Adults with a history of low back pain went nearly twice as long without a recurrence of their back pain if they walked regularly, a world-first study has found.
About 800 million people worldwide have low back pain, and it is a leading cause of disability and reduced quality of life.
Repeated episodes of low back pain are also very common, with seven in 10 people who recover from an episode going on to have a recurrence within a year.
Current best practice for back pain management and prevention suggests the combination of exercise and education. However, some forms of exercise are not accessible or affordable to many people due to their high cost, complexity, and need for supervision.
A clinical trial by Macquarie University’s Spinal Pain Research Group has looked at whether walking could be an effective, cost-effective and accessible intervention.
The trial followed 701 adults who had recently recovered from an episode of low back pain, randomly allocating participants to either an individualised walking program and six physiotherapist-guided education sessions over six months, or to a control group.
Researchers followed the participants for between one and three years, depending on when they joined, and the results have now been published in the latest edition of The Lancet.

The paper’s senior author, Macquarie University Professor of Physiotherapy, Mark Hancock, says the findings could have a profound impact on how low back pain is managed.
“The intervention group had fewer occurrences of activity limiting pain compared to the control group, and a longer average period before they had a recurrence, with a median of 208 days compared to 112 days,” Professor Hancock says.
“Walking is a low-cost, widely accessible and simple exercise that almost anyone can engage in, regardless of geographic location, age or socio-economic status.
“We don’t know exactly why walking is so good for preventing back pain, but it is likely to include the combination of the gentle oscillatory movements, loading and strengthening the spinal structures and muscles, relaxation and stress relief, and release of ‘feel-good’ endorphins.
“And of course, we also know that walking comes with many other health benefits, including cardiovascular health, bone density, healthy weight, and improved mental health.”
Lead author Dr Natasha Pocovi says in addition to providing participants with longer pain-free periods, the program was very cost-effective.

“It not only improved people’s quality of life, but it reduced their need both to seek healthcare support and the amount of time taken off work by approximately half,” she says.
“The exercise-based interventions to prevent back pain that have been explored previously are typically group-based and need close clinical supervision and expensive equipment, so they are much less accessible to the majority of patients.
“Our study has shown that this effective and accessible means of exercise has the potential to be successfully implemented at a much larger scale than other forms of exercise.”
To build on these findings, the team now hopes to explore how they can integrate the preventive approach into the routine care of patients who experience recurrent low back pain.

Scientists have prototyped a new method for “rationally engineering” enzymes to deliver improved performance. They have devised an algorithm, which takes into account an enzyme’s evolutionary history, to flag where mutations could be introduced with a high likelihood of delivering functional improvements.
Their work — published today in leading journal Nature Communications — could have significant, wide-ranging impacts across a suite of industries, from food production to human health.
Enzymes are central to life and key to developing innovative drugs and tools to address society’s challenges. They have evolved over billions of years through changes in the amino acid sequence that underpins their 3D structure. Like beads on a string, each enzyme is composed of a sequence of several hundred amino acids that encodes its 3D shape.
With one of 20 amino acid ‘beads’ possible at each position, there is enormous sequence diversity possible in nature. Upon formation of their 3D shape, enzymes carry out a specific function such as digesting our dietary proteins, converting chemical energy into force in our muscles, and destroying bacteria or viruses that invade cells. If you change the sequence, you can disrupt the 3D shape, and that typically changes the functionality of the enzyme, sometimes rendering it completely ineffective.
Finding ways to improve the activity of enzymes would be hugely beneficial to many industrial applications and, using modern tools in molecular biology, it is simple and cost-efficient to engineer changes in the amino acid sequences to facilitate improvements in their performance. However, randomly introducing as little as three or four changes to the sequence can lead to a dramatic loss of their activity.
Here, the scientists report a promising new strategy to rationally engineer an enzyme called “beta-lactamase.” Instead of introducing random mutations in a scattergun approach, researchers at the Broad Institute and Harvard Medical School developed an algorithm that takes into account the evolutionary history of the enzyme.
“At the heart of this new algorithm is a scoring function that exploits thousands of sequences of beta-lactamase from many diverse organisms. Instead of a few random changes, up to 84 mutations over a sequence of 280 were generated to enhance functional performance,” said Dr Amir Khan, Associate Professor in Trinity College Dublin’s School of Biochemistry and Immunology, one of the co-authors of the research.

