Liverpool and Northumbria University.
Researchers examined trends in life expectancy (LE) following the introduction of austerity policies in 2010, when gains in LE generally stalled.
They selected two case studies — a rural local authority area in the Northwest and an urban local authority area in the South-East of England. Both are in the bottom third of the most disadvantaged areas, with life expectancy below the average of 79.6 for men and 83.2 for women in England.
Changes in LE at birth and at 65 years, between 2010-12 and 2015-17, were identified based on data supplied by Public Health England and the Office for National Statistics.
Both the NW and SE Areas showed greater gains than expected given levels of social and economic disadvantage. Male LE increased by between 1 and 2 years at birth and 0.6 to 1.4 at 65 while female LE rose by between 0.6-1.6 at birth and 0.4 to 1 year at age 65.

Participants interviewed for the study from both areas described population changes as factors. Local action, such as working in partnership and targeting services in areas of need may have contributed to mitigating the worst effects of austerity.
In the NW Area, some thought young families moving into the area were taking advantage of lower house prices and rental costs compared with more expensive areas near the urban centre.
One local authority officer said: “I’d heard about the in-migration of people, from probably from [large city]. And the rental costs for housing in [the town] have gone up according to Rightmove. I think it was in the very recent past, so I do wonder when we look at this question as to whether there might have been an influx of middle-class folks who are escaping the city.”
There were new housing developments and also a suggestion that town centre improvements may have contributed to the area becoming a more attractive place to live for people moving out of the city. While house prices and rental costs were lower compared with surrounding areas, they were rising significantly, which may have implications for the existing population.
One resident from the NW Area said: “It makes it more difficult for people locally, doesn’t it? Because you know, if they’re already struggling too. If they don’t have a car, … if they don’t have access to things, that makes it so much more difficult.”
Whereas in the SE area, there was a perception that young professionals with highly paid jobs were re-locating, against the backdrop of an existing transient and diverse population.

As one health professional said: “The industry has changed; it used to be a car town where [large car manufacturer] was based and there were lots of middle-aged men working in factories. There’s now much less of that and there’s a sort of tech industry so they’ve brought in a younger population. In terms of linking to health issues I think it’s much more the population migration sort of background that has an impact.”
Lead author Dr Rebecca Mead is a Research Fellow from the NIHR School for Public Health Research (SPHR) Health Inequalities Programme from Lancaster University.
She said: “Population changes and austerity, were perceived as more important to stakeholders than what was happening within an area, including local strategies and action. These perceived population changes may have been influenced by policy decisions affecting wider determinants of health’; town centre renewal programmes attracting young families in NW, and improved rail links with the major city attracting young professionals in SW. Inward migration positively affecting health outcomes and LE does not suggest these areas are health resilient.
“Stakeholders within areas of disadvantage might use this knowledge to consider the unintended consequences on existing populations of policies designed to attract more affluent people to their neighbourhoods. For example, increasing house prices and rental costs pushing existing populations out of neighbourhoods.
Professor of Public Health Matt Egan from the London School of Hygiene and Tropical Medicine said: “Our local authorities have the difficult job of trying to improve population health — but they don’t all operate in a level playing field. Some have relatively bigger issues to address and less resources to do it with. Our findings suggest that while those trying to improve the health of those in need try lots of different approaches, they assume their success is likely to be determined by external factors such as local population change and austerity.”

Women are 40% more likely to experience depression in the perimenopause than those who aren’t experiencing any menopausal symptoms, finds a new study led by UCL researchers.
The research, published in the Journal of Affective Disorders, provided a meta-analysis of seven studies involving 9,141 women from across the world (including Australia, USA, China, Netherlands and Switzerland), to understand whether different stages of the menopause were associated with different risk of depression.
The perimenopause usually occurs around three to five years before the onset of menopause. During this stage women’s oestrogen and progesterone levels begin to fluctuate, causing them to experience mood changes, irregular menstrual cycles and other menopausal symptoms, including increased feelings of depression.
This stage of the menopause continues until one year after a woman’s last period and can often last for between four and eight years in total.
The researchers found that perimenopausal women had a significantly higher risk (around 40%) of experiencing depressive symptoms and being diagnosed with depression compared to premenopausal women.
There was no significant increase in depression risk for post-menopausal women compared to those who were premenopausal.
Symptoms were measured using standardised, internationally recognised self-report instruments, including the Patient Health Questionnaire PHQ-9 (which considers factors such as a lack of interest in doing things, issues with sleep, and feelings of low mood).