“And strikingly, the newly designed enzymes had both improved activity and stability at higher temperatures.”
Eve Napier, a second-year PhD student at Trinity College Dublin, determined the 3D experimental structure of a newly designed beta-lactamase, using a method called X-ray crystallography.
Her 3D map revealed that despite changes to 30% of the amino acids, the enzyme had an identical structure to the wild-type beta-lactamase. It also revealed how coordinated changes in amino acids, introduced simultaneously, can efficiently stabilise the 3D structure — in contrast to individual changes that typically impair the enzyme structure.
Eve Napier said: “Overall, these studies reveal that proteins can be engineered for improved activity by dramatic ‘jumps’ into new sequence space.
“The work has wide ranging applications in industry, in processes that require enzymes for food production, plastic-degrading enzymes, and those relevant to human health and disease, so we are quite excited for the future possibilities.”

Your sleep tracker might give you information about more than just your sleep-specifically, it might give you information about chronic conditions such as diabetes and sleep apnea, and illnesses such as COVID-19.
This is one of the findings of a study that analyzed data from 5 million nights of sleep across roughly 33,000 people. Based on the new analyses, the researchers identified five main types of sleep, which they called sleep phenotypes, and which can be further divided into 13 subtypes.
The researchers also found that how and how often a person switches between sleep phenotypes could offer two to ten times more information relevant to detecting health conditions compared with just relying on a person’s average sleep phenotype alone.
The study appears in the journal npj Digital Medicine on June 20, 2024.
Using data collected from Oura Ring-a smart ring that tracks sleep, skin temperature and other information-the researchers looked at individual people over a series of months, noting whether they had chronic health conditions such as diabetes and sleep apnea, or illnesses such as COVID-19 and the flu.
The research team found that people would often move between sleep phenotypes over time, reflecting a change in an individual’s health conditions, and creating what resembles a person’s travel log through the data-driven sleep landscape the researchers created.
“We found that little changes in sleep quality helped us identify health risks. Those little changes wouldn’t show up on an average night, or on a questionnaire, so it really shows how wearables help us detect risks that would otherwise be missed,” said Benjamin Smarr, one of the study’s senior authors and a faculty member in the Jacobs School of Engineering and Halicioglu Data Science Institute at the University of California San Diego.

In addition, the researchers highlighted that tracking changes in sleep over the long term at the population scale could unlock new insights that are relevant for public health, such as whether some changes in patterns through these sleep landscapes can provide early warning for chronic illness or vulnerability to infection.
The research team’s work is based on new analyses from the TemPredict dataset from University of California, San Francisco, which was created using data collected from people wearing the commercially available Oura Ring during the 2020 COVID-19 pandemic.
The analyses were led by Smarr, who is also faculty in the University of California San Diego Shu Chien — Gene Lay Department of Bioengineering, and Professor Edward Wang in the University of California San Diego Department of Electrical and Computer Engineering, collaborating with the study lead at University of California, San Francisco, Professor Ashley E. Mason, a practicing sleep clinician. The lead author was Varun Viswanath, a graduate student in the Department of Electrical and Computer Engineering at the University of California San Diego Jacobs School of Engineering.
The five sleep types
These are the five sleep phenotypes researchers singled out based on data from 5 million nights of sleep across roughly 33,000 people. While many factors went into the study, the researchers also identified some trends that help to intuitively separate the 5 sleep phenotypes. Phenotype 1: What we think of as “normal” sleep. In this phenotype, people get about eight hours of uninterrupted sleep for at least six days in a row. This is the type of sleep recommended by the National Institutes of Health and was the most common sleep type researchers found. Phenotype 2: People sleep continuously about half the nights, but they only sleep for short periods of time in bouts of less than three hours the other half. Phenotype 3: People sleep mostly continuously, but they experience interrupted sleep around one night each week. The interrupted night is characterized by one period of relatively long sleep of about five hours, and one period of short sleep of less than three hours. Phenotype 4: People again sleep mostly continuously. But they experience rare nights, in which long bouts of sleep are separated by a mid-sleep waking. Phenotype 5: People only sleep for very short periods of time every night. This phenotype was the rarest the researchers found, and represents extremely disrupted sleep.Tracking changes in sleep type
To measure how sleep phenotypes changed over time, Viswanath constructed a spatial model of all 5 million nights, in which the phenotypes were represented as different islands, composed of mostly similar weeks of sleep. Different patterns emerged over time that allowed the researchers to model each individual’s routes between islands.

From there, what helped to distinguish people with chronic conditions, such as diabetes and sleep apnea, was not their average phenotype. Instead, it was how frequently they switched between islands in this sleep landscape. In this way, even if someone switched phenotypes only rarely, the fact that they did switch could still provide useful information about their health.
The data showed that it is rare for most people to go multiple months without a few nights of disrupted sleep. “We found that the little differences in how sleep disruptions occur can tell us a lot. Even if these instances are rare, their frequency is also telling. So it’s not just whether you sleep well or not — it’s the patterns of sleep over time where the key info hides,” said Wang, a coauthor and electrical and computer engineering faculty member at UC San Diego.
Conversely, people did not tend to remain in patterns defined by broken up sleep. But how often they visited specific disrupted-sleep patterns says a lot about how well they’re doing.
“If you imagine there’s a landscape of sleep types, then it’s less about where you tend to live on that landscape, and more about how often you leave that area,” said Viswanath, the paper’s corresponding author.
Previous research
In this new paper published June 20, the research team modified the technique used in previous research that had been the largest similar investigation of sleep to date, which had drawn approximately 103,000 nights of data from the UK biobank. That previous study looked at sleep timing and awakenings and many related features, and then constructed a “landscape” of where nights fell in relation to each other. But prior researchers did not do two key things: they could not look across time, as they had only two to three nights per person; and they could not tie the resulting patterns of sleep to health outcomes.
Other large-scale sleep analyses looked at high-level differences in simple sleep characteristics, like the total time people spent asleep.
In contrast, this new work is the first to show that researchers can quantify the changing dynamics of people’s sleep over time and use this quantification to give people better insights into their sleep health. The research also suggests that these changes in sleep may indicate a higher risk for a wide range of conditions.

A wearable health monitor developed by Washington State University researchers can reliably measure levels of important biochemicals in sweat during physical exercise.
The 3D-printed monitor could someday provide a simple and non-invasive way to track health conditions and diagnose common diseases, such as diabetes, gout, kidney disease or heart disease.
Reporting in the journal, ACS Sensors, the researchers were able to accurately monitor the levels of volunteers’ glucose, lactate and uric acid as well as the rate of their sweating during exercise.
“Diabetes is a major problem worldwide,” said Chuchu Chen, a WSU Ph.D. student and first author on the paper. “I think 3D printing can make a difference to the healthcare fields, and I wanted to see if we can combine 3D printing with disease detection methods to create a device like this.”
For their proof-of-concept health monitor, the researchers used 3D printing to make the health monitors in a unique, one-step manufacturing process. The researchers used a single-atom catalyst and enzymatic reactions to enhance the signal and measure low levels of the biomarkers. Three biosensors on the monitor change color to indicate the specific biochemical levels.
Sweat contains many important metabolites that can indicate health conditions, but, unlike blood sampling, it’s non-invasive. Levels of uric acid in sweat can indicate the risk of developing gout, kidney disease or heart disease. Glucose levels are used to monitor diabetes, and lactate levels can indicate exercise intensity.
“Sweat rate is also an important parameter and physiological indicator for people’s health,” said Kaiyan Qiu, Berry Assistant Professor in WSU’s School of Mechanical and Materials Engineering.

But the amount of these chemicals in sweat is tiny and can be hard to measure, the researchers noted. While other sweat sensors have been developed, they are complex and need specialized equipment and expertise to fabricate. The sensors also have to be flexible and stretchable.
“It’s novel to use single-atom catalysts to enhance the sensitivity and accuracy of the health monitor,” said Annie Du, research professor in WSU’s School of Mechanical and Materials Engineering. Qiu and Du led the study.
The health monitor the researchers developed is made of very tiny channels to measure the sweat rate and biomarkers’ concentration. As they’re being fabricated via 3D printing, the micro-channels don’t require any supporting structure, which can cause contamination problems as they’re removed, said Qiu.
“We need to measure the tiny concentrations of biomarkers, so we don’t want these supporting materials to be present or to have to remove them,” he said. “That’s why we’re using a unique method to print the self-supporting microfluidic channels.”
When the researchers compared the monitors on volunteers’ arms to lab results, they found that their monitor was accurately and reliably measuring the concentration of the chemicals as well as the sweating rate.
While the researchers initially chose three biomarkers to measure, they can add more, and the biomarkers can be customized. The monitors were also comfortable for volunteers to wear.
The researchers are now working to further improve the device design and validation. They are also hoping to commercialize the technology. The WSU Office of Commercialization has also filed a provisional patent application to protect the intellectual property associated with this technology.
The work was funded by the National Science Foundation and the Centers for Disease Control and Prevention, as well as through startup funds.