Senior author Dr Roopal Desai (UCL Psychology & Language Sciences) said: “This study shows that women in the perimenopausal stage are significantly more likely to experience depression than either before or after this stage.
“Our findings emphasise the importance of acknowledging that women in this life-stage are more vulnerable to experiencing depression. It also underlines the need to provide support and screening for women to help address their mental health needs effectively.”
The new study comes shortly after the researchers’ previous publication*, which found that therapy — such as mindfulness and cognitive behavioural therapy — could be an effective form of treatment for non-physical symptoms of the menopause.
Corresponding author, Professor Aimee Spector (UCL Psychology & Language Sciences), said: “Women spend years of their lives dealing with menopausal symptoms that can have a huge impact on their wellbeing and quality of life.
“Our findings show just how significantly the mental health of perimenopausal women can suffer during this time. We need greater awareness and support to ensure they receive appropriate help and care both medically, in the workplace and at home.”
Lead author and UCL Masters student, Yasmeen Badawy (UCL Psychology & Language Sciences) said: “Combining data from global studies indicates that these findings cannot be attributed to cultural factors or lifestyle changes alone which have been sometimes used to explain the depressive symptoms that women experience during perimenopause.”

With recent studies having established the presence of nano and microplastic particles in the respiratory systems of both human and bird populations, a new University of Technology Sydney (UTS) study has modelled what happens when people breathe in different kinds of plastic particles and where they end up.
Led by Senior Lecturer of Mechanical Engineering Dr Suvash Saha, the UTS research team has used computational fluid-particle dynamics (CFPD) to study the transfer and deposition of particles of different sizes and shapes depending on the rate of breathing.
The results of the modelling, published in the journal Environmental Advances, have pinpointed hotspots in the human respiratory system where plastic particles can accumulate, from the nasal cavity and larynx and into the lungs.
Dr Saha said evidence was mounting on the significant impact of nano and microplastics on respiratory health and the UTS study would provide essential insights for the development of targeted strategies to mitigate potential risks and ensure effective health interventions.
“Experimental evidence has strongly suggested that these plastic particles amplify human susceptibility to a spectrum of lung disorders, including chronic obstructive pulmonary disease, fibrosis, dyspnea (shortness of breath), asthma, and the formation of what are called frosted glass nodules,” Dr Saha said.
“Plastic particle air pollution is now pervasive and inhalation ranks as the second most likely pathway for human exposure.
“The primary types are intentionally manufactured, including a wide array of cosmetics and personal care products such as toothpaste.

“The secondary ones are fragments derived from the degradation of larger plastic products, such as water bottles, food containers and clothes.
“Extensive investigations have identified synthetic textiles as a principal source of indoor airborne plastic particles, while the outdoor environment presents a multitude of sources encompassing contaminated aerosols from the ocean to particles originating from wastewater treatment.”
Dr Saha said the UTS team’s modelling found that breathing rate along with particle size and shape determined where in the respiratory system plastic particles would be deposited.
“Faster breathing rates led to heightened deposition in the upper respiratory tract, particularly for larger microplastics, whereas slower breathing facilitated deeper penetration and deposition of smaller nanoplastic particles,” he said.
“Particle shape was another factor, with non-spherical microplastic particles showing a propensity for deeper lung penetration compared to spherical microplastics and nanoplastics, potentially leading to different health outcomes.
“These findings highlight the imperative consideration of breathing rates and particle sizes in health risk assessments associated with respiratory exposure to nano and microplastic particles.”

A novel combination of two cancer drugs has shown great potential as a future treatment for patients with acute myeloid leukaemia (AML), one of the most common types of blood cancers.
A new study by WEHI researchers has revealed the combination of two existing drugs eradicated AML cancer cells in lab-based tests.
The discovery, published in Cancer Cell, could soon lead to clinical trials, providing hope for the 1100 Australians diagnosed with AML annually.
At a glance WEHI researchers have for the first time tested a dual drug combination against AML, which proved highly effective in killing cancer cells in lab-based tests. The researchers treated cancer cells with a combination of venetoclax, a current standard-of-care drug for AML, and a STING agonist, an emerging class of immunotherapy drugs. This drug combination was notably successful against the more aggressive and difficult to treat forms of AML. This discovery may also change the way STING agonist drugs are used to treat other cancers.Stimulating the ‘cell death enforcer’
The WEHI research team paired venetoclax, a current standard-of-care anti-cancer drug for AML, with a STING agonist, an emerging class of immunotherapy drugs. Venetoclax was based on a landmark research discovery at WEHI.
Study co-first author Dr Sarah Diepstraten said the team examined a range of different blood cancers, including cancer samples from patients with AML and treated them in the lab with the drug combination, leading to striking results.

“It’s really impressive — combining venetoclax with this emerging immunotherapy treatment can actually eradicate AML,” said Dr Diepstraten.
“This is the one-two punch combo that could be the knockout blow for AML. You could almost paraphrase the famous boxer Muhammed Ali and say this treatment floats like a butterfly, and STINGs like a bee.”
Critically, the combination treatment showed high promise in AML samples that were driven by a mutated p53 protein, a type of AML that is generally more aggressive and harder to treat.
The p53 protein plays a critical role in our bodies. When it is working effectively, it prevents the formation of cancerous cells by enforcing the death, or arresting the growth, of cells that have become damaged or abnormal.
But when the p53 protein is mutated and becomes defective in groups of cells, it can significantly boost a person’s risk of developing cancer.
Mutations of p53 are thought to be the biggest driver of cancer development and are found in half of all human cancers around the globe.

As cancers associated with p53 mutations tend to be more aggressive and resistant to treatment, there is a critical need for better therapies.
“For AML patients that do not have as much therapy-induced death of their leukaemia cells due to this mutated protein, combining venetoclax with a STING agonist causes more killing of AML cells than treating with venetoclax alone,” said Dr Diepstraten.
“The treatment was highly effective at killing cancer cells in samples with and without the p53 mutation, which is exciting given the lack of effective treatments for aggressive cancers driven by mutations in p53.
“We want to see more and more patients getting into long-term remission from blood cancers like AML, and we think adding STING agonists to the treatment regimen could be the key.”
A STING in the cancer tale
The study marks the first time that a STING agonist has been used to directly target mechanisms within the cancer cells themselves, stimulating the natural processes that cause these cells to die.
To date, the STING agonist immunotherapy drugs have been chiefly used to attack solid tumours by activating the body’s immune response.
The new research builds our understanding of how STING agonists work and indicates for the first time that they could be successful in ways that had not been previously anticipated: against blood cancers, and by directly targeting the cancer cells intrinsically.
Associate Professor Gemma Kelly, co-senior author on the study, said that both venetoclax and the STING agonists played complementary roles in killing cancer at the cellular level.
“Within a cancer cell, venetoclax blocks the machinery of the cell that is keeping it alive. In certain blood cancers where this response is sub-optimal, STING agonists can supercharge this effect to deliver cancer a deathly blow,” Assoc Prof Kelly, a laboratory head in WEHI’s Blood Cells and Blood Cancer division, said.
“It is these two drugs, working in tandem, that led to the highly effective killing of AML cancer cells in our lab-based tests, in results that were truly striking.”
WEHI lab head Professor Andrew Wei, co-senior author on the study, said that while further research was needed, the findings were highly promising.
“While early clinical trials in solid cancers have suggested STING agonists are well tolerated in the body, these results offer exciting new hope for patients with the most resistant forms of leukaemia,” said Prof Wei.
“Given STING agonists are currently in clinical trials, we hope to conduct human studies using STING agonists in combination with venetoclax in the near future.
“The research findings are important, as they will inspire a completely new clinical approach for patients affected by the most resistant and deadly forms of acute leukaemia.”
WEHI researchers and clinicians are now translating these highly promising findings into a new clinical trial in AML patients in collaboration with Melbourne-based Aculeus Therapeutics, a local biotechnology company with a proprietary STING agonist.
Dr Mark Devlin, CEO of Aculeus Therapeutics, which has spent the last several years developing a potent STING agonist, couldn’t be more excited about the potential for the recent WEHI discovery.
“Drug discovery and development is the ultimate scientific team sport,” he said.
“Aculeus has developed a promising new drug but the collaboration with the WEHI teams, that have a deep understanding of the disease biology and the clinical landscape, will help shape how that drug will be used most effectively.”
Aculeus’ STING agonist, ACU-0943, is expected to enter clinical development for the treatment of AML later this year.