Women who have their ovaries removed before menopause, particularly before the age of 40, have reduced white matter integrity in multiple regions of the brain later in life. White matter refers to the nerve fibers that connect neurons in different areas of the brain.
The findings appear online today in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
“We know that having both ovaries removed before natural menopause causes abrupt endocrine dysfunction, which increases the risk of cognitive impairment and dementia,” said Michelle Mielke, Ph.D., professor and chair of epidemiology and prevention at Wake Forest University School of Medicine. “But few neuroimaging studies have been conducted to better understand the underlying mechanisms.”
For the study, the research team examined data from the Mayo Clinic Study of Aging to identify women over the age of 50 with available diffusion tensor imaging, a magnetic resonance imaging (MRI) technique that measures white matter in the brain. The cohort was comprised of: 22 participants who had premenopausal bilateral oophorectomy (PBO) before age 40 43 participants who had PBO between the ages of 40 and 45 39 participants who had PBO between the ages of 46 and 49 907 participants who did not have PBO before the age of 50.”Females who had premenopausal bilateral oophorectomy before the age of 40 had significantly reduced white matter integrity in multiple regions of the brain,” said Mielke, the study’s corresponding author. “There were also trends in some brain regions such that women who had PBO between the ages of 40-44 or 45-49 years also had reduced white matter integrity, but many of these results were not statistically significant.”
Mielke said that 80% of participants who had their ovaries removed also had a history of estrogen replacement therapy. Therefore, the study was not able to determine whether the use of estrogen replacement therapy after PBO mitigated the effects of PBO on white matter integrity. She noted that the ovaries secrete hormones both before (primarily estrogen, progesterone and testosterone) and after menopause (primarily testosterone and androstenedione).
“Having both ovaries removed results in an abrupt decrease in both estrogen and testosterone in women,” Mielke said. “Therefore, one possible explanation for our results is the loss of both estrogen and testosterone.”
Mielke said additional research is needed to further understand how white matter changes are associated with cognitive impairment.
“While these findings are important for women to consider before having premenopausal bilateral oophorectomy for non-cancerous conditions, we need a larger and more diverse cohort of women to validate these results.”

Advances in organoids and embryonic models of human development have the potential to prompt social and existential questions — e.g., what defines human individuality? However, bioethicist Insoo Hyun of Harvard Medical School and the Museum of Science in Boston says that these models have the potential to strengthen rather than weaken the concept of human individuality when considered within the philosophical frameworks of “personhood” and sentience. In a commentary publishing June 20 in the journal Cell, Hyun argues that despite huge advances, we are a long way off from developing technologies that would enable embryo models or organoids to achieve personhood.
“In the process of illuminating these biological mysteries, human stem-cell-based modeling could recast much of what we take to be special about ourselves as simply a reproducible series of physical events,” writes Hyun. “Could these new technologies change our view of ourselves? What does it mean for individuality, for example, if the early embryonic history of each cell line donor can be replayed again and again through the artificial generation of identical human embryo models?”
To answer these questions, Hyun dives into the philosophical concepts of personhood and sentience.
To be a person rather than simply an individual, one must possess the ability to make rational decisions and act thoughtfully on desires. Hyun notes that it is the embryo’s potential to become a person, not its current personhood, that matters to most human embryo advocates, and similar issues surround patients at the end of life. However, this potential hinges not only on the embryo’s or end-of-life patient’s biology, but also on their technological and circumstantial situation.
“Ex corporeal embryos, for example, must not only be genetically and morphologically robust to have a biological chance at becoming a human person, but, just as crucially, they must also be chosen — normally by those for whom they were created — to be implanted into a woman’s uterus and carried to term,” writes Hyun. “Likewise for patients at the end of life. Not only must they have the biological potential for their brains to recover functioning, but they must also be cared for in a hospital setting by decision makers who have the right technologies at their disposal.”
For embryos used in research rather than for assisted reproductive purposes, the circumstantial potential for them to become a person is non-existent. Similarly, though organoids can self-assemble and carry out many of the functions of human organs on a small scale, there is no possibility that they could self-assemble into an independently functioning and conscious individual.
“Since the cognitive bar is set so high for personhood, it seems premature to worry about whether brain organoids, neurological chimeras, or embryo models deserve the ethical protections normally afforded to persons,” Hyun writes. “The science simply is not there to support these concerns now and would have to depend on major technical innovations to get there in the future. Not even the most extreme forms of human-to-nonhuman neurological chimerism that one could imagine would support fears about personhood emerging in acutely altered animals.”
Likewise, current in vitro embryo and organoid models are far from reaching sentience — the ability to have sensory experiences like pleasure and pain — which is thought to arise in human fetuses after 24 gestational weeks. The only case in which organoids are likely to experience sentience is when they are transplanted into a living animal model, for example the recent study by Stanford researchers that transplanted human brain organoids into rats — but rats are already considered sentient, and the ethics of such studies are already scrutinized as such.
“In response to the question of whether new technologies for human developmental modeling could destabilize our view of ourselves, the answer is no, not if we remain mindful of the bedrock distinctions between biological individuals and persons, biological and circumstantial potentiality, and sentient and non-sentient biological individuals,” writes Hyun. “Rather than weakening the grounds for which we value human life, perhaps an increased familiarity with developmental models could strengthen our beliefs by reminding us of what really matters-the wellbeing of actual persons and sentient individuals.”

Scientists have discovered a new cause of why people who lack a specific blood group are genetically predisposed to be overweight or obese.
A team of international researchers, led by the University of Exeter, discovered that people with a genetic variant that disables the SMIM1 gene have higher body weight because they expend less energy when at rest.
SMIM1 was only identified 10 years ago, whilst searching for the gene encoding a specific blood group, known as Vel. One in 5,000 people lack both copies of the gene, making them Vel-negative. The findings from the new research suggest that this group is also more likely to be overweight, a conclusion which could one day lead to new treatments. The team now hopes to test whether a cheaply and widely available drug for thyroid dysfunction may be effective in treating obesity in people who lack both copies of SMIM1.
The study also found that people without both copies of the gene have other measures linked to obesity including high levels of fat in the blood, signs of fat tissue dysfunction, increased liver enzymes as well as lower levels of thyroid hormones.
The new research is published in Med and was funded by the National Institute for Health and Care Research and the British Heart Foundation. The collaboration included partners at the University of Cambridge, the Sanger Institute, the Copenhagen University in Denmark, and the Lund University in Sweden.
Lead author Mattia Frontini, Associate Professor of Cell Biology at the University of Exeter Medical School, said: “Obesity rates have nearly tripled in the past 50 years, and by 2030, more than one billion individuals worldwide are projected to be obese. The associated diseases and complications create significant economic burden on healthcare systems. Obesity is due to an imbalance between energy intake and expenditure, often a complex interplay of lifestyle, environmental, and genetic factors. In a small minority of people, obesity is caused by genetic variants. When this is the case, new treatments can sometimes be found to benefit these people — and we’re now hoping to run a clinical trial to find out whether widely-available drug for thyroid supplementation may be beneficial in treating obesity in people who lack SMIM1.”
“Our findings highlight the need to investigate the genetic cause of obesity, to select the most appropriate and effective treatment, but also to reduce the social stigma associated to it.”
To make the discovery, the team analysed the genetics of nearly 500,000 participants in the UK Biobank cohort, identifying 104 people with the variant that leads to loss of function in the SMIM1 gene (46 females and 44 males). The team also used the NIHR National BioResource to obtain fresh blood samples from both Vel negative and positive individuals.The NIHR National BioResource worked in partnership with NHS Blood and Transplant (NHSBT) — which includes more than 100,000 blood donors who signed up to support genetic research studies. Extrapolating the frequencies identified in these cohorts would mean the SMIM1 variant could be a significant factor contributing to obesity for around 300,000 people across the world.

The team interrogated the effects they found in four additional cohorts of people with the SMIM1 gene variant. They found that having the variant had an impact on weight, equating to an average extra 4.6kg in females and 2.4kg in males.
Co-author Jill Storry, Adjunct Professor at Lund University, Sweden, said: “SMIM1 was only discovered a decade ago, as a long-sought blood group protein on red blood cells, but its other function has remained unknown until now. It’s very exciting to find that it has a more general role in human metabolism.”
Co-author Professor Ole Pedersen, at University of Copenhagen, Denmark, said: “The whole team is very much looking forward to seeing how this new knowledge can be translated into practical solutions for people with this genetic make-up.”
First author Dr Luca Stefanucci, at the University of Cambridge, said: “With the increased availability of genetic data, and more information on SMIM1 mechanism, we would like to see that when individuals lacking SMIM1 are identified, they receive information and support.”