The body clock has a significant impact on the performance of NBA players, according to study published in the peer-reviewed journal Chronobiology International.
The authors say their findings, from more than 25,000 matches, show elite basketball coaches and teams should consider the physical and mental effects of time zone travel when planning games and preparing for games.
A first of its kind, the research is based on the achievements at home and away of NBA (National Basketball Association) league players across 21 consecutive seasons. Considered the most competitive in the world, NBA athletes frequently travel to matches across the five US time zones used by NBA teams.
The findings show that there is a near 10% better win ratio difference for home teams from the western time zone area (PDT) when playing against a team from the eastern EDT time zone, compared to when an EDT team hosts a PDT team. When PDT teams play at home against EDT teams the winning percentage is 63.5%. When EDT teams host a PDT team, the winning percentage drops to 55.0%.In addition, the findings also show that teams win more home games when players’ sleep-wake cycles — linked to their circadian rhythm (CR) — are ‘ahead’ of the local time. This is after they have returned west from competing in a city further east where the local time is earlier.
For example, if the LA Lakers play an away match at Miami (EDT) and then return to Los Angeles (PDT) to play a home game without much CR adaptation time (CR is ahead of the local time), the Lakers play the next home game with a CR advantage against whomever their opponents are.
Teams do not have the same success when players’ internal body clocks are either behind or synchronized with the local time where their home arena or stadium is based, according to the results.

Experts from Dokuz Eylül University and Yildiz Technical University, in Turkey, led the study. Dr Firat Özdalyan, a Sport Physiology expert from Dokuz Eylül, explains that they found NBA teams need to become used to the local time when they play away games to perform well.
“One of the most important results of this research for the home games of the NBA teams is that while traveling to the west increases the performance, traveling to the east decreases the performance,” he states.
“Another notable finding is that the success of NBA teams increases when they are fully adapted to the local time for away games.
“Home teams who will be exposed to such a CR phase shift (traveling from west to east) should be mindful of these potential performance detriments when constructing game plans.
“It can be suggested that coaches (of away teams) should bear this (the low shooting success) in mind during the game preparation period.”
A circadian rhythm (CR) is the body’s sleep-wake pattern over a 24-hour day. A CR phase shift means bedtime and wake-up times move earlier or later in the day.