Patients with pancreatic cancer who received chemotherapy both before and after surgery experienced longer survival rates than would be expected from surgery followed by chemotherapy, according to a new study from researchers at Yale Cancer Center (YCC) and Yale School of Medicine.
The study, published June 20 in JAMA Oncology, included patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of pancreatic cancers. An aggressive cancer with a high mortality rate, PDAC is predicted to become the second leading cause of cancer-related deaths in the U.S. by 2030.
The findings, say the researchers, are encouraging for the 15 to 20% of pancreatic cancer patients whose tumors are operable. The single-arm (only one treatment type or regimen) Phase II trial evaluated a modified form of the chemotherapy treatment FOLFIRINOX (a combination treatment consisting of leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin approved in 2011 as a first-line treatment for patients with metastatic pancreatic cancer).
Patients in the trial received six cycles of the modified FOLFIRINOX before surgery, followed by an additional six cycles of the chemotherapy treatment after surgery. The modified regimen consisted of slightly lower doses of FOLFIRINOX to improve tolerability, which was previously shown in a 2016 publication not to impact outcomes negatively.
Of the 46 patients who started the modified treatment, 37 completed all six cycles of chemotherapy before surgery and 27 had successful tumor removal operations. For all enrolled patients, the 12-month progression-free survival rate — meaning the disease did not worsen — was 67%, indicating significant progress in controlling the disease. Furthermore, 59% of all patients lived at least two years after completing the full chemotherapy treatment plan and surgery.
The study was the first of its kind for patients with PDAC when senior author and YCC member Dr. Jill Lacy started it in 2014. The study goal had been a 12-month progression-free survival rate of at least 50% of patients.
“When the study launched, even with operable pancreatic cancers, 90% of patients were still relapsing and dying from their cancer eventually,” said Dr. Michael Cecchini, the first author of the study and the co-director of the colorectal program at the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and YCC. “We sought to move chemotherapy up in their treatment regimen and give it before surgery to see if we could improve the outcome for our patients.”
The study used advanced techniques to monitor the progress of treatment, including analyzing circulating tumor DNA (ctDNA) and using the cancer biomarker keratin 17 to help predict outcomes. For example, patients with detectable ctDNA four weeks post-surgery had significantly worse progression-free survival than those who had no detectable ctDNA.
Cecchini said larger randomized clinical trials are needed to continue to investigate the role of FOLFIRINOX before surgery for patients with operable PDAC.
“I think even though there have been changes in standard of care for patients with this aggressive pancreatic cancer type, we have here very promising data to justify a larger study,” said Cecchini.

Checkpoint inhibitor therapies can be thought of as the molecular “brake release” for the immune system. These drugs eliminate the protein barriers that impede the immune system from recognizing and targeting cancer cells in the body. While there are multiple checkpoint inhibitors approved to treat different types of cancer, many patients don’t respond or develop resistance to available regiments.
A Scripps Research team has now found that ruxolitinib, an approved immunosuppressive drug, supercharged T-cell responses when used alongside checkpoint inhibitors — boosting their effectiveness in fighting cancer. These findings, published in Science on June 21, are supported by a phase I clinical trial of patients with Hodgkin lymphoma, as well as preclinical models.
“There’s a lot of activity in developing the next generation of immunotherapies, and we’re looking beyond therapeutics that target T cells directly,” says co-senior author John Teijaro, PhD, a professor in the Department of Immunology and Microbiology at Scripps Research.
T cells are produced by the immune system to fight off infections, as well as cancer. Patients often stop responding to checkpoint immunotherapy when their T cells begin to wane. This phenomenon, called T-cell exhaustion, happens as T cells become chronically exposed to cancer cells. But based on the results of previous work, Teijaro and his research team wondered whether a JAK inhibitor — like ruxolitinib — could increase T-cell production, while also improving checkpoint inhibitors and their “brake release” effects.
JAK enzymes are important parts of the JAK/signal transducer and activator of transcription (STAT) pathway — a chain of interactions between cells and proteins that are essential for immune cell development. Dysregulation of the pathway is associated with both inflammation and cancer. JAK inhibitors restrict signals believed to cause inflammation, resulting in the immune system “calming down.”
“A lot of this started about 11 years ago, when we originally found that blocking a cytokine that signals through the JAK/STAT pathway, type 1 interferon, can promote immune responses and hasten virus clearance,” says Teijaro. Although JAK inhibitors are typically used to treat inflammatory diseases, there’s a known genetic link between JAK mutations and cancer, he adds.
To determine which existing JAK inhibitors could restore the function of exhausted T cells, Teijaro and his team turned to ReFRAME, a drug repurposing library built by Calibr-Skaggs, the drug discovery and development arm of Scripps Research. ReFRAME permits researchers to rapidly sort through thousands of existing FDA-approved drugs and determine if they could treat any other major illnesses. Using ReFRAME, the researchers identified ruxolitinib as a contender.

Through a range of preclinical models in which mice had various forms of cancer and persistent viral infections, the researchers found that compared with checkpoint therapy alone, combining the treatment with ruxolitinib increased both the number of T cells and natural killer (NK) cells — another type of immune cell that limits the spread of cancer.
With this preclinical data in hand, the team partnered with Veronika Bachanova, MD, PhD, at the University of Minnesota who had initiated a phase I clinical trial of 19 patients with Hodgkin lymphoma who failed to respond to checkpoint inhibitors or relapsed following an initial response.
“Among patients with all types of cancer, fewer than 20% respond to checkpoint inhibitors. Even in cancer types that typically respond well such as Hodgkin lymphoma, about 10% to 20% of patients don’t respond to checkpoint inhibitors, and they have to be treated with a chemotherapy that is fairly nonspecific and is not curative,” explains first author Jaroslav Zak, a postdoctoral fellow at Scripps Research. “It’s very difficult to treat these patients.”
But two years after starting a treatment regimen that combined ruxolitinib with the checkpoint inhibitor nivolumab — a current standard of care — 87% of patients were still alive, and 46% stopped exhibiting signs of cancer progression altogether.
“Anecdotally, we know for sure that at least one patient had a very good response that lasted beyond the two years of the clinical trial,” says Zak. “Unlike chemotherapy, this treatment didn’t just slow down the disease but actually reversed it.”
Myeloid cells, a type of immune cell from the bone marrow, are among the body’s most important lines of defense against infection. But cancer cells often hijack myeloid cells, which leads to tumor growth and metastasis. A high number of myeloid suppressor cells — which are found in many types of tumors and cause weak responses to immune checkpoint inhibitors — as well as a high ratio of neutrophil-to-lymphocyte cells are tied to poor prognosis of several cancers, including Hodgkin lymphoma. But using the ruxolitinib combination therapy resulted in a reduction of both indicators, while also promoting functional T cells.

“We’re now enlisting myeloid cells as helpers for immunotherapy, as it seems that in order for T cells to increase in number and functionality, ruxolitinib needs to modulate the myeloid cells,” explains Teijaro.
These findings, however, were unexpected. For one, past research showed that ruxolitinib didn’t work on its own to treat cancer.
“Ruxolitinib is actually an immunosuppressive drug that’s clinically approved for chronic graft-versus-host disease, so the fact that we saw immune-enhancing effects in patients treated with this drug using combination therapy was definitely surprising,” continues Zak. “This suggests that some drugs can actually have immune-enhancing effects, even if their primary indication is to relieve inflammatory disease pathology.”
Building on their success, the researchers plan to examine whether other JAK inhibitors are even more effective than ruxolitinib at treating cancer. They’re also designing clinical trials to test the efficacy of ruxolitinib combined with checkpoint inhibitors in other forms of cancer, including those with solid tumors.
“It’s very rare to have supporting evidence with preclinical data and a clinical trial in one paper,” says Teijaro. “I’ve been doing this for decades, and I’ve never had that happen in my career.” He continues, “our results are particularly exciting because we are already seeing patients benefit from the combination and we believe this could be applied to several immunotherapy resistant cancers.”
This work and the researchers involved were supported by funding from Bristol- Myers Squibb (grant CA209-9EF), the Cancer Research Institute/Irvington Postdoctoral Fellowship, Incyte Corporation (grant IST-USA-000382), and the National Institutes of Health (grants R01AI123210, R01AI164744, R21AI141842, and UL1TR002550 Pilot Award).

A global alert about fake Ozempic – which has become popular as a way of losing weight – has been issued by the World Health Organization (WHO).