This means the body clock gets out of sync with the environment which can lead to sleeplessness, daytime tiredness and other issues. The body clock needs 24 hours to adapt for every one-hour time zone change.
The study investigated the effect of a CR shift on the performance of professional NBA athletes.
Data was analyzed from 25,016 regular games across 21 consecutive seasons between 2000 to 2021. Information included the date, location, game result and home or away team. Time zones of the cities where all games were played were identified to calculate the CR phase shifts of the teams.
The expert team say teams in the Pacific time zone may have an advantage in regular season home games such as the Los Angeles Lakers, Portland Trail Blazers, and Seattle Supersonics.
Anaerobic performance could explain why home teams who travel from east to west do better, say the authors. This type of activity which is crucial for scoring, defending and other feats peaks later in the day.
The authors add that the body clock adapts more easily to a long rather than a short day. The day becomes longer traveling east to west and a natural circadian rhythm is slightly longer than 24 hours. So this means basketball players are traveling in the direction their bodies want to go.
As for away teams, the authors say that travel fatigue is more likely to blame for poor performance than phase shifts in CR.
Players who have rest time between games or have not traveled across time zones for an away match are more able to synchronize their body with the local time. As such, they are not as tired and play better.
A limitation of this research is that the traveling schedules of the teams are not known. Since this information was not available, it was not possible to determine how long the teams stayed in which city/time zone; how much they adapted to the local UTC; and what extent they were exposed to a CR phase shift with real data. Therefore, the team used a predictive model for the traveling plans and CR adaptations of the teams by following the rules determined by previous research.
Another limitation is that the games were not separated according to teams’ ability differences.

Kumamoto University researchers have identified a novel Heat Shock Factor (HSF), designated as HSF5, which plays a crucial role in the completion of meiosis and the activation of genes essential for sperm formation. This discovery provides valuable insights into underlying causes of spermatogenic failure, the major contributor to male infertility. Furthermore, unlike other typical Heat Shock Factors, which primarily regulate gene expression in response to stress, such as heat shock, HSF5 plays a specific role in male germ production during meiosis under non-stress conditions.
In eukaryotic cell division, genomic information is equally distributed to daughter cells during mitosis, whereas it is halved during a specialized type of cell division called meiosis?which is necessary for germ cell production. In male germ cell, sperm formation follows the completion of meiosis, with multiple gene regulatory programs. However, the mechanisms governing meiotic progression and the specific transcription factors involved remain poorly understood, posing significant challenges in reproductive medicine, particularly concerning male infertility. To address these gaps, Professor Kei-ichiro Ishiguro, Assistant Professor Ryuki Shimada, and their research team aim to clarify the mechanisms regulating male meiosis that lead to sperm production, focusing on the identification and characterizing related transcription factors.
In the previous study, the team identified a meiosis switch gene MEIOSIN, which activates the expression of hundreds of genes involved in sperm formation (Ishiguro et al., Dev Cell 2020). Among these genes, Heat Shock Factor emerged as a focus of interest testes due to the testes’ sensitivity to heat stress, given their external positioning, which maintains a temperature 3-4 degrees Celsius lower than the body’s internal temperature of 37 degrees Celsius. Although the main roles of Heat Shock Factors such as HSF1, HSF2, HSF3, and HSF4 have been well identified, the function of HSF5 remains unclear. “Whether HSF5 shares similar functions with other Heat Shock Factors, or exhibits entirely different functions poses an intriguing question, and addressing this question was the original intension our study.” explains Professor Ishiguro.
Surprisingly, different from other HSFs responding to stress, the study showed that HSF5 plays an essential role in the meiotic prophase progression in male germ cells under non-stress conditions. HSF5 is required for progression beyond the pachytene stage during spermatogenesis, guiding the meiotic program towards completion and activating genes associated with sperm formation.
Just like other transcription factors, HSF5 binds to DNA promoters to regulate gene expression. What distinguishes HSF5 is its unique target specificity. The research revealed that the DNA motif it recognizes for binding to gene promoter, differs from those bound by other canonical HSF family transcription factors.
All these findings underscore HSF5’s atypical role in gene expression during meiotic prophase in males.
The results of this study were validated through experimentation on mice, with a crucial recognition that HSF5 is also present in humans. Given that many underlying causes of infertility in humans, especially in cases of spermatogenic failure, remain elusive, the findings of this study are anticipated to contribute significantly to understanding the pathogenesis of male infertility.